ORCID Profile
0000-0002-9619-3104
Current Organisations
University of New South Wales
,
Università della Svizzera Italiana
,
Ente Ospedaliero Cantonale
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Publisher: Elsevier BV
Date: 04-2003
DOI: 10.1046/J.1523-1755.2003.00897.X
Abstract: Kidneys can be preserved only for a limited time without jeopardizing graft function and survival. Induction of heat shock proteins (HSPs) can protect against ischemia/reperfusion (I/R) injury. Therefore, we investigated whether the induction of the HSP, heme oxygenase-1 (HO-1), improves outcome following isotransplantation after an extended period of cold storage. Rats were subjected to heat preconditioning (HP 42 degrees C for 20 minutes). Kidneys harvested after 24 hours, were preserved in cold University of Wisconsin (UW) solution at 4 degrees C for 45 hours and transplanted into bilateral nephrectomized rats. Cobalt protoporphyrin (CoPP) was administered in another group of animals in order to induce HO-1 pharmacologically, while other groups of animals received the HO-1 inhibitor, tin protophorphyrine (SnPP), following HP or CoPP. Cold ischemia caused a complete attenuation of graft function within 3 days following transplantation and subsequent death of all animals, whereas HP protected graft function and five of nine rats survived for 3 weeks. HP inhibited the induction of osteopontin and induced the expression of HO-1, HSP 70 and 90, and the antiapoptotic factor Bcl-XL. Grafts exposed to HP were protected against structural I/R injuries as revealed by histologic assessment using a semiquantitative score. Furthermore, induction of apoptosis was attenuated and activation of caspase-3 was inhibited. Comparable results were observed after administration of CoPP, whereas SnPP inhibited the effects of HP and CoPP. HP or administration of CoPP induced both HO-1, preserved kidney graft function, and prevented postreperfusion apoptosis after cold preservation.
Publisher: Wiley
Date: 22-03-2017
DOI: 10.1111/HDI.12555
Abstract: Absolute or functional iron (Fe) deficiency is an important determinant of anemia in hemodialysis patients and parenteral Fe is routinely used to treat this condition in conjunction with erythropoiesis stimulating agents. While restoration of hemoglobin toward the target range is a good outcome of Fe replacement, it is well known that Fe overload and toxicity may be adverse consequences of this therapy. Dialysis clinical practice guidelines recommend tailoring Fe therapy based on transferrin saturation and serum ferritin levels. Unfortunately, serum Fe markers may not accurately reflect the amount of Fe in the body, because factors such as infections, inflammation, or malignancy can alter serum ferritin levels. Some recent trials in dialysis patients receiving high intravenous Fe doses have shown increased cardiovascular morbidity and mortality and studies using magnetic resonance imaging (MRI) in this population have shown excessive tissue liver iron content (LIC) suggesting Fe overload. While LIC measured by MRI correlates well with LIC quantitated by liver biopsy, it only represents a surrogate marker for total body Fe and its clinical relevance in dialysis patients in terms of mortality and morbidity remains to be demonstrated. Nevertheless, these recent findings challenge the use of current serum Fe markers recommended by clinical guidelines to guide safe Fe therapy in dialysis patients. While not yet established for the routine screening of dialysis patients for Fe overload, MRI should be considered in patients who have received a high cumulative dose of intravenous Fe, or have long cumulative dialysis vintage. Further studies are needed to assess how MRI will alter management.
Publisher: Proceedings of the National Academy of Sciences
Date: 18-08-1998
Abstract: Severe low-renin hypertension has few known causes. Apparent mineralocorticoid excess (AME) is a genetic disorder that results in severe juvenile low-renin hypertension, hyporeninemia, hypoaldosteronemia, hypokalemic alkalosis, low birth weight, failure to thrive, poor growth, and in many cases nephrocalcinosis. In 1995, it was shown that mutations in the gene ( HSD11B2 ) encoding the 11β-hydroxysteroid dehydrogenase type 2 enzyme (11β-HSD2) cause AME. Typical patients with AME have defective 11β-HSD2 activity, as evidenced by an abnormal ratio of cortisol to cortisone metabolites and by an exceedingly diminished ability to convert [11- 3 H]cortisol to cortisone. Recently, we have studied an unusual patient with mild low-renin hypertension and a homozygous mutation in the HSD11B2 gene. The patient came from an inbred Mennonite family, and though the mutation identified her as a patient with AME, she did not demonstrate the typical features of AME. Biochemical analysis in this patient revealed a moderately elevated cortisol to cortisone metabolite ratio. The conversion of cortisol to cortisone was 58% compared with 0–6% in typical patients with AME whereas the normal conversion is 90–95%. Molecular analysis of the HSD11B2 gene of this patient showed a homozygous C→T transition in the second nucleotide of codon 227, resulting in a substitution of proline with leucine (P227L). The parents and sibs were heterozygous for this mutation. In vitro expression studies showed an increase in the K m (300 nM) over normal (54 nM). Because ≈40% of patients with essential hypertension demonstrate low renin, we suggest that such patients should undergo genetic analysis of the HSD11B2 gene.
Publisher: SMW Supporting Association
Date: 05-03-2015
Publisher: Hogrefe Publishing Group
Date: 1999
DOI: 10.1024/0040-5930.56.1.55
Abstract: Es wird eine Patientin mit fortgeschrittener Niereninsuffizienz vorgestellt, die sich mit einer raschen Verschlechterung der Nierenfunktion nach langjähriger, stabiler, leichtgradiger Niereninsuffizienz zusammen mit dem Auftreten einer schweren Hypertonie präsentierte. Eine eingehende nephrologische Abklärung deckte eine schwere bilaterale Nierenarterienstenose auf. Die Therapie mit einer perkutanen transluminalen renalen Angioplastie (PTRA) verbesserte sowohl die Nierenfunktion als auch die Hypertonie, und die Patientin war auch 12 Monate nach dieser Behandlung noch nicht dialysebedürftig. Die Epidemiologie, Prognose, Diagnostik und Behandlung der atherosklerotischen renovaskulären Erkrankung werden diskutiert. Therapeutisch kann die Revaskularisation sowohl die Hypertonie wie die Niereninsuffizienz günstig beeinflussen. Bei Patienten mit schwerer Niereninsuffizienz und renovaskulärer Erkrankung kann eine PTRA eine Dialysebehandlung um einige Monate hinauszögern.
Publisher: Oxford University Press (OUP)
Date: 27-05-2014
DOI: 10.1093/CKJ/SFU048
Publisher: Informa UK Limited
Date: 1997
DOI: 10.3109/10641969709083166
Abstract: The 11 beta-hydroxysteroid dehydrogenase type II enzyme (11 beta HSD2) converts cortisol into cortisone, thus preventing occupation of the non-selective mineralocorticoid receptor by glucocorticoids in the kidney. Placental 11 beta HSD2 is also thought to protect the fetus from the high maternal circulating levels of glucocorticoids. Mutations generating inactive enzymes have been described in the HSD11B2 gene in the congenital syndrome of apparent mineralocorticoid excess (AME)--a low renin form of hypertension. Recently, a mutation has been identified in a family with AME and in which there is a high incidence of stillbirths. In this study we have expressed the R374X mutation and show that the mutant is devoid of enzyme activity in intact mammalian cells expressing a significant level of the truncated protein. While this observation elucidates the cause of AME in this family the degree to which R374X also contributes to the higher incidence of failed pregnancies remains to be determined.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2002
DOI: 10.1097/01.ASN.0000028640.78526.0F
Abstract: Reduced concentration of serum ionized calcium and increased urinary calcium excretion have been reported in primary aldosteronism and glucocorticoid-treated patients. A reduced activity of the 11 beta-hydroxysteroid dehydrogenase type 2 (11 beta HSD2) results in overstimulation of the mineralocorticoid receptor by cortisol. Whether inhibition of the 11 beta HSD2 by glycyrrhetinic acid (GA) may increase renal calcium excretion is unknown. Serum and urinary electrolyte and creatinine, serum ionized calcium, urinary calcium excretion, and the steroid metabolites (THF+5 alpha THF)/THE as a parameter of 11 beta HSD2 activity were repeatedly measured in 20 healthy subjects during baseline conditions and during 1 wk of 500 mg/d GA. One week of GA induced a maximal increment of 93% in (THF+5 alpha THF)/THE. Ambulatory BP was significantly higher at day 7 of GA than at baseline (126/77 +/- 10/7 versus 115/73 +/- 8/6 mmHg P < 0.001 for systolic P < 0.05 for diastolic). During GA administration, serum ionized calcium decreased from 1.26 +/- 0.05 to 1.18 +/- 0.04 mmol/L (P < 0.0001), and absolute urinary calcium excretion was enhanced from 29.2 +/- 3.6 to 31.9 +/- 3.1 micromol/L GFR (P < 0.01). Fractional calcium excretion increased from 2.4 +/- 0.3 to 2.7 +/- 0.3% (P < 0.01) and was negatively correlated to the fractional sodium excretion during GA (R = -0.35 P < 0.001). Moreover, serum potassium correlated positively with serum ionized calcium (R = 0.66 P < 0.0001). Inhibition of 11 beta HSD2 activity is sufficient to significantly increase the fractional excretion of calcium and decrease serum ionized calcium, suggesting decreased tubular reabsorption of this alent cation under conditions of renal glucocorticoid/mineralocorticoid excess. The likely site of steroid-regulated renal calcium handling appears to be the distal tubule.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 24-11-2008
DOI: 10.1002/LT.21627
Abstract: BK virus (BKV) infection is an established cause of allograft dysfunction in renal transplant recipients. The relationship between BKV infection and chronic kidney disease (CKD) post-orthotopic liver transplantation (OLT) is not well understood. This study aimed to determine the prevalence of BKV infection, its relationship to CKD and renal function loss over time in patients receiving OLT. Prevalence of BK viruria and viremia were studied in 41 post-OLT patients after a mean 6.5 +/- 4.7 years posttransplantation. Renal function was assessed using estimated glomerular filtration rate (eGFR) calculated from the yearly serum creatinine levels using the Modification of Diet in Renal Disease (MDRD) formula. Polymerase chain reaction (PCR) was performed for detection of BKV DNA in urine and plasma. BK viruria was present in 24.2% of patients, but none of these OLT recipients had detectable BK viremia. Decoy cells in the urine were found in 9.7% patients, although none of these patients had BK viruria. CKD, defined as eGFR <60 mL/minute/1.73 m(2), was found in 83% of OLT recipients. The yearly decline in eGFR was -6.9 +/- 17 and -9.2 +/- 18 mL/minute/year in BK viruria-positive and BK viruria-negative patients, respectively (P = 0.39). There was no relationship between the presence or absence of BK viruria and either current eGFR, yearly decline in eGFR, number and type of immunosuppressive agents, or etiology of liver failure. In OLT recipients, BK viruria is not associated with BK viremia or native kidney dysfunction. It appears that the most probable pathway for the development of BKV nephropathy requires a second hit, such as kidney inflammation, kidney ischemia, or donor-recipient human leukocyte antigen mismatch.
Publisher: The Endocrine Society
Date: 12-1998
Publisher: Elsevier BV
Date: 2015
DOI: 10.1053/J.AJKD.2014.06.020
Abstract: Erythropoiesis-stimulating agent (ESA)-hyporesponsive anemia is common in chronic kidney disease (CKD). Pentoxifylline shows promise as a treatment for ESA-hyporesponsive anemia, but has not been rigorously evaluated. Multicenter, double-blind, randomized, controlled trial. 53 adult patients with CKD stage 4 or 5 (including dialysis) and ESA-hyporesponsive anemia (hemoglobin≤120g/L and ESA resistance index [calculated as weight-adjusted weekly ESA dose in IU/kg/wk ided by hemoglobin concentration in g/L]≥1.0IU/kg/wk/g/L for erythropoietin-treated patients and ≥0.005μg/kg/wk/g/L for darbepoetin-treated patients). Pentoxifylline (400mg/d n=26) or matching placebo (control n=27) for 4 months. ESA resistance index at 4 months secondary outcomes: hemoglobin concentration, ESA dose, blood transfusion requirement, serum ferritin level and transferrin saturation, C-reactive protein level, adverse events, quality of life, and health economics. There was no statistically significant difference in ESA resistance index between the pentoxifylline and control groups (adjusted mean difference, -0.39 [95%CI, -0.89 to 0.10] IU/kg/wk/g/L P=0.1). Pentoxifylline significantly increased hemoglobin concentration relative to the control group (adjusted mean difference, 7.6 [95%CI, 1.7-13.5] g/L P=0.01). There was no difference in ESA dose between groups (-20.8 [95%CI, -67.2 to 25.7] IU/kg/wk P=0.4). No differences in blood transfusion requirements, adverse events, or quality of life were observed between groups. Pentoxifylline cost A$88.05 (US $82.94) per person over the trial and produced mean savings in ESA cost of A$1,332 (US $1,255). The overall economic impact over the trial period was a saving of A$1,244 (US $1,172) per person for the pentoxifylline group compared with controls. S le size smaller than planned due to slow recruitment. Pentoxifylline did not significantly modify ESA hyporesponsiveness, but increased hemoglobin concentration. Further studies are warranted to determine whether pentoxifylline therapy represents a safe strategy for increasing hemoglobin levels in patients with CKD with ESA-hyporesponsive anemia.
Publisher: Frontiers Media SA
Date: 23-06-2020
DOI: 10.1111/TRI.13668
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 15-04-2014
Publisher: Springer Science and Business Media LLC
Date: 30-08-2023
DOI: 10.1038/S41586-023-06487-6
Abstract: Currently circulating SARS-CoV-2 variants have acquired convergent mutations at hot spots in the receptor-binding domain 1 (RBD) of the spike protein. The effects of these mutations on viral infection and transmission and the efficacy of vaccines and therapies remains poorly understood. Here we demonstrate that recently emerged BQ.1.1 and XBB.1.5 variants bind host ACE2 with high affinity and promote membrane fusion more efficiently than earlier Omicron variants. Structures of the BQ.1.1, XBB.1 and BN.1 RBDs bound to the fragment antigen-binding region of the S309 antibody (the parent antibody for sotrovimab) and human ACE2 explain the preservation of antibody binding through conformational selection, altered ACE2 recognition and immune evasion. We show that sotrovimab binds avidly to all Omicron variants, promotes Fc-dependent effector functions and protects mice challenged with BQ.1.1 and hamsters challenged with XBB.1.5. Vaccine-elicited human plasma antibodies cross-react with and trigger effector functions against current Omicron variants, despite a reduced neutralizing activity, suggesting a mechanism of protection against disease, exemplified by S309. Cross-reactive RBD-directed human memory B cells remained dominant even after two exposures to Omicron spikes, underscoring the role of persistent immune imprinting.
Publisher: The Endocrine Society
Date: 10-1999
Publisher: American Association for the Advancement of Science (AAAS)
Date: 18-06-2021
Abstract: A better understanding of CD4 + T cell responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is crucial to the design of effective next-generation vaccines. Low et al. defined and estimated the CD4 + T cell repertoire of convalescent COVID-19 patients. After sorting various CD4 + T cell subsets, they generated numerous T cell clones that reacted to the SARS-CoV-2 spike protein. A large number of T cell clones from almost all in iduals recognized a small conserved immunodominant region within the spike protein receptor-binding domain (RBD). The researchers isolated T cell clones that broadly reacted to the spike protein of other coronaviruses, providing evidence for the recall of preexisting cross-reactive memory T cells after SARS-CoV-2 infection. Science , abg8985, this issue p. 1336
Publisher: American Association for the Advancement of Science (AAAS)
Date: 12-08-2022
Abstract: The coronavirus spike glycoprotein attaches to host receptors and mediates viral fusion. Using a broad screening approach, we isolated seven monoclonal antibodies (mAbs) that bind to all human-infecting coronavirus spike proteins from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immune donors. These mAbs recognize the fusion peptide and acquire affinity and breadth through somatic mutations. Despite targeting a conserved motif, only some mAbs show broad neutralizing activity in vitro against alpha- and betacoronaviruses, including animal coronaviruses WIV-1 and PDF-2180. Two selected mAbs also neutralize Omicron BA.1 and BA.2 authentic viruses and reduce viral burden and pathology in vivo. Structural and functional analyses showed that the fusion peptide–specific mAbs bound with different modalities to a cryptic epitope hidden in prefusion stabilized spike, which became exposed upon binding of angiotensin-converting enzyme 2 (ACE2) or ACE2-mimicking mAbs.
Publisher: Elsevier BV
Date: 08-1997
DOI: 10.1016/S0303-7207(97)00106-8
Abstract: The 11beta-hydroxysteroid dehydrogenase type II enzyme (11betaHSD2) endows specificity on the mineralocorticoid receptor by metabolising glucocorticoids. Sequence comparisons with other microsomal proteins showed the strongly preferred topology of a lumenal pentapeptide followed by three transmembrane helices with residues beyond Ala73 on the cytoplasmic side of the membrane, suggesting that 11betaHSD2 is anchored to the endoplasmic reticulum by the N-terminal region. However, deletion of the N-terminus (11betaHSD2 deltaN) and expression of the construct in mammalian cells showed that the enzyme remained bound to the microsomal fraction, indicating that other regions are also involved in membrane anchoring. Crosslinking studies and nonreducing SDS-PAGE demonstrated that 11betaHSD2 is a non-covalently linked dimer. Deletion of the non-conserved C-terminal region (11betaHSD2 deltaC) resulted in an enzyme with a Km of 215 nM for cortisol in whole cell assays, while 11betaHSD2 and 11betaHSD2 deltaN displayed a Km of 62 and 74 nM, respectively. In homogenates 11betaHSD2 and 11betaHSD2 deltaC displayed maximal activity at 140 mM NaCl or KCl, but showed a marked decrease in enzyme activity with increasing salt. 11BetaHSD2 was more stable than 11betaHSD2 deltaC in the presence of NaSCN, suggesting that the C-terminal region plays a role in enzyme stability. There was no detectable activity in homogenates containing 11betaHSD2 deltaN, while 11betaHSD2 deltaC and 11betaHSD2 displayed a Km of 135 and 46 nM, respectively. Although 11betaHSD2 is conventionally considered a unidirectional dehydrogenase all constructs converted 11-dehydrodexamethasone to dexamethasone in whole cell assays, providing an explanation for the potency of the synthetic glucocorticoid in the face of a powerful inactivator of natural glucocorticoids.
Publisher: Frontiers Media SA
Date: 11-07-2018
DOI: 10.1111/TRI.13140
Publisher: Springer Science and Business Media LLC
Date: 08-1991
DOI: 10.1007/BF00265901
Publisher: Elsevier BV
Date: 12-2013
DOI: 10.1016/J.TRIM.2013.09.008
Abstract: Historic red blood cell transfusion (RBCT) may induce anti-HLA antibody which, if donor specific (DSA), is associated with increased antibody-mediated rejection (AMR). Whether post-operative RBCT influences this risk is unknown. We examined the RBCT history in 258 renal transplant recipients stratified according to prevalent recipient HLA antibody (DSA, Non-DSA or No Antibody). AMR occurred more frequently in patients who received RBCT both pre and post transplant compared with all other groups (Pre+Post-RBCT 21%, Pre-RBCT 4%, Post-RBCT 6%, No-RBCT 6%, HR 4.1 p=0.004). In the 63 patients who received Pre+Post-RBCT, 65% (13/20) with DSA developed AMR compared with 0/6 in the Non-DSA group and 2/37 (5%) in the No-Antibody group (HR 13.9 p<0.001). In patients who received No-RBCT, Pre-RBCT or Post-RBCT there was no difference in AMR between patients with DSA, Non-DSA or No-Antibody. Graft loss was independently associated with Pre+Post-RBCT (HR 6.5, p=0.001) AMR (HR 23.9 p<0.001) and Non-AMR (6.0 p=0.003) after adjusting for DSA and delayed graft function. Re-exposure to RBCT at the time of transplant is associated with increased AMR only in patients with preformed DSA, suggesting that RBCT provides additional allostimulation. Patients receiving Pre+Post-RBCT also had an increased risk of graft loss independently of AMR or DSA. Both pre and post procedural RBCT in renal transplantation is associated with modification of immunological risk and warrants additional study.
Publisher: Wiley
Date: 25-04-2011
DOI: 10.1111/J.1440-1797.2010.01421.X
Abstract: Haemodialysis with regional citrate anticoagulation in patients with contraindications for heparin is increasingly performed in the USA and Europe. Most published protocols use trisodium citrate, which is not readily available nor is it licensed in Australia. We established a protocol for citrate-anticoagulation in haemodialysis using acid citrate dextrose solution A (ACDA), which is approved for apheresis procedures in Australia. The aim of the present study was to assess the safety and efficacy of this protocol for routine use in haemodialysis patients. Systemic and post-filter blood ionized calcium, serum sodium and bicarbonate and dialyzer clotting score were analyzed prospectively in 14 patients undergoing 150 consecutive haemodialysis treatments with citrate anticoagulation using calcium-free dialysate. A simple algorithm allowed the attending nurse to adjust citrate infusion (to maintain post-filter ionized calcium at 0.2-0.3 mmol/L) and i.v. calcium substitution. Scheduled dialysis time was 4 h, and point-of-care monitoring of blood ionized calcium during dialysis was done at 0, 15, 60, 120 and 240 min. ACDA infusion rates of 300 mL/h were used in the first 52 treatments, but resulted in high dialyzer clotting score and 6% of treatments were discontinued due to complete clotting. Thereafter, ACDA infusion rate was increased to 350 mL/h, with all 98 subsequent treatments completed successfully. Ionized calcium levels were stable during all procedures with post-dialysis serum sodium averaging 135 ± 3 mmol/L and bicarbonate 23.8 ± 2 mmol/L. Routine use of citrate anticoagulation in the setting of a long-term haemodialysis unit is safe and efficient. Point-of-care measurements of ionized calcium levels are critical to safely and successfully perform citrate anticoagulation.
Publisher: Informa UK Limited
Date: 16-07-2020
Publisher: Frontiers Media SA
Date: 14-08-2012
DOI: 10.1111/J.1432-2277.2012.01541.X
Abstract: In the Australian kidney paired donation (KPD) program matching is based on acceptable mismatches, whereas deceased donor waitlist (DDWL) patients are allocated kidneys based on HLA antigen matching rules. Herein, we compared waiting time for a KPD match to the waiting time on the DDWL and the occurrence of matching in the DDWL for patients who were registered in both programs. Data on first dialysis, matches on the DDWL, KPD program entry, matches and transplant dates were assessed in 26 KPD recipients of the Australian program. There were 22 recipients who were listed in the DDWL and received kidney transplants by KPD. Time on dialysis until KPD transplantation was 808 ± 646 days. Eleven patients had never been matched with a deceased donor (waiting time 345 ± 237 days) and 11 had been matched on average 3 ± 5 times (waiting time 1227 ± 615 days, P < 0.0001 vs. never matched), but did not progress to transplantation because of positive crossmatch or class II donor-specific antibody. Mean time from registration in the KPD program until kidney transplantation was 153 ± 92 days (P < 0.0001 vs. DDWL). KPD allocation using the acceptable mismatch approach is effective in identifying suitable live donors for some recipients within a relatively short time-frame.
Publisher: Springer Science and Business Media LLC
Date: 06-1993
DOI: 10.1007/BF00315543
Abstract: The transmembrane protein ToxR plays a key role in the virulence expression system of Vibrio cholerae. The activity of ToxR is dependent on its periplasmic sensor domain (ToxRp) and on the inner membrane protein ToxS. Herein, we present the Nuclear Magnetic Resonance NMR solution structure of the sensory ToxRp containing an intramolecular disulfide bond. The presented structural and dynamic experiments with reduced and oxidized ToxRp propose an explanation for the increased proteolytic sensitivity of reduced ToxR. Additionally, for the first time, we could identify the formation of a strong heterodimer complex between the periplasmic domains of ToxR and ToxS in solution. NMR interaction studies reveal that binding of ToxS is not dependent on the redox state of ToxR cysteines, and formed complexes are structurally similar. By monitoring the proteolytic cleavage of ToxRp with NMR, we additionally provide a direct evidence of ToxS protective function. Taken together our results suggest that ToxR activity is regulated by its stability which is, on the one hand, dependent on the redox states of its cysteines, influencing the stability of its fold, and on the other hand, on its interaction with ToxS, which binds independent on the cysteines and acts as a protection against proteases.
Publisher: Cold Spring Harbor Laboratory
Date: 17-01-2023
DOI: 10.1101/2023.01.17.523798
Abstract: Currently circulating SARS-CoV-2 variants acquired convergent mutations at receptor-binding domain (RBD) hot spots 1 . Their impact on viral infection, transmission, and efficacy of vaccines and therapeutics remains poorly understood. Here, we demonstrate that recently emerged BQ.1.1. and XBB.1 variants bind ACE2 with high affinity and promote membrane fusion more efficiently than earlier Omicron variants. Structures of the BQ.1.1 and XBB.1 RBDs bound to human ACE2 and S309 Fab (sotrovimab parent) explain the altered ACE2 recognition and preserved antibody binding through conformational selection. We show that sotrovimab binds avidly to all Omicron variants, promotes Fc-dependent effector functions and protects mice challenged with BQ.1.1, the variant displaying the greatest loss of neutralization. Moreover, in several donors vaccine-elicited plasma antibodies cross-react with and trigger effector functions against Omicron variants despite reduced neutralizing activity. Cross-reactive RBD-directed human memory B cells remained dominant even after two exposures to Omicron spikes, underscoring persistent immune imprinting. Our findings suggest that this previously overlooked class of cross-reactive antibodies, exemplified by S309, may contribute to protection against disease caused by emerging variants through elicitation of effector functions.
Publisher: Springer Science and Business Media LLC
Date: 27-10-2006
Abstract: Failure of physicians to adhere to hypertension guidelines may partly account for the failure to achieve blood pressure (BP) goals in clinical practice. The aim of this trial is a comprehensive description of the approach of physicians in the management of high BP among primary care patients. It will primarily assess what are the Reasons for not Intensifying an Antihypertensive Treatment (RIAT), when predefined in idual BP goals are not achieved. Open intervention survey was conducted in 17 countries in Latin America, Eastern Europe, Africa and Asia in family practices, government and private clinics. The registry is based on a three-step epidemiological design. Step one shall identify guidelines and recommendations taken as reference in each country for the management of hypertension. Step two will assess the variance between in idual targets defined by physicians in their practice compared to guidelines and recommendations. Step three is a prospective registry where physicians collect patient data at baseline determine in idual target BP values. Several follow-up visits are proposed to monitor achievement of these targets. Step three of RIAT aims at providing responses to several key objectives. Recruitment is under way aiming at enrolling 33,000 patients. To identify, what is the BP targeted according to the risk factor profile and what are the reasons for not modifying an antihypertensive treatment when BP goals are not reached, and to analyse the type of antihypertensive drugs prescribed according to compelling indications and to assess the percentage of patients reaching target figures.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-1993
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-1991
DOI: 10.1097/00005344-199107000-00014
Abstract: Plasma insulin levels and the sensitivity of peripheral tissue to insulin (SI) have pathophysiological, therapeutic, and possibly also prognostic relevance. To investigate the effects of short-term selective alpha 1-adrenergic receptor blockade in nonobese normotensive humans on glucose and lipoprotein homeostasis, we assessed SI (determined by the minimal model method of Bergman), before and after glucose load plasma, glucose, and insulin levels, serum total triglycerides and lipoprotein cholesterol fractions, and some other variables in 20 healthy young men (26 +/- 1 years old, mean +/- SEM) during placebo and after 5 weeks of terazosin administration at a dose up to 10 mg once daily. Measurements were made after 3 days of standard diet (2,500 kcal/day, 45% carbohydrates, 40% fat, and 15% proteins) and after an overnight fast. Compared to placebo, terazosin decreased the upright systolic blood pressure (placebo vs. terazosin: 125 +/- 2 vs. 117 +/- 2 mm Hg, p less than 0.05) and increased supine (63 +/- 2 vs. 70 +/- 1 beats/min, p less than 0.05) and upright (77 +/- 2 vs. 88 +/- 2 beats/min, p less than 0.01) heart rates, while the body weight was unaltered. Terazosin did not significantly modify fasting plasma glucose (5.08 +/- 0.09 vs. 5.23 +/- 0.08 mmol/L, respectively), or insulin (8.9 +/- 0.5 vs. 8.6 +/- 0.6 microU/ml), SI (14.3 +/- 1.8 vs 11.8 +/- 1.5 x 10(-4)/min/microU/ml), the areas under the insulin or glucose curves, serum total triglycerides, and cholesterol or lipoprotein cholesterol fractions.(ABSTRACT TRUNCATED AT 250 WORDS)
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2002
DOI: 10.1097/00004872-200201000-00018
Abstract: Limitation of systemic and glomerular hypertension reduces urinary protein excretion and prevents renal function deterioration. To investigate whether, in hypertensive patients with glomerulonephritis, a combination of an angiotensin converting enzyme inhibitor (ACEI, fosinopril 20 mg/day) with an angiotensin receptor blocker (ARB, irbesartan 150 mg/day) produces a more profound antiproteinuric effect than either drug alone. Ten non-diabetic patients with glomerulonephritis, normal or slightly reduced but stable renal function (creatinine clearance 40-106 ml/min) without immunosuppression were studied. Clinical evaluations, 24 h blood pressure measurements and laboratory tests were performed as follows: (1) without medication (baseline) and in random sequence (2) ACEI alone (3) ARB alone and (4) combination of ACEI + ARB. Each period lasted for 6 weeks, separated by three washout periods of 4 weeks each without therapy. ACEI and ARB alone reduced proteinuria from 7.9 +/- 7.1 to 5.3 +/- 5.2 and 5.0 +/- 4.9 g/24 h (mean +/- SD), respectively. The combination of ACEI + ARB induced a more remarkable reduction of proteinuria in every patient (to 3.3 +/- 3.7 g/24 h) than either drug alone (P = 0.039 by ANOVA). The enhanced antiproteinuric effect of the combined therapy could not be attributed to a more pronounced reduction of 24 h mean arterial pressure (basal, 106 +/- 8 ACEI, 97 +/- 5 ARB, 98 +/- 5 ACEI+ARB, 95 +/- 5 mmHg) or creatinine clearance (basal, 77 +/- 27 ACEI, 73 +/- 31 ARB 80 +/- 30 ACEI + ARB, 73 +/- 32 ml/min). A combination of ACEI and ARB in patients with glomerulonephritis produces a more profound decrease in proteinuria than either drug alone. This additive antiproteinuric effect is not dependent on changes in blood pressure or creatinine clearance. A long-term controlled study is required to confirm the positive effect of this treatment on the progression of renal function loss.
Publisher: Hogrefe Publishing Group
Date: 12-2003
DOI: 10.1024/0369-8394.92.50.2145
Abstract: Die Inzidenz der Patienten mit chronischer Nierenersatztherapie in der Schweiz auf dem Boden einer Hypertonie und diabetischen Nephropathie ist in den letzten zehn Jahren kontinuierlich angestiegen. Die Höhe des Blutdrucks stellt einen besonderen Risikofaktor dar. Zur primären und sekundären Prävention einer diabetischen Nephropathie, vor allem aber zur Progressionsverzögerung einer chronischen Nierenerkrankung ist deshalb die Blutdrucksenkung von ausserordentlicher Bedeutung. Nach den WHO-Richtlinien zur Behandlung der Hypertonie muss bei Patienten mit einer Niereninsuffizienz und/oder einem Diabetes mellitus als Zielblutdruck 130/80 mmHg empfohlen, bei Patienten mit einer Proteinurie 1 g/d und Niereninsuffizienz unabhängig von deren Ätiologie sollte ein Blutdruck von 125/75 mmHg angestrebt werden. Auf der Grundlage der vorliegenden Studien sind Antagonisten des Renin-Angiotensin-Systems eine obligatorische Komponente der Therapie, da sie neben der antihypertensiven Wirkung blutdruckunabhängig renoprotektive Effekte aufweisen. Insbesondere bei Patienten mit chronischer Niereninsuffizienz ist in den meisten Fällen eine Mehrfachkombination von Antihypertensiva erforderlich die Kombination eines ACE-Hemmers mit einem Kalzium-Kanalblocker ist häufig notwendig. Ziele dieser antihypertensiven Therapie sind neben der Senkung des Blutdrucks und somit des kardiovaskulären Risikos, vor allem die Rückbildung der Proteinurie und die Verzögerung bzw. das Anhalten der Progression des chronischen Nierenfunktionsverlustes.
Publisher: Oxford University Press (OUP)
Date: 02-1989
DOI: 10.1093/AJH/2.2.2S
Abstract: The role of the kidney in "essential" or "genetic" types of hypertension has been evaluated both in a rat model such as the Milan hypertensive strain (MHS) or in humans. In both species, abnormalities of renal function have been demonstrated before the development of hypertension. Moreover hypertension could be "transplanted" with the kidney when kidney cross-transplantation was carried out between MHS and the Milan normotensive strain (MNS). Also in humans, the familiality for hypertension of the donor affected the requirement of antihypertensive therapy of the recipient. Further studies furnished results that were consistent with the hypothesis that a primary increase in Na transport across the tubular cell could be responsible for the pressor effect of the kidney in MHS or in humans. Because many similarities were found between the function of the tubular cell and the red blood cell in MHS, red blood cells were used to gain information about the molecular genetic mechanisms underlying these cellular changes. The results so far obtained showed that red blood cell abnormalities in MHS were genetically determined within the stem cells and genetically associated with the development of hypertension in F2 hybrids obtained by crossing the F1 (MHS X MNS). Moreover, the abnormal Na transport across the cell membrane may be due to an abnormal function of the membrane skeleton proteins. Studies are in progress to evaluate a possible cause-effect relationship between: membrane skeleton protein-ion transport across the cell membrane and the development of hypertension.
Publisher: Elsevier BV
Date: 1990
DOI: 10.1016/0005-2736(90)90377-Z
Abstract: This paper describes experiments to examine Rb+ fluxes via the Na+/K+/Cl- cotransporter in membrane vesicles from renal outer medulla of three strains of rat: (A) Wistar (B) Milan hypertensive (MHS) and normotensive (MNS), and (C) Sabra salt-sensitive hypertensive (SBH) and salt-resistant (SBN). Initially, Na(+)-dependent furosemide- or bumetanide-inhibited 86Rb+ fluxes were characterised using Wistar rat microsomes. The latter were partially purified on a metrizamide cushion, and assay conditions were optimized for use with microsomes from the other rats. The major result is that in microsomes from adult Milan hypertensive (MHS) rats the rate of the Na+/K+/Cl(-)-cotransporter mediated 86Rb flux at sub-saturating concentrations of Rb, appears to be significantly greater than in the normotensive (MNS) controls. The effect reflects an increased apparent Rb affinity of the cotransporter in MHS microsomes. There is no difference in maximal rate or in the apparent Na+ activation affinity of the 86Rb+ flux. In addition bumetanide appears to be a somewhat more effective inhibitor in MHS compared to MNS microsomes. The 86Rb+ flux result is compatible with a previous finding that in red cells, Na+/K+ -cotransporter mediated fluxes are increased in MHS compared to MNS. It supports the notion that the Na+/K+/Cl(-)-cotransporter in in both red cells and kidney is a genetic marker for hypertension. It is of interest that apparently more than one Na+ transport system is affected in MHS hypertensive kidneys (a) the Na+/K+/Cl- cotransporter in the thick ascending limb of Henle and (b) the Na+/H+ exchanger and/o a conductive Na(+)-pathway in brush-border membranes from proximal tubule. It is conceivable that in the hypertensive animals a common regulatory pathway (e.g., phosphorylation) or protein (e.g., cytoskeleton) is affected along the length of the nephron. In Sabra SBH and SBN rat microsomes, no difference was found for the 86Rb+ flux via the Na+/K+/Cl- cotransporter (or via a K+ channel).
Publisher: Springer Science and Business Media LLC
Date: 15-09-2000
Abstract: Amyloidosis (AL) is a rapidly fatal plasma cell dyscrasia causing progressive multiorgan failure. Recently, substantial improvement of survival was reported following high-dose chemotherapy with peripheral blood stem cell (PBSC) rescue. We describe a patient with AL with severe cardiac and renal involvement who received high-dose melphalan followed by fractioned autologous PBSC transplantation (455 ml on day 1 and 350 ml on day 2). Immediately after the second infusion of the PBSCs, life-threatening cardiac arrhythmias occurred and, despite intensive treatment, the patient died less than 24 h later. The infusion of cryopreserved PBSCs may be associated with complications, including cardiac toxicity. Dimethyl sulfoxide (DMSO) is the most frequently used cryopreservation agent. In the present case, we suggest that DMSO could have played an important role in causing the fatal cardiac arrhythmias. The mechanisms of the cardiovascular effects of DMSO and the possible preventive measures are discussed. Given the poor prognosis of AL and the promising results of dose-intensive chemotherapy with autologous PBSC transplantation, careful patient selection and intensive monitoring are mandatory in order to further pursue this therapeutic approach.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-1991
DOI: 10.1097/00003246-199112000-00010
Abstract: To determine circulating atrial natriuretic factor (ANF) concentrations in the postoperative state and to define potential hemodynamic determinants of regional plasma ANF concentrations. Cohort study. Pediatric ICU in a university hospital. Twenty-two children, mean age 4.2 yrs (range 0.9 to 13.5), were studied 18 hrs after corrective surgery on cardiopulmonary bypass. The underlying cardiac malformations were ventricular septum defect (n = 5), transposition of great arteries (n = 5), tetralogy of Fallot (n = 4), pulmonary stenosis (n = 3), and miscellaneous (n = 5). In addition to the commonly monitored variables in postoperative cardiac patients, blood volume was estimated by the 125I albumin method, and plasma s les for radioimmunoassay determination of ANF concentrations were taken simultaneously from indwelling catheters. Compared with normal age-matched values, plasma ANF concentrations were increased in all patients, with values tending to be highest in the left atrium, followed by systemic artery, superior vena cava, and pulmonary artery (345 +/- 158, 333 +/- 169, 311 +/- 154, and 272 +/- 160 pg/mL, respectively [mean +/- SD NS]). Simple regression analysis demonstrated a moderate correlation between blood volume and the concentration of ANF in the superior vena cava (p less than .05). Stepwise multivariate analysis showed no significant independent predictor of plasma ANF concentrations. Plasma ANF concentrations are increased after open-heart surgery in children, with moderate direct correlation to blood volume. The wide scatter of increased hormone concentrations may be explained by the many factors known to influence circulating ANF concentrations, such as age, underlying disease, cardiovascular state, and drugs.
Publisher: The Endocrine Society
Date: 02-2005
DOI: 10.1210/JC.2004-1031
Abstract: Reduced adrenal 11 beta-hydroxylation has been associated with an aldosterone synthase (CYP11B2) polymorphism. The 11 beta-hydroxylase gene (CYP11B1) lies close to CYP11B2. We hypothesize that a molecular variant in CYP11B2 is in linkage disequilibrium (LD) with a key quantitative trait in CYP11B1 determining this phenotype. Polymorphisms and inferred haplotypes at CYP11B loci were studied in two independent populations from Europe (n = 100) and South America (n = 99). The latter underwent detailed hormonal studies. LD was estimated by alternative Bayesian methods for inferring the extent of LD when haplotypes at different loci are inferred. Population differences in single nucleotide polymorphisms were modest, indicating the stability of both genes across populations. Using five of nine potentially informative loci at CYP11B sites with allele frequency greater than 0.1, two major contrasting haplotypes, CwtCG and TconvGTA, were found. In both populations the CwtCG haplotype accounted for 44% and the TconvGTA for 32% of subjects. Haplotype distribution did not differ between Europeans and South Americans (chi(2) = 2.81 P = 0.09). In vivo 11 beta-hydroxylase activity, estimated from urinary steroid profiling, was lower in subjects with an increased aldosterone to renin ratio or with the TconvGTA haplotype. These findings indicate that genotypes at the CYP11B locus are in strong LD and that identified haplotypes predict 11 beta-hydroxylase activity.
Publisher: Oxford University Press (OUP)
Date: 10-2000
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-2006
Publisher: Oxford University Press (OUP)
Date: 07-2022
DOI: 10.1093/PNASNEXUS/PGAC125
Abstract: In the midst of the COVID-19 experience, we learned an important scientific lesson: knowledge acquisition and information quality in medicine depends more on “data quality” rather than “data quantity.” The large number of COVID-19 reports, published in a very short time, demonstrated that the most advanced statistical and computational tools cannot properly overcome the poor quality of acquired data. The main evidence for this observation comes from the poor reproducibility of results. Indeed, understanding the data generation process is fundamental when investigating scientific questions such as prevalence, immunity, transmissibility, and susceptibility. Most of COVID-19 studies are case reports based on “non probability” s ling and do not adhere to the general principles of controlled experimental designs. Such collected data suffers from many limitations when used to derive clinical conclusions. These include confounding factors, measurement errors and bias selection effects. Each of these elements represents a source of uncertainty, which is often ignored or assumed to provide an unbiased random contribution. Inference retrieved from large data in medicine is also affected by data protection policies that, while protecting patients’ privacy, are likely to reduce consistently usefulness of big data in achieving fundamental goals such as effective and efficient data-integration. This limits the degree of generalizability of scientific studies and leads to paradoxical and conflicting conclusions. We provide such ex les from assessing the role of risks factors. In conclusion, new paradigms and new designs schemes are needed in order to reach inferential conclusions that are meaningful and informative when dealing with data collected during emergencies like COVID-19.
Publisher: Massachusetts Medical Society
Date: 19-02-2004
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2019
Publisher: Frontiers Media SA
Date: 02-2003
Publisher: Elsevier BV
Date: 12-1991
DOI: 10.1016/0002-9343(91)90211-F
Abstract: Essential hypertension is, in some patients, complicated by impairment of insulin-mediated glucose disposal and hyperinsulinemia. Whether this metabolic disturbance is a consequence of the hypertensive process or whether it may precede, and thus possibly promote, the development of hypertension has been unknown. Searching for hereditary or familial defects in hypertension-prone humans, we prospectively investigated insulin sensitivity, plasma insulin and glucose, and serum lipoproteins in normotensive offspring of essential hypertensive as compared with age- and body habitus-matched offspring of normotensive families. Compared with 78 control subjects, 70 offspring of essential hypertensive parents had similar age (mean +/- SEM: 24 +/- 1 versus 24 +/- 1 years, respectively) and body mass index (22.3 +/- 0.2 versus 22.4 +/- 0.2 kg/m2), a blood pressure of 127/77 +/- 1/1 versus 123/76 +/- 1/1 mm Hg (p less than 0.05 for systolic), and significantly elevated (p less than 0.01 to 0.001) fasting plasma insulin levels (9.9 +/- 0.3 versus 8.6 +/- 0.3 microU/mL), serum total triglycerides (1.03 +/- 0.06 versus 0.83 +/- 0.03 mmol/L), total cholesterol (4.37 +/- 0.08 versus 3.93 +/- 0.07 mmol/L), low-density lipoprotein cholesterol (2.45 +/- 0.08 versus 2.14 +/- 0.07 mmol/L), and total/high-density lipoprotein cholesterol ratio (4.3 +/- 0.1 versus 3.7 +/- 0.1). Insulin sensitivity was lower (9.4 +/- 0.7 versus 13.2 +/- 1.1 x 10(-4) x minute-1/microU/mL, p less than 0.001), while post-glucose-load plasma insulin levels were higher (p less than 0.05) in the 41 offspring of essential hypertensive parents than in the 38 offspring of normotensive parents so investigated. These findings demonstrate that young normotensive humans in apparently excellent health but with one essential hypertensive parent tend to have an impairment of insulin-mediated glucose disposal, hyperinsulinemia, and dyslipidemia. It follows that a familial trait for essential hypertension seems to coexist commonly with defects in carbohydrate and lipoprotein metabolism that can be detected before or at least at a very early stage of the development of high blood pressure as judged by resting blood pressure measurements.
Publisher: The Endocrine Society
Date: 06-2003
Abstract: Altered control of aldosterone synthase (CYP11B2) gene expression may modulate aldosterone secretion, as suggested by a raised aldosterone to renin ratio (ARR) in some patients with essential hypertension. We compared the frequency of two linked CYP11B2 polymorphisms, one in the steroidogenic factor-1 (SF-1) binding site and the other an intronic conversion (Int2) in relation to ARR in 141 hypertensive patients. Patients were ided into groups with either normal or high supine ARR using a cut-off threshold of 145 pmol/liter per ng/liter. Supine ARR was normal in 104 patients and raised in 37 patients. The two polymorphisms were in strong linkage disequilibrium (chi(2) = 123.8 P < 0.0001). The SF-1 T and Int2 C alleles were more prevalent among patients with high ARR (46% and 43%, respectively) than with normal ARR (22% and 17% P < 0.01 and P < 0.005, respectively). Odds ratios for raised ARR in subjects with a homozygous SF-1 T and Int2 C haplotype were 6.1 (95% confidence interval, 1.6-22.5 P < 0.005) when compared with the contrasting haplotype. Linear modeling of in idual postural changes in renin and aldosterone showed a maximal achievable aldosterone increase of 110 pmol/liter with no mutated haplotype and 500 pmol/liter with two mutated haplotypes. These findings support the view of a molecular basis regulating aldosterone production.
Publisher: Springer Science and Business Media LLC
Date: 07-1991
DOI: 10.1007/BF00403291
Abstract: It has been claimed that symmetric lower zone pleural or diaphargmatic plaques are markers of asbestos exposure both in asbestos workers and the general population. In this study, total pulmonary asbestos burden was analyzed for 29 patients selected because pleural plaques were found at autopsy, and the results were compared with values obtained for 25 patients who had no occupational asbestos exposure. The average number of asbestos bodies in the plaque groups was 1732/g wet lung, and in the control group, 42/g wet lung. Uncoated asbestos fibers were extracted from lung and counted, measured, and identified by morphologic examination, electron diffraction, and energy-dispersive x-ray spectroscopy. The total number of fibers er gram wet lung in the plaque group (114 x 10(3)) was similar to that in the control group (99 x 10(3), as was the number of chrysotile fibers (51 x 10(3) versus 29 x 10(3)). However, the plaque patients had a marked increase in the number of the commercially used high aspect ratio hiboles, amosite and crocidolite (50 x 10(3) versus 1 x 10(3). A retrospective history of fairly certain asbestos exposure was obtained for 16 of the plaque patients, and such a history correlated strongly with increased numbers of commercial hiboles in lung. It is concluded that 1) in this general autopsy population, two subgroups of patients are present. About one half of the patients appear to have developed pleural plaques as a result of asbestos exposure, while the etiology of the plaques in the other half is unclear 2) the presence of pleural plaques correlates with a modest (50-fold) increase in numbers of long high-aspect ratio commercial hiboles in lung tissue but does not correlate with numbers of chrysotile fibers, noncommercial hiboles, or the total number of asbestos fibers 3) asbestos-induced lesions are related to a complex set of mineralogic parameters and not to mere numbers of fibers in lung.
Publisher: Elsevier BV
Date: 1999
DOI: 10.1016/S0002-9343(98)00367-2
Abstract: To investigate whether body sodium content and blood volume contribute to the pathogenesis of orthostatic hypotension in patients with diabetes mellitus. Exchangeable sodium, plasma and blood volumes, and catecholamine, renin, and aldosterone levels were assessed in 10 patients with Type II diabetes mellitus who had orthostatic hypotension and control groups of 40 diabetic patients without orthostatic hypotension and 40 normal subjects of similar age and sex. In subgroups, clinical tests of autonomic function and cardiovascular reactivity to norepinephrine and angiotensin II infusions were performed. In diabetic patients with orthostatic hypotension, mean (+/- SD) supine blood pressure was 165/98 +/- 27/12 mm Hg (P <0.05 compared with other groups) and mean upright blood pressure was 90/60 +/- 38/18 mm Hg. Compared with controls, diabetic patients with orthostatic hypotension had a 10% lower blood volume. They also had less exchangeable sodium than patients with diabetes who did not have orthostatic hypotension (P <0.01). Compared with both groups of controls, diabetic patients with orthostatic hypotension had decreased 24-hour urinary norepinephrine excretion and a reduced diastolic blood pressure response to handgrip (P <0.05). Moreover, they displayed reduced products of exchangeable sodium or blood volume and sympathetic function indexes. Cardiovascular pressor reactivity to norepinephrine was enhanced (P <0.01) and beat-to-beat variation decreased (P <0.01) in both groups of diabetic patients. Microvascular complications were more prevalent in the diabetic patients with orthostatic hypotension (90% vs 35%). Patients who have Type II diabetes mellitus and orthostatic hypotension are hypovolemic and have sympathoadrenal insufficiency both factors contribute to the pathogenesis of orthostatic hypotension.
Publisher: Oxford University Press (OUP)
Date: 10-08-2004
DOI: 10.1093/NDT/GFH417
Publisher: American Diabetes Association
Date: 15-04-2021
DOI: 10.2337/DC20-2676
Abstract: Obesity is an established risk factor for severe coronavirus disease 2019 (COVID-19), but the contribution of overweight and/or diabetes remains unclear. In a multicenter, international study, we investigated if overweight, obesity, and diabetes were independently associated with COVID-19 severity and whether the BMI-associated risk was increased among those with diabetes. We retrospectively extracted data from health care records and regional databases of hospitalized adult patients with COVID-19 from 18 sites in 11 countries. We used standardized definitions and analyses to generate site-specific estimates, modeling the odds of each outcome (supplemental oxygen/noninvasive ventilatory support, invasive mechanical ventilatory support, and in-hospital mortality) by BMI category (reference, overweight, obese), adjusting for age, sex, and prespecified comorbidities. Subgroup analysis was performed on patients with preexisting diabetes. Site-specific estimates were combined in a meta-analysis. Among 7,244 patients (65.6% overweight/obese), those with overweight were more likely to require oxygen/noninvasive ventilatory support (random effects adjusted odds ratio [aOR], 1.44 95% CI 1.15–1.80) and invasive mechanical ventilatory support (aOR, 1.22 95% CI 1.03–1.46). There was no association between overweight and in-hospital mortality (aOR, 0.88 95% CI 0.74–1.04). Similar effects were observed in patients with obesity or diabetes. In the subgroup analysis, the aOR for any outcome was not additionally increased in those with diabetes and overweight or obesity. In adults hospitalized with COVID-19, overweight, obesity, and diabetes were associated with increased odds of requiring respiratory support but were not associated with death. In patients with diabetes, the odds of severe COVID-19 were not increased above the BMI-associated risk.
Publisher: Elsevier BV
Date: 10-2009
DOI: 10.1038/KI.2009.282
Abstract: In patients on hemodialysis, Farese et al. report that inhibition of the enzyme 11beta-hydroxysteroid dehydrogenase type 2 by glycyrrhetinic acid, the active compound of licorice, reduces serum potassium concentration and the frequency of hyperkalemia, possibly by enhancing intestinal potassium loss. This finding could be an important tool to maintain predialysis [K(+)] within safe limits in some dialysis patients at risk of hyperkalemic arrhythmias.
Publisher: The Endocrine Society
Date: 12-2000
Publisher: Elsevier BV
Date: 12-2011
DOI: 10.1016/J.JFMA.2011.11.007
Abstract: Despite availability of effective antihypertensives, blood pressure (BP) control is usually inadequate. The Reasons for not Intensifying Antihypertensive Treatment (RIAT) registry evaluated the reasons behind not modifying treatment in an international, cross-sectional study in 16 countries. The Taiwanese cohort of RIAT consisted of 8922 patients with untreated/uncontrolled essential hypertension recruited from 22 centers in the country. At the first visit, physicians selected target BP and antihypertensive treatment, and at the next three visits they measured BP and modified treatment rovided justification for not modifying treatment. Mean target BP selected by physicians was 134.6/84.6 ± 5.1/5.0 mmHg, respectively. Patients' in idual risk stratification determined the BP goals. More patients achieved targets according to the physicians' opinion than based on actual BP measurements: visit 2-50.6% vs. 48.6% visit 3-58.4% vs. 55.2% and visit 4-61.2% vs. 57.0%. At each visit, treatment remained unchanged for >60% patients not reaching target the most common reason for this at visit 2 was the assumption that the time was too short to assess new drug therapy and at visits 3 and 4 was the assumption that target was reached/had almost been reached. About 40% Taiwanese hypertensive patients in RIAT did not reach BP targets after an average of 4 months' follow-up. The most common reason for not modifying treatment was the assumption that the target had been reached or had almost been reached.
Publisher: Wiley
Date: 17-09-2007
DOI: 10.1111/J.1440-1797.2007.00857.X
Abstract: An adequate total body pool of ascorbate is essential for optimum health in humans. Requirements for ascorbate are increased in peritoneal dialysis (PD) patients most likely due to a combination of poor nutrition and increased dialysate losses. We measured serum ascorbate levels in 45 clinically stable PD patients to assess the prevalence of ascorbate insufficiency (level between 2 and 4 mg/L) and deficiency (level <2 mg/L). We also assessed the efficacy of subsequent supplementation and patients' adherence to the prescribed supplementation. All patients were advised on commencement of dialysis to take a multivitamin tablet containing 100-120 mg ascorbate. Eighteen (41%) PD patients were regularly taking ascorbate-containing multivitamins, while 27 (59%) patients did not take ascorbate supplements. Serum ascorbate levels ranged from <0.2 to 41 mg/L, with wide variations in serum ascorbate at any given intake level. Ascorbate deficiency was present in 1/3 of the current PD population (44% of patients not taking supplements and in 16% of those on supplements), although none of the patients demonstrated clinical manifestations of scurvy. Targeted supplementation of ascorbate insufficient patients increased the median serum ascorbate level from 1.7 mg/L (IQR 1.2-2.2) to 22.5 mg/L (IQR 16.7-32.9). Our results show that, in PD patients, ascorbate deficiency is common and can readily be identified with serum ascorbate measurements. Oral supplements in the form of inexpensive multivitamin preparations restore adequate serum ascorbate levels in the majority of these patients. We therefore suggest measurement of ascorbate levels in all PD patients at the commencement of dialysis with a target level in the normal range (4-14 mg/L).
Publisher: Elsevier BV
Date: 04-2000
DOI: 10.1046/J.1523-1755.2000.00978.X
Abstract: The renal 11beta-hydroxysteroid dehydrogenase type 2 (11betaHSD2) enzyme inactivates 11-hydroxy steroids in the kidney, thus protecting the nonselective mineralocorticoid receptor (MR) from occupation by glucocorticoids. The gene is highly expressed in all sodium-transporting epithelia, but also in human placenta, pancreas, and thyroid. Mutations in the HSD11B2 gene cause a rare monogenic juvenile hypertensive syndrome called apparent mineralocorticoid excess (AME). In AME, compromised 11betaHSD2 enzyme activity results in overstimulation of the MR by cortisol, causing sodium retention, hypokalemia, and salt-dependent hypertension. Recent evidence suggests a role of the 11betaHSD2 in essential hypertension. We found hypertension with no other characteristic signs of AME in the heterozygous father of a child with AME and in a girl with a homozygous gene mutation resulting in a mild deficiency of 11betaHSD2. Moreover, some studies in patients with essential hypertension showed a prolonged half-life of cortisol and an increased ratio of urinary cortisol to cortisone metabolites, suggesting a deficient 11betaHSD2 activity. These abnormalities may be genetically determined. A genetic association of a microsatellite flanking the HSD11B2 gene and hypertension in black patients with end-stage renal disease has been reported. We recently analyzed a CA-repeat allele polymorphism in unselected patients with essential hypertension, but did not find any correlation between this marker and blood pressure. However, we did find an association between this polymorphic CA microsatellite marker and salt sensitivity. Moreover, the activity of the 11betaHSD2, as shown by elevated mean ratios of urinary cortisol to cortisone metabolites, was decreased in salt-sensitive compared with salt-resistant subjects. These findings indicate that variants of the HSD11B2 gene contribute to the enhanced blood pressure response to salt in humans.
Publisher: Oxford University Press (OUP)
Date: 08-06-2009
DOI: 10.1093/NDT/GFP255
Abstract: As survival with an orthotopic liver transplant (OLT) improves, the incidence of chronic kidney disease in OLT recipients increases. Measurement of kidney function using creatinine-based estimates is often inaccurate, while cystatin C may overcome the biases that effect creatinine. The aim of this study was to assess the accuracy of creatinine- and cystatin C-based equations to estimate kidney function in long-term OLT recipients. This was a cross-sectional study performed on OLT recipients within a single liver transplant centre where creatinine (n = 41) and cystatin C (n = 30) were measured and glomerular filtration rate (GFR) estimated using the Modification of Diet and Renal Disease (MDRD), Cockcroft-Gault (CG), Hoek, Larsson, Filler and Le Bricon equations. Comparison was made with the nuclear GFR (nGFR) (n = 41) measured through 51-Cr EDTA clearance. The mean age of recipients was 56 +/- 13 years, and they were 6.5 +/- 4.7 years post-OLT. Fifty-six percent of recipients had a nGFR < or =60 mL/min/1.73 m(2). nGFR correlated significantly with all predictive equations (P < 0.001). The MDRD, CG and Le Bricon equations had the smallest degree of bias (-7.6, -7.3 and 3.4 mL/min/1.73 m(2), respectively), with 22%, 22% and 27% of estimates, respectively, being within 10% of nGFR measurements. In OLT recipients with nGFR < or =60 mL/min/1.73 m(2), the degree of bias of both the creatinine-base MDRD and cystatin-based Hoek equations was within 2 mL/min/1.73 m(2) difference between the measured and estimated GFR, but 41% and 36% of estimates were within 10% of the nGFR measurement. Therefore, the degree of inaccuracy in cystatin C- and creatinine-based predictive equations brings into question their clinical utility in OLT recipients. We have no evidence that cystatin C is superior to creatinine in this population.
Publisher: Oxford University Press (OUP)
Date: 07-10-2014
DOI: 10.1093/NDT/GFU309
Abstract: Due to the ongoing shortage of deceased-donor organs, novel strategies to augment kidney transplantation rates through expanded living donation strategies have become essential. These include desensitization in antibody-incompatible transplants and kidney paired donation (KPD) programs. KPD enables kidney transplant candidates with willing but incompatible living donors to join a registry of other incompatible pairs in order to find potentially compatible transplant solutions. Given the significant immunologic barriers with fewer donor options, single-center or small KPD programs may be less successful in transplanting the more sensitized patients the optimal solution for the difficult-to-match patient is access to more potential donors and large multicenter or national registries are essential. Multicenter KPD programs have become common in the last decade, and now represent one of the most promising opportunities to improve transplant rates. To maximize donor-recipient matching, and minimize immunologic risk, these multicenter KPD programs use sophisticated algorithms to identify optimal match potential, with simultaneous two-, three- or more complex multiway exchanges. The article focuses on the recent progresses in KPD and it also reviews some of the differences and commonalities across four different national KPD programs.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-2002
DOI: 10.1097/00007890-200210270-00016
Abstract: The mechanism of avascular osteonecrosis (AVN) is controversial. Besides an increased bone marrow pressure with reduced blood supply, an enhanced coagulation has been considered. We hypothesize that a genetic variant of the plasminogen activator inhibitor-1 (PAI-1) determines the risk of AVN in glucocorticoid-treated patients. Genotyping for the 4G/5G PAI-1 polymorphism was performed in 228 glucocorticoid-treated renal transplant patients. AVN of the hip was present in 26 patients. Magnetic resonance imaging (MRI) of the hips was obtained in 81 of the remaining renal transplant patients without clinical symptoms of AVN. The presence of the homozygous 4G/4G PAI-1 genotype was higher in patients with AVN (60.3%) as compared with patients without either clinical (20.6%, P<0.007) or radiological signs of AVN (17.3%, P<0.002). The prevalence of AVN by genotype was 1.8% with the 5G/5G, 7.7% with the 5G/4G, and 30.3% with the 4G/4G alleles (P<0.001 vs. 5G/4G and 5G/5G). The prevalence of AVN increased with increasing body mass index (BMI) (P=0.04). The prevalence of AVN by genotype in subjects with persistent hyperparathyroidism was 4.2% with the 5G/5G, 15.2% with the 5G/4G, and 55.5% with the 4G/4G alleles (P<0.003 vs. 5G/4G and P<0.001 vs. 5G/5G). Hypofibrinolysis conferred by the 4G/4G PAI-1 gene variant is a major predisposing factor for AVN in renal transplant patients. The risk is particularly high in obese subjects or patients with persistent hyperparathyroidism. A prospective intervention study of early anticoagulation after renal transplantation is needed to assess whether glucocorticoid-associated AVN can be prevented.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-2017
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-1998
DOI: 10.1097/00041552-199803000-00012
Abstract: The in idual variation in the efficacy of and tolerability to antihypertensive drugs in human essential hypertension is linked to the genetic heterogeneity of this multifactorial disease. Different approaches have been pursued in the attempt to correlate a specific responsiveness to the therapy with some phenotypic traits of the patients, such as the renin-angiotensin profile or the characteristics of cell ion transports. More recently, a genetic approach to the study of the mechanisms underlying hypertension has led to the identification of some quantitative trait loci or genes that influence blood pressure in both animal models and patients. Also, in idual variation to therapy can now be studied from the genetic point of view using pharmacogenomics, that is, the study of the genes or loci which are involved in determining the responsiveness to a given drug. Only a few ex les of this approach are available to date. Our group has identified a polymorphism of the genes for the cytoskeletal protein, adducin, which is linked to both rat and human hypertension, sodium sensitivity and to the pressor responsiveness to diuretic therapy. These results, together with the indication that adducin can play a functional role by modulating the cellular sodium transport, have led to the identification of a new antihypertensive compound, which could be a candidate for the selective treatment of those patients in whom alterations of the renal sodium handling are associated with specific genetic traits such as the polymorphism for adducin.
Publisher: Wiley
Date: 20-12-2011
DOI: 10.1111/J.1399-3062.2011.00700.X
Abstract: Penicillium marneffei is a thermally dimorphic fungus that causes severe human immunodeficiency virus-related opportunistic infection in endemic areas of Southeast Asia and has rarely been reported in solid organ transplant (SOT) recipients. We report here the case of an Australian renal transplant patient who presented with disseminated P. marneffei infection shortly after a 10-day holiday to Vietnam, and review all previously published cases of penicilliosis associated with renal transplantation. This is the first reported case, to our knowledge, of P. marneffei infection in an SOT recipient acquired during travel to an endemic country, and highlights the importance of an accurate travel history when opportunistic infection is suspected, as well as giving appropriate health advice to transplant patients who travel.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-2007
Publisher: Oxford University Press (OUP)
Date: 2003
DOI: 10.1093/NDT/18.1.62
Abstract: The effect of the specific endothelin (A) (ET(A))-receptor antagonist LU 302146 (LU) was assessed in a normotensive model of chronic transplant vasculopathy, i.e. orthotopic allotransplantation of the infrarenal abdominal aorta from spontaneously hypertensive-to-Wistar-Kyoto (SHR-to-WKY) rats. A second experimental setting was used to confirm the results in a different model, which to some extent may also address the issue of blood pressure (BP) in transplant vasculopathy, i.e. orthotopic allotransplantation of infrarenal abdominal aorta from WKY-to-SHR rats. Untreated sham-operated and isografted WKY and SHR served as controls. Allotransplanted animals treated with the angiotensin-converting enzyme (ACE) inhibitor trandolapril served as positive treatment controls. Rats were randomized to receive standard diet or a diet designed to deliver either 30 mg LU/kg bw/day, 0.3 mg/kg bw/day trandolapril or a combination of both. The duration of either experiment was 8 weeks. BP was measured by tail plethysmography. Treatment with LU did not affect systolic BP in either experimental setting. In contrast, trandolapril and combination treatment significantly reduced systolic BP in SHRs. The increase in aortic wall thickness (given in mm) was abrogated to a similar extent in the three treatment groups as compared with untreated allotransplanted animals in either experimental setting (e.g. WKY sham-operated 0.084 +/- 0.013, P < 0.05 vs treatment groups WKY isotransplanted 0.100 +/- 0.010, P < 0.05 vs treatment groups WKY allotransplanted 0.289 +/- 0.077, P < 0.05 vs all groups WKY allotransplanted + trandolapril 0.185 +/- 0.025 WKY allotransplanted + LU 301246 0.192 +/- 0.049 WKY allotransplanted + LU 301246 + trandolapril 0.190 +/- 0.041). This was due to an attenuation of the increase of intima and media thickness. Treatment with LU and trandolapril were similarly effective in attenuating the increase of the number of proliferating cell nuclear antigen (PCNA)-positive cells in the intima. Again, combination treatment did not confer additional benefit. In contrast, trandolapril was more effective than LU in attenuating the increase in the number of PCNA-positive cells in the media. Trandolapril or combination treatment, but not LU, attenuated transforming growth factor-beta expression in aortic allografts. The ET(A)-receptor blockade abrogates allograft vasculopathy in two different aorta allotransplantation models to a similar extent as ACE inhibition even in the absence of concomitant immunosuppression. At least in SHRs the effect of ET(A)-receptor blockade is independent of BP. This finding is consistent with the notion that ET(A)-receptor mediated events play a partly BP-independent role in the genesis of chronic transplant vasculopathy.
Publisher: Elsevier BV
Date: 02-2004
Publisher: Wiley
Date: 09-11-2007
Publisher: Elsevier BV
Date: 10-2000
DOI: 10.1046/J.1523-1755.2000.00303.X
Abstract: Mutations in the 11beta-hydroxysteroid dehydrogenase type 2 (11betaHSD2) gene cause a rare form of low-renin hypertension leading to end-stage renal disease (ESRD) in some affected subjects. To date, no search for mutations in the HSD11B2 gene was performed in a large population to obtain an estimate its prevalence. The HSD11B2 gene was analyzed in 587 subjects, including 260 ESRD patients (either dialysis or transplanted) for mutations in the exons 2 through 5 and corresponding intronic regions by polymerase chain reaction (PCR) using appropriate overlapping primers, gel analysis by single strand conformational polymorphism (SSCP), and sequencing of identified migration variants. The prevalence of single-nucleotide polymorphisms (SNPs) in ESRD patients and controls was 26%. The following genetic variants were found among all subjects investigated: exon 2 T442G (Leu148/Val, N = 70) and C470A (Thr156/Thr, N = 67), exon 3 G534A (Glu178/Glu, N = 69), and exon 5 C1274T (Asp388/Asp, N = 2). Four SNPs were identified in intron 4 only. In the control population, the prevalence of the variants Leu148 and Thr156 was 14% each. Glu178 was 11%, while no variants were found in exon 5. In ESRD patients, the prevalence of the variant Leu148 was 9%, and Thr156 was 8%. Glu178 was 13%, while the Asp388 variant was 0.7%. In patients with a short duration between the time of diagnosis of the renal disease and the onset of ESRD, the prevalence of the Leu148 and Glu178 variants was higher than in subjects with slowly progressing renal disease. The 11betaHSD2 activity of all of these SNPs is predictably unaltered. There is a high prevalence of SNPs of the HSD11B2 gene, without causing exonic mutations generating a 11betaHSD2 enzyme with altered activity. Based on statistical analyses, the frequency of homozygosity for mutated alleles of the HSD11B2 gene can be derived as <1/250,000 when a Caucasian population is considered.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2001
Abstract: Loss-of-function mutations or inhibition of 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD-2) results in overstimulation of the mineralocorticoid receptor by cortisol and causes salt-sensitive hypertension. Traditionally, 11β-HSD-2 activity has been assessed by measurement of the urinary cortisol metabolite ratio (tetrahydrocortisol [THF]+5α-THF)/tetrahydrocortisone (THE). Recently, the ratio of urinary free glucocorticoids, UFF/UFE, has been suggested to be a more reliable parameter, an aspect that has not been investigated systematically. Steroid metabolites were measured repeatedly by gas chromatography–mass spectrometry in 20 healthy subjects at baseline and after 1 week each of a 30- or 180-mmol/d of sodium diet or 500 mg/d of glycyrrhetinic acid. Intrain idual coefficients of variation from 3 random urine collections for (THF+5α-THF)/THE and UFF/UFE ratios were 11±9% and 25±14% ( P .001). (THF+5α-THF)/THE was more sensitive than UFF/UFE for detection of glycyrrhetinic acid–induced increases higher than the upper 95% confidence interval of the coefficient of variation of the corresponding ratio. Low- or high-salt diet did not alter either ratio. Mean (THF+5α-THF)/THE but not UFF/UFE was higher in salt-sensitive than salt-resistant subjects. Absolute glycyrrhetinic acid–related increase in (THF+5α-THF)/THE but not UFF/UFE was higher in salt-sensitive than salt-resistant subjects and correlated with changes in mean BP. Intrain idual variability of (THF+5α-THF)/THE is lower than that of UFF/UFE. The UFF/UFE ratio does not appear to be more sensitive than (THF+5α-THF)/THE for detection of decreased 11β-HSD-2 activity. The (THF+5α-THF)/THE ratio better discriminates between salt-sensitive and salt-resistant subjects. Together with BP responses to glycyrrhetinic acid, these findings support a pivotal role of 11β-HSD-2 in salt sensitivity.
Publisher: The Endocrine Society
Date: 05-1998
DOI: 10.1210/JC.83.5.1814
Publisher: The Endocrine Society
Date: 07-1997
Abstract: The 11beta-hydroxysteroid dehydrogenase type 2 enzyme (11betaHSD2) metabolizes glucocorticoids into their inactive 11-keto metabolites. Although the type 1 enzyme (11betaHSD1) displays both oxidative and reductive activity, to date 11betaHSD2 has been shown to have dehydrogenase activity only. In this study we compared both dehydrogenase and reductase characteristics of the cloned rat 11betaHSD1 and rat and human 11betaHSD2 for three different 11-hydroxysteroid substrates, cortisol (F), corticosterone (B), and dexamethasone (Dex), and the corresponding 11-keto metabolites, cortisone (E), 11-dehydrocorticosterone (A), and 11-dehydrodexamethasone (DH-Dex), respectively. In cell homogenates expressing either the rat or the human 11betaHSD2, the relative potency for the dehydrogenase reaction was B > F > Dex. Although there was no reduction of A or E, DH-Dex was readily converted to Dex with an equilibrium far on the side of the 11-hydroxy metabolite. DH-Dex reduction in homogenates was inhibited by both glycyrrhetinic acid and carbenoxolone, with a 50% inhibition at 80 and 100 nM, respectively. In intact cells transfected with rat 11betaHSD1, the equilibrium was on the reductase side for all substrates. Dehydrogenation of B or F was more potent with rat 11betaHSD2 than with rat 11betaHSD1. There was no detectable 11betaHSD1 oxidation of Dex. These data indicate that both the cloned human and rat 11betaHSD2 reduce DH-Dex and do this more readily than they oxidize Dex. Thus, 11betaHSD2 seems also to be a bidirectional enzyme, although no reduction of the physiological compounds A and E was observed.
Publisher: SAGE Publications
Date: 04-2021
DOI: 10.1177/14604582211009918
Abstract: Kidney Exchange Programs (KEP) are valuable tools to increase the options of living donor kidney transplantation for patients with end-stage kidney disease with an immunologically incompatible live donor. Maximising the benefits of a KEP requires an information system to manage data and to optimise transplants. The data input specifications of the systems that relate to key information on blood group and Human Leukocyte Antigen (HLA) types and HLA antibodies are crucial in order to maximise the number of identified matched pairs while minimising the risk of match failures due to unanticipated positive crossmatches. Based on a survey of eight national and one transnational kidney exchange program, we discuss data requirements for running a KEP. We note large variations in the data recorded by different KEPs, reflecting varying medical practices. Furthermore, we describe how the information system supports decision making throughout these kidney exchange programs.
Publisher: Frontiers Media SA
Date: 25-02-2013
DOI: 10.1111/TRI.12077
Publisher: American Medical Association (AMA)
Date: 16-09-2021
Publisher: Informa UK Limited
Date: 1996
DOI: 10.3109/08037059609062102
Abstract: The amount of, and response of the kidneys to, endogenous natriuretic factor(s) could be important in the pathogenesis of essential hypertension. Searching for possible disturbance(s) related to atrial natriuretic factor (ANF) and its second messenger, cyclic guanosine monophosphate (c-GMP), we assessed plasma immunoreactive (ir) ANF and c-GMP, effective renal plasma flow (ERPF), glomerular filtration rate (GFR), urinary c-GMP, absolute and fractional (FE) excretions of sodium (Na) and chloride (Cl) before and during infusions of low ANF doses or vehicle (V) in 7 normotensive sons of essential hypertensive parents (SEH) compared with 7 sons of normotensive parents (SN). Each subject was infused at 2-week intervals in a single-blind randomized sequence with 4 different solutions: V only or ANF 0.004, 0.008 and 0.016 microgram/kg/min, infused over 90 min. Plasma irANF was lower in SEH than in SN (p < 0.001) during vehicle infusion. Basal plasma c-GMP levels were, on all 4 different study days lower (p < 0.05 to < 0.01) in SEH in SN. Response of plasma c-GMP to infused ANF was also slightly decreased in SEH (p < 0.05 to < 0.01). BP, ERPF and GFR did not differ between SEH and SN and were unchanged during the 4 infusions. Urinary c-GMP excretion, FENa and FECl increased dose-dependently during ANF (p < 0.05 to < 0.0001) but not V infusions. These findings indicate that at the stage of pre-hypertension a disturbance in the ANF-c-GMP regulatory pathway may occur, which is expressed primarily at the circulatory rather than the renal excretory level.
Publisher: Wiley
Date: 10-2005
Publisher: The Endocrine Society
Date: 11-1995
DOI: 10.1210/JCEM.80.11.7593456
Abstract: The 11 beta-hydroxysteroid dehydrogenase type II enzyme (11 beta HSD2) inactivates glucocorticoids in the kidney and thus permits aldosterone to occupy the non-selective mineralocorticoid receptor in epithelial tissues. We have recently described a C to T transition in the HSD11B2 gene which results in an arginine to cysteine mutation (R337C) in the 11 beta HSD2 enzyme in a consanguineous family with three siblings suffering from Apparent Mineralocorticoid Excess (AME). In the present study we have examined the metabolism of cortisol in mammalian cells transfected with plasmids expressing the wild type and mutant enzymes. In whole cells the Km of the normal enzyme was 110nM, while the enzyme containing the R337C mutation displayed a Km of 1010nM. Further experiments revealed that the mutant was totally inactive in cell free preparations, suggesting that it has additional properties which may compromise its activity in whole cells.
Publisher: Informa UK Limited
Date: 2005
DOI: 10.1080/08037050500340018
Abstract: The prevalence of hypertension in type 2 diabetics is high, though there is no published data for Switzerland. This prospective cohort survey determined the frequency of type 2 diabetes mellitus associated with hypertension from medical practitioners in Switzerland, and collected data on the diagnostic and therapeutic work-up for cardiovascular risk patients. The Swiss Hypertension And Risk Factor Program (SHARP) is a two-part survey: The first part, I-SHARP, was a survey among 1040 Swiss physicians to assess what are the target blood pressure (BP) values and preferred treatment for their patients. The second part, SHARP, collected data from 20,956 patients treated on any of 5 consecutive days from 188 participating physicians. In I-SHARP, target BP?135/85 mmHg, as recommended by the Swiss Society of Hypertension, was the goal for 25% of physicians for hypertensives, and for 60% for hypertensive diabetics values >140/90 mmHg were targeted by 19% for hypertensives, respectively 9% for hypertensive diabetics. In SHARP, 30% of the 20,956 patients enrolled were hypertensive (as defined by the doctors) and 10% were diabetic (67% of whom were also hypertensive). Six per cent of known hypertensive patients and 4% of known hypertensive diabetics did not receive any antihypertensive treatment. Diabetes was not treated pharmacologically in 20% of diabetics. Proteinuria was not screened for in 45% of known hypertensives and in 29% of known hypertensive diabetics. In Switzerland, most physicians set target BP levels higher than recommended in published guidelines. In this country with easy access to medical care, high medical density and few financial constraints, appropriate detection and treatment for cardiovascular risk factors remain highly problematic.
Publisher: Elsevier BV
Date: 12-2010
DOI: 10.1016/J.BBADIS.2009.10.017
Abstract: Cortisol and aldosterone have the same in vitro affinity for the mineralocorticoid receptor (MR), although in vivo only aldosterone acts as a physiologic agonist of the MR, despite circulating levels of cortisol in humans and corticosterone in rodents being three orders of magnitude higher than aldosterone levels. In mineralocorticoid target organs the enzyme 11β-hydroxysteroid dehydrogenase type 2 (11βHSD2) inactivates 11-hydroxy steroids, to their inactive keto-forms, thus protecting the nonselective MR from activation by glucocorticoids. The gene is highly expressed in all sodium-transporting epithelia, particularly in the kidney and colon, but also in human placenta and vascular wall. Mutations in the HSD11B2 gene cause a rare monogenic juvenile hypertensive syndrome called apparent mineralocorticoid excess (AME). In AME, compromised 11βHSD2 enzyme activity results in activation of the MR by cortisol, causing sodium retention, hypokalaemia, and salt-dependent hypertension. Whereas mutations or inhibition of 11βHSD2 by licorice have been clearly shown to produce a congenital or acquired syndrome of mineralocorticoid excess, the questions remaining are the extent to which subtle abnormalities in MR/11βHSD2 mechanisms may contribute to essential hypertension. Studies in patients with essential hypertension showed a prolonged half-life of cortisol and an increased ratio of urinary cortisol to cortisone metabolites, suggesting a deficient 11βHSD2 activity. These abnormalities may be genetically determined, as suggested by the association of a microsatellite flanking the HSD11B2 gene with hypertension in black patients with end-stage kidney disease and with salt sensitivity of blood pressure in healthy subjects. These findings indicate that variants of the HSD11B2 gene may contribute to the enhanced blood pressure response to salt and possibly to hypertension in humans.
Publisher: Springer Science and Business Media LLC
Date: 2002
DOI: 10.2165/00003088-200241130-00007
Abstract: To describe the relationship between plasma magnesium (Mg(2+)) concentration and blood pressure response in pregnant women with preecl sia. Fifty-one preecl tic women were studied after receiving two consecutive magnesium sulfate infusions (120 mg/kg for 1 hour and 24 mg/kg for 5 hours). Mg(2+) concentration and systolic/diastolic blood pressure were measured at 0, 0.5, 1, 2, 4, 6, 7, 9, 11, 13 and 15 hours after the beginning of the first infusion. A population pharmacokinetic-pharmacodynamic model was fitted to the data with the computer program NONMEM. Pharmacokinetics were described by a two-compartment model. Population parameter estimates were 5.0 L/h for body clearance (CL), 24L for central volume (V(c), 25L for peripheral volume ((V)(p)) and 5.6 L/h for intercompartment clearance (Q). The interin idual variability in CL, V(c), V(p) and Q was 39, 26, 38, and 59%, respectively. The mean population estimates for systolic (diastolic) blood pressure were 36.8 (27.8) mm Hg for the maximum decrease (E(max)), 0.75 (0.88) mmol/L for the Mg2+ concentration (above baseline) eliciting half-maximum effect (EC(50)) and 0.76 (0.5) h(-1) for the equilibrium rate (k(eo)) of the effect compartment model. Mg(2+ )concentrations within the range (2-4 mmol/L) proposed for treatment of preecl sia produce greater than half-maximal lowering of systolic and diastolic blood pressure.
Publisher: Cold Spring Harbor Laboratory
Date: 07-10-2021
DOI: 10.1101/2021.10.05.21264054
Abstract: Patients on dialysis are at risk of severe course of SARS-CoV-2 infection. Understanding the neutralizing activity and coverage of SARS-CoV-2 variants of vaccine-elicited antibodies is required to guide prophylactic and therapeutic COVID-19 interventions in this frail population. By analyzing plasma s les from 130 hemodialysis and 13 peritoneal dialysis patients after two doses of BNT162b2 or mRNA-1273 vaccines, we found that 35% of the patients had low-level or undetectable IgG antibodies to SARS-CoV-2 Spike (S). Neutralizing antibodies against the vaccine-matched SARS-CoV-2 and Delta variant were low or undetectable in 49% and 77% of patients, respectively, and were further reduced against other emerging variants. The fraction of non-responding patients was higher in SARS-CoV-2-naïve hemodialysis patients immunized with BNT162b2 (66%) than those immunized with mRNA-1273 (23%). The reduced neutralizing activity correlated with low antibody avidity. Patients followed up to 7 months after vaccination showed a rapid decay of the antibody response with an average 21- and 10-fold reduction of neutralizing antibodies to vaccine-matched SARS-CoV-2 and Delta variant, which increased the fraction of non-responders to 84% and 90%, respectively. These data indicate that dialysis patients should be prioritized for additional vaccination boosts. Nevertheless, their antibody response to SARS-CoV-2 must be continuously monitored to adopt the best prophylactic and therapeutic strategy.
Publisher: Wiley
Date: 15-06-2017
DOI: 10.1111/NEP.12815
Abstract: Pentoxifylline has been shown to increase haemoglobin levels in patients with chronic kidney disease (CKD) and erythropoietin-stimulating agent (ESA)-hyporesponsive anaemia in the Handling Erythropoietin Resistance with Oxpentifylline multicentre double-blind, randomized controlled trial. The present sub-study evaluated the effects of pentoxifylline on the iron-regulatory hormone hepcidin in patients with ESA-hyporesponsive CKD. This sub-study included 13 patients in the pentoxifylline arm (400 mg daily) and 13 in the matched placebo arm. Hepcidin-25 was measured by ultra performance liquid chromatography/quadrupole time-of-flight mass spectrometry following isolation from patient serum. Serum hepcidin-25, serum iron biomarkers, haemoglobin and ESA dosage were compared within and between the two groups. Hepcidin-25 concentration at 4 months adjusted for baseline did not differ significantly in pentoxifylline versus placebo treated patients (adjusted mean difference (MD) -7.9 nmol, P = 0.114), although the difference between the groups mean translated into a >25% reduction of circulating hepcidin-25 due to pentoxifylline compared with the placebo baseline. In paired analysis, serum hepcidin-25 levels were significantly decreased at 4 months compared with baseline in the pentoxifylline group (-5.47 ± 2.27 nmol/l, P < 0.05) but not in the placebo group (2.82 ± 4.29 nmol/l, P = 0.24). Pentoxifylline did not significantly alter serum ferritin (MD 55.4 mcg/l), transferrin saturation (MD 4.04%), the dosage of ESA (MD -9.93 U/kg per week) or haemoglobin concentration (MD 5.75 g/l). The reduction of circulating hepcidin-25 due to pentoxifylline did not reach statistical significance however, the magnitude of the difference suggests that pentoxifylline may be a clinically and biologically meaningful modulator of hepcidin-25 in dialysis of patients with ESA-hyporesponsive anaemia.
Publisher: SAGE Publications
Date: 2015
DOI: 10.1186/S40697-015-0066-5
Abstract: Erythropoiesis stimulating agent (ESA)-resistant anemia is common in chronic kidney disease (CKD). To evaluate the determinants of severity of ESA resistance in patients with CKD and primary ESA-resistance. Secondary analysis of a randomized controlled trial (the Handling Erythropoietin Resistance with Oxpentifylline, HERO) 53 adult patients with CKD stage 4 or 5 and primary ESA-resistant anemia (hemoglobin ≤120 g/L, ESA resistance index [ERI] ≥1.0 IU/kg/week/gHb for erythropoietin or ≥0.005 μg/kg/week/gHb for darbepoeitin, no cause for ESA-resistance identified). Iron studies, parathyroid hormone, albumin, liver enzymes, phosphate or markers of oxidative stress and inflammation. Participants were ided into tertiles of ERI. Multinomial logistic regression was used to analyse the determinants of ERI tertiles. All patients, except one, were receiving dialysis for end-stage kidney disease. The mean ± SD ERI values in the low ( n = 18), medium ( n = 18) and high ( n = 17) ERI tertiles were 1.4 ± 0.3, 2.3 ± 0.2 and 3.5 ± 0.8 IU/kg/week/gHb, respectively ( P 0.001). There were no significant differences observed in age, gender, ethnicity, cause of kidney disease, diabetes, iron studies, parathyroid hormone, albumin, liver enzymes, phosphate or markers of oxidative stress and inflammation between the ERI tertiles. The median [inter-quartile range] serum alkaline phosphatase concentrations in the low, medium and high ERI tertiles were 89 [64,121], 99 [76,134 and 148 [87,175] U/L, respectively ( P = 0.054). There was a weak but statistically significant association between ERI and serum alkaline phosphatase (R 2 = 0.06, P = 0.03). Using multinomial logistic regression, the risk of being in the high ERI tertile relative to the low ERI tertile increased with increasing serum alkaline phosphatase levels ( P = 0.02). No other variables were significantly associated with ERI. Small s le size bone-specific alkaline phosphatase, other markers of bone turnover and bone biopsies not evaluated. Serum alkaline phosphatase was associated with severity of ESA resistance in ESA-resistant patients with CKD. Large prospective studies are required to confirm this association. (Trial registration: Australian New Zealand Clinical Trials Registry 12608000199314)
Publisher: Elsevier BV
Date: 09-2000
Publisher: Proceedings of the National Academy of Sciences
Date: 07-02-2022
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-1990
DOI: 10.1097/00004872-199006000-00001
Abstract: The sensitivity of tissue to insulin is of physiological, pathophysiological and therapeutic relevance. The quantity of insulin and the response to insulin are paramount complementary factors in the regulation of glucose metabolism, and may, at least under certain pathophysiological conditions, also affect cardiovascular function. Hypertension has a high prevalence among subjects with decreased insulin sensitivity and/or hyperinsulinaemia due to obesity, impaired glucose tolerance, non-insulin-dependent diabetes mellitus, and certain other conditions. There is evidence that, even in the absence of obesity or diabetes mellitus, essential hypertension tends to be associated with insulin resistance. The latter elicits a compensatory increase in insulin secretion. Hyperinsulinaemia also occurs in diabetes type 1 as a consequence of insulin treatment. Considering the acute effects of insulin on sympathetic nervous activity, transmembranous cation transport, renal sodium reabsorption, cellular proliferation and lipid metabolism, insulin resistance and/or hyperinsulinaemia may possibly contribute to the genesis of essential, obesity-associated and diabetes-associated hypertension, and may also promote dyslipidaemia in these disorders.
Publisher: Hogrefe Publishing Group
Date: 06-2000
DOI: 10.1024/0040-5930.57.6.345
Abstract: Die klinisch gebräuchlichen Diuretika erhöhen die Ausscheidung von Natriumchlorid (NaCl) im Urin, indem sie selektiv spezifische Prozesse des Na-Transportes in der Henle’schen Schleife, im distalen Tubulus und im Sammelrohr hemmen. Während der letzten Jahre wurde eine Vielzahl von Diuretika-sensitiven Na-Transportern kloniert, was zu unserem Verständnis über die zellulären Wirkungsmechanismen der verschiedenen Diuretika wesentlich beigetragen hat. Kürzlich wurden Mutationen in den Genen identifiziert, die für diese Transporter kodieren und die sich als vererbte Leiden mit Störungen im Na-Haushalt manifestieren. Diese Erkrankungen sind in ihrer Auswirkung mit dem Effekt der verschiedenen Diuretika vergleichbar. Beim Guibaud-Vainsel-Syndrom (renal-tubulären Azidose mit Osteopetrose) sind die renalen Manifestationen vergleichbar mit den Effekten einer Acetazolamid-Behandlung. Mutationen in der proximal-tubulären Carboanhydrase Typ II sind für diese seltene Erkrankung verantwortlich. Patienten mit einem Bartter-Syndrom weisen identische biochemische Veränderungen auf wie diejenigen unter einer chronischen Furosemid-Therapie. Dieses Syndrom wird durch Mutationen im Furosemid-sensitiven Na-K-2Cl Cotransporter der Henle’schen Schleife verursacht. Beim Gitelman-Syndrom werden Störungen der Elektrolyte und Hormone im Blut und Urin beobachtet, die denjenigen einer Thiazidtherapie vergleichbar sind. Diese Erkrankung ist die Folge von Mutationen im distal-tubulären Thiazid-sensitiven Na-Cl Cotransporter. Die zwei Formen des Pseudhypoaldosteronismus Typ 1 zeigen die charakteristischen metabolischen Veränderungen wie bei einer Therapie mit kaliumsparenden Diuretika. Die genetische Störung liegt entweder im Amilorid-sensitiven epithelialen Na-Kanal (autosomal-dominante Form) oder im Spironolacton-sensitiven Mineralokortikoid-Rezeptor (autosomal-rezessive Form) im distalen Tubulus und Sammelrohr. Zahlreiche Forscher versuchen derzeit, die Schlüsselstrukturen des Elektrolyttransports zu definieren und die Interaktion der Diuretika mit denselben zu untersuchen. Aus diesen Informationen wird es möglich sein, bereits vorhandene Diuretika sinnvoller einzusetzen und neue Substanzen mit diuretischer Wirkung zu entwickeln.
Publisher: Wiley
Date: 25-02-2013
DOI: 10.1111/NEP.12035
Abstract: Treatment of chronic kidney disease (CKD) includes parenteral iron therapy, and these infusions can lead to iron overload. Secondary iron overload is typically treated with iron chelators, of which deferasirox is one of the most promising. However, it has not been studied in patients with CKD and iron overload. A pilot study was conducted to evaluate the pharmacokinetics and safety of deferasirox in eight haemodialysis-dependent patients, who were receiving intravenous iron for treatment of anaemia of CKD. Deferasirox was administered at two doses (10 mg/kg and 15 mg/kg), either acute (once daily for 2 days) or steady-state (once daily for 2 weeks). A dose of 10 mg/kg in either protocol was not sufficient to achieve a plasma concentration in the therapeutic range (acute peak 14.1 and steady-state 22.8 μmol/L), while 15 mg/kg in either protocol maintained plasma concentration well above this range (acute peak 216 and steady-state 171 μmol/L). Plasma concentration observed at 15 mg/kg was well above that expected for this dose (40-50 μmol/L), although no adverse clinical events were observed. This study highlights the need to profile drugs such as deferasirox in specific patient groups, such as those with CKD and iron overload.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-2003
DOI: 10.1097/01.ASN.0000092789.67966.5C
Abstract: Equivalent long-term effects on the kidney are attributed to angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II type 1 receptor blockers (ARB). Nevertheless, it is unknown to which degree effects of these compounds on in idual inflammatory mediators, including matrix metalloproteinases (MMP), are comparable. On the basis of structural and functional differences, it was hypothesized that ACEI and ARB differentially regulate MMP activity. In a randomized, prospective crossover trial, the effect of an ACEI (fosinopril 20 mg/d) and of an ARB (irbesartan 150 mg/d) on MMP activity was evaluated. Ten hypertensive patients with glomerulonephritis and normal or mildly reduced creatinine clearance were studied. MMP activity and tissue inhibitors of metalloproteinase (TIMP) levels were analyzed in serum and urine: without therapy, with ACEI, with ARB, and with both agents combined. Treatment periods continued for 6 wk separated by periods of 4 wk each without therapy. Untreated patients with glomerulonephritis displayed distinctively higher serum levels of MMP-2 but much lower MMP-1/-8/-9 concentrations compared with healthy control subjects. Immunohistology of MMP-2 and MMP-9 in kidney biopsy specimen was accordingly. However, these patients excreted higher amounts of MMP-2 and MMP-9 in urine than healthy control subjects, possibly reflecting ongoing glomerular inflammation. In patients with glomerulonephritis, ACEI significantly reduced overall MMP serum activity to 25%, whereas ARB did not show any effect. Activities of MMP-1/-2/-8/-9 were also significantly inhibited by fosinopril but not by irbesartan. Levels of TIMP-1/-2 remained unaffected. In conclusion, ACEI and ARB differentially regulate MMP activity, which may ultimately have consequences in certain types of MMP-dependent glomerulonephritis. E-mail: hpmarti@bluewin.ch
Publisher: Oxford University Press (OUP)
Date: 10-05-2005
DOI: 10.1093/NDT/GFH880
Abstract: Mortality rates of critically ill patients with acute renal failure (ARF) requiring renal replacement therapy (RRT) are high. Intermittent and continuous RRT are available for these patients on the intensive care units (ICUs). It is unknown which technique is superior with respect to patient outcome. We randomized 125 patients to treatment with either continuous venovenous haemodiafiltration (CVVHDF) or intermittent haemodialysis (IHD) from a total of 191 patients with ARF in a tertiary-care university hospital ICU. The primary end-point was ICU and in-hospital mortality, while recovery of renal function and hospital length of stay were secondary end-points. During 30 months, no patient escaped randomization for medical reasons. Sixty-six patients were not randomized for non-medical reasons. Of the 125 randomized patients, 70 were treated with CVVHDF and 55 with IHD. The two groups were comparable at the start of RRT with respect to age (62+/-15 vs 62+/-15 years, CVVHDF vs IHD), gender (66 vs 73% male sex), number of failed organ systems (2.4+/-1.5 vs 2.5+/-1.6), Simplified Acute Physiology Scores (57+/-17 vs 58+/-23), septicaemia (43 vs 51%), shock (59 vs 58%) or previous surgery (53 vs 45%). Mortality rates in the hospital (47 vs 51%, CVVHDF vs IHD, P = 0.72) or in the ICU (34 vs 38%, P = 0.71) were independent of the technique of RRT applied. Hospital length of stay in the survivors was comparable in patients on CVVHDF [median (range) 20 (6-71) days, n = 36] and in those on IHD [30 (2-89) days, n = 27, P = 0.25]. The duration of RRT required was the same in both groups. The present investigation provides no evidence for a survival benefit of continuous vs intermittent RRT in ICU patients with ARF.
Publisher: Oxford University Press (OUP)
Date: 09-1991
DOI: 10.1093/AJH/4.9.773
Abstract: Plasma glucose, insulin, triglyceride, and cholesterol concentrations were measured in male rats of the Milan hypertensive strain (MHS) and compared to the Milan normotensive strain (MNS) of the same body weight. Both blood pressure (P less than .001) and left ventricular weight (P less than .005) were higher in rats of the MHS. Although plasma glucose concentrations were similar in both groups, mean (+/- SEM) plasma insulin concentration were significantly higher (P less than .01) in MHS as compared to MNS rats (30 +/- 4 v. 13 +/- 5 microU/mL). In addition mean (+/- SEM) plasma triglyceride concentrations were higher (P less than .01) in MHS rats (112 +/- 9 mg/dL) than in MNS rats (81 +/- 6 mg/dL), as were plasma cholesterol concentrations (114 +/- 3 v 100 +/- 2 mg/dL, P less than .001). These data demonstrate the presence of hyperinsulinemia and hypertriglyceridemia in another genetic model of rat hypertension.
Publisher: Elsevier
Date: 2003
DOI: 10.1016/S0083-6729(03)01004-5
Abstract: Hypertension with hypokalemia, metabolic alkalosis, and suppressed plasma renin activity defines mineralocorticoid hypertension. Mineralocorticoid hypertension is the consequence of an overactivity of the epithelial sodium channel expressed at the apical membrane of renal cells in the distal nephron. This is usually the case when the mineralocorticoid receptor is activated by its physiologic substrate aldosterone. The best known form of mineralocorticoid hypertension is an aldosterone-producing adrenal tumor leading to primary aldosteronism. Primary aldosteronism can also be caused by unilateral or bilateral adrenal hyperplasia and rarely adrenal carcinoma. Interestingly, most of the inherited monogenic disorders associated with hypertension involve an excessive activation of the mineralocorticoid axis. In some of these disorders, mineralocorticoid hypertension results from activation of the mineralocorticoid receptor by other steroids (cortisol, deoxycorticosterone), by primary activation of the receptor itself, or by constitutive overactivity of the renal epithelial sodium channel. The present review addresses the physiology and significance of the key players of the mineralocorticoid axis, placing emphasis on the conditions leading to mineralocorticoid hypertension.
Publisher: Canadian Science Publishing
Date: 10-1991
DOI: 10.1139/Y91-235
Abstract: The pathogenesis of essential hypertension may possibly involve a deficiency in, or a decreased response to, endogenous vasodilator and natriuretic factor(s). Searching for hereditary or familial defects, it is plausible to evaluate blood pressure (BP) regulating factors in (yet) normotensive offspring of hypertensive parents (OHyp), some of whom are in fact in a stage of prehypertension. Studies by our group demonstrated that compared with healthy offspring of normotensive parents, OHyp have plasma atrial natriuretic (ANF) factor levels that are unaltered on a low salt intake but often fail to increase normally in response to a high salt intake. Plasma levels of cyclic GMP, the presumed second messenger of ANF, also may tend to be decreased in certain OHyp. On the other hand, renal excretory responses of cyclic GMP and electrolytes to ANF infused in "physiological" dose were unchanged in some OHyp tested so far. In borderline to moderate, uncomplicated essential hypertension, plasma ANF levels are often "normal." This may be inappropriately low relative to the existing BP, although the relationship of circulating ANF to atrial pressures in essential hypertension remains to be clarified. A conversion to higher plasma ANF values may occur with cardiac complications such as left ventricular hypertrophy, enlargement, dysfunction, or overt heart failure. Acute or short-term elevation of circulating ANF within the physiological and pathophysiological range by ANF infusion produces an exaggerated natriuresis and lowers BP in essential hypertensive patients. We postulate a syndrome of ANF deficiency, characterized by an impaired response of circulating ANF to high salt intake and by low cyclic GMP levels in certain yet normotensive offspring of essential hypertensive parents and by inappropriately "normal" plasma ANF in some patients with uncomplicated essential hypertension. At the stage of prehypertension, a disturbance in the ANF – cyclic GMP pathway may be expressed primarily at the circulatory rather than at the renal level. Hypertension-prone humans also tend to have an exaggerated vascular reactivity to norepinephrine. Whether the two disturbances may be interrelated is presently unknown. Both defects may potentially predispose to the development of essential hypertension. Relative ANF deficiency, an enhanced natriuretic response to ANF, and a sustained antihypertensive effect of infused ANF may represent a rational basis for treatment of essential hypertension with agents that activate the ANF system.Key words: offspring of hypertensive parents, essential hypertension, ANF, ANF deficiency syndrome, cyclic GMP, blood pressure regulation, vascular reactivity, renal function.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 30-04-2002
Publisher: Elsevier BV
Date: 02-2021
Publisher: Cold Spring Harbor Laboratory
Date: 30-09-2022
DOI: 10.1101/2022.09.30.509852
Abstract: Memory B cells (MBCs) generate rapid antibody responses upon secondary encounter with a pathogen. Here, we investigated the kinetics, avidity and cross-reactivity of serum antibodies and MBCs in 155 SARS-CoV-2 infected and vaccinated in iduals over a 16-month timeframe. SARS-CoV-2-specific MBCs and serum antibodies reached steady-state titers with comparable kinetics in infected and vaccinated in iduals. Whereas MBCs of infected in iduals targeted both pre- and postfusion Spike (S), most vaccine-elicited MBCs were specific for prefusion S, consistent with the use of prefusion-stabilized S in mRNA vaccines. Furthermore, a large fraction of MBCs recognizing postfusion S cross-reacted with human betacoronaviruses. The avidity of MBC-derived and serum antibodies increased over time resulting in enhanced resilience to viral escape by SARS-CoV-2 variants, including Omicron BA.1 and BA.2 sub-lineages, albeit only partially for BA.4 and BA.5 sublineages. Overall, the maturation of high-affinity and broadly-reactive MBCs provides the basis for effective recall responses to future SARS-CoV-2 variants.
Publisher: Elsevier BV
Date: 06-1996
DOI: 10.1016/0303-7207(96)03822-1
Abstract: The 11 beta-hydroxysteroid dehydrogenase type II enzyme (11 beta HSD2) protects the non-discriminating mineralocorticoid receptor from occupation by glucocorticoids. In man the enzyme is also highly expressed in the placenta where it is thought to also protect the fetus from the high circulating levels of maternal glucocorticoids. Mutations in the HSD11B2 gene have recently been shown to account for the syndrome of apparent mineralocorticoid excess. In the present study we have used a rat 11 beta HSD2 cDNA to study the distribution and regulation of this enzyme. The rat protein is highly homologous to the mouse, rabbit and human enzymes, except for the carboxy-terminal region which displays extensive ergence between species beyond residue 382. Northern blot analysis of rat total RNA showed that the single copy gene is highly expressed in kidney and adrenal with lower levels in the colon surprisingly, there was no detectable signal in the placenta. There was also no detectable mRNA in the liver, heart, hippoc us, testis, thymus and pancreas. Nuclease protection analysis revealed the presence of moderate 11 beta HSD2 message levels in the parotid and exceedingly low levels in the placenta. Regulation studies showed that administration of dexamethasone, deoxycorticosterone and 9 alpha-fluorocortisol to adrenalectomized rats for 7 days increased renal enzyme activity 33%-50%, while message levels decreased 35%-70%, suggesting that the increased enzyme activity may represent activation of latent enzyme.
Publisher: Elsevier BV
Date: 08-2009
DOI: 10.1016/J.CLINTHERA.2009.08.010
Abstract: Results from clinical studies suggest that the dihydropyridine calcium channel blocker (CCB) lercanidipine may be associated with a lower incidence of peripheral edema than are older dihydro-pyridine CCBs. The objective of the present study was to conduct a meta-analysis of published data from randomized controlled trials (RCTs) to assess the relative risk (RR) of dihydropyridine CCB-specific adverse events with lercanidipine versus the older dihydro-pyridine CCBs (first generation: amlodipine, felodipine, and nifedipine), and versus the other lipophilic dihy-dropyridine CCBs (second generation: lacidipine and manidipine). A systematic literature search (all years through August 11, 2008) of MEDLINE, EMBASE, and the Cochrane Library was conducted for English-language reports of single- or double-blind RCTs of > or = 4 weeks' duration that compared the tolerability of lercanidipine with other dihydropyridine CCBs in participants with mild (140-159/90-99 mm Hg) to moderate (160-179/100-109 mm Hg) hypertension. Eight RCTs (6 used first-generation drugs, and 4 used second-generation drugs) met the criteria for inclusion. Efficacy outcomes for lowering blood pressure did not differ statistically between lercanid-ipine and either generation of medications. Compared with the first generation, lercanidipine was associated with a reduced risk of peripheral edema (52/742 with lercanidipine vs 88/627 with first generation RR = 0.44 [95% CI, 0.31-0.62]), but not flushing or headache. The frequency of peripheral edema, flushing, and headache did not differ statistically between lercanidi-pine and the second-generation drugs. Study participants were less likely to withdraw from the RCTs because of peripheral edema (RR = 0.24 [95% CI, 0.12-0.47]) or any adverse event (RR = 0.51 [95% CI, 0.33-0.77]) when treated with lercanidipine rather than a drug from the first generation, but not when treated with lercanidipine rather than second-generation drugs. In this meta-analysis, lercanidipine was associated with a lower risk of peripheral edema and a lower risk of treatment withdrawal because of peripheral edema than were the first-generation, but not the second-generation, dihydropyridine CCBs.
Publisher: Oxford University Press (OUP)
Date: 03-05-2005
DOI: 10.1093/NDT/GFH873
Abstract: Family studies point to important genetic determinants of diabetic nephropathy (DN). Blood pressure (BP) is higher in offspring of patients with type 2 diabetes and DN, but the pathomechanisms involved have not been elucidated. We examined the salt sensitivity of BP after 5 days equilibration on a low (20 mmol/day) vs high salt diet (220 mmol/day) in three matched groups of 15 subjects each: (i) control in iduals (ii) offspring of type 2 diabetic parents without DN (DN-) and (iii) offspring of type 2 diabetic parents with DN (DN+). Ambulatory BP and hormones involved in sodium homeostasis [plasma renin activity (PRA), aldosterone and atrial natriuretic peptide (ANP)] as well as the tetrahydrocortisol + 5-allotetrahydrocortisol/tetrahydrocortisone (THF + 5alphaTHF)/THE) ratio in the urine as an index of 11beta-hydroxysteroid dehydrogenase type 2 (11betaHSD2) activity were analysed. In offspring of DN+ patients on a high salt diet, systolic and diastolic BP was 137/82+/-10/8 mmHg vs 125/77+/-12/8 mmHg in offspring of DN- patients (P<0.01 for systolic BP). The salt-induced difference in mean BP between high and low salt diet was 5.2+/-3.3 mmHg in offspring of DN+ patients vs 0.7+/-4.7 mmHg in offspring of DN- patients (P<0.002). The proportion of 'salt-sensitive' in iduals was 67% in offspring of DN+ patients vs 20% in offspring of DN- patients (P<0.05). In all groups, a high salt diet caused a comparable decrease of PRA and p-aldosterone accompanied by an increase in ANP. The urinary (THF + 5alphaTHF)/THE ratio was 1.23+/-0.36 in salt-sensitive in iduals and 0.99+/-0.33 (P<0.03) in salt-resistant subjects, consistent with increased activity of 11betaHSD2. BP is more salt sensitive in offspring of type 2 diabetic patients with diabetic nephropathy. The salt sensitivity of BP may be an intermediate phenotype in in iduals with a high risk of future diabetic nephropathy.
Publisher: AMPCo
Date: 06-2009
DOI: 10.5694/J.1326-5377.2009.TB02642.X
Abstract: Falling numbers of deceased organ donors and longer kidney transplant waiting lists have increased the emphasis on live kidney donation to meet demand for kidney transplantation. Several new strategies have been introduced to expand live donation beyond the classic direct donation. These include: altruistic donation paired kidney exchange (PKE) and altruistic donor chains programs. Using incompatible donor-recipient pairs and altruistic donors, the Western Australian PKE program achieved nine successful kidney transplantations between October 2007 and November 2008. If PKE were performed routinely in Australia, the rate of kidney transplants could increase by 7%-10%.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 06-2004
DOI: 10.1097/00004872-200406000-00024
Abstract: Hypertension is often poorly controlled, despite its importance and despite the availability of very effective treatments. An under-recognized problem is the failure of consensus guidelines to acknowledge the important difference between efficacy in clinical trials and effectiveness in clinical practice. The present survey was designed to prospectively assess what is the target blood pressure (BP) goal defined by a general practitioner (GP) for an in idual patient, and what are the reasons for not modifying an antihypertensive drug regimen, when pre-defined in idual BP goals are not achieved. Family practice based, open intervention survey. Participating GPs enrolled 2621 hypertensive patients. At the first visit each physician was required to assess the cardiovascular risk profile of each patient and to define in idual BP targets. Treatment was started with irbesartan alone or in fixed combination with hydrochlorothiazide. Follow-up visits were suggested after 1 month, 2 months and 4 months. Physicians were asked to report BP values under the new treatment regimen and to indicate whether in their opinion pre-defined BP targets set at baseline were achieved or not and whether the antihypertensive regimen was modified or maintained in relation to whether target BP was reached or not. To provide reasons for not changing the treatment even though BP goals were missed. Average target BP values defined by the physicians at baseline were 138 +/- 8 mmHg for systolic and 84 +/- 5 mmHg for diastolic BP. Among GPs, defined target BP values did not depend on in idual risk stratification, but rather depended on baseline BP values. At baseline systolic and diastolic BP averaged 165/97 +/- 17/10 mmHg, while at the last visit achieved BP averaged 140/84 +/- 14/8 mmHg. There were three main reasons for not intensifying antihypertensive treatment when BP targets were not achieved. These reasons were: (1). the assumption that the time after starting the new drug was too short to appreciate its full effect (44% at first, 14% at last follow-up), (2). that there was a clear improvement or the target BP was almost reached (24% at first, 34% at last follow-up) or (3). that self-measurements were considered satisfactorily (10% at the last visit). Failure of physicians to follow guidelines is apparently dependent on the belief that baseline BP dictates the target, that a clear improvement in BP might be sufficient and that the full drug effect may take up to 4 months or more to be attained.
Publisher: No publisher found
Date: 2003
Publisher: Massachusetts Medical Society
Date: 31-05-1990
Publisher: Oxford University Press (OUP)
Date: 08-01-2009
DOI: 10.1093/NDT/GFN738
Abstract: The aim of this study was to analyse the association between chronic kidney disease (CKD) defined by an estimated glomerular filtration rate (eGFR) or =15 years was available for analysis. Haemoglobin was simultaneously available in 8752 (88.8%) subjects. There was a negative relationship between age and median eGFR, and the slope of the regression line was -0.68 ml/min/year for males and -0.74 ml/min/year for females. Over 35% of in iduals > or =65 years were classified as having CKD stage > or =3. Odds ratios for haemoglobin <100 g/l for an eGFR or =60 ml/ min/1.73 m(2) in subjects 25-44 years were 34.2 (30.7-37.7), 23.4 (20.2-26.6) and 7.2 (5.3-9.1), respectively. In comparison, these were 8.9 (6.7-11.1), 5.6 (4.9-7.3) and 1.6 (1.1-2.1), respectively, in subjects > or =65 years. In subjects > or =65 years, odds ratios for haemoglobin or =60 ml/min/1.73 m(2) were 1.9 (1.3-2.5) and 1.2 (0.7-1.7), respectively. An eGFR <60 ml/min/1.73 m(2) is very common in older people. Only an eGFR or =45 ml/min/1.73 m(2) need to be determined.
Publisher: Informa UK Limited
Date: 1999
Abstract: Several isolated abnormalities have been noted in normotensive members of hypertensive families, including exaggerated forearm vascular resistance (FVR), decreased insulin sensitivity and elevated sodium-lithium (Na/Li) countertransport. No family study has investigated the aforementioned abnormalities concurrently within the same hypertensive families. It is therefore unknown whether these disturbances reflect single or different genetic traits. Thus, we studied cardiovascular reactivity of the forearm vasculature, cellular sodium transport mechanisms and insulin sensitivity concomitantly in normotensive (n = 24) and borderline hypertensive (n = 16) members of hypertensive families, compared with normotensive members (n = 24) of normotensive families. At least one abnormality was noted in 27 (67%) out the 40 subjects with a positive family history of hypertension. Na/Li-countertransport was increased in 15 (37%), FVR was increased in 14 (35%) and insulin sensitivity was decreased in 9 (22%) subjects with familial hypertension. The concomitant occurrence of at least 2 out of the 3 abnormalities mentioned was noted in 9 (22%) out of the 40 subjects with family history of hypertension. Decreased insulin sensitivity, increased basal FVR and increased Na/Li countertransport were concurrently observed in two (5%) subjects. This investigation documents the frequent occurrence of abnormalities such as decreased insulin sensitivity, increased basal FVR and Na/Li-countertransport in subjects with family history of hypertension. The concomitant occurrence of at least two of the mentioned abnormalities being observed in less than one-quarter of the subjects with family history of essential hypertension, it is assumed that insulin sensitivity, basal FVR and Na/Li-countertransport reflect more than one genetic trait predisposing to hypertension.
Publisher: S. Karger AG
Date: 2001
DOI: 10.1159/000049999
Abstract: The importance of hypertension in the pediatric population is not as well appreciated as in adults. This might be related in part to the lower prevalence of high blood pressure in this age group. As with height and weight, blood pressure increases with age during childhood. The underlying causes of significant hypertension in children differ considerably from those in adults: while the prevalence of hypertension in pediatrics is lower than in adults, clinically identifiable causes of hypertension are common. Abnormalities in steroid biosynthesis have been known for years to cause hypertension in some cases of congenital adrenal hyperplasia. In these patients, hypertension usually accompanies a characteristic phenotype with abnormal sexual differentiation. Recently, the molecular basis of four forms of severe hypertension transmitted on an autosomal basis has been elucidated: (a) the glucocorticoid-remediable aldosteronism (GRA), (b) the syndrome of apparent mineralocorticoid excess (AME), (c) activating mutation of the mineralocorticoid receptor and (d) Liddle’s syndrome. All these conditions are characterized primarily by low or low-normal plasma renin, normal or low serum potassium and salt-sensitive hypertension, indicating an increased mineralocorticoid effect. These forms of juvenile hypertension are a consequence of abnormal biosynthesis, metabolism or action of steroid hormones: (a) GRA is due to expression of a chimeric gene produced by fusion of 11β-hydroxylase aldosterone-synthase genes. Expression of the chimeric enzyme occurs in the zona fasciculata of the adrenal cortex under the control of ACTH and can be suppressed by administration of glucocorticoids. (b) AME is caused by mutations of the 11β-hydroxysteroid dehydrogenase type 2 enzyme, an enzyme that metabolizes cortisol into its receptor inactive keto-form cortisone, thus protecting the mineralocorticoid receptor (MR) from occupation by glucocorticoids. (c) The activating mutation of the MR results in constitutive MR activity and alters receptor specificity, with progesterone and other steroids lacking 21-hydroxyl groups becoming potent agonists. (d) Liddle’s syndrome is due to mutations in the β or γ chain of the epithelial sodium channel in distal renal tubule cells. The hyperactivity of this channel caused by the mutations results in increased sodium reabsorption. With the advent of molecular biology in clinical practice it has become evident that some genetic defect may present with a more discrete phenotype, with only moderate hypertension with or without hypokalemia as presenting feature. Considering that hypertension in children and adolescents is often ‘nonessential’, a search for disorders should be integral part of the diagnostic work-up in young patients with hypertension.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 04-2007
Publisher: Springer Science and Business Media LLC
Date: 23-12-2021
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 15-10-2012
Publisher: Bioscientifica
Date: 08-2006
DOI: 10.1677/JME.1.02082
Abstract: We have identified a novel cytosine/thymidine polymorphism of the human steroidogenic acute regulatory ( StAR ) gene promoter located 3 bp downstream of the steroidogenic factor-1 (SF-1)-binding site and 9 bp upstream of the TATA box (ATTTAAG). Carriers of this mutation have a high prevalence of primary aldosteronism. In transfection experiments, basal StAR promoter activity was unaltered by the mutation in murine Y-1 cells and human H295R cells. In Y-1 cells, forskolin (25 μM, 6 h) significantly increased wild-type promoter activity to 230±33% ( P .05, n =4). In contrast, forskolin increased mutated promoter activity only to 150±27%, with a significant 35% reduction compared to wild type ( P .05, n =3). In H295R cells, angiotensin II (AngII 10 nM) increased wild-type StAR promoter activity to 265±22% ( P .01, n =3), while mutated StAR promoter activity in response to AngII only reached 180±29% of controls ( P .01, n =3). Gel mobility shift assays show the formation of two additional complexes with the mutated promoter: one with the transcription repressor DAX-1 and another with a yet unidentified factor, which strongly binds the SF-1 response element. Thus, this novel mutation in the human StAR promoter is critically involved in the regulation of StAR gene expression and is associated with reduced promoter activity, a finding relevant for adrenal steroid response to physiological stimulators.
Publisher: Elsevier BV
Date: 07-2001
DOI: 10.1046/J.1523-1755.2001.00769.X
Abstract: Hypertension contributes to the progression to renal failure. A genetic susceptibility to hypertension may predispose to the development of end-stage renal disease (ESRD) and promote a more rapid progression to ESRD in patients with renal diseases. Genes encoding for angiotensinogen (AGT), angiotensin-converting enzyme (ACE), and aldosterone synthase (CYP11B2) are candidates for abnormal blood pressure regulation. Genotyping was performed in 327 control subjects and 260 ESRD patients for the M235T-AGT, the insertion/deletion (I/D)-ACE, and the -344T/C-CYP11B2 gene polymorphisms using polymerase chain reaction, gel analysis, and appropriate restriction digest when required. Genotype frequencies did not differ significantly between ESRD patients and controls. When ESRD diabetic subjects were compared with diabetic patients without nephropathy, the prevalence of the AGT-MM genotype was lower (28.1 vs. 52.8%, P < 0.01), while the AGT-TT genotype was higher (15.6 vs. 2.7%, P < 0.05). The AGT-TT genotype was associated with a faster progression to ESRD in patients with glomerulonephritis (P < 0.05). In the total ESRD population, progression of renal disease was faster with the ACE-DD than with the DI and II alleles (P < 0.05). This association was particularly strong when the interaction with the AGT genotype was analyzed, with a rapid progression in ACE-DD as compared with ACE-DI and II in patients with the AGT-MM genotype (P < 0.01). Susceptibility for ESRD and faster progression to ESRD are linked with the AGT genotype in diabetic patients. Faster progression to ESRD is associated with the ACE genotype when the total population with ESRD and with the AGT genotype when patients with glomerulonephritis are considered. Thus, genes of the renin-angiotensin-aldosterone system are candidate genes for further understanding of the interin idual differences in the development and course of ESRD.
Publisher: Elsevier BV
Date: 02-2016
DOI: 10.1111/AJT.14041
Abstract: Kidney paired donation (KPD) programs offer the opportunity to enable living kidney donation when immunological and other barriers prevent safe directed donation. Children are likely to require multiple transplants during their lifetime therefore, high-level histocompatibility and organ quality matching are key priorities. Details are given for a cohort of seven pediatric renal transplantations performed through the Australian Kidney Exchange (AKX), including barriers to alternative transplantation and outcomes after KPD. Reasons for entering the KPD program were preformed donor-specific antibodies to their registered donor in five cases, ABO mismatch, and avoidance of the risk of exposure to hepatitis B virus. Four recipients were highly sensitized. All patients received transplants with organs of lower immunological risk compared with their registered donors. HLA eplet mismatch scores were calculated for donor-recipient pairs three patients had improved eplet mismatch load with AKX donor compared with their registered donor. All grafts are functioning, with a mean estimated glomerular filtration rate of 77 mL/min/1.73 m
Publisher: Informa UK Limited
Date: 02-01-2016
Publisher: American Diabetes Association
Date: 10-1991
DOI: 10.2337/DIACARE.14.10.911
Abstract: To assess the efficacy and tolerance of a diuretic-free antihypertensive therapy with a Ca2+ antagonist and an angiotensin-converting enzyme (ACE) inhibitor in patients with non-insulin-dependent diabetes mellitus (NIDDM). After a 2-wk washout and a 4-wk placebo phase, 47 hypertensive patients with NIDDM randomly received verapamil or enalapril alone and, if blood pressure remained elevated, both agents combined over 30 wk. Verapamil or enalapril alone normalized blood pressure to & 90 mmHg diastolic in 30 patients verapamil decreased mean ± SE blood pressure from 159/98 ± 3/1 to 146/87 ± 3/2 mmHg (n = 18, P & 0.001) and enalapril from 166/99 ± 5/2 to 146/86 ± 3/1 mmHg (n = 12, P & 0.001). In 17 patients who were still hypertensive after 10 wk of monotherapy, combination of both drugs decreased blood pressure from 170/104 ± 4/2 to 152/90 ± 4/2 mmHg (P & 0.001). Fasting plasma glucose, glycosylated hemoglobin, serum fructosamine, total lipids, high-density and low-density lipoprotein cholesterol, apolipoproteins A-I and B, creatinine, and urinary albumin-creatinine ratio were not significantly modified. In hypertensive patients with NIDDM, a diuretic-free therapy based on the Ca2+ antagonist verapamil and/or the ACE inhibitor enalapril can effectively decrease blood pressure without adversely affecting carbohydrate and lipid metabolism.
Publisher: Springer Science and Business Media LLC
Date: 24-01-2003
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2004
DOI: 10.1097/00004872-200402000-00023
Abstract: In recent years, the assessment of the plasma aldosterone-to-renin ratio (ARR) has become an established screening method for the diagnosis of primary aldosteronism. Plasma renin activity (PRA) is usually measured to define ARR although, increasingly, renin concentration alone is often measured in clinical routine. To determine the threshold of ARR using active renin concentration to screen for primary aldosteronism. To determine the ARR threshold based on plasma immunoreactive renin concentration (irR), we measured plasma aldosterone concentration (PAC), irR and PRA in 36 hypertensive patients, nine thereof with adrenal adenoma, and compared ARRs calculated from irR and PRA, respectively. Single-centre, hypertension clinic in a tertiary care hospital. PRA ranged from 0.41-14.9 ng/ml per h and irR from 1.1-72 ng/l. There was an excellent correlation between PRA and irR (r = 0.98, P < 0.0001) and between ARRPRA and ARRirR (r = 0.96, P 750 pmol/l per ng/ml per h was previously found to be highly predictive of primary aldosteronism because 90% of the corresponding patients failed to suppress PAC upon saline infusion or fludrocortisone. The corresponding threshold value for ARRirR was 150 pmol/ng in our patients. Using these cut-offs, nine subjects had both increased ARRPRA and ARRirR while, in three patients, either ARRPRA or ARRirR were increased. The nine patients with increased ARRPRA and ARRirR also had PAC > 650 pmol/l. Only these patients had adrenal adenomas. The ARR threshold to screen for primary aldosteronism may be based on measurement of irR. An ARRirR > 150 pmol/ng may indicate primary aldosteronism.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2017
Publisher: The Endocrine Society
Date: 10-1999
Abstract: Salt-sensitive subjects (SS) increase their blood pressure with increasing salt intake. Because steroid hormones modulate renal sodium retention, we hypothesize that the activity of the 11β-hydroxy-steroid dehydrogenase type 2 (11βHSD2) enzyme is impaired in SS subjects as compared with salt-resistant (SR) subjects. The 11βHSD2 enzyme inactivates 11-hydroxy steroids in the kidney, thus protecting the nonselective mineralocorticoid receptor from occupation by glucocorticoids. We performed an association study using a recently identified single AluI polymorphism in exon 3 and a polymorphic microsatellite marker of the HSD11B2 gene in 149 normotensive white males (37 SS and 112 SR). The activity of the enzyme 11βHSD2 was assessed by determining the urinary ratio of cortisol (THF+5αTHF) to cortisone (THE) metabolites by gas chromatography in all the 37 SS subjects and in 37 age- and body habitus-matched SR volunteers. Mean (THF+5αTHF)/THE ratio was markedly elevated in SS subjects compared with SR subjects (1.51 ± 0.34 vs. 1.08 ± 0.26, P & 0.00001), indicating enhanced access of glucocorticoids to the mineralocorticoid receptor in SS subjects. In 58% of SS subjects this ratio was higher than the maximum levels in SR subjects. The salt-induced elevation in arterial pressure increased with increasing (THF+5αTHF)/THE ratio (r2 = 0.51, P & 0.0001). A total of 12 alleles of the polymorphic microsatellite marker were detected. Homozygosity for the allele A7 was higher in SS subjects than in SR subjects (41 vs. 28%, P & 0.005), whereas the occurrence of the allele A7 with allele A8 was lower in SS subjects than in SR subjects (8 vs. 15%, P& 0.03). The prevalence of salt sensitivity was 35% in subjects with allele A7/A7, whereas salt sensitivity was present in only 9% of the subjects with allele A7/A8. The (THF+5αTHF)/THE ratio was higher in subjects homozygous for the A7 microsatellite allele as compared with the corresponding control subjects. The prevalence of the AluI allele was 8.0% in SR subjects and 5.4% in SS subjects and did not correlate with blood pressure. The decreased activity of the 11βHSD2 in SS subjects indicates that this enzyme is involved in salt-sensitive blood pressure response in humans. The association of a polymorphic microsatellite marker of the gene with a reduced 11βHSD2 activity suggests that variants of the HSD11B2 gene contribute to enhanced blood pressure response to salt in humans.
Publisher: Wiley
Date: 30-03-2010
DOI: 10.1111/J.1440-1797.2009.01203.X
Abstract: To assess whether pentoxifylline improves anaemia of chronic kidney disease (CKD) via suppression of interleukin-6 (IL-6) and improved iron mobilization. CKD patients may have elevated IL-6 and tumour necrosis factor alpha levels. These cytokines can increase hepcidin production, which in turn reduces iron release from macrophages resulting in reduced availability of iron for erythropoiesis. In experimental models, pentoxifylline was shown to reduce IL-6 expression. We studied 14 patients with stages 4-5 CKD (glomerular filtration rate <30mL/min per 1.73 m(2)) due to non-inflammatory renal diseases. None of the patients had received immunosuppressive or erythropoietin-stimulating agents or parenteral iron. Patients had weekly blood tests for iron studies and cytokines during a control run-in period of 3 weeks and during 4 weeks of pentoxifylline treatment. Ten patients (eGFR 23 + or - 6 mL/min) completed the study. At the end of the run-in period average haemoglobin was 111 + or - 5 g/L, ferritin 92 + or - 26 microg/L, transferrin saturation 15 + or - 3% and circulating IL-6 10.6 + or - 3.8 pg/mL. Tumour necrosis factor alpha values were below threshold for detection. Treatment with pentoxifylline reduced circulating IL-6 (6.6 + or - 1.6 pg/mL, P < 0.01), increased transferrin saturation (20 + or - 5%, P < 0.003) and decreased serum ferritin (81 + or - 25 microg/L, P = NS). Haemoglobin increased after the second week of pentoxifylline, reaching 123 + or - 6 g/L by week 4 (P < 0.001). Pentoxifylline reduces circulating IL-6 and improves haemoglobin in non-inflammatory moderate to severe CKD. These changes are associated with changes in circulating transferrin saturation and ferritin, suggesting improved iron release. It is hypothesized that pentoxifylline improves iron disposition possibly through modulation of hepcidin.
Publisher: The Endocrine Society
Date: 11-1995
Publisher: Wiley
Date: 16-06-2014
DOI: 10.1111/NEP.12239
Abstract: Lower preoperative haemoglobin and older age pose a risk for perioperative allogeneic blood transfusions (ABT). The presence of chronic kidney disease (CKD) is associated with low haemoglobin, greater bleeding and ABT utilization. The interaction between estimated glomerular filtration rate (eGFR) and haemoglobin on perioperative ABT, length-of-stay and mortality was assessed in 86 patients with CKD stage 3 or higher undergoing elective total knee or hip arthroplasty compared with 294 without CKD. Multivariate analyses for ABT risk with haemoglobin, eGFR, age, gender, duration of surgery and primary versus revision surgery were performed. Patients with CKD had lower preoperative haemoglobin and higher incidence of ABT. Haemoglobin was independently associated with increased odds of ABT (0.74 (95% confidence interval 0.71-0.77), P = 0.001), but eGFR was not (0.98 (0.96-1.02), P = 0.089). Length-of-stay and 1 year mortality did not differ between non-transfused CKD patients and controls. Transfused CKD patients had significantly higher length-of-stay compared with transfused controls (25 ± 21 vs 19 ± 16 days, P < 0.0001), although 1 year mortality between transfused CKD patients and controls did not differ significantly. CKD alone, in the absence of anaemia, does not predispose to increased risk of ABT or length-of-stay in patients with mild-to-moderate CKD undergoing elective joint surgery. However, low haemoglobin is associated with increased ABT utilization and increased length-of-stay. Considering that 1 in 4 patients undergoing elective hip or knee arthroplasty has CKD, optimal preoperative patient blood management may improve outcome in this population.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 15-11-2013
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-1998
Publisher: Wiley
Date: 06-2009
DOI: 10.1111/J.1440-1797.2009.01121.X
Abstract: Approximately 12% of bound blood calcium is linked to various anions including phosphate. In patients with end-stage kidney disease (ESKD), serum phosphate is highly variable. We propose that establishing a formula to calculate albumin- and phosphate-corrected total calcium would be more appropriate to estimate free calcium in ESKD patients. In 82 haemodialysis patients, serum ionized calcium (Ca(ion)) and pH were measured by blood gas analyser with ion-selective electrodes at the point-of-care, while bicarbonate, phosphate, albumin, magnesium and total calcium (Ca(tot)) were measured at the central laboratory. Linear regression analysis of measured variables was used to best fit adjusted calcium versus Ca(ion). The most parsimonious multiple linear regression model (r(2) = 0.81) of variables associated with Ca(ion) included Ca(tot) (coeff 0.820, P < 0.0001), albumin (coeff -0.016, P < 0.0001) and phosphate (coeff -0.063, P < 0.002). Modelling of available variables yielded the following equation to adjust calcium for albumin and phosphate: Ca(albPh) = Ca(tot) + (0.015 x (40 - [albumin]) + 0.07 x (1.5 - [phosphate])). At an ambient albumin of 40 g/L, Ca(albPh) would be 0.07 mmol/L lower than Ca(tot) for every mmol/L of phosphate. In vitro data using three different albumin levels and increasing phosphate concentrations demonstrated this relationship, with the slope of the phosphate effect being stronger at lower albumin concentrations. Because guidelines recommendations indicate that corrected serum calcium should be maintained within the normal range in ESKD patients, inclusion of phosphate to correct Ca(tot) in these patients may have clinical implications on the choice of phosphate binders and the prescription of vitamin D or calcimimetic agents.
Publisher: Wiley
Date: 09-1993
DOI: 10.1002/J.1552-4604.1993.TB01965.X
Abstract: The Infectious Diseases Society of America recommends pneumococcal urinary antigen testing (UAT) when identifying pneumococcal infection would allow for antibiotic de-escalation. However, the frequencies of UAT and subsequent antibiotic de-escalation are unknown. We conducted a retrospective cohort study of adult patients admitted with community-acquired or healthcare-associated pneumonia to 170 US hospitals in the Premier database from 2010 to 2015, to describe variation in UAT use, associations of UAT results with antibiotic de-escalation, and associations of de-escalation with outcomes. Among 159 894 eligible admissions, 24 757 (15.5%) included UAT performed (18.4% of intensive care unit [ICU] and 15.3% of non-ICU patients). Among hospitals with ≥100 eligible patients, UAT proportions ranged from 0% to 69%. Compared to patients with negative UAT, 7.2% with positive UAT more often had a positive Streptococcus pneumoniae culture (25.4% vs 1.9%, P < .001) and less often had resistant bacteria (5.2% vs 6.8%, P < .05). Of patients initially treated with broad-spectrum antibiotics, most were still receiving broad-spectrum therapy 3 days later, but UAT-positive patients more often had coverage narrowed (38.4% vs 17.0% UAT-negative and 14.6% untested patients, P < .001). Hospital rate of UAT was strongly correlated with de-escalation following a positive test. Only 3 patients de-escalated after a positive UAT result were subsequently admitted to ICU. UAT is not ordered routinely in pneumonia, even in ICU. A positive UAT result was associated with less frequent resistant organisms, but usually did not lead to antibiotic de-escalation. Increasing UAT and narrowing therapy after a positive UAT result are opportunities for improved antimicrobial stewardship.
Publisher: Elsevier BV
Date: 02-1992
DOI: 10.1038/KI.1992.51
Abstract: In hemodialysis patients with hyperkalemia, i.v. sodium bicarbonate has recently been found to be ineffective in lowering plasma potassium within one hour. In the present study the effect of a prolonged bicarbonate infusion on plasma potassium was investigated. Twelve patients with terminal renal failure who were on hemodialysis were infused i.v. with 8.4% sodium bicarbonate (4 mmol/min) for one hour and with 1.4% (0.5 mmol/min) for five hours (total amount 390 mmol). Plasma bicarbonate rose from 17.5 at baseline to 28.4 and 29.6 mmol/liter, and blood pH from 7.32 to 7.46 and 7.48 at one and six hours, respectively. Plasma potassium did not change significantly after one and two hours (6.04 at baseline, 5.91 and 5.77 mmol/liter, respectively). Only at four and six hours did a moderate decline to 5.44 (P less than 0.05) and to 5.30 (P less than 0.01) occur, of which approximately half was calculated to be due to ECF volume expansion. However, no change or a very moderate decrease was observed in three patients even after six hours (+0.19, -0.32, -0.33 mmol/liter). Five patients with higher baseline plasma potassium (6.15 to 8.15 mmol/liter) behaved like seven with lower levels (5.25 to 5.87 mmol/liter). Tented T-waves in the ECG of seven patients disappeared after one hour only in one patient. Plasma aldosterone, norepinephrine and epinephrine were normal to elevated before and tended to fall during i.v. bicarbonate. Plasma dopamine and insulin were in the normal range.(ABSTRACT TRUNCATED AT 250 WORDS)
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2016
Publisher: Elsevier BV
Date: 05-2013
DOI: 10.1016/J.HUMIMM.2013.01.029
Abstract: An independent pool of 16 incompatible live donor-recipient pairs registered at the Vienna transplant unit was applied to test whether virtual crossmatch allocation used in the Australian kidney paired donation (KPD) program reliably predicts negative crossmatches. High resolution HLA data were entered into the computer-matching algorithm and allocation was performed excluding any DSA>2000MFI. CDC and flow crossmatch data of recipients against any of the donors were available for 112 crossmatch combinations. The computer program identified 19 possible pairings in 2-way or 3-way chains in multiple combinations. The top ranked combination included one 3-way and two 2-way ABO-compatible chains. Where crossmatches were available all recipients were CDC crossmatch negative with the computer-matched donor. Excluding allocation of KPD donors in the presence of DSA>2000MFI had a negative predictive of 99.9% for CDC and 96.4% for flow crossmatch. In the 12 pairings with ⩾1 DSA against crossmatched donors there was a negative CDC and flow crossmatch. These results show excellent correlation between matching using virtual crossmatch and actual crossmatch results. Using the 2000MFI cut-off the number of potentially unacceptable CDC and flow crossmatch positive pairings identified by virtual crossmatching is low, but some potential crossmatch negative pairings are missed.
Publisher: Proceedings of the National Academy of Sciences
Date: 28-12-2020
Abstract: The global outbreak of COVID-19 infections generated an unprecedented need to develop novel therapeutic strategies. The SARS-CoV-2 virus enters host cells after binding to the angiotensin-converting enzyme 2 (ACE2), but whether renin−angiotensin−aldosterone system inhibitors (RAASi) are beneficial remains controversial. Standard statistical approaches may fail in assessing medications effects, due to multiple sources of bias in COVID-19 case series collected on an emergency basis. We present a data-driven approach to tackle these challenges. Multilayer risk stratifications were derived for assessing drugs effect, while Bayesian networks were estimated, to analyze dependencies among risk factors’ and treatments’ impact on survival. We provide strong evidence for protectivity of RAASi on hospitalized patients that call for randomized controlled trials of RAASi as COVID-19 treatment option.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2000
DOI: 10.1097/00004872-200018030-00001
Abstract: The 11 beta-hydroxysteroid dehydrogenase type 2 (11 PHSD2) enzyme inactivates 11 betahydroxy steroids in sodium-transporting epithelia such as the kidney, thus protecting the non-selective mineralocorticoid receptor (MR) from occupation by cortisol in humans. Inhibition by xenobiotics such as liquorice or mutations in the HSD11 B2 gene, as occur in the rare monogenic hypertensive syndrome of apparent mineralocorticoid excess (AME), result in a compromised 11 betaHSD2 enzyme activity, which in turn leads to overstimulation of the MR by cortisol, sodium retention, hypokalaemia, low plasma renin and aldosterone concentrations, and hypertension. Whereas the first patients described with AME had a severe form of hypertension and metabolic derangements, with an increased urinary ratio of cortisol (THF+5alphaTHF) to cortisone (THE) metabolites, more subtle effects of mild 11 beta HSD2 deficiency on blood pressure have recently been observed. Hypertension with no other characteristic signs of AME was found in the heterozygous father of a child with AME, and we described a girl with a homozygous gene mutation resulting in only a slightly reduced 11 beta HSD2 activity causing 'essential' hypertension. Thus, depending on the degree of loss of enzyme activity, 11 beta HSD2 mutations can cause a spectrum of phenotypes ranging from severe, life-threatening hypertension in infancy to a milder form of the disease in adults. Patients with essential hypertension usually do not have overt signs of mineralocorticoid excess, but nevertheless show a positive correlation between blood pressure and serum sodium levels, or a negative correlation with potassium concentrations, suggesting a mineralocorticoid influence. Recent studies revealed a prolonged half-life of cortisol and an increased ratio of urinary cortisol to cortisone metabolites in some patients with essential hypertension. These abnormalities may be genetically determined. A genetic association of a HSD11 B2 flanking microsatellite and hypertension in black patients with end-stage renal disease has been reported. A recent analysis of a CA-repeat allele polymorphism in unselected patients with essential hypertension did not find a correlation between this marker and blood pressure. Since steroid hormones with mineralocorticoid action modulate renal sodium retention, one might hypothesize that genetic impairment of 11 beta HSD2 activity would be more prevalent in salt-sensitive as compared with salt-resistant subjects. Accordingly, we found a significant association between the polymorphic CA-microsatellite marker and salt-sensitivity. Moreover, the mean ratio of urinary cortisol to cortisone metabolites, as a measure for 11betaHSD2 activity, was markedly elevated in salt-sensitive subjects. These findings suggest that variants of the HSD11 B2 gene may contribute to the enhanced blood pressure response to salt in some humans.
Publisher: American Diabetes Association
Date: 03-1991
Abstract: The common association between diabetes mellitus and hypertension may be promoted by several mechanisms. Patients with insulin-dependent (type I) diabetes and prone to develop nephropathy often have a familial predisposition for essential hypertension, whereas normotensive healthy offspring of nondiabetic essential hypertensive parents tend to have a reduced insulin sensitivity and increased plasma insulin levels. Na+ retention occurs as a characteristic alteration in type I or non-insulin-dependent (type II) diabetes exchangeable body Na+ (Naex) is increased by 10% on average. This abnormality develops in the uncomplicated stage of diabetes and differentiates diabetic from nondiabetic essential hypertensive subjects. Possible Na(+)- retaining mechanisms include increased glomerular filtration of glucose leading to enhanced proximal tubular Na(+)-glucose cotransport, hyperinsulinemia (which activates several tubular Na+ transporters), an extravascular shift of fluid with Na+, and, once it occurs, renal failure. The pathogenetic role of Na+ retention in diabetes-associated hypertension is supported by positive correlations between systolic or mean blood pressure and Naex and by normalization of blood pressure after removal of excess Na+ by diuretic treatment in hypertensive diabetic subjects. The latter may also have an enhanced sensitivity of blood pressure to Na+. Plasma levels of active renin, angiotensin II, aldosterone, and catecholamines are usually normal or low in metabolically stable type I or type II diabetes. However, an exaggerated vascular reactivity to norepinephrine and angiotensin II commonly occurs already at uncomplicated stages of type I or type II diabetes. This may be a manifestation of functional (i.e., intracellular electrolytes) and/or morphological (proliferation, narrowing, and stiffening) vasculopathy. Diabetes-associated Na+ retention, vasculopathy, and a presumably inherited predisposition for both diabetes and essential hypertension may represent important complementary factors favoring the frequent occurrence of hypertension in the diabetic population.
Publisher: Springer Science and Business Media LLC
Date: 03-1990
DOI: 10.1007/BF02116055
Publisher: Elsevier BV
Date: 04-2002
Publisher: American Association for the Advancement of Science (AAAS)
Date: 11-11-2022
Abstract: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron sublineages carry distinct spike mutations resulting in escape from antibodies induced by previous infection or vaccination. We show that hybrid immunity or vaccine boosters elicit plasma-neutralizing antibodies against Omicron BA.1, BA.2, BA.2.12.1, and BA.4/5, and that breakthrough infections, but not vaccination alone, induce neutralizing antibodies in the nasal mucosa. Consistent with immunological imprinting, most antibodies derived from memory B cells or plasma cells of Omicron breakthrough cases cross-react with the Wuhan-Hu-1, BA.1, BA.2, and BA.4/5 receptor-binding domains, whereas Omicron primary infections elicit B cells of narrow specificity up to 6 months after infection. Although most clinical antibodies have reduced neutralization of Omicron, we identified an ultrapotent pan-variant–neutralizing antibody that is a strong candidate for clinical development.
Publisher: Springer Science and Business Media LLC
Date: 03-1992
DOI: 10.1007/BF00266348
Publisher: Springer Science and Business Media LLC
Date: 02-2002
DOI: 10.1007/S11906-002-0048-8
Abstract: Abnormalities in steroid biosynthesis have been known for years to cause hypertension in some cases of congenital adrenal hyperplasia. In these patients hypertension usually accompanies a characteristic phenotype with abnormal sexual differentiation. Recently, the molecular basis of four forms of severe hypertension transmitted on an autosomal basis but without additional phenotypic features has been elucidated. All these conditions are characterized primarily by low plasma renin, normal or low serum potassium, and salt-sensitive hypertension, indicating an increased mineralocorticoid effect. These four disorders, the glucocorticoid remediable aldosteronism, the syndrome of apparent mineralocorticoid excess, the activating mutation of the mineralocorticoid receptor, and the Liddle syndrome are a consequence of either abnormal biosynthesis, metabolism, or action of steroid hormones, and are ultimately characterized by an overactivation of the epithelial sodium channel in distal renal tubules. Hyperactivity of this channel results in increased sodium reabsorption and volume expansion leading to an increase in blood pressure as well as potassium loss. With the advent of molecular biology in clinical practice, it has become evident that some genetic defect may present with a more discrete phenotype, with only moderate hypertension with or without hypokalemia as the sole feature. A search for genetic disorders of the mineralocorticoid axis should be an integral part of the diagnostic work-up, particularly in young adults with hypertension.
Publisher: Wiley
Date: 2003
DOI: 10.1002/MICR.10139
Abstract: Renal transplantation in rats is an essential experimental tool in transplantation research. The surgical procedure per se could affect the outcome of an experiment, independent of the hypothesis addressed, therefore requiring a standardized method which should be comparable across studies. To date, however, there is little information on the optimal surgical technique. We performed a Medline search on original articles published between 1965-2001 in order to evaluate whether specific technical issues affecting the outcome of the procedure could be defined. Articles that reported on a novel microsurgical procedure, or whose main purpose was the outcome of a surgical technique itself, were included in the analysis. From 2,060 retrieved publications, 34 corresponded to the selection criteria (rats and microsurgery and technique and kidney or renal transplantation). Among the essential determining factors for a good outcome, body weight >200 g and warm ischemic time <30 min were identified. Other important factors were the techniques used for vascular (end-to-end and end-to-side procedure or sleeve technique) and ureteral (bladder patch or end-to-end procedure) anastomosis. Gender, animal strain, type of anesthesia, prophylactic administration of antibiotics, and type of flushing solution did not affect the success of renal allografts. In order to avoid a bias related to the surgical procedure in rat renal transplantation, a warm ischemia time 200 g seems to be essential. Also, end-to-end or end-to-side vascular anastomoses are preferable to the sleeve technique. Other factors do not influence the immediate function of the graft.
Publisher: The Endocrine Society
Date: 12-1998
Abstract: In the kidney, the 11beta-hydroxysteroid dehydrogenase type 2 enzyme (11betaHSD2) inactivates glucocorticoids to their inactive ketoforms and thus prevents endogenous glucocorticoids from occupying the nonselective mineralocorticoid receptor in epithelial tissues. Several mutations have been described in the 11betaHSD2 gene in the congenital syndrome of apparent mineralocorticoid excess. These mutations generate partially or completely inactive 11betaHSD2 enzymes. In the present work, we describe an already known mutation in a new patient affected by apparent mineralocorticoid excess, which results in an arginine-to-cysteine mutation (R213C) in the 11betaHSD2 enzyme. This mutation has been found in two other independent families. In vitro expression studies of this mutant provide evidence that the mutant protein is normally expressed, but its activity is abolished. The CGC-to-TGC (C-toT) transition at codon 213 can be considered a typical CpG-consequence mutation. The present finding suggests that the codon R213 of 11betaHSD2 is a hot spot for mutations in this gene, as shown by the occurrence of an R213C point-mutation in several families unrelated to each other.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-2002
DOI: 10.1097/00007890-200207150-00012
Abstract: High blood pressure (BP) predicts a poor long-term kidney graft outcome. The mechanisms for hypertension in renal graft recipients are only partly understood. There is evidence that BP is salt dependent in renal transplant recipients. We hypothesize that renal transplantation induces salt sensitivity by decreasing 11beta-hydroxysteroid dehydrogenase type 2 (11betaHSD2) activity. A syngenic uninephrectomized rat transplantation model (Lewis to Lewis) (n=7) was used to demonstrate salt sensitivity after transplantation. Sham-operated (n=5) and denervated rats (n=5) were used as controls. In all rats, BP was measured continuously by telemetry 24 hr a day, whereas the rats were set successively on a normal- (0.45% NaCl), high- (8% NaCl), low- (0.1% NaCl), and, again, normal-salt (0.45% NaCl) diet during a 6-day period to assess salt-related changes in mean arterial pressure (MAP). 11betaHSD2 activity was assessed by determining the ratio of corticosterone to dehydrocorticosterone metabolites (THB+5alphaTHB)/THA in urine. After uninephrectomy and implantation of the telemetry device, MAP was comparable in rats assigned to undergo sham operation (100+/-3 mmHg), denervation (105+/-5 mmHg), or transplantation (102+/-6 mmHg). When animals were switched from the normal- to high-salt diet, the increase in MAP was more pronounced in the transplanted group (13.9+/-5.1 mmHg) than in those undergoing sham operation (5.1+/-1.7 mmHg, P<0.004) or denervation (7.1+/-1.8 mmHg, P<0.021). Urinary (THB+5alphaTHB)/THA increased more than 2-fold in the transplanted rats but remained stable in the sham-operated and denervated animals (P<0.0001), indicating reduced activity of 11betaHSD2. Syngenic renal transplantation causes salt sensitivity with increased BP associated with a reduced activity of 11betaHSD2.
Publisher: Elsevier BV
Date: 12-2001
DOI: 10.1016/S0002-9343(01)00983-4
Abstract: Acute renal failure induced by contrast media is an important cause of hospital-acquired renal insufficiency. Preexisting renal failure and the dose of contrast media are known risk factors for the development of radiocontrast nephropathy. We performed a randomized trial to test whether radiocontrast nephropathy can be avoided by prophylactic hemodialysis immediately after the administration of contrast media in patients with impaired renal function. Renal function and other parameters, hemodialysis requirement, and relevant clinical events were recorded before and during the 6 days after administration of contrast media in 113 patients with a baseline serum creatinine level >200 microm/L (>2.3 mg/dL). Patients were randomly assigned to either hemodialysis (n = 55) or nonhemodialysis (n = 58) treatment after parenteral low-osmolality contrast media. The characteristics of the patients in the two groups were similar. Compared with baseline levels, the mean [+/- SD] serum creatinine level decreased at day 1 (277 +/- 95 microm/L), peaked at day 4 (353 +/- 126 microm/L), and returned to baseline at day 6 (327 +/- 119 microm/L, P <0.05 by analysis of variance) after administration of contrast media in the hemodialysis group, whereas in the nonhemodialysis group, no significant changes in mean serum creatinine level were observed. Eleven patients required 1 or more hemodialyses (8 in the hemodialysis group and 3 in the nonhemodialysis group, P = 0.12), 6 of whom (4 vs. 2, P = 0.44) required 3 or more hemodialyses. Clinically relevant events included pulmonary edema (1 vs. 4 patients, P = 0.36), myocardial infarction (2 vs. 2), stroke (2 vs. 0, P = 0.24), and death (1 vs. 1). The strategy of performing hemodialysis immediately after the administration of low-osmolality contrast media in all patients with a reduced renal function did not diminish the rate of complications, including radiocontrast nephropathy.
Publisher: Elsevier BV
Date: 03-2021
Publisher: American Association for the Advancement of Science (AAAS)
Date: 03-09-2021
Abstract: In the past 20 years, three highly pathogenic β-coronaviruses have crossed from animals to humans, including the most recent: severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A spike protein that decorates these viruses has an S1 domain that binds host cell receptors and an S2 domain that fuses the viral and cell membranes to allow cell entry. The S1 domain is the target of many neutralizing antibodies but is more genetically variable than S2, and antibodies can exert selective pressure, leading to resistant variants. Pinto et al . identified five monoclonal antibodies that interact with a helix in the S2 domain. The most broadly neutralizing antibody inhibited all β-coronavirus subgenera and reduced viral burden in hamsters infected with SARS-CoV-2. —VV
Publisher: Wiley
Date: 24-02-2015
DOI: 10.1111/NEP.12369
Abstract: New approaches to increase kidney transplantation rates through expansion of live donor kidney transplantation have become necessary due to ongoing shortage of deceased donor organs. These strategies include desensitization in antibody-incompatible transplants to overcome the barrier of blood group incompatibility or human leucocyte antigen antibodies between recipient and donor and kidney paired donation (KPD) programmes. In KPD, a kidney transplant candidate with an incompatible live donor joins a registry of other incompatible pairs in order to find potentially compatible transplant solutions. To match the largest possible number of donor-recipient pairs while minimizing immunologic risk, KPD programmes use sophisticated algorithms to identify suitable matches with simultaneous two-way or more complex multi-way exchanges as well as including non-directed anonymous donors to start a chain of compatible transplantations. Because of the significant immunologic barriers when fewer donor options are available, the optimal solution for difficult-to-match, highly sensitized patients is access to more potential donors using large multi-centre or national KPD registries. This review focuses on the first 4 years of experience with the Australian multi-centre KPD programme that was established in October 2010.
Publisher: Wiley
Date: 02-2007
DOI: 10.1111/J.1440-1797.2006.00749.X
Abstract: In Australia the number of patients developing end-stage kidney disease is growing. Almost 70% of new cases of treated end-stage kidney disease are due to diabetes, hypertension or glomerulonephritis. The majority of these patients have a chronic decline of renal function over many years before dialysis is required, even when the initial insult is no longer present. Hypertension and the degree of proteinuria are the most important determinants for this progression and le evidence suggests that angiotensin II is the key player in sustaining both hypertension and proteinuria. Angiotensin II mediates not only haemodynamic changes but also profibrotic and pro-inflammatory processes. Blockade of the renin-angiotensin system decreases proteinuria and slows the progression of both diabetic and non-diabetic proteinuric renal disease. Angiotensin-converting enzyme (ACE) inhibitors are first-line therapy in patients with type 1 diabetes mellitus and nephropathy, whereas angiotensin receptor blockers (ARB) are first-line therapy in patients with type 2 diabetes mellitus and microalbuminuria or overt nephropathy. Finally, treatment with ACE inhibitors delays the progression of proteinuric nephropathy in non-diabetic patients. Combination therapy with ACE inhibitors and ARB may allow a more complete blockade of the renin-angiotensin system and clinical trials show that ACE inhibitor-ARB combinations have an additive antiproteinuric effect of up to 40% compared with ACE inhibitor or ARB alone, without additional blood pressure-lowering effect. Finally, it is important to emphasize that progressive lowering of blood pressure to 120 mmHg is associated with improved renal outcome and that this effect is independent of baseline renal function.
Publisher: Frontiers Media SA
Date: 22-12-2016
DOI: 10.1111/TRI.12719
Abstract: To assess the impact of shipping distance and cold ischaemia time (CIT) of shipped organs in a kidney paired donation (KPD) programme, we evaluated the outcomes of the initial 100 kidney transplants performed in the Australian KPD programme. In a 44-month period, 12 centres were involved in fifteen 2-way, twenty 3-way, one 4-way and one 6-way exchanges. Sixteen kidneys were transplanted at the same hospital (CIT 2.6 ± 0.6 h) and 84 required transport to the recipient hospital (CIT 6.8 ± 2.8 h). A spontaneous fall in serum creatinine by at least 10% within 24 h was observed in 85% of recipients, with no difference between nonshipped and shipped kidneys. There were two cases of transient delayed graft function requiring dialysis and patient and graft survival at 1 year were 99% and 97%, respectively. There was no difference in recipients of nonshipped compared with shipped kidneys with regard to serum creatinine at 1 month (mean difference (MD) 7.3 μmol/l, 95% CI -20.2 to 34.8, P = 0.59), 1-year graft survival (MD 3.9%, 95% CI -5.4 to 13.2, P = 0.41) or patient survival (MD -2.4%, 95% CI -10.0 to 5.2, P = 0.54). Despite prolonged CIT for interstate exchanges, the programme's decision to ship donor kidneys rather than the donor appears to be safe.
Publisher: Elsevier BV
Date: 06-2013
DOI: 10.1016/J.TRIM.2013.05.001
Abstract: The long term effect of donor specific antibodies (DSA) detected by Luminex Single Antigen Bead (SAB) assay in the absence of a positive complement-dependant cytotoxicity (CDC) crossmatch is unclear. DSA at the time of transplant were determined retrospectively in 258 renal transplant recipients from 2003 to 2007 and their relationship with rejection and graft function prospectively evaluated. After a median of 5.6 years follow-up 9% of patients had antibody mediated rejection (AMR) (DSA 11/37 (30%), DSA-Neg 13/221 (6%), HR 6.6, p 8000 MFI than those with DSA <8000 MFI (HR 23, p<0.001). eGFR progressively declined in patients with DSA but was stable in those without DSA (35.7 ± 20.4 mls/min vs 48.5 ± 22.7) and composite patient and graft survival was significantly worse in those with class II (HR 2.9) or both class I+II (HR 3.7) but not class I DSA. Class II DSA alone, or in combination with class I DSA had the strongest association with graft loss and patient death. Patients with DSA not only have increased rates of acute AMR, but also chronic graft dysfunction, graft loss and death. Antibody burden quantified by SAB assay may identify patients at highest immunological risk and therefore influence patient management and improve long-term patient outcome.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2005
Publisher: Oxford University Press (OUP)
Date: 26-07-2005
DOI: 10.1093/NDT/GFI022
Abstract: Smoking increases the risk of end-stage renal failure in patients with primary renal disease. Whether and to what extent smoking affects the kidneys in diabetic patients with normal renal function and variable degrees of proteinuria has not been fully studied. We followed 185 patients with type 1 or 2 diabetes mellitus and with or without signs of overt renal disease for at least 3 years, median 5.1 (3-6.8) years. Each patient had a baseline visit and at least four follow-up visits (average 4.8+/-0.3). Cases were patients who were smoking (n = 44) at the time the survey was started. Controls were patients who had never smoked (n = 141). Glomerular filtration rate (GFR) was estimated using the MDRD formula. Multiple logistic regression was used to correct for confounding factors. At baseline, smokers were younger (47+/-14 vs 54+/-16 years, P < 0.01), and had a lower GFR (95+/-26 ml/min) than non-smokers (107+/-33 ml/min, P < 0.05). Mean GFR remained constant during follow-up in non-smokers (106+/-31 ml/min), but decreased significantly in smokers (83+/-22 ml/min, P < 0.0001), and this relationship persisted when adjusted for retinopathy, glycaemic control, age, body habitus, ACE-inhibitor treatment, blood pressure control or severity of proteinuria. The effect of smoking on GFR decline was stronger in patients with type 1 diabetes or male gender. Cigarette smoking causes a decrease in GFR in diabetic patients with normal or near-normal renal function, independent of confounding factors including severity of proteinuria. The latter finding suggests a mechanism independent of glomerular damage.
Publisher: Elsevier BV
Date: 04-1991
DOI: 10.1016/0002-9149(91)90817-5
Abstract: Effective blood pressure control with traditional high-dose diuretic therapy has led to a distinct decrease in cerebrovascular morbidity and mortality, but failed to achieve a satisfactory reduction of coronary complications and sudden death. The same applies also for beta blockers, although they have been shown to be effective in secondary prevention of myocardial infarction. It is suspected that conventional antihypertensive treatment has an unfavorable effect on coronary risk factors other than hypertension. For instance, thiazide-type diuretics can impair glucose tolerance and increase the potentially atherogenic serum low-density lipoprotein (LDL) cholesterol fraction and triglycerides. Beta blockers without partial intrinsic sympathomimetic activity increase serum triglycerides and tend to lower the potentially antiatherogenic high-density lipoprotein (HDL) cholesterol. Certain beta blockers may also impair glucose tolerance, particularly when they are combined with diuretics. Calcium channel blockers, angiotensin converting-enzyme inhibitors and alpha 1-receptor blockers do not adversely affect lipoprotein or carbohydrate profiles. The latter two drug classes may even increase insulin sensitivity, and alpha 1 blockers may also slightly improve lipid metabolism. The prognostic relevance of drug-induced dyslipidemia and/or glucose intolerance awaits further clarification. In the meantime, it is of clinical interest that several of the generally available antihypertensive drugs seem to be metabolically neutral or sometimes perhaps even potentially beneficial with regard to the lipoprotein and carbohydrate metabolism.
Publisher: Springer Science and Business Media LLC
Date: 31-07-2018
Publisher: Elsevier BV
Date: 02-1993
DOI: 10.1016/0140-6736(93)90135-4
Abstract: Lean, healthy normotensive sons of essential hypertensive parents (OHyp) have lower insulin sensitivity (SI) than sons of normotensive parents (ONorm). We have tried to find out whether this disturbance in insulin metabolism is related to altered body fat distribution, fuel metabolism, or both. 21 OHyp and 21 ONorm of similar age and body-mass index were investigated after fasting overnight. Body composition was assessed by dual-energy X-ray absorptiometry and fuel metabolism by indirect calorimetry and urinary nitrogen excretion. Plasma insulin and glucose concentrations were measured during the frequent s ling intravenous glucose tolerance test, and SI was calculated by the minimum model method. Systolic blood pressure and heart rate were slightly but not significantly higher in OHyp than ONorm but the groups did not differ in fasting plasma insulin or glucose concentrations, carbohydrate or lipid oxidation, lean and fat mass, bone mineral content, or distribution of body fat. By contrast, SI was significantly lower in OHyp than ONorm (8.2 [0.7] vs 13.4 [1.5] 10(-4) L mU-1 min-1, p < 0.01). Within the whole study population upper-body fat mass was positively correlated with fasting plasma insulin (r = 0.33, p < 0.03) and lipid oxidation was positively correlated with SI (r = 0.35, p < 0.04) and negatively correlated with subscapular/triceps skinfold thickness (r = -0.43, p < 0.01). Thus, impairment of SI precedes both the development of overt hypertension and gain or redistribution of body fat. Therefore, the concept that SI is low as a result of altered fat distribution has to be reconsidered, at least in young male offspring of hypertensive parents.
Publisher: Wiley
Date: 07-03-2016
DOI: 10.1111/ANS.13517
Abstract: The Australian kidney paired donation program adopted the principles of within-chain simultaneous live donor surgery and of organ transport, with the requirement of keeping cold ischemia time (CIT) to <12 h. Whether these principles could be adhered to and what impact on transplant outcome they might have is unknown. We evaluated the logistic challenges and outcomes of the first 100 kidney transplants performed in the Australian kidney paired donation program. Within 4 years, 17 donor surgeons at 12 centres were involved in 37 chain exchange surgeries. Sixteen kidneys were transplanted at the same hospital and 84 required transport to the recipient hospital. Mean (±SD) within chain anaesthetic induction time variability was 8 ± 18 min and mean in idual surgeon operating time was 115 ± 44 min. In two cases, delays during donor surgery resulted in increased CIT by 1 h because of deferred transport. CIT was 2.6 ± 0.6 h for non-shipped and 6.8 ± 2.8 h for shipped kidneys, four kidneys had CIT of 12-14 h. Immediate allograft function was observed in 85% of recipients, with no difference between shipped and non-shipped kidneys. There were only two cases of delayed graft function requiring temporary dialysis both had CIT <7 h. There was no difference in serum creatinine at 1 month between non-shipped and shipped kidneys (105 ± 26 versus 112 ± 50 µmol/L) and allograft survival at 1 year was 97%. The study provided a favourable audit of kidney transplant activity, despite challenges of simultaneous surgery, organ transport coordination and prolonged CIT. The decision to ship donor kidneys rather than the donor was demonstrated to be feasible and safe.
Publisher: Springer Science and Business Media LLC
Date: 11-09-2009
DOI: 10.1038/JHH.2008.117
Abstract: Insufficient awareness of hypertension guidelines by physicians may be an impediment to achieving adequate blood pressure (BP) control rates in clinical practice. We therefore conducted an open intervention survey among primary care physicians in 1596 centres from 16 countries in four different continents to prospectively assess what is the BP goal defined by physicians for in idual patients and what are the reasons for not intensifying antihypertensive treatment when BP goals are not achieved. Enrolled patients (N=35,302) were either not treated to goal (N=22,887) or previously untreated (N=12,250). Baseline systolic and diastolic BP averaged 159/95+/-15/12 mm Hg. BP goals defined by physicians averaged 136+/-6 mm Hg for systolic and 86+/-5 mm Hg for diastolic BP. Patients' in idual risk stratification determined BP goals. At last visit BP averaged 132/81+/-11/8 mm Hg and values of <or=140/90 were reached in 92% of untreated and 80% of previously uncontrolled treated hypertensives. The main reasons for not intensifying antihypertensive treatment when BP remained above goal were the assumption that the time after starting the new drug was too short to attain its full effect, the satisfaction with a clear improvement of BP or with a BP nearing the goal, and the acceptance of good self-measurements. In this open intervention program in primary care, a large proportion of patients achieved recommended BP goals. The belief that a clear improvement in BP is acceptable and that the full drug effect may take up to several weeks to be reached are frequent reasons for treatment inertia when goals are not achieved.
Publisher: Elsevier BV
Date: 12-2003
DOI: 10.1016/S1521-690X(03)00053-8
Abstract: Hypertension and osteoporosis are characteristic clinical features in patients with Cushing's syndrome or in those on glucocorticoid (GC) treatment. These two distinct complications of GC excess share one common denominator: an abnormal handling of cations, sodium (Na(+)) and calcium (Ca(2+)), either primarily or in part by the kidney tubule. The principal mechanism of GC-induced hypertension is overstimulation of the non-selective mineralocorticoid receptor (MR), resulting in renal Na(+) retention, volume expansion and finally to an increase in blood pressure. In mineralocorticoid target organs, such as the kidney, the MR is protected from GC occupation by the enzyme 11beta-hydroxysteroid dehydrogenase type 2 (11betaHSD2), a gate-keeping enzyme, which converts cortisol to receptor-inactive cortisone. This enzyme allows aldosterone to be the physiological agonist of the MR despite significantly higher circulating levels of cortisol. Kinetic properties of 11betaHSD2 suggest that saturability of this enzyme can already be achieved at high-normal physiological plasma cortisol levels, thereby leading to ovestimualtion of the MR by cortisol in states of GC excess. The mechanisms of GC action on bone turnover are more complex. GCs increase bone resorption, inhibit bone formation and have an indirect action on bone by decreasing intestinal Ca(2+) absorption, but also inducing a sustained renal Ca(2+) excretion. The latter appears to be mediated through stimulation of the MR by GC. The prevention and treatment of GC-induced hypertension and osteoporosis include the use of the minimal effective dose of GC, some general measures, and the use of some specific drugs. Modulation of renal Na(+) and Ca(2+) excretion with some, but not all, diuretics represents an important specific (for hypertension) or supportive (for bone disease) therapeutic intervention.
Publisher: Oxford University Press (OUP)
Date: 07-2010
DOI: 10.1093/NDT/GFQ383
Abstract: Renal transplant recipients of older deceased-donor kidneys have reduced allograft survival. However, the impact of donor-recipient age difference on live-donor kidney transplant outcomes, where donors are older than recipients, remains unclear. Using the Australia and New Zealand Dialysis and Transplant Registry, all primary live-donor kidney transplant recipients in Australia from 1991 to 2006 were studied. Donor-recipient age difference was ided into four categories (donor-recipient<-10, -10-20, 20-29 and ≥30 years). Outcome measures included serum creatinine, graft and patient survival. In the adjusted model, donor-recipient age difference of ≥30 years showed a trend towards increased risk of graft failure compared with a difference of -10-20 years during the first year post-transplant only (hazard ratio=2.11, 95% CI=1.00-4.47 P=0.05). However, in the multivariate competing risks Cox model, donor-recipient age difference was not associated with increased patient death, death-censored graft failure or serum creatinine at 5 or 10 years, nor was it associated with increased risk of acute rejection within the first 6 months. Recipients of kidney transplants donated by live donors who are significantly older than recipients have similar graft and patient survivals to recipients from organs of similar vintage. Thus, living kidney donors, who are up to 30 years older than their recipients, provide kidneys of excellent quality. These findings are of relevance when considering paired kidney donation programme because the chance of finding a suitable match should not be unnecessarily limited by unjustified restrictions on the perceived disadvantage of high donor-recipient age difference.
Publisher: The Endocrine Society
Date: 10-1990
Abstract: To evaluate the hypothesis of an atrial natriuretic factor (ANF) deficiency in hypertension-prone humans, we investigated plasma ANF and other variables in 116 white offspring of normotensive parents (ONorm) or essential hypertensive parents (OHyp). Ten ONorm and 10 OHyp, all men matched for age and body habitus, were studied after 4 days of low (70 mmol/day) and high (350 mmol/day) dietary sodium intake. After mild sodium restriction, plasma ANF did not differ between ONorm and OHyp (9.7 +/- 0.7 vs. 9.0 +/- 1.3 fmol/L). On high sodium intake, plasma ANF increased in ONorm, but not in OHyp (to 18.3 +/- 1.7 vs. 11.7 +/- 1.7 fmol/L P less than 0.001). On the other hand, acute responses of plasma immunoreactive ANF (irANF) to saline loading or a norepinephrine-induced rise in blood pressure did not differ significantly between 8 ONorm and 8 OHyp. Fifty-one additional ONorm and 45 OHyp were evaluated during liberal sodium intake. Groups were further sub ided according to whether 24-h urinary sodium excretion was 91 mmol/m2 or less (modest salt intake) or more than 91 mmol/m2 (high salt intake). Twenty-four-hour urinary sodium was similar in the 26 ONorm and 21 OHyp on a modest salt intake (121 +/- 6 vs. 116 +/- 9 mmol) and in the 25 ONorm and the 24 OHyp on a high salt intake (226 +/- 10 vs. 221 +/- 9 mmol). However, compared with ONorm, plasma irANF in OHyp was slightly lower on modest sodium intake (7.7 +/- 0.7 vs. 5.3 +/- 0.7 fmol/L P less than 0.05) and markedly reduced on high sodium intake (15.0 +/- 1.3 vs. 8.0 +/- 1.3 fmol/L P less than 0.001). Moreover, the slope of the relationship between plasma irANF and 24-h urinary sodium was flatter in OHyp than in ONorm (z test = 2.4). We postulate a new endocrine syndrome characterized by a relative plasma ANF deficiency during high sodium intake in some hypertension-prone humans. This functional defect becomes apparent during chronic, rather than acute, stimulation of ANF release. It occurs as a familial disturbance and may potentially predispose to the development of hypertension.
Publisher: Hogrefe Publishing Group
Date: 09-2004
DOI: 10.1024/0040-5930.61.9.571
Abstract: Harnsäuresteine stellen nach den Kalziumsteinen die zweithäufigste Nierensteinart mit einer Häufigkeit von etwa 10% dar. Häufigste Ursache der Harnsäuresteinbildung ist ein zu saurer Urin (Urin-pH permanent unter 5.5), deutlich häufiger als eine vermehrte Harnsäureausscheidung. Der hohen Urinazidität können tubuläre Störungen (wie z.B. im Rahmen einer Gicht), chronische Diarrhoen oder eine schwere Dehydratation zugrunde liegen. Der reine Harnsäurestein ist bisher die einzige Steinart, die medikamentös aufgelöst werden kann (=orale Chemolitholyse). Therapeutisch steht nebst der Steigerung der Harnmenge auf über 2000 ml/Tag auch die Alkalinisierung des Urins auf pH 6.2 bis 6.8 im Vordergrund. Eine wirksame Alkalinisierung des Urins kann mit Kalium-Zitrat oder Natrium-Bikarbonat erreicht werden, was in einer hoher Rate an Steinauflösung resultiert. Eine Verminderung der Harnsäureausscheidung kann durch Reduktion purinhaltiger Nahrungsmittel erzielt werden. Kalium-Zitrat ist die Therapie der Wahl für die medikamentöse Prophylaxe des Rezi steines (=Metaphylaxe). Allopurinol reduziert die Häufigkeit der Harnsteine bei hyperurikosurischen Patienten mit Steinrezi en oder Gicht.
Publisher: Frontiers Media SA
Date: 08-11-2018
DOI: 10.1111/TRI.13366
Abstract: Baseline predonation estimated GFR (eGFR) appears to predict the risk of postdonation chronic kidney disease in live donors. New KIDGO guidelines recommend an eGFR ≥90 ml/min/1.73 m
Publisher: The Endocrine Society
Date: 12-2000
Publisher: Wiley
Date: 08-01-2016
DOI: 10.1111/NEP.12735
Abstract: Parenteral iron is integral in the treatment of anaemia of chronic kidney disease patients on haemodialysis (HD). However, increased liver iron concentration (LIC) can result from such treatment, and this correlates poorly with serum ferritin or transferrin saturation values. It is unclear whether increased cardiac iron concentration also occurs in this setting. We aimed to evaluate the relationship of intravenous iron supplementation to hepatic and cardiac iron deposition in chronic HD subjects. A cohort of 10 patients on chronic HD for at least 1 year underwent MRI-based quantitation of hepatic and cardiac iron content to evaluate the relationship between intravenous iron supplements and hepatic and cardiac iron deposition. The results were compared against the cumulative parenteral iron dose and serum iron markers. The median age was 61 years (95% confidence interval (CI) 50-71), HD time 2.5 years (95%CI 2.0-5.3) and cumulative iron dose 4300 mg (95%CI 2110-9045). Hepatic iron concentration was elevated in eight of 10 subjects (median 46 mmol/kg, range 31-76). Cardiac iron levels were within the reference range in all subjects. There was poor correlation between conventional haematinic values and either LIC or cardiac iron levels. None of the study subjects exhibited elevated cardiac iron concentration. Whilst HD patients receiving standard parenteral iron therapy have elevated LICs, this is not associated with cardiac iron deposition. Transferrin saturation and serum ferritin levels are poor markers of either liver or cardiac iron deposition in HD subjects.
Publisher: Springer Science and Business Media LLC
Date: 1990
DOI: 10.1007/BF00314798
Abstract: H-2 antigens on spleen cell membranes absorb antibody to H-2 antigens and induce both humoral and cellular responses. Liver cell membrane H-2 antigens by contrast also absorb antibody but do not influence cellular response and are tolerogenic for the humoral response. This paper demonstrates that syngeneic liver cells contain a substance which can transform the properties of allogeneic spleen cell membranes into those of allogeneic liver cell membranes, i.e., transform a humoral immunogen into a humoral tolerogen. The process appears to be accompanied by cleavage of an antigen component from the spleen membrane and hence to result in a structural change in the H-2 antigen.
Publisher: Hogrefe Publishing Group
Date: 1999
Abstract: Der Blutdruck variiert in der Allgemeinbevölkerung entlang eines Continuums und wird durch zahlreiche Mechanismen reguliert, die eine Vielzahl von Genen und Umweltfaktoren involvieren. Epidemiologische Studien haben gezeigt, daß die Blutdruckvariabilität im gleichen Verhältnis sowohl genetischen Determinaten wie auch Umweltfaktoren zugeschrieben werden kann. In den letzten Jahren wurde die molekulare Basis von drei autosomal-vererbten Formen von schwerer Hypertonie klarifiziert: a) der Glukokortikoid-hemmbare Aldosteronismus (GHA), b) das Liddle Syndrom und c) das Syndrom des Apparenten Mineralokortikoid Exzeß (AME). Der GHA ist die Folge einer Expression eines chimären Gens, welches aus der Fusion des Promoters der 11beta-Hydroxylase mit der kodierenden Region des Enzyms Aldosteron-Synthase resultiert. Die Expression dieses chimären Gens in der Zona fasciculata der Nebennierenrinde steht unter der Kontrolle des ACTH und kann deshalb durch Gabe von Glukokortikoiden wie Dexamethason gehemmt werden. Mutationen der beta- oder gamma-Untereinheit des epithelialen Natrium-Kanals im distalen Nierentubulus verursachen das Liddle Syndrom. Die erhöhte Aktivität des Kanals infolge Mutationen führt zur vermehrten Natrium-Reabsorption. Diese wird durch Gabe von Amilorid oder Triamteren, nicht aber Spironolacton supprimiert. Das AME wird durch Mutationen des Enzyms 11beta-Hydroxysteroid Dehydrogenase Typ 2 hervorgerufen. Dieses Enzym wandelt das aktiv wirkende Kortisol zur Rezeptor-inaktiven Ketoform Kortison um, und schützt somit den nicht-spezifischen Mineralokortikoidrezeptor vor einer Stimulation durch endogene Glukokortikoide. Mit Ausnahme dieser seltenen genetischen Defekte des erweiterten Renin-Angiotensin-Systems existiert eine Vielzahl von potentiellen Genen, die das Risiko einer Hypertonie in einer gegebenen Umgebung erhöhen. Der Zusammenhang zwischen dem Angiotensinogen Gen und der familiären Hypertonie wurde anhand mehrerer Studien dokumentiert. Eine Variante des Angiotensinogen-Gens korreliert mit erhöhten Werten an Plasma-Angiotensinogen und wird häufiger bei Hypertonikern als bei Normotonikern gefunden. Der Zusammenhang zwischen dem Angiotensinogen-Genotyp, dem intermediären Phänotyp (erhöhtes Plasma-Angiotensinogen) und dem fernen Phänotyp (erhöhter Blutdruck) wird durch eine solche Beobachtung deutlich dargestellt. Der Nachweis dieser Gene, zusammen mit anderen informativen genetischen Markern wird erlauben, nach genetischen Verbindungen zwischen arterieller Hypertonie und einem bestimmten Chromosomen-Lokus zu suchen. Thanks to clinical curiosity, biochemical studies and, more recently, advances in molecular genetics, the non-entity called «essential hypertension» is shrinking. Richard D. Gordon Nature Genetics 1995
Publisher: Hogrefe Publishing Group
Date: 1999
Publisher: Springer Science and Business Media LLC
Date: 06-2004
Publisher: SAGE Publications
Date: 07-2014
Abstract: Living-donor kidney transplantation is an established practice. Traditionally a combination of renal scintigram and computed tomography (CT) is used to select the kidney that is to be harvested in each donor. To evaluate the ability of split renal volume (SRV) calculated from volumetric examination of CT images compared to nuclear split renal function (nSRF) derived from gamma camera scintigram to predict donor residual single kidney function after donor nephrectomy. This pilot study comprised a retrospective analysis of CT images and renal scintigrams from 12 subsequent live kidney donors who had at least 12 months post-donation renal function follow-up. nSRF derived from the renal scintigram, expressed as the right kidney’s function in percent of the total, was 50.2 ± 3.3 (range, 44.1–54.0%) and SRV estimated following analysis of CT imaging was 49.0 ± 2.9 (range, 46.4–52.3%). Although the correlation between nSRF and SRV was moderate (R = 0.46), there was 92% agreement on the dominant kidney if a difference of % in nSRF versus SRV was considered. Post-donation glomerular filtration rate (GFR) by CKD-EPI formula was 92 ± 10 mL/min/1.73m2 at 1 year and the correlation between estimated GFR (eGFR) at 1 year and extrapolated single kidney eGFR adjusted by nSRF (R 2 = 0.69, P = 0.0007) or SRV (R 2 = 0.74, P = 0.0003) was similar. Calculation of SRV from pre-donation CT examination is a valid method to estimate nSRF with good concordance with nSRF determined by renal scintigram and could replace the latter in the assessment of potential kidney donors.
Publisher: Cold Spring Harbor Laboratory
Date: 14-12-2021
DOI: 10.1101/2021.12.12.472269
Abstract: The recently emerged SARS-CoV-2 Omicron variant harbors 37 amino acid substitutions in the spike (S) protein, 15 of which are in the receptor-binding domain (RBD), thereby raising concerns about the effectiveness of available vaccines and antibody therapeutics. Here, we show that the Omicron RBD binds to human ACE2 with enhanced affinity relative to the Wuhan-Hu-1 RBD and acquires binding to mouse ACE2. Severe reductions of plasma neutralizing activity were observed against Omicron compared to the ancestral pseudovirus for vaccinated and convalescent in iduals. Most (26 out of 29) receptor-binding motif (RBM)-directed monoclonal antibodies (mAbs) lost in vitro neutralizing activity against Omicron, with only three mAbs, including the ACE2-mimicking S2K146 mAb 1 , retaining unaltered potency. Furthermore, a fraction of broadly neutralizing sarbecovirus mAbs recognizing antigenic sites outside the RBM, including sotrovimab 2 , S2X259 3 and S2H97 4 , neutralized Omicron. The magnitude of Omicron-mediated immune evasion and the acquisition of binding to mouse ACE2 mark a major SARS-CoV-2 mutational shift. Broadly neutralizing sarbecovirus mAbs recognizing epitopes conserved among SARS-CoV-2 variants and other sarbecoviruses may prove key to controlling the ongoing pandemic and future zoonotic spillovers.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 10-1992
DOI: 10.1097/00004872-199210000-00021
Abstract: To assess whether currently normotensive offspring of essential hypertensive parents may have alterations in left ventricular mass (LVM) and function, and how these relate to some potential determinants. Echocardiographical indices of LVM (assessed by two-dimensional guided M-mode echocardiogram), 'clinic' blood pressure and daytime ambulatory blood pressure profiles, blood pressure responses to dynamic and isometric exercise testing, haematocrit, plasma and 24-h urinary electrolytes and catecholamines, and plasma angiotensin II were assessed on a defined Na+ intake in 31 normotensive lean sons of essential hypertensive parents (OHYP group) and 30 body mass index- and age-matched sons of normotensive parents (ONORM group). Clinic supine systolic blood pressure was higher in the OHYP than the ONORM group, but clinic diastolic and daytime ambulatory mean blood pressures, blood pressure loads and blood pressure during dynamic or isometric exercise did not differ significantly. LVM index (LVMI), interventricular septum thickness (IVST), posterior wall thickness (PWT), the IVST:PWT ratio, ejection fraction, fractional shortening, cardiac index and measured biochemical variables also did not differ significantly between groups. In the whole study population the LVMI correlated positively with the body mass index and negatively with plasma noradrenaline. In young lean men with one essential hypertensive parent and blood pressure still in the normal range, left ventricular structure and systolic function, as assessed by echocardiography, seem to be often unaltered and appropriate relative to the existing body habitus and blood pressure. Moreover, an early tendency for increasing resting blood pressure in genetically hypertension-prone humans may be more apparent under clinic than usual ambulatory conditions, whereas the blood pressure reactivity to physical stress seems to be largely normal at this stage.
Publisher: Elsevier BV
Date: 02-2010
Publisher: Elsevier BV
Date: 05-1996
DOI: 10.1016/0303-7207(96)03787-2
Abstract: The 11 beta-hydroxysteroid dehydrogenase type II enzyme (11 beta HSD2) converts cortisol into mineralocorticoid receptor inactive cortisone, thus preventing occupation of the non-selective mineralocorticoid receptor by glucocorticoids in the kidney. Mutations generating inactive enzymes have been described in the HSD11B2 gene in the congenital syndrome of apparent mineralocorticoid excess (AME), although proof of mutant protein synthesis was not provided. In the present study we have examined the metabolism of cortisol in mammalian cells transfected with plasmids expressing the wild type and mutant enzymes from three additional families of patients with mutations in the HSD11B2 gene. These studies revealed that the mutants were enzymatically inactive in intact mammalian cells expressing significant levels of both full length and truncated proteins. This is the first study to definitively show that point mutations in the HSD11B2 gene abolish 11 beta HSD2 enzymatic activity in the syndrome of AME.
Publisher: Springer Science and Business Media LLC
Date: 31-07-2013
DOI: 10.1038/IJO.2013.137
Abstract: To investigate whether ventilatory factors limit exercise in overweight and obese children during a 6-min step test and to compare ventilatory responses during this test with those of healthy weight children. Cross-sectional, prospective comparative study. Twenty-six overweight/obese subjects and 25 healthy weight subjects with no known respiratory illness. Various fatness and fat distribution parameters (using air displacement plethysmography and anthropometry), pulmonary function tests, breath-by-breath gas analysis during exercise, perceived exertion. Young people who are overweight or obese are more likely to experience expiratory flow limitation (expFL) during submaximal exercise compared with their healthy weight peers [OR 7.2 (1.4, 37.3), P=0.019]. Subjects who had lower lung volumes at rest were even more likely to experience exercise-induced expFLs [OR 8.35 (1.4-49.3)]. Both groups displayed similar breathing strategies during submaximal exercise. Young people who are overweight/obese are more likely to display expFL during submaximal exercise compared with children of healthy weight . Use of compensatory breathing strategies appeared to enable overweight children to avoid the experience of breathlessness at this intensity of exercise.
Publisher: Hogrefe Publishing Group
Date: 06-2000
DOI: 10.1024/0040-5930.57.6.380
Abstract: Der Stellenwert der Diuretika in der Behandlung der arteriellen Hypertonie hat in den letzten Jahren deutlich abgenommen. Die vorliegende Zusammenstellung fordert den Leser auf, den schwindenden Einsatz dieser kostengünstigen und gut dokumentierten Antihypertensiva neu zu überdenken. Diuretika wurden in 16 placebokontrollierten Studien als Basismedikation zur Behandlung der arteriellen Hypertonie bei über 13000 Patienten eingesetzt. Sie vermindern das Sterberisiko um 11% und es treten weniger zerebrovaskuläre (–34%) und koronare Ereignisse (–29%) auf. Das Ausmaß der Blutdrucksenkung durch eine niedrig dosierte Thiazidtherapie ist vergleichbar mit demjenigen der ursprünglich eingesetzten, hohen Dosen, ohne dass es aber zu relevanten metabolischen Nebenwirkungen kommt. In Kombination mit anderen Antihypertensiva verhindern sie eine konsekutive Volumenexpansion mit Ödembildung. Zudem wurde gezeigt, dass eine Kombinationstherapie mit niedrig dosierten Thiaziddiuretika nicht nur zu einer zusätzlichen Senkung des Blutdrucks, sondern auch zu einer Verminderung der Mortalität durch zerebrovaskuläre und koronare Ereignisse führt. Die Vorteile von Diuretika bei hypertensiven Patienten in speziellen klinischen Situationen, z.B. beim Vorliegen von Ödemen, Herzinsuffizienz, Niereninsuffizienz, nephrotischem Syndrom und/oder portaler Hypertonie sind unbestritten. Aber auch als Basistherapie bei der unkomplizierten arteriellen Hypertonie können niedrig dosierte Thiaziddiuretika heute noch mit gutem Gewissen eingesetzt werden. Im Gegensatz zu anderen Medikamentenklassen ist bei den niedrig dosierten Thiaziddiuretika die Evidenz gesichert, dass unter einer Behandlung der Hypertonie die Mortalität abnimmt und weniger zerebrovaskuläre und kardiale Ereignisse eintreten.
Publisher: Oxford University Press (OUP)
Date: 03-04-2014
DOI: 10.1093/HMG/DDU154
Abstract: Mutant α-adducin and endogenous ouabain levels exert a causal role in hypertension by affecting renal Na-K ATPase. In addition, mutant β-adducin is involved in glomerular damage through nephrin down-regulation. Recently, the salt-inducible kinase 1 (SIK1) has been shown to exert a permissive role on mutant α-adducin effects on renal Na-K ATPase activity involved in blood pressure (BP) regulation and a SIK1 rs3746951 polymorphism has been associated with changes in vascular Na-K ATPase activity and BP. Here, we addressed the role of SIK1 on nephrin and glomerular functional modifications induced by mutant β-adducin and ouabain, by using congenic substrains of the Milan rats expressing either mutant α- or β-adducin, alone or in combination, ouabain hypertensive rats (OHR) and hypertensive patients. SIK1 co-localized and co-immunoprecipitated with nephrin from glomerular podocytes and associated with caveolar nephrin signaling. In cultured podocytes, nephrin-gene silencing decreased SIK1 expression. In mutant β-adducin congenic rats and in OHR, the podocyte damage was associated with decreased nephrin and SIK1 expression. Conversely, when the effects of β-adducin on podocytes were blocked by the presence of mutant α-adducin, nephrin and SIK1 expressions were restored. Ouabain effects were also reproduced in cultured podocytes. In hypertensive patients, nephrinuria, but not albuminuria, was higher in carriers of mutant SIK1 rs3746951 than in wild-type, implying a more direct effect of SIK1 on glomerular damage. These results demonstrate that, through nephrin, SIK1 is involved in the glomerular effects of mutant adducin and ouabain and a direct effect of SIK1 is also likely to occur in humans.
Publisher: Cold Spring Harbor Laboratory
Date: 10-05-2021
DOI: 10.1101/2021.05.09.442808
Abstract: The repeated spillovers of β-coronaviruses in humans along with the rapid emergence of SARS-CoV-2 escape variants highlight the need to develop broad coronavirus therapeutics and vaccines. Five monoclonal antibodies (mAbs) were isolated from COVID-19 convalescent in iduals and found to cross-react with multiple β-coronavirus spike (S) glycoproteins by targeting the stem helix. One of these mAbs, S2P6, cross-reacts with more than twenty human and animal β-coronavirus S glycoproteins and broadly neutralizes SARS-CoV-2 and pseudotyped viruses from the sarbecovirus, merbecovirus and embecovirus subgenera. Structural and functional studies delineate the molecular basis of S2P6 cross-reactivity and broad neutralization and indicate that this mAb blocks viral entry through inhibition of membrane fusion. S2P6 protects hamsters challenged with SARS-CoV-2 (including the B.1.351 variant of concern) through viral neutralization and Fc-mediated effector functions. Serological and B cell repertoire analyses indicate that antibodies targeting the stem helix are found in some convalescent donors and vaccinees but are predominantly of narrow specificity. Germline reversion of the identified cross-reactive mAbs revealed that their unmutated ancestors are specific for the endemic OC43 or HKU1 viruses and acquired enhanced affinity and breadth through somatic mutations. These data demonstrate that conserved epitopes in the coronavirus fusion machinery can be targeted by protective antibodies and provide a framework for structure-guided design of pan-β-coronavirus vaccines eliciting broad protection.
Publisher: Public Library of Science (PLoS)
Date: 10-02-2022
DOI: 10.1371/JOURNAL.PONE.0263328
Abstract: Patients on dialysis are at risk of severe course of SARS-CoV-2 infection. Understanding the neutralizing activity and coverage of SARS-CoV-2 variants of vaccine-elicited antibodies is required to guide prophylactic and therapeutic COVID-19 interventions in this frail population. By analyzing plasma s les from 130 hemodialysis and 13 peritoneal dialysis patients after two doses of BNT162b2 or mRNA-1273 vaccines, we found that 35% of the patients had low-level or undetectable IgG antibodies to SARS-CoV-2 Spike (S). Neutralizing antibodies against the vaccine-matched SARS-CoV-2 and Delta variant were low or undetectable in 49% and 77% of patients, respectively, and were further reduced against other emerging variants. The fraction of non-responding patients was higher in SARS-CoV-2-naïve hemodialysis patients immunized with BNT162b2 (66%) than those immunized with mRNA-1273 (23%). The reduced neutralizing activity correlated with low antibody avidity. Patients followed up to 7 months after vaccination showed a rapid decay of the antibody response with an average 21- and 10-fold reduction of neutralizing antibodies to vaccine-matched SARS-CoV-2 and Delta variant, which increased the fraction of non-responders to 84% and 90%, respectively. These data indicate that dialysis patients should be prioritized for additional vaccination boosts. Nevertheless, their antibody response to SARS-CoV-2 must be continuously monitored to adopt the best prophylactic and therapeutic strategy.
Publisher: Elsevier BV
Date: 02-2011
DOI: 10.1111/J.1600-6143.2010.03313.X
Abstract: We developed and tested a new computer program to match maximal sets of incompatible live donor/recipient pairs from a national paired kidney donation (PKD) registry. Data of 32 incompatible pairs included ABO and 4 digit-high-resolution donor and recipient HLA antigens and recipient's HLA antibodies. Three test runs were compared, in which donors were excluded from matching to recipients with either donor-specific antibodies (DSA) >8000MFI (mean fluorescent intensity) at low-resolution (Run 1) or >8000MFI at high-resolution (Run 2) or >2000MFI and high-resolution (Run 3). Run 1 identified 22 703 possible combinations, with 20 pairs in the top ranked, Run 2 identified 24 113 combinations, with 19 pairs in the top ranked and Run 3 identified 8843 combinations, with 17 pairs in the top ranked. Review of DSA in Run 1 revealed that six recipients had DSA 2000-8000MFI causing a possible positive crossmatch resulting in breakdown of two 3-way and three 2-way chains. In Run 2, four recipients had DSA 2000-8000MFI, also potentially causing breakdown of three 2-way chains. The more prudent approach of excluding from matching recipients with DSA with >2000MFI reduces the probability of matched pairs having a positive crossmatch without significantly decreasing the number of possible transplants.
Publisher: The Endocrine Society
Date: 03-2001
DOI: 10.1210/JC.86.3.1247
Publisher: Springer Science and Business Media LLC
Date: 1992
DOI: 10.2165/00003495-199200441-00014
Abstract: The purpose of the present study was to assess the efficacy and tolerability of diuretic-free antihypertensive therapy with a calcium antagonist and/or an angiotensin converting enzyme (ACE) inhibitor in patients with diabetes mellitus. 54 hypertensive [blood pressure (BP) above 140/90mm Hg] patients with diabetes mellitus type 1 (n = 7) or 2 (n = 47) and normal serum creatinine levels (mean 82 +/- 6 mumol/L) received either verapamil or enalapril after a 2-week washout and a 4-week placebo phase. If BP remained elevated, both agents were combined. Verapamil or enalapril alone normalised diastolic BP (to less than 90mm Hg) in 36 patients verapamil decreased BP from 159/98 to 147/87mm Hg (n = 19, p < 0.001) and enalapril decreased BP from 166/99 to 146/88mm Hg (n = 17, p < 0.001). In 18 patients who remained hypertensive after 10 weeks of monotherapy, a combination of both drugs decreased BP from 169/104 to 151/90mm Hg (p < 0.001). Overall, 87% of patients achieved a target BP response at 30 weeks. Urinary albumin as related to creatinine excretion (UAE micrograms albumin:mg creatinine) was on average not significantly changed after verapamil or enalapril treatment, alone or combined. Nevertheless, in patients with initial microalbuminuria, UAE decreased (p < 0.05) during enalapril treatment. Serum potassium, total lipids, high density lipoprotein cholesterol, low density lipoprotein cholesterol, glycosylated haemoglobin, serum C peptide and fructosamine levels were not significantly modified by treatment. Subjective tolerability of the drugs was also generally good. Thus, in hypertensive patients with diabetes, a diuretic-free therapy based on the calcium antagonist verapamil or the ACE inhibitor enalapril, alone or combined, can effectively decrease BP without adversely affecting carbohydrate and lipid metabolism.
Publisher: Elsevier BV
Date: 11-2020
Publisher: Oxford University Press (OUP)
Date: 14-11-2016
DOI: 10.1093/NDT/GFV383
Publisher: Informa UK Limited
Date: 1992
DOI: 10.3109/08037059209077498
Abstract: Currently normotensive offspring of essential hypertensive parents often have disturbances in blood pressure (BP) regulation such as abnormalities in electrolyte homoeostasis, increased salt-sensitivity and/or impaired renal Na(+)-excretion. Whether an altered reactivity to mineralocorticoids may also play a role is presently unknown. Therefore, we investigated BP (recorded during 24 h), plasma atrial natriuretic factor (ANF), cyclic guanosine monophosphate (cGMP), aldosterone (PA) and renin activity (PRA), 24-h urine electrolyte and cGMP excretions measured on 4 consecutive days, as well as other variables, after 1 week on placebo and after 3 weeks of 9 alpha-fludrocortisone-acetate (9 alpha F) administration, 0.6 mg/d in 12 normotensive sons of essential hypertensive parents (SEH) and 12 body-mass-index- and age-matched (25 +/- 1[+/-SEM]yr) sons of normotensive parents (SN). On placebo, the 2 groups did not differ significantly in average 24 h BP (mean BP 95 +/- 2 vs 95 +/- 2 mmHg), plasma-ANF (40 +/- 7 vs 30 +5 pg/ml), cGMP (6 +/- 0.4 vs 6 +/- 0.5 nmol/l), PRA (1.3 +/- 0.1 vs 1.6 +/- 0.2 ng/ml/h), PA (9 +/- 0.5 vs 10 +/- 0.9 ng/dl), hematocrit (44 +/- 0.7 vs 44 +/- 0.4%) and 96-h urinary-Na+ (mean 205 +/- 13 vs 195 +/- 16 mmol/d), -K+ (69 +/- 6 vs 78 +/- 7 mmol/d) or -cGMP (461 +/- 35 vs 483 +/- 32 nmol/d). 9 alpha F significantly increased BP in SEH (p < 0.005) but not SN (107 +/- 2 vs 100 +/- 2 mmHg, p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2011
DOI: 10.2215/CJN.04190510
Abstract: Iron (Fe) overload may complicate parenteral Fe therapy used to enhance the efficacy of erythropoietic-stimulating agents in the treatment of anemia of chronic kidney disease. However, serum Fe markers are influenced by inflammation or malignancy and may not accurately reflect the amount of body Fe. We studied the relationship between parenteral Fe therapy, conventional serum Fe markers, and liver iron concentration (LIC) measured using magnetic resonance R2 relaxometry (FerriScan) in 25 Fe-deficient predialysis chronic kidney disease patients before and 2 and 12 weeks after single high-dose intravenous Fe and in 15 chronic hemodialysis patients with elevated serum ferritin ( μg/L). In predialysis patients, there was strong dose dependency between the administered Fe dose and changes in LIC at weeks 2 and 12 however, no dose dependency between Fe dose and changes in ferritin or transferrin saturation (TSAT) were observed. In hemodialysis patients, LIC correlated with the cumulative Fe dose and duration of dialysis but not with current ferritin or TSAT. The cumulative Fe dose remained a significant independent predictor of LIC in a multiple regression model. Two dialysis patients who received g parenteral Fe had substantially elevated LIC μmol/g, which is associated with hemochromatosis. In Fe-deficient predialysis patients, intravenous Fe therapy is associated with increases in LIC unrelated to changes in conventional Fe markers. In hemodialysis patients, TSAT and ferritin are poor indicators of body Fe load, and some patients have LICs similar to those found in hemochromatosis.
Publisher: Oxford University Press (OUP)
Date: 02-2017
DOI: 10.1093/HMG/DDU558
Publisher: American Physiological Society
Date: 11-1990
DOI: 10.1152/AJPRENAL.1990.259.5.F832
Abstract: Urodilatin is a newly identified analogue of human atrial natriuretic factor-(99-126) [ANF-(99-126)], which has recently been isolated from human urine and has 32 amino acid residues [ANF-(95-126)]. To investigate renal and cardiovascular effects in men, eight healthy subjects received injections of 25, 50, and 100 micrograms urodilatin iv compared with 50 micrograms ANF-(99-126) and placebo. Blood pressure decreased (P less than 0.05) after 50 micrograms ANF-(99-126), whereas urodilatin lowered diastolic blood pressure only at the highest dose (P less than 0.01). Heart rate increased (P less than 0.05-0.01) dose dependently after urodilatin injections. Glomerular filtration rate rose after 100 micrograms (from 120 +/- 3 to 156 +/- 7 ml.min-1.1.73 m-2, P less than 0.001) and 50 micrograms urodilatin (from 116 +/- 7 to 149 +/- 13 ml.min-1.1.73 m-2, P less than 0.01) but not after 25 micrograms urodilatin, ANF-(99-126), or placebo. Effective renal plasma flow was not significantly modified. Diuresis and excretion of sodium, chloride, and guanosine 3',5'-cyclic monophosphate increased (P less than 0.001) dose dependently effects of 25 micrograms urodilatin equaled those of 50 micrograms ANF-(99-126). Plasma renin, aldosterone, and catecholamines were unchanged. We conclude that urodilatin can acutely modify renal and cardiovascular function in men and seems to exert more potent renal effects than ANF-(99-126).
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 03-2002
DOI: 10.1097/00007890-200203270-00023
Abstract: Genetic variants of the renin-angiotensin system (RAS) have been implicated in the progression of native kidney diseases. A decreased long-term renal allograft function has also been associated with increased activity of RAS, which may be genetically determined. The effect of the angiotensinogen (AGT), angiotensin-converting enzyme (ACE), angiotensin type 1 receptor (AGT1R), and aldosterone synthase (CYP11B2) genotypes on renal function was investigated in 223 first-allograft recipients. Graft function was estimated by yearly determinations of serum creatinine. Genotyping was performed for the M235T-AGT, the I/D-ACE, the A1166C-AGT1R, and the -344T/C-CYP11B2 gene polymorphisms using polymerase chain reaction. The percentage of patients with preserved stable graft function up to 15 years after transplantation was higher when mean blood pressure was 117 mmHg (60 vs. 25% of patients). The CYP11B2 genotype predicted long-term stable graft function with more patients suffering from worsening renal function with the CYP11B2 TT than the CC genotype (P=0.002). There was a weak association between the AGT1R genotype (P=0.037), but not the AGT or ACE genotypes, and a preserved long-term graft function. Cox proportional hazards estimation showed no interactions between the observed effect of CYP11B2 genotype on renal function over time and the number of HLA class I and II matches, other RAS genotypes, graft function, or mean blood pressure at 1 year after transplantation. The rate of decline in renal allograft function is strongly associated with the CYP11B2 but not AGT, ACE, or AGT1R genotypes. This finding suggests that certain genetic factors related to the RAS are important determinants of long-term renal allograft function.
Publisher: Wiley
Date: 23-09-1991
DOI: 10.1016/0014-5793(91)81259-B
Abstract: The (Na+,K+)-ATPase activity from the kidney cortex of the Milan hypertensive rat strain (MHS) and the corresponding normotensive control (MNS) was measured both in active solubilized enzyme preparations and in isolated basolateral membrane vesicles. Kinetic analysis of the purified enzyme showed that the Vmax value was significantly higher in MHS rats. The difference between MHS and MNS was not linked to a different number of sodium pumps, but was related to the molecular activity of the enzyme. Using basolateral membrane vesicles, an increased ATP-dependent ouabain-sensitive sodium transport was also demonstrated in MHS rats. These results support the hypothesis that a higher tubular sodium reabsorption may be involved in the pathogenesis of hypertension in this rat strain.
Publisher: Elsevier BV
Date: 04-1996
DOI: 10.1016/0039-128X(96)00013-X
Abstract: The 11 beta-hydroxysteroid dehydrogenase type II enzyme (11 beta HSD2) converts cortisol to cortisone, allowing the non-selective mineralocorticoid receptor to bind aldosterone. When the activity of this enzyme is compromised, as occurs in licorice intoxication or in the congenital syndrome of apparent mineralocorticoid excess (AME), there is marked sodium retention, hypokalemia, and hypertension. The first proof that this enzyme was defective in AME came from the identification of the R337C mutation in a number of siblings with the syndrome. Subsequent expression studies showed that the mutant had a Km one order of magnitude higher than the wild-type enzyme while in the cell-free system it was without detectable activity. In the present work we have extended our studies on this mutant and provide evidence that the mutant protein may also partially inhibit the wild-type enzyme in heterozygotes. Furthermore, experiments incorporating the protein synthesis inhibitor cycloheximide show that the mutant enzyme is less stable than the wild-type activity in intact cells. These results suggest that mutations in the 11 beta HSD2 enzyme may have multiple consequences for the mineralocorticoid target cell.
Publisher: Oxford University Press (OUP)
Date: 02-12-1992
DOI: 10.1093/EURHEARTJ/13.SUPPL_G.61
Abstract: Hypertension, dyslipidaemia, glucose intolerance (associated with insulin resistance and compensatory hyperinsulinaemia) and other abnormalities are complementary coronary risk factors which often occur in association. A familial trait for essential hypertension seems to coexist commonly with defects in carbohydrate and lipoprotein metabolism which can be detected before the appearance of hypertension. Diabetes mellitus as well as obesity promotes the development of hypertension and dyslipidaemia. Moreover, certain drugs used for antihypertensive therapy can further modify lipoprotein and glucose metabolism. Thiazides in high dosage and loop-diuretics can increase serum low-density-lipoprotein cholesterol (LDL-C) and/or very-LDL-C and the total C/high-density lipoprotein cholesterol (HDL-C) ratio, while HDL-C is largely unchanged triglycerides (Tg) are also often elevated. Premenopausal women may be protected from this side effect. Whether diuretic-induced dyslipidaemia is dose-dependent and low thiazide doses (i.e. hydrochlorothiazide < or = 12.5 mg daily) are less active, awaits clarification. The diuretic-antihypertensive agent, indapamide, given at a dose of 2.5 mg.day-1, seems to exert no relevant effect on serum lipoprotein or glucose metabolism. The potassium-sparing diuretic, spironolactone, also may be largely neutral with regard to lipids. Moreover, potassium sparing diuretics may possibly counteract, at least in part, a dyslipidaemic influence of potassium-loosing diuretics in medium dose. Drug-induced dyslipidaemia, as well as glucose intolerance, represent potentially adverse influences. In the hypertensive population, effective blood pressure control with traditional drug therapy based on thiazide-type diuretics in high dosage led to a distinct decrease in cerebrovascular morbidity and mortality, but a lesser decrease in coronary events.(ABSTRACT TRUNCATED AT 250 WORDS)
Publisher: American Physiological Society
Date: 05-1996
DOI: 10.1152/AJPENDO.1996.270.5.E900
Abstract: The 11 beta-hydroxysteroid dehydrogenase type 2 (11betaHSD2) enzyme is thought to confer specificity on the mineralocorticoid receptor by inactivating glucocorticoids in mineralocorticoid target organs. The cloned 11 beta HSD2 displayed Michaelis constant values for corticosterone and cortisol of 5.1 and 61 nM, respectively. Linearity in the dose-response curve ranged between 1 and 200 nM for corticosterone and 25 and 2,000 nM for cortisol, with no evidence for complex kinetics. Inhibition of cortisol oxidation by other steroids was purely competitive in nature. Inhibition of 11 beta HSD2 activity by the end product or aldosterone occurred only at supraphysiological levels, whereas corticosterone and deoxycorticosterone displayed significant inhibition at physiological concentrations and progesterone at concentrations that occur during pregnancy. In intact transfected CHOP cells, dexamethasone was converted to 11-dehydrodexamethasone by 11 beta HSD2 but not type 1 11 beta-hydroxysteroid dehydrogenase, an aspect that may be useful in evaluating 11 beta HSD activity in intact cells.
No related grants have been discovered for Paolo Ferrari.