ORCID Profile
0000-0002-4782-8695
Current Organisations
Prince of Wales Hospital and Community Health Services
,
UNSW Prince of Wales Clinical School
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Publisher: Wiley
Date: 12-2021
DOI: 10.1111/IMJ.14976
Abstract: In international studies, cognitive impairment is a common but underdetected issue in dialysis patients. Chronic kidney disease (CKD) shares risk factors with and is an independent risk factor for cognitive impairment. There is a lack of Australian data on cognitive impairment in this at‐risk population. This has implications on service planning because cognitive impairment in CKD is associated with higher mortality, morbidity and healthcare costs. To examine the prevalence, types and clinician recognition of cognitive impairment within an Australian dialysis population. A cross‐sectional study of haemodialysis and peritoneal dialysis patients in South Eastern Sydney screened for cognitive impairment using the Montreal Cognitive Assessment (MoCA). Participant interviews, medical records, physician and carer questionnaires, were used to determine the types of cognitive impairment and rate of recognition. One hundred and six participants were included (median age 66 years, median dialysis duration 2 years) and 58 (54.7%) were cognitively impaired on the MoCA, of whom old age psychiatrists sub‐classified 21 (36.2%) as having dementia, and 31 (53.4%) with ‘cognitive impairment, no dementia’ 36/58 (62.0%) of the cognitively impaired participants on the MoCA were suspected of having cognitive impairment by nephrologists but only 14/58 (24.1%) had this documented in medical records. Although cognitive impairment is common in dialysis patients, there are low levels of detection by clinical teams. Cognitive screening of dialysis patients should be incorporated as part of wider assessment and determination of management goals such as in iduals' capacity to self‐care and provide informed consent to treatments.
Publisher: Elsevier BV
Date: 05-2011
DOI: 10.1038/KI.2010.555
Publisher: Wiley
Date: 19-07-2001
Publisher: Elsevier BV
Date: 03-2008
DOI: 10.1016/J.CMPB.2007.11.011
Abstract: Selected Ion Flow Tube-Mass Spectrometry (SIFT-MS) is an analytical technique for real-time quantification of trace gases in air or breath s les. SIFT-MS system thus offers unique potential for early, rapid detection of disease states. Identification of volatile organic compound (VOC) masses that contribute strongly towards a successful classification clearly highlights potential new biomarkers. A method utilising kernel density estimates is thus presented for classifying unknown s les. It is validated in a simple known case and a clinical setting before-after dialysis. The simple case with nitrogen in Tedlar bags returned a 100% success rate, as expected. The clinical proof-of-concept with seven tests on one patient had an ROC curve area of 0.89. These results validate the method presented and illustrate the emerging clinical potential of this technology.
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: Wiley
Date: 07-2015
DOI: 10.1111/IMJ.12791
Abstract: We aimed to compared estimated glomerular filtration rate (eGFR) according to the Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI), with (mL/min/1.73 m(2) ) and without body surface area (BSA) normalisation (CKD-EPI_noBSA, mL/min) against measured (99m) Technetium - diethylenepentaacetic acid (Tc-DTPA GFR) (mL/min) in 222 in iduals, including 80 with malignancy. BSA was calculated for each in idual using the Du Bois equation. The CKD-EPI and CKD-EPI_noBSA equations were compared with measured Tc-DTPA GFR with respect to bias, proportion within 30% of GFR (P30) and root mean square error for predicting levels of GFR, and concordance in relation to carboplatin dosing. The mean (SD) for BSA and measured GFR for the entire group was 1.99 (0.25) m(2) and 127 (41) mL/min respectively. The P30 for Tc-DTPA GFR was significantly higher with the CKD-EPI_noBSA (80%) than with the CKD-EPI equation (63%, P = 0.0001). In those with body mass index (BMI) > 30 kg/m(2) , the P30 values for the CKD-EPI_noBSA and CKD-EPI were 74% and 42% respectively (P 30 kg/m(2) , concordance in relation to carboplatin dosing using CKD-EPI_noBSA was 65% compared with 26% with the CKD-EPI (P < 0.0001). The CKD-EPI without normalisation (CKD-EPI_noBSA) equation was superior to the CKD-EPI equation in estimating raw-measured Tc-DTPA GFR (mL/min).
Publisher: Wiley
Date: 10-1993
Abstract: Hypoxic injury in the isolated perfused rat kidney (IPRK) was monitored using 23Na-NMR in the presence or absence of 1.5 and 15 mM dimethylthiourea (DMTU) or 15 mM dimethylsulphoxide (DMSO) before and after inducing hypoxia. Hypoxia induced a prompt exponential increase in total renal 23Na+, renal vascular resistance, and sodium excretion and decreased inulin clearance and adenine nucleotides and reduced glutathione concentrations. Lipid peroxide metabolites were unaltered. The increase in 23Na+ was significantly reduced (P < 0.001) by both DMTU and DMSO although hypoxic perturbations of function and biochemical parameters were not. Posthypoxic increases in renal 23Na+ include approximately 10% from the intratubular compartment, but principally reflect the intracellular and interstitial compartments. The results demonstrate that 23Na-NMR is a sensitive indicator of hypoxic renal injury in intact kidney and suggest that DMTU and DMSO protect against hypoxic injury by a mechanism independent of free radical-binding.
Publisher: Elsevier BV
Date: 1996
DOI: 10.1016/0167-4889(95)00142-5
Abstract: [2-(13)C]glycine metabolism was studied in freshly isolated rat renal proximal tubules. Mitochondrial coupling of the glycine cleavage complex (GC) and serine hydroxymethyltransferase (SHMT) was confirmed by the formation of three serine isotopomers, [2-(13)C]-, [3-(13)C]- and [2,3-(13)C]serine, detected by 13C-NMR. Incubation with different fractions of 13C-labelled glycine altered the labelling pattern of the serine isotopomers predictably and allowed calculation of the 13C-labelled fractions of total glycine and methylene in N5,N10-methylenetetrahydrofolate (m-THF) available for serine metabolism. Within 20 min there was a fall in labelled glycine (to 42 +/- 3, 68 +/- 3 and 93 +/- 2%, (n = 4, mean +/- S.D.) from 50%, 75% and 100% 13C-labelled added glycine respectively), followed by a slow rate of endogenous glycine formation for up to 80 min incubation. The C2 of glycine was the source of more than 90% of the methylene group of m-THF formed. Gas chromatography-mass spectroscopy (GC-MS) showed that greater than 50% of serine formed was unlabelled. GC and SHMT proceeded in the direction of serine formation. Serine isotopomer analysis by NMR and GC-MS allowed the actions of GC and SHMT and de novo contributions to glycine, serine and m-THF to be monitored in situ in fresh renal proximal tubules.
Publisher: Elsevier BV
Date: 03-2014
DOI: 10.1038/KI.2013.374
Publisher: Wiley
Date: 19-09-2003
Publisher: Springer Science and Business Media LLC
Date: 28-01-2014
Abstract: Fujii and colleagues define 'subacute' kidney injury (s-AKI) as AKI that takes >7 days to develop, timed from admission or lowest creatinine measurement after admission. Although s-AKI is unlikely to be a distinct syndrome from AKI, the association with increased mortality highlights the need to monitor patient creatinine levels.
Publisher: Wiley
Date: 10-2004
DOI: 10.1111/J.1440-1797.2004.00316.X
Abstract: We have optimized the isolated perfused mouse kidney (IPMK) model for studying renal vascular and tubular function in vitro using 24-28 g C57BL6J mice the wild type controls for many transgenic mice. Buffer composition was optimized for bovine serum albumin concentration (BSA). The effect of adding erythrocytes on renal function and morphology was assessed. Autoregulation was investigated during stepped increases in perfusion pressure. Perfusion for 60 min at 90-110 mmHg with Krebs bicarbonate buffer containing 5.5% BSA, and amino acids produced functional parameters within the in vivo range. Erythrocytes increased renal vascular resistance (3.8 +/- 0.2 vs 2.4 +/- 0.1 mL/min.mmHg, P < 0.05), enhanced sodium reabsorption (FE(Na) = 0.3 +/- 0.08 vs 1.5 +/- 0.7%, P < 0.05), produced equivalent glomerular filtration rates (GFR 364 +/- 38 vs 400 +/- 9 microL/min per gkw) and reduced distal tubular cell injury in the inner stripe (5.8 +/- 1.7 vs 23.7 +/- 3.1%, P < 0.001) compared to cell free perfusion. The IPMK was responsive to vasoconstrictor (angiotensin II, EC50 100 pM) and vasodilator (methacholine, EC50 75 nM) mediators and showed partial autoregulation of perfusate flow under control conditions over 65-85 mmHg autoregulatory index (ARI) of 0.66 +/- 0.11. Angiotensin II (100 pM) extended this range (to 65-120 mmHg) and enhanced efficiency (ARI 0.21 +/- 0.02, P < 0.05). Angiotensin II facilitation was antagonized by methacholine (ARI 0.76 +/- 0.08) and papaverine (ARI 0.91 +/- 0.13). The IPMK model is useful for studying renal physiology and pathophysiology without systemic neurohormonal influences.
Publisher: Annals of Laboratory Medicine
Date: 03-2022
Publisher: IOP Publishing
Date: 08-12-2010
DOI: 10.1088/0967-3334/32/1/008
Abstract: Non-invasive monitoring of breath ammonia and trimethylamine using Selected-ion-flow-tube mass spectroscopy (SIFT-MS) could provide a real-time alternative to current invasive techniques. Breath ammonia and trimethylamine were monitored by SIFT-MS before, during and after haemodialysis in 20 patients. In 15 patients (41 sessions), breath was collected hourly into Tedlar bags and analysed immediately (group A). During multiple dialyses over 8 days, five patients breathed directly into the SIFT-MS analyser every 30 min (group B). Pre- and post-dialysis direct breath concentrations were compared with urea reduction, Kt/V and creatinine concentrations. Dialysis decreased breath ammonia, but a transient increase occurred mid treatment in some patients. Trimethylamine decreased more rapidly than reported previously. Pre-dialysis breath ammonia correlated with pre-dialysis urea in group B (r(2) = 0.71) and with change in urea (group A, r(2) = 0.24 group B, r(2) = 0.74). In group B, ammonia correlated with change in creatinine (r(2) = 0.35), weight (r(2) = 0.52) and Kt/V (r(2) = 0.30). The ammonia reduction ratio correlated with the urea reduction ratio (URR) (r(2) = 0.42) and Kt/V (r(2) = 0.38). Pre-dialysis trimethylamine correlated with Kt/V (r(2) = 0.21), and the trimethylamine reduction ratio with URR (r(2) = 0.49) and Kt/V (r(2) = 0.36). Real-time breath analysis revealed previously unmeasurable differences in clearance kinetics of ammonia and trimethylamine. Breath ammonia is potentially useful in assessment of dialysis efficacy.
Publisher: Elsevier BV
Date: 08-1994
Abstract: Protection against hypoxic injury by supraphysiological glycine and alanine concentrations was investigated in the isolated perfused rat kidney (IPRK). 23Na NMR detects consistent increases in total renal Na in IPRK during hypoxic perfusion. Increasing the concentration of glycine and alanine to 5 mM each produced a 34% (p < 0.001) reduction in the increase in total renal Na following 30 minutes of hypoxia compared to a matched control group supplemented with 5 mM each of serine and glutamine. There was also a trend (p = 0.067) to improvement in the fractional excretion of sodium (FENa) in the glycine plus alanine treated group. Hypoxic alterations of other physiological parameters were not prevented by supraphysiological glycine plus alanine. This suggests that monitoring total renal Na is a more sensitive method of defining renal injury and protection than monitoring changes in FENa, fractional excretion of potassium (FEK) and inulin clearance.
Publisher: Public Library of Science (PLoS)
Date: 09-07-2014
Publisher: S. Karger AG
Date: 2013
DOI: 10.1159/000351542
Abstract: b i Background and Aim: /i /b Neutrophil gelatinase-associated lipocalin (NGAL) is derived from the distal tubule and is both reabsorbed and filtered and also shed into the urine after tubular injury. Plasma NGAL is unique amongst the candidate biomarkers of acute kidney injury (AKI) since elevated concentrations may reflect either a change in renal glomerular function or in structural tubular injury or both. In this study, we compared the performance of plasma NGAL in the diagnosis of functional changes and in the diagnosis of structural injury. b i Methods: /i /b Plasma and urine s les from 528 patients were collected on entry to an intensive care unit (ICU) as well as 12 and 24 h later. Plasma NGAL diagnostic performance was independently assessed for Functional-AKI and Structural-AKI. Functional-AKI was defined by changes in plasma creatinine, whereas Structural-AKI was defined by elevations in urinary NGAL. b i Results: /i /b On ICU entry, the area under the curve (AUC) for the diagnosis of Functional-AKI was 0.74 (95% CI: 0.69-0.79), and for Structural-AKI it was 0.79 (0.74-0.83). Plasma NGAL also predicted the need for dialysis (0.79 0.66-0.81), but not for death. A principal component analysis demonstrated that the maximum plasma NGAL in 24 h reflected structural injury marginally more than functional changes. Plasma NGAL added value to an AKI diagnostic model comprising plasma creatinine, sepsis, age, and APACHE II score (integrated discrimination improvement: 0.073 0.034-0.12). b i Conclusion: /i /b Increased plasma NGAL reflects both decreased filtration and structural injury. For patients at a low calculated risk, the addition of NGAL reduced the risk, and for those at a higher risk, NGAL correctly assigned patients to even a higher risk.
Publisher: Elsevier BV
Date: 07-2011
Publisher: Future Medicine Ltd
Date: 06-2013
DOI: 10.2217/BMM.13.51
Abstract: Toxicant-induced acute kidney injury (ToxAKI) causes substantial morbidity and retards drug development. ToxAKI is relatively underexplored compared with ischemia–reperfusion injury in clinical biomarker studies. We highlight the rationale for novel AKI biomarkers in management of ToxAKI, and review the contemporary evidence supporting their clinical use. Directly-acting nephrotoxins, such as cisplatin, aminoglycosides, vancomycin and radiocontrast, remain widely used and highlight how novel biomarkers can either improve the detection of changes in glomerular filtration rate or directly signal cellular injury and structural damage. Serum cystatin C has already improved clinical risk prediction and drug dosing although its clinical use for early diagnosis awaits validation. The use of novel functional and structural biomarkers to stage ToxAKI and aid prognosis requires robust validation and better understanding of the relationship between biomarkers, morbidity and mortality. Biomarkers that illustrate the probable mechanisms and phase of ToxAKI may guide mechanism-specific diagnosis and therapy.
Publisher: S. Karger AG
Date: 2016
DOI: 10.1159/000444456
Abstract: Post transplant repeated measurements of urine volume and serum creatinine (sCr) are used to assess kidney function. Under non-steady state conditions, repeated measurement of sCr allows calculation of the kinetic estimated GFR (KeGFR). Additional measurement of urinary creatinine allows the calculation of the creatinine excretion to (estimated) production ratio (E/eG). We hypothesized that post-transplant KeGFR and E/eG would predict delayed graft function (DGF), as early as 4 h and outperform a validated clinical model at 12 h. This was a retrospective analysis of prospectively acquired data in a study of 56 recipients of deceased-donor kidney transplant. We assessed predictive performance with the area under the receiver operator characteristic curve (AUC) and the added value to a clinical model with integrated discrimination improvement analysis. At 4 h, the AUC for E/eG was 0.87 (95% CI 0.77-0.96) and for KeGFR 0.69 (95% CI 0.56-0.83). Both E/eG and KeGFR improved the risk prediction of a clinical model for DGF by 32 and 18%, and for non-DGF by 17 and 10%, respectively. While E/eG had better predictive performance of DGF than KeGFR, KeGFR might also facilitate perioperative management including drug dosing after kidney transplantation. Together these measurements may facilitate the possibility of conducting trials of early intervention to ameliorate the adverse effects of ischaemia-reperfusion injury on long-term DGF.
Publisher: American Physiological Society
Date: 21-09-2023
Publisher: Elsevier BV
Date: 2009
Publisher: S. Karger AG
Date: 2013
DOI: 10.1159/000349964
Abstract: Acute kidney injury (AKI) is a common but complex clinical syndrome with multiple etiologies. These etiologies target different sites and pathways within the kidney. Novel biomarkers of 'kidney damage' (which can be tubular or glomerular) can be used to diagnose AKI, even in the absence of an increase in serum creatinine or oliguria. These biomarkers of kidney damage can be combined with biomarkers of kidney function to facilitate classification of AKI. A comprehensive review of the literature was performed using the published methodology of the Acute Dialysis Quality Initiative (ADQI) working group and used to establish consensus statements regarding the use of biomarkers in the differential diagnosis of AKI. We recommend that the pathophysiological terms 'functional change' and 'kidney damage' be used in preference to the anatomical classification using the terms pre-renal, renal and post-renal AKI. We further recommend the use of both renal and non-renal biomarkers in establishing the specific cause of AKI as soon as possible after diagnosis. The presence of underlying CKD or of sepsis poses additional challenges in differential diagnosis, since these conditions alter both baseline biomarker excretion and biomarker performance. We recommend that biomarkers be validated within the clinical context in which they are to be used. Within that context, combinations of biomarkers may, in the future, allow differentiation of the site, mechanism and phase of injury.
Publisher: Informa UK Limited
Date: 10-04-2015
DOI: 10.3109/15563650.2015.1030026
Abstract: Colchicine is an anti-inflammatory alkaloid used for the treatment of acute gout, but has a narrow therapeutic index. Colchicine overdoses are relatively rare, but have high mortality requiring rapid treatment. To evaluate the ability of a newly available ovine fragment antigen-binding (Fab) antibody to colchicine (ColchiFab(™)) to protect rats against renal and other injury 24 h after colchicine ingestion. Rats were gavaged with colchicine (5 mg/kg), then 2 h later injected intraperitoneally with 5 ml of sterile saline, or Fab anti-colchicine, a newly available ovine antibody to colchicine. S les of blood were taken at 1, 2, 5 and 24 h after gavage, and urine was collected from 5 to 24 h after gavage. Concentrations of colchicine in tissue, blood and urine were measured by liquid chromatography/mass spectrometry, concentrations of Fab anti-colchicine, urinary neutrophil gelatinase-associated lipocalin (NGAL) and kidney injury molecule-1 or KIM-1 by enzyme-linked immunosorbent assay or ELISA, while concentrations of creatine kinase and creatinine (Cr) were measured enzymatically. Colchicine equilibrated rapidly throughout the body and increased serum creatine kinase. Fab anti-colchicine also rapidly redistributed to the blood and remained at high concentrations over 24 h. Fab anti-colchicine caused a rapid 7.1-fold increase in serum colchicine level, followed by excretion of both colchicine and Fab anti-colchicine through the urine. This was associated with the accumulation of colchicine in the kidney, a reversal of colchicine-induced diarrhoea, and increasing urinary NGAL level from 168 ± 48 to 477 ± 255 ng/mmol Cr [mean ± standard deviation or SD]. Fab anti-colchicine greatly increased the clearance of colchicine, although increasing NGAL level suggested the presence of mild kidney damage. These data suggest clinical utility for Fab anti-colchicine in the treatment of colchicine overdose.
Publisher: Elsevier
Date: 2008
Publisher: S. Karger AG
Date: 2013
DOI: 10.1159/000349962
Publisher: Elsevier BV
Date: 06-2021
DOI: 10.51893/2021.2.POV1
Abstract: Acute kidney injury (AKI) is a major clinical problem in the community and in hospital, with hospital-acquired AKI reported in about 20% of adult and 30% of paediatric admissions.
Publisher: Wiley
Date: 07-06-2010
DOI: 10.1111/J.1399-3062.2010.00523.X
Abstract: Ochroconis gallopava has rarely been isolated in immunosuppressed patients. We report the first case to our knowledge of O. gallopava peritonitis in a cardiac transplant patient on continuous ambulatory peritoneal dialysis. A 58-year-old man who had undergone cardiac transplant 8 years earlier alerted his dialysis nurses to the presence of black material in his catheter lumen. Fungal hyphae were seen on direct microscopy of the black material and from the dialysate effluent, and O. gallopava was cultured from both after 1 day. He was treated successfully with a single dose of intravenous voriconazole, followed by 2 weeks of oral voriconazole.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-2010
DOI: 10.2215/CJN.08531109
Publisher: American Physiological Society
Date: 09-2006
DOI: 10.1152/AJPRENAL.00302.2005
Abstract: Endothelial dysfunction in ischemic acute renal failure (IARF) has been attributed to both direct endothelial injury and to altered endothelial nitric oxide synthase (eNOS) activity, with either maximal upregulation of eNOS or inhibition of eNOS by excess nitric oxide (NO) derived from iNOS. We investigated renal endothelial dysfunction in kidneys from Sprague-Dawley rats by assessing autoregulation and endothelium-dependent vasorelaxation 24 h after unilateral (U) or bilateral (B) renal artery occlusion for 30 (U30, B30) or 60 min (U60, B60) and in sham-operated controls. Although renal failure was induced in all degrees of ischemia, neither endothelial dysfunction nor altered facilitation of autoregulation by 75 pM angiotensin II was detected in U30, U60, or B30 kidneys. Baseline and angiotensin II-facilitated autoregulation were impaired, methacholine EC 50 was increased, and endothelium-derived hyperpolarizing factor (EDHF) activity was preserved in B60 kidneys. Increasing angiotensin II concentration restored autoregulation and increased renal vascular resistance (RVR) in B60 kidneys this facilitated autoregulation, and the increase in RVR was abolished by 100 μM furosemide. Autoregulation was enhanced by N ω -nitro-l-arginine methyl ester. Peri-ischemic inhibition of inducible NOS ameliorated renal failure but did not prevent endothelial dysfunction or impaired autoregulation. There was no significant structural injury to the afferent arterioles with ischemia. These results suggest that tubuloglomerular feedback is preserved in IARF but that excess NO and probably EDHF produce endothelial dysfunction and antagonize autoregulation. The threshold for injury-producing, detectable endothelial dysfunction was higher than for the loss of glomerular filtration rate. Arteriolar endothelial dysfunction after prolonged IARF is predominantly functional rather than structural.
Publisher: Springer Science and Business Media LLC
Date: 08-02-2003
DOI: 10.1007/S00134-003-1641-2
Abstract: To evaluate the protection afforded by trans-sodium crocetinate against dysoxia in an animal model of recurrent sub-diaphragmatic ischaemia. Prospective experimental animal study. University research laboratory Adult male Sprague-Dawley rats. Twelve adult male Sprague-Dawley rats (340-510 g) were anaesthetised with sodium pentobarbitone 60 mg/kg i.p. and ventilated with oxygen and isoflurane via tracheostomy. Six 2-min episodes of sub-diaphragmatic hypotension (mean pressure 30 mmHg) were induced using a sling around the proximal aorta. Before the third and sixth episodes, saline 1.5 ml/kg was injected into the aortic cannula. In six rats, this saline contained trans-sodium crocetinate 50 microg/ml. Ileal luminal PCO(2) and distal aortic pressure were monitored continuously. Following ischaemic episodes trans-sodium crocetinate had no discernible effect on either degree of PCO(2) elevation or the time to peak PCO(2). No effects on renal energy charge or nucleotide concentrations were detected. UV-visible spectroscopy of the crocetinate preparation showed that some cis isomer was present. The findings, although limited to one drug dosage in one animal model, bring into question whether trans-sodium crocetinate affects plasma oxygen diffusivity in vivo. Alternative explanations for the negative findings include a TSC-induced exacerbation of arterio-venous oxygen shunting, the brevity of the dysoxic episodes, and the presence of cis isomer.
Publisher: Elsevier BV
Date: 07-1995
Publisher: Wiley
Date: 28-07-2015
DOI: 10.1111/IMJ.12826
Publisher: Elsevier BV
Date: 10-2000
Publisher: Springer Science and Business Media LLC
Date: 2010
DOI: 10.1186/CC9014
Publisher: Springer Science and Business Media LLC
Date: 10-02-2005
DOI: 10.1007/S00134-005-2558-8
Abstract: Few comparative data exist on the responses of the subcutaneous and splanchnic circulations to evolving endotoxic shock. We therefore compared continuous subcutaneous pO(2) (pO(2sc)) and pCO(2) (pCO(2sc)) with simultaneous continuous gut luminal pCO(2) (pCO(2gi)) in an animal model of endotoxaemia and examined whether changes in gas tensions track tissue energy charge (EC). Prospective observational study. Fourteen anaesthetized rats, 7 controls and 7 experimental. Controls were injected with saline, the experimental group with 20 mg/kg Klebsiella endotoxin. pCO(2sc), pO(2sc), and pCO(2gi) were measured continuously. Plasma lactate concentrations were measured at defined periods during the study. After 2 h ileal segments were snap frozen and assayed for tissue EC. Endotoxaemia resulted in a significant decrease in mean arterial blood pressure (132+/-9 to 71+/-20 mmHg) and pO(2sc) (71+/-23 to 33+/-22 torr) and a significant increase in pCO(2gi) (58+/-10 to 90+/-20 torr) and pCO(2sc) (56+/-6 to 81+/-25 torr). During endotoxaemia pCO(2gi) was directly correlated with pCO(2sc) (R (2)=0.5) and inversely correlated with pO(2sc) (R (2)=0.63). Plasma lactate concentrations were significantly elevated from baseline in the endotoxin limb. The mean EC was not significantly different in the two groups. Both subcutaneous tissue gas tensions and intestinal luminal carbon dioxide tensions are rapidly responsive during evolving hypodynamic endotoxic shock. Alterations in tissue gas tensions were not associated with dysoxia.
Publisher: Springer Science and Business Media LLC
Date: 09-1992
DOI: 10.1007/BF00873994
Publisher: Elsevier BV
Date: 03-2007
Publisher: American Physiological Society
Date: 06-2008
DOI: 10.1152/AJPRENAL.00426.2007
Abstract: A transient 1D mathematical model of whole-organ renal autoregulation in the rat is presented, examining the myogenic response on multiple levels of the renal vasculature. Morphological data derived from micro-CT imaging were employed to ide the vasculature via a Strahler ordering scheme. A previously published model of the myogenic response based on wall tension is expanded and adapted to fit the response of each level, corresponding to a distally dominant resistance distribution with the highest contributions localized to the afferent arterioles and interlobular arteries. The mathematical model was further developed to include the effects of in vivo viscosity variation and flow-induced dilation via endothelial nitric oxide production. Computer simulations of the autoregulatory response to pressure perturbations were examined and compared with experimental data. The model supports the hypothesis that change in circumferential wall tension is the catalyst for the myogenic response. The model provides a basis for examining the steady state and transient characteristics of the whole-organ renal myogenic response in the rat, as well as the modulatory influences of metabolic and hemodynamic factors.
Publisher: Elsevier BV
Date: 07-2005
Publisher: Elsevier
Date: 2013
Publisher: IEEE
Date: 08-2007
Publisher: Elsevier BV
Date: 11-2002
Publisher: Elsevier BV
Date: 08-2010
DOI: 10.1038/LABINVEST.2010.96
Abstract: The effect of diabetes mellitus vs the effect of the Ren2 gene on the glomerular pathology of (mREN-2)27 heterozygous male rats is controversial. As discrete diabetes-induced glomerular lesions may have been overlooked, we performed a detailed morphometric analysis of glomeruli in diabetic and non-diabetic heterozygous male (mREN-2)27 rats and their normotensive (non-diabetic and diabetic Sprague-Dawley) controls. Glomeruli were scored by light microscopy for nine discrete histological parameters, some of which were graded for extent and/or severity. Mesangiolysis, segmental hypocellularity, and severe tuft-to-capsule adhesions were specific to diabetes severe mesangial matrix expansion, glomerulosclerosis, thickening of Bowman's capsule, and dilatation of the urinary space were specific to the Ren2 gene. Hyalinosis and hypercellularity were associated with both diabetes and the Ren2 gene: the effect was additive for hyalinosis and synergistic for hypercellularity. The histological parameters were then combined with two physiological indices (systolic blood pressure and proteinuria) and principle components analysis (PCA) was used to detect correlations between the variables. Four discrete patterns of pathology were identified three were statistically associated with diabetes and/or the Ren2 gene. These findings suggest that both diabetes and the Ren2 gene make significant, albeit different, contributions to the glomerular pathology of diabetic heterozygous male (mREN-2)27 rats. Despite defining the contribution of diabetes, our work does not support the (mREN-2)27 rat as a model of diabetic nephropathy (DN). Rather, it suggests that these animals remain useful for investigating a particular and limited constellation of DN features.
Publisher: Springer Science and Business Media LLC
Date: 2013
DOI: 10.1186/CC11931
Publisher: Springer Science and Business Media LLC
Date: 28-10-2014
Abstract: FDA approval of the first device to use novel biomarkers of kidney damage to assess risk of acute kidney injury (AKI) potentially brings forward diagnosis of moderate-to-severe AKI to a time frame that could enable early intervention. Although the device awaits greater scrutiny, its approval marks the beginning of a new era.
Publisher: Public Library of Science (PLoS)
Date: 11-06-2014
Publisher: Frontiers Media SA
Date: 28-07-2015
DOI: 10.1111/TRI.12636
Abstract: Early prediction of delayed graft function (DGF) after kidney transplantation would facilitate patient management. Cell cycle arrest and inflammation are implicated in the pathogenesis of DGF. We assessed the utility of two novel acute kidney injury (AKI) biomarkers, urinary tissue inhibitor of metalloproteinases-2 (TIMP-2) and insulin-like growth factor-binding protein 7 (IGFBP7), and five inflammatory markers to predict DGF following deceased-donor kidney transplantation. Serial urine concentrations of TIMP-2 and IGFBP7 were measured immediately after transplantation in 56 recipients along with vascular endothelial growth factor-A (VEGF-A), macrophage migration inhibitory factor (MIF), monocyte chemotactic protein-1 (MCP-1), trefoil factor 3 (TFF3) and chemokine (C-X-C) ligand 16 (CXCL16). Delayed graft function (DGF) was defined as requirement for dialysis within 7 days. Integrated discrimination improvement analysis was used to evaluate whether these biomarkers enhanced prediction of DGF independently of a validated clinical risk prediction model. DGF occurred in 22 patients (39%). At 4 h after kidney reperfusion, the area under the receiver operator characteristic curve (AUC) for VEGF-A was good (AUC > 0.80) for TIMP-2, IGFBP7 and [TIMP-2] × [IGFBP7] fair (AUCs 0.70-0.79) and for MIF, MCP-1, TFF3 and CXCL16 poor (AUC < 0.70). Only TIMP-2 and VEGF significantly enhanced the DGF prediction at 4 and 12 h. The cell cycle arrest marker urinary TIMP-2 and the inflammatory biomarker VEGF-A are potentially useful adjuncts to clinical data for early prediction of DGF.
Publisher: Wiley
Date: 08-1989
Abstract: Sodium and water spectra were acquired from the isolated perfused rat kidney by using a double-tuned probe designed to have high X nucleus sensitivity and low 1H sensitivity. Both DyTTHA and DyPPP were used to distinguish intra and extracellular 23Na resonances before and after the onset of hypoxia. Only DyPPP was useful in separating the two compartments, with a maximal chemical shift difference produced at a concentration of 4.5 mM. Both shift reagents were nephrotoxic at concentrations under 5 mM and produced an immediate decrease in renal-concentrating capacity and increases in fractional sodium and potassium excretion and increased renal vascular resistance. These disturbances of renal physiological parameters were accompanied by progressive broadening of the renal H2O resonance. 1H NMR may be a subtle means of monitoring nephrotoxicity.
Publisher: Wiley
Date: 2003
DOI: 10.1002/PATH.1368
Abstract: Caveolae and their proteins, the caveolins, transport macromolecules compartmentalize signalling molecules and are involved in various repair processes. There is little information regarding their role in the pathogenesis of significant renal syndromes such as acute renal failure (ARF). In this study, an in vivo rat model of 30 min bilateral renal ischaemia followed by reperfusion times from 4 h to 1 week was used to map the temporal and spatial association between caveolin-1 and tubular epithelial damage (desquamation, apoptosis, necrosis). An in vitro model of ischaemic ARF was also studied, where cultured renal tubular epithelial cells or arterial endothelial cells were subjected to injury initiators modelled on ischaemia-reperfusion (hypoxia, serum deprivation, free radical damage or hypoxia-hyperoxia). Expression of caveolin proteins was investigated using immunohistochemistry, immunoelectron microscopy, and immunoblots of whole cell, membrane or cytosol protein extracts. In vivo, healthy kidney had abundant caveolin-1 in vascular endothelial cells and also some expression in membrane surfaces of distal tubular epithelium. In the kidneys of ARF animals, punctate cytoplasmic localization of caveolin-1 was identified, with high intensity expression in injured proximal tubules that were losing basement membrane adhesion or were apoptotic, 24 h to 4 days after ischaemia-reperfusion. Western immunoblots indicated a marked increase in caveolin-1 expression in the cortex where some proximal tubular injury was located. In vitro, the main treatment-induced change in both cell types was translocation of caveolin-1 from the original plasma membrane site into membrane-associated sites in the cytoplasm. Overall, expression levels did not alter for whole cell extracts and the protein remained membrane-bound, as indicated by cell fractionation analyses. Caveolin-1 was also found to localize intensely within apoptotic cells. The results are indicative of a role for caveolin-1 in ARF-induced renal injury. Whether it functions for cell repair or death remains to be elucidated.
Publisher: Elsevier BV
Date: 07-1985
DOI: 10.1038/KI.1985.110
Abstract: High resolution 1H-NMR spectra were obtained from renal cortical slices, homogenates, isolated cells in suspension, and lysates. Experimental conditions for acquisition of high resolution spin-echo spectra are described and assignments of prominent peaks to various metabolites are given. The in situ activity of the highly active cortical enzyme prolidase was determined (1.8 nmoles/min/mg wet kidney wt) by exploiting the marked difference in the spectral features of glycyl-L-proline and that of the free amino acids. The results suggest that this NMR method will be applicable generally to the study of hydrolysis of peptides, as well as to other metabolic processes both in vitro and in vivo.
Publisher: Wiley
Date: 03-03-2008
Publisher: SAGE Publications
Date: 05-11-2012
Abstract: It is well known that plasma creatinine concentration is affected by muscle mass, while some studies have suggested cystatin C is affected by body mass index (BMI). Our aim was to assess the effects of lean versus fat mass on cystatin C and creatinine derivative equations in estimating glomerular filtration rate (GFR) in healthy young men. Three groups of participants were studied: those classified as normal (BMI 18-25 kg/m 2 with body fat, 30%) muscular subjects (BMI .30 kg/m 2 and body fat, 20%) and obese subjects (BMI .30 kg/m 2 and body fat .30%). All underwent diethylenetriamine pentaacetic acid GFR, bio-electrical impedance and dual-energy X-ray absorptiometry body composition analysis, measurement of plasma cystatin C, creatinine and high-sensitivity C-reactive protein and completed a diet record. Cystatin C was highest in the obese group (0.77 mg/L 95% confidence intervals [CI] 0.69-0.77) and creatinine was highest in the muscular group (90.1 μmol/L 95% CI 84.3-96.0). On multivariate analysis, body fat and GFR (P = 0.003) were significant determinants of cystatin C muscle mass and age affected creatinine significantly (P = 0.02). Using cystatin C equations, Le Bricon and Hoek showed significantly lower estimated GFR in the obese group but performed reasonably well within 50%, 30% and 20% of GFR. Creatinine equations showed significant underestimations of GFR for the muscular group. Body fat is a significant determinant of cystatin C while creatinine concentration is highly affected by muscle mass and age. Body composition plays an important role in the interpretation of renal function. Cystatin C equations are still accurate in predicting GFR in our healthy male group without chronic kidney disease.
Publisher: Informa UK Limited
Date: 2003
Abstract: Acute renal failure commonly follows reduced renal perfusion or ischemia. Reperfusion is essential for recovery but can itself cause functional and structural injury to the kidney. The separate contributions of ischemia and of reperfusion were examined in the isolated perfused rat kidney. Three groups were studied: brief (5 min) ischemia, 20 min ischemia, and repetitive brief ischemia (4 periods of 5 min) with repetitive intervening reperfusion of 5 min. A control group had no intervention, the three ischemia groups were given a baseline perfusion of 30 min before intervention and all groups were perfused for a total of 80 min. In addition, the effects of exogenous *NO from sodium nitroprusside and xanthine oxidase inhibition by allopurinol were assessed in the repetitive brief ischemia-reperfusion model. Brief ischemia produced minimal morphological injury with near normal functional recovery. Repetitive brief ischemia-reperfusion caused less functional and morphological injury than an equivalent single period of ischemia (20 min) suggesting that intermittent reperfusion is less injurious than ischemia alone over the time course of study. Pretreatment with allopurinol improved renal function after repetitive brief ischemia-reperfusion compared with the allopurinol-untreated repetitive brief ischemia-reperfusion group. Similarly, sodium nitroprusside reduced renal vascular resistance but did not improve the glomerular filtration rate or sodium reabsorption in the repetitive brief ischemia-reperfusion model. Thus, these studies show that the duration of uninterrupted ischemia is more critical than reperfusion in determining the extent of renal ischemia-reperfusion injury and that allopurinol, in particular, counteracts the oxidative stress of reperfusion.
Publisher: Wiley
Date: 06-02-2008
DOI: 10.1111/J.1440-1797.2007.00905.X
Abstract: Acute kidney injury (AKI) has recently become the preferred term to describe the syndrome of acute renal failure (ARF) with 'failure' or 'ARF' restricted to patients who have AKI and need renal replacement therapy.(1) This allows capture of the broader clinical spectrum of modest reductions in creatinine, which are themselves known to be associated with major increases in both short- and long-term mortality risk.(2-5) It is hoped that this change in nomenclature will facilitate an expansion of our understanding of the underlying pathophysiology and also facilitate definitions of AKI, which allow comparisons among clinical trials of patients with similar duration and severity of illness. This review will cover the need for early detection of AKI and the role of urinary and plasma biomarkers, including enzymuria. The primary message is that use of existing criteria to diagnose AKI, namely elevation of the serum creatinine with or without oliguria, results in identification that is too late to allow successful intervention. New biomarkers are essential to change the dire prognosis of this common condition.
Publisher: Wiley
Date: 06-1999
DOI: 10.1046/J.1440-1711.1999.00826.X
Abstract: For the past decade, an attempt has been made by many research groups to define the roles of the growing number of Bcl-2 gene family proteins in the apoptotic process. The Bcl-2 family consists of pro-apoptotic (or cell death) and anti-apoptotic (or cell survival) genes and it is the balance in expression between these gene lineages that may determine the death or survival of a cell. The majority of studies have analysed the role/s of the Bcl-2 genes in cancer development. Equally important is their role in normal tissue development, homeostasis and non-cancer disease states. Bcl-2 is crucial for normal development in the kidney, with a deficiency in Bcl-2 producing such malformation that renal failure and death result. As a corollary, its role in renal disease states in the adult has been sought. Ischaemia is one of the most common causes of both acute and chronic renal failure. The section of the kidney that is most susceptible to ischaemic damage is the outer zone of the outer medulla. Within this zone the proximal tubules are most sensitive and often die by necrosis or desquamate. In the distal nephron, apoptosis is the more common form of cell death. Recent results from our laboratory have indicated that ischaemia-induced acute renal failure is associated with up-regulation of two anti-apoptotic Bcl-2 proteins (Bcl-2 and Bcl-XL) in the damaged distal tubule and occasional up-regulation of Bax in the proximal tubule. The distal tubule is a known reservoir for several growth factors important to renal growth and repair, such as insulin-like growth factor-1 (IGF-1) and epidermal growth factor (EGF). One of the likely possibilities for the anti-cell death action of the Bcl-2 genes is that the protected distal cells may be able to produce growth factors that have a further reparative or protective role via an autocrine mechanism in the distal segment and a paracrine mechanism in the proximal cells. Both EGF and IGF-1 are also up-regulated in the surviving distal tubules and are detected in the surviving proximal tubules, where these growth factors are not usually synthesized. As a result, we have been using in vitro methods to test: (i) the relative sensitivities of renal distal and proximal epithelial cell populations to injury caused by mechanisms known to act in ischaemia-reperfusion (ii) whether a Bcl-2 anti-apoptotic mechanism acts in these cells and (iii) whether an autocrine and/or paracrine growth factor mechanism is initiated. The following review discusses the background to these studies as well as some of our preliminary results.
Publisher: Public Library of Science (PLoS)
Date: 06-12-2021
DOI: 10.1371/JOURNAL.PNTD.0010011
Abstract: Hump-nosed pit viper (HNV Hypnale spp.) bites account for most venomous snakebites in Sri Lanka. Acute kidney injury (AKI) is the most serious systemic manifestation (1–10%) following HNV envenoming. We aimed to identify the value of functional and injury biomarkers in predicting the development of AKI early following HNV bites. We conducted a prospective cohort study of patients with confirmed HNV envenoming presenting to two large tertiary care hospitals in Sri Lanka. Demographics, bite details, clinical effects, complications and treatment data were collected prospectively. Blood and urine s les were collected from patients for coagulation and renal biomarker assays on admission, at 0-4h, 4-8h, 8-16h and 16-24h post-bite and daily until discharge. Follow-up s les were obtained 1 and 3 months post-discharge. Creatinine (sCr) and Cystatin C (sCysC) were measured in serum and kidney injury molecule-1 (uKIM-1), clusterin (uClu), albumin (uAlb), β2-microglobulin (uβ2M), cystatin C (uCysC), neutrophil gelatinase associated lipocalin (uNGAL), osteopontin (uOPN) and trefoil factor-3 (uTFF-3) were measured in urine. Definite HNV bites were based on serum venom specific enzyme immunoassay. Kidney Disease: Improving Global Outcomes (KDIGO) criteria were used to stage AKI. Two patients had chronic kidney disease at 3 month follow-up, both with pre-existing abnormal sCr, and one developed AKI following HNV envenoming. There were 52 patients with confirmed HNV envenoming median age 48y (Interquartile range [IQR]:40-59y) and 29 (56%) were male. Median time to admission was 1.87h (IQR:1–2.75h). Twelve patients (23%) developed AKI (AKI stage 1 = 7, AKI stage 2 = 1, AKI stage 3 = 4). Levels of five novel biomarkers, the functional marker serum Cystatin C and the damage markers urinary NGAL, cystatin C, β2-microglobulin and clusterin, were elevated in patients who developed moderate/severe acute kidney injury. sCysC performed the best at 0–4 h post-bite in predicting moderate to severe AKI (AUC-ROC 0.95 %CI:0.85–1.0) and no biomarker performed better than sCr at later time points. sCysC appears to be a better marker than sCr for early prediction of moderate to severe AKI following HNV envenoming.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-2009
DOI: 10.2215/CJN.00820209
Publisher: Elsevier BV
Date: 02-2014
DOI: 10.1016/J.TOXLET.2013.12.009
Abstract: Accidental or intentional ingestion of glyphosate surfactant-based herbicides, like Roundup(®), leads to nephrotoxicity as well as death. In this study, a panel of kidney injury biomarkers was evaluated in terms of suitability to detect acute kidney injury and dysfunction. The Roundup(®) intoxication model involved oral administration of glyphosate to rats at dose levels of 250, 500, 1200 and 2500 mg/kg. Urinary and plasma biomarker patterns were investigated at 8, 24 and 48 h after dosing. Biomarkers were quantified by absolute concentration by normalising to urine creatinine and by calculating the excretion rate. The diagnostic performances of each method in predicting of acute kidney injury were compared. By Receiver Operating Characteristic (ROC) analysis of the selected biomarkers, only urinary kidney injury molecule-1 (KIM-1) best predicted histological changes at 8h (best cut-off point>0.00029 μg/ml). Plasma creatinine performed better than other biomarkers at 24 h (best cut-off point>0.21 mg/dl). Urinary KIM-1 was the best early biomarker of kidney injury in this glyphosate-induced nephrotoxicity model.
Publisher: Wiley
Date: 12-2000
Publisher: Elsevier BV
Date: 10-2011
DOI: 10.1038/KI.2011.193
Abstract: Recent clinical trials of remote ischemic preconditioning offer hope that this well-validated experimental method of protecting tissues against ischemic injury will provide a more robust alternative to pharmaceutical prevention against cardiac and renal ischemic injury.
Publisher: Wiley
Date: 02-2005
DOI: 10.1111/J.1440-1797.2005.00363.X
Abstract: Interleukin (IL)-1beta, a pro-inflammatory macrophage-derived cytokine, is implicated as a key mediator of interstitial fibrosis and tubular loss or injury in progressive renal insufficiency. This study investigates some of the mechanisms of action of IL-1beta on the proximal tubule. Confluent cultures of primary human proximal tubule cells (PTC) were incubated in serum-free media supplemented with either IL-1beta (0-4 ng/mL), phorbol-12-myristate 13-acetate (PMA, protein kinase C activator) (6.25-100 nmol/L), or vehicle (control), together with a non-specific protein kinase C inhibitor (H7), a specific protein kinase C inhibitor (BIM-1), an anti-oxidant (NAC) or a NADPH oxidase inhibitor (AEBSF). Interleukin-1beta-treated PTC exhibited time-dependent increases in fibronectin secretion (ELISA), cell injury (LDH release) and reactive nitrogen species (RNS) release (Griess assay). Proximal tubule cell DNA synthesis (thymidine incorporation) was also significantly suppressed. The effects of IL-1beta, which were reproduced by incubation of PTC with PMA (6.25-100 nmol/L), were blocked by H7 but not by BIM-1. The anti-oxidant (4 mmol/L) partially blocked IL-1beta-induced fibronectin secretion by PTC, but did not affect IL-1beta-induced LDH release, RNS release or growth inhibition. The NADPH oxidase inhibitor (AEBSF) significantly attenuated all observed deleterious effects of IL-1beta on PTC. Interleukin-1beta directly induces proximal tubule injury, extracellular matrix production and impaired growth. The anti-oxidant, NAC, appears to ameliorate part of the fibrogenic effect of IL-1beta on PTC through mechanisms that do not significantly involve protein kinase C activation or nitric oxide release.
Publisher: American Physiological Society
Date: 10-2011
DOI: 10.1152/AJPRENAL.00448.2010
Abstract: Acute kidney injury (AKI) is a common and frequently fatal illness in critically ill patients. The reliance on daily measurements of serum creatinine as a surrogate of glomerular filtration rate (GFR) not only delays diagnosis and development of successful therapies but also hinders insight into the pathophysiology of human AKI. Measurement of GFR under non-steady-state conditions remains an elusive gold standard against which biomarkers of renal injury need to be judged. Approaches to the rapid (near real-time) measurement of GFR are explored. Even if real-time GFR was available, absent baseline information will always limit diagnosis of AKI based on GFR or serum creatinine to a detection of change. Biomarkers of renal cellular injury have provided new strategies to facilitate detection and early intervention in AKI. However, the diagnostic and predictive performance of urinary biomarkers of injury vary, depending on both the time after renal injury and on the preinjury GFR. Progress in understanding the role of each novel biomarker in the causal pathways of AKI promises to enhance their diagnostic potential. We predict that combining rapid measures of GFR with biomarkers of renal injury will yield substantive progress in the treatment of AKI.
Publisher: Elsevier BV
Date: 05-2006
Abstract: Administration of human recombinant erythropoietin (EPO) at time of acute ischemic renal injury (IRI) inhibits apoptosis, enhances tubular epithelial regeneration, and promotes renal functional recovery. The present study aimed to determine whether darbepoetin-alfa (DPO) exhibits comparable renoprotection to that afforded by EPO, whether pro or antiapoptotic Bcl-2 proteins are involved, and whether delayed administration of EPO or DPO 6 h following IRI ameliorates renal dysfunction. The model of IRI involved bilateral renal artery occlusion for 45 min in rats (N = 4 per group), followed by reperfusion for 1-7 days. Controls were sham-operated. Rats were treated at time of ischemia or sham operation (T0), or post-treated (6 h after the onset of reperfusion, T6) with EPO (5000 IU/kg), DPO (25 mug/kg), or appropriate vehicle by intraperitoneal injection. Renal function, structure, and immunohistochemistry for Bcl-2, Bcl-XL, and Bax were analyzed. DPO or EPO at T0 significantly abrogated renal dysfunction in IRI animals (serum creatinine for IRI 0.17 +/- 0.05 mmol/l vs DPO-IRI 0.08 +/- 0.03 mmol/l vs EPO-IRI 0.04 +/- 0.01 mmol/l, P = 0.01). Delayed administration of DPO or EPO (T6) also significantly abrogated subsequent renal dysfunction (serum creatinine for IRI 0.17 +/- 0.05 mmol/l vs DPO-IRI 0.06 +/- 0.01 mmol/l vs EPO-IRI 0.03 +/- 0.03 mmol/l, P = 0.01). There was also significantly decreased tissue injury (apoptosis, P < 0.05), decreased proapoptotic Bax, and increased regenerative capacity, especially in the outer stripe of the outer medulla, with DPO or EPO at T0 or T6. These results reaffirm the potential clinical application of DPO and EPO as novel renoprotective agents for patients at risk of ischemic acute renal failure or after having sustained an ischemic renal insult.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2009
Publisher: Elsevier BV
Date: 03-1984
DOI: 10.1016/0167-4889(84)90003-X
Abstract: The 1H spin-echo NMR signal litudes and intensities of low molecular weight solutes in the cytoplasm and extracellular fluid of suspensions of human erythrocytes were shown to depend on the osmotic pressure of the media. At low osmotic pressure (220 mosM/kg) freeze-thaw lysis of the cells resulted in signal enhancement which was greatest for extracellular molecules, but both intra- and extracellular species were almost equally enhanced at 580 mosM/kg. This effect is due to field gradients formed at cell boundaries as a result of differences in magnetic susceptibility between the medium and the cytoplasm. T2 values measured using the Carr-Purcell-Meiboom-Gill pulse sequence, with tau = 0.0003 s, depended little on cell volume and absolute changes in volume magnetic susceptibility were also small. The mean field gradients, calculated from data obtained on cell suspensions at different osmotic pressures, were in the range 0.25-1.98 G/cm and 0.89-2.09 G/cm for intra- and extracellular compartments, respectively. The maintenance of isotonicity of the extracellular fluid during metabolic studies of cell suspensions is important in order to avoid artefacts in the determination of metabolite concentrations when using the spin-echo technique. Conversely it may be possible to perform transport measurements using spin-echo NMR to monitor the cell volume changes which occur during the transmembrane migration of molecules.
Publisher: Wiley
Date: 03-12-2015
DOI: 10.1111/AJCO.12312
Abstract: In cancer patients receiving chemotherapy treatment, accurate assessment of kidney function is required. The aim of our study was to investigate whether the inclusion of cystatin C together with creatinine in prediction equations would improve the prediction of glomerular filtration rate (GFR). Plasma creatinine and cystatin C were analyzed in 155 patients (cancer, n = 80, kidney donors, n = 75) undergoing (99m) Technetium diethylenepentaacetic (Tc-DTPA) GFR clearance. Equations by the CKD-EPI (chronic kidney disease epidemiology) group (creatinine-, creatinine + cystatin C-, cystatin C-based, respectively) and Cockcroft-Gault were compared with Tc-DTPA GFR by difference plots, receiver operator characteristics curve analysis, root mean square error, chi-squared analysis and percentage concordance according to carboplatin dosage. Comparisons between two creatinine methodologies (enzymatic vs Jaffe) were also performed. In the overall group, the combination creatinine and cystatin C equation had 69% of results within 20% of GFR (P20), a sensitivity of 86.3% and a specificity of 73.1% to detect reduced GFR at <90 mL/min/1.73 m(2), and a concordance of 78%. In contrast, the traditional Cockcroft-Gault equation had a P20 of 38.0%, with a large underestimation to predict GFR, thereby accounting for approximately 45% of dosing discordance. No obvious differences were obtained when comparing the performance of equations using the two creatinine methodologies. The inclusion of cystatin C in the CKD-EPI equations improved the prediction of kidney function in the overall population, although probably not sufficiently for it to be favored over radioisotopic GFR for guiding chemotherapy. More research is warranted to further improve estimated GFR equations for these purposes.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 09-1997
DOI: 10.1097/00003246-199709000-00027
Abstract: To test the rapidity of a continuous PCO2 measurement system response to brief reductions in gut perfusion from transient episodes of graded aortic hypotension, and to investigate the relationship between the increase in ileal luminal PCO2 and mean aortic pressure during the episodes. Prospective, experimental animal study. University research laboratory. Adult male Sprague-Dawley rats, weighing 430 to 510 g. Five Sprague-Dawley rats were anesthetized with intraperitoneal sodium phenobarbital and ventilated with 100% oxygen via tracheostomy to a PaCO2 of 30 to 50 torr (4.0 to 6.7 kPa). Distal aortic pressure was monitored invasively, and a sensor was inserted into the ileal lumen. Luminal PCO2 measurements were recorded every 2 secs. Normal saline was infused at 3 mL/hr, and isoflurane was titrated to a mean aortic pressure of 80 to 100 mm Hg. In each rat, paired 2-min inductions of distal aortic hypotension were induced by digital elevation of an aortic silk sling above the celiac artery to as many as possible of the following pressures (mm Hg): 60, 50, 40, 30, 20, and 10. The experiment was stopped if instability of luminal PCO2 or hypotension persisted through the intervening 8-min recovery periods. One rat completed paired inductions of all six goal aortic pressures. Two rats completed five inductions. One rat completed four inductions, and one rat completed three inductions. The times to onset of luminal hypercapnia and to peak luminal hypercapnia were highly consistent and independent of the degree of hypotension. Onset of hypercapnia was usually detected < 1 min after aortic elevation, but peak luminal hypercapnia occurred approximately 1 min after release of the aortic sling. Regression analysis showed an inverse linear relationship between the maximum increase in luminal PCO2 above baseline and mean aortic pressure during induced hypotension (r2 = .6 p < .001). Continuous ileal luminal PCO2 measurement by the sensor is rapidly responsive to brief reductions in aortic pressure in a rat model. Maximum luminal PCO2 increase during such perturbations is inversely related to mean aortic pressure.
Publisher: Elsevier BV
Date: 06-2010
DOI: 10.1038/KI.2010.25
Abstract: We performed a double-blind placebo-controlled trial to study whether early treatment with erythropoietin could prevent the development of acute kidney injury in patients in two general intensive care units. As a guide for choosing the patients for treatment we measured urinary levels of two biomarkers, the proximal tubular brush border enzymes gamma-glutamyl transpeptidase and alkaline phosphatase. Randomization to either placebo or two doses of erythropoietin was triggered by an increase in the biomarker concentration product to levels above 46.3, with a primary outcome of relative average plasma creatinine increase from baseline over 4 to 7 days. Of 529 patients, 162 were randomized within an average of 3.5 h of a positive s le. There was no difference in the incidence of erythropoietin-specific adverse events or in the primary outcome between the placebo and treatment groups. The triggering biomarker concentration product selected patients with more severe illness and at greater risk of acute kidney injury, dialysis, or death however, the marker elevations were transient. Early intervention with high-dose erythropoietin was safe but did not alter the outcome. Although these two urine biomarkers facilitated our early intervention, their transient increase compromised effective triaging. Further, our study showed that a composite of these two biomarkers was insufficient for risk stratification in a patient population with a heterogeneous onset of injury.
Publisher: Oxford University Press (OUP)
Date: 28-03-2010
DOI: 10.1093/NDT/GFQ176
Abstract: Plasma cystatin C (pCysC) has been proposed as an alternative to plasma creatinine (pCr) as a measure of renal function. We compared the detection of functional change by both biomarkers in critically ill patients. pCysC and pCr were measured on admission to one of two intensive care units (ICU) and then daily over 7 days. Patients were classified according to the analyte that first increased by either ≥25 or ≥50% above the admission value. The proportion of patients in each class was compared using McNemar's chi-square test. Sustained acute kidney injury (AKI, a ≥50% increase in pCr from baseline for ≥24 h), dialysis and death within 30 days were recorded. The ability of pCysC and pCr on admission to predict sustained AKI, dialysis or death was assessed from the area under the receiver operator characteristic curve (AUC). Of 442 patients, 83 had a ≥50% increase in one analyte, 17 in both and 342 in neither. Comparable numbers for a ≥25% increase were 163 in one analyte, 45 in both and 234 in neither. pCysC increased prior to pCr more frequently than vice versa in both the cohort with a ≥50% increase (P < 0.0001) and with a ≥25% increase (P < 0.0001). pCysC predicted sustained AKI with an AUC of 0.80 [95% confidence interval (CI) = 0.71-0.88]. pCysC and pCr were similarly moderately predictive of death or dialysis with AUCs of 0.61 [95% CI = 0.53-0.68] and 0.60 [95% CI = 0.51-0.67], respectively. pCysC was an effective and earlier surrogate marker of decreased renal function than pCr in a general ICU population.
Publisher: Oxford University Press (OUP)
Date: 03-2003
DOI: 10.1093/NDT/18.3.543
Abstract: Early detection of acute tubular necrosis (ATN) could permit implementation of salvage therapies and improve patient outcomes in acute renal failure (ARF). The utility of single and combined measurements of urinary tubular enzymes in predicting ARF in critically ill patients has not been evaluated using the receiver-operating characteristic (ROC) plot method. In this prospective pilot study, 26 consecutive critically ill adult patients admitted to the intensive-care unit were studied. Urine s les were collected twice daily for up to 7 days. ARF was defined as an increase in plasma creatinine of > or = 50% and > or = 0.15 mmol/l. ROC plot analysis was applied to the tubular marker data to derive optimum cut-offs for ARF. Four of the 26 study subjects (15.4%) developed ARF. Indexed to urinary creatinine concentration, gamma glutamyl transpeptidase (gamma GT), alkaline phosphatase (AP), N-acetyl-glucosaminidase (NAG), and alpha- and pi-glutathione S-transferase (alpha- and pi-GST) but not lactate dehydrogenase (LDH) were higher in the ARF group on admission (P<0.05). gamma GT, and alpha- and pi-GST remained elevated at 24 h. The onset of ARF based on changes in plasma creatinine varied from 12 h to 4 days (median 36 h). ROC plot analysis showed that gamma GT, pi-GST, alpha-GST, AP and NAG had excellent discriminating power for ARF (AUC 0.950, 0.929, 0.893, 0.863 and 0.845, respectively). The discriminating strength of creatinine clearance, while lower, was still significant (AUC 0.796). Positive and negative predictive values for ARF on admission were 67/100% for gamma GT, 67/90% for AP, 60/95% for alpha-GST, and 67/100% for pi-GST indices. Positive and negative predictive values for ARF for creatinine clearance < or = 23 ml/min were 50 and 91%, respectively. Creatinine clearances tended to be lower in ARF than in non-ARF patients on admission (P=0.06) and were significantly lower (P=0.008) after 12 h. Plasma urea and fractional sodium excretion were unhelpful. Tubular enzymuria on admission to the ICU is useful in predicting ARF. The cheapness and wide availability of automated assays for gamma GT and AP suggests that estimation of these enzymes in random urine s les may be particularly useful for identifying patients at high risk of ARF.
Publisher: Public Library of Science (PLoS)
Date: 27-03-2015
Publisher: Dustri-Verlgag Dr. Karl Feistle
Date: 05-2013
DOI: 10.5414/CN107673
Publisher: S. Karger AG
Date: 1989
DOI: 10.1159/000185573
Publisher: MDPI AG
Date: 27-03-2023
DOI: 10.3390/IJMS24076290
Abstract: Mass spectrometry is a powerful technique for investigating renal pathologies and identifying biomarkers, and efficient protein extraction from kidney tissue is essential for bottom-up proteomic analyses. Detergent-based strategies aid cell lysis and protein solubilization but are poorly compatible with downstream protein digestion and liquid chromatography-coupled mass spectrometry, requiring additional purification and buffer-exchange steps. This study compares two well-established detergent-based methods for protein extraction (in-solution sodium deoxycholate (SDC) suspension trapping (S-Trap)) with the recently developed s le preparation by easy extraction and digestion (SPEED) method, which uses strong acid for denaturation. We compared the quantitative performance of each method using label-free mass spectrometry in both sheep kidney cortical tissue and plasma. In kidney tissue, SPEED quantified the most unique proteins (SPEED 1250 S-Trap 1202 SDC 1197). In plasma, S-Trap produced the most unique protein quantifications (S-Trap 150 SDC 148 SPEED 137). Protein quantifications were reproducible across biological replicates in both tissue (R2 = 0.85–0.90) and plasma (SPEED R2 = 0.84 SDC R2 = 0.76, S-Trap R2 = 0.65). Our data suggest SPEED as the optimal method for proteomic preparation in kidney tissue and S-Trap or SPEED as the optimal method for plasma, depending on whether a higher number of protein quantifications or greater reproducibility is desired.
Publisher: Oxford University Press (OUP)
Date: 02-2004
DOI: 10.1093/NDT/GFG547
Abstract: Erythropoietin (EPO) has recently been shown to exert important cytoprotective and anti-apoptotic effects in experimental brain injury and cisplatin-induced nephrotoxicity. The aim of the present study was to determine whether EPO administration is also renoprotective in both in vitro and in vivo models of ischaemic acute renal failure. Primary cultures of human proximal tubule cells (PTCs) were exposed to either vehicle or EPO (6.25-400 IU/ml) in the presence of hypoxia (1% O(2)), normoxia (21% O(2)) or hypoxia followed by normoxia for up to 24 h. The end-points evaluated included cell apoptosis (morphology and in situ end labelling [ISEL], viability [lactate dehydrogenase (LDH release)], cell proliferation [proliferating cell nuclear antigen (PCNA)] and DNA synthesis (thymidine incorporation). The effects of EPO pre-treatment (5000 U/kg) on renal morphology and function were also studied in rat models of unilateral and bilateral ischaemia-reperfusion (IR) injury. In the in vitro model, hypoxia (1% O(2)) induced a significant degree of PTC apoptosis, which was substantially reduced by co-incubation with EPO at 24 h (vehicle 2.5+/-0.5% vs 25 IU/ml EPO 1.8+/-0.4% vs 200 IU/ml EPO 0.9+/-0.2%, n = 9, P<0.05). At high concentrations (400 IU/ml), EPO also stimulated thymidine incorporation in cells exposed to hypoxia with or without subsequent normoxia. LDH release was not significantly affected. In the unilateral IR model, EPO pre-treatment significantly attenuated outer medullary thick ascending limb (TAL) apoptosis (EPO 2.2+/-1.0% of cells vs vehicle 6.5+/-2.2%, P<0.05, n = 5) and potentiated mitosis (EPO 1.1+/-0.3% vs vehicle 0.5+/-0.3%, respectively, P<0.05) within 24 h. EPO-treated rats exhibited enhanced PCNA staining within the proximal straight tubule (6.9+/-0.7% vs vehicle 2.4+/-0.5% vs sham 0.3+/-0.2%, P<0.05), proximal convoluted tubule (2.3+/-0.6% vs vehicle 1.1+/-0.3% vs sham 1.2+/-0.3%, P<0.05) and TAL (4.7+/-0.9% vs vehicle 0.6+/-0.3% vs sham 0.3+/-0.2%, P<0.05). The frequency of tubular profiles with luminal cast material was also reduced (32.0+/-1.6 vs vehicle 37.0+/-1.3%, P = 0.05). EPO-treated rats subjected to bilateral IR injury exhibited similar histological improvements to the unilateral IR injury model, as well as significantly lower peak plasma creatinine concentrations than their vehicle-treated controls (0.04+/-0.01 vs 0.21+/-0.08 mmol/l, respectively, P<0.05). EPO had no effect on renal function in sham-operated controls. The results suggest that, in addition to its well-known erythropoietic effects, EPO inhibits apoptotic cell death, enhances tubular epithelial regeneration and promotes renal functional recovery in hypoxic or ischaemic acute renal injury.
Publisher: S. Karger AG
Date: 1992
DOI: 10.1159/000173470
Abstract: We examined the effect of acutely lowering the colloid osmotic pressure by removing plasma (36.2 ± 3.1 ml/kg) and replacing it with Hartmann’s solution (93.0 ± 8.2 ml/kg) in 6 conscious merino sheep. The colloid osmotic pressure was reduced significantly (p 0.05) from 20.3 ± 0.9 to 8.5 ± 2.5 mm Hg 0 h after plasmapheresis and to 15.2 ± 0.8 mm Hg 20 h after treatment. The filtration fraction increased from 0.16 ± 0.02 to 0.27 ± 0.02 at 0 h (p 0.05 vs. control) and to 0.20 ± 0.02 at 20 h after treatment (p 0.05 vs. control). At 0 h after plasmapheresis there was an increase in both sodium excretion from 187 ± 69 to 459 ± 82 µmol · min sup -1 /sup (p 0.05) and in fractional sodium excretion from 1.6 ± 0.4 to 4.4 ± 1.0% (p 0.05). The results are consistent with the hypothesis that acute alteration of Starling forces produce clinically significant effects on both glomerular filtration and tubular reabsorption.
Publisher: Wiley
Date: 08-2014
DOI: 10.1111/IMJ.12479
Abstract: Understanding determinants of glomerular filtration rate (GFR) is important in aiding prediction and interpretation of kidney function. Body composition is known to affect GFR but is not included in current screening of kidney disease. We investigated the association between GFR and body composition in healthy young men with differing body mass but without known diabetes or kidney injury. Three groups were recruited: normal BMI (n = 22) with a body mass index (BMI) <25 kg/m(2) , muscular (n = 23) with BMI ≥30 kg/m(2) and bioelectrical impedance body fat ≤20% and obese (n = 22) with BMI ≥30 kg/m(2) and bioelectrical impedance body fat ≥30%. Dietary analyses, GFR clearance by (99m) Tc-DTPA, urine protein and body composition by dual-energy X-ray absorptiometry were measured in all participants. Linear and nonlinear associations of constituents of body composition with GFR were assessed. Muscular men had a higher GFR (mean 186.4 mL/min 95% CI 171.7-201.1) than normal BMI and obese groups (P = 0.0007). Urine protein and albumin excretion were not elevated in any participants. On multiple regression analysis (r(2) = 0.60), the variables with strong associations with GFR were age (P = 0.0009) and lean mass (P = 0.0001). Fat mass, protein intake and smoking status were not associated. Skeletal muscle mass correlated significantly with GFR in all subgroups. Age and lean mass were strong determinants of GFR. Estimates of GFR should therefore be indexed to an estimate of lean mass.
Publisher: S. Karger AG
Date: 1989
DOI: 10.1159/000173191
Abstract: sup /sup Rb, sup /sup Na and sup /sup P nuclear magnetic resonance (NMR) were used to monitor changes in renal cations and energetics during the induction of hypoxia in the isolated perfused rat kidney. The NMR-determined unidirectional Rb sup + /sup flux in normoxic kidneys was shown to be a good measure of net intracellular K sup + /sup influx in the perfused rat kidney model. The changes in sup /sup Rb, sup /sup Na and sup /sup P spectra following the induction of hypoxia are consistent with hypoxic depletion of intracellular adenosine triphosphate (ATP) and a subsequent decrease in Na-K-ATPase transport activity. The exponential rate constant for sup /sup Rb sup + /sup efflux measured during Rb sup + /sup uptake in normoxic kidneys (0.12 ± 0.01 min sup /sup ) was not significantly different to the rate constant for sup /sup Rb sup + /sup efflux during the induction of hypoxia (0.16+0.07 min sup -1 /sup ). We conclude that there is no direct effect of hypoxia on renal cellular membrane integrity and that renal cell sensitivity to hypoxia is due to an inability to sustain cellular ion gradients following depletion of intracellular ATP.
Publisher: Elsevier BV
Date: 23-02-1995
DOI: 10.1016/0304-4165(94)00141-J
Abstract: The difficulty in direct detection of oxygen-derived free radicals (OFR) in the intact kidney has left uncertain the role of OFR in renal hypoperfusion injury. Salicylate hydroxylation was used as a sensitive method of estimating the extent of production of highly reactive hydroxyl radicals in renal ischaemia-reperfusion injury in the intact rat kidney perfused with recirculating cell-free medium. The reaction products were detected and quantified by HPLC with electrochemical detection. Hydroxyl radicals were detected as 2,5-dihydroxybenzoic acid (2,5-DHBA). Ischaemia for 15 min followed by reperfusion for 15 min caused more than a twofold increase in 2,5-DHBA concentration (to 2279 +/- 225 pg/g tissue weight) compared to controls (933 +/- 103, P < 0.001). Addition of 15 mM dimethylthiourea (DMTU) before induction of ischaemia prevented this increase. Induction of hypoxia for 15 min with continued perfusion (as a model of low-flow ischaemia) had no significant effect on hydroxyl radical formation. We conclude that significant quantities of hydroxyl radicals form in the absence of circulating leucocytes during reperfusion following ischaemia, but not during hypoxia in the perfused rat kidney.
Publisher: Oxford University Press (OUP)
Date: 18-03-2011
DOI: 10.1093/NDT/GFR099
Publisher: S. Karger AG
Date: 03-12-2016
DOI: 10.1159/000452318
Abstract: Participation by nephrologists is needed in most intensive care units, even when such units are ‘closed'. This participation should assist with diagnosis and management of intrinsic and complex renal diseases such as vasculitis, complex metabolic and electrolyte disorders including hyponatremia, and acute kidney injury (AKI) with and without underlying chronic kidney disease (CKD). Early nephrologist involvement will also facilitate transition to continuing care and follow-up after an episode of AKI, but may also assist in avoiding dialysis where treatment is futile. Management of AKI by intensivists should be in partnership with nephrologists to oversight and hopefully to minimize progression to CKD.
Publisher: Elsevier BV
Date: 08-1986
DOI: 10.1016/0301-4622(86)85039-6
Abstract: Metabolically active human erythrocytes were incubated with [alpha-13C]glycine which led to the specific enrichment of intracellular glutathione. The cells were then studied using 13C-NMR in which the longitudinal relaxation times (T1) and nuclear Overhauser enhancements of the free glycine and glutathione were measured. The T1 values of labelled glycine were also determined in various-concentration solutions of bovine serum albumin and glycerol and also of the natural abundance 13C of glycerol in glycerol solutions. From the T1 estimates the rotational correlation time (tau r) was calculated using a formula based on a model of an isotropic spherical rotor or that of a symmetrical ellipsoidal rotor for glycine the differences in estimates of tau r obtained using the two models were not significant. From the correlation times and by use of the Stokes-Einstein equations viscosity and translational diffusion coefficients were calculated thus comment can be made on the likelihood of diffusion control of certain enzyme-catalysed reactions in the erythrocyte. Bulk viscosities of the erythrocyte cytoplasm and the above-mentioned solutions were measured using Ostwald capillary viscometry. Large differences existed between the latter viscosity estimates and those based upon NMR-T1 measurements. We derived an equation from the theory of the viscosity of concentrated solutions which contains two phenomenological interaction parameters, a 'shape' factor and a 'volume' factor it was fitted to data relating to the concentration dependence of viscosity measured by both methods. We showed, by using the equation and interaction-parameter estimates for a particular probe molecule in a particular solution, that it was possible to correlate NMR viscosity and bulk viscosity in other words, given an estimate of the bulk viscosity, it was possible to calculate the NMR 'micro' viscosity or vice versa. However, the values of the interaction parameters depend upon the relative sizes of the probe and solute molecules and must be separately determined for each probe-solute-solvent system. Under various conditions of extracellular osmotic pressure, erythrocytes change volume and thus the viscosity of the intracellular milieu is altered. The volume changes resulted in changes in the T1 of [alpha-13C]glycine. Conversely, we showed that alterations in T1, when appropriately calibrated, could be used for monitoring changes in volume of metabolically active cells.
Publisher: Elsevier BV
Date: 03-2014
DOI: 10.1016/J.TOXLET.2014.01.018
Abstract: For improved early detection and assessment of severe acute kidney damage following accidental or intentional ingestion of the herbicide MCPA, we compared a panel of 14 novel kidney injury biomarkers with plasma creatinine. Male Wistar rats received four different oral doses of MCPA and plasma and urine biomarker levels were measured at 8, 24 and 48 h after MCPA exposure. Diagnostic performances using absolute levels, urine levels normalized to urine creatinine or urinary excretion rate were determined by ROC analysis. Plasma creatinine remained the best early biomarker for predicting histological changes at 48 h. The performance of plasma cystatin C in mirroring kidney function was similar to that of plasma creatinine. While urine concentrations were generally less predictive, normalization by urine creatinine greatly improved the performance of several biomarkers. This may be due to an apparent lification of the biomarker signal on normalizing to creatinine, in the presence of a declining glomerular filtration rate prior to reaching steady state. Normalized 8 h osteopontin and albumin concentrations outperformed other normalized biomarkers in predicting histological changes at later times. Normalized urinary kidney injury molecule-1 at 48 h also correlated well with the degree of kidney damage.
Publisher: Springer Science and Business Media LLC
Date: 2012
DOI: 10.1186/CC11391
Publisher: Elsevier BV
Date: 09-2003
DOI: 10.1016/S0270-9295(03)00085-8
Abstract: Toxic nephropathies cause acute and chronic renal failure, primarily as a result of injury to renal tubular epithelium. There is a well-known capacity in the renal nephron for the synchronous occurrence of both apoptosis and necrosis in toxic nephropathies. This has engendered interest in the differing or complementary roles of these modes of cell death. Once thought to be mutually exclusive in incidence and morphologic and biochemical features, recent evidence in renal and other diseases indicates some blurring in the features of apoptosis and necrosis, particularly in the situations in which they are identified, in their molecular pathways, and in the role of inflammation in the processes. Definition of the heterogenic pathophysiologic response of the nephron should provide information useful for promoting the health of the kidney after injury, particularly in relation to controlling the extent and modalities of cell death via the associated renal-specific molecular features. This article indicates the significance and some problems of defining the types of cell death in toxic nephropathies.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 21-09-2021
Abstract: Acute decompensated heart failure (ADHF) is associated with deterioration in renal function—an important risk factor for poor outcomes. Whether ADHF results in permanent kidney damage/dysfunction is unknown. We investigated for the first time the renal responses to the development of, and recovery from, ADHF using an ovine model. ADHF development induced pronounced hemodynamic changes, neurohormonal activation, and decline in renal function, including decreased urine, sodium and urea excretion, and creatinine clearance. Following ADHF recovery (25 days), creatinine clearance reductions persisted. Kidney biopsies taken during ADHF and following recovery showed widespread mesangial cell prominence, early mild acute tubular injury, and medullary/interstitial fibrosis. Renal transcriptomes identified altered expression of 270 genes following ADHF development and 631 genes following recovery. A total of 47 genes remained altered post‐recovery. Pathway analysis suggested gene expression changes, driven by a network of inflammatory cytokines centered on IL‐1β (interleukin 1β), lead to repression of reno‐protective eNOS (endothelial nitric oxide synthase) signaling during ADHF development, and following recovery, activation of glomerulosclerosis and reno‐protective pathways and repression of proinflammatory/fibrotic pathways. A total of 31 dysregulated genes encoding proteins detectable in urine, serum, and plasma identified potential candidate markers for kidney repair (including CNGA3 [cyclic nucleotide gated channel subunit alpha 3] and OIT3 [oncoprotein induced transcript 3]) or long‐term renal impairment in ADHF (including ACTG2 [actin gamma 2, smooth muscle] and ANGPTL4 [angiopoietin like 4]). In an ovine model, we provide the first direct evidence that an episode of ADHF leads to an immediate decline in kidney function that failed to fully resolve after ≈4 weeks and is associated with persistent functional/structural kidney injury. We identified molecular pathways underlying kidney injury and repair in ADHF and highlighted 31 novel candidate biomarkers for acute kidney injury in this setting.
Publisher: Elsevier BV
Date: 10-2013
DOI: 10.1016/J.TOXLET.2013.08.003
Abstract: Paraquat is a widely used herbicide which has been involved in many accidental and intentional deaths. Nephrotoxicity is common in severe acute paraquat poisoning. We examined seven renal injury biomarkers, including cystatin-C, kidney injury molecule-1, β2-microglobulin, clusterin, albumin, neutrophil gelatinase-associated lipocalin and osteopontin, to develop a non-invasive method to detect early renal damage and dysfunction and to compare with the conventional endogenous marker creatinine. Male Wistar rats were dosed orally with four different doses of paraquat, and the biomarker patterns in urine and plasma were investigated at 8, 24 and 48h after paraquat exposure. By Receiver Operating Characteristic analysis, urinary kidney injury molecule-1 was the best marker at predicting histological changes, with areas under the Receiver Operating Characteristic curve of 0.81 and 0.98 at 8 and 24h (best cut-off value>0.000326μg/ml), respectively. Urinary kidney injury molecule-1, urinary albumin and urinary Cystatin-C elevations correlated with the degree of renal damage and injury development. Further study is required to compare biomarkers changes in rats with those seen in human poisoning.
Publisher: Elsevier BV
Date: 07-2002
DOI: 10.1046/J.1523-1755.2002.00401.X
Abstract: Tubulointerstitial lesions, characterized by tubular injury, interstitial fibrosis and the appearance of myofibroblasts, are the strongest predictors of the degree and progression of chronic renal failure. These lesions are typically preceded by macrophage infiltration of the tubulointerstitium, raising the possibility that these inflammatory cells promote progressive renal disease through fibrogenic actions on resident tubulointerstitial cells. The aim of the present study, therefore, was to investigate the potentially fibrogenic mechanisms of interleukin-1beta (IL-1beta), a macrophage-derived pro-inflammatory cytokine, on human proximal tubule cells (PTC). Confluent, quiescent, passage 2 PTC were established in primary culture from histologically normal segments of human renal cortex (N = 11) and then incubated in serum- and hormone-free media supplemented with either IL-1beta (0 to 4 ng/mL) or vehicle (control). IL-1beta significantly enhanced fibronectin secretion by up to fourfold in a time- and concentration-dependent fashion. This was accompanied by significant (2.5- to 6-fold) increases in alpha-smooth muscle actin (alpha-SMA) expression, transforming growth factor beta (TGF-beta1) secretion, nitric oxide (NO) production, NO synthase 2 (NOS2) mRNA and lactate dehydrogenase (LDH) release. Cell proliferation was dose-dependently suppressed by IL-1beta. NG-methyl-l-arginine (L-NMMA 1 mmol/L), a specific inhibitor of NOS, blocked NO production but did not alter basal or IL-1beta-stimulated fibronectin secretion. In contrast, a pan-specific TGF-beta neutralizing antibody significantly blocked the effects of IL-1beta on PTC fibronectin secretion (IL-1beta, 268.1 +/- 30.6 vs. IL-1beta+alphaTGF-beta 157.9 +/- 14.4%, of control values, P < 0.001) and DNA synthesis (IL-1beta 81.0 +/- 6.7% vs. IL-1beta+alphaTGF-beta 93.4 +/- 2.1%, of control values, P < 0.01). IL-1beta acts on human PTC to suppress cell proliferation, enhance fibronectin production and promote alpha-smooth muscle actin expression. These actions appear to be mediated by a TGF-beta1 dependent mechanism and are independent of nitric oxide release.
Publisher: Oxford University Press (OUP)
Date: 07-10-2009
DOI: 10.1093/NDT/GFP501
Abstract: The risk, injury, failure, loss-of-function, end-stage-renal-failure (RIFLE) and acute kidney injury network (AKIN) consensus definitions of acute kidney injury (AKI) were established in part to facilitate comparison of trials. Contrast-induced nephropathy (CIN) has traditionally used a less demanding definition. To review use of RIFLE and AKIN as AKI trial outcome variables and contrast these with outcomes for CIN. We conducted a search of PubMed from 1 January 2005 to 31 December 2008 and 9 trial registries for randomized control trials for preventional or interventional treatment of AKI and CIN. RIFLE or AKIN were outcome variables in 36% (n = 8) of the published (n = 22) and 18% (n = 4) of the current (n = 22) AKI trials. RIFLE was used to triage to intervention in three trials. The urine output definition of RIFLE and AKIN was an outcome in only two trials. In 18% (n = 8) of AKI trials, the CIN definition (increase in serum creatinine of > or =25% and/or > or =44 micromol/l) was the primary outcome. This was also the primary outcome in 56% (n = 13) of published (n = 12) and current (n = 11) CIN trials. Three published CIN trials used RIFLE or AKIN as an outcome (13%). The duration over which outcomes were determined varied from 24 h to 7 days. Considerable heterogeneity remains in outcome variables of AKI and CIN clinical trials. Even when the RIFLE or AKIN criteria were used, they were not applied consistently. There is a need for further consensus on surrogate outcome variables.
Publisher: Wiley
Date: 04-06-2007
Publisher: Springer Science and Business Media LLC
Date: 26-05-2012
DOI: 10.1007/S00467-012-2171-3
Abstract: Apart from supportive dialysis there are no universally accepted interventions in acute kidney injury (AKI). We have summarized the outcomes of all published randomized, placebo-controlled studies of non-dialysis treatment of AKI. Forty-nine trials were identified, only one of which was in a paediatric population. Sixteen trials had positive outcomes these trials are not comparable in terms of methodology used or outcomes assessed, and they share many of the problems of the negative trials. We discuss the flaws in clinical trial design that have contributed to poor or uncertain outcomes and propose minimum requirements for future trials. In particular, future trials should incorporate biomarkers specific to the etiology of the AKI, and treatment should match the phase of injury.
Publisher: Oxford University Press (OUP)
Date: 09-07-2015
DOI: 10.1093/ICVTS/IVV184
Abstract: Acute kidney injury is common following cardiac surgery. Experimental models of acute kidney injury suggest that successful therapy should be implemented within 24-48 h of renal injury. However, it is difficult to detect acute kidney injury shortly after cardiac surgery, because creatinine concentration is diluted by cardiopulmonary bypass. We hypothesized that, following cardiopulmonary bypass, creatinine reduction ratios would correlate with haematocrit reduction ratios and would be associated with the incidence of acute kidney injury. We collected demographic and blood test data from consecutive patients (n = 1137) who had undergone cardiac surgery with cardiopulmonary bypass. The creatinine reduction ratio was calculated as follows: (preoperative creatinine-postoperative creatinine) reoperative creatinine. Patients were assigned to either of two groups. The first group (Group 1) was used to determine the threshold for acute kidney injury, and the second group (Group 2) was used to assess diagnostic performance. Acute kidney injury was defined as an increase in serum creatinine level >0.3 mg/dl or >150% from baseline. The incidence of acute kidney injury was 14.5% (79/545) in Group 1 and 15.5% (92/592) in Group 2. Postoperatively, creatinine concentration correlated strongly with haematocrit concentration (Pearson's r(2): 0.91). In Group 1, the area under the receiver operating characteristic curve, sensitivity and specificity were 0.71, 64.1 and 66.4%, respectively, for creatinine reduction ratios of <20%. In Group 2, the odds ratio, positive predictive value, negative predictive value and relative risk for creatinine reduction ratio performance were 4.3 (95% confidence interval 2.6-7.0), 0.27 (0.21-0.32), 0.92 (0.89-0.95) and 3.42 (2.22-5.27), respectively. The creatinine reduction ratio may be associated with perioperative renal injury. Therefore, it is a good diagnostic indicator with high performance, and may be useful in detecting acute kidney injury at an earlier stage relative to conventional means. In addition, using creatinine reduction ratios in this manner is financially feasible.
Publisher: Informa UK Limited
Date: 23-05-2017
DOI: 10.1080/15563650.2017.1326607
Abstract: Acute kidney injury (AKI) is common following deliberate self-poisoning with a combination washing powder containing oxalic acid (H Multiple measures of change in kidney function were evaluated in 48 consenting patients who had serial sCr and serum cystatin C (sCysC) data available. Thirty-eight (38/48, 79%) patients developed AKI (AKIN criteria). Twenty-eight (58%) had AKIN stage 2 or 3. Initial increases in urine creatinine (uCr) excretion were followed by a substantial loss of renal function. The AKIN stage 2 and 3 (AKIN2/3) group had very rapid rises in sCr (a median of 118% at 24 h and by 400% at 72 h post ingestion). We excluded the possibility that the rapid rise resulted from the assay used or muscle damage. In contrast, the average sCysC increase was 65% by 72 h. In most AKI, sCysC increases to the same extent but more rapidly than sCr, as sCysC has a shorter half-life. This suggests either a reduction in Cystatin C production or, conversely, that the rapid early rise of sCr results from increased production of creatine and creatinine to meet energy demands following severe oxidative stress mediated by H
Publisher: S. Karger AG
Date: 1989
DOI: 10.1159/000173188
Publisher: Wiley
Date: 2004
DOI: 10.1002/CMR.A.20007
Publisher: Elsevier BV
Date: 10-1999
DOI: 10.1046/J.1523-1755.1999.00701.X
Abstract: A major contributor to the development and progression of ischemia-reperfusion (IR)-induced acute renal failure (ARF) is the loss of functioning tubular epithelial cells by means of various cell deletion or death processes. Although the term "acute tubular necrosis" is still used to describe the pathology of ARF, this is a misnomer because apoptotic cell death, as well as necrosis, occurs [1, 2] along with desquamation and loss of viable epithelial cells [3]. Apoptosis was first described in renal disease in 1987 in an animal model of hydronephrosis [4]. In ARF, with reference to only the death processes, the relative contribution of necrosis or apoptosis possibly depends on the extent of the initiating events. For ex le, after prolonged total renal ischemia, necrosis or "accidental cell death" occurs from the resultant negation of the cell's energy and protein levels. In apoptosis, the cells use their own energy processes and proteins to die, and often the initiating ischemia is more mild [5]. Finally, despite prolonged ischemia, within the heterogeneous renal cell populations there are those that are more sensitive to ischemia, such as the proximal straight tubule and to some extent the thick ascending limb (TAL) of the loop of Henle. It may be hypothesized that these cells tend to undergo necrosis in comparison with the less sensitive segments that undergo apoptosis. Because apoptosis is gene driven, its identification is important because of the possibility of its modulation via molecular controls. However, despite these new concepts of ARF, patient death remains high, at approximately 30 to 50% of ARF cases. Recovery from ARF depends not only on the replacement or regeneration of cells deleted by death, the theme of many recent studies, but also on protection of cells from death. Both processes are dependent on many of the cellular and molecular controls that have evolved in multicellular organisms to manage normal development, differentiation and growth processes, but that then become involved in the pathogenesis and progression of many renal diseases, including ARF.
Publisher: Wiley
Date: 03-1993
Abstract: Biomedical NMR experiments rely frequently on data obtained sequentially over time. A method is presented for analysis of time based NMR data, which allows modelling of continuous and discontinuous functions to observed intensity changes by non-linear regression and which uses variance ratio analysis to compare these models statistically. The method eliminates many of the usual problems in the parametric analysis of experimental values obtained at discrete time points and of comparison of the coefficients of model functions which require unsubstantiated assumptions about the distribution of parameters and ignore internal correlations which may exist between such parameters. The variance ratio method is illustrated for multiple time courses obtained with 23Na NMR of perfused rat kidney undergoing hypoxic perturbation in the presence of different treatments.
Publisher: Elsevier BV
Date: 05-2001
DOI: 10.1046/J.1523-1755.2001.0590051779.X
Abstract: The molecular pathogenesis of different sensitivities of the renal proximal and distal tubular cell populations to ischemic injury, including ischemia-reperfusion (IR)-induced oxidative stress, is not well-defined. An in vitro model of oxidative stress was used to compare the survival of distal [Madin-Darby canine kidney (MDCK)] and proximal [human kidney-2 (HK-2)] renal tubular epithelial cells, and to analyze for links between induced cell death and expression and localization of selected members of the Bcl-2 gene family (anti-apoptotic Bcl-2 and Bcl-X(L), pro-apoptotic Bax and Bad). Cells were treated with 1 mmol/L hydrogen peroxide (H2O2) or were grown in control medium for 24 hours. Cell death (apoptosis) was quantitated using defined morphological criteria. DNA gel electrophoresis was used for biochemical identification. Protein expression levels and cellular localization of the selected Bcl-2 family proteins were analyzed (Western immunoblots, densitometry, immunoelectron microscopy). Apoptosis was minimal in control cultures and was greatest in treated proximal cell cultures (16.93 +/- 4.18% apoptosis) compared with treated distal cell cultures (2.28 +/- 0.85% apoptosis, P 0.05) in these cells. Bcl-2, Bax, and Bcl-X(L), but not Bad, were endogenously expressed in control proximal cells. Bcl-X(L) was significantly decreased in treated proximal cultures (P 0.05). Immunoelectron microscopy localization indicated that control and treated but surviving proximal cells had similar cytosolic and membrane localization of the Bcl-2 proteins. In comparison, surviving cells in the treated distal cultures showed translocation of Bcl-X(L) from cytosol to the mitochondria after treatment with H2O2, a result that was confirmed using cell fractionation and analysis of Bcl-X(L) expression levels of the membrane and cytosol proteins. Bax remained distributed evenly throughout the surviving distal cells, without particular attachment to any cellular organelle. The results indicate that in this in vitro model, the increased survival of distal compared with proximal tubular cells after oxidative stress is best explained by the decreased expression of anti-apoptotic Bcl-X(L) in proximal cells, as well as translocation of Bcl-X(L) protein to mitochondria within the surviving distal cells.
Publisher: Elsevier BV
Date: 10-2013
DOI: 10.1038/KI.2013.168
Abstract: Assessment of acute kidney biomarkers against changes in plasma creatinine is beset by issues of heterogeneity of study cohorts and timing of s ling. Siew and colleagues attempt to minimize these issues in a case-control study of three biomarkers in the intensive care unit. The results highlight the inherent methodological difficulties and the need to reference structural injury biomarkers against more meaningful outcomes.
Publisher: Elsevier BV
Date: 04-2009
Publisher: Wiley
Date: 21-04-2014
DOI: 10.1111/NEP.12220
Publisher: Informa UK Limited
Date: 07-09-2015
DOI: 10.1517/17425255.2015.1083011
Abstract: This article addresses general biomarkers of drug-induced acute kidney injury (AKI) and their application in development and progression of AKI in the adult. It also highlights some clinical benefits, but also uncertainties, of biomarker use. Drug-induced AKI is traditionally diagnosed by monitoring serum creatinine (SCr), blood urea nitrogen and albuminuria. The sensitivity of these measures is, however, limited to well-established AKI. Application of selected biomarkers for early diagnosis of drug-induced AKI may inform on progression of AKI and alert clinicians to adopt renoprotective strategies at the earliest times. Novel biomarkers, accepted for early detection of drug-induced AKI (kidney injury molecule-1, neutrophil gelatinase-associated lipocalin and N-acetyl-β-d-glucosaminidase), may be useful additions in panels of biomarkers. Clinical biomarkers of cell cycle arrest, tissue inhibitor of metalloproteinase-2 and insulin-like growth factor binding protein 7 show promise but need further validation in clinical trials. Traditional parameters, such as SCr, provide some guidance for functional decline in drug-induced AKI but early, more sensitive, affordable, clinically acceptable, biomarkers of kidney dysfunction are needed. Basic biological understanding of AKI will improve with high-throughput methodologies such as proteomics and metabolomics, and this should lead to identification and usage of novel biomarkers. Ultimately, a combination of biomarkers indicating kidney dysfunction and damage is likely to be required.
Publisher: Elsevier BV
Date: 2011
Publisher: Oxford University Press (OUP)
Date: 10-1989
Abstract: Skin cancer was found in 31 of 598 patients transplanted in Oxford. No cases occurred during the first 3 years after transplantation but the prevalence rose after 12 years to 18.2 per cent. The main risk factors predisposing to skin cancer were the time after transplantation and male sex. Comparison with data from other centres suggests that exposure to ultraviolet light is a major aetiological factor in the speed of development of skin cancer. As the incidence of new cases rose progressively with time in our patients, it would seem that skin cancer is likely to become a major clinical problem as more patients enjoy prolonged survival after renal transplantation. Preventative and screening measures should be taken by transplant units both in the UK and in other countries with similar temperate climates.
Publisher: Springer Science and Business Media LLC
Date: 2013
DOI: 10.1186/CC12784
Publisher: Oxford University Press (OUP)
Date: 06-2009
DOI: 10.1373/CLINCHEM.2008.121673
Abstract: Background: Urine amino-terminal probrain natriuretic peptide (NT-proBNP) concentrations may exclude the presence of heart failure and provide insight into renal clearance mechanisms for human NT-proBNP. We characterized the molecular forms of urine NT-proBNP detected by immunoassay. Methods: Urine from patients with heart failure was subjected to HPLC and analyzed using immunoassays specific toward different epitopes of NT-proBNP. We assessed urine NT-proBNP immunoreactivity in healthy subjects and patients with heart failure. Results: Size-exclusion chromatography of heart failure urine identified no NT-proBNP immunoreactivity coeluting with NT-proBNP(1–76) multiple immunoreactive NT-proBNP fragments were present. The absence of intact urinary NT-proBNP was supported by reversed-phase HPLC. Urine NT-proBNP immunoreactivity was higher in patients with acute [median 192 (interquartile range 108–1445) pg/mg creatinine] and chronic [52 (15–118) pg/mg creatinine] heart failure than in healthy subjects [4.2 (2.6–5.8) pg/mg creatinine] (P & 0.001). In 40 patients with heart failure, urine NT-proBNP immunoreactivity correlated with plasma NT-proBNP (r = 0.72, P & 0.001) and inversely with left ventricular ejection fraction (r = −0.33, P = 0.04). Conclusions: Our findings clarify previous reported relationships of urine NT-proBNP–like immunoreactivity with plasma NT-proBNP concentrations and the diagnosis of heart failure. As urine NT-proBNP immunoreactivity is not intact NT-proBNP(1–76), but rather reflects assorted metabolites, the diagnostic performance of NT-proBNP assays in urine may be assay specific, necessitating validation of biomarker performance on an assay-by-assay basis. .
Publisher: Elsevier BV
Date: 06-2012
DOI: 10.1038/KI.2012.23
Publisher: Elsevier BV
Date: 1996
DOI: 10.1016/0167-4889(95)00141-7
Abstract: Glycine-serine interconversion is important to numerous metabolic processes and serine release by the kidney. Incubation of freshly isolated rat renal proximal tubules with 5 mM glycine 75% 13C-labelled in the 2-position resulted in 13C-labelled incorporation into serine of 69 micromol.g protein(-1) (+/- 14, n = 16) at 20 min. Addition of 5 mM glucose, 4 mM lactate, 1 mM alanine, 1 mM butyrate and 1 mM glutamate increased 13C-label incorporation into serine to 173 micromol.g protein(-1) (+/- 32, n = 4) at 60 min, 50% greater than tubules incubated with 5 mM glycine alone (P < 0.05). The increase was prevented by hypoxia. Reoxygenation for 20 min restored the rate of incorporation of 13C-label into serine. The fraction of unlabelled serine remained approximately 47% at 20, 40 and 60 min in each group. The results indicate that in the presence of oxygen, TCA and glycolytic intermediates stimulate serine synthesis via the glycine cleavage complex and serine hydroxymethyltransferase pathways and not the phosphorylated pathway. In addition, significant serine production occurs from an unidentified source, which is also tightly coupled to glycine metabolism. Both in the presence and absence of added TCA and glycolytic intermediates, glycine was the principle source of the methylene group in methylene tetrahydrofolate.
Publisher: Elsevier BV
Date: 07-2013
Publisher: Future Medicine Ltd
Date: 12-2014
DOI: 10.2217/BMM.14.86
Abstract: Over 35 years of use has demonstrated the revolutionary therapeutic benefits of calcineurin inhibitors (CNI) in not only preventing transplant rejection, but also the renal and nonrenal toxicity of CNI. Acute reversible and insidious irreversible forms of CNI nephrotoxicity have been identified, with ischemia from an imbalance between vasoconstrictors and vasodilators playing an important role. The ongoing search to define toxicity pathways has been enriched by ‘Omics’ studies. Changes in proteins including those involved in activation of pro-inflammatory responses, oxidative stress, ER stress and the unfolded protein response have been identified, and these may serve as biomarkers of toxicity. However, the current standard of CNI toxicity, histology, lacks specificity, which creates challenges for biomarker validation. This review focuses on progress in nephrotoxic pathway identification of CNI and biomarker validation.
Publisher: American Physiological Society
Date: 10-2010
DOI: 10.1152/AJPRENAL.00727.2009
Abstract: We investigated renal hemodynamics in isolated, perfused kidneys from rat models of diabetes and hypertension. Autoregulation and passive vascular responses were measured using stepped pressure r s in the presence of angiotensin II (pEC50) or papaverine (0.1 mM), respectively. Male diabetic heterozygote m(Ren2)27 rats were compared with three male control groups: nondiabetic, normotensive Sprague-Dawley (SD) rats nondiabetic, hypertensive heterozygote m(Ren2)27 rats and diabetic, normotensive SD rats. Kidney function (proteinuria, creatinine clearance) was monitored before induction and at monthly intervals. Vascular function was measured in vitro in rats of induction age (6–8 wk) and at 2 and 4 mo postinduction. Renal flow correlated with age, but not diabetes or the Ren2 gene. Kidney weight-specific and body weight-specific renal flow differed between diabetic and nondiabetic rats because diabetic rats had higher kidney but lower body weights. Kidneys from all groups showed effective autoregulation in the presence of angiotensin II. The autoregulatory pressure threshold of m(Ren2)27 rats was higher, and the autoregulation pressure range was wider, compared with SD rats. When vascular smooth muscle activity was blocked with papaverine, pressure-flow responses differed between groups and with time. The m(Ren2)27 rat groups showed higher renal vascular resistance at lower pressures, suggesting greater vascular stiffness. In contrast, diabetic SD rat kidneys demonstrated reduced vessel stiffness. Flow was impaired in diabetic m(Ren2)27 rats at 4 mo, and this correlated with a decline in creatinine clearance. The results suggest that the characteristic late decline in renal filtration function in diabetes- and hypertension-related renal disease follows changes in renal vascular compliance.
Publisher: Informa UK Limited
Date: 2002
DOI: 10.1080/0897719021000006181
Abstract: The interrelationship between myofibroblasts and fibrogenic growth factors in the pathogenesis of renal fibrosis is poorly defined. A temporal and spatial analysis of myofibroblasts, their proliferation and death, and presence of transforming growth factor-beta1 (TGF-beta1) and platelet-derived growth factor-B (PDGF-B) was carried out in an established rodent model in which chronic renal scarring and fibrosis occurs after healed renal papillary necrosis (RPN), similar to that seen with analgesic nephropathy. Treated and control groups (N = 6 and 4, respectively) were compared at 2, 4, 8 and 12 weeks. A positive relationship was found between presence of tubulo-interstitial myofibroblasts and development of fibrosis. Apoptotic myofibroblasts were identified in the interstitium and their incidence peaked 2 weeks after treatment. Levels of interstitial cell apoptosis and fibrosis were negatively correlated over time (r = -0.57, p < 0.01), suggesting that as apoptosis progressively failed to limit myofibroblast numbers, fibrosis increased. In comparison with the diminishing apoptosis in the interstitium, the tubular epithelium had progressively increasing levels of apoptosis over time, indicative of developing atrophy of nephrons. TGF-beta1 protein expression had a close spatial and temporal association with fibrosis and myofibroblasts, whilst PDGF-B appeared to have a closer link with populations of other chronic inflammatory cells such as infiltrating lymphocytes. Peritubular myofibroblasts were often seen near apoptotic cells in the tubular epithelium, suggestive of a paracrine toxic effect of factor/s secreted by the myofibroblasts. In vitro, TGF-beta1 was found to be toxic to renal tubular epithelial cells. These findings suggest an interaction between myofibroblasts, their deletion by apoptosis, and the presence of the fibrogenic growth factor TGF-beta1 in renal fibrosis, whereby apoptotic deletion of myofibroblasts could act as a controlling factor in progression of fibrosis.
Publisher: Future Medicine Ltd
Date: 12-2014
DOI: 10.2217/BMM.14.89
Publisher: Public Library of Science (PLoS)
Date: 23-04-2013
Publisher: Elsevier BV
Date: 09-2017
DOI: 10.1016/J.BPA.2017.10.003
Abstract: Acute kidney injury is common in critically ill patients and portends a significant impact on mortality, progressive chronic kidney disease, and cardiovascular disease and mortality. Though most physicians alter therapy depending on changes in serum creatinine, this often represents delayed intervention. Various AKI biomarkers have been discovered and validated to improve timely detection, differentiation and stratification into risk groups for progressive renal decline, need for renal replacement therapy or death. This chapter will review AKI biomarkers validated over the past decade. We also describe the clinical performance of the biomarkers. We suggest that using AKI biomarkers to complement serum creatinine (or cystatin C) and urine output will better integrate patient care through earlier recognition and clinical outcome prediction after AKI.
Publisher: Elsevier BV
Date: 05-1989
DOI: 10.1038/KI.1989.117
Abstract: To assess the prevalence and patterns of cardiac abnormalities as detected by cardiac magnetic resonance imaging (MRI) in systemic sclerosis (SSc). Fifty-two consecutive patients with SSc underwent cardiac MRI to determine morphological, functional, perfusion at rest and delayed enhancement abnormalities. At least one abnormality on cardiac MRI was observed in 39/52 patients (75%). Increased myocardial signal intensity in T2 was observed in 6 patients (12%), thinning of left ventricle (LV) myocardium in 15 patients (29%) and pericardial effusion in 10 patients (19%). LV and right ventricle (RV) ejection fractions were altered in 12 patients (23%) and 11 patients (21%), respectively. LV diastolic dysfunction was found in 15/43 patients (35%). LV kinetic abnormalities were found in 16/52 patients (31%) and myocardial delayed contrast enhancement was detected in 11/52 patients (21%). No perfusion defects at rest were found. Patients with limited SSc had similar MRI abnormalities to patients with diffuse SSc. Seven of 40 patients (17%) without pulmonary arterial hypertension had RV dilatation. This study shows that MRI is a reliable and sensitive technique for diagnosing heart involvement in SSc and for analysing its mechanisms, including its inflammatory, microvascular and fibrotic components. Compared with echocardiography, MRI appears to provide additional information by visualising myocardial fibrosis and inflammation. RV dilatation appeared to be non-specific for pulmonary arterial hypertension but could also reflect myocardial involvement related to SSc. Further studies are needed to determine whether cardiac MRI abnormalities have an impact on the prognosis and treatment strategy.
Publisher: Springer Science and Business Media LLC
Date: 2009
DOI: 10.1186/CC8019
Publisher: Elsevier BV
Date: 06-1984
DOI: 10.1038/KI.1984.113
Abstract: Immunochemical and metabolic studies of complement were performed in 11 patients with acute poststreptococcal glomerulonephritis (AGN) to determine the mechanism(s) of hypocomplementemia. Four patients with profound reduction in serum C3 showed metabolic changes comparable to those seen in hypocomplementemic mesangiocapillary GN (MCGN), that is, nonlinear plasma disappearance of 125I.C3 and a gross (that is, 30-fold) reduction in C3 synthesis (0.01 to 0.02 mg/kg/hr) fractional catabolic rate (FCR) and extravascular/intravascular distribution (EV/IV) ratio were also increased (3.02 to 6.99%/hr 1.14 to 2.96, respectively). The remaining seven patients had less (or no) reduction in C3 and showed normal or elevated values for all three metabolic parameters six had linear plasma disappearance curves. Metabolic data in five simultaneously studied control subjects were FCR: 1.56 to 2.12%/hr EV/IV ratio: 0.12 to 0.41 and synthesis rate: 0.30 to 0.52 mg/kg/hr. C3 nephritic factor (NeF) could not be detected in any sera and a significant reduction in serum C5 accompanied the changes in C3 (r = 0.89 P less than 0.001). Previous studies of C3 NeF-associated MCGN show that the fluid phase alternative pathway convertase seen in this condition has little or no C5 cleaving ability. We propose, therefore, that complement activation in AGN occurs via a surface-bound convertase which is capable of cleaving both C3 and C5. The glomerular capillary could provide such a site for activation.
Publisher: Springer Science and Business Media LLC
Date: 04-11-2014
Publisher: S. Karger AG
Date: 24-09-2014
DOI: 10.1159/000363555
Abstract: The clinical implementation of urinary and plasma renal injury biomarkers has been h ered by the variability associated with nonstandardized commercially available biomarker assays, uncertainty and variations in patient selection criteria, and the absence of context-specific cutoffs for biomarker concentrations. These limitations are increased by comparison with serum creatinine to define acute kidney injury. The critical problem affecting biomarker performance is patient heterogeneity involving the cause, context (including comorbidity and baseline renal function), and timing of the injury. We suggest strategies for stratifying subjects to provide appropriate context, and illustrate a creatinine-independent method for defining thresholds for biomarker concentrations in these contexts which utilizes the same sensitivity for the clinical outcomes of dialysis or death. Large multicenter cohort studies are needed to validate the proposed cutoffs.
Publisher: Elsevier BV
Date: 07-2008
DOI: 10.1053/J.ACKD.2008.04.002
Abstract: Changes in terminology and new consensus definitions of acute kidney injury (AKI) and stages of severity have simplified some of the problems in the clinical approach to this complex syndrome. Nevertheless, new proactive approaches to the diagnosis of kidney injury instead of kidney failure are required to allow clinical translation of successful therapies developed for experimental AKI. The recent development of novel urinary and plasma biomarkers, which predict kidney failure, has allowed the development of new paradigms for detection, prevention, and stage-specific treatment.
Publisher: S. Karger AG
Date: 24-09-2014
DOI: 10.1159/000363678
Abstract: Establishing the prognosis for recovery has enormous clinical implications. The appropriate definition of renal recovery depends on the stage of acute kidney injury (AKI). As definitions of AKI have broadened to encompass small increases in serum creatinine, definitions of recovery have broadened from becoming dialysis independent to full recovery of baseline glomerular function. Damage and functional biomarkers can assist in the prediction of recovery. Both decreases in damage biomarker concentration and increases in kidney function predict recovery. Structural biomarkers that directly predict recovery are awaited.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2012
DOI: 10.2215/CJN.09590911
Abstract: New tests should improve the diagnostic performance of available tests. The area under the receiver operator characteristic curve has been the “metric of choice” to quantify new biomarker performance. Two new metrics, the integrated discrimination improvement (IDI) and net reclassification improvement (NRI), have been rapidly adopted to quantify the added value of a biomarker to an existing test. These metrics require the development of risk prediction models that calculate the probability of an event for each in idual. This study demonstrates the application of these metrics in 528 critically ill patients with risk models of AKI, sepsis, and 30-day mortality to which the biomarker urinary cystatin C was added. Analogous to the receiver operator characteristic curve, we present a new risk assessment plot for visualizing these metrics. The results showed that the NRI was sensitive to the choice of risk threshold. The risk assessment plot identified that the addition of urinary cystatin C to the model decreased the calculated risk for some who did not have sepsis but increased it for others. The category-free NRI for each outcome indicated that most of those without the event had reduced calculated risk. This was driven by very small changes in calculated risk in the AKI and death models. The IDI reflected those small changes. Of the new metrics, the IDI, reported separately for those with and without the events, best represents the value of a new test. The risk assessment plot identified differences in the models not apparent in any of the metrics.
Publisher: Oxford University Press (OUP)
Date: 05-05-2011
DOI: 10.1093/NDT/GFR222
Abstract: Low-molecular weight (LMW) proteins, including albumin and novel urinary biomarkers of acute kidney injury (AKI) such as cystatin C and neutrophil gelatinase-associated lipocalin (NGAL), are normally absorbed from the glomerular filtrate by receptor-mediated transport. We evaluated the effect of albuminuria on urinary excretion of novel biomarkers. Sprague-Dawley rats given four injections over 2 days of 5 mg/g body wt/day bovine serum albumin (BSA) in saline were compared with controls given saline alone. Urinary cystatin C, albumin and protein excretion rates were compared prior to treatment (Day -1), after treatment (Day 2) and 4 days later (Day 6). A preliminary assessment of the clinical effect of proteinuria on the filtered urinary biomarkers cystatin C and NGAL was made by comparison with the effect on urinary interleukin-18 (IL-18) that is not absorbed from the glomerular filtrate, in a cohort of intensive care unit patients. BSA induced transient increases in albuminuria, proteinuria and cystatinuria (P < 0.01, P < 0.001 and P < 0.001, respectively). Beyond a threshold 6-fold increase in albuminuria, cystatin C absorption was reduced by competitive inhibition. The excretion rates of all analytes returned to preinjection levels by Day 6. Clinical proteinuria was associated with increasing cystatin C and NGAL concentrations (n = 90, P < 0.0001) but not IL-18 (P = 0.12). Proteinuria may increase the threshold for detection of AKI by increasing the excretion of LMW protein biomarkers.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2012
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 2015
Publisher: Elsevier BV
Date: 02-2011
DOI: 10.1016/J.CMPB.2010.07.010
Abstract: This paper compares three methods for estimating renal function, as tested in rats. Acute renal failure (ARF) was induced via a 60-min bilateral renal artery cl in 8 Sprague-Dawley rats and renal function was monitored for 1 week post-surgery. A two-compartment model was developed for estimating glomerular filtration via a bolus injection of a radio-labelled inulin tracer, and was compared with an estimated creatinine clearance method, modified using the Cockcroft-Gault equation for rats. These two methods were compared with selected ion flow tube-mass spectrometry (SIFT-MS) monitoring of breath analytes. Determination of renal function via SIFT-MS is desirable since results are available non-invasively and in real time. Relative decreases in renal function show very good correlation between all 3 methods (R²=0.84, 0.91 and 0.72 for breath-inulin, inulin-creatinine, and breath-creatinine correlations, respectively), and indicate good promise for fast, non-invasive determination of renal function via breath testing.
Publisher: Informa UK Limited
Date: 2003
Abstract: ATP-dependent K+ channels (KATP) account for most of the recycling of K+ which enters the proximal tubules cell via Na, K-ATPase. In the mitochondrial membrane, opening of these channels preserves mitochondrial viability and matrix volume during ischemia. We examined KATP channel modulation in renal ischemia-reperfusion injury (IRI), using an isolated perfused rat kidney (IPRK) model, in control, IRI, IRI+200 microM diazoxide (a KATP opener), IRI + 10 microM glibenclamide (a KATP blocker) and IRI + 200 microM diazoxide + 10 microM glibenclamide groups. IRI was induced by 2 periods of warm ischemia, followed by 45 min of reperfusion. IRI significantly decreased glomerular filtration rate (GFR) and increased fractional excretion of sodium (FENa) (p < 0.01). Neither diazoxide nor glibenclamide had an effect on control kidney function other than an increase in renal vascular resistance produced by glibenclamide. Pretreatment with 200 microM diazoxide reduced the postischemic increase in FENa (p < 0.05). Adding 10 microM glibenclamide inhibited the diazoxide effect on postischemic FENa (p < 0.01). Histology showed that kidneys pretreated with glibenclamide demonstrated an increase in injury in the thick ascending limb of outer medulla (p < 0.05). Glibenclamide significantly decreased post ischemic renal vascular resistance (p < 0.05), but had no significant effect on other renal function parameters. Our results suggest that sodium reabsorption is improved by KATP activation and blockade of KATP channels during IRI has an injury enhancing effect on renal epithelial function and histology. This may be mediated through KATP modulation in cell and/or mitochondrial inner membrane.
Publisher: Wiley
Date: 28-05-2015
DOI: 10.1111/BCP.12601
Publisher: Wiley
Date: 10-1983
DOI: 10.1111/J.1445-5994.1983.TB02704.X
Abstract: A 22 year old female was admitted to hospital two hours after ingesting 4 g of dapsone. Over the next 15 h she developed progressive hemolysis and methemoglobinemia. Charcoal hemoperfusion and sequential dialysis were performed because of the serious risk of fatality following such a massive dose of dapsone. Charcoal hemoperfusion led to rapid clearing of dapsone from the circulation. This resulted in clinical improvement and controlled the progression of hemolysis and methemoglobinemia.
Publisher: Elsevier BV
Date: 09-2015
DOI: 10.1016/J.TOXLET.2015.06.008
Abstract: Acute kidney injury (AKI) is common following paraquat ingestion. The diagnostic performance of injury biomarkers was investigated in serial blood and urine s les from patients from 5 Sri Lankan hospitals. Functional AKI was diagnosed using serum creatinine (sCr) or serum cystatin C (sCysC). The 95th centile in healthy subjects defined the urinary biomarker cutoffs for diagnosing structural AKI. 50 poisoned patients provided 2 or more specimens, 76% developed functional AKI [AKIN stage 1 (n=12), 2 (n=7) or 3 (n=19)] 19/26 patients with AKIN stage 2/3 also had functional AKI by sCysC criteria (≥50% increase). Urinary cystatin C (uCysC), clusterin (uClu) and NGAL (uNGAL) increased within 24h of ingestion compared with NoAKI patients and healthy controls. Each biomarker demonstrated moderate diagnostic utility [AUC-ROC: uCysC 0.79, uNGAL 0.79, uClu 0.68] for diagnosis of functional AKI at 16h. Death occurred only in subjects with functional AKI. Structural biomarker-based definitions detected more AKI than did sCr or sCysC, but did not independently predict death. Renal injury biomarkers did not add clinical value to patients who died rapidly due to multi-organ failure. Use of injury biomarkers within 16-24h may guide early intervention for reno-protection in less severe paraquat poisoning.
Publisher: Public Library of Science (PLoS)
Date: 04-05-2015
Location: Australia
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Zoltan Endre.