ORCID Profile
0000-0002-8752-2551
Current Organisations
James Cook University
,
Townsville Hospital and Health Service
,
University of Queensland
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Publisher: Wiley
Date: 05-09-2019
Publisher: Springer Science and Business Media LLC
Date: 18-05-2023
DOI: 10.1007/S00467-022-05606-1
Abstract: Kidney tubules are responsible for the preservation of fluid, electrolyte and acid-base homeostasis via passive and active mechanisms. These physiological processes can be disrupted by inherited or acquired aetiologies. The net result is a tubulopathy. It is important to make a prompt and accurate diagnosis of tubulopathies in children and young adults. This allows timely and appropriate management, including disease-specific therapies, and avoids complications such as growth failure. Tubulopathies can present with a variety of non-specific clinical features which can be diagnostically challenging. In this review, we build from this common anatomical and physiological understanding to present a tangible appreciation of tubulopathies as they are likely to be clinically encountered among affected children and young adults.
Publisher: Elsevier BV
Date: 2022
DOI: 10.1016/J.KINT.2021.09.024
Abstract: Registries are essential for health infrastructure planning, benchmarking, continuous quality improvement, hypothesis generation, and real-world trials. To date, data from these registries have predominantly been analyzed in isolated "silos," h ering efforts to analyze "big data" at the international level, an approach that provides wide-ranging benefits, including enhanced statistical power, an ability to conduct international comparisons, and greater capacity to study rare diseases. This review serves as a valuable resource to clinicians, researchers, and policymakers, by comprehensively describing kidney failure registries active in 2021, before proposing approaches for inter-registry research under current conditions, as well as solutions to enhance global capacity for data collaboration. We identified 79 kidney-failure registries spanning 77 countries worldwide. International Society of Nephrology exemplar initiatives, including the Global Kidney Health Atlas and Sharing Expertise to support the set-up of Renal Registries (SharE-RR), continue to raise awareness regarding international healthcare disparities and support the development of universal kidney-disease registries. Current barriers to inter-registry collaboration include underrepresentation of lower-income countries, poor syntactic and semantic interoperability, absence of clear consensus guidelines for healthcare data sharing, and limited researcher incentives. This review represents a call to action for international stakeholders to enact systemic change that will harmonize the current fragmented approaches to kidney-failure registry data collection and research.
Publisher: Wiley
Date: 18-10-2018
DOI: 10.1111/NEP.13494
Publisher: Oxford University Press (OUP)
Date: 18-02-2019
DOI: 10.1093/NDT/GFY409
Abstract: Primary distal renal tubular acidosis (dRTA) is a rare disorder, and we aimed to gather data on treatment and long-term outcome. We contacted paediatric and adult nephrologists through European professional organizations. Responding clinicians entered demographic, biochemical, genetic and clinical data in an online form. Adequate data were collected on 340 patients (29 countries, female 52%). Mutation testing had been performed on 206 patients (61%) pathogenic mutations were identified in 170 patients (83%). The median (range) presentation age was 0.5 (0-54) years and age at last follow-up was 11.0 (0-70.0) years. Adult height was slightly below average with a mean (SD score) of -0.57 (±1.16). There was an increased prevalence of chronic kidney disease (CKD) Stage ≥2 in children (35%) and adults (82%). Nephrocalcinosis was reported in 88%. Nephrolithiasis was more common with SLC4A1 mutations (42% versus 21%). Thirty-six percent had hearing loss, particularly in ATP6V1B1 (88%). The median (interquartile range) prescribed dose of alkali (mEq/kg/day) was 1.9 (1.2-3.3). Adequate metabolic control (normal plasma bicarbonate and normocalciuria) was achieved in 158 patients (51%), more commonly in countries with higher gross domestic product (67% versus 23%), and was associated with higher height and estimated glomerular filtration rate. Long-term follow-up from this large dRTA cohort shows an overall favourable outcome with normal adult height for most and no patient with CKD Stage 5. However, 82% of adult patients have CKD Stages 2-4. Importance of adequate metabolic control was highlighted by better growth and renal function but was achieved in only half of patients.
Publisher: Elsevier BV
Date: 09-2019
Publisher: Future Science Ltd
Date: 07-2020
Abstract: A survey of kidney transplant recipients receiving two innovative micros ling methods, dried blood spot and volumetric absorptive micros ling using patient reported methodology. A total of 39 adult transplant patients underwent venepuncture and finger prick-based blood draws on two occasions. They completed a survey of blood test understanding, tolerability, preferences and the burden associated with venepuncture compared with micros ling. A total of 85% of participants (n = 33) preferred finger prick-based s ling and 95% (n = 37) were interested in blood collection using self s ling by finger prick at home 33% (n = 13) of participants experienced blood test anxiety. To quantify time burden of providing venous s les a total of 44% (n = 17) spent greater than 1 hour to travel and provide venous s les. This study observed a patient preference for micros ling for blood s ling as an alternative to venepuncture in the management of their kidney transplant.
Publisher: BMJ
Date: 08-2019
DOI: 10.1136/BMJOPEN-2019-029541
Abstract: Recent advances in genomic technology have allowed better delineation of renal conditions, the identification of new kidney disease genes and subsequent targets for therapy. To date, however, the utility of genomic testing in a clinically ascertained, prospectively recruited kidney disease cohort remains unknown. The aim of this study is to explore the clinical utility and cost-effectiveness of genomic testing within a national cohort of patients with suspected genetic kidney disease who attend multidisciplinary renal genetics clinics. This is a prospective observational cohort study performed at 16 centres throughout Australia. Patients will be included if they are referred to one of the multidisciplinary renal genetics clinics and are deemed likely to have a genetic basis to their kidney disease by the multidisciplinary renal genetics team. The expected cohort consists of 360 adult and paediatric patients recruited by December 2018 with ongoing validation cohort of 140 patients who will be recruited until June 2020. The primary outcome will be the proportion of patients who receive a molecular diagnosis via genomic testing (diagnostic rate) compared with usual care. Secondary outcomes will include change in clinical diagnosis following genomic testing, change in clinical management following genomic testing and the cost-effectiveness of genomic testing compared with usual care. The project has received ethics approval from the Melbourne Health Human Research Ethics Committee as part of the Australian Genomics Health Alliance protocol: HREC/16/MH/251. All participants will provide written informed consent for data collection and to undergo clinically relevant genetic/genomic testing. The results of this study will be published in peer-reviewed journals and will also be presented at national and international conferences.
Publisher: MDPI AG
Date: 06-10-2022
Abstract: The choices of participants in nephrology research genomics studies about receiving additional findings (AFs) are unclear as are participant factors that might influence those choices. Methods: Participant choices and factors potentially impacting decisions about AFs were examined in an Australian study applying research genomic testing following uninformative diagnostic genetic testing for suspected monogenic kidney disease. Results: 93% of participants (195/210) chose to receive potential AFs. There were no statistically significant differences between those consenting to receive AFs or not in terms of gender (p = 0.97), median age (p = 0.56), being personally affected by the inherited kidney disease of interest (p = 0.38), or by the inheritance pattern (p = 0.12–0.19). Participants were more likely to choose not to receive AFs if the family proband presented in adulthood (p = 0.01), if there was family history of another genetic disorder (p = 0.01), and where the consent process was undertaken by an adult nephrologist (p = 0.01). Conclusion: The majority of participants in this nephrology research genomics study chose to receive potential AFs. Younger age of the family proband, family history of an alternate genetic disorder, and consenting by some multidisciplinary team members might impact upon participant choices.
Publisher: Elsevier BV
Date: 04-2021
Publisher: Springer Science and Business Media LLC
Date: 04-03-2021
DOI: 10.1038/S41525-021-00184-X
Abstract: Genetic testing in nephrology clinical practice has moved rapidly from a rare specialized test to routine practice both in pediatric and adult nephrology. However, clear information pertaining to the likely outcome of testing is still missing. Here we describe the experience of the accredited Australia and New Zealand Renal Gene Panels clinical service, reporting on sequencing for 552 in iduals from 542 families with suspected kidney disease in Australia and New Zealand. An increasing number of referrals have been processed since service inception with an overall diagnostic rate of 35%. The likelihood of identifying a causative variant varies according to both age at referral and gene panel. Although results from high throughput genetic testing have been primarily for diagnostic purposes, they will increasingly play an important role in directing treatment, genetic counseling, and family planning.
Publisher: Elsevier BV
Date: 04-2023
Publisher: Elsevier BV
Date: 11-2021
Publisher: Springer Science and Business Media LLC
Date: 06-05-2021
Publisher: Elsevier BV
Date: 03-2020
Publisher: Research Square Platform LLC
Date: 17-01-2023
DOI: 10.21203/RS.3.RS-2397081/V1
Abstract: Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most common monogenic cause of kidney failure and primarily associated with PKD1 or PKD2. Approximately 10% of patients remain undiagnosed after standard genetic testing. We aimed to utilise short and long read genome sequencing and RNA studies to investigate undiagnosed families. Patients with typical ADPKD phenotype and undiagnosed after genetic diagnostics were recruited. Probands underwent short-read genome sequencing, PKD1 and PKD2 coding and non-coding analyses and then genome-wide analysis. Targeted RNA studies investigated variants suspected to impact splicing. Those undiagnosed then underwent Oxford Nanopore Technologies long-read genome sequencing. From over 172 probands, 9 met inclusion criteria and consented. A genetic diagnosis was made in 8 of 9 (89%) families undiagnosed on prior genetic testing. Six had variants impacting splicing, five in non-coding regions of PKD1. Short-read genome sequencing identified novel branchpoint, AG-exclusion zone and missense variants generating cryptic splice sites and a deletion causing critical intron shortening. Long-read sequencing confirmed the diagnosis in one family. Most undiagnosed families with typical ADPKD have splice-impacting variants in PKD1. We describe a pragmatic method for diagnostic laboratories to assess PKD1 and PKD2 non-coding regions and validate suspected splicing variants through targeted RNA studies.
Publisher: Springer Science and Business Media LLC
Date: 13-06-2023
Publisher: Wiley
Date: 18-11-2014
DOI: 10.1111/NEP.12331
Publisher: Springer Science and Business Media LLC
Date: 04-05-2022
DOI: 10.1186/S12882-022-02805-8
Abstract: Prevalence of Fabry disease amongst Chronic Kidney Disease (CKD) patients on haemodialysis has been shown to be approximately 0.2%. We undertook a cross-sectional study employing a cascade screening strategy for Fabry Disease amongst 3000 adult, male and female patients affected by CKD stage 1-5D/T at public, specialty renal practices within participating Queensland Hospital and Health Services from October 2017 to August 2019. A multi-tiered FD screening strategy, utilising a combination of dried blood spot (DBS) enzymatic testing, and if low, then lyso-GB3 testing and DNA sequencing, was used. Mean (SD) age was 64.0 (15.8) years ( n = 2992), and 57.9% were male. Eight participants withrew out of the 3000 who consented. Of 2992 screened, 6 (0.20%) received a diagnosis of FD, 2902 (96.99%) did not have FD, and 84 (2.81%) received inconclusive results. Of the patients diagnosed with FD, mean age was 48.5 years 5 were male (0.29%) and 1 was female (0.08%) 4 were on kidney replacement therapy (2 dialysis and 2 transplant) 3 were new diagnoses. Estimated overall FD prevalence was 0.20%. Screening of the broader CKD population may be beneficial in identifying cases of FD. The aCQuiRE Study has been prospectively registered with the Queensland Health Database of Research Activity (DORA, dora.health.qld.gov.au ) as pj09946 (Registered 3rd July 2017).
Publisher: Elsevier BV
Date: 09-2018
Publisher: Springer Science and Business Media LLC
Date: 22-08-2019
Publisher: Wiley
Date: 10-2015
DOI: 10.1111/IMJ.12864
Abstract: This study aimed to report the clinical characteristics and outcomes of Australian patients treated with eculizumab for atypical haemolytic uraemic syndrome (aHUS). A retrospective cohort study was undertaken of all patients in Australia treated with eculizumab provided in a compassionate access programme for a clinical diagnosis of aHUS using prospectively collected clinical data. A total of 10 patients with a median age of 23.5 years (interquartile range (IQR) 24.83 years) received compassionate access eculizumab for aHUS in Australia. Eight patients were female, and three had a family history of aHUS. Three received eculizumab for an initial acute aHUS presentation, three for relapsing and refractory acute aHUS, two for de novo aHUS post-renal transplantation, and one each for aHUS recurrence post-transplantation and facilitation of transplantation with a history of aHUS. The median duration of eculizumab therapy has been 911.5 days (IQR 569 days) with a cumulative exposure of 9184 days. At baseline all patients had renal and extra-renal aHUS involvement, with up to three non-renal organs affected. All but one patient, who died from uncontrollable gastrointestinal aHUS manifestations, have continued. The nine continuing patients achieved remission of aHUS. Two of the four patients requiring renal replacement therapy (RRT) at eculizumab commencement subsequently ceased RRT. Clinical events occurring in this cohort while on eculizumab treatment included neutropenia (two), posterior reversible encephalopathy syndrome (one), cardiomyopathy (one), pulmonary embolus (one), antibody-mediated rejection resulting in renal graft failure (one), iron deficiency (one), gastrointestinal haemorrhage (one) and death (one). Eculizumab has been an effective therapy for aHUS in this cohort, including when other therapies have failed.
Publisher: Springer Science and Business Media LLC
Date: 12-01-2021
Publisher: Wiley
Date: 25-11-2023
DOI: 10.1111/IMJ.15977
Abstract: Comprehensive conservative care (CCC) is an emerging treatment option in kidney failure (KF), but its implementation has been restricted by a limited understanding of KF populations, outcomes and clinician experiences. This pilot study aimed to investigate the characteristics of patients who are opting for (CCC) in North Queensland, Australia. It also aimed to highlight clinician factors impacting treatment discussions. It was an observational study facilitated through an online cross‐sectional survey to nephrologists, nephrology advanced trainees and nurse practitioners working across North Queensland. Study participants disagreed with the statement that patients commencing dialysis are more likely to have cardiac co‐morbidities (46.7%), diabetes (40.0%), stroke (60.0%), liver disease (60.0%), chronic lung disease (53.3%), cognitive impairment (60.0%) and use of mobility aids (80.0%) than those commencing CCC. Conversely, they agreed that patients commencing dialysis are more likely to be independent (66.7%) and living in their private residence (40.0%). The median frailty score in patients choosing dialysis was 3.0 (interquartile range (IQR) 2.8–3.3), while that of patients selecting CCC was 4.5 (IQR 3.8–7.0). Our participants were aware of at least one clinical prognostication tool, and the one most frequently used was the ‘Surprise Question’ (46.2%, n = 6). Overall, our participants demonstrated low confidence (median 8.0%, IQR 6.0–8.0%) in facilitating CCC discussions. Patients who are highly co‐morbid and frail and have functional impairment are suitable candidates for CCC. More focus needs to be placed on objective prognostication of patients and the upskilling of clinicians to advocate for, and deliver, CCC.
Publisher: MDPI AG
Date: 21-10-2022
Abstract: (1) Background: Genomic testing is increasingly utilized as a clinical tool however, its integration into nephrology remains limited. The purpose of this study was to identify barriers and prioritize interventions for the widespread implementation of genomics in nephrology. (2) Methods: Qualitative, semi-structured interviews were conducted with 25 Australian adult nephrologists to determine their perspectives on interventions and models of care to support implementation of genomics in nephrology. Interviews were guided by a validated theoretical framework for the implementation of genomic medicine—the Consolidated Framework of Implementation Research (CFIR). (3) Results: Nephrologists were from 18 hospitals, with 7 having a dedicated multidisciplinary kidney genetics service. Most practiced in the public healthcare system (n = 24), a large number were early-career (n = 13), and few had genomics experience (n = 4). The top three preferred interventions were increased funding, access to genomics ch ions, and education and training. Where interventions to barriers were not reported, we used the CFIR/Expert Recommendations for Implementing Change matching tool to generate theory-informed approaches. The preferred model of service delivery was a multidisciplinary kidney genetics clinic. (4) Conclusions: This study identified surmountable barriers and practical interventions for the implementation of genomics in nephrology, with multidisciplinary kidney genetics clinics identified as the preferred model of care. The integration of genomics education into nephrology training, secure funding for testing, and counselling along with the identification of genomics ch ions should be pursued by health services more broadly.
Publisher: Springer Science and Business Media LLC
Date: 2014
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 20-06-2022
Publisher: Springer Science and Business Media LLC
Date: 22-02-2020
DOI: 10.1186/S12882-020-01717-9
Abstract: Fabry disease (FD) is a rare, lysosomal storage disorder caused by the absence or deficiency of the enzyme alpha-galactosidase A (α-Gal A) that leads to the abnormal accumulation of the lipid globotriaosylceramide (GB3) in a variety of cell types and tissues throughout the body. FD has an x-linked inheritance pattern. Previously thought to be only carriers, females can also experience FD symptomatology. Symptoms vary in type and severity from patient to patient and tend to increase in severity with age. FD symptoms are non-specific and may be shared with those of other diseases. Misdiagnoses and diagnostic delays are common, often resulting in progressive, irreversible tissue damage. The estimated prevalence of FD in the general population is 1:40,000 to 1:117,000 in iduals. However, it is estimated that the prevalence of FD in the dialysis population is 0.12 to 0.7%. Little is known about the prevalence of FD in the broader Chronic Kidney Disease (CKD) population. This is an epidemiological study of the prevalence of FD in CKD patents identified from the public renal speciality practices in Queensland, Australia. A cascade approach to screening is being employed with dried blood spot testing for blood levels of alpha-galactosidase A (Alpha-Gal), with follow-up testing for patients with abnormal results by plasma levels of globotriaosylsphingosine (Lyso-GB3) for females and non-definitive cases in males. A diagnosis of FD is confirmed through genetic testing of the GLA gene in cases suspected of having FD based upon Alpha-Gal and Lyso-GB3 testing. Expected outcomes of this study include more information about the prevalence of FD at all stages of CKD, including for both males and females. The study may also provide information about common characteristics of FD to assist with diagnosis and optimal management/treatment. Screening is also available for family members of diagnosed patients, with potential for early diagnosis of FD and intervention for those in iduals. Queensland Health Database of Research Activity (DORA, dora.health.qld.gov.au) pj09946 (Registered 3rd July 2017).
Publisher: Elsevier BV
Date: 08-2022
Publisher: Frontiers Media SA
Date: 26-05-2022
Abstract: Early identification of genetic kidney disease allows personalised management, clarification of risk for relatives, and guidance for family planning. Genetic disease is underdiagnosed, and recognition of genetic disease is particularly challenging in patients with kidney failure without distinguishing diagnostic features. To address this challenge, the primary aim of this study is to determine the proportion of genetic diagnoses amongst patients with kidney failure of unknown aetiology, using whole genome sequencing (WGS). A cohort of up to 100 Australian patients with kidney failure of unknown aetiology, with onset & years old and approved by a panel of study investigators will be recruited via 18 centres nationally. Clinically accredited WGS will be undertaken with analysis targeted to a priority list of ∼388 genes associated with genetic kidney disease. The primary outcome will be the proportion of patients who receive a molecular diagnosis (diagnostic rate) via WGS compared with usual -care (no further diagnostic investigation). Participant surveys will be undertaken at consent, after test result return and 1 year subsequently. Where there is no or an uncertain diagnosis, future research genomics will be considered to identify candidate genes and new pathogenic variants in known genes. All results will be relayed to participants via the recruiting clinician and/or kidney genetics clinic. The study is ethically approved (HREC/16/MH/251) with local site governance approvals in place. The future results of this study will be disseminated and inform practical understanding of the potential monogenic contribution to kidney failure of unknown aetiology. These findings are anticipated to impact clinical practice and healthcare policy. [ dora.health.qld.gov.au ], identifier [HREC/16/MH/251].
Publisher: Springer Science and Business Media LLC
Date: 30-09-2021
DOI: 10.1038/S41598-021-98935-4
Abstract: Chronic kidney disease (CKD) is a persistent impairment of kidney function. Genome-wide association studies (GWAS) have revealed multiple genetic loci associated with CKD susceptibility but the complete genetic basis is not yet clear. Since CKD shares risk factors with cardiovascular diseases and diabetes, there may be pleiotropic loci at play but may go undetected when using single phenotype GWAS. Here, we used multi-phenotype GWAS in the Norfolk Island isolate (n = 380) to identify new loci associated with CKD. We performed a principal components analysis on different combinations of 29 quantitative traits to extract principal components (PCs) representative of multiple correlated phenotypes. GWAS of a PC derived from glomerular filtration rate, serum creatinine, and serum urea identified a suggestive peak (p min = 1.67 × 10 –7 ) that mapped to KCNIP4 . Inclusion of other secondary CKD measurements with these three kidney function traits identified the KCNIP4 locus with GWAS significance (p min = 1.59 × 10 –9 ). Finally, we identified a group of two SNPs with increased minor allele frequencies as potential functional variants. With the use of genetic isolate and the PCA-based multi-phenotype GWAS approach, we have revealed a potential pleotropic effect locus for CKD. Further studies are required to assess functional relevance of this locus.
Publisher: Elsevier BV
Date: 06-2023
Publisher: Elsevier BV
Date: 09-2018
Publisher: University of Queensland Library
Date: 2016
DOI: 10.14264/414964
Publisher: Elsevier BV
Date: 08-2020
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-09-2022
Publisher: Elsevier BV
Date: 09-2019
Publisher: Elsevier BV
Date: 05-2018
Publisher: F1000 Research Ltd
Date: 26-07-2019
DOI: 10.12688/F1000RESEARCH.19997.1
Abstract: Background: There is an increasing appreciation that variants of the collagen IV genes may be associated with the development of focal segmental glomerulosclerosis (FSGS). On electron microscopy, such variants may produce characteristic changes within the glomerular basement membrane (GBM). These changes may be missed if glomerular lesions histologically diagnosed as FSGS on light microscopy are not subjected to electron microscopy. Methods: We conducted a retrospective cohort analysis of all patients presenting to two hospitals who received a primary histological diagnosis of FSGS to see if these s les underwent subsequent electron microscopy. Each such s le was also scrutinised for the presence of characteristic changes of an underlying collagen IV disorder Results: A total of 43 patients were identified. Of these, only 30 underwent electron microscopy. In two s les there were histological changes detected that might have suggested the underlying presence of a collagen IV disorder. Around one in three biopsy s les that had a histological diagnosis of FSGS were not subjected to electron microscopy. Conclusion: Renal biopsy s les that have a histological diagnosis of primary FSGS not subjected to subsequent electron microscopy may potentially miss ultrastructural changes in the GBM that could signify an underlying collagen IV disorder as the patient’s underlying disease process. This could potentially affect both them and their families’ investigative and management decisions given potential for implications for transplant, heritability and different disease pathogenesis. This represents a gap in care which should be reflected upon and rectified via iterative standard care and unit-level quality assurance initiatives.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 02-2022
Abstract: Biallelic pathogenic variants in SLC12A3 , encoding the thiazide-sensitive sodium chloride cotransporter NCC, cause Gitelman syndrome. Gitelman patients suffer from hypokalemic alkalosis, hypomagnesemia, and salt wasting. A subset of Gitelman syndrome cases remains genetically unsolved. This paper describes the identification of pathogenic mitochondrial DNA (mtDNA) variants in the genes encoding the transfer RNAs for phenylalanine ( MT-TF ) and isoleucine ( MT-TI ) in 13 families with a Gitelman-like phenotype. Six families were additionally affected by progressive CKD. Mitochondrial dysfunction was demonstrated in patient-derived fibroblasts and linked to defective sodium reabsorption by NCC in vitro. These findings advocate for screening for mtDNA variants in unexplained Gitelman syndrome patients and influence genetic counseling of affected families. Furthermore, they provide insight into the physiology of renal sodium handling. Gitelman syndrome is the most frequent hereditary salt-losing tubulopathy characterized by hypokalemic alkalosis and hypomagnesemia. Gitelman syndrome is caused by biallelic pathogenic variants in SLC12A3, encoding the Na + -Cl − cotransporter (NCC) expressed in the distal convoluted tubule. Pathogenic variants of CLCNKB , HNF1B , FXYD2 , or KCNJ10 may result in the same renal phenotype of Gitelman syndrome, as they can lead to reduced NCC activity. For approximately 10 percent of patients with a Gitelman syndrome phenotype, the genotype is unknown. We identified mitochondrial DNA (mtDNA) variants in three families with Gitelman-like electrolyte abnormalities, then investigated 156 families for variants in MT-TI and MT-TF , which encode the transfer RNAs for phenylalanine and isoleucine. Mitochondrial respiratory chain function was assessed in patient fibroblasts. Mitochondrial dysfunction was induced in NCC-expressing HEK293 cells to assess the effect on thiazide-sensitive 22 Na + transport. Genetic investigations revealed four mtDNA variants in 13 families: m.591C T ( n =7), m.616T C ( n =1), m.643A G ( n =1) (all in MT-TF ), and m.4291T C ( n =4, in MT-TI ). Variants were near homoplasmic in affected in iduals. All variants were classified as pathogenic, except for m.643A G, which was classified as a variant of uncertain significance. Importantly, affected members of six families with an MT-TF variant additionally suffered from progressive chronic kidney disease. Dysfunction of oxidative phosphorylation complex IV and reduced maximal mitochondrial respiratory capacity were found in patient fibroblasts. In vitro pharmacological inhibition of complex IV, mimicking the effect of the mtDNA variants, inhibited NCC phosphorylation and NCC-mediated sodium uptake. Pathogenic mtDNA variants in MT-TF and MT-TI can cause a Gitelman-like syndrome. Genetic investigation of mtDNA should be considered in patients with unexplained Gitelman syndrome-like tubulopathies.
Publisher: Wiley
Date: 09-06-2015
DOI: 10.1111/NEP.12447
Abstract: Fibrillary glomerulonephritis is a rare cause of glomerulonephritis characterized by non-amyloid fibrillary deposits of unknown aetiology. It is generally considered idiopathic but may be associated with secondary causes such as monoclonal gammopathy, hepatitis B and C infections, autoimmune diseases and malignancies. We report two Australian families with apparent familial fibrillary glomerulonephritis inherited in an autosomal dominant pattern, and postulate the existence of a primary familial entity. Family 1 consists of an affected father and daughter the daughter progressed to end-stage renal failure within 18 months of diagnosis, despite immunosuppressive therapy. The father, however, remains stable at 10 months follow up. Family 2 comprises an affected mother and son the mother commenced haemodialysis 5 years after diagnosis and subsequently underwent successful renal transplantation. The son is presently stable at last follow-up after 5 years. A further review of the second family history reveals a third family member (maternal father) dying of 'Bright's disease'. We describe their histopathology, clinical progression and treatment outcomes, and provide a review of the current understanding of this heterogeneous condition that is associated with poor renal outcomes.
Publisher: Springer Science and Business Media LLC
Date: 10-09-2018
Publisher: AMPCo
Date: 02-2016
DOI: 10.5694/MJA15.01157
Publisher: Elsevier BV
Date: 09-2021
Publisher: Wiley
Date: 02-2023
DOI: 10.1111/IMJ.16019
Abstract: Syncope is a common presentation to the emergency department with a wide spectrum of aetiology. The identification of the underlying cause can be diagnostically challenging, as are the choice of investigations and the decision for inpatient versus outpatient disposition. This study aimed to evaluate the aetiology of syncope as documented, the diagnostic yield of inpatient investigations and outcomes for adult patients admitted for syncope. A single‐centred, retrospective cohort study was conducted in adult patients admitted for syncope within a 2‐year period. A total of 386 patients were identified after exclusion. Information regarding syncope aetiology, investigations and outcomes were established via chart review of electronic records. The most common cause of syncope was neural‐mediated (43%), followed by orthostatic (36.5%) and cardiogenic (20.5%). The investigations performed in order of frequency included: telemetry electrocardiogram (ECG) (75.4%), computed tomography head non‐contrast (58.8%), transthoracic echocardiogram (TTE) (20.2%), computed tomography pulmonary angiogram (CTPA) (6.5%), MR brain (3.9%), electroencephalogram (1.3%) and carotid ultrasound (0.3%). Telemetry ECG, TTE and CTPA led to the diagnosis of syncope in a minority of patients only. As a result, 17.5% of patients had a new intervention on discharge, 5.4% were readmitted for syncope and 9.6% of patients died. In the context of the inpatient evaluation of syncope, this study supports the use of telemetry ECG and TTE. Neuroimaging demonstrates a low diagnostic yield for the cause of syncope, but it may have a role to play in excluding other pathologies. Our study does not support the routine use of CTPA, EEG or carotid ultrasound in the evaluation of syncope.
Publisher: Elsevier BV
Date: 12-2017
DOI: 10.1016/J.KINT.2017.06.013
Abstract: Inherited kidney disease encompasses a broad range of disorders, with both multiple genes contributing to specific phenotypes and single gene defects having multiple clinical presentations. Advances in sequencing capacity may allow a genetic diagnosis for familial renal disease, by testing the increasing number of known causative genes. However, there has been limited translation of research findings of causative genes into clinical settings. Here, we report the results of a national accredited diagnostic genetic service for familial renal disease. An expert multidisciplinary team developed a targeted exomic sequencing approach with ten curated multigene panels (207 genes) and variant assessment in idualized to the patient's phenotype. A genetic diagnosis (pathogenic genetic variant[s]) was identified in 58 of 135 families referred in two years. The genetic diagnosis rate was similar between families with a pediatric versus adult proband (46% vs 40%), although significant differences were found in certain panels such as atypical hemolytic uremic syndrome (88% vs 17%). High diagnostic rates were found for Alport syndrome (22 of 27) and tubular disorders (8 of 10), whereas the monogenic diagnostic rate for congenital anomalies of the kidney and urinary tract was one of 13. Quality reporting was aided by a strong clinical renal and genetic multidisciplinary committee review. Importantly, for a diagnostic service, few variants of uncertain significance were found with this targeted, phenotype-based approach. Thus, use of targeted massively parallel sequencing approaches in inherited kidney disease has a significant capacity to diagnose the underlying genetic disorder across most renal phenotypes.
Publisher: Elsevier BV
Date: 03-2023
Publisher: Springer Science and Business Media LLC
Date: 09-2023
Publisher: Frontiers Media SA
Date: 07-07-2022
Abstract: Available transcriptomes of the mammalian kidney provide limited information on the spatial interplay between different functional nephron structures due to the required dissociation of tissue with traditional transcriptome-based methodologies. A deeper understanding of the complexity of functional nephron structures requires a non-dissociative transcriptomics approach, such as spatial transcriptomics sequencing (ST-seq). We hypothesize that the application of ST-seq in normal mammalian kidneys will give transcriptomic insights within and across species of physiology at the functional structure level and cellular communication at the cell level. Here, we applied ST-seq in six mice and four human kidneys that were histologically absent of any overt pathology. We defined the location of specific nephron structures in the captured ST-seq datasets using three lines of evidence: pathologist's annotation, marker gene expression, and integration with public single-cell and/or single-nucleus RNA-sequencing datasets. We compared the mouse and human cortical kidney regions. In the human ST-seq datasets, we further investigated the cellular communication within glomeruli and regions of proximal tubules–peritubular capillaries by screening for co-expression of ligand–receptor gene pairs. Gene expression signatures of distinct nephron structures and microvascular regions were spatially resolved within the mouse and human ST-seq datasets. We identified 7,370 differentially expressed genes ( p adj & 0.05) distinguishing species, suggesting changes in energy production and metabolism in mouse cortical regions relative to human kidneys. Hundreds of potential ligand–receptor interactions were identified within glomeruli and regions of proximal tubules–peritubular capillaries, including known and novel interactions relevant to kidney physiology. Our application of ST-seq to normal human and murine kidneys confirms current knowledge and localization of transcripts within the kidney. Furthermore, the generated ST-seq datasets provide a valuable resource for the kidney community that can be used to inform future research into this complex organ.
Publisher: Elsevier BV
Date: 08-2022
Publisher: Elsevier BV
Date: 11-2015
Publisher: Wiley
Date: 02-2017
DOI: 10.1111/NEP.12933
Abstract: Disorders in the regulation of the alternate complement pathway often result in complement-mediated damage to the microvascular endothelium and can be associated with both glomerulonephritis and atypical haemolytic uraemic syndrome. Inherited defects in complement regulatory genes or autoantibodies against complement regulatory proteins are predictive of the severity of the disease and the risk of recurrence post kidney transplantation. Heterozygous mutations in CD46, which codes for a transmembrane cofactor glycoprotein membrane cofactor protein, usually have a lower incidence of end-stage kidney disease and decreased risk of recurrent disease post transplant, as wild-type membrane cofactor protein is present in the transplanted kidney. However, some patients with CD46 mutations have a second variant in other complement regulatory genes increasing the severity of disease. The following case report illustrates the course of a young adult patient with end-stage kidney disease initially ascribed to seronegative systemic lupus erythematosus, who presented with biopsy-proven thrombotic microangiopathy following kidney transplantation. It highlights the complexity associated with disorders of complement regulation and the need for a high index of suspicion and genetic testing in patients who present with thrombotic microangiopathy post-transplant.
Publisher: Wiley
Date: 19-07-2016
DOI: 10.1111/NEP.12658
Publisher: Springer Science and Business Media LLC
Date: 24-06-2015
Publisher: Wiley
Date: 21-01-2016
DOI: 10.1111/NEP.12579
Abstract: This study aimed to identify consumer perspectives on topics and outcomes to integrate in the Kidney Health Australia Caring for Australasians with Renal Impairment (KHA-CARI) clinical practice guidelines on autosomal-dominant polycystic kidney disease (ADPKD). A workshop involving three concurrent focus groups with 18 consumers (patients with ADPKD (n = 15), caregivers (n = 3)) was convened. Guideline topics, interventions and outcomes were identified, and integrated into guideline development. Thematic analysis was used to analyse the reasons for their choices. Twenty-two priority topics were identified, with most focussed on non-pharmacological management (diet, fluid intake, physical activity, complementary medicine), pain management and psychosocial care (mental health, counselling, cognitive and behavioural training, education, support groups). They also identified 26 outcomes including quality of life (QoL), progression of kidney disease, kidney function, cyst growth and nephrotoxity. Almost all topics and outcomes suggested were identified by health professionals with the exception of five topics/outcomes. Six themes reflected reasons for their choices: clarifying ambiguities, resolving debilitating pain, concern for family, preparedness for the future, taking control and significance of impact. Although there was considerable concordance between the priority topics and outcomes of health professionals and consumers for guidelines of ADPKD, there was also important discordance with consumers focused on fewer issues, but particularly on lifestyle, psychosocial support, pain, and QoL and renal outcomes. Active consumer engagement in guidelines development can help to ensure the inclusion of patient-centred recommendations, which may lead to better management of disease progression, symptoms, complications, and psychosocial impact.
Publisher: Springer Science and Business Media LLC
Date: 07-06-2023
DOI: 10.1007/S40620-023-01680-2
Abstract: Chronic kidney disease progression to kidney failure is erse, and progression may be different according to genetic aspects and settings of care. We aimed to describe kidney failure risk equation prognostic accuracy in an Australian population. A retrospective cohort study was undertaken in a public hospital community-based chronic kidney disease service in Brisbane, Australia, which included a cohort of 406 adult patients with chronic kidney disease Stages 3–4 followed up over 5 years (1/1/13–1/1/18). Risk of progression to kidney failure at baseline using Kidney Failure Risk Equation models with three (eGFR/age/sex), four (add urinary-ACR) and eight variables (add serum-albumin hosphate/bicarbonate/calcium) at 5 and 2 years were compared to actual patient outcomes. Of 406 patients followed up over 5 years, 71 (17.5%) developed kidney failure, while 112 died before reaching kidney failure. The overall mean difference between observed and predicted risk was 0.51% ( p = 0.659), 0.93% ( p = 0.602), and − 0.03% ( p = 0.967) for the three-, four- and eight-variable models, respectively. There was small improvement in the receiver operating characteristic-area under the curve from three-variable to four-variable models: 0.888 (95%CI = 0.819–0.957) versus 0.916 (95%CI = 0.847–0.985). The eight-variable model showed marginal receiver operating characteristic-area under the curve improvement: 0.916 (95%CI = 0.847–0.985) versus 0.922 (95%CI = 0.853–0.991). The results were similar in predicting 2 year risk of kidney failure. The kidney failure risk equation accurately predicted progression to kidney failure in an Australian chronic kidney disease population. Younger age, male sex, lower estimated glomerular filtration rate, higher albuminuria, diabetes mellitus, tobacco smoking and non-Caucasian ethnicity were associated with increased risk of kidney failure. Cause-specific cumulative incidence function for progression to kidney failure or death, stratified by chronic kidney disease stage, demonstrated differences within different chronic kidney disease stages, highlighting the interaction between comorbidity and outcome.
Publisher: Elsevier BV
Date: 11-2015
Publisher: Elsevier BV
Date: 11-2015
Publisher: Bentham Science Publishers Ltd.
Date: 26-08-2016
DOI: 10.2174/1874303X01609010088
Abstract: Steroid resistant nephrotic syndrome (SRNS) is increasingly recognised to have a genetic basis following the identification of a number of mutations within genes encoding podocyte and basement membrane proteins. The ARHGAP24 gene product is a recently recognised important player in podocyte interaction with the glomerular basement membrane. The ARHGAP24 gene encodes a protein involved in regulating cell motility, membrane structure and polarity. Mutations in the gene have been shown in vitro to cause cell membrane ruffling. We report a novel missense mutation in exon 4 (c.[284G A] p.[Arg95Gln]) of the ARHGAP24 gene in a child that presented with SRNS at four years of age. Renal biopsy demonstrated unusual polypoid changes of the glomerular basement membrane (GBM). We propose this novel ARHGAP24 mutation as causative for SRNS associated with unusual polypoid basement membrane changes. These biopsy findings, in association with ARHGAP24 mutation and clinical nephrotic syndrome are a novel finding. This finding may advance the understanding of ARHGAP24 gene product function.
Publisher: Springer Science and Business Media LLC
Date: 23-04-2019
DOI: 10.1038/S41467-019-09572-5
Abstract: Genome-wide association studies (GWASs) of medication use may contribute to understanding of disease etiology, could generate new leads relevant for drug discovery and can be used to quantify future risk of medication taking. Here, we conduct GWASs of self-reported medication use from 23 medication categories in approximately 320,000 in iduals from the UK Biobank. A total of 505 independent genetic loci that meet stringent criteria ( P 10 −8 /23) for statistical significance are identified. We investigate the implications of these GWAS findings in relation to biological mechanism, potential drug target identification and genetic risk stratification of disease. Amongst the medication-associated genes are 16 known therapeutic-effect target genes for medications from 9 categories. Two of the medication classes studied are for disorders that have not previously been subject to large GWAS (hypothyroidism and gastro-oesophageal reflux disease).
Publisher: Wiley
Date: 02-2017
DOI: 10.1111/NEP.12934
Abstract: Haemolytic uraemic syndrome is a rare condition with an overall incidence of one to two cases in a population of 100 000 and approximately 10% of these cases are classified as atypical. Atypical haemolytic uraemic syndrome (aHUS) is a thrombotic microangiopathy (TMA) characterized by microangiopathic haemolytic anaemia (MAHA), thrombocytopenia and acute kidney injury. aHUS can be genetic, acquired or idiopathic (negative genetic screening and no environmental triggers). We describe a case of aHUS triggered by monoclonal gammopathy of renal significance (MGRS) successfully treated with plasmapheresis and a bortezomib-based chemotherapy regimen, resulting in marked improvement in renal function and other markers of haemolysis. This patient has been in remission for more than 2 years currently.
Publisher: Wiley
Date: 22-08-2019
DOI: 10.1111/NEP.13640
Publisher: Springer Science and Business Media LLC
Date: 12-08-2022
Publisher: Springer Science and Business Media LLC
Date: 31-10-2017
Publisher: SAGE Publications
Date: 26-10-2012
Abstract: Calciphylaxis continues to present a clinical challenge for patient management. As in this case, it can be associated with connective tissue disease (CTD) such as systemic lupus erythematosus (SLE). Unlike previous reported cases, long-term remission has been attained. This provides some insight into methods of therapy as well as potential pathogenic models for this disease.
Publisher: S. Karger AG
Date: 2015
DOI: 10.1159/000440815
Abstract: b i Background: /i /b Fibrillary glomerulonephritis (FGN) and immunotactoid glomerulopathy (IG) are uncommon and characterised by non-amyloid fibrillary glomerular deposits. The aim of this study was to investigate characteristics and outcomes of patients undergoing renal replacement therapy (RRT) for end-stage kidney disease (ESKD) secondary to FGN and IG. b i Methods: /i /b All ESKD patients who commenced RRT in Australia and New Zealand 1 January 1990 to 31 December 2010 were included. Outcomes were assessed by Kaplan-Meier, multivariate logistic-regression analysis and multivariable Cox proportional-hazards survival analysis. b i Results: /i /b Of 45,216 in iduals with ESKD, 55 (0.12%) had FGN and 11 (0.02%) had IG. The median survival of FGN patients on dialysis (5.63 years, 95% CI 3.31-7.96) was not significantly different from patients with other ESKD causes (median 4.01 years, 95% CI 4.34-4.47 log-rank 1.32, p = 0.25), but was significantly longer than that of IG patients (median 2.93 years, 95% CI 0.00-6.17 log-rank 4.8, p = 0.03). Thirteen (24%) FGN patients received 13 renal-allografts, 4 (36%) IG patients received 4 renal-allografts and 11,528 (26%) other ESKD patients received 12,278 renal-allografts. FGN patients experienced comparable outcomes to other ESKD patients for both 10-year patient survival (100 vs. 84%, p = 0.93) and renal-allograft survival (67 vs. 76%, p = 0.06). For IG, the median follow-up was 3.66 years with 75% patient survival and 100% renal-allograft survival. One (8%) FGN patient and 1 (25%) IG patient experienced recurrent FGN and IG respectively in their allograft. b i Conclusion: /i /b Patients with FGN have comparable dialysis and renal transplant outcomes to patients with other causes of ESKD. IG patients have inferior survival on dialysis, although renal transplant outcomes are acceptable. Disease recurrence in renal-allografts was low for both FGN and IG.
Publisher: Wiley
Date: 14-03-2014
DOI: 10.1111/NEP.12195
Abstract: We present a case of an unsensitized patient with end-stage kidney disease secondary to atypical haemolytic uremic syndrome (aHUS) with mutations in CD46/MCP and CFH who developed severe, intractable antibody-mediated rejection (ABMR) unresponsive to therapy post kidney transplantation. There were no haematological features of thrombotic microangiopathy. The patient received standard induction therapy and after an initial fall in serum creatinine, severe ABMR developed in the setting of urosepsis. Despite maximal therapy with thymoglobulin, plasma exchange and methylprednisolone, rapid graft loss resulted and transplant nephrectomy was performed. Luminex at 4 weeks showed a new DSA and when repeated after nephrectomy showed antibodies to each of the 5 mismatched antigens with high MFI. The rate of recurrence of disease in patients with aHUS referred for transplantation is 50% and is associated with a high rate of graft loss. It is dependent in part on the nature of the mutation with circulating factors CFH and CFI more likely to cause recurrent disease than MCP which is highly expressed in the kidney. There is increasing interest in the role of complement in the development and propagation of ABMR via terminal complement activation. This case suggesting that dysregulation of the alternative complement pathway within the transplant kidney may have contributed to the severe AMR. Very little is known about the impact of complement dysregulation and the development of anti HLA antibodies however the strength of HLA antibody formation was prominent in this case.
Publisher: Elsevier BV
Date: 2021
Publisher: Oxford University Press (OUP)
Date: 24-07-2014
DOI: 10.1093/NDT/GFU254
Abstract: Alport syndrome is a rare inheritable renal disease. Clinical outcomes for patients progressing to end-stage kidney disease (ESKD) are not well described. This study aimed to investigate the characteristics and clinical outcomes of patients from Australia and New Zealand commencing renal replacement therapy (RRT) for ESKD due to Alport syndrome between 1965 and 1995 (early cohort) and between 1996 and 2010 (contemporary cohort) compared with propensity score-matched, RRT-treated, non-Alport ESKD controls. A total of 58 422 patients started RRT during this period of which 296 (0.5%) patients had Alport ESKD. In the early cohort, Alport ESKD was associated with superior dialysis patient survival [adjusted hazard ratio (HR): 0.41, 95% confidence interval (CI): 0.20-0.83, P = 0.01], renal allograft survival (HR: 0.74, 95% CI: 0.54-1.01, P = 0.05) and renal transplant patient survival (HR: 0.43, 95% CI: 0.28-0.66, P < 0.001) compared with controls. In the contemporary cohort, no differences were observed between the two groups for dialysis patient survival (HR: 1.42, 95% CI: 0.65-3.11, P = 0.38), renal allograft survival (HR: 1.01, 95% CI: 0.57-1.79, P = 0.98) or renal transplant patient survival (HR: 0.67, 95% CI: 0.26-1.73, P = 0.41). One Alport patient (0.4%) had post-transplant anti-glomerular basement membrane (anti-GBM) disease. Four female and 41 male Alport patients became parents on RRT with generally good neonatal outcomes. Alport syndrome patients experienced comparable dialysis and renal transplant outcomes to matched non-Alport ESKD controls in the contemporary cohort due to relatively greater improvements in outcomes for non-Alport ESKD patients over time. Post-transplant anti-GBM disease was rare.
Publisher: Frontiers Media SA
Date: 16-09-2021
Abstract: We aimed to describe and analyse clinical features, characteristics, and adherence to surveillance guidelines in an Australian Birt-Hogg-Dubé syndrome (BHD) and hereditary leiomyomatosis and renal cell cancer (HLRCC) cohort. All identified patients with a diagnosis of BHD or HLRCC at RBWH 01/01/2014-01/09/2019 were included (HREC/17/QRBW/276). All patients were initially assessed and counselled by a clinical geneticist and then referred to an adult nephrologist. Baseline and incidental clinical variables were extracted and analysed. Fifty-seven patients were identified (28 BHD, 29 HLRCC) with a median age of 47 years. The median and cumulative follow-up were 1 and 99 years, respectively. Baseline renal MRI occurred in 40/57 patients, and 33/57 had regular MRI as per the national guidelines (eviQ). Of 18/57 without baseline imaging, nine were yet to have imaging, seven were lost follow-up, and two patients had logistic difficulties. RCC was diagnosed in 11/57 patients: two of 28 with BHD were diagnosed with RCC aged 73 and 77, both prior to commencement of surveillance. Nine of 29 patients with HLRCC were diagnosed with RCC (one of 29 during surveillance at 47 years of age) and eight of 29 prior to commencement of surveillance (11–55 years). Amongst BHD patients, cutaneous fibrofolliculomas were noted in 15 patients, lung cysts were detected in seven patients, spontaneous pneumothoraces in five patients, and parotid oncocytoma in two of 28. Amongst those with HLRCC, cutaneous leiomyomas were noted in 19/29, cutaneous leiomyosarcoma diagnosed in one of 29, and uterine fibroids in 13 female patients. Evidence-based RCC screening in BHD and HLRCC cohort is feasible and able to identify incidental renal lesions. Multidisciplinary patient management enables expedited genetic counselling, diagnosis, longitudinal screening, and RCC management. The success of this clinical model warrants consideration of undertaking longitudinal screening of BHD and HLRCC patients by nephrologists.
Publisher: Elsevier BV
Date: 02-2020
Publisher: Elsevier BV
Date: 06-2022
DOI: 10.1016/J.KINT.2022.03.019
Abstract: Numerous genes for monogenic kidney diseases with classical patterns of inheritance, as well as genes for complex kidney diseases that manifest in combination with environmental factors, have been discovered. Genetic findings are increasingly used to inform clinical management of nephropathies, and have led to improved diagnostics, disease surveillance, choice of therapy, and family counseling. All of these steps rely on accurate interpretation of genetic data, which can be outpaced by current rates of data collection. In March of 2021, Kidney Diseases: Improving Global Outcomes (KDIGO) held a Controversies Conference on "Genetics in Chronic Kidney Disease (CKD)" to review the current state of understanding of monogenic and complex (polygenic) kidney diseases, processes for applying genetic findings in clinical medicine, and use of genomics for defining and stratifying CKD. Given the important contribution of genetic variants to CKD, practitioners with CKD patients are advised to "think genetic," which specifically involves obtaining a family history, collecting detailed information on age of CKD onset, performing clinical examination for extrarenal symptoms, and considering genetic testing. To improve the use of genetics in nephrology, meeting participants advised developing an advanced training or subspecialty track for nephrologists, crafting guidelines for testing and treatment, and educating patients, students, and practitioners. Key areas of future research, including clinical interpretation of genome variation, electronic phenotyping, global representation, kidney-specific molecular data, polygenic scores, translational epidemiology, and open data resources, were also identified.
Publisher: Springer Science and Business Media LLC
Date: 07-07-2023
DOI: 10.1038/S41525-023-00362-Z
Abstract: Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic cause of kidney failure and is primarily associated with PKD1 or PKD2 . Approximately 10% of patients remain undiagnosed after standard genetic testing. We aimed to utilise short and long-read genome sequencing and RNA studies to investigate undiagnosed families. Patients with typical ADPKD phenotype and undiagnosed after genetic diagnostics were recruited. Probands underwent short-read genome sequencing, PKD1 and PKD2 coding and non-coding analyses and then genome-wide analysis. Targeted RNA studies investigated variants suspected to impact splicing. Those undiagnosed then underwent Oxford Nanopore Technologies long-read genome sequencing. From over 172 probands, 9 met inclusion criteria and consented. A genetic diagnosis was made in 8 of 9 (89%) families undiagnosed on prior genetic testing. Six had variants impacting splicing, five in non-coding regions of PKD1 . Short-read genome sequencing identified novel branchpoint, AG-exclusion zone and missense variants generating cryptic splice sites and a deletion causing critical intron shortening. Long-read sequencing confirmed the diagnosis in one family. Most undiagnosed families with typical ADPKD have splice-impacting variants in PKD1 . We describe a pragmatic method for diagnostic laboratories to assess PKD1 and PKD2 non-coding regions and validate suspected splicing variants through targeted RNA studies.
Publisher: Elsevier BV
Date: 11-2015
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 08-2021
Abstract: The incidence of bleeding complications after percutaneous kidney biopsies is low. Female sex may be associated with a greater risk for bleeding complications after percutaneous kidney biopsies. This association and the plausible mechanisms require further evaluation in prospective study
Publisher: Elsevier BV
Date: 11-2015
Publisher: Elsevier BV
Date: 11-2015
Publisher: Springer Science and Business Media LLC
Date: 11-09-2023
Publisher: Springer Science and Business Media LLC
Date: 30-01-2018
Publisher: Cold Spring Harbor Laboratory
Date: 20-12-2018
DOI: 10.1101/501049
Abstract: It is common that one medication is prescribed for several indications, and conversely that several medications are prescribed for the same indication, suggesting a complex biological network for disease risk and its relationship with pharmacological function. Genome-wide association studies (GWASs) of medication-use may contribute to understanding of disease etiology, generation of new leads relevant for drug discovery and quantify prospects for precision medicine. We conducted GWAS to profile self-reported medication-use from 23 categories in approximately 320,000 in iduals from the UK Biobank. A total of 505 independent genetic loci that met stringent criteria for statistical significance were identified. We investigated the implications of these GWAS findings in relation to biological mechanism, drug target identification and genetic risk stratification of disease. Amongst the medication-associated genes were 16 known therapeutic-effect target genes for medications from 9 categories.
Publisher: Elsevier BV
Date: 08-2020
DOI: 10.1016/J.KINT.2020.02.022
Abstract: Monoallelic mutations of DNAJB11 were recently described in seven pedigrees with atypical clinical presentations of autosomal dominant polycystic kidney disease. DNAJB11 encodes one of the main cofactors of the endoplasmic reticulum chaperon BiP, a heat-shock protein required for efficient protein folding and trafficking. Here we conducted an international collaborative study to better characterize the DNAJB11-associated phenotype. Thirteen different loss-of-function variants were identified in 20 new pedigrees (54 affected in iduals) by targeted next-generation sequencing, whole-exome sequencing or whole-genome sequencing. Amongst the 77 patients (27 pedigrees) now in total reported, 32 reached end stage kidney disease (range, 55-89 years, median age 75) without a significant difference between males and females. While a majority of patients presented with non-enlarged polycystic kidneys, renal cysts were inconsistently identified in patients under age 45. Vascular phenotypes, including intracranial aneurysms, dilatation of the thoracic aorta and dissection of a carotid artery were present in four pedigrees. We accessed Genomics England 100,000 genomes project data, and identified pathogenic variants of DNAJB11 in nine of 3934 probands with various kidney and urinary tract disorders. The clinical diagnosis was cystic kidney disease for eight probands and nephrocalcinosis for one proband. No additional pathogenic variants likely explaining the kidney disease were identified. Using the publicly available GnomAD database, DNAJB11 genetic prevalence was calculated at 0.85/10.000 in iduals. Thus, establishing a precise diagnosis in atypical cystic or interstitial kidney disease is crucial, with important implications in terms of follow-up, genetic counseling, prognostic evaluation, therapeutic management, and for selection of living kidney donors.
Publisher: Springer Science and Business Media LLC
Date: 15-09-2015
Location: Australia
No related grants have been discovered for Andrew Mallett.