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Background The cause of kidney failure is unknown in approximately 10% of patients with stage 5 chronic kidney disease (CKD). For those who first present to nephrology care with kidney failure, standard investigations of serology, imaging, urinalysis and kidney biopsy are limited differentiators of etiology. We aimed to determine the diagnostic utility of whole-genome sequencing (WGS) with analysis of a broad kidney gene panel in patients with kidney failure of unknown cause. Methods We prospectively recruited 100 participants who reached CKD stage 5 at 50 years of age and had an unknown cause of kidney failure after standard investigation. Clinically-accredited WGS was performed in this national cohort after genetic counselling. The primary analysis was targeted to 388 kidney-related genes with second-tier genome-wide and mitochondrial analysis. Results The cohort was 61% male and the average age of participants at stage 5 CKD was 32 years (9 months to 50 years). A genetic diagnosis was made in 25% of participants. Disease-causing variants were identified across autosomal dominant tubulointerstitial kidney disease (6), glomerular disorders (4), ciliopathies (3), tubular disorders (2), Alport syndrome (4) and mitochondrial disease (1). Most diagnoses (80%) were in autosomal dominant, X-linked or mitochondrial conditions (UMOD; COL4A5; INF2; CLCN5; TRPC6; COL4A4; EYA1; HNF1B; WT1; NBEA; m.3243A>G). Patients with a family history of CKD were more likely to have a positive result (OR 3.29, 95% CI 1.10-11.29). Thirteen percent of participants without a CKD family history had a positive result. In those who first presented in stage 5 CKD, WGS with broad analysis of a curated kidney-disease gene panel was diagnostically more informative than kidney biopsy, with biopsy being inconclusive in 24 of 25 participants. Conclusions In this prospectively ascertained Australian cohort, we identified a genetic diagnosis in 25% of patients with kidney failure of unknown cause.

We write to acknowledge the recent correspondence by Lombardi and Mesnard (2023) and thank them for their positive comments regarding the quality, importance, and novelty of our work. 1 We concur that economic evaluation studies from a wide variety of jurisdictions and health systems are very much needed.

PURPOSE: To assess the relative cost-effectiveness of genomic testing compared with standard non-genomic diagnostic investigations in patients with suspected monogenic kidney disease from an Australian health care system perspective. METHODS: Diagnostic and clinical information was used from a national cohort of 349 participants. Simulation modelling captured diagnostic, health, and economic outcomes during a time horizon from clinical presentation until 3 months post-test results based on the outcome of cost per additional diagnosis and lifetime horizon based on cost per quality-adjusted life-year (QALY) gained. RESULTS: Genomic testing was Australian dollars (AU$) 1600 more costly per patient and led to an additional 27 diagnoses out of a 100 individuals tested, resulting in an incremental cost-effectiveness ratio of AU$5991 per additional diagnosis. Using a lifetime horizon, genomic testing resulted in an additional cost of AU$438 and 0.04 QALYs gained per individual compared with standard diagnostic investigations, corresponding to an incremental cost-effectiveness ratio of AU$10,823 per QALY gained. Sub-group analyses identified that the results were largely driven by the cost-effectiveness in glomerular diseases. CONCLUSION: Based on established or expected thresholds of cost-effectiveness, our evidence suggests that genomic testing is very likely to be cost saving for individuals with suspected glomerular diseases, whereas no evidence of cost-effectiveness was found for non-glomerular diseases.

(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 champions, 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 champions should be pursued by health services more broadly.

Background: Despite the emergence of diagnostic and clinical utility evidence in nephrology, publicly funded access to genomic testing is restricted in most health care systems. To establish genomic sequencing as a clinical test, an evaluation of cost-effectiveness is urgently required. Method(s): An economic evaluation, informed by a primary clinical study and available clinical evidence and guidelines in nephrology, was performed to evaluate the cost-effectiveness and optimal timing of exome sequencing (ES) in adults and children with suspected monogenic glomerular diseases compared with nongenomic investigations (NGIs). Six diagnostic strategies reflecting current practice and recommended models of care in Australia were modeled: (i) NGIs, (ii) late gene panel followed by ES, (iii) late ES, (iv) early gene panel, (v) early gene panel followed by ES, and (vi) early ES. Result(s): ES with targeted analysis achieved a diagnosis in 23 of 63 (36.5%) adults and 10 of 24 (41.6%) children. NGIs were estimated to diagnose 4.0% of children, with an average estimated cost of AU$6120 per child. Integrating ES as a first-line test in children was cost saving, with an incremental cost saving of AU$3230 per additional diagnosis compared with NGIs. In adults, NGIs was estimated to diagnose 8% of patients, with an average estimated cost of AU$1830 per person. In adults, integrating ES early resulted in an incremental cost per additional diagnosis of AU$5460 relative to NGIs. Conclusion(s): Early ES with targeted analysis was effective for diagnosing monogenic kidney disease, with substantial cost savings in children.Copyright © 2021

Aim: To describe the phenotypic spectrum in patients with diagnostic type 4 collagen variants, and to determine phenocopies of Alport Syndrome (AS). Background(s): AS is the second most common form of genetic kidney disease (GKD). Recently, Medicare approved testing for the three genes associated with AS. Pursuing genetic diagnosis has important clinical implications. Method(s): We compared the suspected diagnosis prior to ES with the genomic diagnosis in patients with suspected AS from a cohort of 204 patients with suspected GKD. We also compared the suspected diagnosis to the molecular diagnosis in patients who were found to have type 4 collagen variants following ES. Result(s): 80/204(39%) had diagnostic variants in genes related to kidney disease. 26/80(33%) had diagnostic type 4 collagen variants. Most patients (n = 13) had autosomal dominant (AD) COL4A3/4 nephropathy. Eleven had X-Linked dominant AS and 2 had autosomal recessive AS. ES reclassified the diagnosis in 7/26(27%) of patients with type 4 collagen variants. Furthermore, 3 patients who had clinical symptoms suspicious of AS were found to have an alternate diagnosis following ES (2 had X-linked recessive Dent Disease and 1 had AD hypoparathyroidism, sensorineural deafness and renal dysplasia). Conclusion(s): ES revealed type 4 collagen variants in 6 patients with alternate clinical diagnoses suspected at referral. Three additional patients who were thought to have AS were subsequently given an alternate diagnosis. We suggest that AS is underdiagnosed, and testing should be considered in patients with a suspected monogenic cause of hematuria. We also highlight the importance of expanding analysis to additional genes in the evaluation of patients with suspected AS, in addition to those reimbursed by Medicare. ES allows easier subsequent reanalysis of genomic data.

Purpose: To determine the diagnostic yield and clinical impact of exome sequencing (ES) in patients with suspected monogenic kidney disease. Method(s): We performed clinically accredited singleton ES in a prospectively ascertained cohort of 204 patients assessed in multidisciplinary renal genetics clinics at four tertiary hospitals in Melbourne, Australia. Result(s): ES identified a molecular diagnosis in 80 (39%) patients, encompassing 35 distinct genetic disorders. Younger age at presentation was independently associated with an ES diagnosis (p < 0.001). Of those diagnosed, 31/80 (39%) had a change in their clinical diagnosis. ES diagnosis was considered to have contributed to management in 47/80 (59%), including negating the need for diagnostic renal biopsy in 10/80 (13%), changing surveillance in 35/80 (44%), and changing the treatment plan in 16/80 (20%). In cases with no change to management in the proband, the ES result had implications for the management of family members in 26/33 (79%). Cascade testing was subsequently offered to 40/80 families (50%). Conclusion(s): In this pragmatic pediatric and adult cohort with suspected monogenic kidney disease, ES had high diagnostic and clinical utility. Our findings, including predictors of positive diagnosis, can be used to guide clinical practice and health service design.Copyright © 2020, The Author(s).

Aim: To determine the diagnostic yield and clinical impact of exome sequencing (ES) in patients with suspected GKD. Background(s): Genetic kidney disease (GKD) is increasingly recognized as an important cause of CKD and can be difficult to accurately diagnose using traditional diagnostic strategies. There is a paucity of data on the clinical utility of genomic testing in kidney disease patients. Method(s): We performed clinically accredited singleton ES in a prospectively ascertained cohort of 204 patients assessed in multidisciplinary renal genetics clinics at four tertiary hospitals in Melbourne, Australia. Result(s): ES identified a molecular diagnosis in 80 (39%) patients, encompassing 35 distinct genetic disorders. Younger age at presentation was independently associated with an ES diagnosis (p < 0.001). Of those diagnosed, 31/80 (39%) had a change in their clinical diagnosis following ES. A diagnosis on ES was considered to have contributed to management in 47/80 (59%), including negating the need for diagnostic renal biopsy in 10/80 (13%), changing surveillance in 35/80 (44%) and changing the treatment plan in 16/80 (20%). In cases with no change to management in the proband, the ES result had implications for the management of family members in 26/33 (79%). Cascade testing was subsequently offered to 40/80 families (50%). Conclusion(s): In this pragmatic paediatric and adult cohort with suspected monogenic kidney disease, ES had high diagnostic and clinical utility. Our findings, including predictors of positive diagnosis, can be used to guide clinical practice and health service design.

Aim: To explore barriers and identify specific interventions that may help improve uptake of genomics within nephrology. Background(s): Genomic testing is becoming widely available as a diagnostic tool, although widespread implementation is not yet established in nephrology. Method(s): We designed a cross-sectional qualitative study, building on formative research, using interviews informed by the Consolidated Framework of Implementation Research (CFIR). We identified nephrology units from Australia at random, and unit heads were invited to nominate participants based on background (e.g. unit head, advanced trainee, nephrologist, public/ private, interest in genomics). Data was analysed deductively using the CFIR according to physician type. Result(s): Early interview findings (N = 10) from four states revealed the most common barriers among physicians included limited perceived clinical usefulness of genomic testing, inadequate funding for tests and infrastructure (e.g. dedicated clinic space and staff), and lack of a local genomics champion. Half of the clinicians interviewed did not have access to local renal genetics clinic but were aware of a referral service offered at another hospital. The highest prioritized intervention identified was a local genomics champion who could provide links to genomics expertise within the department (highlighted by almost all interviewees). Other interventions that frequently emerged were a greater focus on genomics within annual scientific meetings, incorporating a genomics rotation for advanced trainees, and access to local multidisciplinary renal genetics clinic. Conclusion(s): Barriers for genomics implementation were multifaceted. Most clinicians looked towards experts within their own speciality for guidance on genetic testing and referral processes. Interventions should focus on improving communication and access to local genomics expertise as a first step in order to improve referrals and access to genomic testing in kidn

Aim: An anonymous electronic survey was administered to investigate experience and confidence with genomic tests, perceived clinical utility of genomic services, preferences for service delivery models, and readiness for implementation among nephrologists. Background(s): Genomic testing is becoming widely available as a diagnostic tool, although widespread implementation is not yet established in nephrology. Method(s): Survey questions were guided by a comprehensive literature review and published tools, including a validated theoretical framework for implementation of genomic medicine: Consolidated Framework for Implementation Research (CFIR). Result(s): Responses were received from 224 clinicians, of which 172 were eligible for analysis. Most clinicians (132[76%]) had referred at least one patient to a genetics clinic. Despite most clinicians (136[85%]) indicating that they believed genetic testing would be useful, only 39 (23%) indicated they felt confident to use results of genomic testing, with paediatric clinicians feeling more confident compared to adult clinicians (12/20 [60%] versus 27/149[18%]), p < 0.001. A multidisciplinary renal genetics clinic was the preferred model among clinicians surveyed (98/172 [57%]). A key implementation barrier highlighted related to the hospital or working culture and/or environment. Specific barriers noted in quantitative and qualitative responses included inadequate staff, learning resources, and funding. Conclusion(s): Our findings suggest support for genomic testing among nephrologists, with a strong preference for a multidisciplinary model (involving a nephrologist, clinical geneticist, and genetic counsellor). Interventions aimed at addressing the working culture are urgently required to ensure successful implementation of genomic in nephrology, including improving knowledge gaps, increased funding and resources, disease-specific guidelines and streamlining of testing processes.

Aim: To evaluate the cost-effectiveness of exome sequencing (ES) in patients with suspected genetic kidney disease (GKD) compared with current standard diagnostic care, and to evaluate the optimal timing of ES. Background(s): There is an urgent need to determine the health economic value of genomic testing in kidney disease patients. Method(s): This model based economic analysis was informed by a pragmatic, multicentre study which included 87 patients with suspected monogenic glomerular disease. Resource use for non-genomic investigations were also informed by data from the cohort, in addition to current guidelines. Six diagnostic strategies reflecting current practice were compared. Result(s): ES achieved a diagnosis in 23/63 (36.5%) adults and 10/24 (41.6%) children. The average cost of ES (including sequencing, analysis, and related consultations) was $2,355 in both children and adults. Children: Standard investigations were estimated to diagnose 4.0%, with an average estimated cost of $6,119 per child. Integrating ES as a first line test was cost saving, with an incremental cost saving per additional diagnosis of $3,230 compared to standard diagnostic care. Adults: Standard investigations were estimated to diagnose 7.9%, with an average estimated cost of $1,834 per adult, (including a biopsy rate of 70%). Integrating ES early resulted in an incremental cost per additional diagnosis of $5,456 relative to standard care. Conclusion(s): Integrating ES early in the diagnostic pathway is likely to be more effective and less costly for establishing a diagnosis and informing care in children. In adults, the incremental cost per additional diagnosis may be justified, depending on the value of a genomic diagnosis. Applying ES as a last resort test resulted in considerably higher cost compared with earlier application in the diagnostic trajectory.

Introduction: Genomic testing is becoming widely available as a diagnostic tool, although widespread implementation is not yet established in nephrology. Method(s): An anonymous electronic survey was administered to investigate experience and confidence with genomic tests, perceived clinical utility of genomic services, preferences for service delivery models, and readiness for implementation among nephrologists. Questions were guided by a comprehensive literature review and published tools, including a validated theoretical framework for implementation of genomic medicine: Consolidated Framework for Implementation Research (CFIR). Result(s): Responses were received from 224 clinicians, of which 172 were eligible for analysis. Most clinicians (132 [76%]) had referred at least one patient to a genetics clinic. Despite most clinicians (136 [85%]) indicating that they believed genetic testing would be useful, only 39 (23%) indicated they felt confident to use results of genomic testing, with pediatric clinicians feeling more confident compared with adult clinicians (12 of 20 [60%] vs. 27 of 149 [18%]), P < 0.01, Fisher exact). A multidisciplinary renal genetics clinic was the preferred model among clinicians surveyed (98 of 172 [57%]). A key implementation barrier highlighted related to the hospital or organizational culture and/or environment. Specific barriers noted in quantitative and qualitative responses included inadequate staffing, learning resources, and funding. Conclusion(s): Our findings suggest support for genomic testing among nephrologists, with a strong preference for a multidisciplinary model (involving a nephrologist, clinical geneticist, and genetic counselor). Broad-ranging interventions are urgently required to shift the current culture and ensure successful implementation of genomics in nephrology, including reducing knowledge gaps, increased funding and resources, disease-specific guidelines, and streamlining of testing processes.Copyright © 2020

Aim: To describe diagnostic outcomes of clinically accredited genomic testing delivered by nationwide multidisciplinary team (MDT) clinics for patients with suspected genetic kidney disease (GKD). Background(s): With increased understanding of GKD, genomic testing is translating from research to clinic. Rigorous evaluation of clinical practice and patient outcomes is required to guide value-based healthcare. Method(s): Sequential incident patients undergoing clinically indicated genomic testing for presumed GKD from 18 Australian MDT clinics 2016-19 were analysed (HREC/16/MH/251). A molecular diagnosis constituted clinical reporting of pathogenic and/or likely pathogenic variant/s in gene/s associated with the patient's kidney phenotype with concordant inheritance. All genomic testing included restriction of variant analysis to a phenotypederived gene list. Result(s): 1088 patients underwent genomic testing between 2016-2019. 48% of the cohort were male, median age at the time of genomic test was 30 years (range < 1 year to 81). The most common sequencing approach was targeted exome (n = 477), exome sequencing (n = 220) and whole genome sequencing (n = 148). 491 patients (45%) received a positive diagnostic on genomic sequencing. Of these, 71/448 (16%) had reclassification of their original diagnosis, 176/448 (39%) had clarification of their diagnosis, and 187/448 (42%) had confirmation of the suspected diagnosis following genomic testing. In addition, 14/448 (3%) patients with a previous unknown cause of renal failure received a diagnosis. The diagnostic yield was highest in infants<1 year of age (68%) and lowest (37%) in those aged above 50 (OR 3.6, 95%CI 19.1-6.72, p < 0.001, for infants compared to age > 50 at time of test). Conclusion(s): In this nationwide, pragmatic paediatric and adult cohort, genetic testing demonstrated substantial diagnostic utility, especially in children and young adults. Clinical utility studies are required to clarify impact of these

PURPOSE: To determine the diagnostic yield and clinical impact of exome sequencing (ES) in patients with suspected monogenic kidney disease. METHODS: We performed clinically accredited singleton ES in a prospectively ascertained cohort of 204 patients assessed in multidisciplinary renal genetics clinics at four tertiary hospitals in Melbourne, Australia. RESULTS: ES identified a molecular diagnosis in 80 (39%) patients, encompassing 35 distinct genetic disorders. Younger age at presentation was independently associated with an ES diagnosis (p < 0.001). Of those diagnosed, 31/80 (39%) had a change in their clinical diagnosis. ES diagnosis was considered to have contributed to management in 47/80 (59%), including negating the need for diagnostic renal biopsy in 10/80 (13%), changing surveillance in 35/80 (44%), and changing the treatment plan in 16/80 (20%). In cases with no change to management in the proband, the ES result had implications for the management of family members in 26/33 (79%). Cascade testing was subsequently offered to 40/80 families (50%). CONCLUSION: In this pragmatic pediatric and adult cohort with suspected monogenic kidney disease, ES had high diagnostic and clinical utility. Our findings, including predictors of positive diagnosis, can be used to guide clinical practice and health service design.

BACKGROUND: Despite the emergence of diagnostic and clinical utility evidence in nephrology, publicly funded access to genomic testing is restricted in most health care systems. To establish genomic sequencing as a clinical test, an evaluation of cost-effectiveness is urgently required. METHODS: An economic evaluation, informed by a primary clinical study and available clinical evidence and guidelines in nephrology, was performed to evaluate the cost-effectiveness and optimal timing of exome sequencing (ES) in adults and children with suspected monogenic glomerular diseases compared with nongenomic investigations (NGIs). Six diagnostic strategies reflecting current practice and recommended models of care in Australia were modeled: (i) NGIs, (ii) late gene panel followed by ES, (iii) late ES, (iv) early gene panel, (v) early gene panel followed by ES, and (vi) early ES. RESULTS: ES with targeted analysis achieved a diagnosis in 23 of 63 (36.5%) adults and 10 of 24 (41.6%) children. NGIs were estimated to diagnose 4.0% of children, with an average estimated cost of AU$6120 per child. Integrating ES as a first-line test in children was cost saving, with an incremental cost saving of AU$3230 per additional diagnosis compared with NGIs. In adults, NGIs was estimated to diagnose 8% of patients, with an average estimated cost of AU$1830 per person. In adults, integrating ES early resulted in an incremental cost per additional diagnosis of AU$5460 relative to NGIs. CONCLUSIONS: Early ES with targeted analysis was effective for diagnosing monogenic kidney disease, with substantial cost savings in children.

INTRODUCTION: Genomic testing is becoming widely available as a diagnostic tool, although widespread implementation is not yet established in nephrology. METHODS: An anonymous electronic survey was administered to investigate experience and confidence with genomic tests, perceived clinical utility of genomic services, preferences for service delivery models, and readiness for implementation among nephrologists. Questions were guided by a comprehensive literature review and published tools, including a validated theoretical framework for implementation of genomic medicine: Consolidated Framework for Implementation Research (CFIR). RESULTS: Responses were received from 224 clinicians, of which 172 were eligible for analysis. Most clinicians (132 [76%]) had referred at least one patient to a genetics clinic. Despite most clinicians (136 [85%]) indicating that they believed genetic testing would be useful, only 39 (23%) indicated they felt confident to use results of genomic testing, with pediatric clinicians feeling more confident compared with adult clinicians (12 of 20 [60%] vs. 27 of 149 [18%]), P < 0.01, Fisher exact). A multidisciplinary renal genetics clinic was the preferred model among clinicians surveyed (98 of 172 [57%]). A key implementation barrier highlighted related to the hospital or organizational culture and/or environment. Specific barriers noted in quantitative and qualitative responses included inadequate staffing, learning resources, and funding. CONCLUSIONS: Our findings suggest support for genomic testing among nephrologists, with a strong preference for a multidisciplinary model (involving a nephrologist, clinical geneticist, and genetic counselor). Broad-ranging interventions are urgently required to shift the current culture and ensure successful implementation of genomics in nephrology, including reducing knowledge gaps, increased funding and resources, disease-specific guidelines, and streamlining of testing processes.

Introduction: The association between acute kidney injury (AKI) and an increased risk of early morbidity and mortality is well established. However, the impact of AKI on long-term outcomes is less clear. Objective(s): To determine the long-term risk of death, chronic kidney disease (CKD), and end stage kidney disease (ESKD) in critically ill patients with AKI. Method(s): A literature search was performed through EMBASE, MEDLINE, and grey literature sources to identify cohort studies reporting an association between AKI and at least one of the outcomes of interest. All studies published between 2004 and 2017 involving critically ill adults were considered eligible if they defined AKI according to consensus definitions (RIFLE, AKIN, or KDIGO), included a non-AKI control group, and followed patients for at least 1 year. Exclusion criteria included solid organ transplant recipients and patients with AKI "syndromes". Risk of bias was assessed by the Newcastle- Ottawa Scale and random effects meta-analysis was used to compare the risk estimates between studies. Result(s): The search retrieved 3435 citations, of which 57 underwent full-text review. Eighteen studies comprising 92,218 patients met the inclusion criteria. The most common sources of bias were poor representativeness of patient cohorts, and insufficient follow up. Across the 10 studies examining mortality, AKI was associated with a significantly increased risk of death (HR 1.71, 95% CI 1.43-2.04), which progressively increased with AKI stage, although heterogeneity was high (I2 84.5%). There was also an association between AKI and ESKD (HR 5.18, 95% CI 3.14-8.53) and a non-significant increased risk of CKD (HR 5.72, 95% CI 0.62-52.67). Conclusion(s): Despite high heterogeneity between studies, AKI was associated with inferior long-term survival and an increased risk of adverse renal outcomes. Strategies to identify patients at greatest risk are required, to ensure appropriate long-term care is coordinated for t

Background: Proteinuria is a common clinical presentation, the diagnostic workup for which involves many non-invasive and invasive investigations. We report on two siblings that highlight the clinically relevant functional role of cubulin for albumin resorption in the proximal tubule and supports the use of genomic sequencing early in the diagnostic work up of patients who present with proteinuria. Case presentation: An 8-year-old boy was referred with an incidental finding of proteinuria. All preliminary investigations were unremarkable. Further assessment revealed consanguineous family history and a brother with isolated proteinuria. Renal biopsy demonstrated normal light microscopy and global glomerular basement membrane thinning on electron microscopy. Chromosomal microarray revealed long continuous stretches of homozygosity (LCSH) representing ~ 4.5% of the genome. Shared regions of LCSH between the brothers were identified and their further research genomic analysis implicated a homozygous stop-gain variant in CUBN (10p12.31). Conclusion(s): CUBN mutations have been implicated as a hereditary cause of megaloblastic anaemia and variable proteinuria. This is the second reported family with isolated proteinuria due to biallelic CUBN variants in the absence of megaloblastic anaemia, demonstrating the ability of genomic testing to identify genetic causes of nephropathy within expanding associated phenotypic spectra. Genomic sequencing, undertaken earlier in the diagnostic trajectory, may reduce the need for invasive investigations and the time to definitive diagnosis for patients and families.Copyright © 2019 The Author(s).

Introduction: Genomic technologies enable the rapid and cost-effective sequencing of DNA and have demonstrated a definitive diagnosis in several patient groups. The clinical utility of whole exome sequencing (WES) in a kidney disease cohort is not yet well established. We describe the patient characteristics and diagnostic yield of a cohort of 200 patients with suspected genetic kidney disease referred for WES via a multidisciplinary renal genetics clinic. Method(s): 200 sequential patients were recruited into a prospective observational cohort study through five tertiary academic centres in Victoria, Australia. Patients were referred by their treating nephrologist to a dedicated renal genetic service funded by the Melbourne Genomics Health Alliance. Following review by a multidisciplinary team, consisting of a nephrologist, clinical geneticist and genetic counsellor, patients were recruited for genomic sequencing, with analysis for a pre-determined list of genes of interest. We measured the diagnostic yield and its effect on short term clinical management. Result(s): Singleton WES was performed on 123 adult patients and 83 paediatric patients. Majority were female (118) and median age was 27 years (range 0-73 years). 100 of these patients were isolated cases (77 had a known positive family history). From 104 exome results available to date (38 paediatric and 66 adults), 43 patients received a positive molecular diagnosis (41%) and of these 22 (51%) resulted in a change from the original clinical diagnosis. The diagnostic yield was greater in the paediatric cohort (53%) compared to the adult cohort (35%). The effects of genomic testing on clinical management is currently being analysed. Conclusion(s): Singleton WES resulted in a substantial number of positive diagnoses in both adult and paediatric patients. The ongoing analysis of this cohort will allow delineation of the sensitivity of exome sequencing to current diagnostic methods, enable health economic analysis

Introduction: 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. Methods and analysis: 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. Ethics and dissemination: 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.Copyright © 2019 Author(s).

There have been few new therapies for patients with chronic kidney disease in the last decade. However, the management of patients affected by genetic kidney disease is rapidly evolving. Inherited or genetic kidney disease affects around 10% of adults with end-stage kidney disease and up to 70% of children with early onset kidney disease. Advances in next-generation sequencing have enabled rapid and cost-effective sequencing of large amounts of DNA. Next-generation sequencing-based diagnostic tests now enable identification of a monogenic cause in around 20% of patients with early-onset chronic kidney disease. A definitive diagnosis through genomic testing may negate the need for prolonged diagnostic investigations and surveillance, facilitate reproductive planning and provide accurate counselling for at-risk relatives. Genomics has allowed the better understanding of disease pathogenesis, providing prognostic information and facilitating development of targeted treatments for patients with inherited or genetic kidney disease. Although genomic testing is becoming more readily available, there are many challenges to implementation in clinical practice. Multidisciplinary renal genetics clinics serve as a model of how some of these challenges may be overcome. Such clinics are already well established in most parts of Australia, with more to follow in future. With the rapid pace of new technology and gene discovery, collaboration between expert clinicians, laboratory and research scientists is of increasing importance to maximize benefits to patients and health-care systems.Copyright © 2018 The Authors Nephrology published by John Wiley & Sons Australia, Ltd on behalf of Asian Pacific Society of Nephrology

There have been few new therapies for patients with chronic kidney disease in the last decade. However, the management of patients affected by genetic kidney disease is rapidly evolving. Inherited or genetic kidney disease affects around 10% of adults with end-stage kidney disease and up to 70% of children with early onset kidney disease. Advances in next-generation sequencing have enabled rapid and cost-effective sequencing of large amounts of DNA. Next-generation sequencing-based diagnostic tests now enable identification of a monogenic cause in around 20% of patients with early-onset chronic kidney disease. A definitive diagnosis through genomic testing may negate the need for prolonged diagnostic investigations and surveillance, facilitate reproductive planning and provide accurate counselling for at-risk relatives. Genomics has allowed the better understanding of disease pathogenesis, providing prognostic information and facilitating development of targeted treatments for patients with inherited or genetic kidney disease. Although genomic testing is becoming more readily available, there are many challenges to implementation in clinical practice. Multidisciplinary renal genetics clinics serve as a model of how some of these challenges may be overcome. Such clinics are already well established in most parts of Australia, with more to follow in future. With the rapid pace of new technology and gene discovery, collaboration between expert clinicians, laboratory and research scientists is of increasing importance to maximize benefits to patients and health-care systems.

BACKGROUND: Proteinuria is a common clinical presentation, the diagnostic workup for which involves many non-invasive and invasive investigations. We report on two siblings that highlight the clinically relevant functional role of cubulin for albumin resorption in the proximal tubule and supports the use of genomic sequencing early in the diagnostic work up of patients who present with proteinuria. CASE PRESENTATION: An 8-year-old boy was referred with an incidental finding of proteinuria. All preliminary investigations were unremarkable. Further assessment revealed consanguineous family history and a brother with isolated proteinuria. Renal biopsy demonstrated normal light microscopy and global glomerular basement membrane thinning on electron microscopy. Chromosomal microarray revealed long continuous stretches of homozygosity (LCSH) representing ~ 4.5% of the genome. Shared regions of LCSH between the brothers were identified and their further research genomic analysis implicated a homozygous stop-gain variant in CUBN (10p12.31). CONCLUSIONS: CUBN mutations have been implicated as a hereditary cause of megaloblastic anaemia and variable proteinuria. This is the second reported family with isolated proteinuria due to biallelic CUBN variants in the absence of megaloblastic anaemia, demonstrating the ability of genomic testing to identify genetic causes of nephropathy within expanding associated phenotypic spectra. Genomic sequencing, undertaken earlier in the diagnostic trajectory, may reduce the need for invasive investigations and the time to definitive diagnosis for patients and families.

INTRODUCTION: 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. METHODS AND ANALYSIS: 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. ETHICS AND DISSEMINATION: 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.

The 2017 KidGen Renal Genetics Symposium was held at the Royal Children's Hospital and Murdoch Children's Research Institute, Melbourne, from 6 to 8 December 2017. This meeting addressed clinical, diagnostic, and research aspects of inherited kidney disease. More than 100 clinicians, researchers, and patient representatives attended the conference. The overall goal was to improve the understanding and direction of genomics in renal medicine in Australia and discuss barriers to the use of genomic testing within this area. It also aimed to strengthen collaborations between local, state, and global research and diagnostic and clinical groups.Copyright © The Author(s). 2018.

Reliable estimates of the long-term outcomes of acute kidney injury (AKI) are needed to inform clinical practice and guide allocation of health care resources. This systematic review and meta-analysis aimed to quantify the association between AKI and chronic kidney disease (CKD), end-stage kidney disease (ESKD), and death. Systematic searches were performed through EMBASE, MEDLINE, and grey literature sources to identify cohort studies in hospitalized adults that used standardized definitions for AKI, included a non-exposed comparator, and followed patients for at least 1 year. Risk of bias was assessed by the Newcastle-Ottawa Scale. Random effects meta-analyses were performed to pool risk estimates; subgroup, sensitivity, and meta-regression analyses were used to investigate heterogeneity. Of 4973 citations, 82 studies (comprising 2,017,437 participants) were eligible for inclusion. Common sources of bias included incomplete reporting of outcome data, missing biochemical values, and inadequate adjustment for confounders. Individuals with AKI were at increased risk of new or progressive CKD (HR 2.67, 95% CI 1.99-3.58; 17.76 versus 7.59 cases per 100 person-years), ESKD (HR 4.81, 95% CI 3.04-7.62; 0.47 versus 0.08 cases per 100 person-years), and death (HR 1.80, 95% CI 1.61-2.02; 13.19 versus 7.26 deaths per 100 person-years). A gradient of risk across increasing AKI stages was demonstrated for all outcomes. For mortality, the magnitude of risk was also modified by clinical setting, baseline kidney function, diabetes, and coronary heart disease. These findings establish the poor long-term outcomes of AKI while highlighting the importance of injury severity and clinical setting in the estimation of risk.Copyright © 2018 International Society of Nephrology

Background: Primary oxaloses are rare genetic disorders that result in hepatic overproduction of oxalate. Primary hyperoxaluria type1(PH1) is themost common and severe form. Clinical manifestations range from renal calculi to progressive renal impairment and systemic deposition of oxalate. Supportive measures may slow kidney disease progression but many cases develop end stage renal disease(ESRD). Combined liver-kidney transplantation may be curative. Case Report: A 65yo male had developed ESRD in 1990 and underwent deceased-donor kidney transplantation in Holland in 2000. The transplant failed within a week, histology revealed oxalate crystals and a diagnosis of PH1 was made by genetic analysis revealing compound pyridoxine-sensitive mutations in the AGXT gene. The patient returned to haemodialysis for 8 years then presented to our unit for simultaneous kidney-liver transplantation( SLK). Aiming to prevent early disease recurrence, Continuous Renal Replacement Therapy(CRRT) was performed during surgery followed by daily CRRT for nine days. Liver allograft functionwas achieved, however the kidney experienced delayed graft function. A renal biopsy showed only acute tubular necrosis and intermittent haemodialysis was continued for a further week by which time kidney function was evident. The patient was discharged on day 26, creatinine 178umol/L. On day 29, creatinine was 202umol/L and a renal biopsy revealed focal oxalate crystals affecting 10% of kidney. A Repeat biopsy at day 39 showed progressive oxalate deposition. Daily dialysis was re-established followed by slow recovery of kidney allograft function. Conclusion(s): Data surrounding transplantation for primary hyperoxyluria are limited to small case series. Risk of disease recurrence caused by renal excretion of residual systemic oxalate may occur despite SLK preventing further production. More data on how to assess oxalate burden and prevent recurrence are required.

Background: Proteinuria is a common kidney presentation. Historically, diagnostic workup of patients with isolated proteinuria involved thorough urinalysis, imaging and blood sampling before potentially proceeding to renal biopsy. However recent advances have resulted in reduced cost and increased availability of genomic sequencing for establishing clinical diagnoses. Case Report: An 8 year old boy was referred with an incidental finding of persistent proteinuria during investigation for nonspecific abdominal pain. He had no haematuria and had normal serum albumin. All other investigations including blood analysis for haematological, biochemical and immunology parameters, renal ultrasound, ophthalmology and audiology assessment were unremarkable. Further assessment revealed consanguineous family history and a brother also with isolated proteinuria. Renal biopsy demonstrated normal light microscopy and global uniform thinning of the glomerular basement membrane on electron microscopy. Chromosomal microarray revealed long continuous stretches of homozygosity (LCSH) representing ~4.5% of the genome. Shared regions of LCSH between the brothers were identified using the Genomic Oligoarray and single nucleotide polymorphism (SNP) Evaluation tool. Examination of these regions implicated CUBN, on chromosome 10p12.31. Research whole genome sequencing of both affected individuals was performed after informed consent (HREC/15/QRCH/126). This revealed a homozygous stop-gained variant in CUBN (NM-001081.3, c.4689-4690del- TAinsAT, p.(CysIle1263*), ACMG Class 5). Conclusion(s): CUBN mutations have been implicated as a hereditary cause of megaloblastic anaemia and variable proteinuria. This is the second reported family with isolated proteinuria due to biallelic CUBN variants in the absence of megaloblastic anaemia. Therefore, we describe how genomics can successfully identify single gene causes of nephropathy. This presents a case for genomic sequencing to be undertaken earlier i

Introduction: Genomics has rapidly advanced understanding of many inherited kidney disorders. However, there is a discrepancy with clinicians' use of genomics in routine clinical care. This study has two aims: Review the literature to identify barriers that may hinder implementation of genomics in adult nephrology; and to set out a theory-informed research plan on adult nephrologist uptake of clinical genomics. Literature Review: We searched PubMed and MEDLINE for original and review articles until 28/02/2018 on nephrologists' knowledge and practice of genomics/genetics. Given the paucity of data, we also included other subspecialists. Most studies focused on oncologists, obstetricians/gynecologists and general physicians. Many lacked a theoretical basis. Emerging themes were needs for effective education strategies and organizational support, and importance of genetic counsellors facilitating implementation. Study Protocol: The literature review informed the study protocol. Specifically, a web-based cross-sectional survey was developed to evaluate barriers and facilitators to the uptake of genomics amongst Australian nephrologists and trainees. The Consolidated Framework for Implementation Research (CFIR) is a well-utilized, multi-level implementation theory-informed framework applicable in study designs. Questions were based around the CFIR, validated by an expert team in implementation and survey design and further revised following feedback from a pilot survey. Participants were queried regarding their perception/attitude towards genetic testing, preferred method of learning about genetics/genomics, and preferences in terms of support and model of service delivery to establish a baseline of practitioner views to guide further research and implementation strategies. Conclusion(s): There is a lack of literature reporting nephrologists' knowledge and practice of genomics/genetics, though themes from other subspecialties are informative. A CFIR-based survey to clari

Aim: Primary central nervous system post-transplantation lymphoproliferative disorder (PCNS-PTLD) is a rare complication of immunosuppresion.Data is limited to case series, with median survival of 47 months reported in the literature. We aimed to identify our cases of PCNS-PTLD and describe clinical and pathological features and outcomes. Method(s): Search of Unit database and Australia and New Zealand Dialysis and Transplant Registry plus review of case records. We included recipients transplanted between 1990 and 2016 who were followed at our unit. Result(s): Ten patients with PCNS-PTLD and no evidence of systemic PTLD were identified and examined. Median age was 52 (range 31-79). Median time to diagnosis after transplant was 13 years (range 1-36). Pathology from cerebral biopsy showed Epstein-Barr virus (EBV)-positive large B cell lymphoma in all patients. Follow-up was complete for all but one patient (lost to followup since 2011). Of these, four died: one was palliated after diagnosis of PCNS-PTLD due to multiple comorbidities. Another withdrew treatment three years after diagnosis aged 82 due to frailty. A third nursing-home patient died three years following PTLD fromaspiration pneumonia. The forth patient withdrew dialysis after a prolonged admission from presumed progressive multifocal leukoencephalopathy 16 years post PTLD. Three patients remained in remission at time of death.All six surviving patients remain in remission and four retain graft function with a median eGFR of 54ml/min/1.73m2 (range 51-63). Two patients incurred graft loss, one at the time of PTLD diagnosis and the second at twelve months caused by chronic allograft nephropathy, however the second was re-transplanted 7 years after curative therapy. Treatment varied between patients and included surgical resection of single lesions, rituximab with systemic and/or intrathecal chemotherapy, localized or whole brain radiotherapy and reduction of immunosuppression. Conclusion(s): Over half PCNS-P

Introduction and Aims: Robust estimatesof the long-term outcomesof acute kidney injury are needed to inform clinical practice and guide optimal allocation of healthcare resources. This systematic review and meta-analysis aimed to quantify the association between acute kidney injury and chronic kidney disease, end stage kidney disease, and death, using consensus definitions of exposure. Method(s): Systematic searches were performed through EMBASE, MEDLINE, and grey literature sources to identify cohort studies reporting an association between acute kidney injury and at least one of the outcomes of interest. All studies in adults published after 2004, using standardised definitions for acute kidney injury (Risk, Injury, Failure, Loss, and End-stage kidney disease; Acute Kidney Injury Network; or Kidney Disease Improving Global Outcomes), which included a non-acute kidney injury control arm, and followed patients for at least 1 year were considered eligible. A modified Newcastle-Ottawa Scale was used to assess risk of bias, random effects meta-analysis was performed to estimate the pooled risk, and meta-regression was completed to identify potential sources of heterogeneity. Result(s): The search retrieved 3435 unique citations, of which 30 cohort studies (comprising 1,012,627 participants) were eligible for inclusion. The most frequent sources of bias related to inadequate follow up and variable adjustment for potential confounders. Compared to those without acute kidney injury, individuals with acute kidney injury were at significantly increased risk of chronic kidney disease (6 studies; 15,925 participants; hazard ratio [HR] 3.71, 95% CI 2.35-5.86; I2 93.1% p<0.001), end stage kidney disease (5 studies; 45,365 participants; HR 4.18, 95% CI 1.93-9.08; I2 88.8% p<0.001), and death (16 studies; 913,682 participants; HR 1.54, 95% CI 1.40-1.71; I2 85.6% p<0.001). The risk of death increased with greater acute kidney injury severity, and was highest in intensive care and

Background and Aims: BK virus is an important cause of renal allograft loss in the renal transplant population. There is limited data regarding intermediate to long-term outcomes in patients with BK viraemia. Effects of routine screening are not well established, with prevalence in prospectively screened cohorts ranging from 11 to 43%. Our aim was to describe the burden of BK viraemia (BKV) and BK nephropathy (BKN) in a large single transplant centre. Method(s): We conducted a retrospective cohort study of 526 patients transplanted between 2008 and 2015, when routine screening (at 3 and 12 months post transplantation) was established. Result(s): 71 patients (13%) developedBKVand 20 (4%) developed BKN during the study period. The median follow-up was 50.9 months (IQR 28.4-82.2) with a minimum follow-up of 12 months. More than 95% of patients were screened for BK at 3 months. All but two patients with BKN had intermediate or high levels of BKV>1000copies/ml. Themajority of patients had basiliximab induction (73%) and maintenance tacrolimus, mycophenolate and prednisolone (94%). Race was strongly associated with BKV (p<0.001), with Asian/ Indian and Aboriginal/Pacific Islander groups both having an increased risk compared to Caucasian (OR Asian/Indian compared to Caucasian 2.49; 95%CI 1.20-5.16). Therewas a trend toward higher rates ofBKV with increasing HLA mismatch (p=0.065). Acute rejection and thymoglobulin use were not associated with BKV (OR 1.16, p=0.751; OR 0.71, p=0.349 respectively). Conclusion(s): BKV was detected in 13%of our cohort and Asian and Indian race was associated with a significantly increased risk. Routine screening for BKV is effective and enables optimal management of immunosuppression to minimise progression.

The 2017 KidGen Renal Genetics Symposium was held at the Royal Children's Hospital and Murdoch Children's Research Institute, Melbourne, from 6 to 8 December 2017. This meeting addressed clinical, diagnostic, and research aspects of inherited kidney disease. More than 100 clinicians, researchers, and patient representatives attended the conference. The overall goal was to improve the understanding and direction of genomics in renal medicine in Australia and discuss barriers to the use of genomic testing within this area. It also aimed to strengthen collaborations between local, state, and global research and diagnostic and clinical groups.