Genomic testing for suspected monogenic kidney disease in children and adults: A health economic evaluation.

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.

Clinical and diagnostic utility of genomic sequencing for children referred to a Kidney Genomics Clinic with microscopic haematuria.

BACKGROUND: Microscopic haematuria in children is associated with the risk of progression to chronic kidney disease. Genetic disease is an important potential aetiology. Genomic sequencing presents the most effective diagnostic route for these conditions, but access remains inequitable internationally. METHODS: We conducted a retrospective review of the electronic medical records of a Kidney Genomics Clinic (KGC) from January 2016 to December 2021. RESULTS: Sixty patients were referred to the KGC with haematuria over this period. Forty-three percent of patients had analysis of a limited haematuria panel (COL4A1, COL4A3, COL4A4, COL4A5, MYH9) with 58% receiving a genetic diagnosis. Forty-two percent of referred patients had further analysis of genes implicated in the development of kidney disease, and 36% received a diagnosis. Eight percent of patients underwent cascade testing for a known familial variant, and all received a diagnosis. Children with the highest levels of haematuria (> 500 × 106/L red blood cells) had the highest diagnostic yield (67%). Proteinuria, defined as a urinary protein to creatinine ratio > 20, increased the diagnostic yield from 31 to 65%. Importantly, negative genetic analysis can still have significant clinical utility for patients by altering surveillance and further management; the genetic result had clinical utility in 60% of patients. CONCLUSIONS: Our KGC review highlights the substantial clinical utility and diagnostic yield of genomic analysis for microscopic haematuria in paediatric patients. Whilst the management of variants of uncertain significance can be challenging, a multidisciplinary team including genetic counselling can help ensure these patients are followed up meaningfully. A higher resolution version of the Graphical abstract is available as Supplementary information.

Theory Designed Strategies to Support Implementation of Genomics in Nephrology.

(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.

Cost-Effectiveness of Targeted Exome Analysis as a Diagnostic Test in Glomerular Diseases.

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.

Attitudes and Practices of Australian Nephrologists Toward Implementation of Clinical Genomics.

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.

Clinical impact of genomic testing in patients with suspected monogenic kidney disease.

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.

Isolated proteinuria due to CUBN homozygous mutation - challenging the investigative paradigm.

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.

Comprehensive evaluation of a prospective Australian patient cohort with suspected genetic kidney disease undergoing clinical genomic testing: a study protocol.

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.

Long-term risk of adverse outcomes after acute kidney injury: a systematic review and meta-analysis of cohort studies using consensus definitions of exposure.

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.

Renal genetics in Australia: Kidney medicine in the genomic age.

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.

Meeting report of the 2017 KidGen Renal Genetics Symposium.

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.