John B. Whitlam

Key Points: We evaluated a hub and spoke mainstreaming model to enable nephrologists to order genomic tests independently in their clinic across the state of Victoria. Over 1000 tests were ordered, with the diagnostic yield remaining similar regardless of ordered by local nephrologists or tertiary genomics services. A mainstreaming model proved feasible, scalable, and clinically effective, offering a practical framework for integrating genomics to routine kidney care. Background: Genomic testing has substantial diagnostic and clinical value in nephrology, yet integrating testing into routine care requires service-level changes to ensure timely and equitable access. Methods: We conducted an observational cohort study at four tertiary centers, with a pragmatic, quasi-experimental design to evaluate evidence-informed, service-level interventions to make genomic testing more accessible and routinely embedded within nephrology practice. We implemented a hub and spoke model which provided nephrologists with training, practical resources, and regular case-based discussions, to support test ordering and interpretation within their own clinics. Laboratory audits (June 2021–July 2024) evaluated how public reimbursement and implementation interventions influenced testing patterns. Three periods were compared: prefunding, postfunding, and postintervention. Results: Across the study period, 1028 genomic tests were ordered (63% adults, 37% children; median age 32 years). Results were available for 1014 tests, with an overall diagnostic yield of 34%, which remained stable across all time points. The diagnostic yield was similar regardless of whether testing occurred at tertiary genomics services (249 of 772, 32%) or via local nephrologists (92 of 242, 38%). The number of unique providers ordering tests was higher (T1: 37, T2: 69, T3: 87). The proportion of testing in mainstream nephrology settings rose from 23% to 74%, while absolute testing numbers in multidisciplinary clinics remained consistent over the study period. Conclusion: Mainstreaming genomic testing in nephrology was feasible, scalable, and clinically effective. This model was associated with better access without compromising diagnostic yield and provides a practical framework for integrating genomic medicine into routine kidney care.

Key Points: Twenty-five percent of those with unexplained kidney failure have a monogenic cause. Whole genome sequencing with broad gene panel analysis is a feasible diagnostic approach in nephrology. 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 the age of ≤50 years and had an unknown cause of kidney failure after standard investigation. Clinically accredited WGS was performed in this national cohort after genetic counseling. 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). Participants with a family history of CKD were more likely to have a positive result (odds ratio, 3.29; 95% confidence interval, 1.10 to 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 the 25 participants. Conclusions: In this prospectively ascertained Australian cohort, we identified a genetic diagnosis in 25% of patients with kidney failure of unknown cause.

Export Kidney transplant recipients undergo lifelong monitoring of allograft function and evaluation for transplant complications. The current monitoring paradigm utilizes blood, urine, and tissue markers that are insensitive, nonspecific, or invasive to obtain. As a result, problems are detected late, after significant damage has accrued, and often beyond the time at which complete resolution is possible. Indeed, most kidney transplants eventually fail, usually because of chronic rejection and other undetected injury. There is a clear need for a transplant-specific biomarker that enables a proactive approach to monitoring via early detection of reversible pathology. A biomarker that supports timely and personalized treatment would assist in achieving the ultimate goal of improving allograft survival and limiting therapeutic toxicity to the recipient. Donor-derived cell-free DNA (ddcfDNA) has been proposed as one such transplant biomarker. Although the test is presently utilized most in the United States, it is conceivable that its use will become more widespread. This review covers aspects of ddcfDNA that support informed use of the test by general nephrologists, including the basic biology of ddcfDNA, methodological nuances of testing, and general recommendations for use in the kidney transplant population. Clinical contexts are used to illustrate evidence-supported interpretation of ddcfDNA results and subsequent management. Finally, knowledge gaps and areas for further study are discussed.

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We present a kidney-pancreas transplant recipient who achieved complete recovery from COVID-19. A 45-year-old patient with T3 paraplegia underwent kidney-pancreas transplantation 18 years ago, followed by a subsequent kidney transplant 9 years ago, and presented with fever, hypoxia and hypotension after exposure to two confirmed cases of COVID-19. History of solid organ transplant, pre-existing renal impairment, asthma and an elevated D-dimer were identified as established risk factors for severe COVID-19. Supportive management was provided, baseline immunosuppression with everolimus was continued, and oral prednisolone was increased. A complete recovery was observed. Given the favourable outcome despite risk factors for severe COVID-19, we identify and review the potential mitigating roles of immunosuppression and mammalian target of rapamycin (mTOR) inhibitors in this disease. Further investigation is required to establish whether mTOR inhibitors could be used as therapeutic agents to treat COVID-19, or as alternative immunosuppression implemented early in the COVID-19 disease course.

The development of antiviral‐resistant cytomegalovirus (CMV) infection complicates the management of transplant recipients. We describe the case of a 65‐year‐old male who developed CMV disease on valganciclovir prophylaxis (donor CMV IgG positive, recipient CMV IgG indeterminate) 30 days after combined liver–kidney transplantation for alcoholic cirrhosis and hepato‐renal syndrome. After an initial complete response to treatment dose oral valganciclovir, he developed recurrent CMV viraemia. Resistance testing revealed a UL97 mutation with in‐frame deletions of codons 595‐596. He was treated successfully with foscarnet and reduction in immunosuppression. This mutation has not been described previously and was suspected to confer ganciclovir resistance. Ganciclovir resistance occurs most commonly due to mutations in the UL97 or UL54 genes, which encode a protein kinase and a DNA polymerase, respectively. The UL97‐encoded protein kinase phosphorylates ganciclovir to ganciclovir triphosphate, which competitively inhibits viral replication. Mutations in the UL97 gene are typically point mutations or deletions. We describe a new mutation, del595‐596 in the CMV UL97 gene, occurring in the context of clinical treatment failure with standard and double‐dose ganciclovir, and successful virological control achieved with foscarnet. This mutation is likely to result in ganciclovir resistance, although recombinant phenotyping is required for confirmation.

Living kidney donors (LKD) for paediatric kidney transplant recipients (KTR) have a heightened motivation to donate for emotional reasons and the clear health benefits to the KTR. We hypothesized that the cohort of LKD for paediatric KTR (LKD‐P) includes motivated young parents with a higher lifetime end‐stage kidney disease (ESKD) risk compared to adult KTR (LKD‐A). Data from the Australia and New Zealand Dialysis and Transplant LKD Registry (2004–2015) was analysed to compare baseline characteristics and predonation ESKD risk in LKD‐P (n = 315) versus LKD‐A (n = 3448). LKD‐P were younger (median age 42 vs. 50 years; P < 0.001) and had a marginally higher lifetime ESKD risk (median 0.44% vs. 0.40%; P < 0.01), with a similar proportion of LKD exceeding 1% risk threshold (5.4% vs. 5.6%; P = NS). Compared to grandparents as LKD‐P, parents (median age 41 vs. 59 years; P < 0.001) had a higher lifetime ESKD (0.44% vs. 0.25%; P < 0.001). Although unique benefits to paediatric KTR justify the minor increase in lifetime ESKD risk in young parents, carefully selected grandparents are an alternative LKD‐P option, allowing parents to donate for subsequent transplants.