A. Mallett

Atypical haemolytic uraemic syndrome treated with the complement inhibitor eculizumab: the experience of the Australian compassionate access cohort.

This study aimed to report the clinical characteristics and outcomes of Australian patients treated with eculizumab for atypical haemolytic uraemic syndrome (aHUS).

End-stage kidney disease due to Alport syndrome: outcomes in 296 consecutive Australia and New Zealand Dialysis and Transplant Registry cases

BACKGROUND Alport syndrome is a rare inheritable renal disease. Clinical outcomes for patients progressing to end-stage kidney disease (ESKD) are not well described. METHODS 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. RESULTS 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. CONCLUSION 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.

Massively parallel sequencing and targeted exomes in familial kidney disease can diagnose underlying genetic disorders

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 individualized to the patients 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.

Identifying and integrating consumer perspectives in clinical practice guidelines on autosomal-dominant polycystic kidney disease

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).

Mutations in mitochondrial DNA causing tubulointerstitial kidney disease

Tubulointerstitial kidney disease is an important cause of progressive renal failure whose aetiology is incompletely understood. We analysed a large pedigree with maternally inherited tubulointerstitial kidney disease and identified a homoplasmic substitution in the control region of the mitochondrial genome (m.547A>T). While mutations in mtDNA coding sequence are a well recognised cause of disease affecting multiple organs, mutations in the control region have never been shown to cause disease. Strikingly, our patients did not have classical features of mitochondrial disease. Patient fibroblasts showed reduced levels of mitochondrial tRNAPhe, tRNALeu1 and reduced mitochondrial protein translation and respiration. Mitochondrial transfer demonstrated mitochondrial transmission of the defect and in vitro assays showed reduced activity of the heavy strand promoter. We also identified further kindreds with the same phenotype carrying a homoplasmic mutation in mitochondrial tRNAPhe (m.616T>C). Thus mutations in mitochondrial DNA can cause maternally inherited renal disease, likely mediated through reduced function of mitochondrial tRNAPhe.

KHA-CARI Autosomal Dominant Polycystic Kidney Disease Guideline: Management of Polycystic Liver Disease.

a. We recommend screening for polycystic liver disease in all patients diagnosed with autosomal dominant polycystic kidney disease using abdominal ultrasound (1C). b. We recommend that all female patients with autosomal dominant polycystic kidney disease and liver cysts undergo counseling regarding the risks of pregnancy and exogenous estrogen exposure in worsening liver cyst growth (1C). c. We recommend that females at risk of symptoms from hepatic cysts avoid estrogen supplements (1D). d. We recommend that a multidisciplinary team (hepatologist, hepatobiliary surgeon, interventional radiologist, and nephrologist) care for patients with severe polycystic liver disease associated with autosomal dominant polycystic kidney disease (1D).

A multidisciplinary renal genetics clinic improves patient diagnosis

Changes in clinical diagnosis at the Royal Brisbane and Women’s Hospital Renal Genetics Clinic (green, unchanged diagnosis; blue, changed diagnosis) Din advance of their translational clinical application. Multidisciplinary clinics are proposed to overcome this in many medicalfields. This is especially so in nephrology, which is typified by significant community disease burden and heritability. Several renal genetics clinics (RGCs) operate overseas, although their models and outcomes are largely unreported. The first multidisciplinary RGC in Australasia commenced at the Royal Brisbane and Women’s Hospital in August 2013, involving a clinical geneticist, nephrologist, genetic counsellor, and ancillary clinical and diagnostic services. The departments of clinical genetics and nephrology jointly operate the RGC. The clinical geneticist and nephrologist see families in the same appointment, maximising use of time. In this article, we report this clinical service’s initial outcomes and model for mainstreaming genetic medicine.

Atypical HUS associated with severe, unexpected antibody‐mediated rejection post kidney transplant

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.

Genomics in the renal clinic - translating nephrogenetics for clinical practice

Genetic Renal Disease (GRD) presents to mainstream clinicians as a mixture of kidney-specific as well as multi-organ entities, many with highly variable phenotype-genotype relationships. The rapid increase in knowledge and reduced cost of sequencing translate to new and additional approaches to clinical care. Specifically, genomic technologies to test for known genes, the development of pathways to research potential new genes and the collection of registry data on patients with mutations allow better prediction of outcomes. The aim of such approaches is to maximise personal and health-system utility from genomics for those affected by nephrogenetic disorders.

Ibuprofen-related renal tubular acidosis in pregnancy

Ibuprofen-related renal tubular acidosis (RTA) has not been previously described in pregnancy but its occurrence outside of pregnancy is being increasingly described. In this case, a 34-year-old woman presented in the third trimester of pregnancy with Type 1 or distal RTA related to ibuprofen and codeine abuse. It was complicated by acute on chronic renal dysfunction and hypokalemia. Delivery at 37 weeks gestation due to concerns of evolving preeclampsia resulted in the birth of a healthy neonate. RTA and hypokalemia were remediated and ibuprofen and codeine abuse ceased. Some renal dysfunction however continued. Thorough and repeated history taking as well as vigilance for this condition is suggested.