REFERRAL TO A JOINT RENAL GENETICS CLINIC IMPROVES DIAGNOSIS FOR PATIENTS WITH AUTOSOMAL DOMINANT TUBULOINTERSTITIAL KIDNEY DISEASE

INTRODUCTION: A joint renal genetics clinic was established at our hospital in 2012. The clinic runs four times per year and sees referrals with a variety of renal manifestations from five hospitals in South West England. Autosomal dominant tubulointerstitial kidney disease (ADTKD), which is characterised by progressive tubulointerstitial fibrosis and progression to end-stage renal disease (ESRD), is now known to be caused by mutations in the genes encoding uromodulin (UMOD), hepatocyte nuclear factor 1β (HNF1B), renin (REN) and mucin-1 (MUC1) in the majority of cases. However, diagnosis can be challenging due to a lack of uniform diagnostic criteria and confusing terminology. Our aim was to review all referrals with possible ADTKD to the joint renal genetics clinic to see if use of the service led to improvements in diagnosis.

METHODS: 4/29 referrals with probable ADTKD were identified from 2012 to 2015. Clinical information was obtained from genetic notes and test results.

RESULTS: A genetic diagnosis was confirmed in 3/4 families with probable ADTKD:

Case 1: 57 year old lady approaching ESRD with absence of renal cysts on imaging, bland urinary sediment, hyperuricaemia and a family history of possible ADTKD in her deceased mother and “small kidneys” in her maternal grandmother. Further questioning revealed a long-standing and unexplained anaemia since adolescence. Genetic testing identified a novel heterozygous and pathogenic variant in the REN gene (c.49T>C, p.Trp17Arg). Absence of this variant in her sister allowed pre-emptive renal transplantation to take place.

Case 2: 15 year old girl with chronic kidney disease (CKD) detected incidentally following appendicectomy with a family history of CKD stage 3b of unknown aetiology in a maternal aunt and CKD with hyperuricaemia and gout in her maternal grandmother. Genetic testing identified a heterozygous pathogenic variant in the UMOD gene (c.628G>C, p.Gly210Arg), including her clinically unaffected mother.

Case 3: 42 year old lady with CKD, hyperuricaemia and a strong family history of nephropathy. Genetic testing identified a heterozygous mutation of the UMOD gene (c.688T>C, p.Trp230Arg).

Case 4: 40 year old lady with CKD and a renal biopsy showing glomerulosclerosis, interstitial fibrosis, tubular cysts and small medullary cysts. Her mother has ESRD of unknown aetiology and there is a strong family history of nephropathy. No mutations were identified in UMOD or HNF1B; the aim is to perform MUC1 genetic testing once clinically available.

CONCLUSIONS: Our results demonstrate that referral of families with probable ADTKD to a joint renal genetics clinic leads to a genetic diagnosis in the majority of cases, which has important implications for both individual patient management and genetic counselling within the extended family. Ongoing follow-up will determine if this leads to increased awareness of this rare condition amongst local clinicians and hence further referrals.