Functional tests to guide management in an adult with loss of function of type-1 angiotensin II receptor

Daan H H M Viering,A H Jan Danser,Anneke P Bech,Jack F M Wetzels,René J M Bindels,Jaap Deinum,Jeroen H F De Baaij,Eric J Steenbergen

doi:10.1007/s00467-021-05018-7

Abstract

BackgroundGenetic loss of function of AGT (angiotensinogen), REN (renin), ACE (angiotensin-converting enzyme), or AGTR1 (type-1 angiotensin II receptor) leads to renal tubular dysgenesis (RTD). This syndrome is almost invariably lethal. Most surviving patients reach stage 5 chronic kidney disease at a young age.MethodsHere, we report a 28-year-old male with a homozygous truncating mutation in AGTR1 (p.Arg216*), who survived the perinatal period with a mildly impaired kidney function. In contrast to classic RTD, kidney biopsy showed proximal tubules that were mostly normal. During the subsequent three decades, we observed evidence of both tubular dysfunction (hyperkalemia, metabolic acidosis, salt-wasting and a urinary concentrating defect) and glomerular dysfunction (reduced glomerular filtration rate, currently ~30 mL/min/1.73 m2, accompanied by proteinuria). To investigate the recurrent and severe hyperkalemia, we performed a patient-tailored functional test and showed that high doses of fludrocortisone induced renal potassium excretion by 155%. Furthermore, fludrocortisone lowered renal sodium excretion by 39%, which would have a mitigating effect on salt-wasting. In addition, urinary pH decreased in response to fludrocortisone. Opposite effects on urinary potassium and pH occurred with administration of amiloride, further supporting the notion that a collecting duct is present and able to react to fludrocortisone.ConclusionsThis report provides living proof that even truncating loss-of-function mutations in AGTR1 are compatible with life and relatively good GFR and provides evidence for the prescription of fludrocortisone to treat hyperkalemia and salt-wasting in such patients.

Highlights

Inhibitors of the renin-angiotensin system (RAS) play an important role in the management of increased cardiovascular and renal risk in the aging population
Are full loss-of-function variants in AGTR1, the gene encoding the most important receptor for angiotensin II, compatible with kidney survival? And how should hyperkalemia, salt-wasting and hypotension be treated in a patient with loss of AGTR1 function? Here, we describe the case of a 28-year-old patient with homozygous pathogenic variants in AGTR1 that provides new insights on these questions
Renal tubular dysgenesis is normally characterized by atrophic tubules, especially seen as an extensive reduction in differentiated proximal tubules

Summary

Introduction

Inhibitors of the renin-angiotensin system (RAS) play an important role in the management of increased cardiovascular and renal risk in the aging population. Children with genetic loss-of-function variants in any of the RAS components develop renal tubular dysgenesis (RTD). This clinical syndrome is characterized by poor development of especially proximal tubules, early onset and persistent anuria (often manifesting prenatally) and ossification defects of the skull. Children with pathogenic variants in a RAS component typically die in utero or in the first days of life and develop stage 5 chronic kidney disease (CKD 5) at a young age [3, 4]. AGT (angiotensinogen), REN (renin), ACE (angiotensin-converting enzyme), or AGTR1 (type-1 angiotensin II receptor) leads to renal tubular dysgenesis (RTD). Most surviving patients reach stage 5 chronic kidney disease at a young age

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