Kidney Week

Abstract: PUB449

Altered Function of TRPC6 May Contribute to Pregnancy-Associated aHUS

Session Information

• Publication Only

Category: Trainee Case Reports

• 1002 Genetic Diseases of the Kidney: Non-Cystic

Authors

• Muench, Johannes, University Hospital Leipzig, Leipzig, Germany

Johannes Muench,

• Häfner, Stephanie, University of Leipzig, Leipzig, Germany

Stephanie Häfner,

• Weber, Marie L., University Hospital Leipzig, Leipzig, Germany

Marie L. Weber,

• Schönauer, Ria, University Hospital Leipzig, Leipzig, Germany

Ria Schönauer,

• Lindner, Tom H., University Hospital Leipzig, Leipzig, Germany

Tom H. Lindner,

• Bergmann, Carsten, Bioscientia, Ingelheim, Germany

Carsten Bergmann,

• Stepan, Holger, University Hospital Leipzig, Leipzig, Germany

Holger Stepan,

• Halbritter, Jan, University Hospital Leipzig, Leipzig, Germany

Jan Halbritter,

Introduction

Pregnancy-associated atypical hemolytic uremic syndrome (p-aHUS) has recently become a well-recognized differential diagnosis of aHUS. Postpartal deficiency of complement system inhibitors is suspected trigger endothelial damage and formation of thrombotic microangiopathy (TMA), leading to hemolytic anemia and kidney failure. The presence of preeclampsia is thought to constitute a risk factor for p-aHUS, as the production of soluble Fms-like tyrosinkinase-1 (sFLT-1) promotes TMA formation (Erpenbeck, JASN 2016) by inhibiting the angiogenic effect of vascular endothelial growth factor (VEGF). However, since sFLT-1 production normally ceases with delivery and genetic defects in complement regulators can only be found in half of the cases (Bruel, CJASN 2018), further mechanisms need to be considered.

Case Description

In a 41 year-old female, delivery by caesarean section was performed in the 25^th gestational week, due to preeclampsia (proteinuria 3,4 g/g creatinine, sFLT-1/PIGF 231). Ten days postpartum, she presented with coombs-negative hemolytic anemia (Hb 3.2 mmol/l, platelets 32 Gpt/l, schistocytes 4.3%, LDH >30 mmol/l, haptoglobin <0.1 mmol/l), and acute renal failure (s-creatinine 472 µmol/l). Kidney biopsy revealed glomerular TMA.
Genetic testing for mutations of known aHUS genes was unremarkable. However, a previously reported heterozygous 12bp insertion in exon 2 of TRPC6 was detected (c.253_264dup, p.(Ala85_Phe88dup)) (Weber, Ped. Neph. 2015). TRPC6 encodes an ubiquitously expressed calcium-permeable channel that also plays a crucial role in human podocytes, where defects have been associated with genetic FSGS by mechanisms of both, gain and loss of function (Riehle, JASN 2016). Patch clamp analysis and calcium influx assays upon overexpression of wildtype versus Ala85_Phe88dupare ongoing.

Discussion

P-aHUS is a major postpartal condition that takes several triggers in order to develop. We suggest that altered TRPC6 function may constitute an alternative trigger for development of acute TMA-related kidney failure, similar to the proposed mechanism in DGKE-related aHUS/TMA (Ozaltin, JASN 2013). As podocytic TRPC6 expression is also influenced by VEGF (Thilo, NDT 2012), sFLT-1 mediated VEGF inhibition in the setting of preeclampsia might further provoke an alteration in podocyte and platelet function.