Clinical and molecular characterization of a family with a dominant renin gene mutation and response to treatment with fludrocortisone

Abstract

Background A family was identified with autosomal dominant inheritance of anemia, polyuria, hyperuricemia, and chronic kidney disease. Mutational analysis revealed a novel heterozygous mutation c.58T > C resulting in the amino acid substitution of cysteine for arginine in the preprorenin signal sequence (p.cys20Arg) occurring in all affected members. Methods Effects of the identified mutation were characterized using in vitro and in vivo studies. Affected individuals were clinically characterized before and after administration of fludrocortisone. Results The mutation affects endoplasmic reticulum co-translational translocation and posttranslational processing, resulting in massive accumulation of non-glycosylated preprorenin in the cytoplasm. This affects expression of intra-renal RAS components and leads to ultrastructural damage of the kidney. Affected individuals suffered from anemia, hyperuricemia, decreased urinary concentrating ability, and progressive chronic kidney disease. Treatment with fludrocortisone in an affected 10-year-old child resulted in an increase in blood pressure and estimated glomerular filtration rate. Conclusions A novel REN gene mutation resulted in an alteration in the amino acid sequence of the renin signal sequence and caused childhood anemia, polyuria, and kidney disease. Treatment with fludrocortisone improved renal function in an affected child. Nephrologists should consider REN mutational analysis in families with autosomal dominant inheritance of chronic kidney disease, especially if they suffer from anemia, hyperuricemia, and polyuria in childhood.

Spectrum of mutations in the renin-angiotensin system genes in autosomal recessive renal tubular dysgenesis

“…Interestingly, it has been shown recently that REN mutations in the heterozygous state, affecting the signal sequence of renin, are associated with the occurrence of autosomal dominant chronic tubulointerstitial nephropathies, with hyperuricemia and early anemia [Bleyer et al, 2010;Zivná et al, 2009]. Blood pressure was normal in these patients, plasma renin and aldosterone levels were normal or low, and renal renin expression was decreased.…”

Autosomal Dominant Tubulointerstitial Kidney Disease

“…These patients will develop worsening hypotension and are prone to acute kidney injury on a low sodium diet. To treat the hyperkalemia and mild hypotension, a higher sodium content diet or fludrocortisone 28 may be beneficial. Fludrocortisone corrects the hypotension, hyperkalemia, and the hyperuricemia but does not improve the hemoglobin levels.…”

Autosomal dominant tubulointerstitial kidney disease: of names and genes

“…In this form, patients also have symptoms of low renin activity: they are mildly hypotensive, hyperkalemic, anemic, and prone to acute kidney injury. 6 The cause of the third type of ADTKD remained elusive for many years. Initially, a large group of families with this condition were identified by Deltas and colleagues on the island of Cyprus.…”