An international research team led by Stan Kmoch, PhD, of the Center for Applied Genomics and Institute for Inherited Metabolic Disorders of Charles University in Prague, Czech Republic, have identified a number of families suffering from a mutation in the signal peptide of the renin gene that lead to the development of autosomal dominant CKD.

This investigation was reported in the American Journal of Human Genetics (2009;85:204-213). Detailed studies concerning the pathogenetic effects of the identified mutations were performed by Martina Živná, a PhD student in Prague and first author of the article.

Renin is generated from the REN gene, which first synthesizes a protein called preprorenin. This protein has a signal sequence that directs it to the rough endoplasmic reticulum for glycosylation and subsequent secretion. All families affected by this condition have been found to have mutations in the signal sequence of preprorenin.

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This mutation results in the inability of the preprorenin molecule to be properly processed, synthesized, and secreted. As the condition is autosomal dominant, only one allele of the gene is affected. Somehow, the product of the altered renin gene also decreases protein synthesis from the normal renin gene, resulting in low or low normal renin and aldosterone levels in affected individuals. 

Because of the low renin and aldosterone levels, patients may have mildly low blood pressures and mild hyperkalemia. In addition, it appears that renin may play a role in erythropoiesis, and children with the disorder have anemia. Curiously, the anemia tends to resolve in the teenage years, possibly because of the increased synthesis of androgens, which stimulate erythropoiesis.

Intracellular accumulation of abnormal renin may lead to accelerated cell death, nephron dropout, and the slow progression of CKD.

Characteristics of autosomal dominant interstitial kidney disease due to renin mutations include:

  • Chronic kidney disease with bland urinary sediment

  • Autosomal dominant inheritance

  • Anemia presenting during childhood with low erythropoietin levels

  • Hyperuricemia due to reduced urinary excretion of uric acid (Gout often present)

  • Low or low normal plasma renin activity

  • Low or low normal serum aldosterone levels and 24 hour urinary aldosterone

  • Mild hyperkalemia

  • Low normal BP in the setting of kidney disease

Diagnosis relies on recognition of the cardinal manifestations: a family history of kidney disease, renal insufficiency with a bland urinary sediment, and a history of anemia and hyperuricemia in childhood. The presence of hyperuricemia (gout) and hyperkalemia in the family are not always present but increase suspicion for this disorder when found. Definitive diagnosis can be obtained by sequencing of the renin gene.

The clinical status of these patients is similar to patients receiving an ACE inhibitor. Therefore, avoidance of volume depletion is important in preventing acute renal failure. Patients with hyporeninemic hypoaldosteronism may benefit from the use of fludrocortisone, though this has not been extensively studied in these families. n

Dr. Bleyer is Professor of Internal 
Medicine/Nephrology at Wake Forest University School of Medicine in 
Winston-Salem, N.C. He also is a member of the Renal & Urology News Editorial Advisory Board.

Editor’s note: Dr. Bleyer, in conjunction with Dr. Kmoch, is developing a registry of families affected by autosomal dominant CKD. Potentially affected families can be tested for mutations. For further information, e-mail Dr. Bleyer at [email protected]