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The Heart of Children with Steroid-Resistant Nephrotic Syndrome: Is It All Podocin?

Yaacov Frishberg^*, Sofia Feinstein^*, Choni Rinat^*, Rachel Becker-Cohen^*, Israela Lerer, Annick Raas-Rothschild, Benjamin Ferber and Amiram Nir

^* Pediatric Nephrology; Pediatric Cardiology, Shaare Zedek Medical Center, and Department of Human Genetics, Hadassah University Medical Center, Jerusalem, Israel

Address correspondence to: Dr. Yaacov Frishberg, Division of Pediatric Nephrology, Shaare Zedek Medical Center, P.O. Box 3235, Jerusalem, Israel 91031. Phone: 972-2-6666144; Fax: 972-2-6555484; E-mail: yaacov{at}md.huji.ac.il

Received for publication June 23, 2005. Accepted for publication October 2, 2005.

Mutations in the gene NPHS2 encoding podocin are responsible for a recessive form of steroid-resistant nephrotic syndrome (SRNS). The common phenotype is of massive proteinuria in early childhood that tends to progress to end-stage renal failure. Extrarenal manifestations have not been described. Twenty-two children with SRNS from six unrelated Arab families were found to be homozygous for the R138X mutation in NPHS2. Eighteen patients underwent cardiac evaluation at diagnosis of SRNS while they had normal BP and preserved renal function. Cardiac anomalies were detected in 16 (89%) children: Left ventricular hypertrophy in eight, pulmonary stenosis in six, discrete subaortic stenosis in two, and Ebstein anomaly and ventricular septal defect in one each. The remaining four affected individuals were assessed only once they had end-stage renal failure. They had severe left ventricular hypertrophy and experienced repeated episodes of heart failure. Two control groups were equally evaluated. The first consisted of 37 siblings without nephrotic syndrome, of whom only one carrier had a cardiac defect (P < 0.001). None of the second group, which included 22 children with persistent nephrotic syndrome as a result of other causes, had a cardiac anomaly (P < 0.001). Cardiac disorders in homozygotes for mutations in NPHS2 cannot be attributed to an association by chance or to a state of persistent nephrotic syndrome. Because human podocin mRNA is expressed in fetal heart, it is speculated that it may have a role in normal cardiac development. Cardiac evaluation is recommended at the time of diagnosis of SRNS due to mutations in podocin.

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Copyright © 2009 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673