Recurrent nephrotic syndrome in homozygous truncating NPHS2 mutation is not due to anti-podocin antibodies.

Mutations in NPHS2 are a common cause of focal segmental glomerulosclerosis (FSGS). It was initially assumed that FSGS caused by a genetically defective protein in the native kidney would not recur after transplantation; however, description of three patients with NPHS2 missense mutations challenged the validity of this assumption. A possible mechanism of recurrence in cases with stop-codon mutations is the formation of auto-antibodies against the truncated protein. In this case report, we describe a 9-year-old girl with the R138X NPHS2 mutation who presented with recurrent nephrotic syndrome 4 years after renal transplantation from a deceased donor, and was treated with plasmapheresis with a partial response. Renal histology did not demonstrate glomerular immunoglobulin deposition and an extensive search for anti-podocin antibodies based on indirect Western blot with recombinant podocin, was negative, as was the test for glomerular permeability factor (Palb). Taken together these findings confirm the possibility of post transplantation nephrotic syndrome in patients with NPHS2 mutations. Lack of immunoglobulin deposition, absence of circulating anti-podocin antibodies, and normal Palb suggest that other, unknown pathogenetic mechanisms are implicated.

Familial inheritance of crossed fused renal ectopia.

A family with dominant inheritance of a rare renal malformation is reported. The father and one son had left crossed fused ectopic and dysplastic kidneys and another son had a horseshoe kidney and vesicoureteral reflux. We discuss various potential pathogenetic mechanisms and propose that a defect in the timing of the proper reciprocal induction of the ureteric bud and the metanephric blastema is involved.

Hypothyroidism in primary hyperoxaluria type 1.

We describe 4 patients, aged 3 months to 23 years, with end-stage renal disease and severe, symptomatic hypothyroidism. All 4 had primary hyperoxaluria type 1 (PH1) with diffuse tissue (kidneys, skeleton, eyes, heart) calcium-oxalate deposition, a condition known as oxalosis. The hypothyroidism responded to thyroid hormone replacement therapy. Clinical hypothyroidism within the framework of PH1/oxalosis was probably caused by thyroid tissue damage from an abundance of calcium oxalate. We recommend that thyroid function be monitored in patients with PH1 and oxalosis.

Primary hyperoxaluria type I: a model for multiple mutations in a monogenic disease within a distinct ethnic group.

Primary hyperoxaluria type 1 is an autosomal recessive inherited metabolic disease in which excessive oxalates are formed by the liver and excreted by the kidneys, causing a wide spectrum of phenotypes ranging from renal failure in infancy to mere renal stones in late adulthood. Mutations in the AGXT gene, encoding the liver-specific enzyme alanine:glyoxylate aminotransferase, are responsible for the disease. Seven mutations were detected in eight families in Israel. Four of these mutations are novel and three occur in children living in single-clan villages. The mutations are scattered along various exons (1, 4, 5, 7, 9, 10), and on different alleles comprising at least five different haplotypes. All but one of the mutations are in a homozygous pattern, reflecting the high rate of consanguinity in our patient population. Two affected brothers are homozygous for two different mutations expressed on the same allele. The patients comprise a distinct ethnic group (Israeli Arabs) residing in a confined geographic area. These results, which are supported by previous data, suggest for the first time that the phenomenon of multiple mutations in a relatively closed isolate is common and almost exclusive to the Israeli-Arab population. Potential mechanisms including selective advantage to heterozygotes, digenic inheritance, and the recent emergence of multiple mutations are discussed.