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Mutations in the NPHS2 gene encoding podocin are implicated in an autosomal-recessive form of nonsyndromic steroid-resistant nephrotic syndrome in both pediatric and adult patients. Patients with homozygous or compound heterozygous mutations commonly present with steroid-resistant nephrotic syndrome before the age of 6 years and rapidly progress to end-stage kidney disease with a very low prevalence of recurrence after renal transplantation. Here, we reviewed all the NPHS2 mutations published between October 1999 and September 2013, and also all novel mutations identified in our personal cohort and in international genetic laboratories. We identified 25 novel pathogenic mutations in addition to the 101 already described. The mutations are distributed along the entire coding region and lead to all kinds of alterations including 53 missense, 17 nonsense, 11 small insertions, 26 small deletions, 16 splicing, two indel mutations, and one mutation in the stop codon. In addition, 43 variants were classified as variants of unknown significance, as these missense changes were exclusively described in the heterozygous state and/or considered benign by prediction software. Genotype-phenotype analyses established correlations between specific variants and age at onset, ethnicity, or clinical evolution. We created a Web database using the Leiden Open Variation Database (www.lovd.nl/NPHS2) software that will allow the inclusion of future reports.

Emphysematous pyelonephritis (EPN) is an acute necrotizing infection with gas presence in the kidney, perinephric space, and/or urinary collecting system that carries a bad prognosis. Some clinical conditions predispose to this entity, such as diabetes mellitus, urinary tract obstruction, and immune-incompetence. Immediate resuscitation, broad-spectrum antibiotics, percutaneous and surgical drainage, and emergent and delayed nephrectomy are therapeutic options that should be applied in a timely fashion. We report our experience of four patients with EPN. Two of the patients were kidney transplant recipients, one patient had bilateral urolithiasis, and one patient was an elderly patient with debilitated general condition and an abdominal mass that could not be defined. Late transplant nephrectomy was performed in one patient, and three patients were treated conservatively. Three patients died, including the patient who had transplant nephrectomy. One patient who presented with lithiasis showed a remarkable recovery with conservative management. The bacteria involved were E. Coli and a resistant Klebsiella. We conclude that EPN is a life-threatening condition that carries a bad prognosis. Early diagnosis is essential for a positive outcome. Therapeutic measures should be applied immediately after diagnosis. An aggressive approach including nephrectomy may be emergently required.

Taken together, these results highlight the clinical and genetic heterogeneity in familial SSNS. Clinical findings sustain an immune origin in all patients, whatever the initial steroid-sensitivity. The absence of a variant shared by two families and the HLA-DQA1 variation enrichments suggest a complex mode of inheritance.

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