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.

Severe reversible renal failure due to naproxen-associated acute interstitial nephritis.

UNLABELLED: Acute interstitial nephritis is uncommon in children and has very rarely been described with naproxen treatment. We report the occurrence of severe acute renal failure in a 10-year-old girl with juvenile rheumatoid arthritis after 1 month of naproxen therapy. Renal biopsy showed severe acute interstitial nephritis. The patient recovered completely after discontinuation of naproxen and administration of methylprednisolone. A review of the literature regarding non-steroidal anti-inflammatory drug-associated acute interstitial nephritis is provided. CONCLUSION: In an era of increasing popularity of non-steroidal anti-inflammatory drugs for use in children, paediatricians should be aware of the potential renal complications of this class of drugs.

Erythropoietin deficiency causes anemia in nephrotic children with normal kidney function.

Anemia in persistent nephrotic syndrome (NS) has been described in a few case reports but has not been studied systematically. We present a group of 19 children with NS who developed anemia before the deterioration of kidney function. The aim of our study is to determine whether erythropoietin (EPO) and/or iron deficiency are causative factors and to evaluate the effect of EPO replacement therapy. Serum EPO levels, iron status, and vitamin B(12) concentrations were measured in nephrotic patients with anemia (NS-A) and compared with those of nephrotic children with normal hemoglobin (Hb) levels (NS-NHb; n = 13). Two control groups consisted of age-matched patients without kidney disease or hypoxemia with either iron deficiency anemia (IDA; n = 19) or normal Hb concentrations (NHb; n = 16). Most NS-A patients experienced persistent steroid-resistant NS, whereas most NS-NHb children had steroid-responsive NS. Although serum iron, ferritin, and B(12) levels were significantly lower in NS-A children, appropriate replacement therapy that resulted in normalization of ferritin and/or cobalamin levels did not lead to correction of the anemia. NS-A patients had greater EPO levels than those without anemia (21.6 +/- 3.3 versus 5.5 +/- 0.8 IU/L; P: < 0.001), but their response to anemia was inappropriately low compared with IDA children (EPO, 94.6 +/- 15.1 IU/L) despite similar Hb concentrations. EPO therapy for 4 to 9 months in 6 NS-A children with Hb levels less than 9 g/dL led to resolution of the anemia. In conclusion, anemia is a common feature of persistent NS that develops before the deterioration of kidney function. Depletion of iron stores may contribute to the development of anemia, but iron replacement therapy is ineffective. Nephrotic patients have EPO deficiency with a blunted response to anemia. The EPO deficiency is amenable to EPO therapy, which is recommended for this group of patients.

Genetic polymorphism in paraoxonase is a risk factor for childhood focal segmental glomerulosclerosis.

Focal segmental glomerulosclerosis (FSGS) is an important cause of end-stage renal failure (ESRF) in children. Our previous studies have shown that Arab children in Israel have a worse prognosis compared with Jewish patients despite similar clinical presentation and management. Progression of proteinuric glomerular diseases has been associated with alterations in lipid metabolism, and similarities have been drawn between the mechanisms underlying atherosclerosis and glomerulosclerosis. Paraoxonase (PON) is a high-density lipoprotein (HDL)-associated enzyme involved in preventing the oxidation of low-density lipoprotein (LDL), and an association has been shown between two genetic polymorphisms in PON1 and the risk of coronary artery disease. The aim of this study was to determine the frequency of these genetic polymorphisms in PON1 in Arab and Jewish children with FSGS and to determine any association with severity of outcome. Forty-seven children (21 Arab and 26 Jewish) with biopsy-proven FSGS and 274 healthy controls of matching ethnic origin were studied. The glutamine (A)-192-arginine (B) and the methionine (M)-55-leucine (L) polymorphisms were analyzed. The frequency of the A allele was similar in patients and controls (0.68 versus 0.71), as was that of the L allele (0.63 versus 0.6). When subgroups were analyzed, the prevalence of the LL genotype in Arab patients was significantly greater than in Jewish patients (57.1% versus 26.9%, P: < 0.05) and Arab controls (57.1% versus 28.9%, P: < 0.03). A trend in association was found between homozygosity for the L allele and progression of renal disease in Arab children. Homozygosity for the L allele is a risk factor for developing FSGS in Arab children and may be associated with a worse prognosis.

Genetic polymorphisms of the renin-angiotensin system and the outcome of focal segmental glomerulosclerosis in children.

BACKGROUND: The clinical course of primary focal segmental glomerulosclerosis (FSGS) in children is variable, with some patients having a much more rapidly progressing course than others. The purpose of our study was to compare the frequency of three polymorphisms of the renin-angiotensin system (RAS) in children with FSGS with that in healthy controls of matching ethnic groups, and to determine whether the clinical outcome of FSGS was associated with different RAS genotypes. METHODS: Three RAS genotypes were examined in 47 Jewish and Arab children with biopsy-proven primary FSGS and in a large control group: the ACE insertion/deletion polymorphism in intron 16, the M235T mutation in the angiotensinogen gene, and the A1166C in the angiotensin II type 1 receptor gene (AT1R). RESULTS: Arab patients showed a greater tendency towards progressive renal disease than their Jewish counterparts (12 of 21 vs. 9 of 26, P = 0.05) and were less likely to achieve remission (3 of 21 vs. 11 of 26, P < 0.04), despite similar clinical presentation, medical management and follow-up. The RAS allele prevalence was similar among patients and controls of matching ethnic backgrounds, and no difference in allele frequency was found between Arabs and Jews. Homozygotes for the ACE insertion genotype (II) were significantly less likely to have progressive renal disease than patients with the other genotypes (ID and DD; 0 of 6 vs. 21 of 41; P < 0.022). The other RAS polymorphisms were not associated with variations in the clinical course of childhood FSGS. CONCLUSIONS: Homozygosity for the ACE insertion allele may have a protective effect in children with FSGS and can serve as a positive prognostic indicator at diagnosis. The D allele may exert a detrimental dominant effect on outcome. Neither the ACE gene polymorphism nor the other RAS polymorphisms studied are associated with disease prevalence. The AT1R and angiotensinogen gene polymorphisms are not associated with progression of renal disease in FSGS. Ethnic differences in the clinical course of the disease are not linked to these polymorphisms.