Focal segmental glomerulosclerosis (FSGS) is a prevalent glomerular disease characterized by proteinuria, progression to end stage renal disease and recurrence of proteinuria after kidney transplantation in approximately one third of patients. It has been suggested that rituximab might treat recurrent FSGS through an unknown mechanism. Rituximab recognizes CD20 on B-lymphocytes but might also bind sphingomyelin-phosphodiesterase-acid-like-3b (SMPDL-3b) and regulates acid-sphyngomyelinase (ASMase) activity. We hypothesized that rituximab prevents recurrent FSGS and preserves podocyte SMPDL-3b expression. We studied 41 patients at high risk for recurrent FSGS, 27 of whom were treated with rituximab at time of kidney transplant. Incidence of nephrotic-range proteinuria and change in estimated glomerular filtration rate (ΔeGFR) were analyzed. SMPDL-3b immunostaining was performed in post-reperfusion kidney biopsies. SMPDL-3b protein, ASMase activity, and cytoskeleton remodeling were studied in cultured normal human podocytes that had been exposed to patient sera with or without rituximab. Rituximab treatment was associated with lower incidence of post-transplant proteinuria and decreased ΔeGFR. The number of SMPDL-3b+ podocytes in post-reperfusion biopsies was reduced in patients who developed recurrent FSGS. Rituximab partially prevented SMPDL-3b and ASMase downregulation that was observed in podocytes treated with the sera of patients with recurrent FSGS. Either SMPDL-3b overexpression or treatment with rituximab prevented disruption of the actin cytoskeleton and podocyte apoptosis induced by patient sera. This effect was diminished in cultured podocytes where the gene encoding SMPDL-3b was silenced. Our study suggests that treatment of high-risk patients with rituximab at time of kidney transplant might prevent recurrent FSGS by modulating podocyte function in an SMPDL-3b–dependent manner.

Until now oligonephropathy to indicate "too few nephrons" has been associated with intrauterine growth restriction and experimentally induced abnormalities of renal development. The purpose of this study was to determine whether there is evidence of abnormal postnatal glomerulogenesis in extremely low birth weight preterm infants. Renal autopsy tissue was studied by computer-assisted morphometry from 56 extremely premature infants (birth weight < or = 1000 g) and 10 fullterm infants as controls. Preterm infants were divided into two groups (short survival < or = 40 days vs. long survival > or = 40 days). Each group was subdivided into those with renal failure (RF) and those with normal renal function. Forty-two of 56 preterm infants (75%) were adequate for gestational age. Glomerulogenesis as measured by radial glomerular counts (RGC) was markedly decreased in all preterm infants as compared to term controls and correlated significantly with gestational age (r = 0.87; P < 0.001). Active glomerulogenesis with "basophilic S-shaped bodies" was absent in longer surviving preterm and all term infants. RGC of preterm infants surviving > or =40 days with RF were significantly less than RGC of those with long survival and no RF (P < 0.001). Only this latter group demonstrated increased glomerular size as measured by mesangial tuft area and Bowman's capsule area compared to all other groups (P < 0.001). The kidney continues to form postnatally in preterm neonates, but glomerulogenesis ceases after 40 days. Moreover, it is further inhibited by RF. Compensatory mechanisms in longer surviving preterm infants include glomerular hypertrophy and mesangial proliferation that could lead to hyperfiltration.

The Nephrotic Syndrome Study Network (NEPTUNE) is a North American multi-center collaborative consortium established to develop a translational research infrastructure for Nephrotic Syndrome. This includes a longitudinal observational cohort study, a pilot and ancillary studies program, a training program, and a patient contact registry. NEPTUNE will enroll 450 adults and children with minimal change disease, focal segmental glomerulosclerosis and membranous nephropathy for detailed clinical, histopathologic, and molecular phenotyping at the time of clinically-indicated renal biopsy. Initial visits will include an extensive clinical history, physical examination, collection of urine, blood and renal tissue samples, and assessments of quality of life and patient-reported outcomes. Follow-up history, physical measures, urine and blood samples, and questionnaires will be obtained every 4 months in the first year and bi-annually, thereafter. Molecular profiles and gene expression data will be linked to phenotypic, genetic, and digitalized histologic data for comprehensive analyses using systems biology approaches. Analytical strategies were designed to transform descriptive information to mechanistic disease classification for Nephrotic Syndrome and to identify clinical, histological, and genomic disease predictors. Thus, understanding the complexity of the disease pathogenesis will guide further investigation for targeted therapeutic strategies.

Posterior reversible leukoencephalopathy syndrome (PRES) clinically presents with seizures, severe headaches, and mental and visual changes. Our goal was to describe the clinical features, triggering factors, neuro-imaging findings, and electroencephalogram (EEG) findings in a pediatric cohort with renal disease. We retrospectively analyzed the records of 18 children with the diagnosis of PRES between January 2001 and June 2006 at the University of Miami/Holtz Children's Hospital, USA. There were 22 PRES episodes. The most common clinical presentation was generalized tonic-clonic seizures in 59% (13/22). The most common identified trigger of PRES was hypertensive crisis in 59% (13/22). Almost half of the children had no evidence of on-going uncontrolled hypertension; 44% (8/18) had normal funduscopic examination findings, and 50% (9/18) had no or mild left ventricular hypertrophy. Two of the 18 patients had recurrent PRES episodes, three episodes each. Diffuse slowing was the most common finding on the EEGs. Atypical magnetic resonance imaging (MRI) findings were more prevalent in the imaged cases (62% vs 25%, P < 0.05). All the computerized tomography (CT) scans were normal, despite the positive MRI findings in four cases when both types of imaging was used. All the episodes had total clinical resolution. In conclusion, despite the diverse initial trigger, acute hypertension seems to be the common pathogenic pathway for pediatric PRES. MRI seems superior to CT, with better sensitivity due to its high resolution and diffusion-weighted imaging. The lesions do not necessarily have to be in the posterior white matter and may not be totally reversible.

Of 155 children with the acquired immunodeficiency syndrome (AIDS) whom we evaluated during a 6 1/2-year period, 12 were found to have proteinuria. Histologic studies of tissue from these 12 patients revealed a wide spectrum of renal disease: focal glomerulosclerosis in 5, mesangial hyperplasia in 5, segmental necrotizing glomerulonephritis in 1, and minimal change disease in 1. In addition, 6 had tubulointerstitial infiltrates, and 10 had glomerular dense deposits. All 10 renal specimens studied by electron microscopy contained endothelial tubuloreticular inclusions. The mean age (+/- SD) of the five patients with focal glomerulosclerosis when this condition was identified was 27 +/- 19 months. All five had severe renal failure within a year and died of other causes during the following year. The mean age of the five patients with mesangial hyperplasia was 38 +/- 31 months. Although none of them went on to have renal failure, four died within 8 +/- 7 months. Ten of the 12 patients with proteinuria died during the study period. Of the two surviving, one had mesangial hyperplasia and the other had minimal change disease. We conclude that children who acquire human immunodeficiency virus (HIV) infection during the perinatal period may have renal disease, most often focal glomerulosclerosis, as is the case in adults, or mesangial hyperplasia. Although 5 of the 12 children we studied had renal failure during the study period, none died of it. Further studies are needed to determine the correlations between clinical and pathological features and the pathophysiology of AIDS nephropathy in children.