Intensified blood-pressure control, with target 24-hour blood-pressure levels in the low range of normal, confers a substantial benefit with respect to renal function among children with chronic kidney disease. Reappearance of proteinuria after initial successful pharmacologic blood-pressure control is common among children who are receiving long-term ACE inhibition. (ClinicalTrials.gov number, NCT00221845.)

Overexpression of soluble urokinase receptor (suPAR) causes pathology in animal models similar to primary FSGS, and one recent study demonstrated elevated levels of serum suPAR in patients with the disease. Here, we analyzed circulating suPAR levels in two cohorts of children and adults with biopsyproven primary FSGS: 70 patients from the North America-based FSGS clinical trial (CT) and 94 patients from PodoNet, the Europe-based consortium studying steroid-resistant nephrotic syndrome. Circulating suPAR levels were elevated in 84.3% and 55.3% of patients with FSGS patients in the CT and PodoNet cohorts, respectively, compared with 6% of controls (P,0.0001); inflammation did not account for this difference. Multiple regression analysis suggested that lower suPAR levels associated with higher estimated GFR, male sex, and treatment with mycophenolate mofetil. In the CT cohort, there was a positive association between the relative reduction of suPAR after 26 weeks of treatment and reduction of proteinuria, with higher odds for complete remission (P=0.04). In the PodoNet cohort, patients with an NPHS2 mutation had higher suPAR levels than those without a mutation. In conclusion, suPAR levels are elevated in geographically and ethnically diverse patients with FSGS and do not reflect a nonspecific proinflammatory milieu. The associations between a change in circulating suPAR with different therapeutic regimens and with remission support the role of suPAR in the pathogenesis of FSGS.

Background Focal segmental glomerulosclerosis (FSGS) is a kidney disease that presents with nephrotic syndrome and is often resistant to glucocorticosteroids and progresses to end-stage kidney disease in 50–70% of patients. Genetic studies in familial FSGS indicate that it is a disease of the podocytes, major components of the glomerular filtration barrier. However the molecular cause of over half of primary FSGS is unknown, and effective treatments have been elusive. Methods We performed whole-genome linkage analysis followed by high-throughput sequencing of the positive linkage area in a family with autosomal recessive FSGS and sequenced a newly discovered gene in 52 unrelated FSGS patients. Immunohistochemistry was performed in human kidney biopsies and cultured podocytes. Expression studies in vitro were performed to characterize the functional consequences of the mutations identified. Results Two mutations (A159P and Y695X) in MYO1E, encoding the non-muscle class I myosin, myosin 1E (Myo1E), which segregated with FSGS in two independent pedigrees were identified. Patients were homozygous for the mutations and were resistant to glucocorticosteroids. Electron microscopy showed thickening and disorganization of the glomerular basement membrane. Normal expression of Myo1E was documented in control human kidney biopsies in vivo and in glomerular podocytes in vitro. Transfection studies revealed abnormal subcellular localization and function of A159P-Myo1E mutant. The Y695X mutation causes loss of calmodulin binding and the tail domains of Myo1E. Conclusions MYO1E mutations lead to childhood onset steroid-resistant FSGS. These data support a role of Myo1E in podocyte function and the consequent integrity of the glomerular permselectivity barrier.

Renal hypodysplasia (RHD) is characterized by reduced kidney size and/or maldevelopment of the renal tissue following abnormal organogenesis. Mutations in renal developmental genes have been identified in a subset of affected individuals. Here, we report the first mutations in BMP4 and SIX2 identified in patients with RHD. We detected 3 BMP4 mutations in 5 RHD patients, and 3 SIX2 mutations in 5 different RHD patients. Overexpression assays in zebrafish demonstrated that these mutations affect the function of Bmp4 and Six2 in vivo. Overexpression of zebrafish six2.1 and bmp4 resulted in dorsalization and ventralization, respectively, suggesting opposing roles in mesendoderm formation. When mutant constructs containing the identified human mutations were overexpressed instead, these effects were attenuated. Morpholino knockdown of bmp4 and six2.1 affected glomerulogenesis, suggesting specific roles for these genes in the formation of the pronephros. In summary, these studies implicate conserved roles for Six2 and Bmp4 in the development of the renal system. Defects in these proteins could affect kidney development at multiple stages, leading to the congenital anomalies observed in patients with RHD.

Background: We aimed to review our experience with childhood lupus nephritis (LN) in respect to the analysis of the clinical and histopathological presentation of LN and prognostic factors affecting the kidney and patient outcomes. Method: Forty-three children (39 girls, 4 boys) with biopsy-proven LN were included in the study. The mean age of the children was 12.0 ± 2.8 years. Based on the renal histopathology and clinical presentation, patients were treated with oral prednisone, intravenous pulses of methylprednisolone or intravenous cyclophosphamide. The final clinical status was classified as follows: (1) renal and extrarenal remission; (2) clinically active renal disease, or (3) adverse outcome, i.e., end-stage renal failure (ESRF) or death. Results: The mean duration of follow-up was 7.2 ± 2.8 years (1 month to 14.2 years). All 43 children had hematuria and 53.5% had proteinuria at admission. Fourteen children were in nephrotic status at the onset of disease. Class IV (diffuse proliferative) nephritis was observed in 29 patients as the most frequent histopathology (67.4%). The patients with class IV nephritis had a tendency to develop nephrotic syndrome, heavy proteinuria, increased Cr levels and persistent hypertension at initial evaluation. Thirty-two of 43 children (74.4%) were in renal remission at the last visit. Five-year kidney and patient survival rates from the time of diagnosis to the endpoints of ESRF or death were 83.7 and 90.7% respectively in the whole group while it was 75.9 and 86.2% respectively in the class IV group. Adverse outcome was significantly associated with the persistent hypertension, anemia, high serum Cr level, heavy proteinuria, nephrotic syndrome and class IV nephritis at presentation. Conclusion: We can conclude that the prognosis of LN in children is primarily dependent on the histopathological lesions. Severity of the clinical renal disease at admission and presence of persistent hypertension are the main poor prognostic factors rather than age, gender, low C3 and C4 levels, ANA positivity and the treatment modalities in Turkish children.