Nephrotic Syndrome and Renin-angiotensin System: Pathophysiological Role and Therapeutic Potential.

Idiopathic Nephrotic Syndrome (INS) is the most frequent etiology of glomerulopathy in pediatric patients and one of the most common causes of chronic kidney disease (CKD) and end-stage renal disease (ESRD) in this population. In this review, we aimed to summarize evidence on the pathophysiological role and therapeutic potential of the Renin-Angiotensin System (RAS) molecules for the control of proteinuria and for delaying the onset of CKD in patients with INS. This is a narrative review in which the databases PubMed, Web of Science, and Sci- ELO were searched for articles about INS and RAS. We selected articles that evaluated the pathophysiological role of RAS and the effects of the alternative RAS axis as a potential therapy for INS. Several studies using rodent models of nephropathies showed that the treatment with activators of the Angiotensin-Converting Enzyme 2 (ACE2) and with Mas receptor agonists reduces proteinuria and improves kidney tissue damage. Another recent paper showed that the reduction of urinary ACE2 levels in children with INS correlates with proteinuria and higher concentrations of inflammatory cytokines, although data with pediatric patients are still limited. The molecules of the alternative RAS axis comprise a wide spectrum, not yet fully explored, of potential pharmacological targets for kidney diseases. The effects of ACE2 activators and receptor Mas agonists show promising results that can be useful for nephropathies including INS.

Is CD44 in glomerular parietal epithelial cells a pathological marker of renal function deterioration in primary focal segmental glomerulosclerosis?

BACKGROUND: The search for risk factors for chronic kidney disease in children with focal segmental glomerulosclerosis (FSGS) is important in defining prognosis and individualized treatment. This study preliminarily investigated whether CD44 immunostaining in glomerular parietal epithelial cells (PECs) is a prognostic marker in pediatric FSGS. METHODS: In this retrospective study, 26 patients with FSGS, biopsied from 1985 to 2010, were evaluated. Immunohistochemistry for CD44 was performed in all cases. For analysis purposes, patients were grouped according to whether or not they were positive for CD44 in PECs. The primary outcome was a decline in baseline estimated glomerular filtration rate (eGFR) of 50% or more. RESULTS: Median follow-up was 6.9 years. Median renal survival was 14.5 years and probability of a 50% decline of eGRF was 30% in 10 years. Nine children exhibited the primary outcome and 7 developed end-stage renal disease (ESRD). In comparison with PEC CD44-negative patients (n = 18), PEC CD44-positive patients (n = 8) presented lower baseline eGFR (99 ± 41 versus 141 ± 44 ml/min/1.73 m2, p = 0.035) and a significant decline in eGFR (-38.6 ± 39.5 versus -5.6 ± 25.3 ml/min/1.73 m2/year, p = 0.018). No difference was observed in FSGS subtypes or other glomerular features. Presence of CD44 staining in PECs was significantly associated with the decline in baseline eGFR of 50% or more. Renal survival was significantly reduced in PEC CD44-positive patients (3.8 vs 14.6 years in C4d-negative, p < 0.05). CONCLUSION: Our preliminary findings indicate, for the first time, that positivity for CD44 in PECs seems to be a pathological marker of renal function deterioration in pediatric patients with FSGS.

A predictive model of progressive chronic kidney disease in idiopathic nephrotic syndrome.

BACKGROUND: There are limited data on the risk factors for chronic kidney disease (CKD) in children with idiopathic nephrotic syndrome (INS). This retrospective cohort study aimed to develop a predictive model for CKD progression in children with INS. METHODS: Between 1970 and 2012, a total of 294 patients with INS were followed up. The primary outcome was progression to CKD stage 3 or higher. A predictive model was developed using a Cox proportional hazards model. A score was calculated using b-coefficients and summing up points assigned to each significant variable. Prognostic score was grouped into categories: low risk, medium risk, and high risk. RESULTS: Median follow-up was 6.9 years. Median renal survival was 26.1 years and probability of CKD stage 3 or higher was 8% in 10 years. Multivariate analysis showed that the most accurate model included initial age, hematuria, and steroid resistance. Accuracy was high with a c-statistic of 0.95 (95% confidence interval [CI] 0.91-0.99), 0.92 (95% CI 0.88-0.96), and 0.92 (95% CI 0.87-0.97) at 2, 5, and 10 years of follow-up respectively. By survival analysis, 10-year renal survival was 100% for the low-risk and 95% for the medium-risk group, while 40% of high-risk patients would exhibit CKD stage 3 or higher (P < 0.001). CONCLUSIONS: Our predictive model of CKD may contribute to the early identification of a subgroup of INS patients at a high risk of renal dysfunction.