What Are the Long-Term Renal Outcomes in Children with Steroid-Resistant Nephrotic Syndrome
Although the majority of children with primary Nephrotic Syndrome respond rapidly to glucocorticoid therapy, about 10% of patients are steroid-resistant nephrotic syndrome (SRNS). The histopathological pattern in SRNS patients is mainly Focal Segmental Glomerular Sclerosis (FSGS). SRNS/FSGS is associated with an increased risk of end-stage renal disease (ESRD). Patients with SRNS who respond to intensive immunosuppression therapy (IIST) have better long-term outcomes than those with IIST resistance.
In recent years, many abnormal genes expressed in podocytes and causing SRNS have been identified. Comprehensive genetic screening currently identifies up to 30% of inherited podocytosis in children with SRNS. The current view is that genetic etiology and responsiveness to IIS information should be considered in the reclassification of SRNS. However, SRNS cohort studies that assessed long-term outcomes based on genetic information and IIS responsiveness had small sample sizes, short follow-up times, or incomplete information.
Therefore, Dr. Franz Schaefer, a pediatric nephrologist from Germany, and his colleagues studied the value of information such as genetic factors, histological characteristics and early treatment response in predicting long-term renal outcomes in children with SRNS. The article was published in JASN magazine in October 2017.
The PodoNet registry is an international patient registration system that comprehensively records the clinical, biochemical, treatment-related, genetic and histological information of steroid-resistant patients with primary childhood nephrotic syndrome, followed up for 15 years. Patients in this cohort study were followed for an average of 3.6 years. From this database, the researchers obtained long-term clinical data of 1,354 patients (the onset of the disease > 3 months and the age <20 years old), of which 612 patients responded to IIS, 115 patients had renal biopsy results, and 212 patients had a clear genetic diagnosis. Multivariate Cox regression model was used to analyze the risk factors of end-stage renal disease (ESRD).
The study found that 24.5% and 16.5% of patients experienced complete and partial remission of proteinuria at the 12th month of onset, respectively, with the highest remission rate in patients using a calcineurin inhibitor (CNI) based regimen, while steroid pulse therapy, cyclophosphamide, and cellcept (MMF) were ineffective in more than 80% of patients.
Among patients with multidrug resistance, the 10-year renal survival rates without ESRD were respectively 43%, 94%, and 72% in patients with IIS resistance, complete remission, and partial remission (P< 0.001). The 15-year renal survival rate was 94% in patients who were fully responsive to initial IIS, compared with 37% in patients with multidrug resistance (P< 0.001).
The diagnosis of a genetic disease significantly affects the risk of ESRD: the 10-year and 15-year ESRD-free renal survival rates in hereditary cases were 27% and 17%, respectively, while the 10-year and 15-year ESRD-free renal survival rates in sporadic cases were 53% and 48%, respectively. The 10-year renal survival rates without ESRD in patients with NPHS2-related kidney disease, WT1-related disease and other rare podocytic diseases were 28%, 23% and 29%, respectively. Patients with familial disease but no established genetic diagnosis had a better 10-year renal survival rate than those with a clear genetic diagnosis (P<0.001).
Genetic diagnosis was present in 27% of the children, and histologic findings were Minmal Change Disease (MCD) and focal segmental glomerulosclerosis (FSGS) in 79% and 52% of the children, respectively. The 5-year renal survival without ESRD was 21% in patients with diffuse mesangiosclerosis. Cox regression analysis showed that responsiveness to IIS, genetic diagnosis, initial renal biopsy histology with FSGS or diffuse mesangiosclerosis, age, serum albumin levels, and CKD stage at onset were risk factors for ESRD.
This study confirms that response to initial IIS treatment and detection of inherited podocytosis are both favorable and unfavorable factors for predicting long-term outcomes in children with SRNS, respectively. Kidney survival is higher in sporadic children with multidrug resistance than in children with inherited disease. In addition, histopathological findings may be prognostic when genetic diagnosis is clearly established.
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