RE: Steroid-resistant nephrotic syndrome: impact of genetic testing

To the Editor: Corticosteroids remain the mainstay of treatment of idiopathic nephrotic syndrome (INS) in children, and about 80% of children respond to this first-line therapy for this disease.¹ A significant number of cases, varying from 20% to 30%, however, fails to respond to corticosteroids, either from the outset (primary resistance) or later on during the course of the disease (secondary resistance). This subset of INS, known as steroid-resistant nephrotic syndrome (SRNS), represents a diagnostic and therapeutic dilemma for pediatric nephrologists.¹ The mechanism of steroid resistance in INS still remains elusive. Histology does not appear to be predictive, and the clinical features are also not helpful. Importantly, a subset of SRNS is caused by mutations in a number of podocyte genes.² Thus, the role of genetic factors in the etiopathogenesis of SRNS is being actively investigated throughout the world. Kari et al,³ in a recent issue of your esteemed journal, have explored the frequency of disease-causing mutations in 3 commonly implicated genes in SRNS in a cohort of Saudi children. The authors merit compliments on this important contribution on the topic from this part of the world. Their results are more or less similar to those observed by our group and provide support to our conclusions regarding the role of genetic factors in the routine diagnosis and management of SRNS in children from this region of the world.⁴

We take this opportunity to highlight a few points related to the aforementioned paper and the subject of genetic testing in SRNS. First, Kari et al³ did not give the mean or median age of the study cohort or still better, the stratified age groups. It is well known and also apparent from Table 1 in their paper that the age of onset of INS is an important determinant factor for the frequency of genetic mutations. In general, the younger the age, the higher the prevalence of genetic abnormalities although there could be exceptions.

Second, the authors have not mentioned the timing of the genetic testing in their children, but we assume that this was done late in the course of the disease, as these children received immunosuppressant drugs for 3 to 6 months. In this regard, Santín et al⁵ recommend genetic testing before renal biopsy in children because according to them it is a noninvasive procedure and the histopathology is not a determinant criterion.

Third, the authors have also included 2 cases each of membranoproliferative GN and IgA nephropathy. In essence, these are distinct disease processes and are not typically caused by the genetic abnormalities tested in this study. Although minute in degree, the inclusion of these cases did decrease the overall frequency of genetic abnormalities in the study.

Finally, it seems that much of the wide discrepancy in the reported results is caused by methodological variations, different inclusion and exclusion criteria, and the different genes tested in different studies. Moreover, the definition of SRNS in itself is also fraught with problems and varies widely. All these factors may contribute to the real differences in the prevalence of genetic abnormalities in different races or populations and different regions. There is a need for more studies of larger scale and prospective nature, ideally involving multiple centers to standardize the methodology of genetic testing of children with SRNS and ultimately to develop international consensus guidelines on the clinical utility of genetic testing in childhood SRNS.