This study showed that monogenic variants in patients meeting the strict SRNS definition account for only 12%, i.e., they are less common than previously reported. The results also demonstrated that the presence of edema is an important parameter to differentiate between SRNS types with a monogenic cause and those without.
A recent report from the United Kingdom identified causative variants in 10% of non-syndromic SRNS, excluding congenital and infantile NS [20]. Although their study did not examine serum albumin levels, the patient population in their study might be similar to ours. The proportion of causative variants detected at 1 year of age was surprisingly 5% possibly due to the high incidence of INS at 1 year of age. Monogenic variants are generally detected with a high probability in congenital and infantile NS; by contrast, the probability of a monogenic cause was very low at 1 year of age in our study. In a previous large cohort from the US, the proportion of families with detected monogenic cause at 1, 2, and 3 years of age remained almost unchanged at approximately 25% [11], while in the present study, the proportion according to age at onset was higher at 3 years of age. This difference may be related to urine screening of 3-year-olds during checkups in Japan. As in our study a certain number of cases with monogenic causes were found even beyond school age, it should be considered that monogenic SRNS is not limited to a specific age group.
The most important point of this study is that the detection of monogenic variants was low (7%) in typical cases with edema at onset but very high (38%) in atypical cases without edema at onset. Our group has previously reported that in a cohort of patients with severe proteinuria, significantly fewer patients with monogenic variants showed edema than those without [10], but it included several patients without hypoalbuminemia. The present study shows, for the first time, that in a cohort of only patients with hypoalbuminemia, those with monogenic variants had a significantly reduced frequency of edema.
In patients with congenital analbuminemia, edema is rare, possibly due to edema-preventive mechanisms, including mitigating effects on the oncotic gradient, a reduction in the hydrostatic blood pressure gradient, and a decrease in the capillary permeability of proteins [21]. Moreover, patients with congenital NS can often escape after some time an albumin-dependent status despite hypoalbuminemia [22]. Patients with monogenic variants are less likely to present with edema probably because edema-compensatory mechanisms play a role in chronic or slowly progressive hypoalbuminemia.
In addition to edema, a significant sex difference was observed between the study groups. The significantly lower detection rate of gene abnormalities in males might be due to the higher incidence of INS in male patients. Furthermore, a significant difference was observed regarding a history of complete remission. Similar to the findings of a previous report [23], our results confirmed that monogenic variants were usually not identified in cases with a history of complete remission, except for two cases with remission after cyclosporine A administration (one case each with a WT1 and a COL4A4 variant). Remission of patients with WT1 variants has previously been reported [9], and the case Neph573 with a COL4A4 variant was considered to be coincidentally complicated by INS because COL4A4 variants do not usually lead to NS.
Although no significant difference was observed in other factors, probably due to the small number of cases, some important findings should be highlighted. Monogenic variants were generally not identified in cases with NS-AKI that required temporary dialysis except for one case with a COL4A4 variant (Neph573) that was considered to be coincidentally complicated by INS because COL4A4 variants do not usually lead to NS and therapy led to complete remission in this patient. The reason why SRNS with monogenic variants is less likely to be accompanied by NS-AKI seems to be that NS develops slowly. In addition, the prevalence of monogenic variants was in this study not particularly high in patients with CKD stage 5. Based on these findings, some cases with CKD stage 5 include immunologically induced SRNS, providing the potential for improving kidney outcomes with more intensive immunosuppressive therapy, such as rituximab.
Regarding the initial histopathologic diagnosis, a high proportion (71%) of monogenic variants was found to be FSGS in this study, similar to 63–74% reported in previous publications [10–13]. However, an initial histopathological diagnosis of minor glomerular abnormalities should not lead to the assumption of a non-monogenic cause because minor glomerular abnormalities may change to FSGS over the course of the disease. Especially in younger patients, the histology might be evaluated in the early stage of the disease.
This study has several limitations. First, not all pediatric patients diagnosed with SRNS underwent genetic analysis. The population referred to our hospital for genetic analysis might be biased towards complicated cases in which local doctors suspect monogenic causes. In practice, the proportion of monogenic causes seems to be much lower. Second, some of the cases without monogenic variants might include cases with genetic abnormalities that cannot be detected by our panels, such as deep intronic variants or genes with no established pathogenicity. Third, the timing of genetic analysis varied among patients; in some cases, genetic analysis was performed immediately after the diagnosis of SRNS, whereas in others, genetic analysis was performed after reaching CKD stage 5.
In the end, even in cases where monogenic variants were identified, most patients received additional immunosuppressive therapy (steroid pulse therapy, cyclophosphamide, rituximab, cyclosporine A, tacrolimus, mizoribine, or mycophenolate mofetil) until the results of the genetic analysis were known. This suggests that determining the presence or absence of genetic abnormalities from clinical history alone is challenging.
Although it is ideal for all patients with suspected SRNS to undergo genetic analysis promptly, cases with edema at disease onset should be more aggressively considered for additional immunosuppressive treatment. Conversely, in patients without edema, additional immunosuppressive treatment should be considered more carefully. We hope that our results may help pediatric nephrologists in the decision-making for SRNS therapy.