Questions Regarding the Analysis of Long-Term Outcomes in Nephrotic Syndrome

We have read with great interest the recent article titled “Long-Term Outcomes in Nephrotic Syndrome by Kidney Biopsy Diagnosis and Proteinuria” published in JASN.1 Although the study provides valuable insights into the long-term outcomes of patients with nephrotic syndrome, we have several concerns regarding the methodology and interpretation of the results, particularly in relation to the adjustment for confounding factors, the dichotomy between pediatric and adult patients, and the static nature of proteinuria metrics used. First, the analysis attributes outcomes primarily to proteinuria levels but inadequately adjusts for critical confounders. Specifically, the study does not account for treatment adherence, which is known to significantly modify proteinuria and disease progression. For instance, previous studies have emphasized that therapy heterogeneity, such as the use of calcineurin inhibitors versus rituximab, significantly affects proteinuria trajectories.2 Without adjusting for these factors, the reported associations may reflect treatment effects rather than intrinsic disease biology. This limitation could lead to misinterpretation of the true relationship between proteinuria levels and long-term outcomes. Second, the reliance on static proteinuria metrics, such as “lowest proteinuria” and time-averaged values, overlooks the dynamic variability within individuals. The study's capture of the dynamic changes in proteinuria is still not comprehensive and in-depth enough, and it has not adequately considered the effect of short-term rapid changes or fluctuations in proteinuria on the prognosis. For example, transient remission followed by relapse is a hallmark of minimal change disease (MCD), but this pattern is not captured by the static metrics used in the study. Dynamic proteinuria patterns have been validated as superior prognostic markers in other glomerular diseases, such as IgA nephropathy.3 By ignoring these dynamic patterns, the study may misclassify patients' risk and provide an incomplete picture of their disease course. More importantly, the fact that the time points for proteinuria measurement in the study (such as 6–12 and 6–24 months after onset) do not match the critical stages of the disease. For patients with rapidly progressive disease, these time points may fail to accurately reflect the activity of the disease in its early stages or the stability in its later stages, leading to a misunderstanding of the relationship between proteinuria and disease progression. For example, if a patient is already in a stage of rapid deterioration of kidney function 6 months after onset, the level of proteinuria at that time may be more influenced by the decline in kidney function, rather than simply reflecting disease activity. Moreover, the study focuses solely on the quantity of proteinuria, without considering the effect of differences in its composition on kidney function impairment and disease prognosis. This may lead to a one-sided assessment of the harmful effects of proteinuria. For example, large-molecule proteinuria and small-molecule proteinuria have different mechanisms and degrees of damage to the renal tubules and interstitium. However, the study fails to distinguish these differences and thus cannot accurately assess the effect of different types of proteinuria on kidney function. In conclusion, although the study provides important data on long-term outcomes in nephrotic syndrome, the limitations mentioned above could affect the validity and generalizability of the findings. Future research should consider more comprehensive adjustments for confounding factors and incorporate dynamic proteinuria metrics to better reflect the true nature of disease progression.

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