Immunophenotyping Profiling in Patients With Nephrotic Syndrome: Emphasis on the Diagnostic and Prognostic Value of Immune Cells in the Different Phenotypes of Nephrotic Syndrome.

Primary nephrotic syndrome caused by membranous nephropathy (MN), focal segmental glomerulosclerosis (FSGS), or minimal change disease (MCD) is, in each case, associated with dysregulation of specific innate and adaptive immune cell populations. However, the relationship between circulating immune cell subsets and key clinical outcomes, specifically treatment response and disease relapse, remains incompletely defined, and the classical clinical and laboratory markers currently used to monitor these diseases are non-specific and have limited predictive value.

The principal parameter used clinically to monitor treatment response remains 24-hour urinary protein excretion. Complete remission is defined as a reduction in proteinuria to below 0.3 g/24h, and partial remission as a reduction of ≥50% from baseline together with total proteinuria below 3.5 g/24h. Non-response is defined as persistent proteinuria above 3.5 g/24h despite guideline-directed therapy, and relapse as recurrence of proteinuria above 3.5 g/24h in a patient who had previously achieved complete remission.

In MN specifically, serum anti-PLA2R antibody titers provide an additional marker of immunological disease activity: a decline in antibody levels can precede and predict clinical response, while re-emergence or a rise in titer in a patient previously in remission can predict relapse.

Despite the established contribution of specific immune cell populations to primary nephrotic syndrome, the literature remains comparatively sparse regarding abnormalities in regulatory T-cell subsets, monocyte subsets, B-cell subsets (including CD5+ B cells), T-helper subsets, and NK cells, and their potential role in disease pathogenesis across MN, MCD, and FSGS. Furthermore, classical clinical and immunological biomarkers of disease activity and treatment response are non-specific, correlate poorly with the degree of underlying renal injury, and in most cases cannot predict renal outcome. Anti-PLA2R1 antibody titers capture humoral activity and glomerular injury, but only partially explain this heterogeneity, are informative in only 70-80% of patients and frequently lag behind cellular events.

Whether changes in specific circulating immune cell subsets are associated with clinical outcomes in primary nephrotic syndrome, and whether they add predictive value beyond classical markers, remains an open question that this study is designed to address.