Association Between Microscopic Hematuria and Proteinuria Remission in Adult Nephrotic Syndrome

The prognostic significance of hematuria in nephrotic syndrome is underappreciated, particularly in Asian populations where outcomes can differ from Western cohorts. Previous large-scale studies were limited by imprecise dipstick testing, which is prone to false-positive and cannot grade severity. This study addresses these gaps by using microscopic urine sediment examination to precisely characterize hematuria's presence and severity, evaluating its association with proteinuria remission in a large Japanese cohort with primary nephrotic syndrome (minimal change disease [MCD], focal segmental glomerulosclerosis [FSGS], and membranous nephropathy [MN]).

This multicenter retrospective study included 430 adults (median age 66) with nephrotic syndrome (proteinuria ≥3.5 g/gCr, albumin ≤3.0 g/dL) who underwent native kidney biopsy at 10 Japanese hospitals (2012–2022). The primary predictor, microscopic hematuria, was assessed by urine sediment examination at biopsy and defined as positive if ≥5 red blood cells/high-power field (RBCs/HPF). Severity was graded as mild (5–9 RBCs/HPF) or severe (≥10 RBCs/HPF). The primary outcome was the first achievement of complete proteinuria remission (urine protein-to-creatinine ratio <0.3 g/gCr). Kaplan-Meier analysis and multivariable Cox proportional hazards models were used, adjusting for age, sex, BMI, hypertension, diabetes, eGFR, urinary protein, and pathological diagnosis.

Microscopic hematuria was present in 44.0% of the cohort, with prevalence differing significantly by histology (MCD 30.0%, FSGS 53.6%, MN 57.7%). Patients with hematuria were older and had a lower proportion of MCD compared to those without. During a 97-day median follow-up, patients with hematuria had a significantly lower complete remission rate than those without (50.3% vs. 66.8%; P=0.001, log-rank test). After full multivariable adjustment, the presence of hematuria remained an independent predictor for a lower likelihood of remission (hazard ratio [HR], 0.68; 95% confidence interval [CI], 0.52–0.90). Analysis by severity revealed a dose-dependent relationship, predominantly driven by severe cases; severe hematuria was associated with a significantly lower remission rate than those without (HR, 0.55; 95% CI, 0.38–0.79), whereas the association for mild hematuria was not statistically significant (HR, 0.84; 95% CI, 0.60–1.17). The findings were robust across multiple sensitivity analyses, and subgroup analysis showed that the association remained significant even within the MCD population.

In this large Japanese cohort, microscopic hematuria at diagnosis is an independent predictor of a lower rate of proteinuria remission in primary nephrotic syndrome. The negative impact is dose-dependent, with severe hematuria being a particularly strong prognostic marker. These findings externally validate prior research in a different ethnic cohort and suggest that hematuria may reflect more severe glomerular damage. Integrating hematuria severity with histology could enable more detailed prognostication. As a low-cost, non-invasive parameter, microscopic hematuria is a valuable tool for risk stratification in patients with nephrotic syndrome.

The preliminary findings have been presented at the 68th Annual Meeting of the Japanese Society of Nephrology.