Fractional excretion of total protein predicts kidney outcome and reflects glomerular lesion severity in patients with biopsy-proven diabetic nephropathy

In diabetic nephropathy (DN), glomerular hyperfiltration often results in elevated estimated glomerular filtration rate (eGFR), and some patients experience disease progression despite normoalbuminuria. Thus, albuminuria and eGFR have limited ability to predict disease progression. The fractional excretion of total protein (FETP), calculated as protein clearance divided by creatinine clearance, has recently gained attention as a marker reflecting protein loss per functioning nephron. Previous studies have reported that a greater early reduction in FETP after administration of sodium–glucose cotransporter 2 inhibitors is associated with a more favorable kidney prognosis, suggesting that FETP reflects glomerular hyperfiltration. However, the associations of FETP with long-term kidney outcomes and with histopathological kidney findings in DN remain unclear. This study examined the association between baseline FETP, incident kidney failure requiring replacement therapy (KFRT), and pathological findings in patients with DN.

This was a single-center, retrospective cohort study of 408 patients with biopsy-proven DN diagnosed between 1981 and 2014. FETP was calculated as (serum creatinine × urine protein) / (serum protein × urine creatinine) × 100 (%). The primary outcome was incident KFRT, defined as kidney failure requiring maintenance kidney replacement therapy. Multivariable Cox regression models and competing-risk regression models, with all-cause mortality as a competing event, were used to evaluate the association between baseline FETP and incident KFRT. Nonlinear associations were assessed using restricted cubic spline (RCS) analyses. Predictive performance was evaluated using the C-statistic, net reclassification improvement (NRI), and integrated discrimination improvement (IDI), based on the 10-year cumulative incidence of KFRT. Associations between FETP and histopathological lesions (glomerular, tubulointerstitial, and vascular) were analyzed using multivariable logistic regression.

During a median follow-up of 6.7 years, 99 patients developed KFRT. In the fully adjusted multivariable Cox model, the highest FETP tertile was significantly associated with an increased risk of KFRT compared to the lowest tertile (hazard ratio (HR), 9.01; 95% confidence interval (CI), 1.97–41.29). This association remained significant in the competing risk analysis (subdistribution HR, 4.68; 95% CI, 1.06–20.54). RCS analysis demonstrated a monotonic, dose-dependent association between FETP and KFRT risk. Adding FETP to a conventional risk model significantly improved the C-index (from 0.895 to 0.906) and enhanced reclassification and discrimination (NRI, 0.258 [95% CI, 0.014–0.502]; IDI, 0.027 [95% CI, 0.003–0.052]). A higher log-transformed FETP was independently and specifically associated with advanced glomerular lesions (Tervaert class ≥IIb) (odds ratio per 1-unit increase, 3.41 [95% CI, 1.63–7.11]), but not with tubulointerstitial or vascular lesions.

This study is the first to demonstrate that FETP is an independent predictor of KFRT and reflects the severity of glomerular lesions in patients with DN. FETP may serve as a novel biomarker for early risk stratification, a better understanding of disease pathophysiology, and monitoring of therapeutic response.