Association of Tamm-Horsfall Protein Extrusion with Progression of Diabetic Nephropathy

Background: Diabetic nephropathy (DN) is the leading cause of end-stage kidney disease. Several histological markers have been linked to poor clinical outcomes, including interstitial fibrosis and tubular atrophy (IFTA). A frequently overlooked feature is Tamm-Horsfall protein (THP, uromodulin) extrusion, where tubules containing THP casts rupture, leading to extruded THP that triggers a brisk inflammatory response. This case-control study aims to investigate the correlation between THP extrusion and DN progression. Methods: Renal biopsies performed at our institution from 2017 to 2023, with a primary diagnosis of DN, were reviewed. Sixty-three biopsies with THP extrusion and 72 without extrusion were matched based on age, race, and sex. Clinicopathological parameters were collected from chart review and biopsy reports. Whole-slide images of each case were reviewed, and a series of image features were measured. Survival was defined as time to initiation of chronic dialysis or 40% eGFR decline, whichever occurred first. Survival analysis and multivariable Cox proportional regression were performed using GraphPad Prism 10. Results: There is no significant difference in clinicopathological parameters between the THP and non-THP groups, including creatinine (sCr), proteinuria, and IFTA. Survival analysis shows that compared to non-THP group, the THP group has a shorter survival (p = 0.0084; median survival: 12.4 vs 21.9 months) (Figure 1). Multivariable Cox proportional regression analysis shows that THP extrusion has a hazard ratio of 1.642 (95% CI: 1.039 to 2.601). Interestingly, the number of intact tubules containing THP casts without extrusion is associated with better survival (hazard ratio: 0.8503). Conclusion: Our case-control study provides evidence that THP extrusion is associated with worse outcomes in DN, independent of traditional biomarkers including sCr, proteinuria, and IFTA. Future studies are necessary to explore molecular and immunologic mechanisms and implications in DN and other kidney diseases.