Proteinuria as a Noninvasive Marker for Renal Allograft Histology and Failure: An Observational Cohort Study

Abstract

Proteinuria is routinely measured to assess renal allograft status, but the diagnostic and prognostic values of this measurement for renal transplant pathology and outcome remain unclear. We included 1518 renal allograft recipients in this prospective, observational cohort study. All renal allograft biopsy samples with concomitant data on 24-hour proteinuria were included in the analyses (n=2274). Patients were followed for ≥7 years post-transplantation. Compared with proteinuria <0.3 g/24 h, the hazard ratios for graft failure were 1.14 (95% confidence interval [95% CI], 0.81 to 1.60; P=0.50), for proteinuria 0.3-1.0 g/24 h, 2.17 (95% CI, 1.49 to 3.18; P<0.001), for proteinuria 1.0-3.0 g/24 h, and 3.01 (95% CI, 1.75 to 5.18; P<0.001), for proteinuria >3.0 g/24 h, independent of GFR and allograft histology. The predictive performance of proteinuria for graft failure was lower at 3 months after transplant (area under the receiver-operating characteristic curve [AUC] 0.64, P<0.001) than at 1, 2, and 5 years after transplant (AUC 0.73, 0.71, and 0.77, respectively, all P<0.001). Independent determinants of proteinuria were repeat transplantation, mean arterial pressure, transplant glomerulopathy, microcirculation inflammation, and de novo/recurrent glomerular disease. The discriminatory power of proteinuria for these intragraft injury processes was better in biopsy samples obtained >3 months after transplant (AUC 0.73, P<0.001) than in those obtained earlier (AUC 0.56, P<0.01), with 85% specificity but lower sensitivity (47.8%) for proteinuria >1.0 g/24 h. These data support current clinical guidelines to routinely measure proteinuria after transplant, but illustrate the need for more sensitive biomarkers of allograft injury and prognosis.

Keywords: histopathology; kidney transplantation; proteinuria; survival.

Figure 1.

The degree of proteinuria associates with graft survival. (A) Kaplan–Meier survival curve for the association between 24-hour proteinuria at different time points after transplantation and graft survival in the unselected cohort of 1197 kidney recipients. (B) Kaplan–Meier survival curve for the association between 24-hour proteinuria at time of an indication biopsy and postbiopsy graft failure. (C) ROC curve of the association between proteinuria and postbiopsy graft failure. (D) ROC curve of the association between proteinuria measured at different time points after transplantation and graft failure 5 years later. (E) Kaplan–Meier survival curves for graft survival according to the degree of proteinuria at time of biopsy with transplant glomerulopathy and at time of diagnosis of de novo/recurrent glomerular disease. cg, transplant glomerulopathy; glom.dis., de novo/recurrent glomerular disease; prot., proteinuria.

Figure 2.

Proteinuria is a marker of renal allograft histology. (A–C) Association between clinical and histologic parameters and 24-hour proteinuria in Cohort 1 (A; n=1335 indication biopsies) and in Cohort 2 (B,C; n=919 biopsies, 200 indication biopsies and 719 protocol biopsies). These parameters were independently and consistently associated with 24-hour proteinuria in mixed-model repeated-measures analysis (Table 4). (D) ROC curve of the association between 24-hour proteinuria and the presence of transplant glomerulopathy, microcirculation inflammation, and/or de novo/recurrent glomerular disease in the concomitant renal allograft biopsy in Cohort 1 (n=1335). (E) ROC curve of the association between 24-hour proteinuria and the presence of transplant glomerulopathy, microcirculation inflammation, and or de novo/recurrent glomerular disease in the concomitant renal allograft biopsy (both protocol-specified and clinically indicated) in Cohort 2 (n=919). (F,G) ROC curves of the association between 24-hour proteinuria and the presence of transplant glomerulopathy, microcirculation inflammation, and or de novo/recurrent glomerular disease in the concomitant renal allograft biopsy, in the indication (F; n=200) and protocol (G; n=719) biopsies of Cohort 2.