The prevalence of immunologic injury in renal allograft recipients with de novo proteinuria

Abstract

Post-transplant proteinuria is a common complication after renal transplantation; it is associated with reduced graft and recipient survival. However, the prevalence of histological causes has been reported with considerable variation. A clinico-pathological re-evaluation of post-transplant proteinuria is necessary, especially after dismissal of the term "chronic allograft nephropathy," which had been considered to be an important cause of proteinuria. Moreover, urinary protein can promote interstitial inflammation in native kidney, whether this occurs in renal allograft remains unknown. Factors that affect the graft outcome in patients with proteinuria also remain unclear. Here we collected 98 cases of renal allograft recipients who developed proteinuria after transplant, histological features were characterized using Banff scoring system. Cox proportional hazard regression models were used for graft survival predictors. We found that transplant glomerulopathy was the leading (40.8%) cause of post-transplant proteinuria. Immunological causes, including transplant glomerulopathy, acute rejection, and chronic rejection accounted for the majority of all pathological causes of proteinuria. Nevertheless, almost all patients that developed proteinuria had immunological lesions in the graft, especially for interstitial inflammation. Intraglomerular C3 deposition was unexpectedly correlated with the severity of proteinuria. Moreover, the severity of interstitial inflammation was an independent risk factor for graft loss, while high level of hemoglobin was a protective factor for graft survival. This study revealed a predominance of immunological parameters in renal allografts with post-transplant proteinuria. These parameters not only correlate with the severity of proteinuria, but also with the outcome of the graft.

Figure 1. Characteristics of patients with different ranges of proteinuria.

*, P<0.05 compared with control group; **, P<0.01 compared with control group; ***, P<0.001 compared with control group. ⁺, P<0.05 compared with urinary protein<1 g/d group; ⁺⁺, P<0.01 compared with urinary protein<1 g/d group; ⁺⁺⁺, P<0.001 compared with urinary protein<1 g/d group. ^O, P<0.05 compared with urinary protein 1–3.5 g/d group; ^OO, P<0.01 compared with urinary protein 1–3.5 g/d group; ^OOO, P<0.001 compared with urinary protein 1–3.5 g/d group.

Figure 2. Histological causes of post-transplant proteinuria.

Figures shows histological causes of proteinuria in all patients (1A), urine protein <1 g/d (1B), between 1–3.5 g/d (1C), and over 3.5 g/d (1D). TG was the leading cause of overall post-transplant proteinuria and each subgroup, followed by IgAN, chronic rejection (TG excluded), and acute rejection. For proteinuria below 1.0 g/d, acute rejection was the second most important cause of proteinuria, accounting for 25% in this subgroup; only one (3%) patient was diagnosed as having IgAN. For proteinuria between 1–3.5 g/d, the incidence of acute rejection decreased to 4.9%, while the incidence of IgAN increased to 24.4%. In proteinuria over 3.5 g/d, IgAN accounted for 19%, and no patient was diagnosed as having acute rejection. TG, transplant glomerulopathy; IgAN, IgA nephropathy; AR, acute rejection; CR, chronic rejection; TA/IF, tubular atrophy and interstitial fibrosis; FSGS, Focal segmental glomerulosclerosis; MPGN, Membranoproliferative glomerulonephritis; HSPN, Henoch-Schönlein purpura nephritis; DN, diabetic nephropathy; MSP, mesangial proliferative glomerulonephritis; MN, Membranous nephropathy.

Figure 3. Prevalence of histological lesions related to immune activity.

Most (95.9%) of the patients with proteinuria had at least one kind of immunological lesion, based on histology. Interstitial inflammation was the most common lesion, which could be detected in 95.9% patients with proteinuria, followed by glomerulitis in 70.4%, C4d deposition in peritubular capillaries in 53.1%, tubulitis in 46.9%, and intimal arteritis in 14.3%. While in the control group, only few recipients have immunological lesion. *, p<0.05 comparing with control group; **, p<0.001 comparing with control group.

Figure 4. Graft survival for patients with different histological causes of proteinuria.

IgAN has the best graft outcome, with a 5-year graft survival of 71.1%, while graft survival was very poor in patients with TG, TA/IF, and CR. TG, transplant glomerulopathy; IgAN, IgA nephropathy; AR, acute rejection; CR, chronic rejection; TA/IF, tubular atrophy and interstitial fibrosis; FSGS, Focal segmental glomerulosclerosis.

Figure 5. Risk factors correlated with the graft survival in patients with post-transplant proteinuria.

Degrees of interstitial inflammation (A) and renal tubular atrophy (B) and levels of hemoglobin (C) were strongly correlated with graft survival. i 0–3, mononuclear cell interstitial inflammation grade 0–3; ct 0–3, tubular atrophy grade 0–3.