Abstract and Introduction

Abstract

Transplant glomerulopathy (TG) is a histologic entity described more than four decades ago. In the last few years, our understanding of TG has improved significantly. Current evidence supports the postulate that TG is a unique pathologic and pathogenic entity distinct from other forms of chronic allograft injury. Detailed electron microscopic studies have shown basement membrane abnormalities in glomerular and peritubular capillaries, indicating that this is a disease of the entire renal capillary network. Staining biopsies for the complement fragment, C4d, showed positivity in subgroups of TG, suggesting the participation of antidonor antibodies. Consistent with this postulate, the incidence of TG is increased in patients with anti-donor HLA antibodies prior to the transplant. The use of surveillance biopsies has demonstrated that TG can develop during the first few months after transplantation, although it may remain clinically quiescent for several years. However, TG is progressive, leading to reduced graft survival. Recent studies demonstrated a close association between TG and anti-HLA class II antibodies. Current therapies for TG are likely of limited value. However, it is also likely that an improved understanding of TG pathogenesis will result in the development of effective therapies for this form of progressive kidney allograft damage.

Introduction

Transplant glomerulopathy (TG) is a pathologic condition of renal allografts recognized more than four decades ago (reviewed in [1]). TG includes a constellation of histologic features on light and electron microscopies.^[2] In this review, we will define TG by the characteristic duplication of glomerular basement membrane (GBM) observed by light microscopy (Figure 1), as recommended by the Banff working group.^[3]

Evidence is accumulating that TG has a unique pathogenesis that distinguishes it from other chronic pathologic conditions of kidney allografts. TG is relatively rare compared to other lesions encountered in protocol biopsies obtained 1 year after transplantation.^[4] However, at least two circumstances highlight the importance of this disease: first, TG is associated with very poor allograft survival and, second, TG is perhaps the first example of a distinct pathologic entity arising from the histologic morass that was first called 'chronic rejection', and then 'chronic allograft nephropathy'. We will argue here that the distinctiveness of TG from other forms of chronic allograft pathologies is given by the coexistence of three features: (i) histologic pattern, (ii) association with the presence of anti-HLA antibodies and (iii) the absence of other conditions that may cause duplication of GBM.

TG is rarely diagnosed clinically within 1 year posttrans-plant. However, recent studies showed that the clinical presentation of TG lags behind the initial histologic stages of the disease.^[5] Advanced TG usually is manifest by protein-uria that can be in the nephrotic range, and by progressive loss of kidney function. In our clinical experience and other's, the clinical manifestations of early TG are nonspecific, consisting of progressive, unexplained loss of kidney function, minor proteinuria and mild hypertension.^[5-7] Particularly in its early histologic phases, TG is a focal lesion, affecting only a few glomeruli (Figure 1).^[3] However, sequential biopsies show progression with increasing percentage of affected capillary loops in an increasing number of glomeruli.^[5] TG is associated with poor long-term graft survival (Figure 2). In our series, the variables associated with reduced graft survival included: graft function and proteinuria at diagnosis and the severity of GBM duplication (Banff 'chronic glomerulopathy [cg]' score).

Given the insidious clinical presentation of TG, it is likely that the reported incidence of this disorder, which is based on clinical biopsies, is an underestimate of its true incidence (reviewed in^[7]). In agreement with this postulate, recent studies of surveillance and clinical biopsies showed that the incidence of TG is higher than expected, affecting 4% of conventional transplants at 1 year posttransplant. Thereafter, the incidence of TG increases progressively, reaching 20% at 5 years.^[4,5]