Renal allograft glomerulopathy and the value of immunohistochemistry

Studies of late renal allograft biopsies focus on chronic damage investigated by light microscopy (LM). We evaluated the use of immunohistochemistry (IH) as applied in the routine study of transplant glomerulopathies. Among renal transplants in 1985 - 1997, 129 were identified where a graft biopsy had been obtained 6 months or more after transplantation, studied by LM and IH and the original renal disease was known. IH results were evaluated in relation to glomerular LM findings and the original diagnosis. The risk of graft loss in relation to recurrent and de novo glomerulopathy was evaluated. By LM, 69 biopsies (53%) showed glomerulopathy, mesangial sclerosis only in 26, proliferative changes in 15, membranous in 15 and combined membranous and proliferative in 13. By IH, 46 biopsies (36%) stained positive with IgM and/or complement only and 24 with immune complexes including IgA and/or IgG. Seven biopsies (5.4%) showed glomerular disease by IH in spite of normal LM. Recurrence was diagnosed in 22 grafts; 12 had IgA nephropathy, 3 had SLE, 6 other immune complex nephritides and 1 systemic vasculitis. Twenty-eight biopsies (22%) with proliferative and/or membranous glomerulopathy lacked clear connection to the original renal disorder. More than half of these had deposits of IgM and C3 only. The further graft survival was significantly reduced in the presence of de novo glomerulopathy by LM, relative risk 2.0 (confidence interval 1.1 - 3.8) in a Cox-proportional hazards analysis also including serum creatinine and Banff chronic allograft nephropathy (CAN) grade, p = 0.03. In conclusion, transplant glomerulopathy should be separated from recurrence. De novo glomerulopathy is frequent and ominous.     

Glomerular pathology of allograft kidneys in Hong Kong

AIMS: Our goal was to define the spectrum of glomerular diseases in allograft kidneys and to correlate them with clinical parameters. METHODS: Eight hundred ninety-one renal graft biopsies and 43 graft nephrectomies from 1980 to 2004 were obtained from 442 allografts transplanted to 425 patients. RESULTS: Glomerular diseases were diagnosed in 33% of kidney grafts. Indications for biopsy were baseline assessment (23 biopsies, 2.5%); renal dysfunction (790 biopsies, 88.7%); proteinuria (154 biopsies, 17.3%); hematuria (11 biopsies, 1.2%); and study protocol (four biopsies, 0.4%). The median time to take a biopsy was less than 8 months posttransplant. The mean time posttransplant when the biopsy diagnosis was made was 70 months for IgA nephropathy (IgAN); 66 months for transplant glomerulopathy (TG); 65 months for focal segmental glomerulosclerosis (FSG); 55 months for mesangiocapillary glomerulonephritis (MCGN); 45 months for membranous glomerulonephritis (GN); 49 months for mesangial proliferative GN; and 101 months for diabetic nephropathy. Recurrent glomerular disease was documented in 31 (7.0%) grafts. Specific glomerular diseases were diagnosed by biopsies in 106 (89.1%) of 119 proteinuric allografts. CONCLUSIONS: Glomerulopathy was common in allografted kidneys. IgAN, TG, FSG, mesangial proliferative GN, and membranous GN were the majority. A higher proportion of grafts from donors related to the recipients than from unrelated donors showed IgAN (P < .05), suggesting that genetic factors might play a role in the pathogenesis of IgAN. Recurrence of glomerulopathy underlying ESRD was frequent for IgAN, FSG, and MCGN, but this was rarely seen in membranous GN.     

Post-transplant nephrotic syndrome: A comprehensive clinicopathologic study

BACKGROUND: Post-transplant (Tx) nephrotic syndrome (NS) is not well defined. METHODS: Seventy-four renal transplant recipients with NS were studied. RESULTS: Biopsies showed chronic allograft nephropathy (CAN) in 31 patients; recurrent glomerular disease (GN) in 15, de novo GN in 18, and undetermined GN in 9. NS developed 0.25 to 384 months post-Tx and was treated with angiotensin-converting enzyme inhibitors (ACEI) or angiotensin receptor blockers (ARB) in 18 patients; calcium channel blockers in 25; or both drugs in 31. NS remitted in 24% of cases 2 to 28 months after onset, and this persisted in all except 3 patients. The remission rate was lowest (9%) for CAN and highest (47%) for de novo GN. Compared with persistent NS, those with remission showed higher prevalence of de novo GN (53% vs. 17%), lower prevalence of CAN (18% vs. 50%), earlier onset of NS (39 vs. 59 months), lower serum SCr at onset (2.3 vs. 2.9 mg/dL), and higher incidence of treatment with ACE or ARB. The 5-year graft loss rates for CAN, recurrent and de novo GN were 57%, 36%, and 23%, respectively. Compared with the functioning grafts, the failed grafts showed higher prevalence of CAN (60% vs. 16%), lower prevalence of de novo GN (12% vs. 46%), earlier onset of NS (47 vs 65 months post-Tx), higher serum SCr at onset (3.3 vs. 2.0 mg/dL), lower prevalence of remission of NS (5% vs. 48%), and higher proteinuria at follow-up (5.1 vs. 2.5 g/day). Graft survival improved with NS remission (88% vs. 18%). CONCLUSION: Post-Tx NS displays distinctive clinicopathologic features with pathogenetic and therapeutic implications.     

Focal segmental glomerulosclerosis in a 32-year-old kidney allograft after 7 years without immunosuppression.

In kidney allografts, focal segmental glomerulosclerosis (FSGS) has been described as recurrent, de novo, or a histological variant of chronic transplant glomerulopathy. We describe a unique case of de novo FSGS in a renal transplant not accompanied by any feature of rejection in a patient who had not been immunosuppressed for several years. A 58-year-old woman received a histoidentical living-related kidney transplant for end-stage renal disease due to chronic pyelonephritis. Twenty-four years after the transplant she voluntarily discontinued all immunosuppressive medication. Seven years later she presented with nephrotic syndrome, mild renal failure, and positive serology for hepatitis C virus (HCV) antibody. The kidney transplant biopsy disclosed de novo FSGS. Features of acute or chronic rejection, including chronic transplant glomerulopathy, were not seen. The pathogenesis of this lesion is probably related to sustained and prolonged glomerular hyperfiltration; alternatively, HCV infection may have triggered or accelerated the appearance of FSGS.     

Proteinuria following transplantation. Correlation with histopathology and outcome

A review of 693 renal transplant recipients revealed 77 (11%) in whom persistent, heavy proteinuria (greater than 2 g/24 hr) developed. Renal histology was available in all 77 patients. Twenty-one patients had received kidneys from living-related donors, the remaining 56 from cadaveric donors. The cause of proteinuria in these 77 patients was as follows: transplant glomerulopathy (30), allograft glomerulonephritis (22), chronic rejection (21), renal vein thrombosis (2), diabetic glomerulosclerosis (1), and hypertensive nephrosclerosis (1). Of the 22 patients who developed glomerulonephritis in the transplanted kidney, 6 had recurrent disease (3--membranous glomerulopathy, 2--focal sclerosis and hyalinosis, 1--membranoproliferative glomerulonephritis); 6 developed de novo glomerulonephritis; and in 10 the type of glomerulonephritis could not be classified as recurrent or as de novo because of lack of characterization of the original kidney disease. Renal vein thrombosis occurred in association with other lesions in an additional 5 cases (3--chronic rejection; 2--membranous glomerulopathy). In follow-up only 23.4% (18 of 77) of the patients maintained prolonged graft function; the majority of grafts being lost within one year of the development of persistent, heavy proteinuria. Of the 18 patients who retained their grafts, 8 had glomerulonephritis, 5 transplant glomerulopathy, and 5 chronic rejection. This study confirms the poor prognosis that has been reported with the development of nephrotic-range proteinuria in renal allograft recipients.     

Recurrent and de novo renal disease after kidney transplantation with or without cyclosporine A

We evaluated the clinical course of 700 renal transplantations, including 1,305 transplant histologies performed in 611 patients between 1970 and 1988, to estimate the influence of cyclosporine A (CsA) after kidney transplantation on the incidence of recurrent or de novo renal disease. Primary renal disease recurred in 11 of 583 functioning transplants (1.9%) with transplant loss in seven patients (1.2%): focal segmental glomerulosclerosis (FSGS, three patients); membranous glomerulonephritis (GN, one patient); mesangiocapillary GN (one patient); rapidly progressive IgA nephropathy (one patient); hemolytic-uremic syndrome (HUS, three patients); and oxalosis in two transplants (one patient). De novo renal disease occurred in six patients (1.0%), including mesangiocapillary GN type I (three patients); nonpurulent focal GN in septicemia (one patient); HUS (one patient); and nodular glomerulosclerosis in steroid diabetes (one patient). De novo membranous GN was seen in 14 additional cases (2.4%). No statistically significant difference could be established between the treatment groups without (n = 225) and with (n = 358) CsA in recurrent and de novo renal disease (n = 7/225 v 10/358, NS); in recurrent and de novo GN (n = 4/225 v 6/358, NS); in recurrent FSGS (n = 1/7 v 2/8, NS); in recurrent and de novo HUS (n - 1/1 v 2/7, NS); and in de novo membranous GN (n = 7/225 v 7/358, NS). Transplant loss by recurrent and de novo GN was higher without than with CsA (n = 4/4 v 1/6, P = 0.004). On the basis of our investigation, we conclude that recurrent and de novo renal disease in the transplant occur rarely and are not prevented by CsA. However, even if the incidence of transplant GN is unchanged by CsA treatment, its clinical course seems to be mitigated. CsA treatment also does not increase the incidence of HUS.     

Immunopathologic features of de novo membranous nephropathy in renal allografts

De novo membranous nephropathy (MN) is now one of the most common forms of posttransplant glomerular disease, second only to allograft glomerulopathy. We investigated several immunopathologic and physicochemical properties of the immune complex (IC) or IC components displayed in the sera of patients with de novo MN. The parameters studied included detection of small (9S) preformed IC by monoclonal rheumatoid factor, determination of IC isoelectric point by chromatofocusing, detection of cationic IgG spectrotypes (pI 8.0-9.2), and demonstration of brush border or tubular epithelial/interstitial antibodies in the sera by indirect immunofluorescence. Of 7 de novo MN sera, 5 demonstrated the presence of each of these four immunopathologic features, whereas normal transplant patients, transplant recipients with recurrent focal sclerosis (FSGN), and those with chronic rejection did not display such features. Sera of patients with untreated idiopathic MN revealed immunochemical properties of IC that were similar to those seen in circulating IC of de novo MN. These studies suggest that a strongly nephritogenic internal milieu exists in transplant recipients with de novo MN. Our data indicate that unique immunochemical properties of IC or their components may predispose to subepithelial immune deposit formation and should provide new insights into the pathogenesis of idiopathic human MN.     

Hepatitis C Virus Infection and de Novo Glomerular Lesions in Renal Allografts

In the present study we examine whether hepatitis C virus (HCV) infection status influences glomerular pathologic findings in renal allografts and its effect on graft outcome. Renal allograft biopsies performed between January 1991 and June 1999 were considered. Exclusion criteria were insufficient sample, unknown HCV serological status at time of biopsy and final diagnosis of acute rejection. Light microscopy and immunofluorescence studies were performed on all biopsies. According to a predefined protocol, electron microscopy was carried out. Of 138 eligible renal allograft biopsies, 42 fulfilled at least one exclusion criterion. Of 96 biopsies selected for the study, 44 (45.8%) were from HCV-positive and 52 from HCV-negative recipients. Renal biopsy was performed 74 +/- 55 and 60 +/- 39 months after transplantation in HCV-positive and HCV-negative groups, respectively (p = 0.12). Of 44 HCV-positive biopsies, 20 (45.4%) showed membranoproliferative glomerulonephritis (MPGN) (16 type I and 4 type III). Conversely, in HCV-negative biopsies there were only three cases of MPGN (2 type I and 1 type III). De novo membranous GN (MGN) was diagnosed in 8/44 (18.2%) HCV-positive and in 4/52 (7.7%) HCV-negative cases. The prevalence of chronic transplant glomerulopathy was similar in HCV-positive and HCV-negative groups (11.4% and 11.5%, respectively). The prognosis of de novo GN (either MPGN or MGN) was worse in HCV-positive than in HCV-negative recipients (relative risk 4.89; 95% confidence interval, 1.15-20.69; p = 0.03). By multivariate analysis, HCV-positive serology infection was the only independent predictor of graft loss (relative risk 2.64; 95% confidence interval, 1.35-5.17; p = 0.005). In diagnostic renal allograft biopsies the presence of de novo immune-mediated glomerulonephritis, especially type I MPGN, is strongly associated with HCV infection and results in accelerated loss of the graft.     

Recurrent and de novo glomerular disease after renal transplantation: a report from Renal Allograft Disease Registry (RADR).

INTRODUCTION: Short-term and long-term results of renal transplantation have improved over the past 15 years. However, there has been no change in the prevalence of recurrent and de novo diseases. A retrospective study was initiated through the Renal Allograft Disease Registry, to evaluate the prevalence and impact of recurrent and de novo diseases after transplantation. MATERIALS AND METHODS: From October 1987 to December 1996, a total of 4913 renal transplants were performed on adults at the Medical College of Wisconsin, University of Cincinnati, University of California at San Francisco, University of Louisville, University of Washington, Seattle, and Washington University School of Medicine. The patients were followed for a minimum of 1 year. A total of 167 (3.4%) cases of recurrent and de novo disease were diagnosed by renal biopsy. These patients were compared with other patients who did not have recurrent and de novo disease (n=4746). There were more men (67.7% vs. 59.8%, P<0.035) and a higher number of re-transplants (17% vs. 11.5%, P<0.005) in the recurrent and de novo disease group. There was no difference in the rate of recurrent and de novo disease according to the transplant type (living related donor vs. cadaver, P=NS). Other demographic findings were not significantly different. Common forms of glomerulonephritis seen were focal segmental glomerulosclerosis (FSGS), 57; immunoglobulin A nephritis, 22; membranoproliferative glomerulonephritis (GN), 18; and membranous nephropathy, 16. Other diagnoses include: diabetic nephropathy, 19; immune complex GN, 12; crescentic GN (vasculitis), 6; hemolytic uremic syndrome-thrombotic thrombocytopenic purpura (HUS/TTP), 8; systemic lupus erythematosus, 3; Anti-glomerular basement membrane disease, 2; oxalosis, 2; and miscellaneous, 2. The diagnosis of recurrent and de novo disease was made after a mean period of 678 days after the transplant. During the follow-up period, there were significantly more graft failures in the recurrent disease group, 55% vs. 25%, P<0.001. The actuarial 1-, 2-, 3-, 4, and 5-year kidney survival rates for patients with recurrent and de novo disease was 86.5%, 78.5%, 65%, 47.7%, and 39.8%. The corresponding survival rates for patients without recurrent and de novo disease were 85.2%, 81.2%, 76.5%, 72%, and 67.6%, respectively (Log-rank test, P<0.0001). The median kidney survival rate for patients with and without recurrent and de novo disease was 1360 vs. 3382 days (P<0.0001). Multivariate analysis using the Cox proportional hazard model for graft failure was performed to identify various risk factors. Cadaveric transplants, prolonged cold ischemia time, elevated panel reactive antibody, and recurrent disease were identified as risk factors for allograft failure. The relative risk (95% confidence interval) for graft failure because of recurrent and de novo disease was 1.9 (1.57-2.40), P<0.0001. The relative risk for graft failure because of posttransplant FSGS was 2.25 (1.6-3.1), P<0.0001, for membranoprolifera. tive glomerulonephritis was 2.37 (1.3-4.2), P<0.003, and for HUS/TTP was 5.36 (2.2-12.9), P<0.0002. There was higher graft failure (64.9%) and shorter half-life (1244 days) in patients with recurrent FSGS. CONCLUSION: In conclusion, recurrent and de novo disease are associated with poorer long-term survival, and the relative risk of allograft loss is double. Significant impact on graft survival was seen with recurrent and de novo FSGS, membranoproliferative glomerulonephritis, and HUS/TTP.     

De novo minimal change disease

Beyond the acute posttransplantation period, glomerular causes of proteinuria in the renal allograft include recurrent glomerulopathy, transplant-associated entities, and de novo disease. We present a case of de novo minimal change disease with reversible acute renal failure occurring 2.5 years posttransplantation in a 56-year-old man. The cause of end-stage renal disease in the native kidney was membranous glomerulopathy. De novo minimal change disease in the renal allograft is an extremely rare entity requiring stringent clinical-pathological criteria for diagnosis. Many of the cases previously reported as de novo minimal change disease fail to meet these criteria. We review the eight reported cases that appear to fulfill a strict definition of minimal change disease in the context of the current report.     

De novo fibrillary glomerulopathy in the renal allograft of a patient with systemic lupus erythematosus

Lupus glomerulonephritis is a complication of systemic lupus erythematosus, with 10% of the patients developing end-stage renal disease. It is accepted that lupus patients are good candidates for kidney transplantation and that the disease activity is subdued after transplantation due to rigorous immunosuppression, with a low rate of graft loss due to recurrent glomerulonephritis. While recurrent fibrillary glomerulopathy has been reported in renal allografts, de novo disease has not. We report a patient with systemic lupus who underwent a renal transplantation and subsequently lost her allograft due to de novo fibrillary glomerulopathy. Four years after her first kidney transplant, the patient presented with acute deterioration of her renal function. A renal biopsy was performed, and it revealed a focal mesangioproliferative pattern with positive amorphous mesangial immunofluorescence staining for IgG and C3. Congo red staining was negative. Electron microscopy demonstrated the presence of randomly oriented nonamyloid fibrils in the mesangiun. The diagnosis of de novo fibrillary glomerulopathy was made. The patient lost her allograft and received a second cadaveric renal transplant 1 year later. She has had a stable renal function since then.     

De novo membranous glomerulonephropathy in renal allografts: a report of ten cases and review of the literature

De novo posttransplantation membranous glomerulonephropathy (MGN) is the most common form of de novo glomerulopathy in renal allografts. The clinical and pathological features of ten patients with de novo MGN were studied and the related literature was reviewed to assess the clinical features, morphologic characteristics, and natural course of this disease. De novo MGN may occur in both living related and cadaveric allografts at any time after transplantation. It presents clinically either as asymptomatic proteinuria or the nephrotic syndrome, a feature of poor prognostic implication. Morphologically, de novo MGN in most instances has distinct differences from idiopathic MGN in native kidneys and is accompanied by varying features of rejection. About 50% of grafts which develop de novo MGN eventually fail. This rather poor outcome may not represent the natural history of de novo MGN per se but rather the consequences of associated chronic rejection. Evidence is presented that many of the cases of so-called de novo MGN may be a complication of transplant glomerulopathy rather than being caused by mechanisms totally independent from rejection.     

De novo glomerulonephritis in renal allografts with hepatitis C virus infection

The purpose of this study was to examine the influence of hepatitis C virus (HCV) infection on the occurrence of posttransplant de novo glomerulonephritis (GN). Of 165 patients selected for the study, 44 were HCV positive and 121 HCV negative. Light and immunofluorescence microscopy were performed on all biopsies and clinical and laboratory findings reviewed. Fifteen (34%) of the 44 HCV positive patients showed de novo GN (4 membranous, 11 membranoproliferative) at a mean of 47 +/- 22 months. But only 8 (6.6%) of 121 HCV negative patients showed de novo GN (5 anti-glomerular basement membrane nephritis in recipients with Alport's disease, 2 membranous GN, 1 membranoproliferative GN) at a mean of 60 +/- 39 months. The risk of development of de novo GN was higher among patients with HCV infection (P < .001). The presence of de novo GN in HCV positive patients impaired graft survival compared with HCV positive patients without de novo GN (P < .01). The incidence of recurrence of primary disease, mainly focal segmental glomerulosclerosis, membranous glomerulonephritis, membranoproliferative glomerulonephritis, and IgA nephropathy, was higher in HCV negative patients (29%) compared with HCV positive patients (6.8%; P = .001), namely, 50%, 57.6%, 25%, and 69%, respectively. In conclusion, HCV infection showed a strong influence on the development of de novo GN. For this reason, it is important to follow HCV positive recipients with a renal biopsy even when there are no significant clinical or laboratory findings.     

Capillary deposition of complement split product C4d in renal allografts is associated with basement membrane injury in peritubular and glomerular capillaries: a contribution of humoral immunity to chronic allograft rejection

Endothelial deposition of the complement split product C4d is an established marker of antibody-mediated acute renal allograft rejection. A contribution of alloantibody-dependent immune reactions to chronic rejection is under discussion. In this study, the association of immunohistochemically detected endothelial C4d deposition in peritubular capillaries (PTC) with morphologic features of chronic renal allograft injury was investigated in a large study cohort. C4d deposits in PTC were detected in 73 (34%) of 213 late allograft biopsies performed in 213 patients more than 12 mo after transplantation (median, 4.9 yr) because of chronic allograft dysfunction. Endothelial C4d deposition was found to be associated with chronic transplant glomerulopathy (CG) (P < 0.0001), with basement membrane multilayering in PTC (P = 0.01), and with an accumulation of mononuclear inflammatory cells in PTC (P < 0,001). Furthermore, C4d deposits in PTC (in biopsies with normal glomerular morphology) were associated with development of CG in follow-up biopsies. Other morphologic features of chronic allograft nephropathy (with exception of tubular atrophy) were not associated with C4d deposits in PTC. Analyses of previous and follow-up biopsies revealed that C4d deposits may occur de novo and may also disappear at any time after transplantation. In conclusion, the data suggest that complement activation in renal microvasculature, indicating humoral alloreactivity, contributes to chronic rejection characterized by chronic transplant glomerulopathy and basement membrane multilayering in PTC.     

Side effects of sirolimus

The mTOR inhibitor sirolimus improves renal transplant function compared with the nephrotoxic calcineurin inhibitors. We evaluated retrospectively the adverse events in 119 of 134 patients getting sirolimus which seemed to be caused by sirolimus. Patients were converted to sirolimus because of malignancies (n = 47), a creeping creatinine (n = 33), or hypertension (n = 26). One cohort had started sirolimus from the time of transplantation (n = 28). A rise in serum lipids and a decrease in hemoglobin were seen relatively regularly, while arthralgia, peripheral edema, gastrointestinal complaints, skin disorders, electrolyte disturbances, and infections occurred only occasionally. Interestingly, 31% of patients developed doubling or more proteinuria. Among renal biopsies, 9/13 showed a glomerulopathy which in 6 cases was de novo and in 3 cases, a presumed recurrence of the primary kidney disease. Thus, we think that caution is required, particularly in connection with preexisting glomerular disease.     

Impact of recurrent glomerulonephritis on renal graft survival

Background

Glomerular disease causes graft loss in the intermediate and long term, especially recurrent primary renal disease, negatively impacting graft survival. Thus, it must be considered a differential diagnosis in the evaluation of chronic graft dysfunction.

Methods

The objectives of our study were to compare the impacts of primary glomerular disease on graft survival and association with interstitial fibrosis/tubular atrophy (IFTA) or transplant glomerulopathy. We examined the influence of the relapse of glomerulonephritis (GN) on renal graft survival in a retrospective study of 1057 patients undergoing renal transplantations between March 1981 and October 2009. Among this group, 128 patients were diagnosed with pretransplant GN by renal biopsy. We examined graft survival on recurrence compared with IFTA and transplant glomerulopathy using Kaplan-Meier analysis.

Results

We analyzed a cohort of 128 patients who were diagnosed with pretransplant GN by renal biopsy, including 28.9% (37) of whom were males. The mean age was 42.04 ± 13.82 years. The most frequent type was immunoglobulin A GN (IgAGN; 31.3%), followed by membranoproliferative GN (MPGN; 28.9%), rapidly progressive GN (RPGN; 16.4%), focal-segmental GN (FSGN; 13.3%), membranous GN (9.4%), and minimal change GN; (0.8%). Among the 16 cases (12.5%) of GN recurrence; MPGN was associated most frequently (n = 10, 28.9%), followed by FSGN (n = 4, 23.5%), RPGN (n = 1, 4.8%), and IgAGN (n = 1, 2.5%). We noted that 11.8% of subjects to be positive for hepatitis C virus; while 3.9% were hepatitis B virus(HBV)-positive. We observed no differences in hepatic serology between patients who experienced recurrence (HBV 6.3% vs hepatitis C virus [HCV] 18.8%) compared with IFTA (HBV 3.1% vs HCV 9.4%). Fifty-one patients (39.8%) were biopsied after transplantation due to impaired renal function: there were recurrences of GN in 12.5% (n = 16), IFTA in 25% (n = 32), and transplant glomerulopathy in 2.3% (n = 3) cases. The average graft survival in our cohort was 8.36 ± 0.59 years. The median patient survival among those who experienced a recurrence was 8.36 ± 1.79 years; 7.19 ± 1.01 years in IFTA patients; and 3.31 ± 0.91 years in patients with transplant glomerulopathy (log-rank P = .06). Upon multivariate analysis, recurrence of GN was not an independent predictor of renal loss.

Conclusions

MPGN was the type of GN that recurred most frequently followed by FSGN. No differences in graft survival were noted between long-term recurrence of GN and other causes of chronic graft dysfunction. The recurrence of primary disease did not worsen the renal graft prognosis versus other causes of chronic graft dysfunction.     

Immunologic risk factors and glomerular C4d deposits in chronic transplant glomerulopathy

BACKGROUND: Chronic transplant glomerulopathy is an uncommon cause of chronic transplant dysfunction of unknown pathogenesis. We evaluated the epidemiologic, clinical, and histologic features of chronic transplant glomerulopathy. To determine the possible contribution of humoral immune responses, we assessed glomerular deposition of C4d. METHODS: From a cohort of 1111 kidney transplants (1983 to 2001) with at least 6 months of graft function, we identified 18 cases with chronic transplant glomerulopathy (1.6%) showing double contours of the glomerular basement membrane (GBM) on light microscopy. To assess the risk factors, this group was compared with 739 patients with stable function using multivariate Cox regression analysis. Paraffin sections of 11/18 biopsies were stained with polyclonal C4d antibodies. Sera of 13/18 patients could be tested for antidonor human leukocyte antigen (HLA) antibodies by enzyme-linked immunosorbent assay (ELISA). Patients with chronic allograft nephropathy without chronic transplant glomerulopathy or predominant cyclosporine nephrotoxicity were used as controls. RESULTS: Chronic transplant glomerulopathy was diagnosed at a median of 8.3 (range 2.6-12.5) years posttransplantation. Panel reactive antibodies at time of transplantation, RR 1.23 (1.05-1.45) per 10% increase, and late acute rejection episodes, RR 7.6 (1.8-31.7), were independently associated with chronic transplant glomerulopathy. We found glomerular C4d deposits in 10/11 biopsies showing chronic transplant glomerulopathy and in only 2/13 controls. Peritubular capillary C4d deposits and donor-specific anti-HLA antibodies were demonstrated in 4 and 3 of the 10 patients with glomerular C4d deposits, respectively. CONCLUSION: Presensitization and late acute rejection episodes were the risk factors identified. Glomerular C4d deposits suggest that chronic transplant glomerulopathy emerges from in situ humoral rejection. Chronic transplant glomerulopathy should be considered as a manifestation of immune-mediated injury.     

Prognostic factors associated with poor graft outcomes in renal recipients with post-transplant glomerulonephritis

BACKGROUND: Little data are available concerning post-transplantation glomerulonephritis (PTx-GN) and its prognostic factors associated with graft outcomes. METHODS: We retrospectively evaluated patients with de novo and recurrent PTx-GN to identify the factors associated with their negative impact on graft and patient outcomes. PTx-GN was diagnosed in 55 patients, wherein 17 (31%) had recurrent glomerulonephritis (GN) and 16 (29%) had de novo. RESULTS: Our enrolled population consisted of 34 +/- 13.7-yr-old male patients (72%), on hemodialysis for a median of 18 months (0-204) and mainly grafted from living donors (76%). The median onset time of proteinuria and hematuria was 50 d (10-2160) and 30 d (4-1170), respectively. One-yr graft survival rates after PTx-GN diagnosis was 64%. The most frequent de novo GN was membranous GN (26%), while focal segmental glomerulosclerosis was the most frequent recurrent GN (41%), with a very early onset (median of three months). One-yr graft survival was better in the recurrent disease than in the de novo patients, 76% vs. 55% (p = 0.24). The best predictor factors that correlated with graft survival were: proteinuria <3.5 g [relative risk (RR) = 0.24, p = 0.017], serum creatinine below 2.0 mg/dL (RR = 0.06, p = 0.016) at the time of biopsy and the use of angiotensin-converting enzyme inhibitors (ACEI) (RR = 0.12, p = 0.005). The use of ACEI markedly improved one-yr graft survival rates (92% vs. 47%, p < 0.001). CONCLUSION: PTx-GN has a strong negative impact on kidney graft survival. De novo GN appears to have a poorer prognosis than the recurrent type. Patients who used ACEI showed a better survival rate in the follow-up.     

Nephrotic Range Proteinuria in Renal Transplantation: Clinical and Histologic Correlates in a 10-year Retrospective Study

Introduction

There is a high incidence of nephrotic proteinuria in renal transplant recipients, which is an accurate predictor of graft loss. Despite this, its histologic correlates and prognostic implications are still not well characterized. We assessed the clinical and histological correlates of kidney transplantation patients with nephrotic range proteinuria.

Pathology after eculizumab in dense deposit disease and C3 GN

Eculizumab might benefit C3 glomerulopathies mediated by dysregulation of the alternative complement pathway. Here, we report renal biopsy findings before and after eculizumab therapy in three patients with dense deposit disease and two with C3 GN. All pretreatment biopsies had glomerular and tubular basement membrane deposits that stained exclusively for C3 without significant Ig. After 1 year of therapy, there was reduction in active glomerular proliferation and neutrophil infiltration in three of five patients, consistent with effective C5 blockade, which prevents production of chemotactin C5a. One individual with mild mesangial disease had no significant change in activity or chronicity. One patient exhibited persistent activity and worsening chronicity despite therapy. Immunofluorescence showed no significant reduction in C3 or C5b-9, and electron microscopy revealed persistent deposits in all cases, suggesting a long t(1/2) of C5b-9 in extracellular matrix. Normal renal biopsies stained positive for C5b-9 in glomeruli, tubular basement membranes, and vessel walls, albeit at lower intensity than in C3 glomerulopathy. This indication of physiologic levels of C5b-9 activation in normal kidney potentially explains the localization of deposits in patients with dysregulation of the alternative complement pathway. All post-treatment biopsies showed de novo monoclonal staining for IgG-κ in the same distribution as C3 and C5b-9, mimicking monoclonal Ig deposition disease (MIDD). Staining of the γ heavy chain was restricted to the IgG2 and IgG4 subclasses, suggesting the binding of monoclonal eculizumab to C5 in renal tissues. The long-term effects of this apparent drug-tissue interaction are unknown.