* Abbreviations: CsA, cyclosporine; ESRD, end-stage renal disease; HLA, human leukocyte antigen.
IgA nephropathy or Berger's disease is the most common cause of glomerulonephritis on a worldwide basis and the incidence varies by geographic location. The disease most commonly occurs in males in the second or third decade of life and is uncommon in the black population(1). A genetic component to this disease is suggested by the occurrence of the disease among family members. The clinical features of IgA nephropathy include microscopic and/or macroscopic hematuria, proteinuria, and in some cases nephrotic syndrome. Although IgA nephropathy may have a generally good prognosis and may present only as benign hematuria, in other cases slow progressive decline of renal function may occur over a 10-year period. In other cases, deterioration of renal function can occur rapidly. The incidence of progression to renal failure in patients with IgA nephropathy has been reported to be less than 10% (2), but may be as high as 50% with long-term follow-up (3, 4). Prognostic factors for progression of disease to renal dysfunction include hypertension, heavy proteinuria, and renal dysfunction at the time of presentation. There is no clear relationship between human leukocyte antigen (HLA*) type and propensity for this disease, progression to renal failure, or recurrence of disease after renal transplantation, despite scattered reports of dominant HLA types in some IgA patient populations. Unfortunately, not much is known about the pathogenesis of the disease and the diagnosis requires histologic confirmation. Immunohistochemical confirmation of this disease entity consists of detection of IgA and complement component 3 mesangial deposition.
Previous reports regarding renal transplantation for IgA nephropathy have generally reported favorable outcomes when compared with renal transplant recipients with end-stage renal disease (ESRD) due to causes other than IgA nephropathy (5-7). Up to a 50% rate of recurrence in the transplant kidney has been reported in the literature(including an earlier report from this institution), but graft loss due to recurrent disease in general has been reported to be a rare event(7-19). Follow-up in previous reports has averaged 20-24 months after transplant. However, there have been some isolated reports of graft loss associated with rapidly progressive recurrent disease(16, 20-23). Furthermore, in a recent single-center report, substantial graft loss occurred in renal allograft recipients with recurrent IgA nephropathy at long-term follow-up(24). The purpose of the following study was to provide long-term follow-up of renal transplant recipients with IgA nephropathy at a single center in the pre- and post-cyclosporine (CsA) era with respect to (1) actuarial graft and patient survival compared with a reference group, (2) incidence of recurrent disease, (3) graft loss due to recurrent disease, (4) correlates of recurrent disease and graft loss after recurrence, and (5) outcome of retransplantation in patients with recurrent disease.
MATERIALS AND METHODS
Data collection. Between June 1980 and December 1994, 2492 renal transplants were performed at the University of California San Francisco. ESRD due to IgA nephropathy was the primary diagnosis in 54 patients (61 renal transplants), which comprised 2.1% of the whole group. Diagnosis was confirmed by pretransplant native kidney biopsy. Data was gathered on donor status, recipient age at transplant, race, sex, recipient and donor HLA type, pretransplant length of disease (from the diagnosis of disease), interval to recurrent disease after transplant, current graft function (serum creatinine), rejection episodes, posttransplant biopsies, and graft loss. Actuarial patient and graft survival were compared to a reference group (matched for donor status, age at transplant, sex, date of transplant within 2 years, transplant number, recipient race, and immunosuppression regimen [with or without CsA]). The cause of ESRD in all of the reference patients was chronic glomerulonephritis. Table 1 shows the demographics of the IgA and reference groups.
Immunosuppression. Transplant recipients before 1983 received azathioprine (2 mg/kg) and a prednisone taper (initiated at 2 mg/kg); transplant recipients since 1983 have received maintenance therapy with CsA(initially at 10 mg/kg), azathioprine (2 mg/kg), and a prednisone taper(initiated at 2 mg/kg). “High-risk” patients who received a second transplant after graft loss due to acute rejection or who had acute tubular necrosis after transplant received antilymphocyte therapy. Treatment of rejection in both groups consisted of an initial course of steroids followed by antilymphocyte therapy when improvement in creatinine was inadequate.
Detection and diagnosis of recurrent disease in IgA patients. Patients who developed hematuria and/or proteinuria and graft dysfunction were assessed with a renal allograft biopsy for light microscopy and immunofluorescent staining for IgA, complement component 3, and electron microscopy. Patients diagnosed with recurrent disease did not receive additional immunosuppressive therapy. No surveillance biopsies were performed. The incidence of recurrence was analyzed with respect to sex, age at transplant, pretransplant disease interval, and donor status.
Graft loss was attributed to recurrent disease in the presence of histologic findings that were most remarkable for advanced stages of IgA nephropathy (mesangial proliferative expansion and glomerular sclerosis). Graft loss was attributed to chronic rejection in the presence of histologic findings that were significant for chronic rejection (chronic inflammatory cell infiltrates, interstitial fibrosis, tubular atrophy, and chronic vascular changes).
Statistical analysis. Data are expressed as means ± SD and were analyzed by Student's t test for statistical significance. Actuarial graft and patient survival curves were generated using the Kaplan-Meier method. Statistical analysis was performed with the Mantel Cox and Breslow methods. Significance between proportions was determined by chi-square analysis (Pearson's or Fisher's exact test using the Statistical Package of the Social Sciences (SPSS version 7.0, Inc., Chicago, IL). Probability <0.05 was considered significant.
Patient and graft survival. Actuarial patient survival was excellent for both IgA and reference non-IgA patients (100% versus 98% at 5 years after transplant, respectively; P=NS) (Fig. 1). Actuarial graft survival for IgA and reference non-IgA patients was also comparable (84% versus 82% at 2 years and 75% versus 73% at 5 years, respectively; P=NS) (Fig. 2). Actuarial graft survival was also analyzed by donor status; there was a trend in the IgA nephropathy group for decreased graft survival in the recipients of living-related donor allografts. Actuarial graft survival in IgA patients was 84% with cadaveric renal allografts and 61% with living-related renal allografts at 5 years after transplant. This difference did not reach statistical significance (P=0.09) (Fig. 3). This result was unlike the reference group, in which recipients of living-related donor allografts tended toward improved graft survival compared with recipients of cadaveric allografts. Actuarial graft survival in the reference group between recipients of living-related donor versus cadaveric allografts was 84% versus 67% at 5 years after transplant (P=NS) (not shown). There were no statistically significant differences in survival of living-related or cadaveric renal allografts between IgA recipients and a reference group. Similarly, actuarial graft survival of IgA patients analyzed by recipient age(less than or greater than 20 years at the time of transplant), gender, race, duration of disease before transplant (less than or greater than 10 years), or by immunosuppression regimens (with or without CsA) did not demonstrate statistically significant differences (not shown).
There were no significant differences in long-term outcome between the IgA and reference groups. The incidence of rejection was 52% (31 of 61) in the IgA group and 45% (28 of 62) in the reference group. There were 18 grafts lost in the IgA group and 20 grafts lost in the reference group. The mean time to graft loss was 35±33 months in the IgA group and 29±31 in the reference group. Four and five deaths occurred in the IgA and reference groups, respectively. The mean serum creatinine of functioning grafts in the IgA group was 2.0±1.1 (n=43) mg/dl and 2.0±1.2 mg/dl (n=41) in the reference group and did not differ based on immunosuppressive regimens. Follow-up for the IgA and reference groups was 61±37 and 55±36 months, respectively (P=NS). Causes of graft loss and patient death are listed in Table 2.
Recurrent disease. The diagnosis of biopsy-proven recurrent disease was precipitated by renal dysfunction, microscopic hematuria, or proteinuria. Thus, histologic recurrence without clinical manifestations was not included in this analysis. Recurrent disease by these criteria developed in 29% (18 of 61) of allografts and was diagnosed an average of 31 months after transplant (range, 1-121 months after transplant)(Table 3). Nine of the 18 patients with recurrent disease received CsA for immunosuppression and the other 9 patients received azathioprine and prednisone alone. Recurrence of disease was not correlated with recipient sex, race, age at transplant, immunosuppression, or donor status. There was no significant difference in graft loss in patients with and without recurrent disease, but the time to graft loss was significantly prolonged for graft loss due to recurrent disease compared with graft loss from other causes. Furthermore, patients with recurrence had a significantly greater length of follow-up (Table 3).
Graft loss in patients with recurrent disease. Thirty-nine percent (7 of 18) of patients with recurrent disease have experienced graft loss. Histopathology was reviewed with respect to findings most consistent with advanced stages of IgA nephropathy (mesangial proliferative expansion and glomerular sclerosis) versus findings associated with chronic rejection(chronic inflammatory cell infiltrates, interstitial fibrosis, tubular atrophy, and chronic vascular changes). Three of seven patients lost grafts without histologic evidence of chronic rejection, three of seven patients had histologic findings of both recurrent disease and chronic rejection but with histopathology most remarkable for recurrent disease, and one of seven patients had findings consistent with chronic rejection. Four additional patients with recurrent disease demonstrated chronic renal dysfunction and had a mean serum creatinine of 4.6±0.4 mg/dl with a mean follow up of 83±35 months. Therefore, with long-term follow up, the incidence of graft loss and clinically relevant renal dysfunction in patients with recurrent disease is approximately 55% (10 of 18). Nevertheless, graft loss occurs slowly and patients experience long-term function despite the recurrence of disease in the allograft. IgA transplant patients who developed recurrent disease and graft loss versus recurrent disease without graft loss tended to have had a shorter duration of disease before dialysis, a shorter time on dialysis, and a concomitantly shorter duration from disease to transplantation (Table 4). Graft loss in patients with recurrent disease was not correlated with sex, race, age at transplant, immunosuppression, mean time to recurrence, or length of follow-up after transplant. However, graft loss in patients with recurrent disease tended to be higher in those who received living-related renal allografts(P=0.14) (Table 4).
Effect of HLA mismatch on renal allograft survival in IgA patients. The effect of donor/recipient HLA mismatch on actuarial graft survival in IgA patients was evaluated by comparing graft survival in several groups of patients. First, actuarial graft survival between IgA patients with≤2 or >2 HLA (AB and DR) mismatches and also with ≤1 or >1 HLA (AB and DR) mismatch were compared. This revealed no significant differences in actuarial graft survival based on the degree of HLA match (not shown). To separately analyze the effect of donor/recipient HLA-AB or -DR mismatch on actuarial graft survival, the patients were separated into those who were: (1) better matched at MHC class I (≤2 HLA-AB mismatches), (2) poorly matched at MHC class I (>2 HLA-AB mismatches), (3) better matched at MHC class II(≤1 HLA-DR mismatch), or (4) poorly matched at MHC class II (2 HLA-DR mismatches). The results of this analysis are shown inFigures 4 and 5. Actuarial graft survival in patients transplanted with renal allografts that were better matched at HLA-AB tended to have poorer graft survival, although this did not reach statistical significance (P=0.09). Similarly, actuarial graft survival in patients transplanted with renal allografts that were better matched at HLA-DR was significantly lower than in those with renal allografts that were poorly matched at HLA-DR (P=0.01).
We next attempted to perform a similar analysis of the effect of HLA mismatch on graft survival when cadaveric and living-related donor allografts were considered separately. The degree of HLA-AB mismatch (≤2 versus >2) did not significantly influence graft survival when analyzed within the cadaveric group alone; however, the majority of patients segregated into the>2 HLA-AB mismatch group (31 of 43). The effect of HLA-AB mismatch upon graft survival could not be adequately analyzed within the living-related donor group alone because too few patients segregated into the >2 HLA-AB mismatch group (1 of 18). Better matching at HLA-DR (≤1 mismatch) correlated with poorer graft survival when analyzed within the cadaveric group alone (P=0.06) but could not be adequately analyzed within the living-related donor group alone because too few patients segregated into the 2 HLA-DR mismatch group (2 of 11).
Retransplantation for recurrent IgA nephropathy. There were five patients with recurrent disease who underwent retransplantation. Three of the five had initially received allografts from living-related donors. Retransplantation occurred at a mean of 70±39 months after the first transplant, with a range of 41 to 138 months; one of the three received a second living-related graft and two of the three received cadaveric second transplants. Two of the five had received a cadaveric allograft initially and also as the second transplant. Three of the five who underwent retransplantation have recurrent IgA nephropathy confirmed by biopsy. Mean time to re-recurrence was 13±6 months. All five patients who underwent retransplantation have good graft function with a mean serum creatinine of 1.8±0.7 mg/dl at an average follow-up of 54±38 months after their second transplant.
This report includes the largest series of patients who have undergone renal transplantation for IgA nephropathy at a single center. Features that distinguish this report from previous reports include the extended long-term follow-up, inclusion of a large number of both living-related and cadaveric renal transplant recipients in the same study population, comparison of results in the pre- and post-CsA era, comparison of actuarial patient and graft survival in IgA patients with a reference (chronic glomerulonephritis) group, and comparison of actuarial graft survival by donor status and HLA match.
Overall patient and graft survival in the IgA group was good and was comparable to the results in a matched reference group. The actuarial graft and patient survival were similar to results reported in the literature for IgA transplant recipients (5-7). The similarity in results for IgA and non-IgA renal transplant recipients confirm other large single-center studies (6, 7) but were in contrast to the results of a multicenter analysis that indicated that graft survival rates in IgA transplant recipients were better than in the general transplant population (5). Overall graft survival rates of IgA patients in the current study were not correlated with age at transplant, recipient gender, recipient race, or immunosuppressive regimen. However, there was a tendency toward decreased graft survival in recipients of living donor allografts. This difference may reflect the closer HLA-AB and -DR match in living-related donor recipients, because a separate analysis of the effect of donor/recipient HLA mismatch on graft survival revealed that better HLA matching (especially at HLA-DR) for IgA patients was detrimental.
Recurrent disease occurred in 27% (15 of 54) of patients and in 29% (18 of 61) of grafts, which is slightly less than in a previous report from our institution in which 6 of 16 (35%) patients developed recurrent disease but is similar to the range in incidence of recurrent disease reported in other series (13-53%) (Table 5). The overall incidence of recurrent disease in this study may have been understimated because the diagnosis of recurrent disease was only prompted by clinical abnormalities. It has previously been noted by others (as well as a previous report from our center) that there was a trend toward a higher incidence of recurrence in the allografts from living-related donors (14, 16, 25)(Table 5). However, in the current study, with a larger number of patients, we found that the incidence of recurrent disease in recipients of living-related and cadaveric renal allografts was similar (33% and 28%, respectively).
Prior reports have emphasized the relatively high occurrence of recurrent disease defined histologically (50%) with only minor clinical significance(hematuria and/or proteinuria without graft dysfunction or loss) in the majority of patients (13, 14)(Table 5). An earlier previous study from our center identified only one patient of six with recurrent disease (16.6%) who experienced graft loss. In this study with a larger number of patients and longer term follow-up, 7 of 18 (39%) patients with recurrent disease lost grafts due to recurrent disease and an additional 4 of 18 (22%) have deteriorating function. Graft loss in patients with recurrent disease was associated with donor status but did not reach statistical significance and was significantly correlated with a shorter time on dialysis and with the interval between diagnosis of disease and transplantation. A recent study by others evaluated primarily cadaveric renal transplant recipients and reported results consistent with the findings in the current report(24). They found that recurrent IgA was not a benign disease, because with long-term follow-up (72 months in 17 patients with recurrent disease) graft loss occurred in 29% (5 of 17) of patients(24, 26).
Thus, despite early reports (including one from our institution) that recurrent disease is a benign process, it is apparent that with longer term follow-up deteriorating renal function and graft loss occurs in a large proportion (55%) of patients. However, similar to the clinical course of primary IgA nephropathy, recurrent IgA nephropathy after renal transplantation in this study tended to be an indolent disease. This is well demonstrated by the increase in mean time to graft loss from recurrent disease compared with graft loss from other causes.
We found only one study that addressed prognostic factors for graft loss once recurrent disease was detected. Kimata et al. (27) found that nine IgA patients with recurrent disease who had proteinuria >1 g/day and significant glomerulosclerosis (>30%) on renal biopsy uniformly developed graft loss by 6 years after transplant. In contrast, 10 patients with recurrent IgA who had proteinuria <1 g/day and minimal glomerulosclerosis (<10%) on renal biopsy uniformly experienced stable graft function up to 9 years after transplant (27).
Immunosuppression after transplant with CsA did not influence recurrent disease or the incidence of progression of recurrent disease to renal failure, despite earlier observations from our institution that there was a trend toward a decrease in recurrence in renal transplant recipients on CsA(28). This finding is similar to a report by Schwarz et al. (11) who reviewed the incidence of recurrent and de novo renal disease with and without CsA and found no difference in any of the immune-mediated disease entities studied, including IgA nephropathy. The failure of CsA to significantly decrease the incidence of recurrent disease is not entirely surprising because trials of immunosuppressive agents including steroids, Cytoxan, and CsA have failed to demonstrate the efficacy of immunosuppression in preventing the progression of primary disease(1, 29). On the other hand, recurrent IgA did not occur uniformly in renal allografts either because of spontaneous remission of the IgA disease or because of posttransplant immunosuppression.
In the current study, we found a decrease in graft survival in IgA patients who were better matched at HLA-AB (≤2 HLA-AB mismatches) or HLA-DR (≤1 DR mismatch). This effect was most marked for allografts that were better matched at HLA-DR. A definitive role of HLA type or donor/recipient HLA match in recurrence of disease after renal transplantation has not previously been established in the literature. Brensilver et al. (22) described a patient who lost two successive HLA identical renal allografts due to the recurrence of crescenteric IgA nephropathy. In a separate report, Seigler et al. (30) described three cases of recurrent IgA nephropathy in three recipients of HLA-identical renal transplants who had good long-term renal function (Table 5). Other groups have reported that there does not seem to be any correlation of HLA type or donor/recipient HLA match with either recurrent disease or graft loss due to recurrent disease, but the authors did provide the caveat that follow-up in these studies was limited (24, 31). Our detection of the negative impact of donor/recipient HLA matching on long-term graft survival in IgA patients and divergence from prior reports by others may reflect the longer duration of follow-up in this study.
There are no reports addressing the issue of retransplantation of IgA patients who experience graft loss due to recurrent disease, although there have been case reports of multiple transplants in patients with IgA nephropathy (8, 32). In this review, we report our results in five patients with recurrent disease and graft loss who were retransplanted and have good long-term graft function despite the re-recurrence of disease in three patients. Thus it seems that the recurrence of disease in the first kidney transplant does not preclude long-term graft function after a second kidney transplant.
In summary, renal transplantation is an appropriate treatment modality for IgA nephropathy patients with ESRD despite the potential for recurrent disease. We still advocate living-related transplantation for patients with IgA nephropathy who have this option but well-matched donor/recipient pairs do not seem to confer an advantage for long-term graft survival. Both recipients and donors need to be counseled regarding the risk of recurrence and graft loss due to recurrent disease. In addition, it may be prudent to offer cadaveric rather than living-related renal transplantation in cases where the progression of renal failure due to IgA nephropathy occurred relatively rapidly, because both a short interval between diagnosis of disease and transplant and the living-related donor status were correlated with graft loss in patients with recurrent disease. Finally, unlike patients with focal glomerulosclerosis, retransplantation is an option for patients who experience graft loss from recurrent disease. Both primary and secondary renal transplantation for IgA patients are compatible with long-term graft survival even if recurrent disease occurs.
Acknowledgments. The authors thank Sue Hoehninger and Jim Rinaldi at the University of California San Francisco (for their participation in the collection of data), Patrick Adams and Matthew Heller in the Histocompatibility Laboratory at the Ohio State University Medical Center (for determination of the recipient/donor HLA mismatch), Dr. Charles G. Orosz (for helpful comments and criticisms), and Karen Wine and Shannon Cox (for preparation of the manuscript).
Presented at the 23rd Annual Scientific Meeting of The American Society of Transplant Surgeons, May 14-16, 1997, Chicago, Illinois.
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