Outcomes of renal transplantation in patients with immunoglobulin A nephropathy in IndiaB Chacko1, JT George1, N Neelakantan2, A Korula3, JK Chakko1
1 Department of Nephrology, Christian Medical College, Vellore-632 004, India
2 Department of Biostatistics, Christian Medical College, Vellore-632 004, India
3 Department of Pathology, Christian Medical College, Vellore-632 004, India
Background: There is a paucity of data on the course of renal transplant in patients with immunoglobulin A (IgA) nephropathy (IgAN) from India. While the natural history of IgAN in the Indian context is rapidly progressive, the post-transplant course remains speculative. Aim: To study the graft survival in renal transplant recipients whose native kidney disease was IgAN and the incidence and correlates of recurrent disease. Settings and Designs: Retrospective case control study from a Nephrology unit of a large tertiary care center. Materials and Methods: The outcomes of 56 transplant patients (58 grafts) with biopsy-proven IgAN and of 116 patients without IgAN or diabetic nephropathy, transplanted during the same period were analyzed. Correlates of biopsy-confirmed recurrent disease were determined. Statistical Analysis: Means were analyzed by Student's t test and Mann-Whitney test; proportions were determined by Chi-square analysis and graft survival curves were generated using the Kaplan-Meier. Results: Five-year graft survival for IgA patients was not significantly different from that in the reference group (90% and 79%, P = 0.6). During a mean follow-up of 42 months (range, 1-144), 28 event graft biopsies were required in 20 grafts of IgAN. Histological recurrence was diagnosed in five of the 20 available biopsies (25%) after a mean duration of 28 months. Recurrence did not correlate with donor status, HLA B35 and A2, recipient age, gender or immunosuppression. Conclusions: Renal transplantation is an appropriate treatment modality for IgA nephropathy patients with end-stage renal disease in India, despite the potential for recurrent disease. The posttransplant course is an indolent one when compared to the malignant pretransplant phase.
Keywords: Immunoglobulin A nephropathy, India, outcomes, renal, transplant
Immunoglobulin A nephropathy (IgAN) is one of the most common glomerulopathies and may lead to renal failure in 20-40% of cases. Recurrent disease is common after transplantation and has been reported in 13-60% of patients. Initially considered a benign condition, graft losses from recurrent IgAN have been reported over the last 20 years, casting doubt on the initial premise. In a cohort of 487 patients with IgAN, we have shown that the disease in the Indian subcontinent has a relatively rapid rate of progression, with renal survival rates of 84, 55 and 33% at one, five and 10 years respectively. Actuarial renal survival at 10 years in adults was between 80 and 85% in most of the European and Asian studies, but it was lower in studies from USA.
Renal transplant is an accepted modality of treatment for patients with end-stage IgAN. In the context of a malignant pretransplant phase and lack of data, the posttransplant course of IgAN in India remains speculative. In this single-center, retrospective analysis on 58 renal allograft recipients with IgAN as the cause of renal failure, we have aimed to study the actuarial graft survival compared to a reference group, the incidence and correlates of recurrent disease and graft loss after recurrence.
In this retrospective study, patient data between January 1990 and May 2004 were retrieved by the same person from the transplant records stored in the Department of Nephrology. Cases included in this study were those recipients whose native kidney disease (NKD) was biopsy-proven IgAN. Data was gathered on donor status, recipient and donor HLA type, pretransplant length of disease, interval to recurrent disease after transplant, rejection episodes, posttransplant biopsies and graft loss.
Actuarial graft survival was compared to a reference group matched (2:1) for donor status, age at transplant, gender, date of transplant within two years and immunosuppression regimen. The reference group included those recipients whose NKD was lupus nephritis, chronic interstitial nephritis, focal segmental glomerulo-scelorosis and those with undetermined NKD. Those with diabetic nephropathy as NKD and recipients with clinical suspicion of end-stage renal disease (ESRD) due to IgAN were excluded from the reference group.
Most of the recipients received cyclosporine (CsA), prednisolone and azathioprine as part of the triple regimen. All patients received 5 mg/kg/day CsA five days prior and 2 mg/kg/day azathioprine orally two days before surgery. The CsA was started at an initial dose of 8 mg/kg/day in two divided doses after transplantation and then tapered monthly by 1 mg/kg/day. The CsA dose was adjusted to 12h whole-blood trough levels of CsA, determined by monoclonal radioimmunoassay, to achieve CsA concentrations of 250 and 150 ng/ml, one and 12 months after transplantation, respectively. Postoperative intravenous methylprednisolone was rapidly tapered from 1g on the day of surgery down to 60 mg by day 4 and then was replaced with oral prednisone. The dosage of prednisolone was gradually tapered to 10mg/day by the end of the sixth month. Neither antibody induction nor cytomegalovirus prophylaxis was used. Mycophenolate mofetil was used to replace azathioprine, in some cases, a few months after transplant. A minority of the patients received only prednisolone and azathioprine as immunosuppression.
Graft biopsy and definitions
After exclusion of mechanical causes of renal deterioration and acute cyclosporine nephrotoxicity, indications for renal biopsy included deterioration in renal function, significant proteinuria with one or more grams of urinary protein per day or gross hematuria. The same policy for transplant biopsy was followed throughout the study, while routine protocol biopsy was not performed. Recurrence of IgAN was diagnosed in patients who had biopsy-proven IgAN as the cause of ESRD and the graft biopsy showed mesangial proliferation with predominant deposition of IgA. Time of graft failure was defined as either the time of the recommencement of chronic dialysis or the time of the second transplant, whichever was earlier. Graft loss was attributed to recurrent IgAN when the renal histology showed diffuse mesangial proliferative expansion and glomerular sclerosis with IgA deposits. Related donors are donors who were genetically related to the recipients, which included parent-child or sibling relationships. Nonrelated donors were either cadaver or spousal donors.
Data are expressed as means ± SD and were analyzed by Student's t test and Mann-Whitney test for statistical significance. Actuarial graft survival curves were generated using the Kaplan-Meier method. Significance between proportions was determined by chi-square analysis (Pearson or Fisher's exact test). Analysis was done using the Statistical Package of the Social Sciences (SPSS version 11.5, Inc, Chicago, IL). Probability <0.05 was considered significant.
During the study period, 1460 renal transplants were performed at the institute. The ESRD due to biopsy-proven IgAN was the primary diagnosis in 56 patients (58 renal transplants). Reference group included 116 recipients. The demographic data for the IgAN and reference groups were essentially comparable, save for HLA B mismatch [Table - 1].
Actuarial graft survival
During the follow-up period, 19 grafts were lost in the entire cohort (n=174), six and 13 in the IgAN and the reference group respectively. Cause of graft loss in patients with IgAN was chronic allograft nephropathy in two (3.4%), noncompliance leading to chronic rejection in one (1.7%), de novo FSGS in one (1.7%) and sepsis with graft dysfunction in two (3.4%) patients. Mean graft survival time for recipients with IgAN was 113.33 ± 10.4 months (95% CI: 93,134), with a five-year and 10-year graft survival of 90% and 49%, respectively. In the reference group the corresponding figures for mean graft survival, five- and 10-year graft survival were 100.2 ± 5 months (95% CI: 90,110), 79% and 73%, respectively ( P = 0.6), as shown in [Figure - 1]. The mean graft survival time for the 42 related grafts (110 ± 12 months) was comparable ( P = 0.6) to that seen in the 16 with unrelated (including cadaver) grafts (111 ± 13 mo). Five-year graft survival for those with related donors was 95%, while in those with unrelated donors it was 80%.
IgA in the graft
During a mean follow-up of 42 months (range, 1-144 months), 28 event graft biopsies were performed in 20 grafts. In five of the 20 (25%) grafts biopsied, recurrence IgAN as evidenced by mesangial IgA deposition with or without mesangial hypercellularity was documented after a mean duration of 28 months. Pathologically, the recurrence in three patients was isolated, but in the other two patients, recurrences were accompanied by varying degrees of chronic rejection. The cumulative incidence of recurrence in patients who had undergone event renal biopsies by different indications was 25%. Although it would have required protocol biopsies of all 58 grafts to clearly determine the prevalence of recurrence, we could state that 20 (34%) of 58 grafts had clinically apparent recurrence. Recurrence of disease did not correlate with recipient sex, age at transplant, immunosuppression, donor status or specific HLA antigens [Table - 2]. However, the recurrence group had a significantly greater degree of proteinuria at last follow-up, when compared to the nonrecurrence group ( P = 0.018). Similarly, graft loss in patients with recurrent disease tended to be higher than those without, but not achieving statistical significance. ( P = 0.07).
Mean graft survival time for recipients with IgAN and recurrence was 80 ± 32 mo (95% CI: 17,143), with a five-year graft survival of 66%, while in the nonrecurrence group it was 88 ± 6 mo (95% CI: 75,100), with a five-year graft survival of 100% ( P= 0.4).
It would be prudent to mention here that IgAN was also documented in five grafts (not included in this study) whose native kidney disease was undetermined. Whether these constituted recurrence or de novo disease, one could never tell as the NKD was undetermined.
IgAN is the most common form of primary GN, accounting for nearly 20% of patients with end-stage renal disease and characterized by a highly variable clinical course; ranging from a benign condition to one with a rapidly progressive course. In India, IgAN seems to have a relatively poor prognosis with five- and 10-year renal survival rates being 55 and 33%, respectively.
The overall graft survival in the IgA group seen in this study was not significantly different from that in the reference group. The similarity in results for IgA and nonIgA renal transplant recipients confirms the results of a multicenter analysis that indicated that graft survival rates in IgA transplant recipients were better than in the general transplant population. The potential role of immunologic dysfunction that includes the effects of the high level of IgA anti-HLA antibody in IgAN patients has been speculated as the mechanism for superior graft survival among patients with IgAN.
Berger et al were the first to describe the recurrence of IgAN and subsequent studies showed 20-60% incidences of recurrence after renal transplantation. This large inter-institutional variability is probably dependent on the circumstances under which recurrence was diagnosed. Indications of graft biopsy, as well as the types of donor kidney and the nature of graft biopsy (event vs. protocol biopsy), differ from center to center. Several studies, which included a total of almost 1200 patients with underlying IgAN, have now established that after a mean follow-up of five years, approximately 13% of the patients will exhibit some recurrence-related renal graft dysfunction and approximately 5% will have lost their graft as a result of recurrent IgAN. Histological recurrence in this study occurred in 25% (five of 20) of the grafts, as opposed to an incidence of 30-61% in other series. As alluded to before, the varying indications for biopsy and the absence of protocol biopsies is a limiting factor while making comparisons. The overall incidence of recurrent disease in this study may have been underestimated because biopsies were undertaken only when prompted by clinical abnormalities.
The predictors of clinically relevant recurrent IgAN after a renal transplant, represents largely a function of time posttransplantation and cannot be predicted by other variables, which is in accordance with the results of this study. Nevertheless, when compared to the nonrecurrence group, the recurrence group had a significantly greater degree of proteinuria ( P = 0.018) and a trend for graft loss ( P = 0.07). Thus, long-term graft survival in IgA patients could be affected by recurrence. A trend towards a higher incidence of recurrence in the allografts from living-related donors is debatable., Furthermore, there are reports of an association of HLA DR4 or B35 with increased susceptibility to recurrent IgAN and a possible protective effect of HLA A2 against recurrence of IgAN., However, in our study, recurrence was not related to the type of donor or presence of specific HLA antigens.
Unlike the clinical course of primary IgAN seen in India, recurrent IgAN after renal transplantation as seen in this study tended to be benign. Although graft loss was higher in the recurrence group, recurrence per se did not contribute to the graft loss. Both the grafts in the recurrence group were lost because of sepsis and consequent graft dysfunction. Despite the obvious limitations of this study namely, lack of protocol biopsies and the small number of patients, it sets the platform for larger studies, which could clearly discern the impact of recurrence on graft survival. Modifications in immunosuppression that could circumvent this problem, is a potential area for future research.
The study indicates that renal transplantation is an appropriate treatment modality for IgAN patients with ESRD in India, despite the potential for recurrent disease. Living-related transplantation for patients with IgAN who have this option should still be advocated. Unlike the progressive nature of the disease pretransplant, the posttransplant course is seemingly indolent. These results are encouraging in the face of a rather dismal scenario encountered while managing progressive IgA nephropathy in India. Further studies are warranted to address the problem of recurrence of IgAN and its effect on graft outcomes with routine protocol biopsies.
[Figure - 1]
[Table - 1], [Table - 2]