The recurrence of IgA nephropathy (IgAN) in kidney transplants was first described over 25 years ago (1, 2). The IgAN recurrent rate has subsequently been described in a number of reports, with rates from 15 to 60% depending on length of follow-up posttransplantation and biopsy policy. However the impact of recurrence on transplant function is debated (3). Other than time since transplantation, there are no factors clearly associated with recurrence. Some studies have suggested an increased risk of recurrence among recipients of well-matched (4) or human leukocyte antigen (HLA)-identical grafts (5, 6), but this has not been confirmed by others (7). Similarly, recipients of grafts from living donors (LDs) are at increased risk of recurrence in some (4, 8) but not all (9,10) series.
These reports are generally based on one or two centers, and numbers of transplants (particularly from LDs and especially HLA-identical LDs) are small. We report here recurrence of IgAN from the Australia & New Zealand Dialysis and Transplant Registry (ANZDATA), which includes all kidney transplants performed in Australia and New Zealand from 1963 to the present.
ANZDATA collects information on all cases of end stage renal disease (ESRD) treated with chronic renal replacement therapy in Australia and New Zealand. Data is collected from all renal units every six months via a report form. For transplant recipients, in addition to data about the transplant matching and procedure, units have been asked since 1987 whether there is any histologically proven recurrence of the primary renal disease in the graft. Since 1997, the date of biopsy demonstrating the disease recurrence has also been sought; for the majority of recurrences over 1987–1996, the date of biopsy was retrospectively obtained by the Registry. The indications for biopsy are not required on the form, nor are details of biopsies which did not show disease recurrence (or rejection) reported to the Registry. Immunosuppressive drugs have been reported since 1981.
This analysis includes all recipients of kidney transplants performed in Australia and New Zealand between October 1, 1987 (when recording of recurrent disease commenced) and December 31, 2004. Follow-up was available to time of death, graft loss, or December 31, 2004. For this analysis, IgAN included those where the primary renal disease was reported as mesangial proliferative glomerulonephritis (GN) with IgA deposits, mesangial proliferative glomerulonephritis where no immunofluourescence (IF) was performed and Henoch-Schonlein purpura. The group without IF were included as it was felt that these were highly likely to be IgAN – 92% of all mesangial proliferative GN reported to ANZDATA with known IF were positive for IgA. The group with Henoch-Schonlein purpura were included as histologically the renal lesion from this condition is the same as IgAN.
Proportions were compared with chi-square tests where expected numbers were greater than five in all cells, and Fisher's exact test otherwise. Confidence intervals were calculated for odds ratios using the Cornfield method. Recurrence was analyzed using time-to-event (survival) techniques. Cox regression was used to adjust for confounding factors, and hazard ratios (95% CI) are quoted. “Failure” for graft survival analyses included loss of graft function requiring a return to dialysis and patient death with a functioning graft. Survival of grafts after diagnosis of recurrence was analyzed using time-dependent analyses, using the date of the transplant biopsy as the time point of recurrence. Cox models used “robust” methods of calculating variance, clustered on transplanting hospital to address correlation of results within centers (11). Analyses were performed using Stata version 9.2 (12).
IgAN was recorded as the native renal disease for 1,306 people, who received 1,386 grafts (including 488 from living donors); further inclusions in this group were 51 grafts among 48 people with mesangial proliferative glomerulonephritis where no IF studies were performed and 68 grafts among 60 people with Henoch-Schonlein purpura. Grafts to recipients with IgAN comprised 14% of the 10,437 grafts performed over the time period. IgAN was significantly more common as the primary renal disease among recipients of grafts from LDs than cadaveric donors (CDs) with an odds ratio (OR) of 1.3 ([95% CI 1.2–1.5], P<0.0001).
Among grafts performed where the recipients had IgAN as native renal disease, 108 had zero HLA-mismatches. This included 36 from cadaveric donors with no HLA- mismatches, and 72 from living donors (four from monozygotic twins, 65 from siblings/dizygotic twins, one maternal donor, one paternal donor, and one filial donor).
Predictors of Recurrences
In those with IgAN as original disease, biopsy proven recurrence had been reported in 110 grafts (7%). The date of biopsy was not available for 10 episodes of recurrent IgAN, and these grafts were excluded from further analysis. The risk of recurrence did not differ significantly between grafts from CD and LD (HR=1.4 [0.97–2.16], P=0.07). The median time to biopsy-proven recurrence was 42.7 months (interquartile range 20.9–81.3 months).
Among LD recipients there was a significant increase in the risk of recurrent disease among those with zero vs. ≥1 HLA-mismatches (Fig. 1, HR 2.7 [1.5–5.1], P=0.001). There was no difference between sibling and non-sibling live donors in this relationship (P=0.2 for interaction term). There was also heterogeneity in this relationship between recipients of CD and LD grafts, with no relationship observed between zero vs. ≥1 HLA-mismatches and recurrence of IgAN among CD recipients (Table 1).
Among LD recipients, IgAN recurrence was not clearly associated with either age at transplantation, gender or the use of calcineurin inhibitors (Table 2).
The occurrence of recurrence of IgAN was further examined in recipients possessing particular HLA antigens previously reported to be associated with recurrence (B12, B35, DR4). There were no recipients of grafts with IgAN who had HLA B12; no significant association was observed either overall (HR for recurrence among all recipients with IgAN 0.79 [95% CI 0.59–1.04], P=0.09) or among LD recipients (HR=0.64 [95% CI 0.34–1.2], P=0.16) between recipients with HLA-B35 or HLA-DR4 antigens and risk of recurrence of IgAN.
Effect of Recurrence on Graft Outcome
There have been 76 graft loss events (including 15 deaths) from all causes in the group of LD recipients with native IgAN, and 314 events among CD recipients (97 deaths). Using this period after diagnosis of recurrence as a time-dependent covariate, the risk of graft loss after IgAN recurrence was increased; the extent of this risk differed between LD recipients (HR for graft loss 8.5 [95% CI 4.8–15.2], P<0.001) and CD recipients (HR 4.5 [95% CI 2.6–7.5], P<0.001, P=0.03 for interaction).
Despite the increased rate of IgAN recurrence in zero HLA-mismatched LD recipients, the overall graft survival of these recipients did not significantly differ from ≥1 HLA-mismatch LD recipients with native IgAN (HR for graft loss 1.2 [95% CI 0.70–2.1], P=0.5). In contrast, recipients without native IgAN of zero HLA-mismatched kidneys from LD did show a graft survival advantage over ≥1 HLA-mismatch recipients (HR 0.55 [95% CI 0.39–0.77], P<0.001). Kaplan-Meier curves illustrating this are shown in Figure 2. A formal statistical test of the difference in the effect of zero HLA mismatches was significant (P=0.009 for interaction term zero-MM*IgAN).
Many centers have reported their experience with recurrent IgAN (1, 4, 5, 8, 13–19). The rates of recurrence reported to ANZDATA are considerably lower than these other reports, which quote recurrence rates of 40–60%. There are several factors relevant to this comparison. Firstly, many of the quoted rates in fact refer to the proportion of a biopsy series found to have mesangial IgA changes on biopsy, rather than the proportion of all grafts performed. When the numbers of recurrences of IgAN are compared with the total number of grafts performed among recipients with IgAN, then recurrence rates range from 15% (8, 18) to 30% (4, 5, 13, 14). Secondly, there may be ascertainment bias: there may be a reluctance to proceed to renal transplant biopsy to confirm the clinical finding of recurrent disease, particularly if there is little suspicion of other processes. As ANZDATA only collects biopsy-proven recurrence, this could lead to underestimation of prevalence. However, for this bias to explain the association observed here, there would have to be a tendency towards a greater likelihood of performing a renal biopsy to confirm recurrent disease in zero compared to ≥1 HLA-mismatch LD recipients. We believe that such a bias is unlikely to be present, given the absence of firm evidence of an association with HLA or number of mismatches which might influence clinical practice in selection of patients for biopsy. Until recurrent IgAN can be diagnosed without transplant renal biopsy, the true prevalence will only be available through centers where all recipients receive protocol biopsies at two to five years posttransplantation.
Although the rate of recurrence is higher among zero HLA-mismatch recipients, there is no clear indication of an increased rate of graft loss compared to recipients of ≥1 HLA-mismatched grafts. One can then draw reassurance from this that there is no rationale for avoiding a zero-HLA mismatch donor for recipients with IgAN. However, this differs from LD recipients with types of renal disease other than IgAN where better graft survival seen among zero compared to ≥1 HLA-mismatch LD recipients.
The effect of histological recurrence on function has been debated. Bumgardner reported a graft loss rate of 40% of those biopsied (4), and Odum et al. (13) found only half of those with mesangial IgA deposits developed deteriorating function. Also, those using a definition of recurrence which incorporates functional deterioration as well as histological evidence report lower rates. Our data suggest a substantially increased risk of graft failure associated with recurrence. However, this is likely to be an overestimate due to ascertainment bias – those grafts whose function is deteriorating are more likely to be biopsied, hence any comparison of grafts which were biopsied (of which those with IgAN are a subset) with those without biopsy will show poorer function among the biopsy group. ANZDATA does not record the results of biopsies which did not show recurrent disease, nor cases of clinical suspected (but not biopsied) recurrence of IgAN, hence we were not able to explore this issue more deeply.
The data here illustrate the strengths as well as weaknesses of national and international Registries. Although IgA nephropathy is a relatively common glomerulonephritis, transplantation between HLA identical donor and recipients is relatively rare, and it is only by national or international aggregation of numbers that questions about small subgroups such as this can be addressed statistically. By their nature, the range of information collected by Registries is broad but may lack depth when individual areas are closely examined. For example, although it would be ideal to regularly collect information about the occurrence and degree of proteinuria and hematuria in all graft recipients with IgAN, this is not practical within the routine Registry data collection.
Other limitations arise from the absence (within Registry data) of histological results at time of transplantation; it has been suggested that rather than recurrent disease, transplants from zero HLA-mismatch siblings might carry asymptomatic IgAN (20). This would be apparent on the initial wedge biopsy performed at the time of transplantation, but this information is not reported to ANZDATA.
There are several plausible biological causes for an increased rate of recurrence among zero HLA-mismatched LD recipients. HLA gene(s) may be playing a role in the IgAN. Several reports have linked various HLA types with IgA nephropathy (recently reviewed by Tang et al. ). However, the data here do not show a clear relationship to any HLA type. Alternatively, immunosuppression might be lesser among zero HLA-mismatched recipients, and might be related to an increased IgAN recurrence rate. However, there has not been any suggestion in reports of others that cyclosporin use was associated with difference in recurrence rates (8, 13, 15).
In summary, we have shown an increased rate of recurrence of IgA nephropathy among recipients of zero HLA-mismatch kidney s from living donors (compared with LD kidneys with ≥1 HLA mismatch). Recurrence of IgAN is associated with a higher rate of graft failure, however, overall graft survival rates were similar among zero and ≥1 HLA mismatch LD recipients.
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Keywords:© 2006 Lippincott Williams & Wilkins, Inc.
IgA nephropathy; Kidney transplantation; Disease recurrence