IgA nephropathy (IgAN*), including its systemic form, Henoch-Schönlein purpura (HSP), is among the most common glomerulonephritis (GN) types. About 25% of primary IgAN patients develop renal failure. About 50-60% of transplanted patients with IgAN and HSP suffer a histological recurrence of the disease (1). Several studies suggested that recurrent IgAN is a benign condition, which accounts for progressive graft failure in less than 10% of the cases (1-3). However, these studies were performed in a small series of patients or over limited posttransplant observation periods. Recent studies have reported that recurrent IgAN induces chronic graft dysfunction in up to 20% of the recipients (4-7).
We have studied the relevance of recurrent IgAN in a single-center population of mostly Caucasian, Northern European patients. All 690 adult transplant recipients with any type of GN as the underlying disease were evaluated. After the exclusion of patients with liver disease or systemic diseases other than HSP and of patients in whom insufficient clinical data were available, 61 patients were recruited. These patients had received a total of 71 renal transplants between January 1984 and February 1995(cadaveric in 66 cases; living related donor in 5 cases but not in HSP patients). The 61 patients were divided into the following groups: (a) patients with a biopsy-proven IgAN (n=47) or HSP (n=4) as the underlying disease; (b) patients with a biopsy-proven mesangioproliferative GN as the underlying disease plus a biopsy-proven IgAN in the renal transplant (n=6); and (c) patients with a clinical history compatible with IgAN, not proven by renal biopsy, but a biopsy-proven IgAN in the renal transplant (n=4).
The following data were recorded: (a) data pertinent to the pretransplant course (see Tables 1-3), including the ACE genotype [determined as described (8)]; (b) data pertinent to the clinical posttransplant course (seeTables 1-3), including follow-up after transplantation (or time until graft failure), slope of 1/serum creatinine(excluding values obtained within the first 6 months after transplantation and based on 12±6 data points obtained over a period of 53±29 months), first proteinuria exceeding 0.5 g/day (excluding data obtained during the first 3 months after transplantation), and latest available determination of proteinuria and persistent hematuria at the latest presentation (excluding data obtained during the first 3 months after transplantation and sporadic demonstration of hematuria in women); and (c) histological findings in the renal transplants and reasons for transplant failure. Indications for graft biopsies included worsening of graft function and proteinuria of >1 g/day.
Each patient was assigned to one of four groups. The central criterion for the assignment to the groups was the slope of 1/serum creatinine. (1) Stable-defined as the slope of 1/creatinine >-1.5×10-5L/(μmol × month), irrespective of the transplant biopsy result. (2) Recurrence=progressive transplant dysfunction due to recurrent IgAN-defined as the slope of 1/creatinine <-1.5×10-5, biopsy-confirmed recurrence of IgAN, and no evidence of other obvious reasons for worsening graft function. (3) Other reason=progressive transplant dysfunction due to other, known reasons-defined as the slope of 1/creatinine < -1.5×10-5 and no evidence of recurrent IgAN in the transplant biopsy or IgA deposits but concomitant significant evidence of chronic rejection or obvious reasons for transplant dysfunction. (4) Unknown reason for progressive transplant dysfunction-defined as the slope of 1/creatinine < 1.5×10-5 and an inconclusive transplant biopsy or patients who have not been biopside or refused a transplant biopsy and had no clinically apparent reason for worsening of the transplant function.
Values are means ± SD. Statistical significance (defined asP<0.05) was evaluated using the chi-square test, Fischer's test,t test, or the Mann-Whitney U test where appropriate.
Twenty-seven patients were assigned to the stable group, 14 to the recurrence group, 12 to the other reason group, and 8 to the unknown reason group (Table 1). Patients in the recurrence group exhibited the highest proteinuria (>0.5 g/day in all patients) and frequency of persistent microhematuria (Table 1). Histological recurrence of glomerular IgA deposits was present in 20 of 33 patients (61%) who underwent transplant biopsies (Table 1).
In the recurrence group, the percentage of patients with underlying nonclassified mesangioproliferative GN was significantly increased(Table 1; in one of these later cases, familial IgAN had been documented). Separate analysis of patients with nonclassified measangioproliferative GN and biopsy-proven IgAN in the recurrence group revealed that the former had all received a native kidney biopsy before 1984, whereas the latter were all biopsied after 1984 (before 1984 immunohistology was not routinely performed). Within the recurrence group, follow-up after renal transplantation was longer in the mesangioproliferative GN patients(7±2 years) than in the IgAN patients (5±1 years;P=0.059). None of the other findings described below were significantly different when the six recurrence patients with biopsy-proven IgAN were compared with the five patients with nonclassified mesangioproliferative GN (data not shown).
In the recurrence group, 10 of 14 patients returned to dialysis at 38-98 months (mean 51 months) after transplantation. Of these 10 patients, five were retransplanted and three developed another recurrence of IgAN without evidence of other apparent reasons for dysfunction and again returned to dialysis (at 21-51 months after transplantation). One of the three patients with repeated graft loss due to recurrent disease had an HSP as his underlying disease(during both transplant periods without evidence of systemic reactivation). The fourth retransplanted patient died during sepsis at 59 months after transplantation (renal function stable, no hematuria but proteinuria of 0.72 g/day). The fifth patient has a stable renal function at 51 months after the second transplantation. In the other reason group, 7 of 12 patients developed terminal graft failure due to chronic rejection and/or acute rejection episodes at 0.5-97 months (mean 30 months) after transplantation.
No significant differences evolved for any of the pretransplant parameters investigated (except for a lower average age in the other reason group as compared with stable patients) (Table 2). Patients with stable graft function had a significantly shorter length of follow-up after renal transplantation than patients with graft dysfunction due to recurrent disease (Table 3). Biopsy-confirmed acute rejection episodes were present in 43% of the recurrence patients, 85% of the other reason patients, 50% of the unknown reason patients, and 67% of the stable patients (differences not significant).
In the present study, we have chosen a conservative definition of dysfunction due to recurrent IgAN, which might understimate the importance of the problem (in particular, because eight of our patients with progressive graft dysfunction did not receive graft biopsies). It seems noteworthy that the group of patients with dysfunction due to other reasons had on average a follow-up that was 1.5 years shorter. Thus, in these later patients the importance of recurrent IgAN may have been masked by the more rapid manifestation of chronic rejection and/or other reasons for graft failure.
In contrast to early data, subsequent studies(3, 4, 6, 9) demonstrated high rates of graft failure due to recurrent IgAN (Table 4). The data of the present study extend these findings by demonstrating that with longer follow-up, the percentage of clinically relevant recurrences increases even further. Similar graft failure rates as in our study have been reported recently (5, 7)(Table 4). However, both of these latter studies are difficult to compare with the present one and may have overemphasized the clinical importance of recurrence, because they only reported clinical details for selected patients: those with either biopsy-proven histological recurrence (5) or those biopsied because of graft dysfunction or urinary abnormalities(7).
Our patients in the recurrence group contained the highest percentage of patients with a nonclassified mesangioproliferative GN as the underlying renal disease, raising concern that patients with non-IgA mesangioproliferative GN may have been included. Several findings argue against this possibility: a positive family history of IgAN in one case; patients with nonclassified mesangioproliferative GN followed a posttransplant course indistinguishable from that of the IgAN patients; in our own experience >95% of primary mesangioproliferative GNs represent IgAN (our unpublished observation); and the lack of a more specific diagnosis than mesangioproliferative GN in our patients was exclusively due to the fact that their native kidneys had been biopsied before 1984 (when immunohistology became a routine component of renal biopsy evaluation). Therefore, our data suggest that the patients with“mesangioproliferative GN” as the underlying renal disease had a high likelihood of suffering from IgAN and that these patients were at the highest risk for clinically relevant recurrence because they had been transplanted longer ago than the remaining patients.
Only the time elapsed since renal transplantation evolved as a predictor of chronic graft failure due to recurrent IgAN. Similarly, histological recurrence of IgAN has also been reported to depend on the length of time posttransplantation (4). The ACE gene polymorphism, which has been linked to the course of IgAN by some studies, did not reveal any significant abnormalities of the allele distribution in our recurrence group. Taken together, these findings suggest that the course of IgAN posttransplantation is very similar to the natural course of the primary disease and that with prolonged time after transplantation, recurrence-related graft failure will increase unless “masked” by chronic alloreactive graft damage. The current study is the first to demonstrate that patients who have already lost a graft due to recurrent IgAN are at very high risk for another IgAN-related graft loss upon retransplantation.
Acknowledgments. The authors thank Dr. Török, Hannover Medical School, for valuable advice in the evaluation of the data.
This study was supported by grants (SFB 244/C12 and SFB 265/C8) and a Heisenberg stipend of the Deutsche Forschungsgemeinschaft to J. Floege.
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