Recurrent IgA nephropathy after renal transplantation despite immunosuppressive regimens with mycophenolate mofetil
Arun Chandrakantan1,2,
Piti Ratanapanichkich1,
Mowaffaq Said1,
Catherine V. Barker1 and
Bruce A. Julian1,2
1 Division of Nephrology, Department of Medicine and 2 Division of Transplantation, Department of Surgery, University of Alabama at Birmingham, Birmingham, AL, USA
Correspondence and offprint requests to: Arun Chandrakantan, MD, Division of Nephrology, Department of Medicine, THT 638B, 1530 Third Avenue South, Birmingham, AL 35294-0006, USA. Email: arunc{at}uab.edu
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Abstract
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Background. Transplantation offers an excellent option for patients with immunoglobulin-A nephropathy (IgAN) with severe renal dysfunction. However, IgAN frequently recurs in allografts treated with azathioprine. We examined the impact of mycophenolate mofetil immunosuppression on recurrence of IgAN.
Methods. We reviewed the charts of patients transplanted for IgAN at our institution in the cyclosporin era. Patients were excluded from further analysis if follow-up was <12 months or if immunosuppression at engraftment did not include azathioprine or mycophenolate mofetil. Laboratory data, medications and allograft biopsy findings were compiled.
Results. 152 kidney transplantations met the study criteria. At engraftment, 61 allografts were treated with azathioprine and 91 with mycophenolate mofetil. By 3 years post-transplant, IgAN developed in six of 60 (10.0%) azathioprine-treated allografts and five of 62 (8.1%) mycophenolate mofetil-treated allografts (P = 0.76). Overall, 13 azathioprine-treated and seven mycophenolate mofetil-treated allografts showed recurrence. As expected in this retrospective study, the duration of observation was longer in the azathioprine group. The interval between engraftment and diagnosis of recurrent disease was also longer. Survival of allografts with recurrent IgAN was similar in the two groups. Survival of allografts with recurrent IgAN was worse than for allografts without recurrence or allografts transplanted into patients with non-IgAN renal failure. Neither switching azathioprine to mycophenolate mofetil nor using an angiotensin-converting enzyme inhibitor or angiotensin-II type 1 receptor blocker ameliorated the clinical course after a biopsy documented recurrent IgAN.
Conclusions. Mycophenolate mofetil, compared with azathioprine, did not lessen the recurrence of IgAN or its clinical impact.
Keywords: IgA nephropathy; mycophenolate mofetil; recurrent IgA nephropathy; renal transplantation
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Introduction
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Immunoglobulin-A nephropathy (IgAN) is the most common primary glomerulonephritis worldwide [1] and 2040% of patients progress to end-stage renal failure after 20 years of clinical disease [2]. For these patients, transplantation offers an excellent option for renal replacement therapy. However, immunohistological recurrence develops in as many as 60% of allografts by 10 years after engraftment [3]. Although early reports suggested recurrent disease had a relatively benign outcome, presumably due to anti-inflammatory effects of immunosuppressive medications [4], longer observation has shown that 216% of affected allografts were lost to progressive disease [3,58].
Currently, there is no consensus about an approach to reduce the risk or severity of recurrent IgAN. The rate of recurrence has not decreased after cyclosporin became the cornerstone of immunosuppressive therapy in 1983. Mycophenolate mofetil was substituted for azathioprine at many transplant centres in the mid-1990s after clinical trials showed reduced rates of acute rejection [9]. Mycophenolic acid, released from mycophenolate mofetil by tissue and systemic esterase activity, inhibits inosine 5'-monophosphate dehydrogenase, a key enzyme for de novo purine synthesis and for glycosylation of adhesion molecules in B and T lymphocytes [10]. Therefore, this agent selectively inhibits proliferation of lymphocytes, synthesis of antibody, generation of cytotoxic T cells and recruitment of leukocytes to sites of inflammation. These actions might be expected to ameliorate the inflammatory response in immune-mediated glomerulonephritis and preliminary reports have shown some promise [11,12]. In 1997, Nowack and colleagues [13] reported that adding mycophenolate mofetil to the immunosuppressive regimen for two patients with IgAN, including one with biopsy-proven recurrent disease, reduced proteinuria and the serum creatinine concentration. An additional report described improvement in renal clearance function for two patients with native-kidney IgAN [12]. These studies prompted us to review our experience with renal transplantation in patients with IgAN in the cyclosporin era. We sought to determine whether the switch from azathioprine to mycophenolate mofetil as the antiproliferative agent in the immunosuppressive regimen had reduced the frequency and clinical impact of recurrent disease.
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Subjects and methods
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Patients
In 1997, after approval from the Institutional Review Board for Human Use, we reviewed the medical records of patients with biopsy-proven IgAN who had undergone renal transplantation at the University of Alabama at Birmingham since the introduction of cyclosporin into the standard immunosuppressive regimen in December 1983. Patients were excluded from further analysis if they met any of the following criteria: (i) the allograft had been lost within 3 months of engraftment due to acute rejection or technical complications; (ii) the interval between transplantation and last follow-up was <12 months; or (iii) immunosuppressive therapy beginning at engraftment did not include azathioprine or mycophenolate mofetil. For patients who had received more than one allograft treated with the same antiproliferative agent (azathioprine or mycophenolate mofetil), we included only the allograft with the longest survival in the analysis. Data recorded upon chart review included gender, age and race; source of allograft; components of immunosuppressive therapy; treatment with an angiotensin-converting enzyme inhibitor, angiotensin-II type 1 receptor blocker, beta-blocker or calcium channel blocker; serial measurements of serum creatinine concentration and proteinuria by dipstick, spot protein/creatinine ratio or timed urine collection, and microscopic haematuria; date and histological findings of allograft biopsies; and cause of allograft loss. Non-compliance was defined as an undetectable blood level of a calcineurin inhibitor in the absence of instructions to omit the medication. Following the review, we have recorded the data prospectively for these patients as well as newly engrafted recipients with IgAN.
Treatment of hypertension
A calcium channel blocker agent (usually nifedipine or amlodipine) was generally the first-line therapy for hypertension and was often combined with a diuretic. Use of an angiotensin-converting enzyme inhibitor increased after 1989, for treatment of proteinuria or post-transplant erythrocytosis or adjunctive therapy for hypertension. Angiotensin-II type 1 receptor blockers were prescribed more recently for similar indications and, occasionally, in conjunction with an angiotensin-converting enzyme inhibitor for treatment of patients with pronounced proteinuria.
Immunosuppression
The immunosuppressive armamentarium evolved substantially over the 20-year interval. In general, a four-drug regimen was used and included induction therapy with an anti-T-cell preparation: Minnesota antilymphoblastic globulin until August 1992 when it was replaced by OKT3® or ATGAM®, which in turn were replaced by Zenapax® (daclizumab) in April 1998. Methylprednisolone 500 mg was given intravenously at the time of engraftment and the dose of methylprednisolone or prednisone was tapered to 30 mg/day by 1014 days after engraftment. The dosage of prednisone was tapered to 1015 mg/day over the next 2 months. Cyclosporin was the customary calcineurin inhibitor; Sandimmune® was used from December 1983 until September 1995, when Neoral® was substituted. Since its commercial availability, tacrolimus was given to patients with delayed graft function and those undergoing repeat transplantation; cyclosporin was occasionally switched to tacrolimus because of extrarenal toxicity. Azathioprine, generally 1.52.0 mg/kg body weight/day, was the antiproliferative agent until August 1995 when CellCept® (mycophenolate mofetil) 15003000 mg/day became standard therapy. A few patients participating in clinical trials had received mycophenolate mofetil as early as 1990. Acute rejection episodes were treated with boluses of methylprednisolone, 15003000 mg cumulative dosages over 36 days; glucocorticoid-resistant acute rejection was treated with one of several anti-T-cell preparations (Minnesota antilymphoblastic globulin, OKT3®, ATGAM® or Thymoglobulin®) for 714 days.
Laboratory measurements
Serum creatinine concentration had been measured by standard laboratory techniques using a multichannel autoanalyser. Pathological proteinuria was defined as a dipstick measurement >1+ or a protein/creatinine ratio >0.3 in a randomly voided sample or timed collection. Haematuria was denoted by more than five red blood cells per high-power field in a resuspended urinary sediment obtained >2 months after engraftment, when the ureteroneocystotomy would be expected to have healed.
Renal outcome
Percutaneous renal allograft biopsy was performed after informed written consent to assess the basis for pathological proteinuria or an increase in serum creatinine concentration. No protocol or surveillance biopsy was performed. The tissue was processed for routine light microscopy studies and for immunofluorescence (IgA, IgG, IgM, C3 and kappa and lambda light-chains) and electron microscopy examination if adequate tissue was available. IgAN was defined by standard criteria, including the typical immunofluorescence features [14]. Acute rejection was diagnosed clinically by a rising serum creatinine concentration in a patient with a tender allograft or cortical retention of the radioisotope on renal scan in the absence of urinary obstruction or cyclosporin nephrotoxicity, or histologically in the presence of lymphocyte-associated tubulitis.
Graft loss was attributed to recurrent IgAN if light microscopy showed diffuse mesangial proliferative lesions accompanied by segmental sclerosis or extracapillary proliferation without significant hyaline arteriolopathy or chronic allograft nephropathy. Electron microscopy showed electron-dense deposits in the mesangium and the patient had not experienced an episode of acute rejection or been non-compliant with the immunosuppressive regimen. Chronic allograft nephropathy (previously termed chronic rejection) was diagnosed when the biopsy specimen showed glomerular basement membranes with double contours due to mesangial interposition, diffuse interstitial fibrosis and arteriolar thickening. Graft dysfunction was attributed to calcineurin-inhibitor toxicity, at least in part, when light microscopy showed hyaline deposits in the arteriolar walls, occasionally accompanied by bands of interstitial fibrosis and tubular atrophy.
Statistical analysis
The MannWhitney U-test was used to compare intervals from transplantation to clinical onset of recurrent IgAN and intervals from clinical onset to allograft biopsy. Fisher's exact test was used to compare frequencies of recurrent IgAN and usage of individual antihypertensive agents in the two treatment groups. Event-free survival curves (time to return to dialysis/retransplantation or time to biopsy-proven recurrent IgAN) were constructed using the product-limit method (KaplanMeier). Differences among survival curves were estimated by the log-rank test. SPSS for Windows® (SPSS® Inc., Chicago, IL, USA) version 11.1 was used in the analyses. A two-tailed P-value of
0.05 was considered statistically significant.
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Results
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Between 1 January 1984 and 31 August 2003, 180 (3.4%) of the 5225 kidney-only transplantations had been performed for patients with biopsy-proven IgAN. We excluded from further analysis the 496 allografts lost to severe acute rejection or technical problems within 3 months, including nine transplanted into patients with IgAN. For the IgAN patients, we also dropped eight allografts with <1 year follow-up after engraftment, seven more in patients not started on azathioprine or mycophenolate mofetil at engraftment (two on everolimus and five on sirolimus) and four others in three patients who had received seven allografts while treated with azathioprine. Immunosuppression at the time of transplantation for the remaining 152 allografts engrafted into patients with IgAN consisted of cyclosporin (n = 145) or tacrolimus (n = 7), prednisone and a third agent: azathioprine for 61 (deceased donor, n = 29; living-related donor, n = 31; living-unrelated donor, n = 1) or mycophenolate mofetil for 91 (deceased donor, n = 39; living-related donor, n = 40; living unrelated donor, n = 12). The ages at engraftment (means±SD) were similar in the azathioprine and mycophenolate mofetil groups (48.8±10.1 and 46.5±13.3 years, respectively; P = 0.22), whereas the follow-up interval was longer in the azathioprine group (9.3±3.6 vs 3.7±2.1 years; P<0.0001). The recipients included 131 Caucasians (105 men and 26 women), 10 African-Americans (five men and five women) and three Asians (one man and two women). Eight Caucasians (six men and two women) received two allografts; immunosuppression included azathioprine with the first and mycophenolate mofetil with the second.
Antihypertensive therapy
One year after transplantation, 126 of the 151 functional allografts were in patients on antihypertensive therapy. The frequencies of usage of angiotensin-converting enzyme inhibitors, calcium channel blockers and beta-blockers did not differ significantly between the azathioprine- and mycophenolate mofetil-treated groups: angiotensin-converting enzyme inhibitors for 10/61 (16%) vs 24/90 (27%) (P = 0.17); calcium channel blockers for 36/61 (59%) vs 39/90 (43%) (P = 0.07); and beta-blockers for 19/61 (31%) vs 42/90 (47%) (P = 0.06). Angiotensin-II type 1 receptor blockers were excluded from the analysis because only four patients were on this therapy. As the interval after transplantation lengthened, therapy differed between groups. Ninety-three of the 122 allografts with
3 years of observation were in patients treated for hypertension. Angiotensin-converting enzyme inhibitors were used less commonly in the azathioprine group than in the mycophenolate mofetil group [12/60 (20%) vs 26/62 (42%); P = 0.01], in contrast to the more frequent usage of calcium channel blockers [31/60 (52%) vs 20/62 (32%); P = 0.04]. The frequency of treatment with a beta-blocker did not significantly differ between the two groups [17/60 (28%) vs 27/62 (44%); P = 0.09].
Onset of proteinuria
Eight of 61 allografts treated with azathioprine developed persistent proteinuria <1 year after engraftment. Proteinuria manifested for 12 more allografts by 3 years after engraftment (of 60 functional allografts). Only one allograft was lost to follow-up through the first 5 years. Forty azathioprine-treated allografts with
3 years of observation were free of proteinuria at the end of this interval. Fifteen of the 91 allografts treated with mycophenolate mofetil since engraftment displayed proteinuria by 1 year later and 11 more did so within 3 years (of 62 functional allografts and excluding those without 3 years of follow-up). Thirty-six mycophenolate mofetil-treated allografts with
3 years of observation had not developed proteinuria.
Biopsy data
The biopsy data are shown in Table 1 as a summation of histopathological findings if multiple biopsies had been performed for an allograft. Thus, each allograft is counted only once. Renal biopsies had been obtained from 28 azathioprine-treated allografts and 23 mycophenolate mofetil-treated allografts. Recurrent IgAN developed in 13 (20%) azathioprine allografts and seven (7.7%) mycophenolate mofetil allografts. Concomitant findings of acute rejection, chronic rejection or both were observed in 0, 3 and 1 and 2, 2 and 0 allografts in the azathioprine and mycophenolate mofetil groups, respectively. For three allografts with IgA-positive immunofluorescence (two on azathioprine and one on mycophenolate mofetil), electron microscopy failed to show electron-dense deposits. Because the follow-up intervals for some of the mycophenolate mofetil-treated allografts had been relatively short and recurrent IgAN may require several years to manifest, we determined the recurrence rate at 3 years after engraftment. At that time point, IgAN developed in six of 60 (10.0%) azathioprine-treated allografts and five of 62 (8.1%) mycophenolate mofetil-treated allografts (P = 0.76). No patient has been shown to have repeat recurrence. Immunofluorescence and electron microscopy studies were not performed for nine (32%) of the 28 biopsies in the azathioprine group and five (22%) of the 23 biopsies in the mycophenolate mofetil group, most of which showed acute rejection (Table 1).
Clinical manifestations of recurrent IgAN
In 15 of the 20 patients with recurrent IgAN in both treatment groups, simultaneous pathological proteinuria and microscopic haematuria was the laboratory finding to herald recurrent disease (Table 2). Proteinuria alone was the first sign in the other five patients, whereas none initially exhibited only microscopic haematuria. The interval between engraftment and onset of any urinary abnormality was 4.6±3.4 years for the azathioprine-treated allografts and 2.6±2.1 years for the mycophenolate mofetil-treated allografts (P = 0.18). Six allografts (three on azathioprine and three on mycophenolate mofetil) manifested an abnormality by 1 year after transplantation whereas the longest interval was 10 years. The interval between clinical onset and biopsy was shorter in the mycophenolate mofetil-treated group (P = 0.046). Proteinuria at the biopsy diagnosis of recurrent disease was 2.8±2.8 g/day for six mycophenolate mofetil-treated allografts (data were missing for one allograft) and 3.1±2.2 g/day for 13 azathioprine-treated allografts. One patient developed macroscopic haematuria shortly before a biopsy showed crescentic IgAN. The only other patient with macroscopic haematuria declined a kidney biopsy and, after the bleeding resolved, has had no pathological proteinuria or microscopic haematuria over the subsequent 7.5 years.
Clinical course in recurrent IgAN
Overall allograft survival did not differ between the azathioprine-treated and mycophenolate mofetil-treated groups (Figure 1) and transplant era (before 1995 vs 1995 and later) showed no effect (data not shown). Unfortunately, recurrent IgAN portended a poor prognosis. Survival of the affected allografts was significantly worse than for kidneys without recurrent IgAN (P = 0.001) as well as for those in non-IgAN recipients (P = 0.037) (Figure 2). However, the type of antiproliferative agent did not alter survival of the allografts with recurrent IgAN (Figure 3). In each treatment group, survival of allografts with recurrent IgAN was worse than of those without recurrent disease (data not shown). Twelve affected allografts developed chronic kidney disease stage V and only three have maintained a serum creatinine concentration of <1.5 mg/dl (Table 3). In contrast, survival was better in the allografts without known recurrent IgAN and the rates in the azathioprine and mycophenolate mofetil groups were similar (Figure 4). The choice of antiproliferative agent did not significantly alter recurrence-free survival (Figure 5) or proteinuria-free survival (data not shown) of kidneys engrafted into patients with IgAN.

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Fig. 1. KaplanMeier plot of survival for the 61 azathioprine (AZA)-treated renal allografts and 91 mycophenolate mofetil (MMF)-treated renal allografts transplanted into patients with end-stage renal disease due to IgAN. The dates of engraftment span from 1 January 1984 to 31 August 2003. The arrow indicates the time at which the number of patients in the mycophenolate mofetil group decreased to 10% of the original cohort.
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Fig. 2. KaplanMeier plot of survival for 152 renal allografts transplanted into patients with end-stage renal disease due to IgAN and 5225 renal allografts transplanted into patients with end-stage renal disease due to non-IgAN causes. The IgAN allografts are subdivided into two groups: 20 with biopsy-proven recurrent IgAN and 132 without known recurrence. The dates of engraftment span from 1 January 1984 to 31 August 2003. The arrows indicate the time at which the number of patients in each group decreased to 10% of the original cohort.
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Fig. 3. KaplanMeier plot of survival for the 20 renal allografts transplanted into patients with end-stage renal disease due to IgAN that developed biopsy-proven recurrent IgAN, separated into two groups based upon the antiproliferative agent started at engraftment: 13 treated with azathioprine (AZA) and seven treated with mycophenolate mofetil (MMF). The arrows indicate the time at which the number of patients in both groups decreased to 10% of the original cohort.
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Fig. 4. KaplanMeier plot of survival for the 132 renal allografts transplanted into patients with end-stage renal disease due to IgAN that have not developed recurrent IgAN, separated into two groups based upon the antiproliferative agent started at engraftment: 48 treated with azathioprine (AZA) and 84 treated with mycophenolate mofetil (MMF). The arrow indicates the time at which the number of patients in the mycophenolate mofetil group decreased to 10% of the original cohort.
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Fig. 5. KaplanMeier plot of IgAN recurrence-free survival for the 152 renal allografts transplanted into patients with end-stage renal disease due to IgAN, separated into two groups based upon the antiproliferative agent started at engraftment: 61 treated with azathioprine (AZA) and 91 treated with mycophenolate mofetil (MMF). The arrow indicates the time at which the number of patients in the mycophenolate mofetil group decreased to 10% of the original cohort.
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Treatment of our patients with recurrent IgAN showed little benefit. Switching from azathioprine to mycophenolate mofetil at the time of the biopsy-proven diagnosis of recurrence rarely retarded the decline in clearance function; seven patients progressed to chronic kidney disease stage V, one to stage IV and one has maintained function at stage III (Table 3). Therefore, neither primary therapy with mycophenolate mofetil nor its substitution for azathioprine after clinical recurrence prevented progression to chronic kidney disease stage V. The use of an angiotensin-converting enzyme inhibitor or angiotensin-II type 1 receptor blocker, alone or in combination, after the diagnosis of recurrent IgAN did not significantly reduce proteinuria. Of 13 treated patients, only one showed a decrement in proteinuria of >33% on serial annual measurements over a 3 year interval.
Donor source in recurrent IgAN
The rate of recurrence of IgAN did not differ between recipients of living donor allografts compared with recipients of non-related-donor allografts (deceased and living-unrelated) overall (P = 0.23) or within treatment groups: azathioprine-treated group (P = 0.36) and mycophenolate mofetil-treated group (P = 0.70) (Table 4). Nor did the survival rate of affected allografts differ by donor source (data not shown). The larger number of living-unrelated donors in the mycophenolate mofetil-treated group reflects the increased use of this donor source over the last several years.
Repeat transplantation after allograft loss to IgAN
Six patients whose first allograft was lost to IgAN while on azathioprine have been retransplanted using immunosuppressive regimens with mycophenolate mofetil. Of these, three patients have stable renal function with serum creatinine concentrations <1.6 mg/dl with the latest proteinuria <130 mg/day, 8 months to 5 years after transplantation. One of these patients had lost a 2-haplotype-matched allograft from a sibling within 2 years, but has done well for 5 years with the second 2-haplotype-matched allograft. The fourth patient has a stable serum creatinine concentration of 2.1 mg/dl and proteinuria 264 mg/day 4 years post-transplant. Two patients have slowly progressive allograft dysfunction with serum creatinine concentrations of 2.0 and 2.2 mg/dl 4 years after engraftment, with daily urinary protein excretion 206 mg and 2.4 g, respectively. The latter patient is the only one of these six recipients to have undergone renal biopsy; the tissue obtained 3.2 years after engraftment exhibited no immune deposits and the findings were most consistent with chronic allograft nephropathy.
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Discussion
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Several investigators have postulated that mycophenolate mofetil, based on its mechanisms of action, might reduce the synthesis of the nephritogenic IgA1 in patients with IgAN or dampen the inflammatory process that ensues after mesangial deposition of IgA-containing circulating immune complexes. Others have speculated that mycophenolate mofetil may reduce the rate of recurrent IgAN or, at least, lessen its clinical impact [8,13]. Indeed, scattered case-reports describing a beneficial effect added to the enthusiasm about treatment with this drug [12,13]. However, the potential benefit of mycophenolate mofetil remains controversial, because Maes et al. [15] recently reported that treatment with mycophenolate mofetil 2 g/day for patients with native-kidney IgAN and clinical features of progressive disease was not beneficial.
Our data showed that immunosuppressive regimens with mycophenolate mofetil failed to prevent the development of recurrent IgAN or to ameliorate its clinical impact. At 3 years after engraftment, the rate of recurrence of IgAN did not differ between the allografts treated with azathioprine or mycophenolate mofetil since engraftment. Nor did mycophenolate mofetil therapy delay the clinical appearance of glomerular injury, as manifested by proteinuria or haematuria. Furthermore, the survival of affected allografts was not better if the immunosuppression had included mycophenolate mofetil rather than azathioprine. However, lower dosages of glucocorticoids prescribed in recent years with mycophenolate mofetil may have permitted more glomerular damage in allografts with IgA mesangial deposits. Nevertheless, recurrent IgAN significantly shortened allograft survival in both groups. Thus, for prevention of recurrent IgAN, immunosuppression regimens with mycophenolate mofetil starting at engraftment were not more efficacious than those with azathioprine.
The prevalence of biopsy-proven recurrent IgAN was substantially lower than the rates reported from other large transplant centres [3,7,8]. The true rate of recurrent IgAN was probably underestimated in our patients, because no surveillance or protocol biopsy was performed. Studies performing such biopsies have shown that some patients without urinary abnormalities have histological recurrence of IgA immune deposits [4]; however, the clinical significance is debatable. Several patients with proteinuria declined renal biopsy, but proteinuria in this setting was sometimes due to causes other than recurrent disease, such as chronic allograft nephropathy or calcineurin-inhibitor toxicity. Immunofluorescence was not performed for a limited subset of biopsy specimens, although in most instances the histological findings showed acute rejection without a mesangial glomerulonephritis to suggest recurrent IgAN. In the tissue specimens with immune complexes, only once was the pattern not consistent with IgAN. An increased use of angiotensin-converting enzyme inhibitors in recent years may have delayed pathological proteinuria for some patients with recurrent IgAN. Moreover, the shorter duration of observation in the mycophenolate mofetil-treated patients may also have reduced the opportunity for recurrent disease to manifest. Both factors would have potentially biased the findings in favour of a lower rate of recurrence or a reduced clinical impact for the mycophenolate mofetil-treated group. Alternatively, the interval between clinical onset and diagnosis was shorter in the mycophenolate mofetil group and may reflect a lower threshold for performing the requisite biopsy due to advances in ultrasound technology and biopsy devices over the last two decades that have lessened the risks for the procedure. It is also plausible that lower prednisone dosages in recent years may have allowed a greater inflammatory mesangial response to deposits of IgA immune complexes in allografts with recurrent disease, leading to proteinuria and, possibly, a renal biopsy. These factors may have increased the prevalence in the mycophenolate mofetil group.
The clinical onset of recurrent IgAN in our centre was most commonly heralded by a combination of proteinuria and microscopic haematuria. No patient initially exhibited only haematuria. This pattern contrasts to findings from other groups that described microscopic haematuria as the leading urinary manifestation of recurrent disease [3]. Similar to other reports [3], macroscopic haematuria was rare. We did not always have the specific histological findings from the native-kidney biopsy specimens. Therefore, we were unable to determine whether the severity of the primary disease correlated with the likelihood of recurrence, as reported by others [2].
Suppression of angiotensin II, by an angiotensin-converting enzyme inhibitor, an angiotensin-II type 1 receptor blocker or both, reduces proteinuria and may slow the decline in creatinine clearance in native-kidney IgAN [1619]. In a study in 10 patients with recurrent IgAN, therapy with an angiotensin-converting enzyme inhibitor reduced proteinuria [19]. However, we did not find a beneficial effect with this therapy. Perhaps, initiating treatment with these agents
3 months after transplantation, when renal function and erythropoiesis have stabilized, may be a more beneficial approach to pre-emptively dampen the impact of recurrent disease.
Some investigators have concluded that recurrence is more common in allografts obtained from living-related donors [20], whereas others did not confirm this finding [6]. Our data showed that recurrent disease was not more common for recipients of living-related allografts vs kidneys from unrelated donors (living and deceased). In an era with extreme shortages of deceased-donor kidneys for transplantation, living-related allografts remain an excellent option for renal replacement therapy.
For patients who have lost an allograft to biopsy-proven recurrent IgAN, repeat transplantation remains a viable option, although our experience has been relatively limited. Six patients have been retransplanted with a second allograft and follow-up exceeds 2 years for five of them. None has a serum creatinine >2.2 mg/dl, although one has urinary protein excretion of 2.4 g/day. While patients who have lost an allograft to recurrent disease may be at significantly increased risk for graft loss due to repeated recurrence [8], this history should not preclude repeat transplantation.
This study clearly shows that immunosuppressive regimens with mycophenolate mofetil did not prevent recurrent IgAN. In addition, IgAN in the allograft was an important contributor to progressive renal dysfunction. Treatment with agents to suppress angiotensin II showed little benefit for patients with clinically apparent recurrent disease. Such therapy may have greater efficacy if initiated shortly after engraftment.
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Acknowledgments
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We thank the University of Alabama at Birmingham Transplant Registry and Mr James C. Hardin for assistance in review of the medical records and Drs Jeannette Y. Lee and Angelo de Mattos for assistance with the statistical analysis. This work was supported by funding from the National Institutes of Health (grants DK 57750 and DK 61525).
Conflict of interest statement. None declared.
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Received for publication: 25. 7.04
Accepted in revised form: 11. 2.05