Recurrence of ANCA-associated vasculitis following renal transplantation in the modern era of immunosupression

original article http://www.kidney-international.org & 2007 International Society of Nephrology Recurrence of ANCA-associated vasculitis following renal transplantation in the modern era of immunosupression M Gera 1, MD Griffin 1, U Specks 2, N Leung 1, MD Stegall 3 and FC Fervenza 1 1 Division of Nephrology and Hypertension, Mayo Clinic College of Medicine, Rochester, Minnesota, USA; 2 Division of Pulmonary and Critical Care Medicine, Mayo Clinic College of Medicine, Rochester, Minnesota, USA and 3 Division of Transplantation Surgery, Mayo Clinic College of Medicine, Rochester, Minnesota, USA Progressive glomerulonephritis and attendant end-stage renal disease (ESRD) result from antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. The optimum time of kidney transplantation in patients with ESRD due to ANCA-associated vasculitis (AAV) and the risk of renal or nonrenal recurrence of vasculitis after transplantation are unknown. To answer some of these questions, we followed 35 transplant recipients with diagnoses of microscopic polyangiitis (20 patients) and Wegener s granulomatosis (15 patients). The median time from diagnosis to transplantation was 25 months with all patients being in clinical remission. Fifteen patients were ANCA-positive at time of the transplant with 13 preemptive transplants. The most common immunosuppressive strategy included antibody induction, corticosteroid, mycophenolate mofetil, and tacrolimus with acute rejection occurring in eight cases. Overall and death-censored graft survivals were 94 and 100%, respectively, 5 years post-transplantation. Nonrenal relapse occurred in three patients with a satisfactory response to treatment. No clear risk factor to relapse emerged and no detrimental effect to renal function was found. We conclude that transplantation should be considered as the treatment of choice for ESRD due to AAV. Potent antirejection regimes are well tolerated in these patients, are associated with a low risk of recurrence and an absence of AAV-related graft dysfunction. Kidney International (2007) 71, 1296 1301; doi:10.1038/sj.ki.5002244; published online 4 April 2007 KEYWORDS: Wegener; microscopic polyangiitis; kidney transplantation; relapse; ANCA; vasculitis Correspondence: FC Fervenza, Division of Nephrology and Hypertension, Mayo Clinic and Foundation, 200 First St SW, Eisenberg Building S24, Rochester, Minnesota 55905, USA. E-mail: fervenza.fernando@mayo.edu Received 13 November 2006; revised 9 January 2007; accepted 6 February 2007; published online 4 April 2007 Pauci-immune glomerulonephritis is the most common cause of rapidly progressive glomerulonephritis. 1 The majority of cases are associated with circulating antineutrophil cytoplasmic antibodies (ANCAs) and with renal histology characterized by glomerular necrosis and crescent formation. 2 Standard treatment for ANCAassociated vasculitis (AAV) consists of the combined use of corticosteroid and cyclophosphamide. 3 This form of therapy is effective in controlling the disease in approximately 90% of patients but is also associated with significant adverse effects and may not prevent permanent targetorgan damage, particularly if started late in the disease course. Overall prognosis continues to be dependent on rapid diagnosis and prompt institution of therapy. The two major subtypes of AAV are Wegener s Granulomatosis (WG) and microscopic polyangiitis (MPA) both of which may cause end-stage renal disease (ESRD). Over 20% of patients with AAV will develop ESRD during their lifetime, and epidemiological studies suggest that this proportion is increasing. 4 7 Kidney transplantation (KTx) improves both the life expectancy and the quality of life in patients with ESRD. Consequently, it is the preferred treatment option for patients needing renal replacement therapy. 8,9 KTx has been successfully performed in patients with ESRD secondary to AAV. 7,10 13 However, relapses of AAV have been reported in as many as 50% of cases following KTx and may adversely affect allograft outcome. 4,5,14 21 A pooled analysis of 127 patients indicated that AAV recurred in 17.3% of patients after KTx. 22 The majority of these patients (65%) received cyclosporin A (CsA) and specific data about immunosuppression were not available in the rest. In contrast, a single center analysis of 33 patients with AAV who underwent KTx between 1968 and 2000 identified only a single extrarenal relapse during an average follow-up of 62757 months. 23 These discrepancies and the paucity of information regarding transplant outcomes for AAV in the modern era of immunosuppression led us to review the outcome of patients with AAV who had received KTx at our center during the past decade. 1296 Kidney International (2007) 71, 1296 1301

RESULTS Patient characteristics Characteristics of the 35 KTx recipients with native kidney failure due to AAV are summarized in Table 1. The primary form of AAV was WG in 15 patients and MPA in 20. The mean age at transplantation was 44720 years. Eighteen were males and 17 females. Living donor source was predominant (88%) and over one-third (37%) of the transplants were carried out preemptively before the need for dialysis. The median time interval between last documented clinical activity of AAV and KTx was 6 months (range 4 120 months). At the time of transplantation, ANCA testing by immunofluorescence was carried out in 34 of 35 patients and was positive in 15 of 34 (43%). For these 15, the pretransplant levels of myeloperoxidase (MPO) and PR3- ANCA were 47.5759.5 (n ¼ 12) and 52.0764 EU/ml (n ¼ 3), respectively. The majority (74%) of patients were receiving some form of maintenance immunosuppression for AAV immediately before KTx (see Table 1 for details). Post-transplant immunosuppression and clinical outcomes Post-KTx immunosuppression and major clinical outcomes are summarized in Table 2. At the time of transplantation all patients received intravenous methylprednisolone (500, 250, 125, and 90 mg on days 1 4 post-ktx, respectively). Twentytwo patients (63%) received intravenous induction therapy with rabbit antithymocyte globulin (1.5 mg/kg/day for a total of 4 6 doses), five (14%) received basiliximab (40 mg on days 0 and 4), one (3%) received anti-cd52 monoclonal antibody, and seven (20%) received no induction antibody. Oral immunosuppression consisted of prednisone 60 mg/day tapered to 5 10 mg/day by 3 months and various combinations of the following agents: mycophenolate mofetil (MMF) 750 1000 mg twice daily; azathioprine (AZA) 100 mg twice daily; tacrolimus (TAC) adjusted to a target trough blood level of 10 15 ng/ml for 3 months and 6 10 ng/ml thereafter; sirolimus adjusted to a target trough blood level of 15 20 mg/ ml for 3 months and 8 15 ng/ml thereafter; and microemulsion CsA adjusted to a target trough blood level of 200 250 ng/ml for 3 months and 150 200 ng/ml thereafter. The most common oral immunosuppressive regimens were TAC/MMF and cyclosporine (CsA)/MMF that were employed in 22 (63%) and seven (20%) cases, respectively. Clinical outcomes were followed until patient death, graft loss with return to dialysis or most recent documentation of graft status. The mean post-ktx follow-up was 4.472.5 years. Biopsy-proven acute rejection occurred in a total of six recipients (23%) and polyomavirus (BK)-associated nephropathy occurred in three (6%). Glomerular filtration rate was measured by iothalamate clearance in 30 patients at routine follow-up 1 year post-ktx. Mean glomerular filtration rate for these recipients was 57719 ml/min/1.73 m 2 indicating generally excellent graft function at this time point. Kaplan Meier plots for overall graft survival and deathcensored graft survival are shown in Figure 1. As shown, a total of four patient deaths occurred between 2 and 6 years Table 1 Baseline characteristics of KTx recipients with native kidney failure due to AAV Patient number 35 Form of AAV (WG : PA) 15:20 History of prior KTx, n (%) 6 (17%) ANCA-positive at time of KTx, n (%) 15/34 (43%) Age at transplant (Mean7s.d., years) 44720 Gender (M:F) 18:17 Donor Source, n (%) LRD 26 (74%) LURD 5 (14%) DD 4 (12%) Preemptive KTx, n (%) 13 (37%) Time on dialysis (median (range), months) 6 (0 60) Time between last AAV activity and KTx 25 (4 120) (Median (range), months) Immunosuppressive therapy at the time of KTx, n (%) None 9 (26%) Prednisone alone 16 (45%) Prednisone plus MMF 7 (20%) MMF alone 1 (3%) AZA alone 1 (3%) AZA plus prednisone 1 (3%) ANCA, antineutrophil cytoplasmic antibody; AAV, ANCA-associated vasculitis; AZA, azathioprine; DD, deceased donor; LRD, living related donor; LURD, living unrelated donor; MMF, mycophenolate mofetil; MPA, microscopic polyangiitis; WG, Wegener s granulomatosis. Table 2 Kidney transplant-related immunosuppression and post-transplant outcomes Induction immunosuppression, n (%) None 7 (20%) Anti-CD25 monoclonal antibody 5 (14%) Antithymocyte globulin 22 (63%) Anti-CD52 (alemtuzumab) 1 (3%) Primary oral immunosuppressant, n (%) TAC/MMF 22 (63%) CsA/MMF 7 (20%) CsA/SRL 2 (5%) SRL/MMF 2 (5%) TAC/SRL 1 (3%) TAC/AZA 1 (3%) Follow-up (mean7s.d., years) 4.472.5 Acute rejection, n (%) 6 (23%) Polyomavirus (BK)-associated nephropathy 3 (6%) GFR at 1 year post-ktx (mean7s.d., ml/min/1.74m 2 ) 57719 (n=30) Clinical relapse (nonrenal) of AAV, n (%) Total group 3/35 (8.6%) WG group 2/15 (13%) MPA group 1/20 (5%) ANCA-positive at time of KTx 2/15 (13%) ANCA-negative at time of KTx 1/19 (5%) CsA-based regimen 2/9 (22%) TAC-based Regimen 1/24 (4%) AZA, azathioprine; CsA, cyclosporine; GFR, glomerular filtration rate; MMF, mycophenolate mofetil; MPA, microscopic polyangiitis; SRL, sirolimus; TAC, tacrolimus; WG, Wegener s granulomatosis. Kidney International (2007) 71, 1296 1301 1297

Proportion surviving 1.0 0.8 0.6 0.4 0.2 0.0 Graft survival Death-censored graft survival 0 12 24 36 48 60 72 84 96 Months post-transplant Number 35 29 18 12 3 followed Figure 1 Kaplan Meier curves are shown for overall kidney transplant survival (Graft Survival) and death-censored kidney transplant survival among 35 recipients with ESRD due to AAV. w Patient death with functioning kidney transplant. following KTx and an additional two grafts were lost between 6 and 8 years post-ktx. Deaths were due to cancer (n ¼ 2), intracranial hemorrhage (n ¼ 1), and unexplained sudden death (n ¼ 1). Other graft losses were due to acute rejection due to noncompliance (n ¼ 1) and chronic allograft nephropathy (n ¼ 1). Overall graft survival at 5 years was 94% with death-censored graft survival of 100% at this time point. Post-KTx relapses of AAV Relapse of AAV was documented in three of 35 (8.6%) patients at 20, 24, and 68 months post-ktx. Two relapses occurred in patients with WG and one in a patient with MPA giving recurrence rates of 13 and 5% for the two forms of AAV (P ¼ NS). One relapse occurred following withdrawal of CsA for gingival hyperplasia and a second occurred in a patient receiving maintenance doses of CsA and AZA. Only one of 24 (4%) KTx recipients receiving a TAC-based regimen had AAV relapse. Of those tested for ANCA at the time of KTx, two of 15 ANCA-positive cases had subsequent AAV (13%) compared with one of 19 ANCA-negative cases (5%) (P ¼ NS). In all three cases, the relapse was nonrenal in nature with normal urinalysis, stable serum creatinine concentration, and/or normal renal allograft biopsy at the time of clinical relapse. Symptomatic presentation involved upper respiratory tract alone (n ¼ 1); upper respiratory tract and multiple joints (n ¼ 1); and upper respiratory tract, joints, and skin (n ¼ 1). All three relapses were associated with elevated ANCA (anti-mpo in one case and anti-pr3 in two cases) and with a tissue biopsy diagnostic of vasculitis. Treatment consisted of increased prednisone and conversion from AZA into MMF (n ¼ 1); increased prednisone and initiation of TAC (n ¼ 1); and combined therapy with methylprednisolone and rituximab (n ¼ 1). Two patients required retreatment for persistent or recurrent symptoms but all have achieved prolonged clinical and laboratory remission with stable renal allograft function at most recent follow-up (Table 2). Post-transplant ANCA assays A total of 18 patients had follow-up ANCA testing carried out 1 or more years post-ktx. Of these, 12 had been ANCAnegative immediately pre-ktx and nine of 12 (75%) remained ANCA-negative post-ktx. Of the three that converted to ANCA-positive post-ktx, one became positive (anti-pr3 9.1 EU/ml) at 1 year, but negative (anti-pr3 o5 EU/ml) at 2 years; one became positive (anti-mpo 15.2 EU/ml) at 1 year, but negative (anti-mpo o5 EU/ml) at 2 and 3 years; and one became ANCA-positive at 8 years. Only the latter case suffered a clinical relapse of AAV. Of the six patients who were ANCA-positive immediately pre-ktx and had post-ktx ANCA testing performed, only one became ANCA-negative at 1 year and remained relapse-free. Four remained ANCA-positive, but had reduced ANCA levels compared with pre-ktx. One of these subsequently relapsed in association with an increased ANCA level (anti-mpo 97.3 to 4320 EU/ml). In total, eight of 18 (44%) patients tested had at least one positive post-ktx ANCA test result, three of whom (38%) suffered a relapse. DISCUSSION We studied 35 patients with AAV who underwent a kidney transplant at Mayo Clinic during the 10-year time period between 1996 and 2005. This is the largest reported cohort of patients with AAV to undergo transplantation in recent years at one center, allowing the assessment of transplant outcomes and relapse rates of AAV in the era of modern immunosuppression. In our series, relapses of AAV were relatively rare (9%), occurred beyond the first post-transplant year and did not directly or indirectly affect allograft function. There are a number of published reports indicating that renal transplantation is an excellent option for the treatment of patients with AAV who reach ESRD. Data from the Collaborative Transplant Study show that patients with AAV who received a deceased donor KTx had a 10-year graft survival rate of 80%. 24 Similarly, in a case series of 22 AAV patients who underwent transplantation, Allen et al. 4 reported post-ktx patient survival of 100 and 85% at 1 and 5 years, respectively, whereas graft survival for the same time periods were 86 and 69%, respectively. Our data for more recently transplanted patients provide similar reassurance of excellent overall patient and graft outcomes for KTx recipients with a history of AAV. In contrast, reports of relapse rates and severity of AAV following KTx have varied widely. 4,14 20,22,23,25 Nachman et al., 22 combining their experience in 26 cases from the University of North Carolina, USA and the University of Lund, Sweden with 101 previously reported cases, derived a post-ktx relapse rate of 17.3%. Renal involvement occurred in 12 of 22 relapse cases (55%) and resulted in graft loss or declining function in four of 12. Extrarenal relapse alone occurred in 10 cases. Among the 85 patients treated with 1298 Kidney International (2007) 71, 1296 1301

CsA, a relapse was documented in 17 patients, corresponding to a relapse rate of 20%. No statistical difference was found between relapse rates in patients diagnosed with WG versus MPA, between patients treated with CsA versus those not receiving CsA, or between patients who were ANCA-positive at the time of transplantation versus those who were ANCAnegative. In a smaller study, Elmedhem et al. 25 evaluated the outcome of nine patients with AAV transplanted between 1987 and 2000 and managed with prednisolone, AZA and CsA. Two patients (22%) with WG had minor relapses affecting the upper respiratory tract that went into remission after prednisolone, cyclophosphamide, and co-trimoxazole treatment. Although no allograft biopsy was performed, serum creatinine levels remained unchanged during the episodes and no allograft was lost due to a relapse of AAV. More recently, Deegens et al., 23 studied the outcome of KTx in 33 patients with AAV transplanted between 1968 and 2000 under varying immunosuppressive regimens. ANCA testing was carried out in 18 patients around the time of transplantation, and positive ANCA by immunofluorescence was found in eight patients (8/18; 44%). Only one patient (3%) with WG developed an extrarenal relapse, with none of the patients developing a renal relapse. Overall, the results we report here are in keeping with low post-ktx relapse rate among patients transplanted during a period characterized by predominant use of induction therapy and potent three-drug oral immunosuppression. Furthermore, AAV relapses among this cohort were exclusively nonrenal and responsive to therapy. If we consider that in two of the three cases of a relapse, it occurred in patients who received no induction therapy and had been treated with AZA, in combination with either prednisone, or prednisone and CsA, then relapses in the group treated with antithymocyte globulin induction, combined with TAC/MMF, and prednisone were even rarer (4%). ANCA screening was not carried out routinely post-ktx in our patients. This and the small number of relapses preclude a formal analysis of ANCA as a predictor of disease or renal relapse. However, our data indicate that ANCA positivity is not uncommon following KTx for AAV, and it does not seem to be useful as a predictor of disease relapse. The production of specific antibodies in AAV suggests an antigen-driven pathogenic mechanism which may depend upon help from T cells. 26,27 Antithymocyte globulin has been used in patients with severe refractory WG, 28 and antithymocyte globulin is commonly used for induction of immunosuppression in transplant patients. It is possible that its use could have a beneficial long-term impact in the disease process of AAV. The potential protective role for MMF in this patient cohort merits specific discussion. The superiority of MMF over AZA in preventing acute rejection in KTx recipients has been well shown in multicenter randomized studies. 29,30 Several recent studies have addressed the use of MMF for the treatment of AAV with varying results. Stegeman et al. 31 have used MMF for induction of remission in patients with active WG who were intolerant of cyclophosphamide. Eleven achieved complete remission, two had partial remissions, and three subsequently relapsed. Nowack et al. 32 used MMF together with low dose prednisone as maintenance therapy for 15 months in 11 patients with AAV. Only one patient relapsed in the fourteenth month of maintenance therapy. Similarly, Langford et al. 33 examined the safety of single therapy with MMF for remission maintenance in 14 patients with WG who had been treated with oral cyclophosphamide and steroids to induce remission. Remission occurred in all patients after a median of 3 months, but six (43%) subsequently relapsed. More recently, Joy et al. 34 reported a study of MMF used in combination with prednisone in 12 patients with relapsing or cyclophosphamide-resistant ANCA vasculitis. Three experienced an early and sustained decrease in disease activity, three experienced an early improvement followed by one relapse and five had delayed or poor response to treatment. Although we postulate that the widespread incorporation of antibody induction, TAC and MMF into immunosuppressive regimens for KTx recipients during the past decade has served to further reduce the risk of AAV relapse from 15 20% to 5 10% and to virtually eliminate renal allograft involvement, no definitive conclusion can be derived from the current or previous studies regarding the role of specific immunosuppressive regimens in modulating disease recurrence. The question of the optimal timing for KTx in AAV patients remains open to debate. Although there is general consensus that AAV should be in clinical remission at the time of transplantation, 22 a minority of WG patients have persistent smoldering disease, especially in the upper respiratory tract. Although successful KTx has been described in such patients, none of the cases reported here were in this category and, in common with published opinion, 19 our ongoing practice is to postpone transplantation until complete clinical remission is achieved. The necessity for negative ANCA testing before proceeding with KTx is less well agreed upon, although most analyses conclude that the presence of ANCA at transplantation is not associated with an increased rate of relapse. 35 In the current study, although there was a trend toward higher relapse rate among patients who had a positive ANCA test before KTx (13 versus 5%), the difference was not statistically significant and relapses among both groups were infrequent and clinically manageable. This study represents one of the larger single-center experiences with KTx for AAV and is specifically relevant to current practice trends in transplantation. Clearly, some important limitations should be borne in mind including the study s retrospective nature and relatively small case number which preclude more robust statistical analysis of risk factors for relapse. Extrapolation of these results to centers in which differing patient demographics and disease severity exist must also be carried out with caution. Nonetheless, when taken together with the results of existing reports, our experience with this patient cohort strongly supports the conclusion that KTx is the treatment of choice for patients Kidney International (2007) 71, 1296 1301 1299

with impending ESRD due to AAV who are in an established clinical remission from systemic manifestations of the disease regardless of ANCA status. Our results also provide reassurance that potent post-ktx immunosuppressive regimens are well tolerated in those previously treated for AAV and are associated with low risk of recurrence and virtual absence of AAV-related graft dysfunction. MATERIALS AND METHODS Study population All KTx performed at Mayo Clinic between January 1996 and December 2005 were reviewed for cause of native kidney failure. Of 2452 KTx performed during this period 35 (1.4%) involved recipients in whom AAV was determined to be the primary cause for native kidney failure. For the purposes of this study, the diagnosis of AAV required clear documentation of each of the following: (a) a compatible clinical syndrome, (b) biopsy-proven vasculitis (e.g. necrotizing pauci-immune crescentic GN in the case of a kidney biopsy or presence of vasculitis and granuloma in the case of a lung or other tissue biopsy), and (c) positive blood assay for perinuclear (p) or cytoplasmic (c) ANCA. Patients were classified as WG or MPA according to the criteria of the American College of Rheumatology and the Chapel Hill consensus. 2,36 Documentation of anti-proteinase 3 (PR3) or anti-mpo antibodies was not a prerequisite for inclusion because antigen-specific ANCA testing was not a routinely performed at our institution until January 2000. However, if a biopsy was performed elsewhere but slides could not be reviewed at our institution, a positive test result for PR3- or MPO-ANCA was required in addition to documentation of clinical and biopsy findings of vasculitis in the medical record. Data acquisition and analysis Clinical, histological, and laboratory data were abstracted from the medical records of all cases meeting study entry criteria. Data regarding demographics, prior transplants, donor source, time on dialysis, and ANCA status before KTx, type of immunosuppression, occurrence of acute rejection, iothalamate glomerular filtration rate at 1 year post-ktx, graft loss, status at most recent follow-up and evidence of AAV relapse were recorded. Criteria for determination of AAV relapse were generated before data acquisition and consisted of one or more of the following: (a) an episode of increased serum creatinine concentration accompanied by nephritic urinary sediment (425% dysmorphic red cells and/or red cell casts) in the absence of other cause for renal allograft dysfunction, (b) an allograft biopsy reported as showing active necrotizing, pauci-immune, crescentic glomerulonephritis, (c) an episode of hemoptysis, pulmonary hemorrhage, or new or expanding nodules without evidence of infection, (d) occurrence of active vasculitis of respiratory or gastrointestinal tracts confirmed by endoscopic or open biopsy, (e) necrotizing vasculitis identified by any other tissue biopsy, (f) an episode of iritis or uveitis without other documented cause, or (g) a new diagnosis of mononeuritis multiplex. 6,37 The effects of AAV subtype, CsA-based versus TAC-based immunosuppression and ANCA status at the time of transplantation on frequency of AVV relapse were examined. 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