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Volume: 15 Issue: 5 October 2017

FULL TEXT

ARTICLE
Outcome of Kidney Transplant in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis

Objectives: Kidney transplant outcomes in patients with antineutrophil cytoplasmic antibody-associated vasculitis are comparable with outcomes in patients transplanted for other causes. Here, we report our single center experience of kidney transplant in patients with this condition and a pooled analysis of published studies.

Materials and Methods: This retrospective study included all patients with end-stage kidney disease secondary to antineutrophil cytoplasmic antibody-associated vasculitis who received a kidney transplant between 1987 and 2013 in the East of Scotland. We examined patient and graft survival and disease recurrence after transplant. We also performed a pooled analysis of published literature.

Results: We identified 24 patients who received a total of 31 kidney allografts. Median age at first transplant was 45.5 years (range, 18-68 y), and median follow-up after transplant was 60 months (range, 0.5-226 mo). All patients were positive for antineutrophil cyto­plasmic antibody (71% by proteinase 3 and 29% by myeloperoxidase) at diagnosis. Patient survival at 1 and 5 years was 92% and 88%, with corresponding death-censored allograft survival of 93% and 71%. Overall patient and allograft relapse rates were 0.022 and 0.016 relapse/patient-years. The pooled analysis comprised 20 studies (1169 patients). Patient/graft survival ranged from 64% to 80%/77% to 100% at 5 years and from 60% to 100%/59% to 84% at 10 years. Relapse rate was significantly higher in patients with positive antineutrophil cytoplasmic antibody at transplant (14% vs 5%; P = .042).

Conclusions: Our experience shows that kidney transplant remains a safe option for patients with end-stage kidney disease secondary to antineutrophil cytoplasmic antibody-associated vasculitis. Disease relapse posttransplant is uncommon and associated with pretransplant relapse. Pooled analyses suggest that relapse rate is higher in patients with positive antineutrophil cytoplasmic antibody at transplant. Multicenter registry data are needed to define renal outcome predictors in antineutrophil cytoplasmic antibody-associated vasculitis.


Key words : Autoimmune diseases, Glomerulonephritis, Immunosuppression, Recurrence, Remission induction

Introduction

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) comprises a group of rare multisystem autoimmune conditions characterized by ANCA-positive serology and small vessel inflammation. The disease subcategories include granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA), eosinophilic granulomatosis with polyangiitis, and renal limited ANCA vasculitis.1 Renal involvement occurs in more than 50% of GPA and 80% of MPA patients, often presenting as rapidly progressive glomerulonephritis.2-4 End-stage kidney disease (ESKD) is reported to occur in 20% to 40% of cases.5,6

Kidney transplant remains the best renal re­placement option for eligible patients with AAV and ESKD. The reported patient and graft outcomes after kidney transplant in AAV have been comparable to those with other primary renal diseases.5-7 The timing of transplant is considered to be safe after at least 12 months from remission due to the high risk of disease recurrence.7

In this case series, we present patient and allograft outcomes in patients with AAV who received a kidney transplant in the East of Scotland. We also include a pooled analysis of published studies on kidney transplant in AAV.

Materials and Methods

Data collection
We included all patients with AAV who received a kidney transplant at the Royal Infirmary of Edinburgh from June 1987 to July 2013. The Royal Infirmary of Edinburgh is the sole kidney transplant center for the East of Scotland. Patients were identified from an electronic database using the following search criteria for a primary kidney diagnosis before transplant: (1) myeloperoxidase or proteinase 3 ANCA-positive assay and (2) kidney biopsy confirming a pauci-immune glomerulonephritis.

A review of case notes and laboratory reports was conducted for each patient. Data collection included timeline from initial diagnosis until transplant, dialysis modality, extent of organ involvement before transplant, AAV induction and maintenance immunosuppressive therapy, any documented AAV relapse before transplant, ANCA status at diagnosis, time of transplant and during any relapse episodes, transplant type (deceased or living donation), transplant induction and maintenance immuno­suppressive therapy, allograft function at 3, 6, 12, 36, and 60 months, and histology reports for graft biopsies. Allograft function was determined by both serum creatinine level and estimated glomerular filtration rate calculated by the Modification of Diet in Renal Disease formula. We also collected documentation of incidence of AAV relapse after transplant. Disease relapse was defined as any 1 of documented clinical, radiologic, or histologic evidence of active organ involvement. Renal relapse was considered in the presence of allograft dysfunction associated with a biopsy showing necrotizing glomerulonephritis. A rising ANCA titer was not considered a criterion for disease relapse.

Pooled analyses
A literature search was performed using Ovid Medline, Embase, Scopus, and PubMed. Subject headings included kidney/renal transplant/­allograft, ANCA/small-vessel vasculitis, rapidly progressive/pauci-immune glomerulonephritis, Wegener/GPA, and MPA. Search was limited to articles published in the English language from 1980 onward and related only to adult populations. Studies looking at outcomes and relapse rates of patients receiving a kidney transplant in the context of AAV were selected on the basis of their title and/or abstract. Case reports and case series with less than 3 patients were excluded.

Patient characteristics, duration of follow-up, relapse episodes, and graft and patient outcomes were analyzed to generate a pooled analysis of all relevant studies.

Statistical analyses
Statistical analysis was carried out using Microsoft Excel and SPSS (SPSS: An IBM Company, version 17.0, IBM Corporation, Armonk, NY, USA). Data on categorical variables were summarized using absolute numbers and percentages. Normally distributed continuous variables were expressed as means ± standard deviation and those not normally distributed as median with maximum and minimum values. Fisher 2-tailed exact test was used for analysis of categorical variables. Survival analysis was per­formed using Kaplan-Meier method.

Results

A total of 24 patients (17 GPA and 7 MPA) were identified and included in this analysis with a total of 31 kidney transplants (2 patients received 2 trans­plants, 1 had 3 transplants, and 1 had 4 transplants). All patients were of white European ethnicity, and 62.5% of patients were females.

Antineutrophil cytoplasmic antibody-associated vasculitis before transplant
The median age at the time of diagnosis was 37.5 years (range, 13-57 y). All patients were ANCA positive with 17 (71%) being proteinase 3 positive and 7 (29%) being myeloperoxidase positive (Table 1). Extrarenal organ involvement included lung (10 patients, 41.7%), joints (9 patients, 37.5%), ear, nose, and throat (9 patients, 37.5%), and skin (6 patients, 25%).

Data on AAV induction therapy were available for 18/24 patients (75%). Cyclophosphamide was used as induction therapy in all but 1 patient (patient 13; see Table 4). Plasma exchange was used in addition to cyclophosphamide in 7/18 patients (39%). Antineutrophil cytoplasmic antibody-as­sociated vasculitis maintenance therapy included azathioprine in 16/18 patients (88%), mycophenolate mofetil in 3/18 patients (16%), and methotrexate in 3/18 patients (16%) (Table 1). Eleven patients reached ESKD within 6 months from diagnosis.

The median time between diagnosis and transplant was 72 months (range, 12-240 mo). Among 19 patients with available data on disease relapse, 9 patients experienced at least 1 episode of relapse before trans­plant, equating to 0.05 relapse/patient-years.

Antineutrophil cytoplasmic antibody-associated vasculitis after transplant
The median age at first transplant was 45.5 years (range, 18-68 y), with a median wait time of 32 months (range, 3-96 mo). The median follow-up after transplant was 60 months (range, 0.5-226 mo). One patient received a preemptive transplant. Living donation accounted for 26% of the transplants (Table 2).

In 26 of the transplanted kidneys (84%) with available data on ANCA status at the time of transplant, 8 (31%) were ANCA positive, 16 (62%) were ANCA negative, and 2 (8%) were equivocal. Induction therapy (basiliximab) was used in 62% of the patients, with maintenance therapy consisting of tacrolimus, mycophenolate mofetil, and prednisolone in most recipients (Table 2).

Patient survival was 92% at 1 year and 88% at 5 years. Five patients died (3 GPA and 2 MPA). The cause of death was available for 3 patients (malignancy, sepsis, and intracranial bleeding). Death-censored allograft survival was 93% at 1 year and 71% at 5 years. Four allograft failures belonged to 1 patient (patient 15; see Table 4). The median serum creatinine level of the functioning grafts was 145 μmol/L (range, 47-257 μmol/L) at 1 year and 135 μmol/L (range, 99-247 μmol/L) at 5 years (Table 2). All allograft biopsies were indication directed. Ten biopsy-proven acute rejections were documented in the first month after transplant. Nine episodes were attributed to T-cell-mediated rejection, and 1 patient developed hyperacute rejection, which required graft neph­rectomy at 2 weeks. Another 6 biopsy-proven acute rejections were documented subsequently in the next 5 years (Table 2). One patient developed renal AAV relapse after a switch from azathioprine (50 mg twice daily) to mycophenolate mofetil (1 g twice daily) after a rejection episode.

Antineutrophil cytoplasmic antibody-associated vasculitis relapse after transplant
Disease relapse occurred in 4 patients (patients 2, 7, 14, and 15; see Table 4), comprising 3 grafts. Overall patient relapse rate was 0.022 relapse/patient-years, and allograft disease recurrence rate was 0.016 recurrence/patient-years (Table 3). Relapse was associated with ANCA seroconversion in 1 patient (patient 7; see Table 4) and persistently positive ANCA in another (patient 15; see Table 4). Two patients had extrarenal relapse (lung and ear, nose, and throat for patient 2 and lung for patient 7), and another 2 patients had combined renal and extrarenal relapse (ear, nose, and throat and renal allograft for patient 14 and lung and renal allograft for patient 15). The latter patient received 4 allografts and developed recurrent AAV with her third and fourth renal allografts, complicated by pulmonary hemorrhage after the fourth transplant. Disease recurrence in allografts was associated with graft loss in only 1 patient (patient 15).

All 4 patients with disease relapse received cyclophosphamide induction therapy at the time of original AAV diagnosis, and all 4 patients had a history of disease relapse pretransplant, whereas, of 20 patients without posttransplant relapse, only 7 had relapse pretransplant (P = 0.03). Antineutrophil cytoplasmic antibody was positive at the time of transplant in 1 patient (patient 15). Treatment of relapse included increasing oral prednisolone dose (patient 14), pulsed intravenous methylprednisolone and intravenous cyclophosphamide (patient 2), pulsed intravenous methylprednisolone, plasma exchange, and intravenous cyclophosphamide (patient 15), and rituximab (patient 7).

Pooled analyses
We identified 20 studies that satisfied our inclusion criteria.4,7-24 Two studies (Briggs and associates8 and Schmitt and associates11; Table 5) did not have data on relapse. All studies were retrospective. A total of 1169 recipients of 1176 kidney transplants from 21 studies (including ours) were included in the final analysis. The median reported age in these studies was between 38 and 53 years. Posttransplant follow-up was between 38 and 125 months.

Six studies with a total of 736 kidney recipients reported 10-year survival data.7,9,18,19,21,24 In these studies, patient survival rates ranged from 64% to 80 % and graft survival rates ranged from 59% to 84%. Four studies4,17,22,23 and our current study with a total of 103 recipients reported 5-year patient survival of 77% to 100% and graft survival of 60% to 100%. Eight studies4,8,10-13,15,16,20 with a total of 318 cases reported 3-year patient survival of 77% to 97% and graft survival of 60% to 87%. We found 2 studies that directly compared graft and patient outcomes with GPA and MPA.7,9 The study by Little and associates7 did not show any difference between GPA and MPA. In contrast, Tang and associates9 reported inferior graft and patient outcomes with MPA compared with GPA at 10 years.

Time from transplant to relapse was available in 11 studies and ranged from 0.5 to 109 months. Data on ANCA status at the time of transplant was available for 277 patients (23.7%), with 99 being positive (35.7%). Relapse rate was significantly higher in kidney recipients with positive ANCA at the time of transplant compared with patients who were ANCA negative (14% versus 5%; P = .042). Disease category analyses showed no significant differences in relapse rate, with 27 relapses in 188 patients with GPA (14%) compared with 19 relapses in 224 patients with MPA (8%) (P = .11). Recurrent disease in renal allograft occurred in 55% of relapse cases, whereas extrarenal organ involvement accounted for 45% of these patients. Figure 1 illustrates relapse rates according to the studies included in the pooled analyses.

Discussion

In this analysis, we retrospectively reviewed 24 patients with ESKD secondary to AAV who received a total of 31 kidney transplants in East of Scotland over a period of 16 years. Induction therapy was cyclophosphamide based in all patients, with addition of plasma exchange in 40% of the patients. Relapse rate before transplant was 47% (0.05 relapse/patient-years). Patient survival at 1 year was 92% and 88% at 5 years after transplant. Death-censored allograft survival at 1 year was 93% and 71% at 5 years. After transplant, AAV relapse occurred in 17% of patients (0.022 relapse/patient-years) with renal allograft relapse rate of 0.016/patient-years.

The 5-year death-censored allograft survival in our series was lower than the reported survival of all renal transplants for the same period covered in this study (71% vs 75%) in Scotland.25 Previous studies reporting survival data 5 years after renal transplant showed graft survival outcomes similar to our series.4,17,23 The lack of a control group in our study makes it difficult to conclude an inferior graft survival in AAV. Interestingly 3 studies reporting 10-year graft survival revealed similar, or higher, graft survival to 5-year graft survival studies. These findings suggest a noninferior renal allograft outcome in AAV. In a 2015 study conducted by Hruskova and associates, patient and graft survival in AAV was compared with patients with diabetes and glomerulonephritis using a number of European renal registries.26 In this study, graft outcomes were similar to the control group at 10 years. The findings of this study further confirmed previous reports of equivalent patient and graft survival in AAV.7,8,17,19,20,23 Most of the published data on graft outcomes involved mainly GPA cases (Table 4); therefore, it is challenging to draw firm conclusions on survival differences between GPA and MPA. Two previous studies addressed this question. Little and associates did not show any difference between GPA and MPA with graft or patient survival.7 Conversely, Tang and associates recently reported an inferior patient and graft survival in MPA patients compared with GPA and a control group.9 It remains difficult to reach a conclusion from these studies largely because of the small numbers and confounding variables, such as disease severity, degree of sensitization, HLA mismatch, and differences in immunotherapy before and after transplant, among the studies.

Antineutrophil cytoplasmic antibody-associated vasculitis is characterized by episodes of relapse of disease activity. In our series, relapse rates after transplant were lower compared with before trans­plant. Graft loss due to recurrent disease occurred in 1 case (3.2%). Disease relapse after transplant was not significantly different in patients with GPA versus MPA or based on ANCA status at transplant. However, pretransplant relapse seems to be associated with a higher probability of post­transplant relapse. Nonetheless, it is difficult to rule out or draw firm conclusions considering the relatively small sample size. Close posttransplant monitoring (eg, protocol biopsies) could be of value in the setting of high probability of posttransplant relapse. Previous studies suggested a higher risk of relapse associated with ANCA positivity at time of transplant.18,20,21,23 However, a larger retrospective study conducted by Little and associates failed to show such an association.7 In our pooled analysis of studies that reported ANCA positivity at the time of transplant, there was a significantly higher relapse rate in those with positive versus negative ANCA. A major limitation was that only 23.7% (compared with 84% in our series) of the total population included in the pooled analysis had data on ANCA status at time of transplant. Overall, it is favorable to wait until ANCA is negative before transplant.

There are several limitations of our study. This study represents a single center experience and involves a relatively small number of patients over a long period of time, with therefore higher chances of sampling error. Second, we did not have a control group to compare patient and graft outcomes. Finally, due to its retrospective nature, there is a possibility of selection bias.

Conclusions

Both our single center experience and the pooled analysis of published literature show that kidney transplant remains a safe option in suitable AAV patients with ESKD. Studies reporting patient and graft outcomes in AAV are heterogeneous in terms of sample size and duration of follow-up. Disease relapse posttransplant is uncommon and may be associated with pretransplant relapse. The pooled analysis suggested that relapse rate was higher in patients with positive ANCA at transplant. Overall, the immediate and long-term outcomes appear to be comparable with other transplant populations. Finally, multicenter collaboration and large registry data are needed to define predictors of renal outcomes in rare diseases such as AAV.


References:

  1. Jennette JC, Falk RJ, Bacon PA, et al. 2012 revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. Arthritis Rheum. 2013;65(1):1-11.
    CrossRef - PubMed
  2. Mukhtyar C, Flossmann O, Hellmich B, et al. Outcomes from studies of antineutrophil cytoplasm antibody associated vasculitis: a systematic review by the European League Against Rheumatism systemic vasculitis task force. Ann Rheum Dis. 2008;67(7):1004-1010.
    CrossRef - PubMed
  3. Guillevin L, Durand-Gasselin B, Cevallos R, et al. Microscopic polyangiitis: clinical and laboratory findings in eighty-five patients. Arthritis Rheum. 1999;42(3):421-430.
    CrossRef - PubMed
  4. Nachman PH, Segelmark M, Westman K, et al. Recurrent ANCA-associated small vessel vasculitis after transplantation: A pooled analysis. Kidney Int. 1999;56(1):1544-1550.
    CrossRef - PubMed
  5. Booth AD, Almond MK, Burns A, et al. Outcome of ANCA-associated renal vasculitis: a 5-year retrospective study. Am J Kidney Dis. 2003;41(4):776-784.
    CrossRef - PubMed
  6. Slot MC, Tervaert JW, Franssen CF, Stegeman CA. Renal survival and prognostic factors in patients with PR3-ANCA associated vasculitis with renal involvement. Kidney Int. 2003;63(2):670-677.
    CrossRef - PubMed
  7. Little MA, Hassan B, Jacques S, et al. Renal transplantation in systemic vasculitis: when is it safe? Nephrol Dial Transpl. 2009;24(10):3219-3225.
    CrossRef - PubMed
  8. Briggs JD, Jones E. Renal transplantation for uncommon diseases. Scientific Advisory Board of the ERA-EDTA Registry. European Renal Association-European Dialysis and Transplant Association. Nephrol Dial Transpl. 1999;14(3):570-575.
    PubMed
  9. Tang W, Bose B, McDonald SP, et al. The outcomes of patients with ESRD and ANCA-associated Vasculitis in Australia and New Zealand. Clin J Am Soc Nephrol. 2013;8(5):773-780.
    CrossRef - PubMed
  10. Kuross S, Davin T, Kjellstrand CM. Wegener’s granulomatosis with severe renal failure: clinical course and results of dialysis and transplantation. Clin Nephrol. 1981;16(4):172-180.
    PubMed
  11. Schmitt WH, Haubitz M, Mistry N, Brunkhorst R, Erbsloh-Moller B, Gross WL. Renal transplantation in Wegener’s granulomatosis. Lancet. 1993;342(8875):860.
    CrossRef - PubMed
  12. Stegeman CA, Tervaert JW, van Son WJ, Tegzess AM. Necrotizing glomerulonephritis associated with antimyeloperoxidase antibodies in a renal transplant recipient with renal failure of unknown origin. Nephrol Dial Transpl. 1994;9(7):839-842.
    PubMed
  13. Grotz W, Wanner C, Rother E, Schollmeyer P. Clinical course of patients with antineutrophil cytoplasm antibody positive vasculitis after kidney transplantation. Nephron. 1995;69(3):234-236.
    CrossRef - PubMed
  14. Frasca GM, Neri L, Martello M, Sestigiani E, Borgnino LC, Bonomini V. Renal transplantation in patients with microscopic polyarteritis and antimyeloperoxidase antibodies: report of three cases. Nephron. 1996;72(1):82-85.
    CrossRef - PubMed
  15. Nyberg G, Akesson P, Norden G, Wieslander J. Systemic vasculitis in a kidney transplant population. Transplantation. 1997;63(9):1273-1277.
    CrossRef - PubMed
  16. Rostaing L, Modesto A, Oksman F, Cisterne JM, Le Mao G, Durand D. Outcome of patients with antineutrophil cytoplasmic autoantibody-associated vasculitis following cadaveric kidney transplantation. Am J Kidney Dis. 1997;29(1):96-102.
    CrossRef - PubMed
  17. Allen A, Pusey C, Gaskin G. Outcome of renal replacement therapy in antineutrophil cytoplasmic antibody-associated systemic vasculitis. J Am Soc Nephrol. 1998;9(7):1258-1263.
    PubMed
  18. Geetha D, Eirin A, True K, et al. Renal transplantation in antineutrophil cytoplasmic antibody-associated vasculitis: a multicenter experience. Transplantation. 2011;91(12):1370-1375.
    CrossRef - PubMed
  19. Moroni G, Torri A, Gallelli B, et al. The long-term prognosis of renal transplant in patients with systemic vasculitis. Am J Transplant. 2007;7(9):2133-2139.
    CrossRef - PubMed
  20. Haubitz M, Kliem V, Koch KM et al. Renal transplantation for patients with autoimmune diseases: single-center experience with 42 patients. Transplantation. 1997;63(9):1251-1257.
    CrossRef - PubMed
  21. Marco H, Mirapeix E, Arcos E, et al. Long-term outcome of antineutrophil cytoplasmic antibody-associated small vessel vasculitis after renal transplantation. Clin Transplant. 2013;27(3):338-347.
    CrossRef - PubMed
  22. Elmedhem A, Adu D, Savage CO. Relapse rate and outcome of ANCA-associated small vessel vasculitis after transplantation. Nephrol Dial Transpl. 2003;18(5):1001-1004.
    CrossRef - PubMed
  23. Deegens JK, Artz MA, Hoitsma AJ, Wetzels JF. Outcome of renal transplantation in patients with pauci-immune small vessel vasculitis or anti-GBM disease. Clin Nephrol. 2003;59(1):1-9.
    CrossRef - PubMed
  24. Schmitt WH, Opelz G, Van Der Woude FJ. Renal transplantation is safe and successful in Wegner’s granulomatosis: data from the Collaborative Transplant Study. J Am Soc Neph. 2002;13:564A-567A.
  25. Scottish Renal Registry Report 2014 (Web site). Available at http://www.srr.scot.nhs.uk/Publications/docs/scottish-renal-registry-report-2013-web.pdf?2. Accessed 28 June, 2016.
  26. Hruskova Z, Stel VS, Jayne D, et al. Characteristics and outcomes of granulomatosis with polyangiitis (Wegener) and microscopic polyangiitis requiring renal replacement therapy: Results From the European Renal Association-European Dialysis and Transplant Association Registry. Am J Kidney Dis. 2015;66(4):613-620.
    CrossRef - PubMed


Volume : 15
Issue : 5
Pages : 509 - 515
DOI : 10.6002/ect.2016.0058


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From the 1Renal Unit, Aberdeen Royal Infirmary, Aberdeen, Scotland; and the 2Renal Transplant Unit, Royal Infirmary of Edinburgh, Edinburgh, Scotland
Acknowledgements: The authors declare that they have no sources of funding for this study, and they have no conflicts of interest to disclose.
Corresponding author: Jesmar Buttigieg, Renal Unit, Nephrology Division, Mater Dei Hospital, Malta
Phone: +356 2545 6080
E-mail: jesmar.buttigieg@gov.mt