Objectives: Systemic lupus erythematosus and granulomatosis with polyangiitis are systemic inflam­matory conditions associated with renal failure that can recur after renal transplant. Patients with these con­ditions are treated with chronic immuno­suppression, potentially increasing risk of secondary malignancies. Here, we investigated long-term outcomes in renal transplant recipients with these conditions.

Materials and Methods: Transplant recipients with end-stage kidney disease due to systemic lupus erythematosus and granulomatosis with polyangiitis seen between 1982 and 2016 at a national kidney transplant center were included. Primary outcome variables were long-term allograft survival and incidence of secondary malignancy. Secondary outcome measures were incidence of delayed graft function, primary disease recurrence, and serum creatinine at follow-up.

Results: Ninety-eight transplant procedures (90 from deceased donors) in 92 consecutive patients (mean age 42.3 ± 14.4 y) were included: 55 with systemic lupus erythematosus and 37 with granulomatosis with polyangiitis. Follow-up duration was 110.53 ± 81.95 months (range, 1-393 mo). Overall renal allograft survival was 94.7% at 1 year, 85.4% at 5 years, and 75.4% at 10 years posttransplant. Patients with systemic lupus erythematosus showed overall allograft survival of 91.6% at 1 year, 84.3% at 5 years, and 74.4% at 10 years. There was 1 allograft failure due to recurrence of primary disease in this group. Patients with granulomatosis with polyangiitis showed overall allograft survival of 100% at 1 year, 92.4% at 5 years, and 92.4% at 10 years. There were 21 mortalities, with 5 (23.8%) due to secondary malignancy. In total, 46 malignancies were diagnosed in 31 patients.

Conclusions: We found excellent long-term renal allograft survival rates in patients with systemic lupus erythematosus and granulomatosis with polyangiitis, with secondary malignancy rates similar to those shown in recipients without autoimmune diseases. These findings provide clinicians with long-term data on transplant recipients with end-stage renal failure due to systemic inflammatory conditions.

Key words : Autoimmune disease, Kidney transplant, Secondary malignancy

Key words: Autoimmune disease, Kidney transplant, Secondary malignancy

Introduction

Progressive renal dysfunction leading to renal transplant is a feature of many systemic inflammatory diseases such as systemic lupus erythematosus (SLE) and granulomatosis with polyangiitis (GPA). In transplant recipients, there is a risk of primary disease recurrence in renal allografts due to the systemic nature of autoimmune conditions. In addition, the mainstay of long-term treatment involves immunosuppression, which can increase the risk of secondary malignancies after transplant.¹ The pathophysiology of SLE is characterized by the development of multiple autoantibodies, including antinuclear antibodies and anti-double-stranded DNA and anti-smooth muscle antibodies. These circulating antibodies form immune complexes when they encounter their target antigen, leading to complement activation and an inflammatory cascade. The clinical manifestations of SLE are defined by the American College of Rheumatology or the more recently developed Systemic Lupus International Collaborating Clinics Criteria and include constitutional symptoms, cutaneous mani­festations, vasculitis, arthritis/arthralgia, and renal disease among others.^2,3

In comparison, GPA is one of several conditions comprising antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides, in conjunction with microscopic polyangiitis and eosinophilic granu­lomatosis with polyangiitis. Definitions of these autoimmune conditions were described in the Chapel Hill Consensus Conference in 19944 and revised in 2012.⁵ Granulomatosis with polyangiitis is defined as follows: “Necrotizing granulomatous inflammation usually involving the upper and lower respiratory tract, and necrotizing vasculitis affecting pre­dominantly small to medium vessels (eg, capillaries, venules, arterioles, arteries, and veins). Necrotizing glomerulonephritis is common.”⁵ Renal disease is reported to develop in the form of necrotizing crescentic glomerulonephritis in ? 75% of patients.⁶

Although allograft outcomes after short- and intermediate-term follow-up have been described for patients undergoing renal transplant with end-stage renal failure (ESRF) due to SLE and GPA, there are no studies that have investigated long-term renal allograft survival with these conditions. In the present study, we present our long-term outcomes of patients undergoing renal transplant for ESRF due to SLE and GPA.

Materials and Methods

Overview of study design
A retrospective institutional review board-approved study was performed on all kidney transplant recipients seen at a national kidney transplant center (Beaumont Hospital, Dublin, Ireland) who had renal failure due to SLE or GPA. Data on all kidney transplant recipients in Ireland are prospectively collected in the national renal transplant database. The primary outcome variable was long-term allograft survival. Secondary outcome variables were overall patient survival, incidence of delayed graft function, serum creatinine level at most recent follow-up, and incidence of secondary malignancy. Data on secondary malignancies were obtained from the Irish National Cancer Registry (www.ncri.ie).

Perioperative immunosuppression
In cases of increased immunologic risk (eg, HLA-incompatible donors), patients received quadruple immunosuppressive induction therapy with a calcineurin inhibitor (cyclosporine prior to 2001 and tacrolimus from 2001 onward), an antimetabolite (azathioprine prior to 2002 and mycophenolate mofetil from 2002 onward), prednisolone, and antithymocyte globulin or basiliximab. The remainder of patients received standard cyclosporine- or tacrolimus-based triple therapy. Tacrolimus levels were maintained between 10 and 15 ng/mL for the first 6 weeks and then maintained at 8 to 12 ng/mL thereafter (microparticle enzyme immunoassay; Abbot IMX, Fujisawa Healthcare Incorporated, Co., Kerry, Ireland). Methylprednisolone at 500 mg intravenously was given 12 hours after transplant. This dose was then tapered to 250 mg twice daily for 2 days and then to 250 mg daily for 2 days. Following this, patients were commenced on a tapering dose of prednisolone, beginning with 20 mg orally once daily and then tapering to a maintenance dose of 5 mg once daily.

As part of our department’s protocol, transplant patients also receive anti-pneumocystis pneumonia prophylaxis antibiotic in the form of trimethoprim-sulfamethoxazole during the first 6 months posttransplant and one dose of a broad-spectrum cephalosporin-based antibiotic for perioperative prophylaxis. Valganciclovir was administered for cytomegalovirus prophylaxis if either the donor or recipient was cytomegalovirus positive.

Follow-up
Patients were followed up twice weekly for the first 6 weeks and then once weekly for up to 3 months. After 3 months, patients were followed every 2 weeks for up to 1 year and monthly thereafter. Serum creatinine level was measured after 1 month and every 3 months thereafter. During the follow-up period, the number of allograft failures and the causes of allograft failure were recorded in recipients with a history of SLE or GPA.

Statistical analyses
Data were analyzed using Stata/IC 12.1 (StataCorp, College Station, TX, USA). Survival results were calculated using Kaplan-Meier analysis for overall survival, graft-specific survival, and death-censored graft-specific survival. Results in the SLE and GPA groups were compared with each other and with a national renal transplant cohort, using log-rank testing for the above parameters. All continuous data are reported as means ± standard deviation, and P values < .05 were considered statistically significant. Continuous variables were compared using t tests or Mann-Whitney U tests, and categorical variables were compared using chi-square tests.

Results

Patient demographics
As shown in Table 1, between 1982 and 2017, 98 transplants were performed in 92 patients (55 with SLE and 37 with GPA). Mean recipient age was 42.5 ± 14.5 years, and 55 were female. Ninety transplants were from deceased donors, and 8 were from living related donors (Table 1). The mean donor age was 35.5 ± 16.6 years. Delayed graft function occurred in 8 cases for8.4 ± 8.1 days (range, 2-27 d). Three patients were lost to follow-up. The duration of follow-up was 110.53 ± 81.95 months (range, 1-393 mo), and mean serum creatinine at most recent follow-up measured 144.5 ± 67.8 ?mol/L. There were no differences in mean serum creatinine at 1-year, 5-year, or 10-year follow-up between both groups (Table 2).

Renal allograft survival
Overall renal allograft survival was 94.7% at 1 year, 85.4% at 5 years, and 75.4% at 10 years posttransplant (Figure 1A). Death-censored allograft survival was 96.9% at 1 year, 92.3% at 5 years, and 88.9% at 10 years (Figure 2A). In total, there were 33 renal allograft failures (34%), of which 1 was due to recurrence of primary disease (SLE). The remaining causes of allograft failure were death with functioning graft (n = 16), chronic allograft nephropathy (n = 4), discontinuation of immunosuppression (n = 2: 1 due to malignancy and 1 due to recurrent sepsis), primary allograft failure (n = 1), BK-virus associated nephropathy (n = 1), chronic allograft nephropathy (n = 4), and unspecified rejection (n = 4) (Table 3). Time to allograft failure was 107 ± 90 months (range, 1-393 mo) (Figure 1). There were no significant differences in incidence of allograft failure among SLE recipients and GPA recipients (P = .19).

Allograft survival in recipients with systemic lupus erythematosus
In the SLE group, overall allograft specific survival was at 91.6% 1 year, 84.3% at 5 years, and 74.4% at 10 years (Figure 1B), whereas death-censored allograft survival was 95% at 1 year, 91.1% at 5 years, and 88.4% at 10 years (Figure 2B).

Allograft survival in recipients with granu­lomatosis with polyangiitis
In the GPA group, overall allograft specific survival was 100% at 1 year, 92.4% at 5 years, and 92.4% at 10 years (Figure 1B), with death-censored graft survival of 100% at 1 year, 94.3% at 5 years, and 89.8% at 10 years (Figure 2B).

Renal allograft survival in transplant recipients without systemic lupus erythematosus or granulomatosis with polyangiitis
Overall renal allograft survival in transplant recipients with ESKD due to causes other than SLE and GPA was 90.5%, 76.7%, and 58.5% after 1, 5, and 10 years posttransplant, respectively (Figure 1B). Death-censored graft survival was 92.7%, 84.3%, and 72.9% after 1, 5, and 10 years, respectively (Figure 2B). There were no differences in graft-specific survival (P = .057) or death-censored graft survival (P = .103) in transplant recipients with ESKD due to other causes and transplant recipients with SLE or GPA.

Overall patient survival
Overall patient survival was 96.7% at 1 year, 91.75% at 5 years, and 84.7% at 10 years (Figure 3A). Overall 1-, 5-, and 10-year survival rates were 94.4%, 90.6%, and 80.3%, respectively, for the SLE group and 100%, 92.4%, and 92.4% for the GPA group (Figure 3B). Survival rates in transplant recipients without SLE or GPA were 96.4%, 87.7%, and 75.3% at 1, 5, and 10 years, respectively. With regard to overall survival, there were no significant differences between transplant recipients with ESKD due to other causes and transplant recipients with SLE or GPA (P = .29) (Figure 3B). Mean duration from transplant to death was 107.5 ± 71.0 months (range, 4-225 mo).

Secondary malignancy
There were 21 mortalities of which 5 (23.8%) were due to a secondary malignancy. In total, 46 malig­nancies were diagnosed in 31 patients: 18 with SLE and 13 with GPA. The overall incidence of secondary malignancy was 5165 per 100?000 patient-years. There were no significant differences in the incidence of secondary cancers between the GPA and SLE groups (7152 per 100?000 patient-years vs 4321 per 100?000 patient-years; incidence rate ratio = 1.65; P = .099). Secondary malignancies included skin cancers (n = 32: 18 with basal cell carcinoma, 13 with squamous cell carcinoma, 1 with malignant melanoma), cervical (n = 2), ovarian (n=1), vulva (n = 1), colorectal (n=1), anus (n = 1), rectal (n = 1), small intestine (n = 1), prostate (n = 1), testicular (n = 1), kidney (n = 1), bladder (n = 1), brain (n = 1), and breast (n = 1) malignancies. Mean duration from transplant to first cancer diagnosis was 107.6 ± 76.1 months (range, 10-334 mo). Malignancy developed earlier in GPA patients than in SLE patients (73.8 ± 48.6 vs 131.9 ± 84 mo; P = .03). There were no associations between development of a secondary malignancy and mean age (P = .77), sex (P = .82), or type of dialysis (P = .91).

Discussion

Renal transplant is a definitive treatment for patients with systemic inflammatory conditions and ESRF, which affects approximately 30% to 50% patients with GPA and 20% to 30% of patients with SLE.⁷ Organ transplant leads to improved overall survival in patients with ESRF due to both SLE8 and GPA.⁹ Importantly, patients should be in remission from their primary disease or have low levels of disease activity prior to renal transplant due to the systemic manifestations that can be associated with autoimmune diseases.^10,11 In ANCA-associated vasculitides (including GPA), superior transplant outcomes have been reported for patients that are in clinical remission for ? 1 year at the time of transplant.¹² However, the presence of detectable levels of cytoplasmic ANCA does not confer an increased risk of renal allograft failure and should not preclude transplantation.^13,14 The main finding of the present study is that renal allograft and overall patient survival for transplant recipients with SLE and GPA compares favorably with renal transplant recipients with nonautoimmune-related diseases after 15-year follow-up.

Traditionally, it has been recommended that patients with ESRF due to SLE should be in clinical remission for 6 to 12 months before renal transplant to minimize the risk of iatrogenic perioperative morbidity.¹⁵ However, more recent studies have demonstrated that inferior patient outcomes and increased risk of graft failure are found in patients with longer wait times to transplant compared with patients who are transplanted as soon as a suitable organ is available.^16,17 Our finding of equivalent renal transplant outcomes in patients with SLE compared with transplant recipients without autoimmune conditions is consistent with other published studies.^18,19 Norby and colleagues described renal allograft survival rates of 88%, 81%, and 71% and overall survival rates of 94%, 83%, and 71% after 1, 5, and 10 years, respectively.²⁰ More recently, Horta-Baas and associates reported 1-year, 2-year, and 5-year graft survival rates of 92%, 66%, and 66%, respectively.²¹ An analysis of the United Network for Organ Sharing database demonstrated that the incidence of recurrent lupus nephritis after transplant was 2.4%.²² These findings are consistent with our study in which the incidence was low at 1.67% (n = 1/60).

Improvements in immunosuppressive protocols have significantly reduced the incidence of acute rejection and improved long-term renal allograft survival in patients with ESRD due to GPA. One systematic review demonstrated 5- and 10-year renal allograft survival rates of 88% and 67%, respectively, for patients with ANCA-associated vasculitis (ie, GPA and microscopic polyangiitis). In addition, overall survival was 92% and 68% after 5 and 10 years.¹¹ The vasculitis relapse rate was 10.3%, with approximately two-thirds of relapses affecting the kidney.11 Recurrence of disease typically manifests as pauci-immune necrotizing glomerulonephritis. Our findings are consistent with these results as we noted an overall renal allograft-specific survival and death-censored graft survival rate of 92.4% and 89.8% after 10 years.

Transplant recipients are at an increased risk of developing malignancies, and the incidence is 1374 cases per 100?000 person-years.²³ This equates to a standardized incidence ratio of 2.10 (95% confidence interval, 2.06-2.14) compared with a nontransplant population. Despite a history of chronic immuno­suppression in transplant recipients with systemic inflammatory conditions, similar overall rates of secondary malignancies have been found. The incidence of secondary malignancy in SLE recipients is 1734 per 100?000 person-years²⁴ and approximately 10% after 5 years for recipients with ANCA-associated vasculitis. In our cohort, skin cancers accounted for > 50% of secondary malignancies that were diagnosed; this likely represents the cumulative risk of long-term immunosuppression. Bouwes Bavinck and associates found that the incidence of skin cancer was 7% at 1 year after renal transplant25 and that the risk increased to 82% after 20 years. The authors suggested that the incidence of skin cancer after transplant is independent of the type or combination of immunosuppressive agents used but rather is a characteristic of immunosuppression in general.²⁵ In comparison, one Dutch study reported an incidence rate of 10% at 10 years and 40% at 20 years posttransplant for skin cancers.²⁶ The incidence of secondary malignancy in our cohort is higher than previously reported, and this is likely due to the longer duration of follow-up compared with other published series.

Our study has limitations, and our results should be viewed with caution. It is a single-center, retro­spective analysis of a prospectively maintained database. However, comprehensive follow-up of all patients with GPA or SLE who underwent renal transplant over a prolonged period was undertaken, and only 3 patients were lost to follow-up. Another potential limitation is that the immunosuppression protocols have changed over time. However, it is likely that expectant alterations to immunosup­pressive protocols over time in patients with long-term autoimmune comorbidities will bias any study investigating factors associated with long-term solid-organ transplant survival and secondary malignancy rate.

Conclusions

The present analysis is the only study to date that has specifically investigated renal allograft survival of ? 10 years in transplant recipients with SLE and GPA. We found that renal transplant is a feasible, safe, and effective treatment strategy for patients with ESRF due to these systemic inflammatory conditions. We also noted excellent long-term renal allograft and overall patient survival rates that were either consistent with or exceeding rates shown in a national transplant recipient cohort (Irish Renal Transplant Cohort). Findings from this study may be useful for providing clinicians with long-term data on transplant in patients with ESRF due to systemic inflammatory conditions.

References:

1. Gutierrez-Dalmau A, Campistol JM. Immunosuppressive therapy and malignancy in organ transplant recipients: a systematic review. Drugs. 2007;67(8):1167-1198.
   CrossRef - PubMed
   
2. Hochberg MC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum. 1997;40(9):1725.
   CrossRef - PubMed
   
3. Petri M, Orbai AM, Alarcon GS, et al. Derivation and validation of the Systemic Lupus International Collaborating Clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum. 2012;64(8):2677-2686.
   CrossRef - PubMed
   
4. Jennette JC, Falk RJ, Andrassy K, et al. Nomenclature of systemic vasculitides. Proposal of an international consensus conference. Arthritis Rheum. 1994;37(2):187-192.
   CrossRef - PubMed
   
5. 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
   
6. Hoffman GS, Kerr GS, Leavitt RY, et al. Wegener granulomatosis: an analysis of 158 patients. Ann Intern Med. 1992;116(6):488-498.
   CrossRef - PubMed
   
7. 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
   
8. Jorge A, Wallace ZS, Lu N, Zhang Y, Choi HK. Renal transplantation and survival among patients with lupus nephritis: a cohort study. Ann Intern Med. 2019 Jan 22 [Epub ahead of print]. doi: 10.7326/M18-1570.
   CrossRef - PubMed
   
9. Wallace ZS, Wallwork R, Zhang Y, et al. Improved survival with renal transplantation for end-stage renal disease due to granulomatosis with polyangiitis: data from the United States Renal Data System. Ann Rheum Dis. 2018;77(9):1333-1338.
   CrossRef - PubMed
   
10. Bumgardner GL, Mauer SM, Payne W, et al. Single-center 1-15-year results of renal transplantation in patients with systemic lupus erythematosus. Transplantation. 1988;46(5):703-709.
    CrossRef - PubMed
    
11. Moran S, Little MA. Renal transplantation in antineutrophil cytoplasmic antibody-associated vasculitis. Curr Opin Rheumatol. 2014;26(1):37-41.
    CrossRef - PubMed
    
12. Little MA, Hassan B, Jacques S, et al. Renal transplantation in systemic vasculitis: when is it safe? Nephrol Dial Transplant. 2009;24(10):3219-3225.
    CrossRef - PubMed
    
13. 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
    
14. Ciszek M, Kisiel B, Czerwinski J, et al. Kidney transplant recipients with rheumatic diseases: epidemiological data from the Polish transplant registries 1998-2015. Transplant Proc. 2018;50(6):1654-1657.
    CrossRef - PubMed
    
15. Moroni G, Tantardini F, Ponticelli C. Renal replacement therapy in lupus nephritis. J Nephrol. 2003;16(6):787-791.
    PubMed
    
16. Plantinga LC, Patzer RE, Drenkard C, et al. Association of time to kidney transplantation with graft failure among U.S. patients with end-stage renal disease due to lupus nephritis. Arthritis Care Res (Hoboken). 2015;67(4):571-581.
    CrossRef - PubMed
    
17. Chung MC, Yu TM, Shu KH, et al. Influence of pretransplantation dialysis time and lupus activity on outcome of kidney transplantation in systemic lupus erythematosus. Transplant Proc. 2014;46(2):336-338.
    CrossRef - PubMed
    
18. Moroni G, Tantardini F, Gallelli B, et al. The long-term prognosis of renal transplantation in patients with lupus nephritis. Am J Kidney Dis. 2005;45(5):903-911.
    CrossRef - PubMed
    
19. Bunnapradist S, Chung P, Peng A, et al. Outcomes of renal transplantation for recipients with lupus nephritis: analysis of the Organ Procurement and Transplantation Network database. Transplantation. 2006;82(5):612-618.
    CrossRef - PubMed
    
20. Norby GE, Leivestad T, Mjoen G, et al. Premature cardiovascular disease in patients with systemic lupus erythematosus influences survival after renal transplantation. Arthritis Rheum. 2011;63(3):733-737.
    CrossRef - PubMed
    
21. Horta-Baas G, Camargo-Coronel A, Miranda-Hernandez DG, Gonzalez-Parra LG, Romero-Figueroa MDS, Perez-Cristobal M. Renal transplantation in systemic lupus erythematosus: Comparison of graft survival with other causes of end-stage renal disease. Reumatol Clin. 2019;15(3):140-145.
    CrossRef - PubMed
    
22. Contreras G, Mattiazzi A, Guerra G, et al. Recurrence of lupus nephritis after kidney transplantation. J Am Soc Nephrol. 2010;21(7):1200-1207.
    CrossRef - PubMed
    
23. Engels EA, Pfeiffer RM, Fraumeni JF, Jr., et al. Spectrum of cancer risk among US solid organ transplant recipients. JAMA. 2011;306(17):1891-1901.
    CrossRef - PubMed
    
24. Ramsey-Goldman R, Brar A, Richardson C, et al. Standardised incidence ratios (SIRs) for cancer after renal transplant in systemic lupus erythematosus (SLE) and non-SLE recipients. Lupus Sci Med. 2016;3(1):e000156.
    CrossRef - PubMed
    
25. Bouwes Bavinck JN, Hardie DR, Green A, et al. The risk of skin cancer in renal transplant recipients in Queensland, Australia. A follow-up study. Transplantation. 1996;61(5):715-721.
    CrossRef - PubMed
    
26. Hartevelt MM, Bavinck JN, Kootte AM, Vermeer BJ, Vandenbroucke JP. Incidence of skin cancer after renal transplantation in The Netherlands. Transplantation. 1990;49(3):506-509.
    CrossRef - PubMed