http://informahealthcare.com/rnf ISSN: 0886-022X (print), 1525-6049 (electronic) Ren Fail, 2014; 36(6): 912–915 ! 2014 Informa Healthcare USA, Inc. DOI: 10.3109/0886022X.2014.915196
CLINICAL STUDY
Outcomes in renal transplant recipients with lupus nephritis: experience at a single center Carolina Steller Wagner, Patricia Malafronte, Daniela Priscila Demetrio, Jose Ferraz de Souza, and Yvoty Alves Sens
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Santa Casa of Sao Paulo School of Medical Sciences, Sao Paulo, SP, Brazil
Abstract
Keywords
Background: The long-term prognosis of renal transplant recipients with systemic lupus erythematosus is still controversial. The outcome of these patients depends on the population studied, race/ethnicity, socioeconomic conditions, donor-related factors and recurrent lupus nephritis (LN), among other factors. Objective: This study was conducted to evaluate kidney transplantation outcomes for adult Brazilian patients with LN at a single center. Subjects and method: The archival records of all patients with LN who had received a kidney transplant at Santa Casa of Sao Paulo Hospı´tal were reviewed. Kaplan–Meier method was used to determine the survival rate. Results: We identified 18 patients with LN subjected to 22 kidney transplants during the 20-year interval. Two patients received three renal grafts. The majority of the patients were female, with 33.7 ± 10 years at the time of the transplantation, and half of them were African descendants or mixed. Sixteen transplants were performed from deceased donors and six from living-related donors. The patient survival rate was 90%, and graft survival was 68% at 10 years. Chronic allograft nephropathy was the major cause of graft loss. Two patients developed extra-renal manifestations of lupus. There was no clinical or histological evidence of recurrent LN. Conclusion: Renal transplantation is a method which can provide a long-term survival for patients with SLE and end-stage renal disease.
Lupus nephritis, outcome, renal transplantation, systemic lupus erythematosus, survival
Introduction Renal involvement of the systemic lupus erythematosus (SLE) is one of the main causes of morbidity and mortality. The risk for progression to end-stage kidney disease secondary to lupus nephritis (LN) in native kidneys has been estimated at up to 26%.1,2 The outcome of the renal disease, as well as of the renal transplantation for recipients with LN depends on the population studied, race/ethnicity, geographical origin, socioeconomic conditions, donor-related factors, among others.3–5 In addition, the reported recurrence rate of LN after transplantation varies in different series.6–8 The longterm prognosis of renal transplant recipients with SLE is still controversial and few studies report results at 10 years or more.4,6,9,10 The aim of this study was to analyze the longterm outcome of patients with LN who underwent renal transplantation from a single Brazilian center.
Patients and methods This was a retrospective study which included all adult patients with LN who had received a kidney transplant at Santa Casa of Sao Paulo Hospital, which attends to the lowincome population, between January 1991 and January 2012. Address correspondence to Yvoty Alves Sens, Santa Casa of Sao Paulo School of Medical Sciences, Rua Robelia 191, Sao Paulo, SP 04648, Brazil. E-mail: [email protected]
History Received 9 March 2014 Accepted 1 April 2014 Published online 5 May 2014
Medical records of hospitalizations and out-patient follow-up on renal transplant patients diagnosed with LN were reviewed. All patients met the American College of Rheumatology Classification criteria for SLE. The diagnosis of LN was based on renal biopsy findings. To perform the analysis, the following variables were examined: age, gender, race, time on dialysis prior to transplantation, type of dialysis (hemodialysis or peritoneal), duration of follow-up (defined as the date of transplantation to the date of death, allograft loss or last follow-up visit) and re-transplantation. Among the laboratory data, analysis was performed on the autoantibody determination (anti-dsDNA antibody testing), C3 and C4 complement fractions, anti-phospholipid antibodies (aPLs), viral serology, serum creatinine and urinalysis before and periodically after renal transplantation. In addition, the type of immunosuppressive drugs used, number of lupus reactivation episodes per patient, the type of renal or extrarenal manifestations and the number of infection events following the renal transplant were analyzed. The renal biopsies were evaluated by means of light microscopy and immunofluorescence. The histopathological diagnosis of the native kidney was made according to the WHO classification.11 The kidney graft biopsies were classified as normal, recurrence of LN, acute or chronic rejection, thrombotic alterations, acute tubular necrosis, chronic allograft nephropathy and/or calcineurin inhibitor toxicity.
Renal transplantation in patients with lupus nephritis
DOI: 10.3109/0886022X.2014.915196
The following donor variables were examined: age, donor type (living-related or deceased). Cold isquemia time and occurrence of delayed graft function (defined as the need for dialysis within the first weeks after transplantation) were also analyzed. Statistical analysis Continuous variables were presented as means and standard deviations. Categorical variables were presented as numbers and percentages. The cumulative survival curves were drawn using the Kaplan–Meier method.
A total of 22 renal transplantations in 18 patients with a diagnosis of LN were performed (two patients received three renal transplants). Eight of these transplantations were performed before 2000. The majority of the patients were female, having the age of 33.7 ± 10 years at the time of the transplantation and half of them were African descendants or mixed (Table 1). Seventeen of these patients (94.4%) had undergone renal biopsy during the course of their disease before transplantation, with diagnoses according to the WHO classification:11 class II in two patients, class III in three patients, class IV in 10 patients, class V in one patient and class VI in one patient, the diagnosis of LN being based on results of serum biochemical and urinalysis. Thirteen patients (72.2%) were submitted to hemodialysis prior to the renal transplantation and the remaining, peritoneal dialysis for 59 ± 45 months. Six (33%) were hepatitis C virus antibody-positive patients. At the time of the renal transplantation, all patients showed lupus quiescence for at least 6 months. Twenty-two renal transplantations were Table 1. Demographic and clinical characteristics and outcomes of 18 renal transplant recipients with lupus nephritis, who received 22 kidney allografts. Age at transplantation, (y) Sex: female/male, (n) Recipient race: Caucasian, n (%) Afro-descendants, n (%) Mixed, n (%) Length of dialysis (mo) Hemodialysis/peritoneal, (n) Anti-Hepatitis C virus (positive), n (%) Transplant donor: deceased/living (n) Donor age (y) Previous transplants: None, n (%) 4One, n (%) Delayed graft function, n (%) Cold ischemia time (h) (deceased–donor) Received mycophenolate/azathioprine (n) Follow-up time post-transplantation (mo) Episodes of acute rejection n (%) Infections, n patients (%) Cause of graft loss: Chronic allograft nephropathy, n (%) Vascular thrombosis of the graft, n (%) Acute vascular rejection, n (%) Allograft rupture, n (%) Death (2 with functioning graft), n (%)
performed: 16 (72.7%) with deceased donors and 6 (27.3%) with living-related donors (Table 1). Two patients received three renal grafts, one of whom lost the renal graft due to renal vein thrombosis immediately following the first deceased-donor transplant; 1 year later this patient received a second deceased-donor graft, also losing this after 10 d due to acute vascular rejection; a third deceased-donor transplantation was performed on the patient 2 years later and this kidney remained functional for 8 years, after which this patient returned to dialysis. The second patient received the first renal transplantation from a living-related donor, losing this graft after 4 years due to chronic allograft nephropathy; this patient received a second deceased-donor transplantation, also losing it to renal arterial thrombosis after 4 years, remaining on dialysis for 8 years and received a third deceased-donor transplantation and subsequently dying of sepsis. aPLs were positive in one of these patients, however two other aPLs antibodies-positive patients developed deep vein thrombosis in lower limbs long after transplantation. The immunosuppressive induction therapy used was anti-IL2 antibodies in 10/22 (45.5%) of the renal transplantation, and maintenance immunosuppressive therapy were calcineurin inhibitors (tacrolimus or cyclosporine) plus steroids associated with mycophenolate in 14 (63.6%) or azathioprine in 8 (36.4%). The post-transplantation follow-up on patients was 97 ± 70 months. At 5- and 10-years patient survival rate was 100% and 90%, respectively (Figure 1). Three patients died, two deaths occurred in patients with functioning graft (myocardial infarction and cerebrovascular accident), and one patient of sepsis. At 5 and 10 years the graft survival rate was 82% and 68%, respectively (Figure 1). Four episodes of acute rejection were diagnosed in four patients, three episodes being controlled with medication. Allograft loss occurred in 10 (loss of renal function requiring renal replacement therapy) during the follow-up, and causes were: acute renal artery thrombosis in one, renal vein thrombosis in one; acute 100
33.7 ± 10 (18–59) 16/2 9 (50.0) 2 (11.0) 7 (39.0) 59 ± 45 (1–144) 13/5 6 (33.3) 16/6 38.6 ± 16 (12–58) 16 (88.0) 2 (11.0) 12 (54.5) 18.4 ± 5 (9–26) 14/8 97 ± 70 4 (18.2) 11 (61.1) 6 (27.3) 2 (9.1) 1 (4.5) 1 (4.5) 3 (16.6)
Notes: Continuous variables are presented as means ± SD. Categorical variables are presented as numbers and percentages.
90 Patient
80 Cumulative Survival (%)
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Results
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50 40 30 20 10 1
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Time after Transplantation (years)
Figure 1. Kaplan–Meier estimates of patient and graft survival in kidney transplant recipients with lupus nephritis.
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vascular rejection in one, renal allograft rupture due to acute tubular necrosis in one, chronic allograft nephropathy in six. There was no clinical or histological evidence of recurrence of LN. Two patients (11%) developed extrarenal manifestations of SLE: one patient with two episodes (at 4 and 6 years after transplantation) and the other with one episode (at 10 years after transplantation) characterized by cutaneous purpura, arthralgia and serological markers activation, but without evidence of renal involvement. These patients were treated successfully with an increased dose of glucocorticoid. Fourteen episodes of infection requiring hospitalization occurred in 11 (61%) patients post-transplantation: viral infection (35.7% events), bacterial infection (35.7% events) and two cases of tuberculosis (pulmonary and intestinal), both of whom responded to treatment.
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Discussion Although still controversial, studies have shown that patient survival is similar in adult renal transplant recipients with or without SLE.3,4,6,9,10,12,13 However, in SLE transplant recipients there are differences in outcomes depending on race and ethnicity, socioeconomic conditions, among others factors.4 In this study, we report the single-center experience with renal transplantation in Brazilian patients with SLE, with a long-term follow-up in a public Hospital which attends to low-income patients. The long-term patient survival was similar to that in other studies, including the only two Brazilian studies which evaluated the outcome of renal transplantation in patients with SLE.13,14 The time of follow-up on patients was 97 ± 70 months. The graft survival at 10 years was 68%, compared with other studies which ranged from 38% to 86% (Table 2). However, the results of this observational study should be interpreted bearing in mind that our findings may not be adequate to establish comparisons with other studies. In the USA, studies4,5 have shown that African-Americans with lupus have a higher risk for allograft failure than CaucasianAmericans. In Brazil, where there are mixtures of races, especially African, European and Native Brazilian, the patients in this study showed this diversity. The time of pretransplantation dialysis was long, and mainly the hemodialysis modality. The longer time of the pretransplantation dialysis period has been associated with worse graft outcomes. Hemodialysis was linked with increased risk of graft
Table 2. Comparison of graft and patient survival in kidney transplant recipients in various series. Graft survival (%) Reference
N 6
35 Moroni et al 23 Ghafari et al9 Bunnapradist et al3 1170 789 23 Yu et al12 10 26 Lionaki et al 48 Azevedo et al13 14 Oliveira et al14 Present study 22
1
5
10 years
– – 89A 94B 95 88 93 93 91
85 – 68A 78B 73 67 81 91 82
76 69 – – 57 38 – 86 68
Patient survival (%) N
1
5
33 97 23 – – 1170 94A 85A 789 98B 92B 23 95 95 26 92 77 45 98 91 14 96 95 18 100 100
Notes: A – Deceased donor; B – Living donor.
10 years 97 83 – – 95 77 – 94 90
failure, while the peritoneal dialysis was associated with decreased risk of graft failure.15 The majority of the patients in our series received deceased-donor kidneys with a prolonged cold isquemia time of kidney allografts, which predisposes delayed graft function, and is also a predictor of rejection.16 In SLE recipients of kidney transplants from deceased donors, Contreras et al.17 showed that African Americans, compared to Caucasian Americans, had worse allograft survival, but when risk factors for poor outcomes (high PRA, kidney from expanded criteria donor, prolonged cold ischemia time, among others) are excluded from the analysis, they have similar rates of allograft failures, independent of the recipient ancestry. In the present study, the patients came from the lowincome population. Nee et al.5 analyzed the effect of the income and racial/ethnic disparities on renal transplant outcomes in recipients with SLE. They verified that income levels were associated with the risk of graft loss and death in African-Americans, but not in non-African-Americans.5 In the present series, two patients received a second and third kidney allograft. Of note, two of the six grafts were lost by renal vein and arterial thrombosis of the graft, one earlier and the other at 4 years post-transplantation, one of these patients was aPLs antibodies-positive. Stone et al.18 examines clinical events associated with the anti-phospholipid antibody syndrome in 96 consecutive patients with SLE who underwent renal transplantation. Twenty-five patients (29.4%) had at least one abnormal test for aPLs, four patients presented renal artery or vein thrombosis, and six patients, deep vein thrombosis. Compared to 60 SLE patients with a negative aPL test, only 5 (8.3%) patients had thrombotic events. Moroni et al.6 reported thrombotic complications in 26% of renal transplantation patients with SLE. Fuentes et al.19 reported vascular thrombosis as the cause of graft loss in 16.3% of the patients with SLE. Thrombosis may occur at any time before or after the transplantation. Thus, it is important to prevent thrombosis in SLE patients who have undergone renal transplantation. In this study, acute rejection occurred in four patients, one of them vascular rejection. Biopsies showing chronic allograft nephropathy could also be cases of chronic rejection. Rejection is the most important risk factor for allograft failure in recipients of kidney transplant. In SLE, recipients of a kidney allograft, 43% allograft failure is due to rejection.20 Advances over time in immunosuppressive therapies for renal transplantation, including the utilization of mycophenolate in immunosuppression, could possibly reflect on survival of lupus transplant recipients and the grafts. Of note, 8 of the 22 cases of transplantation occurred in the azathioprine era. Mycophenolate, which is presumed to be a more potent immunosuppressive agent than azathioprine, is associated with a lower incidence of chronic allograft nephropathy in kidney transplants.21 This might be further reflected in our lupus kidney recipients. There is no clinical or histological evidence of recurrent LN, although two patients developed extrarenal manifestations of SLE, but they did not have clinical signs of renal involvement. A low frequency of recurrent LN has been reported among recipients of kidney allografts, and this varies from center to center. The histological diagnosis of recurrence
Renal transplantation in patients with lupus nephritis
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DOI: 10.3109/0886022X.2014.915196
depends on the examination of the biopsy by immunofluorescence and electron microscopy, and few centers use this procedure. Goral et al.22 and Nyberg et al.,23 evaluating biopsies by light, immunofluorescence and electronic microscopy, reported recurrence in 30% and 44%, respectively, of the recipients with SLE who had undergone renal transplantation. In the present study, a significant number of patients (61%) presented severe infection episodes post-transplantation, the main etiology were viral (especially CMV) and bacterial infections, but only one death occurred due to sepsis. In addition, 33% of the patients presented anti-HCV positive before renal transplantation. Anti-HCV-positive kidney transplant recipients have a higher risk of developing infections and chronic rejection, among other complications. Several interventions to minimize the potentially adverse consequences of HCV infection should be considered: reduced immunosuppression and careful follow-up for early detection of infections in patients with HCV infection.24 The aim of this study was solely to report the single-center experience in renal transplantation in Brazilian patients with SLE, as there are only two other studies on this population. There are limitations in this study, namely it was retrospective, with a small number of patients, the renal transplantation was with deceased and living-donors and there was no control group. Therefore, the interpretation of the results of this study may not be adequate to establish comparisons with other studies. In conclusion, renal transplantation is a method which can provide long-term survival for patients with SLE and end-stage renal disease.
6. 7.
8. 9. 10.
11. 12. 13.
14. 15.
16. 17.
Declaration of interest The authors declare no conflicts of interests. The authors alone are responsible for the content and writing of this article.
18.
19.
References 1. Moroni G, Ventura D, Riva P, et al. Antiphospholipid antibodies are associated with an increased risk for chronic renal insufficiency in patients with lupus nephritis. Am J Kidney Dis. 2004;43:28–36. 2. Adler M, Chambers S, Edwards C, Neild G, Isenberg D. An assessment of renal failure in an SLE cohort with special reference to ethnicity, over a 25-year period. Rheumatology (Oxford). 2006;45:1144–1147. 3. 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;82:612–618. 4. Contreras G, Mattiazzi A, Schultz DR, et al. Kidney transplantation outcomes in African-,Hispanic- and Caucasian-Americans with lupus. Lupus. 2012;21:3–12. 5. Nee R, Jindal RM, Little D, et al. Racial differences and income disparities are associated with poor outcomes in kidney transplant
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recipients with lupus nephritis. Transplantation. 2013;95: 1471–1478. 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;45:903–911. Burgos PI, Perkins EL, Pons-Estel GJ, et al. Risk factors and impact of recurrent lu´pus nephitis in patients with systemic lu´pus erythematosus undergoing renal transplantation: data from a single US institution. Arthrtis Rheum. 2009;60:2757–2766. Pham PT, Pham PC. Graft loss due to recurrent lupus nephritis in living-related kidney donation. Clin J Am Soc Nephrol. 2011;6: 2296–2299. Ghafari A, Eternadi J, Ardalan MR. Renal transplantation in patients with lu´pus nephritis: a single-center experience. Transplant Proc. 2008;40:143–144. Lionaki S, Kapitsinou PP, Iniotaki A, Kostakis A, Moutsopoulos HM, Boletis JN. Kidney transplantation in lu´pus patients: a case-control study from a single center. Lupus. 2008;17: 670–675. Churg J, Bernstein J, Glassock RJ. Renal Disease: Classification and Atlas of Glomerular Diseases. 2nd ed. New York: Igaku-Shoin; 1995. Yu TM, Chen YH, Lan JL, Cheng CH, Wu MJ, Shu KH. Renal outcome aand evolution of disease activity in Chinese lupus patients after renal tarnsplantatio. Lupus. 2008;17:687–694. Azevedo LS, Roma˜o Jr JE, Malheiros D, Saldanha LB, Ianhez LE, Sabbaga E. Renal transplantation in systemic lu´pus erythematosus. A case control study of 45 patients. Nephrol Dial Transplant. 1998; 13:2894–2898. Oliveira CS, d’Oliveira I, Bacchiega AB, et al. Renal Transplantation in lu´pus nephritis: a Brazilian cohort. Lupus. 2012;21:570–574. Tang H, Chelamcharla M, Baird BC, Shihab FS, Koford JK, Goldfarb-Rumyantzev AS. Factors affecting kidney-transplant outcome in recipients with lupus nephritis. Clin Transplant. 2008; 22:263–272. Perico N, Cattaneo D, Sayegh MH, Remuzzi G. Delayed graft function in kidney transplantation. Lancet. 2004;364: 1814–1827. Contreras G, Li H, Gonzalez-Suarez M, et al. Kidney allograft survival of African American and Caucasian American recipients with lu´pus. Lupus. 2014;23:151–158. Stone JH, Amend WJ, Criswell LA. Antiphospholipid antibody syndrome in renal transplantation: occurrence of clinical events in 96 consecutive patients with systemic lupus erythematosus. Am J Kidney Dis. 1999;34:1040–1047. Fuentes L, Hernadez D, Ruiz P, et al. Survival of lupus nephritis patients after renal transplantation in Malaga. Transplant Proc. 2012;44:2067–2068. Contreras G, Mattiazzi A, Guerra G, et al. Recurrence of lupus nephritis after kidney transplantation. J Am Soc Nephrol. 2010;21: 1200–1207. Merville P, Berge F, Deminiere C, et al. Lower incidence of chronic allograft nephropathy at 1st year post transplantation in patients treated with Mycophenolate Mofetil. Am J Transplant. 2004;4: 1769–1775. Goral S, Ynares C, Shappell SB, et al. Recurrent lupus nephritis in renal transplant recipients revisited: it is not rare. Transplantation. 2003;75:651–656. Nyberg G, Blohme´ I, Persson H, Olausson M, Svalander C. Recurrence of SLE in transplanted kidneys: a follow-up transplant biopsy study. Nephrol Dial Transplant. 1992;7:1116–1123. Morales JM, Bloom R, Roth D. Kidney transplantation in the patient with hepatitis C virus infection. Contrib Nephrol. 2012;176: 77–86.
CLINICAL STUDY
Outcomes in renal transplant recipients with lupus nephritis: experience at a single center Carolina Steller Wagner, Patricia Malafronte, Daniela Priscila Demetrio, Jose Ferraz de Souza, and Yvoty Alves Sens
Ren Fail Downloaded from informahealthcare.com by University of Queensland on 10/14/14 For personal use only.
Santa Casa of Sao Paulo School of Medical Sciences, Sao Paulo, SP, Brazil
Abstract
Keywords
Background: The long-term prognosis of renal transplant recipients with systemic lupus erythematosus is still controversial. The outcome of these patients depends on the population studied, race/ethnicity, socioeconomic conditions, donor-related factors and recurrent lupus nephritis (LN), among other factors. Objective: This study was conducted to evaluate kidney transplantation outcomes for adult Brazilian patients with LN at a single center. Subjects and method: The archival records of all patients with LN who had received a kidney transplant at Santa Casa of Sao Paulo Hospı´tal were reviewed. Kaplan–Meier method was used to determine the survival rate. Results: We identified 18 patients with LN subjected to 22 kidney transplants during the 20-year interval. Two patients received three renal grafts. The majority of the patients were female, with 33.7 ± 10 years at the time of the transplantation, and half of them were African descendants or mixed. Sixteen transplants were performed from deceased donors and six from living-related donors. The patient survival rate was 90%, and graft survival was 68% at 10 years. Chronic allograft nephropathy was the major cause of graft loss. Two patients developed extra-renal manifestations of lupus. There was no clinical or histological evidence of recurrent LN. Conclusion: Renal transplantation is a method which can provide a long-term survival for patients with SLE and end-stage renal disease.
Lupus nephritis, outcome, renal transplantation, systemic lupus erythematosus, survival
Introduction Renal involvement of the systemic lupus erythematosus (SLE) is one of the main causes of morbidity and mortality. The risk for progression to end-stage kidney disease secondary to lupus nephritis (LN) in native kidneys has been estimated at up to 26%.1,2 The outcome of the renal disease, as well as of the renal transplantation for recipients with LN depends on the population studied, race/ethnicity, geographical origin, socioeconomic conditions, donor-related factors, among others.3–5 In addition, the reported recurrence rate of LN after transplantation varies in different series.6–8 The longterm prognosis of renal transplant recipients with SLE is still controversial and few studies report results at 10 years or more.4,6,9,10 The aim of this study was to analyze the longterm outcome of patients with LN who underwent renal transplantation from a single Brazilian center.
Patients and methods This was a retrospective study which included all adult patients with LN who had received a kidney transplant at Santa Casa of Sao Paulo Hospital, which attends to the lowincome population, between January 1991 and January 2012. Address correspondence to Yvoty Alves Sens, Santa Casa of Sao Paulo School of Medical Sciences, Rua Robelia 191, Sao Paulo, SP 04648, Brazil. E-mail: [email protected]
History Received 9 March 2014 Accepted 1 April 2014 Published online 5 May 2014
Medical records of hospitalizations and out-patient follow-up on renal transplant patients diagnosed with LN were reviewed. All patients met the American College of Rheumatology Classification criteria for SLE. The diagnosis of LN was based on renal biopsy findings. To perform the analysis, the following variables were examined: age, gender, race, time on dialysis prior to transplantation, type of dialysis (hemodialysis or peritoneal), duration of follow-up (defined as the date of transplantation to the date of death, allograft loss or last follow-up visit) and re-transplantation. Among the laboratory data, analysis was performed on the autoantibody determination (anti-dsDNA antibody testing), C3 and C4 complement fractions, anti-phospholipid antibodies (aPLs), viral serology, serum creatinine and urinalysis before and periodically after renal transplantation. In addition, the type of immunosuppressive drugs used, number of lupus reactivation episodes per patient, the type of renal or extrarenal manifestations and the number of infection events following the renal transplant were analyzed. The renal biopsies were evaluated by means of light microscopy and immunofluorescence. The histopathological diagnosis of the native kidney was made according to the WHO classification.11 The kidney graft biopsies were classified as normal, recurrence of LN, acute or chronic rejection, thrombotic alterations, acute tubular necrosis, chronic allograft nephropathy and/or calcineurin inhibitor toxicity.
Renal transplantation in patients with lupus nephritis
DOI: 10.3109/0886022X.2014.915196
The following donor variables were examined: age, donor type (living-related or deceased). Cold isquemia time and occurrence of delayed graft function (defined as the need for dialysis within the first weeks after transplantation) were also analyzed. Statistical analysis Continuous variables were presented as means and standard deviations. Categorical variables were presented as numbers and percentages. The cumulative survival curves were drawn using the Kaplan–Meier method.
A total of 22 renal transplantations in 18 patients with a diagnosis of LN were performed (two patients received three renal transplants). Eight of these transplantations were performed before 2000. The majority of the patients were female, having the age of 33.7 ± 10 years at the time of the transplantation and half of them were African descendants or mixed (Table 1). Seventeen of these patients (94.4%) had undergone renal biopsy during the course of their disease before transplantation, with diagnoses according to the WHO classification:11 class II in two patients, class III in three patients, class IV in 10 patients, class V in one patient and class VI in one patient, the diagnosis of LN being based on results of serum biochemical and urinalysis. Thirteen patients (72.2%) were submitted to hemodialysis prior to the renal transplantation and the remaining, peritoneal dialysis for 59 ± 45 months. Six (33%) were hepatitis C virus antibody-positive patients. At the time of the renal transplantation, all patients showed lupus quiescence for at least 6 months. Twenty-two renal transplantations were Table 1. Demographic and clinical characteristics and outcomes of 18 renal transplant recipients with lupus nephritis, who received 22 kidney allografts. Age at transplantation, (y) Sex: female/male, (n) Recipient race: Caucasian, n (%) Afro-descendants, n (%) Mixed, n (%) Length of dialysis (mo) Hemodialysis/peritoneal, (n) Anti-Hepatitis C virus (positive), n (%) Transplant donor: deceased/living (n) Donor age (y) Previous transplants: None, n (%) 4One, n (%) Delayed graft function, n (%) Cold ischemia time (h) (deceased–donor) Received mycophenolate/azathioprine (n) Follow-up time post-transplantation (mo) Episodes of acute rejection n (%) Infections, n patients (%) Cause of graft loss: Chronic allograft nephropathy, n (%) Vascular thrombosis of the graft, n (%) Acute vascular rejection, n (%) Allograft rupture, n (%) Death (2 with functioning graft), n (%)
performed: 16 (72.7%) with deceased donors and 6 (27.3%) with living-related donors (Table 1). Two patients received three renal grafts, one of whom lost the renal graft due to renal vein thrombosis immediately following the first deceased-donor transplant; 1 year later this patient received a second deceased-donor graft, also losing this after 10 d due to acute vascular rejection; a third deceased-donor transplantation was performed on the patient 2 years later and this kidney remained functional for 8 years, after which this patient returned to dialysis. The second patient received the first renal transplantation from a living-related donor, losing this graft after 4 years due to chronic allograft nephropathy; this patient received a second deceased-donor transplantation, also losing it to renal arterial thrombosis after 4 years, remaining on dialysis for 8 years and received a third deceased-donor transplantation and subsequently dying of sepsis. aPLs were positive in one of these patients, however two other aPLs antibodies-positive patients developed deep vein thrombosis in lower limbs long after transplantation. The immunosuppressive induction therapy used was anti-IL2 antibodies in 10/22 (45.5%) of the renal transplantation, and maintenance immunosuppressive therapy were calcineurin inhibitors (tacrolimus or cyclosporine) plus steroids associated with mycophenolate in 14 (63.6%) or azathioprine in 8 (36.4%). The post-transplantation follow-up on patients was 97 ± 70 months. At 5- and 10-years patient survival rate was 100% and 90%, respectively (Figure 1). Three patients died, two deaths occurred in patients with functioning graft (myocardial infarction and cerebrovascular accident), and one patient of sepsis. At 5 and 10 years the graft survival rate was 82% and 68%, respectively (Figure 1). Four episodes of acute rejection were diagnosed in four patients, three episodes being controlled with medication. Allograft loss occurred in 10 (loss of renal function requiring renal replacement therapy) during the follow-up, and causes were: acute renal artery thrombosis in one, renal vein thrombosis in one; acute 100
33.7 ± 10 (18–59) 16/2 9 (50.0) 2 (11.0) 7 (39.0) 59 ± 45 (1–144) 13/5 6 (33.3) 16/6 38.6 ± 16 (12–58) 16 (88.0) 2 (11.0) 12 (54.5) 18.4 ± 5 (9–26) 14/8 97 ± 70 4 (18.2) 11 (61.1) 6 (27.3) 2 (9.1) 1 (4.5) 1 (4.5) 3 (16.6)
Notes: Continuous variables are presented as means ± SD. Categorical variables are presented as numbers and percentages.
90 Patient
80 Cumulative Survival (%)
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Results
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50 40 30 20 10 1
2
3
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6
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9
10 11 12 13
Time after Transplantation (years)
Figure 1. Kaplan–Meier estimates of patient and graft survival in kidney transplant recipients with lupus nephritis.
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vascular rejection in one, renal allograft rupture due to acute tubular necrosis in one, chronic allograft nephropathy in six. There was no clinical or histological evidence of recurrence of LN. Two patients (11%) developed extrarenal manifestations of SLE: one patient with two episodes (at 4 and 6 years after transplantation) and the other with one episode (at 10 years after transplantation) characterized by cutaneous purpura, arthralgia and serological markers activation, but without evidence of renal involvement. These patients were treated successfully with an increased dose of glucocorticoid. Fourteen episodes of infection requiring hospitalization occurred in 11 (61%) patients post-transplantation: viral infection (35.7% events), bacterial infection (35.7% events) and two cases of tuberculosis (pulmonary and intestinal), both of whom responded to treatment.
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Discussion Although still controversial, studies have shown that patient survival is similar in adult renal transplant recipients with or without SLE.3,4,6,9,10,12,13 However, in SLE transplant recipients there are differences in outcomes depending on race and ethnicity, socioeconomic conditions, among others factors.4 In this study, we report the single-center experience with renal transplantation in Brazilian patients with SLE, with a long-term follow-up in a public Hospital which attends to low-income patients. The long-term patient survival was similar to that in other studies, including the only two Brazilian studies which evaluated the outcome of renal transplantation in patients with SLE.13,14 The time of follow-up on patients was 97 ± 70 months. The graft survival at 10 years was 68%, compared with other studies which ranged from 38% to 86% (Table 2). However, the results of this observational study should be interpreted bearing in mind that our findings may not be adequate to establish comparisons with other studies. In the USA, studies4,5 have shown that African-Americans with lupus have a higher risk for allograft failure than CaucasianAmericans. In Brazil, where there are mixtures of races, especially African, European and Native Brazilian, the patients in this study showed this diversity. The time of pretransplantation dialysis was long, and mainly the hemodialysis modality. The longer time of the pretransplantation dialysis period has been associated with worse graft outcomes. Hemodialysis was linked with increased risk of graft
Table 2. Comparison of graft and patient survival in kidney transplant recipients in various series. Graft survival (%) Reference
N 6
35 Moroni et al 23 Ghafari et al9 Bunnapradist et al3 1170 789 23 Yu et al12 10 26 Lionaki et al 48 Azevedo et al13 14 Oliveira et al14 Present study 22
1
5
10 years
– – 89A 94B 95 88 93 93 91
85 – 68A 78B 73 67 81 91 82
76 69 – – 57 38 – 86 68
Patient survival (%) N
1
5
33 97 23 – – 1170 94A 85A 789 98B 92B 23 95 95 26 92 77 45 98 91 14 96 95 18 100 100
Notes: A – Deceased donor; B – Living donor.
10 years 97 83 – – 95 77 – 94 90
failure, while the peritoneal dialysis was associated with decreased risk of graft failure.15 The majority of the patients in our series received deceased-donor kidneys with a prolonged cold isquemia time of kidney allografts, which predisposes delayed graft function, and is also a predictor of rejection.16 In SLE recipients of kidney transplants from deceased donors, Contreras et al.17 showed that African Americans, compared to Caucasian Americans, had worse allograft survival, but when risk factors for poor outcomes (high PRA, kidney from expanded criteria donor, prolonged cold ischemia time, among others) are excluded from the analysis, they have similar rates of allograft failures, independent of the recipient ancestry. In the present study, the patients came from the lowincome population. Nee et al.5 analyzed the effect of the income and racial/ethnic disparities on renal transplant outcomes in recipients with SLE. They verified that income levels were associated with the risk of graft loss and death in African-Americans, but not in non-African-Americans.5 In the present series, two patients received a second and third kidney allograft. Of note, two of the six grafts were lost by renal vein and arterial thrombosis of the graft, one earlier and the other at 4 years post-transplantation, one of these patients was aPLs antibodies-positive. Stone et al.18 examines clinical events associated with the anti-phospholipid antibody syndrome in 96 consecutive patients with SLE who underwent renal transplantation. Twenty-five patients (29.4%) had at least one abnormal test for aPLs, four patients presented renal artery or vein thrombosis, and six patients, deep vein thrombosis. Compared to 60 SLE patients with a negative aPL test, only 5 (8.3%) patients had thrombotic events. Moroni et al.6 reported thrombotic complications in 26% of renal transplantation patients with SLE. Fuentes et al.19 reported vascular thrombosis as the cause of graft loss in 16.3% of the patients with SLE. Thrombosis may occur at any time before or after the transplantation. Thus, it is important to prevent thrombosis in SLE patients who have undergone renal transplantation. In this study, acute rejection occurred in four patients, one of them vascular rejection. Biopsies showing chronic allograft nephropathy could also be cases of chronic rejection. Rejection is the most important risk factor for allograft failure in recipients of kidney transplant. In SLE, recipients of a kidney allograft, 43% allograft failure is due to rejection.20 Advances over time in immunosuppressive therapies for renal transplantation, including the utilization of mycophenolate in immunosuppression, could possibly reflect on survival of lupus transplant recipients and the grafts. Of note, 8 of the 22 cases of transplantation occurred in the azathioprine era. Mycophenolate, which is presumed to be a more potent immunosuppressive agent than azathioprine, is associated with a lower incidence of chronic allograft nephropathy in kidney transplants.21 This might be further reflected in our lupus kidney recipients. There is no clinical or histological evidence of recurrent LN, although two patients developed extrarenal manifestations of SLE, but they did not have clinical signs of renal involvement. A low frequency of recurrent LN has been reported among recipients of kidney allografts, and this varies from center to center. The histological diagnosis of recurrence
Renal transplantation in patients with lupus nephritis
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DOI: 10.3109/0886022X.2014.915196
depends on the examination of the biopsy by immunofluorescence and electron microscopy, and few centers use this procedure. Goral et al.22 and Nyberg et al.,23 evaluating biopsies by light, immunofluorescence and electronic microscopy, reported recurrence in 30% and 44%, respectively, of the recipients with SLE who had undergone renal transplantation. In the present study, a significant number of patients (61%) presented severe infection episodes post-transplantation, the main etiology were viral (especially CMV) and bacterial infections, but only one death occurred due to sepsis. In addition, 33% of the patients presented anti-HCV positive before renal transplantation. Anti-HCV-positive kidney transplant recipients have a higher risk of developing infections and chronic rejection, among other complications. Several interventions to minimize the potentially adverse consequences of HCV infection should be considered: reduced immunosuppression and careful follow-up for early detection of infections in patients with HCV infection.24 The aim of this study was solely to report the single-center experience in renal transplantation in Brazilian patients with SLE, as there are only two other studies on this population. There are limitations in this study, namely it was retrospective, with a small number of patients, the renal transplantation was with deceased and living-donors and there was no control group. Therefore, the interpretation of the results of this study may not be adequate to establish comparisons with other studies. In conclusion, renal transplantation is a method which can provide long-term survival for patients with SLE and end-stage renal disease.
6. 7.
8. 9. 10.
11. 12. 13.
14. 15.
16. 17.
Declaration of interest The authors declare no conflicts of interests. The authors alone are responsible for the content and writing of this article.
18.
19.
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