Systemic lupus erythematosus (SLE) is the prototype of systemic autoimmune disease characterized by widespread immunologic abnormalities and multiorgan involvement including the skin, joints, lungs, heart, central and peripheral nervous system, and kidney [
Considering renal involvement, 40% of the SLE patients have lupus nephritis at some stage of their disease [
Lupus nephritis is an important cause of morbidity and mortality in patients with SLE [
Recent surveys indicate that renal transplantation is associated with good outcomes in patients with ESRD due to lupus nephritis that are, in general, similar to transplant recipients with ESRD due to other causes [
The objective of this study was to analyze the outcome and prognostic factors of renal transplantation in patients with ESRD due to SLE from our center.
We examined the medical records of patients diagnosed as having SLE whose cause of ESRD (defined as the need of chronic dialysis therapy or kidney transplantation) was primarily lupus nephritis, who required renal transplantation from January 1986 to December 2013. All patients have been systematically assessed at the Department of Autoimmune Diseases and the Department of Nephrology and Renal Transplantation of Hospital Clinic. All patients fulfilled four or more of the 1982 revised classification criteria for SLE of the American College of Rheumatology [
From the patients’ records, we have documented the following data: gender, age at onset of SLE, onset of clinical renal disease, and time between SLE diagnosis and lupus nephritis and between lupus nephritis and onset of dialysis. Antinuclear antibodies and aPL status, including anti-cardiolipin antibodies (aCL) and lupus anticoagulant (LA), anti-hepatitis B (HBV) and C virus (HCV), and anti-human immunodeficiency virus (HIV) antibodies, were also collected. Finally, SLE treatment prior to ESRD, duration and modalities of dialysis prior to transplantation, date of transplantation, age at transplantation and time between lupus nephritis and transplantation, donor source, posttransplantation immunosuppressive therapy used (especially the use of prednisone, mycophenolic acid, cyclosporine A, and tacrolimus), follow-up time after transplantation, lupus relapse rate and graft, and patient survival were recorded. Regarding immunosuppressive treatment, it was the same for SLE and no SLE patients. Cyclosporine A, tacrolimus, and mycophenolic acid were used according to the transplant era. Induction therapy with anti-lymphocytesantibodies was used according to the anti-HLA immunological risk.
We determined flare-ups of lupus activity and recurrence of lupus nephritis by clinical and laboratory variables. Graft failure was defined as the need to restart chronic dialysis therapy or retransplantation.
Qualitative variables are shown by frequency distributions. Quantitative variables are summarized as a mean ± standard deviation (SD). Kolmogorov Smirnov test was used for evaluation of normality. A comparison of demographic and clinical characteristics between groups (i.e., graft failure and functioning graft) was performed using Mann-Whitney
In the above mentioned period, a total of 3274 renal transplantations were performed in our hospital, 50 (1.5%) of them in 40 SLE patients (32 female (80%)). Overall, 29 transplantations were from a deceased donor whereas 21 were from living donor. In 34 (68%) cases, a first transplantation was performed and in twelve (24%) and four (8%) cases, a second and a third transplantation were performed, respectively. The main demographic and clinical characteristics, histological class of lupus nephritis, immunologic features, and treatments are described in Table
Demographic and clinical characteristics, histological and immunologic features, and treatments used in the cohort of SLE transplanted patients.
Demographic characteristics | |
Gender female | 32 (80%) |
Ethnicity | |
Caucasians | 38 (95%) |
Hispanics | 2 (5%) |
Age at SLE diagnosis (years) | 22.7 ± 10.5 |
Age at renal transplantation (years) | 36 ± 10.4 |
Time between SLE diagnosis and lupus nephritis (months) | 28.4 ± 65.1 |
Time between lupus nephritis and onset of dialysis (months) | 68.8 ± 72.3 |
Time on dialysis (months) | 50 ± 49.4 |
Time between diagnosis of lupus nephritis and transplantation (months) | 118 ± 69 |
Time of followup (months) | 71.4 ± 41 |
Histological diagnosis at onset of lupus nephritis: | |
Type IV | 26 (72%) |
Type III | 3 (8%) |
Type II | 2 (5%) |
Type V | 2 (5%) |
Type VI | 1 (3%) |
Interstitial nephritis | 1 (3%) |
Thrombotic microangiopathy | 1 (3%) |
Unknown | 4 (10%) |
Number of transplantations | |
First transplantation | 34 (68%) |
Second transplantation | 12 (24%) |
Third transplantation | 4 (8%) |
Donor source | |
Cadaveric donor | 29 (58%) |
Living donor | 21 (42%) |
HLA identical siblings | 4 (19%) |
Other genetically related | 13 (62%) |
Unrelated donors | 4 (19%) |
Immunologic features at renal transplantation | |
Antinuclear antibodies | 50 (100%) |
Anti-dsDNA antibodies | 30 (60%) |
Anti-phospholipid antibodies | 12 (63%) |
Treatments | |
Cyclosporine/tacrolimus | 19/27 |
Azathioprine/mycophenolic acid | 6/38 |
Sirolimus | 3 |
ATG/OKT3/Basiliximab/no induction | 23/1/9/17 |
Graft failure (%) | 15 (30%) |
Quantitative variables are presented as mean ± standard deviation and qualitative variables as number (percentage). Treatments are presented as number of transplantations.
SLE: systemic lupus erythematosus; ATG: antithymocyte globulin; OKT3: orthoclone.
The death-censored graft survival rates were 93.9% at 1 year, 81.5% at 5 years, and 67.6% at the end of the study (Figure
Death-censored graft survival rates at 1, 5, and 10 years.
The patient survival rates were 97.9% at 1 and 5 years and 91.4% at the end of the study. Four patients died at 17.6, 11, 10, and 9.4 years of the first renal transplantation, respectively. The first case was a woman who received three renal transplantations, dying as a result of
When patients with graft failure versus functioning graft at time of the study were compared, we did not find significant differences in gender, age at SLE diagnosis, dialysis modality, and age at transplantation (Table
Comparison of demographic features, clinical characteristics and treatment between SLE patients with graft failure and functioning graft.
Graft failure ( |
Functioning graft ( |
| |
---|---|---|---|
Gender female (%) | 14 (93%) | 27 (77%) | 0.169 |
Age at diagnosis SLE (years) | 22.4 ± 10 | 22.8 ± 11 | 0.758 |
Age at renal Tx (years) | 41.3 ± 10.2 | 38.7 ± 12.0 | 0.280 |
Time SLE-nephritis (months) | 17 ± 42.6 | 34.9 ± 75 | 0.412 |
Time nephritis dialysis (months) | 39 ± 45.5 | 88.7 ± 80.6 | 0.038 |
Time on dialysis (months) | 73.9 ± 60.6 | 35.7 ± 35.4 | 0.011 |
Time nephritis-Tx (months) | 114.6 ± 64.2 | 120 ± 73.3 | 0.880 |
Dialysis before renal Tx (%): | |||
HD | 14 (93.3%) | 19 (76.0%) | 0.168 |
CAPD | 2 (13.3%) | 7 (28.0%) | 0.251 |
HD and CAPD | 1 (6.7%) |
3 (12.0%) | 0.516 |
Tx date (years) | 1998 ± 7 | 2004 ± 6 | 0.036 |
Donor source (%): | |||
Cadaveric | 13 (86.7%) | 16 (45.7%) | 0.007 |
Living donor | 2 (13.3%) | 19 (54.3%) | — |
Immunosuppressive regimen at Tx (grafts) (%): | |||
Cyclosporine A | 10 (66.6%) | 9 (25.7%) | 0.006 |
Mycophenolic acid | 8 (53%) | 31 (88.6%) | 0.003 |
Tacrolimus | 4 (27%) | 23 (66%) | 0.012 |
Positive anti-HCV antibodies (patients) (%) | 12 (80%) | 10 (28.6%) | 0.001 |
Positive aPL antibodies (%) | 1 (6.7%) | 11 (31.4%) | 0.058 |
Quantitative variables are presented as mean ± standard deviation and qualitative variables as number (percentage).
SLE: systemic lupus erythematosus; Tx: transplantation; HD: hemodialysis; CAPD: continuous ambulatory peritoneal dialysis; HCV: hepatitis C virus; aPL: anti-phospholipid antibodies.
As posttransplant immunosuppression therapy, all patients received prednisone and different immunosuppressive therapies (Table
No patient had antibodies against HIV. Positive anti-HCV antibodies were detected in 22 (44%) patients; one of them was simultaneously positive for hepatitis B virus (chronic infection). The number of patients with HCV positive serology was significantly higher in the group of patients who had graft failure, whereas in 12 of them, the transplant outcome was toward the graft failure. Studies of association between graft loss and the presence of HCV positive serology showed a positive association (
The retransplantation cases were analyzed separately from the main group. Overall 16 additional transplantations were performed (7 from a deceased donor and 9 from a living donor). In all cases, the initial lupus nephropathy was type IV. There were 6 graft failures whose causes were chronic allograft nephropathy (
Nineteen patients (48%) had at least two aPL determinations, 12 (63%) of them being positive (5 with IgG aCL plus LA, 4 with IgG aCL only, 2 with IgM aCL plus LA, and one with LA plus IgM plus IgGaCL), and only two of them had antiphospholipid syndrome. Within this group, one of the patients that previously received two renal transplantations suffered graft loss due to intraparenchymal graft thrombosis. In another case, a patient suffered the loss of two consecutive grafts due to thrombotic microangiopathy. In both patients, previous studies were negative for aPL, starting to be positive just before the third renal transplant.
In the present study, we have found a graft survival rate of 93.9% at 1 year, 81.5% at 5 years, and 67.6% at the end of the study and the patient survival rates were 97.9% at 1 and 5 years and 91.4% at the end of the study. These observations are similar to those reported in other recent studies from other single centers including patients from different ethnicities [
Currently, graft and patient survival of SLE patients undergoing renal transplantation are similar to those found in renal transplant recipients from other causes. These concepts are supported by the results of the European Transplant Registry and by a cohort of patients in the United States (United States Renal Data System) [
In our series, relapsing lupus nephritis was found only in one case (2%). The recurrence rate of lupus nephritis was reported initially to be around 1–4% [
Our results showed that factors that negatively influenced the survival of the renal transplant were the presence of deceased donor allograft (
A particular feature of this series is the high number of patients with HCV infection, mainly located in the group of transplant failure, showing a significant positive association with the lower graft survival (OR 12.5, 95% CI 2.50–63.34), in the same manner as that described in non-SLE patients [
The reason why HCV recipients are overrepresented in this cohort of patients is probably related to the high rate of repeated transplantations. Twenty-two transplants in HCV positive recipients were distributed between 13 patients: 5 patients with one, 7 patients with two, and one patient with three transplants. By contrast within the 28 transplants in HCV negative recipients, there were 26 patients with one transplant and one patient with two transplants. Many of those HCV positive patients initiated dialysis therapy before the HCV screening test was available.
In our series, the use of mycophenolic acid, tacrolimus, and negative aPL determinations seem to be related with better renal graft survival, supporting the possible multifactorial origin of the improved performance. Moreover, thanks to methodological advances in transplantation procedure, the use of mycophenolic acid and tacrolimus in recent years partly explain the significant differences found in our series, thus, supporting the benefit of their use.
As shown in our series, coronary artery disease was one of the causes associated with mortality in the outcome. Recent studies demonstrate a reduction in cardiovascular risk with the administration of fluvastatin in patients with lupus recipients of kidney transplantation [
Thrombotic events have been reported more frequently in renal transplantation recipients with aPL worsening their functional prognosis [
Current study had some limitations. Due to the retrospective design of our analysis, some points such as the role of activity of SLE in the graft failure or the role of sociodemographic and environmental factors such as educational level, socioeconomic status, or smoking could not be analyzed. Moreover, the limited number of SLE patients who received kidney transplantation is the reason why some significant associations should be considered with caution as indicated by the wide range of confidence intervals. In the data collected, the number of patients with aPL determinations performed before or at the time of kidney transplantation was low; therefore the association between these antibodies and the thrombotic complications was weak and not significant.
Renal transplantation is a good alternative for renal replacement therapy in patients with SLE, but the existence of HCV positive serology and a thrombotic disease associated with the aPL could be related to the development of graft failure. In our series, the patient and graft survival rates as well as factors associated with these end points are similar to that of ESRD caused by other diseases.
The authors declare that there is no conflict of interests regarding the publication of this paper.
Dr. Cairoli received the support of the Agencia Española de Cooperación Internacional y Desarrollo (AECID) (Spain) and the Programa para la Investigación Biomédica (PRO.IN.BIO), Facultad de Medicina, Universidad de la República, Uruguay.