Patients with systemic lupus erythematosus (SLE) constitute approximately 1.2% of end-stage renal disease (ESRD) patients who require renal replacement therapy (1). Kidney transplantation is a successful treatment modality in this patient population, which offers an improved quality of life, better health, and longer survival compared with treatment with maintenance dialysis. In cyclosporine A (CsA)-treated SLE patients, the 1-year graft and patient survival rates have been reported as 71.5% to 83% and 93% to 98%, respectively, whereas 5-year graft and patient survival rates have been reported as 69% and 89% to 96%, respectively, similar to results for other glomerular diseases (2,3) and much better compared with the pre-CsA era (4). A recent study based on data from the United States Renal Data System demonstrated that graft and patient survival after first cadaveric and first living-related adult renal transplants are similar in patients with ESRD caused by SLE and patients with ESRD from other causes (5). Although recurrent lupus nephritis (RLN) was previously reported to be rare, 1% to 4% (6,7), recent studies suggested a higher incidence (8–10). Because of several factors, including underreporting of recurrence, insufficient follow-up to detect all recurrences, the difficulty in distinguishing RLN from other causes of graft dysfunction without a renal biopsy, and the use of only light microscopy (LM) when biopsy is performed, the exact incidence of RLN is difficult to establish. We have studied the clinical course of 54 patients with lupus nephritis who received a renal transplant in our center. In this study, we have specifically addressed the incidence of RLN; the impact of aggressive biopsies and complete tissue examination with LM, immunofluorescence (IF), and electron microscopy (EM) on the diagnosis of RLN; the influence of recurrence on graft survival; and possible risk factors associated with recurrence.
PATIENTS AND METHODS
In 2,199 transplants, a total of 54 patients with ESRD resulting from lupus nephritis received renal transplants at Vanderbilt University Medical Center between 1976 and 2000. Computerized databases, hospital and clinic charts, and biopsy reports and slides were retrospectively reviewed. Demographic information including age, gender, race, donor source, immunosuppressive regimen, time on dialysis before transplantation, and laboratory data including serologies for SLE and hepatitis C were recorded. Two patients had inadequate biopsy samples. Four patients were lost to follow-up (<3 months of follow-up at our center). Fifty patients who had at least 3 months of follow-up after transplantation were included in the final data set. Forty patients received antibody induction with either antithymocyte serum (n=39) or interleukin-2 receptor antibody (n=1). Maintenance immunosuppression consisted of azathioprine (AZA) and prednisone until the addition of CsA in 1985 (n=11); 24 patients were on CsA, AZA, and prednisone; three were on CsA and prednisone; and nine were on CsA, mycophenolate mofetil (MMF), and prednisone. One patient was on a randomized study using either MMF or rapamycin. Data on immunosuppression were missing on two patients. CsA was administered in a dose of 8 to 10 mg/kg/d once serum creatinine fell below 3.0 mg/dL, which was subsequently adjusted to maintain a 12-hr trough level of 300±25 ng/mL for the first 3 months and 200 to 250 ng/mL thereafter, determined by the fluorescence polarization immunoassay method. Prednisone 10 mg/d was the maintenance dose in the majority of patients. The indications for posttransplant renal biopsy included worsening kidney function assessed by serum creatinine, proteinuria, or hematuria, generally to rule out acute rejection. Biopsy evaluation routinely included LM, IF, and EM. All biopsy reports and slides including LM, IF, and EM were reviewed by two of our renal pathologists. Cases of RLN were classified according to the 1974 World Health Organization (WHO) classification scheme (11).
Statistical analyses were performed using the SPSS software package (SPSS, Inc., Chicago, IL). Summary data are expressed as mean±SD unless otherwise specified. Graft and patient actuarial survival were determined by means of the Kaplan-Meier method, and between-group comparisons of the survival data were tested by the log-rank statistic.
RESULTS
Fifty patients with at least 3 months of follow-up were included in the final data set. Thirty-one (62%) of 50 patients underwent biopsy. Two patients who had inadequate biopsy samples were included in the “no-biopsy” group. Table 1 summarizes the demographic data for patients with and without RLN and patients who never underwent kidney biopsy. The mean follow-up was 6.8±4.9 years (range, 3 months–20 years). RLN was present in 15 patients (group 1, 52% of the patients biopsied, 30% of total patients), 3 men and 12 women, with a mean age of 35.5±9 years (range, 20–56 years). The duration of dialysis before transplantation was 40±43 months (range, 3–165 months). Only one patient in this group was clinically active at the time of transplantation. At the time of the biopsy, one patient who also had acute rejection on biopsy had low-grade fever and decreased urine output, one had headache and fatigue, one had arthralgias and myalgias, one had mild arthralgias, one had mild myalgias, one had borderline leukopenia, and a few of the patients had microscopic hematuria. Pathologic examination of native kidney biopsy specimens and RLN is shown in Table 2. Eight of 15 patients with RLN (53.3%) had features consistent with mesangial lupus nephritis (WHO class II) in their transplant biopsy specimens. In these eight patients, native kidney biopsy findings were varied: one had class II, three had class IV, and two had class V lupus nephritis (LN). The number of immune complex deposits in the transplant biopsy specimens varied from small deposits involving some mesangial areas to abundant larger deposits in most mesangial regions. On LM, there were no abnormalities suggestive of RLN in two patients, and only mild-to-moderate mesangial matrix expansion was noted in the remaining six of these patients. One patient with mesangial RLN died and underwent autopsy. Examination of the autopsy material in this case showed mesangial expansion and occasional medium-sized mesangial deposits similar to the biopsy specimen obtained 15 months previously. Another of the patients with class II RLN who had a living-unrelated transplant developed arthralgias, myalgias, and diminished kidney function on postoperative day 6. Kidney biopsy revealed mild acute rejection, mild segmental increase of mesangial matrix (Fig. 1A), and mesangial deposits of C3 and C1q, which were suggestive of early recurrent lupus nephritis. Although she was initially treated with steroids and antithymocyte globulin, on postoperative day 10 she underwent a transplant nephrectomy. The nephrectomy specimen showed extensive areas of cortical necrosis, acute vascular rejection (Fig. 1B), and recurrent lupus nephritis with mesangial staining with C3, C1q, and trace immunoglobulin (Ig) G on IF, and small to medium mesangial electron-dense deposits on EM (Fig. 1C). This particular patient illustrates the possibility of early development of new immune complexes in the graft, within days of transplantation.
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Table 1: Table 1. Characteristics of the patients with and without recurrence of lupus nephritis, and patients who did not undergo any biopsies
Table 2: Table 2. Characteristics of the patients with RLN
Figure 1: (A) Mild segmental increase of mesangial matrix (Jones’ silver stain; magnification × 200). (B) Acute vascular rejection (Jones’ silver stain; magnification × 100). (C) Small to medium electron-dense mesangial deposits (transmission electron microscopy; magnification × 17,125).
Four patients had biopsy findings indicative of focal proliferative LN (WHO class III) in our transplants at 5 weeks, 4 months, 36 months, and 53 months after transplantation. Two cases also had histologic features of acute rejection, potentially confounding the light microscopic interpretations of glomerular proliferation. On LM, three patients had very mild segmental endocapillary proliferation, two had mild expansion of mesangial matrix and mild increase in mesangial cellularity, and one patient had no mesangial changes at all. One of these four patients had serologically active SLE at the time of transplantation. This particular patient underwent transplantation because of dialysis access failure.
Three patients had membranous LN (WHO class V) at 2 years, 34 months, and 35 months posttransplant, respectively. Two had mostly unremarkable looking glomeruli on LM and one patient had mild expansion of mesangial matrix.
All patients with RLN had all three immunoglobulin isotypes (IgG, IgM, and IgA) by IF along with complement components, a pattern that is referred to as “full-house” staining. EM examination revealed abundant reticular aggregates in all biopsy specimens (Fig. 2). The use of IF and EM gave unquestionable support for the recurrence of lupus nephritis in all these patients. Concomitant findings were chronic rejection (n=5), cortical necrosis (n=1), acute rejection (n=9), acute and chronic rejection (n=2), mild diabetic changes (n=1), thrombotic microangiopathy (n=1), CsA toxicity (n=2), and transplant glomerulopathy (n=11).
Figure 2: Reticular aggregates in endothelial cell cytoplasm (transmission electron microscopy; magnification × 51,250).
Fourteen patients did not have RLN on biopsy (group 2: 2 men and 12 women; mean age, 28.5±7.6 years; range, 20–46 years). The duration of dialysis before transplantation was 36±38 months (range, 2.5–125 months), which was not statistically different from group 1. Biopsy specimens (25 biopsies in 18 grafts, four patients having second grafts) from the patients without RLN demonstrated the following: acute cellular rejection (n=4), acute cellular and vascular rejection (n=3), acute cellular rejection and acute pyelonephritis (n=1), acute vascular rejection and transplant glomerulopathy (n=1), chronic rejection (n=2), acute cellular rejection and chronic rejection (n=3), thrombotic microangiopathy (n=2), acute tubular necrosis (n=2), transplant nephropathy and BK virus nephropathy (n=1), acute rejection and BK virus nephropathy (n=1), arterial thrombosis and hemorrhagic infarction (n=2), interstitial and arterial intimal fibrosis (n=2), and mild capsulitis (n=1). The findings on IF were trace segmental mesangial staining with IgG and C3 (n=1); trace arteriolar staining with C3 (n=2); trace granular mesangial staining with IgA and IgM, with additional trace segmental tubular BM staining for IgG, IgA, IgM, C3, and polyvalent antisera without EM deposits in one of the two biopsy specimens (n=2); weak mesangial and vascular C3 (n=1); segmental IgM and C3 in one glomerulus (in five) (n=1); and focal C3 staining of tubular luminal surfaces (n=1). Reticular aggregates were found in only three patients.
Group 3 comprised 21 patients (19 patients without any biopsies and 2 patients with inadequate biopsy specimens, 3 men and 18 women; mean age, 35±11 years; range, 19–58 years). The duration of dialysis before transplantation was 34±28 months (range, 5–105 months).
Serologies before transplantation were not complete. Available data are as follows: in group 1, antinuclear antibody (ANA) was positive in six patients, anti-DNA antibody was negative in three patients, and low complement levels were present in four and normal in three patients. In group 2, ANA was positive in three patients and negative in two patients, anti-DNA antibody was positive in three patients and negative in three patients, and low complement levels were present in only one patient and normal in five patients. In group 3, ANA was positive in three patients and negative in three patients, anti-DNA antibody was positive in three patients and negative in two patients, and low complement levels were present in two patients and normal in four patients.
Hepatitis C was tested in 36 of 50 patients and was positive in 4 of 13 patients with RLN, 1 of 12 patients without RLN, and 1 of 11 patients who did not undergo biopsy. There was no statistically significant difference between patients with RLN and without RLN.
Overall, patient survival of all 50 was 96% at 1 year and 82% at 5 years. Graft survival was 87% at 1 year and 60% at 5 years. There was no statistically significant difference in graft survival between group 1 (RLN) and group 2 (no RLN) (P =0.20). Graft survival was worse (P <0.01) in patients who underwent biopsy (29 patients, 32 grafts) compared with patients who never underwent any biopsies (21 patients, 29 grafts). One- and 5-year survival rates for the biopsy versus no-biopsy groups, respectively, were 84% and 42% versus 90% and 86%. We also found that graft survival was worse in the group with one or more biopsy-documented acute rejection episode compared with the group with no documented episode of acute rejection and no biopsy (P =0.01). Patients with biopsy-documented chronic rejection also had worse graft survival compared with those who had no chronic rejection on their biopsy specimen(P =0.03). The presence or absence of recurrence did not affect patient survival.
DISCUSSION
We reviewed our experience with 54 SLE patients who underwent kidney transplantation at our center between 1976 and 2000. We found that RLN is much more common (30%) than previously reported (6,7). This could be in part because of the increase in the number of biopsies performed at our center over the years and the frequent use of IF and EM in addition to LM on transplant biopsy specimens. LM alone would not permit recognition of RLN, particularly low-grade mesangial, in renal allograft biopsies. Eight of 15 patients with RLN (53.3%) had features consistent with mesangial lupus nephritis (WHO class II) in our transplant biopsy specimens, which could have been missed if LM only was performed. Because the diagnosis of RLN was made on the basis of LM and additional characteristic findings on IF and EM in our study, we do not believe we have overestimated the recurrence rate. Other reports have shown similar high recurrence rates in patients with SLE. Nyberg et al. reported their experience with 16 patients with SLE, in whom seven (44%) had biopsy-proven RLN (9). LM findings in biopsy specimens obtained from these patients were not diagnostic for RLN, which was diagnosed with the use of IF and EM. Six of the seven patients with histopathologic signs of SLE also had proteinuria, hematuria, and/or elevated serum creatinine; three had extrarenal manifestations such as arthralgia, fever, skin rash, and leukopenia; and three had serologic signs of active SLE. In this series, only one graft was lost because of RLN 3 years after transplantation. In contrast, in a recent retrospective study, Grimbert and colleagues reported only one case of RLN in 53 renal transplant recipients with SLE (2). No patient had clinically active SLE at the time of transplantation. The patient who had RLN developed nephrotic syndrome and hypocomplementemia 3 months after transplantation. We argued that in our study transplant biopsies were performed for clinical reasons such as increased serum creatinine, hematuria, or heavy proteinuria. Thus, morphologic recurrence might be underestimated because of subclinical recurrence. Although 41 (68%) of the SLE patients and 63 (60%) of the controls had at least one biopsy-documented episode of acute rejection, there is no information in that particular study regarding whether IF and EM were used routinely on all biopsies or not, a potential limiting factor in detecting all RLN cases.
Ultrastructural evaluation with EM can be crucial, especially in the diagnosis of patients with SLE who, at the time of biopsy, do not have any strong clinical manifestations and serologic markers, and in characterizing the type and extent of renal involvement and activity (12). Furthermore, both IF and EM evaluation play a significant role in accurately diagnosing recurrent lupus nephritis, especially in patients with other accompanying renal abnormalities, such as acute rejection, which could also be associated with mild glomerulitis (12). We believe that transplant kidney biopsy specimens from patients with a history of ESRD resulting from SLE should be evaluated by both IF and EM in addition to LM.
Because there are no studies, except the study by Nyberg et al. (9), with serial elective biopsies in transplant recipients with SLE, it is difficult to predict when RLN will occur after transplantation. In previous studies, graft biopsies were usually performed for certain clinical indications such as proteinuria, hematuria, and worsening kidney function, which might have been continuing for some time. We have now demonstrated that RLN can occur as early as 6 days after transplantation. We believe that without surveillance biopsies, given the silent nature of many of the recurrences, it is impossible to determine the exact timing of recurrence and the rate of recurrence in the patients who did not undergo biopsies. Surveillance biopsies would also help to determine the effect of recurrent lupus nephritis on long-term outcome. Future studies with surveillance biopsies would be very useful to address these issues.
The impact of lupus activity on recurrence is controversial. Although few studies reported otherwise (13,14), it has been previously demonstrated that the incidence of serologic activity and extrarenal manifestations of SLE usually decrease significantly when patients start dialysis (6,15). In our series, there was only one patient with RLN who was clinically and serologically active, only mildly, at the time of transplant. She had no dialysis access left and therefore underwent transplant. In order to minimize the risk of RLN, a few studies suggested waiting for some time, ranging from 3 months to 2 years, before patients with SLE undergo transplantation even if that means initiation of dialysis in some patients (6,15,16). In contrast, in a study by Lochead and colleagues, a longer duration of dialysis before transplant (>25 weeks) was actually shown to worsen graft survival (17) without any significant RLN. No graft survival benefit was seen with any period of pretransplant dialysis (2,17,18). Similarly, ANA and complement levels at the time of surgery have not been reliable markers for predicting either recurrence in the allograft or outcome after transplantation (2,19). Low complement levels and wide variation in ANA titers were reported with no signs of SLE active disease or recurrence (2,3). In a report by Magee and colleagues, 2 of 44 patients had RLN (no information available on IF or EM) with positive serologic markers and moderate to severe extrarenal features of SLE. Both patients with RLN successfully underwent retransplantation (20). Interestingly, recurrence of clinical disease without RLN was also reported. However, no kidney biopsy was performed to confirm this clinical impression (3). Because of the retrospective nature of our study, we do not have complete data on SLE serologies at the time of transplantation to make any conclusions or recommendations as to their potential value.
Although RLN may have the same pattern as the original disease, several cases of transformation of the histologic lesions, either milder or more severe than the original biopsy specimen, have been seen in our series and in cases reported previously (21,22). In 1992, Nyberg and colleagues pointed out the fact that the type of glomerulopathy found in the allografts was not always the same as in the native biopsy specimens (9). We added that this does not preclude recurrence because transformation from one class to another is common during the course of SLE-related kidney disease.
Recurrence of SLE did not have a serious impact on graft survival in our patient population at a mean follow-up of 6.8±4.9 years, but there are reports of worse outcomes for those with RLN in the literature (3,20,23). In a recent retrospective review of the Renal Allograft Disease Registry, Hariharan and colleagues showed that recurrent and de novo disease are associated with poorer long-term survival and that the relative risk of allograft loss is double (23). In a case-controlled study of 45 SLE patients, two patients with five recurrences (mesangial proliferation) lost their graft because of RLN (3).
Although viruses have been blamed as possible etiologic agents or triggering factors in many autoimmune diseases, the role of hepatitis C virus (HCV) as a potential triggering agent in the pathogenesis of SLE is controversial. In our study, a total of 36 patients in 50 were tested for HCV, and there was no statistically significant difference between patients with RLN and without RLN on biopsy specimens. In a study using a third-generation enzyme-linked immunosorbent assay, Ramos-Casals and colleagues demonstrated that the prevalence of HCV infection in SLE patients was higher (13%) than in blood donors (1%) from the same geographic area (24). Although SLE HCV-positive patients showed a lower frequency of cutaneous features, a higher prevalence of liver involvement, hypocomplementemia, and cryoglobulinemia, there was no statistically significant difference in nephropathy between SLE patients with or without HCV infection. Chronic HCV infection can induce clinical and serologic features that can mimic SLE or other autoimmune diseases. Currently, one could only speculate that chronic immune stimulation by the persistent hepatitis C infection could also contribute to heightened autoimmunity and increased RLN. This possibility requires further prospective evaluation of renal transplant recipients with SLE.
There are no studies in the literature comparing the type of immunosuppression after transplantation in SLE patients, which might play a significant role in recurrence. Because our center protocol uses 10-mg daily administration of prednisone for maintenance immunosuppression in a majority of patients, we cannot support the theory that lower doses of prednisone used today may in fact allow for an increased rate of recurrent lupus nephritis. Furthermore, the treatment for recurrent lupus nephritis has not been established. High-dose steroids, cyclophosphamide, switching to tacrolimus from cyclosporine, and plasma exchange have been used with variable results in case reports (25,26). Among new immunosuppressive agents, MMF has been shown to be effective in animal models and in a small number of human trials of SLE (27–29). Most of our patients were on azathioprine for maintenance immunosuppression (group 1, 13 of 15 patients; group 2, 10 of 14 patients). In one of the patients who had recurrence, we increased immunosuppression with methylprednisolone pulses (250 mg, three times) and switched from azathioprine to MMF 1 g twice daily and added angiotensin-converting enzyme inhibitor for proteinuria. Although this particular patient did not tolerate this treatment well and developed severe cytomegalovirus infection, herpes esophagitis, and leukopenia, she survived and kept her graft at a follow-up of 3 years after the biopsy (6 years after transplantation). Ahuja and colleagues recently reported another patient who had a severe recurrence of diffuse proliferative LN and had a partial response to MMF (26).
Our study involves a large number of patients with SLE and allograft biopsies. The shortcoming of the study is that it was retrospective, stretching from 1976 to 2000, making it difficult to complete the information, especially on serologies (ANA, anti-DNA, complement levels, and HCV), both at the time of transplantation and at the time of the biopsy. Nevertheless, it is clear that our data from a single center demonstrate a high recurrence rate of SLE after kidney transplantation. RLN should be in the differential diagnosis of allograft dysfunction, or proteinuria and hematuria. More importantly, LM alone does not permit recognition of RLN. Therefore, we recommend complete morphologic studies with IF and EM in addition to light microscopy in transplant recipients with SLE. Although graft survival was not influenced by the recurrence in our series, in light of the recent data demonstrating worse outcomes with recurrence, it is important to recognize the recurrence of lupus nephritis after transplantation as a significant problem. Recognition of the current facts and complications related to renal transplantation in lupus nephritis will help to design future clinical trials to provide information on the risk factors for the recurrence and treatment of RLN. In most of the previous studies, and ours, CsA was the mainstay of immunosuppressive therapy. The impact of new immunosuppressive agents such as tacrolimus, MMF, and rapamycin on the recurrence of lupus nephritis remains to be seen.
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