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End-stage renal disease and systemic lupus erythematosus
u
REVIEW
End-stage Renal Disease and Systemic Lupus Erythematosus Christopher F. Mojcik, MD, PhD, John H. Klippel, MD, Bethesda, Maryland
To provide an overview of the course of systemic lupus erythematosus (SLE) following the onset of end-stage lupus nephropathy, regarding clinical and serological manifestations, survival on dialysis, and renal transplant outcomes. METHODS: A review of the pertinent literature, identified by a comprehensive Grateful Med search, was performed. RESULTS: There is a tendency for decreased clinical and serological lupus activity following the onset of end-stage renal disease. The pathophysiology of this quiescence remains unclear. Survival of lupus patients on dialysis is no different from that of non-SLE dialysis patients, and is better than that of several other rheumatic diseases. Following renal transplantation, there is no difference in patient or graft survival in lupus versus nonlupus patients. Like their nonlupus counterparts, SLE transplant patients do better with living relative grafts and/or regimens containing cyclosporin A. Transplantation is not recommended within 3 months of the initiation of dialysis to allow possible recovery from the acute renal failure. Transplantation during an acute exacerbation of SLE is controversial, and may increase the risk of poor outcomes. Recurrence of lupus in transplanted allografts, often with the same histopathology as in the native kidney, occurs at a rate (2.7% to 3.8%) comparable to that for all allograft transplant failures (2% to 4%). CONCLUSIONS: End-stage lupus nephropathy patients require less medication owing to decreased disease activity. They are good candidates for dialysis and renal transplantation, with survival and recurrence rates no different from those of other patients with end-stage renal disease. Am .I Med. 1996;101:100-107. OBJECTIVE:
From the National Institute of Allergy and lnfectlous Diseases (CFM) and the National Institute of Arthritis and Musculoskeletal and Skin Diseases (JHK), National lnstltutes of Health, Bethesda, Maryland. Bldg 10, Rm 9s 205, Manuscrlpt
loo
01996 All rights
NIAMS,
submitted
January
by Excerpta reserved.
NIH, 9000
Rockville
29, 1996
Medica,
Inc.
Pike, Bethesda,
and accepted
March
Mary6, 1996.
R
enal involvement is a potentially serious complication of systemic lupus erythematosus (SLE) in which 5% to 22% of patients progress to end-stage renal disease (ESRD) requiriig hemodialysis or transplantation. l-G In the United States, it is estimated that lupus nephropathy accounts for 1.4% of all ESRD.i In this review we have attempted to summarize the literature that addresses several major issues related to end-stage lupus nep:hropathy, in particular: ( 1) the course of extrarenal clinical manifestations of lupus following ESRD; (2) patient survival on dialysis; (3) graft and patient survival after renal transplantation; and (4) recurrence of lupus nephropathy in allografted kidneys.
COURSE OF SLE FOLLOWING ESRD
ONSET OF
Fries et al” were the first to call attention to the effects of ESRD on the clinical course of ;SLE. A comparison of early (near-normal renal function with documented renal involvement) and late (start of dialysis) manifestations of 13 SLE patients revealed marked clinical and serological improvement, such that the diagnosis of SLE could not be made without knowing prior history. Studies assessing the clinical course od SLE in the context of ESRD are summarized in Talble I. In the majority, nonrenal clinical SLE activity appears to have decreased following the progression to ESRD. Among those studies that measured specific manifestations, decreases were observed in the frequency of arthritis/arthralgias (89.5% + 11.4% to 24.8% 2 22.4%), rash (72.5% & 20.9% to 21.3% ? 19.5%), and serositis (52.5% I 13.4% to 26.0% t 7.1%). Two studies (not listed in Table I) used other methods to quantitate SLE clinical activity following the onset of ESRD. Nossent et all7 performed chart reviews on 55 lupus dialysis patients. Maximal nonrenal disease activity (assessed by SLEDAI) decreased from 8.4 (before dialysis) to 4.4 (during dialysis), and clinical event rates per 1,000 months decreased. Rodby and coworkers ” performed chart reviews on 8 SLE ESRD dialysis patients and determined the flare rate per year pre-dialysis (mean 90.1 + 28.8 months) and post-dialysis (mean 20.8 + 4.7 months) to be 0.66 t 0.46 and 0.94 2 0.28, respectively. However, because of the small sample size, the difference was not statistically significant. Serological activity has similarly been shown to decrease following ESRD (Table I). As .might be an0002-9343/96/$15.00 PII SOCKI2-9343(96)00074-5
RENAL DISEASE AND LUPUS ACTIVITY/MOJCIK TABLE
AND KLIPPEL
I
Study
n
Fries8
13
Brown9
30
Jarrett’O
14
Systemic Lupus Erythematosus Activity before and after End-Stage Renal Disease Percent of Patients AntiArthritis Rash Serositis ANA DNA C Prednisone lmmunosuppressives 100* 92 62 100(213)’ 89 (63) w 65$ 69
0
CopIon”
28
Pah112.13
12
Correla14
26
Cheigh15,16
59
97 13 86 36 79 18 75 50 75 33 36 7
15 80 13 43 7 With symptoms
31 NS
62 (87) 88 25
43 21
100
75 50 With activity
83 NS
Clinically
18 (5) 75 33
67 100 (433) 54 (90) 100 (272) 64 (100) NS
active
84 45
84 88 9
100 0
17 100 20 NS
100 0 51 89
15 NS
NS
NS
NS
100
NS
60 81 NS
75 0 NS
79 29
36 13
68 13
NS NS
25 NS
NS
* Top row indicates % of patients preESRD/dlalysis, bottom row indicates values post-ESRD/dialysls, + Parenthesis indicate titer. * Italicized numbers indicate actual mean: C is in mg/dL, prednisone is in muday. ANA = antlnuclear antibody; C = complement; NS = not stated.
ticipated, medication use paralleled the decrease in clinical and serologic activity. The percent of patients on prednisone fell from 89.3% I 18.5%to 19.3% + 6.1%. Further, the percentage of patients on immunosuppressives fell from 72.0% +- 4.2% to 7.5% + 10.6%.In the study by Nossent et al, Ii the percentage of patients using high-dose (greater than 30 mg) prednisone or immunosuppressants dropped from 69.1% to 14.5% and from 72% to 7.2%, respectively. The most comprehensive studies to date of the changes in lupus with ESRD have been done by Cheigh and coworkers.‘“,‘“,‘” Their initial report described 36 SLE patients on dialysis for more than 3 months (4 to 168 months) of whom 38.9% had clinically active disease prior to dialysis, and only 12.5% had evidence of lupus activity 2 years after initiation of dialysis.‘” A follow-up study l6 was expanded to 59 lupus dialysis patients followed a mean 6.5 years from the onset of dialysis. Forty-five percent of the patients were inactive at the start of dialysis and remained inactive throughout. Clinical lupus activity was evident in 35.6% of patients at the start of dialysis, increased to 55.4% in the first year of dialysis, but then steadily dropped to 6.5% by the fifth year, and 0% by the tenth year. Serological activity (defined in this study as the percent of patients with two or more abnormal studies for antinuclear antibodies [ANA], anti-dsDNA, CH50, or C3) also decreased with time during the course of dialysis, to 78.6% in the first year, 29.0% by the fifth year, and 22.2% by the tenth year. The percent.age of patients receiving steroids similarly decreased, from 67.9% in the first year to 12.9%in the fifth, and 5.6% in the tenth year.
Finally, two single case reports are of note, as they are contrary to the observations noted albove. Fialkow and Rubin”” discussed a woman with SLE nephritis and ESRD who had increased clinical and serological activity in the first 2 years after the onset of hemodialysis, with rash, central nervous system (CNS) involvement, fever, increased serologies (ANA and anti-DNA), and decreased complement levels. HernandezJaras et al” presented a case of SLE that developed 2 years after the onset of hemodialysis in a patient with renal failure of unknown cause. The patient developed serositis, CNS involvement, oral ulcers, alopecia, and positive ANA and anti-DNA titers (to 1:2560) in the second year of dialysis.
SURVIVAL OF SLE PATIENTS DIALYSIS
ON
Studies of survival of SLE patient,s on dialysis are summarized in Table II. Overall survival rates were 78.7% ? 11.5% in studies without controls, and 65.0% 2 5.5% in studies in which comparison with controls was possible. Control patient survival rates were 75.1% 2 17.9%. Combining all the lupus survival data, the mean SLE ESRD dialysis survival rate is 73.4% ? 12.1%. This suggests that survival rates of SLE ESRD patients on dialysis is likely comparable to that of nondiabetic control ESRD patients on dialysis. Several survival studies are illustrativ-e. In 63 SLE ESRD patients, Pollack and Ibels”” found the overall survival rate at 5 years (dialysis and/or transplantation) to be 71%, similar to that for nonJuly
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TABLE
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II Systemic Lupus Erythematosus n
Fries8 Brown9 CopIon” Pah112.13 Correia’4,22 Cheigh16 Nossent” Rodby’*
Number Who Died
13 30 28 12 24 59 55 8
3 5 6 2 12 14 6
End-Stage Renal Disease Dialysis Survival Deaths Survival Rate at SLE Infection 5 Years Uncontrolled NS 0 1 0 9 0 NS
1
trials NS 2 3 NS Z’ NS 1
0 Controlled
Kimberlyz3 Ziffz4 JarreV
15 3 NS
8 0 NS
NS NS NS
14 62
6 9 NS NS
0 0 NS NS
4 1
cz
’ Infection was present at time of death, although death + ltalrcs indicate control population data. NS = not stated; SLE = systemic lupus erythematosus.
was attributed
E%, to infection
SLE ESRD patients (60%). Nissenson and Portz6 performed a multicenter study comparing 1,029 SLE ESRD dialysis patients with a variety of other types of ESRD dialysis patients, including 2,114 nondiabetic controls. Overall survival after 33 months was 73% for the SLE group and 65% for the nondiabetic controls. The survival for SLE ESRD was better than that for polyarteritis nodosa, Wegener’s granulomatosis, and scleroderma (62%, 58%, and 35%, respectively). Only 18 of the 70 deaths (25.7%) in patients with ESRD were directly attributable to SLE activity (Table II), and 17 of these occurred in two studies.‘“,“’ In the study by Correira et a1,149 of the 11 deaths occurring within 1 month of the initiation of dialysis were attributed to SLE activity, and almost half of these patients had concomitant infection. Similarly, Kimberly et alz3 found that all of the 8 deaths attributed to SLE occurred within the first 3 months of the initiation of dialysis. Infection accounted for more than one half (22 of 42) of the non-SLE-related deaths, and was a complicating factor in many of the SLE-ascribed deaths. Jarrett et al” attributed 4 of 6 SLE patient deaths to infection, while only 1 of 9 non-SLE dialysis patient deaths were infection related. In the study by Pollack and Ibels,” infection accounted for 27% of the SLE ESRD deaths, compared with 15%of non-SLE ESRD deaths. 102
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76.9% 83.3% 78.6% 83.3% 50.0% 81.1% 89.0% 87.5%
18 months 23 months ND 31 months 23 months 6.5 years 60 months 21 months
NS NS 67% 55% 58.6% 88.5% 71% (65%) 60%
4 months-9
trials
39 36+ 30
Pollack2”
Mean Time on Dialysis
in only 5 of these
years
34 months 3.1 years 3.1 years NS NS
cases.
RENAL TRANSPLANTATION PATIENTS Graft/Patient Survival
IN SLE ESRD
Concerns about poor kidney allograft, survival as a result of accelerated rejection of the new kidney in SLE patients were allayed by a joint report by the American College of Surgeons and the National Institutes of Health Transplant Registry.“7 In 56 SLE patients observed for a mean of 2 years after transplant, patient survival was 66%.Among the survivors, 81% had functioning grafts (which represented 55% of the total transplants). A number of additional studies, summarized in Table III have addressed various issues related to renal transplantation in SLE ESRD. The mean patient and graft survival following renal transplantation in SLE is 87.4% and 63.1%, respectively, data that compare favorably with renal transplantation irrespective of the primary disease. Cats and coworkers37 reviewed 117 transplants in SLE patients and compared graft survival with that in pyelonephritis (PN) , glomerulonephritis (GN) , and diabetes (DM). One-year graft survival rates were 57% for SLE (63% for living relative [ LR 1, 52% for cadaver [CAD]), 68% for PN (82% for LR, 53% for CAD), 66% for GN (79% for LR, 51% for CAD), and 54% for DM (65% for LR, 46% for CAD). Sumrani et aI.46found no differences in the incidence of acute rejection among SLE, DM, adult polycystic kidney
RENAL DISEASE AND LUPUS ACTIVITY/MDJCIK rABLE
AND KLIPPEL
Ill Systemic Lupus Erythematosus
Group Small studies (n ~20) 4mendz8 Brown9 Jarrett’O CopIon” Ziff24 Correia14 RothZg Rivera3D Cattrar?l GOSSIP Contreras33 Bitker34 Sokunbi35 Mean Large studies (n 220) Mejia36 Cats3’ Pollackz5 Bumgardner38*3q Zara40 Schechne? Nyberg42,43 CheigW5,16 Nossenp4 Krishnan45 Sumrani46 Mean Overall Mean
n’ 13/11
7/6 3/3 14/12 8/NS 10/a 15/15
W3 ll/ll 16/14 16/16 ll/lO
6/6
20/18 117fls 22/19 33/32 46/38 20/19 38/31 21/18 28/28 138/l 38 43/40
Patient and Graft Survival after Renal Transplant % Patient Survival % Graft Survival Follow-Up LR (Months) CAD Total LR CAD Total 29.8 NS l-69+ .5-120 64 3-60 37 12-87 NS 44 64 NS O-84
32 NS 41 85 4-14 NS NS 53 32 NS 58
100
100
100
86
100
100 83
100
100
100
84
100
100
100 50 100 92 75 93 100 93 93 93 100 83 90.8
100
50
80
44
0
44 87
75
50
76.5
80 50 59.0
82 63
33 52
95 91 89 94 81 78 87
86 0
41 22
100 86.0 87.4
100 67.7 69.1
100
62 29 33 57 63 40 84 87 53 63 78 100 50 65.2
59 57 78 82 54 20 50 61 68 68 84 62.5 63.1
68 75 55.6 56.3
* Number transplants/number patbents. + Italicized numbers refer to range rather than mean. CAD = cadaveric graft; LR = living related graft; NS = not stated.
and all other kidney recipients. Pollock and though Cattran and Aprile31 found similar patient survival rates between 11 SLE transplant patients IbelsZ5 reported that SLE patient survival following and 555 nonlupus controls, graft survival was sigrenal transplantation was not significantly different from control patients or dialysis-only SLE ESRD pa- nificantly worse in the lupus patients at 6 months tients. Furthermore, graft survival in SLE patients at (63% versus 84%) and 18 months (53% versus 5 years was found to be better than control trans- 81%) _Nyberg et a14”also noted significantly worse plant patients (70% versus 48%). Bumgardener et graft (but not patient) survival in SLE patients al38,39were unable to find significant differences in compared with matched controls (48% versus 84%, allograft survival rates between 32 SLE patients and respectively, P < 0.001). The authors attributed the difference to less potent immunosuppressive matched pair controls. In a study by Cheigh and COworkers16 no differences were found in either graft protocols at their institution. The importance of or patient survival rates comparing 21 transplants in the immunosuppressive regimen following renal 18 SLE patients with 275 nonlupus transplant con- transplantation has been studied by Zara and colrecipitrols. Finally, Krishnan et a14’ using Cox regression leagues, 4o who found that SLE transplant analysis failed to flnd differences in l-year graft sur- ents (either LR or CAD) treated with cyclosporin A ( CsA) did as well as matched controls; however, vival between 138 SLE and 6,125 non-SLE transplant those who received azathioprine (AZA) did signifpatients. Two groups, however, have provided data to icantly worse. Bumgardener et al,38 however, suggest that SLE patients have worse outcomes found no difference in graft survival between CsA following transplantation than do controls. Al- versus AZA-treated groups (though the CsA group
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to 4% of all allograft failures.47 The inciRecurrence of Systemic Lupus Erythematosus following Renal Allograft dence of recurrence Recurrence in varies by disease, the Group n* Graft Patient Immunosuppressive+ most frequent being ASC/‘NIHz7 56/56 0 1 NS GN, with an overall (reAmendz8 13/11 0 1 Aza/Cy gardless of the type of Brown9 7/6 0 0 NS GN) recurrence of Camerons0 0 NS B/6 NS Jarrett’O 17.5% in one series.” 3/3 0 0 NS Coplon” 14/12 NS 1 Aza When the primary GN Correiar4 1 O/8 0 2 Aza causes rapid kidney Mejia36.51 20/18 1 (LRS 3 (3) Aza failure, recurrence in RothZg 15/15 2 U-R) 2 (6) ALG/Aza/CsA the allograft would apNyberg42.52 38/31 7 INS) 3 Aza/CsA Bumgardner 33/32 0 0 (1) pear to be more Aza/CsA Cheigh16 21/18 0 1 Aza/CsA likely.“” Further, the Rivera30 B/8 0 0 Aza/CsA rate of primary disease NosserP 28/28 1 (NS) 0 (7) Aza/CsA recurrence in the graft GosP 16/14 1 (LR) 1 ALG/Aza/CsA does not necessarily Contreras33 16/16 0 0 Aza/CsA Sumrani46 43/40 1 (LR) correlate with graft surNS Aza/CsA Bitker34 1l/10 0 0 Aza/CsA vivaL4’ Although recurSokunbi35 6/6 NS 2 (2) Aza/CsA rence of SL,E has been Total 366/388 13 noted in allografts, luPercent 3.8 pus is thou,ght to have * Number of grafts/number of patients. + All Immunosuppressive regimens include steroids. one of the lowest rates * Parenthesis Indicate type of graft in which SLE recurred: LR = living related; CAD = cadaveric; NS = not stated. of recurrence, and is ALG = anblymphocyte globulin; Aza = azathloprine; Cy = cyclophosphamide; CsA = cyclosportn A. rarely responsible for graft 10~s.“~ Studies reporting the recurrence rates of lupus newas small and had shorter follow-up time as comphritis in renal allografts are summarized in Table pared with the AZA group). The timing of transplantation has also received at- Iv. In these, there have been 13 instances of recurtention. Several authors recommend an arbitrary 3 to rence of nephritis in 346 grafts (3.8%). Among all 6 month or longer interval on dialysis prior to trans- studies, however, including case reports, there are plantation. 10,16,1Q,29 This will allow patients with tem- 20 definite cases in 728 renal transplants, or 2.7%. porary renal failme to recover renal function. A more These numbers fall well within the range of recurcontroversial issue is the control of lupus activity at rence for other diseases.“7Among the patients rethe time of transplantation. Two studies”““’ and several ported, 17 experienced clinical symptoms of extracase reports of recurrent nephritis (see below) suggest renal lupus (5.7%), and 33 had positive serologies that transplantation in serologically active lupus may post-transplant, with or without symptoms ( 11.1%). lead to poor outcomes. These groups suggestdialyzing It is interesting to note that despite the fact that LR until the patient becomes seronegative. Other stud- ahograft survival is greater than CAD allograft suries ‘WWWW however, have not found any significant vival in SLE patients (Table III), for definite recurdifferences in transplantation outcomes of active ver- rences the ratio among LR:CAD grafts (when noted) is 8:4 (Table IV and case report data). sus inactive lupus patients. Yakub et a15:’ described 3 SLE patients with Finally, the influence of graft type (LR versus chronic rejection of CAD allografts, 2 of whom CAD) on outcome has not been adequately studied showed evidence of recurrence in the allograft in SLE. The only published data come from the study One patient was serologically active at the time of by Bumgardener et a1,“8in which no differences in transplant, and rejected the allograft at 7 months graft survival based on the type of graft were found despite AZA treatment. The allograft showed lincomparing SLE with control patients. The data in Taear deposits of IgG, complement, and antibodies ble III, however, would appear to indicate that, like to dsDNA. Following graft removal and cessation controls, SLE patients do better with LR grafts than of immunosuppressive medications, a clinical flare with CAD grafts (69.1% versus 56.3%). ensued with rash, serositis, and cerebritis. The secRecurrence of Lupus Nephritis in Allografts ond patient, also serologically active at the time of Recurrence of the primary disease in renal allo- transplant, began to show evidence of rejection at grafts has been estimated to account for less than 2% 2 months. The patient died 4 months post-transTABLE
104
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RENAL DISEASE AND LUPUS ACTIVITY/MOJCIK
plant because of sepsis. Immunofluorescence of the allograft showed faint staining with anti-IgG and irregular C3 deposits. Amend et al.“” reported two cases of recurrence; it is unclear whether the patients were also included in an earlier report.‘8 One patient was serologically active at CAD transplant and remained so post-transplant. She developed mild clinical activity after 4.5 years, and at 6 years began allograft rejection. An allograft biopsy revealed positive immunofluorescence for IgG, IgM, and C3; electrondense subepithelial deposits were seen on electron microscopy (EM). The second patient developed clinical recurrence of SLE 2 years post-LR transplant, with an active urinary sediment, and was treated with prednisone. One and a half years later an allograft biopsy was performed for worsening renal function with a persistently active urinary sediment. The biopsy was positive for immunofluorescence for IgG and C3 with subendothelial, intramembranous, and subepithelial electron-dense deposits. There is substantial evidence that immunosuppression does not prevent the development of lupus nephritis in the allograft. Sohmiya et al”” reported recurrence in a LR graft 4 months after transplantation in a patient with inactive SLE, despite 550 mg/day of cyclosporin A (CsA) . Immunofluorescence of the allograft biopsy revealed staining for IgG, IgM, Clq, and C3. Kumano et al”” described a 13-year-old patient who received a LR graft while serologically active, who maintained good function for 1.5 years on a regimen of prednisolone, mizoribin, and cyclophosphamide. With the development of proteinuria, rising anti-DNA titer, and falling complement levels, allograft biopsy was done and revealed positive immunofluorescence (IgG, IgM, IgA, Clq, and C3) and electrondense subendothelial deposits. These findings were similar to the histological changes found in the original biopsy done for lupus nephritis. Fernandez et als7 presented a case (in addition to those in the original report by Roth et a12”) of recurrence at 11 months in a patient with a CAD transplant treated with CsA and methylprednisolone. Azathioprine was added at the onset of proteinuria, and allograft biopsy at 2 years showed membranous GN, which transformed to DPGN (similar to the native kidney lesion) on subsequent biopsy. Finally, two possible cases of lupus nephritis recurrence deserve mention. Fox et al”* reported a case of de novo lupus nephritis with clinical and serological activity developing 8 months after CAD allograft for idiopathic end-stage GN (despite treatment with CsA). On biopsy, the allograft had IgG,
AND KLIPPEL
IgA, IgM, and C3 deposits, as well as subendothelial and mesangial deposits on EM. Lauzurica et al”” reported the case of a man with lupus membranous nephropathy, who underwent CAD transplantation while serologies were abnormal and complement low. Immunosuppression consisted of preednisone, CsA, AZA, and antithymocyte globulin. An allograft biopsy was performed for proteinuria at 2.5 months post-transplantation, and showed membranous GN; no immunofluorescence or EM studies were reported.
CONCLUSION In this review we have tried to summarize the literature on end-stage lupus nephropathy. Several conclusions seem reasonable. First, the majority of studies support the tendency toward decreased clinical and serological lupus activity following ESRD. As would be expected, the need for immunosuppression or high-dose prednisone decreased in this period. Several theories have been presented to explain the mechanism responsible for the :reduction in clinical and serologic abnormalities, but little proof has been offered. The theories include depressed cellular and humoral immunity, as a result of uremia ‘J”J lack of renally produced mediators, l1 removal Af lupus factors by dialysis itself, “J” or a natural end point in SLE discernable only by prolongation of life past ESRD.‘“,‘“,‘” Survival of lupus patients on dialysis does not appear significantly different from that of non-SLE dialysis patients, and is perhaps better than for some of the other rheumatic diseases. In SLE dialysis patients, the major cause of death is infection, with SLE activity per se accounting for a minority of deaths. With regard to transplantation, the majority of studies indicate no difference between SLEland nonSLE patients on graft survival. Like non-SLE patients, lupus patients have slightly better loutcomes with LR rather than CAD grafts; they do as well as controls with CsA-containing regimens, but may do somewhat worse with AZA-only regimens. In some studies transplantation during acute exacerbation of SLE led to poor outcome, and based on this it has been recommended that transplantation follow at least 3 months of dialysis. Finally, lupus can recur in transplanted allografts, and is often of the same histologic or immunofluorescent type as in the original kidney, but it is a rare event.
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29. Roth D, Mrlgrom M, Esquenaze V, et al. Renal transplantation In systemrc lupus erythematosus: one center’s experience. Am J Nephrol. 1987;7:367374. 30. Rivera M, Marcen R, Pascual J, et al. Kidney transplanlatron In systemtc lupus erythematosus nephritis: a one-center experrence. Nephron.
6. Austin HA Ill, Klippel JH, Balow JE, et al. Therapy of lupus nephritis: controlled trial of prednrsone and cytotoxic drugs. NEJM. 1986;314:614-619. 7. US Renal Data System, USRDS 1995 Annual Data Report. Bethesda, Mary-
8. Fries JF, Powers
and metabolic diseases: JAMA. 1975;232:148-153,
in
16. Cheigh JS, Kim H, Stenzel KH, et al. Systemic lupus erythematosus in patients with end-stage renal disease: long-term follow-up on the prognosis of patients and the evolution of lupus activity. Am J Kidney Dis. 1990;16:189-
39. Bumgardner transplantation
GL, Mauer SM, Ascher NL, et al. Long-term outcome of renal in patients with systemic lupus erythematosus. Trans Proc.
1989;21:2031-2032. 40. Zara CP, Lrpkowitz GS, Pern N, et al. Renal transplantation lupus nephropathy in the cyclosporine and precyclosporine
and end-stage eras. Trans Proc.
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41. Schechner RS, Greenstein SM, Glicklich D, et al. Renal .transplantation in the black population with systemic lupus erythematosus: a single center expe-
17. Nossent HC, Swawak TJG, Berden JHM. Systemic lupus erythematosus: analysis of disease activity in 55 patients with end-stage renal failure treated with hemodialysis or continuous ambulatory peritoneal dralysrs. Am J Med.
rience. Trans Proc. 1989;21:3937-3938. 42. Nyberg G, Blohme I, Svalander C, et al. Rejection and recurrence of SLE nephritis in cyclosporinetreated kidney transplant recrprents. Trans Proc.
1990;89:169-174. 18. Rodby RA, Korbet acbvity dialysis.
1987;19:1637-1638, SM, Lewis
EJ. Persistence
in patients with systemic lupus Am J Med. 1987;83:613-618.
erythematosus
19. Cheigh JS, Stenzel KH. End-stage renal matosus. Am J Krdney Dis. 1993;21:2-8. 20.
Fialkow
RZ, Rubin
J. Active
lupus
erythematosus
in a patient
and serological
undergoing
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In a patient
alysis. South Med J. 1986;79:516-517. 21. Hernandez-Jaras J, Bernls C, Paraiso lupus
of clinical
peritoneal
in systemrc recervrng
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erythe-
long-term
hemodr-
V, et al. Development
on hemodialysis.
patient
and
graft
survival
and
disease
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Ann
Intern
Med.
of systemic
1992;12:105-
Am JNephrol.
45. Krishnan G, Thacker renal allograft survival
L, Angstadt JD, Capellr JP. Multicenter analysis in lupus patients. Trans Proc. 1991;23:1755-
of
1756. Correia
P, Cameron
JS, Lian JD, et al. Why do patients
die? BMJ. 1985;290:126-131. 23. Kimberly RP, Lockshin MD, Sherman clerical course to and outcome tine. 1981;60:277-287.
with lupus
RL, et al. “End-stage”
on dialysis,
Experience
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25.
and transplantation
in patients
LS. Dralysis
failure due to systemrc lupus erythematosus: the Australian experience. Aust NZ J Med. 1987;17:321-325. 26. Nissenson AR, Port FK. Outcome of end-stage renal with rare causes
of renal failure:
1996
The
N, Miles patients
AM, Delaney with
V, et al. Renal
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MedC
Ill. Systemic/vascular
lupus
ne-
with renal
and New Zealand disease
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in patients Quart J Med.
1990;273:63-74. July
Sumranr
47.
Ramos
EL. Recurrent
diseases
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J Am Sot Nephrol.
1991;2:109-121. in end-stage
CA, lbels
46.
nephritis:
wrth 39 patients.
and transplantation
Pollock
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24. Ziff M, Helderman JH. Dialysis phrrtis. NEJM. 1983;308:218-219.
106
tion:
1991;114:183-188.
107. 22.
43. Nyberg G, Karlberg I, Svalander C, et al. Renal transplar’tatron in patients with systemic lupus erythematosus: increased risk of early graft loss. Stand J Ural Nephrol. 1990;24:307-313. 44. Nossent HC, Swaak TJ, Berden JHM, the Dutch Working Party on Systemic Lupus Erythematosus. Systemic lupus erythematosus after renal transplanta-
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48. Hamburger J, Crosnier J, Noel L-H. Recurrent glomerulonephrrtrs after renal transplantation. Ann Rev Med. 1978;29:67-72. 49. Mathew TH. Recurrence of drsease following renal transplantation. Am J Kidney 01s. 1988;12:85-96. 50. Cameron JS. Glomerulonephritis
in
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Transplant.
1982;34:237-245. 51. Moorthy AV, Ztmmerman (LN) after renal transplantation
SW, MeJra G, et al. Recurrence of lupus (RTX). Krdney fnt. 1987;31:464.
nephritis
RENAL DISEASE AND LUPUS ACTIVITY/MOJCIK 52. Nyberg G, Blohme I, Persson H, et al. Recurrence of SLE in transplanted kidneys: a follow-up transplant biopsy study. Nephrol Dal Trans. 1992; 7: 1116-
1123. 53. Yakub YN. Freeman RB, Pabrco RC. Renal transplantabon In systemic lupus erythematosus. Nephron. 1981;27:197-201. 54. Amend WJC, Vrncenti F, Feduska NJ, et al. Recurrent systemic lupus erythematosus involving renal allografts. Ann Intern Med. 1981;94:444-448.
56.
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after renal transplantatron. C/in Nephrol. 1987;27:94-98. 57. Fernandez JA, Milgrom M, Burke GW, et al. Recurrence of lupus nephritis rn a renal allograft wrth histologic transformation of the lesroii. Transplant.
1990;50:1056-1058.
55. Sohmrya S, Morozumi K, Yosida A, et al. A case of recurrent lupus nephritis after transplantation immunosuppressed with cyclosporrn A. Jpn J Trans.
58. Fox L, Zager PG, Harford AM, et al. Lupus nephrrtis in a pediatrrc renal transplant recipient. Pediatr Nephrol. 1992;6:467-469. 59. Lauzunca R, Bonet J, Vaquero M, et al. Recurrence of membranous lupus glomerulonephritis two months after a renal cadaver transplant. Trans Proc.
1986;21:17-24.
1992;24:108-109.
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REVIEW
End-stage Renal Disease and Systemic Lupus Erythematosus Christopher F. Mojcik, MD, PhD, John H. Klippel, MD, Bethesda, Maryland
To provide an overview of the course of systemic lupus erythematosus (SLE) following the onset of end-stage lupus nephropathy, regarding clinical and serological manifestations, survival on dialysis, and renal transplant outcomes. METHODS: A review of the pertinent literature, identified by a comprehensive Grateful Med search, was performed. RESULTS: There is a tendency for decreased clinical and serological lupus activity following the onset of end-stage renal disease. The pathophysiology of this quiescence remains unclear. Survival of lupus patients on dialysis is no different from that of non-SLE dialysis patients, and is better than that of several other rheumatic diseases. Following renal transplantation, there is no difference in patient or graft survival in lupus versus nonlupus patients. Like their nonlupus counterparts, SLE transplant patients do better with living relative grafts and/or regimens containing cyclosporin A. Transplantation is not recommended within 3 months of the initiation of dialysis to allow possible recovery from the acute renal failure. Transplantation during an acute exacerbation of SLE is controversial, and may increase the risk of poor outcomes. Recurrence of lupus in transplanted allografts, often with the same histopathology as in the native kidney, occurs at a rate (2.7% to 3.8%) comparable to that for all allograft transplant failures (2% to 4%). CONCLUSIONS: End-stage lupus nephropathy patients require less medication owing to decreased disease activity. They are good candidates for dialysis and renal transplantation, with survival and recurrence rates no different from those of other patients with end-stage renal disease. Am .I Med. 1996;101:100-107. OBJECTIVE:
From the National Institute of Allergy and lnfectlous Diseases (CFM) and the National Institute of Arthritis and Musculoskeletal and Skin Diseases (JHK), National lnstltutes of Health, Bethesda, Maryland. Bldg 10, Rm 9s 205, Manuscrlpt
loo
01996 All rights
NIAMS,
submitted
January
by Excerpta reserved.
NIH, 9000
Rockville
29, 1996
Medica,
Inc.
Pike, Bethesda,
and accepted
March
Mary6, 1996.
R
enal involvement is a potentially serious complication of systemic lupus erythematosus (SLE) in which 5% to 22% of patients progress to end-stage renal disease (ESRD) requiriig hemodialysis or transplantation. l-G In the United States, it is estimated that lupus nephropathy accounts for 1.4% of all ESRD.i In this review we have attempted to summarize the literature that addresses several major issues related to end-stage lupus nep:hropathy, in particular: ( 1) the course of extrarenal clinical manifestations of lupus following ESRD; (2) patient survival on dialysis; (3) graft and patient survival after renal transplantation; and (4) recurrence of lupus nephropathy in allografted kidneys.
COURSE OF SLE FOLLOWING ESRD
ONSET OF
Fries et al” were the first to call attention to the effects of ESRD on the clinical course of ;SLE. A comparison of early (near-normal renal function with documented renal involvement) and late (start of dialysis) manifestations of 13 SLE patients revealed marked clinical and serological improvement, such that the diagnosis of SLE could not be made without knowing prior history. Studies assessing the clinical course od SLE in the context of ESRD are summarized in Talble I. In the majority, nonrenal clinical SLE activity appears to have decreased following the progression to ESRD. Among those studies that measured specific manifestations, decreases were observed in the frequency of arthritis/arthralgias (89.5% + 11.4% to 24.8% 2 22.4%), rash (72.5% & 20.9% to 21.3% ? 19.5%), and serositis (52.5% I 13.4% to 26.0% t 7.1%). Two studies (not listed in Table I) used other methods to quantitate SLE clinical activity following the onset of ESRD. Nossent et all7 performed chart reviews on 55 lupus dialysis patients. Maximal nonrenal disease activity (assessed by SLEDAI) decreased from 8.4 (before dialysis) to 4.4 (during dialysis), and clinical event rates per 1,000 months decreased. Rodby and coworkers ” performed chart reviews on 8 SLE ESRD dialysis patients and determined the flare rate per year pre-dialysis (mean 90.1 + 28.8 months) and post-dialysis (mean 20.8 + 4.7 months) to be 0.66 t 0.46 and 0.94 2 0.28, respectively. However, because of the small sample size, the difference was not statistically significant. Serological activity has similarly been shown to decrease following ESRD (Table I). As .might be an0002-9343/96/$15.00 PII SOCKI2-9343(96)00074-5
RENAL DISEASE AND LUPUS ACTIVITY/MOJCIK TABLE
AND KLIPPEL
I
Study
n
Fries8
13
Brown9
30
Jarrett’O
14
Systemic Lupus Erythematosus Activity before and after End-Stage Renal Disease Percent of Patients AntiArthritis Rash Serositis ANA DNA C Prednisone lmmunosuppressives 100* 92 62 100(213)’ 89 (63) w 65$ 69
0
CopIon”
28
Pah112.13
12
Correla14
26
Cheigh15,16
59
97 13 86 36 79 18 75 50 75 33 36 7
15 80 13 43 7 With symptoms
31 NS
62 (87) 88 25
43 21
100
75 50 With activity
83 NS
Clinically
18 (5) 75 33
67 100 (433) 54 (90) 100 (272) 64 (100) NS
active
84 45
84 88 9
100 0
17 100 20 NS
100 0 51 89
15 NS
NS
NS
NS
100
NS
60 81 NS
75 0 NS
79 29
36 13
68 13
NS NS
25 NS
NS
* Top row indicates % of patients preESRD/dlalysis, bottom row indicates values post-ESRD/dialysls, + Parenthesis indicate titer. * Italicized numbers indicate actual mean: C is in mg/dL, prednisone is in muday. ANA = antlnuclear antibody; C = complement; NS = not stated.
ticipated, medication use paralleled the decrease in clinical and serologic activity. The percent of patients on prednisone fell from 89.3% I 18.5%to 19.3% + 6.1%. Further, the percentage of patients on immunosuppressives fell from 72.0% +- 4.2% to 7.5% + 10.6%.In the study by Nossent et al, Ii the percentage of patients using high-dose (greater than 30 mg) prednisone or immunosuppressants dropped from 69.1% to 14.5% and from 72% to 7.2%, respectively. The most comprehensive studies to date of the changes in lupus with ESRD have been done by Cheigh and coworkers.‘“,‘“,‘” Their initial report described 36 SLE patients on dialysis for more than 3 months (4 to 168 months) of whom 38.9% had clinically active disease prior to dialysis, and only 12.5% had evidence of lupus activity 2 years after initiation of dialysis.‘” A follow-up study l6 was expanded to 59 lupus dialysis patients followed a mean 6.5 years from the onset of dialysis. Forty-five percent of the patients were inactive at the start of dialysis and remained inactive throughout. Clinical lupus activity was evident in 35.6% of patients at the start of dialysis, increased to 55.4% in the first year of dialysis, but then steadily dropped to 6.5% by the fifth year, and 0% by the tenth year. Serological activity (defined in this study as the percent of patients with two or more abnormal studies for antinuclear antibodies [ANA], anti-dsDNA, CH50, or C3) also decreased with time during the course of dialysis, to 78.6% in the first year, 29.0% by the fifth year, and 22.2% by the tenth year. The percent.age of patients receiving steroids similarly decreased, from 67.9% in the first year to 12.9%in the fifth, and 5.6% in the tenth year.
Finally, two single case reports are of note, as they are contrary to the observations noted albove. Fialkow and Rubin”” discussed a woman with SLE nephritis and ESRD who had increased clinical and serological activity in the first 2 years after the onset of hemodialysis, with rash, central nervous system (CNS) involvement, fever, increased serologies (ANA and anti-DNA), and decreased complement levels. HernandezJaras et al” presented a case of SLE that developed 2 years after the onset of hemodialysis in a patient with renal failure of unknown cause. The patient developed serositis, CNS involvement, oral ulcers, alopecia, and positive ANA and anti-DNA titers (to 1:2560) in the second year of dialysis.
SURVIVAL OF SLE PATIENTS DIALYSIS
ON
Studies of survival of SLE patient,s on dialysis are summarized in Table II. Overall survival rates were 78.7% ? 11.5% in studies without controls, and 65.0% 2 5.5% in studies in which comparison with controls was possible. Control patient survival rates were 75.1% 2 17.9%. Combining all the lupus survival data, the mean SLE ESRD dialysis survival rate is 73.4% ? 12.1%. This suggests that survival rates of SLE ESRD patients on dialysis is likely comparable to that of nondiabetic control ESRD patients on dialysis. Several survival studies are illustrativ-e. In 63 SLE ESRD patients, Pollack and Ibels”” found the overall survival rate at 5 years (dialysis and/or transplantation) to be 71%, similar to that for nonJuly
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TABLE
AND KLIPPEL
II Systemic Lupus Erythematosus n
Fries8 Brown9 CopIon” Pah112.13 Correia’4,22 Cheigh16 Nossent” Rodby’*
Number Who Died
13 30 28 12 24 59 55 8
3 5 6 2 12 14 6
End-Stage Renal Disease Dialysis Survival Deaths Survival Rate at SLE Infection 5 Years Uncontrolled NS 0 1 0 9 0 NS
1
trials NS 2 3 NS Z’ NS 1
0 Controlled
Kimberlyz3 Ziffz4 JarreV
15 3 NS
8 0 NS
NS NS NS
14 62
6 9 NS NS
0 0 NS NS
4 1
cz
’ Infection was present at time of death, although death + ltalrcs indicate control population data. NS = not stated; SLE = systemic lupus erythematosus.
was attributed
E%, to infection
SLE ESRD patients (60%). Nissenson and Portz6 performed a multicenter study comparing 1,029 SLE ESRD dialysis patients with a variety of other types of ESRD dialysis patients, including 2,114 nondiabetic controls. Overall survival after 33 months was 73% for the SLE group and 65% for the nondiabetic controls. The survival for SLE ESRD was better than that for polyarteritis nodosa, Wegener’s granulomatosis, and scleroderma (62%, 58%, and 35%, respectively). Only 18 of the 70 deaths (25.7%) in patients with ESRD were directly attributable to SLE activity (Table II), and 17 of these occurred in two studies.‘“,“’ In the study by Correira et a1,149 of the 11 deaths occurring within 1 month of the initiation of dialysis were attributed to SLE activity, and almost half of these patients had concomitant infection. Similarly, Kimberly et alz3 found that all of the 8 deaths attributed to SLE occurred within the first 3 months of the initiation of dialysis. Infection accounted for more than one half (22 of 42) of the non-SLE-related deaths, and was a complicating factor in many of the SLE-ascribed deaths. Jarrett et al” attributed 4 of 6 SLE patient deaths to infection, while only 1 of 9 non-SLE dialysis patient deaths were infection related. In the study by Pollack and Ibels,” infection accounted for 27% of the SLE ESRD deaths, compared with 15%of non-SLE ESRD deaths. 102
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76.9% 83.3% 78.6% 83.3% 50.0% 81.1% 89.0% 87.5%
18 months 23 months ND 31 months 23 months 6.5 years 60 months 21 months
NS NS 67% 55% 58.6% 88.5% 71% (65%) 60%
4 months-9
trials
39 36+ 30
Pollack2”
Mean Time on Dialysis
in only 5 of these
years
34 months 3.1 years 3.1 years NS NS
cases.
RENAL TRANSPLANTATION PATIENTS Graft/Patient Survival
IN SLE ESRD
Concerns about poor kidney allograft, survival as a result of accelerated rejection of the new kidney in SLE patients were allayed by a joint report by the American College of Surgeons and the National Institutes of Health Transplant Registry.“7 In 56 SLE patients observed for a mean of 2 years after transplant, patient survival was 66%.Among the survivors, 81% had functioning grafts (which represented 55% of the total transplants). A number of additional studies, summarized in Table III have addressed various issues related to renal transplantation in SLE ESRD. The mean patient and graft survival following renal transplantation in SLE is 87.4% and 63.1%, respectively, data that compare favorably with renal transplantation irrespective of the primary disease. Cats and coworkers37 reviewed 117 transplants in SLE patients and compared graft survival with that in pyelonephritis (PN) , glomerulonephritis (GN) , and diabetes (DM). One-year graft survival rates were 57% for SLE (63% for living relative [ LR 1, 52% for cadaver [CAD]), 68% for PN (82% for LR, 53% for CAD), 66% for GN (79% for LR, 51% for CAD), and 54% for DM (65% for LR, 46% for CAD). Sumrani et aI.46found no differences in the incidence of acute rejection among SLE, DM, adult polycystic kidney
RENAL DISEASE AND LUPUS ACTIVITY/MDJCIK rABLE
AND KLIPPEL
Ill Systemic Lupus Erythematosus
Group Small studies (n ~20) 4mendz8 Brown9 Jarrett’O CopIon” Ziff24 Correia14 RothZg Rivera3D Cattrar?l GOSSIP Contreras33 Bitker34 Sokunbi35 Mean Large studies (n 220) Mejia36 Cats3’ Pollackz5 Bumgardner38*3q Zara40 Schechne? Nyberg42,43 CheigW5,16 Nossenp4 Krishnan45 Sumrani46 Mean Overall Mean
n’ 13/11
7/6 3/3 14/12 8/NS 10/a 15/15
W3 ll/ll 16/14 16/16 ll/lO
6/6
20/18 117fls 22/19 33/32 46/38 20/19 38/31 21/18 28/28 138/l 38 43/40
Patient and Graft Survival after Renal Transplant % Patient Survival % Graft Survival Follow-Up LR (Months) CAD Total LR CAD Total 29.8 NS l-69+ .5-120 64 3-60 37 12-87 NS 44 64 NS O-84
32 NS 41 85 4-14 NS NS 53 32 NS 58
100
100
100
86
100
100 83
100
100
100
84
100
100
100 50 100 92 75 93 100 93 93 93 100 83 90.8
100
50
80
44
0
44 87
75
50
76.5
80 50 59.0
82 63
33 52
95 91 89 94 81 78 87
86 0
41 22
100 86.0 87.4
100 67.7 69.1
100
62 29 33 57 63 40 84 87 53 63 78 100 50 65.2
59 57 78 82 54 20 50 61 68 68 84 62.5 63.1
68 75 55.6 56.3
* Number transplants/number patbents. + Italicized numbers refer to range rather than mean. CAD = cadaveric graft; LR = living related graft; NS = not stated.
and all other kidney recipients. Pollock and though Cattran and Aprile31 found similar patient survival rates between 11 SLE transplant patients IbelsZ5 reported that SLE patient survival following and 555 nonlupus controls, graft survival was sigrenal transplantation was not significantly different from control patients or dialysis-only SLE ESRD pa- nificantly worse in the lupus patients at 6 months tients. Furthermore, graft survival in SLE patients at (63% versus 84%) and 18 months (53% versus 5 years was found to be better than control trans- 81%) _Nyberg et a14”also noted significantly worse plant patients (70% versus 48%). Bumgardener et graft (but not patient) survival in SLE patients al38,39were unable to find significant differences in compared with matched controls (48% versus 84%, allograft survival rates between 32 SLE patients and respectively, P < 0.001). The authors attributed the difference to less potent immunosuppressive matched pair controls. In a study by Cheigh and COworkers16 no differences were found in either graft protocols at their institution. The importance of or patient survival rates comparing 21 transplants in the immunosuppressive regimen following renal 18 SLE patients with 275 nonlupus transplant con- transplantation has been studied by Zara and colrecipitrols. Finally, Krishnan et a14’ using Cox regression leagues, 4o who found that SLE transplant analysis failed to flnd differences in l-year graft sur- ents (either LR or CAD) treated with cyclosporin A ( CsA) did as well as matched controls; however, vival between 138 SLE and 6,125 non-SLE transplant those who received azathioprine (AZA) did signifpatients. Two groups, however, have provided data to icantly worse. Bumgardener et al,38 however, suggest that SLE patients have worse outcomes found no difference in graft survival between CsA following transplantation than do controls. Al- versus AZA-treated groups (though the CsA group
disease,
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to 4% of all allograft failures.47 The inciRecurrence of Systemic Lupus Erythematosus following Renal Allograft dence of recurrence Recurrence in varies by disease, the Group n* Graft Patient Immunosuppressive+ most frequent being ASC/‘NIHz7 56/56 0 1 NS GN, with an overall (reAmendz8 13/11 0 1 Aza/Cy gardless of the type of Brown9 7/6 0 0 NS GN) recurrence of Camerons0 0 NS B/6 NS Jarrett’O 17.5% in one series.” 3/3 0 0 NS Coplon” 14/12 NS 1 Aza When the primary GN Correiar4 1 O/8 0 2 Aza causes rapid kidney Mejia36.51 20/18 1 (LRS 3 (3) Aza failure, recurrence in RothZg 15/15 2 U-R) 2 (6) ALG/Aza/CsA the allograft would apNyberg42.52 38/31 7 INS) 3 Aza/CsA Bumgardner 33/32 0 0 (1) pear to be more Aza/CsA Cheigh16 21/18 0 1 Aza/CsA likely.“” Further, the Rivera30 B/8 0 0 Aza/CsA rate of primary disease NosserP 28/28 1 (NS) 0 (7) Aza/CsA recurrence in the graft GosP 16/14 1 (LR) 1 ALG/Aza/CsA does not necessarily Contreras33 16/16 0 0 Aza/CsA Sumrani46 43/40 1 (LR) correlate with graft surNS Aza/CsA Bitker34 1l/10 0 0 Aza/CsA vivaL4’ Although recurSokunbi35 6/6 NS 2 (2) Aza/CsA rence of SL,E has been Total 366/388 13 noted in allografts, luPercent 3.8 pus is thou,ght to have * Number of grafts/number of patients. + All Immunosuppressive regimens include steroids. one of the lowest rates * Parenthesis Indicate type of graft in which SLE recurred: LR = living related; CAD = cadaveric; NS = not stated. of recurrence, and is ALG = anblymphocyte globulin; Aza = azathloprine; Cy = cyclophosphamide; CsA = cyclosportn A. rarely responsible for graft 10~s.“~ Studies reporting the recurrence rates of lupus newas small and had shorter follow-up time as comphritis in renal allografts are summarized in Table pared with the AZA group). The timing of transplantation has also received at- Iv. In these, there have been 13 instances of recurtention. Several authors recommend an arbitrary 3 to rence of nephritis in 346 grafts (3.8%). Among all 6 month or longer interval on dialysis prior to trans- studies, however, including case reports, there are plantation. 10,16,1Q,29 This will allow patients with tem- 20 definite cases in 728 renal transplants, or 2.7%. porary renal failme to recover renal function. A more These numbers fall well within the range of recurcontroversial issue is the control of lupus activity at rence for other diseases.“7Among the patients rethe time of transplantation. Two studies”““’ and several ported, 17 experienced clinical symptoms of extracase reports of recurrent nephritis (see below) suggest renal lupus (5.7%), and 33 had positive serologies that transplantation in serologically active lupus may post-transplant, with or without symptoms ( 11.1%). lead to poor outcomes. These groups suggestdialyzing It is interesting to note that despite the fact that LR until the patient becomes seronegative. Other stud- ahograft survival is greater than CAD allograft suries ‘WWWW however, have not found any significant vival in SLE patients (Table III), for definite recurdifferences in transplantation outcomes of active ver- rences the ratio among LR:CAD grafts (when noted) is 8:4 (Table IV and case report data). sus inactive lupus patients. Yakub et a15:’ described 3 SLE patients with Finally, the influence of graft type (LR versus chronic rejection of CAD allografts, 2 of whom CAD) on outcome has not been adequately studied showed evidence of recurrence in the allograft in SLE. The only published data come from the study One patient was serologically active at the time of by Bumgardener et a1,“8in which no differences in transplant, and rejected the allograft at 7 months graft survival based on the type of graft were found despite AZA treatment. The allograft showed lincomparing SLE with control patients. The data in Taear deposits of IgG, complement, and antibodies ble III, however, would appear to indicate that, like to dsDNA. Following graft removal and cessation controls, SLE patients do better with LR grafts than of immunosuppressive medications, a clinical flare with CAD grafts (69.1% versus 56.3%). ensued with rash, serositis, and cerebritis. The secRecurrence of Lupus Nephritis in Allografts ond patient, also serologically active at the time of Recurrence of the primary disease in renal allo- transplant, began to show evidence of rejection at grafts has been estimated to account for less than 2% 2 months. The patient died 4 months post-transTABLE
104
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plant because of sepsis. Immunofluorescence of the allograft showed faint staining with anti-IgG and irregular C3 deposits. Amend et al.“” reported two cases of recurrence; it is unclear whether the patients were also included in an earlier report.‘8 One patient was serologically active at CAD transplant and remained so post-transplant. She developed mild clinical activity after 4.5 years, and at 6 years began allograft rejection. An allograft biopsy revealed positive immunofluorescence for IgG, IgM, and C3; electrondense subepithelial deposits were seen on electron microscopy (EM). The second patient developed clinical recurrence of SLE 2 years post-LR transplant, with an active urinary sediment, and was treated with prednisone. One and a half years later an allograft biopsy was performed for worsening renal function with a persistently active urinary sediment. The biopsy was positive for immunofluorescence for IgG and C3 with subendothelial, intramembranous, and subepithelial electron-dense deposits. There is substantial evidence that immunosuppression does not prevent the development of lupus nephritis in the allograft. Sohmiya et al”” reported recurrence in a LR graft 4 months after transplantation in a patient with inactive SLE, despite 550 mg/day of cyclosporin A (CsA) . Immunofluorescence of the allograft biopsy revealed staining for IgG, IgM, Clq, and C3. Kumano et al”” described a 13-year-old patient who received a LR graft while serologically active, who maintained good function for 1.5 years on a regimen of prednisolone, mizoribin, and cyclophosphamide. With the development of proteinuria, rising anti-DNA titer, and falling complement levels, allograft biopsy was done and revealed positive immunofluorescence (IgG, IgM, IgA, Clq, and C3) and electrondense subendothelial deposits. These findings were similar to the histological changes found in the original biopsy done for lupus nephritis. Fernandez et als7 presented a case (in addition to those in the original report by Roth et a12”) of recurrence at 11 months in a patient with a CAD transplant treated with CsA and methylprednisolone. Azathioprine was added at the onset of proteinuria, and allograft biopsy at 2 years showed membranous GN, which transformed to DPGN (similar to the native kidney lesion) on subsequent biopsy. Finally, two possible cases of lupus nephritis recurrence deserve mention. Fox et al”* reported a case of de novo lupus nephritis with clinical and serological activity developing 8 months after CAD allograft for idiopathic end-stage GN (despite treatment with CsA). On biopsy, the allograft had IgG,
AND KLIPPEL
IgA, IgM, and C3 deposits, as well as subendothelial and mesangial deposits on EM. Lauzurica et al”” reported the case of a man with lupus membranous nephropathy, who underwent CAD transplantation while serologies were abnormal and complement low. Immunosuppression consisted of preednisone, CsA, AZA, and antithymocyte globulin. An allograft biopsy was performed for proteinuria at 2.5 months post-transplantation, and showed membranous GN; no immunofluorescence or EM studies were reported.
CONCLUSION In this review we have tried to summarize the literature on end-stage lupus nephropathy. Several conclusions seem reasonable. First, the majority of studies support the tendency toward decreased clinical and serological lupus activity following ESRD. As would be expected, the need for immunosuppression or high-dose prednisone decreased in this period. Several theories have been presented to explain the mechanism responsible for the :reduction in clinical and serologic abnormalities, but little proof has been offered. The theories include depressed cellular and humoral immunity, as a result of uremia ‘J”J lack of renally produced mediators, l1 removal Af lupus factors by dialysis itself, “J” or a natural end point in SLE discernable only by prolongation of life past ESRD.‘“,‘“,‘” Survival of lupus patients on dialysis does not appear significantly different from that of non-SLE dialysis patients, and is perhaps better than for some of the other rheumatic diseases. In SLE dialysis patients, the major cause of death is infection, with SLE activity per se accounting for a minority of deaths. With regard to transplantation, the majority of studies indicate no difference between SLEland nonSLE patients on graft survival. Like non-SLE patients, lupus patients have slightly better loutcomes with LR rather than CAD grafts; they do as well as controls with CsA-containing regimens, but may do somewhat worse with AZA-only regimens. In some studies transplantation during acute exacerbation of SLE led to poor outcome, and based on this it has been recommended that transplantation follow at least 3 months of dialysis. Finally, lupus can recur in transplanted allografts, and is often of the same histologic or immunofluorescent type as in the original kidney, but it is a rare event.
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