Clinical outcomes of systemic lupus erythematosus patients undergoing continuous ambulatory peritoneal dialysis

Yui Pong Siu1, Kay Tai Leung1, Matthew Ka Hang Tong1, Tze Hoi Kwan1 and Chi Chiu Mok2

Divisions of 1 Nephrology and 2 Rheumatology, Department of Medicine, Tuen Mun Hospital, Hong Kong, China

Correspondence and offprint requests to: Dr Matthew Ka Hang Tong, Department of Medicine, Tuen Mun Hospital, Tuen Mun, Hong Kong, China. Email: khmtong{at}netvigator.com



   Abstract
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Objectives. The purpose of this study was to evaluate the outcome of systemic lupus erythematosus (SLE) patients on continuous ambulatory peritoneal dialysis (CAPD).

Methods. Eighteen SLE patients who had been undergoing CAPD for at least 3 months in our unit were compared with 36 other age- and gender-matched non-diabetic CAPD patients with an underlying primary chronic glomerulonephritis (CGn). The clinical outcome, infective complications, lupus activities, biochemical parameters, haemoglobin level and the use of erythropoietin were reviewed.

Results. The duration of dialysis of the two studied groups was not different, with a mean of 35.4 months for the SLE group and 36.7 months for the CGn group. Before dialysis, SLE patients had a significantly lower albumin level (30.4±6.6 vs 35.4±5.59 g/dl, P<0.01), while the mean haemoglobin levels of the two groups were similar (8.5±1.8 g/dl for SLE vs 9.0±1.9 g/dl for the control group). However, the weekly dose of erythropoietin (EPO) used was significantly higher in the SLE group (6000 vs 3818 U/week, P<0.01) to maintain a similar haemoglobin level during dialysis. Regarding the infective complications, the SLE group had a higher peritonitis rate (5.7 episodes/100 patient-months vs 2.4 episodes/100 patient-months, P<0.05), and an increase in the non catheter related infection rate (6.67 episodes/100 patient-months vs 1.1 episodes/100 patient-months, P<0.001). However, no significant difference could be demonstrated in the Tenckhoff catheter exit site infection rate (2 episodes/100 vs 1.7 episode/100 patient-months). The number of patients who received a kidney transplant or required a change of mode to haemodialysis was similar among the two groups. Seven patients died during the follow-up period, and the overall mortality rate was much higher in the SLE group than in the control group (0.83/100 vs 0.15/100 patient-months, P<0.05).

Conclusions. SLE patients on CAPD have a significantly lower pre-dialysis serum albumin level and use a higher dose of Epo to achieve a comparable haemoglobin level than other non-diabetic CGn CAPD patients. They also have a poorer prognosis in terms of infective complications and mortality rate.

Keywords: continuous ambulatory peritoneal dialysis; end-stage renal disease; mortality; systemic lupus erythematosus



   Introduction
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Nephritis remains one of the most important complications in systemic lupus erythematosus (SLE) patients. Up to 20% of lupus nephritis patients develop end-stage renal disease (ESRD) within 10 years [1]. SLE patients with ESRD may be at increased risk from dialysis complications because these patients usually have a history of pre-dialysis exposure to steroid or cytotoxic drugs that would subject them to a number of side effects and complications. Albeit reaching ESRD, some patients may still have extra-renal lupus flares which require additional immunosuppressants or repeated courses of steriod for control, and this may increase the susceptibility to infection. Furthermore, SLE has been shown to be associated with premature atherosclerosis, which may predispose SLE continuous ambulatory dialysis (CAPD) patients to early coronary artery diseases [2]. Consequently, patients on CAPD, who are known to have increased risk of cardiovascular complications, are endangered further by the concomitant lupus disease.

All these adverse risk factors may impact significantly on the outcomes of SLE patients on CAPD in terms of complication rates and mortality. However, data regarding this aspect are scarce. Huang et al. have reported poorer outcomes of SLE patients compared with other patients on CAPD [3]. However, their controls consisted of a group of CAPD patients with heterogenous underlying renal diseases and variable prognosis, including congenital urinary tract anomaly, chronic glomerulonephritis (CGn), interstitial nephritis and hypertension, thus making comparison difficult. Among the CAPD population, primary CGn patients in particular share similarity with lupus nephritis patients in having a history of significant proteinuria and exposure to steroids or other cytotoxic drugs. Hence, we conducted a case–control study comparing the complications and clinical outcomes of CAPD patients with ESRD secondary to lupus nephritis with a group of non-diabetic patients with primary CGn other than SLE.



   Methods
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
The study design was a case–control study matching age, gender and race. Between January 1995 and December 2003, 20 patients with SLE, diagnosed with at least four of the American Rheumatism Association criteria, complicated by lupus nephritis resulting in ESRD and who had undergone CAPD for at least 3 months, were identified. Two patients were excluded from the study because of incomplete medical records, and thus 18 patients were included for analysis. For the control group, all non-diabetic patients on CAPD with a diagnosis of biopsy-proven primary CGn within the same recruitment period as the SLE group were reviewed. A total of 96 patients were identified and, after matching gender and age range, 72 patients were included. We then randomly selected every other patient from the list, and thus 36 patients were chosen as controls.

We made comparisons on five aspects between these two groups, as well as making serial comparisons before and after the initiation of dialysis within the same group: (i) biochemical parameters; (ii) the haemoglobin level, blood transfusion requirements and the use of recombinant erythropoietin (Epo); (iii) lupus disease activities (SLE group); (iv) infectious complications; and (v) the clinical outcome. We classified the clinical outcomes into one of the following four categories: (i) kidney transplantation; (ii) switched over to haemodialysis; (iii) continued on peritoneal dialysis; and (iv) all-cause mortality. The time to achieve these clinical end-points was also analysed.

The biochemical parameters examined were the serum creatinine, albumin, calcium and phosphate levels, fasting total cholesterol, high-density and low-density lipoproteins and the triglyceride levels. The lupus disease activities were monitored serologically by means of the complement C3 and C4 levels, and any clinical symptoms and signs of lupus disease activity were also reviewed. The anti-double-stranded DNA titre was not available in patients recruited before 2000; this can cause comparison bias and therefore this titre level was not included in the present study. We analysed the total units of blood transfused from the start of dialysis till reaching one of the end-points defined above; the use and dosage of Epo received, and the serum ferritin levels were also monitored regularly. All blood results were retrieved and analysed at two time points: the first set of data were obtained at the start of CAPD, and the second set of data were the latest values before reaching clinical end-points. For those who remained on peritoneal dialysis, the second set of data was taken as the latest values available.

For the infectious complications, the incidences of peritonitis, Tenckhoff catheter exit site infection (ESI) and all other infections were recorded. The diagnosis of peritonitis was made clinically in accordance with the International Society of Peritoneal Dialysis guidelines, and the ESI was defined as the presence of erythema, swelling and discharges around the catheter exit area or a positive bacterial culture.

Statistical analysis
Statistical analysis was performed by Statistical Packages for Social Sciences (SPSS version 11.0 for Windows). All continuous variables were expressed as mean±SD unless otherwise stated. Unpaired continuous variables were compared by Student t-test or Mann–Whitney U-test, and paired continuous variables were compared by Student t-test or Wilcoxon test, where appropriate. Categorical data were compared by {chi}2 test. A P-value of <0.05 was considered statistically significant. All tests were two-tailed.



   Results
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Demographic data
Eighteen Chinese SLE patients on CAPD using the Baxter Ultrabag® system were studied. There was a female predominance (72%) with a mean age of 40.8±10.3 years. For the 36 race- and gender-matched CGn controls, the mean age was 43.3±7.3 years (P = 0.57) (Table 1). In the SLE group, there were 11 (61%) WHO class IV lupus nephritis patients and one class V nephritis patient, and the remaining six patients did not have a renal biopsy. Two SLE patients had been withdrawn from all immunosuppressive drugs before the initiation of CAPD. The remaining 16 patients were maintained on prednisolone with a dose ranging from 1 to 10 mg/day, two patients were on concomitant cyclosporin and one patient was on azathioprine. For the control group, all patients had a biopsy-proven diagnosis of primary CGn, including IgA nephropathy (47%), focal segmental glomerulosclerosis (19%), mesangiocapillary (11%), mesangioproliferative (9%) and membranous glomerulonephritis (14%). Two patients were on maintenance low dose prednisolone (5 mg/day) at the initiation of dialysis.


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Table 1. Baseline demographic data of the SLE group and CGn group

 
Biochemical parameters
The SLE group had a significantly lower pre-dialysis albumin level than the CGn group (30.4±6.6 vs 35.4±5.59 g/dl, P<0.01), while there was no difference between the two groups in terms of the post-dialysis albumin levels. For the other biochemical parameters including the serum creatinine level, calcium and phosphate values as well as the lipid profile (total cholesterol, low-density lipoprotein, high-density lipoprotein and triglyceride levels), there were no statistical differences before and after the initiation of dialysis of both groups. The C-reactive protein level, residual renal function, dialysis adequacy and the nutritional status were also similar between the SLE and the CGn group (Table 2).


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Table 2. Comparison of serum biochemical parameters between the SLE and CGn group before and after the initiation of dialysis

 
Lupus activities, haemoglobin level, blood transfusion and EPO use
Four patients (22%) had evidence of active lupus activity manifested as haematological involvement during CAPD with either pancytopenia or thrombocytopenia, two patients (11%) developed vascular complications with retinal vasculitis, two patients (11%) had evidence of active serositis and one patient was complicated by transverse myelitis attributed to systemic lupus flare. Serologically, the complement C3 and C4 levels did not show any significant change before and after the initiation of dialysis (P = 0.1 and 0.69, respectively, Table 3).


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Table 3. Comparison of lupus activities before and after the initiation of dialysis, and the haemoglobin level, blood transfusion and Epo use between the SLE group and CGn group

 
The mean haemoglobin levels were also similar among the SLE and the control groups (8.52±1.78 vs 9.0±1.93 g/dl). The SLE CAPD patients had a trend of requiring more frequent blood transfusions than the CGn CAPD patients (21 units vs 14 units per 100 patient-months), but this did not reach statistical significance. The number of patients that were put on Epo was similar in both groups, but the SLE patients received a significantly higher mean dose of Epo (6000±2309 U/week in the SLE group vs 3818± 603 U/week in the CGn group, P<0.01, Table 3).

Infectious complications
The SLE CAPD patients had a peritonitis rate of one episode per 17.5 patient-months, which was significantly higher than the CGn group (one episode per 41.7 patient-months, P<0.05), but no difference could be demonstrated in the Tenckhoff catheter ESI rate between the two groups (one episode in 50 patient-months in the SLE group vs one episode in 59 patient-months in the CGn group). Analysing the risks of other non-catheter-related infections, the incidence of infectious complications that resulted in hospitalizations was 6-fold higher in the SLE group than in the controls (6.67 episodes vs 1.1 episodes per 100 patient-months, P<0.001). Most infections were respiratory; other infections involved the musculoskeletal system (cellulitis, subcutaneous abscesses and osteomyelitis), the gastrointestinal system (gastroenteritis), the heart (endocarditis and pericarditis) and the genitourinary system (urinary tract infection, epididymo-orchitis and vaginitis) (Table 4).


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Table 4. Total number of episodes and type of infective complications

 
The risk factors for peritonitis and total infections were analysed using logistic regression after we adjusted for age, gender, primary renal disease as SLE and non-SLE, the use of immunosuppressive agents, haemoglobin level and the albumin level before and after the start of dialysis. We found that the serum albumin levels before and after the initiation of dialysis were independent risk factors for CAPD peritonitis (P = 0.005 and P = 0.011, respectively), whereas for all-cause non-catheter-related infectious complications, the pre-dialysis albumin level was the only independent predictor (P = 0.012).

Renal outcomes, transplantation and mortality
In the SLE group, five patients (28%) received a kidney transplant during the study period, two patients were switched over to haemodialysis (11%), while six patients continued with CAPD (33%). For the CGn group, 15 patients were transplanted (42%), two patients changed over to haemodialysis (6%) and 17 patients remained on CAPD (46%). The mean duration of dialysis till reaching any one of the above-defined end-points in the SLE group, excluding those who remained on CAPD, was 32.6±20.7 months, which was comparable with the CGn group (25±16.1 months, P = 0.25).

A subgroup analysis of the duration till renal transplantation showed that the SLE group had a waiting time of 24.8 months, which was also similar to the CGn group that had a mean waiting time of 19.8 months (P = 0.65). However, the SLE patients had a much higher overall mortality rate compared with the patients with CGn (0.83/100 vs 0.15/100 patient-months, P<0.05). Five patients in the SLE group died during the study period. Besides one fungal peritonitis, the most frequent cause of death was cardiovascular events, including three acute myocardial infarctions and one massive cerebral infarction. For the CGn group, there were two mortalities: one patient died of cerebrovascular accident and the other died of miliary tuberculosis.



   Discussion
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Despite the introduction of new immunosuppressive agents and regimens, 11% of SLE patients suffering from nephritis still require renal replacement therapy within 8 years of diagnosis [4]. Alterations of SLE disease activity in patients who have progressed to ESRD have been studied extensively. Many investigators have observed that SLE activities do not remain quiescent in ESRD or dialysis patients. Lupus flares or active disease were reported in up to 54–67% of patients after the initiation of dialysis in several series [5–7], and some investigators have even described an increased activity in dialysis patients [8,9]. In our study, 50% (nine out of 18) of our cases continued to show persistent disease activity clinically after the initiation of peritoneal dialysis. In concordance with previous reports, we found no significant change in the serological activity (complements C3 and C4) before and after starting dialysis. It is difficult to predict the course of lupus disease in SLE dialysis patients, as active disease pre-dialysis does not necessarily predict an increased lupus activity after the initiation of dialysis; however, it has been shown that patients with a history of serositis, vasculitis or seizure have a trend towards elevated lupus disease activity [7].

The haemoglobin levels of our patients in the present study were lower than recommended by international guidelines because of the financial constraints on the use of Epo in our locality, but there was no difference in the haemoglobin level between the SLE and the control groups. Concerning the use of Epo, the weekly dose of Epo used in the SLE group was significantly higher than in the CGn group. This higher Epo dose used may be related to the persistence of lupus activity in the SLE CAPD patients, resulting in increased peripheral red cell destruction or marrow suppression with red cell asplasia [13]. Moreover, SLE patients are apt to produce autoantibodies, and SLE CAPD patients may have circulating anti-Epo antibodies, thus inducing a state of partial Epo resistance, and this may be another reason for a higher Epo requirement in these patients [6].

Patients on dialysis are known to have an increased susceptibility to infections, probably related to the impairment of polymorphonuclear leucocyte phagocytosis, and this will be aggravated further in immunocompromised subjects or patients receiving immunosuppressive drugs [9]. There is no consensus on the optimal immunosuppressive protocol in SLE dialysis patients. In common practice, patients are usually maintained on low dose steroid with or without concomitant cytotoxic drugs such as azathioprine, or cyclosporin. It has been shown that steroid-treated dialysis patients are associated with a less favourable nutritional condition, lower serum albumin level and body mass index, and a higher C-reactive protein [10], and immunosuppressed CAPD patients have also been demonstrated to experience more peritonitis episodes, more frequent hospital admissions and more days off CAPD, and required more laparotomies to remove infected Tenckhoff catheters [11].

In our SLE CAPD patients, 89% (16 out of 18) were maintained on some form of immunosuppressive therapy. They had a lower pre-dialysis albumin level together with a significantly higher peritonitis rate in comparison with the CGn group (2.5 times more episodes per 100 patient-months). When we compared the overall non-catheter-related infectious complications, the SLE group had an incidence rate nearly 6-fold higher than the CGn patients. Most of the serious non-catheter-related infections involved the respiratory tract, and infections of the skin and soft tissue as well as the gastrointestinal tract were also common. Although we could not demonstrate SLE to be an independent risk factor for infection in CAPD patients, SLE patients did have a significantly lower pre-dialysis albumin level (P = 0.01), which we identified to be the only independent predictor. Therefore, SLE may cause increased infection by inducing a poorer nutritional state as a result of chronic inflammation.

We found an increased mortality in SLE patients undergoing CAPD, around five times higher than in patients with an underlying renal pathology of primary CGn. This is in concordance with previous literature which reported a 4.3 times increased risk of death and a 5-year survival rate of 58–73% for SLE dialysis patients in contrast to a 95% 5-year survival in non-SLE patients on dialysis [12,13]. Previous studies have attributed this increased mortality to infection. However, in our present study, only one of the five deaths was due to sepsis, while the remaining four were due to cardiovascular events. SLE has been shown to induce premature atherosclerosis because of its chronic inflammatory, immune complex- and autoantibody-inducing properties [2]. Unfortunately, the antiphospholipid antibody status was not available in our SLE patients to determine its role in the development of cardiovascular complications. The prevalence of antiphospholipid antibodies in SLE patients undergoing CAPD is not known. In a study performed in non-SLE haemodialysis patients, it has been shown that there is an ~30% prevalence of IgG-anticardiolipin antibodies and 22–30% of lupus anticoagulant [14], and we may expect even higher values in SLE dialysis patients. Hence, besides the atherogenic inflammatory effects of SLE, the presence of antiphospholipid antibodies may also play a significant role in the increased incidence of cardiovascular complications in SLE dialysis patients; however, further studies are required for clarification.

It has been reported previously that SLE patients on CAPD have a higher incidence of technique failure and a reduced chance of receiving a kidney transplant [3]. However, in our study, the number of SLE CAPD patients with technique failure requiring a change of mode to haemodialysis, or who received a kidney transplant was similar to the controls. Also, the waiting time for SLE CAPD patients to receive a kidney transplant was not different from that of CGn patients. This discrepancy in the results is probably related to the difference in the selection criteria of the control groups. We have recruited a more homogenous group of patients as controls than in previous series, with underlying idiopathic CGn as the cause of ESRD. Many of these patients had a history of significant proteinuria and of steroid or cytotoxic drug exposure, thus more closely resembling patients with lupus nephritis. Therefore, based on our present data, we concluded that patients on CAPD due to SLE-related glomerulonephritis are not inferior to patients on dialysis due to CGn in terms of CAPD technique survival or the chance of having a kidney transplant.

In conclusion, a significant proportion of lupus ESRD patients still have clinically persistent lupus disease activity after the initiation of dialysis but, despite this, they should not be precluded from CAPD as a group; rather, strategies to minimize the infective complications should be employed. The use of immunosuppressants should be minimized and steroid withdrawn if there is no evidence of any extrarenal lupus activities. However, as SLE CAPD patients who have a low pre-dialysis serum albumin level are at an increased risk of CAPD peritonitis and all-cause infections, and associated with a high mortality, we would advise haemodialysis treatment rather than CAPD in this particular subgroup, at least until the patients have achieved a normalization of their inflammatory and nutritional parameters. We have also demonstrated that SLE CAPD patients have a 5-fold increase in all-cause mortality compared with patients on CAPD secondary to CGn, mostly due to cardiovascular events; therefore, more intense modification of traditional cardiovascular risk factors in SLE patients undergoing CAPD is crucial.

Conflict of interest statement. None declared.



   References
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 

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Received for publication: 19. 4.05
Accepted in revised form: 14. 7.05





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