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Saudi Journal of Kidney Diseases and Transplantation
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ORIGINAL ARTICLE  
Year : 2011  |  Volume : 22  |  Issue : 5  |  Page : 935-940
Comparison of high and low dose of cyclophosphamide in lupus nephritis patients: A long-term randomized controlled trial


1 Department of Medicine, King Khalid University Hospital, Kingdom of Saudi Arabia
2 Department of Family and Community Medicine, King Khalid University Hospital, Kingdom of Saudi Arabia
3 Department of Physiology, King Khalid University Hospital, Kingdom of Saudi Arabia

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Date of Web Publication6-Sep-2011
 

   Abstract 

To evaluate the outcome of low doses of cyclophosphamide (Cyclo) therapy in lupus nephritis (LN) patients, we studied 117 biopsy-proven, de novo LN WHO class IV patients double-blinded and randomized in December 1997 to receive Cyclo in different doses; Group I (n=73) received Cyclo 10 mg/kg monthly for six months then every two months for 12 months. Group II (n=44) received Cyclo 5 mg/kg monthly for six months then every two months for 36 months. The patients were followed-up till January 2007. Six months post-induction values for creatinine clearance were significantly higher in Group I (67.7 ± 28.6 mL/min) compared with Group II (55.1 ± 30.1 mL/min), P = 0.026. Serum C4 and ANA were not significantly different between the groups (P > 0.05). At the mean follow-up of 6.77 ± 3.3 years, the mean creatinine clearance was 44.74 ± 31.7 mL/min in Group I vs. 49.3 ± 38.8 in Group II. Urinary protein was 1.65 ± 1.8 g/dL in Group I vs. 1.02 ± 1.01 in Group II (P = 0.03). The survival curve showed that kidney survival overtime was comparable in both groups (P = 0.2). Complete remission was observed in 25 (34.2%) patients in Group I vs. 11 (25%) in Group II (P = 0.288), while partial remission was similar in both groups; 43 (58.9%) patients in Group I vs. 26 (59%) patients in Group II. End-stage renal disease was observed in 10 (13.7%) patients in Group I vs. 9 (20.4%) patients in Group II (P = 0.359). Side-effects were more frequent in Group I patients than in Group II patients; gonadal toxicity and malignancy were lower in Group II patients (P = 0.0000). Moreover, different infections occurred in 23 (31.3%) patients vs. six (13.6%), digital infarcts occurred in 1.35% vs. 0%, diabetes in 4.1% vs. 2.27%, and vasculitis in 4.1% vs. 2.27% in Group I vs. Group II, respectively. Sustained amenorrhea without pregnancy was observed in both groups; however, significantly more in Group I patients, P ≤ 0.05. We conclude that low-dose Cyclo therapy is sufficiently effective for WHO class IV LN patients with lower side-effects compared with standard dose.

How to cite this article:
Mitwalli AH, Al Wakeel JS, Hurraib S, Aisha A, Al Suwaida A, Alam A, Hammad D, Sulimani F, Memon NA, Askar A, Al Tuwaijri A, Qudsi A. Comparison of high and low dose of cyclophosphamide in lupus nephritis patients: A long-term randomized controlled trial. Saudi J Kidney Dis Transpl 2011;22:935-40

How to cite this URL:
Mitwalli AH, Al Wakeel JS, Hurraib S, Aisha A, Al Suwaida A, Alam A, Hammad D, Sulimani F, Memon NA, Askar A, Al Tuwaijri A, Qudsi A. Comparison of high and low dose of cyclophosphamide in lupus nephritis patients: A long-term randomized controlled trial. Saudi J Kidney Dis Transpl [serial online] 2011 [cited 2020 Jul 12];22:935-40. Available from: http://www.sjkdt.org/text.asp?2011/22/5/935/84574

   Introduction Top


Lupus nephritis (LN) is a quite frequent and most devastating complication of systemic lupus with wide geographical, racial variation and extreme heterogencity. Diffuse proliferate forms (WHO class IV) have low five-year renal (80-86%) and patient survival (67-80%). [1],[2],[3],[4]

The outcome and survival rate of patients with LN has improved due to advancement in the immunosuppressive therapies and better management of complications. [5] However, yet, long-term better outcome and purposeful qualities of life are difficult challenges. Cyclophosphamide (Cyclo) is still the gold standard for induction therapy; in the USA, the controlled studies of the National Institute of Health (NIH) has established Cyclo as the most efficacious therapy for LN. [6],[7],[8] The Cyclo cumulative toxicity including neoplastic potentials, gonadal toxicity, and infertility, [9] create long-term medical and social concerns, impeding the quality of life in LN patients and requiring research for alternative therapies. Sequential therapies with Cyclo have promising responses in LN patients. [10] The long-term impact of Cyclo sequential therapy is not well defined or investigated. Lower dose at a given time and limited exposure to Cyclo may achieve remission and preserve renal function.

In the present study, we evaluate the efficacy and safety of two different dose regimens of Cyclo on the survival and kidney function of patients with LN.


   Patients and Methods Top


The present study is a single-center, randomized, double-blinded, prospective, controlled trial conducted from December 1997 to January 2007. One hundred and seventeen kidney biopsy proven LN adult Saudi patients (WHO class IV) newly diagnosed (de novo) were recruited from the nephrology clinic at King Khalid University Hospital, Riyadh (KKUH), Saudi Arabia. The patients signed written consents and the study was approved by the local Ethical Committee.

Immunosuppressive protocol

Induction therapy: Cyclo was administered intravenously. The patients were randomized in two groups: Group I received an i.v. pulse of Cyclo 10 mg/kg body weight monthly for six months, then every two months for another 12 months (total 12 doses) in addition to oral prednisolone 1 mg/kg once daily for four weeks tapered to 0.2 mg/kg on alternate days for a period of 24 months, and Group II patients received i.v. pulse Cyclo 5 mg/kg body weight monthly for six months, then every two months for another 36 months (total 24 doses), and steroid therapy was administered as in Group I.

Maintenance therapy: Besides prednisolone, Hydroxychloroquine (Plequinal) was continued 200 mg daily orally and azathioprine 1 mg/kg body weight/day for 24 months. Azathioprine was withdrawn in case the patients developed any intolerable side-effects to the drug.

Measured parameters: The following parameters were measured monthly during induction therapy and quarterly thereafter: serum creatinine, urea, albumin, cholesterol, triglycerides (TG), anti-nuclear antibodies (ANA), anti-double strands DNA, complements (C3 and C4), and hematological indices, in addition to 24-hour urinary protein and complete urine analysis.

End points: The primary end points were patient's survival and kidney survival, persistent doubling of serum creatinine levels for six months, and/or unacceptable side-effects of the treatment.

Complete remission: Was defined if urinary protein excretion <0.3 g per 24 hours was accomplished with normal serum albumin levels and/or an improvement in the baseline serum creatinine levels of >50%.

Partial remission: Was defined as an improvement of >50% from baseline protienuria, serum albumin levels of at least 30 g/L, and serum creatinine level of ≥25% from baseline or stable serum creatinine level within 25% of the baseline.

The treatment responses were defined and evaluated by standard methods as described on other studies. [5],[6],[7],[8]


   Statistical Analysis Top


The analysis was performed using BMDP and SPSS Statistical Software (version 10.0 from windows). Survival analysis methods included the Kaplan Meiers survival used to calculate the survival probabilities, and Log rank test used to compare the two survival surveys. Chi-square test and analysis of variance were used wherever appropriate in the analysis of variables. A P-value of <0.05 was considered as statistically significant.


   Results Top


[Table 1] shows the basic clinical and laboratory characteristics of the study patients in both groups, which were not significantly different. In Group I (n=73): 61 (83.6%) patients were females, and 39 (88.6%) in group II (n=44). The mean age was 36.4 ± 12.8 vs. 30.3 ± 10.4 years in group I and II, respectively.
Table 1: Patient's demographic and laboratory results (Before induction phase).

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[Table 2] shows the survival of the patients and response to therapy. After induction period of six months, more than 90% patients responded to the treatment 67 (91.78%) in group I and 38 (87%) in group II, (P = 0.23). Complete remission was observed in 25 (34.3%) patients in group I vs 11 (25%) patients in group II (P = 0.285). Partial remission was observed in 42 (58.9%) patients in Group I vs. 26 (59%) in Group II (P = 0.9). Kidney survival as well as patient survival was 100% in both groups at the end of the induction period. The reduction in urinary protein was observed in 25 (34.3%) patients in Group I compared with II (25%) patients in Group II (P = 0.29). The mean 24hour urinary protein was 1.2 ± 1.1 g/d in Group I vs. 0.91 ± 1.09 in Group II (P = 0.15). Serum creatinine was improved in 24 (32.87%) patients in Group I vs. 20 (45.4%) patients in Group II (P = 0.178). Serum creatinine was stable in 44 (61.6%) patients in Group I vs. 16 (36.3%) patients in Group II (P = 0.007), while deterioration of serum creatinine was found in five (6.85%) patients in Group I vs. seven (15.9%) patients in Group II (P = 0.1482). The mean serum creatinine was 95.5 ± 43.7 μmol/L (range 249) in Group I vs. 126 ± 102 μmol/L (range 453) in Group II (P = 0.04) [Table 3].
Table 2: Number and percentage of patients with various laboratory results after the induction phase.

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Table 3: Comparison of mean (±) value of urinary protein. Creatinine clearance and serum creatinine of
Group I and Group II at baseline. After induction and last follow-up.


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Patients' follow-up

The follow-up period was 6.77 ± 3.3 years for both groups. The mean creatinine clearance (mL/min) was 44.8 ± 31.8 in Group I vs. 49.33 ± 38.7 in Group II (P = 0.33) [Table 2]. A total of 19 (43%) patients in Group II had improvement in their creatinine clearance vs. 23 (31%) patients in Group I (P = 0.30). A statistically significant improvement in the 24-hour urinary protein excretion was observed in Group II patients as compared with Group I. The mean urinary protein (g/d) was 1.65 ± 1.8 in Group I vs. 1.02 ± 1.001 in Group II (P = 0.03) [Table 3]. Improvement in 24-hour urinary protein was found in 26/44 (59%) in Group II vs. 39/73 (53.4%) patients in Group I (P = 0.32). Both groups revealed similar improvement in proteinuria, kidney function, and serology. Moreover, the Kaplan Meier survival curve showed that kidney survival was comparable in both groups with the log rank test (P = 0.27).

[Table 4] shows the adverse effects to the treatment with Cyclo. None of the patients in both groups withdrew from either regimen due to threatening side-effects of the drug. Gonadal toxicity and malignancy were significantly lower in Group II patients (P = 0.006). Kaposi sarcoma, thyroid malignancy, and adenomatous uterine hyperplasia were noted in four patients separately in Group I compared with none in Group II (P = 0.04). Sustained amenorrhea without pregnancy was observed in both groups; however, it was significantly more in Group I patients P ≤0.05 [Table 4]. One viable fetus was born in Group I (out of 61 females), while three viable children were born in Group II (out of 39 females). Kaplan Meier survival curves revealed an insignificant difference in patient's survival (P = 0.56).
Table 4: Summary of the side-effects (%) of Cyclo therapy in Group I and Group II.

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   Discussion Top


National Health Institute-controlled studies have established Cyclo as the most effective therapy for proliferate LN [8],[11] in agreement with previous studies, however, at the cost of substantial toxicity and ovarian failure. [6],[8] In order to minimize the adverse effects and gonadal toxicity, seeking an alternative regimen is prudent.

The desired primary objective of induction treatment for LN is to halt the immune-mediated inflammation in order to minimize the loss of nephrons and preserve the kidney function. Both the low- and high-dose Cyclo treatment regimens were effective in providing remission. Comparable to previous studies, 34.5% complete remission and 58.9% partial remission were observed in Group I patients receiving 10 mg/m² Cyclo (Group I). Although the magnitude of response was greater in Group I treated with higher dose of Cyclo than in Group II, yet the percentage of the patients attaining partial and complete remission were almost equal after the induction phase, and the inter-group difference was statistically insignificant. Both regimens were equally effective in improving the hypocomplimentemia and reducing the titers of ANA and anti DsDNA toward normal. Similar improvement in the serology tests was reported by Mok et al in 2006. [15]

For the markers of kidney function, proteinuria was reduced in 34.3% patients in Group I, which was similar to what was reported in previous studies, [15],[16] and the inter-group difference was statistically insignificant, including the mean 24-hour urinary protein attained. The mean serum creatinine was similar in the baseline, induction and follow-up in both groups.

On the other hand, the side-effects were encountered more in the group treated with the higher Cyclo regimen; one patient developed treatment-induced diabetes mellitus vs. none in Group II. Furthermore, the incidence of gonadal toxicity and malignancy was higher, as also the infective episodes in Group I patients.

Morbidity and mortality were similar in both groups of study patients, including hospital deaths. Similarly, previous authors have also found comparable survival percentages in LN patients. [17],[18]

We conclude that both high and low Cyclo regimens for therapy of LN patients do not differ significantly in their efficacy of producing remissions and kidney and patient survival. However, the reduced dose Cyclo resulted in relatively less long-term toxicity than the high dose. We believe that low-dose Cyclo can be an alternative regimen at least in young women where reproductive considerations rank high.


   Acknowledgment Top


The authors would like to thank Dr. Shaffi Ahmed Sheik for his help in this study.

 
   References Top

1.Boumpas DT, Austin HA, Vaughn EM, et al. Controlled trial of pulse methyl prednisolone versus two regimens of pulse cyclophosphamide in sever lupus nephritis. Lancet 1992; 340:741-5.  Back to cited text no. 1
[PUBMED]    
2.Illei GG. Takada K, Parkin D, et al. Renal flares are more common in patients with severe proliferative lupus nephritis treated with pulse immunosuppressive therapy. Arthritis Rheum 2002;46:995-1002.  Back to cited text no. 2
    
3.Levy As, Lan SP, Corwin HL, et al. Progression and regression of renal disease in the lupus nephritis collaborative study. Ann Intern Med 1992;116:114-23.  Back to cited text no. 3
    
4.Appel GB, Cohen DJ, Pirani CL, et al. Longterm follow-up of lupus nephritis: a study based on the WHO classification. Am J Med 1987; 83:877-85.  Back to cited text no. 4
[PUBMED]  [FULLTEXT]  
5.Chan TM, Tse KC, Tang CS, Lai KN, Li FK. Long term outcome of patients with diffuse proliferative lupus nephritis treated with prednisolone and oral cyclophosphamide followed by azathioprine. Lupus 2005;14:265-72.  Back to cited text no. 5
[PUBMED]  [FULLTEXT]  
6.Boumpas DT, Austin HA, Vaughn EM, et al. Risk of sustained amenorrhea in systemic lupus erythematosus receiving intermittent pulse cyclophosphamide therapy. Ann Intern Med 1993;119:366-9.  Back to cited text no. 6
    
7.Gourley MF, Austin HA, Scott D, et al. Methyl prednisolone and cyclophosphamide alone or in combination, in patients with lupus nephritis: a randomized, controlled trial. Ann Intern Med 1996;125:549-57.  Back to cited text no. 7
[PUBMED]    
8.Conteras G, Tozman E, Nahar N, et al. Maintenance therapies for proliferative lupus nephritis: mycophenolate mofetil, azathioprine and intravenous cyclophosphamide. Lupus 2005; 14:S33-8.  Back to cited text no. 8
    
9.Illie GG, Austin HA, Crane M, et al. Combination therapy with pulse cyclophosphamide plus pulse methyl prednisolone improves long tern renal outcome without adding toxity in patients with lupus nephritis. Ann Intern Med 2001;135(4):248-57.  Back to cited text no. 9
    
10.Kaplan EL, Meier P. Non parametic estimation from incomplete observations. J Am Stat Assoc 1958;53:457-81  Back to cited text no. 10
    
11.Flank RC, Robert MA, Stripoli GF, et al. Treatment of diffuse proliferative lupus nephritis: a meta-analysis of randomized controlled trials. Am J Kidney Dis 2004;43(2):197-208.  Back to cited text no. 11
    
12.Mok CC, Ying KY, Ng WL, et al. Long-term outcome of diffuse proliferative lupus glomerulonephritis treated with cyclophosphamide. Am J Kidney Dis 2006;119(4):355e 25-33.  Back to cited text no. 12
    
13.Dooly MA, Hogan S, Jennet C, et al. Cyclophosphamide therapy for lupus nephritis: poor renal survival in Black Americans. Glomerular disease collaborative network. Kidney Int 1997;51(4):1188-95.  Back to cited text no. 13
    
14.Ong LM, Hooi LS, Lim TO, et al. Randomize control trial of pulse intravenous cyclophosphamide versus mycophenolate mofetil in the induction therapy of proliferative lupus nephritis. Nephrology (Carlton) 2005;10(5):504-10.  Back to cited text no. 14
    
15.Bansal VK, Beto GA. Treatment of lupus nephritis: a meta-analysis of clinical trials. Am J Kidney Dis 1997;29:193-9.  Back to cited text no. 15
    
16.Chan TM, Li FK, Wong KL, et al. Sequential therapies for diffuse proliferative and membranous lupus nephritis: cyclophosphamide and prednisolone followed by azathioprine and prednisolone. Nephron 1995;81(3):321-7.  Back to cited text no. 16
    
17.Petrovic R, Stojanovic R, Nvicic-Sasis R, et al. Comparison of various cyclophosphamide treatment regimens on the course and outcome of lupus nephritis. Srp Arch Celok Lek 2002; 130 Suppl 3:19-25.  Back to cited text no. 17
    
18.Houssiau FA. Vascocelos C, Cruz D, et al. Immunosuppressive therapy in lupus nephritis: Euro-Lupus nephritis trial. A randomized trial of low dose versus high dose intravenous cyclophosphamide. Arth Rheum 2002;46(8): 2121-31  Back to cited text no. 18
    

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Correspondence Address:
Ahmed H Mitwalli
Consultant Nephrologist, King Saud University, P.O. Box 22490, Riyadh
Kingdom of Saudi Arabia
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PMID: 21912022

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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]

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    Abstract
   Introduction
   Patients and Methods
   Statistical Analysis
   Results
   Discussion
   Acknowledgment
    References
    Article Tables
 

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