RENAL DATA FROM THE ASIA - AFRICA
|Year : 2010 | Volume
| Issue : 2 | Page : 372-378
|Pulse cyclophospamide in severe lupus nephritis: Southern Indian experience
Uttara Das1, KV Dakshina Murty1, Neela Prasad1, Aruna Prayag2
1 Department of Nephrology, Nizam's Institute of Medical Sciences, Punjagutta, Hyderabad, India
2 Department of Pathology, Nizam's Institute of Medical Sciences, Punjagutta, Hyderabad, India
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|Date of Web Publication||9-Mar-2010|
| Abstract|| |
To evaluate the efficacy and safety of the monthly pulse IV cyclophosphamide (IVC) therapy in patients with severe lupus nephritis, we studied 39 patients of lupus nephritis on IVC therapy between 1998 to 2002. Single monthly cyclophosphamide (0.75-1 g/m²) was infused intravenously with oral prednisolone (0.5 mg/kg per day) and appropriate hydration. Of the 39 patients 25 (86.2%) patients were females and 4 (13.8%) were males. Six (2%) cases had irregular follow-up and 3 patients had expired during the initial cycles and were excluded from the study. The mean age was 25.6 + 6.72 years (range 10-40 years). The mean duration of the disease from the onset to renal biopsy was 24.2 + 18.5 months. The clinical presentations included nephrotic syndrome (34.5%), acute glomerulonephritis (31.0%), Pyrexia of unknown origin (PUO) (10.3%), and rapidly progressive renal failure (6.7%). Renal insufficiency was present in 47.2% cases. Twenty-two (75.9%) patients had diffuse proliferative glomerulonephritis (class IV), 6 (20.7%) focal proliferative glomerulonephritis (class III), and one (3.4%) class Vd. After a mean follow-up of 15.8 months, out of 29 patients, 13 (44.8%) had achieved complete remission, 7 (24.1%) partial remission and 9 (31.0%) cases did not respond to the therapy. Side effects of the therapy included vomiting and nausea (100%) and hair loss during the first few doses of IVC. In addition, one case had dysfunctional uterine bleeding and two patients had avascular necrosis of femoral head. We conclude that our data indicate that IVC in severe lupus nephritis is effective in Indian patients though longer follow-up is required.
|How to cite this article:|
Das U, Dakshina Murty K V, Prasad N, Prayag A. Pulse cyclophospamide in severe lupus nephritis: Southern Indian experience. Saudi J Kidney Dis Transpl 2010;21:372-8
|How to cite this URL:|
Das U, Dakshina Murty K V, Prasad N, Prayag A. Pulse cyclophospamide in severe lupus nephritis: Southern Indian experience. Saudi J Kidney Dis Transpl [serial online] 2010 [cited 2019 May 25];21:372-8. Available from: http://www.sjkdt.org/text.asp?2010/21/2/372/60218
| Introduction|| |
Systemic lupus nephritis (SLE) is a multisystemic disease with a wide array of immunological abnormalities.  Survival of patients with SLE have improved greatly, but lupus nephritis (LN) remains an important cause of morbidity and mortality.  The aims of treating lupus nephritis are to induce and maintain remission thereby reducing the risk of progression to renal failure. Immunosuppressive drugs are more efficacious than prednisolone alone in controlling clinical signs of active nephritis, preventing renal scarring, and reducing the risk of end-stage renal disease (ESRD).  The most popular therapeutic regimen consists of long-term pulses IVC in combination with corticosteroid.  However, some investigators have drawn attention to the limitation of IVC, including toxicity during long-term use and possibility of relapse.  Despite skepticism, cyclophosphamide remains the most effective therapy for initial treatment for aggressive lupus nephritis.  Several studies showed that neither pulse methyl prednisolone (MP) nor short course of pulse IVC are as efficacious as extended course of pulse cyclophosphamide in reducing the risk of renal progression or in achieving sustained remission of lupus nephritis 
We aimed in this study to analyze our experiences and outcome of severe lupus nephritis treated with pulse cyclophosphamide and to evaluate risk factors for poor renal outcome.
| Methods and Patients|| |
The study was performed in the Department of Nephrology in Nizam's institute of medical sciences, Hyderabad, India, from January 1998 to December 2002. Inclusion criteria were patients who had fulfilled the revised American Rheumatological Association (ARA) criteria for diagnosis of SLE and revealed renal biopsy evidenced severe (proliforetive) lupus nephritis, urinary protein excretion of > 500 mg/24h, and serum creatinine (s. Cr) :5 3.4 mg/dL. Informed consent was obtained from all the patients.
The patients who achieved complete remission and those who did not respond to the treatment were identified and the predictors of poor outcome were evaluated.
Each renal biopsy specimen was evaluated by light and immunofluroscence microscopy by the renal pathologist of the institute. Specimen were required to have minimum 10 glomeruli for light microscopy and findings were categorized based on the recommendations of the World Health Organization (WHO)  and only subjects with severe lupus nephritis (LN) eg; class III/IV and Vc/Vd were included in this study.
Protienuria: Defined as a value for urinary protein excretion of > 250 mg/24h.
Nephrotic syndrome (NS): Defined as a value for urinary protein excretion of > 3 g/24h, serum albumin (s. alb) < 3g/dL, serum cholesterol (s. chol) > 300 mg/dL.
Nephritic syndrome: Defined as a value for protienuria > 0.5 g/d and active urinary sediments (> 5 erythrocyte/HPF or casts). 
Complete remission (CR): Defined as a value for urinary protein excretion of < 0.3 g/24h, normal urinary sediment, s. alb, and value of Cr. was 15% or < from the baseline value.
Partial remission (PR): Defined as a value of urinary protein excretion between 0.3 and 2.9 g/24h, s. alb ≥ 3 g/dL, and stable renal function.
Treatment failure: Defined as a value for urinary protein excretion that remained at or above ≥ 0.3 g/24h and s. alb ≤ 3g/dL, and an increase in s. Cr > 0.6 mg/dL or 15% above the base line value. 
Renal biopsy was repeated if there was an increase in s. Cr or persistent proteinuria
Severe lupus nephritis: Diagnosis of severe nephritis was based on the presence of proliferation and/or necrosis in greater than 50% of glomeruli with or without concominent membranous glomerulonephritis. 
Renal flare: Defined using criteria of Moroni et al  which include:
Poor renal outcome: defined as doubling in s. Cr. values for a period of at least 6 months. 
- Nephritic flare: an increase in s. Cr. of at least 30% above the basal value with a nephritic urinary sediment.
- Protienuric flare: defined as an increase in proteinuria by at least 2 g /day or doubling if basal proteinuria is above 3.5 g/d with out modification of s. Cr.
Lupus duration: Defined as the time from a patient's first documented lupus diagnosis to the renal biopsy diagnosis of SLE. 
Activity and chronicity index (AI/CI): The activity index consisted of the total 4 features each evaluated on zero to 4 + semiquatitive scale: glomerular leucocyte infiltration, interstitial inflammation, glomerular karyorrhexis and fibrinoid necrosis, and cellular crescent. The latter two features were each weighed by a factor of two, for a maximum activity index score of 24. The chronicity index was determined by the score of glomerular sclerosis, interstitial fibrosis, and tubular atrophy each quantitated on a zero to 4 + scale for a maximum chronicity index of 12. 
Database: The data collected on the patients included age at time of onset of SLE, age at time of nephritis, sex, hypertension (HTN), compliments (C3,C4), anti-dsDNA antibody (antiDNAab), proteinuria, s. Cr, creatinine clearance at diagnosis, activity index and chronicity index in renal biopsy, prior to the therapy etc.
Follow up: Patients were followed up monthly for 6 months then quarterly for two years or more, and more frequently if needed. Hemoglobin, total leukocyte count (TLC), blood urea, s. Cr, total serum protein (TSP), serum albumin (s. alb), 24h urinary protein excretion in gram per day (g/d) and creatinine clearance every month, liver function test (LFT) and lipid profile at baseline and every 3rd month and C3, C4 and ds DNA antibody at baseline and every 6 th month interval.
The primary study outcome was the response to the treatment defined by:
- Percentage of patients who achieved renal remission.
- The number of non-reponders (> 10 RBC/HPF, cellular cast, proteinuria > 1 g/d, doubling of creatinine)
- Percentage of adverse events.
Adverse effects noted included major Infections, herpes Zoster, neutropenic fever, premature ovarian failure, avascular necrosis, malignancy, hemorrhagic cystitis, cataracts, and death.
- Progress to ESRD.
- Doubling of s. Cr.
- Renal relapse.
Ovarian failure: Defined as sustained amenorrhea occurring before 45 years of age. 
Serious infection: Defined as any infection needed intravenous antibiotics or hospitalization.
The patients received 6 monthly pulses of cyclophosphamide for induction followed by quarterly pulses for at least one additional year. The standard initial dose of pulse cyclophosphamide was 0.75-1 g/m 2 BSA in patients with normal renal function. The initial dose was reduced to 0.50 g/m 2 if the estimated creatinine clearance was less than 40 mL/min, or in obese patient (BMI > 35) to diminish the risk of toxicity. The patients receive one liter of intravenous fluid (0.45 percent or 0.9 percent saline) over a 2 to 4- hour period. Cyclophosphamide was then reconstituted and diluted in 150 mL of saline and infused over one hour. All the patients were instructed to drink at least one liter of fluid every 6 to 8 hours and void as frequently as possible for 24 hours. Nausea was nearly universal in the treated patients; those with relatively mild nausea were received prochlorperazine 25 mg orally every four hours as needed. For severe vomiting, the patients were treated as per the current NIH protocol that recommends prophylactic dexamethasone (10 mg, four hours after infusion) and ondansetron (4 to 8 mg; four, eight and 12 hours after infusion). The dose of cyclophosphamide was reduced to 0.5 gm/m 2 if a higher dose was not tolerated. The patients had WBC count before every injection of cyclophosphamide and cyclophosphamide continued if WBC count was 4500/cumm or more. If the WBC count was less than 4000/cumm, the injection was deferred for a week and the test was repeated. Repeated injections were administered when the count was above 4000/cum. Mesna (2-Mercaptoethane sulphonate) at 20% of the cyclophosphomide dose was infused i.v. before cyclophosphomide administration and every 3h thereafter for a total of 4 doses.
Oral prednisolone (0.5 mg/kg/day) was prescribed for 3 months or till remission was achieved. Then, the dose of prednisolone was gradually reduced to 0.5 mg/kg on alternate days over 6-9 months. After 1 year, the dose was further tapered to a maintenance dose of 0.3 mg/kg/alternate day.
| Statistical Analysis|| |
Statistical analysis was done using microsoft excel software Student t' test and P value < 0.05 was considered as significant
| Results|| |
A total of 38 patients were included in this study from January 1998 to December 2002. Six patients were excluded from the analysis due to loss of follow-up and 3 patients expired during the initial cycles of therapy. Twenty-nine cases were included in the final analysis.
[Table 1] shows the clinical, biochemical and pathological characteristics of these patients. The mean age group at the time of renal biopsy was 25.6 + 6.70 (range: 10-40) years, and there were 25 females and 4 males. The mean interval between the diagnosis of SLE and lupus nephritis was 24.2 ± 18.5 (range: 160) months. Out of 29 patients, 22 (75.8%) had class IV lupus nephritis, 6 (20.7%) patients had class III, and one (3.4%) had class Vd lupus nephritis. The mean interval of follow-up was 16.6 (8-50) months. Ten patients (34.5%) presented as nephrotic syndrome, 9 (31.0%) as nephritis, 1 (3.40%) as rapidly progressive renal failure (RPRF), and 3 (10.34%) patients presented as pyrexia of unknown origin (PUO). There were 18 (47.1%) patients who had renal insufficiency at presentation and dyslipidemia was present in 27 (71.02%) patients.
The baseline data for non-responding patients to treatment did not differ from the data of responders except hypertension and renal insufficiency, which were more common in the nonresponders group.
[Table 2] shows the parameters of the patients who responded and non-responders at the end of the study. After a mean follow up of 15.75 months, out of 29 patients 13 (44.8%) had achieved CR, 7 (24.2%) PR and 9 (31.0%) were NR.
[Table 3] shows the outcome of the 3 subgroups of the study patients. All the patients in the CR group maintained stable s. Cr throughout the follow-up period, while doubling of s. Cr was observed in 77.8% of the patients in the NR group and 14.3% of those in the PR group. None of the patients in the NR group progressed to ESRD till the end of the follow-up period.
The number of renal flares was the highest in the NR (55.5%) group. There were no differences in the cumulative doses of cyclophosphamide among the 3 groups (mean 0.9 g). The average time to achieve CR was 6 months. The NR group had a mean baseline s. Cr > 2 mg/dL, whereas the mean of s. Cr was normal in the responder group. We observed a persistent reduction of proteinuria and improvement of s. Alb in the responders group from the 3 rd cycle onward.
On histopathological analysis, there were no differences of frequencies of the histological classes of SLE among the responders and the NR except chronicity index was > 3 in the latter group. Out of 9 the NR patients, 8 had a diffuse progressive glomerulonephritis (DPGN). Repeated renal biopsies were performed in 7 cases. Five patients underwent histopathologic transformation; 3 converted from class IV to class V, and all of them achieved complete response subsequently on ponticelli regimen. Two patients converted to class IV and later received pre ESRD management.
There were some complications related to therapy; 2 patient had major infections, 2 herpes Zoster, 2 avascular necrosis of the hip (AVN), 1 cataract, and one amenorrhea. No cases experienced hemorrhagic cystitis till the end of the follow-up period. Most of the patients had vomiting and nauseas during treatment. Alopacia was the most common side effect we observed. One patient became pregnant two times during the treatment period and MTP (medical termination of pregnancy) was done at 11 weeks in both times. This patient achieved partial remission at the end of follow-up period.
| Discussion|| |
In this study, we analyzed prospectively the response of severe lupus nephritis treated with IV cyclophosphomide and predictors of poor outcomes.
The optimum treatment for severe lupus nephritis is unclear because large prospective randomized trials are lacking.  Boumpus et al observed that an extended course of pulse cyclophosphomide is more effective than 6 months of pulse methyl prednisolone in preserving renal function and addition of a quarterly maintenance regimen to monthly pulse cyclophosphomide reduces the rate of exacerbations. 
Gourley et al observed CR in 48% of patients, while 29% failed to respond to treatment; doubling of s. Cr occurred in only 5% and only 3% progressed to ESRD. Our data is comparable to this study.  Ioannidis et al found CR in 78% of patients, but the duration of treatment in this study was 3 years.  Korbet et al observed CR in 43% cases treated with high dose prednisolone and oral CYC.  In G.G. Illei study of DPGN patients, CR was achieved in 70% and PR in 11%. 
We observed that HTN, renal insufficiency, and higher chronicity index at baseline were the predictors of poor outcome though statistically insignificant. G.G. Illei et al  found s. Cr > 2 mg/dL, a severe nephritic flare, and a high chronicity index at baselinet,but not activity index, were associated progression to ESRD. We also observed similar results in our study as well as others. ,,,,
Mosca et al  did not find patient's sex, age or any other serological/clinical variables to be correlating with occurrence of flare. In our study, no significant differences observed in sex, age, serological data among responders and nonresponders. Similarly, in the study of Korbet et al, serological markers failed to predict clinical outcome. 
Korbet et al  and Appel et al  showed that the induction of clinical remission of renal dysfunction is predictive of improved long-term prognosis, even in with most severe form of lupus nephritis. Moreover, Baldwin et al  observed that remission of renal disease achieved in only 17% of patients with severe LN in whom s. Cr levels > 2 mg/dL and 47% of similar patients with s. Cr levels < 2 attained remission. We also found comparable observations in our study patients.
On repeat renal biopsy in the NR group (biopsy was done in 7out of 9 cases of DPGN), we observed transformation of histology in 5 cases; 2 cases showed progressive renal dysfunction with high activity index. Out of 5 transformations, 3 cases transformed to membranous lupus nephritis (class V) and 2 cases transformed to Class VI. A number of studies have evaluated repeated renal biopsy in SLE; although transition from one form of lupus to another occurred, they were not the role. ,,
In the study of Chang Woo et al  out of 21 repeat biopsy cases of DPGN, only 3 cases (14%) underwent histopathologic transformation. Seven cases showed progression to more severe lesion with an increase in s. Cr and blood pressure. These results are comparable to ours. In addition, our study suggests that glomerular activity and interstitial volume density at the initial biopsy are useful histological indices for predicting the renal out-come in patients with DPGN.
Cumulative dose and advancing age have been identified as risk factors for cyclophosphamide induced ovarian failure.  A prolonged course of IVC is associated with more side effects. The profile of side effects was comparable in our study with that most studies. ,,,,,,
In summary, our study showed that long courses of pulse cyclophosphomide are effective in achieving remission in severe lupus nephritis with minimal side effects. High chronicity index and renal insufficiency at presentation are considered as bad prognostic factors. However, a long follow-up study of these patients is required.
| Acknowledgment|| |
Authors thanks all staff, residents and faculty of the Department of Nephrology for their help during the study period.
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Assistant Professor of Nephrology, Nizam's Institute of Medical Sciences, Panjagutta, Hyderabad 500082, Andhra Pradesh
[Table 1], [Table 2], [Table 3]
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