Saudi Journal of Kidney Diseases and Transplantation

RENAL DATA FROM THE ASIA - AFRICA
Year
: 2010  |  Volume : 21  |  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

Correspondence Address:
Uttara Das
Assistant Professor of Nephrology, Nizam«SQ»s Institute of Medical Sciences, Panjagutta, Hyderabad 500082, Andhra Pradesh
India

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;21:372-378


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 2020 Jul 6 ];21:372-378
Available from: http://www.sjkdt.org/text.asp?2010/21/2/372/60218


Full Text

 Introduction



Systemic lupus nephritis (SLE) is a multisys­temic disease with a wide array of immuno­logical abnormalities. [1] Survival of patients with SLE have improved greatly, but lupus nephri­tis (LN) remains an important cause of morbi­dity and mortality. [2] 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). [3] The most popular therapeutic regimen consists of long-term pul­ses IVC in combination with corticosteroid. [4] However, some investigators have drawn at­tention to the limitation of IVC, including toxi­city during long-term use and possibility of re­lapse. [5] Despite skepticism, cyclophosphamide remains the most effective therapy for initial treatment for aggressive lupus nephritis. [6] 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 [7]

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) [8] and only subjects with severe lupus nephritis (LN) eg; class III/IV and Vc/Vd were included in this study.

Definitions

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) 300 mg/dL.

Nephritic syndrome: Defined as a value for protienuria > 0.5 g/d and active urinary sedi­ments (> 5 erythrocyte/HPF or casts). [9]

Complete remission (CR): Defined as a value for urinary protein excretion of 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. [10]

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. [11]

Renal flare: Defined using criteria of Moroni et al [27] which include:



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.Poor renal outcome: defined as doubling in s. Cr. values for a period of at least 6 months. [12]

Lupus duration: Defined as the time from a patient's first documented lupus diagnosis to the renal biopsy diagnosis of SLE. [13]

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. [14]

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.

Outcome measures

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.Secondary outcome:



Progress to ESRD.Doubling of s. Cr.Renal relapse.Adverse effects noted included major Infec­tions, herpes Zoster, neutropenic fever, prema­ture ovarian failure, avascular necrosis, malig­nancy, hemorrhagic cystitis, cataracts, and death.

Ovarian failure: Defined as sustained ame­norrhea occurring before 45 years of age. [26]

Serious infection: Defined as any infection needed intravenous antibiotics or hospitalization.

Treatment protocol

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 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. [15] 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. [3]

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. [16] Ioannidis et al found CR in 78% of patients, but the duration of treatment in this study was 3 years. [17] Korbet et al observed CR in 43% cases treated with high dose predniso­lone and oral CYC. [18] In G.G. Illei study of DPGN patients, CR was achieved in 70% and PR in 11%. [19]

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 [19] 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. [9],[12],[13],[17],[20]

Mosca et al [12] 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. [18]

Korbet et al [18] and Appel et al [14] 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 [21] 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 [21],[22],[23]

In the study of Chang Woo et al [24] 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. [25] 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. [3],[15],[16],[19],[20],[13],[26]

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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