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Saudi Journal of Kidney Diseases and Transplantation
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ORIGINAL ARTICLE Table of Contents   
Year : 2000  |  Volume : 11  |  Issue : 2  |  Page : 167-173
Effect of Intravenous Cyclophosphamide Pulse Therapy on Renal Functions and Histopathology in Patients with Severe Lupus Nephritis


1 Department of Medicine, King Khalid University Hospital, Riyadh, Saudi Arabia
2 Department of Community Medicine, King Khalid University Hospital, Riyadh, Saudi Arabia
3 Department of Pathology, King Khalid University Hospital, Riyadh, Saudi Arabia

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   Abstract 

Despite the wide use of intravenous cyclophosphamide (IC) in lupus nephritis (LN), there are few published studies showing the effect of this treatment on renal histology. In this prospective study, we report the effect of IC on the evolution of histopathologic features in successive renal biopsies in patients with LN. Thirty patients with class IV or V LN were started on IC (10-15 mg/kg) administered once every month for six months followed by three monthly for another six doses making a total of two years of therapy. The clinical course of the disease, serum creatinine and 24 hours urinary protein and creatinine clearance were tested at entry and subsequently during each follow-up visit. Repeat renal biopsy was performed after completion of two years of therapy. The mean serum creatinine of the study patients was 166.3 + 42 tmol/L at entry which decreased to 104 + 46.4 tmol/L at two years (P < 0.01). The mean 24 hours proteinuria decreased from 2.81 + 2.4 g at entry to 1.39 + 1.54 g at two years (P < 0.003) and the mean creatinine clearance increased from 58 + 31 ml/min at the start of treatment to 64 + 32 ml/min at two years of therapy (P < 0.05). Nine patients had serum creatinine of > 200 tmol/L, of whom six progressed to variable degrees of chronic renal failure. Repeat renal biopsy was performed in 21 patients. The original biopsy of these patients showed class IV in 17 and class V in four patients. On repeat biopsy, five of class IV disease had progressed to advanced sclerosis, four to class V, and five remained unchanged. The remaining three patients with class IV LN changed to one each of class I, II and III. Of the four patients with class V, one progressed to advanced sclerosis, one changed to class III and two remained the same. There was a significant decrease (P < 0.05) in the activity index although there was a significant increase in the chronicity index (P < 0.001). Multivariat analysis for possible risk factors for progression to chronic renal failure showed initial high serum creatinine to be a powerful predictor of renal failure. In conclusion, IC pulse therapy is effective in improving or stabilizing renal function in patients with class IV or V LN. The only poor prognostic determinant observed was higher initial serum creatinine value.

Keywords: Lupus nephritis, Cyclophosphamide, Pulse therapy, Renal histology.

How to cite this article:
Huraib S, Abu-Aisha H, Memon N, Al-Wakeel J, Al Ballaa S, Mitwalli AH, Alam A, Al Sohabani M, Askar A. Effect of Intravenous Cyclophosphamide Pulse Therapy on Renal Functions and Histopathology in Patients with Severe Lupus Nephritis. Saudi J Kidney Dis Transpl 2000;11:167-73

How to cite this URL:
Huraib S, Abu-Aisha H, Memon N, Al-Wakeel J, Al Ballaa S, Mitwalli AH, Alam A, Al Sohabani M, Askar A. Effect of Intravenous Cyclophosphamide Pulse Therapy on Renal Functions and Histopathology in Patients with Severe Lupus Nephritis. Saudi J Kidney Dis Transpl [serial online] 2000 [cited 2019 Jul 21];11:167-73. Available from: http://www.sjkdt.org/text.asp?2000/11/2/167/36673

   Introduction Top


Systemic lupus erythematosus (SLE) is being increasingly recognized in the Saudi population. [1] This is mainly because of the increase in awareness of the disease as well as the easy availability of sensitive laboratory tests. The kidney is involved very frequently in SLE and is one of the important deter­minants of the overall prognosis. [2]

Clinical evidence of renal involvement in SLE is seen in 50% of the cases at onset of the disease, 75% after follow-up of one to two years, while silent renal involvement is seen in up to 95% of the cases. [3] The prognosis of SLE has improved markedly in recent years due to an overall improvement in medical care as well as the availability of powerful antibiotics, steroids, diuretics and anti-hypertensive medications[2]. However, this situation has resulted in the emergence of renal involvement as the dominant cause of morbidity and mortality in these patients. [3] Various trials have shown the superiority of intravenous cyclophosphamide (IC) pulse therapy over other regimens in the treatment of diffuse proliferative lupus nephritis.[4],[5],[6],[7],[8] However, there are only few reports showing the effect of such treatment on renal histopathology as also detailing the risk factors for poor response. [9],[10],[11] The aim of this study was to treat severe histo­pathological forms of lupus nephritis (LN) with pulse IC and to monitor their clinical course, biochemical profile and effect on renal histopathology, as well as to determine the risk factors for poor response.


   Materials and Methods Top


Diagnosis of SLE was established on the basis of presence of at least four of the 11 criteria laid down by the American Rheuma­tology Association. [12] Patients with evidence of renal involvement were referred to the Nephrology Unit at King Khalid University Hospital (KKUH), from either the rheuma­tology unit at KKUH or from other centers in the Kingdom. Clinical course as well as the biochemical profile and proteinuria were monitored for all study patients during each visit. Renal biopsy was performed only in those patients who had proteinuria of one gram or more in a 24-hour urine collection and/or elevated blood urea and creatinine levels. Patients with mild urinary sediment abnormalities or proteinuria of less than one gram were not biopsied and were followed-up. The severity of LN was defined according to WHO classification [4] as follows: Class I, normal; II, mesangial; III, focal proliferative; IV, diffuse proliferative; V, membranous, VI, sclerosis. The inclusion criteria to the study included: biopsy-proven class IV or V LN, signing the informed consent to participate in the study and white blood cell (WBC) count of more than 3000/cu mm. In those patients who had WBC count less than 3000/cu mm, bone marrow examination was carried-out and IC was given only to those patients who did not have evidence of bone marrow suppression, thereby suggesting that the leukopenia was due to disease activity. Patients with hemor­rhagic cystitis, malignancy, pregnancy, infection, class I, II, III, and VI LN, and patients already on cytotoxic drugs were excluded from the study.

All the biopsies were read by an experienced renal pathologist. Activity and chronicity indices were determined as described by Austin et al. [10] Activity index included glome­rular proliferation, leukocyte exudation, karyorrhexis, fibrinoid necrosis, cellular cres­cents and interstitial inflammation. Chroni­city index included fibrous crescents and peri­glomerular fibrosis, glomerular sclerosis, tubular atrophy and interstitial fibrosis. These features were scored on a scale from 0 to 3. The maximum chronicity index was 12.

Treatment Protocol

Patients with class IV and V LN were admi­nistered IC in a dose of 10-15 mg/kg each month for six months and then three monthly for another six doses making a total of two years of therapy. The drug was administered in 150 ml of dextrose solution over 30-60 minutes. To ensure good diuresis, one liter of normal saline was administered before therapy (unless patient had advanced renal impairment). Patients were instructed to void urine frequently during the immediate post-treatment period. All patients received in addition, 2-mercaptoethane sulphonate (MESNA) to prevent hemorrhagic cystitis. Oral prednisolone was started in a dose of 60 mg given for four weeks, which was tapered to 10 mg daily over a 4-week period. Plasmapheresis and methylprednisolone pulse therapy, in addition to cytotoxic therapy, were used for patients with rapidly prog­ressive glomerulonephritis (RPGN). Clinical course of the disease, serum creatinine, 24­hours urinary protein and creatinine clearance were estimated at entry to the study and during each follow-up visit. Repeat renal biopsy was performed after completion of two years of therapy. Attempts were made to keep the blood pressure under good control during the treatment period.

Statistical Analysis

All the data were expressed as the mean + SD. Changes from base line were evaluated by Student's paired "t" test. For correlation sta­tistics, Pearson's correlation and Spearman's­rank difference correlation were used.


   Results Top


A total of 30 patients with class IV or V LN were started on IC during the study period. There were 22 female and eight male patients with a mean age of 30.3 + 6.2 years. The mean serum creatinine at entry was 166.3 + 42 pmol/L which decreased to 116.6 + 35 pmol/L and 104 + 46.4 pmol/L at six months and two years respectively (P < 0.01). Mean 24-hours proteinuria decreased from 2.81 + 2.4 g at the start of therapy to 1.37 + 1.8 g and 1.39 + 1.54 g at six months and two years, respectively (P < 0.003). Mean creatinine clearance at the beginning of therapy was 58 + 31 mls/min, 71 + 36.7 mls/min at six months and 64 + 32 mls/min at two years of therapy (P < 0.05) [Table - 1]. [Figure - 1],[Figure - 2],[Figure - 3] show changes in mean serum creatinine, 24 hours urinary protein, and creatinine clearance respectively over the two-year study period.

Nine patients had initial serum creatinine of > 200 pmol/L. Six of these progressed to variable degrees of chronic renal failure while the remaining three remained the same.

Initial renal biopsy of the 30 patients analyzed, showed class IV in 24 and class V in six patients. Repeat renal biopsy was performed in 21 patients. The original biopsy of these 21 patients showed the following: class IV in 17, and class V in four. On repeat biopsy, five of class IV disease had progressed to advanced sclerosis, four to class V, and five remained unchanged. The remaining three patients with class IV changed to one each of class I, II and III. Of the four patients with class V, one prog­ressed to advanced sclerosis, one changed to class III and two remained the same [Table - 2]. There was a significant reduction (P < 0.05) in the activity index and more importantly, a significant increase in the chronicity index (P < 0.001) after treatment [Table - 3]. Initial high serum creatinine emerged to be a powerful predictor of renal failure. Age, sex and degree of proteinuria as well as activity and chronicity indices did not correlate well with progression to chronic renal failure [Table - 4]. Three patients presented with rapidly progressive glomerulo­nephritis and received, in addition to cyto­toxic therapy, methylprednisolone pulse therapy and plasmapheresis. All three improved with this therapy. None of our patients developed hemorrhagic cystitis. Life threatening infections were observed in two of our patients, both of whom deve­loped pneumonia which was successfully treated. One patient developed herpes zoster.

Immunosuppressive therapy was withheld for one month; this was followed by resolution of the herpes. Malignancy was not observed in any of our patients during the study period. Six of the 30 patients who completed the 2-year treatment protocol developed advanced renal failure, which gives a 2-year renal survival of 80%.


   Discussion Top


Steroids have remained the cornerstone of treatment of LN since the early 1960's. [13] However, the side effects of long-term steroid use have become more apparent in recent times and the disease outcome has been relatively poor. [14] Steroid-sparing drugs have therefore been advocated. [15],[16] Donadio et al have shown that a six-month course of cyclophosphamide results in better prog­nosis. 16 Recognition of the patients with LN who are likely to benefit most with cyclo­phosphamide therapy is vital since long­term side effects of cytotoxic drugs are hazardous. In this regard, the activity and chronicity indices have become useful tools in deciding the nature of therapy. [4] Austin et al treated 107 patients with class III, IV or V LN with different regimens including IC and low-dose steroids at NIH trials. [4] From life table analysis, better prognosis was observed with IC after a follow-up of five years [4] and, this was more apparent when patients given IC were compared to those treated with prednisone alone. However, Ponticelli [17] reported a 95% renal survival in class IV LN when treated with methyl­prednisolone pulse therapy alone. Although NIH trials have shown that IC is better, [4] variable five-year renal survival rates have been reported; Dillard et al [18] have shown survival rate of 44% and Hariharan, 35%[19]. Our study has shown a 2-year renal survival of 80%, although the long-term prognosis remains to be seen. The different outcomes reported are probably due to heterogenecity of morphological renal lesions and paucity of controlled studies. [4] Also, Donadio et al [20] have questioned the long-term beneficial effect of IC alone. They contend that the beneficial effect observed may be due to better control of hypertension, infections, hyperlipidemia and metabolic disorders which are commonly associated with steroid treatment.[20]

We found that, IC pulse therapy induced remission of LN in majority of the patients. However, despite the clinical and bioche­mical improvement there was worsening in the histological picture in our patients as evidenced by the significant increase in the chronicity index. This is similar to what has been reported by Valeri et al.[11]

We found that only initial high serum creatinine levels correlated with poor prog­nosis and that chronicity and activity indices did not correlate with poor outcome. This is different from NIH trials [4] where chronicity index was found to be a predictor of poor prognosis. Magil et al [20] also found that serum creatinine and chronicity and activity indices in initial renal biopsy are significant predictors of outcome in class IV LN. However, Schwartz et al [22] did not find chronicity index to be of predictive value.

The exact duration of therapy with IC in LN is yet to be determined. Some workers suggest treatment for one year after achieving remission while others suggest longer duration of treatment. [20] If cumulative dose of IC exceeds 150-250 mg/kg (9-15 gm) the chances of toxicity are high. Therefore, it is suggested to treat LN like cancer chemotherapy with induction and main­tenance phases of therapy. [20] Potential side effects of IC are many, but we saw infections in two (6.7%) of our patients and could be managed easily. Hemorrhagic cystitis was not seen in any of our patients.

In conclusion, IC pulse therapy is effective in improving or stabilizing renal function in patients with class IV or V LN. The only poor prognostic determinant observed was higher initial serum creatinine. Other factors like age, sex, degree of proteinuria, activity and chronicity indices did not correlate with poor outcome. Also, despite apparent clinical and biochemical improvement, there was a significant increase in chronicity index on repeat renal biopsy and six patients (20%) progressed to advanced renal failure.

 
   References Top

1.Al Ballaa SR, Bamboye AR, Al Sekait M, Al Rashed R. Pattern of adult admission into medical wards of King Khalid University Hospital, Riyadh (1986-1990). Saudi Med J 1993;14:225-9.  Back to cited text no. 1    
2.Balow JE. Lupus nephritis: natural history, prognosis and treatment. Clin Immuno­logy Allergy 1986;6;353-65.  Back to cited text no. 2    
3.Bennett WM, Bordana EJ, Norman DJ, Houghton DC. Natural history of "silent" lupus nephritis. Am J Kidney Dis 1982; 1:359-63.  Back to cited text no. 3    
4.Austin HA 3d, Klippel JH, Balow JE, et al. Therapy of lupus nephritis. Controlled trial of prednisone and cytotoxic drugs. N Engl J Med 1986;314:614-9.  Back to cited text no. 4    
5.Balow JE, Austin HA 3d, Tsokos GC, Antonovych TT, Steinberg AD, Klippel JH. NIH conference. Lupus nephritis. Ann Intern Med 1987;106(1):79-94.  Back to cited text no. 5    
6.Steinberg AD, Decker JL. A double-blind controlled trial comparing cyclophos­phamide, azathioprine and placebo in the treatment of lupus glomerulonephritis. Arthritis Rheum 1974;17:923-37.  Back to cited text no. 6  [PUBMED]  
7.Dinant HJ, Decker JL, Klippel JH, Balow JE, Plotz PH, Steinberg AD. Alternative modes of cyclophosphamide and azathio­prine therapy in lupus nephritis. Ann Intern Med 1982;96(6 pt. 1):728-36.  Back to cited text no. 7    
8.Steinberg AD, Steinberg SC. Long-term preservation of renal function in patients with lupus nephritis receiving treatment that includes cyclophosphamide versus those treated with prednisone only. Arthritis Rheum 1991;34(3):945-50.  Back to cited text no. 8    
9.Balow JE, Austin HA 3d, Muenz LR, et al. Effect of treatment on the evolution of renal abnormalities in lupus nephritis. N Engl J Med 1984;311:491-5.  Back to cited text no. 9    
10.Austin HA 3d, Muenz LR, Joyce KM, Antonovych TT, Ballow J. Diffuse proli­ferative lupus nephritis. Identification of specific pathologic features affecting renal outcome. Kidney Int 1984;25:689-94.  Back to cited text no. 10    
11.Valeri A, Radhakrishnan J, Estes D, et al. Intravenous pulse cyclophosphamide treat­ment of severe lupus nephritis: a prospective five-year study. Clin Neph 1994;42: 71-8.  Back to cited text no. 11    
12.Cohen AS, Reynolds WE, Franklin EC, et al. Preliminary criteria for the classi­fication of systemic lupus erythematosus. Bull Rheum Dis 1971;21:643-8.  Back to cited text no. 12    
13.Pollak VE, Pirani CL, Kark RM. Effect of large doses of prednisone on the renal lesions and life span of patients with lupus glomerulonephritis. J Lab Clin Med 1961;57:495-511.  Back to cited text no. 13  [PUBMED]  
14.Steinberg AD, Decker JL. A double-blind controlled trial comparing cyclophos­phamide, azathioprine and placebo in the treatment of lupus glomerulonephritis. Arthritis Rheum 1974;17(6):923-37.  Back to cited text no. 14    
15.Dinant HJ, Decker JL, Klippel JH, Balow JE, Plotz PH, Steinberg AD. Alternative modes of cyclophosphamide and azathio­prine therapy in lupus nephritis. Ann Intern Med 1982;96(6):728-36.  Back to cited text no. 15    
16.Donadio JV Jr, Holley KE, Ferguson RH, Ilstrup DM. Treatment of diffuse prolife­rative lupus nephritis with prednisone and combined prednisone and cyclophos­phamide. N Engl J Med 1978;299:1151-5.  Back to cited text no. 16  [PUBMED]  
17.Ponticelli C, Zucchelli P, Moroni G, Cagnoli L, Banfi G, Pasquali S. Long-term prognosis of diffuse lupus nephritis. Clin Nephrol 1987;28(6):263-71.  Back to cited text no. 17    
18.Dillard MG, Dujovne I, Pollark VE, Pirani CL. The effect of treatment with prednisone and nitrogen mustard on the renal lesions and life span of patients with lupus glomerulonephritis. Nephron 1973; 10(5):273-91.  Back to cited text no. 18    
19.Hariharan S, Pollak VE, Kant KS, Weiss MA, Wadhwa NK. Diffuse proliferative lupus nephritis: long-term observations in patients treated with ancrod. Clin Nephrol 1990;34(2):61-9.  Back to cited text no. 19    
20.Magil AB, Puterman ML, Ballon HS, et al. Prognostic factors in diffuse proliferative lupus glomerulonephritis. Kidney Int 1988; 34:511-7.  Back to cited text no. 20  [PUBMED]  
21.Schwartz MM, Bersntein J, Hill GS, Holley K, Phillips EA. Predictive value of renal pathology in diffuse proliferative lupus glomerulonephritis. Lupus Nephritis Collaborative Study Group. Kidney Int 1989;36:891-6.  Back to cited text no. 21    
22.Donadio JV Jr, Glassock RJ. Immuno­suppressive drug therapy in lupus nephritis. Am J Kidney Dis 1993;21(3):239-50.  Back to cited text no. 22    

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Correspondence Address:
Sameer Huraib
Nephrology Division, King Fahad National Guard Hospital, P.O. Box 22490, Riyadh 11426
Saudi Arabia
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