The nephrotic syndrome defined as urinary protein

Original Article Comparative Study of Angiotensin Converting Enzyme Inhibitor and Calcium Channel Blocker in the Treatment of Steroid-Resistant Idiopathic Nephrotic Syndrome NS Kumar*, AK Singh*, RN Mishra**, J Prakash*** Abstract Background : The aim of this study was to evaluate and compare the anti-proteinuric effect of ramipril and verapamil in patients with steroid-resistant idiopathic nephrotic syndrome. Twenty one (21) cases of steroid-resistant idiopathic nephrotic syndrome were randomized to receive ramipril (11) and verapamil (10) and were followed up for 12 months; monthly for the 1st 3 months and then every 3 months for the remaining study period. The degree of reduction of proteinuria, blood pressure, serum creatinine, serum albumin and side effects were noted between the two groups. The comparison within the groups over different time periods was made using paired t test and between the groups for specific time period by unpaired t test. The level of significance was taken as 5% or below. Results : Seventeen patients (nine in the ramipril group and eight in the verapamil group) completed the study. The mean age of the patients, duration of illness, 24 hours urinary excretion of protein, mean arterial pressure, serum creatinine, cholesterol and albumin were similar in both the groups at time of randomization. The 24 hours urinary protein excretion decreased from 6319.44 ± 1971.70 mg/day to 1852.44 ± 1813.74 mg/day in patients receiving ramipril and from 5332.87 ± 1947.47 mg /day to 2759.37 ± 1929.6 mg/day in patients treated with verapamil after 12 months. There was no statistically significant difference in the reduction of proteinuria between the two groups. However, reduction in proteinuria was statistically significant from 2nd month onwards in Ramipril group and reduction was sustained throughout the study period. Reduction in mean arterial pressure was better achieved in Ramipril groups. The change in the serum potassium, creatinine, cholesterol and albumin were similar in either group of patients. Cough (2), hypotension (1) and reversible rise in serum creatinine (1) were observed with ramipril and no side effect was noted with verapamil. Conclusion : Both ramipril and verapamil can reduce proteinuria in patients suffering from steroidresistant idiopathic nephrotic syndrome. However, ramipril had a better and sustained reduction in proteinuria with well-controlled mean arterial pressure. Verapamil can be considered as an alternative to ramipril when the use of the latter is not tolerated because of side effects and/or worsening of renal function in patients with chronic renal insufficiency. INTRODUCTION The nephrotic syndrome defined as urinary protein excretion of more than 3.5 gm/1.73m 2 /day, accompanied by a distinct lowering of the plasma albumin usually below *Senior Resident; **Reader in Biostatistics; ***Professor, Department of Nephrology, Institute of Medical Sciences, Banaras Hindu University, Varanasi - 221 005, India. Received : 21.6.2001; Revised : 4.12.2003; Accepted : 26.4.2004 3.0mg/dl. It is common clinical problem associated with considerable morbidity. Persistent and heavy proteinuria is the worst prognostic marker in patients with nephrotic syndrome irrespective of etiology and histology. 1-2 Hence reduction of proteinuria is the primary goal in the treatment of nephrotic syndrome. Idiopathic nephrotic syndrome frequently responds to treatment with corticosteroids with or without alkylating agents. However, there are a number of patients who fail to respond to treatment with steroids and / 454 www.japi.org JAPI VOL. 52 JUNE 2004

or alkylating agents. The management of these patients with steroid-resistant idiopathic nephrotic syndrome is a challenging one for clinicians. The antiproteinuric effect of angiotensin converting enzyme inhibitors (ACEI) and calcium channel blockers (CCB) have been well documented in clinical studies. 3-7 There are few studies comparing the antiproteinuric effects of these two drugs in idiopathic nephrotic syndrome. The current study examines the hypothesis with regards to the antiproteinuric effects of ACEI (ramipril) and nondihydropyridine CCB (verapamil) in patients suffering from steroid-resistant nephrotic syndrome. MATERIAL AND METHODS The present study was conducted in the Department of Nephrology, University Hospital, Banaras Hindu University, Varanasi between April 99 and Nov. 2000. Twenty-one cases of steroid-resistant idiopathic nephrotic syndrome were included. Renal biopsy was done in all the patients. The protocol of this study was approved by the institute ethical committee and written informed consent was obtained from each patient. Patients were selected using the following criteria: Inclusion criteria 1. Patients of idiopathic nephrotic syndrome not showing reduction in nephrotic range proteinuria (persistently more than 3.5 gm/day) despite 12 weeks administration of oral prednisolone in the dose 2mg/kg body weight on alternate days were considered to have steroid-resistant nephrotic syndrome irrespective of histologic type. 2. Sex: both sexes were included. 3. Age: Both pediatric and adult patients were included. All patients had biopsy proven histological lesion responsible for nephrotic syndrome in the absence of any specific or associated condition. Exclusion criteria 1. Nephrotic syndrome secondary to a known systemic disease like diabetes mellitus, SLE. 2. Presence of moderate to severe renal failure (S.Cr.>3.5- mg%) 3. History of allergic reactions to the study drugs (ramipril and verapamil). 4. Hypertension requiring / needing multiple drugs (i.e. >3 antihypertensive drugs). 5. Patients who have received ACEI/CCB in the previous two months. The patients were advised to take a protein diet ranging between 0.8-1.0 gm/kg body weight /day depending upon renal function. In addition, all patients were on sodium restricted diet. Normotension was defined as systolic and diastolic blood pressure less than 140 mmhg and 90 mmhg respectively without antihypertensive therapy. The patients are randomized into groups A and B. Group A patients received tablet ramipril (Cardace) 2.5-5.0 mg/day initially which was increased to a maximum of 10 mg/day as tolerated by the patients. The group B patients received tablet verapamil (Calaptin SR 120 mg) initially 120 mg/day and increased to a maximum of 240 mg/day depending on the patients tolerance and side effects. Dose of ramipril and verapamil were titrated to achieve a supine diastolic BP of less than 90 mmhg in each group. If additional blood pressure reduction was required, furosemide 40 mg/day was added. Before randomization and treatment with the study drugs, steroid (oral prednisolone) was stopped for two weeks in each patient. The patients in each group were examined every month during the first three months and every three months for the next nine months. The patients were followed up till the completion of the study period and reasons for dropout (if any) were recorded. Twenty four hours urinary protein excretion, renal functional impairment (assessed by mean serum creatinine concentrations), mean arterial pressure, serum potassium and serum cholesterol and side effects of the drugs were carefully recorded in each patient during follow up. However, GFR was not measured in this study. Statistical Analysis The data was presented in percentage and mean with corresponding standard deviation. The comparisons within the group over different time periods were made using paired t test and between the groups for specific time period by unpaired t test. The level of significant was taken as 5% or below. RESULTS Seventeen patients (group A-9; group B-8) completed the study period of one year. The baseline characteristics of these patients are given in Table 1. The baseline characteristics in both groups of patients at time of randomization were similar. Urinary protein excretion Twenty-four hours urinary excretion of protein in the two groups before and at various intervals of study is shown in Table 2. At the end of 12 months of treatment the mean 24 hours urinary protein excretion in group A decreased from 6319.44 ± 1971.70 mg/day to 1852.44 ± 1813.74 mg/day while in group B the mean 24 hours urinary protein excretion decreased from 5332.87 ± 1947.47 mg/day to 2759.37 ± 1929.6 mg/day. There was no statistically significant reduction of proteinuria between the two groups. However the reduction in proteinuria was statistically significant from the 2nd month onwards in group A and remained lower than the initial level throughout the study period. The statistically significant reduction of proteinuria was observed at the end of 12 months only in group B patients. At the completion of 12 months of treatment in group A, two (22.22%) patients had complete remission of proteinuria (< 300 mg/day) and four (44.44%) patients had proteinuria, ranging between 301-1000 mg/day. The proteinuria was still in the nephrotic range in the remaining three (33.33%) patients. In group B, at the end of twelve months, one (12.5%) patient had complete remission of proteinuria, while three (37.5%) patients still had nephrotic range proteinuria. Proteinuria ranged between 1001 to 3500 mg/day in the remaining four (50%) patients. JAPI VOL. 52 JUNE 2004 www.japi.org 455

Table 1: Baseline characteristic of recruited participants who completed the study (i.e. 12 months) Variable Group A Group B (Ramipril) n=9 (Verapamil) n=8 Age in years Mean ± SD 33.77 ± 13.96 34.87 ± 17.81 (Range) (8-45) (12-59) Sex M/F 7/2 5/3 Duration of illness (months) Mean ± SD 34.11 ± 32.02 31.25 ± 44.4 (Range) (8-90) (6-132) Histopathologic lesion * MGN 05 03 FSGS 03 03 MPGN 01 Mes PGN 02 MAP (mmhg) Mean ± SD 94.55 ± 6.08 94.37 ± 6.37 (Range) (87-107) (84-107) 24 hours urinary protein (mg/day) Mean ± SD 6319.44 ± 1971.70 5332.87 ± 1947.47 (Range) (3800-9350) (3788-8000) Drug Dose (mg/day) Mean ± SD 7.77 ± 3.31 240 ± 0 (Range) (5-10) (120-240) Serum creatinine (mg/dl) Mean ± SD 1.41 ± 0.41 1.08 ± 0.33 (Range) (0.71-2.1) (0.79-1.8) Serum albumin (g%) Mean ± SD 2.65 ± 0.69 2.90 ± 0.75 (Range) (1.9-3.8) (1.9-4.3) Serum cholesterol (mg%) Mean ± SD 300.22 ± 46.16 296 ± 71.5 (Range) (216-362) (209-398) Serum potassium (meq/l) Mean ± SD 3.86 ± 0.45 3.67 ± 0.48 (Range) (3.0-4.2) (3.1-4.2) *MGN = Membranous nephropathy, FSGS = Focal Segmental glomerulosclerosis, MPGN = Membranoproliferative glomerulonephritis, MesPGN = Mesangioproliferative glomerulonephritis. Mean arterial pressure (MAP) Mean arterial pressure was calculated by the sum of diastolic blood pressure and one third of the difference between systolic and diastolic blood pressure. In group A, the mean MAP decreased from 94.55 ± 6.08 mmhg to 88.37 ± 8.45 mmhg at the end of 12 months while in group B it Table 2 : 24 hours urinary protein excretion during treatment Month Group A (9) Group B (8) t value Baseline (0) 6319.44 ± 1971.70 5332.87 ± 1947.47 1.04* 1 4305.00 ± 3854.44 4516.5 ± 2789.07 0.13* 2 3322.44 ± 3124.00 3205.5 ± 2519.81 0.08* 3 2433.55 ± 1551.50 4647.87 ± 4844.59 0.58* 6 2594.00 ± 2425.13 3402.12 ± 3009.28 0.61* 9 1811.66 ± 1708.12 3319.12 ± 2715.11 1.39* 12 1852.44 ± 1813.74 2754.34 ± 1924.6 0.99* * Not significant decreased from 94.37 ± 6.39 mmhg to 88.37 ± 8.48 mmhg. There was no statistically significant difference in the reduction of MAP between the two groups. However, in group A there was a significant reduction in MAP from the 1st moth of treatment, which persisted throughout the study; whereas in group B, the reduction in MAP was not significant till the 12th month of treatment. Serum albumin Mean serum albumin concentration increased from 2.65 ± 0.69 gm% to 3.18 ± 0.49gm% and from 2.9 ± 0.75gm% to 3.15 ± 0.63gm% in the Ramipril and Verapamil group respectively at the end of 12 months. The increase in serum albumin was not statistically significant between the groups at different time intervals. We observed an increase in serum albumin which was statistically significant in group A patients from the 1st month onwards but not in subjects receiving verapamil. Other parameters There was not significant change in the mean S. Creatinine at the end of 12 months of therapy in each group. The renal function remained stable in either group. There was a significant reduction in serum cholesterol level in both groups; however the reduction in level was not statistically significant between the two groups. No significant changes in the serum sodium and potassium levels were noted during the study. The systemic and renal profile of patients who completed the study at base line and the one year is shown in Table 3. Side effects The side effects observed in group A were: cough-two, increase in serum creatinine-one and low blood pressureoneone. Of the two patients who developed cough (both females), one patient improved with continued treatment and completed Table 3 : Baseline and at one year systemic and renal profiles of patients of idiopathic nephrotic syndrome in the two groups Group A Group B Baseline One year Baseline One year MAP (mmhg) 94.55 ± 6.08 88.33 ± 5.45 94.37 ± 6.39 88.37 ±8.48 S Creat (mg%) 1.41 ± 0.47 1.18 ± 0.33 1.08 ± 0.33 1.13 ± 0.41 S Alb (gm%) 2.65 ± 0.69 3.18 ± 0.49 2.90 ± 0.75 3.15 ± 0.63 S Cholesterol (mg%) 300.72 ± 96.16 261.33 ± 119.8 296.00 ± 71.5 220.75 ± 85.26 S. Potassium (meq/l) 3.86 ± 0.45 3.83 ± 0.21 3.76 ± 0.48 3.86 ± 0.21 456 www.japi.org JAPI VOL. 52 JUNE 2004

the study while the other patient had persistent cough, the drug was discontinued and she was excluded from the study. The blood pressure was normalized with dose adjustment in patients with low blood pressure. The rise in serum creatinine was reversible and the level returned to normal. The patients in group B had no side effects. DISCUSSION The severity of proteinuria in patients with nephrotic syndrome correlates strongly with an increase in progression of nephropathy. Moreover, recent clinical trials support the concept that reduction of proteinuria correlates with a slowed progression of nephropathy with preservation of renal function in subjects with proteinuric non-diabetic nephropathies. 8-10 Further, the greater the degree of proteinuria reduction, the greater the slowing of renal disease progression in subjects with non-diabetic nephropathies. 11-12 Thus, heavy proteinuria is responsible for all the clinical manifestations and complications of nephrotic syndrome and the severity of proteinuria is a strong independent risk factor for the progression of renal disease. 13 Therefore, reducing proteinuria should be a therapeutic goal in itself in proteinuric patients with progressive renal failure. This study was the first to evaluate and compare the antiproteinuric effects of ACE inhibitor (ramipril) and non-dihydropyridine CCB (verapamil) in patients of steroid-resistant idiopathic nephrotic syndrome from our country.the present study included 21 steroid resistant idiopathic nephrotic syndrome who were randomized into two groups A and B. Nine of the 11 patients in group A (ramipril), and eight of 10 patients in group B (verapamil) completed the study period. Both groups were comparible at the initiation of the study in terms of mean age, duration of illness, MAP, 24 hours urinary excretion, serum creatinine, albumin, globulin, cholesterol, sodium and potassium. There was a reduction in 24 hours urinary protein excretion in both the groups from baseline but reduction in proteinuria was not statistically significant between the groups at different time intervals of treatment. The significant reduction in proteinuria in patients of type 2 diabetes mellitus treated with verapamil (n=11) and trandolapril (n=12) was noted in a recent study. 7 The anti-proteinuric effect was enhanced when verapamil and trandolapril were combined in comparison to higher doses of either agent alone. The authors observed no statistically significant difference in reduction of proteinuria between verapamil and trandolapril in their study. 7 Thus, our observation was similar to that of Bakris et al. 7 The GISEN group reported significant reduction in proteinuria in patients with non-diabetic nephropathy by one month in ramipril group and it remained below baseline throughout the study period as compared to placebo. In the present study, the group A patients treated with ramipril showed significant reduction in proteinuria by one month and it remained below the initial value throughout the study. Toto et al also reported similar reduction in proteinuria in proteinuric non-diabetic patients. 14 In our study, patients treated with ramipril (n=9); six (66.66%) patients responded to treatment; two (22.22%) patients achieved complete remission of nephrotic syndrome and four (44.44%) patients had proteinuria below nephrotic range. Three (33.33%) patients continued to have nephrotic range proteinuria even at the completion of study. Prashar et al reported reduction of proteinuria in 66.7% of cases below 500 mg/day by 8 weeks treatment with ACE inhibitors in patients of steroid-resistant idiopathic nephrotic syndrome. 15 The decrease in proteinuria was sustained during the follow up of at least 6 months in their study similar to our observation. We observed verapamil also reduced proteinuria significantly in patients of steroid resistant idiopathic nephrotic syndrome. The anti-proteinuric effect of verapamil shown in diabetic patients treated with verapamil (205 ± 16 mg twice daily) was similar to the present study (240mg/day). 7 Bakris et al demonstrated for the first time that nondihydropyridine calcium antagonist has renoprotective effect similar to ACE inhibitors in patients with NIDDM associated nephropathy. 16 Both agents reduce proteinuria by their direct effect on glomerular membrane permeability. The antiproteinuric effect of ramipril and verapamil was independent of cause of nephrotic syndrome and histologic type as well. Of 11 patients in ramipril group, two (18.18%) patients developed cough and one (9.09%) patient each had hypotension and impaired renal function. Toto RD et al reported cough in one (6.67%) patient among 15 patients treated with ramipril. 14 There was no incidence of hypotension in their study. However the dose of ramipril used in their study was lower (1.25 mg/day) than the present study (7.77 ± 3.31 mg/day). Hyperkalemia and death from myocardial infarction during the treatment with ramipril was seen. 9 However we did not observe any episode of hyperkalemia or any cardiac event. The reported side effects of verapamil include; dizziness (25%), constipation (75%), impotence (13%) and insomnia (13%). 16 We observed no side effect in group B (verapamil) patients. This study demonstrated that both ramipril and verapamil have antiproteinuric effect and the degree of reduction in proteinuria was not statistically significant between the two groups. However, reduction in proteinuria was statistically significant from 2nd month onwards in ramipril group and this reduction was sustained throughout the period of 12 months. The significant reduction in proteinuria was achieved only at 12th month of treatment in verapamil group. Reduction in MAP was better achieved in patients treated with ramipril. Ramipril had a sustained antiproteinuric effect with better control of BP and well-maintained serum albumin concentration (within normal limits). Renal function remained stable in both groups. ACE inhibitor (ramipril) can be used safely up to 10 mg/day in patients with steroid-resistant idiopathic nephrotic syndrome. The antiproteinuric effect of verapamil seems to be of clinical relevance in patients with renal insufficiency who cannot tolerate ACE inhibitors due to hyperkalemia or cough. In such patients long-acting nondihydropyridin CCBs should be considered as alternative agents for blood pressure control and as an antiproteinuric measures as well. JAPI VOL. 52 JUNE 2004 www.japi.org 457

REFERENCES 1. Cameron JS, Turner DR, Ogg CS, Chantler C, William DG. The long-term prognosis of patients with focal segmental glomerulosclerosis. Clinical Nephrol 1978;10:213-218. 2. Cameron JS, Turner DR, Heaton J, William DG, et al. Idiopathic mesangiocapillary glomerulonephritis: comparison of type 1 and 2 in children and adult and long term prognosis. Am J Med 1983;74:175-192. 3. Gansevoort RT, de Jong PE. Additive anti-proteinuria effect of ACE inhibition and a low protein diet in human renal disease. Nephrol Dial Transplant 1995;10:497-504. 4. Hemmelder MH, de Zeeruw D, Gansevoort RT, de Jong PE. Blood pressure reduction initiates the antiproteinuric effect of ACE inhibition. Kidney Int 1996;49:174-80. 5. Munter K, Hergenroder S, Joehims K, Kirchengast M. Individual and combined effects of verapamil or trandolapril on glomerular morphology and function in the stroke prone rat. J Am Soc Nephrol 1996;7:681-686. 6. Tarif, Bakris GS. Preservation of renal function: the spectrum of effects by calcium channel blocker. Nephrol Dial Transplant 1997;12:2244-50. 7. Bakris GL, Weir MR, De Quattro V, Mc Mohan FG. Effects of an ACE inhibitor/calcium antagonist combination on proteinuria in diabetic nephropathy. Kidney Int 1998;54:1283-89. 8. Giuserre M, Daniele A, Gerard J, et al. the angiotensinconverting enzyme inhibitor on progressive renal insufficiency. Engl J Med 1996;334:939-45. 9. Peterson JC, Adler S, Burkart J, et al. Blood pressure control, proteinuria and the progression of renal disease. The modification of diet in renal disease study. Ann Intern Med 1995;l23:754-762. 10. Locatelli F, Carbarns M, Mascleia G, et al. Long term progression of chronic renal insufficiency in the AIPRI extension study. The angiotensin-converting enzyme inhibition on progressive renal insufficiency study group. Kidney Int 1997;52(suppl 63):563-566. 11. The GISEN Group (Grupp Italiano di study Epidemiologici in Nephrologia). Randomized placebo controlled trial of effect of ramipril in decline in glomerular filtration rate and risk of terminal renal failure in proteinuric, non-diabetic nephropathy (REIN study). Lancet, 1997; 349: 1857-63. 12. Ruggenenti P, Perne A, Gherard G, et al. (REIN study). Renoprotective properties of ACE inhibitor in non-diabetic nephropathies with non-nephrotic proteinuria. Lancet 1999;354:359-64. 13. Burton C, and Harris KPG. The role of proteinuria in the progression of chronic renal failure. Am J Kid Dis 1996;27:765-75. 14. Toto RD, Adams Huet B, Fenues AZ, Mitchell HC, Mulcahy W, Smith RD. Effect of ramipril on blood pressure and protein excretion rate in normotensive non diabetic patients with proteinuria. Am J Kid Dis 1996;28:832-40. 15. Prasher PK, Varma PP, Baliga KV. Efficiency of enalapril in the treatment of steroid resistant idiopathic nephrotic syndrome. J Assoc Phys India 1999;47:180-182. 16. Bakris GL, Copley JB, Vicknair N, Sadler R, Leurgans S. Calcium channel blockers versus other anti-hypertensive therapies on progression of NIDDM associated nephropathy. Kidney Int 1996;50:1641-50. Announcement Conference on Idiopathic Thrombocytopenic Purpura (ITP) Dr. JC Patel Medical Research Foundation and Smt SC Mehta Hematology Department, BSES MG Hospital, are organizing a Conference on ITP on 9,10, October, 2004 in Mumbai. Topics to be covered in the conference are - Pathogenesis of thrombocytopenia, ITP in children, ITP in adults, Problems in ITP, Clinical diagnosis of ITP, Laboratory diagnosis of ITP, Special investigations in ITP, Differential diagnosis of ITP, Problem solving in ITP, Objectives of treatment in ITP, Treatment of acute ITP, Treatment of chronic ITP, Treatment of refractory ITP, Role of ivig in treatment of ITP, Family physician and ITP, Problems of ITP in obstetric-gynec practice, ITP and menorrhagia, ITP in pregnancy, ITP and surgeon, Splenectomy in ITP, Laparoscopic splenectomy in ITP, Surgery in patients with ITP, ITP and lay people. It is proposed to form ITP Study Group and ITP Support Group during the conference. All clinicians who deal with ITP patients would benefit from the conference. For further details contact : Prof. BC Mehta, BSES MG Hospital, SV Rd, Andheri West, 400 058. E-mail : labmed@ghrc-bk.org 458 www.japi.org JAPI VOL. 52 JUNE 2004