Dual Therapy with ACE Inhibitors and Angiotensin II Receptor Blockers in Proteinuric IgA Nephropathy Patients

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1 Brief Communication Dual Therapy with ACE Inhibitors and Angiotensin II Receptor Blockers in Proteinuric IgA Nephropathy Patients Kai-Ming Chow, Cheuk-Chun Szeto, Bonnie Ching-Ha Kwan, Chi-Bon Leung, Kwok-Yi Chung, Philip Kam-Tao Li Experimental evidence supports dual pharmacologic blockade of the renin angiotensin system with angiotensinconverting enzyme inhibitors and angiotensin II receptor blockers in proteinuric renal disease. Nonetheless, exaggerated therapeutic benefits are frequently the rule rather than the exception in the experimental or trial setting. The difference between the clinical trial setting (efficacy) and actual practice (effectiveness) should be borne in mind before the recommendation of any new therapy as the standard of care. With this in mind, we examined the effectiveness and safety of dual therapy on a cohort of adults with proteinuric IgA nephropathy in a usual clinical setting. The primary end point was reduction in proteinuria, which has been shown to be a significant risk factor for end-stage renal disease. [Hong Kong J Nephrol 2007;9(2):89 93] Key words: angiotensin-converting enzyme (ACE) inhibitor, angiotensin II receptor blocker, IgA nephropathy, outcome, proteinuria!"#$%&'()*+,-./01=e~åöáçíéåëáåjåçåîéêíáåö=éåòóãé=áåüáäáíçêëf=!"#!"=e~åöáçíéåëáå=ff=êéåééíçê=ääçåâéêëf= J!"#$=EêÉåáå ~åöáçíéåëáå=ëóëíéãf=!"#$%&'()*+,-./0123"456789:;<=>?@a/"bcd!"#$%&'!()* +,-./ :;<=>?@ABC=fÖ^!"#$%&'()'*+,-./ !89:;<=>?@A)BCDE!"#$= =!"#$%&'()*+, INTRODUCTION The weight of experimental evidence supports dual pharmacologic blockade of the renin angiotensin system with angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers in proteinuric renal disease [1,2]. Nonetheless, exaggerated therapeutic benefits are frequently the rule rather than the exception in the experimental or trial setting. As compared to the realistic clinical situation, the carefully controlled setting of well-funded trials reveal how treatments work under ideal instead of customary conditions. The difference between the clinical trial setting (efficacy) and actual practice (effectiveness) should be borne in mind before recommendation of any new therapy as the standard of care. With this in mind, we examine the effectiveness and safety of dual therapy on a cohort of adults with proteinuric IgA nephropathy in usual clinical setting. The primary end point was the reduction in proteinuria, which has been shown to be a significant risk factor for end-stage renal disease [3]. METHODS In a single-center observational uncontrolled study, we recruited patients with biopsy-proven IgA nephropathy who demonstrated persistent proteinuria exceeding 1 g daily despite monotherapy with either ACE inhibitors or angiotensin II receptor blockers (using maintenance defined daily dose of at least 1.0) Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong SAR, China. Address correspondence and reprint requests to: Dr. Kai-Ming Chow, Department of Medicine and Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong SAR, China. Fax: (+852) ; Chow_Kai_Ming@alumni.cuhk.net Hong Kong J Nephrol October 2007 Vol 9 No 2 89

2 K.M. Chow, et al for a minimum of 3 months. All subjects had clinically significant proteinuria over 1 g daily on two or more consecutive measurements 8 weeks apart. As such, exclusion criteria were kept to a minimum. After the baseline evaluation, patients were administered dual therapy with ACE inhibitors and angiotensin II receptor blockers, the choice and dose of which were at the discretion of nephrologists. Titration schedule was not mandated. The pragmatic nature of this study allowed the choice of medications to be decided by the physician, in keeping with real life and generalizability. None of them were administered steroids, cyclophosphamide or azathioprine. Chronicity-based histologic grading of IgA nephropathy was defined on the extent of glomerular sclerosis (glomerular grading), the degree of tubular loss or interstitial fibrosis (tubulointerstitial grading), and the evaluation of hyaline arteriolosclerosis [4 6]. Patients were monitored at every 3-monthly outpatient clinic visit. In terms of treatment outcomes, we measured the average blood pressure, serum potassium, creatinine and daily protein excretion. Treatment response was evaluated within 6 months of dual therapy, because the maximum antiproteinuric effect by virtue of the renin angiotensin system blockade is in general observed soon after starting treatment, usually within 6 months [7]. Blood pressure parameters in our study were quantified as the timeaveraged readings over a period of 6 months before and after dual therapy. Glomerular filtration rate was estimated by the abbreviated version of the Modification of Diet in Renal Disease (MDRD) Study equation, which has been modified and validated in Chinese patients with chronic kidney disease [8]. Dose titration of medication was allowed to target blood pressure control, taking into account the control of proteinuria and adverse effects including hyperkalemia. Because prescription of different ACE inhibitors and angiotensin II receptor blockers were allowed, we calculated the defined daily dose (DDD) in order to compare doses of different drugs within a class [9]. RESULTS Between April 2005 and January 2007, 12 patients (mean age, 40.9 ± 6.5 years; 6 men and 6 women) in the outpatient renal department received dual ACE inhibitors and angiotensin II receptor blockers for IgA nephropathy when proteinuria exceeded 1 g daily during monotherapy. No patient was lost to follow-up. Table 1 summarizes their clinical and demographic characteristics. In particular, over half of them (7 patients) had at least stage 3 chronic kidney disease with estimated glomerular filtration rate < 60 ml/min/ 1.73 m 2. The median duration of IgA nephropathy was Table 1. Baseline characteristics of the study cohort* Demographics Age (yr) 40.9 ± 6.5 (30 50) Gender (male/female) 6/6 Weight (kg) 61.4 ± 11.9 BMI (kg/m 2 ) 23.0 ± 3.7 Hypertension Systolic BP (mmhg) ± 15.0 Diastolic BP (mmhg) 75.4 ± 13.0 Number of antihypertensive drugs given 1.5 [1, 2.75] Renal function and biochemistry Serum creatinine (µmol/l) ± 63.0 Estimated GFR (ml/min/1.73 m 2 ) 59.8 ± 22.9 Urinary protein excretion (g/d) 2.35 [1.63, 4.28] Serum potassium (mmol/l) 4.15 ± 0.35 Renal biopsy and histologic finding Median duration of diagnosis (yr) 8.5 Glomerular grade (1/2/3) 8/4/0 Tubulointerstitial grade (1/2/3) 7/5/0 Presence of hyaline arteriolosclerosis (%) 25 *Data are presented as mean ± standard deviation (range) or median [interquartile range] unless otherwise stated; to convert serum creatinine in µmol/l to mg/dl, divide by 88.4; to convert GFR in ml/min to ml/s, multiply by ; estimated GFR was assessed by the modified MDRD equations based on and validated in Chinese patients with chronic kidney disease [8]. BMI = body mass index; BP = blood pressure; GFR = glomerular filtration rate. 8.5 years (mean, 7.7 ± 5.9 years) since biopsy diagnosis. Mean proteinuria values at baseline were 2.84 ± 1.32 g daily (median, 2.35; interquartile range, g daily). Optimal blood pressure control was achieved during monotherapy; the average systolic blood pressure and mean arterial pressure were ± 15.0 mmhg and 89.7 ± 13.3 mmhg, respectively, at baseline. The majority of the patients in this study (11 patients) received ACE inhibitors first, followed by addition of angiotensin II receptor blockers. At baseline, the median DDD of ACE inhibitors received by patients was 2.0 (range, ). None of the patients received concomitant spironolactone or aldosterone antagonists during the observation period. After dual therapy, the dose of ACE inhibitors was reduced in general, with a median DDD of 1.0 (range, ). Median DDD of angiotensin II receptor blockers during dual therapy was 1.0 (range, ). The two most commonly prescribed angiotensin II receptor blockers in the cohort were telmisartan and valsartan. Table 2 shows the detailed data before and after dual therapy. Proteinuria decreased in nine (75%) subjects after dual therapy. The median percentage reduction in proteinuria was 32.6% (median reduction, 900 mg daily) decline over baseline. Despite a similar degree 90 Hong Kong J Nephrol October 2007 Vol 9 No 2

3 Dual therapy in IgA nephropathy Table 2. Detailed laboratory and clinical data before and after dual therapy with ACE inhibitors and angiotensin II receptor blockers* Parameter Before dual therapy After dual therapy p Treatment Lisinopril, 2.5/5/10/20 mg/d 0/0/4/3 1/1/3/2 Ramipril, 2.5/5/10 mg/d 1/2/1 2/2/0 Perindopril, 2 mg/d 0 1 Not Valsartan, 80 mg/d 1 5 applicable Telmisartan, 20/40 mg/d 0 4/2 Losartan, 25 mg/d 0 1 Proteinuria (g/d) 2.35 [1.63, 4.28] 1.65 [0.76, 2.17] Serum potassium (mmol/l) 4.15 ± ± Serum creatinine (µmol/l) ± ± Estimated GFR (ml/min/1.73 m2) 59.8 ± ± Mean arterial pressure (mmhg) 89.7 ± ± *Data are presented as mean ± standard deviation (range) or median [interquartile range] unless otherwise stated; comparison with baseline using Wilcoxon signed rank test; to convert serum creatinine in µmol/l to mg/dl, divide by 88.4; to convert GFR in ml/min to ml/s, multiply by ; estimated GFR was assessed by the modified MDRD equations based on and validated in Chinese patients with chronic kidney disease [8]. GFR = glomerular filtration rate. Urinary protein (g/d) Before dual therapy p = After dual therapy Two patients developed transient hyperkalemia after dual therapy, which normalized by dietary advice and/ or adding diuretic (without discontinuation of dual therapy). In general, no significant increase in serum potassium concentration (4.29 ± 0.37 compared with 4.15 ± 0.35 mmol/l at baseline, p = 0.11) occurred. None of our patients experienced symptomatic postural hypotension, angioedema or acute renal failure. A rising trend of serum creatinine was detected before and after dual therapy, with an increase in the mean value over 6 months from ± 63.0 to ± 56.9 µmol/l (p = 0.002). No conclusion can be made regarding the long-term renoprotective effect owing to the short-term follow-up; it cannot be readily ascertained by measuring serum creatinine concentrations over a period of only 6 months before and after dual therapy. Figure. Effects of dual therapy with ACE inhibitors and angiotensin II receptor blockers on proteinuria. of blood pressure control, dual therapy with ACE inhibitors and angiotensin II receptor blockers resulted in a significant decrease in proteinuria (Figure) from a median value of 2.35 g daily (interquartile range, ) at baseline to 1.65 g daily (interquartile range, ) (p = 0.023). In addition, there were no correlations between proteinuria reduction and changes in mean arterial pressure after dual therapy. DISCUSSION Our results confirm the reproducible antiproteinuric benefit of dual therapy with ACE inhibitors and angiotensin II receptor blockers among patients with proteinuric IgA nephropathy in a routine clinical setting. Another notable finding of the study was that the significant reduction of proteinuria seems to be independent of blood pressure reduction. Compared to the standalone strategy using either ACE inhibitors or angiotensin II receptor blockers, the effect of dual Hong Kong J Nephrol October 2007 Vol 9 No 2 91

4 K.M. Chow, et al therapy in our study was a 32.6% reduction in proteinuria. This is quantitatively comparable to those seen in other randomized trials of dual therapy for nondiabetic proteinuric kidney disease, in which lowering in proteinuria between 10% and 40% have been reported [10 12]. The mechanisms that underlie the observed benefit could relate to additive advantage of blocking angiotensin II production completely in addition to increasing bradykinin levels [1]. In particular, recent evidence suggests that ACE inhibitors may not completely block the formation of angiotensin II due to upregulation of non-ace-dependent pathways, a phenomenon known as ACE escape [1,13]. How about additional mechanisms specific to IgA nephropathy? Recent publications emphasize the putative role of angiotensin II receptor blockers in modifying pore size distribution by reducing the radius of large unselective pores, thus resulting in less leakage of protein into the urine [14]. Another proposed mechanism by which dual therapy exerts a benefit in IgA nephropathy involves the reduction in urinary transforming growth factor- levels [15,16]. Apart from our recent double-blind randomized placebo-controlled study showing the superior antiproteinuric effect of angiotensin II receptor blockers in IgA nephropathy [17], accumulating data support the effect of dual therapy in IgA nephropathy. Buttressing the literature are several clinical trials that reaffirmed the antiproteinuric benefit of dual therapy exclusively in IgA nephropathy subjects, including pediatric [18] and adult patients [19,20]. Notably, the additive antiproteinuric effect after combining ACE inhibitors and angiotensin II receptor blockers in 43 normotensive patients with IgA nephropathy was confirmed regardless of aldosterone breakthrough [19], as measured by the plasma aldosterone rise during treatment. Taken together, systematic reviews and metaanalyses of randomized controlled trials have provided ample evidence that combining an ACE inhibitor with an angiotensin II receptor blocker provides an additional decrease in proteinuria over monotherapy in nondiabetic kidney disease [2]. These findings are bolstered by the consistency or reproducibility as demonstrated in our study, whose setting resembles the real world situation where patients usually come under medical attention after proteinuria has been present for some time already, when treatment was started at a relatively late stage of chronic kidney disease. In fact, the most striking difference between our study and previous controlled trials was our reporting the antiproteinuric effect in an everyday clinical setting. In particular, no significant rise in serum potassium level, a major concern with dual therapy, was observed even in situations outside the judiciously controlled setting, although our sample size was small. Our findings have several implications for ongoing clinical research. There remains a paucity of evidence regarding the optimum dose of ACE inhibitors and angiotensin II receptor blockers. It is anticipated that the growing application of dual therapy for blockade of the renin angiotensin system and dose-escalation studies will help to determine the best strategy of drug dose. Likewise, the growing interest in aldosterone blockade, by spironolactone for instance, holds promise for more effective proteinuria reduction [21]. On the other hand, our observational study has several limitations, related both to being an observational study in general and to this study in particular. Observational studies are never a substitute for a properly performed, adequately powered randomized controlled trial. However, this study provides information on therapeutic benefits in real clinical practice. The second limitation of our study is the uncontrolled and non-blinded design, without a comparison group. We cannot overrule the possibility that the superior antiproteinuric effect achieved by dual therapy may well be obtained by simply increasing the dose of monotherapy, for instance, with ACE inhibitor. Furthermore, a question of interest is whether the additive antiproteinuric effect of dual therapy is sustained over time. However, it is noteworthy that IgA nephropathy constituted 50% of primary diagnosis among recruited subjects from the COOPERATE trial (combination treatment of angiotensin II receptor blocker and ACE inhibitor in nondiabetic renal disease) [22], which is thus far the largest of parallel-group studies with the highest quality and longest treatment duration (3 years) [2] to demonstrate the therapeutic benefit of dual therapy. In addition, according to another long-term parallel-group study, in which 52% of patients had IgA nephropathy, treatment benefit of proteinuria reduction after dual therapy was sustained for 3 years, accompanied by slowing of renal function deterioration [23]. A fourth limitation was that we did not measure plasma renin activities and plasma aldosterone levels, and cannot dissect the effect of dual therapy on the degree of renin angiotensin system blockade. Also, we are underpowered to discern the differences between the responders and nonresponders to dual therapy. Finally, a cautionary note should be made for the putative benefit ascribed to proteinuria reduction as surrogate outcomes [24]. This is based on the premise that amelioration of the progression of renal disease is accompanied by a decrease in proteinuria. There is mounting evidence to suggest that, in addition to blood pressure control, proteinuria should be considered as an independent risk factor and an important treatment target for renal protection [25]. Reduction of proteinuria with renin angiotensin system blockade results in salutary protection against protein-induced renal fibrosis, which should theoretically translate into preservation of renal function in the long run [1,26]. 92 Hong Kong J Nephrol October 2007 Vol 9 No 2

5 Dual therapy in IgA nephropathy Although proteinuria has been shown to correlate with renal outcome, a more definitive evaluation of dual therapy should preferably be based on hard clinical end points (such as doubling of serum creatinine levels and development of end-stage renal disease). In conclusion, we analyzed anecdotal observational data on dual therapy with ACE inhibitors and angiotensin II receptor blockers among IgA nephropathy patients with proteinuria exceeding 1 g daily despite monotherapy, to determine the therapeutic effects in usual clinical practice. Our analysis showed that dual therapy is effective in the reduction of proteinuria, independent of blood pressure lowering effect, compared with monotherapy. REFERENCES 1. Wolf G, Ritz E. Combination therapy with ACE inhibitors and angiotensin II receptor blockers to halt progression of chronic renal disease: pathophysiology and indications. Kidney Int 2005; 67: MacKinnon M, Shurraw S, Akbari A, Knoll GA, Jaffey J, Clark HD. Combination therapy with an angiotensin receptor blocker and an angiotensin receptor blocker and an ACE inhibitor in proteinuric renal disease: a systemic review of the efficacy and safety data. Am J Kidney Dis 2006;48: Wilmer WA, Rovin BH, Hebert CJ, Rao SV, Kumor K, Hebert LA. Management of glomerular proteinuria: a commentary. J Am Soc Nephrol 2003;14: To KF, Choi PC, Szeto CC, Li PK, Tang NL, Leung CB, et al. Outcome of IgA nephropathy in adults graded by chronic histological lesions. Am J Kidney Dis 2000;35: Lai FM, Szeto CC, Choi PC, Li PK, Chan AW, Tang NL, et al. Characterization of early IgA nephropathy. Am J Kidney Dis 2000; 36: Lai FM, Szeto CC, Choi PC, Li PK, Tang NL, Chow KM, et al. Primary IgA nephropathy with low histologic grade and disease progression: is there a point of no return? Am J Kidney Dis 2002;39: Fernandez-Juárez G, Barrio V, de Vinuesa SG, Goicoechea M, Praga M, Luno ~ J. Dual blockade of the renin angiotensin system in the progression of renal disease: the need for more clinical trials. J Am Soc Nephrol 2006;17:S Ma YC, Zuo L, Chen JH, Luo Q, Yu XQ, Li Y, et al. Modified glomerular filtration rate estimating equation for Chinese patients with chronic kidney disease. J Am Soc Nephrol 2006;17: World Health Organization Collaborating Centre for Drug Statistics Methodology Anatomical Therapeutical Chemical (ATC) (1994) Classification Index Including Defined Daily Doses (DDDs) for Plain Substances. Oslo: WHO. Available at [Date accessed: March 25, 2007] 10. Berger ED, Bader BD, Ebert C, Risler T, Erley CM. Reduction of proteinuria; combined effects of receptor blockade and low-dose angiotensin-converting enzyme inhibition. J Hypertens 2002;20: Kincaid-Smith P, Fairley K, Packham D. Randomized controlled crossover study of the effect on proteinuria and blood pressure of adding an angiotensin II receptor antagonist to an angiotensin converting enzyme inhibitor in normotensive patients with chronic renal disease and proteinuria. Nephrol Dial Transplant 2002;17: Rutkowski P, Tylicki L, Renke M, Korejwo G, Zdrojewski Z, Rutkowski B. Low-dose dual blockade of the renin angiotensin system in patients with primary glomerulonephritis. Am J Kidney Dis 2004;43: Hollengberg NK, Osei SY, Lansang MC, Price DA, Fisher ND. Salt intake and non-ace pathways for intrarenal angiotensin II generation in man. J Renin Angiotensin Aldosterone Syst 2001;2: Woo KT, Lau YK, Wong KS, Chiang GS. ACEI/ATRA therapy decreases proteinuria by improving glomerular permselectivity in IgA nephritis. Kidney Int 2000;58: Song JH, Lee SW, Suh JH, Kim ES, Hong SB, Kim KA, Kim MJ. The effects of dual blockade of the renin angiotensin system on urinary protein and transforming growth factor-beta excretion in 2 groups of patients with IgA and diabetic nephropathy. Clin Nephrol 2003;60: Park HC, Xu ZG, Choi S, Goo YS, Kang SW, Choi KH, et al. Effect of losartan and amlodipine on proteinuria and transforming growth factor- 1 in patients with IgA nephropathy. Nephrol Dial Transplant 2003;18: Li PK, Leung CB, Chow KM, Cheng YL, Fung SK, Mak SK, et al; HKVIN Study Group. Hong Kong study using valsartan in IgA nephropathy (HKVIN): a double-blind, randomized, placebocontrolled study. Am J Kidney Dis 2006;47: Yang Y, Ohta K, Shimizu M, Nakai A, Kasahara Y, Yachie A, Koizumi S. Treatment with low-dose angiotensin-converting enzyme inhibitor (ACEI) plus angiotensin II receptor blocker (ARB) in pediatric patients with IgA nephropathy. Clin Nephrol 2005;64: Horita Y, Taura K, Taguchi T, Furusu A, Kohno S. Aldosterone breakthrough during therapy with angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers in proteinuric patients with immunoglobulin A nephropathy. Nephrology (Carlton) 2006;11: Russo D, Pisani A, Balletta MM, De Nicola L, Savino FA, Andreucci M, Minutolo R. Additive antiproteinuric effect of converting enzyme inhibitor and losartan in normotensive patients with IgA nephropathy. Am J Kidney Dis 1999;33: Ponda MP, Hostetter TH. Aldosterone antagonism in chronic kidney disease. Clin J Am Soc Nephrol 2006;1: Nakao N, Yoshimura A, Morita H, Takada M, Rayano T, Ideura T. Combination treatment of angiotensin-converting-enzyme inhibitor in non-diabetic renal disease (COOPERATE): a randomised controlled trial. Lancet 2003;361: Kanno Y, Takenaka T, Nakamura T, Suzuki H. Add-on angiotensin receptor blocker in patients who have proteinuric chronic kidney diseases and are treated with angiotensin-converting enzyme inhibitors. Clin J Am Soc Nephrol 2006;1: Reddan DN, Owen WF Jr. IgA nephropathy inhibitors of the renin angiotensin system: is reduction in proteinuria adequate proof of efficacy? Am J Kidney Dis 2001;38: Jafar TH, Stark PC, Schmid CH, Landa M, Maschio C, de Jong PE, et al; AIPRD Study Group. Progression of chronic kidney disease: the role of blood pressure control, proteinuria, and angiotensin-converting enzyme inhibition: a patient-level metaanalysis. Ann Intern Med 2003;139: Ruggenenti P. Angiotensin-converting enzyme inhibition and angiotensin II antagonism in nondiabetic chronic nephropathies Semin Nephrol 2004;24: Hong Kong J Nephrol October 2007 Vol 9 No 2 93