Treatment of Early Immunoglobulin A Nephropathy by Angiotensin-converting Enzyme Inhibitor

CLINICAL RESEARCH STUDY Treatment of Early Immunoglobulin A Nephropathy by Angiotensin-converting Enzyme Inhibitor Philip Kam-Tao Li, MD, Bonnie Ching-Ha Kwan, MBBS, Kai-Ming Chow, MBChB, Chi-Bon Leung, MBChB, Cheuk-Chun Szeto, MD Department of Medicine & Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong, China. ABSTRACT BACKGROUND: The treatment of immunoglobulin A (IgA) nephropathy with normal renal function and minimal proteinuria is unknown. METHODS: We randomly assigned 60 patients with IgA nephropathy, proteinuria 0.5 g/day, normal blood pressure and renal function to ramipril 2.5 mg daily or no treatment. Patients were followed for 5 years for the development of hypertension, proteinuria, or impaired renal function. RESULTS: The blood pressure of the treatment group was marginally lower than the control group throughout the study period. At 60 months, the event-free survival was marginally higher for the treatment group as compared with the control group (81.1% vs 70.5%, P.27). The proteinuria-free survival was similar at 82.9% and 79.3% for the treatment and control groups, respectively (P.6); hypertension-free survival was 86.4% and 79.3% (P.2). After 60 months of follow-up, the estimated glomerular filtration rate (GFR) was 108.1 29.0 ml/min/1.73 m 2 for the treatment group and 105.7 17.7 ml/min/1.73 m 2 for the control group (P.7), but the difference was not statistically significant. None of the patients developed impaired renal function. The rate of GFR decline was similar between the treatment and control groups ( 0.39 2.57 vs 0.59 1.63 ml/min/1.73 m 2 per year, respectively, P.7). In general, the study medication was well tolerated. Two patients needed to stop prematurely because of cough and dizziness. CONCLUSION: For early IgA nephropathy patients with minimal proteinuria, normal blood pressure, and normal renal function, treatment with 2.5 mg/daily of ramipril for 5 years does not offer any benefit. 2013 Elsevier Inc. All rights reserved. The American Journal of Medicine (2013) 126, 162-168 KEYWORDS: Chronic kidney disease; Proteinuria; Renin-angiotensin system Immunoglobulin A (IgA) nephropathy is the most common type of glomerulonephritis worldwide. 1 It causes end-stage renal disease in 15%-20% of individuals within 10 years of Funding: This study was supported in part by Sanofi-Aventis Pharma Hong Kong Limited, and the Chinese University of Hong Kong research accounts 6901031 and 7101215. The funding sources have no influence on the protocol development, data analysis, or preparation of this manuscript. Conflict of Interest: All authors have completed the Unified Competing Interest form and declare no other support from any organization for the submitted work; no financial relationships with any organizations that might have an interest in the submitted work in the previous 3 years, and no other relationships or activities that could appear to have influenced the submitted work. Authorship: All authors had access to the data and played a role in writing this manuscript. Requests for reprints should be addressed to Cheuk-Chun Szeto, MD, Department of Medicine & Therapeutics, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, Hong Kong, China. E-mail address: ccszeto@cuhk.edu.hk onset, 2,3 and in 30%-35% of individuals within 20 years of onset. Proteinuria, an elevated serum creatinine concentration, hypertension, and advanced, chronic disease in kidney biopsy predict progression. 4 Although patients who present with isolated hematuria, either macroscopic or microscopic, are often believed to have better prognoses, 5,6 recent data show that many of the patients develop hypertension and impaired renal function with time. 7 The treatment of IgA nephropathy with normal renal function and minimal proteinuria is unknown. Previous studies showed that angiotensin-converting enzyme (ACE) inhibitors reduce proteinuria 8-10 and retard the rate of decline of renal function in chronic proteinuric nephropathies, including IgA nephropathy. 11-13 There has been no study on treating early IgA nephropathy. In the present study, we evaluate the efficacy of the ACE inhibitor ramipril in the treatment of early IgA nephropathy. 0002-9343/$ -see front matter 2013 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjmed.2012.06.028

Li et al ACEI for Early IgAN 163 PATIENTS AND METHODS Patient Selection This was an open-label randomized controlled study. From February 2004 to September 2005, a total of 60 IgA nephropathy patients were recruited. We recruited patients who were Exclusion criteria were: expected survival 2 years; pregnant or nursing mother, or women of childbearing potential without an effective method of birth control; history of myocardial infarction, congestive heart failure, or any other medical indication that necessitates the use of ACE inhibitor; evidence of clinically significant hepatic, gastrointestinal, autoimmune disease; history of malignancy, drug or alcohol abuse; participation in any previous trial on ACE inhibitor; taking other investigational drugs within the past 30 days; history of noncompliance to medical regimens and patients who are considered potentially unreliable; or known history of sensitivity or allergy to ACE inhibitor. The study was approved jointly by the Chinese University of Hong Kong New Territories East Cluster Clinical Research Ethics Committee (ClinicalTrials.gov ID NCT01225445). aged between 18 and 65 years, had biopsy-confirmed IgA nephropathy, proteinuria 0.5 g per day, normal blood pressure, and serum creatinine below 120 mol/l. For all recruited patients, renal biopsy specimen was reviewed by pathologists by conventional methods. 4,14 CLINICAL SIGNIFICANCE Treatment Assignment After written informed consent, patients were randomized either to receive ramipril 2.5 mg daily or no treatment. Patients were randomized by a computer-generated list, which was generated and maintained by a third party that was not involved in the conduction of the study. The dosage of ramipril was maintained throughout the study period if there was no adverse effect. After recruitment, patients were followed at 4, 12, and 24 weeks, and then every 24 weeks for 5 years. During every visit, we measured body weight, blood pressure, pulse rate, renal function test, and proteinuria as quantified by spot urine for protein-to-creatinine ratio. Information about adverse events was collected by direct questioning and recorded. An adverse event was defined as any undesirable symptom or medical condition occurring after starting the study medication, whether considered drug related or not. For patients with early IgA nephropathy and minimal proteinuria, normal blood pressure and renal function, ramipril treatment for 5 years does not offer any benefit. A watchful waiting strategy should be adopted for patients with IgA nephropathy and proteinuria 0.5 g/day. Study End Point The primary end point of the study is any one of the following: 1) development of hypertension (defined as blood pressure above 140/90 mm Hg or the need of antihypertensive therapy); 2) development of proteinuria 1 g per day; and 3) 20% decline in the estimated glomerular filtration rate (GFR), which was computed by an equation validate in Chinese. 15 The slope of decline of the estimated GFRs also were compared. Sample Size Estimation The sample size was estimated by the Power Analysis and Sample Size for Windows software (PASS 2000, NCSS, Kaysville, Utah). We use the confidence interval theory to estimate the sample size. Based on our previous study, 7 proteinuria or hypertension develop in 40% of untreated patients in 5 years. On the other hand, prolonged ramipril therapy is expected to prevent the progression of chronic proteinuric nephropathies in approximately 50% of cases. 11-13 A one-sided log-rank test with an overall sample size of 60 subjects achieves, at a 0.05 significance level, detection of a difference of 0.2 between 0.6 and 0.8 the proportions surviving in groups 1 and 2, respectively. This corresponds to a hazard ratio of 0.4368. These results are based on the assumption that the hazard rates are proportional. Statistical Analysis Statistical analysis was performed by SPSS for Windows software version 15.0 (SPSS Inc., Chicago, Ill). Data were expressed in mean SD and analyzed on intention-to-treat basis. Data are compared by chi-squared test or Student s t-test as appropriate between treatment groups. Event-free survival was computed by the Kaplan-Meier analysis; the time to develop primary end point was compared by the log-rank test. A P value of below.05 was considered significant. All probabilities were 2-tailed. RESULTS We recruited 60 patients. Their baseline clinical and histological characteristics are summarized in Tables 1 and 2, respectively. None of the patients had been treated with corticosteroid or fish oil. The CONSORT flowchart is summarized in Figure 1. The blood pressure throughout the study period is summarized in Figure 2. In short, the treatment group had a significantly lower blood pressure than the control group (P.001 for both systolic and diastolic blood pressure), although the absolute difference in blood pressure between the groups was only modest. Primary End Point During the study period, 9 patients (3 men) of the treatment group and 11 of the control group (1 man) developed the

164 The American Journal of Medicine, Vol 126, No 2, February 2013 Table 1 Baseline Characteristics of the Recruited Patients Treatment Control P Value No. of patients 30 30 Sex (M:F) 9:21 4:26.12 Age (years) 42.2 11.0 41.0 7.5.6 Duration of disease 78.5 77.3 75.9 75.0.7 (months) Body weight (kg) 57.1 9.6 57.4 10.9.9 Blood pressure (mm Hg) Systolic 115.5 13.0 114.2 16.3.7 Diastolic 69.6 10.3 70.1 9.3.8 Serum creatinine (ìmol/l) 77.4 16.8 75.4 12.2.6 egfr (ml/min/1.73 m 2 ) 106.8 20.9 102.9 15.2.4 Urine protein (g:g-cr) 0.10 0.13 0.12 0.13.4 egfr estimated glomerular filtration rate. primary end point. Patients who developed primary end point had a higher baseline proteinuria than those who did not (0.18 0.13 vs 0.07 0.11 g/day, P.002). There was no significant difference between age, baseline blood pressure, or estimated GFR between patients who did and did not develop primary end point (details not shown), and their histological characteristics also were similar (Table 2). Patients sex had no significant interaction with treatment group on the development of primary end point (P.6 for interaction). After 60 months of follow-up, the estimated GFR was 108.1 29.0 ml/min/1.73 m 2 for the treatment group and 105.7 17.7 ml/min/1.73 m 2 for the control group (P 0.7). At 60 months, the event-free survival was marginally higher for the treatment group as compared with the control group (81.1% vs 70.5%, P.266) (Figure 3), but the difference was not statistically significant. The rate of GFR decline was similar between the treatment and control groups ( 0.39 2.57 vs 0.59 1.63 ml/min/1.73 m 2 per year respectively, P.7). The cause of primary end point is compared between the groups and summarized in Table 3. At 60 months, the proteinuria-free survival was 82.9% and 79.3% for the treatment and control groups, respectively (P.636); the hypertension-free survival was 86.4% and 79.3% for the treatment and control groups, respectively (P.185) (Figure 4). None of the patients developed impaired renal function during the study period. Adverse Effects In general, the study medication was well tolerated. Among the treatment group, 3 patients reported cough and 2 reported dizziness. The study medication had to be stopped in 2 patients (one for each reason). No other major adverse effect was noted. In addition, 1 patient of the treatment group, and 2 of the control group, were lost to follow-up during the study period. DISCUSSION Although IgA nephropathy is the most common primary glomerulonephritis in the world, its best treatment remains undefined. For patients with minimal proteinuria and normal renal function, it remains unknown whether treatment is necessary. In this open-label randomized control trial, we found that treatment with 2.5 mg daily of ramipril, an ACE inhibitor, for 5 years offers very little, if any, benefit to patients with early IgA nephropathy. Our finding is consistent with previous studies on other chronic proteinuria nephropathy. 11,16 For example, the Ramipril Efficacy in Nephropathy (REIN) study found that patients with proteinuria of 2 g/day or greater gained the most benefit from ACE inhibitor treatment. 11 Similarly, the African American Study of Kidney Disease and Hypertension (AASK) Study found that ramipril, as compared with amlodipine, retards renal disease progression in patients with hypertensive renal disease and proteinuria over 0.3 g/day. 16 It is important to realize that in the present study, we recruited patients with proteinuria below 0.5 g/day. To the best of our knowledge, there is no randomized control study that specifically targets patients with IgA nephropathy (or any other nondiabetic chronic proteinuric disease) and a proteinuria between 0.5 and 1.0 g/day. Further research is Table 2 Baseline Histological Characteristics* Treatment Control P Value No. of patients 30 (9) 30 (11) Morphologic score distribution.7 Grade I 26 (8) 27 (10) Grade II 4 (1) 3 (1) Prognostic score distribution Glomerular grading (GG).08 GG 1 29 (9) 30 (11) GG 2 1 (0) 0 Tubulointerstitial grading.3 (TIG) TIG 1 24 (6) 25 (10) TIG 2 7 (3) 4 (1) Hyaline arteriolosclerosis.3 (HA) Absent 22 (6) 25 (11) Present 8 (3) 5 (0) *Numbers in parentheses indicate the number of patients who developed primary end point. Determined in accordance with the classification by Haas, 4 taking into account the degree of mesangial proliferation, glomerular sclerosis, and tubular atrophy, on a scale of 1 to 5. Grade 1 indicates minimal histological changes, while grade 5 indicates advanced sclerosis and cortical tubular loss. Determined in accordance with the grading by To et al. 14 GG 1 mean sclerosis per glomerulus, 0% to 25%; GG 2 25% to 50%; and GG 3 50%. TIG 1 tubular atrophy and interstitial fibrosis were absent or in an area 5%; TIG 2 5% to 50%; and TIG 3 50%. HA was defined as the presence of arteriolar hyaline or proteinaceous exudation, with or without smooth muscle hyperplasia or luminal reduction.

Li et al ACEI for Early IgAN 165 Assessed for eligibility (n = 64) Excluded (n = 4) Not meeting inclusion criteria (n = 4) Randomized (n = 60) Allocated to intervention (n = 30) Received allocated intervention (n = 30) Allocated to observation only (n = 30) Lost to follow-up (give reasons) (n = 1) Discontinued intervention (n = 2) cough (n = 1) dizziness (n = 1) p Lost to follow-up (give reasons) (n = 2) Analysed (n = 30) Analy Analysed (n = 30) Figure 1 CONSORT flowchart of the study. Figure 2 Systolic and diastolic blood pressure throughout the study period. Open circles indicate the treatment group; closed circles indicate control group. Error bars represent SDs.

166 The American Journal of Medicine, Vol 126, No 2, February 2013 Figure 3 Kaplan-Meier estimate of event-free survival. necessary to determine whether treatment is beneficial in this group of patients. In the present study, around 30% of the control group developed hypertension or proteinuria, or both, during the 5-year study period. In general, hypertensive patients were treated with calcium channel blocker, with or without diuretics. The incidence of hypertension and proteinuria was similar to our previous report, 7 which found that around 40% of patients with early IgA nephropathy progressed to proteinuria or hypertension in 5 years. Furthermore, many of the patients in the present study had the disease for several years before being recruited for this study. It implies that despite a modest clinical presentation and long duration of stable condition, patients with IgA nephropathy have a continuous risk of disease progression and deserve regular monitoring. Our result, however, suggests that treatment with low-dose ACE inhibitor does not offer any benefit to this group of patients over a 5-year period of time. In general, ramipril treatment was well tolerated, and adverse effects were infrequent. Although 2 patients in the treatment group had premature termination of the study medication, their clinical follow-up was continued and data were included for the analysis. The overall result, however, remains similar if they are excluded for a per-protocol analysis (details not shown). Table 3 Primary End point of the Study s Treatment No. of patients 30 30 Any primary end point 9 11* Hypertension 4 8 Proteinuria 5 6 Control *Three patients developed both hypertension and proteinuria. Figure 4 Kaplan-Meier estimate of: (A) proteinuria-free survival; and (B) hypertension-free survival. One potential bias of our study was that the study medicine, ramipril, may obscure the study end points (namely, the development of hypertension and proteinuria). Because the half-lives of ramipril and its major active metabolite ramiprilate, are around 12 hours, we routinely advised our patients to continue to take the morning dose of ramipril on the day before a clinic visit, omit the dose on the morning of visit, and had their blood pressure measured in the afternoon for the study purpose in order to minimize the direct blood pressure-lowering effect of ramipril. Nonetheless, the treatment group had a consistently lower blood pressure than the control group (by around 3 mm Hg). Although the difference was statistically significant, it remains uncertain whether such a small difference in blood pressure has any

Li et al ACEI for Early IgAN 167 clinical effect. Contrary to blood pressure lowering, the antiproteinuric effect of ramipril is more long lasting than its chemical half-life; we could not exclude the possibility that some of the proteinuria end points in the treatment group might have been masked. There are several limitations of our study. First, the sample size of the present study is small, and we may not have the sufficient statistical power to detect a treatment benefit. It is important to note that the sample size of this study was estimated a priori, with the assumption that proteinuria or hypertension developed in 40% of untreated patients in 5 years (as shown in our previous study 7 ), and ramipril therapy was expected to prevent the progression of chronic proteinuric nephropathies in approximately 50% of cases. 11-13 Based on these assumptions, a sample size of 60 subjects was expected to achieve an 80% statistical power with a significance level of.05. From the present study, around 30% of the control group and 20% of the treatment group progressed to proteinuria or hypertension. Based on these data, it is estimated that a total sample size of 630 would be necessary for 80% statistical power to detect the difference. It is of note that the detection of early IgA nephropathy depends on the renal biopsy criteria of individual centers and it may not be easy to have a large cohort of such patients worldwide for a randomized trial. Second, in the present study, we focused on proteinuria and hypertension, which are generally regarded as soft end points for chronic kidney disease. In fact, none of the patients in this study developed renal insufficiency during the follow-up, suggesting that the absolute risk of losing kidney function is low, and any treatment, even if effective in preventing hypertension or proteinuria, may not necessarily offer any benefit in protecting kidney function. In the present study, over 80% of the patients were female. The female preponderance agrees with our previous reports, especially among patients with hematuria and minimal proteinuria. 3,7 In theory, if female patients have a better prognosis, it would be difficult to demonstrate a treatment benefit. However, our previous study did not find that female sex has a lower risk of progression. 3 In addition, the present study was neither placebo-controlled nor double-blinded. It was possible that bias in assessment might be present. However, proteinuria and renal function are objective biochemical measures and the result should not be affected. In this study, blood pressures of all participating subjects were measured and recorded by paramedical staff who were unaware of the clinical record or treatment status of the patient. We believe the bias in blood pressure measurement also should be minimal. Another issue may be related to the drug dosage. We have used 2.5 mg ramipril, and whether an increased dose of 5 mg ramipril may have a different result can only be resolved by separate study. The recent Kidney Disease Improving Global Outcomes (KDIGO) Clinical Practice Guideline for Glomerulonephritis recommends long-term ACE inhibitor or angiotensin-receptor blocker (ARB) treatment when proteinuria is 1 g/day and suggests ACE inhibitor or ARB treatment if proteinuria is between 0.5 and 1 g/day. 17 There are no good data for patients with proteinuria 0.5 g/day. Our study is the first in a reasonably large cohort of IgA nephropathy patients with 5 years follow-up. Although this trial is seemingly a negative study, it does provide supporting evidence for the above KDIGO guidelines that the treatment with 2.5 mg daily of ramipril for this group of early IgA nephropathy patients with proteinuria 0.5 g/day does not provide additional benefit within a study period of 5 years. In trials using ARB in chronic IgA nephropathy, it has previously been shown to be of benefit. 18 Based on the result of our present study and the recent KDIGO guideline, 17 we suggest a watchful waiting strategy for patients with IgA nephropathy and proteinuria 0.5 g/day; ACE inhibitor or ARB treatment should be started if proteinuria is above this level. ACKNOWLEDGEMENTS We thank Ms. Lau Miu Fong and Ms. Cheng Mei-Shan Phyllis for their clerical support. This paper was presented in Abstract form at the American Society of Nephrology Kidney Week 2011 Annual Meeting, November 10-13 in Philadelphia. The results presented in this paper have not been published previously in whole or part, except in Abstract format. References 1. D Amico G. The commonest glomerulonephritis in the world: IgA nephropathy. Q J Med. 1987;245:709-727. 2. D Amico G. Natural history of idiopathic IgA nephropathy: role of clinical and histological prognostic factors. Am J Kidney Dis. 2000; 36:227-237. 3. 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