Does treatment of non-malignant hypertension reduce the incidence of renal dysfunction? A meta-analysis of 10 randomised, controlled trials

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1 (2001) 15, Nature Publishing Group All rights reserved /01 $ ORIGINAL ARTICLE Does treatment of non-malignant hypertension reduce the incidence of renal dysfunction? A meta-analysis of 10 randomised, controlled trials Division of Nephrology, University of California, San Francisco, CA, USA Objective: It remains controversial whether non-malignant benign hypertension causes renal dysfunction. The effect of lowering blood pressure on the incidence of renal dysfunction among patients with non-malignant hypertension is not clear. This meta-analysis was conducted to determine whether antihypertensive drug therapy reduces the incidence of renal dysfunction in patients with non-malignant hypertension. Methods: Randomised, controlled trials of antihypertensive drug therapy of more than 1 year duration that reported renal dysfunction as an outcome were identified through MEDLINE search and literature review. A random effects model was used to obtain summary estimates. Results: Ten trials were identified, involving individuals and person-years. All excluded subjects with advanced baseline renal disease. Definition of renal dysfunction outcome varied among trials but within each trial was applied similarly to both treatment and control groups. Drug treatment consisted mostly of diuretics and adrenergic blockers. Overall, treated patients had lower blood pressure and fewer cardiovascular events. There were a total of 317 cases of renal dysfunction. Patients randomised to antihypertensive therapy (or more intensive therapy) did not have a significant reduction in their risk of developing renal dysfunction (relative risk 0.97; 95% confidence interval (CI) ; P 0.77). Conclusions: Among patients with non-malignant hypertension enrolled in randomised trials, treated patients did not have a lower risk of renal dysfunction. The 95% CI suggests that a 25% or more true protective effect of antihypertensive drugs is unlikely. (2001) 15, Keywords: therapy; high blood pressure; kidney disease Introduction It remains controversial whether non-malignant benign hypertension causes renal dysfunction. 1 5 Although elevated blood pressure predicts subsequent development of end-stage renal disease, 6,7 it is possible that pre-existing renal disease caused both the hypertension and the eventual renal failure. 8,9 The effect of lowering blood pressure on the incidence of renal dysfunction among patients with non-malignant hypertension is also not known. Some observational studies have shown that for hypertensive patients, treated blood pressure level did not protect against subsequent rise in serum creatinine. 10,11 The strongest study design to address whether Correspondence: Dr Chi-yuan Hsu, Division of Nephrology, University of California, San Francisco, Room 672 HSE, 513 Parnassus Avenue, San Francisco, CA , USA. hsuchi medicine.ucsf.edu Received 28 June 2000; accepted 10 July 2000 lowering blood pressure decreases the incidence of renal dysfunction among patients with non-malignant hypertension is a randomised controlled trial. However, renal disease has not been a major focus in the large traditional antihypertensive drug treatment trials. Furthermore, there are too few renal endpoints within any one study to provide sufficient power and to make definitive conclusions. Therefore, this meta-analysis was conducted to integrate the results of previous trials into a more precise estimate of treatment effect. Specifically, it asks whether in randomised, controlled trials, drug treatment of non-malignant hypertension reduces the incidence of renal dysfunction. Methods Identification of trials Randomised controlled trials of antihypertensive drugs among patients with non-malignant hypertension were identified using prior meta-analyses, bib-

2 100 Treatment of non-malignant HTN liographies in recent articles and textbooks and MED- LINE searches. Locating relevant studies was facilitated by the fact that numerous meta-analyses of this literature have been performed that used similar trial selection criteria However, these published systematic analyses have mostly focused on cardiovascular disease outcomes. Extra effort was expended on locating recent publications and a rigorous MED- LINE search strategy designed by the Cochrane Collaboration to identify trials of pharmacological treatment of hypertension 16 was conducted for the period 1995 through A total of 2617 records were produced. The title and abstract of each record were evaluated and full text of 31 articles obtained for further evaluation. No additional trials met eligibility criteria for this review. Inclusion criteria Trials of randomised antihypertensive drug therapy included in the meta-analysis are those published before 1 January, 1999 that: (1) lasted over 1 year; (2) explicitly described random allocation of treatment (ie, did not use alternate allocation or other potentially biased methods); and (3) reported renal dysfunction as an outcome. Trials that compared the effects of two specific antihypertensive therapies with the same blood pressure goal were excluded. Trials of multiple risk factor interventions were excluded because of potential confounding by other therapies. Also excluded were trials that enrolled only patients with known renal insufficiency or established renal parenchymal disease since this study was not designed to examine the effect of blood pressuring lowering in patients who already had renal dysfunction. Extraction of data The author used a standardised abstraction sheet to extract the following data from each study: year of publication, number of subjects, mean age, percent male, baseline systolic and diastolic blood pressures, types of medication used, blinding, use of placebo or a less intensely treated group as control, duration of follow-up, and mean difference in observed blood pressure between treatment and control groups. The proportion of black (or non-white 20 ) participants was also abstracted. This was hypothesised a priori to be a possible source of heterogeneity among studies, as black subjects are believed to be particularly susceptible to renal damage from hypertension. 21,22 Information on whether and how patients with renal disease were excluded from entry into each trial was abstracted. Also noted was how new cases of renal dysfunction were defined in the paper presenting the main findings of each trial. In some instances, renal exclusion criteria and definition of renal dysfunction were found in earlier publications detailing the study protocol or pilot study For example, the paper describing the main findings of the United States Public Health Service Hospitals (USPHS) study listed renal insufficiency as an exclusion criterion and as a secondary outcome. 20 An earlier paper defined renal insufficiency as measured creatinine clearance 80 ml/min/ 1.73m In all trials, whenever possible, intention-to-treat analysis outcome data were used as input data for the meta-analysis. In the European Working Party on High Blood Pressure in the Elderly Trial (EWPHE), serial serum creatinine measurements were performed only during the randomised part of the study, but mortality and cause of death data continued to be collected on all patients after withdrawal from randomisation. 28 During randomisation, one treated patient died of renal disease and four treated and one control patients had doubling of serum creatinine. In the overall intention-to-treat analysis, four treated and one control patient died of renal disease. 28,29 Because ascertainment of serum creatinine doubling may be more reliable than nosologist s coding of cause of death, the on treatment data were used. In the Systolic Hypertension in the Elderly Program (SHEP), a rise in serum creatinine to 265 mol/l (3 mg/dl) was explicitly listed as a secondary endpoint. 30 In addition, it was reported that two patients each in the treatment and control arm died of renal disease, which was not a stated endpoint. These were therefore not counted. Performing the meta-analysis using these alternative endpoints did not significantly change the final conclusions of the study. In two instances, after publication of the paper describing the main trial findings, secondary analyses of trial data were performed which provided more information on renal function changes. 21,31 The meta-analysis was repeated to incorporate the results of these secondary analyses. Statistical analysis The effect of antihypertensive medication on the development of renal dysfunction was determined in each trial using the relative risk (RR), calculated by the ratio of the incidence of renal dysfunction in the treatment vs control group. In cases where there were no events, a 1/6 arithmetic correction was added to all cells. 32 A random-effects model as described by DerSimonian and Laird was used to obtain the summary estimates of log (RR) from the included studies. 33 Effect homogeneity was evaluated by the Q-statistic. 33 Stata Release 6 (College Station, TX, USA) was used to perform the analysis and to produce graphic output (command meta ). Results Ten trials were identified that met the inclusion criteria 20,27,28,30,34 39 (Table 1). These encompassed a total of individuals and person-years

3 Treatment of non-malignant HTN Table 1 Characteristics of randomised trials included in meta-analysis 101 Study Study Treatment Control Mean Male Blacks Mean Renal Main (Year of design a group group age (%) (%) b baseline exclusion c Drugs d publication) patient patient (years) BP (mm Hg) no. no. Treatment vs Control group Wolff 34 DB, PC /110 vs BUN 21 mmol/l RE, CZ, (1966) 175/108 (60 mg/dl); renal GU artery stenosis VA I 23,35 DB, PC /121 vs BUN 21 mmol/l HZ, RE, (1967) 187/121 (60 mg/dl) HD VA II 23,36 DB, PC /104 vs BUN 21 mmol/l HZ, RE, (1970) 165/105 (60 mg/dl) HD USPHS 20,24 DB, PC (non- 148/99 vs creatinine clearance CZ, RU (1977) whites) 146/99 80 ml/min/1.73m 2 ; renovascular hypertension HDFP 21,37,40 open /101 vs none CD, RE, (1979) 159/101 HD ANBPS 27 SB, PC /101 vs Cr 180 mol/l (2 CZ (1980) 157/100 mg/dl) EWPHE 25,28,29 DB, PC N/A 183/101 vs Cr 220 mol/l (2.5 HZ, TT (1985) 182/101 mg/dl); renovascular hypertension Coope 38 open N/A 197/100 vs serious concomitant AT, BF (1986) 196/98 disease SHEP 26,30,31 DB, PC /77 vs Cr 180 mol/l (2 CD (1991) 170/76 mg/dl) Sys-Eur 39 DB, PC N/A 174/86 vs Cr 180 mol/l (2 NT, EN, (1997) 174/86 mg/dl) HZ a DB, double-blind; SB, single-blind; PC, placebo controlled. b N/A, data not available. c Cr, serum creatinine; BUN, blood urea nitrogen. d AT, atenolol; BF, bendrofluazide; CD, chlorthalidone; CZ, chlorothiazide; EN, enalapril; GU, guanethidine; HD, hydralazine; HZ, hydrochlorothiazide; NT, nitrendipine; RE, reserpine; RU, rauwolfia; TT, traimterene. of observation. Eight trials were placebo-controlled and two used less-intensively treated patients as controls. 37,38 Drug treatment consisted mostly of diuretics and adrenergic blockers. Only one trial used angiotensin-converting enzyme (ACE) inhibitors. 39 Overall, treated patients had lower blood pressure and experienced fewer cardiovascular events. All trials excluded subjects with advanced baseline renal disease (Table 1). The Hypertension Detection and Follow-up Program (HDPF) did not have any renal exclusion criteria 40 but there were no enrollees with serum creatinine (Cr) 265 mol/l (3 mg/dl). 21 Coope and Warrender 38 did not mention specific renal exclusion criteria but had a general blanket exclusion of serious concomitant disease. Definition of renal dysfunction outcome varied among trials but within each trial was applied similarly to both treatment and control groups (Table 2). A total of 72 cases of renal dysfunction were identified. Compared with control patients, the relative risk of developing renal dysfunction among patients randomised to antihypertensive therapy (or more intensive therapy) was 0.95 (95% confidence interval (CI) ; P 0.83) (Q-statistic 8.5; P 0.48) (Figure 1). Secondary analyses of trial data were reported by the HDFP and the SHEP investigators that provided additional information on renal function changes. 21,31 Using the HDFP data and redefining renal dysfunction as 5th year creatinine 180 mol/l (2 mg/dl) and 1.25 times baseline value, Shulman et al 21 found that there were a total of 200 cases of renal dysfunction. Pahor et al 31 showed that in the SHEP study, when the definition of renal dysfunction was changed from serum creatinine 265 mol/l (3 mg/dl) to serum creatinine 180 mol/l (2 mg/dl), the number of renal dysfunction cases increased from 18 to (Table 3). Repeating the meta-analysis with 317 outcomes after incorporating the results of the secondary analyses showed that the relative risk of developing renal dysfunction among treatment vs control patients was 0.97 (95%CI ; P 0.77)

4 Treatment of non-malignant HTN 102 Table 2 Renal outcomes Study Mean Systolic New cases of Treatment Control follow-up and renal dysfunction group group (years) diastolic defined as a number of number of BP cases of cases of difference renal renal (mm Hg) dysfunction dysfunction Wolf SBP 33 increase in BUN by 7 mmol/l 2 4 DBP 20 (20 mg/dl) on two occasions VA I 23, SBP 43 doubling of BUN to 21 mmol/l 0 2 DBP 30 (60 mg/dl) OR significant rise in Cr (100 to 265 mol/l [1.1 to 3.0 mg/dl]) VA II 23, SBP 31 increase in BUN by 50% to 0 3 DBP mmol/l (59 mg/dl) OR doubling of BUN or Cr to levels above normal OR proteinuria persistently 1+ USPHS 20, SBP 16 creatinine clearance DBP 10 ml/min/1.73m 2 HDFP 21,37, DBP 5 death from renal disease ANBPS DBP 6 Cr 180 mol/l (2 mg/dl) 1 2 EWPHE 25,28, SBP 21 death from renal causes 5 1 DBP 8 OR doubling of serum Cr Coope SBP 18 death from hypertensive 0 1 DBP 11 nephropathy SHEP 26,30, SBP 12 Cr 265 mol/l (3 mg/dl) 7 11 DBP 4 Sys-Eur SBP 10 doubling of Cr 3 2 DBP 4 OR Cr 360 mol/l (4 mg/dl) on two consecutive measurements a Cr, serum creatinine; BUN, blood urea nitrogen. Figure 1 Result of meta-analysis using original trial data. Graph shows estimates and 95% CI for each trial and overall effect. Box area is inversely proportional to the estimated effect s variance in that study. Vertical dotted line is drawn through combined estimate.

5 Treatment of non-malignant HTN Table 3 Renal outcomes secondary analyses 103 Study Mean Systolic and New cases of Treatment Control follow-up diastolic BP renal dysfunction group group (years) difference redefined as a number of number of (mm Hg) cases of cases of renal renal dysfunction dysfunction HDFP DBP 5 5th year Cr 180 mol/l (2 mg/dl) and 1.25 baseline value SHEP SBP 12 Cr 180 mol/l (2 mg/dl) DBP 4 a Cr, serum creatinine; BUN, blood urea nitrogen. Figure 2 Result of meta-analysis using secondary analyses data. Graph shows estimates and 95% CI for each trial and overall effect. Box area is inversely proportional to the estimated effect s variance in that study. Vertical dotted line is drawn through combined estimate. (Figure 2). There was again failure to detect heterogeneity among the trials (Q-statistic 6.7; P 0.67); therefore the random effects model gave the fixed effects results. Discussion This systematic review of 10 randomised controlled trials of patients treated with antihypertensive medications found no significant reduction in the incidence of renal dysfunction among treated patients. There appeared to be no significant heterogeneity among trials as a result of enrollees racial composition or other variables. The 95% CI suggests that at the observed level of blood pressure reduction, a 25% or more true protective effect of antihypertensive drugs is unlikely. While it is clear that malignant hypertension damages the kidneys, whether non-malignant benign hypertension causes renal dysfunction remains controversial. 1 5 Chronic elevations in blood pressure may lead to narrowing of renal arteriolar lumen and glomerular ischaemia; alternatively, direct transmission of elevated pressure to the glomerulus may lead to glomerulosclerosis. 41 Epidemiological study of the relationship between hypertension and renal dysfunction is difficult. Because hypertension can be a consequence of renal parenchymal disease or decreased glomerular filtration, cross-sectional and retrospective studies cannot be used to establish causal relationship between hypertension and renal dysfunction. 42 Prospective observational studies have shown that among hypertensive male veterans and among men screened for the Multiple Risk Factor Intervention Trial (MRFIT), elevated blood pressure measured over a decade in the past predicted subsequent risk of end-stage renal disease (ESRD). 6,7 However, except in a small subset of the MRFIT cohort ( 4%), 7 baseline renal function data were not assessed in these subjects. Hence it is not possible to discern whether renal dysfunction was

6 104 Treatment of non-malignant HTN already present in those in whom ESRD later developed. In a Japanese study of subjects who had undergone screening with dipstick urinalysis and blood pressure measurement, 5% of subjects had 1+ proteinuria and 4% of men and 12% of women had 1+ hematuria. 8 A subset of subjects had serum creatinine measured. 9 Although higher blood pressure predicted subsequent development of ESRD 10 years post-screening, this relationship was confounded by the presence of underlying renal disease. After adjusting for baseline serum creatinine, proteinuria and hematuria, elevated blood pressure was no longer an independent risk factor for ESRD. 8,9 This supports the contention that many patients with renal failure attributed to essential hypertension actually have undiagnosed renal vascular or renal parenchymal disease 3 that caused both the initial blood pressure elevation and eventual renal failure. Whether treatment of hypertension reduces the incidence of renal dysfunction may be a more relevant public health and clinical question than whether hypertension predicts renal dysfunction. Despite improved detection and control of high blood pressure in the US from , which reduced stroke and coronary disease mortality, the incidence of ESRD attributed to hypertension has increased. 43 One study of 94 patients with treated primary hypertension showed that over a mean observation period of 58 months, individuals with good blood pressure control (diastolic 90 mm Hg) developed increases in serum creatinine concentration at the same rate as those with poor blood pressure control (diastolic 90 mm Hg). 10 Similarly, among 2125 hypertensive men enrolled for treatment, changes in serum creatinine over 5 years were not predicted by in-treatment blood pressure, analysed either as a continuous or as a dichotomous variable. 11 In a subgroup analysis of 5524 MRFIT enrollees, despite a 5-mm Hg difference in diastolic blood pressure between those receiving usual care and special intervention, reciprocal creatinine slopes over 6 years in the two groups were the same. 22 Randomised controlled trials using only antihypertensive medications, however, provide the most direct and unbiased study design to address whether treatment of hypertension reduces the incidence of renal dysfunction among patients with non-malignant hypertension. Patients with diagnosed and undiagnosed renal disease should be evenly distributed in the treatment and the control group so that confounding from this important source is eliminated. The strength of the original randomisation is preserved in a meta-analysis. Although results of antihypertensive drug trials have been used to inform the debate on the relationship between hypertension and renal dysfunction in the past, 4,44,45 a formal meta-analysis has not been performed. The finding that blood pressure lowering had no evident renoprotective effect should be interpreted in light of the fact that these trials did not rigorously exclude patients with reduced glomerular filtration rate or known renal parenchymal disease. The relatively high serum creatinine cutoff used in many trials (eg, 180 mol/l (2 mg/dl)) did not exclude patients with significant loss of glomerular filtration. For example, a 60-year-old woman weighing 60 kilograms with a serum creatinine of 170 mol/l (1.9 mg/dl), and therefore Cockcroft-Gault equation 46 estimated creatinine clearance of only 30 ml/min, would have been enrolled. Many studies included patients with diabetes. Among the SHEP participants, 11% reported a history of kidney problems. 47 Renal parenchymal disease was considered the cause of elevated blood pressure in 8% of EWPWE subjects with systolic hypertension. 48 In the HDFP population, which included patients with known glomerulonephritis, 21 4% had 2+ proteinuria, 5% had hematuria and 7% pyuria. 49 It is generally accepted that blood pressure reduction slows renal function deterioration in patients with established renal parenchymal disease or decreased glomerular filtration rate. 50,51 Therefore, the fact these patients were included in the trial cohorts and blood pressure lowering conferred no overall renoprotection renders it even less likely that antihypertensive medications lowered the risk of renal dysfunction among patients with only nonmalignant essential hypertension. This study has several limitations. Bias may be introduced because a single unblinded author conducted this study. Bias in identification of trials, however, is unlikely given that these are such large and well-known undertakings. Only published data were used but publication bias is doubtful as trials that fulfill the selection criteria for this meta-analysis would almost certainly be published, regardless of the renal outcomes. Furthermore, since trials with positive findings tend to be published, the null result of this meta-analysis is highly unlikely to be a result of publication bias. The two studies that provided the largest number of end-points are both secondary analyses using renal outcome criteria not defined in the original protocol. The SHEP secondary analysis only included 92% of the cohort who had a valid measurement of serum creatinine by the day of randomisation. 31 In HDFP, because of its unblinded design, follow-up serum creatinine ascertainments were more complete in the treatment group (90% vs 83%). 21 However, the similar relative risks obtained from analysing the original and the secondary analyses data argue against significant bias in this case. The 10 trials differed in their definition of renal dysfunction and included patients with varying degrees of blood pressure elevation. Direct comparison, however, was made only between treatment and control patients in the same trial. The inclusion of studies with very small numbers of events (eg, the EWPHE, the Coope, and the two VA trials), resulted

7 in a broad spread of risk estimates with very wide confidence intervals. In actuality, there was no between trial heterogeneity beyond that expected due to chance (Q-statistic 6.7; P 0.67). This study does not address how stricter or longer-term control of blood pressure will impact the incidence of renal dysfunction. The longest follow-up was 7 years for the USPHS trial and most of the other studies lasted 4 to 5 years. It is not clear how low the blood pressure has to be or how long the subjects have to be followed for the renoprotective effect of antihypertensive drug therapy to become apparent in patients with non-malignant hypertension, if such an effect truly exists. This study is unable to evaluate the effects of newer classes of antihypertensive medications, such as ACE inhibitors or angiotensin receptor antagonists. Experimental studies 52 and clinical trials 51,53 in a variety of primary renal diseases with hypertension suggest that agents which specifically reduce intraglomerular pressure, in addition to systemic arterial pressure, attenuation loss of renal function over time. Whether these findings would translate into a worthwhile clinical benefit in patients with non-malignant essential hypertension is unknown. Despite these shortcomings, this meta-analysis represents the best unconfounded estimate that can be derived from the present medical literature of the effect of non-malignant hypertension treatment on risk of subsequent renal dysfunction. It is doubtful that an actual trial designed specifically to examine the renoprotective effect of antihypertensive drug therapy involving individuals and person-years of observation will ever to be conducted. The relatively low disease incidence and the proven treatment benefits in terms of strokes and other more common cardiovascular outcomes alone will make such a study logistically and ethically problematic. Hence, meta-analyses such as this one may be the best approximation of a randomised controlled trial in this field. The results of this meta-analysis obviously should not be used to argue against treating patients with non-malignant hypertension, since there are clear non-renal benefits. Nor should they diminish our enthusiasm for controlling hypertension in patients with primary renal disease, particularly those with proteinuria, where hypertension control has clearly been shown to attenuate the rate of progression to end-stage renal disease. 54,55 The results of this metaanalysis however should encourage rethinking of whether non-malignant hypertension by itself is an important cause of renal dysfunction since the current best available data from randomised clinical trials fail to show that antihypertensive drug therapy reduces the incidence of renal dysfunction in patients with non-malignant hypertension. Acknowledgements The author would like to thank Mr David Owen for his assistance in performing the MEDLINE searches. Treatment of non-malignant HTN Dr Hsu was supported by the American Kidney Fund Clinical Scientist in Nephrology Award. References 1 Kincaid-Smith P. Renal pathology in hypertension and the effects of treatment. Br J Clin Pharmacol 1982; 13: Weisstuch JM, Dworkin LD. Does essential hypertension cause end-stage renal disease? Kidney Int 1992; 41 (Suppl 36): S33 S37. 3 Freedman BI, Iskandar SS, Appel RG. The link between hypertension and nephrosclerosis. Am J Kidney Dis 1995; 25: Beevers DG, Lip GYH. Does non-malignant essential hypertension cause renal damage? A clinician s view. J Hum Hypertens 1996; 10: Howie AJ. Benign essential hypertension and kidney damage: a histopathologist s view. J Hum Hypertens 1996; 10: Perry HM, Jr et al. Early predictors of 15-year end-stage renal disease in hypertensive patients. Hypertension 1995; 25: Klag MJ et al. Blood pressure and end-stage renal disease in men. N Engl J Med 1996; 334: Iseki K, Iseki C, Ikemiya Y, Fukiyama K. Risk of developing end-stage renal disease in a cohort of mass screening. Kidney Int 1996; 49: Iseki K, Ikemiya Y, Fukiyama K. Risk factors of endstage renal disease and serum creatinine in a community-based mass screening. Kidney Int 1997; 51: Rostand SG et al. Renal insufficiency in treated essential hypertension. N Engl J Med 1989; 320: Madhavan S, Stockwell D, Cohen H, Alderman MH. Renal function during antihypertensive treatment. Lancet 1995; 345: Collins R et al. Blood pressure, stroke and coronary heart disease: Part 2, short-term reductions in blood pressure: overview of randomized drug trials in their epidemiological context. Lancet 1990; 335: Mulrow CD et al. Hypertension in the elderly: implications and generalizability of randomised trials. JAMA 1994; 272: Gueyffier F et al. Effect of antihypertensive drug treatment on cardiovascular outcomes in women and men: a meta-analysis of individual patient data from randomised, controlled trials. Ann Intern Med 1997; 126: Psaty BM et al. Health outcomes associated with antihypertensive therapies used as first-line agents: a systematic review and meta-analysis. JAMA 1997; 277: Mulrow C, Lau J, Cornell J, Brand M. Pharmacotherapy for hypertension in the elderly (Cochrane Review). In: The Cochrane Library, Issue 2, Update Software: Oxford. 17 Pettinger WA, Lee HC, Reisch J, Mitchell HC. Longterm improvement in renal function after short-term strict blood pressure control in hypertensive nephrosclerosis. Hypertension 1989; 13: Ihle BU et al. Angiotensin-converting enzyme inhibition in nondiabetic progressive renal insufficiency: a controlled double-blind trial. Am J Kidney Dis 1996; 27: Toto RD et al. Strict blood pressure control and pro- 105

8 106 Treatment of non-malignant HTN gression of renal disease in hypertensive nephrosclerosis. Kidney Int 1995; 48: Smith WM. Treatment of mild hypertension: results of a ten-year intervention trial. Circ Res 1977; 40 (Suppl I): I98 I Shulman NB et al. Prognostic value of serum creatinine and effect of treatment of hypertension on renal function. Hypertension 1989; 13 (Suppl I): I80 I Walker WG et al. Renal function change in hypertensive members of the Multiple Risk Factor Intervention Trial. Racial and treatment effects. JAMA 1992; 268: Fries ED. Organization of a long-term multiclinic therapeutic trial in hypertension. In: Gross F (ed). Antihypertensive Therapy: Principles and Practice. Springer-Verlag: Berlin, 1966, pp US Public Health Service Hospitals Cooperative Study Group. Morbidity and mortality in mild essential hypertension. Circ Res 1972; 31 (Suppl II): II110 II European Working Party on High Blood Pressure in the Elderly (EWPHE). An international trial of antihypertensive therapy in elderly patients. Objectives, protocol and organization. Arch Int Pharmacodyn Ther 1985; 275: Hulley SB et al. Systolic Hypertension in the Elderly Program (SHEP): antihypertensive efficacy of chlorthalidone. Am J Cardiol 1985; 56: Australian National Blood Pressure Study Management Committee. Australian therapeutic trial in mild hypertension. Lancet 1980; 1: Amery A et al. Mortality and morbidity results from the European Working Party on High Blood Pressure in the Elderly Trial. Lancet 1985; 1: de Leeuw PW. Renal function in the elderly: results from the European Working Party on High Blood Pressure in the Elderly Trial. Am J Med 1991; 90 (Suppl 3A): 45S 49S. 30 SHEP Cooperative Research Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated hypertension: final results of the Systolic Hypertension in the Elderly Program (SHEP). JAMA 1991; 265: Pahor M et al. Diuretic-based treatment and cardiovascular events in patients with mild renal dysfunction enrolled in the Systolic Hypertension in the Elderly Program. Arch Intern Med 1998; 158: Mosteller F, Tukey JW. Data Analysis and Regression. Addison-Wesley: Reading, Mass, 1977, pp DerSimonian R, Laird N. Meta-analysis in clinical trials. Controlled Clin Trials 1986; 7: Wolff FW, Lindeman RD. Effects of treatment in hypertension: results of a controlled study. J Chron Dis 1966; 19: VA Cooperative Study Group on Antihypertensive Agents. Effect of treatment on morbidity in hypertension: results in patients with diastolic blood pressure averaging 115 through 129 mmhg. JAMA 1967; 202: VA Cooperative Study Group on Antihypertensive Agents. Effects of treatment on morbidity in hypertension: II Results in patients with diastolic blood pressure averaging 90 through 114 mmhg. JAMA 1970; 213: Hypertension Detection and Follow-up Program Cooperative Group. Five-year findings of the Hypertension Detection and Follow-up Program. I. Reduction in mortality of persons with high blood pressure, including mild hypertension. JAMA 1979; 242: Coope J, Warrender TS. Randomised trial of treatment of hypertension in elderly patients in primary care. BMJ 1986; 293: Staessen JA et al. Randomized double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. Lancet 1997; 350: Hypertension Detection and Follow-up Program Cooperative Group. Therapeutic control of blood pressure in the Hypertension Detection and Follow-up Program. Prev Med 1979; 8: Klahr S. The kidney in hypertension villain and victim. N Engl J Med 1989; 320: Whelton PK, He J, Perneger TV, Klag MJ. Kidney damage in benign essential hypertension. Curr Opin Nephrol Hypertens 1997; 6: The sixth report of the Joint National Committee on prevention, detection, evaluation, and treatment of high blood pressure [Erratum Arch Intern Med 1998; 158(6): 573]. Arch Intern Med 1997; 157: Whelton PK, Klag MJ. Hypertension as a risk factor for renal disease. Review of clinical and epidemiological evidence. Hypertension 1989; 13 (Suppl I): I19 I Mountokalakis TD. The renal consequences of arterial hypertension. Kidney Int 1997; 51: Gault MH, Longerich LL, Harnett JD, Wesolowski C. Predicting glomerular function from adjusted serum creatinine. Nephron 1992; 62: Curb JD, Lee M, Jensen J, Applegate W. Systolic Hypertension in the Elderly Program (SHEP). Part 4: Baseline medical history findings. Hypertension 1991; 17 (Suppl II): II35 II Amery A et al. Antihypertensive therapy in patients above age 60 with systolic hypertension. A progress report of the European Working Party on High Blood Pressure in the Elderly (EWPHE). Clin Exp Hypertens [A] 1982; 4: Lewin A et al. Apparent prevalence of curable hypertension in the Hypertension Detection and Follow-up Program. Arch Intern Med 1985; 145: Parving HH et al. Effective antihypertensive treatment postpones renal insufficiency in diabetic nephropathy. Am J Kidney Dis 1993; 22: Maschio G et al. Effect of the angiotensin-convertingenzyme inhibitor benazepril on the progression of chronic renal insufficiency. N Engl J Med 1996; 334: Anderson S, Rennke HG, Brenner BM. Therapeutic advantage of converting enzyme inhibitors in arresting progressive renal disease associated with systemic hypertension in the rat. J Clin Invest 1986; 77: Lewis EJ, Hunsicker LG, Bain RP, Rohde RD. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. [Erratum N Engl J Med 1993; 330(2): 152] N Engl J Med 1993; 329: Peterson JC et al. Blood pressure control, proteinuria, and the progression of renal disease. Ann Intern Med 1995; 123: The GISEN Group. Randomized placebo-controlled trial of effect of ramipril on decline in glomerular filtration rate and risk of terminal renal failure in proteinuric, non-diabetic nephropathy. Lancet 1997; 349: