Journal of Human (2001) 15, 99–106  2001 Nature Publishing Group All rights reserved 0950-9240/01 $15.00 www.nature.com/jhh ORIGINAL ARTICLE Does treatment of non-malignant hypertension reduce the incidence of renal dysfunction? A meta-analysis of 10 randomised, controlled trials

CY Hsu Division of Nephrology, University of California, San Francisco, CA, USA

Objective: It remains controversial whether non-malig- dysfunction outcome varied among trials but within nant ‘benign’ hypertension causes renal dysfunction. each trial was applied similarly to both treatment and The effect of lowering on the incidence control groups. Drug treatment consisted mostly of of renal dysfunction among patients with non-malignant diuretics and adrenergic blockers. Overall, treated hypertension is not clear. This meta-analysis was con- patients had lower blood pressure and fewer cardio- ducted to determine whether antihypertensive drug vascular events. There were a total of 317 cases of renal therapy reduces the incidence of renal dysfunction in dysfunction. Patients randomised to antihypertensive patients with non-malignant hypertension. therapy (or more intensive therapy) did not have a sig- Methods: Randomised, controlled trials of antihyperten- nificant reduction in their risk of developing renal dys- confidence interval %95 ;0.97 ؍ sive drug therapy of more than 1 year duration that function (relative risk .(0.77 ؍ reported renal dysfunction as an outcome were iden- (CI) 0.78–1.21; P tified through MEDLINE search and literature review. A Conclusions: Among patients with non-malignant random effects model was used to obtain summary esti- hypertension enrolled in randomised trials, treated mates. patients did not have a lower risk of renal dysfunction. Results: Ten trials were identified, involving 26 521 indi- The 95% CI suggests that a 25% or more true protective viduals and 114 000 person-years. All excluded subjects effect of antihypertensive drugs is unlikely. with advanced baseline renal disease. Definition of renal Journal of Human Hypertension (2001) 15, 99–106

Keywords: therapy; high blood pressure; kidney disease

Introduction lowering blood pressure decreases the incidence of renal dysfunction among patients with non-malig- It remains controversial whether non-malignant nant hypertension is a randomised controlled trial. 1–5 ‘benign’ hypertension causes renal dysfunction. However, renal disease has not been a major focus in Although elevated blood pressure predicts subsequent 6,7 the large traditional antihypertensive drug treatment development of end-stage renal disease, it is poss- trials. Furthermore, there are too few renal end- ible that pre-existing renal disease caused both the 8,9 points within any one study to provide sufficient hypertension and the eventual renal failure. power and to make definitive conclusions. There- The effect of lowering blood pressure on the inci- fore, this meta-analysis was conducted to integrate dence of renal dysfunction among patients with the results of previous trials into a more precise esti- non-malignant hypertension is also not known. mate of treatment effect. Specifically, it asks Some observational studies have shown that for whether in randomised, controlled trials, drug treat- hypertensive patients, treated blood pressure level ment of non-malignant hypertension reduces the did not protect against subsequent rise in serum cre- incidence of renal dysfunction. atinine.10,11 The strongest study design to address whether Methods

Correspondence: Dr Chi-yuan Hsu, Division of Nephrology, Identification of trials University of California, San Francisco, Room 672 HSE, 513 Parnassus Avenue, San Francisco, CA 94143-0532, USA. E-mail: Randomised controlled trials of antihypertensive hsuchiȰmedicine.ucsf.edu drugs among patients with non-malignant hyperten- Received 28 June 2000; accepted 10 July 2000 sion were identified using prior meta-analyses, bib- Treatment of non-malignant HTN CY Hsu 100 liographies in recent articles and textbooks and MED- example, the paper describing the main findings of LINE searches. Locating relevant studies was the United States Public Health Service Hospitals facilitated by the fact that numerous meta-analyses of (USPHS) study listed ‘renal insufficiency’ as an this literature have been performed that used similar exclusion criterion and as a secondary outcome.20 trial selection criteria.12–16 However, these published An earlier paper defined ‘renal insufficiency’ as systematic analyses have mostly focused on cardio- measured creatinine clearance Ͻ80 ml/min/ outcomes. Extra effort was expended 1.73m2.24 on locating recent publications and a rigorous MED- In all trials, whenever possible, intention-to-treat LINE search strategy designed by the Cochrane Col- analysis outcome data were used as input data for laboration to identify trials of pharmacological treat- the meta-analysis. In the European Working Party on ment of hypertension16 was conducted for the period High Blood Pressure in the Elderly Trial (EWPHE), 1995 through 1998. A total of 2617 records were pro- serial serum creatinine measurements were perfor- duced.Thetitleandabstractofeachrecordwere med only during the randomised part of the study, evaluated and full text of 31 articles obtained for but mortality and cause of death data continued to further evaluation. No additional trials met eligibility be collected on all patients after withdrawal from criteria for this review. randomisation.28 During randomisation, one treated patient died of renal disease and four treated and one control patients had doubling of serum creatin- Inclusion criteria ine. In the overall intention-to-treat analysis, four Trials of randomised antihypertensive drug therapy treated and one control patient died of renal dis- included in the meta-analysis are those published ease.28,29 Because ascertainment of serum creatinine before 1 January, 1999 that: (1) lasted over 1 year; doubling may be more reliable than nosologist’s (2) explicitly described random allocation of treat- coding of cause of death, the ‘on treatment’ data ment (ie, did not use alternate allocation or other were used. In the in the Eld- potentially biased methods); and (3) reported renal erly Program (SHEP), a rise in serum creatinine to dysfunction as an outcome. Trials that compared the Ͼ265 ␮mol/l (3 mg/dl) was explicitly listed as a sec- effects of two specific antihypertensive therapies ondary endpoint.30 In addition, it was reported that with the same blood pressure goal were excluded. two patients each in the treatment and control arm Trials of multiple risk factor interventions were died of renal disease, which was not a stated end- excluded because of potential confounding by other point. These were therefore not counted. Performing therapies. Also excluded were trials that enrolled the meta-analysis using these alternative endpoints only patients with known renal insufficiency or did not significantly change the final conclusions of established renal parenchymal disease17–19 since the study. this study was not designed to examine the effect of In two instances, after publication of the paper blood pressuring lowering in patients who already describing the main trial findings, secondary analy- had renal dysfunction. ses of trial data were performed which provided more information on renal function changes.21,31 The meta-analysis was repeated to incorporate the Extraction of data results of these secondary analyses. The author used a standardised abstraction sheet to extract the following data from each study: year of Statistical analysis publication, number of subjects, mean age, percent male, baseline systolic and diastolic blood The effect of antihypertensive medication on the pressures, types of medication used, blinding, use of development of renal dysfunction was determined placebo or a less intensely treated group as control, in each trial using the relative risk (RR), calculated duration of follow-up, and mean difference in by the ratio of the incidence of renal dysfunction in observed blood pressure between treatment and con- the treatment vs control group. In cases where there trol groups. The proportion of black (or non-white20) were no events, a 1/6 arithmetic correction was participants was also abstracted. This was hypo- added to all cells.32 A random-effects model as thesised a priori to be a possible source of hetero- described by DerSimonian and Laird was used to geneity among studies, as black subjects are believed obtain the summary estimates of log (RR) from the to be particularly susceptible to renal damage from included studies.33 Effect homogeneity was evalu- hypertension.21,22 ated by the Q-statistic.33 Stata Release 6 (College Information on whether and how patients with Station, TX, USA) was used to perform the analysis renal disease were excluded from entry into each and to produce graphic output (command ‘meta’). trial was abstracted. Also noted was how new cases of renal dysfunction were defined in the paper Results presenting the main findings of each trial. In some instances, renal exclusion criteria and definition of Ten trials were identified that met the inclusion cri- renal dysfunction were found in earlier publications teria20,27,28,30,34–39 (Table 1). These encompassed a detailing the study protocol or pilot study.23–26 For total of 26 521 individuals and 114 000 person-years

Journal of Human Hypertension Treatment of non-malignant HTN CY Hsu 101 Table 1 Characteristics of randomised trials included in meta-analysis

Study Study Treatment Control Mean Male Blacks Mean Renal Main (Year of designa group group age (%) (%)b baseline exclusionc Drugsd publication) patient patient (years) BP (mm Hg) no. no. Treatment vs Control group

Wolff34 DB, PC 45 42 49 32 90 178/110 vs BUN Ͼ21 mmol/l RE, CZ, (1966) 175/108 (60 mg/dl); renal GU VA I23,35 DB, PC 73 70 51 100 54 186/121 vs BUN Ͼ21 mmol/l HZ, RE, (1967) 187/121 (60 mg/dl) HD VA II23,36 DB, PC 186 194 51 100 41 162/104 vs BUN Ͼ21 mmol/l HZ, RE, (1970) 165/105 (60 mg/dl) HD USPHS20,24 DB, PC 193 196 44 80 28 (non- 148/99 vs creatinine clearance CZ, RU (1977) whites) 146/99 Ͻ80 ml/min/1.73m2; renovascular hypertension HDFP21,37,40 open 5485 5455 51 54 44 159/101 vs none CD, RE, (1979) 159/101 HD ANBPS27 SB, PC 1721 1706 50 63 0 158/101 vs Cr Ͼ180 ␮mol/l (2 CZ (1980) 157/100 mg/dl) EWPHE25,28,29 DB, PC 416 424 72 30 N/A 183/101 vs Cr у220 ␮mol/l (2.5 HZ, TT (1985) 182/101 mg/dl); renovascular hypertension Coope38 open 419 465 69 31 N/A 197/100 vs ‘serious concomitant AT, BF (1986) 196/98 disease’ SHEP26,30,31 DB, PC 2365 2371 72 43 14 171/77 vs Cr у180 ␮mol/l (2 CD (1991) 170/76 mg/dl) Sys-Eur39 DB, PC 2398 2297 70 33 N/A 174/86 vs Cr у180 ␮mol/l (2 NT, EN, (1997) 174/86 mg/dl) HZ aDB, double-blind; SB, single-blind; PC, placebo controlled. bN/A, data not available. cCr, serum creatinine; BUN, blood urea nitrogen. dAT, atenolol; BF, bendrofluazide; CD, chlorthalidone; CZ, chlorothiazide; EN, enalapril; GU, guanethidine; HD, hydralazine; HZ, hyd- rochlorothiazide; NT, nitrendipine; RE, reserpine; RU, rauwolfia; TT, traimterene. of observation. Eight trials were placebo-controlled randomised to antihypertensive therapy (or more and two used less-intensively treated patients as intensive therapy) was 0.95 (95% confidence inter- controls.37,38 Drug treatment consisted mostly of val (CI) 0.58–1.55; P ϭ 0.83) (Q-statistic ϭ 8.5; P ϭ diuretics and adrenergic blockers. Only one trial 0.48) (Figure 1). used angiotensin-converting enzyme (ACE) inhibi- Secondary analyses of trial data were reported by tors.39 Overall, treated patients had lower blood the HDFP and the SHEP investigators that provided pressure and experienced fewer cardiovascular additional information on renal function changes.21,31 events. Using the HDFP data and redefining renal dysfunc- All trials excluded subjects with advanced base- tion as 5th year creatinine у180 ␮mol/l (2 mg/dl) line renal disease (Table 1). The Hypertension and у1.25 times baseline value, Shulman et al21 Detection and Follow-up Program (HDPF) did not found that there were a total of 200 cases of renal have any renal exclusion criteria40 but there were no dysfunction. Pahor et al31 showed that in the SHEP enrollees with serum creatinine (Cr) Ͼ265 ␮mol/l (3 study, when the definition of renal dysfunction was mg/dl).21 Coope and Warrender38 did not mention changed from serum creatinine Ͼ265 ␮mol/l (3 specific renal exclusion criteria but had a general mg/dl) to serum creatinine Ͼ180 ␮mol/l (2 mg/dl), blanket exclusion of ‘serious concomitant disease’. the number of renal dysfunction cases increased Definition of renal dysfunction outcome varied from 18 to 8831 (Table 3). among trials but within each trial was applied simi- Repeating the meta-analysis with 317 outcomes larly to both treatment and control groups (Table 2). after incorporating the results of the secondary A total of 72 cases of renal dysfunction were iden- analyses showed that the relative risk of developing tified. Compared with control patients, the relative renal dysfunction among treatment vs control risk of developing renal dysfunction among patients patients was 0.97 (95%CI 0.78–1.21; P ϭ 0.77)

Journal of Human Hypertension Treatment of non-malignant HTN CY Hsu 102 Table 2 Renal outcomes

Study Mean Systolic New cases of Treatment Control follow-up and renal dysfunction group group (years) diastolic defined asa number of number of BP cases of cases of difference renal renal (mm Hg) dysfunction dysfunction

Wolf34 1.4 SBP 33 increase in BUN by Ͼ7 mmol/l 2 4 DBP 20 (20 mg/dl) on two occasions VA I23,25 1.5 SBP 43 doubling of BUN to Ͼ21 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 II23,36 3.3 SBP 31 increase in BUN by Ͼ50% to 0 3 DBP 19 Ͼ21 mmol/l (59 mg/dl) OR doubling of BUN or Cr to levels above normal OR proteinuria persistently Ͼ1+ USPHS20,24 7.0 SBP 16 creatinine clearance Ͻ80 1 2 DBP 10 ml/min/1.73m2 HDFP21,37,40 5.0 DBP 5 death from renal disease 15 10 ANBPS27 4.0 DBP 6 Cr Ͼ180 ␮mol/l (2 mg/dl) 1 2 EWPHE25,28,29 4.7 SBP 21 death from renal causes 5 1 DBP 8 OR doubling of serum Cr Coope38 4.4 SBP 18 death from hypertensive 0 1 DBP 11 nephropathy SHEP26,30,31 4.5 SBP 12 Cr Ͼ265 ␮mol/l (3 mg/dl) 7 11 DBP 4 Sys-Eur39 2.5 SBP 10 doubling of Cr 3 2 DBP 4 OR Cr у360 ␮mol/l (4 mg/dl) on two consecutive measurements

aCr, 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.

Journal of Human Hypertension Treatment of non-malignant HTN CY Hsu 103 Table 3 Renal outcomes—secondary analyses

Study Mean Systolic and New cases of Treatment Control follow-up diastolic BP renal dysfunction group group (years) difference redefined asa number of number of (mm Hg) cases of cases of renal renal dysfunction dysfunction

HDFP21 5.0 DBP 5 5th year Cr у180 ␮mol/l (2 mg/dl) 99 101 and у1.25 × baseline value SHEP31 4.5 SBP 12 Cr Ͼ180 ␮mol/l (2 mg/dl) 44 44 DBP 4 aCr, 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 hetero- may lead to narrowing of renal arteriolar lumen and geneity among the trials (Q-statistic ϭ 6.7; P ϭ 0.67); glomerular ischaemia; alternatively, direct trans- therefore the random effects model gave the fixed mission of elevated pressure to the glomerulus may effects results. lead to glomerulosclerosis.41 Epidemiological study of the relationship between Discussion hypertension and renal dysfunction is difficult. Because hypertension can be a consequence of renal This systematic review of 10 randomised controlled parenchymal disease or decreased glomerular fil- trials of patients treated with antihypertensive medi- tration, cross-sectional and retrospective studies cations found no significant reduction in the inci- cannot be used to establish causal relationship dence of renal dysfunction among treated patients. between hypertension and renal dysfunction.42 Pro- There appeared to be no significant heterogeneity spective observational studies have shown that among trials as a result of enrollees’ racial compo- among 11 912 hypertensive male veterans and sition or other variables. The 95% CI suggests that among 332 544 men screened for the Multiple Risk at the observed level of blood pressure reduction, a Factor Intervention Trial (MRFIT), elevated blood 25% or more true protective effect of antihyperten- pressure measured over a decade in the past pre- sive drugs is unlikely. dicted subsequent risk of end-stage renal disease While it is clear that malignant hypertension dam- (ESRD).6,7 However, except in a small subset of the ages the kidneys, whether non-malignant ‘benign’ MRFIT cohort (Ͻ4%),7 baseline renal function data hypertension causes renal dysfunction remains con- were not assessed in these subjects. Hence it is not troversial.1–5 Chronic elevations in blood pressure possible to discern whether renal dysfunction was

Journal of Human Hypertension Treatment of non-malignant HTN CY Hsu 104 already present in those in whom ESRD later evident renoprotective effect should be interpreted developed. In a Japanese study of 107 192 subjects in light of the fact that these trials did not rigorously who had undergone screening with dipstick urinal- exclude patients with reduced glomerular filtration ysis and blood pressure measurement, 5% of sub- rate or known renal parenchymal disease. The rela- jects had у1+ proteinuria and 4% of men and 12% tively high serum creatinine cutoff used in many of women had у1+ hematuria.8 A subset of 14 609 trials (eg, Ͼ180 ␮mol/l (2 mg/dl)) did not exclude subjects had serum creatinine measured.9 Although patients with significant loss of glomerular filtration. higher blood pressure predicted subsequent devel- For example, a 60-year-old woman weighing 60 kilo- opment of ESRD 10 years post-screening, this grams with a serum creatinine of 170 ␮mol/l (1.9 relationship was confounded by the presence of mg/dl), and therefore Cockcroft-Gault equation46 underlying renal disease. After adjusting for base- estimated creatinine clearance of only 30 ml/min, line serum creatinine, proteinuria and hematuria, would have been enrolled. Many studies included elevated blood pressure was no longer an inde- patients with diabetes. Among the SHEP parti- pendent risk factor for ESRD.8,9 This supports the cipants, 11% reported a history of ‘kidney prob- contention that many patients with renal failure lems’.47 Renal parenchymal disease was considered attributed to actually have the cause of elevated blood pressure in 8% of undiagnosed renal vascular or renal parenchymal EWPWE subjects with systolic hypertension.48 In disease3 that caused both the initial blood pressure the HDFP population, which included patients with elevation and eventual renal failure. known glomerulonephritis,21 4% had у2+ pro- Whether treatment of hypertension reduces the teinuria, 5% had hematuria and 7% pyuria.49 It is incidence of renal dysfunction may be a more rel- generally accepted that blood pressure reduction evant public health and clinical question than slows renal function deterioration in patients with whether hypertension predicts renal dysfunction. established renal parenchymal disease or decreased Despite improved detection and control of high glomerular filtration rate.50,51 Therefore, the fact blood pressure in the US from 1977–1994, which these patients were included in the trial cohorts and reduced stroke and coronary disease mortality, the blood pressure lowering conferred no overall incidence of ESRD attributed to hypertension has renoprotection renders it even less likely that increased.43 antihypertensive medications lowered the risk of One study of 94 patients with treated primary renal dysfunction among patients with only non- hypertension showed that over a mean observation malignant essential hypertension. period of 58 months, individuals with good blood This study has several limitations. Bias may be pressure control (diastolic р90 mm Hg) developed introduced because a single unblinded author con- increases in serum creatinine concentration at the ducted this study. Bias in identification of trials, same rate as those with poor blood pressure control however, is unlikely given that these are such large (diastolic Ͼ90 mm Hg).10 Similarly, among 2125 and well-known undertakings. Only published data hypertensive men enrolled for treatment, changes in were used but publication bias is doubtful as trials serum creatinine over 5 years were not predicted by that fulfill the selection criteria for this meta-analy- in-treatment blood pressure, analysed either as a sis would almost certainly be published, regardless continuous or as a dichotomous variable.11 In a sub- of the renal outcomes. Furthermore, since trials with group analysis of 5524 MRFIT enrollees, despite a ‘positive findings’ tend to be published, the ‘null 5-mm Hg difference in diastolic blood pressure result’ of this meta-analysis is highly unlikely to be between those receiving usual care and special inter- a result of publication bias. vention, reciprocal creatinine slopes over 6 years in The two studies that provided the largest number the two groups were the same.22 of end-points are both secondary analyses using Randomised controlled trials using only anti- renal outcome criteria not defined in the original hypertensive medications, however, provide the protocol. The SHEP secondary analysis only most direct and unbiased study design to address included 92% of the cohort who had a valid whether treatment of hypertension reduces the inci- measurement of serum creatinine by the day of ran- dence of renal dysfunction among patients with domisation.31 In HDFP, because of its unblinded non-malignant hypertension. Patients with diag- design, follow-up serum creatinine ascertainments nosed and undiagnosed renal disease should be were more complete in the treatment group (90% vs evenly distributed in the treatment and the control 83%).21 However, the similar relative risks obtained group so that confounding from this important from analysing the original and the secondary analy- source is eliminated. The strength of the original ses data argue against significant bias in this case. randomisation is preserved in a meta-analysis. The 10 trials differed in their definition of renal Although results of antihypertensive drug trials dysfunction and included patients with varying have been used to inform the debate on the relation- degrees of blood pressure elevation. Direct compari- ship between hypertension and renal dysfunction in son, however, was made only between treatment the past,4,44,45 a formal meta-analysis has not been and control patients in the same trial. The inclusion performed. of studies with very small numbers of events (eg, the The finding that blood pressure lowering had no EWPHE, the Coope, and the two VA trials), resulted

Journal of Human Hypertension Treatment of non-malignant HTN CY Hsu 105 in a broad spread of risk estimates with very wide Dr Hsu was supported by the American Kidney confidence intervals. In actuality, there was no Fund Clinical Scientist in Nephrology Award. between trial heterogeneity beyond that expected due to chance (Q-statistic ϭ 6.7; P ϭ 0.67). This study does not address how stricter or References longer-term control of blood pressure will impact the incidence of renal dysfunction. The longest fol- 1 Kincaid-Smith P. Renal pathology in hypertension and the effects of treatment. Br J Clin Pharmacol 1982; 13: low-up was 7 years for the USPHS trial and most of 107–115. the other studies lasted 4 to 5 years. It is not clear 2 Weisstuch JM, Dworkin LD. Does essential hyperten- how low the blood pressure has to be or how long sion cause end-stage renal disease? 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