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(Hypertension. 2001;37:1069.)
© 2001 American Heart Association, Inc.

Scientific Contributions

Prognostic Significance of Serum Creatinine and Uric Acid in Older Chinese Patients With Isolated Systolic Hypertension

Ji-Guang Wang; Jan A. Staessen; Robert H. Fagard; Willem H. Birkenhäger; Lansheng Gong; Lisheng Liu; for the Systolic Hypertension in China (Syst-China) Trial Collaborative Group¹

From the Hypertension Division (J.-G.W., L.L.), Cardiovascular Institute and Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People’s Republic of China; the Study Coordinating Center (J.-G.W., J.A.S., R.H.F.), Hypertension and Cardiovascular Rehabilitation Unit, Department of Molecular and Cardiovascular Research, University of Leuven, Leuven, Belgium; Erasmus University (W.H.B.), Rotterdam, the Netherlands; and the Shanghai Hypertension Institute (L.G.), Shanghai Second Medical University, Shanghai, People’s Republic of China.

Correspondence to Jan A. Staessen, MD, PhD, Studiecoördinatiecentrum, Laboratorium Hypertensie, Gebouw Onderwijs en Navorsing, Campus Gasthuisberg, Herestraat 49, B-3000 Leuven, Belgium. E-mail jan.staessen{at}med.kuleuven.ac.be

	Abstract

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Abstract—We examined the relation of serum creatinine and uric acid to mortality and cardiovascular disease in older (aged 60 years) Chinese patients with isolated systolic hypertension (systolic/diastolic blood pressure 160/<95 mm Hg). We used Cox regression to correlate outcome with baseline serum creatinine and uric acid measured in 1880 and 1873, respectively, of the 2394 patients enrolled in the placebo-controlled Systolic Hypertension in China (Syst-China) Trial. Median follow-up was 3 years. In multiple Cox regression analysis with adjustment for gender, age, active treatment, and other significant covariates, serum creatinine was significantly associated with a worse prognosis. The relative hazard rates (95% CIs) associated with a 20-µmol/L increase in serum creatinine for all-cause, cardiovascular, and stroke mortality were 1.16 (1.05 to 1.27, P=0.003), 1.15 (1.01 to 1.31, P=0.03), and 1.37 (1.13 to 1.65, P=0.001), respectively. In a similar analysis, which also accounted for serum creatinine, serum uric acid was also significantly and independently associated with excess mortality of cardiovascular disease and stroke. The relative hazard rates associated with a 50-µmol/L increase of serum uric acid were 1.14 (1.02 to 1.27, P=0.02) for cardiovascular mortality and 1.34 (1.14 to 1.57, P<0.001) for fatal stroke. In conclusion, in older Chinese patients with isolated systolic hypertension, serum creatinine and serum uric acid were predictors of mortality.

Key Words: uric acid • creatinine • mortality • cardiovascular diseases • stroke • elderly

	Introduction

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Serum creatinine is associated with all-cause mortality^{1 2 3 4 5 6} or stroke⁷ in middle-aged^{2 7} and elderly¹ people and in patients with insulin-dependent diabetes³ or previous cardiovascular disorders.^{4 5 6} Similarly, several studies have shown that the serum concentration of uric acid predicts mortality,^{8 9 10 11 12 13} cardiovascular events,¹⁴ or stroke.¹⁵ Recently, an update from the Framingham study could not identify uric acid as an independent risk factor for cardiovascular disease.¹⁶ Although serum uric acid levels were significantly correlated with the risk for cardiovascular events and mortality in women, this relationship became insignificant after allowing for 11 additional variables, including hypertension, body mass index, and diuretic use.¹⁶ Other studies^{17 18} also failed to identify serum uric acid as a significant and independent risk factor.

The hypothesis that serum creatinine and uric acid may be predictors of mortality or cardiovascular disease has, to the best of our knowledge, never been tested in the Chinese population, in whom the serum total cholesterol level is lower than that in Western populations and in whom stroke rather than coronary heart disease is the more frequent cardiovascular disorder.¹⁹ In the patients enrolled in the Systolic Hypertension in China (Syst-China) Trial,^{20 21 22 23} serum creatinine and uric acid were measured at entry. The present analysis deals with the prognostic relevance of serum creatinine and uric acid in these patients.

	Methods

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The Chinese Ministry of Health approved the Syst-China Trial. Its design is described in detail elsewhere.^{20 21 22} Eligible patients consented to be enrolled and were aged 60 years. On single-blind placebo during the run-in phase, their sitting systolic blood pressures ranged from 160 to 219 mm Hg, with diastolic blood pressures <95 mm Hg. Patients with severe concomitant cardiovascular or noncardiovascular disorders were excluded. Eligible patients were assigned active treatment or placebo. Active treatment was initiated with nitrendipine (10 to 40 mg/d), with the possible addition of captopril (12.5 to 50 mg/d), hydrochlorothiazide (12.5 to 50 mg/d), or both drugs. The study drugs were titrated stepwise and combined to reduce the sitting systolic blood pressure by 20 mm Hg, ie, to <150 mm Hg.^{20 21 22} Placebos were used in the same way as the active drugs.

Serum creatinine and uric acid concentrations were measured at entry in the laboratories of the 31 participating centers, which participated in a quality control program organized by the Coordinating Office in Beijing at annual intervals.^{20 21 22} Diabetes mellitus at entry was defined according to the criteria of the World Health Organization.²⁴

All end points were independently validated as described in previous publications.^{22 23} Stroke was defined as a neurological deficit with symptoms continuing for >24 hours or leading to death with no apparent cause other than vascular complications. Cardiac end points included fatal and nonfatal heart failure, fatal and nonfatal acute myocardial infarction, and sudden death. Cardiovascular mortality included sudden death and deaths due to stroke, cardiac end points, or other cardiovascular disorders.

The statistical analysis was performed by intention to treat; SAS software (version 6.12, SAS Institute Inc) and 2-sided tests were used. Incidence rates in quartiles of the distributions of serum creatinine and uric acid were calculated with adjustments made for gender and age by use of the direct method.²⁵ Relative hazard rates and 95% CIs were estimated by single and multiple Cox regressions.²⁶ The statistical methods also included single and multiple linear regressions.

	Results

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Serum Creatinine
At entry, measurements of serum creatinine were available in 1880 (78.5%) of the 2394 enrolled subjects. In 136 (7.2%) patients, the serum creatinine concentration was higher than that specified in the protocol of the trial (<176.8 µmol/L).^{20 21 22 23} Mean serum creatinine concentration at baseline was higher in men than in women (115.2±48.8 versus 94.6±39.3 µmol/L, respectively; P<0.001). In single regression, serum creatinine was positively correlated with systolic blood pressure in both genders (P<0.003). In the multiple linear regression analysis, after adjustment for gender, 1% of variance in serum creatinine was explained by systolic blood pressure.

Median follow-up was 3.0 years (range 1 to 94 months). The total number of patient-years accumulated in this group was 5177. In the first step of the analysis, the study population was stratified by quartiles of serum creatinine at baseline. The characteristics of patients in each quartile appear in Table 1. As shown in Figures 1 and 2, the gender- and age-adjusted incidence rates of all-cause mortality, stroke mortality, all fatal and nonfatal cardiovascular end points, and fatal and nonfatal stroke rose with higher baseline levels of serum creatinine.

View this table: [in this window] [in a new window]   Table 1. Characteristics of Patients in Quartiles of Serum Creatinine at Baseline

View larger version (15K): [in this window] [in a new window]   Figure 1. Gender- and age-adjusted death rates in quartiles of serum creatinine at baseline. For each quartile, the number of deaths is given.

View larger version (16K): [in this window] [in a new window]   Figure 2. Gender- and age-adjusted fatal and nonfatal event rates in quartiles of serum creatinine at baseline. For each quartile, the number of events is given.

In single Cox regression, serum creatinine was associated with a worse prognosis (P<0.01), except for cardiac end points (Table 2). After adjustment for gender, age, and active treatment, as well as systolic and diastolic blood pressure at entry, body mass index, total serum cholesterol, smoking and drinking habits, previous cardiovascular complications, and diabetes mellitus, the associations remained significant for mortality. The relative hazard rates associated with a 20-µmol/L higher level of baseline serum creatinine were 1.16 (P=0.003), 1.15 (P=0.03), and 1.37 (P=0.001) for all-cause, cardiovascular, and stroke mortality, respectively (Table 2).

View this table: [in this window] [in a new window]   Table 2. Association Between Outcome and Serum Creatinine at Baseline

Serum Uric Acid
Serum uric acid was measured at entry in 1873 (78.2%) of the 2394 enrolled subjects. At baseline, 213 (17.7%) men and 110 (16.5%) women met the diagnostic criteria of hyperuricemia (>406 µmol/L [7.0 mg/dL] and >348 µmol/L [6.0 mg/dL], respectively). In 1841 (98.3%) of these 1873 patients, serum creatinine was also measured at entry. In single regression, serum uric acid at baseline was positively correlated with body mass index in both genders (P=0.004) and also in men with previous cardiovascular complications (P=0.003). In multiple regression analysis, after adjustment for gender, 2% of variance in serum uric acid was explained by body mass index and previous cardiovascular complications.

The characteristics of the patients are shown by quartiles of serum uric acid at baseline in Table 3. Gender- and age-adjusted incidence rates rose with higher levels of serum uric acid for cardiovascular and stroke mortality and for all fatal and nonfatal cardiovascular end points (Figures 3 and 4).

View this table: [in this window] [in a new window]   Table 3. Characteristics of Patients in Quartiles of Serum Uric Acid at Baseline

View larger version (15K): [in this window] [in a new window]   Figure 3. Gender- and age-adjusted death rates in quartiles of serum uric acid at baseline. For each quartile, the number of deaths is given.

View larger version (16K): [in this window] [in a new window]   Figure 4. Gender- and age-adjusted fatal and nonfatal event rates in quartiles of serum uric acid at baseline. For each quartile, the number of events is given.

In single Cox regression, serum uric acid was positively associated with a higher risk of cardiovascular and stroke mortality and with an increased incidence of all cardiovascular end points (P0.01) (Table 4). All-cause mortality tended to be higher with increasing serum uric acid (P=0.06). After adjustment for gender, age, active treatment, and other potential confounders, statistical significance was maintained only for cardiovascular and stroke mortality. The relative hazard rates associated with a 50-µmol/L increment of serum uric acid were 1.13 (P=0.02) and 1.28 (P=0.002), respectively (Table 4); after further adjustment for serum creatinine, the relative hazard rates (95% CIs) remained similar: 1.14 (1.02 to 1.27, P=0.02) and 1.34 (1.14 to 1.57, P<0.001).

View this table: [in this window] [in a new window]   Table 4. Association Between Outcome and Serum Uric Acid at Baseline

	Discussion

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After adjustment for confounders, serum creatinine and uric acid predicted mortality in older Chinese patients with isolated systolic hypertension. For each 20-µmol/L increment in baseline serum creatinine concentration, all-cause, cardiovascular, and stroke mortality rose by 16%, 15%, and 37%, respectively. Similarly, each 50-µmol/L increment in the baseline serum uric acid concentration was associated with 14% and 34% increases in cardiovascular and stroke mortality, respectively.

The results of the present study should be cautiously interpreted. The study subjects were older Chinese hypertensive patients in whom serum total cholesterol levels at the time of the trial were relatively low²² and in whom stroke but not myocardial infarction was the major complication of hypertension.¹⁹ In the present cohort, 87 strokes but only 43 cardiac end points were observed. Thus, the findings of the present study should not be extrapolated to Western populations or to Asians with higher serum cholesterol levels.

Several studies observed a significant and mostly independent association between outcome and serum creatinine.^{1 2 3 4 5 6 7} In the British Regional Heart Study,⁷ stroke risk was significantly increased in patients with a serum creatinine level equal to or higher than the 90th percentile (relative risk 1.6, 95% CI 1.1 to 2.1; 116 µmol/L versus the rest). The Hypertension Detection and Follow-Up Program showed in 10 940 hypertensive patients that serum creatinine at entry was a significant predictor of death.² For those with a serum creatinine concentration 150 µmol/L (1.7 mg/dL), the 8-year mortality rate was >3 times that of all other participants.² Independent prognostic significance of serum creatinine was also found for mortality in elderly people recruited from the general population,¹ survivors of myocardial infarction⁵ or stroke,⁴ patients with insulin-dependent diabetes,³ or patients with angiographically confirmed coronary heart disease.⁶

The mechanism of the association between serum creatinine and mortality remains unexplained. Atherosclerosis is a common feature of the participants in the studies, demonstrating an association between outcome and serum creatinine. Therefore, the most straightforward explanation may be that generalized vascular degeneration increases mortality and impairs renal function as well. In keeping with this hypothesis, serum creatinine was associated with the severity of atherosclerosis as assessed by angiography of the carotid artery²⁷ or by measurement of the ankle-arm index.^{28 29 30} An alternative or additional explanation may be that renal dysfunction per se may lead to higher mortality in persons with established cardiovascular disease or intermediate risk factors, such as hypertension.

Our findings on the prognostic role of serum uric acid in relation to mortality are in agreement with the Italian Cardiovascular Study in the Elderly,¹² which demonstrated that serum uric acid was an important predictor of overall mortality in 2254 elderly men and women.¹² In several other studies,^{9 10 11} serum uric acid was an independent predictor of mortality only in women. In contrast, in the Hypertension Detection and Follow-Up Program,⁸ the baseline serum uric acid level was a predictor of total mortality only in men. Two studies^{14 31} found that serum uric acid was independently associated with an excess risk of fatal and nonfatal cardiovascular events in hypertensive men and women. More recently, Fang and Alderman¹³ found that increased serum uric acid levels were independently and significantly associated with a higher risk of cardiovascular mortality.

Whether the relationships with uric acid are causal or not remains controversial in light of a host of potential confounding factors.³² The observation that longstanding hyperuricemia in patients with gout is associated with intrarenal crystal deposition, tubulointerstitial injury, and the development of hypertension provides a potential pathogenic mechanism linking elevated serum uric acid with renal disease and hypertension.³³ However, several studies^{16 17 18} could not show a significant relationship between serum uric acid and cardiovascular disease. Furthermore, a recent Framingham analysis showed that diuretic use was the covariate responsible for rendering serum uric acid a statistically nonsignificant predictor of outcome.¹⁶ However, in the active treatment group of the Systolic Hypertension in the Elderly Program (SHEP),³¹ the diuretic-induced increase (1 mg/dL) in serum uric acid at 1 year was associated with a 42% higher rate of coronary heart disease. In the present study, the relationship between serum uric acid and stroke mortality persisted after adjustment for active treatment. Diuretic use was not accounted for in the analysis because only 3% of actively treated patients were given hydrochlorothiazide.

The reasons for the inconsistent findings on serum uric acid as a prognostic factor remain uncertain. Serum uric acid may reflect early renal vascular involvement, in particular, nephrosclerosis in hypertensive patients,^{34 35} and may hence manifest its prognostic value only in the absence of other more predominant risk factors. This may explain the positive findings in our Chinese patients with relatively low serum total cholesterol levels and in several studies involving women.^{9 10 11} Furthermore, the large intraindividual variation in serum uric acid may have weakened the associations observed in some studies. In addition, many factors affect or are related to the level of serum uric acid.^{36 37 38} Failure to correct for these variables in the analysis might inflate or deflate the associations. Finally, the choice of outcome is also important. If serum uric acid predicts only mortality, studies with combined fatal and nonfatal events as an outcome are more likely to have negative findings.

	Acknowledgments

 
Syst-China is a research program conducted under the auspices of the State Commission of Science and Technology and the Public Health Ministry of the People’s Republic of China. The trial was carried out in consultation with the World Health Organization and the World Hypertension League. The trial was financially supported by the State Planning Commission of the People’s Republic of China. The present analysis was facilitated through a fellowship granted by Bayer AG, Wuppertal, Germany, to Dr Wang.

	Footnotes

 
¹ A complete list of members of the Syst-China Trial Collaborative Group appears in Reference 23.

Received July 19, 2000; first decision August 16, 2000; accepted October 6, 2000.

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