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1 J Am Soc Nephrol 15: 16161622, 2004 Development Of Chronic Kidney Disease and Cardiovascular Prognosis in Essential Hypertensive Patients JULIAN SEGURA, CARLOS CAMPO, PALOMA GIL, CECILIA ROLDAN, LUIS VIGIL, JOSE L. RODICIO, and LUIS M. RUILOPE Hypertension Unit, Nephrology Department, Hospital 12 de Octubre, Madrid, Spain. Abstract. The existence of a significant percentage of treated developed CKD (CrCl 60 ml/min per 1.73 m2) attributed to hypertensive patients presenting a diminished renal function hypertensive nephrosclerosis. Initial serum creatinine, age, sys- has been recently described. Mild renal function abnormalities tolic BP at baseline, and average total cholesterol during fol- are recognized as powerful predictors of cardiovascular mor- low-up were independent predictors of CKD development. bidity and mortality. However, longitudinal data demonstrating Forty-nine (17.4%) of 281 patients presented a cardiovascular this association are lacking. The objectives of this study have event during follow-up: 17 patients (40.6%) who developed been analysis of the evolution of GFR, assessed as creatinine CKD and 32 patients (13.3%) with preserved renal function clearance (CrCl), during long-term follow-up of hypertensive (log rank test P 0.001). After adjustment in a Cox multi- patients and evaluation of the impact of the development of variate analysis, age, development of CKD during follow-up, chronic kidney disease (CKD) on cardiovascular prognosis. A and male gender were independent predictors of the appear- historical cohort of 281 patients attending our Hypertension ance of cardiovascular events. In essential hypertensive pa- Unit was selected according to the following criteria: essential tients with normal renal function at baseline, the development hypertension, more than 5 yr of follow-up, and normal GFR at of CKD during the follow-up is strongly and independently baseline (CrCl 90 ml/min per 1.73 m2). Patients had an related with poor cardiovascular prognosis. average follow-up of 13.2 4.8 yr. Forty-one patients (14.6%) The relation between elevated BP and end-stage renal disease with 24-h urine collection is considered as an adequate esti- (ESRD) is well established (1). In fact, high levels of treated mate of GFR. This parameter can also be estimated from serum BP are positively and significantly related to early decline in creatinine levels by using prediction equations (Cockroft-Gault kidney function among hypertensive men (2), and hypertensive or Modification of Renal Disease [MDRD] equations) that take nephrosclerosis is recognized as a major cause of ESRD (3,4). age, sex, race, and body weight into account (15,16), although The prevalence of chronic kidney disease (CKD) in essential it has been described that the MDRD equation consistently hypertension has been considered to be low (2%) on the basis underestimates GFR, whereas the Cockroft-Gault equation of serum creatinine concentration as the index to estimate renal overestimates measured GFR in people with normal renal function (5,6). However, other evidences indicate that renal function (17). Independent of the etiology, the presence of prognosis is not so benign in hypertensive patients (4,79) and CKD is a strong predictor of cardiovascular disease (18). In that CKD is more prevalent than previously expected in treated fact, JNC-7 recognizes an estimated GFR below 60 ml/min as essential hypertension (10 12). Evaluation of renal function in a major cardiovascular risk factor (19). Unfortunately, no pro- long-term treated hypertensive patients has two main difficul- spective therapeutic trials aimed at reducing the cardiovascular ties: first, the slow rate of progression to ESRD of nephroscle- burden in people with CKD are available (18). rosis, requiring very long follow-ups to investigate the evolu- All these facts prompted us to analyze the development of tion of renal function (4); second, the low discriminatory CKD secondary to hypertensive nephrosclerosis in patients capacity of serum creatinine levels as an indicator of the renal referred to our center. Our aims were to establish the incidence filtration capacity and its changes with time (13,14). GFR is the of CKD attributable to hypertension-related benign nephroscle- best measure of overall renal function in health and disease rosis in the long-term follow-up of a cohort of essential hyper- (14). In clinical practice, measurement of creatinine clearance tensive patients with normal renal function at baseline and to analyze the impact of the development of CKD on cardiovas- cular prognosis. Received December 7, 2003. Accepted March 12, 2004. Correspondence to. Dr. Julin Segura, Hypertension Unit. Hospital 12 de Octubre., Av. Crdoba s/n, 28041 Madrid, Spain. Phone: 34-91-3908198; Fax: Materials and Methods 34-91-3908035; E-mail: [email protected] Study Design 1046-6673/1506-1616 This was an observational, long-term follow-up study of a histor- Journal of the American Society of Nephrology ical cohort of essential hypertensive patients with normal renal func- Copyright 2004 by the American Society of Nephrology tion at baseline attending our Hypertension Unit, intended to establish DOI: 10.1097/01.ASN.0000127045.14709.75 the incidence of CKD attributable to hypertension-related nephroscle-
2 J Am Soc Nephrol 15: 16161622, 2004 CKD in Hypertensive Patients 1617 rosis and to analyze the influence of known factors conditioning renal study. Chronic heart failure was defined by two or more of the damage and their impact on cardiovascular outcome. following features: dyspnea on exertion in the absence of new pul- monary disease, bilateral pedal edema, paroxysmal nocturnal dyspnea, Patients orthopnea, pulmonary rales, pulmonary edema or radiographic evi- We selected patients aged between 18 and 75 yr, with any grade of dence of pulmonary congestion, cardiomegaly (cardiac thoracic ratio essential hypertension, normal renal function at baseline (defined as a 0.55), left ventricular ejection fraction 0.40, left ventricular creatinine clearance 90 ml/min per 1.73 m2), and at least 5 yr of fractional shortening 0.25, or S3 gallop on auscultation. Stroke was follow-up in our computerized data system. We excluded patients defined as an acute focal neurologic dysfunction of vascular origin with malignant hypertension, suspected or diagnosed secondary hy- with rapid onset of signs and symptoms and lasting more than 24 h. pertension, renal insufficiency, proteinuria (defined as 300 mg/24 h) CV death was defined as natural death due to cardiac causes, heralded or urinary sediment alterations, urologic diseases, chronic administra- by abrupt loss of consciousness within 1 h of the onset of acute tion of antiinflammatory drugs, and uncontrolled diabetes mellitus symptoms. (defined as an average fasting plasma glucose 200 mg/dl [11.1 mmol/L]). Statistical Analyses Follow-Up Results are expressed as mean and SD or 95% CI as indicated. Statistical analyses were performed with the SPSS version 10.0. The Complete medical history and physical examination were per- significance of the differences in categorical and continuous variables formed at entry. Data about presence of previous diabetes, smoking, among groups was examined by means of the Pearson 2 test and t dyslipidemia (defined as a total cholesterol levels 200 mg/dl), and test, respectively. All tests were two-tailed; P 0.05 was considered hyperuricemia were collected. According to our usual protocol, pa- statistically significant. A survival analysis was performed to evaluate tients were followed at 3-mo intervals for BP measurement and the percentage of patients who developed CKD, both in the whole medication adjustment to achieve the recommended BP goals (140/ group and classifying the patients by quartiles according their baseline 90 mmHg). These BP goals were uniform during follow-up. Blood serum creatinine levels. samples and 24-h urine collection were obtained at least twice a year Kaplan-Meier survival analyses were performed, with log-rank as to measure serum creatinine, glucose, total cholesterol, HDL and LDL significance test for differences, to evaluate the impact of angiotensin- cholesterol, triglycerides, serum uric acid, sodium, and potassium, as converting enzyme inhibitor (ACEI) administration and diabetic sta- well as for the calculation of creatinine clearance and 24-h proteinuria, tus on renal function. The same survival analysis was performed to natriuresis, and kaliuresis. BP was measured using a mercury sphyg- evaluate the appearance of cardiovascular events and its possible momanometer after 5 min in a seated position, using an adequate cuff. relationship with renal function and ACEI administration. Cox regres- Serum and urine creatinine concentrations were determined by the sion analysis was performed, incorporating most important predictors routine Jaffe reaction. of renal outcome (age, gender, weight, body mass index, baseline systolic and diastolic BP, baseline serum creatinine, diabetes, smoking Outcome Variables status, and follow-up mean values of systolic and diastolic BP and The primary end point was defined as a reduction of creatinine serum HDL, LDL, and total cholesterol, triglycerides, glucose, and clearance below 60 ml/min per 1.73 m2 in two consecutive measure- uric acid) to recognize independent predictors of CKD development. ments during follow-up. Due to the fact that the MDRD equation The same analysis was performed to assess the independent predictors underestimates GFR and the Cockroft-Gault equation overestimates of cardiovascular events, including CKD development during follow- measured GFR in people with normal renal function (17), we selected up. A backward elimination method was used to exclude variables for creatinine clearance measured with 24-h urine collection to define the initial model. renal end point. Secondary variables included mean serum glucose, HDL, LDL, and total cholesterol, triglycerides, and systolic and diastolic BP. These mean values were calculated as the average of successive determinations during follow-up for each patient. Baseline Results serum creatinine values were divided into quartiles to facilitate the Baseline Characteristics analysis. Two hundred eighty-one patients with baseline mean age of According to the appearance of renal events, patients were classi- 46.9 4.8 yr (range, 18 to 74 yr; 58% female) were included fied in two groups: renal event-free group (F group) or those who in the study. Mean follow-up was 13.2 4.8 yr (13.1 4.3 yr developed CKD (C group). in group F, n 240; 13.3 4.9 yr in group C, n 41, P Appearance of cardiovascular events (acute myocardial infarction, NS). Table 1 contains baseline characteristics of the whole angina, congestive heart failure, stroke, and/or cardiovascular death) group and of F and C subgroups. Age and systolic and diastolic was considered as a secondary variable. Acute myocardial infarction BP values were higher at baseline in the C group than in the F was defined as an ischemic pain of myocardial origin, persisting at group (53.1 5.7 versus 45.7 3.9 yr, P 0.01; 181.5 31 least 30 min, with electrocardiographic changes (persistent ST-seg- versus 161.8 24 mmHg, P 0.03; and 111.6 17 versus ment elevation of 0.1 mv or new pathologic Q waves, each in at 101.8 14 mmHg, P 0.01). Baseline serum creatinine and least two contiguous leads) and total CK levels higher than two times the upper limit of normal. Angina was defined as typical myocardial serum uric acid were significantly higher in group C compared ischemic pain with electrocardiographic ischemic changes (horizontal with F group (serum creatinine 93.7 17.7 versus 82.2 17.7 or downsloping ST-segment depression of at lest 0.1 mv measured 80 mol/L, P 0.01; serum uric acid 386.6 101.1 versus 345.0 msec from the J point and returning to normal within approximately 95.2 mol/L, P 0.01). Creatinine clearance calculated 1 h), confirmed by angiography (obstructive lesion of at least 70% with 24-h urine sample showed a nonsignificant difference diameter stenosis) or exercise or pharmacologic challenge nuclear between F and C groups.
3 1618 Journal of the American Society of Nephrology J Am Soc Nephrol 15: 16161622, 2004 Table 1. Baseline characteristics, concomitant risk factors, and mean values during follow-upa Total Group Free Renal Event Patients CKD Development Patients Baseline characteristics n (%) 281 240 (85.4) 41 (14.6) age, yr 46.9 4.8 45.7 3.9 53.1 5.7c female (%) 58.0 58.3 56.7 follow-up, yr 13.2 4.8 13.1 4.3 13.3 4.9 weight, kg 73.3 12.4 73.3 12.6 73.7 11.0 BMI, kg/m2 28.1 4.3 28.0 4.2 29.7 4.4b systolic BP, mmHg 165 27 161.8 24 181.5 31b diastolic BP, mmHg 103 15 101.8 14 111.6 17c serum creatinine, mol/L 84.0 17.7 82.2 17.7 93.7 17.7c creatinine clearance, ml/min per 1.73 m2 104 18 105 18 98 19 serum uric acid, mol/L 351.0 95.2 345.0 95.2 386.6 95.2c total cholesterol, mmol/L 5.66 1.39 5.61 1.37 5.90 1.27 Concomitant risk factors smoking (%) 14.1 13.0 17.0 type 2 diabetes (%) 26.6 24.5 38.0 baseline (%) 11.0 10.8 16.9 new onset diabetes (%) 15.6 13.7 21.1 dyslipidemia (%) 17.4 17.0 19.0 Mean values during follow-up systolic BP, mmHg 147 12 146 12 152 11b diastolic BP, mmHg 89 6 89 6 90 6 drugs, n 1.9 0.9 1.8 0.9 2.2 0.8c ACEI (%) 45.4 47.3 34.1 total cholesterol, mmol/L 5.79 0.88 5.71 0.88 6.18 0.70b a Values are mean SD. CKD, chronic kidney disease; BMI, body mass index. b P 0.05 with respect to free renal event patients. c P 0.01 with respect to free renal event patients. Follow-Up During follow-up, mean systolic BP values remained signif- icantly higher in the C group compared with F group (152 11 mmHg versus 146 12 mmHg, P 0.05), albeit patients in group C received more antihypertensive drugs than those in group F (2.2 0.8 versus 1.8 0.9 drugs, P 0.01) (Table 1). Mean total cholesterol values during follow-up were signif- icantly more elevated in group C than in group F (6.18 0.70 versus 5.72 0.88 mmol/L, P 0.05). Evolution of Renal Function Forty-one patients (14.6%) experienced the renal event de- fined as primary end point. The mean time to event was 12.5 5.2 yr. Patients included in the highest quartile of baseline serum creatinine showed the worst renal function prognosis (Figure 1). Considering the whole group, the prognosis of renal function did not differ between patients receiving or not an Figure 1. Risk of chronic kidney disease (CKD) development accord- ACEI (Figure 2A), nor between diabetic and nondiabetic pa- ing baseline serum creatinine distribution. 1st quartile (]; SCr: 1 tients, although a better trend can be seen in nondiabetic mg/dl for male, 0.7 mg/dl for female. 2nd quartile (); SCr: 1.0 to patients (Figure 2B). The analysis of the influence of ACEI 1.1 mg/dl for male, 0.7 to 0.9 mg/dl for female. 3rd quartile (); SCr: administration on renal function was performed with the group 1.1 to 1.2 mg/dl for male, 0.9 to 1.0 mg/dl for female. 4th quartile (F); divided into nondiabetic and diabetic patients (Figure 2, C and SCr: 1.2 mg/dl for male, 1.0 mg/dl for female.
4 J Am Soc Nephrol 15: 16161622, 2004 CKD in Hypertensive Patients 1619 Figure 2. (A) Renal prognosis between patients receiving angiotensin-converting enzyme inhibitors (ACEI) and those receiving other antihypertensive therapies. (B) Renal prognosis between diabetic (DM) and nondiabetic (non-DM) patients. (C) Renal prognosis between nondiabetic patients receiving ACEI and those receiving other antihypertensive therapies. (D) Renal prognosis between diabetic patients receiving ACEI and those receiving other antihypertensive therapies. P significance by log-rank test. D). In patients with type 2 diabetes (n 75), the inclusion of Table 2. Cox regression analysis: independent predictors for an ACEI (n 41) in their antihypertensive therapy facilitated developing of chronic kidney disease a significantly better renal prognosis when compared with other therapies (calcium channel blockers, beta-blockers, and Hazard CI 95% P Ratioa diuretics) (log rank test P 0.05) (Figure 2D). Cox regression analysis showed that baseline serum creatinine, baseline sys- Baseline serum creatinine 6.33 (1.69 to 59.9) 0.0003 tolic BP, age, and mean values of total cholesterol during Baseline systolic BP 1.21 (1.08 to 1.34) 0.0031 follow-up are independent predictors for developing of CKD Age 1.48 (1.10 to 1.87) 0.0328 (Table 2). The analysis of slopes of serum glucose during Mean total cholesterol in 1.25 (1.09 to 1.34) 0.0170 follow-up showed a nonsignificant trend for higher values in follow-up patients developing CKD (84.4 mol/L per yr) compared with a those preserving renal function (63.3 mol/L per yr, P Hazard ratios for baseline serum creatinine, baseline systolic BP, age, and mean total cholesterol in follow-up are 0.1 mg/dl, 10 0.485). mmHg, 10 yr, and 10 mg/dl increases, respectively. Variables excluded for the initial model were as follows: gender, Cardiovascular Events weight, BMI, baseline diastolic BP, diabetes, smoking status, and Forty-nine (17.4%) of 281 patients presented a cardiovascu- follow-up mean values of systolic and diastolic BP and serum HDL lar event (16 acute myocardial infarction, 9 angina, 8 conges- and LDL cholesterol, triglycerides, glucose, and uric acid. tive heart failure, 16 stroke) during follow-up: 17 patients (40.6%) who developed CKD and 32 patients (13.3%) with presented a cardiovascular event compared with 33 (21.6%) of preserved renal function (log rank test P 0.001) (Figure 3A). 153 patients receiving other antihypertensive drugs (log rank Among patients receiving an ACEI (n 128), 16 (12.5%) test P 0.05) (Figure 3B). After adjustment in a Cox multi-
5 1620 Journal of the American Society of Nephrology J Am Soc Nephrol 15: 16161622, 2004 Figure 3. (A) Cardiovascular prognosis between patients developing chronic kidney disease (CKD) and those with preserved renal function. (B) Cardiovascular prognosis between patients receiving angiotensin-converting enzyme inhibitors and those receiving other antihypertensive therapies. variate analysis, age, development of CKD during follow-up, Perneger et al. (9) published an integrated analysis of data and male gender were independent predictors of the appear- from several population studies showing a crude annual inci- ance of cardiovascular events (Table 3). dence of hypercreatininemia in hypertensive patients of 4.61 per 1000 subjects. Adjusting for gender and race, annual rates Discussion of hypercreatininemia were 4.06, 1.84, 8.41, and 4.96 per 1000 There is very little information in the literature about the subjects in white men, white women, African-American men, development of CKD in hypertensive patients. In 500 untreated and African-American women, respectively (9). On average, hypertensive patients followed until death, Perera (20) de- these results suggest that 1 in 13 hypertensive patients scribed that proteinuria was present in 42% and chronic renal progresses to hypercreatininemia every year (9). Nevertheless, failure in 18%. Growing evidence indicates that renal progno- this study assessed renal function according to serum creatinine sis is not so good in either hypertensive patients or the general level, a poor indicator of GFR (13,14). Ronstad et al. (10) population (4,712). The Heart Outcomes Prevention Evalua- showed a deterioration of renal function in a 15% of treated tion (HOPE) study showed a prevalence of CKD of 10.4% hypertensive patients also according serum creatinine levels. A according to serum creatinine values 1.4 mg/dl (21). We similar percentage is observed in our study (14.6%), but ac- have recently described that 7.6% of patients referred to our cording to creatinine clearance, a more sensitive parameter. hypertension unit have a decreased renal function according to Furthermore, in our study the mean follow-up was long enough serum creatinine levels, and one of every four patients has a (13.2 4.8 yr) to ensure a large enough number of renal decreased creatinine clearance (12). The prevalence of CKD in events. the community could be even higher according to the values of Our results show that development of CKD, estimated as a estimated creatinine clearance seen in the Third National creatinine clearance below 60 ml/min per 1.73 m2 in hyper- Health and Nutrition Examination Survey (NHANES III) tensive patients with baseline normal renal function is a not (7,22). infrequent finding along follow-up: 14.6 per 100 patients in- cluded developed CKD during more than 13 yr of mean fol- low-up. This finding means an annual rate of 1.11 per 100 Table 3. Cox regression analysis: independent predictors for patients and it represents more than two times the incidence of the appearance of cardiovascular events hypercreatininemia described by Perneger et al. in white men Hazard CI 95% P (9). Cox regression analysis showed that baseline serum cre- Ratioa atinine level is the strongest predictor of CKD development. Age 1.06 (1.02 to 1.09) 0.001 Every increase of 0.1 mg/dl in serum creatinine level increases CKD development 2.53 (1.32 to 4.81) 0.005 the risk of CKD by six times. Creatinine clearance was not Male gender 2.06 (1.09 to 3.89) 0.026 included in multivariate analysis because its normal values were included among inclusion criteria for the study; therefore, a Hazard ratio for age is for 1-yr increase. Variables excluded for it cannot be considered as a predictor factor. Furthermore, our the initial model were as follows: weight, BMI, baseline diastolic BP, diabetes, smoking status, follow-up mean values of systolic and results show that, in patients with normal renal function (cre- diastolic BP and serum HDL and LDL cholesterol, triglycerides, atinine clearance 90 ml/min per 1.73 m2), the presence of glucose, and uric acid. mild increases of serum creatinine levels could have a high
6 J Am Soc Nephrol 15: 16161622, 2004 CKD in Hypertensive Patients 1621 predictive capacity. This finding was true even in normal range In conclusion, our data indicate that a relevant percentage of of serum creatinine levels (Figure 1). Other independent pre- patients with arterial hypertension develop CKD, defined as a dictors were the age and systolic BP at the beginning of fall in creatinine clearance to values below 60 ml/min per 1.73 follow-up and serum total cholesterol level. Serum glucose was m2. This evolution is not prevented by ACEI treatment in not an independent predictor, albeit the analysis of the slope of essential hypertensive patients, albeit this therapy prevents its evolution with time exhibited a trend for higher values in renal damage when type 2 diabetes is present. The develop- those developing renal failure (84.4 versus 63.3 mol/L per yr; ment of CKD is strongly and independently related with poor P 0.485). In a cross-sectional study intended to define the cardiovascular prognosis. clinical characteristics of hypertensive patients (n 1625) with metabolic syndrome, we found that glucose metabolism disturbance was related with a diminished creatinine clearance References and higher urinary albumin excretion (23). 1. Multiple Risk Factor Intervention Trial Research Group. Multi- The relevance of CKD as a predictor of cardiovascular risk ple Risk Factor Intervention Trial: Risk factor changes and has received ample review recently (24). In hypertensive pa- mortality results. JAMA 248: 14651467, 1982 tients, the presence of a diminished estimated GFR (60 2. Vupputuri S, Batuman V, Muntner P, et al: Effect of blood pressure on early decline in kidney function among hypertensive ml/min per 1.73 m2), microalbuminuria, small elevations in men. Hypertension 42: 1144 1149, 2003 serum creatinine or proteinuria have been recognized by re- 3. 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