Prehypertension: is it relevant for nephrologists?
2009; Elsevier BV; Volume: 77; Issue: 3 Linguagem: Inglês
10.1038/ki.2009.439
ISSN1523-1755
AutoresRigas Kalaitzidis, George L. Bakris,
Tópico(s)Hormonal Regulation and Hypertension
ResumoBlood pressure (BP) in the prehypertensive range is associated with an increased risk for cardiovascular (CV) disease. Patients with co-morbidities are at greater risk for chronic kidney disease (CKD) development in the presence of prehypertension. Lifestyle changes can alter the natural history of prehypertension; however, long-term adherence is rare and thus, their impact on outcomes is limited. Pharmacological therapy in patients with prehypertension and demonstrable target organ damage with blockers of the renin–angiotensin system has demonstrated benefits on markers of CKD outcomes such as microalbuminuria. There are no data, however, on 'hard end points' such as doubling of creatinine or need for renal replacement therapy. In patients with diabetes, monitoring changes in albuminuria, along with assessment of BP in the prehypertensive range, is important to optimize early management and impact the attenuation of CKD progression. Data from natural history studies in patients with type 1 diabetes indicate that increases within the microalbuminuria range antedate increases in BP within the prehypertensive range. Even within the microalbuminuria range, however, systolic BP increases above 125 mm Hg are predictive of nephropathy. Thus, nephrologists need to ensure that their colleagues appreciate the importance of not only early BP intervention but also of monitoring albuminuria changes in order to have maximal impact on CKD prevention. Blood pressure (BP) in the prehypertensive range is associated with an increased risk for cardiovascular (CV) disease. Patients with co-morbidities are at greater risk for chronic kidney disease (CKD) development in the presence of prehypertension. Lifestyle changes can alter the natural history of prehypertension; however, long-term adherence is rare and thus, their impact on outcomes is limited. Pharmacological therapy in patients with prehypertension and demonstrable target organ damage with blockers of the renin–angiotensin system has demonstrated benefits on markers of CKD outcomes such as microalbuminuria. There are no data, however, on 'hard end points' such as doubling of creatinine or need for renal replacement therapy. In patients with diabetes, monitoring changes in albuminuria, along with assessment of BP in the prehypertensive range, is important to optimize early management and impact the attenuation of CKD progression. Data from natural history studies in patients with type 1 diabetes indicate that increases within the microalbuminuria range antedate increases in BP within the prehypertensive range. Even within the microalbuminuria range, however, systolic BP increases above 125 mm Hg are predictive of nephropathy. Thus, nephrologists need to ensure that their colleagues appreciate the importance of not only early BP intervention but also of monitoring albuminuria changes in order to have maximal impact on CKD prevention. It is known that the relationship between the level of blood pressure (BP) and the risk of cardiovascular (CV) disease events is continuous, consistent, and independent of other risk factors. Observational studies involving more than 1 million individuals indicate that death from both ischemic heart disease and stroke increases linearly, starting at BP levels as low as 115 mm Hg systolic and 75 mm Hg diastolic upward.1.Lewington S. Clarke R. Qizilbash N. et al.Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies.Lancet. 2002; 360: 1903-1913Abstract Full Text Full Text PDF PubMed Scopus (7657) Google Scholar Epidemiological studies also support the hypothesis that the level of BP and risk of chronic kidney disease (CKD) progression is linear and extends into the normotensive range.2.Klag M.J. Whelton P.K. Randall B.L. et al.Blood pressure and end-stage renal disease in men.N Engl J Med. 1996; 334: 13-18Crossref PubMed Scopus (1435) Google Scholar,3.Hsu C.Y. McCulloch C.E. Darbinian J. et al.Elevated blood pressure and risk of end-stage renal disease in subjects without baseline kidney disease.Arch Intern Med. 2005; 165: 923-928Crossref PubMed Scopus (339) Google Scholar The term 'prehypertension' was selected by the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High BP to define a group at higher CV risk with BP readings not previously considered significant by clinicians.4.Chobanian A.V. Bakris G.L. Black H.R. et al.Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.Hypertension. 2003; 42: 1206-1252Crossref PubMed Scopus (10557) Google Scholar The range of BPs defined as prehypertension is 120–139/80–89 mm Hg. This range is based on two pieces of data: first, large epidemiological studies, as previously mentioned and second, data obtained from the focus groups of patients with hypertension as gathered by members of the executive committee of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High BP.1.Lewington S. Clarke R. Qizilbash N. et al.Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies.Lancet. 2002; 360: 1903-1913Abstract Full Text Full Text PDF PubMed Scopus (7657) Google Scholar,4.Chobanian A.V. Bakris G.L. Black H.R. et al.Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.Hypertension. 2003; 42: 1206-1252Crossref PubMed Scopus (10557) Google Scholar The purpose of the focus groups was to define a term that resonates with the populace that would prompt them to ask for advice if they were told that they were prehypertensive. The epidemiological analyses provide evidence that the range of BPs defined as prehypertension are associated with an intermediate level of CV risk, higher than normotensive patients, that is, 140/90 mm Hg.5.Gu Q. Burt V.L. Paulose-Ram R. et al.High blood pressure and cardiovascular disease mortality risk among U.S. adults: the third National Health and Nutrition Examination Survey mortality follow-up study.Ann Epidemiol. 2008; 18: 302-309Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar The data for prehypertension contributing to development of CKD are weak. This review summarizes recent information on prehypertension that is relevant for nephrologists. It focuses on prehypertension as a CKD risk factor and its potential contribution to progression of CKD. The presence of prehypertension, especially in the range of ≥130/80 mm Hg, is a harbinger of hypertension and risk of developing hypertension that increases with age.4.Chobanian A.V. Bakris G.L. Black H.R. et al.Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.Hypertension. 2003; 42: 1206-1252Crossref PubMed Scopus (10557) Google Scholar Normotensive individuals at 55–65 years of age have more than a 90% change of developing hypertension by age 80.4.Chobanian A.V. Bakris G.L. Black H.R. et al.Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure.Hypertension. 2003; 42: 1206-1252Crossref PubMed Scopus (10557) Google Scholar,6.Vasan R.S. Beiser A. Seshadri S. et al.Residual lifetime risk for developing hypertension in middle-aged women and men: The Framingham Heart Study.JAMA. 2002; 287: 1003-1010Crossref PubMed Google Scholar Thus, increases in BP are a reflection of advancing age as well as development of co-morbid conditions, such as obesity and diabetes. All of these conditions are known to accelerate vascular aging by a variety of mechanisms, all converging on nuclear factor-κB and discussed later in this paper.7.Camici G.G. Sudano I. Noll G. et al.Molecular pathways of aging and hypertension.Curr Opin Nephrol Hypertens. 2009; 18: 134-137Crossref PubMed Scopus (39) Google Scholar, 8.Cordero A. Laclaustra M. Leon M. et al.Prehypertension is associated with insulin resistance state and not with an initial renal function impairment. A Metabolic Syndrome in Active Subjects in Spain (MESYAS) Registry substudy.Am J Hypertens. 2006; 19: 189-196Crossref PubMed Scopus (80) Google Scholar, 9.Liu K. Ruth K.J. Flack J.M. et al.Blood pressure in young blacks and whites: relevance of obesity and lifestyle factors in determining differences. The CARDIA Study.Circulation. 1996; 93: 60-66Crossref PubMed Scopus (106) Google Scholar The prevalence of prehypertension is approximately 31–37% in the adult population of the United States, much higher than hypertension, which is about 20%.10.Wang Y. Wang Q.J. The prevalence of prehypertension and hypertension among US adults according to the new joint national committee guidelines: new challenges of the old problem.Arch Intern Med. 2004; 164: 2126-2134Crossref PubMed Scopus (464) Google Scholar Prehypertension is most commonly associated with obesity and metabolic syndrome,8.Cordero A. Laclaustra M. Leon M. et al.Prehypertension is associated with insulin resistance state and not with an initial renal function impairment. A Metabolic Syndrome in Active Subjects in Spain (MESYAS) Registry substudy.Am J Hypertens. 2006; 19: 189-196Crossref PubMed Scopus (80) Google Scholar,11.Chen J. Muntner P. Hamm L.L. et al.The metabolic syndrome and chronic kidney disease in U.S. adults.Ann Intern Med. 2004; 140: 167-174Crossref PubMed Scopus (1124) Google Scholar the risk factors also appreciated to accelerate development and progression of CKD.8.Cordero A. Laclaustra M. Leon M. et al.Prehypertension is associated with insulin resistance state and not with an initial renal function impairment. A Metabolic Syndrome in Active Subjects in Spain (MESYAS) Registry substudy.Am J Hypertens. 2006; 19: 189-196Crossref PubMed Scopus (80) Google Scholar, 10.Wang Y. Wang Q.J. The prevalence of prehypertension and hypertension among US adults according to the new joint national committee guidelines: new challenges of the old problem.Arch Intern Med. 2004; 164: 2126-2134Crossref PubMed Scopus (464) Google Scholar, 11.Chen J. Muntner P. Hamm L.L. et al.The metabolic syndrome and chronic kidney disease in U.S. adults.Ann Intern Med. 2004; 140: 167-174Crossref PubMed Scopus (1124) Google Scholar, 12.Lee J.E. Kim Y.G. Choi Y.H. et al.Serum uric acid is associated with microalbuminuria in prehypertension.Hypertension. 2006; 47: 962-967Crossref PubMed Scopus (124) Google Scholar, 13.Greenlund K.J. Croft J.B. Mensah G.A. Prevalence of heart disease and stroke risk factors in persons with prehypertension in the United States, 1999–2000.Arch Intern Med. 2004; 164: 2113-2118Crossref PubMed Scopus (260) Google Scholar, 14.Knight S.F. Imig J.D. Obesity, insulin resistance, and renal function.Microcirculation. 2007; 14: 349-362Crossref PubMed Scopus (68) Google Scholar A marker of CKD progression, proteinuria, is 43–56% higher in overweight and obese persons with nephropathy compared with individuals with body mass index (BMI) 140/90 mm Hg, BP reduction using blockers of the renin–angiotensin system and ensuring maximal reductions in proteinuria are associated with slower CKD progression.24.Kalaitzidis R.G. Bakris G.L. Should proteinuria reduction be the criterion for antihypertensive drug selection for patients with kidney disease?.Curr Opin Nephrol Hypertens. 2009; 18: 386-391Crossref PubMed Scopus (19) Google Scholar Prehypertension as a risk factor is relevant in the setting of concomitant diseases associated with it as well as the age of the patient. Recent data on aging show that mitochondrial production of reactive oxygen species, innate immunity, the local tumor necrosis factor-α-converting enzyme, and the renin–-angiotensin system may underlie nuclear factor-κB induction and endothelial activation in aged arteries. Thus, multiple proinflammatory pathways converge on nuclear factor-κB in the aged arterial wall, and transcriptional activity of nuclear factor-κB is regulated by multiple nuclear factors.25.Csiszar A. Wang M. Lakatta E.G. et al.Inflammation and endothelial dysfunction during aging: role of NF-kappaB.J Appl Physiol. 2008; 105: 1333-1341Crossref PubMed Scopus (364) Google Scholar This is an important observation as prehypertension, as part of the aging process, may simply be the reflection of the magnitude of proinflammatory injury to the vessel. A review of the data dealing with inflammatory markers, put into the perspective of vascular aging and prehypertension, notes that increased production of reactive oxygen species observed in aging and hypertension may provide the missing link interconnecting endothelin-1 and other inflammatory markers.7.Camici G.G. Sudano I. Noll G. et al.Molecular pathways of aging and hypertension.Curr Opin Nephrol Hypertens. 2009; 18: 134-137Crossref PubMed Scopus (39) Google Scholar These data are relevant to CKD progression, as the most common causes of CKD, diabetes, and hypertension are diseases of accelerated vascular aging. Hence, understanding these vascular changes in the context of prehypertension as a marker of these changes is an important first step in stopping CKD development associated with these diseases. Evidence to support prehypertension as a marker of target organ injury comes from a cohort of adolescents with a high prevalence of obesity and diabetes. In this cohort, prehypertension was associated with increased cardiac output, peripheral resistance index, and evidence of increased arterial stiffness.26.Drukteinis J.S. Roman M.J. Fabsitz R.R. et al.Cardiac and systemic hemodynamic characteristics of hypertension and prehypertension in adolescents and young adults: the Strong Heart study.Circulation. 2007; 115: 221-227Crossref PubMed Scopus (173) Google Scholar This increase in arterial stiffness is associated with a lower kidney function even within the normal reference range and more importantly higher CV risk.27.Ilyas B. Dhaun N. Markie D. et al.Renal function is associated with arterial stiffness and predicts outcome in patients with coronary artery disease.QJM. 2009; 102: 183-191Crossref PubMed Scopus (21) Google Scholar The majority of information regarding CKD progression or its development comes from advanced nephropathy studies in people with hypertension.28.Khosla N. Kalaitzidis R. Bakris G.L. The kidney, hypertension, and remaining challenges.Med Clin North Am. 2009; 93 (Table of Contents): 697-715Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar All of the studies dealing with prehypertension, however, are epidemiological analyses of large databases2.Klag M.J. Whelton P.K. Randall B.L. et al.Blood pressure and end-stage renal disease in men.N Engl J Med. 1996; 334: 13-18Crossref PubMed Scopus (1435) Google Scholar, 29.Schaeffner E.S. Kurth T. Bowman T.S. et al.Blood pressure measures and risk of chronic kidney disease in men.Nephrol Dial Transplant. 2008; 23: 1246-1251Crossref PubMed Scopus (38) Google Scholar, 30.Reynolds K. Gu D. Muntner P. et al.A population-based, prospective study of blood pressure and risk for end-stage renal disease in China.J Am Soc Nephrol. 2007; 18: 1928-1935Crossref PubMed Scopus (65) Google Scholar, 31.Obermayr R.P. Temml C. Knechtelsdorfer M. et al.Predictors of new-onset decline in kidney function in a general middle-European population.Nephrol Dial Transplant. 2008; 23: 1265-1273Crossref PubMed Scopus (138) Google Scholar, 32.Haroun M.K. Jaar B.G. Hoffman S.C. et al.Risk factors for chronic kidney disease: a prospective study of 23,534 men and women in Washington County, Maryland.J Am Soc Nephrol. 2003; 14: 2934-2941Crossref PubMed Scopus (404) Google Scholar or small limited-outcome studies and are summarized in Table 1. These epidemiological studies have a range of follow-up between 7 and 21 years and show a graded relationship between BP levels and the risk of CKD. These studies are consistent, however, in that they indicate that people with BP levels >130/80 mm Hg over extended periods of follow-up have between 11 and 90% risk of worsening kidney function due to the prehypertension. It should be noted that many of the people in these studies did have concomitant risk factors, including hyperlipidemia and other metabolic disturbances.Table 1Epidemiological studies of CKD/ESRD risk and prehypertensionStudyNo. of subjects in the studyNo. of subjects with prehypertensionYears or person-years of follow-upBlood pressure levelsRisk of CKDFinal eventMRFIT study2.Klag M.J. Whelton P.K. Randall B.L. et al.Blood pressure and end-stage renal disease in men.N Engl J Med. 1996; 334: 13-18Crossref PubMed Scopus (1435) Google Scholar332,544 men73,798 men16 years follow-up130–139/80–89 mm HgRR 1.9 (95% CI 1.4–2.7)P<0.001Incidence of ESRDHsu et al.3.Hsu C.Y. McCulloch C.E. Darbinian J. et al.Elevated blood pressure and risk of end-stage renal disease in subjects without baseline kidney disease.Arch Intern Med. 2005; 165: 923-928Crossref PubMed Scopus (339) Google Scholar316,675 men and women128,270 men and women21 years/8,210,431 person-yearsBP 120–129/80–84 mm HgBP 130–139/85–89 mm HgRR 1.62 (95% CI 1.27–2.07)RR 1.98 (95% CI 1.55–2.52)P<0.05Incidence of ESRDPhysicians Health Study29.Schaeffner E.S. Kurth T. Bowman T.S. et al.Blood pressure measures and risk of chronic kidney disease in men.Nephrol Dial Transplant. 2008; 23: 1246-1251Crossref PubMed Scopus (38) Google Scholar8093 men2037 men14 years follow-upSBP 130–139 mm HgOR 1.26 (95% CI 1.03–1.53)P<0.002CKDReynolds et al.30.Reynolds K. Gu D. Muntner P. et al.A population-based, prospective study of blood pressure and risk for end-stage renal disease in China.J Am Soc Nephrol. 2007; 18: 1928-1935Crossref PubMed Scopus (65) Google Scholar158,365 men and women54,654 men and women1,236,422 person-years follow-upSBP 120–139 mm HgDBP 80–89 mm HgHR 1.30 (95% CI 0.98–1.74)P<0.001Incidence of ESRDCLUE study32.Haroun M.K. Jaar B.G. Hoffman S.C. et al.Risk factors for chronic kidney disease: a prospective study of 23,534 men and women in Washington County, Maryland.J Am Soc Nephrol. 2003; 14: 2934-2941Crossref PubMed Scopus (404) Google Scholar23,534 men and women20 yearsMen<120/80 mm Hg130–139/80–89 mm HgWomen<120/80 mm Hg130–139/80–89 mm HgHR 1.4 (95% CI 0.2–12.1)HR 3.3 (95% CI 0.4–25.6)HR 2.5 (95% CI 0.05–12.0)HR 3 (95% CI 0.6–14.4)P=NSCKDObermay et al.31.Obermayr R.P. Temml C. Knechtelsdorfer M. et al.Predictors of new-onset decline in kidney function in a general middle-European population.Nephrol Dial Transplant. 2008; 23: 1265-1273Crossref PubMed Scopus (138) Google Scholar17,375 men and women∼70% with normal BP and prehypertension7 yearsPrehypertensionOR 1.11 (95% CI 0.89–1.31)P=NSCKDAbbreviations: CI, confidence interval; CKD, chronic kidney disease, glomerular filtration rate <60 ml/min per 1.72 m2 using the abbreviated Modification of Diet in Renal Disease; DBP, diastolic blood pressure; ESRD, end-stage renal disease, as recipient of renal transplantation or maintenance dialysis; HR, hazard ratio; MRFIT, Multiple Risk Factor Intervention Trial; NS, not significant; OR, odds ratio; RR; risk reduction; SBP, systolic blood pressure. Open table in a new tab Abbreviations: CI, confidence interval; CKD, chronic kidney disease, glomerular filtration rate 130/80 and <140/90 mm Hg, was almost double, compared with optimal BP (RR 1.9, 95% confidence interval (CI) 1.4–2.7, P<0.001, Figure 1).2.Klag M.J. Whelton P.K. Randall B.L. et al.Blood pressure and end-stage renal disease in men.N Engl J Med. 1996; 334: 13-18Crossref PubMed Scopus (1435) Google Scholar Further support for the relationship between prehypertension and risk of ESRD comes from an analysis of the Kaiser Permanente group in northern California. Investigators evaluated 316,675 men and women who participated in health check-ups between 1964 and 1985. In a subset of 128,270 subjects (40.5%) with BPs in prehypertensive range, the adjusted RR for ESRD was significantly increased in both groups with BPs between 120 to 129/80 and 84 mm Hg (RR 1.62, 95% CI 1.27–2.07) and 130 to 139/85 and 89 mm Hg (RR 1.98, 95% CI 1.55–2.52), Figure 1),3.Hsu C.Y. McCulloch C.E. Darbinian J. et al.Elevated blood pressure and risk of end-stage renal disease in subjects without baseline kidney disease.Arch Intern Med. 2005; 165: 923-928Crossref PubMed Scopus (339) Google Scholar compared with those with a BP of <120/80 mm Hg. In addition, data from a prospective cohort study of 158,365 Chinese men and women over the age of 40 years,30.Reynolds K. Gu D. Muntner P. et al.A population-based, prospective study of blood pressure and risk for end-stage renal disease in China.J Am Soc Nephrol. 2007; 18: 1928-1935Crossref PubMed Scopus (65) Google Scholar and the Physicians Health Study of 8093 healthy men without known kidney disease at baseline support this observation. In the Physicians Health Study, 25.1% of the total group (n=2037) of men had BPs in the prehypertensive range and this group had a 26% higher risk of having an estimated glomerular filtration rate of <60 ml/min per 1.73 m2 compared with those with a BP of <120/80 mm Hg.29.Schaeffner E.S. Kurth T. Bowman T.S. et al.Blood pressure measures and risk of chronic kidney disease in men.Nephrol Dial Transplant. 2008; 23: 1246-1251Crossref PubMed Scopus (38) Google Scholar Taken together, these studies support the notion that BP elevations above a systolic BP of 130 mm Hg is associated with a higher risk of CKD development or progression. This is further corroborated by data from the Kidney Early Evaluation Program. In a recent analysis in which 88,559 participants were evaluated, 20,500 (23.1%) were in the prehypertensive range. This analysis found that the greater the systolic BP levels, even in the prehypertensive range, 130–139 mm Hg, the greater is the probability of CKD being present (20% at <130 mm Hg, 28.5% at 130–139 mm Hg, P<0.001), a relationship that held regardless of race or sex.33.Kalaitzidis R. Li S. Wang C. et al.Hypertension in early-stage kidney disease: an update from the Kidney Early Evaluation Program (KEEP).Am J Kidney Dis. 2009; 53: S22-S31Abstract Full Text Full Text PDF PubMed Scopus (26) Google Scholar It is clear that the relationship between prehypertension and CKD is weak, as smaller and shorter-term studies fail to show this association. A community-based, observational study of 23,534 people, followed for 20 years to evaluate CKD risk, found that the RR of developing CKD among those with high normal BP levels was 3.3 (95% CI 0.4–25.6) for men compared with individuals with optimal BP and 3.0 (95% CI 0.6–14.4) for women. The associations of high normal neared statistical significance (P=0.075).32.Haroun M.K. Jaar B.G. Hoffman S.C. et al.Risk factors for chronic kidney disease: a prospective study of 23,534 men and women in Washington County, Maryland.J Am Soc Nephrol. 2003; 14: 2934-2941Crossref PubMed Scopus (404) Google Scholar A second longitudinal cohort study of 17,375 apparently healthy volunteers in Vienna, followed for a median
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