sign in sign up
<<
Home , Hypertension, Systolic hypertension

J Am Soc Nephrol 14: S92–S98, 2003 Prevention of and Its Complications: Theoretical Basis and Guidelines for Treatment

JOHN M. FLACK,* ROSALIND PETERS,† TARIQ SHAFI,‡ HISHAM ALREFAI,§ SAMAR A. NASSER,* and ERROL CROOK¶ *Department of Internal , †College of Nursing, and Divisions of ‡General Internal Medicine, §Endocrinology, and ¶, Department of Internal Medicine, Wayne State University, Detroit, Michigan.

Abstract. Hypertension is a nutritional-hygienic . Long- Nevertheless, in persons with CKD, even those with protein- term caloric intake in excess of energy expenditures, chronic uria below the dipstick positive level (approximately 300 mg/d supraphysiological intake of dietary , excessive or urine protein to ratio of 0.22), aggressive BP consumption, and psychosocial stressors all contribute to the control also may be warranted because of the high risk of development of hypertension throughout the world. Elevated nonrenal . Multiple antihypertensive BP, particularly systolic BP, has been linked to multiple ad- drugs will be required in the vast majority of patients with verse clinical outcomes including , failure, myo- and/or reduced function to attain BP goal. cardial , renal insufficiency/failure, peripheral vascu- -angiotensin system (RAS) modulator therapy is indi- lar disease, , , and premature mortality. cated among persons with diabetes mellitus and CKD. Avail- These undesirable clinical outcomes are typically, although not able data support the use of angiotensin receptor blockers in invariably, preceded by pressure-related target- injury persons with and overt nephropathy for pres- such as left ventricular hypertrophy, renal insufficiency and ervation of kidney function. Among persons with type I dia- . The relation of BP and CKD and, in turn, the betes with or without overt nephropathy, type 2 diabetes with- prevention of CKD or forestalling its progression by hyperten- out overt nephropathy and in nondiabetic CKD, the available sion treatment, will be the focus of this manuscript. In hyper- clinical data support the use of angiotensin-converting enzyme tensive persons with reduced kidney function and/or protein- inhibitors as the RAS modulator of choice. Low therapeutic uria, lowering BP with multidrug therapy that is inclusive of target BP levels Ͻ130/80 mmHg in persons with type 2 dia- pharmacologic modulators of the renin-angiotensin-aldoste- betes mellitus also appear warranted based on available data rone-kinin system is an effective strategy to forestall the pro- mostly for reducing the risk of nonrenal cardiovascular disease gressive loss of kidney function. The totality of data support and overall mortality. low therapeutic BP targets for persons with proteinuria Ͼ1 g/d.

Hypertension, like most cardiovascular conditions, is a nutri- the supply and effective strategies to significantly aug- tional-hygienic disease. The seeds of hypertension are rooted ment energy expenditure above current levels. The widespread in physical inactivity, , high caloric intake, and exces- failure in many countries to implement population-based pub- sive dietary sodium intake as well as alcohol consumption. lic health approaches for hypertension/cardiovascular disease Genetic susceptibility to hypertension remains ill-defined; (CVD) prevention has heightened the importance of successful however, environmental exposures of gene-environment inter- and efficient hypertension treatment strategies to prevent/fore- actions can be favorably influenced by manipulation of life- stall pressure-related complications and premature mortality. style choices. Prevention of hypertension-related complications such as Hypertension Risk Factors reduced kidney function depends on population-wide control Prolonged exposure to sedentary lifestyles and consumption of known hypertension risk factors. Population-based hyper- of calories in excess of energy expenditures lead to a steep rise tension prevention strategies would require widely imple- in BP, particularly systolic BP, with advancing age (1). Thus, mented public health measures such as significant alterations to the default approach in Western societies has been to rely on individuals, particularly high-risk or affected individuals, to voluntarily alter their lifestyle choices. Two hypertension risk Correspondence to Dr. John Flack, Wayne State University Health Center, 4201 St. Antoine, Suite 2E, Detroit, MI 48201. Phone: 313-966-9687; Fax: factors, dietary sodium intake and obesity, will be highlighted 313-993-0645; E-mail: [email protected] because of their possible direct and substantive link not only to 1046-6673/1407-0092 hypertension but to as well. Journal of the American Society of Nephrology Sodium. Daily requirements of dietary sodium for normal Copyright © 2003 by the American Society of Nephrology physiologic functioning, assuming normal kidney function, is DOI: 10.1097/01.ASN.0000070142.14843.8E less than 10 mmol of sodium per day. This amount, however, J Am Soc Nephrol 14: S92–S98, 2003 Prevention of Hypertension and Its Complications S93 is far less than the average daily intake in the as and manifest an attenuated BP response to antihypertensive well as in many other countries (2). Among hypertensive drug therapy (32,33). , dietary sodium intake appears to be in- Physiological Basis for BP as a Mediator of Kidney versely related to education and household income and appears Injury. There is a compelling physiologic basis for the ob- to exceed that of Caucasians (3,4). servations that sustained BP elevations cause CKD, as well as A major focus of the influence of dietary sodium and its for the reasons that BP lowering slows the progressive loss of effect on cardiovascular disease has been on its pressor effect. kidney function. A normal kidney can maintain a relatively Nevertheless, this does not completely characterize the mech- constant GFR across a broad range of BP. This is termed renal anisms through which sodium causes cardiovascular-renal in- autoregulation of the GFR. The glomerular afferent jury. Raising BP, particularly among persons who are over- normally constricts when BP is high to prevent the transmis- weight (5,6), and antagonizing the hypotensive effect of sion of systemic BP to the glomerulus. Conversely, when BP antihypertensives (ACE inhibitor Ͼ antagonist) (7) are falls, the afferent arteriole dilates to stabilize GFR or to at least BP-related venues through which sodium causes target-organ minimize its reduction. However, disordered autoregulation of injury. Sodium also can reversibly disrupt normal autoregula- GFR is known to occur in multiple clinical conditions such as tion of GFR, a mechanism that potentially exposes the glomer- diabetes mellitus, reduced renal mass, proteinuric kidney dis- ulus to inappropriately high systemic BP therefore predispos- ease as well as during exposure to high levels of dietary ing to hemodynamic injury. There is also evidence that dietary sodium. For example, among persons with proteinuric kidney sodium intake worsens proteinuria, especially among -sen- disease, systemic BP levels are high and are more efficiently sitive persons (8,9) and, as well, increases left ventricular mass transmitted to the glomerulus because of dysfunctional glomer- (10,11). Sodium also appears to be a direct vascular toxin. In ular autoregulation. This is highly consistent with clinical experimental models sodium augments the production and studies showing that hypertensives, diabetics (types 1 and 2), release of vascular injury mediators such as TGF-beta (12). and persons with CKD and proteinuria lose kidney function Sodium is also necessary for to inflict fibrosis and faster than those without proteinuria (32,35–40). Furthermore, scarring in target-organs (13). proteinuria activates a multiplicity of cellular injury pathways Obesity. Obesity is a major for the two major that promote glomerulosclerosis and tubulointerstitial fibrosis causes of end-stage kidney disease (ESKD) in the United (41–44). States—diabetes mellitus and hypertension. The major deter- When functioning kidney mass is reduced and global GFR minant of obesity in a given population appears to be energy falls, the hemodynamic on surviving glomeruli increase. expenditure over the long term that is less than habitual caloric One deleterious consequence of the increased hemodynamic intake. In the United States, African Americans, particularly stress is that intraglomerular pressure rises as a consequence of women, are more obese than white women (14,15). Further- efferent arteriolar coupled with afferent arte- more, African-American women residing in the southeastern riolar dilation. The latter allows transmission of raised sys- United States have a significantly higher prevalence than Af- temic BP into the glomerulus. Activation of the local renin rican-American women residing outside this region (16,17). angiotensin system constricts the efferent more than the affer- On average, within the United States, minority women are ent arteriole. These glomerular hemodynamic changes increase more likely to be obese than white women. single nephron GFR in an attempt to maintain global GFR Obesity has been linked to raised BP (18,19), salt-sensitivity despite progressively fewer functioning nephrons. However, if (5,6), as well as glucose intolerance (20,21), and dyslipidemia these glomerular hemodynamic changes are sustained they will (22,23). In young adults, body size is the major determinant of likely result in glomerular injury and an accelerated loss of left ventricular mass (24). In addition, obesity has been asso- kidney function over time. ciated with higher levels of urinary protein excretion (25). There is emerging evidence that obesity may adversely affect Evidence That BP Lowering Slows the Progressive kidney function possibly via activation of the local renin an- Loss of Kidney Function giotensin and sympathetic nervous systems as well as by caus- Type I Diabetes Mellitus. Numerous studies in persons ing excessive renal sodium absorption, mesangial cell hyper- with type 1 diabetes mellitus (45–49) show that BP lowering, trophy, matrix production, and glomerular hyperfiltration even without RAS modulator drugs, slows down the loss of (26,27). kidney function. Another important consideration relates to the optimal treatment of patients with . There BP and Kidney Disease is little controversy regarding the importance of RAS modula- Epidemiology. Epidemiological data have convincingly tor therapy in persons with either type 1 or 2 diabetes mellitus. shown that BP is linked to CKD and proteinuria (28,29), and In type 1 diabetes mellitus with nephropathy and serum creat- kidney disease-related mortality (30). The risk of ESKD, at inine Ͻ2.5 mg/dl, there is very convincing evidence that the least among African-American and white men, is inversely ACE inhibitor , relative to placebo, reduces kidney related to and directly related to BP level disease progression as measured by changes in creatinine clear- (31). Approximately 85% of persons with CKD have hyper- ance and the incidence of ESRD (50). In this study, the risk of tension. Also, persons with proteinuria superimposed on CKD the composite primary endpoint of , dialysis, and trans- have higher BP than persons with nonproteinuric CKD (32,33) plantation was reduced by 50%. Risk of doubling of serum S94 Journal of the American Society of Nephrology J Am Soc Nephrol 14: S92–S98, 2003 creatinine was reduced by 48% in the captopril group (P ϭ mellitus in the HOPE study were recently reported showing 0.007). At present there are no corresponding clinical endpoint significant reductions in microvascular and macrovascular data available for angiotensin receptor blockers in persons with clinical events including the need for coronary revasculariza- type 1 diabetes mellitus and nephropathy. tion with , an ACE inhibitor, compared with placebo, Type 2 Diabetes Mellitus. Multiple studies have shown in persons with type 2 diabetes mellitus without nephropathy the benefits of BP lowering on the preservation of kidney (58). The composite endpoint of MI, stroke, or death was function (49,51). Other studies have shown that initial therapy lowered by 25% with ramipril (P ϭ 0.0004) and the develop- with a multiplicity of classes—, ment of overt nephropathy was decreased by 24% (P ϭ 0.027). beta-blockers, and calcium antagonists—reduce the risk of Two recent reports from the Appropriate BP Control in Dia- nonrenal CVD events compared with placebo (52–54). How- betes (ABCD) trial provided support for low therapeutic BP ever, the major controversy in type 2 diabetes mellitus is targets in persons with type 2 diabetes, although not for pres- whether ACE inhibitors or angiotensin receptor blockers pro- ervation of kidney function (59). Some 470 persons with type vide optimal RAS modulator therapy. Another major question 2 diabetes and hypertension (DBP Ն90 mmHg) were followed is not simply whether BP lowering is beneficial but rather how for an average of 5.3 yr. Participants were randomized either to low should the minimal therapeutic target BP be set. intensive (DBP goal Ͻ75 mmHg) or moderate (DBP goal 80 to Two recently reported clinical trials in persons with type 2 89 mmHg) BP targets. Mean BP achieved in the two groups diabetes mellitus and nephropathy showed the superiority of were 132/78 and 138/86 mmHg, respectively. , a initial therapy with an angiotensin receptor blocker on the dihydropyridine calcium antagonist, was also compared with progressive loss of kidney function, proteinuria reduction, and an ACE inhibitor, . There were no differences in the first hospitalizations for relative to either initial progression of nephropathy, retinopathy, or neuropathy be- treatment with , a dihydropyridine calcium antago- tween the intensive or moderate BP goals or between the nist, and/or a treatment regimen containing neither an ACE nisoldipine and enalapril treatment arms. Nevertheless, total inhibitor or an angiotensin receptor blocker (55,56). However, mortality was lower 5.5% versus 10.7% (P ϭ 0.037) in the there was a trend toward higher stroke and nonfatal MI rates in intensively treated group with target DBP Ͻ75 mmHg. In this the type II Diabetic Nephropathy Trial (IDNT) study same trial (60), normotensive (BP Ͻ140/90 mmHg) persons with irbersartan, an angiotensin receptor antagonist, relative to with type 2 diabetes controlled to 128/75 mmHg had less amlodipine, a dihydropyridine calcium antagonist, despite sim- progression of normoalbuminuria to and of ilar levels of BP control and a more favorable effect of irbe- microalbuminuria to overt albuminuria, fewer , and less sartan on proteinuria. progression of diabetic retinopathy than those controlled to The Hypertension Optimal Treatment (HOT) study was an 137/81 mmHg. Again, there were no differences in clinical important study that documented the benefits of low DBP outcomes between the ACE inhibitor and the calcium targets among persons with type 2 diabetes mellitus (54). HOT antagonist. randomized 50 to 80 yr old (mean age, 61.5 yr) hypertensives to one of three diastolic BP (DBP) targets: (1) Յ90, (2) Յ85, Nondiabetic Kidney Disease. An important study in this or (3) Յ80 mmHg. Initial therapy was with , a regard is the Modification of Diet in Renal Disease Study (MDRD) in 585 persons with directly measured GFR between dihydropyridine calcium antagonist, followed by add-on ther- 2 apy with an ACE inhibitor or beta-blocker, and last, a 13 to 55 ml/min per 1.73 m aged 18 to 70 yr who were to attain the DBP target. In persons with type 2 diabetes over randomized to either a low goal BP ( Յ Յ an average 3.8 yr, major cardiovascular events were incremen- [MAP] 92 mmHg) or a usual goal BP ( 107 mmHg); these Ն tally lower 24.4, 18.6, and 11.9 per 1000 patient-years (P ϭ respective goals were adjusted upward for persons 61 yr of Յ Յ 0.005) in highest to lowest DBP target groups, respectively. age to MAP 98 mmHg or 113 mmHg (34,61). Actual Likewise CVD mortality was lower with more aggressive attained MAP in the low and usual BP groups was 93 and 97.7 therapy being 11.1, 11.2, and 3.7 per 1000 person-years (P ϭ mmHg, respectively, over the mean follow-up of 2.2 yr. No 0.016) in highest to lowest DBP target groups, respectively. particular hypertension drugs were emphasized. Note that ran- The trend toward lower total mortality was in the same direc- domization to the low BP goal was not linked to an increase in tion but did not attain statistical significance (P ϭ 0.068). adverse events or safety issues. The benefit of the low BP goal A subgroup analysis of the Captopril Prevention Project on slowing the decline in GFR was confined to persons with (CAPP) found that persons with diabetes mellitus experienced proteinuria Ͼ1.0 g/d. Nevertheless, despite the lack of benefit 41% fewer composite primary events ( in the overall cohort on the decline in GFR, an important [MI], stroke, or cardiovascular death) than persons taking observation was made regarding overall hospitalizations. That conventional therapy with diuretics or beta-blockers (57). is, higher on-treatment systolic but neither diastolic or MAP The data available for ACE inhibitors in persons with type 2 was associated with a greater risk of hospitalization during diabetes and nephropathy are less well developed (lack of follow-up. The rate of hospitalizations was 9% per annum in clinical endpoint data) compared with those available for an- the lowest on-treatment SBP quartile (Ͻ119 mmHg) and rose giotensin receptor blockers. On the other hand, data support the incrementally to 19.3% in the highest quartile (Ͼ138 mmHg). use of ACE inhibitors among persons with type 2 diabetes Hospitalizations in relation to DBP trended directly opposite of mellitus without nephropathy. Data from persons with diabetes that for SBP. Hospitalizations were highest in the lowest DBP J Am Soc Nephrol 14: S92–S98, 2003 Prevention of Hypertension and Its Complications S95 quartile (13.9%) and incrementally declined through the high- although 45% had BP Ͻ140/90 mmHg (74). Thus, these two est DBP quartile (6.3%). high-risk populations have woefully inadequate BP control. Pooled clinical endpoint data are available among persons with nondiabetic kidney disease showing the superiority of Kidney Function and RAS-Modulating Drugs ACE inhibitors over non-ACE–containing regimens for the Angiotensin converting enzyme inhibitors or angiotensin prevention of ESKD. In a meta-analysis reported by Giatris receptor blockers have been recommended as initial therapy for and co-workers (62) the risk reduction for ESRD with ACE patients with diabetic and nondiabetic kidney disease (72,75– containing regimens versus non-ACE–containing treatments 77). When BP is lowered even without RAS modulators, but was 30% (95% CI, 0.51 to 0.97). No effect on mortality was even more so when these agents are used, GFR often falls—at observed. Patients taking ACE inhibitors did, however, expe- least initially. Furthermore, the initial decline in GFR appears rience greater BP lowering by approximately 5/1 mmHg. The to be more pronounced among persons with proteinuric kidney African-American Study of Kidney Disease (AASK) recently disease (32). This loss of GFR is attributable to disordered reported that among African Americans with nondiabetic autoregulation of the GFR when systemic and/or intraglomeru- CKD, ramipril, an ACE inhibitor, was superior to a regimen lar pressure fall. This rise in creatinine after administration of that initiated therapy with either amlodipine, a dihydropyridine RAS modulating drugs may cause the clinician to unjustifiably calcium antagonist, or , a beta-blocker, for slowing discontinue indicated treatment, especially if the creatinine the loss of kidney function and prevention of kidney-related stabilizes at a level higher than baseline. Consideration should clinical events (32). Furthermore, AASK study trial results be given to either reducing the RAS modulator drug dose or were consistent with a large body of data in discontinuation when the rise in creatinine exceeds 30% or nondiabetic CKD in that the greatest relative superiority of the hyperkalemia develops (78). Diuretic-induced intravascular ACE inhibitor was among those with the highest levels of volume depletion is the most common avoidable reason for the proteinuria (63). Also, note that only kidney-related but not rise in creatinine. Some data suggest that angiotensin receptor overall cardiovascular events were reported in AASK and that blockers may elevate the less than angiotensin con- there was virtually no difference in BP lowering in the amlo- verting enzyme inhibitors among persons with EGFR Ͻ60 dipine and ramipril treatment arms (5). Clinical endpoint data ml/min per 1.73 m2 (72). Thus, the clinical conditions for for angiotensin receptor blockers in persons with nondiabetic which RAS modulator drugs are indicated also predispose to kidney disease are not available. However, these agents will creatinine elevations when systemic and/or intraglomerular likely be the logical alternative RAS modulator for ACE- pressure fall because autoregulation of GFR is abnormal. intolerant patients. Goals of Antihypertensive Therapy in Persons with Re- duced Kidney Function and/or Diabetes. The overall goals Summary of antihypertensive therapy are to lower both systemic and Persons with CKD, whether diabetic in origin or not, need intraglomerular BP. Lowering systemic BP can, but does not aggressive BP control and use of RAS modulator drugs. Inter- invariably reduce intraglomerular pressure. However, angio- estingly, the logic for low BP targets in some high risk popu- tensin converting enzyme inhibitors and angiotensin receptor lations such as persons with diabetes mellitus or CKD, may not blockers will lower intraglomerular pressure in a manner that is always be preservation of kidney function but rather for reduc- not directly dependent on reducing systemic BP (64,65). A tions in nonkidney-related cardiovascular risk, fewer hospital- logical third goal of therapy is to reduce urinary protein ex- izations, and lower total mortality. Thus, treatment recommen- cretion. Lowering BP and use of RAS system modulating dations and clinical decisions for these high-risk patients drugs will reduce urinary protein excretion. Other strategies to should take into account global CVD risk not just kidney- lower urinary protein excretion include dietary sodium restric- related target-organ complications. Finally, the optimal RAS tion (66,67) as well cessation of (68,69) and modulator drug class will depend on the type of CKD and, (70,71). Reductions in urinary protein excretion among persons with diabetes, the stage of nephropathy. correlate with slower loss of kidney function (32,34,63). The clinician should be aware that attainment of low target BP References levels (Ͻ130 to 135/80 to 85 mmHg) will be accomplished 1. Burt VL, Cutler JA, Higgins M, Horan MJ, Labarthe D, Whelton only with prescription of multiple (typically 3 to 4), not soli- P, Brown C, Roccella EJ: Trends in the prevalence, awareness, tary, antihypertensive drugs (72). treatment, and control of hypertension in the adult US popula- BP control rates are poor for persons with diabetes and tion. Data from the health examination surveys, 1960: 1991. reduced kidney function. Coresh and co-workers (73) reported Hypertension 26: 60–69, 1995 data from the NHANES III survey showing that only 11% of 2. Elliott P, Stamler J, Nichols R, Dyer AR, Stamler R, Kesteloot H, Marmot M: Intersalt revisited: Further analyses of 24 hour so- persons with serum creatinine Ն1.6 mg/dl (men) or Ն1.4 Ͻ dium excretion and pressure within and across populations. mg/dl (women) had BP 130/85 mmHg; only 27% had BP Intersalt Cooperative Research Group. BMJ 312: 1249–1253, Ͻ 140/90 mmHg; and an astounding 48% were prescribed only 1996 one antihypertensive drug. Hypertension control rates for per- 3. Ganguli MC, Grimm RH Jr, Svendsen KH, Flack JM, Grandits sons with diabetes from the same NHANES III survey were GA, Elmer PJ: Urinary sodium and potassium profile of blacks similarly low. Only 12% of diabetics had BP Ͻ130/85 mmHg and whites in relation to education in two different geographic S96 Journal of the American Society of Nephrology J Am Soc Nephrol 14: S92–S98, 2003

urban areas. TOMHS Research Group. Treatment of Mild Hy- 22. Brown CD, Higgins M, Donato KA, Rohde FC, Garrison R, pertension Study. Am J Hypertens 12: 69–72, 1999 Obarzanek E, Ernst ND, Horan M: and the 4. Ganguli MC, Grimm RH Jr, Svendsen KH, Flack JM, Grandits prevalence of hypertension and dyslipidemia. Obes Res 8: 605– GA, Elmer PJ: Higher education and income are related to a 619, 2000 better Na:K ratio in blacks: Baseline results of the Treatment of 23. Carmena R, Ascaso JF, Real JT: Impact of obesity in primary Mild Hypertension Study (TOMHS) data. Am J Hypertens 10: hyperlipidemias. Nutr Metab Cardiovasc Dis 11: 354–359, 2001 979–984, 1997 24. Flack JM, Gardin JM, Yunis C, Liu K: Static and pulsatile blood 5. Flack JM, Grimm RH Jr, Staffileno BA, Dnsc, Emler P, Yunis C, pressure correlates of left ventricular structure and function in Hedquist L, Dudley A: New salt-sensitivity metrics: Variability- black and white young adults: The CARDIA study. Am Heart J adjusted change and the urinary sodium-to-creat- 138: 856–864, 1999 inine ratio. Ethn Dis 12: 10–19, 2002 25. Mulyadi L, Stevens C, Munro S, Lingard J, Bermingham M: 6. Rocchini AP, Key J, Bondie D, Chico R, Moorehead C, Katch V, Body distribution and total body fat as risk factors for mi- Martin M: The effect of weight loss on the sensitivity of blood croalbuminuria in the obese. Ann Nutr Metab 45: 67–71, 2001 pressure to sodium in obese adolescents. N Engl J Med 321: 26. Hall JE, Brands MW, Henegar JR: Mechanisms of hypertension 580–585, 1989 and kidney disease in obesity. Ann N Y Acad Sci 18: 91–107, 7. Weir MR, Hall PS, Berhrens MT, Flack JM: Salt and blood 1999 pressure responses to calcium antagonism in hypertensive pa- 27. Adelman RD: Obesity and renal disease. Curr Opin Nephrol tients. Hypertension 30: 422–427, 1997 Hypertens 11: 331–335, 2002 8. Weir MR: Impact of salt intake on blood pressure and proteinuria 28. Martins D, Tareen N, Norris KC: The epidemiology of end-stage in diabetes: importance of the renin-angiotensin system. Miner renal disease among African-Americans. Am J Med Sci 323: Electrolyte Metab 24: 438–45, 1998 65–71, 2002 9. Feldstein CA: Salt intake, hypertension and diabetes mellitus. J 29. Muirhead N: The rationale for early management of chronic Hum Hypertens 16[Suppl 1]: S48–S51, 2002 renal insufficiency. Nephrol Dial Transplant 16 Suppl 7: 51–56, 10. Liebson PR, Grandits GA, Dianzumba S, Prineas RJ, Grimm RH 2001 Jr, Neaton JD, Stamler J: Comparison of five antihypertensive 30. Flack JM, Neaton JD, Daniels B, Esunge P: Ethnicity and renal monotherapies and placebo for change in left ventricular mass in disease: Lessons from the Multiple Risk Factor Intervention Trial patients receiving nutritional-hygienic therapy in the Treatment and the Treatment of Mild Hypertension Study. Am J Kidney Dis of Mild Hypertension Study (TOMHS). Circulation 91: 698– 21[Suppl 1]: 31–40, 1993 706, 1995 31. Klag MJ, Whelton PK, Randall BL, Neaton JD, Brancati FL, 11. Beil AH, Schmieder RE: Salt intake as a determinant of cardiac Stamler J: End-stage renal disease in African-American and hypertrophy. Blood Press Suppl 2: 30–34, 1995 white men. 16 year MRFIT findings. JAMA 277: 1293–1298, 12. Ying WZ, Sanders PW: Dietary salt modulates renal production 1997 of transforming growth factor-beta in rats. Am J Physiol 274: 32. Agodoa LY, Appel L, Bakris GL, Beck G, Bourgoignie J, Briggs F635–F641, 1998 JP, Charleston J, Cheek D, Cleveland W, Douglas JG, Douglas 13. Rocha R, Stier CT Jr, Kifor I, Ochoa-Maya MR, Rennke HG, M, Dowie D, Faulkner M, Gabriel A, Gassman J, Greene T, Hall Williams GH, Adler GK: Aldosterone: a mediator of myocardial Y, Hebert L, Hiremath L, Jamerson K, Johnson CJ, Kopple J, necrosis and renal arteriopathy. Endocrinology 141: 3871–3878, 2000 Kusek J, Lash J, Lea J, Lewis JB, Lipkowitz M, Massry S, 14. Okosun IS, Choi S, Dent MM, Jobin T, Dever GE: Abdominal Middleton J, Miller ER 3rd, Norris J, O’Connor D, Ojo A, obesity defined as a larger than expected waist girth is associated Philips RA, Pogue V, Rahman M, Randall OS, Rostand S, with racial/ethnic differences in risk of hypertension. J Hum Schulman G, Smith W, Thornley-Brown D, Tisher CC, Toto RD, Hypertens 15: 307–312, 2001 Wright JT Jr, Xu S: African-American Study of Kidney Disease 15. American Obesity Association: Fact Sheets 2002. http://ww- and Hypertension (AASK) Study Group: Effect of ramipril vs w.obesity.org amlodipine on renal outcomes in hypertensive nephrosclerosis: A 16. Hall WD, Ferrario CM, Moore MA, Hall JE, Flack JM, Cooper randomized controlled trial. JAMA 285: 2774–2776, 2001 W, Simmons JD, Egan BM, Lackland DT, Perry M Jr, Roccella 33. Duncan K, Ramappa P, Thornburg R, Singh K, Okoye C, Mann EJ: Hypertension-related morbidity and mortality in the south- N, et al: The influence of urinary albumin excretion and esti- eastern United States. Am J Med Sci 313: 195–209, 1997 mated glomerular filtration rate on blood pressure response in 17. Greenlund KJ, Kiefe CI, Gidding SS, Lewis CA, Srinivasan SR, drug-treated hypertensive patients in an academic hypertension Williams OD, Berenson GS: Differences in cardiovascular dis- clinic. Am J Hypertens 14: 578, 2001 ease risk factors in black and white young adults: comparisons 34. Lazarus JM, Bourgoignie JJ, Buckalew VM, Greene T, Levey among five communities of the CARDIA and the Bogalusa heart AS, Milas NC, Paranandi L, Perterson JC, Porush JG, Rauch S, studies. Am Epidemial 8: 22–30, 1998 Soucie JM, Stollar C: Achievement and safety of a low blood 18. Diaz ME: Hypertension and obesity. J Hum Hypertens 16[Suppl pressure goal in chronic renal disease. The Modification of Diet 1]: S18–S22, 2002 in Renal Disease Study Group. Hypertension 29: 641–650, 1997 19. Redon J: Hypertension in obesity. Nutr Metab Cardiovasc Dis 35. Hunsicker LG, Adler S, Caggiula A, England BK, Greene T, 11: 344–353, 2001 Kusek JW, Rogers NL, Teschan PE: Predictors of the progres- 20. Wat NM, Lam TH, Janus ED, Lam KS: Central obesity predicts sion of renal disease in the Modification of Diet in Renal Disease the worsening of glycemia in southern Chinese. Int J Obes Relat Study. Kidney Int 51: 1908–1919, 1997 Metab Disord 25: 1789–1793, 2001 36. Berrut G, Bouhanick B, Fabbri P, Guilloteau G, Bled F, Le Jeune 21. Ryan AS: resistance with aging: Effects of diet and JJ, Fressinaud P, Marre M: Microalbuminuria as a predictor of a . Sports Med 30: 327–346, 2000 drop in glomerular filtration rate in subjects with non-insulin- J Am Soc Nephrol 14: S92–S98, 2003 Prevention of Hypertension and Its Complications S97

dependent diabetes mellitus and hypertension. Clin Nephrol 48: 53. Tuomilehto J, Rastenyte D, Birkenhager WH, Thijs L, Anti- 92–97, 1997 kainen R, Bulpitt CJ, Fletcher AE, Forette F, Goldhaber A, 37. Massy ZA, Khoa TN, Lacour B, Descamps-Latscha B, Man NK, Palatini P, Sarti C, Fagard R: Effects of calcium-channel block- Jungers P: Dyslipidaemia and the progression of renal disease in ade in older patients with diabetes and . chronic renal failure patients. Nephrol Dial Transplant 14: 2392– Systolic Hypertension in Europe Trial Investigators. N Engl 2397, 1999 J Med 340: 677–684, 1999 38. Hannedouche T, Albouze G, Chauveau P, Lacour B, Jungers P: 54. Hansson L, Zanchetti A, Carruthers SG, Dahlof B, Elmfeldt D, Effects of blood pressure and antihypertensive treatment on Julius S, Menard J, Rahn KH, Wedel H, Westerling S: Effects of progression of advanced chronic renal failure. Am J Kidney Dis intensive blood-pressure lowering and low-dose aspirin in pa- 21[Suppl 2]: 131–137, 1993 tients with hypertension: Principal results of the Hypertension 39. Klein R, Klein BE, Moss SE, Cruickshanks KJ, Brazy PC: The Optimal Treatment (HOT) randomised trial. HOT Study Group. 10-year incidence of renal insufficiency in people with type 1 Lancet 351: 1755–1762, 1998 diabetes. Diabetes Care 22: 743–751, 1999 55. Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis 40. Maschio G, Marcantoni C, Bernich P: Systemic hypertension and JB, Ritz E, Atkins RC, Rohde R, Raz I: Collaborative Study antihypertensive agents. J Nephrol 12[Suppl 2]: S100–S104, Group: Renoprotective effect of the angiotensin-receptor antag- 1999 onist Irbesartan in patients with nephropathy due to type 2 41. Nakajima H, Takenaka M, Kaimori JY, Nagasawa Y, Kosugi A, diabetes. N Engl J Med 345: 851–860, 2001 Kawamoto S, Imai E, Hori M, Okubo K: Gene expression profile 56. Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, of renal proximal tubules regulated by proteinuria. Kidney Int 61: Parving HH: Effects of on renal and cardiovascular 1577–1587, 2002 outcomes in patients with type 2 diabetes and nephropathy. 42. Eddy AA: Experimental insights into the tubulointerstitial dis- N Engl J Med 345: 861–869, 2001 ease accompanying primary glomerular lesions. J Am Soc Neph- 57. Hansson L, Lindholm LH, Niskanen L, Lanke J, Hedner T, rol 5: 1273–1287, 1994 Niklason A, Luomanmaki K, Dahlof B, de Faire U, Morlin C, 43. Remuzzi G: Abnormal protein traffic through the glomerular Karlberg BE, Wester PO, Bjorck JE: Effect of angiotensin- barrier induces proximal tubular cell dysfunction and causes converting-enzyme inhibition compared with conventional ther- renal injury. Curr Opin Nephrol Hypertens 4: 339–342, 1995 apy on cardiovascular morbidity and mortality in hypertension: 44. Bruzzi I, Benigni A, Remuzzi G: Role of increased glomerular The Captopril Prevention Project (CAPPP) randomised trial. protein traffic in the progression of renal failure. Kidney Int Lancet 353: 611–616, 1999 [Suppl. 62]: S29–S31, 1997 58. Heart Outcomes Prevention Evaluation Study Investigators: Ef- 45. Rossing P, Hommel E, Smidt UM, Parving HH: Reduction in fects of ramipril on cardiovascular and microvascular outcomes albuminuria predicts a beneficial effect on diminishing the pro- in people with diabetes mellitus: results of the HOPE study and gression of human diabetic nephropathy during antihypertensive MICRO-HOPE substudy. Lancet 355: 253–259, 2000 treatment. Diabetologia 37: 511–516, 1994 59. Estacio RO, Jeffers BW, Gifford N, Schrier RW: Effect of blood 46. Hommel E, Mathiesen E, Edsberg B, Bahnsen M, Parving HH: pressure control on diabetic microvascular complications in pa- Acute reduction of arterial blood pressure reduces urinary albu- tients with hypertension and type 2 diabetes. Diabetes Care min excretion in type 1 (insulin-dependent) diabetic patients with 23[Suppl 2]:B 54–64, 2000 incipient nephropathy. Diabetologia 29: 211–215, 1986 60. Schrier RW, Estacio RO, Esler A, Mehler P: Effects of aggres- 47. Parving HH, Andersen AR, Hommel E, Smidt U: Effects of sive blood pressure control innormotensive type 2 diabetic pa- long-term antihypertensive treatment on kidney function in dia- tients on albuminura, retinopathy and strokes. Kidney Int 61: betic nephropathy. Hypertension 7:II 114–117, 1985 1086–1097, 2002 48. Parving HH, Andersen AR, Smidt UM, Svendsen PA: Early 61. Peterson JC, Adler S, Burkart JM, greene T, Hebert LA, Hun- aggressive antihypertensive treatment reduces rate of decline in sicker LG, King AJ, Klahr S, Massry SG, Seifter JL: Blood kidney function in diabetic nephropathy. Lancet 28: 1:1175– pressure control, proteinuria, and the progression of renal dis- 1179, 1983 ease. The modification of diet in renal disease study. Ann Intern 49. Kasiske BL, Kalil RSN, Ma JZ, Liao M, Keane WF: Effect of Med 123: 754–762, 1995 antihypertensive therapy on the kidney in patients with diabetes: 62. Giatras I, Lau J, Levey AS: Effect of angiotensin-k converting A meta-regression analysis. Ann Intern Med 118: 129–138, 1993 enzyme inhibitors on the progression of nondiabetic renal dis- 50. Lewis EJ, Hunsicker LG, Bain RP, Rohde RD: The effect of ease: A meta-analysis of randomized trials, angiotensin-convert- angiotensin-converting-enzyme inhibition on diabetic nephropa- ing-enzyme inhibition and progressive renal disease study group. thy. The Collaborative Study Group. N Engl J Med 329: 1456– Ann Intern Med 127: 337–345, 1997 1462, 1993 63. Jafar TH, Stark PC, Schmid CH, Landa M, Maschio G, Marcan- 51. UK Prospective Diabetes Study Group: Tight blood pressure toni C, de Jong PE, de Zeeuw D, Shahinfar S, Ruggenenti P, control and risk of macrovascular and microvascular complica- Remuzzi G, Levey AS (AIPRD Study Group): Angiotensin- tions in type 2 diabetes: UKPDS 38. BMJ 317: 703–713, 1998 converting enzyme inhibition and progression of renal disease: 52. Curb JD, Pressel SL, Cutler JA, Savage PJ, Applegate WB, Proteinuria as a modifiable risk factor for the progression of Black H, Camel G, Davis BR, Frost PH, Gonzalez N, Guthrie G, non-diabetic renal disease. Kidney Int 60: 1131–1140, 2001 Oberman A, Rutan GH, Stamler J: Effect of diuretic-based 64. Hollenberg NK: Impact of angiotensin II on the kidney: Does an antihypertensive treatment on cardiovascular disease risk in older angiotensin II receptor blocker make sense? Am J Kidney Dis diabetic patients with isolated systolic hypertension. Systolic 363[Suppl 1]: S18–S23, 2000 Hypertension in the Elderly Program Cooperative Research 65. Sanchez RA, Traballi CA, Marco EJ, Gilbert BH, Ramirez AJ, Group. JAMA 276: 1886–1892, 1996 Long G: Effects of ACE inhibition on renal haemodynamics in S98 Journal of the American Society of Nephrology J Am Soc Nephrol 14: S92–S98, 2003

and hypertension associated with chronic 72. Bakris GL, Siomos M, Richardson D, Janssen I, Bolton WK, renal failure. Drugs 41[Suppl 1]: 25–30, 1991 Hebert L, Agarwal R, Cantanzaro D: ACE inhibitions or angio- 66. Imanishi M, Yoshioka K, Okumura M, Konishi Y, Okada N, tensin receptor blockade: Impact on potassium in renal failure. Morikawa T, Sato T, Tanaka S, Fujii S: Sodium sensitivity VAL-K Study Group. Kidney Int 58: 2084–2092a, 2000 related to albuminuria appearing before hypertension in type 2 73. Coresh J, Wei Gl, McQuillan G, Brancati FL, Levey AS, Jones diabetic patients. Diabetes Care 24: 111–116, 2001 C, Klag MJ: Prevalence of high blood pressure and elevated 67. Campese VM: Salt sensitivity in hypertension. Renal and car- serum creatinin level in the United States: Findings from the diovascular implications. Hypertension 23: 531–550, 1994 third National Health and Nutrition Examination Survey (1988– 68. Pinto-Sietsma S, Mulder J, Janssen WMT, Hillege HL, de Zeeuw 1994). Arch Intern Med 161: 1207–1216, 2001 D, de Jong PE: Smoking is related to albuminuria and abnormal 74. Geiss LS, Rolka DB, Engelgau MM: Elevated blood pressure renal function in nondiabetic persons. Ann Int Med 133: 585– among U.S. adults with diabetes, 1998-1994. Am J Prev Med 22: 591, 2000 42–48, 2002 69. Cirillo M, Senigalliesi L, Laurenzi M, Alfieri R, Stamler J, 75. The Sixth Report of the Joint National Committee on Prevention, Stamler R, Panarelli W, Santo NG: Microalbuminuria in nondi- Detection, Evaluation, and Treatment of High Blood Pressure abetic adults: Relation of blood pressure, body mass index, (JNC VI). Arch Intern Med 157: 2413–2446, 1997 plasma levels, and smoking: The Gubbio Population 76. Standards of Medical Care for Patients with Diabetes Mellitus, Study. Arch Intern Med 158: 1933–1939, 1998 Position Statement 2002 70. Ohashi H, Oda H, Ohno M, Watanabe S: Weight reduction 77. National High Blood Pressure Education Program: 1995 up- improves high blood pressure and microalbuminuria in hyper- date of the working group reports on chronic renal failure and tensive patients with obesity. Nippon Jinzo Gakkai Shi 43: 333– renovascualr hypertension. Arch Int Med 156: 1928–1947, 339, 2001 1996 71. Praga M, Hernandez E, Andres A, Leon M, Ruilope LM, Rodicio 78. Bakris GL, Weir MR: Angiotensin-converting enzyme inhibitor- JL: Effects of body-weight loss and captopril treatment on pro- associated elevations in serum creatinine: Is this a cause for teinuria associated with obesity. Nephron 70: 35–41, 1995 concern? Arch Intern Med 160: 685–693, 2000