REVIEW URRENT C OPINION
What should be the goal blood pressure in nondiabetic chronic kidney disease? Markus P. Schneider and Karl F. Hilgers
Purpose of review To summarize the available evidence on whether a lower blood pressure (BP) treatment target can ameliorate the progression of nondiabetic chronic kidney disease (CKD), and prevent cardiovascular events in CKD patients. Recent findings The three prospective, randomized controlled trials which addressed the question of progression of CKD suggest that a lower BP treatment goal (< 130/80 mmHg) may lead to better preservation of renal function, but only in those patients with proteinuria of more than 300 mg/day. However, the evidence is not conclusive. We are not aware of adequately powered, randomized trials that have assessed the efficacy of lower target BP levels for the prevention of cardiovascular events specifically in nondiabetic CKD patients. The available circumstantial evidence (e.g., subgroup analyses of CKD patients in cardiovascular trials) fails to reveal a clear benefit of a lower BP goal. Summary There is currently no convincing evidence to recommend a lower than standard BP treatment target of less than 140/90 mmHg for all patients with nondiabetic CKD. A lower treatment target of less than 130/80 mmHg may delay renal disease progression but only in patients with proteinuria. Keywords blood pressure, chronic kidney failure, renal insufficiency
INTRODUCTION For the last decade, European and US guidelines for the treatment of arterial hypertension have advocated a low blood pressure (BP) target of less than 130/80 mmHg for patients with chronic kidney disease (CKD) [1–2]. After a reassessment of available evidence, this recommendation has very recently been corrected to a more conservative treatment goal of lower than 140/90 mmHg in the European guidelines [3]. This is the standard treatment goal for all patients with arterial hypertension. In this review, we will present the key evidence underlying the revision of recommendations on BP targets in patients with nondiabetic CKD. This evidence is almost entirely derived from only three randomized studies, which we will discuss in some detail (Table 1). Early observational studies, such as the Multiple Risk Factor Intervention trial, have suggested a graded relationship between systolic BP (SBP) and diastolic BP (DBP) and the development of end-stage renal disease (ESRD) [4]. Similarly, an achieved lower BP under treatment is generally associated with a www.co-nephrolhypertens.com
&&
lower risk for cardiovascular events [5 ]. It is important, therefore, to distinguish the effects of a lower achieved BP from those of a lower goal (or target) BP. In addition, meeting a lower goal BP often requires additional antihypertensive drugs, which may not necessarily confer the same risk reduction as achieving the lower BP with a given drug regimen. For this review, however, we will focus on the evidence available on whether treating to a lower BP confers renal and cardiovascular benefit in nondiabetic CKD patients.
Department of Nephrology and Hypertension, University of ErlangenNuremberg, Erlangen, Germany Correspondence to Markus P. Schneider, MD, Department of Nephrology and Hypertension, University of Erlangen-Nuremberg, Internistisches Zentrum, Ulmenweg 18, 91054 Erlangen, Germany. Tel: +49 9131 85 39002; e-mail: [email protected] Curr Opin Nephrol Hypertens 2014, 23:180–185 DOI:10.1097/01.mnh.0000441050.36783.ba Volume 23 Number 2 March 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Nondiabetic chronic kidney disease Schneider and Hilgers
KEY POINTS Three prospective, randomized controlled trials in patients with CKD investigating the effects of a standard (< 140/90 mmHg) versus a lower ( 300 mg/day) may benefit from a lower BP target in terms of the preservation of renal function. Recent studies have shown that office BP readings are a poor indicator of 24-h BP control in patients with CKD. Whether better control of 24-h BP can improve renal and cardiovascular prognosis in CKD needs to be studied. It is important to reemphasize the necessity to reach the ‘conventional’ BP target of lower than 140/90 mmHg in all patients with CKD.
MODIFICATION OF DIET IN RENAL DISEASE STUDY The Modification Of Diet In Renal Disease (MDRD) study was the first trial to prospectively examine whether a lower BP goal would ameliorate renal function decline in patients with CKD [6]. Using a 2 2 factorial design, it also tested the renal effects of dietary protein restriction. Renal function in this trial was measured using 125I iothalamate clearance. Insulin therapy was an exclusion criterion, and diabetic nephropathy was the underlying renal disease in only 3% of patients. The trial was divided into two substudies according to the degree of renal
impairment; substudy 1 for patients with moderate renal disease, and substudy 2 for patients with more advanced renal disease [minimum glomerular filtration rate (GFR) of 13 ml/min at study entry]. In both substudies, patients were randomized to either a ‘usual’ BP goal, or a low BP treatment goal, as well as to diets containing different amounts of protein. Although a detailed discussion is beyond the scope of this review, the protein restriction diets did not protect from renal function decline. The BP intervention compared the effects of a ‘usual’ mean arterial pressure (MAP) target of less than or equal to 107 mmHg (140/90 mmHg) for patients 18–60 years of age [ 113 mmHg (160/90 mmHg) for patients 61 years of age] versus a low MAP target of less than or equal to 92 mmHg (125/75 mmHg) for patients 18–60 years of age [ 98 mmHg (145/ 75 mmHg) for patients 61 years of age]. There was no effect of the BP intervention on renal function decline after 3 years in study 1 (1.6 ml/min less in the low versus the usual BP group, P ¼ 0.18), or in study 2 (P ¼ 0.28). However, a significant interaction between BP target and baseline proteinuria on renal function decline was noted in both substudies. The benefit of the low BP treatment goal was greatest in those with proteinuria exceeding 3 g per day at baseline, moderate in those with proteinuria between 1 and 3 g per day, and no benefit of a low BP treatment target was detected in those with proteinuria of less than 1 g per day. Cases of ESRD and deaths were registered in a posttrial follow-up period of the MDRD study [7]. During this posttrial period, fewer patients died or reached ESRD in the group that had been allocated to the lower BP treatment target. However, data on antihypertensive drugs and achieved BP values were
Table 1. Key studies on blood pressure targets in patients with chronic kidney disease MDRD study
REIN-2
Year of publication
1994
2005
2010
No. individuals included
840
338
1094
Cause of CKD
Nondiabetic
Nondiabetic
‘Hypertensive’
Baseline kidney
33 (low BP target)
36 (low BP target)
46 (low BP target)
function (ml/min) Proteinuria at baseline Target BP (mmHg) Primary endpoint
AASK
32 (usual BP target)
34 (usual BP target)
45 (usual BP target)
390 mg/day (low BP target)
2.8 g/day (low BP target)
80 mg/day (low BP target)
310 mg/day (usual BP target)
2.9 g/day (usual BP target)
80 mg/day (usual BP target)
Low BP: MAP92 (125/75)
Low BP: < 130/80
Low BP: MAP92 (125/75)
Usual BP: MAP107 (140/90)
Usual BP: DBP < 90
Usual BP: MAP102–107 (the latter 140/90)
Rate of change in GFR
ESRD
Combination of doubling of serum creatinine, ESRD, and death
AASK, African–American Study Of Kidney Disease And Hypertension; ESRD, end-stage renal disease; GFR, glomerular filtration rate; MAP, mean arterial pressure; MDRD, Modification Of Diet In Renal Disease; REIN-2, Renoprotection In Nondiabetic Chronic Renal Disease-2.
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Clinical nephrology
not collected during this follow-up period. A low BP treatment target for all patients with nondiabetic CKD, regardless of degree of proteinuria is, therefore, not justifiable based on these data. Of note, a posthoc analysis of the MDRD study suggested that a lower BP target might be particularly effective in preventing renal disease progression in black versus white patients [8]. However, a limitation of this is that very few black individuals were included in the MDRD study (only 53 in study 1). As another limitation, actually achieved MAP values were very similar between the two BP groups; 90 mmHg ( 125/75 mmHg) in the low and 94 mmHg ( 133/80 mmHg) in the usual BP target group. This may have led to an underestimation of the effects of a lower BP target. Further, the definition of BP targets by MAP may have obscured differential effects in subgroups of patients that had similar MAPs, but different SBP and DBPs. There is experimental evidence that a high SBP is particularly harmful for the kidney, in particular when afferent arteriolar autoregulation, and therefore protection of the renal circulation from high systemic pressures, is compromised [9]. This is underlined by the observation that renal injury in animal models correlates very closely with SBP [10]. However, whether lower SBPs would be protective, perhaps even in patients with proteinuria of less than 1 g/day, must remain speculative at present. In summary, the key message from the MDRD study is that a lower BP target may be effective in slowing the decline of renal function in patients with nondiabetic CKD when proteinuria exceeds 1 g/day, and particularly when it exceeds 3 g/day.
THE RENOPROTECTION IN NONDIABETIC CHRONIC RENAL DISEASE-2 STUDY This study included 338 patients with nondiabetic CKD stage 3–4 with proteinuria of more than 1 g/day, already receiving therapy with an angiotensin converting enzyme (ACE)-inhibitor [11]. Patients with type 1 diabetes were excluded. In contrast, patients with type 2 diabetes were included, if their renal disease was deemed to be unrelated to the diabetes. Patients were randomized to either a conventional BP treatment goal of a DBP of lower than 90 mmHg (n ¼ 169), or an intensified BP treatment goal of lower than 130/80 mmHg (n ¼ 169). To achieve the lower BP goal, the dihydropyridine calcium-channel blocker felodipine was added (5–10 mg/day). The primary endpoint of the study was time to ESRD. As a considerable limitation of this study, actually achieved BP levels were only marginally different between the groups; 130/80 mmHg in the intensified and 134/82 mmHg in the 182
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conventional BP goal group. As the main result of the study, there was no difference in the occurrence of the primary endpoint after a median follow-up of 19 months (P ¼ 0.99).
THE AFRICAN–AMERICAN STUDY OF KIDNEY DISEASE AND HYPERTENSION In the African–American Study Of Kidney Disease and Hypertension (AASK), the effects of an intensive BP control strategy were compared with a standard BP control strategy. A total of 1094 African– American individuals with hypertensive CKD and a GFR of 20–65 ml/min were included [12]. Proteinuria of greater than 2.5 g/g creatinine was an exclusion criterion. Type 1 and type 2 diabetes were exclusion criteria. Similar to the MDRD study, renal function was measured with 125I iothalamate clearance, and BP targets were defined by MAP. Target MAP was 92 mmHg ( 125/75 mmHg) or less in the intensive BP control group, and 102–107 mmHg ( 140/90 mmHg) in the standard BP control group. Using a 3 2 factorial design, individuals were further randomized to one of three initial drug therapies: the ACE-inhibitor ramipril, the b-blocker metoprolol, or the dihydropyridine calciumchannel blocker amlodipine. If target BP was not achieved with the highest dose of the randomly assigned drug, furosemide, clonidine, doxazosine, hydralazine, and minoxidil could be added. The study consisted of two phases; the trial phase, which lasted a median of 3.8 years and a subsequent cohort (observational) phase. After completing the trial phase, all individuals that had not reached ESRD were invited to enroll in the cohort phase in which the BP target was lower than 130/80 mmHg for all patients, with ACE-inhibition as the mainstay of treatment [or angiotensin receptor blockade (ARB) when intolerant to ramipril]. Again, additional drugs could be added if the BP target of lower than 130/80 mmHg was not achieved with ACE-inhibition or an ARB. The primary outcome parameter was a combined endpoint of doubling of serum creatinine levels, a diagnosis of ESRD, or death. During the trial phase, average achieved BP was 130/78 mmHg in the intensive-control group and 141/86 mmHg in the standard-control group. During the cohort phase, BP equalized (131/78 versus 134/78 mmHg). As the main result of the study, no difference in the primary endpoint was detectable between the two groups. This held true regardless of whether the two study phases (trial þ cohort phase) were analyzed together, or whether trial and cohort phase were analyzed separately. When the data were reanalyzed according to post-hoc-defined proteinuria categories Volume 23 Number 2 March 2014
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Nondiabetic chronic kidney disease Schneider and Hilgers
(protein to creatinine ratio or > 0.22 g/g creatinine, considered to correlate with a urinary protein excretion or > 300 mg/day), a significantly lower number of patients reached the primary endpoint as well as outcomes directly related to CKD (doubling of serum creatinine or ESRD) in the intensive-control group when baseline proteinuria was greater than 0.22 g/g creatinine. Of note, the use of ACEinhibitors or ARBs was similar between the two BP groups. An interesting post-hoc analysis of the trial was published, which showed that the magnitude of the change in proteinuria predicted the progression of CKD. In other words, greater reduction of proteinuria with BP lowering predicted better renal protection in the long-term [13]. Further, this study showed that ACE-inhibitors were more effective than b-blockers or calcium channel antagonists in slowing GFR decline [12]. Of note, hypertensive CKD (nephrosclerosis) was accepted in AASK as the underlying renal disease in the absence of renal biopsies. Recent genetic studies have shown that variations in the apolipoprotein L1 gene (APOL1) are strongly related to the excess risk of nondiabetic kidney disease in individuals of African descent [14–15]. This will likely lead to reclassification of nondiabetic kidney disease, including nephropathy that has so far been considered hypertension-related. However, in terms of renal protection, a recent post-hoc analysis of the AASK trial demonstrated that a lower, compared with a standard, BP treatment target was no more effective whether individuals carried an APOL1 variant or not [16 ]. &
GOAL BLOOD PRESSURE AND CARDIOVASCULAR PROTECTION Lowering BP in patients with CKD serves a dual purpose: amelioration of kidney disease progression as well as prevention of cardiovascular mortality and morbidity. We are not aware of any appropriately powered, randomized trial that tested the effects of a lower goal BP on cardiovascular events specifically in patients with nondiabetic CKD. A detailed report on cardiovascular events in patients in the AASK study confirmed the high cardiovascular risk associated with proteinuria but did not provide evidence for an effect of the lower goal BP [17]. However, this trial may have been underpowered to clarify this question unequivocally. Information on cardiovascular outcomes of the MDRD study is limited, but the data that have been published do not suggest a beneficial effect of the lower BP goal on cardiovascular events [18]. Finally, a recent metaanalysis of several randomized trials with different antihypertensive drugs compared the effects on
cardiovascular events in patients with an estimated GFR above or below 60 ml/min per 1.73 m2 [5 ]. This analysis included diabetic patients, and did not consider proteinuria, but nevertheless provides some information on cardiovascular prevention in CKD patients. The authors confirmed that lowering BP provides roughly the same protection from cardiovascular events regardless of estimated GFR. However, no benefit of a lower goal BP was detected [5 ]. &&
&&
24-H CONTROL OF BLOOD PRESSURE IN PATIENTS WITH CHRONIC KIDNEY DISEASE It is possible that the failure of strategies targeting lower BP values in preventing renal disease progression is at least in part attributable to poor 24-h BP control. In patients with CKD, masked daytime or nocturnal hypertension that is normal in office readings but elevated on ambulatory BP monitoring (ABPM) values are common. This has been observed within the AASK study, and, more recently, in a large cross-sectional study in Spain including 5693 hypertensive individuals with CKD stages 1–5. In the latter study, misclassification of BP control was observed in one out of three individuals [19]. Although ABPM values were often better than office-based values (white coat hypertension), a large number of individuals were misclassified by office BP alone and the burden of uncontrolled 24-h BP was substantial. As a consequence, nocturnal dosing of BP medications has been proposed as a means of improving 24-h BP control in CKD. This concept has recently been tested in a cross-over, randomized study. Former participants of AASK were assigned to either receive morning, evening, or combined morning and evening dosing of their antihypertensive drugs [20 ]. BP was measured by office readings and ABPM, and the primary outcome parameter was nocturnal SBP. Disappointingly, evening or morning and evening dosing strategies did not improve nocturnal, 24 h or daytime SBP values over the ‘morning only’ dosing group. Thus, in the era of long-acting antihypertensive drugs, nighttime dosing alone is unlikely to solve the problem of poor 24-h BP control in patients with CKD. Finally, BP variability across clinic visits has been demonstrated to be a novel, independent predictor of death and nonfatal cardiovascular events independent of underlying BP levels in patients with CKD [21 ]. There is even some evidence to suggest that BP variability may predict the decline of renal function in patients with CKD [22]. However, the pathophysiological basis and the clinical relevance of these findings are presently unclear.
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CONCLUSION Taken together, except for patients with proteinuria, there is currently no convincing evidence to support a BP goal of lower than 140/90 mmHg in nondiabetic CKD patients. For patients with proteinuria, there is some evidence to suggest that a BP goal of lower than 130/80 mmHg may be beneficial for renal outcome. The MDRD study suggests that this is the case in individuals with proteinuria greater than 1 g/day; the AASK trial suggests that this may already be the case when proteinuria exceeds 300 mg/day. The Renoprotection In Nondiabetic Chronic Renal Disease-2 (REIN-2) study, however, demonstrates that even in patients with substantial proteinuria, a beneficial effect may not be observed, in particular when there is no further reduction in proteinuria while achieving the lower BP goal. The uncertainties in recommending a lower BP target have also been outlined in a recent systematic review on BP targets in CKD patients [18]. SBP values of lower than 120 mmHg should currently be avoided, as observational studies in the general population, but also in patients with CKD, suggest an increase in mortality [23]. Whether such a low SBP treatment target of lower than 120 mmHg is indeed harmful, or whether there is benefit in some circumstances, including CKD, is currently being examined in the Systolic Blood Pressure Intervention Trial, which enrolled 9250 patients and will be completed in 2018. In this context, there is accumulating evidence that orthostatic hypotension in individuals on antihypertensive treatment is important for prognosis, as it is associated with an increased risk of stroke [24], coronary heart disease [25], and overall cardiovascular mortality [26,27 ]. There is even some evidence linking orthostatic hypotension with more rapid progression of renal disease [28]. It appears to be prudent, therefore, to avoid orthostatic hypotension and BP values lower than 130/80 mmHg in the absence of convincing evidence for renal or cardiovascular benefits [27 ]. Finally, observational studies clearly show the widespread failure to meet the ‘conventional’ BP target of lower than 140/90 mmHg in CKD patients [19,29]. Reaching the target BP of lower than 140/90 mmHg in all CKD patients should, therefore, be our most pressing aim. &
&
Acknowledgements None. Conflicts of interest There are no conflicts of interest. 184
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REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Mancia G, De Backer G, Dominiczak A, et al. 2007 Guidelines for the management of arterial hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Eur Heart J 2007; 28:1462– 1536. 2. Chobanian AV, Bakris GL, Black HR, et al. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 2003; 42:1206–1252. 3. Mancia G, Fagard R, Narkiewicz K, et al. 2013 ESH/ESC guidelines for the management of arterial hypertension: the Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Eur Heart J 2013; 34:2159– 2219. 4. Klag MJ, Whelton PK, Randall BL, et al. End-stage renal disease in African– American and white men. 16-year MRFIT findings. JAMA 1997; 277:1293– 1298. 5. Blood pressure lowering and major cardiovascular events in people with and && without chronic kidney disease: meta-analysis of randomised controlled trials. BMJ 2013; 347:f5680. Comprehensive meta-analysis of trials providing data on the effects of BP lowering on cardiovascular outcomes in patients with and without CKD. 6. Klahr S, Levey AS, Beck GJ, et al. The effects of dietary protein restriction and blood-pressure control on the progression of chronic renal disease. Modification of Diet in Renal Disease Study Group. N Engl J Med 1994; 330:877– 884. 7. Sarnak MJ, Greene T, Wang X, et al. The effect of a lower target blood pressure on the progression of kidney disease: long-term follow-up of the modification of diet in renal disease study. Ann Intern Med 2005; 142:342– 351. 8. Hebert LA, Kusek JW, Greene T, et al. Effects of blood pressure control on progressive renal disease in blacks and whites. Modification of Diet in Renal Disease Study Group. Hypertension 1997; 30:428–435. 9. Bidani AK, Polichnowski AJ, Loutzenhiser R, Griffin KA. Renal microvascular dysfunction, hypertension and CKD progression. Curr Opin Nephrol Hypertens 2013; 22:1–9. 10. Bidani AK, Griffin KA, Williamson G, et al. Protective importance of the myogenic response in the renal circulation. Hypertension 2009; 54:393– 398. 11. Ruggenenti P, Perna A, Loriga G, et al. Blood-pressure control for renoprotection in patients with nondiabetic chronic renal disease (REIN-2): multicentre, randomised controlled trial. Lancet 2005; 365:939–946. 12. Wright JT Jr, Bakris G, Greene T, et al. Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease: results from the AASK trial. JAMA 2002; 288:2421–2431. 13. Lea J, Greene T, Hebert L, et al. The relationship between magnitude of proteinuria reduction and risk of end-stage renal disease: results of the African American study of kidney disease and hypertension. Arch Intern Med 2005; 165:947–953. 14. Genovese G, Friedman DJ, Ross MD, et al. Association of trypanolytic ApoL1 variants with kidney disease in African Americans. Science 2010; 329:841– 845. 15. Tzur S, Rosset S, Shemer R, et al. Missense mutations in the APOL1 gene are highly associated with end stage kidney disease risk previously attributed to the MYH9 gene. Hum Genet 2010; 128:345–350. 16. Lipkowitz MS, Freedman BI, Langefeld CD, et al. Apolipoprotein L1 gene & variants associate with hypertension-attributed nephropathy and the rate of kidney function decline in African Americans. Kidney Int 2013; 83:114– 120. Post-hoc analysis of the AASK study, which revealed that the recently described kidney disease-associated APOL1 variants are strongly related to kidney outcomes in that study. 17. Norris K, Bourgoigne J, Gassman J, et al. Cardiovascular outcomes in the African American Study of Kidney Disease and Hypertension (AASK) Trial. Am J Kidney Dis 2006; 48:739–751. 18. Upadhyay A, Earley A, Haynes SM, Uhlig K. Systematic review: blood pressure target in chronic kidney disease and proteinuria as an effect modifier. Ann Intern Med 2011; 154:541–548. 19. Gorostidi M, Sarafidis PA, de la Sierra A, et al. Differences between office and 24-h blood pressure control in hypertensive patients with CKD: A 5,693patient cross-sectional analysis from Spain. Am J Kidney Dis 2013; 62:285– 294. 20. Rahman M, Greene T, Phillips RA, et al. A trial of 2 strategies to reduce && nocturnal blood pressure in blacks with chronic kidney disease. Hypertension 2013; 61:82–88. Important study that evaluated the impact of nocturnal dosing of BP medication on 24-h BP control in CKD patients.
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Nondiabetic chronic kidney disease Schneider and Hilgers 21. Mallamaci F, Minutolo R, Leonardis D, et al. Long-term visit-to-visit office blood pressure variability increases the risk of adverse cardiovascular outcomes in patients with chronic kidney disease. Kidney Int 2013; 84:381– 389. BP variability across clinic visits is demonstrated to predict cardiovascular outcomes independently of underlying BP level in patients with CKD. 22. Yokota K, Fukuda M, Matsui Y, et al. Impact of visit-to-visit variability of blood pressure on deterioration of renal function in patients with nondiabetic chronic kidney disease. Hypertens Res 2013; 36:151– 157. 23. Weiner DE, Tighiouart H, Levey AS, et al. Lowest systolic blood pressure is associated with stroke in stages 3 to 4 chronic kidney disease. J Am Soc Nephrol 2007; 18:960–966. 24. Eigenbrodt ML, Rose KM, Couper DJ, et al. Orthostatic hypotension as a risk factor for stroke: the atherosclerosis risk in communities (ARIC) study. Stroke 2000; 31:2307–2313.
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25. Rose KM, Tyroler HA, Nardo CJ, et al. Orthostatic hypotension and the incidence of coronary heart disease: the Atherosclerosis Risk in Communities study, 1987–1996. Am J Hypertens 2000; 13:571–578. 26. Rose KM, Eigenbrodt ML, Biga RL, et al. Orthostatic hypotension predicts mortality in middle-aged adults: the Atherosclerosis Risk In Communities (ARIC) Study. Circulation 2006; 114:630–636. 27. Xin W, Lin Z, Mi S. Orthostatic hypotension and mortality risk: a meta-analysis & of cohort studies. Heart 2013. [Epub ahead of print] Important article summarizing the evidence for the harmful effects of orthostatic hypotension on overall mortality. 28. Franceschini N, Rose KM, Astor BC, et al. Orthostatic hypotension and incident chronic kidney disease: the atherosclerosis risk in communities study. Hypertension 2010; 56:1054–1059. 29. Plantinga LC, Miller ER 3rd, Stevens LA, et al. Blood pressure control among persons without and with chronic kidney disease: US trends and risk factors 1999–2006. Hypertension 2009; 54:47–56.
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What should be the goal blood pressure in nondiabetic chronic kidney disease? Markus P. Schneider and Karl F. Hilgers
Purpose of review To summarize the available evidence on whether a lower blood pressure (BP) treatment target can ameliorate the progression of nondiabetic chronic kidney disease (CKD), and prevent cardiovascular events in CKD patients. Recent findings The three prospective, randomized controlled trials which addressed the question of progression of CKD suggest that a lower BP treatment goal (< 130/80 mmHg) may lead to better preservation of renal function, but only in those patients with proteinuria of more than 300 mg/day. However, the evidence is not conclusive. We are not aware of adequately powered, randomized trials that have assessed the efficacy of lower target BP levels for the prevention of cardiovascular events specifically in nondiabetic CKD patients. The available circumstantial evidence (e.g., subgroup analyses of CKD patients in cardiovascular trials) fails to reveal a clear benefit of a lower BP goal. Summary There is currently no convincing evidence to recommend a lower than standard BP treatment target of less than 140/90 mmHg for all patients with nondiabetic CKD. A lower treatment target of less than 130/80 mmHg may delay renal disease progression but only in patients with proteinuria. Keywords blood pressure, chronic kidney failure, renal insufficiency
INTRODUCTION For the last decade, European and US guidelines for the treatment of arterial hypertension have advocated a low blood pressure (BP) target of less than 130/80 mmHg for patients with chronic kidney disease (CKD) [1–2]. After a reassessment of available evidence, this recommendation has very recently been corrected to a more conservative treatment goal of lower than 140/90 mmHg in the European guidelines [3]. This is the standard treatment goal for all patients with arterial hypertension. In this review, we will present the key evidence underlying the revision of recommendations on BP targets in patients with nondiabetic CKD. This evidence is almost entirely derived from only three randomized studies, which we will discuss in some detail (Table 1). Early observational studies, such as the Multiple Risk Factor Intervention trial, have suggested a graded relationship between systolic BP (SBP) and diastolic BP (DBP) and the development of end-stage renal disease (ESRD) [4]. Similarly, an achieved lower BP under treatment is generally associated with a www.co-nephrolhypertens.com
&&
lower risk for cardiovascular events [5 ]. It is important, therefore, to distinguish the effects of a lower achieved BP from those of a lower goal (or target) BP. In addition, meeting a lower goal BP often requires additional antihypertensive drugs, which may not necessarily confer the same risk reduction as achieving the lower BP with a given drug regimen. For this review, however, we will focus on the evidence available on whether treating to a lower BP confers renal and cardiovascular benefit in nondiabetic CKD patients.
Department of Nephrology and Hypertension, University of ErlangenNuremberg, Erlangen, Germany Correspondence to Markus P. Schneider, MD, Department of Nephrology and Hypertension, University of Erlangen-Nuremberg, Internistisches Zentrum, Ulmenweg 18, 91054 Erlangen, Germany. Tel: +49 9131 85 39002; e-mail: [email protected] Curr Opin Nephrol Hypertens 2014, 23:180–185 DOI:10.1097/01.mnh.0000441050.36783.ba Volume 23 Number 2 March 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Nondiabetic chronic kidney disease Schneider and Hilgers
KEY POINTS Three prospective, randomized controlled trials in patients with CKD investigating the effects of a standard (< 140/90 mmHg) versus a lower ( 300 mg/day) may benefit from a lower BP target in terms of the preservation of renal function. Recent studies have shown that office BP readings are a poor indicator of 24-h BP control in patients with CKD. Whether better control of 24-h BP can improve renal and cardiovascular prognosis in CKD needs to be studied. It is important to reemphasize the necessity to reach the ‘conventional’ BP target of lower than 140/90 mmHg in all patients with CKD.
MODIFICATION OF DIET IN RENAL DISEASE STUDY The Modification Of Diet In Renal Disease (MDRD) study was the first trial to prospectively examine whether a lower BP goal would ameliorate renal function decline in patients with CKD [6]. Using a 2 2 factorial design, it also tested the renal effects of dietary protein restriction. Renal function in this trial was measured using 125I iothalamate clearance. Insulin therapy was an exclusion criterion, and diabetic nephropathy was the underlying renal disease in only 3% of patients. The trial was divided into two substudies according to the degree of renal
impairment; substudy 1 for patients with moderate renal disease, and substudy 2 for patients with more advanced renal disease [minimum glomerular filtration rate (GFR) of 13 ml/min at study entry]. In both substudies, patients were randomized to either a ‘usual’ BP goal, or a low BP treatment goal, as well as to diets containing different amounts of protein. Although a detailed discussion is beyond the scope of this review, the protein restriction diets did not protect from renal function decline. The BP intervention compared the effects of a ‘usual’ mean arterial pressure (MAP) target of less than or equal to 107 mmHg (140/90 mmHg) for patients 18–60 years of age [ 113 mmHg (160/90 mmHg) for patients 61 years of age] versus a low MAP target of less than or equal to 92 mmHg (125/75 mmHg) for patients 18–60 years of age [ 98 mmHg (145/ 75 mmHg) for patients 61 years of age]. There was no effect of the BP intervention on renal function decline after 3 years in study 1 (1.6 ml/min less in the low versus the usual BP group, P ¼ 0.18), or in study 2 (P ¼ 0.28). However, a significant interaction between BP target and baseline proteinuria on renal function decline was noted in both substudies. The benefit of the low BP treatment goal was greatest in those with proteinuria exceeding 3 g per day at baseline, moderate in those with proteinuria between 1 and 3 g per day, and no benefit of a low BP treatment target was detected in those with proteinuria of less than 1 g per day. Cases of ESRD and deaths were registered in a posttrial follow-up period of the MDRD study [7]. During this posttrial period, fewer patients died or reached ESRD in the group that had been allocated to the lower BP treatment target. However, data on antihypertensive drugs and achieved BP values were
Table 1. Key studies on blood pressure targets in patients with chronic kidney disease MDRD study
REIN-2
Year of publication
1994
2005
2010
No. individuals included
840
338
1094
Cause of CKD
Nondiabetic
Nondiabetic
‘Hypertensive’
Baseline kidney
33 (low BP target)
36 (low BP target)
46 (low BP target)
function (ml/min) Proteinuria at baseline Target BP (mmHg) Primary endpoint
AASK
32 (usual BP target)
34 (usual BP target)
45 (usual BP target)
390 mg/day (low BP target)
2.8 g/day (low BP target)
80 mg/day (low BP target)
310 mg/day (usual BP target)
2.9 g/day (usual BP target)
80 mg/day (usual BP target)
Low BP: MAP92 (125/75)
Low BP: < 130/80
Low BP: MAP92 (125/75)
Usual BP: MAP107 (140/90)
Usual BP: DBP < 90
Usual BP: MAP102–107 (the latter 140/90)
Rate of change in GFR
ESRD
Combination of doubling of serum creatinine, ESRD, and death
AASK, African–American Study Of Kidney Disease And Hypertension; ESRD, end-stage renal disease; GFR, glomerular filtration rate; MAP, mean arterial pressure; MDRD, Modification Of Diet In Renal Disease; REIN-2, Renoprotection In Nondiabetic Chronic Renal Disease-2.
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not collected during this follow-up period. A low BP treatment target for all patients with nondiabetic CKD, regardless of degree of proteinuria is, therefore, not justifiable based on these data. Of note, a posthoc analysis of the MDRD study suggested that a lower BP target might be particularly effective in preventing renal disease progression in black versus white patients [8]. However, a limitation of this is that very few black individuals were included in the MDRD study (only 53 in study 1). As another limitation, actually achieved MAP values were very similar between the two BP groups; 90 mmHg ( 125/75 mmHg) in the low and 94 mmHg ( 133/80 mmHg) in the usual BP target group. This may have led to an underestimation of the effects of a lower BP target. Further, the definition of BP targets by MAP may have obscured differential effects in subgroups of patients that had similar MAPs, but different SBP and DBPs. There is experimental evidence that a high SBP is particularly harmful for the kidney, in particular when afferent arteriolar autoregulation, and therefore protection of the renal circulation from high systemic pressures, is compromised [9]. This is underlined by the observation that renal injury in animal models correlates very closely with SBP [10]. However, whether lower SBPs would be protective, perhaps even in patients with proteinuria of less than 1 g/day, must remain speculative at present. In summary, the key message from the MDRD study is that a lower BP target may be effective in slowing the decline of renal function in patients with nondiabetic CKD when proteinuria exceeds 1 g/day, and particularly when it exceeds 3 g/day.
THE RENOPROTECTION IN NONDIABETIC CHRONIC RENAL DISEASE-2 STUDY This study included 338 patients with nondiabetic CKD stage 3–4 with proteinuria of more than 1 g/day, already receiving therapy with an angiotensin converting enzyme (ACE)-inhibitor [11]. Patients with type 1 diabetes were excluded. In contrast, patients with type 2 diabetes were included, if their renal disease was deemed to be unrelated to the diabetes. Patients were randomized to either a conventional BP treatment goal of a DBP of lower than 90 mmHg (n ¼ 169), or an intensified BP treatment goal of lower than 130/80 mmHg (n ¼ 169). To achieve the lower BP goal, the dihydropyridine calcium-channel blocker felodipine was added (5–10 mg/day). The primary endpoint of the study was time to ESRD. As a considerable limitation of this study, actually achieved BP levels were only marginally different between the groups; 130/80 mmHg in the intensified and 134/82 mmHg in the 182
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conventional BP goal group. As the main result of the study, there was no difference in the occurrence of the primary endpoint after a median follow-up of 19 months (P ¼ 0.99).
THE AFRICAN–AMERICAN STUDY OF KIDNEY DISEASE AND HYPERTENSION In the African–American Study Of Kidney Disease and Hypertension (AASK), the effects of an intensive BP control strategy were compared with a standard BP control strategy. A total of 1094 African– American individuals with hypertensive CKD and a GFR of 20–65 ml/min were included [12]. Proteinuria of greater than 2.5 g/g creatinine was an exclusion criterion. Type 1 and type 2 diabetes were exclusion criteria. Similar to the MDRD study, renal function was measured with 125I iothalamate clearance, and BP targets were defined by MAP. Target MAP was 92 mmHg ( 125/75 mmHg) or less in the intensive BP control group, and 102–107 mmHg ( 140/90 mmHg) in the standard BP control group. Using a 3 2 factorial design, individuals were further randomized to one of three initial drug therapies: the ACE-inhibitor ramipril, the b-blocker metoprolol, or the dihydropyridine calciumchannel blocker amlodipine. If target BP was not achieved with the highest dose of the randomly assigned drug, furosemide, clonidine, doxazosine, hydralazine, and minoxidil could be added. The study consisted of two phases; the trial phase, which lasted a median of 3.8 years and a subsequent cohort (observational) phase. After completing the trial phase, all individuals that had not reached ESRD were invited to enroll in the cohort phase in which the BP target was lower than 130/80 mmHg for all patients, with ACE-inhibition as the mainstay of treatment [or angiotensin receptor blockade (ARB) when intolerant to ramipril]. Again, additional drugs could be added if the BP target of lower than 130/80 mmHg was not achieved with ACE-inhibition or an ARB. The primary outcome parameter was a combined endpoint of doubling of serum creatinine levels, a diagnosis of ESRD, or death. During the trial phase, average achieved BP was 130/78 mmHg in the intensive-control group and 141/86 mmHg in the standard-control group. During the cohort phase, BP equalized (131/78 versus 134/78 mmHg). As the main result of the study, no difference in the primary endpoint was detectable between the two groups. This held true regardless of whether the two study phases (trial þ cohort phase) were analyzed together, or whether trial and cohort phase were analyzed separately. When the data were reanalyzed according to post-hoc-defined proteinuria categories Volume 23 Number 2 March 2014
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Nondiabetic chronic kidney disease Schneider and Hilgers
(protein to creatinine ratio or > 0.22 g/g creatinine, considered to correlate with a urinary protein excretion or > 300 mg/day), a significantly lower number of patients reached the primary endpoint as well as outcomes directly related to CKD (doubling of serum creatinine or ESRD) in the intensive-control group when baseline proteinuria was greater than 0.22 g/g creatinine. Of note, the use of ACEinhibitors or ARBs was similar between the two BP groups. An interesting post-hoc analysis of the trial was published, which showed that the magnitude of the change in proteinuria predicted the progression of CKD. In other words, greater reduction of proteinuria with BP lowering predicted better renal protection in the long-term [13]. Further, this study showed that ACE-inhibitors were more effective than b-blockers or calcium channel antagonists in slowing GFR decline [12]. Of note, hypertensive CKD (nephrosclerosis) was accepted in AASK as the underlying renal disease in the absence of renal biopsies. Recent genetic studies have shown that variations in the apolipoprotein L1 gene (APOL1) are strongly related to the excess risk of nondiabetic kidney disease in individuals of African descent [14–15]. This will likely lead to reclassification of nondiabetic kidney disease, including nephropathy that has so far been considered hypertension-related. However, in terms of renal protection, a recent post-hoc analysis of the AASK trial demonstrated that a lower, compared with a standard, BP treatment target was no more effective whether individuals carried an APOL1 variant or not [16 ]. &
GOAL BLOOD PRESSURE AND CARDIOVASCULAR PROTECTION Lowering BP in patients with CKD serves a dual purpose: amelioration of kidney disease progression as well as prevention of cardiovascular mortality and morbidity. We are not aware of any appropriately powered, randomized trial that tested the effects of a lower goal BP on cardiovascular events specifically in patients with nondiabetic CKD. A detailed report on cardiovascular events in patients in the AASK study confirmed the high cardiovascular risk associated with proteinuria but did not provide evidence for an effect of the lower goal BP [17]. However, this trial may have been underpowered to clarify this question unequivocally. Information on cardiovascular outcomes of the MDRD study is limited, but the data that have been published do not suggest a beneficial effect of the lower BP goal on cardiovascular events [18]. Finally, a recent metaanalysis of several randomized trials with different antihypertensive drugs compared the effects on
cardiovascular events in patients with an estimated GFR above or below 60 ml/min per 1.73 m2 [5 ]. This analysis included diabetic patients, and did not consider proteinuria, but nevertheless provides some information on cardiovascular prevention in CKD patients. The authors confirmed that lowering BP provides roughly the same protection from cardiovascular events regardless of estimated GFR. However, no benefit of a lower goal BP was detected [5 ]. &&
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24-H CONTROL OF BLOOD PRESSURE IN PATIENTS WITH CHRONIC KIDNEY DISEASE It is possible that the failure of strategies targeting lower BP values in preventing renal disease progression is at least in part attributable to poor 24-h BP control. In patients with CKD, masked daytime or nocturnal hypertension that is normal in office readings but elevated on ambulatory BP monitoring (ABPM) values are common. This has been observed within the AASK study, and, more recently, in a large cross-sectional study in Spain including 5693 hypertensive individuals with CKD stages 1–5. In the latter study, misclassification of BP control was observed in one out of three individuals [19]. Although ABPM values were often better than office-based values (white coat hypertension), a large number of individuals were misclassified by office BP alone and the burden of uncontrolled 24-h BP was substantial. As a consequence, nocturnal dosing of BP medications has been proposed as a means of improving 24-h BP control in CKD. This concept has recently been tested in a cross-over, randomized study. Former participants of AASK were assigned to either receive morning, evening, or combined morning and evening dosing of their antihypertensive drugs [20 ]. BP was measured by office readings and ABPM, and the primary outcome parameter was nocturnal SBP. Disappointingly, evening or morning and evening dosing strategies did not improve nocturnal, 24 h or daytime SBP values over the ‘morning only’ dosing group. Thus, in the era of long-acting antihypertensive drugs, nighttime dosing alone is unlikely to solve the problem of poor 24-h BP control in patients with CKD. Finally, BP variability across clinic visits has been demonstrated to be a novel, independent predictor of death and nonfatal cardiovascular events independent of underlying BP levels in patients with CKD [21 ]. There is even some evidence to suggest that BP variability may predict the decline of renal function in patients with CKD [22]. However, the pathophysiological basis and the clinical relevance of these findings are presently unclear.
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CONCLUSION Taken together, except for patients with proteinuria, there is currently no convincing evidence to support a BP goal of lower than 140/90 mmHg in nondiabetic CKD patients. For patients with proteinuria, there is some evidence to suggest that a BP goal of lower than 130/80 mmHg may be beneficial for renal outcome. The MDRD study suggests that this is the case in individuals with proteinuria greater than 1 g/day; the AASK trial suggests that this may already be the case when proteinuria exceeds 300 mg/day. The Renoprotection In Nondiabetic Chronic Renal Disease-2 (REIN-2) study, however, demonstrates that even in patients with substantial proteinuria, a beneficial effect may not be observed, in particular when there is no further reduction in proteinuria while achieving the lower BP goal. The uncertainties in recommending a lower BP target have also been outlined in a recent systematic review on BP targets in CKD patients [18]. SBP values of lower than 120 mmHg should currently be avoided, as observational studies in the general population, but also in patients with CKD, suggest an increase in mortality [23]. Whether such a low SBP treatment target of lower than 120 mmHg is indeed harmful, or whether there is benefit in some circumstances, including CKD, is currently being examined in the Systolic Blood Pressure Intervention Trial, which enrolled 9250 patients and will be completed in 2018. In this context, there is accumulating evidence that orthostatic hypotension in individuals on antihypertensive treatment is important for prognosis, as it is associated with an increased risk of stroke [24], coronary heart disease [25], and overall cardiovascular mortality [26,27 ]. There is even some evidence linking orthostatic hypotension with more rapid progression of renal disease [28]. It appears to be prudent, therefore, to avoid orthostatic hypotension and BP values lower than 130/80 mmHg in the absence of convincing evidence for renal or cardiovascular benefits [27 ]. Finally, observational studies clearly show the widespread failure to meet the ‘conventional’ BP target of lower than 140/90 mmHg in CKD patients [19,29]. Reaching the target BP of lower than 140/90 mmHg in all CKD patients should, therefore, be our most pressing aim. &
&
Acknowledgements None. Conflicts of interest There are no conflicts of interest. 184
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REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. Mancia G, De Backer G, Dominiczak A, et al. 2007 Guidelines for the management of arterial hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Eur Heart J 2007; 28:1462– 1536. 2. Chobanian AV, Bakris GL, Black HR, et al. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension 2003; 42:1206–1252. 3. Mancia G, Fagard R, Narkiewicz K, et al. 2013 ESH/ESC guidelines for the management of arterial hypertension: the Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Eur Heart J 2013; 34:2159– 2219. 4. Klag MJ, Whelton PK, Randall BL, et al. End-stage renal disease in African– American and white men. 16-year MRFIT findings. JAMA 1997; 277:1293– 1298. 5. Blood pressure lowering and major cardiovascular events in people with and && without chronic kidney disease: meta-analysis of randomised controlled trials. BMJ 2013; 347:f5680. Comprehensive meta-analysis of trials providing data on the effects of BP lowering on cardiovascular outcomes in patients with and without CKD. 6. Klahr S, Levey AS, Beck GJ, et al. The effects of dietary protein restriction and blood-pressure control on the progression of chronic renal disease. Modification of Diet in Renal Disease Study Group. N Engl J Med 1994; 330:877– 884. 7. Sarnak MJ, Greene T, Wang X, et al. The effect of a lower target blood pressure on the progression of kidney disease: long-term follow-up of the modification of diet in renal disease study. Ann Intern Med 2005; 142:342– 351. 8. Hebert LA, Kusek JW, Greene T, et al. Effects of blood pressure control on progressive renal disease in blacks and whites. Modification of Diet in Renal Disease Study Group. Hypertension 1997; 30:428–435. 9. Bidani AK, Polichnowski AJ, Loutzenhiser R, Griffin KA. Renal microvascular dysfunction, hypertension and CKD progression. Curr Opin Nephrol Hypertens 2013; 22:1–9. 10. Bidani AK, Griffin KA, Williamson G, et al. Protective importance of the myogenic response in the renal circulation. Hypertension 2009; 54:393– 398. 11. Ruggenenti P, Perna A, Loriga G, et al. Blood-pressure control for renoprotection in patients with nondiabetic chronic renal disease (REIN-2): multicentre, randomised controlled trial. Lancet 2005; 365:939–946. 12. Wright JT Jr, Bakris G, Greene T, et al. Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease: results from the AASK trial. JAMA 2002; 288:2421–2431. 13. Lea J, Greene T, Hebert L, et al. The relationship between magnitude of proteinuria reduction and risk of end-stage renal disease: results of the African American study of kidney disease and hypertension. Arch Intern Med 2005; 165:947–953. 14. Genovese G, Friedman DJ, Ross MD, et al. Association of trypanolytic ApoL1 variants with kidney disease in African Americans. Science 2010; 329:841– 845. 15. Tzur S, Rosset S, Shemer R, et al. Missense mutations in the APOL1 gene are highly associated with end stage kidney disease risk previously attributed to the MYH9 gene. Hum Genet 2010; 128:345–350. 16. Lipkowitz MS, Freedman BI, Langefeld CD, et al. Apolipoprotein L1 gene & variants associate with hypertension-attributed nephropathy and the rate of kidney function decline in African Americans. Kidney Int 2013; 83:114– 120. Post-hoc analysis of the AASK study, which revealed that the recently described kidney disease-associated APOL1 variants are strongly related to kidney outcomes in that study. 17. Norris K, Bourgoigne J, Gassman J, et al. Cardiovascular outcomes in the African American Study of Kidney Disease and Hypertension (AASK) Trial. Am J Kidney Dis 2006; 48:739–751. 18. Upadhyay A, Earley A, Haynes SM, Uhlig K. Systematic review: blood pressure target in chronic kidney disease and proteinuria as an effect modifier. Ann Intern Med 2011; 154:541–548. 19. Gorostidi M, Sarafidis PA, de la Sierra A, et al. Differences between office and 24-h blood pressure control in hypertensive patients with CKD: A 5,693patient cross-sectional analysis from Spain. Am J Kidney Dis 2013; 62:285– 294. 20. Rahman M, Greene T, Phillips RA, et al. A trial of 2 strategies to reduce && nocturnal blood pressure in blacks with chronic kidney disease. Hypertension 2013; 61:82–88. Important study that evaluated the impact of nocturnal dosing of BP medication on 24-h BP control in CKD patients.
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Nondiabetic chronic kidney disease Schneider and Hilgers 21. Mallamaci F, Minutolo R, Leonardis D, et al. Long-term visit-to-visit office blood pressure variability increases the risk of adverse cardiovascular outcomes in patients with chronic kidney disease. Kidney Int 2013; 84:381– 389. BP variability across clinic visits is demonstrated to predict cardiovascular outcomes independently of underlying BP level in patients with CKD. 22. Yokota K, Fukuda M, Matsui Y, et al. Impact of visit-to-visit variability of blood pressure on deterioration of renal function in patients with nondiabetic chronic kidney disease. Hypertens Res 2013; 36:151– 157. 23. Weiner DE, Tighiouart H, Levey AS, et al. Lowest systolic blood pressure is associated with stroke in stages 3 to 4 chronic kidney disease. J Am Soc Nephrol 2007; 18:960–966. 24. Eigenbrodt ML, Rose KM, Couper DJ, et al. Orthostatic hypotension as a risk factor for stroke: the atherosclerosis risk in communities (ARIC) study. Stroke 2000; 31:2307–2313.
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25. Rose KM, Tyroler HA, Nardo CJ, et al. Orthostatic hypotension and the incidence of coronary heart disease: the Atherosclerosis Risk in Communities study, 1987–1996. Am J Hypertens 2000; 13:571–578. 26. Rose KM, Eigenbrodt ML, Biga RL, et al. Orthostatic hypotension predicts mortality in middle-aged adults: the Atherosclerosis Risk In Communities (ARIC) Study. Circulation 2006; 114:630–636. 27. Xin W, Lin Z, Mi S. Orthostatic hypotension and mortality risk: a meta-analysis & of cohort studies. Heart 2013. [Epub ahead of print] Important article summarizing the evidence for the harmful effects of orthostatic hypotension on overall mortality. 28. Franceschini N, Rose KM, Astor BC, et al. Orthostatic hypotension and incident chronic kidney disease: the atherosclerosis risk in communities study. Hypertension 2010; 56:1054–1059. 29. Plantinga LC, Miller ER 3rd, Stevens LA, et al. Blood pressure control among persons without and with chronic kidney disease: US trends and risk factors 1999–2006. Hypertension 2009; 54:47–56.
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