Most patients with CKD have hyperten-sion6. Elevated blood pressure (BP) is an es-tablished risk factor for the development andprogression of kidney failure7,8. Control of BPto evidence-based targets with appropriateantihypertensive agents has the potential ofpreventing some of the serious consequencesof CKD9,10. This review will focus on the evi-dence for management of hypertension in pa-tients with nondiabetic CKD.

Definition of CKD

CKD is defined as kidney damage for >3months, as defined by structural or functionalabnormalities of the kidney, with or withoutdecreased glomerular filtration rate (GFR).

The presence of significant reduction inGFR (<60 mL/min/1.73 m2) for 3 months,with or without kidney damage or the pres-ence of albuminuria (>30 mg/d) increases therisk of progressive CKD11. Generally, a serumcreatinine of >1.5 mg/dl in men or >1.3 mg/dlin women approximates a GFR of <60mL/min per 1.73 m2. However, more preciseprediction formulas have been developed toestimate GFR from serum creatinine concen-tration, age, sex, and body size, and are con-venient for use in clinical practice12,13.

Non-Diabetic Kidney DiseaseThe term “nondiabetic kidney disease” is

not a diagnosis. It includes a variety of dis-eases that are often grouped together in epi-demiologic studies and clinical trials, but dif-fer widely in terms of patient’s history, clinical

European Review for Medical and Pharmacological Sciences

1

Abstract. – Despite the high prevalenceand significant morbidity and mortality associ-ated with high chronic kidney disease (CKD) inpatients with hypertension, it remains vastlyunder-diagnosed and under-treated. Conse-quently, many patients develop kidney failurerequiring dialysis or kidney transplant. More-over, patients with CKD represent the group athighest risk from cardiovascular complica-tions, even greater than patients with diabetesmellitus. Therefore, management of hyperten-sion in such patients needs to be more aggres-sive compared to those with normal kidneyfunction. This review provides guidelines fortreatment of hypertension in patients with non-diabetic CKD based on updated evidence fromclinical trials data. Following these recommen-dations is likely to minimize the risk of develop-ment of kidney failure and cardiovascular dis-ease.

Key words: Hypertension, Chronic kidney disease, Albuminuria,

Proteinuria, ACE-inhibitors.

Introduction

Chronic Kidney Disease (CKD) is a world-wide public health problem. CKD prevalencewas 11% among U.S. adults surveyed in 1988to 19941. A sharp increase in the incidence ofadvanced CKD is seen in Europe, the UnitedStates, and Australia over the past decade2-4.Emerging evidence from developing coun-tries also indicates a high burden of CKD,which is only expected to rise rapidly as boththe age of the population and the prevalenceof hypertension and diabetes are projected toincrease dramatically5.

2005; 9: 1-12

Systemic hypertension and nondiabetic chronic kidney disease: the best evidence-based therapeutic approach todayT.H. JAFAR

Section of Nephrology, Department of Medicine, Clinical Epidemiology Unit, Department of Community Health Sciences, Aga Khan University - Karachi (Pakistan)Division of Nephrology, Tufts-New England Medical Center, Department of Medicine, Tufts University School of Medicine - Boston, MA (USA)

2

presentation, risk of progression, and re-sponse to treatment. These diseases includeglomerular diseases, vascular diseases, tubu-lointerstitial diseases, and cystic kidney dis-eases, which accounted for about 18%, 20%,7%, and 5% of all cases of kidney failure inthe United States in 1999, respectively14.

Complications of CKDKKiiddnneeyy FFaaiilluurree.. Patients with CKD may

develop progressive kidney damage leadingto kidney failure, which is defined as a GFR<15 ml/min/1.73 m2, and is accompanied inmost cases by signs and symptoms of uremia,or a need to start kidney replacement therapy(dialysis or transplantation)11.

CCaarrddiioovvaassccuullaarr DDiisseeaassee iinn CCKKDD.. Cardio-vascular disease (CVD) is frequently associ-ated with CKD15. CVD risk factors in pa-tients with CKD are those altered by the“uremic” state (for example, hypertension,dyslipidemia, homocysteine) and those thatare characteristic of the “uremic” state (forexample, inflammation, malnutrition, ane-mia, oxidative stress, hyperparathyroidism,and increased calcium-phosphorus concen-tration product)16. Evidence suggests that in-

dividuals with CKD are more likely to die ofCVD than to develop kidney failure17,18. In1998, the National Kidney Foundation(NKF) Task Force on Cardiovascular Dis-ease in Chronic Renal Disease issued a re-port emphasizing the high risk of CVD inCKD19. This report showed that there was ahigh prevalence of CVD in CKD and thatmortality due to CVD was 10 to 30 timeshigher in dialysis patients than in the generalpopulation20 (Figure 1). The task force rec-ommended that patients with CKD be con-sidered in the “highest risk group” for subse-quent CVD events and that treatment rec-ommendations based on CVD risk stratifica-tion should take into account this high riskstatus of patients with CKD.

Both kidney failure and CVD in CKD arepotentially preventable, which are the maingoals of treatment of patients with CKD18.

Pathophysiological Role of BP in CKD

Experimental studies have suggested thatsystemic hypertension can be transmitted toglomeruli and that glomerular hypertension

T.H. Jafar

Figure 1. Cardiovascular mortality defined by death due to arrhythmias, cardiomyopathy, cardiac arrest, myocardialinfarction, atherosclerotic heart disease, and pulmonary edema in general population (GP; National Center forHealth Statistics [NCHS] multiple cause of mortality data files International Classification of Diseases, 9th Revision[ICD 9] codes 402, 404, 410 to 414, and 425 to 429, 1993) compared with kidney failure treated by dialysis or kidneytransplant (United States Renal Data System [USRDS] special data request Health Care Financing Administrationform 2746 Nos. 23, 26 to 29, and 31, 1994 to 1996). Data are stratified by age, race, and sex. CVD mortality is under-estimated in kidney transplant recipients owing to incomplete ascertainment of cause of death. Reproduced and mod-ified with permission from Foley et al. Clinical epidemiology of cardiovascular disease in chronic renal disease68.

exercise, heart failure and poor glycemiccontrol. Hence urine albumin should be re-measured for diagnosis of persistent albu-minuria, which indicates pathology in thekidney.

Protein in the urine, especially when ele-vated, represents mainly albuminuria andsignifies glomerular involvement. However,there are other types of proteins in theurine including low molecular weight pro-teins, which are typically indicative of tubu-lar damage. The prognostic and therapeuticsignificance of this type of proteinuria isnot known. Further, measurement of pro-tein in the urine is rather insensitive, anddoes not give positive results until albuminis raised significantly (>300 mg/d). There-fore, specific measurement of urine albu-min is preferred over that of total urineprotein

Persistent albuminuria is an early, sensi-tive, and important prognostic factor forfaster progression of kidney disease and anincreased risk of CVD29,30. Further, as dis-cussed below, presence of albuminuria alsodictates several therapeutic targets and choic-es of antihypertensive agents.

MMeeaassuurreemmeenntt ooff uurriinnee aallbbuummiinn.. Measure-ment of the excretion of albumin in a timedurine sample is the gold standard for thequantitative assessment of proteinuria. How-ever, 24 hour collection of urine is cumber-some for routine clinical practice. The mostfrequently used screening method for albu-minuria is the urinary dipstick in an untimed“spot” urine specimen. Because it is the con-centration of urine albumin that is measuredwith dipstick, false-negative results may occurwith very dilute urine. Nevertheless, urinedipstick for albumin or even protein could bevaluable in certain settings where cost and dif-ficult access to central laboratory facility areof major concerns. An alternative method forthe detection and monitoring of albuminuriais measurement of the ratio of albumin orprotein to creatinine in a spot urine specimen.This method corrects for variations in urinaryalbumin levels that are due to hydration, ismore convenient than timed urine collections,and provides a reasonably accurate estimateof the rate of excretion of albumin31-33. The ra-tio provides a standardized estimate of dailyexcretion of albumin in grams/body surfacearea of 1.73 m2.

is harmful to the kidney21. The hypertrophichyperplastic processes that follow any loss ofnephrons and the increased protein ultrafil-tration are important factors in progressivekidney damage22. Hypertension itself acceler-ates decline in kidney function, which is likelyto be due to the associated increasedglomerular capillary hypertension. Themarkedly lower BP threshold for kidneydamage necessitates that BP be lowered intothe normotensive range to prevent progres-sive kidney damage23.

Atherosclerosis and arteriosclerosis are thetwo main subtypes of arterial vascular diseasein patients with CKD24,25. Patients with CKDalso have a high prevalence of cardiomyopa-thy26. The complications of arteriosclerosisresult in pressure overload and lead to con-centric left ventricular hypertrophy (in-creased wall-to-lumen ratio), which is com-pounded in the presence of systemic hyper-tension, fluid overload, and arteriovenous fis-tulae. These structural abnormalities maylead to diastolic and systolic dysfunction andmay be detectable by echocardiography. Clin-ical presentations of cardiomyopathy includeheart failure and ischemic heart disease, evenin the absence of arterial vascular disease.Strict control of BP is important for minimiz-ing this risk of CVD.

Importance of Detection of Albuminuria in Patients

with Hypertension

Albuminuria is important in CKD for anumber of reasons. In particular, monitoringalbuminuria over time has been recommend-ed to assess progression or remission of kid-ney damage. In most causes of CKD, an in-crease in the level of albuminuria over time isassociated with a higher risk of progression ofkidney disease.

The normal rate of albumin excretion isless than 20 mg/day. Persistent values be-tween 30 and 300 mg/day are called microal-buminuria. Values above 300 mg/day areconsidered to represent clinical proteinuria(macroalbuminuria) as urine for dipstickgives a positive test for protein at such lev-els27,28. Urine albumin can be excreted tran-siently in certain conditions including fever,

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The best evidence-based therapeutic approach today

4

Lowering of BP in Non-DiabeticCKD – Choice of Treatment

Angiotensin-Converting-Enzyme (ACE) Inhibitors

EEffffiiccaaccyy iinn SSlloowwiinngg PPrrooggrreessssiioonn ooff CCKKDD..Much experimental and clinical evidencehas been published that suggests the renin-angiotensin-aldosterone system (RAAS)has an important role in progression of non-diabetic disease34-36. Apart from its benefi-cial antihypertensive effect, RAAS block-ade normalizes glomerular capillary pres-sure as a result of attenuation of the an-giotensin II vasoconstrictive effect onglomerular efferent arterioles and inhibitionof cellular proliferation. In addition, RAASinhibition is speculated to restore endothe-lial activity, inhibit platelet reactivity, andact as an antioxidant. These properties po-tentially contribute to a decrease in albu-minuria, slowing progression of CKD, andprevention of CVD37.

A number of clinical trials have comparedthe efficacy of ACE-inhibitors with otherclasses of antihypertensive agents in slowingthe progression of nondiabetic CKD. TheACE Inhibition in Progressive Renal Disease(AIPRD) Study Group conducted a pooledanalysis of data from 11 randomized trials, in-cluding two large studies – the ACE Inhibi-tion in Progressive Renal Insufficiency(AIPRI) Study36 and the Ramipril Efficacy inNephropathy (REIN) Study38,39. Its resultsdemonstrated that compared to other antihy-pertensive agents, ACE-inhibitors were supe-rior in decreasing urinary albumin excretion,and slowing the progression of kidney dis-ease. Further, these effects of ACE-inhibitorsappeared to be mediated by factors beyondtheir effects on BP39. Moreover, the beneficialeffect of ACE-inhibitors was greater in pa-tients with higher rates of urine albumin ex-cretion but appeared to extend to patientswithout albuminuria. The findings of AfricanAmerican Study of Kidney Disease and Hy-pertension (AASK) also corroborated thatACE-inhibitors were more efficacious thanother antihypertensive agents in slowing pro-gression of CKD in hypertensive nephroscle-rosis, which is typically not associated with al-buminuria40.

These findings provide strong evidence foruse of ACE-inhibitors as antihypertensive

agents of first choice for slowing progressionof CKD, especially in patients with clinical al-buminuria.

EEffffiiccaaccyy iinn PPrreevveennttiinngg CCVVDD.. Results of dataon the benefit of ACE-inhibitors over other anti-hypertensive agents on prevention of CVD havebeen conflicting. The Heart Outcomes Preven-tion Evaluation (HOPE) study showed thatACE-inhibitors were more beneficial on cardio-vascular outcomes in patients at high risk forCVD. However, a substudy of HOPE showedthat ambulatory BP levels were lower in patientsreceiving ACE-inhibitors41. Thus, it is somewhatunclear whether the observed benefit of ACE-inhibitors in this study was due to a greater re-duction in BP or due to ACE-inhibition per se.

The Second Australian National BP(ANBP), a trial on 6805 hypertensive elderlysubjects aged 60 to 85 years, showed a clearbenefit of ACE-inhibitors over diuretics oncardiovascular outcomes42. The Prevention ofRenal and Vascular Endstage Disease (PRE-VEND) study also showed a trend towardssuperiority of ACE-inhibitors on cardiovas-cular morbidity and mortality in 864 albumin-uric patients, and this benefit was greater inpatients with higher levels of albuminuria.

However, results of the Antihypertensiveand Lipid-Lowering Treatment to PreventHeart Attack Trial (ALLHAT) showed thatrisk of CVD was not improved in hyperten-sive patients receiving ACE-inhibitors or cal-cium channel blockers or beta blockers com-pared to those on thiazide-type diuretic(chlorthalidone)43-45. Moreover, the recentlyreported Prevention of Events with An-giotensin Converting Enzyme Inhibition(PEACE) study also failed to show benefit ofACE-inhibitors in predominantly nondiabet-ic patients at low risk of CVD46.

While these data cannot support recommen-dation for use of ACE-inhibitors in all patientswith hypertension, their use as first line antihy-pertensive agents in patients with albuminuriamay be justifiable for efficacy in BP control aswell as potential benefit on CVD outcomes.

Angiotensin Receptor Blockers (ARBs)EEffffiiccaaccyy iinn SSlloowwiinngg PPrrooggrreessssiioonn ooff CCKKDD..

ARBs are generally considered the appropri-ate alternative medication for patients whohave an indication for ACE-inhibitor therapybut are intolerant to the latter. However, un-

T.H. Jafar

EEffffiiccaaccyy iinn PPrreevveennttiinngg CCVVDD.. The effect ofARBs on cardiovascular outcomes was assessedin a large meta-analysis that evaluated 12,469patients from 17 randomized, double-blind,placebo-controlled trials53. There was no signifi-cant reduction in mortality among patientstreated with an ARB or an ARB plus an ACE-inhibitor. Patients treated with the combination,however, had a lower risk of hospitalization forheart failure compared with patients treatedwith an ACE-inhibitor alone. Thus, at present,strong evidence in favor of combination treat-ment for prevention of CVD is lacking.

Other Antihypertensive AgentsWhile blockers of renin-angiotensin system

have been shown to be particularly beneficialin the presence of albuminuria, the choice ofantihypertensive agent is generally felt to beless important than the achievement of opti-mal BP control, and patients often ultimatelyrequire 3 or more agents54. Thus, in addition toACE-inhibitors and ARBs, thiazide diuretics,beta blockers, and calcium channel blockersare effective antihypertensive agents andshould be used without reservations in pa-tients with CKD. Alpha blockers are the onlyclass of antihypertensive agents which are notrecommended for use in monotherapy40,45.However, they are useful as add-on therapy.

Lowering of BP in Non-Diabetic CKD – Target BP

The seventh report of the Joint NationalCommittee on Prevention, Detection, Evalu-ation, and Treatment of High BP recom-mends a target BP of less than 130/80 mm Hgin patients who have CKD55. However, thissimplistic approach may be less than optimalin patients with albuminuria. Results of clini-cal trials suggest that the even lower levels ofBP achieved during antihypertensive therapymay provide greater benefit in patients withhigh levels of urine albumin excretion56. Thesame for prevention of CVD in patients withCKD has not been well studied.

SSlloowwiinngg PPrrooggrreessssiioonn ooff CCKKDD.. In theModification of Diet in Renal Disease(MDRD) Study 840 patients with predomi-nantly nondiabetic CKD were randomly as-

like ACE-inhibitors, there is little evidence tosupport the use of ARBs in nondiabeticCKD. Therefore, the benefits of ARBs mustoften be extrapolated from studies of ACE-inhibitors14, or from studies of ARBs in pa-tients with diabetic CKD47,48.

EEffffiiccaaccyy iinn PPrreevveennttiinngg CCVVDD.. Results of da-ta on benefit of ARBs versus other antihy-pertensive agents on prevention of CVDhave been conflicting. Findings of the Losar-tan Intervention for Endpoint reduction inhypertension (LIFE) study showed that losar-tan prevented more cardiovascular morbidityand death than atenolol for a similar reduc-tion in BP in patients with hypertension andleft ventricular hypertrophy47. However, sub-sequently reported Valsartan Antihyperten-sive Long-term Use Evaluation (VALUE)trial reported no significant difference in ben-efit between valsartan versus amlodipine inpatients with hypertension, BP albeit levelswere lower in patients receiving amlodipine49.Thus, the evidence for incremental benefit ofARBs over good BP control in prevention ofCVD has not been established.

Combination of ACE-inhibitors and ARBsEEffffiiccaaccyy iinn SSlloowwiinngg PPrrooggrreessssiioonn ooff CCKKDD..

Findings from recent studies suggest thatmonotherapy with ACE-inhibitors may be in-sufficient for complete inhibition of the RAAS,which would prevent progression of non-dia-betic CKD. A small crossover study on 33 pa-tients comparing ACE-inhibitors and ARBs asmonotherapy reported that 18% of patients re-sponded to ACE-inhibitors but not to ARBs,and 15% of patients responded to ARBs butnot to ACE-inhibitors50. This finding may high-light the different mechanisms of action be-tween the two classes of medications, and thusthe potential for combination therapy51.

Results of the COOPERATE study inwhich 263 patients with albuminuric nondia-betic kidney disease were randomly assignedARB (losartan, 100 mg daily), ACE-inhibitor(trandolapril, 3 mg daily), or a combination ofboth drugs at equivalent doses, showed thatthe combination treatment safely retards pro-gression of non-diabetic CKD compared withmonotherapy52. Thus, patients with albumin-uric nephropathies may benefit from combi-nation therapy with an ACE-inhibitor and anARB. However, this needs more study.

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The best evidence-based therapeutic approach today

6

signed to a usual blood pressure goal (targetmean arterial pressure, <107 mm Hg) forpatients or a strict blood pressure goal (tar-get mean arterial pressure, <92 mm Hg).The strict blood pressure goal had a greaterbeneficial effect in persons with higherbaseline proteinuria (>1 g/d). However, inpatients with low levels of proteinuria (<0.5to 1 g/d) enrolled in the MDRD as well asAASK no significant beneficial effect ofstrict blood-pressure versus usual controlwas observed10,40,57.

More recently, findings of the AIPRDStudy metaanalysis on 1860 patients during22,610 patient visits showed that the benefitconferred by the level of BP achieved by an-tihypertensive therapy is determined by thelevel of achieved urine albumin excretion(Figure 2)56. This study showed that the low-est risk for kidney disease progression ap-

peared to be at levels of achieved systolicBP of 110-129 mm Hg. However, the rela-tionship of the level of achieved systolic BPwith the risk of kidney disease progressionvaried with the level of urine albumin excre-tion achieved during antihypertensive thera-py. At levels of urine albumin excretiongreater than 1.0 g/d, there was a steep rise inrisk of kidney disease progression at levelsof achieved systolic BP greater than 120-130mm Hg. However, at levels of urine albuminless than 1.0 g/d; there was little relationshipbetween risk of kidney disease progressionand levels of systolic BP from 110-159 mmHg. At both levels of urine albumin,achieved systolic BP <110 mm Hg was asso-ciated with a higher risk of kidney diseaseprogression. The findings were similar in pa-tients receiving antihypertensive regimenswith or without ACE-inhibitors.

T.H. Jafar

Figure 2. Relative risk for kidney disease progression based on current level of systolic BP and current urine proteinexcretion. The relative risk for patients with a current urine protein excretion of 1.0 g/d or greater represents 9336 pa-tients (223 events), and the relative risk for patients with a current urine protein excretion less than 1.0 g/d represents13 274 visits (88 events). The reference group for each is defined at a systolic BP of 110 to 119 mm Hg. Confidence in-tervals are truncated, as shown. Results are from a single multivariable model including two levels for urine proteinexcretion, six levels for systolic BP, and the interaction of current systolic BP and current urine protein excretion. Co-variates include assignment to angiotensin-converting enzyme inhibitor versus control group, sex, age, baseline sys-tolic BP, baseline diastolic BP, baseline urine protein excretion, baseline serum creatinine concentration (<2.0 or >2.0mg/dL [<177 or >177 µmol/L]), interaction of baseline serum creatinine and baseline urine protein excretion, interac-tion of baseline serum creatinine and current urine protein excretion, and study terms. Reproduced with PermissionFrom: Jafar T: Ann Intern Med, Volume 139(4); August 19, 2003, pp 244-252.

revealed that urine albumin excretion of lessthan 1-2 g/d achieved during follow-up wasassociated with the lowest risk for progres-sion of nondiabetic CKD. However, furtherbenefit was not observed at even lower val-ues56. It is possible that this lack additionalbenefit was because of the small number ofevents in patients with low levels of albumin-uria in these trials.

PPrreevveennttiioonn ooff CCVVDD.. A graded risk forsubsequent cardiovascular morbidity andmortality in hypertensive patients has beenobserved in patients with hypertension andleft ventricular hypertrophy47. More recent-ly, even very low levels of albuminuria havebeen shown to be independent determinantof coronary artery disease and death58.There is evidence that this risk may bemodifiable. Data from Reduction in End-points in type 2 diabetes mellitus with theAngiotensin II Antagonist Losartan (RE-NAAL), a double-blind, randomized trialin 1513 type 2 diabetic patients withnephropathy showed that patients withhigh baseline albuminuria (>3 g/d) had a1.92-fold (95% CI, 1.54 to 2.38) increase inrisk for cardiovascular end points com-pared with patients with low albuminuria(<1.5 g/d). Reducing albuminuria in thefirst 6 months appears to afford cardiovas-cular protection in these patients59. Basedon this, the investigators recommend thatthe lowest achievable level of albuminuriashould be viewed as a goal for future reno-protective treatments59. Data from theLIFE study suggest the same may apply topatients without diabetes as well60. Howev-er, target levels of urine albumin excretionwere not assessed in these studies61.

It must be emphasized that the currentevidence of benefit of lowering urine albu-min excretion on progression of CKD aswell as prevention of CVD, although com-pelling, is based on post hoc analyses.Prospective randomized studies are neededwith pre-specified targets of urine albuminexcretion to conclusively demonstrate abeneficial effect of lowering of urine albu-min excretion on CKD and CVD outcomes.Nonetheless, based on evidence presentedabove, it appears prudent to aim to reduceurine albumin excretion levels to at leastless than 1 g/d.

Thus, these data support the recommenda-tion of lowering systolic BP to about 110-129mm Hg in patients with urine albumin excre-tion of 1 g/d or greater. Reduction of systolicBP to levels less than 110 mm Hg should beavoided.

PPrreevveennttiioonn ooff CCVVDD.. The optimal level ofBP for prevention of CVD in patients withnondiabetic CKD, and its relation to levels ofalbuminuria have not been well studied. Todate, only a few studies have been primarilydesigned to study the same in patients withessential hypertension. In the HypertensionOptimal Treatment (HOT) study in 18,790hypertensive individuals, the lowest incidenceof major cardiovascular events occurred at amean achieved diastolic BP of 82.6 mm Hg,and the lowest risk of cardiovascular mortali-ty occurred at 86.5 mm Hg54. However, ad-vanced CKD was an exclusion criterion inthis study. Moreover, systolic rather than di-astolic BP may be a better predictor of CVDoutcomes in patients with CKD56. Thus, fu-ture studies are needed to assess that impactof various target levels of systolic BP in pa-tients with non CKD.

Lowering of BP in Non-DiabeticCKD – Titrating therapy to Level

of Urine Albumin

The role of albuminuria in prognosis ofCKD and CVD, and modification of this riskby the reduction of albuminuria in CKD hasonly come to light recently.

SSlloowwiinngg PPrrooggrreessssiioonn ooff CCKKDD.. Results ofthe MDRD, REIN and AIPRI studies sug-gested that progression of CKD was signifi-cantly faster in patients with higher levels ofalbuminuria at baseline than those with lowerlevels36,38,57. Findings of the AIPRD Studyconfirmed that albuminuria is independentlyassociated with more rapid progression ofCKD39. In addition, reduction in albuminuriaduring antihypertensive therapy was associat-ed with an incremental benefit over that con-ferred by reduction in the level of BP. Fur-thermore, therapy with ACE-inhibitors led toa greater reduction in albuminuria as com-pared to other antihypertensive agents30,39.Subsequent analysis of the same dataset also

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The best evidence-based therapeutic approach today

8

Conclusions and Recommendations

Evaluation of patients with hypertensionmust include assessment of other CVD riskfactors for risk stratification, and end organdamage55. An essential component of this eval-uation is screening for CKD, even in patientswithout diabetes. In such patients, physiciansshould measure a spot urinary albumin-creati-nine ratio, and estimate GFR from serum crea-tinine using the GFR prediction equation(Table I)13. In those patients where the initialassessments are abnormal, measurementsshould be repeated for confirmation in 3-4weeks. This information is of prognostic value,as well as for making therapeutic decisions.

In nondiabetic patients with reduced GFR(<60 cc/min/1.73 m2) without albuminuria,the target BP should be <130/80 mm Hg. Di-

uretics should be the preferred antihyperten-sive agent of choice. A second or third anti-hypertensive agent may be required to con-trol BP. Other antihypertensive agents mayalso be used, as needed.

In nondiabetic patients with or without re-duced GFR and (micro- or macro-) albumin-uria of less than 1 g/d, the target BP should be<130/80 mm Hg. ACE-inhibitors should be thepreferred antihypertensive agent of choice. Incase of ACE-inhibitor induced cough, ARBswould be good substitute. A second or thirdantihypertensive agent may be required to con-trol BP. Diuretics would be an effective and af-fordable second choice. Other antihyperten-sive agents may also be used, as needed.

In nondiabetic patients with or without re-duced GFR and albuminuria of over 1 g/d, atarget systolic BP of around 120 mm Hg

T.H. Jafar

Hypertension withoutdiabetes

Spot urine albumin/creatinine ratio

No albuminuriaGFR not reduced

Follow guidelinesfor patients without CKD

*GFR = Glomerular Filtration Rate; †Reduced GFR = Glomerular Filtration Rate less than 60 cc/min;°D = Diuretic; ^ACE-i = ACE-inhibitor; ‡CCB = Calcium Channel Blocker;

§ARB = Angiotensin Receptor Blocker

1st: °Dnext: ^ACE-i, ‡CCB,

β-blockersif >4 drugs: α-blockers

1st choice: ACE-inext: (**§ARB), D, CCB, β-blocker if >4 drugs:

α-blocker(**if target UP not achieved)

1st choice: ACE-inext: D, CCB, β-blockersif >4 drugs: α-blocker

No albuminuria†GFR reduced

Target BP <130/80 mm Hg

Target BP <130/80 mm Hg

Target Systolic BP = 110-129 mm HgTarget UP = < 1.0 g/d

Albuminuriabetween > 1.0 g/d

Albuminuria between 0.03 to 1.0 g/d

Repeat in 3-4 weeks for confirmation

Serum creatinine

Calculate estimated GFR*(repeat if reduced)

If ≥ 30 mg/d

Figure 3. Treatment Algorithm for Patient with Hypertension and Chronic Kidney Disease (CKD).

ommended for CVD risk reduction shouldbe recommended as part of the treatmentregimen. Dietary sodium intake of less than2.4 g/d (less than 100 mmol/d), achieving andmaintaining ideal body weight, regular exer-cise, DASH-eating plan, and moderate alco-hol consumption should be recommended inmost adults with CKD and hypertension.Dyslipidemia should be treated with diet anda statin, and smoking cessation should berecommended62-64. These interventions mayslow the progression of kidney disease aswell as reduce the risk of CVD. Finally, time-ly referral to a nephrologist is especially im-portant for improved outcomes in patientswho do progress to kidney failure65-67. It isrecommended that in patients with reducedGFR or clinical albuminuria, a nephrologistshould be consulted at least once with re-spect to detailed evaluation of CKD andplanning the strategy to be followed.

References

1) CORESH J, ASTOR BC, GREENE T, EKNOYAN G, LEVEY AS.Prevalence of chronic kidney disease and de-creased kidney function in the adult US popula-tion: Third National Health and Nutrition Examina-tion Survey. Am J Kidney Dis 2003; 41: 1-12.

2) VAN DIJK PC, JAGER KJ, DE CHARRO F, ET AL. Renal re-placement therapy in Europe: the results of a col-laborative effort by the ERA-EDTA registry andsix national or regional registries. Nephrol DialTransplant 2001; 16: 1120-1129.

3) XUE JL, MA JZ, LOUIS TA, COLLINS AJ. Forecast ofthe number of patients with end-stage renal dis-ease in the United States to the year 2010. J AmSoc Nephrol 2001; 12: 2753-2758.

4) CHADBAN SJ, BRIGANTI EM, KERR PG, ET AL. Preva-lence of kidney damage in Australian adults: TheAusDiab kidney study. J Am Soc Nephrol 2003;14: S131-138.

5) ZIMMET P, ALBERTI KG, SHAW J. Global and societalimplications of the diabetes epidemic. Nature2001; 414: 782-787.

6) BUCKALEW VM, JR., BERG RL, WANG SR, PORUSH JG,RAUCH S, SCHULMAN G. Prevalence of hypertensionin 1,795 subjects with chronic renal disease: themodification of diet in renal disease study baselinecohort. Modification of Diet in Renal DiseaseStudy Group. Am J Kidney Dis 1996; 28: 811-821.

7) KLAG MJ, WHELTON PK, RANDALL BL, ET AL. Bloodpressure and end-stage renal disease in men. NEngl J Med 1996; 334: 13-8.

should be aimed. However, reduction below110 mm Hg should be avoided. In addition,reduction in urine albumin excretion levels toless than 1 to 2 g/d (that is, a spot urinary al-bumin-creatinine ratio <1) is recommended.Levels of systolic and not diastolic BP shouldbe targeted. ACE-inhibitors should be used asantihypertensive agents of first choice. A sec-ond or third antihypertensive agent may berequired to control BP. Diuretics would be aneffective and affordable second choice. Otherantihypertensive agents may also be used, asneeded. Some patients have only a partial re-duction in albuminuria when they are treatedwith an ACE-inhibitor, combining an an-giotensin-receptor blocker with an ACE-in-hibitor, even when systolic BP is controlled toless than 130 mm Hg.

BP, serum creatinine, and serum potassiumshould be measured within one to two weeks af-ter the initiation of therapy with ACE-inhibitorsor ARBs. A mild reduction in the glomerularfiltration rate (usually less than 10 ml perminute per 1.73 m2) and an increase in theserum potassium level should be expected (usu-ally less than 0.5 mmol per liter). The develop-ment of hypotension, acute kidney failure, or se-vere hyperkalemia (defined by a serum potassi-um level of more than 5.5 mmol per liter) aftertreatment with an ACE-inhibitor/ARBs is initi-ated should prompt discontinuation of the drug.

It is important to emphasize that in mostpatients, achieving maximal kidney and car-diovascular protection requires a multidrugregimen, usually including several antihyper-tensive agents. Further, antihypertensivetherapy should be coordinated with othertherapies for CKD as part of a multi-inter-vention strategy. Lifestyle modifications rec-

9

The best evidence-based therapeutic approach today

Cockcroft Gault GFR equation = (140-age in yeas) × (weight in kgs)/serum creatinine

× 72 × (0.85 if female)12.

Abbreviated MDRD GFR equation = 186 × (serum creatinine)–1.154 × (age)–0.203

× (0.742 if female)13.

MDRD indicates Modification of Diet in Renal Dis-ease; and serum creatinine is measured in mg/dl.

Table I. Equations to Predict GFR Based on SerumCreatinine.

10

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The best evidence-based therapeutic approach today

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