Prevention of Progression of Kidney Disease S55

Blood pressure control: targetsDate written: May 2005Final submission: October 2005Author: Adrian Gillin

GUIDELINES

a. Lower systolic blood pressure (SBP) minimizes the risk of progression to end-stage kidney disease (ESKD), espe-cially with proteinuria. (Level II evidence)

b. A target blood pressure (BP) of <<<< 125/75 mmHg (or mean BP <<<< 92 mmHg) if proteinuria > 1 g/24 h, may bebeneficial. (Level II evidence)

c. A target BP of <<<< 130/80 mmHg (or mean BP <<<< 97 mmHg) if proteinuria is 0.25–1 g/24 h, may be beneficial.(Level II evidence)

d. Target BP should be <<<< 130/85 mmHg (or mean BP <<<< 100 mmHg) if proteinuria <<<< 0.25 g/24 h. (Level II evi-dence) However, there may be other potential benefits of achieving lower BP than a mean of 100 mmHg with respectto reduced cardiovascular risk.

There is no evidence concerning target BP for paediatric patients with progressive kidney disease.

SUGGESTIONS FOR CLINICAL CARE

(Suggestions are based on Level III and IV evidence)• There is evidence for a lower BP target with greaterdegrees of proteinuria (> 1 g/day). A precise goal below130/80 mmHg is not clear. These patients should be care-fully monitored.

BACKGROUND

Most forms of chronic kidney disease (CKD) are associatedwith hypertension. Uncontrolled hypertension not onlyincreases the risk of serious cardiovascular morbidity or mor-tality but is also associated with a more rapid progression ofCKD. Studies have suggested that a lower BP target is morebeneficial for slowing progression of CKD than reducingcardiovascular disease risk. The objective of this set ofguidelines is to evaluate the evidence regarding differing BPtargets for differing severity/causes of CKD in preventingprogression.

SEARCH STRATEGY

Databases searched: MeSH terms and text words forchronic kidney disease were combined with MeSH termsand text words for angiotensin II antagonists, ACE inhibi-tors and blood pressure. These were then combined withMeSH terms and text words for locating randomised con-trolled trials. The search was carried out in Medline(1966 – November Week 1, 2004). The Cochrane RenalGroup Register of randomised controlled trials was alsosearched for any additional relevant trials not indexed inMedline.Date of searches: 12 November 2004.

WHAT IS THE EVIDENCE?

REIN-2 Study1: This was a multicentre randomised con-trolled trial (RCT) assessing blood-pressure control forrenoprotection in 338 patients with non-diabetic CKD.Participants were randomly allocated to conventional(diastolic < 90 mmHg) or intensified (130/80 mmHg) bloodpressure control. Patients with a BP target of 130/80 mmHgby addition of felodipine had the same rate of kidney failureprogression as did patients with a higher BP target on rami-pril. A total of 38 of 167 patients in the intensified BP con-trol group and 34 of 168 patients allocated to the controlgroup progressed to ESKD. However, follow-up was only for36 months.

MDRD Study2: A total of 840 patients were enrolled in2 studies. Study 1 (n = 585): GFR 25–55 mL/min/1.73 m2

BSA; Study 2 (n = 255): GFR 13–24 mL/min/1.73 m2 BSA,with two interventions: (a) usual protein diet or low proteindiet (1.3 or 0.58 g/kg/d) and (b) usual or low BP group(MAP 107 or 92 mmHg). At baseline: serum creatinine106–619 µmol/L for females or 124–619 µmol/L for men,age 18–70 yrs, excluded if < 80% or > 160% of standardbody weight, diabetic on insulin, > 10g/d proteinuria orrenal transplant. The primary outcome was rate of change ofGFR (125Iothalamate clearance). The mean follow up was2.2 yrs with 60% being men, 85% white, average age 52 yrs,25% glomerular disease, 24% ADPKD, and 3% NIDDM.Results showed no significant overall benefit of low proteindiet or low blood pressure interventions over the full courseof the study. However, secondary analyses showed benefit oflower blood pressure after a more rapid phase of decline inGFR in the first 4 months with both studies. The averagerate of decline in GFR was 3.3 mL/min/year in all groupscombined. It was a mean 29% lower in the low BP groupthan the usual BP group. GFR declined more rapidly in

December 200510S5Original ArticlePrevention of Progression of Kid-

ney DiseaseThe CARI Guidelines

S56 The CARI Guidelines

Fig. 1 Hypertension and antihyper-tensive agents in nondiabetic kidneydiseaseSource: NKF K/DOQI Guidelines,2002.

patients with a higher degree of proteinuria, in those withADPKD and in blacks. The benefit of low blood pressurewas greatest with > 3 g/day proteinuria, of moderate benefitwith 1–3 g/day and there was no benefit if proteinuria was< 1 g/day. This study was not designed to show which anti-hypertensive agent affected renal function decline. A meanBP of 92 mmHg or less was safe and well tolerated up to the3 years duration of the study. (Level II evidence)

Observational studies and clinical trials of dietary pro-tein restriction (Marcantoni et al3 Brazy et al,4 86 patientswith mean diastolic BP < 90 mmHg had a slower rate ofdecline in 1/serum creatinine. Oldrizzi et al5 enrolled 423patients in a long-term low-protein diet study. Survival at10 years was 96% with mean BP < 100 mHg, 74% withmean BP < 100–110 mmHg and 48% with mean BP >110 mmHg. The Northern Italian Cooperative Study,showed 456 patients on a low protein diet, had a worse renalsurvival with mean BP > 107 mmHg. (Level III evidence)

He and Whelton6 performed a meta-analysis whichshowed systolic BP was associated with a greater risk forESKD than diastolic BP. (Level II evidence).

Wright et al.7 studied 1094 African-Americans withnondiabetic, hypertensive renal disease. It compared 2 lev-els of BP control and 2 antihypertensive drug classes onGFR decline (3 × 2 factorial design). The BP goals wereMAP of (i) 102–107 mmHg or (ii) < 92 mmHg. The drugswere ramipril (2.5–10 mg/day, n = 436), metoprolol (50–200 mg/day, n = 441) and amlodipine (5–10 mg/day,n = 217). It was an open label study. Outcomes were GFRslope alone or GFR slope combined with reduction in GFRby 50% or more, ESKD or death. The lower blood pressuregroup achieved a mean BP of 128/78 mmHg, which was 12/8 mmHg lower than the other BP group (mean achieved BP141/85 mmHg). There was no significant outcome differ-ence between groups. The ramipril group manifested riskreductions in the clinical composite outcome of 22%(95%CI: 1–38%, P = 0.04) compared with the metoprololgroup and 38% (95%CI: 14–56%, P = 0.004) comparedwith the amlodipine group. (Level II evidence)7

There was no evidence from AASK to support a targetBP that is lower than current treatment guidelines forcardiovascular disease. This may be peculiar to African-Americans or to the underlying disease of hypertensivenephro-sclerosis and not be true for other renal diseases.

SUMMARY OF THE EVIDENCE

A meta-analysis has shown that lowering SBP is associatedwith slowing progression to ESKD. Results from an RCTsuggest a target BP of < 125/75 mmHg if proteinuria > 1 g/24 h and a target BP of < 130/80 mmHg if proteinuria is0.25–1 g/24 h.

WHAT DO THE OTHER GUIDELINES SAY?

JNC VI: Recommends mean BP 100 mmHg (130/85 mmHg) in patients with chronic renal disease. If< 0.25 g/d of proteinuria, no benefit of a lower BP thanabove.8 JNC VII recommends less than 130/80 in patientswith CKD and proteinuria (> 300 mg/d).Hypertension Management for Doctors (2004). NHF ofAustralia: Goal is < 130/85 mmHg with chronic renal dis-ease or < 125/75 mmHg if > 1 g/day of proteinuria.Kidney Disease Outcomes Quality Initiative: Target BP innon-diabetic kidney disease should be < 130/80 mmHg.9

(see Fig. 1)UK Renal Association: The previous edition of thisdocument suggested a higher standard, 160/90 mmHg, forpatients over 60 years of age than for younger patients (140/90 mmHg). In the general population, systolic hypertensionis more common in the elderly, probably due to decreasedlarge vessel compliance. Recent studies have shown thatincreased pulse pressure, a result of decreased conduit arterycompliance, is a much more powerful risk factor for death inthe general population than systolic or diastolic blood pres-sure. It has been shown recently that the absolute benefits ofblood pressure reduction are greater in the elderly than inyounger patients, due to the former having higher baselinerisk, and that isolated systolic hypertension or combinedsystolic and diastolic hypertension in patients up to the ageof 80 can be safely treated with good results. However, manyof the elderly patients in these trials had marked systolichypertension, and the question of whether there is benefitfrom reducing systolic blood pressure from 160 mmHg to,say, 130 mmHg, has not been specifically examined in thispatient group, or even in the general population. Setting amore liberal standard for blood pressure in the elderly risksgiving the message that control of hypertension is less

Prevention of Progression of Kidney Disease S57

important in these patients, when the reverse is probablythe case. For these reasons, the targets set here are indepen-dent of age.10

Canadian Society of Nephrology: No recommendation.European Best Practice Guidelines: No recommendation.VA Primary Care Guidelines: In patients with chronickidney disease . . . Vigorous control of hypertension reducesthe glomerular capillary pressure and slows the progressionof glomerulosclerosis. The goal blood pressure shouldbe < 125/75 or mean arterial pressure less then 92 forpatients with proteinuria and 130/85 in patients withoutproteinuria. ACEI or ARB is the preferred antihypertensiveagents.11

IMPLEMENTATION AND AUDIT

No recommendation.

SUGGESTIONS FOR FUTURE RESEARCH

No recommendation.

REFERENCES

1. Ruggenenti P, Perna A, Loriga G et al. Blood pressure control forrenoprotection in patients with non-diabetic chronic renal disease(REIN-2): multicentre, randomised controlled trial. Lancet 2005;365: 939–46.

2. MDRD Study Group. Effects of diet and antihypertensive therapyon creatinine clearance and serum creatinine concentration in theModification of Diet in Renal Disease Study. J. Am. Soc. Nephrol.1996; 7: 556–66.

3. Marcantoni C, Jafar TH, Oldrizzi L et al. The role of systemichypertension in the progression of non diabetic renal disease. Kid-ney Int. Suppl 2000; 75: S44–S48.

4. Brazy PC, Stead WW, Fitzwilliam JF. Progression of renal insuffi-ciency: role of blood pressure. Kidney Int. 1989; 35: 670–4.

5. Oldrizzi L, Rugiu C, De Biase V et al. Factors influencing dietarycompliance in patients with chronic renal failure on unsupple-mented low-protein diet. Contrib Nephrol. 1990; 81: 9–15.

6. He J, Whelton PK. Elevated systolic blood pressure as a risk factorfor cardiovascular and renal disease. J. Hypertens Suppl 1999; 17:S7–S13.

7. Wright JT Jr, Bakris G, Greene T et al. Effect of blood pressure low-ering and antihypertensive drug class on progression of hyperten-sive kidney disease: results from the AASK trial. JAMA 2002; 288:2421–31.

8. Chobanian AV, Bakris GL, Black HR et al. The Seventh Report ofthe Joint National Committee on Prevention, Detection, Evalua-tion, and Treatment of High Blood Pressure: the JNC 7 report.JAMA 2003; 289: 2560–72.

9. National Kidney Foundation. K/DOQI Clinical Practice Guide-lines on Hypertension and Antihypertensive Agents in ChronicKidney Disease. Guideline 9, Pharmacological Therapy: Nondia-betic Kidney Disease. Available from: http://www.kidney.org/Professionals/Kdoqi/Guidelines_Bp/Guide_9.Htm.

10. The Renal Association and the Royal College of Physicians ofLondon. Treatment of adults and children with renal failure: stan-dards and audit measures. 3rd edn. Suffolk: The Lavenham PressLtd; 2002: pp. 75–6.

11. Veterans Health Administration, Department of Defense. VHA/DoD clinical practice guideline for the management of chronic kid-ney disease and pre-ESRD in the primary care setting. Washington(DC): Dept of Veterans Affairs (US), Veterans Health Adminis-tration; 2001 May. Available from: http://www.guideline.gov/summary/summary.aspx?ss=15&doc_id=3099&nbr=2325/.

S58 The CARI Guidelines

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Prevention of Progression of Kidney Disease S59

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