hypertension and ckd

7/28/2019 Hypertension and CKD

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Hypertension and CKD


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The terms nephrosclerosis orhypertensive nephropathy are usuallyapplied to CKD associated with HTN

Nephrosclerosis

is described in patients

with chronic kidney disease and

essential hypertension with no other

cause of kidney disease


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Even though considered the secondmost common cause of ESRD,hypertensive nephrosclerosis has beenhistologically

confirmed in very few

cases

The causal relationship with

hypertension is still a subject for debate


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The most characteristic microscopiclesion is hyalinosis of afferent arterioles The vascular changes causeglomerular ischemia (retraction of theglomerular

tuft with focal or global

sclerosis), and in some areas,interstitial fibrosis and tubular atrophy


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In other cases the hyalinization ofafferent arterioles initially causesglomerular hypertrophy and, in the longterm glomerulosclerosis

lesions that

would favor the development ofproteinuria and disease progression

These abnormalities are more frequentin black patients


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Hypertensive nephropathy is morefrequent in African Americans

Pharmacologic treatment of mild-to- moderate hypertension in AfricanAmericans has little impact on the

incidence of CKD, whereas it

significantly reduces the progression inCaucasians


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Those differences persist despitecontrolling for:

Age

Sex

Initial serum creatinine concentration

Initial and treated blood pressures

Number of missed office visits Antihypertensive medicationsprescribed


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Kopp et al initially identified excess African ancestryon chromosome 22p in African Americans with

idiopathic FSGS and HIV-associated collapsingFSGS

MYH9 was eventually identified as the associatedgene

MYH9 was associated with clinically diagnosedhypertensive ESRD

in African Americans as well

The Family Investigation in Nephropathy and

Diabetes (FIND) study rapidly replicated associationin several nondiabetic

forms of ESRD in African

Americans, including idiopathic FSGS, HIVAN andclinically diagnosed hypertensive-ESRD


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Genovese and colleagues examined largechromosomal regions adjacent to MYH9 Statistically stronger associations weredetected between two independent

sequence variants in theAPOL1 and

nondiabetic nephropathy in AfricanAmericans, with odds ratios of 10.5 inidiopathic FSGS and 7.3 in hypertension- attributed ESRD

The genetic risk that was previouslyattributed to MYH9 may reside, in part or inwhole, in APOL1, although more complex

models of risk cannot be excluded


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Effect of kidney disease on blood

pressure

Sodium retention is generally of primary importance, evenif the degree of extracellular volume expansion isinsufficient to induce edema

Increased activity of the renin-angiotensin

system

(probably due to regional ischemia induced by scarring) isoften responsible for at least part of the hypertension thatpersists even after the restoration of normovolemia

Enhanced activity of the sympathetic nervous system hasbeen demonstrated in patients with chronic kidneydisease

Secondary hyperparathyroidism raises the intracellular

calcium concentration, which can lead to vasoconstrictionand hypertension

Hypertension may occur or be exacerbated in patientswith advanced chronic kidney disease treated with epo

Impaired NO synthesis and endothelium-mediatedvasodilatation has been demonstrated in patients withuremia


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Goal blood pressure


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Klahr et al. MDRD, NEJM 1994


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Peterson et al. MDRD Ann Intern Med 1995


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Cumulative probability ofkidney failure (top) and

cumulative probability of thecomposite of kidney failureor all-cause mortality before

kidney failure (bottom)

Sarnak et al. MDRD Ann Intern Med 2005

A tih t i Th d Bl d


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Antihypertensive Therapy and Blood

Pressure During Follow-up

Wright et al. AASK JAMA 2002


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Mean Change in Glomerular

Filtration Rate by

Randomized Group



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1094 black patients with hypertensive chronic kidneydisease were randomized to receive either intensive

or standard blood-pressure control

After completing the trial phase, patients were invitedto enroll in a cohort phase in which the blood-

pressure target was less than 130/80 mm Hg

The primary clinical outcome in the cohort phasewas the progression of chronic kidney disease,which was defined as a doubling of the serum

creatinine level, a diagnosis of ESRD, or death Follow-up ranged from 8.8 to 12.2 years

Appel

et al. NEJM Sep 2010


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2

Baseline

Characteristicsof

1094Patients

AssignedtoReceive

IntensiveorStandard

BloodPressure

Control,Accordingto

theLevelofUrinary

Protein

Excretion.

Appel et al. NEJM Sep 2010


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3

During the trial phase, the mean

blood pressure was 130/78 mm

Hg in the intensive-control group

and 141/86 mm Hg in the

standard-control group. During

the cohort phase, corresponding

mean blood pressures were

131/78 mm Hg and 134/78 mm

Hg



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5

Event

Rates

for

Primary

and

Secondary

Outcomes,AccordingtoStudyPhaseand

Proteinuria

StatusatBaseline.



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6

CumulativeIncidenceoftheComposite

PrimaryOutcome,AccordingtoBaseline

Proteinuria

Status.Amongpatientswith

baselineproteinuria,whichwasdefinedas

aurinaryproteintocreatinine

ratio(P:C)

ofmore

than

0.22,

those

who

received

intensivebloodpressurecontrolhada

significantlylowercumulativeincidenceof

thecompositeprimaryoutcome(a

doublingoftheserumcreatinine

level,

endstagerenaldisease,ordeath)than

thosewho

received

standard

blood

pressurecontrol(hazardratiointhe

intensivecontrolgroup,0.73;95%

confidenceinterval[CI],0.58to0.93;

P=0.01).However,thebetweengroup

differencewasnotsignificantamong

patientswithaP:Cof0.22orless(hazard

ratio,1.18;

95%

CI,

0.93

to

1.50;

P=0.16).

Thevaluesatthebottomofthegraphare

numbersofpatients.



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Evidence for RAAS blockade in kidneydisease


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Benazepril trial, Maschio et al. NEJM 1996


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Rate of decline in GFR and percentage risk of progression of nephropathy (combined

endpoint=doubling of baseline serum creatinine

or endstage

renal failure) in two

treatment groups according to baseline urinary protein excretion

REINTrialLancet1997

S


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AASK



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ACE inh, ARB or both?

Successful monotherapy: angiotensin-converting enzyme (ACE) inhibitors versusi t i II t bl k (ARB ) Th fi t i b ti l t d i d th


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angiotensin II receptor blockers (ARBs).The first group is observational studies and thesecond group is randomized, controlled trials

Matchar et al. Ann Intern Med. 2008

Withdrawals due to adverse events: angiotensin converting enzyme (ACE) inhibitors versus


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Withdrawals due to adverse events: angiotensin-converting enzyme (ACE) inhibitors versusangiotensin II receptor blockers (ARBs).The first group is observational studies and the

second group is randomized, controlled trials.

Matchar et al. Ann Intern Med. 2008

Reduction in proteinuria at 5 to 12 months


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Kunz et al. Ann Intern Med. 2008

ON TARGET


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ON TARGET

After a 3-week run-in period, 25 620participants were randomly assignedto ramipril 10 mg a day, telmisartan

80 mg a day, or to a combination of

both drugs The primary renal outcome was a

composite of dialysis, doubling ofserum creatinine, and death

Mann et al.Lancet 2008


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The number of events for the compositeprimary outcome was similar fortelmisartan and ramipril hazard ratio butwas increased with combination therapy

(HR 109, 101118, p=0037)

And authors concluded that even thoughcombination therapy reduces proteinuriato a greater extent than monotherapy, itworsens major renal outcomes

Mann et al.Lancet 2008


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Use in advanced kidney disease


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Hou etal.NEngl JMed.2006

Group1had

aserum

creatinine

level

of

1.5

to

3.0mg/dL

(141patients),andgroup2hada

serumcreatinine

levelof3.1to5.0mg/dL

(281

patients)

atbaseline.Significantlyfewergroup2

patientstreatedwithbenazepril

reachedthe

primaryendpoint(41versus60percentwith

placebo),resulting

in

aoverall

risk

reduction

of

43percentwithactivetherapy.Fewerpatients

ingroup1(whowerealltreatedwithbenazepril)

reachedtheprimaryendpoint(22percent).

ACCOMPLISH trial


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ACCOMPLISH trial

11 506 patients with hypertension whowere at high risk for cardiovascularevents were randomly to receivebenazepril (20 mg) plus amlodipine (5 mg)or benazepril (20 mg) plus

hydrochlorothiazide (125 mg), orally oncedaily

Progression of chronic kidney disease, a

prespecified endpoint, was defined asdoubling of serum creatinineconcentration or end-stage renal disease

Bakris etal.LancetApril2010


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The trial was terminated early (meanfollow-up 29 years) because of superiorefficacy of benazepril plus amlodipinecompared with benazepril plushydrochlorothiazide

There were 113 (2%) events of chronickidney disease progression in thebenazepril plus amlodipine group

compared with 215 (37%) in thebenazepril plus hydrochlorothiazidegroup (HR 052, 041065, p


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HTN management in dialysis patients


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The blood pressure targets for hemodialysis

patients

are not currently clear

Routine peri-dialytic BP recordings performed by adialysis unit staff shortly before and after the HDsession are highly variable and poorly reproducible

Achieving KDOQI-recommended peri-dialytic

BP

targets of


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Observational studies in HD patients have shown anincrease in mortality with low or even normal pre-

dialytic BP levels

Chang et al. conducted a secondary analysis of datafrom the HEMO Study, a randomized trial inprevalent HD patients

In this study, a pre-dialysis systolic BP


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Goal pre-dialysis systolic BP between140 and 160 mmHg and a pre-dialysisdiastolic BP between 70 and 90 mmHg

were recommended

For postdialysis, goal systolic BP at135154 mmHg, and diastolic BP wasstill at 7090 mmHg


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The reproducibility of BPmeasurements follows the followingorder: home BP monitoring > ABPM >>

pre-dialysis BP > post-dialysis BP

However measurement of BP duringeach third of the inter-dialytic intervalgives the best precision in predictingambulatory BP


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A meta-analysis of eight relevant trials,which provided data for 1679 patientsand 495 cardiovascular events, was

performed

In actively treated patients, reduction ofblood pressure was associated withlower risks of cardiovascular events,all-cause mortality, and cardiovascular

mortality than control regimens

Heerspink et al. Lancet 2009


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In patients with ESRD treated withdialysis, a direct relationship betweenvolume status and BP has long beenrecognized

Dry-weight reduction by additionalultrafiltration combined with obsessivedaily dietary salt restriction should berecommended to hypertensive HDpatients even in the absence of clinicalsigns of volume overload


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Restricting dialysate sodium can alsoreduce thirst, limit inter-dialytic

weight

gain and assist the achievement of dry- weight Strict volume control makesantihypertensive drug treatment often

unnecessary and even dangerous


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KaplanMeiersurvival

curvesforRPVslopeand

mortality.Thelogranktest

demonstratedasignificant

differenceinsurvival

betweenmediansofRPV

slopes.Multivariable

adjustmentsdidnot

removethe

statistical

significance

Agarwal

et

al.

Hypertension.

September

2010

Conclusions


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HTN is a questionable cause of kidney diseaseespecially in African Americans

BP goal should not be lower than 140/80 in pts with

CKD unless they have more than 1 g of proteinuria

ACE inh

or ARB are considered first line agents but

evidence supports their use only in proteinuric

kidney disease

Ace inh

continues to affect outcomes even if used in

advanced CKD

Combination ACE inh

and ARB is not supported by

evidence

Volume and dry weight should be the focus of BPcontrol in dialysis patients

hypertension and ckd

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