MODULE 3 CHAPTER 2 B HYPERTENSION AND KIDNEY Kidney and Hypertension Kidney is the cause and effect of hypertension Kidney disease predisposes to hypertension

MODULE 3 CHAPTER 2 B

HYPERTENSION AND KIDNEY

Kidney and Hypertension

• Kidney is the cause and effect of hypertension• Kidney disease predisposes to hypertension and

hypertension predisposes to kidney disease• Early detection of kidney disease and treating it will prevent

major kidney damage in future• Similarly control of hypertension in established kidney

disease will retard further progression• Kidney is as important as heart and brain in hypertension

management• End Stage Renal Disease (ESRD) has to be prevented in

Hypertension

Projections for the Year 2010:Incident & Point-Prevalent ESRD Patients

USRDS 2000 Annual Data Report. Bethesda, Md. 2000.

1984 1986 1988 1990 1992 1994 1996 1998 2000 2002 2004 2006 2008 20100

100

200

300

400

500

600

700

IncidenceR2 = 99.8%

Point prevalenceR2 = 99.7%

ProjectionNumber of Patients

95% Confidence Interval

326,217

372,407

661,330

86,82598,953

172,667

Num

ber o

f Pati

ents

, th

ousa

nds

Adjusted ESRD Incident Rates, by Primary Diagnosis and Diabetes in the General Population

Incident ESRD patients; rates adjusted for age, gender, & race. Data on the prevalence of diabetes in the general population obtained from the CDC’s Behavioral Risk Factor Surveillance System. United States Renal Data System. 2003 Annual Data Report Graphics. Available at: http://www.usrds.org/slides.htm. Accessed 31 October 2003.

350

300

200

100

081 83 85 87 89 91 93 95 97 99 01

Rate

per

Mill

ion

Popu

latio

n

50

150

250

Incident Rates in the ESRD Population

GlomerulonephritisCystic KidneyAll

DiabetesHypertension

9

8

6

491 92 93 94 95 96 97 98 99 00 01

5

7

90

Perc

ent o

f Pop

ulati

on

Prevalence of Diabetes in the General Population

http://www.usrds.org/slodes.htm

CVD Mortality Markedly Increased in ESRD

Reprinted with permission from Foley RN et al. Am J Kidney Dis. 1998;32(supple 3):S112–S119.

• CVD mortality 10–20 times higher in ESRD than the general population• 120 times higher for ESRD patients aged 25 to 34

Dialysis maleDialysis femaleDialysis blackDialysis white

GP maleGP femaleGP blackGP white

Annu

al M

orta

lity,

%

Age, years25–34

35–44

45–54 55–64

65–74

75–84

>85

100

10

1

0.1

0.01

GP = General population.

All-Cause Mortality in the General Medicareand Dialysis Populations (Pts. Age 65+)

Deaths/1000 pt-yr at risk

400

350

300

250

200

150

100

50

0Non-CKD CKD Dialysis

CVDNo CVD

Prevention

• Prevent ESRD as well as CVD in hypertensives as ESRD patients most often die of cardiovascular disease




major kidney damage in future• Similarly control of hypertension in established kidney



Hypertension

The lesson

• Kidney is the culprit in the causation of hypertension even in the absence of hypertension

• So keep looking for hypertension in all kidney disease as well as in patients with family history of renal disease

2nd issue:

• Hypertension predisposes as well as worsens kidney disease in established kidney disease patients

Hypertension is the leading cause of renal transplant

Long-term Decline in GFR is Correlated With Poor Control of Blood Pressure:

9 Studies on Nephropathy Progression

–14

–12

–10

–8

–6

–4

–2

095 97 99 101 103 105 107 109 111 113 115 117 119

MAP (mmHg)

GFR

(ml/m

in/y

r.) (m

mHg

)

Untreated HTN

140/90130/85

Graph: (Bakr is GL. J Clan Hyper tens. 1999) Trials: (Paring HH, et al. Br Med J. 1989) (Liberty GC, et al. JAMA. 1993) (Kaur S, et al. N Engle J Med. 1993*) (Herbert L, et al. Kidney Int.

1994) (Levitz H, et al. Kidney Int. 1994) (Moshi G, et al. N Engle J Med. 1996*) (Bakr is GL, et al. Kidney Int. 1996) (Bakr is GL, et al. Hypertension. 1997) (GISEN Group, Lancet. 1997)

121

*Trials marked by * are non-diabetic renal disease patients.

The lesson

• Control of BP is very important in preventing future renal disease

• Control of BP is essential in further progression of renal disease

• So keep looking for early renal disease in hypertension




major kidney damage as well as CVD in future• Similarly control of hypertension in established kidney



Hypertension

Early Detection

• Albuminuria • GFR/Creatinine clearance

URINARY ALBUMIN EXCRETION

alb:creat.(mg/mmol)

overnighturine (ug/min)

24 hr urine collection(mg/24hrs)

normal m:<3.5f :<2.5

<20 <30

microalbumin

m:3.5-30f : 2.5-30

20-200 30-300

proteinuria m:>30f : >30

>200 >300

The lesson

• In all hypertensives keep looking for micro albuminuria

• It predicts not only future renal disease but also cardiovascular disease

Early Detection

• Albuminuria • GFR/Creatinine clearance

CVD Risk Factors

Hypertension* Cigarette smoking Obesity* (BMI >30 kg/m2) Physical inactivity Dyslipidemia* Diabetes mellitus* Micro albuminuria or estimated GFR <60 ml/min Age (older than 55 for men, 65 for women) Family history of premature CVD

(men under age 55 or women under age 65)

*Components of the metabolic syndrome.

Stages of Chronic Kidney Disease: NKF K/DOQI Classification

CKD=chronic kidney disease, ESRD=end-stage renal disease, GFR=glomerular filtration rate, NKF K/DOQI=National Kidney Foundation Kidney Disease Outcomes Quality Initiative, RCN=radio contrast nephropathyAdapted from National Kidney Foundation. Am J Kidney Dis. 2002;39(2suppl 2):S1-S246.

Stage I

CKD risk factors/damagewith preserved

GFR

Stage II

Mild kidney

function

Stage III

Moderate kidney

function

Stage IV

Severe kidney

function

Stage V

Kidneyfailure,ESRD

GFR (mL/min/1.73 m2)130 90 60 30 150

Prevalence 5.8% 12.3% 4.3% 0.2%0.1%

n (x1000) 10,259 21,794 7,553 363300

Risk of RCN, dialysis, and death

Serum creatinine and GFR relationship

Crea

tinin

e cl

eara

nce

CKD AND CVD

15.8

33.1

57.3

71.2

0

10

20

30

40

50

60

70

80

Perc

ent w

ith C

VD

>90 89-60 59-30 <30

Estimated GFR

P<0.0001 for trend

McCullough PA, et al for the KEEP Investigators. J Am Cull Cardio. 2005;45:424A.

Estimation of eGFR,Creatinine clearance

To calculate visit this site and give necessary data

• http://www.medcalc.com/gfr.html

http://www.medcalc.com/gfr.html

The lesson

• Early detection of kidney disease is by albuminuria as well as eGFR, estimated cr.clearance

• Don’t rely upon solely on serum creatinine• Even in the absence of proteinuria , calculate

eGFR/Cr.clearance







Hypertension

Early Treatment Makes a Difference

Brenner, et al., 2001

KDIGO 2012

(CKD IN NON DIABETICS)

KDIGO 2012

KDIGO 2012

KDIGO 2012

KDIGO 2013

Clinical Practice Guidelines for Management of Hypertension in CKD

Type of Kidney Disease Blood Pressure Target

(mm Hg)

Preferred Agents for CKD, with or

without Hypertension

Other Agents to Reduce CVD Risk

and Reach Blood Pressure Target

Diabetic Kidney Disease

<130/80

ACE inhibitor or ARB

Diuretic preferred, then BB or CCBNondiabetic Kidney

Disease with Urine Total Protein-to-Creatinine

Ratio 200 mg/gNondiabetic Kidney

Disease with Spot Urine Total Protein-to-Creatinine

ratio <200 mg/g None preferred

Diuretic preferred, then ACE inhibitor, ARB, BB or CCB

Kidney Disease in Kidney Transplant Recipient

CCB, diuretic, BB, ACE inhibitor, ARB

ACEI AND ARBS

• PREFERED DRUGS IN KIDNEY DISEASE• STILL CERTAIN PRECAUTIONS HAVE TO BE

OBSERVED

Afferentarteriole

Efferentarteriole

Angiotensin II and Renal Disease

1. Deficientauto regulation:

Glomerulus

3. Abnormal matrix metabolism:

2. Increased efferent resistance:

Bowman’scapsule

High BP

Constriction

Increase in intra glomerular pressure

INTRAGLOMULAR HYPERTENSIONAND HYPERFILTERATION

ALTERATION IN PERMSELECTIVITY OF GLOMERULUS BASEMENT MEMBRANE THICKENING

ALBUMINURIA

TUBULO TOXICITY AND LOSS OF NEPHRONS

HYPERFILTERATION IN REMAINING NEPHRONS

RENAL INJURY

HYPERTENSION

Double edged weapon

• Although ACE I and ARB reduce albuminuria and retard progression of renal disease, decrease in GFR due to reduced intra glomerular pressure may result in worsening of renal function

General Concept

A rise in serum creatinine of up to 30% of baseline ( given baseline up to 3 mg/dl) that remains stable in the absence of hyperkalemia ([K+] > 6) correlates with slower renal disease progression.

Bakr is GL & Weir M Arch Intern Med. 2000:160:685-693

©2006. American College of Physicians. All Rights Reserved.

severe cardiac failure

Which ACEI?

• Fosinopril and trandolapril are partially (in general, approximately 50%) excreted by the liver, such that the blood levels are less influenced by kidney failure than levels of other ACE-Is which are predominantly excreted by the kidneys.

Which ARB?Candesartan should not be used in renal disease

Half-Life Bioavailability Volume of % Renal/Hepatic

Drug (h) (%) Distribution Clearance

Candesartan 9 15 0.13 L/kg60/40

Eprosartan 5 13 13 L30/70

Irbesartan 11-15 60-80 53-93 L1/99

Losartan 2 33 34 L10/90

E-3174 6-9 – 12 L50/50

Olmesartan 10-15 28 17 L45/55

Telmisartan 24 42-58 500 L1/99

Valsartan 6 25 17 L30/70

ACEIs and ARBs inChronic Renal Failure

Renal and Pharmacokinetic Differences

Parameter ACEIs ARBs

Proteinuria Uric acid *Glomerular filtration rate Hyperkalemia Dose titration suggested Yes NoBP reduction Systemic accumulation Yes NoAT2 receptor stimulation

* Occurs only with losartan

COOPERATE: UAERcombination

Reprinted with permission from Nakao N et al. Lancet. 2003;361:117–124.

0

1

2

3

0 5 15 20 30 35

TrandolaprilLosartanCombination

Months After Randomization

Med

ian

Urin

ary

Prot

ein

Excr

etion

, g/

day

Baseline

10 25 40

COMBINATION – ACE I AND ARBS

• CAN BE COMBINED IN CHRONIC HEART FAILURE• SHOULD BE AVOIDED IN AMI WITH HF• SERIAL CHECK FOR CREATININE, POTTASIUM• WATCH FOR HYPOTENSION• SPIRANOLACTONE SHOULD BE AVOIDED WITH THIS

COMBINATION –SHOULD BE USED WITH EITHER ONE OF THEM

• USEFUL TO REDUCE BP,FULL ANGIOTENSIN ANTAGONISM WITHOUT LOSING BRADYKININ ADVANTAGE, NEPHRO PROTECTION

• NOT USEFUL IN PATIENTS WITH PRESERVED EF

Safety of Calcium Channel Blockers

• Concern has been expressed in the past about the safety of CCBs with respect to both cardiac and renal outcomes

• The ALLHAT found amlodipine to be equivalent to chlorthalidone and Lisinopril in cardiac outcomes

• The IDNT in a randomized comparison found no beneficial or adverse impact of amlodipine (other than BP reduction) on renal outcomes or proteinuria

• The RENAAL in a secondary analysis found no beneficial or adverse impact on renal outcomes of use of any CCBs

• Should be used along with ACEI,ARB• Effective BP reducing drugs

Cilnidipine Hypertension & Chronic Renal Insufficiency (CRI)

Dual receptor blocker Cilnidipine dilates efferent arterioles leading to lowering of glomerular

pressure

EFFERENTARTERIOLEDILATATION

INTRA GLOMERULARPRESSURE

ALBUMINURIA

Cilnidipine Hypertension & Chronic Renal Insufficiency (CRI)

• 1 year study comparing benazepril with cilnidipine in hypertensive pts with benign nephrosclerosis– Proteinuria is a marker of renal insufficiency & improvement with drug therapy is desired

• 20 pts randomized to receive either– Benazepril – 5 to 10 mg/d– Cilnidipine – 10 to 20 mg/d

• Sr. creatinine & albuminuria were measured at 3 and 6 mth intervals resp.

While Sr. creatinine levels did not change, cilnidipine like benazepril significantly reduced SBP, DBP & albuminuria

Rose WG. Hypertens Res 2001;24:377-83

CNI, calcineurin inhibitor

CA BLOCKERS AND TRANSPLANT• Calcium-channel blockers, particularly non-

dihydropyridines, interfere with the metabolism and excretion of the calcinurine inhibitors (CNIs), cyclosporine and tacrolimus, as well as the mammalian target of rapamycin (mTOR) inhibitors, sirolimus and everolimus.

• This is relevant to the treatment of high BP in kidney-transplant recipients, but also in patients with immune-mediated CKD requiring immunosuppression.

• When such patients are prescribed non-dihydropyridine• calcium-channel blockers, careful monitoring of CNIs and• mTOR inhibitors blood levels is required if drugs or dosages• are changed.

The Need for Sodium Restriction or Adequate Diuresis

• Most classes of antihypertensive agents lead, by compensation for lower BP, to sodium retention. This may substantially blunt the anti-hypertensive effect

• JNC 7 recommends that “most patients should receive a regimen including a thiazide type diuretic, either alone or with other agents.”

• This is particularly important in patients with high sodium intakes, in particular African-American patients. In African-Americans, adequate diuresis restores a responsiveness to RAAS blockers similar to that in Caucasians

Aldosterone antagonists

• All cases of LV dysfunction• Sleep apnea• Resistant hypertension• When K is low in spite of acei/arb it can be

used• KEEP WATCHING FOR HYPERKALEMIA• Eplerenone does not produce gynaecomatia

Renal failure

• Optimization :Always correct Volume overload• Thiazide : Chlorthallidone 12.5-25mg/day if GFR

>40ml/min/1.73 m2• Loop diuretics if GFR is less than this –

Furosemide twice a day, Torsemide once a day• Torsemide is preferred in renal failure • Combination of diuretics : metallazone and loop

diuretics in resistant fluid overload• Optimize doses,timings,and combinations

Diuretics - combination• YES – combine at different sites• Lo op d iu retics + k sparin g d iu retics ( amilo ride, tr iamterene)• Lo op d iu retics + Ald o stero n e in hibit or s• Lo op d iu retics + th iaz ide d iu retics (met allazon e)• NO – do n ’t co mb in e at same site• 2 Lo op d iur etics• 2 k sparin g d iu retics• 2 th iaz ide d iu retics

B BLOCKERS

B BLOCKERS IN RENAL DISEASE

• ALWAYS TO BE USED IF THERE IS CAD, HEART FAILURE,LV DYSFUNCTION AND TACHYARRHYTHMIA

• METOPROLOL, CARVEDILOL ARE PREFERED• ATENOLOL BISOPROLOL NEBIVOLOL MAY BE

AVIODED• DOSAGE ADJUSTMENT ACCORDING HR AND

BP

Alpha blockers

• Alpha-blockers reduce the symptoms of benign prostatic hyperplasia, which may be a co-morbidity to consider in older men with CKD.

• In general, alpha-blockers are not considered a first-line choice because of the common side effects of postural hypotension, tachycardia and headache.

• They should be commenced at a low dosage to avoid a first-dose hypotensive reaction.

• They do not require dosage modification

CENTRALLY ACTING DRUGS

• Doses of methyldopa or clonidine are not generally reduced in patients with impaired kidney function.

• Moxonidine is extensively excreted by the kidney and accordingly it has been recommended that the dosage (usually 200 to 400 mg daily) should be reduced in the presence of a low GFR.

• Clonidine is used in resistant hypertension with renal failure- can produce Brady if used with b blockers

• Abrupt withdrawal should be avoided• Moxonidine is to be avoided in advanced heart failure

Direct vasodilators

• Hydralazine has little value in the management of chronically elevated BP in CKD, although it is sometimes used as a parenteral hypotensive agent.

• Minoxidil is generally used in patients with very resistant hypertension and thus may be helpful in patients with CKD.

• Because of the side effects of fluid retention and tachycardia, direct vasodilators (especially minoxidil) are usually combined with a beta-blocker and loop diuretic.







Hypertension

Progression of Kidney Disease related to level of proteinuria and blood pressure lowering in MDRD Study

Petersen. Annals of Internal Medicine. 1995

NEPHROPATHY

• Lower levels of BP result in slower rates of decline in renal functions • eg. someone 50 years of age with GFR of 50ml/mt and SBP of 144 will be on dialysis 8 years earlier than someone of the same age and GFR with SBP of 134







Hypertension

Conclusions • Kidney initiates hypertension not only in secondary

forms but also in essential hypertension• Once hypertension sets in it further damages the

kidney• Associated kidney disease complicates the

management as it requires careful selection as well as monitoring of therapy

• Nevertheless the identification early kidney disease in hypertension and early hypertension in kidney disease and proper management will retard the progression of not only kidney disease but also cardiovascular disease

END OF MODULE 3 CHAPTER 2B

Documents

MODULE 3 CHAPTER 2 B HYPERTENSION AND KIDNEY Kidney and Hypertension Kidney is the cause and effect of hypertension Kidney disease predisposes to hypertension