HYPERTENSION in ADPKDSabine Karam M.D.

IntroductionADPKD is the most common life-threatening

single-gene disease

It affects over 12 million people worldwide

Fourth leading cause of end-stage renal disease (ESRD) in the US

Hypertension identified as a factor associated with progression to ESRD

HYPERTENSION in ADPKDOccurs in 50-75% of patients prior to the onset

of marked renal insufficiency

Early high incidence correlated with renal structural abnormalities

Most important potentially treatable variable

Important risk factor for cardiovascular death, the most frequent cause of mortality in ADPKD patients

JASN. 2001.Jan;12(1):194-200

Mean renal volume is significantly higher in Hypertensive (HBP) vs Normotensive (NBP) ADPKD patients

Kidney International, Vol. 38 (1990), pp. 1177—1180

147 subjectsCreat<1.5 mg/dLRenal Volume by Ultrasound

The Progression of Renal Disease in Hypertensive and Normotensive ADPKD Patients

Kidney International, Vol. 41(1992), pp. 1311—1319

P<0.001

Does the choice of the

agent matter?

Mean PRA and plasma aldosterone concentration in 14 patients with HTN and ADPKD vs 9 patients with essential hypertension before and after 50 mg of captopril

NEJM.1990;323:1091-6

Pathogenetic role of RAAS in ADPKD.

Robert W. Schrier JASN 2009;20:1888-1893

The annual loss of creatinine clearanceadjusted for initial creatinine clearanceswas significantly larger in the diureticgroup than the ACEI group

Am J Nephrol 2001;21:98–103

Diuretic group: n=14ACEI group: n=19Follow up 5 years

No significant differences in the decline of GFR (ANOVA; P > 0.05) during the 3 years of follow-up of a cohort of 35 patients

randomized to Enalapril or Atenolol

Marjan A. van Dijk et al. Nephrol. Dial. Transplant. 2003;18:2314-2320

Mean GFR (ml/min) as calculated according to Cockcroft and Gault at baseline, 12, 24 months, and at the end of the study in the two treatment groups. **P < 0.01 for GFR at baseline compared

with GFR at the end of the study in both groups.

Raoul Zeltner et al. Nephrol. Dial. Transplant. 2008;23:573-579

Metoprolol=23 Ramipril=23 Follow up 3 years

LVMI (g/m2) according to BP control at baseline and after the 3 years follow-up (end). *P < 0.01 for LVMI in the standard vs the rigorous BP control group at 3 years of follow-up. **P < 0.01 for LVMI at baseline compared with LVMI at the end of the study in the standard BP control group.

Raoul Zeltner et al. Nephrol. Dial. Transplant. 2008;23:573-579

Figure 1

American Journal of Kidney Diseases 2011 57, 856-862DOI: (10.1053/j.ajkd.2011.01.023)

American Journal of Kidney Diseases 2011 57, 856-862DOI: (10.1053/j.ajkd.2011.01.023)

Is there an Ideal Target?

HYPERTENSION IN CKDTREATMENT GUIDELINES

JNCVIII ESH/ESC KDIGO2012

Lifestyle Modifications

Na+<2.4g/dayBMI 20-25Exercise 30x5EtOH≤1-2(f-m)

Na+<2.4g/dayBMI 20-25Exercise 30x5EtOH≤1-2(f-m)

Na+<2g/dayBMI 20-25Exercise 30x5EtOH≤1-2(f-m)

BP Goals <140/90 SBP<140SBP<130 if overt proteinuria

<140/90 mmHg<130/80 mmHgIf UAE>30mg/day

Preferred ACEI or ARB

Yes Yes Yes if UAE>30mg/day

MDRD Study: Mean changes in GFR versus time in patients randomized to a usual (dashed line) or a low blood pressure (solid line) group

JASN.1995; 5:2037-2047

200 participantsFollow up=2.2 yearsUsual” MAP goal =107 mm Hg for age ≤60 yr =113 mm Hg if older than 60 yrLow MAP goal =92 mm Hg for age≤ 60 yr and 98 mm Hg if older than 60 yr.

Effect of rigorous versus standard BP control on left ventricular mass index (LVMI) over 7 yr.

Robert Schrier et al. JASN 2002;13:1733-1739

Effect of rigorous versus standard BP control on 24-h creatinine clearance over 7 yr.

Robert Schrier et al. JASN 2002;13:1733-1739

HALT-PKD TRIAL: Goals and Design

Intervention BP Target(mmHg)

PrimaryOutcome

Study A(CKD1-2)N=558

1.ACE+ARB2.ACE3.ACE+ARB4.ACE

120-130/70-80120-130/70-8095-110/60-7595-110/60-75

Change in renal volume by MRI

Study B(CKD 3)N=470

1.ACE+ARB2.ACE

110-130/70-80110-130/70-80

Doubling in serum creatinineESRD/Death

Goals: 1)ACEI+ARB> ACEI alone (CKD 1-3) 2)Low>standard BP target (CKD1-2)

HALT-PKD TRIAL: Protocol for addition of antihypertensive agents

Step Treatment Control

1-4 Combination ACE-ARB:ACELisinopril 5 mgLisinopril 10 mgLisinopril 20 mgLisinopril 40 mg

Combination ACE-ARB:ARBTelmisartan 40 mgTelmisartan 40 mgTelmisartan 80 mgTelmisartan 80 mg

ACE-I

Lisinopril 5 mgLisinopril 10 mgLisinopril 20 mgLisinopril 40 mg

Placebo

5 Hydrochlorothiazide 12.5 mg Hydrochlorothiazide 12.5 mg

6-8 Metoprolol 50 mg BIDMetoprolol 100 mg BIDMetoprolol 200 mg BID

Metoprolol 50 mg BIDMetoprolol 100 mg BIDMetoprolol 200 mg BID

9 onwards Non dihydropyridine calcium channel blocker (diltiazem), clonidine, minoxidil, hydralazine at discretion of investigator

Non dihydropyridine calcium channel blocker (diltiazem), clonidine, minoxidil, hydralazine at discretion of investigator

Total Kidney Volume and Estimated Glomerular Filtration Rate (eGFR) during Follow-up and Subgroup Analyses, According to Blood-Pressure

Group.

Schrier RW et al. N Engl J Med 2014;371:2255-2266.

Changes in Total Kidney Volume and eGFR during Follow-up, and Subgroup Analyses, According to Treatment Group.

Schrier RW et al. N Engl J Med 2014;371:2255-2266.

Blood-Pressure Levels and Medication Steps between the two groups

Torres VE et al. N Engl J Med 2014;371:2267-2276

Lisinopril–placebo higher systolic blood pressure (difference, 1.23 mm Hg; 95% confidence interval [CI], 0.24 to 2.21; P = 0.02)

Urinary Aldosterone and Albumin Excretion in both groups

Torres VE et al. N Engl J Med 2014;371:2267-2276

P=0.08

Effect of Lisinopril–Telmisartan, as Compared with Lisinopril–Placebo, on the Time to Primary-Outcome Events and on the Estimated Glomerular Filtration Rate (eGFR).

Torres VE et al. N Engl J Med 2014;371:2267-2276

Effect of Lisinopril–Telmisartan, as Compared with Lisinopril–Placebo, on the Time to Primary-Outcome Events and on the Estimated Glomerular Filtration Rate (eGFR).

Torres VE et al. N Engl J Med 2014;371:2267-2276

Effect of Lisinopril–Telmisartan, as Compared with Lisinopril–Placebo, on the Time to Primary-Outcome Events and on the Estimated Glomerular Filtration Rate (eGFR).

Torres VE et al. N Engl J Med 2014;371:2267-2276

Treatment of hypertension in the adult ADPKD population BP target ⩽ 140/90mmHg

Agents that interfere with the renin-angiotensin-aldosterone system (RAAS) are first-line BP-lowering agents

Sodium-restricted diet

Calcium channel blockers and diuretics may be preferred over beta-blockers for cardiovascular protection

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