HYPERTENSION in ADPKD

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HYPERTENSION in ADPKD

• Sabine Karam M.D.

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Introduction

• ADPKD 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

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HYPERTENSION in ADPKD

• Occurs 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.Jan12(1)194-200
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Mean renal volume is significantly higher in
Hypertensive (HBP) vs Normotensive (NBP) ADPKD
patients
147 subjects Creatlt1.5 mg/dL Renal Volume by
Ultrasound
Kidney International, Vol. 38 (1990), pp.
11771180
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The Progression of Renal Disease in Hypertensive
and Normotensive ADPKD Patients
Plt0.001
Kidney International, Vol. 41(1992), pp. 13111319
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Does the choice of the agent matter?
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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.19903231091-6
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Pathogenetic role of RAAS in ADPKD.
Robert W. Schrier JASN 2009201888-1893
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The annual loss of creatinine clearanceadjusted
for initial creatinine clearanceswas
significantly larger in the diureticgroup than
the ACEI group
Diuretic group n14 ACEI group n19 Follow up 5
years
Am J Nephrol 20012198103
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No significant differences in the decline of GFR
(ANOVA P?gt?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. 2003182314-2320
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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 lt 0.01 for GFR at baseline compared
with GFR at the end of the study in both groups.
Metoprolol23 Ramipril23 Follow up 3 years
Raoul Zeltner et al. Nephrol. Dial. Transplant.
200823573-579
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LVMI (g/m2) according to BP control at baseline
and after the 3 years follow-up (end). P lt 0.01
for LVMI in the standard vs the rigorous BP
control group at 3 years of follow-up. P lt 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.
200823573-579
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Figure 1
American Journal of Kidney Diseases 2011 57,
856-862DOI (10.1053/j.ajkd.2011.01.023)
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American Journal of Kidney Diseases 2011 57,
856-862DOI (10.1053/j.ajkd.2011.01.023)
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Is there an Ideal Target?
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HYPERTENSION IN CKDTREATMENT GUIDELINES
JNCVIII ESH/ESC KDIGO 2012
Lifestyle Modifications Nalt2.4g/day BMI 20-25 Exercise 30x5 EtOH1-2(f-m) Nalt2.4g/day BMI 20-25 Exercise 30x5 EtOH1-2(f-m) Nalt2g/day BMI 20-25 Exercise 30x5 EtOH1-2(f-m)
BP Goals lt140/90 SBPlt140 SBPlt130 if overt proteinuria lt140/90 mmHg lt130/80 mmHg If UAEgt30mg/day
Preferred ACEI or ARB Yes Yes Yes if UAEgt30mg/day
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MDRD Study Mean changes in GFR versus time in
patients randomized to a usual (dashed line) or a
low blood pressure (solid line) group
200 participants Follow up2.2 years Usual MAP
goal 107 mm Hg for age 60 yr 113 mm Hg if
older than 60 yr Low MAP goal 92 mm Hg for age
60 yr and 98 mm Hg if older than 60 yr.
JASN.1995 52037-2047
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Effect of rigorous versus standard BP control on
left ventricular mass index (LVMI) over 7 yr.
Robert Schrier et al. JASN 2002131733-1739
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Effect of rigorous versus standard BP control on
24-h creatinine clearance over 7 yr.
Robert Schrier et al. JASN 2002131733-1739
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HALT-PKD TRIAL Goals and Design
Goals 1)ACEIARBgt ACEI alone (CKD 1-3)
2)Lowgtstandard BP target (CKD1-2)
Intervention BP Target (mmHg) Primary Outcome
Study A (CKD1-2) N558 1.ACEARB 2.ACE 3.ACEARB 4.ACE 120-130/70-80 120-130/70-80 95-110/60-75 95-110/60-75 Change in renal volume by MRI
Study B (CKD 3) N470 1.ACEARB 2.ACE 110-130/70-80 110-130/70-80 Doubling in serum creatinine ESRD/Death
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HALT-PKD TRIAL Protocol for addition of
antihypertensive agents
Step Treatment Treatment Control Control
1-4 Combination ACE-ARBACE Lisinopril 5 mg Lisinopril 10 mg Lisinopril 20 mg Lisinopril 40 mg Combination ACE-ARBARB Telmisartan 40 mg Telmisartan 40 mg Telmisartan 80 mg Telmisartan 80 mg ACE-I Lisinopril 5 mg Lisinopril 10 mg Lisinopril 20 mg Lisinopril 40 mg Placebo
5 Hydrochlorothiazide 12.5 mg Hydrochlorothiazide 12.5 mg Hydrochlorothiazide 12.5 mg Hydrochlorothiazide 12.5 mg
6-8 Metoprolol 50 mg BID Metoprolol 100 mg BID Metoprolol 200 mg BID Metoprolol 50 mg BID Metoprolol 100 mg BID Metoprolol 200 mg BID Metoprolol 50 mg BID Metoprolol 100 mg BID Metoprolol 200 mg BID Metoprolol 50 mg BID Metoprolol 100 mg BID Metoprolol 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 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
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Schrier RW et al. N Engl J Med
20143712255-2266.
Total Kidney Volume and Estimated Glomerular
Filtration Rate (eGFR) during Follow-up and
Subgroup Analyses, According to Blood-Pressure
Group.
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Schrier RW et al. N Engl J Med 20143712255-2266.
Changes in Total Kidney Volume and eGFR during
Follow-up, and Subgroup Analyses, According to
Treatment Group.
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Blood-Pressure Levels and Medication Steps
between the two groups
Lisinoprilplacebo higher systolic blood pressure
(difference, 1.23 mm Hg 95 confidence interval
CI, 0.24 to 2.21 P 0.02)
Torres VE et al. N Engl J Med 20143712267-2276
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Urinary Aldosterone and Albumin Excretion in both
groups
P0.08
Torres VE et al. N Engl J Med 20143712267-2276
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Effect of LisinoprilTelmisartan, as Compared
with LisinoprilPlacebo, on the Time to
Primary-Outcome Events and on the Estimated
Glomerular Filtration Rate (eGFR).
Torres VE et al. N Engl J Med 20143712267-2276
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Effect of LisinoprilTelmisartan, as Compared
with LisinoprilPlacebo, on the Time to
Primary-Outcome Events and on the Estimated
Glomerular Filtration Rate (eGFR).
Torres VE et al. N Engl J Med 20143712267-2276
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Effect of LisinoprilTelmisartan, as Compared
with LisinoprilPlacebo, on the Time to
Primary-Outcome Events and on the Estimated
Glomerular Filtration Rate (eGFR).
Torres VE et al. N Engl J Med 20143712267-2276
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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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THANK YOU!