1. HYPERTENSION in ADPKD Sabine Karam M.D.

2. 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

3. 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.Jan;12(1):194-200

4. Mean renal volume is significantly higher in Hypertensive (HBP) vs Normotensive (NBP) ADPKD patients Kidney International, Vol. 38 (1990), pp. 1177—1180 147 subjects Creat<1.5 mg/dL Renal Volume by Ultrasound

5. The Progression of Renal Disease in Hypertensive and Normotensive ADPKD Patients Kidney International, Vol. 41(1992), pp. 1311—1319 P<0.001

6. Does the choice of the agent matter?

7. 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

8. Pathogenetic role of RAAS in ADPKD. Robert W. Schrier JASN 2009;20:1888-1893

9. The annual loss of creatinine clearance adjusted for initial creatinine clearances was significantly larger in the diuretic group than the ACEI group Am J Nephrol 2001;21:98–103 Diuretic group: n=14 ACEI group: n=19 Follow up 5 years

10. 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

11. 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

12. 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

14. Figure 1 American Journal of Kidney Diseases 2011 57, 856-862DOI: (10.1053/j.ajkd.2011.01.023)

16. Is there an Ideal Target?

17. HYPERTENSION IN CKD TREATMENT GUIDELINES JNCVIIIESH/ESCKDIGO 2012 Lifestyle Modifications Na+<2.4g/day BMI 20-25 Exercise 30x5 EtOH≤1-2(f-m) Na+<2.4g/day BMI 20-25 Exercise 30x5 EtOH≤1-2(f-m) Na+<2g/day BMI 20-25 Exercise 30x5 EtOH≤1-2(f-m) BP Goals <140/90 SBP<140 SBP<130 if overt proteinuria <140/90 mmHg <130/80 mmHg If UAE>30mg/day Preferred ACEI or ARB Yes Yes if UAE>30mg/day

18. 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 participants Follow up=2.2 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.

19. 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

20. Effect of rigorous versus standard BP control on 24-h creatinine clearance over 7 yr. Robert Schrier et al. JASN 2002;13:1733-1739

21. HALT-PKD TRIAL: Goals and Design InterventionBP Target (mmHg) Primary Outcome Study A (CKD1-2) N=558 1.ACE+ARB 2.ACE 3.ACE+ARB 4.ACE 120-130/70-80 95-110/60-75 Change in renal volume by MRI Study B (CKD 3) N=470 1.ACE+ARB 2.ACE 110-130/70-80 Doubling in serum creatinine ESRD/Death Goals: 1)ACEI+ARB> ACEI alone (CKD 1-3) 2)Low>standard BP target (CKD1-2)

22. HALT-PKD TRIAL: Protocol for addition of antihypertensive agents StepTreatmentControl 1-4 Combination ACE-ARB:ACE Lisinopril 5 mg Lisinopril 10 mg Lisinopril 20 mg Lisinopril 40 mg Combination ACE-ARB:ARB Telmisartan 40 mg Telmisartan 80 mg ACE-I Lisinopril 5 mg Lisinopril 10 mg Lisinopril 20 mg Lisinopril 40 mg Placebo 5 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 9 onwards Non dihydropyridine calcium channel blocker (diltiazem), clonidine, minoxidil, hydralazine at discretion of investigator

24. 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.

25. 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.

27. 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)

28. Urinary Aldosterone and Albumin Excretion in both groups Torres VE et al. N Engl J Med 2014;371:2267-2276 P=0.08

29. 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

30. 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

31. 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

33. 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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