American Society of Nephrology Presents RENAL WEEKENDS HYPERTENSION

American Society of Nephrology Presents RENAL WEEKENDS: HYPERTENSION Highlights from of the American Society of Nephrology 41 th Annual Meeting November 4 -8, 2008

HEMODIALYSIS

OUTCOMES IN PATIENTS WITH INTRADIALYTIC HYPERTENSION: NOT SO BENIGN? The Growing Problem of Intradialytic Hypertension American Society Nephrology Annual Meeting – November 2008 Jula K. Inrig, MD, MHS Assistant Professor UT Southwestern Medical Center

Intradialytic hypertension associated with lower dry weight 5 P<0. 00 01 4. 5 4 P=0. 26 3. 9 3. 8 P=0. 00 02 3. 7 3. 5 3. 1 3 2. 7 2. 6 2. 5 2 SBP fell SBP unchanged SBP rose SBP fell SBP unchanged IDWG% SBP rose IDWG (kg) Inrig et al. KI, 2007; 71: 454

Serum Creatinine (mg/dl) Intradialytic HTN associated with lower serum creatinine P=0. 01 No difference in serum albumin, calcium, phos, PTH, cholesterol or Hgb Inrig et al. KI, 2007; 71: 454

Increasing SBP with HD and higher 6 -month hospitalization and mortality* Adjusted HR Odds ratio 4 3 P=0. 01 n. Every 10 mm. Hg increase in SBP following HD was associated with a 20% increased odds of 2. 17 2 1. 85 hospitalization or death (OR 1. 20 , CI 1. 10 -1. 30, P=0. 002) 1 1 0 SBP fell SBP unchanged SBP rose *Adjusted for age, race, gender, weight, IDWG, cause of ESRD, comorbid conditions, txt group, medications, and laboratory variables

Conclusion Intradialytic hypertension is associated with increased risk of hospitalization and death Hemodialysis unit BP parameters can be used to identify one particular “high-risk” group of hypertensive HD patients – those with intradialytic HTN Further research is needed to determine whether intradialytic HTN is treatable and if treatment can improve outcomes

RESISTANT HYPERTENSION

Resistant Hypertension 3 Big Issues 1. The doctor is not providing the right treatment 2. The patient is not taking the pills 3. The blood pressure is not properly measured

Diagnostic and Treatment Recommendations Confirm Treatment Resistance Exclude Pseudoresistance Identify & Reverse Lifestyle Factors Discontinue Interfering substances Screen for Secondary HTN Pharmacological Treatment Refer to Specialist Calhoun et al; Hypertension: 2008; 51; 000

Diagnosis of Treatment Resistance (Calhoun et al; Hypertension 2008) • Office blood pressure >140/90 or 130/80 mm Hg in patients with diabetes or chronic kidney disease and • Patient prescribed 3 or more antihypertensive medications at optimal doses, including if possible a diuretic or • Office blood pressure at goal but patient requiring 4 or more antihypertensive medications

Meta-Analysis of Home Monitoring for Improving BP Control (Cappuccio et al, BMJ 2004; 329, 145)

Meta-Analysis of Home Monitoring for Improving BP Control (Cappuccio et al, BMJ 2004; 329, 145) Modest increase in BP control

Improved BP Control with Home BP Monitoring and Web Control (Green et al JAMA 2008: 299; 2857) HBPM + webbased pharmacist % with BP control Usual Care + HBPM 31% 36% 56%

Exclude Pseudoresistance (Calhoun et al; Hypertension 2008) • Is patient adherent with prescribed regimen? • Obtain home, work, or ambulatory BP readings to exclude white coat effect • Identify and Reverse Contributing Lifestyle Factors

Identify and Reverse Contributing Lifestyle Factors (Calhoun et al; Hypertension 2008) • Obesity • Physical inactivity • Excessive alcohol ingestion • High salt, low fiber diet

Identify and Reverse Contributing Lifestyle Factors (Calhoun et al; Hypertension 2008) • Obesity • Physical inactivity • Excessive alcohol ingestion • High salt, low fiber diet

Medications That Can Interfere With BP Control (Calhoun et al; Hypertension 2008) Nonsteroidal antiinflammatory agents, including aspirin Selective COX-2 inhibitors Sympathomimetic agents (decongestants, diet pills, cocaine) Stimulants (dexmethylphenidate, amphetamine, modafinil) Alcohol Oral contraceptives Cyclosporine Erythropoietin Natural licorice Herbal compounds (ephedra or ma huang)

Secondary Causes of Resistant Hypertension Common Obstructive sleep apnea Renal parenchymal disease Primary aldosteronism Renal artery stenosis Uncommon Pheochromocytoma Cushing’s disease Hyperparathyroidism Aortic coarctation Intracranial tumor Calhoun et al; Resistant Hypertension; Scientific Statement from AHA : Hypertension: 2008; 51; 000

Secondary Causes of Resistant Hypertension Common Obstructive sleep apnea Renal parenchymal disease Primary aldosteronism Renal artery stenosis Uncommon Pheochromocytoma Cushing’s disease Hyperparathyroidism Aortic coarctation Intracranial tumor Calhoun et al; Resistant Hypertension; Scientific Statement from AHA : Hypertension: 2008; 51; 000

When to Suspect Sleep Apnea

High Prevalence of Sleep Apnea in Resistant Hypertension (Logan et al J Hypertens 2001: 19: 2271) • 41 consecutive patients with 3 drug-resistant hypertension evaluated with PSG and ABPM • Clinic BP was 168/94 on 3. 6 drugs; most were obese • 83% had OSA (AHI >10); commoner in men (96%) than women (65%) • ABPM showed that 64% were non-dippers; no difference in dipping between those with and without OSA

Concept of Treatment Resistance Adequate Treatment Prescribed Have appropriate pills been prescribed? Is the patient taking the pills ? BP Remains High Is BP measured appropriately?

Concept of Treatment Resistance Adequate Treatment Prescribed Have appropriate pills been prescribed? Is the patient taking the pills ? BP Remains High Blame the Doctor

Pharmacologic Treatment (Calhoun et al; Hypertension 2008) • Maximize diuretic therapy, including possible addition of mineralocorticoid receptor antagonist • Combine agents with different mechanisms of action • Use of loop diuretics in patients with chronic kidney disease and/or patients receiving potent vasodilators (e. g. , minoxidil)

Concept of Treatment Resistance Adequate Treatment Prescribed BP Remains High Have appropriate pills been prescribed? Is the patient taking the pills ? Blame the Patient

Assessment of Compliance in Clinical Practice • • • Talking to Patient Giving Patient a Questionnaire Checking Pill Containers Electronic Pill Containers Medication Possession Ratio (MPR) Number of days of medication dispensed Number of days between prescription refills

Use of Medication Possession Ratio (MPR) (Cramer et al Int J Clin Pract 2008: 62: 76) • Used prescription dates and renewal dates: Number of days of medication dispensed = MPR Number of days between prescription refills • Reviewed publications on hypertension, diabetes, dyslipidemia, and CHD Main finding: 30% of days ‘on therapy’ were not actually covered by medication • Also: Only 59% of patients had medications for more than 80% of days on therapy

Use of Medication Possession Ratio (MPR) (Cramer et al Int J Clin Pract 2008: 62: 76) • Used prescription dates and renewal dates: Number of days of medication dispensed = MPR Number of days between prescription refills • Reviewed publications on hypertension, diabetes, dyslipidemia, and CHD • Main finding: 30% of days ‘on therapy’ were not actually covered by medication • Also: Only 59% of patients had medications for more than 80% of days on therapy

MECHANISMS

Dietary Potassium Deficiency Is Independently Associated with Increased Blood Pressure in a Multi-Ethnic Population-Based Cohort Susan Hedayati, Abu Minhajuddin, Orson Moe, Chou-Long Huang University of Texas Southwestern Medical Center in Dallas American Society of Nephrology 41 th Annual Meeting Free Communication Session November 8, 2008

Hypothesis ■ Low dietary K+ intake, independent of Na+ intake, is associated with increased blood pressure ■ This association is stronger in African Americans than non-African American counterparts

The Dallas Heart Study ■ Cross-sectional observational study ■ Multi-ethnic, population-based cohort – 50% African American – 17% Hispanic – 50% women ■ 3, 303 subjects with first void urine samples ■ Urine [K+] and urine [Na+]/[K+] ratio were analyzed

Linear Regression of Urine [K+] on Systolic Blood Pressure

Linear Regression of Urine [Na+]/[K+] on Systolic Blood Pressure

Summary ■ Lower urine [K+] and higher urine [Na+]/[K+] ratio correlated with higher BP – Association was independent of demographics, e. GFR and cardiovascular risk factors ■ The magnitude of the association between urine [K+] and BP was greater than between urine [Na+] and BP

Conclusions ■ This analysis supports the hypothesis that dietary K+ deficiency plays an important role in the pathogenesis of HTN, independent of Na+ intake ■ The effect of dietary K+ on HTN may be as important as other cardiovascular risk factors ■ The association between urine [K+] and BP was more pronounced in African Americans, suggesting racial differences in the pathogenesis of HTN

K+ Deficiency Increases WNK 1 Expression Huang CL and Kuo E. Nature Clinical Practice Nephrology 2007; 3(11): 623 -630

Outcomes in Pre-dialysis Populations

Objectives This study was designed to: 1) determine prospectively the relationship of 24 hr ambulatory systolic blood pressure (24 hr SBP), daytime SBP, nighttime SBP and clinic SBP with progression of renal disease as defined by the composite of death, doubling of serum creatinine and dialysis 2) determine the relationship between dipping status and progression of kidney disease 3) compare 24 hr SBP, daytime SBP, nighttime SBP, clinic SBP and dipping status as predictors of kidney disease progression.

BP at Start of AASK Cohort Study 24 hr. SBP 136± 18 mm. Hg Nighttime SBP 134± 21 mm. Hg Daytime SBP 138± 17 mm. Hg Clinic SBP 134± 17 mm. Hg MAP 97± 11 mm. Hg Mean ± SDs are presented

Kaplan-Meier survival curves based on various BP variables 0 10 20 30 0. 2 0. 4 0. 6 0. 8 1. 0 p<0. 001 (94, 126] (126, 140] (140, 200] 0. 0 (84. 9, 128] (128, 142] (142, 197] Kaplan-Meier Curves by Tertiles of Clinic SBP Proportion of Patients w/o Renal Events 0. 2 0. 4 0. 6 0. 8 1. 0 p<0. 001 0. 0 Proportion of Patients w/o Renal Events Kaplan-Meier Curves by Tertiles of 24 -hour SBP 40 Months 50 60 0 10 20 30 40 Months 50 60

Kaplan-Meier survival curves based on various BP variables 0 10 20 30 0. 2 0. 4 0. 6 0. 8 1. 0 p<0. 001 (77. 2, 125] (125, 141] (141, 210] 0. 0 (92. 6, 130] (130, 144] (144, 200] Proportion of Patients w/o Renal Events 0. 2 0. 4 0. 6 0. 8 1. 0 p<0. 001 0. 0 Proportion of Patients w/o Renal Events Kaplan-Meier Curves by Tertiles of Daytime SBP Kaplan-Meier Curves by Tertiles of Nocturnal SB 40 Months 50 60 0 10 20 30 40 Months 50 60

Summary • In the setting of aggressive BP management that focused on clinic BP, our population had markedly elevated nighttime SBP • 24 hr, daytime, nighttime and clinic SBP predict subsequent renal outcomes • Dipping status at baseline did not predict renal outcomes

Conclusion • Continued CKD progression in the setting of controlled clinic BP yet high nighttime BP highlights the need for trials to determine whether reducing nocturnal BP can retard kidney disease progression.

ESCAPE Intensified Blood Pressure Control Slows CKD Progression in Children Undergoing Fixed-Dose ACE Inhibition: Final Results of the ESCAPE Trial Franz Schaefer Division of Pediatric Nephrology Center for Pediatric and Adolescent Medicine Heidelberg University

Primary Objective of ESCAPE Trial To evaluate the renoprotective efficacy of intensified blood pressure control, targeting to low- normal 24 h BP, in children with CKD receiving fixed-dose ACE inhibition ESCAPE

468 patients screened: Age 3 -18 years GFR 15 -80 ml/min/1. 73 m² 24 h MAP > 50 th percentile 6 months ‚run-in‘ ≥ 2 months: ACEi wash-out period Stratification according to baseline progression rate 385 patients: Ramipril 6 mg/m² Randomisation Group A (n=189): ‘intensified’ BP control Target BP < 50 th percentile Group B (n=196): ‘conventional’ BP control Target BP 50 th-95 th percentile Follow-up for 5 years 2 -monthly assessment of renal function, proteinuria. 6 monthly 24 -hour ABPM, annual echocardiographies ESCAPE

Patient Characteristics at Randomization Intensified N=189 Conventional N=196 11. 5 ± 4. 1 11. 5 ± 4. 0 56. 6 62. 2 % Glom. / Hypodyspl. / other 14 / 66 / 20 12 / 71 / 17 24 h MAP 89. 5 ± 10. 3 89. 5 ± 9. 5 1. 53 ± 2. 15 1. 45 ± 1. 61 % on diuretics / CCB / BB 9 / 18 / 24 11 / 15 / 21 Estimated GFR 46. 4 ± 19. 1 45. 4 ± 19. 9 Median GFR loss / yr -2. 4 -3. 6 % progressive 48. 7 52. 0 33/ 18 / 49 41 / 21 / 38 Age % male SDS % UPCR <0. 5/0. 5 -1. 5/ >1. 5

Mean Arterial Pressure [mm Hg] Effect of Interventions on 24 h Blood Pressure 90 conventional 85 * 80 * * * intensified 0 6 12 18 24 30 36 42 48 54 60 Observation Period [Months] ESCAPE *

Renal Survival: Intention To Treat Analysis % patients without endpoint 100 intensified P=0. 013 90 80 conventional 70 60 50 182 190 0 165 163 157 154 1 148 142 139 131 2 128 122 118 113 112 108 3 108 97 4 97 85 80 63 5 Observation Period [years] ESCAPE

Conclusions In children with CKD receiving a high, fixed dose of an ACE inhibitor, renal failure progression can be slowed significantly by intensified blood pressure control targeting to low-normal 24 h MAP. By this intervention, the risk of losing 50% GFR or attaining ESRD within 5 years is reduced by almost 50 % (renal survival 70. 1 83. 6 %). Although more prominent in glomerulopathies, the renoprotective benefit from intensified BP control is also significant in children with hypo/dysplastic kidney disease. Ongoing or recurrent proteinuria is a risk factor for progressive renal failure even with excellent BP control.

Systolic Blood Pressure and Carotid Intima-Media Thickness Progression in Chronic Kidney Disease Patients Jessica Kendrick MD 1, Michel Chonchol MD 1, Hannes Gnahn MD 2, Dirk Sander MD 3 1 University 2 INVADE of Colorado at Denver Health Sciences Center, Aurora, CO, U. S. Study Group, Ebersberg, Germany 3 Technical University of Munich, Germany

Hypothesis We tested the hypotheses that participants with a SBP <120 mm. Hg with or without CKD, would have less progression of carotid IMT and fewer cardiovascular events than participants with a SBP >120 mm. Hg

Methods Intervention Project on Cerebrovascular Diseases and Dementia in the Community of Ebersberg, Bavaria Prospective, population-based study in the elderly Established in 2001 Subjects followed for 4 years Sander D et al. Stroke 2006; 37: 351 -357

Baseline Carotid IMT According to Baseline SBP and Kidney Function Carotid IMT (mm) *Fully Adjusted, p=0. 001 for trend *Adjusted for age, sex, body mass index, smoking, prevalent ischemic heart disease and stroke, cholesterol, LDL-C, Hb. A 1 c, hs-CRP, homocysteine and usage of anti-hypertension medications, aspirin and statins. The covariate adjusted

Baseline Characteristics Characteristic NO CKD 83 ± 18 m. L/min/1. 73 m 2 N=2640 CKD 50 ± 9 m. L/min/1. 73 m 2 N=724 P-value 65 ± 6. 6 74 ± 7. 6 <0. 001 Diabetes N (%) 266 (18. 2) 195 (27. 0) <0. 001 Hypertension N(%) 1394 (52. 8) 518 (71. 6) <0. 001 251 (9. 5) 169 (23. 3) <0. 001 1375 (52. 1) 519 (71. 7) <0. 001 137 ± 18 139 ± 18 0. 016 Age (years) Ischemic Heart Disease N (%) Use of antihypertensive medications N(%) Baseline SBP (mm. Hg)

Carotid IMT Progression According to Baseline SBP and Kidney Function Carotid IMT (mm/year) *Fully Adjusted, p=0. 003 for trend *Adjusted for age, sex, body mass index, smoking, prevalent ischemic heart disease and stroke, cholesterol, LDL-C, Hb. A 1 c, hs. CRP, homocysteine, usage of anti-hypertension medications, aspirin and statins and baseline carotid IMT. The covariate

Vascular Events According to SBP and Kidney Function SBP≤ 120 mm. Hg/CKDSBP>120 mm. Hg/CKDSBP≤ 120 mm. Hg/CKD+ SBP>120 mm. Hg/CKD+

Conclusions A SBP >120 mm. Hg is associated with greater carotid IMT progression and an increased risk of vascular events regardless of the presence or absence of CKD In subjects with and without CKD a SBP > 130 mm. Hg predicts vascular events In subjects with and without CKD a SBP < 120 mm. Hg had similar magnitude in the association with vascular events although it did not reach statistical significance Large randomized trials are needed to confirm the optimal SBP target in CKD patients

Digoxin Immune FAB Ovine (Digibind®) Administration in Severe Preeclampsia Reduces the Decline in Creatinine Clearance: Results of the DEEP Trial V. M. Buckalew MD, Wake Forest University School of Medicine; T. M. Danoff MD, Ph. D, Glaxo. Smith. Kline; C. D. Adair MD, Glenveigh Research; S. W. Graves Ph. D, Brigham Young University; and N. Chauhan Ph. D, Protherics PLC; for the DEEP Trial Investigators

Digibind Efficacy Evaluation in Preeclampsia (DEEP) Trial • Investigator initiated, industry sponsored, multicenter pilot trial • Randomized, double blind, placebo controlled • 51 patients enrolled (24 Digibind, 27 placebo) at eight US clinical centers • Clinical. Trials. gov (Registration # NCT 00158743).

Trial Hypotheses • Increased EDLF levels in severe PE cause maternal vasoconstriction contributing to: – Increased blood pressure – Decreased renal hemodynamics • Binding of EDLF by Digibind® would: – Improve renal function – Decrease need for antihypertensive drugs

DEEP Trial Design Cr. Cl baseline

Primary End Point (2) • Use of antihypertensive drugs composite* – Initiation of antihypertensive treatment – For patients already on antihypertensives: change in dose, addition of new drug, or delivery required due to failure to control hypertension *2 -sided test, P <0. 05, & 80% power to detect difference of 35 percentage points between groups requires 25 patients/group

Primary Efficacy Variable - Change in Cr. Cl (6 patients excluded) Difference: 31 m. L/min (95% CI 5 to 58 m. L/min)

Summary and Conclusions • Cr. Cl declined significantly just prior to delivery in • • • women who received placebo The decline was prevented by Digibind administration Digibind reduced the sodium pump inhibitory activity of serum from patients with PE The results support the hypothesis that renal vasoconstriction in severe PE is due in part to increased circulating EDLF

DIABETIC NEPHROPATHY

Diabetologia 2004; 47(11): 1936 -9 • Significantly enhanced rate of GFR decline in breakthroughs compared to non-breakthroughs • 5 ml/min/year vs. 2. 4 ml/min/year

Change in serum aldosterone during RAAS blockade Aldosterone Breakthrough + Aldosterone breakthrough 0 - 6 months Expected decline in aldosterone on ACE-I and/or ARB therapy. 12 months

Twenty-Four Hour Urinary Protein Excretion in Subjects with Resistant Hypertension Pimenta, E. et al. Hypertension 2008; 51: 339 -344

Effects on Blood Pressure and GFR • Blood Pressure » In 6/15 studies, MRB therapy significantly reduced blood pressure » (+) Brought subjects who were not at goal blood pressure for proteinuric CKD either to goal or much closer to goal » (-) Some of the proteinuria reductions could be attributed to blood pressure reduction • Renal Function » “Significant” ↓ GFR in 4/15 studies » Did not change CKD stage (e. g. , e. GFR 74 67) » May reflect short-term, physiologic response to higher RAAS blockade » Some of the proteinuria reductions could be due to GFR reduction Bomback AS, Kshirsagar AV, Amamoo MA, Klemmer PJ. Change in proteinuria after adding aldosterone blockers to ACE inhibitors or angiotensin receptor blockers in CKD: a systematic review. Am J Kidney Dis. 2008; 51(2): 199 -211

Hypotheses § Addition of either an ARB or a MRA to a maximally-dosed ACEi-based regimen will afford greater renoprotection than the ACEi-based regimen alone. § Added value of a MRA is specific for aldosterone and is not explained solely on the basis of reduced time-integral blood pressure burden. §

Randomized Double-Blind Placebo-Controlled Trial Double-Blind Run-in W/O Lisinopril 80 mg daily and SBP goal <130 mm. Hg Placebo daily Two 24 -hour urine UACR > 300 mg/g at end of run-in Losartan 100 mg daily Spironolactone 25 mg daily * -4 -2 0 * 12 24 36 * * 48 52 Weeks * Inpatient CTRC : 24 hour ABP, creatinine clearance and urine albumin/creatinine ratio

Urine Albumin Creatinine Ratio (Median % change from baseline) * P = 0. 04 vs baseline * P < 0. 001 vs baseline † P = 0. 007 spironloactone vs placebo -13. 5% -27% * -51% † * 27 26 27 22 23 20 21 21 17 21 18 17

24 -Hour Systolic Blood Pressure (Median % change from baseline) No. of subjects 27 26 27 22 23 20 21 21 17 21 18 17

Creatinine Clearance (Median % change from baseline) No. of subjects 27 26 27 22 23 20 21 21 17 21 18 17

Serum Potassium Concentration (mean) Spironolactone vs Placebo, p < 0. 001 Losartan vs Placebo, p = 0. 03 Spironolactone vs Losartan, p = 0. 05 Mean serum K 5. 0 (0. 51) 4. 7 (0. 33) 4. 5 (0. 38)

Conclusions • Addition of spironolactone, afforded greater renoprotection than a maximallydosed ACEi-based regimen. • Added value of spironolactone is not explained solely on the basis of reduced time-integral (24 -hour) blood pressure burden.

Efficacy and Safety of the Endothelin Receptor Antagonist Avosentan in Diabetic Nephropathy Viberti GC, Mann JFE, Jamerson K, Ruilope L, Marshall SM, Erhardt LR, Ford I, Littke T, Lindhe J, Kuranoff S for the ASCEND Study Group King’s College London School of Medicine King’s College London, UK

ASCEND: Study Design § Randomised, double-blind, placebo-controlled, parallel group, multi-centre study, investigating the use of avosentan on top of RAS blockade in type 2 diabetes with nephropathy § Sample size calculation: to detect a risk reduction of 25% for 25 mg vs placebo and 30% for 50 mg vs placebo with a 90% power at α=0. 01 at 36 months required 747 events and resulted in a sample size of 788 patients per group

ASCEND: Study Design Randomization Double blind treatment phase Placebo group Screening Run in 2 wk 25 mg avosentan group 0 42 Assessments: monthly for safety 2 monthly for efficacy 50 mg avosentan months group

* ** 105 89 25 mg *p<0. 001 173 167 165 167 161 100 * 89 50 mg ACR change from baseline (%) ACR (mg/mmol) ASCEND: Absolute and Percent Median (IQ range) Albumin/Creatinine Ratio Changes placebo 0 Months 3 Months 6 Months -8 -10 -38 -41 -44 -49 * * 25 mg 50 mg placebo

ASCEND: Frequency of CHF and Fluid Overload * Ratio of patients without CHF/FO % Patients with CHF/fluid overload 1. 0 * 0. 9 0. 8 0. 7 0. 6 0. 5 0. 4 0. 3 Placebo Avosentan 25 mg Avosentan 50 mg 0. 2 0. 1 0. 0 (n=455) (n=479) * p<0. 01 vs placebo (n=461) No. at risk: 25 mg 455 50 mg 478 Placebo 459 2. 0 4. 0 Time (months) 6. 0 299 325 364 177 179 215 225 230 268

Renal Mechanisms of Fluid Retention Induced by the Endothelin Receptor Antagonist Avosentan in healthy subjects J. Smolander, M. Maillard, B. Vogt, T. Littke, T. Hengelage and M. Burnier Department of Nephrology and Hypertension Centre Hospitalier Universitaire Vaudois of Lausanne, Switzerland

Introduction • Endothelin-1 (ET-1) is a potent vasoconstrictor agent which affects renal function • ET-1 functions in a paracrine and autocrine manner - ETA receptors: a) vasoconstriction and growth-promoting functions - ETB receptors: a) vasodilation and inhibition of growth and inflammation (NO, prostacyclin) b) natriuresis, diuresis • ETA receptor blockade may be useful to lower proteinuria • Fluid overload is a known adverse effect of endothelin receptor antagonists

Objective of the study To investigate the acute and sustained effects of increasing doses of the ETA receptor antagonist avosentan on: – Renal and systemic hemodynamics – Renal sodium handling and fluid retention

Study design • Open-label, placebo-controlled, randomized two-period cross-over study • 23 healthy subjects • Oral doses of 0. 5 mg, 1. 5 mg, 5 mg or 50 mg once daily • N = 8 -9 per dose

Clinical parameters • Body weight, blood pressure, heart rate • Clinical chemistry and haematology • Renal hemodynamics (inulin / PAH, creatinine) • Urinary electrolytes (Na+, K+, endogenous Li+)

Effect of increasing doses of avosentan (SPP) on fractional excretion of sodium Day 1 Day 8 D FENa (6 h-baseline) 1. 5 1 1 0. 5 0 0 Placebo SPP 0. 5 N= 8 -9 per group SPP 1. 5 SPP 50 Placebo p for trend <0. 05 SPP 0. 5 SPP 1. 5 SPP 50

Effect of increasing doses of avosentan (SPP) on proximal reabsorption of sodium Day 1 Day 8 D PRNa (6 h-baseline) (%) 12 12 10 10 8 8 6 6 4 4 2 0 2 -2 0 -4 Placebo SPP 0. 5 SPP 1. 5 SPP 50 -2 Placebo p for trend <0. 01 SPP 0. 5 SPP 1. 5 SPP 50

Effect of increasing doses of avosentan on body weight * 2. 5 2. 0 * 1. 5 Delta BW (kg) 1. 0 0. 5 0. 0 -0. 5 -1. 0 -1. 5 -2. 0 Placebo * 0. 5 mg 1. 5 mg 50 mg max Mean and median significantly different from 0 (one sample t-test and Wilcoxon signed-rank test) 75% percentile median 25% percentile min

Conclusions • Avosentan causes : Ø peripheral vasodilation (decrease in DBP, headache) Ø fluid retention and edema by increase in (proximal) salt and water retention by the kidney in healthy subjects • This effect is dose-dependent and predominates at higher doses probably due to a lack of receptor selectivity at these high doses • Avosentan fluid retention and edema are most likely not cardiac in origin • These data support further investigation of the anti-proteinuric effect of avosentan in diabetic kidney disease at doses of 5 mg/d and below

LITERATURE REVIEW

- Literature Review Hypertension and CKD “The Good, The Bad and The Ugly” Karen A. Griffin, M. D. Professor of Medicine Loyola University Medical Center Renal Section Chief Edward Hines, Jr. VA

“The Bad” AASK Cohort Study Event Rates per 100 Person-Years (Doubling of Serum Creatinine, ESRD or Death) 7. 2 ACE-I (40 -50%) 136/82 mm. Hg Event Rates per 100 Person-Years (Doubling of Serum Creatinine, ESRD or Death) 7. 8 ACE-I (85 -90%) 133/78 mm. Hg Appel LJ, et al. Arch Intern Med 2008; 168(8): 832 -839

Limitations of the Cohort Study l “AASK trial phase and the cohort study adjusted antihypertensive therapy based on traditional office BP readings rather than on ambulatory BP readings. ” l “Sustained nocturnal BP, which cannot be detected by office measurements, is commonplace in the setting of CKD and may lead to rapid CKD progression. ” Appel LJ, et al. JAMA 2008; 168(8): 832 -839

CKD PROGRESSION IN AFRICAN-AMERICANS GENETIC FACTORS Kopp, et al: MYH 9 is a major-effect risk gene for focal segmental glomerulosclerosis. Nature Genetics 2008; 40: 1175 -1184 Kao, et al: MYH 9 is associated with nondiabetic end-stage renal disease in African Americans. Nature Genetics 2008; 40: 1185 -1192 Freedman BI, and Sedor JR: Hypertension-associated kidney disease: Perhaps no more. J Am Soc Nephrol 2008; 19: 2047 -2051

Effect of ACEI+ARB vs ACEI Alone on Proteinuria Mac. Kinnon et al. Am J Kidney Dis 2006; 48: 8 -20, Doulton T, et al. Hypertension 2005; 45: 880 -886, Kunz R, et al. Ann Intern Med 2008; 148: 30 -48, Catapano F, et al. AJKD 2008; 52(3): 475 -485

Net Change in Ambulatory SBP and Clinic SBP for ACE-ARB Combination versus ACE-I Alone Doulton T, et al. Hypertension 2005; 45: 880 -886, Mac. Kinnon et al. Am J Kidney Dis 2006; 48: 8 -20, Kunz R, et al. Ann Intern Med 2008; 148: 30 -48, Catapano F, et al. AJKD 2008; 52(3): 475 -485 Copyright © 2005 American Heart Association

ONTARGET: Key Results Number of Patients: Ramipril 8, 576; Telmisartan 8, 542; Combination 8, 502 Outcome Risk ratio (95% CI), telmisartan vs ramipril P Risk ratio (95% CI), combination therapy vs ramipril P CV death/MI/ stroke/ CHF hospitalization CV death/MI/strokea 1. 01 (0. 94– 1. 09) NS 0. 99 (0. 92– 1. 07) NS 0. 99 (0. 91– 1. 07) NS 1. 00 (0. 93– 1. 09) NS Renal Impairmentb 1. 04 (0. 96 -1. 14) NS 1. 33 (1. 22 -1. 44) 0. 001 a. Primary end point in the HOPE trial; b. Secondary Outcome Yusuf S et al. N Engl J Med 2008: 358: 1547 -1559. ONTARGET: Renal Outcomes All dialysis, doubling, death 1. 00 (0. 92 -1. 09) NS 1. 09 (1. 01 -1. 18) 0. 037 All dialysis and doubling 1. 09 (0. 89 -1. 34) NS 1. 24 (1. 01 -1. 51) 0. 038 Mann JF et al. Lancet 2008; 372: 547 -553

ONTARGET: Renal Outcomes Outcome Δ BP (mm. Hg) Ramipril Telmisartan - Combination - 0. 9 -2. 4 P ? e. GFR (ml/min/1. 73 m 2) -2. 82 (17) -4. 12 (17) -6. 11 (17) UACR (mg/mmol) 1. 32 1. 25 1. 22 <0. 0001 0. 0028 Adverse Effects Hyperkalemia Hypotension 283 (3. 3) 149 (1. 7) 287 (3. 4) 480 (5. 6) 229 (2. 7) 406 (4. 8) ARF 60 (0. 7) 68 (0. 8) 94 (1. 1) 0. 001 Acute dialysis 13 (0. 15) 20 (0. 23) 28 (0. 33) 0. 02 0. 001 Mann JF et al. Lancet 2008; 372: 547 -553 Phillips CO et al. Arch Intern Med 2007; 167: 1930 -1936

Proteinuria Grams/24 hour Mean BP, mm. Hg Blunting of Antiproteinuric Efficacy of ACE Inhibition by High Sodium Intake can be Restored by HCTZ 50 mmol 200 mmol 50 mg Buter H, et al. Nephrol Dial Transplant 1998; 13: 1682 -1685 Vogt L, et al. J Am Soc Nephrol 2008; 19: 999 -1007

Preventing Renal Disease Progression -Therapeutic Principles- • Achieving BP goals – normotension around the clock (Home BP monitoring supplemented by ABPM) l Requires adequate use of diuretics l RAS Blockade Synergistic with diuretics – Minimize potassium and magnesium losses – Counteracts pro-hyperglycemic effects of diuretics – Effective and well-tolerated – l Calcium Channel Blockers -Ensure normotension -Monitor proteinuria