Johan Rosman Renal Physician and CMO Specialist in Hypertension Waitemata DHB, and Apollo Centre, Albany Omapere, October 09

A fascinating animal for BP research Why does a giraffe not faint ? Has a heart of 15 kilo’s Has twice the human blood pressure Has a very interesting autonomic nerve system Has a large number of pressure sensors in his carotid arteries Has a different R A A System, poorly understood

What maintains our normal BP ? Intravascular volume Autonomic nervous system Renin Angiotensin Aldosterone System (RAAS) Vascular mechanisms The 2 determinants of BP are Cardiac output Peripheral resistance

 - Blockers ACE Inhibitors AT 1 Blockers Direct renin inhibitors  1 -Blockers  2 -Agonists All CCBs Diuretics Sympatholytics Vasodilators  -Blockers Non-DHP CCBs Diuretics BloodPressure = Cardiac Output  ACE = angiotensin-converting enzyme; AT 1 = angiotensin type 1; CCBs = calcium channel blockers; DHP = dihydropyridine Antihypertensive Drug Classes: Action Sites Total Peripheral Resistance Antihypertensive Drug Classes

Yogi Berra Future antihypertensive treatment:

Importance of BP control

Hypertension - causes 90 % ‘essential hypertension’ 10 % ‘secondary hypertension’ (probably underestimated Of these 10% probably 8% renal artery stenosis (RAS) Important to make the distinction !

Suggestive of sec hypertension Severe or refractory hypertension. An acute rise in blood pressure over a previously stable value. Proven age of onset before puberty. Age less than 30 years in non-obese, non-black patients with a confirmed negative family history of hypertension

Case study Mrs G is a 54 year old lady with diabetes, moderately controlled on oral antidiabetics She was always normotensive, but recently you find bloodpressures of 190/105 with a normal pulse rate You prescribe an ACE inhibitor, as she is also proteinuric with 3.4 g/L of proteinuria For oedema she is treated with frusemide 40 mg OD Three weeks later you get a call that she is in hospital with acute renal failure What happened ?

MRA Gadolinium-enhanced

Case study Mr. C, 79 years old, known with prostate carcinoma Since 6 months worsening hypertension and proteinuria MRA and isotope nephrography requested

Case study Mr. C, 79 years old, known with prostatecarcinoma Since 6 months worsening hypertension and proteinuria MRA and isotope nephrogram: virtually occluded left renal artery Would you give this man an ACE inhibitor ?

ACE Inhibition and RAS

IT STARTS HERE :

Who should be screened for RAS ? (1) Onset of hypertension before the age of 30 years, particularly if there is a negative family history and no other risk factors for hypertension (eg, obesity). Onset of severe hypertension ( ≥160/100 mmHg) after the age of 55 years. Refractory or resistant hypertension, in a patient adhering to therapeutic doses of three appropriate antihypertensive agents (including a diuretic) Acute rise in blood pressure over a previously stable baseline in patients with previously well-controlled hypertension (and includes patients with known renal artery stenosis who may have worsening stenosis) Malignant hypertension (eg, patients with severe hypertension and signs of end-organ damage)

Who should be screened for RAS ? (2) Moderate to severe hypertension in a patient with an unexplained atrophic kidney or asymmetry in renal sizes of >1.5 cm. Moderate to severe hypertension in patients with diffuse atherosclerosis, particularly those over age 50. Moderate to severe hypertension in patients with recurrent episodes of acute (flash) pulmonary edema or otherwise unexplained heart failure. An acute elevation in the plasma creatinine concentration that occurs after the institution of therapy with an angiotensin converting enzyme (ACE) inhibitor or angiotensin II receptor blocker (ARB).

Advantages of blocking RAAS Possible by blocking Angiotensin Converting Enzyme Possible by directly blocking the angiotensin II receptor Excellent blood pressure lowering Cardioprotective Reduction of stroke Renoprotective Reducing renal protein loss Reduces incidence of diabetes

Renal haemodymacical consequences of ACE and ARB Draw on board

Antihypertensive and Antiproteinuric Responses to an Increasing Dose of an Angiotensin-Converting Enzyme Inhibitor* Palla R, et al. Int J Clin Pharmacol Res. 1994;14: % Reduction from Control Blood Pressure Urine Protein 5 mg10 mg15 mg20 mg Lisinopril Dose

Relative Risk Reduction With ACEIs in ABCD, CAPPP and FACET % relative risk reduction Pahor M, et al. Diabetes Care. 2000;23: Acute Myocardial Infarction Cardiovascular Event Stroke All-cause Mortality P<0.001 P=0.01 NS

Angiotensin II Receptor Blockers No generalised effects, sits directly on the receptor It does not have a systemic effect (bradykinin/kallikrein), still works as good as ACE Effects and benefits comparable to ACE inhibitors Similar cardio- and renoprotection Like ACE, reduces risks beyond just BP reduction However significantly less side effects (as only AH agent comparable to placebo !) ARB’s reduce risk of new onset diabetes

Antiproteinuric effects of AT 1 RB

What is better: block ACE or AR ? ( here given in same patient)

The Reduction of Endpoints in NIDDM With the Angiotensin II Antagonist Losartan Study RENAAL Overview Randomized multicentre, double-blind, placebo-controlled study to evaluate the renal protective effects of the angiotensin II receptor antagonist losartan in patients with type 2 diabetes and nephropathy Population 1,513 patients (31 to 70 years old) Diagnosed type 2 diabetes and nephropathy albumin/creatinine ratio  300 mg/g serum creatinine between 1.3–3.0 mg/dL (1.5–3.0 mg/dL for men >60 kg) Brenner BM, et al. N Engl J Med. 2001;345(12):

RENAAL Summary of Important Findings In patients with type 2 diabetes and nephropathy: Losartan, in combination with other antihypertensive therapy (non- ACE or ARB), delayed the onset of the primary composite endpoint* (P=0.02) and delayed progression to end stage renal disease (P=0.002) Losartan reduced proteinuria (P<0.001) and the rate of decline in renal function (P=0.01) Losartan reduced the incidence of first hospitalization for heart failure (P=0.005) These benefits were above and beyond those attributable to blood pressure reduction alone *Composite of a doubling of serum creatinine, end stage renal disease, or death Brenner BM, et al. N Engl J Med. 2001;345(12):

Yogi Berra Future antihypertensive treatment:

Reprinted from Bakris GL, et al. Am J Kidney Dis. 2000;36(3): with permission from National Kidney Foundation. Start ACE inhibitor titrate upwards If BP still not at goal (130/80 mm Hg) BP still not at goal (130/80 mm Hg) Baseline pulse <84 Add low-dose beta blocker or alpha/beta blocker Add other subgroup of CCB (ie, amlodipine-like agent if verapamil or diltiazem already being used and the converse) Refer to a clinical hypertension specialist BP still not at goal (130/80 mm Hg) If BP goal achieved, convert to fixed dose combinations (ACE inhibitor + CCB or ACE inhibitor + diuretic) Baseline pulse  84 Add Thiazide Diuretic or long-acting CCB* Blood pressure >130/80 mm Hg *If proteinuria present (>300 mg per day) non- DHP preferred.

Diabetes: Tight Glucose vs Tight BP Control and CV Outcomes in UKPDS Stroke Any Diabetic Endpoint DM Deaths Microvascular Complications % Reduction In Relative Risk Tight Glucose Control (Goal <6.0 mmol/l or 108 mg/dL) Tight BP Control (Average 144/82 mmHg) 32% 37% 10% 32% 12% 24% 5% 44% * * * * *P <0.05 compared to tight glucose control Bakris GL, et al. Am J Kidney Dis. 2000;36(3): Reprinted by permission from WB Saunders.

Yogi Berra Is two better than one ?? Modern EBM decision making:

The COOPERATE Trial 260 patients with non-diabetic renal disease Randomly assigned to 100 mg losartan, or 3 mg trandolapril or combination Endpoint: doubling of serum creatinine (loss of renal function) Secondary point: proteinuria

The COOPERATE trial, con’t

Interesting recent article Stuart L. Linas: Are two better than one? ACE Inhibitors plus ARB for reducing blood pressure and proteinuria in kidney disease. Clin J Am Soc Nephrol 3: S17-S23, 2008 Concluded: Many smaller combo trials now done Potential safety issues (hypothetical): hyper-K, loss of renal function in advanced stages Strong individual differences, race differences, dose finding issues Strongest effect on proteinuria, how this translates to slowing the progression of renal function loss still unclear, despite COOPERATE (COOPERATE had many design flaws) and ONTARGET No benefit on other outcomes (cardiovascular, stroke etc)

Yogi Berra Future antihypertensive treatment:

New drugs classes Renin inhibitors: Aliskiren AVOID trial: 600 patients with proteinuriac diabetic nephropathy Randomly assigned to Losartan monotherapy and Aliskiren plus Losartan The combination treatment gave an additional 20% reduction in proteinuria No additional serious side effects

The key to good care Communication 021- KIDNEY ( )

(Henry Kissinger, 1976)