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With the last-minute addition of the highly controversial JNC8, this pressure-packed bracket now appears to be one of the most competitive in the tournament. Much anticipated dream matchups included in the first round pit thiazide vs thiazide (HCTZ vs Chlorthalidone), manometry reading vs manometry reading (Systolic vs Diastolic), and guidelines vs guidelines (KDIGO vs JNC8) in nonstop pulsating action. Perennial fan favorite and systemically dominant ACEi/ARB leads the way, but with a stroke of luck there very well could be a Cinderella team emerging from this bracket.

Selection committee member for the Kidney Regeneration Bracket:

George L. Bakris, MD
Professor of Medicine
Director, ASH Comprehensive Hypertension Center
University of Chicago

Dr. Bakris currently serves as an Expert Consultant to the FDA Cardio-Renal Advisory Board and to CMS (Renal Medicare and Medicaid program). He has served on the JNC 6 and 7, ADA and the National Kidney Foundation (KDOQI) blood pressure and diabetes guideline committees. He is the immediate past-president of the American Society of Hypertension. He has published over 600 peer-reviewed publications in the areas of hypertension and diabetic nephropathy as well as 12 Books in the area of hypertension and diabetic kidney disease. He is the editor of American Journal of Nephrology and the hypertension, section editor of UpToDate, as well as an associate editor of Diabetes Care and Hypertension Research.

Meet the competitors for the Hypertension Bracket!

(1) ACE-I/ARB Combination versus (8) Renal Artery Interventions

This is a bracket of two major disappointments, both teams came in with huge expectations and have fallen flat on their faces. These chumps made it to the dance on reputation and expectations alone.

ACEi/ARB  Combination Therapy

ACEi/ARB are the Gonzaga Bulldogs, 16 straight years in the tournament and they never made it past the Sweet 16. Combination therapy with ACE inhibitors (ACEi) and Angiotensin-receptor blockers (ARBs) have individually been shown to decrease proteinuria and prolong renal survival in proteinuric renal disease. However, neither agent can completely block the renin-angiotensin-aldosterone system (RAAS), and studies have shown that various combinations of dual RAAS blockade using ACEi, ARBs, mineralocorticoid-receptor antagonists, and direct renin inhibitors lead to decreased blood pressure and albuminuria. This led to the hypothesis that patients with type 2 diabetes and proteinuria may benefit from combination therapy to slow CKD progression.

Three important studies (ONTARGET, ALTITUDE, and VA NEPHRON D) failed to demonstrate renal and/or cardiovascular benefits from such combination regimens, and instead showed increased adverse events, primarily hyperkalemia, acute dialysis and hypotension. In fact both ALTITUDE and VA NEPHRON D were terminated early due to  lack of  benefit and higher risk of adverse events with dual therapy.

• ACEi with ARB is harmful.
• ARB or ACEi with renin inhibitor is harmful.

Should we be hesitant to also use ACEi or ARB with aldosterone antagonists? Though this promises the benefits as the above combination therapies, reduced proteinuria and blood pressure does it also have the same risks? This has been examined to some degree in the RALES Trial. This landmark study demonstrated the advantage of spironolactone in the treatment of heart failure. In the 822 patients treated with spironolactone (12.5-25 mg daily) there was no increase in potassium over 6 (10 with placebo and 14 with spironolactone). Potassium on average went up by only 0.3 mmol/L and serum creatinine rose by between 0.05 and 0.1 mg/dL. For the purpose of investigating the safety of combined ACEi and aldosterone antagonists, 95% of the spironolactone cohort was concurrently treated with ACEi.

The Library of Celsus in Ephesus, Turkey by Neil Howard

The EPHESUS trial of eplerenone for heart failure following an acute MI provides further data on this combination. In EPHESUS 86% of the aldosterone antagonists arm was on concurrent ACEi. The patients had excellent renal function with average creatinine clearance of 79 mL/min. Use of eplerenone caused an increase in hyperkalemia (180 cases vs 126 with placebo, P=0.002) and an increase in hospitalization for hyperkalemia (12 in the eplerenone group and 3 in the placebo group). The authors found this association with renal function:

In regard to eplerenone’s effect on serum creatinine was only 0.06 mg/dL after 12 months (0.02 in the placebo arm; P<0.001).

There is some suggestion that the incidence of hyperkalemia with combination therapy may vary with race, eg, with blacks with heart failure exhibiting less hyperkalemia and more hypokalemia with spironolactone.

Renal Artery Therapies

The Fab Five by Skoch3.

Renal artery therapies for the purpose of this entry are renal artery revascularization and renal denervation. Collectively they play the role of The University of Michigan’s Fab Five. A lot of hype but in the end they never won anything. No Big 10 championships, two trips to the NCAA finals but no rings.

Revascularization

Revascularization of RAS is done to preserve renal function and correct renal vascular hypertension in the presence of critical renal artery stenosis. It has also been proposed as a treatment of serious conditions as flash pulmonary edema. Several studies (ASTRAL, CORAL)  have shown that renal artery revascularization carried substantial risk and was not associated with any benefit with respect to renal function, blood pressure, renal or cardiovascular events, or mortality

However, a number of retrospective studies have shown a significant improvement in a few patients. For instance, a recent study supports guidelines citing flash pulmonary edema as an indication for renal artery revascularization in atherosclerotic renovascular disease, suggesting that patients presenting with a combination of rapidly declining kidney function and refractory hypertension may benefit from revascularization and may represent a subgroup worthy of further investigation in clinical trials. The challenge is to identify the subgroup of patients if any who benefit from renal artery revascularization.

Renal Denervation

In the 1950s, thoracolumbar sympathectomy (in which sympathetic nerve trunks and splanchnic nerves were destroyed), was utilized to control BP in patients with malignant hypertension. Fraught with intolerable side effects such as postural hypotension, erectile dysfunction, and syncope, this procedure was largely abandoned. In 2009, a proof of principle study utilizing a novel, catheter-based, technique for renal sympathetic denervation for treatment of resistant hypertension was published.

The rationale for this procedure is based on the premise that the sympathetic nervous system plays a major role in initiating and sustaining hypertension, as sympathetic nerves supply the the kidneys’ efferent and afferent renal arterioles,  juxtaglomerular apparatus, and tubules. Enhanced sympathetic activity in chronically hypertensive individuals is believed to play a role in subsequent target-organ damage. Riding on the encouraging findings of SYMPLICITY-1 and SYMPLICITY-2, in terms of BP control and safety, SYMPLICITY-3 (billed as the most rigorous of all renal denervation trials) brought much bravado only to be derailed in January 2014, when it failed to show a sustained reduction in systolic BP.

Another recently published study suggested that adjusted pharmacologic treatment may have superior BP-lowering effects as compared to renal denervation in patients with true treatment resistant hypertension (after excluding those who are noncompliant with pharmacologic treatment), thereby further questioning its value.

On the other hand, it has to be noted that in the SIMPLICITY trials, despite the failure to further reduce BP, no safety issues arose, thereby suggesting that although the catheter device may have been ineffective, there may still be some potential role in conditions characterized by hyperactivity of the sympathetic nervous system, such as heart failure, obstructive sleep apnea, arrhythmias, etc.

(3) Systolic Blood Pressure versus (6) Diastolic Blood Pressure

Since the JNC7 hypertension guidelines were published in 2003, there has been the natural tendency to consider SBP as a much more potent risk factor for coronary artery disease than DBP. For one thing, it has been known that SBP increases steadily with age, while DBP increases until around age 55 then it begins to decline. Age-related changes in blood pressure are naturally brought about by a generalized increase in arterial stiffness due to gradual replacement of elastin by collagen in the large arteries. Pulse pressure also increases with age. A wide pulse pressure is a marker of arterial stiffness that is also associated with increased adverse outcomes.

However, 2 studies have demonstrated a J-shaped association of BP with mortality in older adults, those with pre-existing CAD, and those with non-dialysis dependent CKD. So is lowering the BP (in the above groups) beneficial by dropping the SBP to a safer target or is it harmful because concomitant decreases in DBP are associated with higher mortality rates. This is a serious dilemma that is particularly common in CKD, where elevated SBP frequently pairs with a low DBP.

Agarwal showed that different levels of SBP and DBP have disparate effects on mortality and ESRD in patients with CKD:

• A lower SBP and DBP was associated with better ESRD outcomes
• SBP of less than 110 and DBP less than 70 was associated with increased all-cause mortality
• SBP over 170 mmHg was associated with greater mortality
• The worst outcomes were seen in patients with high SBP and lower DBP

Even the JNC 7 and 8 Guidelines recognize that this is a great match up: although DBP control was more important than SBP control for reducing CV risk in patients over age 60, SBP control remains as the most important factor.

Systolic blood pressure

The SBP supporters emphasize the predominant effect of SBP on risk of CKD progression. In a recently published study, higher SBP was independently associated with higher ESRD risk among persons with established CKD. This risk started at SBP of 140 mm Hg and it was highest among those with SBP of at least 150 mm Hg. The authors also demonstrated that (after accounting for SBP) PP was not independently associated with ESRD risk; most of the wide PP was a result of high SBP rather than low DBP. One study showed that whereas SBP and PP are closely related independent CVD risk factors that yield similar diagnostic and prognostic information, SBP is more robust when compared to DBP as a CVD risk factor.

Diastolic blood pressure

DBP has also been associated with increased mortality. In older individuals in particular, especially those with CKD, as well as those on hemodialysis, low DBP has been shown to be associated with increasing mortality, eg, future CHD.

It has been suggested that the J-shaped association of blood pressure with outcomes could be due to compromised blood flow to vital organs (especially low DBP compromising coronary perfusion) or due to confounding by the presence of stiff arteries or the high burden of comorbid conditions (for example, CHF). Kovesdy et al reported that categories of lower SBP-DBP combinations are associated with lower mortality rates only as long as the DBP component remains greater than approximately 70 mm Hg and that patients with BP in the range of 130 to 159/70 to 89 mm Hg had the lowest mortality rates.

(4) Hydrochlorothiazide versus (5) Chlorthalidone

Hydrochlorothiazide

Thiazide diuretics act by inhibiting the NaCl transporter in the distal convoluted tubules. They were the first antihypertensive agents whose use led to decreased cardiovascular morbidity and mortality in placebo-controlled clinical trials. Furthermore, they are well-tolerated. Discovered in the late 1950’s, thiazides have remained at the forefront of blood pressure management. Hydrochlorothiazide and chlorthalidone were the initial thiazides approved, in 1960, for the treatment of hypertension. For many years they were considered to be interchangeable. However, recently, controversy has been heating up.

When the VA Cooperative Studies on the Treatment of Hypertension were begun in the 1960s, hydrochlorothiazide was the diuretic of choice in both clinical medicine and large research trials. In fact, it was subsequently combined with various classes of antihypertensive agents because of its widespread utility. One study showed lesser incidence of electrolyte abnormalities, eg, hypokalemia, as compared with chlorthalidone.

In a recently published study looking at prevention of calcium containing kidney stones, hydrochlorothiazide was the most frequently prescribed thiazide diuretic, perhaps because it has been a perennial crowd favorite.

Chlorthalidone

Since 2004, several studies have raised the possibility of superiority of chlorthalidone over hydrochlorothiazide, in terms of reducing cardiovascular events, (MRFIT, SHEP, VHAS and ALLHAT among others). This effect is thought to be due to chlorthalidone having longer half-life and stronger efficacy. In one study of patients with resistant hypertension, where a more potent diuretic is particularly required, chlorthalidone was chosen for only 3% of the patients. In a meta-analysis of randomized trials, the antihypertensive efficacy of hydrochlorothiazide at a daily dose of 12.5 to 25 mg was shown to be consistently inferior as compared to other antihypertensive agents. The authors of that study went on to suggest that because outcome data on those doses were lacking, hydrochlorothiazide was an inappropriate first-line drug for the treatment of hypertension.

Another study showed that chlorthalidone reduced 24-hour BP more effectively than hydrochlorothiazide. Additionally, fet ventricular mass was significantly lower for those on chlorthalidone vs hydrochlorothiazide and the authors postulated that this may contribute to mortality benefits seen in other studies (MRFIT). The chlorthalidone fans rally behind the longer half-life and larger volume of distribution allowing the drug to achieve a more evenly distributed BP control throughout the day as compared to hydrochlorothiazide. The chlorthalidone camp points to clinical trials favoring chlorthalidone over hydrochlorothiazide. Although there is more aggregate clinical trial data demonstrating the superiority of chlorthalidone in terms of hard clinical outcomes, the hydrochlorothiazide fans vehemently argue that these trials are not direct comparisons.

(2) JNC8 Hypertension Guidelines versus (7) KDIGO Hypertension Guidelines

JNC8 Hypertension Guidelines

The JNC8 experts attempted to simplify management of hypertension with a simple approach to treat to 150/90 in those over the age of 60 and 140/90 for all others; similarly, they also simplified the drug regimen, that is,  ACEi, ARB, calcium-channel blockers (CCB), and thiazide-type diuretics are reasonable choices, just to get patients to goal BP. However, critiques abound over this somewhat ‘oversimplified approach.’ As compared to its predecessor (JNC7), several differences are particularly noted, namely: the JNC8 Guidelines define the target BP thresholds for initiation of pharmacological intervention, eg, decrease blood pressure to < 150/90 mm Hg in patients aged ≥ 60 or older and a DBP < 90 in those aged 30 to 59 (based on HDFP, Hypertension-Stroke Cooperative, MRC, ANBP, and VA Cooperative); they recommend a broader range of anti-hypertensive agents for initial treatment in non-blacks, including those with DM; and lastly, they recommend ACEi or ARB for all patients with CKD with or without DM regardless of race.

JNC8 adheres closely to the quality standards published by the the National Institute for Health Care Excellence (NICE) Guidelines published in March 2013.

KDIGO Hypertension Guidelines

The Kidney Disease: Improving Global Outcomes Clinical Practice Guideline for management of BP in CKD has been designed to assist clinical decision making in patients with CKD who are not receiving dialysis. In stark contrast to JNC8, these guidelines recommend that no single BP target is optimal for all CKD patients and instead encourage individualization of treatment depending on age, the severity of albuminuria, and comorbidities.

They recommend that for all CKD patients without albuminuria the target SBP should be ≤140 and DBP ≤90 mm Hg diastolic. However, recognizing that microalbuminuria is a risk marker for cardiovascular events and possibly for kidney disease development, in most patients with an albumin excretion rate of ≥30 mg/24 hours, a lower target of SBP ≤130 mm Hg and DBP ≤80 imm Hg has been suggested (with very low level of evidence).

-Written and Edited by Drs. Edgar Lerma and George Bakris

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