Current and Future Approaches to Renal Protection through Blood Pressure Control

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Editor's Note: This is the title of a scheduled May 11 session (8:30-10:00 a.m.) at the National Kidney Foundation's 2012 Spring Clinical Meetings, which is being held at the Gaylord National in National Harbor, Md., May 9-12.

Session moderators are Joseph Vassalotti, MD, Chief Medical Officer, National Kidney Foundation, and George Bakris, MD, Professor of Medicine and Director, Hypertensive Diseases Unit, University of Chicago. Presenters include Rajiv Agarwal, MD, and Vito Campese, MD, and Dr. Bakris. What follows is a summation of their presentations.


BP Control in Kidney Disease

By Rajiv Agarwal, MD

Despite recent advances in the treatment of hypertension, the majority of patients with chronic kidney disease (CKD) still remain above current blood pressure (BP) targets. Improved BP control is expected to slow progression of loss of kidney function as well as reduce the incidence of cardiovascular events and death. Data from NHANES 1999-2004 show adults with CKD are less likely to have awareness, treatment, and control of BP than those without evidence of CKD.1 The inability to achieve goal BP despite three or more antihypertensive drugs is defined as resistant hypertension, and this is more common in CKD patients.

The National Heart, Lung and Blood Institute's Joint National Committee (JNC) 7 2 and National Kidney Foundation's KDOQI clinical practice guidelines3 currently recommend targets lower than 130/80 mm Hg in CKD patients.

However, updated guidelines from KDIGO to be published this year suggest the level of evidence to support this is very low and argues for a goal below 140/90 mm Hg in this patient population. In fact, a recent systematic review of the literature revealed only three randomized controlled trials in which patients with CKD achieved a BP lower than 130/80 mm Hg.4 None of these trials included patients with diabetes, and two of the three trials showed a benefit in terms of slowing CKD progression only in the sub-groups with more than one gram of proteinuria with minor increases in both the number of anti-hypertensive drugs used and adverse effects.

Data from more than 16,000 participants in the National Kidney Foundation's Kidney Early Evaluation Program (KEEP) show associations between BP levels and end-stage renal disease (ESRD), or chronic kidney failure, in patients with stage 3 and stage 4 CKD. A higher risk for developing ESRD was observed among people with BP measurements of 140/90 or higher, but those who had BP measurements of 150/90 and above were at highest risk.

Additionally, the study found that that more than 30% of people with CKD had BP measurements above 150/90. This study highlights the importance of BP control in CKD patients, suggesting that a target of 140/90 may suffice at least in terms of delaying progression to chronic kidney failure.5  

Innovative strategies are needed to lower BP in patients with CKD. Novel approaches to hypertension treatment reviewed subsequently include: baroreceptor sensitization and renal nerve ablation.

Dr. Agarwal is Professor of Medicine at Indiana University School of Medicine, Indianapolis.


Baroreceptor Modulation for Treating Refractory Hypertension

By Vito Campese, MD

The Rheos Baroreflex Hypertension Therapy System is an implantable device that can treat patients with resistant hypertension. It activates the carotid baroreflex through electrical stimulation of the carotid sinus wall. The Rheos Pivotal Trial is a randomized, double-blind, parallel-design, phase 3 trial of baroreflex activation therapy (BAT) on systolic blood pressure (SBP) in 265 patients with resistant hypertension.6 Subjects received either BAT (Group A) for the first six months or delayed BAT initiation following the six-month visit (Group B).

The five coprimary endpoints were:

  1. acute SBP responder rate at six months
  2. sustained responder rate at 12 months
  3. procedure safety
  4. BAT safety
  5. device safety

The trial showed significant benefit for the endpoints of sustained efficacy, BAT safety, and device safety. However, it did not meet the endpoints for acute responders or procedural safety. A protocol-specified ancillary analysis showed 42% of patients in Group A achieved an SBP of 140 mm Hg or less at six months compared with 24% of Group B, a statistically significant difference between the groups. Both groups achieved an SBP of 140 mm Hg or higher at 12 months.

A non-randomized unblinded follow up of the Rheos Pivotal Trial revealed that 76% of subjects qualified as clinically significant responders, and an additional 10% were indeterminate.7 Among long-term responders receiving BAT, the mean BP drop was 35/16 mm Hg. Medication use was reduced by the end of the randomized phase and remained lower through the follow-up period. Among responders, 55% achieved goal BP (less than 140 or less than 130 mm Hg in patients with diabetes or kidney disease). BP measurements of all active patients remained stable from completion of the randomized phase through long-term follow-up. BAT substantially reduced arterial pressure for most patients participating in the Rheos Pivotal Trial, which was maintained over long-term follow-up of 22 to 53 months.

Dr. Campese is Professor of Medicine at the University of Southern California in Los Angeles.


Renal Denervation

By George L. Bakris, MD

Nephrologists are well aware that stimulation of the renal sympathetic nerves causes increased renin release, increased sodium reabsorption, and a reduction of renal blood flow. These elements of the neural homeostatic regulation of kidney function may be overstimulated, resulting in chronically heightened sympathetic tone in hypertensive patients. Therapeutic denervation may also become an option for refractory hypertension.

The “Symplicity” technique uses a catheter inserted into the renal artery via the femoral artery to deliver radiofrequency energy to ablate the renal sympathetic nerve. The Symplicity HTN-1 study included 153 patients treated with this technique at 19 centers in Australia, Europe, and the United States.8

At baseline, the study population had a mean age of 57 years; 39% of subjects were women, 31% were diabetic, and 22% had coronary artery disease. They had a mean office BP of 176/98 mm Hg and were on a mean of five antihypertensive medications. Subjects had a mean estimated glomerular filtration rate of 83 mL/min/1.73 m2.

The median time from first to last radiofrequency energy ablation was 38 minutes. The procedure was without complication in 97% of patients (149 of 153). The four acute procedural complications that occurred included three groin pseudoaneurysms and one renal artery dissection, all managed without further sequelae. Automated clinic pressure with printout (the primary trial endpoint) was reduced by 20/10, 24/11, 25/11, 23/11, 26/14, and 32/14 mm Hg at 1, 3, 6, 12, 18, and 24 months, respectively. These findings support the short-term safety and efficacy treatment of resistant hypertension with catheter-based renal sympathetic denervation.

The Symplicity HTN-2 randomized unblinded trial of renal sympathetic denervation versus usual care for medication-resistant hypertension show a significant reduction in systolic and diastolic blood pressure at six months compared with age-matched, equally hypertensive controls. Although office-based BP measurements provided the sole assessment of BP as a primary endpoint, this intragroup variability of BP assessment requires further explanation, particularly because 35% of controls enjoyed a 10 mm Hg or more decrease in systolic pressure at six months. The major limitations of Simplicity HTN 1 and 2 studies are the absence of data beyond 24 months. There is speculation that functional renal sympathetic reinervation may occur.

The overall evidence suggests that both BAT and renal denervation can safely reduce SBP in patients with resistant hypertension. Unfortuantely, most of the clinical trials with both approaches have avoided patients with Stages 3b or higher CKD. Future clinical trials will address the limitations and long-term outcomes of thsee therapies to further define their potential therapeutic roles.

Dr. Bakris is Professor of Medicine at the University of Chicago.


References

  1. Snyder JJ, Collins AJ. KDOQI hypertension, dyslipidemia, and diabetes care guidelines and current care patterns in the United States CKD population: National Health and Nutrition Examination Survey 1999-2004. Am J Nephrol 2009;30:44-54.
  2. Chobanian AV, Bakris GL, Black HR, et al, The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003;289:2560-2572.
  3. National Kidney Foundation, K/DOQI Clinical Practice Guidelines on Hypertension and Antihypertensive Agents in Chronic Kidney Disease. Am J Kidney Dis 2004;43(suppl 1):S1-S290.
  4. Upadhyay A, Earley A, Haynes SM, et al. Systematic review: blood pressure target in chronic kidney disease and proteinuria as an effect modifier. Ann Intern Med 2011;154:541-548.
  5. Peralta CA, Norris KC, Li S, et al. Blood pressure components and end-stage renal disease in persons with chronic kidney disease: The Kidney Early Evaluation Program (KEEP). Arch Intern Med 2012;172:41-47.
  6. Bisognano JD, Bakris G, Nadim MK, et al. Baroreflex activation therapy lowers blood pressure in patients with resistant hypertension: results from the double-blind, randomized, placebo-controlled rheos pivotal trial. J Am Coll Cardiol 2011;58:765-73.
  7. Bakris GL, Nadim MK, Haller H, et al. Baroreflex Activation Therapy provides durable benefit in patients with resistant hypertension: results of long-term follow-up in the Rheos Pivotal Trial. J Am Soc Hypertens 2012 Feb 14; published online ahead of print.
  8. Symplicity HTN-1 Investigators. Catheter-based renal sympathetic denervation for resistant hypertension: durability of blood pressure reduction out to 24 months. Hypertension 2011;57:911-917.
  9. Symplicity HTN-2 Investigators. Renal sympathetic denervation in patients with treatment-resistant hypertension (The Symplicity HTN-2 Trial): a randomised controlled trial. Lancet 2010;376:1903-1909.
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