Chronic kidney disease (CKD) is associated with poor cardiovascular outcomes, in part because of overactivity in the sympathetic nervous system. Reducing this excessive activation by ablating renal sympathetic nerves can improve blood pressure in patients with moderate to severe chronic kidney disease (CKD) and drug-resistant hypertension, according to a study published online ahead of print by the Journal of the American Society of Nephrology.
Safe reductions in blood pressure following catheter-based renal nerve ablation were previously demonstrated in individuals with resistant hypertension but normal kidney function (Schlaich MP et al: N Engl J Med 2009;361:932–934; Krum H et al: Lancet 2009;373:1275–1281; Symplicity HTN-1 Investigators: Hypertension 2011;57:911–917).
However, it was not known what the outcomes of the approach would be in the CKD population. In particular, these patients are at risk for nephropathy due to exposure to contrast agents for vascular imaging, which is used to determine the catheter position during the procedure.
“This study is really the first one to show that—at least with one year follow-up—it appears to be very safe to do this procedure,” said senior investigator Markus P. Schlaich, MD, Head of Hypertension and Kidney Disease at the Baker IDI Heart and Diabetes Institute in Melbourne, Australia. “We did not see any reduction in their renal function, and the blood pressure reduction was very stable.”
Given that hypertensive patients with a reduced glomerular filtration rate (GFR) are at greater risk for cardiovascular disease than for end-stage renal disease, the new findings could have broad implications.
“This is an innovative intervention that carries a lot of promise,” said Mahboob Rahman, MD, MS, Associate Professor of Nephrology and Hypertension at Case Western Reserve University School of Medicine, who was not involved in the study.
“Blood pressure is a really important intervention in chronic kidney disease, both with regard to slowing the decline of renal dysfunction and also for prevention of cardiovascular disease, so I think for the subset of patients who remain resistant, this will be really of value.”
Safe and Effective
In the new study, funded in part by grants from the National Health and Medical Research Council of Australia and the Victorian government's Operational Infrastructure Support program, 15 patients with resistant hypertension and Stage 3–4 CKD underwent catheter-based renal denervation in one session between 2010 and 2011. The catheter was introduced into each renal artery, where it delivered low-power radiofrequency energy that heated the tissue. This procedure interrupts signaling through incoming and outgoing fibers and is thought to reduce sympathetic outflow from the kidney.
On average, the patients had been taking about six antihypertensive drugs and had experienced hypertension for about 18 years. Eleven individuals had type 2 diabetes associated with diabetic nephropathy.
At baseline, participants' average systolic blood pressure while seated in the office was 174 mmHg, and their diastolic blood pressure was 91 mmHg. Their baseline ambulatory systolic blood pressure was 160 mmHg during the day and 154 mmHg at night, while their diastolic blood pressure was 83 mmHg during the day and 78 mmHg at night.
Within one month, the procedure decreased systolic and diastolic blood pressure in the office by an average of 34 mmHg and 14 mmHg, respectively. These improvements persisted one year after the procedure.
Three months after the procedure, the average nighttime systolic and diastolic blood pressure also had gone down, by 14 mmHg and 8 mmHg, respectively.
Moreover, renal denervation restored the normal drop in blood pressure during sleep in nine patients. Because nighttime blood pressure is better than average or daily blood pressure at predicting cardiovascular outcomes, the findings may have important clinical implications.
“If this nocturnal blood pressure profile improvement holds up and is seen in other studies, then we would anticipate that when we follow these people long enough, we'll see benefits and real outcomes” in terms of heart attack, stroke, heart failure, and progressive kidney function loss, said Raymond R. Townsend, MD, Professor of Medicine at the University of Pennsylvania, who was not involved in the study. Dr. Townsend serves on the advisory board for Medtronic, which produces the radiofrequency catheter used in the new study, and he is an investigator in the Symplicity HTN-3 trial, a Medtronic-sponsored clinical trial investigating catheter-based renal denervation for resistant hypertension.
Dr. Townsend also noted that the ambulatory blood pressure drop was smaller than that seen in the office, which could be a result of the white-coat effect, in which anxiety causes patients' blood pressure to be higher in the doctor's office compared with other settings.
“One of the questions that's being asked about renal denervation is, is it really treating the white-coat effect?” he said in a phone interview.
Beyond improving blood pressure, renal nerve ablation reduced peripheral arterial stiffness and did not cause complications or worsen kidney function, as indicated by estimation of GFR from creatinine or cystatin C levels, renal plasma flow, and the calculated kidney retention index.
Because excessive activity in the sympathetic nervous system is implicated in the development and progression of chronic kidney disease, Dr. Schlaich said he hopes “that this approach may also help to reduce the progression of kidney disease, but this is something that needs to be studied in longer-term studies.”
Preliminary, but Promising
Longer-term studies will also be necessary to confirm the durable improvement in blood pressure, Dr. Rahman said, explaining that the renal nerves could potentially regenerate over time.
“It's reassuring to see that the blood pressure at 12 months is sustained, but how about 18 months or 24 months? I think the question that's lurking in everyone's mind is [whether this procedure is] something that has to be repeated at some point in time,” he said in a phone interview.
In addition, more research is warranted because the pilot study was very small, included highly selected patients, and was not randomized, said Katherine R. Tuttle, MD, Executive Director for Research at the Providence Sacred Heart Medical Center and Children's Hospital in Spokane, WA, and Clinical Professor of Medicine at the University of Washington School of Medicine, who was not involved in the study.
Specifically, patients receiving renal denervation treatment in addition to the current best medical treatment should be compared to patients only receiving the best medical treatment.
“The real question is whether the procedure has any benefits or risks beyond conventional medical therapy,” she said in a phone interview.
It's too early to know whether the findings will generalize to other types of patients aside from those with moderate to severe chronic kidney disease and resistant hypertension, Dr. Tuttle said.
If the treatment “proves to be safe, effective, and sustainable, it could be used pretty often because, especially in the chronic kidney disease population, we treat a lot of people with resistant hypertension who are on multiple medicines, and there are unintended consequences like side effects, cost, and so forth,” she said.
“If there's a durable therapy that reduces the burden of medications and, at the same time, lowers blood pressure and perhaps helps mitigate kidney injury, then that would be a very attractive strategy. But again, I have to emphasize that's pure speculation, with everything going right.”
Dr. Schlaich echoed these sentiments.
“It will be a very attractive kind of treatment alternative for these patients, but we need to prove that it's at least as good as the medications we currently use, that it is safe in the long term, and also that the effects are sustained in the longer term,” he said, pointing out the need for appropriately designed randomized clinical trials to substantiate these findings.
“There's a lot of work to do, but it's a very promising start in the area of chronic kidney disease.”