Hypertension remains the ‘silent killer’ in patients with CKD
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For years, hypertension has shared the pedestal with diabetes as a primary cause of kidney disease.
Sometimes these conditions work together, sometimes alone. Yet, with years of clinical knowledge and treatments to control it, early identification of hypertension has been elusive, clinicians told Nephrology News & Issues.
“The majority of patients diagnosed with kidney failure have diabetes,” George Bakris, MD, professor of medicine and director of the American Heart Association Comprehensive Hypertension Center at the University of Chicago Medicine, said. “About 85% to 90% of those patients will have hypertension.”
The 2020 annual data report from the U.S. Renal Data System indicates most patients with chronic kidney disease had a prior diagnosis of hypertension. However, a small percentage of these patients were receiving treatment and had blood pressure less than 130/80 mm/Hg.
Blood pressure control among patients with CKD and hypertension has improved slightly, from 31.1% in 2003 to 2006 to 37.5% in 2015 to 2018.
“Blood pressure treatment and control were better among individuals without CKD during all periods,” according to the USRDS report.
Source: Andrew Cramer
“It is the silent killer,” Rajiv Agarwal, MD, MS, of the division of nephrology in the department of medicine at Indiana University School of Medicine and Richard L. Roudebush Veterans Administration Medical Center in Indianapolis, “We need to reach and educate patients who are at risk or already have high blood pressure and don’t know it.”
That means a great deal of undetected cases in the early stages of CKD – when treatment therapies can have an impact in slowing progression, Anna Burgner, MD, MEHP, assistant professor of medicine at Vanderbilt University and part of the nephrology and hypertension clinical faculty there, told Nephrology News & Issues. “We don’t do a good job with early identification ... there is a lot of work we can still do” with finding patients who are at risk for hypertension.
Unchecked hypertension does not just harm the kidneys.
“Cardiovascular disease, stroke, myocardial infarction, heart failure, peripheral vascular disease – these are all potential problem areas for uncontrolled hypertension,” Agarwal said.
How to screen
Many studies define the risk of hypertension by racial groups.
“Go into any dialysis clinic and you will see, on average, about 60% of patients will be African Americans,” Bakris said. “If you want to find people at risk, we need to be screening families that have a genetic disposition to kidney disease” to identify high-risk cases earlier, he said. “The common denominator is a positive family history for hypertension and positive parents.
“Family history is the easiest, cheapest way to identify patients at highest risk for hypertension. We should be testing Black individuals in their teens or no later than their 20s for high blood pressure. It is the low-hanging fruit,” Bakris said.
That approach has value, but genetic markers can also tell clinicians more about patients who are at risk years before they end up in a dialysis clinic. “Race is a social construct, not a genetic construct,” Burgner said. “Most trials report race throughout the study, and that’s important so they show that there is an equitable distribution of patients.
“But ultimately, I think we need to look at genetic variances and how those play a role in how patients do in these clinical trials.”
Clinicians can then direct the correct drug therapy based on evidence from the genetic variance – “What are they most likely to respond to – and what the risks could be,” Burgner said.
Agarwal and Bakris acknowledged cases of hidden or masked hypertension; some reports have indicated these could represent more than 40% of cases.
“Is it real? Absolutely. But this is why ultimately, home blood pressures will be the norm in the future,” Bakris said. “People will see a benefit of taking blood pressure checks once or twice a week at home.”
“Part of it depends on how and when you measure [masked hypertension],” Agarwal said. “But it does exist and is an important area that has scarcely received attention. “
Bakris, Burgner and Agarwal said new drugs like dapagliflozin and canagliflozin, that have now completed phase 3 trials, have the potential to slow progression of CKD and indirectly reduce the potential harm caused by hypertension. Those trials demonstrated a reduction in the risk of kidney failure and cardiovascular or renal death in patients with CKD.
In the Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation, or CREDENCE trial, 4,401 patients with type 2 diabetes and albuminuric CKD were randomized to receive the oral sodium–glucose cotransporter 2 (SGLT2) inhibitor canagliflozin at a dose of 100 mg daily or placebo. Patients in the trial had an eGFR of 30 mL/min/1.73 m2 to less than 90 mL/min/1.73 m2 and albuminuria. All patients were treated with renin- angiotensin system blockade.
The primary outcome in the study was a composite of end-stage kidney disease or a sustained eGFR of less than 15 mL/min/1.73 m2, a doubling of the serum creatinine level or death from renal or cardiovascular causes.
The results, published in the June 13, 2019 issue of the New England Journal of Medicine, showed the relative risk of the primary outcome was 30% lower in the canagliflozin group than in the placebo group. Likewise, the relative risk of the renal-specific composite of end-stage kidney disease, a doubling of the creatinine level, or death from renal causes was lower by 34%. The canagliflozin group also had a lower risk of cardiovascular death, myocardial infarction or stroke.
“In patients with type 2 diabetes and kidney disease, the risk of kidney failure and cardiovascular events was lower in the canagliflozin group than in the placebo group at a median follow-up of 2.62 years,” Vlado Perkovic, MB, BS, PhD, and colleagues wrote.
Positive results were also seen in Phase 3 trials with the SGLT2 inhibitor dapagliflozin (Farxiga, AstraZeneca).
“Among patients with chronic kidney disease, regardless of the presence or absence of diabetes, the risk of a composite of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal or cardiovascular causes was significantly lower with dapagliflozin than with placebo,” Hiddo J.L. Heerspink, PhD, and colleagues wrote in the Oct. 8 issue of the New England Journal of Medicine. Dapagliflozin reduced the composite measure of worsening of renal function or risk of cardiovascular (CV) or renal death by 39% compared to placebo in patients with chronic kidney disease (CKD) stages 2-4 and elevated urinary albumin excretion.
The absolute risk reduction (ARR) was 5.3% during the median time in the study of 2.4 years. The trial also met all secondary endpoints, including reducing death from any cause by 31% (ARR = 2.1%, P=.0035) compared with placebo, according to a press release.
“These data show that even the most at-risk patients experienced consistent benefit from dapagliflozin, with a reduction of risk for kidney failure, death from cardiovascular causes or hospitalization for heart failure, as well as prolonged survival,” John McMurray, MD, of the Cardiovascular Research Centre, Institute of Cardiovascular and Medical Sciences, University of Glasgow, UK, and member of the DAPA-CKD Executive Committee, said in a press release.
In the trial, patients (n = 4,304) treated with dapagliflozin experienced fewer serious adverse events compared to placebo (29.5% vs. 33.9%, respectively), according to AstraZeneca. Diabetic ketoacidosis was not reported in the dapagliflozin group vs. in two patients in the placebo group.
While those results are promising, Bakris said SGLT2 inhibitors are not considered blood pressure lowering drugs. Most new therapeutics for hypertension are aimed at patients who are resistant to treatment. “The new drugs that might benefit people with advanced CKD from progressing to [end-stage renal disease] ESRD do not have much in terms of blood pressure lowering benefits,” he said.
Access to care
Other concerns about effectively treating hypertension lie in the structural determinants about how patients can get their medication. “There are patients who don’t trust the health care system. They just stop or never take the medications and decline [in health],” Agarwal said.
“The ZIP code is more important than the genetic code,” he said. “Where you grew up and where you live has a larger effect on hypertension and access to health care. The structural divide is beyond the color of the skin. If you do not have access to a doctor, you are not going to get the medical attention you need.
“We need to think outside the box to get blood pressure under control,” Agarwal said
Bakris said insurance companies need to be more proactive in getting patients screened for hypertension. He recommends the following three steps to lower blood pressure:
- reduce salt intake to about 2,000 mg per day (about one tablespoon);
- limit alcohol to one to two glasses a day; and
- make sure you have at least 6 hours of sleep each day.
The increase in obesity in the United States adds to the risk of developing hypertension, Bakris said, and it is having a greater impact on the younger population.
“Obesity is a major contributor to hypertension and to diabetes,” Bakris said. “If we can succeed at reducing the risk of obesity, we will see major improvements in bringing hypertension under control.” – by Mark E. Neumann
- References:
- https://adr.usrds.org/2020/chronic-kidney-disease/1-ckd-in-the-general-population
- www.astrazeneca.com/content/astraz/ media-centre/press-releases/2020/farxiga-dapa-ckd-phase-iii-trial-reduced-worsening-of-kidney-function-risk-of-cardiovascular-or-renal-death-in-patients-with-chronic-kidney-disease.html
- www.nejm.org/doi/full/10.1056/ NEJMoa1811744
- www.nejm.org/doi/10.1056/NEJMoa2024816
- For more information:
- Rajiv Agarwal, MD, MS, is with the division of nephrology in the department of medicine at Indiana University School of Medicine and Richard L. Roudebush Veterans Administration Medical Center in Indianapolis. He can be reached at ragarwal@iu.edu.
- George Bakris, MD, is professor of medicine and director of the American Heart Association Comprehensive Hypertension Center at the University of Chicago Medicine. He can be reached at gbakris@gmail.com.
- Anna Burgner, MD, MEHP, is an assistant professor of medicine at Vanderbilt University and part of its nephrology and hypertension clinical faculty. She is also an associate editor for Nephrology News & Issues and can be reached at anna.burgner@vumc.org.
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