Study Finds That Treatment-Resistant Hypertension Takes Heavy Toll on Chronic Kidney Disease Patients

George Thomas, MD

By George Thomas, MD

The American Heart Association (AHA), in a Scientific Committee Statement in 2008, defined treatment-resistant hypertension as blood pressure (BP) that remains above goal despite the concurrent use of three different antihypertensive medication classes, or controlled BP that requires four or more antihypertensive medication classes.

The reported prevalence of treatment-resistant hypertension in the literature has varied from 3 to 30 percent of patients with hypertension (HTN), with an increase in prevalence noted in analysis of data from the 1998 to 2008 National Health and Nutrition Examination Survey.

The term “apparent treatment-resistant hypertension” (ATRH) is commonly used in epidemiologic studies to estimate prevalence and assess outcomes, since individuals with pseudo-resistance (including white coat effect, measurement errors or medication noncompliance) cannot be definitively identified and excluded. Recent evidence from epidemiologic analyses in the general population and in those patients with established cardiovascular disease suggests that the presence of ATRH is associated with an increased risk of adverse renal and cardiovascular outcomes.

Probing ATRH’s clinical impact

The association between ATRH and clinical outcomes is not well-studied in those with chronic kidney disease (CKD). We analyzed data on hypertensive participants in the Chronic Renal Insufficiency Cohort (CRIC) to determine prevalence, associations and clinical outcomes of ATRH in nondialysis CKD patients. The CRIC study is a multicenter, prospective, observational study of risk factors for progression of CKD. ATRH was defined as BP ≥140/90 mm Hg while using three or more antihypertensives, or use of four or more antihypertensives with BP at goal at baseline visit.

There was a high prevalence of ATRH (40 percent) in this cohort of CKD patients. Older age, male gender, black race, diabetes, and elevated body mass index (BMI) were independently associated with increased odds of having ATRH. The high prevalence of ATRH in this cohort may be due to the presence of CKD and the inclusion of a large proportion of African-American participants, both of which are predictors of resistant hypertension.

We also found that patients with reduced levels of estimated glomerular filtration rate (eGFR) were more likely to have ATRH. There was a 14 percent higher risk of ATRH with every 5 ml/min/1.73 m2 decrease in eGFR in our study.

While the mechanisms that contribute to resistant hypertension in CKD are not well-defined, it may be speculated that increased salt and water retention, excessive activation of the renin-angiotensin-aldosterone system, and higher levels of sympathetic activation with decreasing eGFR would contribute to uncontrolled BP.

Adverse cardiovascular, renal outcomes

Participants with ATRH had a higher risk of clinical events compared with participants without ATRH. There was a 38 percent increased risk for composite outcome of myocardial infarction, stroke, peripheral arterial disease, congestive heart failure (CHF) and all-cause mortality; and a 28 percent increased risk for renal function decline (defined as a 50 percent decrease in eGFR or development of end-stage renal disease).

Interestingly, the subset of participants with ATRH and BP at goal using four or more medications also had higher risk for CHF and composite outcomes including CHF than did those without ATRH. We also noted that ATRH was associated with significantly higher risk for CHF and renal events only among those with eGFR ≥ 30 ml/min/1.73 m2. This highlights the importance of early recognition and systematic evaluation of underlying factors that may be contributing to ATRH in patients with relatively preserved renal function.

The association of ATRH with adverse cardiovascular and renal outcomes is compelling and has important clinical implications for patients with CKD. Our findings underscore the need for early identification, and systematic evaluation and management of patients with ATRH and CKD. In addition, these data support the need for novel therapeutic strategies to improve BP control in patients with CKD.

Dr. Thomas is Director of the Center for Blood Pressure Disorders and a staff member of the Department of Nephrology and Hypertension in Cleveland Clinic’s Glickman Urological & Kidney Institute. He is also Assistant Professor of Medicine at Cleveland Clinic Lerner College of Medicine.