ANALYSIS OF RECENT PAPERS IN HYPERTENSION
JAN N. BASILE, MD, SENIOR EDITOR; MICHAEL J. BLOCH, MD, SENIOR EDITOR
What Should be the Target Blood Pressure in Patients With Chronic Kidney Disease? Data From the Kidney Early Evaluation Program
Michael J. Bloch, MD, Risk Reduction Center, Saint Mary’s Regional Medical Center, 645 North Arlington Street, Suite 460, Reno, NV 89503
Guidelines, and the majority of clinicians who follow them, have long been of the opinion that when it comes to blood pressure (BP) control in patients with chronic kidney disease (CKD) the lower the better. In fact, however, the clinical trial evidence supporting a BP goal of <130/80 mm Hg, as currently recommended in the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation and Treatment of High Blood Pressure (JNC 7) and by the National Kidney Foundation is rather limited (see commentary below).
The observational data presented from the Kidney Early Evaluation Program (KEEP), a large, diverse, community-based sample, do not support this more aggressive target.1 In KEEP, increased systolic BP (SBP) was associated with an increased risk of progression to end-stage renal disease (ESRD), but that increased risk started at a threshold of 140 mm Hg or higher, not 130 mm Hg. In fact, more than 33% of patients had an SBP >150 mm Hg or a diastolic BP (DBP) >90 mm Hg, reflecting suboptimal control by any standard. But these data are far from conclusive. Given the potential adverse effects of more aggressive BP control in this patient population, including the risk of worsening renal function, future studies need to better determine the optimal BP target in this patient population—Peralto 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. Arch Intern Med. 2012;172:41–47.
We believe that the current recommendation of a BP goal of <130/80 mm Hg as optimal for all patients with CKD (defined as an estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m2) remains largely unproven (except perhaps for those with significant proteinuria). Until future studies are performed, given the diverse nature of the CKD population, we suggest an individualized approach. Most patients with CKD should be treated to an SBP target of <140 mm Hg with more aggressive targets reserved for patients at higher risk for progression to ESRD. Future studies need to be adequately powered to look at individual subgroups of this diverse patient population. Identifying and targeting patients with CKD whose BP remains far from goal should be a major health care priority.
KEEP is a nation-wide, community-based, observational screening program that identifies and enrolls adults who have known kidney disease, diabetes, hypertension, or a family history of these conditions. According to the present report, since 2000, KEEP has screened more than 165,000 persons in 49 states and the District of Columbia. For the current analyses, the KEEP investigators included data on the 16,121 persons in the registry who had established CKD of at least stage 3, defined as an eGFR <60 mg/min/1.73 m2.
In KEEP, baseline eGFR was determined from a single serum creatinine using the Chronic Kidney Disease Epidemiology (CKD-EPI) formula. BP was measured using a standardized procedure at a single baseline study visit. Incident ESRD was ascertained by linkage to the US Renal Data System (USRDS), which has been estimated to capture at least 90% of patients who undergo incident hemodialysis or kidney transplantation. No data concerning incident cardiovascular (CV) events were ascertained. Other variables captured at baseline and used in the statistical analysis included self-reported age, sex, race/ethnicity, smoking history, history of CV events, presence of diabetes mellitus (by self-report or based on fasting serum glucose at baseline), and baseline measurements of urine albumin creatinine ratio (ACR).
Study Results and Commentary
Among the KEEP study population with CKD, the mean age was 69 years, the mean baseline SBP was 139 mm Hg, and the mean baseline DBP was 77 mm Hg. Overall, 43% had apparent or known diabetes mellitus and 93% had apparent or known hypertension. About 45% to 50% of the cohort had public insurance and 20% to 25% reported being uninsured. More than 95% of patients reported having seen a health care professional in the previous 2 years.
Mean baseline eGFR varied modestly by baseline BP ranging from 48.2 mL/min/1.73 m2 in patients with SBP <130 mm Hg to 46.8 in patients with SBP >150 mm Hg. The ACR varied more significantly based on baseline BP. In patients with a baseline SBP <130 mm Hg, 83% had an ACR <30, 14% had an ACR 30 to 300, and 3% had an ACR >300. In patients with a baseline SBP <150 mm Hg, 65% had an ACR <30, 27% had an ACR 30 to 300, and 8% had an ACR >300.
Given the nature of the KEEP methodology for identifying and enrolling participants, this should be considered a fairly representative sample of the US CKD population.
Incidence of Incident ESRD
Only 320 participants, representing just 2% of the study population, progressed to ESRD during the 2.87 years of follow-up. The relatively short duration of follow-up was a major reason for the low rate of progression, a major limitation of this analysis. That being said, we feel, particularly in older patients and in those with higher eGFR, that the lifetime risk of progressing to ESRD is actually much lower than most clinicians believe.
Subjecting this entire patient population with stage 3 CKD to a more aggressive BP target to prevent the incidence of a relatively uncommon outcome may not be the most effective or cost-effective strategy. Future initiatives should focus on identifying those patients with the greatest risk of developing ESRD.
Relationship Between Incident ESRD and Baseline BP: Overall
After adjustment for sex and age, compared with SBP <130 mm Hg, increased baseline SBP was associated with an increased risk of incident ESRD only in patients whose baseline SBP was >140 mm Hg. As compared with the referent group with SBP <130 mm Hg, hazard ratios (HRs) were 1.08 (95% confidence interval [CI], 0.74–1.59) for SBP of 130 mm Hg to 139 mm Hg, 1.72 (95% CI, 1.21–2.45) for SBP of 140 mm Hg to 149 mm Hg, and 3.36 (95% CI, 2.51–4.49) for SBP ≥150 mm Hg. After adjustment for all available socioeconomic and clinical variables, only patients with baseline SBP >150 mm Hg had a statistically significant increased risk for ESRD compared with those with SBP <130 mm Hg.
In terms of other BP variables, when compared with patients with a DBP of 60 mm Hg to 74 mm Hg as a reference group, only those with baseline DBP >90 mm Hg had an increased risk of developing ESRD. While a wide pulse pressure was also associated with an increased risk of ESRD, that risk was significantly attenuated when SBP was taken into account.
While these data are subject to key limitations, including the short duration of follow-up and the strictly observational nature of the KEEP program, in our opinion these findings are actually quite consistent with the bulk of data presently available to us. In the original report of the African-American Study of Kidney Disease and Hypertension (AASK), more aggressive BP goals did not lead to a reduction in the progression of CKD in nondiabetic African American hypertensive patients with CKD.2 Similarly, in the Modification of Diet in Renal Disease (MDRD) trial, more aggressive BP control did not lead to a change in the decline of GFR in the entire cohort of patients with CKD.3
We conclude that in patients with CKD, the hypothesis that more intensive control of SBP to a goal of <130 mm Hg leads to improved clinical outcomes remains unproven.
Relationship Between Incident ESRD and Baseline BP: Effect of Albuminuria
In this analysis from KEEP, there were 3204 persons with CKD who had evidence of elevated ACR (at least 30 mg/g) at baseline. Although the authors of this report fail to highlight this fact, it appears that this subgroup represented only 20% of the overall cohort but accounted for roughly 88% of all incident ESRD. This finding is consistent with findings from AASK, MDRD, and other studies suggesting that elevated ACR is a strong marker for progression to ESRD among patients with baseline renal dysfunction.
In fully adjusted models in KEEP, even among patients with elevated ACR, the relationship between increased SBP and risk of ESRD was seen only in patients with baseline SBP >140 mm Hg. This stands somewhat in contrast to previous studies where there has been a suggestion that among patients with baseline albuminuria or proteinuria, there may be benefit from more intensive BP control. In the long-term follow-up (cohort phase) of AASK, among patients with a baseline protein-to-creatinine ratio of >0.22, there was a significantly lower incidence of the primary end point in patients initially randomized to more intensive BP control.2 Similarly, in MDRD the subgroup with >1 g/d of protein excretion at baseline had less progression to ESRD with more intensive BP treatment.3 Given the limitations of the KEEP data highlighted above, we believe the AASK and MDRD results are probably more meaningful in terms of hypothesis generation.
We conclude that the presence of significant albuminuria or proteinuria in patients with CKD is a marker of risk of progression to ESRD (and CV events as well). While the hypothesis that more intensive control of SBP to a goal of <130 mm Hg leads to improved clinical outcomes in this subgroup remains unproven, it can be reasonably supported from the existing clinical trial data.
The Prevalence of Poorly Controlled Hypertension Among Patients With CKD
Most research and commentary about treatment of BP in patients with CKD focuses on BP goals and whether certain drug classes may be preferred. The KEEP data highlights the fact that we should probably focus more on the elephant in the room—the poor BP control in this population.
In KEEP, 48% of patients with CKD had an SBP >140 mm Hg or DBP >90 mm Hg and shockingly 33% had an SBP >150 mm Hg or DBP >90 mm Hg. This occurred despite the fact that nearly all patients reported having seen a health care provider in the previous 2 years. The group of patients with SBP >150 mm Hg had a nearly 3-fold increase in the risk of developing ESRD (in analysis adjusted for age and sex only) and accounted for the majority of patients who progressed to ESRD. Of course, as this is a purely observational study, it is impossible to draw firm conclusions about cause and effect, and there certainly may have been unrecognized confounding variables that led to both a worsened renal prognosis and poor BP control. Nonetheless, this should be a call to action for us to do a better job of identifying and offering more effective treatment to patients with CKD and poor BP control.
The KEEP data provide an important snapshot of what the CKD population in the United States looks like today. From a public health standpoint, the most striking finding is the number of patients whose BP remains nowhere near goal—identification and effective treatment of this high-risk patient population should become a major priority.
In terms of BP targets, we anxiously await the results of the National Institutes of Health–sponsored Systolic Blood Pressure Intervention Trial (SPRINT).4 SPRINT is a large-scale clinical trial of more than 9000 high-risk hypertensive patients being conducted at more than 70 clinical sites in the United States. Patients in SPRINT will be randomized to an SBP goal of <140 mm Hg (standard) or <120 mm Hg (intensive treatment). More than 40% of patients are expected to have CKD (as measured by eGFR). Hopefully, this subgroup will be sufficiently powered to prove or disprove the hypothesis that more aggressive BP control in patients with CKD offers net clinical benefit. We are particularly interested in seeing the results stratified by the presence or absence of baseline clinical proteinuria (although ≥600 mg of urinary protein is an exclusion criteria).
Since it will be more than 5 years before the SPRINT study results are known, we feel the KEEP observational data, when looked at in the context of other intervention trials, support a BP goal of <140/90 mm Hg for most patients with CKD. Clinicians should identify CKD patients with the highest lifetime risk for progression to ESRD, such as those with clinical proteinuria or those who present with CKD at a very young age, and treat their BP more aggressively. In these individuals, a target of <130/80 mm Hg seems more appropriate.