Intensive Blood Pressure Lowering Should Be the Goal for Most Individuals at High Risk of Cardiovascular Disease Irrespective of Albuminuria

Optimal BP targets for individuals with hypertension and CKD continue to be debated. The evidence base is heavily influenced by three trials: the Modification of Diet in Renal Disease (MDRD) study, the African American Study of Kidney Disease and Hypertension (AASK), and, more recently, the Systolic Blood Pressure Intervention Trial (SPRINT). The MDRD study and AASK randomized predominantly nondiabetic participants with CKD to BP targets of approximately <125/75 versus <140/90 mm Hg. Neither trial demonstrated an overall reduction in kidney outcomes or linear changes in eGFR with lower BP targets (1,2). However, intensive BP lowering among MDRD study participants with a baseline urinary protein excretion ≥1 g/d was associated with slower eGFR decline, and intensive BP lowering among AASK participants with a baseline urine protein-creatinine ratio >0.22 g/g was associated with a decreased risk of CKD progression. Notwithstanding that these were subgroup analyses, they helped steer the Kidney Disease Improving Global Outcomes (KDIGO) 2012 guidelines to recommend targeting a BP of <130/80 mm Hg for patients with proteinuric CKD and <140/90 mm Hg for patients with nonproteinuric CKD.

Published in 2015, SPRINT found that participants at increased risk of cardiovascular disease randomized to a target systolic BP <120 mm Hg compared with <140 mm Hg had a 25% relative risk reduction in cardiovascular disease and a 27% relative risk reduction in all-cause deaths (3). Although only 28% of SPRINT participants had a baseline eGFR <60 ml/min per 1.73 m², cardiovascular disease and mortality benefits seemed to be similar in this subgroup (4). On the basis of these findings, the American College of Cardiology/American Heart Association 2017 hypertension guidelines recommended antihypertensive treatment to target a BP of <130/80 mm Hg for adults at increased risk of cardiovascular disease, including individuals with CKD. The KDIGO Blood Pressure Work Group will also soon publish updated guidelines for BP targets in CKD. Thus, it is timely to revisit BP targets. One important topic not yet addressed by SPRINT is the role of proteinuria. Do findings from SPRINT corroborate prior studies indicating that proteinuric patients may derive greater benefit from lower BP targets with respect to kidney outcomes? Additionally, are the cardiovascular disease and mortality benefits seen with lower BP targets in SPRINT perhaps even greater among patients with proteinuria?

In this issue of CJASN, Chang et al. (5) address these questions by evaluating whether the presence of albuminuria modifies the effect of intensive BP therapy on kidney, cardiovascular disease, and mortality outcomes in SPRINT. The authors find that intensive BP lowering led to similar absolute risk differences in ≥40% eGFR decline, the primary cardiovascular disease outcome, and all-cause death regardless of the presence of baseline albuminuria, which was defined as urine albumin-creatinine ratio ≥30 mg/g. On the relative risk scale, intensive BP lowering among participants without albuminuria was associated with a greater risk of ≥40% eGFR decline.

The authors should be commended for their well designed study and providing these important data. However, several aspects related to the design of SPRINT are important in understanding the authors’ findings in the context of prior studies. First, in contrast to the participants in the MDRD study and AASK, most participants in SPRINT had preserved kidney function and, at most, only mild to moderate albuminuria (Table 1). As a result, participants with albuminuria in SPRINT had milder kidney disease, with a mean eGFR of 63 ml/min per 1.73 m² and a median urine albumin-creatinine ratio of 70 mg/g. These differences limit the comparability of the findings in SPRINT with analyses in the MDRD study and AASK.

Table 1.

Major blood pressure target trials including participants with chronic kidney disease

Trial	eGFR Inclusion Criteria	Key Exclusion Criteria	Mean eGFR	Median Proteinuria	End Stage Kidney Disease Events	Cardiovascular Disease Death Events	All-Cause Death Eventsa
MDRD, n=840	13–55	UPE>10,000 mg/d, insulin-dependent diabetes	33	UPE: 350 mg/d	127	18	30
AASK, n=1094	20–65	UPCR≥2500 mg/g, diabetes	45	UPCR: 80 mg/g	171	31	85
SPRINT, n=9361	≥20	UPCR≥1000 mg/g, UACR≥600 mg/g, diabetes	72	UACR: 10 mg/g	16	102	365

MDRD, Modification of Diet in Renal Disease; UPE, urinary protein excretion; AASK, African American Study of Kidney Disease and Hypertension; UPCR, urine protein-creatinine ratio; SPRINT, Systolic Blood Pressure Intervention Trial; UACR, urine albumin-creatinine ratio.

^aThe MDRD study and AASK only included all-cause deaths prior to ESKD.

Second, although the use of a ≥40% eGFR decline has been endorsed by the Food and Drug Administration as a reliable surrogate kidney outcome, it has unique limitations in trials assessing intensity of BP lowering (6). BP lowering can lead to acute declines in eGFR due to reductions in kidney perfusion pressure. In SPRINT, 10.3% of participants in the intensive BP arm had a ≥20% eGFR decline in the first 6 months compared with 4.4% of participants in the standard BP arm (7). Thus, when using relative eGFR changes from baseline as an outcome, the additional reduction in eGFR required to cross the 40% decline threshold following the acute eGFR decline is less in the intensive BP arm, introducing differential bias across the two treatment arms. Reassuringly, additional studies in SPRINT support the hypothesis that greater eGFR decline following intensive BP-lowering therapy is often related to hemodynamic changes rather than intrinsic injury (7–9). Chang et al. (5) were also limited in the ability to use ESKD events. Few ESKD events occurred in SPRINT as a result of the trial excluding individuals with baseline eGFR <20 ml/min per 1.73 m² and then providing only a mean of 3.1 years of follow-up. In contrast, the MDRD study and AASK had substantially more ESKD events (Table 1). These limitations make it difficult to draw reliable inferences from SPRINT regarding the effect of intensive BP-lowering therapy on kidney outcomes. However, a meta-analysis including BP target trials in nondiabetic CKD populations and additional MDRD and AASK post-trial follow-up data suggest that intensive BP lowering may lead to long-term improvements in kidney outcomes despite short-term reductions in eGFR (10).

Third, a particularly important discovery by Chang et al. (5) relates to SPRINT’s design as a cardiovascular disease end point trial. SPRINT was adequately powered to demonstrate both cardiovascular disease and mortality benefits with intensive BP-lowering therapy overall, with similar results in the CKD subgroup. Chang et al. (5) now demonstrate that these benefits seem consistent regardless of the presence of baseline albuminuria. In contrast, the MDRD study and AASK were designed with primary kidney outcomes without central adjudication of cardiovascular disease, leading to few such events (Table 1). As a result, these trials were unable to reliably detect cardiovascular disease effects.

In summary, the most important and novel finding provided by Chang et al. (5) is that intensive BP lowering in SPRINT reduces the risk of cardiovascular disease and mortality irrespective of albuminuria. It should be noted that, because of SPRINT’s exclusion criteria, this finding may not be generalizable to individuals with diabetes, advanced CKD, or severe albuminuria. In regard to the effects of intensive BP lowering on kidney outcomes, the data are more limited. Although intensive BP lowering was associated with a higher relative risk of ≥40% eGFR decline in SPRINT participants without albuminuria, we believe that clinicians should not avoid intensive BP lowering for this reason. The short-term follow-up and unbalanced hemodynamic effects on eGFR across treatment arms make this finding difficult to interpret, and previous studies indicate that the effects of intensive BP lowering on the kidneys seem to be primarily hemodynamic (7–9). In addition, avoiding intensive BP lowering may deny some the cardiovascular disease and mortality benefits. It remains debatable whether patients with proteinuria derive additional benefit for long-term kidney outcomes with intensive BP lowering, as analyses from the MDRD study and AASK seem to suggest. Unfortunately, this is a question that SPRINT cannot definitively answer. These three BP target trials were also not designed to address the role of proteinuria in patients with diabetes or advanced CKD. Because patients with proteinuric CKD represent those at particularly high risk for adverse outcomes, this should be addressed in prospectively planned randomized trials in the future.

Disclosures

J.H. Ix was an investigator in the SPRINT trial and led the San Diego SPRINT site. He is also serving on the National Academy of Medicine panel “Review of the Dietary Reference Intakes for Sodium and Potassium” and is receiving research grant support from the National Institute of Diabetes and Digestive and Kidney Diseases; the National Heart, Lung, and Blood Institute; and the American Heart Association. All remaining authors have nothing to disclose.

Funding

This article was supported by National Institutes of Diabetes and Digestive and Kidney Diseases grant K24 DK11042 (to J.H. Ix).