Abstract
Context: Eighty-five percent of patients with chronic kidney disease (CKD) have hypertension, and blood pressure (BP) control is the cornerstone in the management of CKD. Although it is widely accepted that BP should be optimized, BP targets in CKD are not known. Subject of Review: Kidney Disease Improving Global Outcomes (KDIGO) clinical practice guideline for the management of BP in CKD (Kidney Int. 2021 Mar 1;99(3S):S1–87) recommends targeting BP to less than 120 mm Hg systolic for patients with CKD. Second Opinion: KDIGO BP target differs from all other hypertension guidelines. This is also a major change from the previous recommendation which was <140 systolic to all patients with CKD and <130 systolic for those with proteinuria. Targeting systolic BP to less than 120 mm Hg is hard to substantiate based on available data and is based primarily on subgroup analysis of a randomized control trial. Intensive BP lowering as suggested by the guidelines may lead to polypharmacy, added cost burden, and risk of serious harms.
Introduction
Kidney Disease Improving Global Outcomes (KDIGO) is a global non-profit organization which develops guidelines for the management of patients with chronic kidney disease (CKD). The 2021 clinical practice guidelines for the management of blood pressure (BP) recommend targeting BP to less than 120 mm Hg systolic for patients with CKD (evidence 2B) [1]. This is a major change to the previous recommendation which was <140 systolic to all patients with CKD and <130 systolic for those with proteinuria [2]. This recommendation is an outlier and differs from other major hypertension guidelines [3‒5]. Elevated BP is not a disease but a risk factor for cardiovascular disease [6]; hence, the goal of the treatment is cardiovascular risk reduction and not aiming for a target BP. This is highlighted in the latest ACC/AHA guidelines which recommend assessing cardiovascular disease risk before considering pharmacotherapy for patients with hypertension. Eighty-five percent of patients with CKD have hypertension, and optimal BP control is the cornerstone in the management of CKD; hence, these new recommendations have significant implications in terms of added cost, polypharmacy, and possible harms of the lower BP targets.
SPRINT CKD Subgroup Analysis: Basis for Recommendation
KDIGO recommendation of BP target is largely based on the pre-specified subgroup analysis of the SPRINT trial – SPRINT CKD [7, 8]. In 2,646 participants with CKD, randomized to standard or intensive BP lowering, after a median follow-up of 3.3 years, hazard ratios for the primary composite cardiovascular outcome and rate of all-cause death were 0.81 (0.61–1.05) and 0.72 (0.53–0.99), respectively. The authors of the trial concluded that among patients with CKD and hypertension without diabetes, targeting an SBP <120 mm Hg reduced rates of major cardiovascular events and all-cause death without evidence of effect modifications by CKD or deleterious effect on the main kidney outcomes [8].
Limited Generalizability of the SPRINT CKD
The SPRINT trial excluded patients with diabetes, proteinuria >1 g/day, polycystic kidney disease, glomerulonephritis, patients with severe CKD, i.e., eGFR <20 mL/min, and those who are younger than 50 years. Trial participants were elderly (mean age of 67 years), had mild decrease in renal function (mean serum creatinine of 1.56 mg/dL), and no significant albuminuria (UACR ∼ 40 mg/g) [7]. This spectrum of CKD in the SPRINT participants resembles more to age-associated decrease in the GFR. In fact, the rate of GFR decline in the trial was similar to the age-related decline in kidney function – about 0.5 mL per min per year. Without significant albuminuria, the clinical significance of this class of CKD is questionable and promotes medicalization of ageing [9]. A study highlighting the limited generalizability of the SPRINT trial noted that most real-world CKD patients are different from the trial participants [10]. CKD patients in the subgroup analysis are different from the participants of landmark randomized controlled trials evaluating antihypertensive therapies in CKD [11‒16]. These trials enrolled patients having kidney disease with significant risk of progression: diabetics, participants who had significant proteinuria or decreased renal function at baseline. In such patients with CKD, CV risk is significantly contributed by non-traditional CKD-specific risk factors in addition to traditional risk factors; therefore, renoprotection and CV risk reduction are likely to go hand in hand, unlike the dissociation of these outcomes noted in the SPRINT trial [17].
Randomized trials (African American Study of Kidney Disease [AASK], Modification of Diet in Renal Disease [MDRD], REIN-2, SPRINT), examining BP targets in patients with CKD, had similar inclusion criteria with regards to kidney function, i.e., eGFR 20–59 mL/min. However, eGFR of enrolled participants in SPRINT trial was higher than the other two. Reasons for enrolling high eGFR patients in SPRINT are not clear, but it may partially be related to the reluctance of the treating physicians to enrol patients with significant kidney disease to intensive BP lowering.
Another difficulty in wider application of the SPRINT trial’s result is the method of BP measurement – ambulatory office blood pressure (AOBP), which gives BP reading approximately 7–14 mm Hg lower than routine office BP measures [18‒20]. If AOBP is to be implemented for CKD patients in primary care settings, additional time (about 7 min more per patient) and restructuring of clinics needed for implementing AOBP can be demanding. Even after adjusting for this difference in the method of BP measurement, none of the above-mentioned CKD hypertension trials achieved target SBP <120 mm Hg. For example, BP in the intervention arm at the end of the study of RENAAL, IDNT, Captopril trial was 140/74, 140/77, and between 128 and 134 mm Hg, respectively. All these factors limit the generalizability of the SPRINT CKD results to practice.
What Is Already Known about BP Targets in CKD?
MDRD and AASK trials evaluating the effect of intensive versus less intensive BP targets in real-world non-diabetic CKD (serum creatinine 2–2.2 mg/dL, >30% participants had UACR >0.22) concluded that a lower target does not offer additional renoprotection than usual targets. Subgroup analysis of patients with proteinuria suggested the benefit of a lower BP target on kidney outcomes. Post-trial follow-up of AASK and MDRD (for 14–15 years) found reduced overall mortality (HR 0.87, 95% CI: 0.76–0.90) and reduced the progression to ESKD (HR 0.88, 95% CI: 0.78–1.00) with lower BP target, but the benefit was confined to those with proteinuria [21]. These findings should be interpreted with caution: they are discordant with the primary outcome of the original trials, observed differences in outcomes are marginal, and there was no difference in the BP between the groups during post-trial follow-up. Meta-analyses combining these trials of various designs, interventions, and different BP targets have reached different conclusions regarding the benefits and harms of intensive BP control [22, 23].
Intensive BP Control May Be Harmful
If we adopt KDIGO 2021 BP target, proportion of CKD patients needed BP-lowering treatment will increase by 15–20% [24, 25]. Intensive BP in CKD may be associated with harm. Two trials that dealt with a very similar BP target in diabetics and non-diabetics (ACCORD BP and SPRINT) reached different primary outcomes; however, both noted an increased incidence of side effects with intensive BP lowering. In the ACCORD BP trial, serious adverse events attributed to BP lowering were more likely in the intensive-lowering arm: hypotension and syncope, bradycardia/arrhythmias [26]. Importantly, in a population at very low risk of progressive CKD (mean creatinine 0.9 mg, median UACR 14 mg/g), risk of eGFR <30 mL (as an adverse lab measure) almost doubled with intensive BP lowering (99 [4.2%] vs. 52 [2.2%] <0.001). Renal failure occurred in 5 patients in the intensive control arm versus 1 patient in the less intensive arm of ACCORD BP trial. In the SPRINT, in addition to increased risk of hypotension, syncope, and electrolyte abnormalities, intensive arm had higher incidence of AKI (204 [4.4%] vs. 120 [2.65], HR 1.71, p < 0.001) and ≥30% reduction in estimated GFR to <60 mL (127 [3.85] vs. 37 [1.1%], HR 3.49, p < 0.001). A post hoc analysis of the SPRINT demonstrated that the CV benefit of intensive BP lowering is no longer significant at eGFR <45 mL/min and showed a higher risk of AKI and eGFR decrease of over 30% and 50% with this intervention [27]. Long-term significance of these adverse kidney events is not known. Dismissing it as a haemodynamic and transient phenomenon may not be wise, given the relationship of these events with adverse CV outcomes [28]. In elderly CKD patients with comorbidities, harms of the intensive BP lowering like falls, fractures, and AKI may be more pronounced [29, 30].
Finally, a post hoc analysis of the SPRINT for patients with higher baseline BP at enrolment and without other traditional CV risk factors (which may be the case with younger patients with CKD), lower target BP was associated with increased risk of death [31]. J curve phenomenon-increased CV mortality at very high and low BP is described in the general population as well as in CKD [32]. In addition, decline in kidney function associated with intensive BP lowering may itself contribute to increased CV risk in these patients.
The SPRINT was terminated early after 3.5 years. Premature termination of trial for benefits decreases the power of the study both for main and subgroup outcomes and underestimates harm. Outside the trial environment, pill burden and increased risk of adverse events in the intensive group can be concerning for patients, physicians and lead to non-adherence.
Knowledge Gap in Hypertension in CKD
Most randomized control trials addressing BP treatment in CKD and its impact on outcomes (like kidney disease progression, kidney failure, cardiovascular events, or all-cause death) enrolled patients with mild to moderate decrease in kidney function. Evidence guiding BP treatment in more severe CKD (and not on dialysis) is sparse (shown in Fig. 1). KDIGO states that some subgroups may not benefit from intensive BP control because potential benefits and harms that may vary with comorbidities, severity of CKD, existing treatment burden, and the presence of white-coat or masked hypertension. However, KDIGO does not make any distinction regarding the severity of CKD, implying that a target <120 mm Hg is valid across the entire spectrum of CKD. Uncertainties about the benefit-risk of lower BP targets should be clearly discussed with the patients, and BP goals should be individualized based on the patient preferences and tolerability.
Conclusions
Considering the indirect nature of the evidence (data from a subgroup analysis), serious risk of bias (open-label design of the trials), and inconsistency of the evidence (previous large trial ACCORD showing futility and harm), we argue that the evidence to support intensive BP lowering in CKD is weak, and evidence for the KDIGO recommendation is 2C and not 2B [33]. Based on the available evidence, it is reasonable to maintain BP <130/80 for proteinuric and <140/90 for non-proteinuric cases, with close monitoring of those targeted to BP <130 mm Hg for the adverse events.
Conflict of Interest Statement
The authors have no conflicts of interest to declare.
Funding Sources
The authors have nothing to disclose.
Author Contributions
Tukaram Jamale: concept, data collection, and draft. Manjunath Kulkarni and Vaibhav Keskar: data collection and draft.