SPRINTing towards trials of blood pressure reduction to reduce CKD progression?

The data supporting an association between elevated blood pressure and risk of cardiovascular death and disease are extensive and consistent.1 Causation has been proved by trials of blood pressure-lowering drugs, which have shown conclusively that they are highly effective in reducing rates of cardiovascular death, heart attack, and stroke. The recent Systolic Blood Pressure Intervention Trial (SPRINT) indicated that this effect extends down to target systolic pressures of 120 mmHg.2 In contrast, while there is also a strong association between elevated blood pressure and reduced kidney function, randomized trials of blood pressure-lowering treatment on the rate of chronic kidney disease (CKD) progression have failed to provide clear evidence of efficacy. CKD is common affecting at least 10% of adults and as the mainstay of treatment is currently blood pressure reduction, this issue is of high importance. Research in to the effect of blood pressure on kidney function is made difficult by the complex, bi-directional nature of the relationship, which involves numerous pathophysiological pathways. Most patients with CKD have elevated blood pressure as a result rather than a cause of the CKD. Guidelines for the management of hypertension in CKD from the Kidney Disease: Improving Global Outcomes (KDIGO) Blood Pressure Working Group are under review following the publication of SPRINT,2 but currently recommend a target office blood pressure of ≤140/90 mmHg for individuals with a urine albumin excretion <30 mg per 24 h, and ≤130/80 mmHg for individuals with higher levels of urine albumin excretion.3 More data are needed to determine whether lower targets might reduce the rate of CKD progression. In this edition of the journal, Okin and colleagues report an analysis of the association of blood pressure with change in estimated glomerular filtration rate (eGFR) using data from the LIFE trial of 8778 hypertensive patients with left ventricular hypertrophy randomized to treatment with losartan or atenolol.4 Entry criteria included subjects with a serum creatinine up to 160 μmol/L (mean eGFR 69 ± 14 mL/min/1.73 m2) and over one-quarter (27%) of participants had microalbuminuria (albumin: creatinine ratio >3.5 mg/mmol) so that patients with early stage CKD were not excluded. The investigators compared the decline in eGFR across three categories of systolic blood pressure control over 4 years of treatment. The decline in eGFR varied significantly between the three groups with a graded association such that the lowest decline in eGFR occurred in patients with the lowest average systolic blood pressure (≤130 mmHg). This effect persisted after adjustments for inter-group baseline differences including those in baseline eGFR, race, sex, and the presence of albuminuria at baseline. There was no impact of treatment allocation on the relationship of change in eGFR to systolic blood pressure.4 The study provides supportive evidence of an association of lower systolic BP with a slower rate of reduction in eGFR in a group of patients with hypertensive heart disease and a modest prevalence of early stage CKD, although of course causation cannot be proven. The authors cite previous studies of hypertensive subjects with which their data are consistent but there are notable exceptions.5 In cohorts of subjects with established CKD, observational studies have also reported an association between blood pressure and progression of CKD. In an incident CKD cohort of over 339 000 patients, Kovesdy et al. found that higher systolic BP was associated with higher rates of progression to end-stage renal disease (ESRD) across all age groups, but with an attenuated effect in older patients.6 In the CRIC cohort study of patients with mild-to-moderate CKD (eGFR 20–70 mL/min/1.73 m2), after a median of 5 years the risk of the composite endpoint of ESRD or halving of eGFR for those subjects whose mean systolic pressure across study visits was always 130–139 mmHg was 2.6 times that of those with systolic pressures of <120 mmHg.7 Such strong observational data from multiple sources suggest that ‘intensive’ blood pressure lowering might slow the progression of CKD. Two large and one small, randomized trials of intensive vs. routine blood pressure control in patients with established CKD, however, provide no conclusive evidence for such an effect. In the Modification of Diet in Renal Disease (MDRD) study of 840 patients with stages 3 and 4 predominantly non-diabetic CKD, after 2 years of treatment there was no difference in the rate of decline in isotopic GFR between subjects randomized to achieve a low (92 mmHg) or usual (107 mmHg) mean arterial blood pressure.8 The African-American Study of Kidney Disease and Hypertension (AASK) study randomized 1094 hypertensive black subjects with non-diabetic and low proteinuric CKD (GFR 20–65 mL/min per 1.73 m2) to mean arterial blood pressure goals of 102 or 92 mmHg for a mean of 4 years in a factorial trial design using ACE inhibitors, β-blockers and calcium channel blockers. Achieved pressures were significantly different (141/85 vs. 128/78 mmHg), but there was no difference between groups in the rate of change in isotopic GFR over 4 years.9 Patients in the intensive blood pressure control group allocated to initial therapy with an ACE inhibitor had a slower decline in the GFR compared with those on β-blockers or calcium channel blockers. Ten-year follow-up in the MDRD study suggested a reduction in progression to ESRD in the lower blood pressure group, although the conclusions are weakened by the lack of blood pressure measurement or targets after the treatment phase.10 Similar long-term follow-up in the AASK study, revealed no significant effect of intensive BP control.11 In both studies, post hoc analysis indicated that subjects with baseline moderate proteinuria (>1 g/day in MDRD and 300 mg/day in AASK) showed slowing of progression of CKD with lower blood pressures. A smaller Italian study of intensive vs. conventional BP control found no detectable effect on progression to ESRD or rate of change of GFR irrespective of proteinuria.12 The data from SPRINT also suggest that there is no benefit of intensive blood pressure lowering on CKD progression. More than 28% of subjects recruited into this study had CKD at baseline (as defined by an eGFR of 20–60 mL/min/1.73 m2) and in this group there was no difference in disease progression between the trial arms. Moreover, in those patients without CKD at baseline, the outcome of a >30% decline in eGFR to a value <60 mL/min/1.73 m2 occurred significantly more frequently in the intensive arm.2 How can we resolve the apparently conflicting outcomes of the observational and randomized studies of the relationship between blood pressure and CKD progression? Firstly, it is possible that the observational studies may have been confounded by an association between lower blood pressure and slowly progressing CKD for reasons other than blood pressure. In the report from Okin and colleagues,4 the group with lowest blood pressure on treatment also had lowest blood pressure before treatment suggesting that they may have had a different baseline phenotype. Secondly, in the randomized trials, the blood pressure differences between groups may have been too small and the duration of the treatment phases too short to allow differences in the rate of CKD progression to have been detected. Thirdly, in contrast to the effects of blood pressure on cardiovascular adverse events, there may be a plateau effect for kidney function below pressures of 140/90 mmHg, so that lowering blood pressure further is not effective. As an added complexity, such a plateau effect may differ widely between patients with CKD, for example according to age or the cause of the GFR decline. Although it is convenient to classify patients with CKD according to KDIGO criteria, the causes of CKD differ widely and CKD of different aetiologies may respond differently to different blood pressure-lowering drugs. Finally, the drugs employed in the randomized trials may have exerted adverse effects on kidney function either directly, or by rendering subjects vulnerable to inter-current insults causing acute on chronic kidney injury that outweighed any beneficial effects of blood pressure reduction. The renal effects of ACE inhibitors in late stage CKD are undergoing re-assessment,13 and the SPRINT trial data provide some support for this possibility. While the study by Okin and colleagues reinforces the possibility that controlling blood pressure in patients with CKD may reduce disease progression, for now the only certain benefit is cardiovascular risk reduction. Randomized trials would be needed to prove the hypothesis that blood pressure reduction to levels lower than current targets will impact upon the progression of CKD. Such trials would need to be both large and long enough with adequate sustained differences in blood pressure to provide definitive answers. Stratification would be required according to age, CKD phenotype (proteinuria at least), and if possible the class of anti-hypertensive drug used; future trials should be designed to provide guidance on treatment according to phenotypic (and even genotypic) characteristics and should not be expected to arrive at a single target value blood pressure value for all. Are we ready for ‘SPRINT-eGFR’? Conflict of interest: none declared.