Long-term metabolic effects of kidney events with intensive SBP control

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The Systolic Blood Pressure Intervention Trial (SPRINT), a landmark study demonstrated that intensive systolic blood pressure (SBP) lowering (SBP target <120 versus <140 mmHg) reduced the risk of death and major cardiovascular events in persons without diabetes but at high cardiovascular risk. In a recent publication, we noted that intensive SBP lowering in SPRINT resulted in a relative mean decline in estimated glomerular filtration rate (eGFR) (intensive versus standard) of −3.31 ± 0.30 mL/min/1.73 m2 by 6 months. The intensive SBP group also had a 3.5-fold higher hazard of incident chronic kidney disease (CKD). The Action to Control Cardiovascular Risk in Diabetes Blood Pressure (ACCORD-BP) trial used a 2 X 2 factorial design to test the same SBP intervention as SPRINT as well as intensive versus standard glycemic control (glycated hemoglobin < 6% versus 7.0 to 7.8%) in persons with type 2 diabetes mellitus (T2DM). In our analysis of ACCORD-BP data, comparisons of the intensive vs. standard SBP groups showed that the intensive SBP intervention in ACCORD-BP led to an even more pronounced early mean eGFR decline and a greater increase in the cumulative incidence of CKD relative to SPRINT (interaction p-value <0.001). It is possible that the decline in eGFR due to blood pressure lowering may have distinct clinical and public health consequences compared with the decline in eGFR due to other conditions, which we have presumed to be related to progression of intrinsic kidney disease. As the follow-up periods are too short to determine the long-term effects of acute, early eGFR decline/incident CKD on hard endpoints, stored specimens from both studies provide an opportunity to study parallel effects on metabolic markers reflecting key outcome domains of inflammation/ iron metabolism and bone and mineral metabolism/ vascular calcification. Herein we propose to examine the long-term metabolic implications of acute, early eGFR decline/incident CKD in SPRINT and ACCORD-BP. The analyses of Aim 1 will address consequences of acute changes in eGFR and incident CKD that are due to the SBP interventions as well as consequences of changes in GFR due to other factors including the natural course of kidney disease. Aim 2 will use modern causal modeling techniques to address the consequences of acute changes in eGFR and incident CKD that are specifically due to the intensive SBP intervention. The current proposal will clarify whether changes in eGFR and incident CKD noted with intensive SBP lowering result in an altered metabolic milieu. Prior to SPRINT, there was no RCT level evidence that intensive SBP control to a goal of <120 mm Hg prolongs survival and reduces the risk of cardiovascular events. While SPRINT findings are novel and significant, there are concerns about the kidney effects of the SPRINT intervention. This proposal seeks to address this knowledge gap in a topic of profound public health significance.