Advertisement

Effect of Intensive Blood Pressure Lowering on Kidney Tubule Injury: Findings From the ACCORD Trial Study Participants

  • Girish N. Nadkarni
    Correspondence
    Address for Correspondence: Girish N. Nadkarni, MD, MPH, CPH
    Affiliations
    Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY
    Search for articles by this author
  • Kinsuk Chauhan
    Affiliations
    Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY
    Search for articles by this author
  • Veena Rao
    Affiliations
    Section of Cardiovascular Medicine, Yale University School of Medicine, New Haven, CT
    Search for articles by this author
  • Joachim H. Ix
    Affiliations
    Division of Nephrology-Hypertension, Department of Medicine, University of California San Diego, San Diego, CA

    Division of Preventive Medicine, Department of Family Medicine and Public Health, University of California San Diego, San Diego, CA

    Nephrology Section, Veterans Affairs San Diego Healthcare System, San Diego, CA
    Search for articles by this author
  • Michael G. Shlipak
    Affiliations
    Kidney Health Research Collaborative, University of California San Francisco, San Francisco, CA

    Department of Medicine, San Francisco VA Medical Center and University of California, San Francisco, San Francisco, CA
    Search for articles by this author
  • Chirag R. Parikh
    Affiliations
    Program of Applied Translational Research, Section of Nephrology, Department of Medicine, Yale University School of Medicine, New Haven, CT

    Veterans Affairs Connecticut Healthcare System, New Haven, CT
    Search for articles by this author
  • Steven G. Coca
    Correspondence
    Steven Coca, DO, MS, Icahn School of Medicine at Mount Sinai, One Gustave L Levy Pl, Box 1243, New York, NY 10029
    Affiliations
    Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY
    Search for articles by this author
Published:October 02, 2018DOI:https://doi.org/10.1053/j.ajkd.2018.07.016

      Rationale & Objective

      Random assignment to intensive blood pressure (BP) lowering (systolic BP < 120 mm Hg) compared to a less intensive BP target (systolic BP < 140 mm Hg) in the Action to Control Cardiovascular Risk in Diabetes BP (ACCORD-BP) trial resulted in a more rapid decline in estimated glomerular filtration rate (eGFR). Whether this reflects hemodynamic effects or intrinsic kidney damage is unknown.

      Study Design

      Longitudinal analysis of a subgroup of clinical trial participants.

      Settings & Participants

      A subgroup of 529 participants in ACCORD-BP.

      Exposures

      Urine biomarkers of tubular injury (kidney injury molecule 1, interleukin 18 [IL-18]), repair (human cartilage glycoprotein 39 [YKL-40]), and inflammation (monocyte chemoattractant protein 1) at baseline and year 2.

      Outcomes

      Changes in eGFR from baseline to 2 years.

      Analytical Approach

      We compared changes in biomarker levels and eGFRs across participants treated to an intensive versus less intensive BP goal using analysis of covariance.

      Results

      Of 529 participants, 260 had been randomly assigned to the intensive and 269 to the standard BP arm. Mean age was 62 ± 6.5 years and eGFR was 90 mL/min/1.73 m2. Baseline clinical characteristics, eGFRs, urinary albumin-creatinine ratios (ACRs), and urinary biomarker levels were similar across BP treatment groups. Compared to less intensive BP treatment, eGFR was 9.2 mL/min/1.73 m2 lower in the intensive BP treatment group at year 2. Despite the eGFR reduction, within this treatment group, ACR was 30% lower and 4 urinary biomarker levels were unchanged or lower at year 2. Also within this group, participants with the largest declines in eGFRs had greater reductions in urinary IL-18 and YKL-40 levels. In a subgroup analysis of participants developing incident chronic kidney disease (sustained 30% decline and eGFR < 60 mL/min/1.73 m2; n = 77), neither ACR nor 4 biomarker levels increased in the intensive treatment group, whereas the level of 1 biomarker, IL-18, increased in the less intensive treatment group.

      Limitations

      Few participants with advanced baseline chronic kidney disease. Comparisons across treatment groups do not represent comparisons of treatment arms created solely through randomization.

      Conclusions

      Among a subset of ACCORD-BP trial participants, intensive BP control was associated with reductions in eGFRs, but not with an increase in injury marker levels. These findings support that eGFR decline observed with intensive BP goals in ACCORD participants may predominantly reflect hemodynamic alterations.

      Graphical Abstract

      Index Words

      To read this article in full you will need to make a payment

      Subscribe:

      Subscribe to American Journal of Kidney Diseases
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Beddhu S.
        • Rocco M.V.
        • Toto R.
        • et al.
        Effects of intensive systolic blood pressure control on kidney and cardiovascular outcomes in persons without kidney disease: a secondary analysis of a randomized trial.
        Ann Intern Med. 2017; 167: 375-383
        • Magriço R.
        • Bigotte Vieira M.
        • Viegas Dias C.
        • Leitão L.
        • Neves J.S.
        BP reduction, kidney function decline, and cardiovascular events in patients without CKD.
        Clin J Am Soc Nephrol. 2018; 13: 73-80
        • Yamout H.
        • Bakris G.L.
        Consequences of overinterpreting serum creatinine increases when achieving BP reduction: balancing risks and benefits of BP reduction in hypertension.
        Clin J Am Soc Nephrol. 2018; 13: 9-10
        • Malhotra R.
        • Nguyen H.A.
        • Benavente O.
        • et al.
        Association between more intensive vs less intensive blood pressure lowering and risk of mortality in chronic kidney disease stages 3 to 5: a systematic review and meta-analysis.
        JAMA Intern Med. 2017; 177: 1498-1505
        • Tsai W.-C.
        • Wu H.-Y.
        • Peng Y.-S.
        • et al.
        Association of intensive blood pressure control and kidney disease progression in nondiabetic patients with chronic kidney disease: a systematic review and meta-analysis.
        JAMA Intern Med. 2017; 177: 792-799
        • National Kidney Foundation
        KDOQI clinical practice guideline for diabetes and CKD: 2012 update.
        Am J Kidney Dis. 2012; 60: 850-886
        • Moledina D.G.
        • Parikh C.R.
        Phenotyping of acute kidney injury: beyond serum creatinine.
        Semin Nephrol. 2018; 38: 3-11
        • Hsu C.-Y.
        • Xie D.
        • Waikar S.S.
        • et al.
        Urine biomarkers of tubular injury do not improve on the clinical model predicting chronic kidney disease progression.
        Kidney Int. 2017; 91: 196-203
        • Fufaa G.D.
        • Weil E.J.
        • Nelson R.G.
        • et al.
        Association of urinary KIM-1, L-FABP, NAG and NGAL with incident end-stage renal disease and mortality in American Indians with type 2 diabetes mellitus.
        Diabetologia. 2015; 58: 188-198
        • Foster M.C.
        • Coresh J.
        • Bonventre J.V.
        • et al.
        Urinary biomarkers and risk of ESRD in the Atherosclerosis Risk in Communities Study.
        Clin J Am Soc Nephrol. 2015; 10: 1956-1963
        • Nadkarni G.N.
        • Rao V.
        • Ismail-Beigi F.
        • et al.
        Association of urinary biomarkers of inflammation, injury, and fibrosis with renal function decline: the ACCORD Trial.
        Clin J Am Soc Nephrol. 2016; 11: 1343-1352
        • Cushman W.C.
        • Evans G.W.
        • Byington R.P.
        • et al.
        • ACCORD Study Group
        Effects of intensive blood-pressure control in type 2 diabetes mellitus.
        N Engl J Med. 2010; 362: 1575-1585
        • Tesch G.H.
        MCP-1/CCL2: a new diagnostic marker and therapeutic target for progressive renal injury in diabetic nephropathy.
        Am J Physiol Renal Physiol. 2008; 294: F697-F701
        • Rovin B.H.
        • Rumancik M.
        • Tan L.
        • Dickerson J.
        Glomerular expression of monocyte chemoattractant protein-1 in experimental and human glomerulonephritis.
        Lab Investig J Tech Methods Pathol. 1994; 71: 536-542
        • Waikar S.S.
        • Sabbisetti V.
        • Ärnlöv J.
        • et al.
        Relationship of proximal tubular injury to chronic kidney disease as assessed by urinary kidney injury molecule-1 in five cohort studies.
        Nephrol Dial Transplant. 2016; 31: 1460-1470
        • Park M.
        • Hsu C.-Y.
        • Go A.S.
        • et al.
        Urine kidney injury biomarkers and risks of cardiovascular disease events and all-cause death: the CRIC Study.
        Clin J Am Soc Nephrol. 2017; 12: 761-771
        • Koyner J.L.
        • Vaidya V.S.
        • Bennett M.R.
        • et al.
        Urinary biomarkers in the clinical prognosis and early detection of acute kidney injury.
        Clin J Am Soc Nephrol. 2010; 5: 2154-2165
        • Shlipak M.G.
        • Scherzer R.
        • Abraham A.
        • et al.
        Urinary markers of kidney injury and kidney function decline in HIV-infected women.
        J Acquir Immune Defic Syndr. 2012; 61: 565-573
        • Coca S.G.
        • Garg A.X.
        • Thiessen-Philbrook H.
        • et al.
        Urinary biomarkers of AKI and mortality 3 years after cardiac surgery.
        J Am Soc Nephrol. 2014; 25: 1063-1071
        • Schmidt I.M.
        • Hall I.E.
        • Kale S.
        • et al.
        Chitinase-like protein Brp-39/YKL-40 modulates the renal response to ischemic injury and predicts delayed allograft function.
        J Am Soc Nephrol. 2013; 24: 309-319
        • Neal B.
        • Perkovic V.
        • Mahaffey K.W.
        • et al.
        Canagliflozin and cardiovascular and renal events in type 2 diabetes.
        N Engl J Med. 2017; 377: 644-657
        • Wanner C.
        • Inzucchi S.E.
        • Lachin J.M.
        • et al.
        Empagliflozin and progression of kidney disease in type 2 diabetes.
        N Engl J Med. 2016; 375: 323-334
        • Zinman B.
        • Wanner C.
        • Lachin J.M.
        • et al.
        Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes.
        N Engl J Med. 2015; 373: 2117-2128
        • Ku E.
        • Bakris G.
        • Johansen K.L.
        • et al.
        Acute declines in renal function during intensive BP lowering: implications for future ESRD risk.
        J Am Soc Nephrol. 2017; 28: 2794-2801
        • Malhotra R.
        • Craven T.
        • Ambrosius W.T.
        • et al.
        Effects of intensive blood pressure lowering on kidney tubule injury in CKD: a longitudinal subgroup analysis in SPRINT.
        Am J Kidney Dis. 2018; 73: 21-30