Renin-Angiotensin System Inhibitor is Associated with Lower Risk of Ensuing Chronic Kidney Disease after Functional Recovery from Acute Kidney Injury

Yu-Hsiang Chou, Tao-Min Huang, Szu-Yu Pan, Chin-Hao Chang, Chun-Fu Lai, Vin-Cent Wu, Ming-Shiou Wu, Kwan-Dun Wu, Tzong-Shinn Chu, Shuei-Liong Lin, Yu-Hsiang Chou, Tao-Min Huang, Szu-Yu Pan, Chin-Hao Chang, Chun-Fu Lai, Vin-Cent Wu, Ming-Shiou Wu, Kwan-Dun Wu, Tzong-Shinn Chu, Shuei-Liong Lin

Abstract

Acute kidney injury (AKI) is an independent risk factor for ensuing chronic kidney disease (CKD). Animal studies have demonstrated that renin-angiotensin system (RAS) inhibitor can reduce ensuing CKD after functional recovery from AKI. Here we study the association between ensuing CKD and use of RAS inhibitor including angiotensin converting enzyme inhibitor or angiotensin II type 1a receptor blocker starting after renal functional recovery in our prospectively collected observational AKI cohort. Adult patients who had cardiac surgery-associated AKI (CSA-AKI) are studied. Patients with CKD, unrecovered AKI, and use of RAS inhibitor before surgery are excluded. Among 587 eligible patients, 94 patients are users of RAS inhibitor which is started and continued after complete renal recovery during median follow-up period of 2.99 years. The users of RAS inhibitor show significantly lower rate of ensuing CKD (users vs. non-users, 26.6% vs. 42.2%) and longer median CKD-free survival time (users vs. non-users, 1079 days vs. 520 days). Multivariate Cox regression analyses further demonstrate that use of RAS inhibitor is independently associated with lower risk of ensuing CKD (hazard ratio = 0.46, P < 0.001). We conclude that use of RAS inhibitor in CSA-AKI patients after renal functional recovery is associated with lower risk of ensuing CKD development.

Conflict of interest statement

The authors declare no competing financial interests.

Figures

Figure 1. Flow diagram of patient enrollment.
Figure 1. Flow diagram of patient enrollment.
Patients hospitalized between January 1, 2000 and December 31, 2011 were screened using inclusion and exclusion criteria. Totally 587 patients were identified for final analysis. Abbreviation: AKI, acute kidney injury; CKD, chronic kidney disease; RAS, renin-angiotensin system.
Figure 2. Kaplan-Meier analysis of CKD-free-survival for…
Figure 2. Kaplan-Meier analysis of CKD-free-survival for users and non-users of RAS inhibitor.
Figure 3. Hazard ratio (95% confidence interval)…
Figure 3. Hazard ratio (95% confidence interval) for ensuing CKD associated with use of RAS inhibitor in subgroups of enrolled patients.
Abbreviation: CI, confidence interval; HTN, hypertension.

References

    1. Lafrance J. P. & Miller D. R. Acute kidney injury associates with increased long-term mortality. J Am Soc Nephrol 21, 345–352 (2010).
    1. Yang L. et al.. Acute kidney injury in China: a cross-sectional survey. Lancet 386, 1465–1471 (2015).
    1. Xu X. et al.. Epidemiology and clinical correlates of AKI in Chinese hospitalized adults. Clin J Am Soc Nephrol 10, 1510–1518 (2015).
    1. Mehta R. L. et al.. Recognition and management of acute kidney injury in the International Society of Nephrology 0by25 Global Snapshot: a multinational cross-sectional study. Lancet 387, 2017–2025 (2016).
    1. Chawla L. S. & Kimmel P. L. Acute kidney injury and chronic kidney disease: an integrated clinical syndrome. Kidney Int 82, 516–524 (2012).
    1. Lai C. F. et al.. Kidney function decline after a non-dialysis-requiring acute kidney injury is associated with higher long-term mortality in critically ill survivors. Crit Care 16, R123 (2012).
    1. Chawla L. S., Eggers P. W., Star R. A. & Kimmel P. L. Acute kidney injury and chronic kidney disease as interconnected syndromes. N Engl J Med 371, 58–66 (2014).
    1. Singer E. et al.. Urinary neutrophil gelatinase-associated lipocalin distinguishes pre-renal from intrinsic renal failure and predicts outcomes. Kidney Int 80, 405–414 (2011).
    1. Thakar C. V., Christianson A., Himmelfarb J. & Leonard A. C. Acute kidney injury episodes and chronic kidney disease risk in diabetes mellitus. Clin J Am Soc Nephol 6, 2567–2572 (2011).
    1. Heung M. et al.. Acute kidney injury recovery pattern and subsequent risk of CKD: An analysis of Veterans Health Administration Data. Am J Kidney Dis 67, 742–752 (2016).
    1. Chou Y. H., Pan S. Y., Yang C. H. & Lin S. L. Stem cells and kidney regeneration. J Formos Med Assoc 113, 201–209 (2014).
    1. Chou Y. H. et al.. The role of brain natriuretic peptide in predicting renal outcome and fluid management in critically ill patients. J Formos Med Assoc 114, 1187–1196 (2015).
    1. Chou Y. H. et al.. Impact of timing of renal replacement therapy initiation on outcome of septic acute kidney injury. Crit Care 15, R134 (2011).
    1. Ferenbach D. A. & Bonventre J. V. Mechanisms of maladaptive repair after AKI leading to accelerated kidney ageing and CKD. Nat Rev Nephrol 11, 264–276 (2015).
    1. Yang L., Besschetnova T. Y., Brooks C. R., Shah J. V. & Bonventre J. V. Epithelial cell cycle arrest in G2/M mediates kidney fibrosis after injury. Nat Med 16, 535–543 (2010).
    1. Chen Y. T. et al.. Platelet-derived growth factor receptor signaling activates pericyte-myofibroblast transition in obstructive and post-ischemic kidney fibrosis. Kidney Int 80, 1170–1181 (2011).
    1. Wu C. F. et al.. Transforming growth factor beta-1 stimulates profibrotic epithelial signaling to activate pericyte-myofibroblast transition in obstructive kidney fibrosis. Am J Pathol 182, 118–131 (2013).
    1. Horbelt M. et al.. Acute and chronic microvascular alterations in a mouse model of ischemic acute kidney injury. Am J Physiiol Renal Physiol 293, F688–695 (2007).
    1. Lin S. L. et al.. Targeting endothelium-pericyte cross talk by inhibiting VEGF receptor signaling attenuates kidney microvascular rarefaction and fibrosis. Am J Pathol 178, 911–923 (2011).
    1. Cheng S. Y. et al.. Losartan reduces ensuing chronic kidney disease and mortality after acute kidney injury. Sci Rep 6, 34265 (2016).
    1. Rodriguez-Romo R. et al.. AT1 receptor antagonism before ischemia prevents the transition of acute kidney injury to chronic kidney disease. Kidney Int 89, 363–373 (2016).
    1. Zhang J. et al.. Competing actions of type 1 angiotensin II receptors expressed on T lymphocytes and kidney epithelium during cisplatin-induced AKI. J Am Soc Nephrol 27, 2257–2264 (2016).
    1. Zuk A. & Bonventre J. V. Acute kidney injury. Annu Rev Med 67, 293–307 (2016).
    1. Rewa O. & Bagshaw S. M. Acute kidney injury-epidemiology, outcomes and economics. Nat Rev Nephrol 10, 193–207 (2014).
    1. Finkenstaedt J. T. & Merrill J. P. Renal function after recovery from acute renal failure. N Engl J Med 254, 1023–1026 (1956).
    1. Newsome B. B., Warnock D. G. & McClellan W. M. et al.. Long-term risk of mortality and end-stage renal disease among the elderly after small increases in serum creatinine level during hospitalization for acute myocardial infarction. Arch Intern Med 168, 609–616 (2008).
    1. Ishani A. et al.. The magnitude of acute serum creatinine increase after cardiac surgery and the risk of chronic kidney disease, progression of kidney disease, and death. Arch Intern Med 171, 226–233 (2011).
    1. Wu V. C. et al.. Long-term risk of coronary events after AKI. J Am Soc Nephrol 25, 595–605 (2014).
    1. Macedo E., Zanetta D. M. & Abdulkader R. C. Long-term follow-up of patients after acute kidney injury: patterns of renal functional recovery. PloS one 7, e36388 (2012).
    1. Macedo E., Bouchard J. & Mehta R. L. Renal recovery following acute kidney injury. Curr Opin Crit Care 14, 660–665 (2008).
    1. Bellomo R. Defining, quantifying, and classifying acute renal failure. Crit Care Clin 21, 223–237 (2005).
    1. Huang T. M. et al.. Preoperative proteinuria predicts adverse renal outcomes after coronary artery bypass grafting. J Am Soc Nephrol 22, 156–163 (2011).
    1. Shiao C. C. et al.. Late initiation of renal replacement therapy is associated with worse outcomes in acute kidney injury after major abdominal surgery. Crit Care 13, R171 (2009).
    1. Shiao C. C. et al.. U-curve association between timing of renal replacement therapy initiation and in-hospital mortality in postoperative acute kidney injury. PloS one 7, e42952 (2012).
    1. Wu V. C. et al.. The impact of acute kidney injury on the long-term risk of stroke. J Am Heart Assoc 3, e000933 (2014).
    1. Wu V. C. et al.. Acute-on-chronic kidney injury at hospital discharge is associated with long-term dialysis and mortality. Kidney Int 80, 1222–1230 (2011).
    1. Uchino S. et al.. Acute renal failure in critically ill patients: a multinational, multicenter study. JAMA 294, 813–818 (2005).
    1. Thiele R. H., Isbell J. M. & Rosner M. H. AKI associated with cardiac surgery. Clin J Am Soc Nephrol 10, 500–514 (2015).
    1. Rosner M. H., Portilla D. & Okusa M. D. Cardiac surgery as a cause of acute kidney injury: pathogenesis and potential therapies. J Intensive Care Med 23, 3–18 (2008).
    1. Chertow G. M., Burdick E., Honour M., Bonventre J. V. & Bates D. W. Acute kidney injury, mortality, length of stay, and costs in hospitalized patients. J Am Soc Nephrol 16, 3365–3370 (2005).
    1. Endo T. et al.. Exploring the origin and limitations of kidney regeneration. J Pathol 236, 251–263 (2015).
    1. Ko G. J. et al.. Transcriptional analysis of kidneys during repair from AKI reveals possible roles for NGAL and KIM-1 as biomarkers of AKI-to-CKD transition. Am J Physiol Renal Physiol 298, F1472–1483 (2010).
    1. Bechtel W. et al.. Methylation determines fibroblast activation and fibrogenesis in the kidney. Nat Med 16, 544–550 (2010).
    1. Chang Y. T. et al.. DNA methyltransferase inhibition restores erythropoietin production in fibrotic murine kidneys. J Clin Invest 126, 721–731 (2016).
    1. Bellomo R. et al.. The pathophysiology of cardiac surgery-associated acute kidney injury (CSA-AKI). Int J Artif Organs 31, 166–178 (2008).
    1. Cao W. et al.. Overexpression of intrarenal renin-angiotensin system in human acute tubular necrosis. Kidney Blood Press Res 41, 746–756 (2016).
    1. Rosen S. & Stillman I. E. Acute tubular necrosis is a syndrome of physiologic and pathologic dissociation. J Am Soc Nephrol 19, 871–875 (2008).
    1. Yang X. et al.. Urinary angiotensinogen level predicts AKI in acute decompensated heart failure: a prospective, two-stage study. J Am Soc Nephrol 26, 2032–2041 (2015).
    1. Venkatachalam M. A. et al.. Acute kidney injury: a springboard for progression in chronic kidney disease. Am J Physiol Renal Physiol 298, F1078–1094 (2010).
    1. Hsu C. Y. et al.. Elevated BP after AKI. J Am Soc Nephrol 27, 914–923 (2016).
    1. Molnar M. Z. et al.. Angiotensin-converting enzyme inhibitor, angiotensin receptor blocker use, and mortality in patients with chronic kidney disease. J Am Coll Cardiol 63, 650–658 (2014).
    1. Lewis E. J. et al.. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med 345, 851–860 (2001).
    1. Brenner B. M. et al.. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 345, 861–869 (2001).
    1. Huang T. M. et al.. Association of pre-operative ACEIs or ARBs with a reduction in post-operative AKI after elective CABG. J Am Soc Nephrol 27, 75A (2010).
    1. Ronco C., Haapio M., House A. A., Anavekar N. & Bellomo R. Cardiorenal syndrome. J Am Coll Cardiol 52, 1527–1539 (2008).
    1. Yancy C. W. et al.. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 62, e147–239 (2013).
    1. Lund L. H., Benson L., Dahlstrom U. & Edner M. Association between use of renin-angiotensin system antagonists and mortality in patients with heart failure and preserved ejection fraction. JAMA 308, 2108–2117 (2012).
    1. McClellan W. M. & Flanders W. D. Risk factors for progressive chronic kidney disease. J Am Soc Nephrol 14, S65–70 (2003).
    1. Li L. et al.. Is hyperuricemia an independent risk factor for new-onset chronic kidney disease?: A systematic review and meta-analysis based on observational cohort studies. BMC Nephrol 15, 122 (2014).
    1. Walsh M. et al.. The association between perioperative hemoglobin and acute kidney injury in patients having noncardiac surgery. Anesth Analg 117, 924–931 (2013).
    1. Sawhney S., Mitchell M., Marks A., Fluck N. & Black C. Long-term prognosis after acute kidney injury (AKI): what is the role of baseline kidney function and recovery? A systematic review. BMJ Open 5, e006497 (2015).
    1. Chen L. I. et al.. Modification of diet in renal disease (MDRD) study and CKD epidemiology collaboration (CKD-EPI) equations for Taiwanese adults. PloS one 9, e99645 (2014).
    1. Okusa M. D. & Davenport A. Reading between the (guide)lines–the KDIGO practice guideline on acute kidney injury in the individual patient. Kidney Int 85, 39–48 (2014).

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