Renal Consequences of Prostaglandin Inhibition in Heart Failure

  • Eric M. Brown
  • Daniel J. Salzberg
  • Matthew R. Weir


Prostaglandins are products of intracellular arachidonate metabolism via the cyclooxygenase pathways. In the kidney, prostaglandins are modulators of afferent arteriole autoregulation. In states of diminished effective intravascular volume, vasodilatory prostaglandins reduce afferent arteriolar resistance, helping to maintain overall glomerular filtration. In subjects who have a low perfusion state, as in congestive heart failure (CHF), hepatorenal syndrome, and cirrhosis, impaired renal autoregulation occurs, predisposing to kidney injury. Adverse effects of prostaglandin inhibition include acute kidney injury, hyperkalemia, hypertension, and edema. Hypertension and edema occur because prostaglandins play an important role in renal regulation of salt and water balance. This review summarizes the renal consequences of using prostaglandin inhibitors in subjects who have CHF.


Chronic Kidney Disease Congestive Heart Failure Acute Kidney Injury Nonselective NSAID Cortical Collect Duct 
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  1. 1.
    Schrier RW. Cardiorenal versus renocardiac syndrome: is there a difference? Nat Clin Pract Nephrol. 2007;3:637.PubMedCrossRefGoogle Scholar
  2. 2.
    Krumholz HM, Chen Y. Correlates and impact on outcomes of worsening renal function in patients ≥65 years of age with heart failure. Am J Cardiol. 2000;85:1110–3.PubMedCrossRefGoogle Scholar
  3. 3.
    Gottlieb SS, Abraham W. The prognostic importance of different definitions of worsening renal function in congestive heart failure. J Card Fail. 2002;8:136–41.PubMedCrossRefGoogle Scholar
  4. 4.
    Smith GL, Vaccarino V. Worsening renal function: what is a clinically meaningful change in creatinine during hospitalization with heart failure? J Card Fail. 2003;9:13–25.PubMedCrossRefGoogle Scholar
  5. 5.
    Cowie MR, Komajda M. Prevalence and impact of worsening renal function in patients hospitalized with decompensated heart failure: results of the prospective study in heart failure (POSH). Eur Heart J. 2006;27:1216–22.PubMedCrossRefGoogle Scholar
  6. 6.
    Nohria A, Hasselblad V, Stebbins A, et al. Cardiorenal interactions: insights from the ESCAPE trial. J Am Coll Cardiol. 2008;51:1268–74.PubMedCrossRefGoogle Scholar
  7. 7.
    Logeart D, Tabet J. Transient worsening of renal function during hospitalization for acute heart failure alters outcome. Int J Cardiol. 2008;127:228–32.PubMedCrossRefGoogle Scholar
  8. 8.
    Metra M, Nodari S. Worsening renal function in patients hospitalized for acute heart failure: clinical implications and prognostic significance. Eur J Heart Fail. 2008;10:188–95.PubMedCrossRefGoogle Scholar
  9. 9.
    Hillege HL, Nitsch D, Pfeffer MA, et al. Renal function as a predictor of outcome in a broad spectrum of patients with heart failure. Circulation. 2006;113:671–8.PubMedCrossRefGoogle Scholar
  10. 10.
    Dries DL, Exner DV, Domanski MJ, et al. The prognostic implications of renal insufficiency in symptomatic and asymptomatic patients with left ventricular systolic dysfunction. J Am Coll Cardiol. 2000;35(3):681–9.PubMedCrossRefGoogle Scholar
  11. 11.
    Dzau VJ. Renal and circulatory mechanisms in congestive heart failure. Kidney Int. 1987;31(6):1402–15.PubMedCrossRefGoogle Scholar
  12. 12.
    Cogan MG. Angiotensin II: a potent controller of sodium transport in the early proximal tubule. Hypertension. 1990;15(5):451–8.PubMedCrossRefGoogle Scholar
  13. 13.
    Rose BD, Post TW. Clinical Physiology of Acid-Base and Electrolyte Disorders. 5th ed. New York: McGraw-Hill; 2001.Google Scholar
  14. 14.
    Hebert RL, Regnier L, Peterson LN. Rabbit cortical collecting ducts express a novel prostacyclin receptor. Am J Physiol. 1995;268:F145–54.PubMedGoogle Scholar
  15. 15.
    Hebert RL, Jacobson HR, Breyer MD. Prostaglandin E2 inhibits sodium transport in rabbit cortical collecting duct by increasing intracellular calcium. J Clin Invest. 1991;87:1992–8.PubMedCrossRefGoogle Scholar
  16. 16.
    Friss UG, Stubbe J, Uhrenholt TR, et al. Prostaglandin E2 EP2 and EP4 receptor activation mediates cAMP-dependent hyperpolarization and exocytosis of renin in juxtaglomerular cells. Am J Physiol Renal Physiol. 2005;289:F989–97.CrossRefGoogle Scholar
  17. 17.
    Chen L, Kim SM, Oppermann M, et al. Regulation of renin in mice with Cre recombinase mediated deletion of G protein Gsα in juxtaglomerular cells. Am J Physiol Renal Physiol. 2005;292:F27–37.CrossRefGoogle Scholar
  18. 18.
    Tang L, Loutzenhiser K, Loutzenhiser R. Biphasic actions of prostaglandin E2 on the renal afferent arteriole. Circ Res. 2000;86:663–70.PubMedCrossRefGoogle Scholar
  19. 19.
    Purdy KE, Arendshorst WJ. EP1 and EP4 receptors mediate prostaglandin E2 actions in the microcirculation of rat kidney. Am J Physiol Renal Physiol. 2000;279:F755–64.PubMedGoogle Scholar
  20. 20.
    Imig JD, Breyer MD, Breyer RD. Contribution of prostaglandin EP2 receptors to renal microvascular reactivity in mice. Am J Physiol Renal Physiol. 2002;283:F415–22.PubMedGoogle Scholar
  21. 21.
    Nasrallah R, Clark J, Hébert RL. Prostaglandins in the kidney: developments since Y2K. Clin Sci. 2007;113:297–311.PubMedCrossRefGoogle Scholar
  22. 22.
    Oida H, Namba T, Sugimoto Y, et al. In situ hybridization studies of prostacyclin receptor mRNA expression in various mouse organs. Br J Pharmacol. 1995;116:2828–37.PubMedCrossRefGoogle Scholar
  23. 23.
    Nasrallah R, Hébert RL. Prostacyclin signaling in the kidney: implications for health and disease. Am J Physiol Renal Physiol. 2005;289:235–46.CrossRefGoogle Scholar
  24. 24.
    Furci L, Fitzgerald DJ, Fitzgerald GA. Heterogeneity of prostaglandin H2/thromboxane A2 receptors: distinct subtypes mediate vascular smooth muscle contraction and platelet aggregation. J Pharmacol Exp Ther. 1991;258:74–81.PubMedGoogle Scholar
  25. 25.
    Wilcox CS, Welch WJ, Snellen H. Thromboxane mediates renal hemodynamic response to infused angiotensin II. Kidney Int. 1991;40:1090–7.PubMedCrossRefGoogle Scholar
  26. 26.
    Paul BZ, Jin J, Kunapuli SP. Molecular mechanisms of thromboxane A2-induced platelet aggregation. Essential role for p2t(ac) and alpha(2a) receptors. J Biol Chem. 1999;274(41):29108–13.PubMedCrossRefGoogle Scholar
  27. 27.
    Okumura M, Imanishi M, Okamura M, et al. Role for thromboxane A2 from glomerular thrombi in nephropathy with type 2 diabetic rats. Life Sci. 2003;72:2695–705.PubMedCrossRefGoogle Scholar
  28. 28.
    Vane JR, Botting RM. Thromb Res. 2003;110(5–6):255–6.PubMedCrossRefGoogle Scholar
  29. 29.
    Weksler BB, Pett SB, Alonso D, et al. Differential inhibition by aspirin of vascular and platelet prostaglandin synthesis in atherosclerotic patients. N Engl J Med. 1983;308(14):800–5.PubMedCrossRefGoogle Scholar
  30. 30.
    Jaffe EA, Weksler BB. Recovery of endothelial cell prostacyclin production after inhibition by low doses of aspirin. J Clin Invest. 1979;63:532–5.PubMedCrossRefGoogle Scholar
  31. 31.
    Roth GJ, Stanford N, Majerus PW. Acetylation of prostaglandin synthase by aspirin. Proc Natl Acad Sci USA. 1975;72:3073–6.PubMedCrossRefGoogle Scholar
  32. 32.
    Whelton A. Nephrotoxicity of nonsteroidal anti-inflammatory drugs: physiologic foundations and clinical implications. Am J Med. 1999;106(5B):13S–24.PubMedCrossRefGoogle Scholar
  33. 33.
    Harris RC. An update on cyclooxygenase-2 expression and metabolites in the kidney. Curr Opin Nephrol Hypertens. 2008;17:64–9.PubMedCrossRefGoogle Scholar
  34. 34.
    Peti-Peterdi J, Komlosi P, Fuson AL, et al. Luminal NaCl delivery regulates basolateral PGE2 release from macula densa cells. J Clin Invest. 2003;112:76–82.PubMedGoogle Scholar
  35. 35.
    Qi Z, Cai H, Morrow JD, Breyer MD. Differentiation of cyclooxygenase 1- and 2-derived prostanoids in mouse kidney and aorta. Hypertension. 2006;48:323–8.PubMedCrossRefGoogle Scholar
  36. 36.
    Swan SK, Rudy DW, Lasseter KC, et al. Effect of cyclooxygenase-2 inhibition on renal function in elderly persons receiving a low-salt diet. A randomized, controlled trial. Ann Intern Med. 2000;133(1):1–9.PubMedGoogle Scholar
  37. 37.
    Laffi G, Daskalopoulos G, Kronborg I, et al. Effects of sulindac and ibuprofen in patients with cirrhosis and ascites. An explanation for the renal-sparing effect of sulindac. Gastroenterology. 1986;90(1):182–7.PubMedGoogle Scholar
  38. 38.
    Pope JE, Anderson JJ, Felson DT. A meta-analysis of the effects of nonsteroidal anti-inflammatory drugs on blood pressure. Arch Intern Med. 1993;153:477–84.PubMedCrossRefGoogle Scholar
  39. 39.
    Wong DG, Spence JD, Lamki L, et al. Effect of non-steroidal anti-inflammatory drugs on control of hypertension by β-blockers and diuretics. Lancet. 1986;1(8488):997–1001.PubMedCrossRefGoogle Scholar
  40. 40.
    Sahloul MZ, al-Kiek R, Ivanovich P, Mujais SK. Nonsteroidal anti-inflammatory drugs and antihypertensives. Cooperative malfeasance. Nephron. 1990;56:345–52.PubMedCrossRefGoogle Scholar
  41. 41.
    Dzau VJ, Packer M, Lilly LS, et al. Prostaglandins in severe congestive heart failure. Relation to activation of the renin–angiotensin system and hyponatremia. N Engl J Med. 1984;310(6):347–52.PubMedCrossRefGoogle Scholar
  42. 42.
    Brater DC. Analysis of the effect of indomethacin on the response to furosemide in man: effect of dose of furosemide. J Pharmacol Exp Ther. 1979;210(3):386–90.PubMedGoogle Scholar
  43. 43.
    Feenstra J, Heerdink ER, Grobbee DE. Association of nonsteroidal anti-inflammatory drugs with first occurrence of heart failure and with relapsing heart failure. Arch Intern Med. 2002;162:265–70.PubMedCrossRefGoogle Scholar
  44. 44.
    Heerdink ER, Leufkens HG, Herings RMC, et al. NSAIDS associated with increased risk of CHF in elderly patients taking diuretics. Arch Intern Med. 1998;158:1108–12.PubMedCrossRefGoogle Scholar
  45. 45.
    Mamdani M, Juurlink DN, Lee DS, et al. Cyclo-oxygenase-2 inhibitors versus non-selective non-steroidal anti-inflammatory drugs and congestive heart failure outcomes in elderly patients: a population-based cohort study. Lancet. 2004;363(9423):1751–6.PubMedCrossRefGoogle Scholar
  46. 46.
    Gislason GH, Rasmussen JN, Abildstrom SZ, et al. Increased mortality and cardiovascular morbidity associated with use of nonsteroidal anti-inflammatory drugs in chronic heart failure. Arch Intern Med. 2009;169(2):141–9.PubMedCrossRefGoogle Scholar
  47. 47.
    Garella S, Matarese RA. Renal effects of prostaglandins and clinical adverse effects of nonsteroidal anti-inflammatory agents. Medicine. 1984;63:165–81.PubMedCrossRefGoogle Scholar
  48. 48.
    Whelton A, Hamilton CW. Nonsteroidal anti-inflammatory drugs: effects on kidney function. J Clin Pharmacol. 1991;31:588–98.PubMedGoogle Scholar
  49. 49.
    Kurata C, Uehara A, Sugi T, et al. Syncope caused by nonsteroidal anti-inflammatory drugs and angiotensin-converting enzyme inhibitors. Jpn Circ J. 1999;63:1002–3.PubMedCrossRefGoogle Scholar
  50. 50.
    Jolobe OMP. Evaluation of renal function in elderly patients on ACE inhibitors. Postgrad Med J. 1999;75:275–7.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2012

Authors and Affiliations

  • Eric M. Brown
    • 1
  • Daniel J. Salzberg
    • 1
  • Matthew R. Weir
    • 1
  1. 1.Division of Nephrology, Department of MedicineUniversity of Maryland, School of MedicineBaltimoreUSA

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