American Journal of Cardiovascular Drugs

, Volume 2, Issue 3, pp 157–162

Cardiovascular Risk in Patients with Early Renal Insufficiency

Implications for the Use of ACE Inhibitors
  • Johannes F. E. Mann
  • Hertzel C. Gerstein
  • Janice Pogue
  • Eva Lonn
  • Salim Yusuf
Leading Article


Patients with end-stage renal disease die from cardiovascular disease at a much younger age than people in the general population do. Here, we review the evidence linking early renal insufficiency (ERI) to an increased cardiovascular risk. A number of cardiovascular risk factors become prevalent with ERI, including night-time hypertension, increase in serum levels of lipoprotein (a), homocysteine and asymmetric dimethyl-arginine, and insulin resistance. Also, an epidemiologic association between coronary artery disease (CAD) and nephrosclerosis, a frequent cause of ERI in the elderly, is documented. In the middle-aged, general population ERI, found in 8% of women and 9% of men, was not associated with cardiovascular disease. However, in a representative sample of middle-aged British men the risk of stroke was 60% higher for the subgroup of individuals with ERI. In people at high cardiovascular risk (mostly CAD), the Heart Outcomes Prevention Evaluation (HOPE) study found a 2-fold (unadjusted) or 1.4-fold (adjusted) higher incidence of cardiovascular outcomes with ERI. The incidence of primary outcome increased with the level of serum creatinine. At least four studies have determined the cardiovascular risk associated with ERI in hypertension. In Hypertension Detection and Follow-up Program, as in HOPE, cardiovascular mortality increased with higher serum creatinine levels (5-fold difference in cardiovascular mortality between the lowest and the highest creatinine strata). In patients with hypertension with low risk, the Hypertension Optimal Treatment and a small Italian trial found about a doubling in cardiovascular outcomes in ERI. However, in the Multiple Risk Factor Intervention Trial, not baseline serum creatinine level, but its increase on follow-up predicted future cardiovascular disease. These observational data suggest that ERI, independent of etiology, is a strong predictor of cardiovascular disease, present in 10% of a population at low, and up to 30% at high, cardiovascular risk. No prospective therapeutic trials aimed at reducing the cardiovascular burden in individuals with ERI are available. Subgroup analyses of the HOPE study indicate that ACE inhibition with ramipril is beneficial without an increased risk of adverse effects like acute renal failure or hyperkalemia. Thus the frequent practice of withholding ACE inhibitors from patients with mild renal insufficiency is unwarranted, especially since this identifies a group at high risk who appears to benefit most from treatment. In addition, there is evidence that ACE inhibitors improve renal outcomes in renal insufficiency. Prospective studies should test the predictive power of ERI for cardiovascular disease and therapeutic options.


  1. 1.
    Parfrey PS, Foley RN. The clinical epidemiology of cardiac disease in chronic uremia. J Am Soc Nephrol 1999; 10: 1053–8Google Scholar
  2. 2.
    Baigent C, Burbury K, Wheeler D. Premature cardiovascular disease in chronic renal failure. Lancet 2000; 356: 147–52PubMedCrossRefGoogle Scholar
  3. 3.
    Raine AEG, Schwarz U, Ritz E. The patient with uremia: hypertension and cardiac problems. In: Davison AM, et al. editors. Oxford textbook of clinical nephrology. Oxford: Oxford University Press, 1998: 1885–919Google Scholar
  4. 4.
    Besarab A, Bolton WK, Browne JK. The effects of normal as compared to low hematocrit values in patients with cardiac disease who are receiving hemodialysis and erythropoietin. N Engl J Med 1998; 339: 584–90PubMedCrossRefGoogle Scholar
  5. 5.
    Stefanski M, Schmidt KG, Waldherr R, et al. Early increase in blood pressure and diastolic left ventricular malfunction in patients with glomerulonephritis. Kidney Int 1996; 50: 1321–6PubMedCrossRefGoogle Scholar
  6. 6.
    Kronenberg F, Kuen E, Ritz E, et al. Lp (a) concentrations in mild and moderate renal failure. J Am Soc Nephrol 2000; 11: 105–15PubMedGoogle Scholar
  7. 7.
    Jungers P, Joly D, Massy Z, et al. Sustained reduction of hyperhomoysteinemia with folic acid supplementation in predialysis patients. Nephrol Dial Transplant 1999; 14: 2903–6PubMedCrossRefGoogle Scholar
  8. 8.
    Fliser D, Pacini G, Engelleiter R, et al. Insulin resistance and hyperinsulnemia are already present in patients with incipient renal disease. Kidney Int 1998; 53: 1343–7PubMedCrossRefGoogle Scholar
  9. 9.
    Kasiske BL. Relationship between vascular disease and age-associated changes in the human kidney. Kidney Int 1987; 31: 1153–9PubMedCrossRefGoogle Scholar
  10. 10.
    Tracy RE, Malcolm GT, Oalmann MC, et al. Nephrosclerosis in coronary artery disease. Mod Pathol 1994; 7: 301–9PubMedGoogle Scholar
  11. 11.
    McCullough PA, Soman SS, Sha SS, et al. Risks associated with renal dysfunction in patients in the coronary care unit. J Am Coll Cardiol 2000; 36: 679–84PubMedCrossRefGoogle Scholar
  12. 12.
    Culleton BF, Larson MG, Wilson PWF, et al. Cardiovascular disease and mortality in a community-based cohort with mild renal insufficiency. Kidney Int 1999; 56: 2214–9PubMedCrossRefGoogle Scholar
  13. 13.
    Wannamethee SG, Shaper AG, Perry IJ. Serum creatinine concentration and risk of cardiovascular disease: a possible marker of increased risk for stroke. Stroke 1997; 28: 557–63PubMedCrossRefGoogle Scholar
  14. 14.
    Mann JFE, Gerstein HC, Pogue J, et al. Renal insufficiency as a predictor of cardiovascular outcomes and the impact of ramipril: the HOPE randomized trial. Ann Intern Med 2001; 134: 629–36PubMedGoogle Scholar
  15. 15.
    Gerstein HC, Mann JFE, Qilong Y, et al. Albuminuria and cardiovascular events, death and heart failure in diabetic and non-diabetic individuals. JAMA 2001; 286: 421–6PubMedCrossRefGoogle Scholar
  16. 16.
    Shulman NB, Ford CE, Hall WD, et al. Prognostic value of serum creatinine and the effect of treatment of hypertension on renal function: HDFP results. Hypertension 1989; 13 Suppl. 1: I–80–I–93Google Scholar
  17. 17.
    Ruilope LM, Salvetti A, Jamerson K, et al. Renal function and intensive lowering of blood pressure in hypertensive participants of the hypertension optimal treatment (HOT) study. J Am Soc Nephrol 2001; 12: 218–25PubMedGoogle Scholar
  18. 18.
    Schillaci G, Reboldi G, VerdecchiaP. High normal serum creatinine concentration is a predictor of cardiovascular risk in essential hypertension. Arch Intern Med 2001; 161: 688–94CrossRefGoogle Scholar
  19. 19.
    Flack JM, Neaton JD, Daniels B, et al. Ethnicity and renal disease: lessons from the MRFIT trial and the treatment of mild hypertension study. Am J Kidney Dis 1993; 21 Suppl. 1: 31–40PubMedGoogle Scholar
  20. 20.
    Maschio G, Alberti D, Janin G, et al. Effects of the ACE inhibitor benazepril on the progression of chronic renal insufficiency. N Engl J Med 1996; 334: 939–45PubMedCrossRefGoogle Scholar
  21. 21.
    Ruggenenti P, Perna P, Gherardi G, et al. Renal function and requirement for dialysis in chronic nephropathy patients on long-term ramipril: REIN follow-up trial. Lancet 1998; 352: 1252–6PubMedCrossRefGoogle Scholar
  22. 22.
    Bakris GL, Weir MR. Angiotensin converting enzyme inhibitor-associated elevations in serum-creatinine: is this a cause for concern? Arch Intern Med 2000; 160: 685–93PubMedCrossRefGoogle Scholar
  23. 23.
    The HOPE study investigators. Effects of an ACE inhibitor, ramipril, on cardiovascular events in high risk patients. N Engl J Med 2000; 342: 145–53CrossRefGoogle Scholar
  24. 24.
    The HOPE Study Investigators. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO HOPE substudy. Lancet 2000; 255: 253–9Google Scholar

Copyright information

© Adis International Limited 2002

Authors and Affiliations

  • Johannes F. E. Mann
    • 1
    • 2
    • 3
  • Hertzel C. Gerstein
    • 3
  • Janice Pogue
    • 3
  • Eva Lonn
    • 3
  • Salim Yusuf
    • 3
  1. 1.Dept. of Nephrology and Hypertension, Schwabing General HospitalLMUMünchenGermany
  2. 2.German Institute for High Blood Pressure ResearchHeidelbergGermany
  3. 3.McMaster UniversityHamiltonCanada

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