Accelerated decline and prognostic impact of renal function after myocardial infarction and the benefits of ACE inhibition: the CATS randomized trial

H.L. Hillegea,*, W.H. van Gilsta,b, D.J. van Veldhuisena, G. Navisc, D.E. Grobbeed, P.A. de Graeffb,e and D. de Zeeuwb

a Trial Coordination Center/Department of Cardiology/Thoraxcenter, University Hospital Groningen, Hanzeplein 1, 9700 Groningen, The Netherlands
b Department of Clinical Pharmacology, State University Groningen, Groningen, The Netherlands
c Division of Nephrology, Department of Internal Medicine, University Hospital Groningen, Groningen, The Netherlands
d Julius Center for Patient Oriented Research, University Medical Center, Utrecht, The Netherlands
e Department of Internal Medicine, University Hospital Groningen, Groningen, The Netherlands

* Corresponding author. Tel.: +31-50-361-8066; fax: +31-50-361-8062
E-mail address: h.hillege{at}tcc.azg.nl

Received 31 May 2002; revised 15 July 2002; accepted 24 July 2002


    Abstract
 Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Aims Information regarding the cardiorenal axis in patients after a myocardial infarction (MI) is limited. We examined the change in renal function after a first MI, the protective effect of angiotensin converting enzyme (ACE) inhibition and the prognostic value of baseline renal function.

Methods and results The study population consisted of 298 patients with a first anterior wall MI who were randomized to the ACE inhibitor captopril or placebo after completion of streptokinase infusion. Renal function, by means of glomerular filtration rate (GFR), was calculated using the Cockroft–Gault equation (GFRc). In the placebo group, renal function (GFRc) declined by 5.5mlmin–1within 1 year, vs only 0.5mlmin–1in the ACE inhibitor group . This beneficial effect of captopril was most pronounced in patients with the most compromised renal function at baseline. The incidence of chronic heart failure (CHF) within 1 year increased significantly with decreasing GFRc(divided into tertiles: 24.0, 28.9, and 41.2%; ). The risk-ratio for GFRc<81mlmin–1vs >103mlmin–1was 1.86 (95% CI 1.11–3.13; ).

Conclusions Renal function markedly deteriorates after a first MI, but is significantly preserved by ACE inhibition. Furthermore, an impaired baseline renal function adds to the prognostic risk of developing CHF in patients after a first anterior MI.

Key Words: Renal function • Myocardial infarction • Prognosis • Angiotensin converting enzyme inhibitors


    1. Introduction
 Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
The degree of renal dysfunction is one of the most powerful prognostic markers in patients with chronic heart failure (CHF).1,2 Recently, it has been demonstrated that moderate renal insufficiency, while tolerated in patients with a normal heart, could independently precipitate the development of overt CHF in patients with asymptomatic CHF.1 ‘Subclinical’ impaired renal function is not uncommon in the general population. In a large community sample, elevated serum creatinine values were found in 8.7% of men and 8.0% of women.3 The Framingham data show that the presence of mild renal insufficiency is associated with other cardiovascular risk factors.4 Some of these risk factors could contribute simultaneously to an increase in cardiovascular risk and to an early decline in renal function. Although there is increasing evidence that renal dysfunction is strongly associated with cardiovascular disease it is not clear whether they are independent or are more likely to interact with each other. To answer this question the cardiorenal axis in patients with acute myocardial infarction (MI) is of interest. An accelerated decline of renal function, even in subjects without renal disease, has been observed in diabetics, severe hypertension, dyslipidemia and CHF.5–8 A history of MI is the strongest predictor of CHF, but the time course and prognostic value of renal function in patients with an MI have never been evaluated. Angiotensin converting enzyme (ACE) inhibition has been demonstrated to reduce cardiac morbidity and improve survival post-MI.9 Furthermore, ACE inhibition was shown to be protective against progressive renal function loss in both diabetic and non-diabetic renal disease patients.10–12

The objectives of the present study were, therefore, threefold. We studied the changes in renal function following a first MI, and the potential renal protective effect of ACE inhibition. In addition, we studied the prognostic value of baseline renal function for the development of CHF.


    2. Methods
 Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
2.1. Patient population and study design
The study population consisted of patients who were enrolled in a post-MI trial (Captopril and Thrombolysis Study, CATS).13 Details of CATS have been described previously. Briefly, the study investigated the effect of captopril relative to placebo on the preservation of left ventricular volume as measured by serial echocardiography. The study was conducted in 12 centres in the Netherlands and 298 patients with a first anterior wall MI were randomized to captopril or placebo, initiated immediately upon completion of the streptokinase infusion. Patients were excluded in case of severe CHF (Killip class III or IV), severe renal insufficiency (serum creatinine >180µmoll–1), systolic blood pressure (SBP) >200mmHg or <100mmHg, diastolic blood pressure >120mmHg or <55mmHg. Double-blind medication was initiated provided SBP was stable and above or equal to 100mmHg and continued provided that the SBP was above or equal to 95mmHg. If the SBP was below 95mmHg, study medication was withheld until the next dosing scheme. The target maintenance dose of captopril was 25mg t.i.d. During the 12 months of double-blind therapy, concomitant therapy with calcium antagonists, beta-blockers or nitrates was instituted for specific reasons, e.g. angina pectoris and hypertension. The recommended dose of aspirin was 80mg.

2.2. Renal endpoint parameter
The glomerular filtration rate (GFR) is the standard indicator of renal function. Under steady-state conditions, GFR can be estimated from serum creatinine using the Cockgroft–Gault formula that accounts for the influence of age and body weight on creatinine production: . In women, the value is multiplied by 0.85.14 This formula has been validated in several studies in different patient populations and is frequently used in patients with increased cardiovascular risk and CHF.1,2,15,16 Patients were studied on six separate occasions over a 12-month period, with the day of MI taken as baseline assessment (day 0), days 3, 10, 90, 180 and 360 after infarction.

2.3. Cardiac endpoint parameters
CHF was defined as classified by the CATS investigators.13 All patients were considered to have CHF in whom open treatment with diuretics, digoxin, and/or an ACE inhibitor was started for typical signs and/or symptoms related to CHF, or in whom hospitalization was prolonged or were hospitalized due to the presence of symptoms of CHF. Details of the echocardiography in CATS and the definition of left ventricular dilatation have been described previously.13 Left ventricular end-systolic and end-diastolic volumes were calculated from a two- and four-chamber view using the modified biplane Simpson's rule.17 In addition, regional wall abnormalities were evaluated using the wall motion score recommended by the American Society of Echocardiography.17 The left ventricle, assessed by two-dimensional echocardiography on apical four- and two-chamber views, was considered dilated if one of the following conditions was fulfilled: (1) left ventricular volume index (either end-systolic or end-diastolic) had to be one standard deviation above the reference value which was obtained from all patients with small enzymatic infarct sizes, (2) the sum of the end-systolic and end-diastolic volume index had to be 1.5 standard deviation above the sum of the respective reference values.

2.4. Statistical analysis
To estimate and compare the time course of renal function, adjusting for patient covariates, a mixed model of repeated analyses (ANOVA) was performed (Analysis I). This is a type of repeated-measures analysis that allows for incomplete data. We assumed a model with a random intercept and a compound symmetry covariance structure among serial GFRccalculations and introduced GFRcat baseline as a covariate. The computations proceeded in two stages. First, an intention to treat approach, in which an appropriate regression model was selected for all measurements available to characterize the typical renal function response curve for patients after a MI. Second, a more unbiased analysis, in which individual time course curves were calculated at the patient level of analysis, excluding GFRccalculations following the moment the clinical diagnosis of CHF was made (Analysis II). Individual slopes (Analysis II) could be calculated in 225 patients: 104 were treated with placebo and 121 were treated with captopril. A slope calculation was not possible because of development of CHF within a time period of 10 days after inclusion , and because of missing baseline and/or follow-up data or patient withdrawal . Patients without slope estimation were slightly older, had a higher prevalence of diabetes, used more often diuretics, showed an increased infarct size, and their wall-motion score was significantly more impaired. CHF was diagnosed in the group without slope estimation in 54 (74.0%) out of 73 patients compared to 37 (16.4%) out of 225 patients for the group with slope estimation. Between-group differences in stratified baseline renal function groups are expressed as medians and analyzed by the Mann–Whitney U test or Wilcoxon rank sum test. Because patients with diabetic nephropathy have a progressive decline in glomerular function, a secondary analysis was performed in patients with diabetes mellitus.

We used stepwise Cox proportional-hazards regression analyses to evaluate the association between baseline renal function and the risk of CHF adjusting for important risk modifiers as presented in Table 1. For those who had died before the development of CHF, follow-up was censored at the time of death. Continuous variables were modelled into tertiles and relative risks were calculated for the second and third vs the first tertile. Test for trends are presented. P values for entry and removal of 0.10 were used. To examine effect modification, interaction terms were used for variables that showed significant main effects. Observations with missing values for contributing variables in the multivariate model were excluded.


View this table:
[in this window]
[in a new window]
 
Table 1 Clinical baseline characteristics classified by GFRctertiles

 
The statistical computer packages SPSS and SAS were used for the statistical analysis. Results are expressed as means±SEM, except when stated otherwise. All reported P values are two-tailed, and a P value <0.05 was considered statistically significant.


    3. Results
 Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
3.1. Study population
During the enrolment period of CATS, 298 patients were included with 149 patients in each treatment group. A complete clinical follow-up over the 12-month period was obtained in 245 patients. Twenty-three patients died (all were classified as cardiovascular), 92 patients developed CHF within 1 year of follow-up (53 in the placebo and 39 patients in the captopril group), and 30 patients withdrew from the study during the 1 year of follow-up; 13 in the placebo group, from which six due to intolerance and seven for other reasons, and 17 patients in the captopril group, from which 11 due to intolerance and six for other reasons. The clinical baseline characteristics of the entire study population, classified by GFRctertiles, are presented in.Table 1 Patients randomized to captopril were almost similarly distributed (47, 52, and 53%) across the three groups. Renal function correlated negatively with age, male gender, Killip class and smoking, and positively with left ventricular injection fraction (LVEF), and left ventricular end-systolic volume index (LVESVI).

3.2. Renal function after MI and the effects of ACE inhibition
The time course of renal function for the entire study population after MI, adjusted for baseline GFRc, using all measurements available, is shown in Fig. 1. A prompt decrease in GFRcin the first 3–10 days of 2.8mlmin–1year–1and a slower decline in the next 12 months, of 2.6mlmin–1year–1accounted for an overall loss of 5.4mlmin–1in the first year after MI. The best fit was achieved by modelling time exponentially. Significant effects were found for age , baseline GFRc, study medication and the interaction term medicationxtime .



View larger version (8K):
[in this window]
[in a new window]
 
Fig. 1 Loss of GFRcfor the total group vs baseline GFRc(day 0) over the first year after the MI. Values are expressed in mean±SEM.

 
The time course of renal function after MI for placebo- and captopril-treated patients, in which all calculations of GFRcfollowing the moment of the diagnosis CHF were excluded, is shown in Fig. 2. In placebo-treated patients the loss over the first year amounted to 5.5mlmin–1year–1from 3 days post-MI. For the group treated with captopril, the GFRcdecreased, particularly in the first 3 days, but remained stable during the 1-year follow-up (0.5mlmin–1year–1). The impact of initial GFRc, grouped into tertiles, on GFRcslope calculations starting from day 3, is shown in Fig. 3. For the placebo group, a relatively constant rate of decline in GFR over different baseline tertiles was found with a significant difference between the highest and lowest tertile . Losses, in contrast, were for the captopril-treated group not related to baseline renal function. Within each tertile the loss in GFRcwas significantly less for captopril when compared with placebo (highest , intermediate and lowest tertile). Finally, a secondary analysis was carried out in which diabetic patients were excluded. Almost similar results were found (data not shown).



View larger version (10K):
[in this window]
[in a new window]
 
Fig. 2 Loss of GFRcfor the groups treated with placebo ({circ}, ) or captopril (•, ) vs baseline GFRc(day 0) over the first year after the MI without GFRcestimations at and after the moment the diagnosis of CHF was made. Values are expressed in mean±SEM.

 


View larger version (14K):
[in this window]
[in a new window]
 
Fig. 3 Median slope values of renal function loss stratified for baseline GFRcdivided into tertiles. *, **, ***; {blacksquare}=placebo; {square}=captopril.

 
3.3. Prognostic value of baseline renal function
In the total group, 7.6% of the patients had a baseline GFRcbelow 60mlmin–1. Incidence of CHF, but not of left ventricular dilatation, increased significantly with decreasing baseline tertiles of GFRc: 24.0, 28.9, 41.2%; vs 53.8, 53.3, 54.4%; , respectively. Table 2 summarizes the results by hazard (risk) ratios of the Cox regression analysis for CHF. The risk ratio (RR) for CHF increased with decreasing GFRc. The multivariate RR for CHF of the lowest tertile of GFRccompared with the highest tertile was 1.86 (95% CI 1.11–3.13; ). A clear separation of the curve with a marked increase in the cumulative incidence of CHF for the lowest tertile of GFRcwas found (Fig. 4). Of interest is the relationship of GFRcwith age. Age is a strong univariate predictor of CHF, which is expected because age is used to calculate GFRc. When age and GFRcare examined stepwise, GFRcremains in the model while age does not, indicating that GFRcprovides predictive information additive to age alone.


View this table:
[in this window]
[in a new window]
 
Table 2 Univariate and multivariate Cox proportional hazards regression analysis of the development of CHF according to GFRc

 


View larger version (13K):
[in this window]
[in a new window]
 
Fig. 4 The proportional relationship of GFRcwith CHF in Cox-proportional hazard analysis.

 
Finally, the incidence of CHF, when stratified for GFRcat baseline, increased with decreasing baseline tertiles for the placebo group (10, 15, and 30%) but not for the group treated with captopril (16, 17, and 14%). Because of the small sample sizes of the different strata, these differences were not statistically significant. The incidence of left ventricular dilatation did not change with decreasing tertiles of renal function in either groups 61, 64, and 50% for the placebo and 46, 44 and 44% for the group treated with captopril.


    4. Discussion
 Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
The data presented show that a first anterior MI is associated with progressive loss in renal function during the first year of follow-up. This loss seems to be particularly increased in patients with an already impaired renal function. Importantly, in this type of patient, treatment with the ACE inhibitor captopril appears to protect the kidney against progressive long-term function loss. Furthermore, an impaired baseline renal function is an additive prognostic risk factor in the development of CHF in patients after a first anterior MI. It should be noted that these observations were made in subjects with mostly subclinical renal function impairment, not normally requiring medical attention in itself, and not in patients with overt disease.

4.1. Time course of renal function
We found a distinct loss of renal function of 2–3mlmin–1year–1in the first days after an acute MI, with a subsequent steady decline of approximately 3mlmin–1year–1in excess of the normal age-related rate of renal function loss. In a longitudinal population study a yearly mean loss of 1mlmin–1year–1of GFR in normal subjects has been reported.18 The loss observed in our study might be clinically relevant since its magnitude is comparable to the rate of renal function loss observed in renal disease.10,19 Although an early decline in GFR occurred at initiation of therapy, our data show that ACE inhibition preserves renal function, with an yearly loss close to normal (1mlmin–1year–1), with the highest benefit compared to placebo in patients with the most impaired renal function. Long-term information regarding renal function and ACE inhibition post-MI is limited. Beneficial renal effects of captopril after MI have been reported in a 6-month follow-up study, but ACE inhibition in this study was started on day 7 post-MI.20 The authors explained these effects by improved cardiac function that is mediated by ACE inhibition. However, another phenomenon could also explain the observed reno-protection of ACE inhibition in this type of patient. It is well known from patients with renal disease due to various aetiologies that ACE inhibitors or angiotensin II antagonists retard the progression of renal disease.10,12,21,22 Angiotensin II in the kidney constricts the efferent arteriole much more than the afferent arteriole, contributing to elevated glomerular pressure implicated in the pathogenesis of most experimental and human renal diseases. Moreover, neurohormonal activation, in particular angiotensin II, plays an important role in the pathophysiology and prognosis of heart failure and renal disease. There is now ample evidence that pharmacological inhibition of angiotensin II attenuates the decline of cardiac as well as renal function.

The initial fall of GFR in the group treated with captopril, initiated immediately upon completion of the streptokinase infusion, has not been reported before. It might be speculated that starting ACE inhibition later on might prevent this early decline in renal function. However, the decline may be important, and beneficial, since in renal patients an inverse correlation was observed between the amount of initial renal function loss at onset of ACE inhibition therapy and the subsequent rate of long-term decline in renal function.23,24 Thus, the magnitude of the early renal haemodynamic effect of ACE inhibition predicts its efficacy in long-term renal protection.

4.2. Prognostic value of renal function
A number of studies have reported serum creatinine as a marker for increased risk of cardiac disease.16,25–27 Preliminary data showed that pre-existing chronic renal insufficiency in patients presenting with an acute MI have higher rates of adverse events than patients with out chronic renal insufficiency.28 Another study reported the independent prognostic value of serum creatinine during a 5-year follow-up in survivors of MI.29 However, in this study, baseline serum creatinine measurements were performed 6 months after an MI, and therefore, the results may have only been secondarily related to the event. In our study, renal function was measured within 6h after onset of MI symptoms and distinction was made in patients with and without impaired renal function by dividing them in tertiles. The kinetics of creatinine generation and excretion are well characterized, and even an abrupt change in renal function will not result in gross changes in serum creatinine within 6h.30 The 6-h time period is too short to measure a change in serum creatinine due to changed renal haemodynamics.30 Thus, our estimation of renal function should reflect the renal status before the event.

Why does an impaired renal function add prognostic risk to the development CHF? Clearly, a subclinical decreased renal function is unlikely to be the direct cause. An impaired renal function is, however, associated with several other risk factors that may themselves be causal or linked with causal processes. First, renal function is known to correlate with a variety of cardiovascular risk factors, such as insulin resistance, dyslipidemia, hyperuricemia, and hyperparathyroidism.31 The same risk factors that lead to the cardiovascular disease (MI) could contribute to the pathogenesis of renal disease. So, renal function, which has been associated with several cardiovascular risk factors and other morbidity parameters including age, could be an indicator for more generalized atherosclerosis. Second, a large number of metabolic abnormalities are related to impaired renal function and induce myocardial dysfunction and damage and elevate the risk of cardiovascular disease. Thirdly, neurohormonal activation is not only apparent in patients with CHF, but also after MI.20,29,32–34 Angiotensin II, in particular, the central product of the renin–angiotensin system, may play a central role in the pathophysiology and progression of cardiovascular and renal diseases.35–37

4.3. Interactive therapeutic kidney and cardiac effects
Of major interest in this study is the protective effect of ACE inhibition. The incidence of CHF in the CATS study was significantly reduced by captopril.13 Several other large prospective studies have examined the effect of ACE inhibitors on mortality after MI in unselected patients and showed that the incidence of CHF was reduced by ACE inhibitors.9 This study demonstrates that the use of captopril is associated with a decreased risk of CHF, particularly in patients with an impaired renal function at baseline. This finding suggests that the beneficial effect of ACE inhibition on the development of CHF might be mediated, at least in part, by its effect on renal function. It could also imply that therapy capable of improving or stabilizing renal function may improve prognosis in patients after MI. On the basis of these findings and the results of several clinical trials studying the effect of ACE inhibition in patients with acute MI, the need to start ACE inhibitors as soon as possible should be anticipated.9

4.4. Limitations of the study
This study is limited by its observational nature and the relatively small number of patients included. This is expressed in the wide confidence intervals, and thus, can only be used to generate new hypotheses. Furthermore, whether GFRcaccurately quantifies the GFR may be doubtful. This estimated GFR could potentially overestimate the true GFR, especially in the lower ranges, because creatinine is actively secreted by the proximal tubule and the secretion of creatinine tends to increase to a maximum with increasing creatinine in the serum. However, if one takes that into account the results could even be more convincing. Finally, patients were excluded with, for example, low blood pressure or severe renal insufficiency and the results cannot, therefore, be generalized to the MI population at large.

4.5. Clinical implications
The results of the present study indicate that an acute MI is associated with progressive loss in renal function. This loss seems to be particularly increased in patients with an already impaired renal function. Also, subclinical impairment in renal function, which would not require medical attention in itself, predicts the development of CHF in patients with an MI. Most importantly, treatment with ACE inhibitors appears to counteract the progressive loss of both cardiac and renal function. Better understanding of the factors that contribute to these beneficial effects may ultimately allow improved management of patients suffering from MI.


    References
 Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

  1. Dries DL, Exner DV, Domanski MJ et al. The prognostic implications of renal insufficiency in asymptomatic and symptomatic patients with left ventricular systolic dysfunction. J Am Coll Cardiol. 2000;35:681–689.[CrossRef][Medline]
  2. Hillege HL, Girbes AR, de Kam PJ et al. Renal function, neurohormonal activation, and survival in patients with chronic heart failure. Circulation. 2000;102:203–210.[Abstract/Free Full Text]
  3. Culleton BF, Larson MG, Evans JC et al. Prevalence and correlates of elevated serum creatinine levels: the Framingham Heart Study. Arch Intern Med. 1999;159:1785–1790.[Abstract/Free Full Text]
  4. Culleton BF, Larson MG, Wilson PW et al. Cardiovascular disease and mortality in a community-based cohort with mild renal insufficiency. Kidney Int. 1999;56:2214–2219.[CrossRef][Medline]
  5. Lindeman RD, Tobin JD, Shock NW. Association between blood pressure and the rate of decline in renal function with age. Kidney Int. 1984;26:861–868.[Medline]
  6. Manttari M, Tiula E, Alikoski T et al. Effects of hypertension and dyslipidemia on the decline in renal function. Hypertension. 1995;26:670–675.[Abstract/Free Full Text]
  7. Fliser D, Franek E, Joest M et al. Renal function in the elderly: impact of hypertension and cardiac function. Kidney Int. 1997;51:1196–1204.[Medline]
  8. Krop JS, Coresh J, Chambless LE et al. A community-based study of explanatory factors for the excess risk for early renal function decline in blacks vs whites with diabetes: the Atherosclerosis Risk in Communities study. Arch Intern Med. 1999;159:1777–1783.[Abstract/Free Full Text]
  9. Indications for ACE inhibitors in the early treatment of acute myocardial infarction: systematic overview of individual data from 100,000 patients in randomized trials. ACE Inhibitor Myocardial Infarction Collaborative Group. Circulation. 1998;97:2202–2212.[Abstract/Free Full Text]
  10. Lewis EJ, Hunsicker LG, Bain RP et al. The effect of angiotensin-converting-enzyme inhibition on diabetic nephropathy. The Collaborative Study Group. N Engl J Med. 1993;329:1456–1462.[Abstract/Free Full Text]
  11. Knight EL, Glynn RJ, McIntyre KM et al. Predictors of decreased renal function in patients with heart failure during angiotensin-converting enzyme inhibitor therapy: results from the studies of left ventricular dysfunction (SOLVD). Am Heart J. 1999;138:849–855.[Medline]
  12. Maschio G, Alberti D, Janin G et al. Effect of the angiotensin-converting-enzyme inhibitor benazepril on the progression of chronic renal insufficiency. The Angiotensin-Converting-Enzyme Inhibition in Progressive Renal Insufficiency Study Group. N Engl J Med. 1996;334:939–945.[Abstract/Free Full Text]
  13. van Gilst WH, Kingma JH, Peels KH et al. Which patient benefits from early angiotensin-converting enzyme inhibition after myocardial infarction? Results of one-year serial echocardiographic follow-up from the Captopril and Thrombolysis Study (CATS). J Am Coll Cardiol. 1996;28:114–121.[CrossRef][Medline]
  14. Cockroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976;16:31–41.[Medline]
  15. Luke DR, Halstenson CE, Opsahl JA et al. Validity of creatinine clearance estimates in the assessment of renal function. Clin Pharmacol Ther. 1990;48:503–508.[Medline]
  16. Mann JF, 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;134:629–636.[Abstract/Free Full Text]
  17. Schiller NB, Shah PM, Crawford M et al. Recommendations for quantitation of the left ventricle by two-dimensional echocardiography. American Society of Echocardiography Committee on Standards, Subcommittee on Quantitation of Two-Dimensional Echocardiograms. J Am Soc Echocardiogr. 1989;2:358–367.[Medline]
  18. Lindeman RD, Tobin J, Shock NW. Longitudinal studies on the rate of decline in renal function with age. J Am Geriatr Soc. 1985;33:278–285.[Medline]
  19. Parving HH, Andersen AR, Smidt UM et al. Early aggressive antihypertensive treatment reduces rate of decline in kidney function in diabetic nephropathy. Lancet. 1983;1:1175–1179.[Medline]
  20. Motwani JG, Fenwick MK, McAlpine HM et al. Effectiveness of captopril in reversing renal vasoconstriction after Q-wave acute myocardial infarction. Am J Cardiol. 1993;71:281–286.[CrossRef][Medline]
  21. Randomised placebo-controlled trial of effect of ramipril on decline in glomerular filtration rate and risk of terminal renal failure in proteinuric, non-diabetic nephropathy. The GISEN Group (Gruppo Italiano di Studi Epidemiologici in Nefrologia). Lancet. 1997;349:1857–1863.[CrossRef][Medline]
  22. Lewis EJ, Hunsicker LG, Clarke WR et al. Renoprotective effect of the angiotensin-receptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Engl J Med. 2001;345:851–860.[Abstract/Free Full Text]
  23. Bakris GL, Weir MR. Angiotensin-converting enzyme inhibitor-associated elevations in serum creatinine: is this a cause for concern? Arch Intern Med. 2000;160:685–693.[Abstract/Free Full Text]
  24. Apperloo AJ, de Zeeuw D, de Jong PE. A short-term anti-hypertensive treatment-induced fall in glomerular filtration rate predicts long-term stability of renal function. Kidney Int. 1997;51:793–797.[Medline]
  25. McCullough PA, Soman SS, Shah SS et al. Risks associated with renal dysfunction in patients in the coronary care unit. J Am Coll Cardiol. 2000;36:679–684.[CrossRef][Medline]
  26. Shulman NB, Ford CE, Hall WD et al. Prognostic value of serum creatinine and effect of treatment of hypertension on renal function. Results from the hypertension detection and follow-up program. The Hypertension Detection and Follow-up Program Cooperative Group. Hypertension. 1989;13:180–193.
  27. Wannamethee SG, Shaper AG, Perry IJ. Serum creatinine concentration and risk of cardiovascular disease: a possible marker for increased risk of stroke. Stroke. 1997;28:557–563.[Abstract/Free Full Text]
  28. Kovar D, Rogers WJ, Ganto JG et al. Poor outcome of patients with chronic renal insufficiency presenting with myocardial infarction. Circulation. 2000;102(Suppl):II-792.
  29. Matts JP, Karnegis JN, Campos CT et al. Serum creatinine as an independent predictor of coronary heart disease mortality in normotensive survivors of myocardial infarction. POSCH Group. J Fam Pract. 1993;36:497–503.[Medline]
  30. Hallynck T, Soep HH, Thomis J et al. Prediction of creatinine clearance from serum creatinine concentration based on lean body mass. Clin Pharmacol Ther. 1981;30:414–421.[Medline]
  31. Kasiske BL. The kidney in cardiovascular disease. Ann Intern Med. 2001;134:707–709.[Free Full Text]
  32. Abildgaard U, Andersen JS, Daugaard G et al. Renal function in patients with untreated acute myocardial infarction. Scand J Clin Lab Invest. 1992;52:689–695.[Medline]
  33. Efendigil MC, Harley A, Deegan T et al. Changes in glomerular filtration rate following myocardial infarction. Cardiovasc Res. 1975;9:741–744.[Medline]
  34. Laragh JH. Role of renin secretion and kidney function in hypertension and attendant heart attack and stroke. Clin Exp Hypertens A. 1992;14:285–305.[Medline]
  35. Klahr S, Morrissey JJ. The role of vasoactive compounds growth factors and cytokines in the progression of renal disease. Kidney Int. 2000;57(Suppl. 75):S7–S14.
  36. Matsusaka T, Hymes J, Ichikawa I. Angiotensin in progressive renal diseases: theory and practice. J Am Soc Nephrol. 1996;7:2025–2043.[Abstract]
  37. Matsusaka T, Katori H, Homma T et al. Mechanism of cardiac fibrosis by angiotensin. New insight revealed by genetic engineering. Trends Cardiovasc Med. 1999;9:180–184.[CrossRef][Medline]

Related articles in EHJ:

Looking for people at high cardiovascular risk? Look at serum-creatinine
J.F.E Mann, I Dulau-Florea, and J Franke
EHJ 2003 24: 381-383. [Extract] [Full Text]