Skip Navigation


NDT Advance Access first published online on May 25, 2008
This version published online on June 4, 2008
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfn233
This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
23/10/3103    most recent
gfn233v2
gfn233v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Windt, W. A. K. M.
Right arrow Articles by van Dokkum, R. P. E.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Windt, W. A. K. M.
Right arrow Articles by van Dokkum, R. P. E.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The Author [2008]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org


Myocardial infarction does not further impair renal damage in 5/6 nephrectomized rats

Willemijn A. K. M. Windt, Robert H. Henning, Alex C. A. Kluppel, Ying Xu, Dick de Zeeuw and Richard P. E. van Dokkum

Department of Clinical Pharmacology, Groningen Institute for Drug Evaluation (GUIDE), University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

Correspondence and offprint requests to: Richard P. E. van Dokkum, Department of Clinical Pharmacology, University Medical Center Groningen, PO Box 196, NL-9700 AD, Groningen, The Netherlands. Tel: +31-50-363-2810, Fax: +31-50-363-2812, E-mail: r.p.e.van.dokkum{at}med.umcg.nl



   Abstract
Top
 Abstract
Introduction
 Subjects and methods
 Functional parameters
 Histology
 Results
 Discussion
 References
 
Background. Recent observational studies show that reduced renal function is an independent risk factor for the development of cardiovascular disease. Previously, we reported that myocardial infarction (MI) indeed enhanced mild renal function decline in rats after unilateral nephrectomy (NX) and that RAAS intervention inhibited this decline. The effects of an MI on pre-existing severe renal function loss and the effects of RAAS intervention interrupting this hypothesized cardiorenal interaction are however unknown and clinically even more relevant.

Methods. Male Wistar rats underwent MI, sham MI, 5/6NX, or 5/6NX and MI. Six weeks later, the NX rats were treated with an angiotensin-converting enzyme inhibitor (ACEi) or vehicle for 6 weeks.

Results. An MI did not significantly induce more proteinuria (303 ± 46 versus 265 ± 24 mg/24 h) and glomerulosclerosis (40 ± 11 versus 28 ± 4 arbitrary units) in 5/6NX+MI compared to 5/6NX, and ACEi therapy was equally effective in reducing renal damage in these groups. In the 5/6NX+MI group, decreased renal blood flow and creatinine clearance were observed compared to 5/6NX (2.2 ± 0.6 versus 3.6 ± 0.4 ml/min/kg and 2.1 ± 0.3 versus 2.9 ± 0.3 ml/min/kg), which both increased after ACEi to levels comparable found in the group that underwent 5/6NX alone.

Conclusions. MI does not further deteriorate structural renal damage induced by 5/6NX compared with 5/6NX alone. Furthermore, renal haemodynamic impairment occurs after MI, which can be improved applying ACEi therapy. Therefore, we conclude that treatment with ACEi should be optimized in patients with chronic kidney disease after MI to improve renal function.

Keywords: 5/6 nephrectomy; ACEi therapy; cardiorenal interaction; myocardial infarction



   Introduction
Top
 Abstract
 Introduction
Subjects and methods
 Functional parameters
 Histology
 Results
 Discussion
 References
 
An intriguing interaction is present between the heart and the kidney when either organ function is compromised. Clinical studies indicate that high serum creatinine levels, as an intrinsic measure for renal damage, and decreased filtration ability are independent risk factors for the development of cardiovascular disease [1,2]. Conversely, a myocardial infarction (MI) may lead to decreased renal function and therefore an increase in serum creatinine levels [3,4]. Both mechanisms are thought to induce a vicious circle of cardiorenal interaction, which may account for increased morbidity and mortality in patients with cardiovascular and renal disease. Several mechanisms have been hypothesized including haemodynamic alterations: involvement of the RAAS, the endothelin and the sympathetic nervous system, endothelial dysfunction, NO, reactive oxygen species and inflammation [5], which are also thought to interact with each other. First, as far as the role of haemodynamics in explaining the observed cardiorenal interaction is concerned, reduced cardiac output after MI may lead to reduced renal perfusion, which in turn could lead to compensatory RAAS activation. This RAAS activation in turn can be detrimental to both heart and kidneys. An elevated angiotensin II level is known to interact with cardiac function leading to progressive cardiac function loss [6], and elevated angiotensin II levels may lead to progressive renal damage [7]. RAAS intervention by angiotensin-converting enzyme inhibitors (ACEi) might be able to interrupt this vicious circle.

The effect of renal function loss on the heart has been investigated in experimental and clinical studies [1,8–13]. The effect of the opposite, effects of cardiac function loss on renal outcome, has been studied only in experimental settings so far. In our laboratory, we recently observed progressive proteinuria after MI in uninephrectomized rats [3], which gives only mild renal function impairment, and this proteinuria showed to be responsive to ACEi [14]. The importance of this model is that with further deterioration of renal function one would assume that cardiac risk even further increased, thus establishing a vicious circle. In this perspective, it is thus far not known if an MI compromises renal function even more in rats with already more severe renal damage. Therefore, the aim of the present study was to investigate whether an MI would further increase proteinuria and end-stage renal damage measured as focal glomerulosclerosis in rats with already a high serum creatinine level (and therefore low creatinine clearance) induced by 5/6 nephrectomy. In addition, we explored whether RAAS intervention could interfere in this interaction and therefore improve renal outcome after MI.



   Subjects and methods
Top
 Abstract
 Introduction
 Subjects and methods
Functional parameters
 Histology
 Results
 Discussion
 References
 
Experimental protocol
Male Wistar rats (275–350 g; n = 95) were housed under standard conditions with free access to food and drinking water. Rats received a standard chow diet. Animal experiments were approved by the institutional animal ethical committee.

Rats were divided into four groups: (1) 5/6NX+MI (n = 28), (2) 5/6NX (n = 29), (3) MI (n = 14) and (4) sham MI (n = 9). At T = 0 weeks 5/6NX, and at T = 2 weeks MI or sham MI were performed (Figure 1). After 6 weeks, rats with 5/6NX (groups 1 and 2) were randomized based on proteinuria into a vehicle group (VEH n = 13 or 14) and a group treated with lisinopril (Merck, Sharp & Dohme, Haarlem, The Netherlands) 2.5 mg/kg/day in the drinking water (ACEi n = 15). In all groups, the experiment was ended at T = 12 weeks.


Figure 1
View larger version (5K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 1 Experimental protocol.

 
At the end of the experiment, functional cardiac parameters were measured under 2.5% isoflurane anaesthesia, laparotomy was performed, renal blood flow was measured and afterwards the rats were exsanguinated by taking blood samples from the abdominal aorta for plasma measurements. The remaining kidney was flushed with saline and the heart and kidney were removed and weighed.

Surgical interventions
The 5/6 nephrectomy was performed by taking out one kidney and by ligation of two of the three branches of the contralateral kidney under anaesthesia with 2.0% isoflurane in N2O/O2 (2:1) as described before [15–17]. Before the induction of MI, rats were intubated, ventilated (AIV, Hoek/Loos, The Netherlands) and anaesthetized using 2.0% isoflurane in O2. MI was induced by ligation of the left anterior descending coronary artery (LAD) as described previously [18–20].



   Functional parameters
Top
 Abstract
 Introduction
 Subjects and methods
 Functional parameters
Histology
 Results
 Discussion
 References
 
Urine, plasma and tissue measurements
For the measurement of urinary total protein excretion, 24-h urine samples were collected in metabolic cages at baseline, before start of therapy and at the end of the experiment. Urinary total protein was analysed using endpoint measurement with TCA (Nephelometer Analyzer II, Dade Behring, Marburg, Germany). As a measure for renal function, creatinine clearance was investigated. For the calculation of creatinine clearance, urinary creatinine and plasma creatinine levels were measured at baseline, before start of therapy and at the end of the experiment. Creatinine was determined using photometric determination with the Jaffe method (Ecoline Mega, DiaSys Diagnostic Systems GmbH, Holzheim, Germany).

Haemodynamic, cardiac and renal characteristics
Systolic blood pressure (SBP) was measured using tail-cuff plethysmography (IITC Life Science, Woodland Hills, CA, USA) in trained awake, restrained animals. SBP was measured at baseline, before start of therapy and at the end of the experiment.

Cardiac performance was measured with a pressure transducer catheter under anaesthesia, (2.5% isoflurane in O2) inserted through the right carotid artery (Micro-Tip 3 French, Millar Instruments Inc., Houston, TX, USA), connected to a personal computer equipped with an analogue-to-digital converter and appropriate software (Millar Instruments, Germany). After a 3-min period of stabilization, left ventricular end diastolic pressure (LVEDP) and left ventricular peak systolic pressure (LVPSP) were recorded. Thereafter, the catheter was withdrawn into the aortic root to measure SBP. As a parameter of global myocardial contractility and relaxation, we determined the maximal rates of increase and decrease in left ventricular pressure (systolic +dP/dtmax and diastolic –dP/dtmax) that were normalized to left ventricular pressure change (i.e. LVPSP-LVEDP) for individual rats.

Renal blood flow was measured at the end of the study to investigate the effects of ACEi therapy in the 5/6NX and 5/6NX+MI group on renal blood flow using a 1-mm flow probe around the left renal artery (1RB; Transonic, Ithaca, NY, USA), connected to a flow meter (T106 Small Animal Research Flow meter; Transonic, Ithaca, NY, USA).



   Histology
Top
 Abstract
 Introduction
 Subjects and methods
 Functional parameters
 Histology
Results
 Discussion
 References
 
Kidney
Kidneys were fixed by immersion for 48 h in a 4% buffered formaldehyde solution (Klinipath, Duiven, The Netherlands) after longitudinal bisection and subsequently embedded in paraffin according to standard procedures. Sections of 3 µm were stained with periodic acid Schiff (PAS). The degree of mesangial matrix expansion (MME) and focal glomerulosclerosis were assessed in 50 glomeruli by scoring semi-quantitatively on a scale of 0–4. MME was scored positive when mesangial matrix expansion was present. Focal glomerulosclerosis was scored positive when mesangial matrix expansion and adhesion to Bowman's capsule were present in the same quadrant. When 25% of the glomerulus was affected, a score of 1+ was adjudged, 50% was scored as 2+, 75% as 3+ and 100% as 4+. The overall MME and focal glomerulosclerosis score is expressed as arbitrary units (AU) with a maximum of 200. Interstitial fibrosis (IF) was defined as expansion of the interstitial space, with or without the presence of atrophied and dilated tubules and thickened tubular basement membranes. The degree of IF was assessed at 20x magnification by scoring semi-quantitatively on a scale of 0–5; 0: no IF, 1: 1–10%, 2: 10–25%, 3: 25–50%, 4: 50–75% and 5: 75–100% IF. The score is given as the mean of the scored slices. An examiner blinded for the groups evaluated all sections.

Interstitial alpha-smooth muscle actin ({alpha}-SMA) was determined as a profibrotic marker and detected in paraffin-embedded sections by means of a mouse monoclonal {alpha}-SMA antibody (Sigma Chemical, St Louis, MO, USA). First, the antibody was incubated for 60 min and its binding was detected by sequential incubations with peroxidase (PO)-labelled rabbit anti-mouse and PO-labelled goat anti-rabbit antibody (both from Dakopatts, DAKO, Glostrup, Denmark) for 30 min. The expression of interstitial {alpha}-SMA was measured by computerized morphometry. Therefore, 40 fields were scored at x20 magnification in the cortical region; glomeruli and vessels were excluded from measurement along Bowman's capsule and the vessel wall. Total staining was expressed as the percentage of the total area surface.

Heart
The heart was arrested in diastole in a cold 1 M KCl solution and weighed. The ventricles were dissected from the atria, and the right free wall was separated from the left ventricle. A left ventricular mid-sagital slice (of ~2 mm) was fixed in 4% buffered formaldehyde solution, embedded in paraffin, cut into 5 µm slices and stained with 0.1% Sirius Red F3B and 0.1% Fast Green FCF (Klinipath, Duiven, The Netherlands). Endo- and epicardial circumference of the left ventricle and scar tissue was determined by means of a computerized planimeter (Image-Pro plus, Media Cybernetics Inc., Bethesda, MD, USA). MI size was expressed as the sum of scar lengths divided by the total left ventricular circumference, and all sections were evaluated by an examiner blinded for the groups. Deparaffinized 5-µm-thick transverse cardiac sections at the midventricular level were stained with Lectin GSL staining (Sigma-Aldrich) to stain endothelial cells for analysis of capillary density. Capillary density was obtained by counting the number of capillaries per total tissue area (No/mm2).

Calculations and statistical analysis
All data are presented as mean ± SEM. If normally distributed, differences between the groups were compared using a one-way ANOVA, followed by a Fisher's protected LSD post hoc test to identify the groups that were different from each other; otherwise a non-parametric test was used. The effect of ACEi was tested with an independent sample t-test compared to the vehicle-treated group, or if the data were not normally distributed with a non-parametric Mann–Whitney test. To identify differences in one animal between two time points, a paired sample t-test was used, when the data was not normally distributed, a Wilcoxon signed ranks test was used. In all tests, P < 0.05 was considered statistically significant.



   Results
Top
 Abstract
 Introduction
 Subjects and methods
 Functional parameters
 Histology
 Results
Discussion
 References
 
Survival and overall condition
All animals survived the nephrectomy. In the 5/6NX group, out of 39 animals that additionally received an MI, 28 survived and 11 animals died within 1 day after MI. In the group receiving only an MI, 4 out of 18 animals undergoing surgery died within 1 day. All sham-operated animals recovered well after surgery. At the end of the 12-week follow-up, the animals in the 5/6NX+MI group had a significantly lower body weight compared to the other groups (Table 1). Treatment with ACEi did not influence bodyweight in 5/6NX and 5/6NX+MI (Table 2).


View this table:
[in this window]
[in a new window]

  		Table 1 Renal and haemodynamic characteristics at the end of the follow-up

 

View this table:
[in this window]
[in a new window]

  		Table 2 Animal and renal characteristics before and after treatment with ACEi

 
Cardiorenal interaction: effects on the kidney
Renal effects were assessed by proteinuria, kidney weight, renal histology and creatinine clearance. Compared to sham-operated animals, MI did not induce a change in these renal parameters (Table 1 and Figures 2B and 3). The 5/6NX alone resulted in renal damage, as demonstrated by an increased proteinuria from 19 ± 3 mg/24 h at baseline to 265 ± 24 mg/24 h, and increased kidney weight, focal glomerulosclerosis, mesangial matrix expansion, IF and interstitial {alpha}-SMA (Figures 2B and 3), and a significantly decreased creatinine clearance from 5.5 ± 1.3 ml/min/kg at baseline to 2.9 ± 0.3 ml/min/kg (Table 1).


Figure 2
View larger version (23K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 2 Effect of cardiac and renal damage on heart weight and kidney weight. White bar: sham, black bar: MI, light grey bar: 5/6NX, dark grey bar: 5/6NX+MI, striped bars: ACEi treatment. The weight of a single kidney is given for all groups. *P < 0.05 versus sham and in panel B versus sham and MI, **P < 0.05 versus all other groups, #P < 0.05 versus vehicle-treated animals.

 

Figure 3
View larger version (45K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 3 Renal histology with representative pictures. Panel A: focal glomerulosclerosis and mesangial matrix expansion, panel B: interstitial {alpha}-smooth muscle actin staining, panel C: interstitial fibrosis. White bar: sham, black bar: MI, light grey bar: 5/6NX, dark grey bar: 5/6NX+MI, striped bars: ACEi treatment. *P < 0.05 versus sham and MI, #P < 0.05 versus vehicle-treated animals.

 
In the 5/6NX+MI group, additional changes in renal parameters were noted compared to 5/6NX. While kidney weight, proteinuria, focal glomerulosclerosis, mesangial matrix expansion, IF and interstitial {alpha}-SMA were comparable between these groups, a further decline in creatinine clearance (P = 0.05) and renal blood flow (2.2 ± 0.6 versus 3.6 ± 0.4 ml/min/kg) was observed in the 5/6NX+MI group compared to sole 5/6NX (Figure 4). Thus, cardiorenal interaction resulted in no increase in renal damage measured as proteinuria and glomerular and interstitial damage, while an additional change in renal haemodynamic function was observed as demonstrated by reduced clearance and reduced renal blood flow.


Figure 4
View larger version (19K):
[in this window]
[in a new window]
[Download PowerPoint slide]
  		Fig. 4 Effect ACEi treatment on renal blood flow and creatinine clearance in 5/6NX and 5/6NX+MI. Light grey bar: 5/6NX, dark grey bar: 5/6NX+MI, striped bars: ACEi treatment. *P < 0.05 versus 5/6NX, #P < 0.05 versus vehicle treated animals.

 
Cardiorenal interaction: effects on the heart
Compared to sham, the MI group displayed cardiac hypertrophy and a decrease in cardiac function. Left ventricular end diastolic pressure (LVEDP) was higher compared to sham-operated animals (P = 0.06), and cardiac contractility (+dP/dtmax, P = 0.1) and cardiac dilation (–dP/dtmax, P < 0.01) were lower. Heart weight was significantly higher after MI compared to sham (Figure 2A), while cardiac capillary density was lower after MI.

Following 5/6NX, both systolic and diastolic blood pressures were significantly higher compared to sham-operated animals (Table 1). Further, 5/6NX impaired cardiac contractility and cardiac dilation and increased heart weight (Figure 2A) to a level comparable to the cardiac hypertrophy after MI. Cardiac capillary density was increased after 5/6NX compared to sham and compared to MI.

In the 5/6NX+MI group, additional changes in cardiac parameters were observed compared to the 5/6NX group and the MI group. While cardiac function parameters did not differ, 5/6NX+MI featured a significant increase in cardiac hypertrophy (Figure 2A) and a decrease in cardiac capillary density (Table 3) compared to sole 5/6NX or sole MI. Thus, cardiorenal interaction resulted in an excess cardiac hypertrophy.


View this table:
[in this window]
[in a new window]

  		Table 3 Haemodynamic characteristics after treatment with ACEi

 
Effect of RAAS intervention on the vicious circle after cardiac and renal function loss
To investigate whether intervention in the RAAS by ACE inhibition is effective in interrupting the hypothesized vicious circle of cardiac and renal impairment, the above mentioned parameters were studied in 5/6NX and 5/6NX+MI groups treated for 6 weeks with lisinopril or vehicle. Treatment with lisinopril effectively normalized the blood pressure in 5/6NX from 146 ± 6 mmHg to 115 ± 4 mmHg (P < 0.001), and in the 5/6NX+MI from 143 ± 6 to 122 ± 7 mmHg (P = 0.02). In both 5/6NX and 5/NX+MI, plasma renin activity was increased comparably after ACEi treatment (Table 3).

ACEi treatment prevented renal damage to a similar extent in 5/6NX and 5/6NX+MI, as demonstrated by a similar reduction in proteinuria (Table 2) and a significantly lower interstitial {alpha}-SMA (Figure 3B), while a trend towards lower focal glomerulosclerosis (5/6NX P = 0.07, 5/6NX + MI P = 0.1) and mesangial matrix expansion (5/6NX P = 0.07, 5/6NX + MI P = 0.1) was observed (Figure 3A). ACEi had no significant effect on IF (Figure 3C). Moreover, while ACEi treatment did not affect creatinine clearance and renal blood flow in the 5/6NX group, it normalized the decrease in both parameters observed in the 5/6NX+MI (Figure 4). Furthermore, while functional cardiac parameters were unaffected by the therapy (Table 3), ACEi treatment significantly reduced cardiac hypertrophy in 5/6NX and 5/6NX+MI groups (Figure 2A). ACEi therapy did increase cardiac capillary density in the 5/6NX+MI group, while no influence was observed in the 5/6NX group (Table 3).



   Discussion
Top
 Abstract
 Introduction
 Subjects and methods
 Functional parameters
 Histology
 Results
 Discussion
References
 
This is the first experiment in which the long-term renal effect of cardiac function loss was established in animals with already severely impaired kidney function to explore a vicious circle between the heart and the kidney. Moreover, it is the first time that the protective effects of ACEi in combined severe cardiac and renal damage were established trying to break through this alleged vicious circle. The main finding of this study is that cardiac function loss due to MI causes no further impairment in structural kidney function measured as proteinuria and focal glomerulosclerosis after 5/6 nephrectomy. However, creatinine clearance and renal blood flow were further reduced, which could be improved by ACEi to levels comparable to isolated renal damage, 5/6NX only.

Recent studies have disclosed a complex relationship between cardiovascular and renal disease. Impaired renal function is detrimental to the heart both in clinical [1,13,21–26] and experimental [9,11] settings. Conversely, impaired cardiac function is detrimental to the kidney, although the latter is less well established [3,27]. In our experiment and in the time span we used, an MI did not cause a decrease in renal function, nor did it cause renal damage in previously healthy rats. This is in line with earlier experiments [28]. Subtle renal alterations might be present in response to haemodynamic adaptation after the MI. However, with the means applied in this study, these tenuous alterations were not detected.

In contrast to the absence of renal effects of an MI, severe nephron number loss caused by 5/6NX induced a reduction in cardiac contractility and an increase in heart weight to a similar extent as observed by MI. This observed decrease in cardiac contractility could be explained by left ventricular hypertrophy [29–31], which is associated with an increase in cardiomyocyte diameter and volume [11] and a decrease in capillary length density [32,33] in experimental renal failure. In this study an increase in cardiac capillary density was found, which is not in line with this literature.

Cardiac function loss caused by MI did lead to a further decrease in creatinine clearance and renal blood flow. Apparently, reduced cardiac output after MI may lead to reduced renal perfusion, which in turn could lead to compensatory RAAS activation. This is confirmed by the decrease in renal blood flow observed in the nephrectomized rats with an additive MI, which is thought to be associated with angiotensin II levels [34]. An elevated angiotensin II level is known to interact with cardiac function leading to progressive cardiac function loss [6]. In addition, elevated angiotensin II may lead to progressive renal damage [7] as well, resulting in a vicious circle. In the current study, no increase in renal damage was observed in the nephrectomized rats with additive MI: proteinuria, kidney weight, focal glomerulosclerosis, mesangial matrix expansion, IF and interstitial {alpha}-SMA staining were comparable in both 5/6NX and 5/6NX+MI. Blood pressure was comparable in both groups as well. This phenomenon could be explained by the RAAS activation after renal ablation by 5/6 nephrectomy: in an animal with an already highly activated RAAS, an MI will not lead to more RAAS activation and therefore not to more renal damage. A plateau of damage is reached. This is confirmed by the comparable amount of renin activity in both 5/6 nephrectomized rats and 5/6 nephrectomized rats plus MI. Out of the previous could be concluded that no vicious circle is activated after MI in animals with already-established renal function loss.

We found a higher mortality from MI in the 5/6 nephrectomized rats than in the sham group. This might be explained by a decreased ischaemia tolerance in 5/6 nephrectomized rats. Dikow et al. found that a greater proportion of nonperfused myocardium underwent total necrosis after MI in 5/6 nephrectomized rats [6], which could lead to a higher mortality after MI in these rats.

RAAS intervention with either the ACEi or angiotensin receptor blocker is known to protect both heart and kidney [35,36]. However, in the clinical situation, ACE inhibitors are not always prescribed to patients with combined renal and heart failure, while ACE inhibitors improve the long-term outcome on cardiovascular morbidity and mortality [37,38]. Therefore, it is of the utmost importance to get insight into the pharmacological effects of ACEi in combined cardiac and renal damage. In a model with both severe renal and cardiac function loss, a dual or combined activation of the RAAS is present. Thus far, the effects of RAAS intervention with ACEi on cardiac and renal outcome in the model mentioned are unknown. In the current study, ACEi therapy was very effective in both 5/6NX and 5/6NX+MI in reducing haemodynamic parameters, like SBP, DBP, LVPSP and cardiac hypertrophy. Moreover, it was effective in reducing renal damage, i.e. proteinuria, focal glomerulosclerosis and interstitial {alpha}-SMA staining. Besides these comparable effects, ACEi therapy was able to restore the impaired creatinine clearance and renal blood flow in 5/6NX+MI to the levels in sole 5/6NX. These results are in favour of the important role of RAAS stimulation after 5/6 nephrectomy and MI to decrease renal function and renal blood flow. Besides the beneficial effects on renal function, ACEi therapy was able as well to increase cardiac capillary density in animals with 5/6NX+MI. It should, however, be taken into account that RAAS inhibition is invariably associated with blood pressure reduction. Therefore, lowering blood pressure by means of a calcium channel blocker would be an interesting strategy to further allow for a distinction between blood pressure lowering per se and blockade of the RAAS.

In conclusion, our results showed that an MI did not cause a decrease in structural renal function in animals with already severely decreased renal function. The responsiveness of renal damage to RAAS intervention was comparable between combined cardiac and renal function loss and sole renal function loss. Although no difference in renal function could be observed, a detrimental haemodynamic effect of an additive MI to nephrectomized rats on creatinine clearance and renal blood flow was observed, which showed to be responsive to ACEi therapy. Therefore, our study supports the view that a great concern is needed in the treatment of patients with renal disease to prevent further decline in renal function, because these patients are already more prone to experience an MI. In addition, ACE inhibitor therapy should be prescribed after MI in patients with compromised renal function to prevent a further decline in renal haemodynamics caused by combined cardiac and renal damage. The hesitation to treat a cardiac patient with high serum creatinine levels with RAAS intervention should thus be re-evaluated [38], since it is in fact those subjects that are at the highest risk and need these therapies the most.



   Acknowledgments
 
The authors acknowledge Mr J.J. Duker, Dr H. van Goor, Mrs B.G. Haandrikman, Mr F. Hut, Mrs B. Meijeringh, Dr R. Schoemaker, Mrs J.W.J.T van der Wal and Mrs C. Wisselink for their valuable advice and technical assistance. Lisinopril was a kind gift from Merck, Sharp & Dohme (Haarlem, The Netherlands).

Conflict of interest statement. Parts of this study were presented at the ASN Renal Week 2006, San Diego, CA, USA, and have been published in abstract form (J. Am. Soc. Nephrol. 17: 433A, 2006).



   References
Top
 Abstract
 Introduction
 Subjects and methods
 Functional parameters
 Histology
 Results
 Discussion
 References
 

  1. Go AS, Chertow GM, Fan D, et al. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med (2004) 351:1296–1305.[Abstract/Free Full Text]
  2. 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) 113:671–678.[Abstract/Free Full Text]
  3. van Dokkum RP, Eijkelkamp WB, Kluppel CA, et al. Myocardial infarction enhances progressive renal damage in an experimental model for cardio-renal interaction. J Am Soc Nephrol (2004) 15:3103–3110.[Abstract/Free Full Text]
  4. Jose P, Skali H, Anavekar N, et al. Increase in creatinine and cardiovascular risk in patients with systolic dysfunction after myocardial infarction. J Am Soc Nephtol (2006) 17:2886–2891.[CrossRef]
  5. Bongartz LG, Cramer MJ, Doevendans PA, et al. The severe cardiorenal syndrome: ‘Guyton revisited’. Eur Heart J (2005) 26:11–17.[Abstract/Free Full Text]
  6. Swedberg K, Eneroth P, Kjekshus J. CONSENSUS Trial Study Group. Hormones regulating cardiovascular function in patients with severe congestive heart failure and their relation to mortality. Circulation (1990) 82:1730–1736.[Abstract/Free Full Text]
  7. Remuzzi G, Perico N, Macia M, et al. The role of renin–angiotensin–aldosterone system in the progression of chronic kidney disease. Kidney Int Suppl (2005) 99:S57–S65.[Medline]
  8. Dikow R, Kihm LP, Zeier M, et al. Increased infarct size in uremic rats: reduced ischemia tolerance? J Am Soc Nephrol (2004) 15:1530–1536.[Abstract/Free Full Text]
  9. Raine AE, Seymour AM, Roberts AF, et al. Impairment of cardiac function and energetics in experimental renal failure. J Clin Invest (1993) 92:2934–2940.[Web of Science][Medline]
  10. Amann K, Buzello M, Simonaviciene A, et al. Capillary/myocyte mismatch in the heart in renal failure—a role for erythropoietin? Nephrol Dial Transplant (2000) 15:964–969.[Abstract/Free Full Text]
  11. Amann K, Tyralla K, Gross ML, et al. Cardiomyocyte loss in experimental renal failure: prevention by ramipril. Kidney Int (2003) 63:1708–1713.[CrossRef][Web of Science][Medline]
  12. Mann JF, Gerstein HC, Yi QL, et al. Development of renal disease in people at high cardiovascular risk: results of the HOPE randomized study. J Am Soc Nephrol (2003) 14:641–647.[Abstract/Free Full Text]
  13. Hillege HL, Fidler V, Diercks GF, et al. Urinary albumin excretion predicts cardiovascular and noncardiovascular mortality in general population. Circulation (2002) 106:1777–1782.[Abstract/Free Full Text]
  14. Windt WA, Eijkelkamp WB, Henning RH, et al. Renal damage after myocardial infarction is prevented by renin–angiotensin–aldosterone-system intervention. J Am Soc Nephtol (2006) 17:3059–3066.[CrossRef]
  15. Leenen FH, Skarda V, Yuan B, et al. Changes in cardiac ANG II postmyocardial infarction in rats: effects of nephrectomy and ACE inhibitors. Am J Physiol (1999) 276:H317–H325.[Web of Science][Medline]
  16. Schoemaker RG, Debets JJ, Struyker-Boudier HA, et al. Delayed but not immediate captopril therapy improves cardiac function in conscious rats, following myocardial infarction. J Mol Cell Cardiol (1991) 23:187–197.[CrossRef][Web of Science][Medline]
  17. Johnston KM, MacLeod BA, Walker MJ. Responses to ligation of a coronary artery in conscious rats and the actions of antiarrhythmics. Can J Physiol Pharmacol (1983) 61:1340–1353.[Web of Science][Medline]
  18. Leenen FH, Skarda V, Yuan B, et al. Changes in cardiac ANG II postmyocardial infarction in rats: effects of nephrectomy and ACE inhibitors. Am J Physiol (1999) 276:H317–H325.[Web of Science][Medline]
  19. Schoemaker RG, Debets JJ, Struyker-Boudier HA, et al. Delayed but not immediate captopril therapy improves cardiac function in conscious rats, following myocardial infarction. J Mol Cell Cardiol (1991) 23:187–197.[CrossRef][Web of Science][Medline]
  20. Johnston KM, MacLeod BA, Walker MJ. Responses to ligation of a coronary artery in conscious rats and the actions of antiarrhythmics. Can J Physiol Pharmacol (1983) 61:1340–1353.[Web of Science][Medline]
  21. 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]
  22. Henry RM, Kostense PJ, Bos G, et al. Mild renal insufficiency is associated with increased cardiovascular mortality: the Hoorn study. Kidney Int (2002) 62:1402–1407.[CrossRef][Web of Science][Medline]
  23. Hillege HL, Janssen WM, Bak AA, et al. Microalbuminuria is common, also in a nondiabetic, nonhypertensive population, and an independent indicator of cardiovascular risk factors and cardiovascular morbidity. J Intern Med (2001) 249:519–526.[CrossRef][Web of Science][Medline]
  24. Janssen WM, Hillege H, Pinto-Sietsma SJ, et al. Low levels of urinary albumin excretion are associated with cardiovascular risk factors in the general population. Clin Chem Lab Med (2000) 38:1107–1110.[CrossRef][Web of Science][Medline]
  25. de Zeeuw D, Remuzzi G, Parving HH, et al. Albuminuria, a therapeutic target for cardiovascular protection in type 2 diabetic patients with nephropathy. Circulation (2004) 110:921–927.[Abstract/Free Full Text]
  26. Anavekar NS, McMurray JJ, Velazquez EJ, et al. Relation between renal dysfunction and cardiovascular outcomes after myocardial infarction. N Engl J Med (2004) 351:1285–1295.[Abstract/Free Full Text]
  27. Eijkelkamp WB, Hillege H, de Graeff PA, et al. Effect of first myocardial ischemic event on renal function. Am J Cardiol (2007) 100:7–12.[CrossRef][Web of Science][Medline]
  28. Westendorp B, Schoemaker RG, Van Gilst WH, et al. Hydrochlorothiazide increases plasma or tissue angiotensin-converting enzyme-inhibitor drug levels in rats with myocardial infarction: differential effects on lisinopril and zofenopril. Eur J Pharmacol (2005) 527:141–149.[CrossRef][Web of Science][Medline]
  29. Rambausek M, Ritz E, Mall G, et al. Myocardial hypertrophy in rats with renal insufficiency. Kidney Int (1985) 28:775–782.[Web of Science][Medline]
  30. Mall G, Rambausek M, Neumeister A, et al. Myocardial interstitial fibrosis in experimental uremia—implications for cardiac compliance. Kidney Int (1988) 33:804–811.[Web of Science][Medline]
  31. Parfrey PS, Foley RN, Harnett JD, et al. Outcome and risk factors for left ventricular disorders in chronic uraemia. Nephrol Dial Transplant (1996) 11:1277–1285.[Abstract/Free Full Text]
  32. Amann K, Wiest G, Zimmer G, et al. Reduced capillary density in the myocardium of uremic rats—a stereological study. Kidney Int (1992) 42:1079–1085.[Web of Science][Medline]
  33. Buzello M, Boehm C, Orth S, et al. Myocyte loss in early left ventricular hypertrophy of experimental renovascular hypertension. Virchows Arch (2003) 442:364–371.[Web of Science][Medline]
  34. Mento PF, Maita ME, Wilkes BM. Renal hemodynamics in rats with myocardial infarction: selective antagonism of angiotensin receptor subtypes. Am J Physiol (1996) 271:H2306–H2312.[Web of Science][Medline]
  35. Chiurchiu C, Remuzzi G, Ruggenenti P. Angiotensin-converting enzyme inhibition and renal protection in nondiabetic patients: the data of the meta-analyses. J Am Soc Nephrol (2005) 16(Suppl_1):S58–S63.[Abstract/Free Full Text]
  36. Boos CJ. Cardiovascular protection with ace inhibitors—more HOPE for EUROPA? Med Sci Monit (2004) 10:SR23–SR28.[Web of Science][Medline]
  37. Ezekowitz J, McAlister FA, Humphries KH, et al. The association among renal insufficiency, pharmacotherapy, and outcomes in 6,427 patients with heart failure and coronary artery disease. J Am Coll Cardiol (2004) 44:1587–1592.[Abstract/Free Full Text]
  38. Lee DS, Tu JV, Juurlink DN, et al. Risk-treatment mismatch in the pharmacotherapy of heart failure. JAMA (2005) 294:1240–1247.[Abstract/Free Full Text]
Received for publication: 15. 8.07
Accepted in revised form: 4. 4.08


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?



This Article
Right arrow Abstract Freely available
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
23/10/3103    most recent
gfn233v2
gfn233v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Windt, W. A. K. M.
Right arrow Articles by van Dokkum, R. P. E.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Windt, W. A. K. M.
Right arrow Articles by van Dokkum, R. P. E.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?