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Keywords:

  • ACE-inhibitors;
  • chronic renal failure;
  • malnutrition;
  • TNF-α

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Abstract. Stenvinkel P, Andersson P, Wang T, Lindholm B, Bergström J, Palmblad J, Heimbürger O, Cederholm T (Huddinge University Hospital and Karolinska Institute, Stockholm; Sweden). Do ACE-inhibitors suppress tumour necrosis factor-α production in advanced chronic renal failure? J Intern Med 1999; 246: 503–507.

Objectives. The serum levels of the catabolic cytokine TNF-α are often raised in malnourished chronic heart failure patients as well as in chronic renal failure (CRF) patients. Angiotensin-converting enzyme (ACE) inhibitors are often used in these patients and may decrease TNF-α and IL-1β levels in vitro and in vivo. The aim of this study was to find out whether CRF patients with ongoing ACE-inhibitor treatment have lower TNF-α levels.

Design. Cross-sectional study.

Setting. Tertiary Referral Center and University Hospital.

Subjects. Ninety-six predialysis patients (mean age 52 ± 1 years) with advanced CRF (glomerular filtration rate 7 ± 1 mL min–1).

Main outcome measures. Plasma levels of TNF-α, subjective global assessment of nutritional status and data on ongoing antihypertensive treatment (ACE-inhibitors, beta blockers, calcium channel blockers and angiotensin II (AII) receptor blockers).

Results. Patients treated with ACE-inhibitors (n = 44) had significantly lower plasma TNF-α levels (18.5 ± 1.2 vs. 26.6 ± 2.2 pg mL–1; P < 0.01) and were less frequently malnourished, relative to 52 patients not treated with ACE-inhibitors. No significant difference in TNF-α levels were observed when comparing patients with or without treatment with beta, calcium channel, or AII receptor blockers, respectively.

Conclusions. The present data suggest that the use of ACE-inhibitors is associated with lower plasma TNF-α and CRP levels as well as a lower prevalence of malnutrition in patients with advanced CRF. Further studies are needed to establish if there is a casual relationship between these findings and, if so, the molecular mechanism(s).


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Protein-energy malnutrition with muscle wasting is present in a large proportion of patients with chronic renal failure (CRF) and is, in addition to atherosclerosis, a strong risk factor for mortality in patients undergoing haemodialysis (HD) or peritoneal dialysis (PD) [1]. Although emergence of malnutrition is multifactorial, a role for catabolic cytokines, e.g. interleukin 1β (IL-1β) and tumour necrosis factor (TNF-α), has been proposed [2–4] since elevated plasma levels of IL-1β and TNF-α have been shown in both nondialysed patients with CRF [5] as well as in patients on PD [5 6] and HD [5 7]. In addition, increased concentrations of IL-1β and TNF-α might be a feature of protein–energy malnutrition in other chronic disorders such as congestive heart failure [8 9] or chronic obstructive pulmonary disease [10].

Angiotensin-converting enzyme (ACE) inhibitors are widely used to halt progression of diabetic and nondiabetic CRF [11–13] and chronic heart failure [14 15]. Apart from the effect of these drugs on the renin-angiotensin axis, recent reports suggest that ACE-inhibitors also may suppress production of catabolic cytokines such as TNF-α or IL-1β, both in vitro[16–19] and in vivo, in mice [18]. Based on these considerations, we asked whether ongoing ACE-inhibitor treatment was associated with lower plasma TNF-α levels in patients with advanced CRF.

Patients and methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Ninty-six patients (55 male) with advanced CRF were studied prior to the start of dialysis treatment. Part of this cross-sectional patient material has been described previously [20]. Patients who were hospitalized with clinical signs of overt infection at the time of admission were not included in the analysis of data. The mean (± SEM) clearance of creatinine and urea at the time of examination was 7 ± 1 mL min–1 (range 2–15 mL min–1). The mean age of the patients was 52 ± 1 years and the body-mass index was 24.3 ± 0.5 kg m–2. The causes of CRF were chronic glomerulonephritis in 32 patients (33%), diabetic nephropathy in 27 patients (28%), polycystic kidney disease in 8 patients (9%), interstitial nephritis in 5 patients (5%) and other, or unknown, aetiologies in 24 patients (25%). A majority of patients (86%) were on antihypertensive medications which included beta blockers (n = 43), calcium channel blockers (n = 59), ACE-inhibitors (n = 44) or angiotensin II receptor blockers (n = 6). Mean systolic and diastolic blood pressures were 147 ± 2 and 86 ± 1 mmHg in 83 patients receiving ongoing antihypertensive treatment and 141 ± 5 and 81 ± 2 mmHg in 13 patients not receiving antihypertensive treatment, respectively. Most of the patients were also on other commonly used drugs in terminal CRF such as phosphate- and potassium-binders, loop-diuretics and vitamin B, C and D supplementation. The study protocol was approved by the Ethics Committee of Karolinska Institutet at Huddinge University Hospital, Stockholm and informed consent was obtained from each patient.

Patients were interviewed and examined close to the start of dialysis treatment and their current antihypertensive medication was recorded. After an overnight fast, blood samples for analysis of S-albumin, C-reactive protein (CRP), S-creatinine, S-urea and TNF-α were drawn the following morning. A 24-h urinary sample for analysis of creatinine and urea excretion was also collected. Nutritional status was analysed using subjective global assessment (SGA) as previously described [21]. Plasma TNF-α was measured by photometric enzyme-linked immunosorbent assay (ELISA). The ELISA kits were obtained from Boehringer Mannheim (Mannheim, Germany). The limit of detection was 5 pg mL–1. Determinations of S-albumin (bromcresol purple), CRP, S-creatinine and S-urea were performed by routine methods in the Department of Clinical Chemistry, Huddinge Hospital. The applied detection limit of CRP was 10 mg L–1 and all values < 10 mg L–1 were treated as 9 mg L–1 in the statistical evaluation.

Data are presented as mean ± SEM with P < 0.05 taken to indicate a statistical significance. Comparisons between two groups of patients were performed using Student’s t-test or Mann–Whitney’s U-test as appropriate. Comparisons between groups for nominal variables were made by Fisher’s exact test. Independent associations between one dependent variable and two independent variables were assessed by multiple regression analysis.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Patients on ACE-inhibitors (n = 44) had significantly lower CRP (11 ± 1 vs. 25 ± 4 mg l–1; P < 0.01) and TNF-α (18.5 ± 1.2 vs. 26.6 ± 2.2 pg mL–1; P < 0.01) levels compared to the 52 patients not on ACE-inhibitors ( Table 1). Moreover, patients not on antihypertensive medication had significantly higher TNF-α levels (33.6 ± 6.8 pg mL–1; n = 13) than patients on various antihypertensive drugs, with (18.5 ± 1.2 pg mL–1; n = 44) or without ACE-inhibitors (24.2 ± 1.7 pg mL–1; n = 39), respectively ( Fig. 1). No significant difference in plasma TNF-α levels were recorded between male (22.5 ± 1.4 pg mL–1; n = 58) and female (23.4 ± 2.7 pg mL–1; n = 38) CRF patients. There was no significant difference in CRP levels between patients on (17 ± 2 mg l–1; n = 13) or not on (28 ± 8 mg l–1; n = 83) antihypertensive medication. In a stepwise multiple regression model adjusting for age, gender and inflammation (log CRP), a weak but significant (P < 0.05) association was observed between ongoing ACE-inhibitor treatment and TNF-α levels.

Table 1.  Clinical data (mean ± SEM) on 96 CRF patients without (n = 52) or with (n = 44) ACE-inhibitors (ACEI)
 ACEINo ACEISignificance
Age (years)49 ± 254 ± 2P < 0.05
BMI (kg m–2) 25.0 ± 0.823.6 ± 0.6NS
CRP (mg L–1) 11 ± 125 ± 4P < 0.01
TNF-α (pg mL–1) 18.5 ± 1.226.6 ± 2.2P < 0.01
Serum albumin (g L–1) 33 ± 133 ± 1NS
GFR (mL min–1) 7 ± 17 ± 1NS
Prevalence of malnutrition (%) 32 54 P < 0.05
Prevalence of diabetes mellitus (%) 32 23 NS
image

Figure 1. Plasma TNF-α levels in 13 patients not on antihypertensive (anti-HT) drugs, 39 patients on antihypertensive drugs but not on ACE-inhibitors, and 44 patients on antihypertensive drugs including ACE-inhibitor treatment.

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No significant differences were found in TNF-α (21.5 ± 1.3 vs. 24.5 ± 2.5 pg mL–1) or CRP (19 ± 4 vs. 18 ± 3 mg L–1) levels when CRF patients were divided into patients on (n = 43) or not on (n = 53) beta blockers. Moreover, no significant differences in TNF-α (21.9 ± 1.3 vs. 24.5 ± 2.9 pg mL–1) or CRP (17 ± 3 vs. 21 ± 4 mg L–1) levels were found when CRF patients were divided into patients on (n = 59) or not on (n = 37) calcium channel blockers. Finally, in six patients with ongoing AII receptor blocker treatment, TNF-α (25.4 ± 1.3 vs. 22.7 ± 2.9 pg mL–1) and CRP (17 ± 6 vs. 19 ± 2 mg L–1) levels were not significantly different from 90 patients not taking AII receptor blockers. The 44 patients on ACE-inhibitors were also divided into three groups according to type of ACE-inhibitor treatment; enalapril (n = 26), captopril (n = 3) and lisinopril / ramipril (n = 15), respectively. No significant differences in TNF-α levels were observed between the enalapril (17.2 ± 1.1 pg mL–1), captopril (21.5 ± 4.4 pg mL–1) or lisinopril / ramipril (20.2 ± 2.8 pg mL–1) patient groups.

The prevalence of malnutrition was significantly lower (32% vs. 54%; P < 0.05) in the group of patients on ACE-inhibitors, whereas the levels of S-albumin or the prevalence of diabetes mellitus did not differ significantly ( Table 1).

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

This study shows that CRF patients receiving ongoing ACE-inhibitor treatment have markedly lower plasma levels of TNF-α compared with patients not on ACE-inhibitors. Previously, Schindler et al. [16] have demonstrated that captopril dose dependently suppressed the IL-1β-induced synthesis of TNF-α by 74% in human monocytes. In their study also enalapril and cilazapril suppressed cytokine-induced TNF-α synthesis whereas ramipril, lisinopril, perindopril and spirapril had no significant effect on TNF-α synthesis. We have preliminary in vitro data showing that captopril reduces TNF-α-induced IL-1β generation in human monocytes [17]. Moreover, recent results presented by Fukuzawa et al. [18] have demonstrated that various ACE-inhibitors, such as captopril, delapril and cilazapril, not only inhibited TNF-α production in vitro but also in vivo in mice. On the other hand, Peeters et al. [19] have found that, whereas captopril has potent inhibitory effects on lipopolysaccharide-stimulated production of TNF-α and IL-1 in vitro, administration of one dose of captopril did not influence LPS-stimulated production of cytokines by whole blood in essential hypertensives.

The mechanism(s) by which ACE-inhibitors may suppress plasma TNF-α are not evident. We could not find any difference in plasma TNF-α levels between three different groups of ACE-inhibitors, suggesting that ACE-inhibitors in general may suppress TNF-α levels. However, it must be pointed out that only three patients in the present material were on captopril treatment. In the present study, six patients receiving ongoing AII receptor blocking treatment did not have lower TNF-α levels compared to 90 patients without AII receptor blocking, which may suggest that ACE-inhibitors suppress TNF-α by a mechanism independent of AII receptor blocking.

In several experimental models, inhibition of cytokine activity can positively affect food intake and may thereby reverse nutritional depletion [22]. Moreover, recently reported data has suggested that high TNF-α levels are associated with a poor nutritional status in dialysis patients [6]. In the present study, we found a lower prevalence of malnutrition in patients receiving ACE-inhibitors. It cannot be excluded that this may reflect differences in the selection of patients. Alternatively, it may indicate a beneficial effect of ongoing ACE-inhibitor treatment on TNF-α contributing to a better nutritional state. Further studies are therefore needed to evaluate the possible impact of ACE-inhibitors on changes of the nutritional status in patients with CRF. Although in vitro data suggest a cellular mechanism for the reduced TNF-α generation by ACE-inhibitors [16–19] we cannot exclude that the use of ACE-inhibitors in CRF patients resulted in a systemic effect due to improved cardiovascular stability and thereby reduced the stimuli for TNF-α generation. It is thus possible that the observed effect of ACE-inhibitors on TNF-α levels may, at least partly, be an effect secondary to improved haemodynamics.

In summary, the present cross-sectional data suggest that CRF patients on ACE-inhibitors have lower plasma TNF-α and CRP levels as well as a lower prevalence of malnutrition. This may reflect a causal effect: either cellular, due to the previously observed inhibition of TNF-α production, or systemic, due to improved haemodynamics; or it could reflect a selection bias. Prospective randomized studies are therefore needed to study whether or not ACE-inhibitors, by inhibiting TNF-α, may lower the high prevalence of mortality related to malnutrition, inflammation and cardiovascular disease in patients with advanced CRF.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

We acknowledge the skilled technical assistance of Ms I. Sjödin, Ms A. Lif and Ms Hui-hong Cheng. This work was funded by the Baxter Extramural Grant Program (PS).

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
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Received 27 January 1999; accepted 31 March 1999.