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ABSTRACT: Chronic kidney disease is associated with a unique cardiomyopathy, characterised by a combination of structural and cellular remodelling, and an enhanced susceptibility to ischaemia-reperfusion injury. This may represent dysfunction of the reperfusion injury salvage kinase pathway, due to insulin resistance. Aims: The susceptibility of the uraemic heart to ischaemia-reperfusion injury and the cardioprotective effects of insulin and rosiglitazone were investigated. Methods and Results: Uraemia was induced in Sprague-Dawley rats by subtotal nephrectomy. Functional recovery from ischaemia was investigated in vitro in control and uraemic hearts ±insulin ±rosiglitazone. The response of myocardial oxidative metabolism to insulin was determined by 13C NMR spectroscopy. Activation of reperfusion injury salvage kinase pathway intermediates (Akt and GSK3β) were assessed by SDS-PAGE and immuno-precipitation. Insulin improved post-ischaemic rate pressure product in control but not uraemic hearts, (recovered rate pressure product (%), control 59.6±10.7 vs 88.9±8.5, p<0.05; uraemic 19.3±4.6 vs 28.5±10.4, p=ns). Rosiglitazone resensitised uraemic hearts to insulin-mediated cardio-protection (recovered rate pressure product (%) 12.7±7.0 vs. 61.8±15.9, p<0.05). Myocardial carbohydrate metabolism remained responsive to insulin in uraemic hearts. Uraemia was associated with increased phosphorylation of Akt (1.00±0.08 vs. 1.31±0.11, p<0.05) in normoxia, but no change in post-ischaemic phosphorylation of Akt or GSK3β. Akt2 isoform expression was decreased post-ischaemia in uraemic hearts (p<0.05). Conclusion: Uraemia is associated with enhanced susceptibility to ischaemia-reperfusion injury and a loss of insulin-mediated cardio-protection, which can be restored by administration of rosiglitazone. Altered Akt2 expression in uraemic hearts post ischaemia-reperfusion and impaired activation of reperfusion injury salvage kinase pathway may underlie these findings.
AJP Renal Physiology 08/2012; · 4.42 Impact Factor
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ABSTRACT: Uremic cardiomyopathy is a classic complication of chronic renal failure whose cause is unclear and treatment remains disappointing. Insulin resistance is an independent predictor of cardiovascular mortality in chronic renal failure. Underlying insulin resistance are defects in insulin signaling through the protein kinase, Akt. Akt acts as a nodal point in the control of both the metabolic and pleiotropic effects of insulin. Imbalance among these effects leads to cardiac hypertrophy, fibrosis, and apoptosis; less angiogenesis; metabolic remodeling; and altered calcium cycling, all key features of uremic cardiomyopathy. Here we consider the role of Akt in the development of uremic cardiomyopathy, drawing parallels from models of hypertrophic cardiac disease.
Journal of the American Society of Nephrology 02/2011; 22(2):207-15. · 9.66 Impact Factor
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ABSTRACT: Cardiovascular complications are the leading cause of death in patients with chronic kidney disease (CKD). The uraemic heart undergoes substantial remodelling, including left ventricular hypertrophy (LVH), an important determinant of heart failure. LVH results in a shift in myocardial substrate oxidation from fatty acids towards carbohydrates however, whether this metabolic adaptation occurs in the uraemic heart is unknown. The aim of this study was to investigate the progression of kidney dysfunction in parallel with cardiac remodelling in experimental uraemia. Experimental uraemia was induced surgically via a subtotal nephrectomy. At 3, 6 and 12 weeks post-surgery, renal function, LVH, in vitro cardiac function and metabolic remodelling using 13C-NMR were assessed. Uraemic animals exhibited anaemia and kidney dysfunction at 3 weeks, with further deterioration as uraemia progressed. By 12 weeks, uraemic hearts showed marked LVH, preserved cardiac function and markedly reduced fatty acid oxidation. This change in substrate preference may contribute to the deterioration of cardiac function in the uraemic heart and ultimately failure.
Frontiers in bioscience (Elite edition) 01/2010; 2:1492-501.
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ABSTRACT: The use of erythropoietin (EPO) has revolutionized the treatment of anaemia associated with many conditions including chronic kidney disease (CKD). However, little is known of the cellular impact of EPO on the uraemic heart. The discovery that the EPO receptor (EPOR) is also expressed on non-haematopoietic cells including cardiomyocytes highlights a role of EPO beyond haematopoiesis. Animal models of heart failure have shown EPO can potentially reverse cardiac remodelling and improve myocardial function. Damage to the kidney, during uraemia, results in a decreased EPO production, which may render the uraemic heart more susceptible to damage and heart failure. Here we review current data on the cellular actions of EPO in models of left ventricular hypertrophy and heart failure and highlight parallels with the uraemic heart.
European Journal of Heart Failure 09/2009; 11(8):732-8. · 4.90 Impact Factor
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ABSTRACT: Progressive ventricular hypertrophy can lead to the development of insulin resistance, a feature of both chronic kidney disease and heart failure. Here we induced uremia in adult male Sprague-Dawley rats using a remnant kidney model and studied the expression of glucose transporters. As expected, the reduction of nephron mass resulted in impaired renal function, cardiac hypertrophy, glucose intolerance, hyperinsulinemia, anemia, and hypertension. Insulin sensitivity was significantly reduced in the uremic animals as determined by oral glucose tolerance tests. After six weeks of uremia, at a point when cardiac hypertrophy had been established, left ventricle tissue had a marked increase in the expression of GLUT4 (insulin-dependent glucose transporter 4), consistent with hypertrophic remodeling, but not GLUT1 (insulin-independent glucose transporter 1). However, although uremic animals had systemic insulin resistance and glucose intolerance, there was no evidence of impaired GLUT4 translocation in the heart at 6 weeks of uremia, suggesting that other mechanisms may underpin insulin resistance in the uremic heart.
Kidney International 02/2009; 75(7):711-8. · 6.61 Impact Factor
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ABSTRACT: Our aim was to determine the prevalence, morbidity, and mortality associated with the presence of significant renal artery stenosis (RAS) in patients with chronic heart failure (HF), and to explore the use of angiotensin-converting enzyme (ACE) inhibitors and diuretics in this population during a 3-year follow-up period. We identified 97 patients with significant renal dysfunction (RD, defined as a calculated glomerular filtration rate of <60 ml/min) and 38 patients without RD, with ejection fractions of <40%. A stenosis of >50% using magnetic resonance angiography of the renal arteries was used to define significant RAS. Seventy-three (54%) patients had significant RAS of >or=1 artery. Mean follow-up time was 37.3 (+/- 7.9) months. Compared with patients with no significant RAS, these patients were on higher doses of diuretics, lower doses of ACE inhibitors, had prolonged hospital admissions, were admitted with exacerbation of HF, and had a higher mortality (p = 0.007 for mortality). In conclusion, RAS is common in patients with chronic HF, especially among patients with RD and is a predictor of a poor clinical outcome. Interventional trials on renal revascularization are underway that contain subsets of patients with HF that may provide evidence on how best to manage RAS in this setting.
The American Journal of Cardiology 08/2007; 100(2):273-9. · 3.37 Impact Factor
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ABSTRACT: No specific guidelines exist on how to manage renal dysfunction (RD) in patients with chronic heart failure (CHF).
To identify the proportion of patients with moderate to severe RD and CHF who showed an improvement in their renal function in response to a systematic management algorithm.
Stable patients with CHF and RD (defined by a serum creatinine (SCr) of >130 micromol/l (>1.5 mg/dl)) were enrolled into a systematic management algorithm. The following changes were implemented: switching aspirin to clopidogrel, halving the dose of both diuretics and angiotensin converting enzyme (ACE) inhibitors and switching between bisoprolol and carvedilol.
Two thirds of patients in whom diuretics were reduced, and one fifth of patients in whom ACE inhibitors were reduced, improved their SCr by >25.5 micromol/l (0.3 mg/dl). All these changes were more marked in the presence of bilateral renal artery stenosis. Compared to a reference group, in whom no changes were implemented, the treatment group showed an improvement in their mean SCr by 35 micromol/l (0.4 mg/dl), p<0.001.
Manipulation of pharmacological therapy for patients with CHF and RD results in a substantial recovery of renal function in a minority of patients.
European Journal of Heart Failure 04/2007; 9(4):415-23. · 4.90 Impact Factor
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ABSTRACT: Cardiac complications are the leading cause of mortality in patients with chronic renal failure. Secondary carnitine deficiency, which is frequently observed in hemodialysis patients, has been associated with cardiac hypertrophy and heart failure and may impair myocardial fatty acid oxidation. In chronic kidney disease, impaired carnitine homeostasis also may affect myocardial metabolism. In this study, myocardial function and substrate oxidation in conjunction with carnitine deficiency were investigated in experimental renal failure. Uremia was induced in male Sprague-Dawley rats via a two-stage five-sixths nephrectomy. Cardiac function and substrate oxidation were assessed in vitro by means of isovolumic perfusion using 13C nuclear magnetic resonance at 3 and 6 wk of uremia. Renal impairment as assessed by serum creatinine was more severe initially and was associated with a significant deficiency in serum free carnitine (43%; P < 0.001) and elevated acyl carnitine/free carnitine ratio. Myocardial tissue carnitine concentrations, however, were unaffected. A moderate degree of cardiac hypertrophy (10 to 14%; P < 0.05) was observed in uremia without evidence of dysfunction or changes in myocardial substrate utilization. It is concluded that renal dysfunction is associated with cardiac hypertrophy in the presence of normal myocardial carnitine levels, despite a significant depletion in serum carnitine. This may be a factor in maintaining normal cardiac function and metabolism.
Journal of the American Society of Nephrology 01/2007; 18(1):84-92. · 9.66 Impact Factor
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ABSTRACT: Anemia and renal dysfunction (RD) are frequent complications seen in chronic heart failure (HF). However, the prevalence and interaction of these co-morbidities in a representative population of outpatients with chronic HF is poorly described. In this study, it was sought to determine the association between RD and anemia in patients with HF enrolled in a community-based HF program. Nine hundred fifty-five patients with HF due to left ventricular systolic dysfunction were investigated for the prevalence of anemia and its cause and followed for a median of 531 days. Anemia was defined as hemoglobin < 12.0 g/dl in women and < 13.0 g/dl in men. RD was defined as a calculated glomerular filtration rate of < 60 ml/min. The prevalence of anemia was 32%. Fifty-three percent of patients with and 27% of those without anemia had > or = 1 test suggesting hematinic deficiency. The prevalence of RD was 54%. Forty-one percent of patients with and 22% of patients without RD had anemia, with similar proportions associated with iron deficiency in the presence or absence of RD. Anemia and RD independently predicted a worse outcome, and this effect was additive. In conclusion, in outpatients with chronic HF, anemia and RD are common and co-exist but confer independent prognostic information. A deficiency of conventional hematinic factors may cause about 1/3 of anemia in this clinical setting.
The American Journal of Cardiology 08/2006; 98(3):391-8. · 3.37 Impact Factor
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ABSTRACT: To determine the prevalence and incidence of renal dysfunction (RD) in patients with chronic heart failure (CHF), to identify contributory factors and predictors of worsening renal function (WRF), and to explore the relationship between RD and mortality.
Prospective data on 1216 patients with CHF were analysed. The glomerular filtration rate (GFR) was used to determine renal function, and WRF was defined as an increase in serum creatinine of >26.5 micromol/L (>0.3 mg/dL). The prevalence of RD defined as a GFR of <60 mL/min was 57%. During 6 months, WRF occurred in 161 (13.0%) patients. Predictors of WRF were vascular disease, the use of thiazide diuretics, and a baseline urea >9 mmol/L. Two hundred and sixty-three (21.6%) patients died, and baseline RD and WRF both predicted a higher mortality (P<0.001), whereas an improvement in renal function over the first 6 months predicted a lower mortality (hazard ratio 0.8, 95% confidence interval 0.6-1.0).
In ambulatory patients with CHF, RD is common, commonly deteriorates over a relatively short period of time, is unlikely to recover substantially, and augurs a poor prognosis.
European Heart Journal 04/2006; 27(5):569-81. · 10.48 Impact Factor
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ABSTRACT: Renal artery stenosis (RAS) is most commonly caused by atherosclerosis, which is also the most common cause of chronic heart failure (CHF). One-third of patients with CHF are reported to have significant renovascular disease. The presence of RAS confers a worse outcome in studies of hypertension and coronary disease, though data are lacking for patients with CHF. As the kidney is intricately involved in the fluid retention that occurs in CHF, an adverse effect of RAS on outcome would be expected. Presentations of RAS in CHF include flash pulmonary oedema, hypertension, worsening of CHF, and worsening renal function. RAS commonly progresses and may cause worsening of renal function in patients with CHF and previously stable renal function. A variety of investigations that can safely and accurately identify RAS in CHF are available, although none is recommended in current guidelines for the management of CHF. Treatment for RAS, whether for hypertension, for renal dysfunction, or for pulmonary oedema, is at the discretion of the physician due to the lack of adequate randomized controlled trials demonstrating the efficacy and safety of intervention. As it is not clear how RAS should be managed in CHF, screening cannot be advocated. Currently, a multicentre randomized outcome trial, which includes a cohort of patients with RAS and CHF, is in progress to provide answers in this area of uncertainty.
European Heart Journal 09/2005; 26(16):1596-605. · 10.48 Impact Factor
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ABSTRACT: We reviewed our experience of surgical and radiological intervention in 43 patients between 1987 and 1994 with angiographic
renovascular disease. We retrospectively compared the effect of angioplasty with stenting versus reconstructive surgery on
renal function and blood pressure in those patients with significant atherosclerotic renovascular stenosis. Twenty patients
with moderate/non ostial stenosis (less than 60% stenosis) and two with fibromuscular displasia underwent renal angioplasty
only. Indications for intervention were refractory hypertension (n=20), flash pulmonary oedema (n=8) and/or renal salvage
(n=31). All patients were hypertensive. Angioplasty with stenting was performed in ten patients, (2 female, 8 male), mean
age 69 years, 9 with bilateral disease. Plasma creatinine was greater than 240 µmol/L in seven patients. A unilateral procedure
was performed in 9 patients. Unilateral reconstructive surgery was performed in eleven patients (4 female, 7 male), mean age
63 years. Plasma creatinine was greater than 240 µmol/L in eight patients. Ten had bilateral disease. In the angioplasty/stenting
group there were three technical failures. The mortality rates in the angioplasty/stenting group and surgical group were 10%
and 27% respectively. Fifty-one and 165 patient months had elapsed in the stenting and surgical groups respectively. Blood
pressure fell in each group, mean decrease in mean arterial pressure (MAP) 16 mmHg (p=0.025) and 30 mmHg (p<0.01) respectively.
Improvement or stabilisation of renal function was achieved in 67% and 91% of cases respectively. Two surgical patients were
able to discontinue haemodialysis. The two methods of treatment appear to be equally effective in lowering blood pressure.
Reconstructive surgery offers greater improvement in renal function with the possibility of withdrawal of dialysis, at the
expense of a higher mortality rate.
Geriatric Nephrology and Urology 04/1997; 7(2):87-94.
