The Interpretation of Standard Cardiopulmonary Exercise Test Indices of Cardiac Function in Chronic Kidney Disease.

BACKGROUND AND AIMS: As there is growing interest in the application of cardiopulmonary exercise test (CPX) in chronic kidney disease (CKD), it is important to understand the utility of conventional exercise test parameters in quantifying the cardiopulmonary fitness of patients with CKD. Merely extrapolating information from heart failure (HF) patients would not suffice. In the present study, we evaluated the utility of CPX parameters such as the peak O2-pulse and the estimated stroke volume (SV) in assessing the peak SV by comparing with the actual measured values. Furthermore, we compared the anaerobic threshold (AT), peak circulatory power, and ventilatory power with that of the measured values of the peak cardiac power (CPOpeak) in representing the cardiac functional reserve in CKD. We also performed such analyses in patients with HF for comparison. METHOD: A cross sectional study of 70 asymptomatic male CKD patients [CKD stages 2-5 (pre-dialysis)] without primary cardiac disease or diabetes mellitus and 25 HF patients. A specialized CPX with a CO2 rebreathing technique was utilized to measure the peak cardiac output and peak cardiac power output. The peak O2 consumption (VO2peak) and AT were also measured during the test. Parameters such as the O2-pulse, stroke volume, arteriovenous difference in O2 concentration [C(a-v)O2], peak circulatory power, and peak ventilatory power were all calculated. Pearson's correlation, univariate, and multivariate analyses were applied. RESULTS: Whereas there was a strong correlation between the peak O2-pulse and measured peak SV in HF, the correlation was less robust in CKD. Similarly, the correlation between the estimated SV and the measured SV was less robust in CKD compared to HF. The AT only showed a modest correlation with the CPOpeak in HF and only a weak correlation in CKD. A stronger correlation was demonstrated between the peak circulatory power and CPOpeak, and the ventilatory power and CPOpeak. In HF, the central cardiac factor was the predominant determinant of the standard CPX-derived surrogate indices of cardiac performance. By contrast, in CKD both central and peripheral factors played an equally important role, making such indices less reliable markers of cardiac performance per se in CKD. CONCLUSION: The results highlight that the standard CPX-derived surrogate markers of cardiac performance may be less reliable in CKD, and that further prospective studies comparing such surrogate markers with directly measured cardiac hemodynamics are required before adopting such markers into clinical practice or research in CKD.

Beta Blockade Prevents Cardiac Morphological and Molecular Remodelling in Experimental Uremia.

Heart failure and chronic kidney disease (CKD) share several mediators of cardiac pathological remodelling. Akin to heart failure, this remodelling sets in motion a vicious cycle of progressive pathological hypertrophy and myocardial dysfunction in CKD. Several decades of heart failure research have shown that beta blockade is a powerful tool in preventing cardiac remodelling and breaking this vicious cycle. This phenomenon remains hitherto untested in CKD. Therefore, we set out to test the hypothesis that beta blockade prevents cardiac pathological remodelling in experimental uremia. Wistar rats had subtotal nephrectomy or sham surgery and were followed up for 10 weeks. The animals were randomly allocated to the beta blocker metoprolol (10 mg/kg/day) or vehicle. In vivo and in vitro cardiac assessments were performed. Cardiac tissue was extracted, and protein expression was quantified using immunoblotting. Histological analyses were performed to quantify myocardial fibrosis. Beta blockade attenuated cardiac pathological remodelling in nephrectomised animals. The echocardiographic left ventricular mass and the heart weight to tibial length ratio were significantly lower in nephrectomised animals treated with metoprolol. Furthermore, beta blockade attenuated myocardial fibrosis associated with subtotal nephrectomy. In addition, the Ca++- calmodulin-dependent kinase II (CAMKII) pathway was shown to be activated in uremia and attenuated by beta blockade, offering a potential mechanism of action. In conclusion, beta blockade attenuated hypertrophic signalling pathways and ameliorated cardiac pathological remodelling in experimental uremia. The study provides a strong scientific rationale for repurposing beta blockers, a tried and tested treatment in heart failure, for the benefit of patients with CKD.

Cardiac and Noncardiac Determinants of Exercise Capacity in CKD.

BACKGROUND: Impaired exercise capacity is a significant symptom of CKD and is associated with poor survival. Furthermore, there is a growing interest in applying exercise as a diagnostic tool or as therapy in CKD. However, an in-depth understanding of exercise physiology in CKD is still lacking. METHODS: To evaluate the role of cardiac (central) and noncardiac (peripheral) determinants of exercise capacity in CKD, we conducted a cross-sectional study of 70 male patients with CKD (stages 2-5) without diabetes or cardiac disease, 35 healthy controls, and 25 patients with heart failure. An integrated cardiopulmonary exercise test using a CO2 rebreathing technique was used to measure peak O2 consumption (VO2peak) and peak cardiac output simultaneously, and to calculate peak peripheral O2 extraction (C[a-v]O2), the peripheral determinant (the ability of exercising skeletal muscles to extract oxygen). We performed multiple regression analysis and used Bayesian information criteria (BIC) changes to quantitatively assess the individual contribution of central and peripheral factors. RESULTS: Compared with healthy controls, in patients with CKD, the VO2peak was impaired proportionate to its severity. Peak cardiac output was the predominant determinant of VO2peak in healthy controls and patients with heart failure, whereas C(a-v)O2 played a more significant role in determining VO2peak in CKD (ß=0.68, P<0.001) compared with cardiac output (ß=0.63, P<0.001). In addition, the magnitude of BIC reduction was greater for C(a-v)O2 compared with cardiac output (BIC, 298.72 versus 287.68) in CKD. CONCLUSIONS: In CKD, both peak cardiac output and peak C(a-v)O2 are independent predictors of VO2peak, and the more significant roleplayed by peak C(a-v)O2 highlights the importance of noncardiac factors in determining exercise capacity in CKD.

Association between Protein-Bound Uremic Toxins and Asymptomatic Cardiac Dysfunction in Patients with Chronic Kidney Disease.

Although the relationship between protein-bound uremic toxins (PBUTs) and cardiac structure and cardiac mortality in chronic kidney disease (CKD) has been studied in the past, the association between cardiac dysfunction and PBUTs has not yet been studied. We therefore evaluated the association between impaired peak cardiac performance and the serum free and total concentrations of potentially cardiotoxic PBUTs. In a cross-sectional study of 56 male CKD patients (stages 2⁻5 (pre-dialysis)) who were asymptomatic with no known cardiac diseases or diabetes we measured peak cardiac power (CPOmax), aerobic exercise capacity (VO2max), and echocardiographic parameters of cardiac morphology and evaluated their association with PBUTs. The serum total and free concentrations of indoxyl sulfate (IXS), p-cresyl sulfate (PCS), p-cresyl glucuronide, indole acetic acid, and hippuric acid showed significant negative correlation with CPOmax and VO2max. IXS and PCS were independently associated with CPOmax and VO2max even after controlling for eGFR. No correlation between left ventricular mass index (LVMI) and PBUTs was seen. The present study for the first time has demonstrated the association between subclinical cardiac dysfunction in CKD and serum levels of a panel of PBUTs. Further studies are required to evaluate the mechanism of cardiotoxicity of the individual uremic toxins.

Early and asymptomatic cardiac dysfunction in chronic kidney disease.

Background: Heart failure (HF) is highly prevalent and associated with high mortality in chronic kidney disease (CKD). However, the pathophysiology of cardiac dysfunction in CKD, especially in the early asymptomatic stage, is not well understood. We studied subclinical cardiac dysfunction in asymptomatic CKD patients without comorbid cardiac disease or diabetes mellitus by evaluating peak cardiac performance. Methods: In a cross-sectional study (n = 130) we investigated 70 male non-diabetic CKD patients (21 CKD stage 2-3a, 27 CKD stage 3b-4 and 22 CKD stage 5) employing specialized cardiopulmonary exercise testing to measure peak cardiac output and cardiac power output non-invasively. Data from 35 age-matched healthy male volunteers were obtained for comparison. In addition, as a positive control, data from 25 age-matched male HF patients in New York Heart Association class II and III were also obtained. Results: The study subjects showed a graded reduction in peak cardiac power, with 6.13 ± 1.11 W in controls, 5.02 ± 0.78 W in CKD 2-3a, 4.59 ± 0.53 W in CKD 3b-4 and 4.02 ± 0.73 W in CKD 5, although not as impaired as in HF, with 2.34 ± 0.63 W (all P < 0.005 versus control). The central haemodynamic characteristics of the cardiac impairment in CKD mirrored that of HF, with reduced flow and pressure-generating capacities, reduced chronotropic reserve and impaired contractility. Conclusions: The study demonstrates for the first time impaired peak cardiac performance and cardiac functional reserve in asymptomatic CKD patients. The evidence of myocardial dysfunction in the absence of comorbid cardiac disease and diabetes warrants further evaluation of current pathophysiological concepts of cardiovascular disease in CKD.

Is uremic cardiomyopathy a direct consequence of chronic kidney disease?

Heart failure is a major cause of morbidity and mortality in chronic kidney disease (CKD). Rather than merely secondary to traditional vascular factors, CKD is also an independent risk factor for heart failure, termed uremic cardiomyopathy (UCM). Echocardiography commonly reveals structural left ventricular hypertrophy in CKD, without clarifying whether it is adaptive or maladaptive. Corresponding functional assessments have been mostly conducted at rest. To unravel the extents and mechanisms UCM, a next step involves the adoption of direct measurements of CKD-induced cardiac pumping incapacity at peak exercise. This could potentially lead to future novel interventions to ameliorate or reverse UCM.

Principles governing heart failure therapy re-examined relative to standard evidence-based medicine-driven guidelines.

Although all aspects of clinical work nowadays are modified by the pervading influence of evidence-based medicine (EBM) and multiplicative guidelines, not many clinicians realize that the underlying premise of EBM-driven guidelines is a particular strain of consequentialist ideology. Subservience to this ideology has transformed modern medical practice, but there is a real risk of distorting good medical practice, of belittling clinical judgement, of disempowering clinicians, and subjecting patients to skewed medical reality and treatment options. With so many heart failure (HF) guidelines issued by various august bodies, it is therefore timely to reappraise principles governing modern HF therapy with a fresh examination of the hierarchy of medical imperatives, the role of alternatives to consequentialism including deontological principles in HF therapy. In addition, other ideology worth re-examining, aside from EBM, are the principle of appropriate definition of HF underlying therapeutic goals and the principle of prioritizing objectives of HF therapy. Even within standard EBM, there are many questions to reconsider: about what types of evidence are admissible, different interpretations of available evidence, emphasizing patient-centered outcome measures instead of randomized controlled trials quantifiable therapeutic outcomes, how to prescribe drugs for prognostic versus symptomatic benefits, and how to deliver HF therapy based on pathophysiological features through mechanistic considerations and not just confined to randomized controlled trials or meta-analytical statistical imperatives. Through re-examination of these fundamental principles of HF therapy, it is hoped that clinicians will be empowered to manage HF patients more holistically and better deliver HF therapies in the best interest of each individual patient.

Influence of intravenous iron therapy on novel markers of iron deficiency.

BACKGROUND: Detection of iron deficiency in patients with end-stage renal disease (ESRD) remains challenging due to the lack of reliable markers. The immature reticulocyte fractions (IRF) RET-Y and RBC-Y may serve as useful novel markers. We investigated the ability of IRF to detect functional iron deficiency in ESRD patients in comparison to Serum ferritin (SF) and Transferrin saturation (TSAT) and the influence of intravenous iron therapy on these markers. METHODS: Cross sectional (n=40) and prospective (n=20) studies of hemodialysis patients were performed; 20 patients received intravenous iron (200 mg) monthly and were followed up for 5 months. Iron deficiency was defined as SF < or =200 microg/L and/or TSAT < or =20%. A RBC-Y < or =171 and/or RET-Y < or =168.7 were criteria for iron deficiency. Correlations between traditional and novel markers were examined. Results are given as mean+/-SEM. Paired t-test was used to test for significance. RESULTS: 27 male and 13 female patients, mean age of 56.7+/-3.02 years were enrolled in the cross-sectional study. TSAT correlated with RBC-Y and RET-Y, r=0.47 and 0.61, respectively. Correlations for SF with RBC-Y and RET-Y were r=0.23 and 0.22, respectively. In the prospective component (11 males and 9 females of mean age 60+/-3.4 years), RET-Y and RBC -Y remained stable during iron therapy. The coefficients of variation were RBC-Y 2.54%, RET-Y 4.23%, TSAT 28.74% and SF 35.34%. CONCLUSIONS: RBC-Y and RET-Y correlated with TSAT and SF allowing detection of functional iron deficiency. These measures were less susceptible to fluctuations than traditional markers.