Pathways to Improving Functional Capacity in Older Patients With Chronic Kidney Disease and Cardiovascular Disease

Patients with chronic kidney disease (CKD) have a high morbidity and mortality from cardiovascular disease (CVD). Both conditions are common in older patients. Reduced exercise capacity predicts poorer outcomes in patients with CVD2 and CKD. Although exercise tolerance is impaired in CKD4 limited improvement in these patients is possible. A critical gap in knowledge is how to optimize exercise capacity in these patients to improve quality and possibly length of life. In CKD, both structure and function of skeletal muscle are deranged. In addition, energy production by mitochondria which falls with age, and various diseases is also reduced in CKD. Recent studies from our group have reported that differences in mitochondrial function are associated with variances in physical ability, exercise capacity, and gait speed. In preliminary data, patients entering our Cardiac Rehabilitation (CR) with Stage III CKD \[glomerular filtration rate (GFR) of \<60 ml/min/1.73 m2\] had a decreased improvement in exercise capacity compared to those with a normal GFR (Δ1.7 vs 2.7 Metabolic Equivalents of Exercise or METs, p\<0.05) despite the same degree of adherence. Exercise capacity after CR in patients with a reduced GFR was greater in n-3 polyunsaturated fatty acids (n-3 PUFA) users than in non-users \[Δ MET 2.0 (1.4-2.5) vs 1.4 (1.1-1.7), p\<0.05\], suggesting that n-3 PUFA with exercise may be better than exercise alone. With beneficial clinical effects in CKD, n-3 PUFA are now being extensively investigated in the dialysis population. In other patient populations, including those with chronic obstructive pulmonary disease and dilated cardiomyopathy daily ingestion/use of n-3 polyunsaturated fatty acids (n-3 PUFA) or fish oil improves exercise capacity. This intervention is safe, simple and well-tolerated. Multiple lines of evidence suggest muscle and mitochondrial function improve with exercise and n-3 PUFA supplementation.Such treatment may improve mitochondrial bioenergetics by various mechanisms including up-regulation of mitochondrial biogenesis and genes involved in mitochondrial fatty acid oxidation, as well as increase in mitochondrial content, and function. Flow mediated vasodilation is impaired in CKD. It too may be improved by n-3 PUFA supplementation which could be an alternative mechanism for improved oxygen delivery to muscle in older patients with CAD and CKD as in the non-CKD population. A further possible benefit of n-3 PUFA is suppression of inflammation. Current practice, however, is to enter patients with CAD and CKD into standard CR without prescription of n-3 PUFA. Experimental and epidemiological studies indicate that acidemia and metabolic acidosis are associated with the development and progression of CKD and with increased mortality in these patients. Metabolic acidosis associated with CKD also contributes to skeletal muscle atrophy by activation of the ubiquitin-proteasome axis. Even slight correction of acidosis can improve the anabolic state of muscle by downregulation of the ubiquitin-proteasome system. Clinically, bicarbonate supplementation may improve muscle function. This intervention is also safe, simple and well-tolerated. Given that muscular function is abnormal in CKD and that both n-3 PUFA and bicarbonate supplementation have been shown to improve muscular function and exercise capacity, it is our purpose in this investigation to study the effects of these substances on exercise capacity in patients with CAD and CKD. The investigators propose a double-blind, placebo-controlled, randomized, 2x2 factorial design, pilot study of n-3 PUFA and/or oral bicarbonate use in older (age \>60 years) CAD patients with concomitant CKD enrolling in a standard, 3-month CR program. The investigators will assess the effects of this intervention on exercise capacity, markers of inflammation and serum bicarbonate concentration. The investigator's goal is to obtain 8 evaluable patients per group. Exercise capacity will be measured by Oxygen (VO2) peak. Response to bicarbonate will be monitored by serum bicarbonate concentration. Since CKD may adversely affect muscle function both by acidosis and/or mitochondrial function, the investigator's propose that these may be mechanisms for the poorer exercise capacity in these patients. The investigator's overarching hypothesis is that exercise capacity response to CR in older patients with CKD may be modifiable by concomitant n-3 PUFA and/or bicarbonate use to suppress acidosis.