Evaluation of Hydroxymethylbutyrate Supplementation in Lung Transplant Candidates Receiving Pulmonary Rehabilitation

Lung transplantation (LTx) is an accepted treatment option for patients with end-stage lung disease who do not respond to non-transplant treatments. Lung transplantation (LTx) is an accepted treatment option for patients with end-stage lung disease who do not respond to non-transplant treatments. Primary indications for lung transplantation in the world are; 34% chronic obstructive pulmonary disease (COPD), 24% idiopathic pulmonary fibrosis (IPF), 17% cystic fibrosis (CF), 6% alpha-1-antitrypsin deficiency, 3% idiopathic pulmonary arterial hypertension (IPAH), 4% pulmonary fibrous (non-IPF), 3% bronchiectasis, 2.6% re transplantation and 2.5% of them are classified as sarcoidosis. Absolute contraindications for lung transplantation are; active malignancy, coronary artery disease without revascularization ability, significant extrapulmonary organ dysfunction, active tobacco or bad substance use, the presence of extremely serious active infections such as tuberculosis, morbid obesity and lack of psychosocial support. Absolute contraindications for lung transplantation are; active malignancy, coronary artery disease without revascularization ability, significant extrapulmonary organ dysfunction, active tobacco or bad substance use, the presence of extremely serious active infections such as tuberculosis, morbid obesity and lack of psychosocial support. Some relative contraindications are critical illness, mechanical ventilation (MV) and extracorporeal membrane oxygenation (ECMO) support, each transplant center has a different attitude. The upper age limit for lung transplantation varies according to each center, but is generally accepted as between 70 and 75 years of age. Beta-hydroxy-beta-methylbutyrate (HMB) is an active metabolite of the branched-chain essential amino acid leucine.roxy-beta-methylbutyrate (HMB) is an active metabolite of the branched-chain essential amino acid leucine. HMB is found in very small amounts in some foods such as avocados, citrus fruits, caulidroxy-beta-methylbutyrate (HMB) is an active metabolite of the branched-chain essential amino acid leucine. HMB is found in very small amounts in some foods such as avocados, citrus fruits, cauliflower and catfish. Leucine has a specific role in the regulation and control of protein synthesis in muscle cells. About 5% of leucine in the body is converted into HMB. Many studies have shown that HMB supplements alone or in combination with other amino acids and in combination with exercise training are beneficial for maintaining and restoring lean body mass, muscle strength and function in older adults. Many studies have shown that HMB supplements alone or in combination with other amino acids and in combination with exercise training are beneficial for maintaining and restoring lean body mass, muscle strength and function in older adults. Leucine is the most effective branched chain amino acid in important cellular processes such as protein synthesis and energy metabolism. The first step in leucine metabolism in the body is the reversible transamination that occurs in skeletal muscles to form α-ketoisocaproate with simultaneous production of glutarate from α-ketoglutarate. The first step in leucine metabolism in the body is the reversible transamination that occurs in skeletal muscles to form α-ketoisocaproate with simultaneous production of glutarate from α-ketoglutarate. The second stage is the irreversible oxidative decarboxylation of α-ketoisocaproate by branched-chain α-keto acid dehydrogenase (BCKD) and α-ketoisocaproate dehydrogenase (KICD) enzymes. In liver mitochondria, 90% of the α-ketoisocaproate produced causes the formation of acetoacetate and acetyl CoA, while in liver cytosol, the remaining 5-10% α-ketoisocaproate is oxidized to HMB by the enzyme KICD. Liver mitochondria, 90% of the α-ketoisocaproate produced causes the formation of acetoacetate and acetyl CoA, while in liver cytosol, the remaining 5-10% α-ketoisocaproate is oxidized to HMB by the enzyme KICD. HMB provides a decrease in muscle protein breakdown along with an increase in muscle protein synthesis. In addition, it stimulates muscle protein synthesis by activating the mechanical target of the rapamyc November (mTOR) system and growth hormone/insulin-like growth hormone. HMB has also been shown to be associated with a decrease in muscle proteolysis by inhibiting the ubiquitin-proteasome and autophagy-lysosome systems. Given the very low amounts of HMB present in foods and the low conversion rate of leucine to HMB (5-10%), optimal HMB dose requirements cannot be met with a standard diet. Therefore, oral HMB supplementation is considered an alternative to alleviate adult metabolic diseases, muscle wasting, and functional loss. Pulmonary rehabilitation (PR) aims to prevent further progression of respiratory disease and improve patients' physical and mental health, while also encouraging patients to adopt healthy behavioral habits. The European Respiratory Society and the American Thoracic Society define PR as "patient-specific treatments, including but not limited to exercise training and behavior modification, designed to improve the physical and psychological well-being of individuals with chronic respiratory diseases and to promote long-term health-promoting behaviors." PR, which includes exercise training, is a powerful intervention designed to improve exercise tolerance, skeletal and respiratory muscle function, movement efficiency, symptoms of dyspnea and fatigue, and health-related quality of life. PR aims to stabilize or reverse the pathophysiological and psychopathological symptoms of the disease and strives to restore the patient to the highest possible functional capacity. The optimal exercise type, duration, intensity, and frequency for PR have not yet been determined. A minimum of eight weeks is generally recommended for PR programs to provide lasting benefits to the patient. Exercise sessions are generally scheduled 3-5 times a week, each session lasting 20-45 minutes. It is suggested that the improvement mechanism of exercise training is related to increasing aerobic capacity and peripheral muscle performance in patients. Exercise intolerance and decreased quality of life often persist after transplantation. Physiological changes associated with severe chronic lung disease, extremity muscle dysfunction, inactivity/deconditioning, and nutritional deficiencies can affect exercise capacity and physical functioning in lung transplant candidates. Prolonged post-transplant hospital and intensive care unit stays, prolonged immobilization, immunosuppressant medications, and organ rejection can all impact lung recipients' recovery in terms of exercise tolerance and quality of life. Decreases in muscle mass and quadriceps strength are frequently observed in the pre-transplant period and have been reported to persist for up to 3 years post-transplant. Pre-transplant PR helps individuals maintain or optimize their pre-operative functional status. The nutritional status of patients on the waiting list is associated with post-transplant survival. Studies have identified obesity, low body mass index, and low serum albumin concentration as significant risk factors for increased mortality after lung transplantation. Nutritional status in lung transplant candidates is associated with post-transplant survival. Obesity, as well as pre-transplant malnutrition, is considered a contraindication and appears to increase the risk of post-transplant mortality independently of other risk factors. Lean body mass (FFM) is an important indicator of nutritional status. It is associated with muscle mass, muscle function, lung function, and quality of life. A decrease in FFM is significantly associated with increased mortality while waiting for transplantation and prolonged intensive care unit stay after transplantation. Body mass index (BMI) is a parameter used to assess nutritional status, calculated by dividing body mass by the square of height in meters. The resulting BMI is evaluated according to the World Health Organization (WHO) classification. A BMI above 30 kg/m² or below 18.5 kg/m² has been shown to increase post-transplant mortality and primary graft dysfunction. Furthermore, low albumin levels have frequently been associated with adverse post-transplant outcomes. In patients with end-stage lung disease, significant loss of lung function, respiratory failure, recurrent infections, decreased appetite caused by hypoxia and depression, and gastrointestinal dysfunction all contribute to inadequate energy intake and, consequently, malnutrition and even cachexia. The various complications associated with malnutrition lead to increased frequency and duration of hospitalization and shortened survival after transplantation. Therefore, it is crucial to assess the nutritional status of lung transplant candidates before transplantation, identify any risks of malnutrition in a timely manner, and provide an individualized nutrition program tailored to each patient. Optimizing nutrition and health status in lung transplant candidates during the listing period is crucial for achieving recovery as quickly as possible after transplantation, shortening hospital stays, and promoting survival. The study aimed to investigate the positive/negative effects of pulmonary rehabilitation and HMB supplementation, which supports muscle mass and protein synthesis, compared to pulmonary rehabilitation alone in lung transplant candidates.