The Role Of Lifestyle Intervention, in Addition To Drugs, For Diabetic Kidney Disease With Sarcopenic Obesity

Abstract: Diabetic kidney disease is the leading cause of end-stage renal disease in developing and developed countries. The growing prevalence and clinical challenges of sarcopenic obesity have been associated with the frailty and disability of diabetic kidney disease. It has been reported that insulin resistance, chronic inflammation, enhanced oxidative stress, and lipotoxicity contribute to the pathophysiology of muscle loss and visceral fat accumulation. Sarcopenic obesity, which is diagnosed with dual-energy X-ray absorptiometry, is associated with worse outcomes in kidney disease. Growing evidence indicates that adherence to healthy lifestyles, including a low protein diet, proper carbohydrate control, vitamin D supplements, and regular physical training, has been shown to improve clinical prognosis. Based on the higher risk of sarcopenic-obesity-related renal function decline, has led to the exploration and investigation of the pathophysiology, clinical aspects, and novel approaches to these controversial issues in daily practice. 

A NEW HERB FOR CURE KIDNEY DISEASE

Keywords: sarcopenic obesity; muscle mass; fat mass; diabetes; chronic kidney disease; dual-energy X-ray absorptiometry

1. Introduction

The prevalence of end-stage renal disease (ESRD) is up to 10 times higher in people with diabetes than in non-diabetic individuals. Glycemic control continues to be focused on the targeting of glycohemoglobin (HbA1C) among individuals with diabetes and chronic kidney disease (CKD) over the last decades [1]. Despite intensive medical therapies, there remains a significant residual risk of diabetic kidney disease onset and progression. Diabetic nephropathy begins as glomerular hyperfiltration with increased glomerular filtration rate (GFR), and then GFR begins to normalize for several years. As a result of progressive metabolic and hemodynamic changes of the glomerulus, renal injury is characterized by mimicroalbuminuria (between 30–300 mg/day) over time. It is of note that the maximal benefits of good glycemic control occur before the onset of macroalbuminuria (≥300 mg/day), which is inevitable to progress to renal failure [2]. Nephrotic syndrome (≥3 g/day), elevated serum creatinine level, low serum albumin, hyperlipidemia, edema, and hypertension precede ESRD, on average, by about 3 to 5 years, but this timing is extremely variable [3]. According to the USRDS ESRD available database, the percentage change in the incidence of treated ESRD attributed to diabetes appears to be strongest in Asia [4]. The pathogenesis of diabetic kidney disease (DKD) begins with vascular endothelial damage, mesangial cell proliferation, and matrix expansion due to hyperglycemic hyper-filtration, advanced glycosylation of tissue protein and cytokines release, e.g., interleukin (IL)-1β, IL-6, tumor necrosis factor-α (TNF-α), and transforming growth factor-β (TGF- β) [5]. 

Pathologic nodular glomerulosclerosis appears to correlate with following tubular atrophy and interstitial fibrosis. Furthermore, other hemodynamic factors, such as vasoconstrictors, the renin-angiotensin system, endothelin-1, vasodilators, prostacyclin (PGI2), and nitric oxide, are responsible for oxidative stress and the hyalinosis of afferent and efferent arterioles as well as arteriosclerosis. Advanced kidney disease is characterized by metabolic acidosis, electrolyte imbalance, and uremia clinically, which promote excessive protein degradation, anorexia, muscle loss, edema, and body weight loss. To increase awareness of the comorbid catabolic/anabolic alterations of chronic disease, it is important to identify the major pathophysiologic issues that show the way to minimize disability and slow down complications and comorbidities. Metabolic disorders are common in diabetic kidney diseases, such as chronic inflammation, oxidative stress, malnutrition, physical inactivity, muscle depletion, and high body fat. Given the upcoming aging and the increasing sedentary behavior, progressive accumulation of adipose tissue and impairment of muscle quantity and quality have been implicated as both a cause and consequence of altered glucose disposal, as skeletal muscle accounts for more than 80–90% of glucose clearance during hyperinsulinemia-euglycemic clamps [6]. It has become apparent that the human skeletal muscle is an endocrine organ, which can secrete many myokines for the regulation of either autocrine, paracrine, or endocrine actions. At a relatively lower mean body mass index (BMI) compared with those of European descent, East Asians have a greater amount of total body fat mass and a growing tendency to visceral adiposity, which increases metabolic risk [7]. In this review article, we focus on early recognition of negative changes in body composition in diabetic nephropathy, and setting up its clinical algorithm of diagnosis and management. 

2. Early Detection the Sarcopenic Obesity in Diabetes Kidney Disease 

Diabetic nephropathy is asymptomatic in its early stages following the development of microalbuminuria. Progressive tubulointerstitial fibrosis has been proven to correlate with the magnitude of proteinuria. If left untreated, urine-filtered albumin itself may damage proximal tubular cells by the synthesis of endoplasmic reticulum (ER) stress-related protein, e.g., caspase-12, and the accumulation of misfolded protein, e.g., glucose-regulated protein 78 (GRP78) and oxygen-regulated protein 150 (ORP150) [8]. Caspase-12, in turn, is responsible for the apoptosis of the cultured kidney epithelial cells (NRK-52E) by its potential regulation of nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome with bovine serum albumin [9]. In addition, the upregulation of NLRP3 inflammasome leads to the processing of caspase-1 and the secretion of the proinflammatory cytokines interleukin (IL)-1β and IL-18 with neutrophil infiltration into kidney tissues of mouse models [10]. Uremic toxin indoxyl sulfate also contributes to ER stress and reactive oxygen species (ROS) production in cultured human proximal tubular cells, demonstrated by the increase in C/EBP homologous protein (CHOP) in Western blot [11]. In addition to reduced GFR with disease progression, overt proteinuria both directly and indirectly increases other organs' damage. A cross-section study of the general population in Japan revealed a significantly positive correlation between the number of components of the metabolic syndrome and the corresponding prevalence of microalbuminuria (p < 0.001) [12]. In reality, the Heart Outcomes Prevention Evaluation (HOPE) study showed that an increased quartile of albuminuria is extremely associated with cardiovascular disease and all-cause mortality independently of traditional cardiovascular risk factors in patients with type 2 diabetes [13]. Furthermore, the reduced clearance of insulin or glucose-lowering medicine may lead to untoward hypoglycemia and metformin-associated lactic acidosis in advanced CKD per se. Early detection and intervention of kidney disease in diabetes, complications, and comorbidities can be effectively slowed down.

Increased muscle protein catabolism and the obesity-related downregulation of adiponectin are also common among frail persons with progressive diabetic kidney disease. The coexistence of sarcopenia and obesity has an extremely high risk of metabolic abnormalities, hyperglycemia, and chronic inflammation. Fukuda et al. reported that eGFR significantly caused a more than 30% decline in people with type 2 diabetes and sarcopenic obesity, which was evaluated by dual-energy X-ray absorptiometry (DXA), in a retrospective observational study [14]. In the National Health and Nutrition Examination Survey (NHANES), there was an underestimation of obesity by BMI (41% obese) compared with DXA (71% obese) in adult participants with an estimated glomerular filtration rate (eGFR) of 15–29 mL/min per 1.73 m2 [15]. 

Various pathophysiological changes link metabolic abnormalities and muscle deficits. Increased insulin resistance, free fatty acid, inflammatory cytokines, advanced glycosylated end-products (AGE), and decreased mitochondrial oxidative capacity-related lipid accumulation are associated with subsequent kidney disease. Following glucose intolerance and diabetes, insulin resistance plays a relevant role in impaired glucose transport by reduced insulin receptor tyrosine kinase activity, diminished glucose mitochondrial oxidative phosphorylation for generating adenosine triphosphate (ATP), and reduced glycogen synthase [16]. It is also well-established that insulin is a potent inhibitor of lipolysis from adipocytes. The chronic elevation of plasma fatty acid concentrations a markedly causative role in the insulin resistance of skeletal muscle and results in lipotoxicity in the kidney, heart, and other organs, which leads to inflammation, cellular dysfunction, and death [17]. Adiposity may be a potential risk factor for the development of kidney disease due to upregulated renal plasma flow, intraglomerular pressure, and renin-angiotensin-aldosterone system activity. The accumulation of AGEs has been identified in muscle atrophy and poor regenerative capacity in mouse and human myoblasts. AGEs reduced myotube diameters in vitro in a dose = dependent manner [18]. Hyperglycemia is also correlated with increased inflammatory markers, including tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and C-reactive protein (CRP). TNF-α has been shown to impair insulin signals in peripheral tissues. It is well known that elevated serum TNF-α and leptin in type 2 DM are associated with obesity. On the contrary, IL-6 has been reported to cause muscle atrophy. In a longitudinal prospective aging study in Amsterdam in the elderly population, it was shown that high serum IL-6 (>5 pg/mL) and CRP (>6.1 mmgmL) levels were involved in ta two-to-three-fold greater risk of muscle strength loss [19]. There are novel explorations of inflammation factors that mark frailty and predict complications in diabetic subjects, such as neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR). A retrospective study showed NLR and PLR is positively correlated with lower extremity vascular lesions in diabetes with available ankle-brachial index data and superior predictive ability achieved by PLR [20]. Furthermore, different levels of NLR and PLR have substantial influences on the survival of frail patients with maintenance hemodialysis [21]. 

3. Diagnosis of Sarcopenia Obesity

Sarcopenia has just been referred to as loss of skeletal muscle mass and strength that both accrue across a lifetime span and lead to difficulty with daily living activities. In CKD, sarcopenia is not just an age-related change; it occurs as a result of the negative net protein balance from the disease as well, especially from the dialysis session in itself, either hemodialysis or peritoneal dialysis. Foley et al. have verified the correlation between increased sarcopenia prevalence and declining glomerular filtration rate based on bioimpedance measurements in community indwelling adults [22]. Traditionally, muscle wasting is common among persons with lower eGFR and high BMI may be protective in patients with CKD. In that regard, an accurate understanding of how to measure body composition beyond BMI affects outcome variables of a nutritional disturbance known as protein-energy wasting in CKD. DXA is a well-defined tool to accurately classify sarcopenia and obesity with a low X-ray beam for noninvasive assessment of muscle quantity and fat mass. The updated European Working Group on Sarcopenia in Older People (EWGSOP2, version 2019) adopted appendicular skeletal muscle mass (ASM)/height2 based on DXA, with cut-off points for males <7.0 kg/m2 and females <5.5 kg/m2 to define sarcopenia [23]. Applying the EWGSOP2 diagnostic criteria, reduced chair stand capacity (time to perform five repeated chair stands >15 s), gait speed test ≤0.8 m/s, or reduced grip strength (<16 kg for women and <27 kg for men) are advised as indicators of severe sarcopenia.