Robert H. Mak

Obesity and Obesity-Initiated Metabolic Syndrome: Mechanistic Links to Chronic Kidney Disease

There is an epidemic of obesity and the metabolic syndrome in the United States and across the world. Both entities are associated with high mortality, mainly as a result of cardiovascular disease. The epidemic of obesity has been paralleled by an increase in the incidence of chronic kidney disease (CKD). Several recent epidemiologic studies have shown that obesity and the metabolic syndrome are independent predictors of CKD. In addition to diabetes and hypertension, several other mechanisms have been postulated to initiate and maintain kidney injury in patients with obesity and the metabolic syndrome. This article reviews the recent epidemiologic data linking obesity and the metabolic syndrome to CKD and summarizes the potential mechanisms of renal injury in this setting, with a focus on the role of inflammation, lipotoxicity, and hemodynamic factors. Potential preventive and therapeutic modalities based on the limited evidence available are discussed.

Wasting in chronic kidney disease

Wasting/cachexia is prevalent among patients with chronic kidney disease (CKD). It is to be distinguished from malnutrition, which is defined as the consequence of insufficient food intake or an improper diet. Malnutrition is characterized by hunger, which is an adaptive response, whereas anorexia is prevalent in patients with wasting/cachexia. Energy expenditure decreases as a protective mechanism in malnutrition whereas it remains inappropriately high in cachexia/wasting. In malnutrition, fat mass is preferentially lost and lean body mass and muscle mass is preserved. In cachexia/wasting, muscle is wasted and fat is relatively underutilized. Restoring adequate food intake or altering the composition of the diet reverses malnutrition. Nutrition supplementation does not totally reverse cachexia/wasting. The diagnostic criteria of cachexia/protein–energy wasting in CKD are considered. The association of wasting surrogates, such as serum albumin and prealbumin, with mortality is strong making them robust outcome predictors. At the patient level, longevity has consistently been observed in patients with CKD who have more muscle and/or fat, who report better appetite and who eat more. Although inadequate nutritional intake may contribute to wasting or cachexia, recent evidence indicates that other factors, including systemic inflammation, perturbations of appetite-controlling hormones from reduced renal clearance, aberrant neuropeptide signaling, insulin and insulin-like growth factor resistance, and metabolic acidosis, may be important in the pathogenesis of CKD-associated wasting. A number of novel therapeutic approaches, such as ghrelin agonists and melanocortin receptor antagonists are currently at the experimental level and await confirmation by randomized controlled clinical trials in patients with CKD-associated cachexia/wasting syndrome.

Diets and enteral supplements for improving outcomes in chronic kidney disease

Protein-energy wasting (PEW), which is manifested by low serum levels of albumin or prealbumin, sarcopenia and weight loss, is one of the strongest predictors of mortality in patients with chronic kidney disease (CKD). Although PEW might be engendered by non-nutritional conditions, such as inflammation or other comorbidities, the question of causality does not refute the effectiveness of dietary interventions and nutritional support in improving outcomes in patients with CKD. The literature indicates that PEW can be mitigated or corrected with an appropriate diet and enteral nutritional support that targets dietary protein intake. In-center meals or oral supplements provided during dialysis therapy are feasible and inexpensive interventions that might improve survival and quality of life in patients with CKD. Dietary requirements and enteral nutritional support must also be considered in patients with CKD and diabetes mellitus, in patients undergoing peritoneal dialysis, renal transplant recipients, and in children with CKD. Adjunctive pharmacological therapies, such as appetite stimulants, anabolic hormones, and antioxidative or anti-inflammatory agents, might augment dietary interventions. Intraperitoneal or intradialytic parenteral nutrition should be considered for patients with PEW whenever enteral interventions are not possible or are ineffective. Controlled trials are needed to better assess the effectiveness of in-center meals and oral supplements.

Inflammation and cachexia in chronic kidney disease

Chronic inflammation is associated with cachexia and increased mortality risk in patients with chronic kidney disease (CKD) and end-stage renal disease (ESRD). Inflammation suppresses appetite and causes the loss of protein stores. In CKD patients, increased serum levels of pro-inflammatory cytokines may be caused by reduced renal function, volume overload, oxidative or carbonyl stress, decreased levels of antioxidants, increased susceptibility to infection in uremia, and the presence of comorbid conditions. Cachexia is brought about by the synergistic combination of a dramatic decrease in appetite and an increase in the catabolism of fat and lean body mass. Pro-inflammatory cytokines act on the central nervous system to alter appetite and energy metabolism and to provide a signal—through the nuclear factor-κB and ATP-ubiquitin-dependent proteolytic pathways—that causes muscle wasting. Further research into the molecular pathways leading to inflammation and cachexia may lead to novel therapeutic therapies for this devastating and potentially fatal complication of chronic disease.

Metabolic Abnormalities, Cardiovascular Disease Risk Factors, and GFR Decline in Children with Chronic Kidney Disease

BACKGROUND AND OBJECTIVES Metabolic abnormalities and cardiovascular disease (CVD) risk factors have rarely been systematically assessed in children with chronic kidney disease (CKD). We examined the prevalence of various CKD sequelae across the GFR spectrum. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS Data were used from 586 children participating in the Chronic Kidney Disease in Children (CKiD) study (United States and Canada) with GFR measured by iohexol plasma disappearance. Laboratory values and CVD risk factors were compared across GFR categories and with an age-, gender-, and race-matched community sample. RESULTS CKiD participants were 62% male, 66% Caucasian, 23% African American, and 15% Hispanic with a median age of 11 years and a median GFR of 44 ml/min per 1.73 m(2). Compared with those with a GFR ≥ 50 ml/min per 1.73 m(2), having a GFR < 30 ml/min per 1.73 m(2) was associated with a three-fold higher risk of acidosis and growth failure and a four- to five-fold higher risk of anemia and elevated potassium and phosphate. Median GFR change was -4.3 ml/min per 1.73 m(2) and -1.5 ml/min per 1.73 m(2) per year in children with glomerular and nonglomerular diagnoses, respectively. Despite medication and access to nephrology care, uncontrolled systolic hypertension was present in 14%, and 16% had left ventricular hypertrophy. Children with CKD frequently were also shorter and had lower birth weight, on average, compared with norms. CONCLUSIONS Growth failure, metabolic abnormalities, and CVD risk factors are present at GFR >50 ml/min per 1.73 m(2) in children with CKD and, despite therapy, increase in prevalence two- to four-fold with decreasing GFR.

Association of Proteinuria with Race, Cause of Chronic Kidney Disease, and Glomerular Filtration Rate in the Chronic Kidney Disease in Children Study

BACKGROUND AND OBJECTIVES Proteinuria is associated with chronic kidney disease (CKD), and heavy proteinuria predicts a rapid decline in kidney function. However, the epidemiologic distribution of this important biomarker study is not well described in the pediatric CKD population. DESIGN, SETTING, PARTICIPANTS & MEASUREMENTS This cross-sectional study of North American children with CKD examined the association of proteinuria among the baseline clinical variables in the cohort. Urinary protein-to-creatinine ratios (Up/c) were used to measure level of proteinuria. RESULTS Of the 419 subjects studied, the median GFR as measured by iohexol disappearance (iGFR) was 42 ml/min per 1.73 m(2), median duration of CKD was six yr, and glomerular diseases accounted for 22% of the CKD diagnoses. Twenty-four percent of children had normal range (Up/c <0.2), 62% had significant, and 14% had nephrotic-range proteinuria (Up/c >2.0). A decrease in iGFR was associated with an increase in Up/c. At any level of GFR, a higher Up/c was associated with a glomerular cause of CKD and non-Caucasian race. Among subjects with a glomerular cause of CKD, Up/c was lower in subjects reporting utilization of renin-angiotensin system (RAS) antagonists (median Up/c = 0.93) compared with those who did not (median Up/c = 3.78). CONCLUSIONS Proteinuria is associated with level of iGFR, cause of CKD, and race. The longitudinal study design of Chronic Kidney Disease in Children (CKiD) cohort study and the large number of subjects being studied has created an opportunity to better define the association between proteinuria and CKD progression.

Pathogenesis of urinary tract infection: an update.

Purpose of review Urinary tract infection is the second most common bacterial infection in children. It may cause renal scarring leading to secondary hypertension and chronic kidney disease. Recent information has greatly improved our understanding of the pathogenesis of urinary tract infection and renal scarring. Recent findings Urothelium, an anatomical barrier for innate immune responses, expresses toll-like receptors with the capacity to recognize pathogen-associated molecular patterns. Engagement of toll-like receptors can lead to uroepithelial cell activation and production of inflammatory mediators. These include complement proteins, other bactericidal peptides, cytokines, chemokines, defensins and adhesion molecules. The resulting inflammatory infiltrate serves to aid bacterial clearance but can also lead to renal damage. Furthermore, interactions between urinary proteins, such as Tamm-Horsfall protein, and TLR-4 add to the complexity of this defense system. Interindividual variability in cellular response may in part be responsible for variable clinical outcomes. Polymorphisms in a number of candidate genes in this host defense mechanism may be involved in determining those patients who are susceptible to recurrent infections and renal scarring following urinary tract infection. Summary Further understanding of the basic molecular mechanisms of urinary tract infection and translating these bench data to the bedside holds the promise of improving diagnosis and therapeutic strategies of treating urinary tract infection and preventing recurrence and renal scarring.

Predictors of Rapid Progression of Glomerular and Nonglomerular Kidney Disease in Children and Adolescents: The Chronic Kidney Disease in Children (CKiD) Cohort

BACKGROUND Few studies have prospectively evaluated the progression of chronic kidney disease (CKD) in children and adolescents, as well as factors associated with progression. STUDY DESIGN Prospective multicenter observational cohort study. SETTING & PARTICIPANTS 496 children and adolescents with CKD enrolled in the Chronic Kidney Disease in Children (CKiD) Study. PREDICTORS Proteinuria, hypoalbuminemia, blood pressure, dyslipidemia, and anemia. OUTCOMES Parametric failure-time models were used to characterize adjusted associations between baseline levels and changes in predictors and time to a composite event of renal replacement therapy or 50% decline in glomerular filtration rate (GFR). RESULTS 398 patients had nonglomerular disease and 98 had glomerular disease; of these, 29% and 41%, respectively, progressed to the composite event after median follow-ups of 5.2 and 3.7 years, respectively. Demographic and clinical characteristics and outcomes differed substantially according to the underlying diagnosis; hence, risk factors for progression were assessed in stratified analyses, and formal interactions by diagnosis were performed. Among patients with nonglomerular disease and after adjusting for baseline GFR, times to the composite event were significantly shorter with urinary protein-creatinine ratio > 2mg/mg, hypoalbuminemia, elevated blood pressure, dyslipidemia, male sex, and anemia, by 79%, 69%, 38%, 40%, 38%, and 45%, respectively. Among patients with glomerular disease, urinary protein-creatinine ratio >2mg/mg, hypoalbuminemia, and elevated blood pressure were associated with significantly reduced times to the composite event by 94%, 71%, and 67%, respectively. Variables expressing change in patient clinical status over the initial year of the study contributed significantly to the model, which was cross-validated internally. LIMITATIONS Small number of events in glomerular patients and use of internal cross-validation. CONCLUSIONS Characterization and modeling of risk factors for CKD progression can be used to predict the extent to which these factors, either alone or in combination, would shorten the time to renal replacement therapy or 50% decline in GFR in children with CKD.

Peripheral Administration of the Melanocortin-4 Receptor Antagonist NBI-12i Ameliorates Uremia-Associated Cachexia in Mice

We have recently shown that genetic or pharmacological blockade of the melanocortin-4 receptor (MC4-R) attenuates uremia-associated cachexia. However, the potential clinical utility of this approach has been limited by the need to deliver a peptide MC4-R antagonist into the ventricles of the brain. NBI-12i is a recently developed small molecule MC4-R antagonist, with high affinity and selectivity that penetrates the central nervous system after peripheral administration. We tested whether NBI-12i would also be effective in attenuating uremia-associated cachexia in a mouse model. Intraperitoneal administration of NBI-12i stimulated food intake and weight gain in uremic mice. Furthermore, NBI-12i-treated uremic mice gained lean body mass, fat mass, and had a lower basal metabolic rate compared to vehicle-treated and diet-supplemented uremic mice, which lost both lean body mass and fat mass and had an increase in basal metabolic rate. We found that NBI-12i normalizes the expression of uncoupling protein, which is normally upregulated in uremic mice, and we speculate that this may contribute to the drugs protective effect. These data underscore the importance of melanocortin signaling in the pathogenesis of uremia-associated cachexia and demonstrate the potential of peripheral administration of MC4-R antagonists as a novel therapeutic approach.

The effect of vitamin D status on risk factors for cardiovascular disease

Vitamin-D-related pathways are implicated in various endocrine, inflammatory and endothelial functions. An estimated 1 billion people in the world have vitamin D deficiency or insufficiency, and undiagnosed vitamin D deficiency is common. Vitamin D deficiency is associated with substantial increases in the incidence of hypertension, hyperlipidaemia, myocardial infarction and stroke, as well as in diseases such as chronic kidney disease and type 2 diabetes. Low vitamin D levels also upregulate the renin–angiotensin–aldosterone system, increase inflammation and cause endothelial dysfunction. However, the role of vitamin D deficiency in cardiovascular morbidity and mortality is an emerging and hotly debated topic. Epidemiological studies suggest an association between low vitamin D levels and risk factors for cardiovascular disease, but a causal relationship has not been established, and clinical trials and meta-analyses have not demonstrated convincing evidence that vitamin D therapy improves cardiovascular outcomes. Some evidence suggests that vitamin D status is a biomarker of lifestyle, since unhealthy and sedentary lifestyles are associated with vitamin D insufficiency or deficiency and are also risk factors for cardiovascular complications.