Biruh Workeneh

Review of muscle wasting associated with chronic kidney disease

Muscle wasting increases the morbidity and mortality associated with chronic kidney disease (CKD) and has been attributed to malnutrition. In most patients, this is an incorrect diagnosis because simply feeding more protein aggravates uremia. Instead, there are complex mechanisms that stimulate loss of skeletal muscle, involving activation of mediators that stimulate the ATP-dependent ubiquitin-proteasome system (UPS). Identified mediators of muscle protein breakdown include inflammation, metabolic acidosis, angiotensin II, and neural and hormonal factors that cause defects in insulin/insulin-like growth factor I (IFG-I) intracellular signaling processes. Abnormalities in insulin/IGF-I signaling activate muscle protein degradation in the UPS and caspase-3, a protease that disrupts the complex structure of muscle proteins to provide substrates for the UPS. During the cleavage of muscle proteins, caspase-3 leaves behind a characteristic 14-kD actin fragment in the insoluble fraction of muscle, and characterization of this fragment identifies the presence of muscle catabolism. Thus, it could become a marker of excessive muscle wasting, providing a method for early detection of muscle wasting. Another consequence of activation of caspase-3 in muscle is stimulation of the activity of the proteasome, which increases the degradation of muscle proteins. Treatment strategies for blocking muscle wasting include correction of metabolic acidosis, which can suppress muscle protein losses in patients with CKD who are or are not being treated by dialysis. Correcting acidosis also improves bone metabolism in CKD and hence should be a goal of therapy. Exercise training is a potentially beneficial approach, but more information is needed to optimize exercise regimens. Replacing testosterone deficits can improve muscle mass in men, but dosing and side effects in women have not been adequately tested. Although insulin resistance occurs early in the course of CKD, there are no effective means of correcting it. Consequently, new therapies that can safely suppress muscle wasting are needed.

Development of a Diagnostic Method for Detecting Increased Muscle Protein Degradation in Patients with Catabolic Conditions

Muscle atrophy in catabolic illnesses is due largely to accelerated protein degradation. Unfortunately, methods for detecting accelerated muscle proteolysis are cumbersome. The goal of this study was to develop a method for detecting muscle protein breakdown and assess the effectiveness of anticatabolic therapy. In rodent models of catabolic conditions, it was found that accelerated muscle protein degradation is triggered by activation of caspase-3. Caspase-3 cleaves actomyosin/myofibrils to form substrates for the ubiquitin-proteasome system and leaves a characteristic 14-kD actin fragment in the insoluble fraction of a muscle lysate. Muscle biopsies were obtained from normal adults and three groups of patients: 14 who were undergoing hip arthroplasty, 28 hemodialysis patients who were participating in exercise programs, and seven severely burned patients. In muscle of patients who were undergoing hip arthroplasty, the 14-kD actin fragment level was correlated (r = 0.787, P < 0.01) with the fractional rate of protein degradation. In muscle of hemodialysis patients who were undergoing endurance exercise training, the 14-kD actin fragment decreased to values similar to levels in normal adults; strength training did not significantly decrease the actin fragment. Severely burned patients had increased muscle protein degradation and actin fragment levels, but the two measures were not significantly correlated. The experimental results suggest that the 14-kD actin fragment in muscle biopsies is increased in catabolic states and could be used in conjunction with other methods to detect and monitor changes in muscle proteolysis that occur in patients with mild or sustained increases in muscle proteolysis.

Transcription factor FoxO1, the dominant mediator of muscle wasting in chronic kidney disease, is inhibited by microRNA-486

Chronic kidney disease (CKD) accelerates muscle protein degradation by stimulating the ubiquitin proteasome system through activation of the E3 ligases, Atrogin-1/MaFbx and MuRF-1. Forkhead transcription factors (FoxO) can control the expression of these E3 ligases, but the contribution of individual FoxOs to muscle wasting is unclear. To study this we created mice with a muscle-specific FoxO1 deletion. The absence of FoxO1 blocked 70% of the increase in E3 ligases induction by CKD as well as the proteolysis and loss of muscle mass. Thus, FoxO1 has a role in controlling ubiquitin proteasome system-related proteolysis. Since microRNA (miR)-486 reportedly dampens FoxO1 expression and its activity, we transfected a miR-486 mimic into primary cultures of myotubes and found this blocked dexamethasone-stimulated protein degradation without influencing protein synthesis. It also decreased FoxO1 protein translation and increased FoxO1 phosphorylation by down-regulation of PTEN phosphatase, a negative regulator of p-Akt. To test its efficacy in vivo, we electroporated miR-486 into muscles and found expression of the E3 ligases was suppressed and muscle mass increased despite CKD. Thus, FoxO1 is a dominant mediator of CKD-induced muscle wasting and miR-486 coordinately decreases FoxO1 and PTEN to protect against this catabolic response.

Effects of aging on glomerular function and number in living kidney donors

To elucidate the pathophysiologic changes in the kidney due to aging, we used physiological, morphometric, and imaging techniques to quantify GFR and its determinants in a group of 24 older (≥ 55 years) compared to 33 younger (≤ 45 years) living donors. Mathematical modeling was used to estimate the glomerular filtration coefficients for the whole kidney (K(f)) and for single nephrons (SNK(f)), as well as the number of filtering glomeruli (N(FG)). Compared to younger donors, older donors had a modest (15%) but significant depression of pre-donation GFR. Mean whole-kidney K(f), renocortical volume, and derived N(FG) were also significantly decreased in older donors. In contrast, glomerular structure and SNK(f) were not different in older and younger donors. Derived N(FG) in the bottom quartile of older donors was less than 27% of median-derived N(FG) in the two kidneys of younger donors. Nevertheless, the remaining kidney of older donors exhibited adaptive hyperfiltration and renocortical hypertrophy post-donation, comparable to that of younger donors. Thus, our study found the decline of GFR in older donors is due to a reduction in K(f) attributable to glomerulopenia. We recommend careful monitoring for and control of post-donation comorbidities that could exacerbate glomerular loss.

The regulation of muscle protein turnover in diabetes.

Diabetes cannot be considered simply a disease of glucose dysregulation; it is a chronic inflammatory disease that affects nearly every biological process, including protein metabolism. Diabetes is associated with disturbances in muscle protein metabolism that results in decreased muscle mass and in some cases, loss in the activities of daily living, decreased productivity and diminished quality of life. Alteration in protein metabolism and its effect on muscle mass and function is one of the most challenging and least understood issues in the management of diabetes. Central among insulin action in muscle is suppression of protein degradation pathways and up-regulation of anabolic pathways. In type 1 diabetes, muscle wasting essentially results from insulin deficiency and this induces of genes involved in the ubiquitin proteasome pathway. On the other hand, the chief defect that leads to muscle atrophy in type 2 diabetes is decreased insulin responsiveness primarily in muscle. Decreased insulin responsiveness has been attributed to defects in the insulin signaling pathways secondary to inflammation (e.g., NF-κB activation and elevated levels of TNF-α, IL-1 and IL-6), metabolic acidosis, increased circulating free fatty acids and glucotoxicity. Furthermore, emerging pathways, such as myostatin/activin A system are beginning to be uncovered. We conclude with a discussion of possible interventions to slow, mitigate or reverse muscle wasting associated with diabetes. This article is part of a Directed Issue entitled: Molecular basis of muscle wasting.

Hypernatremia in the geriatric population

Hypernatremia in the geriatric population is a common disorder associated with significant morbidity and mortality. Older people are predisposed to developing hypernatremia because of age-related physiologic changes such as decreased thirst drive, impaired urinary concentrating ability, and reduced total body water. Medications may exacerbate this predisposition. Hypernatremia and dehydration occurring in nursing homes are considered indicators of neglect that warrant reporting, but there are other nonavoidable causes of hypernatremia, and consideration at time of presentation is essential to prevent delay in diagnosis and management. We describe a case illustrating the importance of the consideration of alternate explanations for hypernatremia in a nursing home resident, followed by a review of hypernatremia in the elderly population, to underscore that neglect is the etiology of exclusion after alternatives have been considered.

Trends in the outcomes of end-stage renal disease secondary to human immunodeficiency virus-associated nephropathy

BACKGROUND Little is known about the trends in the incidence and outcomes of patients with end-stage renal disease (ESRD) attributed to human immunodeficiency virus-associated nephropathy (HIVAN). We sought to define relative incidence among ESRD patients, changes in mortality among patients with ESRD attributed to HIVAN, as well as changes in the excess mortality experienced by patients with ESRD attributed to HIVAN compared with otherwise similar ESRD patients with non-HIVAN causes. METHODS We used the US Renal Data System to identify all individuals with reported HIVAN who initiated treatment for ESRD between 1989 and 2011. We plotted their counts and proportions among all incident ESRD patients and tabulated their characteristics across years. We then compared mortality within the HIVAN group across years using Cox regression. In addition, we studied the trends in relative mortality of HIVAN patients versus those with ESRD not reported as HIVAN. RESULTS Overall, 14 719 individuals with HIVAN-ESRD were recorded, with significant reductions in recent years (893 in 2006; 525 in 2011). Compared with patients initiating dialysis between 1989 and 1992, mortality declined by 40% (HR = 0.60; 95% CI, 0.55-0.65) and 64% (HR = 0.36; 95% CI, 0.32-0.40) for patients initiating dialysis in 1999/2000 and 2009-11, respectively. The adjusted excess mortality of HIVAN-ESRD patients versus incident ESRD patients from other causes was >5-fold in 1989-92 (HR = 5.21; 95% CI, 4.84-5.60); this excess mortality has subsequently declined but remained at almost 3-fold in recent years (e.g. HR = 2.58; 95% CI, 2.37-2.80, 2009-11 incidence cohort). CONCLUSIONS Concurrent with the increasing availability of highly active antiretroviral therapy (HAART), both the incidence of ESRD due to HIVAN and the mortality of such patients have decreased substantially. However, HIVAN patients reaching ESRD continue to experience substantial excess mortality compared with other ESRD patients even in the current era of modern HAART.

Spectrum of sodium hypochlorite toxicity in man-also a concern for nephrologists.

Sodium hypochlorite (NaOCl) is the active ingredient in household bleach and is a very common chemical. It has been used in medical and commercial situations dating back to the 18th century for its disinfectant properties, including topical use in medicine as an antiseptic. For this indication, NaOCl is a proven and safe chemical. However, exposure of NaOCl beyond topical use, whether it is intentional or accidental, is associated with significant risks due to its strong oxidizing properties. Potentially damaging scenarios include ingestion, inhalation, deposition into tissue or injection into the bloodstream. All of these scenarios can lead to significant morbidity and even mortality. In this review, we examine the toxicity associated with NaOCl exposure and analyze potential mechanisms of injury, placing special emphasis on the potential for renal toxicity. Due to the extreme ease of access to household bleach products and its use in medicine, it is important for the clinician to understand the potential damage that can occur in NaOCl exposures so that complications can be prevented before they arise.

Sodium hypochlorite-induced acute kidney injury

Sodium hypochlorite (bleach) is commonly used as an irrigant during dental procedures as well as a topical antiseptic agent. Although it is generally safe when applied topically, reports of accidental injection of sodium hypochlorite into tissue have been reported. Local necrosis, pain and nerve damage have been described as a result of exposure, but sodium hypo-chlorite has never been implicated as a cause of an acute kidney injury (AKI). In this report, we describe the first case of accidental sodium hypochlorite injection into the infraorbital tissue during a dental procedure that precipitated the AKI. We speculate that oxidative species induced by sodium hypochlorite caused AKI secondary to the renal tubular injury, causing mild acute tubular necrosis.

Fasting urine pH is independent of insulin sensitivity.

BACKGROUND It has recently been suggested that a low urine pH be added to the abnormalities linked to insulin resistance. This conclusion is based on the finding of a low urine pH in individuals with clinical syndromes associated with insulin resistance and not on studies in which a direct measure of insulin sensitivity was shown to be significantly related to differences in urine pH. OBJECTIVE To address this issue, we quantified insulin-mediated glucose uptake (IMGU) by using the insulin suppression test in 96 apparently healthy, nondiabetic individuals and defined its relation to fasting urine pH. DESIGN Urine samples were collected and analyzed from a cohort of healthy subjects within a narrow body mass index range who were recruited to determine insulin sensitivity. RESULTS There was an approximate 6-fold variation in values for IMGU in this population, with no relation to urine pH (r = 0.02). Furthermore, there was no relation between body mass index, as a surrogate estimate of insulin resistance, and urine pH (r = 0.06). CONCLUSION On the basis of these findings, we question the view that a low urine pH be added to the abnormalities linked to insulin resistance in low-risk populations.