MicroRNAs: a new therapeutic frontier for muscle wasting in chronic kidney disease

Multiple microRNAs (miRs) are implicated in muscle cell differentiation and muscle mass regulation. Pharmacological agents targeting miR-486 and other miRs, involved in muscle mass regulation, could potentially be developed into therapeutic agents for muscle wasting. Muscle wasting is prevalent among patients with chronic kidney disease (CKD). Xu et al. showed that miR-486 mimetic ameliorated muscle wasting in mice with CKD. miR mimetics may represent a new therapeutic frontier for muscle wasting in CKD.     

Mechanisms stimulating muscle wasting in chronic kidney disease: the roles of the ubiquitin-proteasome system and myostatin

Catabolic conditions including chronic kidney disease (CKD), cancer, and diabetes cause muscle atrophy. The loss of muscle mass worsens the burden of disease because it is associated with increased morbidity and mortality. To avoid these problems or to develop treatment strategies, the mechanisms leading to muscle wasting must be identified. Specific mechanisms uncovered in CKD generally occur in other catabolic conditions. These include stimulation of protein degradation in muscle arising from activation of caspase-3 and the ubiquitin-proteasome system (UPS). These proteases act in a coordinated fashion with caspase-3 initially cleaving the complex structure of proteins in muscle, yielding fragments that are substrates that are degraded by the UPS. Fortunately, the UPS exhibits remarkable specificity for proteins to be degraded because it is the major intracellular proteolytic system. Without a high level of specificity cellular functions would be disrupted. The specificity is accomplished by complex reactions that depend on recognition of a protein substrate by specific E3 ubiquitin ligases. In muscle, the specific ligases are Atrogin-1 and MuRF-1, and their expression has characteristics of a biomarker of accelerated muscle proteolysis. Specific complications of CKD (metabolic acidosis, insulin resistance, inflammation, and angiotensin II) activate caspase-3 and the UPS through mechanisms that include glucocorticoids and impaired insulin or IGF-1 signaling. Mediators activate myostatin, which functions as a negative growth factor in muscle. In models of cancer or CKD, strategies that block myostatin prevent muscle wasting, suggesting that therapies that block myostatin could prevent muscle wasting in catabolic conditions.     

Potential deleterious effects of vasopressin in chronic kidney disease and particularly autosomal dominant polycystic kidney disease

The antidiuretic hormone vasopressin is crucial for regulating free water clearance in normal physiology. However, it has also been hypothesized that vasopressin has deleterious effects on the kidney. Vasopressin is elevated in animals and patients with chronic kidney disease. Suppression of vasopressin activity reduces proteinuria, renal hypertrophy, glomerulosclerosis and tubulointerstitial fibrosis in animal models. The potential detrimental influence of vasopressin is probably mediated by its effects on mesangial cell proliferation, renin secretion, renal hemodynamics, and blood pressure. In this review, we discuss the increasing body of evidence pointing towards the contribution of vasopressin to chronic kidney disease progression in general and to autosomal dominant polycystic kidney disease in particular. These data allude to the possibility that interventions directed at lowering vasopressin activity, for example by the administration of vasopressin receptor antagonists or by drinking more water, may be beneficial in chronic kidney disease.     

Malnutrition is an unusual cause of decreased muscle mass in chronic kidney disease.

Patients with chronic kidney disease (CKD), including those who are treated with hemodialysis, frequently develop hypoalbuminemia and a decrease in body weight. These abnormalities are usually attributed to malnutrition, but true malnutrition (ie, a disorder due to an abnormal diet) is rarely the mechanism causing decreased protein stores. Hypoalbuminemia is closely related to evidence of inflammation, and a decrease in muscle mass is caused by activation of muscle protein breakdown. In uremic rodents and patients, the initial step in the loss of muscle protein is activation of caspase-3, which cleaves the complex structure of muscle to provide substrates for the ubiquitin-proteasome pathway (UPP). The activity of caspase-3 can be detected by the presence of a characteristic 14-kDa actin fragment in the insoluble fraction of a muscle biopsy specimen. Abnormalities in cell signaling activate caspase-3 and the UPP; a key abnormality is decreased activity in the phosphatidylinositol-3-kinase/Akt pathway, leading to activation of caspase-3 and a specific E3 ubiquitin conjugating enzyme, atrogin-1/MAFbx. Inflammatory cytokines also represent a potential cell signaling abnormality that activates muscle protein breakdown, possibly because cytokines activate the E3 ubiquigin conjugating enzyme, MuRF1. An understanding of these pathways could help the clinician to identify therapeutic targets for preventing loss of muscle protein.     

Post-streptococcal glomerulonephritis is a strong risk factor for chronic kidney disease in later life

Although unusual in western countries and in Australia in general, post-streptococcal glomerulonephritis (PSGN) is still common in Australian Aboriginal children living in remote communities. Here, we evaluated whether episodes of acute PSGN increased the risk for chronic kidney disease in later life in 1519 residents of a remote Aboriginal community (85% of those age eligible), with high rates of renal and cardiovascular disease, who participated in a health screen over a 3-year period. Of these, 200 had had at least one episode of PSGN, with 27 having had multiple episodes, usually in childhood. High levels of albuminuria (albumin/creatinine ratio) with increasing age were confirmed. All PSGN episodes were associated with group A streptococcal skin infections, often related to scabies. In both genders, aged 10-39 years at screening, about one in five had such a history. Among them, PSGN (5 years or more earlier) was significantly associated with higher levels of albuminuria than those without. In women, aged 30-39 years, a history of PSGN was associated with a significantly higher frequency of estimated glomerular filtration rates <60 ml/min. The adjusted odds ratios for an albumin/creatinine ratio over 34 g/mol (overt albuminuria) in males and females with a history of PSGN were 4.6 and 3.1, respectively, compared with those without a history. Thus, PSGN contributes to the very serious burden of chronic kidney disease in this community. Rigorous strategies to prevent scabies and Group A streptococcal infections will reduce this burden.     

Elevated serum parathyroid hormone is a cardiovascular risk factor in moderate chronic kidney disease

Introduction  

Over 8% of adults in the United States are estimated to have moderate (stages 3 and 4) chronic kidney disease (CKD), which is increasingly recognized as one of the independent predictors for cardiovascular (CV) disease and related mortality. Secondary hyperparathyroidism with elevated serum intact parathyroid hormone (iPTH) is associated with increased CV mortality in end-stage renal disease and this relationship is unclear in moderate CKD.     

Lipoprotein lipase deficiency in chronic kidney disease is accompanied by down-regulation of endothelial GPIHBP1 expression

Background  

Chronic renal failure (CRF) is associated with hypertriglyceridemia and impaired clearance of very low density lipoprotein (VLDL) and chylomicrons which are largely due to lipoprotein lipase (LPL) deficiency/dysfunction. After its release from myocytes and adipocytes, LPL binds to the endothelium in the adjacent capillaries where it catalyzes hydrolysis of triglycerides in VLDL and chylomicrons. The novel endothelium-derived molecule, glycosylphosphatidylinositol-anchored binding protein 1 (GPIHBP1), plays a critical role in LPL metabolism and function by anchoring LPL to the endothelium and binding chylomicrons. GPIHBP1-deficient mice and humans exhibit severe hypertriglyceridemia and diminished heparin-releasable LPL, pointing to the critical role of GPIHBP1 in regulation of LPL activity. Given its central role in regulation of LPL activity and triglyceride metabolism, we explored the effect of chronic kidney disease (CKD) on GPIHBP1 expression.     

Association of chronic kidney disease with muscle deficits in children

The effect of chronic kidney disease (CKD) on muscle mass in children, independent of poor growth and delayed maturation, is not well understood. We sought to characterize whole body and regional lean mass (LM) and fat mass (FM) in children and adolescents with CKD and to identify correlates of LM deficits in CKD. We estimated LM and FM from dual energy x-ray absorptiometry scans in 143 children with CKD and 958 controls at two pediatric centers. We expressed whole body, trunk, and leg values of LM and FM as Z-scores relative to height, sitting height, and leg length, respectively, using the controls as the reference. We used multivariable regression models to compare Z-scores in CKD and controls, adjusted for age and maturation, and to identify correlates of LM Z-scores in CKD. Greater CKD severity associated with greater leg LM deficits. Compared with controls, leg LM Z-scores were similar in CKD stages 2 to 3 (difference: 0.02 [95% CI: -0.20, 0.24]; P = 0.8), but were lower in CKD stages 4 to 5 (-0.41 [-0.66, -0.15]; P = 0.002) and dialysis (-1.03 [-1.33, -0.74]; P < 0.0001). Among CKD participants, growth hormone therapy associated with greater leg LM Z-score (0.58 [0.03, 1.13]; P = 0.04), adjusted for CKD severity. Serum albumin, bicarbonate, and markers of inflammation did not associate with LM Z-scores. CKD associated with greater trunk LM and FM, variable whole body LM, and normal leg FM, compared with controls. In conclusion, advanced CKD associates with significant deficits in leg lean mass, indicating skeletal muscle wasting. These data call for prospective studies of interventions to improve muscle mass among children with CKD.     

HLA-B27 is a potential risk factor for posttransplantation diabetes mellitus in autosomal dominant polycystic kidney disease patients

The aim of this work was to investigate HLA phenotype predisposition to posttransplantation diabetes mellitus (PTDM) in kidney transplant recipients stratified according to kidney failure etiology. Ninety-eight transplant recipient pairs with kidney grafts from the same cadaveric donor were qualified for the study. In each pair, 1 kidney was grafted to an individual with autosomal dominant polycystic kidney disease (ADPKD group) and 1 to recipient with a different cause of kidney failure (non-ADPKD group). All class II HLA antigens were determined with the PCR-SSP molecular method. To identify class I HLA molecules we used both molecular and serologic methods. Diabetes was diagnosed according to the American Diabetes Association criteria. The posttransplantation observation period was 12 months. In the ADPKD group, HLA-B27 was more common in PTDM than non-PTDM patients; 31.6% versus 11.4% (P = .069). The difference achieved significance when comparing insulin-treated with non-insulin-treated patients (44.4% vs 12.4%; P = .029). In the non-ADPKD group, HLA-A28 and HLA-B13 were observed more frequently in patients with PTDM than in recipients without diabetes (22.2% vs 2.5% [P = .0099] and 22.2% vs 3.8% [P = .020]). All of these associations were significant upon multivariate analysis. HLA-B27 allele is a factor predisposing ADPKD patients to insulin-dependent PTDM. Antigens predisposing to PTDM among kidney graft recipients without ADPKD include HLA-A28 and B13.     

Acute kidney injury in idiopathic nephrotic syndrome of childhood is a major risk factor for the development of chronic kidney disease

Background: Acute kidney injury (AKI) is an important complication of idiopathic nephrotic syndrome (INS) and is associated with adverse outcomes, especially the development of chronic kidney disease (CKD). We aimed to determine the clinical profile of children with INS who developed AKI and its short-term outcome.

Material and methods: This prospective study was conducted from March 2014 to October 2015. A total of 119 children of INS (age: 2–18 years) fulfilling the pediatric RIFLE criteria for the diagnosis of AKI were enrolled and followed up for 3 months to determine the outcome. Factors predisposing to CKD were studied.

Results: The mean age at presentation was 8.8?±?3.59 years and males were 74 (62.2%). At presentation, 61 (51.3%) children were in Risk category, 43 (36.1%) in Injury category, and 15 (12.6%) in Failure category. Most of them (41.2%) had steroid-resistant nephrotic syndrome (SRNS) and focal segmental glomerulosclerosis (FSGS) on histopathology (33.6%).

Infections were the major predisposing factor for AKI in 67 (56.3%) cases. Drug toxicity was the next common, found in 52 (43.7%) children. A total of 65 (54.6%) children recovered from AKI, while 54 (45.4%) did not. CKD developed in 49 (41.2%) non-recovered cases and 5 (4.2%) children succumbed to acute illness. SRNS, cyclosporine use, FSGS on histology, and drug toxicity were significant factors associated with the development of CKD.

Conclusion: AKI associated with INS is a reversible condition in most cases but it can progress to CKD, especially among those who have SRNS, FSGS, and drug toxicity.     

Muscle wasting in chronic kidney disease: the role of the ubiquitin proteasome system and its clinical impact

Muscle wasting in chronic kidney disease (CKD) and other catabolic diseases (e.g. sepsis, diabetes, cancer) can occur despite adequate nutritional intake. It is now known that complications of these various disorders, including acidosis, insulin resistance, inflammation, and increased glucocorticoid and angiotensin II production, all activate the ubiquitin–proteasome system (UPS) to degrade muscle proteins. The initial step in this process is activation of caspase-3 to cleave the myofibril into its components (actin, myosin, troponin, and tropomyosin). Caspase-3 is required because the UPS minimally degrades the myofibril but rapidly degrades its component proteins. Caspase-3 activity is easily detected because it leaves a characteristic 14kD actin fragment in muscle samples. Preliminary evidence from several experimental models of catabolic diseases, as well as from studies in patients, indicates that this fragment could be a useful biomarker because it correlates well with the degree of muscle degradation in dialysis patients and in other catabolic conditions.     

Fibroblast growth factor 23 is elevated before parathyroid hormone and phosphate in chronic kidney disease

Fibroblast growth factor 23 (FGF23) regulates phosphorus metabolism and is a strong predictor of mortality in dialysis patients. FGF23 is thought to be an early biomarker of disordered phosphorus metabolism in the initial stages of chronic kidney disease (CKD). We measured FGF23 in baseline samples from 3879 patients in the Chronic Renal Insufficiency Cohort study, which is a diverse cohort of patients with CKD stage 2-4. Mean serum phosphate and median parathyroid hormone (PTH) levels were in the normal range, but median FGF23 was markedly greater than in healthy populations, and increased significantly with decreasing estimated glomerular filtration rate (eGFR). High levels of FGF23, defined as being above 100 RU/ml, were more common than secondary hyperparathyroidism and hyperphosphatemia in all strata of eGFR. The threshold of eGFR at which the slope of FGF23 increased was significantly higher than the corresponding threshold for PTH based on non-overlapping 95% confidence intervals. Thus, increased FGF23 is a common manifestation of CKD that develops earlier than increased phosphate or PTH. Hence, FGF23 measurements may be a sensitive early biomarker of disordered phosphorus metabolism in patients with CKD and normal serum phosphate levels.     

Role of keratinocyte growth factor in the pathogenesis of autosomal dominant polycystic kidney disease.

BACKGROUND: Previous studies have shown that the expression and distribution of keratinocyte growth factor (KGF), also known as FGF-7 (fibroblast growth factor-7) or HBGF-7 (heparin-binding growth factor-7), may be implicated in kidney cyst formation and expansion. However, there are no data on KGF expression in human autosomal dominant polycystic kidney disease (ADPKD) tissue, and it is unknown whether it affects ADPKD cyst-lining epithelial cell epithelial cell proliferation. METHODS: The expression and distribution of KGF and KGF receptor (KGFR) mRNA in ADPKD cystic and normal kidney tissues were examined using quantitative real-time polymerase chain reaction (PCR) and in situ hybridization. KGF and KGFR protein expression in the above tissues was analysed by immunohistochemistry and western blot. The effect of KGF on cyst-lining epithelial cell proliferation was assessed by MTT assay, and its effect on the cyst-lining epithelial cell cycle was analysed by flow cytometry. The effect of KGF on cyclin D1 and P21(wafl) gene expression in cyst-lining epithelial cells was also determined. RESULTS: KGF and KGFR mRNA expression in ADPKD cysts was higher than in normal kidney tissues. KGF and KGFR protein expression was also higher in ADPKD cysts and was localized to cyst-lining epithelial cells, tubular and interstitial cells. In vitro experiments revealed that KGF promoted cyst-lining epithelial cell proliferation, and decreased the ratio of G0/G1 phase but increased that of S phase. In response to KGF, the expression of the cyclin D1 gene in cyst-lining epithelial cells increased markedly while P21(wafl) expression decreased. CONCLUSIONS: KGF and KGFR expression was upregulated in ADPKD kidney tissues. KGF stimulated the proliferation of cyst-lining epithelial cell in vitro by regulating the expression of cyclin D1 and P21(wafl) genes. KGF may play a role in pathogenesis of ADPKD.     

Progressive loss of renal function is an age-dependent heritable trait in type 1 autosomal dominant polycystic kidney disease

Significant intrafamilial phenotypic variability is well documented in autosomal dominant polycystic kidney disease (ADPKD) and suggests a modifier effect. In this study, variance components analysis was performed to estimate the contribution of genetic factors for within-family renal disease variability in 406 patients from 66 type 1 ADPKD families. Overall, 39% of the study patients had ESRD at their last follow-up, and their renal survival did not differ by gender (P = 0.35, log-rank test). Because their frequency plot of creatinine clearance (Ccr) assumed a bimodal distribution with a marked kurtosis that was not improved by transformations, the study cohort was decomposed into two separate groups (non-ESRD [n = 247] and ESRD [n = 159]) in which the Ccr plots were normally distributed. The heritability (h(2)) of Ccr and age at ESRD (age(ESRD)) and the genetic correlations between these measures and their covariates were estimated. In patients without ESRD, a significant heritability was found for Ccr (h(2) = 0.42; P = 0.0015) after adjusting for age (P = 0.0001), systolic BP (P = 0.0006), and treatment with angiotensin-converting enzyme inhibitor/angiotensin receptor blocker (P = 0.00001). Birth year, gender, BMI, diastolic and mean BP, and pack-years of cigarette smoking did not significantly influence the heritability of this trait. In patients with ESRD, age(ESRD) provides a better measure than Ccr, which was very narrowly distributed. A significant heritability was found for age(ESRD) (h(2) = 0.78; P = 0.00009) in these latter patients. None of the above covariates influenced the heritability of this trait. It is concluded that a significant modifier gene effect influences the progression of renal disease in type 1 ADPKD.