Interdisciplinary management of FGF23-related phosphate wasting syndromes: a Consensus Statement on the evaluation, diagnosis and care of patients with X-linked hypophosphataemia.

X-linked hypophosphataemia (XLH) is the most frequent cause of hypophosphataemia-associated rickets of genetic origin and is associated with high levels of the phosphaturic hormone fibroblast growth factor 23 (FGF23). In addition to rickets and osteomalacia, patients with XLH have a heavy disease burden with enthesopathies, osteoarthritis, pseudofractures and dental complications, all of which contribute to reduced quality of life. This Consensus Statement presents the outcomes of a working group of the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases, and provides robust clinical evidence on management in XLH, with an emphasis on patients' experiences and needs. During growth, conventional treatment with phosphate supplements and active vitamin D metabolites (such as calcitriol) improves growth, ameliorates leg deformities and dental manifestations, and reduces pain. The continuation of conventional treatment in symptom-free adults is still debated. A novel therapeutic approach is the monoclonal anti-FGF23 antibody burosumab. Although promising, further studies are required to clarify its long-term efficacy, particularly in adults. Given the diversity of symptoms and complications, an interdisciplinary approach to management is of paramount importance. The focus of treatment should be not only on the physical manifestations and challenges associated with XLH and other FGF23-mediated hypophosphataemia syndromes, but also on the major psychological and social impact of the disease.

A Pilot Study of Gut-Brain Signaling After Octreotide Therapy for Unintentional Weight Loss After Esophagectomy.

BACKGROUND: Recurrence-free patients after esophageal cancer surgery face long-term nutritional consequences, occurring in the context of an exaggerated postprandial gut hormone response. Acute gut hormone suppression influences brain reward signaling and eating behavior. This study aimed to suppress gut hormone secretion and characterize reward responses and eating behavior among postesophagectomy patients with unintentional weight loss. METHODS: This pilot study prospectively studied postoperative patients with 10% or greater body weight loss (BWL) beyond 1 year who were candidates for clinical treatment with long-acting octreotide (LAR). Before and after 4 weeks of treatment, gut hormone secretion, food cue reactivity (functional magnetic resonance imaging), eating motivation (progressive ratio task), ad libitum food intake, body composition, and symptom burden were assessed. RESULTS: Eight patients (7 male, age: mean ±â€…SD 62.8 ±â€…9.4 years, postoperative BWL: 15.5 ±â€…5.8%) participated. Octreotide LAR did not significantly suppress total postprandial plasma glucagon-like peptide-1 response at 4 weeks (P = .08). Postprandial symptom burden improved after treatment (Sigstad score median [range]: 12 [2-28] vs 8 [3-18], P = .04) but weight remained stable (pre: 68.6 ±â€…12.8 kg vs post: 69.2 ±â€…13.4 kg, P = .13). There was no significant change in brain reward system responses, during evaluation of high-energy or low-energy food pictures, nor their appeal rating. Moreover, treatment did not alter motivation to eat (P = .41) nor ad libitum food intake(P = .46). CONCLUSION: The protocol used made it feasible to characterize the gut-brain axis and eating behavior in this cohort. Inadequate suppression of gut hormone responses 4 weeks after octreotide LAR administration may explain the lack of gut-brain pathway alterations. A higher dose or shorter interdose interval may be required to optimize the intervention.

Regular exercise and branched-chain amino acids prevent ischemic acute kidney injury-related muscle wasting in mice.

Acute kidney injury (AKI) causes glucose and protein metabolism abnormalities that result in muscle wasting, thereby affecting the long-term prognosis of critical illness survivors. Here, we examined whether early intervention with treadmill exercise and branched-chain amino acids (BCAA) can prevent AKI-related muscle wasting and reduced physical performance in mice. Unilateral 15 min ischemia-reperfusion injury was induced in contralateral nephrectomized mice, and muscle histological and physiological changes were assessed and compared with those of pair-fed control mice, since AKI causes severe anorexia. Mice exercised for 30 min each day and received oral BCAA for 7 days after AKI insult. By day 7, ischemic AKI significantly decreased wet weight, myofiber cross-sectional area, and central mitochondrial volume density of the anterior tibialis muscle, and significantly reduced maximal exercise time. Regular exercise and BCAA prevented AKI-related muscle wasting and low physical performance by suppressing myostatin and atrogin-1 mRNA upregulation, and restoring reduced phosphorylated Akt and PGC-1α mRNA expression in the muscle. Ischemic AKI induces muscle wasting by accelerating muscle protein degradation and reducing protein synthesis; however, we found that regular exercise and BCAA prevented AKI-related muscle wasting without worsening kidney damage, suggesting that early rehabilitation with nutritional support could prevent AKI-related muscle wasting.

Dimethylaminoparthenolide reduces the incidence of dysplasia and ameliorates a wasting syndrome in HPV16-transgenic mice.

The nuclear factor kappa light chain enhancer of activated B cells (NF-κB) has been implicated in the progression of cancers induced by high-risk human papillomaviruses (HPV). In cancer patients, NF-κB is also thought to drive a chronic systemic inflammatory status, leading to cachexia. This study addressed the ability of dimethylaminoparthenolide (DMAPT), a water-soluble NF-κB inhibitor, to block the development of HPV-induced lesions and wasting syndrome in HPV16-transgenic mice. Mice received DMAPT orally (100 mg/kg/day), once a day, for 6 consecutive weeks. Body weight was monitored weekly along with food and water intake. After 6 weeks the animals were submitted to a grip strength test and sacrificed for specimen collection. Skin samples were analyzed histologically and for expression of NF-κB-regulated genes Bcl2 and Bcl2l1. Gastrocnemius muscles were weighted and analyzed for expression of NF-κB subunits p50, p52, p65, and Rel-B. DMAPT reduced the incidence of epidermal dysplasia (18.2% versus 33.3% in HPV16+/- untreated mice). This was associated with reduced expression of Bcl2 and Bcl2l1 (p = .0003 and p = .0014, respectively) and reduced neutrophilic infiltration (p = .0339). Treated mice also showed partially preserved bodyweight and strength, which were independent of the expression levels of NF-κB subunits in skeletal muscle.These results suggest that NF-κB inhibition may be a valid strategy against HPV-induced lesions in vivo and warrant further preclinical tests particularly in the set of combination therapies. In addition, the data may support the use of DMAPT to prevent wasting syndrome.

Measurement of the α1-proteinase inhibitor (α1-antitrypsin) of common marmoset and intestinal protein loss in wasting syndrome.

Although wasting marmoset syndrome (WMS) is one of the biggest problems facing captive marmoset colonies, the mechanisms underlying its pathogenesis remain unclear. In our clinical experience, it is difficult to cure WMS-affected marmosets with severe hypoalbuminemia. Thus, the mechanisms underlying hypoalbuminemia in WMS must be understood. In the present study, we investigated whether intestinal protein loss, a known reason for hypoalbuminemia, occurs in this disease. Fecal α1-proteinase inhibitor (α1-PI, also known as α1-antitrypsin) has been used to diagnose intestinal protein loss in other species. To develop an assay system for this protein, marmoset α1-PI was purified from plasma and antibodies against it were developed using the purified protein. Using the antibodies, a sandwich enzyme-linked immunosorbent assay (ELISA) to measure marmoset α1-PI was developed, and its detection sensitivity for fecal samples was ∼20-fold higher than that of a commercial kit for human α1-PI. From this ELISA, the reference intervals for serum and feces of healthy marmosets were 0.87-1.85 mg/ml and 0.53-395.58 µg/g, respectively. The average concentrations of α1-PI in serum and feces of seven WMS-affected marmosets were 1.17 mg/ml and 1357.58 µg/g, respectively. Although there were no significant differences in the serum concentrations between healthy and WMS-affected marmosets, the fecal concentrations were significantly higher in WMS-affected marmosets than in healthy individuals, suggesting that intestinal protein loss occurs in WMS. Intestinal protein loss of WMS-affected marmosets was significantly attenuated with treatment, suggesting that it is one of the mechanisms involved in the hypoalbuminemia observed in WMS.

Ibudilast attenuates doxorubicin-induced cytotoxicity by suppressing formation of TRPC3 channel and NADPH oxidase 2 protein complexes.

BACKGROUND AND PURPOSE: Doxorubicin is a highly effective anticancer agent but eventually induces cardiotoxicity associated with increased production of ROS. We previously reported that a pathological protein interaction between TRPC3 channels and NADPH oxidase 2 (Nox2) contributed to doxorubicin-induced cardiac atrophy in mice. Here we have investigated the effects of ibudilast, a drug already approved for clinical use and known to block doxorubicin-induced cytotoxicity, on the TRPC3-Nox2 complex. We specifically sought evidence that this drug attenuated doxorubicin-induced systemic tissue wasting in mice. EXPERIMENTAL APPROACH: We used the RAW264.7 macrophage cell line to screen 1,271 clinically approved chemical compounds, evaluating functional interactions between TRPC3 channels and Nox2, by measuring Nox2 protein stability and ROS production, with and without exposure to doxorubicin. In male C57BL/6 mice, samples of cardiac and gastrocnemius muscle were taken and analysed with morphometric, immunohistochemical, RT-PCR and western blot methods. In the passive smoking model, cells were exposed to DMEM containing cigarette sidestream smoke. KEY RESULTS: Ibudilast, an anti-asthmatic drug, attenuated ROS-mediated muscle toxicity induced by doxorubicin treatment or passive smoking, by inhibiting the functional interactions between TRPC3 channels and Nox2, without reducing TRPC3 channel activity. CONCLUSIONS AND IMPLICATIONS: These results indicate a common mechanism underlying induction of systemic tissue wasting by doxorubicin. They also suggest that ibudilast could be repurposed to prevent muscle toxicity caused by anticancer drugs or passive smoking.

Severe dermatitis, multiple allergies and metabolic wasting (SAM) syndrome caused by de novo mutation in the DSP gene misdiagnosed as generalized pustular psoriasis and treatment of acitretin with gabapentin.

Severe dermatitis, multiple allergies and metabolic wasting (SAM) syndrome is a recently recognized syndrome caused by mutations in the desmoglein 1 (DSG1) and desmoplakin (DSP) genes. Only two cases of SAM-DSP have been reported. We report on a 2-year-old girl presenting with pustular lakes within areas of erythema and large accumulations of intraepidermal neutrophils, which initially led to our misdiagnosis of generalized pustular psoriasis. No mutation was found in either the IL36RN or CARD14 genes by Sanger sequencing. The distinctive manifestations of erythroderma with severe itching, hypotrichosis, enamel defects, onychodystrophy, palmoplantar keratoderma and the crucial result of de novo missense mutation in exon 14 of the DSP gene (c.1828T>C, p.S610P) discovered by next-generation sequencing finally confirmed the diagnosis of SAM syndrome. The eruptions significantly improved after a 4-week treatment with oral acitretin and topical pimecrolimus. Oral gabapentin was prescribed simultaneously for 4 months, relieving her skin pruritus and suggesting that early treatment with pimecrolimus, acitretin and gabapentin for SAM-DSP syndrome is effective. It may even inhibit multiple allergies induced by skin barrier injury. In this work we also review the clinical features, differential diagnoses and pathological manifestations of SAM-DSP syndrome.

Amino acid profile after oral nutritional supplementation in hemodialysis patients with protein-energy wasting.

OBJECTIVES: Protein-energy wasting (PEW) is highly prevalent in patients on hemodialysis (HD). Oral nutritional supplementation (ONS) is recommended for malnourished patients on HD. The aim of this study was to evaluate ONS on plasma amino acid in HD patients with PEW. METHODS: Thirty-two HD patients with a mean age 59.1 ± 9.5 y with PEW were enrolled into the study. Patients were prescribed ONS (125 mL twice a day for 3 mo) together with dietary advice. The nutritional status was evaluated by means of body mass index, Subjective Global Assessment, and serum albumin and prealbumin levels. The percentages of body fat and lean body mass were measured by means of the near-infrared method. The lean body mass-to-body weight ratios were calculated. Tumor necrosis factor, interleukin-6 and high-sensitivity C-reactive protein, were measured by the enzyme-linked immunosorbent assay method. Serum concentrations of amino acids were measured by the high-performance liquid chromatography method. RESULTS: After 3 mo of ONS, a significant increase of both serum prealbumin and albumin was observed. The concentration of most of the amino acids increased independently on inflammation. CONCLUSIONS: Dietary advice, combined with ONS, is effective in HD patients with PEW. Both dietary advice and ONS are needed to be sure that patients consume an adequate daily amount of calories and protein.

Muscle Wasting Diseases: Novel Targets and Treatments.

Adequate skeletal muscle plasticity is an essential element for our well-being, and compromised muscle function can drastically affect quality of life, morbidity, and mortality. Surprisingly, however, skeletal muscle remains one of the most under-medicated organs. Interventions in muscle diseases are scarce, not only in neuromuscular dystrophies, but also in highly prevalent secondary wasting pathologies such as sarcopenia and cachexia. Even in other diseases that exhibit a well-established risk correlation of muscle dysfunction due to a sedentary lifestyle, such as type 2 diabetes or cardiovascular pathologies, current treatments are mostly targeted on non-muscle tissues. In recent years, a renewed focus on skeletal muscle has led to the discovery of various novel drug targets and the design of new pharmacological approaches. This review provides an overview of the current knowledge of the key mechanisms involved in muscle wasting conditions and novel pharmacological avenues that could ameliorate muscle diseases.

Blockade of activin type II receptors with a dual anti-ActRIIA/IIB antibody is critical to promote maximal skeletal muscle hypertrophy.

The TGF-ß family ligands myostatin, GDF11, and activins are negative regulators of skeletal muscle mass, which have been reported to primarily signal via the ActRIIB receptor on skeletal muscle and thereby induce muscle wasting described as cachexia. Use of a soluble ActRIIB-Fc "trap," to block myostatin pathway signaling in normal or cachectic mice leads to hypertrophy or prevention of muscle loss, perhaps suggesting that the ActRIIB receptor is primarily responsible for muscle growth regulation. Genetic evidence demonstrates however that both ActRIIB- and ActRIIA-deficient mice display a hypertrophic phenotype. Here, we describe the mode of action of bimagrumab (BYM338), as a human dual-specific anti-ActRIIA/ActRIIB antibody, at the molecular and cellular levels. As shown by X-ray analysis, bimagrumab binds to both ActRIIA and ActRIIB ligand binding domains in a competitive manner at the critical myostatin/activin binding site, hence preventing signal transduction through either ActRII. Myostatin and the activins are capable of binding to both ActRIIA and ActRIIB, with different affinities. However, blockade of either single receptor through the use of specific anti-ActRIIA or anti-ActRIIB antibodies achieves only a partial signaling blockade upon myostatin or activin A stimulation, and this leads to only a small increase in muscle mass. Complete neutralization and maximal anabolic response are achieved only by simultaneous blockade of both receptors. These findings demonstrate the importance of ActRIIA in addition to ActRIIB in mediating myostatin and activin signaling and highlight the need for blocking both receptors to achieve a strong functional benefit.

Digoxin Attenuates Murine Experimental Colitis by Downregulating Th17-related Cytokines.

BACKGROUND: Digoxin, a cardiac glycoside used for the treatment of heart failure, was reported to inhibit the retinoid-related orphan receptor gamma t (RORγt) and attenuate the severity of experimental autoimmune encephalomyelitis and arthritis in mice. However, the effects of digoxin in a mice model of inflammatory bowel disease have not been elucidated. METHODS: Colitis was induced in severe combined immunodeficiency mice by adoptive transfer of CD45RB CD4 T cells. Digoxin or a vehicle was injected into mice with colitis intraperitoneally every other day and changes in body weight were evaluated. After 6 to 8 weeks, the treated mice were killed and evaluated for histological score, T-cell subset, and cytokine messenger RNA (mRNA) expression in the colonic tissue. RESULTS: Wasting disease and histological damage were significantly attenuated in digoxin-treated mice with colitis compared with those in the vehicle-treated mice. In addition, the mRNAs of Th17-related cytokines were downregulated, whereas those of interleukin-10 were upregulated in the colonic mucosa of digoxin-treated mice. However, unexpectedly, the mRNA expression level of tumor necrosis factor alpha did not decrease in the colonic mucosa of digoxin-treated mice with colitis. This observation suggests that digoxin may ameliorate colitis by a tumor necrosis factor alpha-independent pathway. CONCLUSIONS: This study has shown for the first time that treatment with digoxin can ameliorate murine experimental colitis. This finding suggests that the suppression of Th17 using reagents such as digoxin could be effective in treating Crohn's disease refractory to anti-tumor necrosis factor alpha therapy.

HPV16 induces a wasting syndrome in transgenic mice: Amelioration by dietary polyphenols via NF-κB inhibition.

Cancer patients often show a wasting syndrome for which there are little therapeutic options. Dietary polyphenols have been proposed for treating this syndrome, but their usefulness in cases associated with human papillomavirus (HPV)-induced cancers is unknown. We characterized HPV16-transgenic mice as a model of cancer cachexia and tested the efficacy of long-term oral supplementation with polyphenols curcumin and rutin. Both compounds were orally administered to six weeks-old HPV16-transgenic mice showing characteristic multi-step skin carcinogenesis, for 24weeks. Skin lesions and blood, liver and spleen inflammatory changes were characterized histologically and hematologically. Hepatic oxidative stress, skeletal muscle mass and the levels of muscle pro-inflammatory transcription factor NF-κB were also assessed. Skin carcinogenesis was associated with progressive, severe, systemic inflammation (leukocytosis, hepatitis, splenitis), significant mortality and cachexia. Curcumin and rutin totally suppressed mortality while reducing white blood cells and the incidence of splenitis and hepatitis. Rutin prevented muscle wasting more effectively than curcumin. Preservation of muscle mass and reduced hepatic inflammation were associated with down-regulation of the NF-κB canonical pathway and with reduced oxidative stress, respectively. These results point out HPV16-transgenic mice as a useful model for studying the wasting syndrome associated with HPV-induced cancers. Dietary NF-κB inhibitors may be useful resources for treating this syndrome.

Suppression of Tumor Growth and Muscle Wasting in a Transgenic Mouse Model of Pancreatic Cancer by the Novel Histone Deacetylase Inhibitor AR-42.

PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer death in the United States. This study was aimed at evaluating the efficacy of AR-42 (formerly OSU-HDAC42), a novel histone deacetylase (HDAC) inhibitor currently in clinical trials, in suppressing tumor growth and/or cancer-induced muscle wasting in murine models of PDAC. EXPERIMENTAL DESIGN: The in vitro antiproliferative activity of AR-42 was evaluated in six human pancreatic cancer cell lines (AsPC-1, COLO-357, PANC-1, MiaPaCa-2, BxPC-3, SW1990). AsPC-1 subcutaneous xenograft and transgenic KPfl/flC (LSL-KrasG12D;Trp53flox/flox;Pdx-1-Cre) mouse models of pancreatic cancer were used to evaluate the in vivo efficacy of AR-42 in suppressing tumor growth and/or muscle wasting. RESULTS: Growth suppression in AR-42-treated cells was observed in all six human pancreatic cancer cell lines with dose-dependent modulation of proliferation and apoptotic markers, which was associated with the hallmark features of HDAC inhibition, including p21 upregulation and histone H3 hyperacetylation. Oral administration of AR-42 at 50 mg/kg every other day resulted in suppression of tumor burden in the AsPC-1 xenograft and KPfl/flC models by 78% and 55%, respectively, at the end of treatment. Tumor suppression was associated with HDAC inhibition, increased apoptosis, and inhibition of proliferation. Additionally, AR-42 as a single agent preserved muscle size and increased grip strength in KPfl/flC mice. Finally, the combination of AR-42 and gemcitabine in transgenic mice demonstrated a significant increase in survival than either agent alone. CONCLUSIONS: These results suggest that AR-42 represents a therapeutically promising strategy for the treatment of pancreatic cancer.

Emerging therapies for the treatment of skeletal muscle wasting in chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is a progressive lung disease that constitutes a major global health burden. A significant proportion of patients experience skeletal muscle wasting and loss of strength as a comorbidity of their COPD, a condition that severely impacts on their quality of life and survival. At present, the lung pathology is considered to be largely irreversible; however, the inherent adaptability of muscle tissue offers therapeutic opportunities to tackle muscle wasting and potentially reverse or delay the progression of this aspect of the disease, to improve patients' quality of life. Muscle wasting in COPD is complex, with contributions from a number of factors including inflammatory cytokines, oxidative stress, growth and anabolic hormones, nutritional status, and physical activity. In this review, we discuss current and emerging therapeutic approaches to treat muscle wasting in COPD, including a number of pharmacological therapies that are in development for muscle atrophy in other pathological states that could be of relevance for treating muscle wasting in COPD patients.

Signal transducer and activator of transcription 3 signaling as a potential target to treat muscle wasting diseases.

PURPOSE OF REVIEW: The review summarizes our current knowledge of the role of signal transducer and activator of transcription 3 (STAT3) signaling in skeletal muscle regeneration and the maintenance of muscle mass. RECENT FINDINGS: STAT3 signaling plays a pivotal role in regulating the function of multiple cell types in skeletal muscle. This includes muscle stem cells, myofibers, and macrophages. It regulates muscle stem cell function by antagonizing self-renewal. STAT3 also functions in myofibers to regulate skeletal muscle mass. This is highly relevant under pathological conditions where STAT3 activation promotes protein degradation and muscle atrophy. Transient pharmacological inhibition of STAT3 partially prevents muscle wasting. However, the mechanisms responsible for the improvement of muscle condition are not currently well understood. This is because of the complexity of the system, as STAT3 has a critical role in regulating the function of several cell types residing in skeletal muscle. SUMMARY: Muscle wasting is associated with several human diseases such as muscle dystrophies or cancer cachexia. However, currently there are no effective treatments for this condition, and there is a critical need to identify new potential targets for the development of efficient therapeutic approaches.

The Efficacy and Safety of Megestrol Acetate in Protein-Energy Wasting due to Chronic Kidney Disease: A Systematic Review.

OBJECTIVE: To assess the efficacy and safety of oral megestrol acetate (MA) in the management of protein-energy wasting in patients with chronic kidney disease (CKD). DESIGN: A systematic review of English published literature from 1970 until April 1, 2014. SUBJECTS: All adult patients with CKD including both dialysis and non-dialysis-dependent. INTERVENTION: Oral MA. MAIN OUTCOME MEASURE: Efficacy outcomes included changes in body weight, serum albumin, and appetite. Safety outcomes examined included adverse events (AEs) and deaths. RESULTS: A total of 9 studies met the inclusion criteria. No data on MA in non-dialysis CKD patients were available. Statistically significant increases in body weight (range 1.5-5 kg) were reported in 6 trials. Statistically significant increases in albumin (range of 0.22 g/dL-0.52 g/dL) were observed in 5 trials. Improved appetite was observed in 7 trials. All trials were limited by small sample sizes (range 9-32 subjects), short duration (range 8-24 weeks), a high degree of bias, and absence of clinical outcomes such as quality of life or hospitalizations. Forty-seven AEs were reported and included overhydration/excessive fluid gain, diarrhea, hyperglycemia, excessive weight gain, suppressed cortisol levels, thrombophlebitis, nausea/vomiting, confusion/hallucinations, vaginal bleeding, headache/dizziness, and elevated lactate dehydrogenase. There were 26 discontinuations due to death. CONCLUSION: The current evidence for treatment with MA in patients receiving dialysis is sparse with few high-quality trials. The safety of using MA beyond 24 weeks is unknown, and use of MA is associated with significant AEs. At this time, oral MA should be used with significant caution, and only when other treatment options are unavailable.

CYP24 inhibition as a therapeutic target in FGF23-mediated renal phosphate wasting disorders.

CYP24A1 (hereafter referred to as CYP24) enzymatic activity is pivotal in the inactivation of vitamin D metabolites. Basal renal and extrarenal CYP24 is usually low but is highly induced by its substrate 1,25-dihydroxyvitamin D. Unbalanced high and/or long-lasting CYP24 expression has been proposed to underlie diseases like chronic kidney disease, cancers, and psoriasis that otherwise should favorably respond to supplemental vitamin D. Using genetically modified mice, we have shown that renal phosphate wasting hypophosphatemic states arising from high levels of fibroblast growth factor 23 (FGF23) are also associated with increased renal Cyp24 expression, suggesting that elevated CYP24 activity is pivotal to the pathophysiology of these disorders. We therefore crossed 2 mouse strains, each with distinct etiology for high levels of circulating FGF23, onto a Cyp24-null background. Specifically, we evaluated Cyp24 deficiency in Hyp mice, the murine homolog of X-linked dominant hypophosphatemic rickets, and transgenic mice that overexpress a mutant FGF23 (FGF23R176Q) that is associated with the autosomal dominant form of hypophosphatemic rickets. Loss of Cyp24 in these murine models of human disease resulted in near-complete recovery of rachitic/osteomalacic bony abnormalities in the absence of any improvement in the serum biochemical profile. Moreover, treatment of Hyp and FGF23R1760-transgenic mice with the CYP24 inhibitor CTA102 also ameliorated their rachitic bones. Our results link CYP24 activity to the pathophysiology of FGF23-dependent renal phosphate wasting states and implicate pharmacologic CYP24 inhibition as a therapeutic adjunct for their treatment.

Using megestrol acetate to ameliorate protein-energy wasting in chronic kidney disease.

BACKGROUND: Various populations are affected by chronic kidney disease (CKD), and a low dose appetite stimulant megestrol acetate (MA) is sometimes recommended in patients with CKD to ameliorate protein-energy wasting (PEW). Patients with CKD are at greater risk of developing PEW since the progression of their disease can cause decreased nutrient intake, catabolic effects, systemic inflammation and metabolic changes. Providers can detect PEW in CKD by identifying low serum levels ≤3.8 g/dl of albumin, <30 mg/dl of transthyretin, or <100 mg/dl of cholesterol. Other characteristics include BMI <22 kg/m(2) (for ≤65 years), unintentional weight loss of ≥5% in three months or ≥10% in six months, body fat percentage <10%, with muscle wasting of a reduction of ≥5% in three months or ≥10% in six months of muscle mass. METHOD: A review of research was completed and data collected from small population-based retrospective studies to determine the effect of MA. RESULTS: Clinical trials demonstrated the effectiveness of MA by showing increases in BMI up to 9%, albumin levels up to 1.1 g/dl, with reported protein and energy intake increases from 27% to 42%. There are potential adverse effects of using MA in CKD. CONCLUSION: After reviewing the available literature, the benefits of using MA should be evaluated against the potential side effects. For further examination of MA's potential benefits, long-term, prospective, large clinical trials should be carried out.

Tranexamic Acid and Supportive Measures to Treat Wasting Marmoset Syndrome.

Wasting marmoset syndrome (WMS) has high incidence and mortality rates and is one of the most important problems in captive common marmoset (Callithrix jacchus) colonies. Despite several reports on WMS, little information is available regarding its reliable treatment. We previously reported that marmosets with WMS had high serum levels of matrix metalloproteinase 9 (MMP9). MMP9 is thought to be a key enzyme in the pathogenesis of inflammatory bowel disease, the main disease state of WMS, and is activated by plasmin, a fibrinolytic factor. In a previous study, treating mice with an antibody to inhibit plasmin prevented the progression of inflammatory bowel disease. Here we examined the efficacy of tranexamic acid, a commonly used plasmin inhibitor, for the treatment of WMS, with supportive measures including amino acid and iron formulations. Six colony marmosets with WMS received tranexamic acid therapy with supportive measures for 8 wk. The body weight, Hct, and serum albumin levels of these 6 marmosets were increased and serum MMP9 levels decreased after this regimen. Therefore, tranexamic acid therapy may be a new and useful treatment for WMS.