Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0235394 (wasting)
 8,040 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Loss of lean body mass is common in chronic renal failure and may adversely affect morbidity and mortality of patients. The pathogenesis of protein wasting in chronic renal failure is multifactorial and is reviewed by the authors. When protein kinetics are determined in patients with uncomplicated uremic on conservative treatment by isotopically labeled amino acids, the results indicate that the rates of both protein synthesis and degradation are decreased both at whole body and skeletal muscle levels. On the other hand, if a complication is superimposed (ie, acidosis or infection), protein turnover accelerates, primarily because of proteolysis increase. Therapeutical implications are analyzed in this article. Recently, a cytokine-induced chronic inflammatory response has been proposed to explain the progressive protein loss often observed in these patients even in the absence of complications. Cytokine concentrations often have been found to be increased in both dialyzed and undialyzed chronically uremic patients. Tumor necrosis factor (TNF)-alpha clearance is reduced in uremia because this cytokine is catabolized and excreted mainly by the kidneys. In addition, we found that gene expression for TNF-alpha in circulating blood cells is enhanced in chronically uremic patients, suggesting that an activation of the systemic inflammatory response may contribute to the metabolic, vascular, and immune complications of this disease.
 ...
PMID:Mechanisms of malnutrition in uremia. 1267 41

Many of the end-organ effects of cystinosis are known to be risk factors for osteopenia; these include deposition of cystine crystals in bone, hypothyroidism, diabetes mellitus, primary hypogonadism, urinary phosphate wasting, and chronic renal failure. While transplantation may correct the latter, it exposes the child to other risk factors for diminished bone mass, notably the use of high-dose glucocorticoids. Our objective was to determine if these multiple risk factors translate into an increased occurrence of osteopenia, as measured by dual-energy X-ray absorptiometry (DEXA), and/or fractures in this population. We examined the charts, X-rays, and bone mineral density (BMD) of all cystinotic patients post renal transplant for whom this information was available. Lumbar spine BMD was measured by DEXA scan (Hologic 4500). Z-scores were corrected for growth parameters using previously published reference data. Fracture history and pertinent serum markers of bone metabolism were also analyzed. Of the 63 renal transplants performed at our institution, 11 children were transplanted due to cystinosis. Nine of these patients, 5 male and 4 female, had had BMD evaluations, with an average age of 14.3 years (range 5-17 years) at the time of initial BMD post transplant. The mean interval between transplant and BMD evaluation was 39 months (range 3-90 months). Surprisingly, 7 of 9 patients had normal uncorrected BMD values (z-scores -1.92 to +0.02) and 7 of 9 patients had normal corrected values (z-scores -1.20 to +1.93). Three patients suffered from a total of eight fractures. Of the 3 fracture patients, 2 had normal BMD. All patients maintained good graft function and had normal calcium/phosphate mineral status. Of note, 3 of 5 male patients had evidence of primary testicular failure at earlier ages than often described, and this may be an unrecognized risk factor for bone disease in this population. Despite the numerous risk factors for developing osteopenia, these results suggest that the majority of cystinotic patients post renal transplant do not experience reduced bone mineral content as measured by DEXA. However, the significant fracture history among these patients demonstrates that DEXA cannot be used to assess fracture risk in patients with nephropathic cystinosis.
 ...
PMID:Osteopenia and fractures in cystinotic children post renal transplantation. 1270 Sep 67

Somatomedin-1 binding protein-3 [insulin-like growth factor-1 binding protein-3, SomatoKine] is a recombinant complex of insulin-like growth factor-1 (rhIGF-1) and binding protein-3 (IGFBP-3), which is the major circulating somatomedin (insulin-like growth factor) binding protein; binding protein-3 regulates the delivery of somatomedin-1 to target tissues. Somatomedin-1 binding protein-3 has potential as replacement therapy for somatomedin-1 which may become depleted in indications such as major surgery, organ damage/failure and traumatic injury, resulting in catabolism. It also has potential for the treatment of osteoporosis; diseases associated with protein wasting including chronic renal failure, cachexia and severe trauma; and to attenuate cardiac dysfunction in a variety of disease states, including after severe burn trauma. Combined therapy with somatomedin-1 and somatomedin-1 binding protein-3 would prolong the duration of action of somatomedin-1 and would reduce or eliminate some of the undesirable effects associated with somatomedin-1 monotherapy. Somatomedin-1 is usually linked to binding protein-3 in the normal state of the body, and particular proteases clip them apart in response to stresses and release somatomedin-1 as needed. Therefore, somatomedin-1 binding protein-3 is a self-dosing system and SomatoKine would augment the natural supply of these linked compounds. Somatomedin-1 binding protein-3 was developed by Celtrix using its proprietary recombinant protein production technology. Subsequently, Celtrix was acquired by Insmed Pharmaceuticals on June 1 2000. Insmed and Avecia, UK, have signed an agreement for the manufacturing of SomatoKine and its components, IGF-1 and binding protein-3. CGMP clinical production of SomatoKine and its components will be done in Avecia's Advanced Biologics Centre, Billingham, UK, which manufactures recombinant-based medicines and vaccines with a capacity of up to 1000 litres. In 2003, manufacturing of SomatoKine is planned to move to Avecia's larger facility with a capacity of 10 000 litres. Somatomedin-1 binding protein-3 was originally licenced to Welfide for Japan. On October 1 2001, Welfide Corporation merged with Mitsubishi-Tokyo Pharmaceuticals to form Mitsubishi Pharma Corporation. The new company is a subsidiary of Mitsubishi Chemical. In April 2003 Insmed initiated a named patient programme in Europe, that will make available somatomedin-1 binding protein-3 for the treatment of growth hormone insensitivity syndrome (GHIS)--Laron syndrome. The treatment of patients was initiated in Scandinavia, with authorisation pending in several other European countries. Somatomedin-1 binding protein-3 will be made available to those GHIS patients who, in the opinion of their doctor, may benefit from IGF-1 therapy. At precommercial scale quantities, the drug will be available on a limited basis. Safety data generated from the named patient programme will be used to support marketing applications in 2004. A phase II dose-ranging study in children with GHIS was completed at Saint Bartholomew's and the Royal London School of Medicine, London, UK. A single dose of somatomedin-1 binding protein-3 delivered the same amount of IGF-1 as two daily injections of unbound IGF-1. There were no adverse events reported. GHIS is a genetic condition in which patients do not produce adequate quantities of IGF because of a failure to respond to the growth hormone signal. This results in a slower growth rate and short stature. Insmed has acquired an exclusive licence to Pharmacia's regulatory filings concerning yeast-derived IGF-1. These filings were used by Pharmacia to receive marketing approvals in several European countries and also in the investigational New Drug Application with the US FDA. This licence will facilitate the development of SomatoKine for the treatment of children with GHIS. In January 2003, Insmed announced positive results from a double-blind, placebo-controlled, dose-ranging study of SomatoKine in adolescent patients with type 1 diabetes mellitus redolescent patients with type 1 diabetes mellitus receiving insulin therapy. The study was conducted at the University of Cambridge, Cambridge, UK, under the supervision of Professor D. Dunger. It has also been granted orphan drug status for the treatment of GHIS--Laron syndrome in the US and in Europe. Celtrix has been granted 11 US patents for its recombinant protein production technology, which it used for developing somatomedin-1 binding protein-3. Subsequently, Celtrix was acquired by Insmed Pharmaceuticals on June 1 2000. Following the acquisition, Insmed announced that it intends to maintain the US rights to Celtrix's products portfolio. These US patents will expire between 2010 through 2017. Insmed is holding a US patent (expires in 2019) for the use of SomatoKine in the treatment of both type 1 and type 2 diabetes mellitus.
 ...
PMID:Somatomedin-1 binding protein-3: insulin-like growth factor-1 binding protein-3, insulin-like growth factor-1 carrier protein. 1449 68

Mutations in the PHEX gene are responsible for X-linked hypophosphatemia, a renal phosphate-wasting disorder associated with defective skeletal mineralization. PHEX is predominantly expressed in bones and teeth and in the parathyroid gland of patients with chronic renal failure and tertiary hyperparathyroidism. The purpose of the present study was to examine the effects of renal insufficiency and 1,25-dihydroxyvitamin D3 [1,25(OH)2D3] on the regulation of PHEX expression in rat tibia and parathyroid gland. In rats fed a high-phosphate (Pi) diet, nephrectomy elicited a significant increase in the serum parathyroid hormone (PTH) concentration that was associated with a significant increase in the abundance of PHEX mRNA and protein in the tibia and a significant increase in PHEX mRNA in the parathyroid gland. In contrast, 1,25(OH)2D3 administration to intact rats fed a control diet elicited a significant decrease in the serum PTH concentration that was accompanied by a significant decrease in PHEX mRNA and protein abundance in the tibia and a significant decrease in PHEX mRNA in the parathyroid gland. In addition, the increases in serum PTH levels and PHEX mRNA in the tibia and parathyroid gland in nephrectomized rats fed a high-Pi diet were blunted by 1,25(OH)2D3. Serum PTH concentration was positively and significantly correlated with tibial PHEX mRNA and protein abundance. In summary, we demonstrate that PHEX expression in the tibia and parathyroid gland is increased by chronic renal insufficiency and decreased by 1,25(OH)2D3 administration and suggest that PTH status may play an important role in mediating these changes in PHEX expression.
 ...
PMID:Differential regulation of PHEX expression in bone and parathyroid gland by chronic renal insufficiency and 1,25-dihydroxyvitamin D3. 1469 75

There is a paucity of data regarding the prevalence and clinical consequences of protein-energy malnutrition (PEM) in the chronic renal failure, maintenance dialysis, and renal transplant population in developing countries. Malnutrition, which is reported to be present in 42% to 77% of the end-stage renal disease population in developing countries, is strongly associated with morbidity and mortality. Many religious practices in developing countries promote abstinence from meat, fish, and eggs. Both a vegetarian dietary pattern, which is being adopted by an increasing number of people, and ingestion of inadequate protein and calories in the diet to arrest the progression of chronic renal failure, may lead to malnutrition. The attendant complications of PEM, malaise, wasting, anemia, and decreased immunity, may predispose these patients to infections. This is commonly seen in both the maintenance hemodialysis and peritoneal dialysis population and may decrease their survival. There is an urgent need for nutritional counseling by a dietitian to contain the damage of malnutrition and to provide important nutritional information to the patient. Consultation with a dietitian should take place at least 3 times yearly and, in malnourished patients, more often, as needed. Dietetic documentation should include reports of food intake, subjective global assessment, anthropometric measurements, estimation of the nPNA, serum albumin, and prealbumin, the serum lipid profile, sodium and potassium intake, calcium and phosphorus status, and any changes in body weight.
 ...
PMID:Malnutrition and nutritional therapy of chronic kidney disease in developing countries: the Asian perspective. 1470 74

We present a successful pregnancy in a 37-year-old women with severe renal impairment due to medullary cystic disease. She presented five years earlier with hypertension and chronic renal failure with creatinine was 2.1 mg/dl (Ccr 35 ml/min). She had had two successful pregnancies in the past, nine and seven years earlier. Diagnosis of medullary cystic disease (MCD) was made based on typical ultrasound appearance, sodium wasting and acidosis out of the proportion to the degree of renal failure. Over the next 5 years, a slow progression of chronic renal failure was observed with creatinine reaching 5.1 mg/dl (Ccr 15,4 ml/min), shortly before she became pregnant in December 2001. Her hypertension remained well-controlled and serum creatinine decreased at the beginning of the second trimester to 3.7 mg/dl with subsequent increase toward the end of the pregnancy. She required increasing doses of erythropoietin and intravenous iron supplementation to maintain hemoglobin levels. The polyhydramnios developed necessitating five procedures of amnio reduction. She was not treated by dialysis. A boy weighing 1,600 g was delivered by cesarean section in the 35th week of gestation. The mother's creatinine rose to 5.2 mg/dl (Ccr 15 ml/min) post partum and her renal function declined only slightly over the next 20 months. Our report illustrates that successful fetal and maternal outcome can be achieved even in cases of advanced renal failure preceding gestation. It appears that the type of renal disease influences the pregnancy course and outcome and thus should be considered in patient counseling and therapeutic decisions.
 ...
PMID:Successful pregnancy in a patient with medullary cystic disease and severe renal impairment. 1567 98

It has long been recognized that chronic renal failure (CRF) in children is associated with growth delay. Still In our days nevertheless, growth retardation remains today a major impediment to the full rehabilitation of children with CRF. The reduction of in height velocity frequently results in diminished final adult height. Available evidence suggests that growth retardation might be the result of late referral and/or suboptimal clinical care in children with CRF. Management of malnutrition, renal osteodystrophy, metabolic acidosis, salt wasting and anemia should be optimal before recombinant human growth hormone initiation.
 ...
PMID:Growth and nutrition of children with chronic renal failure. 1588 61

Familial hypomagnesemic hypercalciuria and nephrocalcinosis (FHHNC [MIM 248250]) is a rare renal tubular disorder characterized by impaired reabsorption of magnesium and calcium in the thick ascending limb of Henle's loop (tALH), causing renal magnesium wasting and hypercalciuria. Patients with FHHNC usually present with recurrent urinary tract infections, polyuria, nephrolithiasis (NL) and nephrocalcinosis (NC) with many progressing to chronic renal failure (CRF). We have shown recently that loss of function mutations in paracellin-1 PCLN-1/claudin-16, a renal tight junction protein located in the TAL, are causative of FHHNC. We present clinical and molecular studies on a highly inbred family with FHHNC in association with an unusual phenotype in that all affected members were extremely short. Affected individuals were found to be homozygous for marker D3S1314 on chromosome 3q. Sequencing of the PCLN-1/claudin-16 gene revealed a previously unknown point mutation at S235Y on exon 4 on the 4th transmembrane domain, providing additional evidence that inactivating mutations in the PCLN-1/claudin-16 gene result in FHHNC.
 ...
PMID:A novel PCLN-1 gene mutation in familial hypomagnesemia with hypercalciuria and atypical phenotype. 1712 17

Wasting of lean tissue as a consequence of metabolic acidosis is a serious problem in patients with chronic renal failure. A possible contributor is inhibition by low pH of the System A (SNAT2) transporter, which carries the amino acid L-glutamine (L-Gln) into muscle cells. The aim of this study was to determine the effect of selective SNAT2 inhibition on intracellular amino acid profiles and amino acid-dependent signaling through mammalian target of rapamycin in L6 skeletal muscle cells. Inhibition of SNAT2 with the selective competitive substrate methylaminoisobutyrate, metabolic acidosis (pH 7.1), or silencing SNAT2 expression with small interfering RNA all depleted intracellular L-Gln. SNAT2 inhibition also indirectly depleted other amino acids whose intracellular concentrations are maintained by the L-Gln gradient across the plasma membrane, notably the anabolic amino acid L-leucine. Consequently, SNAT2 inhibition strongly impaired signaling through mammalian target of rapamycin to ribosomal protein S6 kinase, ribosomal protein S6, and 4E-BP1, leading to impairment of protein synthesis comparable with that induced by rapamycin. It is concluded that even though SNAT2 is only one of several L-Gln transporters in muscle, it may determine intracellular anabolic amino acid levels, regulating the amino acid signaling that affects protein mass, nucleotide/nucleic acid metabolism, and cell growth.
 ...
PMID:Acidosis-sensing glutamine pump SNAT2 determines amino acid levels and mammalian target of rapamycin signalling to protein synthesis in L6 muscle cells. 1742 52

A prospective study was carried out in the Department of Pediatrics, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh, from October, 2001 to October, 2003 to find out the impact of different etiology of chronic renal failure on growth in children. Fifty children of both sexes under 15 years of age with clinical and biochemical evidence of chronic renal failure (CRF) with creatinine clearance (Ccr) of <75 ml/min/1.73m2 were included in the study. On the basis of underlying causes of CRF, the children were divided into congenital (n=30) and acquired (n=20) groups. All patients' height, weight, radiographs of different bones was obtained to evaluate the presence of renal osteodystrophy (ROD) and for assessment of bone age. Serum intact parathormone (iPTH) level was also assayed in all patients. These parameters were evaluated in two groups. CRF children due to congenital anomalies had stunting and wasting in 23 (76.7%) and 20 (66.7%) cases respectively and the difference between two groups was highly significant (P<0.001). Alkaline phosphatase (467.70+/-218.55 U/L) and iPTH (91.43+/-33.42 pg/ml) were also significantly higher in the congenital group (P<0.001 and P<0.05 respectively). Radiographic features of ROD were present in 15 (50%) cases in congenital group in comparison to 4 (20%) in acquired group and the growth zone lesion was the commonest type of ROD in congenital group (66.7%). CRF should be diagnosed as early as possible to maintain growth potential.
 ...
PMID:Impact of etiology of chronic renal failure on growth in children. 1791 29


<< Previous 1 2 3 4 5 Next >>