Publications (5)20.55 Total impact
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Article: Apoptosis and myostatin mRNA are upregulated in the skeletal muscle of patients with chronic kidney disease.
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ABSTRACT: Apoptosis and myostatin are major mediators of muscle atrophy and might therefore be involved in the wasting of uremia. To examine whether they are expressed in the skeletal muscle of patients with chronic kidney disease (CKD), we measured muscle apoptosis and myostatin mRNA and their related intracellular signal pathways in rectus abdominis biopsies obtained from 22 consecutive patients with stage 5 CKD scheduled for peritoneal dialysis. Apoptotic loss of myonuclei, determined by anti-single-stranded DNA antibody and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assays, was significantly increased three to fivefold, respectively. Additionally, myostatin and interleukin (IL)-6 gene expressions were significantly upregulated, whereas insulin-like growth factor-I mRNA was significantly lower than in controls. Phosphorylated JNK (c-Jun amino-terminal kinase) and its downstream effector, phospho-c-Jun, were significantly upregulated, whereas phospho-Akt was markedly downregulated. Multivariate analysis models showed that phospho-Akt and IL-6 contributed individually and significantly to the prediction of apoptosis and myostatin gene expression, respectively. Thus, our study found activation of multiple pathways that promote muscle atrophy in the skeletal muscle of patients with CKD. These pathways appear to be associated with different intracellular signals, and are likely differently regulated in patients with CKD.Kidney International 01/2011; 79(7):773-82. · 6.61 Impact Factor -
Article: Mechanisms of renal ammonia production and protein turnover.
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ABSTRACT: Renal synthesis and excretion of ammonia are critical for efficient removal of acids from the body. Besides the rate of ammonia production, the intrarenal distribution of produced ammonia is a crucial step in the renal regulation of acid-base balance. Various acid-base disorders are associated not only with changes in ammonia production but also with its distribution between the urine and the renal veins. The final effect of ammonia production on acid-base balance largely depends on the events that determine the distribution of ammonia produced between urine and blood. Several factors, among which urine pH, urine flow, total ammonia production "per se" and renal blood flow may affect the percent of ammonia excreted into urines in humans with different acid-base disturbances. Among these factors, urine pH is the most important. An additional effect of stimulated ammoniagenesis is kidney hypertrophy. In tubule epithelial cells, the associated increase in ammonia production, rather than the acidosis per se, is responsible for favoring tubular hypertrophy. This effect is related to the inhibition of protein degradation, owing to changes in lysosomal pH and cathepsin activity, without effects on cell cycle. Both changes of PI-3 kinase pathway and the suppression of chaperone-mediated autophagy are candidate mechanism for ammonia-mediated inhibition of protein degradation in tubule cells. Available data in humans indicate that the response of kidney to metabolic acidosis includes both changes in amino acid uptake and suppression of protein degradation. The latter effect is associated with the increase in ammonia excretion and partition into the urine.Metabolic Brain Disease 01/2009; 24(1):159-67. · 2.20 Impact Factor -
Article: Effects of uremia and inflammation on growth hormone resistance in patients with chronic kidney diseases.
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ABSTRACT: Resistance to the anabolic action of growth hormone may contribute to the loss of strength and muscle mass in adult patients with chronic kidney disease. We tested this hypothesis by infusing growth hormone in patients to levels necessary to saturate hormone receptors. This led to a significant decrease of plasma potassium and amino acid levels in control and hyperkalemic patients with chronic kidney disease. These effects were completely or partially blunted in patients with elevated C-reactive protein levels. In forearm perfusion studies, growth hormone caused a further decrease in the negative potassium and protein balance of hemodialysis patients without inflammation but no effect was seen in patients with inflammation. Only IL-6 levels and age were found to be independent correlates in these growth hormone-induced variations in plasma potassium and blood amino acids. This shows that although a resistance to pharmacologic doses of growth hormone is not a general feature of patients with chronic kidney disease, there is a subgroup characterized by blunted growth hormone action. Our results support the hypothesis that uremia with inflammation, but not uremia per se, inhibits downstream growth hormone signaling contributing to muscle atrophy.Kidney International 10/2008; 74(7):937-45. · 6.61 Impact Factor -
Article: Kidney and splanchnic handling of interleukin-6 in humans.
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ABSTRACT: Chronic elevation of circulating Interleukin-6 (IL-6) is observed in elderly individuals as well as in several illnesses, including chronic kidney diseases. A number of cells and tissues possess the ability to metabolize significant amounts of IL-6 in vitro. However, information on signals and mechanisms by which IL-6 is removed from blood in humans is still incomplete. To assess the individual role of splanchnic organs and kidney on IL-6 inter-organ exchange we used the IL-6 mass-balance technique across the hepato-splanchnic bed and kidney in six subjects with normal renal and liver function undergoing diagnostic venous catheterizations. Both in the hepatic and renal veins IL-6 levels were significantly lower (p=0.041 and 0.038, respectively), than in the artery. The fractional extraction of IL-6, i.e., the percentage of arterial IL-6 extracted after a single pass, was greater across the splanchnic organs (18%) than across the kidney (8%). Accordingly, IL-6 plasma clearance across splanchnic organs was greater than across the kidney and the sum of kidney and splanchnic removal accounted for as much as 63% of the estimated adipocyte IL-6 release. Our data demonstrate that, although the individual contribution to removal is different, both splanchnic organs and kidneys affect in a significant way the disposal of IL-6 in humans. According, both liver and kidney dysfunction could affect the handling of this proinflammatory cytokine and favour a chronic inflammatory response.Cytokine 02/2007; 37(1):51-4. · 3.02 Impact Factor -
Article: Causes of hyperhomocysteinemia in patients with chronic kidney diseases.
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ABSTRACT: Plasma homocysteine (Hcy) levels are increased significantly in patients with moderate renal failure and increase markedly in patients with end-stage renal disease. An increase in plasma Hcy level theoretically could be caused by an increased production rate (ie, transmethylation), a decreased rate of removal by transsulfuration or remethylation, or a decrease in the excretion of Hcy. Current evidence indicates that the major mechanism for hyperhomocysteinemia in renal failure is a decrease in Hcy removal from the body. However, it is debated whether this effect is the result of a decrease in the renal metabolic clearance or a result of extrarenal metabolic changes. The human kidney plays a major role in the removal of several aminothiols or Hcy-related compounds from the circulation (eg, cysteine-glycine, glutathione, AdoMet, and AdoHcy). However, the glomerular filtration of Hcy seems to be restricted because of protein binding. Besides glomerular filtration, the normal kidney can remove Hcy by plasma flow and peritubular uptake. Although in the low normal range in absolute terms, the flow through the transsulfuration pathway is reduced if related to Hcy levels in uremia; in addition, the remethylation pathway also is impaired. Besides the potential effect of the reduced renal mass on Hcy removal, available evidence suggests the occurrence of a generalized down-regulation of the methionine cycle and catabolism in uremia. AdoHcy, sulfate, and dimethylglycine currently are being investigated as retained solutes that can inhibit 1 or more pathways of Hcy metabolism. In addition, the high Hcy levels decrease in malnourished end-stage renal disease patients and change according to nutrient intake and several other nutritional parameters, indicating that circulating Hcy levels become an expression of nutritional status.Seminars in Nephrology 02/2006; 26(1):3-7. · 2.12 Impact Factor
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- Kidney International (2)
- Seminars in Nephrology (1)
- Metabolic Brain Disease (1)
- Cytokine (1)
