Protein-energy wasting (PEW) is common in patients with chronic kidney disease (CKD) and is associated with an increased death risk from cardiovascular diseases. However, while even minor renal dysfunction is an independent predictor of adverse cardiovascular prognosis, PEW becomes clinically manifest at an advanced stage, early before or during the dialytic stage. Mechanisms causing loss of muscle protein and fat are complex and not always associated with anorexia, but are linked to several abnormalities that stimulate protein degradation and/or decrease protein synthesis. In addition, data from experimental CKD indicate that uremia specifically blunts the regenerative potential in skeletal muscle, by acting on muscle stem cells. In this discussion recent findings regarding the mechanisms responsible for malnutrition and the increase in cardiovascular risk in CKD patients are discussed. During the course of CKD, the loss of kidney excretory and metabolic functions proceed together with the activation of pathways of endothelial damage, inflammation, acidosis, alterations in insulin signaling and anorexia which are likely to orchestrate net protein catabolism and the PEW syndrome.

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.

The rate of kidney protein turnover in humans is not known. To this aim, we have measured kidney protein synthesis and degradation in postabsorptive humans using the arterio-venous catheterization technique combined with 14 C-leucine, 15 N-leucine, and 3 H-phenylalanine tracer infusions. These measurements were compared with those obtained across the splanchnic bed, the legs ( Ϸ muscle) and in the whole body. In the kidneys, protein balance was negative, as the rate of leucine release from protein degradation (16.8 Ϯ 5.1 mol/min и 1.73 m 2 ) was greater ( P Ͻ 0.02) than its uptake into protein synthesis (11.6 Ϯ 5.1 mol/min и 1.73 m 2 ). Splanchnic net protein balance was Ϸ 0 since leucine from protein degradation (32.1 Ϯ 9.9 mol/min и 1.73 m 2 ) and leucine into protein synthesis (30.8 Ϯ 11.5 mol/min и 1.73 m 2 ) were not different. In the legs, degradation exceeded synthesis (27.4 Ϯ 6.6 vs. 20.3 Ϯ 6.5 mol/min и 1.73 m 2 , P Ͻ 0.02). The kidneys extracted ␣ -ketoisocaproic acid, accounting for Ϸ 70% of net splanchnic ␣ -ketoisocaproic acid release. The contributions by the kidneys to whole-body leucine rate of appearance, utilization for protein synthesis, and oxidation were Ϸ 11%, Ϸ 10%, and Ϸ 26%, respectively; those by the splanchnic area Ϸ 22%, Ϸ 27%, and Ϸ 18%; those from estimated total skeletal muscle Ϸ 37%, Ϸ 34%, and Ϸ 48%. Estimated fractional protein synthetic rates were Ϸ 42%/d in the kidneys, Ϸ 12% in the splanchnic area, and Ϸ 1.5% in muscle. This study reports the first estimates of kidney protein synthesis and degradation in humans, also in comparison with those measured in the splanchnic area, the legs, and the whole-body.

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The absence of surgical and general complications and the nearly immediate resumption of PD indicate the anterior tension-free repair under local anesthesia as a safe and effective technique for CAPD patients even in an ambulatory or day-surgery setting.

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In the present study, we used organ balance across the kidney, splanchnic organs, and lower limb in subjects undergoing diagnostic central venous catheterizations to gain insight into the renal and extrarenal exchange of aminothiols in humans. Although Hcy was released only in low amounts from leg tissues, Cys-Gly (a peptide derived from GSH hydrolysis) was released by both the leg and splanchnic organs, whereas Cys was released by the kidney and taken up by splanchnic organs. The kidney removed ∼90% of the Cys-Gly released into the circulation. Removal of Cys-Gly by the kidney depended on Cys-Gly arterial levels and showed a high fractional extraction (∼26%), with clearance rates slightly higher than the glomerular filtration rate (GFR). Although the average kidney removal of Hcy was not statistically significant, the fractional extraction of Hcy across the kidney varied directly with renal plasma flow. Our data show that thiol metabolism in humans is a compartmentalized interorgan process involving fluxes of individual aminothiols that are parallel and of opposite sign among peripheral tissues, splanchnic organs, and kidney. Cys-Gly is released by peripheral tissue and splanchnic organs from GSH hydrolysis and is taken up by the kidney by GFR; the kidney returns Cys to the circulation to preserve substrate availability for GSH synthesis. On the other hand, Hcy is released by peripheral tissues in low amounts, and its removal by the kidney seems to depend on blood supply. These findings may help explain several alterations in aminothiol metabolism observed in patients with chronic diseases.