The principal physiologic roles of the kidney are to maintain normal plasma volume and composition, to regulate calcium metabolism by controlling the synthesis of 1,25-dihydroxy-cholycalciferol (1,25-D3), to regulate hematocrit and to metabolize low molecular weight peptides. Alterations in protein metabolism result principally from losses of these functions. Metabolic acidosis causes increased skeletal muscle protein catabolism through regulated activation of the ATP-ubiquitin-proteasome proteolytic pathway. Increased proteolysis is followed by oxidation of branch chain essential amino acids. Alanine and glycine released from muscle and glutamine and glu-tamate released from liver serve as substrate for renal ammoniagenesis, ultimately correcting acidosis. The cycle is subverted when kidneys are absent. Secretion of a variety of proteins is also perturbed. Hepatic secretion of insulin like growth factor-1 (IGF-I) in response to growth hormone is reduced. This in turn contributes to growth retardation, adding to the effects of acidosis. Muscle is also resistant to insulin in renal failure. Renal production of 1,25-D3 is reduced contributing to hyperparathyroidism, which in turn causes increased intracellular calcium in a variety of tissues contributing to decreased synthesis of immunoglobulins, mitogen-stimulated T-cell proliferation, and decreased glucose-stimulated insulin secretion. Hepatic synthesis of some proteins, such as apolipo-protein A-I and IGF-I are decreased, but synthesis of others, such as albumin, is normal. Low molecular weight peptides such as β2-microglobulin, normally filtered and catabolized in the proximal tubule, accumulate in plasma and may have deleterious effects.

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