Renal tubular

Usual dose schedules of streptozotocin involve 500 mg/m2 i.v. during five consecutive days. The major toxicity is renal tubular damage. Treatment of metastatic insulinomas may result in the release of insulin from the tumor and subsequent hypoglycemic coma. Less severe toxicities include diarrhea, anemia, and mild alterations in glucose tolerance or liver function tests. 

Diuretics promote the urinary excretion of sodium and water by inhibiting the absorption of filtered fluid across the renal tubular epithelium. The ensuing reduction in Na reabsorption reduces the Na content of the body, the critical determinant of extracellular and plasma fluid volumes. Thus, the use of diuretics is primarily indicated in the treatment of edematous diseases and of arterial hypertension. 

The co-administration of drugs which inhibit the transporters involved in renal tubular secretion can reduce the urinaty excretion of drugs which are substrates of the transporter, leading to elevated plasma concentrations of the drugs. For example, probenecid increases the plasma concentration and the duration of effect of penicillin by inhibiting its renal tubular secretion. It also elevates the plasma concentration of methotrexate by the same mechanism, provoking its toxic effects. 

LRP2/ megalin Loss-of-function (familial, autosomal recessive) Donnai-Barrow syndrome (brain malformation, renal tubular deficiency, diaphragmatic hernia)... 

A major regulator of bone metabolism and calcium homeostasis, parathyroid hormone (PTH) is stimulated through a decrease in plasma ionised calcium and increases plasma calcium by activating osteoclasts. PTH also increases renal tubular calcium re-absorption as well as intestinal calcium absorption. Synthetic PTH (1-34) has been successfully used for the treatment of osteoporosis, where it leads to substantial increases in bone density and a 60-70% reduction in vertebral fractures. 

Vasopressin (Rtressin Synthetic) and its derivatives, namely lypressin (Diapid) and desmopressin (DDAVP), regulate the reabsorption of water by the kidneys. Vasopressin is secreted by the pituitary when body fluids must be conserved. An example of this mechanism may be seen when an individual has severe vomiting and diarrhea with little or no fluid intake. When this and similar conditions are present, die posterior pituitary releases the hormone vasopressin, water in die kidneys is reabsorbed into die blood (ie, conserved), and die urine becomes concentrated. Vasopressin exhibits its greatest activity on die renal tubular epithelium, where it promotes water resoqition and smooth muscle contraction throughout die vascular bed. Vasopressin has some vasopressor activity. 

Glycinuria results from a defect in renal tubular reabsorption. The defect in primary hyperoxaluria is the failure to catabolize glyoxylate formed by deamination of glycine. Subsequent oxidation of glyoxylate to oxalate results in urohthiasis, nephrocalcinosis, and early mortality from renal failure or hypertension. 

Osteopetrosis (marble bone disease), characterized by increased bone density, is due to inability to resorb bone. One form occurs along with renal tubular acidosis and cerebral calcification. It is due to mutations in the gene (located on chromosome 8q22) encoding carbonic anhydrase II (CAII), one of four isozymes of carbonic anhydrase present in human tissues. The reaction catalyzed by carbonic anhydrase is shown below ... 

Osbome-Mendel rats appeared to be the most sensitive to the renal effeets of trichloroethylene. At a dose of 500 mg/kg/day, toxic nephrosis occurred in 78% of male and 60% of female Osbome-Mendel rats, 37% of male and 45% female ACI rats, 36% of male and 63% of female Marshall rats, and 20% of male and 17% female August rats. Another chronic study revealed renal tubular nucleocytosis in 50% of male rats exposed to 250 mg/kg/day trichloroethylene for 52 weeks by oil gavage (Maltoni et al. 1986). Further explanation of these studies is in Section 2.2.2.8. 

Hesse, I.F.A. and Johns, E.J. (1984). The subtype of a-adrcnoceptor involved in the neural control of renal tubular sodium reabsorption in the rabbit. J. Physiol. 328, 527-538. 

Ueda, N. and Shah, S.V. (1992). Endonuclease-induced DNA damage and cell death in oxidant injury to renal tubular epithelial cells. J. Clin. Invest. 90, 2593-2597. 

Renal losses (e.g., proximal [Type II] renal tubular acidosis [RTA])... 

The normal UAG ranges from 0 to 5 mEq/L (mmol/L) and represents the presence of unmeasured urinary anions. In metabolic acidosis, the excretion of NH4+ and concurrent CP should increase markedly if renal acidification is intact. This results in UAG values from -20 to -50 mEq/L (mmol/L). This occurs because the urinary CP concentration now markedly exceeds the urinary Na+ and K+ concentrations. Diagnoses consistent with an excessively negative UAG include proximal (type 2) renal tubular acidosis, diarrhea, or administration of acetazo-lamide or hydrochloric acid (HC1). Excessively positive values of the UAG suggest a distal (type 1) renal tubular acidosis. 

Sodium bicarbonate increases renal tubular reabsorption of amphetamine, resulting in a prolonged amphetamine elimination half-life be aware of this combination. 

Azacitidine, a cytidine analog, causes hypomethylation of DNA, which normalizes the function of genes that control cell differentiation to promote normal cell maturation. The suspension is administered as a subcutaneous injection daily for 7 days for the treatment of myelodysplastic syndrome, a preleukemia disease. The pharmacokinetics of azacitidine are best described by a two-compartment model, with a terminal half life of 3.4 to 6.2 hours, whereas peak concentrations are achieved 30 minutes after a subcutaneous injection.7 Azacitidine has been shown to be clinically active in the treatment of myelodysplastic syndromes. The side effects include myelosuppression, renal tubular acidosis, renal dysfunction, and injection-site reactions. 

Hydroxyurea is an oral drug that inhibits ribonucleotide reductase, which converts ribonucleotides into the deoxyribuon-cleotides used in DNA synthesis and repair. The time to peak concentrations of hydroxyurea is 1 to 2 hours after oral administration. Approximately 50% is degraded by the liver to form urea and respiratory carbon dioxide. The remainder is excreted by the kidney. The half-life ranges from 3.5 to 4.5 hours. Hydroxyurea has shown clinical activity in the treatment of chronic myelocytic leukemia, polycythemia vera, and thrombocytosis. The major side effects are myelo-suppression, nausea and vomiting, diarrhea, and constipation. Rash, mucositis, and renal tubular dysfunction occur rarely. 

Around 99% of calcium is contained in the bones, whereas the other 1% resides in the extracellular fluid. Of this extracellular calcium, approximately 40% is bound to albumin, and the remainder is in the ionized, physiologically active form. Normal calcium levels are maintained by three primary factors parathyroid hormone, 1,25-dihydroxyvitamin D, and calcitonin. Parathyroid hormone increases renal tubular calcium resorption and promotes bone resorption. The active form of vitamin D, 1,25-dihydroxyvitamin D, regulates absorption of calcium from the GI tract. Calcitonin serves as an inhibitory factor by suppressing osteoclast activity and stimulating calcium deposition into the bones. 

Abbreviations GER. gastric-emptying rate Vj, volume of distribution /, 2r half-life GFR, glomerular filtration rate ARTS active renal tubular secretion. 

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