chondroitin-sulfates and Kidney-Diseases

Cisplatin (CDDP) is an anticancer drug. The clinical limitations associated with CDDP have stimulated the development of macromolecular drug-carrier systems, in attempts to decrease its toxicity. A complex (CDDP-CSA-23) between CDDP and chondroitin sulfate (CSA), a natural polysaccharide with a mean molecular weight of 23 kDa, proved to have the same anticancer activity as CDDP. A toxicodynamic study was performed on perfused kidneys to determine the effect of CDDP-CSA-23 on renal functions and the extent of platinum accumulation. The results showed that CDDP-CSA-23 attenuates the reduction in urine flow and creatinine clearance induced by CDDP. Moreover, significantly lower amounts of platinum were excreted into the urine in the case of CDDP-CSA-23, compared with CDDP alone. Meanwhile, CDDP-CSA-23 effectively retarded the rapid perfusion of platinum into kidney tissues, as occurs when CDDP is being perfused alone. The cytoprotective effects of CDDP-CSA on human proximal tubular (HK-2) cells were examined by measuring the growth of HK-2 cells in the presence of CDDP or CDDP-CSA-23. Interestingly, CDDP-CSA-23 was found to have a significantly reduced cytotoxicity, compared to CDDP. These results suggest that CDDP-CSA-23 greatly decreased the negative effects of CDDP on glomerular filtration and tubular transport in kidneys at early stages of its administration.

Topics: Animals; Antineoplastic Agents; Cells, Cultured; Chondroitin Sulfates; Cisplatin; Creatinine; Disease Models, Animal; Disease Progression; Drug Combinations; Glomerular Filtration Rate; Humans; Kidney Diseases; Kidney Tubules, Proximal; Male; Neoplasms, Experimental; Perfusion; Rats, Sprague-Dawley

To assess the effects of a macromolecular prodrug in reducing the nephrotoxicity of cisplatin (CDDP), chondroitin sulfate A (CSA) with a mean molecular weight of 23,000 Da was used to form a complex with CDDP, and the pharmacokinetics and toxicology of the resulting complex were examined in rats in comparison with those of CDDP. The total plasma platinum levels and urinary accumulation were determined up to 3 h following a bolus injection of 2 mg/kg. The results of the pharmacokinetic analysis showed that the complex suppressed the rapid distribution of CDDP, decreased the renal clearance and resulted in over fivefold higher AUC values within 3 h in comparison with CDDP treatment. In addition, the plasma levels of the drug following administration of the complex decreased greatly with time throughout the experimental period (3-24 h), whereas a slow elimination was observed following CDDP administration, which was due to the irreversible protein binding of CDDP. The tissue-to-plasma partition ratio at 10 min also indicated that the CDDP-CSA complex controlled the perfusion of CDDP to tissues, especially to the kidney. The accumulation in various tissues was evaluated at 3 h and 24 h following the injection of 5 mg/kg. Marked differences in renal accumulation were found within 3 h. Significant reductions in accumulation in the kidney, lung, muscle and whole blood were found within 24 h of administration of the complex. The renal toxicity of the CDDP-CSA complex was evaluated by measuring blood urea nitrogen (BUN), serum creatinine (Cr) and the ratio of terminal kidney weight to body weight at doses of 2 mg/kg and 5 mg/kg. The complex displayed a much lower nephrotoxicity at 5 mg/kg in comparison to CDDP, and similar results were obtained at 2 mg/kg. This suggests that the complex changed the toxicodynamics of CDDP. Moreover, the anticancer activity of the CDDP-CSA complex, tested against SW 4800 human colon cancer cells and HeLa human cervix cancer cells in vitro, showed no decrease as compared with that of free CDDP. We conclude that the CDDP-CSA complex had the same activity as the parent drug but showed reduced nephrotoxicity at high doses of CDDP through an improvement in the pharmacokinetics of CDDP, which resulted from both the minimization of entry into normal tissues and renal clearance. In addition, it is also possible that different intracellular interactions in renal cells play a role in protection against the nephrotoxicity of high doses of CDDP

Topics: Animals; Antineoplastic Agents; Blood Urea Nitrogen; Chondroitin Sulfates; Cisplatin; Creatinine; Drug Carriers; Drug Interactions; Kidney; Kidney Diseases; Male; Organ Size; Rats; Rats, Wistar

Glycosaminoglycan administration has favourable effects on morphological and functional renal abnormalities in different models. The possibility that exogenous glycosaminoglycans modulate glomerular matrix synthesis was explored in both primary and SV40-MES13 murine mesangial cell cultures. On both cell types, both low-molecular-weight heparin and different glycosaminoglycans showed dose-dependent inhibition of proliferation and increase of 35SO4(2)-uptake. After 36 h the cell compartment contained a spectrum of 35S-molecules of less than 200 kDa; under heparin treatment, the two main 35SO4(2)-components (high and medium MW) increased by 16 and 37% respectively. Susceptibility to glycosidases revealed that heparin promotes the expression of heparan sulphate and increases that of chondroitin sulphate. Moreover, heparin modifies the expression of decorin and biglycan, involved in adhesion and fibrillogenesis, while not affecting perlecan. The extracellular matrix modulation in renal cells, for which the sulphation type and ratio of heparin are crucial, may thus explain the beneficial renal effects of heparin.

Topics: Animals; Cell Division; Cell Line, Transformed; Cells, Cultured; Chondroitin Sulfates; Cytoskeletal Proteins; DNA; Dose-Response Relationship, Drug; Extracellular Matrix; Glomerular Mesangium; Heparin, Low-Molecular-Weight; Heparitin Sulfate; Immunoenzyme Techniques; Kidney Diseases; Mice; Mice, Inbred C57BL; Proteoglycans; Sulfates

Analyses of the cystic fluid from a patient with massive tissue calcification showed a significant amount of acid mucopolysaccharides (mainly hyaluronic acid) and phospholipid-polypeptide complexes. The possible role of those molecules in this type of calcinosis is discussed.

Topics: Calcinosis; Calcium; Chondroitin Sulfates; Cysts; Female; Glycosaminoglycans; Humans; Hyaluronic Acid; Hyperparathyroidism, Secondary; Kidney Diseases; Middle Aged; Phospholipids; Proteins

Topics: Animals; Chondroitin; Chondroitin Sulfates; Kidney Diseases; Nephrocalcinosis; Rats