Localization of heparin and low-molecular-weight heparin in the rat kidney

Abstract

Unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) are cleared, at least in part, by the kidneys through a poorly understood process. This study was undertaken to explore the mechanism of renal clearance of these drugs. Rats were given fluorescein-5-isothiocyanate (FITC)-labeled UFH or LMWH intravenously. At intervals after injection, rats were euthanized and the kidneys were harvested and subjected to immunohistochemical analysis and fluorescence microscopy. Both UFH and LMWH were localized to renal tubular cells and no immunoperoxidase staining or fluorescence was detected in glomeruli. Autoradiography demonstrated similar intracellular distribution of radio-labeled UFH suggesting that this phenomenon is independent of the method used to label heparin. Fluorescence in the tubules increased as a function of time after UFH injection, but reached a plateau after LMWH injection suggesting that the rate of renal tubular uptake depends on the molecular size of the heparin. When administered prior to FITC-labeled UFH or LMWH, probenecid, a renal organic anion inhibitor, decreased the renal tubular uptake of the heparins, whereas cimetidine, a renal organic cation inhibitor, had no effect. These findings suggest that renal excretion of UFH and LMWH primarily reflects tubular uptake via an organic anion transport mechanism.

Tinzaparin and other low-molecular-weight heparins: what is the evidence for differential dependence on renal clearance?

“…A study of fluorescence-labeled UFH and dalteparin in rats has shown that both are localized to renal tubular cells and not the glomeruli after intravenous injection [16]. This supports clearance mainly due to an active renal tubular process.…”

“…It is best described as a combination of one saturable and one non-saturable elimination mechanism, with the saturable mechanism being the more efficient of the two in the low-dose range. The saturable mechanism has been attributed to binding and uptake by cellular systems, for example, the reticuloendothelial system (RES) and/or endothelial cells, while the non-saturable elimination is related to renal excretion [16-18]. Clinical data indicate that clearance of low doses of UFH is not affected by poor renal function; however, as doses increase, non-renal elimination processes become saturated and renal elimination plays a larger role, giving rise to accumulation [19].…”

“…In contrast, the lower-MW fractions are likely to be taken up directly by the renal tubular cells. Probenecid, a renal organic anion inhibitor, decreased the renal tubular uptake of the heparins, whereas cimetidine, a renal cation inhibitor, had no effect [16]. These findings suggest that renal excretion of UFH and LMWH primarily reflects tubular uptake via an organic anion transport mechanism.…”

Synthetic oligosaccharides can replace animal-sourced low–molecular weight heparins

“…This is likely due to an increased renal blood flow and glomerular filtration rate described in children and young adults with SCD as well as sickle cell mice (28, 29). Renal hyperfiltration in SCD increases proximal tubular transport, which is the dominant mechanism responsible for renal excretion of LMWH (38) and, most likely, excretion of 12-mer-1. Renal filtration in SCD normalizes with age or after the development of nephropathy and is reduced below normal as nephropathy progresses into overt renal failure.…”

RAGE Control of Diabetic Nephropathy in a Mouse Model

“…We observed that LMWH treatment could inhibit AGE-induced TGF-␤ upregulation in cultured mesangial cells from wild-type mice but not in those from RAGE-null mice (data not shown). As LMWH is also known to be cleared principally by the renal route (42), it may help facilitate the renoprotection from diabetic insult.…”