ALTERED ELIMINATION IN CHRONIC RENAL FAILURE

Altered Elimination in Chronic Renal Failure

Altered Elimination in Chronic Renal Failure

The progression of chronicrenalfailure (CRF) is characterized by the development of glomerular and tubular lesions about which multiple factors can be involved . Regarding renal tubules, numerous studies have been performed to understand the pathological process , but it is less known about changes in tubular function. In the experimental model of subtotal nephrectomy, functional tubular changes and elevated filtration rate per remaining nephron are expected because of compensatory renal hypertrophy . The increase per nephron of several tubular activities is proof of it . Some authors have provided evidences that tubular dysfunction occurs in CRF , and . It has been demonstrated that CRF induced a reduction in the expression and/or activity of several enzymes located in brush-border membranes and of type II Na-Pi cotransporter . Other studies have also reported reduced expression per cellular unit of other enzymes or transporters present in the proximal and distal parts of the nephron. (Nagai and Inui 2007)

The tubular secretion of organic anions is an important function of the kidney by eliminating potentially toxic organic anions from the body . A number of drugs, such as ß-lactamic antibiotics, diuretics, nonsteroidal anti-inflammatory drugs, and several antiviral drugs are also classified as organic anions, therefore, the renal organic anion transport system plays a key role in the pharmacokinetics of these drugs . Organic anions are taken up from the peritubular plasma across the basolateral membrane and effluxed into the tubular fluid across the luminal membrane. The systems involved in organic anion secretion can be functionally subdivided in the well-characterized sodium-dependent p-aminohippurate (PAH) system and a recently discovered sodium independent system. Both systems mediate two membrane translocation steps arranged in series: uptake from blood across the basolateral membrane of renal epithelial cells, followed by efflux into urine across the apical membrane. A lot of organic anions transporters have been recently cloned. Among them, there were the organic anion transporter 1 (OAT1) and the organic anion transporter 3 (OAT3), which are considered the principal contributors to the classical renal organic anion secretory process , , and . Both OAT1 and OAT3 support OA/a-KG exchange . PAH is a substrate for both rodent and human orthologs of OAT1 and OAT3 , , and . In the apical membrane, multidrug resistance protein 2 (MRP2) has been described as one of PAH transporters and . Recently, multidrug resistance protein 4 (MRP4) has been identified as a novel PAH transporter . Organic anion transporters k1 and k2 (OAT-K1 and OAT-K2) are also present in luminal membrane of proximal tubule, but they do not transport PAH . The functional and molecular changes in these organic ion transporters would result in impaired renal excretion of drugs, thereby causing unexpected adverse effects of administered ionic drugs. (Mathias and Portale 2010)

Whether drug secretion by renal tubules is modified in CRF is questioned because of frequent accumulation of various toxins in ...