J)O-0H ^-O-GlucT ^ -O-O-Gluc

ABC carrier/"] e.g. MRP1.3 |

'Phase 4 c:z_?

capillary basolateral luminal urine membrane membrane or bile

Figure 1. Schematic principle of vectorial drug evasion in liver and kidney. Phase 0 = drug uptake out of blood, Phases 1 and 2 = biotransformation exemplified by hydroxylation andglu-curonidation, Phase 3 = transport of xenobiotics/metabolites towards excretion, Phase 4 = efflux into excreted fluids and/or backward into blood. Adapted with permission from [43].

tribute to drug nephrotoxicities, reside in the proximal tubule. These transporters are involved in both secretion and reabsorption and share properties with hepatic drug transporters. Five different drug transport families have been identified in human kidneys [44]. Organic anion transporters (OATs) are present in both the brush border and basolateral membrane of the proximal tubule. Among the drugs transported by OATs are PAH, methotrexate, NSAIDs and antiviral nucleoside analogues. This is the transporter with affinity for ochratoxin A. P-glycoprotein (P-gp), better knows as multi-drug resistant transporter (MDR) , is located on the brush border of the proximal tubule and acts as an efflux transporter of drugs. Substrates for P-gp include anticancer drugs such as vincristine, vinblastine and doxorubicin, cyclosporine, verapamil, digoxin and steroids including aldosterone. Peptide transporters (PEPT1, PEPT2) ) are localized to the brush border of the proximal tubule where they facilitate the uptake of p-lactams, ACE inhibitors, and valacyclovir. Organic Cation Transporters (OCTs) ) are localized in the basolateral membrane of the proximal tubule and are primarily involved in tubular secretion. In addition to tetraethyl ammonium (TEA), other substrates for the OCTs include cimetidine, choline, dopamine, acyclovir and zidovudine. OCTN is a novel organic cation transporter which is located in the brush border of the proximal tubule. While OCTN1 accepts a variety of drugs, cephaloridine, verapamil, quinidine and TEA, its exact role in either reabsorption or secretion remains to be define. PEPT1 is an example is the organic ion transport system, which is instrumental in the intracellular accumulation of nephrotoxic cepha-losporin's due to the lower transport capacity of the luminal membrane when compared to the basolateral membrane [45]. Another way in which proximal tubular transport is implicated in nephrotoxicity involves glutathione S-conjugates of xenobiotics, a phase 2 reaction. Once transported into the cell, these xenobiotic conjugates undergo biotransformation to electrophils, which then bind to macrophilic sites of intracellular macromolecules such as DNA. An example is tris (2, 3 dibromopropyl) phosphate, which undergoes metabolic activation and eventually covalently binds to DNA [46]. Other examples are cadmium-metal-lothionein complexes which are formed in the liver but eventually are filtered by the kidneys where they are reabsorbed in the proximal tubule by the same proc ess as other low molecular weight proteins. Following lysosomal uptake, metallothionein production is stimulated, but once saturated; the inorganic cadmium is released within the renal cell causing cell death [47]. In a similar manner, aminoglycoside antibiotics, due to their cationic charge, attach to the proximal tubular membrane where they undergo pinocytotic uptake and accumulate within the cell inducing phospholipidosis, which leads to mitochondrial damage and cell death [48]. For more distal portions of the nephron, passive concentration of xenobiotics can occur due to the physiologic concentrating mechanism that provides a favorable gradient for the xenobiotic to undergo backdiffusion into the papillary region of the kidneys [42].

Another aspect of renal function, which contributes to drug nephrotoxicity, involves the renal enzyme systems that play key roles in maintaining body homeosta-sis. The flame retardant tris, which enters the proximal tubular cell conjugated with glutathione, undergoes bioactivation by glutathione-S-transferase resulting in reactive episulfonium ions that can cause cell death [46]. While the P-450 system of the liver is more abundant, substantial sex-linked renal P-450 activity causing bioactivation of xenobiotics has been documented in animals [42]. A similar role in human nephrotoxicity has yet to be established. However, medullary pros-taglandin synthetase has been assigned a prominent role in analgesic nephropathy where it is hypothesized to co-oxidize acetaminophen to N-acetyl-p-benzoqui-noneimine that then arylates cellular macromolecules to cause cell death [49]. Thus, the unique role of the kidneys in regulating body solute and water content, also make them targets for nephrotoxic drugs.

It is worth emphasizing that the same drug is capable of inducing several types of renal injury, e.g. NSAIDs may lead to intrarenal hemodynamic disturbances as well as to acute tubular necrosis, acute interstitial nephritis with or without nephrotic syndrome, and sometimes to various glomerular and arteriolar diseases [50,51].

Traditionally, when searching for the etiology of AKI, the clinician's will subdivides the potential causes of a sudden decline of GFR into one of three general pathophysiologic processes: pre renal failure, intrare-nal failure or post renal failure [1]. Recently, Miet et al [ 52] in discussing drug-induce acute kidney injury detailed two additional mechanisms that need to be considered in addition to those outlined in Table 2.

The 8 mechanisms recognized as causing drug induced

AKI include:

1. Vasoconstriction: Two of the most common drugs which induce AKI are calcineurin inhibitors and contrast agents, both involve significant renal vasoconstriction. In addition, amphotericin also share this mechanism.

2. Altered intraglomerular hemodynamics: This mechanism is also responsible for two of the most common drugs which induce AKI, inhibitors of Renin-Angiotensin System and Non-steroidal Anti-inflammatory drugs. Recently, Huerta et al [53] reported a nested case-control study involving almost 400,000 patients. Their analysis indicated that NSAID users had a 3-fold greater risk of developing AKI compared to non-users. Risk factors that were important included hypertension and heart failure.

3. Tubular cell toxicity: This involves the cellular transport systems mentioned previously and is thus dose dependent to a degree. Examples of tubular cell toxins include: aminoglycosides, calcineurin inhibitors, amphotericin, antiviral agents, cisplatin, methotrexate, contrast agents and cocaine.

4. Interstitial nephritis: This is immunologically mediated event involving the activation of cytokines and is non-dose dependent. Examples include several antibiotics, NSAIDs, diuretics, anticonvulsants and a variety of other drugs [54]. Acute interstitial nephritis is increasingly being recognized as a cause of drug-induced AKI [56, 58-61]. Over 100 drugs have been implicated in kidney-related hypersensitivity reactions [62], the most common being listed on Table 3. For the other drugs, the number of cases reported is low and often anecdotal. In humans, cell-mediated immunity is probably involved with most cases of drug-induced acute interstitial nephritis [62].The true incidence of acute interstitial nephritis is difficult to assess since renal biopsy is needed for definitive diagnosis [56, 62]. In a series of 976 patients presenting with AKI, renal biopsy was done in 218 cases for diagnostic purposes; drug-induced interstitial nephritis was found in only 8 patients, i.e. 0.8% of all cases of AKI [58]. A similar frequency was found in the French collaborative study [11]. The proportion of patients with interstitial nephritis is higher in biopsied AKI patients, ranging from 2.5% [60] to 8.3% [55] to 54%

Table 2. Classification of various drugs based on pathophysiologic categories of acute kidney injury.

1. Vasoconstriction/altered intraglomerular hemodynamics (prerenal failure)

NSAIDs, ACE-inhibitors, cyclosporine, norepinephrine, angiotensin receptor blockers, diuretics, interleukins, cocaine, mitomycin C, Tacrolimus, Estrogen, quinine.

2. Tubular cell toxicity (acute tubular necrosis)

Antibiotics: aminoglycosides, cephaloridine, cephalothin, amphotericin B, rifampicin, vancomycin, foscarnet, pentamidine. NSAIDs, glafenin, contrast media, acetaminophen, cyclosporine, cisplatin, mannitol, heavy metals.

3. Acute interstitial nephritis

Antibiotics: ciprofloxacin, methicillin, penicillin G, ampicillin, cephalothin, oxacillin, rifampicin.

NSAIDs, glafenin, ASA, fenoprofen, naproxen, phenylbutazone, piroxacam, tolemetin, zomepirac, contrast media, sulfonamides, thiazides, phenytoin, furosemide, allopurinol, cimetidine, omeprazole, phenindione.

4. Tubular obstruction

Sulfonamides, methotrexate, methoxyflurane, glafenin, triamterene, ticrynafen, acyclovir, ethylene glycol, protease inhibitors, cidoforvir, adeforvia.

5. Hypersensitivity angiitis

Penicillin G, ampicillin, sulfonamides, methamphetamine.

6. Thrombotic microangiopathy

Mitomycin C, cyclosporine, oral contraceptives, ticidipine, clopidogrd, cocaine.

7. Osmotic Nephrosis

Immunoglobulins, dextrans, starches, maltose and sucrose

8. Rhabdomyolysis

Statins, cocaine, methamphetamines, heroin.

Table 3. Outcome of drug-induced acute interstitial nephritis with and without granulomas (modified from ref. [61]).
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