Objectives of this lecture are to:

1. General ToxicologyToxic Responses of the KidneyLec. 104th Year2017-2018University of Mustansiriyah/College of PharmacyDepartment of Pharmacology & ToxicologyLecturer: Rua Abbas Al-Hamdy

2. Objectives of this lecture are to: • determine the mechanism of toxicity & the nephrotoxic effects of two examples of halogenated hydrocarbons. • determine the mechanism of toxicity & the nephrotoxic effects caused by some therapeutic agents.

3. Halogenated hydrocarbons: Halogenate hydrocarbons are a diverse class of compounds & are used extensively as chemical intermediates, solvents, & pesticides. Consequently, humans are exposed to these compounds not only in the workplace but also through the environment.

4. Chloroform: • The primary cellular target is the proximal tubule, with no primary damage to the glomerulus or the distal tubule. • Proteinuria, glucosuria, & increased BUN levels are all characteristic of chloroform-induced nephrotoxicity. • The nephrotoxicity produced by chloroform is linked to its metabolism by renal cytochrome P450, which biotransforms chloroform to trichloromethanol, which is unstable & releases HCl to form phosgene which injuriously reacts with cellular macromolecules.

5. Tetrafluoroethylene: • Tetrafluoroethyleneis conjugated with glutathione in the liver. • The GSH conjugate is secreted into the bile & small intestine where it is degraded to the cysteine S-conjugate, reabsorbed & transported to the kidney. Although several metabolites are formed , the cysteine S-conjugate is the penultimate nephrotoxicant.

6. Following transport into the proximal tubule, which is the primary cellular target for haloalkenes, the cysteine S-conjugate is a substrate for the cytosolic & mitochondrial forms of the enzyme cysteine conjugate β-lyase. • The products of the reaction are ammonia, pyruvate, & a reactive thiol that is capable of binding covalently to cellular macromolecules causing cellular damage.

7. The nephrotoxicity produced by haloalkenes is characterized morphologically by proximal tubular necrosis, primarily affecting the S3segment, & functionally by increases in urinary glucose, protein, cellular enzymes, & BUN.

8. Therapeutic agents: Acetaminophen: Large doses of acetaminophen [acetyl-para-aminophenol (APAP)] are commonly associated with hepatoxicity. However, large doses of APAP can also cause nephrotoxicity in humans & animals.

9. APAP nephrotoxicity is characterized by: • proximal tubular necrosis with increases in BUN & plasma creatinine; • decreases in glomerular filtration rate (GFR) & clearance of para-aminohippurate (PAH); • increases in the fractional excretion of water, sodium, potassium; & • increases in urinary glucose, protein, & brush-border enzymes.

10. There appears to be a marked species difference in the nature & mechanism of APAP nephrotoxicity. • Morphologically, the primary targets in the mouse kidney are the S1& S2segments of the proximal tubule, whereas in the rat kidney the S3segment is the target. • In the mouse, renal cytochrome P4502E1 has been associated with APAP biotransformation to a reactive intermediate, N-acety-p-amino-benzoquinoneimine (NAPQI), that arylates proteins in the proximal tubule & initiates cell death.

11. Although renal cytochrome P450 plays a role in APAP activation & nephrotoxicity, glutathione conjugates of APAP may also contribute to APAP nephrotoxicity.

12. Nonsteroidal anti-inflammatory drugs (NSAIDs): • NSAIDs such as aspirin, ibuproen, indomethacin, & cyclooxygenase-2 inhibitors (e.g., celecoxib) are extensively used as analgesics & anti-inflammatory drugs. • At least three different types of nephrotoxicity have been associated with NSAID administration, which are: • acute kidney injury (AKI) • analgesic nephropathy • interstitial nephritis

13. Acute kidney injury (AKI): • It may occur within hours of a large dose of a NSAID, usually reversible upon withdrawal of the drug, & is characterized by decreased renal blood flow (RBF) & GFR & by oliguria. • When the normal production of vasodilatory prostaglandins (eg, PGE 2 , PGI 2) is inhibited by NSAIDs, vasoconstriction induced by circulating catecholamines & angiotensin II is unopposed, resulting in decreased RBF & ischemia.

14. A number of risk factors (eg, renal insufficiency, congestive heart failure, hemorrhage, hypertension) are known to facilitate the development of AKI following NSAIDs consumption.

15. Analgesic nephropathy: • Chronic consumption of combinations of NSAIDs &/or APAP (>3 years) results in an often irreversible form of nephrotoxicity known as analgesic nephropathy. • Impaired urinary concentration & acidification are the earliest clinical manifestations. • The primary lesion in this nephropathy is papillary necrosis with chronic interstitial nephritis.

16. interstitial nephritis: • The third, even though rare, type of nephrotoxicity associated with NSAIDs is an interstitial nephritis with a mean time of NSAID exposure to development of approximately five months. • This nephrotoxicity is characterized by a diffuse interstitial edema with mild-to-moderate infiltration of inflammatory cells. Patients normally present with elevated serum creatinine, proteinuria, & nephritic syndrome. • If NSAIDs are discontinued, renal function improves in one to three months.

17. Aminoglycosides: • The incidence of renal dysfunction following aminoglycoside administration ranges from 0% to 50%, but seldom leads to a fatal outcome. • Renal dysfunction by aminoglycosides is characterized by a nonoliguric renal failure with reduced GFR & an increase in serum creatinine & BUN. • Polyuria is an early event following aminoglycoside administration & may be due to inhibition of chloride transport in the thick ascending limb.

18. Within 24 hours, increases in urinary brush-border enzymes, glucosuria, aminoaciduria, & proteinuria are observed. • Histologically, there is damage to the brush border, endoplasmic reticulum, mitochondria, & cytoplasm, ultimately leading to tubular cell necrosis. • The earliest lesion observed following clinically relevant doses of aminoglycosides is an increase in the size & number of lysosomes, which contain phospholipids.

19. The renal phospholipidosis produced by the aminoglycosides is thought to occur through their inhibition of lysosomal hydrolases, such as sphingomyelinase & phospholipases.

20. Amphotericin B: • Amphotericin B is a very effective antifungal agent whose clinical utility is limited by its nephrotoxicity. • With respect to hemodynamics, Amphotericin B administration is associated with decreases in RBF & GFR. • Amphotericin B nephrotoxicity is characterized by anti-diuretic hormone (ADH)-resistant polyuria, renal tubular acidosis, hypokalemia, & either acute or chronic renal failure. • Amphotericin B nephrotoxicity is unusual in that it impairs the functional integrity of the glomerulus & of the proximal & distal portions of the nephron.

21. Cyclosporine: • Cyclosporine is an important immunosuppressive agent & is widely used to prevent graft rejection in organ transplantation. • Nephrotoxicity is a critical side effect of cyclosporine, with nearly all patients who receive the drug exhibiting some form of nephrotoxicity. • Clinically, calcineurin inhibitor (CNI)-induced nephrotoxicity may manifest as: • acute reversible renal dysfunction, • acute vasculopathy, & • chronic CNI nephrotoxicity with interstitial fibrosis.

22. Acute renal dysfunction is characterized by dose- related decreases in RBF & GFR & increases in BUN & serum creatinine. The decrease in RBF & GFR is related to marked vasoconstriction induced by cyclosporine. • Acute vasculopathy or thrombotic microangiopathy following cyclosporine treatment affects arterioles & glomerular capillaries, without an inflammatory component. The lesion consists of fibrin–platelet thrombi & fragmented red blood cells occluding the vessels.

23. Long-term treatment with cyclosporine can result in chronic nephropathy with interstitial fibrosis & tubular atrophy. Histologic changes are profound ; they are characterized by arteriolopathy, global & segmental glomerular sclerosis, striped interstitial fibrosis, & tubular atrophy. These lesions may not be reversible if cyclosporine therapy is discontinued & may result in end-stage renal disease.

24. Cisplatin: • Cisplatin is a valuable drug in the treatment of solid tumors, with nephrotoxicity limiting its clinical use. • The kidney is not only responsible for the majority of cisplatin excreted but is also the primary site of accumulation. • Cisplatin nephrotoxicity includes acute & chronic renal failure, renal magnesium wasting, & polyuria. • Patients treated with cisplatin regimens permanently lose 10% to 30% of their renal function.

25. The nephrotoxicity of cisplatin can be grouped as: • tubular toxicity, • vascular damage, • glomerular injury, & • interstitial injury. • Early effects of cisplatin are decreases in RBF & polyuria that is concurrent with increased electrolyte excretion. • Although the primary cellular target associated with AKI is the proximal tubule S3segment in the rat, in humans the S1& S2segments, distal tubule, & collecting ducts can also be affected.

26. Interestingly, the trans isomer of cisplatin is not nephrotoxic even though similar concentrations of platinum are observed in the kidney after dosing. Thus, it is not the platinum atom per se that is responsible for the toxicity but rather the geometry of the complex or a metabolite. • Cisplatin may produce nephrotoxicity through its ability to inhibit DNA synthesis as well as transport functions. In addition, cisplatin is known to induce mitochondrial dysunction.

27. Radiocontrast agents: • Iodinated contrast media used for the imaging of tissues have a very high osmolality (> 1200 mOsm/L) & are potentially nephrotoxic, particularly in patients with existing renal impairment, diabetes, or heart failure or who are receiving other nephrotoxic drugs. • The newer nonionic contrast agents (e.g., iotrol & iopamidol) have lower nephrotoxicity. • The nephrotoxicity of these agents is due to both hemodynamic alterations (vasoconstriction) & tubular injury (via ROS).