Exogenous And Endogenous Chemicals That Cause Acute Renal Failure

Antibiotics

Immunosuppressive agents

Vasoactive agents

Other drugs

Aminoglycosides (gentamicin, tobramycin,

Cyclosporin A

Nonsteroidal anti-inflammatory

Acetaminophen

amikacin, netilmicin)

Tacrolimus (FK 506)

drugs (NSAIDs)

Halothane

Amphotericin B

Antiviral agents

Ibuprofen

Methoxyflurane

Cephalosporins

Acyclovir

Naproxen

Cimetidine

Ciprofloxacin

Cidovir

Indomethacin

Hydralazine

Demeclocycline

Foscarnet

Meclofenemate

Lithium

Penicillins

Valacyclovir

Aspirin

Lovastatin

Pentamidine

Heavy metals

Piroxicam

Mannitol

Polymixins

Cadmium

Angiotensin-converting

Penicillamine

Rifampin

Gold

enzyme inhibitors

Procainamide

Sulfonamides

Mercury

Captopril

Thiazides

Tetracycline

Lead

Enalopril

Lindane

Vancomycin

Arsenic

Lisinopril

Endogenous compounds

Chemotherapeutic agents

Bismuth

Angiotensin receptor antagonists

Myoglobin

Adriamycin

Uranium

Losartan

Hemoglobin

Cisplatin

Organic solvents

Calcium

Methotraxate

Ethylene glycol

Uric acid

Mitomycin C

Carbon tetrachloride

Oxalate

Nitrosoureas

Unleaded gasoline

Cystine

(eg, streptozotocin, lomustine)

Radiocontrast media

Ionic (eg, diatrizoate, iothalamate)

Nonionic (eg, metrizamide)

Exogenous and endogenous chemicals that cause acute renal failure.

Papillae

Phenacetin

Renal vessels NSAIDs ACE inhibitors Cyclosporin A

Cadmium Tubule Nal

Interstitium

Cephalosporins Cadmium NSAIDs

Proximal convoluted tubule (S1/S2 segments) Aminoglycosides Cephaloridine Cadmium chloride Potassium dichromate

Renal vessels NSAIDs ACE inhibitors Cyclosporin A

Glomeruli

Interferon-a Gold

Penicillamine

Proximal straight tubule (S3 segment) Cisplatin

Mercuric chloride Dichlorovinyl-L-cysteine

Interstitium

Cephalosporins Cadmium NSAIDs

FIGURE 15-5

Nephrotoxicants may act at different sites in the kidney, resulting in altered renal function. The sites of injury by selected nephrotoxi-cants are shown. Nonsteroidal anti-inflammatory drugs (NSAIDs), angiotensin-converting enzyme (ACE) inhibitors, cyclosporin A, and radiographic contrast media cause vasoconstriction. Gold, interferon-alpha, and penicillamine can alter glomerular function and result in proteinuria and decreased renal function. Many nephrotoxicants damage tubular epithelial cells directly. Aminoglycosides, cephaloridine, cadmium chloride, and potassium dichromate affect the S1 and S2 segments of the proximal tubule, whereas cisplatin, mercuric chloride, and dichlorovinyl-L-cysteine affect the S3 segment of the proximal tubule. Cephalosporins, cadmium chloride, and NSAIDs cause interstitial nephritis whereas phenacetin causes renal papillary necrosis.

Renal vasoconstriction [

=£> Prerenal azotemia

n

E

e

x

p

p

h

o

r

s

o

t

u

r

o

e

x i

t

c

o

a

n

t

^Increased tubular pressure

} Tubular obstruction "Back-leak" of glomerular filtrate

Intratubular Functional casts abnormalties

Tubular damage

IntrarenTi factors Persistent medullary hypoxia

Physical constriction * of medullary vessels

Hemodynamic « I Glomerular alterations hydrostatic

^^ pressure

Intrarenal ^

vasoconstriction I Perfusion pressure ^vj \ Efferent tone

Glomerular factors \

\ Afferent tone

\ Afferent tone

Obstruction i

I Glomerular ultrafiltration

Postrenal failure

FIGURE 15-6

I Intravascular volume t Capillary permeability

t Sympathetic tone

Endothelial injury y>

t Endothelin I Nitric oxide t Thromboxane I Prostaglandins

Hypertension

Renal and systemic I vasoconstriction I

t Vascular smooth muscle sensitivity to vasoconstrictors

Cyclosporin A ! Angiotensin iz

Striped interstitial fibrosis

Tubular cell injury r

Striped interstitial fibrosis

Mechanisms that contribute to decreased glomerular filtration rate (GFR) in acute renal failure. After exposure to a nephrotoxicant, one or more mechanisms may contribute to a reduction in the GFR. These include renal vasoconstriction resulting in prerenal azotemia (eg, cyclosporin A) and obstruction due to precipitation of a drug or endogenous substances within the kidney or collecting ducts (eg, methotrexate). Intrarenal factors include direct tubular obstruction and dysfunction resulting in tubular backleak and increased tubular pressure. Alterations in the levels of a variety of vasoactive mediators (eg, prostaglandins following treatment with nonsteroidal anti-inflammatory drugs) may result in decreased renal perfusion pressure or efferent arteriolar tone and increased afferent arteriolar tone, resulting in decreased in glomerular hydrostatic pressure. Some nephrotoxicants may decrease glomerular function, leading to proteinuria and decreased renal function.

FIGURE 15-7

Renal injury from exposure to cyclosporin A. Cyclosporin A is one example of a toxicant that acts at several sites within the kidney. It can injure both endothelial and tubular cells. Endothelial injury results in increased vascular permeability and hypovolemia, which activates the sympathetic nervous system. Injury to the endotheli-um also results in increases in endothelin and thromboxane A2 and decreases in nitric oxide and vasodilatory prostaglandins. Finally, cyclosporin A may increase the sensitivity of the vascula-ture to vasoconstrictors, activate the renin-angiotensin system, and increase angiotensin II levels. All of these changes lead to vasoconstriction and hypertension. Vasoconstriction in the kidney contributes to the decrease in glomerular filtration rate (GFR), and the histologic changes in the kidney are the result of local ischemia and hypertension.

FIGURE 15-8

The nephron's response to a nephrotoxic insult. After a population of cells are exposed to a nephrotoxicant, the cells respond and ultimately the nephron recovers function or, if cell death and loss is extensive, nephron function ceases. Terminally injured cells undergo cell death through oncosis or apoptosis. Cells injured sublethal-ly undergo repair and adaptation (eg, stress response) in response to the nephrotoxicant. Cells not injured and adjacent to the injured area may undergo dedifferentiation, proliferation, migration or spreading, and differentiation. Cells that were not injured may also undergo compensatory hypertrophy in response to the cell loss and injury. Finally the uninjured cells may also undergo adaptation in response to nephrotoxicant exposure.

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    What is exogenous cause in kidney disease?
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