Welcome to Scribd, the world's digital library. Read, publish, and share books and documents. See more
Download
Standard view
Full view
of .
Save to My Library
Look up keyword
Like this
1Activity
0 of .
Results for:
No results containing your search query
P. 1
Kidney Diseases - VOLUME ONE - Chapter 15

Kidney Diseases - VOLUME ONE - Chapter 15

Ratings:

5.0

(1)
|Views: 54 |Likes:
Published by Firoz Reza
Chapters are from VOL 1 of Atlas of Kidney Diseases. There are more 4 VOLUME. To get other VOLUME log on to http://www.kidneyatlas.org
Chapters are from VOL 1 of Atlas of Kidney Diseases. There are more 4 VOLUME. To get other VOLUME log on to http://www.kidneyatlas.org

More info:

Categories:Types, School Work
Published by: Firoz Reza on Feb 24, 2009
Copyright:Attribution Non-commercial

Availability:

Read on Scribd mobile: iPhone, iPad and Android.
download as PDF or read online from Scribd
See more
See less

01/29/2013

 
1
Pathophysiology ofNephrotoxic AcuteRenal Failure
H
umans are exposed intentionally and unintentionally to avariety of diverse chemicals that harm the kidney. As the listof drugs, natural products, industrial chemicals and environ-mental pollutants that cause nephrotoxicity has increased, it hasbecome clear that chemicals with very diverse chemical structures pro-duce nephrotoxicity. For example, the heavy metal HgCl
2
, the myco-toxin fumonisin B
1
, the immunosuppresant cyclosporin A, and theaminoglycoside antibiotics all produce acute renal failure but are notstructurally related. Thus, it is not surprising that the cellular targetswithin the kidney and the mechanisms of cellular injury vary with dif-ferent toxicants. Nevertheless, there are similarities between chemical-induced acute tubular injury and ischemia/reperfusion injury.The tubular cells of the kidney are particularly vulnerable to toxi-cant-mediated injury due to their disproportionate exposure to circu-lating chemicals and transport processes that result in high intracellu-lar concentrations. It is generally thought that the parent chemical ora metabolite initiates toxicity through its covalent or noncovalentbinding to cellular macromolecules or through their ability to producereactive oxygen species. In either case the activity of the macromole-cule(s) is altered resulting in cell injury. For example, proteins andlipids in the plasma membrane, nucleus, lysosome, mitochondrion andcytosol are all targets of toxicants. If the toxicant causes oxidativestress both lipid peroxidation and protein oxidation have been shownto contribute to cell injury.In many cases mitochondria are a critical target and the lack of adenosine triphosphate (ATP) leads to cell injury due to the depen-dence of renal function on aerobic metabolism. The loss of ATP leads
Rick G. Schnellmann Katrina J. Kelly 
C H A PT ER
 
15.2
Acute Renal Failure
to disruption of cellular ion homeostasis with decreased cellularK
+
content, increased Na
+
content and membrane depolariza-tion. Increased cytosolic free Ca
2+
concentrations can occur inthe early or late phase of cell injury and plays a critical role lead-ing to cell death. The increase in Ca
2+
can activate calcium acti-vated neutral proteases (calpains) that appear to contribute tothe cell injury that occurs by a variety of toxicants. During thelate phase of cell injury, there is an increase in Cl
-
influx, fol-lowed by the influx of increasing larger molecules that leads tocell lysis. Two additional enzymes appear to play an importantrole in cell injury, particularly oxidative injury. Phospholipase A
2
consists of a family of enzymes in which the activity of thecytosolic form increases during oxidative injury and contributesto cell death. Caspases are a family of cysteine proteases that areactivated following oxidative injury and contribute to cell death.Following exposure to a chemical insult those cells sufficientlyinjured die by one of two mechanisms, apoptosis or oncosis.Clinically, a vast number of nephrotoxicants can produce avariety of clinical syndromes-acute renal failure, chronic renalfailure, nephrotic syndrome, hypertension and renal tubulardefects. The evolving understanding of the pathophysiology of toxicant-mediated renal injury has implications for potentialtherapies and preventive measures. This chapter outlines someof the mechanisms thought to be important in toxicant-mediat-ed renal cell injury and death that leads to the loss of tubularepithelial cells, tubular obstruction, “backleak” of the glomeru-lar filtrate and a decreased glomerular filtration rate. The recov-ery from the structural and functional damage following chemi-cal exposures is dependent on the repair of sublethally-injuredand regeneration of noninjured cells.
CLINICAL SIGNIFICANCE OFTOXICANT–MEDIATED RENAL FAILURE
Nephrotoxins may account for approximately 50%of all cases of acute and chronicrenal failure.Nephrotoxic renal injury often occurs in conjunction with ischemic acute renal failure.Acute renal failure may occur in 2%to 5%of hospitalized patients and 10%to 15%ofpatients in intensive care units.The mortality of acute renal failure is approximatley 50%which has not changedsignificantly in the last 40 years.Radiocontrast media and aminoglycosides are the most common agents associatedwith nephrotoxic injury in hospitalized patients.Aminoglycoside nephrotoxicity occurs in 5%to 15%of patients treated withthese drugs.
REASONSFOR THE KIDNEY’SSUSCEPTIBILITY TO TOXICANT INJURY
Receives 25%of the cardiac outputSensitive to vasoactive compoundsConcentrates toxicants through reabsorptive and secretive processesMany transporters result in high intracellular concentrationsLarge luminal membrane surface areaLarge biotransformation capacityBaseline medullary hypoxia
FIGURE 15-1
Clinical significance of toxicant-mediated renal failure.
FIGURE 15-2
Reasons for the kidney’s susceptibility to toxicant injury.
FACTORSTHAT PREDISPOSE THEKIDNEY TO TOXICANT INJURY
Preexisting renal dysfunctionDehydrationDiabetes mellitusExposure to multiple nephrotoxins
FIGURE 15-3
Factors that predispose the kidney to toxicant injury.
Clinical Significance of Toxicant-MediatedAcute Renal Failure
 
15.3
Pathophysiology of Nephrotoxic Acute Renal Failure
EXOGENOUSAND ENDOGENOUSCHEMICALSTHAT CAUSE ACUTE RENAL FAILURE
AntibioticsAminoglycosides (gentamicin, tobramycin,amikacin, netilmicin)Amphotericin BCephalosporinsCiprofloxacinDemeclocyclinePenicillinsPentamidinePolymixinsRifampinSulfonamidesTetracyclineVancomycinChemotherapeutic agentsAdriamycinCisplatinMethotraxateMitomycin CNitrosoureas(
eg
, streptozotocin, Iomustine)Radiocontrast mediaIonic (
eg
, diatrizoate, iothalamate)Nonionic (
eg
, metrizamide)Immunosuppressive agentsCyclosporin ATacrolimus (FK 506)Antiviral agentsAcyclovirCidovirFoscarnetValacyclovirHeavy metalsCadmiumGoldMercuryLeadArsenicBismuthUraniumOrganic solventsEthylene glycolCarbon tetrachlorideUnleaded gasolineVasoactive agentsNonsteroidal anti-inflammatorydrugs (NSAIDs)IbuprofenNaproxenIndomethacinMeclofenemateAspirinPiroxicamAngiotensin-convertingenzyme inhibitorsCaptoprilEnaloprilLisinoprilAngiotensin receptor antagonistsLosartanOther drugsAcetaminophenHalothaneMethoxyfluraneCimetidineHydralazineLithiumLovastatinMannitolPenicillamineProcainamideThiazidesLindaneEndogenous compoundsMyoglobinHemoglobinCalciumUric acidOxalateCystine
FIGURE 15-4
Exogenous and endogenous chemicals that cause acute renal failure.
Renal vesselsNSAIDsACEinhibitorsCyclosporin AProximal convoluted tubule(S1/S2 segments)AminoglycosidesCephaloridineCadmium chloridePotassium dichromateProximal straight tubule(S3 segment)CisplatinMercuric chlorideDichlorovinyl– 
L
 –cysteineGlomeruliInterferon– 
α
GoldPenicillaminePapillaePhenacetinInterstitiumCephalosporinsCadmiumNSAIDs
FIGURE 15-5
Nephrotoxicants may act at different sites in the kidney, resultingin 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 functionand result in proteinuria and decreased renal function. Manynephrotoxicants damage tubular epithelial cells directly.Aminoglycosides, cephaloridine, cadmium chloride, and potassiumdichromate affect the S1 and S2 segments of the proximal tubule,whereas cisplatin, mercuric chloride, and dichlorovinyl-L-cysteineaffect the S3 segment of the proximal tubule. Cephalosporins, cad-mium chloride, and NSAIDs cause interstitial nephritis whereasphenacetin causes renal papillary necrosis.

You're Reading a Free Preview

Download
/*********** DO NOT ALTER ANYTHING BELOW THIS LINE ! ************/ var s_code=s.t();if(s_code)document.write(s_code)//-->