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Toxic Responses of the Kidney

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Kidney: Functions, Injury, Detection, and Response

Kidney - Functions

Removal and Excretion of toxic metabolic waste

from blood

Regulation of homeostasis of organism

Elimination/conservation of water and

electrolytes

Hormonal functions: renin production (regulation

of blood pressure)

erthropoietin production (regulation of Hb synthesis

Vit. D (1,25 dihydroxycholecalciferol) formation

Parathyroid hormone metabolism – Ca2+

regulation D TA

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Acute Kidney InjuryOne of the most common manifestations ofnephrotoxic damage is acute renal failure (ARF)or acute kidney injury (AKI).AKI is characterized by an abrupt decline in GFRwith resulting azotemia, or a build up ofnitrogenous wastes in the blood .AKI describes the entire spectrum of the diseasean is defined as a complex disorder thatcomprises multiple causative factors with clinicalmanifestations ranging from minimal elevation inserum creatinine to anuric renal failure.

Adaptation Following Toxic InsultThe kidney has a remarkable ability to compensate ora loss in renal functional mass. Following a unilateralnephrectomy, GFR of the remnant kidney increasesby approximately 40% to 60%. Compensatoryincreases in single-nephron GFR are accompanied byproportionate increases in proximal tubular waterand solute reabsorption; glomerulotubular balance(i.e., constant fractional reabsorption of GFR by allsegments of the nephron) is therefore maintained anoverall renal function.Chemically induce changes in renal function may notbe detected until these compensatory mechanisms areoverwhelmed by significant nephron loss and /ordamage.

Abnormal findings

Azotemia: BUN, creatinine

Uremia: azotemia

Acute renal failure: oliguria

Chronic renal failure: prolonged

uremia

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Glomerular diseases

• Minimal change disease• Focal segmental

glomerulosclerosis• Membranous

nephropathy

Post-infectious

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Specificity of Renal Injury

➢ Various nephrotoxicants cause site-

selective injury

➢ Mechanistic Basis

• Complex

• Blood flow

• Transport mechanisms

• Biotransformation capability of various

regions

• Physicochemical properties of

chemicals

• Specific functions of the cells in regionD TA

Detection of Renal Toxicity – Endpoints/Biomarkers

Symptoms

• Acute Renal Failure

Alterations in excretion of wastes

• Glomerular filtration rate

• Use of inulin (5,200 mwt polymer)

• Renal plasma flow

• Some organic acids (complete removal from plasma)

• Additional tests pH, volume, glucose, salts (Na, K)

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RENAL FAILURE

• Results when the kidneys cannot remove the

body’s metabolic wastes or perform their

regulatory functions. The substances normally

eliminated in the urine accumulate in the body

fluids as a result of impaired renal excretion,

leading to a disruption in endocrine and

metabolic functions as well as fluid, electrolyte,

and acid-base disturbances.

• It is a systemic disease and is a final common

pathway of many different kidney and urinary

tract diseasesD TA

ACUTE RENAL FAILURE

- Is a reversible clinical syndrome where there is a

sudden and almost complete loss of kidney function

(decreased GFR) over a period of hours to days with

failure to excrete nitrogenous waste products and to

maintain fluid and electrolyte homeostasis.

- ARF manifests as an increase in serum creatinine

(M=53-132umol/L; F=44-97umol/L) and BUN (7-

20mg/dl).

Urine volume may be normal, or changes may occur.

Possible changes include oliguria (<400ml/day),

nonoliguria (>400ml/ day), or anuria (<50 ml/day)D TA

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ACUTE INTERSTITIAL NEPHRITISDRUG INDUCED

PENICILLINS

SULFONAMIDES

CEPHALOSPORIN

RIFAMPIN ( 2ND TIME)

QUINOLONES

NSAID (FENOPROFEN)

ALLOPURINOL

PHENYTOIN

THIAZIDES

FUROSEMIDE

CIMETIDINE D TA

FeverRashEosinophiliaPyuriaEosinophiluriaWBC Casts

RENAL --ACUTE RENAL FAILURE

ACUTE TUBULAR NECROSIS

ISCHEMIC INJURY

TOXIC INJURY

ENDOGENOUS TOXINS

HEMOGLOBINURIA

RHABDOMYOLYSIS

ENDOTOXEMIA

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EXOGENOUS TOXINS

AMINOGLYCOSIDES

RADIOGRAPHIC CONTRAST

HEAVY METAL COMPOUNDS

ETHYLENE GLYCOL

METHANOL

CARBON TETRACHLORIDE

CISPLATIN

Treatment of ARF

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SUSCEPTIBILITY OF THE RENAL SYSTEM

Several factors are involved in the sensitivity of the

kidney to a number of toxicants, the high renal blood

flow and the increased concentration of excretory

products following reabsorption of water from the

tubular fluid are clearly of major importance.

Although the kidneys comprise less than 1% of the

body mass, they receive around 25% of the cardiac

output. Thus, significant amounts of exogenous

chemicals and/or their metabolites are delivered to

the kidney.D TA

SUSCEPTIBILITY OF THE KIDNEYTO TOXIC INJURY

• Incidence and Severity of ToxicNephropathy

• Site-Selective Injury• Glomerular Injury• Proximal Tubular Injury• Loop of Henle/Distal Tubule/Collecting

Duct Injury• Papillary Injury

BIOCHEMICAL MECHANISMS/MEDIATORS OF RENAL CELL INJURY

Cell Death: Cell death may occur througheither necrosis or apoptosis.Apoptosis is a tightly controlled , organizeprocess that usually affects scatteredindividual cells, which break into smallfragments that are phagocytose by adjacentcells or macrophages without producing aninflammatory response.

Mediators of Toxicity

A chemical can initiate cell injury by variousmechanisms. The chemical may initiate toxicity dueto its intrinsic reactivity with cellularmacromolecules, may require renal or extrarenalbioactivation to a reactive intermediate, or mayinitiate injury in directly by inducing oxidative stressvia increase production of ROS, such as superoxideanion, hydrogen peroxide, and hydroxyl radicals.

ROS and reactive nitrogen species from nitric oxide,such as peroxynitrite (ONOO− ), can attack proteins,lipids, an DNA to induce cellular injury and death.

A second important factor affecting the kidneys

sensitivity to chemicals is its ability to concentrate the

tubular fluid and, as a consequence, as water and salts

are removed, to concentrate any chemicals it contains.

Thus, a nontoxic concentration in the plasma may

be converted to one that is toxic in the tubular fluid.

The transport characteristics of the renal tubules also

contribute to the delivery of potentially toxic

concentrations of chemicals to the cells.

If a chemical is actively secreted from the blood into

the tubular fluid, it will accumulate initially within the

cells of the proximal tubule or, if it is reabsorbed from

the tubular fluid, it will pass into the cells in relatively

high concentration. D TA

The biotransformation of chemicals to

reactive, and thus potentially toxic, metabolites

is a key feature of nephrotoxicity.

Many of the same activation reactions found in

the liver are also found in the kidney and many

toxicants can be activated in either organ,

including acetaminophen, bromobenzene,

chloroform, and carbon tetrachloride, thus

having potential for either hepatotoxicity or

nephrotoxicity.

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As with toxicity in other organs the

ultimate expression of a toxic end point

is the result of a balance between the

generation of reactive metabolites and

their detoxication.

The high levels of glutathione found in

the kidney doubtless play an important

role in the detoxication process.

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Kidney (nephro) ToxicantsMetals

Cadmium

Mercury

lead

Halogenated Hydrocarbons

CCl4

Chloroform

Methoxyflurane (surgical anesthetic)

Perchlorethylene

Other Chemicals

MTBE (methyl-tert-butyl ether) (Gasoline additive)

Acetaminophen

Various antibioticsD TA

EXAMPLES OF NEPHROTOXICANTS

Metals

Many heavy metals are potent nephrotoxicants, and

relatively low doses can produce toxicity characterized by

glucosuria, aminoaciduria, and polyuria.

As the dose increases, renal necrosis, anuria, increased

BUN, and death will occur.

Several mechanisms operate to protect the kidney from

heavy metal toxicity. After low dose exposure and often

before detectable signs of developing nephrotoxicity,

significant concentrations of metal are found bound to

renal lysosomes.D TA

Uranium

About 50% of plasma uranium is bound, as the

uranyl ion, to bicarbonate, which is filtered by the

glomerulus. As a result of acidification in the

proximal tubule, the bicarbonate complex

dissociates, followed by reabsorption of the

bicarbonate ion.

The resultant loss of cell function is evidenced by

increased concentrations of glucose, amino acids,

and proteins in the urine.D TA

Chemically Induced α 2u-GlobulinNephropathy

A diverse group of chemicals, includingunleaded gasoline, jet fuels, d-limonene, 1,4-dichlorobenzene, decalin, tetrachloroethylene,and lindane, causes α2u-globulin nephropathy orhyaline droplet nephropathy in male rats.Binding to α2u-globulin decreases lysosomalproteases breakdown of α2u-globulin.Chronic exposure to these compounds results inprogression of these lesions an ultimately inchronic nephropathy

ChloroformChloroform is a common industrial organic solvent that

can be a hepatotoxicant or a nephrotoxicant in both

humans and animals. As a nephrotoxicant it is both species

and gender dependent. For example, following chloroform

administration male mice develop primarily kidney

necrosis whereas female develop liver necrosis.

As a nephrotoxicant, chloroform most probably undergoes

metabolic activation in the kidney itself.D TA

Halogenated HydrocarbonsHalogenate hydrocarbons are a diverse class ofcompounds and are use extensively as chemicalintermediates, solvents, and pesticides.

Chloroform is metabolized to phosgene by a

cytochrome P450-dependent reaction, probably

proceeding via an unstable hydroxylated product,

trichloromethanol.

Phosgene is capable of binding to cellular

proteins to produce the cellular necrosis

associated with chloroform toxicity to the kidney.

Phosgene can also be further metabolized by a

number of reactions, and as with most chemical-

induced toxicity, the final expression of toxicity

depends on a balance between activation and

detoxication.D TA

Hexachlorobutadiene

Hexachlorobutadiene is an industrial solvent and

heat-transfer agent. It is a widespread environmental

contaminant that is a potent and relatively specific

nephrotoxicant.

Hexachlorobutadiene first forms a glutathione

conjugate, which is further metabolized by the

mercapturic acid pathway to a cysteine conjugate.

In the kidney, the cysteine conjugate is cleaved to a

reactive intermediate by the enzyme, cysteine

conjugate β-lyase.D TA

Tetrafluoroethylene

The nephrotoxic mode of action of

tetrafluoroethylene is similar to that of

hexachlorobutadiene.

It is first metabolized to a cysteine conjugate,

which is metabolized by cysteine conjugate

β-lyase to a reactive product that can bind to

cellular macromolecules.

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Therapeutic Agents

Acetaminophen—Acetaminophen nephrotoxicity ischaracterized by proximal tubular necrosis withincreases in BUN and plasma creatinine, decreases inGFR an clearance of para-aminohippurate, increases inthe fractional excretion of water, sodium, andpotassium, an increases in urinary glucose, protein, andbrush-border enzymes.Although renal cytochrome P450 plays a role inacetaminophen activation and nephrotoxicity,glutathione conjugates of acetaminophen maycontribute to acetaminophen-induce nephrotoxicity.

Cyclosporine—Cyclosporine is an importantimmunosuppressive agent an is widely use toprevent graft rejection in organ transplantation.

Nonsteroidal Anti-inflammatory Drugs—NSAIDs such as aspirin, ibuprofen, naproxen,indomethacin, and cyclooxygenase 2 inhibitors(e.g., celecoxib) are extensively use as analgesicsand anti-inflammatory drugs and produce theirtherapeutic effects through the inhibition ofprostaglandin synthesis.

Aminoglycosides

Certain antibiotics, most notably the aminoglycosides, are

known to be nephrotoxic in humans, especially in high

doses or after prolonged therapy.

The group of antibiotics includes streptomycin, neomycin,

kanamycin, and gentamycin. Aminoglycosides are polar

cations that are filtered by the glomerulus and excreted

unchanged into the urine.

In the proximal tubule, the aminoglycosides are reabsorbed

by binding to anionic membrane phospholipids, followed

by endocytosis and sequestration in lysosomes. It is thought

that when a threshold concentration is reached, the

lysosomes rupture, releasing hydrolytic enzymes that cause

tissue necrosis. D TA

Amphotericin B

With some drugs, renal damage may be related to the

drugs’ biochemical mechanism of action. For example, the

polymycins, such as amphotericin B, are surface-active

agents that bind to membrane phospholipids, disrupting the

integrity of the membrane and resulting in leaky cells.

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MycotoxinsMycotoxins are products of molds and fungi, and anumber of mycotoxins produce nephrotoxicity.Citrinin nephrotoxicity is characterize by decreaseurine osmolality, GFR and RBF, glycosuria, anincrease urinary enzyme excretion.

Medical Management:

1. Pharmacologic therapy

a. hyperkalemia is the most life-threatening of the changes

that occur in RF, the elevated K levels may be reduced by

administering cation-exchange resins (sodium polystyrene

sulfonate [Kayexalate] orally or by retention enema. It works by

exchanging sodium ions for potassium ions in the intestinal

tract.

b. Sorbitol may be administered in combination with

Kayexalate to induce diarrhea type effect (induce water loss in

the GIT)

c. If hemodynamically unstable, IV dextrose 50%, insulin and

calcium replacement may be administered to shift potassium

back into the cells.

d. Diuretics are often administered to control fluid volume, but

they have not been shown to hasten the recovery form ARF.D TA

Medical Management

2. Nutritional Therapy

a. Dietary proteins are individualized to provide

the maximum benefit. Caloric requirements are

met with high-carbohydrate meals, because

carbohydrates have a protein sparing effect.

b. Foods and fluids containing potassium or

phosphorous such as banana, citrus fruits and

juices, coffee are restricted

Medical Management1. Pharmacologic Therapy

a. calcium carbonate (Os-cal) or calcium acetate

(Phoslo) are prescribed to treat hyperphosphatemia

and hypocalcemia

b. Antiseizure agents – diazepam (Valium) or

phenytoin (Dilantin)

c. Antihypertensive and CV drugs - digoxin (Lanoxin)

and dobutamine (Dobutrex)

d. Erythropoietin (Epogen) to treat anemia. It is

initiated to reach a hematocrit of 33% and a target

hemoglobin of 12g/dl.

2. Nutritional Therapy

a. low sodium, and low K diet

3. DialysisD TA

DIALYSISIs used to substitute some kidney functions

during renal failure.

It is used to remove fluid and uremic

waste products from the body when the kidneys

are unable to do so.

It may be indicated to treat patients with

edema that do not respond to treatment.

Acute dialysis is indicated when there is a high and

increasing level of serum potassium, fluid overload,

or impending pulmonary edema, increasing

acidosis, pericarditis and severe confusion. It may

also be used to certain medications or other toxins

in the blood.D TA

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