Drug_Induced_renal_disorder

8/7/2019 Drug_Induced_renal_disorder

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Drug Induced renal disorder


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Hemodynamic changes Direct injury to cells and tissue

Inflammatory tissue injury

Obstruction of renal excretion

Renal toxicity Result of

delay onset renal fn.


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Manifestations of drug-induced renal disorders

Acute renal failure

Chronic renal failure

Nephrotic syndrome (Acute/Chronic)

Fluid and Electrolyte disturbances

Acid-base disorders

Most episodes of drug-induced renal disorders are reversible

discontinue drug renal fn. return to baseline.

Chronic renal injury (due to medication) Chronic tubulointerstitial

inflammation, pallillaly necrosis or prolonged proteinuria.


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Risk Injury Failure Loss ESRD Criteria

Urine Output GFRCr 1.5 2 or GFR >25%

Cr 2 3 or GFR >50%

Persistent Acute Renal Failure

Cr 3 or GFR > 75%or

Cr 4 mg/dl

(acute rise 0.5mg/dl)

End Stage Renal Failure

UO< 0.3 ml/kg/hr x24hr.

or Anuria x 12 hr.

(oliguria)

UO< 0.5 ml/kg/hr x12hr.

UO< 0.5 ml/kg/hr x 6 hr.

Risk

Injury

Failure

Loss

ESRD


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Stage of Chronic kidney disease

CLCr Stage

120 Stage 1

Stage 2

Stage 3

Stage 4

Stage 5

60-90

30-59

15-29


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Causes of Renal failure

1.Hypoperfusion

2.Vasoconstriction3.Glomerulonephritis

4.Tubular necrosis

5.Interstitial nephritis

6.Interstitial edema

7.Outflow obstruction


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Drug-induce renal structural-functional changes

Proximal convoluted tubule (s1/s2 segment)

Aminoglycoside

Cephaloridine

Cadmium Cl

K dichromate

Renal vessel

NSAIDs

ACE Inhibitor

Cyclosporin A

Pappillae

Phenacetin

Interstitium

Cephalosporin

Cadmium

NSAIDs

Glomeruli

Interferon-

Gold

Penicillamine

Proximal straigttubule (s3 segment)

Cisplatin

Mercuric Cl

Dichlorovinyl-L-

cysteine


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Pseudo renal failure

Steroids, tetracycline BUN (hypercatabolic effect)

ScrTrimethoprim. cimetidine, probenecid, triamterene,

amiloride, spironolactone Scr (competitive withcreatinine for tublar secretion)

Ascorbic acid, cefoxitin, cephalothin, cefazolin,cefotaxime, flucytosine, levodopa, methyldopa

interfere enzymatic measurement of creatinine byJeffe method


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Hemodynamically mediated renal failure

Decrease total renal blood flow

Vasoconstriction of glomerular afferent

arterioles Vasodilation of glomerular efferent

arterioles

Increase Vascular permeability Increase collioid oncotic pressure and

blood viscocity

Mechanism


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Diuretic, alone or combination with otherantihypertensives

ACEI & ARBs NSAIDs & COX inhibitor

CyclosporinZreduce GFR in adose

dependent and reversible manner) Tacrolimus, triamterene, propanolol,

OKT3,dextran, epoietin

Drug


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Large volume losses

Renal vasoconstriction with marked tubular avidity

for NaCl uptake

Decrease urine output

Prolong vasoconstriction

Tubular dysfunction and tubular necrosis


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When the rate perfusion decrease,

the renal bed autoregulates

Prostaglandin Angiotensin II

Afferent arterioles Efferent arterioles

Tubule

NSAIDs, COX II inhibitor ACEI ,ARBs


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Risk Group RAS/Prostaglandin dependent

Nephrosclerosis

Bilateral renal artery stenosis renal

stenosis artery

Hypovolumia

Heart failure Chronic kidney disease


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Reversal is possible if the problem ispromptly recognized.

Unrecognized prerenal failure can lead to

serious tubular injury and tubular necrosis.

Changes in urine sediment are relatively

benign

Renal function 1-2 duration~8-48 .Prostaglandin24-48 .


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Some issue

NSAIDs-induced acuteinterstitial nephritis (with or without

nephrotic syndrome)

ACEI short-acting titrate long-acting ACEI renalfailure ACEI

Misoprostol (PGE analog) COX-2 inhibitor/Low dose

aspirin/sulindac


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Intrarenal toxicity

vasculature, tubules, glomeruli

/ renalinterstitium

Acute intrinsic renal failure


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Intrinsic renal injury

Vascular effect:thombotic, microangiopathy, Cyclosporin, tacrolimus, mitomycin C,

conjugate estrogens,quinine-6- fluorouracil,

ticlopidine, clopidogrel, interferon,valaciclovir, gemcitabine, bleomycin

Clinical finding: fever,microangiopathic,hemolytic anemia,

thrombocytopenia Treatment: d/c medication, supportive

care,plasmapheresis if indicate


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Intrinsic renal injury

Vascular effect: cholesterol emboli Heparin, warfarin, streptokinase

Clinical finding: fever,

microangiopathic,hemolytic anemia,thrombocytopenia,

Treatment: d/c medication, supportive

care,plasmapheresis if indicate


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Glomerular injury

Glomerular histology and permeabilityalteration often cause nephrotic rangeprotienuria.

Toxic lymphokines of interstitialinflammation might be implicated.Humeral

factor might also be involve eosinophils &

lymphocyte present in the interstitial

infiltrate.

Red cell and white cells might be observed

in the urine,even though hypersensitivity is

not clinically event.


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Glomerular injury

Renal biopsyGlomerular injury

NSAIDs(mefenamic, fenbufen): minimalchange

Gold,D-penicillamine,ACEI,foscarnet:

membranous lesion Interferon alfa:severe glomerular lesion


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Glomerular injury

Gold, penicillamine, captopril, NSAIDs,

lithium, mefenamic, fenoprofen, mercury,

interferon-alfa, pamidronate, fenclofenac,foscarnet

Clinical finding: edema, moderate to

severe proteinuria, RBC and RBC casts

possible

Treatment: discontinue medication andsupportive care


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Tubular injury

Damage can be toxic / ischemic /

inflammatory / obstructive.

Urine sediment abnormalities range from no

cell trough numerous red cells. White cells,

and/or brown granular casts,to proteinuria

and crystaluria, depending on site and

mechanism of injury


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Tubular Damage

Loss of polarity ,tight junction, integrity, cell-substrate adhesion,simplication of brush border

Cell death

Necrosis/apoptosisSloughing of viable

cells with intraluminalcell-cell adhesion

Cell-cell adhesion

Cast tubular obstruction tubular damage

Cast formation andtubular obstruction


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Tubular injury

T

ubular toxicity: aminoglycosides, radio contrastmedia, cisplatin, neaplatin, methoxtfluran, outdated

tetracycline, amphotericinB, cephaloridine,

streptozocin, tacrolimus, carbamazepine,

mithramycin, quinolone,foscarnet, pentamidine, IVgammaglobulin, fosfamide, zoledronate, cidofovir,

adefovir, tenofovir, mannitol,dextran,hydroxyethylstarch

Clinical finding: FeNa>2%,UOsm


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Aminoglycoside

Prototype of drug-induce Acute tubular necrosis(ATN)

Usually reversible:gradual rise in Scr(5-7 d), renal

Mg++&K+ wasting, non-oligouria*

Pertubation of glomerular filtration is late

manifestation of aminoglycoside nephrotoxicity.

The number of cationic amino moieties seems to

correlate with the degree of nephrotoxicity:Neomycin>Genta>Tobra>Amikacin>Netil>Streptomycin


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Aminoglycoside

Swelling


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Risk factor for Aminoglycoside Nephrotoxicity

Related to AMG dosing

Large total cummulative dose

Prolong therapy

High peak or trough conc.

Recet previous AMG therapy

Related to Predisposing condition

in the patient

Preexisting renal insufficiency

Increased age

Poor nutrition

Shock

Gramnegative bactermia

Liver disease

HypoalbuminemisObstructive jaundice

K+ orMg++ deficiency

Related to synergistic

nephrotoxicity

AMG combination with

Cyclosporin

Amphotericin B

Vancomycin

Diuretics

Irreversible Damage!


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Aminoglycoside Nephrotoxicity

Prevention

Switching to alternative

antibiotics

Avoid volume depletion,

concomitant therapy with

other nephrotoxic drugs

Limit total doseDecreasing the frequency

of AMG dosing to at least

daily (as direct by renalclearance)

Management

Monitor Scr, concentration,

renal fn and electrolytes

Discontinue AMG if

changes are seen.


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Toxic tubular necrosis (Derange Na/K-ATPase loss

of brush border and apoptosis): Bisphosphonatezoledronate 4 mg IV over 15 min (high dose)

Osmotic nephrosis (cellular uptake

nonmetabolizable compounds such as

sucroseswellingtubular cell injury) : IV Ig, mannitol,

dextran, hydroxyethyl starch Ischemic tubular injury (acute vasoconstriction) :

immunosupressives, radiocontrast agents,amphotericin B


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Amphotericin BMech.

tubular cell

Afferent arterioconstriction tubuloglomerular

feedback

Deoxycholate(solvent) tubular cell

Renal vasoconstrictioneffect

amphotericin

B

Dose-dependent acuterenal vasoconstriction

Cumulative dose>2-3

g:direct distal tubular

Clinical presentation

Non-oligouria,distal

RTA,impaired renal activity toconcentrate

urine,K+/Na+/Mg++wasting,inc

rease BUN,Scr

Tubular fn & filtration may

improve but damage may beirreversible

Risk

Baseline renal dysfunction

Higher average daily dose

Diuretic use with depletion

Rapid infusion

Concomitant use with

nephrotoxins

Prevention

Limiting cumulative

dose

Avoid concomitant

nephrotoxiin

Avoid volume

depletion,hypoKProvide

hydration,Na+ load(full Na+ diset ifno C/I, 1L NSS daily)

-Ca blocker,mannitol ManagementSwitch to another drug

Avoid systemic

administrationK/M re lacement


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Interstitial InjuryMech.

Drug-renal tubular

Ag. induceimmuneRx(mediated=

T cell)depositioninterstitium tublitis

Some drug induce

deposition ofantitubular basement

membrane Ab.

Numerous drugs

Acute interstititial

nephritis

Penicillin, methicillin, ampicillin, rifampin, sulfonamide, thiazide,

cimetidine, phenytoin, allopurinol, cephalosporins, cytosine,

arabinoside, furosemide, interferon, NSAIDs, ciprofloxacin, ranitidine,clarithromycin, telithromycin, pantoprazole, omeprazole, atazanavir, etc

Clinical finding

1/3 pt. hypersens classic

symtomp (fever, rash,arthralgia, eosinophilia,

urine sediment show pyuria,

white cell cast, hematouria,

mild-moderate proteinuria

Renal failure occurs inearly stages

Treatment

d/c drug supportive

care

Steriod 0.5-1 mg/kg/d

no of day of renal

failure lower than no

treat (in some study)

careful evaluation of

renal fn for initiation newmedication


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Obstructive nephropathy Intratubularcrystalluria and/or renal lithiasis

High dose acyclovir, ganciclovir, MTX, indinavir

intratubular obstruction, tubular injury, acuterenal compromise, CRF

Clinical finding

Renal colic with frank or loin pain, or dysuria

Risk

similarto those formetabolic etiology of

nephrolithiasis

Hx/presence of renal

lithiasis,low urine

vollume,abnarmality

low/high

pH,hypercalciuria and

hypocitraturia.

High/prolonged dosingregimentsincreaseurinary drug excretion

and poor aqueous srugsolubility


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Extrinsic renal blockage:

1.Ureteral obstruction

2nd to retropertoneal fibrosis

Methylsergide, ergotamine, dihydroergotamine, methyldopa,pindolol, hydralazine, atenolol

Clinical finding: benign urine sediment, hydronephrosis on

ultrasound.

Treatment: d/c drug, decompress uretal obstruction

2.Bladder dysfunction

Tricyclic antidepressants, disopyramideAnticholinergic effect

Cyclophosphamide, isophosphamideBladder fibrosis

Hemorrhagic cystitis

Obstructive nephropathy


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Chemotherapy ObstructiveTumor-lysis syndrome (hematologic malignancy)-Acute oliguria/anuria

-Acute uric nephropathy

chemotherapy

hydration,alkalinization,allopurinol (600-800 mg/day*3-4 day)

Obstructive nephropathy


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(not true nephrotoxicity (with out renal failure))

Formation of kidney stone

Triamterene

Sulfadiazinetoxoplasma gondii >>> hydration, alkalinization

Indinavir Crystaluria, nephrolithiasis >>> maintain urine

volincrease daily fluid intake to at least 1.5 L during indinavirtherapy

Mg trisilicate-Al(OH)3 Mg-Ammonium phosphate stone Ca phosphate precipitation

Laxative abuse Unusual formation of ammonium urate stone

Allopurinol

Nephrolithiasis


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Rhabdomyolysis

Lovastatin ,ethanol, cocaine or heroine abuse, codeine,

barbiturate, diazepam

Clinical finding: elevate CPK,ATN urine sediment

Treatment: d/c drug + supportive care

Severe hemolysis

Quinine, quinidine, sulfonamides, hydralazine, triamterene,nitrofurantoin, mephenytoin

Clinical finding:high LDH, decrease hemoglobin

Treatment: d/c drug + supportive care


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Chronic Interstitial fibrosis

Lithium,5-aminosalicylic acid, mesalazine,

ifosfamide

Cidofovir, acyclovir, indinavir

Cyclosporin, tacrolimus

Usually progressive, irreversible with interstitailfibrosis, no systemic symptoms


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Lithium

Risk

Elevated lithium

level,particularly inassociation with dehydration

Concomitant with neuroleptic

agent and ACEI

Cumulative damage chronicnephrotoxicity

Nephrogenic diabetic

insipidus Nephrogenicdiabetic insipidus: most

common

Interstitial fibrosis

Decrease urinary

concentration, increased Naexcretion and polyuria

Prevention & management

Maintaining Li level

Avoid dehydration

Monitoring renal fn.d/c drug if Scr drop

polyuria,polydipsia

amiloride NSAIDs Li


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Tubulointerstitial nephritis: papillary necrosis

Analgesic nephropathy

Papillotoxin: paracetamol, phenacetin, ASA

Hemodynamic factor: NSAIDs

High-dose Dapsone


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Mech.

Drug = high reactive metabolite +glutathione tissue damge

High levels at the papillary tip

Inhibit of vasodilation PGs by NSAIDs medullary ischemia

PGs oxidise reactive metabolite medulla Diagnosis criteria (most sensitive & specific)

Hx chronic daily anagesic ingestion

IV pyelography, renal ultrasound/CT decreased renal massand bumpy

renal contours

Papillary calcification( pyelonephritis: small kidney with thin renalcortices and blunted calyces)

Analgesic use is most common cause of papillary necrosis


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Analgesic syndrome

HT& atherosclerosis CVD

GI cp\omplication

Hematologic complication:

anemia, agranulocytopenia

Skeletal complication

Psychosomatic aspect

Urogenital transitional

carcinomas& renal cell

cancers

Prevention

Limit dose

Avoid 2 or more analgesic

combination

Maintain good hydration

renal ischemic & papillaryconc.

Use para in renal

insufficiency pt.


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Hyponatremia

increase ADH secretion and sensitivity

Thiazide,

chlopropramide,

vincristine,

IV cyclophosphamide,

cytoxan, clofibrate,

narcotics, haloperidal,

thioridazine,

amitriptyline,fluphenazine, NSAIDs,acetaminophen

Clinical finding:

urine osmolality

is less thanmaximally

diluted in

presence of lowserum Na

Treatment

Discontinue drug, consider fluid


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Hypokalemia/ hypomagnesemia(increase urinary excretion)

Gentamycin,

cisplatin,

diuretics,

carboplatin,nedaplatin

Clinical finding:

Increase urine

excretion of K+ &

Mg++ despite lowserum levels

Treatment

Discontinue drug,replace K+ and Mg++


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Hyperkalemia(antialdersterone or antiadrenergic effect:

blocking Na channel)

ACEIs,

Beta-blockers,

heparin,

NSAIDs,

K+sparing

diuretics,trimethoprim,

cyclosporin,

pentamidine

Clinical finding

Decreased urine K+excretion with high serumK+

Treatment

Discontinue drug, treathyperkalemia,low K+ diet


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Renal tubular acidosis from renal tubular injury(decreased acid excreation:inability to reabsorb bicarbonate)

Amphotericin B, toluene,

Li, cyclamate, analgesics,

vitamin D intoxication,

foscarnet,

Carbonic anhydrase

inhibitor, outdated

tetracycline, mafenideacetate, 6-

mercaptopurine,

sulfanilamide, cidofovir,

tenofovir,

Clinical finding

Hyperchloremic metabolicacidosis with orhypokalemia

Treatment

Discontinue drug,

supportive treatment,

HCO3 replacement if

indicated


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Renal tubular acidosis(decreased aldersterone levels and response)

Cyclosporin,

tacrolimus

Clinical finding

Hyperkalemia,hyperchloremic

metabolic acidosis

Treatment

Treat hyper K+, consider HCO3 therapy, low K+ diet,avoid concurrent medications associated with hyper K+


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Metabolic alkalosis(increase K+ and H+ secretion in distal nephron)

Loop and thiazide diuretics

Clinical finding

Alkalemia,hypo K+, hypo Cl-

Treatment

Discontinue drug,

volume replace if neccessary


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Nephrogenic diabetes inspidus(decreased ADH response in collecting tubule)

Li,demeclocycline,

cyclophosphamide,

ifosphamide,vincristine, cidofovir,

tenofovir, didanosine,foscarnet

Clinical finding

Polyuria

Unresponsive to ADH

Treatment

Discontinue drug, supportive therapy


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Principles for pharmacotherapy

Knows the potential nephrotoxicity of Dxand therapeutic pharmacologic agents.

Compare the potential risks and expected

benefits for each course of treatment. Consider alternative diagnostic and

therapeutic approaches.

Use the lowest dose and shortest courseof therapy that is efficacious.

Monitor appropriately for potential toxicity.

Monitor therapy if toxicity is occurs.

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Drug_Induced_renal_disorder