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983 A&B 15

Drug-induced Kidney Disease

Drug-induced Kidney disease

1


(1) In-community

AKI() 20% community acquired DIKD

ARF()()CHF(

) phenylephrinenorepinephrine ()

(2) In-hospital

AKI 60% drug induced ( AKI)

(3) DIN antibiotic (36%)NASIDsACEIs

Chemotherapeutic

agentsantiviral drugs antibiotic

(4) Antibiotic NASIDs DIN

Drug induced kidney disease

DIN GFR ScrBUN(2X)

1. Scr ( 20%)

(1) Scr(ex: )

(2) catabolism ()

2. Scr

Baseline Scr (mg/dL) Scr (mg/dL)

2 0.5

24.9 1

5 1.5

Scr2 mg/dL 30% Serum creatinine 0.5~1.5mg/dL

3. (Correlated temporally)(

)

DINDrug-induced nephrotoxicity DIKDdrug-induced kidney disease ARFAcute renal failure AKIAcute kidney injury DIN = DINKARF = AKI

2

urine output ()(

)

(contrast media)NSAIDACEI

(malaise)(anorexia)(SOB )

:SOB=shortness of breath ()

Glomerular filtration

1.

(1) (metabolic acidosis)(bicarbonaturia)

(2) (glycosuria) DM

(3) PKMg ()

2.

(1) (polyurea)

(2)

(3)

()

1.

(1) N-acetyl- D-glucosaminase-glutamyltranspeptidaseglutathione S-

transferaseInterlukin-18 marker

2. kidney injury molecular-1 (KIM-1)

(1) KIM-1 12

12

3. 3 neutrophil gelatinase-associated lipocalin(NGAL)

RIFLE Criteria (2002) for acute renal dysfunction

: Acute Dialysis Quality Initiative Group (ADQI) AKI

GFR Criteria Urine output (UO) Criteria

Risk Creatinine 1.5x GFR25%

UO0.5ml/kg/h 6 hrs

Injury Creatinine 2x GFR50%

UO0.5ml/kg/h 12 hrs

Failure Creatinine 3x GFR75%

UO0.3ml/kg/h 12 hrs Anuria 12 hrs

Loss Persistent ARF = complete loss of kidney function4 weeks

ESKD End Stage Kidney Disease (3 month)

()

: 2005 Acute Kidney Injury Network (AKIN) RIFLE criteria AKIN criteria

AKIN criteria RIFLE criteria


3

: AKIN criteria

Diagnostic criteria: within 48 hrs

a. absolute increase in serum creatinine 0.3 mg/dl.

b. or a percentage increase in serum creatinine 50%

c. or a reduction in urine output ( 6 hours)

()

Drug induced renal structural-functional alterations

:

1. (Tubular epithelial cell damage)

(1) (Acute tubular necrosis)intrinsic ARF

(2) (Osmotic nephrosis)

2. (Hemodynamically-mediated kidney injury)functional ARF

3. (Obstructive nephropathy)postrenal ARF

(1) (Intratubular obstruction)

(2) (Nephrolithiasis)

(3) (Nephrocalcinosis)

: Nephrocalcinosis Ca2+ Ca2+

4. (Glomerular disease)intrinsic ARF

5. (Tubulointerstitial disease)

(1) (Acute allergic interstitial nephritis)intrinsic ARF

(2) (Chronic interstitial nephritis)

(3) (Papillary necrosis)

6. (intrinsic ARF)

: ( AKI AKI )

~ ? :

A. B.

C. D.

4

(ARF)

Prerenal ARFFunctional ARF()

Intrinsic ARF

1. Wegener's granulomatosis()

2. (Acute tubular necrosis, ATN)

3. (Acute interstitial nephritis, AIN)

: Wegener's granulomatosis()

Ab(ANCAs (antineutrophil cytoplasmic antibody))

(97 )

Postrenal ARF(ureter obstruction)BPH anticolinergic


5

Agents implicated in drug-induced acute kidney injury

AKI ()

Drug Incidence % Level of evidence

Hemodynamic-mediated

Diuretic (furosemide>hydrochlorothiazide) 5-12 B

ACEI, ARB 6-38 B

cyclosporine 25-38 A

NSAID, COX 2 inhibitors 1-7 A

Acute tubular necrosis

aminoglycosides 5-25 A

Amphotericin B desoxycholate 20-65 A

Amphotericin B lipid-based 15-25 A

Radiocontrast media

CKD 0-10 A

11-20 A

CKD 15-55 A

CKD, 27-81 A

Cisplatin (dose dependent) 10-30 A

Ifosfamide 6 A

Acute interstitial nephritis

allopurinol NK C

-lactam antibiotics NK C

Ciprofloxacin NK C

Erythromycin NK C

H2 receptor antagonists NK C

Lithium NK B

Loop diuretics NK C

NSAIDs NK C

Phenytoin NK C

Proton pump inhibitors NK C

rifampin NK B

Thiazide diuretics NK C

Valproic acid NK C

6

Nephrolithiasis

Acyclovir NK C

Allopurinol NK C

Foscarnet 1-5 A

Furosemide 14 B

Indinavir 12.4 A

Topiramate 1-3 A

sulfonamides 29 B

Zonisamide 1.9-4 B

Glomerulonephritis

Allopurinol NK B

Gold NK C

Hydralazine NK C

Lithium NK B

NSAIDs NK B

Penicillamine NK C

Phenytoin NK C

Propylthiouracil NK C

Rifampin NK C

1. General/Scr

2.

3. Mg (cisplatin/carboplatin-induced)

4. (Glomerulonephritis)

5. ()

Diuretics in edema

1. Furosemide vs torsemide( PO ) = 1:4

Furosemide vs bumetanide = 1:40

furosemide torsemide long duration ()

2. Ethacrynic acid sulfa drugs

3. Furosemide : ()()

: variable oral bioavailability(ex:

)rapid high bolus


7

4. diuretic resistance CIV (Continue IV)

intermittent bolus

CIV natriuresis high serum con

5. Furosemide loading 40-80mg CIV 10-20mg/hMax:480mg/day(!)

6. Clcr < 20mL/min HF, cirrhosis, nephrotic syn.

IV furosemide 30 oral metalazone 5mg (thiazide diuretics)

CKD ()

Drug Incidence % Level of evidence

Aristolochic acid NK B

Antipyretic analgesics 0.8-9% B

Carmustine NK C

Cidofovir NK C

Cisplatin NK C

Cyclosporine NK A

Gold salts 1-5% B

Ifosfamide 7-9% B

Indinavir NK C

Lithium 0.2-21% B

Lomustine NK C

Mitomycin NK C

D-Penicillamine 7% B

Propylthioruacil NK C

Streptozocin NK C

Tacrolimus NK A

~ ? A.

8

:signs sym.

1.

BPnocturiaPeripheral edemaPulmanary edema

2.

(1) erthropoietin(Epotin )darbepoetin

(2) RBCDDAVP(desmopressin)conjugated estrogenerythropoietin

:Desmopressin vesopressin analogue Vesopressin

(3) SOB

3. phosphate binder (Sevelamer) Ca Vit. D analogs

: Sevelamar

Ca Vit D

4. ()

5. ()

6. Na polystyrene sulfonateIV CaInsulin + glucoseIV NaHCO3

1: Na polystyrene sulfonate Na K

2: K

K IV insulin + Glucose K

3: IV NaHCO3

7. ()

8. ()

9. ()

10. /()

11. ()Gold saltsD-penicilamineNSAID

12. ()

13. ()

14.


9

Tubular epithelial cell damage

2.

3. (Acute tubular necrosis, ATN)

(1) ATN Urinary indicesUrine Na40 mEq/LFENa2%urine / plasma Cr20

spGr1.01urine osm.300 mOsm/Kg

(2) ATN

Aminoglycosides Radiographic contrast media () Cisplatin

Carboplatin Amphotericin B

4. Osmotic nephrosis

(1) osmotic nephrosis

Mannitol(osmotic diuretics) Dextran

IV immunoglobulin Hyperosmolar sucrose

: !!!!

( 97 98 )

Aminoglycoside 10-25% 6-10( 5-7) 3-5

1. ScrClCr 2. (500ml/d)Mg K (

) : Oliguria (urine

10

1. Drug-specific risk factors for acute kidney injury

Risk factor

ACEI NSAID Aminoglycosides Amphotericin B

Contrast media

CKD

D D D D D

D D D NK D

D D D D D

D D NK NK D

Dose / duration

P D D D P

2. (predisposing conditions)(Patient factor) (hypoalbuminemia)(diabetes, obstructive jaundice)G(-)K Mg

3. (AG factor) (1) AG ()(cationic amino group)

: amine group cation amine group !

Neomycin 6 GentamicinTobramycin 5 Amikacin 4 StreptomycinNetilmycin 3

(2) NMGM = tobramycin = amikacin = netilmycinSM (:) (3) AGs dosing(7-10 ) (4) Trough conc.2 mg/Lcp:

: AGs trough level < 2mg/L

(5) AG 4. Concomitant drug therapy(synergistic nephrotoxicity)

ExCyclosporineAmphotericin BVancomycindiureticsFurosemideCisplatin Iodinated radiocontrast mediaFoscarnetNSAID()

1. 2-4 Scr (Scr 0.5 mg/dL ) 2. 3. 4. ( AGs ) 5. ( Cockroft & Gault equation) (97 ) Cockroft & Gault equationmenCLcr = (140-age) ABW / Scr x 72

womenCLcr0.85

6. Modification of Diet in Renal Disease Study (MDRD) GFR GFR = 170 plasma Cr-0.999 age-0.176 0.762() 1.180() serum nitrogen conc.-0.17 serum albumin-0.318


11

1. FQ3rd 4th Cephalosporin

2. AGs

3. Once daily dosing(QD) ( TID)

(1) AGs concentration dependent activity ( Penicillin Time dependent)

(2) high peak concentrationAGs

uptake

(3) AGs Ctrough(Trough conc.2mg/L)

(4) Continuous rate gentamicin infusion AGs

uptake (!!)

(5)

a. AGs post-antibiotic effect (PAE)

b.

c.

d.

e.

f.

(6)

a. T1/2

b. post-antibiotic effect

c. MIC

d.

(7) Once daily regimen

a. Clcr60ml/min

b. Scr 0.5 mg/dL 48h 30%

c. (20% BSA )

d.

e. volume status ()

f. enterococcalendocarditismeningitis (AGs BBB)

: Enterococcal endocarditis G(+) gentamicin penicillin synergic effect() one-daily-dose

g.

4. Usual dose4-7mg/kg qd ( 4~5mg/kg qd)

:One daily dose (5mg/kg qd) 5mg/kg/d

5. Cmax/MIC10 ( ) 24h AUC/MIC70

12

Radiographic contrast media()

7% AKI

1. ARF (34% vs 7%)(delirium) 2. (typical course) (enzymuria) 2 Scr (1-2 5 peak)4-10

3. 50%(oliguria) (500mL/d) 4. (granular cast)

1. (enzymuria) (1) GFR60mL/min/1.73m2 (decompensated kidney ) endothelinadenosine vasoconstrictor () (2)

2. (1) RBC crenation ()aggregation

( O2) NO (protective vasodilator) (2) (900~1780mOsm/kg)( 280~300mOsm/kg)

3.


Risk factor


Contrast media

CKD

D D D D D

D D D NK D

D D D D D

D D NK NK D

Dose / duration

P D D D P

2. ( 2 ) 3. dehydration (-BUNScr201)

4. NSAIDCOX-2 inhibitorACEI hemodynamics 5. (multiple myeloma) 6. older hyperosmolar contrast agent (

)


13

: CIN Contrast induced nephropathy

(97 )

(ionic monomers)(>1400mOsm/kg)

(nonionic monomers)(500~850)(ionic

dimer) Ioxaglate 600

(nonionic dimer)iodixanol 290

() ()

(osmoticdieresis)

histamine

CIN v.s. = 1 v.s. 2

Cost-effective

()

(Scr2mg/dL)

()

Dialysis ( irreversible oliguric 500mL/d)

1. (low osmolality)

(1) Nonionic (iohexol, iopamidol)

(2) Ionic dimer (ioxaglate)

(3) Iso-osmolar dimeric nonionic (iodixanol)CKD

+Diabetes CIN

(4) Noniodinated contrast A2

2. (MRI)

3. ( A1)

4. medical history Scr

5. mL/sec / baseline Clcr

14

ATN()

24 ()

1. CCBs 2. NSAIDCOX-2 ACEI

ARBDiuretics 3. 48h Metformin ARF

12h 12h Hydration0.45% NaCl 1mL/Kg/h (0.5mL/Kg/h in CHF)

N-acetylcysteine 600mg po bid x 1 doses N-acetylcysteine 600mg po bid x 3 dose 12h

Scr for 48-72h :(Risk Score6)

(97 )

Score

Hypotension SBP80

inotropic (dobuatamine) 5

IABP

() 24 5

CHF III & IV 5

Anemia()

HCT (Hematocrit )

39%for men

36%for women

3

3

100c.c. 1

Serum creatinine 1.5mg/dl 4

Estimate GFR 60ml/min/1.73m2

40-602

20-404

202

Risk Score6


15

Risk Score6 ()

Yes No

Yes No

1h IV 3ml/kg/h 1. D5W+NaHCO3 154mEq/l 2. NS

:NaHCO3 pH dependent

IV 1. 3ml/kg/h D5W+NaHCO3 154mEq/l 2. 6-12h NS 1mL/Kg/h

Vit C 3g

Vit C 2g bid 2 dose :Vit C

1. Acetylcysteine 600-1200mg bid 2 dose

2. 2h Vit C 3g Vit C 2g bid 2doses

Nonionic low osmolar

iso-osmolar contrast

Nonionic low osmolar

iso-osmolar contrast

1mL/kg/h

(6h for NaHCO312h for NS)

1mL/kg/h

(6h for NaHCO312h for NS)

NaHCO3

pH dependent

1

1h 3ml/Kg/h D5W

+NaHCO3 154mEq/L

,

6-12h NS 1mL/Kg/h

2 +

Acetylcysteine B1 600-

1200mg bid x 2doses

1 3(4)

2h Vit C 3g, 2g

bid x 2doses

1 1h 3ml/Kg/h

D5W +NaHCO3 154mEq/L B2

NS

2 Vit C 3g,

2g bid x 2doses

3 Nonionic low osmolar or

isoosmolar contrast

4 1mL/Kg/h

6h NaHCO3

12h NS

6

slide 31

16

CisplatinCarboplatin

1980 70%(GFR 20-40%) 20-30% total dose(1mg/min in CHF)hydration ( pretreatment) :Cisplatin, Carboplatin

platinum

analog

1. cisplatin 2.

(1) Carboplatin 90 AUCGFR (2) Oxaliplatin

1. 10-12 Scr peak21 2. Scr 3. (renal Mg wasting)() :premedicaiton

4. () (1) seizureneuromuscular irritabilitypersonality change (2) IV Mg 16mEq/d PO 20mEq tid

Calvert

formula

Total dose (mg) = target AUC (GFR + 25) 1. usual target AUCs()

(1) AUC = 6-8 (2) AUC = 4-6 (:AUC 4-5)

: Drug Information Handbook 18th Ed. 2009

1. (1) Cisplatin CYP2E1 reactive oxygen cell energy production : Cisplatin

Cisplatin (2) cellular protein SH groups mitochondrial DNA

2.

renal irradiation() AGsalcohol abuse()

1. 2. premedication : (1) MgSO4 ( Mg )

(2) Hydration () 3. vigorous saline

(1) 24h 1-4L (150-250mL/h)cisplatin (up to 24h) 4-8hurine output100mL/h 6h

(2) carboplatin ( AUC=8) 3L/m2 4. Cisplatin/NS ( cisplatin )

(1) cisplatin Cl ligand reactive aquated cmpd (Cl cisplatin aquation reaction reactive platinum)

(2) D5W :

Amphotericin B antifungal agent IV D5W Normal Saline NS Amphotericin B Cisplatin IV Normal Saline Cl Cisplatin D5W cisplatin Cl reactive Compound


17

5. Cisplatin 30 furosemide 20-40mgmannitol () 12.5-50g (10g/h 3h)

(1) urine output 100mL/h cisplatin ( saline 250mL/h) cisplatin

Amifostine

Amifostine (renoprotection, prodrug) 1. renoprotectionorganic thiophosphate (free thiol)

(1) normal cells cisplatin (2) (3) (neutropenia)

: ASCOThe American Society of Clinical Oncology

2. cisplatin 30 amifostine 910mg/m2/dIV 15 3. : 4. :

amifostine 24h (1) 5 (2) saline (3) (15-61% dose dependent)

: amifostine 5. Cisplatin/ifosfamide solid tumor amifostineGFR 6. pretreatment amifostine

Elderlyvolume depleted(CKD)

() (97 )

hypertonic saline (3% 250mL) tubular cisplatin uptake(HF )

Intraperitoneal() cisplatin + IV sodium

thiosulfate

sod thiosulfate cisplatin

: sod thiosulfate

N-acethylcysteine SH donor oxidative damage

disulfiram metabolite diethyldithiocarbamate CYP2E1 OH

radical ()

Melatonin

cisplatin-incorporated polymeric micelles

:

()

1. supportive care (dialysis) 2. ScrBUNMgKCa

3. Clcr30-60mL/min 50% dose

4. Clcr10-30mL/min

18

Amphotericin B Desoxycholate

1. 300-400mg 2-3g 80%

2. (ARF) ARF mortality = 54% vs 16%

:Amphotericin B Antifungal drugs

3. GFR(azotemia)( KNaMg )

H+

4. GFR ScrBUN

5. BUN50mg/dL

1. ()

2.

(1) (amphotericin sterols

ionophore NaK ) cell lysis cytokine

(2) (amphotericin B )GFR

(3)


Risk factor


Contrast media

CKD

D D D D D

D D D NK D

D D D D D

D D NK NK D

Dose / duration

P D D D P

2. (CKDchronic kidney disease)

3. mean daily dose35mg

4.

5. CSA(cyclosporine)

6. 24h vs 4h GFR pretubular effect 24h

: 4h 4h 24h

7. BW 90Kg


19

1. 1.5-2g ( 6-10 )

2. CSA(cyclosporine)

3. (hydration)1L NS daily (sodium load 150mEq

)(H/T)(CHF)(edema)

4. mannitol infusion

5. D5W 250-500mL 0.1mg/mL () 0.25mg/mL ()

4-6h

(1) (chillsfeverhypotensionnausea) Premedication (

30-60 )

a. NSAID diphenhydramune

b. Acetaminophen+ diphenhydramune

c. Hydrocortisone50-100mg

d. (rigor) meperidine

6. liposomal amphotericin B (Ambisome)

lipid based AmB ( 8-28%)

(1) mammalian cell membrane amphotericin B

(2) AmB encapsulated liposome fungal ergosterol human ergosterol

translocate ()

(3) Lipid-based AmB is taken up by macrophages ()

macrophage AmB lipid AmB

(4) extracellular phospholipase lipid based AmB lipid

encasing AmB

(5) AmB HDL-C LDL-C ( HDL-C receptor )

(6) Lipid based AmB AmB toxic cytokineTNFinterleukin-1

1.

2. ScrBUN MgKCa

~ ? B.

20

Hemodynamic mediated kidney injury

3.

(1)

(2) (angiotensin)

: (macula densa) renin

4.

()

NSAIDs PG (A II )

Mannitol tubuloglomerular feedback

ACEIARB Angiotensin II

neurohumoral renal hemodynamic control

CCBs

RBF


21

5.

(1) intraglomerular pressure

()

(2)

ACEIARBNSAID()CSATacrolimus()

6.

ACEIARB

1. 2-5 ( prodrug)

Scr 30% (0.1-0.3mg/dL)GFR urine output

(1) 1-2wkScr 0.5mg/dL ( hemodynamic mediated acute kidney injury) (2) 2-3wk Scr (3) : ACEI angiotensin II

ARB angiotensin II 2. Angiotensin GFR

(1) aldosterone (2)

3. ARB ACEI (ARF) (1) Angiotensin II receptors AT IAT II (2) ARB AT I AT I (CV effect)aldosterone - adrenergic stimulation

(3) ACEIARB ARF ARF

ACEI angiotensin II ARB (glomerular capillary hydrostatic pressure)


Risk factor


Contrast media

CKD

D D D D D

D D D NK D

D D D D D

D D NK NK D

Dose / duration

P D D D P

2. angiotensin II (CHFGI fluid loss ) 3. (CSANSAIDs)

22

1.

(1) captopril 6.25-12.5mg patient

(2)

2. 2-3

(1) CHF

(2) ACEI Bradykinin

3. NSAID ()( replete the

intravascular fluid volume, )

1. Scr ( ACEI Scr 20-30%2-3 ) Scr

urine output (ARF)

2. sodium polystyrene sulfate ()

3. (CHF) hydralazinenitrates

: hydralazine afterloadnitrates preload

4. CHF Scr 2-3mg/dL(97 )

NSAID

500,000 2.5million

1. NSAID ibuprofen

2. (low urine vol. & sodium)(edema) +/- BUN

ScrK

Pathogenesis

1. stressed angiotensinIInorepinephrine

endothelinvasopressin PG

2. renal PG (prostacyclinPGE2) vascular endothelial

glomerular mesangial cells

3. cyclooxygenase PG

AKI

Risk factor

1. high plasma renin

CHF (ejection fraction


23

1. acetaminophennonacetylated salicylatesaspirinnabumetontramadol selective COX-2 inhibitormeloxicamcelecoxibvaldecoxib GI

2. NSAID 3. sulindac

( potent NSAIDrenal PG renal sparing effect) (1) sulindac sulfide (active) reversibly oxidized back to sulindac

(prodrug renal PG ) (2) sulindac sulfide CYP450 dependent mixed function oxidases

sulindac sulfoxide (3) Sulindac (cirrhosis)(ascites) Sulindac renal sparing effect

Management

1. 2. 3. NSAID +/-( steroid-

prednisone 1mg/Kg/d for 4 wks)

Cyclosporine(CSA) and Tacrolimus

1. Calcineurin inhibitors : Calcineurin IL-2 cytotoxin T lymphocyte

2. Acute hemodynamic mediated kidney injury

CSA 80%

1. 4 presentations asym

(1) Scr (2) (ARF) (3) delay graft function () (4) hemolytic uremic sydrome.()

2.

Pathogenesis

1. thromboxane A2endothelin RAA 2. nitric oxideprostacyclin 3. >

Risk factor

1. 65 (AGs amphotericin BacyclovirketoconazolecotrimoxazoleNSAIDs)

2. CSA (CYP450)(ketoconazoleitraconazolefluconazole ClarithromycinEMTelithromycinRitonavirCCB) 3. CSA (rifampinisoniazidphenytoinphenobarbitalcarbamazepine)

1. PKPD 24h 2. trough conc. 100-250ng/mLAUC trough 4400-5500mcg/h/L 3. CSA(cyclosporine)tacrolimus

Management

24

Obstructive Nephropathy

1.

2.

3. Scr

4.

Intratubular obstruction ()

Acyclovirsulfadiazineindinavirfoscarnetmethotrexate

Extrarenal obstruction ()

TCAindinavir

Nephrolithiasis() Triamtereneindinavir

1.

2. (tumor lysis syn. in high-grade lymphomas (Burkitt subtype)

acute lymphoblastic leukemia ) :

(1) K catabolism

ARF(acute oliguric)

(anuric renal failure)

(2) tumor lysis syn.urine uric acid/Cr1

(3)

a. Pretreatment hydration (NS)2.5L/d pH 7chemo

2-3d allopurinol 300-600mg

b. Rasburicaserecombinant urate-oxidase uric acid

allantoin ( tumor lysis syn.)

chemo 4-24h IV 0.15-0.2mg/Kg/d for 5days

3. (Rhabdomyolysis)Myoglobin

a. HMG CoA reductase inhibitor (statin ) gemfibrozilniacinCYP3A4 inhibitors

(CSAEMitraconazole statin )

b. CNS (alcohol, )(pressure necrosis)

c. CNS stimulants (amphetamines, cocaine, ecstasy, phencyclidine)


25

4. Urine pH = 4.5)

(1) acyclovir

(2) sulfadiazine acetylsulfadiazine

!

(3) (AKI, acute kidney injury) (congenital nephrotic syndrome)

Vit C oxalate

a. Thiazide Ca

b. Allopurinol 200mg/d purineuric acid Ca oxalate

c. K citrateK-Mg citrate (10meq, 1.08g 2-4 /d)

Ca oxalate

(4) MTX (methotrexate) 300mg/m2

a. MTX 12h 24-48h hydration urine output 1.5-2L/m2

b. urine pH7 sodium bicarbonate

: methotrexate (oligo-anuric kidney injury)

c. Leucovorin rescueMTX infusion24h leucovorin 10-15mg/m2 q6h for 8-10 doses

rescue therapy MTX 48h MTX level leucovorin

MTX 5 x 10-8M

5. pH = 6 Indinavir (protease inhibitor)(8%)

(nephrolithiasis -) 2-3L fluid/d

() 75% Indinavir ( indinavir )

6. Foscarnet (Antiviral pyrophosphate analog CMV retinitis CMV )

Ca+2 Ca foscarnet (glomerulonephritis)

7. LMW dextran dextran (volume expansion, rheological effect)

filtered dextran kidney injury

8. Triamterene calculi

(@@)

26

(1) (volume expansion)(100-200mL/h 24h)

(2)

(3)

a. (methotrexate, sulfonamide)

b. (indinavir, other protease inhibitors)

c. (PH>7.15) ARF

d.

a. NaHCO3 50mEq/L

b. acetazolamide 500mg 2-4 /d ()

: Acetazolamide : carbonic anhydrase inhibitor Diuretic Cl HCO3-

FDA

c. pot. Citrate(K citrate) 10meq, 1.08g 2-4 /d

d.

Glomerular Disease

1.

(1) NASID (2) penicillamine (3) Gold

(4) Heroin abuse

a. focal segmetnal glomerulosclerosis (FSGS)++

b. Heroin

c. IV virus

(5) Pamidronate ()

malignancy-associated hypercalcemia FSGS

2. NSAID Nephrotoxicity

Hemodynamic mediated kidney injury

Glomerular disease Acute allergic interstitial nephritis

Papillary necrosis ()

intraglomerular pressure

Immune(lymphokines )

Delayed hypersensitivity idiosyncratic

phenacetin acetaminophen

+/- GFR ()

humoral immune reactions cell-mediated injury

Prednisolone 0.5-1mg/Kg /d for 3-4wks

Prednisolone 1mg/Kg/d for 4wks

acetaminophen reduced glutathione


27

Tubulointerstitial disease

1.

2. delayed hypersensitivity(type IV)

3.

(1)

a.

b. (humoral immune reactions)

hapten host protein

c. (cell-mediated injury) mononuclear

inflammation

(2)

a.

b. (originates) papillae ()

4.

Acute allergic interstitial nephritis PenicillinNSAIDs

Chronic interstitial nephritis CSALiAritolochic acid

Papillary necrosis Combined phenacetinaspirincaffeine analgesic

acute allergic interstitial nephritis

(acute allergic interstitial nephritis)( AKI 3)

( Penicillins NSAIDs)

(1) Antimicrobials Acyclovir, AGs, amphotericin B, aztreonam, cephalosporins, ciprofloxacin, EM, EMB, indinavir, PNs(methicillin), rifampin, sulfonamides, tetracyclins, trimethoprim, sulfamethoxazole, vancomycin

(2) Diuretics Acetazolamide, amiloride, chlorthalidone, furosemide, triamterene, thiazides

(3) Neuropsychiatrics Carbamazepine, Li, phenobarbital, phenytoin, valproic acid

(4) NSAIDs Aspirin, indomethacin, naproxen, ibuprofen, diflunisal, piroxicam, ketoprofen, phenylbutazone, diclofenac, zomepirac

(5) Miscellaneous Acetaminophen, allopurinol, INF-, azathioprine, captopril, cimetidine, clofibrate, CSA, glyburide, gold, methyldopa, omeprazole, PAS, phenylpropanolamine, propylthiouracil, , ranitidine, sulfinpyrazone, warfarin sodium

( 97)

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1. Penicillins

(1) Methicillin prototype ()

(2) 14 (6-10) fever (80%)

maculopapular rash (25%)eosinophilia (80%)pyuria +hematuria

(90%), low-level proteinuria (90%)oliguria (20%) in severe cases of AIN

leukocytosisIgE

: EosinophiluriaAIN marker eosinophil

(3)

(4) Corticosteroids ARF ( guideline )

(5) Prednisone 1mg/Kg for 7 days

(6) Dialysis in oliguria

: Penicillins corticosteroids

2. NSAIDs

(1) Clinical presentationfenoprofen allergic interstitial nephritisprototype 50%

(2) T cell

(3)

(4)

(5) Gallium-67 renal imaging

a. minimal change disease

b. positive scan

(6) allergic hypersensitivity response idiosyncratic hypersensitivity

(7) Prevention idiosyncratic S/S

(8) Management

a. Prednisone 1mg/Kg/d for 4 wks

b. NSAID (fenoprofen) idiosyncratic hypersensitivity type-2

reaction steroid

~ ? C.


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Chronic interstitial nephritis

Li 1.

(1) (Nephrotic diabetes insipidus) () 87% (2) (acute tubular necrosis) (3) chronic tubulointestitial (4) nephritis ( ) (5) incomplete distal renal tubular acidosis

: 2. U/A : RBC, WBC, granular cast( urine ) 3. Pathogenesis ADH () 4. Risk factor

(1) Li conc.() (2)

(3) Scr2.5mg/dlBUN (4) neuroleptic agents

(5) Li + furosemide Li Li conc weakness, tremor, excessive thirst, confusion

5. Prevention

, ( )

6. Management Li amiloride()

~ ? D.

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Renal Replacement Therapy (RRT ) ~ AEIOU

Indication for Renal Replacement Therapy

Clinical Setting

A Acidbase abnormalities

() Metabolic acidosis resulting from the accumulation of organic and inorganic acid

E Electrolyte imbalance

() Hyperkalemia, hypermagnesemia

I Intoxications

() Salicylates, lithium, methanol, ethylene glycol, theophylline, phenobarbital

O fluid overload () Postoperative fluid gain

U Uremia () High catabolism of acute renal failure

Continuous renal replacement therapy (CRRT)

1. ARF , uremic toxin, K CRRTCRRT 2. , hypercatabolism CRRT

(1) CAVH / CVVH (Continuous arteriovenous or venovenous hemofiltration) sepsis

cytokine HDvasopressor (2) CAVHD / CVVHD (Continuous arteriovenous or venovenous hemodialysis) (3) CAVHDF / CVVHDF (Contnuous arteriovenous or venovenous hemodiafiltration) Li, MTX, procainamide, valproic acid

3. H- hemofiltration R(replacement) HD hemodialysis Di(dialysate) HDF hemodiafiltration R Di

4. CRRT mode (1) CAVH / CVVH convection / ultrafiltration ( plasma water into

the ultrafiltrate ) (2) CAVHDF / CVVHDF CAVH / CVVH convection / ultrafiltration plasma water

5. (HDF)(sieving coefficient SC) blood flow rate, Ultrafiltration rate, dialysate flow rateCRRT


31

Cyclosporine (CSA) Tacrolimus 1.

(1) acute hemodynamically mediated kidney injury GFR ()

:(p20) (2) >6-12 chronic interstitial nephritis (3) 6-12 - dose limiting adverse effect

2.

endothelin-1 nitric acid transforming growth factor-

3. Risk factor 50y/ocyclosporine / tacrolimus ARF 3-12m postOP ARF

4. (1) (2) twice weekly -

5. prednisolone, azathioprine

Aristolochic scid 1.

(1) Aristolochia fangchi (Guang fang ji ) aristolochic acid () (2) Chinese herb nephropathy ()3-5%

2.

(1) Scr

(2) atopical urothelial cell

(3) 6-24 ESRD (end-stage reanal disease) (4) nephroureterectomy 40-46% urothelial transitional cell

carcinoma() 3.

aristolactam Iaristolactam II DNA adducts () , DNA

4. (1) (2) dexfenfluramine +/- phentermine

5.

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Renal thrombosis

1. Thrombotic microangiopathy ( Hemolytic uremic syn thrombotic thrombocytopenic purpura , CNS , )

2. mitomycin C (


33

Renal vasculitis

(Thrombotic microangiopathy) hemolytic uremic syndrome thrombotic thrombocytopenic purpuraCNS

mitomycin C (

34

(1)9. CpCtrough Tobramycin Theophylline Li carbamazepine

(2)10.Aminoglycosides once daily dosing T1/2 Postantibiotic effect MIC

(A)11. gentamicin

gentamicin

(A)5 mg/kg, qd (B)1 mg/kg, tid (C)5 mg/kg, q8h (D)2 mg/kg, q12h

(D)12.gentamicin

(A)25 g/mL (B)25 mg/mL (C)30 g/mL (D)

(D) 13. gentamicintrough

(A) (B) (C) (D)

(1)14. ARF ionic contrast medium NS

NaHCO3 N-acetylcystine

(2)15. CT propranolol diclofenac

acetaminophen amlodipine

(B)16.radiocontrast media

acute tubular necrosis

(A)0.45% 0.9% NaCl (B)ACE inhibitors (C)Calcium channel blocker (D)Dopamine

(B)17.radiocontrast mediaacute

tubular necrosis

(A)

(B) 0.45%0.9% NaCl

(C) dopamine

(D) captopril

(3)18. Contrast mediumAcetylcysteine CCB

Diuretics Labetalol

(B)19.

(A)NSAIDs (B)Calcium channel blocker (C)ACE inhibitors (D)Metformin

(C)20.

(A)Celecoxib (B)Nifedipine (C)N-Acetylcysteine (D)Enalapril

(D)21 cisplatin

(A)mannitol (B) (C)amifostine (D)

(A)22. cisplatin

(A) 2-3 (B) (C) 4 furosemide

100-200 mL (D) 4 mannitol 100-200 mL

(B)23.

( A ) Azacytidine ( B ) Cisplatin ( C ) Dacarbazine ( D ) Vincristine


35

(B)24. amphotericin B desoxycholate

(A)diluent (B)

250 mL (C) (D)

(C)25. postrenal acute renal failure ? triamterene aspirin indinavir

methotrexate

(A) (B) (C) (D)

(D)26.10%AIDSindinavir

( A ) indinavir ( B ) ( C ) ( D )

(C)27.postrenal acute renal failure

(A)Penicillin (B)Aminoglycoside (C)Methotrexate (D)Amphotericin B

(C)28.postrenal obstruction

(A)Ampicillin (B)Celecoxib (C)Methotrexate (D)Tobramycin

(B)29. methotrexate

(A) 48 leucovorin rescue (B)Leucovorin methotrexate

(C) 24 100-200 mL (D)

methotrexate

(3)30.Acute myelogenous loukemia 28mg/dLScr 26mg/ dL Tumor lysis

syndrone ? probenecid colchicine allopurinol indomethacin

(2)31.? naproxen labetalol cyclosporine amphotericin B

(B)32.

(A)Aminoglycosides (B)Erythromycin(C)

NSAIDs (D)

(1)33. Carboplatin Doxorubicin 5FU

Paclitaxel

Calvert formula (Drug Information Handbook 18th Ed. 2009)

total dose (mg) = target AUC x (GFR + 25)

usual target AUCs

previously untreated patients: 6-8

previously treated patients: 4-6

(A)34. ATNacute tubular necrosis

furosemide 80 mg 1 1 mL/kg/hr

(A) furosemide 400 mg (B) 6-8 furosemide 100 mg (C)

furosemide 200 mgchlorothiazide 500 mg (D) 12

chlorothiazide 500 mg

36

(C)35. ATNacute tubular

necrosis1. NSAID 2. aminoglycoside 3. acyclovir 4. amphotericin B 5. hydralazine

(A)1, 2, 3 (B)1, 4, 5 (C)2, 4 (D)3, 5

(B)36.

( A ) Enalapril ( B ) Metoprolol ( C ) Naproxen ( D ) Trichlormethiazide

(B)37. 22 mg/dL 2.1 mg/dLurine

alkalinization

(A)Sodium bicarbonate IVpotassium bicarbonate IV

(B) potassium citrate 1 g 3 6

(C)Acetazolamide

(D) pH 8.5

(B)38. (A)-Aminocaproic acid

(B)Aristolochic acid (C)-Hydroxybutyric acid (D)Pipemidic acid

(A)39.aristolochic acid (A)interstitial

nephritis (B)hemodynamic (C)postrenal obstruction

(D)acute tubular nephritis

(B)40. (A) (B)

(C) (D)

(D)41.

(A) (B) (C) (D)

(A)42. captopril losartan

(A) (B) (C) (D)

983 A&B 15 ~ ~

983 A&B

O

藥物治療學共筆15 線上搶先看

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