1DRUG-INDUCED NEPHROTOXICITY

acute renal failure, nephrotic syndrome electrolyteimbalance

drug-induced nephrotoxicity1. 1

4 cardiac output 2. renal tubular epithelium glomerular filtrate tubular lumen 3. specific transport mechanism

4. luminal fluid tubular cell 5. Renal tubule

6. Renal tubular cell co-factor

Clinical spectrum drug induced nephrotoxicity - Acute functional renal failure - Renal vasculitis

- Glomerulonephritis - Lithiasis - Acute tubular necrosis - Electrolyte imbalance - Acute interstitial nephritis - Acid-base disorder

I. Acute functional renal failure

2 glomerular filtration rate pre post glomerular resistance arteriole functional renalfailure angiotensin converting enzyme inhibitor (ACEI) non-steroidal anti-inflammatory drug (NSAID)

1.1 ACEI 1, nephrosclerosis2, bilateral renal arterystenosis renal artery stenosis angiotension II (A II) efferent arteriole glomeruli GFR ACEI A II GFR functional renal failure

1. 2 NSAID hypovolemia prostaglandin dilatation effect renal blood flow prostaglandin renin mediator angiotensin II prostaglandin AII NSAID functional renal failure

2. Glomerulonephritis proteinuria glomerulonephritis nephrotic syndrome glomerulonephritis membranousglomerulonephritis proteinuria nephrotic syndrome sediments GFR D-penicillamine, gold salt, lithium, NSAID captopril Captopril proteinuria 1 450-600/ Pigott3 65 proteinuria captopril 13 nephrotic syndrome renal biopsy membranous glomerulonephritisproteinuria glomerulonephritis captopril sulfhydryl group D-penicillamine proteinuria nephroticsyndrome procainamide4, hydantoin5, probenecid6 , tolbutamide7 chlorpropamide8,quinidine9, dapsone10, psolaren11, methiamazole, interferon12, phenidione13 carbutamide14

3. Acute tubular necrosis (ATN)

3 ATN nephropathy acute renal failure dialysis 3.1 Antibiotics aminoglycoside, cephalosporin, Vancomycin, Polymyxin ciprofloxacin 3.2 NSAID 3.3 Contrast media 3.4 Antitumor drug cisplatin, streptozotocin, semustin (methy CCNU), metho-trexate, mithramycin cytosine arabinoside

4. Acute interstitial nephritis (AIN) acute interstitial nephritis 1 antibiotic B-lactam NSAID sulphonamide, rifampicin, phenidione,thiazide, triamterene, cimetidine allopurinol acute interstitial nephritis 0.8 ARF

Clinical manifestation AINAIN

hematuria gross eosinophilia ARF proteinuria nephrotic range ( NSAID) cast ARF AIN non-oliguric hyperchloremic metabolicacidosis mononuclear cell infiltration interstitium (lymphocyte, monocyte, macrophage eosinophil ) epitheloid granuloma interstitium granuloma AIN oliguric permanent renal impairment AIN antibody penicillin, rifampicin antibody tubular basement membrane AIN methicillin, cephalothin hydantoin prednisolone high dose AIN ARF prednisolone Neilson prednisolone AIN azotemia 1 3-4 prednisolone AIN GFR renal impairment AIN epithelioid granuloma 2 drug-related AIN 1 Drugs associated with acute interstitial nephritis

4Antibiotics Analgesics and NSAIDs OthersB-lactam antibiotics Analgesic DiureticsAmoxicillin Aminopyrin ChlorthalidoneAmpicillin Antrafenin FurosemideCarbenicillin Aspirin ThiazidesMethicillin Floctafenin Tienilic acidNafcillin Glafenin TriamtereneOxacillin Paracetamol Anticonvulsive agentsPenicillin G (acetaminophen) CarbamazepinePiperacillin Sulphinpyrazone DiazepamCefaclor NSAIDs DiphenylhydantoinCefotaxime Alclofenac PhenobarbitoneCephalothin Diclofenac PhenytoinCephradine Diflunisal Valproic acidOther antibiotics Fenclofenac Erythromycin Fenoprofen OthersEthambutol Ibuprofen AmalineGentamicin Indomethacin AllopurinolIsoniazid Ketoprofen Alpha-methyldopaLincomycin Mefenamic acid AmphetaminePolymyxin sulphate Naproxen AzathioprineQuinolones Niflumic acid Bethanidine

Piromidic acid Phenylbutazone Captopril Ciprofloxacin Piroxicam Cimetidine Norfloxacin Pirprofen Clofibrate

Rifampicin Sulindac Contrast agentsSpiramycin Tolmetin D-PenicillamineSulphonamides Zomepirac Gold and bismuth salts

Co-trimoxazole Herbal medicinesTetracyclines Interferon-alfaMinocycline PhenidioneVancomycin Warfarin sodium

4.1 Antibiotics

5 4.1.1 B-lactam beta-lactam AIN methicillin AIN 12-20 15 2-60 renal extrarenal penicillin G16-17,ampicillin18 amoxycillin AIN cephalosporin AIN cross-reaction penicillin AIN 4.1.2 Sulfonamide Co-trimoxazole AIN 18,19 AIN sulfonamide extrarenal manifestation methicillin renal manifestation 4.1.3 Rifampicin AIN rifampicin20-22 1970 fever, chill, myalgia, lumbar pain, nausea vomiting skin rash, eosinophilia, thrombocytopenia, hemolysis hepatitis AIN rifampicin oliguric ARF dialysis AIN steroid 4.1.4 vancomycin21,22, erythromycin23,24 quinolone derivatives piromidic acid19, norfloxacin25 ciprofloxacin26,27

4.2 NSAID AIN NSAID28 AIN extrarenal manifestation methicillin progressive renal impairment nephrotic syndrome 80 interstitium AIN glomeruli minimal change NSAID AIN NSAID steroid 3 AIN beta-lactam NSAIDs

4.3 Glafenin analgesic18 AIN

4.4 Diuretics Thiazide, triamterene furosemide19,30 AIN methicillin steroid

2 Diagnostic features in drug-related, acute interstitial nephritis

6 Proteinuria 1 /24 ( NSAIDs) FENa >1 Increased urinary leucocytes Macroscopic hematuria Fever, skin rash, arthralgias, and/or hepatocellular damage Blood eosinophilia Eosinophiluria Thrombocytopenia, autoimmune hemolysis Gallium scanning Renal biopsy

3 Clinical and pathologic features AIN B-lactams NSAIDs

B-lactams NSAIDsAge Any Older

Male : female 3:1 1:2 Time of development 2-60 days months Fever, rash, blood eosinophilia, and/or eosinophiluria Frequent Rare Non-oliguric, acute renal failure Frequent Frequent Nephrotic syndrome Very rare Frequent Requirement for dialysis 15-20% 30-40% Cellular infiltrates in renal biopsy Lymphocytes Common Common Eosinophils Frequent Sometimes Epithelioid granulomas Sometimes Rare Circulating anti-TBM antibodies Inconstant Absent Renal recovery Usual Frequent Efficacy of steroid therapy ? ?

4.5 Other Cimetidine16,19,32,33, allopurinol16,31 AIN methicillin AIN 1

5. Drug-induced renal vasculitis

7 vasculitis extrarenal manifestation vasculitis renal artery ARF penicillin,sulfonamide amphetamine34 proteinuria, hematuria,hypertension renal impairment cutaneous eruption nodule,abdominal pain, pancreatitis, arthritis pulmonary hemorrhage fibrinoid necrosis intima media cellular infiltration fibrin high dosesteroid

6. Drug-induced lithiasis 1-2 3

6.1 Sulfonamides sulfonamide sulfonamide sulfaperine, sulfaguanidine sulfadiazine N-acetylated sulfonamide sulfonamide sulfametrole, sulfamethopyrazine, sulfamethoxazole 6.2 Allopurinol Allopurinol uric acid , Lesch-Nyhan syndrome leukemia allopurinol . Allopurinol xanthine oxidase xanthine hypoxanthine 30 uric acid xanthine hypoxanthine

. Allopurinol oxypurinol 6.3 Glafenine glafenic acid hydroxylated form glafenic acid calcium oxalate glafenine 2-3 6.4 Carbonic anhydrase inhibitors Acetazolamide glaucoma aceta-zolamide

8 . Acetazolamide carbonic anhydrase inhibitor bicarbonate proximal tubule bicarbonate calcium phosphate . citrate magnesium 2 stone inhibitor 2 6.5 Triamterene Triamterene 150-300 / . Triamterene metabolite NaCl . Triamterene metabolite monohydrated calcium oxalate

6.6 Antacid Antacid silicate, aluminum hydroxide magnesium hydroxide metabolic alkalosis calcium phosphate 6.7 Furosemide nephrocalcinosis hypercalciuria piridoxilate, phenazopyridine

7. Electrolyte imbalance 7.1 Hyponatremia hyponatremia 7.1.1 Decreased total body sodium 7.1.1.1 Diuretic mannitol 7.1.1.2 Laxative abuse 7.1.2 Normal total body sodium 7.1.2.1 ADH-like action oxytocin, deamino-D-arginine vasopressin 7.1.2.2 ADH chlorpropamide, clofibrate, cyclophosphamidevincristin, carbamazepine, amitriptyline, isoproterenol, nicotin morphine 7.1.2.3. ADH chlorpropamide, cyclophosphamide indomethacin

7.2 Hypernatremia hypernatremia 7.2.1 Decreased total body sodium osmotic diuretic mannitol, urea

7.2.2 Increased total body sodium - Hypertonic saline hyponatremia abortion - Sodium bicarbonate acidosis CPR

9 - Mineralocorticoid7.3 Hypokalemia hypokalemia 7.3.1 Transcellular redistribution

- Beta2-adrenergic agonist salbutamol, terbutaline - Theophylline intoxication 7.3.2 Extrarenal loss - Laxative abuse 7.3.3 Renal loss - Diuretic K-sparing diuretics - Antibiotics aminoglycoside, penicillin high dose penicillin non-absorbable anion K+ K+ - Steroid - Mineralocorticoid

7.4 Hyperkalemia Hyperkalemia 7.4.1 Transcellular redistribution

- Mannitol - Beta2-adrenergic blockade propanolol - Succinylcholine 7.4.2 Excessive potassium intake - Potassium supplement (excess) - Potassium penicillin 7.4.3 Impaired renal excretion - NSAID - ACEI - Heparin - K-sparing diuretic amiloride, triamterene spironolactone - Cyclosporin A

7.5 Hypocalcemia Hypocalcemia 7.5.1 Calcium chelating agents citrate EDTA 7.5.2 Phosphate excess 7.5.3 Vitamin D deficiency dilantin, phenobarbiturate

7.6 Hypercalcemia hypercalcemia 7.6.1 Vitamin overdosage vitamin A D 7.6.2 Chlorothiazide diuretic

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7.6.3 Theophyllin toxicity 7.6.4 Antacid milk-alkali syndrome

7.7 Hypomagnesemia hypomagnesemia 7.7.1 Aminoglycoside 7.7.2 Cisplatin 7.7.3 Cyclosporin A 7.7.4 Amphotericin-B 7.7.5 Diuretic furosemide thiazide K-sparing diuretic acetazolamide hypomagnesemia

7.8 Hypermagnesemia MgSO4 eclampsia, milk ofmagnesia Mg (OH)2 antacid severe hypermagnesemia

8. Acid-base disorder 8.1 Metabolic acidosis metabolic acidosis 8.1.1 Wide anion gap metabolic acidosis - Lactic acidosis biguanide, INH overdose - Salicylate - Paraldehyde - Nalidixic acid 8.1.2 Normal anion gap metabolic acidosis - Intravenous amino acid solution for hyperalimentation - Laxative abuse - Diuretic Acetazolamide, amiloride - Antibiotic Amphotericin B - Lithium

8.2 Metabolic alkalosis 8.2.1 Saline responsive metabolic alkalosis 8.2.1.1 Renal alkalosis - Diuretic loop diuretic chlorothiazide - Antibiotic carbenicillin, penicillin 8.2.1.2 Exogenous alkalosis - NaHCO3 excess

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- Antacid - Citrate excess Blood transfusion 8.2.2 Saline unresponsive metabolic alkalosis exogenousmineralocorticoid

- Licorice, carbenoxolone - Mineralocorticoid hormone - Steroid

drug-induced nephrotoxicity

1. nephropathy 2. nephropathy 3. dehydration renal ischemia

4. sodium chloride drug induced nephrotoxicity Cis-platin sodium chloride tubular flow renin renal blood flow 0.9%NaCl hydration sodium chloride 5. furosemide drug induced nephropathy furosemide renal blood flow O2 chloride co-transport thick ascending limb furosemide hypovolemia electrolyte imbalance calcium channel inhibitor renin-angiotensin ACEI, renin antagonist

Clinical spectrum drug-induced nephropathy

1. Antibiotics1.1 Aminoglycoside

Aminoglycoside aminoglycoside (nephrotoxicity) (ototoxicity) (vestibulotoxicity) aminoglycoside gentamicin, tobramycin, amikacin, netilmicin, streptomycin neomycin nephrotoxicity neomycin > gentamicin >tobramycin > amikacin > netilmicin > streptomycin nephrotoxicity

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aminoglycoside 4-10 amino- glycoside35 aminoglycoside gentamicin 14.0 46, tobramycin 12.0, amikacin 9.4 netilmicin 8.7

1.1.1 aminoglycoside nephrotoxicity - 1. Age 2. Sex 3. Obesity 4. Preexisting liver disease 5. Preexisting kidney disease 6. Underlying disease - 41 1. Daily dose, interval, duration 2. Specific aminoglycoside 3. volume depletion 4. Hypokalemia 5. Hypomagnesemia 6. Metabolic acidosis 7. Concurrent medical agents (furosemide, amphotericin B, vancomycin,cephalosporin, NSAID, ACEI, cyclosporin A, cisplatin contrast media) aminoglycoside GFR renal tubular cell aminoglycoside

aminoglycoside

aminoglycoside renal tubular cell amino-glycoside

45 hemodynamic, volume electrolyte serum creatinine

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GFR

aminoglycoside GFR aminoglycoside Underlying disease aminoglycoside sepsis clinicalhypotension44 aminoglycoside Aminoglycoside therapeutic range 1-2 aminoglycoside aminoglycoside gentamicin, tobramycin, amikacin,netilmicin Volume depletion hypokalemia aminoglycoside tubular cell magnesium aminoglycoside brush border proximal tubule aminoglycoside Metabolic acidosis aminoglycoside brush border proximal tubule aminoglycoside

1.1.2 Clinical manifestation of aminoglycoside nephrotoxicity1.1.2.1 ARF

ARF aminoglycoside 4-10 1-2 nonoliguric43 aminoglycoside polyuria36 ARF polyuria aminoglycoside adenylate cyclase ADH collectingtubule aminoglycoside tubulointerstitium medullary interstitium hypertoxicity aminoglycoside proximal tubule glycosuria, aminoaciduria Fanconi-like syndrome proteinuria, leukocyturia enzymuria37 enzyme brush border alkaline phosphatase39,leucine aminopeptidase, r-glutamyltransferase enzyme lysosome N-acetyl-

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glucosaminidase (NAG) enzymuria proximal tubule aminoglycoside ARF 1.1.2.2 Electrolyte imbalance Aminoglycoside renal loss39 hypokalemia hypomagnesemia proximal tubule amino-glycoside non-depolarized neuromuscular blocking effect hypokalemia muscle paralysis

1.1.3 Pathogenesis Aminoglycoside glomeruli phospholipid receptor brush border proximal tubule aminoglycoside 42 aminoglycoside proximal tubular cell endocytosis tubular cell permeability lysosome40 enzyme 38 mitochondria aminoglycoside half-life tubular cell 10 cortex aminoglycoside 1 2 1.1.4 Prevention and Treatment (1) indication aminoglycoside

(2) risk factors amino- glycoside

(3) aminoglycoside nephrotoxicity netilmicin (4) aminoglycoside creatinine clearance 24 Cockcroft andGault ( 1) aminoglycoside creatinine clearance ( 1) Ccr 0 / aminoglycoside 10 % Ccr 120 / aminoglycoside 100% CCr = 20 / aminoglycoside 25 % (5) (interval) aminoglycoside 8 12 aminoglycoside56 (single daily dose) aminoglycoside postantibiotic effect

1 aminoglycoside ( A) dose fraction

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creatinine clearance

ARF (devided dose) aminoglycoside glomeruli proximal tubular cell

(6) (duration) 10-12 7 (7) aminoglycoside serum creatinine 2-3 serum creatinine 24 creatinine clearance enzymuria serum creatinine proximal tubule (8) ARF does aminoglycoside peak trough level (9) ARF aminoglycoside ARF recovery 2-3 (10) polyaspartic acid52-57 aminoglycoside tubular cell aminoglycoside bacteria

1.2 Amphotericin B antifungal drug

amphotericin B 80-90

1.2.1 Clinical manifestation Amphotericin B nephrotoxicity 1.2.1.1 Acute renal failure (ARF) amphotericin B47 serum creatinine - hypovolemia - nephrotoxic drug aminoglycoside, cyclosporin A, NSAID - amphotericin B 0.5 // 600

ARF - Amphotericin B tubular cell sterol cellmembrane - Afferent arteriolar constriction tubuloglomerular feedback - Deoxycholate amphotericin B tubular cell - Amphotericin B renal vasoconstriction

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1.2.1.2 Distal renal tubular acidosis (RTA) distal RTA back leak sterol cell membrane tubular cell H+ intercalated cell circulation 1.2.1.3 Hypomagnesemia

1.2.2 Prevention (1) amphotericin B 0.5 // 600 ARF (2) amphotericin B hypovolemia nephrotoxic drug (3) 0.9% NaCl 1000 ml 3-4 amphotericin B (4) calcium channel blocker renal vasoconstriction amphotericin B (5) amphotericin B phospholipid vesicle (liposome) liposome reticuloendothelial system amphotericin B amphotericin B

1.3 Vancomycin Vancomycin methicillin resistant staphylococcusaureus (MRSA) pseudomembranous enterocolitis Clostridium deficile vancomycin ARF purity ARF vancomycin purity ARF aminoglycoside vancomycin ARF vancomycin acute interstitial nephritis

1.4 Sulfonamide ARF Intratubular crystallization AIN trimethoprim creatinine secretion creatinine

1.5 Tetracycline antianabolic azotemia hyperkalemia renalinsufficiency doxycycline antianabolic tetracycline demeclocycline ADH collecting tubule nephrogenic DI tetracycline proximal RTA

1.6 Acyclovir

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acyclovir ARF intratubular crystalobstruction acyclovir bolus

1.7 Foscanet antiviral drug cytomegalovirus (CMV) retinitis ARF acute tubular necrosis 65 renal insufficiency nephrotoxic drug aminoglycoside hydration 0.9% NaCl foscanet nephrotoxicity

1.8 Pentamidine pneumocystis pneumonia AIDS azotemia 25 RTA type IV

2. Analgesic analgesic salicylate, anilides pyrazolone aspirin, phenacetin,acetaminophen antipyrine analgesic aspirin NSAID anti-inflammatory analgesic combination phenacetin + caffeine + antipyrine aspirin + caffeine (codeine) + phenacetin (acetaminophen) 58

2.1 Renal manifestation analgesic nephrotoxicity Analgesic nephropathy chronic tubulointerstitial nephropathy papillarynecrosis 59,60 analgesic 49-51 analgesic syndrome Analgesic nephropathy tubular function urinaryconcentration, acidification electrolyte handling polyuria, renal tubularacidosis, hyponatremia natriuresis mild proteinuria, leukocyturia,hematuria ( papillary necrosis infection) papilla renal impairment chronic renal failure renal pelvis, ureter bladder uroepithelial carcinoma analgesic nephropathy

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(1) Papillotoxin analgesic paracetamol(acetaminophen), phenacetin acetylsalicylic acid61 medulla acetaminophen cytochrom P-450 high reactive metabolite glutathione reactivemetabolite acetaminophen medulla glutathione reactive metabolite protaglandin62 oxidation reactive metabolite medulla acetylsalicylic acid prostaglandin reactive metabolite analgesic phenacetin acetaminophen acetylsalicylic acid analgesicnephropathy (2) Hemodynamic factor analgesic NSAID63 prostaglandin vasodilatory prostaglandin medulla papillary necrosis acetaminophen phenoacetin prostaglandin acetylsalicylic acid

2.2 3 59 2.2.1 Capillary sclerosis mucosa renal pelvis ureter 2.2.2 Renal papillary necrosis 2.2.3 cortical parenchyma cortical atrophy, interstitial fibrosis lymphocyte infiltration interstitium analgesic nephropathy analgesic analgesic syndrome - Cardiovascular complication64,65 atherosclerosis

- Gastrointestinal complication66 peptic ulcer, erosive gastritis - Hematological complication67 anemia, agranulocytosis - Skeletal complication68 - Psychosomatic aspect69 depression, irritation, anxiety headache, insomnia

2.3 Treatment 2.3.1 analgesic nephropathy 2.3.2 Hydration 2 2.3.3 2.3.4 papilla51 2.3.5

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2.4 Prevention analgesic analgesic phenacetin,acetaminophen, salicylate pyrazolone analgesic nephropathy codeine, caffeine barbiturate analgesic nephropathy codine, caffeine barbiturate analgesic

3. Non-steroidal anti-inflammatory drugs (NSAID) NSAID NSAID NSAID acute renalfailure, nephrotic syndrome hyperkalemia NSAID prostaglandin anti-inflammatory, analgesic antipyretic

3.1 Prostaglandin (PG) PG unsaturated fatty acid phospholipid cell membrane phospholipase A270 phospholipid arachidonic acid cycloxygenase arachidonic acid protaglandin endoperoxide prostaglandin synthetase specific prostaglandin PG PGE2, PGF2 ,prostaclcycline PGI2 thromboxane A2 PGI2 renal cortex PGE2 renal medulla

prostaglandin (1) Renal blood flow (RBF) glomerular filtration rate (GFR) 71 PG GFR angiotensin IIcathecholamine alpha-adrenergic stimuli renal vessels GFR PG renal vessel PG renal vessels, renal blood flow GFR (2) Renin renin72 baroreceptor, adrenergic stimuli prosglandin (PGE2, PGI2) NSAID hypo-reninemia, hypoaldosteronism hyperkalemia

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NSAID hypokalemia Bartter's syndrome hypokalemia PG

4 Chemical classification of some of the more commonly prescribed non-steroidal anti-inflammatory drugs

Chemical family Generic name Carboxylic acids Salicylates Aspirin Diflunisal Benorylate Acetic acids Tolmetin Diclofenac Indoles Indomethacin Sulindac Propionic acids Ibuprofen Naproxen Ketoprofen Flubiprofen Fenoprofen Fanamates Mefenamic acid Flufenamic acid Pyrazoles Phenylbutazone Oxyphenbutazone Oxicams Piroxicam 5 The important renal effects of prostaglandins and thromboxane Site of action Action Effect PGI2 (prostacyclin) Glomeruli Vasodilatation Increased GFR PGE2 Medulla Vasodilatation Increased Na excretion Inhibition of ADH PGE2, PGI2 Intrarenal Vasodilatation Increased renal perfusion arterioles Efferent Vasodilatation Increased Na excretion arterioles Juxtaglomerular Increased cAMP Increased renin release apparatus PGE2, PGI2 and Distal tubules Inhibition of Inhibition of ADH PGF2 alfa cAMP TxA2 Intrarenal Vasoconstric- Decreased renal perfusion arterioles tion

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(3) Natriuresis diuresis PG renal tubule natriuresis73 ADH collecting tubule diuresis PG cirrhosis, nephrotic syndrome heart failure

3.2 Clinical nephrotoxicity NSAID 3.2.1 Acute renal failure (ARF) renin cirrhosis, heart failure, chronic renal failure sodiumdepletion PG renal blood flow GFR NSAID PG ARF ARF hemodynamic change renal ischemia ARF recovery functional renalfailure tubule organic renal failure acute tubular necrosis NSAID ARF 2-3 NSAID ARF NSAID ARF dialysis recovery phase 3.2.2 Acute interstitial nephritis (AIN) NSAID AIN ARF NSAID NSAID allergic reaction AIN methicillin , , eosinophilia AIN74 heavy proteinuria nephrotic syndrome 29 NSAID AIN fenoprofen75 sterile leukocyturia albuminuria nephrotic range azotemia renal biopsy tubulointerstitialmononuclear cell infiltration mononuclear cell T lymphocyte patchy tubular cell necrosis T-lymphocyte tubulointerstitium pathogenesis immune NSAID PG cyclooxygenase leukotriene lipoxygenase leukotriene protent chemotactic lymphocyte immunological control AIN proteinuria lymphokine T-lymphocyte glomerular permeability nephrotic syndrome NSAID AIN proteinuria dialysis renal function interstitial fibrosis chronic renal failure prednisolone 30-60 2-4 renal function streoid 3.2.3 Renal papillary necrosis (RPN)

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Renal papillary necrosis NSAID analgesic nephropathy renal papillary necrosis 2 3.2.3.1 NSAID renal medullary blood flow PG medulla NSAID PG medulla ischemicnecrosis 3.2.3.2 medulla PG high reactive metabolite NSAID PG medulla high reactive metabolite renal papillary necrosis hematuria papilla

medullary cavities, papillary calcification, calyceal horn, ringshadow clubbed calyces NSAID superimposedinfection obstruction infection obstruction papilla renal papilla necrosis azotemia chronic renal failure 3.2.4 Chronic renal failure (CRF) NSAID CRF76 chronic tubulointersitial nephritis histopathology tubulointerstitial fibrosis,tubular atrophy patchy mononuclear cell infiltration proteinuria strile leukocyturia CRF AIN renal papillarynecrosis NSAID CRF NSAID end-stage renal disease 3.2.5. Edema PG natriuresis diuresis NSAID hyponatremia NSAID diuretic severe hyponatremia77 3.2.6 Hyperkalemia PG renin renin angiotensin II aldosterone NSAID hyporeninemic hypoaldosteronism 78-79 potassium hyperkalemia mild metabolic acidosis hyperkalemia NSAID chronic renal failure NSAID hyperkalemia 3.2.7 Glomerulonephritis NSAID glomerulonephritis mesangial proliferation glomerulo-nephritis vasculitis NSAID

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piroxicam 80 NSAID vasculitis glomerulonephritis steroid 81 Sulindac (Clinoril) NSAID PG sulindac 82 NSAID metabolize active product sulfide active sulindac oxidation sulfoxide inactive product sulindac PG sulindac PG sulindac NSAID PG

4. Antineoplastic drugs 4.I Alkylating agent 4.1.1 Cisplatin Cisplain cis-diammine dichloroplatinum (CDDP) antineoplastic drug solid tumor97 testicular carcinoma, ovarian carcinoma, bladder carcinoma, osteosarcoma, neuroblastoma, headand neck carcinoma cisplatin , , cisplatin 100 /. acute renal failure Cisplatin chronic renal failure

4.1.1.1 Clinical manifestation Cisplatin nephropathy (1) Acute renal failure (ARF) Cisplatin ARF Cisplatin ARF Cisplatin 100 /. Cisplatin glomerular filtration tubular secretion Cisplatin renal blood flow renal vasoconstriction tubularcell Cisplatin tubular cell 5 99 Cisplatin renal function chronic renal failure (2) Hypomagnesemia Cisplatin hypomagnesemia98 50 hypomagnesemia magnesium Cisplatin renal tubule distal collecting tubule hypomagnesemia hypocalcemia hypokalemia

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4.1.1.2 Pathogenesis Cisplatin nephrotoxicity hypothesis

(1) platinum atom Cisplatin cell (2) Stereospecificity Cisplatin cis trans-dichlorodiamine cis-form (3) Biotransformation Cisplatin Cisplatin chloride monochloro-monoaquodiammine platinum diaquodiammine platinum100 purine pyrimidine base nucleus (4) Cisplatin reactive metabolites macro-molecule

4.1.1.3 Prevention (1) Cisplatin 120/ ARF slow infusion 30 0.9% NaCl 250 200 /. 3% NaCl 102 ARF (2) saline hydration 0.9% NaCl KCl 20 mEq/ 150-200/ 12 Cisplatin 12-24 (3) tubular flow furosemide mannitol tubular cell (4) probenecid Cisplatin tubule (5) Cisplatin intraperitoneal route103 advanced stageovarian carcinoma, mesothelioma malignant carcinoid ARF Cisplatin circulation thiosulfate104 Cisplatin antineoplastic drug Cisplatin 270 /. ARF

4.1.2 Cyclophosphamide (CPA) CPA antineoplastic drug hematologic malignancy, lymphoma, multiple myeloma solid tumor bone marrow, CPA active metabolite antineoplastic drug

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4.1.2.1 Clinical manifestation Cyclophosphamide nephrotoxicity

(1) Acute hemorrhagic cystitis CPA CPA 1 active form CPA urothelium active form CPA

(2) Hyponatremia CPA 50/ hyponatremia hyponatremia active metabolite CPA distal collecting tubule105 ADH dilutional hyponatremia ADH

4.1.2.2 Prevention (1) Acute hemorrhagic cystitis CPA high does saline hydration 150-200 / 24 active metabolite CPA (2) Hyponatremia 0.9% NaCl solution hydration105 (150-200 /)4-6 , 24 CPA ADH

4.1.3 Streptozotocin (ST) ST nitrosourea streptomyces acromogenes metastatic islet cell carcinoma pancreas carcinoid tumor ST metabolite 70

4.1.3.1 Clinical manifestation ST (1) Hypophosphatemia ST proximal tubule106 Fanconi'ssyndrome ST 2 /./ (2) Proteinuria glomerular proteinuria107 ST nephrotic range ST renal failure

4.1.3.2 Prevention (1) ST 1.5 /./ 0.5 /./ 5

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(2) proteinuria tubular dysfunction ST (3) saline hydration

4.1.4 Semustine Semustine (methyl CCNU) lipid-soluble nitrosourea malignantmelanoma, brain tumor malignant lymphoma108 Semustine blood brainbarrier 20 60 metabolite 72

4.1.4.1 Clinical manifestation Semustine nephrotoxicity renal function impairment 1 4-5 chronic renal failure chronic dialysis 1,400 /. 109 glomerulosclerosis, tubular atrophy, interstitial fibrosis

4.1.4.2 Prevention Semustine 1,400 /. nephro-toxicity

4.2 Antimetabolites 4.2.1 Methotrexate (MTX) antineoplastic drug gestational trophoblasticchoriocarcinoma, acute lymphocytic leukemia, bladder cancer, breast carcinoma, squamous cellcarcinoma head and neck osteogenic sarcoma myelosuppression, mucositis, diarrhea, dermatitis hepatitis MTX folic acid anologue dihydrofolate reductase folic acid folate metabolism

4.2.1.1 Clinical manifestation MTX nephrotoxicity (1) Acute renal failure (ARF) MTX ARF high does (50-250 /)110 ARF nonoliguric serum creatinine GFR ARF

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- MTX metabolite glomerular filtration tubular secretion MTX metabolite distal tubule pH MTX high dose dehydration MTX metabolite intrarenal obstruction 111 ARF - High dose MTX direct toxicity renal tubule ARF high doseMTX Intrarenal MTX precipitation proximal tubular necrosis - High does MTX renal blood flow renal vasoconstriction

4.2.1.2 Prevention (1) high dose MTX (2) Hydration alkalinization pH 7.0 5%D/W1000 + sodium bicarbonate 44-66 mEq 150-200 /

4.2.2 5-Fluorouracil (5-FU) 5-FU fluoro-deoxyuridine monophosphate thymidylate synthetase DNA

4.2.2.1 Clinical manifestation 5-FU nephrotoxicity Hemolytic uremic syndrome (HUS) 5-FU Mitomycin-C112,113 ARF, microangiopathic hemolytic anemia thrombocytopenia intimal hyperplasia artery, fibrin thrombi arteriole, glomerular necrosis, tubular atrophy HUS

4.2.3 5-Azacytidine (5-AZ) 5-AZ pyrimidine compound refractory acute nonlymphocytic leukemia 5-AZ proximal tubular dysfunction114 glucose, bicarbonate, phosphate, sodium renal glycosuria, polyuria,hypophosphatemia proximal RTA 5-AZ

4.2.4 Cytosine Arabinoside (CA) 6-Thiogaunine

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CA DNA polymerase DNA acute leukemia non-Hodgkin's lymphoma 6-thiogaunine acute leukemia renal insufficiency

4.3 Antitumor antibiotics 4.3.1 Mitomycin-C (MMC) antibiotic Streptomyces caespitosis squamous cell CA cervix, transitional cell CA bladder 5-FU doxorubicin MMC MMC

Clinical manifestaion MMC nephrotoxicity Hemolytic uremic syndrome (HUS) MMC proteinuria ARF MMC course 6 1.5-4.0 / ARF microangiopathic hemolytic anemia thrombocytopenia115 HUS plasma exchange ARF HUS MMC 5-FU

4.3.2 Mithramycin antibiotic Streptomyces tanashiensis testicular carcinoma glioblastoma

Clinical manifestation Mithramycin nephrotoxicity Acute renal failure mithramycin 25-50 / 5 proteinuria creatinine clearance swelling,hydropic degeneration necrosis tubule proximal distal tubule glomeruli mithramycin low does 25 /116 hypercalcemia boneabsorption mithramycin low does renalinsufficiency

4.3.3 Doxorubicin (Adriamycin)

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solid tumor doxorubicin cardiomyopathy

5. Biologic agent 5.1 Interferon Interferon glycoprotein antitumor, antiviral, immune modulation

3 - Alfa interferon (leukocyte lymphoblastoid) - Beta interferon (fibroblast) - Gamma interferon (immune) interferon hairy-cell leukomia, ALL

5.1.1 Clinical manifestation interferon nephrotoxicity 5.1.1.1 Nephrotic syndrome interferon proteinuria117 2 proteinuria nephrotic range 2 proteinuria nephrotic syndrome minimal-change disease immune complex nephrotic syndrome interferon mediator glomerular basementmembrane permeability albumin 5.1.1.2 Acute renal failure ARF interferon acute interstitial nephritis 117 interstitial edema, interstitial filtration lymphocyte, eosinophil plasmacell focal necrosis tubule immune complex nephrotic syndrome interferon immune interstitial nephritis acute tubular necrosis interferon 118

5.2 Interleukin-2 Interleukin-2 glycoprotein 15,000 natural killer cell immune antigen interleukin-2

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recombinant DNA technique interleukin-2 lymphokine-activated killer cell metastasis melanoma, renal cell colorectal cancer

5.2.1 Clinical manifestation Interleukin-2 nephrotoxicity 5.2.1.1 Acute renal failure interleukin-2 ARF 119 IL-2 ARF IL-2 (1) Capillary leak syndrome IL-2 permeability intravascular compartment hypotension, oliguria, sodium retention 119 (2) Uric acid overproduction lymphokine-activated killer cell uric acid crystal renal tubule acute uric acid nephropathy (3) NSAID (Indocid) IL-2 IL-2 NSAID vasodilatory prostaglandin renal ischemia

5.2.2 Prevention ARF IL-2 IL-2 infusion bolus IL-2 lymphokine activated killer cell initialcourse maintenance course IL-2

6. Lithium Lithium 197083 bipolar unipolar affective disorder lithium therapeutic range lithium glomeruli sodium proximal tubule secretion reabsorption distal collecting tubule clearance lithium 20-25 GFR lithium proximal tubule sodium 84 sodium proximal tubule lithium

6.1 Clinical manifestation lithium nephrotoxicity 6.1.1 Polyuria (Nephrogenic DI) lithium polyuria ihvp]t 40 lithium collecting tubule ADH nephrogenic DI 85 lithium cycle AMP adenylcyclase ADH receptor collecting tubule 6.1.2 Distal renal tubular acidosis (Distal RTA)

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lithium lithium distal tubule86 acidification acid loading urine pH 5.5 fractional excretion bicarbonate distal RTA incomplete 6.1.3 Progressive impairment of urinary concentrating ability lithium polyuria polyuria nephrogenic DI lithium polyuria chronic focal interstitialnephropathy lithium interstitium concentrating capacity87 6.1.4 Decreased Glomerular filtration rate (GFR) Lithium ARF acute intoxication overdose lithiumARF acute tubular necrosis (ATN) lithium GFR lithium 88-89 chronic focal interstitial nephropathy lithium chronic focal interstitial nephropathy neuroleptic lithium 6.1.5 Nephrotic syndrome nephrotic syndrome lithium minimal changedisease lithium

6.2 Prevention and Treatment 6.2.1 lithium toxicity 0.4-0.6 / 6.2.2 polyuria nephrogenic DI thiazide polyuria nephrogenic DI hypovolemia lithium proximal tubule acute intoxication amiloride90 thiazide amiloride lithium proximal tubule acute intoxication 6.2.3 Chronic focal interstitial nephropathy lithium acute intoxication lithium acute intoxication dehydration lithium lithium creatinine clearance

7. Constrast media

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Contrast media nephropathy nephrotoxic agent contrast media diatrizoate,Iothalamate matrizoate intravenous urography, angiography,cholecystography computerized tomography contrast media ..1970 contrast media 120 contrast media nephrotoxic agent

7.1 Risk factors - Dose of contrast media

- Abdominal aortic angiography - Multiple studies in 72 hours - Dehydration - Advanced age - Diabetes mellitus - Impaired renal function - Multiple myeloma - Impaired liver function - Congestive heart failure

contrast media nephropathy risk factor 10 risk factor impaired renalfunction contrast media contrast media renal function 31 contrast media nephropathy serum creatinine contrast media nephropathy risk factors hypertension arteriosclerotic peripheral vascular change contrastmedia nephropathy Multple myeloma risk factor contrast media nephropathy impaired renal function multiple myeloma Bence-Jone protein Tamn-Horsfallprotein renal tubule contrast media contrast media diatrizoate Bence-Jone protein renal tubule risk factors dose route contrast media contrast media contrast media

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artery vein abdominal aorta renal bloodflow dehydration, congestive heart failure

7.2 Clinical manifestation Contrast media nephropathy renal function oliguric renal failure dialysis acute renal failure dialysis chronic renal failure Acute renal failure contrast media 50 oliguric serum creatinine BUN 2 3-5 10-14 Dialysis impaired renal function

6 Prevalence of Contrast Nephropathy by Route of Injection (Intravenous or Intraarterial),Renal Function, and Presence or Absence of Diabetes Mellitus Prevalence of contrast nephropathy Intravenous Intraarterial Risk factor Retrospective Prospective Retrospective Prospective (3)a (5)a (4)a (6)a

Nondiabetics Creatinine 1%(3/264) 6%(18/283) 7%(38/509) 7%(27/396) 1.5 mg/dl Diabetics Creatinine 3%(1/35) 28%(2/7) 7%(2/30) 9%(13/147) 1.5 mg/dl

ARF contrast media hyalin cast, calcium oxalate amophous urate crystal .. urine sodium fractional excretion sodium (FENa)

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Contrast media nephropathy contrast media hyperosmolarity, ionic activity, iodine content contrastmedia renal tubule

7.3.1 Direct nephropathy121 renal tubule contrast media vacuolization proximal renal tubule thick ascending limb pinocytosis contrast media tubule cell 7.3.2 Renal ischemia122,123 contrast media renal artery renal ischemia hyperosmolarity contrast media tubuloglomerular feedback afferent arteriole contrast media solute distal tubule ARF mannitol 7.3.3 Contrast media peripheral vasodilation cardiac output nonionic contrast media 7.3.4 Rheologic effect contrast media osmolarity microcirculation contrast media osmolarity 7.3.5 Intratubular obstruction contrast media proteinuria calcium oxalate uric acid Tamm-Horsfall glycoprotein multiple myeloma124 Bence-Jone protein contrast media renal tubule 7.3.6 Hypersentivity reaction125 contrast media drug-induced acute interstitial nephritis

7 Mechanisms and Evidence of Radiographic Contrast Agent Nephrotoxicity Volume depletion in "preparation" for study After contrast administration Renal ischemia Decreased cardiac output and peripheral vasoconstriction Selective renal vasoconstriction Decreased blood flow in microcirculation Osmotic diuresis with volume depletion Glomerular damage Nonselective proteinuria Tubular injury Cytoplasmic vacuolization ("osmotic nephrosis")

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Enzymuria Intratubular obstruction Increased uric acid and oxalate excretion Possible Tamm-Horsfall protein-contrast medium precipitation Possible light chain-contrast medium precipitation Acute interstitial nephritis Renal biopsy results Eosinophiluria

7.4 Prevention therapy 7.4.1 contrast media risk factors - contrast media - contrast media 4-5 contrast media - contrast media nonionic126 osmolarity metrizamide, iohexol iopamidol - dehydration - saline hydration 200 / contrast media cardiovascular instability - mannitol127 furosemide contrast media intratubular obstruction prostaglandin NSAID mannitol/ furosemide - pH 7 contrastmedia, uric acid Bence-Jones protein intratubular obstruction 7.4.2 contrast media nephropathy ARF ARF dialysis ARF contrast media

8. Gold salts gold salts rheumatoid arthritis gold salts sodiumaurothiopropanol sulfonate, sodium aurothiosulfate aurothioglucose

8.1 Clinical manifestaion Gold salt nephrotoxicity

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8.1.1 Nephrotic syndrome Gold salt rheumatoid arthritis proteinuria 2.6-5.3 91 nephrotic syndrome 40 proteinuria proteinuria gold salts 5-6 proteinuria 92 90 membranous nephropathy 10 minimalchange disease mesangial glomerulonephritis nephropathy gold salt gold immune complex gold glomerular basement membrane

8 Prevention of Contrast Nephropathy in High-Risk Patient

Procedure Mechanism of prevention Avoid contrast studies Limit unnecessary exposure to contrast medium. Use nonionic, less hyperosmolar Decrease direct toxicity and osmotic diuresis contrast media Reduce does of contrast medium Limit dose-dependent toxicity Avoid multiple sequential Limit cumulative toxicity from contrast media and studies dehydration from preparations. Avoid concomitant nephrotoxic Concomitant B-blocker and calcium antagonist therapy or vasoactive drugs can potentiate contrast medium-induced systemic hypotension. Nonsteroidal ntiinflammatory drugs can decrease renal blood flow Saline hydration Improve renal blood flow and decrease intratubular concentration of contrast medium uric acid oxalate, and protein Furosemide and/or mannitol Increas renal blood flow and decrease intratubular infusion solute and protein concentration Alkalinize urine to pH 7.5 Increase uric acid solubility and decrease tubular damage by Bence Jones proteins Allopurinol therapy for Decrease uricosuria, particularly with patient with hyperuricemia cholecystographic agents.

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antibody in situ gold antigen glomeruli nephroticsyndrome hypertension, hematuria renal insufficiency 8.1.2 Prevention Treatment - nephropathy gold salt gold salt auranofin auranofin92 proteinuria 1-2 proteinuria gold salt - proteinuria nephrotic syndrome gold salt proteinuria 4-18 prednisolone immunosuppressive drug nephrotic syndrome gold salt

9. D-Penicillamine inflammation rheumatoid arthritis chelatingagent heavy metal Wilson's disease94, chronic lead poisoning

9.1 Clinical manifestation D-penicillamine nephrotoxicity Nephrotic syndrome proteinuria D-penicillamine 10-20 mild nephrotic syndrome nephrotic syndrome 50 proteinuria D-penicillamine proteinuria 7-18 95 5-10 proteinuria proteinuria 85 membranous nephropathy minimal change disease, mesangioproliferativeglomerulo nephritis focal necrotizing glomerulonephritis D-penicillamine lupus-like syndrome96 renal involvement D-penicilliamine rapidly progressive glomerulonephritis (RPGN) dyspnea, hemoptysis, pleural effusion gross hematuria Goodpasture's syndrome anti GBMantibody

9.2 Treatment - proteinuria nephrotic syndrome D-penicillaine 6-8 proteinuria D-penicillamine proteinuria proteinuria nephrotic syndrome

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- lupus-like syndrome renal involvement D-penicillamine high does prednisolone, cyclophosphamide plasmapheresis

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