Nephrotoxic Drugs

中國醫藥大學北港附設醫院

曾裕雄

全民健康保險雙月刊第 85 期 (99 年 5 月號 )

台灣腎臟病現況• 腎臟病已成台灣新國病，洗腎人數突破 6 萬人– 扣除死亡，每年約以 2,000 人的速度淨增加

• 全球慢性腎臟病盛行率為 10 ％ -12 ％，台灣為 11.9 ％，亦即平均每 10 人中至少有 1 人罹患慢性腎– 溫啟邦研究室 ,2008

• 43 ％是糖尿病患合併症、腎絲球腎炎占 20 ％，高血壓合併症占 15 ％，不當用藥及老化占 12 ％，其他原因占 10 ％

Drugs cause approximately 20 percent of community- and hospital-acquired episodes of acute renal failure

Cynthia A. Naughton, PharmD, BCPS North Dakota State University College of Pharmacy, Nursing, and Allied Sciences in Fargo

Possible Mechanisms

• Altered intraglomerular hemodynamics• Tubular cell toxicity• Inflammation• Crystal nephropathy• Rhabdomyolysis• Thrombotic microangiopathy.

Risk Factors-patients

• Age & Sex• Previous renal disease• DM ,multiple myeloma, lupus, Proteinuric disease• Salt retaining disease (liver cirrhosis, heart

failure)• Acidosis or K or Mg depletion• Hyperuricemia or hyperuricosuria• Kidney transplantation

Risk factors-Drugs

• Inherent nephrotoxic effects• Dose• During, frequency , and form of

administration• Repeated exposure• Drug intoxication

The situation We meet

Acute interstitial nephritis• Etiology:– Drug

• Antibiotic• NSAIDs• Diuretics: furosemide,Thiazide• Cimetidine• Allopurinol• Proton pump inhibitor

– Infection:– Idiopathic– Autoimmune disease

• Sarcoidosis,SLE,Sjogren’s syndrome– Tubulointerstitial nephritis and uveitis(TINU) syndrome

Drug –induced interstitial nephritis • Diagnosis

– Renal biopsy– History of drug exposure

• 3-5 days after second exposure• Several weeks to many months after first exposure

– Rifampin:One day– NSAIDs:18 months

• S/S:– Allergic – Urine sediment

• White cell• Red cell• White cell casts

Allergic interstitial nephritis• An idiosyncratic reaction• Antibiotic are the most common causes– Penicillins– Cephalosporins– Fluoroquinolone

• Symptoms and signs– Rash– Fever– Eosinophilia– Triad:10%– Progressive renal failure

Nephrotoxic drugs

• Antibiotics• Chemotherapy and Immunosuppressants• Heavy Metals• Anti-Hyperlipidemics• Chemotherapy• Miscellaneous Drugs• Drugs of abuse

Antibiotics• Aminoglycosides• Sulfonamides• Amophotericin B• Levofloxacin• Rifampin• Tetracycline• Acyclovir• Pentamidine• Penicilline• Cephalosporine• Ciprofloxacin

Aminoglycosides

• Pathogenesis– Tubular cell toxicity

• Risk factors:– Duration of therapy is > 10 days – Trough concentrations > 2 µg/mL• maintaining trough levels at 1 µg/mL or less

– Gentamicin>Amikin,Tobramycin• Prevention:– Single daily dose

Sulfonamides• Crystal nephropathy• Insoluble in acid urine– Risk:7% in pH<5.5

• Shape:– Needle, rosettes ,shock of wheat

• Lignin test– 1 drop of urine + 1drop of 10% HCL

• Yellowish orange color• Prevention– alkalinization of the urine to a pH > 7.15 – Sulfadiazine solubility more than 20-fold

Amphotericin B• Pathogenesis– Tubular cell toxicity– Renal vasocontriction

• Dose-dependent nephrotoxicity– Irreversible if cumulative dose >4g

• Rates of acute renal failure– 49%-65%– 15%:hemodialysis

• Prevention:– Liposomal formulation (AmBisome)– Stop if 25% increment of serum Cr

Acyclovir• Crystal nephropathy– Most common: Ua and Acyclovir

• Ganciclvir: little or no risk• Birefringent needle-shaped acyclovir crystals can

be seen in the urine • Complete recovery typically occurs within four to

nine days after acyclovir is discontinued • Prevention– Prior hydration: urine output>75 ml/h– Slow drug infusion for 1-2 hrs

Chemotherapy and Immunosuppressants

• Cisplantin• Methotrexate• Mitomycin• Cyclosporine• Ifosphamide

Cisplantin• Pathogenesis– Tubular cell toxicity

• Proximal tubule(S3) ： fanconi like syndrome– Vasoconstriction– Proinflammation

• Dose dependent• Prevention– Carboplatin: less nephrotoxic analog– Isotonic saline

• 1000cc of isotoic saline +20 meg KCl+2g MgSO4– 1000cc 2-3 hrs before cisplatin treatment– 500 cc 2 hrs after cisplatin treatment

Methotrexate• Crystal nephropathy• 90% excreted unchanged in urine• Insoluble in acid urine• Poor dialyzable and large volume distribution• Reversible in almost all cases

– within one to three weeks • Prevention

– Hydration– Urine pH>7.0

• Increase solubility as much as 10 fold– 1000 cc D5W + 44-66 meg NaHCO3

• 3 L/day• 12 hrs befor and 24-48 hrs after

Mitomycin-C

• Thrombotic microangiopathy

Cyclosporine&Tacrolimus

• Pathogenesis– Altered intraglomerular hemodynamics– Thrombotic microangiopathy

• Acute nephrotoxicity– Oliguric TIN– Dose dependent

• Chronic nephrotoxicity– Less dose dependent

Heavy Metals

• Lead• Cadmium• Mercury• Lithium• Arsenic• Bismuth

為何藥物 , 毒物 , 重金屬容易傷害腎臟

• High Blood Flow– Increase delivery to kidney

• Organic solute and ion transporters– Increase entry to renal parenchyma

• Intracellular xenobiotic metabolizing enzymes– Local release of toxic metabolites

• Concentrate urine– Facilitate precipitation or crystallization

為何重金屬容易傷害腎臟• Defense mechanisms of the Kidney– Glutathione(GSH)• Bind free metals via sulfhydryl groups• GSH-Metal in the kidney release Metal to entry into cell

– Induced by g-glutamyltransferase/cysteinyl glycinase

– Metallothionein(MT)• Low molecular weight protein rich in cysteinyl residues• MT-Metal in liver deliver slowly to kidney

– Release metal in kidney

Heavy Metal nephropathyAcute Renal failure Nephrotic

syndromeChronic interstitial nephritis

Arsenic 砷 Bismuth Bismuth

Bismuth 鉍 Gold Cadmium

Cadmium 鎘 Mercury Chromium

Chromium 鉻 Nickel 鎳 Copper

Copper 銅 Iron

Gold Lead

Iron Lithium

Lead Mercury

Mercury Platinum 鉑Silver Silicon

Uranium 鈾 Uranium

Lead nephropathy

• Most common and nephrotoxic metal– Lead & Cadmium

• Environment and industry• USA: removed from gasoline (since 1973)and

house paint (1978)

• Toxic blood level– Decrease with time

NHANES 1976-1980 1988-1991 1999-2002

Mean blood lead level (Ug/dl) 12.8 2.8 1.64

Adult Child

>80 mg/dl >40mg/dl

Lead nephropathy

• Acute Renal failure• Chronic interstitial nephritis– Proximal tubule– Nuclear inclusion body in proximal tubule– Absent or minimal albuminuria– Hyperuricemia• Inhibit uric acid secretion• 50% have gout

Lead nephropathy

Exposure

Chronic Lead toxicity-Diagnosis

• Bone X-ray fluorescence• EDTA stimulation Test– 1 gm x2– Collect urine– Result• Positive:>650 mg

Normal GFR Cr>1.5 mg/dl

24 hr urine 48-72 urine

Cadmium Toxicity

Pulmonary FailureGI toxicity

Bone:Mixed OsteoporosisAnd osteomalacia

KidneyCancer

日本神通川 (Jinzu river) 鎘污染 -1950痛痛病 Itai-Itai disease(Ouch ouch disease)

痛痛病 Itai-Itai disease

• 三井金屬礦業經營的富山縣神岡礦山 , 大量排放鎘，導致神通川及其支流的污染

• 直至 1955 年，鎘才被荻野昇醫生和同僚懷疑是致病的原因。荻野醫生也創造了「痛痛病」一詞

Cadmium nephropathy• Environment and industry• Proximal tubule– Fanconi syndrome– Type 1 RTA– Hypercalciuria– Excretion of tubular protein

• Beta 2-microglobulin • retinol binding protein • alfa 1-microglobulin• NAG(N-acetyl-b-D-glucosaminidase)

• Outcome: irreversible

Nephrolithiasis

Mercury• The principal organ systems – the central nervous system :ataxia , tremor, brain atrophy– the kidneys

• Human exposure– amalgam fillings ( 汞合金補牙 )are the most important

source of inorganic mercury• the average exposure from dental amalgam is approximately 10

µg/day • normal value less than 5 µg/L in blood

– fish are the most important source of methylated or organic mercury• Salt water: shark, swordfish, and tuna( 金槍魚 )• Case:Minamata disease (水俣病 )---1956

Minamata disease (水俣病 )---1956

• 新日本窒素肥料（窒素，即氮）於水俁（音：予）工場生產氯乙烯與醋酸乙烯，其製程中需要使用含汞的催化劑。由於該工廠任意排放廢水，這些含汞的劇毒物質流入成海，被水中生物所食用，並轉成甲基氯汞（化學式 CH3HgCl ）与二甲汞（化學式 (CH3)2Hg ）等有機汞化合物

• 人類食用遭污染的魚蝦致病

Minamata disease (水俣病 )---1956經過

• 1950 年，有大量的海魚成群在水俣湾海面游泳，任人網捕，海面上常見死魚、海鳥屍體

• 1952 年，水俁當地許多貓隻出現不尋常現象，走路顛顛跌跌，甚至發足狂奔，當地居民稱【跳舞病】

• 1953 年 1 月有貓發瘋跳海自殺，一年內，投海自殺的貓總數達五萬多隻。接著，狗、豬也發生了類似的發瘋情形

• 1956 年 4月 21 日，來自入江村的小女孩田中靜子成為第一位患病者，被送至窒素公司（ Chisso Minamata Chemical Company ）附屬醫院，病況急速惡化，一個月後雙眼失明，全身性痙攣，不久死亡。死者二歲的妹妹也罹患相同的病症

Minamata disease (水俣病 )---1956定名

• 1959 年，熊本大學醫學部水俁病研究班發表研究報告– 原因為當地窒素工場所排出的有機水銀– 1932 至 1966 年間有數百噸的汞被排入水俁灣

• 1960 年正式將「甲基汞中毒」所引起的工業公害病，定名為「水俁病」

• 1966 年新潟又爆發水俁病，史稱「第二水俁病」，這次的禍首是昭和電工

• 1997 年 10 月，由官方所認定的受害者高達12,615 人，當中有 1,246 人已死亡

Mercury

• Nephrotic syndrome– usually reversible, although it may take several

months

• Tubular dysfunction– Acute– Chronic

Lithium

• Treatment of manic depressive illness

• High mortality rate – 25 % with an acute overdose – 9 % in patients intoxicated during maintenance

therapy

prophylactic treatment Intoxication

Mild Moderate Severe

Plasma level mEq/L

0.6 to 1.2 1.0 to 1.5 1.5 to 2.5 2.5 to 3.5 >3.5

Lithium

• Almost completely excreted by the kidneys.– Most of the filtered lithium is reabsorbed in the

proximal tubule• approximately 20 percent being excreted in the urine.

– Lithium reabsorption follows that of sodium

• Risk factor of lithium intoxication– volume depletion – renal ischemia

Lithium

• Inflammation– Chronic interstitial nephropathy

• Nephrogenic diabetes insipidus• Minimal change glomerulonephropathy• Other– Neuromuscular irritability – Confusion– Goiter

Arsenic• Elemental (0), arsenite (trivalent, +3), and arsenate

(pentavalent, +5)– Trivalent Arsenic or arsenite compounds

• Earth‘s crust and numerous ores （礦石）• Acute high-dose exposure

– gastrointestinal system– dehydration, hypotension, irregular pulse and cardiac instability– shock, acute respiratory distress syndrome, and sometimes

death(600 mcg per kg body weight per day or higher )• Lower dose chronic arsenic exposure

– peripheral neurologic and skin manifestations• distal paresthesias, followed rapidly by an ascending sensory loss and

weakness• Hyperpigmentation or hypopigmentation

Arsenic

• Renal injury– proteinuria,– Hematuria– acute tubular necrosis

Anti-Hyperlipidemics

• Statins• Gemfibrozil• Fenofibrate

Statins

• Rhabdomyolysis– The average incidence of hospitalization for

rhabdomyolysis : 0.44 per 10,000 patient-years (95% CI 0.20-0.84) for patients treated with atorvastatin, pravastatin, or simvastatin monotherapyGraham DJ :Incidence of hospitalized rhabdomyolysis in patients treated with lipid-lowering drugs JAMA 2004 Dec 1;292(21):2585-90

• Pathogensis– Volume depletion– Tubular obstruction due to heme pigment casts– Tubular injury from free chelatable iron

Miscellaneous • Chronic Stimulant Laxative• Radiographic contrast• ACE inhibitors• NSAIDs• Aspirin• Mesalamine• Diuretics• Allopurinol• Cimetidine• Dilantin

Radiographic contrast

• Pathogenesis– Tubular cell toxicity– Renal hemodynamic

• Ionic vs nonionic• High-osmolal vs Iso-osmolal

Radiographic contrast

• First generation-Ionic monomers,hyperosmolal– Diatrizoate, Iothalamate

• Second generation-Nonionic monomers, lower osmolal– Iopamidol, Iohexol, Iopromide, Ioversol

• Newer agents-Nonionic dimers, iso-osmolal– Iodixanol

Radiographic contrast

• Contrast associated (induced) nephropathy– High risk• CKD• DM

– Prevention:• Hydration (Normal saline or isotonic sodium

bicarbonate) • N-AC(N-acetylcysteine)

Mautone A :J Interv cardiol 2010 Feb;23(1):78-85

Radiographic contrast

• Incidence– 4-11% :Cr 1.5-4.0 mg/dl– 50% :Cr>4.0 mg/dl and DM

ACE Inhibitors

INTRAGLOMERULAR PRESSUREINTRAGLOMERULAR PRESSURE

+

Bowman’sCapsule

20 mmHgAfferent arteriole

Efferentarteriole

Angiotensin II ACEI s

+X X

NSAIDs

• Inflammation– Acute interstitial nephropathy (proteinuria)– Chronic interstitial nephropathy

• Hemodynamic– Inhibition of prostaglandins systhesis– Unproportional hyperkalemia • Hyporeninemic hypoaldosteronism

• Papillary necrosis (Analgesic nephropathy)• Salt and water retention

Analgesic nephropathy

Fearture Incidence

Excessive consumption

100%

Women 80%

Headache 80%

GI disturbance 35%

UTI 40%

Papillary Necrosis 20%

Papillary calcification

65%

Analgesic nephropathy

Aspirin

• Inflammation• Chronic interstitial nephropathy

Drugs of abuse

• Cocaine– Cocaine-induced rhabdomyolysis is a significant

cause of acute renal failure• increased sympathomimetic activity• vasospasm• inhibition of the reuptake of catecholamines at alpha

adrenergic receptors– high intracellular calcium levels in muscle cells

台灣引發腎毒性的前五大可疑藥物

全國藥物不良反應通報中心 90-96 年通報案例摘錄自財團法人台灣醫療改革基金會

排名 成份 藥理分類1 Gentamicin 抗生素2 Vancomycin 抗生素3 Warfarin 抗凝劑4 Amphotericin B 抗黴菌藥5 Cyclosporin 免疫調解劑

如何保護腎臟• 一般原則– 力行健康生活

• 三少：少鹽、少糖、少油• 三多：多纖維、多蔬果、多喝水• 四不：不抽煙、不憋尿、不熬夜、不吃來路不明的藥• 一沒有：沒有鮪魚肚

• 治療原則– 控制糖尿病– 控制高血壓– 因病使用具腎毒性藥物時，注意腎臟功能的變化– 使用顯影劑做檢查時，注意檢查前後的腎臟功能

• 追蹤原則– 40 歲以後每年檢查一次– 第 1 型糖尿病患發病五年後，每年一次尿液篩檢– 第 2 型糖尿病診斷時，做尿液篩檢

怎麼知道腎臟受損• 用 Serum Cr ，帶入 MDRD 公式算 eGFR• 用 Spot urine 測 urine albumin/urine Cr

ratio(ACR)• Blood pressure• 臨床症狀– 泡、水、高、貧、倦

4 變數4 變數

怎麼算 ?

找 GFR calculator

哪裡找 ?

nkdep.nih.govwww.nephron.com

MDRD formula 的運用• 分類系統適用於年輕人與老年人• 新診斷出 eGFR<60 ml/min/1.73m2 時– 先當作急性腎衰竭評估– 五天內應再追蹤一次 Scr– 評估急性腎衰竭時若無基礎值可以假定 eGFR

為 75 ml/min/1.73m2

• 若有以前的腎功能資料可計算惡化速度

於適當時機轉診

於適當時機轉診

CKD 分級的目的

須立刻轉診• 腎功能快速惡化• 新診斷為 CKD stage 5• Accelerated hypertension• 高血鉀症（ >7 mmol/L)