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Nephrotoxic Drugs
中國醫藥大學
北港附設醫院
曾裕雄
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％
全民健康保險雙月刊第85期 (99年5月號)
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
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Altered intraglomerular hemodynamics
Tubular cell toxicity
Inflammation
Crystal nephropathy
Rhabdomyolysis
Thrombotic microangiopathy.
Risk Factors-patients
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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
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Inherent nephrotoxic effects
Dose
During, frequency , and form of administration
Repeated exposure
Drug intoxication
The situation We meet
Older
Multiple comorbilities
& Drugs
Diagnostic &
therapeutic
procedures
Acute interstitial nephritis
• Etiology:
– Drug
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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
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Rash
Fever
Eosinophilia
Triad:10%
Progressive renal failure
Nephrotoxic drugs
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Antibiotics
Chemotherapy and Immunosuppressants
Heavy Metals
Anti-Hyperlipidemics
Chemotherapy
Miscellaneous Drugs
Drugs of abuse
Antibiotics
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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
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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
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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
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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 nephropathy
Acute Renal failure
Nephrotic
syndrome
Chronic 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)
NHANES
1976-1980
1988-1991
1999-2002
Mean blood lead level (Ug/dl)
12.8
2.8
1.64
• Toxic blood level
– Decrease with time
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
Renal failure
Hypertension
Exposure
Gout
Chronic Lead toxicity-Diagnosis
• Bone X-ray fluorescence
• EDTA stimulation Test
– 1 gm x2
– Collect urine
– Result
Normal GFR
Cr>1.5 mg/dl
24 hr urine
48-72 urine
• Positive:>650 mg
Cadmium Toxicity
Pulmonary Failure
GI toxicity
Bone:
Acute
Chronic
Mixed Osteoporosis
And osteomalacia
Kidney
Cancer
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
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Fanconi syndrome
Type 1 RTA
Nephrolithiasis
Hypercalciuria
Excretion of tubular protein
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Beta 2-microglobulin
retinol binding protein
alfa 1-microglobulin
NAG(N-acetyl-b-D-glucosaminidase)
• Outcome: irreversible
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
prophylactic
Plasma
level
0.6 to 1.2
treatment
1.0 to 1.5
Intoxication
Mild
Moderate
Severe
1.5 to 2.5
2.5 to 3.5
>3.5
mEq/L
• High mortality rate
– 25 % with an acute overdose
– 9 % in patients intoxicated during maintenance
therapy
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 monotherapy
Graham 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
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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 PRESSURE
Afferent
arteriole
+
Angiotensin II
X
X
20 mmHg
Bowman’s
Capsule
ACEI s
+
Efferent
arteriole
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
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
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
如何保護腎臟
• 一般原則
– 力行健康生活
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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
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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
怎麼算?
找GFR calculator
哪裡找?
nkdep.nih.gov
www.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
CKD分級的目的
建立分
類系統
找出
病人
整合診
斷見解
於適當時機
轉診
給于適
切治療
須立刻轉診
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腎功能快速惡化
新診斷為CKD stage 5
Accelerated hypertension
高血鉀症（>7 mmol/L)