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Nephrotoxic Drugs

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 ).

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Nephrotoxic Drugs

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  1. Nephrotoxic Drugs 中國醫藥大學 北港附設醫院 曾裕雄

  2. 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)

  3. Drugs cause approximately 20 percent of community- and hospital-acquired episodes ofacute renal failure Cynthia A. Naughton, PharmD, BCPS North Dakota State University College of Pharmacy, Nursing, and Allied Sciences in Fargo

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

  5. 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

  6. Risk factors-Drugs • Inherent nephrotoxic effects • Dose • During, frequency , and form of administration • Repeated exposure • Drug intoxication

  7. The situation We meet

  8. 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

  9. 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

  10. 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

  11. Nephrotoxic drugs • Antibiotics • Chemotherapy and Immunosuppressants • Heavy Metals • Anti-Hyperlipidemics • Chemotherapy • Miscellaneous Drugs • Drugs of abuse

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

  13. 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

  14. 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

  15. 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

  16. 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

  17. Chemotherapy and Immunosuppressants • Cisplantin • Methotrexate • Mitomycin • Cyclosporine • Ifosphamide

  18. 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

  19. 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

  20. Mitomycin-C • Thrombotic microangiopathy

  21. Cyclosporine&Tacrolimus • Pathogenesis • Altered intraglomerular hemodynamics • Thrombotic microangiopathy • Acute nephrotoxicity • Oliguric TIN • Dose dependent • Chronic nephrotoxicity • Less dose dependent

  22. Heavy Metals • Lead • Cadmium • Mercury • Lithium • Arsenic • Bismuth

  23. 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

  24. 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

  25. Heavy Metal nephropathy

  26. 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

  27. 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

  28. Lead nephropathy Exposure

  29. Chronic Lead toxicity-Diagnosis • Bone X-ray fluorescence • EDTA stimulation Test • 1 gm x2 • Collect urine • Result • Positive:>650 mg

  30. Cadmium Toxicity Bone: Mixed Osteoporosis And osteomalacia Kidney Cancer Pulmonary Failure GI toxicity 日本神通川(Jinzu river)鎘污染 -1950 痛痛病 Itai-Itai disease(Ouch ouch disease)

  31. 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

  32. 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

  33. 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:Minamatadisease (水俣病)---1956

  34. Minamatadisease (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

  35. Minamatadisease (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

  36. Minamatadisease (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

  37. Mercury • Nephrotic syndrome • usually reversible, although it may take several months • Tubular dysfunction • Acute • Chronic

  38. Lithium • Treatment of manic depressive illness • High mortality rate • 25 % with an acute overdose • 9 % in patients intoxicated during maintenance therapy

  39. 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

  40. Lithium • Inflammation • Chronic interstitial nephropathy • Nephrogenic diabetes insipidus • Minimal change glomerulonephropathy • Other • Neuromuscular irritability • Confusion • Goiter

  41. 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

  42. Arsenic • Renal injury • proteinuria, • Hematuria • acute tubular necrosis

  43. Anti-Hyperlipidemics • Statins • Gemfibrozil • Fenofibrate

  44. 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

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

  46. Radiographic contrast • Pathogenesis • Tubular cell toxicity • Renal hemodynamic • Ionic vs nonionic • High-osmolal vs Iso-osmolal

  47. 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

  48. 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

  49. Radiographic contrast • Incidence • 4-11% :Cr 1.5-4.0 mg/dl • 50% :Cr>4.0 mg/dl and DM

  50. ACE Inhibitors INTRAGLOMERULAR PRESSURE Angiotensin II ACEI s X X 20 mmHg + + Afferent arteriole Efferent arteriole Bowman’s Capsule

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