Drug-induced nephrotoxicity

Transcription

1 Drug-induced nephrotoxicity Sayamon Sukkha Pharm.D. Faculty of Pharmacy, Mahidol University 3 June

2 Outline Epidemiology Clinical presentation of DIKD Renal susceptible to nephrotoxic agents Mechanism of renal injury Examples: ACEI/ARB, NSAID, ATB, antiviral, chemotherapy Case study 2

3 Epidemiology of druginduced kidney disease The incidence of community-based AKI 1 Required dialysis :29.5/100,000 person years Not requiring dialysis: 522.4/100,000 person years Community-acquired DIKD in up to 20% of hospital admissions due to AKI 2 Some reports showed cases of hospitalacquired AKI owing to the use of NSAIDs, ACEI/ARB, chemotherapy, and antiviral agents is increasing Kidney Int Jul;72(2): Semin Dial 1996;9: Kidney Int May;71(10):971-6.

4 Four drug-related renal syndromes Acute kidney injury (AKI) Chronic kidney disease (CKD) Nephrotic syndrome Electrolyte and acid-based abnormalities 4

5 Symptoms Manifestation of drug induced kidney disease Acid-base abnormalities Electrolyte imbalance Urine sediment abnormalities Proteinuria, pyuria, hematuria, oliguria Signs Rise in serum creatinine (Scr) and blood urea nitrogen (BUN) 5

6 Renal susceptible to nephrotoxic agents Drug kidney Host 6

7 Drug Direct toxic by drugs or its toxic metabolite Large dose or extended drug exposure Nephrotoxic drug combinations 7

8 kidney Renal blood flow approximately 25% of cardiac output Loop of Henle & renal medulla frequents prone to renal injury Renal drug metabolism from CYP450 and generate local toxic metabolite e.g., ROS Renal pathway excretion by uptake mechanism and transporter 8

9 Host True or effective volume depletion e.g., N/V/D, HF, liver disease, ascites, sepsis Patient with AKI or CKD Age Female under-recognized reduced GFR Hypoalbuminemia Pharmacogenetic difference 9

10 Mechanism of renal injury Hemodynamic changes Direct injury to cells and tissue Inflammatory tissue injury Obstruction of renal excretion 10

11 Principles for prevention of drug-induced kidney disease To avoid the use of nephrotoxic agents for patients at increased risk for toxicity Adjustment of medication dosage regimen based on accurate estimate renal function Adequate hydration to establish high urine flow rate Avoid combination of drug-induced kidney disease 11

12 Renal structural-functional alteration Pre-renal impairment Intrinsic-renal impairment Glomerular injury Tubulointerstitial Tubular obstruction Dipiro, et al. Pharmacotherapy, 2011 post-renal impairment 12

13 Hemodynamicmediated kidney injury ACEIs/ARBs NSAIDs Tubular epithelial cell damage 13 Acute tubular necrosis AMGs Amphotericin B Cisplatin Radiocontrast agents Osmotic nephrosis EXAMPLES Glomerular disease Tubulointerstitial disease: AIN, CIN Obstructive nephropathy Intratubular obstruction, neprholithiasis, nephrocalcinosis Renal vasculitis, thrombosis, and cholesterol emboli

14 Pseudo-renal failure Competitive tubular secretion of Scr Nat Clin Pract Nephrol Feb;2(2):

15 Hemodynamic-mediated kidney injury ACEIs/ARBs NSAIDs 15

16 Glomerular regulation 16

17 Drugs that alter renal hemodynamics GFR Scr, BUN Urine output Volume overload, hypertension 17

18 ACEIs/ARBs Recommendations interval to monitor SE after initiation or change in dose of ACEI/ARB Baseline value SBP (mmhg) <110 Baseline GFR (ml/min/1.73 m 2 ) Early GFR decline (%) <30 < >30 Serum K (meq/l) >5.0 Interval (wk) K/DOQI Clinical Practice Guidelines on Hypertension and Antihypertensive Agents in Chronic Kidney Disease

19 Changes in management based on magnitude of early decrease in GFR (%) Dosage adjustment Recommend ation interval for monitoring GFR 0-15% 15-30% 30-50% >50% None None Reduce Discontinue As per GFR Once after days. If repeat GFR remains within 15-30% of baseline value, resume monitoring schedule as per GFR Every 5-7 days until GFR is within 30% of baseline value K/DOQI Clinical Practice Guidelines on Hypertension and Antihypertensive Agents in Chronic Kidney Disease Every 5-7 days until GFR is within 15% of baseline value 19

20 Drug-induced renal structural changes 20

21 Proximal tubule Reabsorption HCO 3 Glucose PO 4 Uric acid K Mg Proximal tubule MA with bicarbonaturia Glucosuria Reductions in serum PO 4, uric acid, K, Mg ATN Direct tubular toxic Ischemia Distal tubule Maximum concentration of urine Urine acidification K excretion Distal tubule Polyuria MA Hyperkalemia Cellular debris-filled muddy brown, granular casts in urine sediment 21

22 Interstitium T-cell mediated hypersensitivity Interstitial inflammatory cell infiltrates Systemic symptoms: fever, rash, eosinophilia Glomeruli Immunemediated mechanism Proteinuria, hematuria Nephrotic syndrome 22

23 Drug-induced renal structural changes Proximal-straight tubule (S3 segment) Cisplatin Distal tubule Amphotericin B Cisplatin Proximal convoluted tubule (S1/S2 segments) Aminoglycosides Glomeruli Interferon-α Gold Penicillamine Interstitium Cephalosporines Cadmium NSAIDs 23

24 NSAIDs and the kidney: various clinical presentation Pre-renal azotemia Hemodynamicmediated kidney injury ATN AIN Nephrotic syndrome Analgesic nephropathy 24

25 Aminoglycosides (AG) The report incidence ranges between 7% and 36% of patients receiving these drugs This rate increases with the duration of drug administration and may approach 50% with > 2 wk of treatment 25

26 AGs: pathogenesis and presentation 26 Clinical presentation Onset: <5-10 days Serum creatinine/bun rising and non-oliguria Microscopic hematuria/proteinuria, renal Mg wasting More cationic, more nephrotoxic Neomycin > Gentamicin > Tobramycin~Amikacin ~ Netilmycin > Streptomycin Am J Kidney Dis Feb;55(2):

27 Afferent arteriole vasoconstriction Amphotericin B: pathogenesis Direct toxicity Clinical presentation Pre-renal azotemia Polyuria Renal Mg, K wasting Distal RTA 27

28 Cisplatin: mechanism of nephrotoxicity Non-oliguric renal failure Inability to reabsorb Mg > Mg wasting Tubular injury ---> glucosuria, aminoaciduria Kidney Int May;73(9):

29 Tenofovir-induced nephrotoxicity Nat Rev Nephrol Oct;5(10):

30 Nat Rev Nephrol Oct;5(10):

31 Crystal nephropathy NephSap, Obstructive nephropathy Intratubular obstruction Extra-renal obstruction: ureter, urethra Nephrolithiasis (kidney stone) Sign and symptoms Pain, hematuria Infection Scr rising Urine sediment: RBC, WBC, and crystals Vitamin C Aspirin Acyclovir Methotrexate Indinavir Foscarnet Sulfonamide Triamterene Ciprofloxacin Ampicillin Cephalexin 31

32 Herb and the kidney 32

33 Licorice Licorice metabolite, glycyrrhetinic acid, inhibits renal 11b-OH steroid dehydrogenase leading to a pseudoaldosterone-like effect Clin Nephrol Jun;77(6): Na and water retention, hypo K, metabolic alkalosis HTN, HF, cardiac arrest This may potentiate the action of drugs such as digoxin 33

34 Herb that contain high oxalic acid มะเฟ อง Star fruit Nephrolithiasis แคนเบอร ร Obstructive nephropathy 34

35 35

36 Case study 36

37 Case study ผ ป วยชาย 60 ป น าหน ก 80 ก โลกร ม ส วนส ง 152 เซนต เมตร U/D: HIV infection on efavirenz, emtricitabine, tenofovir CC: ซ มส บสน ม ไข (BT=38.3º C) Empirical tx: acyclovir 800 mg iv q 8 h Labs: BUN 17 mg/dl, Scr 0.7 mg/dl, CrCL 127 ml/min 37

38 Microscopic analysis Birefringent needle-shaped crystals His Scr increased from 0.7 to 1.1 mg/dl N Engl J Med Mar 27;358(13):e14 38

39 ค ดถ งอะไรบ างในผ ป วยรายน??? Acyclovir induced crystal nephropathy ป จจ ยเส ยงต อการเก ดพ ษต อไต ขนาดยา acyclovir ท เหมาะสมในผ ป วยท ม obesity และ ปร บตามการทางานของไต BMI=35.5 kg/m 2 - obesity class II IBW=52.3 kg ยาขนาด 10 mg/kg---> 800 mg IV q 8 h 39

40 PK of acyclovir It is cleared primarily by the kidneys, with approximately 70-80% excreted unchanged in the urine Excreted by glomerular filtration and tubular secretion T1/2 in normal renal fn 3 h and ESRD 20 h Therefore, dose should be reduced proportionately from a normal dose 40

41 Renal toxicity from acyclovir Asymptomatic renal insufficiency (most common) Flank or abdominal pain Crystal nephropathy often develops within h of acyclovir administration Acyclovir is relatively insoluble in urine with a maximum solubility of 2.5 mg/ml at physiologic ph 41

42 Risk factor of acyclovir induced crystal nephropathy High dose (>500 mg/m 2 ) Rapid IV bolus Volume depletion Am J Kidney Dis May;45(5):

43 Obesity and drug adjustment Hydrophilic Hydrophilic Dose may correlate with LBW/ABW/IBW Lipophilic Lipophilic Using TBW may more appropriate Clin Obes Dec;4(6): , Clin Pharmacokinet. 2010;49(2):

44 Recommendation for BW formula 44 Clin Obes Dec;4(6):

45 Acyclovir dose according to renal function Acyclovir Adjustment for renal failure Supplement for dialysis Dose for normal renal function 5-10 mg/kg q 8 h > <10 IHD: dose after HD PD: dose for GFR<10 100% q 8 h 10 mg/kg= 10 mg (52.3 kg) 500 mg IV q 8 h 100% q h 50% q 24 h CRRT: mg/kg q 12 h

46 Prevention of acyclovir induced crystal nephropathy Adequate hydration to maintain good urine flow ( ml/h) Acyclovir dose should be infused over the course of 1 hour Nephrotoxicity is usually reversible on discontinuation of the drug or reduction of the dose Am J Kidney Dis May;45(5):

47 Acyclovir and hemodialysis Am J Kidney Dis May;45(5): Dialysis can remove drugs that show these properties Hydrophilic agents Low MW. Low Vd HD can remove significant amount of acyclovir (40-60%) may be indicated when renal failure is severe 47

48 Take home message Drug-induced kidney disease is best prevented by avoiding nephrotoxic agents Recognition of risk factors and specific techniques of risk factors may be used to reduce potential nephrotoxicity Nephrotoxicity is often reversible if discontinuation the use of offending agents 48