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Microsoft powerpoint - drug-induced acute renal dysfunction - rx mar10.ppt [read-only]

„ Pseudo Renal Failure„ Acute Renal Failure „ NSAIDs, CyA/Tacrolimus, ACEI/ARB, Diuretics „ ATN – Aminoglycosides, Amphotericin B, „ ↑ BUN due to protein catabolism
„ ↑ SCr due to competitive inhibition of creatinine
„ 15-35% rise SCr fully expressed after 3 days „ More sig in pts with pre-existing renal dysfunction „ Completely reversible when drug is discontinued (J Int Med 1999l246:247-52; TDM 1987;9:161-5) „ baseline creatinine 159umol/L; BP 148/92 Non-ACE
„ Ramipril 5 mg daily started and 2 weeks later: Pathways
(e.g. chymase,
„ Case 2: 82 yo female with osteoarthritis „ Admitted to hospital for CAP & dehydration „ Meds: Losartan 100mg daily + Naproxen 250mg BID Benefits of ACEI/ARB: decreased intraglomerular Glomerular Capillary Pressure → ↑ Permeability → ↑ Proteinuria „ Decreased intravascular volume (dehydration, diuretic overuse, CHF, vomiting, diarrhea) „ Use of afferent vasoconstrictor agents Renal function becomes dependent on sustained constriction of efferent arteriole from angiotensin II (NEJM 2002;347:1256-61, Arch Int Med 2000;160:685-93) Case 1: Creatinine ↑ 159 to 194 in 2 weeks
Case 2: Creatinine on admission 250
„ accept 20-30% increase in serum creatinine within 1-2 umol/L in patient with CAP and
dehydration
„ in fact, this could be an indication that the drugs are exerting their desired actions to help preserve renal „ discontinue NSAID and hold ARB until infection treated and patient is rehydrated/creatinine „ check serum creatinine 1-2 weeks after initiation, then in „ resume ARB and monitor serum creatinine „ if > 30% change, decrease ACEI/ARB dose by 50% and repeat Ser Cr in 4 weeks (exclude hypovolemia/NSAIDs, „ if > 50% rise in Ser Cr – rule out RAS „ repeat serum creatinine in this patient in 1-2 weeks to „ Case # 2:
Constitutive
Inducible
„ Physician would like to switch previous patient Selective COX-2
Inhibitors
„ Are Cox II inhibitors less likely to cause acute Protection of Gastric Mucosa
Renal Effects
Pain, Inflammation, Fever
Platelet Aggregation
Inhibits Platelet Aggregation
Note: ASA has an irreversible effect, while other NSAIDS are competitive In Vitro Selectivity: COX-2/COX-1 Ratio
lumiracoxib
rofecoxib
etoricoxib
valdecoxib
> 50-fold COX-2 selective
„ Use with caution in CKD (grade 3 or greater) etodolac
meloxicam
„ Inhibit renal vasodilatory prostaglandins E2 & I2 celecoxib
5- 50-fold COX-2 selective
diclofenac
sulindac
„ Produced by COX-2
fenoprofen
< 5-fold COX-2 selective
ibuprofen
tolmetin
„ Higher risk if intravascular volume depletion naproxen
indomethacin
„ Management: D/C drug, use alternate analgesia ketoprofen
flurbiprofen
ketorolac
Increasing COX-2 Selective
Increasing COX-1 Selective
Range of COX Selectivity for COX-1 and COX-2
COX-2/1)
Adapted from: Warner et al. FASEB J. 2004:18:790-804 mediated) or chronic interstitial nephritis „ preglomerular arteriolar vasoconstriction or direct „ ↑ SCr ~ 30%„ More common in first 6 mos of therapy „ Reversible with lowering dose (caution rejection)„ Monitor blood levels„ Renal biopsy to distinguish acute CyA Clinical
Features
Urinalysis
„ Tubular epithelial cell damage leading to obstruction of Diganosis
RF should begin to recover ~7d; Usually reversible and „ Non-oliguria > 500mL/day; granular casts in urine Treatment
related); if persists: Prednisone** (can be dose-related) „ Combination therapy with other nephrotoxic drugs „ Total cumulative dose; trough levels > 2 mg/L; repeated courses of A/G therapy; prolonged therapy > 10 days Other: NSAIDs, PPI, Cimetidine, Contrast Media, Cisplatin „ Management – Reversible if D/C drug, adequate *NSAIDs - onset 2-3mos; no eosinophilia/uria, fever or rash; proteinuria > 3g/24h; **Reserve if delayed renal recovery (> 1 wk), prolonged exposure to agent (> 2-3 wks) „ Theory why once daily A/G therapy works: „ Concentration-dependent kill (10x MIC)„ Post-antibiotic effect „ Burns > 20%, Septic Shock, Synergy„ GFR < 60 mL/min, Dialysis „ Proximal tubular A/G update appears to be limited during „ Low A/G concs for a greater proportion of dosing interval „ Only 1/4 meta-analyses showed reduced nephrotoxicity (from 7.7% to 5.5%); rest showed no difference
„ Incidence: ~80% when cumulative dose reaches 2 g „ Are Liposomal formulations less nephrotoxic „ Direct tubular epithelial cell damage; binds to cell wall resulting in ↑ tubular permeability and necrosis „ ↑ SCr, BUN, ↓ Mg, K (urinary wasting) – monitor q1-2d„ Distal RTA, polyuria (nephrogenic DI) „ Combination therapy with other nephrotoxic drugs„ Total cumulative dose; daily dose > 0.5mg/kg/day„ Dehydration „ Management – Reversible if D/C drug, Hydration (1L NS „ Reduced nephrotoxicity by enhancing the delivery to „ Voriconazole (~$100
„ Fluconazole – 1st line for
sites of infection, thus reducing exposure to „ Cochrane review April 2000 – all lipid-based preps decreased the occurrence of nephrotoxicity
„ Echinocandin
„ AKI still occurs, esp if concurrent exposure to other „ Amphotericin B deoxycholate vs Liposomal „ VGH guidelines: only prescribe Ampho B if GFR > „ Drawback Liposomal - Very expensive ($440-
„ Incidence: 40-50% in high risk pts (CKD, DM) „ Which is best proven prevention strategy?
„ Onset: within 12-24 hrs, SCr peaks 2-5 days o NS 1-2 mL/kg/hr starting 12 hours pre and after exposure, recovery usually after 4-10 days „ Direct tubular necrosis, renal ischemia o Sodium Bicarbonate 150mEq/L D5W infused at 3mL/kg/h x 1 hours pre, then 1mL/kg/h x 6 hours „ Typically non-oliguric (high risk may require HD) „ Urinalysis – hyaline and granular casts, low F Na „ Risk Factors: DM, CKD, prestudy dehydration o N-acetylcysteine 600mg PO BID x 4 doses on „ Management – Low-osmolality nonionic contrast day prior to and on day after admin of contrast agents (eg. Iohexol), smallest dose, Hydration Recommended Interventions for Prevention of
Contrast Nephrotoxicity
Contrast
Medications
Normal Saline
Bicarbonate
150 mEq/L D5W post contrast
Acetylcysteine
aStrength of Recommendation A, B, C (Good, Moderate, Poor) Quality of Evidence: 1 (R, Controlled), 2 (R, Cohort), 3 (Expert opinion) „ Rhabdomyolysis
„ Drug insoluble in urine and crystallizes in distal tubule „ Intratubular precipitation of myoglobulin „ Statins: simvastain, atorvastatin – risk ↑‘ed with Cyp 3A4 inhibitors (clarithromycin, erythro, itraconazole) or
„ High concentration of drug in tubular fluid „ Prevention
„ ↑ amount of drug excreted per functioning nephron „ Hold Statin while on clarithro/erythro or itraconazole
„ Pravastatin, Rosuvastatin not metabolized by CYP 3A4 „ Dosage adjustment for underlying renal failure„ Volume expansion to enhance urinary output„ Urinary alkalinization (for weak acids) (Drug insoluble in urine and crystallizes in distal tubule) „ Methotrexate
„ Acyclovir
„ Indinavir
„ Sulphonamides
„ Risks/Prevention
„ Risk/Prevention
„ Prevention
„ Risk/Prevention
Meperidine metabolite (normeperidine) is neurotoxic and
may cause seizures – C/I GFR < 50 mL/min
Fentanyl and Methadone preferred for chronic pain
„ Guo X, Nzerue C. How to prevent, recognize, and treat drug-induced nephrotoxicity. Clev Clinic J Med Hydromorphone preferred over Morphine (less 3-
glucuronide metabolite - myoclonus, hallucinations) „ Nolin TD, Himmelfarb J. Drug-induced kidney disease. In. Caution if GFR < 30-60 mL/minute ARF, ↑ K, hypertension „ Molony DA, Craig JC (eds). Evidence-based Nephrology. Sulfonylureas Chlorpropamide –↑’ed half-life, prolongs hypoglycemia
Glyburide has active metabolite - ↑ t1/2 hypoglycemia
„ Bakris GL, Weir MR. ACEI-associated elevations in serum Gliclazide preferred agent – no active metabolite (needs SA)
creatinine. Is this a cause for concern? Arch Int Med (glyburide 5mg = gliclazide 80mg = gliclazide MR 30mg) Metformin
Do not use if GFR < 30-60 mL/min lactic acidosis „ Brar SS et al. Sodium bicarbonate for the prevention of contrast induced-acute kidney injury: A systematic reivew ↓ renal clearance – potential for hypoglycemia and meta-analysis. Clin J Am Soc Nephrol 2009;4:1584- Allopurinol
Dosage adjustment; 100mg/day max in Stage 5 (dialysis)

Source: http://www.vhpharmsci.com/Presentations/2010/Drug-Induced%20Acute%20Renal%20Dysfunction-K%20Shalansky%20(Mar10).pdf