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
„ 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:
„ Physician would like to switch previous patient Selective COX-2
„ 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
> 50-fold COX-2 selective
„ Use with caution in CKD (grade 3 or greater) etodolac
„ Inhibit renal vasodilatory prostaglandins E2 & I2 celecoxib
5- 50-fold COX-2 selective
„ Produced by COX-2
< 5-fold COX-2 selective
„ Higher risk if intravascular volume depletion naproxen
„ Management: D/C drug, use alternate analgesia ketoprofen
Increasing COX-2 Selective
Increasing COX-1 Selective
Range of COX Selectivity for COX-1 and COX-2
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
„ 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

Normal Saline
150 mEq/L D5W post contrast
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)



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