Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download Hemodynamically Mediated Kidney Injury
Transcript
Drug-Induced Acute Kidney Injury Medications, Mechanisms of Injury, and Management Learning Objectives Review common medications implicated in acute kidney injury (AKI) and their mechanisms of nephrotoxicity Differentiate between clinical presentations and risk factors of drug-induced AKI Outline strategies used to prevent and manage drug-induced AKI 2 Epidemiology AKI is reported to occur in up to 7% of hospitalized patients and 20-30% of critically ill patients, with 6% eventually requiring renal replacement therapy Drugs have been implicated in up to 60% of inhospital AKI cases and 19-25% of cases of severe acute renal failure 3 Drug-Induced AKI: Classification Hemodynamically-Mediated Kidney Injury ACE Inhibitors NSAIDs Calcineurin Inhibitors Tubuloepithelial Injury & Tubulointerstitial Nephritis Acute Tubular Necrosis (ATN) Acute Interstitial Nephritis (AIN) Crystal Nephropathy Direct Intratubular Obstruction & Nephrolithiasis Indirect Intratubular Obstruction 4 Hemodynamically-Mediated Kidney Injury Prerenal Injury 5 Hemodynamically Mediated Kidney Injury “Prerenal” injury related to reduced renal blood flow (i.e. hypovolemia, CHF, bleeding, sepsis, ascites) Injury results from decreased tissue perfusion and decrease in GFR Normally, the kidney attempts to maintain the GFR by altering renal blood flow via prostaglandins (afferent) and angiotensin II (efferent arteriole) The insult is exacerbated when this response is inhibited by medications (i.e. ACEIs/ARBs and NSAIDs) 6 Hemodynamically Mediated Kidney Injury Prostaglandins are primarily involved in vasodilation of the afferent or “incoming” arteriole while angiotensin II is involved in vasoconstriction of the efferent or “outgoing” arteriole 7 NSAIDs Unlikely to affect renal function in the absence of diminished renal perfusion Mechanism: ↓ prostaglandin synthesis → afferent arteriole vasoconstriction → ↓ glomerular pressure → ↓ GFR Clinical Presentation: ↓ urine output ↑ edema, BUN, Scr, K+, blood pressure Fractional excretion Na < 1% Risk Factors: age > 60 years, CKD, heart failure, concurrent nephrotoxic medications, and hepatic disease with ascites 8 NSAIDs Prevention: Use alternative analgesics Use low-dose/short duration treatment Avoid potent NSAIDs (i.e. indomethacin) Avoid ACEIs/ARBs and diuretics in high-risk or dehydrated patients Appropriate monitoring (Scr, BUN, etc.) Management: Discontinue NSAID Recovery is rapid and baseline function is usually restored 9 Angiotensin Converting Enzyme Inhibitors & Angiotensin Receptor Blockers Mechanism: ↓ angiotensin II production/action → efferent arteriole vasodilation → ↓ glomerular pressure → ↓ GFR Clinical Presentation: Moderate vs. detrimental rise in serum creatinine Moderate: ↑ Scr ≤ 30% within 3-5 days of initiation with stabilization in 1-2 weeks is expected and reasonable Detrimental: ↑ Scr > 30% within 1-2 weeks of initiation Risk Factors: renal artery stenosis, volume depletion, heart failure, CKD including diabetic nephropathy 10 Angiotensin Converting Enzyme Inhibitors & Angiotensin Receptor Blockers Prevention: Recognize patients at highest risk Initiate at very low doses Titrate every 2-4 weeks as opposed to every 3-5 days Avoid NSAIDs and diuretics in high-risk or dehydrated patients Appropriate monitoring (Scr, K+, etc.) Management: Discontinue ACEI/ARB (reinitiate once volume is corrected or at a point where the diuretic dose can be decreased) Manage hyperkalemia accordingly Baseline function is usually restored several days after discontinuation 11 Calcineurin Inhibitors The nephrotoxic potential of cyclosporine and tacrolimus complicates their use, as they are the most common immunosuppressive agents used in kidney transplantation Mechanism: ↑ renal vasoconstriction (thromboxane A2, endothelin, RAAS) + ↓ renal vasodilation (prostaglandins) → afferent vasoconstriction → ↓ glomerular pressure → ↓ GFR Clinical Presentation: ↓ urine output ↑ Scr, blood pressure, K+ Sodium retention 12 Calcineurin Inhibitors Risk Factors: age > 65 yrs, high dose, concurrent nephrotoxic drugs (diuretics, NSAIDs), interactions that ↑ calcineurin inhibitor concentrations (CYP 3A4 inhibitors) Prevention: Therapeutic drug monitoring of cyclosporine/tacrolimus Decreased dose (balance nephrotoxicity with risk of graft rejection) Appropriate monitoring (Scr, BUN, etc.) Management: Treat contributing illness and/or remove interacting drug Switch immunosuppressant if nephrotoxicity is progressive/severe 13 Tubuloepithelial Injury & Tubulointerstitial Nephritis Intrarenal Injury 14 Acute Tubular Necrosis (ATN) “Intrarenal” injury involving ischemia or cellular injury due endogenous toxins (i.e. myoglobin), or exogenous toxins (i.e. aminoglycosides) Direct cellular toxicity or ischemia leads to cellular degeneration and sloughing from the proximal and/or distal tubules → inability to reabsorb electrolytes, ↓ GFR, tubular obstruction Urine contains cellular debris/cast and will appear muddybrown often without evidence of hematuria Oliguric phase (2-3 weeks) is often followed by tubular regeneration or a recovery phase (2-3 weeks) 15 Acute Tubular Necrosis (ATN) Damaged cells with Na+/K+/ATPase pumps unable to resorb Na+ leads to increased Na+ sensed at the macula densa. Negative feedback then leads to afferent vasoconstriction and ↓ GFR 16 Aminoglycosides Gentamicin, Tobramycin, Neomycin, Amikacin Nephrotoxicity occurs in up to 10-25% of patients undergoing a therapeutic course Aminoglycosides are non-protein bound medications primarily excreted by glomerular filtration Toxicity is a result of their cationic charge, facilitating their binding to negatively charged tubular epithelium phospholipids and intracellular lysosomal transport Most cationic (and therefore toxic) → least cationic Neomycin > tobramycin, gentamicin, amikacin > streptomycin 17 Aminoglycosides Mechanism: uptaken by proximal tubule → ↑ reactive oxygen species → mitochondrial injury → cellular necrosis Clinical Presentation: Within 5-10 days of initiation ↑ Scr, BUN, urine electrolytes Typically non-oliguric (urine > 500mL/d) Mild proteinuria (< 1g/d) Risk Factors: ↑ dose/duration/trough concentration, concurrent nephrotoxic drugs (i.e. cyclosporine, diuretics, NSAIDs, vancomycin), patient related factors (↑ age, diabetes, CKD, dehydration, shock, liver disease) 18 Aminoglycosides Prevention: Alternate antibiotics if possible Limit total aminoglycoside dose and duration (< 7 days if possible) Extended interval dosing (once daily) associated with less nephrotoxicity than traditional dosing (TID) – 0-5% vs. 17% Renal tubule accumulation is saturated during peak concentrations Avoid volume depletion Avoid concurrent nephrotoxic drugs Management: Discontinue aminoglycoside or alter regimen Discontinue other nephrotoxic drugs if possible Maintain adequate hydration Kidney injury is generally reversible after discontinuation 19 Amphotericin B Nephrotoxicity related to amphotericin B is associated with the cumulative dose administered It is estimated that approximately 80% of patients treated with amphotericin B will develop some renal dysfunction Toxicity is related to a combination of direct proximal tubular cell toxicity and afferent arteriole vasoconstriction Liposomal formulations are able to reduce direct amphotericin B interaction with tubular epithelial cell membranes 20 Amphotericin B Clinical Presentation: ↑ Scr, BUN, urine electrolytes Typically non-oliguric (urine > 500mL/d) Impaired urinary concentrating ability Risk Factors: large cumulative doses, pre-existing kidney disease, volume depletion, ↑ age, concurrent use of diuretics or nephrotoxic drugs (i.e. cyclosporine) 21 Amphotericin B Prevention: Use the liposomal formulation in high risk patients or an alternative antifungal agent if possible (i.e. voriconazole, micafungin) Normal saline 10-15mL/kg prior to each dose Consider longer infusion times Appropriate monitoring (Scr, serum electrolytes) Management: Discontinuation of amphotericin B and substitution with alternative antifungal therapy if possible Kidney injury may be reversible or irreversible after discontinuation 22 Radiographic Contrast Media Contrast media-induced nephrotoxicity (CIN) can occur in up to 50% of patients with pre-existing CKD or diabetes mellitus Nephrotoxicity results from acute renal ischemia and direct cellular toxicity due to increased exposure to contrast media following reduced blood flow Kidney injury may be irreversible, especially in those with pre-existing kidney disease 23 Radiographic Contrast Media Clinical Presentation: ↑ Scr, BUN Non-oliguric or irreversible oliguria (urine < 500mL/d) in high-risk patients granular casts on urinalysis (not always) Fractional excretion of sodium <1% Risk Factors: CKD (GFR <60mL/min), volume depletion, heart failure, hypotension, diabetic nephropathy, large volumes/doses, concurrent nephrotoxic drugs 24 Radiographic Contrast Media Prevention: Use alternative diagnostic procedures if possible Avoid volume depletion and nephrotoxic drugs (i.e. NSAIDs) Use lowest volumes of contrast agents possible Volume expansion – normal saline prior to and continued for several hours after contrast exposure Oral N-acetylcysteine given prior to and following exposure Management: Supportive (monitoring, renal replacement therapy if irreversible damage occurs) 25 Acute/Allergic Interstitial Nephritis (AIN) It consists of an acute idiosyncratic reaction involving inflammatory infiltration and edema of the intersititium Signs of renal injury include oliguria, sterile pyuria, eosinophiluria (frequently absent) Systemic signs and symptoms include fever, rash, arthralgia and eosinophilia More common in antibiotic-associated AIN than NSAID-associated AIN is a hypersensitivity reaction and is expected to recur with rechallenge 26 β-lactams (including cephalosporins) & NSAIDs Mechanism: Allergic hypersensitivity response via an antibody- or cell-mediated (commonly a T-cell interstitial infiltrate) immune mechanism Clinical Presentation: β-lactams – Average onset of 2 weeks from initiation Fever (27-80%), maculopapular rash (15-25%), eosinophilia (2380%) arthralgia (45%), oliguria (50%) NSAIDs – Average onset of 6 months from initiation Fever, rash, and eosinophilia occur in <10% while nephrotic syndrome (proteinuria >3.5g/d) occurs in >70% or patients Risk Factors: None identified 27 β-lactams (including cephalosporins) & NSAIDs Prevention: No specific preventative measures Appropriate monitoring so that prompt discontinuation can improve the chances of complete renal recovery Management: Discontinue offending drug High-dose oral prednisone Monitor renal function (Scr, BUN, etc.) for signs of improvement Document the reaction to avoid re-exposure Kidney injury may be reversible or irreversible 28 Other drugs Associated with ATN and AIN Acute Tubular Necrosis Chemotherapy Cisplatin, carboplatin, cytarabine, 5-fluoruracil, ifosfamide, Acute Interstitial Nephritis Ciprofloxacin Omeprazole, lansoprazole Cimetidine, ranitidine Tenofovir, cidofovir, adefovir Loop diuretics Zoledronate Allopurinol Vancomycin Sulfonamides Rifampin 5-aminosalicylates IVIG 29 Crystal Nephropathy Postrenal Injury 30 Crystal Nephropathy Direct Intratubular Obstruction & Nephrolithiasis via drug precipitation (crystallization) Volume depletion and the resulting production of concentrated, acidic urine can precipitate drugs unable to remain in solution at ↓ pH Abnormal crystal precipitation in the renal collecting system leading to pain, hematuria, infection, or urinary tract obstruction Indirect Intratubular Obstruction Drugs may indirectly produce large amounts of endogenous toxins (i.e. uric acid, myoglobin) leading to intratubular obstruction and direct cellular damage 31 Crystal Nephropathy • Indinavir, a protease inhibitor, can lead to crystalluria • Dysuria, urinary frequency, back and flank pain, or nephrolithiasis in approximately 8% of treated patients 32 Direct Intratubular Obstruction & Nephrolithiasis Medications: Acyclovir Indinavir Tenofovir Atazanavir Methotrexate (IV) Sulfadiazine Triamterene Ciprofloxacin Mechanism: Insolubility of drug in either alkaline or acidic urine + low urine volume → precipitation of drug → crystalluria → obstruction of tubule Poor alkaline solubility: Indinavir Poor acidic solubility: Acyclovir, triamterene, sulfadiazine, methotrexate 33 Direct Intratubular Obstruction & Nephrolithiasis Clinical Presentation: May have asymptomatic crystalluria ↓ urine output ↑ Scr, hematuria, pyuria, pain and crystalluria 34 Direct Intratubular Obstruction & Nephrolithiasis Risk Factors: Volume depletion (fluid loss or sequestration) Prevention: Hydration and prevention of volume depletion (crystal precipitation can be prevented in 75% of indinavir treated patients if they consume 2-3L of fluid per day) Urinary alkalinisation for drugs with poor acidic solubility Potassium citrate or sodium bicarbonate Management: Discontinue drug (kidney injury is usually reversible) Volume resuscitation 35 Indirect Tubular Obstruction Tumor Lysis Syndrome Antineoplastic agents increase circulating byproducts of tumor breakdown Acute oliguric or anuric kidney injury is a result of uric acid crystal obstruction Treatment includes hydration, allopurinol and urinary alkalinisation Rhabdomyolysis Statin-induced rhabdomyolysis is rare (1 in 1000) but the risk is increased with drug interactions Tubular precipitation of myoglobin results in AKI and production of red-brown urine Treatment includes hydration/volume expansion and potentially, urinary alkalinisation 36
