Acute Kidney Injury and Drug-induced Kidney Injury PDF

Acute Kidney Injury and Drug Induced Kidney Injury PHARM 343 Dr. Rene Breault Clinical Professor Resources Pharmacotherapy A Pathophysiologic Approach - 12th ed ○ Chapter 61 Acute Kidney Injury ○ Chapter 65 Drug-Induced Kidney Injury Patient Assessment in Clinical Pharmacy - 1st Editio...

Acute Kidney Injury and Drug Induced Kidney Injury PHARM 343 Dr. Rene Breault Clinical Professor Resources Pharmacotherapy A Pathophysiologic Approach - 12th ed ○ Chapter 61 Acute Kidney Injury ○ Chapter 65 Drug-Induced Kidney Injury Patient Assessment in Clinical Pharmacy - 1st Edition ○ Chapter 24 -Kidney Function Assessment 2 Abbreviations AKI - Acute Kidney Injury GFR - Glomerular Filtration Rate ACEi - Angiotensin Converting Enzyme Inhibitors ARB - Angiotensin Receptor Blocker 3 Part 1 - Acute Kidney Injury Learning Objectives Upon completion of the lecture and seminar you should be able to: Define Acute Kidney Injury Describe the different types of AKI and their potential causes Assess a patient with AKI based on history, presentation, clinical symptoms and urine/laboratory findings Describe treatment and prevention of AKI 5 Acute Kidney Injury Common diagnosis in hospitalized patients ○ 5-10% of hospitalized patients ○ Up to ~60% of of patients admitted to critical care Associated with significant increase in short and long-term morbidity and mortality Variety of causes ○ Disease processes ○ Drugs 6 AKI: A Definition An acute decrease in kidney function or Glomerular Filtration Rate (GFR) over a period of hours, days, or even weeks and is associated with an accumulation of waste products and (usually) volume 7 AKI: A Definition Acute kidney injury is defined when one of the following criteria is met ○ Serum creatinine rises by ≥ 26µmol/L within 48 hours OR ○ Serum creatinine rises ≥ 1.5 fold from the reference value, which is known or presumed to have occurred within 7 days OR ○ Urine output is < 0.5ml/kg/hr for ≥ 6 consecutive hours Kidney Disease Improving Global Outcomes (KDIGO) 8 Staging of AKI Stage Serum Creatinine Criteria Urine Output Criteria increase ≥ 26 μmol/L within 48hrs or /=12 hrs 3 increase 354 μmol/L or commenced on renal replacement therapy (RRT) irrespective of stage 9 Examples (Menti) Patient 1 - Charlotte Charlotte (62 year old female) is currently in the ICU after being in a serious car accident and suffering major internal injuries. They have been monitoring her serum creatinine daily while in ICU: Measured Serum Creatinine Day 1 - 82 umol/L Measured Serum Creatinine Day 2 - 117 umol/L Does this patient have acute kidney injury? Yes/No? 11 Patient 2 - Thomas Thomas is a 76 year old male currently in the cardiovascular surgery ICU after undergoing cardiac bypass surgery. He had a complicated surgery and remains intubated and sedated in the ICU. He is 5’11 and weighs 82 kg. The nurse records his urine output as follows: Time/Volume 0400 - 1030: 465 ml 1030 - 1630: 350 ml Does this patient have AKI? Yes/No 12 Patient Assessment AKI: Risk Factors Pre-existing chronic kidney disease (CKD) Volume depletion Use of nephrotoxic agents Obstruction of the urinary tract 14 Assessment Past Medical History ○ Renal disease-related chronic conditions Hypertension, diabetes Medication History Patient symptoms ○ Change in urinary habits, sudden weight gain, flank pain 15 ASSESSMENT Signs ○ Edema (sometimes) ○ Coloured or foamy urine ○ Orthostatic hypotension ○ Hypertension Laboratory tests ○ (see previous lecture) Other diagnostic tests 16 ASSESSMENTS OF KIDNEY FUNCTION Serum Creatinine Urea/BUN (2.9-7.1 mmol/L) Both are elevated when acute changes in kidney function are observed 17 TYPES OF ACUTE KIDNEY INJURY  There are 3 types of AKI blood supply kidney [nephron, Pre-renal interstitium] Intra-renal collecting system [ureter, bladder, urethra] Post-renal 19 THREE TYPES OF AKI 1. Prerenal https://www.osmosis.org/learn/Prerenal_azotemia 2. Intrarenal (Intrinsic) https://www.osmosis.org/learn/Renal_azotemia 3. Postrenal https://www.osmosis.org/learn/Postrenal_azotemia 20 PRERENAL AKI Most common cause of AKI (>60% of cases) Occurs over hours-days Generally a result of renal hypoperfusion Glomerular filtration is restored on re-establishment of more renal perfusion ○ *no actual structural damage or injury to the kidney itself. 21 PRERENAL AKI Hypovolemia ○ Hemorrhage ○ Gastrointestinal fluid losses ○ Renal fluid losses ○ Extravascular 22 PRERENAL AKI Altered renal hemodynamics ○ Low cardiac output state ○ Systemic vasodilation (sepsis) ○ Renal vasoconstriction ○ Impaired renal autoregulatory responses ○ Hepatorenal syndrome 23 PRERENAL AKI Symptoms ○ Thirst ○ Orthostatic hypotension Dehydration: ○ Tachycardia ○ Reduced jugular venous pressure ○ Decreased skin turgor ○ Dry mucous membranes 24 PRERENAL AKI Laboratory Findings ○ [↑ Urea]; ↑ creatinine; Urine Studies ○ Hyaline casts ○ FENa 40 FENa (%) 2 >2 Urea ⬆⬆ ⬆ or ↔ ⬆ or ↔ 32 MANAGEMENT OF AKI AKI: GOALS OF THERAPY Minimize the degree of injury to the kidney Reduce extrarenal complications Expedite patients’ recovery of renal function 34 GENERAL TREATMENT OF AKI Hydrate - IV Fluids Stop nephrotoxic agent Treat the underlying disease state Diuretics – loop diuretics – Furosemide ○ Only if volume overloaded Dopamine – X (no longer recommended) Dialysis (Renal Replacement Therapies) Adjust medication dosages/frequency for level of kidney function 35 TREATMENT - AKI Intravenous Fluids ○ 0.9% NaCl: >200ml/hr until SCr returns to baseline Stop nephrotoxic agent ○ Stop any drugs that could potentially cause renal failure or make it worse: ACE inhibitors (or ARBS), and NSAIDS ○ Stop anticholinergic agents Treat the underlying disease state (see glomerular diseases) 36 DIURETICS For fluid overloaded patients ○ prevent pulmonary edema and heart failure For patients who still have some urine output in AKI Controversial !! ○ worsen outcomes in some studies or have no effect Most common diuretics used are ○ loop diuretics furosemide ○ metolazone 37 DIALYSIS Advantages Disadvantages ○ Corrects electrolyte imbalances ○ Hypotension can exacerbate AKI ○ Treats fluid overloaded patients ○ Poor venous access makes ○ Removes uremic toxins dialysis difficult ○ IV site is a source of infection ○ Kidney may not recover 38 WHEN TO DIALYZE A Acid-base abnormalities (metabolic acidosis) E Electrolyte imbalance (hyperkalemia) I Intoxications O Fluid Overload U Uremia (decline in mental status, neuropathy) 39 SUMMARY AKI is a significant burden on the healthcare system ○ Can lead to CKD 3 types of AKI ○ Multiple causative factors (disease, drugs etc) Treatment is largely preventive and supportive 40 Quick Menti Review What is the most common cause of prerenal acute kidney injury (AKI)? A) Acute glomerulonephritis B) Hypovolemia C) Obstruction of the urinary tract D) Acute tubular necrosis 42 Which of the following criteria can be used to define AKI according to the KDIGO guidelines? A) Serum creatinine rises by ≥ 26 µmol/L within 7 days B) Urine output is < 0.5 mL/kg/hr for ≥ 24 consecutive hours C) Serum creatinine rises ≥ 1.5 times the reference value within 48 hours D) Urine output is < 0.5 mL/kg/hr for ≥ 6 consecutive hours 43 In postrenal AKI, which of the following is a common cause? A) Hepatorenal syndrome B) Prostate hypertrophy C) Renal artery stenosis D) Sepsis 44 Which type of AKI is characterized by damage to the kidney’s tubules, often due to ischemia or toxins? A) Prerenal AKI B) Intrarenal AKI C) Postrenal AKI D) Chronic kidney disease 45 End of Part 1 Part 2: Drug Induced Kidney Injury OBJECTIVES – DRUG INDUCED KIDNEY INJURY Upon completing this section of the course you should be able to: Explain the mechanism of kidney injury secondary to commonly used drugs Assess a patient with drug-induced AKI based on history, presentation, clinical symptoms and laboratory/urine findings Explain protective/management strategies for various drug induced kidney injuries 48 EPIDEMIOLOGY Nephrotoxic drugs were contributing factors in 19-25% of cases of severe acute kidney injury ○ Older adults – as high as 66% Common complication of several diagnostic and therapeutic agents Source of significant morbidity and mortality 49 DRUGS  DRUGS Type of Injury Drug Prerenal ACE inhibitors/ARBs NSAIDS Calcineurin inhibitors Intrarenal Acute Tubular Necrosis Amphotericin B Aminoglycosides Radiographic Contrast Dye Acute Interstitial Nephritis Penicillins Lithium Chronic Interstitial Nephritis Calcineurin inhibitors Lithium, NSAIDs Post renal Acyclovir Indinavir Sulfonamide antibiotics 51 Drug-Induced Prerenal AKI AUTOREGULATION Autoregulation ↑ PGE2 ↑↑ Angiotensin II ↑ Angiotensin II Efferent Afferent Arteriole Arteriole GFR Maintained 53 Angiotensin Converting Enzyme Inhibitors (ACEi) Angiotensin Receptor Blockers (ARBs) Patients at higher risk: ○ Patients with severe atherosclerotic disease ○ Renal artery stenosis (bilateral) ○ Heart Failure (acute, decompensated) ○ Chronic Kidney Disease (severe later stages) ○ Volume depleted Examples ○ ACEI: Ramipril, Lisinopril, Perindopril ○ ARBS: Telmisartan, irbesartan, valsartan 54 ACE INHIBITORS/ARBS Presentation ○ ≥ 25-30% rise in serum creatinine within 2 to 7 days following initiation of therapy ○ Usually stabilizes within 1 week Mechanism ○ Normally, in cases of decreased renal blood flow, intraglomerular blood pressure is maintained by vasodilation of the afferent arteriole and vasoconstriction of the efferent arteriole ○ ACE inhibitors dilate the efferent arteriole and thus reduce glomerular hydrostatic pressure = ↓ GFR 55 AUTOREGULATION Autoregulation ↑ PGE2 ↑↑ Angiotensin II ↑ Angiotensin II Efferent Afferent Arteriole Arteriole GFR Maintained 56 ACE INHIBITORS/ARBS ACE Autoregulation Inhibitor or ARB ↑ PGE2 ↓ Angiotensin II ↓ Angiotensin II Afferent Efferent Arteriole ↓ GFR Arteriole 57 ACE INHIBITORS/ARBS Urine findings ○ Urinalysis: relatively normal ○ Low urine volume Specific gravity >1.010 No casts or cellular elements ○ Low urine sodium concentration (< ○ High urea, High Creatinine 20 mmol/L) ○ FeNa amikacin>streptomycin ▪ Urine Findings ▪ Muddy brown epithelial cell casts and free epithelial cells ▪ High urine sodium (> 40 mmol/L) ▪ FeNa >3% ▪ Urinalysis ▪ Specific Gravity ~1.010 69 AMINOGLYCOSIDES ▪ Management ▪ Prevention ▪ D/C aminoglycoside ▪ Avoid hypovolemia ▪ Supportive therapy ▪ Avoid prolonged therapy ▪ Correct volume derangements ▪ Therapeutic drug monitoring ▪ Correct metabolic acidosis ▪ Avoid other nephrotoxins ▪ Hemodialysis/Renal Replacement ▪ Alternate dosing strategies Therapy ▪ Avoid high risk populations – elderly, pre-existing renal failure 70 Amphotericin B Antifungal used to treat systemic fungal infections Risk factors: ○ Cumulative Dose ○ Pre-existing kidney disease ○ Concurrent nephrotoxic drugs ○ dehydration or volume depletion ○ Conventional Ampho B vs. liposomal formulations 71 Amphotericin B - Mechanism Acute Tubular Necrosis Direct toxicity to cells in the distal nephron Cell death and necrosis Impairs kidneys ability to filter and concentrate urine 72 Prevention and Management Hydration Use of liposomal formulations Limiting dose and duration Monitoring renal function Avoiding concurrent nephrotoxins 73 DRUG INDUCED ACUTE INTERSTITIAL NEPHRITIS INTERSTITIAL NEPHRITIS ▪ Up to 3% of all cases of acute kidney injury ▪ Presentation ▪ Fever ▪ Rash ▪ Pyuria/hematuria ▪ Oliguria ▪ Other ▪ Metabolic acidosis ▪ Hyperkalemia ▪ Salt wasting ▪ Occur ~ 14 days after exposure to drug 75 INTERSTITIAL NEPHRITIS ▪ Mechanism ▪ Hypersensitivity reaction ▪ Lymphocytic infiltration of the interstitium ▪ Urine Findings ▪ WBC (pyuria) ▪ FeNa >1% ▪ Urine Na > 40mmol/L ▪ Hematuria ▪ White cell casts ▪ Mild proteinuria ▪ Eosinophils ▪ Implicated drugs: penicillins, lithium (Chronic Interstitial Nephritis) 76 INTERSTITIAL NEPHRITIS ▪ Management ▪ D/C offending drug ▪ Supportive therapy ▪ Correct volume derangements ▪ Prednisone therapy for up to 4 weeks ▪ Intermittent hemodialysis 77 DRUG INDUCED OBSTRUCTIVE NEPHROPATHY (post renal AKI) OBSTRUCTIVE NEPHROPATHY ▪ Refers to problems in the ureters, Patients at high risk: bladder and urethra Volume depleted ▪ Must be in both kidneys Underlying renal insufficiency ▪ 3 presentations Concomitant metabolic disorders ▪ Renal tubular obstruction ▪ Extrarenal urinary tract obstruction ▪ Nephrolithiasis (kidney stones) 79 OBSTRUCTIVE NEPHROPATHY ▪ Renal Tubular Obstruction ▪ Intratubular precipitation of drug crystals or other tissue degradation products ▪ Ex: acyclovir, rhabdomyolysis with statins ▪ Extrarenal urinary tract obstruction ▪ Males with BPH given anticholinergic drugs ▪ Nephrolithiasis ▪ Precipitation of stone forming components into ureters ▪ Indinavir 80 OBSTRUCTIVE NEPHROPATHY ▪ Urine Findings ▪ Management ▪ Red/white blood cells ▪ d/c offending drug ▪ Crystals ▪ Hydration ▪ Acyclovir – needle shaped ▪ Loop diuretic ▪ Indinavir – rectangular plates or ▪ Supportive therapy rosettes 81 OBSTRUCTIVE NEPHROPATHY ▪ Prevention ▪ Aggressive hydration ▪ Avoid rapid infusions and large bolus doses of acyclovir (or other drugs that crystalize) ▪ Urine alkalinization 82 DRUG-INDUCED STONES 1-2 % of all stones Risk Factors ▪ Daily dose ▪ Duration of treatment ▪ Urinary excretion of drug or metabolite ▪ Solubility of drug or metabolite ▪ Concentration peaks in the urine – rate of elimination ▪ Morphology of the crystals 83 DRUG INDUCED STONES - CAUSES Crystallize in the urine ▪ Antibacterials – sulphonamides, cephalosporins, quinolones, furanes, pyridines, aminopenicillins ▪ Protease inhibitors (indinavir, nelfinavir, acyclovir) ▪ Antihypertensives (triamterene) ▪ Others: primidone, methotrexate, guaifenisin, allopurinol, sulfasalazine 84 DRUG INDUCED STONES - CAUSES Metabolically induced ○ Change in fluid balance – furosemide, corticosteroids, laxative abuse ○ Change pH – carbonic anhydrase inhibitors, carbonate/bicarbonates, alkalinizing agents, acidifying drugs ○ Hypercalciuria – calcium and vitamin D supplements, furosemide, corticosteroids ○ Hypophosphatemia – aluminum hydroxide ○ Hyperoxaluria – Vitamin C, uricosurics, antibacterials 85 SUMMARY -DRUG INDUCED KIDNEY INJURY Drugs can be implicated in all 3 types of AKI Focus largely on prevention ○ Identifying high risk patients and avoid use ○ Discontinue as soon as possible Treatment is largely supportive Important role for pharmacists to assess patients who may be at risk for AKI due to medications both in hospital and community 86 End of Part 2 Knowledge Check - Menti Which of the following drugs is most commonly associated with acute tubular necrosis (ATN) as a cause of drug-induced AKI? A) ACE inhibitors B) NSAIDs C) Amphotericin B D) Furosemide 89 Which of the following mechanisms describes how NSAIDs induce acute kidney injury? A) Inhibition of afferent arteriole vasodilation B) Increased renal perfusion via prostaglandin production C) Direct toxicity to renal tubular epithelial cells D) Formation of crystals in the urinary tract 90 ACE inhibitors and Angiotensin II Receptor Blockers (ARBs) can cause drug-induced AKI primarily by: A) Reducing blood flow through the efferent arteriole B) Increasing filtration pressure in the glomerulus C) Blocking afferent arteriole vasoconstriction D) Enhancing tubular reabsorption of sodium 91 Which class of antibiotics is most frequently associated with acute interstitial nephritis (AIN), a form of drug-induced AKI? A) Aminoglycosides B) Beta-lactams (e.g., penicillins) C) Fluoroquinolones D) Tetracyclines 92 Which of the following is a risk factor for developing drug-induced AKI when using aminoglycosides? A) Low serum potassium levels B) Hyperhydration C) Short duration of therapy D) Pre-existing renal impairment 93