Rhodes University Pharmacotherapy Acute Kidney Injury 2024 PDF

Faculty of Pharmacy Pharmacotherapy Acute Kidney Injury 2024 Ms L Allan  1 LEARNING OBJECTIVES Upon completion of this topic, t...

Faculty of Pharmacy Pharmacotherapy Acute Kidney Injury 2024 Ms L Allan  1 LEARNING OBJECTIVES Upon completion of this topic, the student will be able to: 1. Assess a patient’s kidney function based on clinical presentation, laboratory results, and urinary indices 2. Identify pharmacotherapeutic outcomes and endpoints of therapy in a patient with acute kidney injury (AKI) 3. Apply knowledge of the pathophysiology of AKI to the development of a treatment plan 4. Develop strategies to minimize the occurrence of drug-induced AKI Rhodes University | Faculty of Pharmacy | Pharmacotherapy | Lecture slides | 2024 | Ms L Allan  2 INTRODUCTION Acute Kidney Injury (AKI) is a potentially life-threatening syndrome that occurs primarily in hospitalized patients, especially critically ill adults (between 30% - 60% critically ill patients develop AKI) AKI used to be called acute renal failure. The new term, AKI, aims to capture the entire spectrum: from mild changes to kidney function, to end-stage disease requiring Renal Replacement Therapy (RRT) such as dialysis There is an abrupt ↓ in kidney function leading to rapid ↓ GFR, accumulation of nitrogenous waste products (azotaemia or uraemia) and fluid and electrolyte imbalance It is evidenced by changes in serum creatinine and blood urea nitrogen (BUN). AKI is defined as: Increase in serum creatinine (SCr) of at least 27 𝜇mol/L within 48 hours, or Increase in baseline SCr by 1.5 times or more within 7 days, or A urine output of less than 0.5 mL/kg/h for at least 6 hours Only one criterion needs to be met for the diagnosis of AKI (compare with hospital-level STGs, s7.1.4) With prompt intervention AKI is often reversible. If left untreated it leads to permanent renal damage. AKI is associated with increased length of stay, cost, readmission, ventilator days, and need for post-hospitalization care. Rhodes University | Faculty of Pharmacy | Pharmacotherapy | Lecture slides | 2024 | Ms L Allan  3 AKI or CKD? Rhodes University | Faculty of Pharmacy | Pharmacotherapy | Lecture slides | 2024 | Ms L Allan  4 BASIC TERMINOLOGY What is the difference between blood, plasma and serum? Blood: fluid that circulates throughout the body, via the arteries and veins. It is composed of blood cells which are suspended in a liquid medium known as the plasma. An average person has 70 mL of blood/kg body weight (approximately 5 L in an average adult male). Plasma: The straw-coloured fluid in which blood cells are suspended. It consists of a solution of various inorganic salts (Na, K, Ca, etc) with a high concentration of protein (approximately 70 g/L) and a variety of trace substances. Serum: Similar to plasma, but has had all the substances that are used in the coagulation process removed. In other words, no blood cells and no fibrinogen (and other clotting factors). What is the difference between creatine and creatinine? Creatine: A product of protein metabolism found in muscle. Creatinine: A substance derived from creatine in muscle, and excreted in the urine. Rhodes University | Faculty of Pharmacy | Pharmacotherapy | Lecture slides | 2024 | Ms L Allan  5 RISK FACTORS FOR AKI Diabetes Mellitus Hypertension Heart and liver disease Albuminuria Major surgery (especially cardiac surgery) Acute decompensated heart failure Sepsis Hypotension Volume depletion (diarrhoea, vomiting or dehydration) Medication (exposure to ACE Inhibitors, ARBs, aminoglycosides) Advanced age Male sex Chronic kidney disease Rhodes University | Faculty of Pharmacy | Pharmacotherapy | Lecture slides | 2024 | Ms L Allan  6 PATHOPHYSIOLOGY Rhodes University | Faculty of Pharmacy | Pharmacotherapy | Lecture slides | 2024 | Ms L Allan  7 AETIOLOGY (Classification of AKI is based on aetiology) Pre-renal Intrinsic Post-renal AKI AKI AKI Due to volume Due to damage to Due to prostrate depletion tubules disease Due to damage to Due to hypotension Due to bladder tumours glomerulus Causes ↓ perfusion of Causes obstruction of the kidneys urine flow Rhodes University | Faculty of Pharmacy | Pharmacotherapy | Lecture slides | 2024 | Ms L Allan  8 PRE-RENAL AKI ❖ Reduced blood flow (perfusion) to the kidneys Caused by intravascular volume depletion due to haemorrhage, dehydration, GI fluid losses, extensive burns, diuretic therapy (nephrons have high metabolic activity, so reduced perfusion will affect function) To maintain GFR the kidneys require 20-25% of cardiac output. Conditions that ↓ cardiac output (CHF, MI), septic shock, hypotension can also ↓ renal blood flow and ↓ glomerular perfusion, leading to prerenal AKI and ischaemic changes to the renal tissue Rhodes University | Faculty of Pharmacy | Pharmacotherapy | Lecture slides | 2024 | Ms L Allan  9 DRUG-INDUCED PRE-RENAL AKI a) In the case of a mild ↓ in renal blood flow, compensatory mechanisms are activated to maintain normal GFR: intraglomerular pressure is maintained by dilation of afferent arterioles, constriction of the efferent arterioles, and redistribution of renal blood flow to the oxygen-sensitive renal medulla. This stimulates the sympathetic nervous system and RAAS, and the release of ADH (if patient is hypotensive). BP is then maintained via vasoconstriction and stimulation of thirst – increased fluid intake & sodium and water retention. b) Some drugs that may cause a functional AKI by interfering with the autoregulatory mechanism in a). They can ↓ intraglomerular pressure, resulting in ↓ GFR NSAIDs (e.g., naproxen) Impair prostaglandin-mediated dilation of afferent arterioles ACE Inhibitors (e.g., enalapril) Inhibit angiotensin II-mediated efferent arteriole vasoconstriction Angiotensin II receptor blockers (ARBs) Same as ACE inhibitors Rhodes University | Faculty of Pharmacy | Pharmacotherapy | Lecture slides | 2024 | Ms L Allan  10 INTRINSIC AKI ❖ Structural damage to the kidney Instrinsic or intrarenal AKI is caused by diseases that can affect the structure of the nephron and the renal parenchyma (such as the tubules, glomerulus, interstitium, blood vessels). Examples of these diseases include glomerulonephritis, systemic lupus erythematosus (LSE), interstitial nephritis, vasculitis, and acute tubular necrosis. Rhodes University | Faculty of Pharmacy | Pharmacotherapy | Lecture slides | 2024 | Ms L Allan  11 ACUTE TUBULAR NECROSIS The most common cause of intrinsic AKI is acute tubular necrosis (ATN). ATN relates to the necrosis of tubular epithelial cells resulting from nephrotoxins (such as aminoglycosides, contrast media, amphotericin B), sepsis or ischaemia. The tubular epithelial cells are damaged as a result of poor renal blood flow or toxins (drugs or bacteria), and die (necrosis), blocking the tubules with debris. This ↑ tubular pressure, causing poor elimination of Na, H2O and metabolic waste. Prerenal AKI can progress to ATN if the underlying cause is not promptly correctly. Rhodes University | Faculty of Pharmacy | Pharmacotherapy | Lecture slides | 2024 | Ms L Allan  12 POSTRENAL AKI ❖ Obstruction of urinary outflow May affect the ureters, urinary bladder or urethra (the urinary collection system) Causes include benign prostatic hyperplasia (BPH), pelvic tumours and precipitation of renal calculi (kidney stones / nephrolithiasis) Rhodes University | Faculty of Pharmacy | Pharmacotherapy | Lecture slides | 2024 | Ms L Allan  13 CLINICAL PRESENTATON & DIAGNOSIS Rhodes University | Faculty of Pharmacy | Pharmacotherapy | Lecture slides | 2024 | Ms L Allan  14 SIGNS & SYMPTOMS The signs and symptoms of AKI are highly variable and dependent on the underlying aetiology (i.e., they are nonspecific). Examples include: Weight gain Nausea, vomiting, diarrhoea, anorexia Fatigue Shortness of breath Pruritus Weight loss (prerenal AKI) Anuria alternating with polyuria (postrenal AKI) Colicky abdominal pain radiating from flank to groin (postrenal AKI) Electrolyte disturbances Oedema Signs of hypovolaemia: tachycardia, hypotension, postural hypotension, reduced skin turgor, reduced ocular tension (“sunken eyes”), collapsed peripheral veins and cold extremities. Rhodes University | Faculty of Pharmacy | Pharmacotherapy | Lecture slides | 2024 | Ms L Allan  15 PHYSICAL EXAMINATION Increased blood pressure Peripheral oedema Change in mental status Jugular venous distention (JVD) – suggests systemic venous congestion and volume overload Pulmonary oedema Crackles – crackling noises in the lungs Asterixis – involuntary jerking movements, especially in the hands Pericardial or pleural friction rub Hypotension or orthostatic/postural hypotension (prerenal AKI) Rash (intrinsic AKI due to acute interstitial nephritis) Bladder distention (postrenal bladder outlet obstruction) Prostatic enlargement (postrenal AKI) Rhodes University | Faculty of Pharmacy | Pharmacotherapy | Lecture slides | 2024 | Ms L Allan  16 AKI STAGING SYSTEM South African Renal Society (SARS) guidelines published in 2015. The staging system is based on changes to the serum creatinine (SCr). Stage Serum creatinine Urine output 1.5 – 1.9 X baseline OR < 0.5 mL/kg/h for 6-12 hours 1 ≥ 27 𝜇mol/L increase 2.0 – 2.9 X baseline < 0.5 mL/kg/h for ≥ 12 hours 2 3.0 X baseline OR < 0.3 mL/kg/hr for ≥ 24 hours ↑ SCr to 354 𝜇mol/L OR Initiation of RRT OR OR 3 In patients > 18 years, ↓ eGFR to < 35 mL/min per 1.73 m2 Anuria for ≥ 12 hours Rhodes University | Faculty of Pharmacy | Pharmacotherapy | Lecture slides | 2024 | Ms L Allan  17 DIAGNOSTIC PARAMETERS (1) Urine output and osmolality ❖ Polyuria = Excessive excretion of urine resulting in profuse micturition ❖ Oliguria (i.e., the production of a small volume of urine) = daily urine output < 400 mL/day ❖ Non-oliguric AKI = urine output > 400 mL/day ❖ Anuria (i.e., the failure to produce urine) = daily urine output < 50 mL/day ❖ Urine is more concentrated with prerenal AKI, and has a higher osmolality compared with intrinsic or postrenal AKI eGFR (estimated glomerular filtration rate) It is a test used to assess how well the kidneys are working The test estimates the volume of blood that is filtered by the kidneys over a given period of time, by measuring the creatinine levels in the blood. The eGFR is calculated using the patient’s age, sex and blood creatinine level. Rhodes University | Faculty of Pharmacy | Pharmacotherapy | Lecture slides | 2024 | Ms L Allan  18 DIAGNOSTIC PARAMETERS (2) BUN to SCr ratio BUN = Blood Urea Nitrogen. Urea is a product of amino acid metabolism. Urea is eliminated via glomerular filtration, but also undergoes reabsorption in the proximal tubules ↑ blood urea reabsorption occurs at lower urine flow rates within the kidney Lower urine flow rates occurs in prerenal AKI ↑ BUN to SCr ratio can indicate prerenal AKI Other conditions that can ↑ BUN: excessive protein intake and GI bleeding (blood breakdown to amino acids in the gut) FENa (fractional excretion of sodium) ✓ Used to differentiate between different types of AKI ✓ FENa is a measure of the percentage of sodium excreted by the kidney ✓ Patients with prerenal AKI have enhanced sodium reabsorption which leads to low urine sodium concentration and low FENa ✓ Normally 1% to 2% of sodium intake is excreted by the kidneys ✓ A FENa < 1% may indicate prerenal AKI (the response of the kidney to ↓ renal perfusion by ↓ sodium excretion) ✓ Loop diuretics (e.g., furosemide) enhance sodium excretion and increase FENa Rhodes University | Faculty of Pharmacy | Pharmacotherapy | Lecture slides | 2024 | Ms L Allan  19 LABORATORY TEST FBC or CBC with differential (↑ white blood cell count, infection) Arterial blood gases (metabolic acidosis) Urea & Electrolytes (U & E) Elevated SCr (reference range: 53 to 106 𝜇mol/L) Elevated BUN (reference range: 2.9 to 8.9 mmol/L) BUN-to-creatinine ratio > 10:1 (prerenal AKI) Hyperkalaemia Urinalysis Sediment Scant or bland (prerenal or postrenal AKI) Brown, muddy granular casts (intrinsic ATN) Proteinuria (glomerulonephritis or allergic interstitial nephritis) Eosinophiluria (acute interstitial nephritis) Haematuria or red blood cell casts (glomerular disease or bleeding in urinary tract) WBC or casts (acute interstitial nephritis or severe pyelonephritis) Rhodes University | Faculty of Pharmacy | Pharmacotherapy | Lecture slides | 2024 | Ms L Allan  21 CASE STUDY 1 A 65-year-old woman presents to the clinic with complaints of nausea and vomiting. She has a past medical history of stage 2 chronic kidney disease with proteinuria (baseline SCr 88 𝜇mol/L), gout, hypertension, type 2 diabetes mellitus and osteoarthritis. Her eGFR is 60 mL/min/1.73m 2. She reports having nausea, vomiting, and low-grade fever last week. Her fever resolved with ibuprofen, but she still feels weak and nauseated. She states that “her feet are swollen” even though she takes her “water pill”. Her weight is usually about 68 kg, and she weighs 70.5 kg. Upon preliminary examination, she was found to have bilateral 2+ pitting oedema up to the knees, BP 170/94 mmHg, and crackles on auscultation. Meds: Losartan / Hydrochlorothiazide 100/25 mg orally once daily Simvastatin 40 mg orally daily in the evening Metformin 500 mg orally twice daily Glimepiride 1 mg orally daily Atenolol 50 mg orally daily in the evening Allopurinol 300 mg orally daily Ibuprofen 400 mg orally four times daily as needed for arthritis and fever Rhodes University | Faculty of Pharmacy | Pharmacotherapy | Case Discussion | 2024 | Ms L Allan  22 CASE STUDY 1 QUESTIONS What signs and symptoms suggest AKI? What risk factors does she have for developing AKI? What additional laboratory information do you need to fully assess the patient? What questions would you ask her regarding the pharmacotherapy? Rhodes University | Faculty of Pharmacy | Pharmacotherapy | Case Discussion | 2024 | Ms L Allan  23 What signs and symptoms suggest AKI? Bilateral 2 + pitting oedema up to the knees Weight gain Elevated blood pressure Crackles on auscultation (may indicate fluid retention) Nonspecific symptoms such as weakness and nausea may be present in AKI Rhodes University | Faculty of Pharmacy | Pharmacotherapy | Case Discussion | 2024 | Ms L Allan  24 What risk factors does she have for developing AKI? Age History of diabetes mellitus History of chronic kidney disease (although her SCr is normal, she has proteinuria that is likely secondary to diabetic nephropathy) Taking medications that may cause (or worsen) AKI, such as ibuprofen (highly likely), and losartan/hydrochlorothiazide (may be contributory). In addition, the combination of an ARB, diuretic, and NSAID results in an increased risk of AKI, particularly in the first 30 days of co-administration. More information regarding her medication history is needed at this time. Recent bout of gastroenteritis (likely led to prerenal AKI) Rhodes University | Faculty of Pharmacy | Pharmacotherapy | Case Discussion | 2024 | Ms L Allan  25 What additional laboratory information do you need to fully assess the patient? A full set of blood chemistries, particularly: BUN, SCr, bicarbonate, and potassium WBC to help rule out infection Previous laboratory results (such as BUN and SCr) to determine baseline kidney function Urinalysis HbA1c & HGT (hyperglycaemia → glycosuria → osmotic diuresis) Rhodes University | Faculty of Pharmacy | Pharmacotherapy | Case Discussion | 2024 | Ms L Allan  26 What questions would you ask her regarding the pharmacotherapy? How long have you been taking ibuprofen? How many ibuprofen tablets do you take per day? How often do you take them in a day? How long have you been taking your other medications, particularly losartan/hydrochlorothiazide? Do you take your medications every day as prescribed? Have you been taking any other over-the-counter or herbal medications? Rhodes University | Faculty of Pharmacy | Pharmacotherapy | Case Discussion | 2024 | Ms L Allan  27 TREATMENT Rhodes University | Faculty of Pharmacy | Pharmacotherapy | Case Discussion | 2024 | Ms L Allan  28 TREATMENT GOALS Ameliorating (i.e., making better) identifiable underlying causes of AKI such as: hypovolaemia, nephrotoxic drugs, or ureter obstruction. Pre-renal and post-renal AKI can be reversed if the underlying problem is promptly identified and corrected. Treatment of intrinsic renal failure is primarily supportive until kidney function recovers. Supportive therapies include: renal replacement therapy (RRT), nutritional support, avoidance of nephrotoxins, and BP and fluid management. Rhodes University | Faculty of Pharmacy | Pharmacotherapy | Case Discussion | 2024 | Ms L Allan  29 FLUID THERAPY To ensure adequate tissue perfusion in patients with pre-renal AKI: Isotonic crystalloid fluid (0.9% normal saline) to expand intravascular volume and return volume status to neutral fluid balance (euvolaemia). Crystalloids (e.g., normal saline, balanced solutions such as Ringer’s Lactate or Plasma-Lyte A) are preferred over colloidal solutions (e.g., albumin, hydroxyethyl starch) for fluid resuscitation. 0.9% normal saline is generally preferred over lower tonicity saline fluids (e.g., 0.45% normal saline) as a smaller fraction of hypotonic fluid remains in the intravascular space. Dextrose 5% in water is isotonic, but after the dextrose is absorbed, only water is left in the intravascular space. Too much fluid resuscitation can cause pulmonary oedema, increased postoperative complications, increased mortality. Excess chloride from 0.9% normal saline can cause hyperchloraemic metabolic acidosis (chloride content in isotonic saline is 1.5 times that of plasma). Rhodes University | Faculty of Pharmacy | Pharmacotherapy | Case Discussion | 2024 | Ms L Allan  30 LOOP DIURETICS Examples: bumetanide, furosemide, torasemide Improves urine output but shows no improvement in survival or need for dialysis Reserved for treating volume overload Should not be given to prevent AKI or hasten recovery of kidney function in euvolaemic or hypovolaemic individuals, as it may lead to severe cardiovascular volume depletion. Dosage regimen: ≤ Furosemide 1G IVI at ≤ 4 mg/min (higher infusion rates may cause deafness) Diuretic resistance is common in patients with AKI. Reasons include: Excessive sodium administration (e.g., normal saline) may override the ability of diuretics to eliminate sodium Patients with ATN have reduced number of functioning nephrons on which the diuretic can act Patients with glomerulonephritis may experience heavy proteinuria – intraluminal loop diuretic is extensively protein bound in the urine, and cannot exert its effect in the loop of Henle. If fluid therapy followed by a furosemide challenge fails to achieve a diuresis, this therapy should be discontinued as the kidneys are incapable of mounting any response. Rhodes University | Faculty of Pharmacy | Pharmacotherapy | Case Discussion | 2024 | Ms L Allan  31 RENAL REPLACEMENT THERAPY (RRT) Purpose ❖ to treat pulmonary oedema and volume overload that is unresponsive to diuretics ❖ to minimize accumulation of nitrogenous waste products ❖ to correct electrolyte and acid-base abnormalities (e.g. hyperkalaemia) and metabolic acidosis Two types of RRT: haemodialysis & peritoneal dialysis Two processes of solute removal: diffusion and convection Two types of modalities: intermittent haemodialysis (IHD) and continuous renal replacement therapy (CRRT). Continuous Venovenous Haemodiafiltration (CVVH-DF) is a type of CRRT that is preferred in haemodynamically unstable patients Rhodes University | Faculty of Pharmacy | Pharmacotherapy | Case Discussion | 2024 | Ms L Allan  32 HAEMODIALYSIS & PERITONEAL DIALYSIS Haemodialysis Peritoneal dialysis Rhodes University | Faculty of Pharmacy | Pharmacotherapy | Case Discussion | 2024 | Ms L Allan  34 THE PHARMACISTS’ PATIENT CARE PROCESS (PPCP) Rhodes University | Faculty of Pharmacy | Pharmacotherapy | Case Discussion | 2024 | Ms L Allan  35 COLLECT DATA Patient characteristics (e.g., age, sex, muscle mass) Chief complaint/reason for admission Patient medical history including other related comorbid conditions (e.g., CKD, diabetes, HTN, cirrhosis) Current medication list Current or recent administration of nephrotoxins (e.g., nonsteroidal anti-inflammatory drugs [NSAIDs], ACEI/ARBs, contrast dyes, aminoglycosides, vancomycin) Blood pressure, heart rate, respiratory rate, weight Complete blood count and chemistry panel Changes in serum creatinine since last visit or admission (if available) Volume status (e.g., fluid intake, urine output, patient weight) Haemodynamic status (eg, BP, MAP) Microbiology results (if available) Urinalysis results (e.g., WBCs, RBCs, protein, granular casts, FENa) Acidbase status (e.g., arterial or venous blood gases) Kidney imaging results (e.g., obstruction, hydronephrosis) Rhodes University | Faculty of Pharmacy | Pharmacotherapy | Case Discussion | 2024 | Ms L Allan  36 ASSESS DATA Stage and severity of AKI using SARS criteria (SCr and/or urine output) Most likely cause of AKI (e.g., medication-induced, sepsis, volume depletion) Hemodynamic status / presence of acute hemodynamic changes Presence of baseline CKD Presence of sepsis, severe sepsis, or septic shock Presence of acidbase and/or electrolyte disturbances RRT modality and parameters, if applicable Rhodes University | Faculty of Pharmacy | Pharmacotherapy | Case Discussion | 2024 | Ms L Allan  37 PLAN Review all medications for appropriateness and ensure doses and frequencies are adjusted for patient’s current kidney function or RRT Approach to symptom relief and need for electrolyte corrections Recommend therapeutic drug monitoring when necessary, especially for drugs with a narrow therapeutic index Referrals to other providers when appropriate (e.g., nephrologist, dietician) Rhodes University | Faculty of Pharmacy | Pharmacotherapy | Case Discussion | 2024 | Ms L Allan  38 SELF-STUDY: DEVELOP YOUR OWN GLOSSARY 1. Define the following medical terms: Azotaemia Glomerular Filtration Rate (GFR) Renin-Angiotensin-Aldosterone System (RAAS) Congestive heart failure (CHF) Ischaemia Blood urea nitrogen (BUN) Urinary casts Specific gravity Asterixis 2. What is the difference between acute kidney injury (AKI) and chronic kidney disease (CKD)? 3. What is the difference between serum creatinine (SCr) and creatinine clearance (CrCl)? 4. Why is adrenaline used to treat persistent hypotension? Rhodes University | Faculty of Pharmacy | Pharmacotherapy | Case Discussion | 2024 | Ms L Allan  39 THE END Rhodes University | Faculty of Pharmacy | Pharmacotherapy | Case Discussion | 2024 | Ms L Allan