Integrated Pharmacology and Therapeutics IB PDF

Integrated Pharmacology and Therapeutics IB Pathophysiology of Renal Diseases Ahmad Abuhelwa, PhD Assistant Professor Department of Pharmacy Practice & Pharmacotherapeutics College of Pharmacy -University of Sharjah ah...

Integrated Pharmacology and Therapeutics IB Pathophysiology of Renal Diseases Ahmad Abuhelwa, PhD Assistant Professor Department of Pharmacy Practice & Pharmacotherapeutics College of Pharmacy -University of Sharjah [email protected] Course Code 1102359 1 2 Outline Overview of the kidneys' role in maintaining homeostasis. Quantitative and semi-quantitative indices of kidney function Serum creatinine and estimation of GFR Acute kidney Injury (AKI) Chronic Kidney Disease (CKD) – next lecture CKD secondary complication – 3rd lecture 3 Urinary System Key Structures Plays an important role in maintaining body homeostasis! 4 Normal Kidney functions Excretory: excretes urea, medications, environmental toxins excess, and excess fluid and electrolytes It accomplishes this through the combined processes of glomerular filtration, tubular secretion, and reabsorption. Endocrine: produces and secretes erythropoietin (EPO, by peritubular fibroblasts), and renin by juxtaglomerular apparatus Metabolic: activation of vitamin D, metabolism and clearance of insulin, steroids, and other drugs 5 When kidney functions is lost or diminished, all the above functions are affected! 6 Think About! It is common for patients with diabetes and stages 4 to 5 CKD to have reduced requirements for exogenous insulin, and require supplemental therapy with activated vitamin D3 (calcitriol)  Think About! Patients with stages 3 to 5 CKD and those with moderate-to-severe AKI may develop normocytic anemia, fatigue, dyspnea, and angina We’ll talk about secondary complications of kidney diseases later! Quantification of Kidney function Important component of a diagnostic evaluation Serves as a useful indicator of the ability of the kidneys to eliminate drugs from the body. An important parameter for monitoring the success of treatment. 9 Quantitative and semi-quantitative indices of kidney function Serum creatinine (Scr) to estimate GFR; Serum electrolytes, including Na, K, CL, HCO3; Urinalysis: pH; glucose, protein (albumin), heme, WBC, nitrite, specific gravity, albumin-to-creatinine ratio (ACR). Kidney ultrasound may aid in evaluating the etiology of kidney disease. 10 Serum Creatinine (Scr) The most widely used endogenous biomarker for detection of kidney disease. The conc of Scr is a function of creatinine production (metabolism from muscle) and kidney excretion (eliminated primarily by glomerular filtration). As GFR declines, the Scr rises At steady state, the “normal” Scr range is generally reported as 0.5 to 1.2 mg/dL (44-106 μmol/L) for males and females. 11 (GFR) Glomerular Filtration Rate (GFR) Can be measured (mGFR) or estimated (eGFR) A mGFR remains the single best index of kidney function, and is routinely employed worldwide in the evaluation of kidney transplant recipients and donors. GFR progressively decline (age-related loss, diseases such as hypertension or diabetes). The rate of GFR decline can be used to predict the time to onset of stage 5 CKD (End Stage Renal disease –ESRD), and the risk of complications of CKD. The normal values for GFR are 127 ± 20 mL/min/1.73 m2 and 118 ± 20 mL/min/1.73 m2 in healthy men and women, respectively. 12 Measuring GFR (mGFR) Calculated by determining renal clearance (CLr) of a substance (marker) that undergoes glomerular filtration without tubular secretion or reabsorption mGFR = CLr = Ae / AUC0-t, Ae: amount excreted in the urine Several markers have been used (e.g. inulin, sinistrin, iothalamate, radiolabeled markers, creatinine?) However, they requires specialized administration techniques and detection methods for the quantification of concentrations in serum and urine so are not practical for routine clinical use. 13 Estimation of GFR (eGFR) Several equation have been introduced to estimate GFR based on Scr and other clinical variables (e.g. age, weight, race). Cockcroft-Gault formula (CG): Jelliffe’s equation: We will use the CG equation (recommended by FDA) in this course & exams! 14 Estimation of GFR (eGFR) Modification of Diet in Renal Disease (MDRD) study equation: Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI): κ is 0.7 for females and 0.9 for males, min indicates the minimum of Scr/κ or 1, and max indicates the maximum of Scr/κ or15 1. Cockroft-Gault (CG) equation By default, use the patient’s ideal body weight (IBW) in CG CrCl (known as modified CG equation) because it more accurately reflects renal function o However, you MUST always use actual body weight (ABW) if it is < IBW IBW for males: IBW = 50 kg+ 2.3 kg (for each inch > 5 foot) IBW for Females: IBW = 45.5 kg + 2.3 kg (for each inch > 5 foot) o If height in cm convert to inches: 1 inch = 2.54 cm. Note that 1 foot = 12 inch o If weight is in pounds (lb) convert to (kg) by dividing lb mass by 2.205. If serum creatinine is in micromoles divide by 88.4 to convert to mg/dl 16 Calculation example Calculate the CrCl for an 85-year-old 6’-0” 145.2 lb. male with a SCr = 2.5 mg/dL. Solution: o WT in Kg = 145.2/2.205 = 65.9 kg o IBW = 50 kg + 2.3 kg (12) = 77.6 kg o CrCl = [(140-85)x 65.9]/(72x2.5) = 20.136 ml/min Why didn’t we use his IBW? 17 Acute Kidney Injury Pathophysiology 18 AKI at a glance! Terminology: Acute renal failure → AKI AKI is defined as an abrupt reduction in kidney function (↓GFR) as evidenced by changes in serum creatinine (Scr), blood urea nitrogen (BUN), with/without a change in urine output. Occurs in 3-18.3% of hospitalized non-critically ill patients and 30% to 60% of critically ill adults. A potentially life-threatening syndrome 19 Diagnosis of AKI An increase in serum creatinine (SCr) of at least 0.3 mg/dL (27 µmol/L) within 48 hours OR At least 50% increase in baseline serum creatinine 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 a diagnosis of AKI! 20 Risk factors associated with AKI Presence of CKD, diabetes, heart or liver disease, albuminuria, major surgery (especially cardiac surgery), acute decompensated heart failure, sepsis, hypotension, volume depletion (diarrhea, vomiting, or dehydration) Medications: exposure to aminoglycosides, ACE inhibitors, ARBs,etc. Advanced age, male gender, and African American race 21 Classification of AKI (Stages) Different Classification Systems. Based on changes in Scr, GFR, and urine output RIFLE: Risk, Injury, Failure, Loss of Kidney Function, and End-Stage Kidney Disease AKIN: Acute Kidney Injury Network *KDIGO: Kidney Disease: Improving Global Outcomes *The most comprehensive and globally accepted guideline 22 Classification of AKI 23 KDIGO Classification The KDIGO criteria have been validated across different patient populations and their staging correlates closely with hospital mortality, cost, and length of stay 24 AKI → AKD → CKD AKI can either rapidly reverse within the first 48 hours or persist over a period of up to 7 days. Kidney impairment that persists > 7 days is termed acute kidney disease (AKD) and can lead to chronic kidney disease (CKD) if its duration exceeds 90 days. 25 Classification of AKI based on etiology. Divided into three broad categories based on the anatomic location of the injury associated with the precipitating factor(s) a) Prerenal: results from decreased renal perfusion (blood flow) to the kidney b) Intrinsic: the result of structural damage to the kidney, most commonly the tubule from an ischemic or toxic insult, and c) Postrenal: caused by obstruction of urine outflow. 26