Renal Disease I and II: Acute and Chronic Kidney Conditions

Pharmacotherapy II PHAR 5204

Randall Sharp, Pharm.D.,BCPS Pharmacotherapy II PHAR 5204

Recommended Readings

Dowling TC. Evaluation of Kidney Function. In:DiPiro JT, et al. ed. Pharmacotherapy: A Pathophysiologic Approach, 11th ed. New York, New York: McGraw-Hill; 2020 [Ch 59] Halilovic J, Roller L. Acute Kidney Injury. In: DiPiro JT, et al. ed. Pharmacotherapy: A Pathophysiologic Approach, 11th ed. New York, New York: McGraw-Hill; 2020 [Ch 60] Hudson JQ, Wazny LD. Chronic Kidney Disease. In: DiPiro JT, et al. ed. Pharmacotherapy: A Pathophysiologic Approach, 11th ed. New York, New York: McGraw-Hill; 2020 [Ch 61] Sowinski KM, Churchwell MD, Decker BS. Hemodialysis and Peritoneal Dialysis. In: DiPiro JT, et al. ed. Pharmacotherapy: A Pathophysiologic Approach, 11th ed. New York, New York: McGraw-Hill; 2020 [Ch 62] Nolin TD, Perazella MA. Drug-Induced Kidney Disease. In: DiPiro JT, et al. ed. Pharmacotherapy: A Pathophysiologic Approach, 11th ed. New York, New York: McGraw-Hill; 2020 [Ch 63] Hogan JJ. Glomerular Diseases. In: DiPiro JT, et al. ed. Pharmacotherapy: A Pathophysiologic Approach, 11th ed. New York, New York: McGraw-Hill; 2020 [Ch 64] Barton-Pai, A, Bingham AL. Disorders of Calcium and Phosphorus Homeostasis. In: DiPiro JT, et al. ed. Pharmacotherapy: A Pathophysiologic Approach, 11th ed. New York, New York: McGraw-Hill; 2020 [Ch 67] The National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF KDOQI™M) guidelines. National Kidney Foundation. Available at: http://www.kidney.org/professionals/ KDOQI/guidelines.cfm. Bakris GL, Agarwal R, Anker SD, Pitt B, Ruilope LM, Rossing P, et al. Effect of Finerenone on Chronic Kidney Disease Outcomes in Type 2 Diabetes. NEJM 2020 Dec;383(23):2219-29. Heerspink HJL, Vefansson BV, Correa-Rotter R, Chertow GM, Greene T, Hou FF, et al. Dapagliflozin in Patients with Chronic Kidney Disease. NEJM 2020 Oct;383(15):1436-46. Cheung AK, Chang TI, Cushman WC, et al. Executive Summary of the KDIGO 2021 Clinical Practice Guideline for the Management of Blood Pressure in Chronic Kidney Disease. Kidney International 2021;99:559-569. 1Eknoyan G, Wheeler DC, Jadoul M, et al. KDIGO 2022 Clinical Practice Guideline for Diabetes Management In Chronic Kidney Disease. 2022;1-101. Inrig JK. ASN Dialysis Curriculum: Drug Dosing in Dialysis Patients. https://www.asn- online.org/education/distancelearning/curricula/dialysis/DrugDosingInrig.pdf Bhatt DK, Szarek M, Pitt B, et al. Sotagliflozin in Patients with Diabetes and Chronic Kidney Disease. NEJM 2020 Nov;384:129-39.

Learning Objectives

1. Define the basic functions of the kidneys.
2. Describe the patient variables, differences, limitations, and when the following equations are used to estimate glomerular filtration rate: Cockcroft-Gault and MDRD.
3. Define acute kidney injury and chronic kidney disease.
4. Recognize the major criteria by which acute kidney injury is assessed.
5. Describe the utility of urine sodium, fractional excretion of sodium, fractional excretion of urea, and serum creatinine in evaluating acute kidney injury.
6. Differentiate types of acute kidney injury by pathophysiology, etiology, risk factors, patient history, and/or laboratory data.
7. Recommend therapeutic interventions for a patient with acute kidney injury.
8. List common drugs which may cause acute kidney injury and describe common mechanisms of drug-induced kidney injury, such as ACEI-induced, NSAID-induced, and radiocontrast- induced AKI.
9. Recommend strategies to prevent and/or treat drug-induced acute kidney injury.
10. Describe the role of the renin-angiotensin-aldosterone system and drugs that affect it in the development and management of both acute & chronic kidney disease.
11. Identify common risk factors for the development of chronic kidney disease.
12. Create appropriate treatment plans for disease-modifying therapies for chronic kidney disease.
13. Describe complications of chronic kidney disease.
14. Identify abnormal laboratory parameters that are used to evaluate complications of chronic kidney disease.
15. Develop a pharmacotherapeutic plan for managing complications of chronic kidney disease including hypertension, anemia, bone mineral disease, hyperparathyroidism, and electrolyte disturbances.
16. Describe physiology, pharmacologic treatment, and therapeutic targets in the management of anemia of chronic kidney disease and secondary hyperparathyroidism.
17. Evaluate the safety and efficacy of pharmacotherapy in the management of chronic kidney disease and complications based on given clinical data.
18. Modify a pharmacotherapeutic plan of a patient being treated for chronic kidney disease and complications based on current pharmacotherapy and clinical data.
19. Describe the general indications for and procedure of hemodialysis
20. Explain general concepts of drug dosing in dialysis patients.

Renal Physiology

The Nephron- the functional unit of the kidney. Normal healthy adult kidney has over 800,000 nephrons. These are located in the renal cortex and medulla.

Renal capsule Proximal convoluted tu bule Loop of Henle Distal convoluted tubule Collecting duct a fferent arterio le efferent- arterio le glomerulus (capillary network) to ureter

Glomerulus and Arterioles

Glomerulus: site at which wastes are filtered from arterial blood Renal arterioles: provide and regulate blood flow to the glomerulus Afferent arteriole: leads into the glomerulus Efferent arteriole: continues out of the glomerulus These arterioles are important because certain drugs directly impact them (e.g. NSAIDS, ACE Inhibitors, Angiotensin II receptor blockers) Juxtaglomerular apparatus is located in the afferent arteriole; responsible for secretion of renin

Renal Tubule

Renal tubule: site after the glomerulus where filtrate is further altered through Na+, other electrolytes, and water reabsorption Proximal convoluted tubule (PCT): highly permeable to water; site of the majority of Na+ and water reabsorption, as well as bicarbonate, glucose, and amino acids Distal convoluted tubule (DCT): may be subdivided into "early" and "late DCT" Loop of Henle: may be further subdivided into descending and ascending limbs Collecting duct: final portion of the tubule, where urine responds to antidiuretic hormone (ADH); urine is concentrated

Renal Functions

I. Filtration

• Normal glomerular filtration rate [GFR]: 90-140 ml/min
• Water & waste removal
  • Filtrate removed from blood at site of glomerulus enters tubule
  • Large proteins not filtered (remain in blood ... e.g. albumin)

II. Reabsorption

• Regulation of water & electrolytes
  • Filtered Na+ is reabsorbed throughout the tubule & goes back into circulation. About 65% occurs in the proximal tubule and 25% in the loop of Henle
  • Water Osmotically reabsorbed (except in collecting duct) Responds to ADH in the late DCT and collecting duct

III. Secretion

• Organic ions: e.g. creatinine, histamine
• Other electrolytes: e.g, K+, Hydrogen ions (H+) are exchanged for Na+ to maintain acid-base balance
• Drugs and toxins: e.g. ammonia, penicillins, cimetidine, probenecid, procainamide, trimethoprim

IV. Excretion

• Urine is normally produced at a rate of ~1 ml/min
• Elimination of waste products/drugs and maintenance of homeostasis

V. Endocrine Function

• Renin
  • Released from juxtaglomerular cells in afferent arterioles
  • Increases in response to decreased renal perfusion pressure & other mechanisms .... "the kidney is blind"= automatically released when it thinks it is under perfused
  • Activation of the Renin-angiotensin-aldosterone system (RAAS) = increases BP, contributes to HTN, ventricular remodeling, etc.
• Erythropoietin
  • 90% is produced by the kidneys. Tells the bone marrow to produce more red blood cells (RBCs) .... reason for chronic anemia with CKD patients

VI. Metabolic Function

• Activation of vitamin D= kidney converts inactive vitamin D produced by the liver into its active form, 1,25(OH)2D. Patients with CKD have a deficiency in being able to have this activation
• Site of some drug metabolism (CYP450)
• Some gluconeogenesis, insulin and glucocorticoid handling

Quantification of Renal Function

Glomerular Filtration Rate (GFR)

• Best indicator of renal function
• Quantitative measure of changes in function
  • Normal range: 90-140 ml/min/1.73 m2
  • Age related decline: decreases ~0.75 to 1 ml/min/year after age 30
• Cannot directly measure GFR; must use surrogate markers to estimate
  • Rate of excretion = rate of filtration + rate of secretion - rate of reabsorption " Ideally, rate of excretion = rate of filtration
  • For this to be true, there should be no secretion and reabsorption of the marker

Ideal Surrogate Markers

• Freely filters across glomerulus
• Not secreted, not reabsorbed
• Cystatin C
  • Close to ideal
  • Endogenous marker, urinary or serum
  • Freely filtered, reabsorbed & catabolized in proximal tubule
  • Independent of muscle mass, but may be affected by age, gender, cigarette smoking, inflammation, etc.
  • May be more sensitive than Cr in acute renal dysfunction
• BUN
  • Less than ideal
  • Undergoes filtration
  • Highly reabsorbed
  • Reabsorption rate is dependent upon water reabsorption
• Creatinine
  • Mostly ideal, inexpensive
  • Endogenous substance
  • Constant production (breakdown of muscle creatine phosphate)
  • Undergoes little secretion (10%), not reabsorbed
  • Secretion may be inhibited by certain drugs (e.g. cimetidine, trimethoprim)
  • Interpatient variability (see table below

Factors Affecting Serum Creatinine Concentration

6Factors affecting serum concentration of creatinine (other than renal disease)

Estimation of Creatinine Clearance

• Actual creatinine clearance (CrCl) is measured by 24-hour urine collection
  • CrCl (ml/min) = Urine Cr (mg/dL) x Urine vol (ml) SCr (mg/dL) x Time (min)

Serum levels of Cr rise as CrCl (GFR) declines

• Equations to estimate CrCl
  • Recommended only in stable renal function
  • Cockcroft-Gault equation . May overestimate function in moderate to several renal impairment . Most commonly used method in clinical studies and "the real world"
  • Based on 4 variables: age, gender, weight, and creatinine Estimated CrCl = (140 - age) x weight (kg) *Multiply by 72 x SCr 0.85 for females
  • Other estimating equations: CKD-EPI, Mayo Clinic Quadratic, Jelliffe, Salazar-Corcoran, Schwartz

Weight Considerations for Creatinine Clearance

Weight considerations: Actual body weight (ABW) vs Ideal body weight (IBW)

• For males: IBW = 50kg ± 2.3 for every inch above/below 60"
• For females: IBW = 45.5kg ± 2.3 for every inch above/below 60" . Use ABW if ABW < IBW
• Use IBW if ABW > IBW but < 120% IBW
• Some experts suggest only using IBW if ABW > 130% IBW

Estimation of GFR (eGFR)

• Modification of Diet in Renal Disease (MDRD) Study
  • Based on 6 or 4 (Abbreviated) variables: age, gender, race, creatinine ± BUN, serum albumin