PHP 327 Clinical and Therapeutic Sciences Renal Pathophysiology: Part 1 PDF

10/19/2024 PHP 327 Clinical and Therapeutic Sciences Renal Pathophysiology: Part 1 Todd Brothers Pharm D, BCCCP, BCPS Clinical Associate Professor...

10/19/2024 PHP 327 Clinical and Therapeutic Sciences Renal Pathophysiology: Part 1 Todd Brothers Pharm D, BCCCP, BCPS Clinical Associate Professor Department of Pharmacy Practice College of Pharmacy University of Rhode Island 1 Lecture Outline Basic kidney physiology and functionality Urine formation Determinants, clinical estimation, and medication dosing based upon filtration rate Na+ and water homeostasis 2 Learning Objectives Review the fundamental principles of renal physiology as they relate to the filtration and excretion process Examine and Evaluate the complex relationship between water, sodium, and the regulation of plasma osmolality alterations to maintain homeostasis Describe and Apply pathophysiologic mechanisms by which kidney disease alters glomerular filtration rate (GFR) Calculate eGFR utilizing clinical estimate equations as they apply to medication therapy in pharmacy practice 3 1  10/19/2024 ‘Story’ of Your Kidneys Every minute of every day, your body is faced with a number of challenges to maintain homeostasis The metabolic processes necessary to keep us alive require fuel and result in the production of chemical waste products and acids The pH of the blood and other bodily fluids that exist within and outside of cells must be carefully regulated to allow enzymatic reactions to proceed efficiently Water and the concentration of key electrolytes, such as sodium and potassium, must be monitored and adjusted to maintain appropriate blood pressure and cellular function The kidneys are vital organs that play a critical role to ensure that the body is able to successfully meet these challenges When renal function is damaged, these processes are altered, homeostasis is altered and death may result 4 Simplistic View: Why do we have kidneys? We produce water-soluble metabolites which are hard to transport across cells and are toxic beyond a certain concentration, we need a direct pathway for elimination Yet, directly pumping out extracellular fluid would kill us within minutes, unless we succeed in reabsorbing everything we need with utter efficiency, in a precisely regulated process, beginning with water 5 PHYSIOLOGIC FUNCTIONS OF THE KIDNEY? 1) Regulation/filtration of electrolytes 2) Regulation of fluid balance 3) Removal of toxins 4) Maintain acid/base balance 5) Regulation of blood pressure 6) Production of hormones (erythropoietin) 7) Activation of Vitamin D 8) Absorption of glucose, amino acids 6 2  10/19/2024 Basic Renal Principles Principle # 1 Principle # 2 Maintenance of a relatively constant extracellular Secretes hormones that participate in the environment that is necessary for the cells (and regulation of systemic and renal hemodynamics organism) to function normally (renin, angiotensin II, and prostaglandins), red Achieved by excretion of some waste products of cell production (erythropoietin), and mineral metabolism (such as urea, creatinine, and uric acid) metabolism (calcitriol, the major active and of water and electrolytes that are derived metabolite of vitamin D) primarily from dietary intake Balance is a key principle in understanding renal functions (Excretion = Net Intake + Endogenous production) 7 (4) Main Functions of the Kidney 1) Maintains overall fluid balance by constantly regulating the extracellular environment 2) Filters and Excretes the waste products of metabolism (such as urea, creatinine, and uric acid) a) Adjusts the amount of urinary excretion of water and electrolytes to match net intake and endogenous production 3) Regulates the excretion of water and solutes a) Sodium, potassium, and hydrogen, largely by changes in tubular reabsorption or secretion 4) Develops and Secretes hormones that participate in the regulation of systemic and renal hemodynamics, RBC production and bone health: 1) Renin, prostaglandins, and bradykinin 2) Red blood cell production (erythropoietin) 3) Calcium and phosphorus balance 4) Bone metabolism (1,25-dihydroxyvitamin D3 or calcitriol) 8 Anatomy/Physiology ❑ Size: 12cm long ❑ Weight: 150g ❑ Receives: 25% of Cardiac Output = ❑ 0.75 L/min ❑ Produces: 0.4 – 2.0 L/day of urine ❑ Adults: 0.5-1ml/kg/hr ❑ Filters: 180 L /day or 125ml/min of plasma 9 3  10/19/2024 10 The capacity of the renal system to eliminate wastes is much greater than required in the normal physiology of the human Each kidney contains about one million functional units, the nephrons This represents about 75% more renal capacity than needed Kidney Context: One complete kidney could be Physiology removed and still leave about 25% more capacity than required This excess renal capacity may seem superficially to be beneficial, not always the case Concept: Because of the excess capacity, renal disease can become quite advanced before it is symptomatic and detectable 11 Anatomy of the Nephron 12 4  10/19/2024 Mechanism of Urine Formation (3) Major Processes 1. Glomerular Filtration: The glomerular membrane consists anatomically of the capillary walls of the glomerulus in close association with the epithelial layer that comprises the wall of the Bowman’s capsule By design, fluids that filter across the glomerular capillary walls from pressure differences will also cross the capsule layer to end up in the lumen of the Bowman’s capsule The glomerular filtration, is poorly selective and basically, everything except blood cells and high molecular weight proteins will cross the membrane This filtrate contains both nutrients and wastes, if allowed to remain in the nephron, essential nutrients would be lost with the urine 2. Tubular Reabsorption 3. Tubular Secretion 13 2. Tubular Reabsorption Nephron tubule cells, especially the proximal tubule, selectively reabsorb the nutrients back into blood leaving only the wastes in the lumen of the nephron Reabsorbs 50% of the filtered sodium and water, and it reabsorbs almost all of the filtered glucose, phosphate, amino acids, and other organic solutes by linking their transport to sodium Tubular reabsorption occurs by selective membrane transport mechanisms and each material exhibits a maximal threshold of reabsorption (Tmax) If the concentration of a material in the filtrate is greater than the maximal threshold, the excess will not be reabsorbed and will appear in the urine Knowledge Check: the solutes appearing in the urine can inform us of kidney disease 14 3. Tubular Secretion To enhance the kidney’s capacity to cleanse the blood of wastes: Nephron tubule cells have the added capacity to extract materials from blood of the peritubular capillaries and vasa recta and secrete them directly into urine H+ ions, electrolytes, creatinine and medications 15 5  10/19/2024 Kidneys = Waste Removal System Filtration vs. Excretion Survival requires that virtually all of the filtered solutes and water be returned to the systemic circulation by tubular reabsorption leaving the ‘waste’ behind Balance, or steady state, is maintained by keeping the rate of excretion equal to the sum of net intake plus endogenous production By altering both the amount and the composition of what is reclaimed, the kidney determines the body’s net balance, which can be defined as follows: Net balance = (amount ingested + amount created) - amount eliminated 16 Net Balance Concept The kidney is able to individually regulate the excretion of water and solutes (such as sodium, potassium, and hydrogen) largely by changes in tubular reabsorption or secretion Disease, (renal pathophysiology), to the tubules will alter the ability of the to reabsorption or secrete water and solutes 17 Summary: Na and Water Transport Proximal tubule: reabsorbs 50% of the filtered Na+ and water Loop of Henle: 40% of the filtered Na+ & Cl- is reabsorbed in the ascending limb of the loop Distal tubule: reabsorbs 5% to 8% of the filtered Na+ & Cl- 18 6  10/19/2024 Why Discuss Tubules and Loops? Commonly prescribed class of medications named: Diuretics Loop diuretics (Ex: furosemide): interfere with the transport of salt and water across the loop of Henle Thiazide diuretics (Ex: hydrochlorthiazide): inhibit reabsorption of Na+ and Cl- ions from the distal tubules by blocking the thiazide-sensitive Na+ Cl− symporter 19 How do we know the kidneys are functioning well? Visually… 20 Kidney Function Assessment Laboratory Data… Generalized screening and simple blood tests are readily available to detect initial kidney problems Blood Urea Nitrogen (BUN): increases in blood levels of nitrogenous wastes, which may be indicative of early stage kidney failure Albumin: produced by the liver, aids in maintaining oncotic pressure (intravascular volume) “Carrier molecule” of medications, hormones, vitamins and enzymes Serum creatinine level: screens for accumulation of the muscle waste product creatinine, which is derived from muscle stores of creatine phosphate and is normally excreted by the kidneys 21 7  10/19/2024 Renal Function Lab Indice: Blood Urea Nitrogen (BUN) Definition: measurement of the amount of urea Amount of urea in blood dependent on: nitrogen found in blood Protein in diet (intake) Liver produces urea in the urea cycle as a Liver function (metabolism) waste product of the digestion of protein Amino acids → liver→ urea + ammonia Renal filtration (excretion) Hydration status Normal range (measured in blood): 7-20mg/dL Normal BUN/SCr ratio: 10-15 : 1 (surrogate marker of hydration status) Ratio > 20:1 suggestive of dehydration 22 Renal Function Lab Indice: Protein (Albumin) Kidney insult/injury = evidence of elevated urine protein/urine albumin Calculate (termed: proteinuria/albuminuria) Urine albumin (mg) to Creatinine (g) ratio: Test/Assess with urine dipstick sensitive Normal range: to albumin < 30mg albumin/g of creatinine Observation of (+) albumin in the urine on three occasions over 3-6 months Micro-albuminuria range (damage): Normal range (measured in the urine) of 30 – 300mg healthy kidney excretion: albumin/g of creatinine 30 to 150mg/day of total protein (< 30mg of which is albumin) 23 Renal Function Lab Indice: Creatinine Creatinine is derived from the metabolism of creatine in skeletal muscle and from dietary meat intake Released into systemic circulation at a relatively constant rate It is freely filtered across the glomerulus and is neither reabsorbed nor metabolized by the kidney Renal elimination - 90% glomerular filtration, 10% active tubular secretion 24 8  10/19/2024 Creatinine Limitations: Variations in Muscle Mass May have low serum creatinine with decreased muscle mass May have high serum creatinine with increased May have varied serum and/or inactivity creatinine with muscle mass and/or overactivity decreased muscle mass and/or inactivity 25 Assessment of Kidney Filtration/Elimination Most useful information is obtained from: Estimation of the GFR is used clinically to: Estimation of the glomerular filtration Assess the degree of kidney impairment rate (eGFR) Follow the course of the disease Best indicator of overall kidney function: -examination of urinary sediment GFR provides no information on the cause of the kidney disease Achieved by the urinalysis, measurement of urinary protein excretion, and radiologic studies and/or kidney biopsy 26 Glomerular Filtration Rate Normal (GFR) Definition: GFR = rate (mL/min) at which substances in the plasma are filtered through the glomerulus GFR is equal to the sum of the filtration rates in all of the functioning nephrons: GFR gives a rough measure of the number of functioning nephrons Can be measured or calculated using a variety of markers Normal value for GFR depends upon age, sex, and body size: 130mL/min/1.73 m2 (men) 120mL/min/1.73 m2 (women) *considerable variation even among normal individuals 27 9  10/19/2024 Marker for Determining (GFR) Estimation Measurement Most common methods utilized to (3) Estimation equations based upon SCr: estimate the GFR 1) Cockcroft-Gault equation – developed 1976 in adult males 2) Modification of Diet in Renal Disease (termed = eGFR) is the measurement of (MDRD) study equation - developed 1999, revised to MDRD4 2002 3) Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation- developed Creatinine Clearance 2009 Endogenous filtration markers can only be used to estimate GFR in individuals with STABLE kidney function 28 GFR Caveats Stable GFR does not necessarily equate to Increase in GFR may indicate: stable disease Improvement in the kidney disease Imply a counterproductive increase in Signs of disease progression other than a filtration (hyperfiltration) due to change in GFR must be investigated: hemodynamic factors Increased activity of urine sediment Rise in protein excretion Underlying renal disease may go unrecognized Elevation in blood pressure because they have a normal GFR 29 Why Estimate GFR? Clinical situations in which it is important to have more precise knowledge 30 10  10/19/2024 Glomerular Filtration Rate Declining GFR reduction implies: No exact correlation between the loss of kidney mass (i.e. nephron loss) and the loss of GFR progression of the underlying disease Development of a superimposed and often Kidney (works harder) and adapts to the loss of nephrons by compensatory hyperfiltration reversible problem: and/or increasing solute and water reabsorption (Ex: decreased renal perfusion due to volume depletion/dehydration) Ex: a patient who has lost one-half of total kidney mass will not necessarily have one-half Degree of GFR decline has prognostic the normal amount of GFR implications (i.e. staging of CKD) 31 Creatinine and eGFR Utilization GFR can be estimated using creatinine “fairly” accurately if the following remain constant: creatine intake (i.e. diet) creatinine pool size (i.e. muscle mass) creatinine secretion (by the renal tubules) Concept: Reduction in GFR is not directly proportional to the magnitude of SCr increase: Example: a 50% reduction in GFR does not produce a doubling of serum creatinine Rather likely a small rise in serum creatinine 32 Advantages/Disadvantages Creatinine for eGFR Advantages Disadvantages Endogenous Provides an estimation of GFR Produced at a constant rate per day Is secreted by the renal tubules Routinely measured Dependent upon muscle mass Freely filtered at the glomerulus Dietary influence Inversely related to GFR Not reabsorbed or metabolized by the renal Concept Check: tubules Increased serum creatinine levels are considered a marker of decreased renal function Assays are standardized (note: inverse relationship) 33 11  10/19/2024 Equations to Estimate GFR Stable Unstable (Acute kidney injury) Cockcroft-Gault: (Clcr) Jeliffe: Gender, age, changes in SCr, BSA MDRD4: The equation does not require weight or Brater: height variables because the results are reported normalized to 1.73 m2 BSA Gender, age, changes in SCr Use is intended to stage CKD with a patient has renal dysfunction * both equations assume at least 24hrs between SCr values Less accurate in patients with GFR > 60 34 Equations Estimate eGFR Bedside Schwartz Equation CKD-EPI formula Pediatric (< 18 y/o) eGFR equation Staging CKD eGFR equation a. eGFR = 0.413 x (height/SCr) Recommended by Kidney Disease if height is expressed in centimeters Improving Global Outcomes (KDIGO) b. eGFR = 41.3 x (height/SCr) https://www.mdcalc.com/ckd-epi-equations- if height is expressed in meters glomerular-filtration-rate-gfr https://www.mdcalc.com/revised-schwartz- equation-glomerular-filtration-rate-gfr-2009 35 Estimated Creatinine Clearance (Clcr) Remember the estimate of GFR includes clearance and tubular secretion of creatinine: 90% (cleared) by glomerulus, 10% tubular (secretion) Clcr is expressed in mL/min Equations to assess creatinine clearance include: Serum Creatinine (mg/dL) Age Weight Gender 36 12  10/19/2024 Stable eGFR assessment Cockroft-Gault Equation Memorize! Clcr (mL/min) = {(140 – age) x (body weight in kg)} 72 x SCr (mg/dL) Multiply entire result by 0.85 [if female] Controversy exists over use of actual body weight, ideal body weight, adjusted body weight Controversy exists over rounding up (to 1.0) for low SCr (Ex: elderly/low muscle mass) FDA approved method for adjusting medication dosages 37 CLINICAL PRACTICE APPLICATION STABLE CREATININE A 65-year-old white female has a serum creatinine of 1.3 mg/dL. She weighs 129lbs and is 5’4” tall. {(140 – age) x (body weight in (kg)} x 0.85 [if female] 72 x SCr (mg/dL) What is her estimated Clcr (rounded to the nearest whole number) using the CG equation? 1. 103 mL/min 2. 88 mL/min 3. 47 mL/min 4. 40 mL/min 38 Determinants of GFR: Physics + Physiology As with other capillaries, fluid movement across the glomerulus is governed by Starling’s law, determined by the net permeability of the glomerular capillary wall and the hydraulic and oncotic pressure gradients A reduction in GFR in disease is most often due to a decrease in net permeability resulting from a loss of filtration surface area induced by some form of glomerular injury In normal subjects, GFR is primarily regulated by alterations in hydraulic pressures in the glomerular capillary (Pgc) that are mediated by changes in glomerular arteriolar resistance Concept check: loss of pressure within the glomerulus can reduce GFR in the diseased kidney if the arterioles can’t adapt 39 13  10/19/2024 Physics and Physiology Hydrostatic pressure in the renal vasculature Renal blood flow (RBF) is determined by: the mean pressure in the renal artery the contractile state of the smooth muscle in the afferent and efferent arterioles 40 Can you think of common diseases that may influence the physics and physiology of renal blood flow? 41 Medication Dosing Creatinine Clearance Significant disease progression can occur with little or no elevation in plasma creatinine concentration, particularly in patients with a GFR above 60 mL/min Generally most renally adjusted medications are warranted when CrCl < 50 mL/min Summary of Estimation Equations of Kidney Function for Prescription Medication Dosage in Adults https://www.niddk.nih.gov/health-information/professionals/advanced-search/ckd-drug-dosing- providers ❑ Why is it necessary to ‘renally reduce’ the dose or interval of renally eliminated medications? ❑ What are the risks? ❑ How does the FDA provide (legal) guidance for medication approvals to the market? 42 14  10/19/2024 You will spend your entire career recommending medication dosage adjustments due to impaired renal function 43 44 Na+ and Water Balance 45 15  10/19/2024 Os·mo·lal·i·ty vs Os·mo·lar·i·ty (noun) the concentration of a solution expressed as the total number of solute particles per kilogram (noun) the concentration of a solution expressed as the total number of solute particles per liter 46 Clinical Context: Osmolarity Lack of volume intake Loss of volume = DKA Acute ingestion 47 Na+ and Water Balance Balance is regulated independently by Clinical manifestations of impaired regulation: specific pathways designed to prevent large Too much water—hyponatremia changes in the plasma osmolality (low plasma sodium concentration) Primarily determined by plasma Na+ Too little water—hypernatremia concentration and the effective (high plasma sodium concentration) circulating volume Too much sodium—volume expansion (edema); little or no effect on plasma sodium concentration Too little sodium—volume depletion; little or no effect on plasma sodium concentration 48 16  10/19/2024 Osmotic pressure generated by a solute is proportional to the number of solute particles Osmotic The unit of measurement of Pressure osmotic pressure is osmole Principles Solutes generate an osmotic pressure by their inability to cross membranes 49 Osmotic Pressure and Distribution of Water Osmotic pressure physiologically determines the distribution of the body water between the different fluid compartments 50 Contributors to Plasma Osmolality and Oncotic Pressure Summary Urea contributes to the plasma osmolality but not to osmotic pressure (because it is permeable and crosses the lipid bilayer) Osmolality measured in the laboratory and Sodium contributes to the plasma osmolality reflects the total number of particles in and to the osmotic pressure at the cell solution membrane (between intracellular and interstitial compartments of the extracellular space) Osmotic pressure determines fluid Plasma proteins, particularly albumin, are the distribution and reflects the number of main determinants of the plasma oncotic osmotically active particles in each pressure (because they are essentially the only compartment effective osmoles in the plasma) Concept check: “Wherever Na+ goes, water follows” 51 17  10/19/2024 Osmotic Pressure: Fluid Shifts Oncotic = Osmotic pressure Arterial: Osmotic pressure is the pressure exerted In arterial capillaries, the hydrostatic against the flow of water out of the pressure is slightly greater than oncotic intravascular space pressure, favoring filtration, or movement (“holds fluids in”) of the water into the interstitium Hydrostatic pressure: Venous: Hydrostatic force can be seen as its Oncotic pressure is slightly higher favoring opposite, that is, the pressure of water fluid movement into the plasma space flow out of the intravascular space into the interstitium 52 Clinical Context 53 (2) Major Hormonal Factors Regulating Osmolality and Volume 1. ANP hormone secreted from the cardiac atria Tells your kidneys to increase renal Na+ excretion when too much ECF is present 2. ADH hormone made by the hypothalamus and stored in the posterior pituitary gland ADH = antidiuretic hormone; ANP = atrial natriuretic peptide; RAAS = Renin-Angiotensin-Aldosterone System Tells your kidneys how much water to conserve 54 18  10/19/2024 ADH (also termed arginine vasopressin) Vasopressin Receptors and Prostaglandins (ADH) Vasopressin Receptors Prostaglandins Absence or presence of ADH is the major Renin–angiotensin and sympathetic physiologic determinant of urinary free water nervous systems are of much greater excretion or retention importance There are three major receptors for ADH: ADH stimulates the production of the V1a, V1b (also called V3), and V2 receptors prostaglandins (particularly prostaglandin E2 [PGE2] and V1 receptors stimulate phospholipase C and prostacyclin [PGI2]) primarily act to increase vascular resistance (hence, the name vasopressin) They impair both the antidiuretic and vascular actions of ADH 55 Hormone Regulation: Na+ Excretion Factors involved in the regulation of sodium excretion are different from those involved in water excretion The only important area of overlap is the hypovolemic stimulus to ADH release and thirst The presence of multiple receptors for the hormonal control of sodium excretion (volume vs osmoregulation chart) illustrates an important difference between the regulation of volume and that of osmolality 56 Na+ Excretion Hormones: What is actually being regulated? Concept Check: What = Effective Circulating Volume Effective Circulating Volume: (def.) effective circulating volume is an unmeasurable parameter that refers to that part of the extracellular fluid that is in the arterial system that is effectively perfusing the tissues Maintenance of the effective circulating volume and regulation of Na+ balance (by alterations in urinary sodium excretion) are closely related functions Na+ loading will tend to produce volume expansion Na+ loss will lead to volume depletion 57 19  10/19/2024 Family Member with High Blood Pressure? Why do we advise them to consume a low Na+ diet? What hemodynamic effects can occur in the setting of ‘too much’ Na+ Extracellular fluid compartment? Water retention, high flow in arterial vessels, increase systemic blood pressure Increase morbidity and mortality 58 Heart Failure Example Action Reaction CHF = reduced effective Activation of sodium-retaining circulating volume hormones (in an attempt to (underfilled arterial limb) increase perfusion toward due to a primary decrease in normal) leads to edema cardiac output formation and increases in the plasma volume and total extracellular fluid volume 59 Disease and Volume Influence Effective Extracellular Plasma Volume Cardiac Output Circulating Fluid Volume Volume Hypovolemia due ↓ ↓ ↓ ↓ to vomiting Heart Failure ↓ ↑ ↑ ↓ Hepatic Cirrhosis ↓ ↑ ↑ ↑ 60 20  10/19/2024 Kidney Disease Assessment Summary Patients with kidney disease may have a Many patients are asymptomatic variety of clinical presentations Routine examination (ex: annual physical) found to have an elevated serum creatinine concentration or an abnormal urinalysis Symptoms can be directly referable to either: Once kidney disease is discovered: The kidney [itself]: the presence/degree of kidney (ex: gross hematuria, flank pain) dysfunction and rapidity of progression are assessed Extrarenal symptoms: underlying disorder is diagnosed (ex: edema, hypertension, signs of uremia) 61 Synopsis Understanding basic kidney physiology and functionality is key to understanding the concepts of pathophysiology or diseases of the kidney Fluid balance is maintained by a complex system of water, sodium and hormone alterations Osmolality, hydrostatic and oncotic pressures play a pivotal role in determining ‘how’ the kidneys osmo and volume regulate eGFR is the most practical way of determining renal filtration; yet it is far from perfect due to the pitfalls associated with serum creatinine inaccuracies 62 21