PPA Module 1 Renal

Renal Functions

• Metabolic waste removal, like urea, uric acid, creatine, and urobilin, is a primary function.
• Eliminates foreign chemicals and bioactive substances, including drugs.
• Regulates water and electrolyte balance, impacting blood volume.
• Regulates blood pressure.
• The kidneys aid in gluconeogenesis, particularly during fasting, using amino acids and glycerol.
• Synthesizes hormones and enzymes such as erythropoietin for the production of red blood cells, renin for blood pressure control, and calcitriol (1,25-dihydroxyvitamin D) for calcium absorption.
• Chronic kidney disease can lead to anemia due to decreased erythropoietin production.

Kidney Anatomy

• Bean-shaped, located behind the peritoneum, spanning from the 12th thoracic to the 3rd lumbar vertebra.
• Kidneys constitute less than 0.5% of total body weight; males generally have heavier kidneys.
• A fibrous capsule surrounds the kidney.
• The hilus on the concave surface serves as the entry/exit point for the renal artery/vein, nerves, lymphatic system, and ureter.
• The renal sinus contains calices, the pelvis, blood vessels, nerves, and fat.

Components of the Kidney

• Cortex: Outer layer, granular due to glomeruli; primary function is filtration; has higher pressure and oxygen levels but lower interstitium osmolarity.
• Medulla: Inner layer, darker color, containing 8-18 renal pyramids; primary function is reabsorption; has lower pressure and oxygen levels but higher interstitium osmolarity.
• Minor Calices: Urine drains into the kidney here from the renal pyramids.
• Major Calices: Receive urine from the minor calices.
• Renal Pelvis: Urine exits the kidney into the ureter at this point.
• Ureter: Passageway for urine to the bladder.

Renal Vascular System

• Receives approximately 20% of cardiac output.
• Starts with a high-resistance afferent arteriole, flowing to the glomerular capillary network for filtration, then through the efferent arteriole.
• A low-pressure capillary network surrounds the tubular system.

Nephron Structure and Function

• The basic functional unit is made up of the glomerulus and tubular system.
• Approximately one million nephrons per kidney, each operating independently.
• Glomerulus: A capillary ball for filtration.
• Bowman's Capsule: Collects filtrate from the glomerulus.
• Tubular System: Blood filtrate is converted into urine, beginning with the proximal convoluted tubule (PCT); this system includes the PCT, loop of Henle, distal convoluted tubule (DCT), and collecting tubule.

Key Processes in the Kidney

• Glomerular Filtration: Water and solutes move from the blood through a filtration barrier into Bowman's capsule.
• Tubular Secretion: Substances move from peritubular capillaries into the tubular lumen.
• Tubular Reabsorption: Substances move from the tubular lumen back into the capillaries.
• Excretion: The final amount of a substance excreted in urine is the result of filtration + secretion - reabsorption. The rates of these processes can undergo physiological changes.

Basic Renal Processes and Substance Handling

• Glomerular filtration, tubular secretion, and tubular reabsorption determine the final urine composition.
• There are three basic processes and not all substances undergo all three.
• The kidneys handle each differently based on the body's needs and the substance's characteristics.
• Substances can undergo multiple processes, like filtration, partial reabsorption, and/or secretion.
• The rate of each process can undergo physiological changes allowing the kidney to adjust handling based on the body's state.
• Amount excreted = amount filtered + amount secreted - amount reabsorbed.
• Glucose is normally almost completely reabsorbed; toxins are almost entirely secreted.

Glomerulus in Detail

• Surrounded by Bowman's capsule, including an afferent arteriole (blood in) and efferent arteriole (blood out).
• The urinary space collects the filtrate.
• The filtration barrier is made up of podocytes (PO) and the glomerular basement membrane (GBM).
• Selectively allows substances to pass based on size and charge.

Juxtaglomerular Apparatus (JGA)

• Macula Densa (MD): Where the tubular system meets the capillary system.
• Granule Cells (GC): Produce renin.
• Extraglomerular Mesangial Cells (EGM): Helps move filtration through.

Filtration Barrier

• The barrier is made up of the capillary endothelium, glomerular basement membrane (GBM), and podocytes.
• Size and charge determine filtration capability.
• Large molecules such as blood cells and large proteins are generally restricted.
• A negative charge repels negatively charged proteins.
• Glomerular damage can cause red blood cells and proteins to appear in urine.

Glomerular Filtration Determinants

• Arterioles: Small blood vessels branching from an artery to capillaries.
• Filtrate: Portion of blood that is filtered.
• Hydrostatic Pressure: Aids filtration by forcing liquid against a membrane.
• Afferent and efferent arterioles control hydrostatic pressure within glomerular capillaries.
• Sympathetic nervous system controls the vascular tone of the arterioles.
• Renin, produced by GC cells, leads to angiotensin II, a vasoconstrictor that increases resistance and facilitates filtrate formation.

Role of the Sympathetic Nervous System (SNS)

• Granular cells (GC cells) in the juxtaglomerular apparatus (JGA) are innervated by the sympathetic nervous system. These are responsible for producing renin.
• Increased sympathetic nervous activity stimulates the granular cells to produce and release renin.
• Renin initiates the renin-angiotensin-aldosterone system (RAAS).
• Renin helps to produce angiotensin II, which is a strong vasoconstrictor.
• Angiotensin II increases total peripheral resistance, increasing blood pressure, and causes vasoconstriction of the efferent arteriole, leading to increased glomerular pressure and glomerular filtration rate (GFR).

Control of Renal Blood Flow and GFR

• Must be maintained within normal limits to prevent capillary damage.
• Autoregulation helps maintain stable blood flow using the Myogenic Response and Tubuloglomerular Feedback.
• Accomplished by controlling the blood vessel resistance.

Myogenic Response

• If systemic blood pressure is high, the afferent arteriole will constrict, increasing resistance, decreasing renal blood flow, and decreasing hydraulic pressure.

Tubuloglomerular Feedback

• Macula densa senses sodium and chloride levels.
• A decrease in sodium and chloride delivery to the glomerulus will result in the macula densa producing prostaglandins, which activate the renin-angiotensin system.
• Renin is produced, which leads to the production of angiotensin II.
• Angiotensin II causes vasoconstriction of the efferent arteriole.
• Vasoconstriction at the efferent arteriole increases the hydraulic pressure in the glomerulus.
• This increases filtration, resolving the initial problem of decreased sodium and chloride delivery.
• Maintains GFR and prevents damage to the glomerulus by controlling blood flow.

Review of Three Biological Processes

• Glomerular filtration: Substances from the blood are filtered into the nephron.
• Secretion: The movement of substances from the blood into the tubular lumen.
• Reabsorption: The movement of substances from the tubular lumen back into the blood.

Filtration Process and Tubular System

• Glomerulus: Filtration occurs here.
• Bowman's capsule: Filtrate collects after filtration.
• Proximal Convoluted Tubule (PCT): 67% of the filtered load is reabsorbed here.
• Descending Loop of Henle: Part of the U-shaped tubular system.
• Thick Ascending Loop of Henle: 25% of the filtered load is reabsorbed here.
• Macula Densa: The point where the tubular system meets the capillary system for the second time. Tubuloglomerular feedback regulation occurs here.
• Distal Convoluted Tubule (DCT): 5% of the filtered load can be reabsorbed here.
• Collecting Tubule: 3% of filtered load can be reabsorbed here.
• 0.4% of filtered load remains to be excreted as urine.

Kidney Function Overview

• A dynamic organ that receives 20% of cardiac output, that filters almost everything except large components like red blood cells and proteins.
• Reabsorption is crucial to return necessary substances to the blood, and only waste products are excreted.

Reabsorption Process

• Substances move from the tubular system back into the vasculature.
• The lectures use a fish analogy to visualize this movement.

Detailed Look at Tubular and Capillary System

• The tubular system has a lumen that contains filtered substances.
• The cell layer surrounding the lumen has the Apical membrane (side facing the lumen), and Basolateral membrane (side away from the lumen).
• Reabsorption requires substances to cross the LAB (Lumen, Apical membrane, Basolateral membrane) to get from the tubular lumen to the blood vessels.

Sodium Reabsorption

• Sodium moves from the lumen across the apical membrane, into the tubular cell.
• Sodium-potassium ATPase pump: Located on the basolateral membrane, pumps three sodium ions out of the cell and two potassium ions into the cell, needing energy (ATP), and is crucial for sodium reabsorption back into the vasculature.
• Creates a negative intracellular environment with more positive sodium ions pumped out of the cell than potassium ions into it; this environment attracts positively charged sodium from the tubule lumen into the cell, enhancing reabsorption.

Proximal Convoluted Tubule (PCT) Details

• The first segment after Bowman's capsule.
• Most absorption of fluid and solutes occurs here (67% of filtered load), like sodium, chloride, bicarbonate, water, calcium, monohydrogen phosphate, sulfate, glucose, and amino acids.
• In a normal individual, glucose is completely reabsorbed and therefore, should not be present in the urine.
• Involved in sodium reabsorption, glucose reabsorption, acid-base balance, and regulation of calcium and phosphate.
• The Peritubular Capillary secretes hydrogen ions into the tubular lumen.
• The PCT excretes endogenous and exogenous solutes, including drugs.

PCT Reabsorption Mechanisms

• Glucose and sodium are reabsorbed into the vascular system.
• In exchange for sodium, hydrogen is secreted into the tubular system.
• Water follows sodium due to osmotic pressure.
• Molecular level: Sodium-potassium ATPase is on the basolateral membrane and a sodium-glucose co-transporter on the apical membrane brings both sodium and glucose into the cell.
• A sodium-hydrogen exchanger on the apical membrane reabsorbs sodium and secretes hydrogen.
• Aquaporins (water channels) allow water to follow sodium into the cell.

Loop of Henle Details

• The U-shaped segment following the PCT that contains a descending Loop of Henle (permeable to water but not ions) and a thick ascending Loop of Henle (permeable to ions but not water).
• The main function is to create a hyperosmotic interstitium in the medulla.
• Permeability differences are due to the presence/absence of aquaporins (water channels).
• About 25% of filtered sodium is reabsorbed in the ascending limb where active transport of sodium out of the ascending limb makes the interstitium fluid in the medulla very concentrated.

Thick Ascending Loop of Henle:

• Sodium-potassium ATPase on the basolateral membrane.
• Sodium-potassium-chloride co-transporter on the apical membrane moves all three ions into the cell where chloride is a limiting factor for this transporter's activity.
• Sodium is pumped into the vasculature via the sodium-potassium ATPase.
• Loop diuretics work here by blocking the reabsorption of chloride (and thereby blocking sodium and water reabsorption), decreasing blood pressure.
• A potassium ion channel on the apical membrane recycles potassium back into the lumen as chloride is moved back into the vasculature through a chloride channel on the basolateral membrane.
• Other positive ions like calcium and magnesium are also reabsorbed through tight junctions.

Countercurrent System

• Opposing flow of blood and filtrate.
• Sodium is reabsorbed in the thick ascending loop of Henle into the interstitium.
• Water moves from the descending loop of Henle to the interstitium.
• Sodium concentration is higher towards the bottom of the U-shape creating a concentration gradient.

Distal Convoluted Tubule (DCT)

• After the loop of Henle and begins at the macula densa and ends at the connecting tubule.
• A major site for the active regulation of urinary calcium excretion.
• A site for fine control of salt and water excretion.
• Reabsorbs 5-8% of the filtered sodium and chloride through the sodium-chloride co-transporter.
• Thiazide diuretics work here by inhibiting the sodium-chloride co-transporter.
• Combining both loop diuretics and thiazide diuretics can enhance sodium and water excretion.

Autoregulation: Tubuloglomerular Feedback

• Occurs at the macula densa area.
• Decreased GFR leads to decreased sodium and chloride delivery to the macula densa.
• The macula densa responds by producing prostaglandin and renin.
• Renin leads to the production of angiotensin II, which causes vasoconstriction of the efferent arteriole.
• This increases hydraulic pressure in the glomerulus and increases GFR.
• The goal of this feedback system is to maintain GFR.

Detailed Look at the DCT

• Sodium-potassium ATPase on the basolateral membrane and a sodium-chloride co-transporter on the apical membrane which is inhabited by thiazide diuretics exists here.
• Calcium reabsorption is regulated.
• Influenced by parathyroid hormone and vitamin D.
• The process requires a Vitamin D dependent calcium-binding protein on the apical membrane to bring calcium into the cell.
• Facilitate calcium reabsorption into the vasculature utilizing both calcium channels and calcium-sodium exchangers on the basolateral membrane.

Collecting Tubule

• Last tubular system, collecting filtrate from various nephron segments, including the initial collecting tubule, cortical ducts, and medullary ducts.
• Intercalated cells secrete hydrogen and bicarbonate and reabsorb potassium.
• Reabsorbs the final 3-4% of the filtrate.
• Relatively impermeable to water unless water channels are inserted in the presence of arginine vasopressin (AVP).
• Sodium channels are inserted by aldosterone.
• Aldosterone increases sodium reabsorption by inserting sodium channels on the apical membrane and Atrial Natriuretic Peptide (ANP) inhibits sodium reabsorption (opposite of aldosterone).
• Arginine vasopressin (AVP) increases water reabsorption by inserting aquaporin (water) channels on the apical membrane.

Water Reabsorption in the Collecting Tubule

• The countercurrent system creates a sodium concentration gradient, which is highest in the medulla, where the collecting tubule sits.
• In the presence of AVP, water channels are inserted in the collecting tubule, allowing water to move to the interstitium by reabsorbing water when needed and leads to concentrated urine.
• This process is activated during dehydration or decreased blood pressure.

Glomerular Filtration Rate (GFR)

• The rate at which fluid is filtered through the glomeruli into Bowman's capsule.
• Measured in milliliters per minute (mL/min).
• Used to assess kidney disease, measured by summing of filtration rates of all functioning nephrons.
• Decrease in GFR means kidney disease is progressing and an increase means the kidney is improving.

Clearance

• Evaluates the kidney's ability to handle solutes in water.
• Estimates the net amount reabsorbed or secreted by the renal tubules.
• Provides information about filtration, reabsorption, and secretion.
• Used to estimate GFR.
• All solutes excreted in urine come from the blood perfusing the kidney.
• The amount entering the kidney via the artery equals the amount exiting via the vein and ureter.
• A substance that is completely cleared is ideal for estimating GFR.

Inulin Clearance

• Not produced or metabolized by the body, or reabsorbed by the kidneys.
• Inulin must be given intravenously (IV).
• To perform; urine output and inulin concentration in urine and blood are measured to estimate clearance.
• Is freely filtered at the glomerulus.
• Not reabsorbed, secreted, synthesized, or metabolized by the kidney making it, theoretically, a good candidate for GFR measurement.

Creatinine Clearance

• A product of muscle metabolism that is present in everyone who is freely filtered at the glomerulus.
• Has a relatively stable plasma concentration.
• Not reabsorbed, synthesized, or metabolized by the kidney but secreted into the urine in the proximal tubule.
• Exceeds creatinine filtration by 10-20%, overestimating GFR.
• Normal GFR ranges approximately 120 +/- 25 mL/min for males and 95 +/- 20 mL/min for females.
• Affected by muscle mass.

GFR and Creatinine Relationship

• There is an inverse relationship between GFR and plasma creatinine concentration.
• Healthy kidney filters creatinine efficiently = low plasma concentration, and a poorly functioning kidney leads to higher plasma creatinine.
• The range of creatinine concentration from 1.0 to 1.5 corresponds to the normal GFR range of 80-120 and is the most sensitive region of the curve with normal adult serum creatinine concentration ranging from 0.8 to 1.3.
• Levels increase with muscle mass and meat intake where switching to a meat-free diet can lower plasma creatinine by 15%.
• Muscle mass and creatinine excretion decrease with age

Osmotic Pressure

• Normal serum osmolality, around 280 to 290 milliosmols per kilogram (mOsm/kg), fluctuates in urine according to hydration.
• Antidiuretic hormone (ADH or AVP) increases water reabsorption in the collecting duct, concentrating urine.
• The pressure generated by solutes that attract water, proportional to the number of particles, is measured in osmols or milliosmols with glucose generating one milliosmol and sodium chloride generating two due to dissociation.
• Substances that can’t freely cross create osmotic pressure.
• Effective osmoles are those that cannot cross the membrane.

Physiological Role of Osmotic Pressure

• Determines water distribution in the body with water comprising 55-60% of lean body weight in men and 45-50% in women, and, total body water at about 60% of body weight. For example, a 70 kg person has 42 L of water.
• Two-thirds of total body water is intracellular fluid and one-third is extracellular fluid where of the extracellular fluid, one quarter is in the intravascular volume and three quarters is in the interstitium.
• Osmolality is the same among all three compartments (intracellular, interstitial, and intravascular).
• Electrolyte concentrations are similar between the blood and interstitium because the capillary endothelium is leaky where Proteins in the blood cause oncotic pressure.

Summary of Electrolytes Within the Body

• Potassium - Generating osmotic pressure inside the cell.
• Sodium - Generating osmotic pressure outside the cell.
• Plasma proteins (especially albumin) - The main determinants of Plasma oncotic pressure but do not contribute much to plasma osmolality.
• It is important to consider the properties of a molecule and the barrier around it when determining its role in osmotic or oncotic pressure.

Osmoregulation and Volume Regulation

• Adding sodium chloride to the extracellular fluid increases plasma sodium and attracts water to the extracellular space which increases sodium excretion.
• Adding water to the system dilutes plasma sodium which leads to increased intracellular and extracellular fluid as well as increased sodium excretion.
• Adding an isotonic solution increases extracellular fluid without changes in osmolality or plasma sodium, but does increase urine sodium excretion.

Hormonal Role in Water and Sodium Balance

• Plasma sodium concentration and extracellular fluid volume are independently regulated.

Osmoregulation

• Concentration regulation sensed by osmoreceptors in the hypothalamus that regulates arginine vasopressin (AVP)/anti-diuretic hormone (ADH) release and thirst.
• Regulating osmolality is controlled by water, not directly by sodium, where AVP reduces water excretion by acting on the collecting tubule.

Volume Regulation

• Has multiple receptors and effectors, that include:
  • Cardiopulmonary baroreceptors.
  • Arterial baroreceptors.
  • Intrarenal baroreceptors in the afferent arteriole [JGA cells (or GC cells)] that can stimulate renin production.
  • Macula densa, which plays a role in the tubuloglomerular feedback and renin productions.
• Volume regulation is also regulating blood pressure.

Regulations

• Osmoregulation: Plasma osmolality sensed by hypothalamus osmoreceptors and regulates AVP secretion and thirst to control volume.
• Volume regulation: Baroreceptors detect tissue perfusion and pressure and Factors include renin-angiotensin-aldosterone system, ANP, norepinephrine, and AVP all to regulate volume.
• AVP plays a role in both osmoregulation and volume regulation.

Osmoreceptors and AVP Release/Thirst

• Osmoreceptors in the OVLT region of hypothalamus sense the osmotic gradient between plasma and receptors, triggering AVP and relying heavily on regulators such as plasma sodium concentration.
• Example: Eating too much salt increases plasma osmolality which shrinks osmoreceptors, stimulating neurons in the PVN and SON regions, leading to AVP release.
• AVP acts on the kidney via V2 receptors (increasing aquaporin channels for water reabsorption) and on blood vessels via V1 receptors (causing vasoconstriction).

Defects of Avp

• Nephrogenic diabetes insipidus is characterized by polyuria caused by issues with V2 receptors or aquaporin channels.
• Lithium therapy or hypocalcemia can also cause this condition.
• AVP stimulates renal prostaglandin production in a negative feedback loop where NSAIDs suppressing prostaglandin facilitates AVP.

Volume Depletion

• Small volume changes have little effect on AVP, it takes a severe loss for AVP response.
• AVP is more sensitive to osmolality changes than to small volume changes.
• Volume-regulated AVP secretion is much more intense with large volume loss.
• Volume depletion (over 10%) significantly increases AVP.
• Severe hypotension markedly increases AVP, and thirst is stimulated via angiotensin II activation.

Thirst

• Elevated plasma sodium concentration triggers thirst and AVP reduces water excretion.

Central Diabetes Insipidus

• A problem in AVP production leading to patients experiencing strong thirst and drinking a lot of water.

Renin-Angiotensin-Aldosterone System (RAAS)

• Activated in response to loss of extracellular fluid and decreased blood pressure, which plays a large role in in blood pressure regulation, urinary sodium excretion, and Renal hemodynamics.
• When hypovolemia/low blood pressure occurs renin is produced, which induces angiotensin II.
• Angiotensin II causing vasoconstriction (increases blood pressure) by stimulating aldosterone production from the adrenal gland which induces sodium reabsorption in the collecting tubule which assists Water reabsorption.

Sodium Retention

• Angiotensin II induces aldosterone release, leading to water reabsorption that directly stimulates sodium reabsorption in the proximal convoluted tubule, aiding in increased vascular volume and blood pressure.

Control of Renin Secretion

• Main determinant: Salt intake
• High salt intake expands extracellular volume, suppressing renin release.
• Volume depletion causes renin secretion.
• Requires normal sodium intake and excretion which are roughly balanced at 80-250 mEq/day and utilizes afferent arteriole baroreceptors (JGA or GC cells) regulated by prostaglandins, cardiopulmonary baroreceptors activating the sympathetic nervous system, macula densa cells in the distal tubule through tubuloglomerular feedback.

Aldosterone

• Synthesized in the adrenal gland (zona glomerulosa) that activates mineralocorticoid receptors in the tubular cell to induce sodium reabsorption while AVP induces water reabsorption
• Sodium channels are increased on the apical membrane via synthesis while on the basolateral membrane sodium goes back to the blood via sodium-potassium ATPases.

Control of Aldosterone Secretion

• Volume depletion induces angiotensin II release, stimulating aldosterone secretion.
• Plasma potassium concentration directly stimulates aldosterone secretion.

Atrial Natriuretic Peptide (ANP)

• Released from stretched myocardial cells, in contrast to the steroid released Aldosterone, which acts on intercellular membrane receptor, and exerts direct vasodilator effect, increasing urinary sodium/water excretion.
• This is done by closing sodium channels on the apical membrane of the tubular cells within the CD and suppressing renin/aldosterone release.

Control of ANP Secretion

• Released from atria in response to volume expansion and wall stretching while opposing the effects of other hormones to increase volume.
• Has opposite effect to renin.

Hyponatremia

• A decreased sodium concentration that may cause hyperhydration.

Acute vs. Chronic Hyponatremia

• Acute hyponatremia rapidly develops and are Dangerous and can be fatal.
• Chronic hyponatremia develops over a longer period of time and is less lethal due to the brain's adaption.

Considerations

• Treatment depends on if acute vs chronic.
• Rapid correction causes Osmotic demyelination with must be done carefully.

Etiology

Occurs when sodium concentration falls below 135 mEq/L from causes such as: - Water retention - Sodium loss

• High levels of Arginine Vasopressin (AVP) and ADH bring more water back into circulation causing hyponatremia.
• SIADH is the inappropriate AVP/ADH release also promotes hyponatremia.

Diagnosis

• Patient history, physical examination and lab tests all must be considered.
• Lab tests includes:
  • Plasma concentration
  • Evaluation of adrenal and thyroid
  • Plasma osmolality, urine osmolality, and urine sodium concentration

Plasma Osmolality in Hyponatremia

• True hyponatremia will have a proportional reduction in plasma osmolality except under conditions such as hyperglycemia where higher osmolality may be displayed.

Urine Osmolality in Hyponatremia

• Urine osmolality below 100 mOsm/kg indicates excessive drinking.

Urine Sodium Concentration in Hyponatremia

• In effective circulating volume depletion, the body tries to conserve sodium in urine (less than 25 mEq/L).
• Normovolemic'ly through the urine sodium concentration is usually above 40 mEq/L and volume is normal.

Hypernatremia

• Associated with hyperosmolality.
• Occurs as result from:
  • Water loss - Insensible and sweat losses
  • Urinary losses - Central/nephrogenic diabetes insipidus & Osmotic diuresis
  • GI losses.
  • Actual salt intake - Hypertonic saline
  • Impaired thirst

Etiology of Hypernatremia

• AVP and Thirst help defend against hypernatremia
• Patients Who cannot drink are more prone to hypernatremia.

Diabetes Mellitus and Hypernatremia

• Hypernatremia in Uncontrolled diabetes is caused by Osmotic diuresis and treated with insulin.

Diagnosis of Hypernatremia involves

• Identifying the cause, such as diabetes and water balance through measurement of lab results from urine and electrolytes, and measuring urine osmolality can help.

Central vs. Nephrogenic Diabetes Insipidus

• Central diabetes = brain no AVP.
• Nephrogenic diabetes = kidney no respond AVP.
• Treatment for differentiation = give synthesized AVP (DDAVP):
  • Urine osmolality increases indicating a central and AVP release problem
  • Urine osmolality remains low indicating AVP problems.

Polyuria

Defined as excessive urine production from

• Osmotic diuresis & water diuresis as caused by a result from: - decreased avp production & Reduced renal response to avp. - Other like, chronic lithium use & hypercalcemia

Diagnosis of Polyuria

Involves Water restriction & Measuring plasma/urine osmolality Delivery of synthesized AVP (DDAVP) can differentiate between central and nephrogenic diabetes insipidus: - DDAVP decreases urine volume indicating central where AVP was not produced. - If the kidney is receiving AVP but failing to function, DDAVP will not fix the problem.

Physiological Roles of Potassium

• Crucial for Intracellular Potassium Concentration Roles(Cell Vol / pH / Enzyme & Synthesize) and Transmembrane Potassium Ratio Roles (muscle & cardiac activity and cell membrane potential)

Parameters of Potassium

• Plasma Potassium = Tightly maintained at 3.5 to 5 millimoles and regulated through use of the widely distributed Sodium-Potassium ATPase Pump.

Potassium Intake and Regulation

• The kidney regulates potassium balance by excretion where Dietary potassium matches excretion to maintain balance which is influenced by Insulin & Epinephrine stimulating potassium uptake into cells for Urinary potassium.

Regulation of Cellular Uptake and Urinary Excretion of Potassium

• Hormones (Insulin, Epinephrine, & Aldosterone) increase the risk of developing hypokalemia.

Kidney Regulation of Potassium

• The kidneys must excrete between 80-120 millimoles to maintain potassium balances but has the adaption to reabsorb with Potassium is filtered from the kidney through the Glomerulus.

Mechanisms of Potassium Reabsorption

• Kidney segments function differently.
  • PT = Passive diffustion & Solvetn drag
  • Thick Ascending Loop of Henle = Na/K/Cl pump & Channels
  • Cortical Collectiong Tubule = 2.5% via H and K-ATPase
  • Medullar Collectiong Tubule= passive with channel. Concentation increase.

Potassium Secretion and Excretion

• Excess potassium must be removed.
• It is excreted through low luminal chloride & the negative charge draws K.
• If Aldosterone is high = K output. If Aldosterone is low = K retention.
• Kidney segments function differently
  • Secretion increase in urine if
    • high flow
    • low Cl
    • Lumen has negative charge Aldosertone increases sodium uptake (makes Lumen more negative) via 3 methods
    • increase sodium pump
    • inrease surface channels
    • increases K channels

Potassium and Acid-Base Balance

• Acid base disturbances are associated with potassium which has an exchange that can shift the concentration within body.
• Hydrogen and potassium exchanger shifts the concentration by either absorbing and secreting ions depending on the environment.

Metabolic Alkalosis

• Characterized by a primary elevation in plasma bicarbonate concentration and increased extracellular pH through losses of either gastro or kidney function Hypokalemia due to hyperaldosteronism facilitates Bicarb absorbtion since hydrogen needs to be excretred. H and K exchanges shift based on charge needs

Metabolic Acidosis

• Characterized by a reduction in plasma bicarbonate concentration through lactic / ketoacidosis + Ingestion of acids (aspirin, ethylene glycol, methanol) or kidney malfunction.
• Renal failure reduces the ability to excrete acid, decreasing excretion and excess waste is buffered (which is then expelled).
• NaHCO3 helps remove waste, but does not improve ammonia excretion rate as it tends to degrade with Renal failure.

Acute Renal Failure/Acute Kidney Injury (AKI)

• Sudden and often reversible reduction in kidney function that's measured by GFR.
• Untreated acute failure progresses to chronic failure. If untreated, acute renal failure can progress to chronic renal failure, which is irreversible.
• KDIGO 2012 Clinical Practice Guideline defines AKI by:
• Increase in serum creatinine
• Increase in serum creatinine over 50%
• Urine volume less than 0.5 mL

Types of Acute Kidney Injury

• Postrenal AKI: Obstruction of urine flow. Caused by blood clots, kidney stones, tumors, and the most common is bladder neck
• Prerenal AKI: Reduction of Blood flow. This occurs before blood reaches the kidney with decreased fluid and hydrostatic pressure.
• Intrinsic/Intrarenal AKI: Damage to kidney Structures. Intrinsic/Intrarenal AKI Is caused by direct damage.
• ATN: Acute tubular necrosis

Prerenal Disease vs. Acute Tubular Necrosis (ATN)

• Occurs with severe volume depletion.
• Can be difficult to differentiate based on similarities in symptoms based on severity, but IV fluids help where
  • (Prerenal) IV fluids improve GFR
  • (ATN) IV fluids don't fix problems caused by other issues but is still important

Renal Artery Stenosis and Hypertension

• Narrowing of the renal artery that goes into the kidneys causing Hypertensions with compensatory functions such as increasing blood pressure and pressure

Acute Tubular Necrosis (ATN)

• ATN Is the most common issue in Prerenal AKI caused by (ischemia, infection, & toxins) and produces two histological changes tubular necrosis or occlusion where damage leads to GFR to go close to zero.

Chronic Renal Failure/Chronic Kidney Injury (CKD)

• CKD Can lead to Renal failure and it is irreversible through common causes such as Hypertensive, Polycistic and chronic diabetes.
• Causes renal disease.

Stages of CKD based on GFR

• Stage 1: GFR over 90 mL/min.
• Stage 2: GFR 60-89 mL/min.
• Stage 3: GFR 30-59 mL/min.
• Stage 4: GFR 15-29 mL/min.
• Stage 5: GFR less than 15 mL/min.

Disturbed Homeostasis Caused by CKD

• causes Hyperkalemia & hypernatremia + Edma (K,Na,Water) and coagulation issues
• causes Bone damange and osteoprosis (Ca,PO4) and kidney vitamin absorption damage
• causes kidney hormone (RBC & hormones release problems)
• Causes acid-base disturbance

Mechanisms of CKD

• Progressive Mechanisms such as Hyperfiltration and hypertrophy of the remaining Nephrons increase pressure on the Glomerulus, causing further damage.

Renal Regulation of Calcium

1. Low Ca =High PTH
2. High PTH =High Vitamin D
3. High Vitamin D and Calcium creates

• kidney reabsorbtion of Ca
• phosphate dump in the piss
• increase Gl absorbtion of Ca phosphate

In CRF these are inhibited. In CRF the excess production of PTH can damage the kidney. Therefore the treatment is adding vitamin D, which lowers calcium absorption, and use of Ca-binders.

Renal Function

• Pharmacists care since many requires dose adjustments when patients kidneys goes bad.

Measurements of Renal Function is evaluated through:

 Blood Test and Urine Sample

Measured Blood Tests

• Serum Creatinine: (Main Test)
• Blood Urea Nitrogen
• Serum Electrolytes Measured Urine Test :
• Urine Output: Rate in time period
• Urinalysis: Physical and Checmial comp
• Albumin to Creatinine Ratio: Albumin and Creatinine concentrations in the urine are measured to produce ratio.

Terminology of Measurements Renal Fucntion

• Estimated Glomerular Filtration Rate (eGFR)
• Glomerulus is primary functional component of the kidney, defines volume of fluid filtered per minute. Useful on chronic issues.
• Serum Creatinine (SCr):
• Used to estimate renal function, but has limits. Changes in serum creatinine levels lag behind changes in renal function.
• Creatinine Clearance (CrCl)
• Estimated GFR that uses C-G formula to evaluate. Used to asses drug adjustments.

Formulaic Equations of Renal Function

• Modified Diet in Renal Disease (MDRD) equation
• Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation
• Requires serum creatinine, age, sex, and race but can be to use clinical diagnosis .

Cockcroft-Gault Formula Uses

• Cockcroft-Gault Formula that has limitations but can be used for drug dosing
• This forumla uses ideal as well as adjusted body weight based on clinical indications. Using other can lead to major impacts in renal diagnosis

Limitation Examples: Amputees and Elderly

• A limitation is with elderly and amputee where this results from Loss of muscle mass leads to lower serum creatinine as well as amputated mass which can also lead to kidney issues

Other Renal Function Measurements

• (BUN)Blood Urea Nitrogen and (electrolyte concentration) are used too
• Electrolytes: Potassium are cleared by the kidney as well and need maintenence and Urine Output: which can be a signs a kidney is at Risk
• Need output 24/7 to measure. Normal is .5 mL/Kg per hour.

Urinalysis

• Midstream must be clean and look at physical, chemical, and Microscopic test. Tests for UTI and protien leaks.

Albumin-to-Creatinine Ratio

• Used to evaluate glomerular perm vs diabetes and blood preasure.

Understanding renal function vs using equation

• eGFR is good for the overviw of the function of the whole organ.
• Drug dose relies from renal functions so you must evaluate how patient will respond and caluclate.
• If your using a calculator follow all rules to limit mistakes.
• Urinalysis shows whats happening inside

Explore the vital functions of the kidneys, including metabolic waste removal and blood pressure regulation. Learn about kidney anatomy, its location, and the significance of hormones and enzymes synthesized. Understand how chronic kidney disease impacts erythropoietin production.