Kidney Physiology Notes

Introduction

• Kidney physiology, presented by Dr. Sarah Bailey (s.g.bailey@surrey.ac.uk). The module code is 27AY04 along with a Onetime Passcode. This module delves into the intricate functions of the kidneys, crucial for maintaining overall health and homeostasis.

• Student feedback and consultation available during specific weeks; Week 2 (Friday, 14th February, 13:30-14:30) and Week 3 (Thursday, 20nd February, 12:00-13:00). These sessions provide opportunities for students to clarify doubts and deepen their understanding of the subject matter.

• Appointments can be booked via a provided link. This ensures students have dedicated time to discuss specific issues with the instructor.

Learning Outcomes

• Describe the kidney's functional role in:-

  • Blood composition: Kidneys regulate the levels of various components in the blood, including electrolytes, glucose, and proteins, ensuring optimal physiological conditions.

  • Blood pressure maintenance: Through the renin-angiotensin-aldosterone system (RAAS) and other mechanisms, kidneys play a vital role in long-term blood pressure regulation.

  • Hormone production: Kidneys produce hormones like erythropoietin (EPO) and calcitriol that are essential for red blood cell production and calcium regulation, respectively.

• Identify clinically relevant readouts regarding kidney function. These include Glomerular Filtration Rate (GFR), urine protein levels, and serum creatinine, which provide insights into kidney health.

• Explain the relevance of these readouts and how they are measured. Understanding how GFR, urine protein, and serum creatinine are measured and interpreted is crucial for diagnosing and managing kidney diseases.

Structure of the Kidney

• Key parts:-

  • Hilum: entry/exit point for blood vessels, veins, and the ureter. The hilum is the gateway for essential structures that support kidney function.

  • Cortex: the outer pale layer containing nephrons. The cortex is where the initial filtration of blood occurs.

  • Medulla: the pinkish central area containing nephrons. The medulla is responsible for concentrating urine.

• Nephrons are complex tubular structures that refine filtrate and enable excretion based on blood component needs. These structures are the functional units of the kidney and play a key role in maintaining blood homeostasis.

The Nephron

• The nephron is the functional unit of the kidney, responsible for blood processing and refining the filtrate.

• Change in the types of cells along the length of the nephron to enable it to perform its function. Different segments of the nephron have specialized cells adapted for specific tasks such as reabsorption and secretion.

• Three main areas:-

  • Renal Corpuscle: Site of filtration, consisting of the glomerulus and Bowman's capsule.

  • Renal Tubule: A long, convoluted tubule responsible for reabsorbing essential substances and secreting waste products.

  • Collecting Duct: Collects urine from multiple nephrons and transports it to the renal pelvis.

• Two kinds: juxtamedullary (long loops of Henle, important for concentrating urine) and cortical (short loops of Henle). The distribution and structure of these nephrons dictate their specific roles in urine formation.

Refining the Filtrate

• Isosmotic fluid leaving the proximal tubule becomes progressively more concentrated in the descending limb due to water reabsorption.

• Removal of solute in the thick ascending limb creates hyposmotic fluid, diluting the filtrate.

• Permeability to water and solutes in the distal tubule and collecting duct is regulated by hormones like ADH and aldosterone, allowing for precise control of urine concentration.

• Final urine osmolarity depends on reabsorption in the collecting duct, which is influenced by hormonal signals.

• Variable reabsorption of water and solutes occurs in the distal tubule based on the body's needs.

• The cortex is isosmotic to plasma (300 mOsM).

• The renal medulla becomes progressively more concentrated, creating an osmotic gradient for water reabsorption.

• Urine excreted ranges from 50-1200 mOsM, depending on hydration status and hormonal influences.

Glomerular Filtration

• Occurs at the Renal Corpuscle, where plasma moves from glomerulus blood vessels into Bowman's Capsule lumen.

• 20% of plasma moves into Bowman's Capsule, most of which is reabsorbed later. This filtration fraction is vital for waste removal.

• 80% proceeds to peritubular capillaries (or vasa recta) so secretion of necessary solutes into the nephron lumen occurs, ready for excretion; over 99% of fluid reabsorbed to maintain fluid balance.

• Plasma volume entering afferent arteriole = 100%.

• Less than 1% of volume is excreted to the external environment, demonstrating the efficiency of kidney function.

• Greater than 99% of plasma entering the kidney returns to systemic circulation, ensuring minimal fluid loss.

• The rate of filtration is called Glomerular Filtration Rate (GFR), which is a key indicator of kidney function.

Factors Affecting Filtration Rate

• Glomerular Filtration Rate (GFR) is the volume of plasma from which a given substance is removed by glomerular filtration, typically measured in mL/min.

• 20% plasma moves into Bowman's space, dependent upon:-

  • Hydrostatic pressure: Pressure exerted by the blood in the glomerulus, promoting filtration.

  • Colloid osmotic pressure: Pressure exerted by proteins in the plasma, opposing filtration.

  • Hydrostatic fluid pressure: Pressure exerted by the fluid in Bowman's capsule, also opposing filtration.

Control of Glomerular Filtration Rate

• GFR is generally constant to maintain stable blood composition and volume.

• Controlled by:-

  • Net filtration pressure: The balance between hydrostatic and osmotic pressures that drives filtration.

  • Changes in renal blood flow and blood pressure:影響腎臟的血流和血壓變化。

  • Filtration Coefficient: Permeability and surface area of the filtration barrier.

  • Changes in diameter of the afferent and efferent arterioles to alter the GFR. Constricting or dilating these arterioles affects blood flow in the glomerulus.

Mechanisms of GFR Control

• Hormonal:-

  • Angiotensin II: Constricts efferent arterioles, increasing GFR and sodium reabsorption.

  • Prostaglandins: Dilate afferent arterioles, increasing GFR.

• Nervous:-

  • Sympathetic nerves release noradrenaline -> arteriole constriction, reducing GFR during stress.

• Autoregulation:-

  • Myogenic response: Response to pressure changes in the afferent arteriole to maintain constant GFR.

  • Tubuloglomerular feedback: Macula densa release of hormones due to physical changes in afferent and efferent arterioles and ascending limb of loop of Henle.

Tubuloglomerular Feedback

1. GFR increases.

2. Flow through tubule increases.

3. Flow past macula densa increases.

4. Paracrine from macula densa to afferent arteriole.

5. Afferent arteriole constricts.

6. Resistance in afferent arteriole increases.

7. Hydrostatic pressure in glomerulus decreases.

8. GFR decreases (back to normal).

Clinical Use of GFR

• Evaluation of kidney function = assessment of filtering capabilities.

• Glomerular filtration rate (GFR) estimates the efficiency with which substances are cleared from the blood by glomerular filtration.

• Measure of nephron function and an indicator of kidney disease severity.

• Glomerular filtration rate does not allow us to diagnose kidney disorders but can point to its severity. Other additional tests are needed.

GFR Estimation: Methods

• Can be performed using an exogenous or endogenous substance (S).

• Clearance of substance S can be measured if it: is present at stable concentration in plasma, is physiologically inert, is freely filtered at the glomerulus, and is not secreted, reabsorbed, synthesized, or metabolized in the kidney. This ensures that any change in the substance's concentration is due solely to filtration.

• Therefore, Filtered S = Excreted S in the urine.

• $GFR[S]{plasma} = [S]{urine}urinary flow rate (V_{excreted}/unit time)$

• GFR varies with body size (10-200 ml/min) depending on Body Surface Area and age.

GFR Estimation: Exogenous Substances

• Most accurate measurements of GFR, providing a gold standard for kidney function assessment.

• Can be radioisotopes ($^{51}Cr$-EDTA) or non-radioisotopes (inulin). These substances are easily detectable and quantifiable in both plasma and urine.

• Inulin: A plant product that is filtered but not reabsorbed or secreted, making it an ideal marker for GFR measurement.

Creatinine Metabolism

• Creatinine is the breakdown product of creatine phosphate, a high-energy compound found in muscle.

• Its production is relatively constant depending on the amount of muscle mass, making it a reliable endogenous marker for GFR estimation.

• Passes through the glomerulus into the filtrate during glomerular filtration.

• A small amount is also excreted in the proximal convoluted tubule, which must be considered in GFR calculations.

• Virtually not creatinine is reabsorbed, further enhancing its utility as a GFR marker.

• CRTR = specific creatine transporter (also known as CT1), which plays a role in creatinine handling in the kidneys.

GFR Estimation: Endogenous Substances (Creatinine)

• Urinary clearance involves measuring the amount of creatinine excreted in the urine over a specific period.

• Timed urine collection throughout 24-h allows for accurate measurement of creatinine excretion.

• Large intra-individual day-to-day coefficient of variation for repeated measures of creatinine clearance due to variations in diet, exercise, and hydration.

• Creatinine is affected by a number of parameters:-

  • 7-10% of creatinine in urine comes from tubular secretion (increases in renal insufficiency), complicating GFR measurements.

  • Age: Creatinine production decreases with age due to reduced muscle mass.

  • Exercise: Intense exercise can temporarily increase creatinine levels.

  • Diet: High protein intake can increase creatinine production.

  • Supplements: Creatine supplements can significantly elevate serum creatinine levels.

  • Creatine (meat) converted to creatinine, affecting serum levels.

  • Muscle mass: Individuals with higher muscle mass tend to have higher creatinine levels.

  • Drugs (e.g., Trimethoprim, cimetidine): These drugs can interfere with creatinine secretion, leading to falsely elevated serum creatinine levels.

Basic Functions of the Kidney

1. Control of blood composition (fluid and electrolyte balance):-

   • Regulation of osmolarity: Maintaining proper concentration of solutes in the blood.

   • Maintenance of ion balance: Regulating levels of sodium, potassium, calcium, and other ions.

   • Homeostatic regulation of pH: Maintaining acid-base balance.

2. Control of blood volume, influencing cardiac output and blood pressure.

3. Control of blood pressure through the renin-angiotensin-aldosterone system (RAAS) and other mechanisms.

4. Production of hormones: erythropoietin and calcitriol, essential for red blood cell production and calcium regulation.

5. Excretion of waste: urea, urate, creatinine in urine, removing toxic byproducts of metabolism.

Changes in Blood Composition

• Osmolarity and volume can change independently, requiring precise regulatory mechanisms.

• Dehydration decreases blood volume/pressure and increases osmolarity, triggering compensatory responses.

• Compensation involves cardiovascular responses, Angiotensin II (ANG II), vasopressin, and thirst to restore fluid balance.

• pH changes:-

  • $H^{+}$ concentration is closely regulated because even small changes can have significant physiological effects.

  • Changes can alter the three-dimensional structure of proteins, affecting their function.

  • Abnormal pH affects the nervous system, leading to neurological symptoms.

  • Acidosis: neurons become less excitable; CNS depression.

  • Alkalosis: hyperexcitable, leading to seizures and other neurological issues.

  • pH disturbances (often associated with $K^{+}$ disturbances) due to shared regulatory mechanisms.

Controlling Fluid and Electrolyte Balance

• Achieved by the countercurrent exchanger mechanism in the loop of Henle, which creates an osmotic gradient in the renal medulla.

• Permeability to water of the collecting duct is controlled by antidiuretic hormone (ADH), also known as vasopressin, which increases water reabsorption.

• Permeability of the descending limb of the loop of Henle is not directly controlled by aldosterone; this statement might be incorrect.

• Filtrate entering the descending limb becomes progressively more concentrated as it loses water to the hyperosmotic medulla.

• Blood in the vasa recta removes water leaving the loop of Henle, maintaining the osmotic gradient.

• The ascending limb pumps out $Na^{+}, K^{+},$ and $Cl^{-}$, and filtrate becomes hyposmotic, diluting the urine.

Products That Change the Acid-Base Balance

• Acid:-

  • Organic acids (from diet and metabolic intermediates), such as lactic acid and ketoacids.

  • Under extraordinary conditions, metabolic organic acid production can increase significantly.

  • Ketoacids (Diabetes) due to increased fat metabolism.

  • Production of $CO_2$ ($→ H^+$ production), as carbon dioxide combines with water to form carbonic acid.

• Base (Few dietary or metabolic sources of bases), making acid-base balance primarily dependent on acid excretion.

How Acid-Base Balance Is Achieved

• NHE secretes $H^{+}$ into the tubular lumen.

• $H^{+}$ in filtrate combines with filtered HCO3 ^{-}$ to form CO2$and water.$CO_2$diffuses into cell.$CO2$combines with water to form$H^{+}$and$HCO3 ^{-}$. This reaction is catalyzed by carbonic anhydrase.$H^{+}$is secreted again.$HCO_3 ^{-}$is reabsorbed with$Na^{+}$into the bloodstream.Glutamine is metabolized to ammonium ion ($NH4 ^{+}$) and$HCO3 ^{-}$, contributing to both acid excretion and base reabsorption.$NH_4 ^{+}$is secreted and excreted.Secreted$H^{+}$and$NH_4 ^{+}$will be excreted, maintaining acid-base balance.Principles of Blood Volume ControlKidneys recycle fluid efficiently to conserve water.Kidneys conserve volume by reabsorbing water and electrolytes.Volume loss in the urine is carefully regulated to match intake and physiological needs.Regulated$H_2O$reabsorption is controlled by hormones like ADH.If volume falls too low, GFR stops to prevent further fluid loss.GFR can be adjusted to maintain adequate fluid balance.Volume loss can be replaced only by volume input from outside the body through drinking and intravenous fluids.Hormonal Control of the KidneyVasopressin = Anti-diuretic hormone (ADH), crucial for regulating water reabsorption in the collecting ducts.ARGININE VASOPRESSIN (AVP), ANTIDIURETIC HORMONE (ADH)-Origin: Hypothalamic neurons, which synthesize and secrete ADH.Released from posterior pituitary in response to increased plasma osmolarity or decreased blood volume.Chemical Nature: 9-amino acid peptide, with a specific amino acid sequence essential for its function.Transport in the Circulation: Dissolved in plasma, allowing it to reach its target tissues quickly.Half-Life: 15 min, requiring continuous release to maintain its effects.Factors Affecting Release: Osmolarity (hypothalamic osmoreceptors), Blood pressure or volume (carotid, aortic, atrial receptors).Target Cells or Tissues: Renal collecting duct, where it increases water permeability and reabsorption.Receptor/Second Messenger: V2 receptor/cAMP, activating intracellular signaling pathways.Tissue Action: Increases renal water reabsorption, reducing urine volume and concentrating urine.Action at Cellular-Molecular Level: Inserts AQP water pores in apical membrane, facilitating water movement across the cell membrane.Renal Control of Blood Pressure[Diagram illustrating the renal control of blood pressure as depicted in Fig 19.6 of Human Physiology; An Integrated Approach (2017)]Hormone ProductionErythropoietin:-Production stimulated by a decrease in$PO_2$$ in the kidney.

• Produced in interstitial cells in the kidney, specifically peritubular fibroblasts.

• Stimulates erythrocyte production through differentiation of CFU-E into proerythroblast in the bone marrow.

Kidney Disease

• Can be acute or chronic, with different causes and prognoses.

  • Acute: rapid metabolic imbalance, high mortality but commonly reversible with treatment if identified and managed promptly.

  • Chronic: associated with a number of disorders such as:-

    • Diabetes mellitus: High blood sugar levels damage kidney structure and function.

    • Hypertension: Chronic high blood pressure can lead to kidney damage.

    • Glomerulonephritis: Inflammation of the glomeruli, impairing filtration.

    • Polycystic kidney disease: Genetic disorder causing cysts to form in the kidneys, disrupting their function.