Prostaglandin and Renal Regulation

Prostaglandins play a significant role in the secretion of various substances by extraglomerular mesangial cells and the macula densa, which includes cytokines, interleukin-2, tumor necrosis factor, and thromboxane A2. These substances are crucial for the regulation of glomerular blood flow and glomerular filtration rate (GFR).

Myogenic Mechanism

The myogenic mechanism is a response to increased blood flow to the kidneys. When blood flow increases, it stretches the elastic walls of the afferent arterioles, leading to:

Increased influx of calcium ions (Ca²⁺) from extracellular fluid into the smooth muscle cells.
Contraction of smooth muscle in the afferent arterioles, resulting in vasoconstriction.
Decreased blood flow to the glomerulus, thereby reducing GFR.

This mechanism is based on the Law of Laplace, which states that pressure (P) is proportional to tension (T) divided by radius (r): P = 2T/r.

Calcium's Role in Smooth Muscle Contraction

Calcium ions contribute to smooth muscle contraction through the following process:

Depolarization of the cell membrane opens voltage-dependent Ca²⁺ channels, allowing Ca²⁺ to flow into the cell.
Increased intracellular Ca²⁺ triggers the release of more Ca²⁺ from the sarcoplasmic reticulum (SR).
Ca²⁺ binds to calmodulin, forming a Ca²⁺-calmodulin complex that activates myosin light chain kinase (MLCK).
Activated MLCK phosphorylates myosin, enabling it to bind to actin, resulting in contraction.
Dephosphorylation of myosin leads to relaxation.

Role of Renin

Renin is an enzyme secreted by granular cells in the afferent arterioles, playing a critical role in blood pressure regulation and fluid balance.

Tubuloglomerular Feedback Mechanism

The tubuloglomerular feedback mechanism regulates GFR in response to changes in renal arterial pressure:

Increased renal blood flow (RBF) and GFR lead to enhanced delivery of solutes and water to the macula densa.
The macula densa senses increased Na⁺ and Cl^- concentrations and responds by secreting vasoactive substances like adenosine, ATP, and thromboxane.
These substances cause constriction of afferent arterioles, reducing blood flow and returning GFR to normal levels.

Macula Densa

The macula densa is a specialized structure located at the end of the thick ascending limb of the nephron, part of the juxtaglomerular apparatus. Its primary function is to regulate renal blood flow and GFR through the detection of Na⁺ and Cl^- concentrations in the tubular fluid.

Importance of Autoregulation

Autoregulation is the kidney's intrinsic ability to maintain stable GFR despite fluctuations in systemic blood pressure, crucial for ensuring adequate waste elimination and blood pressure regulation while preventing excessive water loss.

Effects of Changes in GFR

When GFR Increases

Increased GFR elevates NaCl concentration in tubular fluid.
This triggers the macula densa to enhance NaCl uptake, leading to increased ATP and adenosine levels.
ATP and adenosine bind to receptors on smooth muscle cells, increasing intracellular Ca²⁺ and causing vasoconstriction of afferent arterioles, thereby reducing GFR.
Both ATP and adenosine inhibit renin release from granular cells.

When GFR Reduces

Decreased GFR leads to reduced NaCl concentration in tubular fluid.
This results in decreased ATP and adenosine release, lowering intracellular Ca²⁺ and stimulating GFR.
Prostaglandin (PGE₂) is produced, which also stimulates renin release, promoting vasodilation of afferent arterioles and constriction of efferent arterioles, increasing GFR.

Mechanisms of Autoregulation

Two primary mechanisms are involved in renal autoregulation:

Myogenic Response: Involves constriction of afferent arterioles in response to increased blood flow.
Tubuloglomerular Feedback: Involves feedback from the macula densa regarding NaCl concentration.

Factors Affecting Tubuloglomerular Feedback Sensitivity

Factors Increasing Sensitivity:
- Adenosine
- Thromboxane
- Prostaglandin E₂
- Hydroxyeicosatetranoic acid
Factors Decreasing Sensitivity:
- Atrial natriuretic peptide (ANP)
- Prostaglandin I₂
- Cyclic AMP (cAMP)
- Nitric oxide

Starling Forces

Ultrafiltration in the kidneys occurs due to Starling forces, which include hydrostatic and oncotic pressures:

Hydrostatic Pressure in Glomerular Capillaries (PGC): The only force favoring filtration, typically around 60 mm Hg.
Oncotic Pressure in Glomerular Capillaries (πGC): Opposes filtration, approximately 25 mm Hg.
Hydrostatic Pressure in Bowman Capsule (PBS): Also opposes filtration, about 15 mm Hg.
Oncotic Pressure in Bowman Capsule (πBS): Generally 0, as it is protein-free.

The net filtration pressure is calculated as: GFR = Kf [(PGC - PBS) - σ (πGC - πBS)].

Urine Formation Events

The process of urine formation involves:

Glomerular Filtration: Plasma is filtered into Bowman’s capsule.
Tubular Reabsorption: Reabsorption of essential substances like glucose, amino acids, and electrolytes occurs in the renal tubules.
Tubular Secretion: Unwanted substances are secreted into the tubule from peritubular blood vessels.

Glomerulotubular Balance

Glomerulotubular balance refers to the relationship between filtration and reabsorption in the kidneys:

When GFR increases, the tubular load of solutes and water also increases, leading to enhanced reabsorption.
This balance is maintained by osmotic pressure in the peritubular capillaries.

Significance of Filtration Fraction

The filtration fraction is the ratio of renal plasma flow to GFR, typically around 19.2-20%. It indicates the efficiency of filtration in the kidneys.

Substances Reabsorbed in the Nephron

Different segments of the nephron are responsible for the reabsorption of various substances:

Proximal Convoluted Tubule: Reabsorbs approximately 88% of filtrate, including glucose, amino acids, sodium, potassium, bicarbonates, chlorides, and water.
Loop of Henle: Primarily reabsorbs sodium and chloride.
Distal Convoluted Tubule: Reabsorbs sodium, calcium, bicarbonate, and water.

Colloidal Osmotic Pressure

Colloidal osmotic pressure is exerted by plasma proteins in the glomeruli, typically around 25 mm Hg, and opposes glomerular filtration.

Factors Affecting GFR

Several factors regulate GFR, including:

Renal blood flow
Tubuloglomerular feedback mechanism
Starling forces
Constriction of afferent or efferent arterioles
Systemic arterial pressure
Sympathetic stimulation
Contraction of glomerular mesangial cells
Hormonal influences

Significance of High, Low, and Non-threshold Substances

Substances are classified based on their reabsorption characteristics:

High Threshold Substances: 100% reabsorbed, do not appear in urine.
Low Threshold Substances: Under normal conditions, they appear in urine, not fully reabsorbed.
Non-threshold Substances: 0% reabsorption, e.g., creatinine.

Secretion and Reabsorption Mechanisms in the Nephron

HCO3- Reabsorption

Proximal Tubule:
- Mechanisms:
  - Na+-H+ Antiport
  - H+-ATPase
- Regulation:
  - Increased filtered load of HCO3- (+)
  - Decreased ECF volume (+)
  - Increased PCO2 (+)
  - Decreased plasma [HCO3-] (+)
  - Endothelin (+)
  - Glucocorticoid (+)
  - Acute PTH (-)
Henle Loop:
- Thin descending limb: None
- Thin ascending limb: None
- Thick ascending limb: Na+-H+ antiport, H+-ATPase
- Regulation:
  - Increased PCO2 (+)
  - Decreased plasma [HCO3-] (+)
  - Chronic PTH (+)
Early Distal Tubule:
- Mechanisms: H+-ATPase, Na+-H+ antiport
Late Distal Tubule and Collecting Duct:
- Mechanisms: H+-ATPase, H+-K+-ATPase
- Regulation: Decreased plasma [HCO3-] (+), Aldosterone

HCO3- Secretion

Proximal Tubule: None
Henle Loop:
- Thin descending limb: None
- Thin ascending limb: None
- Thick ascending limb: None
Early Distal Tubule: None
Late Distal Tubule and Collecting Duct:
- Mechanisms: H+/ATPase, Cl-/HCO3- antiport
- Regulation: Metabolic alkalosis (+)

Water Reabsorption

Proximal Tubule:
- Mechanism: AQP water channel
- Regulation: Starling forces
Henle Loop:
- Thin descending limb: AQP water channel
- Thin ascending limb: None
- Thick ascending limb: None
Early Distal Tubule: None
Late Distal Tubule and Collecting Duct:
- Mechanism: AQP water channel
- Regulation:
  - ADH (+)
  - ANP, BNP, Urodilatin (-)
  - Uroguanylin, guanylin (-)

Clearance

Clearance is a general concept that describes the rate at which substances are removed (or cleared) from plasma. For example, clearance can be calculated as follows: Clearance= \frac{150}{1} \times 1.44 \text{ L/24 hour} = 150 \text{ ml/L}.

Phosphate Reabsorption

Proximal Tubule:
- Mechanism: 3Na+-Pi symport
- Regulation:
  - PTH (+)
  - Pi Depletion (+)
  - Decreased ECF volume (+)
  - Acidosis (-)
  - Glucocorticoids (-)
Henle Loop: None
Early Distal Tubule: None
Late Distal Tubule and Collecting Duct: None

Calcium Reabsorption

Proximal Tubule:
- Mechanism: Ca++ Channel, Paracellular
- Regulation:
  - PTH (-)
  - Decreased ECF volume (+)
  - Decreased Plasma [Pi] (+)
Henle Loop:
- Thin descending limb: None
- Thin ascending limb: None
- Thick ascending limb: Paracellular
- Regulation:
  - PTH (+)
  - Decreased Plasma [Pi] (+)
Early Distal Tubule:
- Mechanism: Ca++ Channel
- Regulation:
  - PTH (+)
  - Calcitonin (+)
  - Calcitriol (+)
  - Decreased Plasma [Pi] (+)
  - Acidosis
Late Distal Tubule and Collecting Duct: None

Urinary Bladder

The urinary bladder is a triangular hollow organ located in the lower abdomen. It consists of a body and neck, with walls formed by smooth muscle known as the detrusor muscle, which has three ill-defined layers: inner longitudinal, middle circular, and outer longitudinal. The inner surface is lined by a mucous membrane, and in an empty state, the mucosa folds into rugae.

Trigone

The trigone is a triangular area on the posterior surface of the bladder wall where two ureters enter the bladder at the upper angles. The lower part of the bladder forms the neck, which opens into the urethra via the internal urethral sphincter.

Sodium Reabsorption

Sodium reabsorption occurs in three steps:

Transport from the lumen of renal tubules into the tubular epithelial cells (e.g., Na+/H+ antiporter and Na+/Glucose symporters).
Transport from tubular cells into the interstitial fluid (e.g., Na+/K+ ATPase).
Transport from interstitial fluid to the blood (e.g., due to concentration gradient).

Urethra Functions

Male Urethra:
- Functions: Urinary and reproductive (carries urine and semen).
- Length: Approximately 20 cm; traverses the prostate gland and runs through the penis.
Female Urethra:
- Function: Only urinary (carries urine).
- Length: About 3.5 to 4 cm; traverses the urogenital diaphragm and runs along the anterior wall of the vagina.

Transport Proteins in Na+ and Cl– Movement

Internal Urethral Sphincter:
- Location: Between the neck of the bladder and the upper end of the urethra.
- Composition: Smooth muscle fibers, innervated by autonomic nerve fibers.
- Function: Closes the urethra when the bladder is emptied.
External Urethral Sphincter:
- Location: In the urogenital diaphragm.
- Composition: Circular skeletal muscle fibers, innervated by somatic nerve fibers.

Reflex Processes

Reflex activity is a response to peripheral nervous stimulation that occurs without consciousness, serving as a protective mechanism to prevent irreparable damage. Components include receptors, afferent pathways, central processing, efferent pathways, and effector organs.

Stretch Receptors

Stretch receptors respond to tissue stretching and are found in the lungs, digestive system, blood vessels, walls of the urinary bladder, and urethra.

Na-K-2Cl Transporters

These transporters are involved in the movement of sodium and chloride across the apical membranes of renal tubular cells.

Water Reabsorption Mechanisms

Obligatory Water Reabsorption: Occurs in the proximal convoluted tubule, secondary to sodium reabsorption, leading to osmotic movement of water.
Facultative Water Reabsorption: Occurs in the distal convoluted tubule and collecting duct, regulated by antidiuretic hormone (ADH), which increases permeability to water.

Significance of Trigone

The trigone is significant as it serves as a stable anatomical landmark in the urinary bladder, facilitating the entry of urine from the ureters and the exit through the urethra.

Nephron Sites for Water Reabsorption

Proximal Convoluted Tubule: 80% of water reabsorbed.
Distal Collecting Tubule: Influenced by ADH.
Collecting Duct: Influenced by ADH.

Acid-Base Balance and Kidney Function

The kidneys play a crucial role in maintaining acid-base balance in the body through various mechanisms, primarily involving the reabsorption of bicarbonate ions and the secretion of hydrogen ions. This process is essential to prevent acidosis, which can occur due to the metabolic activities that produce excess acids.

Key Concepts

Acidification of Urine: The kidneys regulate the acidity of urine, which typically has a pH ranging from 4.5 to 6.
Metabolic Acidosis: The body generates large amounts of acids, leading to a potential decrease in pH. The kidneys counteract this through two primary mechanisms:
- Reabsorption of bicarbonate ions (HCO3^-)
- Secretion of hydrogen ions (H⁺)

Bicarbonate Reabsorption

Approximately 4,320 mEq of HCO3^- is filtered daily by the glomeruli, known as the filtered load. To maintain acid-base balance, this bicarbonate must be reabsorbed rather than excreted.

Reabsorption Rates: According to Ganong, 4,900 mEq of HCO3^- is filtered and reabsorbed, indicating a 100% reabsorption rate.
Plasma Concentration: Normal plasma concentration of HCO3^- is between 26 to 28 mEq/L. If levels exceed 28 mEq/L, HCO3^- is excreted; if below 26 mEq/L, all filtered HCO3^- is reabsorbed.
Urine Acidity: A decrease in plasma HCO3^- concentration leads to more acidic urine and increased NH₄⁺ production.

Hydrogen Ion Secretion

Hydrogen ions are secreted primarily in the proximal and distal convoluted tubules, with maximum secretion occurring in the proximal tubule (80-90%).

Secretion Mechanisms: H⁺ secretion involves two main pumps:
- Sodium-hydrogen antiport pump
- ATP-driven proton pump (located in distal tubules and collecting ducts)

Mechanism of H⁺ Secretion

The secretion of H⁺ in the renal tubule occurs through Na-H exchange, a form of secondary active transport. The process involves:

Extrusion of Na⁺ from cells into the interstitium via Na, K ATPase, lowering intracellular Na⁺ levels.
Na⁺ enters the cell from the tubular lumen, coupled with H⁺ extrusion.
H⁺ is derived from the dissociation of carbonic acid (H₂CO₃), with HCO3^- diffusing into the interstitial fluid.

Three Mechanisms of H⁺ Secretion

Bicarbonate Mechanism: H⁺ combines with filtered HCO3^- to form carbonic acid, which dissociates into CO₂ and H₂O. This process is facilitated by carbonic anhydrase.
Phosphate Mechanism: H⁺ reacts with sodium hydrogen phosphate (Na₂HPO₄) to form sodium dihydrogen phosphate (NaH₂PO₄), which is excreted in urine.
Ammonia Mechanism: Ammonia (NH₃) is produced from glutamine and combines with H⁺ to form ammonium (NH₄⁺), which is excreted in urine.

Buffer Systems in the Nephron

H⁺ reacts with three buffer systems in the nephron:

Bicarbonate Buffer: Predominantly in the proximal tubule.
Phosphate Buffer: Mainly in the distal tubules and collecting ducts.
Ammonia Buffer: Occurs in both proximal and distal tubules.

Protein Buffer System

Proteins serve as the largest buffer pool in the body, functioning as both acids and bases (amphoteric). Major extracellular protein buffers include:

Serum albumin
Hemoglobin in erythrocytes

Hemoglobin has approximately six times more buffering capacity than plasma proteins.

Properties and Composition of Normal Urine

Understanding the properties and composition of urine is vital for assessing renal function.

Properties of Urine

Parameter	Value
Volume	1000 to 1500 mL/day
Reaction	Slightly acidic (pH of 4.5 to 6)
Osmolarity	1,200 mOsm/L
Colour	Straw-colored (pale yellow)
Odour	Fresh urine has an aromatic odor

Composition of Urine

Urine consists of water and solids, which include both organic and inorganic substances.

Renal Function Tests

Renal function tests assess kidney functions through three main types:

Examination of urine alone
Examination of blood alone
Examination of both blood and urine

Urinalysis

Urinalysis involves a routine examination of urine through:

Physical examination
Microscopic examination
Chemical analysis

Physical Examination of Urine

Volume: Increased volume may indicate renal disorders.
Color: Abnormal coloration can indicate various conditions.
Appearance: Normal urine is clear; turbidity may suggest pathology.
Specific Gravity: Measures dissolved solutes; variations indicate different conditions.
Osmolarity: Changes in osmolarity can indicate diabetes insipidus.
pH: Useful for determining metabolic or respiratory acidosis/alkalosis.

Microscopic Examination of Urine

This examination helps identify renal diseases through:

Red Blood Cells: Presence indicates glomerular disease.
White Blood Cells: Increased numbers suggest infection.
Epithelial Cells: Many cells indicate nephrotic syndrome or tubular necrosis.
Casts: Cylindrical bodies indicating various renal conditions.
Crystals: Presence of certain crystals can indicate metabolic disorders.
Bacteria: Culture studies necessary to determine bacterial presence.

Chemical Analysis of Urine

Chemical analysis identifies abnormal constituents or quantities, revealing renal abnormalities:

Glucose: Presence indicates high blood glucose levels, potentially diabetes mellitus.
Protein: Excess protein may indicate renal impairment.

Kidney and Nephron Overview

The kidneys play a crucial role in maintaining fluid and electrolyte homeostasis by filtering blood, producing urine, and regulating various bodily functions. Understanding the structure and function of the nephron, the kidney's functional unit, is essential for grasping renal physiology.

Kidney Structure

Three Areas of the Kidney:
- Cortex
- Medulla
- Pelvis
Renal Pyramids: The renal pyramids appear striped due to the arrangement of nephrons and the presence of collecting ducts.
Blood Supply: The renal artery delivers approximately 25% of cardiac output to the kidneys.
Renal Artery Length: The right renal artery is longer than the left because it has to cross over the aorta to reach the right kidney.

Nephron Structure and Function

A nephron is defined as the structural and functional unit of the kidney, with each kidney containing approximately 1 to 1.3 million nephrons. The number of nephrons decreases with age, starting around 45 to 50 years at a rate of 0.8% to 1% per year.

Components of the Nephron

Two Main Parts:
- Renal Corpuscle (Malpighian Corpuscle)
- Renal Tubule
Nephron Types:
- Cortical Nephrons: Approximately 85% of nephrons, primarily located in the cortex with short loops.
- Juxtamedullary Nephrons: About 15%, with renal corpuscles near the corticomedullary junction and long loops extending deep into the medulla.

Nephron Functionality

The nephron functions through three interrelated processes:

Filtration: The process where water and dissolved solutes in blood plasma move from the glomerulus into the capsular space due to pressure differences.
Tubular Reabsorption: Substances in the filtrate move back into the blood through diffusion or active transport, modifying the filtrate into tubular fluid.
Tubular Secretion: Active transport of solutes from the blood into the tubular fluid.

Renal Corpuscle

Two Portions:
- Glomerulus
- Bowman Capsule
Glomerulus Features: A tuft of capillaries enclosed by Bowman capsule, consisting of glomerular capillaries that arise from the afferent arteriole.
Afferent vs. Efferent Arteriole: The afferent arteriole has a larger diameter than the efferent arteriole, creating a higher hydrostatic pressure necessary for effective glomerular filtration.
Histology of Glomerular Capillaries: Composed of a single layer of endothelial cells with fenestrae (filtration pores) allowing for filtration.
Bowman Capsule Structure: Comprises two layers:
- Inner Visceral Layer
- Outer Parietal Layer

Podocytes and Filtration Membrane

Podocytes are modified epithelial cells of the visceral layer of the glomerular capsule, featuring foot-like processes (pedicels) that interdigitate to form filtration slits. These slits, along with the fenestrated endothelium of glomerular capillaries, create the filtration membrane, allowing selective passage of materials from blood plasma into the capsular space.

Tubular Portion of the Nephron

The tubular portion of the nephron is a continuation of Bowman capsule and consists of:

Proximal Convoluted Tubule
Loop of Henle
Distal Convoluted Tubule

Proximal Convoluted Tubule

Location: Situated in the cortex, it is the coiled portion arising from Bowman capsule.
Length: Approximately 14 mm.
Diameter: About 55 μm.
Histology: Formed by a single layer of cuboidal epithelial cells with a brush border, enhancing surface area for reabsorption and secretion.

Loop of Henle

The loop of Henle consists of:

Descending Limb:
- Thick Segment: Continuation of the proximal convoluted tubule, lined with brush-bordered cuboidal epithelial cells.
- Thin Segment: Composed of flattened epithelial cells without a brush border.
Ascending Limb:
- Thin Ascending Segment: Continuation of the hairpin bend, lined by flattened epithelial cells.
- Thick Ascending Segment: About 9 mm long, lined by cuboidal epithelial cells without a brush border, forming the macula densa.

Substances and Their Reabsorption in the Kidneys

Understanding the reabsorption of various substances in the kidneys is crucial for comprehending renal function and homeostasis.

Non-threshold Substances

Creatinine: Exhibits 0% reabsorption, serving as a marker for kidney function.

Significance of Non-threshold Substances

Renal Blood Flow: The primary factor for glomerular filtration rate (GFR). Normal renal blood flow is approximately 1,300 mL/minute, and GFR is directly proportional to this flow.
Autoregulation: Renal blood flow is regulated by autoregulatory mechanisms.

Significance of Transport Maximum (Tm)

Tubuloglomerular Feedback: Regulates GFR through communication between renal tubules and macula densa.
Glomerular Capillary Pressure: Normal pressure is 60 mm Hg; increases in this pressure raise GFR, while decreases lower it.

Functions of Key Substances

Sodium: Essential for various physiological processes.
Water: Critical for maintaining fluid balance.
Glucose: Vital energy source, completely reabsorbed under normal conditions.
Amino Acids: Important for protein synthesis and metabolism.
Bicarbonates: Key in maintaining acid-base balance.

Colloidal Osmotic Pressure

Inversely proportional to GFR; normal pressure is 25 mm Hg.
Increased colloidal osmotic pressure (e.g., dehydration) decreases GFR, while decreased pressure (e.g., hypoproteinemia) increases GFR.

Sodium Transport Mechanisms

Na+/H+ Antiporters: Facilitate sodium reabsorption.
Na-Glucose Transporters: Transport sodium along with glucose and other solutes.
Influence of Chloride: Chloride movement into cells creates a positive lumen charge, promoting sodium reabsorption.
Aldosterone: Increases sodium reabsorption in the distal convoluted tubule.

Hydrostatic Pressure in Bowman Capsule

Inversely proportional to GFR; normal pressure is 15 mm Hg.
Increased hydrostatic pressure (e.g., urethral obstruction) decreases GFR.

Effects of Afferent and Efferent Arteriole Constriction

Afferent Arteriole: Constriction reduces blood flow to glomeruli, decreasing GFR.
Efferent Arteriole: Initial constriction increases GFR due to blood stagnation, but prolonged constriction decreases GFR as fresh blood flow is restricted.

Mechanism of Na+/H+ Exchangers

Located in the apical membrane; carbon dioxide and water form H+ and HCO3- via carbonic anhydrase.
Basolateral membrane contains Na/K ATPase and Cl-/HCO3- antiporters.

Systemic Arterial Pressure and GFR

Renal blood flow and GFR remain stable within a mean arterial pressure range of 60-180 mm Hg.
Pressure variations outside this range affect renal blood flow and GFR due to autoregulatory failure.

Na+ Glucose Transporters (SGLT2)

Na+ absorption is coupled with other solutes like amino acids and phosphates.

Sympathetic Stimulation Effects

Moderate stimulation does not significantly affect renal blood flow or GFR.
Strong stimulation causes vasoconstriction, initially increasing filtration but later decreasing it.
Continued stimulation for over 30 minutes leads to recovery of renal blood flow and GFR due to reduced sympathetic neurotransmitter levels.

Na, K, 2Cl Transporters Mechanism

The sodium-potassium ATPase pump maintains low intracellular sodium concentration.
The 1-sodium, 2-chloride, 1-potassium co-transporter transports ions from the tubular lumen into cells.
Positive tubular lumen charge facilitates diffusion of cations like Mg++ and Ca++ via paracellular pathways.

Surface Area and Permeability of Capillary Membrane

GFR is directly proportional to the surface area of the capillary membrane.
Increased permeability in various conditions can lead to abnormal filtration of plasma proteins.

ENaC Location

Found on principal cells of the nephron.

Principal vs. α-Intercalated Cells

Principal cells are involved in sodium reabsorption and potassium secretion.
α-Intercalated cells are involved in acid-base balance through hydrogen ion secretion.

Glomerular Mesangial Cells

Contraction decreases capillary surface area, resulting in reduced GFR.

Obligatory Water Reabsorption

Water reabsorption is linked to the reabsorption of solutes, primarily sodium.

Hormonal and Other Factors Affecting GFR

Factors Increasing GFR: Atrial natriuretic peptide, brain natriuretic peptide, cAMP, dopamine, nitric oxide, prostaglandins (PGE2).
Factors Decreasing GFR: Angiotensin II, endothelins, noradrenaline, platelet activating factor, platelet-derived growth factor, prostaglandins (PGF2).

Sites of Water Reabsorption

Proximal Convoluted Tubule: 80% of water reabsorbed.
Distal Collecting Tubule: Under the influence of ADH.
Collecting Duct: Also under the influence of ADH.

Aquaporins

Integral membrane proteins that facilitate water transport; 13 types identified, with 4 key types in the kidney.
Aquaporin-1: Located in proximal tubule and descending limb of the loop of Henle.
Aquaporin-2: Located in the collecting duct, regulated by vasopressin.

Mechanism of Reabsorption

Involves both active and passive transport mechanisms.

Biologic Half-life of Vasopressin

Approximately 18 minutes; rapidly inactivated in the liver and kidneys.

Routes of Reabsorption

Transcellular Route: Through the cells.
Paracellular Route: Between the cells.

Glucose Reabsorption Mechanism

Occurs primarily in the proximal convoluted tubule via SGLT and GLUT2 transporters.
Steps include sodium-glucose cotransport, maintenance of sodium gradient, and facilitated diffusion into blood.

Regulation of Tubular Reabsorption

Regulated by glomerulotubular balance, hormonal factors, and nervous factors.

Glucosuria

Occurs when plasma glucose exceeds renal threshold (180 mg/dL), leading to glucose excretion in urine.
Common in uncontrolled diabetes and during pregnancy.

Renal Threshold

Plasma concentration at which a substance appears in urine; for glucose, it is 180 mg/dL.

Tubular Secretion

Process of transporting substances from blood into renal tubules, also known as tubular excretion.
Examples of secreted substances include para-aminohippuric acid (PAH), diodrast, and penicillin.

Types of Threshold Substances

High Threshold: Appear in urine only at high plasma concentrations (e.g., glucose, amino acids).
Low Threshold: Appear in urine under normal conditions (e.g., urea, uric acid).
Non-threshold: Not reabsorbed at all, excreted regardless of plasma levels (e.g., creatinine).

Transport Maximum (Tm) Value

Rate at which a substance is maximally reabsorbed; for glucose, Tm is 375 mg/min in males and 300 mg/min in females.

Cortical-Medullary Interstitium Gradient

Generated by countercurrent multipliers in the loop of Henle and urea recycling.
Maintained by vasa recta through countercurrent exchange mechanisms.

Reabsorption of Important Substances

Sodium: Reabsorbed in various nephron segments.
Water: Reabsorbed primarily in proximal convoluted tubule and influenced by ADH in distal segments.
Glucose: Completely reabsorbed in the proximal convoluted tubule.
Amino Acids: Reabsorbed alongside sodium.
Bicarbonate: Important for acid-base balance.

Kidney's Role in Preventing Acidosis

Reabsorption of bicarbonate and secretion of hydrogen ions.

Sodium Reabsorption Mechanisms

Proximal Tubule: Na-H antiport, Na+-solute symport, Cl- anion exchange.
Henle Loop: Paracellular reabsorption.
Distal Tubule: Na+-Cl- symport.
Late Distal Tubule and Collecting Duct: Na+ channels influenced by aldosterone.

Bicarbonate Filtration and Reabsorption

Filtered and reabsorbed in the proximal tubule and influenced by various factors.

Potassium Reabsorption and Secretion

Proximal Tubule: Paracellular reabsorption.
Henle Loop: Na-K-2Cl symport in thick ascending limb.
Late Distal Tubule and Collecting Duct: K+ channels regulated by plasma K+ levels and aldosterone.

Clearance

Clearance refers to the rate at which substances are removed from plasma, providing insight into renal function.

Use of Inulin to Measure GFR

Inulin is ideal for measuring GFR as it is completely filtered and neither reabsorbed nor secreted.

Facultative Water Reabsorption

Occurs in the distal convoluted tubule and collecting duct under the influence of ADH.

Significance of Trigone

Trigone is an anatomical region of the bladder that plays a role in urinary function.

Sympathetic and Parasympathetic Nervous System Influence

Sympathetic: Preganglionic fibers arise from lumbar segments, influencing detrusor muscle and internal sphincter.
Parasympathetic: Preganglionic fibers from sacral segments, affecting bladder function.

Mechanism of ADH Action

ADH increases water permeability in principal cells by promoting the insertion of aquaporin-2 channels into the luminal membrane.

Diuretics

Diuretics are used to treat conditions involving increased extracellular fluid volume, such as hypertension and congestive heart failure.

Mechanism of Glucose Reabsorption

Glucose is reabsorbed in the proximal convoluted tubule via sodium-dependent glucose cotransporter 2 (SGLT2) and glucose transporter 2 (GLUT2).

Mechanism of Dialysis

Dialysis involves the diffusion of solutes through a semipermeable membrane, allowing for the removal of waste products from the blood while retaining essential substances.

Artificial Kidney and Dialysis

The artificial kidney operates on the principle of diffusion, where substances move from an area of higher concentration to an area of lower concentration through a semipermeable membrane. This mechanism is crucial for the process of dialysis.

Patient's arterial blood is continuously or intermittently circulated through the artificial kidney and returned to the body via the veins.
Heparin is administered as an anticoagulant to prevent blood clotting during the process.
The blood flows through a dialyzer, known as a hemofilter, which consists of tiny channels between two cellophane membranes.
These cellophane membranes are porous, allowing for the exchange of substances. The outer surface is immersed in a dialyzing fluid called dialysate, which is regularly replaced with fresh fluid.
Waste products such as urea, creatinine, and phosphates diffuse from the blood into the dialysate due to the concentration gradient, while essential substances move from the dialysate back into the blood.
Most substances, excluding plasma proteins, are exchanged between blood and dialysate through the membranes.
The dialysis machine includes blood pumps with pressure monitors to facilitate blood flow and manage the dialysate flow.
The machine typically contains about 500 mL of blood at a time, with a blood flow rate of 200 to 300 mL/minute and a dialysate flow rate of approximately 500 mL/minute.

Renal Failure

Acute Renal Failure

Acute renal failure is characterized by a sudden decline in kidney function, leading to the accumulation of waste products in the blood.

Chronic Renal Failure

Chronic renal failure is a gradual loss of kidney function over time, often resulting from long-term conditions such as diabetes or hypertension.

Renal Tubular Function

Potassium Reabsorption and Tubular Secretion

Potassium: Actively secreted by sodium-potassium pumps in the proximal and distal convoluted tubules and collecting ducts.
Ammonia: Secreted in the proximal convoluted tubule.
Hydrogen Ions: Secreted in both proximal and distal convoluted tubules, with the maximum secretion occurring in the proximal tubule.
Urea: Secreted in the loop of Henle.

Composition of Urine

Substance	Concentration
Na+	50 – 130 mEq/L
K+	20 – 70 mEq/L
Ammonium	30 – 50 mEq/L
Ca++	5 – 12 mEq/L
Mg+	2 - 18 mEq/L
Cl-	50 -130 mEq/L
Inorganic phosphate	20- 40 mEq/L
Urea	200 – 400 mM
Creatinine	6 – 20 mM
pH	5.0 – 7.0
Osmolality	500 – 800 mOsm/kg H2O
Glucose	0
Amino acids	0
Protein	0
Blood	0
Ketones	0
Leukocytes	0
Bilirubin	0

Summary of Urine Formation

Glomerular Filtration: Plasma is filtered in the glomeruli, and substances along with water form the filtrate.
Tubular Reabsorption: Approximately 99% of the filtrate is reabsorbed in various segments of the renal tubules.
Tubular Secretion: Certain substances are transported from the blood into the renal tubule, transforming the filtrate into urine.

Urine Concentration and Excretion

The kidneys regulate urine concentration based on the body's hydration state:

Excess water leads to a hypotonic extracellular fluid (ECF).
Water deficit results in a hypertonic ECF.

The regulation of urine concentration is influenced by the reabsorption of water in the renal tubules, particularly in:

Proximal tubules (65% water reabsorption)
Loop of Henle (15% water reabsorption)

The final adjustments in urine volume and osmolarity occur in the collecting ducts, influenced by:

Blood levels of antidiuretic hormone (ADH)
Medullary interstitium hypertonicity (medullary concentration gradient)

Requirements for Concentrated Urine Formation

High levels of ADH to increase permeability.
High osmolarity of the renal medullary interstitial fluid to create osmotic gradients.

Medullary Countercurrent System

The medullary countercurrent system is essential for urine concentration:

Juxtamedullary nephrons establish a vertical osmotic gradient through their long loops of Henle (Countercurrent multiplier).
The vasa recta maintain this gradient while supplying blood to the renal medulla (Countercurrent exchanger).
Collecting ducts utilize this gradient, along with vasopressin, to produce urine of varying concentrations.

Urinalysis and Chemical Analysis

Common Chemical Tests of Urine

Glucose: Presence indicates glycosuria, often a sign of diabetes mellitus.
Protein: Excess protein (proteinuria) suggests renal disease, particularly glomerulonephritis.
Ketone Bodies: Ketonuria may occur in conditions like diabetes and prolonged starvation.
Bilirubin: Indicates hepatic or posthepatic jaundice when present in urine.
Urobilinogen: Elevated levels suggest hemolytic jaundice.
Bile Salts: Presence indicates jaundice.
Blood: Hematuria may indicate various renal issues, including infections or malignancies.
Hemoglobin: Hemoglobinuria occurs during excessive hemolysis.
Nitrite: Indicates bacterial presence as some bacteria convert nitrate to nitrite.

Examination of Blood

Estimation of Plasma Proteins

Normal plasma protein values:

Total proteins: 7.3 g/dL (normal range: 6.4 to 8.3 g/dL)
Serum albumin: 4.7 g/dL
Serum globulin: 2.3 g/dL
Fibrinogen: 0.3 g/dL

Plasma protein levels are altered during renal failure.

Estimation of Urea, Uric Acid, and Creatinine

Normal values:

Urea: 25 to 40 mg/dL
Uric acid: 2.5 mg/dL
Creatinine: 0.5 to 1.5 mg/dL

Increased levels of these substances indicate renal failure.

Plasma Clearance

Plasma clearance refers to the volume of plasma cleared of a substance per unit time, also known as renal clearance. It is based on the Fick principle and is used to assess:

Glomerular filtration rate (GFR)
Renal plasma flow
Renal blood flow

To determine plasma clearance, the following factors are needed:

Volume of urine excreted
Concentration of the substance in urine
Concentration of the substance in blood

The formula for calculating clearance value is essential for evaluating renal function.

Measurement of Glomerular Filtration Rate (GFR)

Inulin is the ideal substance for measuring GFR as it is fully filtered and neither reabsorbed nor secreted. The process involves:

Injecting a known amount of inulin.
Estimating the concentration of inulin in plasma and urine, along with urine volume.

Creatinine clearance is also commonly used to measure GFR due to its steady plasma concentration and complete filtration.

Measurement of Renal Plasma Flow

To measure renal plasma flow, para-aminohippuric acid (PAH) is used, as it is filtered and secreted but not reabsorbed. The procedure involves:

Injecting a known amount of PAH.
Estimating the concentration of PAH in plasma and urine, along with urine volume.

Diuretics

Diuretics, commonly referred to as "water pills," are medications that promote the excretion of water and electrolytes through urine. The major classes of diuretics include:

Osmotic Diuretics: Increase osmolarity of the filtrate, promoting water excretion.
Loop Diuretics: Inhibit electrolyte reabsorption in the thick ascending limb of the loop of Henle (e.g., Furosemide).
Thiazide Diuretics: Inhibit active transport of electrolytes in the distal convoluted tubule.
Potassium-Sparing Diuretics: Inhibit aldosterone action (e.g., Spironolactone).
Carbonic Anhydrase Inhibitors: Affect bicarbonate reabsorption.
Diuretics Increasing GFR: Such as caffeine and theophylline.
ADH Inhibitors: Such as water and ethanol.
ADH Receptor Inhibitors: Block the action of ADH.

Peritoneal Dialysis

Peritoneal dialysis utilizes the peritoneal membrane as a semipermeable barrier to treat renal failure. The procedure involves:

Inserting a catheter into the peritoneal cavity.
Passing dialysate through the catheter under gravity.
Electrolytes from the dialysate diffuse into the blood, while waste products move from blood vessels into the dialysate.
Draining the used dialysate from the peritoneal cavity.

Peritoneal dialysis is a simpler and less expensive technique compared to hemodialysis, allowing patients to manage their treatment on an outpatient basis. However, it is less efficient in removing certain toxins and carries a risk of infection.

Complications of Dialysis

Complications associated with dialysis can vary based on the patient's overall health and existing conditions. Common complications include:

Sleep disorders
Anxiety
Depression

Renal Function and Micturition

Glomerular Filtration Rate (GFR)

The GFR is a critical measure of kidney function, indicating the rate at which blood is filtered through the glomeruli. A common method to assess GFR is through inulin clearance, as inulin is neither reabsorbed nor secreted by the kidneys.

Example Calculation: In a 24-hour period, a man receiving an infusion of inulin produces 1.44 L of urine with an inulin concentration of 150 mg/mL in urine and 1 mg/mL in plasma. The clearance of inulin can be calculated using the formula:
C_{inulin} = \frac{(U_{inulin} \times V)}{P_{inulin}}

Measurement of Renal Plasma Flow (RPF)

To measure RPF, a substance that is filtered and secreted but not reabsorbed is used, such as para-aminohippuric acid (PAH).

PAH clearance reflects the amount of plasma that passes through the kidneys.
A known amount of PAH is injected, and its concentration in plasma and urine is measured along with urine volume.
Example: Concentration of PAH in urine = 66 mg/dL, in plasma = 0.1 mg/dL, and urine output = 1 mL/min.

Measurement of Renal Blood Flow (RBF)

RBF can be calculated using the following factors:

Renal Plasma Flow: Measured using PAH clearance.
Percentage of Plasma Volume in Blood: Determined indirectly via packed cell volume (PCV).
Calculation: If PCV = 45%, then plasma volume = 100 - 45 = 55%. Thus, RBF can be calculated as:
RBF = \frac{660}{(55/100)} = 1,200 mL/min.

Urea Clearance Test

This clinical test assesses renal function by measuring the clearance of urea from plasma by the kidneys.

Requires a blood sample for urea level and two urine samples collected at 1-hour intervals.
Normal urea clearance value is approximately 70 mL/min.
Urea is a waste product from protein metabolism, and its clearance is a specific test for renal function.

Micturition

Micturition is the process of voiding urine from the urinary bladder, primarily a reflex action that can be voluntarily controlled in adults.

Functional Anatomy: The urinary bladder consists of:

Urethra: Different in males and females.
Urethral Sphincters: Internal and external sphincters control urine flow.

Nerve Supply: Involves sympathetic and parasympathetic systems.

Micturition Reflex

The micturition reflex is triggered by stretch receptors in the bladder wall when it fills with approximately 300-400 mL of urine.

Increased intravesical pressure stimulates sensory impulses.
Definition: Periodic evacuation of the urinary bladder through the urethra.

Physiological Anatomy of the Urinary Bladder

The bladder has a complex structure that allows it to store and expel urine effectively.

Body of Bladder: Contains a triangular zone called the trigone.
Wall Structure: Composed of three layers:

Mucosa and Submucosa: Transitional epithelium allows for expansion.
Detrusor Muscle: Smooth muscle that contracts to expel urine.
Adventitia: Outer connective tissue layer.

Compliance: The bladder can expand from 10 mL to 400 mL with minimal pressure change, due to rugae flattening.

Nerve Supply to the Urinary Bladder

The bladder receives both autonomic and somatic innervation:

Parasympathetic Supply: Via pelvic nerve, responsible for bladder contraction and relaxation of the bladder neck.
Sympathetic Supply: Via hypogastric nerve, facilitates urine storage by contracting the bladder neck.
Pudendal Nerve: Somatic nerve controlling the external urethral sphincter.

Phases of Bladder Activity

The bladder operates in two phases:

Storage Phase: Low pressure maintained due to high compliance.
Voiding Phase: Urine is expelled through the urethra.

Cystometrogram

A cystometrogram assesses the relationship between intravesical pressure and bladder volume.

Method: A catheter is used to fill and empty the bladder while recording pressure changes.
Segments: The cystometrogram shows different phases of pressure response as the bladder fills.

Micturition Mechanism

Micturition is a spinobulbospinal reflex influenced by higher brain centers.

Center: Located in sacral segments S2, S3, and S4.
Response: Contraction of the detrusor muscle and relaxation of the internal and external sphincters.

Voluntary Control of Micturition

Higher brain centers regulate micturition by facilitating or inhibiting the reflex:

Cerebral cortex allows voluntary control.
Hypothalamus and pons facilitate micturition.

Effects of Lesions on Micturition

Various neurological injuries can impact micturition:

Tabetic Bladder: Interruption of afferent fibers leads to overflow incontinence.
Denervated Bladder: Affects both afferent and efferent fibers, resulting in a shrunken bladder.

Renal Physiology: Mechanisms of Filtration and Regulation

Renal Physiology: Mechanisms of Filtration and Regulation