Renal Physiology: Kidney Structure, Function, and Non-Protein Nitrogenous Compounds

The Urinary Tract: Kidney Structure and Function

Renal Anatomy

• Kidneys: Paired, bean-shaped organs located on the posterior part of the abdomen.

• Parenchyma:

  • Cortex (outer layer): Contains glomeruli, proximal convoluted tubules, and distal convoluted tubules. These are:

    1. Glomerulus: Also known as Bowman's capsule.

    2. Proximal convoluted tubule (PCT)

    3. Distal convoluted tubule (DCT)

  • Medulla (inner layer): Primarily composed of loops of Henle and collecting ducts. These are:

    1. Loop of Henle: Extends into the renal medulla, composed of a thin descending limb and an ascending limb.

    2. Collecting duct: Formed by two or more distal convoluted tubules.

• Urine Pathway: Renal pelvis collects urine $\rightarrow$ Ureter for storage in the bladder $\rightarrow$ Voided out the Urethra.

• Overall Kidney Function: Filters plasma, removes waste, exchanges electrolytes, and reabsorbs nutrients.

• Nephrons: Each kidney contains approximately $1.3$ million nephrons, which are the functional units.

  • Each nephron has $5$ distinct areas crucial for water and salt balance:

    • Bowman’s capsule (beginning of nephron): Filters liquid plasma into urinary ultrafiltrate.

    • Pathway of ultrafiltrate: Proximal convoluted tubule $\rightarrow$ Loop of Henle $\rightarrow$ Distal convoluted tubule $\rightarrow$ Collecting ducts.

      • Along this pathway, water and nutrients (e.g., glucose, amino acids) are reabsorbed, electrolytes are exchanged, and other compounds are secreted into the urine.

Basic Processes of Renal Anatomy

There are $3$ fundamental processes:

1. Glomerular Filtration:

   • First part of the nephron, functions to filter incoming blood.

   • Non-selective filtration: Occurs across the semi-permeable membrane of the capillary tuft.

   • Driven by high hydrostatic pressure because afferent arterioles have a larger diameter than efferent arterioles, creating a pressure gradient.

2. Tubular Function (Reabsorption & Secretion):

   • Takes place in the proximal convoluted tubule, loop of Henle, and distal convoluted tubule.

   • Tubular reabsorption: Primarily for conserving water and nutrients.

Tubular Function: Reabsorption & Secretion

Proximal Convoluted Tubule

• Focuses on the reabsorption of "precious stuff" (essential nutrients and large amounts of water/electrolytes).

• Eliminates waste products, medications, and Tamm-Horsfall protein via tubular secretion.

Loop of Henle

• Concentration: Urine concentration occurs due to the hypertonic environment of the descending limb.

• Dilution: Achieved in the ascending limb.

Distal Convoluted Tubule

• Under hormonal control for water and sodium reabsorption and potassium secretion.

• Regulates acid/base balance through tubular secretion.

Collecting Ducts

• In the cortical area: Reabsorbs $H_{2}O$ and $Cl^{-}$ passively, and $Na^{+}$ actively.

• In the medullary zone: Passively absorbs $H_{2}O$ and urea.

• Active transport mechanisms are regulated by hormones like ADH (Antidiuretic Hormone, or AVP for Arginine Vasopressin) and Aldosterone.

Tubular Secretion Details

• Proximal Tubule: Secretes $H^{+}$, $NH_{3}$, weak acids and bases (including some drugs) to control plasma pH.

• Loop of Henle: Secretes urea.

• Distal Tubule: Secretes $H^{+}$, $NH_{3}$, uric acid, and some drugs.

• Collecting Tubule: Secretes $H^{+}$, $NH_{3}$, $K^{+}$, and some drugs.

Renal Functions Beyond Filtration

Elimination of Waste Products

• Kidneys are the site for eliminating non-nitrogenous compounds, primarily formed from the degradation of nucleic acids, amino acids, and proteins.

• Key NPN compounds include: Urea, Creatinine, and Uric Acid.

Electrolyte & Acid-Base Homeostasis

• Regulated by the kidneys.

Water Balance

• Kidneys contribute to water balance through water loss or conservation, regulated by the hormone AVP (Arginine Vasopressin).

Endocrine Functions

• The kidneys also possess endocrine functions (though not detailed here).

Renal Circulation

• Blood Flow: Kidneys constitute $0.5\%$ of total body mass but receive $25\%$ of the cardiac output.

  • This high blood flow ensures sufficient blood pressure, which is essential for proper glomerular filtration.

  • Blood pressure drives the glomerular filtration of plasma to form urinary ultrafiltrate.

• Unique Vascular System: The kidney is the only human organ where arterioles subdivide into a capillary bed, become an arteriole again (efferent arteriole), and then subdivide into another capillary network (peritubular capillaries/vasa recta).

Nephron Types

1. Cortical nephrons: Glomeruli and short loops of Henle are in the outer cortex, extending partially into the medulla.

2. Juxtamedullary nephrons: Glomeruli are near the cortex-medulla junction, with long loops of Henle extending deep into the medulla.

Glomerulus & Bowman's Capsule

• The specialized network of capillaries is called the glomerulus.

• The glomerulus is in direct contact with Bowman's capsule.

• High blood pressure in the glomerulus is crucial for liquid plasma to move from the capillaries into Bowman's space.

• After filtration, blood leaves the glomerulus via the efferent arteriole, which forms a capillary web (peritubular capillaries) around the tubules of the nephron.

  • This is where reabsorption of compounds back into the plasma and electrolyte exchange occur.

Ultrafiltration Pressures

• Afferent arteriole hydrostatic pressure: $+55$ mmHg

  • The only force pushing plasma out of the capillaries into Bowman's space.

• Afferent arteriole oncotic pressure: $-30$ mmHg

  • Plasma has a higher protein concentration than Bowman's capsule filtrate, leading to lower oncotic pressure in the filtrate.

  • This causes water to move toward the plasma.

• Bowman’s space hydrostatic pressure: $-15$ mmHg

  • Pushes fluid towards the capillaries.

• Net pressure: $+10$ mmHg

  • Favors the formation of urinary filtrate.

  • Blood pressure, which creates hydrostatic pressure, is critical for urine formation.

Urine Formation

Three Steps

1. Plasma ultrafiltration

2. Selected solute reabsorption

3. Selected solute secretion

Plasma Ultrafiltration: Glomerular Filtration Barrier (GFB)

• Mechanism: Blood pressure drives the formation of the filtrate.

• What does NOT get into the ultrafiltrate: Proteins, lipoprotein particles, platelets, and other cellular components.

• Components and Properties of the GFB:

  1. Endothelial cells lining the capillary: Have spaces of approximately $50-100$ nm. Their negatively charged surface helps repel proteins.

  2. Three-layered basement membrane: Separates Bowman's space. Composed primarily of proteins and heparin sulfate, which helps repel plasma proteins.

  3. Podocytes: Line Bowman's capsule. Distances between them are about $20-30$ nm, and their surface is also negatively charged.

  4. Slit diaphragm: A specialized compartment of the basement membrane located between podocytes, with regularly spaced openings of about $4$ nm.

• Overall Effectiveness: These components together form an effective filtration system.

  • Cannot pass the GFB: Anything larger than $4$ nm (approx. $67,000$ Da), negatively charged substances, most proteins (e.g., albumin), and cells (RBCs, WBCs, platelets).

    • Clinical Significance: A large amount of albumin in the plasma means its presence in urine is an early indicator of glomerular damage.

  • Can pass the GFB: Solutes dissolved in body water.

    • Nonelectrolytes: Glucose, free amino acids.

    • Electrolytes: Dissociated and dissolved into plasma water ($Na^{+}$, $Ca^{++}$, $Cl^{-}$), varying in valency and charge.

Selected Solute Reabsorption Details

1. Proximal Convoluted Tubule:

   • First tubule the filtrate enters.

   • Reabsorbs all vital nutrients such as glucose and amino acids.

   • Surface has microvilli to increase surface area.

   • Reabsorbs >66\% of filtered water, sodium, and chloride.

   • Passive reabsorption of water, potassium, and urea also occurs.

2. Loop of Henle:

   • Begins when the proximal tubule enters the renal medulla and makes a hairpin turn.

   • Most reabsorption here is passive: water, urea, and $NaCl$.

   • Active reabsorption of $NaCl$ takes place in the ascending limb.

3. Distal Convoluted Tubule:

   • Begins at the juxtaglomerular apparatus.

   • Involved in the active transport of $NaCl$, sulfate, and uric acid.

4. Collecting Ducts:

   • Pass through the renal cortex and medulla.

   • Cortical area: Reabsorbs $H_{2}O$ and $Cl^{-}$ passively, and $Na^{+}$ actively.

   • Medullary zone: Passively absorbs $H_{2}O$ and urea.

How Urine Concentration Happens

• Bowman's Capsule: Filtrate is iso-osmotic (same concentration of dissolved solutes as protein-free plasma).

• Loop of Henle: Extends into the renal medulla, which is the only tissue in the body hypertonic to normal plasma.

  • High salt concentration in the medulla allows water to leave the filtrate from the descending limb and enter the interstitial fluid, concentrating the filtrate by the hairpin turn.

  • The ascending loop actively pumps $NaCl$ into the interstitial fluid and is impermeable to water, making the filtrate leaving the loop hypotonic.

• Distal Tubule: Additional water is removed.

• Collecting Duct: By the time the filtrate enters the collecting duct, it is again iso-osmotic before final concentration adjustments.

Non-Protein Nitrogenous (NPN) Compounds and Renal Clearance

Sources and Properties

• Origin: Building blocks and breakdown products of proteins and nucleic acids.

• Characteristics: Small, soluble in aqueous solutions (plasma & urine).

• Filtration: Pass through the glomerular filtration barrier and are present in urine.

• Creatinine Exception: Unique NPN that is not a protein or nucleic acid metabolism product. It is a byproduct of phosphocreatine, a high-energy compound in muscle cells that maintains ATP levels for muscle contraction.

NPN Concentration in Plasma and Urine

• Mainly from continuous biosynthesis and degradation of proteins, amino acids, and their metabolites.

• Variability: Concentrations change with diet, exercise, and environmental stress.

• Clinical Relevance: Plasma concentrations provide diagnostic and treatment information for diseases.

1. Amino Acids

• Represent $20\%$ of plasma NPN compounds.

• Filtration & Reabsorption: Enter urinary filtrate but are actively transported back into the plasma.

• Urine Concentration: Make up <5\% of NPN compounds in urine.

• Sources: Metabolized proteins or amino acid pools used for protein production.

• Clinical Significance:

  • Genetic disorders: Deficiencies in enzymes for amino acid conversion/metabolism lead to their accumulation in plasma and urine, causing problems.

  • Renal tubule damage: Can result in amino acids in urine if reabsorption is impaired.

2. Ammonia ($NH<em>{3}$, $NH</em>{4}^{+}$)

• Represents $0.2\%$ of plasma NPN compounds.

• Excretion: Excreted in urine, accounting for $2.8\%$ of urinary NPN compounds.

• Detoxification: The liver converts toxic ammonia (damaging to CNS) into non-toxic urea.

• Hyperammonemia (increased ammonia):

  • Causes: Liver damage, renal disease, or deficiencies in urea cycle enzymes.

  • Normal Adult Levels: $10-30 \; \mu mol/L$ (higher in infants).

• Production: By intestinal flora and tissues; product of amino acid breakdown and intermediate in amino acid synthesis.

• Removal: Normally removed by portal circulation in the liver and converted to urea.

Ammonia Specimen Types

• Plasma: EDTA or heparin tubes.

• Collection tubes: Must be evaluated for ammonia interference.

• Handling: Specimen must be placed in an ice bath immediately to prevent amino acid deamination.

• Processing: Centrifuged at $0-4 \; ^{\circ}C$; plasma must be separated within $20$ minutes of collection.

Ammonia Interferences

• Hemolysis: Avoided because ammonia concentration in RBCs is $2-3$ times greater than in plasma.

• Cigarette smoking: Can falsely elevate plasma ammonia levels.

  • No smoking after midnight before blood draw.

  • One cigarette one hour before venipuncture can increase venous blood ammonia by $10-20 \; \mu g/dL$.

  • Heavy smokers should shower before testing to minimize contamination.

Ammonia Potential Sources of Error

• Smoking by patient and laboratory personnel.

• Ammonia contaminants in the lab (water, glassware, reagents).

• Poor venipuncture technique.

• Improper specimen processing.

3. Urea (Blood Urea Nitrogen - BUN)

• Major NPN: The highest concentration NPN in the blood, major secretory product of protein metabolism.

• Synthesis: Synthesized in the liver from $CO_{2}$ and ammonia, by hepatocytes.

• Plasma Concentration Variability: Influenced by diet protein, protein catabolism rate, and liver function.

• Excretion: $90\%$ excreted by kidneys, $10\%$ by skin and GI tract.

  • Urinary excretion is related to renal blood flow, glomerular filtration rate (GFR), and urine flow.

  • $40-70\%$ diffuses back through renal tubules into plasma.

Azotemia (Increased Blood Urea)

• Definition: An increase in plasma urea concentration.

• Uremia/Uremic Syndrome: Azotemia due to renal failure.

• Significance: Urea itself is not toxic, but increased concentrations indicate severity of kidney disease.

  • Plasma urea concentrations are affected by renal blood flow, as GFR depends on renal blood pressure.

  • Decreased blood pressure increases plasma urea concentrations.

• Types of Azotemia:

  • Pre-renal azotemia: Caused by reduced renal blood flow (e.g., due to congestive heart failure, dehydration, shock).

    • Less blood to kidney $\rightarrow$ less urea filtered $\rightarrow$ increased plasma urea.

    • Congestive Heart Failure: Decreased cardiac output results in decreased renal blood flow and increased plasma urea.

    • Lab findings for Prerenal Azotemia: Increased BUN/creatinine ratio (often >20:1), normal creatinine, concentrated urine (higher osmolality, higher specific gravity).

  • Renal azotemia: Caused by intrinsic renal disease (e.g., acute/chronic renal failure, glomerulonephritis, tubular necrosis).

    • Kidneys cannot filter or reabsorb properly.

    • Lab findings for Renal Azotemia: Normal BUN/creatinine ratio ($10:1$ to $20:1$), both BUN and creatinine rise together, poorly concentrated urine (low osmolality, low specific gravity).

  • Post-renal azotemia: Caused by obstruction of renal flow after urine leaves the kidneys (e.g., kidney stone, prostate tumor).

    • Lab findings for Post-renal Azotemia: Increased BUN/creatinine ratio, increased creatinine.

Causes of Decreased BUN (Plasma Urea Concentration)

• Liver disease (leading to increased ammonia concentration).

• Starvation (fewer proteins consumed).

• Severe vomiting and diarrhea (proteins not consumed/absorbed).

• Repeated hemodialysis (removes urea).

• Inborn errors of metabolism (less urea production).

Urea Concentration Parameters

• Variability: Varies with age (increases), decreases during pregnancy.

• Units: mg/dL of urea nitrogen, mg/dL of urea, or mmol/L urea.

• Serum/Plasma Reference Ranges:

  • $5-17 \; mg/dL$ urea nitrogen

  • $10.7-36 \; mg/dL$ urea

• Anticoagulants: Cannot contain ammonium or fluoride when determining urea concentration.

• Stability: Stable in plasma at room temperature for $24$ hours, several days refrigerated, several months frozen.

Urea: Indirect Analytical Methods

• Urea is not measured directly.

1. Hydrolysis of urea by urease: Forms ammonia.

2. Quantification: Measure the amount of ammonia formed.

3. Standards: Can use either urea or ammonia standards.

4. Urine samples: A specimen blank must be run to account for endogenous ammonia.

4. Uric Acid

• Origin: Major product of the metabolism of purine nucleosides (adenosine and guanine).

• Production: Approximately $400 \; mg$ daily, plus $300 \; mg$ from diet.

• Excretion: $75\%$ into urine, remainder into GI tract.

• Reabsorption: $90-95\%$ is reabsorbed; only $6-12\%$ of filtered uric acid is excreted.

Uric Acid Plasma Concentrations

• Hyperuricemia (increased production or decreased excretion):

  • Increased production: Rapid turnover of nucleated cells (e.g., chemotherapy).

  • Decreased excretion: Renal failure, Gout.

• Hypouricemia (decreased plasma concentration):

  • Liver diseases.

  • Defective reabsorption (e.g., Fanconi syndrome).

• Gout: Caused by high uric acid levels leading to crystal formation.

5. Creatinine/Creatine

• Plasma Creatinine Concentration: Dependent on relative muscle mass, creatine turnover rate, and renal function.

Creatinine: Renal Excretion

• Filtration: Freely filtered by the glomeruli.

• Reabsorption: Not reabsorbed under normal conditions.

• Secretion: A small amount is secreted by the proximal tubules, which increases as plasma concentration rises.

Creatinine: Clinical Utility & GFR Determination

• Primary Use: Assesses renal function, specifically as a measure of the GFR (mL plasma cleared/minute).

• Normal Values:

  • Adult male: $0.6-1.2 \; mg/dL$

  • Adult female: $0.5-1.1 \; mg/dL$

• Advantages for GFR Determination:

  • Endogenous marker: No need for external substance injection.

  • Relatively stable production: Constant rate of production.

  • Easy to measure: Readily measurable.

• Elevated Creatinine: Indicates abnormal renal/glomerular function.

• Plasma Creatine & Urinary Creatinine Elevation (without renal disease): Muscular dystrophy, hyperthyroidism, trauma.

  • Plasma creatine concentration generally not elevated in renal disease; creatinine is.

Creatinine Methodology

• Jaffe reaction: Creatinine reacts with picric acid in an alkaline solution to form a red-orange chromogen.

• Specificity Improvement: Two approaches:

  • Kinetic Jaffe method.

  • Reaction with various enzymes.

Cystatin C

• Properties: Reabsorbed by renal tubular cells, not present in urine.

• Monitoring: Requires a blood sample.

• Correlation: Strong correlation between plasma/serum cystatin C and creatinine.

• Cost: More expensive than creatinine assays.

Estimated GFR

• Labs cannot charge for tests that are solely calculated values.

• Serves as a free screening tool for patients.

Renal Function Tests

Assessment Areas

• The nephron is the functional unit; different parts perform different functions.

• Damage can occur to the glomerulus, renal tubules, or the kidney’s ability to concentrate urine.

• Glomerular Function: Assessed by clearance tests, which measure the rate kidneys remove compounds from plasma.

• Renal Secretory Function: Assessed by measuring titratable acids or ammonium salts in urine.

• Reabsorptive Function: Assessed by urine and plasma concentrations, osmolality, and specific gravity.

Three Requirements for GFR Determination

For a substance to be used for GFR measurement, it must:

1. Be freely filtered at the glomerulus.

2. Not be reabsorbed or secreted by the renal tubules.

3. Be produced at a constant rate in the body (if endogenous) or administered at a known constant rate (if exogenous).

• These requirements ensure the measured substance directly reflects the filtration rate at the glomerulus.

Renal Clearance Tests: Overview

• Definition: Measures the ability of the glomerulus to clear substances from the plasma.

• Calculation: The volume of plasma cleared of a particular substance in a specific unit of time.

• Formula: Clearance rate $= \frac{\text{(urine concentration} \times \text{urine volume)}}{\text{plasma concentration}}$

  • Urine volume is variable; high water intake leads to low analyte concentration, and vice-versa.

Clearance Calculation Example

• Scenario: Urine specimen collected over $12$ hours, volume $750 \; mL$. Creatinine result $80 \; mg/dL$.

• Calculate mg excreted in $12$ hours: $\frac{80 \; mg}{100 \; mL} = \frac{X \; mg}{750 \; mL} \Rightarrow X = 600 \; mg$

• Calculate mg in $24$ hours: $600 \; mg \times 2 = 1,200 \; mg$ or $1.2 \; g$

• Another example (assuming $1500 \; mL$ urine volume): $\frac{60 \; mg}{100 \; mL} = \frac{X \; mg}{1500 \; mL} \Rightarrow X = 900 \; mg$ or $0.9 \; g/day$

Renal Clearance Tests: Plasma Clearance & Collection

• Plasma Clearance Formula (adjusted for body surface area): Clearance rate $= \frac{\text{(urine concentration} \times \text{urine volume)}}{\text{plasma concentration}} \times \frac{1.73}{\text{body surface area}}$

• Collection: A $24$-hour urine sample is typically collected to account for diurnal variation.

• Substances Measured: Can be endogenous or exogenous.

  • Plasma level of substance should be constant.

  • Must pass the glomerular filtration barrier.

  • Cannot be reabsorbed or secreted by renal tubules.

Specific Clearance Tests

Urea Clearance Test

• Limitation: Urea is passively reabsorbed throughout the nephron ($40-60\%$).

• Dependence: Urine urea concentration depends on GFR and tubular reabsorption.

• Effect of Flow: Slower urinary filtrate flow through tubules leads to more urea reabsorption.

• Methodology: Indirect methods measure ammonia formed after urea hydrolysis.

Inulin Clearance Test

• Reference Method: Considered the gold standard.

• Properties: Exogenous, non-toxic fructopolysaccharide.

• Filtration: Readily filtered, not reabsorbed or secreted by tubules.

• Usage: Rarely used due to requirement for continuous IV infusion to maintain constant plasma concentration.

Creatinine Clearance Tests

• Advantages: Endogenous substance with fairly constant plasma concentration.

• Measurement: Creatinine measurements are easy to perform.

• Approximation: Approximately equals inulin clearance, especially if the Jaffe analytical method is used.

Urine Concentration Measurements

Importance & Definition

• Importance: Crucial for correct kidney function; tubules must properly reabsorb and secrete solutes.

• Regulation: Kidneys control body water by adjusting urine concentration.

• Definition: Concentration $= \frac{\text{amount of solutes}}{\text{volume of water}}$

Specific Gravity (SG)

• Description: A measure of urine concentration based on density.

• Method: Compares the density of urine to the density of pure water.

• Factors: Depends on the number of solutes (moles) and their mass.

• Methods of Measurement:

  • Indirect: Refractometer, Reagent strip.

  • Direct: Harmonic oscillation densitometry, Urinometer.

Osmolality

• Description: Number of solutes per kg of solvent.

• Factors: Affected only by solute number, not molecular weight.

• Colligative Properties: Osmolality is a colligative property, meaning it depends on the ratio of solute particles to solvent particles, not the chemical nature of species.

  • These properties include:

    1. Osmotic pressure

    2. Vapor pressure

    3. Boiling point

    4. Freezing point

• Freezing Point Osmometers: Used to measure osmolality. More solutes $\rightarrow$ lower freezing point.

• Vapor Pressure Osmometer: Measures decrease in dew point temperature caused by decreased vapor pressure.

  • Limitation: Unable to detect volatile solutes.

  • Advantage: Can be done on small sample sizes.

Osmolality in Serum vs. Urine

• Serum: $275-300 \; mOsm/kg$ water.

• Urine: $275-900 \; mOsm/kg$ (can range up to $1200 \; mOsm/kg$ for maximally concentrated urine).

• Urine/Serum Ratio: $1:3$

  • Decreased ratio: Increased fluid intake.

  • Increased ratio: Indicates the opposite (fluid restriction/dehydration).

Disturbances in Serum Osmolality

• Increased Serum Osmolality:

  • Water loss: Urine osmolality decreases.

  • Diabetes insipidus: Urine osmolality decreases.

  • Sodium overload: Urine osmolality increases.

  • Hyperglycemia: Urine osmolality increases.

  • Uremia: Urine osmolality increases.

• Decreased Serum Osmolality:

  • Hyponatremia: Urine osmolality varies.

Urine Solutes

• Average Solute Load: Excreted about $600-700 \; mOsm/day$.

• Water Requirement: Approximately $500 \; mL$ of water per day is required to eliminate the solute load.

• Primarily: Urea, $Na^{+}$, $Cl^{-}$, Ammonia, Phosphate, Sulfate.

• Should NOT be present: Glucose, protein.

Calculated Osmolality & Osmolal Gap

• Osmolal Gap: Helps determine if unexpected solutes are present in the plasma.

• Normal Gap: Should be less than $10$, ideally near $0$.

• Clinical Significance: A gap greater than $10$ suggests the need for further testing (e.g., for toxic ingestions).

Clinical Use of Osmolality

• Monitoring mannitol therapy.

• Screening for ingestion of toxic or volatile substances (e.g., alcohols).

• Screening for metabolic disorders.

SG vs. Osmolality Comparison

• Specific Gravity: Easy and fast to measure.

• Osmolality: More accurate but not as rapid.

• Serum SG: Not typically performed.

• Relationship: A linear relationship should exist between SG and osmolality in healthy states.

• Disease State: In disease, this linear relationship may be lost due to urinary excretion of high molecular weight solutes.

  • Osmolality might remain relatively stable, but SG increases (due to mass of solutes).

Tubular Secretory Function & Regulation of Blood pH

Hydrogen Ions & Ammonia

• The secretion of hydrogen ions ($H^{+}$) and ammonia ($NH<em>{3}$ / $NH</em>{4}^{+}$) plays a crucial role in maintaining plasma pH.

• Transport Mechanisms: Some compounds move passively, while others require active transport.

  • Active transport can move compounds out of urinary filtrate back into blood or into urinary filtrate from blood.

  • Examples of compounds removed from blood for elimination in urine: $K^{+}$, uric acid, penicillin.

  • The ability of renal tubules to secrete ions into urine is a way to eliminate metabolic wastes unable to pass the glomerular filtration barrier.

Mechanisms for Blood pH Maintenance

Kidneys use three primary mechanisms, all dependent on the tubular secretion of $H^{+}$ ions:

1. Secretion of $H^{+}$ in exchange for $Na^{+}$: Prevents bicarbonate ($HCO_{3}^{-}$) loss, which is vital for maintaining blood pH.

2. Formation of monobasic phosphates: (e.g., $NaH<em>{2}PO</em>{4}$, also known as titratable acids).

3. Sodium/ammonium exchange: $Na^{+}/NH_{4}^{+}$ exchange.

Summary of Key Renal Functions and NPN Compounds

Kidney Responsibilities

1. Excretion of waste products.

2. Regulation of electrolytes, water, and acid-base balance.

3. Endocrine functions.

• Renal Function Tests: Measure how well kidneys clear NPN compounds from blood, encompassing glomerular filtration, tubular reabsorption, and tubular secretion.

• Nephron Components (in order): Bowman's capsule $\rightarrow$ Proximal convoluted tubule $\rightarrow$ Loop of Henle $\rightarrow$ Distal convoluted tubule $\rightarrow$ Collecting duct.

NPN Compounds Overview

1. Urea (BUN - Blood Urea Nitrogen):

   • Formed in the liver from protein metabolism via hepatocytes.

   • Primarily excreted by kidneys.

   • Increased in: Renal failure, dehydration, high protein diet, GI bleeding.

   • Decreased in: Severe liver disease, low protein intake.

   • Highest concentration NPN in blood.

   • Elevated urea concentration is termed azotemia.

2. Creatinine/Creatine:

   • Produced at a constant rate from creatine phosphate.

   • Secreted by renal tubules.

   • Filtered by glomerulus, with little to no reabsorption.

   • Best simple test for GFR (volume of plasma filtered by glomerulus per unit time).

   • Creatinine Clearance (CrCl): A measure of creatinine eliminated from blood by kidneys.

   • Elevated creatinine concentration: Indicates abnormal renal/glomerular function.

   • Elevated plasma creatine & urinary creatinine (without renal disease): Muscular dystrophy, hyperthyroidism, trauma.

   • Plasma creatine concentration is not elevated in renal disease; creatinine is.

3. Uric Acid:

   • End product of purine metabolism.

   • Reabsorbed in proximal tubules.

   • Increased in: Gout, renal failure, high cell turnover (e.g., chemotherapy).

   • Can form crystals.

4. Ammonia:

   • Produced from amino acid deamination.

   • Excreted as ammonium ion by the kidney to buffer urine.

   • Converted to urea in the liver.

   • Increased in: Severe liver disease, Reye's syndrome (associated with confusion).

Clinical Use of Urea & Creatinine

• Together: Differentiate pre-renal, renal, and post-renal azotemia (causes of elevated nitrogen compounds).

• Creatinine Clearance: Provides an estimate of GFR.

• BUN/Creatinine Ratio: Helps distinguish causes of azotemia.

  • High Ratio (often >20:1): Prerenal Azotemia:

    • Cause: Reduced blood flow/pressure to kidneys (dehydration, heart failure, shock).

    • Mechanism: Kidneys are functional but not sufficiently perfused, leading to less filtration.

    • Lab findings: BUN rises more than creatinine. Urine is concentrated (higher osmolality, higher specific gravity).

  • Normal Ratio ($10:1$ to $20:1$): Renal Disease:

    • Cause: Actual kidney damage (acute tubular necrosis, glomerulonephritis).

    • Mechanism: Kidneys cannot filter or reabsorb properly.

    • Lab findings: BUN and creatinine both rise together (everything is high). Urine is poorly concentrated (low osmolality, low specific gravity).

  • Low Ratio (<10:1): Postrenal Azotemia (less common for low ratio due to obstruction than other causes): (The transcript has this listed, but typically post-renal also has an increased ratio while creatinine is high).

    • Cause: Obstruction to urine flow (stones, tumors, enlarged prostate). (Note: This type of azotemia typically presents with an increased BUN/creatinine ratio and increased creatinine, not a low ratio, which is usually associated with liver disease or low protein intake).

Osmolality in Clinical Assessment

• Measurement: Number of dissolved particles per kg of water.

• Osmolal Gap: A high gap suggests the presence of unmeasured solutes (e.g., toxins).

• Reflection of Kidney Ability: Reflects the kidney's ability to concentrate or dilute urine.

  • Urine osmolality of $500-800 \; mOsm/kg$ indicates well-concentrating kidneys.

  • Urine osmolality near $300 \; mOsm/kg$ indicates a loss of concentrating ability (iso-osmotic with plasma).