Human Biology - Renal Unit

Kidney Function

• Removes waste and excess water (to regulate blood volume)

  • 2 quarts of urine (waste + water) per 200 quarts of blood daily

• Produces:

  • Erythropoietin (EPO) - Increases RBC production rate under hypoxia

  • Renin - Regulates blood pressure

  • Active form of Vitamin D - Maintains calcium for bones and chemical balance in body

Kidney Location

• Posterior to diaphragm, abdominal wall and at retroperitoneal position

• T12-L3 (superior lumbar region)

• Encased in perirenal fat

• Anchored by fibrous renal fascia

• Due to liver, right kidney (reaches 12th rib) is lower than left kidney (reaches 11th rib)

Kidney Shape and Structures

• Pair of beans

• Renal hilum

  • Concave

  • Entering and exiting of structures like:

    • Renal veins, arteries, ureter, lymph vessels, nerves

• Pelvis (transitional epithelium) funnels kidney products to ureter

External Supporting Kidney Structures (internal to external)

• Renal capsule - Thin fibrous connective tissue; Attached to kidney

• Perirenal fat - Provides cushion around kidney

• Renal fascia (of Gerota) - Dense fibrous tissue enclosing kidney and suprarenal gland

• Pararenal fat - Adipose tissue holding to abdominal wall

Renal Ptosis

• Floating kidney (sinks below normal)

• Found in anorexic people

• Decline of adipose tissue

• Ureter distends

• Urine builds up pressure (hydronephrosis) leading to necrosis

Internal Kidney Structures

Renal cortex (outer 1/3) - Granular

• Lighter colored

• Cortical tissue

• Renal corpuscle and tubule of nephron

• Has renal columns through medulla to sinus

Renal medulla (inner 2/3) - Striated

• Dark and reddish/brown

• Has 5-8 renal pyramids

Renal Lobe

• Renal pyramid + surrounding cortical tissue

Renal Lobule

• Tissue between renal pyramid and kidney surface

• Has nephrons with single collecting duct

Renal Pyramid Structure

• Cone-shapped and striated

• Renal papilla

  • Has perforated end called area cribrosa

  • Connects to minor calyx

Kidney Drainage Anatomy

• Apex of renal pyramid

• Minor Calyx - Cup-shaped enclosing papilla

• Major Calyx - 2 to 3 branches

• Renal Pelvis

• Ureter

• Bladder

Peristalsis is movement of urine through calyces and pelvis using smooth muscle

Renal Arteries and Veins

• Arteries come off aorta at right angles from L1-L2

• Reach glomeruli where filtration starts

• Right renal arteries longer than left

• Aorta → Renal arteries → Segmental → Lobar → Interlobar → Arcuate → Interlobular → Afferent arteriole → Glomerulus → Efferent arteriole

• Peritubular capillary network → Interlobular veins → … → Renal → IVC

Renal Nerves

Renal plexus

• Autonomic

• Alters arteriole size

• Sympathetic innervation (preganglions at T10-L1) vasoconstrict arterioles → reduce blood flow to glomerulus

• Parasympathetic innervation (CN X) vasodilate arterioles → increase blood flow to glomerulus

Nephron Structure and Parts

• Functional unit of kidney

• 1-2 million per kidney

• Renal corpuscle

  • Bowman’s capsule

  • Glomerulus sits in Bowman’s space

• Renal tubule - Proximal tube, loop of Henle, distal tube

  • Urine from multiple tubules drain to collecting ducts

Two types of nephrons

Cortical nephrons

• Majority (85%)

• Almost entirely in cortex

• Short loop of Henle that dips into medulla

• Peritubular capillaries entwine around nephron

Juxtamedullary nephrons

• Minor (15%)

• Found in corticomedullary region

• Longer loop of Henle that is deep into medulla

  • More concentrated urine made (can reabsorb more water)

• Peritubular capillaries from hairpin vascular loops called vasa recta

Ureters

• Long slender tubes of smooth muscle

• Pushes urine through peristaltic waves

• Diameter is ~3mm

• Starts from L2 of renal pelvis and descends to bladder

• Passes anterior to iliac arteries

• 3 constriction areas (kidney stones here are dangerous)

  • Uretopelvic junction - Near hilus

  • Pelvic Brim - Crossing iliac vessel

  • Uretovesical junction - Near bladder

Kidney Stones

• Renal calculi (calcium, magnesium, and uric acid crystals)

• Larger than 5 mm can block ureter and cause hydronephrosis

• Caused by bacterial infection or blood with high calcium and alkaline levels

• Shock wave lithotripsy or open surgery used to treat

• Drink lots of water (to dilute urine) or cranberry juice and orange juice (to acidify urine)

Bladder

• Carries up to 2 cups of urine

• Trigone - Thick smooth muscle where urine enters

• Detrusor - Smooth muscle of bladder wall

• Urethra - Outlet of bladder

  • Internal urethral sphincter - Smooth muscle at bladder neck

  • External urethral sphincter - Skeletal muscle at pelvic floor

Bladder innervation

Parasympathetics - Pelvic splanchnic nerves (S2-4)

• Motor to detrusor muscle for contraction

• Relaxes internal urethral sphincter for micturition (peeing)

Sympathetics

• Exact opposite mechanism of parasympathetics

Somatic nervous system

• Controls external urethral sphincter

• “Toilet training” muscle

Sensory stretch receptors

• Signal afferent fibers from stretched bladder when full

• Provides urge to urinate

Renal Corpuscle Histology

Bowman’s capsule (from urinary pole)

• Parietal layer - bowman’s capsule proper (flattened epithelial cells)

• Visceral layer - podocytes

• Bowman’s space

Glomerulus (from vascular pole)

• Afferent arterioles

• Efferent arterioles

Be able to identify all 3 layers of bowman’s capsule histologically

Proximal Convoluted Tubule Histology

• Has long convoluted part (pars convoluta) and straight part (pars recta)

• Does 75% of water and ion reabsorption

• Long columnar epithelial cells with brush border

Loop of Henle Histology

• Thin descending limb - simple squamous epithelium

• Thick ascending limb - low cuboidal epithelium

• Uses countercurrent system to generate high osmotic pressure in renal medulla

Distal Convoluted Tubule Histology

• Actively reabsorbs sodium ions via aldosterone

• Secretes hydrogen/potassium ions

• Lumen is clearer (lacking brush border) and fewer in number than PCT

Collecting Tubule and Collecting Duct Histology

• End of nephron

• Urine is concentrated from passive water reabsorption in medulla

• CT is simple cuboidal epithelium

• CD is simple columnar epithelium

Duct of Bellini Histology

• Formed when CDs merge

• Drain urine from papilla to calyx

Renal Vasculature Components

Artery

• Renal Artery (from aorta)

• Segmental Artery

• Lobar Artery

• Interlobar artery (between pyramids and reaches corticomedullary junction)

• Arcuate artery (at junction perpendicular to interlobar arteries)

• Interlobular (cortical radial) arteries

• Afferent glomerular arterioles

• Efferent glomerular arterioles supply cortical labyrinth in cortex and form arteriolae recta in medulla

Veins

• Venae recta in medulla; interlobular veins in cortex

• Follows artery system from Arcuate vein to Renal vein and then IVC

Juxtaglomerular Apparatus Histology

• Regulates systemic blood pressure via RAAS system

• Macula Densa

  • Specialized cells of DCT

  • Sensitive to sodium ion concentration

  • Use osmoreceptors for renin secretion

• Juxtaglomerular cells

  • Specialized smooth muscles cells of afferent arterioles

  • Contain renin granules

  • Use renal baroreceptors for renin secretion

• Extraglomerular mesangial cells

  • Conical mass of cells between afferent and efferent arterioles

Ureter Histology

• Convoluted lumen

• Transitional epithelium

• Lamina propria

• Smooth muscle - longitudinal

• Smooth muscle - circular

Urinary Bladder Histology

• Transitional epithelium

• Lamina propria

• Smooth muscle - longitudinal

• Smooth muscle - circular

• Smooth muscle - longitudinal

Urethra Histology

Kidney Functions

• Maintain H₂O balance (vasopressin)

• Maintain osmolarity

• Maintain plasma volume (aldosterone)

• Regulate ECF ions

• Use RAAS system to modulate blood pressure

• Eliminate waste products

• Maintain acid-base balance in body

• Convert vitamin D to D3 (active form)

• Produce erythropoietin

Vascular Parts of Nephron

• Afferent Arteriole - Carries unfiltered blood to glomerulus

• Glomerulus - Tuft of capillaries filtering protein-free plasma

• Efferent Arteriole - Carries filtered blood from glomerulus

• Peritubular capillaries - Supply renal tissue and exchange fluid in tubular lumen

Tubular Parts of Nephron

• Bowman’s capsule - Collects glomerular filtrate

• Proximal tubule - Uncontrolled reabsorption and secretion of some substances

• Loop of Henle (of juxtamedullary nephrons) establishes osmotic gradient in medulla to produce urine of varying concentration

• Distal Tubule and Collecting Duct - Variable reabsorption of K⁺ and H⁺; urine leaves

Juxtaglomerular Apparatus

• Combines vascular and tubular components

• Macula Densa

  • Distal Tubule

  • Responds to sodium changes (decrease causes renin release)

• Granular (Juxtaglomerular) cells

  • Smooth muscles of afferent arteriole

  • Produces renin when innervated by sympathetic fibers

  • Detect decrease in blood pressure or NaCl

• Extraglomerular mesangial/lacis cells

  • Innervated by sympathetic fibers

  • Have actin filaments

  • Modulate GFR

Kidney Fun Facts

• 180 L of plasma filtered and 1.5 L is eliminated

• Kidney filters plasma about 65 times a day

• If no reabsorption happens, the entire plasma volume will be urinated in <30 minutes

• 1 in 7 adults have kidney disease (90% do not know about it)

• Up to 75% kidney tissue can be destroyed before loss of kidney function is detected

Glomerular Filtration

• Plasma is passively forced through glomerular membrane

  • Damage (from high BP, diabetes, family history, infection, autoimmune disease, toxic agents, obstruction, or loss of blood supply) causes protein and RBC leakage

• Fluid passes through three layers

  • Glomerular capillary wall (single endothelial cell layer; 100x more permeable to water and other solutes)

  • Basement membrane (collagen and negatively charged glycoproteins)

  • Inner layer of bowman’s capsule (podocytes encircling glomerulus tuft)

• Correlation of Charge and Size of Proteins

  • Freely at below 7000D

  • From 7000-70000D, it becomes difficult with increased size

• Three forces

  • Glomerular capillary blood pressure - Depends on heart contraction and blood flow resistance by arterioles (55 mm Hg)

  • Plasma-colloid osmotic pressure (oppose filtration) - Osmotic pressure on plasma proteins across membrane (30 mm Hg)

  • Bowman’s capsule hydrostatic pressure (oppose filtration) - Pressure exerted by initial part of tubule (15 mm Hg)

• GFR = K_f * Net Filtration Pressure

  • K_f depends on surface area and permeability

Unregulated and Controlled Influences on GFR

Unregulated Influences

• Liver disease causes loss of plasma proteins (inc GFR)

• Dehydrating Diarrhea is loss of fluid (dec GFR)

• Obstructions such as kidney stones (dec GFR)

Controlled Adjustments

• Autoregulation - Preventing spontaneous GFR changes by keeping MAP at 80-180 mmHg, prevents dangerous salt/water balance changes, protects glomerular capillaries from hypertensive damage

  • Myogenic Mechanism - Responds to high GFR from high blood pressure by constricting afferent arteriole when high oxygen or sympathetic activity occurs to reduce GFR

  • Tubuloglomerular Feedback - Macula densa in distal tubule will respond to NaCl levels in filtrate: high GFR → high NaCl → ATP production → vasoconstriction decreasing GFR; low GFR → low NaCl → Nitric Oxide production → vasodilation increasing GFR

• Extrinsic Sympathetic Control - Long-term regulation of arterial blood pressure overriding autoregulation via sympathetic nervous system to afferent arterioles

  • Low arterial blood pressure → Detection by baroreceptors → increase sympathetic activity → arteriolar vasoconstriction → dec GFR → conservation of fluid and salt → increase arterial blood pressure

Tubular Reabsorption

• Transfer of substances from tubular lumen to peritubular capillaries

• Substance must cross luminal cell membrane, then cytosol, then basolateral cell membrane, then interstitial fluid, and then the capillary wall

• Can be passive (ex: water or urea) or active (ex: glucose, amino acid, Na⁺, PO₄^3-)

Na⁺ Reabsorption

• Active (using Na⁺/K⁺ ATPase)

• Early and Unregulated

• Occurs in proximal tubule, ascending limb of loop of Henle (causing varying urine concentrations), and distal/collecting tubules (hormonal; renin release results in aldosterone [places more Na⁺ leak channels and Na⁺/K⁺ pumps])

• Reabsorption of nutrients in proximal tubule mechanism

  • Primary active transport: Epithelial cell removes all sodium using Na/K pump

  • Secondary active transport: Sodium and glucose enter epithelial cell via symport carrier (SGLT)

  • Facilitated diffusion: High concentration of glucose uses GLUT to move glucose out of cell to blood

• Water follows reabsorbed sodium by osmosis, affecting blood volume and pressure

• Inhibited by ACE inhibitors (prevents Angiotensin II formation), ARB (Angiotensin II Receptor Blocker), and Aldosterone Receptor Blocker

• ANP (in atria) and BNP (in ventricle) are released when cardiac muscle is stretched (indicating high volume) to promote natriuresis and diuresis

  • Inhibits RAAS system, dilates afferent arterioles to increase GFR, and inhibits sympathetic activity

• Only substance that does not have tubular maximum

Unique Drugs inhibiting Sodium Reabsorption

• Loop diuretics - Inhibit Na/K/Cl cotransporter in thick ascending limb

• Thiazide diuretics - Inhibit Na/Cl transporter in distal tubule (less efficacious and most commonly used)

• Potassium sparing diuretics - Prevents aldosterone-based sodium reabsorption in distal tubule (does not cause hypokalemia)

PO₄^3- Reabsorption

• Subject to control

• Most filtered phosphate is reabsorbed in proximal tubule via sodium symporter

• Tubular maximum is very similar to normal plasma concentration unless an excessive amount is present

Urea Reabsorption

• Made from protein degradation

• Water reabsorption causes urea concentration in tubular fluid to increase → 50% of urea passively diffuses and gets reabsorbed in proximal tubule

• Improper urea elimination causes high BUN and prevents hemostasis (increases bleeding)

Tubular Secretion

• Transfer of substances from peritubular capillaries to tubular lumen

• Can add substances to hasten elimination

• K⁺ Secretion

  • Actively secreted in distal tubule by Na/K ATPase with help of aldosterone

  • Depending on stimulus, aldosterone performs either sodium reabsorption or potassium secretion

• H+ Secretion

  • Regulates acid-base balance and secreted in proximal and distal tubules

• Organic ion secretion

  • Usually are foreign compounds in body like food additives, pollutants or drugs

  • Removed in proximal tubule

  • Can not adjust to increased dosages

Stages of CKD

• Stage 1 - Kidney damage with normal function (GFR > 90 mL/min)

• Stage 2 - Kidney damage with mild function loss (60-89)

• Stage 3a - Mild to moderate kidney function loss (45-59)

• Stage 3b - Moderate to severe kidney function loss (30-44)

• Stage 4 - Severe kidney function loss (15-29)

• Stage 5 - Kidney failure (GFR < 15)

Types of Renal Failure

• Acute - Sudden onset, rapidly reduced urine formation, reversible

• Chronic - Slow, progressive, insidious loss of renal function

• End-Stage - 90% of kidney function is lost and every organ system is affected

Kidney Failure Symptoms and Treatment

Symptoms

• Nausea, vomiting, fatigue, abnormal swelling of feet, puffiness around eyes, anemia

Treatment

• Hemodialysis - Blood cleaned through special filter in dialysis machine via artificial kidney

• Peritoneal Dialysis - Blood uses peritoneal lining as natural filter (self-administered)

• Kidney Transplant - Long wait list, compatibility and medical tests needed, better quality of life and less restricted diet, needs immunosuppressant medications

Dental Management of End Stage Kidney Disease

• Patients with stage 4-5 kidney disease require special considerations

• Patients on dialysis have higher risk of bleeding from anti-coagulants and dental procedures should be avoided on dialysis days

• Patients with kidney transplant have high risk of infection due to immunosuppression medications and need dental examination pre and post-transplant

• Patients with oral lesions have low GFR values

• Oral lesions are very common in CKD patients

Kidney Disease Warning Signs

• Hypertension

• Hematuria or Proteinuria

• Creatinine and BUN levels outside normal range (indicating metabolic waste buildup)

  • BUN accumulates for other reasons too like dehydration or high protein meal so BUN/creatinine test is recommended

• GFR < 60 mL/min

• More frequent and painful urination

• Puffiness around eyes, swelling of hands and feet

Plasma Clearance

• Volume of plasma cleared of substance per minute

• C = U_con*U_vol/P_con

• Inulin (produced from Jerusalem artichokes) is not reabsorbed or secreted. Used to calculate GFR because C_inulin = GFR

• Glucose is filtered and completely reabsorbed (C = 0)

• Urea is filtered and partially reabsorbed, but not secreted (C < GFR)

• Creatinine, H⁺ and PAH are filtered and secreted but not reabsorbed (C > GFR)

  • PAH is almost completely removed in one pass

• Filtered Fraction = GFR/RPF (renal plasma flow = total urine excretion) = C_inulin/C_PAH

Kangaroo Rats

• Survive with very little water from seeds

• Do not pant or sweat

• Have long loops of Henle from juxtamedullary nephrons to retain water

• Excrete urine pellets

Countercurrent Multiplication

• Osmotic gradient formed by hairpin loop deep in medulla only

• Countercurrent flow allows for multiplication in concentrating effect

• Ascending limb actively transports only NaCl allowing descending limb to diffuse only water

• Entering fluid is isotonic, exiting fluid is hypotonic, bottom of loop is hypertonic

• Interstitial fluid has concentration gradient from 300-1200 mOsm/L

  • Vasa Recta maintains this same gradient to allow for proper reabsorption

• Benefit is that urine exiting distal tubule is dilute and interstitial fluid can make more concentrated urine

Vasopressin

• Independent of solute reabsorption

• Produced in hypothalamus and stored in posterior pituitary

• Signals distal tubule and collecting duct to reabsorb water (using AQP-2 channels)

• AQP-3 and 4 used for outside tubule osmosis to blood

• Alcohol inhibits vasopressin

Micturition

• High urine levels in bladder → stretch receptors activate parasympathetics → smooth muscle of bladder wall contracts to urinate

• Internal (involuntary) and external (voluntary) urethral sphincters

• Micturition is stopped by voluntarily tightening external sphincter and pelvic diaphragm

• Urinary Incontinence - Inability to prevent urine discharge (impaired external sphincter decreases incontinence)

Water Inputs, Outputs, and Breakdown in Body

Inputs -

• Drinking liquids and eating solid foods

• Metabolically produced water

Output -

• Lungs (insensible)

• Non-sweating skin (insensible)

• Sweating

• Feces and urine

Body Composition -

• 60% water (fairly constant within individuals; variation between different tissue types like adipose tissue vs muscle)

  • ICF - 2/3 of H₂O

  • ECF - 1/3 of H₂O (20% plasma, 80% interstitial fluids like cerebrospinal, synovial and digestive fluid)

Differences between ECF and ICF

• Proteins in ICF do not permeate the cell membrane to leave cells

• Na⁺ and K⁺ levels differ in each because of ATPase pump

Mechanisms to regulate blood pressure using ECF Volume

Short-term

• Baroreceptor reflex alters cardiac output and total peripheral resistance

• Bulk flow between plasma and interstitial fluid

• Modify sodium levels

  • Low blood pressure → sympathetic stimulation (→ decreased GFR → decreased Na⁺ filtered) or RAAS (→ increased aldosterone → increased Na⁺ reabsorbed) → decreased Na⁺ and Cl^- excretion → conserve NaCl and fluid → increases blood pressure

    • Afferent arterioles in nephrons have more alpha-1 adrenergic receptors than efferent arterioles causing decreased GFR in sympathetic stimulation

Long-term

• Kidneys and thirst mechanism control urinary output and fluid intake

Congestive Heart Failure

• BP and CO decrease

• Patients have increased ECF volume

  • Granular cells respond as if ECF has decreased, triggering RAAS system and NaCl/water retention

• ECF increases but not in vascular system causing pulmonary and generalized edema

Tonicity

• Deficit of free water in ECF causes hypertonicity causing cells to shrink

  • Caused by insufficient water intake, excessive water loss (sweating/vomiting/diarrhea) or ADH deficiency by either alcohol consumption or diabetes insipidus

  • Results in brain neuron shrinkage, circulatory disturbances, and dry skin, sunken eyeballs, dry tongue

• Excess free water in ECF causes hypotonicity causing cells to swell

  • Caused by patients with renal failure who drink lots of water, healthy people who rapidly ingest water, or improper use of vasopressin

  • Results in brain failure, weakness (muscle cell swelling), hypertension and edema, water intoxication

ADH Trigger Mechanisms

• Hypothalamic osmoreceptors and thirst centers of hypothalamus secret ADH when osmolarity increases

• Left atrial volume receptor monitors blood pressure. When artery pressure reduces, vasopressin is released and stimulates thirst (large scale changes only)

• Angiotensin II stimulates ADH and thirst (also does arteriolar vasoconstriction) when RAAS is activated to conserve Na⁺

Factors that do not link vasopressin and thirst

• Dry Mouth triggers thirst

• Alcohol and Caffeine inhibit ADH; Pain and infection trigger ADH

Exercise Physiology

• Heat exhaustion causes hypotension, sweating and disorientation

• Heat stroke causes failure of temperature control center in hypothalamus causing extreme confusion/unconsciousness

• Exercising muscles and cooling mechanisms compete for plasma volume and exercising muscles win tug of war

• Adaptations include increased sweating at lower temperatures and more dilute

Urinalysis

Detects kidney disorders in three ways:

• Appearance

  • Pale yellow or clear indicates hydration

  • Red or red-brown indicates blood or drug

  • Cloudy indicates excess salts, protein, or pus

• Dipstick

  • pH range from 6-7.4 normally

    • High pH may indicate kidney stones or urinary infection

    • Low pH indicates acidosis

  • 1.002 to 1.03 specific gravity normally

    • Increases with dehydration, proteinuria, or excess ADH secretion

    • Decreases with diabetes insipidus or nephritis (inability to concentrate urine)

• Microscopic

  • Tamm Horsfall protein appears in small amounts

  • Albumin is abnormal and represents leak

  • Proteinuria is represented from 0 to 1+ to 4+ for creatinine or albumin

  • Athletes undergo athletic pseudonephritis where many have proteinuria after strenuous exercise from decreased glomerular flow rate caused by RAAS (renin)

Positive cases in Urinalysis

• Positive test for glucose (tastes sweet) - diabetes mellitus

• Lack of anything (tastes bland) - diabetes insipidus

• Positive test for ketones - diabetic ketoacidosis (body breaks down fat in absence of insulin causing ketone buildup)

• Positive test for nitrite - urinary tract infection

• Positive test for leucocyte esterase - white blood cell presence

• Positive test for bilirubin - liver or gall bladder dysfunction

• Positive test for RBC - urinary tract damage or kidney stones

• Positive test for WBC - Urinary tract infection

Ultrasound, CT Scan, Kidney Biopsy

• Ultrasounds - abnormalities in size or position of kidneys and obstructions like stones or tumors using sound waves

• CT Scan - structural abnormalities and presence of obstruction using X-rays

• Kidney Biopsy - Identify disease process and extent of damage of kidney. It’s also why kidney transplant may not be doing well

Fluoride

• Fluoride is associated with hard tissue such as bone and teeth because of affinity to calcium

• 99% of fluoride is in bones and teeth

• Fluoride reduces incidence of dental caries and reverses progression of lesions

• US Public Health Services optimal range of 0.7 ppm fluoride with upper limit of 2.0 ppm (recommended) and 4.0 ppm (enforceable)

• Major route of fluoride removal from body is by kidneys

• Amount of H₂O, beverages, toothpaste, plasma concentration, GFR and urine flow, and partial reabsorption of F^- affect renal clearance of F^-

• Because HF can diffuse back to blood and not F^-, diets that promote acidic urine help F^- remain deposited on bones

• Person with advanced kidney disease and high fluoride consumption risks fluorosis

Potassium

• Needed for action potentials and maintaining resting membrane potential (Potassium Nitrate used in sensitivity relief toothpastes due to depolarization)

• Intake remains constant despite dietary fluctuations (K⁺ excretion only occurs during high intake)

• ATPase maintains high potassium levels in cell

• Adrenal gland tumor increases aldosterone causing increased plasma Na⁺ levels and decreased K⁺ levels; Addison’s Disease causes opposite effect

• Diuretics cause potassium depletion (only potassium sparing diuretics do not cause hypokalemia)

• End-stage renal disease causes hyperkalemia

• Insulin (diabetics have hyperkalemia), epinephrine (beta2 stimulation; prevents hyperkalemia during exercise; beta blockers cause hyperkalemia), and aldosterone promote K⁺ uptake into cells

• High K⁺ levels, ADH, and aldosterone cause K⁺ excretion

  • Aldosterone paradox allows K⁺ secretion or Na⁺ reabsorption based on stimulus

H⁺ and pH of Blood

• Normal H⁺ concentration is 4×10^-8 M (pH of 7.4)

• Beyond 7.35-7.45 is considered acidosis/alkalosis

• Beyond 6.8-8.0 is not compatible with life

• Acidosis causes CNS depression; alkalosis causes over excitability

• H⁺ levels affect shape of function of proteins

• H⁺ levels affect K⁺ levels in body

• Carbonic acid formed from combining CO₂ and H₂O and releases H⁺ and HCO₃^-

• Inorganic acids produced during breakdown of nutrients

• Organic acids result from intermediary metabolism

Chemical Buffer Mechanism

First line of defense against pH changes

• H₂CO₃:HCO₃^- buffer system against non-carbonic acids in ECF

  • (H₂CO₃ ←> H⁺ + HCO₃^-)

  • Shifts to H₂CO₃ production when exercising muscles

  • Shifts to H⁺ production during vomiting and loss of digestive juices

  • pH = pK + log[HCO₃^-]/[CO₂]

  • [HCO₃^-]/[CO₂] = kidney function/lung function = 20/1

  • When pH is near pK, the buffering power is very strong

• Protein buffer system works intracellularly and contains both acidic and basic groups that can accept or give H⁺ ions

• Hemoglobin buffer system buffers H⁺ generated from CO₂ between tissues and lungs

• Phosphate buffer system undergoes intracellular buffering and is only buffer system in kidneys (most HCO₃^- and CO₂ is reabsorbed)

Respiratory Buffering Mechanism

• Second line of defense against pH changes (can partially return pH to normal)

• Acts in minutes

• Ventilation eliminates acid from body

Kidney Buffering System

• Third line of defense against pH changes acting in hours to days

• Either secretes excess H⁺ or adds new HCO₃^- to plasma during acidosis; does opposite for alkalosis

• Renal H⁺ secretion in proximal tubule uses ATPase pumps and Na⁺-H⁺ antiporters

• Renal H⁺ secretion in distal and collecting tubules uses Type A and B intercalated cells interspersed among principal cells

  • CO₂ (from blood vessel) and H₂O combine to make HCO₃^- and H⁺

    • Under acidosis, Type A Intercalated disks have ATPase in luminal membrane, causing hydrogen ion secretion along with potassium and bicarbonate reabsorption

    • Under alkalosis, Type B Intercalated disks have ATPase in basolateral membrane, causing hydrogen ion reabsorption along with potassium and bicarbonate secretion

• In acidosis, secreted H⁺ ions are buffered by either NH₃ or phosphate before being excreted

Renal Handling of Potassium and Acid-Base Balance

• Na⁺ reabsorption is matched by either K⁺ or H⁺ secretion by Aldosterone

• Acute Metabolic Acidosis causes H⁺ secretion and K⁺ retention/hyperkalemia

• Hypokalemia causes K⁺ retention and H⁺ secretion

• Hyperkalemia causes K⁺ secretion and H⁺ retention

Metabolic and Respiratory Alkalosis and Acidosis

Respiratory Acidosis

• CO₂ retention from hypoventilation caused by lung disease, reduced respiratory activity from nerve/muscle disorders or holding breath

Respiratory Alkalosis

• CO₂ loss from hyperventilation caused by fever, anxiety and high altitudes

Metabolic Alkalosis

• Caused by vomiting or ingesting alkaline drugs

• Relieved by buffers liberating H⁺, reducing ventilation to retain CO₂, or kidneys conserving H⁺ and excreting HCO₃^-

Metabolic Acidosis

• Caused by severe diarrhea, diabetes mellitus, strenuous exercise, or uremic acidosis

• Relieved by buffers taking up more H⁺, or lungs blowing off H⁺ by removing CO₂, or kidneys excreting more H⁺ and conserving HCO₃^-