Renal Physiology

• 1. Intermediate mesoderm forms urogenital ridge
• 2. Part of urogenital ridge forms nephrogenic cord
• 3. Nephrogenic cord develops into:
•      -pronephros
•      -mesonephros
•      -metanephros
• 

• -develops at week 4
• -most rostral portion
• -degenerates, never functional

• -functions as interim kidney for 1st trimester
• -later contributes to male genital system (Wolffian Duct)

• -permanent
• -first appears during 5th week of gestation
• -nephrogenesis continues through 32-36 weeks
• -most caudal portion
• 
  Ureteric Bud
• -derived from the caudal end of the mesonephros
• -gives rise to ureter, renal pelvis, calyces and collecting ducts
• -fully canalyzed by 10th week

• Metanephric Mesenchyme
• -ureteric bud penetrates metanephric mesenchyme
• -interaction induces differentiation and formation of glomerulus through distal convoluted tubule
• *aberrant interaction can result in congenital malformations

• 
• Ureter → major calyx → minor calyx → papilla → pyramid

Renal artery → segmental artery → interlobar artery → arcuate artery → interlobular artery → afferent arteriole

• Layers of Glomerular Filtration
• 1. Vascular endothelium (fenestrated)
• 2. Basement membrane (negative charge)
• 3. Podocyte foot processes (visceral epithelial cells)

• Mesangial cells:
• -phagocytic properties
• -contractile properties
• -synthesize ECM

• Juxtaglomerular cells:
• -smooth muscle cells in btwn macula dense and efferent/afferent arterioles
• -secrete renin (tubuloglomerular feedback)

• Macula Densa:
• -epithelium of thick ascending limb
• -lies in close proximity to its parent glomerulus
• -detect changes in tubular ionic composition
• -send signals to JG cells to secrete renin
• 

Ureters pass under uterine artery and under ductus deferens (retroperitoneal)

"Water (ureters) under the bridge (uterine artery, vas deferens)"

Total body water = 60% Total body weight (kgs)

• TBW
• 1/3 Extracellular Fluid
• 2/3 Intracellular Fluid

• Extracellular Fluid
• 1/4 Plasma
• 3/4 Interstitial Volume

• 
• 60-40-20 Rule (% of body weight)
• -60% TBW
• -40% ICF
• -20% ECF

"HIKIN': HIgh K INtracellular"

Plasma volume can be measured by radiolabeled albumin

ECF volume measured by inulin, osmolarity = 290 mOsm/L

-responsible for filtration of plasma according to size and net charge

• Composed of:
• 1. Fenestrated capillary endothelium (size barrier)
• 2. Fused basement membrane with heparan sulfate (negative charge barrier)
• 3. Epithelial layer (podocyte foot processes)

*Charge barrier is lost in nephrotic syndrome → albuminuria, hypoproteinemia, generalized edema and hyperlipidemia

C_x = U_xV/P_x

• where:
• C_x is clearance (mL/min)
• U_x is urine concentration of x
• P_x is plasma concentration of x
• V is urine flow rate

Volume of plasma from which the substance is completely cleared per unit time

• C_x < GFR: net tubular reabsorption of X
• C_x > GFR: net tubular secretion of X
• C_x = GFR: no net secretion or reabsorption

• Calculated by:
• -inulin clearance
• -inulin is freely filtered and neither reabsorbed nor secreted

GFR = C_inulin (UV/P)

• Also calculated by Starling's Law:
• =Kf[(P_GC-P_BS) - (π_GC-π_BS)]
• *π_BS usually equals zero

Normal GFR = 100 mL/min

• Creatinine Clearance and GFR:
• -an approximate measure of GFR
• -slightly overestimates GFR b/c creatinine is moderately secreted by the renal tubules

Incremental reductions in GFR define the stages of CKD

• -can be estimated using PAH clearance
• -PAH is both filtered and actively secreted in the PT (all PAH entering the kidney is excreted)

ERPF = C_PAH

RBF = RPF/(1- Hct)

ERPF underestimates true RPF by ~ 10%

• Filtration Fraction (FF) = GFR/RPF
• -Normal FF = 2-%

Filtered Load = GFR x plasma concentration

• Things that dilate afferent arteriole:
• -PGs (inhibited by NSAIDs)
• -↑RPF, ↑GFR → FF remains constant

• Things that constrict efferent arteriole:
• -AngII (inhibited by ACEIs)
• -↓RPF, ↑GFR → FF increases

Filtered Load = GFR x P_x

Excretion Rate = V x U_x

Reabsorption = filtered - excreted

Secretion = excreted - filtered

-normal plasma levels of glucose are completely reabsorbed in the proximal tubule by Na⁺/glucose cotransporter

-plasma glucose ~ 160 mg/dL → glucosuria

-Tm = all transporters are fully saturated, 350 mg/dL

Glucosuria: important clinical clue to DM

Normal pregnancy reduce reabsorption of glucose and amino acids in the PT → glucosuria and aminoaciduria

-Sodium-dependent transporters in PT reabsorb AAs

*Hartnup's Disease: deficiency of neutral AA (tryptophan) transporter → pellagra (4D's: diarrhea, dermatitis, dementia, death)

• -contains brush border
• -isotonic reabsorption
• -generates and secretes ammonia (acts as a buffer for secreted H⁺)

• Reabsorbs all:
• -glucose
• -AAs

• Reabsorbs Most:
• -bicarb
• -Na⁺
• -Cl^-
• -phosphate
• -water

• Na+ Reabsorption
• -Na+/solute cotransport (glucose, AAs)
• -NHE
• -65-80% of Na+ reabsorbed

• Bicarbonate Reabsorption:
• -bicarb combines with H+ (secreted by NHE) in tubular lumen → CO2 (needs CA)
• -CO2 diffuses into tubular epithelial cells
• -not direct reabsorption

-85-90% of bicarb reabsorbed

• Hormonal Regulation:
• 1. PTH
• -inhibits Na/Phosphate cotransport → phosphate excretion
• 2. AngII
• -stimulates NHE → increased Na, H₂O and HCO₃ absorption
• -permits contraction alkalosis

• Pharmacology:
• -Carbonic Anhydrase Inhibitors

• Functions:
• -passively reabsorbs water via medullary hypertonicity
• -concentrating segment
• -makes urine hypertonic

• Physiology:
• -permeable to water (AQP1)
• -impermeable to NaCl

• Functions:
• -actively reabsorbs Na⁺(10-20%), K⁺ and Cl^- (NKCC2 transporter)
• -K⁺ backleak by ROMK channel (+ lumen)
• -indirectly induces paracellular reabsorption of Mg²⁺ and Ca²⁺ through (+) lumen potential

• Physiology:
• -impermeable to water
• -makes urine less concentrated

• Pharmacology:
• -Loop diuretics block NKCC2

• Functions:
• -early DCT actively absorbs Na⁺ (5-10%), Cl^- (NCC Transporter)
• -makes urine hypotonic

• Hormonal Regulation:
• 1. PTH: increases Na⁺/Ca²⁺ exchanger activity (sets up a gradient for Ca²⁺ reabsorption)

• Pharmacology:
• -Thiazide diuretics block NCC

• Functions:
• 1. Principal Cells
• -ENaC: Na+ reabsorption (3-5%)
• -ROMK: passive secretion of K+
• 2. Intercalated Cells
•      -Type A: secrete H+
•      -Type B: secrete HCO3- for Cl- (pendrin)

• **Na+ reabsorption in exchange for secreting K+ and H+ (lumen potential) (regulated by aldosterone)
• **water reabsorption regulated by ADH

• Hormonal Regulation:
• 1. Aldosterone: acts on mineralocorticoid receptor → insertion of ENac on luminal side

2. ADH: acts at V2 receptor → insertion of aquaporin on luminal side

• Pharmacology:
• 1. K+ Sparing Diuretics (inhibit ENaC)
• 2. Aldosterone Antagonists

• TF/P Ratio:
• -tubular fluid to plasma ratio

• TF/P > 1:
• -solute reabsorbed less quickly than water
• -Urea
• -Cl^-

• TF/P = 1:
• -solute and water reabsorbed at the same time
• -Na⁺
• -K⁺

• TF/P < 1:
• -solute is reabsorbed more quickly than water
• -Phosphate
• -HCO3^-
• -Amino Acids
• -Glucose

• Cl^- Reabsorption:
• -occurs at a slower rate than Na⁺ in the proximal 1/3 of the PT and then matches the rate of Na⁺ reabsorption more distally (thus its relative concentration increases before it plateaus)

• Angiotensinogen:
• -produced by liver

• Renin:
• -produced by JG cells
• -converts angiotensinogen to angiotensin I
• -release stimulated by: ↓BP, ↓Na⁺ delivery to MD cells, ↑ sympathetic tone (β1 receptors)

• ACE:
• -expressed on surface of renal and pulmonary epithelium
• -converts Angiotensin I to Angiotensin II
• *also breaks down bradykinin
• 
  

• 1. Vasoconstriction (AT1 receptors on SM) → HTN
• 2. Vasoconstriction of efferent > afferent arteriole (↑FF to preserve renal function in low volume states)
• 3. Aldosterone secretion from adrenal gland (Na^₊ and H₂O retention)
• 4. ADH secretion from posterior pituitary (H₂O reabsorption)
• 5. ↑ PT Na⁺/H⁺ activity (Na⁺, HCO3^-, H₂O reabsorption → can permit contraction alkalosis)
• 6. Stimulates hypothalamus → thirst

• Affects baroreceptor function:
• -limits reflex bradycardia, which normally accompanies pressor effects
• -helps maintain blood volume and blood pressure

• -released from atria in response to increased volume
• -may act as a check on RAAS
• -relaxes vascular smooth muscle via cGMP
• -causes ↑GFR, ↓renin

• -released from posterior pituitary
• -primarily regulates osmolarity but also responds to low blood volume (protect volume over tonicity)

• Functions:
• -increases aquaporin insertion in principal cells of collecting duct → H₂O reabsorption

-released from adrenal gland in response to ATII

• Functions:
• -↑ENaC and Na⁺/K⁺ ATPase insertion in principal cells (Na⁺ and water reabsorption)
• -upregulates principal cell ROMK channels and intercalated cell H⁺ channels (enhances K⁺ and H⁺ excretion)

• -primarily regulates blood volume
• -in low volume states both ADH and aldo protect blood volume

• Consists of:
• -JG cells (modified smooth muscle of afferent arteriole)
• -Macula densa (NaCl sensor, part of DCT)

• JG cells secrete renin in response to:
• -↓ renal BP
• -↓ NaCl delivery to distal tubule
• -↑ sympathetic tone

• β-Blockers:
• -decrease BP by inhibiting renin release from JG cells

• 1. Erythropoietin
• -released by interstitial cells in the peritubular capillary bed in response to hypoxia

• 2. 1,25-(OH)₂ Vitamin D
• -PT cells convert 25-OH vitamin D to active form
• -PTH inhibits 1α-hydroxylase

• 3. Renin
• -secreted by JG cells in response to ↓ renal arterial pressure and ↑ renal sympathetic discharge (β1 effect)

• 4. Prostaglandins
• -paracrine secretion vasodilates the afferent arteriole to ↑GFR
• **NSAIDs can cause acute renal failure by inhibiting PG synthesis, which keep the afferent arterioles vasodilated to maintain GFR

• 
• 1. ANP
• -acts on PT
• -secreted in response to increase atrial pressure
• -causes increase in GFR and Na⁺ filtration with no compensatory Na⁺ reabsorption in distal nephron
• -NET EFFECT: Na⁺ loss and volume loss

• 2. PTH
• -acts on PT, DCT
• -secreted in response to: ↓ plasma Ca²⁺, ↑ plasma PO₄ or ↓ plasma vitamin D

-Causes: ↑ Ca²⁺ reabsorption (DCT), ↓ PO₄ reabsorption (PT), ↑ vitD production, also ↑ Ca²⁺ and PO₄ absorption from gut

• 3. ATII
• -secreted in response to: decreased BP
• -Causes: efferent arteriole constriction leading to ↑GFR and ↑FF with compensatory Na+ reabsorption in proximal and distal nephron
• -NET EFFECT: preservation of renal function in low volume state with simultaneous Na+ reabsorption to decrease additional volume loss

• 4. Aldosterone
• -acts at CD
• -secreted in response to: decreased blood volume (by ATII) and increased plasma K⁺
• -Causes: increased Na⁺ reabsorption, increased K⁺ secretion, increased H⁺ secretion

• 5. ADH
• -acts at CD
• -secreted in response to: increased plasma osmolarity and decreased blood volume
• -Causes: increased number of aquaporins and increases H_²O reabsorption

• "Patient with hyperkalemia? DO Insulin LAβ work"
• Digitalis
• HyperOsmolarity
• Insulin deficiency
• Lysis of cells
• Acidosis
• β-Antagonist

"Insulin shifts K⁺ into cells"

• Hypo-osmolarity
• Insulin (↑ Na⁺/K⁺ ATPase)
• Alkalosis
• β-Agonist

• Low serum concentration
• -nausea
• -malaise
• -stupor
• -coma

• High serum concentration:
• -irritability
• -stupor
• -coma

• Low serum concentration:
• -U waves on EKG
• -flattened T waves
• -arrhythmias
• -muscle weakness

• High serum concentration:
• -wide QRS
• -peaked T waves
• -arrhythmias
• -muscle weakness

• Low serum concentration:
• -tetany
• -seizures

• High serum concentration:
• -stones (renal)
• -bones (pain)
• -groans (abdominal pain)
• -psychiatric overtones (anxiety, altered mental status)
• -not necessarily calciuria

• Low serum concentration:
• -tetany
• -arrhythmias

• High serum concentration:
• -decrease DTRs
• -lethargy
• -bradycardia
• -hypotension
• -cardiac arrest
• -hypocalcemia

• Low serum concentration:
• -bone loss
• -osteomalacia

• High serum concentration:
• -renal stones
• -metastatic calcifications
• -hypocalcemia