Renal Epithelial Cell (cells exposed to interstitium and urinary space) “luminal” membrane (urinary space) specific transport proteins(reabsorption/ secretion area), villi, microvilli (surface area).Absent Na-K ATPase, Tight junctions Abundant Na-K ATPase Exposed to interstitium Apical membrane: Basolateral membrane

Proximal Nephron Proximal convoluted tubule and Proximal straight tubule The Loop of Henle: thin descending limb, thin ascending limb, medullary thick ascending limb, cortical thick ascending limb The proximal nephron is considered to end at the macula densa segment which occurs at the end of the cortical thick ascending limb

Proximal Tubule Proximal convoluted tubule (cortex) Proximal straight tubule (descends to the corticomedullary junction)

Loop of Henle Thin descending limb Thin ascending limb Thick ascending limb (medullary and cortical portions) Note: cortical nephrons are “short loop” juxtomedullary nephrons are “long loop” nephrons

Distal Nephron Distal convoluted tubule Connecting segment Cortical collecting duct Medullary collecting duct (outer and inner portions)

Proximal Tubule Functions Reabsorption occurs in an isotonic manner (isotonic fluid enters and isotonic fluid exits, but the composition is altered) Bulk reabsorption: ~50-55%NaCl and H20 ~90% NaHCO3 Organic nutrients: 100% glucose, amino acids Organic anion and cation secretory pathways PO4 and urate reabsorption Major site of NH3 production (via glutamine metabolism) Major site of glomerulotubular balance

Definitions Filtered Load: The amount of a substance, X, that is deposited in Bowman’s space by filtration: (GFR) x (Px) Transport Maximum The maximal amount of substance X that can be reabsorbed or secreted: Tmx

Glomerulotubular balance Normal matching of proximal tubule reabsorptive capacity to the filtering capacity of its glomerulus (euvolemic conditions) Alternative meaning: The phenomenon that the fraction of filtered Na+ that is reabsorbed by the proximal tubule is constant Incr GFR, incr FL, but 50-55% reabsorbed Decr GFR, decr FL, but 50-55% reabsorbed

Thin descending limb H20 permeable (aquaporins- H20 channels) Minimal NaCl permeability Thin ascending limb H20 impermeable (absent H20 channels) NaCl permeable (NaCl reabsorption, passive)

Thick Ascending Limb Active NaCl transport ~ 20-25% NaCl reabsorption Oxygen requiring H20 impermeable (absent H20 channels) Responsible for producing hypertonic medulla Essential for dilution and concentration of urine Major site of calcium and magnesium reabsorption Major site of NH4+ reabsorption (medullary trapping)

Loop of Henle Thin ascending limb Thick ascending limb Combined: ~ 35% of total NaCl reabsorption

Tubuloglomerular feedback (TGF) Autoregulation of single nephron GFR by the rate of fluid delivery to the macula densa Example: Decreased renal perfusion pressure, decreased GFR, decreased delivery to macula densa, local response (adenosine, NO), afferent arteriolar dilatation, increased glomerular capillary pressure, increased GFR, return to normal delivery to macula densa segment

Tubuloglomerular feedback Example: increased renal perfusion pressure (which increases GFR) Afferent arteriole constricts and GFR falls in the presence of increased renal perfusion pressure TGF contributes to maintaining distal delivery of tubular fluid at a relatively constant rate.

Juxtaglomerular apparatus TGF (macula densa) Renal renin secretion (afferent arteriole) (decreased renal perfusion pressure results in enhanced renin secretion and activation of TGF) Both contribute to maintaining GFR and to maintaining a normal distal tubular flow rate. Proximal nephrons segments: Bulk reabsorption. Distal nephron segments: Fine tuning of final urine composition

Distal Convoluted Tubule 5-8% of NaCl reabsorption H20 and urea impermeable Major site of calcium reabsorption (stimulated by PTH) Important for maximal urinary diluting ability (i.e., for maximal free H20 excretion)

Collecting Duct Cortical and medullary segments 2-3 % NaCl reabsorption Built for fine tuning of solute and H20 handling Not built for bulk reabsorption

Collecting duct Principal cells (cortical collecting duct and inner medullary collecting duct) Sodium chloride and water reabsorption, potassium secretion Intercalated cells (cortical collecting duct and outer medullary collecting duct) acid-base maintenance Alpha intercalated cells -H+ secretion (H+ATPase) Beta intercalated cells- HCO3 secretion (Cl-HCO3 exchanger

Final Urinary Contents Are Greatly Influenced by Collecting Duct reabsorption And/or Secretion H20 (Uosm 50-1200 mOsm/kg) Na+ and CL- (Una < 10 mEq/L to >100 mEq/L) NH4+ (renal acidification, urine pH – 4.5 – 8.0) K+ (secretion, especially cortical collecting duct) Urea (influenced by urine flow rate and AVP)

Solute and water excretion Solute excretion obligates H20 excretion “diuretics” increase solute excretion by inhibiting tubular NaCl reabsorption Currently used “diuretics” are natriuretic Osmotic diuretics (hyperglycemia, mannitol, excessive urea excretion) See syllabus re diuretics

Multiple mechanisms exist within the proximal nephron which function to avoid excessive delivery of filtrate to the distal nephron. These mechanism include: glomerulotubular feedback tubuloglomerular feedback autoregulation of arteriolar resistance at the afferent and efferent arterioles ability to shift cortical blood flow from superficial cortical nephrons to juxtamedullary nephrons which have a greater capacity for salt and water reabsorption

Effect of Angiotensin II Vasoconstriction (especially efferent arteriole) Stimulates aldosterone secretion Enhances proximal tubule Na+ reabsorption Augments sympathetic stimulation May augment vasopressin secretion Contraction of mesangial cells which decreases glomerular capillary surface area and reduces permeability; thus,decreasing single nephron GFR

Slides to augment small groupsessions The following slides are to supplement the small group sessions, Problems 1 and 2 and the sodium chloride and water problems (3-8)

Creatinine Serum creatinine is a function of GFR, but also influenced by skeletal muscle mass Increased age, female gender, malnutriton, cirrhosis lead to less muscle mass 20 yr old male, creatinine 1.0mg/dl has higher GFR than 60yr old female with creatinine of 0.9mg/dl

Neuro-endocrine responses to volume changes ↓ ECFV ↑ ECFV Renin ↑ ↓ Angiotensin II ↑ ↓ Aldosterone ↑ ↓ Plasma ANP ↓ ↑ SANS ↑ ↓ Non-osmotic AVP ↑ ↓

Glomerular Responses to Volume Changes ↓ ECFV ↑ ECFV RPF ↓ ↑ GFR (Creat. Clearance) unchanged unchanged FF ↑ ↓ Aff. Arteriole Vasodilated unchanged or vasoconstricted Eff.Arteriole Vasoconstricted Vasodilated Glomerular capillary Unchanged Unchanged pressure

Tubular Response to Volume Changes ↓ ECFV ↑ ECFV Peritubular capillary ↓ ↑ hydrostatic pressure Peritubular capillary ↑ ↓ oncotic pressure Proximal reabsorption ↑ ↓ Na excretion ↓ ↑ H20 excretion ↓ ↑ Urea excretion ↓ ↑ or unchanged Urine flow rate ↓ ↑ FENA ↓ ↑ Urine osmolality ↑ approaches plasma osmolality (~300 mOsm/kg H20)