Renal Physiology

Anatomy 

• Nephron = renal tubule + glomerulus, 45- 65mm 
  • 1.3 million units per kidney 
  • Tuft of capillaries invaginate Bowman’s capsule, supplied by afferent and efferent vessels  
  • Cellular layers: BLOOD in capillary lumen – endothelium (pores) – basal lamina + mesangial cells – podocytes (pseudopodia = filtration slits) – FILTRATE in Bowman’s space – capsule endothelium

• Glomerular membrane permits free passage of neutral substances up to 4nm diameter, area of ~0.8m² 

• Substance size/ charge affect passage.  

Nephrons comprised of:  

Proximal convoluted tubule = 15mm long, walls are made up of single layer of cells which interdigitate and are united by apical tight junctions. Have brush border (microvilli) on luminal edges of cells. 

Loop of Henle  

• Thin portion = Descending and proximal ascending limb, made of permeable cells  
• Thick portion = Remaining proximal limb contains mitochondria. Reaches glomerulus of nephron and have specialised cells at the end called macula densa which lie close to afferent/efferent arterioles forming juxtaglomerular apparatus 

Cortical nephrons have short loops of Henle and juxtamedullary nephrons have long loops of Henle.  

Distal convoluted tubule = 5mm long, starts at macula densa  

Collecting ducts = 20mm long, 2 types of cells: 

• Principal ‘P’ cells = Na+ reabs and ADH stimulated H2O reabsorption 
• Intercalated ‘I’ cells =  acid secretion and HCO3- transport, pass through renal cortex and medulla to empty into renal pelvis 

• Blood vessels = interlobar a – arcuate a – interlobular a – afferent arteriole – glomerulus – efferent arteriole – peritubular capillary bed – interlobular v – arcuate vein 
  • Arcuate vein also forms vasa recta = dip into medullary pyramids with loop of Henle  

• Vasa recta: 
  • Descending has non-fenestrated endothelium containing urea transporter 
  • Ascending has fenestrated endothelium for conserving solute  

• Lymphatics = drains via thoracic duct into venous circulation into thorax  
• Capsule = limits swelling if kidney becomes oedematous, tissue pressure (renal interstitial pressure) rises ->  decreased glomerular filtration rate -> enhances anuria in ARF  
• Innervation of renal vessels: 
  • Preganglionic sympathetic nerves from lower thoracic/upper lumbar segments of spinal cord – sympathetic ganglion chain + superior mesenteric ganglion – postganglionic sympathetic efferent/ afferent fibers to arterioles + PCT/DCT + juxtaglomerular apparatus 
  • Nociceptive afferents mediate pain + renorenal reflex (increase ureteral pressure in one kidney = decrease in efferent nerve activity to contralateral kidney, permits increase in excretion of Na and H2O) 

Renal Circulation 

• Blood flow ~25% CO per minute (1.2-1.3L per minute) 
• Measuring effective renal plasma flow using p-aminohippuric acid (PAH): 
  • P-aminohippuric acid is filtered by the glomeruli and secreted by tubular cells, so that its extraction ratio is high (~90% is removed in single circulation through kidney) 
  • Concentration PAH in urine (mg/mL)  x urine flow (mL/min) / concentration PAH in plasma (mg/mL) = clearance of PAH (mL/min) 

• Pressure in renal vessels at MAP 100mmHg = 45mmHg in glomerular capillaries, 8mmHg in peritubular capillaries and 4mmHg in renal vein  
• Regulation of blood flow via norepinephrine (VC), dopamine (renal VD, natriuresis), angiotensin II (VC, efferent> afferent), PG (increase flow in medulla), ACh (VD) 
•  Functions of renal nerves:  
  • NE ->  beta 1 adrenergic R juxtaglomerular cells ->  renin secretion 
  • NE ->  renal tubular cells ->  increases Na reabsorption 
  • NE ->  vasoconstriction, decreased GFR and blood flow 

• Autoregulation of renal blood flow = kidney is perfused at moderate pressures thus renal vascular resistance varies with pressure so that blood flow remains constant  
• Regional blood flow and oxygen consumption: 
  • Renal cortex – high blood flow and lower oxygen consumption 
  • Medulla – low blood flow but higher oxygen consumption due to metabolic work

Glomerular filtration 

• Measuring GFR  
  • Could measure excretion and plasma level of a substance freely filtered by glomeruli and not reabsorbed by tubules, such as inulin  (polymer of fructose) 
    • GFR = U_x x V / P_x 
    • U_x is concentration of substance in urine, V is urine flow per unit time and P_x is arterial plasma concentration of X  

• Normal GFR = average sized man is 125mL/min with 99% or more of filtrate being reabsorbed  
• Control of GFR: 
  • Size of capillary bed  
    • Mesangial cells contract to decrease size 
    • Angiotensin II, vasopressin, NE, PDGF, TA2, PGF2, histamine, leukotrienes C4/D4 ->  contraction 
    • ANP, DA, PGE2, cAMP ->  relaxation  
  • Permeability of capillaries 
    • Molecules diameter <4nm or cations freely filtered  
    • Proteins in capillary walls are negatively charged = repel negatively charged molecules in blood (albumin) 
    • Nephritis – negative charges in glomerular wall dissipated, thus albuminuria occurs  
  • Hydrostatic and osmotic pressure gradients  
    • Higher pressure in afferent – glomerulus – higher resistance in efferent 
    • Capillary hydrostatic pressure opposed by Bowman’s capsule hydrostatic pressure 
    • Net filtration pressure is 15mmHg at afferent end of glomerular capillaries -> 0mmg at efferent end – fluid leaves plasma and oncotic pressure rises  
    • Exchange across glomerular capillaries is flow limited  

• Factors affecting GFR – 
  • Renal blood flow (reduction in blood flow decreases GFR) 
  • Glomerular capillary hydrostatic pressure  
    • Systemic BP (reduction in BP decreases GFR) 
    • Afferent arteriole constriction (decreases GFR) 
    • Efferent arteriole constriction (increases GFR) 
  • Bowman’s capsule hydrostatic pressure 
    • Ureteral obstruction (decreases GFR) 
    • Oedema of kidney in tight renal capsule (decreases GFR) 
  • Changes in concentration of plasma proteins  
    • Dehydration, hypoproteinaemia (decreases GFR) 
  • Changes in Kf (glomerular ultrafiltration coefficient) 
    • Glomerular capillary permeability (increase GFR) 
    • Effective filtration surface area 
  • GFR tends to be maintained when constriction efferent > afferent  

• Filtration fraction = ratio of GFR to renal plasma flow (normal = 0.16-0.2) 

Tubular Function and Regulation 

• GFR x P_x + T_x = U_xV 
  • P_x is plasma conc, T_x is net amount transferred by tubules, U_xV is amount filtered  
  • Clearance = GFR x P_x 
  • Clearance of substance = GFR, if no net tubular secretion or reabs (Tx = 0) 
  • Clearance > GFR = tubular secretion (Tx = positive) 
  • Clearance < GFR = tubular reabsorption (Tx = negative) 

• Movement via ion channels, exchangers, co-transports and pumps  
  • Transport maximum (Tm), can become saturated  
• Paracellular pathway “leaky tubular epithelium” for water/ electrolytes  
• ADPKD = abnormality in polycystin 1 (PKD-1 = Ca2+ R) and PKD-2  
• Na+, K+, Cl-, HCO- and glucose all ~100% reabsorbed  
• Urea/ creatinine variable amount reabsorbed  

NA REABSORPTION  

• Transport coupled with H+/ glucose/ amino acid/ lactate and Cl-  
• Actively reabsorbed via co-transport or exchange in all parts of tubule, except thin loop of Henle  
• Tubular cells connected by tight junctions – Na transported into lateral intercellular spaces (extension of interstitium) via Na/K ATPase  
• 60% filtered Na reabsorbed in PCT via Na+/H+ exchange ->  30% in thick ascending loop Henle Na+/Cl-/K+ co-transporter ->  70% in DCT via Na+/Cl- co-transporter ->  3% via ENaC channels in collecting ducts (regulated by aldosterone) 

• Regulation depends on GFR (above) and Na reabsorption: 
  • Aldosterone – increases ENaCs = increase reabs of Na+ plus secretion of K+/H+. Enhanced by reducing dietary salt. 
  • PGE2, ANP and natriuretic hormones – inhibit Na+/K+ ATPase + inhibits ENaCs = increased excretion Na+. PGE2 enhanced by endothelin and IL-1. 
  • Angiotensin II – increases reabs Na+ and HCO3- by action on PCT  
• Escape phenomenon = prolonged exposure to high levels of mineralocorticoid in normal individuals does not cause oedema as kidneys ‘escape’ from effect of hormones (absent in nephrosis, cirrhosis, heart failure)  

GLUCOSE REABSORPTION  

• Glucose/ amino acids/ bicarb reabsorbed with Na+ in early PCT via secondary active transport  
• All essentially reabsorbed  
• Renal threshold = plasma level at which glucose appears in urine, 180mg/dL (10 mmol/L) venous glucose  
• Glucose/ Na+ co-transporter SGLT-2 (same as intestine) ->  glucose into cell, transported by GLUT-2 into interstitium  

• Inhibited by phlorhizin (competes with glucose for SGLT2) 

OTHER SECONDARY ACTIVE TRANSPORT  

• Amino acids – early PCT via co transporter with Na+ then passive/ facilitated diffusion to interstitium  
• Cl- reabsorbed with Na+ and K+ in thick ascending loop  

Tubuloglomerular feedback  

• Rate of flow in ascending loop and early DCT increased ->  GFR will be decreased  
• Maintains consistency of load delivery to distal tubule  
• Sensor is macula densa via Na: Na/Cl enter via Na/K/2CL co transporter in apical membrane ->  increased Na/K ATPase activity ->  increased ATP hydrolysis ->  increased adenosine, secreted from basal membrane ->  adenosine A1 R on macular densa cells ->  release Ca2+ to vascular smooth muscle of arterioles ->  vasoconstriction ->  decrease in GFR. 

Glomerulotubular balance 

• Increase in GFR causes increase in solute/water reabsorption in PCT (mainly Na+) 
• Constant percentage of solute reabsorbed  
• Change in Na+ reabsorption occurs seconds after GFR change 

WATER EXCRETION  

• 180L water filtered, only 1L excreted in urine ->  high water reabsorption ability 
• Same amount of solute can be excreted in urine volume 500mL vs 2L ->  concentration ability  
• Reabsorbed via aquaporins: 
  • PCT – H2O moves passively along osmotic gradient set up by active solutes (isotonicity maintained) via aquaporin I, 60-70% reabs 
  • Loop of Henle: 15% reabs 
    • Descending thin loop – permeable to H2O ->  water OUT, filtrate hypertonic 
    • Ascending thin loop – permeable to Na/Cl 
    • Ascending thick loop – impermeable to H2O, permeable to Na/K/Cl ->  filtrate dilute  
  • DCT – relatively impermeable to water (5% reabs), continues removing solutes 
  • CD – changes depend on antidiuretic hormone from posterior pituitary ->  increases permeability to water via aquaporin II (stored in vesicles of principal cells). Filtrate is hypotonic at this stage. 2 segments = 
    • VASOPRESSIN PRESENT  
      • Cortical – 10% H2O reabsorbed  
      • Medullary (hypertonic interstitium) – 4.7% H2O reabsorbed  
      • Urine osmolality high (up to 14000 mosm/kg) 
    • VASOPRESSIN ABSENT  
      • Impermeable to water, fluid remains hypotonic  
      • Urine osmolality low (30 mosm/kg)  
      • Diabetes insipidus = vasopressin deficiency or failure to respond (gene for V2 R on X Chromosome mutated or gene for aquaporin II mutated) 
• Na+ actively transported from cells to interstitium via Na/K ATPase or Na/K/2Cl co-transporter. K+ diffuses back into lumen via ROMK channel, Cl- into interstitium via ClC-Kb channels. 
• Bartter’s Syndrome = defective transport in thick ascending loop = chronic Na+ loss in urine ->  hypovolaemia ->  RAAS without hypertension ->  hyperkalaemia, alkalosis. Loss of function mutations of Na/K/Cl co-transporter, ROMK K+ channel or ClC-Kb Cl- barrtin channel. If both ClC-Kb and Ka are mutated ->  deafness, as Cl- channel responsible for high K+ concentration inner ear, essential for normal hearing

COUNTERCURRENT MECHANISM = concentrating mechanism depends on maintaining gradient of increasing osmolality along medullary pyramids ->  created by loops of Henle (countercurrent multipliers) and vasa recta (countercurrent exchangers)  

• Inflow runs parallel to/ counter to/ close in proximity to outflow for some distance  
• Isotonic fluid keeps running into TDL, hypotonic in TAL 
• Loops: 
  • TDL – water moves OUT, hypertonic filtrate ->  TAL – solutes move OUT, hypotonic filtrate 
  • MI – deeper into medulla, becomes more hypertonic (gradient of osmolality) 
  • Longer loops = gradient spread over greater distance = osmolality at tip is greater

• Vasa recta: 
  • Solutes diffuse OUT of vessels towards cortex – and IN to vessels towards medulla 
  • Water diffuses OUT of descending vessels and IN to ascending vessels  
  • Hypertonicity maintained in MI 

• Role of urea = contributes to establishment of osmotic gradient in pyramids and ability to concentrate urine in CD  
  • Transport mediated by urea transporters (UT-A) via facilitated diffusion 
• Water diuresis ->  act of drinking produces small decrease in ADH before absorption, inhibition of ADH produced by drop in plasma osmolality  
• Water intoxication ->  intake higher than maximal urine flow of water diuresis (16mL/min) causes swelling of cells in brain, coma/convulsions. Can occur if water intake is not reduced following vasopressin (exogenous administration or endogenous) 

• OSMOTIC DIURESIS ->  presence of large quantities of un-reabsorbed solutes in tubules causes increase in urine volume “hold water in tubules” 
  • Concentration against which Na+ pumped out of PCT is limited 
  • Normally, movement of water prevents gradient from developing 
  • BUT if presence of unreabsorbable solutes in filtrate ->  decreased water reabsorption ->    Na+ concentration in filtrate falls ->  limiting concentration gradient reached ->  Na+ and H2O remain in PCT  
  • Loop of Henle presented with: increased volume of isotonic fluid with decreased Na+ concentration (but increased total amount Na+) ->  medullary hypertonicity decreased (due to decreased reabs of Na/K/Cl in ascending loop as conc for Na+ reached) ->  decreased reabsorption of Na+ and water 
  • Produced by mannitol, glucose, large amounts NaCl, urea 
  • As solute load increases, concentration of urine approaches that of plasma inspite of normal ADH secretion – large fraction of excreted urine is isotonic proximal tubular fluid 
  • Increased flow through countercurrent mechanism = decreased osmotic gradient in pyramids ->  urine more dilute  
• Difference between WATER and OSMOTIC diuresis =  
  • Water -amount of water reabsorbed in PCT is normal ->  max urine flow 16mL/min 
  • Osmotic- decreased water reabsorbed in PCT ->  increased urine flow  

• Relation of urine concentration to eGFR – decreased eGFR ->  decreased flow of fluid through countercurrent mechanism ->  increased osmotic gradient in pyramids ->  urine more concentrated  

• Free water clearance, CH2O = gain or loss of water by excretion of concentrated or dilute urine (difference between urine volume and clearance of osmoles) = negative if urine is hypertonic and positive if urine is hypotonic  

ACIDIFICATION OF URINE AND BICARBONATE EXCRETION  

• Cells of PCT, DCT and collecting ducts can all secrete H+ 
• Secondary active transport of Na+ out of cells via Na+/K+ ATPase = decreased intracellular Na+, allowing Na+ to enter cell coupled with H+ OUT  
• H+ comes from CO2 + H2O ->  H2CO3 via carbonic anhydrase (only in PCT) 

• Drugs which inhibit CA, depress secretion of acid  
• Maximal H+ gradient against which transport mechanisms can secrete H+ ~ urine pH 4.5 (N is 4.5-8.0), reached in collecting ducts) 

• Three buffers exist to remove H+ from urine, permitting more acid secretion: 
  • H⁺ + HCO3- ->  H2CO3 ->  CO2 + H2O 
    • pK 6.1 
    • Higher conc of HCO3- in PCT  
    • CO2 reabs into tubular cell to add to H2CO3 pool 
  • H⁺ + HPO₄^2- ->  H2PO4- (dibasic phosphate ->  monobasic phosphate) 
    • pK 6.8 
    • Higher conc in DCT and CD (some in PCT) 
  • H⁺ + NH3 ->  NH4+ 
    • pK 9.0 
    • Reactions in tubular cells produce NH4+ and HCO3-  
      • Glutamine ->  glutamate + NH4+ via glutaminase 
      • Glutamate ->  a ketoglutarate + NH4+ via glutamic dehydrogenase 
    • NH4+ in equilibrium with NH3+H+ in cells – ratio of NH3+ : NH4+ is 1: 100 ->  however NH3+ lipid soluble and diffuses across cell membranes to tubular urine ->  combines with H+ to form NH4+    
    • ‘Nonionic diffusion’ – process by which NH3+ secreted to urine and changed to NH4+, thus maintaining gradient for NH3+  
    • In chronic acidosis, more NH3+ enters urine thus increased amount of NH4+ excreted = enhanced H+ excretion  

• Titratable acidity = measured by determining amount of alkali to restore urine pH to 7.4 
  • Measures only fraction of acid secreted, as acid converted to H2O + CO2 not counted 
  • Ammonia system contributes little due to pK 9.0 
• pH change along nephron = more acidic in PCT however most of the secreted H+ has little effect (buffered by HCO3-) ->  DCT has less capacity to secrete H+ but greater effect on pH (reduced buffer capacity) 
• Factors affecting acid secretion: 
  • Intracellular PCO2 – if high (respiratory acidosis), more H2CO3 available to buffer H+ ->  enhanced secretion  
  • K+ – depletion enhances acid secretion, loss of K+ causes intracellular acidosis  
  • CA level – inhibition reduces acid secretion as formation H2CO3 decreased  
  • Adrenocortical hormone changes – aldosterone enhance tubular reabs of Na+ thus increasing secretion of H+ and K+  
• Bicarb excretion: 
  • HCO3- reabs decreased when ECF expanded  
  • Plasma HCO3- low = filtered HCO3- reabs  
    • Falls below 26, more H+ available to combine with other buffers in urine ->  acidic urine and higher NH4+ content  
  • Plasma HCO3- high = HCO3- in urine 
• K excretion:  
  • K+ actively reabs in PCT then secreted in DCT/ CD 
  • Rate of secretion is proportional torate of tubular fluid flow, rapid flow = less opportunity for tubular K+ concentration to rise to a value that stops secretion  
  • DCT/CD: 
    • Na+ reabs/ K secreted via electrical coupling ->  Na+ INTO cell lowers potential different ->  favours K+ OUT cell  
    • K+ excretion decreased when reduced Na+ in DCT or H+ secretion increased 

DIURETICS  

EFFECTS OF DISORDERED RENAL FUNCTION 

1. Proteinuria “albuminuria” 
   • Loss of negative charge in capillary walls ->  bigger membrane pores ->  increased permeability ->  protein filtered  

2. Loss of concentrating/diluting ability (polyuria, nocturia) 
   • Advanced renal disease ->  disruption of countercurrent mechanism OR loss of functional nephrons ->  osmolality of urine fixed = plasma  
3. Uraemia = breakdown products of protein metabolism accumulate in blood 
   • Can be removed via dialysis  
   • Feature of CRF (as well as anaemia, 2 hyperparathyroidism)  
4. Acidosis = failure to excrete acid products  
   • CRF – urine is maximally acidified, tubular cells cannot make more NH4+  
   • Renal tubular acidosis – impaired ability to make urine acidic   
5. Abnormal Na+ metabolism: Na retention and oedema in renal disease  
   • 3 causes: 
     • Amount Na+ filtered reduced (GN) 
     • Increase aldosterone – Na+ retention (nephrotic syndrome) 
       • Plasma protein low ->  fluid moves into interstitium ->  plasma volume falls ->  RAAS ->  aldosterone  
     • Heart failure – renal disease predisposes to heart failure due to HTN 

THE BLADDER 

• Walls of ureters have smooth muscle – regular peristaltic contractions move urine from renal pelvis to bladder  
  • Micturition 
    • Spinal reflex facilitated and inhibited by higher brain centres 
    • Caused by detrusor muscle contraction + relaxation of perineal/ external urethral sphincter   
    • Ability to keep external urethral sphincter contracted = adults can consciously delay urination  
    • Female urethra empties via gravity, male urethra via contraction of bulbocavernosus muscle  
    • Urge to void at ~150mL urine ->  marked at 400mL  
    • Intravesicular pressure only rises significantly at volume of 400mL  
  • Reflex control  
    • Stretch R in bladder wall ->  reflex contraction ->  adjusted by facilitatory (pontine)/ inhibitory (midbrain) centres  
    • Pelvic nerves (S2-S4) = parasympathetic efferents + voiding reflex afferents  
    • Hypogastric nerves (L1-L3) = sympathetic nerves mediate contraction of bladder muscle that prevents semen entering bladder on ejaculation 
    • Pudendal nerves (S2-S4) = external sphincter  
• Abnormalities: interruption of nerve pathways = bladder contracts, insufficient to empty completely ->  residual urine  
• Tabes dorsalis = sacral dorsal roots cut ->  no bladder reflex contractions ->  distended and hypotonic 
• Denervation = tumours of cauda equina ->  afferent and efferent nerves destroyed ->  flaccid and distended bladder initially then small, hypertrophied due to muscle contractions 
• Spinal cord transection: 
  • Spinal shock ->  bladder flaccid and unresponsive ->  overfilled = overflow incontinence 
  • Recovery ->  voiding reflex returns however no input from higher centres = spastic neurogenic bladder if reflex is overactive  

Last Updated on September 24, 2021 by Andrew Crofton