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Renal physiology (Renal Solute Reabsorption (Clinical Correlations…

- - - - To prevent excessive electrolyte loss and water loss.
      - Glucose is 100% reabsorbed by proximal tubule.
      - 99% of water and salt are reabsorbed.
      - Creatinine is secreted by the proximal tubule and excreted > inulin.
  - - - Fractional Excretion Rate (FEx) is the % of filtered substance that is excreted in the urine , also the net results of tubular reabsorption and secretion. (reabsorption - secretion = excretion)
      - FEx is the ratio or urinary concentration of X (Ux) to the plasma concentration of X (Px) ÷ urinary/plasma ratio of a reference substance, that is neither secreted nor reabsorbed.
      - FEx = Ux/Px ÷ U creatinine/ P creatinine.
      - Fractional Reabsorption Rate (FRx)= proportion of the filtered x that is reabsorbed by the tubule.
      - FRx = 1 - FEx
  - - - Rate of reabsorption and secretion varies among renal segments.
      - Proximal convoluted tubule (PCT) reabsorb > 60% of filtered substances.
      - 2 pathways of tubule fluid transport;- (1) transcellular. (2) paracellular.
      - (1)Transcellular pathway =→ basolateral Na+/K+ATPase pump out Na+ actively →the interstitial fluid→ peritubular capillary.
      - Intracellular [Na+] ↓, create electrochemical gradient for Na+,promote Na+ reabsorption.
      - Glucose, amino acid enter the cell by carrier-mediated secondary active transport with Na+ on the apical membrane.→↑ intracellular concentration → move across basolateral membrane down its concentration gradient.
      - Na+ uptake facilitated by Na+ co-transport, and Na+ counter-tranport.
      - Apical plasma membrane have microvilli projection (brush border).
      - Basolateral plasma membrane have many extensive membrane infoldings ( micropedici-tiny feet).
      - The brush border and micropedici help ↑ surface area for transport.
      - (2) Paracellular pathway =→ substance tranport across the zonula occludens (tight junction) between cells.
      - Mostly by passive diffusion, and solvent drag (entrained by water flow).
      - Substance enter the intercellular space, where it interact with the interstitial fluid, transport to the peritubular capillary.
      - Transcellular transport of Na+ out of the cell, makes the lumen become slightly -ve , favors the Cl- transport paracellularly through the tight junction.
      - Movement of water and solute from the interstitial fluid into bloodstream is driven by (1) Starling’s force (2) proximity of peritubular capillary.
      - ↑ peritubular plasma oncotic pressure and ↓ peritubular capillary hydrostatic pressure → favor fluid and solute uptake from the interstitium into bloodstream.
      - In Birds, renal portal veins anastomose with efferent glomerular arterioles supply mixture of portal venous and arterial blood to the reptilian-type nephrons.
      - Rate of renal portal supply controlled by smooth muscle valve.
      - Reabsorption of solutes ( favoring forces) ;= (1) passive diffusion, (2) solvent drag, (3) Primary active transport, (4) Carrier-mediated secondary active transport.
      - Active reabsorption of Na+ by the basolateral Na+/K+ ATPase pump drives the secretion of H+ through the Na+/H+ exchanger in the apical plasma membrane.
      - The secreted H+ and the filtered HCO3- form water and CO2 under influence of apical carbonic anhydrase.
      - The CO2 readily diffuse across the apical plasma membrane into the cell and combines with the intracellular water to form H+ and HCO3-,(catalysed by cytoplasmic carbonic anhydrase).
      - The H+ is secreted into the tubule fluid, and the HCO3- is transported to the blood side of the cell through Na+ co-tranporter/ Cl- counter-transporter.
      - The PCT reabsorbs 60-80 % of filtered HCO3-.
      - Cl- reabsorption through both paracellular and transcellular pathways.
      - As Glucose, amino acids, Na+, HCO3- and water reabsorbed with solutes, [Cl-] in tubule fluid ↑, form chemical gradient for Cl- towards the blood side.
      - In PCT, selective Na+ uptake > anions reabsorption → slightly +ve in blood side → create electrical gradient favoring anion reabsorption.
      - As Cl- move down its concentration gradient from tubule to blood side, it carries Na+ along by electrostatic attraction.
      - The Cl- movement also create the lumen become slightly +ve → favor passive transport of Na+ to blood side.
      - 90% of Ca2+ uptake is by paracellular pathway by solvent drag,
      - Paracellular K+ reabsorption thru K+ channel in apical and basolateral membrane.
      - PCT also reabsorb filtered peptides and low- molecular- weight protein.
      - Filtered proteins bind to the coated pits on the apical membrane, which invaginates to form endocytic vessicles.
      - The endocytic vessicles transport the protein to the endosomal-lysosomal system to be degraded to amino acids→ reabsorbed to the blood side.
      - Short chain peptides transported by PEPT1 and PEPT2 co-transporter in brush border.
      - Most dipeptide and tripeptide degraded by intracellular peptidase to amino acids.
  - - - Collecting duct contains ;- DCT cells, connecting segment cells, intercalated cells and principal cells.
      - Intercalated and principal cells are 2 main cell type in collecting duct(CD).
      - Intercalated cells- many intracytoplasmic vessicles and mitochondria.
      - Intercalated cells- reabsorb K+ from the apical in exchange for H+, which is similar to the parietal cell of stomach. H+ secretion out acidify the urine.
      - Principal cells - few intracytoplasmic vessicles and mitochondria, but many basolateral micropedici.
      - Principal cells - major cell type of CD, reabsorps NaCl with Na+,K+ ATPase pump → lumen -ve electrical potential→ Cl- absorption paracellularly.
      - K+ is pump from interstitium to cell by Na+,K+ ATPase,↑ intracellular [K+].
      - Net K+ secretion occurs for 2 reasons ;-(1) apical K+ channel > permeable than basolateral K+ channel.(2) lumen -ve electrical potential favors K+ secretion.
      - Aldosterone enhances Na+,K+ ATPase activity and ↑ Na+ and K+ permeability of the apical plasma membrane, thus enhancing Na+ reabsorption and K+ secretion.
  - - - Endogenous waste products and exogenous drugs/ toxins are poorly filtered by glomerulus.
      - The waste product are reabsorbed by carrier-mediated process, clearing them from the plasma.
      - Endogenous organic compounds are bile salt, oxalate, urate, creatinine, prostagladin, epinephrine, hippurate.
      - Exogenous drugs/ toxins secreted are ;-(1) antibiotic (penicillin G, trimethoprim),(2) diuretics ( chlorothiazide, furosemide),(3) analgesic morphine. (4) herbicide paraquat.
      - Exogenous p- aminohippurate used to estimate renal plasma flow.
      - Antibiotic secretion use to enhance urinary tract infection treatment.
      - Furosemide secretion = enhance drug delivery to action site.
      - mammal protein metabolism end product is urea. Birds = uric acid.
  - - - PCT have many mitochondria, brush border and pronounced basolateral micropedici →↑ volume of substances (active & passive ) transport.
      - Straight part of PCT & thin limb of Henle’s loop → low columnar epithelium, few mitochondria, few micropedici → no active transport of solute.
      - Thin limb of Henle’s loop = passive permeability for water reabsorption.
      - Ascending Henle’s loop = low columnar epithelium → tall columnar epithelium.( many mitochondria, many micropedici)→↑ active transport.
      - DCT have even taller epithelium and dense array of mitochondria.
      - DCT reabsorb Na+,K+,Cl-,Ca2+,Mg2+ against high gradient.
      - 90% of salts are reabsorbed at DCT.
      - Na+ ,K+ ATPase pump at basolateral mambrane. Pump Na+ from the cell to interstitium, ↓ intracellular [Na+], form electrochemical gradient across the apical membrane.
      - The electrochemical gradient drives Na+,K+,2Cl- co-transporter in apical membrane.
      - Cl- diffuse out by Cl- channel at basolateral membrane, K+ also same.
      - Cl- absorption and K+ secretion → lumen +ve charged voltage to interstitium.
      - Cation diffuse into interstitium through paracellular pathway.
      - Apical Na+,K+,2Cl- co -transporter inhibited by loop diuretics ( bumetanide & furosemide).
      - DCT have NaCl co-transporter & Na+ channel on apical → promote Na+ reabsorption.
      - Apical NaCl co-transporter inhibited by thiazide diuretics.
      - Both thick ascending limb (TAL) and DCT are impermeable to water.
      - Rapid salt reabsorption without water → hypotonic tubule fluid → “diluting segment”.
      - Dillution is important for fluid volume regulation, excrete excess water without salt → prevent water overload and plasma hyportonocity.
      - Na+,K+,Cl- enter the cell by secondary active co-transport.
      - Cl- enter by basolateral Cl- channel, K+ leaves the cell by apical and basolateral K+ channels.
      - The lumen-to-blood gradient for cations is present, → drives reabsorption of Na+,K+,Ca2+,Mg2+ through the cation selective paracellular pathway.
  - - - DCT and CD control ultimate excretion rate of electrolytes and water to maintain homeostasis.
      - Homeostasis respond to aldosterone, angiotensin II, ADH, endothelin, Atrial Natriuretic Peptide, PTH, calcitonin, 1α,25-(OH)2- Vitamin D3.
      - In Birds, Na+ balance regulated by NaCl secretion by nasal (supraorbital )gland rather than renal excretion.
      - Ureteral urine → cloaca → digestive tract → additional Na+ reabsorption.
  - - - Aldosterone is an mineralcorticoid hormone ,secreted adrenal cortex, released by systemic hypotension stimulation by renin-angiotensisn aldosterone system and hyperkalemia ( ↑ plasma K+ level).
      - Act on connecting segment cell (CS cells) and principal cells.
      - ↑Na+ reabsorption, ↑ water reabsorption.
      - ↑ apical Na+ channel permeability and stimulates Na+,K+-ATPase activity, ↑ [Na+] uptake.
      - Chronic aldosterone stimulation → cell adaptation → proliferation of basolateral plasma membrane, ↑ Na+,K+ ATPase pump activity.
      - Also ↑ transcription of apical NaCl co-transporter in DCT and epithelial Na+ channel ( ENaC) in CD.
      - Aldosterone regulate K+ homeostasis, by enhance K+ entry by stimulating Na+,K+ ATPase activity →↓ serum K+.
      - Chronic aldosterone stimulation ↑ no.of apical K+ channel of CS cells and principal cells→↑ K+ permeability and ↑ K+ secretion.
  - - - Angiotensin II enhance Na+ reabsorption at PCT, TAL and CD.
      - Angiotensin II receptors (AT1 receptors),↑ Na+ transport.
      - PCT, angiotensin II ↑ Na+ uptake thru- (1) apical Na+/H+ exchanger,(2) Basolateral Na+(HCO3-) co-transporter, (3) Na+,K+ ATPase pump.
      - TAL, angiotensin II ↑ Na+/H+ exchanger & Na+,K+,2CL- transporter.
      - CD, angiotensin II ↑ Na+ uptake by ENaC.
      - Some species, ADH & vasopressin released when dehydrated -↑ salt reabsorption from TAL and CD.
      - maximal salt & water conservation → water reabsorption in CD.
      - Endothelin (peptide hormone) produced by CD endothelial cells and TAL.-acts on specific receptors,↑ renal NaCl & water excretion, mediated by NO & prostagladin.
      - Na+/K+ ATPase & ENaC transport inhibited.
      - Atrial Natriuretic Peptides (ANP), produced by cardiac atria, ↑ Na+ secretion in DCT &CD, by inhibiting aldosterone release and vasopressin effect on CD.
  - - - 60% of filtered Ca2+ is reabsorbed in PCT ( paracellular and passive transport).
      - 20% of filtered Ca2+ is reabsorbed in TAL ( passive paracellular and active transcellular ).- suppressed when serum Ca2+ ↑, basolateral calcium-sensing receptor (CaSR) activated.
      - 10% of filtered Ca2+ is reabsorbed in DCT and CS ( active transcellular); - (1)basolateral Ca2+ ATPase pump out Ca2+ actively to interstitium ;-(2) Ca2+ transporter by basolateral Na+/Ca2+ antiporter ( Na+ in, Ca2+ out);- (3) Ca2+ enter apical membrane via Ca2+ channel, facilitated by Ca2+-binding protein (calbindin 28K).
      - 1-2% of filtered Ca2+ is reabsorbed in CD.
      - Regulation of Ca2+ occurs in DCT,SC, TAL.
      - PTH, 1α,25-(OH)2- Vitamin D3, and calcitonin control renal Ca2+ excretion.
      - Hypocalcemia (↓ plasma Ca2+ level) → stimulates PTH release → bone, intestine, kidney to ↑ plasma Ca2+ level.
      - PTH ↑ apical Ca2+ uptake by ↑ apical Ca2+ channel activity
      - -In DCT, PTH ↑ Cl- conductance at basolateral → hyperpolarize cells (interior become more electrically -ve)→ ↑ driving force of Ca2+ entry.
      - PTH inhibit Pi reabsorption in PCT→ internalization of Na-dependent Pi transporters (NaPi-2) in brush border.
      - PTH also stimulates 1α,23-(OH)2-Vitamin D3 converted to active form in PCT.
      - Vitamin D3 receptors located at DCT & CS, Vitamin D3 ↑ Ca2+-binding protein (calbindin28k)→↑ Ca2+ reabsorption.
      - Vitamin D3 ↑ NaPi-2 expression in PCT, ↑ phosphate reabsorption.
      - Calcitonin ↓ serum [Ca2+] → deposit Ca2+ in bone.
      - Calcitonin ↑ renal Ca2+ reabsorption in TAL,DCT,CS, by hyperpolarize cells and ↑ Ca2+ uptake from tubule fluid.
  - - - Clinical examination
        
        A 10 year old female dog, has increased in water consumption and urine volume for previous 2 weeks. The dog appears alert,moderately overweight, urinalysis reveals 4+ glucose ( normally negative),plasma glucose level is tested immediately and is 275 mg/dL (normal ,80-120 mg/dL).The dog has diabetes mellitus which caused by insulin deficiency secreted by pancreas B-cells, plasma glucose level rised. The glucose level exceeds the reabsorption capacity of the proximal tubule (the renal threshold of 180 mg/dL).Glucose appears in the urine (glucosuria). The glucose acts as osmotic agent, increases the volume of urine excreted.The dog drinks more water to replace the excessive fluid loss.
      - Treatment
        
        Insulin injection 2-3 times a day.When the insulin dosage is appropriate, the plasma glucose level is normalized, the glucosuria disappears and urine volume back to normal.
    - - Clinical Examination
        
        A 1 year old spayed female dog with severe weakness , inappetence, vomiting for several days. The dog is lethargic, weak, extremely dehydrated. The heart rate is normal but pulses are weak.Urinalysis is normal. Thoracic radiographs demonstrate a small cardiac silhouette and small thoracic vessels. The serum creatinine level is 2.5 mg/dL (normal, 0.6-1,2 mg/dL).Serum K+level is 6.5 mEq/L (normal, 3.6-5.6 mEq/L).Serum Na+ level is 129 mEq/L (normal, 141-155 mEq/L).Serum CL- level is 97 mEq/L (normal, 103-115mEq/L) and serum HCO3- level is 12 mEq/L (normal, 18-24 mEq/L).The dog has hypoadrenocorticism. The metabolic disturbances are due to deficiency of mineralcorticoid hormone aldosterone. In the absence of aldosterone,Na+ conservation and K+ secretion are impaired.Cl- and water follow the path of Na+ and also are excreted excessively by the kidney.
        Hyperkalemia affects the excitable tissue,(nerve and muscle cells) and results in muscle weakness, decreased cardiac output and decreased size of the heart and thoracic blood vessels thus exacerbates the hypotension and poor tissue perfusion.Poor tissue perfusion is caused by elevated serum creatinine level(azotemia) due to inadequate renal blood flow and reduced glomerular capillary hydrostatic pressure,that prevent adequate glomerular filtration(prerenal azotemia). Hyponatremia blunt the azotemia by the absence of glucocoticoids. The decreased serum HCO3- level indicates metabolic acidosis.
      - Treatment
        
        Hypokalemia and metabolic acidosis can cause fatal cardiac arrhythmias. Volume repletion with normal saline and correction of the "base deficit"( low serum HCO3-).Replacement therapy with mineralcorticoid hormones ( desoxycorticosterone acetate, desoxycortocosterone pivalate, flurocortisone acetate) restores apical Na+ channels and basolateral Na+/K+ ATPase activity. Glucocorticoid hormones are given to treat hypoglycemia and correcting hyperkalemia and hyponatremia. Oral therapy with flurocortisone acetate to control the serum K+ and Na+ level.
- - - - Renin- Angiotensin - Aldosterone system
        
        Renin hormone is produced by afferent arteriole mesangial cell ( specialized juxtaglomerular cells ).
        
        Renin release is stimulated by ↓ renal perfusion pressure ( systemic hypotension).
        
        Renin convert angiotensin (from liver) to angiotensin I.
        
        Angiotensin Converting Enzyme (ACE) convert angiotensin I to angiotensin II.
        
        Angiotensin II is a vasoconstrictor, ↑ systemic blood pressure and renal perfusion pressure.
        
        Angiotensin II also stimulates adrenal gland to release aldosterone , pituitary to release vasopressin → activates Na uptake in proximal convoluted tubule(PCT) and collecting duct (CD).
        
        Enhance salt and water retention, intracellular volume ↑, vascular resistance ↑ ==→ ↑ systemic blood pressure and renal perfusion pressure.
        
        Renin release is suppressed by ;- (1) high renal perfusion. (2) high plasma angiotensin II → -ve feedback mechanism for the system.
        
        Angiotensin II release PGE2 and Prostacyclin , without this, vasoconstriction ↓ renal blood flow and GFR.
    - - Myogenic reflex
        
        Glomerular arteriole respond to changes in arteriolar wall tension.
        
        Arteriolar wall tension ↑, afferent arteriole constrict, ↑ blood flow resistant,↑ blood pressure.
        
        Arteriolar wall tension ↓, afferent arteriole dilate, ↓blood flow resistant,↓ blood pressure.
      - Tubuloglomerular feedback
        
        Macula densa at DCT, located between afferent and efferent glomerular arteriole.
        
        Juxtaglomerular apparatus;- (1) macula densa, (2) extraglomerular mesangial cell,(3) afferent arteriole, (4) efferent arteriole.
        
        ↑[NaCl] in tubule fluid, activate macula densa signaling cascade.
        
        Signaling paracrine factors ;- NO, adenosine, ATP- suppress renin release, ↑ resistance,↓ renal perfusion pressure, mesangial cell contract,↓ Kf.
        
        This tubuloglomerular feedback only respond to single nephron GFR, prevent tubule fluid flow rates > transport capacity, prevent excessive fluid and solute loss.
        
        Glomerular endothelium produce endothelin thromboxane A2 ( metabolic arachidonic acid ) and angiotensin II as vasoconstrictor.
        
        And produce vasoldilator/ relaxing factor = NO, prostacyclin, PGE2
        
        NO produced by oxidation of L-arginine by NO synthase isoform.
        
        NO quench reactive O2 species, inhibit intrarenal vasoconstriction, glomerular hypertension, mesangial cell proliferation, and mesangial matrix production.
        
        Angiotensin II, aldosterone, vasopressin ( antidiuretic hormone) - enhance water and solute reabsorption ,↑ blood volume.
        
        Atrial Natriuretic peptides (ANP) cause natriuresis( Na wasting) and diuresis (water wasting) and ↓ blood volume.
      - Vessel tone systemic factor ;- systemic blood pressure, renal perfusion, ultrafiltration.
        
        Vasopressin and catecholamines → systemic vasocontriction → ↑BP.
        
        β- adrenergic stimulation activate renin- angiotensin - aldosterone system.
        
        α- adrenergic stimulation cause renal vasoconstriction → ↓renal blood flow.
        
        vasoconstrictors → mesangial cell contract → ↓ area available for filtration.↓Kf.
        
        Kf = area available for filtration x hydraulic permeability.
        
        mesangial cell contract, ↓ area availablle for filtration,↓ Kf, ↓ GFR.
        
        Insulin-like growth factor & high dietary protein→ enhance GFR.
        
        Insulin-like growth factor ↑ GFR.
        
        High dietary protein ↑ renal blood flow,↑GFR.- rapid progression of glomerular injury→ renal failure.
        
        In Birds, GFR more variable, exhibit intermittent filtration in reptilian type glomeruli←dehydration and ↓GFR,← release or arginine vasotocin.
        
        Arginine vasotocin cause constriction in reptilian nephron.
        
        Macula densa is absent/ rudimentary and no tubuloglomerular feedback in birds.
  - - - Kidney maintains homeostasis , receive 25% of cardiac output.
      - Filters blood and respond to water,electrolyte and acid base disturbance → alter rate of reabsorption/secretion.
      - Produce hormones to regulate blood pressure & RBC production.
      - Functional unit = nephrons, consist of glomerulus(filtration),renal tubule segment ( reabsorption & secretion) and collecting duct ( empty into renal pelvis).
  - - - Glomerular wall creates barrier.
      - Force favoring filtration ;- (1) hydrostatic pressure of the blood in the capillary{main driving force},(2) Oncotic pressure in Bowman’s space ultrafiltrate.
      - Oncotic pressure of ultrafiltrate is inconsequential because medium to high-molecular-weight proteins are not filtered.
      - Force opposing filtration = plasma oncotic pressure in glomerular capillary & hydrostatic pressure in Bowman’s space.
      - Net filtration pressure(Pf) = Capillary hydrostatic pressure - ( capillary oncotic pressure + hydrostatic pressure of ultrafiltrate).
      - Plasma protein retained in capillary lumen, plasma oncotic pressure ↑, capillary hydrostatic pressure ↓, net filtration pressure ↓ along the capillary bed.
      - GFR = Pf x permeability of filtration barrier x surface area for filtration.
      - Permeability of filtration barrier x surface area for filtration = ultrafiltrate coefficient (Kf)
      - GFR = Pf x Kf
  - - - Clinical examination
        
        A 15 years old cat, listless, inappetent, thin, drinking more water, urinate large volume, vomiting frequently. The cat is moderately dehydrated, mucous membrane pale, kidney small and slightly irregular, hematocrit 22%( normal, 30-42%), serum creatine level is 8.7mg/dL ( normal, 0.5-1.2 mg/dL). The cat has chronic renal failure and common in old cat,serum creatinine level high as the glomerular loss function and reduced GFR. The urine is not cconcetrated in response to dehydration because tubular function compromised. The small kidney is due to gradual nephron loss. Anemia is common due to decreased erythropoietin production by the kidney.
      - Treatment
        
        Rehydration by intravenous fluids and correction of electrolyte and acid base disturbances.Diet with low total protein, low sodium, low phosphorus. Supplementing with water-soluble vitamin could help. Anabolic steroid help improve anemia with exogenous erythropoietin.
    - - Clinical examination
        
        A 3 year old spayed dog not eating well, and tire easily for several days. The dog seems bright , alert, and in good flesh. The dog has slight pitting edema in distal extremities.Left kidney is palpable and feels smooth with normal size. Urinalysis shows 3+ proteins ( normal, -ve to trace amount), presence of few RBC, complete blood cell count is normal. Serum albumin level of 1.5g/dL (normal. 2.3 -4.3 g/dL). The dog has acute glomerulonephritis because the filtration barrier for protein is damaged and become leaky, thus protein appear in urine. Loss of albumin cause the serum albumin level drops.The peripheral edema is caused by hypoalbuminemia, which lower the intracapillary oncotic pressure and leakage of fluid into extravascular space.Renal biopsy is necessary to verify the type and severity of glomerular injury. Potential cause of glomerulonephritis is concurrent bacterial or viral infections or autoimmune diseases.
      - Treatment
        
        Immunosuppressive and anti-inflammatory agents are used to combat ongoing damage from glomerular inflammation. Hypoalbuminemia must be treated with plasma/ other colloids . Frequent assessment of urine protein/ creatinine ratios and serum creatinine is warranted to monitor disease progression.
  - - - Glomerulus is a network of capillaries, retaining medium and large-molecular -weight proteins.
      - Glomerular filtrate have nearly same [electrolyte] and [water] to plasma.
      - Glomerular filtration rate (GFR),-unit= mL/mim/kg.
  - - - Glomerular tuft encased within Bowman’s capsule.
      - Mammals have 1 renal artery, birds have 3 renal arteries ( anterior, middle, posterior).
      - Renal artery → afferent arteriole → glomerular capillaries → efferent arteriole.
      - Avian have both mammalian and reptilian -type nephrons.
      - Glomerular space collect glomerular filtrate.
      - Capillary wall 3 layers → (1) capillary endothelium, (2) basement membrane, (3) visceral epithelium.
      - (1) capillary endothelium fenestrae - provide passage for water and non-cellular components.
      - (2) basement membrane made up of glycoprotein, type IV-type V collagens & proteoglycans.→ have 3 layers = lamina rara interna, lamina densa, lamina rara externa.
      - (3) visceral epithelium have podocytes with primary and secondary foot processes, interdigitate with other podocyte foot process → “ epithelial slit”.
  - - - Selectivity permeability = permeability
      - Factor 1 = molecular size, size > 4mm radius cannot be filtered, while size < 2 mm can be filtered freely.
      - Factor 2 = electrical charge of molecule ( cation > neutral > anion).
      - Anion form the charge- selective barrier by incorporated in glomerular basement membrane, form repulsion to anion.
      - Factor 3 = shape and deformability of molecule
      - Neutral,long, flexible molecule crosses the filtration barrier 7 times more easily then globular protein.
  - - - GFR= renal function parameter
      - GRR- clearance concept = rate of plasma is cleared of a substance.
      - Rate clearance , Cx = rate of elimination of a substance ÷ plama concentration.
      - Cx = (UxV)/Px
      - Cx = volume of plasma cleared of substance X per unit time.
      - Ux = Urine concentration of substance X.
      - V = Volume of urine collected ÷ time period of collection
      - Px = plasma concentration of substance X.
      - Net clearance rate = ( rate of filtration + secretion ) - rate of reabsorption of substance.
      - “Inulin” is a substance administer intravascularly as it is not produced from the body , it filter freely and is neither secreted nor reabsorbed.
      - Inulin is used as a reference.
      - GFR = Cinulin = ( Uinulin V)/Pinulin.
      - Unit = ml/min.
      - Creatinine clearance is used as clinical reference, it is a by product of muscle metabolism.
      - It is not secreted in dogs or 10% in other species, and not reabsorbed.
      - C creatinine = U creatinine V / P creatinine.
      - In Birds, creatinine clearance cannot be used as reference as it is secreted when plasma level↑, and reabsorbed when plasma level normal.
- - - - Maintain water content & plasma tonicity.
      - Dog produce concentrated urine 7-8 times concentrated than plasma osmolarity.
      - Dog produce hypotonic urine 1/3 of the plasma osmolarity.
  - - - Reabsorbs solute by active and passive transport.
      - Active transport drive by basolateral Na+/K+ ATPase → secondary active transport and passive paracellular transport.
      - PCT brush border ,rapid reabsorption ,↑ permeable to water.
      - Abudant aquaporin-1 and aquaporin-7 in the membrane.
      - ↑ oncotic pressure & ↓ hydrostatic peritubular capillary → favor solute uptake.
      - Water reabsorbed nearly isotonic with salt.
  - - - (1) Generation of a hypertonic medullary interstitium → concentrated urine.
      - (2) Dilution of tubule fluid by the TAL and DCT → dilute urine.
      - (3) Variability in water permeability of CD in response to antidiuretic hormone ADH & vasopressin → determine the final urine concentration.
  - - - Mammalian kidney have superficial and juxtamedullary nephrons
      - Superficial nephron = short Henle’s loop, extend from inner to outer medulla.
      - Juxtamedullary nephron = long Henle’s loop,deep into inner medulla, concentrate urine at higher level > plasma osmolarity .
      - Avian,= reptilian -type nephron → near surface cortex → no loop of Henle.;- mammalian -type nephron → excrete urine hypertonic to plasma.
  - - - TAL- reabsorb NaCl without water, impermeable to water.
      - ↑ interstitial fluid osmolarity → medullary interstitial hypertonicity and osmotic gradient.
      - Inner medullary CD reabsorbs urea, while cortical and outer medulla CD does not.
      - Terminal inner medullary collecting duct (IMCD)- highly permeable to urea through carrier-mediated urea transport.
      - Urea conserved in IMCD in medulla, reabsorption into interstitium by ADH,when body demand for water conservation.
      - ↑[urea] uptake, ↑ osmotic gradient for water uptake.
      - Thin limb of Henle’s loop permeable to urea.