Physio Theory

• Kidneys


  Have essential functions: filtration, regulation of body fluids, electrolyte balance, acid-base balance, production/activation of hormones
• Filtration


  Removing metabolic products and toxins from the blood and excreting them through the urine
• Kidneys


  • Paired, bean-shaped structures that lie behind the peritoneum on each side of the vertebral column
  • Extend from the 12th thoracic vertebra to the 3rd lumbar vertebra
  • Covered by a fibrous (almost nondistensible) capsule
  • Hilus in the middle of the concave surface is the port of entry for the renal artery, nerves, and the site of the exit for the renal vein, lymphatics, and ureter
  • Renal sinus is surrounded by renal parenchyma except where it connects with the upper end of the ureter

  
• Kidney structure


  • Cortex - granular outer layer with glomeruli and convoluted tubules
  • Medulla - darker inner region without glomeruli, consists of renal pyramids

  
• Kidney blood supply


  1. Renal artery enters the hilus and divides into anterior and posterior branches, which give rise to interlobar and then arcuate arteries

  2. Arcuate arteries branch into ascending interlobular arteries that enter the cortex and give rise to afferent arterioles

  3. Afferent arterioles give rise to glomerular capillaries that rejoin to form efferent arterioles

  4. Efferent arterioles of superficial nephrons form a dense peritubular capillary network in the cortex

  5. Efferent arterioles of juxtamedullary nephrons descend into the renal papillae to form vasa recta in the medulla

  
• Kidney innervation


  • Sympathetic fibres - most of the nervous fibres, from the inferior thoracic and superior lumbar segments of the spinal cord, release norepinephrine and dopamine
  • Parasympathetic fibres - only few fibres of vagus nerve, function unknown
  • Nociceptive afferent fibres - transmit pain sensation, arranged in parallel with sympathetic fibres

  
• Kidney autoregulation


  1. Myogenic response - afferent arterioles constrict when arterial pressure increases

  2. Tubulo-glomerular feedback - macula densa cells sense high NaCl concentrations and release paracrine agents that cause afferent arteriole constriction

  
• High-protein diet


  Increases glomerular filtration rate by reducing tubulo-glomerular feedback sensitivity
• Reduced renal blood flow

  Increases angiotensin II concentration, constricts efferent arteriole, maintains glomerular filtration rate

  
• Renal autoregulation is abolished by substances that alter smooth muscle activity or exposure to reduced temperature, and is depressed by haemorrhage and anoxia
• Nephron


  • Functional unit of the kidney, 800,000 to 1,200,000 per kidney
  • Consists of a renal corpuscle (glomerulus and Bowman's capsule) and a tubule (proximal convoluted, loop of Henle, distal convoluted, connecting tubule)
  • Superficial nephrons have short loops, juxtamedullary nephrons have long loops extending to the tip of the medulla

  
• Nephron function


  1. Forms an ultrafiltrate of blood plasma, then selectively reabsorbs or secretes solutes

  2. Proximal tubule reabsorbs NaCl, NaHCO3, nutrients, divalent ions, water, and secretes NH4+ and other solutes

  3. Loop of Henle participates in forming concentrated or diluted urine

  4. Distal tubule and collecting duct system perform fine control of NaCl and water excretion

  
• Kidney as an endocrine organ

  • Produces renin, erythropoietin (EPO), thrombopoietin (TPO)
  • Releases prostaglandins and kinins that control circulation within the kidney
  • Tubule cells secrete angiotensin, bradykinin, cAMP

  
• Proerythroblasts


  Cells in bone marrow that secrete thrombopoietin (TPO) and stimulate platelets synthesis
• Proerythroblasts secrete


  1. Thrombopoietin (TPO)

  2. Prostaglandins (PGE2, PGD2, PGA2)

  3. Kinins
• Substances secreted by proerythroblasts

  • They are paracrine agents that control circulation within the kidney
  • They are generally vasodilators and may play a protective role when renal blood flow is compromised
  • PGE2 inhibits the Na+ reabsorption => natriuresis

  
• Tubule cells secrete into the lumen

  1. Angiotensin

  2. Bradykinin

  3. cAMP

  4. ATP
• Tubule cells secreting substances

  • Increases glomerular filtration rate
  • Increases renal blood flow
  • Inhibits the Na+ reabsorption => natriuresis

  
• Mesangial cells


  Produce angiotensin II and prostaglandins
• Proximal tubule cells


  Convert circulating 25-hydroxyvitamin D to the active metabolite 1,25-dihydroxyvitamin D
• Renal corpuscle


  The site of formation of the glomerular filtrate, consisting of the glomerulus, Bowman's space, and Bowman's capsule

  
• Glomerular membrane


  • Formed by capillaries with fenestrations (70 nm-holes) that provide no restrictions to the movement of water and small solutes
  • Endothelial cells probably serve only to limit the filtration of cellular elements
  • Capillary endothelium is 40 nm thick with a glycocalyx (12 nm) of negatively charged glycosaminoglycans
  • Basement membrane has 3 layers (lamina rara interna, lamina densa, lamina rara externa) and contributes to the permeability characteristics of the filtration barrier
  • Epithelial cells (podocytes) have foot processes with filtration slits connected by a thin diaphragm structure (4-14 nm pores) covered in negatively charged glycoproteins
• Mesangial cells


  • Support the glomerular capillary loops and secrete the extracellular matrix
  • Continuous with the smooth muscle cells of the afferent and efferent arterioles
  • Extend to the extraglomerular mesangial cells

  
• Juxtaglomerular apparatus (JGA)


  • Includes the extraglomerular mesangial cells, macula densa, and juxtaglomerular (granular) cells
  • Part of a complex feedback mechanism that regulates renal blood flow, filtration rate, Na+ balance, and systemic blood pressure

  
• Macula densa


  • Specialized epithelial cells of the thick ascending limb that contact the glomerulus
  • Act as osmoreceptors and chemoreceptors that respond to modifications of Na+ and Cl- concentrations in the urine

  
• Macula densa stimulates


  Renin secretion from the juxtaglomerular cells
• Juxtaglomerular cells


  • Specialized smooth muscle cells in the wall of afferent arterioles that produce, store and release renin
  • Act as baroreceptors that increase renin synthesis when not stretched (low blood pressure) or when urinary Cl- concentration in DCT is decreased
• Mesangial cells


  Located in the space between the afferent arteriole, efferent arteriole and the macula densa
• Arterial blood pressure below 80 mm Hg or over 200 mm Hg


  Filtration stops in collapse or decreases when the afferent arteriole is constricted (catecholamine) or the efferent arteriole is constricted (angiotensin II)
• Plasma colloid osmotic pressure

  Decreased by dehydration or decreased concentration of proteins in blood => Filtration is modified
• Increased pressure in Bowman's capsule


  Filtration is blocked, e.g. in ureter obstructions or renal parenchyma edema where the tubules are compressed
• Renin-angiotensin-aldosterone axis


  • When effective circulating volume decreases, juxtaglomerular cells release renin which cleaves angiotensinogen to form angiotensin I, then angiotensin-converting enzyme converts angiotensin I to the active angiotensin II
  • Angiotensin II causes intense arteriolar constriction, increases arterial pressure, and stimulates aldosterone secretion and the sympathetic-adrenergic system
• In renal stenosis, there are high levels of renin, angiotensin and aldosterone, and hypertension of renal origin can be treated with ACE inhibitors to lower blood pressure
• Sympathetic nerves


  • Increase sympathetic tone to the kidney, either as a general response or a selective renal response to decreased effective circulating volume
  • Release norepinephrine, increase afferent and efferent arteriolar resistance to decrease renal blood flow and glomerular filtration rate
  • Trigger juxtaglomerular cells to increase renin release and tubule cells to increase Na+ reabsorption

  
• Antidiuretic hormone (ADH)


  Released by the posterior pituitary, increases water reabsorption in collecting ducts and vascular resistance to maintain systemic blood pressure in severe decreases in circulating volume
• Atrial natriuretic peptide (ANP)

  • Released by atrial myocytes in response to increased atrial pressure, vasodilates afferent and efferent arterioles to increase renal blood flow and glomerular filtration rate
  • Inhibits renin secretion and Na+ reabsorption, decreases systemic arterial pressure and increases capillary permeability

  
• Other vasoactive agents


  • Epinephrine - vasoconstriction
  • Dopamine - vasodilation
  • Endothelins - strong local vasoconstriction
  • Prostaglandins - prevent excessive vasoconstriction
  • Leukotrienes - strong vasoconstrictors
  • Nitric oxide - renal vasodilation
• Glucose reabsorption in proximal tubule

  1. Glucose is freely filtered at the glomerulus and then reabsorbed, mostly in the first third of the proximal tubule

  2. Glucose moves from the lumen to the proximal tubule cell through Na+-glucose cotransport, then exits the cell across the basolateral membrane by facilitated diffusion

  3. The real renal threshold for glucose excretion is around 200 mg% in arterial plasma

  
• Protein reabsorption


  • Glomerular membrane does not let pass molecules with MW > 70,000 Da
  • Low MW proteins are filtered and reabsorbed by receptor-mediated endocytosis in the proximal tubule
  • Normal urinary protein concentration is < 100 mg/24h

  
• Amino acid transport


  1. Transported against a concentration gradient at the apical membrane by active transport systems

  2. Exit the cell across the basolateral membrane by amino acid exchangers and facilitated diffusion