BASIM ZWAIN LECTURE NOTES

1. Renal system Factors affecting GFR Renal blood supply Nephrons Glomerular capillary membrane Functions of kidney Measurements of GFR and RBF Kidney consists of 8-10 conical pyramids, bases in outer cortex, apices toward pelvis, medulla subdiv-ided into outer & inner zones, outer zone into outer & inner stripes, pyramid pours urine into minor calyx, every 2-3 calyces unite to form major calyx which unites with other major calyces to form renal pelvis that leads urine through ureter which emerges through hilum of kidney from which renal artery enters & renal vein leaves. Ureters pour into urinary bladder from which urethra emerges. Structural & functional units, more than million, in each kidney, composed of the following structures:Glomerulus: globular tuft of capillaries, afferent & efferent arteriole, inside Bowman's capsule, Bd is filtered & transferred to renal tubules: proximal tubule(PCT or pars convoluta& PST or pars recta) , ﴾tDHL﴿ , ﴾tAHL﴿, ﴾TAHL﴿, distal tubule, JGA, DCT, collecting tubules, collecting tubes, cortical & medullary CD, main duct, minor & major calyx. GFR = Kf * (net ultrafiltration pressure) = Kf * (PG + ΠB – PB - ΠG) = Kf * (60 + 0 – 18 - 32) respectively = Kf * (+10 mmHg) Kf=ultrafiltration coefficient (=surface area*capill-ary permeability), P=hydrostatic pr., Π=smotic pr. of colloids, B=inside Bowman's capsule, G=inside glomerular capillaries. These are Starling forces Measurement of RBF RBF = RPF \ (1-hematocrit) When x is 100% extracted from plasma& excreted; its extraction ratio Ex= 1.0 & its clearance= Cx RPF = Cx \ Ex = Cx \ 1.0=Cx Substance (x) is not found yet. Instead, substance called paraaminohippuric acid (PAH) its extraction ratio is 0.9 (EPAH = 0.9) RPF = CPAH \ EPAH = CPAH \ 0.9 RBF: increases GFR FF: increases GFR Vasoconstriction of afferent arterioles decreases GFR (decreased PG) Slight vasoconstriction of efferent arterioles increases GFR (increased PG) Severe vasoconstriction of efferent arterioles decreases GFR (increased ΠG) Measurement of GFR Endogenous (creatinine) or exogenous (inulin) substance used to measure GFR. GFR = Cin = Uin * V \ Pin Where Cin = Clearance of inulin Uin = Urinary concentration of inulin V = Urine flow Pin = Plasma concentration of inulin Glomerular filtration rate ﴾GFR﴿ GFR = RPF * FF FF = filtration fraction, RPF = renal plasma flow GFR = 625 ml\min * 20% GFR = 125 ml\min Substance used to measure GFR & RBF must: 1. Not be toxic. 2. Not be stored, or metabolized by kidney. 3. Not be produced, secreted or reabsorbed by renal tubules. 4. Not affect GFR or RBF by itself. Three layers: capillary endothelium, BM & visceral layer of Bowman's capsule (podocytes). Endothelial layer: fenestrated, even proteins ﴾but not cells﴿ can pass. BM: high permeability, ﴾>100 times other capillary membranes﴿. Other filtered materials & ions pass easily through membrane & slit pores between feet of podocytes. Regulation of ECF vol., osmolarity & composition, regulation of BP, acid-base balance, bone metaboli-sm (excretion of calcium & phosphate ions & formation 1, 25 dihydroxycholecalcipherol), produ-ction of erythropoietin hormone, excretion of various metabolic waste products, drugs, toxic substances & poisons. 25% of cardiac output ﴾1.25 L\min﴿ supplies renal tissue, greater flow to cortex ﴾97%﴿. Renal artery, segmental, interlobar, arcuate arteries, interlobular ﴾radial art.s or medullary rays﴿, afferent arterioles & glomerular capillaries, efferent arterioles , peri-tubular capillaries, (vasa recta,) interlobular veins, arcuate, interlobar, segmental and renal veins. Renal clearance (Cx) = GFR – TR + TS GFR = glomerular filtration rate of x TR = tubular reabsorption of x TS = tubular secretion of x RPF = renal blood flow ﴾ RBF ﴿* (1-hematocrit) = 1250 ml\min * 0.5 = 625 ml\min Cortical nephrons: 70%-80%, outer two thirds of cortex, no tAHL, efferent narrower than afferent. Juxtamedullary nephrons: inner third of cortex, long tAHL, efferent wider than afferent. Home Exit BASIM ZWAIN LECTURE NOTES

2. Renal system Factors affecting tubular reabsorption Regulation of blood volume and pressure Control of GFR Regulation of ECF osmolarity Tubular reabsorption Body control of ECF osmolarity Control of tubular reabsorption Countercurrent mechanism When GFR is decreased; tubular flow slows down, increased tubular reabsorption of NaCl, decrease NaCl near osmoreceptors, macula densa send impulses to JG cells to relax, vasodilatation of afferent arterioles, increase Bd flow to glomerular capillaries, increase GFR & vice versa Renin is also produced by JG cells in response to increase in GFR or RBF, production of angiotensin I & angiotensin II to decrease GFR & RBF. 1- Sympathetic activity: increases Na+ reabsorption 2- Hormonal activity: A-Aldosterone: adrenal cortex, acts on principal cells of distal tubules, increase Na+ reabsorption & K+ excretion. It increases permeability of luminal membrane to Na+ & stimulates Na+-K+ pump in basolateral membrane. Adrenal insufficiency (Addison's disease) results in excessive Na+ loss & K+ retention while adrenal hyperactivity (Cushing syndrome) results in Na+ retention & K+ depletion Highly selective process, passive or active, Some substances completely reabsorbed: aa & glucose, some are mostly reabsorbed: bicarbonates & some electrolytes, some are mostly reabsorbed in the presence of hormones:water reabsorption increases in presence of antidiuretic hormone, sodium ions reabsorption in presence of aldosterone and\or angiotensin II hormones. B-Angiotensin-II: Produced by lungs from angiotensin-I (produced in liver from angiotensino-gen or called renin). Renin is formed in kidneys. It acts directly (or indirectly after stimulation of aldosterone) to increase sodium ions reabsorption. C-Antidiuretic hormone (vasopressin): produced from posterior pituitary gland and it acts on distal and collecting tubules and ducts to increase water reabsorption and urine concentration. 4- Plasma levels of amino acids & glucose: tubular reabsorption of amino acid and glucose is unlimited , when plasma levels of amino acids and glucose increase; tubular reabsorption increase, decreased amounts of NaCl near osmoreceptors of macula densa, send impulses to JG cells to relax resulting in vasodilatation of afferent arterioles, increase Bd flow to glomerular capillaries, increase GFR. Human body must get rid of not less than 600 mosm of metabolic wastes per day. So, it is very necessary to excrete not less than 0.5 liters of highly concentrated urine daily: TR = Kf * (net reabsorption pressure) = Kf * (Pif – Pc + Πc - Πif) = Kf * (6 – 13 + 32 – 15) mmHg respectively = Kf * (+10 mmHg) Kf is constant depends on surface area, thickness & permeability, P is hydrostatic pr., Π is osmotic pr. of colloids, c is peritubular capillaries, and if is interstitial fluid Plasma osmolarity (Posm) calculated from plasma sodium conc. (PNa+)…. Posm = 2.1 * PNa+ But, in patients with renal diseases, plasma conc.s of urea & glucose are also calculated. When Posm decreases; excretion of large amounts of diluted urine (down to 50 mosm\L) while when Posm increases; excretion of small amounts of highly conc. urine (up to 1200 mosm\L). 1-Sympathetic nervous activity:Strong sympathetic activity decreases GFR e.g., in severe hemorrhage & cerebral ischemia while role of parasympathetic (vagal) innervations is yet unknown. 2-Hormones&autacoids:Adrenaline, noradrenaline , angiotensin II, aspirin& endothelin decrease GFR. Nitric oxide, prostaglandin & bradykinin increase GFR Many substances are reabsorbed along with other substances like chloride ions which follow sodium ions, sodium chloride salt which follows water. Some substances 50% reabsorbed (50% excreted) like urea. Some substances completely excreted like creatinine and some drugs and poisons. Thirst center in brain stem increases the desire for water intake & increase secretion of ADH. Thirst center is also stimulated by decreased ECF volume, decreased BP, angiotensin II & dryness of mouth, pharynx & esophagus & vice versa. Inhibited also by gastric distension. Salt appetite center in the brain stem increases the desire for salt intake. D- Atrial natriuretic peptide (ANP): Produced by cardiac atria in response to any increase in Bd vol. & acts especially on collecting ducts to decrease sodium and water reabsorption and so, increase urine excretion to restore normal Bd vol. E-Parathyroid hormones:Produced by parathyroid glands & act especially on TAHL (& DCT) to increase calcium and magnesium ions reabsorption and decrease phosphate reabsorption. There is glomerulotubular balance, when GFR increases; tubular reabsorption increases. But active transport processes may be saturated when tubular lumen overloaded. Maximum tubular load just before saturation is transport maximum (Tm). Maximum plasma conc. before a substance starts to appear in urine is its renal threshold=Tm\GFR b.Myogenic mechanism: Increased RBF that causes increase in GFR; at the same time causes distension of afferent arterioles and stretch of smooth muscles lining their walls. This stretch results in myogenic contraction of smooth muscles & vasoconstriction of afferent arterioles & decreased RBF & GFR. 3-Autoregulation: a.Juxtaglomerular feedback mechanism: Juxtaglo-merular apparatus (JGA): specific distal tubular epithelial cells (macula densa: osmoreceptors, sensitive to changes in conc. of NaCl) in contact with specific smooth muscle cells in wall of afferent arterioles, juxtaglomerular cells. Osmoreceptor cells lie in anterior hypothalamus & sensitive to any increase in Na+ conc., send signals to supraoptic nuclei to stimulate posterior pituitary gland to increase secretion of ADH (vasopressin) to increase water reabsorption. ADH is stimulated by decreased Bd vol., decreased BP, nausea, vomiting, morphine & nicotine & vice versa. ADH inhibited by alcohol intake. According to equation, when no conc. urine; the minimum obligatory urine volume will increase resulting in excessive loss of body fluids (diabetes insipidus). Excessive intake of hyperosmotic fluids like sea water will seriously increase Posm & min. obligatory urine vol. even with maximum urine conc. resulting in death from dehydration. Descending & ascending limbs of Henle's loop and vasa recta run long distance parallel, counter & in close proximity to each other. Descending limbs are called countercurrent multipliers because they continuously bring new NaCl to medulla while ascending vasa recta are called countercurrent exchangers because they continuously draw back water from medulla to the systemic circulation. Tm of glucose(TmG) is about 325 mg\min, its ideal renal threshold is 325\125 =2.6 mg\ml = 260 mg\dL But actual renal threshold for glucose is about 180 mg\dL, this difference may be due to that not all of renal tubules have the same Tm and that some of the filtered glucose molecules before Tm bypass reabsorption. About 15% of water reabsorption occurs in tDHL which is carried back to the systemic circulation via ascending vasa recta. But tDHL is impermeable to solutes which stay within thin segment not reabsorbed. So, tubular fluid reaches the ascending limbs highly hyperosmotic (1200 mosm\L). The major active reabsorption of electrolytes occurs in TAHL (about 30%) which is mainly due to 1Na+-2Cl¯-1K+ active cotransport process which works against as much as 200 mosm\L conc. gradient. So, tubular fluid reaches distal tubules hypoosmotic (100 mosm\L). Starting from tAHL, all the following segments are impermeable to water in absence of ADH but very little amounts of solutes are passively reabsorbed in tAHL. So, tubular fluid reaches the following segment still hyperosmotic (900 mosm\L). Small increase in Bd vol., large increase in CO.... Small increase in CO, large increase in BP.. Small increase in BP, large increase in urine excretion. Acute increase in BP balanced by direct increase in Na+ excretion due to increase GFR & decrease in Na+ reabsorption with increase in Na+ leak back to tubular lumen (pressure natriuresis) which is always accompanied by pressure diuresis Remaining reabsorption processes of electrolytes (about 5%) occur in distal segments. Net result is hyperosmotic medulla which favours further water reabsorption (about 19%) from collecting ducts in presence of ADH & only about 1% of filtered water excreted in urine. While in absence of ADH, about 20% of filtered water is excreted. Urea recirculation is responsible for about 40% of the process of urine concentration when urea is reabsorbed from medullary colleting tubules to the medullary interstitium to be secreted again from the tubular cells of thin segments to their lumen where the cycle is repeated again and again. Chronic increase in BP is balanced by decrease in angiotensin II production which results in decrease Na+ reabsorption directly or indirectly by decreas-ing aldosterone production from adrenal cortex. Ability of kidney to conc. urine requires presence of hyperosmotic medulla created by countercurrent mechanism & urea recirculation & ADH. 1-Sympathetic nervous activity 2-Hormones and autacoids 3-Autoregulation 4-Plasma levels of amino acids and glucose 1-Osmoreceptors-ADH feedback 2-Thirst center in brain stem 3-Salt appetite center in brain stem The major bulk of tubular reabsorption of water & solutes (about 65%) occurs in proximal tubules. So, tubular fluid reaches the thin segments within its original osmolarity (300 mosm\L). Normal ECF osmolarity is about 280-300 mosm\L and it is mostly dependant on sodium ions conc. (142 mEq\L). Normal daily sodium ions intake must equals its daily output = 10-20 mEq Home Exit BASIM ZWAIN LECTURE NOTES

3. Renal system Body regulation of acid-base balance Physiology of micturition Urine enters bladder in spurts synchronous with regular peristaltic contractions of ureteric smooth muscles (1-5/minute), oblique insertion of ureters into vicinity of bladder walls prevents back flow of urine. Bladder parasym.:S2, S3& S4 with pelvic nn. Sym. from L1, L2 &L3 via hypogastric nn after relay in inferior mesenteric ganglion. Somatic sensory & motor from S2, S3 & S4 via pudendal nn. Sensory also via pelvic & hypogastric Buffer systems: 1-Bicarbonate buffer system: the most important buffer system in ECF. when [H+] is increased: H+ +HCO3¯ → H2CO3 → H2O + CO2 (expired) While when [OH-] is increased: OH¯ + H2CO3 → H2O + HCO3¯ (excreted) The power of dissociation constant (pK) for this system is 6.1, so Henderson-Hasselbalch equation: pH = 6.1 + log [HCO3¯]\0.03 PCO2 The first urge to void is felt at volume of 150 ml & the marked sense of fullness is at 400 ml. But this is relieved by property of plasticity. Micturition is initiated after relaxation of muscles of pelvic floor, downward pull on detrusor muscle, excitation of stretch receptors in its wall, reflex contraction. The afferent & efferent limbs of voiding reflex run with pelvic nerves to sacral cord, threshold is adjusted by activity of facilitatory (pons & posterior hypoth-alamus) & inhibitory (midbrain) centers. The internal urethral sphincter, smooth muscles on either sides, plays no role in micturition, in male it prevents retrograde ejaculation (reflux of semen into urinary bladder). External sphincter, skeletal muscle, contracts voluntarily, delay micturition or interrupt its starting. Delay micturition is learning ability of brain in adults. After micturition; female urethra empties by gravity while male urethra by several contractions of bulbocavernosus muscle. Any change in [H+] will affect all cellular and body functions due to its effects on many reactions. Normal [H+] in ECF is only 0.00000004 mol\L, so; it is better to use pH (which is –log [H+] = 7.4). Nobody can survive more than hours when pH raises to 8.0 or falls to 6.8 Regulation of [H+] is by one or more of the following systems: Chemical acid-base buffer systems in body fluids, respiratory and renal regulation of acid-base balance.` 2-Phosphate buffer system: important buffer in intracellular & renal tubular fluids. Its pK is 6.8 When [H+] increases: H+ + HPO42¯ → H2PO4¯ When [OH¯] is increased: OH¯ + H2PO4¯ → HPO42¯ + H2O 3-Protein buffer systems:the most available intra-cellular systems but also work extracellularly. the most important is hemoglobin in RBCs. H+ + Hb → HHb c. Renal regulation: excretion of acidic or alkaline urine. Daily renal secretion of H+ is 4400 mmol. Bicarbonates system buffers 4320 mmol & other 80 mmol buffered by phosphates & then ammonium systems. Most renal tubular cells utilize secondary active transport to secrete H+ like Na+-H+ antiport, but the intercalated cells of distal tubules utilize primary active transport called proton pump When HCO3¯ decreases; metabolic acidosis When PCO2 increases; respiratory acidosis When HCO3¯ increases; metabolic alkalosis When PCO2 decreases; respiratory alkalosis 4-Ammonium buffer system:the last choice system in renal tubules when bicarbonate and phosphate systems are saturated. Ammonium is formed from metabolism of glutamine inside renal tubular cells. When [H+] increases: H+ + NH3 → NH4+When [OH-] is increased: OH¯ + NH4+ → NH4OH Respiratory regulation:stimulation of respiratory center by central chemosensitive areas which are bilateral aggregations of neurons beneath ventral surface of medulla sensitive to changes in H+&PCO2 Double alveolar ventilation reduces PCO2 & raises pH from 7.4 to 7.63 while 1\4th alveolar ventilation raises PCO2 & reduces pH to 6.95 Home Exit BASIM ZWAIN LECTURE NOTES