Kidney 2024 PDF

KIDNEY 2024 0  Functions of the kidney Maintain constant internal environment= homeostasis 1. Regulation of Water, electrolyte balance (excretion matched to intake) Arterial blood pressure Short term regulation via (renin-angiotensin-aldosterone system)...

KIDNEY 2024 0  Functions of the kidney Maintain constant internal environment= homeostasis 1. Regulation of Water, electrolyte balance (excretion matched to intake) Arterial blood pressure Short term regulation via (renin-angiotensin-aldosterone system) Long term regulation via (excreting variable amount of Na & H2O). Acid-base balance via: Regulation of buffer stores Excretion of acids produced from protein metabolism e.g. sulphuric & phosphoric acid acid 2. Excretion of Metabolic waste products e.g. urea, uric acid, creatinine, bilirubin, metabolites of hormones Foreign chemicals e.g. drugs, food additives 3. Endocrine: secrete Erythropoietin: stimulate erythropoiesis (anemia in kidney disease), treated by EPO injection Renin (regulation of RAAS): see later Prostaglandins (PGE2, PGl2), bradykinins (paracrine hormones): regulate renal blood flow Active form of Vitamin D (1,25 dihydroxycholecalciferol) by hydroxylating vitamin at number (1) position → control plasma Ca2+, PO-4 homeostasis Renal osteodystrophy in Chronic renal failure , due to ↓Activation of vitamin D →impair intestinal absorption of calcium Retention of phosphate →disturb calcium level → Cause 2nd hyperparathyroidism to correct the calcium level → Leads to bone weakness & ↑ incidence of fracture 4. Gluconeogenesis (synthesize glucose from amino acids) during fasting to maintain blood glucose level 1  Causes of anemia in CKD 1. EPO deficiency = predominant cause → leading to normocytic normochromic anemia 2. Uremia →inhibit erythropoiesis 3. Shortened RBC’s life span 4. Nutritional deficiencies of folate and vitamin B12, due to anorexia & dialysis losses 5. Iron deficiency: a) Chronic bleeding from uremia-associated platelet dysfunction, b) ↓iron absorption, especially in hemodialysis patients due to ↑Hepcidin due to ↑expression by inflammatory cytokines ↓renal clearance ❖ Oral iron is less effective than IV iron for improving anemia in hemodialysis patients In impaired renal blood flow (as if there is systemic hypotension) due to Atherosclerosis Bilateral renal artery stenosis Diabetes mellitus kidney correction →via ↑renin angiotensin formation→ cause hypertension Main line of treatment of hypertension in these cases is Inhibition of angiotensin II formation or Blocking its receptors 2  Physiologic Anatomy of Kidney Site: on posterior abdominal wall outside peritoneal cavity Size 150 grams = size of clinched fist, 12 cm in length and < 8 cm in width Surrounded by thin, = tough capsule. Renal artery, vein, lymphatics, nerve supply and ureter enter the kidney at the hilum on its medial side. Structure: formed of Outer cortex Inner medulla Granular, deeper in color Striated, paler in color Divided into renal pyramids→ Tapers to form renal papilla, Projects into pelvic space via minor calyx Minor calices converge into 2 or 3 major calices (chambers) Major calices converge to form the pelvis of ureter. Calices, renal pelvis and ureters are surrounded by smooth fibers, →force the urine from the pelvis to the urinary bladder by peristaltic contractions 3  Nephron Functional unit of the kidney (forming urine), 1.3 million nephrons in each kidney, Consists of 1. Renal Glomerulus Tuft of glomerular capillaries (supplied by afferent arteriole & drained by efferent arteriole) Within Bowman's capsule (dilated end of renal tubule) High pressure capillary bed= 60 mmHg 2. Renal tubule: thin A- Proximal Convoluted Tubule= 15 mm in cortex, Made up of a single layer of cells At apex At base Tight junction between cells lateral intercellular space (extensions of the extracellular space) Brush luminal border (microvilli) B- Loop of Henle= U-shaped extension of PCT that dips in the medulla, consists of Descending Ascending limb Lower half Upper half (its way back to the cortex Thin segment of loop of Henle Thick segment of loop of Henle (attenuated flat epithelium) cuboidal cells with extensive basilar C- Distal Convoluted Tubule: 5 mm in cortex Made of epithelium is lower than that of the proximal tubule. No distinct brush border, (few microvilli) D- Collecting Ducts: distal tubules coalesce to form collecting ducts = 20 mm long → pass through renal cortex , medulla to empty into the pelvis at the apexes of the medullary pyramids. Lined by 2 types of cells Principal cells (P cells) Intercalated cells (I cells) Predominant relatively tall cells Smaller number, found also in DCT Concerned with Concerned with H secretion + Na reabsorption in exchange with K or H,Controlled by aldosterone Water reabsorption controlled by ADH 4  Types of nephrons According to location of glomeruli in cortex Cortical nephron (85 %) Juxtamedullary (15 %) Glomeruli In outer cortex, close to surface In inner cortex (deep), near to medulla Loop of Henle Short Long Penetrate short distance in medulla Penetrate long distance in medulla no further than the junction between (dips deeply) inner & outer medulla Capillaries Network of peritubular capillaries Vasa recta surround tubule (specialized U shaped peritubular capillaries) (lie side by side with loop of Henle) Special Function Play a role in concentration of urine Juxtaglomerular Apparatus Definition Specialized tubular and vascular cells at vascular pole where afferent & efferent arterioles enter and leave the glomerulus Function 1. Autoregulation of renal blood flow & GFR during changes in ABP 2. Regulation of ABP via RAAS Consists of 1- Macula densa 2- Juxtaglomerular cells Modified tubular cells in early (initial) distal tubule Epithelioid granular cells in the media of afferent that comes in contact with afferent & efferent arterioles.arterioles (lesser in efferent arterioles). Function: chemoreceptor: monitor composition of the Function: baroreceptors, stimulated by ↓ renal tubular fluid (NaCl load) perfusion pressure or hypovolemia→ secrete renin 5  Renal blood flow 1.2 -1.3 liter / minute = 21 % of cardiac output. Two capillary beds associated with nephron: Glomerular capillary bed Peritubular capillary Arise from afferent arteriole. Arise from efferent arteriole. High pressure = 60 mmHg→ cause rapid filtration Low pressure =13 mmHg → cause fluid reabsorption from ISF to blood ✓ Highest capillary pressure due to: Renal artery: direct branch of abdominal aorta Afferent arterioles: short, straight branches of interlobular arteries Efferent arterioles resistance higher than afferent arteriole Regional Blood Flow Renal cortex: receive 98 % of RBF for filtration Renal medulla: receive 2 % (sluggish blood flow) to form concentrated urine Measurement of RBF: see later 6  Regulation of the renal blood flow 1. Autoregulation of the renal blood flow & GFR: Renal blood flow & GFR are kept constant despite marked changes in ABP (90 – 220 mmHg) by auto-regulatory mechanisms (by change in vascular resistance) Present in denervated & isolated kidney (independent on nerves or hormones) A- Myogenic autoregulation: 1st line rapid defense against rapid change in ABP ↑ABP up to 200 mmHg→ stretch afferent arteriole→ open Ca++ channels → VC →↑resistance →prevent excessive increase in flow (vice versa) At low pressure: VD (relaxation) →↓resistance→ maintain constant flow B- Tubulo-glomerular balance (feedback mechanism) buffer changes of ABP on GFR ↑ ABP→↑RBF & GFR ↓ABP→↓ RBF & HPGC →↓GFR → ↑Solutes, H2O delivery at macula dense → ↓ flow rate at loop of Henle → macula dense cells ↑active Na →↑ Na, Cl reabsorption in ascending loop of Henle → reabsorption with ↑production of adenosine ↓Na, Cl at macula dense by breakdown of ATP → Macula dense stimulate release of renin from JGC → that cause VC of afferent arterioles → ↑ formation of angiotensin I, converted to AgII→ →↓RBF, HPGC, GFR back to normal → VC of efferent arteriole→↑ HPGC & ↑GFR + VD of afferent arteriole Aim: maintain constant GFR & precise control of renal excretion of water and solutes despite marked changes in ABP 2. Nervous regulation (sympathetic) of renal blood flow (α receptor)→ cause VC →↓ RBF & GFR as in (exercise & hypovolemic shock) 7  Formation of urine 1- Glomerular filtration 2- Tubular reabsorption 3- Tubular secretion From glomerular capillaries into Transfer of water & solutes From Transfer of solutes From peritubular Bowman's capsule tubular lumen (filtrate) back into capillaries into tubular lumen. Fluid free of proteins (colloid). peritubular capillaries Urinary excretion rate = Filtration rate - reabsorption rate + secretion rate Glomerular membrane o Separates blood in capillaries from filtrate in Bowman's capsule (3 layers) 1- Capillary endothelium 2- Basement membrane 3- Podocytes Have relatively large fenestration Meshwork of Collagen & Epithelial cells line outer surface (holes) (perforation) -ve charges proteoglycan fibril Have many pseudopodia 70-90nm (have large spaces) → Interdigitate to form slit pores → Not barrier for filtration of Major barrier (25 nm) proteins prevent filtration of proteins Total surface area of glomerular membrane= 0.8m2 Mesangial cells: stellate contractile cells between basement membrane & endothelium at bifurcation of the capillaries Functions of the mesangial cells: 1. Regulation of GFR: Have receptors for vasoactive substances Contraction of mesangial cells →↓surface area →↓filtration (vice versa). 2. Immune function→ Take up immune complexes and secrete cytokines 8  Permeability of glomerular membrane 50 times > capillaries in skeletal muscle. Highly selective: determined by A- Size of solutes Neutral substances < 4 nm Neutral substances > 8 nm Freely filtered (Na, glucose: freely filtered) Not filtered Between values, filtration is inversely proportionate to diameter B- Charge of solutes o -ve charged are filtered less easily than +ve charged molecules of equal diameter due to -ve charges in basement membrane o Albumin glomerular concentration = 0.2% of its plasma concentration in spite of its effective molecular diameter of 7 nm (due to its negative charge). o In kidney diseases: -ve charge are lost without ↑in pores size → cause Albuminuria Glomerular filtration rate (GFR) Definition Volume of filtrate formed by glomeruli of both kidneys/minute Normal GFR 125 ml/min in men. 10% less in women. 125 ml/min = 7.5 L/h =180 L/day. (60 times plasma volume) Whereas normal urine volume is 1 L/day, ≥ 99% is reabsorbed Both blood urea nitrogen and plasma creatinine ↑when GFR ↓. GFR ↓ by 1 ml/min/year with age, although plasma creatinine remains constant because of ↓muscle mass. GFR = best kidney function test 9  Control of GFR (forces) Starling equation: GFR = KF (HPGC - HPBC) - (GC - BC) = KF (HPGC — HPBC — GC +  BC) 1. Hydrostatic pressure gradient across capillary wall HPGC= hydrostatic pressure in glomerular capillaries (mmHg). HPBC= hydrostatic pressure in Bowman's capsule 2. Osmotic pressure gradient across capillary wall GC = osmotic pressure of plasma proteins in glomerular Capillaries BC = osmotic pressure of proteins in the filtrate 3. KF = glomerular ultrafiltration co-efficient (ml/min/mmHg), depends on Permeability of glomerular membrane 3 Effective surface area 4 Not measured directly GFR = KF X NFP 125 𝑚𝑙 /𝑚𝑖𝑛 KF= GFR/ NFP= = 12.5 ml/min/1mmHg = GFR / 1mmHg of filtration pressure. 10 𝑚𝑚𝐻𝑔 Forces favoring filtration (mmHg): Forces opposing filtration HPGC =60 mmHg HPBC = 18 mmHg BC= 0 mmHg (no protein is filtered) (repelled by –ve charge) GC = 32 mmHg. Net filtering pressure = 60 - 18 - 32 = 10 mmHg. Measurement of GFR: see later 10  Factors affect GFR Starling equation:……. 1. Filtration coefficient (Kf): o ↑KF→ ↑GFR (vice versa) o Depends on Permeability & Surface area Permeability: ↑thickness of glomerular membrane (as in uncontrolled DM & HTN)→↓permeability Surface area of glomerular capillaries: affected by A- Contraction of mesangial cells B- Relaxation of mesangial cells At point where capillary loop bifurcate shift blood from some capillary e.g. by Vasopressin, Norepinephrine, Endothelin, e.g. by ANP, CAMP, PGE2, thromboxane, leukotrienes A, D, histamine, PGF2 dopamine ↓surface area→↓ GFR ↑surface area→↑ GFR C- Some diseases as chronic uncontrolled DM→↓ number of functional capillaries→ ↓surface area 2. Glomerular capillary hydrostatic pressure ↑ HPGC→ ↑ GFR: Diameter of afferent arteriole Diameter of efferent arteriole Arterial blood pressure VD: bradykinins, PGE2, PGI2 Renal blood flow & GFR are kept constant despite marked → ↑HP GC →↑ GFR changes in ABP (90 – 220 VC: noradrenaline (sympathetic) Moderate VC (angiotensin II) →↑ mmHg) by auto-regulatory → ↓ HPGC → ↓ GFR resistance→↑ HPGC → slight mechanisms. ↑ Sympathetic e.g. during ↑GFR. When Mean systemic exercise→↓GFR < 50% of normal pressure drop < 75 mmHg→ sharp drop in GFR Mechanism of Auto-regulation of RBF & GFR: Myogenic autoregulation & Tubulo-glomerular feedback see before 11  3. Bowman’s capsule hydrostatic pressure o ↑ HPBC e.g., stone in ureter→↓GFR 2. 4. Glomerular colloid osmotic pressure concentration of plasma proteins ↑ GC e.g., dehydration → ↓ GFR ↓ GC e.g., hypoproteinemia→↑ GFR. 5. Renal Vasodilators: o PGE2, PGl2 & bradykinin → cause VD →↑ RBF and GFR. o Anti-inflammatory drug (aspirin & ibuprofen) →↓PG formation →↓GFR → may lead to renal failure o Sympathetic & angiotensin II→↑PG synthesis → protect kidney from severe VC as in severe CVS stress like hemorrhage. 6. Autonomic nerves (sympathetic) (α receptor) → cause VC →↓ RBF & GFR 7. Effect of protein intake ↑RBF and GFR. o ↑protein intake →↑amino acids in blood→ filter in Bowman's capsule →↑ amino acids and Na+ reabsorption in proximal tubules (cotransport) →↓ Na delivery at macula dense→ tubule-glomerular feedback 12  Plasma Clearance/ Renal Clearance of a substance Definition volume of plasma cleared from certain amount of substance excreted in urine / minute. Volume of the plasma necessary to supply the amount of substance excreted in urine / unit time Calculation Amount of substance (X) cleared from plasma / min = amount of substance (X) excreted in urine / min 𝑈 ×𝑉 CX X PX= UX X V C (clearance) = 𝑃 ✓ CX= Cleared volume of plasma from X / minute. ✓ PX = Plasma concentration of X / ml plasma ✓ UX= Urine Concentration of X / ml urine. ✓ V = Volume of urine / min. (Urine flow rate) Importance 1- Study tubular handling of different substances in the filtrate Substance Clearance ml / min Tubular Handling Inulin 125 Neither reabsorbed nor secreted Urea < 125 Partially reabsorbed Glucose 0 Completely reabsorbed Creatinine 125-650 Partially secreted PAHA 650 Completely secreted 2- Measurement of GFR A- Inulin Clearance test Steps large dose of inulin is injected IV followed by sustained infusion →to keep constant arterial plasma level After equilibration, urine and plasma samples are collected to determine inulin conc. Characters of Inulin Polymer of fructose , with M.W. 5200, found in dahlia tubers Easy to measure in plasma and urine Not metabolized, No effect on GFR Freely filtered (not bound to plasma proteins) Concentration of inulin in plasma = concentration of inulin in filtrate. Not reabsorbed or secreted. Amount filtered/min = amount excreted in urine / min. Cin X Pin= Uin X V Not stored in the kidneys 13 B- Creatinine Clearance = Creatinine is an endogenous substance formed from creatine in muscle at constat rate Characters of creatinine Easy to measure, Endogenous→ used as an index of renal function Freely filtered Not reabsorbed Partially secreted → GFR measured by creatinine clearance is slightly higher than GFR measured with inulin Cockcroft and Gault formula: estimate creatinine clearance (GFR) from plasma creatinine level without any urinary measurement. (140−𝑎𝑔𝑒)𝑋 𝑤𝑒𝑖𝑔ℎ𝑡 (𝐾𝑔) 𝐆𝐅𝐑 = ( X 0.85 For woman), because of less muscle mass 𝑷𝒄𝒓 𝑿 𝟕𝟐 3- Measurement of renal plasma flow Para-amino Hippuric acid (PAH) clearance Characters of Para-amino Hippuric acid Freely filtered Not reabsorbed Completely secreted (from peritubular capillaries) in a single circulation via the kidney. ▪ Extraction ratio of PAH =90% (Only 90% of PAH in renal arterial blood is removed in a single circulation through the kidney) ▪ Amount of PAH in the effective plasma of renal artery = amount of PAH excreted in urine. ▪ U X V ERPF = PAH CPAH = effective renal plasma flow (ERPF) PPAH ▪ Actual renal plasma flow (RPF) = ERPF / extraction ratio ▪ Renal blood flow = RPF /1 – Hematocrit Value 4. Calculation of filtration fraction: ratio of the GFR to the renal plasma flow. (fraction of RPF that is filtered) GFR is determined by inulin clearance/ RPF is determined by PAH clearance. Normal value = 0.16 - 0.20 filtered, (remaining 80% pass via efferent arteriole) Problem Concentration of PAHA in urine (UPAH) = 14 mg/ml 14 x 0.9 ERPF = = 630 ml/min. Urine flow (V) = 0.9 ml/min 0.02 Concentration of PAHA in plasma (PPAH) = 0.02 mg/ml RPF = 630 / 0.9 = 700 ml/min. Extraction ratio = 0.9 700 HV = 45% RBF = = 1273 ml/min. 1 - 0.45 Calculate the RBF 14  Tubular Processing of the Glomerular Filtrate Result in ↓volume Change composition by processes of tubular reabsorption and secretion Urinary excretion rate: see before Tubular Reabsorption involves: Transport of the substance across tubular epithelium into ISF Transported from ISF into peritubular capillaries. Type of transport across the tubular epithelium Transcellular: Solutes are reabsorbed or secreted through cells Paracellular: solutes are reabsorbed or secreted through the tight junctions between cells. Mechanism of tubular transport Active transport Passive transport Primary active transport Secondary active transport Co-transport Counter-transport A. Active transport: against concentration or electrical gradient 1- Primary active transport Energy: from ATP hydrolysis by membrane bound ATPase (component) of a carrier (transporter) that binds and moves solutes across the cell membrane. Example: Sodium reabsorption across PCT At the basolateral border At the luminal border Na+ - K+ ATPase pump: Na+ diffuses across the luminal membrane Extrudes 3 Na+ into ISF in exchange for 2 K+ in → from the tubular lumen into the cell Creating a negative potential - 70 mV within the cell. due to electrochemical gradient Low intracellular Na+ concentration 15 2. Secondary active transport: Energy: not directly from ATP or high-energy phosphate sources. 2 types: A- Co-transport: reabsorption of glucose is linked to passive reabsorption of sodium dependent on active sodium potassium pump at basolateral border At the luminal border At the basolateral border Glucose and Na+ bind to a common carrier SGLT-2 Na+ is pumped out of the cell into lateral in the luminal membrane. intercellular spaces. As Na+ diffuses along its electrochemical gradient Glucose is transported by GLUT-2 into ISF by Glucose is introduced into the cell. facilitated diffusion B- Counter transport: reabsorption of one substance is linked to secretion of another substance secondary active secretion of H + into the tubule At luminal membrane, of PCT Sodium - hydrogen counter transport As Na+ is carried to the interior of the cell, H+ is forced outward in opposite direction into the lumen B-Passive Reabsorption: 1. Passive Reabsorption of Chloride: via paracellular pathway following Na+ reabsorption. Reabsorption of Na+→ create negatively charged lumen → causes passive diffusion of Cl 2. Osmosis of Water Reabsorption of solutes → ↓ their concentration inside the tubule & ↑ in ISF →creates concentration gradient →causes osmosis of water from the tubular lumen into ISF mainly through paracellular route. 3. Passive Reabsorption of Urea Reabsorption of water→↑urea concentration in tubular lumen → creates concentration gradient →favoring reabsorption of urea. About 50% of the filtered urea is passively reabsorbed from tubule and the remainder passes into urine. 16 Tubular Transport Maximum→ maximum transport rate for actively transported substances (mg/minute). Require specific carriers and enzymes When carrier system is saturated→ Tm is reached→ no further increase in transport as tubular load increase. Glucose reabsorption exhibit Tm Threshold for substances that have a tubular maximum: threshold concentration in plasma Below which→ none of substance appears in the urine Above which → progressively large quantities appear in urine Gradient - time Transport (For passively transported substances by diffusion), determined by: 1. Electro-chemical gradient for the substance across the membrane. 2. Tubular flow rate (the time that the fluid containing the substance remain within the tubule) Na+ obey gradient-time transport in PCT (Despite actively transported), as rate of active transport at basolateral borders > >>> rate of its diffusion at brush border Absorption by peritubular capillaries by bulk flow as venous end of capillary Forces favor reabsorption Forces oppose reabsorption Hydrostatic pressure in renal ISF (6mmHg) Hydrostatic pressure inside peritubular capillaries (13mm). Colloidal osmotic pressure of peritubular Colloidal osmotic pressure of renal ISF capillaries (32 mmHg) (15mmHg) Net reabsorptive Force = (32 + 6) - (13 + 15) = 38-28= 10 mmHg Uptake of fluid & solutes by the peritubular capillaries is matched to the net reabsorption of water & solutes from tubular lumen into ISF 17 Na+ Handling / Reabsorption by the Renal Tubule Na is the main ECF cation, 90 % of osmotically active solutes→ maintain ECF volume Na+ is reabsorbed at all segments except descending segment of loop of Henle 1. Proximal Tubule reabsorb 65% of filtered Na+ (not depend on aldosterone) Mechanism of Na reabsorption Primary active transport (obey gradient time transport) At basolateral border: Na+ K+ ATPase pump → keep low intracellular Na+ concentration At luminal border: Na+ diffuses from tubule into cell (electrochemical gradient) First half= early PCT Late half Na+ reabsorbed by Na+ is reabsorbed with Co-transport with (sulphate, PO4, organic acid (lactate, citrate) Cl- (passive diffusion) Co-transport with all filtered glucose, amino acids through paracellular route Responsible for reabsorption of HCO3 (85-90 %), consequent with H secretion Counter-transport with H+ via (Na+ - H+ exchange) 2. Loop of Henle &early distal tubule: Thin descending limb Ascending limb =25% No capacity to reabsorb Na+ Thin part: (Absence of Na+ channel Reabsorb NaCl passively / impermeable to water→↓ tubular osmolarity Thick part: from luminal membrane) Reabsorb 25% of filtered Na via 1Na+, 1K+ & 2Cl- co-transport Reabsorb water in luminal membrane (2nd active transport) Most K+ that enters the cell, refluxes back into lumen via K+ leak channels to: a) Ensures sufficient K+ conc. for optimal function of co-transporter. b) Cause Net positive potential in lumen → facilitates paracellular reabsorption of several cations as Ca++, Mg++ ,Na+, 1K Bartter's Syndrome Cause Defect in Na+ - K+ - 2 Cl- cotransporter in luminal membrane of thick ascending limb Result Loss of Na+, K+, Cl-, ca2+ → salt wasting, volume depletion, hypercalciuria, hypokalemia, metabolic alkalosis. 18 3. Early distal tubule Cortical diluting segment. ▪ Reabsorption NaCl by Na+-Cl- cotransporter ▪ impermeable to water (Ascending limb and early distal tubule are called diluting segment) 4. Late Distal Tubule and Collecting Duct: Final adjustment, under hormonal control (aldosterone) to achieve (Na homeostasis) ▪ Principal cells: reabsorb < 10 % of filtered Na+ in exchange with K+ secretion ▪ Mechanism: At basolateral membrane: Na+ - K+ ATPase? In luminal membrane: Na+ and K channels o Na diffuse into P-cells (electrochemical gradient) , K diffuse out in ISF (chemical gradient) o Concomitant paracellular passive reabsorption of Cl (as a result of luminal negative potential caused by Na transport) 19  Regulation of Na+ Excretion Amount excreted (1 – 400 mEq/L) adjusted to the amount ingested Variation in Na excretion: affected by (amount filtered , amount reabsorbed) Factors affecting GFR, tubular reabsorption will affect renal excretion of Na 1. GFR: "Glomerulo-tubular Balance" ↑GFR → ↑ filtered Na+ →↑reabsorption of Na+ (solutes), H2O →slight ↑in excreted Na. Mechanism in isolated kidney (independent of hormones) Renal tubules reabsorb constant % of filtered Na + (2/3 or 65%) rather than a constant amount Site PCT mainly, Loop of Henle Importance a. Prevent overloading of DCT when GFR increase b. Prevent inappropriate losses of Na+ and water in urine when GFR suddenly increase 2. Rate of Tubular Flow Slow flow rate (as in ↓GFR) →↑tubular reabsorption of Na+ 3. Effect of ABP on tubular reabsorption "Pressure Natriuresis & Diuresis " ↑ABP →↑ Na+ & H2O excretion Mechanism compensatory mechanism for regulation of ABP independent of nervous or hormone 1. ↑ABP →↓angiotensin II secretion 2. ↑ ABP →↑hydrostatic pressure in peritubular capillaries → ↑hydrostatic pressure in ISF →enhance back leak of Na+ into lumen →↓net reabsorption of Na & H2O→↑urine output 4. Hormonal Control: Hormones →↑Na+ reabsorption Aldosterone (mineralocorticoid) Mechanism: Acts on P cells on DCT & CD o At basolateral membrane: ↑Na-K ATPase o In luminal (apical) membrane: ↑ Na+ channel → ↑Na+ reabsorption in exchange with K+ or H+ Glucocorticoid Mechanism: weak mineralocorticoid effect=↑Na+ reabsorption Sex Hormones (estrogen) ↑Na+ reabsorption 20 Angiotensin II: Mechanism: ↑Na+ reabsorption Most powerful Stimulates aldosterone secretion Direct action on PCT: Stimulates Na+ - K+ ATPase pump. sodium-retaining hormone Stimulates Na+ - H+ counter transport. VC of efferent arterioles → ↓hydrostatic pressure, ↑osmotic pressure of peritubular capillaries (through increasing filtration fraction) Hormones →↓Na+ reabsorption Atrial natriuretic peptide (ANP) Mechanism: ↑ NaCL & water Excretion in case of ✓ ↑ GFR → ↑filtered Na+ →↑Na+ excretion via marked expansion of ECF. Relaxation of mesangial cells→↑ surface area VD of afferent ✓ Inhibit renin secretion →↓angiotensin-II & aldosterone. ✓ On collecting ducts: Inhibit Na+ channels & Na+ - K+ ATPase PGE2 ↑Na+ excretion through: o At basolateral membrane: Inhibit Na+ - K+ ATPase. o At apical membrane: Inhibit Na+ channels. Endothelin ↑PGE2. 5. Sympathetic stimulation: ↑Na+ reabsorption &↓Na+ excretion by VC of renal vessels (via 1 receptor) →↓RBF and GFR ↑renin ((via 1receptors on Juxtaglomerular apparatus) & angiotensin II Direct action on renal tubule (Via  & ) →↑ Na reabsorption 6. Diuretics →↑ Na+ excretion Carbonic anhydrase inhibitor= acetazolamide = Diamox:↓ H secretion + ↑ Na, K, HCO3 and water loss Loop diuretic= Lasix (furosemide): inhibit Na+ K+2Cl- at thick ascending limb of loop of Henle → ↑ electrolyte excretion in urine Thiazide diuretic: inhibit NaCl reabsorption by early DCT Aldosterone inhibitor= Aldactone: inhibit Na- K exchange at DCT & CD→ ↑Na excretion & K retention Xanthine as caffeine: ↑GFR + ↓Na reabsorption by renal tubule Ethanol: inhibit ADH secretion 21  Tubular Handling of K+ by the Renal Tubule ✓ Both reabsorbed and secreted ✓ Normal rate of k+ filtration = 756 mEq/day (GFR x plasma K+ level = 180 x 4.2). 1. PCT Reabsorb 65% of filtered K+ 2. Thick ascending limb of Loop of Henle Reabsorb 25% of filtered K+ actively with Na+ and Cl- (co-transport) 3. Distal tubule and Collecting Tubule Reabsorb or secrete K+ depending on dietary intake. A- K+ reabsorption by intercalated cells: Occurs only on a low K+ (K+ depletion) Reabsorb 5% of filtered K+ actively (1ry) Mechanism A- At luminal membrane: ATP dependent K+ - H+ antiporter B- At basolateral membrane: K+ channels B- K+ Secretion by principal cells into tubular lumen in late DCT & collecting tubule Amount: variable, depends on dietary K+, aldosterone level, urine flow rate and acid-base status Mechanism: under effect of aldosterone A. At basolateral membrane: o Na+-k+ ATPase pump Na+ into ISF & K+ into cell → ↑intracellular K+ conc. B. At luminal membrane: K+ diffuses through o K+ - channels (electrochemical gradient) o K+ Cl- co-transporter 22 Regulation of Tubular Potassium Secretion: DCT, CD 1. Plasma Potassium Concentration ↑ plasma K+ conc. →↑ K+ secretion Mechanism: a) At basolateral membrane: ↑activity of Na+ - K+ ATPase by: Direct effect of extracellular K+ ↑aldosterone secretion (by ↑K+ level). b) At luminal membrane: ↑number of K+ channels by aldosterone. 2. Flow rate in the distal tubule ↑flow rate → flushing down the secreted potassium → ↓K+ conc. in the tubular lumen → enhance the diffusion gradient →↑ K+ secretion Diuretic therapy → cause K+ depletion. 3. Aldosterone Hyperaldosteronism→↑K+ secretion→ cause hypokalemia (vice versa) 4. Acid - Base Status Acidosis: ↓K+ secretion. (vice versa) Mechanism: Acidosis→ ↓ intracellular K+ concentration in P-cells →↓ diffusion gradient →↓ K+ secretion via Inhibition of Na+ - K+ ATPase efflux of K+ and uptake of H+ from ECF 23  Glucose reabsorption by renal tubules Site all filtered glucose is reabsorbed in early proximal tubule urine is nearly free of glucose Mechanism: 2nd active transport At luminal brush border 2nd active transport Glucose & Na+ bind SGLT-2 (sodium dependent glucose transporter) (97 %), SGLT-1 in late PCT reabsorb 3 % As Na+ diffuse along its electrochemical gradient glucose is carried into the cells against concentration gradient Glucose transport at luminal border is blocked by: o Ouabain: blocks Na+ - K+ ATPase. o Phlorizin: competes with glucose for SGLT-2 carrier At basolateral border Glucose is carried into ISF by GlUT-2 (facilitated diffusion down chemical gradient) ↑glucose reabsorption maintain hyperglycemia in type II DM Management: SGLT-2 inhibitors as canagliflozin, dapagliflozin Transport Maximum of glucose (TmG) Definition maximum amount of glucose (in mg) reabsorbed / minute. Indicator of reabsorptive capacity of the kidney Determined by number of glucose carriers in PCT Value 300 mg / min in female 375 mg /min in male Renal threshold for glucose Definition plasma glucose level at which glucose appears in urine rather than normal minute amount Value Arterial blood: 200 mg / dl Venous blood: 180 mg % ( at lower plasma conc. Than Tm) 24  Glucose Titration Curve and Tm Relationship between plasma glucose concentration and glucose reabsorption, filtration and excretion Obtained experimentally by infusion of glucose Measuring rate of reabsorption as plasma concentration is increased. A- Filtered load of glucose = GFR x [P] glucose as Glucose is freely filtered ↑plasma glucose concentration →↑filtered load linearly. B- Reabsorption of glucose At plasma glucose At plasma glucose At plasma glucose concentrations concentration < 200 mg/dl concentration > 200 mg/dl > 300 mg/dl All filtered glucose is reabsorbed Some filtered glucose is not no↑ in rates of reabsorption as (many Na+ glucose carriers) reabsorbed as some carriers Carriers are fully saturated are saturated (limited number) Reabsorption curve is identical to Reabsorption curve bends Reabsorption reaches maximal filtration curve value Tm (reabsorption = filtration) C- Excretion of glucose At plasma glucose concentration At plasma glucose concentrations At plasma glucose conc. < 200 mg/dl > 200 mg/dl > 300 mg/dl All filtered glucose is reabsorbed Most filtered glucose is reabsorbed, Additional filtered glucose is None is excreted Some is excreted excreted in urine Excretion curve increases linearly paralleling that for filtration. Tm for glucose is reached gradually, rather than sharply producing splay Splay bending of reabsorption curve between threshold (200) and Tm (300) (as reabsorption is approaching saturation) Explanation: due to heterogeneity of nephrons Tm reflects the average Tm of all nephrons Some nephrons reach Tm at lower plasma concentration than others, and glucose will be excreted in urine before the average Tm is reached. 25 Glycosuria Definition excretion of glucose in urine in considerable amounts. Causes Diabetes Mellitus Renal glucosuria (congenital defect in glucose transport) Blood glucose level > renal threshold Glucosuria at Normal plasma glucose level Renal threshold for glucose is ↓ < 180 mg % TmG is markedly ↓ Excretion of osmotic active glucose → cause loss of water (osmotic diuresis), Na+ , K+ 26  H2O reabsorption Passive process throughout the whole nephron except ascending loop of Henle 2 types A- Obligatory water reabsorption 87% of filtered water reabsorbed by osmosis independent of ADH 1- Proximal tubule (65%) 2- Loop of Henle: (15%) 3- Early Distal tubule Main site Descending limb Ascending limb Reabsorb 65% of solutes No solutes Actively reabsorb solutes Reabsorb Solutes (create osmotic gradient) (Na+) reabsorption (Na+ Cl-, K+ , Ca++) into medullary ISF Highly permeable Highly permeable Impermeable Relatively impermeable Reabsorb 65% of H2O Reabsorb 15% of H2O by No H2O reabsorption to H2O via aquaporin-1 channel in osmosis into hypertonic the luminal membrane) medullary ISF Osmolarity of tubular Osmolarity of tubular fluid = Osmolarity of tubular Osmolarity of tubular fluid fluid = Plasma hypertonic medullary ISF fluid is ↓= very diluted is ↓= diluted (iso-osmotic) (Equilibrium) (100 mOsm/L), (60 mOsm/L.). (300 m Osmo/L) 1200 -1400 at end of by end of ascending limb descending limb of juxta medullary nephron Diluting segment? B- Facultative water reabsorption: 13% of filtered water is controlled by ADH in late DCT, collecting duct Final adjustment of water according to body needs Role of ADH ADH ↑ H2O permeability via insertion of aquaporin-2 channel in luminal membrane of principal cells of late DCT, cortical, medullary CD Water diffuse from the cell into ISF through aquaporin-3,4 at basal border of P cells until osmotic equilibrium is reached (same as medullary ISF) 27  Urine concentration and dilution Depends only on the extent of facultative water reabsorption. In dehydration: water is conserved, concentrated urine with high osmolarity is excreted (vice versa) Requirements for excreting concentrated urine 1. High ADH: (role of ADH)? 2. Hyperosmotic renal medulla a. Osmolarity of medullary ISF increases from 300 mOsm/L in superficial layer of medulla to 1200 mOsm/L in deep parts in the tips of papillae. b. High osmolarity →cause H2O osmosis from renal tubule into renal ISF (carried by vasa recta) Mechanisms produce hyperosmotic renal medullary ISF 1. Countercurrent multiplier system inflow runs parallel to, counter to , in close proximity to outflow for some distance. Function of loop of Henle of juxtamedullary nephron Adds solutes to medullary ISF→ creates medullary hyperosmolarity Ascending limb Descending limb Thick segment: Much less Impermeable to Na+, Cl, urea At basolateral border: Na K ATPase pump At luminal border: Na+, K+ and Cl- are co transported Ca, HCO3, Mg are also reabsorbed Thin segment: passive reabsorption of Na+ & Cl Down conc. gradient Impermeable to water Permeable to water (H2O diffuse from into medullary ISF by osmosis) ↑ Osmolarity of medullary ISF to 1200 at the tip ↑ Osmolarity of Tubular fluid from 300 to 1200 Tubular fluid → become diluted (100 mosm/L) at tip of the loop as it enter DCT = reach osmotic equilibrium with medullary ISF (cause ???) 28 2. Countercurrent exchange system of (U shaped Vasa recta Highly permeable to water and solute Descending limb of the vasa recta Ascending limb of vasa recta Na+, Cl (solutes) diffuse from medullary ISF into Na+, Cl diffuse back from blood into medullary ISF blood along concentration gradient along concentration gradient H2O diffuses from blood into ISF H2O diffuses from ISF into blood (vasa recta) Blood is hypertonic at tip of vasa recta= 1200 mOsm /L (Reach osmotic equilibrium with medullary ISF). Vasa recta does not create medullary hyperosmolarity but prevent it from being lost (dissipated) (minimize loss of solute) Fluids & solutes is reabsorbed into blood by bulk flow through colloid and hydrostatic pressures 3. Role of urea to hyperosmotic renal medullary ISF: urea cycling (trapping) (urea handling) a. 40 % of the filtered Urea is passively reabsorbed n PCT Mechanism: as water is reabsorbed→↑ urea concentration in the tubular fluid → create concentration gradient→ favoring passive reabsorption of urea b. Loop of Henle is slightly permeable to urea (from ISF to renal tubule) c. Late DCT, cortical collecting duct, outer medullary collecting ducts are relatively impermeable to urea →↑ urea conc. When ADH is present. d. At inner medullary CD→ urea is reabsorbed (diffuse) into medullary ISF (facilitated by ADH through insertion of UT-1 and UT-3) → adding 50% of osmolarity (500 mOsm/L) of renal medullary ISF High protein diet →↑ability of the kidney to form concentrated urine in CD (vice versa) e. Urea cycle: urea diffuses back from medullary ISF into thin loop of Henle → then back to medullary CD again Circulate through theses terminal parts several times before it is excreted 4. Sluggish medullary blood flow receive 1-2 % of total renal blood flow → minimize solute loss from medullary ISF 29  Requirements for Excreting a Dilute Urine Solutes are reabsorbed > water in certain segments of renal tubule. Ascending limb of the loop of Henle DCT, cortical collecting duct, medullary collecting ducts Impermeable to water Impermeable to water in absence of ADH Reabsorb Na+, K+, Cl- Reabsorb NaCl. Tubular fluid → become dilute as it enters DCT Tubular fluid → become more diluted (Osmolarity = 100 mOsm/L) (osmolarity =50 mOsm/L) Disorders of urinary concentration A- Diabetes Insipidus Causes Central diabetes insipidus Nephrogenic diabetes insipidus Deficiency of ADH secretion due to lesion of Inability of the kidney to respond to ADH due to Hypothalamus Congenital defect in V2 receptors in collecting duct Hypothalamo-hypophyseal tract posterior pituitary Manifestations a. Polyuria: large amounts of dilute urine. b. Polydipsia: Drinking of large amounts of fluid→ keeps patients alive. If sense of thirst is depressed by loss of consciousness→ fatal dehydration. B- Syndrome of inappropriate ADH secretion (SIADH) Cause; Excessive secretion of ADH from Posterior pituitary Ectopic source as malignant tumor (e.g. bronchogenic carcinoma) Manifestations a. H2O retention→ expansion of ECF volume. b. Hyponatremia Cause: water retention →↓aldosterone secretion →↑urinary excretion of Na+ c. ↑urine osmolarity: because of ↓ H2O excretion & continuous excretion of Na+ d. Edema: due to ↓plasma osmolarity → water shift into the interstitial space. Treatment: drugs block ADH receptors. 30  Diuresis (↑rate of urine output ) Types 1. Water diuresis Cause drinking of large volume of H2O or hypotonic fluid. Onset start 15 min after drinking of water load → reaches maximum in 40 min. Mechanism ↓plasma osmolarity →Inhibit ADH →↓ facultative H2O reabsorption (impermeable CD) Result excretion of large volume of hypotonic Urine 2. Osmotic diuresis Cause presence of large amount of Un-reabsorbed solutes in renal tubule: e.g. a. ↑ filtered glucose (Uncontrolled diabetes mellitus) b. Infusion of large amounts of urea c. Infusion of osmotically active substances, not reabsorbed by renal tubule (as Mannitol) Mechanism a. Un-reabsorbed Solutes in PCT →hold water →↓ obligatory H2O reabsorption. b. H2O retention→↓Na+ concentration in tubular fluid → ↓ active Na+ reabsorption→ leads to Na+ retention in the renal tubule & consequently water. ↓medullary osmolarity due to ↓ active Na+ reabsorption from ascending loop of Henle → ↓ H2O reabsorption in collecting duct & descending limb of loop of Henle →↓ facultative H2O reabsorption. Result excretion of large volume of isotonic or hypertonic Urine (↑Na+ & electrolytes excretion) H2O diuresis Osmotic diuresis Production Drinking of large volume Presence of large amount of un- of H2O reabsorbed solutes in renal tubule. ADH secretion Inhibited Normal or increased H2O reabsorption ↓Facultative ↓Facultative and obligatory Solute excretion Not increased. Increased. Maximal urine flow Large volume 16 mL/min Large volume. Osmolarity of urine Hypotonic Isotonic or hypertonic 3. 3. Pressure diuresis see before. 4. Diuretic drugs see before 31  Secretion of Hydrogen & Reabsorption of Bicarbonate (Renal Control of Acid - Base Balance Most powerful (efficient) buffer mechanism. Site H+ is secreted in all renal tubule except descending and ascending thin limbs of the loop of Henle For each H+ secreted, one bicarbonate is reabsorbed. Bicarbonate is reabsorbed mainly by o Proximal tubule (85%) o Thick ascending loop of Henle (10%) o Collecting duct (4.8%) Renal tubules are poorly permeable to HCO3-. Reabsorbed HCO3- is formed in tubular epithelium from CO2 CA o CO2 (coming from the blood or formed by metabolism) + H2O→ H2CO3 →H+ + HCO3- H+ are secreted into tubular fluid →buffered by Bicarbonate/ Phosphate buffer in tubular fluid Ammonia synthesized by tubular epithelium Mechanism of H+ secretion and HCO3 reabsorption Secondary active transport Primary active secretion A- In PCT (85 %) C- in late DCT and collecting ducts. (4.8%) B- loop of Henle (thick ascending) and initial DCT (10 %) H+-ATPase pump at the luminal membrane Counter-transport mechanism of the intercalated cells Antiport carrier at luminal borders H+ is actively secreted → binds H+ and Na+ Na+ - independent Na+ diffuses into tubular cell Stimulated by aldosterone →↑900 folds. H+ diffuses into tubular lumen. For each H+ secreted, one bicarbonate is No H handling in……………………. reabsorbed Hydrogen secretion by these segments represent the fixed acids produced from metabolism of ingested proteins and phospholipids and responsible for regeneration of new HCO3 Hydrogen secretion in PCT, returns back the filtered HCO3 to the blood Hydrogen secretion by DCT, collecting duct generate new HCO3 32  Fate of H+ secreted 1. In PCT by NaHCO3 buffer (as before) 2. In Distal tubule and collecting duct A- Buffering by phosphate buffer a) 30 - 40 mEq of Na2HP04 is available/ day→ concentrated as it reaches DCT and collecting duct. b) H+ + Na2HP04→ NaH2PO4 + Na+ c) NaH2PO4 is excreted → cause most of titratable acidity in urine d) Na+ is reabsorbed with intracellular HCO3- e) Results: H+ secretion + net reabsorption of newly synthesized HCO3- B- Buffering by ammonia (NH3) a. NH3 is formed from glutamine Glutaminase i. Glutamine ⎯⎯⎯⎯⎯⎯⎯→Glutamic acid + NH3 b. NH3: is lipid-soluble →diffuses into tubular fluid c. H+ + NH3 → NH4+ d. NH4+ + Cl → NH4Cl (excreted in urine) e. Na+ is reabsorbed with intracellular HCO3- Importance of H+ buffering o H+ secretion in DCT and collecting ducts as long as ▪ pH of the fluid in these segments > 4.5 (limiting pH for H+ secretion). o If secreted H+ is not buffered→ this pH is reached rapidly → cause stop of H+ secretion. Factors affecting acid secretion 1. Aldosterone: ↑ H+ secretion in exchange with Na 2. Intracellular PCO2: ↑PCO2 (respiratory acidosis) →↑ intracellular H2CO3→↑ H+ secretion. 3. ECF K+ concentration: in hyperkalemia →↓H+ secretion (since both compete for secretion in DCT, CD) 4. Carbonic anhydrase inhibitor: inhibit hydrogen secretion 33  Kidney Function Tests 1. Blood Analysis A- Blood urea & blood urea nitrogen (BUN)= amount of nitrogen contained in urea. o Normal blood urea =20-40 mg/dL. o Importance: Poor guide to renal function as it varies with Protein intake Liver metabolic capacity Impaired kidney function. B- Plasma creatinine: Produced from muscle at a constant rate and completely filtered at glomerulus and very little is secreted by renal tubule. o Normal level= 0.6 - 1.5 mg/dL o Important measure of kidney function Normal BUN: creatinine ratio = 10:1. With dehydration, ratio = 20:1 or higher due to ↑urea reabsorption. C- Potassium level = 3.5- 5 mEq/L. (↑in renal insufficiency) D- Blood pH: Arterial pH = 7.4 Venous pH = 7.35 (Acidosis in renal failure) 2. Urine Analysis: A- Volume: normal 500 - 1500 ml/day I- Polyuria: ↑volume of urine= urine output > 3 L/day or > 40 ml/kg/24hrs in adults or > 2 L/m 2/24 hrs in children. ❖ Must be differentiated from frequency or nocturia, which may not be associated with an ↑in total urine output. ❖ Possible causes ↑fluid intake. Osmotic diuresis "diabetes mellitus" Diabetes insipidus. 34  II- Oliguria: decreased volume of urine= Urinary output < 400,ml per day in adult Or < 0.5 ml/ kg/h in children , < 1 mL/kg/h in infants ❖ Importance: one of the earliest signs of impaired renal function or acute kidney injury (AKI) ❖ Classification and causes Prerenal causes e.g. dehydration Intrinsic causes due to parenchymal damage e.g. glomerulonephritis Postrenal causes (obstructive uropathy): 2nd to urinary retention e.g. benign prostatic hypertrophy. III- Complete anuria: Acute vascular thrombosis, Total urinary obstruction. B- Presence of proteins in urine is indicative of glomerular damage. C- Specific gravity: normal 1010 -1020 Low: diabetes insipidus. High: diabetes mellitus Low fixed specific gravity (1010) occurs in chronic renal failure. 3. Tests depending on blood and urine analysis (Plasma Clearance): Creatinine clearance: best index for kidney function & GFR measurement. ↓in renal dysfunction Used in follow up in chronic kidney disease and to determine the proper time for initiation of dialysis or replacement therapy. 4. Imaging Techniques: Plain - X-Ray→ shows opaque calculi and calcifications in the urinary tract. Intravenous urography: injection of iodine -containing compound that is excreted by kidney e.g. diodrast. Radiographs are taken at intervals after injection → detects non - opaque calculi, strictures of urinary tract. Ultrasonography→ shows Renal size and position. Dilatation of the collecting system suggesting obstruction. Tumors and cysts. Computed Tomography (CT): detect tumors 35  Physiologic Anatomy of the urinary bladder 1. Body: smooth muscles = detrusor muscle → functional syncytium →↑ pressure in the bladder to 40-60 mm Hg → to cause emptying of the bladder. 2. Neck: 2-3 cm funnel - shaped extension of the body, surrounded by internal urethral sphincter (extension of the detrusor muscle) Functions of the internal sphincter a. Its natural tone→ keeps the posterior urethra empty of urine → prevents emptying of the bladder until the pressure in the bladder body rises > threshold level. b. Prevents reflux of semen into the bladder during ejaculation. External urethral sphincter voluntary skeletal muscle →consciously controls micturition. Innervation of the bladder and sphincters Parasympathetic Sympathetic Somatic Supplies Urinary bladder wall internal urethral External urethral (detrusor muscle) sphincter sphincter. internal urethral sphincter Origin S2 and S3 L2 S2 and S3 Afferent 1. Detect stretch in the 1. Fullness Sensation Transmits sensation of urine bladder & posterior urethra 2. Pain sensation due to flow from stretch receptors initiate micturition reflex over stretch or infection. in posterior urethra Efferent Contraction of bladder wall Contraction of internal Control external urethral urethral sphincter to sphincter Relaxation of internal prevent reflux of semen urethral sphincter. into the bladder during ejaculation 36 Micturition is emptying of urinary bladder when it becomes filled. 2 steps: 1- Filling of the bladder, 2- Micturition reflex: see later Mechanism of Bladder filling ▪ Peristaltic contractions along the ureter → force the urine from renal pelvis towards the bladder. ▪ Backflow (reflux) of urine from the urinary bladder into the ureters is prevented as ✓ Oblique course of ureters through the bladder wall for several cms and 1-2 cm beneath the bladder mucosa ✓ Normal tone of detrusor muscle compresses the ureters with ↑of pressure. ▪ Not much increase in intravesical pressure until the bladder is well filled. 2T Explained by Laplace law: P= r ✓ With bladder filling →↑ wall tension & radius→ slight ↑pressure ✓ At certain volume, T markedly increases & intravesical pressure increase sharply Cystometrogram Intravesical pressure = 0 when there is no urine in the bladder. Volume of urine intravesical pressure Segment la 50 ml ↑to 5-10 cm water Segment Ib ↑ to 200 - 300 ml Small ↑in pressure Segment II 400 ml Sharp rise in pressure 1st urge to void is felt at a bladder volume of 150 ml Marked sensation of fullness at 400 ml. 37 Micturition reflex Spinal autonomic reflex, initiated when tension in the wall rise > threshold level as volume reach 300 - 400 ml (in adult) Can be inhibited or facilitated by higher centers in cerebral cortex or brain stem Components: 1. Receptors: stretch receptors in the bladder wall and posterior urethra. 2. Afferent: Pelvic parasympathetic. 3. Center: S2 and S3. 4. Efferent: pelvic parasympathetic. 5. Effector and response: Detrusor muscle: contraction. Internal urethral sphincter: relaxation. Micturition reflex is self-regenerative: o Once it begins, Contraction of the bladder further activates the stretch receptors → further ↑in sensory discharge from the bladder & posterior urethera →further ↑in reflex contraction of the bladder. ▪ Once the micturition reflex becomes powerful enough, it causes another reflex → passes through pudendal nerve→ inhibit the external urethral sphincter Higher control of the micturition reflex in cerebral cortex & brain stem  Cortical Micturition Centre (CMC): in superior frontal gyrus →facilitate or inhibit micturition reflex. Facilitatory centers: a) Pontine centers: b) Posterior hypothalamus Inhibitory center: mid-brain Control micturition in the following way a) Partially inhibit micturition reflex except when micturition is desired. b) Prevent micturition even if micturition does occur by contraction of the external urethral sphincter. c) at appropriate time, cortical areas facilitate sacral centers to initiate micturition reflex & inhibit external urethral sphincter. 38 Mechanism of initiation of voluntary urination 1. Relaxation of the pelvic floor muscles leads to downward tug on detrusor muscle to initiate its contraction. 2. Voluntary contraction of the abdominal muscle→↑intravesical pressure → entry of urine in the bladder neck→ stretch of the bladder neck → stimulate stretch receptors→ excite micturition reflex. 3. Simultaneous relaxation of the external urethral sphincter. After urination, the female urethra empties by gravity. urine remaining in the male urethra is emptied by contraction of the bulbocavernosus muscle. Abnormalities of micturition =Urinary incontinence Deafferentation Denervation Spinal Cord damage Cause Damage of dorsal root by e.g. Destruction of Transection of the spinal cord syphilis (Tabes dorsalis) afferent & efferent leaving sacral segments intact. Micturition Abolished. Abolished 1.Spinal shock: lost. reflex 2.Recovery stage: return. Voluntary Lost. Lost. Lost. control Bladder Thin-wall Thick-wall Shock stage: Flaccid. Distended shrunken hyperactive. Recovery stage: Hypertrophied Hypotonic. (denervation with reduced capacity. Hypersensitivity) Urination The bladder fills to capacity Hyperactive Retention with overflow in and overflows few drops at a bladder expels shock stage. time because of intrinsic dribbles of urine. Automatic bladder in recovery response of detrusor muscle stage. hypersensitivity) 39  Acid Base Balance ❖ Total amount of H+ in ECF= very small compared to the amount produced / day. ❖ pH=-l og10 (H) =- Log 0.00004= 7.4 Slightly alkaline. Life is compatible within narrow range of pH= 7.35-7.45 Death occurs if the pH < 6.8 or > 8.0 ❖ Regulation of Abid - Base Balance (pH): 3 major systems 1. Buffer systems: minimize change in free H + concentration. 2. Respiratory system: eliminates H + derived from C02. 3. kidneys: excrete fixed acids and restores ECF buffers. Buffer System Combination of many buffers in the body, determines free H + concentration. Relation between pH and ratio of concentration of the buffer members. 𝒔𝒂𝒍𝒕 Expressed by: Henderson-Hasselbalch equation: pH of a buffer = pK+ log 10𝒂𝒄𝒊𝒅 pK: minus log dissociation constant. ✓ When Henderson-Hasselbalch equation is applied to the bicarbonate-carbonic acid buffer: ▪ [HCO3] = 24 mmol/L ▪ [H2C03] = PC02 x solubility co-efficient (0.03ml carbonic acid formed for each 1 mmHg PC02) =40 x 0.03 ▪ pK= 6.1 𝑯𝑪𝑶𝟑 (𝟐𝟒) ▪ pH of arterial blood = 6.1 + Log10 𝑯𝟐𝑪𝑶𝟑 (0.03 X40) = 6.1 + 1.3= 7.4 The effectiveness the buffer depends on: a) Amount of the buffer pair. b) PK of the buffer system: The buffer is most effective when its pH = PK. The nearer the PK to the pH of ECF→ the more is the effective of the buffer Role of buffers in regulation of acid-base balance Immediately trap H+ temporarily until respiratory and renal mechanisms act. They Only minimize the change in H + concentration. 40  Types of buffer systems: 1. Bicarbonate buffer system H2CO3/ BHCO3 B= Na or K 2. Phosphate buffer system BH2PO4/ B2HPO4 3. Protein buffer system: a) Plasma proteins. b) Hemoglobin c) Tissue proteins. Physiological importance of main buffers: Bicarbonate Buffer 1- Its concentration in ECF = 24mmol/L 2- Very effective buffer as its components can be controlled HCO3] is regulated by the kidneys. [H2C03] is regulated by the respiratory system. 3- Changes in pH that result from an alteration in either HC03- concentration or PC02 can be corrected by changing the other variable to preserve the buffer ratio. Hemoglobin Buffer: plays an important role in buffering C02 produced at the tissues (chloride shift phenomenon). 41 Respiratory control of pH (( Mechanism A- in metabolic acidosis: H+ stimulates R.C. via peripheral chemoreceptors→ Hyperventilation →↓C02 →↓carbonic acid and H + concentration incomplete correction of pH is but it is compatible with life. Final correction is brought about by the kidney B- In metabolic alkalosis: vice versa Effectiveness: Respiratory system return [H+] and pH 2/3 the way back to normal within minutes to hours after a sudden disturbance Buffering power = 1 - 2 times as all the chemical buffers combined, but has limited ability. Renal control of pH kidneys return pH back to normal within 12-24 hours in most cases. ( when respiratory system fails to completely restore [H+] to normal) Most efficient & powerful buffer mechanism through: Reabsorption of nearly most of the filtered HCO3 Regeneration of new HCO3 with secretion of fixed acids 42  𝑯𝑪𝑶𝟑 Acid - Base disturbance pH depends on ratio 𝑷𝑪𝑶𝟐 Acidosis (Arterial pH < 7.35) Alkalosis (pH > 7.45) Primary change is in PCO2 Primary change is in HCO3 Respiratory acidosis Respiratory alkalosis Metabolic acidosis Metabolic alkalosis Causes pH?? pH ?? PH pH ↑ arterial PCO2 >45 ↓ arterial ↓ plasma HCO328 Respiratory centers PCO27.45 Acidosis Alkalosis HCO3< 22 mEq/L PCO2>45 mmHg HCO3> 28 mEq/L PCO2