Renal Physiology PDF

Department of Physiology Lecture note On Renal physiology for PCI-Medical & Dental Students Abebaye A (BSC, MSc, PHD, AAU- Dept of medical 11/4/2024...

Department of Physiology Lecture note On Renal physiology for PCI-Medical & Dental Students Abebaye A (BSC, MSc, PHD, AAU- Dept of medical 11/4/2024 physiology) 1  Objectives To discus the – General functions of the system – Blood supply and innervation – Nephrons, parts and types – Renal autoregulation – Basic processes in the kidney Filtration, reabsorption and secretion – Diuretics, Acid-base balance – Renal diseases Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 2 medical physiology)  Renal system System of structures involved in :- – Excretion – Fluid balance – Electrolyte balance Consists of – Kidneys, ureters, urinary bladder and urethra and other microscopic structures Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 3 medical physiology)  Structure where vessels, nerves and ureter pass Kidney Renal Hilum Shape: bean shaped (humans) Weight: in humans, 300-400g Blood flow: ~1/3 of CO (~ 1000 ml/min at rest) Encased in a renal capsule Main excretory route Surrounded by fibrous tissue and limits its distention Fig 1: Anatomy of Kidney Renal pyramid is originated from the cortex and ends on to the renal pelvis Cortex--Pyramids--papillae--minor calyx--major calyx -- renal pelvises--ureter--urinary bladder --urethra Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 4 medical physiology)  Structures in the Kidney  Hilum: entrance of nerves, blood vessels, lymph, ureter Cortex: light outer region More blood flow Contains glomerli, PCTs,DCTs and cortical collecting ducts  Medulla: dark inner most layer Less blood Contains loop of henle and collecting duct Pyramids and their apex form renal papilea and then to calyx Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 5 medical physiology)  General Functions 1) Maintains homeostasis : regulation of :-  Plasma volume and pressure  Osmolality  Acid-base balance  Electrolytes balance 2) Metabolic function Glucose Synthesis (gluconeogenesis): From glycerol, lactate, propionate, & certain amino acids… metabolic function  During fasting and only organ makes glucose, next to liver  Stimulated by diabetic hormones: Glucagon, growth hormone, epinephrine, cortisol Producing ammonia Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 6 medical physiology)  General Functions… 3) Endocrine function – Erythropoietin (90%) and renin (juxtaglomerular cells ) – Renin production is in response to Decreased renal arterial pressure, increased renal sympathetic activation (beta-1 adrenergic receptors, or decreased sodium delivery to macula densa Hypoxia, renal artery vasoconstriction – Calcitriol (vitamin D)/1,25dihydroxycholecalciferol By PCTs in response to PTH and activates osteoclasts) – Prostaglandins : using cyclooxygenase and inhibited by NSAIDs Dilate afferent arterioles Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 7 medical physiology)  Effects of Renin JG cells Stimulated by SNS & hypovolumia Renin ACE Bradykinin breakdown Angiotensinogen AngI AngII Stimulates thirst center Constrict efferent arteriole eRPF, GFR, FF Aldosterone production Fig 2: Effects of Renin in RAAS Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 8 medical physiology)  Calcitriol Synthesis Diet Abebaye A (BSC, MSc, PHD, AAU- Dept of Fig 11/4/2024 3: Calcitriol Synthesis medical physiology) 9  General Functions… 4) Excretion – Wastes: urea, bilirubin, creatinine – Drugs – Foreign bodies – Hormones Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 10 medical physiology)  Renal Blood Supply Kidneys need nutrients and oxygen At rest (SNS less, vasodilation), about 22-25% of CO Flow reduced during exercise About 99% to cortex ,and 1% to medulla via vasa recta Blood flow in the cortex is fast than in the medulla The slow flow in the medulla help more water to be reabsorbed Proportional to ABP, and inversely proportional to renal resistance Affected by age ( by 10% /yr after 50), ABP, metabolism, nerve and chemicals Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 11 medical physiology)  Arteries in the kidney Renal artery segmental arteries  interlobar arteries  Arcuate arteries  interlobular arteries  afferent arterioles  glomerular capillaries  efferent arteriole  peritubular capillaries  interlobular vein  arcuate vein  interlobar vein  renal vein Fig 4: Blood supply in the kidney Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 12 medical physiology)  Tubular systems and supply with blood Fig 5: Blood system and blood supply Abebaye A (BSC, MSc, PHD, AAU- Dept of 13 11/4/2024 medical physiology)  Renal innervation Afferent – Mediates pain and reflex Efferent – Somatic nerve – Autonomic nerve Sympathetic nerve and distributed to » Glomerular arterioles (Constrict afferent arterioles) » PCTS, DCTs » Juxtaglomerular cells (contain B1 receptor),  renin secretion and Na+ reabsorption » Thick ascending loop of Henle Important for body fluid and electrolytes handling and micturition Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 14 medical physiology)  Nephrons The functional unit, large in number (1 million/kidney) – Reduced by aging (>40 yrs) and diseases – The reaming nephrons take the load (major functional change may not be seen) Most of nephrons are reserved Work independently Has two main parts – Renal corpuscle = Glomerulus + Bowman's capsule (space) Filtration – Renal Tubules : reabsorption and secretion Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 15 medical physiology)  Glomerulus Tuft of capillaries for filtration Fenestrated capillaries High pressures (60 mmHg) and is due to more narrowing of efferent arterioles than afferent Helps filtration Different from peritubular capillaries (13- 15 mmHg) – For reabsorption Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 16 medical physiology)  Two capillaries in the kidney: glomerular and peritubular capillaries Fig 6: glomerular an peritubular capillaries Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 17 medical physiology)  Renal Tubules Proximal tubule – Single layer of ECs, convoluted and non-convoluted Loop of Henle – Descending and ascending limb Distal tubule – Intercalated cells (responsible for the secretion of acid):- H+ secretion and HCO3- reabsorption – Principal cells : Na+ reabsorbed ADH dependent water reabsorption  For urine concentration Collecting tubule and collecting duct Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 18 medical physiology)  Anatomy of a nephron Fig 7: Anatomy of a nephron Abebaye A (BSC, MSc, PHD, AAU- Dept of Renal pelvis 11/4/2024 19 medical physiology)  Types of nephron 1. Cortical nephrone  In cortical area of kidney  Has short loop of henle  Larger (70-80%).  The tubular system is surrounded by peritubular capillaries 2. Juxtamedullary nephrons  Deep in central medulla  Less in percentage (20 to 30%)  Has long loop of henle, for urine concentration  The tubular system is surrounded by vasa recta Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 20 medical physiology)  Types of nephron Fig 7.1: Types of nephrons Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 21 medical physiology)  Urinary tracts Structures where urine formed and pass to outside Kidneys and ureters (upper urinary tract) Bladder and urethra (lower urinary tract) Urinary tract infection (UTI) – Pain/burning while urinating, frequent urination, feeling the need to urinate despite having an empty bladder, hematuria, pressure/cramping in the groin or lower abdomen Fig 8: Urinary tracts Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 22 medical physiology)  Juxtaglomerular apparatus Structures contain secretary cells Includes – Macula densa: secrete paracrine – Juxtaglomerular cells: secret renin (contain Adrenergic receptor) – Lacis cells (Extraglomerular mesangial cells) Contractile cells affecting area of glomerulus o Mesangial cells contraction (by SNS) reduces GFR o Have receptors for chemicals G-protein receptors will lead to constriction cAMP receptors will lead to relaxation Fig 9: Mesangial cells in the Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 kidney 23 medical physiology)  Mesangial cells … Modified smooth muscle cells surrounding glomerular capillaries One of the intrinsic filtration control systems (myogenic, tubuloglomerualr feedback) High arterial pressure causes stretch reflex/myotatic reflex and decrease surface area for filtration – Muscle contraction in response to passive stretching Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 24 medical physiology)  Macula densa Small specialized cells at the beginning of distal tubule Crowded and more dense Sensitive to NaCl concentration in the filtrate Less NaCl brings – Reduction of afferent arteriole resistance – Production of renin – Increases GFR Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 25 medical physiology)  Renal plasma flow and determination Volume of plasma flows into kidney per time Methods used to measure this volume – Clearance method: Clearance of a substance – Amount of plasma cleared from a substance per given time – Example: amount of plasma free from para-aminohippuric acid (PAH) after given known amount » Filtered and actively secreted completely in one circulation (proximal tubule), not reabsorbed » Not made in the body » Not metabolized Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 26 medical physiology)  Determination of RPF: Clearance method Volume of urine per given time, ml/min=V Concentration of PAH in urine, mg/ml =U Concentration of PAH in plasma, mg/ml = P – If V=1ml/min, U =5.58 mg/ml and P = 0.01 mg/ml – Then Amount of PAH excreted = VxU =1X5.58 = 5.58mg/min – Then calculate RPF – RPF=UXV/P=585ml/min Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 27 medical physiology)  Determination of RPF: Clearance method … 585ml/min represents 90% of the actual RPF This 90% called extraction ratio of PAH – 585ml/min = 90% x actual RPF – Actual RPF = 650 ml/min – Normally: 600-700 ml/min Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 28 medical physiology) RBF determination using hematocrite (H) value Plasma is 55% of blood flow – RPF = 55% x RBF Plasma which is 55% = 1-H RPF= 1-H X RBP RBP=RPF/ 1-H = 1-H =55% = RBF=RPF/ 55% RBF =650ml/min/55% = 1182ml/min The normal value = 1200-1300ml/min Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 29 medical physiology)  Basic renal processes Filtration, reabsorption and secretion Filtration – Formation of filtrate (differ from plasma) – Movement of fluid from plasma to the lumen of bowman’s capsule – First process in the urine formation – In the glomerulus via glomerular capillary membrane/ filtration barrier Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 30 medical physiology)  Filtration… Fig 9: Basic Renal Processes Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 31 medical physiology)  Filtration membrane and layers Endothelium : endothelial cells – Fenestration (70-90nm diameter) with some negative charged elements – Selection based on size and charge Basement membrane: collagen IV, proteoglycan, laminin (Q-) – No cells, gelatinous structure, repulse albumin – Selection based on charge Epithelium : Capillary outer surface – Made up of podocytes with their foot-like process (podocyte foot process) – With proteins, podocine an synthesize negatively charged proteins Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 32 medical physiology)  Glomerular/filtration membrane Fig 10: Components o Filtration Membrane Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 33 medical physiology)  Glomerular filtration rate (GFR) Amount of plasma filtered into bowman's space per given time About 180 L/day =125-130 ml/min and 99% reabsorbed The entire plasma is filtered 60 times a day180,000 ml filtrate/3000ml Plasma = 60X , average plasma volume = =3L) 1/5 of the RPF, filtration fraction (FF) – FF= GFR/RPF *100= 125/600*100=20% Large amount (4/5) of the RPF goes to efferent arterioles The minimum urine produced per day: 1.5-2L/day If the kidney concentrate urine up to 1200msom/L, then the minimum amount of urine removed by the kidney is called obligatory urine volume per a day and a normal 70kg man excretes 6000mosm solutes per day=1200/6000= 0.5L/day Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 34 medical physiology)  Forces affecting filtration and GFR Fig 11: Filtration Facilitating and Opposing Pressures Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 35 medical physiology)  Net filtration pressure for GFR Direct factors: net filtration pressure (NFP) & filtration coefficient ( Kf) GFR =NFP x Kf (Area (0.8m2) and Permeability of capillary membrane – NFP affected by other pressures NFP = (GCHP+BCcp) = (GCcp+BCHP) = (60+0)-(18+32)= 10 mmHg Fig 12: Net Filtration Pressure Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 36 medical physiology)  Other factors affecting GFR Arteriolar resistance (Afferent and efferent) Systemic BP Chemicals – Autacoids, hormones – NE/EN from SNS/ adrenal medulla : constrict afferent arterioles – Endothelin From damaged endothelial cells Constricts afferent arterioles Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 37 medical physiology)  Chemicals... Angiotensin II – Constricts efferent arterioles than afferent Endothelial-Derived Nitric Oxide (NO) – Dilates afferent arterioles Prostaglandins (PGE2 and PGI2) and Bradykinin – Reduce effects of vasoconstrictors Thromboxane A2: constricts afferent arterioles Atrial natriuretic peptide (ANP): reduces renin secretion & Na+ reabsorption in the collecting duct – Increases GFR Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 38 medical physiology)  Ang II in RAAS Fig 13 : RAAS and physiological effects of Ang II Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 39 medical physiology) Atrial natriuretic peptide (ANP) e.g Afferent arterioles Fig 14: Physiological effects of ANP Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 40 medical physiology)  Clearance method to calculate GFR The Renal Clearance – Volume of plasma free from a substance at a given time by kidney – Provides a useful way of quantifying the excretory function of the kidneys – If a substance is freely filtered but not secreted and reabsorbed Amount removed from plasma = Amount excreted in the urine (GFR × Ps) = (Us × V) = GFR= Us × V/ Ps Inulin is an example of such substance Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 41 medical physiology)  Criteria of substances used to measure GFR Freely filtered (not combined with proteins) Neither secreted nor reabsorbed Removed by only filtration Not to be – Metabolized – Store in the kidney and toxic Easy to measured in the plasma & urine Examples inulin, manitole, radioactive iothalamate, creatinine (not good, less secreted and reabsorbed) Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 42 medical physiology)  Urea clearance(Curea) Filtered freely Partially reabsorbed Not secreted Has greater filtration rate than excretion rate Curea= VX Uurea/purea = 70ml/min This much amount of plasma is cleared from urea per minute Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 43 medical physiology)  Creatinine clearance (Ccreatinin) Freely filtered Partially secreted in the PCTs Not reabsorbed Excretion rate is greater than its filtration rate Ccreatinin = V XUcreatinin/Pcreatinin= 140ml/min This amount of plasma becomes free from creatinin per minute Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 44 medical physiology)  Glucose clearance (Cglucose) Freely filtered Completely reabsorbed Not secreted Its excretion rate is 0 Cglucose= 0 Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 45 medical physiology)  Paraaminohippuric acid clearance (CPAH) Freely filtered Completely secreted in the single flow Not reabsorbed Excretion rate is much higher than its filtration rate Its clearance value is high, almost RPF that come to the glomeruli become free from the PAH in one circulation Note – A Substance made in the tubular cells has clearance value greater than the RPF Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 46 medical physiology) Renal autoregulation Intrinsic processes in the kidney maintaining the constancy of RBF and GFR at changed ABP Self - control in RBF and GFR Protect hypertensive kidney damage With a limited pressure (75 - 160 mmHg) Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 47 medical physiology)  Renal autoregulation … The intrinsic control system is working at this BP changes Out of this range, sympathetic effect overrides the effect of the intrinsic control Fig 15: Renal autoregulation Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 48 medical physiology)  Mechanisms of renal autoregulation Myogenic response Tubuloglomerular feedback – Myogenic response Regulated by muscle (afferent arteriolar muscle) ABP  transit blood flow into afferent arterioles (initially)  cell stretched Ca++   contraction afferent arterioles constrict   RBF and GFR Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 49 medical physiology)  Mechanisms of renal autoregulation … Tubuloglomerular feedback mechanism – ABP  GFR  fluid movement   time for reabsorption of Na+ an Cl- Nacl in the macula densa  Increased in the renin production and RAAS activation Afferent arterioles dilated (prostaglandin from macula densa) Efferent arteriole constriction Increase in the Ang II production GFR increased Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 50 medical physiology)  Tubuloglomerular feedback Fig 16: Tubuloglomerular Feedback in Regulation of GFR Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 51 medical physiology)  Extrinsic control of GFR Nerve: SNS: – At rest, autoregulation mechanisms overcome – Under stress: SNS activated – Norepinephrine is released from SNS/adrenal Afferent arterioles constrict and filtration is inhibited – Note: during fight/flight blood is shunted away from kidneys Chemicals Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 52 medical physiology)  Sympathetic effect Fig 17: Effects of Renal Sympathetic Innervation on Blood Volume Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 53 medical physiology)  Other factors affecting GFR Diet – High protein diet (amino acids) and high CHO-diet (glucose) increase GFR – These nutrient's reabsorbed together with Na+ co- transportation – Less sodium in the macula densa – Increased in renin secretion and Ang II formation Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 54 medical physiology)  Tubular reabsorption Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 55 medical physiology)  Tubular Reabsorption Movement of filtered substance back into the blood from renal tubules Selective and crosses two membranes – Tubular epithelial membrane – Peritubular capillary membrane Urine volume varies according to needs of body Minimum of 400-500 ml/day urine necessary to excrete metabolic wastes (obligatory water loss) Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 56 medical physiology) Classification of substance based on degree of reabsorption Completely reabsorbed (amino acids + glucose) Highly reabsorbed (water and electrolytes) Poorly reabsorbed (Cr, urea, uric acid) Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 57 medical physiology)  Reabsorption processes Fig 18: Reabsorption Processes: Trans and Paracellular Transportation Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 58 medical physiology) Reabsorption processes … Reabsorption processes include:- – Simple diffusion – Facilitated diffusion – Active transport – Cotransport (in 20 active transport) – Osmosis Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 59 medical physiology)  Active Transport  Primary or secondary Na+- K+ pump, H+ pump, H+- K+ pump, Ca++ pump Na+- K+ pump on the basolateral sides of the tubular epithelial cell Na+ reabsorption in the apical membrane is passive: conc gradient , inside is less and negative (-70 mv) Fig 19: 10 Active Reabsorption processes Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 60 medical physiology)  Secondary Active Reabsorption Kind of co- transport One sub. moved down concentration gradient helps the movement of another sub against concentration gradient. – Cl- with Na+, Na+ with glucose & amino acids Phlorhizin competes the glucose binding site on the SGLUT and inhibit sodium and glucose reabsorption Fig 20: 20 Active Reabsorption processes Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 61 medical physiology)  GLUTs and glucose reabsorption Abebaye A (BSC, MSc, PHD, AAU- Dept of Fig 21: 11/4/2024 Glucose Transporter Proteins medical physiology) 62  Glucose & amino acids reabsorption 100% reabsorbed from filtrate in the PCT and is with Na+ – Transporter displays saturation – Level needed to saturate carriers & achieve Glucose & amino acid transporters don't saturate under normal conditions but is in diabetic patients Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 63 medical physiology)  Reabsorpation processes at each tubule 1. Proximal Tubule – Filtrate in PCT is isosmotic to blood (300 mOsm/L) – Reabsorption of H20 by osmosis cannot occur without active transport (AT) – Loss of +ve charges from filtrate causes Cl- to passively follow +ve charges ( Na+ ) – However, H+ and NH3+, uric acid are secreted into the tubule – Water reabsorption here is Obligatory , while it is facultative in the late distal and collecting duct (ADH involved) Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 64 medical physiology)  Proximal tubule reabsorption Fig 22: Proximal Tubule Reabsorption Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 65 medical physiology)  Tubular fluid concertation along the length of the proximal tubule Tubular fluid concentration Fig 23: Tubular Fluid conc. Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 66 medical physiology)  Reabsorption in the proximal tubule … Maximum filter load is reabsorbed (65 %) Because, – High metabolic activities – Have large numbers of mitochondria – Extensive brush border – Rich in proteins for transporting processes Na+ and glucose reabsorbed in the first half of the proximal tubule Na+ is reabsorbed mainly with chloride ions in the second half of the proximal tubule. Counter transport of Na+ with the secretion of H+ Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 67 medical physiology)  2. Loop of Henle Descending Loop of Henle – Highly permeable to water (20%) and impermeable to solutes – Makes the filtrate concentrated – Water is then taken by blood vessels – Constantly, 85% water reabsorbed in the early tubules – The reabsorption of water is passive Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 68 medical physiology)  2. Loop of Henle … Ascending loop of Henle Impermeable to water, Permeable solutes (Na+, Cl-, and K+ , Ca++, bicarbonate) 1Na+-2Cl- -1K+ symporter foound Filtrate made diluted (100 mOsm) by the end of the loop Fig 24: Reabsorption in the descending and ascending loop of Henle Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 69 medical physiology)  Ascending loop of Henle… NaCl is actively extruded from thick ascending limb into interstitial fluid Na+-K+ pumps at basolateral membrane is used Cl- flows the direction of Na+ in the basolateral membrane Fig 25: Reabsorption in the Ascending Loop of Henle Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 70 medical physiology) 17-39  3. Early Distal Tubule  The first portion of the distal tubule forms part of the juxtaglomerular complex (macula densa)  Impermeable to water and urea  Permeable to ions (5%)  Variable reabsorption started  Hormones act Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 71 medical physiology)  4. Late Distal Tubule Principal and the intercalated cells – Principal cells: reabsorb Na+ and secrete K+ – Intercalated Cells: secrete H+ , K+ and bicarbonate reabsorb – Primary sites of action of the K+-sparing diuretics Spironolactone, eplerenone, amiloride, and triamterene Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 72 medical physiology)  5. Medullary Collecting Duct Water and Na+ reabsorbed Permeability to water is controlled by the level of ADH. Permeable to urea Urine is concentrated H+ is secreted, key role in regulating acid-base balance. Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 73 medical physiology)  Regulation of Tubular Reabsorption Nerve, hormones , local chemicals, and pressures control reabsorption Glomerulotubular balance – The higher the filter load ,the higher the reabsorption – To prevent overloading of the distal tubular segments when GFR increases – A second line of defence to buffer the effects of spontaneous changes in GFR on urine output Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 74 medical physiology)  Reabsorption determinant factors  Reabsorption = net reabsorption pressure (NRP)xKr  The NRP is depend on two forces – Hydrostatic and colloid osmotic pressures Hydrostatic pressure – Peritubular capillary and Interstitial hydrostatic pressure Colloid osmotic pressure – Peritubular capillary and interstitial colloid osmotic pressure Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 75 medical physiology)  Net reabsorptive force Net reabsorptive force = (IHP+Pc)- (PcHp + i) Fig 26: Net Reabsorption Pressure Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 76 medical physiology) Peritubular capillary hydrostatic and oncotic pressure This pressures is affected by:- – Arterioles resistances These indirectly affect reabsorption rate – The higher the resistance in both arterioles is the less the peritubular capillary hydrostatic pressure » This increase reabsorption Plasma proteins – Plasma protein   Peritubular capillary colloid osmotic pressure   Reabsorption Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 77 medical physiology)  Transport Maximum Maximum amount of substance actively reabsorbed/secreted per given time (mg/min) For the same substance at the same time Depends on the carrier proteins and enzymes At this time – No free carrier proteins found – Proteins are finite and saturated – No more sub. are reabsorbed after – Glucose threshold occur In the case of glucose, (Tm) occurs when glucose filter load is 375mg/min and blood glucose is 300 mg/dl Transport maximum of glucose = 375mg/min Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 78 medical physiology)  Filterload Amount of a substance filtered into the bowman’s capsule per time – FL= GFR* plasma concentration of a substance – The more the substance in the blood, the more the FL – FL is greater than reabsorption rate (RR) for a substance reabsorbed Highly Poorly Is equal the RR for substance reabsorbed completely Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 79 medical physiology) Transport maximum … Substance filtered beyond the Tm is excreted, not reabsorbed Amount of a particular substance filtered per minute called filter/tubular load = GFR*Pc (plasma conc of a substance) If 100 mg of glucose is found in a dl of blood, glucose filter (FL) load is 125mg/min Calculate blood glucose level in dl if the FL is 450mg/min Calculate glucose filter load and amount of glucose lost from the subject in a minute if blood glucose level is 500 mg/dl Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 80 medical physiology)  Glucose Transport Maximum and renal handling of glucose Relationship b/n plasma glucose level, FL, Reabsorption and excretion Why glucose could be observe in the urine before transport maximum is reached? At FL= 375mg/min and BGL=300 mg/dl Fig 27: Transport Maximum Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 81 medical physiology)  Transport Maximum … Each substance has its own tubular maximum Normally, glucose concentration in the plasma is lower than the tubular maximum and all of it is reabsorbed. In diabetes mellitus, tubular load exceeds tubular maximum transportation and glucose appears in urine. Urine volume increases because glucose in filtrate increases osmolality of filtrate reducing the effectiveness of water reabsorption Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 82 medical physiology)  All substance not reach into transport maximum at the same concentration Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 83 medical physiology)  Reasons for splay to appear Splay is the concentration difference between a substance's maximum renal reabsorption vs. appearance in the urine. How much is for glucose? Saturation refers to a condition where all carriers are occupied by a solute. Reason for glucose splay: heterogeneity in glomerular size, proximal tubular length and number of carrier proteins for glucose reabsorption Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 84 medical physiology)  Hormonal Control of tubular Reabsorption Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 85 medical physiology)  1. Aldosterone Causes variable reabsorption in the distal and collecting duct Binds to the cytoplasmic principal cells receptors The complex inter into nucleus – Rapid apical Na+ channel increases Na+ entry – Increases Na+-K+ ATPase activity – Increases new channel and pump synthesis – New proteins activate pre-existing channels & pumps Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 86 medical physiology)  Actions of Aldosterone Na+ Facilitates Aldosterone secretion  Excess EC K+  EC osmolality  Dehydration  BP Na+   Filtrate passing the macula densa Fig 28: Actions of Aldosterone Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 87 medical physiology)  2. Angiotensin II By hypovolemia Stimulates Aldosterone secretion Constricts efferent arterioles –  Peritubular capillary hydrostatic pressure –   the concentration of proteins   reab. Stimulates the Na+-K+ pump Stimulates Na+- H+ exchange in the luminal membrane Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 88 medical physiology)  3.ADH Acts in the late distal tubule and collecting duct Regulate expression of water channels (aquaporins) Water inter in to cell via AQP2 via apical membrane ADH:- – Binds with GPCR – cAMP produced and activates kinases Pre-existing AQP2 migrate and then return to the cytoplasm – Its reduction causes diabetes insipidus Central (brain fails to produce ADH) Nephrogenic (if kidney doesn’t give response to ADH) Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 89 medical physiology)  Action of ADH AQP3 Water channel expressed in the collecting duct V2R Fig 29 : Actions of ADH Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 90 medical physiology)  Factors affecting ADH secretion Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 91 medical physiology)  4. ANP and PTH  ANP  Produced against right atrial over stretching and causes :- Surface area for filtration and GFR Na+ and water reabsorption (Na+ channel/AQP capabilities and expression Inhibits the release of renin and formation of Ang-II and aldosterone  PTH Ca++ reabsorption in the distal tubules  reabsorption of phosphate Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 92 medical physiology)  Concentrated urine formation Concentrated urine formation is used to conserve water Two mechanism  ADH  Medullary interstitial hyperosmolality Counter current multiplier  Urea reabsorption from collecting duct Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 93 medical physiology)  Countercurrent multiplier Repeated process at w/c medullary interstitium becomes hyperosmolar Descending LH reabsorbs water and taken by blood vessels Reabsorption of salt in the thick ascending LH raises osmolarity around descending limb, causing more H20 to diffuse out. – This raises osmolarity of filtrate in descending limb which causes more concentrated filtrate to be delivered to ascending limb – As this concentrated filtrate is subjected to ascending LH, more salt reabsorbed causes even higher osmolarity around descending limb (positive feedback) – Process repeats until osmolarity of medulla is 1400 Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 94 medical physiology)  Steeps in counter current multiplayer 1. Isoconcentrated filtrate enters to proximal tubule (300mosm) 2. Solutes released out from thick ascending loop of Henle until the difference in concentration b/n the interstitium and tubule is 200mosm 3. Equilibrium b/n descending loop of Henle and interstitium developed 4. Fluid from the tubules pushed out 5. Solutes released out from thick ascending loop of Henle Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 95 medical physiology)  Counter current exchanger in the Vasa recta Reabsorbed solutes washed out from medullary interestittium Used to maintain medullary hyperosmolarity developed by countercurent multiplier Vasa recta is used – Takes H20 coming out of descending limb Fig 30 : Vasa Recta Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 96 medical physiology)  Tubular Secretion Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 97 medical physiology)  Secretion Release of substances (Creatinine, NH3, urea, uric acid , drugs, K+ & H+) into the lumen of renal tubule from – Blood ( ions, drugs, creatinine) Penicillin enters into tubules from blood by secretion – Tubular cells (H+ , NH3) – Interestitium The process is mainly active K+ is manly secreted along the initial and Fig 31 : Secretion Process cortical collecting tubule Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 98 medical physiology) K+ secretion and Excretion Extracellular K+ is regulated precisely at about 4.2 mEq/L K+ can leave or inter to cell is first line of defense Shift into the cells ( EC K+) Insulin, aldosterone  Adrenergic stimulation Alkalosis Shift out the cells( EC K+) DM, Addison's disease  Adrenergic blockage Acidosis Cell lysis Strenuous exercise High EC fluid osmolarity Fig 32 : Potassium Handling Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 99 medical physiology)  Factors control K+ Secretion Activity of the Na+-K+ ATPase, Na+-K+ pump Electrochemical gradient for K+ secretion Aldosterone and ANP level Permeability of the luminal membrane for K+ Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 100 medical physiology)  Renal Excretion Remove of substance from the body in the form of urine Excretion rate (ER) = FR +SR- RR For glucose, SR= 0 and FR= RR as all glucose filtered is reabsorbed back Then glucose Excretion rate is 0 Drug’s volume of distribution, degree of protein binding, and the glomerular filtration rate affects Excretion drug excretion by kidneys Fig 33: Renal Excretion · 11/4/2024 Abebaye A (BSC, MSc, PHD, AAU- Dept of 101 medical physiology)  Example Urine – Volume = 1ml/min, K+ = 100mEq/l, Na+ = 140mEq/l, cr = 1mg/100ml and urea = 25mg/100ml Plasma – K+ = 100mEq/l, Na+ = 120mEq/l, cr = 200mg/100ml and urea = 2050mg/100ml Then calculate the potassium excretion rate Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 102 medical physiology)  Ammonia synthesis for Hydrogen excretion Fig 34: Ammonia synthesis Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 103 medical physiology)  Electrolytes and fluid balance by kidney Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 104 medical physiology)  Ca2+ handling Maintained at= 2.4 mEq/L Maintained by – Parathyroid hormone (PTH) – Plasma concentration of phosphate – Metabolic acidosis: luminal H+ inhibits Ca2+ reabsorption proteins – Metabolic alkalosis:  Ca2+ reabsorption Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 105 medical physiology)  Phosphate handling Maximum transported= 0.1 mM/min out of 0.8 mM/L produced Maximum transported reduced by PTH PTH increases its excretion to increase free calcium level in the blood Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 106 medical physiology)  Phosphate handling … FGF-23: Fibroblast growth factor-23 and serum Ca +2 Fig 35: Phosphate handling Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 107 medical physiology)  Diuretics and renal system Diuretics are drugs that increase the rate of urine flow Enter the tubule primarily by secretion in the proximal tubule They are classified into different types Used to manage bloody fluid volume, HTN and edema via –  GFR –  tubular reabsorption Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 108 medical physiology)  The different classes of diuretics and their effects Carbonic anhydrase inhibitors: acetazolamide – Inhibit reabsorption of bicarbonate/H+ excretion – Their abnormality causes metabolic acidosis Osmotic diuretics: mannitol, glucose – Inhibit water reabsorption acting in proximal convoluted tubule, thin descending loop of Henle and collecting duct – Osmotic diuretics are freely filterable but not reabsorbed Loop diuretics: furosemide, torsemide – Reduces Na+ reabsorption in the thick ascending loop of Henle by inhibiting Na+/K+/2Cl-) co-transporter Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 109 medical physiology)  Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 110 medical physiology)  Action mechanism of carbonic anhydrase (CA) inhibitor diuretics Note: Bicarbonate ion not reabsorbed in its form in the apical membrane of the tubule cells CO2 +H20 Fig 36 : Action Mechanism of CA Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 111 medical physiology) The different classes of diuretics and their effects … Thiazide diuretics : chlorothiazide, Metolazone ,chlorthalodone – Inhibit Na+-Cl- symporter and their abnormality cause Electrolyte imbalance: volume depletion, hyponatremia, hypochloremia, Potassium sparing diuretics: spironolactone, amiloride, eplerenone – Prevent Na+ reabsorption (collecting tubule) by binding ENaCs (amiloride, triamterene) or by inhibiting aldosterone receptors (spironolactone, eplerenone). – Prevent excretion of potassium Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 112 medical physiology)  Thiazide (a) and Potassium sparing diuretics (b) (a) (b) Fig 37 : Action mechanism of Thiazide (a) and Potassium sparing diuretics (b) Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 113 medical physiology) Summary: Site of diuretics action Proximal convoluted tubule Fig 38: Site in the Renal Tubules where Diuretics Act Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 114 medical physiology)  Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 115 medical physiology)  Diuresis and Diuretics  Ethanol (alcohol) Leads to diuresis by inhibiting ADH secretion.  Xanthine drugs ( e.g caffeine and theophylline): Cause vasodilation of afferent arterioles, which consequently increases the GFR. This accelerates the flow of the tubular fluid which result in deficient Na+ reabsorption from the renal tubules. Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 116 medical physiology)  Neural control of micturition … When the detrusor muscle relax, stretch sensitive receptors activated…afferent fibers getting into the spinal dorsal horn stimulated – Sympathetic outflow inhibited – Parasympathetic outflow activated – Somatic input into the external urethral sphincter inhibited Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 117 medical physiology)  Neural control of micturition … Pons involved in the voluntary control Normal volume - 1 to 2 L/day Polyuria > 2L/day Oliguria < 500 mL/day Anuria - 0 to 100 mL/day Note: in children (2-3 years), the ability to voluntarily inhibit urination is not possible as d/f structures not well developed 3 S2 and S3 spinal segment (PNS) in M3(+) the pelvic nerve: Ach This pudendal nerve passes via 1 sacral plexus (L4-5, S1-4) 11/4/2024 Abebaye A (BSC, MSc, PHD, AAU- Dept of Fig 39: Micturition 118 medical physiology)  Spinal cord micturition reflex is under the control of cerebrum Fig 39.1: Micturition … Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 119 medical physiology)  Regulation of Acid base balance Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 120 medical physiology)  Regulation of Acid-Base Balance The acid-base balance aims at keeping the (H+) in the body fluids constant. H+ affects the PH of the blood PH= -Log H+ = 7.4 at [H+]= 0.00004 mEq/L Acidosis: PH< 7.4 Alkalosis: PH> 7.4 Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 121 medical physiology)  Acids, Bases and Alkalies Acids: substances dissociate in a solution and produce H+( HCl → H+ + Cl-) Bases: substances that bind H+ and remove it from solution (HCO3- which binds to H+ to form H2CO3). Alkalies :water soluble bases – Alkali solution has a pH that is higher than 7. Buffer: solution containing weak base and acid Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 122 medical physiology)  Equilibrium Constant (K) K is a value at which reactants an products get equal K is number represents when it reaches to equilibrium K =products/reactants H+ + HCO3- (22-26 meq/L)↔H2CO3H Reactants go to products and products back to the reactants Initially, k= 0 (as no product is formed) Overtime reaches to equilibrium Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 123 medical physiology)  Equilibrium Constant (K)… Reactants Product Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 124 medical physiology)  Henderson-Hasselbalch equation PH= pKa + log ([HCO3-] / [ CO2 solubility *PCO2]) – Important to determine the PH of buffer solution – pKa (a=acid)= -log [ka] – pKa indicates whether an acid is strong acid or weak – Ka = Acid dissociation constant (carbonic acid = 1*10-5  Given : PC02= 40 mmHg, [HCO3-] = 24 mMol/L, CO2 solubility = 0.03, then calculate the PH of the solution PH= 7.4 Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 125 medical physiology)  Henderson-Hasselbalch equation… A buffer solution is made from 0.4M CH3COOH and 0.6M CH3COO–. If the acid dissociation constant of CH3COOH is 1.8*10-5, what is the pH of the buffer solution? pH = pKa + log([CH3COO–]/[CH3COOH]) and pKa = -log [ka] Here, Ka = 1.8*10-5 ⇒ pKa= 4.7 pH = 4.7 + log(0.6M /0.4M) = 4.7 + log(1.5) = 4.7 + 0.17 = 4.87 Therefore, the pH of the solution is 4.87 Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 126 medical physiology)  Chemical Buffering systems Bicarbonate buffer system – In the ECF and contains H2CO3 (weak acid) and HCO3- (weak base) – The major PH determinant and the pk of this buffer is 6.1 – PH of arterial plasma = PK +log HC03/H2C03 – Regulated by : C02 by respiratory system and HCO3- by the kidneys Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 127 medical physiology)  Phosphate and protein buffer system Phosphate buffering system – Consists of NaHPO4 (weak base) and NaH2PO4 (weak acid) – Its concentration outside is less (0.8-1.5) – It is the major buffer in the ICF and renal tubular fluid. Protein buffering system – Mostly take hydrogen ion – Hemoglobin is the most important buffer in the body. – Buffer H+ inside the cell – Proteins have carboxyl (CooH) & amino groups (NH2) – When pH increases, the carboxyl group can dissociate & release H+. – When pH decreases, amino group acts as H+ acceptor. Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 128 medical physiology)  (a) Kidney in the acid-base balance (a) (b) Fig 41: Systemic buffer : Lung and Kidney in response to Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 129 medical physiology) Acidosis (b)  Kidney diseases Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 130 medical physiology)  Kidney diseases Problems affecting kidney functions Risk factors:- – Diabetes – Hypertension – Atherosclerosis – Infections – Hypercalcemia – Cancer – Stone Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 131 medical physiology)  1. Obstruction Blockage of the urinary tract Brings buildup of urine and lead to infection Caused by – Cancer – Kidney stone – Expanding uterus during pregnancy – Enlargement of prostate gland Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 132 medical physiology)  2. Urinary tract infection (UTI) Caused by obstruction, infection in the other part of the body – Cystitis (inflammation of bladder) – Pyelonephritis : inflammation of kidney tissue Symptoms: fever, frequent urination, sudden and urgent need to urinate, and pain or a burning feeling during urination , pressure in the lower abdomen and back, bloody urine Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 133 medical physiology)  Nephritic diseases In the nephritic diseases, the urine contains red blood cells, red cell casts, and mild to modest amounts of protein. Nephritic diseases are usually associated with a fall in GFR, accumulation of nitrogenous wastes (urea, creatinine) in the blood, and hypervolemia (hypertension, edema). Most nephritic diseases are due to immunological damage. Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 134 medical physiology)  3. Glomerular diseases Diseases of blood filtration unit in the kidney Hypertension, diabetes, nephritic syndrome or glomerulonephritis, drugs, x-ray are the main causes Glomerulonephritis in its various forms is the major cause of renal failure in people. Brings hypertension, edema, azotaemia (building up of waste products like urea) Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 135 medical physiology)  Chronic glomerulonephritis Characterized by proteinuria and/or hematuria (blood in the urine), hypertension, and renal insufficiency that progresses over years. The disease is accompanied by a progressive loss of functioning nephrons and proceeds relentlessly even though the initiating insult may no longer be present. Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 136 medical physiology)  4. Nephrotic syndrome Renal disorder characterized by excessive loss of proteins in the urine Caused by:- – Increase glomerular permeability (glomerulonephritis) – Reduction of –ve charged proteins (minimal charge nephrotic syndrome) – Glomerular injury and results in:- Hypoalbuminemia generalized edema, and hyperlipidemia An increase in the catabolism of the reabsorbed proteins in the kidney proximal tubules and protein excretion in the urine Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 137 medical physiology)  5. Acidosis and alkalosis Acidosis – Respiratory acidosis Increase in the PCO2 and caused by:- – Respiratory depression (e.g., drugs, sedatives cause hypoventilation) – Pulmonary diseases that cause hypoventilation : Emphysema, asthma etc Compensated by increase HCO3- reabsorption and production Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 138 medical physiology)  Acidosis … Metabolic acidosis – Acidity of blood caused by metabolic disorders including:- Starvation: exhaustion of glycogen in the liver (12-24 hrs fasting), liver produces ketones from fat for energy and increases blood acidity : ketoacidosis – Normal ketone level: < 0.6mmol/L – Ketone bodies contain carboxylic acid that reduces blood PH DM: reduction of insulin, body produces enzymes breakdown fat Hypoxia : less O2, lactic acid formed Severe diaharria: HCO3- lost » Compensated by hyperventilation Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 139 medical physiology) Ketones (acetoacetate, acetone, and 3- hydroxybutyrate (βHB) formation an energy production + CO2 They are formed during fat oxidation Fig 42: Ketone Bodies for ATP Formation Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 140 medical physiology)  5. Acidosis and alkalosis … Alkalosis – Respiratory alkalosis Reduction of PCO2 caused by Hyperventilation (higher altitude, anxiety, heart failure, cancer, seizures, liver failure, prolonged lack of oxygen, and low blood sugar) Compensated by excessive loss of HCO3- by kidney – Metabolic alkalosis Excessive secretion of H+/over production of HCO3- by kidney an caused by – Prolonged vomiting: HCl acid from the stomach is lost and this effect elevates blood HCO3- level. – Hyper-aldosteronism: increases HCO3- reabsorption Compensated by Abebaye hypoventilation A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 141 medical physiology)  6. Urine incontinence Unintentional passing of urine. Caused by – Stress : stress incontinence: when your bladder is under pressure; for example, when you cough or laugh – Bladder over activation (urge incontinence) – Unable to drink water: concentrated urine in the bladder irritates the wall of the bladder Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 142 medical physiology)  7. Neurogenic bladder Lack of bladder control due to brain, spinal cord/other nerve problems This nerve damage can be the result of multiple sclerosis (MS), Parkinson's disease or diabetes, infection, stroke, spinal cord injury, or major pelvic surgery and birth defect Normal albumin excretion: 300 mg/24 hours Nephrotic range proteinuria: >3 g/24 hours Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 143 medical physiology)  8. Micturition Reflex Problems Unable to urinate or loss of urination control Sphincter muscles lose tone: – Leading to urine incontinence Control of micturition reflex can be lost due to: – a stroke – Alzheimer’s disease – CNS problems affecting cerebral cortex or hypothalamus – Enlarged prostate gland (male) Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 144 medical physiology)  9. Renal failure Acute – Large number of nephrons stop activities suddenly – Caused by Acute glomerulonephritis Necrosis (ischemia by circulatory shock and poisons) Incompatible blood transfusion – The transfused blood RBCs ruptured and haemoglobin released – Haemoglobin precipitated and block renal blood vessels Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 145 medical physiology)  Renal failure … Chronic – Gradual loss of kidney functions – Caused by Chronic glomerulonephritis, aAbs Pyelonephritis (infection of the renal pelvis and nephrons) Urinary tract obstruction (stones and enlarged prostate) Polycystic disease – Cysts are formed in the kidney that compress and damage the nephrons Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 146 medical physiology)  Chronic kidney diseases … In terms of GFR, the presence of GFR 300mg Sever anemia Generalized edema and hypertension Uncompensated metabolic acidosis – Dialysis required Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 151 medical physiology)  Renal replacement therapy (RRT) 1. Dialysis Hemodialysis – In-center, 3/week Peritoneal dialysis – Daily, at home 2. Kidney transplantation Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 152 medical physiology)  Indication for renal replacement therapy Hyperkalemia Metabolic acidosis Fluid overload Uremic pericarditis Other non specific uremic symptoms: anorexia and nausea, decreased energy level, attentiveness, and cognitive tasking Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 153 medical physiology)  Dialysis Artificial washing of the blood using DF instead of kidneys – Hemodialysis Arteries and veins of the patient connected with membranous tube (cellophane) The tube through which blood flow is passing/bathing via the dialysis fluid (DF) Waste products and excesses substances filtered into the fluid from the blood Note: If K+ is excess in the blood, filtered into the dialysis fluid Important to control BP and blood components Usually done three times a week for 4hrs Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 154 medical physiology)  Dialysis… – Peritoneal dialysis a cleansing fluid flows through a tube (catheter) put into the abdomen The lining of the abdomen (peritoneum) acts as a filter/membrane and removes waste products from the blood The waste products flow in the abdomen and taken by the catheter in the abdomen Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 155 medical physiology)  Procedure during hemodialysis Two needles insert into the blood vessels in the arm Each needle is attached to flexible plastic tube that connects to a dialyzer in the dialysis machine. Blood from the body pass via dialyzer The dialysis machine pumps blood through the filter and returns the blood to the body Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 156 medical physiology)  Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 157 medical physiology)  Arterial BP monitoring during dialysis Fig 44: BP Monitoring Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 158 medical physiology)  Peritoneal dialysis(PD) The PD fluid is allowed to dwell in the peritoneal cavity for a period of 4-6hrs/ each of three daytime exchanges and 8-0 hours during the overnight exchange Time at which the dialysate lasts in the abdomen Patients will usually carry PD fluid in the peritoneum continuously, 24 hours a day Fig 45: Peritoneal Dialysis Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 159 medical physiology) Pros and cons of hemodialysis and peritoneal dialysis Hemodialysis Peritoneal dialysis – 4 dialysis-free days/week – Home dialysis: one decide when – Made in centers – More diet restriction – Blood is pumped out from – carried out every da the body into the machine – Greater lifestyle flexibility and return back to the and independence body – More risky for infection Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 160 medical physiology)  Characteristics of dialysis fluid The concentration of Ca++, HCO3- and glucose high in the DF The concentration of Na+, Cl-, Mg++ and lactate are equal (their concentration in the plasma not affected by the kidney disease) Concentration of K+ in the DF is less, filtered out from the blood into the DF via the membrane The concentration of urea, creatinine , urate, phosphate and sulphate is zero in the DF Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 161 medical physiology)  Assignment in your life National Kidney Disease Education Program Raise awareness among people at risk for CKD about the need for testing; Educate people with CKD about how to manage their disease; Provide information, training, and tools to help health care providers better detect and treat CKD; and Support health system change to facilitate effective CKD detection and management Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 162 medical physiology)  THANK YOU Thank you Abebaye A (BSC, MSc, PHD, AAU- Dept of 11/4/2024 163 medical physiology)