Farmakoterapi II RENAL DISEASE FISIOLOGI RENAL oleh: Tunggul Adi P., M.Sc., Apt. Laboratorium Farmasi Klinik FKIK UNSOED Farmakoterapi II RENAL DISEASE

TUJUAN PEMBELAJARAN Mahasiswa mampu: Menjelaskan fungsi fisiologis ginjal Menjelaskan struktur ginjal Menjelaskan proses filtrasi, reabsorpsi, dan sekresi

FUNGSI UTAMA GINJAL Pengaturan volume dan osmolalitas cairan tubuh Pengaturan keseimbangan elektrolit Pengaturan keseimbangan asam basa Ekskresi (metabolic product, foreign substance, excess substance) Produksi dan sekresi hormon (erythropoitin, 1,25-dihydroxy vitamin D3 (vitamin D activation), renin)

Renal system – important points Kidneys have excellent blood supply: 0.5% total body weight but ~20% of CO (cardiac output). Kidneys process plasma portion of blood by removing substances from it, and in a few cases, by adding substances to it. Works with cardiovascular system (and others!) in integrated manner

Ascending loop of Henle GINJAL DAN NEFRON Renal Vein Renal Artery Ureter Medulla Renal Pelvis Cortex Ascending loop of Henle Descending loop of Henle Peritubular capillaries Proximal tubule Glomerulus Distal tubule                                                                                                                                                     

The functional unit of the kidney: the nephron Total of about 2.5 million in the 2 kidneys. Each nephron consists of 2 functional components: The tubular component (contains what will eventually become urine) The vascular component (blood supply) The mechanisms by which kidneys perform their functions depends upon the relationship between these two components. Responsible for urine formation: Filtration Secretion Reabsorption

Characteristics of the renal blood flow: 1, high blood flow. 1200 ml/min, or 21 percent of the cardiac output. 94% to the cortex 2, Two capillary beds High hydrostatic pressure in glomerular capillary (about 60 mmHg) and low hydrostatic pressure in peritubular capillaries (about 13 mmHg) Vesa Recta

Functions of the Nephron Secretion Reabsorption Excretion Filtration

Overview of nephron function From http://www.emc.maricopa.edu/faculty/farabee/BIOBK/BioBookEXCRET.html

HUMAN RENAL PHYSIOLOGY Four Main Processes: Filtration Reabsorbtion Secretion Excretion

HUMAN RENAL PHYSIOLOGY Functions of the Kidney: Filtration: First step in urine formation Bulk transport of fluid from blood to kidney tubule Isosmotic filtrate Blood cells and proteins don’t filter Result of hydraulic pressure GFR = 180 L/day

HUMAN RENAL PHYSIOLOGY Functions of the Kidney: Reabsorbtion: Process of returning filtered material to bloodstream 99% of what is filtered May involve transport protein(s) Normally glucose is totally reabsorbed

HUMAN RENAL PHYSIOLOGY Functions of the Kidney: Secretion: Material added to lumen of kidney from blood Active transport (usually) of toxins and foreign substances Saccharine Penicillin

HUMAN RENAL PHYSIOLOGY Functions of the Kidney: Excretion: Loss of fluid from body in form of urine: Amount of solute excreted= amount filtered + amount secreted – amount reabsorbed

Filtration

THE GLOMERULUS

Plasma is filtered through the glomerular barrier Components of plasma cross the three layers of the glomerular barrier during filtration Capillary endothelium Basement membrane (net negative charge) Epithelium of Bowman’s Capsule (Podocytes –filtration slits allow size <60kD) The ability of a molecule to cross the membrane depends on size, charge, and shape Glomerular filtrate therefore contains all molecules not contained by the glomerular barrier - it is NOT URINE YET!

Glomerular filtration GFR controlled by diameters of afferent and efferent arterioles Sympathetic vasoconstrictor nerves ADH and RAAS also have an effect on GFR. Autoregulation maintains blood supply and so maintains GFR. Also prevents high pressure surges damaging kidneys. Unique system of upstream and downstream arterioles. Remember: high hydrostatic pressure (PGC) at glomerular capillaries is due to short, wide afferent arteriole (low R to flow) and the long, narrow efferent arteriole (high R).

GFR depends on diameters of afferent and efferent arterioles Glomerulus Afferent arteriole Efferent arteriole GFR GFR Glomerular filtrate Eff. Art. constriction Aff. Art. constriction Eff. Art. dilatation Aff. Art. dilatation Prostaglandins, Kinins, Dopamine (low dose), ANP, NO Ang II (high dose), Noradrenaline (Symp nerves), Endothelin, ADH, Prost. Blockade) Angiotensin II (low dose) Angiotensin II blockade

Glomerular Filtration Rate (GFR) Measure of functional capacity of the kidney Dependent on difference in pressures between capillaries and Bowman’s space Normal = 120 ml/min =7.2 L/h=180 L/day!! (99% of fluid filtered is reabs.)

Oncotic pressure Oncotic pressure is the component of total osmotic pressure due to colloid particles. Water molecules cross the membrane to equalize the concentration of colloid particles on each side.

Glomerular filtration rate (GFR) Depends on the difference in hydrostatic and oncotic pressure on either side of the glomerular basement membrane GFR = Kf(PGC - PBS - COPGC) P = hydrostatic pressure COP = colloid osmotic pressure Kf determined by surface area and permeability of H2O Glomerular Capillary (GC) Bowman’s space (BS) PGC PBS COPGC COPBS

Reabsorption and secretion

Peritubular reabsorption Peritubular capillaries provide nutrients for tubules and retrieve the fluid the tubules reabsorb. Oncotic P is greater than hydrostatic P in these capillaries, so therefore get reabsorption NOT filtration. Must occur since we filter 180l/day, but only excrete 1-2l/day of urine. Reabsorb 99% H2O, 100% glucose, 99.5% Na+ and 50% urea. Most of this occurs at proximal convoluted tubule.

Reabsorption Active Transport –requires ATP Passive Transport- Na+, K+ ATP pumps Passive Transport- Na+ symporters (glucose, a.a., etc) Na+ antiporters (H+) Ion channels Osmosis

Renal transport systems Lots of transporter proteins for different molecules/ions so they can be reabsorbed. They all have maximum transport (TM) capacities where transport saturates i.e. 10mmol/l for glucose. Over this value, you excrete the excess in urine, so can be useful sign of disease either in kidneys or other systems. Amino acids also have a high TM value because you try and preserve as much of these useful nutrients as possible.

Factors influencing Reabsorption Saturation: Transporters can get saturated by high concentrations of a substance - failure to resorb all of it results in its loss in the urine (eg, renal threshold for glucose is about 180mg/dl). Rate of flow of the filtrate: affects the time available for the transporters to reabsorb molecules.

What is Reabsorbed Where? Proximal tubule - reabsorbs 65 % of filtered Na+ as well as Cl-, Ca2+, PO4, HCO3-. 75-90% of H20. Glucose, carbohydrates, amino acids, and small proteins are also reabsorbed here. Loop of Henle - reabsorbs 25% of filtered Na+. Distal tubule - reabsorbs 8% of filtered Na+. Reabsorbs HCO3-. Collecting duct - reabsorbs the remaining 2% of Na+ only if the hormone aldosterone is present. H20 depending on hormone ADH.

Secretion Proximal tubule – uric acid, bile salts, metabolites, some drugs, some creatinine Distal tubule – Most active secretion takes place here including organic acids, K+, H+, drugs

Countercurrent exchange The structure and transport properties of the loop of Henle in the nephron create the Countercurrent multiplier effect. A substance to be exchanged moves across a permeable barrier in the direction from greater to lesser concentration. Image from http://en.wikipedia.org/wiki/Countercurrent_exchange

Loop of Henle Goal= make isotonic filtrate into hypertonic urine (don’t waste H20!!) Counter-current multiplier: Descending loop is permeable to Na+, Cl-, H20 Ascending loop is impermeable to H20- active NaCl transport Creates concentration gradient in interstitium Urine actually leaves hypotonic but CD takes adv in making hypertonic

Na+ absorption Na+ absorbed by active transport mechanisms, NOT by TM mechanism. Basolateral ATPases establish a gradient across the tubule wall. Proximal tubule is very permeable to Na+, so ions flow down gradient, across membranes. Microvilli create large surface area for absorption. Electrical gradient created also draws Cl- across. H2O follows Na+ due to osmotic force. Means fluid left in tubule is concentrated.

Glucose handling Glucose absorption also relies upon the Na+ gradient. Most reabsorbed in proximal tubule. At apical membrane, needs Na+/glucose cotransporter (SGLT) Crosses basolateral membrane via glucose transporters (GLUT’s), which do not rely upon Na+.

Amino acid handling Preserve as much of these essential nutrients as possible. Can be absorbed by GI tract, products of protein catabolism, or de novo synthesis of nonessential amino acids. TM values lower than that of glucose, so can excrete excess in urine. Amino acid transporters rely upon Na+ gradient at apical membrane, but a couple of exceptions don’t. Exit across basolateral membrane via diffusion , but again, some exceptions rely on Na+.

K+ handling K+ is major cation in cells and balance is essential for life. Small change from 4 to 5.5 mmoles/l = hyperkalaemia = ventric. fibrillation = death. To 3.5 mmoles/l = hyperpolarise = arrhythmias and paralysis = death. Reabsorb K+ at proximal tubule. Changes in K+ excretion due to changes in K+ secretion in distal tubule Medullary trapping of K+ helps to maximise K+ excretion when K+ intake is high.

K+ handling K+ reabsorption along the proximal tubule is largely passive and follows the movement of Na+ and fluid (in collecting tubules, may also rely active transport). K+ secretion occurs in cortical collecting tubule (principal cells), and relies upon active transport of K+ across basolateral membrane and passive exit across apical membrane into tubular fluid.

Hormones Produced by the Kidney Renin: Released from juxtaglomerular apparatus when low blood flow or low Na+. Renin leads to production of angiotensin II, which in turn ultimately leads to retention of salt and water. Erythropoietin: Stimulates red blood cell development in bone marrow. Will increase when blood oxygen low and anemia (low hemoglobin). Vitamin D3: Enzyme converts Vit D to active form 1,25(OH)2VitD. Involved in calcium homeostasis.

Renin, Angiotensin, Aldosterone: Regulation of Salt/Water Balance

Renin/AII and Regulation of GFR GFR = Kf(PGC - PBS - COPGC) “flight or fright”  sympathetic tone afferent arteriolar constriction (divert cardiac output to other organs) PGC GFR and renal blood flow

Renin/AII and Regulation of GFR GFR = Kf(PGC - PBS - COPGC) Low BP sensed in afferent arteriole or low Na in distal tubule renin released renin converts angiotensinogen to Angiotensin I ACE converts AI to AII efferent > afferent arteriolar constriction  PGC   GFR (this is AUTOREGULATION of GFR) PGC constricts

Aldosterone Secreted by the adrenal glands in response to angiotensin II or high potassium Acts in distal nephron to increase resorption of Na+ and Cl- and the secretion of K+ and H+ NaCl resorption causes passive retention of H2O

Anti-Diuretic Hormone (ADH) Osmoreceptors in the brain (hypothalamus) sense Na+ concentration of blood. High Na+ (blood is highly concentrated) stimulates posterior pituitary to secrete ADH. ADH upregulates water channels on the collecting ducts of the nephrons in the kidneys. This leads to increased water resorption and decrease in Na concentration by dilution