Renal physiology and regulation of water and inorganic ions by Marc Imhotep Cray, M.D.

Photo: Glomerulus in a human kidney scanning electron micrograph. From: Widmaier EP, Raff H & Strang KT. Vanderâ&#x20AC;&#x2122;s Human Physiology: The Mechanisms Of Body Function, 13th Ed. New York, NY: McGraw-Hill Companies, Inc., 2014: 490

Physiological Basis of Renal Pharmacology: A Rapid Review

Marc Imhotep Cray, M.D.

Interdigitation of Renal system with Cardiovascular and Endocrine systems  Heart is principal source of atrial natriuretic peptide (ANP) acts in classic endocrine fashion to induce natriuresis at a distant target organ (kidney)  Erythropoietin, a traditional circulating hormone, is made in kidney and stimulates erythropoiesis in bone marrow Kidney is also integrally involved in renin-angiotensin-aldosterone axis and is a primary target of several hormones, including parathyroid hormone (PTH), mineralocorticoids, and vasopressin  Hormones play an important role in maintenance of blood pressure, intravascular volume, and peripheral resistance in cardiovascular system  Vasoactive substances such as catecholamines, angiotensin II, endothelin, and nitric oxide are involved in dynamic changes of vascular tone in addition to their multiple roles in other tissues Marc Imhotep Cray, M.D.

Le T and Bhushan V. First Aid for the USMLE Step 1 2016. NY, New York: McGraw-Hill Education, 2016.

Overview of Renal Pharmacology  For many drugs, kidney is major organ of elimination  In healthy human, kidney receives between 20% and 25% of blood pumped by each beat of heart  Kidney’s primary function is 2-fold: 1. to eliminate unwanted substances (eg, toxic substances, drugs, and their metabolites) and 2. to retain (reabsorb, recycle) wanted materials (eg, water and electrolytes)  Amount of drug and metabolites eliminated (cleared) from body depends on several factors, including  glomerular filtration rate (GFR)  urine flow rate and  pH Marc Imhotep Cray, M.D.

Overview (2)  Rate of renal elimination is net result of glomerular filtration, secretion, and reabsorption  Functional microscopic unit of kidney is nephron a tube that is open at one end and closed at other end by a selectively permeable membrane  Nephron has 5 distinct anatomical and functional units: 1. glomerulus 2. proximal convoluted tubule 3. loop of Henle 4. distal convoluted tubule 5. collecting duct  Large drug molecules (>5-6 kd) and drug molecules that are bound to plasma proteins do not pass into nephron of a healthy kidney Marc Imhotep Cray, M.D.

Overview (3)  Most of water and other substances that enter nephron are reabsorbed into surrounding tissue and blood supply  The small residual amount is excreted as urine  Flow and contents of urine are determined by 3 processes, most of which are coupled: 1. filtration through glomerulus 2. reabsorption of water and other substances from tubule, and 3. secretion of substances into tubule

 Processes involve  active transport  passive transport, or  osmotic gradients Marc Imhotep Cray, M.D.

Overview (4) Most of water and solutes (eg, sodium, glucose, bicarbonate, amino acids) are reabsorbed during passage through proximal convoluted tubule (PCT)  Further concentration occurs in countercurrent system of loop of Henle

Thick ascending limb and distal convoluted tubule (DCT) are involved in Na+-K+ and H+ exchange under tight homeostatic control and hormonal influence, including adrenal steroid hormones such as aldosterone Collecting duct is primary site of action of antidiuretic hormone (ADH) Marc Imhotep Cray, M.D.

Overview (5) Each class of diuretics affects different processes located at different sites along nephrons  Therefore, each class has its own set of associated therapeutic advantages or drawbacks  Each also has characteristic effects on electrolyte balance an important consideration for long-term use  Many effects can be anticipated on basis of a drug’s mechanism of diuretic action and can be ameliorated by dietary or drug regimens  Combinations of diuretics may offer a remedy for resistance to a single agent  A decline in renal function, whether caused by advanced age or disease, has a significant effect on clearance of drugs that are eliminated predominantly via the kidney  Dosages Marc Imhotep Cray, M.D. must be adjusted in these situations

Organization and Functions of Renal System

Marc Imhotep Cray, M.D.

Gross Anatomy

Anterior surface of right kidney

 Kidneys are a pair of specialized, retroperitoneal organs located at level between lower thoracic and upper lumbar vertebrae  Each kidney is reddish brown and has a characteristic shape:  a convex lateral edge and concave medial border with a marked depression or notch termed hilus  Each adult kidney is approx. 11 cm Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated long, 2.5 cm thick, and 5 cm wide Pharmacology, Updated Edition. Saunders, 2014 and weighs 120 to 170 g Marc Imhotep Cray, M.D.

Gross Anatomy (2)

Seeley R. et.al. Seeleyâ&#x20AC;&#x2122;s Anatomy & Physiology 10th ed. New York, NY: McGraw-Hill , 2010.

Marc Imhotep Cray, M.D.

Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edition. Saunders, 2014

Normal Kidney, gross

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015. 13

Functional Anatomy  Kidneys contribute to several important processes, including  regulation of fluid volume  regulation of electrolyte and acid-base balance  excretion of metabolic wastes and  elimination of toxic compounds, drugs, and their metabolites  Kidney also acts as an endocrine organ  Each kidney is divided into a cortex and a medulla, both parts containing nephrons (approx. 1.25 million per kidney) Fluid that exits a nephron flows out papilla of a pyramid (8-15 per medulla), enters a minor calyx, joins effluent of other minor calyces in major calyx, and is eliminated as urine through ureter Marc Imhotep Cray, M.D.

Functions of Kidneys Kidneys perform a host of functions (5), including: 1. Regulation of fluid and electrolyte balance:  kidneys regulate volume of extracellular fluid (ECF) through reabsorption and excretion of NaCl and water They are also site of regulation of plasma levels of other key substances (Na+, K+, Cl−, HCO3−, H+, Ca2+, and phosphates)

Marc Imhotep Cray, M.D.

Key renal processes involved in regulation of circulating substances: fluid and electrolyte balance Filtration of fluid and solutes from plasma into nephrons

Reabsorption of fluid and solutes from renal tubules into peritubular capillaries

Secretion of select substances from peritubular capillaries into tubular fluid, which facilitates their excretion  both endogenous (e.g., K+, H+, creatinine, norepinephrine, and dopamine) and exogenous (e.g., para-aminohippurate [PAH], salicylic acid, and penicillin) substances can be secreted into tubular fluid and subsequently excreted in urine

Excretion of excess fluid, electrolytes, and other substances (e.g., urea, bilirubin, and acid [H+])

Marc Imhotep Cray, M.D.

Functions of Kidneys cont. 2. Regulation of plasma osmolarity:  “Opening” and “closing” of specific water channels (aquaporins) in renal collecting ducts produces concentrated and dilute urine (respectively) allowing regulation of plasma osmolarity and ECF volume

3. Elimination of metabolic waste products:     

Urea (from protein metabolism) Creatinine (from muscle metabolism) Bilirubin (from breakdown of hemoglobin) Uric acid (from breakdown of nucleic acids) Metabolic acids, and foreign substances such as drugs are excreted in urine

Marc Imhotep Cray, M.D.

Functions of Kidneys cont. 4. Production/conversion of hormones:  kidney produces erythropoietin and renin  Erythropoietin stimulates red blood cell production in bone marrow  Renin, a proteolytic enzyme, is secreted into blood and converts angiotensinogen to angiotensin I which is then converted to angiotensin II by angiotensin-converting enzyme (ACE) in lungs and other tissues o renin-angiotensin system is critical for fluid-electrolyte homeostasis and long-term blood pressure regulation  Renal tubules also convert 25-hydroxyvitamin D to active 1,25dihydroxyvitamin D, which can act on kidney, intestine, and bone to regulate calcium homeostasis Marc Imhotep Cray, M.D.

Functions of Kidneys cont. 5. Metabolism: ď ą Renal production of ammonia through ammoniagenesis has an important role in acid-base homeostasis ď ą Kidney, like the liver, has ability to produce glucose through gluconeogenesis

Marc Imhotep Cray, M.D.

Microscopic Anatomy: The Nephron  Each kidney contains approximately 1 to 2.5 million tubular nephrons (Greek nephros, meaning kidney)  A nephron originates in glomerular apparatus  part adjoining this corpuscle is termed proximal convoluted tubule because of its tortuous course that remains close to its point of origin  Tubule then straightens in direction of center of kidney and forms Henle loop, by making a hairpin turn and returning to vascular pole of its parent renal corpuscle Marc Imhotep Cray, M.D.

Nephron (2)  The Henle loop extends to distal convoluted tubule and then to collecting tubule  Collecting tubules unite to form larger collecting ducts  Most nephrons originate in kidney cortex, are short, and extend only to outer medullary zone  Other nephrons originate close to medullary level (juxtamedullary glomeruli) and extend deep into medulla, almost as far as the papilla  Each part of nephron acts in physiologic processes that affect or are affected by metabolism of drug molecules (or their metabolites) Marc Imhotep Cray, M.D.

Marc Imhotep Cray, Widmaier EP, Raff H &M.D. Strang KT Vanderâ&#x20AC;&#x2122;s Human Physiology: The Mechanisms Of Body Function, 13th Ed. McGraw-Hill, 2014.

Nephron (3) Renal blood flow 1-1.2 L/min Glomerular filtration rate 100-125 mL/min 140-180 L/d Urine flow rate 0.5-18 L/d Number of nephrons Cortical Juxtamedullary

2.5 million 2.1 million 0.4 million

Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edition. Saunders, 2014

Blood Vessels Surrounding Nephrons  Critical to multiple kidney functions is close association of nephrons with blood vessels water and other substances pass from nephron to blood and vice versa  Kidneys have a great influence on volume and composition of plasma and urine, so architecture of renal vasculature reflects functions other than tissue oxygenation  In outer renal cortex, each afferent arteriole enters a glomerulus, divides, forms a capillary network, becomes an efferent arteriole, and exits glomerulus Glomerulus (human); H and E stain 3500X P = Proximal tubule D = Distal tubule P = Juxtaglomerular cells

Marc Imhotep Cray, M.D.

Blood Vessels Surrounding Nephrons (2) Neurotransmitters, drugs, and environmental factors that relax afferent arteriole or constrict efferent arteriole increase GFR Contrastly; Neurotransmitters, drugs, and environmental factors that constrict afferent arteriole or relax efferent arteriole reduce GFR Blood vessels surround and outnumber tubular segments of each nephron and form a peritubular network of capillaries allows exchange of water, electrolytes, and other substances  This exchange is target for actions of many drugs, especially diuretics Marc Imhotep Cray, M.D.

Pattern of Blood Vessels in Parenchyma of Kidney: Schema

Marc Imhotep Cray, M.D.

Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edition. Saunders, 2014

Microscopic Anatomy: The glomerulus  Glomerulus is an important interface between afferent arteriolar blood flow and nephron  Glomerulus filters plasma, and fluid, minus cells, enters nephron as an ultrafiltrate

 Glomerulus is also a barrier to molecules larger than approx. 5 kd (eg, plasma proteins)  Thus, plasma proteins and drug molecules bound to them do not pass into nephrons of a healthy kidney only smaller free drug or metabolite molecules do so o However, damaged glomeruli allow passage of plasma proteins, and presence of these proteins in urine indicates a renal disorder Marc Imhotep Cray, M.D.

Glomerulus (2)  In renal disease, drugs enter nephron and are excreted at a rate greater than normal, which is noted as a shorter plasma half-life of drugs (or metabolites) subtherapeutic levels  renal disease also cause reduced elimination of drugs normally excreted via the kidney longer plasma half-life of drugs (or metabolites) toxicity  Hormones and hormone-mimetic drugs that alter GFR include  angiotensin II (AT-II) (constricts afferent arterioles and thereby reduces GFR)  atrial natriuretic peptide (ANP) (dilate afferent arterioles and thus increase GFR)  prostaglandin E2 (dilate afferent arterioles and thus increase GFR) Marc Imhotep Cray, M.D.

Histology of Renal Corpuscle

Le T and Bhushan V. First Aid for the USMLE Step 1 2015 . McGraw-Hill 2015.

Marc Imhotep Cray, M.D.

Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edition. Saunders, 2014

Diagram of renal corpuscle structure: A – Renal corpuscle B – Proximal tubule C – Distal convoluted tubule D – Juxtaglomerular apparatus 1. Basement membrane (Basal lamina) 2. Bowman's capsule – parietal layer 3. Bowman's capsule – visceral layer 3a. Pedicels (Foot processes from podocytes) 3b. Podocyte 4. Bowman's space (urinary space) 5a. Mesangium – Intraglomerular cell 5b. Mesangium – Extraglomerular cell 6. Granular cells (Juxtaglomerular cells) 7. Macula densa 8. Myocytes (smooth muscle) 9. Afferent arteriole 10. Glomerulus Capillaries 11. Efferent arteriole

https://en.wikipedia.org/wiki/Renal_corpuscle#/media/File:Renal_corpuscle.svg30

Normal Kidney, microscopic

Klatt EC. Robbins and Cotran Atlas of Pathology, 3rd Ed. Philadelphia: Saunders, 2015.

Microscopic Anatomy: Tubular Segments  Structure and function of tubular segments are important for understanding drug effects on kidney  Proximal portion and thick segment of descending limb have a similar structure (slight variation in cell size and shape)  Tight junctions between cells prevent escape of material in tubular lumen  Proximal segment cells act to reabsorb water and other substances  Proximal segment’s brush border is replaced in thin tubular segment by fewer short microvilli

 Permeability to water and position of descending and ascending limbs of Henle loop create a countercurrent multiplier for urine concentration Marc Imhotep Cray, M.D.

Tubular Segments (2) Distal segment of nephron consists of thick ascending limb of Henle loop and distal convoluted tubule The ultrastructure and large surface area of distal segment  serve energy requirements of active Na+ transport from luminal fluid  formation of ammonia, and  urine acidification Drug action in each segment alters kidney function in specific ways Marc Imhotep Cray, M.D.

Tubular Segments (3)

Marc Imhotep Cray, M.D.

Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edition. Saunders, 2014

Ion and Water Reabsorption More than 99% of glomerular ultrafiltrate is reabsorbed from tubular lumen kidney is thus more an organ of retention than of elimination Driving factor for water and Na+ reabsorption in nephron is active Na+ transport Drugs affecting Na+ transport can alter urine flow and composition Na+ reabsorption occurs against conc. and electrical potential gradients (lumen is electrically negative compared with Marcperitubular Imhotep Cray, M.D. fluid) and is an active process requiring energy (ATP)

Ion and Water Reabsorption (2) Active uptake mechanism (pump) for Na+ involves a cotransporter that exchanges Na+ for K+, an important factor for drugs that affect Na+ transport Cl− and other ions move by cotransport with Na+ or other ions or by passive diffusion Osmotic gradient (established by ion transport) drives water out of lumen Hormones and drugs that decrease ion transport or osmotic gradient reduce ion and water reabsorption and thus increase flow Marcurine Imhotep Cray, M.D. (diuresis) and ion content

Bicarbonate Reabsorption A notable ion with regard to drug metabolism is bicarbonate, or HCO3 − HCO3− and Cl− are most relevant ions for class of diuretic drugs known as carbonic anhydrase inhibitors  HCO3− is freely filtered through glomerulus and enters nephron Almost all of it is reabsorbed along the tubule—most of it (80%– 85%) in proximal convoluted tubule—in a process that involves H+ secretion, thus reabsorption of HCO3 − is inhibited by carbonic anhydrase inhibitors Marc Imhotep Cray, M.D.

Bicarbonate Reabsorption (2) Although usually all filtered HCO3− is reabsorbed and none is excreted in urine, a number of factors influence H+ secretion by nephron, and a small amount of HCO3− can be lost in urine Kidneys generate new HCO3 − to replenish this loss

 Acetazolamide is a diuretic that affects HCO3− exchange, predominantly at proximal convoluted tubule (more on this in diuretics subsection)

Marc Imhotep Cray, M.D.

Potassium Excretion  Kidneys are primary route of excretion of K+ from body  Although a large fraction of filtered K+ is reabsorbed along proximal convoluted tubule and loop of Henle, amount of K+ excretion in urine is determined mainly by highly variable secretory activity of distal convoluted tubule  Several diuretics and other drugs cause excess urinary K+ loss as a side effect  by increasing distal tubular flow rate and Na+ delivery (eg, ethacrynic acid and furosemide)  by alkalinizing distal tubular fluid (eg, carbonic anhydrase inhibitors such as acetazolamide), or  by blocking tubular K+ reabsorption (eg, ouabain)

 Some diuretics, known as potassium-sparing diuretics, do not cause K+ loss Cray, M.D. Marc Imhotep

Renal Physiology: Fluid compartments  “HIKIN”: HIgh K+ INtracellularly 60–40–20 rule (% of body weight for average person):  60% total body water  40% ICF  20% ECF  Plasma volume can be measured by radiolabeling albumin  Extracellular volume can be measured by inulin or mannitol  Osmolality = 285–295 mOsm/kg H2O Le T and Bhushan V. First Aid for the USMLE Step 1 2016. NY, New York: McGrawHill Education, 2016.

Practical Application: Measuring Glomerular Filtration Rate (GFR) GFR is an important characteristic of normal kidney functioning and an important variable in elimination of drugs and their metabolites  In general, greater GFR is, greater rate of elimination is GFR can be measured noninvasively by determining rate at which a substance is removed from plasma (or appears in urine) requires use of a substance that is freely filtered by glomerulus and is neither reabsorbed nor secreted within nephron  These criteria are fulfilled by the 5-kd fructose polysaccharide inulin Marc Imhotep Cray, M.D.

Measuring GFR (2) For the assay, after a uniform blood level of inulin is established, measurement of concentration of inulin in plasma (Pin), concentration of inulin in urine (Uin), and urine flow rate (V) yields the GFR from equation: GFR = (V × Uin)/Pin

GFR of a healthy adult kidney is approximately 120 mL/min Decreased clearance, which is common in elderly, usually results in slower drug elimination and requires an appropriate dosage adjustment Note: Creatinine clearance is an Marc Imhotep Cray, M.D.

approximate measure of GFR. Slightly overestimates GFR because creatinine is moderately secreted by renal tubules.

Measuring GFR (3)

Marc Imhotep Cray, M.D.

Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edition. Saunders, 2014

Renal Clearance Principle  “Clearance” describes volume of plasma that is cleared of a substance per unit time  Renal clearance (C) of a substance provides information on how kidney handles that substance

 Because inulin is freely filtered and not reabsorbed or secreted, all of filtered inulin is excreted in urine  thus, Cinulin is equated with glomerular filtration rate (GFR), and  Net handling of other substances can be determined, depending on whether their clearance is  greater than (indicating net secretion)  less than (indicating net reabsorption) or  equal to Cinulin Marc Imhotep Cray, M.D.

Renal clearance Cx = UxV/Px = volume of plasma from which the substance is completely cleared per unit time If Cx < GFR: net tubular reabsorption of X If Cx > GFR: net tubular secretion of X If Cx = GFR: no net secretion or reabsorption Cx = clearance of X (mL/min). Ux = urine concentration of X (eg, mg/mL). Px = plasma concentration of X (eg, mg/mL). V = urine flow rate (mL/min).

Marc Imhotep Cray, M.D.

Glomerular filtration rate Inulin clearance can be used to calculate GFR b/c it is freely filtered and is neither reabsorbed nor secreted GFR = Uinulin x V/Pinulin = Cinulin = Kf [(PGc – PBs) – (πGC – πBS)] (Gc = glomerular capillary, Bs = Bowman space) πBS normally equals zero; Kf = filtration constant. Normal GFR ≈ 100 mL/min Creatinine clearance is an approximate measure of GFR Slightly overestimates GFR b/c creatinine is moderately secreted by renal tubules Incremental reductions in GFR define the stages of chronic kidney disease.

Le T and Bhushan V. First Aid for the USMLE Step 1 2016. NY, New York: McGraw-Hill Education, 2016.

Effective renal plasma flow  Effective renal plasma flow (eRPF) can be estimated using para-aminohippuric acid (PAH) clearance b/c between filtration and secretion there is nearly 100% excretion of all PAH that enters the kidney  eRPF = UPAH x V/PPAH = CPAH Renal blood flow (RBF) = RPF/(1 − Hct) Plasma = 1 − hematocrit eRPF underestimates true renal plasma flow (RPF) slightly

Marc Imhotep Cray, M.D.

Filtration  Filtration fraction (FF) = GFR/RPF  Normal FF = 20%

 Filtered load (mg/min) = GFR (mL/min) x plasma conc. (mg/mL)  GFR can be estimated with creatinine clearance  RPF is best estimated with PAH clearance

Marc Imhotep Cray, M.D.

Le T and Bhushan V. First Aid for the USMLE Step 1 2016. NY, New York: McGraw-Hill Education, 2016.

Glucose clearance  Glucose at a normal plasma level (range 60–120mg/dL) is completely reabsorbed in PCT by Na+/glucose cotransport  In adults, at plasma glucose of ∼ 200 mg/dL, glucosuria begins (threshold)  At rate of∼ 375 mg/min, all transporters are fully saturated (Tm)  Normal pregnancy may decrease ability of PCT to reabsorb glucose & amino acids  glucosuria and aminoaciduria  Glucosuria is an important clinical clue to diabetes Le T and Bhushan V. First Aid for the USMLE Step 1 2016. NY, mellitus New York: McGraw-Hill Education, 2016.  Splay is region of substance clearance between threshold and Tm due to heterogeneity of nephrons

Nephron physiology: Early PCT  Early PCT—contains brush border  Reabsorbs all Glu and AAs and most HCO3– , Na+, Cl–, PO4 3–, K+, H2O, and uric acid  Isotonic absorption  Generates and secretes NH3, which acts as a buffer for secreted H+  PTH—inhibits Na+/PO43– cotransport PO43– excretion  AT II—stimulates Na+/H+ exchange  ↑Na+, H2O, and HCO3− reabsorption (permitting contraction alkalosis)  5–80% Na+ reabsorbed

Le T and Bhushan V. First Aid for the USMLE Step 1 2016. NY, New York: McGraw-Hill Education, 2016.

Nephron physiology: Thin descending loop of Henle  Thin descending loop of Henle passively reabsorbs H2O via medullary hypertonicity (impermeable to Na+)  Concentrating segment  Makes urine hypertonic

Marc Imhotep Cray, M.D.

Le T and Bhushan V. First Aid for the USMLE Step 1 2016. NY, New York: McGraw-Hill Education, 2016.

Nephron physiology: Thick ascending loop of Henle  Thick ascending loop of Henlereabsorbs Na+, K+, and Cl−  Indirectly induces paracellular reabsorption of Mg2+ and Ca2+ through ⊕ lumen potential generated by K+ backleak  Impermeable to H2O  Makes urine less concentrated as it ascends  10–20% Na+ reabsorbed Marc Imhotep Cray, M.D.

Le T and Bhushan V. First Aid for the USMLE Step 1 2016. NY, New York: McGraw-Hill Education, 2016.

Nephron physiology: Early DCT Early DCT—  reabsorbs Na+, Cl−  Makes urine fully dilute (hypotonic)  PTH—↑Ca2+/Na+ exchange Ca2+ reabsorption  5–10% Na+ reabsorbed

Marc Imhotep Cray, M.D.

Le T and Bhushan V. First Aid for the USMLE Step 1 2016. NY, New York: McGraw-Hill Education, 2016.

Nephron physiology: Collecting tubule Collecting tubule reabsorbs Na+ in exchange for secreting K+ and H+ (regulated by aldosterone)  Aldosterone—acts on mineralocorticoid receptor mRNA protein synthesis  In principal cells: ↑ apical K+ conductance, ↑Na+/K+ pump, ↑ epithelial Na+ channel (ENaC) activity  lumen negativity ↑ K+ secretion  In α-intercalated cells: lumen negativity ↑H+ ATPase activity ↑H+ secretion ↑HCO3 −/Cl− exchanger activity  ADH—acts at V2 receptor insertion of aquaporin H2O channels on apical side.  3–5% Na+ reabsorbed

Le T and Bhushan V. First Aid for the USMLE Step 1 2016. NY, New York: McGraw-Hill Education, 2016.

Sodium reabsorption in successive segments of the nephron

Modified from: Pollock CA, Harris D, & Field MJ. The Renal System: Basic Science and Clinical Conditions 2nd Ed. Elsevier, 2010

Marc Imhotep Cray, M.D.

Nephron Physiology Capsule Proximal convoluted tubule • Reabsorbs glucose, amino acids, water, bicarbonate ions, Na+ and Cl− ions • Contains a brush border

Distal convoluted tubule • Actively reabsorbs Na+ and Cl− ions • Simple cuboidal epithelium

Thin descending loop of Henle • Reabsorbs water by medullary hypertonicity • It is impermeable to Na+ ions

Collecting tubule • Aldosterone: increases the number of Na+ ion channel in the collecting tubules • Antidiuretic hormone (ADH): binds to V2 receptors and consequently increases the number of aquaporins

Thick ascending loop of Henle • Permeable to Na+ ions • Impermeable to water • Contains the Na+/K+/2Cl− transporter

Volume Regulation

Marc Imhotep Cray, M.D.

Antidiuretic Hormone (ADH) ď ąAntidiuretic hormone, also known as arginine vasopressin in humans, is a 1-kd nonapeptide that is synthesized in hypothalamus and released into blood from posterior pituitary gland ď ą It is structurally similar to oxytocin but is a more potent (>100 times) antidiuretic

ď ą ADH alters morphology of cells of collecting duct and increases their permeability Marc Imhotep Cray, M.D.

ADH (2)

Water passes from collecting duct lumen into renal interstitium, so an osmotic equilibrium between interstitium and fluid in duct occurs In presence of ADH, amount of water that can be reabsorbed from collecting ducts is limited only by amount flowing through them

Various stimuli induce ADH release thus production of a small volume of concentrated urine:  plasma osmolality, pain, emotion, trauma, and drugs(eg, nicotine, morphine, ether, some barbiturates)  ADH is inhibited by ethanol Marc Imhotep Cray, M.D.

ADH (3)

Note: Normal human reference range of osmolality in plasma is about 285-295 milli-osmoles per kilogram Marc Imhotep Cray, M.D.

Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edition. Saunders, 2014

Diabetes Insipidus (DI)  Vasopressin is an important regulator of urine osmolarity, as it increases permeability of collecting ducts in kidney to water  An inadequate vasopressin effect leads to diabetes insipidus

 Diagnosis of cause of diabetes insipidus is based on administration of vasopressin  If there is a pituitary deficiency of vasopressin, administered vasopressin will increase urine osmolarity central diabetes insipidus  If DI is nephrogenic, administered vasopressin will have no effect on urine osmolarity nephrogenic diabetes insipidus Marc Imhotep Cray, M.D.

Diabetes Insipidus (2)  Treatment depends on cause  If DI is due to a pituitary deficiency, replacement therapy is instituted o Vasopressin (Pitressin) can be given intramuscularly, but it can increase blood pressure due to vasoconstriction o Lypressin (Diapid), administered intranasally, lasts 4 hours o Desmopressin (DDAVP), administered intranasally, lasts 12 hours and does not increase blood pressure • It is also available in tablet form  If DI is nephrogenic, thiazides (unexpectedly) are effective treatment Marc Imhotep Cray, M.D.

Renin-Angiotensin-Aldosterone System In addition to ADH, a second volume-regulating system-the RAAS-involves the kidney Kidneys synthesize and secrete renin, a proteolytic enzyme of approximately 40 kd, in response to  decreased blood pressure  decreased fluid volume, and  Na+ and increased H+ Renin secretion results in conversion of angiotensinogen (a blood-borne α globulin produced by the liver) to decapeptide angiotensin I Marc Imhotep Cray, M.D.

RAAS (2) Angiotensin I is converted (primarily in lungs) to angiotensin II a potent vasoconstrictor and a stimulator of aldosterone release from adrenal gland Enzyme that catalyzes conversion of angiotensin I to angiotensin II, termed angiotensin converting enzyme (ACE) is target of ACE inhibitor (ACEI) class of antihypertensive drugs Angiotensin II and aldosterone stimulate NaCl and water reabsorption by PCT and collecting duct, respectively Marc Imhotep Cray, M.D.

RAAS (3)

Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edition. Saunders, 2014 Marc Imhotep Cray, M.D.

RAAS (4) Mechanisms of Renin Release

Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edition. Saunders, 2014 Marc Imhotep Cray, M.D.

Aldosterone production and secretion controlled through RAAS  Juxtaglomerular (JG) apparatus monitors perfusion pressure of glomerulus and sodium concentration in distal convoluted tubule (DCT)  Renin is released in cases of ↓ renal perfusion or ↓ sodium conc. in DCT Renin cleaves angiotensinogen to angiotensin I Angiotensinconverting enzyme (ACE) converts angiotensin I to angiotensin II predominantly in lung Angiotensin II has direct vasoconstrictive effects, stimulates sodium reabsorption by proximal convoluted tubule (PCT), and stimulates thirst, antidiuretic hormone (ADH) release, catecholamine release (Epi & NE), and aldosterone synthesis and secretion  Aldosterone ↑sodium reabsorption, and as water follows salt, blood volume ↑along with blood pressure  Overall these effects act to restore renal perfusion

Marc Imhotep Cray, M.D.

Aldosterone production and secretion controlled through RAAS

Marc Imhotep Cray, M.D.

Burtis CA, Ashwood, ER & Bruns DE. Tietz Textbook of Clinical Chemistry and Molecular Diagnostics, 5th Ed, Saunders, 2012.

Renin-Angiotensin-Aldosterone System Capsule

Le T and Bhushan V. First Aid for the USMLE Step 1 2016. NY, New York: McGraw-Hill Education, 2016.

RAAS Capsule (2)  Renin Secreted by JG cells in response to ↓renal arterial pressure and renal sympathetic discharge (β1 effect)  AT II Affects baroreceptor function; limits reflex bradycardia, which would normally accompany its pressor effects 

Helps maintain blood volume and blood pressure

 ANP, BNP Released from atria (ANP) and ventricles (BNP) in response to ↑volume; acts as a “check” on RAAS; relaxes vascular smooth muscle via cGMP ↑ GFR, ↓renin  Dilates afferent arteriole, constricts efferent arteriole, promotes natriuresis

 ADH Primarily regulates osmolarity; also responds to low blood volume states  Aldosterone Primarily regulates ECF volume and Na+ content; Marc Imhotep Cray, M.D. to low blood volume states responds

See next slide for sources and links further study. Marc Imhotep Cray, M.D.

Sources and further study: eLearning Renal cloud folder tools and resources MedPharm Guidebook: Unit 9 Drugs Used to Affect Renal Function Renal Pharmacology eNotes Clinical Pharmacology Cases 7, 8, & 55 (Learning Triggers) Textbooks Brunton LL, Chabner BA , Knollmann BC (Eds.). Goodman and Gilmanâ&#x20AC;&#x2122;s The Pharmacological Basis of Therapeutics. 12th ed. New York: McGraw-Hill, 2011 Katzung, Masters, Trevor. Basic and Clinical Pharmacology, 12th ed. New York: McGraw-Hill, 2012 Mulroney SE. and Myers AK. Netter's Essential Physiology. Philadelphia: Saunders, 2009 Raff RB, Rawls SM, Beyzarov EP. Netter's Illustrated Pharmacology, Updated Edition. Philadelphia: Sanders, 2014 Toy E C. et.al. Case Files-Pharmacology Lange 3rd ed. New York: McGraw-Hill 2014. Marc Imhotep Cray, M.D.