LECTURE 1: RBC, ANEMIA/WBC, INFLAMMATION

 Explain the origin of blood cells and lineage derivation.

 Appearance of centrifuged blood (top to bottom):
 Plasma 55%;
 buffy coat, composed of WBC and platelets; RBC 45%
 Components of blood:
 Whole blood 8% of body weight; other fluids and tissues are
92%
 Whole blood volume:
 55% volume is Blood plasma, which consists of
 Proteins: Albumin, globulin, fibrinogen and others
 water
 and other solutes: electrolytes, nutrients, gases, regulatory substances, waste products.
 45% volume is formed elements, contains platelets, WBC, RBC.
 WBC consists of neutrophils, lymphocytes, monocytes, eosinophils, basophils.
 RBC – erythrocyte:
 RBC:
 Plasma membrane is strong and flexible. Ability to squeeze through capillaries (diapedesis).
 Cytosol contains hemoglobin which constitutes 33% cell weight.
 Hematocrit:
 The percentage of total blood volume occupied by RBCs is called the hematocrit
 Normal range for adult males is 41-51% (avg 47); female: 36-44% (avg 42)
 RBC production:
 Mainly in vertebra,
 Lower in order: sternum, rib,
 Stop RBC production at ~18-20 years old: femur (shaft), tibia (shaft)
 RBC life cycle:
 Approximate 120 days.
 RBCs burst when the permeable membrane gets weak and are removed
by phagocytic macrophages in the spleen and liver.
 Break down products are recycled and used in many metabolic processes
including the formation of new RBCs.
 Understand the process of blood cell formation and destruction.
 Formation and destruction of RBCs steps:
 1. Macrophages in spleen, liver, or red bone marrow phagocytize ruptured and worn-out RBCs
 2. The globin and heme portions of hemoglobin are split apart
 3. Globin is broken down into amino acids which can be reused for protein synthesis.
 4. Iron is removed from heme as Fe+3, which combines with transferrin
 5. In liver, spleen, and muscle, Fe+3 detaches from transferrin and attaches to ferritin.
 6. On release from a storage site or absorption from the GI tract, Fe3+ reattaches to transferrin
 7. Fe3+ - transferrin complex is transported to the bone marrow for hemoglobin synthesis (requires Fe3+, globin, vit. B12).
 8. Erythropoiesis leads to the
production of RBCs
 9. When iron is removed from
heme, the non-iron portion of
heme is converted to biliverdin
(green) which leads to bilirubin
(yellow)
 10. Bilirubin enters the blood and is
transported to the liver.
 11. Bilirubin is released by liver into
bile into small intestine and then to
large intestine.
 12. In the large intestine, bacteria
convert bilirubin into urobilinogen.
 13. Urobilinogen is converted in
urobilin and excreted in urine.
 14. Most urobilinogen is eliminated
in feces as stercobilin.

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 Hemopoiesis:
 Process of making formed elements in blood
(make blood cells and platelets)
 Red bone marrow is the primary site of
hemopoiesis.
 Highly vascularized connective tissue
located in the microscopic spaces between
trabeculae of spongy bone and tissue
 In humerus, femur, pelvic girdle
 0.05 - 0.1% of red bone marrow cells are
derived from mesenchyme and are called
pluripotent stem cells
 Process of RBC production:
 Pluripotent stem cell  myeloid stem cell
 Colony-forming unit (CFU): CFU-E
(erythrocyte); CFU-Meg (megakaryocyte);
CFU-GM (Granulocyte macrophage)
 Pluripotent stem cell  Progenitor cells 
precursor cells or “blasts”  formed
elements of circulating blood  tissue cells (oxygenation)
 Myeloid stem cell  mast cell
 Myeloid stem cell  CFU-GM  monoblast  monocyte (agranular leukocytes)
macrophage
 Pluripotent stem cell  lymphoid stem cell  B Lymphoblast  B-lymphocyte
(agranular leukocyte) plasma cell.
 Proerythroblast  basophil erythroblast  polychromatophil erythroblast 
orthochromatic erythroblast  reticulocyte  erythrocytes
 Erythropoiesis (make RBC in bone marrow):
 Negative feedback regulation of erythropoiesis:
 In absence of erythropoietin, hypoxia has little or no effect to stimulate RBC production.
 With functional erythropoietin system, hypoxia causes an increase in erythropoietin
production which increased RBC production until hypoxia is relieved.
 Process:
 Some stimulus disrupts homeostasis  by decreasing oxygen delivery to kidneys (and
other tissues)  receptors: Kidney cells detect low oxygen level  input: increased
erythropoietin secreted into blood  control center: proerythroblasts in red bone
marrow mature more quickly into reticulocytes  output: Increased erythropoietin
secreted into blood  effectors larger number of RBCs in circulation  increased
oxygen delivery to tissues  negative feedback: Return to homeostasis when oxygen
delivery to kidneys increases to normal.
 Function of the erythropoietin mechanism to increase production of RBCs when tissue oxygenation decreases:
 Tissue oxygenation decreases when:
 Low blood volume; anemia; low hemoglobin; poor blood flow; pulmonary disease
 Decrease in tissue oxygenation  decreases in erythropoietin production
 Increase in erythropoietin caused by kidneys.
(i) Hormone released from kidney in response to low renal oxygenation
(ii) Stimulates stem cells to form pro-normoblasts
(iii) Promotes release of reticulocytes
(iv) Red cell production increases within 24 hours.
(v) Erythropoietin life span is 4-12 hours
(vi) Increase in red blood cell number in 5 days.
 Formation of erythropoietin
 Production is 90% in kidney, 10% in liver.
 Renal tissue hypoxia leads to increased tissue levels of “hypoxia-induced factor-1” (HIF-1)
 HIF-1 is a transcription factor for many hypoxia-inducing genes including the erythropoietin gene.
 10% of total erythropoietin production is caused by norepinephrine, epinephrine, and several prostaglandins.
 Vitamin B12 and folic acid:
 Both required for production of thymidine triphosphate, an essential building block of DNA. Lack of either vitamin causes
abnormal and diminished DNA, leading to failure of nuclear maturation and cell division, blockage of erythropoiesis.

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 Describe the role of hemoglobin
 Hemoglobin has:
 2 Beta polypeptide chains (globin)
 Fe2+ and Iron-containing heme
 2 Alpha polypeptide chains (globins)
 Role of hemoglobin:
 Transport O2 and CO2.
 also plays a role in the regulation of blood flow and blood pressure.
 Nitric oxide at certain times which causes vasodilation (improves blood flow)
 RBCs also contain carbonic anhydrase which catalyzes the reversible conversion of CO2 to bicarbonate  regulates the pH of
blood plasma.
 Iron:
 Iron overload and tissue damage:
 Free iron ions (Fe2+ and Fe3+) bind to and damage molecules in cells or blood  as a result, blood plasma contains virtually no
free iron; all iron is escorted by transferrin.
 Iron overload – ferritin becomes saturated  can damage liver, pancreatic islets, and gonads.
 Iron transport and storage:
 Total Iron Binding Capacity (TIBC) when high associated with iron deficiency anemia, low is normal
 Transferrin:
 2 iron binding sites; 1/3 of sites are occupied.
 Responsible for pink color of plasma
 Ferritin:
 30% of total iron in tissue; Plasma levels indicative of iron deficiency.
 Iron metabolism:
 Absorption enhanced by meat, poultry, fish.
 Absorption of iron from animal products and some plant products, are in the form of heme iron and more efficient
 Duodenum and upper jejunum major site absorption
 HCl promotes absorption
 Loss 1 mg/day males average; menstruating women additional 14 mg/period loss.
 Calculate the Reticulocyte Production Index
 The number of reticulocytes as a percentage of the number of RBC: ReticIndex = ReticCount * Hematocrit / Normal Hematocrit
 RPI used in anemia: When patient’s RBCs are depleted, creating an
erroneously elevated reticulocyte count.
 RPI = ReticIndex/ Maturation Correction
 Maturation Correction or Retic survival (days):

Retic survival (days) = Maturation correction Hematocrit (%)

1.0 36-45
1.5 26-35
2.0 16-25
2.5 15 and below
 Differentiate the 3 types of anemia and examples of each
 Hematocrit and the cardiovascular system:
 Hematocrit normal rang for adult males 41-51% (avg 47) and female
36-44% (avg 42)
 Anemia:
 Hematocrit <30% decrease in work; Hematocrit <25% poorly tolerated
 Decreased vascular resistance; Elevated cardiac output
 Polycythemia (primary or secondary)
 Increased viscosity
 Increased cardiac workload
 Genesis of normal RBCs and characteristics of RBCs in different types of anemias:
 Normal RBC genesis:
 Proerythroblast  basophil erythroblast  polychromatophil erythroblast
 orthochromatic erythroblast  reticulocyte  erythrocytes
 Distribution of RBC sizes:
 Normal RBC sizes at 90 MCV. There are potential causes of increasing size of
RBCs, such as medicine for HIV (AZT), methotrexate, pernicious anemia,
folic acid deficiency.

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 Anemia !!!?????
 4 main types based on causes:
 Microcytic hypochromic anemia;
 Blood loss anemia (and iron is lost) – Chronic blood loss, cannot absorb enough iron from intestines to form hemoglobin
as rapidly as it is lost, smaller RBCs (microcytic, hypochromic anemia)
 Megaloblastic anemia; 7u
 Megaloblastic anemia - Loss of vitamin B12 and folic acid, atrophy of stomach mucosa (pernicious anemia), intestinal
sprue, RBCs grow too large (megaloblastic)
 Sickle cell anemia and erythroblastosis fetalis.
 They are Hemolytic anemia (iron is recycled)– abnormalities make RBCs fragile and rupture passing through capillaries
(i) Sickle cell anemia – abnormal beta chains in hemoglobin molecule
(ii) Erythroblastosis fetalis (Rh-positive RBCs in fetus are attacked by antibodies from Rh-negative mother)
 Aplastic anemia – lack of functioning bone marrow (caused by radiation, certain toxic chemicals (benzene, gasoline),
autoimmune disorders), also idiopathic aplastic anemia.
 Anemia and causes:
 Hypoproliferative, RI = low – 3 subtypes:
 Marrow damage
 Stimulation: renal disease, inflammation, metabolic disease; Iron deficiency
 Lead to condition - aplastic anemia:
 Primary: idiopathic (40-70~ total)
 Secondary causes:
(i) Drugs chemotherapy, antibiotics, antidepressants, ethanol (most
common cause chemical injury)
(ii) Chemicals benzene, radiation, immune suppression of stem cell
(iii) Malignancy (non-hematopoietic tumors and transformation of
hemopoietic stem cells)
(iv) Infectious infiltration of the marrow.
(v) Decrease in all RBC, WBC, platelets number.
(vi) Reduced erythropoietin responses:
 Acute inflammatory state (acute or chronic bacterial infections, AIDS)
 Renal disease
 Hypometabolic state (protein deficiency: hypothyroidism, hypopituitarism)
 Iron deficiency: almost always blood loss, exceptions (children, adult poor absorption)
 Men and post-menopausal women – GI blood loss
 Depletion of stores; Decrease iron – microcytic hypochromic; Major deficiency misshapen RBCs
 Maturation disorders, RI = low
 Cytoplasmic defects  thalassemia
 Nuclear maturation defect  folate deficiency, Vitamin B12 deficiency
 Conditions:
 Thalassemia:
(i) South European, African, Asian;
(ii) Defect in hemoglobin synthesis; Microcytic, hypochromic; Transfusions, folic acid
 Folic acid deficiency
(i) Inadequate diet, dialysis, cirrhosis, vegetarian; Impaired absorption; Folate very heat labile
 Vitamin B12 deficiency  pernicious anemia (lack of intrinsic factor)
(i) Inadequate diet; Dialysis; Impaired absorption
(ii) Intrinsic factor (glycoprotein secreted by gastric parietal cells)
 Extra notes:
(i) Increased MCV increased MCH
(ii) Folate and B12 are required for DNA synthesis; Folic acid: green leafy vegetables, dairy products 3-6 months stored;
B12 diet not a problem 3-6 years; B12 not in fruits and vegetables
(iii) Absorbed in ileum after binds to intrinsic factor; Pernicious anemia (lack intrinsic factor)
(iv) mucosal damage, endocrine, immune, partial excision of stomach.
 Hemorrhage/hemolysis, RI = high  blood loss, intravascular hemolysis, autoimmune, metabolic membrane, hemoglobinopathy.
 Hereditary: sickle cell (mutation of the 6th amino acid – glutamic acid to valine – in the beta chain of hemoglobin leads to
irregular structure, rigid and rupture membrane), spherocytosis (RBCs are small and round, not biconcave, defected membrane
– impair flexibility);
 Acquired: microangiopathic hemolytic anemia; immune responses (complement activation, newborn, drug induced), mismatch
typing; MAHA (disturbance in the microvessel environment causing RBC fragmentation; fibrin deposition, hypertension, vessel
abnormalities); DIC: disseminated intravascular clotting. Blood loss

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 Understand the effects of polycythemia
 Polycythemia Vera – Caused by genetic aberration I the hemocytoblastic cells that produce RBCs, continues producing excess RBCs,
increased hematocrit and blood volume. A mutation in the JAK2 kinase (V617F) is strongly associated with Polycythemia Vera.
 Secondary polycythemia – tissues become hypoxic at high altitudes, produce extra RBCs, reversible.
 Blood doping:
 Increase RBC count by injecting erythropoietin alpha (Procrit or Epogen) a drug that is used to treat anemia (stimulate the
production of RBCs)
 Danger – raise viscosity of blood, increase blood pressure and risk of stroke.
 Difficulty in enforcing ban on erythropoietin because it is identical to naturally occurring erythropoietin
 Natural body doping – training at high altitudes.
 Understand the process of inflammation and the role of white blood cells in the mediation
 WBCs has 5000-10000/mcg blood - Lower WBC is called leukopenia and is usually caused by radiation, shock, chemotherapy
 Leukocyte  Granular and agranular leukocytes  types:
 Granulocytes (65%)
 Made from myeloid stem cell CFU-GM.
 Formed in bone marrow:
 Types:
 Eosinophil – Large, uniform-sized granules, stain with acidic dyes, nucleus usually has 2 lobes
 Basophil – Round, variable sized granules stain with basic dyes, granules often obscure the nucleus which has 2 lobes.
 Neutrophil – Small granules that do not attract acidic or basic stain, nucleus has 2-5 lobes that increase in # w/age.
 Agranulocyte:

 Types:
 Lymphocytes (30%)– Cytoplasm forms a ring around the nucleus, classified as small (6-9 mcm) or large (10-12 mcm),
number of large lymphocytes increases with infection.
(i) Made from lymphoid stem cell  Lymphoblast
(ii) Formed in lymph tissue
(iii) T, B, NK lymphoblast  T, B, NK cell; B-cell can later become Plasma cell
 Monocytes (5%)– Large, kidney shaped nucleus, migrate from blood to tissues where they become macrophages, fixed
macrophages remain in tissues, wandering macrophages roam tissues to gather at sites of infection or inflammation.
(i) Made from myeloid stem cell CFU-GM  Monoblast.
(ii) Formed in bone marrow;
(iii) Monocytes becomes tissue macrophages
 Classify leukocytes according to morphology and function
 Agranulocytes are phagocytic cells:
 Polymorphonuclear neutrophils  non-diving, short-lived; dominant number in bloodstream
 Monocytes/Macrophages  long-lived cells; present in tissue, particularly in lungs, spleen, liver, lymph nodes  tissue macrophage
system
 Neutrophil – tissue injury:
 Emigration of WBCs (Diapedesis) – adhesion molecules (selectins, integrins) help WBCs stick to epithelium
 Selectins stick on endothelial cells; integrins on neutrophil.
 Neutrophil has integrins on its membrane  rolling and sticking on endothelial cells via interaction with Selectins  squeezing
between endothelial cells.
 Chemotaxis – several different chemicals released by microbes and inflamed tissues attract phagocytes  toxins by microbes, CSF
by tissues
 Neutrophils release:
 Chemicals to destroy bacteria (including lysozyme and oxidants)
 Defensins that poke holes in microbe membranes.
 after phagocytes migrate from blood to site of tissue injury  release chemicals, defensins to attack chemotaxis, microbe.
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 Inflammation:
 Eosinophils release histaminase that combat the effects of histamine involved in inflammation during allergic reactions. Also
phagocytize antigen antibody complexes effective against parasites.
 Basophils release granules that contain heparin, histamine, and serotonin that are involved in hypersensitivity (allergic reactions)
 Mast cells release heparin, histamine, and proteases involved in inflammation.
 Results of inflammation:
 Vasodilation; increased capillary permeability; clotting of interstitial fluid; swelling of cells
 Substances involved: bradykinin, histamine, serotonin, complement, coagulation factors, lymphokines
 Lymphocytes:
 B cells – effective in destroying bacteria and inactivating their toxins.
 T cells – attack fungi, viruses, transplanted cells, cancer cells, and some bacteria
 Natural Killer cells – attack a wide variety of infectious microbes and certain spontaneously arising tumor cells.
 Infection - Macrophages:
 Monocytes take longer to reach a site of infection but arrive in large numbers and destroy more microbes.
 Increase in WBCs indicates inflammation or infection
 Determining the percentage of each cell type is important in diagnosing the condition.

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LECTURE 2: IMMUNOLOGY – OVERVIEW, BLOOD CLOTTING, BLOOD TYPE, TRANSFUSIONS

 Classify immune responses and the role of B and T cells.

 Lymphocytes:
 B cells – effective in destroying bacteria and inactivating their toxins.
 T cells – attack fungi, viruses, transplanted cells, cancer cells, and some bacteria
 Natural Killer cells – attack a wide variety of infectious microbes and certain spontaneously arising tumor cells.
 Introduction to immunology:
 Dormant lymphocytes; Invasion of body by foreign antigen; Phagocytosis by macrophages;
Presentation of antigen to lymphocytes
 Immunity:
 Innate (born with it) = ability to resist damaging organisms and toxins (Skin, gastric acids,
tissue neutrophils and macrophages, complement)
 Acquired = specific (Humoral  circulating antibodies; Cellular  activated cells)
 Differentiate classes of Immunoglobulins.
 B-Cell and Antibodies:
 Antigen binding site, variable region and constant region, heavy chain and light chain, Fab fragment and Fc fragment over hinge
region
 IgA, IgD, IgD, IgE, IgG, IgM
 Antibodies:
 IgG - 80% total, cross placenta, opsonization (Ab adheres to bacterial  susceptible for
phagocytosis)
 IgM – first produced – precursor for IgG, 10-15% total activate complement
(Complement system of protein that lyses target cells’ plasma membrane);
 Most antibodies are either IgG or IgM
 margination – sticking process; entire moving of leukocyte out of the blood vessel.
 IgD – Not known, may help CD4 Th (Helper T cells)
 IgA – Body fluid, tears, bronchiole secretions, saliva
 IgE – Allergic reactions, histamine release.
 Production IgM  IgG:
 Virgen cells  first/second exposure to antigen  memory cells + activated, combat ready cells
 Primary response  Antibody titer (arbitrary
units): IgM is produced first  IgM makes IgG 
2nd response: IgM is not amplified but IgG is
amplified.
 T-Cells:
 Act over a short range
 Interact with another cell in body  Can kill or signal
other cell; Only recognize antigen when presented on
surface of target cell
 Helper cells – 2 types:
 Activate macrophage and B-cells:
 Cytotoxic cells – kill infected cells
(i) MHC-I  Present foreign peptides to cytotoxic cells
(ii) Cytotoxic T-Cells recognize viral protein fragments on surface of infected cells
(iii) Cytotoxic T-Cells induce infected cells to kill themselves:
 Bind to infected cells  Induce cell death  Punch hole in cell membrane With CD8  perforin discharge.
 Suppressor cells – regulate activity – Helper T-Cells:
(i) MHC-II  Present foreign peptides to helper cells
(ii) Activation of helper T-cells:
 Antigen interact with antigen-presenting cell  Interact and bind to CD4 – Th  activation: Il-2 receptor 
proliferation  Effector T-Cell
 Helper T-cells stimulate macrophages and B-cells
 Helper T-cells recognize foreign antigen bound to MHC-II proteins on surface of antigen-presenting cells
 Natural Killer cells:
 Destroy virus-infected cells  Do not express antigen specific receptors  Cells with low levels of
MHC I  Induce cells to undergo apoptosis
 MHC-I + CD8  kill the virus-infected cell (inside the cell)
 But if there is no MHC class 1  NK receptor  recruit NK  kill infected cells
 5 cells (horizontal)l: RBC, neutrophils, eosinophils, basophils,
 Lymphocytes, monocytes, platelets (thrombocytes)
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 Platelets:
 General:
 Formed in bone marrow, 150,000-350,000/mcl
 Production regulated by thrombopoietin (liver and kidney); Sequestered in spleen (30%)
 2-4 um in diameter, life span 8-12 days (RBC 100 days~); No nucleus; Have mitochondria, make ATP, ADP
 Have COX enzymes that make prostaglandins (bleed out with aspirin  prostaglandins is vasodilator)
 Regulate smooth muscle contraction
 Cytoplasm has fibrin-stabilizing factor (in Common pathway)
 Activation of platelets:
 Collagen and microfibrillar proteins (vWF)
 ADP released from damaged RBCs and activated
platelets
 ADP makes stickiness of platelets
 Thromboxane from activated platelets (vasoconstricted
 promote clotting)
 Platelet activating factor from basophils; Epinephrine
(stress); Thrombin
 Clotting process:
 Hemostasis – prevents hemorrhage by:
 Vascular spasms  Platelet plug formation Blood
clotting
 Steps in traumatized blood vessel: (1) severed vessel 
(2) platelets agglutinate  (3) fibrin appears  (4)
fibrin clot forms  (5) clot retraction occurs to seal the
bleeding, tight the clot.
 Platelet formation:
 Has early stage, intermediate stage, late stage
 Platelets have PDGF (Platelet derived growth factor)
which causes proliferation of vascular endothelial cells
 1. Platelet adhesion @ where collagen fibers and
damaged endothelium are.
 2. Platelet release reaction – Liberated ADP, serotonin, and
thromboxane A2
(i) ADP and thromboxane A2 – activate nearby platelets
(ii) Serotonin and thromboxane A2 – vasoconstrictors (constrict
vascular smooth muscle), reduce blood flow through vessel
(iii) Release of ADP – makes nearby platelets sticky to adhere
together and promote platelet plug
 3. Platelet aggregation – Platelet plug  at late stage, RBCs are
trapped in fibrin threads.
 Detailed diagram:
 (1) Injured tissues and platelets release the clotting factor
prothrombin activator and calcium ions
 (2) Prothrombin activator converts the blood protein
prothrombin to thrombin
 (3) Thrombin splits fibrinogen to form fibrin
 (4) fibrin fibers form a mesh over wound, trapping RBCs and
platelets
 (5) bleeding stops
 (6) clot hardens and becomes smaller
 (7) new cells grow to repair wound site
 (8) enzyme plasmin is released to dissolve clot
 Blood-Clotting Cascade:
 Steps in the cascade:
 (1) Extrinsic and intrinsic pathways converge in the Common pathway
 (2) Prothrombinase converts Prothrombin into the enzyme, thrombin
 (3) Thrombin converts soluble fibrinogen into insoluble fibrin
 Fibrin form the thread of the clot
 All step needs Calcium
 (4) strengthened fibrin threads

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 Identify the clotting factors involved in the Extrinsic, Intrinsic, and
Common Pathways.
 Intrinsic clotting: within the blood vessels; Extrinsic clotting: outside
of the blood vessels, which is in muscles; Common pathways:
 In such detailed of the cascade:
 Extrinsic vs. Intrinsic pathways
 Similarity:
 They need activation, activated by previous factors of
cascade effect and related Calcium in all steps.
 Differences:
 Intrinsic need more time (slower process), more
steps
(i) Blood trauma, contact with collagen or activated platelets
(ii) Not in number order, 12119 (+8I) 10 activation
(iii) Slower (2-6) minutes), cascade, many components
(iv) Need to know order of factor:
 (1) Trauma to the blood converts Factor XII to the proteolytic active Factor XIIa.
 (2) Enzymatic activation of Factor XI.
 (3) Enzymatic activation of Factor IX.
 (4) Activated factor IX and activated factor VIII work together to activate factor X.
 (5) Factor Xa combines with Factor V and phospholipids to form Prothrombin Activator.
 Extrinsic pathway
(i) By order:
 (1) Tissue trauma releases “tissue factor” which functions as a proteolytic enzyme  tissue thromboplastin (VII)
 (2) Tissue factor complexes with factor VII + Calcium + Factor X to activated Factor X (Xa)
 (3) Factor Xa + Ca2+ + Factor V = Prothrombin Activator
(ii) Prothrombin Activator + Platelet phospholipids + Prothrombin + Ca2+  Thrombin
(iii) Rapid and explosive in nature (15s)
 Common pathway:
 Order:
 Formation of prothrombin activator
 Conversion of prothrombin (Factor II) to Thrombin
 Conversion of Fibrinogen (Factor I) to Fibrin.
 Prothrombin splits into Thrombin (proteolytic enzyme)  acts on
fibrinogen and stimulates fibrin; and stabilizing factor to act on
prothrombin (clotting factors – positive feedback
 Note:
 Factor Xa combined with Factor V and platelet phospholipids
(PF3) + Ca++  Thrombin
 Prothrombin activator:
(i) prothrombin  thrombin;
(ii) fibrinogen loose fibrin threads
 Thrombin + Ca2+ + factor XIIIa + Loose fibrin threads 
Strengthened fibrin threads.
 Intravascular anticoagulants:
 1. Endothelial Cells
 thrombomodulin (protein bound to endothelial membrane) - binds thrombin and stops clotting process
 2. Antithrombin III (alpha-globulin, combines with heparin)
 inhibits factors II, X, VII, XI, and XII; antithrombin III inactivates thrombin
 3. Heparin: conjugated polysaccharide, negative charge
 little action alone, when combined with antithrombin III; increased affinity of antithrombin III for thrombin by 100-1000-fold
 We want majorly to amplify it.
 Fibrinolytic system:
 Plasminogen = circulating globulin
 Plasmin =proteolytic enzyme, similar to trypsin  digest fibrin threads, fibrinogen, and other clotting factors
 Significance: removal of small clots
 Plasminogen activators:
 Tissue Plasminogen Activator (TPA) – break down fibrin for stroke, clot in brain; urokinase; streptokinase
 Plasminogen inhibitors:
 plasminogen activator inhibitor (PAI-1) inhibits TPA

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 Calculate PT-INR
 Blood coagulation tests:
 Pathways:
 Intrinsic: XII-XI-IX-VIIIX
 Extrinsic: VII VIIa X Xa
 Common pathway: V
 Prothrombin (II)  Thrombin
 Blood coagulation tests
 PROTHROMBIN TIME (PT)
 Form tissue
 time to form clot when tissue-thromboplastin is added
 ~12-14 seconds, test of extrinsic and common pathway,
 factors II, V, VII, X
 vitamin K factors – make the blood clot, warfarin therapy (commonly use, has to monitor);
 small salad everyday  incorporated into PT-INR measurement.
 ACTIVATED PARTIAL THROMBOPLASTIN TIME (aPTT)
 For plasma
 time to form clot when plasma-thromboplastin is added
 ~30 seconds, test of intrinsic pathway and common pathway; Not VII, but VIII, IX, XI
 Good to test for heparinzed patients
 PT-INR: Prothrombin Time-International normalized ratio
 INR = PT test/PT normal
 INR – 0.9-1.3 for normal people; INR = 2-3 people on anticoagulation therapy (Warfarin)
 Lower clotting process  slower the bleeding  could bleeding out; Longer time but not too long
 Xarelto (Rivaroxaban) is an oral anticoagulant that is a direct factor Xa inhibitor. With its use, we cannot measure PT-INR
 Effect both in-, ex- and common pathway; Monitor but can’t measure
 Understand anticoagulation and diseases caused by coagulation defects
 Coagulation defects:
 Vitamin C deficiency: causes a lack of stable collagen (elderly, alcoholics)
 Hepatic failure: almost all clotting factors are made in the liver
 Vitamin K deficiency: required for II (prothrombin), VII, IX, and X; caused by fat malabsorption due to lack of bile secretion
 von Willebrand Disease:
 most common congenital bleeding disorder, affects 1% population; Results from loss of the large component of Factor VIII;
symptoms in vWD similar to platelet disorders; bleeding time is prolonged.
 Hemophilia – bleeding that occurs due to a clotting factor deficiency
 Hemophilia A, affects 1/10,000  Deficiency of/nonfunctional VIII (intrinsic pathway); X-linked, almost exclusively in males
 Hemophilia B affects 1/100,000; Deficiency of /nonfunctional IX (intrinsic pathway)
 Thrombocytopenia
 presence of low numbers of platelets; Tendency to bleed, however bleeding comes from many small venules rather than large
vessels as in hemophiliacs.
 Disseminated Intravascular Clotting
 Abnormal bleeding and clot formation in critically ill patients. Due to massive tissue damage. Depletion of clotting factors
 In vivo coagulation
 Thromboembolic conditions
 venous thrombosis, pulmonary embolism; artificial heart valves, by-pass surgery
 long-term bed immobilization  As blood flows, the clot detaches, causing a freely flowing clot = embolus
 a blood clot = thrombus: when blood cells and fibrin strands clump together. A clot that blocks blood flow  thrombus
 Deep venous thrombosis  Deep Vein Thrombosis (DVT)
 Know the role of the drug targets presented for anticoagulation.
 Anticoagulants for clinical use:
 HEPARIN
 Activates antithrombin III by binding to its inhibitor; Causes blood clotting time to increase from ~6 min to ~30 min
 Change in clotting time occurs instantaneously; Action lasts 1.5 -4 hrs (inactivated by heparinase)
 WARFARIN (Coumadin)
 Decreases the available form of vitamin K
 Decreases the amount of prothrombin, factors VII, IX, X
 Delay for activity (~24 hrs), time for degradation of active prothrombin
 XARELTO (rivaroxaban)
 Inhibition of Factor Xa interrupts both the intrinsic and extrinsic pathways
 Associated with lower rates of serious and fatal bleeding events than warfarin yet higher rates of G.I. bleeding

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 Understand the role of blood typing and the role in transfusions, immune responses.
 Blood types A, B, AB, O
 RBC has A-antigen on its surface and anti-B antibody in plasma
 Blood groups:
 Genotypes: OO – O types – Agglutinogens: None – Agglutinins: Anti-
A and Anti-B
 Case report from 1939 Levine and Stetson:
 Woman (type O) gave birth to stillborn fetus who had died from
hemolytic anemia: Second pregnancy for the woman; Transfused
with blood from husband (type O) following delivery and developed
a severe transfusion reaction (O- and O+ complication)
 Hypothesis
 Fetus inherits antigen from father
 A few fetal red cells crossed the placenta into mother’s
circulation Mother made antibody against foreign antigen
 Antibody crosses the placenta and attacked fetal red cells
 Fetus dies from severe hemolytic anemia
 Hemolytic Disease of the Newborn Erythroblastosis fetalis
 ABO incompatibility
 O mother and A or B fetus
(i) Most anti-A is IgM which does not cross placenta
(ii) ABO antigens are not well developed in fetus
 Rh incompatibility
 Rh-positive fetus and a Rh-negative mother
(i) 0.1 ml fetal blood crossing placenta cause immunization
(ii) due to fetal-maternal bleeding during delivery
(iii) Mother develops Anti-Rh agglutinins
(iv) More critical with 2nd Rh positive child
 Treatment - mild cases simple transfusion
 severe cases exchange transfusion
(i) corrects fetal anemia
(ii) removes mothers antibodies
 Prevention - Rh immunoglobin injection into mother after delivery
destroys fetal cells in mother
 Blood Transfusion:
 1. Packed Red Cells: Increase O2 carrying capacity
 2. Platelets
 Single donation or apheresis (separates 1 constituent of blood from donor)
 if count is <20,000/ml, add platelets with plasma
 3. Plasma
 Single donation or apheresis
 Usually for coagulation deficiency where platelet counts are sufficient
 Transfusion reaction:
 Transfusion reaction due to agglutination of donor blood
 Agglutination of red blood cells due to antigen-antibody reaction
 Activation of complement system
 Agglutination destroyed by white cells, with hemoglobin
 released into plasma
 Shock, chills, fever, shortness of breath, renal shutdown
 Note:
 Activation of complement
 ABO activation is immediate
 Delayed due to Rh

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LECTURE 3: KIDNEY ANATOMY AND FUNCTION, EDEMA

 Describe the functional anatomy of the kidney.

 2 types of nephron:
 Cortical nephron
 Juxtamedullary nephron (80%)
 Renal pyramid has nephron located
 Flow:
 Afferent arteriole – glomerulus (filtration) – bowman’s capsule – proximal convoluted tubule – descending limb of the loop of Henle
 thin ascending limb of the loop of Henle  thick ascending limb of the loop of Henle (less permeable for water)  distal
convoluted tubule  collecting duct
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 Explain the multiple functions of the kidney - Summary of Kidney functions:
 Excretion of metabolic waste products (urea, creatinine, bilirubin, hydrogen)
 Urea (protein metabolism); uric acid (nuclei acid metabolism); creatinine (muscle metabolism); bilirubin (Hb metabolism)
 High Creatinine – Kidney is not function well (should filter out creatinine as product of muscle break down)
 Excretion of foreign chemicals (drugs, toxins, pesticides, food additives)
 Secretion, metabolism, and excretion of hormones
 Hormones produces in the kidney
 Renal erythropoietic factor - Regulation of erythrocyte production:
 Decrease in oxygen delivery kidney leads to erythropoietin  Increase
erythrocyte production in bone marrow  positive feedback to decrease
oxygen delivery kidney.
 1,25 dihydroxycholecalciferols (Vitamin D) - Regulation of Vitamin D activity:
 Kidney produces active form of vitamin D (1,25-dihydroxy Vitamin D3)
 Vitamin D3 is important in calcium and phosphate metabolism.
 Renin
 Hormones metabolized and excreted by the kidney (most peptide hormones, e.g. insulin, angiotensin II.
 Regulation of acid-base balance
 Excrete acids (kidneys are the only means of excreting non-volatile acids)
 Regulate body fluid buffers (e.g. bicarbonate)
 Gluconeogenesis: glucose synthesis from amino acids
 Kidneys synthesize glucose from precursors (e.g. amino acids) during prolonged fasting.
 Control of arterial pressure
 Endocrine organ: renin-angiotensin system, prostaglandins.
 Control of extracellular fluid volume
 Regulation of water & electrolyte excretion
 Sodium and water; potassium; hydrogen ions; Calcium, phosphate, magnesium.
 Edema: water in extracellular
 Effect of increasing sodium intake 10-fold on urinary sodium excretion and extracellular
fluid volume
 Within 2-3 days after raising the sodium intake, renal excretion also increases.
 During the 2-3 days of adaptation, there is an increase in extracellular fluid volume that causes an increase in sodium excretion.
 Describe the process of glomerular filtration
 Basic of mechanisms of urine formation:
 Excretion = Filtration – Reabsorption + Secretion
 Filtration: Somewhat variable, not selective (except for proteins), averages 20% of renal plasma flow.
 Reabsorption: Highly variable and selective; most electrolytes (e.g. Na+, K+, Cl-) and nutritional substances (e.g.) glucose are
almost completely reabsorbed; most waste products (e.g. urea) poorly reabsorbed.
 Secretion: Highly variable; important for rapidly excreting some waste products (e.g. proton), foreign substances (including
drugs), and toxins.
 Renal handling of different substances:
 Renal can do only filtration for A; Filtration + partial reabsorption for B; Filtration + Complete reabsorption for C; Filtration +
Secretion for D.
 For water and solutes:
FILTRATION REABSORPTION EXCRETION Note
Water (liters/day) 180 179 1 Mostly reabsorption
Sodium (mmol/day) 25,560 25,410 150 Mostly reabsorption
Glucose (gm/day) 180 180 0 100% reabsorption
Creatinine (gm/day) 1.8 0 1.8 No reabsorption
 Calculate the glomerular filtration rate and the amount excreted by the kidneys.
 Glomerular filtration rate:
 GFR = 125 ml/min = 180 liters/day
 Plasma filtration: 60 times per day
 Glomerular filtrate composition is about the same as plasma, except for large
proteins  GFR ~ GPR
Glomerular Flow Rate 125
 𝐹𝑖𝑙𝑡𝑟𝑎𝑡𝑖𝑜𝑛 𝑓𝑟𝑎𝑐𝑡𝑖𝑜𝑛 = = = 0.2
Renal Blood or Plasma Flow 650
 (i.e. 20% of plasma is filtered)
 Glomerular capillary filtration barrier:
 The cells that line the outer surface of the glomerulus have foot-like processes (podocytes) that encircle the capillaries.
 The podocytes are separated by gaps called slit pores through which the glomerular filtrate moves.

Page 13 of 28
  Effects of size and electrical charge on filterability of glomerular capillaries:
 Filterability of solutes is inversely related to their size.
 Positively charged large molecules are filtered more easily than negatively
charged molecules of equal size
 Understand the role of hydrostatic pressure and oncotic pressure in determining the glomerular
filtration rate
 Determinants of glomerular filtration rate:
 Net filtration pressure (10 mmHg) = Glomerular hydrostatic pressure PB (60 mmHg) –
Bowman’s capsule pressure PG (18 mmHg) – Glomerular oncotic pressure (32 mmHg)
𝑮𝑭𝑹 𝟏𝟐𝟓 𝒎𝒍/𝒎𝒊𝒏
 𝑲𝒇 = = = 𝟏𝟐. 𝟓𝒎𝒍/𝒎𝒊𝒏/𝒎𝒎
𝑵𝒆𝒕 𝒇𝒊𝒍𝒕𝒓𝒂𝒕𝒊𝒐𝒏 𝒑𝒓𝒆𝒔𝒔𝒖𝒓𝒆 𝟏𝟎 𝒎𝒎𝑯𝒈
 Normally not highly variable.
 Diseases that can reduce Kf and GFR: chronic hypertension, obesity/diabetes
mellitus, glomerulonephritis.
 Bowman’s Capsule hydrostatic pressure (PB)
 Normally changes as a function of GFR, not a physiological regulator of GFT.
 Tubular obstruction, kidney stones, tubular necrosis.
 Urinary tract obstruction, prostate hypertrophy/cancer.
 Glomerular Hydrostatic pressure (PG)
 Is the determinant of GFR most subject to physiological control
 Factors that influence PG:
(i) Arterial pressure (effect is buffered by autoregulation)
(ii) Afferent arteriolar resistance.
(iii) Efferent arteriolar resistance.
Glomerular Flow Rate
 Factor to change Rate of Filtration Fraction 𝑹𝑭𝑭 =
Renal Blood or Plasma Flow
 Increase in colloid osmotic pressure in plasma flowing through glomerular capillary
 Increase the rate of filtration fraction
 Effect of afferent (Ra) and efferent (Re) arteriolar constriction on glomerular pressure (PG)
 increase Ra  decrease GFR + decrease RBF  unchanged RFF
 Increase Re  increase GFR + decrease RBF  unchanged RFF
 RBF:
 High blood flow (~22% of cardiac output)
 High blood flow needed for high GFR.
 Oxygen and nutrients delivered to kidneys normally greatly exceeds their
metabolic needs.
 A large fraction of renal oxygen consumption is related to renal tubular
sodium reabsorption.
 Autoregulation of renal blood flow and GFR but not urine flow:
 Feedback mechanisms intrinsic to the kidneys keep the renal blood flow and
GFR relatively constant.
 Control of GFR and renal blood flow
 Neurohumoral; local (intrinsic)
 (1) Sympathetic NS (epinephrine, norepinephrine)/catecholamines
  GFR +  RBF  vasoconstrictors.
 (2) Angiotensin II – constricts efferent arterioles
  RE   GFR +  RBF  prevents a decrease in GFR that occurs with low
sodium diet, or volume depletion.
 (3) Prostaglandins:
  GFR +  RBF  cause vasodilation, under stressful conditions (post-
surgery, volume depletion). Blockade of prostaglandin synthesis with NSAIDS
  GFR
 (4) Endothelial-Derived Nitric Oxide (EDRF):
  GFR+  RBF  Protects against excessive vasoconstriction; patients with
endothelia dysfunction (e.g. atherosclerosis) may have greater risk for
excessive decrease in GFR in response to stimuli such as volume depletion.
 (5) Endothelin:
  GFR +  RBF 
(i) vasoconstrictor peptide released from damaged vascular endothelial cells of kidney.
(ii) Increased in toxemia, acute renal failure, hypertensive patients with chronic renal failure.
(iii) Endothelin antagonists may be useful in these conditions.

Page 14 of 28
  Summary of neurohumoral control of GFR and renal blood flow:

Effect on GFR Effect on RBF

 Sympathetic activity  
 Catecholamines  
 Angiotensin II  
 EDRF  
 Endothelin  
 Prostaglandins  
 Explain examples of changes in GFR and associated disorders
 Conditions that influence GFR:
 Macular densa:
 Structure of the juxtaglomerular apparatus: macula densa.
 Macula densa feedback mechanism for regulating GFR:
 NaCl causes dilation of afferent arterioles
 Increased renin release, angiotensin I & II (angiotensin receptor
antagonists decrease GFR, useful in patients with HTN,
congestive heart failure), efferent resistance, BP
 Returns GFR to normal
 Fever, pyrogens   GFR
 Glucocorticoids   GFR
 Aging   GFR 10%/decade after 40 years
 Hyperglycemia   GFR (diabetes mellitus)
 Dietary protein  high protein  GFR; low protein  GFR
 Clinical significance of Proteinuria:
 Early detection of renal disease in at-risk patients
(i) Hypertension – Hypertensive renal disease
(ii) Diabetes – Diabetic nephropathy
(iii) Pregnancy – Gestational proteinuria HTN (pre-eclampsia)
(iv) Annual “check-up” – Renal disease can be silent.
 Assessment an monitoring of known renal disease.
 Microalbuminuria:
 Definition: Urine excretion of >30 but <150 mg albumin per day
 Causes: early diabetes, hypertension, glomerular, hyperfiltration
 Prognostic Value: Diabetic patients with microalbuminuria are 10-20
folds more likely to develop persistent to proteinuria.
 Review a brief background on edema:
 Abnormal accumulation of fluid in the interstitium, causing swelling  Edema.
 Disruption of the balance of fluid homeostasis, i.e. increased secretion or impaired removal of fluid into the interstitium
 Conditions causing edema:
 (1) High capillary hydrostatic pressure:
 Excess fluid retention by kidneys: Acute or chronic kidney failure; glomerulonephritis
 Decreased arteriolar resistance
 Increased venous pressure
 (2) Decreased plasma proteins (low oncotic pressure):
 Loss of proteins
 Failure to produce proteins.
 (3) Increased capillary permeability (increased filtration coefficient – Kf)
 Immune reactions (histamine); toxins; burns; Vitamin deficiency (E.g. Vitamin C); pre-eclampsia
 (4) Blockage of lymphatics
 Cancer, surgery, infections.

Page 15 of 28
LECTURE 4: KIDNEY REABSORPTION AND SECRETION

 Illustrate the mechanisms of tubular reabsorption and secretion throughout the Loop of
Henle
 Side note:
 Know where the transporter, what are they, what nephron they are located,
what do they transport, what is the mechanism
 Main mechanism: active, passive, facilitated mechanism
 Na-Cl facilitated mechanism
 Angiotensin  Increase BP; Aldosterone – uptake Na  increase BP; ADH
 increase BP
 Atrial natriuretic peptide (ANP): increase Na secretion  decrease BP
 Basic mechanisms of urine formations – 4 steps:
 Filtration
 Reabsorption to capillary  secreted (such as K)
 Secretion (Na, Cl + H2O increase BP) - H2O secret more at the capillaries.
 Excretion (Drink extra fluid  extra fluid goes to urinary secretion)
 Excretion = Filtration – Reabsorption + Secretion
 Reabsorption by Paracellular (TJ) and transcellular transport:
 Luminal side on the left - Basolateral is on the right
 Tight junction is regulated  paracellular transport @ it
 Na transport: transcellular  from luminal side to basolateral side
 Using active transport to transport Na out  and favor:
reabsorption to blood stream  affect BP
 Diffusion follow concentration
 Flow:
 Proximal tubule  Loop of Henle (Descending limb  Thin
ascending limb  Thick ascending limb) Distal tubule 
Collecting duct
 Proximal convoluted tubules - Tubular reabsorption and secretion:
 Bowman’s capsule is right on nephron
 Bottom line: reabsorption of Glucose by Na/Glu symporters in cells
 @proximal convoluted tubules: Na is taking out via active transport, Glu goes for a ride  facilitated/secondary transport  Glu
comes along with it.
 (1) Na+ reabsorption and H+ secretion:
 Na + /H + antiporter carries Na + down its conc. gradient into PCT cell and is reabsorbed
 H + secreted into tubular fluid
 CO2 drives reaction to produce HCO3- which is reabsorbed by facilitated diffusion
 Na is transported via AT; HCO3-: facilitated diffusion to take it out.
 Input of H + CO2  HCO3-  H+ is recycled into the lumen (make it acid)  Na is taking out
 (2) HCO3- reabsorption
 For every proton secreted into tubular, 1 proton and 1 HCO3- are reabsorbed
 (3) Other ions Cl-, K+, Ca2+, Mg2+, Urea undergo diffusion; water: osmosis to peritubular capillary
 Electrochemical gradient of Cl- promotes passive transport of cation into peritubular capillary by paracellular (tight junction)
and transcellular transport (diffusion).

Page 16 of 28
  Thick ascending limb of Loop of Henle:
 Apical membranes are impermeable to
water.
 Apical membranes have Na+ - K+ - 2Cl-
symporters that actively transport into
capillaries.
 Water is not transported here (because
of impermeable membrane)
 Promote reuptake/reabsorption of Na
and Cl forward to capillary
 Recycle K through its own channels and
back to lumen.
 Collecting Duct:
 Reabsorption of Na+ - and secretion of K+
 Using Na-K-ATPase: K goes back to lumen; Na
goes to basolateral  reabsorption at
capillary
 Characterize specific transporters and their locations
 Determinants of Sodium Reabsorption:
 (1) Na+ diffuses across the luminal
membrane by an electrochemical gradient
established by the Na+/K+ ATPase (always)
on the basolateral side.
 (2) Na+ is transported across the basolateral side against an
electrochemical gradient by the Na+/K+ ATPase
 (3) Na+, H2) and other substances are reabsorbed from the
interstitial fluid into the peritubular capillaries’ ultrafiltration
(driven by hydrostatic and colloid osmotic pressure gradients)
 Mechanisms of secondary active transport = facilitated transport:
 Two or more substances are transported by the same carrier
protein:
 As 1 substance (Na+) diffuses down its electrochemical
gradient, the energy released is used to drive another
substance (glucose) against its electrochemical gradient.
 Na/Glu  basolateral membrane  Glucose goes through
GLUT
 Na-H counter transport to transport proton back to lumen.
 Transport maximum:
 Some substances have a maximum rate of tubular transport
due to saturation of carriers, limited ATP, etc.
 Transport maximum: Once the transport maximum is reached
for all nephrons, further increased in tubular load are NOT
reabsorbed and are excreted.
 Threshold is the tubular load at which transport maximum is exceeded in some
nephrons  not exactly the same as the transport maximum of the whole
kidney because some nephrons have a lower transport max than others.
 Examples: Glucose, amino acids, phosphate, sulphate.
 Glucose transport maximum:
 The transport maximum is the maximum rate at which glucose can be
reabsorbed from the tubules.
 Glucose transport works until it reaches max  after max: Glucose will be
secreted and excreted
 The threshold refers to the filtered load of glucose at which glucose first begins
to be excreted in the urine.

Page 17 of 28
 Transport characteristics
 proximal tubule by the third orientation:
 Transport into lumen (secreted); Reabsorbed out to
nephron.
 Reabsorbed: Na+, Cl-, HCO3-, K+, water, glucose, amino
acids
 Secreted proton, organic acids, bases.
 Na can do both secretion and reabsorption here.
 Thin and thick loop of Henle:
 Thin descending  VERY permeable to water
Reabsorption of H2O
 Thick ascending loop of Henle  NOT permeable to water;
 Reabsorption of Na+, Cl-, K+, HCO3-, Ca++, Mg++
 Secretion of proton
 Drug use on thick ascending loop of Henle
(i) Basolateral on the left; lumen on the right; Using
Na-K ATPase antiporter, symporter on lumen
transports of Na, 2Cl. K is at the tubular lumen, and Na, Cl- get reabsorption to capillaries; K goes back to lumen.
(ii) Drugs:
 Loop diuretics  increase urine output  block Na-K-Cl symporter  stop Na, Cl, K  water is usually be back
to blood (increase BP)  but now increase urine output  decrease BP.
 E.g. furosemide ethacrynic acid, bumetanide
Page 18 of 28
  Early distal tubule:
 Reabsorption Na, Cl, Ca, Mg
 NaCl reabsorbed into capillaries 
(i) being blocked by thiazide diuretics.
 ~5% of filtered load, NaCl reabsorbed.
 NOT permeable to water; NOT VERY permeable to
urea
 Late distal tubule and Cortical collecting tubules:
 PERMEABLE to water depends on ADH; NOT VERY
permeable to urea.
 Reabsorption of Na+, Cl, H20 (when +ADH), HCO3, K+
 Secretion of K+, H+
 2 types of cells:
 Principal cells – Promote secretion of K
 Intercalated cells – Promote reabsorption of K
 Drug uses:
 Blocking transporters that will block sodium reabsorption, maintain adequate serum
potassium concentration.
(i) Aldosterone antagonists – inhibits Na/K antitransport at interstitial fluid:
Spironolactone, eplerenone
(ii) Na+ channel blockers – inhibit at lumen site  Amiloride, triamterene
 Medullar collecting ducts:
 Reabsorption of Na, Cl, water (when +ADH), HCO3-, Urea (instead of K+ before)
 Secretion of proton.
 Because of Na, Cl reabsorption, BP is increased.
 Calculate changes in peritubular hydrostatic pressure and capillary colloid osmotic pressure
 General concepts:
 Concentrations of solutes in different parts of the tubule depend on relative reabsorption of the solutes compared to water.
 If water is reabsorbed to a greater extent than the solute, the solute will become more concentrated in the tubule (e.g.
creatinine, inulin(carbohydrate))
 If water is reabsorbed to a lesser extent than the solute, the solute will become less concentrated in the tubule (e.g. glucose,
amino acids)
 Peritubular hydrostatic pressure:
 Net = C - if + Pif – PC = 32 – 15 + 6 – 13 = 10 mmHg
 reabsorption happens.
 Reabsorptions = Net Reabsorption Pressure (NRP) x Kf
 Reabsorption = 10 mmHg x 12.4 ml/min/mmHg = 124 ml/min
 Determinants of Peritubular capillary reabsorption:
 Kf = glomerular pressure (more fluid goes through)   Reabsorption
  C = capillary colloid osmotic pressure  Reabsorption
  PC = hydrostatic pressure of capillary   Reabsorption
 Determinants of Peritubular capillary hydrostatic pressure:
 Side note:
 Clamp:
(i) Clamp Ra  lower rate of filtration at glomerular capillary
(ii) Clamp Efferent (angiotensin II causes it)  upstream swell up 
increase filtration of Glomerular Capillary  decrease in hydrostatic
 Reduce the rate of flow  hydrostatic: decrease
(i) Clamp (increase Ra/Re)  SwellingDecrease hydrostatic pressure
 increase reuptake at the peritubular capillary.
(ii) Increase arterial Pressure  Increase hydrostatic pressure Pc  decrease reabsorption.
(iii) 2 restriction at the  …  don’t want to take more water
 What happens at the peritubular capillary/glomerular capillary?  increase hydrostatic at Glomerular capillary  it will
increase filtration.
 Osmotic pressure is opposite: higher particles like more
water  promote h2o uptake (higher rate of uptake)
 Effect of increased hydrostatic pressure or decreased colloid
osmotic pressure in peritubular capillaries to reduce reabsorption

Page 19 of 28
 Describe the mechanisms for hormonal regulation of ion secretion/reabsorption (angiotensin, aldosterone, ADH, Atrial natriuretic peptide)
 Regulation of tubular reabsorption
 Glomerulotubular balance; Peritubular physical forces
 Hormones: Aldosterone, angiotensin II, antidiuretic hormone (ADH), natriuretic hormones (ANF), parathyroid hormone
 Sympathetic nervous system
 Arterial pressure (pressure natriuresis)
 Osmotic factors.
 Renin-Angiotensin pathway:
 When blood volume and blood pressure decrease, the walls of the afferent arterioles are stretched less and the juxtaglomerular
cells secret renin (also sympathetic stimulation)
 Renin and angiotensin converting enzyme remove amino acids from angiotensin I to form angiotensin II
 Angiotensin II
 Prevents decrease of GFR by causing vasoconstriction of efferent arterioles.
 Constricts efferent arterioles:
(i) Decreases peritubular capillary hydrostatic pressure
(ii) Increases filtration fraction, which increases peritubular colloid osmotic pressure.
(iii) Increase Ang II  restriction efferent will increase Rc Pc goes down  and reduce renal blood flow  increase
hydrostatic upstream and increase filtration; increase uptake fluid.
 Enhances reabsorption of Na+, Cl-, and water in the proximal convoluted
tubules by stimulating the activity of the Na+/H+ antiporter.
 Angiotensin II constriction of efferent arterioles causes Na+ and water
retention and maintains excretion of waste products:
(i) Sodium depletion cause increasing in Ang.II  Increase Resistance
efferent arterioles cause:
 Increase in glomerular capillary pressure  prevent decrease
in GFR and retention of waste products
 Decrease renal bloods flow  increase filtration fraction 
increase Na+ and water reabsorption
 Decrease peritubular capillary pressure  increase Na+ and
water reabsorption
 Stimulates the adrenal cortex to release aldosterone which stimulates the
principal cells of the collecting ducts to reabsorb more Na+ and Cl- and
secrete more K+
 Angiotensin II increases Na+ and water reabsorption:
(i) Stimulates aldosterone secretion
(ii) Directly increases Na+ reabsorption (proximal, loop, distal,
collecting tubules)
 Luminal membrane Angiotensin II stimulates sodium-hydrogen
exchange (NHE)
 Basolateral membrane: Angiotensin II stimulates sodium-
potassium ATPase and sodium-bicarbonate co-transport.
 Angiotensin II blockade decreases Na+ reabsorption and blood pressure:
 ACE inhibitors (captopril, benazepril, ramipril)
 Angiotensin II antagonists (losartan, candesartan, irbesartan)
 Renin inhibitors (aliskirin)
(i) Decrease aldosterone
(ii) Directly inhibit sodium reabsorption
(iii) Decrease efferent arteriolar resistance.
 So that: Natriuresis and Diuresis + DECREASE BP
 Control of Aldosterone secretion:
 Factors that increase aldosterone secretion: Angiotensin II, Increased K+,
adrenocorticotrophic hormone (ACTH)
 Factors that decrease aldosterone secretion: Atrial natriuretic peptide (ANP),
increased [Na+] (osmolality)
 ANP has opposite with the other 3: increasing secretion of Na by kidneys
dilate, inhibit renin secretion.
 Na-Cl facilitated mechanism
(i) Angiotensin, Aldosterone (uptake Na), ADH  increase BP
(ii) Atrial natriuretic peptide (ANP): increase Na secretion  decrease
BP

Page 20 of 28
  ANP increases sodium excretion:
(i) Secreted by cardiac atria in response to stretch (increased blood volume)
(ii) Directly inhibits Na+ reabsorption; increases GFP; helps to minimize blood volume expansion
(iii) Inhibits renin and aldosterone formation
 Abnormal aldosterone production:
 Excess aldosterone (primary aldosteronism Conn’s syndrome) – Na+ retention, hypokalemia, alkalosis, hypertension
 Aldosterone deficiency – Addison’s disease – Na+ wasting (low Na), hyperkalemia, hypotension (low BP)
 Control by Antidiuretic hormone (ADH)
 ADH:
 ADH synthesis in the hypothalamus, secreted by posterior pituitary and acts on kidneys.
 ADH (arginine vasopressin) binds to V2 receptors causing the stimulation of Aquaporin-2 to form water channels  Increases
water permeability and reabsorption in distal and collecting tubules
 Allows differential control of water and solute excretion
 Important regulator of extracellular fluid osmolarity
 Abnormalities of ADH
 Inappropriate ADH syndrome (excess ADH)  decreased plasma osmolarity, hyponatremia
 “Central” diabetes insipidus (insufficient ADH)  increased plasma osmolarity, hypernatremia, excess thirst.
 Classify the diseases associated with defects in transporters with relevant drug classes and targets:
 Almost all the conditions have low BP
 Abnormal Tubular Function: Increased reabsorption
 Conn’s syndrome:
 Primary aldosterone excess, caused by aldosterone secreting tumor
 Renin secreting tumor:
 Excess angiotensin II formation
 Liddle’s Syndrome:
 Excess activity of amiloride sensitive Na+ channel in collecting tubules (excess of Na channel, generic  Na channel blockers)
 Diabetes Insipidus:
 Decreased water reabsorption, nephrogenic; lack of ADH
 Addison’s disease:
 Decreased Na+ reabsorption and decreased potassium; lack of aldosterone.
 Bartter’s syndrome:
 Decreased Na+, Ca++, HCO3- reabsorption, hypotension
 Decreased activity of Na+ - K+ - 2Cl- transporter in thick ascending loop of Henle (loop diuretics)
 Gitleman’s syndrome:
 Decreased NaCl reabsorption, hypotension (same as thiazide diuretics block Na-Cl symporter for reabsorption)
 Fanconi syndrome:
 Generalized decrease in reabsorption often in proximal tubules;
 Causes: Genetic, heavy metal damage, drugs (tetracyclines), multiple myeloma, tubular necrosis (ischemia)
 Renal tubular acidosis:
 Decreased proton secretion
 Increased HCO3- excretion, acidosis
 Causes: genetic, renal injury, etc.
 Assessing Kidney function:
 Plasma concentration of waste products (e.g. BUN, creatine)
 Urine specific gravity, urine concentrating ability
 Urinalysis test reagent strips (protein, glucose, etc.)
 Biopsy
 Albumin excretion (microalbuminuria)
 Isotope renal scans
 Imaging methods (MRI, PET, ultrasound etc.)
 Clearance methods (e.g. 24-hr creatinine clearance, etc.)
 Clearance:
 “Clearance” describes the rate at which substances are removed (cleared) from the plasma
 Renal clearance of a substance is the volume of plasma completely cleared
 At steady state: inverse relationship between GFR and plasma creatinine phosphate
 In muscle mass remains constant, creatinine production will be relatively constant.
 With severe acute renal failure, the GFR is markedly reduced but takes time for plasma creatinine accumulation to reflect the
degree of renal dysfunction.

Page 21 of 28
LECTURE 5 – URINE CONCENTRATION/DILUTION REGULATION OF ION SECRETION

 Describe the role of ADH in urine concentration and dilution

 Role of ADH in Urine concentration:
 When solutes in body fluids become too concentrated (increased osmolarity), posterior pituitary
secretes ADH. ADH increases permeability of collecting ducts and distal convoluted tubules. Large
amounts of water is reabsorbed without changing solute concentration, leading to concentrated
urine.
 When extracellular fluid osmolarity is reduced, secretion of ADH is reduced, reducing permeability
to water, reducing reabsorption of water, and diluting the urine.
 Diuretic  increase output.
 Antidiuretic  decrease output  increase BP  reduced extracellular fluid osmolarity as
ADH is reduced.
 Relationship between urine osmolarity and specific gravity:
 Usually they have a linear relationship
 Specific gravity is affected by number and size of solutes.
 Osmolarity determined only by number of molecules. It is influenced by glucose in urine,
protein in urine.
 Water diuresis in a human after ingestion of 1 liter of water:
 Decreased osmolarity
 Increased flow rate
 Solute excretion remains constant.
 Formation of dilute urine:
 Continue electrolyte reabsorption
 Decrease water reabsorption
 Mechanism:
 Decreased ADH release and reduced water permeability in distal and collecting tubules.
 Increased ADH release which increases water permeability in distal collecting tubules.
 High osmolarity of renal medulla
 Countercurrent flow of tubular fluid
 Formation of a concentrated urine when antidiuretic hormone (ADH) is high.
 Factors that contribute to buildup of solute in Renal Medulla – Countercurrent multiplier:
 Active transport of Na+, Cl-, K+ and other ions from thick ascending loop of Henle into medullary
interstitium
 Active transport of Ions from medullary collecting ducts into interstitium
 Passive diffusion of urea from medullary collecting ducts into interstitium
 Diffusion of only small amounts of water into medullary interstitium
 Why maintain a high osmolarity in the renal medullary interstitial fluid?
 It provides the osmotic gradient necessary for water reabsorption to occur in the presence of
ADH
 Countercurrent multiplier in vasa recta vs nephron
 (1) More salt in continually added by the PCT
 (2) Higher the osmolarity of the ECF, the more water leaves the descending limb by osmosis
 (3) The more water that leaves the descending limb, the saltier the fluid is that remains in
the tubule.
 (4) The saltier the fluid in the ascending limb, the more salt the tubule pumps into the ECF
 (5) The more salt that is pumped out of the ascending limb, the saltier the ECF is in the
renal medulla.
 Countercurrent multiplier system in the loop of Henle:
 The descending limb of the loop of Henle is very permeable to H2O and becomes equal to the renal medullary osmolarity.
 (1) at homeostasis
 (2) at thick ascending limb: Ions move out  Thin descending limb has high
osmolarity compare to thick ascending limb
 (3) at the thin descending limb: horizontal gradient of about 200 between
the thin descending limb and the thick ascending limb
 (4) balance the gradient: ions move from high concentration to lower
concentration
 (5) Ions are continuing to move out of thick ascending limb and to collecting
duct. Osmolarity in the interstitial space is increasing correspondingly.
 (6) the water is going out of the thin descending limb and equalize the renal
medullary osmolarity with the interstitial space.
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  Net effects of the countercurrent multiplier:
 More solute than water is added to the renal medulla, i.e. solutes are “trapped” in the renal medulla (High conc.)
 Fluid in the ascending loop is diluted
 Most of the reabsorption occurs in the cortex (i.e. in the PT and in the DCT rather than in the medulla)
 Horizontal gradient of solute [] established by the active pumping of NaCl is “multiplied” by countercurrent flow of fluid.
 Recirculation of UREA absorbed from medullary collecting duct into interstitial fluid:
 Contributes to the hyperosmolarity of the renal medulla
 Percentages of filtered urea that remain in the tubules are indicated by blue boxes.
 Urea is moving in and out and create air in the interstitial space.
 Urea recirculation:
 Urea is passively reabsorbed in proximal tubule (~50% of filtered load is reabsorbed)
 The inner medullary collecting tubule is highly permeable to urea, which diffuses into the
medullary interstitium
 ADH increased urea permeability of medullary collecting tubule by activating urea
transporters.
 Explain the mechanism of the creation of the countercurrent multiplier to create a hyperosmotic renal
medullary interstitial fluid - Identify relative values for osmolarity in the nephron:
 Flow of fluid through a juxtamedullary nephron:
 Glomerular (Bowman’s) capsule  Proximal convoluted tubule (PCT) 
Descending limb of the loop of Henle  Thin ascending limb of the loop
of Henle  Thick ascending limb of the loop of Henle  Distal
convoluted tubule (DCT, drain into collecting duct)
 Horizontal capillary  Peritubular capillary;
 Vertical capillary: Vasa recta – follow along perimeter of nephron
 The Vasa Recta preserve hyperosmolarity of renal medulla:
 The vasa recta serve as countercurrent exchangers.
 U-shaped vasa recta help to maintain the medullary hyperosmolarity
 Processes:
 Descending limb gets more concentrated as it loses water to ascending part
vasa recta  water reabsorption to blood stream, also create lower salts
concentration in the ascending part of vasa recta so that salts will move from
high concentration at descending part to ascending part.
 Thick ascending limb: all salts are coming out to vasa recta, but water. High
concentration of salts in interstitial space will go to blood stream via vasa
recta
 At the collecting duct entrance: the ascending limb pumps out Na, K and Cl,
and filtrate becomes hypoosmotic (diluted)
 Summary of water reabsorption and osmolarity in different parts of the tubule:
 Proximal tubule – 65% reabsorption, isosmotic
 Descending loop – 15% reabsorption, osmolarity increases.
 Ascending loop – 0% reabsorption, osmolarity decreases.
 Early distal – 0% reabsorption, osmolarity decreases
 Late distal and collecting tubules: ADH dependent water
reabsorption and tubular osmolarity.
 Disorders of Urine concentrating ability:
 Failure to produce ADH – “central” diabetes insipidus (causes by
head injury, tumor, etc)
 Failure to respond to ADH: “Nephrogenic” diabetes insipidus:
 Impaired loop NaCl reabsorptions (Loop diuretics)
 Drug induced renal damage (lithium, analgesics)
 Malnutrition (decreased urea concentration)
 Kidney disease: hydronephrosis, chronic renal failure
 Development of isosthenuria with nephron loss in Chronic Renal failure (inability to concentrate or
dilute the urine)
 Lose more nephron functionality  lose ability to concentrate/dilute the urine
 Osmoreceptor antidiuretic hormone (ADH) feedback mechanism for regulating extracellular fluid
osmolarity.
 After  in water excreted, the negative feedback will send signal to inhibit water deficit
 Water deficit   EC osmolarity  through osmoreceptors:  ADH secretion   plasma ADH 
 H2O permeability in Distal tubules, collecting ducts   water reabsorption   water excreted

Page 23 of 28
  ADH secretion:
Stimuli for ADH secretion: Factors that decreases ADH Secretion
Increased osmolarity Decreased osmolarity
Decreased blood volume (cardiopulmonary reflexes); Increased blood volume
Decreased blood pressure (arterial baroreceptors) Increased blood pressure (arterial baroreceptors)
input from cerebral cortex (fear), angiotensin II, nausea, alcohol, clonidine (antihypertensive drug), haloperidol
nicotine, morphine. (antipsychotic)
 Angiotensin, ADH, aldosterone  increase BP; ANP decrease BP
 Control of extracellular osmolarity (NaCl concentration)
 ADH and Thirst  ADH- thirst osmoreceptor system
 Mechanism: Increased extracellular osmolarity (NaCl)  stimulates ADH release, which increases H2O reabsorption and
stimulates thirst
Stimuli for Thirst Factors that Decrease Thirst
Increased osmolarity Decreased osmolarity
Decreased blood volume (cardiopulmonary reflexes); Increased blood volume
Decreased blood pressure (arterial baroreceptors) Increased blood pressure (arterial baroreceptors)
Dryness of mouth Gastric distention
 Discuss factors that cause increased and decreased potassium levels
 Renal regulation of Potassium concentration:
 Normal potassium intake, distribution and output from the body:
 98% of the total body K+ is contained within the cells
 Potassium regulation internal and external:
 Internal: Cell lysis, strenuous exercise, beta blockade, acidosis
 External: insulin, aldosterone, beta-adrenergic, alkalosis.
 Control of potassium excretion:
 Excretion = filtration – reabsorption + secretion
 Potassium undergoes all processes (not all ions do)
 Renal tubular sites of potassium reabsorption and secretion:
 65% at proximal tubule, 27% at thick ascending loop of
Henle, 4% at distal tubule, 12% at collecting duct
 @Late distal and cortical collecting tubules:
 PRINCIPAL CELLS  secrete K+
 Block by aldosterone antagonists (Na-K-ATPase antiporter)
 Effect of collecting tubule flow rate on K+ secretion:
(i) High flow rate will increase potassium secretion in all
low, normal, high K diet.
 INTERCALATED CELLS – Reabsorb K+
 Using K-H-ATP antiporter at lumen and Na-K-ATPase at basolateral site.
 Activity is reduced by low K+
 Potassium level role:
 Increased serum potassium stimulates aldosterone secretion.
 Aldosterone is also regulated by angiotensin II
 Hyperkalemia:
 Cause of hyperkalemia in the blood
 Renal failure, Metabolic acidosis, Diabetes (decrease in insulin)
 Decreased distal nephron flow (heart failure, severe volume depletion, NSAID, etc)
 Decreased aldosterone or decreased effect of aldosterone (adrenal insufficiency, K+ sparing
diuretics – spironolactone, eplerenone)
 Clinical manifestations: muscle weakness, abnormal EKG readings, cardiac arrhythmias, paralysis if severe.
 Intervention: In mild case – restriction of dietary potassium; in severe case: intravenous insulin and glucose
 Medications that inhibit the renin-Angiotensin-aldosterone pathway should be reduced or discontinued (not high BP med)
 Hypokalemia:
 Cause of hypokalemia in the blood
 Low intake K+, GI loss of K+ (diarrhea), metabolic alkalosis, excess insulin
 Increased distal tubular flow/ salt wasting nephropathies, osmotic diuretics, loop diuretics
 Excess aldosterone or other mineralocorticoids.
 Clinical manifestations (indicators): abnormal skeletal and cardiac muscle cell function due to abnormal action potential or
changes in renal tubular cell function
 Intervention: mild – dietary potassium; severe – intravenous potassium chloride.
Page 24 of 28
 Describe the pathophysiology of chronic renal failure and how dialysis works.
 Integration of Renal mechanisms for regulation of body fluids:
 Excretion = filtration – reabsorption + secretion
 At steady state:
 Fluid excretion = fluid intake
 Electrolyte excretion = electrolyte intake
 Hierarchy of response to disturbances of body fluid regulation:
 (1) local renal responses
 Changes in GFP
 Changes in tubular reabsorption
 Changes in tubular secretion
 (2) systemic mechanism (which can affect the whole body)
 Changes in hormones
 Changes in sympathetic activity
 Changes in blood pressure
 Changes in blood composition
 Effect of changes in fluid intake on blood volume – relatively constant:
 If daily fluid intake (water and electrolytes) is less than 0.5 - 1L/day  death
 Normal: 1-3.5 L/day
 It is the result of countercurrent multiply to get constant blood volume.
 Normal relationship between extracellular fluid volume and blood volume:
 When ECF is less than 12.5L and Blood volume is less than 2.5L  Death
 Normal value of ECF is 16L and 5L blood
 Edema when ECF is more than 22L and more than 7L blood
 Conditions that cause large increases in ECF with normal blood volume:
 Nephrotic syndrome
 Loss of plasma proteins in urine due to increased glomerular permeability and
sodium retention by the kidneys
 Liver cirrhosis:
 Decreased synthesis of plasma proteins by the liver and sodium retention by
the kidneys.
 Chronic renal failure:
 Result from progressive and irreversible loss of large numbers of nephrons to
below 75% of normal  requires remaining nephrons to excrete more water and solutes.
 Causes: Injury to renal vasculature, glomeruli (glomerulonephritis), renal interstitium (interstitial nephritis)
 Treatment: kidney transplantation or dialysis with an artificial kidney.
 Plasma concentrations of solutes in chronic renal failure:
 Sodium and chloride plasma concentrations are maintained even with severe
decreases in GFR
 Creatinine and urea are poorly reabsorbed as GFR decreases.
 Dialysis:
 Dialysis is based on the principles of the diffusion of solutes and ultrafiltraion of fluid across a
semipermeable membrane.
 The membrane blocks the passage of larger subtances (RBC, large proteins)
 Dialysis can not affect the hormones but can balance electrolyte
 Need to monitor BP carefully (because can’t affect angiotensin, aldosterone pathways)
 Dialysis is imperfect treatment to replace kidney function because it does not correct the
compromised endocrine functions of the kidney
 Dialysis treatments replace some of these functions through diffusion (waste removal) and
ultrafiltration (fluid removal)

Page 25 of 28
LECTURE 6 – ACID-BASE REGULATION

 Explain the importance of the bicarbonate buffering system to the respiratory and renal
systems
 Alkalosis/acidosis:
 Alkalosis – Excess removal of proton from body fluids.
 Acidosis – Excess addition of proton to body fluids
 Strong acid – rapidly dissociates and releases proton; Weak acid e.g. H2CO3;
 Strong base – rapidly reacts with proton; Weak base e.g. HCO3-
 Mechanisms of hydrogen ion regulation:
 (1) Body fluid chemical buffers: Bicarbonate, ammonia, proteins, phosphate
 (2) Lungs: Increase [proton]  increase ventilation  increase CO2 loss
 (3) Kidneys: Eliminates non-volatile acids  Secretes proton; reabsorbs
bicarbonate, generate new bicarbonate.
 Buffer systems in the body (60-70% of buffering is in the cells):
 Phosphate and ammonia – important renal tubular buffer
 Proteins – important intracellular buffers.
 Bicarbonate – most important ECF buffer - BASE
 Even the concentrations of the components are low
 Effectiveness of buffer system depends on [] of reactants, pK of system and
pH of body fluids (pH=pK+log HCO3-/pCO2)
 Reason: The components of the system (CO2-ACID and HCO3-_BASE) are
closely regulated by the lungs and kidneys.
 Titration curve for bicarbonate buffer system:
 The more acid added  the lower the pH  the higher the percent of buffer in
form of H2CO3 and CO2
 The more base added  the higher the pH  the higher the percent of buffer in
form of HCO3-
 pK = 6.1  varying pH as percent acidic or basic buffers are present
 Respiratory regulation of Acid-Base balance:
 Corrects 50-75%, partially compensate by the lung.
 Diseases of the lung (e.g. emphysema) which decrease the ability of the lung to eliminate CO2
lead to respiratory acidosis.
 Kidney is then the sole means for returning pH toward normal
 Partially compensate issues  diseases
 Follow the transport of H+ and HCO3- through the renal tubules
 Kidney filtration:
 Large amounts of HCO3- are filtered into tubules, excreted in urine  removes
base from blood
 Large amounts of H+ are secreted into lumen  removes acid from blood
 If more proton is secreted than HCO3- filtered, net loss of acid
 If more HCO3- is filtered than H+ secreted, net loss of base
 Regulation process: Generate new HCO3- or reabsorption HCO3-
 Renal regulation of acid-base balance:
 Kidneys eliminate non-volatile acids (H2SO4, H3PO4)  secretion of proton
 Regulation of HCO3-
 Filtration – reabsorption – production of new HCO3 -- Excretion of HCO3-
 Kidneys conserve HCO3- and excrete acidic or basic urine depending on body
needs.
 Reabsorption of bicarbonate (and H+ secretion) in different segments of renal
tubule.
 Key point:
 For each HCO3- reabsorbed, there must be a proton secreted.
 Mechanisms for HCO3- reabsorption and Na+-H+ exchange in proximal tubule
and thick loop of Henle (85% of reabsorption)
 Na+ gradient moves H+ in the opposite direction (to the tubular lumen).
 HCO3- reabsorption and proton secretion in intercalated cells of late distal and
collecting tubules (10% + 5% of reabsorption):
 The primary proton ATPase secretes proton into tubular lumen.

Page 26 of 28
 Describe the processes of respiratory acidosis, metabolic acidosis, respiratory
alkalosis, metabolic alkalosis and the feedback mechanisms.
 Causes of Acid-Base disorders:
 Respiratory acidosis:
 Decreased ventilation, increased PCO2; Conditions: Pneumonia,
emphysema, obstruction of pulmonary passageways.
 Respiratory alkalosis:
 Increased ventilation, decreased PCO2; Conditions: High altitude
 dry out oxygen  increase oxygen to get more oxygen  too much CO2
comes out  respiratory alkalosis.
 Metabolic acidosis:
 Decreased extracellular HCO3-; Conditions: defect in renal secretion of
H+ and/or reabsorption, renal failure, diabetic ketoacidosis, methanol
ingestion and polyethylene glycol, infection
 Metabolic alkalosis:
 Increased extracellular HCO3-, excess loss of proton and/or retention of
HCO3-; Conditions: administration of most diuretics, excess
aldosterone, vomiting of gastric contents, ingestion of alkaline drugs
(sodium bicarbonate for ulcer)
 How does the kidney compensate for acid-base disorders?
 For acidosis:
 Increased H+ secretion
 Increased HCO3- reabsorption
 Production of new HCO3-
 For alkalosis:
 Decreased H+ secretion
 Decreased HCO3- reabsorption
 Loss of HCO3- in urine.
 Kidney/lung partial compensations: Initial Response; Result:
Type of Arterial Blood conditions
Partial compensation
imbalance pH shift HCO3- (base) - Kidney PCO2 (acid) - Lung
Initial Response Increase as Partial Result: Increase  acidosis,
Respiratory Kidney – Increased H+ secretion
Decrease compensation has limits degree of major blood condition altered by
acidosis and increase HCO3- reabsorption
initially pH imbalance imbalance
Metabolic (to lower Decrease  major blood Decrease partial compensation Alveoli – hyperventilation; faster
acidosis pH) condition altered by imbalance has limits degree of pH imbalance and deeper breathing than normal
Decrease  Partial Decrease  alkalosis, major Kidney – increase HCO3- secretion
Respiratory Increase compensation has limits degree of blood condition altered by and increase reabsorption of
alkalosis initially pH imbalance imbalance proton
(to higher Alveoli – hypoventilation; slower
Metabolic  Increase  major blood  Increase partial compensation
pH) and shallower breathing than
alkalosis condition altered by imbalance has limits degree of pH imbalance
normal
 Classification of Acid-Base disorders from plasma pH, pCO2, and HCO3-
 Acidosis: pH < 7.4
 Metabolic - alveoli try hyperventilation to give more CO2 into the circulation  compensate partially but still,  HCO3-;
 Respiratory – Kidneys try to increase proton secretion and HCO3- reabsorption compensate partially but still,  pCO2
 Alkalosis: pH > 7.4
 Metabolic – alveoli try hypoventilation to compensate partially but still,  HCO3-
 Respiratory - Kidneys try to increase HCO3- secretion and increase H+ reabsorption to compensate partially but still, pCO2
 Symptoms of metabolic acidosis:
 Headache, lethargy; nausea, vomiting, diarrhea, coma, death.
 Compensation for metabolic acidosis:
 Increased ventilation; renal excretion of proton if possible  proton moves into cells as K+ moves to ECF.
 Calculate the anion gap
 Anion Gap can be used as a diagnostic tool:
 In body fluids: Total Cations = total anions
 Na+ = Cl- + HCO3- + Unmeasured anions
 Cation – Anion = Anion Gap (gap in needed anions, unmeasured anions)
 Normal anion gap = 8 – 16 mEq/L
 More positive (10 mEq/L)  Lead to acidosis (more cation)

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  Normal anion gap vs abnormal one (acidosis)

Cation (mEq/L) Anions (mEq/

Measured Na+ 142 Cl- 108
HCO3- 24
Unmeasured K+ 4 Proteins 17
Ca++ 5 Phosphate, sulfate, lactate, etc 4
Mg++ 2
Total 153 153
 Unmeasured anions = Na+ - (Cl- + HCO3-) = ANION GAP  142 – 108 – 24 = 10 mEq/L
 Use of “Anion Gap” as a Diagnostic tool for metabolic acidosis:
 Increased Anion Gap:
 Diabetes mellitus (ketoacidosis); lactic acidosis; aspirin (acetylsalicylic acid) poisoning; methanol poisoning; starvation
 Normal Anion Gap:
 Diarrhea, renal tubular acidosis, Addison’s disease, carbonic anhydrase inhibitors.
 Kidney stones:
 Clinical presentation – Flank pain, hematuria, decreased urine production
 Etiology – Most cases are due to idiopathic hypercalciuria
 Pathogenesis – Dietary protein load causing transient metabolic acidosis and increased GFR, increased Ca+ resorption from bone,
increased glomerular filtration of Ca++, inhibition of distal Ca++ reabsorption
 Glomerulus forms kidney stones (then pass through ureters)
 Clinical manifestations – Pain due to dissension of the ureter, renal pelvis, or renal capsule; small stones are passed with fluids.
 Complication – Infection can destroy kidney. Renal damage from repeat kidney stones. Hypertension from increased renin
production by obstructed kidney.
 Features of urinary tract calculi:
 Type – 75% calcium oxalate (phosphate), 15% magnesium ammonium phosphate, 10% uric acid or cystine
 Prevalence – Approximately 12% in the united states, highest in Southeast 2-3 times more common in men than in women;
uncommon in African-Americans and Asians.
 Risk factors – Concentrated urine, heredity, diet, associated diseases (sarcoidosis, inflammatory bowl disease, cancer)

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