pathophys final exam

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1

diabetes mellitus

  • abnormally high plasma glucose concentration (hyperglycemia)

  • results from inadequate insulin secretion, abnormal target cell responsiveness or both

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what are the types of diabetes?

  • type 1 diabetes

  • type 2 diabetes

  • gestational diabetes → around 20 wks pregnant

  • pre-diabetes (impaired glucose metabolism or borderline diabetes → can lead to type 2 diabetes)

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contributing factors of diabetes

  • hereditary (not exclusively genetic)

  • diet related

  • lifestyle

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symptoms of diabetes

  • polyruria - frequent urination due to excessive production of urine

  • polydipsia - frequent drinking due to excessive thirst

  • polyphagia - frequent eating due to excessive hunger → weight loss despite an increase in appetite

above symptoms are more for type 1 diabetes

  • type 2 diabetes symptoms are usually insidious (have no symptoms)

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type 1 Diabetes

  • onset usually during childhood ( < age 10 )

  • faster onset and can be more dramatic (e.g. overnight)

  • autoimmune → possibly triggered by a virus

  • body attacks pancreatic β cells

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type 2 diabetes

  • onset is for > 35 year olds

  • onset takes longer to occur

  • metabolic disorder → variations in enzymes → may not be optimal

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risk factors of type 2 diabetes

  • obesity (high BMI)

  • physical activity

  • risk increases with age

  • ethnicity

  • gender (male > female)

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urine measurements for diabetes

  • glucosuria → measuring the amount of glucose in urine

  • ketouria → if ketone bodies are being made in urine = high blood ketone levels → possible type 1 diagnosis / uncontrolled long term type 2 diabetes

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fasted blood glucose

  • fast overnight (10-12 hrs)

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glucose tolerance test

  • fast overnight, then take blood sample, then drink a set glucose load, then take blood sample again an hr and 2 hrs from zero

fasted state

  • normal person: 3.5 - 5.5 mmol/L

  • diabetic person: > 7.0 mmol/L

fed state (2hrs post)

  • normal person: <7.8 mmol/L

  • diabetic person: >11.0 mmol/L → even after 2 hrs glucose levels have not dropped

<ul><li><p>fast overnight, then take blood sample, then drink a set glucose load, then take blood sample again an hr and 2 hrs from zero</p></li></ul><p><u>fasted state</u></p><ul><li><p>normal person: 3.5 - 5.5 mmol/L</p></li><li><p>diabetic person: &gt; 7.0 mmol/L</p></li></ul><p><u>fed state (2hrs post)</u></p><ul><li><p>normal person: &lt;7.8 mmol/L</p></li><li><p>diabetic person: &gt;11.0 mmol/L → even after 2 hrs glucose levels have not dropped</p></li></ul>
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glycated haemoglobin

  • aka glycosylated haemoglobin (HbA1c)

  • action of glucose non-enzymatically binding to haemoglobin

  • once haemoglobin is glycated (glucose bound), it loses its ability to transport oxygen

  • is a reliable indicator of diabetic control over the past 3-4 months

  • normal HbA1c: 4-6%

  • ↑ HbA1c = ↑ risk of progression of diabetic complications (e.g. diabetic nephropathy)

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blood insulin

not commonly measured

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complications of diabetes mellitus

  • neuropathy → weakness, numbness and pain from nerve damage

  • nephropathy → kidney disease

  • retinopathy → patchy vision

  • diabetic ulcers

  • amputations

  • diabetic coma

  • death

  • increased chance of having a stroke

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blood glucose control

  • glucose dependent insulin secretion is modulated by a number of hormones and neurotransmitters released from peripheral ANS

  • ACh facilitates the release of insulin in a glucose-dependent fashion via M₃ receptors on pancreatic β-cells

  • hormones: glucagon and adrenalin indirectly stimulate insulin release by promoting glucose entry into the blood stream

    • somatostatin inhibits glucagon and insulin release

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glucose levels and fed/fasted state

  • before eating, an individuals glucose levels are low

  • after eating, blood glucose levels rise

  • glucose levels fall over time

    • insulin amounts should correlate with blood glucose levels

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what are incretins?

  • promote secretion of insulin to decrease blood glucose levels

  • produced and secreted by GIT (enteroendocrine cells - L cells in ileum)

  • e.g. glucagon-like peptide 1 (GLP-1)

<ul><li><p>promote secretion of insulin to decrease blood glucose levels</p></li><li><p>produced and secreted by GIT (enteroendocrine cells - L cells in ileum)</p></li><li><p>e.g. glucagon-like peptide 1 (GLP-1)</p></li></ul>
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what are the physiological effects of incretins on the pancreas?

  • increase insulin secretion from β cells

  • suppress glucagon secretion from α cells

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what are the physiological effects of incretins on the GIT?

  • delay gastric emptying

  • decrease gastrointestinal peristalsis

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what is the bioavailability of incretins?

  • has a short half-life (1-2 min) in blood

  • rapidly degraded by dipeptidyl peptidase-4 (DPP4) → inactivates incretins

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what is the hormonal balance in the fed state?

  • insulin dominates to reduce blood sugar levels and package glucose away after eating

<ul><li><p>insulin dominates to reduce blood sugar levels and package glucose away after eating</p></li></ul>
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what is the hormonal balance in the fasted state?

  • glucagon dominates to increase blood sugar levels

    • after 18 hrs of fasting - starved state → liver depleted of glycogen → gluconeogenesis

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glucose transporters

  • are protein channels in cell membranes that facilitates movement of glucose across membrane

    • cell membranes are fatty lipid bilayers while glucose is hydrophilic

      → as such, glucose cannot easily cross cell membranes

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GLUT 1

  • glucose transporter 1 protein

  • location:

    • brain

    • kidney

    • colon

    • placenta

    • erythrocyte

  • function:

    • uptake of glucose

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GLUT 2

  • location:

    • pancreatic β cells

    • liver

    • small intestine

    • kidney

  • function:

    • rapid uptake and release of glucose

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GLUT 3

  • location:

    • brain

    • kidney

    • placenta

  • function:

    • uptake of glucose

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GLUT 4

  • location:

    • adipocyte

    • heart

    • skeletal muscle

  • function:

    • insulin stimulated glucose uptake

    • GLUT 4 is the only glucose transporter that requires insulin

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GLUT 5

  • location:

    • small intestine

  • function:

    • absorption of glucose

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membrane effects of insulin

  1. insulin binds to an insulin receptor in the cell membrane

  2. activated receptor promotes recruitment of insulin-sensitive glucose transporters from the intracellular pool to the cell membrane

  3. glucose transporters then become embedded in the cell membrane and increase insulin mediated uptake of glucose into cell

    • this then promotes the storage of glucose into glycogen, protein or fat

  4. when insulin levels decrease, glucose transporters move from cell membrane to the intracellular storage pool, where they can be recycled

  5. vesicles fuse to form an organelle called the endosome

<ol><li><p>insulin binds to an insulin receptor in the cell membrane</p></li><li><p>activated receptor promotes recruitment of insulin-sensitive glucose transporters from the intracellular pool to the cell membrane</p></li><li><p>glucose transporters then become embedded in the cell membrane and increase insulin mediated uptake of glucose into cell</p><ul><li><p>this then promotes the storage of glucose into glycogen, protein or fat</p></li></ul></li><li><p>when insulin levels decrease, glucose transporters move from cell membrane to the intracellular storage pool, where they can be recycled</p></li><li><p>vesicles fuse to form an organelle called the endosome</p></li></ol>
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what is hyperglycaemia?

increased blood glucose levels in blood

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normal response to hyperglycaemia

  • an increase in BSL is detected by the pancreas

  • pancreas releases insulin

    • graded amount depending on what level of glucose is detected

  • insulin binds to insulin receptors on adipocytes and muscle cells

  • glucose transporters (GLUT4) are recruited to the surface of the cell membrane to allow for glucose entry into the cell → contributes to the production of TGs and amino acids

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renal absorption of glucose

  • glucose is reabsorbed thru the proximal tubule via sodium-glucose transporters (SGLT1 and 2)

    • concentration gradient of sodium pulls glucose back in (glucose goes against its concen gradient)

    • transporter requires both Na and glucose to bind for it to work

<ul><li><p>glucose is reabsorbed thru the proximal tubule via sodium-glucose transporters (SGLT1 and 2)</p><ul><li><p>concentration gradient of sodium pulls glucose back in (glucose goes against its concen gradient)</p></li><li><p>transporter requires both Na and glucose to bind for it to work</p></li></ul></li></ul>
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SGLT₁ + SGLT₂

  • location:

    • small intestine

    • kidney

  • function:

    • active uptake and reabsorption of glucose

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glucose homeostasis via kidneys

  • transfers all plasma glucose into urine within the nephron, but subsequently completely reabsorbs the filtered glucose (via SGLT1 and SGLT2), unless plasma glucose reaches a threshold of ~180mg/dL (10mmol/L)

    • therefore, under physiological conditions, no glucose is present in the urine

    • when threshold is exceeded, SGLTs become saturated and excess glucose is excreted → glucosuria

  • SGLT2 is highly expressed in the epithelial cells of the proximal tubule

    • in healthy humans, SGLT2 is responsible for 80-90% of renal glucose reabsorption

    • SGLT2 is the recent target for drug therapy in patients with type II DM

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pathophysiology of type 1 diabetes

  • high blood glucose levels

  • pancreas produces little to no insulin

  • person will start shedding muscle because adipocytes (muscle cells) will think there is no sugar available → rapid weight loss

    • tissues require insulin to uptake glucose

    • insulin sensitive cells do not identify glucose as there is no insulin

    • therefore they feel starved and will try to make glucose for energy

      • solubilise muscle and fat deposits → produces glucose and ketone bodies

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ketogenesis

  • more ketone body synthesis than normal

  • breakdown of glucose for energy (glycolysis), fatty acids and amino acids = acetyl CoA formation

  • acetyl CoA enters TCA cycle

  • if there is excess acetyl CoA, it forms ketone bodies

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<p>diabetic ketoacidosis</p>

diabetic ketoacidosis

  • insulin deficiency → increased glucose production (gluconeogenesis) BUT decreased glucose uptake = hyperglycaemia → increased excretion of glucose (and water) via kidneys = dehydration

  • insulin deficiency → increased fat metabolism (lipolysis) → ketonemia (high amount of formation of ketone bodies) = acetone breath, metabolic acidiosis → hyperventilation respiratory distress

<ul><li><p>insulin deficiency → increased glucose production (gluconeogenesis) BUT decreased glucose uptake = <u>hyperglycaemia</u> → increased excretion of glucose (and water) via kidneys = <u>dehydration</u></p></li><li><p>insulin deficiency → increased fat metabolism (lipolysis) → ketonemia (high amount of formation of ketone bodies) = acetone breath, <u>metabolic acidiosis</u> → hyperventilation respiratory distress</p></li></ul>
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pathophysiology of type 2 diabetes

  • diminished effects of insulin → pancreas produces a normal amount of insulin but it is ineffective

    • blood glucose levels are normal, insulin builds up so insulin levels are high

  • however shedding of fats and proteins still occur, but at a slower rate

    • adipocytes break down to produce glycerol → undergoes gluconeogenesis to produce glucose

    • although they are shedding more than normal, you may not pick up any ketone bodies as it is happening at a much slower rate

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glucose lowering medications

  • replenish insulin

    • insulin injections (mainly for type 1 but may be used in combination therapy for type 2) → but risk of hypoglycaemia if too much insulin is used

    • increase insulin secretion

    • promote insulin action

  • increase incretin levels

  • slow intestinal digestion/absorption of carbohydrates

  • reduce glucose reabsorption in kidneys (SGLT2 inhibitors)

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important drug related sites for diabetes

gut

  • small instestine

    • different glucose transporters → absorption

    • incretins = ↑ insulin secretion

pancreas

  • rapid glucose uptake

    • GLUT2

    • glucokinase metabolism

  • synthesis, storage and release of insulin

liver

  • rapid uptake and release of glucose

    • GLUT2

    • insulin receptor binding stimulates glycolysis and inhibits gluconeogenesis

fat and striated muscle (heart and skeletal)

  • insulin dependent uptake of glucose

    • GLUT4

kidneys

  • active reabsorption of glucose

    • filters all, reabsorbs with sodium

    • SGLT co transporters

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diabetes insipidus

  • occurs when the body cannot balance fluid levels in a healthy way

  • fluid in the blood is filtered thru kidneys to remove waste and afterwards most of it is reabsorbed with a small amount leaving the kidneys along with waste

  • ADH (vasopressin) is required to reabsorb the fluid filtered by the kidneys back into the blood stream

  • in diabetes insipidus, conditions that cause the brain to make too little ADH/ disorders that block the effect of ADH cause the body to make too much urine

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central diabetes insipidus

  • lack of ADH released in the body due to the pituitary gland or hypothalamus in the brain being damaged/unable to respond to a decrease in osmolality

  • as such the production, storage and release of ADH is affected

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nephrogenic diabetes insipidus

  • kidneys are unable to respond to ADH

    • due to V2 ADH receptor mutation and/or AQP2 gene mutation

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urinary system

  • 2 kidneys → produce urine from blood

  • urine travels down paired ureters

  • stored in urinary bladder

  • forced through urethra and expelled

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function of the kidney

  • to maintain homeostasis by regulating volume and composition of blood:

    • achieving electrolyte balance

    • controlling blood pH

    • excretion of nitrogenous and other waste products

  • but more specifically:

    • H₂O regulation

    • inorganic ion balance

    • body pH regulation

    • removal of metabollic waste from blood

    • gluconeogenesis (glucose from amino acids)

    • hormone secretion

      • erythropioetin → stimulates production of RBCs

      • renin → BP regulation

    • activation of vitamin D

      • gives hormonally active metabolite → calcitriol

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water balance

  • urine → 60% of water loss

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dehydration

  • results in ↑ water retention (reabsorption) = ↓ urine volume → rehydration

  • also results in thirst → if person responds to it, they will drink → rehydration

<ul><li><p>results in ↑ water retention (reabsorption) = ↓ urine volume → rehydration</p></li><li><p>also results in thirst → if person responds to it, they will drink → rehydration</p></li></ul>
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kidney anatomy

  • located close to spinal chord

  • account for 0.4% of body weight (150g) each

  • surrounded by adipose tissue → limits injury

  • collagen fibres hold renal capsule to surrounding tissue

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secretional anatomy of the kidneys

  • has 1.25million nephrons per kidney

    • cortical nephron - most abundant (85%), most reabsorption/secretion

    • juxtamedullary nephron - less abundant (15%), concentration of urine

      • has a more pronounced loop of Henle (deep into the medulla) → better at concentrating urine

<ul><li><p>has 1.25million nephrons per kidney</p><ul><li><p><u>cortical nephron</u> - most abundant (85%), most reabsorption/secretion</p></li><li><p><u>juxtamedullary nephron</u> - less abundant (15%), concentration of urine</p><ul><li><p>has a more pronounced loop of Henle (deep into the medulla) → better at concentrating urine</p></li></ul></li></ul></li></ul>
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vascular components of the nephron

  • afferent arteriole

  • glomerulus (glomerular capillaries)

  • efferent arteriole

  • peritubular capillaries

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afferent arteriole

carries blood towards/to the glomerulus

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glomerulus

tuft of capsules that filters a protein free plasma into the tubular component

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efferent arteriole

carries blood away from the glomerulus

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peritubular capillaries

  • supplies the renal tissue

  • involved with exchanges with the fluid in tubular lumen

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tubular component of the nephron

  • Bowman’s capsule

  • proximal tubule

  • loop of Henle

  • distal tubule and collecting duct

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Bowman's tubule

collects the glomerular filtrate

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proximal tubule

  • uncontrolled reabsorption + secretion of selected substances

  • due to high concentration of mitochondria

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loop of Henle

  • in juxtamedullary nephrons only → establishes osmotic gradient in renal medulla which allows kidney to produce urine of various concentrations

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distal tubule + collecting duct

  • variable, controlled reabsorption of Na⁺ and H₂O

  • variable secretion of K⁺ and H⁺

  • fluid leaving duct is urine, which then enters renal pelvis

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juxtaglomerular apparatus

produces substances involved in the control of kidney function

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epithelial cells of segments of nephron tubules

  • proximal tubule

    • high no. of mitochondria

    • promote reabsorption of glomerular filtrate

  • intercalated cells

    • secrete H+/HCO3-

    • reabsorb K+

  • principal cells

    • reabsorb Na+ and H2O

    • secrete K

<ul><li><p><u>proximal tubule</u></p><ul><li><p>high no. of mitochondria</p></li><li><p>promote reabsorption of glomerular filtrate</p></li></ul></li><li><p><u>intercalated cells</u></p><ul><li><p>secrete H+/HCO3-</p></li><li><p>reabsorb K+</p></li></ul></li><li><p><u>principal cells</u></p><ul><li><p>reabsorb Na+ and H2O</p></li><li><p>secrete K</p></li></ul></li></ul>
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glomerular filtration (GF)

  • non-discriminant filtration of protein-free plasma from glomerulus into Bowman's capsule

  • mostly protein free → all constituents except for red blood cells and plasma protein

    • i.e. H2O, nutrients, electrolytes (ions Na+, Cl-, HCO3-, wastes (urea), etc.

  • fluid must pass through 3 layers of glomerular membrane:

    1. pores between fenestrations within endothelial cells of the glomerular capillary wall

    2. an acellular basement membrane composed of collagen and glycoproteins (negatively charged)

    3. filtration slits between the foot processes of the podocytes in the inner layer of the Bowman’s capsule

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tubular reabsorption (TR)

  • highly selective movement of filtered substances from the tubular lumen into the peritubular capillaries

    • essential materials returned to blood (maintain composition and volume for constancy of internal environment)

    • keeps unwanted filtered material in tubular fluid to be excreted as urine

      • amount excreted = amount secreted + amount filtered - amount reabsorbed

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tubular secretion (TS)

  • selective movement of non-filtered substances from the peritubular capillaries into the tubular lumen

    • involves trans-epithelial transport but in opposite direction to reabsorption

    • second route of entry into tubules for select substances

      • therefore hastens elimination of certain compounds

    • amount excreted > amount filtered

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basement membrane

  • acellular → lacking cells

  • large plasma proteins cannot be filtered → can’t pass thru capillary pores

    • however pores are just barely large enough to allow albumin to pass thru

      • albumin → smallest plasma protein

  • gelatinous layernegatively charged layer of collagen and glycoproteins

    • discourages filtration of small plasma proteins (repels albumin + other plasma proteins which are also negatively charged)

      • however the <1% of albumin that filters thru are picked up by the proximal tubule (via receptor mediated endocytosis) → degraded into AAs that are returned to the blood

      • urine is generally protein free

      • diseases characterised by albuminuria (albumin in urine) are a result of disruption of the -ve charges within the basement membrane which makes the glomerular membrane more permeable to albumin

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forces involved in glomerular filtration

  • filtration as per other capillaries, except:

    • glomerular capillaries are more permeable than other capillaries

    • balance of forces across the glomerular membrane is such that filtration occurs across the entire length of the capillaries

      • efferent is narrower than afferent

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three passive physical forces that accomplish GF

  1. glomerular capillary blood pressure (P GC)

    • pressure exerted by blood in glomerular capillaries

    • depends on heart contraction and resistance of blood flow offered by afferent and efferent

  2. plasma-colloid osmotic pressure (𝛑 GC)

    • proteins do not pass to Bowman’s capsule (BC)

    • concentration of H2O is higher in Bowman’s capsule

    • results in H2O moving by osmosis down its concen gradient from the BC into glomerulus → opposes the GF

  3. Bowman’s capsule hydrostatic pressure (P BC)

    • pressure exerted by the fluid in the initial part of the tubule

    • tends to push fluid out of BC and opposes filtration of fluid from glomerulus into BC

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effect of arterial pressure on glomerular filtration rate (GFR)

  • efferent arteriole is narrower than afferent

    • afferent carries blood to glomerulus

    • efferent carries blood away from glomerulus

      • basically: whatever doesn’t leave the glomerulus via the efferent arteriole will get filtered out - hence the glomerular filtration rate

  • vasoconstriction: ↓ blood flow into glomerulus = ↓ GFR

  • vasodilation: ↑ blood flow into glomerulus = ↑ GFR

<ul><li><p>efferent arteriole is <em>narrower </em>than afferent</p><ul><li><p>afferent carries blood to glomerulus</p></li><li><p>efferent carries blood away from glomerulus</p><ul><li><p>basically: whatever doesn’t leave the glomerulus via the efferent arteriole will get filtered out - hence the glomerular filtration rate</p></li></ul></li></ul></li><li><p><u>vasoconstriction:</u> ↓ blood flow into glomerulus = ↓ GFR</p></li><li><p><u>vasodilation:</u> ↑ blood flow into glomerulus = ↑ GFR</p></li></ul>
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glomerular filtration rate (GFR) is directly related to…

  • renal blood flow

  • which is regulated by:

    • autoregulatory mechanism (tubuloglomerular feedback)

    • neural regulation

    • hormonal regulation

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tubuloglomerular feedback

  • is the principal intrinsic autoregulatory mechanism

  • keeps renal blood flow, and thus GFR relatively constant

  • macula densa cells in distal tubule sense change in filtered Na+

    • ↑GFR and ↑Na+ = macula densa cells stimulate afferent arteriole to vasoconstrict, thus reducing GFR

    • ↓GFR & ↓Na+ = macula densa cells stimulate afferent arteriole to vasodilate therefore increasing GFR

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neural regulation

  • kidney blood vessels (afferent and efferent arterioles) are innervated by the ANS mainly by sympathetic fibres

    • stimulation → renal arteriolar vasoconstriction = ↓renal blood flow = ↓GFR

    • stimulation is achieved when…

      • there is a decrease in the systemic arterial bp

      • exercise

      • haemorrhage

      • severe hypoxia (low O2 levels)

    • also participates in hormonal regulation of renal blood flow

  • no significant parasympathetic innervation

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hormonal regulation

  • renin-angiotensin system activation ↳ ↑ renal blood flow → ↑ GFR

  • renin: an enzyme made and stored in cells of arterioles in juxtaglomerular apparatus

    • its release is stimulated by:

      • ↓ BP in afferent arterioles

      • ↓ [NaCl] in distal convoluted tubule

      • sympathetic nerve stimulation of β-adrenergic receptors on juxtaglomerular cells

  • RAAS exerts physiological effects stabilise blood pressure and preserve extracellular fluid (ECF) volume during hypotension / hypovolemia

    • this occurs via:

      • ↑ Na⁺ reabsorption

      • sympathetic nerve stimulation

      • systemic vasoconstriction

      • thirst stimulation and drinking

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tubular processes

  • highly selective + variable

    • quantity reabsorbed depends on amount required to maintain proper composition and volume of internal fluid volume

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tubular reabsorption

  • transfer of substances from tubular lumen into the peritubular capillaries (involves transepithelial transport)

  • essential materials filtered are returned to the blood

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tubular secretion

  • involves transepithelial transport but in the opposite direction to reabsorption

  • second route of entry into tubules for select substances

    • therefore hastens elimination of certain compounds

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trans-epithelial transport

  • passive transport → occurs down electrochemical / osmotic gradient

  • active transport → occurs against electrochemical gradient

    • requires energy (e.g. ATP or cotransporter, SGLT1)

    • e.g. movement of glucose, amino acids and other organic nutrients, Na⁺, electrolytes (PO₄³⁻)

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Na⁺ (and Cl⁻) absorption

  • basolateral Na⁺ / K⁺ pump actively transports Na⁺ from tubular cell to interstitial fluid within the lateral space

  • establishes concentration gradient for passive movement of Na+ from interstitial fluid to peritubular capillary

    • high concen of Na+ in interstitial fluid → low concen in capillary

  • active Na⁺ reabsorption allows for passive reabsorption of Cl⁻ and H₂O in urea

    • electrochemical gradient generated by Na⁺ → drives reabsorption

<ul><li><p>basolateral Na⁺ / K⁺ pump actively transports Na⁺ from <u>tubular cell</u> to <u>interstitial fluid</u> within the lateral space</p></li><li><p>establishes concentration gradient for <em>passive </em>movement of Na+ from <u>interstitial fluid</u> to <u>peritubular capillary</u></p><ul><li><p>high concen of Na+ in interstitial fluid → low concen in capillary</p></li></ul></li><li><p>active Na⁺ reabsorption allows for passive reabsorption of Cl⁻ and H₂O in urea </p><ul><li><p>electrochemical gradient generated by Na⁺ → drives reabsorption </p></li></ul></li></ul>
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H₂O reabsorption

  • passive reabsorption through length of tubule

  • osmotically follows actively reabsorbed Na⁺

  • via water channels (aquaporins, AQPs)

    • AQP-1 → proximal tubule which are always open

    • AQP-2 → in principle cells in distal parts of nephron which open in response to ADH/vasopressin

<ul><li><p>passive reabsorption through length of tubule</p></li><li><p>osmotically follows actively reabsorbed Na⁺</p></li><li><p>via water channels (aquaporins, AQPs)</p><ul><li><p><u>AQP-1</u> → proximal tubule which are always open </p></li><li><p><u>AQP-2</u> → in principle cells in distal parts of nephron which open in response to ADH/vasopressin</p></li></ul></li></ul>
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glucose + amino acids

  • kidneys maintain glucose levels in blood

    • transfers all plasma glucose into urine within the nephron, but subsequently completely reabsorbs the filtered glucose (via SGLT1 and SGLT2) UNLESS plasma glucose reaches a threshold of 180mg/dL (10mmol/L)

      • therefore, under physiological conditions, no glucose is present in urine

      • when exceed threshold, SGLTs become saturated and excess glucose is excreted → glucosuria

      • SGLT2 is highly expressed in the epithelial cells of the proximal tubule

      • in healthy humans, under normal conditions, SGLT2 is responsible for 80-90% of renal glucose reabsorption

    • recent target for drug therapy in patients with type 2 diabetes → SGLT2

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glucose reabsorption

  • Na⁺ dependent secondary active transport in proximal tubule

    • uses energy provided by concentration gradient of one Na+ molecule across the cell membrane to push another molecule (glucose/amino acid) against its concen gradient

      • Na+ is going down its concen gradient (higher in urine than blood)

      • while glucose is going against its concen gradient

  • Active SGLT₂ and GLUT₂ transport glucose in renal proximal tubule cell

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tubular maximum

  • each carrier is specific for a specific type of substance

    • SGLT → glucose, not amino acids

  • limited number of each carrier type is present in tubular cells

    • upper limit on how much of a particular substance can be actively transported

    • tubular maximum (TM) is reached when all carriers are occupied → i.e. cannot take additional passengers at that time

  • any quantity of substance filtered beyond its TM is not reabsorbed and escapes into urine

    • with the exception of Na+, all actively reabsorbed substances have a Tm

      • aldosertone promotes the insertion of more active Na+/K pumps in the distal and collecting tubular cells

  • kidneys can regulate the reabsorption of some of the substances that display carrier-limited reabsorption, e.g. kidneys regulate PO₄³⁻ but not glucose

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active reabsorption of electrolytes (PO₄³⁻)

  • PO₄³⁻ is actively reabsorbed + regulated by kidneys

  • transport carriers are located in proximal tubule

    • tubules can reabsorb PO₄³⁻ up to normal plasma concentration and excess spills into urine → excretion

  • reabsorption of PO₄³⁻ and Ca²⁺ is subject to hormonal control (parathyroid hormone can adjust the quantity conserved)

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descending limb of the loop of Henle

  • highly permeable to H₂O → via abundant, always open AQP1 channels

  • doesn't actively reabsorb Na⁺

    • Na+ is leaked in but is not actively reabsorbed into tubular cell from lumen

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ascending thin limb of the loop of Henle

  • impermeable to H2O

  • permeable to NaCl

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ascending thick limb of the loop of Henle

  • impermeable to H2O

  • active reabsorption of NaCl

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tubular secretion

  • same basic principle as reabsorption but in reverse direction

  • many substances that are reabsorbed are secreted at different parts of tubule

    • e.g. urea

  • most important substances are secreted by tubules:

    • H⁺, K⁺, urea and other organic anions and cations

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urea movement in the nephron

always via passive diffusion

  • proximal tubule

    • mildly permeable to urea

    • reabsorption occurs as H₂O is reabsorbed so urea becomes concentrated in tubule

  • thin loop of Henle

    • secretion of urea due to greater concentration in surrounding interstitium compared to tubule

  • thick loop of Henle and distal convoluted tubule (DCT)

    • highly impermeable to urea

    • given large amount of H2O reabsorption → urea is highly concentrated

  • collecting ducts

    • highest permeability to urea

    • ADH promotes specific urea transporters to be added increasing permeability → reabsorption into interstitium

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K⁺ secretion

  • one of the most abundant cations in the body → very impt in maintaining the resting membrane potential

  • majority (98%) of potassium is in intracellular fluid due to the Na⁺/K⁺ pump

    • since a relatively small amount of K⁺ is in the extracellular fluid (ECF), a slight change in the K⁺ load in the ECF can have a pronounced effect on the plasma K⁺ conc → huge effect on membrane excitability

  • plasma concentration is tightly controlled by kidneys

  • renal handling is complex

    • filtered K⁺ is almost completely reabsorbed in proximal tubule

    • most K⁺ in urine is from controlled K⁺ secretion in distal parts of nephron

      • secreted by principal cells

      • secretion is regulated to maintain desired K⁺ concentration

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H⁺ secretion

  • important in regulating acid-base balance

  • secreted via

    • proximal tubule

    • intercalated cells of distal collecting tubules

  • extent secreted is dependent on acidity of body fluids → pH range of blood must be kept between pH 7.35 → 7.45

    • ↑ [H⁺] = ↑ acidity → ↑ H⁺ secretion

    • ↓ [H⁺] = ↑ alkalinity → ↓ H⁺ secretion

  • rate of secretion affected by K⁺ in distal parts of kidney (opposite effect)

    • ↑ K⁺ secretion = ↓ H⁺ secretion

    • ↑ H⁺ secretion = ↓ K⁺ secretion

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kidney/renal function tests

used to indicate the health of the kidneys

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blood tests

  • plasma/serum creatinine concentration → useful for chronic rather than acute kidney disease

    • ↓GFR = ↑ plasma creatinine levels

  • blood urea nitrogen

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urine tests

  • urinalysis → colour, turbidity, protein, pH, specific gravity, sediment and supernatant

    • urine protein

  • microalbuminuria

  • creatinine clearance

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renal clearance

  • involves the liver, lungs and kidneys

  • is the volume of blood from which a substance/drug is completely removed by the kidneys per unit time (i.e. mL/min) per kg of body weight

  • reflects the excretion of a particular substance into the urine by the kidneys

    • drugs differ greatly in the rate at which they are excreted by the kidney

  • is an indirect measure of:

    • GFR

    • tubular reabsorption

    • tubular secretion

    • renal blood flow

  • CL renal = (urine flow rate x urine concentration)/plasma concentration

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creatinine

  • is a waste product that comes from the normal wear and tear of muscles in the body

    • a breakdown product of creatine phosphate in muscle cells

    • usually produced at a constant rate

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creatinine clearance (CrCl) rate

  • is used as a measure of renal function, and is a better indicator of than serum creatinine

  • is the vol. of plasma that is cleared of creatinine per unit time

  • is an approx. measure of the GFR

  • compares creatinine in a 24hr urine sample to blood creatinine levels from one blood sample

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GFR and creatinine clearance

  • GFR is usually estimated (eGFR) from the results of a creatinine blood test and is normalised for body surface area → units are mL/min/1.73m²

  • for males: CrCl = [(140-age) x Wt] / [0.815 x Secr]

    • CrCl = creatinine clearance (mL/min)

    • age = years

    • Secr = serum creatinine (μmol/L)

    • Wt = ideal or actual weight, whichever is lower (kg)

  • for females: multiply the estimated value by 0.85

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blood urea nitrogen (BUN)

  • test measures amount of nitrogen in blood that comes from the waste product urea

    • protein breakdown → urea

    • reflects GFR and urine-concentrating capacity

  • BUN rises if:

    • kidneys are not able to remove nitrogen from blood normally

    • may be due to:

      • ↓ GFR = ↑ plasma urea concentration

      • heart failure

      • dehydration

      • diet high in protein

  • BUN drops if:

    • liver disease/damage

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regulation of fluid balance involves…

  • ECF volume - includes circulating plasma volume

  • ECF osmolality - solute concentration

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ECF volume

  • controlled by maintenance of salt balance

    • Na+ load determines ACF volume

    • primarily controlled by aldosterone

  • important in long term control of arterial BP

  • ↓ ECF volume = ↓ arterial BP and vice versa

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ECF osmolality

  • controlled by maintenance of water balance

    • primarily controlled via aldosterone

  • important in prevention of detrimental osmotic movement of water between ECF and ICF

  • ↑ ECF osmolality (hypertonicity) → H2O leaves the cells → cells shrink

  • ↓ ECF osmolality (hypotonicity) → H2O enters cells → cells swell

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causes of hypertonicity (dehydration)

(in hypertonicity, H2O leaves the cells → cells shrink)

  • insufficient H2O intake

  • excessive H2O loss

  • diabetes insipidus (urinating a lot)

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