Differentiate hypovolemia and dehydration
Hypovolemia = decreased effective circulating volume. Volume depletion - loss of salt and water - (intravascular space is low). May be hypo/iso/hypernatremia. Dehydration = isolated loss of water; implies hypernatremia or hypertonicity
Principle Determinants of GFR (in simple terms (2) and in detailed terms (4)):
In simple terms: Pgc (glomerular capillary pressure) & Qa (glomerular plasma flow rate.
In more detailed terms:
- Transcapillary hydraulic pressure difference
- Transcapillary colloid oncotic pressure difference
- Glomerular capillary filtration coefficient
- Glomerular plasma flow rate
Starling Forces at play in movement o fluid across glomerular capillaries
Balance between mean transcapillary hydraulic pressure (favouring filtration) and mean transcapillary oncotic pressure (which opposes filtration)
Hydraulic pressure
it’s really the same as hydrostatic pressure - the pressure pushing water out of the capillary
Glomerular capillary filtration coefficient
Kf; Changes in Kf probably do not provide a primary mechanism for day to day regulation of GFR; Can be lowered by disease states such as kidney stones.
What would happen to GFR if there was an increased hydrostatic pressure in bowman’s capsule?
GFR would decrease because the pressure of bowman’s capsule would oppose the pro-filtration pressure int he glomerular capillaries.
what would happen to GFR if the glomerular capillary colloid oncotic pressure increased?
GFR would decrease because the oncotic pressure in glom capillaries opposes filtration.
Effect of afferent arteriole tone (RA) on GFR.
Increased tone would decrease renal blood flow, therefore decreasing GFR.
Effect of efferent arteriole tone on GFR
○ Biphasic effect on GFR: With moderate efferent arteriole constriction, GFR increases, but with severe constriction, GFR decreases due to an increase in the capillary oncotic pressure
Renal Autoregulation (3)
Refers to the kidney’s ability to immediately respond to hemodynamic changes in order to keep mean arterial pressure in the the kidney, and therefore the GFR, constant.
Includes a (1) myogenic mechanism and (2) tubuloglomerular feedback.
Myogenic mechanism of renal autoregulation
- primarily in afferent arteriole arterial smooth muscle contracts/relaxes in response to increased/decreased vascular wall tension
- RAPID (seconds) goal: to prevent excessive renal blood flow and GFR at high pressure
when is tubuloglomerular feedback more and less effective?
- Less sensitive during volume expansion, which allows a greater delivery of fluid and electrolytes to the distal nephron to allow for correction of volume expansion
- More sensitive during extracellular volume contraction, which helps conserve fluid and electrolytes
where does renin come from?
juxtaglomerular cells of afferent arteriole in the nephron
source of angiotensinogen (2)
synthesized by proximal convoluted tubules and in the liver (main source)
Sympathetic Nervous System (SNS) Effects on GFR
The renal sympathetic nerves seem to be the most important in reducing GFR during severe, acute disturbances (i.e., hemorrhage); Rich innervation of kidney blood supply.
- Mild activation of SNS causes decreased Na and water excretion
- Mild to moderate activation of SNS has little effect on renal blood flow and GFR
- Strong activation of SNS can constrict the renal arterioles and decrease renal blood flow and GFR
Effect of NE and Epinephrine on GFR
decreased GFR
Effect of prostaglandins on GFR
Increased GFR
Effect of NO on GFR
Increased GFR
What may happen to GFR in Diabetes?
- With sustained hyperglycemia, SGLT2 (glucose transporter in the proximal tubule) expression increases to absorb more glucose
- Early Diabetic Neuropathy - increased proximal tubule glucose absorption leads to hyperfiltration ( increased GFR)
Diuresis
generally describes an increase in urine output
Natriuresis
an increase in urinary excretion of sodium, with or without an increase in urine volume
Effective circulating volume vs extracellular fluid volume
for most healthy people with no kidney, heart or liver disease, effective circulating volume is a fixed fraction of total extracellular fluid volume, so the 2 meanings can be used interchangeably
Modalities for sensing ECFV (3)
- low pressure sensors in atria, ventricles, and pulmonary circulation
- high pressure sensors in arteries (carotid, aortic arch, renal arteries)
- others in CNS and hepatic circulation
what do high levels of BNP in blood indicate? Clinical relevance?
Higher levels can be indicative of congestive heart failure as they indicate increased volume loading on the ventricle.
Use of this test may help differentiate shortness of breath due to CHF from shortness of breath due to lung disease.
where are the low pressure sensors
areas of lower BP; Cardiac atria, R ventricle, pulmonary circulation; Places where changes in blood volume do not cause large changes in BP
where are the high pressure sensors?
stretch receptors in carotid artery, aortic arch, an arterioles of the kidney; Places that are more sensitive to pressure than volume;
how does sympathetic NS output respond to decreased ECFV (5)
Sympathetic output increases;
Results in:
- increased HR, CO
- Increased vascular tone
- decreased GFR
- increased renin secretion
- increased renal Na+ reabsorption
overall: Decrease renal Na+ excretion
how much NaCl is filtered into the filtrate
NaCl solution is freely filtered across the glom basement membrane, so Na concentration as the start of the proximal tubule is that same as Na concentration in serum.
Site of action of loop diuretics and how they work (3)
the NKCC2 transporter in the LoH. This transporter is on the apical membrane and reabsorbs 1 Na, 1 K, and 2 Cl.
Inhibition of NaCl and K reabsorption at this point can cause natriuresis (and K+ aliuresis).
By poisoning the medullary concentration gradient, loop diuretics also impair urine concentrating, therefore causing further diuresis.
Thiazides - where they work and how they work
- Inhibit the NCC NaCl transporter in the early distal convuluted tubule
- Not as potent as loop diuretics but commonly used to treat HTN
Can be combined w loop diuretics to block 2 sites simultaneously when chronic use of loop diuretics leads to upregulation of DCT Na reabsorption.
action of aldosterone in the nephron
Upregulates ENaC channels in Principal cells of the collecting duct, which reabsorb Na in exchange for K secretion. Countered by K-sparking diuretics
K sparing diuretics
inhibit ENaC channels of Principal Cells of the collecting duct, therefore inhibiting Na reabsorption and retaining K+.
Role of prostaglandins (PG) in the kidney
- stimulation
- main players
- effect
- inhibited by
Arachidonic acid, released from membrane phospholipids, is metabolized to PGs by cyclooxygenase (COX-1 and 2) in the presence of Na+ conserving and vasoconstricting stimuli. In the kidney, the main PG is PGI2 aka prostacyclin’;
The overall effect is of afferent arteriolar vasodilation and natriuresis. PGI2 is only synthesized in disease states such as CHF or cirrhosis in order to maintain renal perfusion in the context of high AII, SNS activity, etc. Counterregulated by NSAIDs, which will result in Na retention, HTN, and lower GFR.
Where to prostaglandins (PGs) come from?
Arachidonic acid, released from membrane phospholipids, is metabolized to PGs by cyclooxygenase (COX-1 and 2)
Effects of ANP and BNP in nephron
- increased GFR and natriuresis (similar to how K sparing diuretics work in the DCT)
- Antagonism of RAAS
What regulators would come into play after eating a lot of pop and chips
Increased ANP and BNP
Results: diuresis and natriuresis
- Increased GFR
- decreased renin
- decreased aldosterone
- Decreased Na reabsorption
osmolality
the number of dissolved particles in 1 kg of body fluid
tonicity (2)
the ability of a solution to actually influence the movement of water across the cell membrane;
depends on how effective the solute is as an osmole;
Clinically, tonicity is a function of [Na]
How is plasma osmolality estimated?
Mostly by Na because K levels are so low in ECF.
what kind of nephron is most involved in water regulation?
Juxtamedullary location with long loops of henle (loop turns back in the inner medulla)
Hypertonic medullary interstitium
in the renal medulla, interstitial fluid osmolarity is very high due to mass movement of solutes into the interstitium from the nephron.
Special feature of the loop of henle
countercurrent multiplier system
Countercurrent multiplier system
- opposing flows in descending (water out) and ascending (salt out) limbs of LoH
- Generated by NaCl and urea outflow. Urea is passively reabsorbed, whereas NaCl requires active transport
- Thick ascending limb, DT, and cortical collecting duct are impermeable to urea
2 mains systems that regulate plasma osmolarity
- osmoreceptor-ADH system
- thirst mechanism
transiency of ADH
ADH has a short halflife (15-20 mins) before it is metabolized by the liver and kidney. This alows for rapid alteration of water excretion to manage osmolarity in the body.
Vasopressin
= ADH
water reabsorption in the nephron
- passive diffusion through aquaporins down osmotic gradient
- 99% of filtered water is reabsorbed
- 70% from proximal tubule, 15% from descending limb of loop of henle
- Reabsorption of water in DCT and CD are under control of ADH
Production, storage and release of ADH (4)
- synthesized as a preprohormone by specialized nuclei in the hypothalamus
- Transported down axons axons to the posterior pituitary where it is stored
- released in response to osmotic and non-osmotic stimuli (change in plasma osmolality detected by chemoreceptors in the anterior hypothalmus) (change in BP or blood volume detected by arterial baroreceptors and atrial stretch receptors)
stimulus for thirst
osmoreceptors in the anterior hypothalamus stimulate release of ADH and thirst
Non-osmotic stimuli for ADH release
Decreased blood pressure/volume is detected by arterial baroreceptors inthe carotid sinus and aortic arch. Increased blood volume is detected by cardiopulmonary reflexes, including atrial stretch receptors
Hemodynamic ADH release
- occurs when there is >10% change in volume/pressure (late responder; insensitive)
- Baroreceptors in the venous and arterial circulation respond to low volume and stimulate RAS
- Results in Na retention and thirst
Where does ADH bind and what are the effects at each site? (3)
V1 receptors in vascular smooth muscle (contraction)
Anterior pituitary (ACTH release)
Basolateral membrane of Principle Cells in the late DCT and collecting duct (AQP insertion)
Thirst
conscious desire for water, different from dry mouth
Thirst mechanism
Same area of the brain that stimulates ADH release (osmoreceptors of hypothalamus) also stimulates the thirst mechanism.
Obligatory urine volume
the minimum volume of water needed to excrete ingested and waste-produced osmoles. Determined by the maximum concentrating ability of the kidney. Typically about 0.5 L/day.
oliguria
urine output below the obligatory urine volume. A pathologic state.
How does ADH affect urea transporters
urea transporters are upregulated with ADH (to enhance the countercurrent mechanism and draw more water into the interstitium)
Symptoms of hyponatremia
- edema, hypotension, fatigue
- lethargy, anorexia
- confusion, ataxia, seizures
- Causes of death: brain swelling, herniation/arrhythmias, respiratory failure
Symptoms of hyperosmolality (hypernatremia/hyperglycemia)
- thirst
- polyuria
- fatigue
- hypotension
- confusion
- seizures
- Cause of death: cerebral shrinking
- hemorrhage/arrhythmia/respiratory failure
Distribution of water in different body compartments
Water is 60% of body weight. 2/3 of that if ICF and 1/3 of that is ECF. Of the ECF, 3/4 is interstitial, and 1/4 is plasma.
equation of plasma osmolality
plasma osmolality = 1(plasma[Na]) + [glucose] + urea
Explain the different responses in fluid movement based on transfusion of isotonic, hypertonic, or hypotonic fluid.
Transfusing isotonic Na+ solution will result in increased ECF and no change in ICF
Transfusing hypotonic Na+ solution will result in increased ECF and increased ICF as water is drawn into cells to reduce relatively high [Na] in the ICF.
Transfusing hypertonic Na+ will result in increased ECF and decreased ICF as water is drawn out of cells to reduce the relatively high [Na+] in ECF.
Define effective circulating volume
portion of ECF in the vascular system ‘effectively’ perfusing tissue. Not directly measurable. Not the same as plasma volume.
Briefly, what are the immediate and longterm regulatory mechanisms of osmole concentrations in body fluid compartments?
- Immediately by the physiologic principles of the compartment and by the properties of the membrane
Long term by the afferent signaling of the baroreceptors and their efferent effects on the kidney
What kind of drug is ramipril?
ACE inhibitor
Low pressure sensors for ECFV
- where are they (1)
- their effects (2)
Located in areas of lower BP
- cardiac atria, R ventricle, pulmonary circulation.
They are stimulated by increasing pressure/stretch. They respond by
(a) inhibiting ADH (increase diuresis); and
(b) stimulating release of ANP & BNP (increase natriuresis).
Collectively, these responses cause lowering of blood volume.
HIgh pressure sensors of ECFV.
- where are they? (1)
- what do they respond to? (1)
- How do they respond? (4)
Stretch receptors in carotid artery, aortic arch, and arterioles of the kidney.
Stimulated by decreases in arterial pressure.
Respond by
(a) increasing sympathetic activity (increase HR, CO, vascular tone);
(b) stimulating ADH (increase Na reabsorption);
(c) activating RAAS (increase renin secretion);
(d) inhibiting ANP (decrease GFR).
Collectively, these cause decreased of Na excretion.
What stimulates action of renal sympathetic nerves (2) and how do they respond (1)?
They are stimulated by low BP and stress and result in increased renin secretion. Renin promotes increase Na and H2O reabsorption.
Causes of exercise-associated hyponatremia (4)
1) increased fluid intake
2) ADH secretion prolonged or inappropriate (normally ADH can compensate for excessive water intake)
3) Loss of Na in sweat (minor role; sweat is actually hypotonic)
4) inability to mobilize Na stores
Symptoms of hyponatremia (a range from…)
Range from nausea, headache to confusion, seizures, coma, death (from cerebral edema)
Treatment of exercise-induced hyponatremia
Blood analysis to determine hypo or hypernatremia. Administer hypertonic saline; If asymptomatic, provide salty broth.
Is hypo or hypernatremia more common/dangerous?
Hypernatremia is more common, but hyponatremia is much more dangerous
Symptoms of exercise-induced hypernatremia.
May be similar to hyponatremia. Lethargy, weakness, irritability, can progress to twitching, seizures, coma.
Treatment for exercise-induce hypernatremia
replace free water deficit.
What kind of babies can be delivered at a Level 1, Level 2, or level 3 hospital?
What is the maternity care gap?
Decline in # physicians who are doing deliveries. DOubled numbers of midwives graduating UBC to help fill this gap.
When do we test for group b strep?
35-37 wks
when do we do OGTT in pregnancy?
24-28 wks (checked diabetes canada)
when do we start anti-rho gamma treatmemt?
28 wks
HOw much should we feel baby move?
6 movements in 2 hours or more after 26 weeks.
Phases of Parturition
Parturition
Utuerus rapidly changes from a structure that resists contraction to one that is capable of delivering a fetus and a placenta.
Preogressed from Phase 0 to Phase III
The initiation of labour between phases of quiescence and preparedness
Model for parturition
Sheep model
ALteration in estrogen/progesterone balance leads to an initiation of labour in sheep. But in humans, progesterone does not fall, estradiol does not rise. We still don’t know what exactly initiates parturition in humans.
Non-pharmacologic pain management in labour
Frequent position changes;
Supportive partner, care provider;
Cool cloth;
Uterotropins
Include: estrogen, relaxin, Ca2+ dependent phospholipases, arachidonic acids (prostaglandins)
Set the stage for contractions and cervical change.
Progesterone counteracts these actions and maintains uterine quiescence
Uterotonins
DIrectly involved in contraction of myometrial smooth muscle cells. Increase intracellular Ca in myometrium.
Include: oxytocin, prostaglandins (specifically PGF2alpha), and endothelin-1
How is human parturition different from sheep parturition?
We don’t know exactly what initiates parturition in humans!
Prior to onset of active labour
- serum progesterone levels do not fall
- Serum estradiol levels do not rise
- Administration of progesterone does not reliability prevent preterm labour
- Adminsitration of estrogen does not induce labour
- Prostaglandins, arachidonic acid, relaxin, phospholipases, cortisol, oxytocin do not rise until active labour.
Methods to diagnose pregnancy (3)
Use history, physical, beta-hCG, US after 7 wks to date and diagnose pregnancy
Methods to date a pregnancy
What SFH do you expect throughout pregnancy? You should know this!
So stop contact sports at 12 wks because this is when the uterus leaves the pelvis.
GTPAL
Utility of ultrasound
- Dating pregnancy (after 7 weeks for crown rump measurement)
- Confirming viability
- Assess for early complications
- Spontaneous abortions
- Ectopic pregnancy
- Limited anatomy and structural anomalies
- Assess for multiple gestations (twins, triplets)
Kinds of ultrasound
- Transvaginal = endovaginal
- Good for obese and fine detail
- GOod for early pregnancy assessment (<10 wks)
- Transabdominal
- Standard technique; typical for anatomic scans
Are beleding and cramps dangerous in early pregnancy?
They’re very common and majority will progress with normal pregnancy. Yeast infections are also not risky in pregnancy!!
These are signs and symptoms that will need investigation to assess and rule out ectopic pregnancy.
Define spontaneous abortion
The medical term for for an intrauterine pregnancy loss before 20 wks
Define pregnancy of unknown location
Positive hCG test, but cannot determine location on ultrasound (may be too early to tell).
Define ectopic pregnancy
An extra-uterine pregnancy
how to assess for early complications in pregnancy (4)
History
Phsical
Serial beta-hCG
transvaginal/endovaginal US
Nuchal translucency scan
A scan that is added to SIPS workup to make it an IPS workup. Not covered unless something is identified on IPS.
Performed in a first trimester ultrasound. Widened gap at back of neck suggests a positive result.
Scans for downe syndrome, Turner’s syndrome, and cardiac anomalies.
Assess fetal wellness throughout pregnancy
- Fetal movement starts by around 16 weeks
- counting after ~26 wks when consistent movement is typical
- By mother and care provider at visit
- Should feel movements 6x in 2h
- Non-stress test
- COntraction stress test
- Ultrasound/biophysical profile
- counting after ~26 wks when consistent movement is typical
- Growth: SFH for most normal pregnancies (accurate within 3 cm) or ultrasound if more complicated or to confirm
- Measurements compared to population curves to create percentile and estimated fetal weight.
Non-stress test
- Indirect assessment of fetal oxygenation and wellbeing
- Very common
- Involves 20-40 mins of monitoring fetal heart rate and contractions.
- Looks for basline heart rate that varies, accelerates without contractions
Contractions stress test
- Another way to indirectly assess fetal oxygenation and well being, but not done very often
- Assesses fetal heart patterns is in the non-stress test, but this time during contractions.
- Induce contractions by administering IV oxytocin (most common) or increasing endogenous oxy via nipple sitmulation
- A ‘failed test’ would prompt further monitoring.
How may ultrasound be used to assess fetal wellbeing?
Assess growth, amniotic fluid volume, anatomy. Visual assessment by ultrasound of fetal movement and breathing to develop a biophysical profile (not frequently used in BC).
Explain the role of beta-hCG in monitoring pregnancy and how levels change over time.
Beta-hCG is produced exclusively by syncytiotrophoblasts. It’s role is to rescue and maintain the corpus luteum and therefore production of rpgesterone until the placenta takes over progesterone production.
It is specific to pregnancy and can be detected in serum ~8-9 days post implantation and in urine ~10-12 days post implantation. Expected to rise significantly in the beginning of pregnancy and plateau at 10 wks.
It can be used to detect pregnancy, but doesn’t necessarily predict a normal pregnancy! Not a predictor of gestational age because it is too variable!
Dating my ultrasound
Most accurate technique for dating pregnancy (except for IV conception).
The first scan can be done after 7 weeks. Ideally should be done between 7-14 weeks because after then growth is variable.
Assess:
- crown rump length (for determining gestational age)
- Gestational sac
- Yolk sac
- Fetal cardiac activity
HIstory to ask in early pregnancy assessment
- LMP
- Proior pregnancy history (ectopic, spontaneous abortion, infertility, IVF)
- prior gyne history (PID, tubal surgery, IUD)
- current symptoms (bleeding, cramps, pain)
Physical assessment in early pregnancy
- VITALS!!!
- abdominal exam for pain
- Pelvic exam
- speculum visualization of cervix (is os open or closed, tissue or blood coming from os)
- Bimanual exam: feel for uterus size, adnexal masses
(would then do ultrasound)
What tests would we do if we were concerned about an ectopic pregnancy or spontaneous abortion?
- Quantitative beta hCG - serial measurements
- Should see 30-50% rise in 48 hours
- Abnormal rise is suggestive of non-viable pregnancy (ectopic or abortive), but cannot distinguish location of pregnancy
- Transvaginal ultrasound is becoming more popular to assess early in pregnancy
- FEtal pole, fetal cardiac activity
- adnexal masses, free fluid in pelvis suggests ectopic
Genetic screening during pregnancy
Principles
What is considered? (4)
Modalities (5)
- Non-judgement; offered to all pts.
- Screening tests - therefore chance of false positives and negatives
- Consider a combination of serum, altrasound, and maternal factors:
- Factors: maternal age, medical conditions, ethnicity, fetal age
- Modalities
- Maternal serum analytes (increase or decrease based on aneuploidy or placental abnormalities) (SIPS)
- Add ultrasound (turns SIPS into IPS) to to nuchal translucency scan (first trimester)
- Detailed anatomic scan (2nd trimester)
- NIPT
- Diagnostic genetic testing
Detailed anatomic scan
Performed in second trimester. Screen for structural abnormalities, growth, gluid, placenta
NIPT
= non-invasive prenatal testing
- Find cell-free fetal DNA in maternal serum
- High sensitivitiy and specificity, but not perfect. Abnormal results should be followed by diagnostic testing (amniocentesis or chorionic villus sampling)
- Not consistently funded by MSP…
What are the diagnostic genetic testing options?
Amniocentesis (done later, less dangerous)
chorionic villus sampling (done earlier - 11-13 wks, more dangerous)
How to assess for fetal growth and well being (5)
- SFH
- Fetal movement counting
- Non-stress test / Contraction stress test
- Ultrasound <14 wks to measure crown rump length (dating)
- Ultrasound >14 wks for anatomy parameters (measurements compared to population curves to estimate fetal weight)
About how much of filtered water and Na is reabsorbed?
99%
