Renal Systems Flashcards
Effective osmolality equation (calculate in renal patients like you would do AG or winters. Don’t skip on this equation). Normal range:
2 (Na+ plasma) + (plasma Glucose/18)
Normal range: 285-295 mOsm/kg serum H2O
Body’s default physiologic state
Conservation (antidiuresis)
AVP (ADH, Vasopressin)
Arginine vasopressin: Works to increase bp. Secreted from posterior pituitary. Triggers Aquaporins
Where is most fluid stored?
In the cells (intracellularly). Note that the least amount of fluid is stored in blood. Also note Oxidation of carbs, protein, and fats produces water. (eating food, and drinking it gives us water)
How do we lose water?
Urine, FECES, sweat, respiratory. Note that we MAY or MAY NOT know we are losing it.
Why is intracellular and interstitial (1st and 2nd place respectively) water important?
They act as reserves in cases of low bp and blood volume
What is special about effective circulating volume (ECV)?
Effective circulating pressure is approximately equal to perfusion pressure. ECV is the pressure sensed by baroreceptors and afferent arterioles (kidneys) in the carotid sinus. We can’t sense volume, so we sense pressure instead.
What 3 things contribute to venous return? Difference between stressed and stressed volume.
Mean systemic filling pressure (Pmcf), RA pressure, and vascular resistance Stressed becomes stressed volume. Used to generate perfusion pressure.
Pathway of congestive heart failure in euvolemic patient. 1. Heart fails. Note: ECF = plasma + interstitium. Cost and benefit analysis of this compensatory pathway
- Decreased CO.
- Reduece effective circulating volume due to low pressure at baroreceptors
4.Compensation by fluid retention at kidneys (note sns did not kick in to increase hr and inotropy for an increase in perfusion) - Expansion of extracellular fluid volume depletion in face of increased extracellular volumes
End result: EFFECTIVE volume takes the L (less blood is in circulation). However, there is an increase in plasma and extracellular volume (edema).
Benefit: increased intracardiac filling pressure (RAP).
Cost: Volume overload and pulmonary/peripheral edema
Osmole
Total particle in solution. Effective osmoles creates osmotic pressure, used o drive fluid direction
Main (MOST) effective osmole
Na+. NEEDS an active transport (which is why it’s so effective). Effects body water distribution.
What is an effective osmole?
Osmole which stays in compartment unless transported by active transport into another compartment. Tends to hold onto H2O in the compartment that the osmole lives.
Describe glucose as an osmole
Effective osmole. Needs primary or secondary active transport. Does not create large osmotic gradient like Na+ (most of glucose is in muscle or brain, so it doesn’t have a deep enough squad to do so). If you screw up Glucose re-uptake (insulin deficiency or resistance) in blood, it stays there
Describe BUN (blood urea nitrogen) as an osmole
Ineffective. Lipid soluble, so it readily equilibriates between plasma membranes,
Plasma: Na+ K+ Cl- Glucose (F) BUN Osmolality Specific gravity
Plasma: Na+ 136-145 meq/L (140) K+ 3.5-5.0 meq/L (4) Cl- 98-106 meq/L (100) Glucose (F) 75-115 mg/dl (<110) BUN 10-20 mg/dl (10) Osmolality 285-295 mOsm/kg (290) Specific Gravity (1.005 - 1. 030)
Why do you need Na, K, Cl, and Ca? How does water fit into this?
All of these ions ore osmoles used to keep H2O in the body. Separately, they deal with electrophysiology (Na and K), Acid Base (Cl-), and Contractility (Ca)
Na flows (in/out) K flows (in/out)
Na flows into cell, K flows out
Describe the blood path from the renal artery, bypassing proximal tubule. Job of peritubular capularies
Renal artery –> Afferent arteriole –> glomerulus –> efferent arteriole –> vasa recta –> renal vein
Peritubular caps. are ion destination during reabsorption/ ion source during secretion. They also keep kidneys alive.
Job of glomerulus
Filtration. 100%. Nothing else. Filtration occurs no where else either.
What gets filtered in glomeruli?
Everything, including small proteins (albumin). 100% of albumin is reabsorbed in a normal glomeruli. Same as RBCs.
Job of secretion
Osmoles from the efferent arteriole, peritubular caps., or just interstitium are transported INTO the lumen of the proximal tubule to become a part of forming urine.
Job of reabsorption
Opposite of secretion. Moving stuff from forming urine in proximal tubule into the interstitium (efferent arteriole) to eventually, likely, become of the the blood circulation
What creates filtration barrier of glomerulus?
Podocytes and their foot processes, as well as filtration slits.
Describe filtering fate of the following osmoles:
- Most proteins
- Inulin (NOT INSULIN!)….note that this is no longer used to measure kidney function
- Urea
- Glucose
- Creatinine (kidney function measuring standard)
- Most proteins - NOT filtered. Clearance through gfr = 0 (as in, you will NORMALLY not find this in urine)
- Inulin (NOT INSULIN!) - Filtered. Not reabsorbed, Not secreted. Clearance therefore = GFR (100% of the cleared inulin will be found in the urine)
- Urea - Filttered, partially reabsorbed. Clearence is therefore less than GFR
- Glucose - Filtered, completely reabsorbed. Clearance = 0 (will NOT find in urine, NORMALLY)
- Creatinine - Filtered and secreted. Clearence is about the same as GFR
Standard gfr.
What level gfr equates to kidney failure?
60 minimum for ANY age. Men have higher gfr than females.
Kidney failure gfr: less than 15 (dialysis or kidney transplant suggested)
Scenario: Protein found in urine, but gfr is lit (100). Reason:
Kidney is screwed up/kidney damage. Remember, no protein is filtered through glomeruli.
Formation of creatinine. normal amount:
Cratine phosphate -> Creatine –> metabolized to form creatinine, which is freely filtered in glomeruli. NOT reabsorbed, Some is secreted. Normal volume: 0.5-1.5 mg/dl
Relative creatinine of a vegetarian? Male? Obesisty?
Creatinine filtered is higher in male than female. Vegetarians have lower creatinine levels. Note that it is a function of protein metabolism. Also note that creatinine levels are effected by race among other things. Creatinine levels have ZERO correlation to obesisty. Note that ketoacidosis patients have higher creatinine levels
Difference between BUN and Creatinine?
BUN (normal = 10-20) is a function of hydration status. Creatinine is a function of glomeruli status. They tend to be similarly affected though. If one goes up, expect the other one to go up too. Also, it’s assumed creatinine production was steady during measurement. Like, no diet changes or something lie that
Filtered load vs fractional excretion
Filtered load: amount of substance filtered per unit of time (GFR function. Fraction excretion = ratio of amount of the substance that is actually excrete in urine compared to its filtered load…as in, it accounts for reabsorption)
Most influential pressure in renal capillaries? Where is highest and lowest pressure located?
- Hydraulic pressure of blood entering renal artery and afferent arteriole = highest pressure
- Lowest pressure is in renal vein. Note that glomerulus capillaries dramatically lower pressure because of the vascular smooth muscle in the afferent arteriole
Describe result of glomerular scenario: 1. Constrict afferent 2.Constrict efferent 3.Constrict both afferent and efferent. Note that baseline glomeruli pressure is 40-50
- Constrict afferent - GFR decreased, renal blood flow decreased (blood is not making it to efferent)
- Constrict efferent - GFR increased, renal blood flow decreased (blood still not getting to efferent)
- Constrict both afferent and efferent (high sns tone): GFR stays about constant (but less than basal), renal blood flow still decreased
What’s the consequence of only a small amount of albumin being filtered through glomeruli?
Efferent blood has less h20 and volume (lowers its hydraulic pressure) and a ton of albumin…meaning high oncotic pressure. Note the low pressure in the peritubular capillaries (efferent arteriole side), as compared to the higher pressure in the proximal tubule (hydraulic pressure gradient). Result: high pressure of interstitial fluid (from proximal tubule) plus high oncotic pressure from the albumin in the peritubular capillary fosters a high drive of fluid out of the proximal tubule and into the peritubular capillary.
Kidneys prefer to increase gfr instead of shuttle blood into circulation in time of lower bp BECAUSE….How do the kidneys do this?
You need an optimal gfr pressure in order to reabsorb vital osmoles like Na and K, which are both used to maintain bp. Kidenys do this by summoning Renin Angiotenin Aldosterone System
How do kidneys sense high bp? (slide 58)?
Sensed as a result of increased GFR. This correlates to high NaCl concentration as blood enters THICK ASCENDING LIMB and passes macula densa . Note that the elevated bp would increase the gfr (the notable factor), and the resulting blood would flow through proximal tubule to thick ascending limb before actually contacting the macula densa.
How do kidneys respond to increased gfr?
Summons macula densa, which has receptors for NaCl. Upon high NaCl, macula densa secretes vasoconstrictors, which vasoconstrict AFFERENT arteriole, thus reducing gfr and subsequently reducing flow proximal tubule and thick ascending limb.
Are the kidneys innervated by psns? Does the kidney talk to the brain?
- Hell no. SNS only fam, which triggers vasoconstriction, renin secretion, Na reabsorption .and h2o reabsorption
- Yes, the kidney talks to the brain (has afferents to the brain)
Goal of RAAS
Regultate fluids to regulate bp to maintain perfusion pressure. You cannot survive with low bp. Only high bp or normal bp.
Describe job of endothelial tissues of glomerulus.
- Releases prosteglandins and nitric oxide to promote vasodilation of the AFFERENT arteriol’s vascular smooth muscle.
- Produces antiotensin II, which binds to AT1 receptor, specific for vasoconstriction, of the Efferent arteriole.
Describe angiotensin biochemical pathway
. ANgiotensinogen is converted to Angiotensin I (AI) through the rpesense of RENIN (secreted by the kidney’s juxtaglomerular cells). AI is converted to AII by angiotensin-converting enzyme (ACE). This is done by essentially all organs (brain, heart, proximal tubule brush border, etc). Now that AII is made, it can bind to either AT1 receptors or AT2 receptors.
How does one kill renin production? AII production? How does one stop AT1 binding?
- Kill with a renin blocker (Aliskiren)inhibitor
- Kill with an ACE inhibitor (Enalapril, lisinopril, or captopril)
- Use angiotensin receptor blockers (losartan or irbesartan)
Note that all of these drugs exist to cut off RAAS in some way. The mechs are all different. You must know the difference
What is the job of ACE 2?
Likely causes AII to create Angiotensin 1-7, which binds to Mas Receptor, which leads to vasodilation, diureissis/natriuresis, increase concentrations of nitric oxid and bradykinin, and an anitfibrotic
Describe job of juxtaglomerular (JG) cells
In times of low bp, it creates renin in macula densa, which converts angiotensinogen to AI in peritubular cells of proximal tubule. AI is converted to AII via ACE. AII then acts as a negative feedback to renin, so that renin can stop activating angiotensinogen.
What does glomerulus do in times of low bp? How is the glomerulus able to do this? Consequence of low gfr:
Triggers AII production, which vasoconstricts the EFFERENT side, decreasing renal bloodflow and maintaining/increasing GFR because it fosters renal REABSORPTION later on). It can do this because efferent arteriole is filled to the brim with AT1 receptors. Note that low GFR would lead to kidney ischemia…death sentence.
What are the jobs of AII?
- Vasoconstricts efferent side to increase/maintain gfr
2. Call upon aldosterone production to foster Na reabsorption
How are the heart, anterior pituitary, and kidneys effected in low bp?
Heart: Low systemic bp reaches RA and signals low pressure baroceptors, calling sns to create AVP (ADH)
Anterior Pit: SNS is called upon, along with osmoceptors and SNS and the face that there is now too much NaCl and not enough fluid, in order to secrete ADH
Kidneys: Low volume conveyed as low renal bp activates ras. Ras increases gfr and summons aldosterone.
Are there ever cases where SNS, AII, and AVP are strong enough to triggor arteriole constriction which lowers, instead of increases, gfr?
Yes (and it also lowers renal blood flow). Only increase where one must preserve the systemic bp. In such cases, the system also uses AVP and AII to retain more Na and AVP specifically antidiuresis in order to retain fluid volume and ultimately systemic bp. end goal is to reestablish RA , preload, and cardiac output.
Effects of AII binding to AT1
Stimulates vasoconstriction, Na reabsorption inside kidneys. Outside of them, it causes vasoconstriction and aldosterone secretion. Overall fosters conservation
Effects of AII binding to AT2. Note pathway is not confirmed. What is the theory behind AT1 antagonsits (losartan, valsartan)?
Bradykinin secretion which leads to natriuresis. it also triggers nitric oxide production, which vasodilates. End goal for these is elimination. Theory of AT1 antagonists is that it triggers AII binding to AT2 instead, which leads to these listed effects.
What happens if you cut off AT1 receptors with Angiotenson receptor blockers (losartan, valsartan)
Plasma renin activity will still increase because the body will still sense low bp. That means, AII will still be produced. However, if AT1 is blocked, AII would bhave no choice but to bind to AT2, which causes natriuresis and vasodilation or efferent arteriole (thoeretically)
Job of aldosterone? Why it’s bad for you?
Secreted from kidneys. Leads to Na conservation since its a mineralcorticoid. Also leads to K+ eleimination (must know this part. Na and K are in an antiport). Problems with it:hypertension, fibroblasts in heart, reduces baroceptor sensitivity, induces cardiomyocyte apoptosis/
Job of AII. Consequences:
II leads to vasoconstriciton and aldosterone secretion, but problems include glomerular damage, hypertension, left ventricular hypertroph, fibrosis in kidneys and hear, and atherosclerosis. If anythign good coem from it, it is assumed that AII binded to AT2 instead of AT1. AT2 binding leads to bradykinin for vasodilation, as well as possible reversing/blocking fibrosis to the heart and kidneys and being an antiinflammatory.
Important goals of kidneys. Note what happens in physiologically (daily) low bp.
Maintain O2 delivery and maintain hydrostatic and oncotic pressure for reabsorption. Note that in physiologically low bp, afferent arteriole baroreceptors sense this and trigger vasodilation prostoglandins on arteriole side as well as RAS (triggers vasoconstriction on efferent side) in order to maintain GFR since reabsorption is more important.
What happens to kidneys in pathologically low bp?
Constriction of afferent arterioles VIA A1 receptor SIGNALING. In other words, GFR takes the L for the greater good of the systemic bp. Consequence is that reabsorption gradients in kidneys between intratubular and peritubular flows suffer. renal blood flow tanks and renal ischemia can result
Causes of renal hypertension
IMPAIRED CARDIAC OUTPUT (note that 20% of your blood live in the kidneys at any given time)
Volume depletion
RENAL ARTERY STENOSIS (note that the kidneys would read this as low bp and signal renin…)
drugz
Job of proximal tubule. Explain osmole transportation in proximal tubule.
Main job: Na and Glucose reabsorption
Paraccellular flow: H2O and Na flow from forming urine into interstitiom
Wall adjacent to forming urine: SGLT synporter brings in glucose and Na. In addition, AII (AT1 receptor binding) fosters NHE antiporters which secrets H into forming urine and reabsorbes Na into the epithelial cell cytoplasm (note how this regulates pH)
Wall adjeacent to intersition: GLUT transporter reabsorbds glucose. AII fosters Na/K ATPase reabsorbs Na into circulation and secretes K into the cell epithelium. K and Cl synporters reabsorbs K and Cl into interstitium (note that the charges cancel).
Na and HCO3- synporter reabsorbsNa and HCO3 into interstitum (again, note that the charges cancel).
- Note* Every times H is secreted into lumen of proximal tubule, HCO3 is formed.
- Note* Na is never secreted. It is alwasy being reabsorbed. It is secreted once o the wall adjacent to the interstitum, then reabsorbed again. This happens later in the nephron.
Job of loop of henle
Na reabsorption from ascending limb. Further concentrates urine in the renal medulla. Note that it is impermeable to water, so no water is reabsorbed. Na is reabsorbed from the ascending limb.
Job of Thin Ascending Limb. Describe ion flow.
Main Job: Na and K handling
Wall adjacent to forming urine: AII fosters NKCC channel, which reabsorbs Na, K, and 2 Cl’s. LOOP DIURETICS ACT HERE TO KILL REABSORPTION (furesomide). ROMK2 Seecretes K. NHE3 secretes H and reabsorbs Na.
Wall adjacent to interstition: CLC-Kb reabsorbs Cl. Na/K atpase reabsorbs Na and secretes K. K leak channel leaks K into interstitium. Antiport secretes cl- while reabsorbing HCO3- to the interstitium.
How does Thin ascending limb affect K handling?
When ROMk secretes K into the forming liumen, the NKCC reabsorbs it, along with an Na and 2 Cl. In addition, the presence of K in the urine creates a positive charge increase. Since Ca is already in the urine (you need to know this), the 2 charges collide and the only solution if fro Ca to be reabsorbed int o the cytoplasm instead of staying in the forming urine.
What is the job of the distal collecting tubule? Describe the ion flow.
Job: Na, Cl, and Ca reabsorption.
Wall adjacent to forming urine: AII fosters NCC, which reabsorbs Na and Cl. THIAZIDES ACT HERE to kill Na and Cl reabsorption, keeping Na and Cl in the forming urine. Ca channel reabsorbs Ca. AII fosters ENaC (epithelial sodium channel), which reabsorbs Na.
Wall adjacent to interstitium: Cl chennal reabsorbs Cl. Na/K atpase reabsors K and secretes K. K channel reabsorbs K. NCX channel reabsorbs Ca and SECRETES Na, which is then reabsorbed in Na/K atpase.
Where does AII act? What is end result?
Acts on adrenal zona glomerulosa, which stimulates aldosterone secretion, which targets distal nephron. End result is Na reabsorption (always) and K secretion (not always).
How does one make aldosterone?
HDL and LDL are converted to cholesterol, which is convertered to pregnenolone. This is then converted to progesterone, whichis converted to corticosterone. Corticosterone is converted to aldosterone. All of this happens in zona glomerulosa of adrenal gland.
Kideny’s response to high bp
Pressure natriuresis. Note that kidney response takes the longest to fully kick in. more rapidly active is sns, but sns calls upon kidneys, which will take over fully a a few days.
Does aldosterone lead to hyperkalemia? Describe aldosterone paradox.
No.
Aldosterone paradox: In cases of hypovolemia, AII acts on NHE3 in proximal tubule, NCC in distal convoluted tubule (both NCC and NHE3 reabsorbe Na, rmemeber?), and summons aldosterone production. ALdosterone Further triggers NCC, but it also triggers EnAc in corical collecting tubule, to further reabsorb Na. Note that ROMK was not touched, so K was not secreted. Hence, you will not become hypokalemic with aldosterone production. Alodosterone is being biochemically blocked from ROMK.
When would have have K secretion without hypervolemia?
Hyperaldosteroneism would do this, However, hyperkalemia would also trigger this. In this case, hyperkalemia, activates aldosterone in disctal convoluted tubule, which then aldosterone now has access to ROMK.activates WNKs and SGK1 (you need to know these 2), which is the only reason K is then secreted into forming urine. Aldosteroen will still act on ENaC to reabsorb Na from corticle convoluted tubule from forming urine.
What causes secretion of aldosterone?
- Hyperkalemia
2. AII
Normal response to high bp. What happens if high pressure baroceptors are desensitized?
High pressure sensors in carotid sinus and aortic arch talk to cardiovascular center in medulla. This triggers psns to slow heart rate and reduce inotropy. Vascular smooth muscles are relaxed (alpha 1 receptors are cut off). And the increased mean arterial pressure causes kidnesy to pressure natriures. Desensitized high pressure baroceptors in hypertensive patients lead to the excretion of urine only after reaching a higher set bp. The rate of urine excretion does not change.
Describe the normal and abnormal physiology triggering pressure natriuresis.
Normal: Increased total peripheral resistence or increase in Na intake will raise bp up to a threshuold, after which you pressur enatriureis.
Pathological: Equivalen increase sin MAP will no properly lead to pressure natriuresis. It takes a higher bp (so, more Na) to cause pressure natriuresis. Increase in Na does not elicit normal proportional excretion of Na.
Mineral Corticoid hypertension (type 1 and 2)
Distinction between type 1 and type 2:
Presentation:
Mineral Corticoid hypertension Type 1: Gland is oversecreting aldosterone. Type 2: Something in otherwise healthy adrenal cortex causes it to pump aldosterone. Reason could be a renal stenosis, since this would convince kidney that it is hypotensive, telling it to make more AII, and ultimately leading to chronic hypertension.
Distinction: Run a blood test to confirm increase in aldosterone concentration. Once you confirm that it is aldosterone, you check plasma renin concentration. If it is high, then renin is high, and that would mean it’s a secondary issue. If Plasma renin activity is low, and aldosterone is still high (keep in mind that SNS would have shut off renin in the face of high bp. Meaning, it would have turned off RAAS), then it must be a primary issue. Confirm with a CT ans you should find a cancer growing on adrenal gland, leading to the constant secretion of renin.
Presentation:
1. Hypertension (alsdosterone would be called, reabsorbing Na).
2. Hyper natremia (becasue of aldosterone)
3. Reduced urine output because of aldosterone.
4. Na in blood may be high, but should be counteracted by pressure natriuresis.
5. Hypokalemic (chronically reabsorbing Na means you are chronically spitting out K.
6. Metabolic alkalosis since aldosterone causes H secretion (H channel and H/K atpase both are affected by aldosterone and secrete H. They are in convoluted collecting tubule. Also think NHE3 in proximal tubule), leading to reabsorption of HCO3- (happens every time H is secreted).
Which association between hypertension and K.
Hypertension –> hyPOkalemia. Reason: generally aldosterone is involved. That mean Na/K channels are being touched. Which means, K is constantly being secreted.
Pseudeohypoaldosteronism presentation:
Treatment:
Presentation:
- Hypotenstion
- Fainting
- Hyperkalemia
- Hyponatremia.
- Metabolic acidosis becasue there would be less bicarb produciton since less H is being secreted.
- SNS would be constantly on because of the low bp, so you’ll see high heart rate.
- urine would see elevated Na and decreased K. Macula densa would not see this change.
- Decreased urine output since body would be compensating for the low bp.
You would not see edema since edema is a result of a combo of other disorders. You would not see weight loss either.
Treatment: Increase Na in their diet. Prescribe synthetic aldosrerone
Explain problem with hyponatremia
Decreases plasma osmolality, which decreases osmotic h2o diffusion into cells, ultimately disrupting transmembrane potential
Reasons for hyponatremia
- Too much water rentention (primary polydipsia…person drinks too much water). Could also have SIADH syndrome which casues reabsorption of water.
- Kideny would be excreting too much Na. Person could also be secreting too low amounts of aldosterone.
Reasons for hypovolemic hyponatremia
GI fluid loss, hemorrhage, sweating, diuretics, mineralcorticoid deficiency could all do this. Result: loss in both Na and H2o. THis triggers baroceptors, calling upon AVP (aka ADH) and signaling ingestion/admin of h2o.
Reasons for hypervolemic hyponatremia
Essentialy, increase in total body water is greater than increase in total Na. This can be due to heart failure or renal failure. The result of this is a decrease in effective circulating volume, triggering ADH and RAAD to withhold h2o from secretion.
Reasons for euvolemic hyponatremia
Most unusual one. Essentially, Drugs or pain can do this. But most likely it is do to SIADH disorder. This causes person to reabsorb too much water, way more than Na. They stay euvolemic because patient will still pressure natriureis if too much water is withheld.
Is water reabsorption predominantly hormonal or nonhormonal regulated? What causes it? What is the response of AVP secretion?
Hormonal regulated only. Caused by hypotension or hyperosmolality (osmoceptors).. This triggers magnocellular neurons to call posterior pituitary, which secretes AVP (ADH). AVP binds to V2 receptors on the kidnet, fostering water reabsoroption. It aslo binds to V21receptors on vascular smooth muscle to cause vasoconstriction.
What allows water reabsorption in collecting tubule? WHat is the trrend in osmolality as you go further down collectign tubule?
The presence of AVP.
And decent further into the collecting tubule leads to increases in osmolality. Osmolality is closer to that of plasma (285-295) at the beginning of the collecting tubule.
How does AVP work in kidneys?
AVP binds to V2 receptors, which triggers AQP2 (aquaporin). Aquaporin activation allows water into the cell cytoplasm from urine. AQP 3 and 4 allows that same water to then enter from the cytoplasm back into the interstitum to re-enter circulation.
Correlation between alcohol and AVP.
Alcohol kills AVP. if you drink too much alcohol, AVP won’t work well, so diurese.
ANP
Atrial natriuretic peptide, activates in times of high bp. Works to trigger pressure natriuresis. Pathway: High pressure/volume (heart failure) distends RA, summoning ANP. ANP vasodilated afferent arteriole, increasing GFR. Also leads to natriuresis. It Kills renin secretion
Diabetes insipidus
Diabetes as a result of AVP insensitivity or loss of AVP production. End result: can’t reabsorb water, so excess urine produciton. SNS may kick in because too much urine is being produced, leading to low bp. Na concentrations will rise and this increases plasma osmolality. In the case of urine, it will be dilute. Hyperosmotic patients produce dilute urine (becaue they are ditching urine instead of keeping to fluid within, leaving them hyperosmolar). If issue is neuro, AT2 receptor issue is suspected. If nephrogenic, then the kidney has a issue. Patients have extremem thirst (polydipsia) and yet have hypotonic and high volumes of urine (hypotonic polyuria). You won’t find albumin or glucose in their urine. CNS issue would imply that Posterior pit was not producin AVP. Nephrogenic issue would imply that V2 receptor was missing.
1.0003 v. 1.03 specific gravity for urine
First is more dilute urine. Normal. The other is not normal.
SIDAH
Inappropriate AVP secretion. Person may complain of cognitive or neuro issue. May come in complaining of dark urine. Thirst would not change. If issue is neurogenic, V2 receptor is being improperly stimulated. If nephrogenic, there is a problem with the kidney itself. Patient will have concentrated urine and antidiuresis like crazy. There will be a drop in plasma osmolality and patient’s bp will go up, unless pressure natriuresis is still normally active, in which case bp will not change much except for having occasional hypertensive episodes. Urine’s specific gravity will go up too. Edema is not likely, it’s just a skewing of water balance. They would be hypervolemic. Patients may have muscle weakness and Na concentrations less than 120, which is why their brain functions tank. A CNS issue implies that AVP is being over produces, and a nephrogenic issue would imply that there are too many V2 receptors, or is is constantly being stimulated by something.
How do kidneys handle H and HCO3 on the daily? What happens if kidneys fail?
They secrete H and create/reabsorb HCO3. Upon kidney failure, metabolic acidosis (since you can no longer secrete H and moreso because you no longer make HCO3). This leads to protein catabolism, as well as bone demineralization (which leads to osteoporosis and osteodystophy)
Describe H to HCO3 reclammation biochemical pathway in kidneys.
H is secreted into cytoplasm of proximal tubule cell. The H is further secreted via NHE3 channel (Na reabsorbed). The H links with OH to make water which is reabsorbed. The reabsorbed water becoms OH inside th ecytoplasm, linking with CO2 to become HCO3. 3 HCO3 is reabsorbed with 1 Na. H secretion - HCO3 reabsorption always.
Describe HCO3 creation via H2O and CO2. Note that this happens in proximal tubule.
Filtered HCO3 splits to become OH and CO2, OH and H link to make H2o, which is reabsorbed into cytoplasm. the CO2 made earlier is also reabsorbed. The water reabsorbs splits to make H and OH (H is secreted, OH stays.) The OH joins with the Reabsorbed CO2 to make HCO3. 23 HCO3 leaves with 1 Na in a symporter.
Describe the presense of HPO4 in the forming urine.
HPO4 links with H that’s secreted vie NHE3 channels in proximal tubule. The H links with it to make H2PO4, in addition to making HCO3. H is excreted from body as H2PO4 acid.
How is glutamine involved in HCO3 reabsorption?
Secreted Glutamine from interstitum links with NH4 to ultimately make 2 HCO3. The HCO3 is shuttled back to interstitum with Na. (1:1 ratio via the channel.) NH4 in the cytoplasm can also be secreted further into urine vie NHE3 channel. The NH4’s H become a park of HCo3, and the rest is secreted.
Describe importance of NH3 and NH4 in acid base regulation of kidneys.
NH3 freely floats between forming urine and interstitum. However, in the case of it bing in forming urin, it links with previously secreted H to make NH4. and is excrteded as such. H that is secreted from the lumen links with NH3 that freely entered the lumen to make NH4, which is still secretes. Please not that HCO3 is made at every stage of the nephron.
Where does aldosterone act in the nephron?
- ENaC channels, fostering Na reabsorption. It’s entering of the cytoplasm creates a lack of a negative charge in the forming urine, which is remedies by H’s secretion into the forming urine.
- Na/K atpase. Note that this reabsorbes Na, and secretes K.
- H atpase, which solely secretes H.
- K/H atpase, which secretes H and reabsorbs K.
* **All of this happens in distal convoluted tubule.
What are the 3 types of sick kidneys?
Type 1: Impaired distal acidification, leading to decreased NH4 excretion.
Type 2: Issue with NHE3, Na/K atpase, or carbonic anhydrase. Patient shows normal blood glucose. Patient will be defective in HCO3, Glucose, PO4, and Vitamin D. Metabolic acidosis.
Type 4: Aldosterone deficience/resistence. H ATPase issue. NH4 handling is impaired as a result. AG would be normal, and acidemias would be mild.
What is the body’s normal response to metabolic acidosis?
Increased H concentration leads to H moving intracellularly and K moving extracellularly in order to mediate the acidity and maintain the charge balance. Hyperkalemia = metabolic acidosis. Hypokalemia = metabolic alkalosis. Note that metabolic acidosis and hyperkalemia lead to poor electrophys such as peaked T waves, ST elevations, and the elimination of P waves.
Describe pathway of primary hyperaldosteronism, and how it relates to K and H concentrations.
It leads tot he increased production of aldosterone, which causes H secretion (NHE3 channels…). The increased H secretion increases HCO3 concentrations in plasma, raising plasma pH. This leads to H being spit out if cells and K being reabsorbed in order to deal with the alkalemia.. end result is the hypokalemic metabolic alkalosis.
Describe pathway of hypoaldosteronism, and how it relates to K and H concentrations.
Hypoaldosteronism leads to low aldosterone. This low aldosterone means less H is secreted, and also means less HCO3 is generated. As a result, pH drops. There is now a swap, with cells spiting out K to take in H. the end result is hyperkalemic metabolic acidosis.
Where does urea come from? Describe its pathway.
Protein metabolism leads to NH4 production, which creates urea. Urea is converted to BUN, and 50% of filtered load in proximal tubule is reabsorbed. By the time you reach the collecting tubule, 110% of the filtered load is present. s the load travels collecting tubule, urea transporters (UT1 through UT4) reabsorb urea to keep it in the kidneys. The final filtered load is 20% at the end of the collecting tubules.
Describe concentration of collecting tubule and why it’s important
50:50 NaCl and Urea. Most of what is filtered stays in kidney. We don’t reabsorb it because it is toxic. Urea is kept int he kidneys in order to maintain the concentration gradient for reabsorption.
Where is the most glycogen stored?
Skeletal muscle,. Liver is second place.
Job of insulin
Lowers plasma hormone. Remember that insulin is an anabolic hormone. It causes one to store glycogen. The storage is predominantly into skeletal muscle. Then it goes to liver.
Explain the biochem leading to insulin secretion, starting with glucose.
When glucose concentrations get high enough, they run through GLUT2, which triggers glucokinase. The glucokinase increase G-6-P, which increases ATp presence. The increase in ATp depolarizes ATP sensitive K channels. Depolarization of K channels increases conduciveness of voltage gates Ca channel activation. When Ca flows in, the influx triggers insulin secretion.
Where does sulfonylureas drug act? What does it do?
It acts on ATP sensitive K channles, making them depolarize more. End result is an increase in Ca channel depol, which leads to an increase in insulin secretion.
Where does insulin promote glucose storage? What kind of receptor does insulin respond to?
Liver, adipocytes, resting skeletal muscle (which takes up the most glucose). Responds to insulin receptors operating as a tyrosine kinase.. It is still responsible for storage, and insulin is still anabolic.
What does insulin do in the liver, skeletal muscl, and adipocytes?
Skeletal muscle: promotes glucose uptake, which leads to glycogenesis, which creates GLYCOGEN.
Liver: It kills glycogenolysis and gluconeogenesis. It instead promotes glucose uptake, which leads to glycogenesis and then glycogen production. Glucose uptake here also leads to the creating of as, Tgs, triglycerids, and lipoproteins.
Adipocytes: Kills lipolysis, but it increases glucose presence with the increases of free fatty aciods. They create FAs, which make triglycerides, which make lipids and VLDLs
What are the 2 general jobs of glucose?
- At LOOOOW LEVELS (and levels above), it promotes K uptaake vis Na/K atpase.
- Glucose uptake.
What does insulin do at medium and high physiological levels?
FOsters FFA uptake, which leads to lipogenesis. Then it kills off gluconeogenesis. The way we all recognize insulin is actiually the last stage of its activity. It causes peripheral glucose uptake, which leads to gluconeogenesis.
What happens in diabetic ketoacidotic (DKA) patients)
These patients lack insulin (type 1 mellitus) or are insulin resistant (type 1 mellitus). They end up having hyperglycemia, and are unable to uptake glucose. Without the uptake of glucose, glycolysis shifts to lipolysis. Lypolisis leads o the oxidation of FAs, which creates Ketone bodies (ketoacids and acetone) to create oxidative fuel. However, it ketone producrion exceeds usage, the ketoacids buildup and you get ketoacidosis. This happens during starvation or a lack of carb indigestion. End result is keotacidosis…a form of metabolic acidosis. This isssue is more common in type 1 since they have zero insulin to begin with.
How would you describe type 2 diabetes mellitus?
Syndrom of metabolic obesity, meaning that there is an abnormal distribution of fat that causes metabolic problems. THe result is that patients are hyperinsulinemic, but thay are resistive to the diabetes. They have hyperglycemia. These patients have abdominal (visceral/android) fat dristributions….not good.
How would you describe type 1 diabetes mellitus?
This si an autoimmune disorder in which there is a destruction of beta cells. They do not have enough, if any insullin being made, so they cannot uptake glucose. They get glucose by breaking down skeletal muscle, liver, and adipose. Patients present with the 3 P’s (polydipsia (very thirsty), polyuria, and polyphagia (very hungry)). they Also suffer weight loss, infection, and blurred vision.
Describe pathogeneisis of DM1
No insulin leads to hyperglycemia. Glycolysis shifts to lipolysis, which increases production of ketoacids and ultimately deiabetic ketoacidosis.
Describe pathogeneisis of DM2
There is some insuline, but not enough, so the patients are still hyperglycemia. The insulin that is present leads got glycolysis. There is still metabolic acidosis, but only a modest, if any AG elevation.
What happens in the case of hyperosmolar hyperglycemic state (in other words, when DM2 patient does not take their meds)?
This is a fucntion of type 2 diabetics. Insulin is low, so you will still get some lipolisis (metabolic acidosis comes up occasionally). However, the low insulin leads to hyperglycemia, and thus an increase in the filtered load of glucose in the kidneys. This leads to an increase of OSMOTIC DIURESIS (too much sugar means strong osmole, casueing patients to hold onto more water, and causing body to diuresis in order to balance this.). There is then an increase in the excretion of water, Na, and K to balance the osmolarity, butt his leads to dehydration, which furthers the hyperglycemia. The dehydration calls upon the thirst drive, but it also kills of intravascular volume, taking away perfusion pressure and leading to hypotension. Of course, hypotention leads to and increase in sns (whcih causes tachycardi), RAAS, and AVP. RAAS kills of renal perfusion and GFR suffers. The loss in renal perfusion removes more filtered load of glucose (as in, glucose is literally not being filtered. Its stuck in the blood since renal side is cut off because of the hypotention), which even further propagates the hyperglycemia. This Hyperglycemia leads to hyperosmolality.
How to recognize a hyperosmolar hyperglycemic state
GLucose above 600, Osmolality above 320
dehydrated patient
NO SIGNIFICANT KETOACIDOSIS…pH is above 7.30 and HCO3 will be above 15.
How to test for DM
- Comprehensive metabolic panel. Check glucose numbers. Will be above 125
- Oral Glucose Tolerance Test, where patient drinks sweet drink and glucose number is checked 2 hours later. A DM patient will have glucose levels above 199 after 2 hours pass.
- HbA1c…long time marker of blood sugar status. The patient will have a number above or at 6.5%.
What are the consequences of DM?
MICROvascular disease, which leads to
1. Kidney failure
2. Non-traumatic lower limb amputation due to neuropathy
3. Adult blindness caused by retinopathy, caused by neuropathy.
Honorable mentions stem from MACROvascular disease, which results in stroke and cardiovascular disease.
How to assess insulin resistance in DM2 patients
There is a long period during which insulin resistance is undetectable because you still have normal glycemia. The only clue is the steady increase in plasma insulin that the pancrease is being forced to crank out. There will come a time when the pancreases gets tires and it will stop making insulin. This it the point in which blood sugars stay up and insulin levels start to steadily drop no mater what the blood glucose concentration is. Eventually the pancrease beta cells just die off.
Describe the vicious cycle of DM2
Insulin resistance leads to hyperglycemia, which leads to increased insulin demand. the increased insulin demand leads to the progressive loss of beta cell function. This leased to more insulin resistance which further leads to hyperglycemia.
What is metabolic obesity? What is the biochem behind it?
Basically, it’s the storage of VISCERAL fat. this raises you waist to hip ratio. You’ll see hypertension, hyperlipidemia, and insulin resistance. Insulin resistance syndrome = DM2. The biochem starts with adipocytes. this leads to an increase in insulin resistance and elevated FFA. The increase in FFA decreases insulin secretion (remember, the fat gets in the way. Leads to resistance), which propagates cycle of insulin resistance and hyperglycemia.
Describe “good obesity”
Sumo wrestlers, NFL linemen…they all have modified diets which lends to accumulation of SUBCUTANEOUS fat, and they regularly exercise. The incidence of DM and cardiovascular disease is low in these people.
When you think bilateral rales, think:
Pulm edema
What is the largest source of gluconeogenesis?
Liver. Without question. Kidney helps.
What is the normal pathway regarding insulin and the kidneys?
Elevated blood glucose triggers pancreatic beta cells, which activates insulin. Note that insulin in the kidneys leads to glucose uptake for glycogenesis and for general renal function (kidneys gotta eat too). Random association: Kidneys always work to break apart insulin so that insulin levels are normal, and so is the resulting glycemic state. Meaning, if you kill off the kidney, you have nothing to break apart excess insulin. This leads to hyperinsulinemia, and a resulting hypoglycemic state.
What is the general handling of glucose?
GLucsoe is gernally dealt with from 80 to 150, maybe 180 mg/dl of blood. This is the point where the amount of glucose filtered = the amount of glucose absorbed. If glucose levels pass this 180 mark, the limit of the SGLT channels in the proximal tubule are exceeded and you get “spillover”. in otherwords, there is too much glucose available for the channels to reabsorb. SO the remaining glucose is excreted in urine…not good. DM1 and DM2 patients.
Job of SGLT and GLUT in the proximal tubule
SGLT reabsorbes glucose and Na. Glucose is further reabsorbed into interstitum by GLUT channels. The Na is reabsorbed by the Na/K atpase and the Na/HCO3 channel.
Describe the temporal progression of diabetic kidney
In a DM2 patient, Rising bp leads to glomeruler hyperfiltration and microalbuminuria. Over time, the hypertension leads to proteinuria (large amount of protein in urine) and there’s a progressive loss of renal function until you reach end stage renal disease.
Describe the early pathogenesis of diabetic kidney
Hyperglycemis leads to hyperfiltration, and the resulting filtered load of glucose spikes up SGLT expression in proximal tubule. More Na is reabsorbed too because SGLT channels bring in both glucose and Na. That means less Na makes it to the distal tubule, and the the macula densa reads this a low pressure…activating afferent arteriole vasodilators, and further increasing the hyperfiltration…cycle continues.
What screws up glomeruli integrity?
- Hyperlipidemia
2. Hyperglycemia
What is a consequence of hyperfiltration, in terms of osmolarity?
The hypertension leads to increased filtered load of glucose and albumin in the forming urine. THis increases urine’s osmolarity, adn leads to osmotic diuresis (too mcuh sugar and microalbumin in urine)
Relate hyperglycemia to polyuria and polydipsia
Hyperglycemia leads to glucosuria, which reduces H2O reabsorption (urine osmole is too high…), increasing osmotic diuresis and urine output, which may lower effective circulating volume. At the same time, hyperglycemia increases hyperosmolality of blood, triggering osmoceptors and activating thirst.
Describe the progression of the diabetic kidney
The assault of glucose, albumin, shear stress, and RAAS on the glomerulus leads to basement membrane thickening, hypertrophy, glomerulosclreosis, and podocyte injury/lose, which takes away single nephron gfr. GFR starts to take an L as this occurs to more and more nephrons. at first, you may not notice the difference in kidney lab values.
Describe the kidney in advanced diabetic kidney disease.
Glucoseuria and albuminuria in the forming urine leads to activation of cytokines and growth factors, which leads to tubulointerstitial fibrosis. this leads to suggested hypoperfusion of nephron. Of course, this then triggers RAAS, increasing glomerular pressure and causing more glomerulosclerosis. End result is proteinuria. And since RAAS is being summoned, the heart is taking a beating too. You can check failing kidney by periodically looking at increasing creatinine value. The point of renal failure is a GFR of 15.
Give overview of regulation of Ca and PO4
Parathyroid glands (4 of them) secrete PTH only when Ca is less than 9 (hypocalcemia). PTH talks to bone, which then resorpts (gives up/spits out) Ca and PO4. Remember, bone = Ca warehouse.
What Re the fucntion so PTH?
- PTH causes resorption of Ca and PO4 from bones.
- PTH causes Ca reabsorption and PO4 excretion from the kidneys.
- Causes kidneys to makes 1,25-OH Vitamin D aka calcitriol.
Describe PTH regulation
When PTH is secreted and acted on bone, the bone resorpts Ca and PO4. However, the presence of Calcitriol also triggers bone, in addition to cutting off PTH. Remember, PTH increases calcitriol production in kidneys, and calcitriol stimulate small intestine to absorb dietary Ca and PO4.
How does one make vitamin D?
IN THE PROXIMAL TUBULE: PTH calls upon 1alpha-hydroxylase aka CYP27B1. CYP27B1 is killed off by Ca, hyperphosphatemia, and calcitriol. CYP27B1 is linked with 25-OH Vit D (inactive precurser) to make 25-(OH)2 aka calcitriole (active version)
What are the relative reabsorption sites of Ca and PO4 in the nephron?
Largest resorption site is the proximal tubule. Note that the filtered load is low for both by the time they reach medullary collecting duct
Describe differnce in causes of PO4 vs Ca reabsorption
PO4 reabsorption is hormone dependent
Ca reabsorption is gradient dependent.
WHat allows Ca to be reabsorbed in thin ascending loop? In distal convoluted tubule?
IN the thin ascending look, its the NKCC channel. IN the distal convoluted tubule its the NCC channel.
How does PTH affect PO4 and Ca reabsorption? Where does Vitamine D come in?
PTH kills reabsorption of PO4 and promotes Ca reabsorption. Calcitriol works with PTH to help absorb Ca.
Where do loop diuretics work? Thiazides? Amiloride?
Loop diuretics work on NKCC channels.
Thiazides work in distal convoluted tubuel, preserve Ca’s ability to be reabsorbes. Actually helps with Ca reabsorption.
Amiloride: Blocks Na reabsorption and enhances Ca reabsorption. Both done in collecting tubule
In terms of the effects of PTH and Vitamin D on PO4, which is stronger?
The effect of PTH on promoting urinary PO4 excretion if WAY more powerful than the effect of calcitriol on stimulating PO4.
Describe the pathway of the downfall of the kidneys in chronic kidney disease (Secondary Hyperparathydroism).
In chronic kidney disease, Vitamin D production adn Ca reabsorption is utterly wwrecked. AS a result, you have hypocalcemia sine a lot of Ca is being dumpied in urine instead of being rebsorbed. Sick kidneys can’t respond to PTH, even though concetrations of Ca are below 9. As a result, parathyroid keeps secreting PTH. Even thought the kidneys cannot respond, the bones can. PTH still causes bones to resopt PO4 and Ca. The result of this is hyperphosphatemia. Note that the increase in PO4 concentrations will yet again cause PTH to to be secreted since the job of PTH is to cause PO4 to be excreted and reabsorb Ca. As this cycle continues, bone is continuously being decriminalized, leading to osteoporosis. All the excess Ca is literally just being excreted or accumulating i joints and valves of the heart. Excreted Ca leads to hypocalcemia since Vitamin D is not being produced and nothing is happening to help reabsorb Ca from urine since the kidneys are wrecked.
Describe the pathway of hypoparathyroidism (due to loss of PTH or PTH resistence)
There would be no more PTH, so you could not make Vitamin D in the proximal tubule, and you could not absorb Ca in the small intesting. Vitamin d lacking would also prevent you dfrom absorbing Ca from bones. Patient would present with hypocalcemia since you could not mobilize Ca. Hyperphosphatemia results since you would not be able to get rid of PO4. Hypocalciuria would result because the lack of Ca mobilization would mean that less Ca is inherently in the blood than normal. This lowers the Ca filtered load, and the fractional excretion of Ca in the patient would also be lowered. You would also have heart arrhythmias if severe enough. They would likely present with cramps and gi problems since the smooth muscle, along with all the other muscle in the body, would be dysfunctional. Treat patient by prescribing PTH.
What are examples of ketone bodies?
Ketoacids (beta-hydroxybutyrate, Acetoacetate) and
Acetone
What converts 25-Oh Vitamin D to Calcitriol?
1alpha-hydroxylase (CYP27B1)
