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Kidney functions. Primary: water regulation and electrolyte balance--homeostasisThe renal system functions to maintain the intravascular volume (of body fluids)Other: Endocrine: renin, erythropoieten, calcitriolLiver-like fxns: glucose synthesis. Basic Concepts. Excretion = Filtration - Reabsorption SecretionFiltration: Bowman's capsuleReabsorption: Peritubular capillariesSecretion: Peritubular capillaries.
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1. Renal Review Ana Ivkovic and Rahul Dave
2. Kidney functions Primary: water regulation and electrolyte balance--homeostasis
The renal system functions to maintain the intravascular volume (of body fluids)
Other:
Endocrine: renin, erythropoieten, calcitriol
Liver-like fxns: glucose synthesis
3. Basic Concepts Excretion = Filtration - Reabsorption + Secretion
Filtration: Bowmans capsule
Reabsorption: Peritubular capillaries
Secretion: Peritubular capillaries
4. Measuring Fluid Compartments NoteNote
5. Osmolarity and Oncotic Pressure Normal plasma osmolarity = 285-290 mOsm/L
Tightly controlled
Osmolarity vs. Osmolality
Osmolarity = mmol solute/L solution
Osmolality = mmol solute/kg h2O
Reflection coefficient:
0 = ineffective osmolyte (urea, ethanol--freely permeable)
1 = effective osmolyte (Na, K, glucose w/o insulin; draw water)
Oncotic Pressure: the fraction of plasma osmolarity that is due to plasma proteins
6. Tonicity vs. Osmolarity Osmolarity
Describes the osmotic properties of a solution
Tonicity
Refers to the osmotic effect on the volume of a cell
Ex: hypotonic soln--water moves in, cell swell
Isosmotic solns not necessarily isotonic (has to do w/ concept of reflection coefficient--ex of urea solution and RBC)
7. Darrow-Yanet Diagrams--Think Logically! All volume disturbances originate in the ECF compartment
Changes in the ICF compartment are in response to changes in the ECF
hyposmotic contraction refers to the volume of fluid that remains
8. Volume contractions Diarrhea, vomiting, loss of blood--isosmotic volume contraction
Diaphoresis (sweating), dehydration--hyperosmotic contraction
Remember that sweat is hyposmotic
Addisons disease (lack of aldosterone)--hyposmotic volume contraction
9. Volume expansions (rarer) Isotonic volume expansion (isotonic saline IV): ECF expands, ICF doesnt change
Hypertonic volume expansion: ECF osmolarity increases, draws fluid from ICF
Hypotonic volume expansion: ECF osmolarity decreases, adds fluid to ICF (examples: psychogenic polydipsia, SIADH)
10. Renal vascularization Renal artery --> interlobar artery --> arcuate artery --> interlobular artery--> afferent arteriole* --> glomerular capillaries--> efferent arteriole* --> peritubular capillaries
*serial arrangement of arterioles--important!
11. Juxtamedullary vs. Superficial Nephron JMN has long Loop of Henle
Generates a concentrated urine
JMNs are what we lose with age
12. Renal Clearance and Blood Flow C.O. = 5.2 L/min
RBF = 1.2 L/min (20% of cardiac output)
RPF = .66 L/min (plasma = 55% of blood); also equal to the clearance of PAH (filtered and secreted)
GFR = Clearance of inulin or creatinine
Inulin is filtered but not secreted or reabsorbed
Creatinine clearance a slight overestimate of GFR because it is partly secreted (GFR = 0.9 X Ccreatinine)
Filtration Fraction = GFR/RPF, normally 20%
13. PAH Used to measure RPF
Effective RPF = ([U]PAH x V) / [P]PAH = CPAH
14. Clearance Ratio CR = Cx/Cin
If CR = 1, substance x is only being filtered
If CR < 1, substance x is being reabsorbed
If CR > 1, substance x is being secreted
15. GFR: Is dependent on hydrostatic pressure inside glomerular capillaries
Depends on the oncotic pressure inside glomerular capillaries
Is equal to the clearance of inulin
Under normal conditions, is rarely dependent on the oncotic pressure inside Bowmans space
Creatinine is used to calculate it
Three of the above
All of the above
16. Starlings Forces of capillary exchange GFR = Kf (PGC - PBS - ?GC)
Hypoalbuminemia increases GFR
PBS: low unless obstruction present (kidney stones increase GFR)
Basement membrane has fixed negative charge--> neg. charged prots cant get across --> oncotic pressure in Bowmans space = 0
17. Contd Hydrostatic Pressure is high and relatively constant (due to serial arterioles)
Oncotic Pressure increases along length of glomerular capillary (as more fluid is filtered out)
Filtration occurs upstream while reabsorption occurs downstream
Q: why does a low GFR result in increased reabsorption?
A: more time to filter --> oncotic pressure increases
20. Autoregulation Myogenic Mechanism (Bayless): intrinsic reflex mechanism of smooth muscle; increased pressure causes vasoconstriction
Tubuloglomerular feedback: macula densa senses increased filtered load of NaCl--> sends signals to afferent arteriole to vasoconstrict, thereby decreasing the filtered load (by decreasing GFR back to normal)
Both processes serve to keep RBF and GFR constant
21. Sympathetic Innervation There is no parasympathetic input to the kidneys
Sympathetic innervation of the afferent and efferent arterioles is the major regulator of RBF and GFR
Vasoactive compounds also act on afferent and efferent arterioles: NE, Angiotensin II, Endothelin--> constrict; Ach, NO, PGs, etc --> dilate
Low vs. severe sympathetic drive--examples of exercise and hemorrhage
22. Urine formation Ultrafiltration of plasma
Reabsorption of H2O and solutes from tubular fluid
Active and passive processes
Transcellular and paracellular (lateral space) transport; latter occurs in proximal tubule due to leaky tight junctions--> ions pass, followed by H2O
In collecting duct tight jxns are very tight and do not allow passage of water, proteins, or solutes
23. Solute Regulation in Nephron Segments
24. Reabsorption and Secretion along Proximal Tubule Isosmotic fluid reabsorption
Reabsorbs 2/3 of filtered load of Na and water (Aquaporin 1)
Highly permeable to H2O; solvent drag of K and Ca
Understand TF/P graph
25. Upper Segment of PT Na cotransported along with bicarb, glc, amino acids, phosphate (luminal membrane)
H+ secreted as counter-transport with Na (luminal membrane)
Sodium bicarbonate is reabsorbed (basolateral membrane)
Under normal conditions, reabsorption will increase as plasma [gluc] increases
Once plasma [gluc] reaches a certain level, all glucose carriers in the PT will be saturated, leaving some glucose behind
Tm of SGLT-2 (sodium coupled) is 200g/dl, which is exceeded in diabetics; osmotic diuresis results
26. Lower Segment of PT NaCl reabsorbed transcellularly (1/3) and paracellularly (2/3); due to transepithelial voltage
Amino Acids and Bicarbonate have been completely reabsorbed
Glucose SGLT-1 (2 Sodium coupled) transporters move glucose against higher gradient
27. Thick Ascending Limb Reabsorbs 1/4 of filtered Na
Has the Na-K-2Cl cotransporter
Inhibited by Furosemide (loop diuretic)
Impermeable to water; tubular osmolarity decreases (diluting segment)--> separation of movement of water and solute
Lumen becomes positively charged, causing paracellular transport of Na, K, Ca, and Mg
28. Early Distal Tubule/Collecting Duct Also impermeable to water (like TAL)
Continues the dilution of urine; the cortical diluting segment
Reabsorption of Na/Cl (cotransporter)
Inhibited by Thiazide diuretics
Thiazide diuretics unique in that they increase Ca++ reabsorption (Loop diuretics increase Ca++ excretion by diminishing NaK2Cl + lumen effect)
29. Late Distal Tubule/Collecting Duct: fine tuning Principal cells--reabsorb Na, H2O, and secrete K+
Impermeable to water, except in presence of ADH (Vasopressin)
ADH causes water channels to relocate to apical cell membrane (AQUAPORIN 2)
Na (transcellularly) and Cl (paracellularly) are reabsorbed
Aldosterone causes an increase in Na absorption and increases K secretion
Spironolactone (K-sparing) blocks aldosterone; other K-sparing diuretics (Triamterene, Amiloride) act directly on the Na channel, independent of aldosterone
Intercalated cells--secrete H+ through primary active transport
exchange H+ out of cell for K+ into cell; K+ reabsorption
possess carbonic anhydrase activity for bicarb reabsorption
30. Miscellaneous Renal Stuff Na+, Ca++ are never secreted; rather, fail to reabsorb
Prostaglandins released during hypovolemic shock to increase RPF and prevent renal ischemia
Aldosterone: promotes Na reabsorption and K secretion (via action on principal cells); also promotes H+ secretion (via action on intercalated cells)-->a link between volume and acid-base regulation
Posm = 2[Na] + 2[Glucose] + [BUN]
ADH: OSMOREGULATION
ALDOSTERONE: Na+/VOLUME REGULATION
31. Genetic Defects that Target Tenal Transport Mechanisms Bartters Syndrome: defect in NaK2Cl transporter
Gettelmans Syndrome: defect in Na/Cl cotransporter
Liddels: defect in ENaC (turned on)
Pseudohypoaldosteronism: defect in ENaC (turned off--> Na doesnt get reabsorbed--> volume contraction
32. Graphs to be familiar with:
34. Urine flow rate is never zero
There is an inverse relationship between urine flow and osmolarity
Normal urine osmolarity 600 mOsm/L
Range = 50 - 1200!! (kidneys can concentrate urine up to 4x the plasma concentration)
35. Control Mechanisms of Osmoregulation Osmoreceptors
Increase in plasma osm--> hypothalamus stimulated to release ADH (hypothalamic set point 285 mOsm/L solution)
Respond to < 2% change in plasma osmolarity
Most important control in osmoregulation
Baroreceptors
Respond to changes in Blood Pressure
Require a 15-20% change in BP before activation
36. Disorders of Osmoregulation Psychogenic Polydipsia, Hypothalamic/Central Diabetes Insipidus: low ADH
Nephrogenic Diabetes Insipidus: ineffective ADH (kidney unable to respond to ADH)
37. Mechanisms to Concentrate Urine
Countercurrent Multiplication--creation of osmotic gradient
Loop of Henle
Generates a urine that is concentrated as high as 600 mosm/L
Urea recycling
Medullary Collecting Duct
Needed to increase the osmolar gradient from 600 to 1200 mosm/L
Kidneys use urea to do osmotic work when in state of antidiuresis
Countercurrent exchange--vasa recta maintains the medullary insterstitial osmotic gradient set up by the countercurrent multiplier
38. Diuresis vs Antidiuresis Understand the diagrams on p. 9
Water diuresis: most concentrated urine just before ascending limb and TAL; most dilute at end of CD
Antidiuresis: most concentrated in lumen at level of renal papillae (in medulla); most dilute at TAL
40. Renin, Angiotensin, Aldosterone Renin secretion stimulated by:
Decrease in effective circulating volume (decreased pressure at afferent arteriole)
Increase in sympathetic nerve activity
Tubuloglomerular feedback (decreased Na load sensed by macula densa, causing renin release)
Angiotensin II:
Arteriolar constriction--> increases TPR
Increases Aldosterone
Increases ADH and thirst
Aldosterone causes:
Na reabsorption at principal cells
K secretion in CD
41. Aldosterone secretion: Increased by ACTH, Angiotensin II, high plasma [K+], cases of volume contraction
Decreased by *ANP* and high plasma Na+ (feedback inhibition)
ANP: OPPOSES RAAS; increases Na+ excretion during cases of volume expansion (cardiac myocytes are stretched)
42. Aldosterone escape A protective mechanism during cases of abnormal aldosterone elevation (example of adrenal tumor); system becomes insensitive to aldosterone.
43. Renal Physiology Lectures 41 to 48
Rahul Dave (rdave2@uic.edu)
44. I cant go through everything in detail.
Know the handout.
My goal is to make this make sense to you, and orient your studying.
Pay attention to major vs minor factors.
Minor doesnt mean less important to study, but helps you keep changes in perspective
You need to memorize the regulation, etc and understand the logic. Its easy to talk yourself into something wrong.
45. Potassium Balance
46. K+ distribution and homeostasis Plasma K is low must be controlled well
Determines membrane potential
Metabolic alkalosis causes hypokalemia (and vice-versa)
Rules of thumb: understand mechanisms
Na and K go opposite
47. K+ Transport
See diagrams in handout for cellular transport pathways in different sections
48. MAJOR FACTORS
K+ itself (K promotes its own secretion)
Aldosterone (Na+ excr., K+ reabs., H+ excr.)
MINOR FACTORS
Tubular flow increases secretion
ADH no net effect
Alkalosis (acute) increases secretion
Tubular Na+ increases secretion
Insulin Increase reabsorption
Epinephrine Decreases secretion (fight/flight)
49.
See diagrams of cell transport pathways Diuretics
50. Control of Circulating Volume
51. Small fraction of TBW cant detect it directly. Also, since detection and changes are indirect, the changes must occur slowly
Measured by BP (myogenic feedback) or [Na+] (tubuloglomerular)
Controlled by changing Na+
52. Baroreceptors detect pressure
Central (Left atrium; carotid sinus)
ADH ? Na reabs; collecting duct permeability
Intrarenal volume sensors
Pressure: myogenic feedback
Na (also K & Cl, maybe): tubuloglomerular
Low ECF volume makes you thirsty
Sympathetic overdrive (fight/flight) conserve water & ? peripheral blood flow
Volume Sensors & Effectors
53. Mechanisms Controlling ECF
54. Calcium andPhosphate Balance
55. Hitchhiking only takes you so far. But try to understand why & how these are true.
In the PCT & TAL: Ca2+ follows Na+ paracellularly
In the DCT & CD: Ca2+ is regulated by PTH
56. Try to understand why & how these are true.
In the nephron it undergoes paracellular transport
Controlled by PTH in the proximal tubule
57. Phosphate Trashing Hormone in urine
Absorb (P) from gut & bone to incr. plasma (P)
Excrete it in the urine
But Ca2+ and PO4 cant be together
So if (P) is low, Ca2+ is high, and vice-versa
PTH, not calcitonin, is a major controller of Ca2+. PTH
58. This is a stupid detail, but winds up being tested sometimes (No promises about Hudson)
Vit D is synthesized in liver & Kidney
D ? (liver)? 1-OH-D ? (kidney) ? 1,25-OH-D
You need Vitamin D to absorb Ca2+
Think: Vit-D fortified milk Vitamin D Synthesis
59. Acid-Base: Basics
60. Buffers
Blood seconds
Intracellular minutes
Lung hours
compensated state
Kidneys days
Net acid excretion counts NH4, Titratable Acid, HCO3-
Titratable (weak) acids include lactic acid, ketone bodies, etc.
Strong acids are secreted as their Na salts (eg, Na2SO4) Removing Acid or Base
61.
[HCO3-] = 24
pH = 6.1 + log = 7.4
0.03 x P-CO2 = 40
Know this and make sure you can calculate it! Buffering Mechanisms
62. CO2 is an acid and gets blown out by respiration.
So when you sprint, you develop lactic acidosis. This is metabolic acidosis. To get rid of the acid, you hyperventilate and breathe faster. Lung Mechanisms
63. Mainly by HCO3-
H2O + CO2 ?CA? H2CO3 ? HCO3- + H+ Kidney Mechanisms
64. Locations: look at cell diagrams
Regulation
Proximal tubule: follows Na+ (understand why)
Na/H antiport. Whenever one H+ exits, a tubular HCO3- is used up to neutralize it. Also, to regenerate that H+, a HCO3 is made, which is transported to the blood.
Systemic Acidosis (in PCT, Henle, CD)
65. H+ is usually tied to other ions
In the intercalated cell of collecting duct, there is a ATP-dependent H+ pump that secretes H+
Upregulated by aldosterone Kidney: H+
66. The mechanisms are complicated
Know that H+ acidifies & traps NH3 in the lumen (as NH4+)
K+ also regulates NH4+ production dont worry
(The mechanisms are important if you want to do really well) Nitrogen Removal (NH3 or NH4+)
67.
Clinical Evaluation of
Acid-Base Disorders
the simple way
68. Remember compensation is never 100%
pH < 7.4 . Acidosis
pH > 7.4 . Alkalosis
pH = 7.4 .. Youre fine (or mixed)
69. If its acidosis (or alkalosis) look for the source of acid (or base)
HCO3 < 24 CO2 > 40
HCO3 > 24 CO2 < 40
metabolic respiratory
70. Check with the formulas
Fig 43.23 in Berne & Levy
Im not sure whether he gave you these formulas. If he didnt dont worry.
Check the nomogram
It will tell you acute vs chronic.
71. Note that HCO3- and CO2 move in opposite directions
If they move in the same direction you have a mixed disorder.
72. Metabolic Acidosis: Diabetic ketoacidosis, diarrhea
Metabolic Alkalosis: antacid, vomiting (will loose Cl too)
Respiratory Acidosis: Hypoventiliation, pulmonary edema
Respiratory Alkalosis: Hyperventilation
73.
You can find these in Costanzo, Hudsons H/O or Berne & Levy.
Best study tool: Draw these out yourself. Know them cold.