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Phase 1 SUGER > Renal Physiology > Flashcards

Renal Physiology Flashcards

1
Q

What can pass through fenestrated capillaries?

A

Anything less than 100nm in diameter:
Electrolytes,
Small proteins
Water
Nutrients
Waste products etc

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2
Q

What is the filtration barrier composed of?

A
  • Podocytes
  • Glomerular basement membrane
  • fenestrated capillary endothelium
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3
Q

What is the glomerluar basement membrane made up of?

A

Three layers:

  1. Lamina rare interna - Heparin sulfate (HS)
  2. Lamina dense - type 4 collagen and laminin
  3. Lamina rara externa - HS

HS - extremely negatively charged - restricts movement of negatively charged molecules

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4
Q

What is the fenestrated capillary endothelium made of?

A

Perforations called fenestrae (70nm pores) prevent filtration of blood cells

Not: water, proteins or large molecules

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5
Q

How do podocytes act as a filter?

A

Foot-processes project and form Filtration slits (25-30nm) - space between podocytes - nephrin interconnects podocytes - creates slit diaphragm (7-9nm)

Molecule must be less than 7-9nm to pass through podocytes

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6
Q

What can pass through the filtration barrier?

A

Less than 25-30nm
Less than 7-9nm
Positively charge molecules can pass through
e.g.electrolytes, nutrients, water, creatinine, amino acids, lipids, glucose etc

Some -ves?

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7
Q

What do mesangial cells do?

A
  1. Phagocytes molecules stuck in slit diagram
  2. Can contract and control blood flow into afferent arteriole and glomerular capillaries
  3. Has gap junctions that connect to juxtaglomerular cells from macular densa cells which allow passage of diff types of positive ions to stimulate and release renin.
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8
Q

Define Glomerular filtration rate

A

Volume of plasma filtered from glomerulus for every minute

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9
Q

How do you calculate the average GFR?

A

125ml/min:

1200ml/min plasma start
625ml/min - used
575ml/min leaves

Of 625 ml used only 20% is filtered = 125ml/min

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10
Q

What is the average measurements of GHP, COP and CHP that is exerted and what are they each trying to do?

A

GHP = Glomerular hydrostatic pressure = 55mmHg
Pushes things out of capillaries into bowman’s space

COP = colloid osmotic pressure = 30mmHg
Exerted by plasma proteins like albumin - trying to keep water in blood stream

CHP = capsular hydrostatic pressure = 15mm Hg
Exerted by pressure built up in bowman’s capsule
Trying to push things back into the glomerular capillaries

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11
Q

What is the relationship between Net filtration pressure (NFP) and Glomerular filtration rate (GFR)?

A

NFP = 10mmHg
Directly propotional so Changes in pressure affect GFR
Increase in NFP = increase in GFR
Decrease in NFP = decrease in GFR

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12
Q

What components affect GFR?

A

Surface area and permeability of glomerulus
Smaller SA = lower GFR
Larger SA = greater GFR
Less permeability = less GFR
Higher permeability = greater GFR

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13
Q

What components make up KF?

A

SA + permeability = KF = filtration coefficient

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14
Q

How do you calculate GFR?

A

GFR = NFP X KF

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15
Q

What affects Glomerular hydrostatic pressure?

A

Blood pressure
Increased BP = increased GHP
Decreased BP = Decreased GHP

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16
Q

What affects Colloid Osmotic Pressure ?

A

Increased proteins e.g. multiple myeloma
Increased COP

Decreased proteins (hypoproteinemia)
Decreased COP
Lose fluids into bowman’s space

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17
Q

What affects Capsular hydrostatic pressure?

A

Renal calculus e.g. Kidney stone stuck in nephron loop
Pressure backs up
Increased CHP
Hydronephrosis (due to Renal ptosis)
Increased CHP

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18
Q

Define Osmolality

A

Volume of particles per kg of solvent (?)
= moles of solute /kg of solvent

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19
Q

What is the average osmolality?

A

300 million osmoles/L

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20
Q

What is tubular secretion?

A

Substances moved from blood into kidney tubules

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21
Q

What is tubular reabsorption?

A

Substances moved from kidney tubules into blood - can be active or passive

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22
Q

How does Na+/K+ ATPase work?

A

3 Na out of cell
2 K in cell
Against conc. grad
Using ATP
= Active transport
At the basolateral membrane where?
Why?

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23
Q

What percentage of products does the proximal tubes reabsorb?

A

65% water, sodium, potassium and chloride
100% of glucose and amino acids
85-90% of bicarbonate

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24
Q

What is a symporter?

A

transporters that move two (or more) molecules in the same direction e.g. SGLTs

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25
Q

What is a antiporte?

A

transporters that move two (or more) molecules in opposite directions e.g. Na+/H+ antiporte

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26
Q

Define co-transport?

A

Movement of multiple solutes through the same channel

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27
Q

What does the Na/K/ATPase pumps do?

A

Create an electrochemical gradient for sodium on the base lateral surface using primary active transport to favour movement of Na into the cell form the tubule lumen

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28
Q

What is the structure of the PCT like?

A

Made up of the:
1. Pars convolute - 2 segments: S1 and proximal S2
- in the renal cortex
2. Pars recte - straight segment: distal S2 and S3
- in the outer medulla

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29
Q

What are the two routes of reabsorption in the PCT?

A

Paracellular - transports solutes through the cell
Transcellular - transports solutes between the cells through intercellular space

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30
Q

What is the driving force for reabsorption?

A

Sodium

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31
Q

How does SGLTs work?

A

Sodium glucose linked transporter
Secondary AT
Apical membrane - check?
Glucose, lactate and amino acids
100% reabsorbed into blood

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32
Q

What occurs to bicarbonate ions?

A
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33
Q

How is water reabsorbed?

A

As Na moves in cells, obligatory water reabsorption occurs - waters feels obliged to follow from kidney tubules into bloodstream via osmosis
65% each - Na and Water reabsorbed

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34
Q

What is at the hilum of every glomerulus?

A

Juxtaglomerular cells + macula densa

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35
Q

What is the benefit of a modified muscular layer of the afferent arteriole?

A

Modified muscular layer of the afferent arteriole
•Increased number of smooth muscle cells
•Less actin/myosin but many granules (renin)

Low BP → less distended walls → renin release

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36
Q

What are the values of blood supply?

A

Cardiac output ~ 5 L/min
Renal blood flow ~ 1 L/min

Urine flow ~ 1 ml/min

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37
Q

Wat is the path of kidney blood supply?

A

AA
↓
Renal artery
↓
Interlobar artery
↓
Arcuate artery
↓
Interlobular artery
↓
Afferent arteriole
↓
Glomerular Capillary -> IVC -> Renal vein -> Interlobar veins -> Arcuate veins -> Interlobular veins -> Vasa recta -> Peritubular capillaries -> Efferent arteriole

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38
Q

What is teh distal part of the nephron responsible for?

A

Distal part of the nephron (tubule) responsible for secretion and reabsorption

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39
Q

What factors determine filtration?

A

Factors determining filtration:
A.Pressure
B.Size of the molecule
C.Charge
D.Rate of blood flow
E.Protein binding

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40
Q

What pressure favors filtration?

A

Glomerular capillary blood pressure (PG)

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41
Q

What pressures oppose filtration?

A

Fluid pressure in Bowman’s space (PBS)
Osmotic forces due to protein (πG)

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42
Q

How does size affect filtration?

A

Small molecules and ions up to 10kDa can pass freely
e.g. glucose, uric acid, potassium, creatinine
Larger molecules increasingly restricted
e.g. plasma proteins

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43
Q

How does charge affect filtration?

A

Fixed negative charge in GBM (glycoproteins and proteoglycans) repels negatively charged anions
e.g. albumin, phosphate, sulfate, organic anions

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44
Q

How does protein binding affect filtration?

A

E. Protein binding

Albumin has a molecular weight of around 66kDa but is negatively charged ∴ cannot easily pass into the tubule

Filtered fluid is essentially protein-free

Tamm Horsfall protein in urine produced by tubule

Affects substances that bind to proteins e.g. drugs, calcium, thyroxine etc

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45
Q

What is GFR?

A

filtration volume per unit time (minutes)

GFR = KF (PG - PBS) - (πG)

KF is the filtration coefficient

Net filtration is normally always positive

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46
Q

What is GFR determined by?

A

GFR determined by
1.Net filtration pressure
2.Permeability of the filtration barrier
3.Surface area available for filtration (approx. 1.2-1.5m2 total)

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47
Q

Is GFR measured directly?

A

Calculated by measuring excretion of marker (M)
CM = UMV/PM

V = urine flow rate (ml/min)
UM = urine concentration of marker
PM = plasma concentration of marker

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48
Q

What are the properties of a good marker?

A

Properties of a good marker:
-freely filtered
-not secreted or absorbed
-not metabolised

∴ All the M that is filtered will end up in the urine, no more (as it is not secreted) and no less (as it is not reabsorbed)

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49
Q

What is teh normal value of GFR?

A

Normal GFR = 125ml/min

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50
Q

What marker is commonly used for GFR?

A

Creatinine usually used
-muscle metabolite
-constant production

Properties of a good marker:
-freely filtered ✓
-not secreted or absorbed ✗ (tubular secretion)
-not metabolised ✓

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51
Q

What thing affect creatinine?

A
  • medications
  • creatinine supplements
  • dietary protein intake
  • age, gender, ethnicity, height and weight
  • renal tubular handling
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52
Q

What other markers can be used?

A

Endogenous:

Cystatin C
Non-glycosylated protein produced by all cells

Properties of a good marker:
-freely filtered
-not secreted or absorbed
-not metabolised

Influenced by thyroid disease, corticosteroids, age, sex and adipose tissue

Others - Exogenous:

Inulin (gold standard)
Properties of a good marker:
-freely filtered
-not secreted or absorbed
-not metabolised

51Cr EDTA, 99mTc-DTPA , Radioisotopes, Iohexol

Inulin (gold standard)
Properties of a good marker:
-freely filtered ✓
-not secreted or absorbed ✓
-not metabolised ✓

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53
Q

What is the optimum range of renal blood flow and GFR?

A

Aim to maintain renal blood flow and GFR over defined range 80-180 mmHg

Protects against extremes of pressure

Independent of renal perfusion

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54
Q

What regulates GFR?

A
  1. Renal auto regulation
  2. Neural regulation
  3. Hormonal regulation
  4. Intrarenal regulation
  5. Extracellular fluid volume
  6. Blood colloid osmotic pressure
  7. Inflammatory mediators
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55
Q

What occurs in renal auto regulation?

A

Myogenic mechanism:
•Intrinsic ability of renal arterioles
•Able to constrict or dilate

Tubuloglomerular feedback:
•Juxtaglomerular apparatus
•Stimulus NaCl concentration
•Influences AFFERENT arteriolar resistance

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56
Q

Describe the myogenic mechanism of renal auto regulation

A

BP → stretches blood vessel wall → opens stretch-activated cation channels → membrane depolarisation → opens voltage-dependent calcium channels → ↑ intracellular calcium → smooth muscle contraction → ↑ vascular resistance → minimises changes in GFR

↓BP causes the opposite

ONLY PRE-GLOMERULAR RESISTANCE VESSELS

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57
Q

Describe tubuloglomerular feedback in renal auto regulation

A
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58
Q

What occurs in neural regulation?

A

Sympathetic nervous system:
•Vasoconstriction of AFFERENT arterioles
•Important in response to stress, bleeding or low BP

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59
Q

What occurs in hormonal regulation?

A

Renin-Angiotensin-Aldosterone System (RAAS):
•Renin released from JGA
•Initiates cascade
•Aldosterone influences Na reabsorption at distal tubule which influences blood volume and pressure

Atrial Natriuretic Peptide (ANP):
•Released by atria
•Stimulus of blood volume
•Vasodilation of AFFERENT arterioles

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60
Q

What occurs in RAAS?

A
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61
Q

What occurs in intrarenal baroreceptors?

A

•Respond to changes in pressure in glomerulus
•Influence diameter of AFFERENT arterioles

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62
Q

How does extracellular fluid volume regulate GFR?

A

•Changes in blood volume
•Resultant hydrostatic pressure

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63
Q

How do blood colloid osmotic pressure and inflammatory mediators regulate GFR?

A

•Oncotic pressure exerted by proteins

•Local release of prostaglandins, nitric oxide, bradykinin, leukotrienes, histamine, cytokines, thromboxanes

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64
Q

What is the effect of norepinephrine, epinephrine, endothelin, angiotensin, endothelial-derived nitric oxide and prostaglandins on GFR?

A

N - decrease
Epinephrine - Decrease
Endothelin - decrease
Angiotensin 2 - same - prevents decrease
Endothelial derived nitric oxide - increase
Prostaglandins - increase

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65
Q

What causes vasodilation of afferent arterioles?

A

(Decreased resistance)

  • prostaglandins
  • nitric oxide
  • high blood pressure

Results in:
- increased RBF
- increased Pg
- Increased GFR

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66
Q

What causes vasoconstriction of afferent arteriole?

A

(Increased resistance)
- sympathetic NS
- angiotensin 2

Results in:
- decreased RBF
- decreased Pg
- decreased GFR

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67
Q

What causes vasodilation of afferent arteriole?

A

(Decreased resistance)

  • prostgalndins
  • increased RBF?
  • High blood pressure

Results in:
- increased RBF
- increased Pg
- increased GFR

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68
Q

What causes vasoconstriction of efferent arteriole?

A

(Increased resistance)

  • sympathetic NS
  • angiotensin 2

Results in:
- decreased RBF
- decreased Pg
- Decreased GFR

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69
Q

What is the causes and presentation of glomerulonephritis?

A

Umbrella term
•Causes: infection (bacterial/viral), autoimmune disorders, systemic diseases
•Presentation: haematuria, proteinuria, hypertension, impaired kidney function

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70
Q

What is nephrotic syndrome?

A

Umbrella term
•Increased permeability of glomerular filtration barrier
•Presentation: triad of oedema + proteinuria + low albumin

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71
Q

What is IgA nephropathy?

A

Deposition of IgA antibody in the glomerulus
•Resultant inflammation and damage
•Cause: immune-mediated
•Presentation: haematuria, potentially following resp/GI infection

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72
Q

What is membranous nephropathy?

A

Thickening of GBM
•Most common cause of nephrotic syndrome in adults
•Cause: primary or secondary
•Presentation: proteinuria (often leading to nephrotic syndrome)

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73
Q

What is diabetic nephropathy?

A

Prolonged exposure to high blood glucose
•Presentation: initially asymptomatic then progresses to proteinuria, hypertension and reduced kidney function

74
Q

What is minimal change disease?

A

Type of nephrotic syndrome, only in children
•Only visible under electron microscope

75
Q

What is Alport syndrome?

A

Genetic disorder affecting GBM (X linked or autosomal recessive)
•Progressive kidney damage
•Potentially includes hearing loss and eye abnormalities

76
Q

How much of cardiac output does the kidney receive?

A

20-25% - 1200ml/min blood flow

77
Q

What can cross glomeruli structures?

A

Only plasma can cross glomeruli structures
600-700ml/min plasma flow (RPF) – organic and anorganic solutes freely filtered
GFR – 120 ml/min or 180 L/d
UO 1.5 L/d

78
Q

What occurs at the PCT?

A

Confined to renal cortex

Active reabsorption of multiple things –amino acids, glucose, bicarbonate, phosphate, salt and water, potassium, chloride, urate

Metabolically active cells

79
Q

What causes renal glycosuria at PCT?

A

PCT is the only site of glucose reabsorption
Glu is co-transported with Na via sodium glucose transporter 2 (SGLT2)
Defect → failure of glucose reabsorption

glucose in urine

SGLT2 inhibitors (gliflozins) are now establishes as treatement for type 2 diabetes

80
Q

What causes amino acid uria - cystinuria?

A

AR inherited disorder - tubular defect in uptake of amino acids
Defect: mutations in the SLC3A1 and SLC7A9 genes which encode basic amino acid transporter (rBAT)
Genetic test available, but not routinely used in clinical practice
Failure of cystine reabsorption, increased urinary cystine concentration – stone formation

Renal colic, recurrent stone formation usually in childhood or adolescence

81
Q

What is the treatment for cystinuria?

A

High fluid intake: High urine flow, lower concentration
Dietary restriction (reduced animal protein intake)
Alkalinise urine: Increases solubility of cystine
Chelation: Penicillamine, captopril
Management of individual stones (percutaneous treatment, surgery etc)

82
Q

What causes hypophosphataemic rickets?

A

Unable to reabsorb phosphate
Commonest form is X-linked hypophosphataemic rickets (XLH)
Defect in PHEX gene – zinc dependent metalloprotease
PHEX mutation results in increased FGF-23 levels, (overactivity of the protein), reduces phosphate reabsorption by the kidneys, leading to hypophosphatemia and the related features of hereditary hypophosphatemic rickets

83
Q

What are clinical features and treatment for Hyophophataemic rickets?

A

Bow legged deformity, muscle weakness, slow growth and are shorter than their peers.
They develop bone abnormalities that can interfere with movement and cause bone pain.

Phosphate replacement

84
Q

What are clinical features and treatment for Hyophophataemic rickets?

A

Bow legged deformity, muscle weakness, slow growth and are shorter than their peers.
They develop bone abnormalities that can interfere with movement and cause bone pain.

Phosphate replacement

85
Q

What causes proximal RTA type 2?

A

Defect: Na/H antiporter
Mechanism: Failure of bicarbonate reabsorption

Bicarbonate wasting, acidosis, impaired growth
Associated with myeloma, Fanconi syndrome, drugs or inherited

Alkali replacement

86
Q

How is bicarbonate reabsorbed in PCT?

A
87
Q

Role of SGLTs in pCT?

A
88
Q

What is Fanconi syndrome?

A

Mechanism: Generalised proximal tubular dysfunction, possibly due to failure to generate sodium gradient by Na/K ATPase
Causes: Genetic (eg cystinosis, Wilson’s disease), myeloma, lead poisoning, cisplatin
Commonly seen with T2 RTA

Glycosuria, aminoaciduria, phosphaturic rickets, renal tubular acidosis

89
Q

What occurs at the loop of henle?

A

Generates medullary concentration gradient via countercurrent system

Active Na reabsorption in thick ascending limb

Development of a hypertonic interstitum in the medullary regions of the kidney

Production of a dilute (hypo-osmotic) filtrate entering the distal tubule.

90
Q

What is the function of the thick ascending limb?

A
91
Q

What is barters syndrome?

A

Defect: NKCC2, ROMK, ClCKa/b, Barrtin

AR inherited disorder

Mechanism: Failure of sodium, potassium and chloride cotransport

Salt wasting, hypokalaemic alkalosis, volume depletion, failure of voltage dependent calcium & magnesium absorption

92
Q

What are the clinical features and treatment of barters syndrome?

A

Similar to effects of loop diuretics (eg furosemide, bumetanide)

Clinical features
Antenatal: Polyhydramnios, prematurity, delayed growth, nephrocalcinosis
Classical: Delayed growth, polyuria, polydipsia, cramps, lower BP

Treatment:
- Replace potassium, amiloride, ACEI

93
Q

What occurs at the DCT?

A

Distal tubule and cortical collecting ducts allow “fine tuning” of sodium reabsorption, potassium and acid-base balance

Impermeable to passive movement of water and sodium

Uses NCCT co transporter to reabsorb 5% of sodium

Specific epithelial channel absorbs calcium, paracellular route Ca and Mg

Hypokalemia due to increased delivery of sodium to collecting duct

94
Q

What is Gitelman’s syndrome?

A

Defect: NCCT (thiazide sensitive chloride channel)
Mechanism: Failure of sodium/chloride cotransport in distal tubule, hypokalaemic alkalosis due to volume contraction, impaired magnesium absorption, increased calcium reabsorption (unknown mechanism)

Similar to thiazide diuretics

Polyuria, polydipsia, tetany

95
Q

What is distal RTA type 1?

A

Defect: AD = SCL4A1 (Na channel), AR = H-ATPase
Mechanism: Failure of acid secretion

Hypercalciuria, nephrocalcinosis, stones
Associated with autoimmune diseases, drugs, medullary sponge kidney

Treat underlying cause, alkaline treatment

96
Q

What is Liddles syndrome?

A

Defect: Activating mutation of ENaC, AD
Mechanism: Sodium channel always open so constant aldosterone like effect
Increased Na absorption, loss of K, hypertensive

Amiloride (blocks ENaC)

97
Q

What is nephrogenic diabetes insipidus?

A

Defect: Vasopressin V2 receptor in principal cells or aquaporin 2 water channel
Mechanism: Failure of water reabsorption in the collecting duct, resulting in inability to concentrate urine

Clinical features
Polyuria, polydipsia, hypernatraemia

98
Q

What are the clinical correlations of nephrogenic diabetes insipidus?

A

Clinical correlations
Tolvaptan: V2 receptor antagonist
Induces polyuria and free water loss (“aquaresis”)
Licensed for hyponatraemia related to SIADH
Also reduces cyst formation/progression in adult polycystic kidney disease

99
Q

What are diuretics?

A
100
Q

What are the values of urine, PH, Na, K, glucose, amino acids and HCO3?

A

180L/days of filtrate

volume - 400ml-20L/24h
pH - 4.5-8
Na - 100-300mmol/24h
K - 50-450mmol/24h
glucose <1mmol/24h
amino acids v. little
HCO3 - 1mmol/24h

101
Q

What is the principle function of the PCT and DCT?

A

Proximal = bulk absorption = leaky

Distal = fine tuning = impermeable

102
Q

What are the functions of the pCT, LoH, DCT and CDS?

A

Proximal Tubule
bulk reabsorption: Na, Cl, glucose, amino acids, HCO3; secretion of organic ions
Loop of Henle
more Na reabsorption, urinary dilution and generation of medullary hypertonicity
Distal Tubule
fine regulation of Na, K, Ca, Pi, separation of Na from H2O
Collecting Duct
similar to distal tubule, + acid secretion, regulated H2O reabsorption concentrating urine

103
Q

What occurs in the pCT?

A

Bulk reabsorption

•Driven by the basolateral NaKATPase
•Secondary active transport for reuptake of glucose, amino acids, lactate
•Highly efficient; mostly achieved in first half
•Cl follows Na in the second half
•Big workload, determined by filtered load
•High H2O permeability

104
Q

What pathways are involved in the pCT?

A
105
Q

What occurs in AA reabsorption?

A

Similar to glucose
•Various cotransporters responsible for groups of amino acids (cationic, anionic, neutral,…)
•Aminoaciduria, glycosuria and bicarbonate wasting are features of proximal tubule pathology

106
Q

What pathway does aa reabsorption occur?

A

Transcellular and paracellular

107
Q

What are the organic cation/anion transporters?

A

Endogenous compounds
•Creatinine
•Urate
•Bile salts
•…

Drugs
•Furosemide
•Penicillin
•Salicylate
•Acetazolamide
•Trimethoprim*
•Cimetidine*

*Inhibit creatinine secretion

108
Q

What occurs ro maintain glomerulotubular balance?

A

•More filtered load is matched by more proximal tubular reabsorption:
1.Greater filtration fraction increases the osmotic pressure in the downstream peritubular capillaries; sucks more back
2.Efferent arteriolar constriction reduces peritubular capillary hydrostatic pressure

109
Q

What is the loop of henle like?

A

The descending limb is water permeable and the ascending limb is H2O impermeable

Solute reabsorption occurs in the thick ascending limb

110
Q

What is the aim of countercurrent multiplication?

A

Aim: to generate a hypertonic medullary interstitium so that H2O can be sucked out of the tubule in impermeable distal segments, thus concentrating the urine.

111
Q

How does countercurrent multiplication work?

A
  1. Solute reabsorption in the impermeable ascending limb lowers the lumenal osmolality and increases the medullary interstitial osmolarity
  2. Increased interstitial osmolarity draws H2O out of the permeable thin descending limb, increasing the lumenal osmolality.
  3. The continuous flow of fluid pushes the hyperosmotic fluid from end of the thin limb in to the ascending limb.

Process repeats

Generating a medullary interstitial osmotic gradient

112
Q

What else contributes to the medullary hypertonicity?

A

backleak of urea out of the medullary collecting
duct also contributes to medullary hypertonicity

113
Q

Why doesn’t blood flow wash out osmotic gradient?

A

Due to:

  • Vasa recta
    •Long capillaries extend into the medulla
    •Permeable to solute/water
114
Q

What occurs in the distal tubule?

A

Continues the active dilution of urine by reabsorption of Na+ in water-impermeable setting.
We want distal delivery of dilute urine which can be concentrated at will

115
Q

What occurs in the collecting duct?

A

highly water impermeable, surrounded by hypertonic medullary interstitium
•regulated Na reabsorption and K secretion
•acid secretion
•regulated water reabsorption
•2 cell types: principal cell and intercalated cell

116
Q

What is aldosterone action?

A

Increases transcription (steroid receptor) of ENaC (and NaKATPase)
•This increases apical Na influx
•This charge movement facilitates K efflux
•Thus aldosterone drives both Na reabsorption and K secretion

117
Q

How is water reabsorption regulated?

A

Hypotonic urine enters the collecting duct
•Main osmolyte is urea (most Na reabsorbed)
•The limits of urine osmolarity are determined by how dilute it can enter the distal segment and how hypertonic the medullary interstitium is (driving H2O reabsorption)

118
Q

What occurs in ADH - vasopressin action?

A

principal cells
•adenylyl-cyclase coupled vasopressin receptor (V2R)
•kinase actions culminate in insertion of vesicles containing aquaporin 2 into the apical membrane
•increases water permeability

119
Q

What is the action of carbonic anhydrase in the tubules?

A

Genetic defects in carbonic anhydrase produce a mixed proximal/distal renal tubular acidosis
●Inhibited by acetazolamide – mild diuretic effect and induces a metabolic acidosis
●Used to treat altitude sickness – allows more rapid compensation of respiratory alkalosis

120
Q

What are the actions of aldosterone?

A

Steroid hormone – predominantly acts on transcription
●Increase expression of ENaC, Na/K ATP-ase
●Mineralocorticoid receptor also activated by cortisol
●Cortisol entry to renal tubular cells prevented by 11-beta hydroxysteroid dehydrogenase

121
Q

What is glucocorticoid remediable aldosterone’s?

A

Defect: Chimeric gene – 11beta hydroxylase and aldosterone synthetase
●Mechanism: Aldosterone is produced in the adrenal in response to ACTH, so levels inappropriately high
●Treatment: Suppress ACTH using glucocorticoids

122
Q

What is the syndrome of apparent minerslcorticoid excess? AME

A

●Defect: 11-beta hydroxysteroid dehydrogenase
●Mechanism: Cortisol not broken down in the renal tubules, therefore activates mineralocorticoid receptor.
●Treatment: Spironolactone (mineralocorticoid receptor antagonist)

123
Q

What is hyperkalaemic distal renal tubular acidosis type 4?

A

●Defect: Low aldosterone levels
●Mechanism: Reduced generation of electrochemical gradient, resulting in failure of H+ and K+ excretion
●Common in elderly patients with diabetes
●Treatment: Diuretics or fludrocortisone

124
Q

How is pH calc?

A

Negative log [H+]

125
Q

What is acidosis?

A

Disorder tending to make blood more acid than normal

126
Q

What is alkalosis?

A

Disorder tending to make blood more alkaline than normal

127
Q

What is acidemia and alkalemia?

A

Acidemia = Low blood pH
•Alkalemia = High blood pH

128
Q

What is bicarbonate?

A

Measures of metabolic component of any acid-base disturbance
•Absolute bicarbonate is affected by both respiratory and metabolic components
•Standard bicarbonate is the bicarbonate concentration standardised to pCO2 5.3kPa and temp 37
•Bicarbonate and std bicarbonate are calculated not actually measured

129
Q

What is the base excess?

A

Quantity of acid required to return pH to normal under standard conditions
•Standard base excess corrected to Hb 50g/L
•Can be used to calculate bicarbonate dose to correct acidosis 0.3xWtxBE (but not generally used in practice)
•Base excess is negative in acidosis, can be referred to as base deficit

130
Q

What is measured in acid-base balance?

A

pH
•pO2
•pCO2
•Std HCO3-
•Std Base excess
•May include other measures (eg lactate, Na+, K+)

131
Q

What are the two acid-base theories?

A

•Henderson
•Stewart’s theory (strong ion difference)

132
Q

What are the Henderson-hasselbalch equation?

A

pH = pKa + log([A-]/[HA])
•pH = pKaH2CO3 + log([HCO3-]/[H2CO3])
•pH = 6.1 + log([HCO3-]/0.03 x pCO2)

133
Q

What is Stewart’s strong ion difference?

A

Principle: pH and HCO3- are dependent variables governed by:
•pCO2
•Concentration of weak acids (ATOT)
◦ATOT = Pi + Pr + Alb
•Strong ion difference (SID)
◦SID = Na+ + K+ + Mg2+ + Ca2+ – Cl- – other strong anions (eg lactate, ketoacids)

134
Q

What is useful about Stewart’s strong ion difference? Identifies the factors controlling pH

A

Identifies the factors controlling pH

135
Q

What can disorders be divided into?

A

Disorders can be divided into acidoses – disorders that tend to make the blood acid and alkaloses
•Disorders can be respiratory (ie driven by changes in CO2 excretion) or metabolic (ie driven by changes in acid load, acid excretion or bicarbonate recycling)
•Different disorders can co-exist (mixed patterns)

136
Q

What are the causes of metabolic acidosis?

A

Dilutional
•Failure of H+ excretion: Renal failure, hypoaldosteronism, type 1 renal tubular acidosis
•Excess H+ load: Lactic acidosis, Ketoacidosis, ingestion of acids (eg salicylate, ethylene glycol
•HCO3- loss: Diarrhoea, type 2 renal tubular acidosis

137
Q

What are the causes of metabolic acidosis?

A

Dilutional
•Failure of H+ excretion: Renal failure, hypoaldosteronism, type 1 renal tubular acidosis
•Excess H+ load: Lactic acidosis, Ketoacidosis, ingestion of acids (eg salicylate, ethylene glycol
•HCO3- loss: Diarrhoea, type 2 renal tubular acidosis

138
Q

What are the Clinical features of metabolic acidosis?

A

Clinical features: Sighing respirations (Kussmaul’s resps), tachypnoea
•Compensatory mechanism: Hyperventilation to increase CO2 excretion

139
Q

What are the clinical features of metabolic acidosis?

A

Clinical features: Sighing respirations (Kussmaul’s resps), tachypnoea
•Compensatory mechanism: Hyperventilation to increase CO2 excretion

140
Q

What are some investigations for metabolic acidosis?

A

Difference between measured anions and cations
•Anion gap = [Na+] + [K+] – [Cl-] – [HCO3-]
•Normal 10-16
•Wide anion gap: Lactic acidosis, ketoacidosis, ingestion of acid, renal failure
•Narrow anion gap (ie high chloride): GI HCO3- loss, renal tubular acidosis

141
Q

What are some investigations for metabolic acidosis?

A

Difference between measured anions and cations
•Anion gap = [Na+] + [K+] – [Cl-] – [HCO3-]
•Normal 10-16
•Wide anion gap: Lactic acidosis, ketoacidosis, ingestion of acid, renal failure
•Narrow anion gap (ie high chloride): GI HCO3- loss, renal tubular acidosis

142
Q

What are the causes of metabolic alkalosis?

A

Causes:
◦Alkali ingestion
◦Gastrointestinal acid loss: Vomiting
◦Renal acid loss: Hyperaldosteronism, hypokalaemia
•Compensatory mechanism: Hypoventilation (but limited by hypoxic drive), renal bicarbonate excretion

143
Q

What are the causes of respiratory acidosis?

A

CO2 retention, leading to increased carbonic acid dissociation
•Causes: Any cause of respiratory failure
•Compensatory mechanism: Increased renal H+ excretion and bicarbonate retention (but only if chronic)

144
Q

What are the causes of respiratory alkalosis?

A

CO2 depletion due to hyperventilation
•Causes: Type 1 respiratory failure, anxiety/panic
•Compensation: Increased renal bicarbonate loss (if chronic)

145
Q

What is regular pH?

A

7.35-45

146
Q

What occurs in acid-base homeostasis?

A
  • Normal diet generates non-volatile acid such as sulphuric and phosphoric acid from Protein metabolism, lactate from anaerobic metabolism of Glucose and volatile acid co2 primarily from carbohydrate metabolism.
    •Kidneys excrete the acid load and also reclaim filtered bicarbonate.
    •Lungs mediate excretion of co2.
147
Q

What is the role of kidneys in acid-base metabolism?

A
  • reclaim the filtered HCO3-
  • regenerate HCO3 -
  • excretion of H+ ions buffered by phosphate or ammonia
148
Q

What is the pH of urine?

A

4.5-8

149
Q

How is H ions excreted in kidneys and filtered bicarbonate reclaimed?

A
150
Q

What is metabolic acidosis defined as?

A

It is defined as low arterial pH with in conjunction with a reduced serum HCO3- concentration

151
Q

What are the causes of metabolic alkalosis?

A

Causes:
•Alkali ingestion
•Gastrointestinal acid loss: Vomiting
•Renal acid loss: Hyperaldosteronism, hypokalaemia
•Compensatory mechanism: Hypoventilation (but limited by hypoxic drive), renal bicarbonate excretion

152
Q

What is respiratory acidosis?

A

CO2 retention, leading to increased carbonic acid dissociation
•Causes: Any cause of respiratory failure
•Compensatory mechanism: Increased renal H+ excretion and bicarbonate retention (but only if chronic)

153
Q

What is the pathogenesis of respiratory acidosis?

A
  • depressed central drive
  • abnormal neuromuscular transmission
  • muscle dysfunction
  • enhanced ventilatory demand
  • increased dead space ventilation
  • augmented airway flow resistance
  • lung stiffness
  • pleural/chest wall stiffness
154
Q

What are the causes of respiratory alkalosis?

A

•CO2 depletion due to hyperventilation
•Causes: Type 1 respiratory failure, anxiety/panic
•Compensation: Increased renal bicarbonate loss (if chronic)

155
Q

What are the compensations in acid-base disorders?

A
156
Q

What is the intermediate mesoderm?

A

Forms a ridge of issue on the posterior abdominal wall
•Both the renal and genital systems develop from it

157
Q

What are the stages of kidney development?

A

From intermediate mesoderm:

  1. Pronephros - develops in week - 4/40 (disappears by 5/40), Non-functional, rudimentary
  2. Mesonephros - develops In week - 4/40, Part of it persists in males.
  3. Metanephros - 5/40; starts to function at 12/40, Definitive kidney
158
Q

What occurs in the mesonephros?

A

•Excretory tubules develop with a group of capillaries
•Capillaries > glomerulus
•Tubules > Bowman’s capsule

•Collecting duct called the mesonephric duct forms

•Gonad starts to develop

159
Q

What occurs in the mesonephros?

A

•Excretory tubules develop with a group of capillaries
•Capillaries > glomerulus
•Tubules > Bowman’s capsule

•Collecting duct called the mesonephric duct forms

•Gonad starts to develop

160
Q

What does the mesonephros become?

A

Females:
Tubules and mesonephric duct degenerate

Males:
A few tubules and the mesonephric ducts remain:
•mesonephric duct = vas deferens
•tubules = ducts of testis

161
Q

What occurs in the metanephros?

A

Definitive kidney
•Develops in the pelvic region
•Collecting system and excretory system develop differently
•Starts to function in week 12 of gestation

162
Q

What occurs in the metanephros?

A

Definitive kidney
•Develops in the pelvic region
•Collecting system and excretory system develop differently
•Starts to function in week 12 of gestation

163
Q

What happens to the collecting system 1?

A

Develops from the ureteric bud
•The ureteric bud grows out from the mesonephric duct
•Covered over by a ‘cap’ of metanephric tissue
•Bud grows into the cap = renal pelvis

164
Q

What happens to collecting system 2?

A

Bud splits into two parts = major calyces
•Continued subdivision and formation of tubules = ureter, renal pelvis, major and minor calyces, collecting tubules

165
Q

What happens to the excretory system?

A

Develops from metanephric cap
•Development promoted by the developing collecting tubules
•Development of each is dependent on the other
•Metanephric tissue forms renal vesicles
•Vesicles become tubular and capillaries develop = glomerulus
•Form nephrons

166
Q

What does the ureteric bud form?

A

Ureter
•Renal pelvis
•Major and minor calyces
•Collecting tubules

167
Q

What does the metanephric tissues form?

A

Nephrons

168
Q

Where does the kidney ascend into?

A

•Kidney ascends in utero
•During ascent, new vessels are derived from more proximal parts of the aorta and lower vessels regress
•Kidney starts to function in week 12 (12/40)
•Urine is formed and excreted into the amniotic fluid

169
Q

What happens if kidneys don’t develop?

A

Renal agenesis
•Nephrons and collecting ducts don’t develop
•Can result if signaling between ureteric bud and metanephric tissue fails
•Unilateral or bilateral – bilateral is rare but incompatible with life
•Seen in many genetic conditions

170
Q

What is a horseshoe kidney?

A

1/600
•Lower poles of the kidneys fuse
•Ascent obstructed by the IMA
•Usually asymptomatic and found incidentally

171
Q

What is a pancake kidney?

A

Fusion of the upper and lower poles of the kidney.

172
Q

What happens to accessory renal vessels as kidneys ascend?

A

As the kidneys ascend,
lower vessels do not regress

173
Q

What occurs in the development of the bladder?

A

Cloaca = common cavity for urogenital system and the gut

Urorectal septum divides cloaca:
•urogenital sinus
•anal canal

174
Q

What does the urogenital sinus give rise to?

A

Gives rise to 3 parts:

•Upper part = bladder
•Middle / pelvic part = part of the male urethra
•Phallic part = develops differently in males and females

175
Q

When does exstrophy of the bladder occur?

A

Rare
•Failure of anterior abdominal wall to close
•Bladder is exposed

176
Q

How does the ureter develop?

A

Develops from the ureteric bud
•Ureter directly enters the bladder after the distal part of the mesonephric duct merges into the bladder wall.

177
Q

What does the mesonephric duct develop into in females?

A

Mesonephric duct: develops into the vas deferens in males, regresses in females)

178
Q

What does the mesonephric duct develop into in females?

A

Mesonephric duct: develops into the vas deferens in males, regresses in females)

179
Q

What causes the double ureter?

A

Double ureter (duplication)
•Ureteric bud splits early in development

180
Q

What causes an ectopic ureter?

A

Ectopic ureter
•Development of two ureteric buds
•One enters bladder
•Other enters bladder, urethra, vagina or epididymal region

181
Q

Where does the fetal kidney go?

A

The fetal kidney is functional. The fetal kidney ascends from the pelvis to the abdomen

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