Glomerular Filtration & Assessment Of Renal Function

Question 1

What are the 3 main processes performed by the nephron and how are they put together in an equation to make the urinary excretion rate?

Answer 1

1. Filtration
2. Reabsorption
3. Secretion

= filtration rate + secretion rate - reabsorption rate

Question 2

Is there a high/low rate of filtration in the glomerulus capillary and what are the 2 reasons for this?

Answer 2

High as we want to get everything into filtrate, excreting waste at a high rate and also because the kidneys regulate electrolyte levels so they need to respond to changes in their levels rapidly

Question 3

How much of the cardiac output do the kidneys receive and how much filtrate do they form per day?

Answer 3

~20% - 1L/min of cardiac output

~ 180L/day of filtrate

Question 4

What are the 3 components of the glomerular filtration barrier, what does it do and how can it be affected in disease states?

Answer 4

1. Glomerular capillary fenestrated endothelium
2. Negatively charged basement membrane
3. Epithelial cells (podocytes with interdigitating foot processes & filtration slits)
   - > limit passage of substances based on size, charge + shape so blood cells and most plasma proteins excluded from filtrate
   - > in disease e.g. minimal change disease, the BM has lost its negative charge so large amounts of plasma proteins get into filtrate

Question 5

What is the main difference between the composition of filtrate and plasma?

Answer 5

Plasma has plasma proteins and cells in it, filtrate should not (unless in some disease states)

Question 6

What is the glomerular filtration rate (GFR) and what are the 2 factors that determine it?

Answer 6

The volume of filtrate formed by all the nephrons in both kidneys per unit time, determined by:
1. Glomerular capillary filtration coefficient (Kf) i.e. property of filtration barrier
2. Net filtration pressure (NFP) e.g. forces acting driving fluid from capillary to form filtrate
GFR = Kf x NFP

Question 7

What does the glomerular capillary filtration coefficient (Kf) reflect? What would happen if there was a reduction in nephron number/processes which damage the filtration barrier?

Answer 7

1. Surface area available for filtration
2. Hydraulic conductivity (‘permeability’) of filtration barrier
   - > SA would decrease and so would permeability therefore decreasing GFR although changes in Kf are not the major part of physiological regulation of GFR

Question 8

What are the 2 main things that cause the GFR to stray away from its day-to-day consistency?

Answer 8

1. Disease

2. Age

Question 9

What are the Starling forces acting across the filtration barrier that make up the net filtration pressure (NFP)?

Answer 9

1. Sum of hydrostatic pressures i.e. fluid exerting pressure on of glomerulus capillary (PG) and fluid sitting in Bowmans capsule (opposing pressure) (PB)
2. Sum of the colloid osmotic (oncotic) pressures i.e. the osmotic pressure exerted on the glomerulus capillaries (πG) and to some extent in Bowmans capsule (πB) due to an excess of proteins in the lumen

NFP = PG – PB – πG + πB - typical NFP = 10 mmHg

Question 10

Where does most physiological regulation of GFR come from?

Answer 10

Changes in glomerular hydrostatic pressure which depends on arterial BP, afferent arterial resistance + efferent arteriole resistance (smooth muscle valves)

Question 11

How can the afferent arterial and efferent arteriole resistance increase or decrease GFR?

Answer 11

Afferent arteriole dilation/efferent arteriole constriction increase GFR
Afferent arteriole constriction/efferent arteriole dilation reduces GFR

Question 12

What 3 vasoactive substances can have an effect on hydrostatic pressures in the glomerular capillary and thus, GFR?

Answer 12

1. Angiotensin 2 usually constricts efferent arterioles increasing pressure and GFR
2. Prostaglandins and atrial natriuretic peptide (ANP) vasodilate afferent arterioles increasing pressure and GFR
3. Noradrenaline (SNS), adenosine + endothelin tend to vasoconstrict afferent arterioles reducing pressure and GFR

Question 13

What changes in pressure occur in the peritubular capillaries and what does this mean for its function?

Answer 13

Hydrostatic pressure is lower whilst colloid osmotic pressure is higher (plasma proteins been concentrated as 20% of plasma has been removed) meaning that reabsorption rather than filtration is favoured here instead

Question 14

GFR and renal blood flow are relatively constant across a range of systemic BPs. What does this prevent and what are the 2 mechanisms of autoregulation?

Answer 14

Prevents large changes in renal excretion of water + solutes, & regulated by:

1. Myogenic response
2. Tubuloglomerular feedback

Question 15

What is the myogenic response based on and what would happen if there was increase in arterial BP?

Answer 15

Ability of smooth muscle in afferent arterioles to respond to changes in vessel circumference by contracting/relaxing in a negative feedback loop so an increase in BP would cause:
Increased renal blood flow/GFR -> increased stretch of AA SMCs -> Ca2+ channels stretched open -> reflex contraction of AA SMCs -> vasoconstriction of AA -> increased resistance to flow -> prevents change in renal blood flow/GFR

Question 16

What is the tubuloglomerular feedback?

Answer 16

Most important negative feedback response where changes in [NaCl] in the tubule lumen are linked to control of own afferent arteriole resistance in the glomerulus in the same nephron utilising the juxtaglomerular apparatus (JGA) i.e. [NaCl] is sampled in filtrate where early part of distal tubule loops back causing the JGA, feedback then goes back to afferent arteriole regarding if the concentration is appropriate/needs to be changed

Question 17

What cells are involved in tubuloglomerular feedback and how does it work?

Answer 17

Macula densa cells in early part of distal tubule sense [NaCl] so for e.g. when arterial BP increases -> transient increase in renal blood flow/GFR -> increases flow and [NaCl] delivered to distal tubule macula densa cells -> release of paracrine factors e.g. adenosine -> constriction of AA SMCs -> AA vasoconstriction -> increased resistance -> restoration of renal blood flow/GFR and vice versa for decreased arterial BP

Question 18

What paracrine factor will be released in tubuloglomerular feedback when BP has dropped?

Answer 18

Renin from granular cells which stimulates the release of angiotensin II (both will have systemic effects too on various blood vessels of body) which will constrict the EA SMCs increasing pressure in glomerular capillaries and restoring GFR

Question 19

What are the 4 functions of the kidneys and what examples of disorders can be given for each one if they went wrong?

Answer 19

1. Regulation of body fluid volume -> hypertension,oedema
2. Regulation of body fluid composition -> electrolyte disorders,acid base disorders
3. Excretion of metabolic waste + toxins -> uraemia, drug toxicity
4. Endocrine functions -> anaemia, renal bone disease

Question 20

What are the investigations that can be performed for kidney function (list in order you would perform them in)?

Answer 20

1. Urine - look for what is being filtered/excreted e.g. protein, blood, glucose, leucocytes, osmolarity
2. Blood - waste products accumulating, electrolyte abnormalities, underlying cause e.g. urea, creatinine, eGFR/GFR, Na, K, pH, osmolarity, autoimmune disease
3. Imaging - structural/functional abnormalities in US, X-ray, CT, MRI, contrast studies, nuclear imaging
4. Biopsy - microscopic structural abnormalities in light microscopy, immunohistochemistry, electron microscopy
   (order may differ in elderly as may want to rule out bladder cancer straight away if there is haematuria)

Question 21

What are the indicators of renal decline and what do they show?

Answer 21

Proteinuria/albuminuria/haematuria = indicate kidney damage
Estimated GFR/eGFR/serum creatinine/urea = indicate kidney function problem
Calcium/phosphate homeostasis, electrolytes/pH, fluid balance/urine volume, haemoglobin = indicate function but not quantitative

Question 22

Explain what proteinuria/albuminuria show, how it is tested and if there are better methods of doing so.

Answer 22

Indicate damage to filtration barrier -> proteins leaking through can further damage filtration barrier so disease progression in chronic kidney disease (CKD) will be enhanced - can be detected by urine dipsticks but more sensitive methods include protein-creatinine ratio (PCR) and albumin creatinine ratio (ACR)

Question 23

What are the different types of haematuria and what can skew the urine results?

Answer 23

Either visible (macroscopic) or invisible (microscopic)
Menstrual bleeding and false positives due to myoglobin would appear on urine dipsticks

Question 24

Why is GFR considered the best overall index of kidney function and what are its disadvantages?

Answer 24

GFR is directly related to the function of the nephrons and declines in all forms of progressive kidney diseases however, does not tell you the cause/location of problem
Linked to age, sex + body size (body SA) = typically 120ml/min in a young healthy male (declines with age) but difficult to measure directly

Question 25

What is the definition of renal clearance?

Answer 25

Volume of plasma from which a substance is completely cleared by the kidneys per unit time so it quantifies the kidneys ability to eliminate substances from the plasma

Question 26

What are the different ways in which the kidneys can deal with a substance/molecule (link this to renal clearance/GFR)? Give examples.

Answer 26

1. Substance is filtered and partially reabsorbed so small amount being cleared from blood and going into urine (low renal clearance/< than GFR) e.g. urea 2. Substance completely reabsorbed/just passes through so none is in the urine (no renal clearance) e.g. proteins just pass through and glucose is completely reabsorbed 3. Substance is filtered and secreted into urine so large amount excreted in the urine (high renal clearance/> than GFR) e.g. creatinine 4. Substance is just filtered so renal clearance = GFR e.g. inulin (good marker of GFR/renal function)

Question 27

What is the equation for renal clearance?

Answer 27

Urine production (ml/min) (V) x substance concentration in urine (mg/ml) (U) -------------------------------------------------------- Substance concentration in plasma (mg/ml) (P)

Question 28

What are the 4 essential properties of a substance that make its renal clearance equal GFR?

Answer 28

1. Freely filtered across the glomerulus 2. Glomerulus is only route of excretion (not reabsorbed/secreted) 3. Non-toxic 4. Easily measured

Question 29

What are the issues with using inulin to get the GFR?

Answer 29

Inulin (plant polysaccharide) or radioisotopes can be used to measure this and although it is very accurate, it is technically difficult as needs to be infused into body in lab conditions hooked onto a drip until there is steady plasma levels, urine then must be measured over time so it is not a routine measurement of GFR

Question 30

Explain how creatinine clearance can be used to calculate GFR and the problems associated with it.

Answer 30

Creatinine is produced in body from the breakdown of creatinine, a skeletal muscle component and it is produced at a steady rate normally, freely filtered at glomerulus + not reabsorbed However, small amount of secretion means it overestimates GFR and requires 24 hour urine collection (compliance issues, results not instant) so not suitable for routine measure of GFR

Question 31

What are the routine measures of GFR?

Answer 31

Single serum blood measurement testing for serum urea, serum creatinine and estimated GFR (eGFR) (in increasing accuracy) because they are normally filtered by kidneys thus, build up in blood indicates decreased GFR/renal function -> gives indication but not GFR number

Question 32

How can serum urea be used to get GFR and what are the problems?

Answer 32

Urea is a nitrogen containing metabolic waste product from the metabolism of proteins also known as blood urea nitrogen (BUD) - it is filtered and partially reabsorbed so serum levels typically rise in kidney disease as GFR falls BUT serum levels reflect more than GFR so need to consider other factors that may alter it

Question 33

What factors increase urea production?

Answer 33

High protein diet Increased catabolism e.g. trauma, infection, surgery, cancer GI bleed (increases proteins too due to plasma proteins) Drugs e.g. corticosteroids, tetracyclines

Question 34

What factors reduce urea elimination?

Answer 34

Renal disease causing decreased GFR | Poor renal blood flow e.g. dehydration, hypotension

Question 35

When can you be confident that GFR has truly fallen in terms of blood test results?

Answer 35

If both serum urea and serum creatinine have increased in parallel; if urea is disproportionately higher consider other factors

Question 36

How can serum creatinine be used to get GFR and what are its downfalls?

Answer 36

More accurate than urea as usually produced at a steadier rate Useful for monitoring trends but relatively inaccurate as a point GFR measure as production varies between individuals as it relates to muscle mass (further affected by age, sex, amputation, malnutrition, muscle wasting + ethnicity) and is affected by diet too (veggie vs. meat rich)

Question 37

How does muscle mass affect serum creatinine levels?

Answer 37

If someone has a increased muscle mass, it will increase whereas if someone has muscle wasting, it will decrease which means diseased kidneys can be falsely predicted or missed completely

Question 38

Why is serum creatinine not a useful way on its own to detect early decline in renal function?

Answer 38

You can lose ~50% (~60ml/min) of renal function/GFR and serum creatinine levels can still lie within the normal range so it will not identify people with kidney disease early

Question 39

How can eGFR be used to calculate GFR?

Answer 39

GFR can be estimated by incorporating simple clinical information along with a single serum measurement - most use serum creatinine (newer/more accurate tests use serum cystatin C), age, sex + ethnicity e.g.'s MDRD, CKD-EPI (NICE recommends) + Cockroft-Gault (uses body weight too to estimate creatinine clearance so may be used for dose adjustments)

Question 40

What does MDRD stand for?

Answer 40

Modification of diet in renal disease

Question 41

What can eGFR be used for and what are the problems with using it to predict GFR?

Answer 41

Useful in monitoring renal function + detecting early decline BUT Muscle mass still affects creatinine and no part of the equations include a measure of body size Limitations on use in children, acute kidney injury + drug dose calculations for highly toxic drugs e.g. chemo (need to be very accurate so perhaps use Cockroft-Gault equation for this)