Lecture 10 - Assessment of Renal Function

Question 1

Normal Real Blood Flow (RBF)?

Answer 1

1200 mL/min, ~20% of cardiac output

Question 2

What is GFR? Normal GFR?

Answer 2

GFR = volume of fluid filtered from the kidney glomerular capillaries into the Bowman’s capsule per unit time

Normal: 180 L/day, 110-140 mL/min
(Filtration fraction = RBF/GFR ~20%)

Question 3

Normal volume of urine formation?

Answer 3

1.5 L/day, 1 mL/min

Question 4

How much of water in glomerular ultra filtrate is reabsorbed by kidneys?

Answer 4

~99%

Question 5

Where in the kidneys is the major site of reabsorption?

Answer 5

~65% occurs in proximal renal tubules, accompanied by Na+ and Cl- reabsorption

Question 6

What are the 3 major functions of the kidneys?

Answer 6

• regulation of water, electrolyte and acid-base balance
• excretion of waste products of intermediary metabolism, e.g. urea, creatinine, uric acid, phosphate, sulphate, organic acids
• production and elaboration of hormones, e.g. renin, erthryopoietin, 1,25(OH)2-D3

Question 7

At what urinary output is azotemia inevitable?

Answer 7

Waste products of metabolism = ~550 mOsm/day
Maximal urinary concentration attainable = ~1300-1400 mOsm/L

Maximal volume of urine water = 550/1400 = 400 mL/day

Therefore, azotemia inevitable if urine output <400 mL/day

Question 8

What properties does the ideal substance for GFR estimation possess?

Answer 8

• freely filtered at the glomerulus
• not reabsorbed by the renal tubules
• not secreted by the renal tubules or other organs
• not synthesized or metabolized by the renal tubules

Question 9

How is UV/P derived?

Answer 9

• assume a substance M, not reabsorbed/secreted/metabolized by kidneys and freely filtered at glomerulus
• mass M excreted/time = mass M filtered/time
• mass M filtered = volume of plasma filtered into Bowman’s space X concentration of M in glomerular filtrate
• concentration of M in filtrate = concentration of M in plasma

Therefore:
GFR = (U_M X V) / P_M
- where U_M and P_M are concentrations of M in urine and plasma respectively, V is volume of urine per unit time

Question 10

What is needed to maintain normal GFR?

Answer 10

• adequate number of neprhons with intact glomerular function
• nromal renal perfusion

Question 11

What is used experimentally to estimate GFR?

Answer 11

Inulin

• polysaccharide that is filtered as the same rate as water, and not secreted nor reabsorbed by renal tubules
• normal: 7.5 L/hour, 125 mL/min
• tends to overestimate true GFR
• not used in clinical settings becuase requires infusion at a continuous and constant rate for several hours

Question 12

What is most often used to estimate GFR in a clinical setting, and why?

Answer 12

Creatinine

• metabolic end-product of skeletal muscle, released into blood at relatively constant rate (when renal fxn, protein intake, muscle mass are stable)
• endogenous, no need for intravenous infusion
• freely filtered, not metabolized
• BUT small amount of creatinine is secreted by renal tubules into glomerular filtrate, therefore tends to overestimate GFR

Question 13

What are some limitations of using creatinine to assess renal fxn?

Answer 13

• cannot detect mild to moderate reduction in GFR (needs to decrease by ~40-50% before plasma creatinine is raised above normal limits)
• age, gender, ethic-related differences in muscle mass
• within-subject variation up to 4.3%, between-subject variation up to 13%
• rise of >=20% should warrant investigation, regardless of whether or not it is within reference interval
• renal tubular and GI mucosal secretion become increasingly significant as blood levels rise
• subject to analytical interference (eg very high level of bilirubin -> surprisingly low creatinine; very high level of acetoacetate -> surprisingly high creatinine)

Question 14

What is urea?
What factors affect to amount of urea excreted?
How is it filtered?
What does it clearance depend on?

Answer 14

• urea is a waste product of amino acid production, synthesized by the liver from ammonia and CO2
• excretory load dependent on amino acid, protein intake, net body protein metabolism (increased catabolism eg Cushing syndrome/severe burns -> accelerated protein breakdown)
• filtered freely by glomeruli, readily passively diffuses back into circulation through renal tubular membrane (therefore clearance depends on urine flow rate)

–> in low GFR states, better to average creatinine and urea clearances (CrCl overestimates, UrCl underestimates)

Question 15

Why is plasma urea level a poor indicator of GFR?

Answer 15

• low production (due to low protein intake) can lower the [blood urea] sufficiently to enable normal levels to <-> significant renal in sufficiency
• GFR has to drop ~40% before [blood urea] rises above normal upper limit
• high production (due to high protein intake) in the face of minor renal impairment can <-> disproportionately high [blood urea]

Question 16

What are non-GFR conditions that affect plastma urea levels?

Answer 16

High:

• high protein diet
• GI bleeding (becuase blood = proteins)
• tissue trauma
• glucocorticoids
• tetracycline/some drugs

Low:

• liver disease
• malnutrition

Question 17

What is the conventional renal function test? What are the limitations?

Answer 17

• profile includes creatinine, urea, Na+, K+, Cl-, HCO3- concentrations in blood
• convenient but rather insensitive, needs significance GFR reduction to see changes
  *- subject to various non-renal fxn factors affecting their blood levels
• many clinical labs nowadays report MDRD-eGFR along with creatinine values

Question 18

How is creatinine clearance measured?

Answer 18

U_cfV / P_cf

V = volume of urine produced over a fixed period (usually 24 hours)

Usually expressed in mL/min

Question 19

What are the pros and cons of using creatinine clearance to estimate GFR?

Answer 19

Pros:
- more reliable than formula-predicted GFR in some circumstance

Cons:

• 24-hour urine collection is inconvenient and error-prone
• measurement uncertainty is up to 30%

Question 20

What is the Cockroft & Gault formula used for?

What are the parameters involved?

What makes the formula more accurate?

Answer 20

Used to estimate creatinine clearance.

Parameters:

• age
• body weight (kg - ideal BW commonly recommended in place of actual BW for overweight/obese patients)
• plasma creatinine concentration (umol/L)

More accurate correlation with measure values of GFR if:

• [plasma creatinine] not within normal range
• renal impairment not severe and relatively stable (overestimate GFR in advanced renal failure)
• no inhibition of tubular secretion of creatinine by medications

Question 21

What are the limitations of the Cockroft & Gault formula?

Answer 21

• developed from only 249 patients, most of whom were hospitalized men, only 9 female subjects
• positive bias is observed due to renal tubular secretion of creatinine
  *- information on patient’s weight is not availble for most clinical labs

Question 22

What is the MDRD formula used for?

What are the parameters involved?

Answer 22

Used to estimate GFR

Parameters:

• PCR (plasma creatinine)
• age
• sex
• +/- a factor for African Americans

Question 23

What are the pros and cons of the MDRD formula?

Answer 23

Pros:
*- validated against a reference method for GFR based on renal clearance of ¹²⁵I-iothalamate
- estimates GFR and not creatinine
- predicts GFR over a wide range of values adjusted for body size (standardized to 1.73m²)
- more accurate than other equations tested, especially at GFR < 60 mL/min/1.73m²

Cons:
*- underestimates eGFR in subjects with GFR > 60 mL/min/1.73m²
- extensively evaluated in Caucasians/African Americans with varying degrees of renal insufficiency, but not those with normal renal fxns
- not validated in <18 and >70yos, pregnant women
- further validation needed for Chinese

Question 24

What are some other equations for GFR estimations?

Answer 24

• CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) formula
  > as accurate as MDRD in eGFR<60; less bias at eGFR>60
  > will probably emerge as equation of choice for eGFR
• Schwartz formula
  > eGFR in children
  > parameters: muscle mass, height, serum creatinine

Question 25

What is CKD?

How is it diganosed and staged?

Answer 25

• defined by the presence of kidney structural or functional abnormalities for at least 3 months
• kidney damage can be present with or without decreased GFR < 60
• associated with proteinuria, urine sediment abnormalities, renal tubular damage, abnormalities on imaging studies
• staging based primarily on GFR expressed in mL/min/1.73m²