Measurement of Kidney Function

Question 1

Patients at risk of developing renal failure

Answer 1

Extremes of age
Polypharmacy
Specific disease states (hypertension, diabetes, chronic HF, rheumatoid arthritis, renal disease, UTIs)
Patients receiving analgesia (NSAIDs)
Transplant patients
Drug Therapy
Patients undergoing imaging procedures (radio contrast agents can be nephrotoxic)

Question 2

Monitoring a patient’s renal function

Answer 2

1 Patients clinical condition - clinical assessment, use of bedside clinical data
Modern imaging techniques (macroscopic views of renal blood flow, filtration and excretory function)
Biochemical data (measurement of renal clearance of various substances)

Question 3

1a clinical assessment

Answer 3

Basic function affected, e.g. fluid balance
Clinical signs, e.g. oedema
Symptoms, e.g. breathlessness

Question 4

1b use of bedside clinical data

Answer 4

Weight charts, fluid balance charts, degree of oedema, results of urine dipstick testing (blood glucose and protein)

Question 5

2 Modern Imaging techniques

Answer 5

Include macroscopic views of renal blood flow, filtration and excretory function
Some of these are used clinically but some can only be currently used experimentally in the lab
Renography: Gamma camera planar scintigraphy, Positron emission tomography (PET), Single photon emission computerised tomography (SPECT)

Question 6

3 Biochemical Data

Answer 6

useful for identifying renal impairment
Blood (plasma or serum) markers of renal function
Plasma or serum creatinine
Plasma or serum urea or blood urea nitrogen (BUN)

Question 7

Creatinine

Answer 7

Breakdown product of creatine phosphate in muscle
Generally produced at a constant rate
Filtered at the glomerulus with some secretion into the proximal tubule
Normal range in plasma: 40-120 micromol/L

Question 8

Plasma creatinine

Answer 8

Increased by:
Large muscle mass, dietary intake
Drugs which interfere with analysis (Jaffe reaction) e.g. methyldopa, dexamethasone, cephalosporins
Drugs which inhibit tubular secretion e.g. cimetidine, trimethoprim, aspirin
Ketoacidosis (affects analysis)
Ethnicity (higher creatine kinase activity in black population).
Decreased by:
Reduced muscle mass (e.g. the elderly)
Cachexia / starvation
Immobility
Pregnancy (due to increased plasma volume in the mother)
Severe liver disease (as liver is also a source of creatinine)

Question 9

Urea

Answer 9

Liver produces urea in the urea cycle as a waste product of protein digestion
Filtered at the glomerulus, secreted and reabsorbed in the tubule
Plasma urea described as BUN – Blood urea nitrogen: Normal range: 2.5-7.5 mmol/L, >20 mmol/L indicates moderate to severe renal failure

Question 10

BUN - blood urea nitrogen

Answer 10

Increased by:
High protein diet
Hypercatabolic conditions e.g. severe infection, burns, hyperthyroidism
Gastrointestinal bleeding (digested blood is a source of urea)
Muscle injury
Drugs e.g. Glucocorticoids, Tetracycline
Hypovolaemia.
Decreased by:
Malnutrition
Liver disease
Sickle cell anaemia (due to  GFR)
SIADH (syndrome of inappropriate ADH)

Question 11

Biochemical Data

Answer 11

Useful for :
Identifying renal impairment
Evaluation of the ability of the kidneys to handle water and solutes
Modifying dosages of drugs which are cleared by the kidneys.
Some methods involve measurement of renal clearance of various substances
An ideal marker of kidney function would be:
A naturally occurring molecule
Not metabolised
Only excreted by the kidney
Filtered but not secreted or reabsorbed by the kidney

Question 12

Examples of renal clearance

Answer 12

Some are filtered by the glomerulus and are NOT reabsorbed (Substance A)
- Excretion rate = rate it was filtered, e.g. insulin.
Some are filtered and some of the filtered portion is reabsorbed (B)
- Excretion rate = filtration rate – reabsorbed (e.g. electrolytes e.g. Na+).
Some are filtered and completely reabsorbed (C)
- No excretion (normally) (glucose/amino acids).
Some are primarily secreted into the tubule (D)
- Not reabsorbed, fully secreted (eg PAH)

Question 13

Renal Clearance

Answer 13

Clearance = the volume of plasma completely cleared of a given substance in unit time
Compares rate at which glomeruli filter a substance with the rate at which the kidneys excrete it via the urine
Measurement of difference in amount filtered and excreted allows estimation of the net amount reabsorbed or secreted by the renal tubules
Provides information about the 3 basic functions of the kidney:
- Glomerular filtration (F)
- Tubular reabsorption (R)
- Tubular secretion (S)
The “clearance” of a solute is the virtual volume of blood that would be totally cleared of a solute in a given time
Solutes come from blood perfusing kidneys
Rate at which kidneys excrete solute into urine = rate at which solute disappears from blood plasma
Cx = (Ux x V)/Px

Question 14

Drawbacks of measuring renal clearance

Answer 14

Measuring clearance means measurement of overall nephron function i.e. all ~2 million nephrons in both kidneys
This gives the sum of ALL transport processes occurring along nephrons but no information about precise tubular sites or mechanisms of transport

Question 15

Glomerular Filtration Rate

Answer 15

This is the rate at which filtrate is produced in the kidneys = 125 mL/min (180 L/day)
GFR can be measured clinically and used as an indicator of renal function
GFR can be estimated by measurement of the clearance of creatinine
BUT creatinine is filtered and secreted into tubule
A more accurate estimation is provided by measurement of insulin clearance – it is filtered but not secreted into tubule

Question 16

Insulin Clearance for GFR

Answer 16

Insulin is a plant polysaccharide Mw 5200Da
It is freely filtered - i.e. plasma and tubular concentration is same but it is NOT secreted and is NOT reabsorbed
Therefore rate of excretion in urine equals the rate of filtration by the kidneys
So Inulin clearance = GFR
If a substance has clearance greater than inulin, then it must also be being secreted; less means that it must be being reabsorbed or not filtered freely at the glomerulus

Question 17

Drawbacks of insulin clearance to measure GFR

Answer 17

Inulin must be administered by IV to get relatively constant plasma or serum levels.
Chemical analysis of inulin is technically demanding.
Could use radiolabelled compounds instead, e.g. radioactive Vit B or EDTA
However, these may also bind to proteins and distort results.
Problems of IV infusion of GFR marker are avoided by using an endogenous substance with inulin-like properties – i.e. creatinine

Question 18

Creatinine clearance

Answer 18

Creatinine is filtered at glomerulus, but some is also secreted at PT
Using equation over-estimates GFR by 20%
However, the colorimetry methods used (Jaffe method) under-estimates creatine by 20% - cancel each other out
Cheap, easy, reliable, used clinically
Avoids IV infusion (requires venous blood and urine samples)
Creatinine usually produced by creatinine phosphate metabolism in muscles
Take into account muscle disease/eating large amounts of meat
Measure over 24 hour period

Question 19

Adjustments due to body surface area

Answer 19

Creatinine clearance can be adjusted to take account of body surface area (BSA)
= (CrCl x 1.73)/BSA - in m2
Most adults ~ 1.7m2
Produces corrected CrCl in mL/min/1.73

Question 20

Cockcroft-Gault formula

Answer 20

((140-age) x mass (kg) x multiplier) / plasma creatinine (micromol/L)
this allows estimation of GFR using plasma creatinine only - don’t need urine samples

Question 21

Using PAH clearance to measure renal blood flow

Answer 21

If a substance is completely cleared from the plasma, its clearance rate will be equal to the renal plasma flow (RPF)
Clearance of PAH - para-aminohippuric acid can be used to estimate this:
PAH not normally present in blood
When given, almost all (~90%) cleared from kidney in one passage - some is filtered in glomerulus and remainder secreted by proximal tubules
~10% by-passes tubule - travels from efferent arterioles into peritubular capillaries and then venous renal blood, and is not secreted

Question 22

Using PAH clearance to measure renal blood flow - calculation

Answer 22

Consider: plasma PAH of 0.01 mg/mL, urine PAH 5.85 mg/mL, urine flow rate of 1 mL/min
Clearance of PAH = 5.85/0.01 = 585 mL/min (uncorrected = ERPF)
If PAH extraction rate is 90% then total renal plasma flow = 585/0.9 = 650 mL/min
Plasma is only one part of blood Blood = plasma (55%) + haematocrit (45%)
…so if haematocrit = 0.45 then total renal blood flow = 650 / (1 - 0.45) = 1,182 mL/min
(i.e. ~1,200 mL/min = 20 % of CO [6L])

Question 23

Biomarkers of Kidney Disease - future for monitoring renal function

Answer 23

Indicators of renal function such as plasma creatinine or BUN increase only after there is significant loss of renal function: typically a 60% loss in renal function before plasma creatinine or BUN increases
Urinary albumin/protein excretion can also be used as an indicator of chronic kidney disease
Currently a lot of research (and commercial) interest in identifying blood and urinary markers which increase in the early stages of renal failure and can be measured
These are mostly proteins released into the plasma and/or urine:
- Kidney injury molecule – 1 (KIM-1) (urine)
- Interleukin (IL)-18 (urine)
- Fatty-acid binding proteins (FABPs) (urine)
- Neutrophil gelatinase-associated lipocalin (NGAL) (plasma & urine)
- Cystatin C (plasma)