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Renal Function Tests
Prof. Dr. Raid M. H. Al-Salih
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Clinical Chemistry
Prof. Dr. Raid M. H. Al-Salih
Renal Functions
Production of urine
◦ Elimination of metabolic end products (Urea/Creatinine)
◦ Elimination of foreign materials (Drugs)
◦ Control of volume & composition of ECF
Water and electrolyte balance
Acid/Base status
Endocrine Functions
Vit D, Erpo, Renin
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Clinical Chemistry
Prof. Dr. Raid M. H. Al-Salih
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Clinical Chemistry
Prof. Dr. Raid M. H. Al-Salih
GLOMERULAR FUNCTION
The glomerulus has three layers separating the blood in the
glomerular capillaries from the glomerular lumen : capillary
endothelial, basement membrane, and visceral epithelium.
The basement membrane is the primary barrier. An overall
negative charge due to abundant sialic acid groups in the
glomerular layers helps prevent large anions, such as most
proteins, from crossing. The hydrostatic pressure across the
membrane which carries the ultrafiltrate is only about 1 kPa,
and if blood pressure falls only moderately, the oncotic
pressure due to the plasma proteins is sufficient to cause
filtration to slow or even stop. This explains the oliguria in
shocked patients.
(polyuria = more than normal urine; oliguria = less than
normal; anuria = no urine).
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Clinical Chemistry
Prof. Dr. Raid M. H. Al-Salih
TUBULAR FUNCTION
1. PROXIMAL TUBULE
Designed to reabsorb only what you need - 80% of sodium
and water
- K+ : 95% absorbed usually, but diet dependant
- phosphate : active reabsorption which is inhibited by PTH
- HCO3- : mostly absorbed, but see acid-base lectures for
details
- glucose and amino acid absorption is normally nearly
complete
- also secretes: organic acids, urate, drugs
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Clinical Chemistry
Prof. Dr. Raid M. H. Al-Salih
2. LOOP OF HENLE
It is responsible about creating either dilute or
concentrated urine. Key features are an active NaCl pump in
the thick ascending limb, and water impermeability of the
whole of the ascending limb.
Fluid emerges hypotonic at the end of the loop of Henle, at
about ½ the osmolality of body fluids (~ 120-150
mosmoles/l, as compared with 250-300 mosmoles/l in
plasma). Further salt may be removed in the collecting ducts
under conditions of water diuresis, causing further dilution.
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Clinical Chemistry
Prof. Dr. Raid M. H. Al-Salih
3. DISTAL CONVOLUTED TUBULE (DCT)
Little change in volume or concentration
Secretion of Aldosterone causes sodium to be exchanged
for K+ and/or H+. Conn's syndrome, Addisons disease,
and RTA type I all affect DCT function.
4. COLLECTING DUCTS
Anti Diuretic Hormone (ADH, Vasopressin, Pitressin),
synthesized in the hypothalamus and released from the
posterior pituitary in response to an increase in
extracellular osmolality, increases water permeability of
tubular cells (and urea permeability in the lower medullary
part).
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Clinical Chemistry
Prof. Dr. Raid M. H. Al-Salih
ADH linked pathology exerts its effect here and
consists of:-
4.1 Diabetes insipidus
: pituitary form, where no ADH is synthesized due to
damage to the pituitary.
: nephrogenic form, where renal tubular cells do not
respond to normal levels of ADH. Both forms give rise to
polyuria with dilute urine.
4.2 Syndrome of inappropriate secretion of ADH
(SIADH): low output of inappropriately concentrated
urine in the presence of hypervolaemia and dilutional
hyponatraemia.
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Clinical Chemistry
Prof. Dr. Raid M. H. Al-Salih
Renal function tests
Glomerular function tests: all the clearance tests (innulin, creatinine, urea)
Tubular function test: urine concentration or dilution test or urine acidification test
Analysis of blood/serum: blood urea, serum creatinine, protein and electrolytes
Urine examination: simple routine examination of urine for volume, pH, proteins, blood, ketone bodies, glucose
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Clinical Chemistry
Prof. Dr. Raid M. H. Al-Salih
Renal Function Tests
Why Test Renal Function? To identify renal dysfunction.
To diagnose renal disease.
To monitor disease progress.
To monitor response to treatment.
To assess changes in function that may
impact on therapy (e.g. chemotherapy).
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Clinical Chemistry
Prof. Dr. Raid M. H. Al-Salih
GLOMERULAR FUNCTION TESTS:
These depend on examination of substances which
depend on glomerular function for their elimination:
• SERUM CREATININE:
1- Filtered at the glomerulus and eliminated without
significant reabsorption or secretion in the tubules.
2- Derived from creatine phosphate in muscle.
3- Serum levels are related to muscle mass, and
influenced by dietary meat intake.
4- Increases as renal mass is lost in chronic renal
disease and acute renal failure.
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Clinical Chemistry
Prof. Dr. Raid M. H. Al-Salih
Clinical Chemistry
Prof. Dr. Raid M. H. Al-Salih 12
• CREATININE CLEARANCE (Cr Cl): Owing
to creatinine not being significantly reabsorbed or
secreted by the renal tubules, Cr Cl provides a
measure of the glomerular filtration rate (GFR). It
is calculated as follows:
Cr Cl. = (Urine Creatinine conc. x volume) /
(Plasma Creatinine conc.)
Note that the units are a flow rate, ml/min. It can
be difficult to measure well since the timed urine
collection (should be over 24 hrs) is in practice
unreliable and requires good patient and staff
cooperation. Normal Cr Cl. is about 120 ml/min.
• BLOOD UREA: Derived in the liver from protein
breakdown: is a useful measure of decreased filtration. About
30-40 % is normally reabsorbed in tubules. Levels are affected
by high protein intake, catabolic states, post-surgery and
trauma, and gastro-intestinal haemorrhage, all of which cause
increased urea production from protein.
• Estimated GFR (eGFR): This is only used in adults (>18
years) estimated GFR (eGFR) should be calculated using the 4-
variables (i.e. serum creatinine concentration, age, gender and
ethnic origin):
GFR (mL/min/1.73 m2) = 175 x [serum creatinine
(µmol/L) x 0.011312]-1.154 x [age]-0.203 x [1.212 if
black] x [0.742 if female]
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Clinical Chemistry
Prof. Dr. Raid M. H. Al-Salih
CAUSES OF ABNORMAL SERUM UREA TO CREATININE RATIO
Decreased Increased
Low protein intake High protein intake
Dialysis (urea crosses
dialysis membrane easier)
G.I. haemorrhage
Severe liver disease
(decreased urea synthesis)
Hypercatabolic state
Dehydration
Urinary Stasis
Muscle wasting or amputation
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Clinical Chemistry
Prof. Dr. Raid M. H. Al-Salih
Clinical Chemistry
Prof. Dr. Raid M. H. Al-Salih 15
1. TUBULAR FUNCTION TESTS
1.1 Urinary Na+ concentration. Normally low
relative to serum concentration unless on a dietary
high salt intake.
1.2 Concentration tests and Dilution tests, after a
water load. Ratio of osmolality (or urea) in urine
relative to that in plasma is a simple practical
measure.
2.3 Acidification tests, after administration of NH4Cl
( → NH3 + H+ + Cl- ). Seldom done except in
differentiation of type I and II renal tubular
acidoses (RTA).
Clinical Chemistry
Prof. Dr. Raid M. H. Al-Salih 16
MISCELLANEOUS TESTS:
3.1 Microscopy : look for casts, cells, or crystals.
3.2 Protein :> 2.5 g/day indicates nephrotic syndrome
:Bence-Jones Protein indicates myeloma
:ß2-microglobulin, small protein, filtered then absorbed by
tubules, which is a sensitive test of tubular function (but also ↑
in some malignancies and inflammatory conditions).
:Modest proteinuria is associated with many types of
pathology but a mild increase can sometimes be normal
(pregnancy).
3.3 Urinary cAMP :Administer ADH: No increase in urinary
cAMP indicates nephrogenic diabetes insipidus
:Administer PTH: No increase in urinary cAMP indicates
pseudohypoparathyroidism.
Clinical Chemistry
Prof. Dr. Raid M. H. Al-Salih 17
RENAL DISORDERS
NEPHROTIC SYNDROME
Characterised by increased permeability of the
glomerulus to proteins, with proteinuria of greater
than 2.5 g/day, & oedema (why?), hypoproteinaemia, and
increased serum lipids. It is sometimes useful to
measure the selectivity index, which is the ratio of the
clearance of a high M.W. protein such as IgG and a low
MW protein such as albumin:
UIgG/PIgG
Selectivity Index = ------------- x 100
Ualb/Palb
This index will increase as the disease
progresses.
Clinical Chemistry
Prof. Dr. Raid M. H. Al-Salih 18
There are many causes of the nephrotic syndrome; some of
them responsive to steroid therapy.
Note the ↑ in α2 globulins (α2 macroglobulin - too large to
be filtered easily, and increased as part of an attempt by the
liver to compensate for the protein loss by increasing overall
synthesis of serum proteins)
There is also hypercholesterolaemia and ↑ in other serum
lipids (cause of elevated β globulins above)
Clinical Chemistry
Prof. Dr. Raid M. H. Al-Salih 19
ACUTE RENAL FAILURE (ARF)
Definition: Urine output less than 450 ml/day
(in adult) with a rising blood urea (N = 1.7 -
6.7 mmoles/l)
The blood urea typically rises by 5
mmoles/l/day, but in surgical, trauma, or gastro-
intestinal bleeding it can rise by up to 15
mmoles/l/day.
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Prof. Dr. Raid M. H. Al-Salih 20
ARF is a common medical emergency with some
critical urgent decisions facing the clinician (i.e. -
you): the diagnostic problem is : has the patient got :
1. Pre-renal failure (defect before the kidney)
2. Intra-renal failure (defect in the kidney e.g. acute
tubular necrosis, glomerulonephritis)
3. Post-renal failure (defect after the kidney, e.g.
prostatic enlargement, urolithiasis).
Clinical Chemistry
Prof. Dr. Raid M. H. Al-Salih 21
To decide between these three categories of acute renal failure
is urgent because
1. Pre-renal failure if not rapidly treated can progress to the
much more serious intra-renal failure (acute tubular
necrosis).
2. Some aspects of the treatment of intra-renal failure are the
opposite of those for pre-renal failure.
Tubular function will be defective in Intra-renal failure but
normal (for a while) in pre-renal failure. Some
appropriate tests to distinguish between these two are
therefore:
Clinical Chemistry
Prof. Dr. Raid M. H. Al-Salih 22
PRE-RENAL INTRA-RENAL
Urinary sodium
concentration < 20 > 40 mmol/l
Urine/plasma
osmolality ratio > 1.4 < 1.1
Urine/plasma
urea ratio > 14 < 10
* The urinary Na+ is low in pre-renal failure because the low
blood volume causes a marked stimulation of aldosterone-
mediated Na+ uptake. In Intra-renal failure the damaged
tubules can't respond fully.
Clinical Chemistry
Prof. Dr. Raid M. H. Al-Salih 23
MANAGEMENT OF ACUTE RENAL FAILURE
1. Post-renal - relieve the obstruction, but then watch
out for subsequent polyuria
2. Pre-renal - restore blood volume, then blood pressure and
GFR will return to normal levels.
3. Acute tubular necrosis –
3.1 Water : if blood volume is low, replace with care, since fluid
overload can lead to cardiac failure
3.2 Na+ : if oliguric – restrict, in diuretic phase - may need to
administer Na+ ++.
Clinical Chemistry
Prof. Dr. Raid M. H. Al-Salih 24
3.3 K+ :if oliguric - restrict - administer if hypokalaemia.
3.4 H+ :high anion gap metabolic acidosis, may need
bicarbonate to neutralise a severe acidosis, but danger of
Na+ overload if too much NaHCO3 is given in oliguric
phase.
3.5 Dialysis is indicated if
: blood urea is greater than 50 mmol/l and rising
: bicarbonate is less than 10 mmol/l
: K+ is greater than 7.0 mmol/l (or ECG changes)
Clinical Chemistry
Prof. Dr. Raid M. H. Al-Salih 25
Clinical Chemistry
Prof. Dr. Raid M. H. Al-Salih 26
CHRONIC RENAL FAILURE (CRF)
This has many causes, of which the most common are
glomerulonephritis,
diabetes mellitus,
hypertension,
but the net effect is a progressive loss in the number
of functioning nephrons.
The key characteristic of well developed CRF is
polyuria - the opposite to the oliguria or anuria of
ARF.
Clinical Chemistry
Prof. Dr. Raid M. H. Al-Salih 27
Initial features are those of decreasing
glomerular function
-increase in urea, giving chronic uraemia, (sometimes
called azotaemia)
-increase in creatinine and progressive decrease in Cr
clearance
-increase in urate, phosphate, sulphate.
Clinical Chemistry
Prof. Dr. Raid M. H. Al-Salih 28
Later are added features of decreasing
tubular function caused by:
-actual tubular damage
-increased tubular flow due to (urea) osmotic
diuresis
Features are then:
- polyuria with fixed output
- loss of concentrating and diluting abilities
- metabolic acidosis with increased anion gap
- sodium instability - overload or deficiency can easily
occur
Clinical Chemistry
Prof. Dr. Raid M. H. Al-Salih 29
MANAGEMENT OF CRF:
1. Water intake is controlled by thirst since output is
fixed.
2. Careful control of Na+, K+ and protein intake.
3. Treatment of anaemia with erythropoietin.
4. Oral bicarbonate if acidosis is severe.
5. In end-stage CRF : dialysis - haemodialysis or
peritoneal dialysis
: renal transplantation.
Clinical Chemistry
Prof. Dr. Raid M. H. Al-Salih 30
POLYURIA
1. Water diuresis (urinary osmolality <200)
1.1 Compulsive water drinking
1.2 Diabetes insipidus - neurogenic or nephrogenic
2. Osmotic diuresis (urinary osmolality + 300)
Caused by the presence of incompletely reabsorbed
solutes in the tubular lumen:
2.1 Na+ - dietary, iatrogenic, diuretics, salt-losing
nephritis.
2.2 Urea – CRF, recovery phase of acute tubular
necrosis or post-renal failure
2.3 Glucose (diabetes mellitus)
2.4 Mannitol, and some other therapeutic agents.
Clinical Chemistry
Prof. Dr. Raid M. H. Al-Salih 31
RENAL STONES (Nephrolithiasis)
Causes
1. A high concentration of a substance in the
urine due to:
- low urine volume
- high excretion rate
2. pH changes
- alkaline urine predisposes to Ca deposition (e.g.
infection)
- acid urine predosposes to uric acid deposition.
3. Stagnation, usually due to obstruction.
Clinical Chemistry
Prof. Dr. Raid M. H. Al-Salih 32
Types of stones (or calculi)
1. Calcium - oxalate (+ phosphate)
- phosphate
2. Uric acid - in about 10% of gouty cases. May
be associated with low urinary pH due to
inadequate buffer production.
3. Rare forms
- cystine: cystinuria,
- xanthine: xanthine oxidase deficiency
- 2,8 dihydroxyadenine:
Calculi are only partly mineral; up to 60% may
consist of protein, the rest being varying
proportions of calcium, magnesium, ammonium,
phosphate.
Clinical Chemistry
Prof. Dr. Raid M. H. Al-Salih 33
Treatment
-fluids ++ to keep urine dilute (in all cases)
-Potassium citrate and thiazide diuretics may help
prevent Ca stone formation - urinary citrate helps
solubilise calcium.
- alkalinisation may help prevent uric acid (but not 2,8
dihydroxyadenine) stone formation
Clinical Chemistry
Prof. Dr. Raid M. H. Al-Salih 34
RENAL ACIDOSIS
There are 2 components to H+ excretion by the
kidney:
(i) reabsorption of filtered bicarbonate in the
proximal tubule
(ii) H+ secretion in the distal tubule.
1. URAEMIC ACIDOSIS.
Seen in acute or chronic renal failure. Decreased H+
excretion due to both glomerular and tubular
failure.
Clinical Chemistry
Prof. Dr. Raid M. H. Al-Salih 35
2. RENAL TUBULAR ACIDOSIS (RTA).
Type 1 (distal) RTA:
Due to inability of distal nephron to excrete H+. The
urine pH is inappropriately high (pH > 5.5), with
hypokalemia.
Type 2 (proximal) RTA:
Due to defective proximal bicarbonate reabsorption.
urine pH can be appropriately acidic (< 5.5) since
distal tubular H+ excretion is normal. Associated with
hypokalemia, glycosuria, phosphaturia and amino
aciduria – (Fanconi syndrome).
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