RENAL FUNCTION TESTS:

BACKGROUND / SIGNIFICANCE
Most renal disease causes no symptoms until 50-75% of kidney function is destroyed. Lab
tests often provide the initial recognition of renal impairment and can be used to direct
further therapy. In therapeutics kno!ledge of renal function is essential for recommending
proper doses of prescription drugs. Many drugs are renally cleared and decreased renal
clearance can lead to to"icity. #ose ad$ustments are based on assessments of renal function.
EXCRETORY FUNCTION OF KIDNEY
%he kidney serves to rid the body of undesirable end products of metabolism. %he non-
protein nitrogenous compounds that are e"creted by the kidney are listed belo!&
Contributors Other inor Contributors
'rea (ucleotides
'ric acid )urine
*reatinine )olypeptides
*reatine +lutathione
,mino acids
,mmonia
%he t!o most popular screening tests for renal function are serum urea nitrogen and serum
creatinine. -etter measures of glomerular function are clearance tests. %his is especially true
in the aged !here serum creatinine measurements are less reliable due to decreasing muscle
mass.
In uremia .kidney failure/ the increase is mainly in urea creatinine and uric acid. 'ric acid
and the other nonprotein nitrogenous compounds are measured rarely in this conte"t. 0erum
urea nitrogen .0'(/ is normally 125% of total non-protein nitrogenous compounds but may
be 30% in some disease states. In hepatic failure the ratio of non-urea4urea nitrogen
increases because of the inability of the liver to synthesi5e urea and to deaminate amino
acids.
!" Ure# Nitro$en
Ma$or nitrogen-containing metabolic product of protein catabolism
)rimarily synthesi5ed by hepatocytes
6reely filtered by glomeruli reabsorbed .amount varies/ by tubules
7istorically urea !as reported as blood urea nitrogen .-'(/ and this terminology has
been incorrectly carried over to the present. 'rea nitrogen is no! measured using serum
and is reported as 8serum urea nitrogen9 .0'(/. 'rea is synthesi5ed mostly in the liver
as a by-product of the deamination of amino acids.
'rea is filtered by the glomeruli: ho!ever about 20-70% .amount depends on urine
flo!/ is reabsorbed by passive diffusion into blood across the renal tubular epithelium.
6or this reason urea clearance tests are less informative than creatinine clearance tests
and have been discontinued.
Reference Range for serum urea nitrogen& 3-;< mg4dL
%he serum urea nitrogen level is greatly influenced by diet.
T#b%e !
D#i%& 'rotein Int#(e
)$/($ bo*& +ei$ht,
Ure#-N
Average
..$/*L,
Lo! protein diet& 0.5 15
,verage protein diet& = 1=;
7igh protein diet& ; 1;;
0'( is not a sensitive indicator of renal dysfunction because renal function must be
reduced by more than 50% to result in a rise of 0'(.
/" Cre#tinine
#erived from muscle creatine .about =-;% of total muscle mass per day/
,mount e"creted daily is fairly constant and independent of urinary volume
,verage men e"crete =.5 g4d into the urine:
!omen less: athletes more
)atients !ith hepatic disease muscular dystrophy paraplegia and poliomyelitis may
e"crete less creatinine due to decreased production. It should be noted that many
laboratories use the alkaline picrate .>affe/ method for measuring creatinine.
Reference Range for serum creatinine& M& 0.? - =.<
mg4dL
6& 0.5 - =.=
mg4dL
0" G%o.eru%#r Fi%tr#tion R#te
, useful assessment of renal function is the measurement of the glomerular filtration rate
.+6@/ especially in older people. %he inulin clearance rate closely appro"imates the true
+6@ since inulin is freely filtered by the glomerulus !ith minimal tubular absorption or
secretion. 7o!ever this test is difficult to perform routinely. Measuring the clearance of
endogenous creatinine .clearance of creatinine produced by metabolic processes/ is much
more practical and convenient but less accurate. *reatinine for the most part is freely
filtered. (ormally only small amounts .A ?%/ are reabsorbed by the tubules and an eBual
amount may be secreted by the tubules. %he endogenous creatinine clearance rate is
computed by the follo!ing formula&
C
1re#t
2
U
1re#t
3
C
3
!"40 .
/
S
1re#t
A
!here *
creat
D creatinine clearance rate in mL4min '
creat
D urinary creatinine in mg4dL
C D urine flo! in mL4min .volume of timed urine4collection time/ and 0
creat
D serum
creatinine in mg4dL. 0ince creatinine clearance is related to patient si5e a more accurate
formula includes an estimation of body surface area in sBuare meters obtained from a
nomogram using the height and !eight of the patient. , D body surface area in m
;
and
=.7< m
;
is the average body surface area. In essence this formula 8normalizes9 the
clearance to that of a normal-si5ed person. )atients being tested for the +6@ must be !ell
hydrated to provide a urine flo! of E ; mL4 min.
Reference Range: male D ==7 ;0 mL4min: female D F5 ;0 mL4min
%he relationship bet!een serum creatinine and creatinine clearance is logarithmic .see
Fi$ure !/. %hus initially for small numeric changes in serum creatinine there are
significant numeric changes for creatinine clearance. In later stages of uremia small
numeric changes in the clearance are associated !ith significant changes in serum
creatinine. (ote the decrease in the number of nephrons !ith decrease of clearance and
increase in serum creatinine.
3
2
;
=
*reatinine *learance .ml4min/
=;0 ?0 <0 =5
0
e
r
u
m

c
r
e
a
t
i
n
i
n
e

.
m
g
4
d
L
/
@emaining (ephrons .millions/
;.0 =.0 0.5
3
2
;
=
*reatinine *learance .ml4min/
=;0 ?0 <0 =5
0
e
r
u
m

c
r
e
a
t
i
n
i
n
e

.
m
g
4
d
L
/
@emaining (ephrons .millions/
;.0 =.0 0.5 ;.0 =.0 0.5
Fi$ure !& @elationship bet!een serum creatinine creatinine clearance
and number of remaining nephrons.
%he endogenous creatinine clearance rate is primarily an estimate of +6@: ho!ever a
small amount of tubular secretion augments glomerular filtration. %herefore total urinary
creatinine is slightly higher than the amount actually filtered by the glomeruli. %he
amount of urinary creatinine derived from tubular secretion rises proportionally in renal
failure !ith an increase in serum creatinine. Gith advancing renal failure and increase in
serum creatinine the tubular secretion proportionally increases up to 20-?0%. 6rom an
interpretation standpoint this is important. Gith normal or early renal failure creatinine
clearance appro"imates true +6@. Gith advanced renal failure creatinine clearance
overestimates true +6@ due to the increased amount of creatinine in urine due to tubular
secretion caused by the high concentration of creatinine in circulation.
,lternatively more accurate isotopic methods for measuring +6@ can be utili5ed e.g. the
clearance of in$ected
5=
*r-labelled H#%, from the blood. %his compound is completely
filtered by the glomeruli and is not secreted or reabsorbed by the tubules. 7o!ever this
method reBuires a special laboratory eBuipped to handle and measure radioactive
isotopes.
,n alternative to measuring +6@ is to use the *ockroft and +ault eBuation
=
to estimate
creatinine clearance based on a single measurement of serum creatinine. Ghere 0
creat
is
serum creatinine .mg4dL/ and !eight is in kilograms.
TUBULAR FUNCTION
%he most often used function tests are renal concentrating po!er and the ability to produce
an acid urine .in suspected renal tubular acidosis/.
Urine Os.o%#%it& #n* Ren#% Con1entr#tin$ Abi%it&
Ismolality refers to the concentration of osmotically active particles .osmolutes/ in
solution e"pressed in mIsm4kg of !ater. 'rine osmolality varies !idely in health
bet!een about ?0 and =;50 mIsm4kg. %he failing kidney loses its capacity to concentrate
urine. , patient !ith polyuria due to chronic renal failure .*@6/ is unable to produce
either a dilute or a concentrated urine. Instead urine osmolality in these patients is
generally !ithin 50 mIsm4kg of the plasma osmolality .i.e. bet!een about ;20 and <50
mIsm4kg/. 'rine osmolality is a measure of concentrating po!er of the kidney. 'rine
specific gravity is usually directly proportional to osmolality. -oth give misleadingly
high results if there is significant glycosuria or proteinuria. %he error can be
=
C
1re#t
).#%es, 2
)!56-#$e,)7ei$ht,
)S
1re#t
, )4/,
C
1re#t
)8e.#%es, 2
)!56-#$e,)7ei$ht,
)S
1re#t
, )4/,
)6"9:, C
1re#t
).#%es, 2
)!56-#$e,)7ei$ht,
)S
1re#t
, )4/,
C
1re#t
)8e.#%es, 2
)!56-#$e,)7ei$ht,
)S
1re#t
, )4/,
)6"9:,
mathematically corrected. Measurement of osmolality !ith an osmometer is more
accurate but also more difficult than specific gravity measurements.
@andom testing of either specific gravity or osmolality is not very informative due to the
effect of fluid intake. @epeated measurements or measurements under controlled fluid
intake are more reliable. 0pecific gravity values of more than =.0;5 or osmolality values
more than 375 mIsm4kg indicate adeBuate renal concentrating ability. @ecurring values
of =.0=0 .=.003 - =.0=;/ indicate isosthenuria .fi"ed specific gravity/. %his finding
suggests loss of tubular concentrating and diluting ability and is freBuently a prelude to
anuria.
SUN/CREATININE RATIOS IN ;ARIOUS CONDITIONS
(ormal ratio& 1=;-;0 .or =0-=3 !ith less specific methods/
In practice the greatest increase in the ratio may be seen in prerenal a5otemia !here ratios
of <04= or <54= may be observed. 7o!ever other conditions may also change the ratio
depending on the rate of urea synthesis kidney blood flo! or glomerular filtration rate.
Ghen evaluating 0'(4creatinine ratios reali5e that 0'( production is dependent on
available protein .increased protein intake increases the ratio/ and liver function .decreased
liver function lo!ers the ratio/. In addition the ratio is affected by the specificity of the
creatinine method. .Less specific methods give higher creatinine values./
%he ratio is increased in conditions in !hich there is increased urea synthesis as observed in
the presence of blood in the +I tract in muscle !asting disease and in severe tissue trauma.
Ither conditions such as intraperitoneal e"travasation of urine and urinary enteric fistulas
lead to greater urea reabsorption. Increased tubular reabsorption of urea occurs !ith
decreased tubular flo! as a result of dehydration decreased cardiac output or shock .D
prerenal a5otemia/ or due to renal disease such as early acute glomerulonephritis malignant
nephrosclerosis or postrenal obstruction.
Decreased ratios are seen in the presence of decreased urea synthesis .chronic
glomerulonephritis !ith protein deficiency severe hepatic insufficiency and starvation/ and
decreased urea reabsorption .overhydration and rapid hydration/. %he decrease in ratio due to
hemodialysis is caused by the more efficient dialysis of urea vs. creatinine. In acute tubular
necrosis urea and creatinine are eBually and passively returned to the tubular blood.
%herefore the ratio is decreased.
" RENAL FAILURE
,cute renal failure occurs rapidly and is potentially reversible if the initial illness or insult is
survived .?0% survival rate/. *hronic renal failure usually develops over years in an
insidious manner leading to endstage renal disease reBuiring lifelong dialysis or renal
transplant.
Azotemia (increase of urea or other non-protein nitrogenous - compounds) is divided
into 3 categories:
=. )rerenal a5otemia is caused by a decrease in renal blood flo! e.g. due to
decreased cardiac output
;. @enal a5otemia results from damage to the kidney
<. )ostrenal a5otemia is due to obstruction of urine flo! e.g. by prostatic
hypertrophy or tumor
!" L#bor#tor& Fin*in$s in A1ute G%o.eru%one<hritis
,cute diffuse inflammatory changes in the glomeruli !ith hematuria @-* casts mild
proteinuria and often hypertension edema and a5otemia
A, Seru. 1he.istries
Hlevated 0'(
Hlevated
creatinine
Hlevated uric
acid
0'(4creatinine
E ;0
#ecreased creatinine clearance
+6@ decreased
,cidosis due to retention of phosphate sulfate
amino acids and other metabolic acids
B, Urin#%&sis
Microscopic hematuria .smoky
urine/
Macroscropic hematuria .red
urine/
*asts& @ed cell casts .blood
casts/
)roteinuria mild to moderate
C, Se%e1ti=it& r#tio
%he ratio of the clearances of a high and a lo! molecular !eight protein .Ig+ and
albumin respectively/ gives an indication of the nature of glomerular damage in
glomerular proteinuria .selective vs. non-selective/.
Selectivity
ratio
=
g! clearance
al"umin
clearance
7igh selectivity A 0.=5: e.g. minimal change glomerulonephritis
)oor selectivity E 0.<0: other than minimal change disease
/" L#bor#tor& Fin*in$s in Chroni1 G%o.eru%one<hritis
0lo!ly progressive glomerular disease& the syndrome is due to several diseases of
different etiology: the disease is characteri5ed by diffuse sclerosis of glomeruli and loss
of nephrons
A, Seru. 1he.istr& =#%ues
'remia .elevated 0'( creatinine and
uric acid/
7yponatremia
7yperkalemia
7ypocalcemia
7yperphosphatemia
#ecreased creatinine
clearance
,cidosis
Hlevated alkaline
phosphatase
0'(4creatinine A =0
+6@ decreased
B, Urin#%&sis
)roteinuria
Hpisodic
hematuria
Isosthenuria .0p. +r. fi"ed bet!een =.003 and
=.0=;/
*ylindruria .presence of tubular casts in the
urine/
C, Ane.i#
0" L#bor#tor& Fin*in$s in Ne<hrosis )Ne<hroti1 S&n*ro.e,
*omple" condition that follo!s prolonged increase in glomerular permeability for
proteins.
Tri#*
)roteinuria E <.5 g4day
7ypoalbuminemia
7yperlipidemia
In addition edema is generally present
0'(4creatinine 1=; .normal/
+6@ normal
%he decreased oncotic pressure stimulates hepatic lipoprotein synthesis and thus
hyperlipidemia is often seen in this condition. Increase in lipoproteins is also caused by
loss of factors regulating lipoprotein synthesis. In the nephrotic syndrome there is a loss
of a variety of proteins such as transferrin cortisol-binding globulin thyro"ine-binding
globulin and some coagulation factors. 7o!ever some coagulation factors are increased
e.g. 6actor C and CIII leading to thrombosis.
A, #>or *i#$nosti1 8in*in$s
Lo! albumin =-;.5 g4dL
.normal <.2-2.3 g4dL/
'rea nitrogen normal
*reatinine normal
Increase in triglycerides
Increase in cholesterol and
lipoproteins
B, Less s<e1i8i1 8in*in$s
Increase in phospholipids
Lo! ceruloplasmin
,4+ .albumin4globulin/ ratio
reversed
Lo! complement
Lo! transferrin
C, Urin#%&sis
@educed volume
Large amounts of protein usually <.5 - =0 g4d: values up to 50 g4;2 h are possible
H"cretion of red and !hite cells is common
*asts& many hyaline and finely granular casts due to lo! urine flo!
*asts may contain fat .fat is doubly refractile/
Ival fat bodies .epithelial cells and macrophages loaded !ith fat/
D, Seru.
%hyro"ine-binding globulin may be decreased: accordingly total %
2
.thyro"ine/ may
be decreased: thyroid function ho!ever is normal .normal free thyro"ine/. %otal
globulin concentration may be normal but
;
-globulins are increased and -globulins
may be lo! .see serum protein section/.
5" L#bor#tor& Fin*in$s in A1ute '&e%one<hritis
,cute infective tubulo-interstitial nephritis: acute pyogenic infection of the kidney - one
of the most common diseases of the kidney
A, Seru. 1he.istr& =#%ues
'rea ( creatinine and uric acid are normal
0'(4creatinine 1=; .normal/
+6@ normal
B, Urin#%&sis
)yuria .pus in urine/
Microhematuria
Ghite cell casts
-acteriuria
C, ?e.#to%o$&
Leukocytosis
:" L#bor#tor& Fin*in$s 8or Di88erenti#tin$ 'reren#% #n* Ren#% F#i%ure
T#b%e /
Prerenal
Failure
Renal
Failure
'rine osmolality .mIsmol4kg/ E 500 A <50
'rine& plasma ratio of urea concentration E =0&= A <&=
'rine& plasma ratio of osmolality E =.5&= A =.=&=
0erum urea 4 creatinine ratio E ;0&= variable
?" URINALYSIS
%he routine urinalysis is carried out in three phases& macroscopic chemical and microscopic
analysis.
!" #1ros1o<i1 E@#.in#tion )Gross E@#.in#tion,
*olor
%urbidity
/" Che.i1#% E@#.in#tion
0pecific gravity .normal ;2 hours& =.0=0 - =.0;5/
)rotein
+lucose
Jetone bodies
7emoglobin .occult blood/ .note& myoglobin also reacts/
-ile .direct or con$ugated bilirubin reacts but not uncon$ugated/
'robilinogen
0" i1ros1o<i1 E@#.in#tion
Larger elements are& casts mucous threads parasites ova foreign bodies etc. .lo!
po!er/
*asts if present are also e"amined under the high po!er field to determine their
types
%he numbers of red cells !hite cells epithelial cells bacteria yeast trichomonas
and crystals are also counted and an average count for each is recorded
5" Urine C#sts
*asts are found in the urine sediment. %hey are formed in t!o !ays by precipitation and
gelling of proteins in tubular fluid and by clumping of cells in tubules. *asts are molded
in the lumen of the distal renal tubules or collecting ducts. %he matri" of all casts is a
specific mucoprotein common to all casts namely %amm-7orsfall protein. %he
classification of casts is based on appearance physical properties and type of cellular
components. *ells !ithin the matri" can degenerate into coarse and finely granular casts
and to !a"y casts.
T&<es o8 urine 1#sts
!, Hyaline casts" %he casts consist only of %amm-7orsfall protein. %hey are
e"creted by the normal kidney in small amounts. H"cretion of numerous casts is
seen in all renal diseases associated !ith benign essential hypertension and
nephrotic syndrome.
/, White blood cell (leukocyte) casts" %hese casts are formed !hen G-*Ks are
incorporated into the protein matri". %hey enter the urine stream by ameboid
movement through and bet!een tubular epithelial cells and sometimes they cross
the glomerular capillary lumen. %hese casts are associated !ith diseases !ith
leukocytic e"udation and interstitial inflammation. H"ample& pyelonephritis.
0, Red cell (erythrocyte) casts. )resence of these casts indicates severe in$ury to the
glomerular basement membrane. %he reddish orange color is secondary to
hemoglobin pigmentation. Hrythrocytes .@-*Ls/ are biconcave disks packed in
fibrin mesh!ork !ithin the cast matri". %hese casts are associated !ith acute
glomerulonephritis .most common/ lupus nephritis +oodpastureLs syndrome
and subacute bacterial endocarditis .0-H/.
5, Renal epithelial casts. %hese casts are due to constant desBuamation and rene!al
of the renal epithelium. %heir presence points to a pathological process occurring
in the kidney and affecting the tubular portion of the nephron .tubular damage/.
Hpithelial casts are associated !ith e"posure to nephroto"ic agents and e"posure
to some viruses.
:, ranular casts" %hese casts are formed from breakdo!n products of cellular casts
and immunoglobulins. %here is a progression from coarsely granular to finely
granular casts.
A, Wa!y casts. %hese are the result of progressive degenerative changes occurring in
cellular casts and they are associated !ith severe chronic renal disease and
amyloidosis.
4, Fatty casts. %hese casts are probably due to leakage of lipoproteins through the
glomerular filter and are associated !ith nephrotic syndrome diabetes mellitus
and damaged renal tubular epithelial cells.
9, "i!ed cell casts.
0ome commonly seen urinary crystals
Cr&st#% A<<e#r#n1e Urine <?
*alcium o"alates 8#nvelopes9 acid
0odium urates 8$hetstones9 acid
%riple phosphates
.magnesium ammonium
phosphate/
8%offin lids9 alkaline
,mmonium biurates 8&horn apples9 alkaline
,morphous phosphates ,morphous debris alkaline
%yrosine (eedles in rosettes acid
Leucine 0pheres acid
0ulfonamides 0heaves acid
*ystine 7e"agons acid
#rug crystals .e.g. ampicillin needles primidone he"agons/ are formed from drugs that
are present in relatively high concentrations and that are relatively insoluble in !ater at
the urinary p7.