++
Routine screening of renal function in healthy children is not
cost-effective and is therefore not recommended. Renal function
assessment is useful in children in whom a renal disorder is suspected,
in longitudinal assessment in children with known renal disease
or those likely to be exposed to nephrotoxic therapies, and in calculating
the dosage of specific drugs eliminated through the kidney.
++
A rough assessment of glomerular function is obtained by measuring
serum urea and creatinine. In contrast, precise measurement of glomerular
function is complicated by a variety of factors, the most important
being that the normal kidney alters its glomerular function in response to
the workload.8Following protein loading, normal individuals
can increase the glomerular filtration rate (GFR) by 50% to
100%. In early renal disease, unaffected nephrons increase
their single-nephron GFR to compensate for diseased nephrons and
can thus maintain relatively normal renal function until there is
significant nephron loss, masking the severity of the renal disease.
Furthermore, GFR actually increases in newly diagnosed diabetics9 and
children with sickle cell disease,10 despite later renal
disease.
++
Blood urea nitrogen (BUN) is actually a serum
measurement. Levels reflect glomerular function but are influenced
by numerous factors: The net balance of production from catabolism
of both endogenous and dietary protein, filtration by the glomerulus, and
reabsorption by the distal nephron determines the BUN level. Increased
protein catabolism such as occurs with stress or corticosteroid
therapy will increase BUN independent of any change in renal function.
Tubular reabsorption of urea is altered by changes other than glomerular
filtration, so it is not a reliable marker of glomerular function. Dehydration
alone can raise BUN. Since dietary protein intake alters BUN, the
BUN may decrease in children with renal failure who are placed on
low-protein diets despite any real change in renal function. Furthermore,
a rise in BUN with declining GFR is curvilinear, so that only small
changes in BUN occur until a 50% to 60% decline in
renal function happens, making it an insensitive and unreliable marker
of glomerular function.
++
Creatinine is the nonenzymatic end product of
creatine metabolism. It is freely filtered by the glomerulus and
is secreted by the tubule in a concentration-dependent manner such that
about 5% is excreted by tubular secretion when the creatinine
is normal and as much as 50% when the serum creatinine
is 10 mg/dL. Serum levels are essentially independent of
the diet, making it a better marker of GFR than BUN. However, creatinine
levels correlate to lean body mass, because creatinine is generated
from muscle creatine. Muscle wasting lowers serum creatinine levels independent
of renal function. Because of this association with muscle mass,
serum levels rise with age. After the age of 4 years, boys have
a higher serum creatinine level than girls, although this difference
is not significant until after puberty. Serum creatinine is traditionally
measured using the Jaffé reaction with picric acid, which also
measures noncreatinine chromagens that falsely elevate the measured
level. A number of clinically relevant substances can interfere
with this reaction and can alter the true serum level, including
bilirubin (which can lower the level) and ketones (which can raise
the level).
++
Recent methods analyze creatinine enzymatically and are not influenced
by noncreatinine chromagens, ketones, or bilirubin. Newborns, especially
premature infants, have higher creatinine levels than older children,
and these levels are inversely correlated to gestational and postnatal
age (see Table 467-2). Serum creatinine levels fall rapidly
over the first weeks of life as GFR increases postnatally. Like BUN,
serum creatinine rises in an exponential curvilinear, rather than
a linear, pattern with a decline in GFR; therefore, only minimal increases
are observed until 50% to 60% of function is lost.
The serum creatinine doubles for each halving of GFR, so a serum
creatinine of 0.8 mg/dL that increases to 1.6 mg/dL
would indicate that GFR had decreased by 50%.
++
++
Cystatin C, a low-molecular-weight protein produced
by all nucleated cells, can also be used as a marker of GFR.11 Cystatin
C levels are independent of gender and body composition. They are
highest in preterm infants and decline to adult values by age 1.5
years (Table 467-2). Some studies suggest
that cystatin C levels can show a decrease in GFR before serum creatinine. Cystatin
C is not cleared by the placenta; thus, it is a more accurate indicator
of renal dysfunction in fetuses12 and newborn infants with
renal malformations.13 Several formulas have been devised
to estimate GFR from serum cystatin C levels, but most are quite
complex, limiting their application in clinical medicine.
++
Clearance is the classical method of describing
glomerular renal function and is the volume of plasma completely
cleared of a given substance per unit of time. Mathematically, clearance
is the excretion rate of that substance divided by its plasma or
serum concentration:
++
++
where Ux is the urine concentration of x, V
is the urine flow rate, and Px is the plasma concentration.
Substances that are freely filtered across the glomerular capillary wall
and are not reabsorbed or secreted by the renal tubule can be used
to determine the glomerular filtration rate (GFR). Traditionally,
inulin, a polymer of fructose, has been the reference method for measuring
GFR. However, inulin clearance measurements are difficult and are
performed only in specialized renal units.
++
Creatinine clearance (Ccr) is the most widely used method to
estimate GFR, but because creatinine is secreted by the tubule,
Ccr overestimates the GFR, and this overestimate increases
with decreasing GFR. At normal levels of GFR, the Ccr is
about 10% to 20% above the actual GFR, but at
a GFR below 10 mL/min, the creatinine clearance is nearly
twice the inulin clearance, although this usually does not alter
management. Ccr requires a complete collection of urine
over 24 hours to minimize collection and timing errors. Obtaining
a complete urine collection is often problematic and can be assessed
by comparing the measured creatinine excretion with the expected
excretion of urinary creatinine (10 to 20 mg/kg per day,
or in postpubertal girls, 1 g/d and in postpubertal boys,
2 g/d). Because of the difficulties in performing timed
urine collections, estimates of Ccr have been devised based
on the child’s height, which is better correlated with
creatinine excretion than weight, and serum creatinine. One such
formula for estimating creatinine clearance is
++
Ccr(mL/min/1.73m2) = k × Ht
(cm)/Scr(mg/dl)
++
where k = 0.55 for children and adolescent girls,
0.7 for adolescent boys, 0.45 in term infants, and 0.33 in low-birth-weight
infants.14 Scr is serum creatinine concentration. Despite
limitations, in the clinical setting in which glomerular filtration
rate (GFR) is being followed over time in the same patient, an estimate
of GFR based upon creatinine clearance is both practical and helpful
in tracking the course of renal function. Single-injection techniques
provide an alternative for measuring GFR without collecting urine.
The radioisotope 99m technetium diethylenetriaminepentaacetic
acid (DTPA) is not metabolized and is eliminated only by glomerular
filtration, so the disappearance of the DTPA from the plasma is
related to the GFR. This test is readily available in most nuclear
medicine laboratories and is therefore quite useful. A less available
but accurate method of determining GFR is the constant-infusion
technique, which takes advantage of the fact that the urine excretion
of a substance (UxV) is the same as the infusion rate when
the serum concentration of the infused substance is in steady state.
Iothalamate clearances use this technique and are quite accurate,
but they are not routinely available.
++
The GFR rises rapidly and curvilinearly over the first year of
life and then increases gradually until puberty. After 2 years of
age, the GFR or creatinine clearance, when expressed per unit surface
area (typically 1.73 m2), is relatively constant. Before
2 years of age, knowledge of the different values for GFR for each conceptual
and gestation age is necessary (see Table 467-2).
++
Although glomerular function can simply be described in terms
of the GFR, tubular function and its assessment is more complex. The
tubule can be divided into the proximal and distal portions, although
this is a gross oversimplification. The proximal nephron reabsorbs
the bulk of the filtered load, and the distal nephron “fine-tunes” the
final urine composition. The proximal nephron reabsorbs virtually
all the filtered glucose and amino acids, 60% to 80% of
the filtered sodium and phosphate, and 85% of the filtered
HCO3. The distal nephron is responsible for net H+ion
secretion and urine concentration, and it adjusts the final excretion
of other electrolytes and solutes.
++
Tubular function is usually described in terms of the clearance
of a solute that is handled by a specific segment of the nephron
or in terms of the overall clearance of a solute that is handled
in several sites along the nephron, which is the case for most solutes.
Another way of describing tubular function is to compare the clearance
of a solute to the GFR, usually estimated by the creatinine clearance. This
is termed the fractional excretion (FE) of that
solute. The FE of any solute x can be determined
by the ratio of the urine concentration of x to
the plasma concentration of x, divided by the ratio
of urine creatinine concentration to the plasma concentration:
++
++
This is usually multiplied by 100% to generate the percent
fractional excretion. Subtracting the %FE from 100% will
give the percent tubule reabsorption.
++
Disorders of the proximal tubule vary from excess loss of a single
solute, such as renal glucosuria, to global loss of virtually all
solutes reabsorbed in the proximal nephron, as observed in the Fanconi
syndrome. The distal nephron has many functions, but the ability
to concentrate and acidify the urine are most often used to assess
distal nephron function. The maximal urine-concentrating ability
is determined by measuring the urine concentration after an overnight
fast. A normal response is for urine specific gravity to exceed
1.020 or a urine osmolality to exceed 800 mOsm/kg. This
test should be done only in a closely monitored setting if the child
typically drinks fluid during the night or if there is a strong
possibility of diabetes insipidus (see Chapter 525). A urine pH of less than 5.5, either spontaneously or
after an acid load, indicates that the distal nephron can generate
acid urine, ruling out the diagnosis of type I distal RTA. Other
methods of testing the distal nephron acidification mechanisms are
measuring the urinary titratable acid excretion, ammonium excretion,
and the concentration of CO2 in alkaline urine. A positive
urinary ion gap, UCl – (UNa + UK) can
be used to infer intact ammonium excretion; a negative urinary ion
gap during acidosis suggests inadequate ammonium generation.15 Subjects
with normal distal nephron hydrogen ion pumps are able to raise
the urine pCO2 above 60 mm Hg, as measured with a standard
blood gas instrument. This test requires an excess of urinary bicarbonate.
Individuals with absent or impaired H+ion pumps
cannot raise the urinary pCO2.15