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W. Greg Miller, et al. Optimal Use of Biomarkers for Chronic Kidney Disease. Clin Chem 2019;65:949-955.
Dr. Greg Miller is a professor in the Department of Pathology and Director of Clinical Chemistry at Virginia Commonwealth University.
This is a podcast from Clinical Chemistry, sponsored by the Department of Laboratory Medicine at Boston Children’s Hospital. I am Bob Barrett.
Chronic kidney disease, or CKD, affects approximately 15% of the U.S. population. People with diabetes, hypertension, cardiovascular disease, family history of CKD, as well as several ethnic groups are at increased risk for CKD. There are two primary laboratory tests for diagnosis of CKD. The first is serum creatinine concentration, along with a calculation of estimated glomerular filtration rate, called EGFR based on that creatinine result.
The second is performed with urine samples, and here both albumin and creatinine are measured and the ratio of those two tests calculated. A challenge for care of people living with chronic kidney disease has been poor awareness of having the disease, because there are no symptoms until advanced stages and people at risk are not adequately screened with the laboratory tests. In the 2013–2016 U.S. National Health and Nutrition Examination survey, only 8% of the population with abnormally low EGFR results were aware of having CKD.
In the August 2019 issue of Clinical Chemistry, a Q&A feature titled “Optimal Use of Biomarker for Chronic Kidney Disease” asked five experts in laboratory medicine and nephrology to examine laboratory ordering, testing, and reporting practices, and recommend how those practices should be optimized to better serve patients with CKD.
In this podcast, Dr. Greg Miller from the Department of Pathology at Virginia Commonwealth University in Richmond who moderated the Q&A will summarize the expert advice from his colleagues. So first off, Dr. Miller, just what is a kidney profile and when should it be ordered?
Well, a kidney profile is an order set consisting of serum creatinine and urine albumin and creatinine. The main reportable results are the estimated GFR and the urine albumin creatinine ratio that are most useful to identify people with chronic kidney disease and to classify the risk status. There is not currently a CPT code for billing the kidney profile in the United States, but the individual measured test values are billable irrespective of how they are ordered.
A Laboratory Advisory Group convened by the U.S. National Kidney Foundation recommends implementing the kidney profile for targeted testing of risk groups such as patients with hypertension, diabetes, cardiovascular disease, rheumatic conditions, or who have a family history of CKD. The kidney profile is also useful for patients with known CKD to evaluate the progression which is defined as a change in GFR over time.
I’m wondering, how does a kidney profile differ in use from a renal function panel?
The kidney profile includes only tests to detect CKD, or chronic kidney disease, and to classify its severity based on the levels of the estimated GFR and albuminuria. The renal function panel consists of a larger number to tests: serum glucose, creatinine, urea nitrogen, calcium, phosphorus, albumin, sodium chloride, potassium, carbon dioxide and anion gap. The renal function panel is used to detect complications of CKD such as abnormalities of mineral metabolism, nutrition status, hyperkalemia, or acidosis, that typically occur when the EGFR falls below 30 to 40 mL per minute per 1.73 m² of body surface area.
A renal function panel is also useful at higher eGFR values to set a baseline to evaluate progression of complications. A renal function panel can also be used to evaluate side effects of medications such as hyponatremia, hypokalemia, or metabolic alkalosis from diuretics. Glucose concentrations are important as hyperglycemia can cause acute kidney injury as well as increased risk for CKD progression.
What is the preferred equation to estimate eGFR from serum, plasma, or blood creatinine?
Well, the two common eGFR equations for use of creatinine are the IDMS traceable version of the modification of diet and renal disease--we call that the MDRD Study equation—and the chronic disease epidemiology collaboration equation, referred to as the CKD-EPI equation, which was developed using IDMS-traceable creatinine results. Both of these equations are valid for patients over the age of 18 and contain variables that adjust the eGFR to account for creatinine differences due to age, gender, an African-American versus non-African-American ethnicity. Use of these variables improves agreement of the estimated GFR with GFR measured using inulin or iohexol clearance.
The CKD-EPI equation is more accurate and less biased than the IDMS-traceable MDRD Study equation in the population with EGFR near and above about 60 mL/min/1.73 m². The IDMS-traceable MDRD Study equation underestimates GFR when values exceed 60. Therefore, such values should be reported as ≥ 60 mL/min/1.73 m² when using the MDRD equation. With the CKD-EPI equation, there is no increase in error at higher levels of GFR and therefore the eGFR can be reported through the full range of GFR.
Observational studies comparing these two widely used equations show the CKD-EPI creatinine equation more accurately predicts adverse kidney, cardiovascular, and mortality outcomes for people with CKD. There is a strong need to harmonize the equation used and thus decrease the variability in eGFR values among different laboratories, supporting uniform use of the best available CKD-EPI equation. For these reasons, the kidney disease improving global outcomes, usually called KDIGO 2012 guideline, and U.S. National Kidney Foundation both supports using only the CKD-EPI equation.
It is important to remember that all estimating equations have errors relative to measured GFR. The 2002 Kidney Disease Outcomes Quality Initiative guidelines concluded that an eGFR within 30% of a measured GFR was satisfactory for clinical interpretation. Errors will be greater for people who have non-GFR determinants that are different than the populations from which the equations were derived, for example, vegetarians, bodybuilders, or people with muscle wasting diseases. In children, the “Bedside” Schwartz equation is suitable for use with creatinine results from IDMS-traceable enzymatic creatinine measurement procedures and is recommended in pediatric patients.
Should enzymatic methods replace Jaffe-based methods for measuring creatinine?
Jaffe creatinine measure procedures are typically influenced by interferences from what had been called pseudo-chromogens, or non-creatinine chromogens, in the reaction. These include glucose, protein, pathological amounts of acetoacetate, acetone, ascorbate, pyruvate, and many drugs such as dobutamine and cephalosporin present in serum plasma. Attempts to reduce the influence of interfering substances in Jaffe methods by using kinetic measurements and compensated methods are common but only partially successful. The compensation approach subtracts a fixed value from the creatinine measurement to adjust for the average amount of pseudo-chromogens in
adult serum or plasma. When abnormal amounts of
pseudo-chromogens are present, the compensation is
inadequate and erroneously high creatinine values typically
occur. Of particular concern is pediatric testing when
proteins in particular is lower than in adults causing falsely
low creatinine results and an incorrect assessment of kidney
Because of their better analytical specificity, enzymatic
creatinine methods have largely eliminated the analytical
interferences caused by pseudo-chromogens. However,
some enzymatic methods do have some interferences
particularly from hemoglobin and bilirubin. Current
automated measuring systems automatically check for
hemolysis and elevated bilirubin, so a laboratory can easily
identify affected creatinine results.
Investigations of patient sample results measured by both
Jaffe and enzymatic methods have shown reduced bias for
enzymatic methods compared to the IDMS reference
measurement procedure and better precision performance
than for Jaffe methods. The superior analytic performance
of enzymatic method is particularly important that the
critical decision value of 60 mL/min/1.73 m² of body surface
area for classifying patients with CKD and for pediatric
patients who have lower creatinine values even in the
presence of kidney disease.
So, in summary, laboratories should use enzymatic methods
for improvements in all aspects of performance. This is
particularly important in pediatric samples and is formally
recommended in Australian guidelines. However, in
resource-limited parts of the world, the use of Jaffe method
is less expensive, but attention should always be given to
ensure IDMS-traceability of the calibration.
Doctor, when should cystatin C be ordered?
Cystatin C is a protein produced by all nucleated cells and is
freely filtered through the glomerulus. Its principal
advantage over creatinine is that cystatin C is not affected
by muscle mass. Consequently, cystatin C is used as a
confirmatory test in situations when eGFR from creatinine is
less reliable. Creatinine production is abnormally low for
example in sarcopenia, in patients with a low muscle mass
due to a neuromuscular disorder, muscle wasting disease,
limb amputation, malnutrition, or vegetarian diet.
Creatinine is abnormally high in situations such as
bodybuilders, elite athletes, those taking creatinine
supplements or on a high red meat diet. Cystatin C should
be considered when a more accurate level of eGFR is needed
for clinical decisions. For example, administration or dosing of toxic medications cleared by the kidneys, such as
cisplatin, carboplatin, several antibiotics or contrast agents.
eGFR from cystatin C is also useful for decisions for kidney
donation or determination of GFR prior to decisions for heart
or liver transplant alone or simultaneous with kidneys. In
most populations, several studies have demonstrated that
the eGFR from an equation that combines creatinine and
cystatin C provides the most accurate estimate.
The 2012 KDGO CKD Guideline recommends assessment of
cystatin C in persons with creatinine-based eGFR between
45-59 mL/min//1.73 m² without any albuminuria based on
data showing that the eGFR from creatinine may misclassify
Persons with eGFR based on creatinine between 45 and 59
without albuminuria and whose eGFR from the combined
creatinine cystatin or from cystatin alone values are above
60 have a very low risk for CKD complications. Estimating
equations that incorporate cystatin C require standardized
calibration of serum cystatin C measurement procedures to
the certified reference material ERMDA471/IFCC Human
Serum (Cystatin C) introduced in 2010.
When should urine albumin and/or urine total protein be
measured in patients with chronic kidney disease?
Serum creatinine is a measure of a number of functional
nephrons. Albuminuria allows assessment of the quality of
the glomerular membrane itself. Urea albumin and urine
total protein tests are often used interchangeably in
practice. The urine albumin creatinine ratio is a more
sensitive and specific measure of kidney damage.
Moreover, only the urine albumin is currently being
standardized whereas the urine total protein will probably
never be standardized. For these reasons, urine albumin is
the preferred test for routine screening of targeted risk
groups such as diabetes, hypertension, cardiovascular
disease, relatives of patients with end-stage renal disease,
systemic vasculitis, recurrent urinary tract infections, and in
patients with a history of chronic non-steroidal anti-inflammatory
For glomerular disease, urine albumin should be
approximately 60%-70% of the urine total protein present.
Most kidney diseases, such as diabetes or hypertension,
affect the glomerulus. Consequently, for most causes of
kidney disease, theoretically both albumin and protein can
provide similar information. However, because assays for
albumin are more accurate and can detect lower
concentrations, urine albumin is recommended as the
primary test to detect CKD. However, there are conditions
where the presence of non-albumin proteins is important to detect. The most important are immunoglobulins which
could indicate myeloma or more generally monoclonal
gammopathy of renal significance. Thus, both total protein
and albumin should be ordered when physicians are
concerned about these conditions, and if the total protein is
more than 30% greater than the urine albumin, it might
indicate non-albumin proteins in the urine, and further
diagnostic tests should be considered.
Well finally then doctor, how should urine albumin and the
albumin creatinine ratio, or urine total protein and protein
creatinine ratio, be reported?
Historically, the urine albumin excretion rate calculated from
a 24-hour urine collection was the gold standard test used
for assessing albuminuria. Due to frequent incomplete
collection of 24-hour specimens, the urine albumin to urine
creatinine ratio (UACR) is now recommended by most
practice guidelines including the KDIGO 2012. The urine
albumin creatinine ratio from a first morning void has been
shown to have equivalent diagnostic accuracy to a properly
collected 24-hour urine albumin excretion.
Physicians need to know the quantitative amount of the
urine albumin creatinine ratio to properly manage risk and
progression of CKD, as well as the effectiveness of
treatment. When urine albumin values exceed the upper
limit of the analytical measuring range for that
measurement procedure, the urine should be diluted, remeasured
and a quantitative value reported. If a result is
obtained that exceeds the extended measuring interval for
diluted samples, a result for the albumin and the urine
albumin creatinine ratio should be reported as “greater
than” the maximum value that could possibly be obtained
for the upper limit of the extended measuring interval after
the dilution procedures.
The terms “microalbumin” and “microalbumin” also caused
confusion since practitioners may incorrectly conceptualize
that microalbumin testing is for excretion of a small albumin
molecule rather than elevated level of urinary albumin
excretion. Recent clinical practice guidelines recommend
that the term “microalbumin” be replaced with “urine
albumin” as the name for the test, and the result always be
reported as a ratio of albumin to urine creatinine.
The units for measuring urine albumin and creatinine are
not uniformed and can cause confusion for physicians.
Reporting units for urine albumin should be mg/L and for
urine albumin creatinine ratio should be mg/g creatinine or
mg/mmole of creatinine depending on in what country a
laboratory is located.
That was Dr. Greg Miller from the Department of Pathology at Virginia Commonwealth University in Richmond. He has been our guest in this podcast from Clinical Chemistry on “Optimal Use of Biomarkers for Chronic Kidney Disease.” That Q&A feature appears in the August 2019 issue of Clinical Chemistry. I’m Bob Barrett. Thanks for listening!