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Clinical Assessment of a Patient

with Chronic Kidney Disease 2

Mustafa Arici

Before You Start: Facts You Need to Know 2.1 History and Physical
A focused history and physical exami- Examination of a Chronic
nation is essential in the assessment of Kidney Disease Patient
patients with chronic kidney disease
(CKD). Chronic kidney disease (CKD) is usually a
A CKD patients history should differ- silent condition. Signs and symptoms, if pres-
entiate CKD from acute kidney disease, ent, are generally nonspecific (Box 2.1) and
define duration and chronicity, find a unlike several other chronic diseases (such as
causative or contributory disease, and congestive heart failure, chronic obstructive
assess complications and comorbidities. lung disease), they did not reveal a clue for diag-
Physical examination should cover all nosis or severity of the condition. Typical symp-
systems but has a special emphasis on toms and signs of uremia (Box 2.2) appear
blood pressure and orthostatic changes, almost never in early stages (Stage 1 to 3A/B,
volume assessment, and cardiovascular even Stage 4) and develop too late only in some
examination. patients in the course of CKD. Still, all newly
Serum creatinine and estimation of glo- diagnosed CKD patients, patients with an acute
merular filtration rate (GFR) with an worsening in their kidney function, and CKD
equation using serum creatinine should patients on regular follow-up should have a
be done as a part of initial assessment in
all CKD patients.
A complete urinalysis and measurement Box 2.1. Symptoms and Signs of Early
of albumin in the urine should be carried Stages of CKD
out in all CKD patients. Weakness
Decreased appetite
Changes in urination (nocturia, polyuria,
Blood in urine or dark-colored urine
Foamy or bubbly urine
Loin pain
M. Arici, MD
Elevated blood pressure
Department of Nephrology, Faculty of Medicine,
Hacettepe University, Ankara 06100, Turkey Pale skin

M. Arici (ed.), Management of Chronic Kidney Disease, 15

DOI 10.1007/978-3-642-54637-2_2, Springer-Verlag Berlin Heidelberg 2014
16 M. Arici

Box 2.2. Symptoms and Signs of Late Box 2.3. Clues to the Underlying
(Uremic) Stages of CKD (Causative or Contributory) Disease
General (lassitude, fatigue, elevated blood in a CKD Patient
pressure, signs of volume overload, Previous lab tests, imaging, or biopsy find-
decreased mental acuity, intractable ings (provide definite evidence for CKD if
hiccups, uremic fetor) they show previously decreased GFR
Skin (sallow appearance, uremic frost, and/or presence of kidney damage, pres-
pruritic excoriations) ence of bilateral small kidneys)
Pulmonary (dyspnea, pleural effusion, pul- System review:
monary edema, uremic lung) Cardiovascular (history of myocardial
Cardiovascular (pericardial friction rub, infarction, coronary intervention, and
congestive heart failure) heart failure provide evidence for car-
Gastrointestinal (anorexia, nausea, vomit- diorenal connection and impaired renal
ing, weight loss, stomatitis, unpleasant perfusion)
taste in the mouth) Immunologic/Infectious (provide evi-
Neuromuscular (muscular twitches, dence for autoimmune or infectious
peripheral sensory and motor neuropa- causes of CKD)
thies, muscle cramps, restless legs, Gastrointestinal (history of hepatitis,
sleep disorders, hyperreflexia, seizures, cirrhosis)
encephalopathy, coma) Genitourinary (frequent urinary tract
Endocrine-metabolic (decreased libido, infection, recurrent kidney stones, and
amenorrhea, impotence) urinary symptoms related to bladder
Hematologic (anemia, bleeding diathesis) neck obstruction provide evidence for
pyelonephritis, obstruction, and stones)
Past medical history (history of long-
focused history and physical examination. This standing hypertension or diabetes, glo-
will be the key to perceive real implications of merulonephritis in early childhood, renal
health associated with decreased kidney func- complications during pregnancy, any pre-
tion in CKD. vious acute kidney injury episode, any pre-
In a newly diagnosed CKD patient, the his- vious urologic intervention)
tory should be focused to differentiate an acute Family history (anyone with CKD diag-
kidney injury/disease from CKD and get clues nosis among first-degree relatives)
for duration and chronicity of kidney dysfunc- Medication history (frequent use of
tion. Any previous kidney function tests, urine NSAIDs or pain killers, long-term expo-
findings, and imaging studies should be obtained sure to nephrotoxic antibiotics, frequent
and reviewed. If CKD diagnosis is confirmed, exposure to radiocontrast agents, chemo-
history should be focused to find an underlying therapeutic use, etc.)
cause. Patients should be questioned for any sign Source: Reprinted from KDOQI clini-
or symptom of an underlying (causative or con- cal practice guidelines for chronic kidney
tributory) disease(s) for CKD. All medications disease: evaluation, classification, and
(including current and prior medications, over- stratification [1], Copyright 2002, with
the-counter and non-prescription medications) permission from Elsevier. Available from:
should be carefully reviewed and documented.
Any previous surgical intervention, especially KDOQI/guidelines_ckd/toc.htm
genitourinary interventions, should be reviewed.
A detailed family history should be obtained to
exclude presence of a familial, hereditary kidney In each visit, the stage of CKD and presence
disorder (Box 2.3). of any comorbidity and complications related to
2 Clinical Assessment of a Patient with Chronic Kidney Disease 17

loss of kidney function and cardiovascular status

should be evaluated. All body systems should be Box 2.4. What the Guidelines Say You
thoroughly reviewed as CKD may have various Should Do: History and Physical
manifestations in any of them. Patients should be Examination
specifically questioned for dermatological, pul- Review past history and any previous
monary, cardiovascular, cerebrovascular, periph- measurement for GFR or markers of
eral vascular, gastrointestinal, genitourinary, kidney damage to determine the dura-
musculoskeletal, and neurological symptoms. tion of kidney disease.
Potential risk factors for sudden deterioration Evaluate the clinical context, includ-
and progression of CKD, along with a careful ing personal and family history, social
review of medications, should be sought in each and environmental factors, medications,
visit. physical examination, laboratory mea-
Physical examination of a CKD patient sures, imaging, and pathologic diagno-
includes a few specific points beyond general sis to determine the causes of kidney
rules. Patients general health, nutritional status, disease.
appetite, and weight changes should be deter- Source: Data from KDIGO 2012 clinical
mined in each visit. Blood pressure and pulse practice guideline for the evaluation and
should be assessed both in upright and supine management of chronic kidney disease [2]
positions for determining orthostatic changes.
Hypertensive or diabetic changes in the eye
should be examined by fundoscopy. Patients the absence of any marker for kidney damage.
should be examined for signs of hypovolemia or GFR usually correlates well with the prognosis
volume overload. Skin should be evaluated for and complications of CKD like anemia, mineral-
finding an underlying disease and signs of CKD bone disorders, and cardiovascular disease. GFR
(anemia, pruritus, sallow appearance). A careful should be determined for confirming diagnosis,
evaluation of the cardiovascular system is impor- staging the disease, estimating the prognosis and
tant. The abdomen should be palpated for large making decisions about treatment in all CKD
kidneys and bladder distention. Abdominal bruits patients. GFR level may also be used to decide
should be noted for potential renovascular dis- appropriate timing to start renal replacement
ease. Costovertebral tenderness may be a sign of therapies. GFR should be regularly monitored in
infection and/or stone disease in kidneys. In men, CKD patients according to the stage and severity
rectal examination is required for determining of CKD. There is however no consensus on the
prostatic enlargement. Neurological evaluation monitoring frequency of GFR in various stages
should be focused on signs of neuropathy and (Table 2.1).
muscular problems. Examination for any sign of GFR is traditionally measured as renal clear-
a systemic disease causing or contributing to ance of an ideal filtration marker, such as inulin
CKD should be carefully sought. Findings con- from plasma. This measured GFR is considered
sistent with uremia should be determined and fol- the gold standard but is not practical for daily
lowed in each visit (Box 2.4). clinical use due to complexity of the measure-
ment procedure. Estimating GFR based on a fil-
tration marker (usually serum creatinine) is now
2.2 Estimating or Measuring widely accepted as an initial test. Several GFR
Glomerular Filtration Rate prediction equations that use serum creatinine or
in CKD some other filtration markers along with certain
patient characteristics (like age, gender, and race)
Glomerular filtration rate (GFR) is usually are giving precise estimates of GFR in various
accepted as the best index of kidney func- clinical settings [3].
tion. Persistently decreased GFR (<60 ml/ 1. Serum creatinine, Creatinine clearance, and
min/1.73 m2) is a hallmark for CKD, even in GFR estimating equations: These are the most
18 M. Arici

Table 2.1 How often should GFR be monitored in CKD? reductions (~3040 %) in real GFR due to
Stage Testing frequency (once in every)a increased tubular secretion and extrarenal
Stage 1 and 2 612 months elimination of creatinine [5].
Stage 3A 46 months Serum creatinine is commonly mea-
Stage 3B 34 months sured by alkaline picrate (Jaff method),
Stage 4 23 months enzymatic, or high-performance liquid
Stage 5 1 month chromatography (HPLC) methods. These
Source: Adapted by permission from Macmillan Publishers different methods of measuring serum cre-
Ltd: Kidney Disease: Improving Global Outcomes (KDIGO) atinine are recently standardized to the
CKD Work Group [2] and National Institute for Health and
Clinical Excellence (NICE) [4]. Available from: http://www. isotope dilution mass spectrometry (IDMS). Standardized measurements usu-
Testing frequency may change according to progression ally yield 5 % lower values for serum cre-
rate and albuminuria level in each stage. All CKD patients atinine concentrations. The alkaline
have GFR measurement during any intercurrent illness,
any operation, any hospitalization, and any radiocontrast picrate method is subject to interference
administration by various serum constituents and drugs.
The differences in assays and inter- and
intra-laboratory variability may also affect
common methods used for assessing kidney the accuracy of serum creatinine measure-
function in clinical practice. ments [6].
Serum creatinine measurement is a very con- All these factors (differences in creati-
venient, cheap, and readily available tech- nine generation, tubular secretion, extrare-
nique. It is, therefore, the most commonly nal elimination, and variations in assay
used parameter to evaluate kidney function methods) may affect diagnostic sensitivity
in routine clinical practice. Serum creatinine and correct interpretation of serum creati-
(SCr) levels are largely determined by the nine. Serum creatinine alone is not any-
balance between its generation and excretion more accepted as an adequate marker of
by the kidneys. Creatinine generation is kidney function.
affected by muscle mass and dietary meat Creatinine clearance (Ccre) measurement
intake. Age, gender, and racial differences in is a frequently used clinical method for
creatinine generation depend to changes in measuring GFR. Its calculation depends
muscle mass. In a CKD patient, reduced pro- on 24-h urine collection. This is a cum-
tein intake, malnutrition, and muscle wasting bersome procedure, especially in elderly.
may reduce creatinine generation. These fac- An incomplete or prolonged collection of
tors may blunt the rise of serum creatinine in urine alters the accuracy of the results. If
spite of a decrease in GFR levels, especially creatinine generation is stable and there is
in late stages of CKD. no extrarenal elimination of creatinine, a
Creatinine is freely filtered through the complete collection may be determined by
glomerulus and is also secreted by the calculating total excretion of creatinine in
proximal tubules (510 % of the excreted the urine as follows:
creatinine). Tubular secretion of creatinine
Urine creatinine urine volume
increases with decreasing kidney function.
= 20 25 mg / kg / day for men ,
Another problem is the increased extrare-
10 15 mg / kg / day for women
nal elimination of creatinine with decreas-
ing kidney function. Both factors lead to Calculation of creatinine clearance
underestimation of kidney function by assumes that all of the filtered creatinine
using only serum creatinine levels. In early (equal to the product of the GFR and the
stages of CKD, serum creatinine usually serum creatinine concentration (SCr))
stays in normal limits despite large is equal to all of the excreted creatinine
2 Clinical Assessment of a Patient with Chronic Kidney Disease 19

(equal to product of the urine creatinine levels with other determinants of GFR
concentration (UCr) and the urine flow rate) like age, gender, and race and body size.
and ignores the tubular secretion of cre- The most common equations used are the
atinine. In this condition, the formula is as Cockcroft-Gault, the Modification of Diet
follows: in Renal Disease (MDRD) Study, and the

Ccre = [ UCr V ] / SCr, where Ucr ( Urine creatinine ) is mg / ml, V ( urine volume ) is ml
and SCr ( Serum creatinine ) is mg / dl.If the finding is divided to 1, 440 ( 24h 60 min ) ,
creatinine clearance is expressed as ml / min .

Creatinine clearance formula overesti- Chronic Kidney Disease Epidemiology

mates true GFR by approximately Collaboration (CKD-EPI) equations.
1020 % because of disregarding tubular The Cockroft-Gault equation is the oldest
secretion. As already mentioned, tubular (developed in 1973) but simplest equa-
secretion of creatinine increases with tion for everyday clinical use. It has been
decreasing kidney function causing derived using data from 249 men with a
higher overestimations in late stages of creatinine clearance ranging from approxi-
CKD. mately 30130 ml/min [7].

Ccre ( ml / min ) = {(140 age ) body weight / ( 72 Scr )} (0.85 if female), where age is expressed
in years, weight in kilograms, and serum creatinine ( Scr ) in milligrams per deciliter.

The reciprocal serum creatinine concen- This equation was derived when stan-
tration (1/SCr) curve is used to follow dardized creatinine assays were not in use.
changes in the kidney function of patients In labs where standardized creatinine assays
with CKD. It assumes that GFR is inversely were used, this equation will cause an over-
proportional to the serum creatinine. If cre- estimation (1040 %) of actual GFR. This
atinine generation, extrarenal elimination, equation has not been adjusted for body sur-
and tubular secretion remain stable, a plot face area. It is less accurate in obese patients
of 1/SCr against time will be linear with a (overestimate), in patients with normal or
constant decrease in GFR. Due to several mildly decreased GFR (underestimates),
caveats, this method is not popular any- and in the elderly (underestimates) [6, 8].
more for following progression among The MDRD Study equation was developed
CKD patients. in 1999 by using data from 1628 CKD
GFR estimating equations based on serum patients (primarily white subjects, with
creatinine were developed in order to nondiabetic kidney disease) with a GFR
eliminate several limitations of serum cre- range between 5 and 90 ml/min/1.73 m2.
atinine use. These equations were derived The equation was re-derived in 2006 for
from different studies and populations use with the standardized serum creatinine
and usually combine serum creatinine assays [9, 10].

GFR (ml/min/1.73 m2) = 186.3 Scr1.154 age0.203 (0.742 if female) (1.210 if African American),
where Scr is expressed in mg/dl and age is expressed in years.
GFR (ml/min/1.73 m2) = 175 Scr1.154 age0.203 (0.742 if female) (1.210 if African American),
where a standardized Scr (mg/dl) measurement is done.
20 M. Arici

MDRD equation is the most widely used for- are linked to the populations and studies
mula in recent years. Many laboratories automat- that the equations have been derived. All
ically report MDRD equation GFR estimate GFR equations should be used in stable
along with serum creatinine measurements. This settings where serum creatinine has no
equation is more accurate in estimating GFR than rapid alterations (i.e., not used in acute kid-
24-h urine creatinine clearance and Cockroft- ney injury/disease). They are not
Gault formula. It is also more accurate in patients recommended for use in patients under the
with lower GFR levels (<60 ml/min/1.73 m2). Its age of 18, in patients with extremes in body
accuracy differs in various ethnic groups. It is size or muscle mass, in patients with severe
less accurate in obese patients and in patients with alterations in dietary intake (vegetarians,
normal or mildly decreased GFR. using creatine supplements), in very elderly
The CKD-EPI equation has been derived in (>85 years), or in pregnant patients.
2009 from a large study population that 2. Blood urea and Urea clearance: Urea is the
included patients with or without kidney most well-known nitrogenous waste and it
disease with a wide range of GFR. When was used as one of the first indicators to mea-
compared with MDRD, CKD-EPI has sure GFR. It is also measured as an indicator
found to be more accurate in people espe- of uremic burden and uremic symptoms in
cially with higher GFR levels (>60 ml/ late stages of CKD. Although blood urea
min/1.73 m2) [11]. nitrogen (BUN) has an inverse relationship

GFR (ml/min/1.73 m2) = 141 min(SCr/, 1) max(SCr/, 1)1.209 0.993Age

(1.018 if female) (1.159 if African American),
where SCr is serum creatinine (in mg/dl), is 0.7 for females and 0.9 for males,
is 0.329 for females and 0.411 for males, min indicates the minimum of SCr/ or 1,
and max indicates the maximum of SCr/ or 1
<0.7 mg/dl GFR = 144 (Scr/0.7)0.329
>0.7 mg/dl GFR = 144 (Scr/0.7)1.209
(0.993)Age 1.157 [if black]
<0.9 mg/dl GFR = 141 (Scr/0.9)0.411
>0.9 7mg/dl GFR = 141 (Scr/0.9)1.209

The CKD-EPI equation has been found with GFR, it is not an ideal filtration marker.
to result in lower prevalence estimate of Urea production is variable and is largely
CKD across a broad range of populations dependent on protein intake. BUN concentra-
and categorized mortality and ESRD risk tion increases as its production increases with
better than MDRD. Given the data on the high protein intake, tissue breakdown, trauma,
improved performance, especially in gen- hemorrhage, or glucocorticoid use. In contrast,
eral population at higher levels of GFR, BUN concentration decreases when its
KDIGO 2012 clinical practice guideline production decreases with low protein intake
for the evaluation and management of or in liver disease.
chronic kidney disease recommends to use Urea is freely filtered from the glomerulus,
CKD-EPI equation for GFR estimation. but 4050 % is reabsorbed in the tubules. Urea
All GFR equations have some impreci- reabsorption increases substantially in states
sion and do not provide an accurate esti- of decreased renal perfusion (volume deple-
mate of GFR due to several limitations. tion, congestive heart failure, diuretic use). In
Some of the limitations are related to the all these conditions, BUN levels will increase
serum creatinine itself (Box 2.5) and some out of proportion to a decrease in GFR and
2 Clinical Assessment of a Patient with Chronic Kidney Disease 21

nine are the major drive for seeking alternative

Box 2.5. Sources of Error by Using Serum filtration markers in the serum. Among them,
Creatinine in GFR Estimation cystatin C is considered to be a potential alter-
Non-steady state (e.g., acute kidney injury) native to serum creatinine for estimating GFR.
Variable creatinine generation (e.g., race, Cystatin C is a low molecular weight (13-kDa)
extremes of muscle mass, extremes of cysteine protease inhibitor that is produced by
body size, high protein diet, creatinine all nucleated cells. It is freely filtered by the
supplements, muscle wasting) renal glomerulus. It is reabsorbed and com-
Variable tubular secretion (e.g., decrease by pletely catabolized by tubular cells. In contrast
trimethoprim, cimetidine, fenofibrate) to creatinine, cystatin C does not undergo any
Variable extrarenal elimination (e.g., tubular secretion. The generation of cystatin C
decrease by inhibition of gut creatini- was believed to be less variable and affected less
nase by antibiotics, increase by large by age and sex. Later epidemiological studies,
volume losses) however, have suggested that cystatin C genera-
Higher GFR (e.g., higher measurement tion rate and serum levels have been influenced
errors in patients with higher GFR) by age, sex, cell turnover rate, steroid use, body
Interference with assay (e.g., spectral inter- mass index, inflammation, and diabetes. Studies
ferences from bilirubin and some drugs have also shown that there is an extrarenal elimi-
or chemical interferences from glucose, nation of cystatin C at low levels of GFR. Serum
ketones, bilirubin, and some drugs) cystatin C measurements are not standardized
Source: Adapted by permission from yet and still evolving. Studies have shown that
Macmillan Publishers Ltd: Kidney cystatin C measurements also have higher intra-
Disease: Improving Global Outcomes individual variation than serum creatinine.
(KDIGO) CKD Work Group [2]. Copyright Several studies have shown that cystatin C
2013. Available from: http://www.nature. concentrations may correlate more closely with
com/kisup/index.html GFR than serum creatinine. Similarly, GFR esti-
mates based on cystatin C may be more powerful
predictors of clinical outcomes than creatinine-
will result in an increased ratio of BUN to based eGFR. These findings have been the
SCre. Increased BUN-to-SCre ratio is sugges- strongest for mortality and CVD events, and
tive of a prerenal state and may indicate an the prognostic advantage of cystatin C is most
acute deterioration in a CKD patient. apparent among individuals with GFR >45 ml/
Urea clearance is not a reliable indicator of min/1.73 m2. Recently, a single equation com-
GFR also due to variable tubular reabsorption bining both serum creatinine and cystatin C has
rates of urea. GFR may be underestimated been found to be more accurate in determining
almost as half as the real level by urea clear- GFR [13]. The role of cystatin C measurements
ance. The only clinical setting where urea or use of cystatin C-based equations in CKD
clearance use has been advocated is the late care has yet to be determined. KDIGO 2012
stages of CKD for deciding appropriate timing clinical practice guideline for the evaluation and
of dialysis [12]. As urea clearance underesti- management of chronic kidney disease has
mates and creatinine clearance overestimates recommended to measure cystatin C to confirm
GFR, it is recommended that the average CKD in adults if eGFR based on serum cre-
of these two clearances (GFR = (creatinine atinine was between 45 and 59 ml/min/1.73 m2
clearance + urea clearance)/2) is preferred for without any markers of kidney damage. KDIGO
estimating GFR in advanced CKD. The use of recommends to use either cystatin C-based
this formula is also compromised by problems eGFR equation or cystatin C and creatinine-
related to proper urine collection. based eGFR equations in confirming the pres-
3. Serum cystatin C and GFR equations: ence of CKD. The use of cystatin C equations
Limitations inherent to the use of serum creati- has also several limitations (Boxes 2.6 and 2.7).
22 M. Arici

Box 2.6. Sources of Error by Using Serum Box 2.7. What the Guidelines Say You
Cystatin in GFR Estimation Should Do: Glomerular Filtration Rate
Non-steady state (e.g., acute kidney injury) Use serum creatinine and a GFR esti-
Variable cystatin generation (e.g., race, mating equation for initial assessment.
thyroid function disorders, corticoste- Use a GFR estimating equation to derive
roid use, diabetes, obesity) GFR from serum creatinine (eGFR-
Variable extrarenal elimination (e.g., creat) rather than relying on the serum
increase by severe decrease in GFR) creatinine concentration alone.
Higher GFR (e.g., higher measurement Understand clinical settings in which
errors in patients with higher GFR) eGFRcreat is less accurate.
Interference with assay (e.g., heterophilic Clinical laboratories should report
antibodies) eGFRcreat in adults using the 2009
Source: Adapted by permission from CKD-EPI creatinine equation.
Macmillan Publishers Ltd: Kidney Clinical laboratories that measure cys-
Disease: Improving Global Outcomes tatin C should report eGFRcys and
(KDIGO) CKD Work Group [2]. Copyright eGFRcreat-cys in adults using the 2012
2013. Available from: http://www.nature. CKD-EPI cystatin C and 2012 CKD-
com/kisup/index.html EPI creatinine-cystatin C equations.
Source: Data from KDIGO 2012 clinical
practice guideline for the evaluation and
CKD-EPI Cystatin C equation: management of chronic kidney disease [2]

GFR (ml/min/1.73 m2) = 133 min(SCysC/0.8, 1)0.499 max(SCysC/0.8, 1)1.328

0.996Age [ 0.932 if female],
where SCysC is serum cystatin C (in mg/l), min indicates the minimum of SCysC/0.8 or 1,
and max indicates the maximum of SCysC/0.8 or 1.

CKD-EPI Creatinine-Cystatin C equation:

GFR (ml/min/1.73 m2) = 135 min(SCr/, 1) max(SCr/, 1)0.601 min(SCysC/0.8, 1)0.375

max(SCysC/0.8, 1)0.711 0.995Age [ 0.969 if female] [ 1.08 if black],
where SCr is serum creatinine (in mg/dl), SCysC is serum cystatin C (in mg/l),
is 0.7 for females and 0.9 for males, is 0.248 for females and 0.207 for males,
min(SCr/, 1) indicates the minimum of SCr/ or 1,and max(SCr/, 1) indicates the maximum of
SCr/ or 1; min(SCysC/0.8, 1) indicates the minimum of SCysC/0.8 or 1 and max(SCysC/0.8, 1)
indicates the maximum of SCysC/0.8 or 1.

All these equations may be reached in vari- estimating equations cannot be performed
ous websites as electronic calculators, such as (such as pregnancy, acute kidney disease, etc.) or http://www. or when there is a need for a more precise determination (such as for living donor assess-
4. Measuring GFR with exogenous markers: In ment) of GFR, clearance measurements
clinical settings where GFR estimates from should be performed with several filtration
serum creatinine or creatinine-based GFR markers (inulin, iothalamate, iohexol, DTPA,
2 Clinical Assessment of a Patient with Chronic Kidney Disease 23

or EDTA) [14]. Measuring GFR with the use There is, however, no evidence-based infor-
of these markers is complex, expensive, and mation whether urinalysis is required in each
difficult to do in clinical practice. The mea- follow-up visit of a CKD patient.
surement of GFR with these markers has also A detailed discussion of the diagnostic
some limitations and rarely used in clinical uses of urinalysis or specific tests of urine
practice for CKD care except research set- (metabolic diseases, urine electrolytes, etc.) is
tings. In a CKD patient, a measured GFR may beyond the scope of this chapter and may be
only be required if the patient is chronically ill found in other sources. Here, only essential
with severe reduction in muscle mass, if there features of urinalysis for the care of CKD
will be a prolonged exposure to nephrotoxic patients will be covered.
drugs, or if there is a discrepancy between An accurate urine analysis should start
severely reduced eGFR and symptoms of ure- with a proper collection of a urine sample.
mia before deciding to start renal replacement First-void (early) morning urine is usually
therapy. preferred as formed elements will more likely
5. Novel biomarkers: There is still ongoing be seen in concentrated urine with a low pH.
research for finding one or more potential, The sample should be analyzed within 24 h
alternative markers for estimating GFR. In from collection.
this sense, several low molecular weight mol- A complete urinalysis consists of three
ecules such as beta-trace protein (BTP), components, as physical (gross) examination,
beta(2)-microglobulin (B2M), and symmetric chemical (dipstick) analysis, and microscopic
dimethyl arginine have been investigated. evaluation of the urinary sediment. In rou-
BTP and B2M have been found to be more tine clinical practice, most of the physical and
accurate than serum creatinine in some stud- chemical parameters are examined by a dip-
ies. It is yet to be determined whether one or stick. A dipstick provides a semiquantitative
several of them have a role in CKD patients examination of several urinary characteristics
alone or in combination with creatinine or by a series of tests embedded on a reagent strip.
cystatin C. Among physical parameters, color (usually
normal in CKD), turbidity (usually normal in
CKD), and specific gravity (usually a fixed,
2.3 Urinalysis and Albuminuria isosthenuric urine is produced in CKD, i.e.,
in CKD specific gravity is 1010) are assessed. In chemi-
cal analysis, urine dipstick assesses pH (low or
Urinalysis and assessment of albuminuria are very normal in CKD), glucose (usually normal in
informative, noninvasive tests for both screening CKD), ketones (usually normal in CKD), biliru-
and diagnosing CKD. Albuminuria is also an bin and urobilinogen (usually normal in CKD),
important measure for defining severity of kidney nitrite and leukocyte esterase (usually normal
dysfunction, estimating prognosis of CKD-related in CKD), blood, and protein. The dipstick test
outcomes, and associated cardiovascular risk. The for blood detects peroxidase activity of eryth-
presence of albuminuria and its severity also rocytes. The dipstick test is commonly consid-
guides treatment alternatives in CKD. ered to be sensitive for detection of microscopic
1. Urinalysis: A complete urinalysis should be hematuria. False-negative results are unusual,
carried out in the first examination of all CKD i.e., a negative dipstick for blood excludes
patients. Along with a targeted history and hematuria. However, myoglobin and hemoglo-
physical examination, urinalysis provides bin also will catalyze this reaction, so a positive
important information for differential diagno- test result may indicate hematuria, myoglobin-
sis of acute and chronic kidney disease. uria (from rhabdomyolysis), or hemoglobin-
Urinalysis may also provide clues for under- uria (from intravascular hemolysis). When it is
lying etiologies of chronic kidney disease. positive, visualization of intact erythrocytes on
24 M. Arici

microscopic examination of the urinary sedi- tein levels are greater than 1 g/l, spot protein-
ment should be done for confirmation of hema- creatinine correlation with 24-h urine may not
turia. Hematuria may be observed in patients be accurate. Thus, spot protein-creatinine level
with CKD due to various underlying causes. may act as a simple screening for proteinuria,
The dipstick test for protein is most sensitive to i.e., if it is negative, there is no need for a 24-h
albumin and may not detect low concentrations urine collection.
of globulins, tubular proteins, and Bence Jones In cases where presence of non-albumin
proteins. The dipstick measurement of urine proteins (such as gamma globulins, Bence
protein allows only an approximate quantifica- Jones proteins) is suspected, other precipitation
tion of urine albumin, expressed on a scale from methods like sulfosalicylic acid test should be
negative trace to 1(+) to 4(+). Dipstick tests for used. Trichloroacetic acid can be used in place
trace amounts of protein yield positive results of sulfosalicylic acid to increase the sensitiv-
at concentrations of 510 mg/dllower than ity to gamma globulins.
the threshold for clinically significant protein- Microscopic examination of urine sedi-
uria. Dipstick protein may miss moderately ment should be done in all patients with CKD
increased albuminuria levels in the range of and in patients with high risk for CKD. In the
30300 mg/day (formerly called microalbumin- urine sediment, cellular elements (red blood
uria) in most cases. A result of 1+ corresponds cells, white blood cells), casts, and crystals
to approximately 30 mg of protein per dl and is should be thoroughly examined. Some find-
considered positive; 2+ corresponds to 100 mg/ ings in the urine sediment may help to diag-
dl, 3+ to 300 mg/dl, and 4+ to 1,000 mg/dl. nose some underlying causes of CKD. There
In addition, dipstick protein measurement is is, however, no characteristic finding in the
dependent on the concentration of the urine urinary sediment of a CKD patient, except
specimen, where concentrated urine may give broad casts which are typically associated
false-positive and dilute urine may give false- with advanced stages of CKD.
negative results. Thus, it is important to quan- 2. Albuminuria: Albumin is the predominant
tify the amount of proteinuria detected on urine protein in major proteinuric diseases causing
dipstick analysis with other methods. Protein CKD. Albumin measurement in urine has
can be quantified in random samples, in timed greater sensitivity and improved precision for
or untimed overnight samples, or in 24-h col- the detection of low levels of proteinuria com-
lections. Although 24-h urine protein amount pared to protein measurements. It is therefore
represents the gold standard method, problems accepted as a more sensitive method for
related with 24-h collection (over or under col- screening/diagnosing not only diabetic but
lection) are a major source of error. It is also a also nondiabetic CKD. Most of the recent
cumbersome procedure for many patients. Still, studies also showed strong evidence linking
adequately collected 24-h urine protein con- increased albuminuria and outcomes of CKD.
centrations are accepted as the most accurate Urinary concentrations of albumin
way to monitor proteinuria under active treat- <150 mg/l are below the detection limit of the
ment (such as active immunosuppressive use). dipstick tests used in routine urinalysis.
A complete collection may be determined by Albumin in the urine may be detected by radio-
the amount of expected 24-h urine creatinine immunoassay, immunoturbidimetric tech-
excretion (see above). Protein-creatinine ratio nique, and nephelometry, ELISA, or HPLC.
(PCR) in a random urine sample is accepted Reagent strip methods were also developed for
as an alternative to 24-h urine collection. PCR urine albumin screening but have increased
may correct problems arising from variability false-positive or false-negative ratios.
of urine volume and concentration. It is easy Twenty-four-hour urine collection is also
to obtain and showed a strong correlation with the gold standard for the detection of high
24-h urine collection. However, when urine pro- albuminuria (formerly, microalbuminuria).
2 Clinical Assessment of a Patient with Chronic Kidney Disease 25

Box 2.8. Sources of Error When Using ACR Box 2.9. What the Guidelines Say You
for Albuminuria Should Do: Albuminuria
Transient, false elevations in albuminuria Use the following measurements for ini-
(e.g., menstrual blood contamination, tial testing of proteinuria (in descending
urinary tract infection, fever, exercise, order of preference, in all cases an early
orthostatic, severe uncontrolled hyper- morning urine sample is preferred):
glycemia, or hypertension) 1. Urine albumin-to-creatinine ratio
Variability due to sample storage (e.g., deg- (ACR)
radation of albumin before analysis) 2. Urine protein-to-creatinine ratio
Variability in creatinine excretion (e.g., (PCR)
lower in children, women, or elderly, 3. Reagent strip urinalysis for total pro-
higher in black, lower due to decreased tein with automated reading
muscle mass, variability due to non- 4. Reagent strip urinalysis for total pro-
steady state) tein with manual reading
Interference with assay (e.g., samples with Confirm reagent strip-positive albumin-
very high albumin levels may falsely be uria and proteinuria by quantitative lab-
reported as low or normal due to anti- oratory measurement and express as a
gen excess effect in some assays) ratio to creatinine wherever possible
Source: Adapted by permission from Confirm ACR >30 mg/g (>3 mg/mmol)
Macmillan Publishers Ltd: Kidney on a random untimed urine with a sub-
Disease: Improving Global Outcomes sequent early morning urine sample
(KDIGO) CKD Work Group [2]. Copyright Measure albumin excretion rate or total
2013. Available from: http://www.nature. protein excretion rate in a timed urine
com/kisup/index.html sample for a more accurate estimate
Source: Data from KDIGO 2012 clini-
cal practice guideline for the evaluation and
Albuminuria screening however may be done management of chronic kidney disease [2]
with spot early morning urine collections,
timed urine collections, or as a ratio of albu-
min to creatinine in the urine (ACR). The ACR Most national and international guidelines
is the preferred method as it does not require (including KDIGO 2012 clinical practice guide-
timed collections, it correlates with the 24-h line for the evaluation and management of
urine values over a large range of proteinuria, chronic kidney disease) recommend ACR mea-
it is cheap to perform, and repeat values can be surement with an early morning urine sample
easily obtained to be certain that high albumin- over other methods. Albuminuria assessment
uria, if present, is persistent. A value of is recommended to be done at least annually in
30300 mg/g of creatinine (or, using standard CKD patients. The frequency of assessment of
(SI) units, 3.434 mg/mmol of creatinine) sug- albuminuria may depend on clinical situation,
gests that albumin excretion is between 30 and i.e., rate of progression or monitoring the effect of
300 mg/day and therefore that high albumin- anti-albuminuric treatment (Boxes 2.9 and 2.10).
uria is probably present. A false reading for
ACR may occur after vigorous exercise, in the
presence of fever, urinary infection, congestive 2.4 Other Lab Tests in CKD
heart failure, acute severe elevations of blood
pressure or blood sugar, or menstruation. CKD patients may need further tests as a part
There are some other sources of error in the of their general assessment or for finding any
assessment of ACR (Box 2.8) [15]. other marker of kidney damage like renal tubular
26 M. Arici

Box 2.10. Relevant Guidelines

1. KDIGO Guideline: guideline2009.pdf
Kidney Disease: Improving Global 5. National Institute for Health and Clinical
Outcomes (KDIGO) CKD Work Group. Excellence (NICE) Guideline
KDIGO 2012 clinical practice guideline Chronic Kidney Disease. National clini-
for the evaluation and management of cal guideline for early identification and
chronic kidney disease. Kidney Int Suppl. management in adults in primary and
2013;3:1150. secondary care. 2008, Royal College of Physicians.
guidelines/CKD.php h t t p : / / w w w. n i c e . o rg . u k / n i c e m e d i a /
2. CARI Guideline: live/12069/42116/42116.pdf
Diagnosis, classification and staging of 6. Canadian Society of Nephrology
chronic kidney disease. July 2012 Guideline: Guidelines for the management of chronic
Diag_Classification_Staging_ECKD.pdf kidney disease. CMAJ. 2008;179(11):
3. The Renal Association Guideline 115462.
Detection, monitoring and care of patients h t t p : / / w w w. c m a j . c a / c o n t e n t /
with CKD. Final Version (28 February suppl/2008/11/17/179.11.1154.DC1
2011). 7. NKF KDOQI Guideline:
h t t p : / / w w w. r e n a l . o r g / C l i n i c a l / KDOQI Clinical practice guidelines for
GuidelinesSection/Detection-Monitoring- chronic kidney disease: evaluation, classi-
and-Care-of-Patients-with-CKD.aspx fication, and stratification. Am J Kid Dis.
4. Japanese Society of Nephrology Guideline 2002;39(2 Suppl 1):S11266.
Evidence-based Practice Guideline for the
Treatment of CKD. Clin Exp Nephrol. KDOQI/guidelines_ckd/toc.htm

disorders or for assessment of the complications diagnostic and/or therapeutic importance. With a
of CKD (such as anemia, mineral-bone disor- decrease in GFR, there is a trend of false altera-
ders, malnutrition, neuropathy, cardiovascular tions in these tests: Liver transaminases tend to
tests). These tests will not be covered in detail decrease to very low levels, pancreatic amylase
here. It is however important to note that some and lipase, troponins, and BNP/NT-proBNP
tests need a cautious interpretation especially in levels tend to increase above cutoff concentra-
patients who are in the late stages (Stages 4 or 5) tions. All these alterations should be interpreted
of CKD. Among those tests, there are serum ALT, carefully, and real implications of test results
AST, amylase, lipase concentrations, troponins, should be assessed within the clinical context of
and BNP/NT-proBNP levels which may have the patient.
2 Clinical Assessment of a Patient with Chronic Kidney Disease 27

Before You Finish: Practice Pearls
for the Clinician 1. KDOQI clinical practice guidelines for chronic kid-
In each visit, a CKD patient should be ney disease: evaluation, classification, and stratifi-
cation, 2002. Am J Kidney Dis. 2002;39(2 Suppl
assessed for general well-being, for pro-
gression and any factor for acute deteri-
oration of CKD, for presence of any 2. Kidney Disease: Improving Global Outcomes
complications or comorbidity, and for (KDIGO) CKD Work Group. KDIGO 2012 clinical
cardiovascular health. practice guideline for the evaluation and manage-
Patients who are in late stages of the dis- ment of chronic kidney disease. Kidney Int Suppl.
ease should be assessed for the presence tice_guidelines/CKD.php.
of any uremic symptom, and the need 3. Stevens LA, Coresh J, Greene T, Levey AS. Assessing
for renal replacement therapy should be kidney function-measured and estimated glomerular
evaluated. filtration rate. N Engl J Med. 2006;354:247383.
4. National Institute for Health and Clinical Excellence
Blood pressure, orthostatic changes, (NICE). Chronic kidney disease. National clinical
volume, and cardiac status should be guideline for early identification and management
checked in all visits. in adults in primary and secondary care [internet].
CKD patients should have an assess- London: Royal College of Physicians; 2008. http://
ment of eGFR and albuminuria as a part pdf. Cited 6 Mar 2013.
of their initial assessment. eGFR and 5. Levey AS, Perrone RD, Madias NE. Serum creati-
albuminuria should be rechecked at nine and renal function. Annu Rev Med. 1988;39:
least annually in all CKD patients. 46590.
6. Myers GL, Miller WG, Coresh J, Fleming J,
eGFR should be calculated by 2009 Greenberg N, Greene T, National Kidney Disease
CKD-EPI equation derived from serum Education Program Laboratory Working Group, et al.
creatinine. Patients who are in the late Recommendations for improving serum creatinine
stages, who have a higher risk for pro- measurement: a report from the Laboratory Working
Group of the National Kidney Disease Education
gression, who have any intercurrent ill- Program. Clin Chem. 2006;52:518.
ness/medication use/operation, and who 7. Cockcroft DW, Gault MH. Prediction of creatinine
have changes in treatment may have fre- clearance from serum creatinine. Nephron. 1976;16:
quent eGFR assessments. 3141.
8. Creatinine Standardization Recommendations
Keep in mind the limitations of eGFR or [Internet]. Bethesda: National Kidney Disease
ACR measurements mostly caused by Education Program.
creatinine measurements. evaluation/gfr/creatinine-standardization/recommen-
The use of direct methods to measure dations.shtml#pharmacists. Updated 1 Mar 2012;
cited 3 Mar 2013.
GFR should be considered in clinical 9. Levey AS, Bosch JP, Lewis JB, Greene T, Rogesr N,
situations in which estimation equations Roth D. A more accurate method to estimate glomeru-
are known to be suboptimal. lar filtration rate from serum creatinine: a new predic-
Albuminuria should be assessed by tion equation. Modification of Diet in Renal Disease
Study Group. Ann Intern Med. 1999;130:46170.
albumin-creatinine ratio measured from 10. Levey AS, Coresh J, Greene T, Stevens LA, Zhang
an early morning urine sample. Patients YL, Hendriksen S, et al. Using standardized serum
who have severely increased albumin- creatinine values in the modification of diet in renal
uria or patients who are under antipro- disease study equation for estimating glomerular fil-
tration rate. Ann Intern Med. 2006;145:24754.
teinuric treatment may have frequent 11. Levey AS, Stevens LA, Schmid CH, Zhang YL,
albuminuria assessments. Castro 3rd AF, Feldman HI, et al. Using standardized
28 M. Arici

serum creatinine values in the modification of diet in filtration rate from serum creatinine and cystatin C. N
renal disease study equation for estimating glomeru- Engl J Med. 2012;367:209.
lar filtration rate. Ann Intern Med. 2009;150:60412. 14. Stevens LA, Levey AS. Measured GFR as a confirma-
12. Tattersall J, Dekker F, Heimbrger O, Jager KJ, tory test for estimated GFR. J Am Soc Nephrol.
Lameire N, Lindley E, ERBP Advisory Board, et al. 2009;20:230513.
When to start dialysis: updated guidance following 15. Miller WG, Bruns DE, Hortin GL, Sandberg S, Aakre
publication of the Initiating Dialysis Early and Late KM, McQueen MJ, National Kidney Disease
(IDEAL) study. Nephrol Dial Transplant. 2011;26(7): Education ProgramIFCC Working Group on
20826. Standardization of Albumin in Urine, et al. Current
13. Inker LA, Schmid CH, Tighiouart H, Eckfeldt JH, Issues in Measurement and Reporting of Urinary
Feldman HI, Greene T, et al. Estimating glomerular Albumin Excretion. Clin Chem. 2009;55:2438.