Approach to the Patient

with Renal Disease

Edgar V. Lerma, MD, FACP, FASN, FAHA
a,b,
*
a
Section of Nephrology, Department of Medicine, University of Illinois at Chicago
College of Medicine, 820 S. Wood Street, Chicago, IL 60612, USA
b
Associates in Nephrology, SC, 210 South Desplaines, Chicago, IL 60661, USA
There are various ways by which a patient who has renal disease can pres-
ent as an initial outpatient or through inpatient consultation. Some patients
may be referred because of abnormal urinary ndings such as hematuria or
proteinuria that may have been incidentally discovered during routine
clinical evaluation or as part of initial employment requirements. Depending
on the stage of renal disease, patients can present with mild edema, general-
ized pruritus, or more advanced signs and symptoms of uremia, such as de-
creased appetite, weight loss, and alterations in mental status. Still others
may present only with elevation in serum creatinine.
To narrow the dierential diagnosis, the rst question that needs to be
addressed is whether the disease is acute, subacute, or chronic on presenta-
tion. Because there is usually an overlap in these stages, this determination
may not always be clear. Certainly, a patient who presents with an elevated
serum creatinine level that was documented to be normal a few days previ-
ously has an acute presentation, and a patient who presents with a previously
elevated serum creatinine level that has been rising steadily over the past sev-
eral months to years has a chronic disease. Oftentimes, acute exacerbations
of chronic renal disease are common presentations.
The next question addresses which particular segment or component of
the renal anatomy is involved: prerenal, postrenal, or renal.
Prerenal disease refers to any process that decreases renal perfusion, such
as intravascular volume depletion, hypotension, massive blood loss, or third
spacing of uids. It can also be due to congestive heart failure, whereby de-
creased eective circulating volume decreases blood ow toward the kidneys
(see the article by Khalil and colleagues found elsewhere in this issue).
* Section of Nephrology, Department of Medicine, University of Illinois at Chicago
College of Medicine, Chicago, IL.
E-mail address: edgarvlermamd@pol.net
0095-4543/08/$ - see front matter 2008 Elsevier Inc. All rights reserved.
doi:10.1016/j.pop.2008.02.001 primarycare.theclinics.com
Prim Care Clin Office Pract
35 (2008) 183194
Postrenal disease refers to any obstruction that impedes urinary ow
through the urinary tract. Examples include benign prostatic hypertrophy
or cervical malignancy (see the article by Khalil and colleagues found else-
where in this issue).
Renal involvement is further subdivided into vascular, glomerular, or tu-
bulointerstitial disease (see the article by Beck and Salant found elsewhere in
this issue), depending on which segment is involved.
Assessment of renal function
The most common method of assessing renal function is by estimation of
the glomerular ltration rate (GFR). The GFR gives an approximation of the
degree of renal function. Daily GFR in normal subjects ranges from 150 to
250 L per 24 hours or 100 to 120 mL/min/1.73 m
2
of body surface area.
GFR is decreased in those who have renal dysfunction and is used to monitor
renal function in those who have chronic kidney disease. It is also used to de-
termine the appropriate timing for initiation of renal replacement therapy.
To date, there are several methods by which GFR is measured, namely,
serum creatinine concentration, 24-hour creatinine clearance, and estima-
tion equations such as the Cockroft-Gault formula and the Modication
of Diet in Renal Disease Study (MDRD) formula.
Using the serum creatinine alone to estimate renal functioning is inaccu-
rate for several reasons. First, a small amount of creatinine is normally se-
creted by the tubules, and this amount tends to increase as progressive renal
decline occurs, thereby overestimating the true GFR value. Similarly, there
are factors that increase serum creainine without truly aecting renal func-
tion, such as dietary meat (protein) intake, volume of muscle mass, and
medications that interfere with tubular secretion of creatinine (eg, cimeti-
dine, trimethoprim, and probenecid). Elderly patients, patients who have ca-
chexia, amputees, and patients who have spinal cord injury or disease tend
to have lesser muscle mass; hence, lower serum creatinine values.
The 24-hour urine collectionis usedtodetermine creatinine clearance. Its main
limitationis that it is cumbersome, andparticularly inelderly individuals or those
who have fecal or urinary incontinence, an incomplete or prolonged (over
24 hours) urine specimen collection tends to provide erroneous information.
To determine whether a 24-hour urine collection is complete, the follow-
ing reference is used: for male patients, urine creatinine volume 20 to
25 mg/kg/24 hours; for female patients, urine creatinine volume 15
to 20 mg/kg/24 hours.
Acommon method of assessing GFRis by the use of estimation equations.
Cockroft-Gault formula:
Creatinine Clearance
140 Age in years Weight kg
Plasma creatinine 72
184 LERMA
Due to less muscle mass in female patients, a factor of 0.85 is multiplied
to the creatinine clearance to arrive at the estimated GFR.
The Cockroft-Gault formula also has limitations: it tends to overestimate
GFR in patients who are morbidly obese or who have signicant edema.
MDRD formula:
GFR; in mL=min per 1:73 m
2
175 serum creatinine
1:154
age in years
0:203
0:742 if female
1:21 if black
The MDRD formula is recommended for use when staging chronic kidney
disease. According to recent published reports, this formula is reasonably
accurate inpatients whohave stable chronic kidneydisease. Similar tothe Cock-
roft-Gault formula, it appears to be inaccurate in morbidly obese individuals,
normal subjects, andpopulations of dierent ethnicities fromoutside the United
States. Insuchpopulations outside the UnitedStates, the MDRDformulatends
to overestimate GFR due to dierences in body mass and dietary habits.
Clinical ndings
Symptoms and signs
Most patients who have renal disease are asymptomatic and only inciden-
tally discovered on routine examination to have abnormal laboratory nd-
ings (eg, elevated serum creatinine or abnormal ndings on urinalysis).
For those who have symptomatic renal disease, most of the symptoms are
nonspecic and can be referred to almost any body organ. Examples include
constitutional symptoms such as generalized weakness, lack of energy,
decreased appetite, shortness of breath, diculty sleeping, and so forth.
Some patients can present with symptoms referable to the urinary tract
such as gross hematuria or ank discomfort. Although abnormalities in uri-
nation such as increased urgency or frequency may commonly indicate
underlying urologic pathology, they are also seen in infections or inamma-
tory diseases involving the urinary tract.
Laboratory studies
Urinalysis
The most important diagnostic test used in the patient who has renal dis-
ease is the urinalysis. The urine specimen is obtained by doing a midstream
catch for male patients, whereas for female patients, the labia majora should
be cleaned and then separated to avoid contamination. After collection, the
urine specimen should be examined within 60 minutes of voiding.
185 APPROACH TO THE PATIENT WITH RENAL DISEASE
Initially, a dipstick examination is performed, which includes assessment
of the urine specic gravity, pH, protein, blood, glucose, ketones, bilirubin,
nitrite, and leukocyte esterase (Table 1).
Microscopic examination of the urine sediment corroborates the ndings
on the initial dipstick analysis. The presence of various crystals, cells, casts,
bacteria, and fungal elements are then reported (Table 2).
Certain patterns of ndings on urinalysis are indicative of certain specic
diagnoses. For instance, in the patient presenting with acute renal failure,
the nding of muddy brown, granular casts points to acute tubular necrosis,
whereas the presence of red blood cell casts and dysmorphic red blood cells
is indicative of glomerulonephritis. High-grade proteinuria may be sugges-
tive of glomerular disorders.
Urinary indices
Measurement of urine sodium (urine Na) in a random urine specimen is
helpful in the dierential diagnosis of acute renal failure. A urine Na level
less than 20 mEq/L points to prerenal causes of acute renal failure (eg,
Table 1
Urine dipstick testing
Measure False-negative results False-positive results
Specic gravity Reduced values in the presence
of glucose, urea, alkaline urine
Increased values in the presence
of protein O1 g/L, ketoacids
PH Reduced values in the presence
of formaldehyde

Hemoglobin Ascorbic acid, high nitrite

concentration, delayed
examination, high density of
urine, formaldehyde (0.5 g/L)
Myoglobin, microbial
peroxidases, oxidizing
detergents,
hydrochloric acid
Glucose Ascorbic acid, urinary tract
infection
Oxidizing detergents,
hydrochloric acid
Albumin Immunoglobulin light chains,
hydrochloric acid, tubular
proteins, globulins, colored urine
Alkaline urine (pH 9),
quaternary ammonium
detergents, chlorhexidine,
polyvinylpyrrolidone
Leukocyte
esterase
Isotonic urine, vitamin C
(intake g/d), protein O5 g/L,
glucose O20 g/L, mucous specimen,
cephalosporins, nitrofurantoin;
mercuric salts, trypsin inhibitor
oxalate, 1% boric acid
Oxidizing detergents,
formaldehyde (0.4 g/L),
sodium azide, colored urine
due to beet ingestion,
or bilirubin
Nitrites No vegetables in diet, short bladder
incubation time, vitamin C,
gram-positive bacteria
Colored urine
Ketones Improper storage Free sulfhydryl groups
(eg, captopril) L-dopa,
colored urine
From Fogazzi GB. Urinalysis. In: Johnson R, Feehally J, editors. Comprehensive clinical
nephrology. 2nd edition. Philadelphia: Elsevier; with permission.
186 LERMA
intravascular volume depletion due to uid losses or sequestration, hypoten-
sion, sepsis, and so forth). A urine Na level greater than 40 mEq/L suggests
acute tubular necrosis. To adjust for the inuence of urine output, the fol-
lowing equation is recommended:
Fractional Excretion of Na FE Na%

Urine Na Plasma Creatinine 100

Plasma Na Urine Creatinine
A FE Na value less than 1% points to prerenal disease, whereas a FE Na
value greater than 2% suggests acute tubular necrosis. Limitations to the
use of urinary indices include prior infusion with normal saline and prior
administration of diuretics. This topic is discussed further in the article by
Khalil and colleagues found elsewhere in this issue.
Imaging studies
In the evaluation of the patient who has renal disease, various radiographic
studies are available. They are performed alone or in combination to diagnose
the dierent pathologies aecting the genitourinary tract (Table 3).
The most common imaging modality used is that of renal ultrasonography
because it is safe, easy to do, and avoids the use of radiation or contrast media
that can be nephrotoxic. Important detailed information that can be obtained
Table 2
Clinical signicance of urinary casts
Cast Main clinical associations
Hyaline Normal subject
Renal disease
Granular Renal disease
Waxy Renal insuciency
Rapidly progressive
Glomerulonephritis
Fatty Marked proteinuria
Nephrotic syndrome
Erythrocyte Glomerular bleeding
Proliferative/necrotizing glomerulonephritis
Hemoglobin Glomerular bleeding
Proliferative/necrotizing glomerulonephritis
Hemoglobinuria
Leukocyte Acute pyelonephritis
Acute interstitial nephritis
Proliferative glomerulonephritis
Epithelial Acute tubular necrosis
Acute interstitial nephritis
Glomerulonephritis
Myoglobin Rhabdomyolysis
From Fogazzi GB. Urinalysis. In: Johnson R, Feehally J, editors. Comprehensive clinical
nephrology. 2nd edition. Philadelphia: Elsevier; with permission.
187 APPROACH TO THE PATIENT WITH RENAL DISEASE
through ultrasonography includes the size and shape of the kidneys, the pres-
ence of calculi, and the dierentiation of the presence of a mass or a cyst.
Asymmetry of the kidneys usually indicates a unilateral disease process.
The presence of hydronephrosis is an indication of obstruction along the ip-
silateral ureter (if unilateral) or at the level of the bladder or lower (if bilateral).
Increased echogenicity is a common nding that signies chronic medical
renal disease.
The plain lm of the abdomen gives information about the kidney size
and shape in addition to radiopaque (calcium-containing) calcications.
A common limitation of plain lm is its inability to detect radiolucent stones
(uric acid).
CT scanning provides more detailed information about the structure of
the kidneys because it can dierentiate simple cysts from complex cysts.
Noncontrast-enhanced spiral CT scan is the imaging modality of choice
for the diagnosis of nephrolithiasis. CT angiography is used in the staging
of renal cell carcinoma and in demonstrating renal vein thrombosis. The
main disadvantages to using this modality are the use of large volumes of
contrast media and radiation.
MRI also provides detailed structural information about the kidneys.
In the past, magnetic resonance angiography with gadolinium contrast
Table 3
First choice imaging techniques in renal disease
Disease Imaging technique
Renal failure, unknown cause Ultrasound
Hematuria Intravenous urography or ultrasound plain
radiograph of kidneys, ureter, and bladder
Proteinuria/nephrotic syndrome Ultrasound
Hypertension
with normal renal function CT angiography including imaging of the
adrenal glands
with impaired renal function MRA
Renal artery stenosis
with normal renal function MRA
with impaired renal function MRA
Renal infection CT
Hydronephrosis detected by ultrasound Intravenous urography (if renal function is
preserved) or Tc 99m DTPA renography
Retroperitoneal brosis CT
Papillary necrosis Intravenous urography
Cortical necrosis Contrast-enhanced CT
Renal vein thrombosis Contrast-enhanced CT
Renal infarction Contrast-enhanced CT
Nephrocalcinosis Noncontrast CT
Abbreviations: DTPA, diethylene triamine pentaacetic acid; MRA, magnetic resonance
angiography.
From Parsons RB, Simpson WL Jr. Investigation of renal disease. In: Johnson R, Feehally J,
editors. Comprehensive clinical nephrology. 2nd edition. Philadelphia: Elsevier; with
permission.
188 LERMA
has been used extensively in the evaluation of the renal vasculature
(eg, renovascular diseases). Recently, however, with several published re-
ports on nephrogenic systemic brosis linked to the use of gadolinium, there
has been a signicant decline in its use. Some experts recommend to avoid
the use of gadolinium as contrast agent in those who have an estimated
GFR of less than or equal to 30 mL/min, including those who are dependent
on renal replacement therapy or dialysis.
Renal angiography is commonly used in the diagnosis of renal artery
stenosis. Because iodinated contrast media is used, caution is advised, espe-
cially in patients who have baseline renal insuciency due to increased risk
of contrast-induced nephropathy.
The main indications for radionuclide studies (radioisotope scanning with
technetium 99m dimercaptosuccinic acid) include early detection of urinary
obstruction, urine leak, and vesicoureteric reux (voiding cystourethrogram).
Retrograde and antegrade pyelography are used primarily during place-
ment of ureteral stents or nephrostomy tubes. Because pyelography uses
radiation and potentially nephrotoxic contrast media, other noninvasive im-
aging modalities such as ultrasonography and CT scanning have been used
more commonly in the diagnosis of urinary tract obstruction, including
identication of the site of obstruction.
Renal biopsy
Percutaneous renal biopsy is used in situations in which evaluation of the
patients history, physical examination, and noninvasive testing (including
serum and urine tests and imaging studies) has failed to reveal a diagnosis.
The major indications for doing a renal biopsy include (1) unexplained
persistent hematuria or proteinuria, especially when accompanied by pro-
gressive renal decline; (2) nephritic syndrome; (3) acute nephritis; and (4)
unexplained acute or rapidly progressive renal decline.
The most common complication arising from a percutaneous renal bi-
opsy is bleeding. The patients ability to coagulate normally should be ascer-
tained by closely monitoring the coagulation prole (partial thromboplastin
time, prothrombin time, international normalized ratio, platelet count, and
bleeding time). Patients should also be advised to hold o aspirin and non-
steroidal anti-inammatory drugs at least 1 week before the planned renal
biopsy. Patients requiring maintenance chronic anticoagulation should be
placed on heparin the day before the biopsy.
Post biopsy, most patients develop transient microscopic hematuria,
whereas transient gross hematuria has been described in 3% to 10% of
cases. Rare case reports of arteriovenous stulae arising as complications
of renal biopsies and demonstrated by color Doppler studies have been
described in the literature.
The major contraindications to percutaneous renal biopsy can be divided
into those involving the kidneys and those involving the patient. Examples
189 APPROACH TO THE PATIENT WITH RENAL DISEASE
of contraindications aecting the kidneys are presence of multiple unilateral
or bilateral cysts, presence of a renal mass, a solitary functioning kidney,
presence of active renal or perirenal infection, and unilateral or bilateral
hydronephrosis. Patient-related contraindications include an uncooperative
patient, uncontrolled severe hypertension, intractable bleeding disorder, and
morbid obesity. It must be noted, however, that with the exception of intrac-
table bleeding disorder, most of the contraindications are relative rather
than absolute. Therefore, the actual clinical situation often dictates whether
a contraindication can be overridden. Recently, it has been shown that
percutaneous renal biopsy may be performed in those who have solitary kid-
neys. Several published reports have demonstrated that even for those who
have solitary functioning kidneys, the risk of general anesthesia during open
renal biopsy far outweighs the risk of requiring surgery and subsequent
nephrectomy. Therefore, in selected cases, percutaneous renal biopsy may
be performed in the presence of a solitary functioning kidney.
Asymptomatic urinary ndings
Hematuria
Hematuria can be gross or microscopic. Gross hematuria is the presence
of red or brown urine. In the initial evaluation of a patient who has gross
hematuria, it must be determined whether the urine discoloration is truly
secondary to pathologic bleeding within the urinary tract. It is not ideal
to evaluate a female patient for hematuria if she is menstruating or in the
postpartum state. Conditions in which the urine may appear grossly red
in the absence of actual bleeding include intake of certain medications
such as rifampin, phenothiazine, or phenazopyridine (analgesic) and intake
of beets in certain predisposed individuals. It is also important to dieren-
tiate hematuria from other causes of red urine, such as hemoglobinuria
and myoglobinuria. The latter is usually seen in those who have acute
rhabdomyolysis.
Microscopic hematuria is dened as the presence of more than two red
blood cells per high-power eld. It is usually detected incidentally by urine
dipstick examination (Fig. 1).
Careful history taking is of paramount importance in the evaluation of
patients who have hematuria. Important historical information usually pro-
vides diagnostic clues. For instance, the occurrence of concomitant ank
pain with radiation to the ipsilateral testicle or labia suggests underlying
nephrolithiasis; burning on urination or dysuria may point to possible uri-
nary tract infection; and a recent upper respiratory tract infection may sug-
gest postinfectious glomerulonephritis or immunoglobulin A nephropathy.
A family history of hematuria is also vital because certain diseases tend to
run in families, such as polycystic kidney disease or sickle cell nephropathy.
Likewise, thin basement membrane disease and benign familial hematuria
190 LERMA
tend to occur in families and are notable for having a benign course despite
the presentation. Exercise-induced hematuria is seen in adolescents who ex-
ercise vigorously.
In elderly individuals or in those older than 50 years, the nding of gross
or microscopic (even transient) hematuria should trigger an extensive eval-
uation to rule out malignancy involving the genitourinary tract. The inci-
dence of bladder cancer and other malignancies involving the kidneys and
the ureters is signicantly elevated, particularly in those who have a pro-
longed history of chronic smoking and analgesic use. The occurrence of
symptoms of increased urgency and frequency with hematuria in this popu-
lation should suggest urinary tract obstruction secondary to benign pros-
tatic hypertrophy or prostatic malignancy.
An important aspect of the evaluation of patients who have hematuria is
to dierentiate glomerular from extraglomerular bleeding (Table 4).
For those who have glomerular bleeding, especially in the presence of
progressive renal decline, a percutaneous renal biopsy may be necessary.
Proteinuria
Normal urine protein excretion is 150 mg/d. Any value higher than this is
considered overt proteinuria. Proteinuria usually implies that there is a de-
fect in glomerular permeability. In general, proteinuria can be classied into
three types: glomerular, tubular, or overow.
Fig. 1. Workup for hematuria. (From Mazhari R, Kimmel PL. Hematuria: an algorithmic
approach to nding the cause. Cleve Clin J Med 2002;69:87084; with permission. Copyright
2002 Cleveland Clinic. All rights reserved.)
191 APPROACH TO THE PATIENT WITH RENAL DISEASE
Examples of glomerular proteinuria include diabetic nephropathy and
other common glomerular disorders (see the article by Beck and Salant
found elsewhere in this issue). It is usually caused by increased ltration
of albumin across the glomerular capillary wall. There are also causes of glo-
merular proteinuria that have a benign course, such as orthostatic and exer-
cise-induced proteinuria. These causes are characterized by signicantly
lesser degrees of proteinuria (!2 g/d).
Tubular proteinuria is usually seen in those who have underlying tubu-
lointerstitial diseases. These patients usually have defective reabsorptive
capacities in the proximal tubules, such that instead of the proteins being
Table 4
Glomerular versus extraglomerular bleeding
Evaluation Glomerular Extraglomerular
Color (if macroscopic) Red or pink Red, smoky brown, or Coca-Cola
Clots May be present Absent
Proteinuria !500 mg/d May be O500 mg/d
Red blood cell morphology Normal Dysmorphic
Red blood casts Absent May be present
Fig. 2. Algorithm A: evaluation of proteinuria. BUN, blood urea nitrogen. (Reproduced with
permission from Rose BD, Fletcher SW. Proteinuria: the primary care approach. In: Rose
BD, editor. UpToDate. UpToDate: Waltham, MA; 2007. Copyright 2007 UpToDate Inc.
For more information, visit www.uptodate.com.)
192 LERMA
normally reabsorbed, they are excreted in the urine. In contrast to glomer-
ular proteinuria, whereby macromolecules such as albumin are leaked out,
in tubular proteinuria, it is mostly low molecular weight proteins such as
immunoglobulin light chains and so forth.
Lastly, overow proteinuria is exemplied by multiple myeloma in which
there is an overabundance of immunoglobulin light chains secondary to
overproduction. Simply put, proteinuria occurs as a result of the amount
of protein produced, basically exceeding the maximum threshold for reab-
sorption in the tubules.
Glomerular and tubular proteinuria are secondary to abnormalities
involving the glomerular capillary and tubular walls, respectively, whereas
in overow proteinuria, the problem lies in overproduction of certain
proteins.
When performing a urinalysis, the dipstick examination can detect only
albumin, not the low molecular weight proteins. In fact, it can only detect
albumin when proteinuria is greater than 300 to 500 mg/d. Hence, one of
the dipstick examinations most important limitations is its inability to detect
microalbuminuria, which corresponds to the earliest phase of diabetic
nephropathy. The sulfosalicylic acid test, however, can detect all types of
proteins in the urine, including the low molecular weight proteins and others.
Fig. 3. Algorithm B: evaluation of proteinuria. BUN, blood urea nitrogen; CBC, complete
blood count. (Reproduced with permission from Rose BD, Fletcher SW. Proteinuria: the primary
care approach. In: Rose BD, editor. UpToDate. UpToDate: Waltham, MA; 2007. Copyright
2007 UpToDate Inc. For more information, visit www.uptodate.com.)
193 APPROACH TO THE PATIENT WITH RENAL DISEASE
Quantication of the degree of proteinuria is accomplished by performing
a 24-hour urine collection, which can be cumbersome, especially in elderly in-
dividuals or those who have concomitant fecal or urinary incontinence.
The urine protein-to-creatinine ratio (using a random urine specimen) has
been shown have a good correlation with the 24-hour urine protein determi-
nation (Figs. 2 and 3).
Orthostatic or postural proteinuria, by denition, is demonstration of
increased urine protein excretion in the upright position and normal urine
protein excretion in the supine position. It is a benign condition, mostly
seen among adolescents, the mechanism of which is not clearly understood.
The diagnosis is established by performing a split urine collection. The pro-
tocol for a split urine collection is as follows: (1) the rst morning void is
discarded; (2) a 16-hour upright collection is obtained between 7 AM and
11 PM, with the patient performing normal activities and nishing the collec-
tion by voiding just before 11 PM (the times can be adjusted according to the
normal times at which the patient awakens and goes to sleep); (3) the patient
should assume the recumbent position 2 hours before the upright collection
is nished to avoid contamination of the supine collection with urine formed
when in the upright position; and (4) a separate overnight 8-hour collection
is obtained between 11 PM and 7 AM.
Patients who have orthostatic proteinuria do not progress to end-stage
renal disease; in fact, orthostatic proteinuria resolves spontaneously in
most aected patients.
194 LERMA