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256 SECTION V Renal Disease
TABLE 23.2 Solute Excretion
Solute Filtration Reabsorption Secretion Fe (%) Regulation
Water Yes Yes No 0.3-6.0 Responds primarily to body tonicity but also EABV.
+
Na
+
K
2+
Ca
2+
Mg
−
HCO
3
Phosphate Yes Yes No 5-20 Responds to serum phosphate concentration and body phosphate status.
Glucose Yes Yes No 0.2-0.5 The proximal tubule reclaims almost all filtered glucose except when the filtered load
Uric acid Yes Yes Yes 10-50 Major routes of uric acid clearance are (1) renal excretion and (2) intestinal secretion
Creatinine Yes No Yes 1.0-1.2 Filtered at the glomerulus and secreted by the proximal tubule.
ADH, Antidiuretic hormone; EABV, effective arterial blood volume; FE, fractional excretion under normal physiology.
Yes Yes No 0.2-2.0 Responds to EABV.
Yes Yes Yes 5-20 Responds to total body potassium status.
Yes Yes No 2-10 Responds to serum ionized [Ca2+] and body need for calcium.
Yes Yes No 3-5 Responds to total body magnesium status and requirements.
Yes Yes Yes 0.1-0.5 Most bicarbonate reabsorption is to reclaim the filtered load.
ADH is the major regulator of collecting duct water permeability.
Reabsorption is stimulated by sympathetic nerves, angiotensin II, aldosterone; inhib-
ited by atrial natriuretic peptides, dopamine, uroguanylin.
Secretion is controlled primarily by aldosterone and distal Na+ delivery.
Major calciotropic hormones include parathyroid hormone, vitamin D, and calcitonin.
Renal epithelia directly respond to ionized calcium via the calcium sensing receptor.
Paracrine regulation is via epidermal growth factor.
Responds to systemic acid-base status, which can be mediated by direct sensing by
the renal epithelia or via hormonal actions (e.g., angiotensin II, endothelin).
Bicarbonate can also be secreted in the collecting duct when alkali excretion is required.
Reabsorption primarily resides in the proximal tubule and is regulated by parathyroid
hormone and fibroblast growth factor-23.
exceeds reabsorptive capacity.
The cortical proximal tubule performs gluconeogenesis from other organic substrates.
and uricolysis.
Handling of both secretion and reabsorption in the proximal tubule is complex, and
regulatory mechanisms are unclear.
The contribution of the tubules to creatinine clearance increases when GFR declines.
TABLE 23.3 Some Endocrine Hormones Elaborated by the Kidney
Hormone Source Function Drugs
Renin JGA Converts angiotensinogen to angiotensin I as an
integral part of the renin-angiotensin-aldosterone
system
1,25(OH)2 vitamin D Mostly proximal tubule Converts the precursor 25(OH) vitamin D to its active
form, 1,25(OH)2 vitamin D
Erythropoietin Renal interstitial cells Stimulates erythropoiesis in the bone marrow Recombinant human erythropoietin
ACE, Angiotensin-converting enzyme; JGA, juxtaglomerular apparatus.
The amount of filtered organic molecules far exceeds the metabolic
consumption by the kidney. Very large amounts of organic metabolic
substrates are passively filtered daily; these substrates are not meant to
be excreted, but the high GFR and lack of retention at the glomerular
capillaries obligate their presence in the glomerular urine. In the proximal tubule, the bulk of the filtered organic molecules are reclaimed
from the urine and returned to the systemic circulation. Several thousands of millimoles of amino acids, glucose, and organic cations and
critical physiologic function, there are no clinical examples of hypoglycemia stemming purely from lack of renal gluconeogenesis.
In addition to the prominent and more obvious roles in solute and
water balance, the kidney also is an important endocrine organ. The
autocrine and paracrine substances elaborated by the kidney are important for both intrarenal and systemic regulation. Although this subject
is not addressed fully here, three of these substances are highlighted
because they represent important pharmacologic targets (Table 23.3).
Renin inhibitor
ACE inhibitor
Angiotensin receptor blocker
Mineralocorticoid receptor blocker
25-Hydroxyvitamin D
1,25-Dihydroxyvitamin D
Synthetic vitamin D analogues
Glycosylated recombinant human erythropoietin
Other “EPO mimetic” erythropoiesis-stimulating agents
anions are retrieved each day by the kidney from the urine.
Renin
Metabolic and Endocrine Function
The kidney rivals the liver as a gluconeogenic organ that sustains circulating blood glucose levels. Although there is no doubt that this is a
As the initiating component of the RAAS, renin is important for maintenance of the circulation. The RAAS permits the kidney to have a
constant GFR in the face of low and fluctuating salt intake, a property
CHAPTER 23 Renal Structure and Function
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257
that is vital for terrestrial existence. Renin is produced by the JGA (see
earlier discussion). Despite the benefits and importance of the RAAS
in physiology, its continuous and excessive activation in many disease
states appears to be maladaptive and contributes to kidney and cardiovascular injury. Pharmacologic blockade of RAAS pathways at various
levels has proved beneficial in animal disease models and human clinical studies, and agents to block RAAS signaling are now in clinical use,
with others under development (see Table 23.3).
Vitamin D
1α-Hydroxylase (cytochrome P-450 isoenzyme 27B1) is found primarily in the proximal tubule, where the major body defense for
maintaining phosphate homeostasis is localized. The kidney is one of
the most important organs for maintaining calcium and phosphate
homeostasis, not just as the major controller of external balance but
as an elaborator of systemic factors such as vitamin D and the Klotho
protein. Conversion of the precursor 25(OH)-hydroxyvitamin D to
its active form, 1,25(OH)2dihydroxyvitamin D, is achieved not exclusively but substantially in the kidney and is mediated by 1α-hydrox-
ylase. Vitamin D deficiency is an important complication in chronic
kidney disease. Replacement of vitamin D is efficacious in reducing the
complications of chronic kidney disease.
Erythropoietin
Erythropoietin, which is produced mainly in the kidney, stimulates
erythropoiesis. The erythropoietin-producing cells are strategically
located in the cortical interstitium to sense the balance between
oxygen delivery and consumption. The current model suggests that
upregulation of renal erythropoietin production (mainly by anemia and hypoxia) occurs via an increase in the number of latent
erythropoietin-producing cells. The mechanism of erythropoietin
deficiency in kidney disease is not well known, although it does not
simply involve destruction of erythropoietin-producing interstitial
cells. One possible mechanism is decreased renal oxygen consumption as a consequence of reduced GFR; this results in higher renal
tissue oxygen tension and suppression of erythropoietin production.
Another theory is direct inhibition of the erythropoietin-producing
cells by inflammatory cytokines. Others have proposed transdifferentiation of erythropoietin-producing cells into myofibroblasts and
a decrease in the number of interstitial cells that can be recruited to
produce erythropoietin.
The use of erythropoiesis-stimulating agents (ESAs) has revolutionized the treatment of anemia associated with chronic kidney disease, but because of incomplete understanding of erythropoietin and
erythropoietin receptor biology, the clinical outcome is far from ideal
due to inability to tailor the optimal hematocrit for individual patients
and uncertainty about possible extra-erythropoietic effects of erythropoietin. The new class of hypoxia-inducible factor prolyl hydroxylase
inhibitors as ESAs increases endogenous erythropoietin production.
SUGGESTED READINGS
Kaissling B, Le Hir M: The renal cortical interstitium: morphological and
functional aspects, Histochem Cell Biol 130:247-262, 2008.
Maezawa Y, Cina D, Quaggin SE: Glomerular cell biology, Waltham, 2013,
Academic Press, pp 721-757.
Moe OW, Giebisch G, Seldin DW: Logic of the kidney. In Lifton RP, Somio
S, Glebisch GH, et al, editors: Genetic diseases of the kidney, New York,
2009, Elsevier, pp 39-73.
Reiser J, Sever S: Podocyte biology and pathogenesis of kidney disease, Annu
Rev Med 64:357-366, 2013.
24
Approach to the Patient With
Renal Disease
Rajiv Agarwal
INTRODUCTION
Chronic kidney disease (CKD) is commonly defined as having an estimated
glomerular filtration rate (GFR) of less than 60 mL/min/1.73 m2 for at least
3 months. Most patients with CKD are seen in the outpatient setting, and at
first consultation an important objective is to uncover the cause of CKD. In
the long term the objectives of care are the preservation of kidney and cardiovascular function and the prevention of the long-term complications of
CKD. Once kidney function deteriorates to the extent that it can no longer
sustain an appropriate quality of life the objective of care evolves to the provision of renal replacement therapy. In some patients, discussion may be
about withholding the provision of renal replacement therapy. In contrast
to the clinical approach to patients with CKD, most patients with acute
kidney injury (AKI) are hospitalized. The focus of their care also starts with
accurate determination of the cause of AKI, but over a period of days to
weeks it is important to reverse the kidney failure if possible, replace kidney
function if needed, and manage the many potential adverse consequences
of AKI. Thus, the approach to the care of patients with AKI and CKD are
largely non-overlapping and are discussed separately.
Distinction of AKI From CKD
Because of the widespread use of automated systems for serum chemistry analysis, an elevated serum creatinine concentration is the most
common initial manifestation of kidney disease. This test is performed
as a screen for renal function abnormalities in most metabolic panels; in most cases, an elevated serum creatinine concentration reflects
reduced filtration function of the kidney. After ensuring that intravascular volume is appropriate, the approach to the patient depends on
whether kidney failure is acute or chronic. Accordingly, the initial step
in evaluating an elevated serum creatinine level is to assess the time
course and duration of the changes to distinguish AKI from CKD.
A careful history, physical examination, and laboratory evaluation, including imaging studies, are all fundamental to this process.
The highest priority is to address acute volume depletion, bleeding,
and other causes of intravascular volume loss. Evidence of chronicity
may be discovered by searching the records for prior abnormalities of
serum creatinine, albuminuria or proteinuria, abnormal urine sediment, or anatomic features such as the presence of multiple cysts in
both kidneys discovered on an ultrasound or CT scan. Similarly, a call
to the primary care doctor may provide clues to suggest the presence
of kidney disease at an earlier time. In the United States, electronic
medical record systems are ubiquitous and deep knowledge of this
electronic record is often essential to discover the onset date of CKD.
Small kidney size, as assessed by ultrasound, can be highly suggestive of CKD. The size of the kidney depends on the height of the patient,
but in general, a kidney length on ultrasound images of less than 9 cm
in an adult male is considered small. The presence of normal-sized or
even large kidneys does not exclude the diagnosis of CKD. In fact, it
is common in patients with diabetic nephropathy for kidneys to be
11 or 12 cm long. Radiography of clavicles or hands is not commonly
performed but may demonstrate renal osteodystrophy and suggest the
presence of CKD.
Anemia is common in both AKI and CKD and therefore is not a
differentiating feature. However, the presence of secondary hyperparathyroidism points toward CKD. Rarely, if the initial evaluation is unrevealing, a kidney biopsy may be required to distinguish AKI from CKD
and to define the etiology of injury.
APPROACH TO THE PATIENT WITH CHRONIC
KIDNEY DISEASE
If the elevated creatinine concentration is thought to be chronic in
nature, the history and physical examination should focus initially on
detection of diabetes mellitus and hypertension, the two most common causes of CKD. In all cases, the evaluation also includes laboratory testing of renal function, serum electrolytes, complete blood
count, testing for albuminuria, and microscopic urine sediment analysis. Kidney ultrasound is almost always obtained early in the evaluation
to eliminate ureteral or bladder obstruction, a cause of reversible renal
failure. In addition, the ultrasound provides important information
about kidney size, symmetry, and echogenicity. Kidney biopsy may
be needed in some patients, but parenchymal scarring is common in
many forms of CKD so the biopsy may not be diagnostic.
Because diabetes and hypertension are common causes of kidney
disease, it is important to recognize the associated presentations. To
establish a likely diagnosis of diabetic nephropathy, a long-standing
history of documented diabetes mellitus is typical. An eye exam that
notes diabetic retinopathy often goes hand-in-hand with diabetic
nephropathy; however, the absence of diabetic retinopathy does not
rule out CKD due to diabetes mellitus. Albuminuria and large kidneys
on ultrasound are often seen. However, as many as a third of patients
with CKD due to type 2 diabetes mellitus do not have albuminuria. In
patients with diabetes mellitus or hypertension, the urinary sediment
is usually unremarkable, so the presence of red blood cells (RBCs) casts
or a significant number of dysmorphic erythrocytes should initiate a
careful evaluation for other causes of CKD.
In cases of hypertensive nephrosclerosis, established hypertension
typically antedates the diagnosis of renal failure for many years, and the
presence of hypertensive retinopathy or cardiovascular disease (e.g., left
ventricular hypertrophy) is common. Proteinuria is typically minimal or
absent (<2 g/day), and the kidneys are symmetrically small on ultrasound.
Although hypertension and type 2 diabetes mellitus are common,
among patients with CKD it is important not to assume that diabetes
258
CHAPTER 24 Approach to the Patient With Renal Disease
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259
and hypertension are always the cause of CKD. The diagnosis of hypertension or diabetes mellitus as the cause of CKD requires that no other
identifiable cause of kidney disease is apparent after a thorough evaluation.
Notably, in individuals with hypertension, genes such as APOL1 have been
identified that appear to be associated with a greater risk of renal disease,
and genetic analysis may emerge as one approach to identify those most at
risk so that strategies for prevention can be tested in the future.
Once a diagnosis of CKD is established, ongoing evaluation is
required, because those with CKD are at increased risk for complications such as hypertension, metabolic bone disease, anemia, hyperkalemia, and metabolic acidosis. Furthermore, the initial diagnosis of CKD
may be modified over time, such as by the discovery of RBC casts in a
patient with diabetes mellitus. AKI may be superimposed on CKD. The
assessment of hypertension requires an accurate assessment of blood
pressure. Measurements of three readings after quiet rest at intervals of
1 minute using an oscillometric device is now recommended; auscultatory methods utilizing Korotkoff sounds are no longer recommended.
If hypertension or volume overload becomes difficult to manage, the
dietary intake of sodium can be estimated by 24-hour urine collection.
The number of medications prescribed to patients with CKD is substantial, which calls for monitoring for medication adherence. The latter, for instance, may provide clues to lack of control of BP. For a more
detailed approach and slightly different opinion on the measurement
of the arterial blood pressure, see Chapter 12.
History and Examination
The signs and symptoms of CKD depend on the stage at presentation.
Early in the clinical course, nonspecific fatigue is typical, and there
may be no discernable clues to CKD on examination, highlighting
the need for laboratory screening. As filtration rate declines, the signs
and symptoms of CKD become more common and may include pedal
edema, facial puffiness, flank pain, polyuria, nocturia, and hypertension. Symptoms referable to uremia, such as nausea, dysgeusia, and
vomiting, tend to occur late and should not be relied on to make a
diagnosis of early CKD.
Sometimes the manifestations of the primary disease predominate.
For example, the presence of fever, arthralgia, and rash in a young
woman with renal failure and active urinary sediment is highly suggestive of lupus nephritis; or intravenous drug use, cardiac murmur, vegetations on cardiac valve, and positive blood culture should alert to a
possible diagnosis of endocarditis-associated glomerulonephritis. A
family history of deafness, hematuria, and CKD can point to the diagnosis of Alport’s syndrome; or a history of cerebral hemorrhage due to
a ruptured aneurysm may suggest underlying polycystic kidney disease.
Medication history should focus on exposure to nephrotoxins,
including long-term use of nonsteroidal anti-inflammatory drugs
(NSAIDs), lithium, exposure to cisplatin, and recent escalation of the
dose of diuretics. Some nonprescription drugs can lead to CKD (e.g.,
cocaine-induced glomerulonephritis, Ma Huang–induced ephedrine
kidney stones).
Past medical history may clue in to possible etiologies; for example,
diabetic retinopathy to diabetic nephropathy; recurrent urinary tract
infection to renal calculi; and hepatitis C, infective endocarditis, or
Wegner’s granulomatosis to glomerulonephritis.
Physical examination can reveal the presence of anemia, skin rash
(such as in endocarditis, Fabry’s disease, Henoch-Schönlein purpura,
or cryoglobulinemia), rales, pericardial or pleural friction rub, pedal
edema, abdominal bruit, or enlarged kidneys. Retinal examination is of
particular importance and may reveal diabetic retinopathy or changes
associated with hypertension; in a patient with rapid deterioration of
renal function, retinal examination may show cholesterol emboli or septic emboli, pointing to the existence of cholesterol emboli or bacterial
endocarditis as possible causes. Rectal examination to assess prostate
enlargement in men and pelvic examination in women may point to
clues to urinary tract obstruction such as a tumor or neurogenic bladder. Examination of the muscle mass is important when interpreting
serum creatinine concentration (see later discussion).
The assessment of blood pressure is particularly important. Often,
blood pressure is elevated in the clinic but normal at home (white coat
hypertension). Occasionally, the blood pressure is elevated at home but
not in the clinic (masked hypertension). In patients who complain of
orthostatic symptoms but appear to have normal or high blood pressure in the clinic, home blood pressure measurements or 24-hour
ambulatory blood pressure monitoring may be required. The latter
may reveal very low blood pressure with orthostatic symptoms, and
antihypertensive therapy may need to be modified.
The overall condition of the patient and level of functional status
is important in deciding therapies. For example, transplantation may
be an option for a patient with correctable cardiovascular disease and
dialysis for someone with calcified iliac arteries where kidney transplant may not be possible. However, the physician and the patient’s
family may share the decision to forego renal replacement in an elderly
person with advanced dementia and poor functional status.
Assessment of Kidney Function
Knowledge of both the severity of renal impairment and the rate of
change in renal function is important in managing CKD. Rapid deterioration of kidney function over a few weeks to a few months may
not reflect native renal disease progression; rather, it may reflect superimposed volume depletion (e.g., escalation in the dose of diuretics),
exposure to nephrotoxins (e.g., NSAID use), or urinary tract obstruction. Alternatively, rapid progression of kidney disease may be seen
in certain disease states such as malignant hypertension, crescentic
glomerulonephritis, microangiopathic hemolytic anemia (thrombotic
thrombocytopenic purpura, scleroderma), vasculitides (lupus nephritis, Wegener’s granulomatosis), atheroembolic renal disease, or multiple myeloma. In general, a slower progression of decline in kidney
failure is anticipated in patients with CKD caused by polycystic kidney
disease, hypertension, or diabetes mellitus.
Serum creatinine is the most commonly measured of kidney functions. Along with the assessment of albuminuria, it is an important
component for staging CKD (Fig. 24.1). If estimated GFR is less than
60 mL/min/1.73 m2 for 3 months or longer, kidney disease is said to
be chronic.
Notably, serum creatinine concentration does not rise to above the
population threshold of normal (about 1.3 mg/dL in men and 1.1 mg/
dL in women) until approximately 40% of kidney function is lost. In
earlier stages of kidney disease, serum creatinine is maintained in the
normal range by enhanced tubular secretion of creatinine. This process
of creatinine secretion requires cationic transporters, and drugs that
compete with creatinine secretion (e.g., cimetidine, triamterene, trimethoprim) may cause elevation of serum creatinine without depressing true GFR. A clinical clue to an impairment in cationic transport of
creatinine is the lack of rise in blood urea nitrogen despite an increase
in serum creatinine concentration.
With advanced kidney failure, the magnitude of absolute changes
in serum creatinine concentration may be more rapid. The relationship between serum creatinine and GFR is nonlinear, accelerating as
the GFR declines. This means, for example, that an increase in serum
creatinine concentration from 3 to 3.5 mg/dL is associated with a lesser
decline in GFR than is a change from 1 to 1.5 mg/dL. Specific knowledge of the baseline level of serum creatinine is important; for example,
change from 0.6 to 1.2 mg/dL is still within the normal range in an
adult man but actually reflects an approximately 57% loss of GFR.
260 SECTION V Renal Disease
Green:
Orange: high risk; Red: very high risk.
Persistent albuminuria categories
Description and range
Prognosis of CKD by GFR
and Albuminuria Categories:
)
2
Description and range
GFR categories (ml/min/1.73 m
Low risk (if no other markers of kidney disease, no CKD); Yellow: moderately increased risk;
Fig. 24.1 Chronic kidney disease (CKD) nomenclature used by the Kidney Disease Improving Global Out-
comes (KDIGO) consortium. CKD is defined as abnormalities of kidney structure or function, present for
3 months or longer, with implications for health. CKD is classified on the bases of cause, glomerular filtration rate (GFR), and albuminuria. (From KDIGO: 2012 clinical practice guideline for the evaluation and
management of chronic kidney disease, Kid Intl Suppl 3:18, 2013. Available at http://www.kdigo.org/clinical_
practice_guidelines/pdf/CKD/KDIGO_2012_CKD_GL.pdf. Accessed June 1, 2014.)
KDIGO 2012
G1
Normal or high
G2
Mildly decreased
Mildly to moderately
G3a
decreased
Moderately to
G3b
severely decreased
G4
Severely decreased
G5
Kidney failure
90
60–89
45–59
30–44
15–29
15
A1 A2 A3
Normal to
mildly
increased
30 mg/g
3 mg/mmol
Moderately
increased
30–300 mg/g
3–30 mg/mmol
Severely
increased
300 mg/g
30 mg/mmol
The relationship between GFR and serum creatinine is best interpreted at steady state and not when the GFR is changing rapidly. For
example, bilateral nephrectomy in a patient with previously normal
kidney function (as might occur in a patient with renal cell carcinoma)
results in a drop in GFR from 100 to 0 mL/min. However, serum creatinine would be expected to increase by only about 1 mg/dL/day, and a
plateau may not be achieved before 1 week. This delay reflects the fact
that the generation of creatinine is insufficient to saturate the volume
of distribution of creatinine. A plateau will be reached more rapidly
if the rate of creatinine generation is increased, the volume of distribution of creatinine is small, or residual renal function is substantial.
Given these variables, it is important to be aware that serum creatinine may be a poor marker of GFR in non–steady-state conditions.
Similarly, among patients with end-stage renal disease receiving renal
replacement therapy although the laboratory may report eGFR (estimated GFR), this is a poor estimate of GFR given that the creatinine is
being removed by extracorporeal means.
There also are several conditions in which serum creatinine may
be falsely low in relation to the GFR. Because creatinine generation
is dependent on muscle mass, low creatinine generation occurs in
diseases associated with sarcopenia, such as motor neuron diseases
(amyotrophic lateral sclerosis), wasting illnesses (advanced cancer,
tuberculosis, cardiac cachexia), and even malnutrition. Visual examination of muscle mass (thighs, arms, temporal muscles) may therefore
be important in the interpretation of serum creatinine concentrations.
Other conditions associated with low creatinine generation include
cirrhosis and advanced age. Creatinine generation is reduced in sepsis,
and kidney function may be worse than is detectable by estimation of
GFR through measurement of serum creatinine.
Among patients with severe CKD (e.g., GFR <20 mL/min), creatinine is secreted and urea is absorbed by the tubule. Tubular secretion
of creatinine is fortuitously balanced by tubular reabsorption of urea,
making measurements of urea clearance and creatinine clearance useful in estimating true GFR. An average of creatinine and urea clearance
closely approximates true GFR in such situations.
At steady state—that is, when the patient is neither gaining nor losing weight—the 24-hour urine urea nitrogen measurement can be used
to estimate dietary protein intake. In addition to its excretion in urine,
nitrogen is lost through the gut, through the skin, and, as non-urea nitrogen, through the kidney in proportion to body weight. It is estimated that
31 mg/kg/day of non-urea nitrogen is excreted in this fashion. Dietary
protein intake can be calculated as 6.25 g protein per gram of total daily
nitrogen excretion. Accordingly, the formula for dietary protein intake in
grams per day is (urine urea nitrogen + 0.031 × body weight in kg) × 6.25.
Although urea by itself is less useful to assess kidney function, it
can be helpful in conjunction with the serum creatinine measurement.
Urea is reabsorbed by the tubule in sodium-avid states. The normal
ratio of urea to creatinine is 10:1. In states of volume depletion such
as diuretic use, diarrhea, sweat losses, or third spacing (e.g., leakage
of fluid outside the vascular compartment such as in peritoneal cavity [ascites] or pleural space [pleural effusion]), the urea-to-creatinine
ratio may be greater than 20:1. Sometimes, ratios greater than 20:1 are
also seen in catabolic states (e.g., long-bone fracture, corticosteroid
use, burns, sepsis), increased gut protein load (upper gastrointestinal bleeding, high-protein diet), or obstructive uropathy. In contrast,
creatinine may rise disproportionally more than urea, for example in
advanced cirrhosis, low-protein diets, or states associated with the use
of cationic transport inhibitors (e.g., cimetidine).
CHAPTER 24 Approach to the Patient With Renal Disease
GFR
2
×
− 1.154
×
×
]
α
×
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261
For many decades, the assessment of creatinine clearance by a
24-hour urine collection has been the mainstay of assessing renal
function. However, given that creatinine may be secreted (and not
just filtered), this test may overestimate GFR. Furthermore, voiding
outside the collection jug is common and may lead to errors in estimating GFR. Although a 24-hour urine collection is not routinely
reflects a profound disorder of glomerular permselectivity. Common
causes of nephrotic syndrome in adults are diabetic nephropathy,
focal segmental glomerulosclerosis, membranous nephropathy, and
amyloidosis. Among children, minimal change nephropathy and
focal segmental glomerulosclerosis are important causes of nephrotic
syndrome.
recommended to assess renal function, it may still be useful for estimating GFR in sarcopenic individuals and in those with advanced
liver disease. Creatinine clearance can be easily calculated as the urinary flow rate (in mL/min) times the ratio of urinary creatinine to
plasma creatinine. A timed collection is needed. Creatinine excretion approximates 15 mg/kg/day. Although this rate is variable (the
coefficient of variation from day to day over 28 days on a standard
diet varies from 6% to 22%) and depends on meat intake, it can be
used to estimate whether urine has been grossly undercollected or
overcollected.
Usually, GFR is estimated through the use of equations that account
for age in years, race, sex, and serum creatinine. The Modification of
Diet in Renal Disease (MDRD) equation uses a creatinine measurement (Scr) that has been calibrated to an isotope dilution mass spectrometry standard:
in mL/min / 1
− 0 .203
(Age)
.73 m
= 175
0. 742 [if female]×1.212 [if black
(Scr)
A newer equation, called the Chronic Kidney Disease Epidemiology
Collaboration (CKD-EPI) equation, is less likely to estimate GFR as
low if the GFR is higher than 60 mL/min/1.73 m2. This equation is
more complicated:
GFR 60 ml / min / 1 . 73 m2= 141×min(Scr / k , 1)
× max(Scr / k , 1)
1.018 [if female]×1.159 [if black]
− 1209
× 0.993
Age
where Scr is serum creatinine (in mg/dL), κ is 0.7 for females and 0.9
for males, α is −0.329 for females and −0.411 for males, min indicates
the minimum of Scr/κ or 1, and max indicates the maximum of Scr/κ
or 1. Several calculators to estimate GFR using the CKD-EPI equation
or the MDRD equation are available on the World Wide Web or as
applications for personal devices.
Assessment of Blood Pressure
Hypertension is a common accompaniment of CKD, yet the evaluation of hypertension often is performed poorly. Current management
of hypertension is directed most often to management of blood pressure measurements obtained during clinic visits. Measurement of BP
during clinic visits therefore should be accurately performed. At present, measurement of three readings of BP in the nondominant arm,
after seated rest for 5 minutes, is the standard of care. The average
of the three readings is used to make clinical decisions regarding the
management of hypertension. Despite accurate measurements of BP
in the clinic, BP may be falsely higher in the clinic (white coat hyper-
tension) or lower in the clinic (masked hypertension) compared with
24-hour ambulatory blood pressure measurements. At present, in the
United States, the latter technique is mostly limited to research or to
management of hypertension in a few difficult cases. However, home
blood pressure recordings self-measured by the patient twice daily for
about 1 week every month can help diagnose and manage hypertension more effectively. Self-performance of these measurements may
promote adoption of a more healthful diet and better medication
adherence by the patient, as well as reducing therapeutic inertia on the
part of the physician.
An important cause of poor control of BP in patients with
or without CKD is poor medication adherence. Pill burden
directly relates to nonadherence with medications, and patients
with CKD are often prescribed multiple medications. Thus, the
assessment of adherence to medications should be a routine part
of assessment.
Assessment of Dietary Sodium Intake
At steady state, when body weight is neither increasing nor decreasing, the dietary sodium intake can be judged by 24-hour urine collection. To establish adequacy of urine collection, the measurement
of urine creatinine in 24-hour urine sample is important. The creatinine excretion rate in an adequately collected specimen should
Assessment of Albuminuria
The assessment of albuminuria is fundamental because it may point
to the cause of the CKD. Furthermore, the severity of albuminuria is
directly associated with an accelerated progression of CKD and cardiovascular disease. As a result, albuminuria is now used to stage CKD
(see Fig. 24.1).
Albumin excretion rate is normally less than 10 mg/24 hr, and an
excretion rate of 30 mg/24 hr or higher is considered abnormal and
approach 1 g/day for women and 1.5 g/day for men. Dietary potassium and protein intake can be monitored similarly. Measurement
of urine urea nitrogen in the 24-hour urine sample can reveal the
adequacy of dietary protein intake. Dietary sodium restriction can
improve blood pressure, can enhance the biologic actions of inhibitors of the renin-angiotensin system, and may protect the heart,
blood vessels, and kidneys independent of improvement in blood
pressure.
moderately increased. An albumin excretion rate of 300 mg/24 hr or
higher is considered severely increased. Albuminuria can be more conveniently assessed by measuring the ratio of urine albumin and urine
creatinine concentrations in a spontaneously voided urine specimen.
Given that the creatinine excretion rate averages 1 g/day, an albumin-to-creatinine ratio of 30 mg/g creatinine or higher is considered
abnormal and moderately increased; a ratio of 300 mg/g creatinine is
considered severely increased.
Microscopic Urinalysis
Microscopic urinalysis at initial evaluation and on an ongoing basis
can reveal vital information about the health of the kidney. Evaluation
should be performed by centrifugation of at least 12 mL of a freshly
voided specimen. Cells, casts, crystals, and other elements can corroborate the diagnosis of the cause of CKD. Examples are shown in
Figs. 24.2 through 24.5. (See also E-Fig. 29.1 and Table 29.3.)
An albumin excretion rate higher than 2200 mg/24 hr (which
corresponds to approximately 3000 mg protein/24 hr) is considered
nephrotic. Such a degree of albuminuria/proteinuria is often accompanied by edema, hypoalbuminemia, and hyperlipidemia. The combination of these disorders is referred to as the nephrotic syndrome and
Renal Imaging
Bladder ultrasonography is a tool that can be used to assess residual
urine volume. The wide availability of this tool allows diagnosis of
bladder outlet obstruction without the need to catheterize the patient.
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Fig. 24.2 Cells often found in urine of patients with kidney disease. (A) Sternheimer-Malbin–stained urine
sediment (100× objective) in a patient with urinary tract infection. Solid line shows a leukocyte and hollow
line indicates bacteria. (B) Sternheimer-Malbin–stained urine sediment (40×) in a patient with fungal urinary
tract infection. Solid line shows a pseudohypha and hollow lines indicate leukocytes. (C) Unstained urine
sediment (40×) shows an oval fat body in a patient with nephrotic syndrome. (D) Sternheimer-Malbin–stained
urine sediment (100×) in a patient with immunoglobulin A (IgA) nephropathy. Solid line shows an acanthocyte
characterized by outpouching of the red blood cell (RBC) membrane. (E) Sternheimer-Malbin–stained urine
sediment (40×) in a patient with IgA nephropathy shows many acanthocytes (solid line). When acanthocytes
constitute more than 5% of the RBCs, their presence is considered significant. (F) Sternheimer-Malbin–
stained urine sediment (100×) in a patient with recovering acute tubular necrosis (ATN). Solid lines indicate
glitter cells. The granules of these leukocytes have a Brownian motion and appear to glitter under the microscope. These cells can be seen in large numbers during the recovery stage of ATN and in patients with urinary tract infection. (G) Sternheimer-Malbin–stained urine sediment (40×) shows numerous squamous cells,
indicating poor collection technique. (H) Hansel-stained urine sediment (100×) shows eosinophils that can be
seen in patients with allergic interstitial nephritis, cholesterol emboli, or, sometimes, urinary tract infection.
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Fig. 24.3 Tubular cells often found in urine of patients with acute kidney injury. (A) Unstained urine sediment
(40× objective) in a patient recovering from acute tubular necrosis (ATN). Solid lines show intact renal tubular
epithelial cells. (B) Same specimen as in A but stained with acridine orange-propidium iodide and viewed
with a triple excitation band fluorescence filter (triple-cube). Red cells are dead and green cells are live. Both
tubular cells appear viable. Smaller cells are leukocytes. (C) Unstained urine sediment (40×) shows several
renal tubular cells that appear monomorphic (as in images A and B), indicating acute tubular injury. The arrow
indicates a binucleate tubular cell. (D) Unstained urine sediment (40×) shows several renal tubular cells
(solid lines) that appear dysmorphic. Instead of being round, the cells are angular. Furthermore, these cells
are multinucleated, indicating failure of the cell to divide. Large numbers of dysmorphic renal tubular cells
are often seen if the acute tubular injury is substantial. (E) Unstained urine sediment (100×) shows two teardrop-shaped dysmorphic renal tubular epithelial cells (solid lines). Because the patient had jaundice, the cells
appear to have a color despite lack of staining. (F) Unstained urine sediment (100×) shows one dysmorphic,
binucleate renal tubular epithelial cell (line). This is the same patient as in E. (G) Unstained urine sediment
(40×) shows severe ATN. No dirty-brown granular casts were seen, but the tubular cells were dysmorphic
(lines). The large amount of granular debris and absence of casts suggests failure to form Tamm-Horsfall
protein and more severe tubular injury. This patient also had jaundice, as is evident from the yellow hue. (H)
Unstained urine sediment (40×) shows dysmorphic renal tubular epithelial cells (triangular, cigar-shaped, and
polygonous), often multinucleated as denoted by lines.
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Fig. 24.4 Crystals commonly found in urine sediment. All images were made with the use of polarized light
and a diffusion interference contrast microscope. (A) Uric acid crystals (40× objective). (B) Calcium oxalate
dihydrate crystals (white lines) (40×). Large numbers are seen in patients with ethylene glycol poisoning.
(C) Calcium oxalate monohydrate crystals (solid line) (40×). (D) Magnesium ammonium phosphate crystals,
or triple phosphate crystals, are often found in patients with a complicated urinary tract infection (40×). (E)
Coffin-lid appearance of magnesium ammonium phosphate crystals (100×). (F) Bilirubin crystals in a patient
with acute tubular necrosis and obstructive jaundice (100×). Inset shows 40× view of the bilirubin crystals.
(G) Calcium phosphate crystals (40×) in a patient with tumor lysis syndrome. Sequential images (left to right,
top to bottom) show dissolution of the crystals within a few minutes after urine was acidified by adding 2%
perchloric acid. (H) Fiber artifact in the urine is of no clinical significance.
Renal ultrasonography is the most accurate way of determining kidney size. It is commonly performed to detect renal masses, cysts, and
evidence of obstruction characterized by dilatation of the pelvicalyceal
system and to evaluate the size and shape of the kidneys. The presence
of small kidneys (i.e., <9 cm on both sides) suggests the presence of
scarring and therefore CKD. However, kidneys that are larger, typically in the range of 11 to 13 cm, are often seen in conjunction with
CKD due to diabetes mellitus, amyloidosis, and multiple myeloma.
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Fig. 24.5 Casts in urine. (A) Unstained urine sediment (40× objective) in a patient with glomerulonephritis.
Solid line shows a granular cast, and hollow line shows a hyaline cast. (B) Sternheimer-Malbin–stained urine
sediment (40×). The solid line points to an erythrocyte cast in a patient with immunoglobulin A nephropathy.
(C) Unstained urine sediment (40×) shows several renal tubular cells and an epithelial cell cast (solid line)
indicating acute tubular injury. (D) Papanicolaou-stained urine sediment (solid line) (100×) shows an epithelial cell cast in an otherwise stable patient with diabetic nephropathy. (E) Unstained urine sediment (40×)
shows bilirubin-stained granular cast (solid line) indicating renal inflammation in a patient with liver disease.
(F) Unstained urine sediment (10×) shows dirty-brown granular casts (solid line) indicative of acute tubular
necrosis (ATN). (G) Unstained urine sediment (40×) shows severe ATN. No dirty-brown granular casts were
seen, but the tubular cells (solid lines) were dysmorphic and multinucleated. (H) Sternheimer-Malbin–stained
urine sediment (40×) shows a fatty cast (solid line) in a patient with nephrotic syndrome.
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