# 49 - 55 Azotemia and Urinary Abnormalities

### 55 Azotemia and Urinary Abnormalities

diagnosis of exclusion is based largely on history and physical examina­
tion and its treatment is based on a minimally invasive algorithm, with 
the focus on the patient’s clinical phenotype and the initial implemen­
tation of conservative therapeutic measures, IC/BPS can be well man­
aged even in resource-poor settings. As with many poorly understood 
and difficult-to-treat conditions, the greatest barrier to its diagnosis 
and treatment may perhaps be its recognition.
■
■FURTHER READING
Clemens JQ et al: Urologic chronic pelvic pain syndrome: Insights 
from the MAPP Research Network. Nat Rev Urol 16:187, 2019.
Clemens JQ et al: AUA guideline for the diagnosis and treatment of 
interstitial cystitis/bladder pain syndrome. J Urol 208:34, 2022.
Cox A et al: CUA guideline: Diagnosis and treatment of interstitial 
cystitis/bladder pain syndrome. Can Urol Assoc J 10:E136, 2016.
Moldwin RM et al: Interstitial cystitis/bladder pain syndrome and 
related disorders, in Campbell-Walsh-Wein Urology, 12th ed. AW 
Partin et al (eds). Philadelphia, Elsevier, 2021.
Nickel JC et al: MV140 sublingual vaccine reduces recurrent urinary 
tract infection in women. Results from the first North American 
clinical experience study. Can Urol Assoc J 18:25, 2024.
David B. Mount

Azotemia and Urinary 
Abnormalities
Normal kidney functions occur through numerous cellular processes 
to maintain body homeostasis. Disturbances in any of these functions 
can lead to abnormalities that may be detrimental to survival. Clini­
cal manifestations of these disorders depend on the pathophysiology 
of renal injury and often are identified as a complex of symptoms, 
abnormal physical findings, and laboratory changes that constitute 
specific syndromes. These renal syndromes (Table 55-1) may arise 
from systemic illness or as primary renal disease. Nephrologic syn­
dromes usually consist of several elements that reflect the underlying 
pathologic processes, typically including one or more of the following: 
(1) reduction in glomerular filtration rate (GFR), (2) abnormalities 
of urine sediment (red blood cells [RBCs], white blood cells [WBCs], 
casts, and crystals), (3) abnormal urinary excretion of serum proteins 
(proteinuria), (4) disturbances in urine volume (oliguria, anuria, poly­
uria), (5) presence of hypertension and/or expanded total body fluid 
volume (edema), (6) electrolyte abnormalities, and (7) in some syn­
dromes, fever/pain. The specific combination of these findings should 
permit identification of one of the major nephrologic syndromes 
(Table 55-1) and allow differential diagnoses to be narrowed so that the 
appropriate diagnostic and therapeutic course can be determined. All 
these syndromes and their associated diseases are discussed in more 
detail in subsequent chapters. This chapter focuses on several aspects 
of renal abnormalities that are critically important for distinguishing 
among those processes: (1) reduction in GFR, (2) alterations of the 
urinary sediment and/or protein excretion, and (3) abnormalities of 
urinary volume.
AZOTEMIA
■
■ASSESSMENT OF GFR
Monitoring the GFR is important in both hospital and outpatient set­
tings, and several different methodologies are available. GFR is the pri­
mary metric for kidney “function,” and its direct measurement involves 
administration of a radioactive isotope (such as inulin or iothalamate) 

that is filtered at the glomerulus into the urinary space but is neither 
reabsorbed nor secreted throughout the tubule. GFR—i.e., the clear­
ance of inulin or iothalamate in milliliters per minute—is calculated 
from the rate of appearance of the isotope in the urine over several 
hours. In most clinical circumstances, direct GFR measurement is not 
feasible, and the plasma creatinine level is used as a surrogate to esti­
mate GFR. Plasma creatinine (PCr) is the most widely used marker for 
GFR, which is related directly to urine creatinine (UCr) excretion and 
inversely to PCr. On the basis of this relationship (with some important 
caveats, as discussed below), GFR will fall in roughly inverse propor­
tion to the rise in PCr. Failure to account for GFR reductions in drug 
dosing can lead to significant morbidity and death from drug toxicities 
(e.g., digoxin, imipenem). In the outpatient setting, PCr serves as an 
estimate for GFR (although much less accurate; see below). In patients 
with chronic progressive renal disease, there is an approximately linear 
relationship between 1/PCr (y axis) and time (x axis). The slope of that 
line will remain constant for an individual; when values deviate, an 
investigation for a superimposed acute process (e.g., volume depletion, 
drug reaction) should be initiated. Signs and symptoms of uremia, 
the clinical symptom complex associated with renal failure, develop at 
significantly different levels of PCr, depending on the patient (size, age, 
and sex), underlying renal disease, existence of concurrent diseases, 
and true GFR. Generally, patients do not develop symptomatic uremia 
until renal insufficiency is severe (GFR <15 mL/min).

Azotemia and Urinary Abnormalities
CHAPTER 55
A significantly reduced GFR (either acute or chronic) is usually 
reflected in a rise in PCr, leading to retention of nitrogenous waste 
products (defined as azotemia) such as urea. Azotemia may result from 
reduced renal perfusion, intrinsic renal disease, or postrenal processes 
(ureteral obstruction; see below and Fig. 55-1). Precise determination 
of GFR is problematic, as both commonly measured indices (urea and 
creatinine) have characteristics that affect their accuracy as markers 
of clearance. Urea clearance may underestimate GFR significantly 
because of urea reabsorption by the tubule. In contrast, creatinine is 
derived from muscle metabolism of creatine, and its generation varies 
little from day to day.
Creatinine clearance (CrCl), an approximation of GFR, is measured 
from plasma and urinary creatinine excretion rates for a defined period 
(usually 24 h) and is expressed in milliliters per minute: CrCl = (Uvol × 
UCr)/(PCr × Tmin). The “adequacy” or “completeness” of the urinary 
collection is estimated by the urinary volume and creatinine content; 
creatinine is produced from muscle and excreted at a relatively con­
stant rate. For a 20- to 50-year-old man, creatinine excretion should be 
18.5–25.0 mg/kg body weight; for a woman of the same age, it should 
be 16.5–22.4 mg/kg body weight. For example, an 80-kg man should 
excrete between ~1500 and 2000 mg of creatinine in an “adequate” col­
lection. Creatinine is useful for estimating GFR because it is a small, 
freely filtered solute that is not reabsorbed by the tubules. PCr levels can 
increase acutely from dietary ingestion of cooked meat, however, and 
creatinine can be secreted into the proximal tubule through an organic 
cation pathway (especially in advanced progressive chronic kidney 
disease [CKD]), leading to overestimation of GFR. When a timed col­
lection for CrCl is not available, decisions about drug dosing must be 
based on PCr alone. Two formulas are used widely to estimate kidney 
function from PCr: (1) Cockcroft-Gault and (2) four-variable MDRD 
(Modification of Diet in Renal Disease).
Cockcroft-Gault:
CrCl(mL/min)
(140 age)
Lean Body Weight (kg)
Serum Creatinine (mg/dL)

( 0.85 if female)
=
−
×
×
×
MDRD: eGFR (mL/min per 1.73 m2) = 186.3 × PCr (e−1.154)
× age (e−0.203) × (0.742 if female) × (1.21 if black).
Numerous websites are available to assist with these calcula­
tions (www.kidney.org/professionals/kdoqi/gfr_calculator.cfm). A newer 
Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) esti­
mated GFR (eGFR), which was developed by pooling several cohorts

TABLE 55-1  Initial Clinical and Laboratory Database for Defining Major Syndromes in Nephrology
SYNDROME
IMPORTANT CLUES TO DIAGNOSIS
COMMON FINDINGS
Acute or rapidly progressive renal 
failure
Anuria
Hypertension, hematuria
321, 326, 328, 331
Oliguria
Proteinuria, pyuria
 
Documented recent decline in GFR
Casts, edema
 
Acute nephritis
Hematuria, RBC casts
Proteinuria

Azotemia, reduced GFR, oliguria
Pyuria
 
Edema, hypertension
Circulatory congestion
 
PART 2
Cardinal Manifestations and Presentation of Diseases
Chronic renal failure
Azotemia for >3 months
Proteinuria, casts

Symptoms or signs of uremia, (late 
manifestation), casts
Symptoms or signs of renal osteodystrophy
Polyuria, nocturia
 
Kidneys reduced in size bilaterally
Edema, hypertension
 
Broad casts in urinary sediment
Hyperkalemia, metabolic acidosis
 
Nephrotic syndrome
Proteinuria, with >3.5 g/24 h per 1.73 m2
Casts

Hypoalbuminemia
Lipiduria
 
Edema
Hypercoagulable state
 
Hyperlipidemia
 
 
Asymptomatic urinary abnormalities
Hematuria
 

Proteinuria (below nephrotic range)
 
 
Sterile pyuria, casts
 
 
Urinary tract infection/pyelonephritis
Bacteriuria, with >105 cfu/mL
Hematuria

Other infectious agent documented in urine
Mild azotemia and reduced GFR
 
Pyuria, leukocyte casts
Mild proteinuria
 
Frequency, urgency
Fever
 
Bladder tenderness, flank tenderness
 
 
Renal tubular defects
Electrolyte disorders
Hematuria
327, 328
Polyuria, nocturia
“Tubular” proteinuria (<1 g/24 h)
 
Renal calcification
Enuresis
 
Large kidneys
Electrolyte and/or acid-base abnormalities
 
Renal transport defects
Other electrolyte issues, e.g., hypomagnesemia
 
Hypertension
Systolic/diastolic hypertension
Proteinuria
288, 329
 
Casts
 
 
Azotemia
 
Nephrolithiasis
Previous history of stone passage or removal
Hematuria

Previous history of stone seen by x-ray
Pyuria
 
Renal colic
Frequency, urgency
 
Urinary tract obstruction
Azotemia, oliguria, anuria
Hematuria

Polyuria, nocturia, urinary retention
Pyuria
 
Slowing of urinary stream
Enuresis, dysuria
 
Large prostate, large kidneys
 
 
Flank tenderness, full bladder after voiding
 
 
Abbreviations: cfu, colony-forming units; GFR; glomerular filtration rate; RBC, red blood cell.
with and without kidney disease who had data on directly measured 
GFR, appears to be more accurate:
CKD-EPI: eGFR = 141 × min (PCr/k, 1)a × max (PCr/k, 1)−1.209 
× 0.993Age × 1.018 [if female] × 1.159 [if black],
where PCr is plasma creatinine, k is 0.7 for females and 0.9 for males, a is 
–0.329 for females and –0.411 for males, min indicates the minimum of 
PCr/k or 1, and max indicates the maximum of PCr/k or 1 (https://www.
mdcalc.com/ckd-epi-equations-glomerular-filtration-rate-gfr).
There are limitations to all creatinine-based estimates of GFR. Each 
equation, along with 24-h urine collection for measurement of creati­
nine clearance, is based on the assumption that the patient is in steady 
state, without daily increases or decreases in PCr as a result of rapidly 
changing GFR. The MDRD equation is better correlated with true GFR 
when the GFR is <60 mL/min per 1.73 m2. The gradual loss of muscle 

CHAP(S). DISCUSSING 
DISEASE-CAUSING 
SYNDROME
Hypocalcemia, hyperphosphatemia, 
hyperparathyroidism
 
from chronic illness, chronic use of glucocorticoids, or malnutrition 
can mask significant changes in GFR with small or imperceptible 
changes in PCr.
The coefficient of 1.159 in the CKD-EPI equation to adjust for 
self-reported black race reflects that measured GFR was 16% higher 
in blacks than nonblacks with similar age, sex, and creatinine in the 
data set used to develop the equation. Race is a social rather than a 
biological construct, for which reason the use of the “race modifier” 
in calculating eGFR using CKD-EPI and other equations has come 
under scrutiny. In particular, given the implications of utilizing selfreported race to modify clinical laboratory results, many medical 
centers have recently stopped reporting eGFRs that have been calcu­
lated using a race modifier. This change is projected to have positive 
consequences, in particular, improved access to waitlisting for renal 
transplantation in black patients at an earlier stage of CKD. Potential

AZOTEMIA
Urinalysis and
renal ultrasound
Hydronephrosis
Renal size parenchyma
Urinalysis
Urologic evaluation
Relieve obstruction
Normal size kidneys
Intact parenchyma
Bacteria
Pyelonephritis
Small kidneys, thin cortex,
bland sediment,
isosthenuria
<3.5 g protein/24 h
Acute Renal Failure
Normal
urinalysis
with oliguria
Chronic Renal Failure
Symptomatic treatment
delay progression
If end-stage, prepare
for dialysis
Urine
electrolytes
Muddy brown
casts,
amorphous
sediment
+ protein
FeNa <1%
U osmolality >500 mosmol
FeNa >1%
U osmolality <350 mosmol
Renal biopsy
Prerenal Azotemia
Volume contraction,
cardiac failure,
vasodilatation, drugs,
sepsis, renal
vasoconstriction,
impaired autoregulation
Acute Tubular Necrosis
Glomerulonephritis
or vasculitis
Immune complex,
anti-GBM disease
FIGURE 55-1  Approach to the patient with azotemia. FeNa, fractional excretion of sodium; GBM, glomerular basement membrane; RBC, red blood cell; U, urine; WBC, white 
blood cell.
negative consequences include “overdiagnosis” of CKD, inadequate or 
inaccurate dosing of drugs that are eliminated through the kidney (e.g., 
metformin), reduced access to imaging modalities for black patients 
with CKD with a lower reported eGFR, and reductions in living kidney 
donation among blacks. These and the other limitations in creatinine-based 
eGFR have led to the development of alternative methods for estimat­
ing GFR.
Cystatin C, a member of the cystatin superfamily of cysteine prote­
ase inhibitors, is produced at a relatively constant rate from all nucle­
ated cells. Serum cystatin C has been proposed to be a more sensitive 
marker of early GFR decline than is PCr, with lesser effects of muscle 
mass on circulating levels; however, cystatin C levels are influenced by 
the patient’s sex and the presence of diabetes mellitus, smoking, and 
inflammation. To the extent that cystatin C–based calculation of eGFR 
is less affected by self-reported race and muscle mass, it is an increas­
ingly important adjunct to creatinine-based eGFR. Recently, eGFR 
equations that include both creatinine and cystatin C have been shown 
to be more accurate than the single-measurement equations. Clinical 
judgement and clinical assessment also play an important role in inter­
preting eGFR values. For example, a bodybuilder may have an elevated 
creatinine level due to increased muscle mass, with an underestimate 

Azotemia and Urinary Abnormalities
CHAPTER 55
WBC, casts
eosinophils
Interstitial
nephritis
Abnormal
urinalysis
Red blood
cells
Renal artery
or vein
occlusion
RBC casts
Proteinuria
Angiogram
of GFR based on a creatinine-based eGFR; in that case, the cystatin C 
eGFR may be more accurate.
APPROACH TO THE PATIENT
Azotemia
Once GFR reduction has been established, the physician must 
decide if it represents acute or chronic renal injury. The clinical 
circumstances, history, and laboratory data often make this an easy 
distinction. However, the laboratory abnormalities characteristic of 
chronic renal failure, including anemia, hypocalcemia, and hyper­
phosphatemia, are also often present in patients presenting with 
acute renal failure. Radiographic evidence of renal osteodystrophy 
(Chap. 322) can be seen only in chronic renal failure but is a very late 
finding, typically in patients with end-stage renal disease (ESRD) 
maintained on dialysis. The urinalysis and renal ultrasound can 
facilitate distinguishing acute from chronic renal failure. An approach 
to the evaluation of azotemic patients is shown in Fig. 55-1. Patients 
with advanced chronic renal insufficiency often have some protein­
uria, nonconcentrated urine (isosthenuria; isosmotic with plasma),

and small kidneys on ultrasound, characterized by increased echo­
genicity and cortical thinning. Treatment should be directed toward 
slowing the progression of renal disease and providing symptomatic 
relief for edema, acidosis, anemia, and hyperphosphatemia, as 
discussed in Chap. 322. Acute renal failure (Chap. 321) can result 
from processes that affect blood flow and glomerular perfusion 
(prerenal azotemia), intrinsic renal diseases (affecting small vessels, 
glomeruli, or tubules), or postrenal processes (obstruction of urine 
flow in ureters, bladder, or urethra) (Chap. 331). 
PRERENAL FAILURE
Decreased renal perfusion accounts for 40–80% of cases of acute 
renal failure and, if appropriately treated, is readily reversible. The 
etiologies of prerenal azotemia include any cause of decreased 
circulating blood volume (gastrointestinal hemorrhage, burns, 
diarrhea, diuretics), volume sequestration (pancreatitis, peritonitis, 
rhabdomyolysis), or decreased effective arterial volume (cardio­
genic shock, sepsis). Renal and glomerular perfusion also can be 
affected by reductions in cardiac output from peripheral vasodi­
lation (sepsis, drugs) or profound renal vasoconstriction (severe 
heart failure, hepatorenal syndrome, agents such as nonsteroidal 
anti-inflammatory drugs [NSAIDs]). True or “effective” arterial 
hypovolemia leads to a fall in mean arterial pressure, which in turn 
triggers a series of neural and humoral responses, including activa­
tion of the sympathetic nervous and renin-angiotensin-aldosterone 
systems and vasopressin (AVP) release. GFR is maintained by pros­
taglandin-mediated dilatation of afferent arterioles and angiotensin 
II–mediated constriction of efferent arterioles. Once the mean arte­
rial pressure falls below 80 mmHg, GFR declines steeply.
PART 2
Cardinal Manifestations and Presentation of Diseases
Blockade of prostaglandin production by NSAIDs can result in 
severe vasoconstriction and acute renal failure. Blocking angioten­
sin action with angiotensin-converting enzyme (ACE) inhibitors or 
angiotensin receptor blockers (ARBs) decreases efferent arteriolar 
tone and in turn decreases glomerular capillary perfusion pres­
sure. Patients taking NSAIDs and/or ACE inhibitors/ARBs are 
most susceptible to hemodynamically mediated acute renal failure 
when blood volume or arterial perfusion pressure is reduced for 
any reason; under these circumstances, preservation of GFR is 
dependent on afferent vasodilation due to prostaglandins and effer­
ent vasoconstriction due to angiotensin II. Patients with bilateral 
renal artery stenosis (or stenosis in a solitary kidney) can also be 
dependent on efferent arteriolar vasoconstriction for maintenance 
of glomerular filtration pressure and are particularly susceptible to 
a precipitous decline in GFR when given ACE inhibitors or ARBs.
Prolonged renal hypoperfusion may lead to acute tubular necro­
sis (ATN), an intrinsic renal disease that is discussed below. The 
urinalysis and urinary electrolyte measurements can be useful in 
distinguishing prerenal azotemia from ATN (Table 55-2). The 
TABLE 55-2  Laboratory Findings in Acute Renal Failure
OLIGURIC ACUTE 
RENAL FAILURE
INDEX
PRERENAL AZOTEMIA
BUN/PCr ratio
>20:1
10–15:1
Urine sodium UNa, meq/L
<20
>40
Urine osmolality, mosmol/L H2O
>500
<350
Fractional excretion of sodiuma
<1%
>2%
Urine/plasma creatinine UCr/PCr
>40
<20
Urinalysis (casts)
None or hyaline/granular
Muddy brown
=
×
×
×
FE
U
P

P
U
a
Na
Na
Cr
Na
cr
Abbreviations: BUN, blood urea nitrogen; PCr, plasma creatinine concentration; PNa, 
plasma sodium concentration; UCr, urine creatinine concentration; UNa, urine sodium 
concentration.

urine Na and osmolality of patients with prerenal azotemia can be 
predicted from the stimulatory actions of norepinephrine, angio­
tensin II, AVP, aldosterone, and low tubule fluid flow rate. In pre­
renal conditions, the tubules are intact, leading to a concentrated 
urine (>500 mosmol), avid Na retention (urine Na concentration, 
<20 mmol/L; fractional excretion of Na [FENa], <1%), and UCr/PCr 
>40 (Table 55-2). The FENa is typically >1% in ATN but may be <1% 
in patients with milder, nonoliguric ATN (e.g., from rhabdomyolysis) 
and in patients with underlying “prerenal” disorders, such as con­
gestive heart failure (CHF) or cirrhosis or hepatorenal syndrome. 
The prerenal urine sediment is usually normal or has hyaline and 
granular casts, whereas the sediment of ATN usually is filled with 
cellular debris, tubular epithelial casts, and dark (muddy brown) 
granular casts. Microscopic examination of a urine sediment is a 
key test in AKI, since the presence of dark granular casts and/or 
tubular epithelial cells in the urine is highly predictive of ATN. The 
measurement of urinary biomarkers associated with tubular injury 
is a promising technique to detect subclinical ATN and/or help 
further diagnose the exact cause of acute renal failure. 
POSTRENAL AZOTEMIA
Urinary tract obstruction accounts for <5% of cases of acute renal 
failure but is usually reversible and must be ruled out early in the 
evaluation (Fig. 55-1). Since a single kidney is capable of adequate 
clearance, complete obstructive acute renal failure requires obstruc­
tion at the urethra or bladder outlet, bilateral ureteral obstruction, 
or unilateral obstruction in a patient with a single functioning 
kidney. Obstruction is usually diagnosed by the presence of ure­
teral and renal pelvic dilation on renal ultrasound. However, early 
in the course of obstruction or if the ureters are unable to dilate 
(e.g., encasement by pelvic or periureteral tumors or by retroperito­
neal fibrosis), the ultrasound examination may be negative. Other 
imaging, such as a furosemide renogram (MAG3 nuclear medicine 
study), may be required to better define the presence or absence of 
obstructive uropathy. The specific urologic conditions that cause 
obstruction are discussed in Chap. 331. 
INTRINSIC RENAL DISEASE
When prerenal and postrenal azotemia have been excluded as 
etiologies of renal failure, an intrinsic parenchymal renal disease is 
present. Intrinsic renal disease can arise from processes involving 
large renal vessels, intrarenal microvasculature and glomeruli, or 
the tubulointerstitium. Ischemic and toxic ATN account for ~90% 
of cases of acute intrinsic renal failure. As outlined in Fig. 55-1, the 
clinical setting and urinalysis are helpful in separating the possible 
etiologies. Prerenal azotemia and ATN are part of a spectrum of 
renal hypoperfusion; evidence of structural tubule injury is pres­
ent in ATN, whereas prompt reversibility occurs with prerenal 
azotemia upon restoration of adequate renal perfusion. Thus, ATN 
often can be distinguished from prerenal azotemia by urinalysis and 
urine electrolyte composition (Table 55-2 and Fig. 55-1). Ischemic 
ATN is observed most frequently in patients who have undergone 
major surgery, trauma, severe hypovolemia, overwhelming sepsis, 
or extensive burns. Nephrotoxic ATN complicates the administra­
tion of many common medications, usually by inducing a combi­
nation of intrarenal vasoconstriction, direct tubule toxicity, and/
or tubular obstruction. The kidney is vulnerable to toxic injury by 
virtue of its rich blood supply (25% of cardiac output) and its ability 
to concentrate and metabolize toxins. A diligent search for hypo­
tension and nephrotoxins usually uncovers the specific etiology of 
ATN. Discontinuation of nephrotoxins and stabilization of blood 
pressure often suffice without the need for dialysis, with ongoing 
regeneration of tubular cells. An extensive list of potential drugs 
and toxins implicated in ATN is found in Chap. 321.
Processes involving the tubules and interstitium can lead to 
acute kidney injury (AKI), a subtype of acute renal failure. These 
processes include drug-induced interstitial nephritis (especially by 
antibiotics, NSAIDs, and proton pump inhibitors), severe infections

(both bacterial and viral), systemic diseases (e.g., systemic lupus 
erythematosus), and systemic disorders (e.g., sarcoidosis, Sjögren’s 
syndrome, lymphoma, or leukemia). A list of drugs associated with 
allergic interstitial nephritis is found in Chap. 328. Urinalysis usu­
ally shows mild to moderate proteinuria, hematuria, and pyuria 
(~75% of cases) and occasionally WBC casts. The finding of RBC 
casts in interstitial nephritis has been reported but should prompt 
a search for glomerular diseases (Fig. 55-1). Renal biopsy will 
be needed to distinguish among these possibilities. The classic 
sediment finding in allergic interstitial nephritis is a predominance 
(>10%) of urinary eosinophils with Wright’s or Hansel’s stain; how­
ever, urinary eosinophils can be increased in several other causes of 
AKI, such that measurement of urine eosinophils has no diagnostic 
utility in renal disease. This test is no longer recommended in the 
workup of AKI.
Occlusion of large renal vessels, including arteries and veins, 
is an uncommon cause of acute renal failure. A significant reduc­
tion in GFR by this mechanism suggests bilateral processes or, in 
a patient with a single functioning kidney, a unilateral process. 
In patients with preexisting renal artery stenosis, a substantial 
renal collateral circulation can develop over time and sustain renal 
perfusion—typically not enough to sustain glomerular filtration, 
but enough to maintain tissue viability—in the event of total renal 
artery occlusion. Renal arteries can be occluded with atheroemboli, 
thromboemboli, in situ thrombosis, aortic dissection, or vasculitis. 
Atheroembolic renal failure can occur spontaneously but most 
often is associated with recent aortic instrumentation. The emboli 
are cholesterol-rich and lodge in medium and small renal arteries, 
with a consequent eosinophil-rich inflammatory reaction. Patients 
with atheroembolic acute renal failure often have a normal urinaly­
sis, but the urine may contain eosinophils and casts. The diagnosis 
can be confirmed by renal biopsy, but this procedure is often unnec­
essary when other stigmata of atheroemboli are present (livedo 
reticularis, distal peripheral infarcts, eosinophilia). Renal artery 
thrombosis may lead to mild proteinuria and hematuria, whereas 
renal vein thrombosis typically occurs in the context of heavy pro­
teinuria and hematuria. These vascular complications often require 
angiography for confirmation and are discussed in Chap. 329.
Diseases of the glomeruli (glomerulonephritis and vasculitis) 
and the renal microvasculature (hemolytic-uremic syndromes, 
thrombotic thrombocytopenic purpura, and malignant hyperten­
sion) usually present with various combinations of glomerular 
injury: proteinuria, hematuria, reduced GFR, and alterations of 
sodium excretion that lead to hypertension, edema, and circulatory 
congestion (acute nephritic syndrome). These findings may occur 
as primary renal diseases or as renal manifestations of systemic dis­
eases. The clinical setting and other laboratory data help distinguish 
primary renal diseases from systemic diseases. The finding of RBC 
casts in the urine is an indication for early renal biopsy (Fig. 55-1), 
as the pathologic pattern has important implications for diagnosis, 
prognosis, and treatment. Hematuria without RBC casts can also 
be an indication of glomerular disease, since RBC casts are highly 
specific but very insensitive for glomerulonephritis. The specificity 
of urine microscopy can be enhanced by examining urine with a 
phase contrast microscope capable of detecting dysmorphic red 
cells (“acanthocytes”) that are associated with glomerular disease. 
This evaluation is summarized in Fig. 55-2. A detailed discussion 
of glomerulonephritis and diseases of the microvasculature is found 
in Chap. 328. 
OLIGURIA AND ANURIA
Oliguria refers to a 24-h urine output <400 mL, and anuria is the 
complete absence of urine formation (<100 mL). Anuria can be 
caused by complete bilateral urinary tract obstruction; a vascular 
catastrophe (dissection or arterial occlusion); renal vein throm­
bosis; acute cast nephropathy in myeloma; renal cortical necrosis; 
severe ATN; severe rapidly progressive glomerulonephritis; com­
bined therapy with NSAIDs, ACE inhibitors, and/or ARBs; and 

HEMATURIA
Proteinuria (>500 mg/24 h),
Dysmorphic RBCs or RBC casts
Pyuria, WBC casts
Urine culture
Urine eosinophils
Serologic and
hematologic
evaluation: blood
cultures, anti-GBM
antibody, ANCA,
complement levels,
cryoglobulins,
hepatitis B and C
serologies, VDRL,
HIV, ASLO
Azotemia and Urinary Abnormalities
CHAPTER 55
Hemoglobin electrophoresis
Urine cytology
UA of family members
24 h urinary calcium/uric acid
IVP +/– Renal
ultrasound
As indicated: retrograde
pyelography or
arteriogram,
or cyst aspiration
Renal biopsy
Cystoscopy
Urogenital biopsy
and evaluation
Renal CT scan
Renal biopsy of
mass/lesion
Follow periodic
urinalysis
FIGURE 55-2  Approach to the patient with hematuria. ANCA, antineutrophil 
cytoplasmic antibody; ASLO, antistreptolysin O; CT, computed tomography; GBM, 
glomerular basement membrane; IVP, intravenous pyelography; RBC, red blood cell; 
UA, urinalysis; VDRL, Venereal Disease Research Laboratory; WBC, white blood 
cell.
hypovolemic, cardiogenic, or septic shock. Oliguria is never nor­
mal, since at least 400 mL of maximally concentrated urine must 
be produced to excrete the obligate daily osmolar load. Nonoliguria 
refers to urine output >400 mL/d in patients with acute or chronic 
azotemia. With nonoliguric ATN, disturbances of potassium and 
hydrogen balance are less severe than in oliguric patients, and 
recovery to normal renal function is usually more rapid.
ABNORMALITIES OF THE URINE
■
■PROTEINURIA
The evaluation of proteinuria is shown schematically in Fig. 55-3 and 
typically is initiated after detection of proteinuria by dipstick examina­
tion. The dipstick measurement detects only albumin and gives falsepositive results at pH >7.0 or when the urine is very concentrated or 
contaminated with blood. Because the dipstick relies on urinary albu­
min concentration, a very dilute urine may obscure significant protein­
uria on dipstick examination. Quantification of urinary albumin on a 
spot urine sample (ideally from a first morning void) by measurement 
of an albumin-to-creatinine ratio (ACR) is helpful in approximating a 
24-h albumin excretion rate (AER), where ACR (mg/g) ≈ AER (mg/24 h). 
Furthermore, proteinuria that is not predominantly due to albumin 
will be missed by dipstick screening. This information is particularly 
important for the detection of Bence-Jones proteins in the urine of 
patients with multiple myeloma. Tests to measure total urine protein 
concentration accurately rely on precipitation with sulfosalicylic or 
trichloroacetic acid (Fig. 55-3). As with albuminuria, the ratio of

PROTEINURIA ON URINE DIPSTICK
Quantify by 24-h urinary excretion of protein and
albumin or first morning spot albumin-to-creatinine ratio
*Severely increased
albuminuria
300–3500 mg/d or
300–3500 mg/g
*Moderately increased
albuminuria
30–300 mg/d or
30–300 mg/g
PART 2
Cardinal Manifestations and Presentation of Diseases
RBCs or RBC casts on urinalysis
In addition to disorders listed
under *moderately increased
albuminuria consider
Myeloma-associated kidney
disease (check UPEP)
Intermittent proteinuria
Postural proteinuria
Congestive heart failure
Fever
Exercise
Consider
Early diabetes
Essential hypertension
Early stages of
glomerulonephritis
(especially with RBCs,
RBC casts)
*Moderately and severely increased albuminuria were previously termed “microalbuminuria” and “macroalbuminuria,” respectively.
FIGURE 55-3  Approach to the patient with proteinuria. Investigation of proteinuria is often initiated by a positive 
dipstick on routine urinalysis. Conventional dipsticks detect predominantly albumin and provide a semiquantitative 
assessment (trace, 1+, 2+, or 3+), which is influenced by urinary concentration as reflected by urine specific gravity 
(minimum, <1.005; maximum, 1.030). However, more exact determination of proteinuria should employ a spot morning 
protein/creatinine ratio (mg/g) or a 24-h urine collection (mg/24 h). FSGS, focal segmental glomerulosclerosis; RBC, red 
blood cell; UPEP, urine protein electrophoresis.
protein to creatinine in a random “spot” urine can also provide a rough 
estimate of protein excretion; for example, a protein/creatinine ratio 
of 3.0 correlates to ~3.0 g of proteinuria per day. Formal assessment of 
urinary protein excretion requires a 24-h urine protein collection (see 
“Assessment of GFR,” above).
The magnitude of proteinuria and its composition in the urine 
depend on the mechanism of renal injury that leads to protein losses. 
Both charge and size selectivity normally prevent virtually all plasma 
albumin, globulins, and other high-molecular-weight proteins from 
crossing the glomerular wall; however, if this barrier is disrupted, 
plasma proteins may leak into the urine (glomerular proteinuria; 
Fig. 55-3). Smaller proteins (<20 kDa) are freely filtered but are read­
ily reabsorbed by the proximal tubule. Typically, healthy individuals 
excrete <150 mg/d of total protein and <30 mg/d of albumin. However, 
even at albuminuria levels <30 mg/d, risk for progression to overt 
nephropathy or subsequent cardiovascular disease is increased. The 
remainder of the protein in the urine is secreted by the tubules (TammHorsfall, IgA, and urokinase) or represents small amounts of filtered β2microglobulin, apoproteins, enzymes, and peptide hormones. Another 
mechanism of proteinuria entails excessive production of an abnormal 
protein that exceeds the capacity of the tubule for reabsorption. This 
situation most commonly occurs with plasma cell dyscrasias, such as 
multiple myeloma, amyloidosis, and lymphomas, that are associated 
with monoclonal production of immunoglobulin light chains. Other 
causes include lysozyme-associated nephropathy, a rare cause of kidney 
injury in patients with chronic myelomonocytic leukemia (CMML); 
overproduction of lysozyme results in excessive reabsorption of the 
enzyme by the proximal tubule, resulting in a severe tubulopathy with 
intracytoplasmic, membrane-bound vacuoles containing homogenous 
or granular electron dense material on electron microscopy.
The normal glomerular endothelial cell forms a barrier composed 
of pores of ~100 nm that retain blood cells but offer little impediment 
to passage of most proteins. The glomerular basement membrane traps 
most large proteins (>100 kDa), and the foot processes of epithelial 
cells (podocytes) cover the urinary side of the glomerular basement 

membrane and produce a series of nar­
row channels (slit diaphragms) to allow 
molecular passage of small solutes and 
water but not proteins. Some glomeru­
lar diseases, such as minimal change 
disease, cause fusion of glomerular epi­
thelial cell foot processes, resulting in 
predominantly “selective” (Fig. 55-3) loss 
of albumin. Other glomerular diseases 
can present with disruption of the base­
ment membrane and slit diaphragms 
(e.g., by immune complex deposition), 
resulting in losses of albumin and other 
plasma proteins. The fusion of foot pro­
cesses causes increased pressure across 
the capillary basement membrane, 
resulting in areas with larger pore sizes 
(and more severe “nonselective” protein­
uria) (Fig. 55-3).
Nephrotic range
>3500 mg/d or
>3500 mg/g
Go to
Fig. 55-2
Nephrotic syndrome
  Diabetes
  Amyloidosis
  Minimal change disease
  FSGS
  Membranous glomerulopathy
  IgA nephropathy
When the total daily urinary excretion 
of protein is >3.5 g, hypoalbuminemia, 
hyperlipidemia, and edema (nephrotic 
syndrome; Fig. 55-3) are often present 
as well. However, total daily urinary pro­
tein excretion >3.5 g can occur without 
the other features of the nephrotic syn­
drome in a variety of other renal diseases, 
including diabetes (Fig. 55-3). Plasma cell 
dyscrasias (multiple myeloma) can be 
associated with large amounts of excreted 
light chains in the urine, which may not 
be detected by dipstick. The light chains 
are filtered by the glomerulus and over­
whelm the reabsorptive capacity of the 
proximal tubule. Renal failure from these disorders occurs through a 
variety of mechanisms, including but not limited to proximal tubule 
injury, tubule obstruction (cast nephropathy), amyloid deposition, and 
light chain deposition (Chap. 328). The specific renal lesion is dictated 
by the sequence and structural characteristics of the monoclonal light 
chain; however, not all excreted light chains are nephrotoxic.
Hypoalbuminemia in nephrotic syndrome occurs through excessive 
urinary losses and increased proximal tubule catabolism of filtered 
albumin. Edema results from renal sodium retention and reduced 
plasma oncotic pressure, which favors fluid movement from capillaries 
to interstitium. To compensate for the perceived decrease in effective 
intravascular volume, activation of the renin-angiotensin system, stim­
ulation of AVP, and activation of the sympathetic nervous system take 
place, promoting continued renal salt and water reabsorption and pro­
gressive edema. Filtered proteases, normally retained by the glomerular 
filtration barrier, can also directly activate sodium reabsorption by the 
epithelial Na channels in principal cells (ENaC) in nephrotic syndrome. 
Despite these changes, hypertension is uncommon in primary kidney 
diseases resulting in the nephrotic syndrome (Fig. 55-3 and Chap. 326). 
The urinary loss of regulatory proteins and changes in hepatic synthe­
sis contribute to the other manifestations of the nephrotic syndrome. 
A hypercoagulable state may arise from urinary losses of antithrombin 
III, reduced serum levels of proteins S and C, hyperfibrinogenemia, 
and enhanced platelet aggregation. Hypercholesterolemia may be 
severe and results from increased hepatic lipoprotein synthesis. Loss of 
immunoglobulins contributes to an increased risk of infection. Many 
diseases (some listed in Fig. 55-3) and drugs can cause the nephrotic 
syndrome; a complete list is found in Chap. 326.
■
■HEMATURIA, PYURIA, AND CASTS
Isolated hematuria without proteinuria, other cells, or casts is often 
indicative of bleeding from the urinary tract. Hematuria is defined as 
two to five RBCs per high-power field (HPF) and can be detected by 
dipstick. A false-positive dipstick for hematuria (where no RBCs are 
seen on urine microscopy) may occur when myoglobinuria is present,

often in the setting of rhabdomyolysis. Common causes of isolated 
hematuria include stones, neoplasms, tuberculosis, trauma, and pros­
tatitis. Gross hematuria with blood clots usually is not an intrinsic renal 
process; rather, it suggests a postrenal source in the urinary collecting 
system. Evaluation of patients presenting with microscopic hematuria 
is outlined in Fig. 55-2. A single urinalysis with hematuria is common 
and can result from menstruation, viral illness, allergy, exercise, or 
mild trauma. Persistent or significant hematuria (>3 RBCs/HPF on 
three urinalyses, a single urinalysis with >100 RBCs, or gross hematu­
ria) is associated with significant renal or urologic lesions in 9.1% of 
cases. The level of suspicion for urogenital neoplasms in patients with 
isolated painless hematuria and nondysmorphic RBCs increases with 
age. Neoplasms are rare in the pediatric population, and isolated hema­
turia is more likely to be “idiopathic” or associated with a congenital 
anomaly. Hematuria with pyuria and bacteriuria is typical of infection 
and should be treated with antibiotics after appropriate cultures. Acute 
cystitis or urethritis in women can cause gross hematuria. Hypercalci­
uria and hyperuricosuria are also risk factors for unexplained isolated 
hematuria in both children and adults. In some of these patients 
(50–60%), reducing calcium and uric acid excretion through dietary 
interventions can eliminate the microscopic hematuria.
Isolated microscopic hematuria can be a manifestation of glo­
merular diseases. The RBCs of glomerular origin are often dysmor­
phic when examined by phase-contrast microscopy. Irregular shapes 
of RBCs may also result from pH and osmolarity changes produced 
along the distal nephron. Observer variability in detecting dysmorphic 
RBCs is common. The most common etiologies of isolated glomerular 
hematuria are IgA nephropathy, hereditary nephritis, and thin base­
ment membrane disease. IgA nephropathy and hereditary nephritis 
can lead to episodic gross hematuria. A family history of renal failure 
is often present in hereditary nephritis, and patients with thin base­
ment membrane disease often have family members with microscopic 
hematuria. A renal biopsy is needed for the definitive diagnosis of these 
disorders, which are discussed in more detail in Chap. 326. Hematuria 
with dysmorphic RBCs, RBC casts, and protein excretion >500 mg/d 
is virtually diagnostic of glomerulonephritis. RBC casts form as RBCs 
that enter the tubule fluid and become trapped in a cylindrical mold 
of gelled Tamm-Horsfall protein. Even in the absence of azotemia, 
these patients should undergo serologic evaluation and renal biopsy as 
outlined in Fig. 55-2.
Isolated pyuria is unusual since inflammatory reactions in the 
kidney or collecting system also are associated with hematuria. The 
presence of bacteria suggests infection, and WBC casts with bacteria 
are indicative of pyelonephritis; “sterile pyuria” with negative urinary 
bacterial cultures can be seen in urogenital tuberculosis. WBCs and/or 
WBC casts also may be seen in acute glomerulonephritis as well as in 
tubulointerstitial processes such as interstitial nephritis and transplant 
rejection.
Casts can be seen in chronic renal diseases. Degenerated cellular 
casts called waxy casts or broad casts (arising in the dilated tubules that 
have undergone compensatory hypertrophy in response to reduced 
renal mass) may be seen in the urine.
ABNORMALITIES OF URINE VOLUME
■
■POLYURIA
By history, it is often difficult for patients to distinguish urinary fre­
quency (often of small volumes) from true polyuria (>3 L/d), and a 
quantification of volume by 24-h urine collection may be needed 
(Fig. 55-4). Polyuria results from two potential mechanisms: (1) excre­
tion of nonabsorbable solutes (such as glucose) or (2) excretion of water 
(usually from a defect in AVP production or renal responsiveness). To 
distinguish a solute diuresis from a water diuresis and to determine 
whether the diuresis is appropriate for the clinical circumstances, urine 
osmolality is measured. The average person excretes between 600 and 
800 mosmol of solutes per day, primarily as urea and electrolytes. If 
the urine output is >3 L/d and the urine is dilute (<250 mosmol/L), 
total osmolar excretion is normal and a water diuresis is present. This 
circumstance could arise from polydipsia, inadequate secretion of AVP 

POLYURIA (>3 L/24 h)
Urine osmolality
<250 mosmol
>300 mosmol
Solute diuresis
Glucose, mannitol,
radiocontrast, urea
(from high protein feeding), 
medullary cystic diseases,
resolving ATN, or obstruction,
diuretics
Azotemia and Urinary Abnormalities
CHAPTER 55
Water
  deprivation
test or
ADH level
History, low
serum sodium
Diabetes insipidus (DI)
Central DI (vasopressin-sensitive)
Posthypophysectomy, trauma,
supra- or intrasellar tumor/cyst
histiocystosis or granuloma,
encroachment by aneurysm,
Sheehan’s syndrome, infection,
Guillain-Barré, fat embolus,
empty sella
Primary polydipsia
Psychogenic
Hypothalamic disease
Drugs (thioridazine,
chlorpromazine,
anticholinergic agents)
Nephrogenic DI (vasopressin-insensitive)
Acquired tubular diseases: pyelonephritis, analgesic nephropathy,
multiple myeloma, amyloidosis, obstruction, sarcoidosis, hypercalcemia,
hypokalemia, Sjögren’s syndrome, sickle cell anemia
Drugs or toxins: lithium, demeclocycline, methoxyflurane, ethanol,
diphenylhydantoin, propoxyphene, amphotericin
Congenital: hereditary, polycystic or medullary cystic disease
FIGURE 55-4  Approach to the patient with polyuria. ADH, antidiuretic hormone; 
ATN, acute tubular necrosis.
(central diabetes insipidus), or failure of renal tubules to respond to 
AVP (nephrogenic diabetes insipidus). If the urine volume is >3 L/d and 
urine osmolality is >300 mosmol/L, a solute diuresis is clearly present 
and a search for the responsible solute(s) is mandatory.
Excessive filtration of a poorly reabsorbed solute such as glucose or 
mannitol can depress reabsorption of NaCl and water in the proximal 
tubule and lead to enhanced excretion in the urine. Poorly controlled 
diabetes mellitus with glucosuria is the most common cause of a sol­
ute diuresis, leading to volume depletion and serum hypertonicity. 
Since the urine sodium concentration is less than that of blood, more 
water than sodium is lost, causing hypernatremia and hypertonicity. 
Common iatrogenic solute diuresis occurs in association with man­
nitol administration, radiocontrast media, and high-protein feedings 
(enteral or parenteral), leading to increased urea production and 
excretion. Less commonly, excessive sodium loss may result from 
cystic renal diseases or Bartter’s syndrome or may develop during a 
tubulointerstitial process (such as resolving ATN). In these so-called 
salt-wasting disorders, the tubule damage results in direct impairment 
of sodium reabsorption and indirectly reduces the responsiveness of 
the tubule to aldosterone. Usually, the sodium losses are mild, and the 
obligatory urine output is <2 L/d; resolving ATN and postobstructive 
diuresis are exceptions and may be associated with significant natri­
uresis and polyuria.
Formation of large volumes of dilute urine is usually due to poly­
dipsic states or diabetes insipidus. Primary polydipsia can result from 
habit, psychiatric disorders, neurologic lesions, or medications. During