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The Diagnosis of Glomerular Diseases
Acute Glomerulonephritis and the Nephrotic Syndrome
Michael P. Madaio, MD;
John T. Harrington, MD
Arch Intern Med. 2001;161:25-34.
ABSTRACT
Rapid and efficient diagnosis of diseases presenting as acute glomerulonephritis
and/or nephrotic syndrome is critical for early and appropriate therapy aimed
at preservation of renal function. Although there may be overlap in clinical
presentation, and some patients present with clinical features of both syndromes,
this analysis serves as an initial framework to proceed with serologic testing
and/or pathologic confirmation en route to final diagnosis. Efficient and
timely diagnosis is essential in these situations because progression to end-stage
renal disease may result if the underlying disease is not promptly treated.
INTRODUCTION
Glomerular injury leads to impairment of the selective filtering properties
of the kidney and reduction in the glomerular filtration rate (GFR).1, 2, 3 Consequently, blood
constituents normally excluded from the urinary space pass into the urine
and are excreted. The nature and severity of the defect (ie, underlying disease
and pathologic lesion) determine the quantity of red blood cells (RBC), white
blood cells, and proteins lost in the urine and the extent of functional impairment.4 These variables determine the clinical presentation.
While the GFR is reduced initially in many patients, the severity, reversibility,
and progression of disease are dependent on many factors, including the nature,
location, and extent of the insult and the renal and systemic response to
glomerular injury.3, 4 Prompt recognition
of the cause of glomerular disease results in a more rational, safer, and
effective therapeutic approach. Early diagnosis is especially important in
patients with fulminant disease, where delay in treatment greatly reduces
the likelihood of a beneficial response.4, 5
In this review, we delineate our approach to the diagnosis of acute
glomerular injury in adults, focusing on glomerulonephritis and nephrotic
syndrome. Our intent is to provide a framework that will enable efficient
and timely diagnosis. A few introductory points warrant particular emphasis.
We do not discuss the evaluation of asymptomatic abnormalities discovered
on routine urinalysis (ie, isolated hematuria and/or non–nephrotic-range
proteinuria). The clinician should be aware that these manifestations may
represent less severe forms of the full-blown entities. However, there are
many nonglomerular causes of isolated hematuria and proteinuria that must
also be considered in these situations, and the reader is referred to recent
reviews of these entities.2, 6, 7, 8, 9, 10, 11, 12
Although our approach distinguishes between nephritic and nephrotic
states (the two classic clinical presentations of acute glomerular injury),
many of the underlying diseases can produce nephritis or nephrotic syndrome.
Furthermore, this distinction is not always easily made in individual patients.
For example, some patients present with nephrotic-range proteinuria and active
urine sediments, whereas others present with nephrotic-range proteinuria and
acute renal failure. In some instances the clinical presentation represents
the initial manifestation of an acute disease, whereas in others the physician
initially detects a more chronic disturbance. Simply stated, multiple variables
influence the final clinical picture, including the inciting event and the
host response to the immune reactants. Nevertheless, the clinical distinction
between acute glomerulonephritis and nephrotic syndrome provides a reasonable
starting point to form an initial differential diagnosis, en route to serologic
and pathologic determination of the underlying glomerular disease. Our discussion
focuses on the initial diagnostic evaluation, and not on either the pathogenesis
or the subsequent management of the underlying diseases. The reader is referred
to excellent recent reviews for these further considerations.13, 14, 15
ACUTE GLOMERULONEPHRITIS
Acute glomerulonephritis is defined as the sudden onset of hematuria,
proteinuria, and RBC casts.12 Although RBC
casts are diagnostic of glomerular bleeding, they may be difficult to find.
Visualization of dysmorphic RBC under phase-contrast microscopy by an experienced
observer is a useful surrogate.16 Proteinuria
in patients with acute glomerulonephritis typically ranges from 500 mg/d to
3 g/d, but nephrotic-range proteinuria (>3.5 g/d) may be present.
Acute glomerulonephritis can be due to a primary renal disease or a
systemic disease. A thorough history and physical examination should focus
on identification of an underlying systemic disease, and serologic evaluation
should be performed for a prompt diagnosis (Table 1 and Table 2).
Serologic evaluation is essential and, together with the clinical presentation,
focuses the differential diagnosis.12 The serum
complement levels provide useful information; if any component is depressed,
assessment of the levels of other components may be helpful. Initially determine
the CH50 level; if results are abnormal, proceed with evaluation
of individual components (eg, C3 and C4 levels). If an abnormality of the
alternate pathway is suspected, determine AH50 activity.
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Table 1. Major Causes of Acute Nephritis*
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Table 2. Diagnostic Approach in Patients With Acute Glomerulonephritis*
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For the diagnostic approach, we arbitrarily divide the causes of glomerulonephritis
into those with low and normal serum complement levels. This provides for
an efficient and practical tool for the initial approach to patients in clinical
practice (Table 1 and Table 2).
Estimation of GFR (ie, serum creatinine level) and quantitation of urine
protein excretion (ie, 24-hour urine protein excretion rate or urine protein:creatinine
ratio) also should be performed. If the GFR is depressed, evaluation of renal
size (eg, by ultrasound) is a useful guide to determine the extent of fibrosis.
Small kidneys (<9 cm) suggest extensive scarring; reversibility is low
in this setting, whatever the underlying diagnosis. The presence of nephrotic-range
proteinuria is more common in certain diseases. The use of renal biopsy will
be discussed.
Acute Glomerulonephritis With Low Serum Complement Levels
Low serum complement levels in patients with glomerulonephritis most
often result from activation of complement within the kidney or other sites.
Most often production does not keep up with consumption,12
although patients with congenital or acquired complement deficiencies are
more prone to develop glomerulonephritis.17
The systemic diseases consistently producing hypocomplementemic glomerulonephritis
include systemic lupus erythematosus, subacute bacterial endocarditis, shunt
nephritis, and cryoglobulinemia. These diseases usually are apparent from
the history and results of physical examination, and serologic testing is
performed to confirm these diagnoses (Table
2). Some patients (approximately 10%) with heavy proteinuria may
have negative serologic findings at initial presentation due to loss of antibodies
in the urine, tissue deposition, or other factors.18, 19
Blood cultures should be obtained in all febrile patients to exclude infection,
since endovascular infection must be treated promptly.
Systemic Diseases
The diagnosis of lupus usually is determined by the presence of extrarenal
disease (eg, arthritis or rash) and serologic findings (eg, anti–double-stranded
DNA antibodies; Table 2). Nephrotic-range
proteinuria and reduced GFR are indicative of a more severe proliferative
lupus nephritis. Renal biopsy is, however, necessary to distinguish the disease
subtype in more severe forms,18 and therefore
is recommended in patients with lupus and decreased GFR and/or nephrotic syndrome.
Renal biopsy elucidates the degree of inflammation (ie, assessment of disease
activity and confirmation of diagnosis) and the level of fibrosis (eg, scarring
or chronicity).20, 21, 22, 23, 24
With clinical assessment of extrarenal lupus activity, these pathologic variables
are useful in guiding administration and withdrawal of immunosuppressive therapy.
Purpura, arthralgias, and other signs of vasculitis in patients with
glomerulonephritis and low serum complement levels raise the suspicion of
cryoglobulinemia. Patients may present with clinical features associated with
glomerulonephritis or/and nephrotic syndrome, although the former is more
common. Cryoglobulinemia (75%) and rheumatoid factor activity (70%) are frequently
present; however, the levels fluctuate, and they may not be detectable at
initial presentation.25 More than 80% will
have reduced serum complement levels sometime during the course of disease,
and C4 and C2 complement levels may be markedly depressed.25
Pathologically, membranoproliferative glomerulonephritis (MPGN) usually is
present. Most cases of essential mixed cryoglobulinemia and associated glomerulonephritis
are associated with hepatitis C infection,26, 27, 28
and the majority of these patients have hepatitis C RNA or anti–hepatitis
C antibodies in the serum.25 Therefore hepatitis
C assays (ie, polymerase chain reaction and antibody evaluations) should be
performed in patients with undiagnosed glomerulonephritis.29
Liver enzyme levels and other liver function tests may be normal at disease
onset.25, 28, 29 Characteristic
lesions on kidney biopsy (eg, intraluminal thrombi or "fingerprint" pattern
of the electron-dense deposits) also should raise suspicion of hepatitis C–associated
disease.
Primary Renal Diseases
Primary renal diseases associated with glomerulonephritis and low serum
complement levels include acute postinfectious glomerulonephritis and idiopathic
MPGN (IMPGN). The former has been most extensively studied after streptococcal
infections, although the syndrome has been reported after other bacterial,
viral, parasitic, rickettsial, and fungal infections.30
Although IMPGN remains an important cause of glomerular disease in children,
the incidence of primary disease in adults has declined.31, 32
Secondary forms of the disease may be associated with autoimmune diseases,
chronic infections, microangiopathies, and paraprotein deposition diseases.33 Most patients with IMPGN have recurrent bouts of
glomerulonephritis (and/or nephrotic syndrome). By contrast, with glomerulonephritis
after streptococcal infections, recovery (lack of progression to end-stage
renal disease) is the rule, especially in children (<2% progression to
end-stage renal disease), and, thus the disease course is helpful in confirming
the diagnosis. Nevertheless, persistent urinary abnormalities may last for
years, and a small percentage of adults develop slowly progressive renal failure.30 For diagnosis, repeated evaluation of serum complement
levels, determination of autoantibodies to complement pathway components,
and renal biopsy findings are especially helpful in distinguishing glomerulonephritis
after streptococcal infections from IMPGN (Table 3). These serologic determinations are especially useful in
situations where the distinction between glomerulonephritis after streptococcal
infections and MPGN is difficult on clinical grounds alone (eg, where there
is persistent or recurrent disease).
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Table 3. Complement Levels and Kidney Deposits to Distinguish Idiopathic
Membranoproliferative Glomerulonephritis (MPGN) and Poststreptococcal Glomerulonephritis
(GN)*
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Acute Glomerulonephritis With Normal Serum Complement Levels
One should initially consider glomerulonephritis associated with systemic
diseases, then evaluate the possibility of primary renal diseases (Table 1).
Systemic Diseases
Multi-organ involvement strongly suggests a systemic process, and typical
symptoms of an underlying disease may be useful in narrowing the diagnostic
possibilities, eg, sinusitis, pulmonary infiltrates (Wegener granulomatosis),42 pulmonary hemorrhage (Goodpasture's syndrome),43 nausea, vomiting and abdominal pain, and purpura
(Henoch-Schönlein purpura).12 Serologic
evaluation, including measurement of anti-neutrophil cytoplasmic antibodies
(ANCA) and anti–glomerular basement membrane (GBM) antibodies, along
with hepatitis serologic evaluation, is essential, especially for prompt diagnosis
in patients with rapidly progressive glomerulonephritis (RPGN).
A few caveats warrant mention. Most patients with polyarteritis associated
with hepatitis B or C display normal or near-normal complement levels (>80%);
however, decreased levels occur more frequently in patients with cryoglobulinemia.
The liver enzyme levels and liver function tests may be normal at disease
onset, although the serologic findings are typically positive.25, 28, 29
Patients with hepatitis B and glomerulonephritis typically have positive findings
for hepatitis B surface antigen and antibodies to hepatitis B core, and negative
findings for antibodies to hepatitis B surface antigen in serum.29, 44
Among this group, the incidence of systemic involvement (ie, polyarteritis)
varies widely by geography, from as high as 84% in cities with increased drug
use, to a much lower incidence in rural areas.29
Patients with glomerulonephritis associated with abscess typically have normal
complement levels (unless there is endocarditis), and the site of infection
is usually apparent from the history and results of physical examination.39, 45
Primary Renal Diseases
The clinical presentation of IgA nephropathy varies considerably (eg,
asymptomatic hematuria, RPGN, nephrotic syndrome).46
Most often it is idiopathic, although liver disease is the most frequent association.47, 48, 49, 50, 51
Renal biopsy is required for definitive diagnosis.
Rapidly progressive glomerulonephritis may be associated with any form
of glomerulonephritis, including those associated with low complement levels.
Most patients, however, present without systemic symptoms and with normal
levels (>95% have normal complement levels).52
The majority of patients with idiopathic RPGN are ANCA positive. Less commonly
(10%-20%), patients have anti-GBM disease (eg, linear GBM deposits and crescentic
glomerulonephritis); occasionally (5%-10%), patients will have positive findings
for ANCA and anti-GBM antibodies.53, 54, 55, 56
The latter group is more likely to have vasculitis in organs other than the
lungs and kidneys. Occasionally ANCA may be found in patients with lupus nephritis,
although its significance is unclear.56
Serologic Evaluation, Use of the Kidney Biopsy in Clinical Practice,
Referral to a Nephrologist
The clinical presentation provides clues, but serologic testing facilitates
rapid diagnosis, especially in patients without systemic symptoms. We recommend
initially obtaining C3 and C4 levels, along with determination of serum ANCA,
anti–DNA, and anti–GBM antibody levels (Table 2). The perinuclear (pANCA) and cytoplasmic (cANCA) patterns
of staining for ANCA should be determined. These serologic evaluations are
especially important in patients with RPGN and should be determined immediately
in this situation. The results may obviate the need for immediate kidney biopsy,
and the serologic results should dictate initial therapy.52, 53
Determination of hepatitis serologies and evaluation of cryoglobulin levels
also should be performed.
Patients with Wegener granulomatosis typically have serum ANCA (80%-95%),
and the most common pattern is cANCA, with antigenic specificity for proteinase
3. Most of the rest of the ANCA are directed at myeloperoxidase (pANCA).57 Almost all patients with idiopathic, pauci-immune
glomerulonephritis have ANCA; however, 75% of this group express pANCA.58 In the clinical setting of RPGN, these assays are
especially useful, with high positive and negative predictive values (>90%).57 However, they have much lower predictive values in
other clinical settings (eg, hematuria or nonnephrotic-range proteinuria with
normal serum creatinine levels), and the utility of ANCA vs other intracellular
antigens is less clear.
Pathologic evaluation also is useful for rapid diagnosis, for distinguishing
primary renal diseases, and for determining disease severity.58
In most cases, systemic diseases associated with glomerulonephritis are apparent
from the clinical presentation, and serologic testing confirms the diagnosis.
In some instances, however, the serologic findings are not diagnostic or not
readily available, and histologic examination of the kidney is required. Although
the pathologic findings are not always diagnostic, they help to narrow the
differential diagnosis. The pathologic findings also are helpful in determining
the degree of disease activity (eg, the level of inflammation or the extent
of fibrosis), and this information may help guide therapy.
Renal biopsy may be especially important for patients with RPGN, where
prompt diagnosis and treatment are essential.52
For example, in a patient with RPGN (crescentic glomerulonephritis) for whom
serologic findings are not rapidly available, the absence of immune deposits
(ie, pauci-immune glomerulonephritis) on evaluation of biopsy is consistent
only with vasculitis or Wegener granulomatosis; anti-GBM disease (ie, linear
immune deposits) and the major immune deposit–mediated diseases are
excluded by that finding. In this regard, if systemic vasculitis is suspected,
angiography or biopsy of other affected organs provides a more specific diagnosis.58 As mentioned previously, the extent of disease activity
in this situation is also useful in guiding therapy.
Pathologic evaluation is also particularly helpful in diagnosing glomerulonephritis
in patients with unexplained, acute renal failure, when the diagnosis is uncertain
from the clinical findings. For example, in patients with progressive renal
failure without significant urinary or systemic symptoms, the pathologic findings
may be very helpful in confirming or excluding a diagnosis. The results derived
from the biopsy are also very useful in patients with slowly progressive renal
failure due to glomerular disease, where it is difficult to determine the
level of disease activity (eg, the extent of fibrosis and irreversible disease)
from the clinical presentation alone.59 For
example, in some instances it may be difficult to distinguish disease activity
(ie, exacerbation amenable to further immunosuppression) from progressive
fibrosis, unassociated with a disease flare. Treatment in the latter situation
would not be specific to the underlying disease, but it would include control
of systemic hypertension (preferably by use of an angiotensin-converting enzyme
inhibitor) and hyperlipidemia.
Nevertheless, the clinician must be aware of limitations of the use
and interpretation of the kidney biopsy results. If the kidneys are small
(eg, <9 cm in length for a 70-kg patient), the risk associated with biopsy
(ie, major bleeding requiring transfusion and other intervention) is increased,
and the probability of obtaining clinically useful, diagnostic information
is substantially reduced.59 In this setting,
severe and irreversible glomerulosclerosis and interstitial fibrosis will
be present, whatever the underlying cause of the primary renal disease, and
diagnostic interpretation will be limited. Furthermore, the probability of
response to subsequent therapeutic intervention is greatly reduced.59
In situations where the patient is asymptomatic (eg, RBC and RBC casts
present on urinalysis, without systemic findings) and the GFR is normal, the
physician should observe the serum creatinine level closely over time, while
proceeding with the evaluation. We emphasize that in cases of isolated hematuria
(ie, without casts or proteinuria), the source of bleeding from other sites
within the urinary tract (eg, bladder, prostate, or ureters), should be explored
by means of visualization of the kidney and the collecting system (ie, cystoscopy
and intravenous pyelogram and/or computed tomographic scan). Depending on
the results, renal biopsy may be performed to confirm or elucidate the diagnosis
of glomerulonephritis and to determine the level of disease activity. Sometimes,
lack of abnormal findings on histologic evaluation is helpful in excluding
a renal cause of the bleeding.
The urgency for referral to a nephrologist for further consideration
and renal biopsy depends on the GFR. For example, in situations where there
are isolated urinary abnormalities, history and physical examination are unrevealing,
and serum creatinine level is normal and stable (ie, <88.4 µmol/L
[1.0 mg/dL] in a 70-kg man), proceed with the serologic workup while closely
monitoring renal function, before consultation, consideration of biopsy, and
treatment. However, if the GFR is abnormal or rapidly deteriorating, or if
there are systemic symptoms, immediate consultation (ie, that day) is advisable
for clinical decisions regarding treatment, biopsy, need for dialysis, etc.
NEPHROTIC SYNDROME
Nephrotic-range proteinuria in adults is defined as urinary excretion
of more than 3.5 g protein per 1.73 m2 in 24 hours. Although an
arbitrary definition, persistent proteinuria at or above this level usually
leads to hypoalbuminemia, resulting in edema. Furthermore, we have known for
more than 20 years that patients with urinary protein excretion rates of less
than 2 g/d have a better prognosis.60 The clinical
complex referred to as nephrotic syndrome results from heavy proteinuria and
includes edema, hypoalbuminemia, hyperlipidemia, and lipiduria. Many factors
influence the onset and severity of edema, including the degree and duration
of proteinuria, the serum albumin level, the patient's underlying renal disease
(ie, sodium retentive state and renal function), dietary sodium intake, accompanying
cardiovascular and liver function, etc. The presence or severity of nephrotic
syndrome does not predict the underlying pathological disturbance, and the
syndrome can be due to a primary renal or a systemic disease. The incidence
of diseases associated with the nephrotic syndrome varies markedly with age,
thus providing important diagnostic information. In most children and adults,
the initial manifestation of disease is peripheral edema. The elderly (aged
>65 years) may be misdiagnosed with congestive heart failure. Many patients
are asymptomatic.
Systemic Diseases
Initial diagnostic evaluation includes consideration of systemic diseases
and drugs; the most common associations are listed in Table 4. Diabetes mellitus is the most common cause of nephrotic
syndrome in adults in the United States.62, 63, 64
Approximately one third of patients with juvenile-onset (type 1) diabetes
mellitus develop nephrotic syndrome, predictably leading to renal failure,65 and recent evidence indicates that there is genetic
susceptibility to the development of nephropathy.66
In patients with type 1 diabetes mellitus in whom nephropathy develops, the
natural history of the disease is fairly predictable and has diagnostic utility.
Asymptomatic microalbuminuria, the initial manifestation, occurs 5 to 10 years
into the illness; overt proteinuria (0.5-3.0 g/d) occurs 13 to 20 years after
disease onset, and nephrotic-range proteinuria (>3.5 g/d) develops a few years
thereafter. The period between onset of microalbuminuria and renal failure
can be extended by rigorous control of blood glucose level and blood pressure,
use of angiotensin-converting enzyme inhibitors, and, perhaps, restriction
of dietary protein and reduction of hyperlipidemia.67, 68
Nevertheless, progression to end-stage renal failure is fairly predictable
within a few years after the onset of nephrotic syndrome.69
In patients with type 2 diabetes mellitus, the prevalence and expression of
diabetic nephropathy are more variable, as the nephropathy is often complicated
by hypertensive and atherosclerotic disease in older patients.63
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Table 4. Major Causes of Nephrotic Syndrome
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Diabetic retinopathy is a useful marker of diabetic nephropathy in patients
with nephrotic syndrome, especially in patients with type 1 diabetes (>90%
of patients with nephropathy have retinopathy); microvascular disease in the
retina is indicative of diabetic nephropathy and usually precedes it.63, 64 Fluorescein angiography is necessary
to adequately evaluate the retinal microvasculature, and it should be performed
in patients with diabetes and proteinuria when the diagnosis is uncertain.
Nevertheless, retinopathy is less predictable in patients with type 2 disease
and proteinuria (approximately 50%-80% will have diabetic lesions), and those
without retinopathy are more likely to have nondiabetic glomerular disease.
We reserve renal biopsy for diabetic patients with nephrotic syndrome with
atypical history, examination results, or clinical course for diabetic nephropathy
(eg, early-onset renal failure, rapid progression of renal failure, lack of
evidence of microvascular disease elsewhere, or evidence of overt glomerulonephritis).
Nephrotic syndrome in patients with lupus nephritis is most often indicative
of a severe proliferative or inflammatory lesion.20, 21, 22, 23, 24
However, some patients develop noninflammatory, membranous, lupus lesions
and present with a normal GFR and heavy proteinuria. Acute renal failure for
another reason (eg, use of nonsteroidal anti-inflammatory drugs or interstitial
nephritis) in a patient with membranous lupus nephropathy may confuse the
situation.19 As discussed previously, loss
of autoantibodies in the urine can result in negative serologic findings and
delay diagnosis. However, depressed serum complement levels or/and other clinical
features of systemic lupus should raise suspicion of this disorder. Pathological
evaluation of the kidney is necessary for determination of disease activity
and the extent of fibrosis. Less commonly, nephrotic syndrome has been associated
with other rheumatologic diseases5, 52, 59, 70
(Table 4).
Amyloidosis and the dysproteinemias should be considered in patients
older than 40 years, although most patients are older than 50 years. Eighty
percent of patients with amyloidosis have proteinuria, and the nephrotic syndrome
occurs in about one third.71 Amyloidosis may
be idiopathic or associated with multiple myeloma, long-standing rheumatoid
arthritis, or chronic infections, although the latter are much less common
in recent decades.71, 72 Most patients
with amyloidosis in the United States have immunoglobulin light chain–associated
disease.73 Accompanying systemic symptoms (eg,
fatigue or weight loss) and/or cardiac involvement are common, although other
organs may be affected. A monoclonal spike is found in the serum or urine
by electrophoresis in more than 80% of proteinuric individuals and more than
90% of patients with nephrotic syndrome; approximately 20% of these patients
will have free light chains.71, 72
The yield of abdominal fat-pad biopsy is approximately 75% in this group,
and the procedure should be performed in patients older than 40 years with
unexplained proteinuria.73 Skin, gingival,
and rectal biopsy findings are less sensitive, unless there is overt clinical
involvement.73, 74 Results of bone
marrow examination may demonstrate evidence of monoclonal restriction.73
Other related disorders, including immunotactoid and/or fibrillary glomerulopathy
and heavy chain–deposition disease, may present as nephrotic syndrome
(with or without progressive renal failure). These entities are difficult
to diagnose on clinical grounds alone, and renal biopsy is required for diagnosis.75, 76, 77, 78, 79, 80, 81
The size, shape, and nature of the immune deposits and microfibrils distinguish
these entities from amyloid deposits and each other.
Recognition of the association of nephrotic syndrome with infections
has been rekindled with the epidemic of acquired immunodeficiency syndrome
(AIDS).82, 83, 84 Patients
with AIDS may present with a variety of nephrologic syndromes (Table 5).85 The varied clinical presentations
and pathologic entities observed in these patients likely reflect differences
in pathogenesis and host response to viral infection. Renal involvement may
occur at any stage of infection, although the entity occurs more commonly
in patients with established AIDS. The pathologic abnormality in patients
with nephrotic syndrome is typically focal and segmental glomerulosclerosis.86 A more severe form, termed collapsing
glomerulopathy, more common in patients who are seropositive for human
immunodeficiency virus (HIV), is associated with rapid progression to end-stage
renal failure within months.87 It has been
postulated that HIV infection of renal cells (eg, mesangial or epithelial)
contributes to fibrosis and the more rapid progression to renal failure observed
in these patients.88 Urinary protein excretion
can exceed 20 g/d in some patients (ie, supernephrotic syndrome), and therefore
this level of proteinuria should raise suspicion of the diagnosis.89 Less common forms of glomerulopathies associated
with HIV include IgA deposition, microangiopathy, and acute renal failure.85 Regarding the latter, renal biopsy may be necessary
to distinguish the cause of acute renal failure in these individuals. Other
infections associated with the nephrotic syndrome are given in Table 4.30
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Table 5. Human Immunodeficiency Virus Glomerulopathies*
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A variety of neoplasms and drugs have been linked to the nephrotic syndrome;
the more common pathologic associations are indicated in Table 4.61, 90 In most
cases, the neoplasm is obvious from the history and results of physical and
laboratory examinations, although occasionally the nephrotic syndrome represents
the initial manifestation of disease. Nonsteroidal anti-inflammatory drugs
are the most common drugs associated with the nephrotic syndrome, probably
the result of their widespread use. With drug-induced disease, determining
causality may be difficult, as resolution of nephrosis may take weeks to months
after discontinuation of use of the offending agent.
Primary Glomerular Diseases
Idiopathic nephrotic syndrome is the term used
to describe nonsystemic disease or disease without another pathogenically
relevant association. Patients typically present with edema and heavy proteinuria.91 The cause of these entities is uncertain, although
circumstantial evidence of an immune-mediated pathogenesis exists in most
instances. The terms used to categorize these patients refer to the typical
pathologic description of the light microscopy findings of kidney tissue (Table 4). Accordingly, histologic evaluation
of kidney biopsy specimens is required to make a definitive diagnosis. These
lesions usually are indistinguishable from those of patients with systemic
diseases. In fact, kidney biopsy specimens from patients with systemic diseases
frequently are categorized as having "disease like" the idiopathic varieties
(ie, membranous-like or minimal change–like lesions). Nevertheless,
although the causes of these entities are uncertain, identification of the
abnormality using results of kidney biopsy has utility in classifying the
disease and in predicting outcome and response to therapy.
Diagnosis of Nephrotic Syndrome
Because of these considerations, our recommendations for the initial
workup of adults with nephrotic syndrome are outlined in Table 6. Unless the GFR is abnormal or rapidly deteriorating, proceed
with the diagnostic evaluation and subsequently refer the patient to a nephrologist
to assist with management. Further evaluation (and therapy) should be driven
by the results of the initial studies. If the results of the initial workup
are normal, the patient most likely has idiopathic nephrotic syndrome. The
results of the kidney biopsy distinguish among primary renal diseases and
occasionally uncover unsuspected systemic diseases. Kidney biopsy findings
also provide prognostic information, thereby influencing therapeutic decisions.59 Thus, we recommend renal biopsy when the diagnosis
is uncertain or knowledge of the severity of disease will influence therapy.
Nevertheless, if the probability of a specific disease or group of diseases
is high, the risk of complication due to biopsy is high, and the risks of
therapy appear reasonable (eg, short course of high-dose oral steroids), then
empirical therapy without biopsy should be strongly considered.60
Empirical use of steroids in children with minimal-change disease is a good
example of this approach.
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Table 6. Evaluation of Nephrotic Syndrome in Adults*
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As noted in the discussion of glomerulonephritis, pathological evaluation
of the kidney also has utility in defining the disease subtype and determining
the severity of disease. The results of renal biopsy are also very helpful
when attempting to sort out the potential contribution of 2 or more diseases.
In this regard, it is sometimes difficult to determine whether activity of
the underlying disease or superimposition of another primary disease is the
cause of the worsening situation. For example, nephrotic syndrome in a patient
with well-controlled diabetes without retinopathy or other manifestations
of microvascular disease should raise suspicion of another cause. The pathological
results often are very helpful in the setting of rapidly progressive renal
failure in an HIV-seropositive patient; this clinical presentation should
evoke a diagnostic workup for other causes of glomerular disease.
RENAL DISORDERS THAT MASQUERADE AS ACUTE
GLOMERULONEPHRITIS AND/OR
NEPHROTIC SYNDROME
Patients with the diseases listed in Table 7 may present with significant hematuria, RBC casts, and/or
nephrotic-range proteinuria, thus mimicking acute glomerulonephritis or nephrotic
syndrome. These conditions should be considered in patients without an obvious
disease association. The clinical history, results of physical examination,
and laboratory findings are useful in constructing a differential diagnosis.
Renal biopsy, however, often is necessary to make a precise diagnosis.
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Table 7. Other Considerations in the Diagnosis of Glomerular Diseases*
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CONCLUSIONS
Early recognition and prompt diagnosis of glomerular disease are essential,
because delay in therapy may result in irreversible loss of renal function.
The clinical presentation (eg, nephritis vs nephrosis, normal vs abnormal
GFR, or systemic symptoms or lack thereof) provides clues to the underlying
cause. Serologic evaluations and repeated measurement of serum creatinine
levels should be performed in all patients for diagnosis, to determine disease
severity and monitor disease progression. Renal biopsy should be performed
when either rapid diagnosis is essential, the presence of multiple diseases
contributing to the clinical picture confounds diagnosis, and/or the level
of disease activity requires pathological determination. Collectively, this
diagnostic approach provides rapid evaluation en route to specific therapy.
AUTHOR INFORMATION
Accepted for publication July 20, 2000.
This work was supported by grant DK45191 from the George M. O'Brien
Kidney and Urological Research Center, Public Health Service awards DK 33694
and AI 27915; the DCI RED FUND, the Lupus Foundation of Philadelphia and the
Philadelphia Chapter of the American Heart Association, Philadelphia, Pa.
We thank Ajay Singh, MD, for careful review of the manuscript and constructive
criticisms.
From the Renal Electrolyte and Hypertension Division, Department of
Medicine, University of Pennsylvania, Philadelphia (Dr Madaio), and the Nephrology
Division, Department of Medicine, New England Medical Center and Tufts University
School of Medicine, Boston, Mass (Dr Harrington).
Corresponding author and reprints: Michael P. Madaio, MD, University
of Pennsylvania Medical Center, Renal Electrolyte and Hypertension Division,
700 Clinical Research Bldg, 415 Curie Blvd, Philadelphia, PA 19104-6144 (e-mail: Madaio{at}mail.med.upenn.edu).
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