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Differential diagnosis of glomerular di

Offic ial reprint from UpToDate

www.uptodate.com
2010 UpToDate

Differential diagnosis of glomerular disease

Author
Burton D Rose, MD

Section Editor
Richard J Glassock, MD, MACP

Last literature review version 18.3: Setembro 2010 |

2010

Deputy Editor
Alic e M Sheridan, MD

This topic last updated: Maio 28,

INTRODUCTION The presence of some form of glomerular disease, as opposed to primary

tubulointerstitial or vascular disease, is usually suspected from the history and from one or more
of the following urinary findings: hematuria (particularly if the red c ells have a dysmorphic
appearance), red c ell c asts, lipiduria (sinc e glomerular permeability must be increased to allow
the filtration of large lipoproteins), and proteinuria, which may be in the nephrotic range (greater
than 3 g/day). (See "Hematuria: Glomerular versus extraglomerular bleeding" and "Significance of
lipiduria" and "Evaluation of isolated proteinuria in adults" and "Evaluation of proteinuria in
children".)
Despite these clues, the ability to distinguish renal disease due to some form of glomerular
disorder from that due to c hronic tubulointerstitial involvement may be difficult. Although
tubulointerstitial disease does not directly increase protein exc retion, nephron loss can induce
secondary glomerulosclerosis leading to proteinuria that may reac h the nephrotic range. Such
patients may be erroneously c onsidered to have a primary glomerular disease. Severe vascular
disease, such as malignant essential hypertension or a thrombotic microangiopathy can also lead
to marked proteinuria and hematuria and thus resemble primary glomerular diseases. This topic
will review those clinic al features most c onsistent with the various forms of glomerular disease.
CLINICAL PATTERNS OF GLOMERULAR DISEASE Although there are many causes of
glomerular disease, the patient's age and the c haracteristic s of the urine sediment usually allow
the differential diagnosis to be substantially narrowed prior to renal biopsy. In general, two
different urinary patterns may be seen: nephritic, and nephrotic. As will be described below,
these patterns help narrow the differential diagnosis in patients presenting with signs of
glomerular disease (table 1). In patients with systemic disease, the c linical findings may suggest
a focal and segmental or a diffuse and global pattern of glomerular involvement. A review of the
immune mechanisms responsible for the different patterns of c linical presentation is available
elsewhere. (See "Types of renal disease in systemic lupus erythematosus".)
Focal nephritic Foc al glomerulonephritis is assoc iated with inflammatory lesions in less than
one-half of glomeruli on light mic roscopy. The urinalysis reveals red cells (which often have a
dysmorphic appearanc e), occasionally red cell casts, and mild proteinuria (usually less than 1.5
g/day) (pic ture 1A-C). The findings of more severe disease are usually absent, including
nephrotic range proteinuria, edema, hypertension, and renal insufficiency.
Diffuse nephritic Diffuse glomerulonephritis, in c omparison, affects most or all of the
glomeruli. Thus, the urinalysis is similar to focal disease, but heavy proteinuria (whic h may be in
the nephrotic range), edema, hypertension, and/or renal insufficiency may be seen.
Nephrotic The nephrotic sediment, in comparison, is associated with heavy proteinuria and
lipiduria, but few cells or casts (pic ture 2A-B). Patients who also have edema and hyperlipidemia
(the full-blown nephrotic syndrome) tend to have a more marked glomerular leak than those with
heavy proteinuria alone. The diagnostic c onsiderations are generally similar, since any of the
conditions associated with a nephrotic sediment can produc e a spectrum of disease ranging from
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asymptomatic proteinuria to marked edema. However, some form of secondary focal segmental
glomerulosc lerosis (as with reflux nephropathy) is more likely in patients with nephrotic range
proteinuria (more than 3.5 g/day) who have neither hypoalbuminemia nor edema [1]. (See
"Pathogenesis and diagnosis of focal segmental glomerulosclerosis".)
The relatively bland sediment seen more commonly in the nephrotic disorders results from the
lack of inflammatory cell infiltration in the glomeruli. This finding is in large part due to the
absenc e of immune complex deposition in most of these disorders, suc h as minimal change
disease, diabetic nephropathy, and amyloidosis. Immune complexes are deposited in membranous
nephropathy, but this occurs across the glomerular basement membrane in the subepithelial
space. Thus, complement c an be activated but the c hemoattractants (C3a and C5a) are
separated from the vasc ular space by the basement membrane and therefore do not have
acc ess to the circ ulating mononuclear c ells and neutrophils [2].
The lack of inflammation also results in the plasma creatinine c oncentration being normal or only
slightly elevated at presentation in the nephrotic disorders listed below. Acute renal failure can
occ ur, but in a limited number of settings:
Concurrent acute tubular nec rosis, usually in minimal c hange disease, and primarily in
patients over 50 years of age. (See "Acute kidney injury (acute renal failure) in minimal
change disease and other forms of nephrotic syndrome".)
Tubular injury in collapsing focal segmental glomerulosclerosis, either idiopathic or
associated with HIV infection. (See "Collapsing focal segmental glomerulosc lerosis not
associated with HIV infection" and "Collapsing focal segmental glomerulosclerosis and other
renal diseases associated with HIV infec tion".)
Minimal change disease with ac ute interstitial nephritis induced by nonsteroidal
antiinflammatory drugs. (See "NSAIDs: Acute kidney injury (acute renal failure) and
nephrotic syndrome".)
Cresc entic glomerulonephritis superimposed upon membranous nephropathy. (See "Causes
and diagnosis of membranous nephropathy", section on 'Crescentic glomerulonephritis'.)
Nephrotic syndrome secondary to monoclonal immunoglobulin deposition disease may also
develop myeloma cast nephropathy and ac ute renal failure. (See "Types of renal disease in
multiple myeloma".)
Superimposed thrombotic microangiopathy.
Severe volume depletion in an ac utely developing hypoalbuminemia associated with minimal
change disease.
Deregulated complement metabolism with a membranoproliferative pattern of injury.
As a result, the triad of the nephrotic syndrome, a nephrotic sediment, and acute renal failure
substantially narrows the differential diagnosis. Bilateral renal vein thrombosis is also rarely
considered as a cause of renal insufficiency in this setting, mostly in children. (See "Renal vein
thrombosis and hypercoagulable state in nephrotic syndrome".)
If the c haracteristic s of the urinalysis and the patient's age are taken into account, then the
most likely diagnoses can be identified [3,4]. (See 'Diagnosis ac cording to urinalysis and patient
age' below.) (See also topic s on the individual diseases).
Nonspecific nature of the histologic patterns It is important to appreciate that eac h of the
histologic patterns c an be produced by a number of different diseases. As examples:
Membranoproliferative glomerulonephritis is often produced by a systemic immune complex
disease (eg, infective endocarditis, systemic lupus erythematosus, hepatitis C virus) or by
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complement dysregulation, chronic thrombotic microangiopathy or a monoc lonal

immunoglobulin deposition disease. (See "Classification and c auses of
membranoproliferative glomerulonephritis".)
Membranous nephropathy can be induced by drugs (eg, gold, penicillamine, merc ury),
systemic lupus erythematosus, chronic hepatitis B virus infec tion, and underlying
malignancy. (See "Causes and diagnosis of membranous nephropathy".)
Focal segmental glomerulosclerosis can be a primary c ondition that may be related
pathogenetic ally to minimal change disease, or can be a secondary change induc ed by
intraglomerular hypertension or healing of previous glomerular injury. (See "Pathogenesis
and diagnosis of focal segmental glomerulosclerosis".)
DIAGNOSIS ACCORDING TO URINALYSIS AND PATIENT AGE When approaching a patient
with apparent glomerular disease, the urinalysis, other laboratory tests of renal function, and
patient age help to narrow the differential diagnosis (table 1). However, these correlations may
vary by geographic region as indications for biopsy can vary substantially by country.
Despite this, there are some general observations that appear to hold ac ross widely disparate
regions. As an example, in a collection of studies based upon renal biopsy registries from multiple
countries, the princ ipal causes of ac ute glomerulonephritis (focal and diffuse disease) generally
included rapidly progressive (c rescentic) glomerulonephritis, IgA nephropathy, and endocapillary
proliferative glomerulonephritis (often of a postinfectious nature) [5-11]. In addition,
membranous nephropathy and foc al segmental glomerulosc lerosis (FSGS) are among the most
common causes of the nephrotic syndrome in adults in the developed world.
Thus, although many differences exist according to specific geographic region [5-11], the
following is an approximate guide to the histologic lesions c ommonly noted to occ ur among
patients of varying ages:
Focal glomerulonephritis
Less than 15 years Mild postinfectious glomerulonephritis, IgA nephropathy, thin
basement membrane disease, hereditary nephritis, Henoch-Schnlein purpura, mesangial
proliferative glomerulonephritis
15 to 40 years IgA nephropathy, thin basement membrane disease, lupus, hereditary
nephritis, mesangial proliferative glomerulonephritis
Greater than 40 years IgA nephropathy
Diffuse glomerulonephritis Several of these disorders, suc h as postinfec tious
glomerulonephritis, lupus nephritis, membranoproliferative glomerulonephritis, and mixed
cryoglobulinemia, are commonly associated with hypocomplementemia [5,12,13]. (See
"Hypocomplementemia in glomerular disease".)
They also may be assoc iated with characteristic serologic findings, suc h as: antistreptococ cal
antibodies in poststreptococ cal glomerulonephritis, antinuc lear antibodies in lupus nephritis, antiGBM antibodies in anti-GBM antibody disease, circ ulating cryoglobulins in mixed cryoglobulinemia,
and antineutrophil cytoplasmic antibodies in Wegener's granulomatosis and related diseases.
(See "Hematuria following an upper respiratory infection" and "Pathogenesis and diagnosis of
anti-GBM antibody (Goodpasture's) disease" and "Clinic al manifestations and diagnosis of
essential mixed cryoglobulinemia" and "Clinical spectrum of antineutrophil c ytoplasmic
antibodies".)
Less than 15 years Postinfectious glomerulonephritis, membranoproliferative
glomerulonephritis
15 to 40 years Postinfectious glomerulonephritis, lupus, rapidly progressive
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glomerulonephritis, fibrillary glomerulonephritis, membranoproliferative glomerulonephritis

Greater than 40 years Rapidly progressive glomerulonephritis, vasculitis (inc luding mixed
cryoglobulinemia), fibrillary glomerulonephritis, postinfectious glomerulonephritis
Nephrotic syndrome
Less than 15 years Minimal change disease, focal segmental glomerulosclerosis,
mesangial proliferative glomerulonephritis
15 to 40 years Focal segmental glomerulosc lerosis, minimal change disease, membranous
nephropathy (including lupus), diabetic nephropathy, preeclampsia, postinfectious
glomerulonephritis (later stage)
Greater than 40 years Focal segmental glomerulosclerosis, membranous nephropathy,
diabetic nephropathy, minimal change disease, IgA nephropathy, primary amyloidosis or the
related disorder light c hain deposition disease (which can acc ount for 15 to 20 perc ent of
cases in patients over the age of 60), benign nephrosclerosis, postinfectious
glomerulonephritis (later stage).
INFORMATION FOR PATIENTS Educ ational materials on this topic are available for patients.
(See "Patient information: Glomerular disease overview" and "Patient information: The nephrotic
syndrome".) We encourage you to print or e-mail these topic reviews, or to refer patients to our
public web site, www.uptodate.com/patients, which includes these and other topics.
SUMMARY
Glomerular disease is distinguished from primary tubulointerstitial or vasc ular disease by the
history and by the presenc e of hematuria, red cell casts, lipiduria, and proteinuria, which
may be in the nephrotic range (greater than 3 g/day). (See 'Introduction' above.)
Charac teristics of the urine sediment may narrow the differential diagnosis of glomerular
disease prior to biopsy. Three different urinary patterns are observed including nephritic ,
and nephrotic. (See 'Clinical patterns of glomerular disease' above.)
The urinalysis charac terizing foc al glomerulonephritis shows dysmorphic red cells,
oc casionally red cell c asts, and mild proteinuria (usually less than 1.5 g/day). Nephrotic
range proteinuria, edema, hypertension, and renal insuffic iency are usually absent. (See
'Focal nephritic' above.)
The urinalysis charac terizing diffuse glomerulonephritis is similar to that in focal disease,
but heavy proteinuria, edema, hypertension, and/or renal insufficiency may be present.
(See 'Diffuse nephritic ' above.)
The nephrotic sediment contains few cells or casts and is associated with heavy
proteinuria and lipiduria. (See 'Nephrotic' above.)
The differential diagnosis of nephrotic glomerular disease may be narrowed by the
presenc e or absence of hypoalbuminemia and edema. Patients with nephrotic range
proteinuria (more than 3.5 g/day) who have neither hypoalbuminemia nor edema are more
likely to have a secondary form of focal segmental glomerulosclerosis rather than primary
focal sc lerosis. (See 'Nephrotic ' above.)
The differential diagnosis of nephrotic glomerular disease may be narrowed by the
presenc e or absence of acute renal failure. Acute renal failure oc curs in patients with
idiopathic minimal c hange disease, collapsing focal segmental glomerulosclerosis, minimal
change disease with acute interstitial nephritis induc ed by nonsteroidal antiinflammatory
drugs, crescentic glomerulonephritis or interstitial nephritis superimposed upon membranous
nephropathy, and nephrotic syndrome secondary to monoclonal immunoglobulin deposition
disease due to myeloma cast nephropathy. Bilateral renal vein thrombosis may rarely c ause
renal insuffic ienc y in pediatric patients with nephrotic syndrome. (See 'Nephrotic ' above.)
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Measurement of serum complement levels may narrow the differential diagnosis of diffuse
glomerulonephritis. Among patient with diffuse glomerulonephritis, hypocomplementemia
suggests postinfectious glomerulonephritis, lupus nephritis, membranoproliferative
glomerulonephritis (that may be idiopathic or secondary) or mixed c ryoglobulinemia. (See
'Diffuse glomerulonephritis' above and "Classification and c auses of membranoproliferative
glomerulonephritis", section on 'Etiology'.)
Measurement of specific serologic studies may narrow the differential diagnosis of diffuse
glomerulonephritis. Characteristic serologic tests include antistreptococc al antibodies in
poststreptococcal glomerulonephritis, antinuclear antibodies in lupus nephritis, anti-GBM
antibodies in anti-GBM antibody disease, c irculating cryoglobulins in mixed
cryoglobulinemia, and antineutrophil c ytoplasmic antibodies in Wegener's granulomatosis
and related diseases. (See 'Diffuse glomerulonephritis' above.)
Patient age may help to narrow the differential diagnosis of glomerulonephritis and of
nephrotic syndrome. (See 'Diagnosis according to urinalysis and patient age' above.)

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REFERENCES
1. Praga, M, Borstein, B, Andres, A, et al. Nephrotic proteinuria without hypoalbuminemia:
clinic al characteristics and response to angiotensin-converting enzyme inhibition. Am J
Kidney Dis 1991; 17:330.
2. Fries, JW, Mendrick, DL, Rennke, HG. Determinants of immune complex-mediated
glomerulonephritis. Kidney Int 1988; 34:333.
3. Rose, BD. Clinical charac teristics of glomerular disease. In: Sc ientific American Medicine,
Rubinstein, E, Federman DD (Eds), Sc ientific American, New York, 1989, section X (IV):1.
4. Haas, M, Meehan, SM, Karrison, TG, Spargo, BH. Changing etiologies of unexplained adult
nephrotic syndrome: a comparison of renal biopsy findings from 1976-1979 and 1995-1997.
Am J Kidney Dis 1997; 30:621.
5. Rivera, F, Lpez-Gmez, JM, Prez-Garca, R, Spanish Registry of, Glomerulonephritis.
Clinicopathologic correlations of renal pathology in Spain. Kidney Int 2004; 66:898.
6. Iseki, K, Miyasato, F, Uehara, H, et al. Outcome study of renal biopsy patients in Okinawa,
Japan. Kidney Int 2004; 66:914.
7. Gesualdo, L, Di Palma, AM, Morrone, LF, et al. The Italian experience of the national
registry of renal biopsies. Kidney Int 2004; 66:890.
8. Heaf, J. The Danish Renal Biopsy Register. Kidney Int 2004; 66:895.
9. Simon, P, Ramee, MP, Boulahrouz, R, et al. Epidemiologic data of primary glomerular
diseases in western Franc e. Kidney Int 2004; 66:905.
10. Nair, R, Bell, JM, Walker, PD. Renal biopsy in patients aged 80 years and older. Am J Kidney
Dis 2004; 44:618.
11. Bahiense-Oliveira, M, Saldanha, LB, Mota, EL, et al. Primary glomerular diseases in Brazil
(1979-1999): is the frequency of foc al and segmental glomerulosclerosis increasing? Clin
Nephrol 2004; 61:90.
12. Lewis, EJ, Carpenter, CB, Schur, PH. Serum complement c omponent levels in human
glomerulonephritis. Ann Intern Med 1971; 75:555.
13. Rose, BD. Pathophysiology of Renal Disease, 2d ed, Mc Graw-Hill, New York, 1987, p. 166.

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GRAPHICS
Classification of glomerular disease according to clinical features
Focal glomerulonephritis
Active urine sediment without renal insufficiency or nephrotic syndrome
Less than 15 years - Mild postinfectious glomerulonephritis, IgA nephropathy, thin basement
membrane disease, hereditary nephritis, Henoch-Schnlein purpura, mesangial proliferative
glomerulonephritis
15 to 40 years - IgA nephropathy, thin basement membrane disease, lupus, hereditary nephritis,
mesangial proliferative glomerulonephritis
Greater than 40 years - IgA nephropathy

Diffuse glomerulonephritis
Active urine sediment with renal insufficiency and variable proteinuria, which can include
nephrotic syndrome
Less than 15 years - Postinfectious glomerulonephritis, membranoproliferative
glomerulonephritis
15 to 40 years - Postinfectious glomerulonephritis, lupus, rapidly progressive glomerulonephritis,
fibrillary glomerulonephritis, membranoproliferative glomerulonephritis
Greater than 40 years - Rapidly progressive glomerulonephritis, vasculitis (including mixed
cryoglobulinemia), fibrillary glomerulonephritis, postinfectious glomerulonephritis

Nephrotic syndrome
Heavy proteinuria, bland sediment although some hematuria allowed
Less than 15 years - Minimal change disease, focal glomerulosclerosis, mesangial proliferative
glomerulonephritis
15 to 40 years - Focal glomerulosclerosis, minimal change disease, membranous nephropathy
(including lupus), diabetic nephropathy, preeclampsia, postinfectious glomerulonephritis (later
stage)
Greater than 40 years - Focal glomerulosclerosis, membranous nephropathy, diabetic
nephropathy, minimal change disease, IgA nephropathy, primary amyloidosis or the related
disorder light chain deposition disease (which can account for 15 to 20 percent of cases in
patients over the age of 60), benign nephrosclerosis, postinfectious glomerulonephritis (later
stage)

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Dysmorphic red cells

Phase contrast microscopy showing dysmorphic red cells in a

patient with glomerular bleeding. Acanthocytes can be
recognized as ring forms with vesicle-shaped protrusions
(arrows). Courtesy of Hans Khler, MD.

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Dysmorphic red cells

Scanning microscopy showing dysmorphic red cells in a patient

with glomerular bleeding. Acanthocytes can be recognized as
ring forms with vesicle-shaped protrusions (arrows). Courtesy of
Hans Khler, MD.

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Red cell cast

Urine sediment showing free red cells and a red cell cast that is
tightly packed with red cells. It is more common for red cell
casts to have fewer red cells trapped within a hyaline or
granular cast. Red cell casts are virtually diagnostic of
glomerulonephritis or vasculitis. Courtesy of Harvard Medical School.

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Fatty cast

Urine sediment showing a fatty cast. The fat droplets (or

globules) can be distinguished from red cells (which also have
a round appearance) by their variable size (from much smaller
to much larger than a red cell), dark outline, and "Maltese
cross" appearance under polzarized light. Courtesy of Frances
Andrus, BA, Victoria Hospital, London, Ontario.

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Fatty cast

Urine sediment showing fatty cast under polarized light. The

fat droplets have a characteristic "Maltese cross" appearance
(arrow). Courtesy of Harvard Medical School.

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