Glomerular disease: Evaluation and differential diagnosis in adults

INTRODUCTION — Glomerular disease can result from many inherited or acquired disorders and can manifest in a variety of ways, ranging in severity from asymptomatic urinary abnormalities to acute kidney injury (AKI) or end-stage kidney disease.

A kidney biopsy is often required to diagnose the underlying pathology in patients with suspected glomerular disease, particularly in those with nephrotic syndrome or suspected glomerulonephritis. Rarely, a biopsy cannot be performed or is not needed to secure a diagnosis.

More than one glomerular disease can be present in the same individual (eg, underlying diabetic nephropathy with superimposed glomerulonephritis).

An overview of the differential diagnosis and evaluation of glomerular disease is presented in this topic. Certain clinical syndromes of glomerular disease are presented in other topics:

●Isolated hematuria (see "Isolated and persistent glomerular hematuria in adults")

●Isolated non-nephrotic proteinuria (see "Assessment of urinary protein excretion and evaluation of isolated non-nephrotic proteinuria in adults")

●Nephrotic syndrome (see "Overview of heavy proteinuria and the nephrotic syndrome")

●Rapidly progressive glomerulonephritis (see "Overview of the classification and treatment of rapidly progressive (crescentic) glomerulonephritis")

Detailed discussions of specific glomerular disorders are found elsewhere. (See appropriate topic reviews.)

GLOMERULAR ANATOMY AND TERMINOLOGY — The glomerulus is the basic filtering unit of the kidney (figure 1). Each glomerulus is essentially a tuft of capillaries formed by the branching of the afferent arteriole and supported by a structural matrix called the mesangium, which is maintained by specialized mesangial cells. The glomerular basement membrane (GBM) provides both a size- and charge-selective barrier to the passage of circulating macromolecules from the plasma (picture 1). On the urinary side of the GBM is a lining composed of a layer of podocytes, which are specialized epithelial cells possessing a specialized intercellular junction, the slit diaphragm. The slit diaphragm provides another barrier to the filtration of plasma macromolecules. The glomerular capillary tufts are surrounded by the Bowman's capsule, a single layer of parietal epithelial cells forming a cup-like sac that is continuous with the renal tubule, and into which the filtrate from the glomerular capillaries is collected and passed to the renal tubule [1,2].

On a pathological basis, glomerular lesions can be diffuse (all glomeruli are involved) or focal (only some glomeruli are involved [typically less than 50 percent]). At the level of the individual glomerulus, a process is global if the whole glomerular tuft is involved or segmental if only a portion is involved (less than 50 percent). Histologic descriptions include the terms "proliferative" (an increase in the number of cells in the glomerulus), "sclerosing" (presence of scarring), and "necrotizing" (areas of cell death). Proliferation may occur predominantly in the mesangium (mesangial proliferative glomerulonephritis), within the capillary wall (endocapillary hypercellularity), and in an extracapillary location. Extracapillary proliferation (also known as crescents) are lesions associated with accumulations of macrophages, fibroblasts, proliferating epithelial cells, and fibrin within Bowman's space and represent rupture of the glomerular membrane, signifying severe injury to the glomerular capillary wall. Some examples of how this terminology is used include "focal and segmental necrotizing glomerulonephritis" and "diffuse global proliferative glomerulonephritis" (picture 2). Lastly, interstitial fibrosis, which accompanies uncontrolled glomerular disease, is a poor prognostic sign [3].

Several mechanisms lead to glomerular dysfunction [2]. Podocyte dysfunction can occur in genetic disease, affecting key podocyte and basement membrane proteins such as collagen IV mutations in Alport syndrome. In diseases such as minimal change disease and focal segmental glomerulosclerosis (FSGS), putative circulating factors are thought to directly affect podocyte function and lead to proteinuria [4]. In diabetes mellitus and amyloidosis, there is mechanical disruption of the glomerulus due to accumulation of normal or abnormal protein both in the capillary loops of the glomerulus and the mesangium. Immune mechanisms include in situ formation of immune complexes in membranous glomerulopathy [5] or the localized effects of anti-GBM antibodies in Goodpasture's disease; in conditions such as systemic lupus erythematosus, immune-mediated kidney injury is caused by deposition of circulating immune complexes [6]. Lastly, activated neutrophils and macrophages could directly injure the glomerulus in diseases such as antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis [2]. (See "Mechanisms of immune injury of the glomerulus" and "Mechanisms of glomerular crescent formation".)

CLINICAL MANIFESTATIONS OF GLOMERULAR DISEASE — Clinical manifestations associated with glomerular disease include the following:

●Hematuria and/or proteinuria – Glomerular disease should be suspected when hematuria and/or proteinuria are seen on urinalysis. Glomerular hematuria is established by the presence of urinary red blood cell (RBC) casts (of any number) or hematuria in which a substantial proportion of RBCs are acanthocytes (picture 3).

Although interstitial and vascular disorders of the kidney may also cause these abnormalities (and therefore mimic glomerular disease), the findings of dysmorphic RBCs and RBC casts in the urine sediment and/or nephrotic-range proteinuria (ie, more than 3 to 3.5 g/day of proteinuria) are more specific for a glomerular origin. (See "Urinalysis in the diagnosis of kidney disease".)

●Kidney function impairment – Patients with acute onset of nephrotic syndrome do not typically present with acute kidney injury (AKI). However, AKI may be seen at the time of presentation in patients with podocytopathies such as minimal change disease or primary focal segmental glomerulosclerosis (FSGS). (See "Acute kidney injury (AKI) in minimal change disease and other forms of nephrotic syndrome".)

However, kidney function impairment (acute or chronic) is commonly seen in patients with glomerulonephritis:

•AKI may occur with acute glomerulonephritis, especially in patients who have crescentic glomerulonephritis, which is often due to antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis or anti-glomerular basement membrane (GBM) disease. (See "Overview of the classification and treatment of rapidly progressive (crescentic) glomerulonephritis".)

•Patients with chronic glomerular diseases may develop a progressive decline in glomerular filtration rate and chronic kidney disease.

●Hypertension – Acute onset of hypertension in someone with previously normal blood pressure or acute worsening of hypertension in someone with preexisting, controlled hypertension should raise suspicion for glomerular disease, particularly if other manifestations (eg, hematuria, edema) are also present.

●Edema – The presence of peripheral and/or periorbital edema in patients with hematuria or proteinuria may be a sign of primary renal sodium retention as a result of glomerular disease.

●Hypercoagulability – Some types of glomerular disease, in particular membranous nephropathy or, less commonly, other causes of nephrotic syndrome, may produce a hypercoagulable state. Thus, thrombotic events, such as pulmonary embolism, may be a manifestation of glomerular disease.

●Systemic findings – Glomerular disease may be limited primarily to the kidney or may be associated with systemic conditions such as infections, autoimmune disorders, malignancy, and drug reactions. Thus, in patients with suspected glomerular disease, the history, examination, and initial laboratory studies should include evaluation for a systemic disorder, as examples:

•Constitutional – Fevers, chills, weight loss, night sweats, fatigue

•Eye – Retinitis or uveitis

•Ear, nose, and throat – Epistaxis, sinusitis, oral ulcers

•Cardiovascular – Murmurs, pain (pericarditis), or heart failure

•Lungs – Hemoptysis, infiltrates, or nodules

•Abdomen – Enteritis, colitis, or pancreatitis

•Nervous system – Seizures or peripheral neuropathy

•Extremities – Digital ischemia or infarction

•Skin – Purpura or rash

•Musculoskeletal – Arthritis, arthralgias, myalgias

•Infections – Particularly evidence of Staphylococcus, Streptococcus, hepatitis virus, or HIV, syphilis

EVALUATION AND DIFFERENTIAL DIAGNOSIS OF MAJOR GLOMERULAR PRESENTATIONS — Glomerular disease syndromes are typically classified based upon the pattern of urinary abnormalities, the existence of systemic features, and the degree of kidney dysfunction (algorithm 1).

The nephrotic syndrome and glomerulonephritis are the prototypical presentations of glomerular disease. In the nephrotic syndrome, leakage of plasma proteins without inflammation is the primary pathogenic mechanism. Conversely, in glomerulonephritis, inflammation within the glomerulus leads not only to the passage of plasma proteins but also of inflammatory cells (leukocytes) and RBCs into the renal tubule. These classifications, however, are not exclusive, as some conditions may present with both patterns, and some disorders (eg, lupus nephritis) may progress from one pattern to the other. In addition, patients may present with mild manifestations such as isolated proteinuria or isolated hematuria.

Proteinuria — Proteinuria may be caused by glomerular disease (in which there is albuminuria) or other disorders (table 1) (see "Assessment of urinary protein excretion and evaluation of isolated non-nephrotic proteinuria in adults", section on 'Types of proteinuria'):

●Proteinuria due to glomerular disease (in which there is albuminuria) is identified on a urine dipstick or with a quantitative measurement of urine albumin excretion.

●Proteinuria that is not due to glomerular disease may be due to one of three mechanisms:

•Tubular proteinuria, in which low-molecular-weight proteins that are filtered across the glomerulus are incompletely reabsorbed by the renal tubule

•Overflow proteinuria, in which overproduction of low-molecular-weight proteins (eg, light chains in the patients with multiple myeloma) leads to an increase in filtration and excretion

•Postrenal proteinuria, which is typically associated with a urinary tract infection and leukocyturia

Proteinuria discovered by a semiquantitative urine dipstick typically reflects glomerular proteinuria because the dipstick is insensitive to nonalbumin proteins. However, if proteinuria is discovered by a quantitative test for urinary protein (ie, a 24-hour urine collection or a random urine protein-to-creatinine ratio), the origin of the proteinuria can be determined with a dipstick, a quantification of urine albumin excretion (ie, a 24-hour urine collection or a random urine albumin-to-creatinine ratio), or with a urine protein electrophoresis and immunofixation. (See "Assessment of urinary protein excretion and evaluation of isolated non-nephrotic proteinuria in adults", section on 'Types of proteinuria'.)

The evaluation and differential diagnosis of patients with glomerular proteinuria depends, in part, upon whether or not the patient has nephrotic syndrome.

Nephrotic syndrome (heavy proteinuria and hypoalbuminemia) — The nephrotic syndrome is characterized by the following (see "Overview of heavy proteinuria and the nephrotic syndrome"):

●A urine protein excretion of greater than 3500 mg per 24 hours or, if a random urine protein-to-creatinine ratio is measured, a ratio greater than 3000 mg/g in an adult

●Hypoalbuminemia, usually less than 3.5 g/dL, depending on the method of measurement

Other common findings in patients with nephrotic syndrome include edema (peripheral or periorbital, occasionally ascites or pleural effusions), hyperlipidemia, and lipiduria. Lipiduria is identified by the presence of fat droplets, which may be free within sloughed tubular cells (oval fat bodies) or inside fatty casts (picture 4). Fat droplets have a characteristic "Maltese cross" appearance under polarized light (picture 5).

The evaluation and differential diagnosis of nephrotic syndrome are displayed in the algorithm (algorithm 1) and also discussed below.

Evaluation of nephrotic syndrome — Most adults with nephrotic syndrome should be evaluated by a nephrologist and undergo a kidney biopsy to obtain a definitive diagnosis. However, a kidney biopsy may be deferred in certain patients:

●If there is an obvious etiology (eg, longstanding diabetes mellitus with progressive proteinuria) (see "Diabetic kidney disease: Pathogenesis and epidemiology")

●If amyloidosis is suspected in a patient with a monoclonal gammopathy (in which case a fat pad biopsy may secure the diagnosis) (see "Clinical presentation, laboratory manifestations, and diagnosis of immunoglobulin light chain (AL) amyloidosis")

●If the patient with nephrotic syndrome has a positive anti-phospholipase A2 receptor (anti-PLA2R) autoantibody (see "Membranous nephropathy: Pathogenesis and etiology")

●If a biopsy cannot be performed or is refused (eg, a patient in the later stages of pregnancy) (see "The kidney biopsy")

In addition to a kidney biopsy, certain laboratory tests, which are often performed in nephrotic patients, include:

●Glycated hemoglobin (HbA1C, to diagnose diabetes)

●Antinuclear antibody and anti-double stranded DNA (dsDNA) antibody

●Anti-PLA2R autoantibody

●In patients older than 50 years – Serum free light chains and serum protein electrophoresis with immunofixation

●Tests for hepatitis B and C viruses and HIV (see "Hepatitis B virus: Screening and diagnosis in adults", section on 'Diagnostic algorithms' and "Screening and diagnosis of chronic hepatitis C virus infection", section on 'Initial testing' and "Screening and diagnostic testing for HIV infection", section on 'Testing algorithm')

●Serum C3 and C4 complement levels

Other serologic, microbiological, and genetic tests are sometimes performed in patients once a specific histologic diagnosis is established.

Differential diagnosis of nephrotic syndrome — The nephrotic syndrome may be primary (table 2) or secondary to a systemic disease (table 3). Secondary nephrotic syndrome due, for example, to diabetes, infection, or autoimmune disease, is more common than primary nephrotic syndrome. Overall, diabetic kidney disease is the most common cause of nephrotic syndrome. (See "Diabetic kidney disease: Pathogenesis and epidemiology" and "Overview of heavy proteinuria and the nephrotic syndrome", section on 'Etiology'.)

Although minimal change disease is the most common cause of primary nephrotic syndrome in children, membranous nephropathy and focal segmental glomerulosclerosis (FSGS) are the most common causes of primary nephrotic syndrome in adults. In adults, membranous nephropathy predominates in White patients and FSGS in Black patients. (See "Membranous nephropathy: Pathogenesis and etiology" and "Focal segmental glomerulosclerosis: Clinical features and diagnosis" and "Minimal change disease: Etiology, clinical features, and diagnosis in adults".)

Some disorders (eg, C3 glomerulonephritis or other causes of a membranoproliferative pattern of injury) can present as nephrotic syndrome, glomerulonephritis, or both. (See "Overview of heavy proteinuria and the nephrotic syndrome".)

Proteinuria without nephrotic syndrome — Glomerular proteinuria without nephrotic syndrome can range in severity from several hundred mg per day to the nephrotic range (ie, more than 3000 to 3500 mg per day). Such patients may also have variable degrees of kidney function impairment, hypertension, and hematuria. Glomerular proteinuria is said to be isolated when it occurs in the absence of systemic disease, hypertension, hematuria, or azotemia.

The evaluation and differential diagnosis of proteinuria without nephrotic syndrome are presented below (algorithm 1).

Evaluation of proteinuria without nephrotic syndrome — The evaluation of proteinuria in patients without nephrotic syndrome depends upon whether or not the proteinuria is isolated (ie, proteinuria in the absence of systemic disease, hypertension, hematuria, or azotemia).

●Isolated proteinuria – Patients with isolated proteinuria who are asymptomatic and have no obvious etiology should be evaluated for transient proteinuria and, if the patient is younger than 30 years, orthostatic proteinuria (see "Assessment of urinary protein excretion and evaluation of isolated non-nephrotic proteinuria in adults"):

•Transient proteinuria is common, especially in young individuals. Transient proteinuria is diagnosed if a repeat qualitative test is no longer positive for proteinuria. These patients need no further evaluation and should be reassured that they do not have kidney disease. (See "Assessment of urinary protein excretion and evaluation of isolated non-nephrotic proteinuria in adults", section on 'Rule out transient proteinuria'.)

•Orthostatic (also referred to as postural) proteinuria is characterized by an elevated protein excretion while in the upright position and normal protein excretion in a supine or recumbent position. It is the most frequent cause of isolated proteinuria in children, especially adolescents, and can be diagnosed by performing a split urine collection (table 4). Orthostatic proteinuria is discussed in detail elsewhere. (See "Orthostatic (postural) proteinuria" and "Assessment of urinary protein excretion and evaluation of isolated non-nephrotic proteinuria in adults", section on 'Rule out orthostatic proteinuria'.)

Patients who have isolated proteinuria that is persistent (ie, not transient and not orthostatic) should undergo kidney ultrasound to evaluate for structural disorders (eg, reflux nephropathy) and measurement of serum free light chains and a serum protein electrophoresis with immunofixation to evaluate for a monoclonal gammopathy.

A kidney biopsy is seldom indicated for low levels of urinary protein (eg, less than 1 g per day). However, a biopsy may be helpful in patients with higher amounts of proteinuria. As an example, kidney biopsies in pediatric patients with proteinuria below the nephrotic range (ie, less than 3000 to 3500 mg per day) have shown membranous nephropathy, FSGS, infection-related glomerulonephritis, focal global sclerosis, mesangial proliferative glomerulonephritis, and normal kidneys [7]. Rarely, a biopsy in subnephrotic patients may show findings suggestive of systemic disease (eg, amyloidosis, Fabry disease), which, if found, could lead to specific therapy. (See "Assessment of urinary protein excretion and evaluation of isolated non-nephrotic proteinuria in adults" and "Evaluation of proteinuria in children".)

A kidney biopsy is usually indicated if a monoclonal gammopathy is present, if proteinuria is greater than 3000 to 3500 mg per day, or if the patient subsequently develops hematuria, azotemia, or a progressive increase in proteinuria. (See "Diagnosis and treatment of monoclonal gammopathy of renal significance", section on 'When to suspect MGRS' and "Assessment of urinary protein excretion and evaluation of isolated non-nephrotic proteinuria in adults", section on 'Persistent isolated proteinuria'.)

●Proteinuria that is not isolated – Patients who have proteinuria that is accompanied by hematuria or reduced kidney function should be evaluated by a nephrologist and possibly undergo kidney biopsy. A kidney biopsy is often deferred if the etiology of the proteinuria is obvious (eg, diabetic nephropathy) or if the kidney function is chronically reduced, the kidneys appear atrophic by kidney imaging, and a biopsy is not likely to impact management. In addition, if amyloidosis is suspected in a patient with monoclonal gammopathy, a subcutaneous fat pad biopsy may secure the diagnosis noninvasively. (See "Renal amyloidosis".)

Differential diagnosis of proteinuria without nephrotic syndrome — The differential diagnosis of proteinuria in the absence of nephrotic syndrome or glomerulonephritis is broad. Most commonly, such patients have secondary FSGS due, for example, to diabetes, to reduced nephron mass, or to a prior inflammatory or other form of injury that resulted in fibrosis. (See "Focal segmental glomerulosclerosis: Pathogenesis", section on 'Pathogenesis of secondary FSGS'.)

Less common causes of glomerular proteinuria without nephrotic syndrome include early or mild membranous nephropathy, a mild form of glomerulonephritis (which may occasionally present without hematuria), or deposition disorders such as Fabry disease or amyloidosis. (See "Membranous nephropathy: Pathogenesis and etiology" and "Fabry disease: Clinical features and diagnosis".)

In addition, patients with no structural glomerular lesions but who have cardiovascular disease (or who are at high risk for cardiovascular disease) may excrete abnormal amounts of albuminuria (usually less than 300 mg per day), which possibly results from endothelial dysfunction. (See "Moderately increased albuminuria (microalbuminuria) and cardiovascular disease", section on 'Possible mechanisms'.)

Glomerular hematuria — The hallmark of glomerular hematuria is the presence of dysmorphic RBCs (picture 3), with or without RBC casts. Glomerular hematuria may be associated with other manifestations, such as proteinuria, hypertension, a decreased glomerular filtration rate, or systemic features noted above (see 'Clinical manifestations of glomerular disease' above). By contrast, glomerular hematuria may occur in isolation without any of these other abnormalities.

Glomerulonephritis (hematuria with proteinuria, kidney function impairment, or other manifestations) — The nephritic syndrome (ie, glomerulonephritis) is caused by glomerular inflammation that results in hematuria, variable degrees of proteinuria (which can sometimes be in the nephrotic range), and leukocyturia in the absence of urinary tract infection. Such patients may also have hypertension, kidney function impairment, and, if the inflammation is not limited to the kidney, findings that suggest involvement of other organ systems (eg, pulmonary hemorrhage, palpable purpura, arthritis). Glomerular inflammation is typically due to one of three major mechanisms (figure 2). (See 'Clinical manifestations of glomerular disease' above and "Mechanisms of immune injury of the glomerulus".)

Glomerulonephritis can present in a variety of ways, including a smoldering course characterized by a chronic, slowly progressive rise in serum creatinine and proteinuria (eventually leading to advanced chronic kidney disease and end-stage kidney disease), an acute, self-limited course, and a fulminant course with acute, progressive deterioration of kidney function. This last pattern is referred to as "rapidly progressive glomerulonephritis" and is typically associated with extensive crescents on the kidney biopsy. (See "Overview of the classification and treatment of rapidly progressive (crescentic) glomerulonephritis".)

The evaluation and differential diagnosis of suspected glomerulonephritis are presented below (algorithm 1).

Evaluation of glomerulonephritis — All patients with glomerulonephritis should be evaluated by a nephrologist and many should undergo a kidney biopsy to obtain a definitive diagnosis. A kidney biopsy may be deferred in patients with advanced kidney function impairment who have small (likely fibrotic) kidneys by imaging since the diagnostic information gained is unlikely to have substantial benefit that outweighs the risks associated with kidney biopsy. Similarly, patients with normal kidney function, normal serological tests, and hematuria with low-grade proteinuria (<500 mg/day) may be observed without a biopsy since, even with a definitive diagnosis, it is unlikely that specific treatment will be instituted. (See "The kidney biopsy".)

In addition to a kidney biopsy, certain laboratory tests should be obtained in patients with suspected glomerulonephritis, including:

●Serum C3 and C4 complement levels

●Antineutrophil cytoplasmic autoantibodies (ANCA; using enzyme-linked immunosorbent assays [ELISAs] specific for proteinase-3 and myeloperoxidase)

●Anti-glomerular basement membrane (GBM) autoantibodies

●Antinuclear antibodies

●Anti-dsDNA antibodies

●Serology for hepatitis C virus, hepatitis B virus, and HIV

●Serum free light chains and serum immunofixation

In addition, some laboratory tests are indicated by the clinical context or biopsy findings. As examples:

●Serum cryoglobulins should be measured in patients with clinical features of cryoglobulinemic vasculitis or a known history of hepatitis C virus infection.

●A workup for underlying infection including blood cultures and relevant imaging should be obtained in patients with persistent fever or other signs of chronic infection, especially if the kidney biopsy is suggestive of infection-related glomerulonephritis.

Differential diagnosis of glomerulonephritis — Serum complement levels may be useful in differentiating the underlying etiology of glomerulonephritis; complement levels are typically normal in anti-GBM disease and pauci-immune glomerulonephritis but low in immune complex-mediated glomerulonephritis (with the exception of immunoglobulin A [IgA] nephropathy). However, in practice, a kidney biopsy is almost always required to secure the diagnosis.

In patients with an acute presentation of microangiopathic hemolytic anemia, thrombocytopenia, and kidney failure, the diagnosis of thrombotic microangiopathy (TMA) is a clinical one, and such patients typically do not need a kidney biopsy to secure the diagnosis. However, patients with subacute and chronic TMA may exhibit minimal or no hematological or systemic abnormalities but present with progressive kidney failure with or without proteinuria and hematuria (eg, in drug-induced TMA) [8,9]. Such patients do need to be biopsied to secure the diagnosis. (See "Diagnostic approach to suspected TTP, HUS, or other thrombotic microangiopathy (TMA)".)

Certain clinical findings suggest specific etiologies of glomerulonephritis:

●Gross hematuria may sometimes accompany glomerulonephritis and be associated with upper respiratory infection. The time elapsed between the respiratory infection and the appearance of hematuria may sometimes be helpful: If a latent period of 7 to 10 days occurs between the onset of infection and gross hematuria, poststreptococcal glomerulonephritis (especially in children) is the usual culprit. Gross hematuria occurring concurrently with the onset of infection (ie, "synpharyngitic glomerulonephritis") is typical of IgA nephropathy.

●The presence of palpable purpura or a petechial rash suggest an underlying small-vessel vasculitis (eg, ANCA-associated vasculitis, IgA vasculitis [Henoch-Schönlein purpura], or cryoglobulinemia). Rarely, lupus nephritis may be associated with vasculitis. (See "Overview of cutaneous small vessel vasculitis".)

●The presence of pulmonary hemorrhage ("pulmonary renal syndrome") also suggests an underlying vasculitis. (See "The diffuse alveolar hemorrhage syndromes".)

Isolated glomerular hematuria — Persistent glomerular hematuria is distinguished from transient hematuria by repeating the urinalysis over a period of weeks to months. Transient hematuria is a relatively common finding over time in adults and may be induced by factors such as exercise or infection. (See "Isolated and persistent glomerular hematuria in adults" and "Etiology and evaluation of hematuria in adults" and "Exercise-induced hematuria".)

Persistent glomerular hematuria is isolated if the patient is asymptomatic (ie, the systemic findings mentioned above are all absent) and has a normal urine albumin excretion rate, a normal glomerular filtration rate, normal blood pressure, and if the laboratory tests that are typically obtained to evaluate glomerulonephritis are all negative. (See 'Evaluation of glomerulonephritis' above.)

The evaluation and differential diagnosis of isolated, persistent glomerular hematuria are discussed below (algorithm 1).

Evaluation of isolated glomerular hematuria — In such patients, a careful workup for extrarenal etiologies should be undertaken, which may include imaging of the upper and lower urinary tract, cystoscopy, and evaluation for sickle cell disease or trait in appropriate patients (see "Etiology and evaluation of hematuria in adults" and "Diagnosis of sickle cell disorders"). A kidney biopsy is usually not performed in the absence of proteinuria and/or reduced kidney function, especially if there is a strong family history of hematuria or kidney disease. (See "Clinical manifestations, diagnosis, and treatment of Alport syndrome (hereditary nephritis)" and "Thin basement membrane nephropathy (benign familial hematuria)".)

Differential diagnosis of isolated glomerular hematuria — Generally, patients with isolated glomerular hematuria are likely to have mild IgA nephropathy, a disorder associated with membranoproliferative glomerulonephritis, a genetic mutation in type IV collagen associated with Alport syndrome, or thin basement membrane nephropathy. (See "Isolated and persistent glomerular hematuria in adults" and "IgA nephropathy: Clinical features and diagnosis" and "Genetics, pathogenesis, and pathology of Alport syndrome (hereditary nephritis)" and "Clinical manifestations, diagnosis, and treatment of Alport syndrome (hereditary nephritis)" and "Thin basement membrane nephropathy (benign familial hematuria)".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Glomerular disease in adults".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Beyond the Basics topics (see "Patient education: Glomerular disease (Beyond the Basics)" and "Patient education: The nephrotic syndrome (Beyond the Basics)")

SUMMARY

●Overview – Glomerular disease can result from many inherited or acquired disorders and can manifest in a variety of ways, ranging in severity from asymptomatic urinary abnormalities to acute kidney injury (AKI) or end-stage kidney disease. Occasionally, more than one glomerular disease is present in the same individual. (See 'Introduction' above.)

●Clinical manifestations – Clinical manifestations associated with glomerular disease include the following (see 'Clinical manifestations of glomerular disease' above):

•Hematuria and/or proteinuria – Glomerular disease should be suspected when hematuria and/or proteinuria are seen on urinalysis. Glomerular hematuria is established by the presence of urinary erythrocyte casts (of any number) or hematuria in which a substantial proportion of erythrocytes are acanthocytes (picture 3).

•Kidney function impairment – Kidney function impairment (acute or chronic) is commonly seen in patients with glomerular disease. AKI may occur with acute glomerulonephritis, especially in patients who have crescentic glomerulonephritis, or, rarely, in patients with acute onset of nephrotic syndrome. Patients with chronic glomerular diseases may develop a progressive decline in glomerular filtration rate and chronic kidney disease.

•Other manifestations – Hypertension, edema, hypercoagulability, and systemic findings.

●Evaluation and differential diagnosis – Glomerular disease syndromes are typically classified based upon the pattern of urinary abnormalities, the existence of systemic features, and the degree of kidney insufficiency (algorithm 1). (See 'Evaluation and differential diagnosis of major glomerular presentations' above.)

•Proteinuria – Proteinuria may be caused by glomerular disease (in which there is albuminuria) or other disorders (table 1). Proteinuria due to glomerular disease (in which there is albuminuria) is identified on a urine dipstick or with a quantitative measurement of urine albumin excretion. The evaluation and differential diagnosis of patients with glomerular proteinuria depend, in part, upon whether the patient has nephrotic syndrome (ie, proteinuria greater than 3500 mg per 24 hours and hypoalbuminemia):

-Adults with nephrotic syndrome should be evaluated by a nephrologist and most should undergo a kidney biopsy to obtain a definitive diagnosis (table 2 and table 3). (See 'Nephrotic syndrome (heavy proteinuria and hypoalbuminemia)' above.)

-The evaluation of proteinuria in patients without nephrotic syndrome depends upon whether or not features of glomerulonephritis are present (eg, systemic disease, hypertension, hematuria, or kidney function impairment). The differential diagnosis of proteinuria in the absence of nephrotic syndrome or glomerulonephritis is broad. Most commonly, such patients have secondary focal segmental glomerulosclerosis (FSGS) due, for example, to diabetes, to reduced nephron mass, or to a prior inflammatory or other form of injury that resulted in fibrosis. (See 'Proteinuria without nephrotic syndrome' above.)

•Glomerular hematuria – Glomerular hematuria may be associated with other manifestations, such as proteinuria, hypertension, a decreased glomerular filtration rate, or systemic features (glomerulonephritis). By contrast, glomerular hematuria may occur in isolation without any of these other abnormalities (isolated glomerular hematuria).

-All patients with glomerulonephritis should be evaluated by a nephrologist and many should undergo a kidney biopsy to obtain a definitive diagnosis (figure 2). (See 'Glomerulonephritis (hematuria with proteinuria, kidney function impairment, or other manifestations)' above.)

-A kidney biopsy is usually not performed in patients with isolated glomerular hematuria. Generally, patients with isolated glomerular hematuria are likely to have mild immunoglobulin A (IgA) nephropathy, a disorder associated with membranoproliferative glomerulonephritis, a genetic mutation in type IV collagen associated with Alport syndrome, or thin basement membrane nephropathy. (See 'Isolated glomerular hematuria' above.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Lee A Hebert, MD, and Samir V Parikh, MD, who contributed to earlier versions of this topic review.