on 22-Feb-2021 (Mon)

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

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

Lastly, interstitial fibrosis, which accompanies uncontrolled glomerular disease, is a poor prognostic sign [3]

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)

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)

However, renal 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.

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

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

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

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.

● 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

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

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 immunofixation

● Tests for hepatitis B and C viruses and HIV (see "Hepatitis B virus: Screening and diagnosis", 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

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 nephropathy is the most common cause of nephrotic syndrome.

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 persons.

Some disorders (eg, C3 glomerulonephritis or other causes of a membranoproliferative pattern of injury) can present as nephrotic syndrome, glomerulonephritis, or both

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 renal insufficiency, hypertension, and hematuria. Glomerular proteinuria is said to be isolated when it occurs in the absence of systemic disease, hypertension, hematuria, or azotemia

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

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.

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 urine protein electrophoresis with immunofixation to evaluate for a monoclonal gammopathy

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.

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.

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.

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, renal insufficiency, and, if the inflammation is not limited to the kidney, findings that suggest involvement of other organ systems (eg, pulmonary hemorrhage, palpable purpura, arthritis)

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.

A kidney biopsy may be deferred in patients with advanced renal insufficiency 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.

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:

● A cryocrit should be measured in patients with clinical features of cryoglobulinemia or a known history of hepatitis C virus infection.

● Blood cultures should be obtained in patients with persistent fever or other signs of chronic infection

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, 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.

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. 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 vasculitis (eg, ANCA-associated vasculitis, IgA vasculitis [Henoch-Schönlein purpura], or cryoglobulinemia). Rarely, lupus nephritis may be associated with vasculitis.

The presence of pulmonary hemorrhage ("pulmonary renal syndrome") also suggests an underlying vasculitis.

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.

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.