Acute glomerulonephritis and rapidly progressive glomerulonephritis

1. What is the syndrome of acute glomerulonephritis?

Acute glomerulonephritis is an acute kidney injury (AKI) syndrome characterized by the sudden onset of edema and new-onset or worsening hypertension. Urinalysis demonstrates an active sediment, including abnormal proteinuria (usually >30 mg/dL or 1+ on a semiquantitative scale), hematuria, and red cell casts. Patients with acute glomerulonephritis are often azotemic (i.e., they have elevated serum blood urea nitrogen and creatinine concentrations) and occasionally develop severe kidney injury requiring dialysis. Acute glomerulonephritis can be a primary kidney disease, which is usually classified on the basis of kidney histopathology, or can result from a number of systemic diseases. Although this chapter focuses on primary acute glomerulonephritis, the diagnostic and therapeutic approaches for kidney-limited glomerulonephritis and glomerulonephritides associated with systemic diseases are similar. The reader is referred to the sections on primary (Part IV) and secondary (Part V) glomerular disorders for additional information.

2. What are the major causes of acute glomerulonephritis? What approaches should be used to develop an appropriate differential diagnosis?

The patient’s history and a physical examination can provide clues to the diagnosis of acute glomerulonephritis. Looking for skin lesions and disease in other organ systems can help determine if the cause of the acute glomerulonephritis syndrome is a result of kidney-limited or systemic disease. A focused laboratory examination, including serologic studies, directed by the findings in the patient’s history and physical examination, can also be useful in establishing a diagnosis. Hematuria with dysmorphic red cell morphology and red cell casts are usually detected on urinalysis. Moderate proteinuria, usually in the non-nephrotic range, is typical. Nephrotic-range proteinuria occurs in <30% of patients. Mild to severe azotemia is universally present.

Table 14.1 presents major causes of acute glomerulonephritis stratified by their association with serum complement levels (low vs. normal or high). Complement levels can help a clinician focus on a differential diagnosis on the most likely causes of the acute glomerulonephritis syndrome. Measuring serum complement levels (C3, C4) and/or activity (CH50) is a somewhat arbitrary choice of initial tests, but they provide a practical approach to further testing and management of the patient with presumptive glomerulonephritis. A kidney biopsy is almost always indicated to establish a definitive diagnosis and direct treatment. The extent of acute inflammation and fibrosis present in the biopsy can provide important data on prognosis and can be used to project responsiveness to therapy. In order to optimize patient care, a standardized kidney biopsy classification system based on current concepts of glomerulonephritis etiology/pathogenesis has been proposed.

3. What are dysmorphic red cells?

Phase-contrast morphology can be used to characterize urinary erythrocyte morphology. Glomerular bleeding, a characteristic of glomerulonephritis, causes red cells in the urine to have a non-uniform morphology with irregular outlines and small blebs projecting from their surfaces (i.e., the red cells are “dysmorphic”). Red cells in the urine from non-glomerular bleeding in the urinary tract are uniform in shape and similar in appearance to red cells in the circulation. Urine can be analyzed by the clinical laboratory for the presence of dysmorphic red cells. The sensitivity, specificity, and predicative values for this test are limited, and results need to be interpreted in the context of other clinical and diagnostic data. Clinical labs most often quantify numbers of dysmorphic red cells as a percentage of total red cells, and define the upper limit of normal to aid in the interpretation of the test.

4. Describe glomerulonephritis in the setting of infection.

Glomerulonephritis associated with infection is varied. Post-infectious glomerulonephritis occurs after an infection and latent period in which the patient returns to her or his baseline health. Beta-hemolytic Streptococcus is almost exclusively the etiology of post-infectious glomerulonephritis. In contrast, infection-associated glomerulonephritis occurs concurrently with the infection. While an active staphylococcal infection is a classically recognized cause of infection-associated glomerulonephritis, it can be caused by many different viruses, bacteria, and fungi. Complement levels, especially C3, are often—but not always—depressed in infection-associated glomerulonephritis. Recognizing the distinction between these clinical presentations is necessary for appropriate clinical management. The management of post-streptococcal glomerulonephritis is supportive, primarily managing hypertension and volume overload. For infection-associated glomerulonephritis, the primary goal is to treat the infection.

5. Define the syndrome of rapidly progressive glomerulonephritis (RPGN).

Patients with RPGN have evidence of glomerular disease (proteinuria, hematuria, and red cell casts) accompanied by rapid loss of kidney function over days to weeks. If untreated, RPGN often results in kidney failure. The pathologic hallmark of RPGN is the presence of crescents on kidney biopsy, and RPGN is also described as crescentic nephritis (see later for further discussion). Fortunately, the disorders associated with this syndrome are rare, so that RPGN makes up only 2% to 4% of all cases of glomerulonephritis. Importantly, RPGN is not a specific diagnosis, and multiple different diseases can cause this syndrome. Diagnosis almost always requires a biopsy of the affected tissue if the presentation suggests systemic involvement, or of the kidney if it is kidney-limited.

6. What are crescents in kidney biopsies?

Crescent formation is a nonspecific response to severe injury of the glomerular capillary wall. As a result, fibrin leaks into Bowman’s space, causing parietal epithelial cells to proliferate and mononuclear phagocytes to migrate into the glomerular tuft from the circulation. Large crescents can compress glomerular capillaries and impair filtration. Although crescent formation can resolve, some inflammatory chemotactic signals recruit fibroblasts into Bowman’s space, which ultimately can cause both the crescents and glomeruli to scar. Extensive scarring results in end-stage kidney disease (ESKD). Similar to RPGN, crescentic nephritis is not a specific pathologic diagnosis. Crescents can be seen with a number of specific glomerular diseases (see question 9).

7. Do crescentic nephritis and RPGN describe the same syndrome?

Although the terms crescentic nephritis and RPGN are used interchangeably, these diagnoses are not synonymous. RPGN describes a clinical syndrome of rapid loss of kidney function over days to weeks in patients with evidence of glomerulonephritis. In contrast, crescentic nephritis is a histopathologic description of kidney biopsy specimens, which demonstrate the presence of crescents in more than 50% of glomeruli. Biopsies of patients with RPGN very commonly reveal crescentic nephritis. However, RPGN can occur in the absence of crescentic nephritis, and extensive glomerular crescent formation is rarely identified in kidney biopsy specimens from patients without the clinical syndrome of RPGN.