Glomerulonephritis (GN) is a condition characterized by acute inflammation of glomeruli. This category can be divided into infectious and non-infectious etiologies. Glomerulonephritis results in acute kidney injury and a urinalysis demonstrating hematuria, dysmorphic red blood cells, red blood cell casts and proteinuria.
Infectious causes of GN are characterized by white blood cells and white blood cell casts in addition to the other findings mentioned above. Non-infectious causes encompass a broad range of diseases and will be discussed below.
II. Diagnostic Approach
A. What is the differential diagnosis for this problem?
The differential diagnosis of GN can be organized into three categories using serologic testing: anti-GBM antibodies, immune complex, and pauci-immune (or ANCA-associated).
Anti-GBM glomerulonephritis can either affect the kidneys alone or the renal and pulmonary system. The immune complex glomerulonephritides are a collection of diseases which are manifested by antigen-antibody complexes. These complexes can be seen in lupus, endocarditis, membranoproliferative GN, post-infectious, IgA and cryoglobulinemia.
Pauci-immune reflects the minimal or complete lack of glomerular immune complex deposition. Pauci-immune GN are small and medium sized vessel vasculitides which are associated with the anti-neutrophil cytoplasmic antibody (ANCA) and include granulomatosis with polyangiitis and microscopic polyangiitis (MPA).
B. Describe a diagnostic approach/method to the patient with this problem
Patients may present with clinical symptoms and signs of GN such as hematuria, edema and hypertension (either worsening of baseline hypertension or new onset hypertension). This should prompt evaluation of kidney function with a basic metabolic panel and a urinalysis with both dip and microscopy testing.
There are occasions when testing for kidney function or obtaining a urinalysis may be related to other medical conditions which may have a direct correlation to potential glomerulonephritides such as hepatitis B or C, lupus, granulomatosis with polyangiitis, endocarditis, etc. Evaluation for any of these conditions may then lead to testing for both renal function and for checking a urinalysis.
1. Historical information important in the diagnosis of this problem.
Historical questions for acute GN are best determined by serologic testing once it has been established the patient has acute kidney injury and a urinalysis consistent with nephritis (red blood cells, red blood cell casts, proteinuria, white blood cells, white blood cell casts).
2. Physical Examination maneuvers that are likely to be useful in diagnosing the cause of this problem.
There are no specific findings of GN except for hypertension and edema. However, specific findings would correlate to the serologic evidence of any of the associated diseases such as granulomatosis with polyangiitis, hepatitis B or C, lupus, streptococcal infection, endocarditis, etc.
For example, in lupus, assessing for 4 of the 11 diagnostic criteria, which would support the diagnosis of lupus could be sought (facial rash, oral ulcers, photosensitivity, serositis, etc.). Similarly, if there is consideration of cryoglobulinemia, assess for Raynaud’s, palpable purpura, or peripheral neuropathy.
3. Laboratory, radiographic and other tests that are likely to be useful in diagnosing the cause of this problem.
Initial testing to confirm acute GN would include basic metabolic panel, urinalysis with microscopy and spot protein to creatinine ratio (to determine degree of proteinuria). Once the diagnosis of acute GN is established, then further testing for specific disease entities would begin.
Checking complement levels can be a quick place to start as the differential for low complements is a specific list of diagnoses which can then allow further testing for lupus (ANA and if positive double-stranded DNA), cryoglobulinemia (rheumatoid factor, cryoglobulin), endocarditis (blood cultures, echo if appropriate), and post infectious GN (ASO titers for pharyngitis Streptococcus and anti-DNAse B antibodies for Streptococcus soft tissue infections).
If the complement level is normal, then test for pauci-immune causes such as granulomatosis with polyangiitis (c-ANCA), microscopic polyangiitis (p-ANCA) or anti-GBM related diseases, Goodpasture’s syndrome or disease (anti-GBM antibodies). IgA nephropathy is the most common glomerulonephritis often with normal complement levels.
C. Criteria for Diagnosing Each Diagnosis in the Method Above.
Low complements (C3 and C4); consider this diagnosis in young women, African-Americans and Hispanic persons. Use the American College of Rheumatology criteria for diagnosing lupus; however recognize that achieving 4 of the 11 criteria to consider a diagnosis of lupus applies to clinical research.
The criteria for lupus include: malar rash, discoid rash, photosensitivity, oral ulcers, arthritis, serositis, renal disorder (cellular casts or proteinuria), neurologic disorders (seizures, psychosis), hematologic disorders (hemolytic anemia, leukopenia, lymphopenia, thrombocytopenia), immunologic disorders (anti-double stranded DNA, Anti-Sm antibody or false positive testing for syphilis) or abnormal titer of antinuclear antibody (ANA).
Though not a specific disease in itself, membranoproliferative GN is a histopathologic finding on renal biopsy which should prompt a search for possible secondary causes of which hepatitis C, mixed cryoglobulinemia, hepatitis B, lupus and shunt-associated endocarditis are the most common.
Each of these diseases should be considered when complement levels are low.
Consider this disease in persons in their fifth and sixth decades of life with either no symptoms or extra-renal symptoms of purpura, arthralgias, leg ulcers, systemic vasculitis, Raynaud’s, or peripheral neuropathy. Most cryoglobulinemias are associated with hepatitis C.
Given the complexity of cryoglobulinemias, consider this diagnosis in patients with hepatitis C, monoclonal gammopathies, or lupus. In order to detect cryoglobulins, blood must be drawn in tubes that have been pre-warmed to 37 degrees C and contain no anticoagulants. After centrifugation, the tube is refrigerated to allow for cryoglobulin precipitation.
This diagnosis should be considered when there is renal involvement and low complements. There are a number of conditions associated with endocarditis that may cause renal disease including acute interstial nephritis, shunt-associated nephritis or a post-infectious GN (see below).
Blood cultures from two different sites prior to antibiotic use is crucial for the diagnosis. Echocardiography should be considered in patients with new and/or pathologic holosystolic murmurs or persistent bacteremia. Duke’s criteria should also be utilized to make a diagnosis of endocarditis.
Post-infectious GN should be suspected in a patient who reports an antecedal bacterial infection and presents with signs and symptoms of GN. Presentation of GN with hematuria usually occurs 1 to 3 weeks following a bacterial infection (in contrast to IgA nephropathy in which hematuria immediately follows the infection, “synpharyngitic”).
Streptococcal infections are most commonly associated with post-infectious GN; however, many other infectious agents have also been identified including Staphylococcus and Pneumococcus. Complements are low at presentation but will usually recover within weeks. Post-infectious GN will resolve within weeks.
Granulomatosis with polyangiitis (GPA) should be considered in pauci-immune GN or ANCA-associated GN. GPA is rare in African Americans and affects men and women equally. Consider GPA when c-ANCA and specifically PR3-ANCA is positive; however, a renally-limited vasculitis can be present in which MPO-ANCA is positive.
In the setting of a pauci-immune GN, history should be directed toward upper respiratory symptoms of sinusitis, bloody nasal discharge, dyspnea, hemoptysis, cough, hoarseness (secondary to subglottic stenosis) and skin findings of nodules, ulcers, or purpura.
Pulmonary findings can be asymptomatic; thus, chest x-ray or CT scan is a necessity if GPA is being considered and will reveal nodules with or without cavitation. Biopsy of either nasal or pulmonary findings should reveal granulomatous lesions consistent with GPA. Renal biopsies will reveal crescentic GN.
Microscopic polyangiitis (MPA)
This disorder should be considered in the same differential with GPA. MPA is usually associated with MPO-ANCA (p-ANCA) and does not have granulomas on biopsy.
Goodpasture's disease (Anti-GBM antibody disease)
Consider this disease when the patient presents with urinalysis findings of GN and pulmonary hemorrhage. Goodpasture’s is a relatively rare condition and is considered when testing for anti-GBM antibody is positive. Anti-GBM GN is the most aggressive form of GN with a large number of crescents seen on biopsy.
Untreated, anti-GBM antibody disease can have a very poor prognosis; thus, identification and treatment is crucial. Consider this disease in patients who are either smokers or have hydrocarbon exposure.
This disease often presents asymptomatically or with episodic gross hematuria and the hematuria may occur in isolation or with proteinuria. Renal biopsy will demonstrate IgA deposits in the renal mesangium. Trials have shown an angiotensin-converting enzyme inhibitor (ACE-I) or angiotensin II receptor blocker (ARB) can slow the progression of proteinuria and control hypertension. Corticosteroid therapy is equivocal based on several studies and other immunosuppressives have not been shown to be effective.
D. Over-utilized or “wasted” diagnostic tests associated with the evaluation of this problem.
Testing for GN is often extensive as described above and there is no particular test that is either wasted or over-utilized. Starting with complement levels can be a judicious beginning to the work-up of GN.
III. Management while the Diagnostic Process is Proceeding
A. Management of glomerulonephritis
If GN is suspected, the work-up as suggested above should begin immediately. Nephrology consult is imperative as biopsy will likely be key to not only the diagnosis but treatment options and success. Each disease has its own specific treatment and should be directed by nephrologists:
Lupus: Induction therapy with cyclophosphamide and glucocorticoids is essential. Plasmapheresis has no added benefit. Maintenance therapy should include azathioprine or mycophenolate. Rituximab has been shown to be effective but a large trial (RITUXILUP) is underway to compare its performance with other conventional treatments.
Cryoglobulinemia: Plasmapheresis, cyclophosphamide, and glucocorticoids are the mainstay of treatment. If hepatitis C is found, consider treatment of the hepatitis C.
Post-infectious glomerulonephritis: Because this disease is self-limited, no specific therapy other than supportive therapy is recommended.
GPA and MPA: Cyclophosphamide and glucocorticoids are the initial mainstay of treatment. If pulmonary hemorrhage is present, plasma exchange should also be considered. Once the disease is under control, patients are placed on maintenance therapy with either azathioprine or methotrexate.
Anti-GBM antibody disease: Treatment is plasmapheresis, cyclophosphamide and glucocorticoids.
B. Common Pitfalls and Side-Effects of Management of glomerulonephritis
The most important management of treatment is to ensure proper prophylaxis for pneumocystis. Otherwise, management of the side effects of this problem are specific to each disease as noted above.
What's the evidence?
Jennette, JC. “Rapidly Progressive Crescentic Glomerulonephritis”. Kidney International. vol. 63. 2003. pp. 1164-1177.
Seo, P, Stone, JH. “The Anti-Neutrophilic Cytoplasmic Antibody Associated Vasculitides”. American Journal of Med. vol. 39. 2004. pp. 117
Rodriguez-Iturbe, B, Musser, JM. “The Current State of Post Streptococcal Glomerulonephritis”. J Am Society of Nephrology. vol. 19. 2008. pp. 1855-64.
Mok, CC. “Towards new avenues in the management of lupus glomerulonephritis”. Nature Reviews: Rheumatology. vol. 12. 2016. pp. 221-34.
Floege, J, Amann, K. “Primary glomerulonephritides”. Lancet. vol. 387. 2016. pp. 2036-48.
Kambham, N. “Crescentic glomerulonephritis: An update on pauci-immune and anti-GBM diseases”. Adv Anat Pathol. vol. 19. 2012. pp. 111-24.
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- I. Problem/Condition.
- II. Diagnostic Approach
- A. What is the differential diagnosis for this problem?
- B. Describe a diagnostic approach/method to the patient with this problem
- 1. Historical information important in the diagnosis of this problem.
- 2. Physical Examination maneuvers that are likely to be useful in diagnosing the cause of this problem.
- 3. Laboratory, radiographic and other tests that are likely to be useful in diagnosing the cause of this problem.
- C. Criteria for Diagnosing Each Diagnosis in the Method Above.
- D. Over-utilized or “wasted” diagnostic tests associated with the evaluation of this problem.
- III. Management while the Diagnostic Process is Proceeding
- A. Management of glomerulonephritis
- B. Common Pitfalls and Side-Effects of Management of glomerulonephritis