Membranous glomerulonephritis other diagnostic studies: Difference between revisions
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==Overview== | ==Overview== | ||
==Other Diagnostic Studies== | |||
In patients with a positive serum anti-PLA2R antibody test, the approach depends upon whether the patient has functional kidney impairment and/or evidence of secondary disease (ie, positive testing for ANA and anti-dsDNA, hepatitis B or C, or HIV; low serum complement levels; abnormal SFLCs or SPEP; or radiographic findings consistent with sarcoidosis): | |||
•If the patient has normal kidney function and no evidence of secondary disease or other atypical features, a diagnosis of primary PLA2R-associated MN can be established without the need to perform a kidney biopsy. | |||
•If the patient has abnormal kidney function (ie, serum creatinine above the upper limit of the normal range adjusted for gender and age) or evidence of secondary disease or other atypical features, we perform a kidney biopsy, unless contraindicated (see "Indications for and complications of renal biopsy", section on 'Relative contraindications'). Although such patients most likely have a diagnosis of primary PLA2R-associated MN based upon serologic testing, a biopsy is obtained to exclude secondary causes of MN and superimposed disease (eg, crescentic glomerulonephritis) and to evaluate the chronicity of kidney damage (such as the extent of glomerulosclerosis, tubular atrophy, and interstitial fibrosis). The evaluation of the kidney biopsy and subsequent approach is the same as that discussed below for patients with a negative serum anti-PLA2R antibody test. | |||
●In patients with a negative serum anti-PLA2R antibody test, we perform a kidney biopsy, unless contraindicated, to determine the cause of proteinuria and/or nephrotic syndrome. If a kidney biopsy cannot be performed (due to patient preference, lack of availability, or contraindication to biopsy), we repeat serum anti-PLA2R antibody testing in three to four months, since some patients with an initially negative serum antibody test may have delayed seroconversion. If repeat serum anti-PLA2R testing is negative, a kidney biopsy should be performed, if possible. (See 'Phospholipase A2 receptor' above and 'When to monitor anti-PLA2R titers' below.) | |||
In addition to routine light microscopy, immunofluorescence, and electron microscopy, staining for PLA2R should be performed in patients with the characteristic histologic lesions of MN | |||
•Nearly all patients with positive staining for PLA2R have a diagnosis consistent with primary PLA2R-associated MN. The rare exception is in patients with positive PLA2R staining and restriction to a single light chain subtype (kappa or lambda) by immunofluorescence; such patients do not have a diagnosis of primary PLA2R-associated MN but rather a diagnosis of MN associated with monoclonal antibodies toward PLA2R. (See 'MN associated with monoclonal antibodies to PLA2R'above and "Diagnosis and treatment of monoclonal gammopathy of renal significance".) | |||
•Patients with negative staining for PLA2R may have either primary or secondary MN, and further diagnostic testing may be required. In such patients, if there is no clinical or histologic evidence of secondary disease, staining for the immunoglobulin subclasses should be performed. Although determination of the relative amounts of immunoglobulin G (IgG) subclasses is only semiquantitative and may vary from patient to patient and with chronicity of disease, it may be helpful in the following manner: | |||
-Patients with a predominance of IgG1, IgG2, or IgG3 have a diagnosis that is most likely consistent with secondary MN. If a cause for secondary MN has not yet been identified by serologic testing, such patients, in our opinion, should undergo more frequent age- and risk-appropriate screening for cancer. (See 'Screening for malignancy' below.) | |||
However, while predominant staining for IgG1 and/or IgG3 in the absence of PLA2R staining is suggestive of a secondary form of MN, this is not always the case. In one series, IgG1 dominant or codominant staining was found in 59.3 percent of cases with early-stage primary MN, with concurrent absence of PLA2R staining in most of the cases [133]. Since it is unlikely that such a high proportion of new cases of MN would have a secondary cause, the presence of predominant IgG1 or IgG3 staining does not entirely preclude a diagnosis of primary MN, including PLA2R-associated MN. | |||
-Patients with negative staining for PLA2R and predominance of IgG4 have a diagnosis consistent with primary MN. Serologic testing for anti-thrombospondin type-1 domain-containing 7A (THSD7A) antibodies and biopsy staining for THSD7A should be performed, if available [131]. Patients with either a positive anti-THSD7A antibody test or positive staining for THSD7A have a diagnosis consistent with primary THSD7A-associated MN. Such patients, in our opinion, should undergo more frequent age- and risk-appropriate screening for cancer, given the association between THSD7A-associated MN and malignancy (see 'Screening for malignancy' below and 'Thrombospondin type-1 domain-containing 7A' above and 'Malignancy' above). Patients with negative testing for anti-THSD7A antibody and negative staining for THSD7A antigen have a diagnosis of primary non-PLA2R-, non-THSD7A-associated MN. | |||
-Patients with negative staining of PLA2R and negative staining for IgG and its subclasses may have a diagnosis of "masked" MN. This diagnosis should be suspected when there is evidence of subepithelial deposits on electron microscopy resembling those in MN. In such patients, antigen retrieval methods (eg, pronase digestion) should be performed to determine if masked IgG deposits are present. (See 'Membranous-like nephropathy with masked IgG-kappa' above.) | |||
Utility of anti-PLA2R testing — As mentioned above, we suggest that all patients with suspected MN be tested for anti-phospholipase A2 receptor (PLA2R) autoantibodies. In 2014, the US Food and Drug Administration (FDA) approved two commercially available tests for anti-PLA2R autoantibodies, including an indirect immunofluorescence assay and an ELISA. The utility of testing for anti-PLA2R is summarized as follows (see 'Phospholipase A2 receptor' above): | |||
●Approximately 70 to 80 percent of patients presumed to have primary MN have a positive test for anti-PLA2R antibody at the time of renal-biopsy diagnosis of MN. By contrast, some patients with primary MN will have a negative anti-PLA2R antibody test. In addition, a small percentage of patients presumed to have MN secondary to hepatitis viruses or malignancy will have a positive test for anti-PLA2R antibody (some of these patients may in fact have primary MN with superimposed but unrelated hepatitis virus infection or cancer) [27,134,135]. Thus, a positive test, although highly suggestive of primary MN, does not exclude the coexistence of hepatitis virus infection, malignancy, or another associated rheumatologic or inflammatory disease. | |||
●Nephrotic patients without MN seldom (and perhaps never) have a positive test for the anti-PLA2R antibody. Thus, a positive test essentially rules out other causes of nephrotic syndrome (such as minimal change disease or focal segmental glomerulosclerosis) [29,136]. | |||
●Among patients with primary MN, testing for anti-PLA2R antibodies may provide additional information regarding treatment response. In one study involving 514 patients with primary MN and positive staining for PLA2R on kidney biopsy, patients with anti-PLA2R antibodies at the time of biopsy had a lower rate of complete remission (proteinuria of <0.4 g/day) at 24 months compared with those without anti-PLA2R antibodies (36 versus 61 percent) [137]. In addition, some data suggest that a falling anti-PLA2R titer indicates that an immunological remission is underway, whereas a persistently high titer is associated with a less favorable clinical course [29,30,137]. | |||
When to monitor anti-PLA2R titers — Serial assessment of anti-phospholipase A2 receptor (PLA2R) antibody titers may be useful for both diagnosis and for monitoring the immunological activity of disease when treatment decisions are being considered (see "Treatment of idiopathic membranous nephropathy"). As mentioned above, there are several reported cases of patients who were initially negative for anti-PLA2R and subsequently tested positive several months later as their disease progressed [35,37] (see 'Phospholipase A2 receptor' above). Thus, in an otherwise-stable patient who has an initially negative serum anti-PLA2R antibody test but wishes to avoid kidney biopsy, we would repeat testing three to four months later as part of an ongoing diagnostic evaluation of their kidney disease. | |||
The trajectory of the immunologic disease course in MN may also be determined by monitoring serial anti-PLA2R titers, several months apart. A declining titer in the absence of immunosuppressive treatment may suggest that the patient is undergoing a spontaneous remission, while increasing or persistently high titers of anti-PLA2R suggest worsening disease that is likely to require immunosuppressive treatment. | |||
==References== | ==References== | ||
Revision as of 13:03, 20 May 2018
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief:
Overview
Other Diagnostic Studies
In patients with a positive serum anti-PLA2R antibody test, the approach depends upon whether the patient has functional kidney impairment and/or evidence of secondary disease (ie, positive testing for ANA and anti-dsDNA, hepatitis B or C, or HIV; low serum complement levels; abnormal SFLCs or SPEP; or radiographic findings consistent with sarcoidosis):
•If the patient has normal kidney function and no evidence of secondary disease or other atypical features, a diagnosis of primary PLA2R-associated MN can be established without the need to perform a kidney biopsy.
•If the patient has abnormal kidney function (ie, serum creatinine above the upper limit of the normal range adjusted for gender and age) or evidence of secondary disease or other atypical features, we perform a kidney biopsy, unless contraindicated (see "Indications for and complications of renal biopsy", section on 'Relative contraindications'). Although such patients most likely have a diagnosis of primary PLA2R-associated MN based upon serologic testing, a biopsy is obtained to exclude secondary causes of MN and superimposed disease (eg, crescentic glomerulonephritis) and to evaluate the chronicity of kidney damage (such as the extent of glomerulosclerosis, tubular atrophy, and interstitial fibrosis). The evaluation of the kidney biopsy and subsequent approach is the same as that discussed below for patients with a negative serum anti-PLA2R antibody test.
●In patients with a negative serum anti-PLA2R antibody test, we perform a kidney biopsy, unless contraindicated, to determine the cause of proteinuria and/or nephrotic syndrome. If a kidney biopsy cannot be performed (due to patient preference, lack of availability, or contraindication to biopsy), we repeat serum anti-PLA2R antibody testing in three to four months, since some patients with an initially negative serum antibody test may have delayed seroconversion. If repeat serum anti-PLA2R testing is negative, a kidney biopsy should be performed, if possible. (See 'Phospholipase A2 receptor' above and 'When to monitor anti-PLA2R titers' below.)
In addition to routine light microscopy, immunofluorescence, and electron microscopy, staining for PLA2R should be performed in patients with the characteristic histologic lesions of MN
•Nearly all patients with positive staining for PLA2R have a diagnosis consistent with primary PLA2R-associated MN. The rare exception is in patients with positive PLA2R staining and restriction to a single light chain subtype (kappa or lambda) by immunofluorescence; such patients do not have a diagnosis of primary PLA2R-associated MN but rather a diagnosis of MN associated with monoclonal antibodies toward PLA2R. (See 'MN associated with monoclonal antibodies to PLA2R'above and "Diagnosis and treatment of monoclonal gammopathy of renal significance".)
•Patients with negative staining for PLA2R may have either primary or secondary MN, and further diagnostic testing may be required. In such patients, if there is no clinical or histologic evidence of secondary disease, staining for the immunoglobulin subclasses should be performed. Although determination of the relative amounts of immunoglobulin G (IgG) subclasses is only semiquantitative and may vary from patient to patient and with chronicity of disease, it may be helpful in the following manner:
-Patients with a predominance of IgG1, IgG2, or IgG3 have a diagnosis that is most likely consistent with secondary MN. If a cause for secondary MN has not yet been identified by serologic testing, such patients, in our opinion, should undergo more frequent age- and risk-appropriate screening for cancer. (See 'Screening for malignancy' below.)
However, while predominant staining for IgG1 and/or IgG3 in the absence of PLA2R staining is suggestive of a secondary form of MN, this is not always the case. In one series, IgG1 dominant or codominant staining was found in 59.3 percent of cases with early-stage primary MN, with concurrent absence of PLA2R staining in most of the cases [133]. Since it is unlikely that such a high proportion of new cases of MN would have a secondary cause, the presence of predominant IgG1 or IgG3 staining does not entirely preclude a diagnosis of primary MN, including PLA2R-associated MN.
-Patients with negative staining for PLA2R and predominance of IgG4 have a diagnosis consistent with primary MN. Serologic testing for anti-thrombospondin type-1 domain-containing 7A (THSD7A) antibodies and biopsy staining for THSD7A should be performed, if available [131]. Patients with either a positive anti-THSD7A antibody test or positive staining for THSD7A have a diagnosis consistent with primary THSD7A-associated MN. Such patients, in our opinion, should undergo more frequent age- and risk-appropriate screening for cancer, given the association between THSD7A-associated MN and malignancy (see 'Screening for malignancy' below and 'Thrombospondin type-1 domain-containing 7A' above and 'Malignancy' above). Patients with negative testing for anti-THSD7A antibody and negative staining for THSD7A antigen have a diagnosis of primary non-PLA2R-, non-THSD7A-associated MN.
-Patients with negative staining of PLA2R and negative staining for IgG and its subclasses may have a diagnosis of "masked" MN. This diagnosis should be suspected when there is evidence of subepithelial deposits on electron microscopy resembling those in MN. In such patients, antigen retrieval methods (eg, pronase digestion) should be performed to determine if masked IgG deposits are present. (See 'Membranous-like nephropathy with masked IgG-kappa' above.)
Utility of anti-PLA2R testing — As mentioned above, we suggest that all patients with suspected MN be tested for anti-phospholipase A2 receptor (PLA2R) autoantibodies. In 2014, the US Food and Drug Administration (FDA) approved two commercially available tests for anti-PLA2R autoantibodies, including an indirect immunofluorescence assay and an ELISA. The utility of testing for anti-PLA2R is summarized as follows (see 'Phospholipase A2 receptor' above):
●Approximately 70 to 80 percent of patients presumed to have primary MN have a positive test for anti-PLA2R antibody at the time of renal-biopsy diagnosis of MN. By contrast, some patients with primary MN will have a negative anti-PLA2R antibody test. In addition, a small percentage of patients presumed to have MN secondary to hepatitis viruses or malignancy will have a positive test for anti-PLA2R antibody (some of these patients may in fact have primary MN with superimposed but unrelated hepatitis virus infection or cancer) [27,134,135]. Thus, a positive test, although highly suggestive of primary MN, does not exclude the coexistence of hepatitis virus infection, malignancy, or another associated rheumatologic or inflammatory disease.
●Nephrotic patients without MN seldom (and perhaps never) have a positive test for the anti-PLA2R antibody. Thus, a positive test essentially rules out other causes of nephrotic syndrome (such as minimal change disease or focal segmental glomerulosclerosis) [29,136].
●Among patients with primary MN, testing for anti-PLA2R antibodies may provide additional information regarding treatment response. In one study involving 514 patients with primary MN and positive staining for PLA2R on kidney biopsy, patients with anti-PLA2R antibodies at the time of biopsy had a lower rate of complete remission (proteinuria of <0.4 g/day) at 24 months compared with those without anti-PLA2R antibodies (36 versus 61 percent) [137]. In addition, some data suggest that a falling anti-PLA2R titer indicates that an immunological remission is underway, whereas a persistently high titer is associated with a less favorable clinical course [29,30,137].
When to monitor anti-PLA2R titers — Serial assessment of anti-phospholipase A2 receptor (PLA2R) antibody titers may be useful for both diagnosis and for monitoring the immunological activity of disease when treatment decisions are being considered (see "Treatment of idiopathic membranous nephropathy"). As mentioned above, there are several reported cases of patients who were initially negative for anti-PLA2R and subsequently tested positive several months later as their disease progressed [35,37] (see 'Phospholipase A2 receptor' above). Thus, in an otherwise-stable patient who has an initially negative serum anti-PLA2R antibody test but wishes to avoid kidney biopsy, we would repeat testing three to four months later as part of an ongoing diagnostic evaluation of their kidney disease.
The trajectory of the immunologic disease course in MN may also be determined by monitoring serial anti-PLA2R titers, several months apart. A declining titer in the absence of immunosuppressive treatment may suggest that the patient is undergoing a spontaneous remission, while increasing or persistently high titers of anti-PLA2R suggest worsening disease that is likely to require immunosuppressive treatment.