Standardized Classification and Reporting of Glomerulonephritis

Sanjeev Sethi; Fernando C. Fervenza

Disclosures

Nephrol Dial Transplant. 2019;34(2):193-199. 

In This Article

What Is the Diagnosis?

The Answer Lies in the Diagnosis of GN Based on Etiology

To promote a standardized classification of GN based on etiology, a group of pathologists and nephrologists met at the Mayo Clinic on 14–15 February 2015.[4] Based on the discussions of the group, GN was classified into five basic groups and within each group there are specific disease entities. It is important to state up front that every attempt should be made to carry out the diagnosis of the specific disease in each group. The diagnosis of the specific disease when identified takes precedence over placing it in the overall class it belongs to. At the outset it should also be stated that the etiologic classification of GN is based on immunofluorescence (IF) microscopy findings in combination with light microscopy (LM) and electron microscopy (EM) findings. Thus good IF microscopy is a prerequisite for the diagnosis of GN based on etiology.

One of the purposes of the overall classification of GN into the five principal groups is that, in general, placement within one class means that other classes of GN can be excluded and this can then guide one toward correct evaluation, diagnosis and management of the GN. Thus the finding of polyclonal Ig (immune complex GN) rules out monoclonal Ig GN, the finding of immune complex GN rules out C3 GN and the lack of immune complexes (or pauci-immune deposits) and/or complement rules out other groups such as C3 GN, immune-complex GN and so on. While immune complex–mediated GN is most heterogeneous and contains many specific diseases, other groups such as ANCA-associated GN, antiglomerular basement membrane (GBM) GN, monoclonal Ig GN and C3 glomerulopathy are rather specific and in themselves point to the specific etiology of the GN (Figure 1).

Figure 1.

Overview of standardized classification and reporting of GN.

Immune complex–mediated GN. This is the most heterogeneous group and is comprised of a variety of disease entities that are characterized by the presence of Ig on IF microscopy. Thus it includes the well-defined glomerular diseases and common diseases such as IgA nephropathy, lupus nephritis, infection-related GN and less common diseases such as fibrillary GN.[5–8] All of these diseases are characterized by findings of Ig on IF microscopy, and specific findings on LM, IF and EM are then required to make the correct etiological diagnosis of the specific immune complex disease, such as IgA nephropathy, lupus nephritis and fibrillary GN. In most forms of immune complex GN, with the help of clinical findings and LM/IF/EM, the underlying specific disease entity can be identified and appropriate laboratory tests can be performed to confirm the diagnosis in the majority of cases. LM in immune complex–mediated GN can be quite variable, with varying patterns of injury, even within a specific disease type. However, in a small subset, even though Igs are present on the biopsy and an underlying etiology is not detected, it seems reasonable to label these cases as 'idiopathic' immune complex GN. Based on the experience of evaluating these cases at the Mayo Clinic, our impression is that 'idiopathic' immune complex GN is quite rare and is more likely to be seen in the pediatric population.

ANCA-associated GN. This group of diseases is characterized by the finding of ANCA against myeloperoxidase or proteinase 3 (PR3) in the serum of patients with GN.[9,10] On IF microscopy, the GN is typically negative for Ig or complement, although small amounts of Ig and C3 are not uncommon and are more likely to be present in a segmental distribution (quite unlike the diffuse distribution of immune complex GN). LM shows a necrotizing and crescentic GN in varying stages of evolution and progression. Thus cellular and fibrocellular and fibrous crescents may all be present.

Anti-GBM GN. Anti-GBM GN is characterized by the finding of anti-GBM antibodies in circulation. On IF microscopy there is linear staining against IgG along the GBM; breaks in the linear staining may be seen in areas of necrosis. Segmental granular C3 is also often present. LM shows an aggressive crescentic and necrotizing GN, with crescents that are large and cellular and typically all in the same stage when biopsied early in the course.

Monoclonal Ig–mediated GN. This group of diseases is characterized by the finding of monoclonal Ig deposits on IF microscopy.[11–13] IF microscopy is essential for the diagnosis, demonstrating the monotypic deposits with light chain and/or heavy chain restriction. It includes proliferative GN with monoclonal Ig deposits (PGNMID), monoclonal Ig deposition disease (MIDD), immunotactoid GN, type I and some of the type II cryoglobulinemic GN and rarely fibrillary GN with monoclonal Ig deposits.[14,15] LM is variable and depends on the specific diseases. Membranoproliferative GN is the most common pattern in PGNMID and immunotactoid GN, while MIDD typically shows a nodular sclerosing GN.

C3 glomerulopathy. C3 glomerulopathy is characterized by the finding of bright C3 staining and minimal or absent Ig staining on IF microscopy.[16–19] If small amounts of Ig are present, the C3 staining should be two grades brighter than the Ig staining.[20] LM often shows a membranoproliferative pattern of injury, although other patterns including mesangial proliferative, endocapillary proliferative, crescentic and sclerosing patterns are also frequently present.

Other Ancillary Studies may be Required to Reach the Etiologic Diagnosis

In a small number of cases ancillary studies may be required to confirm the etiology of GN. Ancillary studies may also be used in limited biopsy samples. For example, pronase-based retrieval techniques may be used to confirm the diagnosis of PGNMID when the IF material does not contain glomeruli.[21] Pronase-based retrieval techniques may also be used in C3 glomerulopathy associated with monoclonal gammopathy to rule out masked monoclonal Ig deposits.[22] Negative C4d studies are helpful in confirming a diagnosis of C3 glomerulopathy.[23] The diagnosis of fibrillary GN may be difficult in some cases. The deposits in fibrillary GN are Congo red negative and the fibrils measure between 16 and 24 nm in thickness compared with Congo red–positive amyloid fibrils that measure 7–13 nm in thickness and Congo red–negative microtubular deposits of immunotactoid glomerulopathy that measure 10–60 nm in diameter.[24] Most importantly, positive staining for DNAJB9 has recently been shown to be a marker for fibrillary GN.[25] Laser dissection and mass spectrometry is also useful in determining the identity of glomerular deposits.[26–28]

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