Classification based on the broad clinical presentations: nephrotic versus nephritic syndromes, rapidly progressive glomerulonephritis (GN), renal limited versus systemic diseases
Classification based on histopathologic findings: This has been traditionally largely based on the light microscopic appearance of the glomeruli but has evolved to include the findings of immunofluorescence microscopy and electron microscopy.
Classification based on the underlying pathogenic mechanism of disease: including direct antibody-mediated diseases, immune complex-mediated diseases, pauci-immune diseases, primary diseases of the basement membrane, primary diseases of the podocytes, diseases of primary complement dysregulation, and diseases associated with monoclonal gammopathies
Classification based on the association of the kidney disease with underlying pre- or coexisting diseases to, for example: genetic, metabolic, infectious, oncologic diseases or secondary to medications, drugs, or environmental exposures (so-called secondary as opposed to primary or idiopathic kidney diseases)
None of the classifications are completely accurate, and all contain some level of arbitrariness and significant overlap between categories of diseases.
In general, a single classification scheme is unlikely to provide, by itself, a sufficient diagnostic tool. Rather, the work of the nephrologist will be to integrate information from each of these approaches to arrive at the correct diagnosis.
Although there are general associations between some mechanisms of disease and some histopathologic features, keep in mind that a common histopathologic pattern of injury could result from very different pathogenic pathways, and conversely, a pathogenic pathway may result in very different histopathologic and clinical features. This is likely the result of our still incomplete understanding of the intricacies of pathogenesis or the interaction of the underlying main pathogenic mechanisms as they are modified by the patients’ metabolism, genetic factors, and environment or timing of kidney biopsy relative to disease course.
In most cases, the histopathologic, clinical, and even immunologic/pathogenic pathway-based diagnosis still requires further investigation to determine whether an underlying infectious, environmental, genetic, or oncologic “cause” exists.
As our understanding of pathophysiology improves, our classification of diseases will move away from histology-based classifications to genetic and/or pathogenesis-based terminology.
evaluating a suspected glomerular disease is described in Chapter 3. This chapter discusses the main categories of pathogenic mechanisms of glomerular diseases. However, regardless of the mechanism, in each case, it is important to fully evaluate a patient for coexisting diseases or processes—whether causally related or not—that may influence the best course of treatment.
FIGURE 1.1: Conceptual categorization of glomerular diseases based on the main pathogenic mechanism involved.
Search for underlying possible causes or coexisting disease.
Importance of complete history
Possible autoimmune or other systemic diseases
Systemic lupus erythematosus, small vessel vasculitis
Inflammatory bowel disease or abnormal mucosal diseases (eg, celiac disease)
Possible infectious associations
May be causative, for example, peri-infectious GN: bacterial or viral
May be noncausative, but important to rule out before immunosuppressive therapy. Important to test for clinically silent bacterial or viral diseases (eg, hepatitis B or C virus, severe acute respiratory syndrome coronavirus 2 [SARS-CoV2], mycobacterial or treponemal disease, and Mycobacterium tuberculosis)
Possible oncologic associations
May be causative, for example, paraneoplastic glomerular disease
May be noncausative, but important to rule out before immunosuppressive therapy
TABLE 1.1 Broad Categories of Glomerular Diseases Based on the Main Pathogenic Mechanisms
Common Histopathologic Pattern of Glomerular Injury
Structural abnormalities of the GBM
Alport syndrome, nail-patella syndrome, Pierson syndrome
Intermittent areas of thickening, thinning, and disorganized GBM with lamellation on EM
Endothelial injury and thrombosis
Mesangiolysis, fragmented red blood cells, glomerular endothelial cell swelling, and subendothelial space widening. Capillary lumen fibrin thrombi may be present.
Direct antibody attack
Crescentic glomerulonephritis with linear IgG deposition along the GBM
Antibody-mediated activation of neutrophils and monocytes
ANCA-associated vasculitis and glomerulonephritis
Pauci-immune, necrotizing, and crescentic glomerulonephritis and vasculitis
Nephrotoxic monoclonal antibody mediated:
Glomerular deposition of M-Ig
Dysregulation of the alternative complement pathway (see later)
Glomerular disease associated with monoclonal antibody or fragments thereof (including monoclonal gammopathy of renal significance-associated diseases)
Nodular glomerulopathy, proliferative GN; monotypic staining on IF
Glomerular immune-type and/or organized deposits on EM
Immune Complex Mediated
Intrinsic target antigen
Membranous nephropathy: thickened capillary wall by subepithelial immune-type deposits and spike appearance of the GBM. Granular IgG deposits along the capillary wall on IF
Planted target antigen
Diffuse proliferative endocapillary glomerulonephritis, with numerous neutrophils, coarse granular C3 and IgG wall, and mesangial deposits. Large subepithelial “hump” deposits on EM
Circulating immune complexes
Proliferative, crescentic glomerulonephritis with subendothelial and subepithelial deposits. “Full-house” immune reactant deposits
Endocapillary, mesangial hypercellularity with predominant mesangial IgA deposits
Membranoproliferative glomerulonephritis with infiltrating histiocytes and cryoglobulin precipitates in glomerular capillaries (“hyalin pseudothrombi”). Variable IF staining according to cryoglobulin composition
Primary Alternative Complement Pathway Dysregulation
C3-GN, dense deposit disease
Membranoproliferative GN with predominant C3 staining on IF. Dense deposits within the GBM, mesangial and subepithelial “hump” deposits on EM
See thrombotic microangiopathy.
Podocyte Injury and Dysregulation
Minimal change disease, FSGS
Minimal change disease: normal glomeruli on light microscopy, absence of immune deposits, with diffuse foot process effacement on EM
FSGS: segmental solidification of the tuft by matrix material, with overlying swollen podocytes, hyalin deposits and adhesion. No immune deposits. Variable foot process effacement on EM
“Full-house” immune reactant deposits: IgG, M-Ig, IgA, C1q, C3, C4, κ and λ light chains.
ANCA, antineutrophil cytoplasmic antibody; EM, electron microscopy; FSGS, focal segmental glomerulosclerosis; GBM, glomerular basement membrane; GN, glomerulonephritis; HUS, hemolytic uremic syndrome; IF, immunofluorescence; Ig, immunoglobulin; M-Ig, monoclonal immunoglobulin.
Possible exposures (eg, medications/therapeutic agents)
May be causative
May modify or amplify underlying disease
Possible genetic association
May be part of an identifiable syndrome (eg, Alport syndrome with ocular, auditory, or other recognizable features)5
May be familial or sporadic
Primary structural abnormalities of the glomerular basement membrane (GBM): These are diseases resulting from the abnormal structure of type IV collagen—because of genetic abnormalities of the genes encoding for one of the molecules involved in the formation of the normal collagen trimers clinically related to Alport syndrome, namely, COL4A3 or COL4A4 (associated with autosomal modes of transmission) or COL4A5 on the X chromosome (associated with X-linked Alport syndrome), and more rarely, LMX1B coding for a transcription factor involved in the regulation of several GBM and podocyte-associated genes or LAMB2 coding for laminin β2, which is an important component of the GBM.
Diseases resulting in glomerular endothelial injury and thrombosis: These include thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome (HUS), and microangiopathies associated with a variety of underlying diseases or exposures. HUS has traditionally been subdivided between diarrheal HUS and “atypical” hemolytic uremic syndrome (aHUS).6 Although similar clinically and histologically, these three syndromes differ in their pathogenic mechanisms. TTP results from defective activity of ADAMTS 13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13), either because of a hereditary deficiency or from acquired inhibitory antibodies. The deficient ADAMTS13 activity results in abnormally large von Willebrand factor molecules on the surface of endothelial cells, which entrap platelets resulting in microvascular thrombi.7,8,9 Diarrheal HUS results from the direct injury of endothelial cells by Shiga toxin. Finally, aHUS is now recognized as the result of a dysregulation of the alternative pathway of complement activation (see #5 subsequently).
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