Introduction to the Pathogenesis of Glomerular Diseases

Patrick H. Nachman

Michelle N. Rheault

Virginie Royal

The study of glomerular disease is a rich and exciting, yet challenging field of nephrology. Glomerular diseases represent a large number of diseases, which are rapidly evolving in number and complexity as our understanding of their underlying pathogenic mechanisms is improving. Glomerular diseases are often rare diseases; thus, patients may require referral to specialized centers for diagnosis and management. Because of this complexity, the diagnosis of glomerular disease epitomizes the investigative work of an expanding multidisciplinary care team. Indeed, in addition to the nephrologist and nephropathologist core, the complete evaluation of patients with glomerular disease will increasingly involve providers from the fields of genetics, immunology, rheumatology, hematology, oncology, infectious diseases, pharmacy, and nursing. It is the role of the nephrologist to conduct and coordinate this sometimes intricate investigation to arrive at the accurate diagnosis and direct the appropriate therapy. When done in a timely and complete manner, the management of glomerular diseases frequently offers the reward of halting, if not reversing, disease progression. Few events in nephrology—indeed medicine—offer the exceptional reward of reversing severe kidney failure needing kidney replacement therapy to a level of well-preserved kidney function.

APPROACH TO THE CLASSIFICATION OF GLOMERULAR DISEASES

The complexity of glomerular diseases stems in part from its rich history and evolution and by different classification schemes that are used in parallel. These are unfortunately sometimes used in ways that have contributed to confusion when terms are inappropriately applied interchangeably. To take full advantage of these classifications, it is helpful to think of them as complementary tools rather than separate schemas.

The large variety of glomerular diseases, however, has common fundamental concepts that are the primary focus of this introductory chapter. It is beyond the scope of this chapter to discuss in detail the mechanisms or an exhaustive listing of associations. A detailed discussion of more specific diseases or disease groups is provided in the corresponding subsequent chapters.

The main approaches to classifying glomerular diseases include:

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)

In considering these classifications, it is important to keep in mind the following principles:

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.
Finally, current classification schemes are rapidly evolving, and some terminologies used a decade ago are now considered obsolete if not erroneous—and it is likely that current terms will change and continue evolving (Figure 1.1 and Table 1.1).

APPROACH TO DIAGNOSIS

It derives from the earlier discussion that the nephrologist’s approach to diagnosis must integrate information from all the abovementioned sources. Each approach provides additional and complementary pieces of the puzzle to arrive at a clear picture. When encountered in the clinic for the first time, it is helpful to start from the data gleaned from a thorough and complete history and physical examination, including a careful review of the systems, social history, family history, and medication and drug exposures. A more complete discussion of the approach to
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
- Metabolic causes
- Familial/genetic history
- Birth history/prematurity
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
GN may be a complication of the treatment of the underlying cancer (eg, thrombotic microangiopathy (TMA) associated with anti-vascular endothelial growth factor agents,¹ or collapsing focal segmental glomerulosclerosis (FSGS) associated with high-dose bisphosphate therapy).²

TABLE 1.1 Broad Categories of Glomerular Diseases Based on the Main Pathogenic Mechanisms

Pathogenic Mechanism	Disease Entities	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	Thrombotic microangiopathies	Mesangiolysis, fragmented red blood cells, glomerular endothelial cell swelling, and subendothelial space widening. Capillary lumen fibrin thrombi may be present.
Antibody Mediated
Direct antibody attack	Anti-GBM disease	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)	Variable patterns 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	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	Peri-infectious GN	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	Lupus nephritis	Proliferative, crescentic glomerulonephritis with subendothelial and subepithelial deposits. “Full-house” immune reactant deposits
	IgA nephropathy	Endocapillary, mesangial hypercellularity with predominant mesangial IgA deposits
	Cryoglobulinemia	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
Fluid phase	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
Membrane bound	Atypical HUS	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 directly causative versus noncausative risk factors (eg, APOL1)³,⁴
- May be part of an identifiable syndrome (eg, Alport syndrome with ocular, auditory, or other recognizable features)⁵
- May be familial or sporadic

GENERAL PATHOGENIC MECHANISMS OF GLOMERULAR DISEASES

Conceptually, glomerular diseases could be categorized in six broad categories (Table 1.1):

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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