Introduction

Figure 1. Cross section of the filtration barrier.

Figure 1. Cross section of the filtration barrier.

• Etiologic factors
• Mechanisms of injury
• Response to that injury

Etiologic factors

Categories of GN

[C] Pauci-immune crescentic GN

These subtypes have no immune deposits in the glomerular space and so are immunofluorescence negative. Almost 90-95% of these cases are associated with the ANCA i.e., the Anti-neutrophil cytoplasm antibody and the rest 5-10% are idiopathic or even ANCA negative. ANCA is associated with neutrophil damage and vasculitis(necrotizing inflammation of small blood vessels) and can manifest into three different conditions, namely:

• Granulomatosis with polyangiitis {GPA} (previously known as Wegner’s disease)
• Microscopic polyangiitis
• Eosinophilic granulomatosis with polyangiitis {EPGA} (previously known as Chrug-Strauss syndrome)

All these conditions are grouped under the umbrella term ANCA-associated vasculitis because they’re associated with a key protein factor in the blood called ANCA and they all cause inflammation of the small blood vessels. The major organs affected are the Kidneys, lungs, joints, ears, and nose. ANCA is a type of IgG antibody that specifically binds to two proteins that are normally found in the fluid within the neutrophil (cytoplasm). The two proteins are named proteinase 3 (PR3) and myeloperoxidase (MPO). Patients with ANCA-associated vasculitis may have autoantibodies against PR3 (PR3-ANCA) or MPO (MPO-ANCA) but not both. The binding of ANCA to neutrophils in the blood, results in:

• The release of toxic substances from neutrophils leads to damage to the small blood vessel walls.
• Neutrophil migration through blood vessel walls causing inflammation in surrounding tissues.
• Release of signaling factors which in turn attract more neutrophils, perpetuating the inflammation and destruction of small blood vessels.

They can cross the placental barrier (especially the MPO-ANCA)and damage the fetal lungs and kidneys if they’re present in the mother.

Furthermore, many medicines are associated with the development of ANCA-positive vasculitis leading to RPGN. These include:

• Hydralazine
• Levamisole-contaminated cocaine
• Propylthiouracil and methimazole
• Allopurinol
• Sulfasalazine
• Minocycline
• Penicillamine
• Rifampicin
• Aminoguanidine
• Sofosbuvir
• Anti-TNF therapy for rheumatoid arthritis and ankylosing spondylitis (Naik and Shawar 2023)

The appearance of ANCA antibodies in the body is poorly understood but certain speculations are that they may be triggered by infections mainly Staph aureus, or by molecular mimicry between the bacterial and self-antigens or by defective neurotrophic cell death resulting in the exposure of immune cells to the internal neutrophil contents.

Whatever may be the pathway the ultimate result is damage to the glomerular capillary wall which leads to fibrin deposition and parietal epithelial infiltration into the bowman’s space culminating in crescent formation.

Mechanisms of glomerular capillary wall injury:

The second stage in the pathogenesis after the discussion on etiologic factors is the discussion on the mechanism of injury to the glomerular capillary wall.

Figure 2. Schematic diagram of the relationship between the mechanisms of injury and the pathogenesis of Crescents formation (dotted lines may suggest a relation but it isn’t established yet).

Figure 2. Schematic diagram of the relationship between the mechanisms of injury and the pathogenesis of Crescents formation (dotted lines may suggest a relation but it isn’t established yet).

Studies show that the deposition of anti-GBM antibodies directly leads to capillary wall damage as they’re targeted against the collagen in the basement membrane [8]. Furthermore, both linear antibody deposition as well as granular immune complex deposition lead to the activation of the complement system leading to the activation of membrane attack complex C59-b that can produce severe capillary wall damage independent of inflammatory cells [9]. Neutrophils too play a direct role in damaging the capillary wall as established through ANCA associated vasculitis as well their activation via the complement system. Similarly, macrophages damage the capillary wall through their activation via the complement system [10]. Lastly, cell-mediated immunity also plays a significant role in damaging the glomerular capillary wall, particularly in those idiopathic cases.

Whatever may be the mechanism of the injury to the glomerular capillary wall, the ultimate consequence is the rents/gaps in the capillary wall (wider than the already present fenestrations) along with rupture in the glomerular capillary basement membrane that lead to fibrin exudation as well as cellular and humoral components of inflammation into the Bowman’s capsule, generating a response from the parietal epithelial cells and causing them to proliferate. This leads to extra capillary proliferations that narrow the remaining space in the capsule and appear as crescents on renal biopsy.

Response to the glomerular capillary wall injury: formation of the glomerular crescents

The initiating event or the very first stage in the formation of glomerular crescents is the induction of rents in the glomerular capillary wall, resulting in the movement of plasma products, including fibrinogen, into Bowman’s space and with subsequent fibrin formation, the influx of macrophages and T cells (Th1 and Th17 CD4+ T cells), and the release of proinflammatory cytokines, such as interleukin-1 and tumor necrosis factor-alpha and procoagulant and fibrinolytic inhibitory factors [11]. As crescent formation is the final common pathway of severe glomerular inflammatory disease, many immune factors cross often generating an elaborated response.

Crescents contain inflammatory cells including macrophages, the proliferating parietal epithelial cells of the glomerulus, and also fibroblasts. Fibrin deposits are central in the role played by the infiltration of glomerular macrophages near the site of injury [12] as thrombin in chemotactic for monocytes it is believed that macrophages in glomeruli generate procoagulant activity, presumably in the form of tissue factor that can activate the extrinsic coagulation pathway. subsequently, the glomerular procoagulant activity may also be derived from the endothelial damage. This results in the second stage of crescents formation i.e., active proliferative inflammation resulting in the development of cellular, microcellular, and then fibrous crescents with time. Fibroblast growth factors promote fibroblast proliferation and collagen deposition mainly type III. This final fibrous stage is unlikely to respond to immunosuppressive therapy and has a high risk of ESKD [13] Apart from macrophages and T-cells, parietal and visceral epithelial cells also contribute to active crescent formation. The stimuli for the proliferation of Epithelial cells and fibroblasts are unknown, but macrophages, platelets, or intrinsic glomerular cell-derived cytokines are considered likely candidates. While the presence of scarring will not decrease renal function per se, the age of presence does serve as a marker of disease duration and hence the probability of successful therapeutic intervention.

Conclusion

• RPGN, characterized by Rapid loss of renal function (Clinical manifestations include gross hematuria, proteinuria, oliguria, hypertension, and edema.) over a very short period (days to weeks)
• Glomerular crescents are the histologic hallmark of the disease
• They are best diagnosed by renal biopsy electron microscopic studies.
• Mainly three types of crescentic GN: Anti GBM antibody disease; immune complex deposition, pauci immune GN
• Diagnostic approaches should include immunofluorescence studies on the biopsy as well as the detection of plasma ANCA.
• Prompt diagnosis is a must to reverse the damage. As final fibrous stages are unlikely to respond to immunosuppressive therapy.

References

1. Satchell, S.C.; Braet, F.; Qureshi, S.H.; Patel, N.N.; Murphy, G.J.; Fu, J.; Lee, K.; Chuang, P.Y.; Liu, Z.; He, J.C.; et al. Glomerular endothelial cell fenestrations: an integral component of the glomerular filtration barrier. Am. J. Physiol. Physiol. 2009, 296, F947–F956. [Google Scholar] [CrossRef]
2. Immunotactoid Glomerulopathy. Diagnostic Pathology: Kidney Diseases [Internet]. 2016 [cited 2023 Dec 5];266–9. Available from: https://linkinghub.elsevier.com/retrieve/pii/B9780323377072500549.
3. discussant P, Charles Jennette J. Rapidly progressive crescentic glomerulonephritis. Kidney Int. 2003;63:1164–77. https://doi.org/10.1046/j.1523-1755.2003.00843.x. [CrossRef]
4. Moorani KN, Aziz M, Amanullah F. Rapidly progressive glomerulonephritis in children. Pak J Med Sci [Internet]. 2022 [cited 2023 Dec 2];38(2):417. https://doi.org/10.12669/pjms.38.icon-2022.5774. [CrossRef]
5. Lionaki S, Liapis G, Boletis JN. Pathogenesis and Management of Acute Kidney Injury in Patients with Nephrotic Syndrome Due to Primary Glomerulopathies. Medicina (B Aires) [Internet]. 2019 [cited 2023 Dec 2];55(7). https://doi.org/10.3390/medicina55070365. [CrossRef]
6. Naik RH, Shawar SH. Rapidly Progressive Glomerulonephritis. StatPearls [Internet]. 2023 May 1 [cited 2023 Dec 2].. https://doi.org/10.20944/preprints202312.0614.v1. [CrossRef]
7. Naik RH, Shawar SH. Rapidly Progressive Glomerulonephritis. StatPearls [Internet]. 2023 May 1 [cited 2023 Dec 2]. https://doi.org/10.20944/preprints202312.0614.v1. [CrossRef]
8. Naik RH, Shawar SH. Rapidly Progressive Glomerulonephritis. StatPearls [Internet]. 2023 May 1 [cited 2023 Dec 2]. https://doi.org/10.20944/preprints202312.0614.v1. [CrossRef]
9. Kaartinen K, Safa A, Kotha S, Ratti G, Meri S. Complement dysregulation in glomerulonephritis. 2019 [cited 2023 Dec 2]. https://doi.org/10.1016/j.smim.2019.101331. [CrossRef]
10. Kaartinen K, Safa A, Kotha S, Ratti G, Meri S. Complement dysregulation in glomerulonephritis. 2019 [cited 2023 Dec 2]. https://doi.org/10.1016/j.smim.2019.101331. [CrossRef]
11. Overview of the classification and treatment of rapidly progressive (crescentic) glomerulonephritis - UpToDate [Internet]. [cited 2023 Dec 2]. Available from: https://www.uptodate.com/contents/overview-of-the-classification-and-treatment-of-rapidly-progressive-crescentic-glomerulonephritis.
12. Overview of the classification and treatment of rapidly progressive (crescentic) glomerulonephritis - UpToDate [Internet]. [cited 2023 Dec 2]. Available from: https://www.uptodate.com/contents/overview-of-the-classification-and-treatment-of-rapidly-progressive-crescentic-glomerulonephritis.
13. Moorani KN, Aziz M, Amanullah F. Rapidly progressive glomerulonephritis in children. Pak J Med Sci [Internet]. 2022 [cited 2023 Dec 2];38(2):417–25. https://doi.org/10.12669/pjms.38.ICON-2022.5774. [CrossRef]