Background
Autoimmune-mediated damage to the kidneys can be triggered by autoantibodies directed against specific proteins or renal structures, for example, the phospholipase A2 receptor or the glomerular basement membrane, resulting in glomerular diseases such as primary membranous nephropathy or Goodpasture's disease. Moreover, secondary damage to the kidney such as lupus nephritis can be part of the wide-reaching effects of systemic autoimmune diseases such as vasculitis or systemic lupus erythematosus (SLE). The main four clinically relevant renal autoimmune diseases are membranous nephropathy (MN), Goodpasture's disease, lupus nephritis (LN), and anti-neutrophil cytoplasmic autoantibodies (ANCA)-associated vasculitis (AAV).
Fig. 1 The kidney in auto-immune and auto-inflammatory processes.
Pathology
Autoimmune nephropathies involve complex interactions between the immune system and renal tissues. In diseases like Systemic Lupus Erythematosus (SLE), autoantibodies bind to self-antigens, forming immune complexes which triggers the complement cascade and causes tissue damage and glomerulonephritis. In diseases like Anti-Glomerular Basement Membrane (GBM) Disease, autoantibodies specifically target components of the glomerular basement membrane, leading to direct injury, and also activating complement and Fc receptors on immune cells, leading to localized inflammation and damage to the basement membrane. In IgA Nephropathy (Berger's Disease), there is defective glycosylation of IgA molecules, leading to the formation of abnormal IgA1 and form immune complexes. These immune complexes deposit in the mesangial region of the glomeruli, causing local inflammation and glomerular injury.
Types of Autoimmune Nephropathies
- Membranous Nephropathy (MN)
MN is characterized by the in-situ formation of immune complexes in the glomerular basement membranes, leading to the damage of the glomeruli and the disruption of the renal filter function. It results in proteinuria, frequently combined with hypoproteinemia, hypolipoproteinemia and the formation of edema (nephrotic syndrome). Most cases (70-80%) of MN belong to the idiopathic or primary form (pMN), while in 20-30% of patients another disease can be found that causes MN (secondary MN). Autoantibodies against phospholipase A2 receptor (PLA2R), which is expressed in podocyte cell membrane, are highly specific for pMN and are found in the serum of around 75% of patients at baseline.
Fig. 2 Membranous Nephropathy
Goodpasture's Syndrome is also known as anti-glomerular basement membrane (anti-GBM) disease, characterized by the production of autoantibodies targeting antigens in the glomerular and alveolar basement membranes. These antibodies, primarily directed against the non-collagenous domain of the α-3 chain of type IV collagen, trigger inflammatory responses involving local complement activation and recruitment of polymorphonuclear leukocytes. Symptoms include coughing up blood and trouble breathing.
Lupus nephritis is a common manifestation of SLE. It is primarily caused by a type-3, hypersensitivity reaction, which results in the formation of immune complexes. Anti-double-stranded DNA (anti-dsDNA) binds to DNA, which forms an anti-dsDNA immune complex. These immune complexes deposit on the mesangium, subendothelial, and/or subepithelial space near the glomerular basement membrane of the kidney, leading to lupus nephritis. Signs of the disease include blood or excess protein in the urine, edema, weight gain, and high blood pressure.
Renal Vasculitis is also called ANCA glomerulonephritis, presents as rapidly progressive glomerulonephritis and comprises of a group of conditions characterized by acute kidney injury (AKI), hematuria and proteinuria. The two main types are Microscopic polyangiitis (MPA) and Granulomatosis with polyangiitis (Wegner's disease).
Table 1: Renal autoimmune diseases and associated autoantigens.
Diagnosis
1. Urinalysis
Proteinuria and Hematuria: Common in various autoimmune nephropathies, including SLE and IgA nephropathy.
2. Renal Biopsy
Commonly performed using imaging guidance to obtain a small tissue sample from the kidney for histopathological analysis:
SLE: Biopsy often shows immune complex deposition and glomerular inflammation.
IgA Nephropathy: Renal biopsy shows mesangial IgA deposits and abnormal IgA glycosylation patterns.
Anti-GBM Disease: Shows crescentic glomerulonephritis with GBM damage.
Vasculitis-Associated Nephropathies: Renal biopsy shows inflammatory infiltrates.
3. Autoantibody detection
- Anti-PLA2R antibodies
Phospholipase A2 receptor (PLA2R) autoantibodies are highly specific for the primary form of MN. PLA2R antibody titers decline in the course of spontaneous remission and during successful therapy. In addition to differential diagnosis of MN, the ELISA-based quantification of PLA2R autoantibodies allows assessment of disease activity and severity as well as prediction of disease outcome (remission, relapse) and risk of recurrence of MN after kidney transplantation. - Anti-THSD7A Antibodies
THSD7A was discovered as a second antigenic target in approx.
2.5 % to 5 % of patients with idiopathic MN. As PLA2R, THSD7A is an N-glycosylated high molecular mass protein expressed on the podocyte membrane and similar to PLA2R antibodies, an association between THSD7A antibody levels and disease activity is suggested. - Anti-Glomerular Basement Membrane (GBM) Antibodies
Autoantibodies to GBM are highly specific and sensitive markers for Goodpasture's syndrome.The relevant antigenic target is the non-collagenous 1 (NC1) domain of the alpha-3 chain of type IV collagen within the GBM. High titers usually occur in patients with rapidly progressive kidney disease, and indicate an unfavourable prognosis. - Anti-Neutrophil Cytoplasmic Antibodies (ANCA)
Serological determination of ANCA is an essential tool for the identification and differentiation of ANCA-associated vasculitis (AAV). The most important ANCA target either proteinase 3 (PR3) which are sensitive and specific markers for Wegener's granulomatosis, or MPO which occur in microscopic polyangiitis and the Churg Strauss syndrome. The consensus on ANCA testing requires screening with indirect immunofluorescence (IIF) and confirmation in MPO- and PR3-ANCA specific assays. - Anti-Nucleosome Antibodies (ANuA)
ANuA represent the first serological marker described in SLE and are particularly suitable as a prognostic indicator for SLE with renal involvement: in lupus nephritis patients requiring transplantation a considerably high prevalence (79%) was observed compared to less severe cases (18%) and SLE patients without nephritis (9%). - Anti-dsDNA Antibodies
Anti-dsDNA is found in about 30% of people with systemic lupus and high levels of anti-dsDNA antibodies often suggests severe lupus, and kidney involvement (lupus nephritis). When the disease is active, especially in the kidneys, high amounts of anti-DNA antibodies are usually present. They can be used to monitor disease flare-ups and responses to therapy.
