Iga Nephropathy
IgA nephropathy, also known as Berger's disease, is a chronic glomerulonephritis characterized by the deposition of immunoglobulin A (IgA) in the glomerular mesangium of the kidney. The pathogenesis involves an abnormal immune response, leading to the formation of galactose-deficient IgA1, which is recognized as an autoantigen by circulating anti-glycan antibodies. This results in the formation of immune complexes that deposit in the glomeruli, triggering local inflammation, mesangial proliferation, and subsequent glomerular injury. Over time, these immunological events can lead to progressive renal dysfunction, proteinuria, hematuria, hypertension, and, in a subset of patients, end-stage renal disease (ESRD). The clinical course is highly variable, with some individuals experiencing a benign course, while others progress to significant renal impairment. Health impacts include not only renal morbidity but also reduced quality of life, increased cardiovascular risk, and the socioeconomic burden associated with chronic kidney disease.
Primary IgA nephropathy refers to cases where the disease occurs as an isolated renal disorder without association with systemic diseases. It is characterized by the predominant deposition of IgA in the glomerular mesangium, leading to variable clinical presentations ranging from asymptomatic microscopic hematuria to rapidly progressive glomerulonephritis. The pathogenesis is believed to be driven by intrinsic defects in IgA1 glycosylation and subsequent formation of immune complexes.
Secondary IgA nephropathy develops in the context of systemic diseases or external triggers, such as chronic liver disease, inflammatory bowel disease, infections, or autoimmune disorders. In these cases, IgA deposition in the kidneys occurs as part of a broader systemic process, and management often focuses on treating the underlying condition in addition to addressing renal involvement.
This type is characterized by an aggressive clinical course with rapid deterioration of renal function, often associated with crescentic glomerulonephritis on biopsy. Patients present with acute kidney injury, nephritic syndrome, and extensive glomerular crescent formation. Early recognition and intervention are crucial to prevent irreversible renal damage.
IgA vasculitis, formerly known as Henoch-Schönlein purpura, is a systemic small-vessel vasculitis that frequently involves the skin, joints, gastrointestinal tract, and kidneys. Renal involvement manifests as IgA nephropathy-like lesions, but is distinguished by the presence of systemic vasculitic features such as palpable purpura, arthralgia, and abdominal pain.
IgA nephropathy is the most common primary glomerulonephritis worldwide, accounting for approximately 20–40% of biopsy-proven glomerular diseases in some regions. The incidence varies geographically, being highest in East and Southeast Asia (notably Japan and China), with reported annual incidence rates of 2–10 cases per 100,000 population, and lower in North America and Western Europe. The disease predominantly affects males, with a male-to-female ratio of approximately 2:1 in most populations. Onset commonly occurs in the second and third decades of life, though it can present at any age. Familial clustering has been observed, suggesting a genetic predisposition. The long-term prognosis is variable; approximately 20–40% of affected individuals progress to end-stage renal disease within 20 years of diagnosis, while others maintain stable renal function for decades. Risk factors for progression include sustained proteinuria, hypertension, reduced glomerular filtration rate at presentation, and certain histopathological features such as glomerulosclerosis and tubulointerstitial fibrosis.
The diagnosis of IgA nephropathy is based on a combination of clinical, laboratory, and histopathological findings. Clinically, patients may present with recurrent episodes of macroscopic hematuria, often following upper respiratory tract infections, or with persistent microscopic hematuria and variable degrees of proteinuria. Laboratory evaluation includes urinalysis, quantification of proteinuria, assessment of renal function (serum creatinine, estimated glomerular filtration rate), and exclusion of secondary causes. Definitive diagnosis requires a renal biopsy, which reveals mesangial proliferation and the presence of dominant or co-dominant IgA deposits in the glomerular mesangium on immunofluorescence microscopy. Additional findings may include C3 and IgG deposition, and variable degrees of crescent formation or sclerosis on light microscopy. The Oxford Classification is widely used to grade histopathological lesions and assess prognostic implications. Diagnostic criteria also necessitate the exclusion of systemic diseases that may cause secondary IgA deposition, such as liver cirrhosis or vasculitis. Ancillary investigations may include serological tests to rule out other glomerulopathies, and imaging studies to assess renal size and structure if indicated.
Iptacopan hydrochloride is utilized in the treatment of IgA nephropathy as a targeted oral complement factor B inhibitor, aiming to modulate the alternative complement pathway implicated in the disease's pathogenesis and thereby reduce proteinuria and preserve renal function. Sparsentan is administered as a dual endothelin angiotensin receptor antagonist, providing therapeutic benefit by lowering proteinuria and offering renal protection through its combined blockade of endothelin type A and angiotensin II type 1 receptors, which are both involved in the progression of glomerular injury in IgA nephropathy.
| Structure | Generic Name | CAS Registry Number | Molecular Formula | Molecular Weight |
|---|---|---|---|---|
 | iptacopan hydrochloride (Rec INNM; USAN) | 1644670-37-0 (free base); 2447007-60-3 | C25 H30 N2 O4 . Cl H . H2 O | 476.993 |
 | sparsentan (Rec INN; USAN) | 254740-64-2 | C32 H40 N4 O5 S | 592.749 |
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