Immunoglobulin-Mediated Membranoproliferative Glomerulonephritis
DISEASE DEFINITION
Membranoproliferative glomerulonephritis (MPGN) is characterized histologically by glomerular basement membrane (GBM) thickening and proliferative changes on light microscopy. Historically, MPGN was classified into types I, II, and III, based on the location of deposits on electron microscopy examination:
Type I
Characterized by electron-dense deposits in the mesangium and subendothelial space, consisting of both immunoglobulin and C3.
Type II (dense deposit disease)
Characterized by electron-dense ribbon-like deposits along the basement membranes of the glomeruli, tubules, and Bowman's capsule, consisting mostly of complement.
Type III
Characterized by both subepithelial and subendothelial deposits.
However, advances in the understanding of the pathogenesis of MPGN has revealed that the classification based on electron microscopy has limitations and can result in overlap among the different types. ► The preferred classification is based on pathophysiologic processes and informed by findings on immunofluorescence microscopy. This classification scheme broadly divides MPGN into:
- Immunoglobulin/immune complex–mediated MPGN
- Complement-mediated MPGN
- MPGN without immunoglobulin or complement deposition
WHAT IS THE CAUSE?
An underlying (secondary) cause is present in the majority of cases regardless of type. Idiopathic (primary) cases are less common and usually observed within the immunoglobulin/immune complex–mediated category.
Primary forms affect children and young adults between ages 8 and 30 and account for 10% of cases of nephrotic syndrome in children; secondary forms tend to affect adults > 30. Men and women are affected equally. Reported familial cases of some types suggest genetic factors play a role in at least some cases. Many factors contribute to hypocomplementemia.
SYMPTOMS
A primary form of membranoproliferative glomerulonephritis (MPGN) characterized by deposition in the renal glomeruli of immunoglobulin with complement fractions, especially C3. Clinical presentation may range from nephrotic syndrome and acute kidney injury to asymptomatic proteinuria and hematuria.
Symptoms and signs are similar to those for other types of glomerulonephritis:
- The urine sediment may reveal hematuria (with dysmorphic red cells and/or red cell casts) and proteinuria. The degree of proteinuria is variable. The serum creatinine may be normal or elevated
- Hypocomplementemia is frequently present in all types of MPGN and provides supportive evidence for the diagnosis
Patients with dense deposition disease, a subtype of complement-mediated MPGN, have a greater incidence of:
- Ocular abnormalities which ultimately impair vision (basal laminar drusen, diffuse retinal pigment alterations, diskiform macular detachment, choroidal neovascularization)
DIAGNOSIS
Renal Biopsy
Diagnosis is confirmed by renal biopsy. The pattern of immunoglobulin and complement deposition on immunofluorescence microscopy helps classify the type of MPGN lesion. Additional tests are also done to help identify the underlying cause of the MPGN lesion.
Serum complement profile
Hypocomplementemia is frequently present. In immunoglobulin/immune complex–mediated MPGN, the classic complement pathway is activated; C3 is normal or mildly decreased, and C4 is typically decreased. In complement-mediated MPGN, the alternate complement pathway is activated; C3 is decreased, but C4 is normal. In MPGN without immunoglobulin complement deposition, C3 and C4 are normal.
Specific laboratory tests
Testing for secondary causes is based on their associations with the types of MPGN. Complete blood count (CBC), often obtained in the course of diagnostic evaluation, demonstrates normochromic-normocytic anemia, often out of proportion to the stage of renal insufficiency (possibly because of hemolysis), and thrombocytopenia from platelet consumption.
TREATMENT
Treatment for MPGN is complex and depends on several factors, including the type of MPGN, the severity of kidney involvement, and the underlying cause, if known. Some treatment options and considerations may include:
Immunosuppressive Medications
In some cases, corticosteroids and other immunosuppressive drugs may be used to suppress the immune system's abnormal response. Frequently given as treatment to children with nephrotic-range proteinuria.
Complement Inhibitors
Eculizumab and other drugs that target the complement system are of particular interest in MPGN, as this disease is often associated with complement dysregulation.
Control of Blood Pressure
Managing hypertension is crucial to protect the kidneys. Medications called angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) are commonly prescribed.
Management of Proteinuria
Reducing proteinuria is essential to slow down the progression of kidney damage. Medications like angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) may be used.
Dialysis or Kidney Transplant
In advanced cases of MPGN with kidney failure, dialysis or kidney transplantation may be necessary.
PROGNOSIS
The prognosis for individuals with MPGN varies depending on the type, underlying causes, and response to treatment. Early diagnosis and appropriate management can help slow down the progression of the disease and improve long-term outcomes. Regular follow-up with a nephrologist (kidney specialist) is essential for monitoring kidney function and adjusting treatment as needed.