One bad form of kidney disease, membranoproliferative glomerulonephritis (we docs call it MPGN), may be "enjoying" a resurgence. Since I have not seen a case for a few years, an update seems in order. I pulled a 2011 review by Howard Trachtman, a pediatric nephrologist at the Albert Einstein College of Medicine.
MPGN is inflammation of the filtering units of the kidney (glomerulonephritis or GN) that occurs with activation of the complement system of immunity. Other forms of GN that do this include post-streptococcal GN and systemic lupus erythematosus. A number of secondary causes of complement activation and MPGN include chronic liver disease, cryoglobulinemia, and subacute bacterial endocarditis. These disorders may result in circulating immune complexes that lead to complement activation.
Kidney biopsy is the only way to make the diagnosis. (For a 9-minute review of normal kidney structure, click here.) The "membrano" part of the name refers to characteristic changes in the glomerular basement membrane (GBM) of the filtering capillaries (see arrow in micrograph). Abnormal material "splits" the GBM and fills this space, giving a duplicated or tram-track appearance on light microscopy. Mesangial cells multiply (or "proliferate"), completing the name. Other studies demonstrate components of the complement system depositing within the glomeruli.
What is the complement system? Glad you asked! Complements form a protein-based immune response (see figure above). In the classical pathway, an antigen-antibody complex activated C1 which activates C4, and so on, ultimately consuming C3 and/or C5, resulting in a membrane attack complex (MAC) that can, well, attack the membrane of the foreign invader. The alternate pathway activates C3 directly with the same end result, often via contact with a surface that can adsorb the complement component. Clinical laboratories usually measure C3, C4, and a measure of total complement consumption. If C4 is low, then the classical pathway has been stimulated; C3 may be suppressed as well. If C4 remains normal with a low C3, the alternative pathway is the culprit.
The primary form of MPGN is a rare disease, affecting 1 to 2 per million population per year. Unlike many kidney diseases, MPGN is "equal-opportunity" and does not disproportionately affect any ethnicity or gender. The disorder tends to be slowly progressive, with approximately half of affected patients requiring replacement of kidney function within 5-10 years. The prognosis and course does not differ for children and adults with MPGN. Less than 5% of patients with permanent kidney failure have this as the cause. Three forms have been described:
- Type 1: Subendothelial deposits (between the cells lining the capillaries and the GBM)
- Type 2: Large, ribbon-like intramembranous deposits (dense deposit disease); this form has a somewhat worse prognosis and is associated with partial lipodystrophy in ~25% of cases
- Type 3: Subendothelial (like type 1) and subepithelial deposits (between the foot processes and the GBM)
In addition to the kidney biopsy, patients need lab studies for hepatitis, cryoglobulinemia, and complements: C3, C4, and C3 nephritic factor. The latter, an autoantibody to C3bBb, is positive in 60-70% of patients with type 2 disease, but only 20% of other types.
At this time, treatment for MPGN includes normalizing blood pressure and reducing proteinuria as with all chronic kidney disorders. In children, immunosuppression with oral steroid every other day for several years may retard progression of disease; in adults, steroids are not recommended. If a secondary cause of MPGN is demonstrated, treatment of that disorder may also benefit the kidney involvement. The development of drugs that specifically target complement activation (eculizumab) offer novel options to explore in these rare forms of GN.
Kidney tranplant can be performed in these patients, but the disease may recur in the graft. Once again, type 2 disease fares worse with 80-90% risk of recurrence, compared to ~30% in those with the other forms. MPGN can be a persistent pest.