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Complement, not Compliment

December 30, 2011

Membranoproliferative glomerulonephritis (MPGN) is inflammation of the filtering units of the kidney (glomerulonephritis or GN) that occurs with activation of the complement system of immunity.

The Complement System

Complement Cartoon; Click to Enlarge

The complement system of proteins provides immunity through 2 pathways. In the classical pathway (blue half of cartoon), an antigen-antibody forms an immune complex that activates C1. C4 gets activated and consumed. After a couple of steps it activates C3. Ultimately C5 and other complements come together, resulting in a membrane attack complex (MAC) that can, well, attack the membrane of the foreign invader. The alternative pathway (pink half of cartoon) activates C3 directly with the same end result, often via contact with a surface that consumes the C3 protein. Clinical laboratories usually measure C3 and C4. 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.

Diagnosing MPGN

MPGN must be diagnosed by kidney biopsy. The “membrano” part of the name refers to characteristic changes in the glomerular basement membrane (GBM) of the filtering capillaries. Abnormal material “splits” the GBM and fills this space, giving a duplicated appearance on light microscopy. Mesangial cells “proliferate,” completing the name. Other studies demonstrate components of the complement system depositing within the glomeruli.

In addition to the kidney biopsy, patients need lab studies for hepatitis, cryoglobulinemia (a circulating immune complex disorder), and complements: C3, C4, and C3 nephritic factor. The latter, an antibody to the activated form of C3 that can activate C5, is positive in 60-70% of patients with type 2 disease, but only 20% of other types.

The pattern of immune complexes in the kidney defines 3 forms of MPGN:

  • Type 1: Subendothelial deposits (between the cells lining the capillaries and the GBM)
  • Type 2: Large, ribbon-like intramembranous (within the GBM) deposits (dense deposit disease); patients with this form do worse
  • Type 3: Subendothelial and subepithelial deposits (on both sides of the GBM)

Natural History and Treatment

MPGN is a rare disease, affecting 1 to 2 per million population per year. Unlike many kidney diseases, MPGN is “equal-opportunity.” All ethnic groups, both genders, and all ages suffer the same. The disorder progresses slowly. Approximately half of affected patients require treatment of permanent kidney failure in 5-10 years.

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. Drugs that specifically target complement activation (eculizumab) offer novel options for research. Kidney transplant can be performed in these patients, but MPGN may recur. Once again, type 2 disease fares worse with 80-90% risk of recurrence, compared to ~30% in those with the other forms.

For a more technical discussion of this disorder see this post or this review article.

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