The serums of patients with hypocomplementemic glomerulonephritis contain a substance that combines with a normal serum cofactor in the presence of magnesium ion to specifically cleave the third component of complement. This lysis of C'3 is 80 to 90 percent complete in 20 minutes at 37 degrees C and pH 7. Neither the nephritic factor nor its cofactor is identifiable with the complement system.

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Membranoproliferative glomerulonephritis (MPGN), recognized since 1965, is now known to have three forms, designated types I, II, and III. The types are similar in the frequency of hypocomplementemia and clinical course but are dissimilar in glomerular ultrastructure, pathogenesis, mechanisms of complement activation, predisposition to recur in the renal transplant, and, to some extent, in clinical presentation. Although glomerular proliferation is usually diffuse, it may be focal and segmental particularly in mild cases of MPGN I. Hypocomplementemia, present in about 80% of patients, is the result of hypercatabolism of C3 by three mechanisms as well as of diminished C3 synthesis. The hypocomplementemia is unrelated to clinical course or prognosis. Although MPGN I and III both have a high frequency of an extended haplotype on chromosome 6, which has known associations with autoimmune phenomena, and both have a high frequency of inherited complement defects, they are nevertheless dissimilar in glomerular ultrastructure, complement profile, and immunohistology in ways which suggest a wide difference in pathogenesis. Abnormalities in humoral immunity appear not to be involved in MPGN III. Treatment with anticoagulant, antiplatelet and cytotoxic drugs have, in controlled trials, been either ineffective or marginally effective. Long-term use of alternate-day prednisone in high dosage appears to be the most efficacious regimen in both controlled and uncontrolled studies.

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Summary. Evidence has been obtained for the presence in vivo of alpha2D-globulin, a breakdown product of serum f10-globulin, in patients with acute and persistent hypocomplementemic glomerulonephritis. The protein has been identified by immunoelectrophoretic analysis, and the amounts present have been determined by direct measurement of specific antigenic determinants present on alpha2D. 831A-Globulin, another breakdown product of Plcglobulin, may also be present in vivo in severely hypocomplementemic patients, but its levels are much lower than those of alpha2D-globulin.Alpha2D-globulin has been identified by immunoelectrophoretic analysis of fresh EDTA plasma from patients with hypocomplementemic nephritis as an arc in the alpha2 region that shows a reaction of identity with the arc representing alpha2D-globulin produced by aged normal serum. 831A-Globulin was not seen in these patterns.Measurement of specific antigenic determinants has been carried out in both fresh EDTA plasma and aged serum. In the fresh plasma, the concentration of D antigen, found on both Plw-and alpha2D-globulins, has been related to that of B antigen, found only on /31c and taken as a measure of the concentration of this protein. In the hypocomplementemic patients, the concentration of D antigen, in comparison to that of B, was greater than in the normal subjects. Similarly, in aged serum, the level of alpha2D was greater than would be expected from the amount of flic that had been broken down in vitro, measured by the concentration of ,81A.Calculations indicated that the in vivo alpha2D level in severely hypocomplementemic patients ranged from 7.5 to 18% of that which would be found in a pool of aged normal serum in which /3ic is completely broken down. The levels tended to be lower in less severely hypocomplementemic patients, and none could be detected in normal plasma.Only small quantities of A and D antigens are detectable in the urine of patients with hypocomplementemic nephritis. The rate of excretion is about equal to that of the normal subject.The study indicates that the low serum levels of fl3c-globulin that may be present over long periods in patients with persistent hypocomplementemic glomerulonephritis can be ascribed, in part, to in vivo breakdown of this pro-