Mechanisms of hypocomplementemia in glomerulonephritis

Although Ounn [1] in 1914 first observed the low serum complement levels in acute post-streptococcal nephritis, it was Kellett [2] who in 1935 first hypothesized that the bypocomplementemia was the result of an antigen-antibody reaction occurring in the tissues. Observing three patients with low serum complement levels at the onset of acute nephritis, he stated "I suggest that acute glomerulonephritis may be a condition, essentially generalized, resulting from reaction between antibodies elaborated by the body and toxins elaborated by the organisms that played a part in the original infection, the toxins having been fixed in some way to the tissue cells, and more particularly to those of the kidney … ." Another24 years passed before it was suggested that the reaction of complement with immune complexes, rather than toxins, produced the nephritis. Schwab and associates [3], studying experimental hypersensitivity in rabbits, suggested in 1950 that fixed complement played an active role in the production of renal cellular damage during the in vivo antigen-antibody reaction which occurs after the injection of a foreign protein. This concept was obviously greatly strengthened and made applicable to human disease by the demonstration of Lachmann and associates [4] that with labeled antibody the third component of complement could be detected in the renal glomeruli in acute glomerulonephritis and lupus nephritis as well as in certain other nephritides. The great advances in understanding of complement and of nephritis which have occurred in recent years have allowed further exploration of these concepts. With time paradoxes have emerged. Complement can be demonstrated in the glomeruli in nephritides which are not associated with a reduction in serum complement. Complement profiles have shown that in some hypocomplementemic nephritides, certain components are in normal concentration while in others, all components tend to be low [5–8]. In hypocomplementemic patients with membrano-proliferative nephritis a factor has been found in the serum which appears to be responsible for the hypocomplementemia [9]. Recent studies have indicated that the serum from patients with systemic lupus erythematosus and active nephritis often contains factors directly reacting with C1q [10]. It becomes apparent from these observations that in these two forms of nephritis, at least, the hypocomplementemia could be the result almost entirely of a complement reaction occurring in the circulation rather than, as Kellett [2] implied, in the kidneys. Supporting this concept is the observation that in membrano-proliferative nephritis, hypocomplementemia continues in the absence of kidneys [11]. A problem yet to be solved is how the mechanism producing the hypocomplementemia relates to that producing the nephritis. This is an especially difficult question in acute post-streptococcal and membrano-proliferative nephritis. In this paper some of the recent observations concerning the origin of the hypocomplementemia in lupus nephritis, acute post-streptococcal glomerulonephritis and membranoproliferative glomerulonephritis will be summarized and further observations added. The potential for greater understanding in this area has recently increased as a result of the demonstration of an alternate pathway of complement activation which can be initiated in vitro by a number of substances and has as its primary target the third component of complement [12]. Despite this advance there are still many gaps in our comprehension of some of the intimate details of the mechanism responsible for the hypocomplementemia and, more particularly, of the factors responsible for the glomerular inflammation.