Argument for the Classical Concept:

The Immunofluorescence Microscopic Findings

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In most patients with glomerulonephritis a microscopic investigation of the renal tissue using immunofluorescence microscopy shows deposits of antibodies and complement factors in the glomeruli. The presence of both antibodies and complement in the glomeruli strongly suggests that a formation of immune complexes has taken place with unfortunate consequences for the glomerular filters. Plasma proteins, that normally are unable to pass the glomerular basement membrane because of their size, now leak to the urine and eventually, renal function goes down.

Counter-Argument

Immune complexes in the glomeruli may have been formed outside the kidneys and thereafter trapped in the glomeruli. Even if they have been formed in the glomeruli, their formation may not necessarily damage the kidneys, as has been demonstrated in numerous animal experiments (see later). 

It is said that the permeability of the glomerular basement membrane is increased due to the destructive processes that occur when immune complexes are formed. It is therefore most curious that immune complexes may be located to the outside of the glomerular basement membrane. In healthy individuals this membrane does not allow a passage of molecules larger than albumin. As some of the components of the immunological deposits seen in glomerulonephritis are several times larger than albumin, how did they pass he glomerular basement membrane? The most logical explanation is, that the membrane must have been damaged before the deposition or formation of the immune complexes. The increased permeability of the membrane is a prerequisite for their formation, not the result of that formation, and the cause of the increased permeability may either be a direct effect of toxic chemicals, or the production of lymphokines due to a sensibilisation against these chemicals.

That the mere presence of immune complexes in the glomeruli may be unimportant for glomerular function is obvious from numerous clinical observations. For instance, patients with cancer, various internal diseases, and even healthy individuals, often have immune complexes located to the glomeruli without having any signs or symptoms of renal disease (Sutherland et al 1974, Pascal et al 1976, Larsen 1979, Helin et al 1980, Hoorntje et al 1980, Waldherr et al 1989, Rosenberg et al 1990, Suganuma et al 1994). Glomerular immune complexes are also found in normally functioning kidney grafts (Antignac et al 1988). Very often such findings have been classified as glomerulonephritis, but to call a deposition of immune complexes for a kidney disease when the kidneys are functioning normally and the urine is normal, is misuse of medical terminology.

There are disturbing observations from the animal kingdom also. Great amounts of glomerular immune deposits have been found in a large proportion of sheep, steers, guinea pigs, horses, mice and rabbits with normal urine and normal kidney function (Lerner & Dixon 1966, Lerner et al. 1968, Steblay & Rudofsky 1971, Banks & Henson 1972, Markham et al 1973, Neale et al 1984). Again, these findings have been classified as glomerulonephritis, but if the presence of immune complexes alone is a disease you could equally well call dirty nails for a disease.

Also, if a glomerular formation of immune complexes were the direct cause of glomerulonephritis, the amount of immune complexes should correlate with the renal function and the course of the disease. Patients with many deposits should more often have renal failure than patients with little or no deposits, and many deposits should also mean that the disease has a more serious outcome, this is pure logic. But there is no association whatsoever between the amount of glomerular deposits or the degree of glomerular damage, and the renal function and the outcome; this has been documented in numerous studies (Riemenschneider et al 1980, Ramzy et al 1981, Wehrmann et al 1989, Lee & Koh 1993. More references can be found in these papers). In fact, about a fifth of all patients with serious glomerulonephritis have no glomerular deposits at all.

Another fact, that has gained little interest among nephrologists is that many patients with glomerulonephritis have deposits of immunoglobulins but not of complement. If the disease were the result of immune complex formation in the glomeruli, both immunoglobulins and complement should be present because complement is always participating in the formation of an immune complex.

These observations are difficult to understand if the classical hypothesis were true, but as seen in the following they are easily explained by the toxic-allergic hypothesis, which says that the deposits are secondary to the real cause, the toxic-allergic damage of the tubulointerstitial tissue and the glomerular basement membrane. Any macromolecule may be caught in the glomerular filters, in particular if the glomerulus is damaged by toxic or allergic reactions. In the following sections I shall tell about the many studies that in various ways have shown that the depostion of immune components in the glomeruli is a secondary phenomenon secondary to the toxic-allergic damage of the kidneys.

Next section: Human Anti-GBM-Nephritis