The middle molecule hypothesis in perspective.

The middle molecule (MM) hypothesis states that molecules in the molecular weight range of 500 to 2000 daltons/molecule accumulate in uremia and are one cause of peripheral neuropathy. Evidence for and against this hypothesis is reviewed and evaluated. The course of events in the core of early hemodialysis patients who developed neuropathy provides important support ofr the hypothesis. Failure of early peritoneal dialysis patients to develop neuropathy suggested that the peritoneum is more permeable to MM's than early hemodialysis membranes, a fact that was later hemodialysis membranes, a fact that was later confirmed by appropriate investigations. Several investigators have demonstrated that MM's actually do accumulate in uremia and disappear rapidly following a renal transplant, which suggests a high clearance by the human kidney. Retrospective and prospective studies have demonstrated a protective effect of residual renal function against MM intoxication. Our prospective studies to produce MM intoxication are reviewed and their strengths and weaknesses delineated. Similarly, the investigations of others that are cited as evidence against the MM hypothesis are reviewed. It is the opinion of hte authors that the weight of evidence supports the validity of the MM hypothesis; but that final proof still is lacking. A protocol for more definitive studies is discussed.