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The middle molecule hypothesis in perspective.

A L Babb, S Ahmad, J Bergström

    American Journal of Kidney Diseases : the Official Journal of the National Kidney Foundation
    |July 1, 1981
    PubMed
    Summary
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    The middle molecule (MM) hypothesis suggests that accumulating MM in uremia causes neuropathy. Evidence supports this, showing MM clearance by kidneys and dialysis, but definitive proof is still needed.

    Area of Science:

    • Nephrology
    • Uremia Pathophysiology
    • Neurology

    Background:

    • The middle molecule (MM) hypothesis proposes that molecules of 500-2000 daltons/molecule accumulate in uremia, causing peripheral neuropathy.
    • Evidence for and against the MM hypothesis has been reviewed and evaluated.
    • Uremic neuropathy is a significant complication in patients with kidney failure.

    Purpose of the Study:

    • To review and evaluate the evidence supporting and refuting the middle molecule (MM) hypothesis of uremic neuropathy.
    • To assess the role of MM accumulation in the pathogenesis of peripheral neuropathy in uremia.
    • To discuss the implications of MM levels in relation to dialysis efficacy and residual renal function.

    Main Methods:

    • Review of existing literature and clinical observations.

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  • Evaluation of early hemodialysis and peritoneal dialysis patient data regarding neuropathy development.
  • Analysis of studies investigating MM accumulation and clearance in uremia, post-renal transplant, and with residual renal function.

    • Main Results:

    • Early hemodialysis patients developing neuropathy provided support for the MM hypothesis.
    • Peritoneal dialysis patients' lack of neuropathy suggested higher peritoneal membrane permeability to MM compared to early hemodialysis membranes.
    • MM accumulation in uremia was demonstrated, with rapid disappearance post-renal transplant, indicating high renal clearance.

    Conclusions:

    • The weight of evidence supports the validity of the middle molecule (MM) hypothesis in uremic neuropathy.
    • Residual renal function appears to have a protective effect against MM intoxication.
    • Further definitive studies are required to conclusively prove the MM hypothesis, and a protocol for such studies is discussed.