This is a randomized, double-blinded dietary intervention in hemodialysis patients to
determine the clinical and metabolic effects of soy isoflavones on disease activity,
including improvement of blood markers of acute-phase response, and decreased blood levels
of markers of metabolic bone disease.
Up to 40 percent of end stage renal disease (ESRD) patients suffer from a chronic
inflammatory process which is not currently amenable to specific treatment and is associated
with high morbidity and mortality. High circulating levels and production of
pro-inflammatory cytokines are an essential part of this ongoing acute-phase response and
they are believed to exacerbate many of the clinical manifestations of ESRD, including renal
osteodystrophy. Like in all other inflammatory processes that have undergone more extensive
investigation, the nuclear factor, Nuclear Factor Kappa-B (NFKB) promises to be a critical
cellular intermediate of this acute-phase response and to be both mediator and target of
inflammatory cytokine effects. In the current search for agents that may be able to negate
the ongoing acute-phase response of ESRD, the soy isoflavones genistein and daidzein have
emerged as potentially useful. These isoflavones are present in many soyfoods, are available
as over-the-counter nutritional supplements and have received growing attention due to their
biological properties and potential as therapeutic agents. Inhibitory effects of the
isoflavones on tyrosine kinase and NFKB activity, on inflammatory cytokine production and on
oxidative stress have been demonstrated by this group and by many other investigators and
they may be highly relevant to the renal failure population. Additionally, we have found
recently that intake of soy food by ESRD patients results in very high blood levels of
isoflavones and it is well tolerated.
It is our working hypothesis that in chronic renal failure a variety of endogenous and
exogenous factors trigger acute-phase response with activation of NFKB and production of
pro-inflammatory cytokines, and that intervention with soy isoflavones inhibits NFKB
activation and cytokines production, thus blocking the ongoing acute-phase response and
affecting positively clinically relevant parameters of disease activity in ESRD.
The specific objective of this proposal is to conduct a randomized, double-blinded dietary
intervention trial in hemodialysis patients to determine whether:
1. Dietary intake of the soy isoflavones by ESRD patients with clinical signs of ongoing
acute-phase response decreases the production of the proinflammatory cytokines
TNF-alpha, IL-1 and IL-6 in peripheral blood, thus changing the balance between these
cytokines and their antagonists sTNF RI, sTNF RII, and IL-1ra.
2. Suppression of inflammatory cytokine production by soy isoflavones is associated with
improvement of clinically relevant parameters of disease activity, including
improvement of blood markers of acute-phase response, and decreased blood levels of
markers of metabolic bone disease.
3. Intake of soy isoflavones suppresses NF-KB activity in peripheral blood monocytic cells
of ESRD patients, in a manner consistent with change of cytokine levels and of clinical
parameters of disease.
- Initiation of chronic hemodialysis therapy more than 6 months prior to enrollment in
- Routine dialysis with highly biocompatible dialysis membranes, including polysulfone,
polycarbonate, polyamide, or polymethylmethacrylate membranes.
- Historical compliance with three times weekly routine hemodialysis therapy.
- Ability and willingness to adhere to the intake of soy protein isolate drinks during
- Use of calcitriol within the last six weeks
- Acute illness known to cause acute-phase response, including clinically detectable
infections, trauma, surgery, burns, and tissue infarction, within the last 6 weeks.
- Chronic conditions known to cause acute-phase response, including
immunologically-mediated and crystal-induced illnesses, cancer, and psychiatric
- Hematocrit below 30%
- Aluminum intoxication
- Gastrointestinal disturbances that can interfere with isoflavone absorption,
including acute gastrointestinal illness and/or intestinal microflora depletion
following use of antibiotics within the last three months, chronic malabsorption
syndrome, chronic liver disease.
- Other significant medical illnesses including decompensated heart failure, unstable
coronary artery disease, advanced chronic obstructive pulmonary disease,
decompensated thyroid disease, alcoholism, substance abuse.