This pilot study found some improvements in GAG concentration, hair morphology, and cognitive function in these pediatric patients with Sanfilippo syndrome treated with genistin-rich soy isoflavone extract for 1 year. Clinical trials are needed to evaluate the efficacy and safety of this potential treatment.

The present study focused on the evaluation of constitutive and cytokine-stimulated human peritoneal mesothelial cell (HPMC) IL-6 and 6-keto-PGF1 alpha release following pre-exposure to peritoneal dialysis fluid (PDF). Exposure of HPMC to PDF pH 5.2 resulted in a time-dependent increase in cell cytotoxicity [as assessed by lactate dehydrogenase (LDH) release] and concomitant inhibition of constitutive and IL-1 beta stimulated IL-6 and 6-keto-PGF1 alpha synthesis. After 15 minutes of exposure to PDF constitutive and IL-1 beta stimulated IL-6 release were reduced by 32.0 +/- 9.7% and 76.0 +/- 7.4% (N = 6, P < 0.046 and P < 0.027, respectively). PCR amplification of reverse transcribed mRNA from HPMC pre-exposed to PDF pH 5.2 demonstrated suppression of IL-1 beta stimulated IL-6 and cyclooxygenase (Cox-1 and Cox-2) transcripts. In order to mimic the dialysis cycle in vivo, an in vitro dialysis system was established. HPMC were exposed first to control medium, PDF pH 5.2 or PDF 7.3 for 15 minutes and then sequentially to pooled spent peritoneal dialysis effluent for up to four hours. The cells were subsequently allowed to recover in control medium for 12 hours in the presence or absence of IL-1 beta or TNF-alpha (both at 1000 pg/ml). There was no evidence of significant cell toxicity as assessed by LDH release during either the 'in vitro dialysis' or 'recovery' phases. Under these conditions short term exposure to PDF pH 5.2 followed by 'in vitro dialysis' resulted in significant inhibition of cytokine stimulated IL-6 (69.6 +/- 18.2 vs. 96.7 +/- 27.9 pg/microgram, N = 13; P < 0.020 for IL-1 beta) and 6-keto-PGF1 alpha (197.5 +/- 89.2 vs. 289.6 +/- 114.5 pg/microgram, N = 13; P < 0.020 for IL-1 beta) and 6-keto-PGF1 alpha (197.5 +/- 89.2 vs. 289.6 +/- 114.5 pg/microgram, N = 13; P < 0.003) release when compared to cells incubated in control medium. Adjustment of the pH of PDF to 7.3 reversed its inhibitory effects. We conclude that short-term exposure to PDF pH 5.2 significantly inhibits HPMC cytokine and prostaglandin release, an effect which appears to be related to its initial pH. Repeated exposure to nonphysiological PDF might impair mesothelial cell function and thus modulate intraperitoneal inflammatory processes.

In order to elucidate the mechanism of peritoneal dialysis fluid inhibition of cell functions, laboratory-prepared fluids were used to investigate the specific influences of low pH and high lactate concentration on neutrophil viability, phagocytosis, respiratory burst activation and leukotriene B₄ (LTB₄) generation. In the absence of any reduction of viability, respiratory burst activation, stimulated by serum-treated zymosan (STZ), was significantly inhibited by fluids of low pH containing high concentrations of sodium lactate. Neither low pH nor lactate concentration alone, however, caused significant suppression of this parameter of cell activation. Under the same conditions, the phagocytosis of STZ was partially inhibited in a lactate- and pH-dependent manner. In contrast, the generation of LTB₄ in response to STZ was unaffected by pH and lactate concentration. The incubation of polymorphonuclear leukocytes (PMN) in fluids containing 35 mM lactate at pH 5.2 resulted in an immediate and profound lowering in intracellular pH {[ρH]_i} which was not observed in lactate-containing fluids at neutral pH or at low pH in the absence of lactate. We postulate that the critical lowering of [pH]_i in PMN, caused by the combination of high lactate concentration and low pH of the dialysis fluids, is responsible for the observed inhibition of respiratory burst activation. It is also possible that under these conditions, the lactate ion acts as a proton carrier across the cell membrane following the [H⁺] gradient. The time course ofthis [pH]i change suggests that host defence mechanisms may be impaired following short-time exposure to unused dialysis fluid prior to its equilibration in vivo.

These results suggest that therapy with new pH-neutral low-GDP solutions contribute to an intraperitoneal milieu that improves mesothelial cell proliferation and viability. It may positively impact on the preservation of the peritoneal membrane integrity during long-term dialysis.