Hemodialysis Hypotension: Interaction of Inhibitors, iNOS, and the Interdialytic Period

Abstract

Hypotension during hemodialysis in end-stage renal disease (ESRD) not explained by excessive ultrafiltration has been linked to an apparent increase in the synthesis of nitric oxide (NO). The authors tested whether the induction of NO synthase (iNOS) by cytokines or differences in the concentrations of inhibitors of NOS or both could account for variability in the amount of NO synthesized during hemodialysis. Plasma levels of an inhibitor of NOS, asymmetric dimethylarginine (ADMA), L-arginine, the substrate for NOS, the end-products N02 + N03, iNOS activity in circulating buffy coat cells, and their interdialytic changes were measured in 10 patients during three treatments. Predialysis (0') levels of ADMA were markedly elevated with a mean of 0.008 ± 0.002 μmol/mL of deproteinized plasma, compared to controls where ADMA is present in trace amounts. ADMA levels from 30 minutes to the end of dialysis correlated directly with the drop in blood pressure (BP), with levels being much higher in patients with severe hypotension. Postdialysis ADMA levels correlated directly with the 0' systolic BP and the drop in BP at the next dialysis treatment. NOS activity was detected in two thirds of the predialysis buffy coat samples, and appeared to increase as dialysis progressed. 0' iNOS activity correlated inversely with the 0' BP, but activities did not differ based on percent drop in BP. iNOS activity in the 0' samples correlated inversely with the time since the last dialysis, reflecting the greater accumulation of dialyzable inhibitors of NOS as the interval is prolonged. The interdialytic change in iNOS activity correlated inversely with the drop in BP. The isoform detected immunochemically in the buffy coat samples had an Mr of 130 kDa and was reactive with antihuman iNOS. Thus, iNOS is already induced in the cells of the buffy coat in many intermittently hemodialyzed ESRD subjects, but its expression may be masked by inhibitors. After 60 minutes of dialysis (too brief a time for the de novo induction of iNOS,) the appearance of or increase in iNOS activity suggests that an inhibitor had been removed. Because ADMA levels are associated with higher predialysis systolic BPs that result in a greater severity of hypotension, reduction in ADMA concentrations would appear to play a major role in the resumption of NO synthesis by various isoforms.