Zn²⁺ metabolism affects apoptosis rate and proliferative responsiveness of PBMC from patients on chronic hemodialysis

Patients with end-stage renal failure suffer from severe plasma trace metal deficiency that is not corrected by dialysis. Trace metals, including Zn²⁺, are critical for cell differentiation and replication. Zn²⁺also plays important role in cell apoptosis. Both processes are known to be impaired in uremia. The present study was undertaken to evaluate the effect of Zn²⁺ supplementation on apoptosis of cultured peripheral blood mononuclear cells (PBMC) from patients on chronic hemodialysis versus those from healthy control subjects, concomitantly with assessment of mitogen-induced cell proliferation. The results showed that (1) basal total cell-associated Zn²⁺ was elevated in uremic PBMC, compared to normal controls (23.9 [plusmn] 5.64 v 10.5 [plusmn] 2.64 [mu ]mol/L/mg protein). The gap persisted following incubation in Zn²⁺-enriched medium (63.3 [plusmn] 26.12 v 81.6 [plusmn] 13.4 [mu ]mol/L/mg protein, P [lt ] .005). (2) Basal proliferative response to phytohemagglutinin (PHA) was significantly decreased in uremic PBMC compared to normal controls (12,000 [plusmn] 1,560 cpm v 16,600 [plusmn] 1,460 cpm, P [lt ] .01). Incubation of uremic PBMC in Zn²⁺-enriched medium improved their proliferative response to PHA, yielding counts per minute significantly higher compared to their normal counterparts (37,000 [plusmn] 7,500 cpm v 22,000 [plusmn] 3,000 cpm, P [lt ] .001). (3) Basal apoptosis rate in uremic PBMC was significantly elevated compared to normal control cells (7.6% v 2.6%, P [lt ] .05). Following incubation in Zn²⁺-enriched medium, apoptosis was increased both in normal and uremic PBMC. Percent apoptosis of uremic PBMC remained significantly elevated compared to control cells (11.7% v 5.7%). We conclude that uremic PBMC are more responsive to exogenous Zn²⁺ in culture than their normal counterparts. This, among other abnormalities, might reflect an abnormal regulation of Zn²⁺ transport by uremic mononuclear cell menbranes. The resultant increase in total cell-associated Zn²⁺ content improves poor proliferative responsiveness of uremic PBMC. On the other hand, increased total cell-associated Zn²⁺ stimulates enhanced apoptosis in uremic PBMC, which, probably by eliminating defective cells, contributes to the functional capability of the population as a whole. The net effect of the 2 processes is still augmentation of cell proliferation.