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IMMUNE DEFICIENCY IN UREMIA : INTERLEUKIN-2 PRODUCTION AND RESPONSIVENESS AND INTERLEUKIN-2 RECEPTOR EXPRESSION AND RELEASE

We have studied the role of interleukin-2 (IL-2) and its receptors in the impaired in vitro lymphocyte response characteristic of hemodialysis patients treated by means of cuprophane membranes. The proliferative response of T lymphocytes as well as T-cell-dependent B cell proliferation after stimulation with mitogens was significantly reduced in hemodialysis patients. The in vitro production of IL-2 after such stimulation in parallel cultures was found to be similar in patients and in controls. The expression of IL-2 receptor on the lymphocyte cellular membrane in the hemodialysis group was also similar to controls. The in vitro proliferative response of uremic lymphocytes to exogenous IL-2, however, was significantly depressed suggesting a reduced availability of biologically active IL-2 receptor. The release of soluble IL-2 receptor by lectin-stimulated lymphocytes in culture was also significantly lower in the patient group; yet, hemodialysis patients has a strikingly elevated level of plasma soluble IL-2 receptor, and similar high levels were also found in three other groups of end-stage renal disease patients dialyzed by means of cellulose acetate, polysulfone and polyacrylonitrile membranes, as well as in a group of uremic patients on conservative treatment. In the hemodialysis patient group a significant positive correlation between levels of soluble IL-2 receptor and the duration of hemodialysis was found. Since soluble IL-2 receptor has been reported to down-regulate lymphocyte responses, the elevation in plasma levels of soluble IL-2 receptor in hemodialysis patients may be a pathogenetic factor in the progressive development of impaired immunity associated with end-stage renal disease.

Controlled Trial of Thymopentin in Hemodialysis Patients Who Fail to Respond to Hepatitis B Vaccination

Uremic patients are at high risk of hepatitis B virus (HBV) infection and, despite the availability and efficacy of hepatitis B vaccine, a high rate of non responders has been reported. Forty uremic patients undergoing maintenance hemodialysis who failed to produce any measurable anti-HBs antibody response after 4 administrations of 5 micrograms of Hevac B Pasteur vaccine were admitted to a randomized controlled clinical trial. Group A (14 patients) received 3 doses of 5 micrograms s.c. each of vaccine at monthly intervals and 12 doses of 50 mg s.c. of thymopentin on alternate days between the first and the second vaccination. Group B (11 patients) received 3 doses of 5 micrograms s.c. each of vaccine at monthly intervals. Group C (15 patients) received 3 doses of 10 micrograms s.c. each of vaccine at monthly intervals. Immunization rates were 86% in group A (on both 1-month and 6-month checks), 36% on the 1-month and 27% on the 6-month check in group B, 53% on the 1-month and 47% on the 6-month check in group C. Anti-HBs antibody titers were similar in group A and C but notably lower in group B. Thymopentin seems as useful therapeutical tool for non responder patients. As it promotes T cell maturation and responsiveness, which are impaired in uremia, it could play a major part in the management of uremic immunodeficiency.

Production and Kinetics of Interleukin-1 in Hemodialysis

Interleukin-1-beta (IL-1-beta) was measured in the plasma and peripheral blood mononuclear cell lysates of uremic patients undergoing maintenance hemodialysis by means of either cuprophane or polysulfone membranes. Basal plasma levels of IL-1-beta in hemodialyzed patients were strikingly higher than those of uremic patients on conservative treatment or of healthy subjects. Plasma levels of IL-1-beta in uremic patients increased significantly after 3 and 6 months of hemodialysis. The study of the kinetics of IL-1-beta concentration during a single hemodialysis session revealed that the concentration of IL-1-beta fell to 21 and 22% of the predialysis level with cuprophane and polysulfone, respectively. Hemodialysis patients also had a significantly higher intracellular IL-1-beta level than normal controls. During the hemodialysis session, an increase in cell-associated IL-1-beta was seen regardless of the membrane employed. In a parallel study, normal mononuclear cells were subjected to closed-loop in vitro dialysis with either cuprophane or polysulfone membranes, with or without acetate buffer. After 120 min of recirculation, an increase in cell-associated IL-1-beta was detected, but no changes were seen in the circulating medium. IL-1-beta production was not significantly influenced by either membrane or the dialysate composition. Hemodialysis has been associated with high plasma- and cell-associated IL-1 levels. The kinetics of intradialytic changes of IL-1-beta levels make IL-1 an unlikely cause of acute complications in hemodialysis. On the other hand, a chronic elevation of IL-1 in plasma of patients on maintenance hemodialysis may contribute to the development of some of the long-term complications of this treatment.

Does Lead Overload Develop in Hemodialysis Patients

Marco Martegani, MD, Divisione di Nefrologia, Ospedale Multizonale di Varese, USSL no 3, v. le Borri 57, I-21100 Varese (Italy) Dear Sir, Lead has been variously associated with gout, hypertension, and renal failure. Thomson et al. [1] described a significant but slight increase in concentrations of red blood cell lead in patients with chronic renal failure (CRF) and on hemodialysis. After EDTA chelation test, Batuman et al. [2] found higher levels of urinary lead in gouty patients with CRF than in gouty patients with normal renal function. The same author measured larger amounts of mobilizable lead in hypertensive patients with reduced renal function than in patients who had hypertension without renal impairment but suggested that this increase could not be due to the renal disease since normotensive CRF patients did not excrete such large amounts [3]. Among CRF patients, Colleoni and D’Amico [4] found a linear correlation between serum creatinine and mobilizable lead only in gouty patients. On the other hand, Behringer et al. [5] and Ritz et al. [6] observed elevated chelatable lead in patients with impaired renal function and lead exposure. Environmental pollution leads to an increasing body lead content in healthy subjects [7], which means that, as lead is mainly removed by urinary excretion [8], a lead overload could occur in patients affected by CRF even without a known or suspected exposure. In a preliminary study, the erythrocyte zinc protopor-phyrin IX (Zn PP IX) level (the increase of which may reflect a lead overload) was determined in 3 groups of patients: healthy subjects, mild to moderate chronic renal failure patients and hemodialysis patients. The results are shown in table I. The differences among the three groups were highly significant; moreover, a linear correlation between serum creatinine and Zn PP IX levels was observed (p < 0.001). Fifteen dialysis patients without lead exposure and high Zn PP IX levels were tested for serum lead. The Table I. Erythrocyte Zn PP IX levels in healthy subjects, CRF and hemodialysis patients determined by direct hematoñuorimetric method (Model 4000; Experimental Sciences Associated) Healthy subjects CRF patients Hemodialysis patients