Clinical efficacy, safety and anti-inflammatory activity of two sevelamer tablet forms in patients on low-flux hemodialysis.

Sevelamer hydrochloride is an ionic exchange resin with high affinity for phosphate. This phosphate-binding agent has few serious adverse reactions with the advantage of reducing total and low density lipoprotein (LDL) cholesterol levels. However, it is controversial as to whether sevelamer hydrochloride can modulate the inflammatory response via endotoxin reduction. Therefore, a single-center, open-label, prospective and randomized study was performed to compare the clinical efficacy, safety and anti-inflammatory activity of two sevelamer hydrochloride tablet forms a branded tablet form, Renagel (Genzyme manufacturer) and its generic equivalent (EMS manufacturer). Twenty-eight chronic kidney disease volunteer patients at stage 5 (CDK 5D), on chronic low-flux hemodialysis carried out in 4-hour sessions, three times a week, were studied. The serum phosphorus, ionic calcium, total cholesterol and fractions, bicarbonate, blood pH, interleukin (IL)-6, IL-10, IL-1 beta and tumor necrosis factor-alpha (TNF-alpha) levels were collected prior to dialysis at mid-week. The incidence of gastrointestinal adverse effects were determined at the end of the phosphate-binder washout period as well as at the end of the fourth and eighth weeks of use of both tablet forms. The same magnitude of reduction in serum phosphorus was observed with both sevelamer tablet forms. Only the Renagel group showed lower total cholesterol and lower LDL cholesterol levels at the fourth and eighth week versus baseline. No significant differences in serum cytokine levels were identified in either drug group. However, the incidence of intestinal obstipation was higher among patients who used the generic equivalent form. In conclusion, Renagel and its EMS generic equivalent tablet forms have a similar clinical efficacy in reducing phosphorus in CKD 5D patients on low-flux hemodialysis and a similar safety profile.

Immune response in hemodialysis patients: is there any difference when low and high iPTH levels are compared?

BACKGROUND: Chronic renal failure is frequently associated with secondary hyperparathyroidism and immunological disorders. Recent studies support the hypothesis that high levels of parathyroid hormone (PTH) may contribute to the impairment of the cellular and humoral immune response by an immunosuppressive effect on T- and B-cell functions. However, many studies indicate that excess PTH exerts a stimulatory effect on T lymphocytes. Since reports about the immunomodulatory effect of PTH are controversial, our aim was to compare the effect of low and high levels of intact PTH (iPTH) in hemodialysis patients. METHODS: The study was performed on 14 hemodialysis patients with high levels of iPTH (GI), 12 patients with low levels of iPTH (GII) and 13 volunteers (GIII), for whom time of dialysis, iPTH, total number of lymphocytes, B, CD4+, CD8+, lymphoproliferative response to phytohemagglutin (PHA), pokeweed mitogen (PWM) and candidin, IgG and IgM production in vitro in response to PWM, and interleukin (IL)-2 and IL-6 production in vitro in response to PHA were determined. RESULTS: Patients with high iPTH levels had significantly higher responses to PHA than patients with low iPTH. Lymphocyte transformation by PWM and candidin antigen was similar in both groups of patients, but significantly decreased when compared to controls. CD4+ cell counts were significantly increased in GI, and there was a positive correlation between the lymphoproliferative response to PHA and iPTH levels and CD4+ number. CONCLUSION: The present study suggests that high levels of iPTH in hemodialysis patients affect T-cell function, increasing the lympho-proliferative response to PHA and the CD4+ number.

Restoration of impaired T-cell proliferation after parathyroidectomy in hemodialysis patients.

BACKGROUND/AIMS: Severe secondary hyperparathyroidism is not infrequent in hemodialysis patients and recent studies suggest that parathyroid hormone (PTH) may play a role in the genesis of cell immunity abnormalities in uremia. The aim of the present study is to describe the effect of parathyroidectomy on T- and B-cell functions in hemodialysis patients. METHODS: The study was performed on 6 patients with severe secondary hyperparathyroidism. iPTH, B, CD4(+), CD8(+), total number of lymphocytes, lymphoproliferative response to PHA, PWM and Candidin, and IgG, IgM, IL-2 production in vitro were determined 1 day before and 4 months after parathyroidectomy. RESULTS: The lymphoproliferative response to PHA increased significantly after parathyroidectomy. We also observed a trend to an increase in production of IgG and IgM after PWM stimulation before therapy. CONCLUSION: The present study suggests that patients with extremely high levels of PTH show a complete restoration of impaired T-cell proliferation after parathyroidectomy.

Histochemical staining of bone aluminum: comparison of aluminon and acid solochrome azurine and their correlation with bone aluminum content.

Aluminum (Al) may be a pathogenic factor in dialysis associated osteodistrophy. Aluminon and Acid Solochrome Azurine have been used for the detection of Al deposits in bone. We compared Aluminon and Acid Solochrome Azurine stains in normal (N) and uremic (U) rats. Both received intraperitoneal injections of aluminum chloride (AlCl3), until a cumulative dose of 5 mg/Al (NAL5; UAL5) or 30 mg/Al (NAL30; UAL30). The control groups received an equal volume of distilled water by means of intraperitoneal injections. Histomorphometric analysis showed that formation parameters (osteoid volume-OV/BV and osteoid surface-OS/BS), were significantly greater in the uremic groups than the control groups. In addition, the aluminum intoxication increased these values. When we compared the aluminum deposits in the undecalcified bone detected by both staining methods, we observed that Acid Solochrome Azurine was more sensitive than Aluminon in the normal renal function group and uremic treated with 5 mg of AlCl3. All our results were compared with atomic absorption spectrophotometry, showing that Al content presented a positive correlation with Aluminon stain in U and N rats, nevertheless it was not observed using Acid Solochrome Azurine stain. We conclude that histochemistry is important in diagnosing and monitoring aluminum bone disease.

The role of experimental chronic renal failure and aluminium intoxication in cellular immune response.

BACKGROUND: A positive correlation between successful kidney transplantation, few rejection episodes, greater susceptibility to infection and morbidity in patients with high tissue levels of aluminium (Al) indicate that the metal may play a role in the immune response. The aim of this study was to determine if experimental aluminium intoxication could result in significant changes in lymphocyte activity in uraemic and nonuraemic rats. METHODS: Lewis rats were divided into four groups: normals (N), nephrectomized control (U), and Al-treated (N + Al) and nephrectomized Al-treated (U + Al), which received a cumulative dose of 30 mg Al over a 4-week period. Al quantification, histology, histochemical analysis and immunological assays were performed after Al intoxication. RESULTS: High tissue levels of Al and positive histochemical staining in bones were seen in Al-treated rats. Bone histology revealed osteomalacia in U + Al rats. No statistical differences were observed in mixed lymphocyte cultures from controls and Al-treated rats, whereas U and Al-treated rats showed a decrease in lymphoproliferative response to mitogen and natural killer cell cytotoxic activity. A decreased helper T lymphocyte: cytotoxic T lymphocyte cell ratio and a reduction in interleukin-2 production were observed only in the U + Al group. A reduced number of total T lymphocytes was detected in the spleens of all Al-treated rats. CONCLUSIONS: These findings suggest that aluminium toxicity may contribute to immunological impairment in chronic renal failure.

The role of experimental aluminum intoxication in allogeneic immunoresponse.

To evaluate the immunological properties of aluminum (Al) in experimental Al intoxication in rats, we performed heart transplantation and in vitro experiments. Lewis (Lew) rats were intoxicated with intraperitoneal injections of AlCl3. heart transplants were performed using Brown-Norway (BN) rats as donors. Isotransplants and normal Lew were used as controls. No differences in survival were observed. Unidirectional mixed lymphocyte cultures (MLC) and Concanavalin A (Con A)-stimulated cultures were prepared using spleen cells from normal and Al-intoxicated Lew rats. No differences were found in unidirectional MLC. Intoxicated cells showed a less intense response to con A than did normal cells. In conclusion, we could not detect an immunosuppressive role of Al intoxication in experimental cardiac transplantation or in MLC. However, the depressed Con A blastogenic response of Al-intoxicated cells may reflect an immunological role yet to be defined.