thymic-factor--circulating and Kidney-Failure--Chronic

Patients undergoing successful kidney transplantation often manifest overt hypophosphatemia associated with exaggerated phosphaturia during the early post-transplant period (2 weeks to 3 months). The mechanism for this phenomenon has not been fully elucidated. We tested the hypothesis that a circulating serum factor [non-parathyroid hormone (non-PTH)], which operates during chronic renal failure (CRF) to maintain phosphate (Pi) homeostasis, can increase fractional excretion of Pi (FE(PO4)) in normal functioning kidney grafts during the early post-transplant period, thereby causing phosphaturia and hypophosphatemia.. Five groups of patients were studied: control subjects (group 1, N = 16), "early" (2 weeks to 1 month) post-transplant patients (group 2, N = 22), "late" (9 to 12 months) post-transplant patients (group 3, N = 14), patients with advanced CRF (glomerular filtration rate = 30 to 40 mL/min; group 4, N = 8), and patients who suffered from end-stage renal failure and were treated by chronic hemodialysis (group 5, N = 14). Group 2 manifested significant hypophosphatemia and phosphaturia when compared with groups 1 and 3 (Pi = 0.9 +/- 0.003 mg/dL, FE(PO4) = 68+/- 5%, P < 0.0005 vs. groups 1 and 3). Sera were taken from each of the five subject groups and applied to the proximal tubular opossum kidney (OK) cells. The activity of Na/Pi-type 4 (that is, OK-specific type II transporter) was evaluated by measuring Na(+)-dependent (32)Pi flux. The expression of Na/Pi type II mRNA and the abundance of Na/Pi protein were determined by Northern and Western blot assays, respectively.. When compared with sera from groups 1 and 3, 10% sera taken from groups 2, 4, and 5 (incubated overnight with OK cells) inhibited (32)Pi flux by 25 to 30% (P < 0.0003). Both Na/Pi mRNA and the expression of Na/Pi protein were markedly augmented under the same conditions (P < 0.05 groups 2, 4, and 5 vs. groups 1 and 3). Time-course analysis revealed that the up-regulation of Na/Pi protein by sera from groups 2, 4, and 5 was observed as early as four hours of incubation, whereas augmented abundance of Na/Pi mRNA was only seen after eight hours of incubation. The addition of PTH (1-34) to sera from groups 2, 4, and 5 abolished the augmented expression of NaPi protein. We labeled OK cell surface membrane proteins with N-hydroxysuccinimide bound to biotin (NHS-SS-biotin). Biotinylated transporters incubated with the different sera were precipitated by strepavidin and identified by Western blot analysis. Cells incubated in sera from group 2 showed increased membrane bound transporter when compared with control sera, whereas the intracellular pool of the transporter was comparable between the two groups.. A non-PTH circulating serum factor (possibly phosphatonin) that increases FE(PO4) during CRF is also responsible for phosphaturia and hypophosphatemia in the early period following successful kidney transplantation. The putative factor inactivates Na/Pi activity along with inhibition of the transporter trafficking from the cell membrane into the cytosol.

Topics: Adult; Aged; Animals; Biological Transport; Blood; Carrier Proteins; Cell Line; Female; Humans; Hypophosphatemia; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Opossums; Phosphorus Radioisotopes; Postoperative Complications; RNA, Messenger; Sodium-Phosphate Cotransporter Proteins; Sodium-Phosphate Cotransporter Proteins, Type II; Symporters; Thymic Factor, Circulating

High serum PRL and low zinc (Zn) levels are common findings in patients with chronic renal failure (CRF); in such patients serum Zn concentrations have been reported to be inversely correlated to serum PRL levels. Moreover, Zn regulates both thymus growth and the biological activity of the thymic hormone thymulin, and PRL-thymic interrelationships have been described. To determine whether hypozincemia alters serum PRL and plasma thymulin concentrations in CRF, 9 men with CRF treated by chronic hemodialysis were given 400 mg/day Zn sulfate, orally (4.96 meq/day Zn), for 6 months. Before treatment, serum PRL levels were significantly higher (P less than 0.001) in these patients than in normal men [mean, 28.7 +/- 20.7 (+/-SD) vs. 7.5 +/- 3.7 micrograms/L], and their serum PRL response to TRH (200 micrograms, iv) was impaired (mean maximal percent increase, 38.2 +/- 10.9 vs. 641 +/- 335; P less than 0.001). The plasma Zn-bound bioactive thymulin titer (1.3 +/- 0.7 1/log2), total thymulin titer (Zn-bound plus Zn-unbound forms, 2.1 +/- 0.8 1/log2), and serum Zn (13.1 +/- 2.4 mumol/L) were lower (P less than 0.001) in men with CRF than in normal men. Zn therapy did not induce any significant change in basal and TRH-stimulated serum PRL levels, while serum Zn levels significantly increased, reaching the normal range after the first week of treatment (17.8 +/- 6.3 mumol/L). Plasma total thymulin increased rapidly, reaching normal levels after 1 week, but Zn-bound thymulin increased modestly during the first month of treatment and more after 3 and 6 months of treatment. There was no age-related difference in plasma thymulin levels during therapy. We conclude that oral Zn administration in patients with CRF significantly increases both total and Zn-bound thymulin, but does not modify basal and TRH-stimulated serum PRL levels. The observation that Zn supplementation markedly increased plasma thymulin levels in uremic patients suggests that Zn is a potent stimulus for thymic hormone synthesis, and it can reverse the age-related diminution of thymic activity in CRF patients.

Topics: Adult; Humans; Kidney Failure, Chronic; Male; Middle Aged; Prolactin; Thymic Factor, Circulating; Thymus Hormones; Zinc

Topics: Adjuvants, Immunologic; Adolescent; Adult; Antibody Formation; Chronic Disease; Drug Therapy, Combination; Female; Glomerulonephritis; Hemostasis; Humans; Hypertension; Immunity, Cellular; Kidney Failure, Chronic; Male; Middle Aged; Nephrotic Syndrome; Thymus Hormones

Monoclonal antibody assays were employed to monitor modifications induced in human peripheral lymphocyte subsets by thymectomy or the administration of a series of immunomodulating drugs: synthetic thymic factor, cimetidine or various combinations of anti-thymocyte globulin, azathioprine and steroids. In patients with myasthenia gravis, thymectomy produced a gradual progressive decrease in the elevated OKT4/OKT8 ratios associated with this disease until normal ratios were achieved after one year. Administration of synthetic thymic factor to three immunodeficient children for one month produced increased serum IgA levels accompanied by a normalization of proportions of total T cells and T cell subsets. Four of five uremic patients receiving cimetidine exhibited a marked increase in the percentage of OKT8+ T cells observed in subsequent blood samples with a concomitant increase in immature (OKT4+, OKT8+) lymphocytes that suggested an increase in release of such lymphocytes from the thymus. Assessment of 29 longterm renal allograft recipients by repeated T cell monitoring over an extended period of time confirmed the findings of other investigators that an increase in the OKT4+/OKT8+ ratio was predictive of subsequent allograft rejection episodes while subnormal OKT4+/OKT8+ ratios were indicative of possible cytomegalovirus or herpes virus infections.

Topics: Animals; Antibodies, Monoclonal; Cimetidine; Cytomegalovirus Infections; Graft Rejection; Humans; Immune Tolerance; Immunoglobulin A; Kidney Failure, Chronic; Kidney Transplantation; Lymphocyte Activation; Mice; Myasthenia Gravis; T-Lymphocytes; Thymectomy; Thymic Factor, Circulating

Topics: Humans; In Vitro Techniques; Kidney Failure, Chronic; Rosette Formation; Thymic Factor, Circulating; Thymus Hormones