Are 'middle molecules' responsible for toxic phenomena in chronic renal failure?
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Biomedical subjects
Publications and source records attributed to P Contreras.
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Although hyperprolactinemia and galactorrhea occur in primary hypothyroidism, factors influencing their presence are not well established. To further define these factors, the duration of illness and serum levels of PRL and TSH were investigated in a group of 50 patients with spontaneous (27 females and 7 males) and iatrogenic (16 females) primary hypothyroidism. To test the hypothesis of reduced hypothalamic dopamine content in over long-standing primary hypothyroidism, the percent increase in serum PRL after the administration of metoclopramide, a dopamine blocker (2.5 mg, iv bolus), was studied in 13 women with spontaneous primary hypothyroidism and compared with that in 10 euthyroid women. While 88.2% of the patients with spontaneous primary hypothyroidism were hyperprolactinemia, only 31% of those with iatrogenic disease had elevated PRL levels. Women with spontaneous primary hypothyroidism had a longer duration of illness (72 +/- 12 vs. 6.7 +/- 1.8 months; P less than 0.001) and higher serum TSH (189 +/- 32 vs. 68 +/- 14 microunits/ml; P less than 0.01) and PRL levels (49.8 +/- 5.6 vs. 20.9 +/- 0.8 ng/ml; P less than 0.001) than women with iatrogenic hypothyroidism. A linear correlation existed between PRL and duration of illness (r = 0.53; P less than 0.001), while a logarithmic correlation was found between PRL and TSH levels (r = 0.44; P less than 0.01). Even though the duration of illness and TSH levels were similar in women with spontaneous disease with (n = 7) or without (n = 20) galactorrhea, the former were significantly younger (39.3 +/- 1.8 vs. 56.6 +/- 3 yr; P less than 0.001), and their PRL levels were significantly higher (69.3 +2- 8.9 vs. 42.9 +/- 2.2 ng/ml; P less than 0.001). The PRL response to metoclopramide in women with spontaneous disease was significantly smaller than that in controls (194 +/- 39% vs. 446 +/- 40%; P less than 0.001) and inversely correlated with basal PRL levels (r = -0.55; P less than 0.05). These data indicate that in primary hypothyroidism 1) the duration of illness is important in the development of hyperprolactinemia, 2) galactorrhea is more common in young women with spontaneous disease and high PRL levels, and 3) hypothalamic dopamine appears reduced in spontaneous disease.
The cell-mediated immunodeficiency secondary to renal failure is well established and is largely dependent on toxic or inhibitory serum factors. Our approach was to investigate the effect of so-called middle molecules (MM) on in vitro and in vivo immunological functions. A crude fraction of MM isolated from the serum or urines of uremic patients by chromatography on Sephadex G-25 fine was shown to markedly inhibit the lymphocyte proliferation induced in vitro by various phytomitogens or by allogeneic cells. A marked depression of the graft-versus-host reaction was demonstrated in vivo. When rats were continuously infused with MM, a significant delay of skin allograft rejection was obtained. From these results it is clear that the MM fraction contains a potent inhibitor of several T lymphocyte functions.
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A potent inhibitor of cell proliferation was found in the urine of a patient with chronic renal failure. This substance included in "middle molecules" (MM) fraction, was obtained by chromatography. This factor was shown to inhibit noticeably the proliferation of various cells : lymphocytes stimulated by allogeneic cells, monolayer cell lines of normal or tumorous origin and leukemic cell lines derived from acute lymphoblastic leukemia. This effect was reversible and thus could not be related to a direct, rapid cytotoxic effect of MM. Such substances could play an important part in uremic symptoms, such as immunodeficiency, anemia, thrombopenia, gastrointestinal or skin manifestations.
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Pregnant albino rats were treated during the eighth day of gestation (GD 8), with two IP injections, spaced by 4 hours, of either ethanol (2.9 g/kg in 24% v/v saline solution) or saline. Maternal blood alcohol levels reached a peak of 457 mg/dl 60 min after the second dose. At the age of 45 days, an equal number of male and female offspring were injected with 3.5 g/kg ethanol and sleep time and blood ethanol levels were determined upon awakening. Ethanol metabolic rate was studied in other individuals injected with the same dose of ethanol and the slope of the linear descending portion of the curves was calculated. Animals that received ethanol in utero exhibited shorter sleep time and higher blood ethanol levels at the moment of awakening than controls. The rate of ethanol metabolism was similar in both groups. These results show that an acute intoxication with ethanol during GD 8 induced long-term changes in the CNS of offspring which caused reduced sensitivity to ethanol hypnotic effects.
In order to evaluate the S-100 concentration in cerebrospinal fluid from subjects with nonischemic brain damage, a total of 33 samples were analyzed: 11 from subjects in whom no organic disease could be found; 14 from patients with a diagnosis of lymphocytic or bacterial-fungal meningitis, and 8 from patients with acute lymphatic leukemia but no demonstrable signs of meningeal involvement. In all cases, the subjects considered had no previous history of melanoma or ischemic brain damage. The mean levels +/- SEM found for each study group were 1.00 +/- 0.11, 1.67 +/- 0.23 and 1.17 +/- 0.14 microg/l, respectively. Significant differences appeared between the groups when applying the Kruskal-Wallis nonparametric test (p = 0.035). The highest levels were found in the meningitis group and were significantly different from those of the control group (p = 0.015). No significant differences were found with regard to age or sex. Based on the pathophysiology of meningitis and on previous studies, the results suggest the existence of brain damage caused by an infection as a possible cause of increased S-100 levels.