Disorders of calcium metabolism at various times after renal transplantation.

OBJECTIVES: Increased parathyroid hormone (PTH) production and related defects of calcium-phosphorus metabolism could persist even after successful kidney transplantation. Much more serious long term consequences after the transplantation are bone defects caused by immunosuppressive drugs. Many authors consider steroid therapy as one of the factors that maintain this process. Our study aimed to investigate calcium-phosphorus and bone pathological features during the various post transplantation periods, using non-invasive bone research methods (bone ultrasound structurally-densitometric analysis), and also to analyse the risk of hyperparathyroidism and steroid therapy in the development of post transplantation osteopathy. METHODS: 52 patients after successful kidney transplantation were investigated. All patients were divided in three groups according to the time after transplantation. 1st group-patients in the earlier post transplantation period, up to 1 year (n = 12); 2nd group-patients in the period from 1 to 5 years after transplantation (n = 25); 3rd group-patients in later post transplantation period (more than 5 years after the transplantation, n = 15). RESULTS: 8 patients from the 1st group (66.7%), 18 patients from the 2nd group (72%) and 8 patients from the 3rd group (53.3%) had an increased level of serum creatinine. The level of corrected serum Ca was increased (p < 0,05) in the first year after the transplantation. Hypercalcaemia was noted in 5 patients (41.7%) from the 1st group, in 3 patients (12%) from the 2nd group and in 2 patients (13.3%) from the 3rd group. Urine Ca level was lower (p < 0.05) in patients with post transplantation period over 5 years. Serum iPTH level as well as the level of osteocalcin was higher in all groups. The highest iPTH and osteocalcin level (p < 0.05) were observed during the first post transplantation year, but in the later post transplantation period they had a tendency to decrease, but never reached the norm for healthy subjects even in later post transplantation period. The decreased speed of ultrasound in the trabecular bones and osteopenia were noted in 6 patients from the 1st group (50%), osteoporosis -- in 1 patient from the 1st group(8.3%). In the 2nd group 8 patients had osteopenia (32%) and 1 patient had osteoporosis (4%), and in the 3rd group 7 patients had osteopenia (46.7%) and 4 patients -- osteoporosis (26.7%). A negative correlation was noted between patient age and speed of sound in all patient populations (r = -0.39, p<0,01), both in the early post transplantation period (r = -0.67, p<0.01), and during the period 1-5 years after transplantation (r = -0.5, p <0.01). The whole patient population showed negative correlation (r = -0.28, p<0.05) between Z-score and time after the transplantation. Z-score negatively correlates with a cumulative steroid dose in all investigated patients groups(r = -0.35, p<0.02). CONCLUSIONS: Disorders of calcium metabolism and immunosuppression related bone disease are the most common complications after transplantation, especially in patients with an impaired graft function. The mild hyperparathyroidism is usually noted in these patients at various times after transplantation. We also can note hypocalciuria in the later post transplantation period in these patients, which is based on the parathyroid glands hyperfunction and on the negative effects of the steroid therapy. The cumulative steroid dose and patient age are the determining factors for the development of osteopenia in transplantation patients at the stage of 5 or more years after transplantation.

Does the switch from sandimmun to Sandimmun neoral reduce patient need for Phenihydine?

In patients receiving cyclosporine A (CyA)-based immunosuppressive therapy, Ca2+ channel blockers (CCBs) prevent the development of CyA-related nephrotoxicity in which increased Ca2+ content plays an important role. We evaluated the dynamics of the intracellular (erythrocytes) and extracellular (plasma) Ca2+ levels and the influence of the CCB, Phenihydine, on this process during the conversion from Sandimmun (S) to Sandimmun Neoral (SN). Forty-two patients were enrolled. The conversion from S to SN normalized the elevated CA2+ level of erythrocytes in groups with Phenihydine (n = 20) and without Phenyhidine (n = 12) 4 weeks after the switch (P < 0.05); this level remained stable until the end of study. Therefore we suggest that the switch from S to SN is effective in reducing elevated intracellular Ca2+ levels. The decrease of Ca2+ content in erythrocytes was similar in all groups switched to SN (with or without Phenihydine). The last effect should be an important argument to focus the further long-term investigations on the ability of CCBs to act as cytoprotective and neophroprotective agents during immunosuppressive protocols with the new microemulsion formulation of CyA.

Effect of Sandimmun Neoral on the level of bivalent cations in erythrocytes of kidney transplant recipients.

In a 4 month study, a group of 16 patients with stable renal graft function receiving triple immunosuppressive therapy including cyclosporin A (Cy A) were investigated for the levels of calcium, magnesium and zinc in erythrocytes. The patients were randomized to be converted to the new microemulsion formulation (Sandimmun Neoral) in a 1:1 fashion (n = 8) or to continue with the classical formulation (Sandimmun) (n = 8). The concentrations of creatinine, phosphate, alkaline phosphatase activity, calcium, magnesium and zinc were measured twice a month in blood plasma. The concentration of calcium, magnesium and zinc in erythrocytes was also measured. The concentration of magnesium in blood plasma and erythrocytes during the study showed no deviation from normal values. The level of zinc in erythrocytes was almost twice as high as in normal healthy controls and was not dependent on Cy A formulation. Calcium content in erythrocytes of patients receiving Sandimmun was 27.6% higher than in healthy persons. Conversion of the patients to Sandimmun Neoral normalized the calcium concentration in erythrocytes and caused a transient increase of calcium levels in blood plasma.

[The metabolism of heavy metals depends on the vitamin-D status of the body]. / Obmen tiazhelykh metallov zavisit ot D-vitaminnogo statusa organizma.

The effect of vitamin D3 and its two metabolites 1,25(OH)2D3 and 24,25(OH)2D3 on the metabolism of heavy metals--Sr, Pb and Cd was studied. The experiments were carried out on chickens, the heavy metals were added to the chicken's ration. The results obtained demonstrated that vitamin D3 caused accumulation of those metals in tissues and their toxicity in organisms. When increasing the vitamin dose from 200 to 500 IU on 1 kg of ration that tendency was being heightened. On the three steroids which had been studied the metabolite 1,25(OH)2D3 displayed the greatest activity in accumulating metals in tissues, Pb in particular. The effect of 24,25(OH)2D3 on the indices being studied was comparable with that of vitamin D3.

[Effects of calcium on the course of strontium toxicosis]. / Vliianie kal'tsiia na techenie strontsievogo toksikoza.

Chronic intake of Sr for 20 days by chickens caused in them a delay in body mass increase and symptoms of rickets in spite of complete provision with vitamin D. There were low levels of Ca, P, enhanced activity of alkaline phosphatase in the serum, inhibited mineralization of bone tissue, reduced levels of vitamin D-dependent calcium-binding protein, Sr accumulation in various tissues. Enrichment with Ca of the chickens ration diminished the above signs of Sr toxicosis. It is suggested that a protective effect of Ca in chronic Sr toxicity may be due to more active discrimination of Sr against Ca in intestinal assimilation of these cations.

[Experience in treating metabolic osteopathies with 1 alpha-hydroxyvitamin D3 (oksidevit)]. / Opyt lecheniia metabolicheskikh osteopatii 1 al'fa-gidroksivitaminom D3 (oksidevitom).

The action of 1 alpha-hydroxycholecalciferol (oxydevit) was estimated in 204 patients with renal osteodystrophy, osteoporosis of varying etiology, osteomalacia because of malabsorption, congenital rickets-like diseases. The drug was shown to be highly effective in the treatment of secondary hyperparathyroidism in uremia, steroidal and senile osteoporosis. The treatment involved replacement therapy.

[24,25-Dihydroxyvitamin D3 modulates the effect of 1alpha-hydroxyvitamin D3 on B lymphocyte maturation in chickens]. / 24,25-Digidroksivitamin D3 moduliruet deistvie 1alpha-gidroksivitamina D3 na sozrevanie B-limfotsitov u tsipliat.

Patterns of calcium metabolism and maturation of lymphocytes in chicken Fabricius bursa were studied in presence of various doses of I alpha-hydroxy vitamin D3 and 24,25-dihydroxy vitamin D3 administered separately and at various combinations. 24,25(OH2)D3 was distinctly less effective in the antirickets activity as compared with I alpha (OH)D3. A decrease in mass of Fabricius bursa and inhibition of lymphocytes maturation within early steps were observed in the birds with rickets. A toxic dose of I alpha (OH)D3 caused pseudohypertrophy of Fabricius bursa. Small doses of these drugs administered simultaneously exhibited higher effect both on rickets and on stimulation of B lymphocytes maturation. 24,25(OH)2D3 attenuated the negative effect of either subtoxic (0.65 nmol/day) or toxic (1.3 nmol/day) doses of I alpha (OH)D3 on an increase in body mass, calcemia, ash content of bones, content of small lymphocytes in Fabricius bursa.

[Treatment of severe postmenopausal osteoporosis]. / Lechenie tiazhelogo postmenopauzal'nogo osteoporoza.

The paper is concerned with the results of therapy of a severe form of postmenopausal osteoporosis in 5 patients using the combination of estrogens, 1-alpha-hydroxycholecalciferol and calcitonin. The treatment with the above drugs was accompanied by marked improvement of the general status. It was characterized by an increase in daily calcium excretion with urine, normalization of the concentration of calcium, inorganic phosphorus and serum alkaline phosphatase activity. A conclusion was made that the combined use of estrogens and 1-alpha-hydroxycholecalciferol produced a more marked clinical effect than each drug separately.

[Immunocorrecting properties and effect on the phosphorus-calcium metabolism of oxidevit (1 alpha-hydroxyvitamin D3)]. / Immunokorrigiruiushchie svoistva i vliianie na fosforno-kal'tsievyi obmen oksidevita (1 alpha-hydroksivitamina D3).

Effect of oxidevite (I alpha-hydroxyvitamin D3) on the patterns of immunity system and metabolism of calcium and phosphorus were studied in 45 patients with chronic bronchitis, which, were treated with the drug at doses of 2 or 4 micrograms during 1 or 2 weeks. Specific patterns of calcium and phosphorus metabolism were altered in the patients depending on dose of the drug and duration of the course treatment. The dose of 4 micrograms per a day within 2 weeks was excessive. All the immunity patterns studied involving amount of total and rosette-forming cells, T-lymphocyte helpers and T-lymphocyte suppressors, B lymphocytes, were normalized independently on the initial level of these patterns: the elevated values decreased, the decreased values-increased. The normal values of the immunity patterns studied were not altered during the oxidevite treatment course. Content of blood inorganic phosphorus correlated with leukocytes dynamics.

[Effect of strontium on the anti-rickets activity of vitamin D3 and its hydroxy analogs]. / Deistvie strontsiia na antirakhiticheskuiu aktivnost' vitamina D3 i ego gidroksilirovannykh analogov.

Antirickets activity of vitamin D3 and of its derivatives 1 alpha- and 25-hydroxy vitamin D3 1.25- and 24,25-dihydroxy vitamin D3 and 1,24,25-trihydroxy vitamin D3 was studied in chicken maintained on a diet containing various amount (0.01-2.40 mg) of strontium. Vitamin D3 as well as its 24-hydroxy and 24,25-dihydroxy derivatives lost their antirickets activity in presence of high strontium concentrations. Under the same conditions I alpha-hydroxy, 1,25-dihydroxy and 1,24,25-trihydroxy vitamins D3 retained the ability both to induce calcium-binding protein synthesis in intestinal epithelium and to stimulate bone tissue mineralization, although to a lesser degree as compared with controls, kept on strontium-free diet. These results suggest that presence of I alpha-OH-group in the steroid molecule is necessary for expression of maximal biological activity under conditions of elevated strontium content in diet while the activity of hydroxylase is inhibited in kidney. At the same time, the vitamin D3 derivatives containing the OH-group are responsible for impairments caused by increased accumulation of strontium.

[Renal osteodystrophy and its possible correction in patients on chronic hemodialysis]. / Pochechnaia osteodistrofiia i vozmozhnosti ee korrektsii u bol'nykh, nakhodiashchikhsia na khronicheskom gemodialize.

Results of diagnosis and treatment of renal osteodystrophy are discussed concerning 162 patients with chronic renal failure treated by hemodialysis. In most cases (15%) osteopenia and hyperparathyroidism were revealed. Roentgenologic investigation revealed metastatic calcification mostly in foot vessels, whereas microscopic study of internal organs in the lungs. The increase of calcium concentration in dialysate from 1.75 to 2.5 Mmol/l was not followed by greater calcinosis in patients with hyperphosphatemia. Uremic pruritus was treated by ultraviolet irradiation and administration of prednisolone for 3-5 days. The effect of I alpha-hydroxy-vitamin D3 was studied in 30 patients. Improvement of clinical status and, principally, relief of muscular pains in the extremities was observed as well as positive changes in blood serum biochemical indices.

[Plasma zinc content in patients with chronic renal insufficiency before and after kidney transplantation]. / Soderzhanie tsinka v plazme bol'nykh khronicheskoi pochechnoi nedostatochnost'iu do i posle transplantatsii pochki.

Zinc content in blood plasma was measured in patients with chronic renal failure (CRF) before and after kidney transplantation by atomic-absorption spectrophotometry. Plasma zinc was revealed to be lowered. However, routine intake of vitamin A by the patients led to an elevation in zinc content. Hemodialysis did not alter blood plasma zinc concentration. It was noted that during the postoperative period, the zinc level returned to normal. Patients with CRF show marked disturbances of taste sensitivity, which are manifested in the increased threshold of taste sensitivity and perversion of taste sensations.

Vitamin D3 and 1,25-dihydroxyvitamin D3 stimulate the skeletal muscle-calcium mobilization in rachitic chicks.

The Ca content in skeletal muscle relative to vitamin D3 intake was studied in chicks. It was found that the Ca content in rachitic chick muscle was significantly higher than normal and it decreased with vitamin D3 treatment. In 4-week-old chicks fed a vitamin D-deficient diet, the Ca content in leg muscle reached 9.86 +/- 1.07 mg/100 g wet wt, although in chicks receiving vitamin D3 in doses of 100 and 500 IU/kg diet, it was 7.80 +/- 0.72 and 6.08 +/- 0.61 mg/100 g wet wt, respectively. A single i.m. dose of 0.50 micrograms of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) or vitamin D3 caused a dramatic decrease in the muscle Ca content by 3 to 6 h after the injection. A simultaneous rise in the Ca level in blood serum was observed. However, at this time the Ca binding protein content in duodenal mucosa and the stimulation of Ca absorption were negligible. These findings allow the conclusion that the vitamin D deficiency in chicks leads to a surplus Ca accumulation in skeletal muscle. The administration of vitamin D3 or its metabolites causes rapid Ca release during the first 6 h. This may be the source of the Ca level increase in blood serum. In this respect 1,25(OH)2D3 was much more effective than vitamin D3.

[Hypophosphatemia after successful transplantation of the kidney. Clinico-experimental study]. / Hypophosphatämie nach erfolgter Transplantation der Niere. Klinisch-experimentelle Untersuchung.

The dynamic of indices changes of phosphorus treatment with nefrons in 16 patients after kidney transplantation was studied. The transitory hypophosphatemia accompanied with urine was typical in the majority of patients. The decrease of reabsorption and elevation of phosphorus clearance were noted. In a number of cases the phosphatemia level was increased due to reduction of prednisolone doses. It was experimentally revealed that prednisolone reduces the phosphorus absorption in intestine at 25% and the treatment by 1,25-dihydroxy-vitamin D3 and 1 alpha-hydroxyvitamin D3 promotes the normalization of this process.