The effect of 1alpha-hydroxyvitamin D3 in patients with chronic renal failure, with particular emphasis on the renal handling of phosphate.
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Biomedical subjects
Publications and source records attributed to K Olgaard.
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The influence of extracellular fluid volume expansion on the plasma aldosterone concentration (PAC) was investigated in five anephric and six non-nephrectomized patients on regular haemodialysis, and compared to a control group of four anephric and four non-nephrectomized patients. Plasma-renin activity, cortisol, Na+, and K+ were measured together with the PAC during the investigation. In anephric patients the PAC remained constant during the control period as well as during extracellular fluid volume expansion by infusion of 350 mmol of 20% mannitol. In the non-nephrectomized patients PAC diminished after mannitol infusion. The decline in PAC was correlated with the basal levels of PAC and the plasma renin activity. It is concluded that 5% extracellular fluid volume expansion has no direct influence on the regulation of PAC in patients without the renal renin-angiotensin system and that the regulation of PAC in anephric patients in the present investigation is probably mediated by changes in potassium and ACTH.
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To investigate whether a direct influence exists between the prolactin suppressive effect of alpha-bromoergocriptine (CB 154) and the aldosterone response to a potassium stimulation, the present study was performed in 7 anephric patients and in 7 non-nephrectomized patients, all on regular haemodialysis. The increase in the plasma potassium concentration between dialysis was used as a stimulus to the adrenals, and was correlated to the increase in the plasma aldosterone concentration (PAC). Plasma samples were obtained during a control period and during a corresponding period of treatment with bromocriptine. Despite a significant fall in the prolactin levels during the bromocriptine treatment, no differences in the aldosterone response to the increasing potassium concentration in the two periods were found neither in the anephric nor in the non-nephrectomized patients. It is concluded that depression of prolactin levels by the dopamine agonist (bromocriptine) has no influence on the ability of the adrenals to react with an increase in aldosterone secretion following potassium stimulation in dialysis patients with and without preserved renin-angiotensin system.
We evaluated a new automatic analyzer for ionized calcium (Ca2+), the Orion Model SS-20, based on a flowthrough ion-exchange electrode. Ca2+ was measured in heparinized whole blood and serum. Within-day variation was 1.2%, day-to-day variation1.6%, and analytical recovery 92.4%. Over the phsiological range interference by K+ and Mg2+ was negligible; major changes in ionic strength, induced by changes in N+ concentration, made correction for a sodium error necessary. Within the physiological range, Ca2+ was inversely correlated to variations in pH. Therefore, to compare Ca2+ values, correction to an apparent pH of 7.40 should be made. The calcium binding effect of heparin was negligible when minimal (4.4 int. units/ml) concentrations of heparin were used. Storage of serum at 4 degrees C for one week resulted in a 4 degrees decrease in apparent serum Ca2+, primarily owing to an increase in pH during storage. In normal material, mean values for blood-and serum-Ca2+(1.10 and 1.07 mmol/liter, respectively) were close to results obtained by previous systems. Errors caused by disturbances in the fluid flow and non-function of half the electrodes we received were the major inconveniences of the analyzer. We conclude that this new analyzer gives decisive advantages in measurement of Ca2+, making this importnant analysis possible as a routine laboratory test for the first time.
The circadian rhythm of plasma aldosterone (PAC) and cortisol concentration (PCC), and renin activity (PRA) was measured in five steroid and five non-steroid treated kidney transplanted patients--all with denervated kidney grafts--and compared with four normal controls and two steroid-treated patients with non-renal disease and thus normal renal innervation. The non-steroid treated patients had a normal circadian thythm of PAC and PCC, but without variation of PRA, suggesting that denervation of the kidneys has no influence on the circadian rhythm of PAC. In both steroid treated groups the PAC showed an inverse diurnal variation--now correlating to the diurnal variation in PRA. The inverse circadian rhythm of PAC in patients with suppressed ACTH secretion remains unexplained, but is in accordance with the nocturnal peak of sodium and water excretion in steroid treated patients.
In order to investigate the possible reversibility of renal osteodystrophy, eleven necrograft recipients were investigated six years after transplantation, when treatment with prednisone had been withdrawn for 1.5 years. Serum ionised calcium, phosphorus, alkaline phosphatases, PTH, skeletal radiography, Technetium polyphosphate (Tc-PP) bone scintigraphy and radial bone mineral content (BMC) were studied. Normal blood biochemistry, radiography and Tc-PP scintigraphy were found in nine (82%) of the patients, in contrast to the considerably higher frequency of abnormalities ordinarily found in haemodialysis patients. However, the radial BMC was significantly reduced (mean 13.5%) and identical with the BMC value in haemodialysis patients. We conclude that some regression of renal osteodystrophy may take place after a successful kidney transplantation, but that decreased mineralisation of the appendicular skeleton persists. Whether this latter finding is due to long-term steroid treatment or is an indicator of an irreversible component in renal osteodystrophy cannot be stated.
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The evaluation of a recently introduced kit (Cortipac (R)) for measuring plasma cortisol by competitive protein binding technique without prior extraction of steroids from plasma, is presented. The blank value was less than 2.5 mug/100 ml, and the lowest measurable value was 2.5 mug/100 ml. The coefficients of variation within- and between-batch determinations were 8.64% and 9.21% respectively. By adding known amounts of cortisol to pre-extracted plasma a linear correlation between calculated and measured cortisol was obtained. In comparison with the double isotope derivate technique, a linear correlation was found. A high degree of cross-reaction was found with nearly all of 11 tested steroids. Due to the considerably higher plasma cortisol concentration in most clinical cond-tions, the lack of specificity may be of minor importance, but must be considered in evaluating increased plasma cortisol values. The mean plasma cortisol concentration in normal subjects (20.3 mug/100 ml) was equal to or slightly higher than found by other methods. The kit was found appropriate for routine clinical application, due to the easy, rapid and inespensive performance with an acceptable recovery and reliability, but it cannot entirely replace more specific methods.
Five adult patients with chronic renal failure and associated renal osteodystrophy have been treated for 6 months with 1-alpha-hydroxycholecalciferol (1 alpha-OH-D3), a synthetic vitamin D analogue. All 5 patients had severe metabolic bone changes as estimated by bone scintigraphy. Three patients were hypocalcemic, 4 had elevated serum alkaline phosphatases, 5 had elevated serum immunoreactive parathyroid hormone (i-PTH) concentration and 3 had bone pains. During treatment serum calcium increased in all patients (mean 11.4%) and 3 originally hypocalcemic patients became normocalcemic. Serum alkaline phosphatases decreased (mean 27.3%) and became normal in 4 patients, who initially had elevated values. A pronounced decline in the serum concentration of i-PTH (mean 53%) was seen in all patients and 1 patient obtained normal i-PTH levels after 4 months of treatment. The intestinal calcium absorption, which was low initially, even when calcium intake was considered, rose almost threefold (mean 273%) and reached normal values in all cases. The bone mineral content increased in all patients, but the changes were small (mean 4.9%) and insignificant. Finally, bone pain disappeared in 2 patients and improved in 1 of 3 patients exhibiting this symptom. A linear correlation (r = 0.48, p less than 0.001) was found between the dose of 1 alpha-OH-D3 and serum calcium. But in spite of this and the frequent control, all patients developed one episode of hypercalcemia. This disappeared within 48 hours after discontinuing the drug. It is concluded that treatment with 1 alpha-OH-D3 appears to be of therapeutic value in metabolic bone disease associated with chronic renal failure, but frequent control of blood biochemistry seems mandatory.
The relation between the renal handling of phosphate, expressed as the maximal tubular reabsorption of phosphate (TmP)/glomerular filtration rate (GFR) index, and the serum concentration of immunoreactive parathyroid hormone (i-PTH) has been ivestigated in 15 patients with a very wide range of GFR, TmP/GFR and i-PTH. Seven patients had well functioning kidney allografts, with GFR ranging from 43.1 to 64.9 ml/min, while eight had varying degrees of chronic nephropathy, with GFR ranging from 26.7 to 2.3 ml/min. The TmP, the i-PTH concentration, the 51Cr EDTA clearance, the extracellular volume and the serum concentrations of calcium and standard bicarbonate were estimated during conditions where tubular reabsorption of phosphate was maximal. An inverse significant correlation was demonstrated between TmP/GFR and i-PTH (p less than 0.001), while none of the other investigated factors correlated to the TmP/GFR index. It is therefore concluded that the parathyroid hormone has a key role in the regulation of the tubular handling of phosphate in patients with impaired renal function.
The effect of 1-alpha-hydroxycholecalciferol (1alpha-OH-D3) on the renal handling of phosphate and the immunoreactive parathyroid hormone in serum (i-PTH) has been studied in 10 patients with a wide range of glomerular filtration rate (GFR), maximal tubular reabsorption of phosphate (TmP) and i-PTH. The patients were treated with 2 mug 1alpha-OH-D3 per day for approximately 80 days. Before and after this period of treatment, the TmP, i-PTH, 51Cr EDTA clearance, extracellular volume, standard bicarbonate, and serum calcium were measured in each patient. The TmP/GFR ratio was used as an index of the renal handling of phosphate. The index increased significantly (mean 26.5%, p less than 0.01) during the treatment, while i-PTH decreased significantly (mean 37.0%. p less than 0.01). An inverse significant correlation was demonstrated between TmP/GFR index and i-PTH both before (r = -0.87, p less than 0.001) and after (r = -0.79, p less than 0.01) the administration o alpha-OH-D3, while none of the other factors investigated were correlated to the index. It is concluded that 1alpha-OH-D3 increases the TmP/GFR index and reduces i-PTH in a parallel manner and it is therefore suggested that the 1alpha-OH-D3-induced changes in the renal handling of phosphate may be explained as being mediated solely via the suppression of i-PTH.
99Tcm-polyphosphate (Tc-PP) bone scintigraphy was performed in 30 consecutive uremic patients on regular hemodialysis and compared with a normal control group. 27 of the patients (90%) had pathological accumulation on the scintigrams, while roentgenographic abnormalities were present in only 10 patients (33%), indicating that scintigraphy is superior to X-ray in the early detection of skeletal changes in uremic patients. In the group with the most pronounced uptake on the scintigrams there was a preponderance of previously kidney-transplanted patients, while no correlation could be demonstrated between the severity of the scintigraphic findings and the duration of the hemodialysis period, the anephric state of the patients, the underlying kidney disease or the sex. It is suggested that intensive glucocorticoid treatment, even of short duration in the previously kidney-transplanted patients, may aggravate uremic osteodystrophy.
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It has recently been suggested that the measurement of the glycoprotein hormones and their subunits in human serum may serve as biochemical markers of non-endocrine tumours. Using radioimmunoassays for LH, FSH, HCGbeta-, LHbeta- and the common alpha-subunit, significant differences in the levels of these substances could not be detected between patients with oat cell lung tumours and patients with chronic renal failure. However, compared to normal subjects the alpha-subunit levels in serum were elevated in 12% of the male and 30% of the female patients with oat cell carcinoma of the lund and in 80 and 50% of the male and female patients, respectively, with chronic renal failure. The LHbeta-subunit concentration was normal in all tumour patients and none of these patients had detectable (less than 4 ng/ml) levels of HCGbeta-subunit. While such measurements may be of value in relationship to particular neoplasms, it appears that raised levels of glycoproteins and their subunits may be found in other disease states.
After increasing the intracellular potassium concentration of seven anephric patients without changing the total body potassium, by administration of insulin-glucose, the plasma-aldosterone concentration increased significantly to 180 percent of the pre-infusion value despite a drop in plasma potassium. A significant correlation between the decrease in the plasma potassium and the increase in plasma aldosterone concentration was found. Plasma cortisol remained unaffected. ACTH stimulation of five anephric patients resulted in a significant simultaneous increase in plasma aldosterone as well as in plasma cortisol. These studies indicate that changes in the intracellular potassium concentration, as well as ACTH stimulation, are important regulators of the aldosterone secretion in anephric patients.
In a consecutive material of 42 female patients, who were treated with intermittent dialysis for chronic renal failure between May 1964 and Nov. 1971, 21 developed ovarian cysts. The cysts were found only among the 29 women, who had menstrual periods from commencement of dialysis (16 cases) or who started menstruating on dialysis after a period of secondary amenorrhoea (13 cases). No cysts were found in the remaining 13 patients, who had amenorrhoea throughout, and of whom 6 were in all probability postmenopausal. Seven of the 21 patients with ovarian cysts had pronounced symptoms, necessitating acute surgery in 4. Fourteen asymptomatic cases were diagnosed at routine gynaecological examination, which was performed at regular intervals in all patients. There is strong evidence suggesting that the development of ovarian cysts was somehow related to the dialytic treatment and neither to the uraemic state nor to the nature of the primary renal disease. The mechanism by which dialytic treatment may be opertional in the development of this hitherto undescribed complication is discussed, but no clear-cut explanation can be given.