Pulsed doses of calcitriol in the treatment of secondary hyperparathyroidism in patients on hemodialysis

Administration of pulse doses of calcitriol is a better way of conservative treatment of secondary hyperparathyroidism (2HPT), making use of the direct suppression of parathormone (PTH) secretion. In a group of 29 haemodialyzed patients the authors evaluated during a six-month follow-up the effect of intravenous Calcijex in 12 and of oral Rocaltrol in 8 subjects. In responders of the calcijex group the PTH level declined by 67.6%, the mean baseline PTH value being 787.8 pg/ml, as compared with non-responders where the decline of PTH at the end of the investigation was 7.5%, the baseline PTH being 1296.4 pg/ml. The difference was significant (p < 0.05). In patients treated with Rocaltrol the therapeutic effect was apparent also in subjects with a lower baseline PTH. An associated phenomenon of treatment are as a rule parallel changes of kALP and ACP levels with those of PTH. It was however revealed that the drop of serum activities can occur also without a concurrent drop of PTH which indicates a dissociation between the level of bone metabolism and PTH secretion. The therapeutic effect can be influenced not only by the stage of 2HPT but also by the route of administration and quantity of calcitriol doses, as ensues from a long-term follow up of one patient. Moreover, the morphological substrate of the hyperplastic tissue of the parathyroid gland and their receptors for 1,25(OH)2D3 must be taken into account. Successfully performed parathyroidectomy, a still justified therapeutic step, is associated as a rule with rapid restoration of PTH levels. TO CONCLUDE: Pulse doses of calcitriol seem to be at present the effective treatment of diagnosed 2HPT, conventional oral calcitriol doses are useful in 2HPT prophylaxis. 2. The i.v. form should be the last resort of conservative treatment before parathyroidectomy. 3. Calcitriol treatment should attempt to maintain slightly raised PTH levels. 4. The limiting indicators of treatment are hypercalcaemia, hyperphosphataemia and the development of extraosseous calcifications. 5. In order to adhere to these criteria it is necessary to use dietary provisions, the dialyzation technique and check biochemical indicators of bone metabolism and possibly change doses of pharmaceutical preparations.     

Low-dose intravenous calcitriol treatment of secondary hyperparathyroidism in hemodialysis patients. Italian Group for the Study of Intravenous Calcitriol

Intravenous calcitriol is known to directly suppress PTH secretion and release. We evaluated the effect of four months of treatment with low-dose intravenous calcitriol on PTH levels in 83 hemodialysis patients. The criteria for including patients in the study were a serum PTH levels at least four times the normal limit, a serum total calcium less than 10 mg/dl and good control of the serum phosphorus level. All patients underwent standard bicarbonate or acetate dialysis; dialysate calcium level was maintained at the usual 3.5 mEq/liter concentration. Initial calcitriol dose was 0.87 +/- 0.02 (SEM) micrograms (0.015 micrograms/kg body wt) thrice weekly at the end of dialysis, and it was reduced in case of hypercalcemia or elevated calcium-phosphate product. Seven out of 83 patients dropped out during treatment. Among the 76 patients who completed the study, 58 (76%) showed a highly significant decrease of intact PTH levels (average reduction 48%) and of alkaline phosphatase levels after four months of therapy. Total serum calcium increased slightly but significantly in the responder group but remained unchanged in the non-responders. No significant changes in ionized calcium levels could be detected, even in responders. Treatment was well tolerated by patients, but 60% of them had transient episodes of hyperphosphatemia. Mean serum phosphate was 4.95 mg/dl at the beginning of the study. It increased significantly after four months of treatment in patients who showed a decrease of PTH levels, although it remained within acceptable limits, below 5.5 mg/dl. Twenty-eight of 76 patients (37%) reduced the dose of calcitriol because their calcium-phosphate products exceeded 60.(ABSTRACT TRUNCATED AT 250 WORDS)     

Intermittent calcitriol therapy in secondary hyperparathyroidism: a comparison between oral and intraperitoneal administration

BACKGROUND: Intermittent oral or intravenous doses of calcitriol given two or three times per week are commonly used to treat secondary hyperparathyroidism (secondary HPT). This study was undertaken to compare the biochemical and skeletal responses to thrice weekly intraperitoneal (i.p.) versus oral doses of calcitriol in children with secondary HPT undergoing peritoneal dialysis (CCPD). METHODS: Forty-six patients aged 12.5+/-4.8 years on CCPD for 22+/-25 months were randomly assigned to treatment with oral (p.o.) or i.p. calcitriol for 12 months; 17 subjects given p.o. calcitriol and 16 subjects given i.p. calcitriol completed the study. Bone biopsies were performed at the beginning and at the end of the study, while determinations of serum and total ionized calcium, phosphorus, alkaline phosphatase, parathyroid hormone (PTH) and calcitriol levels were done monthly. RESULTS: Serum total and ionized calcium levels were higher in subjects treated with i.p. calcitriol, P < 0.0001, whereas serum phosphorus levels were higher in those given p.o. calcitriol, P < 0.0001. For the i.p. group, serum PTH levels decreased from pre-treatment values of 648+/-125 pg/ml to a nadir of 169+/-57 pg/ml after nine months. In contrast, serum PTH levels did not change from baseline values of 670+/-97 pg/ml in subjects given p.o. calcitriol, P < 0.0001 by multiple regression analysis. Serum alkaline phosphatase levels were also lower in patients treated with i.p. calcitriol, P < 0.0001, but there was no difference between groups in the average dose of calcitriol given thrice weekly. The skeletal lesions of secondary HPT improved in both groups, 33% of patients developed adynamic bone lesion. CONCLUSION: Differences in the bioavailability of calcitriol and/or in phosphorus metabolism may account for the divergent biochemical response to p.o. and i.p. calcitriol.     

Limitations of pulse oral calcitriol therapy in continuous ambulatory peritoneal dialysis patients

Calcitriol is increasingly used for therapy of secondary hyperparathyroidism in patients with end-stage renal disease. Its therapeutic efficacy, however, often has been limited by the associated increase in intestinal calcium and phosphorus absorption. Previous studies reported that these side effects could be avoided by intermittent administration of calcitriol in high doses, subsequently referred to as pulse therapy. The present study was designed to investigate pulse oral calcitriol therapy in a patient subgroup especially susceptible to the development of hypercalcemia and hyperphosphatemia under standard continuous calcitriol treatment. We examined 15 peritoneal dialysis patients with moderate degrees of hyperparathyroidism (intact parathyroid hormone [iPTH] levels, 150 to 903 pg/mL) ingesting between 1.5 and 6 g of calcium salts as the sole phosphate binders. Treatment consisted of 0.5 microgram calcitriol twice weekly. Eight of these patients had been previously converted to low calcium dialysate to tolerate the necessary doses of phosphate-binding calcium salts. During the study period, comprising 8 pretreatment weeks and 8 weeks of therapy, dialysates and doses of calcium salts were not changed, so that only calcitriol influenced the determined parameters. As expected, iPTH levels decreased rapidly in all patients (P < 0.0001). However, within 4 weeks of treatment a marked increase in calcium phosphorus products was observed (P < 0.0001). Overt hypercalcemia developed in five patients. We concluded that pulse oral calcitriol has to be carefully monitored in peritoneal dialysis patients receiving high doses of calcium salts because of the increased risk for hypercalcemia and hyperphosphatemia.     

Surgical treatment of secondary hyperparathyroidism in patients treated with renal replacement]

Between January 1990 and July 1997, in 15 maintenance dialyzed patients and in 3 patients after renal transplantation manifesting hyperparathyroidisms surgical treatment was performed. The diagnosis was based both on the estimation of serum PTH level, total and ionised calcium, phosphates, alkaline phosphatase and imaging procedures: ultrasonography and 99-mTc subtraction scintigraphy. Indications to surgical treatment included ailments like generalized prurigo, bone and joint pains and muscular weakness with no response to pharmacological treatment. The commonly used procedure was subtotal parathyroidectomy (94%), its extent, however, was in each case determined during surgery, depending on the quantity and size of parathyroid glands found. In all cases the immediate intraoperative histopathological examination of the resected tissues was performed. In 10 patients resection of the thyroid gland tissues was carried out because of goiter (56%), among them in 1 case occult papillar carcinoma was found in histopathological examination. In the postoperative period 4 patients (22%) manifested transient hypocalcemia with good response to pharmacological treatment. Good results of surgical treatment reflected by both ailment relief and normalization of serum PTH and phosphates were obtained in 16 patients (89%). In 2 patients (11%) the ailments subsided but did not completely disappear. Surgical treatment of secondary hyperparathyroidism by subtotal parathyroidectomy is efficacious and entails a low risk of complications.     

Controlled trial of falecalcitriol versus alfacalcidol in suppression of parathyroid hormone in hemodialysis patients with secondary hyperparathyroidism

Since the first reports in the late 1950's, a large amount of data have been collected. The analysis of the main evidence from the major randomized trials will be analyzed in this paper according to preoperative, postoperative and chemoradiation approaches. Fifteen randomized preoperative trials were reported; they have been grouped according to the fractionation schedule. In the hypofractionation group (5 Gy for fraction), all five studies that delivered 3-5 doses in one week had a significant improvement in local control and one of them also showed improvement in survival. Operative mortality was higher in the radiotherapy arm if inadequate techniques had been applied. In 3 out of 8 studies with conventional fractionation there was a significant improvement in local control, but no impact in survival was detected. No studies with total dose lower than 34 Gy had an improvement in local control. None of the six randomized postoperative studies showed an improvement in local control or survival. In all trials the local control rate was uniform; ranging from 76% to 84%. Toxicity was higher in the radiotherapy arm. One preoperative and five postoperative randomized studies that used chemoradiation were analyzed. One postoperative chemoradiation study showed a significant improvement in survival in comparison to the surgery arm, and another showed the same advantage compared to the postoperative arm. Protracted infusional administration of 5FU concomitant to radiotherapy showed better survival than bolus administration. No advantages were shown in using MeCCNU or Levamisole in two studies. Toxicity was high and related to the dose and the modality of administration of the drugs in order to adequately treat the different stages of rectal cancer, patients must be carefully selected in order to prescribe the most effective and the least toxic treatment for the individual stage; organ preservation should be an essential goal for its impact on quality of life, and the cost estimates should be taken into account.     

Indications for parathyroidectomy and extent of treatment for patients with secondary hyperparathyroidism

Some manifestations of secondary hyperparathyroidism affect most if not all patients with chronic renal failure and can affect many different organ systems. Proper medical treatment is essential and should be attempted before considering surgical intervention. The symptoms that most often resolve after parathyroidectomy include bone pain and intractable pruritus. Other useful indications for operation include a marked elevation of the parathyroid hormone level and the elevation of the calcium x phosphate product over 70. Both subtotal parathyroidectomy and total parathyroidectomy with autotransplantation have been advocated as the best operative approach. Each of these procedures has its own advantages and disadvantages which should be considered for each individual case. Localizing procedures should be reserved for patients with persistent or recurrent hyperparathyroidism, as diffuse parathyroid hyperplasia is the most common operative finding in secondary hyperparathyroidism.     

Language therapy effects in long term aphasia

This report describes the results of language therapy initiated 1 to 6 years after the onset of aphasia in 14 patients. During the course of treatment, each of the 14 patients improved strongly in their communicative abilities (PICA), according to clinical observation and reports from family, hospital ward personnel, or both.     

In vitro parathyroid hormone release in patients with secondary hyperparathyroidism

BACKGROUND: The purpose of this study was to determine the precise endocrine characteristics of parathyroid function in secondary hyperparathyroidism (sHPT). METHODS: We examined the effects of extracellular ionized calcium (Ca2+) varying from 0.5 to 2.0 mM on parathyroid hormone (PTH) release in parathyroid cell suspensions using a mid-regional PTH assay. Cells were obtained from 26 patients with sHPT who were divided into two groups according to the type of hyperplasia they exhibited, either nodular (n = 16) or diffuse (n = 10). For comparison, we also analyzed data from nine patients with primary hyperparathyroidism (pHPT; adenomas). RESULTS: Significant in vitro suppression of PTH release by Ca2+ was observed in the majority of subjects, regardless of the histologic abnormality. The pHPT group exhibited no significant relationship between clinical and in vitro data. In contrast, in the sHPT group (taken as a whole), suppression of PTH release by Ca2+ exhibited a plateau at a total serum calcium concentration of 2.5 mmol/L, and a parathyroid gland weight of 2 g. CONCLUSIONS: These findings suggest that there is a curvilinear relationship in sHPT, but not pHPT, between the in vitro calcium sensitivity of parathyroid cells and total serum calcium, as well as gland weight. The in vitro calcium sensitivity in sHPT remains constant when the total serum calcium concentration exceeds 2.5 mmol/L, or when the gland weight exceeds 2 g.     

Intravenous calcitriol therapy restores reduced antigen-induced T-lymphocyte response in 1,25-(OH)2D3-deficient hemodialysis patients

Phosphatidylinositide-specific phospholipase Cs (PI-PLCs) catalyze the calcium-dependent hydrolysis of phosphatidylinositides in response to diverse stimuli in higher eukaryotes. Mammalian PI-PLCs contain divergent regulatory regions, but all share three conserved regions: an N-terminal pleckstrin homology (PH) domain, X, and Y. We report the high-level expression and characterization of a recombinant "catalytic core" of rat PI-PLC delta 1 that contains the catalytically essential X and Y regions, but not the PH domain. The expressed protein, PI-PLC delta delta 1-134, is catalytically active versus phosphatidylinositol 4,5-bisphosphate in deoxycholate micelles with a K(m) of 182 microM and a Vmax of 27 mumol/min/mg. PI-PLC delta delta 1-134 is monomeric and monodisperse as judged by dynamic light scattering. Far-UV CD indicates a structure with approximately 35% alpha-helix. A reversible change in the near-UV CD spectrum is observed on addition of calcium, suggesting that calcium can bind PI-PLC delta delta 1-134 in the absence of phospholipid. Triclinic crystals of PI-PLC delta delta 1-134 have been obtained that diffract beyond 2.4 A resolution under cryogenic conditions. Based on Vm = 2.72 Da/A3 and on the self-rotation function, there are two PI-PLC delta delta 1-134 molecules per asymmetric unit that are related to each other by a noncrystallographic axis of approximate twofold symmetry parallel to a.     

Altered instantaneous and calcium-modulated oscillatory PTH secretion patterns in patients with secondary hyperparathyroidism

The relative contributions of increased parathyroid cell mass and altered control mechanisms of parathyroid hormone (PTH) secretion in secondary hyperparathyroidism are still controversial. In this study, endogenous pulsatile PTH secretion was analyzed by the multiparameter deconvolution technique to differentiate alterations in cell mass-dependent (PTH burst mass) and regulation-dependent (frequency, synchrony, calcium responsiveness) PTH release in uremic patients. PTH concentration versus time profiles were obtained in 13 uremic and 16 healthy adults under baseline conditions and during acute hypo- and hypercalcemia. Plasma PTH half-life was increased in patients compared with control subjects (4.7+/-1.9 versus 2.6+/-0.1 min, P < 0.005). The baseline PTH secretion rate was elevated eightfold in the patients as a result of an increased PTH mass secreted per burst (17.1+/-4.7 versus 2.0+/-0.4 pM, P = 0.0001), higher burst frequency (8.0+/-0.3 versus 6.8+/-0.3 h(-1), P < 0.01), and a higher tonic secretion rate (343+/-99 versus 30+/-4 pM/h, P = 0.0001). Acute hypocalcemia elicited an immediate, frequency- and amplitude-mediated selective increase in the pulsatile secretory component, which was fractionally weaker in patients (+595%) than control subjects (+1755%, P < 0.001). The acceleration and the amplification of PTH bursts were 35 and 60% lower in the patient group. Acute hypercalcemia suppressed total PTH secretion by 79% in control subjects but only by 63% in patients (P < 0.002). PTH burst frequency was reduced during hypercalcemia by 30% in control subjects, but remained unchanged in patients. In conclusion, uremic hyperparathyroidism is mediated by a marked increase in glandular secretion, but also by reduced PTH elimination. The increased spontaneous PTH burst frequency and the blunted responsiveness to changes in Ca2+ indicate partial uncoupling of hyperplastic parathyroid glands from the physiologic regulatory mechanisms that direct pulsatile PTH release.     

Iron therapy in patients undergoing maintenance hemodialysis

Studies were conducted of the effect of temperature and humidity, variant of plague microbe, frequency and duration of feeding and specificity of the host on the blockformation in the souslik fleas C. tesquorum and N. setosa infected with plague. 28 tests on the effect of temperature and humidity on the blockformation were undertaken, for which 14411 fleas of the above species were used. A temperature of 16 to 22 degrees proved to be optimal; at this temperature the number of blocked fleas (C. tesquorum) varied from 21.2 to 42.7% and that of N. setosa--from 41.9 to 54.2%. Marmot variant of plague microbe caused the formation of the "block" in 53.3 to 55.1% of fleas of N. setosa in 3-4 days and in 28.0 to 42.7% of C. tesquorum in 10-14 days after the infection. In C. tesquorum the process of blockformation is affected by the frequency of feeding, in N. setosa--by the duration of each feeding.     

Oral DMSO therapy in 3 patients with lipoidproteinosis. Results of long-term therapy

Lipoid proteinosis is a rare autosomal recessive disorder with a chronic, benign course. There is no generally accepted systemic therapy apart from the experimental oral use of dimethyl sulphoxide (DMSO) and etretinate in two single cases. We treated two sisters and an unrelated man with lipoid proteinosis with longterm oral DMSO (60 mg/kg/d). At the end of an average treatment time of 3 years, DMSO was withdrawn because it produced no beneficial effects with regard to their skin, mucosal lesions or hoarseness. Additionally, one patient showed progression of her disease with worsening hoarseness and onset of dyspnea, requiring surgical removal of vocal cord infiltrates. Three patients with lipoid proteinosis failed to show any beneficial response to long term treatment with DMSO.     

Safety and efficacy of pulse and daily calcitriol in patients on CAPD: a randomized trial

BACKGROUND: Calcitriol therapy is the mainstay of therapy for the treatment of secondary hyperparathyroidism. Oral administration of calcitriol is necessary in CAPD patients, but no studies have directly compared different routes of administration in this patient population. METHODS: To determine if the peak serum calcitriol level (pulse therapy) is more important than the total delivered dose, we randomized CAPD patients with mild to moderate secondary hyperparathyroidism to receive either pulse (3.0 microg twice a week, n = 10) or daily (0.75 microg a day, n = 8) oral calcitriol in comparable weekly doses. The main comparison was the rate of decline of serum intact parathyroid hormone (PTH) levels to reach the desired end-point of 100 pg/ml. The patients were dialysed with low-calcium dialysate and received only calcium-containing phosphate binders. RESULTS: Pharmacokinetic analysis after a single dose of 3.0 microg (pulse) vs 0.75 microg (daily) revealed 1,25(OH)2-vitamin D levels to be higher in the pulse group at 3 and 6 h, but equivalent by 12 h. The area under the curve for 1 week of daily and 1 week of pulse therapy was equal. The patients in the 2 arms had equivalent basal serum levels of PTH (pulse = 562 +/- 291 vs daily = 454 +/- 113 pg/ml), calcium (pulse = 2.32 +/- 0.20 vs daily = 2.32 +/- 0.12 mmol/l) and phosphorus (pulse = 1.32 +/- 0.52 vs daily = 1.35 +/- 0.26 mmol/l). The time required for the PTH to decrease to 100 pg/ml and the rate of decline in PTH were similar (time: pulse = 14.2 +/- 6.8 weeks, daily = 12.2 +/- 7 weeks; rate: pulse = 7.4 +/- 4.2 vs daily = 8.4 +/- 4.2% PTH/week; P = NS). The serum calcium increased similarly in both groups. Hypercalcaemia (> 2.9 mmol/l) was rare (pulse = 3, daily = 2 episodes). CONCLUSIONS: This study demonstrates that pulse and daily calcitriol are similarly effective and safe for the treatment of mild to moderate secondary hyperparathyroidism in CAPD patients despite higher peak levels of 1,25(OH)2-vitamin D with pulse therapy.     

Serum folic acid in anticonvulsant long term therapy (author''s transl)

Forty Holstein heifer calves were assigned at random among four dietary treatments: 1) an all-concentrate ration; 2) a pelleted complete ration of 20% alfalfa and 80% concentrate; 3) concentrate and alfalfa pellets fed separately, free-choice; and 4) concentrate and long-stem alfalfa hay fed separately, free-choice. Treatment diets were continued for 12 wk. Calves fed the concentrate only had reduced weight gains, feed intakes, and poorer feed efficiencies compared to treatments 2 and 4. Calves fed long-stem alfalfa hay as a roughage consumed more feed and had larger weight gains than calves fed alfalfa pellets as a roughage free-choice. The pelleted complete ration containing 20% alfalfa was comparable to a ration containing long-stem alfalfa hay free-choice for weight gains and feed efficiencies. The digestibility of dry matter and crude protein of the pelleted complete feed was similar to the digestibility of equal amounts and proportions of concentrate and alfalfa pellets fed separately. Thus, when fed free choice to early-weaned calves, pelleted alfalfa is inferior to long-stem hay for stimulating intake of dry matter. However, increasing the proportion of alfalfa pellets in a complete ration compensates for its partial loss of efficacy for elevating feed intake and growth rates.