Lisbet Brandi

No difference between alfacalcidol and paricalcitol in the treatment of secondary hyperparathyroidism in hemodialysis patients: a randomized crossover trial

Alfacalcidol and paricalcitol are vitamin D analogs used for the treatment of secondary hyperparathyroidism in patients with chronic kidney disease, but have known dose-dependent side effects that cause hypercalcemia and hyperphosphatemia. In this investigator-initiated multicenter randomized clinical trial, we originally intended two crossover study periods with a washout interval in 86 chronic hemodialysis patients. These patients received increasing intravenous doses of either alfacalcidol or paricalcitol for 16 weeks, until parathyroid hormone was adequately suppressed or calcium or phosphate levels reached an upper threshold. Unfortunately, due to a period effect, only the initial 16-week intervention period for 80 patients was statistically analyzed. The proportion of patients achieving a 30% decrease in parathyroid hormone levels over the last four weeks of study was statistically indistinguishable between the two groups. Paricalcitol was more efficient at correcting low than high baseline parathyroid hormone levels, whereas alfacalcidol was equally effective at all levels. There were no differences in the incidence of hypercalcemia and hyperphosphatemia. Thus, alfacalcidol and paricalcitol were equally effective in the suppression of secondary hyperparathyroidism in hemodialysis patients while calcium and phosphorus were kept in the desired range.

Changes in fibroblast growth factor 23 during treatment of secondary hyperparathyroidism with alfacalcidol or paricalcitol

BACKGROUND Fibroblast growth factor 23 (FGF23) increases renal phosphate excretion and decreases the formation of 1,25 dihydroxyvitamin D. In patients with chronic kidney disease, plasma FGF23 levels are markedly elevated by unknown mechanisms. We explored the changes in FGF23 during treatment of secondary hyperparathyroidism (SHPT) with alfacalcidol or paricalcitol in haemodialysis patients. METHODS Intravenous alfacalcidol and paricalcitol were compared in haemodialysis patients with SHPT in a randomized 2 × 16-week cross-over study, with 6 weeks washout period preceding treatment and between treatment periods. In 57 of the enrolled patients, blood samples were frozen before and after each treatment period and available for measurement of FGF23. RESULTS Treatment with both analogues increased FGF23 (P < 0.05 in all treatment periods). The magnitude of increase was similar for alfacalcidol and paricalcitol (Period 1: 223 versus 314%; P = 0.384 and Period 2: 174 versus 227%; P = 0.510) and the levels returned to pre-treatment levels during the washout period. Independent predictors of rise in FGF23 were baseline levels of FGF23 (P < 0.01), changes in ionized calcium (P < 0.01) and phosphate (P < 0.01) and cumulative dose of vitamin D analogues (P = 0.024). CONCLUSION Alfacalcidol and paricalcitol increase the plasma levels of FGF23 equally and substantially in haemodialysis patients.

Five to 10 years follow-up after total parathyroidectomy and autotransplantation of parathyroid tissue : evaluation of parathyroid function by use of ischaemic blockade manoeuvre

The aim of the present study was to assess the long-term function of autotransplanted parathyroid tissue in patients with chronic renal disease. We examined the medical records of a consecutive series of 21 patients with chronic renal failure, who had undergone total parathyroidectomy with autotransplantation. During the time of follow-up, on average 79 months, one patient developed graft-dependent recurrent hyperparathyroidism and one patient suffered from persistent hypoparathyroidism. Nine of the patients were available for a clinical study. In these patients we measured the plasma concentration of intact PTH in blood from the arm contralateral to the graft-bearing arm at rest and during a short-lasting ischaemic blockade of the graft site from the circulating blood. At rest all nine patients had parathyroid hormone (PTH) values within the normal range. The ischaemic blockade produced a marked reduction in the plasma concentration of intact PTH in eight of the patients indicating well functioning autografts. Prior to the examination the patient with recurrent hyperparathyroidism had undergone resection of the autograft. In this patient, ischaemia of the former graft site did not cause any change in the concentration of PTH indicating normally functioning residual parathyroid tissue in the neck. Thus, the ischaemic blockade manoeuvre seems suitable for the assessment of autografted parathyroid tissue. Our results indicate that total parathyroidectomy with autotransplantation provides a rational alternative to the surgical treatment of secondary hyperparathyroidism.

Treatment of secondary hyperparathyroidism in haemodialysis patients: a randomised clinical trial comparing paricalcitol and alfacalcidol

BackgroundSecondary hyperparathyroidism is a common feature in patients with chronic kidney disease. Its serious clinical consequences include renal osteodystrophy, calcific uremic arteriolopathy, and vascular calcifications that increase morbidity and mortality.Reduced synthesis of active vitamin D contributes to secondary hyperparathyroidism. Therefore, this condition is managed with activated vitamin D. However, hypercalcemia and hyperphosphatemia limit the use of activated vitamin D.In Denmark alfacalcidol is the primary choice of vitamin D analog.A new vitamin D analog, paricalcitol, may be less prone to induce hypercalcemia and hyperphosphatemia.However, a randomised controlled clinical study comparing alfacalcidol and paricalcitol has never been performed.The primary objective of this study is to compare alfacalcidol and paricalcitol. We evaluate the suppression of the secondary hyperparathyroidism and the tendency towards hyperphosphatemia and hypercalcemia.Methods/DesignThis is an investigator-initiated cross-over study. Nine Danish haemodialysis units will recruit 117 patients with end stage renal failure on maintenance haemodialysis therapy.Patients are randomised into two treatment arms. After a wash out period of 6 weeks they receive increasing doses of alfacalcidol or paricalcitol for a period of 16 weeks and after a further wash out period of 6 weeks they receive the contrary treatment (paricalcitol or alfacalcidol) for 16 weeks.DiscussionHyperparathyroidism, hypercalcemia and hyperphosphatemia are associated with increased cardiovascular mortality in patients with chronic kidney disease.If there is any difference in the ability of these two vitamin D analogs to decrease the secondary hyperparathyroidism without causing hypercalcemia and hyperphosphatemia, there may also be a difference in the risk of cardiovascular mortality depending on which vitamin D analog that are used. This has potential major importance for this group of patients.Trial registrationClinicalTrials.gov NCT004695

Oral Magnesium Supplementation in Chronic Kidney Disease Stages 3 and 4: Efficacy, Safety, and Effect on Serum Calcification Propensity—A Prospective Randomized Double-Blinded Placebo-Controlled Clinical Trial

Introduction Chronic kidney disease (CKD) is associated with high cardiovascular morbidity and mortality. Recent evidence suggests that increases in both serum and intracellular magnesium (Mg) can slow or even prevent the development of vascular calcification seen in CKD. Serum calcification propensity (T50) is a novel functional test, which is associated with all-cause mortality in CKD and measures the ability of serum to delay the formation of crystalline nanoparticles. Theoretically, increasing serum Mg should improve T50 and thereby reduce the propensity towards ectopic calcification. Methods We conducted a randomized placebo-controlled double-blinded clinical trial to investigate the safety of 2 different doses of oral Mg supplementation in subjects with CKD stages 3 and 4 as well as their effects on intracellular Mg and T50. Thirty-six subjects with CKD stages 3 and 4 were randomized to one of 3 groups (placebo, elemental Mg 15 mmol/d or elemental Mg 30 mmol/d) given as slow-release Mg hydroxide and followed for 8 weeks. Results Thirty-four subjects completed the trial. Intracellular Mg remained stable throughout the trial despite significant increases in both serum and urine Mg. T50 increased significantly by 40 min from 256 ± 60 (mean ± SD) to 296 ± 64 minutes (95% confidence interval, 11–70, P < 0.05) in the Mg 30 mmol/d group after 8 weeks. No serious adverse events related to the study medication were reported during the study. Discussion Oral Mg supplementation was safe and well tolerated in CKD stages 3 and 4 and improved T50, but did not increase intracellular Mg. Further studies are needed to investigate the long-term effects of Mg supplementation in CKD stage 3 and 4 and whether improvement in calcification propensity is related to clinical endpoints.

The effect of magnesium supplementation on vascular calcification in chronic kidney disease—a randomised clinical trial (MAGiCAL-CKD): essential study design and rationale

Introduction Chronic kidney disease (CKD) is associated with an increased risk of cardiovascular disease and mortality, which is thought to be caused by increased propensity towards vascular calcification (VC). Magnesium (Mg) inhibits phosphate-induced VC in vitro and in animal models and serum Mg is inversely associated with cardiovascular mortality in predialysis CKD and in end-stage renal disease. This paper will describe the design and rationale of a randomised double-blinded placebo-controlled multicentre clinical trial, which will investigate whether oral Mg supplementation can prevent the progression of coronary artery calcification (CAC) in subjects with predialysis CKD. Methods and analysis We will randomise 250 subjects with estimated glomerular filtration rate of 15 to 45 mL/min/1.73 m2 to 12 months treatment with either slow-release Mg hydroxide 30 mmol/day or matching placebo in a 1:1 ratio. The primary end point is change in CAC score as measured by CT at baseline and after 12 months treatment. Secondary end points include change in pulse wave velocity, bone mineral density, measures of mineral metabolism and clinical end points related to cardiovascular and renal events. Ethics and dissemination This trial has been approved by the local biomedical research ethics committees and data protection agencies and will be performed in accordance with the latest revision of the Helsinki Declaration. The trial will examine for the first time the effect of increasing the uptake of a putative VC inhibitor (ie, Mg) on progression of CAC in subjects with predialysis CKD. Trial registration number NCT02542319, pre-results.

The Effect of High Dose Cholecalciferol on Arterial Stiffness and Peripheral and Central Blood Pressure in Healthy Humans: A Randomized Controlled Trial.

Background Low levels of serum 25-hydroxy vitamin D are associated with increased arterial stiffness and hypertension. Supplementation with vitamin D precursors has been proposed as a treatment option for these conditions. We examined the effect of oral cholecalciferol on arterial stiffness and blood pressure in healthy normotensive adults. Methods 40 healthy adults were randomised in this double-blinded study to either oral cholecalciferol 3000 IU/day or matching placebo and were followed for 16 weeks to examine any effects on pulse wave velocity (PWV), augmentation index (AIx), peripheral and central blood pressure and 24-hour ambulatory blood pressure. Results 22 subjects in the cholecalciferol arm and 18 subjects in the placebo arm completed the 16 weeks of follow-up. There was no difference in changes in PWV, AIx corrected for heart rate or central or peripheral blood pressure between the two groups. There was no correlation between serum 25-hydroxy vitamin D and any of these parameters. Conclusions Oral cholecalciferol 3000 IU/day does not affect arterial stiffness or blood pressure after 16 weeks of treatment in healthy normotensive adults. Trial Registration ClinicalTrials.gov NCT00952562

Comparison between 1α(OH)D3 and 1,25(OH)2D3 on the Suppression of Plasma PTH Levels in Uremic Patients, Evaluated by the ‘Whole’ and ‘Intact’ PTH Assays

Background/Aims: The aim was to evaluate the acute effects of intravenous 1α(OH)D₃ and 1,25(OH)₂D₃ on (1) plasma parathyroid hormone (PTH) and Ca²⁺ levels in chronic uremic patients and (2) circulating large C-terminal PTH fragments as measured by the ‘whole PTH’ assay compared to two different ‘intact PTH’ assays. Methods: 11 patients on chronic hemodialysis with plasma intact PTH >90 pg/ml were studied. At time zero 10 µg 1,25(OH)₂D₃ (Calcijex, Abbott, USA), or 10 µg 1α(OH)D₃ (Etalpha, LEO, Denmark) or 10 ml of isotonic saline was injected as a bolus. Blood samples for analyses of plasma Ca²⁺ and plasma PTH were drawn at 0, 6, 12, 24, 48 and 72 h. The same patient was studied 3 times in a random fashion with an interval of 3 weeks. Further, 7 of the patients were studied after an injection of 6 µg 1,25(OH)₂D₃ intravenously. Results: No significant changes in plasma Ca²⁺ and PTH were seen after administration of saline. Twenty-four hours after administration of 1,25(OH)₂D₃, plasma PTH decreased from a maximum level of PTH_WHOLE 151 ± 27 to a minimum of 58 ± 13 pg/ml; from a maximum level of PTH_TOTAL 247 ± 40 to a minimum of 99 ± 26 pg/ml and from a maximum level of PTH_INTACT 205 ± 29 to a minimum of 83 ± 18 pg/ml (p < 0.001). Twenty-four hours after administration of 1α(OH)D₃, plasma PTH levels decreased from a maximum level of PTH_WHOLE 155 ± 21 to a minimum of 116 ± 15 pg/ml; from a maximum level of PTH_TOTAL 265 ± 33 to a minimum of 221 ± 35 pg/ml and from a maximum level of PTH_INTACT 222 ± 26 to a minimum of 182 ± 23 pg/ml (p <0.05). Regardless of which of the three assays that was applied, the percentage suppression of PTH following administration of 1,25(OH)₂D₃ was approximately 60% and following administration of 1α(OH)D₃ approximately 20%. Significant correlations were demonstrated between the Whole and the intact PTH assays, and as expected between the 2 intact assays (‘Whole’/‘Intact’, r = 0.92, p < 0.0001, ‘Whole’/‘Total’, r = 0.94, p < 0.0001, ‘Intact’/‘Total’, r = 0.97, p < 0.0001) with no influence of the two vitamin D analogs administered. Plasma Ca²⁺ remained stable after administration of saline. After 24 h, no increase in plasma Ca²⁺ was observed after administration of 1α(OH)D₃ or after administration of 6 µg 1,25(OH)₂D₃, while plasma Ca²⁺ after administration of 10 µg 1,25(OH)₂D₃ increased to 1.31 ± 0.03 mmol/l (p < 0.008). After 72 h, 1α(OH)D₃ increased plasma Ca²⁺ to 1.22 ± 0.02 mmol/l (p < 0.05) and 10 µg 1,25(OH)₂D₃ to 1.27 ± 0.03 mmol/l. Plasma phosphate was within the normal range before administration of saline (1.24 ± 0.13 mmol/l), 1,25(OH)₂D₃ (1.28 ± 0.12 mmol/l) and 1α(OH)D₃ (1.46 ± 0.21 mmol/l). Plasma phosphate increased significantly after 24, 48 and 72 h to a maximum of 2.06 ± 0.27 mmol/l after administration of 1,25(OH)₂D₃ and a maximum of 1.94 ± 0.31 mmol/l after administration of 1α(OH)D₃. Plasma phosphate was significantly higher after 1,25(OH)₂D₃ than after 1α(OH)D₃ at 48 (p = 0.016) and 72 h (p < 0.010). Conclusion: A single intravenous dose of both 10 µg 1,25(OH)₂D₃ and 1α(OH)D₃ significantly suppressed plasma PTH. The acute suppressive effect of 1,25(OH)₂D₃ was 3 times greater than that of 1α(OH)D₃. The increase in plasma Ca²⁺ after intravenous administration of 10 µg of 1,25(OH)₂D₃ was, however, significantly greater than that of 10 µg of 1α(OH)D₃ (p < 0.005). The PTH response to acute administration of 10 µg of the two vitamin D analogs was in principle the same, when measured by the three different assays and resulted in a parallel shift of the PTH response curves. Thus, circulating levels of large C-terminal PTH fragments were not influenced by differences in plasma Ca²⁺ or by the vitamin D analog given.

Claus Brun (1914-2014)

With the death of Claus Brun, just a few months after his 100th birthday, Danish, European and international nephrology have lost one of their great founding personalities. Claus Brun was a pioneer in nephrology, who, in the late 40s, introduced the technique of performing a percutaneous kidney biopsy. He created the basis for our understanding of renal histopathology and its correlation with functional and clinical data. He eagerly participated in the international exchange of ideas during these early days and became the President of the International Society of Nephrology (ISN) from 1963 to 1966. Claus Brun was born in 1914 in Copenhagen. He graduated from the University of Copenhagen in 1940 and worked for almost his entire professional life at the Municipal Hospital in Copenhagen until his retirement in 1984. Claus Brun became a specialist in clinical biochemistry in 1948 and in nephrology in 1969. Together with Poul Iversen, he was the first to publish the method of performing a percutaneous kidney biopsy in the classic paper, ‘Aspiration Biopsy of the Kidney’ (Am J Med 11:324–330, 1951). The authors obtained adequate biopsy tissue in 42 out of 66 patients with a minimum of bleeding complications. They also described how to diagnose amyloidosis, diabetic nephropathy, hypercalcaemia and glomerulonephritis based on the pathology. The introduction of the percutaneous kidney biopsy has created the possibility of obtaining an accurate diagnosis, and as such, has provided the optimal treatment for a very great number of patients with kidney diseases worldwide. In 1956, Jean Hamburger, from the Hôpital Necker, invited Claus Brun to come to Paris and demonstrate the kidney biopsy technique and to explain the histological results, leading to the establishment of an international network of scientists interested in kidney function and disease. In 1960, they organized the First International Congress of Nephrology with 400 participants. Jean Hamburger became the first President of ISN and Claus Brun the second. He became President of the Danish Society of Nephrology in 1969 and was awarded the prestigious Novo Nordic Award in 1964 and later received the Knight’s Cross of the Order of the Dannebrog. Claus Brun’s path to nephrology was based upon a lifelong scientific and clinical interest in patients with acute and chronic kidney diseases. The theme of his doctoral thesis from 1954 was ‘Acute anuria, a study based on renal function tests and aspiration biopsy of the kidney’ and was based upon his clinical observations at the Municipal Hospital in Copenhagen, his work at Department of Clinical Biochemistry and the experiences from his sabbatical in the USA at the Department of Physiology, at New York University and Mt. Desert Island Biological Laboratory, Maine, where, from 1952 to 1953, he had the great fortune to work together with the esteemed Homer Smith. He was interested in clinical nephrology and in the physiological aspects of acute and chronic kidney failure and was the first to introduce an artificial kidney in Denmark. Claus Brun published a great number of scientific papers, many in the best scientific medical journals. Claus Brun became Chief Physician in 1956 at the Department of Clinical Biochemistry at the Municipal Hospital in Copenhagen where he created his kidney pathology laboratory. He was known all over the world for his high-quality work. His biopsies were always of the best quality and his meticulous descriptions extremely precise. For years, his work has been the gold standard for histology, and his histological atlas on glomerulonephritis, written together with Steen Olsen, is used all over the world.

The Effect of Increasing Dialysate Magnesium on Serum Calcification Propensity in Subjects with End Stage Kidney Disease: A Randomized, Controlled Clinical Trial

BACKGROUND AND OBJECTIVES Serum calcification propensity is a novel functional test that quantifies the functionality of the humeral system of calcification control. Serum calcification propensity is measured by T50, the time taken to convert from primary to secondary calciprotein particle in the serum. Lower T50 represents higher calcification propensity and is associated with higher risk of cardiovascular events and death in patients with ESKD. Increasing magnesium in serum increases T50, but so far, no clinical trials have investigated whether increasing serum magnesium increases serum calcification propensity in subjects with ESKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We conducted a single-center, randomized, double-blinded, parallel group, controlled clinical trial, in which we examined the effect of increasing dialysate magnesium from 1.0 to 2.0 mEq/L for 28 days compared with maintaining dialysate magnesium at 1.0 mEq/L on T50 in subjects undergoing hemodialysis for ESKD. The primary end point was the value of T50 at the end of the intervention. RESULTS Fifty-nine subjects were enrolled in the trial, and of these, 57 completed the intervention and were analyzed for the primary outcome. In the standard dialysate magnesium group, T50 was 233±81 minutes (mean±SD) at baseline (mean of days -7 and 0) and 229±93 minutes at follow-up (mean of days 21 and 28), whereas in the high dialysate magnesium group, T50 was 247±69 minutes at baseline and 302±66 minutes at follow-up. The difference in T50 between the two groups at follow-up (primary analysis) was 73 minutes (between-group difference; 95% confidence interval, 30 to 116; P<0.001), and the between-group difference in serum magnesium was 0.88 mg/dl (95% confidence interval, 0.66 to 1.10; P=0.001). CONCLUSIONS Increasing dialysate magnesium increases T50 and hence, decreases calcification propensity in subjects undergoing maintenance hemodialysis. PODCAST This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2018_08_21_CJASNPodcast_18_9_B.mp3.