Ditte Hansen

Randomized controlled trial of cholecalciferol supplementation in chronic kidney disease patients with hypovitaminosis D

BACKGROUND Hypovitaminosis D is common in chronic kidney disease (CKD). Effects of 25-hydroxyvitamin D replenishment in CKD are not well described. METHODS An 8-week randomized, placebo-controlled, double-blind parallel intervention study was conducted in haemodialysis (HD) and non-HD CKD patients. Treatment consisted of 40,000 IU of cholecalciferol orally per week. Plasma 25-hydroxyvitamin D (25-OHD), plasma 1,25-dihydroxyvitamin D (1,25-diOHD), plasma parathyroid hormone (PTH), serum phosphate, ionized serum calcium and serum fibroblast growth factor 23 (FGF-23) were analysed. We also investigated biomarkers related to cardiovascular disease (plasma D-dimer, plasma fibrinogen, plasma von Willebrand factor antigen and activity, plasma interleukin 6, plasma C-reactive protein, blood pressure, aortic augmentation index, aortic pulse wave velocity and 24-h urinary protein loss). Objective and subjective health variables were assessed (muscle function tests, visual analogue scores and Health Assessment Questionnaire). RESULTS Fifty-two CKD patients with 25-OHD <50 nmol/L at screening were included. Cholecalciferol supplementation led to a significant increase to a median of 155 nmol/L 25-OHD (interquartile range 137-173 nmol/L) in treated patients (n = 25, P < 0.001). In non-HD patients, we saw a significant increase in 1,25-diOHD (n = 13, P < 0.01) and a lowering of PTH (n = 13, P < 0.001). This was not observed in HD patients. Cholecalciferol supplementation caused a significant increase in serum calcium and FGF-23. CONCLUSIONS 25-OHD replenishment was effectively obtained with the employed cholecalciferol dosing. In non-HD patients, it had favourable effects on 1,25-diOHD and PTH. Vitamin D-supplemented patients must be monitored for hypercalcaemia. The present study could not identify significant pleiotropic effects of 25-OHD replenishment.

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.

Severe hypercalcaemia, nephrocalcinosis, and multiple paraffinomas caused by paraffin oil injections in a young bodybuilder

A 23-year-old bodybuilder presented in August, 2013, with a 24 h history of scrotal pain. Swabs for infection, and abdominal CT scan for nephrolithiasis, were negative, but blood tests showed anaemia, renal insuffi ciency, and severe hypercalcaemia (free calcium 2·29 mmol/L, normal: 1·18–1·32 mmol/L). C-reactive protein was normal. He had suppressed parathyroid hormone, raised angiotensin-converting enzyme and interleukin receptor levels, low 25-hydroxyvitamin D, and high 1,25-dihydroxyvitamin D. Physical examination revealed many warm, dense nodules in the skin and subcutaneous tissue overlying the pectoral, trapezius, and biceps muscles. For cosmetic reasons, he had injected paraffi n oil into his chest, arms, and back for the past 3 years. After the last injection, 6 months previously, he had developed local infl ammation, treated with oral antibiotics twice, but he felt ongoing discomfort, and reported diffi culties breathing, associated with a tightening in the chest and neck. He had also been taking non-prescribed vitamin D, unspecifi ed dietary supplements, and anabolic steroids. A PET-CT scan showed increased metabolic activity in the subcutis of the anterior thorax and upper arms (fi gure). There were no signs of sarcoidosis. Skin punch biopsies showed paraffi nomas with vacuoles and a chronic, non-necrotising infl ammatory response, and immuno histochemical staining showed high expression of CYP27B1 (appendix). PCR for bacteria was negative. Pulmonary examinations showed diff use pulmonary infi ltration, segmental perfusion defects, reduced diff usion capacity, lipoid pneumonia, and foreign-body infl ammatory reaction (appendix). Tuberculosis microscopy and culture were negative. A kidney biopsy showed pronounced nephrocalcinosis (appendix). We treated the patient with intravenous fl uid infusion, diuretics, and pamidronate, and after the PET-CT with prednisolone 40 mg, moxifl oxacin 400 mg, and azithromycin 1000 mg daily. Despite poor adherence, at last follow-up in October, 2013, his calcium and creatinine had almost returned to normal, and skin infl ammation was substantially decreased. Complications of subcutaneous paraffi n oil injection have been known since the 19th century, but bodybuilders still use the technique to enhance muscle contouring. It causes acute local infl ammation usually followed by a latent phase. Dependent on the volume injected and potential contamination, chronic foreign-body granulomas may form, appearing as dense nodules with occasional ulceration or fi stulas secreting oily materials. Our patient developed paraffi nomas, which contributed to severe hypercalcaemia resulting in nephrocalcinosis and reduced renal function. Paraffi n oil migration caused respiratory problems. The initial scrotal pain, which did not recur, might have been caused by ureteral colic. Hypercalcaemia is common, usually caused by hyperparathyroidism, malignancy, or sarcoidosis, and can be life-threatening. Granulomatous foreign-body reactions are a rare but important diff erential diagnosis. Calcium is normally tightly regulated by parathyroid hormones and vitamin D, which is converted to the active form, 1,25-dihydroxyvitamin D (calcitriol), by CYP27B1. In granuloma-induced hyper calcaemia, as in our patient, calcitriol production is catalysed by abnormal activity of CYP27B1 in infl ammatory cells, particularly macro phages. This extrarenal activity does not appear to be regulated by classic feedback mechanisms, allowing calcitriol (and calcium ions) to rise to pathological levels.

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

Fibrin thrombi in deceased donor kidneys: Prevalence and influence on graft function and graft survival in transplanted patients

Fibrin thrombi (FT) are occasionally found in the pre‐implantation biopsy of kidneys from deceased donors. The aim of this study was to monitor the prevalence and answer the question whether FT has any impact on future graft function in a Danish patient cohort. We looked for FT in all donor kidney biopsies taken at the time of renal transplantation in a Danish transplantation unit during a 10‐year period. Every recipient transplanted with a FT donor kidney (n = 15) were matched with up to five control recipients (n = 69), and graft function and graft survival were assessed. FT was present in 3% of the transplanted donor kidneys. Graft function was reduced in the FT group 6 months after transplantation (median estimated glomerular filtration rate (eGFR): 29 mL/min vs 46 mL/min; p = 0.017), but at 12 months, an apparent difference did not reach statistical significance. More patients were on dialysis in the FT group after 12 months compared with the control group (27% vs 6%; p = 0.049). In conclusion, FT in donor kidney biopsies at time of transplantation is a risk factor for the development of reduced renal function during the first year of transplantation.

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.

Importance of Differentiation Between Phosphorous and Phosphate

ELEVATED PLASMA PHOSPHATE is considered a major risk factor for cardiovascular disease and mortality in patients with chronic kidney disease. Hyperphosphatemia is caused by excessive intake of phosphate-containing foods and other sources of phosphate, whereas the renal phosphate excretion is reduced. The average daily diet in the US adult population contains 1,200 to 1,600 mg phosphorous which is far above the recommended maximal daily intake of 800 to 1,000 mg for patients with advanced chronic kidney disease. Accordingly, such patients have major dietary challenges. The importance of identifying any major nondietary sources of phosphates is obvious. Recently, Nelson et al published a very interesting study of phosphate-containing prescription medications of Canadian hemodialysis patients. At least 30% of the patients were taking at least 1 medication that contained phosphate, and their estimated median daily intake of phosphate was 111 mg. Accordingly, the authors conclude that prescribed medications may contribute with a median of around 10% to the maximal daily load of phosphate in a considerable proportion of hemodialysis patients. However, this is an unjustified exaggeration. Phosphorous is an element with a molar weight of 30.97 g. Phosphate is a salt of phosphoric acid with a molar weight of 95.97 g for HPO4 22 and 96.97 g for H2PO4 . A recommended daily intake of phosphorous of 1,000 mg thus equals a little more than 3,000 mg of phosphate. Accordingly, the median phosphorous burden from prescribed medications in the study by Nelson et al was only 35 to 40 mg/day or approximately 4% of the recommended maximal intake for a dialysis patient. This may be the reason why the study did not find any association between phosphate load from medication and the phosphate level in the studied patients.