Nonskeletal and skeletal effects of high doses versus low doses of vitamin D3 in renal transplant recipients: Results of the VITALE (VITamin D supplementation in renAL transplant recipients) study, a randomized clinical trial.

Vitamin D sufficiency is associated with a reduced risk of fractures, diabetes mellitus, cardiovascular events, and cancers, which are frequent complications after renal transplantation. The VITALE (VITamin D supplementation in renAL transplant recipients) study is a multicenter double-blind randomized trial, including nondiabetic adult renal transplant recipients with serum 25-hydroxy vitamin D (25(OH) vitamin D) levels of <30 ng/mL, which is randomized 12 to 48 months after transplantation to receive high (100 000 IU) or low doses (12 000 IU) of cholecalciferol every 2 weeks for 2 months and then monthly for 22 months. The primary outcome was a composite endpoint, including diabetes mellitus, major cardiovascular events, cancer, and death. Of 536 inclusions (50.8 [13.7] years, 335 men), 269 and 267 inclusions were in the high-dose and low-dose groups, respectively. The serum 25(OH) vitamin D levels increased by 23 versus 6 ng/mL in the high-dose and low-dose groups, respectively (P < .0001). In the intent-to-treat analysis, 15% versus 16% of the patients in the high-dose and low-dose groups, respectively, experienced a first event of the composite endpoint (hazard ratio, 0.94 [0.60-1.48]; P = .78), whereas 1% and 4% of patients in the high-dose and low-dose groups, respectively, experienced an incident symptomatic fracture (odds ratio, 0.24 [0.07-0.86], P = .03). The incidence of adverse events was similar between the groups. After renal transplantation, high doses of cholecalciferol are safe but do not reduce extraskeletal complications (trial registration: ClinicalTrials.gov; identifier: NCT01431430).

[Use of iron in nephrology: Results of a French practical survey]. / Utilisation du fer en néphrologie : enquête sur les pratiques des néphrologues français.

The French-speaking Society of Nephrology, Dialysis and Transplantation conducted, in 2018, a survey among French nephrologists into their iron prescribing habits for patients with chronic kidney disease stages 3 to 5 before dialysis. The results show that 73% of nephrologists use intravenous iron before dialysis stage. When a patient has gastrointestinal symptoms under oral iron therapy, only 48% of nephrologists use intravenous route. The starting thresholds for iron are for 78% of nephrologists a transferrin saturation <20% and for 80% a serum ferritin <100 µg/L. Only 14% start iron when a transferrin saturation <25% or higher and 29% start iron when serum ferritin <200 µg/L or higher. High dosages of iron (500 and 1000 mg) are used by 58% of nephrologists. Finally, about 30% of nephrologists refer to various barriers to intravenous iron prescription, such as cost, unavailability of intravenous iron in their facility or lack of day hospital unit. The correction of iron deficiency without anemia remains controversial. It is performed by only 43% of nephrologists. These results show an improvement of the practices compared to a 2006 survey. However, they indicate a sub-prescription of iron compared to the European recommendations which recommend a starting threshold of iron of transferrin saturation <25% and ferritinemia <200 µg/L in anemic patients not treated with erythropoietin-stimulating agents.

Extracellular Fluid Volume Is an Independent Determinant of Uncontrolled and Resistant Hypertension in Chronic Kidney Disease: A NephroTest Cohort Study.

Background Hypertension is highly prevalent during chronic kidney disease ( CKD ) and, in turn, worsens CKD prognosis. We aimed to describe the determinants of uncontrolled and resistant hypertension during CKD . Methods and Results We analyzed baseline data from patients with CKD stage 1 to 5 (NephroTest cohort) who underwent thorough renal explorations, including measurements of glomerular filtration rate (clearance of 51Cr-EDTA) and of extracellular water (volume of distribution of the tracer). Hypertension was defined as blood pressure ( BP ; average of 3 office measurements) ≥140/90 mm Hg or the use of antihypertensive drugs. In 2015 patients (mean age, 58.7±15.3 years; 67% men; mean glomerular filtration rate, 42±15 mL/min per 1.73 m2), prevalence of hypertension was 88%. Among hypertensive patients, 44% and 32% had uncontrolled (≥140/90 mm Hg) and resistant (uncontrolled BP despite 3 drugs, including a diuretic, or ≥4 drugs, including a diuretic, regardless of BP level) hypertension, respectively. In multivariable analysis, extracellular water, older age, higher albuminuria, diabetic nephropathy, and the absence of aldosterone blockers were independently associated with uncontrolled BP . Extracellular water, older age, lower glomerular filtration rate, higher albuminuria and body mass index, male sex, African origin, diabetes mellitus, and diabetic and glomerular nephropathies were associated with resistant hypertension. Conclusions In this large population of patients with CKD , a lower glomerular filtration rate, a higher body mass index, diabetic status, and African origin were associated with hypertension severity but not with BP control. Higher extracellular water, older age, and higher albuminuria were independent determinants of both resistant and uncontrolled hypertension during CKD . Our results advocate for the large use of diuretics in this population.

Randomized Clinical Trial of Sevelamer Carbonate on Serum Klotho and Fibroblast Growth Factor 23 in CKD.

BACKGROUND AND OBJECTIVES: Epidemiologic studies suggest that higher serum phosphaturic hormone fibroblast growth factor 23 levels are associated with increase morbidity and mortality. The aim of the FGF23 Reduction Efficacy of a New Phosphate Binder in CKD Trial was to evaluate the effect of sevelamer carbonate on serum C-terminal fibroblast growth factor 23 levels in normophosphatemic patients with CKD stage 3b/4. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Patients with CKD, eGFR between 45 and 15 ml/min per 1.73 m2, fasting serum phosphate concentration >3.1 mg/dl, and serum C-terminal fibroblast growth factor 23 >80 relative units/ml were included in our double-blind, placebo-controlled, randomized multicenter study. All patients received 100,000 IU cholecalciferol at time of randomization. Participants received either placebo or sevelamer carbonate 4.8 g daily during a 12-week period. Biologic parameters, including serum C-terminal fibroblast growth factor 23, intact fibroblast growth factor 23, and α-klotho, were evaluated at baseline and 12 weeks after inclusion. RESULTS: Of 96 screened patients, 78 (mean±SD age: 63±13 years old; 70% men; mean eGFR: 27±9 ml/min per 1.73 m2) met the inclusion criteria. At baseline, mean eGFR was 27±9 ml/min per 1.73 m2, mean serum phosphate level was 3.8±0.5 mg/dl, and median (interquartile range) serum C-terminal fibroblast growth factor 23 level was 157 (120-241) relative units/ml. After 12 weeks of treatment, urinary phosphate-to-creatinine ratio fell significantly in the sevelamer group. The sevelamer and placebo groups did not differ significantly in terms of median change in serum C-terminal fibroblast growth factor 23 levels: the median (interquartile range) change was 38 (-13-114) relative units/ml in the placebo group and 37 (-1-101) relative units/ml in the sevelamer group (P=0.77). There was no significant difference in serum intact fibroblast growth factor 23, α-klotho, or phosphate levels changes between the two groups. Serum total and LDL cholesterol levels fell significantly in the sevelamer group. CONCLUSIONS: In our double-blind, placebo-controlled, randomized study performed in normophosphatemic patients with CKD, a 12-week course of sevelamer carbonate significantly reduced phosphaturia without changing serum phosphorus but did not significantly modify serum C-terminal fibroblast growth factor 23 and intact fibroblast growth factor 23 or α-klotho levels.

VITamin D supplementation in renAL transplant recipients (VITALE): a prospective, multicentre, double-blind, randomized trial of vitamin D estimating the benefit and safety of vitamin D3 treatment at a dose of 100,000 UI compared with a dose of 12,000 UI in renal transplant recipients: study protocol for a double-blind, randomized, controlled trial.

BACKGROUND: In addition to their effects on bone health, high doses of cholecalciferol may have beneficial non-classic effects including the reduction of incidence of type 2 diabetes mellitus, cardiovascular disease, and cancer. These pleiotropic effects have been documented in observational and experimental studies or in small intervention trials. Vitamin D insufficiency is a frequent finding in renal transplant recipients (RTRs), and this population is at risk of the previously cited complications. METHODS/DESIGN: The VITALE study is a prospective, multicentre, double-blind, randomized, controlled trial with two parallel groups that will include a total of 640 RTRs. RTRs with vitamin D insufficiency, defined as circulating 25-hydroxyvitamin D levels of less than 30 ng/ml (or 75 nmol/l), will be randomized between 12 and 48 months after transplantation to blinded groups to receive vitamin D3 (cholecalciferol) either at high or low dose (respectively, 100,000 UI or 12,000 UI every 2 weeks for 2 months then monthly for 22 months) with a follow-up of 2 years. The primary objective of the study is to evaluate the benefit/risk ratio of high-dose versus low-dose cholecalciferol on a composite endpoint consisting of de novo diabetes mellitus; major cardiovascular events; de novo cancer; and patient death. Secondary endpoints will include blood pressure (BP) control; echocardiography findings; the incidences of infection and acute rejection episodes; renal allograft function using estimated glomerular filtration rate; proteinuria; graft survival; bone mineral density; the incidence of fractures; and biological relevant parameters of mineral metabolism. DISCUSSION: We previously reported that the intensive cholecalciferol treatment (100 000 IU every 2 weeks for 2 months) was safe in RTR. Using a pharmacokinetic approach, we showed that cholecalciferol 100,000 IU monthly should maintain serum 25-hydroxyvitamin D at above 30 ng/ml but below 80 ng/ml after renal transplantation. Taken together, these results are reassuring regarding the safety of the cholecalciferol doses that will be used in the VITALE study. Analysis of data collected during the VITALE study will demonstrate whether high or low-dose cholecalciferol is beneficial in RTRs with vitamin D insufficiency. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01431430.

Relation between circulating levels of 25(OH) vitamin D and parathyroid hormone in chronic kidney disease: quest for a threshold.

CONTEXT: Vitamin D deficiency is common in patients with chronic kidney disease (CKD). Current guidelines recommend treatment strategies in these patients similar to those for the general population, but the vitamin D nutritional status sufficient to prevent PTH levels from increasing in CKD is unknown. OBJECTIVE, MAIN OUTCOME MEASURE: Our aim was to study the relation between circulating PTH and 25(OH)D levels and to search for a 25(OH)D threshold associated with a significant PTH increase. DESIGN, SETTING, AND PATIENTS: In the hospital-referred NephroTest cohort study, we measured 25(OH)D, PTH, and glomerular filtration rate (mGFR) by 5¹Cr-EDTA renal clearance in 929 adult patients with nondialysis CKD stages 1 to 5 and no vitamin D supplementation. Patients' mean age was 60.1 ± 14.7 years; 71% were men, and 9% were black. Their median mGFR was 37.8 mL/min/1.73 m². RESULTS: We found a 25(OH)D threshold of 8 ng/mL with an upper limit of 20 ng/mL (95% confidence interval) by linear piecewise regression modeling of log-PTH for 25(OH)D adjusted for mGFR, age, race, and ionized calcium level. The smoothed curve confirmed that PTH concentration rose steeply when circulating 25(OH)D levels fell to less than 20 ng/mL. CONCLUSIONS: Spontaneous 25(OH)D levels greater than 20 ng/mL seem sufficient to control serum PTH in CKD patients. This result reinforces guidelines to supplement vitamin D only if less than 30 ng/mL.

Determination of optimal cholecalciferol treatment in renal transplant recipients using a population pharmacokinetic approach.

PURPOSE: No information on optimal cholecalciferol dosing in kidney transplant patients is currently available because the time-course of serum 25-hydroxy vitamin D [25(OH)D] concentration has never been investigated. The aim of this study was to investigate 25(OH)D pharmacokinetics in renal transplant recipients and to determine the optimal dosage scheme allowing 25(OH)D concentrations to be maintained between 30-80 ng/mL during the first year post-transplantation. METHODS: Four months after renal transplantation, 49 patients received four oral doses of 100,000 IU cholecalciferol every 2 weeks (intensive phase), then every 2 months until 1 year after transplantation (maintenance phase). A control group of 47 transplanted patients was not supplemented but underwent blood sampling. In the treated group, 74 samples were collected before the first cholecalciferol administration and 119 thereafter. Two blood samples per patient were collected in the control group. Serum 25(OH)D concentrations were analyzed using a population approach. The turnover of 25(OH)D was modeled using a one-compartment-model with first-order formation and elimination and basal concentration. RESULTS: The mean population parameter estimates and the associated between-subject variability were: formation rate constant (k(f)), 0.11 day(-1); clearance (CL/F), 2.5 L/day (0.42); central volume of distribution (V(C)/F), 237 L; basal concentration (C(0)),12.82 ng/mL (0.41). Based on these values, in order to maintain 25(OH)D concentrations between 30 and 80 ng/mL, cholecalciferol dosing should be six successive administrations of 100,000 IU at 2-week intervals, followed by 100,000 IU once a month until the end of the first year. CONCLUSIONS: We present here the first pharmacokinetic model describing the time-course of 25(OH)D. We propose an optimal and practical scheme for the treatment of vitamin D insufficiency after renal transplantation. Taking into account the numerous effects of vitamin D on health, this scheme could help clinicians improve the care of kidney recipients.

Cholecalciferol supplementation does not protect against renal allograft structural and functional deterioration: a retrospective study.

BACKGROUND: Apart from their important role in mediating calcium homeostasis, vitamin D derivatives regulate numerous vitamin D receptor-mediated renoprotective cellular functions including cell differentiation, negative regulation of inflammation, and fibrosis. Renal models of chronic kidney injury and clinical observational studies have suggested that vitamin D analogues may protect against the epithelial-to-mesenchymal transition (EMT), interstitial inflammation, and fibrosis. METHODS: The aim of this retrospective study is to test whether oral supplementation with cholecalciferol (vitamin D3) between 3 and 12 months posttransplantation confers a structural and functional nephroprotection in a population of 64 renal transplant patients, using historical controls. We analyzed glomerular filtration rates using iohexol clearance, urinary procollagen III aminoterminal propeptide excretion, and epithelial phenotypic changes as markers of the EMT and Banff scores at 3 and 12 months after transplantation in 64 renal transplant recipients with or without cholecalciferol supplementation between months 3 and 12. RESULTS: Cholecalciferol supplementation in stable renal transplant recipients did not prevent EMT, interstitial fibrosis, tubular atrophy, or renal function deterioration. CONCLUSION: Our results challenge the experimental data, suggesting that vitamin D-analog supplementation confers nephroprotection. These findings should be confirmed by randomized prospective studies.

Effects of vitamin D supplementation on the calcium-phosphate balance in renal transplant patients.

Low serum levels of 25-hydroxy vitamin D frequently occur after renal transplantation, but few studies have evaluated the effects of normalizing this on serum parathyroid hormone and calcium levels or urinary calcium excretion. To determine this we compared the outcomes of 94 renal transplant patients with low 25-hydroxy vitamin D and normal serum calcium levels who were either treated or not with cholecalciferol every 2 weeks for 2 months (intensive phase) followed by an every other month maintenance phase. The biological characteristics of the two equally divided patient groups did not differ before treatment. After the intensive phase, serum 25-hydroxy vitamin D levels were normalized in all but 3 patients and the serum parathyroid hormone decreased and calcium levels increased with no severe adverse effects. During the maintenance phase, the serum 25-hydroxy vitamin D level decreased but remained significantly higher than in controls. In the control group, the serum 25-hydroxy vitamin D concentration increased slightly but became normal in only three patients. Serum 25-hydroxy vitamin D levels were significantly higher and parathyroid hormone levels were lower in treated patients compared to controls one year following transplant. Hence, cholecalciferol treatment significantly increased serum 25-hydroxy vitamin D and decreased parathyroid hormone levels with no adverse effects in 25-hydroxy vitamin D-deficient renal transplant patients.