Guillaume Jean

Vitamin D and musculoskeletal health, cardiovascular disease, autoimmunity and cancer: Recommendations for clinical practice

BACKGROUND There is increasing evidence that, in addition to the well-known effects on musculoskeletal health, vitamin D status may be related to a number of non-skeletal diseases. An international expert panel formulated recommendations on vitamin D for clinical practice, taking into consideration the best evidence available based on published literature today. In addition, where data were limited to smaller clinical trials or epidemiologic studies, the panel made expert-opinion based recommendations. METHODS Twenty-five experts from various disciplines (classical clinical applications, cardiology, autoimmunity, and cancer) established draft recommendations during a 2-day meeting. Thereafter, representatives of all disciplines refined the recommendations and related texts, subsequently reviewed by all panelists. For all recommendations, panelists expressed the extent of agreement using a 5-point scale. RESULTS AND CONCLUSION Recommendations were restricted to clinical practice and concern adult patients with or at risk for fractures, falls, cardiovascular or autoimmune diseases, and cancer. The panel reached substantial agreement about the need for vitamin D supplementation in specific groups of patients in these clinical areas and the need for assessing their 25-hydroxyvitamin D (25(OH)D) serum levels for optimal clinical care. A target range of at least 30 to 40 ng/mL was recommended. As response to treatment varies by environmental factors and starting levels of 25(OH)D, testing may be warranted after at least 3 months of supplementation. An assay measuring both 25(OH)D(2) and 25(OH)D(3) is recommended. Dark-skinned or veiled individuals not exposed much to the sun, elderly and institutionalized individuals may be supplemented (800 IU/day) without baseline testing.

Monthly cholecalciferol administration in haemodialysis patients: a simple and efficient strategy for vitamin D supplementation

BACKGROUND There is growing evidence of the usefulness of vitamin D supplementation in dialysis patients who are most often vitamin D deficient. Due to the long half-life of vitamin D, there is much interest in administering it intermittently for long-term adherence. However, there are no data to indicate which dosage would be most efficient. Objective. The aim was to assess the long-term efficiency and safety of a monthly oral dose of cholecalciferol (100 000 IU) in vitamin D-deficient haemodialysis (HD) patients. METHODS HD patients with a serum 25-hydroxyvitamin D (25(OH)D) level <75 nmol/L were enrolled in a 15-month prospective study. The exclusion criteria were as follows: use of any vitamin D derivatives, prescription of cinacalcet and bisphosphonates, uncontrolled hypercalcaemia (>2.55 mmol/L), hyperphosphataemia (>2 mmol/L) and severe secondary hyperparathyroidism (SHPT; serum PTH >600 pg/mL). Biological data were recorded in the following months: M-3, M0, M1, M3, M9 and M15. We aimed to maintain stable levels of the phosphate binder and oral and dialysate calcium during the course of the study. RESULTS Of the 250 patients screened, 161 were enrolled, and the results from 107 were recorded at the end of the study. Of these 107 patients, 56% were males, and the average age of the patient group was 66.4 +/- 15 years. Diabetics accounted for 36% of the total patients. The dialysis schedule ranged from 3 x 5 to 3 x 8 h, with a mean dialysate calcium concentration of 1.48 +/- 0.6 mmol/L. After 15 months, the mean serum 25(OH)D level increased from 32 +/- 13 to 105.8 +/- 27 nmol/L (P < 0.001) and plateaued after M3. Of the patients, 91% had a level higher than the target level (>75 nmol/L), while none had levels >200 nmol/L. The serum calcitriol (1,25(OH)(2)D) level increased from 13.7 +/- 14 to 45 +/- 13 pmol/L (P < 0.001) and plateaued after M9. The levels of serum PTH (median 295-190 pg/mL, P < 0.001), bone alkaline phosphatase (20.5 +/- 9-17.1 +/- 7 microg/L, P < 0.05) and beta-cross-laps (2.5 +/- 1-2.07 +/- 0.8 microg/L, P < 0.05) decreased significantly. No significant changes were observed in the values of the following: calcaemia, phosphataemia, blood pressure, serum albumin, haemoglobin and C-reactive protein. CONCLUSIONS Long-term monthly administration of oral cholecalciferol (100 000 IU) was a safe, effective, inexpensive and simple method for correcting vitamin D deficiency in almost 90% of the HD patients in this study and led to optimal compliance. The most evident consequences were a slight decrease in the levels of PTH and bone markers and an increase in the level of serum 1,25(OH)(2)D.

Evidence for Persistent Vitamin D 1-Alpha-Hydroxylation in Hemodialysis Patients: Evolution of Serum 1,25-Dihydroxycholecalciferol after 6 Months of 25-Hydroxycholecalciferol Treatment

Background: End-stage renal disease (ESRD) patients are thought to have impaired 1-α-hydroxylase capacity, but an extrarenal source of 1,25(OH)2D has been recognized. Objective: The aim of this study was to assess the evolution of serum 1,25(OH)2D in hemodialysis (HD) patients with vitamin D deficiency after 6 months of 25(OH)D3 supplementation, and to identify the factors associated with persistent 1,25(OH)2D production. Methods: HD patients in a HD center with vitamin D deficiency (i.e. 25(OH)D <75 nmol/l) who were not receiving any vitamin D derivatives or calcimimetics were studied. Patients who had previously undergone parathyroidectomy or nephrectomy or those with uncontrolled hypercalcemia or hyperphosphatemia were excluded from this study. The patients were administrated a dose of 10–30 µg/day of oral 25(OH)D3 based on the severity of their deficiency. The serum levels of 25(OH)D and 1,25(OH)2D evolution after 6 months were recorded. Responders were defined as patients with an increase in serum 1,25(OH)2D levels greater than the median value. Changes in mineral metabolism parameters were compared with those in the nonresponders. Results: Of the 253 patients, 225 (89%) were vitamin D-deficient, and 43 met the inclusion criteria. The patients were 72.6 ± 10 years old and had been on dialysis for 71 ± 70 months; 39% of the patients were female and 45% were diabetics. From baseline to 6 months of treatment, serum 25(OH)D levels increased from 27.8 ± 18 to 118 ± 34 nmol/l (p < 0.001) and serum 1,25(OH)2D levels increased from 7.7 ± 5 to 30.5 ± 15 pmol/l (p < 0.001) with a median increase of 20 pmol/l. The mean serum calcium level increased from 2.19 ± 0.1 to 2.25 ± 0.1 mmol/l (p = 0.009), the intact parathyroid hormone (iPTH) level decreased from 144 ± 108 to 108 ± 63 pg/ml (p = 0.05), and the bone alkaline phosphatase (BALP) level remained unchanged. The serum phosphate level increased slightly from 1.22 ± 0.3 to 1.34 ± 0.2 mmol/l (p = 0.04) with reduced hypophosphatemia. Compared with the responders (n = 24), most of the nonresponders (n = 19) were diabetic (63 vs. 29%, p = 0.02) and had a lesser increase of their 25(OH)D serum level. The serum level of FGF-23 was not significant. A positive correlation was observed between serum 1,25(OH)2D and serum 25(OH)D levels after 6 months of 25(OH)D3 treatment (p = 0.02). Conclusion: The Kidney Disease Outcomes Quality Improvement (KDOQI) guidelines do not recommend checking and treating vitamin D deficiency in chronic kidney disease (CKD) stage 5 patients due to the supposed lack of 1,25(OH)2D production. These data confirm persistent renal or extra-renal production of 1,25(OH)2D in HD patients after 6 months of 25(OH)D3 administration. Diabetes is the main factor associated with impaired 1,25(OH)2D production. 25(OH)D3 administration corrects vitamin D deficiency with few effects on mineral metabolism and stability of bone turnover markers.

Control of mineral metabolism and bone disease in haemodialysis patients: which optimal targets?

BACKGROUND There is a high drug treatment burden on patients receiving long-term dialysis therapy. Abnormalities of calcium and phosphate metabolism are associated with increased mortality, and attempts to correct these disturbances may improve survival. METHODS We prospectively evaluated the targets of the currently used Kidney Disease: Improving Global Outcomes (KDIGO) guidelines in 8377 prevalent patients receiving intermittent haemodialysis therapy in France from July 2007 to December 2009. RESULTS Adjusted Cox analyses showed that only one among six targets was predictive of mortality, i.e. a serum intact parathyroid hormone (iPTH) <130 pg/mL. A continuous risk analysis using fractional polynomials showed a 10% increase in hazard ratio (HR) for mortality for a serum phosphate <0.71 (2.2) and >1.98 (6.14) mmol/L (mg/dL), a non-corrected serum calcium <1.59 (6.37) and >2.41 (9.66) mmol/L (mg/dL) and a serum iPTH <100 and >1090 pg/mL. CONCLUSION The findings of our observational study confirm the existence of a grey zone, in which precise biochemical targets are difficult to define, with the exception of avoiding extreme values. Given the absence of intervention trials proving the clinical usefulness of phosphorus control, and pending the results of large clinical trials on the effect of optimal PTH and calcium control on hard outcomes, the present findings may help to refine future recommendations for the treatment of chronic haemodialysis patients.

The advantages and challenges of increasing the duration and frequency of maintenance dialysis sessions.

The duration and frequency of hemodialysis was determined empirically when this therapy first came into use, and treatment was commonly three 8 h sessions per week by the end of the 1960s. Subsequently, however, the growing number of patients who required this therapy had to be reconciled with the shortage of equipment; therefore, dialysis time was decreased to three 4 h sessions per week. At the same time, on the basis of data from the first randomized controlled trial of dialysis—the National Cooperative Dialysis Study—Kt/Vurea was devised as the optimum measure of dialysis adequacy. Nowadays, although Kt/Vurea targets are fulfilled in an increasing number of patients, observational studies show that individuals on hemodialysis continue to experience a high rate of complications, including hypertension, left ventricular hypertrophy, cardiac failure, hyperphosphatemia, malnutrition and death. Although no randomized controlled trial has yet been published, observational data indicate that increasing hemodialysis time and/or frequency improves a number of these complications, especially the death rate. This Review outlines the advantages of longer and/or more frequent dialysis sessions and highlights the barriers to adoption of such regimens, which largely relate to economics, patient willingness, and organization of dialysis units.

Impact of hypovitaminosis D and alfacalcidol therapy on survival of hemodialysis patients: results from the French ARNOS study.

Background: In chronic kidney disease and dialysis patients, vitamin D deficiency is associated with mortality. In some observational studies, calcitriol analogue therapy was associated with a better survival rate in hemodialysis (HD) patients. The aim of this study was to determine the relationship between serum 25-hydroxyvitamin D (25-OHD) levels and alfacalcidol therapy with HD patients’ outcomes. Methods: We measured baseline 25-OHD levels using a cross-sectional analysis in 648 HD prevalent patients from the regional ARNOS French cohort. A 42-month survival analysis was applied according to serum 25-OHD level and calcitriol analogue therapy. Results: The prevalence of 25-OHD insufficiency <30 ng/ml was high (73%), with only 22% taking native vitamin D supplementation. A baseline 25-OHD level above the median value (18 ng/ml) was associated with lower all-cause mortality [hazard ratio (HR), 0.73 (0.5–0.96); p = 0.02] after adjustment for age, gender, dialysis vintage, calcemia, phosphatemia, cardiovascular disease, and diabetes. Only in monovariate analysis was low-dose oral alfacalcidol therapy associated with a better survival rate in patients with and without 25-OHD deficiency [HR, 0.7 (0.5–0.92); p = 0.05]. Conclusions: Our study shows that, among prevalent HD patients, low 25-OHD levels affect mortality. Alfacalcidol therapy, especially in small doses, may provide compensation, but this needs to be further confirmed using prospective controlled studies comparing native and active vitamin D compounds.

Increased Levels of Serum Parathyroid Hormone and Fibroblast Growth Factor-23 Are the Main Factors Associated with the Progression of Vascular Calcification in Long-Hour Hemodialysis Patients

The aim of the present study was to assess the frequency and factors associated with the progression of vascular calcifications (VCs) using a semiquantitative X-ray score. We included all prevalent hemodialysis patients with initial radiological scores ranging from 0 to 3 according to the severity of the VCs. Patients were classified as non-progressors or progressors after 3 years. Among the 85 patients, 44.7% were classified as progressors. Only exhibiting high levels of serum intact parathyroid hormone (PTH, >190 pg/ml) and fibroblast growth factor (FGF)-23 levels (>3,000 RU/ml) is associated with the risk of VC progression (OR 5.8, 95% CI 1.7–19.8, p = 0.004). Calcitriol analogs (38%), cinacalcet (15%), dialysate calcium (mean 1.48 mmol/l), dialysis session time (4–8 h) and calcium- (10%) and non-calcium-based phosphate binders (38%) were prescribed on an individual basis. Hyperphosphatemia (<10%) and, especially, hypercalcemia (1%) and hyperparathyroidism (>585 pg/ml = 0%) were infrequently observed. In conclusion, the main factor associated with VC progression was the association of higher serum PTH and FGF-23 levels. It remains to be seen whether patients should be treated to lower their PTH value, even within the target range, using calcitriol analogs, calcimimetics, parathyroidectomy, or by modifying the Klotho-FGF-23 axis.

Fluid overload correction and cardiac history influence brain natriuretic peptide evolution in incident haemodialysis patients

OBJECTIVES Brain natriuretic peptide (BNP) is a cardiac peptide secreted by ventricle myocardial cells under stretch constraint. Increased BNP has been shown associated with increased mortality in end-stage renal disease patients. In patients starting haemodialysis (HD), both fluid overload and cardiac history are frequently present and may be responsible for a high BNP plasma level. We report in this study the evolution of BNP levels in incident HD patients, its relationship with fluid removal and cardiac history as well as its prognostic value. METHODS Forty-six patients (female/male: 21/25; 68.6 ± 14.5 years old) surviving at least 6 months after HD treatment onset were retrospectively analysed. Plasma BNP (Chemoluminescent Microparticule ImmunoAssay on i8200 Architect Abbott, Paris, France; normal value < 100 pg/mL) was assessed at HD start and during the second quarter of HD treatment (Q2). RESULTS At dialysis start, the plasma BNP level was 1041 ± 1178 pg/mL (range: 14-4181 pg/mL). It was correlated with age (P = 0.0017) and was significantly higher in males (P = 0.0017) and in patients with cardiac disease history (P = 0.001). The plasma BNP level at baseline was not related to the mortality risk. At Q2, predialysis systolic blood pressure (BP) decreased from 140.5 ± 24.5 to 129.4 ± 20.6 mmHg (P = 0.0001) and the postdialysis body weight by 7.6 ± 8.4% (P < 0.0001). The BNP level decreased to 631 ± 707 pg/mL (P = 0.01) at Q2. Its variation was significantly correlated with systolic BP decrease (P = 0.006). A high BNP level was found associated with an increased risk of mortality. CONCLUSIONS Hence, plasma BNP levels decreased during the first months of HD treatment during the dry weight quest. Whereas initial BNP values were not associated with increased mortality risk, the BNP level at Q2 was independently predictive of mortality. Hence, BNP is a useful tool to follow patient dehydration after dialysis start. Initial fluid overload may act as a confounding factor for its value as a prognostic marker because of cardiac disease.

Can we use circulating biomarkers to monitor bone turnover in CKD haemodialysis patients? Hypotheses and facts

Assessing bone turnover is a key diagnostic tool in the global management of chronic kidney disease-mineral and bone disorder (CKD-MBD). Since bone biopsy is invasive and cannot be repeated in clinical practice and because bone histomorphometry is less available due to the lack of specialized laboratories, we will focus on potential biomarkers used to assess and monitor bone turnover. After briefly reviewing the pathophysiology of bone turnover in CKD and haemodialysis patients, we will focus on the strengths and limitations of the now recommended biomarkers, i.e. parathormone and bone-specific alkaline phosphatase. We will consider the clinical and also the biological aspects of the topic and also insist on the use of these biomarkers for the monitoring, and the follow-up of the turnover in haemodialysis subjects. Finally, we will discuss some of the most promising, but still not recommended, emerging biomarkers.

When should we measure Vitamin D concentration in clinical practice

Abstract The many recently published data on vitamin D have raised much interest in the medical community. One of the consequences has been a great increase in the prescription of vitamin D concentration measurements in clinical practice. It must be reminded that only the measurement of 25-hydroxyvitamin D (25(OH)D) concentration is indicated to evaluate vitamin D status. Furthermore, since vitamin D insufficiency is so common, since treatment is inexpensive and has a large safety margin, and since we already have much data suggesting that besides its classic effects on bone and mineral metabolism, vitamin D may potentially be helpful for the prevention/management of several diseases, perhaps should it be prescribed to everyone without prior testing? In our opinion, there are however groups of patients in whom estimation of vitamin D status is legitimate and may be recommended. This includes patients in whom a “reasonably” evidence-based target concentration (i.e., based on randomized clinical trials when possible) should be achieved and/or maintained such as patients with rickets/osteomalacia, osteoporosis, chronic kidney disease and kidney transplant recipients, malabsorption, primary hyperparathyroidism, granulomatous disease, and those receiving treatments potentially inducing bone loss. Other patients in whom vitamin D concentration may be measured are those with symptoms compatible with a severe vitamin D deficiency or excess persisting without explanation such as those with diffuse pain, or elderly individuals who fall, or those receiving treatments which modify vitamin D metabolism such as some anti-convulsants. Measurement of Vitamin D concentrations should also be part of any exploration of calcium/phosphorus metabolism which includes measurement of serum calcium, phosphate and PTH.