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WO2007001969A1 - Carence en vitamine d et dialyse - Google Patents

Carence en vitamine d et dialyse Download PDF

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Publication number
WO2007001969A1
WO2007001969A1 PCT/US2006/023774 US2006023774W WO2007001969A1 WO 2007001969 A1 WO2007001969 A1 WO 2007001969A1 US 2006023774 W US2006023774 W US 2006023774W WO 2007001969 A1 WO2007001969 A1 WO 2007001969A1
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vitamin
patient
dialysis
levels
threshold level
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Ravi Thadhani
Myles Wolf
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General Hospital Corp
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General Hospital Corp
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/82—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving vitamins or their receptors

Definitions

  • PTH parathyroid hormone
  • vitamin D therapy is linked to the development of adverse effects such as hypercalcemia and hyperphosphatemia.
  • the invention is based, at least in part, on the discovery that low serum vitamin D levels correlate with higher rates of mortality in hemodialysis patients, and that administration of vitamin D therapy to patients with low vitamin D levels can reduce mortality rates.
  • the invention includes methods of treating dialysis patients by measuring the patients' vitamin D levels, and administering vitamin D therapy to those with low levels to improve their survival on dialysis.
  • the invention includes methods for reducing the risk of mortality associated with dialysis (e.g., cardiovascular- or infectious-related mortality) by: (a) assaying an amount of endogenous vitamin D, e.g., 25-hydroxyvitamin D and/or 1,25-dihydroxyvitamin D, in a sample e.g., a body fluid (e.g., blood, plasma, serum, or lymph), of a dialysis patient or a patient in need of dialysis; (b) comparing the endogenous vitamin D levels to a threshold level; and (c) if the endogenous vitamin D levels are below the threshold level, administering to the patient vitamin D, e.g., active or activated vitamin D (e.g., calcitriol, doxercalciferol, paricalcitol, or 1,25-dihydroxyvitamin D), in an amount effective to reduce the patient's risk of mortality while on dialysis.
  • a body fluid e.g., blood, plasma, serum, or lymph
  • the decision to administer active vitamin D is made irrespective of an amount of parathyroid hormone (PTH) in a sample from the patient.
  • the threshold level of 25-hydroxyvitamin D is typically a level between 1 and 30 ng/ml, e.g., between 5 and 15 ng/ml, e.g., between 8 and 12 ng/ml, e.g., between 9 and 11 ng/ml, e.g., about 10 ng/ml of 25-hydroxyvitamin D in the sample, e.g., the patient's serum or plasma.
  • the threshold level of 25-hydroxyvitamin D is about 1, 2, 5, 8, 9, 10, 11, 12, 15, 20, 25, or 30 ng/ml of 25-hydroxyvitamin D the sample, e.g., the patient's serum or plasma.
  • the threshold level of 1,25-dihydroxyvitamin D is typically a level between about 1 and 25 pg/ml, e.g., between 5 and 15 pg/ml or between 10 and 20 pg/ml, e.g., between 12 and 18 pg/ml, e.g., between 14 and 16 pg/ml, e.g., about 15 pg/ml of 1,25-dihydroxyvitamin D in the sample, e.g., the patient's serum or plasma.
  • the threshold level of 25- hydroxyvitamin D is about 1, 2, 5, 8, 10, 12, 14, 15, 16, 18, 20, or 25 pg/ml of 1,25- dihydroxyvitamin D in the sample, e.g., the patient's serum or plasma.
  • the invention also includes methods of monitoring and treating a dialysis patient by: (a) identifying a patient who is undergoing dialysis, will undergo dialysis, or is suspected to require dialysis; and (b) assaying an amount of endogenous vitamin D, e.g., 25-hydroxyvitamin D and/or 1,25-dihydroxyvitamin D, in a sample, e.g., a body fluid (e.g., blood, plasma, serum, or lymph), of the patient; (c) comparing the amount of vitamin D to a threshold level; and (d) if the amount of vitamin D is below the threshold level, providing exogenous vitamin D, e.g., active or activated vitamin D (e.g., calcitriol, doxercalciferol, paricalcitol, or 1,25-dihydroxyvitamin D),to the patient irrespective of serum levels of parathyroid hormone, calcium, or phosphorous.
  • a body fluid e.g., blood, plasma, serum, or lymph
  • the threshold level of 25-hydroxyvitamin D is typically a level between 1 and 30 ng/ml, e.g., between 5 and 15 ng/ml, e.g., between 8 and 12 ng/ml, e.g., between 9 and 11 ng/ml, e.g., about 10 ng/ml of 25-hydroxyvitamin D in the sample, e.g., the patient's serum or plasma.
  • the threshold level of 25-hydroxyvitamin D is about 1, 2, 5, 8, 9, 10, 11, 12, 15, 20, 25, or 30 ng/ml of 25-hydroxyvitamin D the sample, e.g., the patient's serum or plasma.
  • the threshold level of 1,25-dihydroxyvitamin D is typically a level between about 1 and 25 pg/ml, e.g., between 5 and 15 pg/ml or between 10 and 20 pg/ml, e.g., between 12 and 18 pg/ml, e.g., between 14 and 16 pg/ml, e.g., about 15 pg/ml of 1,25- dihydroxyvitamin D in the sample, e.g., the patient's serum or plasma.
  • the threshold level of 25-hydroxyvitamin D is about 1, 2, 5, 8, 10, 12, 14, 15, 16, 18, 20, or 25 pg/ml of 1,25-dihydroxyvitamin D in the sample, e.g., the patient's serum or plasma.
  • the patient has been diagnosed with end-stage renal disease.
  • the invention also includes methods to estimate risk of mortality (e.g., cardiovascular-related mortality or infectious-related mortality) following initiation of hemodialysis for a given vitamin D level by assaying an endogenous amount of vitamin D, e.g., 25-hydroxyvitamin D and/or 1,25-dihydroxyvitamin D, in samples, e.g., samples of a body fluid (e.g., blood, plasma, serum, or lymph), of a population of dialysis patients; and associating the vitamin D levels with risk of mortality (e.g., a differential risk of mortality among or between groups with differing vitamin D levels).
  • risk of mortality e.g., cardiovascular-related mortality or infectious-related mortality
  • the invention can further include methods of estimating mortality (e.g., cardiovascular- related or infectious-related mortality) in patients following initiation of dialysis by performing the above method, and further assaying vitamin D levels in a patient who is undergoing dialysis, will undergo dialysis, or is suspected to require dialysis, and comparing the vitamin D levels to the levels of the population, thereby estimating a risk of mortality.
  • the patient population can be analyzed to determine threshold levels for a population, e.g., a subset of the patient population, based on patient risk factors included in the individuals within the population, including, e.g., age, sex, race, or ethnicity, and/or whether the patients have been diagnosed with diabetes.
  • the invention further includes methods for treating a patient undergoing dialysis, will undergo dialysis, or is diagnosed to require dialysis to reduce the risk of mortality (e.g., cardiovascular- or infectious-related mortality) associated with dialysis.
  • the methods include first selecting the patient on the basis that the patient is undergoing dialysis, will undergo dialysis, or is diagnosed to require dialysis, and on the basis that the patient has or is known to have a level of endogenous vitamin D (e.g., 25- hydroxyvitamin D and/or 1,25-dihydroxyvitamin D) below a threshold level, and then administering to the patient (e.g., because the patient has a level of endogenous vitamin D below the threshold level) vitamin D, e.g., active or activated vitamin D (e.g., calcitriol, doxercalciferol, paricalcitol, or 1,25-dihydroxyvitamin D), or a vitamin D composition in an amount effective to lower the risk of mortality associated with dialysis.
  • the threshold level of 25-hydroxyvitamin D is typically a level between 1 and 30 ng/ml, e.g., between 5 and 15 ng/ml, e.g., between 8 and 12 ng/ml, e.g., between 9 and 11 ng/ml, e.g. about 10 ng/ml of 25-hydroxyvitamin D.
  • the threshold level of 25- hydroxyvitamin D is about 1, 2, 5, 8, 9, 10, 11, 12, 15, 20, 25, or 30 ng/ml of 25- hydroxyvitamin D.
  • the threshold level of 1,25-dihydroxyvitamin D is typically a level between about 1 and 25 pg/ml, e.g., between 5 and 15 pg/ml or between 10 and 20 pg/ml, e.g., between 12 and 18 pg/ml, e.g., between 14 and 16 pg/ml, e.g., about 15 pg/ml of 1,25-dihydroxyvitamin D.
  • the threshold level of 25- hydroxyvitamin D is about 1, 2, 5, 8, 10, 12, 14, 15, 16, 18, 20, or 25 pg/ml of 1,25- dihydroxyvitamin D.
  • the invention also includes methods for characterizing a patient's risk of mortality (e.g., cardiovascular- or infectious-related mortality) associated with dialysis that include obtaining a level of endogenous vitamin D (e.g., 25-hydroxyvitamin D and/or 1 ,25-dihydroxyvitamin D) in the patient, comparing the level of endogenous vitamin D to a threshold value, and characterizing the patient's risk of mortality associated with dialysis (e.g., based upon the level of endogenous vitamin D in comparison to the threshold value).
  • a patient's risk of mortality e.g., cardiovascular- or infectious-related mortality
  • the threshold level of 25-hydroxyvitamin D is typically a level between 1 and 30 ng/ml, e.g., between 5 and 15 ng/ml, e.g., between 8 and 12 ng/ml, e.g., between 9 and 11 ng/ml, e.g., about 10 ng/ml of 25-hydroxyvitamin D.
  • the threshold level of 25-hydroxyvitamin D is about 1, 2, 5, 8, 9, 10, 11, 12, 15, 20, 25, or 30 ng/ml of 25-hydroxyvitamin D.
  • the threshold level of 1,25-dihydroxyvitamin D is typically a level between about 1 and 25 pg/ml, e.g., between 5 and 15 pg/ml or between 10 and 20 pg/ml, e.g., between 12 and 18 pg/ml, e.g., between 14 and 16 pg/ml, e.g., about 15 pg/ml of 1,25-dihydroxyvitamin D.
  • the threshold level of 25-hydroxyvitamin D is about 1, 2, 5, 8, 10, 12, 14, 15, 16, 18, 20, or 25 pg/ml of 1,25-dihydroxyvitamin D.
  • the invention further includes methods for evaluating the likelihood that an patient will benefit from treatment with an agent for reducing the risk of mortality (e.g., cardiovascular- or infectious-related mortality) associated with dialysis, the agent selected from the group consisting of calcitriol, doxercalciferol, paricalcitol, a compound that activates the vitamin D receptor, and 1,25-dihydroxyvitamin D.
  • the invention includes obtaining a level of endogenous vitamin D (e.g., 25-hydroxyvitamin D and/or 1,25-dihydroxyvitamin D) in the patient; and comparing the level of endogenous vitamin D to a threshold value, wherein a level of endogenous vitamin D below threshold value indicates that the patient will benefit from treatment with the agents.
  • the threshold level of 25-hydroxyvitamin D is typically a level between 1 and 30 ng/ml, e.g., between 5 and 15 ng/ml, e.g., between 8 and 12 ng/ml, e.g., between 9 and 11 ng/ml, e.g. about 10 ng/ml of 25-hydroxyvitamin D.
  • the threshold level of 25- hydroxyvitamin D is about 1, 2, 5, 8, 9, 10, 11, 12, 15, 20, 25, or 30 ng/ml of 25- hydroxyvitamin D.
  • the threshold level of 1,25-dihydroxyvitamin D is typically a level between about 1 and 25 pg/ml, e.g., between 5 and 15 pg/ml or between 10 and 20 pg/ml, e.g., between 12 and 18 pg/ml, e.g., between 14 and 16 pg/ml, e.g., about 15 pg/ml of 1,25-dihydroxyvitamin D.
  • the threshold level of 25- hydroxyvitamin D is about 1, 2, 5, 8, 10, 12, 14, 15, 16, 18, 20, or 25 pg/ml of 1,25- dihydroxyvitamin D.
  • a risk of mortality described herein can be a risk of mortality within a certain period of time following initiation of hemodialysis.
  • the period of time can be within 360 days of initiating dialysis (e.g., within 360, 330, 300, 270, 240, 210, 180, 150, 120, 90, 60, 30, or 15 days).
  • the period of time is within 5 years of initiating dialysis, e.g., 4, 3, 2, or 1 year.
  • a treatment described herein can reduce the risk of mortality of a patient undergoing dialysis by about 1.2-fold to 10-fold, e.g., 9-fold, 8-fold, 7-fold, 6-fold, 5-fold, 4-fold, 3-fold, 2-fold, 1.5- fold, or 1.2-fold, compared to the risk of mortality the patient would have without the treatment.
  • the invention also includes vitamin D assays (e.g., assay kits) for measuring vitamin D levels, e.g., 25-hydroxyvitamin D and/or 1,25-dihydroxyvitamin D levels, in a body fluid, e.g., blood, plasma, serum, or lymph, that include a standard corresponding to a threshold level of vitamin D.
  • the threshold level of 25-hydroxyvitamin D is a level between 1 and 30 ng/ml, e.g., between 5 and 15 ng/ml, e.g., between 8 and 12 ng/ml, e.g., between 9 and 11 ng/ml, e.g., about 10 ng/ml of 25-hydroxyvitamin.
  • the threshold level of 25-hydroxyvitamin D is about 1, 2, 5, 8, 9, 10, 11, 12, 15, 20, 25, or 30 ng/ml of 25-hydroxyvitamin D.
  • the threshold level of 1,25-dihydroxyvitamin D is a level between about 1 and 25 pg/ml, e.g., between 5 and 15 pg/ml or between 10 and 20 pg/ml, e.g., between 12 and 18 pg/ml, e.g., between 14 and 16 pg/ml, e.g., about 15 pg/ml of 1,25-dihydroxyvitamin D.
  • the threshold level of 25-hydroxyvitamin D is about 1, 2, 5, 8, 10, 12, 14, 15, 16, 18, 20, or 25 pg/ml of 1,25-dihydroxyvitamin D.
  • the assay kits include instructions to use the result of the assay to determine whether to administer vitamin D therapy to the patient if the vitamin D levels are below the threshold.
  • the assay kits include instructions for performing a method described herein.
  • kits for measuring an amount of endogenous vitamin D e.g., 25-hydroxyvitamin D and/or 1,25-dihydroxyvitamin D
  • kits for measuring an amount of endogenous vitamin D include a reference standard corresponding to a threshold level of vitamin D (e.g., a threshold level described herein) and/or a protein that binds specifically to vitamin D (e.g., vitamin D binding protein (VDBP) or an antibody), and instructions to use the kit to compare an amount of endogenous vitamin D in a sample from the patient to the threshold level.
  • the kit can further include instructions to administer vitamin D therapy to the patient if the measured amount is below the threshold level.
  • an antibody or protein that "binds specifically to" an antigen binds preferentially to the antigen in a sample containing other components (e.g., proteins).
  • FIG. 1 is a histogram showing the distribution of 25-hydroxyvitamin levels among hemodialysis patients in this study.
  • the vertical dashed line indicates the lower limit of the normal range for 25D of 30 ng/ml.
  • FIG. 2 is a histogram showing the distribution of 1 ,25-dihydroxyvitamin levels among hemodialysis patients in this study.
  • FIG. 3 is a chart showing the distribution of 25D levels according to base-line parathyroid hormone (PTH) levels.
  • PTH levels are divided into groups according to the ascending 10th percentiles of the distribution in the entire study population.
  • Mean 25D levels are represented by the central point and bars represent the interquartile ranges (25th and 75th percentiles).
  • FIG. 4 is a chart showing the distribution of 1 ,25D levels according to base-line PTH levels. PTH levels are divided into groups according to the ascending 10th percentiles of the distribution in the entire study population. Mean 1,25D levels are represented by the central point and the bars represent the interquartile ranges (25th and 75th percentiles).
  • FIGs. 5 A and 5B are charts showing the multivariable-adjusted risk of 90-day all- cause and cardiovascular-related mortality on hemodialysis according to 25D levels and whether or not patients received treatment with injectable active vitamin D.
  • FIG. 5A shows mortality by all causes.
  • FIG. 5B shows cardiovascular-related mortality.
  • FIGs. 6A and 6B are charts showing the multivariable-adjusted risk of 90-day all- cause and cardiovascular-related mortality on hemodialysis according to 1,25D levels and whether or not patients received treatment with injectable active vitamin D.
  • FIG. 6A shows mortality by all causes.
  • FIG. 6B shows cardiovascular-related mortality.
  • vitamin D e.g., 25-hydroxyvitamin D (25-OH D) levels and 1,25- dihydroxyvitamin D (1 ,25-(OH) 2 D
  • this application describes methods of monitoring and treating dialysis patients to reduce mortality by assaying vitamin D levels in body fluids and administering vitamin D therapy to patients whose levels are below a threshold level.
  • vitamin D 3 cholesterolcalciferol
  • vitamin D 2 ergocalciferol
  • 25-hydroxy (25-OH) and 1,25-dihydroxy (1,25-(OH) 2 ) forms of each of D 3 and D 2 a form of endogenous vitamin D
  • 25-OH D 25-OH D 2 and 25-OH D 3
  • Synthesis of 25-OH D occurs primarily in the liver
  • synthesis of 1,25-(OH) 2 D (1,25-(OH) 2 D 2 and 1,25-(OH) 2 D 3 ) occurs in the kidneys and, to a smaller extent, in other tissues.
  • vitamin D can refer to either 25-OH or 1,25-OH 2 , in either the D 3 or D 2 form, or both, or any compound that activates the vitamin D receptor.
  • Vitamin D levels e.g., levels of 25-OH D and/or 1,25-(OH) 2 D
  • a sample to be assayed includes blood, plasma, serum, or lymph. Samples of body fluids can be obtained from patients by standard means and assayed before, after, or both before and after commencement of dialysis treatment. Vitamin D levels can be assayed regularly following commencement of dialysis, e.g., monthly, biweekly, weekly, daily, or more often. If at any point the patient's vitamin D levels fall below the threshold, vitamin D therapy can be administered to the patient.
  • levels of 25-OH D and/or 1,25-(OH) 2 D are measured using any means known in the art, e.g., HPLC, competitive binding assays, and/or assays that utilize proteins that bind to vitamin D, e.g., vitamin D binding protein (VDBP) or antibodies against 25-hydroxyvitamin D and/or 1,25-dihydroxyvitamin D.
  • the assays can be enzyme-linked immunosorbent assays (ELISA), enzyme immunoassays (EIA), or radioimmunoassays (RIA).
  • Assay kits to measure 25-OH D and 1,25- (OH) 2 D that utilize ELISA and RIA methods are commercially available, e.g., from DiaSorin (Stillwater, MN), Alpco (Wyndham, NH), and IDS Ltd (Tyne and Wear, United Kingdom).
  • any vitamin D assay can be used as long as it has good sensitivity and reproducibility in the range of the threshold level selected, such that an accurate assessment can be made as to whether the patient's levels are above or below the threshold.
  • the assays can be performed simultaneously with known quantities of vitamin D to create a standard curve. One of the known quantities can correspond to a threshold level of vitamin D.
  • the threshold level of 25-hydroxyvitamin D is typically about 10 ng/ml, e.g., between 8 and 12 ng/ml of 25-hydroxyvitamin D, but can be 1, 2, 5, 8, 9, 10, 11, 12, 15, 20, or 30 ng/ml of 25-hydroxyvitamin D in the patient's serum or plasma.
  • the threshold level of 1,25-dihydroxyvitamin D is typically about 15 pg/ml, e.g., between 5 and 15 pg/ml or 10 and 20 pg/ml of 1,25-dihydroxyvitamin D, but can be 1, 2, 5, 8, 10, 12, 14, 15, 16, 18, 20, or 25 pg/ml of 1,25-dihydroxyvitamin D in the patient's serum or plasma.
  • the threshold levels are chosen based on data from a population of patients indicating that administering vitamin D therapy to patients with vitamin D levels below the threshold significantly improves their chances of survival relative to patients with vitamin D levels above the threshold. Vitamin D therapy may or may not significantly improve the survival of patients with vitamin D levels above the threshold.
  • the threshold can be adjusted based on other patient risk factors included in the individuals within the patient population, including, e.g., age, sex, race or ethnicity, and whether the patient has been diagnosed with diabetes. The results described herein indicate that vitamin D deficiency cannot be reasonably predicted by parameters currently used as a surrogate for vitamin D levels (e.g., PTH, calcium, and phosphorus).
  • vitamin D administration has been associated with adverse consequences in dialysis patients, including alterations in serum minerals and the potential for arterial calcification (Mallick and Berylne, Lancet, 2:1316-20 (1968); Cunningham, Kidney Int. Suppl, 73:S59-S64 (1999); and Quinibi et al., Kidney Int. Suppl, 83:73-80 (2002))
  • the threshold is chosen to improve the outcome of patients with levels below the threshold and to avoid potential adverse consequences of unnecessary vitamin D therapy for patients with levels above the threshold.
  • vitamin D therapy e.g., 25-OH D and/or 1,25-(OH) 2 D levels
  • the patient can be administered vitamin D therapy.
  • forms of vitamin D that can be administered include vitamin D 3 (cholecalciferol), vitamin D 2 (ergocalciferol), calcitriol (1 ,25-(OH) 2 D 3 , CALCIJEXTM ,
  • vitamin D e.g., forms that mimic the effect of 1,25-(OH) 2 D, e.g., calcitriol, doxercalciferol, or paricalcitol, or any other compound that activates the vitamin D receptor, are administered.
  • Exemplary compounds useful in the methods described herein can be found in WO 2005/051893, WO 2005/051940, WO 2005/051938, WO 2005/051936, WO 2005/051898, WO 2005/037755, WO 2004/048309, US 6,410,523, US 6,603,031, WO 01/07405, WO 00/10958, US 5,380,720, and WO 98/39292.
  • Some forms of vitamin D e.g., paricalcitol, may provide a greater benefit than other forms, e.g., calcitriol, for a given patient.
  • the route of administration and dosage can be tailored to the type of therapy administered to provide a pharmaceutically effective amount.
  • vitamin D therapy is administered orally or intravenously.
  • paricalcitol was reported to provide a significant long-term survival advantage over calcitriol (Teng et al., New Engl. J. Med., 349:446-456 (2003)).
  • the biologically active form of vitamin D is the calcitropic hormone 1,25- dihydroxyvitamin D. This form is produced by hydroxylation of 25-hydroxyvitamin D in the kidney, after which the active form circulates in the blood in about picogram quantities. Measures of circulating 1 ,25-dihydroxyvitamin D primarily reflect kidney conversion of 25-OH D to 1,25-(OH) 2 D. In patients with end-stage renal disease (ESRD), the kidneys are no longer capable of converting 25-OH D to 1,25-(OH) 2 D, although a small amount of 1,25-(OH) 2 D is produced in other tissues of the body, where it is utilized locally (Reviewed in Dusso et al., Am. J. Physiol.
  • therapy can include activated vitamin D (e.g., calcitriol, doxercalciferol, paricalcitol, or 1 ,25-(OH) 2 D) to overcome this impaired conversion and to provide cells throughout the body with the activated hormone form of vitamin D.
  • activated vitamin D e.g., calcitriol, doxercalciferol, paricalcitol, or 1 ,25-(OH) 2 D
  • kits used to measure vitamin D levels and determine whether to administer vitamin D therapy to a hemodialysis patient.
  • the kits include directions to determine whether an amount of vitamin D in a patient sample is above or below a threshold level described herein.
  • the kits include instructions to compare a measured level of vitamin D in a patient sample to a threshold level described herein.
  • the kits can include a reference standard that corresponds directly to a threshold level of vitamin D described herein, or instructions to prepare a reference standard (e.g., by dilution of a stock solution) that corresponds to a threshold level described herein.
  • the kits include
  • kits can utilize a radioimmunoassay (RIA) or enzyme immunoassay (EIA) method (e.g., an enzyme immunosorbent assay (ELISA) method).
  • RIA radioimmunoassay
  • EIA enzyme immunoassay
  • ELISA enzyme immunosorbent assay
  • the amount of vitamin D in a sample can be measured, e.g., by assaying binding to the protein that binds vitamin D and/or by measuring competition for binding to the protein that binds vitamin D between vitamin D in the patient sample and a labeled (e.g., radiolabeled) or immobilized vitamin D.
  • the kits can include reagents for extracting vitamin D from other components of the patient sample.
  • Vitamin D therapy alleviates an increased risk of mortality in patients with low levels of 25-OH D
  • Patient data included information from 140 patients who initiated hemodialysis but died within the first 90 days of starting dialysis, and approximately 300 patients who initiated dialysis and survived the first 90 days dialysis. For all patients, serum samples were collected within the first 14 days of starting hemodialysis. Serum levels of 25- hydroxyvitamin D (25-OH D) and 1,25-dihydroxyvitamm D (1,25-(OH) 2 D) were measured in these samples. Information on therapy with active vitamin D was also included in the patient data.
  • the risk of mortality is mitigated at all levels of 25-OH D by therapy with activated vitamin D. 3.
  • the threshold level of 25-OH D that determines whether a given patient should receive vitamin D therapy is about 10 ng/ml.
  • the Odds Ratio indicates the ratio of the estimated risk of death, as compared to a reference value.
  • the 95% confidence interval (95% CI) gives an estimate of the range in which a given odds ratio is 95% likely to fall.
  • the P value (P) indicates the probability that the measured odds ratio is not different from the measured reference value. A lower P value indicates higher statistical significance.
  • Table 1 presents a univariate analysis of 90-day survival according to 25-OH D levels at the start of hemodialysis expressed as a continuous variable. This analysis shows that risk of death in the first 90 days of dialysis decreases as 25-OH D levels increase. The measured odds ratio of 0.98 indicates that there is on average a 2% reduction in risk of mortality for each increase of 1 ng/ml of 25-OH D at the start of hemodialysis.
  • Table 2 presents a bivariate analysis of 90-day survival according to baseline 25-OH D levels at the start of dialysis.
  • Table 3 presents a bivariate analysis comparing 90-day survival of patients who did not receive intravenous vitamin D therapy with patients who received some form of intravenous vitamin D.
  • the odds ratio of 0.46 for IV vitamin D indicates that patients who received intravenous vitamin D therapy had less than half the risk of mortality compared to those who did not receive intravenous vitamin D. This result was statistically significant (P ⁇ 0.001).
  • Table 4 presents a bivariate analysis comparing 90-day survival of patients who received no intravenous vitamin D, with patients who received paricalcitol or either calcitriol or doxercalciferol.
  • the intravenous vitamin D agents decreased the risk of mortality by similar levels.
  • the odds ratio for patients treated with calcitriol or doxercalciferol compared to no treatment was 0.54, whereas the odds ratio for patients treated with paricalcitol compared to no treatment was 0.41. Both results were statistically significant. The apparent difference between the sets of vitamin D agents is not seen when the data are analyzed by multivariate analysis.
  • Table 5 presents a bivariate analysis comparing 90-day survival among patients with high initial vitamin D levels ( > 10 ng/ml) who received intravenous vitamin D therapy (High D - IV D+) with each of: patients with high initial vitamin D levels who did not receive intravenous vitamin D therapy (High D - IV D-), patients with low initial vitamin D levels ( ⁇ 10 ng/ml) who received intravenous vitamin D therapy (Low D - IV D+), and patients with low initial vitamin D levels who did not receive intravenous vitamin D therapy (Low D - IV D-). All of the groups had a higher risk of mortality than the High D - IV D+ group (odds ratio of 2.11 for patients with high initial levels of
  • 25-OH D who did not receive intravenous D 2.02 for patients with low initial levels of 25-OH D who did receive intravenous D, and 5.74 for patients with low initial levels of 25-OH D who did not receive intravenous D, all compared to patients with high initial levels of 25-OH D who did receive intravenous D).
  • the greatest risk of mortality was seen in those patients with low initial vitamin D levels who did not receive intravenous vitamin D therapy. Those patients had almost six times the risk of death in the 90 days following dialysis as patients with high initial vitamin D levels who received vitamin D therapy (Odds Ratio of 5.74 compared to the reference group, P ⁇ 0.001).
  • Table 6 presents abivariate analysis comparing 90-day survival of patients with high ( > 20 ng/ml), intermediate (10-20 ng/ml), or low ( ⁇ 10 ng/ml) initial 25-OH D levels who received intravenous vitamin D treatment or none.
  • the least risk of mortality was seen in patients with high initial 25-OH D levels who received some form of intravenous vitamin D therapy.
  • the highest risk of mortality was seen in patients with low initial 25-OH D levels who did not receive intravenous vitamin D therapy (odds ratio of 6.11 compared to patients with high initial 25-OH D levels who did receive intravenous vitamin D therapy, P ⁇ 0.001).
  • the risk of mortality P I - was similar for patients with high and intermediate initial 25-OH D levels in both the treated and untreated groups.
  • the primary exposures were circulating serum levels of 25D and 1,25D measured at base-line (within 14 days of initiating hemodialysis), prior to the start of any oral or injectable vitamin D.
  • 25D and 1,25D levels were measured using radioimmunoassay (DiaSorin Inc., Stillwater, MN).
  • the coefficients of variation (CVs) for 25D measurements were ⁇ 3% at levels ⁇ 30 ng/ml and for 1,25D the CVs were ⁇ 6.5% at levels ⁇ 32.5 pg/ml. Based on clinically accepted definitions (Holick, Mayo Clin.
  • Standard descriptive statistics were used to present demographic and laboratory characteristics of the overall study population at the initiation of chronic hemodialysis.
  • To test whether routine laboratory tests of mineral metabolism could predict decreased vitamin D levels we examined correlation between vitamin D levels and biomarkers of mineral metabolism, and compared levels of these parameters according to the 25D and 1,25D cut points.
  • Cox proportional hazards analysis was used to examine survival on hemodialysis according to base-line vitamin D levels. Subjects were censored if they underwent kidney transplantation or recovered renal function within the study period. We performed separate analyses for 25D and 1,25D.
  • dialysis we adjusted for the first results of laboratory tests obtained after initiating dialysis (serum sodium, potassium, bicarbonate, blood urea nitrogen, creatinine, calcium, phosphate, PTH, albumin, hemoglobin, white blood cell count, ferritin and total cholesterol levels) and whether patients initiated hemodialysis as an outpatient in the dialysis center versus in the hospital.
  • vitamin D binding protein the primary binding protein for circulating vitamin D
  • DBP vitamin D binding protein
  • Dialysis initiation site (% inpatient) 78.9
  • Coronary artery disease/myocardial infarction ( %) 16.7
  • Table 9 illustrates mineral and nutrition metabolites according to 25D levels. Subjects with vitamin D deficiency had slightly lower serum calcium and albumin levels, and increased PTH and alkaline phosphatase levels compared to subjects with normal 25D stores.
  • FIGs. 3 and 4 illustrate the overlap in the distributions of 25D and 1,25D levels, respectively, according to base-line PTH levels, and suggest that PTH levels are poor surrogate measures of vitamin D levels.
  • Multivariate analyses were adjusted for age, gender, race, ethnicity, BMI, vascular access, BP, cause of ESRD, comorbidities, serum albumin, calcium, phosphate, PTH, white blood cells, hemoglobin, vitamin D binding protein levels, season, latitude, and facility-specific standardized mortality rates.
  • FIGs. 5 and 6 illustrate the risk of all-cause and cardiovascular mortality among groups defined by their vitamin D levels and whether or not they received injectable vitamin D therapy.
  • the reference groups included subjects who were treated with injectable vitamin D and who had 25D levels > 10 ng/ml (FIG.
  • African Americans Compared with Caucasians, African Americans had significantly lower mean 25D levels (17 ⁇ 10 vs. 24 ⁇ 13 ng/ml; P ⁇ 0.01) and were significantly more likely to be severely 25D deficient (30% vs. 14%; P ⁇ 0.01). Although there was no significant difference in base-line 1,25D levels, African- Americans also had significantly increased base-line PTH levels compared with Caucasians (349 ⁇ 272 vs. 218 ⁇ 181; P ⁇ 0.01), were significantly more likely to have a PTH level > 300 (40% vs. 19%; P ⁇ 0.01), and were significantly more likely to be treated with injectable vitamin D (75% vs.
  • African- Americans with 1,25D levels ⁇ 15 pg/ml who did not receive injectable vitamin D therapy were at markedly increased risk of all-cause (HR 5.4, 95% CI 1.4, 21.5) and cardiovascular-related (HR 15.0, 95% CI 2.5, 95.7) mortality compared with those who had 1,25D levels > 15 pg/ml and who received injectable vitamin D therapy.
  • Those with similarly low levels of 1,25D but who were treated were at slightly lower risk for all-cause (HR 4.6, 95% CI 2.6, 12.7) and cardiovascular related mortality (HR 7.4, 95% CI 1.9, 29.5) compared to patients who were treated.

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Abstract

L'invention concerne des procédés et trousses permettant de réduire le risque de mortalité des dialysés. Ces procédés consistent à effectuer l'analyse biologique des niveaux de vitamine D endogène dans le sérum ou le plasma d'un patient dialysé ou nécessitant une dialyse ; à comparer les niveaux de vitamine D endogène à un niveau seuil et à fournir de la vitamine D exogène (notamment de la vitamine D activée) à des patients ayant des niveaux de vitamine D endogène en deçà du niveau seuil.
PCT/US2006/023774 2005-06-27 2006-06-19 Carence en vitamine d et dialyse Ceased WO2007001969A1 (fr)

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009095758A2 (fr) 2008-01-30 2009-08-06 Clipper Windpower Technology, Inc. Structure de pale rétractable à bord de fuite fendu
US20130324505A1 (en) * 2011-01-07 2013-12-05 Beth Israel Deaconess Medical Center, Inc. Assays and methods of treatment relating to vitamin d insufficiency
US20140113885A1 (en) 2011-01-07 2014-04-24 Ravi Thadhani Assays and methods of treatment relating to vitamin d insufficiency
EP2927692A1 (fr) * 2014-04-04 2015-10-07 Winfried März Approche de biomarqueurs multiples pour la prédiction de la mortalité chez des patients dialysés
US9606131B2 (en) 2011-01-07 2017-03-28 The General Hospital Corporation Assays and methods of treatment relating to vitamin D insufficiency
CN111544449A (zh) * 2020-05-29 2020-08-18 甘肃锦东医疗器械有限公司 一种补充维生素d的枸橼酸血液透析浓缩物
CN119080938A (zh) * 2023-06-05 2024-12-06 东莞市朋志生物科技有限公司 抗25羟维生素d抗体、检测25羟维生素d的试剂和试剂盒

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009095758A2 (fr) 2008-01-30 2009-08-06 Clipper Windpower Technology, Inc. Structure de pale rétractable à bord de fuite fendu
US20130324505A1 (en) * 2011-01-07 2013-12-05 Beth Israel Deaconess Medical Center, Inc. Assays and methods of treatment relating to vitamin d insufficiency
US20140113885A1 (en) 2011-01-07 2014-04-24 Ravi Thadhani Assays and methods of treatment relating to vitamin d insufficiency
US9052308B2 (en) * 2011-01-07 2015-06-09 The General Hospital Corporation Assays and methods of treatment relating to vitamin D insufficiency
US9329190B2 (en) 2011-01-07 2016-05-03 The General Hospital Corporation Assays and methods of treatment relating to vitamin D insufficiency
US9606131B2 (en) 2011-01-07 2017-03-28 The General Hospital Corporation Assays and methods of treatment relating to vitamin D insufficiency
US9671414B2 (en) 2011-01-07 2017-06-06 Beth Israel Deaconess Medical Center, Inc. Assays and methods of treatment relating to vitamin D insufficiency
EP2927692A1 (fr) * 2014-04-04 2015-10-07 Winfried März Approche de biomarqueurs multiples pour la prédiction de la mortalité chez des patients dialysés
CN111544449A (zh) * 2020-05-29 2020-08-18 甘肃锦东医疗器械有限公司 一种补充维生素d的枸橼酸血液透析浓缩物
CN119080938A (zh) * 2023-06-05 2024-12-06 东莞市朋志生物科技有限公司 抗25羟维生素d抗体、检测25羟维生素d的试剂和试剂盒

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