J Nephrol DOI 10.1007/s40620-015-0196-y
ORIGINAL ARTICLE
Efficiency of delivery observed treatment in hemodialysis patients: the example of the native vitamin D therapy Pierre Delanaye1 • Etienne Cavalier2 • Coraline Fafin3 • Bernard E. Dubois1 Jean-Marie Krzesinski1 • Olivier Moranne3,4
•
Received: 29 December 2014 / Accepted: 28 March 2015 Ó Italian Society of Nephrology 2015
Abstract Introduction Adherence to therapy is a relevant challenge in chronic hemodialysis patients. The directly observed therapy (DOT) could be an effective method to increase adherence for specific therapies. We aimed to study the performance of DOT versus home medication. We follow the impact of providing native vitamin D directly by the nurse after a dialysis session on the 25-hydroxyvitamin [25(OH)D] concentrations. Methods In this observational study, we included 38 dialysis patients treated by stable dosage of cholecalciferol. DOT was implemented in December 2010. We considered the concentrations of 25-OH vitamin D three times before (T1 = June 2010, T2 = July 2010 and T3 = September 2010) and three times after the modification of prescription (T4 = February 2011, T5 = March 2011 and T6 = April 2011). Results Median age was 72 [62; 79] years and 48 % were diabetics. Mean body mass index was 26 ± 5 kg/m2 and median dialysis vintage was 20 [8; 46] months. The patients were compared to themselves. Before DOT, median concentrations of 25(OH)D were 27 (14–36), 23 (17–31),
& Pierre Delanaye [email protected] 1
Department of Nephrology-Dialysis-Transplantation, University of Lie`ge, CHU Sart Tilman, Lie`ge, Belgium
2
Department of Clinical Chemistry, University of Lie`ge, CHU Sart Tilman, Lie`ge, Belgium
3
Division of Nephrology and Public Health, CHU de Nice, Nice, France
4
Biostatistics, Epidemiology and Public Health, Institut Universitaire de Recherche Clinique, University of Montpellier, EA 2415, Montpellier, France
31 (22–38) ng/mL at T1, T2 and T3, respectively. When DOT was effective, the concentrations significantly increased to 34 (28–44), 35 (29–41), 39 (32–47) ng/mL at T4, T5 and T6, respectively. Before DOT, 19 patients (50 %) reached the target of 30 ng/mL. After DOT, 29 patients (76 %) reached the target concentration of 30 ng/ mL. Conclusions In hemodialysis patients, DOT is both simple and effective to increase the therapeutic impact to native vitamin D. Keywords Cholecalciferol Adherence Hemodialysis Directly observed therapy
Introduction End-stage renal disease (ESRD) is the quintessence of the chronic disease. The dialysis subjects are also the group of patients with the highest daily pill burden and several of these pills must be taken for ever [1, 2]. It is thus not surprising that many authors describe a low adherence of drug therapy in this specific population [1, 3]. For example, adherence to phosphate chelators has been reviewed and a range of 24–74 % is observed, depending on the method used to assess adherence [1, 4]. Improving adherence to therapy in chronic patients is not an easy task. Among others, the directly observed therapy (DOT) could be both a simple and effective method to increase adherence for specific therapies [5]. To the best of our knowledge, the efficacy of DOT has not been studied in dialysis patients. In this context, native (or nutritional) vitamin D could be the therapy of choice to evaluate DOT in this specific population. Indeed, treatment by native vitamin D is recommended by the K-DIGO guidelines, including for
123
J Nephrol
dialysis patients [6]. It is a chronic therapy and, contrary to active vitamin D, this drug can be monitored by measuring plasma 25-hydroxyvitamin [25(OH)D]. Indeed, measuring 25(OH)D is easy, accurate, relatively cheap and intra-individual variation is low in dialysis patients [7]. Lastly, this medication is frequently given once a week or once a month, making the DOT both possible and relevant in thrice weekly dialyzed patients. In this study, we aimed to study the performance of DOT versus home medication by studying the impact of providing native vitamin D directly by the nurse on the 25(OH)D concentrations of the patients.
Materials and methods In December 2010, we considered all hemodialyzed patients treated by cholecalciferol in our university dialysis center. At that time, most of the patients were treated at home with one weekly phial containing 25,000 U of cholecalciferol (D-Cure, SMB, Belgium). Some others took one phial every 2 weeks or once a month. We then decided to deliver the vitamin both at the same dose and frequence, but after a dialysis session and under the supervision of a nurse. We only considered the patients treated with a stable load of cholecalciferol, 5 months before and after the implementation of DOT. We used the DiaSorin Liaison 25(OH)D TOTAL assay (Diasorin, Liaison, Stillwater, MN, USA) to measure 25(OH)D. All measurements were performed at the Laboratory of Clinical Chemistry of the University Hospital of Lie`ge (EC). The tests are accredited against the ISO 15189 and the laboratory participates to the DEQAS (for ‘‘Vitamin D external quality assessment scheme’’), CAP (for ‘‘College of American Pathologists’’) and RPCAQ (for ‘‘Royal Australasian Pathologists assurance quality program’’) proficiency testings. Because a stable concentration of 25(OH)D is reached after 3 months of therapy in hemodialyzed patients [8], we considered the concentrations of 25-OH vitamin D three times before (T1 = June 2010, T2 = July 2010 and T3 = September 2010) and three times after the modification of prescription (T4 = February 2011, T5 = March 2011 and T6 = April 2011), that occurred in December 2010. We considered 30 ng/mL as the therapeutic target [9]. We defined vitamin D deficiency by serum 25(OH)D levels below 10 ng/mL, and insufficiency by serum 25(OH)D levels below 30 ng/mL [10]. This study was observational. The treatment by vitamin D (dosage and frequence) was not influenced by the results of the study but only decided by nephrologists taking care of the patients. This study was performed in accordance with the institutional research and Helsinki declaration. Notably, all data were treated confidentially and anonymously. All patients signed informed consent.
123
Normally distributed variables were expressed as means (SD), non-normally distributed variables were expressed as median and interquartile [IQ] values and qualitative values were expressed as percentage. At baseline, groups were compared using one-way ANOVA test in case of normally distributed variables or Kruskall–Wallis test in case of nonnormally distributed variables. We compared group by group using Tukey tests to account for multiple comparisons for normally distributed variables and Mann–Whitney tests for non-normally distributed variables and Chi square for qualitative value with Bonferroni correction to account for multiple comparisons. The SAS software version 9.1 (SAS Institute, Cary, NC, USA) was used to perform the analyses.
Results Among the 96 hemodialyzed patients in December 2010, 46 (48 %) were treated by cholecalciferol. Dosage of cholecalciferol was stable 5 months before and 5 months after the implementation of DOT in 38 patients who were thus considered for the analysis. Eight patients were actually excluded from the analysis because dosage of cholecalciferol were modified during this period of time. The included patients were treated with cholecalciferol for a median time of 14.5 [6; 22] months. Twenty-seven patients (71 %) received 25,000 U once a week. Nine (24 %) and two (5 %) received 25,000 U once every two weeks and once a month, respectively. Twenty-eight men and ten women were included. Median age was 72 [62; 79] years and 48 % were diabetics. Mean body mass index was 26 ± 5 kg/m2 and median dialysis vintage was 20 [8; 46] months. Other clinical and biological variables are summarized in Table 1. When cholecalciferol was taken at home, the median concentrations of 25(OH)D were 27 (14–36), 23 (17–31), 31 (22–38) ng/mL at T1, T2 and T3, respectively. Concentrations at T3 were significantly higher than at T1 and T2 (p = 0.003 and p = 0.0002, Table 1 Clinical and biological characteristics of the population at baseline (n = 38) Gender (women/men) Age
10/28 72 (62; 79)
Dialysis vintage (months)
20 (8; 46)
Dry weight (kg)
70 (69; 77.5)
PTH (pg/mL)
306 ± 212
Serum calcium (mEq/L)
2.15 ± 0.20
Serum phosphorus (mmol/L)
1.68 ± 0.64
Treated by non-calcium chelators (%)
11 (29 %)
Treated by cinacalcet (%)
3 (8 %)
Results are expressed in median (interquartile range) or mean ± SD
J Nephrol
respectively). When DOT was effective, the concentrations increased to 34 (28–44), 35 (29–41), 39 (32–47) ng/mL at T4, T5 and T6, respectively. The 25(OH)D at T6 was significantly higher than at T4 and T5 (p = 0.0158 and p = 0.0014, respectively). Compared to concentrations prior to the change of prescription (T1, T2, T3), all the concentrations of 25(OH)D were significantly higher at T6 (p = 0.0001) (Fig. 1). Before the change of prescription, 19 patients (50 %) reached the target of 30 ng/mL at T3 (13 were treated by 25,000 U once a week, 5 every 2 weeks and one once a month). Eight patients (21 %) were even below 10 ng/mL. At the end of the observational period (T6), 29 patients (76 %) reached the target concentration of 30 ng/mL (Fig. 2). Among the 19 patients who did not reached the target level at T3, eleven then improved their vitamin D status between T3 and T6. The median concentration of 25(OH)D at T6 in the 9 patients who did not reach the target was 27 [25; 29] ng/mL. All these patients were treated by stable doses of 25,000 U once a week, except one treated every 2 weeks. No subject had 25(OH)D concentrations below 10 ng/mL anymore and only one had a 25(OH)D concentration below 20 ng/ mL.
Discussion In this observational analysis, we showed that DOT effectively improves the efficiency of cholecalciferol therapy in dialysis patients. Indeed, after implementation of the
DOT, the 25(OH)D concentrations significantly improved and most patients reached the therapeutic target or at least were very close to, whereas it was not the case before DOT. Dialysis patients have a high level of comorbidities. Indeed, in the last decades, the proportion of diabetic and hypertensive patients reaching ESRD has constantly increased [11]. By definition, dialysis patients are chronic patients. This is thus not surprising that these patients are treated by high number of pills associated with a high risk of non-adherence [1–3]. DOT is one of the strategies proposed to improve adherence in medicine. Several studies have shown that DOT could be of some interest in infectious diseases, like HIV and tuberculosis [12–14]. Vitamin D has a key role in the mineral metabolism of dialysis patients. The prevalence of 25(OH)D concentration below 30 ng/mL is very high (&80 %) in dialysis patients and is associated with a higher mortality risk [10, 15, 16]. 25(OH)D deficiency is associated with higher PTH levels in these patients and several prospective studies, including randomized studies, have demonstrated that cholecalciferol therapy in hemodialysis patients could effectively improve the 25(OH)D concentrations [8, 17–19]. Other potential benefits have been suggested on PTH levels and risk of fracture [8, 18]. KDIGO recommend to measure 25(OH)D in dialysis patients and to treat them when concentration is lower than 30 ng/mL [6]. Treatment by cholecalciferol (or ergocalciferol) is a chronic therapy, usually delivered once a week [8] or once a month [20]. It is possible, even if not proven, that this non-daily
Fig. 1 Evolution of 25(OH)D concentrations (median, IQR and range) before (black) and after (grey) DOT implementation. T1 June 2010, T2 July 2010, T3 September 2010, T4 February 2011, T5 March 2011, T6 April 2011
123
J Nephrol
better characterize these patients but our sample was definitively too low. Also, the effect of vitamin D therapy on other parameters (like parathormone) is beyond the scope of the actual study on DOT [8]. In this observational study, we show that DOT is effective on 25(OH)D levels in dialysis patients in the context of native vitamin D therapy. Although the dosage was constant, DOT significantly increased both the 25(OH)D concentrations and the proportion of patients reaching the therapeutic target. DOT is a very simple and inexpensive way to improve adherence and therapeutic impact to native vitamin D in dialysis patients. Conflict of interest Fig. 2 Proportion of patients with 25(OH)D concentrations under 10 ng/mL (black), between 10 and 30 ng/mL (dark grey) and over 30 ng/mL (light grey). DOT was implemented after T3. T1 June 2010, T2 July 2010, T3 September 2010, T4 February 2010, T5 March 2010, T6 March 2010
prescription could negatively impact the adherence to therapy in dialysis patients. In our study, several patients improved their vitamin D status, only with the implementation of DOT. It is more than likely that these patients were in fact non or poorly adherent to the therapy. There are limitations to our study. First, this is a single center observational study with a limited sample. Ideally, our results should be confirmed with a randomized design and a larger cohort. However, such a study could be difficult nowadays from an ethical point of view, as this therapy is recommended by the International guidelines. Second, native vitamin D can be prescribed once a week or once a month, which makes it an ideal candidate to apply DOT in dialysis units. The DOT strategy is obviously more difficult to implement with daily therapeutic drugs. Third, 25(OH)D is influenced by season and days of sunshine. Because we moved to DOT in December, the month with the lowest sunshine in Belgium, this factor had not influenced the 25(OH)D measurements observed in February and after [8]. In our prior randomised study, also performed in Belgium, we clearly showed that 25(OH)D levels are very low between January and April in the placebo group (see Fig. 2 in [8]). Fourth, we missed some data like mood disorders and exact number of pills. The main objective of our study is to evaluate DOT and therefore, our estimation of the non-adherence is not ideal. The best methodology would be the electronic monitoring (microelectronic monitoring devices) but it is costly and not easy to implement. Last, even after DOT, some patients are still below the therapeutic target. These patients could be considered either as ‘‘resistant’’ to native vitamin D therapy or as requiring higher doses. It could be of high interest to
123
We have no conflict of interest to declare.
Ethical approval This study was performed in accordance with the institutional research and Helsinki declaration. Notably, all data were treated confidentially and anonymously. Informed consent
All patients signed informed consent.
References 1. Burnier M, Pruijm M, Wuerzner G, Santschi V (2015) Drug adherence in chronic kidney diseases and dialysis. Nephrol Dial Transplant 30(1):39–44 2. Neri L, Martini A, Andreucci VE, Gallieni M, Rey LA, Brancaccio D (2011) Regimen complexity and prescription adherence in dialysis patients. Am J Nephrol 34(1):71–76 3. Schmid H, Hartmann B, Schiffl H (2009) Adherence to prescribed oral medication in adult patients undergoing chronic hemodialysis: a critical review of the literature. Eur J Med Res 14(5):185–190 4. Karamanidou C, Clatworthy J, Weinman J, Horne R (2008) A systematic review of the prevalence and determinants of nonadherence to phosphate binding medication in patients with endstage renal disease. BMC Nephrol 9:2 5. Volmink J, Garner P (2007) Directly observed therapy for treating tuberculosis. Cochrane Database Syst Rev (4):CD003343 6. (2009) KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of chronic kidney diseasemineral and bone disorder (CKD-MBD). Kidney Int Suppl (113):S1–S130 7. Cavalier E, Delanaye P, Moranne O (2013) Variability of new bone mineral metabolism markers in patients treated with maintenance hemodialysis: implications for clinical decision making. Am J Kidney Dis 61(5):847–848 8. Delanaye P, Weekers L, Warling X et al (2013) Cholecalciferol in haemodialysis patients: a randomized, double-blind, proof-of-concept and safety study. Nephrol Dial Transplant 28(7):1779–1786 9. Cavalier E, Delanaye P, Chapelle JP, Souberbielle JC (2009) Vitamin D: current status and perspectives. Clin Chem Lab Med 47(2):120–127 10. Wolf M, Shah A, Gutierrez O et al (2007) Vitamin D levels and early mortality among incident hemodialysis patients. Kidney Int 72(8):1004–1013 11. Foley RN, Parfrey PS, Sarnak MJ (1998) Clinical epidemiology of cardiovascular disease in chronic renal disease. Am J Kidney Dis 32(5 Suppl 3):S112–S119 12. Kangovi S, Mukherjee J, Bohmer R, Fitzmaurice G (2009) A classification and meta-analysis of community-based directly
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13.
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observed therapy programs for tuberculosis treatment in developing countries. J Community Health 34(6):506–513 Hill AR, Manikal VM, Riska PF (2002) Effectiveness of directly observed therapy (DOT) for tuberculosis: a review of multinational experience reported in 1990–2000. Medicine (Baltimore) 81(3):179–193 Hart JE, Jeon CY, Ivers LC et al (2010) Effect of directly observed therapy for highly active antiretroviral therapy on virologic, immunologic, and adherence outcomes: a meta-analysis and systematic review. J Acquir Immune Defic Syndr 54(2):167–179 Bhan I, Camargo CA Jr, Wenger J et al (2011) Circulating levels of 25-hydroxyvitamin D and human cathelicidin in healthy adults. J Allergy Clin Immunol 127(5):1302–1304 Jean G, Lataillade D, Genet L et al (2011) Impact of hypovitaminosis D and alfacalcidol therapy on survival of hemodialysis
17.
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patients: results from the French ARNOS study. Nephron Clin Pract 118(2):c204–c210 Armas LA, Andukuri R, Barger-Lux J, Heaney RP, Lund R (2012) 25-Hydroxyvitamin D response to cholecalciferol supplementation in hemodialysis. Clin J Am Soc Nephrol 7(9):1428–1434 Massart A, Debelle FD, Racape J et al (2014) Biochemical parameters after cholecalciferol repletion in hemodialysis: results from the VitaDial randomized trial. Am J Kidney Dis 64(5):696–705 Wasse H, Huang R, Long Q, Singapuri S, Raggi P, Tangpricha V (2012) Efficacy and safety of a short course of very-high-dose cholecalciferol in hemodialysis. Am J Clin Nutr 95(2):522–528 Jean G, Souberbielle JC, Chazot C (2009) Monthly cholecalciferol administration in haemodialysis patients: a simple and efficient strategy for vitamin D supplementation. Nephrol Dial Transplant 24(12):3799–3805
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ORIGINAL ARTICLE
Efficiency of delivery observed treatment in hemodialysis patients: the example of the native vitamin D therapy Pierre Delanaye1 • Etienne Cavalier2 • Coraline Fafin3 • Bernard E. Dubois1 Jean-Marie Krzesinski1 • Olivier Moranne3,4
•
Received: 29 December 2014 / Accepted: 28 March 2015 Ó Italian Society of Nephrology 2015
Abstract Introduction Adherence to therapy is a relevant challenge in chronic hemodialysis patients. The directly observed therapy (DOT) could be an effective method to increase adherence for specific therapies. We aimed to study the performance of DOT versus home medication. We follow the impact of providing native vitamin D directly by the nurse after a dialysis session on the 25-hydroxyvitamin [25(OH)D] concentrations. Methods In this observational study, we included 38 dialysis patients treated by stable dosage of cholecalciferol. DOT was implemented in December 2010. We considered the concentrations of 25-OH vitamin D three times before (T1 = June 2010, T2 = July 2010 and T3 = September 2010) and three times after the modification of prescription (T4 = February 2011, T5 = March 2011 and T6 = April 2011). Results Median age was 72 [62; 79] years and 48 % were diabetics. Mean body mass index was 26 ± 5 kg/m2 and median dialysis vintage was 20 [8; 46] months. The patients were compared to themselves. Before DOT, median concentrations of 25(OH)D were 27 (14–36), 23 (17–31),
& Pierre Delanaye [email protected] 1
Department of Nephrology-Dialysis-Transplantation, University of Lie`ge, CHU Sart Tilman, Lie`ge, Belgium
2
Department of Clinical Chemistry, University of Lie`ge, CHU Sart Tilman, Lie`ge, Belgium
3
Division of Nephrology and Public Health, CHU de Nice, Nice, France
4
Biostatistics, Epidemiology and Public Health, Institut Universitaire de Recherche Clinique, University of Montpellier, EA 2415, Montpellier, France
31 (22–38) ng/mL at T1, T2 and T3, respectively. When DOT was effective, the concentrations significantly increased to 34 (28–44), 35 (29–41), 39 (32–47) ng/mL at T4, T5 and T6, respectively. Before DOT, 19 patients (50 %) reached the target of 30 ng/mL. After DOT, 29 patients (76 %) reached the target concentration of 30 ng/ mL. Conclusions In hemodialysis patients, DOT is both simple and effective to increase the therapeutic impact to native vitamin D. Keywords Cholecalciferol Adherence Hemodialysis Directly observed therapy
Introduction End-stage renal disease (ESRD) is the quintessence of the chronic disease. The dialysis subjects are also the group of patients with the highest daily pill burden and several of these pills must be taken for ever [1, 2]. It is thus not surprising that many authors describe a low adherence of drug therapy in this specific population [1, 3]. For example, adherence to phosphate chelators has been reviewed and a range of 24–74 % is observed, depending on the method used to assess adherence [1, 4]. Improving adherence to therapy in chronic patients is not an easy task. Among others, the directly observed therapy (DOT) could be both a simple and effective method to increase adherence for specific therapies [5]. To the best of our knowledge, the efficacy of DOT has not been studied in dialysis patients. In this context, native (or nutritional) vitamin D could be the therapy of choice to evaluate DOT in this specific population. Indeed, treatment by native vitamin D is recommended by the K-DIGO guidelines, including for
123
J Nephrol
dialysis patients [6]. It is a chronic therapy and, contrary to active vitamin D, this drug can be monitored by measuring plasma 25-hydroxyvitamin [25(OH)D]. Indeed, measuring 25(OH)D is easy, accurate, relatively cheap and intra-individual variation is low in dialysis patients [7]. Lastly, this medication is frequently given once a week or once a month, making the DOT both possible and relevant in thrice weekly dialyzed patients. In this study, we aimed to study the performance of DOT versus home medication by studying the impact of providing native vitamin D directly by the nurse on the 25(OH)D concentrations of the patients.
Materials and methods In December 2010, we considered all hemodialyzed patients treated by cholecalciferol in our university dialysis center. At that time, most of the patients were treated at home with one weekly phial containing 25,000 U of cholecalciferol (D-Cure, SMB, Belgium). Some others took one phial every 2 weeks or once a month. We then decided to deliver the vitamin both at the same dose and frequence, but after a dialysis session and under the supervision of a nurse. We only considered the patients treated with a stable load of cholecalciferol, 5 months before and after the implementation of DOT. We used the DiaSorin Liaison 25(OH)D TOTAL assay (Diasorin, Liaison, Stillwater, MN, USA) to measure 25(OH)D. All measurements were performed at the Laboratory of Clinical Chemistry of the University Hospital of Lie`ge (EC). The tests are accredited against the ISO 15189 and the laboratory participates to the DEQAS (for ‘‘Vitamin D external quality assessment scheme’’), CAP (for ‘‘College of American Pathologists’’) and RPCAQ (for ‘‘Royal Australasian Pathologists assurance quality program’’) proficiency testings. Because a stable concentration of 25(OH)D is reached after 3 months of therapy in hemodialyzed patients [8], we considered the concentrations of 25-OH vitamin D three times before (T1 = June 2010, T2 = July 2010 and T3 = September 2010) and three times after the modification of prescription (T4 = February 2011, T5 = March 2011 and T6 = April 2011), that occurred in December 2010. We considered 30 ng/mL as the therapeutic target [9]. We defined vitamin D deficiency by serum 25(OH)D levels below 10 ng/mL, and insufficiency by serum 25(OH)D levels below 30 ng/mL [10]. This study was observational. The treatment by vitamin D (dosage and frequence) was not influenced by the results of the study but only decided by nephrologists taking care of the patients. This study was performed in accordance with the institutional research and Helsinki declaration. Notably, all data were treated confidentially and anonymously. All patients signed informed consent.
123
Normally distributed variables were expressed as means (SD), non-normally distributed variables were expressed as median and interquartile [IQ] values and qualitative values were expressed as percentage. At baseline, groups were compared using one-way ANOVA test in case of normally distributed variables or Kruskall–Wallis test in case of nonnormally distributed variables. We compared group by group using Tukey tests to account for multiple comparisons for normally distributed variables and Mann–Whitney tests for non-normally distributed variables and Chi square for qualitative value with Bonferroni correction to account for multiple comparisons. The SAS software version 9.1 (SAS Institute, Cary, NC, USA) was used to perform the analyses.
Results Among the 96 hemodialyzed patients in December 2010, 46 (48 %) were treated by cholecalciferol. Dosage of cholecalciferol was stable 5 months before and 5 months after the implementation of DOT in 38 patients who were thus considered for the analysis. Eight patients were actually excluded from the analysis because dosage of cholecalciferol were modified during this period of time. The included patients were treated with cholecalciferol for a median time of 14.5 [6; 22] months. Twenty-seven patients (71 %) received 25,000 U once a week. Nine (24 %) and two (5 %) received 25,000 U once every two weeks and once a month, respectively. Twenty-eight men and ten women were included. Median age was 72 [62; 79] years and 48 % were diabetics. Mean body mass index was 26 ± 5 kg/m2 and median dialysis vintage was 20 [8; 46] months. Other clinical and biological variables are summarized in Table 1. When cholecalciferol was taken at home, the median concentrations of 25(OH)D were 27 (14–36), 23 (17–31), 31 (22–38) ng/mL at T1, T2 and T3, respectively. Concentrations at T3 were significantly higher than at T1 and T2 (p = 0.003 and p = 0.0002, Table 1 Clinical and biological characteristics of the population at baseline (n = 38) Gender (women/men) Age
10/28 72 (62; 79)
Dialysis vintage (months)
20 (8; 46)
Dry weight (kg)
70 (69; 77.5)
PTH (pg/mL)
306 ± 212
Serum calcium (mEq/L)
2.15 ± 0.20
Serum phosphorus (mmol/L)
1.68 ± 0.64
Treated by non-calcium chelators (%)
11 (29 %)
Treated by cinacalcet (%)
3 (8 %)
Results are expressed in median (interquartile range) or mean ± SD
J Nephrol
respectively). When DOT was effective, the concentrations increased to 34 (28–44), 35 (29–41), 39 (32–47) ng/mL at T4, T5 and T6, respectively. The 25(OH)D at T6 was significantly higher than at T4 and T5 (p = 0.0158 and p = 0.0014, respectively). Compared to concentrations prior to the change of prescription (T1, T2, T3), all the concentrations of 25(OH)D were significantly higher at T6 (p = 0.0001) (Fig. 1). Before the change of prescription, 19 patients (50 %) reached the target of 30 ng/mL at T3 (13 were treated by 25,000 U once a week, 5 every 2 weeks and one once a month). Eight patients (21 %) were even below 10 ng/mL. At the end of the observational period (T6), 29 patients (76 %) reached the target concentration of 30 ng/mL (Fig. 2). Among the 19 patients who did not reached the target level at T3, eleven then improved their vitamin D status between T3 and T6. The median concentration of 25(OH)D at T6 in the 9 patients who did not reach the target was 27 [25; 29] ng/mL. All these patients were treated by stable doses of 25,000 U once a week, except one treated every 2 weeks. No subject had 25(OH)D concentrations below 10 ng/mL anymore and only one had a 25(OH)D concentration below 20 ng/ mL.
Discussion In this observational analysis, we showed that DOT effectively improves the efficiency of cholecalciferol therapy in dialysis patients. Indeed, after implementation of the
DOT, the 25(OH)D concentrations significantly improved and most patients reached the therapeutic target or at least were very close to, whereas it was not the case before DOT. Dialysis patients have a high level of comorbidities. Indeed, in the last decades, the proportion of diabetic and hypertensive patients reaching ESRD has constantly increased [11]. By definition, dialysis patients are chronic patients. This is thus not surprising that these patients are treated by high number of pills associated with a high risk of non-adherence [1–3]. DOT is one of the strategies proposed to improve adherence in medicine. Several studies have shown that DOT could be of some interest in infectious diseases, like HIV and tuberculosis [12–14]. Vitamin D has a key role in the mineral metabolism of dialysis patients. The prevalence of 25(OH)D concentration below 30 ng/mL is very high (&80 %) in dialysis patients and is associated with a higher mortality risk [10, 15, 16]. 25(OH)D deficiency is associated with higher PTH levels in these patients and several prospective studies, including randomized studies, have demonstrated that cholecalciferol therapy in hemodialysis patients could effectively improve the 25(OH)D concentrations [8, 17–19]. Other potential benefits have been suggested on PTH levels and risk of fracture [8, 18]. KDIGO recommend to measure 25(OH)D in dialysis patients and to treat them when concentration is lower than 30 ng/mL [6]. Treatment by cholecalciferol (or ergocalciferol) is a chronic therapy, usually delivered once a week [8] or once a month [20]. It is possible, even if not proven, that this non-daily
Fig. 1 Evolution of 25(OH)D concentrations (median, IQR and range) before (black) and after (grey) DOT implementation. T1 June 2010, T2 July 2010, T3 September 2010, T4 February 2011, T5 March 2011, T6 April 2011
123
J Nephrol
better characterize these patients but our sample was definitively too low. Also, the effect of vitamin D therapy on other parameters (like parathormone) is beyond the scope of the actual study on DOT [8]. In this observational study, we show that DOT is effective on 25(OH)D levels in dialysis patients in the context of native vitamin D therapy. Although the dosage was constant, DOT significantly increased both the 25(OH)D concentrations and the proportion of patients reaching the therapeutic target. DOT is a very simple and inexpensive way to improve adherence and therapeutic impact to native vitamin D in dialysis patients. Conflict of interest Fig. 2 Proportion of patients with 25(OH)D concentrations under 10 ng/mL (black), between 10 and 30 ng/mL (dark grey) and over 30 ng/mL (light grey). DOT was implemented after T3. T1 June 2010, T2 July 2010, T3 September 2010, T4 February 2010, T5 March 2010, T6 March 2010
prescription could negatively impact the adherence to therapy in dialysis patients. In our study, several patients improved their vitamin D status, only with the implementation of DOT. It is more than likely that these patients were in fact non or poorly adherent to the therapy. There are limitations to our study. First, this is a single center observational study with a limited sample. Ideally, our results should be confirmed with a randomized design and a larger cohort. However, such a study could be difficult nowadays from an ethical point of view, as this therapy is recommended by the International guidelines. Second, native vitamin D can be prescribed once a week or once a month, which makes it an ideal candidate to apply DOT in dialysis units. The DOT strategy is obviously more difficult to implement with daily therapeutic drugs. Third, 25(OH)D is influenced by season and days of sunshine. Because we moved to DOT in December, the month with the lowest sunshine in Belgium, this factor had not influenced the 25(OH)D measurements observed in February and after [8]. In our prior randomised study, also performed in Belgium, we clearly showed that 25(OH)D levels are very low between January and April in the placebo group (see Fig. 2 in [8]). Fourth, we missed some data like mood disorders and exact number of pills. The main objective of our study is to evaluate DOT and therefore, our estimation of the non-adherence is not ideal. The best methodology would be the electronic monitoring (microelectronic monitoring devices) but it is costly and not easy to implement. Last, even after DOT, some patients are still below the therapeutic target. These patients could be considered either as ‘‘resistant’’ to native vitamin D therapy or as requiring higher doses. It could be of high interest to
123
We have no conflict of interest to declare.
Ethical approval This study was performed in accordance with the institutional research and Helsinki declaration. Notably, all data were treated confidentially and anonymously. Informed consent
All patients signed informed consent.
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