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Does vitamin D really impact survival after lung transplantation?
Comments and Opinions
789 tribute to expanding the pool of available donor organs, but careful consideration is warranted.
Disclosure statement The authors have no conflicts of interest to disclose. We thank Dr I. Martinez-Bendayan (Cardiology Department) and Dr J. J. Cuenca (Cardiac Surgery Department) for their scientific assistance with manuscript preparation.
Figure 1 Intra-operative image showing the PFO occluder from the left atrial side. Note the legs of the device covered by fibrotic tissue and their relationship to the surrounding cardiac structures.
significant neo-aortic valve regurgitation and progressively impaired ventricular function. He was not considered suitable for Fontan completion and was listed for heart transplantation (weight 25 kg). The organ donor was a 33-yearold woman (weight 45 kg) who had brain death consequent to a cerebrovascular accident (CVA). Two years earlier, a CVA in the donor prompted the diagnosis of a patent foramen ovale (PFO) and an occluder was successfully implanted using supportive anti-coagulation. On visual inspection of the donor heart, the atrial occluder was well positioned and covered by neo-endothelium (Figure 1). The inferior edge of the device was close to the mitral valve. Thus, we left the occluder in situ and performed heart transplantation using a bicaval anastomotic technique. The donor left atrial cuff was trimmed so a large anastomosis could be performed. The post-operative course was uneventful. Early catheterization for myocardial biopsy showed a correctly positioned device with no step-up on oxygen saturation. At 6 months after transplantation the patient continued to be asymptomatic. Although some investigators have reported the use of a donor heart after heart surgery,1,2 previous cardiac procedures have been classically considered a contraindication for heart donation. The prevalence of a PFO among patients with a cryptogenic stroke is 40% to 50% and about 20% in the general population. Although lacking strong supportive clinical evidence, percutaneous PFO closure is becoming increasingly frequent.3 As with our donor, careful consideration of this potentially large population could expand the pool of donors. Anti-coagulation in patients with atrial septal devices is an important yet unresolved issue. Thrombus formation is not infrequent (2.5% to 27% of cases). Although neurologic events usually occur within the first 12 months after implantation, late formation of thrombus has also been reported.4 Moreover, immunosuppressive therapy may delay epithelialization of implanted devices and thus require extended periods of anti-coagulation. Our recipient did not receive anti-coagulation therapy post-transplant because the device demonstrated complete neo- endothelialization with no thrombus detected on visual inspection. Follow-up echocardiograms depicted good positioning of the device with no residual shunt or thrombus formation. Consideration of patients with intracardiac devices could con-
References 1. Drummond-Webb JJ, Schmitz ML, et al. Expanding the donor pool: use of a donor heart having undergone recent cardiac surgery. J Heart Lung Transplant 2004;23:639-40. 2. Maltais S, Carrier M, Pellerin M, et al. Closure of ventricular septal defect in the donor heart before transplantation: toward expanded acceptance criteria. J Thorac Cardiovasc Surg 2005;129:1187-9. 3. Furlan AJ, Reisman M, Massaro J, et al. Study design of the CLOSURE I Trial: a prospective, multicenter, randomized, controlled trial to evaluate the safety and efficacy of the STARFlex septal closure system versus best medical therapy in patients with stroke or transient ischemic attack due to presumed paradoxical embolism through a patent foramen ovale. Stroke 2010;41:2872-83. 4. Zaidi AN, Cheatham JP, Galantowicz M, et al. Late thrombus formation on the Helex septal occluder after double-lung transplant. J Heart Lung Transplant 2010;29:814-6.
Does vitamin D really impact survival after lung transplantation? Stijn E. Verleden, Msc, Geert M. Verleden, MD, PhD, and Bart M. Vanaudenaerde, PhD From the Leuven Lung Transplant Unit, Katholieke Universiteit (K.U.Leuven), Leuven, Belgium
We read with great interest the article by Lowery et al1 reporting that 25-hydroxyvitamin D (25-OHD) deficiency occurs in lung transplant patients with various important clinical implications, the major being a greater mortality in the group deficient in vitamin D. Because we recently published a similar cross-sectional study2 and are also conducting a randomized placebo-controlled trial with vitamin D supplementation in lung transplant patients, we still have some unresolved questions. Vitamin D has been linked to pulmonary function,3 and one of the major outcomes of our pilot study was an effect of vitamin D deficiency on forced expiratory volume in 1 second (FEV1) showing 75% predicted in 25-OHD– deficient patients vs 89% in non-deficient patients, but information regarding post-transplant FEV1 is lacking in the report by Lowery et al.1 We were curious if the authors could corroborate this. The other major outcome of our study was an effect of vitamin D deficiency on higher grades of lymphocytic bronchiolitis (grade B ⱖ 2). Did the authors find a similar effect if they divided B grades into lower and higher grades? Moreover, we believe that there is a lack of adjustment for confounding variables; 25-OHD levels are indeed influ-
790
The Journal of Heart and Lung Transplantation, Vol 31, No 7, July 2012
enced by a lot of other possible confounders, which are not corrected for, such as seasonal variations and the level of immunosuppression. Tacrolimus and cyclosporine increase the vitamin D serum level4; hence, it is entirely plausible that there was a lower level of immunosuppression in the deficient group leading to a higher number of acute rejections and death. Moreover, azithromycin is routinely introduced in most lung transplant centers throughout the world due to its immunomodulatory effects, with possible similar effects as vitamin D on inflammation and immunoregulation (eg, a role on Treg/Th17 cells5). It has already been shown that azithromycin can prevent the development of bronchiolitis obliterans syndrome (BOS), so clearly, it has an influence on some outcomes assessed in their study, but their manuscript does not mention its potential use. We were surprised by the influence of 25-OHD levels on survival, despite having no effect on the development of BOS. We were wondering if the authors could link the vitamin D deficiency in some way to the cause of death and how the 25-OHD deficiency could cause this, if not by an effect on the development of BOS. We clearly believe in the importance of vitamin D in lung transplantation, but it is important not to over-exaggerate the potential of vitamin D supplementation. It seems unlikely that just supplementing the patient with vitamin D will lead to a spectacular increase in survival. Only a randomized placebocontrolled trial can definitely prove this, which is ongoing at this moment in our center (NCT01212406).
Disclosure statement GMV is holder of the GlaxoSmithKline (Belgium) Chair in Respiratory Pharmacology at the Katholieke Universiteit Leuven (K.U.Leuven), and is supported by the Research Foundation Flanders (FWO: G.0723.10, G.0705.12, and G.0679.12) and “Onderzoeksfonds K.U.Leuven” (OT/10/050). BMV is a senior research of the FWO. None of the authors has a financial relationship with a commercial entity that has an interest in the subject of the presented manuscript.
References 1. Lowery EM, Bemiss B, Cascino T, et al. Low vitamin D levels are associated with increased rejection and infections after lung transplantation. J Heart Lung Transplant 2012 [E-pub ahead of print: March 3, 2012.] 2. Verleden SE, Vos R, Geenens R, et al. Vitamin D deficiency in lung transplant patients: is it important? Transplantation 2012;93:224-9. 3. Black PN, Scragg R. Relationship between serum 25-hydroxyvitamin d and pulmonary function in the third national health and nutrition examination survey. Chest 2005;128:3792-8. 4. Lee CT, Ng HY, Lien YH, et al. Effects of cyclosporine, tacrolimus and rapamycin on renal calcium transport and vitamin D metabolism. Am J Nephrol 2011;34:87-94. 5. Tang J, Zhou R, Luger D, et al. Calcitriol suppresses antiretinal autoimmunity through inhibitory effects on the Th17 effector response. J Immunol 2009;182:4624-32.
789 tribute to expanding the pool of available donor organs, but careful consideration is warranted.
Disclosure statement The authors have no conflicts of interest to disclose. We thank Dr I. Martinez-Bendayan (Cardiology Department) and Dr J. J. Cuenca (Cardiac Surgery Department) for their scientific assistance with manuscript preparation.
Figure 1 Intra-operative image showing the PFO occluder from the left atrial side. Note the legs of the device covered by fibrotic tissue and their relationship to the surrounding cardiac structures.
significant neo-aortic valve regurgitation and progressively impaired ventricular function. He was not considered suitable for Fontan completion and was listed for heart transplantation (weight 25 kg). The organ donor was a 33-yearold woman (weight 45 kg) who had brain death consequent to a cerebrovascular accident (CVA). Two years earlier, a CVA in the donor prompted the diagnosis of a patent foramen ovale (PFO) and an occluder was successfully implanted using supportive anti-coagulation. On visual inspection of the donor heart, the atrial occluder was well positioned and covered by neo-endothelium (Figure 1). The inferior edge of the device was close to the mitral valve. Thus, we left the occluder in situ and performed heart transplantation using a bicaval anastomotic technique. The donor left atrial cuff was trimmed so a large anastomosis could be performed. The post-operative course was uneventful. Early catheterization for myocardial biopsy showed a correctly positioned device with no step-up on oxygen saturation. At 6 months after transplantation the patient continued to be asymptomatic. Although some investigators have reported the use of a donor heart after heart surgery,1,2 previous cardiac procedures have been classically considered a contraindication for heart donation. The prevalence of a PFO among patients with a cryptogenic stroke is 40% to 50% and about 20% in the general population. Although lacking strong supportive clinical evidence, percutaneous PFO closure is becoming increasingly frequent.3 As with our donor, careful consideration of this potentially large population could expand the pool of donors. Anti-coagulation in patients with atrial septal devices is an important yet unresolved issue. Thrombus formation is not infrequent (2.5% to 27% of cases). Although neurologic events usually occur within the first 12 months after implantation, late formation of thrombus has also been reported.4 Moreover, immunosuppressive therapy may delay epithelialization of implanted devices and thus require extended periods of anti-coagulation. Our recipient did not receive anti-coagulation therapy post-transplant because the device demonstrated complete neo- endothelialization with no thrombus detected on visual inspection. Follow-up echocardiograms depicted good positioning of the device with no residual shunt or thrombus formation. Consideration of patients with intracardiac devices could con-
References 1. Drummond-Webb JJ, Schmitz ML, et al. Expanding the donor pool: use of a donor heart having undergone recent cardiac surgery. J Heart Lung Transplant 2004;23:639-40. 2. Maltais S, Carrier M, Pellerin M, et al. Closure of ventricular septal defect in the donor heart before transplantation: toward expanded acceptance criteria. J Thorac Cardiovasc Surg 2005;129:1187-9. 3. Furlan AJ, Reisman M, Massaro J, et al. Study design of the CLOSURE I Trial: a prospective, multicenter, randomized, controlled trial to evaluate the safety and efficacy of the STARFlex septal closure system versus best medical therapy in patients with stroke or transient ischemic attack due to presumed paradoxical embolism through a patent foramen ovale. Stroke 2010;41:2872-83. 4. Zaidi AN, Cheatham JP, Galantowicz M, et al. Late thrombus formation on the Helex septal occluder after double-lung transplant. J Heart Lung Transplant 2010;29:814-6.
Does vitamin D really impact survival after lung transplantation? Stijn E. Verleden, Msc, Geert M. Verleden, MD, PhD, and Bart M. Vanaudenaerde, PhD From the Leuven Lung Transplant Unit, Katholieke Universiteit (K.U.Leuven), Leuven, Belgium
We read with great interest the article by Lowery et al1 reporting that 25-hydroxyvitamin D (25-OHD) deficiency occurs in lung transplant patients with various important clinical implications, the major being a greater mortality in the group deficient in vitamin D. Because we recently published a similar cross-sectional study2 and are also conducting a randomized placebo-controlled trial with vitamin D supplementation in lung transplant patients, we still have some unresolved questions. Vitamin D has been linked to pulmonary function,3 and one of the major outcomes of our pilot study was an effect of vitamin D deficiency on forced expiratory volume in 1 second (FEV1) showing 75% predicted in 25-OHD– deficient patients vs 89% in non-deficient patients, but information regarding post-transplant FEV1 is lacking in the report by Lowery et al.1 We were curious if the authors could corroborate this. The other major outcome of our study was an effect of vitamin D deficiency on higher grades of lymphocytic bronchiolitis (grade B ⱖ 2). Did the authors find a similar effect if they divided B grades into lower and higher grades? Moreover, we believe that there is a lack of adjustment for confounding variables; 25-OHD levels are indeed influ-
790
The Journal of Heart and Lung Transplantation, Vol 31, No 7, July 2012
enced by a lot of other possible confounders, which are not corrected for, such as seasonal variations and the level of immunosuppression. Tacrolimus and cyclosporine increase the vitamin D serum level4; hence, it is entirely plausible that there was a lower level of immunosuppression in the deficient group leading to a higher number of acute rejections and death. Moreover, azithromycin is routinely introduced in most lung transplant centers throughout the world due to its immunomodulatory effects, with possible similar effects as vitamin D on inflammation and immunoregulation (eg, a role on Treg/Th17 cells5). It has already been shown that azithromycin can prevent the development of bronchiolitis obliterans syndrome (BOS), so clearly, it has an influence on some outcomes assessed in their study, but their manuscript does not mention its potential use. We were surprised by the influence of 25-OHD levels on survival, despite having no effect on the development of BOS. We were wondering if the authors could link the vitamin D deficiency in some way to the cause of death and how the 25-OHD deficiency could cause this, if not by an effect on the development of BOS. We clearly believe in the importance of vitamin D in lung transplantation, but it is important not to over-exaggerate the potential of vitamin D supplementation. It seems unlikely that just supplementing the patient with vitamin D will lead to a spectacular increase in survival. Only a randomized placebocontrolled trial can definitely prove this, which is ongoing at this moment in our center (NCT01212406).
Disclosure statement GMV is holder of the GlaxoSmithKline (Belgium) Chair in Respiratory Pharmacology at the Katholieke Universiteit Leuven (K.U.Leuven), and is supported by the Research Foundation Flanders (FWO: G.0723.10, G.0705.12, and G.0679.12) and “Onderzoeksfonds K.U.Leuven” (OT/10/050). BMV is a senior research of the FWO. None of the authors has a financial relationship with a commercial entity that has an interest in the subject of the presented manuscript.
References 1. Lowery EM, Bemiss B, Cascino T, et al. Low vitamin D levels are associated with increased rejection and infections after lung transplantation. J Heart Lung Transplant 2012 [E-pub ahead of print: March 3, 2012.] 2. Verleden SE, Vos R, Geenens R, et al. Vitamin D deficiency in lung transplant patients: is it important? Transplantation 2012;93:224-9. 3. Black PN, Scragg R. Relationship between serum 25-hydroxyvitamin d and pulmonary function in the third national health and nutrition examination survey. Chest 2005;128:3792-8. 4. Lee CT, Ng HY, Lien YH, et al. Effects of cyclosporine, tacrolimus and rapamycin on renal calcium transport and vitamin D metabolism. Am J Nephrol 2011;34:87-94. 5. Tang J, Zhou R, Luger D, et al. Calcitriol suppresses antiretinal autoimmunity through inhibitory effects on the Th17 effector response. J Immunol 2009;182:4624-32.