Canadian Journal of Cardiology 30 (2014) 428e433
Clinical Research
Lower Blood Vitamin D Levels Are Associated With an Increased Incidence of Contrast-Induced Nephropathy in Patients Undergoing Coronary Angiography Irfan Sahin, MD,a Baris Gungor, MD,b Mehmet Mustafa Can, MD,a Ilhan Ilker Avci, MD,a Gamze Babur Guler, MD,c Ertugrul Okuyan, MD,a Halil Biter, MD,a Suleyman Sezai Yildiz, MD,a Burak Ayca, MD,a Seckin Satilmis, MD,b and Mustafa Hakan Dinckal, MDa a b
Department of Cardiology, Bagcılar Research and Education Hospital, Istanbul, Turkey
Department of Cardiology, Siyami Ersek Cardiovascular and Thoracic Surgery Center, Istanbul, Turkey c
Department of Cardiology, Istınye State Hospital, Istanbul, Turkey
ABSTRACT
RESUM E
Background: Vitamin D deficiency may be associated with an increased risk of renovascular disease. We assessed the correlation between vitamin D levels and contrast-induced nephropathy (CIN) in patients undergoing coronary angiography (CAG). Methods: Vitamin D and parathyroid hormone (PTH) levels were assessed before CAG in 403 patients. Estimated glomerular filtration rate (eGFR) was calculated using the Cockcroft-Gault equation. Patients with eGFR < 60 mL/min/1.73 m2 were hydrated with 0.9%saline at 1 mL/kg/h for 12 hours before and after CAG. CIN was defined as serum creatinine increase of > 0.5 mg/dL or > 25% within 48-72 hours after CAG. Results: CIN developed in 74 participants. Baseline eGFR, blood urea and creatinine in CIN (þ) and () groups were not significantly different (P ¼ 0.14, P ¼ 0.07, and P ¼ 0.61, respectively). Total volume of contrast medium (CM) was higher in the CIN (þ) group (132 64 mL vs 90 41 mL; P ¼ 0.01). Vitamin D levels were lower (median 8.5 [range, 0.5-26.6] ng/mL vs 14.9 [range, 1.9-93.5] ng/mL; P ¼ 0.01)
e à un risque Introduction : Une carence en vitamine D peut être associe leve de maladie re novasculaire. Nous avons e value la corre lation entre e phropathie induite par les niveaux sanguins de vitamine D et la ne les produits de contraste (NPC) chez les patients subissant une coronarographie. thodes : Avant de proce der à la coronarographie, nous avons Me value les niveaux de vitamine D et d’hormone parathyroïdienne (HPT) e bit de filtration glome rulaire chez 403 patients. L’estimation du de te calcule e en utilisant la formule de Cockcroft & Gault. Les (DFGe) a e te perfuse avec patients ayant un DFGe < 60 ml/min/1,73 m2 ont e une solution de NaCl 0,9 % à 1 ml/kg/h pendant 12 heures avant et te de termine e lors d’une après la coronarographie. La NPC a e atinine se rique > 0,5 mg/dl ou > 25 % dans augmentation de la cre les 48-72 heures suivant la coronarographie. sultats : La NPC s’est de veloppe e chez 74 participants. Le DFGe Re e et de cre atinine n’ont basal ainsi que la concentration sanguine d’ure re statistiquement entre les deux groupes NPC (þ) et (-) pas diffe
Contrast-induced nephropathy (CIN) is a generally reversible form of acute kidney injury that occurs mostly within 23 days of exposure to contrast medium (CM).1-3 The estimated incidence of CIN ranges from 2%-50%, and coronary angiography (CAG) or percutaneous coronary intervention (PCI), or both, are associated with CIN in about half of cases.4-7 It accounts for 10% of all causes of hospitalacquired renal failure, results in a prolonged in-hospital
stay, and represents a powerful predictor of poor early and late outcomes.8,9 Experimental data suggest that an activated renin-angiotensinaldosterone system, increased endothelin-1, and reactive oxygen species may play a role in the pathogenesis of CIN. Vitamin D is a potent negative regulator of the renin-angiotensin-aldosterone system and inflammation.10 Recently, vitamin D deficiency has been shown to be associated with increased risk for renovascular disease.11-14 Although many studies demonstrate that pre-existing renal dysfunction, diabetes mellitus, older age, and reduced left ventricular function are the most important factors for CIN, the association between vitamin D deficiency and CIN has not been investigated to date. Therefore, in this study we aimed to investigate the relationship between vitamin D deficiency and CIN in patients undergoing CAG.
Received for publication December 1, 2013. Accepted December 30, 2013. Corresponding author: Dr Baris Gungor, Mehmet Akif Mah, Hicret Sok, Bulvar Sit, A Blok D 3 Umraniye/Istanbul, Turkey. Tel.: þ90-216-5458695; fax: þ90-216-4592766. E-mail: [email protected] See page 432 for disclosure information.
0828-282X/$ - see front matter Ó 2014 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cjca.2013.12.029
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and PTH levels were higher (median 73.9 [range, 22-530] pg/mL vs 44.2 [range, 5-361] pg/mL; P ¼ 0.01) in the CIN (þ) group. Multivariate logistic regression analysis revealed that lower vitamin D levels (odds ratio [OR], 1.18; 95% confidence interval [CI], 1.11-1.26; P ¼ 0.01) and increased CM volume (OR, 1.01; 95% CI, 1.008-1.017; P ¼ 0.01) were independently correlated with CIN. In patients who had undergone percutaneous coronary intervention, lower levels of vitamin D were independently associated with CIN development. Conclusions: Lower vitamin D levels, implying possible vitamin D deficiency, are associated with a higher incidence of CIN.
(respectivement P ¼ 0,14, P ¼ 0,07, and P ¼ 0,61). Le volume total tait plus e leve dans le groupe NPC (þ) de produits de contraste e (132 64 ml vs 90 41 ml; P ¼ 0,01). Les niveaux sanguins de taient moins e leve s (me diane 8,5 ng/ml [intervalle, vitamine D e 0,5-26,6] vs 14,9 ng/ml [intervalle, 1,9-93,5]; P ¼ 0,01) tandis que les taient plus e leve s (me diane 73,9 pg/ml [intervalle, niveaux d’HPT e 22-530] vs 44,2 pg/ml [intervalle, 5-361]; P ¼ 0,01) dans le groupe gression logistique d’analyse multivarie e a NPC (þ). Le modèle de re ve le que des niveaux sanguins infe rieurs de vitamine D (ratio d’inre [RIA], 1,18; intervalle de confiance [IC] de 95 %, cidence approche 1,11-1,26; P ¼ 0,01) et une augmentation du volume des produits de le s contraste (RIA, 1,01; IC à 95 %, 1,008-1,017; P ¼ 0,01) sont corre pendante avec la NPC. Chez les patients ayant subi une de façon inde e, des niveaux bas de vitamine D intervention coronarienne percutane taient inde pendamment associe s avec le de veloppement de la NPC. e Conclusion : Des niveaux bas de vitamine D, soulignant une carence s à une incidence plus e leve e de la possible de vitamine D, sont associe NPC.
Methods
respectively. Serum vitamin D levels < 15 ng/mL were classified as vitamin D deficiency. Serum PTH levels were determined in serum by electrochemiluminescence ımmunoassay on an Elecsys 2010 immunoanalyzer (Roche Diagnostics, Mannheim, Germany), with a normal range of 12-65 pg/mL. Serum creatinine concentrations were measured before and within 48-72 hours of administration of the CM. Further measurements were performed in patients in whom CIN developed. Renal function was assessed by the eGFR using the Cockcroft-Gault equation adjusted per 1.73 m2 (mL/min/1.73 m2): (140 age in years) body weight in kg 0.85 (if female patient)/(72 SCr in mg/ dL).15 Renal function was categorized by the stages set by the National Kidney Foundation,16 with > 90 mL/min being normal, 60-89 mL/min being mildly impaired, 30-59 mL/min being moderately impaired, and < 30 mL/min being severely impaired. CIN was defined as the elevation of serum creatinine levels by > 0.5 mg/dL or > 25% occurring within 48-72 hours after the intravascular administration of CM, without another cause.17
Study population Consecutive patients who were to undergo CAG under elective conditions between October 1, 2009 and October 21, 2011 were prospectively recruited. All the patients were informed about the aim of the study and gave their consent; the protocol was approved by the institutional ethics committee. Patient demographics, clinical features, and medical therapies were assessed. Patients with acute coronary syndrome, active cancer, or metabolic bone disease; those receiving vitamin D supplementation; those with exposure to CM within the previous 3 days, those who had used nephrotoxic drugs within the previous 7 days, those whose serum creatinine level was > 2.0 mg/dL, and those receiving chronic dialysis were excluded from the study. Fasting blood tests were performed and estimated glomerular filtration rate (eGFR) was calculated. Patients with reduced renal function (eGFR < 60 mL/min/1.73 m2) were hydrated with 0.9 % saline at 1 mL/kg/h for 12 hours before and after CAG. In patients with a left ventricular ejection fraction (LVEF) < 40% or overt heart failure, the hydration rate was reduced to 0.5 mL/kg/h. None of the drugs, including angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs), were withheld before the procedure. A nonionic low-osmolality contrast agent (iohexol) was used exclusively in our catheter laboratory, and the total volume of CM used was recorded. The decision to perform coronary intervention by either angioplasty or stent implantation was left to the discretion of the operator. Patients undergoing PCI received chewable aspirin (300 mg, unless contraindicated), clopidogrel (300 mg, loading dose) and heparin (10,000 U) before PCI. After stent placement, clopidogrel was used for > 1 year and aspirin was used indefinitely. LVEF assessment was performed by echocardiography before CAG during the index hospitalization. Study protocols and definitions Serum concentrations of vitamin D were measured by a radioimmunoassay (DiaSorin Saluggia, Italy) with an intra- and interassay coefficient of variation of 8.6% and 9.2%,
Statistical analysis Mean standard deviation and median (minimum and e maximum values) were used for continuous variables, whereas percentages were used for categorical variables. Normal distribution was tested with 1 sample Kolmogorov-Smirnov test. An unpaired t test was used to test the difference between the continuous variants that showed normal distribution between patient and control groups. Two-group nonparametric comparisons were calculated with the Mann-Whitney U test when non-normally distributed. The correlation of vitamin D levels with CIN was investigated using 2 statistical methods: (1) between CIN (þ) and CIN (þ) patients and (2) the incidence of CIN in tertiles of vitamin D. The Pearson c2 test, Fisher exact test, and continuity correction (Yate’s correction) test were used to test the categorical variants. Binary logistic regression analysis was used to find the possible independent predictors of CIN in the study population. Receiver-operating characteristic curves for the prediction of CIN after procedures were constructed, and the area under the curve (AUC) was calculated for vitamin D and PTH levels. P < 0.05 was considered significant for all
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Table 1. Baseline clinical characteristics of patients with and without CIN
Age, y Male sex, n (%) Diabetes mellitus, n (%) Hypertension, n (%) Hyperlipidemia, n (%) Previous CAD, n (%) Previous heart failure, n (%) Smoking history, n (%) LVEF, % PCI performed, n (%) Volume of CM, mL Baseline eGFR, mL/min/1.73 m2 Participants with available eGFR < 30 mL/min, n (%) 30-60 mL/min, n (%) 60-90 mL/min, n (%) > 90 mL/min, n (%) Drugs, n (%) Aspirin ACE inhibitor ARB Calcium channel blocker b-Blocker
CIN (þ) n ¼ 74
CIN (e) n ¼ 329
P value
65.5 10.7 41 (55.4) 35 (47.3) 58 (78.3) 33 (44.6) 22 (29.7) 20 (27) 19 (25.6) 51 8 30 (40.5) 132 64 64 23
64.0 11.2 215 (65.3) 127 (38.6) 237 (72) 167 (50.7) 51 (15.5) 44 (13.4) 95 (28.9) 53 7 92 (27.9) 90 41 68 21
0.26 0.11 0.19 0.19 0.42 0.01 0.01 0.58 0.05 0.03 0.01 0.14
5 30 29 10
(6.7) (40.5) (39.2) (13.6)
4 131 156 37
(1.0) (40.1) (47.4) (11.2)
0.01 0.90 0.20 0.56
54 32 14 15 25
(73) (43.2) (18.9) (20.3) (33.8)
250 144 78 45 95
(75.9) (43.7) (23.7) (13.7) (28.9)
0.59 0.93 0.38 0.15 0.40
ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; CAD, coronary artery disease; CIN, contrast-induced nephropathy; CM, contrast medium; eGFR, estimated glomerular filtration rate; LVEF, left ventricular ejection fraction; PCI, percutaneous coronary intervention.
tests. SPSS, version 11.0 (SPSS Inc, Chicago, IL) was used for analysis.
Results A total of 403 patients undergoing CAG were prospectively recruited. CIN was observed in 74 (18.3%) of the patients. None of the patients required dialysis during the hospitalization period or in the first 30 days. The baseline clinical characteristics and laboratory findings of the patients with CIN (þ) and CIN () are summarized in Tables 1 and 2. Two groups were similar regarding age, sex, and frequency of atherosclerotic risk factors. Baseline levels of serum urea, creatinine, hemoglobin, glucose, cholesterol, calcium, and phosphorus and the eGFR were similar between CIN (þ) and CIN () patients. The total volume of CM used was higher in the CIN (þ) group than in the CIN () group (132 64 mL vs 90 41 mL; P ¼ 0.01), mostly because of the higher rate of PCI performed in the CIN (þ) group (40.5% vs 27.9%; P ¼ 0.03). In 230 participants (57.1%), vitamin D levels were < 15 ng/mL. The incidence of CIN was 27.2% in patients with vitamin D deficiency, which was significantly higher than in patients with normal vitamin D levels (6.9%) (P ¼ 0.01). Vitamin D levels were lower (median, 8.5 [range, 0.526.6] ng/mL vs median, 14.9 [range, 1.9-93.5] ng/mL; P ¼ 0.01) and PTH levels were higher (median, 73 [range, 22530] pg/mL vs median, 44 [range, 5-361] pg/mL; P ¼ 0.01) in the CIN (þ) group. When tertiles of vitamin D were considered, the incidence of CIN was 34.3% in the lowest tertile (n ¼ 134; vitamin D < 10.1 ng/mL) and was 2.9% in the highest tertile (n ¼ 134; vitamin D > 17.2 ng/mL), which was significantly higher (P ¼ 0.01).
Table 2. Laboratory parameters in patients with and without CIN CIN (þ) n ¼ 74
CIN (e) n ¼ 329
Hemoglobin, g/dL 12.6 1.9 13.0 1.9 Fasting glucose, mg/dL (range) 114 (52-388) 113 (62-548) Total cholesterol, mg/dL (range) 183 (75-285) 182 (68-456) Triglycerides, mg/dL (range) 146 (57-622) 141 (39-930) LDL cholesterol, mg/dL 112 33 112 39 HDL cholesterol, mg/dL 41 10 42 12 AST, U/L (range) 26 (10-122) 24 (6-283) ALT, U/L (range) 21 (9-67) 23 (3-71) Serum calcium, mg/dL 9.01 1.28 9.20 1.15 Serum phosporus, mg/dL 3.64 0.85 3.49 0.89 Serum urea, mg/dL Baseline 50.5 25.7 44.6 18.6 After 48 h 77.9 43.2 47.9 22.5 Serum creatinine, mg/dL Baseline 1.08 0.29 1.06 0.26 After 48 h 1.78 0.74 1.07 .027 Vitamin D, ng/mL (range) 8.5 (0.5-26.6) 14.9 (1.9-93.5) PTH, pg/mL (range) 74 (22-530) 44 (5-361)
P value 0.10 0.18 0.67 0.66 0.88 0.64 0.68 0.67 0.21 0.28 0.07 0.01 0.61 0.01 0.01 0.01
ALT, alanine aminotransferase; AST, aspartate aminotransferase; CIN, contrast-induced nephropathy; LDL, low-density lipoprotein; PTH, parathyroid hormone.
To define a cutoff for vitamin D and PTH levels predicting CIN, we used receiver-operating characteristic analysis that established a value of 10 ng/mL, with 74% sensitivity and 62% specificity for vitamin D (AUC, 0.762) and a value of > 73 pg/mL with 60% sensitivity and 70% specificity for PTH (AUC, 0.710) (Fig. 1). The frequency of CIN was highest in participants with an eGFR < 30 mL/min (5.4% vs 1.5%; P ¼ 0.04). However, the frequency of CIN was similar in other subgroups of renal function defined by eGFR (Table 1). The incidence of CIN was significantly higher in patients with vitamin D deficiency than in participants with normal vitamin D levels in each stage of renal function (50% vs 0% for eGFR < 30 mL/min; 23.4% vs 10.2% for eGFR between 30 and 60 mL/min; 26.7% vs 8.1% for eGFR between 60 and 90 mL/min; and 37.1% vs 3.1% for eGFR > 90 mL/min, respectively; P ¼ 0.01 for each comparison). Thus, a higher incidence of CIN in patients with lower levels of vitamin D was not correlated with the severity of renal disease. The incidence of CIN was not different between patients who received ACEI/ARB therapy and those who did not (17.1% vs 20.7%, respectively; P ¼ 0.38). In subgroup analysis, when only patients with vitamin D deficiency were considered, the incidence of CIN was not different between patients who received ACEI/ARB therapy and those who did not (28.6% vs 25.3%, respectively; P ¼ 0.58). The medications were not stopped before the procedure, and the distribution of medications was similar between the CIN (þ) and CIN () groups. By univariate logistic regression analysis, total volume of CM used, LVEF, presence of heart failure, and hemoglobin, vitamin D, and PTH levels were correlated with CIN. These variables were included in the multivariate logistic regression model (by a forward stepwise method) to determine the independent predictors of CIN. Vitamin D levels were analyzed in 2 ways: as a binary variable (vitamin D deficiency, present vs absent) and as a continuous variable. In addition, vitamin D/PTH levels and the presence of heart failure/LVEF were entered into the multivariate model separately to prevent
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Figure 1. Receiver operating curve characteristics of vitamin D (Vit D) and parathyroid hormone (PTH) levels for predicting contrast-induced nephropathy in the study population.
multicollinearity. Lower levels of vitamin D or the presence of vitamin D deficiency or increased levels of PTH were found to be independent predictors of CIN when analyzed separately in the model adjusted for total volume of CM used, LVEF, and hemoglobin levels (Table 3). The other independent variable was the total volume of CM used. When only participants who had undergone PCI were considered (n ¼ 122), lower levels of vitamin D (OR, 1.31; 95% CI, 1.042-1.227; P ¼ 0.01) and higher volumes of total CM used (OR, 1.025; 95% CI, 1.014-1.035; P ¼ 0.01) were still independently associated with higher rates of CIN in multivariate analysis. Discussion The main finding of our study was that decreased vitamin D levels measured before CM exposure were associated with an increased incidence of CIN development in patients undergoing CAG. The increased risk was observed in every stage of renal disease, even in patients with mild impairment of
renal function. The other independent predictor was the total volume of CM used. CIN is one of the most important clinical complications associated with coronary diagnostic and interventional procedures. Its development is associated with increased morbidity and mortality, including the need for transient dialysis or extended hospitalization, or both, and can lead to chronic end-stage renal disease.18 Many factors play a role in the development of CIN, such as diabetes mellitus, hypertension, age, amount and type of CM used, urgent interventions, patient dehydration, and drugs used. The pathophysiology of CIN is complex, pivoting around the concepts of vasoconstriction, vascular remodelling, inflammation, and thrombosis. Although the causes of CIN are not completely known, an activated renin-angiotensin-aldosterone system, increased levels of endothelin-1, and reactive oxygen species may play a role in the pathogenesis of CIN.19 Endothelin-1, renin, and angiotensin II are some of the potential mediators leading to intrarenal vasoconstriction in experimental models of CIN.20 Whether certain medications,
Table 3. Univariate and multivariate predictors of contrast-induced nephropathy in the study group Univariate analysis OR (95% CI) Age, 1 SD increase Male sex Hypertension Smoking history Diabetes mellitus Heart failure* LVEF, 1 SD decrease* Hemoglobin, 1 SD decrease Baseline eGFR, 1 SD decrease Creatinine, 1 SD increase Volume of CM, 1 SD increase Presence of ACEI/ARB therapy Vitamin D levels, 1 SD decreasey PTH levels, 1 SD increasey Presence of vitamin D deficiencyy
1.01 0.66 1.52 0.59 1.36 2.39 1.03 1.31 1.01 1.21 1.016 0.79 1.17 1.012 5.01
(0.99-1.04) (0.39-1.09) (0.81-2.86) (0.39-1.19) (0.82-2.26) (1.31-4.38) (1.01-1.07) (0.99-1.29) (0.99-1.02) (0.48-3.05) (1.01-1.021) (0.47-1.33) (1.10-1.23) (1.007-1.017) (2.62-9.76)
Multivariate analysis P value
OR (95% CI)
0.26 0.11 0.20 0.16 0.23 0.01 0.03 0.07 0.12 0.70 0.01 0.39 0.01 0.01 0.01
e e
1.37 1.02 1.05 1.01 1.18 1.01 5.96
e e (0.65-2.88) (0.98-1.06) (0.90-1.21) e e (1.008-1.017) e (1.11-1.26) (1.006-1.016) (2.79-12.7)
P value
0.41 0.22 0.54 0.01 0.01 0.01 0.01
Variables with P < 0.10 in univariate analyses were included in multivariate regression analysis. ACEI/ARB, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker; CI, confidence interval; CM, contrast medium; eGFR, estimated glomerular filtration rate; OR, odds ratio; SD, standard deviation. * These parameters were analyzed separately in a multivariate model adjusted for total volume of CM used and hemoglobin and vitamin D levels. y These parameters were analyzed separately in a multivariate model adjusted for the presence of heart failure, total volume of CM used, and hemoglobin levels.
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specifically renin-angiotensin-aldosterone system blocking agents, are risk factors for the development of CIN remains controversial.21-23 In our study, we did not observe any impact of ACEI/ARB therapy on the incidence of CIN after CAG. In addition, even in patients with vitamin D deficiency, ACEI/ARB therapy did not affect CIN rates. In concordance with previous studies, total volume of CM used was an independent predictor of CIN in our study population. The association of changes in the renin-angiotensinaldosterone system in CIN are not new, but very limited data are available, especially with regard to the impact of vitamin D deficiency on renovascular functions. Vitamin D receptors have been found in cardiomyocytes,24 vascular smooth muscle cells,25 and endothelial cells.26 Vitamin D is a potent negative regulator of the renin-angiotensin-aldosterone system.27 Experimental studies indicate that vitamin D participates in the regulation of the renin-angiotensin axis by directly suppressing renin gene expression.28-31 Renin overexpression can be produced in wild-type mice by pharmacologic inhibition of vitamin D synthesis.27 These data suggest that vitamin D deficiency may increase plasma renin activity,32 raise blood pressure,33 and promote adverse arterial and ventricular remodelling.34 In their experimental study, Kedrah at al. showed that the direct renin inhibitor aliskiren has a potential role in the prevention of experimental CIN in the rat.35 Also, Ari et al. used paricalcitol (active vitamin D analogue) in an experimental CIN model and demonstrated antioxidant and renoprotective effects of paricalcitol.36 On the basis of these facts, vitamin D deficiency may be associated with the pathophysiological processes causing CIN. In our study, we found that lower levels of vitamin D were independently associated with a higher incidence of CIN. However, our study does not give clues regarding the pathophysiological role and possible theuropathic application of vitamin D in CIN. There are a few limitations of this study worth mentioning. Although compatible in size with other similar investigations, many potentially important biomarkers and cytokines of CIN indices were not measured in the index study. The follow-up assessment of renal function in our study was 2-3 days after CAG; therefore, we might have missed a later increase in serum creatinine in some patients who did not have renal function deterioration within 72 hours of the procedure. This might result in a slight underestimation of CIN. Second, we did not know the cause of vitamin D deficiency in the vast majority of patients. Conclusions In summary, we found that vitamin D deficiency was associated with a higher incidence of CIN in our cohort. Further studies to confirm the degree of the association, as well as the pathophysiological characteristics, are warranted. Acknowledgements We thank Fatma Avsar, (statistician at the East Marmara Development Agency, Kocaeli, Turkey) for statistical assistance. Disclosures The authors have no conflicts of interest to disclose.
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35. Kedrah AE, Ari E, Alahdab Y, et al. Effect of the direct renin inhibitor aliskiren in the prevention of experimental contrast-induced nephropathy in the rat. Kidney Blood Press Res 2012;35:425-30.
28. Li YC, Kong J, Wei M, et al. 1,25-Dihydroxyvitamin D(3) is a negative endocrine regulator of the renin-angiotensin system. J Clin Invest 2002;110:229-38.
36. Ari E, Kedrah AE, Alahdab Y, et al. Antioxidant and renoprotective effects of paricalcitol on experimental contrast-induced nephropathy model. Br J Radiol 2012;85:1038-43.
Clinical Research
Lower Blood Vitamin D Levels Are Associated With an Increased Incidence of Contrast-Induced Nephropathy in Patients Undergoing Coronary Angiography Irfan Sahin, MD,a Baris Gungor, MD,b Mehmet Mustafa Can, MD,a Ilhan Ilker Avci, MD,a Gamze Babur Guler, MD,c Ertugrul Okuyan, MD,a Halil Biter, MD,a Suleyman Sezai Yildiz, MD,a Burak Ayca, MD,a Seckin Satilmis, MD,b and Mustafa Hakan Dinckal, MDa a b
Department of Cardiology, Bagcılar Research and Education Hospital, Istanbul, Turkey
Department of Cardiology, Siyami Ersek Cardiovascular and Thoracic Surgery Center, Istanbul, Turkey c
Department of Cardiology, Istınye State Hospital, Istanbul, Turkey
ABSTRACT
RESUM E
Background: Vitamin D deficiency may be associated with an increased risk of renovascular disease. We assessed the correlation between vitamin D levels and contrast-induced nephropathy (CIN) in patients undergoing coronary angiography (CAG). Methods: Vitamin D and parathyroid hormone (PTH) levels were assessed before CAG in 403 patients. Estimated glomerular filtration rate (eGFR) was calculated using the Cockcroft-Gault equation. Patients with eGFR < 60 mL/min/1.73 m2 were hydrated with 0.9%saline at 1 mL/kg/h for 12 hours before and after CAG. CIN was defined as serum creatinine increase of > 0.5 mg/dL or > 25% within 48-72 hours after CAG. Results: CIN developed in 74 participants. Baseline eGFR, blood urea and creatinine in CIN (þ) and () groups were not significantly different (P ¼ 0.14, P ¼ 0.07, and P ¼ 0.61, respectively). Total volume of contrast medium (CM) was higher in the CIN (þ) group (132 64 mL vs 90 41 mL; P ¼ 0.01). Vitamin D levels were lower (median 8.5 [range, 0.5-26.6] ng/mL vs 14.9 [range, 1.9-93.5] ng/mL; P ¼ 0.01)
e à un risque Introduction : Une carence en vitamine D peut être associe leve de maladie re novasculaire. Nous avons e value la corre lation entre e phropathie induite par les niveaux sanguins de vitamine D et la ne les produits de contraste (NPC) chez les patients subissant une coronarographie. thodes : Avant de proce der à la coronarographie, nous avons Me value les niveaux de vitamine D et d’hormone parathyroïdienne (HPT) e bit de filtration glome rulaire chez 403 patients. L’estimation du de te calcule e en utilisant la formule de Cockcroft & Gault. Les (DFGe) a e te perfuse avec patients ayant un DFGe < 60 ml/min/1,73 m2 ont e une solution de NaCl 0,9 % à 1 ml/kg/h pendant 12 heures avant et te de termine e lors d’une après la coronarographie. La NPC a e atinine se rique > 0,5 mg/dl ou > 25 % dans augmentation de la cre les 48-72 heures suivant la coronarographie. sultats : La NPC s’est de veloppe e chez 74 participants. Le DFGe Re e et de cre atinine n’ont basal ainsi que la concentration sanguine d’ure re statistiquement entre les deux groupes NPC (þ) et (-) pas diffe
Contrast-induced nephropathy (CIN) is a generally reversible form of acute kidney injury that occurs mostly within 23 days of exposure to contrast medium (CM).1-3 The estimated incidence of CIN ranges from 2%-50%, and coronary angiography (CAG) or percutaneous coronary intervention (PCI), or both, are associated with CIN in about half of cases.4-7 It accounts for 10% of all causes of hospitalacquired renal failure, results in a prolonged in-hospital
stay, and represents a powerful predictor of poor early and late outcomes.8,9 Experimental data suggest that an activated renin-angiotensinaldosterone system, increased endothelin-1, and reactive oxygen species may play a role in the pathogenesis of CIN. Vitamin D is a potent negative regulator of the renin-angiotensin-aldosterone system and inflammation.10 Recently, vitamin D deficiency has been shown to be associated with increased risk for renovascular disease.11-14 Although many studies demonstrate that pre-existing renal dysfunction, diabetes mellitus, older age, and reduced left ventricular function are the most important factors for CIN, the association between vitamin D deficiency and CIN has not been investigated to date. Therefore, in this study we aimed to investigate the relationship between vitamin D deficiency and CIN in patients undergoing CAG.
Received for publication December 1, 2013. Accepted December 30, 2013. Corresponding author: Dr Baris Gungor, Mehmet Akif Mah, Hicret Sok, Bulvar Sit, A Blok D 3 Umraniye/Istanbul, Turkey. Tel.: þ90-216-5458695; fax: þ90-216-4592766. E-mail: [email protected] See page 432 for disclosure information.
0828-282X/$ - see front matter Ó 2014 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cjca.2013.12.029
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and PTH levels were higher (median 73.9 [range, 22-530] pg/mL vs 44.2 [range, 5-361] pg/mL; P ¼ 0.01) in the CIN (þ) group. Multivariate logistic regression analysis revealed that lower vitamin D levels (odds ratio [OR], 1.18; 95% confidence interval [CI], 1.11-1.26; P ¼ 0.01) and increased CM volume (OR, 1.01; 95% CI, 1.008-1.017; P ¼ 0.01) were independently correlated with CIN. In patients who had undergone percutaneous coronary intervention, lower levels of vitamin D were independently associated with CIN development. Conclusions: Lower vitamin D levels, implying possible vitamin D deficiency, are associated with a higher incidence of CIN.
(respectivement P ¼ 0,14, P ¼ 0,07, and P ¼ 0,61). Le volume total tait plus e leve dans le groupe NPC (þ) de produits de contraste e (132 64 ml vs 90 41 ml; P ¼ 0,01). Les niveaux sanguins de taient moins e leve s (me diane 8,5 ng/ml [intervalle, vitamine D e 0,5-26,6] vs 14,9 ng/ml [intervalle, 1,9-93,5]; P ¼ 0,01) tandis que les taient plus e leve s (me diane 73,9 pg/ml [intervalle, niveaux d’HPT e 22-530] vs 44,2 pg/ml [intervalle, 5-361]; P ¼ 0,01) dans le groupe gression logistique d’analyse multivarie e a NPC (þ). Le modèle de re ve le que des niveaux sanguins infe rieurs de vitamine D (ratio d’inre [RIA], 1,18; intervalle de confiance [IC] de 95 %, cidence approche 1,11-1,26; P ¼ 0,01) et une augmentation du volume des produits de le s contraste (RIA, 1,01; IC à 95 %, 1,008-1,017; P ¼ 0,01) sont corre pendante avec la NPC. Chez les patients ayant subi une de façon inde e, des niveaux bas de vitamine D intervention coronarienne percutane taient inde pendamment associe s avec le de veloppement de la NPC. e Conclusion : Des niveaux bas de vitamine D, soulignant une carence s à une incidence plus e leve e de la possible de vitamine D, sont associe NPC.
Methods
respectively. Serum vitamin D levels < 15 ng/mL were classified as vitamin D deficiency. Serum PTH levels were determined in serum by electrochemiluminescence ımmunoassay on an Elecsys 2010 immunoanalyzer (Roche Diagnostics, Mannheim, Germany), with a normal range of 12-65 pg/mL. Serum creatinine concentrations were measured before and within 48-72 hours of administration of the CM. Further measurements were performed in patients in whom CIN developed. Renal function was assessed by the eGFR using the Cockcroft-Gault equation adjusted per 1.73 m2 (mL/min/1.73 m2): (140 age in years) body weight in kg 0.85 (if female patient)/(72 SCr in mg/ dL).15 Renal function was categorized by the stages set by the National Kidney Foundation,16 with > 90 mL/min being normal, 60-89 mL/min being mildly impaired, 30-59 mL/min being moderately impaired, and < 30 mL/min being severely impaired. CIN was defined as the elevation of serum creatinine levels by > 0.5 mg/dL or > 25% occurring within 48-72 hours after the intravascular administration of CM, without another cause.17
Study population Consecutive patients who were to undergo CAG under elective conditions between October 1, 2009 and October 21, 2011 were prospectively recruited. All the patients were informed about the aim of the study and gave their consent; the protocol was approved by the institutional ethics committee. Patient demographics, clinical features, and medical therapies were assessed. Patients with acute coronary syndrome, active cancer, or metabolic bone disease; those receiving vitamin D supplementation; those with exposure to CM within the previous 3 days, those who had used nephrotoxic drugs within the previous 7 days, those whose serum creatinine level was > 2.0 mg/dL, and those receiving chronic dialysis were excluded from the study. Fasting blood tests were performed and estimated glomerular filtration rate (eGFR) was calculated. Patients with reduced renal function (eGFR < 60 mL/min/1.73 m2) were hydrated with 0.9 % saline at 1 mL/kg/h for 12 hours before and after CAG. In patients with a left ventricular ejection fraction (LVEF) < 40% or overt heart failure, the hydration rate was reduced to 0.5 mL/kg/h. None of the drugs, including angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs), were withheld before the procedure. A nonionic low-osmolality contrast agent (iohexol) was used exclusively in our catheter laboratory, and the total volume of CM used was recorded. The decision to perform coronary intervention by either angioplasty or stent implantation was left to the discretion of the operator. Patients undergoing PCI received chewable aspirin (300 mg, unless contraindicated), clopidogrel (300 mg, loading dose) and heparin (10,000 U) before PCI. After stent placement, clopidogrel was used for > 1 year and aspirin was used indefinitely. LVEF assessment was performed by echocardiography before CAG during the index hospitalization. Study protocols and definitions Serum concentrations of vitamin D were measured by a radioimmunoassay (DiaSorin Saluggia, Italy) with an intra- and interassay coefficient of variation of 8.6% and 9.2%,
Statistical analysis Mean standard deviation and median (minimum and e maximum values) were used for continuous variables, whereas percentages were used for categorical variables. Normal distribution was tested with 1 sample Kolmogorov-Smirnov test. An unpaired t test was used to test the difference between the continuous variants that showed normal distribution between patient and control groups. Two-group nonparametric comparisons were calculated with the Mann-Whitney U test when non-normally distributed. The correlation of vitamin D levels with CIN was investigated using 2 statistical methods: (1) between CIN (þ) and CIN (þ) patients and (2) the incidence of CIN in tertiles of vitamin D. The Pearson c2 test, Fisher exact test, and continuity correction (Yate’s correction) test were used to test the categorical variants. Binary logistic regression analysis was used to find the possible independent predictors of CIN in the study population. Receiver-operating characteristic curves for the prediction of CIN after procedures were constructed, and the area under the curve (AUC) was calculated for vitamin D and PTH levels. P < 0.05 was considered significant for all
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Table 1. Baseline clinical characteristics of patients with and without CIN
Age, y Male sex, n (%) Diabetes mellitus, n (%) Hypertension, n (%) Hyperlipidemia, n (%) Previous CAD, n (%) Previous heart failure, n (%) Smoking history, n (%) LVEF, % PCI performed, n (%) Volume of CM, mL Baseline eGFR, mL/min/1.73 m2 Participants with available eGFR < 30 mL/min, n (%) 30-60 mL/min, n (%) 60-90 mL/min, n (%) > 90 mL/min, n (%) Drugs, n (%) Aspirin ACE inhibitor ARB Calcium channel blocker b-Blocker
CIN (þ) n ¼ 74
CIN (e) n ¼ 329
P value
65.5 10.7 41 (55.4) 35 (47.3) 58 (78.3) 33 (44.6) 22 (29.7) 20 (27) 19 (25.6) 51 8 30 (40.5) 132 64 64 23
64.0 11.2 215 (65.3) 127 (38.6) 237 (72) 167 (50.7) 51 (15.5) 44 (13.4) 95 (28.9) 53 7 92 (27.9) 90 41 68 21
0.26 0.11 0.19 0.19 0.42 0.01 0.01 0.58 0.05 0.03 0.01 0.14
5 30 29 10
(6.7) (40.5) (39.2) (13.6)
4 131 156 37
(1.0) (40.1) (47.4) (11.2)
0.01 0.90 0.20 0.56
54 32 14 15 25
(73) (43.2) (18.9) (20.3) (33.8)
250 144 78 45 95
(75.9) (43.7) (23.7) (13.7) (28.9)
0.59 0.93 0.38 0.15 0.40
ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; CAD, coronary artery disease; CIN, contrast-induced nephropathy; CM, contrast medium; eGFR, estimated glomerular filtration rate; LVEF, left ventricular ejection fraction; PCI, percutaneous coronary intervention.
tests. SPSS, version 11.0 (SPSS Inc, Chicago, IL) was used for analysis.
Results A total of 403 patients undergoing CAG were prospectively recruited. CIN was observed in 74 (18.3%) of the patients. None of the patients required dialysis during the hospitalization period or in the first 30 days. The baseline clinical characteristics and laboratory findings of the patients with CIN (þ) and CIN () are summarized in Tables 1 and 2. Two groups were similar regarding age, sex, and frequency of atherosclerotic risk factors. Baseline levels of serum urea, creatinine, hemoglobin, glucose, cholesterol, calcium, and phosphorus and the eGFR were similar between CIN (þ) and CIN () patients. The total volume of CM used was higher in the CIN (þ) group than in the CIN () group (132 64 mL vs 90 41 mL; P ¼ 0.01), mostly because of the higher rate of PCI performed in the CIN (þ) group (40.5% vs 27.9%; P ¼ 0.03). In 230 participants (57.1%), vitamin D levels were < 15 ng/mL. The incidence of CIN was 27.2% in patients with vitamin D deficiency, which was significantly higher than in patients with normal vitamin D levels (6.9%) (P ¼ 0.01). Vitamin D levels were lower (median, 8.5 [range, 0.526.6] ng/mL vs median, 14.9 [range, 1.9-93.5] ng/mL; P ¼ 0.01) and PTH levels were higher (median, 73 [range, 22530] pg/mL vs median, 44 [range, 5-361] pg/mL; P ¼ 0.01) in the CIN (þ) group. When tertiles of vitamin D were considered, the incidence of CIN was 34.3% in the lowest tertile (n ¼ 134; vitamin D < 10.1 ng/mL) and was 2.9% in the highest tertile (n ¼ 134; vitamin D > 17.2 ng/mL), which was significantly higher (P ¼ 0.01).
Table 2. Laboratory parameters in patients with and without CIN CIN (þ) n ¼ 74
CIN (e) n ¼ 329
Hemoglobin, g/dL 12.6 1.9 13.0 1.9 Fasting glucose, mg/dL (range) 114 (52-388) 113 (62-548) Total cholesterol, mg/dL (range) 183 (75-285) 182 (68-456) Triglycerides, mg/dL (range) 146 (57-622) 141 (39-930) LDL cholesterol, mg/dL 112 33 112 39 HDL cholesterol, mg/dL 41 10 42 12 AST, U/L (range) 26 (10-122) 24 (6-283) ALT, U/L (range) 21 (9-67) 23 (3-71) Serum calcium, mg/dL 9.01 1.28 9.20 1.15 Serum phosporus, mg/dL 3.64 0.85 3.49 0.89 Serum urea, mg/dL Baseline 50.5 25.7 44.6 18.6 After 48 h 77.9 43.2 47.9 22.5 Serum creatinine, mg/dL Baseline 1.08 0.29 1.06 0.26 After 48 h 1.78 0.74 1.07 .027 Vitamin D, ng/mL (range) 8.5 (0.5-26.6) 14.9 (1.9-93.5) PTH, pg/mL (range) 74 (22-530) 44 (5-361)
P value 0.10 0.18 0.67 0.66 0.88 0.64 0.68 0.67 0.21 0.28 0.07 0.01 0.61 0.01 0.01 0.01
ALT, alanine aminotransferase; AST, aspartate aminotransferase; CIN, contrast-induced nephropathy; LDL, low-density lipoprotein; PTH, parathyroid hormone.
To define a cutoff for vitamin D and PTH levels predicting CIN, we used receiver-operating characteristic analysis that established a value of 10 ng/mL, with 74% sensitivity and 62% specificity for vitamin D (AUC, 0.762) and a value of > 73 pg/mL with 60% sensitivity and 70% specificity for PTH (AUC, 0.710) (Fig. 1). The frequency of CIN was highest in participants with an eGFR < 30 mL/min (5.4% vs 1.5%; P ¼ 0.04). However, the frequency of CIN was similar in other subgroups of renal function defined by eGFR (Table 1). The incidence of CIN was significantly higher in patients with vitamin D deficiency than in participants with normal vitamin D levels in each stage of renal function (50% vs 0% for eGFR < 30 mL/min; 23.4% vs 10.2% for eGFR between 30 and 60 mL/min; 26.7% vs 8.1% for eGFR between 60 and 90 mL/min; and 37.1% vs 3.1% for eGFR > 90 mL/min, respectively; P ¼ 0.01 for each comparison). Thus, a higher incidence of CIN in patients with lower levels of vitamin D was not correlated with the severity of renal disease. The incidence of CIN was not different between patients who received ACEI/ARB therapy and those who did not (17.1% vs 20.7%, respectively; P ¼ 0.38). In subgroup analysis, when only patients with vitamin D deficiency were considered, the incidence of CIN was not different between patients who received ACEI/ARB therapy and those who did not (28.6% vs 25.3%, respectively; P ¼ 0.58). The medications were not stopped before the procedure, and the distribution of medications was similar between the CIN (þ) and CIN () groups. By univariate logistic regression analysis, total volume of CM used, LVEF, presence of heart failure, and hemoglobin, vitamin D, and PTH levels were correlated with CIN. These variables were included in the multivariate logistic regression model (by a forward stepwise method) to determine the independent predictors of CIN. Vitamin D levels were analyzed in 2 ways: as a binary variable (vitamin D deficiency, present vs absent) and as a continuous variable. In addition, vitamin D/PTH levels and the presence of heart failure/LVEF were entered into the multivariate model separately to prevent
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Figure 1. Receiver operating curve characteristics of vitamin D (Vit D) and parathyroid hormone (PTH) levels for predicting contrast-induced nephropathy in the study population.
multicollinearity. Lower levels of vitamin D or the presence of vitamin D deficiency or increased levels of PTH were found to be independent predictors of CIN when analyzed separately in the model adjusted for total volume of CM used, LVEF, and hemoglobin levels (Table 3). The other independent variable was the total volume of CM used. When only participants who had undergone PCI were considered (n ¼ 122), lower levels of vitamin D (OR, 1.31; 95% CI, 1.042-1.227; P ¼ 0.01) and higher volumes of total CM used (OR, 1.025; 95% CI, 1.014-1.035; P ¼ 0.01) were still independently associated with higher rates of CIN in multivariate analysis. Discussion The main finding of our study was that decreased vitamin D levels measured before CM exposure were associated with an increased incidence of CIN development in patients undergoing CAG. The increased risk was observed in every stage of renal disease, even in patients with mild impairment of
renal function. The other independent predictor was the total volume of CM used. CIN is one of the most important clinical complications associated with coronary diagnostic and interventional procedures. Its development is associated with increased morbidity and mortality, including the need for transient dialysis or extended hospitalization, or both, and can lead to chronic end-stage renal disease.18 Many factors play a role in the development of CIN, such as diabetes mellitus, hypertension, age, amount and type of CM used, urgent interventions, patient dehydration, and drugs used. The pathophysiology of CIN is complex, pivoting around the concepts of vasoconstriction, vascular remodelling, inflammation, and thrombosis. Although the causes of CIN are not completely known, an activated renin-angiotensin-aldosterone system, increased levels of endothelin-1, and reactive oxygen species may play a role in the pathogenesis of CIN.19 Endothelin-1, renin, and angiotensin II are some of the potential mediators leading to intrarenal vasoconstriction in experimental models of CIN.20 Whether certain medications,
Table 3. Univariate and multivariate predictors of contrast-induced nephropathy in the study group Univariate analysis OR (95% CI) Age, 1 SD increase Male sex Hypertension Smoking history Diabetes mellitus Heart failure* LVEF, 1 SD decrease* Hemoglobin, 1 SD decrease Baseline eGFR, 1 SD decrease Creatinine, 1 SD increase Volume of CM, 1 SD increase Presence of ACEI/ARB therapy Vitamin D levels, 1 SD decreasey PTH levels, 1 SD increasey Presence of vitamin D deficiencyy
1.01 0.66 1.52 0.59 1.36 2.39 1.03 1.31 1.01 1.21 1.016 0.79 1.17 1.012 5.01
(0.99-1.04) (0.39-1.09) (0.81-2.86) (0.39-1.19) (0.82-2.26) (1.31-4.38) (1.01-1.07) (0.99-1.29) (0.99-1.02) (0.48-3.05) (1.01-1.021) (0.47-1.33) (1.10-1.23) (1.007-1.017) (2.62-9.76)
Multivariate analysis P value
OR (95% CI)
0.26 0.11 0.20 0.16 0.23 0.01 0.03 0.07 0.12 0.70 0.01 0.39 0.01 0.01 0.01
e e
1.37 1.02 1.05 1.01 1.18 1.01 5.96
e e (0.65-2.88) (0.98-1.06) (0.90-1.21) e e (1.008-1.017) e (1.11-1.26) (1.006-1.016) (2.79-12.7)
P value
0.41 0.22 0.54 0.01 0.01 0.01 0.01
Variables with P < 0.10 in univariate analyses were included in multivariate regression analysis. ACEI/ARB, angiotensin-converting enzyme inhibitor/angiotensin receptor blocker; CI, confidence interval; CM, contrast medium; eGFR, estimated glomerular filtration rate; OR, odds ratio; SD, standard deviation. * These parameters were analyzed separately in a multivariate model adjusted for total volume of CM used and hemoglobin and vitamin D levels. y These parameters were analyzed separately in a multivariate model adjusted for the presence of heart failure, total volume of CM used, and hemoglobin levels.
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specifically renin-angiotensin-aldosterone system blocking agents, are risk factors for the development of CIN remains controversial.21-23 In our study, we did not observe any impact of ACEI/ARB therapy on the incidence of CIN after CAG. In addition, even in patients with vitamin D deficiency, ACEI/ARB therapy did not affect CIN rates. In concordance with previous studies, total volume of CM used was an independent predictor of CIN in our study population. The association of changes in the renin-angiotensinaldosterone system in CIN are not new, but very limited data are available, especially with regard to the impact of vitamin D deficiency on renovascular functions. Vitamin D receptors have been found in cardiomyocytes,24 vascular smooth muscle cells,25 and endothelial cells.26 Vitamin D is a potent negative regulator of the renin-angiotensin-aldosterone system.27 Experimental studies indicate that vitamin D participates in the regulation of the renin-angiotensin axis by directly suppressing renin gene expression.28-31 Renin overexpression can be produced in wild-type mice by pharmacologic inhibition of vitamin D synthesis.27 These data suggest that vitamin D deficiency may increase plasma renin activity,32 raise blood pressure,33 and promote adverse arterial and ventricular remodelling.34 In their experimental study, Kedrah at al. showed that the direct renin inhibitor aliskiren has a potential role in the prevention of experimental CIN in the rat.35 Also, Ari et al. used paricalcitol (active vitamin D analogue) in an experimental CIN model and demonstrated antioxidant and renoprotective effects of paricalcitol.36 On the basis of these facts, vitamin D deficiency may be associated with the pathophysiological processes causing CIN. In our study, we found that lower levels of vitamin D were independently associated with a higher incidence of CIN. However, our study does not give clues regarding the pathophysiological role and possible theuropathic application of vitamin D in CIN. There are a few limitations of this study worth mentioning. Although compatible in size with other similar investigations, many potentially important biomarkers and cytokines of CIN indices were not measured in the index study. The follow-up assessment of renal function in our study was 2-3 days after CAG; therefore, we might have missed a later increase in serum creatinine in some patients who did not have renal function deterioration within 72 hours of the procedure. This might result in a slight underestimation of CIN. Second, we did not know the cause of vitamin D deficiency in the vast majority of patients. Conclusions In summary, we found that vitamin D deficiency was associated with a higher incidence of CIN in our cohort. Further studies to confirm the degree of the association, as well as the pathophysiological characteristics, are warranted. Acknowledgements We thank Fatma Avsar, (statistician at the East Marmara Development Agency, Kocaeli, Turkey) for statistical assistance. Disclosures The authors have no conflicts of interest to disclose.
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