Active Vitamin D analog and SARS-CoV-2 IgG after BNT162b2 vaccination in patients with hemodialysis

doi:10.21203/rs.3.rs-3023032/v1

Vaccination is the effective strategy for coronavirus disease 2019 (COVID-19). However, few studies have investigated the association between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immunoglobulin (Ig)G and vitamin D. This study aimed to investigate the association between SARS-CoV-2 IgG and active vitamin D analogs in hemodialysis patients. Blood samples were collected four times: before vaccination and 30, 60, and 90 days after vaccination. We analyzed patients who were supposed to receive a third vaccination, BNT162b2 (Pfizer©). A total of 418 patients were enrolled. The mean age was 71.1 ± 12 years. Almost two thirds of the patients were prescribed active vitamin D analogs. The distribution of SARS-CoV-2 IgG before vaccination was 235 (93–454) AU/ml. The changes in the IgG after vaccination were 15582 (7233–36445) AU/ml at 30 days, 13184 (5910–30529) AU/ml at 60 days, and 10239 (4566–24971) AU/ml at 90 days. The SARS-CoV-2 IgG level of patients with active vitamin D analog use was higher in all periods. After multiple regression analyses, active vitamin D analog use was found to be associated with higher SARS-CoV-2 IgG levels from pre-vaccination to 90 days post-vaccination. This study showed an association between higher SARS-CoV-2 IgG and active vitamin D analog in hemodialysis patients.

Health sciences/Nephrology/Renal replacement therapy

Health sciences/Diseases/Infectious diseases/Viral infection

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been spreading for years and has infected millions of people worldwide ¹. The SARS-CoV-2 infection causes coronavirus disease 2019 (COVID-19) and leads to severe pneumonia, acute respiratory syndrome, and deaths². In patients with chronic kidney disease (CKD), because of immunodeficiency due to uremic toxins, oxidative stress, malnutrition, and chronic inflammation, the morbidity of COVID-19 has been reported to be approximately 2–3 times higher than that in the general population, and the mortality is also 2–4 times higher^3,4.

Vaccination for SARS-CoV-2 is the most effective preventive strategy for morbidity and severity of COVID-19^5,6. Although patients with CKD are administered the SARS-CoV-2 vaccine, the morbidity of COVID-19 remains higher⁷. Recently, some studies have reported that SARS-CoV-2 vaccine antibodies depict difficulty in binding to the virus in patients with CKD, and SARS-CoV-2 vaccine IgG in patients with CKD has been reported to be lower than that in the general population^8,9. Other vaccines, such as influenza virus, pneumococcus, and hepatitis B virus, are also difficult to attach enough antibody titer¹⁰. A search for factors leading to the maintenance of appropriate SARS-CoV-2 immunoglobulin (Ig)G after vaccination has been called for.

Vitamin D has been reported to protect against infectious diseases including SARS-CoV-2 infection¹¹. Recent studies have reported that lower serum 25-hydroxyvitamin D (25OHD) level is a risk factor for severity and mortality in COVID-19^12,13. Because the activation of vitamin D decreases with CKD progression, active vitamin D analogs are usually used in patients with CKD¹⁴. Active vitamin D analogs have been reported to protect against infectious diseases in patients with dialysis^15,16. However, few studies have investigated the association between SARS-CoV-2 IgG and vitamin D (25OHD and active vitamin D analogs) in patients with CKD. We designed a prospective cohort study to investigate the association between vitamin D and SARS-CoV-2 IgG concentration in patients undergoing hemodialysis.

Patient characteristics

At the start of the study, 460 patients were enrolled. All patients received the BNT162b2 (Pfizer©) vaccination twice and received a third vaccination with BNT162b2 (Pfizer©). During the study period, 42 patients were excluded for the following reasons: death (n = 10), hospitalization (n = 18), kidney transplantation (n = 1), and transfer to another institution (n = 1). As 12 patients were sick with COVID-19, they were also excluded. Ultimately, 418 patients were included in the analysis (Table 1). The mean age was 71.1 ± 12 years, and the median dialysis vintage was 83 (31–160) months. The proportion of patients with diabetes mellitus was 47.5% (197 patients), and the history of COVID-19 was 2.2% (9 patients). The rate of active vitamin D analog use was 67.5%. The rates of oral and intravenous vitamin D analogs were almost identical. None of the patients had received native vitamin D supplementation. The concentration of 25OHD was 12.2 (8.4–17.5) ng/ml. No significant differences were evident for active vitamin D analog use in terms of age, diabetes mellitus, 25OHD concentration, phosphate, and iPTH concentrations. In contrast, patients who used active vitamin D analogs had longer dialysis vintage, higher serum creatinine levels, and a higher ratio of phosphate binders and calcimimetics than those who did not use active vitamin D analogs.

Table 1

Patient characteristics
	Total population		Active vitamin D analog		Non-active vitamin D analog
Number	418		282 (67.5%)		136 (32.5%)		P-value
Age (year)	71.1	± 12	70.0	± 11.4	73.3	± 12.9	0.065
Male (%)	306	(73.2)	203	(72.0)	103	(75.7)	0.417
Dialysis vintage (mo)	83	(31–160)	95	(39–189)	55	(24–108)	< 0.001
Diabetes Mellitus (%)	197	(47.5)	126	(44.7)	71	(53.4)	0.098
Days since first vaccination	250	± 22	250	± 21	252	± 23	0.294
Days since second vaccination	229	± 22	228	± 21	231	± 23	0.275
History (%)
COVID-19 infection	9	(2.2)	7	(2.5)	2	(1.5)	0.536
Malignancy	117	(28.3)	80	(28.4)	37	(28.0)	0.943
BMI (kg/m²)	22.9	± 9.7	23.3	± 11.5	22.1	± 4.1	0.243
WBC (/µL)	5950	(4800–7380)	5990	(4900–7200)	5600	(4600–7500)	0.62
Albumin (g/ dl )	3.6	± 0.3	3.6	± 0.3	3.7	± 0.3	0.07
Calcium (mg/dl )	8.4	± 3.4	8.5	± 4.1	8.2	± 0.6	0.379
Phosphate (mg/dl)	5.2	± 1.4	5.2	± 1.4	5.1	± 1.4	0.477
CRP (mg/dl)	0.2	(0.1–0.5)	0.2	(0.1–0.5)	0.2	(0.1–0.6)	0.213
iPTH (pg/ml)	155	(93–240)	176	(102–248)	146	(88–236)	0.079
25OHD (ng/dl)	12.2	(8.4–17.5)	12.9	(8.8–18.6)	12	(8.2–17.2)	0.109
Steroid (%)	20	(4.9)	6	(2.1)	14	(10.7)	< 0.001
Immunosuppressive drug (%)	4	(1.0)	1	(0.4)	3	(2.3)	0.062
Phosphate binder (%)	242	(58.6)	182	(64.5)	60	(45.8)	< 0.001
Calcimimetics (%)	200	(48.5)	153	(54.5)	47	(35.9)	< 0.001
Active vitamin D analog (%)
Oral	140	(33.5)	140	(49.7)	0	(0)
Intravenous	142	(34.0)	142	(50.3)	0	(0)
Abbreviations: COVID-19, coronavirus disease 2019; BMI, body mass index; WBC, white blood cell; CRP, C-reactive protein; iPTH, intact parathyroid hormone; 25OHD, 25-hydroxyvitamin D

Changes in SARS-CoV-2 IgG titers

The distribution of SARS-CoV-2 IgG before the third vaccination was 235 (93–454) AU/ml (Fig. 1). The interval between the first and third vaccinations was 250 ± 22 days. In addition, the interval between the second and third vaccinations was 229 ± 22 days. The cutoff value of effectiveness was > 50 AU/ml, and almost all patients had sufficient SARS-CoV-2 IgG titers (86.8%) before the third vaccination. The changes in SARS-CoV-2 IgG after the third vaccination were 15582 (7233–36445) AU/ml at 30 days, 13184 (5910–30529) AU/ml at 60 days, and 10239 (4566–24971) AU/ml at 90 days. All patients who received the third vaccination had sufficient SARS-CoV-2 IgG levels in 90 days. The SARS-CoV-2 IgG levels of patients with active vitamin D analog use were higher in all periods from pre-vaccination to 90 days post-vaccination (Fig. 2). In contrast, 25OHD was not associated with SARS-CoV-2 IgG titers (Fig. 3).

Multiple regression analyses for SARS-CoV-2 IgG

Multiple regression analyses were performed to clarify the association between the log10 of SARS-CoV-2 IgG and the active vitamin D analog. The active vitamin D analog was significantly associated with log10 of pre-vaccination SARS-CoV-2 IgG titers using unadjusted model, model I, model II, and model III (Table 2). The same trends were observed after vaccination at 30 and 90 days, and the active vitamin D analog use was significantly associated with antibody titers. Factors significantly related to each vaccine antibody titer were as follows: pre-vaccination (positive: albumin, CRP, and phosphate binders; negative: age and steroid use), 30 days (positive: history of COVID-19, CRP, and WBC; negative: calcium), and 90 days (positive: history of COVID-19, and CRP; negative: age, steroid use, statin use, and calcium).

Table 2

Multiple regression analysis for logarithmic SARS-CoV-2 IgG with active vitamin D analog
	Pre-vaccination			30 days			60 days			90 days
	Coef	SE	P-value	Coef	SE	P-value	Coef	SE	P-value	Coef	SE	P-value
Unadjusted	0.28	± 0.07	< 0.001	0.25	± 0.07	< 0.001	0.26	± 0.06	< 0.001	0.27	± 0.07	< 0.001
Model I	0.21	± 0.06	0.001	0.17	± 0.07	0.012	0.18	± 0.06	0.006	0.18	± 0.07	0.007
Model II	0.21	± 0.06	0.001	0.19	± 0.07	0.006	0.19	± 0.07	0.004	0.19	± 0.07	0.006
Model III	0.20	± 0.07	< 0.001	0.18	± 0.07	0.009	0.18	± 0.07	0.006	0.19	± 0.07	0.008
Abbreviations; SARS-CoV-2 IgG, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immunoglobulin (Ig)G; Coef, coefficient of determination; SE, standard error
Model I: Adjusted for age, sex, diabetes mellitus, body mass index,
history of coronavirus disease 2019 steroid, statin, angiotensin II-receptor blocker or angiotensin-converting enzyme inhibitor, albumin, white blood cell, hemoglobin, platelet, C-reactive protein, history of malignancy, history of ischemic heart disease, and history of fracture.
Model II: Adjusted for model I plus phosphate, calcium, parathyroid hormone, phosphate binders, and calcimimetics.
Model III: Adjusted for model II plus 25-hydroxyvitamin D.

Subgroup analysis for SARS-CoV-2 IgG

Subgroup analysis for association between active vitamin D analog and SARS-CoV-2 IgG at 90 days after vaccination was performed using data about age, diabetes mellitus, albumin, 25OHD, and PTH (Fig. 4). No significant associations or interactions were found.

Side reactions and vitamin D analog

The questionnaire about side reactions of vaccination was analyzed (Fig. 5).

There were no significant differences in injection site pain, redness, swelling, fever of ≥ 37.5°C, cold, tiredness, nausea, muscle pain, and joint pain between the use and non-use of active vitamin D analogue. Only diarrhea was higher in the group using active vitamin D analog.

We conducted a prospective cohort study and showed that an active vitamin D analog was associated with a high SARS-CoV-2 IgG titer after the third BNT162b2 vaccination in patients undergoing hemodialysis. These associations were not influenced by age, diabetes mellitus, 25OHD, and PTH concentrations in the subgroup analysis. In addition, the serum 25OHD concentration was not associated with SARS-CoV-2 IgG titers pre- and post-vaccination.

Vitamin D, mainly through calcitriol, influences immune function, produces gamma-globulin, and protects against infectious diseases. Several observational studies have reported that vitamin D deficiency (low 25OHD status) is a risk factor for infectious diseases and is associated with the severity of COVID-19^17–19. In addition, some studies have reported that native vitamin D supplementation protects against infectious diseases, particularly respiratory diseases²⁰. In research on SARS-CoV-2 vaccination studies, several reports showed the association between 25OHD levels and SARS-CoV-2 IgG titers^21,22. These studies reported that higher 25OHD levels were associated with higher SARS-CoV-2 IgG after vaccination. However, because these studies did not include patients with CKD, especially patients undergoing dialysis, the influence of 25OHD on SARS-CoV-2 IgG after vaccination has not been clarified in patients with CKD. In our study, serum 25OHD levels were not associated with SARS-CoV-2 IgG titers. In patients with CKD, the activation of vitamin D decreases because the expression of 1α-hydroxylase decreases in the proximal tubule during CKD progression, and FGF-23 inhibits the expression and activation of 1α-hydroxylase²³. As the influence of vitamin D on the immune system is mainly caused by 1,25(OH)2D, patients with CKD who had decreased 1α-hydroxylase activity were not associated with SARS-CoV-2 IgG titers or 25OHD in this study.

This study is the first to show that active vitamin D analog use is associated with higher SARS-CoV-2 IgG after vaccination in patients undergoing hemodialysis. Although there are several meta-analyses on SARS-CoV-2 vaccination in patients with CKD, the association between active vitamin D analog use and SARS-CoV-2 IgG was first reported in this study^9,24. A previous study showed that active vitamin D analogs influence T-cells and B-cells through vitamin D receptors and increase IgG levels after vaccination in an animal model²⁵. Moreover, there are few clinical studies on active vitamin D analogs and IgG after vaccination. Although IgG levels after vaccination for the influenza virus, pneumococcus, and hepatitis B virus are lower in patients on dialysis, the association between active vitamin D analogs and IgG has not been reported. The vitamin D metabolite calcitriol regulates the proliferation and differentiation of immune cells. Vitamin D influences and promotes the tolerogenicity of immune cells, such as dendritic cells, by disturbing MHC expression and downregulating inflammatory cytokines. Additionally, vitamin D promotes the production of anti-inflammatory interleukin-10^26,27. Another study reported that the treatment of T cells with vitamin D decreased the secretion of pro-inflammatory T helper (TH)1 cell mediators while increasing the production of TH2 cell cytokines^28,29. A recent study reported that paricalcitol is associated with improved survival in hemodialysis patients with COVID-19³⁰. In addition, patients with CKD, including those on dialysis who are prescribed low-dose alfacalcidol, are at risk of contracting COVID-19³¹.

25OHD is well correlated with 1,25OHD in general healthy people because the activation of 1α-hydroxylase in the kidney is maintained³². Therefore, vitamin D interventions are usually made through natural vitamin D supplementation(cholecalciferol or ergocalciferol). On the other hand, there is a weak correlation between 25OHD and active vitamin D in patients with CKD, so the use of active vitamin D analog is important³³.

In this study, there was no correlation with COVID-CoV-2 IgG at 25OHD concentrations, but there was a correlation with active vitamin D analog, indicating the importance of vitamin D analog in patients with CKD.

Previous studies that investigated SARS-CoV-2 IgG reported lower levels of IgG titers in patients with CKD than in patients with non-CKD after vaccination^8,9. Several factors induce lower IgG titers in patients with CKD, including malnutrition, chronic inflammation, uremic toxins, and anemia³⁴. In basic research, immune function decreases in CKD animal models, and these conditions influence the production of gamma globulin. As these factors are difficult to improve, alternative interventions for SARS-CoV-2 IgG in patients with CKD are required. In this study, several factors were associated with SARS-CoV-2 IgG titers. The factors that were significant over the entire period were age, serum albumin level, steroid use, and CRP level. Higher age and malnutrition have been reported as risk factors for decreased IgG titers after vaccination. In addition, steroid preparation and immunosuppressants have also been associated with a decrease in IgG titers in previous studies. CRP is an inflammation marker that influences the immune system. A previous study reported that patients with a higher inflammatory status had lower IgG titers after vaccination, and this increased the morbidity and mortality of patients with COVID-19. As older age, malnutrition, immunosuppressive status, and higher inflammation are risk factors for lower SARS-CoV-2 IgG after vaccination in patients undergoing hemodialysis, these patients should be vaccinated regularly, and IgG titers should be monitored. However, these risk factors are difficult to improve immediately; therefore, we suggest the use of an active vitamin D analog to maintain SARS-CoV-2 IgG in patients with CKD.

This study has several limitations. First, as this was an observational study, we could not refer to causality. Second, although several active vitamin D analogs were used and the dosing method (oral or injective) and medication dose were multiple, the sample size was small. Third, although this study showed the association between SARS-CoV-2 IgG and active vitamin D analog, it is uncertain whether it protects against COVID-19. Fourth, although this study measured 25OHD concentrations, 1,25(OH)2D concentration was not measured. However, because serum 1,25(OH)2D concentrations are usually difficult to measure accurately, it is difficult to assess the effect of vitamin D analog activation using serum 1,25(OH)2D concentrations.

In summary, this study showed an association between higher SARS-CoV-2 IgG and active vitamin D analog use, but not 25OHD concentration, in patients undergoing hemodialysis. There is a possibility that an active vitamin D analog maintains the IgG titer after vaccination. Further interventional studies on active vitamin D for COVID-19 are needed.

Study design

This observational study was conducted on patients undergoing hemodialysis at three dialysis centers in Tokyo, Japan. Baseline visits for patient enrollment were conducted between January 1, 2022, and April 31, 2022, and the enrolled patients were followed-up until September 31, 2022. Patients undergoing hemodialysis who received BNT162b2 twice (Pfizer© only) and were supposed to receive the third-vaccination BNT162b2 (Pfizer© only) were analyzed. Inclusion criteria were as follows: age > 20 years, dialysis vintage ≥ 3 months, and regular hemodialysis 3 times/week (3–5 h/session). We excluded patients who received vaccines other than BNT162b2 and those who had acute gastrointestinal bleeding, acute coronary syndrome, or liver dysfunction at baseline. In addition, we excluded those who had been hospitalized during the course of treatment, had contracted COVID-19, could not receive the third vaccination, or had changed the third vaccine to a different vaccine type.

Ethics

The study protocol was reviewed and approved by the ethics committee of Jikei University School of Medicine and the Institutional Review Boards of Jikei University Hospital and affiliated hospitals and clinics (approval number: 33–325(10948)). The study information was registered in the UMIN-CTR (UMIN 000046906). All the study procedures were performed in accordance with the Declaration of Helsinki and its revisions. Signed informed consent was obtained from all patients prior to inclusion in the study.

Data collection

Data about age, sex, dialysis vintage, primary illness leading to kidney dysfunction, and medical history were extracted from medical records. Medication information (use of vitamin D receptor agonists, vitamin D supplementation, sevelamer, lanthanum, bixalomer, ferric citrate, sucroferric oxyhydroxide, calcium-containing phosphate binder, evocalcet, etelcalcetide, upacicalcet, antihypertensive medications, steroids, and immunosuppressants) was obtained from the prescription records. Comorbidities and medications were determined by chart review and standardized interviews at baseline. Routine biochemical measurements included serum sodium, potassium, phosphorus, calcium, and magnesium; serum albumin; blood urea nitrogen; alkaline phosphatase; creatinine; hematocrit; intact parathyroid hormone; and C-reactive protein (CRP) levels. The delivered dialysis dose was measured using single-pool Kt/V.

Blood samples were collected four times: study entry (before vaccination) and 30, 60, and 90 days after vaccination. Blood samples were obtained before the hemodialysis session and after the longest interdialytic period. All samples were centrifuged for 10 min and divided into tubes maintained at − 80°C until analysis. Serum levels of 25OHD (ng/ml) were measured at SRL Inc. (Hachioji, Tokyo, Japan) using an electrochemiluminescence immunoassay. The anti-spike (anti-S) SARS-CoV-2 IgG (cutoff value, ≥ 50.0 AU/ml) and anti-nucleocapsid (anti-N) SARS-CoV-2 IgG (cutoff value, 1.40 Index) levels were analyzed using SARS-CoV-2 IgG II Quant Kits (Abbott©). Previous studies have reported cutoff values of ≥ 50 AU/ml for anti-S SARS-CoV-2 IgG and 1.4 for anti-N SARS-CoV-2 IgG and have stratified recently infected patients and vaccinated patients³⁵.

Statistical analysis

Non-normally distributed data are expressed as medians (interquartile ranges). Normally distributed data are summarized as mean ± standard deviation. Binary data are summarized as numbers and percentages. Patient characteristics were divided into two groups: the use of active vitamin D analogs and no use of active vitamin D analogs. Nominal variables were analyzed using the χ² test, and continuous variables were analyzed using the Student’s t-test. Chronological SARS-CoV-2 IgG values were represented in the box plot and categorized using the active vitamin D analog. SARS-CoV-2 IgG values were analyzed after logarithmic transformation. To investigate the association between SARS-CoV-2 IgG and vitamin D levels, multivariate regression analysis was performed. We used age, sex, diabetes mellitus, body mass index, history of COVID-19, steroid, statin, angiotensin II-receptor blocker or angiotensin-converting enzyme inhibitor, albumin, white blood cell (WBC), hemoglobin, platelet, CRP, history of malignancy, history of ischemic heart disease, and history of fracture as model I. Model II included model I plus phosphate, calcium, parathyroid hormone (PTH), phosphate binders, and calcimimetics. Model III was a combination of model II plus 25OHD. At the outset of the study, group stratification for subgroup analysis was planned, stratified by age, 25OHD concentration, PTH concentration, and use of calcimimetics. Patients answered a questionnaire about side reactions 30 days after vaccination. The questionnaire consisted of the following items: injection site pain, redness, swelling, fever of ≥ 37.5°C, cold, tiredness, nausea, diarrhea, muscle pain, and joint pain. The associations between the ratio of side reactions and vitamin D analog and between the ratio of side reactions and 25OHD concentrations were analyzed.

All statistical analyses were performed using STATA version 16.0 (STATA Corp., College Station, TX, USA).

Acknowledgements

We appreciate the patients who participated in the study. This work was supported by JSPS KAKENHI Grant Number 20K17259 and 23K07727.

Author Contributions

A.N. had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: A.N., I.Y., T.H., I.O., and T.Y.

Acquisition, analysis, or interpretation of data: A.K., K.K., T.Y., S.N., K.K., and R.K.

Drafting of the manuscript: A.N.

Critical revision of the manuscript for important intellectual content: A.N., K.K., and A.K.

Statistical analysis: A.N.,K.K., and A.K.

Supervision: T.Y.

Data availability statement

The data that support the findings of this study are available on request from the corresponding author

Additional information statement

The authors have no competing interests to declare.

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No competing interests reported.

Active Vitamin D analog and SARS-CoV-2 IgG after BNT162b2 vaccination in patients with hemodialysis

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Status:

Journal Publication

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