Objectives: The association between vitamin D deficiency and anemia is known. Vitamin D deficiency and anemia are common in kidney transplant recipients. We examined the relationship between vitamin D levels and anemia in pediatric kidney transplant recipients.
Materials and Methods: We reviewed retrospectively the data of 75 pediatric kidney transplant recipients (0-18 years of age). Patients were evaluated in 3 groups according to serum 25-hydroxyvitamin D levels (<20, 20-30, and >30 ng/mL) in the first year posttransplant: group 1 was the vitamin D deficiency group, group 2 was the vitamin D insufficiency group, and group 3 was normal vitamin D level group, respectively. Groups were compared in terms of anemia parameters, calcium, phosphorus, alkaline phosphatase, and parathyroid hormone levels, as well as infection, rejection, and graft loss status. All patients included in the study were grouped as those with anemia and without anemia, and the 2 groups were compared in terms of vitamin D levels, serum parathyroid hormone values, estimated glomerular filtration rate, and infection, rejection, and graft loss status.
Results: There were 41 patients (54.7%) in group 1, 24 patients (32%) in group 2, and 10 patients (13%) in group 3. There were 65 patients (86.7%) with vitamin D deficiency/insufficiency. When groups were compared, the hematocrit level was found to be lower in groups 1 and 2 (P < .05) and ferritin level was found to be lower in group 1 (P < .05). Anemia was present in 20 patients (26.6%): 61% of patients with anemia had vitamin D deficiency and 33% had vitamin D insufficiency (P > .05). In total, 94% of patients with anemia had vitamin D deficiency/insufficiency.
Conclusions: Vitamin D deficiency/insufficiency is common in pediatric kidney transplant recipients. Vitamin D levels should be measured, especially in all kidney transplant recipients with persistent anemia. Thus, risk factors associated anemia can be reduced by treating the deficiency/insufficiency.
Key words : Child, Hemoglobin concentration, Renal transplantation
Vitamin D is an important hormone for bone and mineral metabolism that regulates serum calcium and phosphorus balance. In addition to its effects on bone and mineral metabolism, it also has proapoptotic, anti-inflammatory, and immunomodulatory properties.1 It has been suggested that vitamin D also plays a role in erythropoiesis. In vitro studies have shown that 1,25-dihydroxyvitamin D increases erythropoietin receptor expression in erythroid precursor cells and synergistically increases erythropoietin stimulation.2 Low levels of vitamin D have been shown to be associated with low hemoglobin concentration in patients with chronic kidney disease (CKD), and vitamin D replacement has been shown to contribute to reducing the dose of erythrocyte-stimulating agents and to increasing reticulocytosis in patients with stage 5 CKD.3,4 Studies have shown an association between vitamin D deficiency and anemia in both healthy children and adults, as well as in patients with chronic diseases such as heart failure, diabetes mellitus, and CKD.5-7
Anemia that exists before kidney transplant in patients with stage 5 CKD continues after transplant as a result of immunosuppressive drug use, rejection, and infections.8 Vitamin D deficiency is common in kidney transplant recipients for a number of reasons, including low sun exposure, low vitamin D intake with diet, use of multiple immunosuppressive drugs, and steroid use.9 Because of the known relationship between vitamin D deficiency and anemia, it can be predicted that vitamin D deficiency may be one of the causes of persistent anemia after kidney transplant. In this study, we examined the relationship between vitamin D levels and anemia in pediatric kidney transplant recipients.
Materials and Methods
Patients and data collection
We retrospectively examined the records of pediatric kidney transplant recipients (age range of 0-18 years) who were followed up in our center between January 2011 and June 2021 for at least 1 year after kidney transplant. Patients with acute or chronic rejection and any infection that might influence iron metabolism and patients treated for any anemia and/or vitamin D deficiency in the 3 months before the start of the study were excluded from the study. For this study, 75 patients met the inclusion criteria. Age at transplant, donor type, immunosuppressive treatments, laboratory data (complete blood count, serum iron, total iron binding capacity, ferritin, urea, creatinine, calcium, phosphorus, alkaline phosphatase [ALP], parathyroid hormone [PTH] values obtained in regularly controls), infection, rejection, graft loss status, and glomerular filtration rate (GFR) values were analyzed.
Patients used prednisolone, mycophenolate mofetil, or mycophenolate sodium and a calcineurin inhibitor (tacrolimus or cyclosporin A) as maintenance immunosuppressive therapy posttransplant. The calcineurin serum levels of patients included in the study were in the normal ranges during regular control examinations.
Estimated GFR (eGFR) were calculated with the “modified Schwartz” equation,10 and transferrin saturation was calculated with the following formula: serum iron (in µg/dL)/total iron binding capacity (in µg/dL) × 100.”11
Vitamin D levels were classified as <20 ng/mL, 20-30 ng/mL, and >30 ng/mL, which was defined as vitamin D level deficiency, insufficiency, and normal, respectively.12,13
According to the specifications of the World Health Organization, patients with hemoglobin levels of <11 g/dL were understood as having anemia.14
Comparison of patient groups
According to serum 25-hydroxyvitamin D levels in patients in the first year after kidney transplant (12 months posttransplant), patients were evaluated in 3 groups: group 1 included those with vitamin D deficiency (serum 25-hydroxyvitamin D level of <20 ng/mL); group 2 included those with vitamin D insufficiency (serum 25-hydroxyvitamin D level of 20-30 ng/mL); and group 3 included those with normal vitamin D level (serum 25-hydroxyvitamin D level of >30 ng/mL). The groups were compared in terms of patient hemoglobin, hematocrit, serum iron, and ferritin levels; transferrin saturation values; serum calcium, phosphorus, ALP, and PTH values; and infection, rejection, and graft loss status.
All patients included in the study were grouped as those with and without anemia (anemia positive and anemia negative groups, respectively). These 2 groups were compared in terms of vitamin D levels, serum PTH values, eGFR, and infection, rejection, and graft loss status.
Statistical analysis was performed with SPSS for Windows 22.0 (IBM). Categorical variables expressed as frequencies (percentage) and numerical data expressed as means ± SD were used for normally distributed data, and medians (IQR) were used for abnormally distributed data. Differences were analyzed with the use of chi-square and the Fisher exact tests. We used t tests for normally distributed data and Mann-Whitney U tests for abnormally distributed data. P < .05 was considered significant.
Demographic results in the study groups
The mean age of the total 75 (34 girls and 41 boys) kidney transplant recipients included in the study was 11.73 ± 4.89 years. There were 41 patients (54.7%) in group 1 (vitamin D deficiency), 24 patients (32%) in group 2 (vitamin D insufficiency), and 10 patients (13%) in group 3 (normal vitamin D levels). There were 65 patients (86.7%) with vitamin D deficiency/insufficiency. The groups were similar in terms of sex, age at transplant, donor type, immunosuppressive therapy, and follow-up times (Table 1).
Laboratory results and infection, rejection, and graft loss status in the study groups
The hematocrit level was found to be significantly lower in group 1 and group 2 compared with group 3 (P < .05). The ferritin level was found to be significantly lower in group 1 compared with the other groups (P < .05). However, there were no significant differences between the groups in terms of other parameters of anemia (hemoglobin, serum iron, transferrin saturation) and serum laboratory results for calcium, phosphorus, ALP, and PTH (P > .05). Serum iron levels were lower in group 1 than in the other groups, but no statistically significant difference was found.
The groups were similar in terms of infection, rejection, graft loss, and year 3 eGFR results (P > .05). Although there was no statistically significant difference, the prevalence of infection was observed to be higher in group 1 than in group 3 (Table 2).
Comparison of patients with and without anemia
Anemia was present in 20 study patients (26.6%). Of patients with anemia, 61% had vitamin D deficiency and 33% had vitamin D insufficiency; therefore, 94% of patients with anemia had vitamin D deficiency or insufficiency. The vitamin D level was within normal limits in 7 patients (12.7%) without anemia, whereas the vitamin D level was normal in only 1 patient with anemia (5.6%). Although we observed no statistically significant difference, the prevalence of vitamin D deficiency/insufficiency was observed to be higher in the group with anemia.
Parathyroid hormone levels (75.36 ± 37.16 vs 61.30 ± 46.19 pg/mL; P > .05) and eGFR values (84.43 ± 30.81 vs 91.95 ± 23.6 mL/min/1.73 m2; P > .05) were similar in patients with versus without anemia.
There was no significant difference between groups with and without anemia in terms of infection (45% vs 38%; P > .05), rejection (45% vs 29%; P > .05), and graft loss (5% vs 1.8%; P > .05). The mean year 3 eGFR was 88.31 ± 32.46 mL/min/1.73 m2 in patients with anemia and 91.32 ± 27.76 mL/min/1.73 m2 in patients without anemia (Table 3).
This study retrospectively collected the serum vitamin D levels and anemia parameters of 75 pediatric kidney transplant recipients who had not received any treatment for anemia and/or vitamin D deficiency in the last 3 months before the start of the study. We detected that vitamin D deficiency/insufficiency was common in pediatric kidney transplant patients (86.7%). Although there was no significant association in parameters of anemia, hematocrit and ferritin values were found to be statistically lower in the group with vitamin D deficiency. The prevalence of vitamin D deficiency/insufficiency was observed to be higher in the group with anemia (94%). We can say that the results of this study suggested that low serum vitamin D levels are associated with anemia, in agreement with other studies that evaluated the relationship between vitamin D and anemia.
Previous studies have demonstrated the association of serum vitamin D and hemoglobin levels in healthy people and patients with chronic diseases.4,5,15-19 Liu and colleagues evaluated previous studies in their meta-analysis and showed that vitamin D deficiency was associated with an increased incidence of anemia.20 Vitamin D deficiency has been shown to be associated with anemia in patients with kidney failure and early-stage CKD.7 Anemia is a common complication in CKD as a result of low erythropoietin levels, chronic inflammation, iron deficiency, and shortened erythrocyte lifespan. Vitamin D deficiency in patients with CKD contributes to decreased erythropoiesis and anemia by causing immunomodulation and cytokine production.21 Moreover, it has also been shown that vitamin D treatment in CKD reduces the use of erythrocyte-stimulating agents and increases hemoglobin levels.22-24
In this study, we found that patients with anemia had lower vitamin D levels. Consistent with our results, low vitamin D levels have been shown to be associated with increased risk of anemia and that, compared with children with normal vitamin D levels, children with vitamin D deficiency have a 3-time greater chance of anemia development, with anemia risk increased in patients with serum vitamin D levels of <17.6 ng/mL.25
Vitamin D deficiency is common in kidney transplant recipients due to reasons such as low sun exposure, low vitamin D intake with diet, use of multiple immunosuppressive drugs, and steroid use.9 Previously, the rate of vitamin D deficiency was found to be 30% and rate of insufficiency was found to be 81% in kidney transplant patients.26 Low 25-hydroxyvitamin D levels continue after kidney transplant,27 with only 12% of recipients above 30 ng/mL at 1 year after kidney transplant.28 In our study, vitamin D levels were measured at month 12 after kidney transplant, and we detected vitamin D deficiency in 54.7% and insufficiency in 32% of recipients. Vitamin D levels were above 30 ng/mL in 13.3% of the recipients. Ebbert and colleagues compared vitamin D levels in pediatric kidney transplant recipients versus a healthy group and found the prevalence of vitamin D deficiency to be 76%, which was similar to that shown in the healthy group.29 However, vitamin D deficiency is important, as it has been shown to be associated with posttransplant bone metabolism disorders, cardiovascular system diseases, and graft loss in kidney transplant recipients.27,30 In our study, although no graft loss was observed in the vitamin D deficiency group, graft loss developed in 1 patient (4.3%) in the vitamin D insufficiency group. Although low vitamin D levels at month 3 after kidney transplant has been associated with low GFR in the first year,31 we found no statistically significant difference in the third year GFR comparison according to the vitamin D levels detected at month 12 after transplant. Similar to our study, Mosca and colleagues showed that low vitamin D levels at month 3 were not associated with low GFR in pediatric kidney transplant recipients.32
In previous examinations of vitamin D deficiency versus infection, there was an increased risk of infection development with vitamin D deficiency.33,34 This relationship was also examined in kidney transplant recipients, and it was found that the incidence of various bacterial infections, especially urinary system infections, cytomegalovirus, and polyoma BK virus infections, as well as opportunistic viral infections, were found to be increased in those with vitamin D deficiency.35 Although there was no statistically significant difference between vitamin D deficiency and infection in our study, infections were observed less frequently in patients with normal vitamin D levels.
Anemia present before transplant in kidney transplant recipients has been shown to continue posttransplant due to the use of immunosuppressive drugs, rejection, and the development of infection.8 Anemia is an important and treatable risk factor for increased graft failure and cardiovascular mortality in kidney transplant recipients.36-38 Anemia was detected in 26.6% of the patients included in our study. As reported by the European Society of Pediatric Nephrology, 49.8% of pediatric renal transplant recipients according to the 2007 NKF/KDOQI classification and 7.8% of recipients according to the 2015 UK-NICE classification have subtarget hemoglobin values. In addition, it was emphasized that low hemoglobin levels increase the risk of graft failure and mortality due to graft failure and that high hemoglobin levels are associated with better graft survival.39 Because anemia is associated with low graft survival and high mortality risk and vitamin D deficiency is common in kidney transplant recipients, based on the relationship between vitamin D deficiency and anemia, we examined this relationship in pediatric recipients. In our study, 94% of patients with anemia had vitamin D deficiency or insufficiency. Vitamin D levels were within normal limits in 7 patients (12.7%) without anemia, whereas vitamin D levels were normal in only 1 patient (5.6%) with anemia. Although no statistically significant difference was observed, the prevalence of vitamin D deficiency/insufficiency was higher in the anemia-positive group.
There are also studies that do not support a relationship between vitamin D deficiency and anemia.2,40,41 Moreover, in a randomized, double-blind, placebo-controlled study from Madar and colleagues, supplementation of vitamin D in patients with vitamin D deficiency did not significantly affect hemoglobin levels and other parameters of anemia.42 It was observed that the group who did not have an association between vitamin D and anemia consisted of healthy individuals without chronic disease. Our study group was a kidney transplant patient group with previous inflammation due to kidney failure. Considering that the negative effect of vitamin D deficiency on hematopoiesis is associated with inflammation pathways, we can attribute the cause of anemia in patients with low vitamin D levels to inflammation.
The limitations of this study were our small number of study patients, the limited number of patients with normal vitamin D levels, and our retrospective design. As suggested previously by various studies, prospective and cohort studies with large numbers of participants are needed to further examine the findings.
In conclusion, vitamin D deficiency/insufficiency is common in pediatric kidney transplant recipients. Vitamin D deficiency is a graft loss and mortality risk factor that is treatable in patients with persistent anemia after kidney transplant. Vitamin D may prevent the development of anemia by supporting erythropoiesis, and vitamin D levels should be measured, especially in all kidney transplant recipients with persistent anemia. Risk factors that may cause mortality could be reduced by treating vitamin D deficiency/insufficiency, which can contribute to the prolongation of graft survival.
Volume : 20
Issue : 5
Pages : 39 - 44
DOI : 10.6002/ect.PediatricSymp2022.O6
From the 1Department of Pediatric Nephrology and the 2Department of General Surgery, Başkent University Faculty of Medicine, Ankara, Turkey
Acknowledgements: The authors have not received any funding or grants in support of the presented research or for the preparation of this work and have no declarations of potential conflicts of interest.
Corresponding author: Begüm Avcı, 53. Sokak No:48, 06490 Bahçelievler/Ankara Turkey
Phone: +90 506 764 36 10
E-mail: firstname.lastname@example.org, email@example.com
Table 1. Demographic Characteristics of Study Groups
Table 2. Laboratory Values in Study Groups
Table 3. Comparison of Patients With and Without Anemia