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ARTICLE
Factors Affecting Bone Health in Kidney Transplant Recipients: Klotho Gene Single-Nucleotide Polymorphisms and Other Clinical Features

Objectives: Posttransplant bone diseases are a major cause of morbidity in kidney transplant recipients. We investigated the relationship between klotho gene single-nucleotide polymorphisms and bone diseases after kidney transplant. We also aimed to identify possible risk factors for development of bone disease.

Materials and Methods: The study consisted of 251 kidney transplant recipients (164 men and 87 women) with minimum follow-up of 3 years after kidney transplant. Patients with prolonged immobilization, malignancy, parathyroidectomy, glomerular filtration rates less than 30 mL/min/1.73 m2, hypo- or hyperthyroidism, and treatment with drugs that affect bone metabolism were excluded. We investigated the relationship between 6 single-nucleotide polymor­phisms of the klotho gene (rs480780, rs211234, rs576404, rs211235, rs9536314, and rs1207568) and development of osteoporosis, avascular bone necrosis, and persistent hyperparathyroidism.

Results: Longer dialysis treatment (odds ratio, 1.13; P = .002) and rs211235 single-nucleotide polymor­phism in the klotho gene (odds ratio, 9.87; P = .001 for GG genotype) were significantly associated with persistent hyperparathyroidism. A higher magnesium level was detected as a protective factor from development of persistent hyperparathyroidism (odds ratio, 0.19; P = .009). Persistent hyperparathyroidism was defined as a risk factor for development of osteopenia/osteoporosis (odds ratio, 2.76; P = .003) and avascular bone necrosis (odds ratio, 2.52; P= .03). Although the rs480780 (odds ratio, 8.73; P = .04) single-nucleotide polymorphism in the klotho gene was defined as a risk factor for development of osteopenia/osteoporosis, none of the klotho single-nucleotide polymorphisms was found to be associated with development of avascular bone necrosis.

Conclusions: Persistent hyperparathyroidism could be an important indicator for development of bone disease in kidney transplant recipients. Also, some of the klotho gene single-nucleotide polymorphisms are associated with higher risk for bone disease after kidney transplant.


Key words : Avascular bone necrosis, Hyperparathyroidism, Osteoporosis

Introduction

Kidney transplant is the best renal replacement therapy for end-stage renal disease. Advances in immunosuppressive treatment and surgical techniques have improved graft and patient survival.1 Prolonged survival leads to increased frequency of long-term complications and morbidities. Posttransplant bone disease is a major cause of morbidity in kidney transplant recipients, with significantly higher risk of fractures and higher costs for hospitalization and health care.1,2 Preexisting renal osteodystrophy, posttransplant diabetes, and immunosuppressive drugs including glucocorticoids and calcineurin inhibitors contribute to posttransplant bone disease.3 Also, well-known risk factors for osteoporosis in the general population such as age, sex, race, obesity, smoking, and menopausal status could facilitate development of osteoporosis in kidney transplant recipients. However, the same cumulative gluco­corticoid usage in a similar time course causes more bone microarchitecture disorders in some patients. In addition, bone avascular necrosis (AVN) may develop in some patients under similar circumstances. The exact mechanism of this difference is not completely understood. Another cause of bone disease after kidney transplant is persistent hyperparathyroidism (PHP). Secondary hyper­parathyroidism is typically resolved with the improvement of kidney function. This normalization lasts about 1 year, but high levels of serum parathyroid hormone (PTH) levels persist after 1 year in 15% to 50% of patients.4

Recent studies have shown that the homeostasis of bone turnover and PTH depends on other factors such as fibroblast growth factor 23 (FGF-23) and its cofactor, the klotho protein.5 The klotho gene, first identified in 1997, which is expressed in distal convoluted tubules of kidney and parathyroid cells, has been studied in patients on hemodialysis, and it has been shown that klotho is associated with atherosclerosis, cardiovascular disease, and bone mineral disorders.6 The klotho gene is located on chromosome 13q2 and encodes a single-pass transmembrane protein that contains 3 members: α-klotho, β-klotho, and klotho-related protein.6 It is essential for endogenous FGF-23 function. Studies suggest that α-klotho is a circulating hormone that has an effect on FGF-23 stabilization and protection of FGF-23 from degradation; also, α-klotho has a phosphaturic activity independent of FGF-23.7 The FGF-23+α-klotho+FGF receptor complex inhibits the type 2 Na-P cotransporter in the renal tubules and decreases its expression. This signal pathway also inhibits 1α-hydroxylase and activates 24α-hydroxylase in kidney and directly suppresses PTH synthesis.8,9 Defects in the klotho-FGF-23 system can cause high serum levels of 1,25-hydroxyvitamin D and PTH.2

In the literature, there is only one study that investigated the relationship between klotho gene single-nucleotide polymorphism (SNP) and bone disorders in patients with kidney transplant. This study was conducted by Ozdem and colleagues with 25 kidney transplant recipients and 26 healthy control patients. They investigated the effect of SNP at the 352 amino acid position of the klotho gene (phenylalanine to valine; F352V or rs9536314) on vitamin D status and osteoporosis in kidney transplant recipients. They found an inverse association with F352V polymor­phism and vitamin D status but no association with development of osteoporosis.10 In a study from 2016 in patients treated with hemodialysis, it was shown that the F352V SNP was not associated with serum calcium, phosphorus, and PTH levels.5 On the other hand, several studies were conducted to define the association between the klotho gene polymorphism and AVN or osteoporosis in other specific disease populations.11-13 Baldwin and colleagues reported that AVN is associated with the rs480780, rs211234, rs576404, and rs211235 polymorphisms of the klotho gene in patients with sickle cell anemia.11 However, there is no study in the literature that has reported the relationship between the klotho gene polymorphism and AVN in kidney transplant recipients.

The objective of this study was to answer the question of whether the klotho gene SNPs rs480780, rs211234, rs576404, rs211235, rs9536314, and rs1207568 are associated with osteoporosis, AVN, and PHP in patients with kidney transplant; also, we sought to determine other possible risk factors for bone disease after kidney transplant.

Materials and Methods

Study population and ethical statement
This study was conducted in the Gazi University Nephrology and Transplantation department. Kidney transplant recipients who were older than >18 years of age and fulfilled the necessary criteria were included in the study.

We evaluated the patients who had kidney transplant between 2010 and 2018. Exclusion criteria were as follows: follow-up less than 3 years; prolonged immobilization, systemic illness, or malignancy; parathyroidectomy; glomerular filtration rates (GFR) less than 30 mL/min/1.73 m2; hypo- or hyperthyroidism; and/or treatment with drugs that affect bone metabolism (except immunosuppressive agents, vitamin D, and calcium supplementation, eg, bisphosphonates and cinacalcet). Prednisolone treatment was initiated at postoperative day 0 in doses of 1000, 500, 250, 160, 80, 40, and 20 mg/day, until the end of first month. Between the first and third months, prednisolone was tapered every 2 weeks and then continued at a maintenance dose of 5 mg/day thereafter. Standard immunosuppressive therapy consisted of glucocorticoids, a calcineurin inhibitor [80% of patients (200/251) received tacrolimus, and 12% (29/251) received cyclosporine] and an antimetabolite [74% of patients (186/251) received mycophenolate mofetil, and 15% (38/251) received azathioprine]. We treated 13% of patients (32/251) with one of two mammalian target of rapamycin (mTOR) inhibitors (28/32 patients received everolimus, and 4/32 received sirolimus), to mitigate calcineurin or antimetabolite side effects. Vitamin D supplementation was given to all patients who had vitamin D levels below 30 ng/mL.

The study protocol conformed to ethical guidelines of the Declaration of Helsinki, and all participants gave written informed consent and expressed a willingness to participate. The ethics committee of Gazi University approved the study protocol (approval date, December 2, 2018; project No. 87)

Data collection
The hospital’s electronic medical records system was used for baseline information such as patients’ sex, age, transplant type, dialysis vintage (ie, length of time on dialysis), and cumulative glucocorticoid dose. Total follow-up time and development of AVN in follow-up were determined for all patients. Data for serum creatinine, albumin, PTH, and vitamin D were collected. We used the abbreviated Chronic Kidney Disease Epidemiology Collaboration equation to estimate GFR.14 The laboratory values of patients in the past 3 years were averaged, and these average values were used for demographic evaluation. Serum PTH level below 65 ng/dL was accepted as normal at the end of first year of follow-up.

For the diagnosis of osteoporosis, we used dual-energy x-ray absorptiometry (Horizon DXA system, Hologic Inc.) to measure bone mineral density (BMD) at the hip (neck of the femur) and lumbar spine. All patients were followed up with measurements of BMD annually according to the KDIGO 2009 guideline in our clinic.15 We used the World Health Organization classification for osteopenia and osteoporosis, in terms of Z scores and T scores, to determine bone health as follows: group 1, normal (Z or T score, +1 to -1); group 2, osteopenia (Z or T score, -1 to -2.5); and group 3, osteoporosis (Z or T score ≤ 2.5). For premenopausal women and men under age 50 years, the Z score was considered. We used the BMD scores to divide the patients into 2 groups as follows: normal BMD and abnormal BMD (osteopenia or osteoporosis). All patients had multiple BMD assessments, and we used the third year BMD results for evaluation. Cases of symptomatic AVN were diagnosed by standard anterior-posterior x-ray views of pelvis or magnetic resonance imaging of pelvis, hip, knee, or shoulder.

Klotho gene polymorphism analysis
We used the automated magnetic bead method (MagPurix model ZP0200, Zinexts) according to the manufacturer’s instructions to prepare genomic DNA extracts from whole blood samples containing EDTA, and all extracts were stored at -80 ºC until analysis. We used specific oligonucleotide primers with real-time polymerase chain reaction to genotype the klotho SNPs rs480780, rs211234, rs576404, rs211235, rs9536314, and rs1207568 (as shown in Table 1). The reaction results were visualized with 2% agarose gel electrophoresis. The polymerase chain reaction pools generated for each sample were purified by NucleoFast 96 (Macherey-Nagel). We used a NanoDrop N-1000 spectrophotometer (Thermo Fisher Scientific) to measure purified samples. To analyze the samples, we used the New Generation Sequencing kit (model v2-300cy, Illumina), a MiSeq benchtop sequencer apparatus (Illumina), and MiSeq Reporter software (Illumina), as well as the Integrative Genomics Viewer software (IGV version 2.3) developed by the Broad Institute.

Statistical analyses
We used the Kolmogorov-Smirnov test to determine data distribution, and we used the 1-way analysis of variance homogeneity of variance test for homo­geneity of variables. Symmetrically distributed variables in the text and tables are shown as means ± SD. If the distribution was heterogeneous, then the variables are shown as median values (with interquartile range). Categorical variables are expressed as percentages. We used the t test or the Mann-Whitney U test to compare continuous variables according to the data distribution; the chi-square test to compare categorical variables; univariate logistic regression analysis to identify variables associated with osteoporosis, AVN, and PHP; and multivariate logistic regression analysis to identify possible risk factors for osteoporosis, AVN, and PHP. P ≤ .05 was considered statistically significant. We used the Statistical Package for the Social Sciences software for Windows (SPSS version 20.0.0) to perform the statistical analyses.

Results

A total of 251 patients were evaluated. We retro­spectively studied 164 men (65%) and 87 women (35%), with a mean age at transplant of 40.9 years. Median follow-up time was 8.06 ± 5 years. Although 28% of total patients underwent preemptive kidney transplant, median dialysis vintage of other patients was 2 years.

Persistent hyperparathyroidism
Persistent hyperparathyroidism was detected in 34% of total patients (85/251) at the end of first year of follow-up. Patients with PHP had longer dialysis vintage than the patients with normal PTH levels (3 years [interquartile range, 1-7.5 years] vs 1.45 years [interquartile range, 0-3 years]; P < .001). In patients who received preemptive kidney transplant, higher rates of remission were achieved than in the patients who received dialysis treatment (52 patients [74%] vs 18 patients [26%]; P = .05). Although the mean serum calcium level was higher in patients in the PHP group (9.73 ± 0.76 vs 9.45 ± 0.55 mg/dL; P = .009), the mean serum phosphorus levels were similar in both groups (3.09 ± 0.64 vs 3.26 ± 0.64 mg/dL; P = .07). Mean serum magnesium level was significantly higher in patients with normal PTH levels versus patients with PHP (1.8 ± 0.25 vs 1.73 ± 0.26 mg/dL; P = .05). Other demographic parameters of patients were similar between groups (Table 2). We used logistic regression analysis to analyze risk factors for PHP. Although rs480780 (odds ratio [OR] = 2.13 [95% CI, 1.14-3.97] for GT genotype; and OR = 8.05 [95% CI, 2.96-21.92] for GG genotype) and homozygous polymorphisms of rs211234 (OR, 6.84; 95% CI, 2.61-17.89), rs576404 (OR, 5.48; 95% CI, 2.22-13.55), and rs211235 (OR, 7.90; 95% CI, 3.15-19.77) were found to be associated with PHP, only the homozygous rs211235 SNP (OR, 9.87; 95% CI, 2.42-40.21) was identified as a risk factor for development of PHP by multivariate logistic regression analysis. Also, long-term dialysis treatment (OR, 1.13; 95% CI, 1.05-1.20) was defined as a risk factor for development of PHP by multivariate logistic regression analysis. On the other hand, higher magnesium levels were detected as a protective factor against development of PHP (OR, 0.19; 95% CI, 0.06-0.66) (Table 3).

Osteopenia or osteoporosis
A total of 240 patients were evaluated. Osteopenia or osteoporosis was detected in 40% of patients (96/240). The incidence of PHP and the mean eGFR were significantly higher in patients with osteopenia or osteoporosis compared with patients with normal BMD. That is, PHP was diagnosed in 46 patients with osteopenia or osteoporosis (48%) versus 31 normal BMD patients (22%) (P < .001); and eGFR in patients with osteopenia or osteoporosis was 79.5 ± 25.3 mL/min/1.73 m2, whereas the eGFR in patients with normal BMD was 71.5 ± 23.3 mL/min/1.73 m2 (P = .03). Also, mean serum creatinine level was significantly higher in patients with normal BMD (1.19 ± 0.37 mg/dL) than in patients with osteopenia or osteoporosis (1.1 ± 0.32 mg/dL) (P = .05). Other demographic parameters of patients were similar between groups (Table 4). Univariate logistic regression analysis showed that rs480780 (OR, 5.29; 95% CI, 2.85-9.81), rs211234 (OR, 4.24; 95% CI, 2.30-7.82), rs576404 (OR, 4.72; 95% CI, 2.52-8.84), and rs211235 (OR, 3.13; 95% CI, 1.51-6.49) SNPs of the klotho gene and PHP (OR, 3.09; 95% CI, 1.75-5.46) were associated with osteopenia and osteoporosis in patients with kidney transplant. Multivariate logistic regression analysis revealed that PHP (OR, 2.76; 95% CI, 1.43-5.33) and the rs480780 SNP of the klotho gene (OR, 8.73; 95% CI, 1.03-73.96) were risk factors for the development of osteopenia or osteoporosis in kidney transplant recipients (Table 5).

Avascular necrosis
A total of 251 patients were analyzed for AVN. Avascular necrosis was observed in 9.5% of patients (24/251). The cumulative glucocorticoid dose that was used until the development of AVN was found to be significantly lower in patients with AVN compared with patients without AVN (11.4 ± 8 vs 15.6 ± 9 g; P < .001). Other demographic parameters were similar in both groups (Table 6). Although no significant association was found between AVN and the klotho gene SNPs, hemoglobin, dialysis vintage, and drugs commonly used in patients with kidney transplant (calcineurin inhibitor, mTOR inhibitor, statins, and acetylsalicylic acid), we found that glucocorticoid dosage and PHP were associated with AVN by univariate logistic regression analysis. However, multivariate logistic regression analysis indicated that only PHP (OR, 2.52; 95% CI, 1.08-5.87) could predict the development of AVN (Table 7).

Discussion

The frequency of complications affecting long-term quality of life may increase with the prolongation of allograft survival in kidney transplant recipients. One of the most important of these complications is the occurrence of bone mineral disorders, and kidney transplant recipients are a unique population with substantial risk factors for bone disease and associated complications. Our study revealed the importance of PTH for bone health in kidney transplant recipients. Despite adequate vitamin D supplementation, we found that 34% of patients had PHP at the end of the first year of follow-up. Persistent hyperparathyroidism has been identified as an important risk factor for osteopenia and osteoporosis in our study. It also appears to be the risk factor for AVN development according to our results. Although the klotho SNPs rs480780, rs211234, rs576404, rs211235, rs9536314, and rs1207568 were not associated with AVN, some of these, including rs211235 for the development of PHP and rs480780 for osteopenia or osteoporosis, were defined as nonmodifiable risk factors for bone disease in patients with kidney transplant.

Parathyroid hormone is an important hormone in calcium, phosphorus, and bone metabolism.16 High PTH level can still be observed in 30% to 60% of patients 1 year after transplant, and high PTH levels prior to transplant, long dialysis vintage, and nodular hyperplasia are defined as risk factors for PHP in the literature.16,17 Dialysis vintage was found to be a risk factor for PHP in our study, similar to the reports in the literature. In addition, we defined hypomagnesemia as a risk factor for PHP. Several in vivo and in vitro studies have demonstrated that magnesium can modulate PTH secretion.18,19 Also, an inverse relationship between serum PTH levels and magnesium levels has been shown among patients on dialysis.20,21 Although there are a few studies that describe this relationship in kidney transplant recipients, Van de Cauter and colleagues demonstrated that hypomagnesemia at year 5 is an independent predictor of PHP in kidney transplant recipients.19 Therefore, we can speculate that the suppressive effect of hypermagnesemia in the pretransplant period is absent and that development of hypomagnesemia after kidney transplant may contribute to PHP.

Another important finding of our study is that the rs211235 SNP of the klotho gene, which is located in the intron region, increases the risk of PHP develo­pment after kidney transplant. α-Klotho is essential for endogenous FGF-23 function, including phosphate homeostasis and suppression of vitamin D and PTH synthesis.22 Over the past decade, klotho has been one focus for the progression of bone mineral disease in chronic kidney disease.23,24 However, most of those studies were based on soluble klotho, klotho protein expression, and association with FGF-23.23-25 Also, klotho gene SNPs have not been well studied. To our knowledge, the present study is the first study to investigate the relationship between klotho gene SNPs and PHP in kidney transplant recipients. The only previous publication to report that the rs211235 SNP is associated with bone mineral diseases is a study by Baldwin and colleagues related to the frequency of AVN in patients with sickle cell anemia.11 The mecha­nism by which this polymorphism is related to PHP is probably different, because AVN and PHP develop with different mechanisms. In addition, in our patient population, this SNP was not associated with AVN.

Osteoporosis is one of the major problems for kidney transplant recipients. However, clinical focus has been aimed at allograft function after kidney transplant, and as a result the management of bone disease has often been neglected. Kidney transplant recipients may have legacy bone mineral disease from chronic kidney disease that may be exacerbated by the posttransplant drug regimen. The risk of hip fracture in kidney transplant recipients during the first 6 months of transplant is 34% higher than for patients on dialysis.26 The prevalence of osteoporosis in kidney transplant recipients ranges between 11% and 56% in the literature, and bone loss occurs at the highest rate in the first year after transplant.16,27 In our study, the incidence of osteopenia or osteoporosis was found to be 40% at the end of the first year after kidney transplant, which is in accordance with the literature. We showed that PHP is a modifiable risk factor for bone disease independent of age, sex, use of glucocorticoids and calcineurin inhibitors, and calcium supplementation.

In this group of patients, the most important factor that triggers bone disease is the use of glucocorticoids.1,2,28 With the introduction of modern immunosuppressive drugs, the use of glucocorticoids is substantially reduced. However, it has been shown that discontinuation of glucocorticoid treatment increases rejection rates and frequency of chronic allograft nephropathy.29,30 Therefore, it is not practicable to interrupt glucocorticoid treatment. In addition, the same cumulative glucocorticoid treatment in similar time courses causes higher incidence of bone disorder in some patients, as in our study. In this case, it is important to control hyperparathyroidism, which could be treatable, for bone health in kidney transplant recipients.

In our study, the nonmodifiable risk factor for osteoporosis in kidney transplant recipients is the rs480780 SNP of the klotho gene. Although we showed the association between osteoporosis and other klotho gene SNPs, including rs211234, rs576404, and rs211235, by univariate regression analysis, it is important to note that all of these SNP associations lost statistical significance when we applied multivariate logistic regression analysis. Also, we showed no association between rs9536314 and osteoporosis; this polymor­phism is defined as the SNP of a functional variant of the klotho gene in humans.31 It has been suggested that the rs9536314 allele influences the trafficking and catalytic activity of the klotho protein.31 Riancho and colleagues showed that the rs9536314 SNP of the klotho gene is associated with osteoporosis in Spanish postmenopausal women.32 On the other hand, Ozdem and colleagues found an inverse association between this polymorphism and vitamin D status but no association with development of osteoporosis in kidney transplant recipients; however, that study was conducted with a small number of patients, which included 25 kidney transplant recipients and 26 healthy control patients.10 Although the rs9536314 SNP seems to be a risk factor for osteoporosis in the general population, it appears to be unassociated with osteoporosis in special patient populations such as kidney transplant recipients. In addition, the rs480780 SNP that we identified as a risk factor for development of bone disorder was determined as a predictor of AVN development in patients with sickle cell disease in previous studies.11,33 However, our study is the first study to define the rs480780 SNP, which is located in the intron region of the klotho gene, as a risk factor for development of osteoporosis.

Another bone disorder that could be seen after kidney transplant, which decreases in frequency, is AVN, which could adversely affect the quality of life and increase health costs.2 Prevalence has been reported to be between 3% and 40% in different studies.2 Although multiple risk factors have been reported in the literature, these risk factors have been largely attributed to the use of glucocorticoids.34 However, the predictive value of the treatment duration and cumulative doses of glucocorticoids is controversial.35,36 In our study, the absence of AVN in the majority of patients, despite more cumulative glucocorticoid exposure compared with patients who developed AVN, suggests that mechanisms other than glucocorticoids may be more determinant in the development of AVN. Although the exact mechanism of AVN development remains unclear, some of the proposed mechanisms are glucocorticoid-induced decrease in vascular endothelial growth factor, circulating lipids with resultant fat emboli, increased apoptosis of osteoblast and osteoclasts, and procoagulant state.37 In our study, the incidence of AVN was found to be 9.5%, similar to other values reported in the literature.

One of the important points in our study on AVN is the time of development. Our data indicate that AVN can be seen very early after transplant and may occur after many years. Therefore, AVN should be considered in patients who present with unexpected joint or bone pain.

Some risk factors that have been defined in the literature include glucocorticoid treatment, presence of antiphospholipid antibodies, alcohol use, dyslipi­demia, sickle cell anemia, and HIV infection.38 However, there is no facilitating factor in 25% of cases. We could not show the relationship of AVN development with glucocorticoids, statin, and antiaggregant therapy and dyslipidemia. However, we defined PHP as a risk factor of AVN. Until now, the only well-known risk factor in kidney transplant recipients is the use of glucocorticoids; in contrast, PHP has not been well studied.2 Felten and colleagues demonstrated that abnormal BMD and glucocorticoid treatment are risk factors for AVN development in kidney transplant recipients. They also found an association between PTH level > 300 ng/L and AVN development by univariate analysis; however, this association lost its significance in multivariate analysis.39 It is important to note that the threshold value they used in their study was very high. If lower values were used, then multivariate analysis could be significant. Also, Nehme and colleagues demonstrated that high serum PTH was associated with AVN development in kidney transplant recipients.40

This study has some limitations. First, we did not measure serum klotho levels. This was important to determine the effect of polymorphisms on serum klotho level. This could help to explain how these SNPs contribute to serum PTH level and osteoporosis. Second, bone fractures, which represent another important bone mineral problem, could not be evaluated. Because it was observed only in 2 patients, the association of bone fractures with other possible risk factors could not be examined. The strengths of the present study are the long follow-up time, sufficient number of patients, use of average laboratory values of patients in the past 3 years for demographic evaluation, and exclusion of advanced chronic kidney disease, which is an important contributor for bone mineral disorder.

Conclusions

Bone health in kidney transplant recipients is an important issue that affects quality of life in the long-term. Bone metabolism disorders are frequently seen in this patient population. Modifiable risk factors such as PHP should be recognized and treated in a timely manner in cases for which the use of glucocorticoid therapy is mandatory. Also, the klotho gene seems to have important effects on bone metabolism. However, our results are not sufficient to establish a cause-effect association for klotho on bone metabolism, because there is very little information about these SNPs in the literature. Further studies, conducted as randomized controlled trials, are needed to clarify the association between klotho gene and bone metabolism.


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DOI : 10.6002/ect.2020.0130


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From the 1Department of Nephrology, Gazi University, Ankara, Turkey; the 2Yildirim Beyazit University Yenimahalle Education and Research Hospital, Ankara, Turkey; and the 3Department of Immunology, Gazi University, Ankara, Turkey
Acknowledgements: All expenditures of this study were supported by the Gazi University Scientific Research Project Unit. The study was presented as oral presentation No. 21 at the Hypertension and Kidney Disease Congress May 1-5, 2019, Bafra, Cyprus. Other than described above, 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 further declarations of potential interest.
Corresponding author: Hasan Haci Yeter, Department of Nephrology, Gazi University Medical School, Ankara, Turkey
Phone: + 90 554 2397449
E-mail: hasanyeter@hotmail.com