الفهرس 
Definition of chronic Kidney Disease
Chronic Kidney Disease-Mineral and Bone chronic Kidney Disease-Mineral and Bone DisorderDisorderOnly 14 pages are availabe for public view
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Abstract
Chronic kidney disease is one of the most problematic diseases in our country, a leading cause of morbidity and mortality worldwide.
Chronic kidney disease-mineral and bone disease is a common complication of CKD and an important cause of morbidity and decreased life quality. It comprises a group of inter-related abnormalities of either one or a combination of the following: i) serum bone biomarkers: calcium, phosphorus, parathyroid hormone or vitamin D metabolism, ii) bone: bone turnover, mineralization, volume, linear growth or strength and iii) the vasculature: arterial stiffness and calcification.
Serum levels of 25-hydroxy vitamin D and iPTH provide an accurate picture of bone turnover and mineralization states therefore they could be used with other serum bone biomarkers as non-invasive sensitive bone markers to help management of MBD in CKD patients.
The biological activity of 1,25-dihydroxy vitamin D is mediated by the activation of the high affinity nuclear VDR bonds. The VDR gene is located on chromosome 12q12.14 and is composed of 8 protein-coding exons (exons 2–9) and 6 untranslated exons (1a-1f) that are alternatively spliced. Many isolated single -nucleotide polymorphisms in the VDR gene were found to be associated with CKD and CKD-MBD.VDR BsmI and TaqI gene polymorphism are regarded as strong markers of the disturbed vitamin D signaling pathway.
In view of the previous observations, the aim of the present work was to study the association of vitamin D receptor gene polymorphisms BsmI and TaqI with the development of chronic kidney disease, in addition to assessment of its relationship with development and progression of chronic kidney disease-mineral bone disease. To achieve this aim, the study was conducted on two age and sex-matched groups of 90 subjects; group 1 (CKD-MBD; n=60) which was further subdivided into subgroup 1a (CKD-MBD stages 3 and 4; n=30) & subgroup 1b (CKD-MBD stage 5; n=30) according to eGFR, group 2 (healthy control group; n=30).
Exclusion criteria included the presence of patients suffering from diabetes mellitus, those who underwent parathyroidectomy or have previous renal transplantation.
All individuals included in this study were subjected to full history taking focusing on previous symptoms of CKD and its complications, thorough clinical examination with special emphasis bone examination. Routine laboratory investigations: urea, creatinine, uric acid, fasting and 2 hours postprandial blood glucose (to exclude DM). Serum bone biomarkers (total and ionized calcium, inorganic phosphate, alkaline phosphatase, vitamin D and intact parathyroid hormone) and estimation of glomerular filtration rate using MDRD formula were done. VDR BsmI (rs1544410) and TaqI (rs731236) genetic polymorphisms were detected by PCR-RFLP technique.
Regarding the frequency of VDR BsmI (rs1544410) gene polymorphism, data of the present study revealed that, a non-significant difference was observed between both group 1 (CKD-MBD patients) and group 2(healthy control). A non-significant difference was also observed between both subgroup 1a (CKD-MBD stages 3 and 4) and subgroup 1b (CKD-MBD stages 5) regarding the distribution of VDR BsmI genotypic polymorphisms.
Moreover, the distribution and comparison of VDR TaqI (rs731236) genotypic polymorphisms revealed that the frequency of the wild type (TT) was significantly higher in the healthy control group (23 TT; 76.6%) compared to CKD-MBD group (9 TT; 15%). Meanwhile, the frequencies of both heterotype (Tt) and homotype (tt) were significantly higher in CKD-MBD group (16 Tt; 26.7% and 35 tt; 58.3%, respectively) compared to healthy control group (5 Tt; 16.7% and 2 tt; 6.7%, respectively). The VDR TaqI gene T (wild) alleles were significantly higher in the healthy control group (51 T; 85%) compared to the CKD-MBD group (34 T; 28.4%).
However, the t (mutant) alleles of the same gene were significantly higher in the CKD-MBD group (86 t; 71.6%) compared the healthy control group (9.0 t; 15%). The presence of the homotypic tt gene variant increase the Odds ratio of having CKD-MBD 19.6 times (95% CI=4.3-89.9) compared to having the wild TT gene variant (Odds ratio 0.05, 95% CI=0.02-0.16) or having the heterotypic Tt gene variant (Odds ratio 1.82, 95% CI=0.6-5.6).
Moreover, the distribution and comparison of VDR TaqI genotypic polymorphisms revealed that the frequencies of the wild genotype (TT) was significantly higher in subgroup 1a (8 TT; 26.7%) compared to subgroup 1b (1 TT; 3.3%). Meanwhile, the frequencies of both heterotype (Tt) and homotype (tt) were significantly higher in subgroup 1b (11 Tt; 36.7% and 18 tt; 60%, respectively) compared to subgroup 1a (5 Tt; 16.7% and 17 tt; 56.6%, respectively). Surprisingly, a non-significant difference was observed regarding the number of VDR TaqI gene alleles (the wild alleles; T and the mutant alleles; t) between both groups.
A significant difference was observed between different genotypes of VDR BsmI regarding serum ionized Ca being lower in the wild genotype compared to heterotype in subgroup 1b. A statistically significant difference was also observed between different genotypes regarding serum iPTH levels being higher in wild type compared to heterotype in group 1, subgroup 1a and subgroup 1b. Serum iPTH levels were also significantly higher in the wild type compared to the homotypic in subgroup 1a and subgroup 1b. Moreover, 25 OH vitamin D levels were significantly lower in the wild type compared to heterotype in all studied groups. In addition, 25-OH vitamin D was significantly lower in the wild type compared to homotype in group 1 and subgroup 1b.
A significant difference was observed between different genotypes of VDR TaqI regarding serum ionized Ca being lower in the homotype compared to heterotype in both group 1 and subgroup 1b. A statistically significant difference was also observed between different genotypes regarding serum iPTH levels being higher in homotype compared to heterotype in group 1, subgroup 1a and subgroup 1b. Serum iPTH levels were also significantly higher in the homotype compared to the wild type in group 1 and subgroup 1a. Moreover, 25 OH vitamin D levels were significantly lower in the homotype compared to heterotype in group 1, subgroup 1a and subgroup 1b. In addition 25 OH vitamin D levels were significantly lower in the homotype compared to the wild type in group 1, subgroup 1a and group 2.
A statistically significant difference was observed regarding VDR BsmI genotypes in different serum 25-OH vitamin D levels in group 1 and subgroup 1a. However, anon significant difference was observed regarding VDR BsmI genotypes in different serum 25-OH vitamin D levels in subgroup 1b and group 2.The association between the presence of different VDR BsmI genotypic polymorphisms in different serum 25-OH vitamin D levels in CKD-MBD patients was studied using the Odds ratio and the 95% confidence interval. The presence of the mutant types (homotype; bb, heterotype; Bb) was not associated with having 25-OH vitamin D deficiency or insufficiency in CKD-MBD patients. A statistically significant difference was observed regarding VDR TaqI genotypes in different serum 25-OH vitamin D levels in group 1 and subgroup 1a. However, anon significant difference was observed regarding VDR BsmI genotypes in different serum 25-OH vitamin D levels in subgroup 1b and group 2. The presence of the homotypic tt gene variant increase the Odds ratio of having 25-OH vitamin D deficiency and insufficiency in CKD-MBD patients 7.25 times (95% CI=2.21-23.80) and 3.86 times (95% CI=1.1-12.81) compared to having the wild TT and heterotypic Tt gene variant).
In conclusion; this study revealed that vitamin D receptor BsmI (rs1544410) gene polymorphism is not associated with susceptibility to the chronic kidney disease or development and progression of chronic kidney disease-mineral bone disease in the studied Egyptian patients with CKD. However, having the gene variants of VDR TaqI (rs731236) tt homotypic genotype increased the susceptibility to chronic kidney disease and chronic kidney disease-mineral bone disease compared to having the gene variant TT wild genotype and Tt heterotypic genotype.
Moreover, our study concluded that VDR polymorphisms were associated with the mineral status in chronic kidney disease-mineral bone disease Egyptian patients. The VDR BsmI wild (BB) genotypes and the VDR TaqI homotypic (tt) variant were found to be associated with development of severe secondary hyperparathyroidism, hypocalcemia and vitamin D deficiency in the studied Egyptian patients with chronic kidney disease-mineral bone disease patients.