Low Calcitriol Levels Research Articles

Low lymphocyte-to-monocyte ratio, calcitriol level, and CD206 level predict the development of acute-on-chronic liver failure in patients cirrhosis with acute decompensation.

Cirrhosis-related acute-on-chronic liver failure (ACLF) is associated with high morbidity and mortality rates. Prognostic models of ACLF have been developed; however, few studies have focused on the occurrence of ACLF. This study aimed to identify the factors that predict the development of ACLF, hepatic encephalopathy (HE), and infection in patients with cirrhosis. Patients with cirrhosis were enrolled, and the serum levels of calcitriol, Cluster of Differentiation 26 (CD206), and macrophage-inducible lectin receptor (Mincle) were measured, and lymphocyte-to-monocyte ratio (LMR) and neutrophil-to-lymphocyte ratio were calculated; all the patients were tracked for 6 months. A generalized estimating equation (GEE) was used to assess the factors associated with ACLF development, HE, and infection. The aforementioned model was derived based on immunological markers, and receiver operating characteristic analysis with area under the curve (AUC) was adopted to evaluate accuracy. After screening 325 patients with cirrhosis, 65 patients were eligible. In the GEE model, low levels of calcitriol (odds ratio [OR] = 3.259; 95% confidence interval [CI] = 1.118-8.929) and CD206 (OR = 2.666; 95% CI = 1.082-6.567) were associated with the development of ACLF, and the LMR was a protective factor (OR = 0.356; 95% CI = 0.147-0.861). Low calcitriol levels were a risk factor for HE (OR = 3.827) and infection (OR = 2.489). LMR was found to be a protective factor against HE (OR = 0.388). An immunological model for the discrimination of ACLF development within 6 months was proposed, with an AUC of 0.734 (95% CI = 0.598-0.869). Single and combined immunological markers, including low LMR and low levels of calcitriol and CD206, were promising for early prediction of the development of ACLF, HE, and infection in patients with cirrhosis.

Calcitriol levels and the stage of chronic kidney disease in children

Background Kidney damage in chronic kidney disease (CKD) disrupts the 1?-hydroxylase enzyme, preventing the conversion of vitamin D into the active form of calcitriol. To our knowledge, no previous studies have assessed calcitriol levels in children with CKD. Decreased vitamin D levels may occur at an early stage of the disease, so it is important to evaluate calcitriol levels in children with early stage CKD.
 Objective To assess calcitriol levels in children with CKD according to disease stage and other characteristics.
 Methods This cross-sectional study was conducted on 43 pediatric CKD patients at Dr. M Djamil Hospital, Padang, Indonesia. We recorded patient characteristics and performed laboratory tests, including routine hematology, blood urea nitrogen (BUN), creatinine, uric acid, electrolytes, calcium, and calcitriol levels. Based on estimated glomerular filtration rate (GFR), patients were grouped into either early-stage (stages I and II), or advanced-stage (stages III to V) CKD. Univariate and multivariate analyses were conducted to determine the association between calcitriol levels with disease stage and other characteristics.
 Results The overall mean calcitriol level of our subjects was 108.77 (SD 10.79) pmol/L. Mean levels at each CKD stage from I to V were 164.28 (SD 160.90), 94.14 (SD 50.63), 72.16 (SD 13.18), 62.92 (SD 4.87), and 67.51 (SD 4.87) pmol/L, respectively. Calcitriol levels did not differ significantly by CKD stage (P=0.114) when each stage from I to V was considered separately. There was no significant difference in calcitriol levels by growth characteristics (P=0.944), etiology (P=0.311), or anemic status (P=0.104). However, low calcitriol levels were found in all subjects with advanced stage CKD, compared to 63.6% subjects with early stage CKD (P=0.004). Mean calcitriol levels were significantly lower in CKD stage IV (P=0.049) and stage V (P=0.027) compared to stage I.
 Conclusions The decrease in calcitriol level occurs at an early stage in CKD. Calcitriol levels are significantly lower in advanced stage than in early stage CKD.

Metabolic Bone Disease of Prematurity.

Metabolic Bone Disease of Prematurity.

Renal Phosphate Wasting Due to Tumor-Induced (Oncogenic) Osteomalacia

Osteomalacia is a widely prevalent bone disorder that is caused by an imbalance in body calcium and phosphate. Tumor-induced osteomalacia (TIO) is a rare form of osteomalacia that is associated with mesenchymal tumors. It is caused by overproduction of fibroblast growth factor 23 (FGF-23), a hormone involved in phosphate regulation.A 59-year-old male with a history of factor V Leiden mutation, pulmonary embolism, and deep vein thrombosis was diagnosed with oncogenic osteomalacia in 2008 following laboratory findings significant for low phosphorus and elevated FGF-23 levels. He underwent a resection of a right suprascapular notch mass with the biopsy confirming a phosphaturic mesenchymal tumor. He was maintained on oral phosphorus and calcitriol replacements with a regular follow-up with oncology and nephrology. Eight years later, the patient’s phosphorus levels started declining despite replacement. A repeat test showed FGF-23 levels once again elevated. A whole-body magnetic resonance imaging (MRI) scan showed no significant findings. The patient was continued on oral replacement therapy with a close follow-up. Two years later, urine phosphorus excretion was elevated at 2494 mg per 24 hours with low plasma phosphorus (1.2 mg/dL) and an elevated FGF-23 level of 1005 relative units (RU)/mL. A repeat MRI of the right shoulder revealed a mass in the supraspinatus muscle and another in the spinal glenoid notch. The masses were resected and the biopsy was consistent with a recurrence of the phosphaturic mesenchymal tumor. Follow-up serum phosphate levels remained in the normal range.FGF-23 plays a critical role in bone mineralization through the regulation of phosphate levels. Overproduction, as seen in mesenchymal tumors, results in hyperphosphaturia, hypophosphatemia, and low calcitriol levels. While the definitive treatment of TIO involves the resection of the mesenchymal tumor, localization of the tumor is often challenging given its small size and slow growth. This leads to delayed diagnosis and treatment. For individuals whose tumor cannot be resected or detected, burosumab is the preferred form of therapy. Interestingly, FGF-23 is shown to have a potential cardiovascular (CV) morbidity and mortality through various mechanisms like activation of myocardial FGF-23 receptors, endothelial dysfunction, inflammation, and altered phosphorus and vitamin D metabolisms. While studies have shown possible FGF-23 effects on CV outcomes in patients with chronic kidney disease, this has not been proven in cases of TIO.

S179D Prolactin Sensitizes Human PC3 Prostate Cancer Xenografts to Anti-tumor Effects of Well-Tolerated Doses of Calcitriol.

Calcitriol has been shown to have multiple anti-prostate cancer effects both in vitro and in xenograft models, and associations between low levels of calcitriol and more aggressive forms of prostate cancer have been observed clinically. However, the concentrations of calcitriol required to have a substantive anti-cancer effect in vivo are toxic. In previous work, we had observed that the selective prolactin receptor modulator, S179D PRL, sensitized prostate cancer cells in vitro to physiological concentrations of calcitriol through an ability to increase expression of the vitamin D receptor. Here, we have investigated whether administration of S179D PRL would likewise sensitize androgen-insensitive human PC3 xenografts in vivo and do so without inducing tissue damage akin to hypervitaminosis D. Using low concentrations of both S179D PRL (250 ng/h) and calcitriol (up to 220 pg/h), we found no effect of each alone or in combination on the growth rate of tumors. However, there was increased central tumor death with their combination that was more than additive at 250 ng S179D PRL and 220 pg calcitriol per hour. Both S179D PRL and calcitriol alone were antiangiogenic, but their antiangiogenic effects were not additive. Also, both S179D PRL and calcitriol alone increased the number of apoptotic cells in tumor sections, but their combination reduced the number, suggesting more effective clearance of apoptotic cells. Histopathology of the livers and kidneys showed no changes consistent with hypervitaminosis D. We conclude that dual therapy holds promise as a means to harness the anti-tumor effects of well-tolerated doses of calcitriol.

25-Hydroxyvitamin D Inhibits Hepatitis C Virus Production in Hepatocellular Carcinoma Cell Line by a Vitamin D Receptor-Independent Mechanism.

Previously, we have reported that the active vitamin D metabolite, calcitriol and vitamin D3 (cholecalciferol), both remarkably inhibit hepatitis C virus production. The mechanism by which vitamin D3 exerts its effect is puzzling due to the low levels of calcitriol produced in vitamin D3-treated Huh7.5 cells. In this study, we aimed to explore the mechanism of vitamin D3 anti-hepatitis C virus effect. We show that vitamin D3 activity is not mediated by its metabolic conversion to calcitriol, but may be due to its primary metabolic product 25(OH)D3. This is inferred from the findings that 25(OH)D3 could inhibit hepatitis C virus production in our system, and that adequate concentrations needed to exert this effect are produced in Huh7.5 cells treated with vitamin D3. Using the CRISPR-Cas9 editing technology to knockout the vitamin D receptor, we found that the antiviral activity of vitamin D3 and 25(OH)D3 was not impaired in the vitamin D receptor knockout cells. This result indicates that 25(OH)D3 anti-hepatitis C virus effect is exerted by a vitamin D receptor-independent mode of action. The possibility that vitamin D3 and 25(OH)D3, being 3β-hydroxysteroids, affect hepatitis C virus production by direct inhibition of the Hedgehog pathway in a vitamin D receptor-independent manner was ruled out. Taken together, this study proposes a novel mode of action for the anti-hepatitis C virus activity of vitamin D3 that is mediated by 25(OH)D3 in a vitamin D receptor-independent mechanism.

Modulation of renal calcium and phosphate transporting proteins by dietary nitrogen and/or calcium in young goats.

In young goats, a reduction in dietary nitrogen (N) had an impact on mineral homeostasis although ruminants are able to recycle N effectively due to rumino-hepatic circulation. A solitary calcium (Ca) reduction stimulated calcitriol synthesis and Ca concentrations remained unchanged, whereas a dietary N reduction led to a decrease in calcitriol, which could not be prevented by a simultaneous reduction of N and Ca. In a previous study, it was shown that a reduced dietary N intake caused a decrease in intestinal Ca absorption due to a reduction of intestinal Ca transporting proteins. As no data on the potential role of the kidneys are available, it was the aim of the present study to evaluate whether an N- and/or Ca-reduced diet had an impact on renal Ca and phosphate (Pi) transporting protein expression in young goats. The animals were divided into 4 feeding groups, each receiving an adequate N and Ca supply, a reduced N supply, a reduced Ca supply, or a combined N and Ca reduction for 6 to 9 wk. The protein expression of the renal Ca channel transient receptor potential cation channel subfamily V member 5 (TRPV5) was diminished in N-reduced fed goats (P = 0.03), whereas in Ca restricted animals, the expression remained unaltered. The mRNA and protein expression of the Ca-binding protein calbindin-D28K (CaBPD28K) and the sodium-Ca exchanger 1 (NCX1) were significantly decreased due to the N-reduced feeding (mRNA, P = 0.003; P < 0.0001; protein, P = 0.002; P = 0.02), whereas dietary Ca reduction increased the CaBPD28K and NCX1 mRNA expression (P = 0.05; P = 0.01). The mRNA and protein expression of the parathyroid hormone receptor (PTHR) decreased due to the N-reduced feeding (P = 0.02; P = 0.03). These results confirm that a reduced dietary N intake led to decreased TRPV5, CaBPD28K, PTHR, and NCX1 expression levels, contributing to low levels of calcitriol and plasma Ca. In contrast to this, sodium-phosphate cotransporter type IIa expression and plasma Pi concentration were increased during dietary N reduction, thus indicating that Pi homeostasis is modulated in a calcitriol-independent manner. In conclusion, the modulation of Ca transporting proteins expression in the kidney is not able to prevent changes in mineral homeostasis in young goats receiving an N-reduced diet.

Role of CYP24A1, VDR and GC gene polymorphisms on deferasirox pharmacokinetics and clinical outcomes

β-Thalassemia patients develop deficiency in vitamin D absorption and liver hydroxylation, resulting in extremely low calcitriol levels. We explored the role of single-nucleotide polymorphisms (SNPs) involved in vitamin D metabolism, transport and activity on deferasirox pharmacokinetics and outcomes (effectiveness trough levels (Ctrough) and the area under the curve (AUC) cutoffs of 20 μg ml-1 and 360 μg ml-1 h-1, respectively; nonresponse AUC limit of 250 μg ml-1 h-1). Ninety-nine β-thalassemic patients were enrolled. Drug plasma Ctrough and AUC were measured by the high-performance liquid chromatography system coupled with an ultraviolet determination method. Allelic discrimination for VDR, CYP24A1, CYP27B1 and GC gene SNPs was performed by real-time PCR. CYP24A1 22776 TT significantly influenced Cmin and negatively predicted it in regression analysis. CYP24A1 3999 CC was associated with Ctrough and Cmin and was a negative predictor of Tmax, whereas CYP24A1 8620 GG seemed to have a role in Ctrough, AUC, t1/2 and Cmin, and was an AUC negative predictor factor. Considering treatment outcome, Cdx2 and GC 1296 were retained in regression analysis as AUC efficacy cutoff negative predictors.

Vitamin D and Inflammatory Cytokines in Healthy and Preeclamptic Pregnancies.

Preeclampsia is a pregnancy disease characterized by hypertension and proteinuria. Among several disorders, the imbalance of inflammatory cytokines and the alteration of vitamin D metabolism have been reported in preeclampsia. The effects of calcitriol upon inflammatory cytokines has been demonstrated. In healthy pregnant women there is a shift toward a Th2 cytokine profile, which is necessary for an adequate pregnancy outcome. As compared with normal pregnancy, high pro-inflammatory and low anti-inflammatory cytokine levels have been observed in preeclamptic women. Preeclampsia has been associated with low calcitriol levels and vitamin D deficiency is correlated with a higher risk of the development of this disease. It has been demonstrated that placenta is a source as well as the target of calcitriol and cytokines and placental dysfunction has been associated with preeclampsia. Therefore, the present manuscript includes a review about serum calcitriol levels in non-pregnant, pregnant, and preeclamptic women as well as a review on the fetoplacental vitamin D metabolism in healthy and preeclamptic pregnancies. In addition, circulating and fetoplacental inflammatory cytokines in healthy and preeclamptic pregnancies are reviewed. Finally, the effects of calcitriol upon placental pro-inflammatory cytokines are also explored. In conclusion, maternal and placental calcitriol levels are low in preeclampsia which may explain, at least in part, high pro-inflammatory cytokine levels in this disease.

Aspects of the blood chemistry of kidney transplant patients

Introduction:Normal renal function is a prerequisite for maintaining the normal balance of calcium and phosphorus. The incidence of 1,25-dihydroxyvitamin D (1,25(OH)2D, or calcitriol) deficiency in renal transplant patients is 50%. The causes are multifactorial, including low availability of 25-hydroxyvitamin D (25(OH)D). Although kidney transplant is the treatment of choice, some patients maintain bone changes resulting from the interplay of several factors, such as persistence of mineral disorders due to graft dysfunction and effect of immunosuppressive drugs.Objective:To evaluate the dynamics of some biochemical parameters after kidney transplant.Material and methods:Thirteen patients followed from pre-transplant to three months post-transplant, with measurements of creatinine, calcium, phosphate, parathyroid hormone (PTH), 25(OH)D, and calcitriol.Results:Normalization of calcium was observed in 10 of the 13 patients (77%), and only one did not have phosphate levels reduced after transplant; all patients presented elevated PTH in pre-transplant, four of which (31%) maintained this change; nine of the 13 patients (69%) had low levels of 25(OH)D, which remained essentially unchanged after transplantation. Low pre-transplant levels of calcitriol were observed in 46% of the patients, and remained in only one. This patient had a very low pre-transplant level of 25(OH)D (8 ng/ml) that did not change after surgery. A possible explanation for this is the reduced substrate availability for 1-alpha-hydroxylase.Conclusion:Our data, in agreement with the literature, confirm that even patients with good outcomes after renal transplantation can still present important biochemical changes associated with deterioration of bone quality.

Cinacalcet for Management of Tertiary Hyperparathyroidism Associated with Chronic Treatment of Hypophosphatemia in an Adult with Tumor-Induced Osteomalacia

ABSTRACT Objective: To report the effectiveness of cinacalcet in treating tertiary hyperparathyroidism (THPT) associated with chronic treatment of hypophosphatemia in a patient with fibroblast growth factor-23 (FGF-23)-mediated tumor-induced osteomalacia (TIO). Methods: We review the clinical course, imaging studies, pathology, and results of laboratory testing of our patient and review relevant literature. Results: A 52-year-old woman presented with hypercalcemia. At age 26, she developed hypophosphatemia, inappropriately low levels of calcitriol, calcium, and intact parathyroid hormone (iPTH) and was diagnosed with vitamin D–resistant osteomalacia. She was initiated on high-dose phosphate but remained hypophosphatemic and developed progressive elevation in iPTH levels along with hypercalcemia. Twenty years after the initial presentation, a mass was found on her right forearm, and surgical resection revealed a phosphaturic mesenchymal tumor diagnostic of TIO. Her hypophosphatemia resolved and she was tit...

68Ga DOTA-TATE PET/CT allows tumor localization in patients with tumor-induced osteomalacia but negative 111In-octreotide SPECT/CT

Tumor-induced osteomalacia (TIO) is a paraneoplastic syndrome characterized by renal phosphate wasting, hypophosphatemia and low calcitriol levels as well as clinical symptoms like diffuse bone and muscle pain, fatigue fractures or increased fracture risk. Conventional imaging methods, however, often fail to detect the small tumors. Lately, tumor localization clearly improved by somatostatin-receptor (SSTR) imaging, such as octreotide scintigraphy or octreotide SPECT/CT. However, recent studies revealed that still a large number of tumors remained undetected by octreotide imaging. Hence, studies focused on different SSTR imaging methods such as 68Ga DOTA-NOC, 68Ga DOTA-TOC and 68Ga DOTA-TATE PET/CT with promising first results. Studies comparing different SSTR imaging methods for tumor localization in TIO are rare and thus little is known about diagnostic alternatives once a particular method failed to detect a tumor in patients with TIO.Here, we report the data of 5 consecutive patients suffering from TIO, who underwent both 111Indium-octreotide scintigraphy (111In-OCT) SPECT/CT as well as 68Ga DOTA-TATE PET/CT for tumor detection. While 111In-OCT SPECT/CT allowed tumor detection in only 1 of 5 patients, 68Ga DOTA-TATE PET/CT was able to localize the tumor in all patients. Afterwards, anatomical imaging of the region of interest was performed with CT and MRI. Thus, successful surgical resection of the tumor was achieved in all patients. Serum phosphate levels returned to normal and all patients reported relief of symptoms within weeks. Moreover, an iliac crest biopsy was obtained from every patient and revealed marked osteomalacia in all cases. Follow-up DXA revealed an increase in BMD of up to 34.5% 1-year postoperative, indicating remineralization. No recurrence was observed.In conclusion our data indicates that 68Ga DOTA-TATE PET/CT is an effective and promising diagnostic tool in the diagnosis of TIO, even in patients in whom 111In-OCT prior failed to detect a tumor.

Uric acid suppresses 1 alpha hydroxylase in vitro and in vivo

ObjectivePatients with gout have lower calcitriol levels that improve when uric acid is lowered. The mechanism of these observations is unknown. We hypothesized that uric acid inhibits 1-αhydroxylase. Materials and methodsIn vivo, Sprague Dawley rats were randomized to control (n=5), allantoxanamide (n=8), febuxostat (n=5), or allantoxanamide+febuxostat (n=7). Vitamin D, PTH, and 1-αhydroxylase protein were evaluated. In order to directly evaluate the effect of uric acid on 1-αhydroxylase, we conducted a series of dose response and time course experiments in vitro. Nuclear factor κ-B (NFκB) was inhibited pharmacologically. Finally, to evaluate the potential implications of these findings in humans, the association between uric acid and PTH in humans was evaluated in a cross-sectional analysis of data from the NHANES (2003–2006); n=9773. Results1,25(OH)2D and 1-αhydroxylase protein were reduced in hyperuricemic rats and improved with febuxostat treatment. Uric acid suppressed 1-αhydroxylase protein and mRNA expression in proximal tubular cells. This was prevented by NFκB inhibition. In humans, for every 1mg/dL increase in uric acid, the adjusted odds ratio for an elevated PTH (>65pg/mL) was 1.21 (95% C.I. 1.14, 1.28; P<0.0001), 1.15 (95% C.I. 1.08, 1.22; P<0.0001), and 1.16 (95% C.I. 1.03, 1.31; P=0.02) for all subjects, subjects with estimated GFR ≥60, and subjects with estimated GFR <60mL/min/1.73m2 respectively. ConclusionHyperuricemia suppresses 1-αhydroxylase leading to lower 1,25(OH)2D and higher PTH in rats. Our results suggest this is mediated by NFκB. The association between uric acid and PTH in NHANES suggests potential implications for human disease.

Effects of iron deficiency anemia and its treatment on fibroblast growth factor 23 and phosphate homeostasis in women

Fibroblast growth factor 23 (FGF23) is an osteocyte-derived hormone that regulates phosphate and vitamin D homeostasis. Through unknown mechanisms, certain intravenous iron preparations induce acute, reversible increases in circulating FGF23 levels that lower serum phosphate in association with inappropriately low levels of calcitriol, similar to genetic diseases of primary FGF23 excess. In contrast, studies in wild-type mice suggest that iron deficiency stimulates fgf23 transcription but does not result in hypophosphatemia because FGF23 is cleaved within osteocytes by an unknown catabolic system. We tested the association of iron deficiency anemia with C-terminal FGF23 (cFGF23) and intact FGF23 (iFGF23) levels in 55 women with a history of heavy uterine bleeding, and assessed the longitudinal biochemical response over 35 days to equivalent doses of randomly-assigned, intravenous elemental iron in the form of ferric carboxymaltose (FCM) or iron dextran. Iron deficiency was associated with markedly elevated cFGF23 (807.8 ± 123.9 relative units [RU]/mL) but normal iFGF23 (28.5 ± 1.1 pg/mL) levels at baseline. Within 24 hours of iron administration, cFGF23 levels fell by approximately 80% in both groups. In contrast, iFGF23 transiently increased in the FCM group alone, and was followed by a transient, asymptomatic reduction in serum phosphate <2.0 mg/dL in 10 women in the FCM group compared to none in the iron dextran group. Reduced serum phosphate was accompanied by increased urinary fractional excretion of phosphate, decreased calcitriol levels, and increased parathyroid hormone levels. These findings suggest that iron deficiency increases cFGF23 levels, and that certain iron preparations temporarily increase iFGF23 levels. We propose that intravenous iron lowers cFGF23 in humans by reducing fgf23 transcription as it does in mice, whereas carbohydrate moieties in certain iron preparations may simultaneously inhibit FGF23 degradation in osteocytes leading to transient increases in iFGF23 and reduced serum phosphate.

RARE VARIANTS IN THE CYP27B1 GENE ARE ASSOCIATED WITH MULTIPLE SCLEROSIS

Multiple sclerosis (MS) is a complex neurological disease. Genetic linkage analysis and genotyping of candidate genes in families with four or more affected individuals more heavily loaded for susceptibility genes...

Earlier Decrease of FGF-23 and Less Hypophosphatemia in Preemptive Kidney Transplant Recipients

Levels of fibroblast growth factor (FGF)-23, a phosphaturic hormone, increase from the early stages of CKD and are dramatically elevated in dialysis patients. Excessive FGF-23 may be involved in the hypophosphatemia and inappropriately low calcitriol levels observed after kidney transplantation (KT).This prospective observational cohort study was carried out to determine whether there are any differences in the changes in FGF-23 levels after surgery in KT recipients according to whether they were or not on dialysis before transplantation and to assess the influence of FGF-23 in the development of posttransplantation hypophosphatemia. Consecutive KT recipients at the Hospital Clinic of Barcelona were recruited. Patients developing delayed graft function were excluded. Mineral metabolism parameters, including C-terminal fragment of FGF-23, intact parathyroid hormone, and 1,25(OH)(2)D(3), were measured in 72 KT recipients (58 on dialysis before transplantation and 14 preemptive transplant recipients) at baseline, on day 15, and at 1, 3, and 6 months after transplantation. No patients received treatment with calcimimetics, bisphosphonates, vitamin D, or phosphate supplementation during the follow-up. FGF-23 decreased significantly in the first month after transplantation. Baseline and FGF-23 levels within the first posttransplantation month were lower in preemptive transplant recipients than in patients on dialysis at transplantation. Serum phosphate levels were lower in dialysis patients until the third month after transplantation. Pretransplantation FGF-23 was the main predictor of posttransplantation phosphate blood levels. FGF-23 levels and the risk of developing posttransplantation hypophosphatemia were lower in preemptive kidney transplant recipients than in patients on dialysis before transplantation.

Evidence in Favor of a Severely Impaired Net Intestinal Calcium Absorption in Patients with (Early-Stage) Chronic Kidney Disease

Introduction: Calcium and phosphorus are essential to many vital physiological processes. Little is known about the net and fractional intestinal absorption of calcium and phosphorus in patients with chronic kidney disease (CKD) and their clinical and hormonal determinants. Methods: Blood and 24-hour urine samples were collected in 20 healthy volunteers (HV) and 72 stable CKD stage 1–4 patients and analyzed for parameters of mineral metabolism including calcidiol, calcitriol, and parathyroid hormone (PTH). Dietary intake was assessed by dietary history. Results: The 24-hour urinary calcium excretion, as opposed to the phosphorus excretion, showed a stepwise decrease across CKD stages (median of 219, 84, 40, and 22 mg/day in HV and patients with CKD stages 1–2, 3 and 4, respectively). Younger age, high serum calcitriol, and high estimated GFR were associated with a high 24-hour urinary calcium excretion. High serum calcitriol levels and dietary phosphorus intake were associated with a high 24-hour urinary phosphorus excretion. The fractional intestinal calcium absorption, as estimated by the urinary-to-ingested calcium ratio, decreased across CKD stages. Conclusions: The 24-hour urinary excretion of calcium, as opposed to phosphorus, is markedly decreased in CKD, even in early-stage disease. This is partly explained by low calcitriol levels and older age. Assuming a neutral calcium balance at the time of urine collection, we infer that net intestinal calcium absorption may be severely impaired in CKD.

Rare variants in the CYP27B1 gene are associated with multiple sclerosis

Multiple sclerosis (MS) is a complex neurological disease. Genetic linkage analysis and genotyping of candidate genes in families with 4 or more affected individuals more heavily loaded for susceptibility genes has not fully explained familial disease clustering. We performed whole exome sequencing to further understand the heightened prevalence of MS in these families. Forty-three individuals with MS (1 from each family) were sequenced to find rare variants in candidate MS susceptibility genes. On average, >58,000 variants were identified in each individual. A rare variant in the CYP27B1 gene causing complete loss of gene function was identified in 1 individual. Homozygosity for this mutation results in vitamin D-dependent rickets I (VDDR1), whereas heterozygosity results in lower calcitriol levels. This variant showed significant heterozygous association in 3,046 parent-affected child trios (p = 1 × 10(-5)). Further genotyping in >12,500 individuals showed that other rare loss of function CYP27B1 variants also conferred significant risk of MS, Peto odds ratio = 4.7 (95% confidence interval, 2.3-9.4; p = 5 × 10(-7)). Four known VDDR1 mutations were identified, all overtransmitted. Heterozygous parents transmitted these alleles to MS offspring 35 of 35× (p = 3 × 10(-9)). A causative role for CYP27B1 in MS is supported; the mutations identified are known to alter function having been shown in vivo to result in rickets when 2 copies are present. CYP27B1 encodes the vitamin D-activating 1-alpha hydroxylase enzyme, and thus a role for vitamin D in MS pathogenesis is strongly implicated.

Cross Talk Between the Renin-Angiotensin-Aldosterone System and Vitamin D-FGF-23-klotho in Chronic Kidney Disease

There is increasingly evidence that the interactions between vitamin D, fibroblast growth factor 23 (FGF-23), and klotho form an endocrine axis for calcium and phosphate metabolism, and derangement of this axis contributes to the progression of renal disease. Several recent studies also demonstrate negative regulation of the renin gene by vitamin D. In chronic kidney disease (CKD), low levels of calcitriol, due to the loss of 1-alpha hydroxylase, increase renal renin production. Activation of the renin-angiotensin-aldosterone system (RAAS), in turn, reduces renal expression of klotho, a crucial factor for proper FGF-23 signaling. The resulting high FGF-23 levels suppress 1-alpha hydroxylase, further lowering calcitriol. This feedback loop results in vitamin D deficiency, RAAS activation, high FGF-23 levels, and renal klotho deficiency, all of which associate with progression of renal damage. Here we examine current evidence for an interaction between the RAAS and the vitamin D-FGF-23-klotho axis as well as its possible implications for progression of CKD.

Severe osteomalacia caused by short bowel syndrome in a patient on long-term hemodialysis after parathyroidectomy

In January 2009, a 70-year-old Japanese woman on long-term dialysis was admitted to our hospital for evaluation of a painful left leg. Maintenance dialysis was started in 1982, and parathyroidectomy was performed for secondary hyperparathyroidism in 2004. Most of her small intestine was resected because of superior mesenteric artery thrombosis in 2006, and the remaining small bowel only extended 50 cm distal to the ligament of Treitz. Parenteral nutrition was started after bowel resection. Fracture of her left leg occurred suddenly without any precipitating factors in January 2009, and iliac bone biopsy revealed severe osteomalacia with an increase of total osteoid volume (57.6%) (>15%) and no fibrous tissue (0%) (<0.5%). Although phosphorus and active vitamin D were administered intravenously to correct her hypophosphatemia and vitamin D deficiency, significant improvement was not achieved. This case indicates that when a patient on long-term dialysis with parathyroidectomy also suffers from short bowel syndrome, osteomalacia may become very severe. Lack of healing of the fracture, persistence of pain, and subsequent fracture even after vigorous treatment for low serum phosphate and calcitriol levels implied that these medications were not necessarily sufficient for this patient.