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      Hypervitaminosis A is prevalent in children with CKD and contributes to hypercalcemia

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          Abstract

          Background

          Vitamin A accumulates in renal failure, but the prevalence of hypervitaminosis A in children with predialysis chronic kidney disease (CKD) is not known. Hypervitaminosis A has been associated with hypercalcemia. In this study we compared dietary vitamin A intake with serum retinoid levels and their associations with hypercalcemia.

          Methods

          We studied the relationship between vitamin A intake, serum retinoid levels, and serum calcium in 105 children with CKD stages 2–5 on dialysis and posttransplant. Serum retinoid measures included retinol (ROH), its active retinoic acid (RA) metabolites [all-trans RA (at-RA) and 13-cis RA] and carrier proteins [retinol-binding protein-4 (RBP4) and transthyretin (TTR)]. Dietary vitamin A intake was assessed using a food diary.

          Results

          Twenty-five children were in CKD 2–3, 35 in CKD 4–5, 23 on dialysis and 22 posttransplant; 53 % had vitamin A intake above the Reference Nutrient Intake (RNI) value. Children receiving supplemental feeds compared with diet alone had higher vitamin A intake ( p = 0.02) and higher serum ROH ( p < 0.001). Notably, increased ROH was seen as early as CKD stage 2. For every 10 ml/min/1.73 m 2 fall in estimated glomerular filtration rate (eGFR), there was a 13 % increase in ROH. RBP4 levels were increased in CKD 3–5 and dialysis patients. The lowest ratios of ROH:RBP4 were seen in dialysis compared with CKD 2–3 ( p = 0.03), suggesting a relative increase in circulating RBP4. Serum ROH, RBP4 and at-RA were associated with serum calcium. On multivariable analysis RBP4 levels and alfacalcidol dose were significant predictors of serum calcium (model R 2 32 %) in dialysis patients.

          Conclusions

          Hypervitaminosis A is seen in early CKD, with highest levels in children on supplemental feeds compared with diet alone. Serum retinoid levels significantly predict hypercalcemia.

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          Most cited references43

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          Mechanistic Insights into Vascular Calcification in CKD

          Cardiovascular disease begins early in the course of renal decline and is a life-limiting problem in patients with CKD. The increased burden of cardiovascular disease is due, at least in part, to calcification of the vessel wall. The uremic milieu provides a perfect storm of risk factors for accelerated calcification, but elevated calcium and phosphate levels remain key to the initiation and progression of vascular smooth muscle cell calcification in CKD. Vascular calcification is a highly regulated process that involves a complex interplay between promoters and inhibitors of calcification and has many similarities to bone ossification. Here, we discuss current understanding of the process of vascular calcification, focusing specifically on the discrete and synergistic effects of calcium and phosphate in mediating vascular smooth muscle cell apoptosis, osteochondrocytic differentiation, vesicle release, calcification inhibitor expression, senescence, and death. Using our model of intact human vessels, factors initiating vascular calcification in vivo and the role of calcium and phosphate in driving accelerated calcification ex vivo are described. This work allows us to link clinical and basic research into a working theoretical model to explain the pathway of development of vascular calcification in CKD.
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            Advanced coronary and carotid arteriopathy in young adults with childhood-onset chronic renal failure.

            Cardiovascular mortality is excessive in young adults with end-stage renal disease (ESRD). The factors contributing to ESRD-related vascular disease are incompletely understood. Young adults with childhood-onset chronic renal failure (CRF) are uniquely suited for risk factor assessment because of their long-term exposure at an age when vascular pathology in the general population is still minimal. We used novel noninvasive technologies to screen for coronary and carotid artery disease in 39 patients with ESRD aged 19 to 39 years with childhood-onset CRF presently treated by dialysis or renal transplantation. Coronary artery calcification burden was assessed by CT scan with ECG gating and the intima-media thickness (IMT) of the carotid arteries by high-resolution ultrasound. Coronary artery calcifications were present in 92% of patients; calcium scores exceeded the 95th age- and sex-specific percentiles >10-fold on average. Carotid IMT was significantly increased compared with matched control subjects. Both coronary calcium scores and IMT were associated with cumulative dialysis and ESRD time and the cumulative serum calcium-phosphate product. Coronary calcium scores were strongly correlated with C-reactive protein and Chlamydia pneumoniae seropositivity, time-averaged mean serum parathyroid hormone, and plasma homocysteine. C-reactive protein and parathyroid hormone independently predicted coronary calcium accumulation. Smoking, obesity, and HbA1c were correlated with IMT in the control subjects but not in the patients. Young adults with childhood-onset CRF have a high prevalence of arteriopathy associated with indicators of microinflammation, hyperparathyroidism, calcium-phosphate overload, and hyperhomocysteinemia but not traditional atherogenic risk factors. These risk factors persist even after successful renal transplantation.
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              The effects of diseases of the liver, thyroid, and kidneys on the transport of vitamin A in human plasma.

              The effects of diseases of the liver, the thyroid, and the kidneys on the retinol-binding protein (RBP)-prealbumin (PA) system responsible for the transport of vitamin A in plasma were examined, using a radial gel diffusion immunoassay for PA and the previously described radioimmunoassay for RBP. Measurements were made on plasma samples from 118 normal subjects, 31 patients with cirrhosis, 5 with chronic active hepatitis, 27 with acute viral hepatitis, 14 patients with hyperthyroidism, 7 with hypothyroidism, and 26 patients with chronic renal disease of varying etiologies. In the patients with liver disease, the levels of vitamin A, RBP, and PA were all markedly decreased and were highly significantly correlated over a wide range of concentrations. Serial samples were available in 19 patients with acute hepatitis; as the disease improved the plasma concentrations of vitamin A, RBP, and PA all increased. In patients with acute hepatitis RBP concentrations correlated negatively with the levels of plasma bilirubin, glutamic-oxaloacetic transaminase, and alkaline phosphatase. In the hyperthyroid patients both RBP and PA concentrations were significantly lower than normal; in hypothyroidism, neither protein showed levels significantly different from normal. In both hyper- and hypothyroidism and in liver disease, the molar ratios of RBP:PA and of RBP:vitamin A were not significantly different from normal.Patients with chronic renal disease had marked abnormalities in the plasma concentrations of RBP and vitamin A and in the molar ratios examined. In renal disease the levels of both RBP and vitamin A were greatly elevated, while the PA levels remained normal. The molar ratios of RBP:PA and of RBP:vitamin A were both markedly elevated. In many patients RBP was present in molar excess as compared with PA. The presence of a relatively large proportion of free RBP, not complexed to PA, in some patients with chronic renal disease was confirmed by gel filtration. The free RBP, present in molar excess, was capable of forming a complex with additional purified PA added to the plasma. The kidneys appear to play an important role in the normal metabolism of RBP.
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                Author and article information

                Contributors
                Rukshana.Shroff@gosh.nhs.uk
                Journal
                Pediatr Nephrol
                Pediatr. Nephrol
                Pediatric Nephrology (Berlin, Germany)
                Springer Berlin Heidelberg (Berlin/Heidelberg )
                0931-041X
                1432-198X
                15 August 2014
                15 August 2014
                2015
                : 30
                : 317-325
                Affiliations
                [ ]Department of Dietetics, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom
                [ ]Nephrology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom
                [ ]Department of Nutrition, University of Oslo, Oslo, Norway
                Article
                2916
                10.1007/s00467-014-2916-2
                4282719
                25119682
                d465109f-97d7-4e94-b858-c6d956937879
                © The Author(s) 2014

                Open Access This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.

                History
                : 25 January 2014
                : 24 May 2014
                : 14 July 2014
                Categories
                Original Article
                Custom metadata
                © IPNA 2015

                Nephrology
                vitamin a,retinol,retinol binding protein 4 (rbp4),hypercalcemia,children
                Nephrology
                vitamin a, retinol, retinol binding protein 4 (rbp4), hypercalcemia, children

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