Calcium Balance in Chronic Kidney Disease Hill Gallant, Kathleen M.; Spiegel, David M.
Current osteoporosis reports,
06/2017, Letnik:
15, Številka:
3
Journal Article
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Purpose of Review
The kidneys play a critical role in the balance between the internal milieu and external environment. Kidney failure is known to disrupt a number of homeostatic mechanisms that ...control serum calcium and normal bone metabolism. However, our understanding of calcium balance throughout the stages of chronic kidney disease is limited and the concept of balance itself, especially with a cation as complex as calcium, is often misunderstood. Both negative and positive calcium balance have important implications in patients with chronic kidney disease, where negative balance may increase risk of osteoporosis and fracture and positive balance may increase risk of vascular calcification and cardiovascular events. Here, we examine the state of current knowledge about calcium balance in adults throughout the stages of chronic kidney disease and discuss recommendations for clinical strategies to maintain balance as well as future research needs in this area.
Recent Findings
Recent calcium balance studies in adult patients with chronic kidney disease show that neutral calcium balance is achieved with calcium intake near the recommended daily allowance. Increases in calcium through diet or supplements cause high positive calcium balance, which may put patients at risk for vascular calcification. However, heterogeneity in calcium balance exists among these patients.
Summary
Given the available calcium balance data in this population, it appears clinically prudent to aim for recommended calcium intakes around 1000 mg/day to achieve neutral calcium balance and avoid adverse effects of either negative or positive calcium balance. Assessment of patients’ dietary calcium intake could further equip clinicians to make individualized recommendations for meeting recommended intakes.
Patients with chronic kidney disease (CKD) are given calcium carbonate to bind dietary phosphorus, reduce phosphorus retention, and prevent negative calcium balance; however, data are limited on ...calcium and phosphorus balance during CKD to support this. Here, we studied eight patients with stage 3 or 4 CKD (mean estimated glomerular filtration rate 36ml/min) who received a controlled diet with or without a calcium carbonate supplement (1500mg/day calcium) during two 3-week balance periods in a randomized placebo-controlled cross-over design. All feces and urine were collected during weeks 2 and 3 of each balance period and fasting blood, and urine was collected at baseline and at the end of each week. Calcium kinetics were determined using oral and intravenous 45calcium. Patients were found to be in neutral calcium and phosphorus balance while on the placebo. Calcium carbonate supplementation produced positive calcium balance, did not affect phosphorus balance, and produced only a modest reduction in urine phosphorus excretion compared with placebo. Calcium kinetics demonstrated positive net bone balance but less than overall calcium balance, suggesting soft-tissue deposition. Fasting blood and urine biochemistries of calcium and phosphate homeostasis were unaffected by calcium carbonate. Thus, the positive calcium balance produced by calcium carbonate treatment within 3 weeks cautions against its use as a phosphate binder in patients with stage 3 or 4 CKD, if these findings can be extrapolated to long-term therapy.
Intestinal phosphorus absorption is an important component of whole-body phosphorus metabolism, and limiting dietary phosphorus absorption is particularly of interest as a therapeutic target in ...patients with chronic kidney disease to manage mineral bone disorders. Yet, mechanisms and regulation of intestinal phosphorus absorption have not been adequately studied and discrepancies in findings exist based on the absorption assessment technique used. In vitro techniques show rather consistent effects of dietary phosphorus intake level and age on intestinal sodium-dependent phosphate transport. But, the few studies that have used in vivo techniques conflict with these in vitro studies. Therefore, we aimed to investigate the effects of dietary phosphorus intake level on phosphorus absorption using the in situ ligated loop technique in three different aged rats. Male Sprague-Dawley rats (n = 72), were studied at 10-, 20-, and 30-weeks-of-age on a low (0.1%), normal (0.6%), or high (1.2%) phosphorus diet in a 3x3 factorial design (n = 8/group). Rats were fed their assigned diet for 2-weeks prior to absorption testing by jejunal ligated loop as a non-survival procedure, utilizing 33P radioisotope. Metabolic cages were used for determination of calcium and phosphorus balance over the final four days prior to sacrifice, and blood was collected at the time of sacrifice for biochemistries. Our results show that phosphorus absorption was higher in 10-week-old rats compared with 20- and 30-week-olds and this corresponded to higher gene expression of the major phosphate transporter, NaPi-2b, as well as higher whole-body phosphorus balance and net phosphorus absorption. Dietary phosphorus intake level did not affect jejunal phosphorus absorption or NaPi-2b gene expression. Our results contrast with studies utilizing in vitro techniques, but corroborate results of other rodent studies utilizing in situ or in vivo methods. Thus, there is need for additional studies that employ more physiological methods of phosphorus absorption assessment.
The rising incidence of cardiometabolic diseases and chronic kidney disease (CKD) is a leading public health problem in East Asia. Diet is an important modifiable risk factor; thus, adopting a ...healthy diet such as the Dietary Approaches to Stop Hypertension (DASH) diet may help combat these chronic diseases. The DASH diet was originally developed in a U.S. population, and East Asia is demographically and culturally different from the U.S. Therefore, it is important to examine the evidence regarding the DASH diet and chronic disease in this unique population. This narrative review summarizes the evidence on the DASH diet and cardiometabolic health and CKD in East Asia. Culturally-modified DASH diets have been developed in some East Asian countries. Studies suggest the DASH diet is effective at lowering blood pressure in this population, though the long-term benefits remain unclear. Evidence also suggests the DASH diet may reduce the risk of type 2 diabetes and metabolic syndrome. Further research indicates the DASH diet and its components may reduce CKD risk. However, recommending the DASH diet in those who already have CKD is controversial, as it conflicts with current CKD dietary guidelines, especially in advanced CKD. Notably, current intakes in the general population differ from the DASH dietary pattern, suggesting public health efforts would be needed to encourage adoption of the DASH diet.
The purpose of this review is to discuss recent findings in intestinal phosphorus absorption pathways, particularly the contributions of paracellular versus transcellular absorption, and the ...differential findings from studies using in vitro versus in vivo techniques of assessing phosphorus absorption in experimental animal studies.
Experimental animal studies show that in vivo effects of low phosphorus diets, 1,25D, and chronic kidney disease on intestinal phosphorus absorption efficiency contradict effects previously established ex vivo/in vitro. Recent in vivo studies also suggest that the paracellular pathway accounts for the majority of phosphorus absorption in animals across very low to high luminal phosphate concentrations. The data from experimental animal studies correspond to recent human studies showing the effectiveness of targeted inhibition of paracellular phosphate absorption. Additionally, recent human studies have demonstrated that NaPi-2b inhibition alone does not appear to be effective in lowering serum phosphate levels in patients with chronic kidney disease. Pursuit of other transcellular phosphate transporter inhibitors may still hold promise.
In vivo animal and human studies have added to our understanding of intestinal phosphorus absorption pathways, regulation, and mechanisms. This is beneficial for developing effective new strategies for phosphate management in patients with chronic kidney disease.
Background:
Obesity is associated with hyperparathyroidism and increased bone mass and turnover, but their pathogeneses are unclear.
Aims:
Our aim was to determine in obesity interrelationships among ...serum levels of leptin, the mineral-regulating hormones, bone turnover markers, and sclerostin.
Methods:
This case-control study was performed in 20 women having bariatric surgery and 20 control women matched for race and age. Anthropometrics and fasting serum biochemistries were measured in controls and in bariatric patients the morning of surgery.
Results:
Body mass index (48.9 vs. 25.4 kg/m2), weight (128.6 vs. 71.9 kg), serum leptin (74.6 vs. 25.2 ng/ml), PTH (44.5 vs. 28.8 pg/ml), fibroblast growth factor 23 (FGF23) (42.4 vs. 25.9 pg/ml), and bone alkaline phosphatase (BAP) (25.8 vs. 17.5 U/liter) were higher, but height (162.3 vs. 167.7 cm) and 1,25-dihydroxyvitamin D (1,25D) (39.2 vs. 48.7 pg/ml) were lower in bariatric surgery patients than controls. There was no difference in serum sclerostin, amino-terminal collagen cross-links, 25-hydroxyvitamin D (25D), calcium, phosphate, and creatinine between groups. In the combined sample, leptin was positively related to PTH, FGF23, and BAP but not to 1,25D or sclerostin. Multiple regression analysis demonstrated that PTH was predicted by leptin and Ca (R2 = 0.39); 1,25D by 25D, FGF23, and phosphate (R2 = 0.43); FGF23 by leptin and 1,25D (R2 = 0.27); BAP by leptin, PTH, and Ca (R2 = 0.39); and sclerostin by leptin and PTH (R2 = 0.20).
Conclusions:
Women having bariatric surgery had higher leptin, PTH, FGF23, and BAP and lower 1,25D than controls. Leptin predicted the serum levels of PTH, 1,25D, and FGF23, the mineral-regulating hormones, and BAP, a bone formation marker, in women with body mass index ranging from 13.9–65.8 kg/m2. The results suggest that leptin has an endocrine or paracrine effect on PTH and FGF23 production and that PTH may be one of the signals in obesity that leads to increased bone mass.
The treatment of hyperphosphatemia remains challenging in patients receiving hemodialysis. This phase 1b study assessed safety and efficacy of EOS789, a novel pan-inhibitor of phosphate transport ...(NaPi-2b, PiT-1, PiT-2) on intestinal phosphate absorption in patients receiving intermittent hemodialysis therapy. Two cross-over, randomized order studies of identical design (ten patients each) compared daily EOS789 50 mg to placebo with meals and daily EOS789 100 mg vs EOS789 100 mg plus 1600 mg sevelamer with meals. Patients ate a controlled diet of 900 mg phosphate daily for two weeks and began EOS789 on day four. On day ten, a phosphate absorption testing protocol was performed during the intradialytic period. Intestinal fractional phosphate absorption was determined by kinetic modeling of serum data following oral and intravenous doses of 33Phosphate (33P). The results demonstrated no study drug related serious adverse events. Fractional phosphate absorption was 0.53 (95% confidence interval: 0.39,0.67) for placebo vs. 0.49 (0.35,0.63) for 50 mg EOS789; and 0.40 (0.29,0.50) for 100 mg EOS789 vs. 0.36 (0.26,0.47) for 100 mg EOS789 plus 1600 mg sevelamer (all not significantly different). The fractional phosphate absorption trended lower in six patients who completed both studies with EOS789 100 mg compared with placebo. Thus, in this phase 1b study, EOS789 was safe and well tolerated. Importantly, the use of 33P as a sensitive and direct measure of intestinal phosphate absorption allows specific testing of drug efficacy. The effectiveness of EOS789 needs to be evaluated in future phase 2 and phase 3 studies.
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We propose a computational method to measure and visualize interrelationships among any number of DNA sequences allowing, for example, the examination of hundreds or thousands of complete ...mitochondrial genomes. An "image distance" is computed for each pair of graphical representations of DNA sequences, and the distances are visualized as a Molecular Distance Map: Each point on the map represents a DNA sequence, and the spatial proximity between any two points reflects the degree of structural similarity between the corresponding sequences. The graphical representation of DNA sequences utilized, Chaos Game Representation (CGR), is genome- and species-specific and can thus act as a genomic signature. Consequently, Molecular Distance Maps could inform species identification, taxonomic classifications and, to a certain extent, evolutionary history. The image distance employed, Structural Dissimilarity Index (DSSIM), implicitly compares the occurrences of oligomers of length up to k (herein k = 9) in DNA sequences. We computed DSSIM distances for more than 5 million pairs of complete mitochondrial genomes, and used Multi-Dimensional Scaling (MDS) to obtain Molecular Distance Maps that visually display the sequence relatedness in various subsets, at different taxonomic levels. This general-purpose method does not require DNA sequence alignment and can thus be used to compare similar or vastly different DNA sequences, genomic or computer-generated, of the same or different lengths. We illustrate potential uses of this approach by applying it to several taxonomic subsets: phylum Vertebrata, (super)kingdom Protista, classes Amphibia-Insecta-Mammalia, class Amphibia, and order Primates. This analysis of an extensive dataset confirms that the oligomer composition of full mtDNA sequences can be a source of taxonomic information. This method also correctly finds the mtDNA sequences most closely related to that of the anatomically modern human (the Neanderthal, the Denisovan, and the chimp), and that the sequence most different from it in this dataset belongs to a cucumber.
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