The Vitamin D Metabolite Ratio (VMR) is a Biomarker of Vitamin D Status That is Not Affected by Acute Changes in Vitamin D Binding Protein.

BACKGROUND: 25-hydroxyvitamin D[25(OH)D] may be a poor marker of vitamin D status due to variability in levels of vitamin D binding protein (VDBP). The vitamin D metabolite ratio (VMR) is the ratio of 24,25-dihydroxyvitamin D[24,25(OH)2D3] to 25(OH)D3 and has been postulated to reflect vitamin D sufficiency independent of variability in VDBP. Therapeutic plasma exchange (TPE) is a procedure that removes plasma, including VDBP, and may lower bound vitamin D metabolite concentrations. Effects of TPE on the VMR are unknown. METHODS: We measured 25(OH)D, free 25(OH)D, 1,25-dihydroxyvitamin D[1,25(OH)2D], 24,25(OH)2D3, and VDBP in persons undergoing TPE, before and after treatment. We used paired t-tests to assess changes in these biomarkers during a TPE procedure. RESULTS: Study participants (n = 45) had a mean age of 55 ± 16 years; 67% were female; and 76% were white. Compared to pretreatment concentrations, TPE caused a significant decrease in total VDBP by 65% (95%CI 60,70%), as well as all the vitamin D metabolites-25(OH)D by 66% (60%,74%), free 25(OH)D by 31% (24%,39%), 24,25(OH)2D3 by 66% (55%,78%) and 1,25(OH)2D by 68% (60%,76%). In contrast, there was no significant change in the VMR before and after a single TPE treatment, with an observed mean 7% (-3%, 17%) change in VMR. CONCLUSIONS: Changes in VDBP concentration across TPE parallel changes in 25(OH)D, 1,25(OH)2D, and 24,25(OH)2D3, suggesting that concentrations of these metabolites reflect underlying VDBP concentrations. The VMR is stable across a TPE session despite a 65% reduction in VDBP. These findings suggest that the VMR is a marker of vitamin D status independent of VDBP levels.

Differences in Phosphate and Parathyroid Hormone Concentrations over the Day among Patients on Hemodialysis.

BACKGROUND: Elevated serum phosphate and parathyroid hormone (PTH) concentrations are associated with cardiovascular events, bone disease, and mortality in patients on maintenance hemodialysis. Although circadian changes are known in people with CKD, it is unknown whether differences occur in these parameters over the course of a day in people receiving hemodialysis. METHODS: We used clinical data from Fresenius Medical Care US dialysis clinics to determine how the time of day when measurements were collected (hemodialysis treatment start time) may be associated with serum phosphate and PTH concentrations. We used harmonic regression to assess these associations while accounting for demographic data and treatment parameters. RESULTS: A total of 96,319 patients receiving maintenance hemodialysis were included in this analysis. Patients had a mean age of 64±14 years, 43% were women, and dialysis start times ranged from 3:00 am to 7:59 pm. The mean serum phosphate concentration was 5.2±1.5 mg/dl, and the median PTH was 351 pg/ml (interquartile range [IQR], 214-547). In fully adjusted models, serum phosphate had a nadir at 11:00 am of 4.97 (IQR, 4.94-5.01) mg/dl and a peak at 7:00 pm of 5.56 (IQR, 5.50-5.62) mg/dl. Serum PTH had a nadir at 9:00 am of 385 (IQR, 375-395) pg/ml and a peak at 7:00 pm of 530 (IQR, 516-547) pg/ml. CONCLUSIONS: Among patients receiving maintenance hemodialysis, concentrations of PTH and phosphate before a dialysis session vary with the time of day that these values are measured. Consideration of whether these values were obtained at peak or nadir times of the day may be important in treatment decisions.

Diagnosis and Management of Osteoporosis in Advanced Kidney Disease: A Review.

Osteoporosis and fractures are common in persons with advanced chronic kidney disease (CKD) and on maintenance dialysis. Although the diagnosis of osteoporosis in this population can be difficult, imaging, especially with dual-energy x-ray absorptiometry (DXA), is helpful in identifying persons with CKD at the highest risk of fracture. Although blood biomarkers including parathyroid hormone and bone-specific alkaline phosphatase concentrations can aid in assessing bone turnover state, bone biopsy remains the gold standard in determining bone turnover in persons with advanced kidney disease and osteoporosis. With the increasing armamentarium of osteoporosis drugs, it now may be possible to prevent many fractures in advanced CKD. Unfortunately, data on these drugs are limited in persons with advanced CKD. Clinicians, aided by advances in imaging, biomarkers, and bone biopsy can now use these novel agents to target bone turnover abnormalities such as adynamic bone disease and high bone turnover disease. This review will discuss the most recent literature surrounding the diagnosis, management, and monitoring of osteoporosis and fractures in persons with advanced CKD or on maintenance dialysis.

Marathon Runners' Knowledge and Strategies for Hydration.

OBJECTIVE: To study hydration plans and understanding of exercise-associated hyponatremia (EAH) among current marathon runners. DESIGN: Cross-sectional study. SETTING: Southern California 2018 summer marathon. PARTICIPANTS: Two hundred ten marathon runners. INTERVENTIONS: Survey administered 1 to 2 days before the race. Race times were obtained from public race website. MAIN OUTCOME MEASURES: Planned frequency of hydration; awareness of, understanding of, and preventative strategies for dehydration and EAH; resources used to create hydration plans; drink preferences. RESULTS: When the participants were split into 3 equal groups by racing speed, the slower tertile intended to drink at every mile/station (60%), whereas the faster tertile preferred to drink every other mile or less often (60%), although not statistically significant. Most runners (84%) claimed awareness of EAH, but only 32% could list a symptom of the condition. Both experienced marathoners and the faster tertile significantly had greater understanding of hyponatremia compared with first-time marathoners and the slower tertile, respectively. Less than 5% of marathoners offered "drink to thirst" as a prevention strategy for dehydration or EAH. CONCLUSION: Slower runners plan to drink larger volumes compared with their faster counterparts. Both slower and first-time marathoners significantly lacked understanding of EAH. These groups have plans and knowledge that may put them at higher risk for developing EAH. Most marathon runners did not know of the guidelines to "drink to thirst," suggesting the 2015 EAH Consensus statement may not have had the desired impact.

The Vitamin D Metabolite Ratio Is Independent of Vitamin D Binding Protein Concentration.

BACKGROUND: 25-Hydroxyvitamin D [25(OH)D] may be a poor marker of vitamin D status as it reflects differences in vitamin D binding protein (VDBP) between individuals. The vitamin D metabolite ratio [VMR, ratio of 24,25(OH)2D3 to 25(OH)D3] is a marker of vitamin D status that has been hypothesized to be independent of variability in VDBP. This hypothesis has not been directly evaluated. METHODS: We measured 25(OH)D3, 24,25(OH)2D3, 1,25(OH)2D3, and VDBP in 377 community-dwelling older adults that participated in the Health Aging and Body Composition Study. 24,25(OH)2D3 and 25(OH)D3 were used to calculate the VMR. We used linear regression to assess the relationship between VDBP with the VMR, 24,25(OH)2D3, 25(OH)D3, and 1,25(OH)2D3. RESULTS: Participants had mean age 75 ± 3 years, 52% were female, 40% were black, and 24% had chronic kidney disease. VDBP concentrations were associated with sex, serum albumin, and VDBP phenotype in multivariable models. In fully adjusted models, each 1% higher VDBP was associated with a 0.92%[95% CI(0.37,1.49%)], 0.76% (0.39, 1.13%), and 0.57% (0.29, 0.85%), higher 24,25(OH)2D3, 25(OH)D3, and 1,25(OH)2D3. The VMR was independent of VDBP concentration, [0.16%(-0.11, 0.44) higher VMR per 1% higher VDBP, P = .25]. CONCLUSIONS: The VMR was independent of VDBP concentration, whereas VDBP was strongly directly associated with the individual vitamin D metabolite concentrations. Prior studies evaluating only 25(OH)D3 may have been confounded by absence of data on VDBP status. The VMR may serve as an important biomarker of vitamin D status and clinical outcomes that can be utilized in populations with a large spectrum of VDBP concentrations.

Differential effects of phosphate binders on vitamin D metabolism in chronic kidney disease.

BACKGROUND: Phosphate binders are commonly used in the treatment of patients with hyperphosphatemia. While phosphate binders are used to lower phosphate, the effects of specific phosphate binder types on vitamin D metabolism are unknown. METHODS: We performed a secondary analysis of the Phosphate Normalization Trial in which patients with moderate to advanced chronic kidney disease were randomized to receive either placebo, sevelamer carbonate, lanthanum carbonate or calcium acetate for 9 months. We evaluated changes in serum concentrations of vitamin D metabolites including 24,25-dihydroxyvitamin D3 [24,25(OH)2D3], 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], the ratio of 24,25(OH)2D3 to 25-hydroxyvitamin D [the vitamin D metabolite ratio (VMR)] and the ratio of serum 1,25(OH)2D to 25-hydroxyvitamin D. RESULTS: Compared with placebo, randomization to the calcium acetate arm was associated with a 0.6 ng/mL (95% CI 0.2, 1) and 13.5 pg/ng (95% CI 5.5, 21.5) increase in 24,25(OH)2D and VMR, respectively, and a 5.2 pg/mL (95% CI 1.1, 9.4) reduction in 1,25(OH)2D. Randomization to sevelamer carbonate was associated with a 0.5 ng/mL (95% CI -0.9, -0.1) and 11.8 pg/ng (95% CI -20, -3.5) reduction in 24,25(OH)2D3 and VMR, respectively. There was no association of the sevelamer arm with the change in 1,25(OH)2D3, and randomization to lanthanum carbonate was not associated with a change in any of the vitamin D metabolites. CONCLUSION: Administration of different phosphate binders to patients with moderate to severe CKD results in unique changes in vitamin D metabolism.

Serum Calcitriol Concentrations and Kidney Function Decline, Heart Failure, and Mortality in Elderly Community-Living Adults: The Health, Aging, and Body Composition Study.

RATIONALE & OBJECTIVES: Lower 25-hydroxyvitamin D concentrations have been associated with risk for kidney function decline, heart failure, and mortality. However, 25-hydroxyvitamin D requires conversion to its active metabolite, calcitriol, for most biological effects. The associations of calcitriol concentrations with clinical events have not been well explored. STUDY DESIGN: Case-cohort study. SETTING & PARTICIPANTS: Well-functioning community-living older adults aged 70 to 79 years at inception who participated in the Health, Aging, and Body Composition (Health ABC) Study. PREDICTOR: Serum calcitriol measured using positive ion electrospray ionization-tandem mass spectrometry. OUTCOMES: Major kidney function decline (≥30% decline in estimated glomerular filtration rate from baseline), incident heart failure (HF), and all-cause mortality during 10 years of follow-up. ANALYTIC APPROACH: Baseline calcitriol concentrations were measured in a random subcohort of 479 participants and also in cases with major kidney function decline [n=397]) and incident HF (n=207) during 10 years of follow-up. Associations of serum calcitriol concentrations with these end points were evaluated using weighted Cox regression to account for the case-cohort design, while associations with mortality were assessed in the subcohort alone using unweighted Cox regression. RESULTS: During 8.6 years of mean follow-up, 212 (44%) subcohort participants died. In fully adjusted models, each 1-standard deviation lower calcitriol concentration was associated with 30% higher risk for major kidney function decline (95% CI, 1.03-1.65; P=0.03). Calcitriol was not significantly associated with incident HF (HR, 1.16; 95% CI, 0.94-1.47) or mortality (HR, 1.01; 95% CI, 0.81-1.26). We observed no significant interactions between calcitriol concentrations and chronic kidney disease status, baseline intact parathyroid or fibroblast factor 23 concentrations. LIMITATIONS: Observational study design, calcitriol measurements at a single time point, selective study population of older adults only of white or black race. CONCLUSIONS: Lower calcitriol concentrations are independently associated with kidney function decline in community-living older adults. Future studies will be needed to clarify whether these associations reflect lower calcitriol concentrations resulting from abnormal kidney tubule dysfunction or direct mechanisms relating lower calcitriol concentrations to more rapid loss of kidney function.

Relationship of femoral artery ultrasound measures of atherosclerosis with chronic kidney disease.

BACKGROUND: Chronic kidney disease (CKD) is strongly associated with peripheral artery disease (PAD). Detection of subclinical PAD may allow early interventions for or prevention of PAD in persons with CKD. Whether the presence of atherosclerotic plaque and femoral intima-media thickness (IMT) are associated with kidney function is unknown. METHODS: We performed a cross-sectional observational study of 1029 community-living adults. We measured superficial and common femoral artery IMT and atherosclerotic plaque presence by ultrasound. Estimated glomerular filtration rate (eGFR; continuous) and eGFR <60 mL/min/1.73 m2 (binary) were evaluated as outcomes. RESULTS: Mean age was 70 ± 10 years, mean eGFR was 78 ± 17 mL/min/1.73 m2, and 156 (15%) individuals had eGFR <60 mL/min/1.73 m2; 260 (25%) had femoral artery plaque. In models adjusted for demographics and cardiovascular risk factors, individuals with femoral artery plaque had mean eGFR approximately 3.0 (95% confidence interval, -5.3 to -0.8) mL/min/1.73 m2 lower than those without plaque (P < .01). The presence of plaque was also associated with a 1.7-fold higher odds of eGFR <60 mL/min/1.73 m2 (95% confidence interval, 1.1-2.8; P < .02). Associations were similar in persons with normal ankle-brachial index. The directions of associations were similar for femoral IMT measures with eGFR and CKD but were rendered no longer statistically significant with adjustment for demographic variables and cardiovascular disease risk factors. CONCLUSIONS: Femoral artery plaque is significantly associated with CKD prevalence in community-living individuals, even among those with normal ankle-brachial index. Femoral artery ultrasound may allow evaluation of relationships and risk factors linking PAD and kidney disease earlier in its course.

Nicotinamide and phosphate homeostasis in chronic kidney disease.

PURPOSE OF REVIEW: Higher serum phosphate concentration is a central driver of the chronic kidney disease (CKD) mineral bone disorder (MBD). Although phosphate binders are commonly used to lower phosphate, they are minimally effective in CKD. Nicotinamide (vitamin B3) decreases intestinal phosphate transport in animals. Its efficacy and safety in CKD is uncertain. RECENT FINDINGS: We review data differentiating nicotinamide from nicotinic acid (niacin) and compare the metabolism and side-effect profile of each. Several recent studies have tested the safety and efficacy of nicotinamide in patients with CKD and the general population. Available data on efficacy and safety, gaps in knowledge, and ongoing studies to address them are described. SUMMARY: Nicotinamide is a novel potential tool to treat hyperphosphatemia in patients with CKD, but additional data on safety and efficacy are required before widespread clinical use.

CKD-induced wingless/integration1 inhibitors and phosphorus cause the CKD-mineral and bone disorder.

In chronic kidney disease, vascular calcification, renal osteodystrophy, and phosphate contribute substantially to cardiovascular risk and are components of CKD-mineral and bone disorder (CKD-MBD). The cause of this syndrome is unknown. Additionally, no therapy addresses cardiovascular risk in CKD. In its inception, CKD-MBD is characterized by osteodystrophy, vascular calcification, and stimulation of osteocyte secretion. We tested the hypothesis that increased production of circulating factors by diseased kidneys causes the CKD-MBD in diabetic mice subjected to renal injury to induce stage 2 CKD (CKD-2 mice). Compared with non-CKD diabetic controls, CKD-2 mice showed increased renal production of Wnt inhibitor family members and higher levels of circulating Dickkopf-1 (Dkk1), sclerostin, and secreted klotho. Neutralization of Dkk1 in CKD-2 mice by administration of a monoclonal antibody after renal injury stimulated bone formation rates, corrected the osteodystrophy, and prevented CKD-stimulated vascular calcification. Mechanistically, neutralization of Dkk1 suppressed aortic expression of the osteoblastic transcription factor Runx2, increased expression of vascular smooth muscle protein 22-α, and restored aortic expression of klotho. Neutralization of Dkk1 did not affect the elevated plasma levels of osteocytic fibroblast growth factor 23 but decreased the elevated levels of sclerostin. Phosphate binder therapy restored plasma fibroblast growth factor 23 levels but had no effect on vascular calcification or osteodystrophy. The combination of the Dkk1 antibody and phosphate binder therapy completely treated the CKD-MBD. These results show that circulating Wnt inhibitors are involved in the pathogenesis of CKD-MBD and that the combination of Dkk1 neutralization and phosphate binding may have therapeutic potential for this disorder.

Early chronic kidney disease-mineral bone disorder stimulates vascular calcification.

The chronic kidney disease-mineral and bone disorder (CKD-MBD) syndrome is an extremely important complication of kidney diseases. Here we tested whether CKD-MBD causes vascular calcification in early kidney failure by developing a mouse model of early CKD in a background of atherosclerosis-stimulated arterial calcification. CKD equivalent in glomerular filtration reduction to human CKD stage 2 stimulated early vascular calcification and inhibited the tissue expression of α-klotho (klotho) in the aorta. In addition, osteoblast transition in the aorta was stimulated by early CKD as shown by the expression of the critical transcription factor Runx2. The ligand associated with the klotho-fibroblast growth factor receptor complex, FGF23, was found to be expressed in the vascular media of sham-operated mice. Its expression was decreased in early CKD. Increased circulating levels of the osteocyte-secreted proteins, FGF23, and sclerostin may have been related to increased circulating klotho levels. Finally, we observed low-turnover bone disease with a reduction in bone formation rates more than bone resorption. Thus, the CKD-MBD, characterized by cardiovascular risk factors, vascular calcification, increased circulating klotho, FGF23 and sclerostin levels, and low-turnover renal osteodystrophy, was established in early CKD. Early CKD caused a reduction of vascular klotho, stimulated vascular osteoblastic transition, increased osteocytic secreted proteins, and inhibited skeletal modeling producing the CKD-MBD.

Left ventricular mass progression despite stable blood pressure and kidney function in stage 3 chronic kidney disease.

BACKGROUND/AIMS: Progressive chronic kidney disease (CKD) is associated with worsening cardiovascular (CV) risk not explained by traditional risk factors. Left ventricular (LV) hypertrophy (LVH) is an important CV risk factor, but its progression has not been documented in early CKD. We explored whether progression of LVH in early CKD would occur despite stable kidney function. METHODS: We conducted a post hoc analysis of a 12-month study of lanthanum carbonate in stage 3 CKD, which included longitudinal assessments of CV biomarkers. Primary outcome for the analysis was the change in LV mass (LVM) indexed to height in meters(2.7) (LVM/Ht(2.7)). Secondary outcomes were changes in blood pressure (BP), pulse-wave velocity, LV systolic/diastolic function, fibroblast growth factor 23 (FGF23), klotho, and estimated glomerular filtration rate (eGFR). RESULTS: Thirty-one of 38 original subjects had sufficient data for analysis. LVM/Ht(2.7) increased (47 ± 13 vs. 53 ± 13 g/m(2.7), p = 0.006) over 12 months despite stable BP, stable eGFR and normal LV systolic function. Vascular stiffness and LV diastolic dysfunction persisted throughout the study. Klotho levels decreased (748 ± 289 to 536 ± 410 pg/ml, p = 0.03) but were unrelated to changes in LVM/Ht(2.7). The change in FGF23/klotho ratio was strongly correlated with changes in LVM/Ht(2.7) (r2 = 0.582, p = 0.03). CONCLUSION: Subjects with stage 3 CKD exhibited increasing LVM, persistent LV diastolic dysfunction and vascular stiffness despite stable kidney function, BP and LV systolic function. Abnormal FGF23 signaling due to reduced klotho expression may be associated with increasing LVM.

The Vitamin D Metabolite Ratio Is Associated With Volumetric Bone Density in Older Men.

CONTEXT: Serum 25-hydroxyvitamin D (25(OH)D) is the current marker of vitamin D adequacy, but its relationship with bone health has been inconsistent. The ratio of 24,25-dihydroxyvitamin D3 to 25(OH)D3 (vitamin D metabolite ratio or VMR) is a marker of vitamin D that has been associated with longitudinal changes in bone mineral density (BMD) and fracture risk. OBJECTIVE: High-resolution peripheral quantitative computed tomography (HR-pQCT) provides information on bone health beyond standard dual-energy x-ray absorptiometry, in that it measures volumetric BMD (vBMD) as well bone strength. The relationship of the VMR with vBMD and bone strength remains unknown. METHODS: We evaluated the associations of the VMR and 25(OH)D3 with vBMD and bone strength in the distal radius and tibia, assessed by HR-pQCT in 545 older men participating in the Osteoporotic Fractures in Men (MrOS) Study. Primary outcomes were vBMD and estimated failure load (EFL, a marker of bone strength) at the distal radius and tibia. RESULTS: The mean age was 84 ± 4 years, 88.3% were White, and 32% had an estimated glomerular filtration rate <60 mL/min/1.73 m2. In adjusted models, each twofold higher VMR was associated with a 9% (3%, 16%) higher total vBMD and a 13% (5%, 21%) higher EFL at the distal radius. Results were similar at the distal tibia. 25(OH)D3 concentrations were not associated with any of the studied outcomes. CONCLUSION: Among older men, a higher VMR was associated with greater vBMD and bone strength while 25(OH)D3 was not. The VMR may serve as a valuable marker of skeletal health in older men.

Risk factors for hip and vertebral fractures in chronic kidney disease: the CRIC study.

Fracture risk is high in chronic kidney disease (CKD) and underlying pathophysiology and risk factors may differ from the general population. In a cohort study of 3939 participants in the chronic renal insufficiency cohort (CRIC), we used Cox regression to test associations of putative risk factors with the composite of first hip or vertebral fracture assessed using hospital discharge codes. Mean age was 58 years, 45% were female, 42% were Black, and 13% were Hispanic. There were 82 hip and 24 vertebral fractures over a mean (SD) 11.1 (4.8) years (2.4 events per 1000 person-years [95% CI: 2.0, 2.9]). Measured at baseline, diabetes, lower body mass index (BMI), steroid use, proteinuria, and elevated parathyroid hormone (PTH) were each associated with fracture risk after adjusting for covariates. Lower time-updated estimated glomerular filtration rate (eGFR) was associated with fractures (HR 1.20 per 10 mL/min/1.73m2 lower eGFR; 95% CI: 1.04, 1.38) as were lower time-updated serum calcium and bicarbonate concentrations. Among time-updated categories of kidney function, hazard ratios (95% CI) for incident fracture were 4.53 (1.77, 11.60) for kidney failure treated with dialysis and 2.48 (0.86, 7.14) for post-kidney transplantation, compared with eGFR ≥60. Proton pump inhibitor use, dietary calcium intake, measures of vitamin D status, serum phosphate, urine calcium and phosphate, and plasma fibroblast growth factor-23 were not associated with fracture risk. In conclusion, lower eGFR in CKD is associated with higher fracture risk, which was highest in kidney failure. Diabetes, lower BMI, steroid use, proteinuria, higher serum concentrations of PTH, and lower calcium and bicarbonate concentrations were associated with fractures and may be modifiable risk factors.

People with chronic kidney disease are at high risk of fractures. Our research assessed the relationship between several patient characteristics and the risk of fractures in 3939 patients with chronic kidney disease. We found that the following characteristics were associated with a higher risk of a hip or spine fracture: having diabetes, lower body mass index, use of steroid-containing medications, lower kidney filtration rate ("eGFR"), higher amounts of protein spilled in the urine, lower calcium and bicarbonate levels, and higher parathyroid hormone levels. Future studies should assess if improving these characteristics decreases the risk of fractures in patients with chronic kidney disease.

Difference between kidney function by cystatin C versus creatinine and association with muscle mass and frailty.

BACKGROUND: A higher difference in estimated glomerular filtration rate by cystatin C versus creatinine (eGFRDiff = eGFRCys - eGFRCreat) is associated with decreased frailty risk. Since eGFRCreat is influenced by muscle more than eGFRCys, muscle mass may explain this association. Previous work could not account for this when considering regional muscle measures by imaging. Deuterated creatine (D3Cr) dilution measures whole body muscle mass (kilograms). We aimed to determine whether eGFRDiff is associated with D3Cr muscle mass and whether muscle mass explains the association between eGFRDiff and frailty. METHODS: Cross-sectional analysis within the multicenter MrOS Study at Year 14 (visit 4). 490 men of the original cohort of 5994 MrOS participants (aged ≥65 at enrollment) were included. Exposure was eGFRDiff (= eGFRCys - eGFRCreat), calculated using CKD-EPI equations 2012/2021. Primary outcome was D3Cr muscle mass. Secondary outcome was phenotypic pre-frailty (one or two criteria) and frailty (≥three criteria) including the following: weight loss, weakness, slow gait, physical activity, poor energy. The association of eGFRDiff with D3Cr muscle mass was examined by linear regression, that with prefrailty / frailty by multinomial logistic regression. RESULTS: Mean ± SD age was 84 ± 4 years, eGFRCreat 68 ± 16, eGFRCys 52 ± 16, eGFRDiff -15 ± 12 mL/min/1.73 m2 and D3Cr muscle mass 24 ± 4 kg. For each SD increment in eGFRDiff, D3Cr muscle mass was 1.4 kg higher on average, p < 0.0001 (fully adjusted). Higher eGFRDiff was associated with lower odds of frailty (OR = 0.63 95% CI [0.45;0.89]), but this was partially attenuated and insignificant after additionally adjusting for D3Cr muscle mass (OR = 0.85 95% CI [0.58; 1.24]). CONCLUSIONS: Higher eGFRDiff is associated with lower odds of frailty among late-life men. D3Cr muscle mass accounts for some of this association. This suggests that non-GFR determinants of creatinine and cystatin C, such as muscle mass, play a role in explaining the association of eGFRDiff with frailty. Future studies are needed to confirm.

32-year-old diabetic patient with progressive vision loss and crystalline retinopathy.

PURPOSE: To report the case of severe bilateral retinal vascular occlusion in a patient with hyperoxalosis and chronic renal failure. METHODS: Observational case report. Medical and imaging records were retrospectively reviewed. The patient was imaged with ultra-widefield (UWF) fundus photography and fluorescein angiography (UWF-FA), cross sectional and en face spectral-domain optical coherence tomography (SD-OCT), and OCT angiography. RESULTS: A 32-year-old diabetic patient receiving peritoneal dialysis was referred because of severe vision loss. UWF color fundus photography showed diffuse sclerotic retinal vessels and diffuse intraretinal crystals in both eyes. UWF-FA illustrated near-complete retinal vascular occlusion and capillary wipe out in both eyes. SD-OCT demonstrated diffuse inner and middle retina thinning in both eyes and multiple intraretinal hyperreflective foci consistent with crystalline deposits in all retina layers of both eyes. OCT angiography revealed severe capillary and large vessel non-perfusion in the superficial and deep retinal capillary plexus of each eye. The serum oxalate levels were increased at 28 µmol/L (reference range < 2 µmol/L) and genetic testing was positive for a heterozygous mutation of the AGXT (Alanine-Glyoxylate Amino Transferase) gene that causes type 1 autosomal recessive primary hyperoxaluria. CONCLUSION: A diagnosis of hyperoxalosis causing severe retinal vascular occlusion was rendered. Hyperoxalosis was the result of multiple factors including heterozygous AGXT mutation, chronic renal failure insufficiently treated with peritoneal dialysis, and a diet high in oxalate. This case highlights the importance of ruling out retinal oxalosis in patients on peritoneal dialysis in order to initiate prompt hemodialysis and prevent severe retinal vascular occlusion.

Development and Validation of Novel Free Vitamin D Equations: The Health Aging and Body Composition Study.

Vitamin D deficiency is prevalent in 25% of Americans. However, 25(OH)D may not be an accurate measure of vitamin D because the majority (85%-90%) of 25(OH)D is bound to vitamin D binding protein (VDBP), which varies by over 30% across individuals. Free 25(OH)D may be a better measure, but it is difficult to measure accurately and precisely. The existing free 25(OH)D estimating equation does not include VDBP phenotypes; therefore, new equations that include this variable may be more accurate. A total of 370 participants in the Health, Aging, and Body Composition Study, a cohort of healthy community-dwelling individuals aged 70-79 years old, underwent VDBP and vitamin D metabolite [25(OH)D, 24,25(OH)2D, 1,25(OH)2D, free 25(OH)D] measurements and were randomly allocated into equation development (two out of three) and internal validation (one out of three) groups. New equations were developed with multiple linear regression and were internally validated with Bland-Altman plots. The mean age was 75 ± 3 years, 53% were female, and the mean measured free 25(OH)D was 5.37 ± 1.81 pg/mL. Three equations were developed. The first equation included albumin, 25(OH)D3, 25(OH)D2, VDBP, 1,25(OH)2D3, and 24,25(OH)2D3. The second equation included all variables in Eq. (1) plus VDBP phenotypes. The third equation included albumin, 25(OH)D3, intact parathyroid hormone, and 1,25(OH)2D3. In internal validation, all three new equations predicted free 25(OH)D values within 30% and 15% of the measured free 25(OH)D concentrations in 76%-80% and 48%-52% of study participants, respectively. Equation (2) was the most precise, with a mean bias of 0.06 (95% limits of agreement -2.41 to 2.30) pg/mL. The existing equation estimated free 25(OH)D within 30% and 15% of measured free 25(OH)D in 43% and 22% of participants, respectively. Free 25(OH)D can be estimated with clinically available biomarkers as well as with more laboratory-intensive biomarkers with moderate precision. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Vitamin D Metabolites and Risk of Cardiovascular Disease in Chronic Kidney Disease: The CRIC Study.

Background The ratio of 24,25-dihydroxyvitamin D3/25-hydroxyvitamin D3 (vitamin D metabolite ratio [VDMR]) may reflect functional vitamin D activity. We examined associations of the VDMR, 25-hydroxyvitamin D (25[OH]D), and 1,25-dihydroxyvitamin D (1,25[OH]2D) with cardiovascular disease (CVD) in patients with chronic kidney disease. Methods and Results This study included longitudinal and cross-sectional analyses of 1786 participants from the CRIC (Chronic Renal Insufficiency Cohort) Study. Serum 24,25-dihydroxyvitamin D3, 25(OH)D, and 1,25(OH)2D were measured by liquid chromatography-tandem mass spectrometry 1 year after enrollment. The primary outcome was composite CVD (heart failure, myocardial infarction, stroke, and peripheral arterial disease). We used Cox regression with regression-calibrated weights to test associations of the VDMR, 25(OH)D, and 1,25(OH)2D with incident CVD. We examined cross-sectional associations of these metabolites with left ventricular mass index using linear regression. Analytic models adjusted for demographics, comorbidity, medications, estimated glomerular filtration rate, and proteinuria. The cohort was 42% non-Hispanic White race and ethnicity, 42% non-Hispanic Black race and ethnicity, and 12% Hispanic ethnicity. Mean age was 59 years, and 43% were women. Among 1066 participants without prevalent CVD, there were 298 composite first CVD events over a mean follow-up of 8.6 years. Lower VDMR and 1,25(OH)2D were associated with incident CVD before, but not after, adjustment for estimated glomerular filtration rate and proteinuria (hazard ratio, 1.11 per 1 SD lower VDMR [95% CI, 0.95-1.31]). Only 25(OH)D was associated with left ventricular mass index after full covariate adjustment (0.6 g/m2.7 per 10 ng/mL lower [95% CI, 0.0-1.3]). Conclusions Despite modest associations of 25(OH)D with left ventricular mass index, 25(OH)D, the VDMR, and 1,25(OH)2D were not associated with incident CVD in chronic kidney disease.

Renal Clearance of Fibroblast Growth Factor-23 (FGF23) and its Fragments in Humans.

Relative abundance of fibroblast growth factor-23 (FGF23) measured by the C-terminal (cFGF23, which measures both intact FGF23 and C-terminal fragments) versus intact (iFGF23, measures only intact hormone) assays varies by kidney function in humans. Differential kidney clearance may explain this finding. We measured cFGF23 and iFGF23 in the aorta and bilateral renal veins of 162 patients with essential hypertension undergoing renal angiography. Using multivariable linear regression, we examined factors associated with aorta to renal vein reduction of FGF23 using both assays. Similar parameters and with addition of urine concentrations of cFGF23 and iFGF23 were measured in six Wistar rats. Mean ± standard deviation (SD) age was 54 ± 12 years, 54% were women, and mean creatinine clearance was 72 ± 48 mL/min/100 g. The human kidney reduced the concentrations of both cFGF23 (16% ± 12%) and iFGF23 (21% ± 16%), but reduction was higher for iFGF23. Greater kidney creatinine and PTH reductions were each independently associated with greater reductions of both cFGF23 and iFGF23. The greater kidney reduction of iFGF23 compared to cFGF23 appeared stable and consistent across the range of creatinine clearance evaluated. Kidney clearance was similar, and urine concentrations of both assays were low in the rat models, suggesting kidney metabolism of both cFGF23 and iFGF23. Renal reduction of iFGF23 is higher than that of creatinine and cFGF23. Our data suggest that FGF23 is metabolized by the kidney. However, the major cell types involved in metabolization of FGF23 requires future study. Kidney clearance of FGF23 does not explain differences in C-terminal and intact moieties across the range of kidney function. © 2022 American Society for Bone and Mineral Research (ASBMR).