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Purpose: This study was undertaken to evaluate the safety and efficacy of CSF-1 (0.4% pilocarpine hydrochloride ophthalmic solution) for use in individuals with presbyopia., Methods: Two Phase 3 multicenter, randomized, double-masked, vehicle-controlled, parallel-group clinical trials were conducted in 35 private ophthalmology clinics in the United States from October 2020 to February 2022. Key inclusion criteria were the following: (1) age 45-64 years, (2) distance-corrected near visual acuity (DCNVA) at 40 cm ≥0.40 and ≤0.90 logarithm of the minimum angle of resolution (logMAR, approximately 20/50-20/160 Snellen) in at least 1 eye, (3) manifest refraction (MR) between -4.50 and +2.00 diopter (D) sphere in each eye with ≤2.00D difference between eyes, (4) <2.00D of cylinder MR in each eye, (5) ≤0.04 logMAR (20/20-2 or better) corrected distance visual acuity (CDVA) at 4 m in each eye. Key exclusion criteria were the following: (1) >0.14 logMAR (7 letters) improvement in post-vehicle treatment in monocular DCNVA in either eye at visit 1, (2) introcular pressure (IOP) <9 or >22 mm Hg, (3) average dark-adapted pupillometry <3.5 mm in either eye, (4) prior refractive surgery or intraocular lens (IOL) implantation. Participants applied CSF-1 or vehicle twice per day for 2 weeks. Efficacy and safety assessments were performed at several times on days 1, 8, and 15. Response was defined as ≥3-line gain in DCNVA without loss of ≥1-line in CDVA in the study eye under mesopic room lighting conditions. The primary efficacy endpoint was measured 1 hour post-dose 1 on day 8. Key secondary endpoints were 2 hours post-dose 1, and 1 and 2 hours post-dose 2, also on day 8. Safety endpoints were ocular and non-ocular treatment-related adverse events (TRAE), conjunctival redness, drop comfort, slit-lamp biomicroscopy, intraocular pressure, indirect fundoscopy, and CDVA at 4 m., Findings: Six hundred thirteen participants were randomized to CSF-1 (n = 309) or vehicle (n = 304). Participants were predominantly White (80.8%) and female (62.0%), with mean age (standard deviation) of 54.7 (4.8). CSF-1 met the primary and key secondary endpoints. At the primary endpoint, 40.1% of the CSF-1 group achieved response versus 19.1% of the vehicle group (P < 0.0001). The percentage of responders was significantly greater in CSF-1 compared with vehicle at all tested times. Changes from baseline in all safety endpoints were comparable between groups. Most adverse events (AEs) were mild and transient. Neither serious nor severe AEs were reported with CSF-1., Implications: CSF-1, a low-dose pilocarpine ophthalmic solution, demonstrated superiority to vehicle in improving near vision in individuals with presbyopia without compromising distance vision. CSF-1 demonstrated a favorable safety profile., Clinicaltrials: gov identifier: NCT04599933 (NEAR-1), NCT04599972 (NEAR-2)., Competing Interests: Declaration of competing interest Edward Holland is a consultant for Alcon, Aurion Biotech and Orasis. Paul Karpecki is a consultant for Alcon, Aldeyra, Allergan/Abbvie, Apellis, Atlas, Aurion, Avellino, Azura, B+L, BioTissue, Bruder, Bruno, Dompe, Eyedetec, Healthe, Horizon, Imprimis, Iveric, Konan, Mitotech, Neurolens, Novartis, Oasis Medical, Ocuphire, Oculus, OcuMedic, OcuSoft, Olympic Ophthalmics, Orasis, RegenerEyes, Rendia, Reichert, RVL, RxSight, Santen, Science Based Health, Scope, Sentiss, Sight Sciences, Silk Technologies, Sun Pharmaceuticals, Surface, Sydnexis, Tarsus, TearClear, Thea, Vial, Viatris, Visant Medical, Vital Tears, WebMD and is part of the Speaker's Bureau for Bausch + Lomb, Dompe, Mallinckrodt and Sun pharmaceuticals. Murray Fingeret is a consultant for Alcon, Allergan, Bausch + Lomb, Carl Zeiss Meditec, Glaukos, Orasis, Topcon, Tarsus Therapeutics, Visus Therapeutics. Jack Schaeffer has received honorarium, compensation, or serves as an advisor to Alcon, Allergan, AMO/Abbott, Arctic/DX, Bausch & Lomb, Brien Holden Institute, Bruder, Coopervision, Clearpath, Essilor, Hoya, Miboflow, Nicox, Optovue, Optos, Orasis, Sydnexis, Sight Science, Reed, Rodenstock, Tarsus, Tearscience, Topcon, Valeant, Vistakon, WebMD/Jobson, Zeiss Vision. Preeya Gupta is a consultant for Azura, Alcon, Aldeyra, Allergan, Expert Opinion, HanAll Biopharma, J&J Vision, Kala, New World Medical, Novartis, Ocular Science, Ocular Therapeutix, Orasis, Oyster Point, Santen, Sight Sciences, Spyglass, Surface Ophthalmics, Sun Pharmaceuticals, Tarsus, Tear Lab, Tear Clear, Tissue Tech, Inc, Visionology, Zeiss and has stock options for Azura, Expert Opinion, Orasis, Tarsus, Tear Clear, Surface, Spyglass, Visionology, Visant. Nicole Fram is on the Medical Advisory Board of Orasis. Gerard Smits is a consultant for Orasis. Teresa Ignacio is an employee of Orasis. Richard Lindstrom is a consultant for Allergan and J&J Vision, and is a shareholder and part of the medical advisory board of Orasis Pharmaceuticals., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: To compare the prediction accuracy of the Argos biometer using standard keratometry to the prediction accuracy of the IOLMaster 700 biometer using Total Keratometry., Methods: This was a randomized, prospective, single surgeon study of 80 right eyes of 80 patients that had preoperative biometry with both the Argos and IOLMaster 700 devices, followed by cataract surgery and intraocular lens (IOL) implantation. Prediction errors (directional and absolute) for each device were determined from the 1 month postoperative manifest refraction., Results: The directional prediction error was 0.07 ± 0.32 D for the Argos and 0.08 ± 0.34 D for the IOLMaster 700. The mean of the difference in prediction error (directional) was 0.02 D, which was not statistically significant (p > 0.05). The absolute prediction error was 0.21 ± 0.25 D for the Argos and 0.25 ± 0.24 D for the IOLMaster 700. The mean of the difference in absolute prediction error was 0.04 D, which was statistically significant (p < 0.004) but not clinically significant. The percentage of eyes with absolute prediction error ≤ 0.5 D was 91% (73 eyes) for the Argos and 88% (70 eyes) for the IOLMaster 700. This difference was not statistically significant., Conclusion: The prediction accuracies were similar between the Argos and IOLMaster 700 in eyes with normal axial length. There was a significant difference in mean absolute prediction error between devices; however, this was not clinically meaningful., Competing Interests: Sam Multack reports consulting fees from Alcon Vision LLC, EyeCheck LLC, and EyeDX LLC. Gerard Smits reports consulting fees from Carl Zeiss Meditec. Brad Hall reports consulting fees from Ace Vision Group. The authors report no other conflicts of interest in this work., (© 2023 Multack et al.)

Background: Oral microbial therapy has been studied as an intervention for a range of gastrointestinal disorders. Though research suggests that microbial exposure may affect the gastrointestinal system, motility, and host immunity in a pediatric population, data have been inconsistent, with most prior studies being in neither a randomized nor placebo-controlled setting. The aim of this randomized, placebo-controlled study was to evaluate the efficacy of a synbiotic on increasing weekly bowel movements (WBMs) in constipated children., Methods: Sixty-four children (3-17 years of age) were randomized to receive a synbiotic (n = 33) comprising mixed-chain length oligosaccharides and nine microbial strains, or placebo (n = 31) for 84 days. Stool microbiota was analyzed on samples collected at baseline and completion. The primary outcome was a change from baseline of WBMs in the treatment group compared to placebo., Results: Treatment increased (p < 0.05) the number of WBMs in children with low baseline WBMs, despite broadly distinctive baseline microbiome signatures. Sequencing revealed that low baseline microbial richness in the treatment group significantly anticipated improvements in constipation (p = 0.00074)., Conclusions: These findings suggest the potential for (i) multi-species-synbiotic interventions to improve digestive health in a pediatric population and (ii) bioinformatics-based methods to predict response to microbial interventions in children., Impact: Synbiotic microbial treatment improved the number of spontaneous weekly bowel movements in children compared to placebo. Intervention induced an increased abundance of bifidobacteria in children, compared to placebo. All administered probiotic species were enriched in the gut microbiome of the intervention group compared to placebo. Baseline microbial richness demonstrated potential as a predictive biomarker for response to intervention., (© 2022. The Author(s).)

Purpose: To compare the astigmatism prediction accuracy for toric intraocular lens (IOL) implantation between two swept-source optical coherence tomography (SS-OCT) devices: Argos (Movu, a Santec Company) and the IOLMaster 700 (Carl Zeiss Meditec)., Methods: This was a retrospective chart review of 59 eyes (44 patients) with corneal astigmatism and cataract that underwent cataract surgery or refractive lens exchange surgery with a toric IOL. Biometry was performed on all patients prior to cataract surgery and the Barrett toric IOL calculator was used. Visual acuity was measured postoperatively. Manifest refraction was measured at 1 month and compared to the predicted postoperative residual refraction. Preoperative K measurements between devices were also compared., Results: Mean cylinder prediction error was -0.17 ± 0.43 for Argos and 0.12 ± 0.56 for IOLMaster 700. The cylinder prediction error 0.5 D or less was not significantly different between the devices, with 83.1% (49 eyes) for Argos and 76.3% (45 eyes) for IOLMaster 700 (p = 0.206). Spherical equivalent prediction error was 0.13 ± 0.39 for Argos and 0.25 ± 0.50 for IOLMaster 700. The mean spherical equivalent prediction error 0.5 D or less was significantly different between the devices, with 79.7% (47 eyes) for Argos and 61.0% (36 eyes) for IOLMaster 700 (p = 0.016)., Conclusion: The prediction accuracies were similar between the devices, except for spherical equivalent, where a higher percentage of eyes were 0.5 D or less of the prediction with the Argos compared to the IOLMaster., Competing Interests: Robert F. Melendez reports that he is a consultant for Alcon Laboratories. Gerard Smits reports personal fees from Juliette Eye during the conduct of this study; and that he is a consultant for Zeiss Medical. Brad Hall reports personal fees from Juliette Eye during the conduct of this study; personal fees from Ace Vision Group, outside the submitted work. The authors report no other conflicts of interest for this work., (© 2022 Melendez et al.)

Purpose: The purpose of this study was to compare the Barrett (BTC) and Emmetropia Verifying Optical (EVO) Toric Calculators' performance with regards to prediction of residual post-operative astigmatism after cataract surgery., Methods: This was a secondary analysis of de-identified data that was collected as part of a prospective multicenter clinical trial in which 109 eyes from 109 patients were implanted with a monofocal toric intraocular lens (IOL). Post-operative biometry was used to calculate the predicted post-operative residual astigmatism for each eye using the two different calculators. The vector difference between the actual and predicted residual astigmatism was calculated., Results: The mean absolute astigmatism prediction errors were 0.59 ± 0.38 D and 0.59 ± 0.36 D for the BTC and EVO calculators, respectively (p = 0.98). The centroid of the prediction errors were 0.18 D @ 89° ± 0.68 D and 0.20 D @ 89° ± 0.66 D, respectively (p = 0.21). The proportion of eyes in which the astigmatism prediction error was ≤0.5 D was 50% for BTC and 46% for EVO (p = 0.28). The proportion of eyes in which the post-operative astigmatism orientation was correctly predicted as being against-the-rule, with-the-rule, or oblique was 81% for BTC and 77% for EVO (p = 0.15)., Conclusion: The Barrett and Emmetropia Verifying Optical Toric Calculators had similar performance with regards to their astigmatism prediction accuracy., Competing Interests: SMP serves as an advisory board member and consultant for Carl Zeiss Meditec, he is also a consultant for Bausch & Lomb and reports an unrestricted research grant from Bausch & Lomb to cover the open-access publication fees associated with this work. GS is a consultant for Bausch & Lomb and reports remuneration for his assistance with statistical analysis. The authors report no other conflicts of interest in this work., (© 2022 Pantanelli et al.)

Objective: This report presents a cross-sectional analysis of the baseline characteristics of subjects with Leber hereditary optic neuropathy enrolled in the gene therapy trials RESCUE and REVERSE, to illustrate the evolution of visual parameters over the first year after vision loss., Methods: RESCUE and REVERSE were 2 phase III clinical trials designed to assess the efficacy of rAAV2/2-ND4 gene therapy in ND4-LHON subjects. At enrollment, subjects had vision loss for ≤6 months in RESCUE, and between 6 and 12 months in REVERSE. Functional visual parameters (best-corrected visual acuity [BCVA], contrast sensitivity [CS], and Humphrey Visual Field [HVF]) and structural parameters assessed by spectral-domain optical coherence tomography were analyzed in both cohorts before treatment. The cross-sectional analysis of functional and anatomic parameters included the baseline values collected in all eyes at 2 different visits (Screening and Inclusion)., Results: Seventy-six subjects were included in total, 39 in RESCUE and 37 in REVERSE. Mean BCVA was significantly worse in RESCUE subjects compared with REVERSE subjects (1.29 and 1.61 LogMAR respectively, P = 0.0029). Similarly, mean CS and HVF were significantly more impaired in REVERSE vs RESCUE subjects (P < 0.005). The cross-sectional analysis showed that the monthly decrease in BCVA, ganglion cell layer macular volume, and retinal nerve fiber layer thickness was much more pronounced in the first 6 months after onset (+0.24 LogMAR, -0.06 mm3, and -6.00 μm respectively) than between 6 and 12 months after onset (+0.02 LogMAR, -0.01 mm3, and -0.43 μm respectively)., Conclusion: LHON progresses rapidly in the first months following onset during the subacute phase, followed by relative stabilization during the dynamic phase., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the North American Neuro-Opthalmology Society.)

Purpose: To evaluate the efficacy of a single intravitreal injection of rAAV2/2-ND4 in subjects with visual loss from Leber hereditary optic neuropathy (LHON)., Design: RESCUE is a multicenter, randomized, double-masked, sham-controlled, phase 3 clinical trial., Participants: Subjects with the m.11778G>A mitochondrial DNA mutation and vision loss ≤6 months from onset in 1 or both eyes were included., Methods: Each subject's right eye was randomly assigned (1:1) to treatment with rAAV2/2-ND4 (single injection of 9 × 10 10 viral genomes in 90 μl) or to sham injection. The left eye received the treatment not allocated to the right eye., Main Outcome Measures: The primary end point was the difference of the change from baseline in best-corrected visual acuity (BCVA) between rAAV2/2-ND4-treated and sham-treated eyes at week 48. Other outcome measures included contrast sensitivity, Humphrey visual field perimetry, retinal anatomic measures, and quality of life. Follow-up extended to week 96., Results: Efficacy analysis included 38 subjects. Mean age was 36.8 years, and 82% were male. Mean duration of vision loss at time of treatment was 3.6 months and 3.9 months in the rAAV2/2-ND4-treated eyes and sham-treated eyes, respectively. Mean baseline logarithm of the minimum angle of resolution (logMAR) BCVA (standard deviation) was 1.31 (0.52) in rAAV2/2-ND4-treated eyes and 1.26 (0.62) in sham-treated eyes, with a range from -0.20 to 2.51. At week 48, the difference of the change in BCVA from baseline between rAAV2/2-ND4-treated and sham-treated eyes was -0.01 logMAR (P = 0.89); the primary end point of a -0.3 logMAR (15-letter) difference was not met. The mean BCVA for both groups deteriorated over the initial weeks, reaching the worst levels at week 24, followed by a plateau phase until week 48, and then an improvement of +10 and +9 Early Treatment Diabetic Retinopathy Study letters equivalent from the plateau level in the rAAV2/2-ND4-treated and sham-treated eyes, respectively., Conclusions: At 96 weeks after unilateral injection of rAAV2/2-ND4, LHON subjects carrying the m.11778G>A mutation treated within 6 months after vision loss achieved comparable visual outcomes in the injected and uninjected eyes., (Copyright © 2020 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.)

REVERSE is a randomized, double-masked, sham-controlled, multicenter, phase 3 clinical trial that evaluated the efficacy of a single intravitreal injection of rAAV2/2- ND4 in subjects with visual loss from Leber hereditary optic neuropathy (LHON). A total of 37 subjects carrying the m.11778G>A ( MT-ND4 ) mutation and with duration of vision loss between 6 to 12 months were treated. Each subject's right eye was randomly assigned in a 1:1 ratio to treatment with rAAV2/2- ND4 (GS010) or sham injection. The left eye received the treatment not allocated to the right eye. Unexpectedly, sustained visual improvement was observed in both eyes over the 96-week follow-up period. At week 96, rAAV2/2- ND4 -treated eyes showed a mean improvement in best-corrected visual acuity (BCVA) of -0.308 LogMAR (+15 ETDRS letters). A mean improvement of -0.259 LogMAR (+13 ETDRS letters) was observed in the sham-treated eyes. Consequently, the primary end point, defined as the difference in the change in BCVA from baseline to week 48 between the two treatment groups, was not met ( P = 0.894). At week 96, 25 subjects (68%) had a clinically relevant recovery in BCVA from baseline in at least one eye, and 29 subjects (78%) had an improvement in vision in both eyes. A nonhuman primate study was conducted to investigate this bilateral improvement. Evidence of transfer of viral vector DNA from the injected eye to the anterior segment, retina, and optic nerve of the contralateral noninjected eye supports a plausible mechanistic explanation for the unexpected bilateral improvement in visual function after unilateral injection., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Purpose: To compare predictability of postoperative refractive astigmatism (RA) using the Emmetropic Verifying Optical (EVO) Toric Formula v2.0 to one that accounts only for anterior corneal astigmatism., Methods: This is a secondary analysis of de-identified data from a clinical trial including 9 sites across the United States. Preoperative biometry was used to predict postoperative RA with the implanted toric IOL using legacy enVista and EVO online calculators. The RA prediction error was computed between back-calculated postoperative RA and predicted residual RA. Outcome measures included vector (centroid) and arithmetic mean RA prediction error., Results: Comparison of calculators was based on 109 eyes, 97 (89%) of which were implanted with a toric IOL with an effective astigmatism power of 1.4 D or less. Centroid of the RA prediction errors was 0.37 D @ 178 and 0.17 D @ 090 for the legacy and EVO calculators, respectively (p < 0.0001). The proportion of eyes with an absolute RA prediction error ≤0.5 was 47.3% and 49.1% (p = 0.78), while the proportion of eyes ≤1.0 D was 82.7% and 89.1% (p = 0.03). Differences in the proportions ≤0.5 D existed for WTR (p = 0.015) but not ATR (p = 0.75) eyes. The proportion in which orientation of the predicted RA (ATR, WTR, or oblique) matched the actual RA was 62% and 78% for legacy and EVO calculators, respectively (p = 0.0029)., Conclusion: The EVO Toric Formula v2.0 out-performed the legacy calculator with regards to predictions in eyes with low astigmatism., Competing Interests: Author S.M.P. serves as an advisory board member, consultant, and Medical Monitor for Carl Zeiss Meditec, and as a consultant for Bausch & Lomb, and reports personal fees from Bausch & Lomb, during the conduct of the study, and personal fees from Carl Zeiss Meditec, outside the submitted work. Author G.S. serves as a consultant for both Carl Zeiss Meditec and Bausch & Lomb, outside the submitted work. The authors report no other potential conflicts of interest for this work., (© 2020 Pantanelli et al.)

Background: Researchers have yet to determine the optimal care of patients with advanced CKD. Evidence suggests that anemia and CKD-related disordered mineral metabolism (including abnormalities in phosphate and fibroblast growth factor 23 [FGF23]) contribute to adverse outcomes in this population., Methods: To investigate whether fixed-dose ferric citrate coordination complex favorably affects multiple biochemical parameters in patients with advanced CKD, we randomly assigned 203 patients with eGFR≤20 ml/min per 1.73 m 2 2:1 to receive a fixed dose of ferric citrate coordination complex (two tablets per meal, 210 mg ferric iron per tablet) or usual care for 9 months or until 3 months after starting dialysis. No single biochemical end point was designated as primary; sample size was determined empirically., Results: The two groups had generally similar baseline characteristics, although diabetes and peripheral vascular disease were more common in the usual-care group. Ferric citrate coordination complex significantly increased hemoglobin, transferrin saturation, and serum ferritin, and it significantly reduced serum phosphate and intact FGF23 ( P <0.001 for all). Of the 133 patients randomized to ferric citrate coordination complex, 31 (23%) initiated dialysis during the study period, as did 32 of 66 (48%) patients randomized to usual care ( P =0.001). Compared with usual care, ferric citrate coordination complex treatment resulted in significantly fewer annualized hospital admissions, fewer days in hospital, and a lower incidence of the composite end point of death, provision of dialysis, or transplantation ( P =0.002)., Conclusions: The beneficial effects of fixed-dose ferric citrate coordination complex on biochemical parameters, as well as the exploratory results regarding the composite end point and hospitalization, suggest that fixed-dose ferric citrate coordination complex has an excellent safety profile in an unselected population with advanced CKD and merits further study., (Copyright © 2019 by the American Society of Nephrology.)

Obesity is a risk factor for hypertension, diabetes mellitus (DM), dyslipidemia, and hyperuricemia. Here, we evaluated whether the same body mass index (BMI) for the U.S. population conferred similar metabolic risk in Japan. This was a cross-sectional analysis involving 90,047 Japanese adults (18⁻85 years) from St. Luke's International Hospital, Tokyo, Japan and 14,734 adults from National Health and Nutrition Examination Survey (NHANES) collected in the U.S. We compared the prevalence of hypertension, DM, dyslipidemia, and hyperuricemia according to BMI in Japan and the U.S. The prevalence of hypertension, DM, and dyslipidemia were significantly higher in the U.S. than Japan, whereas the prevalence of hyperuricemia did not differ between countries. Higher BMI was an independent risk factor for hypertension, DM, dyslipidemia, and hyperuricemia both in Japan and in the U.S. after adjusting for age, sex, smoking and drinking habits, chronic kidney disease, and other cardiovascular risk factors. The BMI cut-off above which the prevalence of these cardio-metabolic risk factors increased was significantly higher in the U.S. than in Japan (27 vs. 23 kg/m² for hypertension, 29 vs. 23 kg/m² for DM, 26 vs. 22 kg/m² for dyslipidemia, and 27 vs. 23 kg/m² for hyperuricemia). Higher BMI is associated with an increased prevalence of hypertension, DM, dyslipidemia, and hyperuricemia both in Japan and U.S. The BMI cut-off above which the prevalence of cardio-metabolic risk factors increases is significantly lower in Japan than the U.S., suggesting that the same definition of overweight/obesity may not be similarly applicable in both countries.

Objective: In the kidney disease clinic setting, higher-than-usual blood pressure is often ascribed to recent dietary sodium indiscretion. While clinical trials demonstrate a clear relationship between salt intake and blood pressure on the population level, it is uncertain whether real-world variation in sodium intake within individual chronic kidney disease (CKD) patients is associated with fluctuations in blood pressure., Methods: We analyzed data from the Phosphorus Normalization Trial, in which participants with CKD eating their usual diets completed at least three 24-hour urine collections over 9 months, from which we measured sodium. Blood pressure was measured at the time of 24-hour urine collections. For each individual participant, we assessed the slope of the relationship between sodium intake and mean arterial blood pressure (MAP)., Results: Among 119 participants (mean age 67 years and mean estimated glomerular filtration rate 31 mL/minute/1.73 m 2 ), there was substantial variation in sodium intake as measured by 24-hour urine collections (mean intake 3,903 mg/day, standard deviation 1037 mg/day). Individual participants had highly variable associations between their sodium intake and their MAP; 47% (n = 56) had inverse associations between sodium and MAP, whereas the remainder had positive (salt-sensitive) associations., Conclusions: Among CKD patients, there is substantial variation in sodium intake but no predictable relationship between dietary sodium and blood pressure in individuals. The frequent dismissal of elevated blood pressure readings as related to recent sodium intake in clinic may be a misapplication of large-scale population data to explain individual variability and may contribute to clinical inertia regarding high blood pressure treatment., (Copyright © 2017 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Vascular calcification is common among patients with chronic kidney disease (CKD), and it is associated with all-cause and cardiovascular disease mortality. Deoxycholic acid, a metabolite of circulating bile acids, is elevated in CKD and induces vascular mineralization and osteogenic differentiation in animal models., Study Design: Cohort analysis of clinical trial participants., Setting & Participants: 112 patients with moderate to severe CKD (estimated glomerular filtration rate, 20-45mL/min/1.73m 2 ) who participated in a randomized controlled study to examine the effects of phosphate binders on vascular calcification., Predictor: Serum deoxycholic acid concentration., Outcomes: Baseline coronary artery calcification (CAC) volume score and bone mineral density (BMD) and change in CAC volume score and BMD after 9 months., Measurements: Deoxycholic acid was assayed in stored baseline serum samples using liquid chromatography-tandem mass spectrometry, CAC was measured using a GE-Imitron C150 scanner, and BMD was determined using computed tomographic scans of the abdomen with calibrated phantom of known density., Results: Higher serum deoxycholic acid concentrations were significantly correlated with greater baseline CAC volume and lower baseline BMD. After adjusting for demographics, coexisting illness, body mass index, estimated glomerular filtration rate, and concentrations of circulating markers of mineral metabolism, including serum calcium, phosphorus, vitamin D, parathyroid hormone, and fibroblast growth factor 23, a serum deoxycholic acid concentration > 58ng/mL (the median) was positively associated with baseline CAC volume (β=0.71; 95% CI, 0.26-1.16; P=0.003) and negatively associated with baseline BMD (β = -20.3; 95% CI, -1.5 to -39.1; P=0.04). Serum deoxycholic acid concentration > 58ng/mL was not significantly associated with change in CAC volume score after 9 months (β=0.06; 95% CI, -0.09 to 0.21; P=0.4). The analysis for the relationship between baseline deoxycholic acid concentrations and change in BMD after 9 months was not statistically significant, but was underpowered., Limitations: The use of nonfasting serum samples is a limitation because deoxycholic acid concentrations may vary based on time of day and dietary intake. Few trial participants with complete data to evaluate the change in CAC volume score (n=75) and BMD (n=59). No data for changes in deoxycholic acid concentrations over time., Conclusions: Among patients with moderate to severe CKD, higher serum deoxycholic acid concentrations were independently associated with greater baseline CAC volume score and lower baseline BMD., (Published by Elsevier Inc.)

Background: Data regarding the effect of a solitary kidney during pregnancy have come from studies of living kidney donors. We evaluated the risk for adverse pregnancy outcomes in women with a single kidney from renal agenesis., Study Design: Matched cohort study., Setting & Participants: Using data from 7,079 childbirths from an integrated health care delivery system from 1996 through 2015, we identified births from women with renal agenesis. Only first pregnancies and singleton births were included. After excluding those with diabetes and kidney disease, 200 women with renal agenesis were matched 1:4 by age (within 2 years), race, and history of hypertension to women with 2 kidneys., Predictor: Renal agenesis defined by International Classification of Diseases, Ninth Revision (ICD-9) codes prior to pregnancy., Outcomes: The primary outcome was adverse maternal outcomes, including preterm delivery, delivery by cesarean section, preeclampsia/eclampsia, and hospital length of stay. Adverse neonatal end points were considered as a secondary outcome and included low birth weight (<2,500g) and infant death/transfer to acute inpatient facility., Results: Mean gestational age at delivery was 37.9±2.1 weeks for women with renal agenesis compared to 38.6±1.8 weeks for women with 2 kidneys. Compared with women with 2 kidneys, those with renal agenesis had increased risk for preterm delivery (OR, 2.88; 95% CI, 1.86-4.45), delivery by cesarean section (OR, 2.11; 95% CI, 1.49-2.99), preeclampsia/eclampsia (OR, 2.41; 95% CI, 1.23-4.72), and length of stay longer than 3 days (OR, 1.81; 95% CI, 1.18-2.78). Renal agenesis was not significantly associated with increased risk for infant death/transfer to acute facility (OR, 2.60; 95% CI, 0.57-11.89) or low birth weight after accounting for preterm delivery (OR, 2.11; 95% CI, 0.76-5.88)., Limitations: Renal agenesis was identified by ICD-9 code, not by imaging of the abdomen., Conclusion: Women with unilateral renal agenesis have a higher risk for adverse outcomes in pregnancy., (Copyright © 2017 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Hyperuricemia may contribute to endothelial dysfunction in CKD. We evaluated whether lowering serum uric acid levels with allopurinol improves endothelial dysfunction in 80 participants ≥18 years of age with stage 3 CKD and asymptomatic hyperuricemia (≥7 mg/dl in men and ≥6 mg/dl in women) randomized in a double-blinded manner to receive placebo or allopurinol for 12 weeks. Randomization was stratified according to presence or absence of diabetes mellitus. We measured vascular endothelial function by brachial artery flow-mediated dilation. No significant differences existed between groups at baseline; 61% of the participants had diabetes mellitus in both groups. The placebo and the allopurinol groups had baseline serum uric acid levels (SDs) of 8.7 (1.6) mg/dl and 8.3 (1.4) mg/dl, respectively, and baseline flow-mediated dilation values (SDs) of 6.0% (5.0%) and 4.8% (5.0%), respectively. Compared with placebo, allopurinol lowered serum uric acid significantly but did not improve endothelial function. In participants without diabetes mellitus, allopurinol associated with a trend toward improved flow-mediated dilation (+1.4% [3.9%] versus -0.7% [4.1%] with placebo), but this was not statistically significant ( P =0.26). Furthermore, we did not detect significant differences between groups in BP or serum levels of markers of inflammation and oxidative stress. In conclusion, allopurinol effectively and safely lowered serum uric acid levels in adults with stage 3 CKD and asymptomatic hyperuricemia but did not improve endothelial function in this sample of patients., (Copyright © 2017 by the American Society of Nephrology.)

Vascular endothelial dysfunction and increased arterial stiffness contribute to increased cardiovascular risk in patients with CKD who exhibit chronic systemic inflammation. Because chronic inflammation contributes to vascular dysfunction, blocking inflammation may reduce cardiovascular risk in patients with CKD. In a two-site, double-blind trial, we randomized 42 adult patients with stage 3-4 CKD who were already receiving optimal background therapy to receive either IL-1 trap rilonacept or placebo for 12 weeks. Coprimary end points included change in brachial artery flow-mediated dilation (FMD BA ) and aortic pulse-wave velocity (aPWV) after 4, 8, and 12 weeks. Exploratory end points included change in high-sensitivity C-reactive protein (hsCRP), FMD BA after acute ascorbic acid infusion, and vascular endothelial cell protein expression of NADPH oxidase. Participants were 63±11 (mean±SD) years of age and 24% were women; mean eGFR was 38±13 ml/min per 1.73 m 2 Compared with placebo, rilonacept improved FMD BA (baseline: 3.36%±2.06% [mean±SD], 12 weeks: 2.45%±2.29% with placebo and baseline: 3.75%±3.12%, 12 weeks: 4.86%±3.20% with rilonacept; P <0.01), without changing aPWV ( P =0.56). Rilonacept also reduced hsCRP levels (median [interquartile range]) (baseline: 4.60 [1.90-8.22] mg/L, 12 weeks: 2.16 [0.92-7.38] mg/L; P <0.01) and endothelial cell NADPH oxidase expression ( P <0.05). Acute infusion of ascorbic acid to inhibit superoxide production associated with a nonsignificant trend toward increased FMD BA in the placebo group ( P =0.07) but not the rilonacept group ( P =0.56). Rilonacept was well tolerated (five adverse events versus two with placebo). In conclusion, treatment with an IL-1 trap improved FMD BA without changing aPWV and reduced systemic inflammation in patients with CKD., (Copyright © 2017 by the American Society of Nephrology.)

Background: Sodium intake influences blood pressure and proteinuria, yet the impact on long-term outcomes is uncertain in chronic kidney disease (CKD). Accurate assessment is essential for clinical and public policy recommendations, but few large-scale studies use 24-h urine collections. Recent studies that used spot urine sodium and associated estimating equations suggest that they may provide a suitable alternative, but their accuracy in patients with CKD is unknown., Objective: We compared the accuracy of 4 equations [the Nerbass, INTERSALT (International Cooperative Study on Salt, Other Factors, and Blood Pressure), Tanaka, and Kawasaki equations] that use spot urine sodium to estimate 24-h sodium excretion in patients with moderate to advanced CKD., Design: We evaluated the accuracy of spot urine sodium to predict mean 24-h urine sodium excretion over 9 mo in 129 participants with stage 3-4 CKD. Spot morning urine sodium was used in 4 estimating equations. Bias, precision, and accuracy were assessed and compared across each equation., Results: The mean age of the participants was 67 y, 52% were female, and the mean estimated glomerular filtration rate was 31 ± 9 mL · min(-1) · 1.73 m(-2) The mean ± SD number of 24-h urine collections was 3.5 ± 0.8/participant, and the mean 24-h sodium excretion was 168.2 ± 67.5 mmol/d. Although the Tanaka equation demonstrated the least bias (mean: -8.2 mmol/d), all 4 equations had poor precision and accuracy. The INTERSALT equation demonstrated the highest accuracy but derived an estimate only within 30% of mean measured sodium excretion in only 57% of observations. Bland-Altman plots revealed systematic bias with the Nerbass, INTERSALT, and Tanaka equations, underestimating sodium excretion when intake was high., Conclusion: These findings do not support the use of spot urine specimens to estimate dietary sodium intake in patients with CKD and research studies enriched with patients with CKD. The parent data for this study come from a clinical trial that was registered at clinicaltrials.gov as NCT00785629., (© 2016 American Society for Nutrition.)

Background: Hyperuricemia is an independent predictor of impaired fasting glucose and type 2 diabetes, but whether it has a causal role in insulin resistance remains controversial. Here we tested the hypothesis that lowering uric acid in hyperuricemic nondiabetic subjects might improve insulin resistance., Methods: Subjects with asymptomatic hyperuricemia (n = 73) were prospectively placed on allopurinol (n = 40) or control (n = 33) for 3 months. An additional control group consisted of 48 normouricemic subjects. Serum uric acid, fasting glucose, fasting insulin, HOMA-IR (homeostatic model assessment of insulin resistance), and high-sensitivity C-reactive protein were measured at baseline and at 3 months., Results: Allopurinol-treated subjects showed a reduction in serum uric acid in association with improvement in fasting blood glucose, fasting insulin, and HOMA-IR index, as well as a reduction in serum high-sensitivity C-reactive protein. The number of subjects with impaired fasting glucose significantly decreased in the allopurinol group at 3 months compared with baseline (n = 8 [20%] vs n = 30 [75%], 3 months vs baseline, P < 0.001). In the hyperuricemic control group, only glucose decreased significantly and, in the normouricemic control, no end point changed., Conclusions: Allopurinol lowers uric acid and improves insulin resistance and systemic inflammation in asymptomatic hyperuricemia. Larger clinical trials are recommended to determine if lowering uric acid can help prevent type 2 diabetes.

Background and Objective: The optimal BP target to reduce adverse clinical outcomes in patients with CKD is unclear. This study examined the relationship between BP and death, cardiovascular events (CVEs), and kidney disease progression in patients with advanced kidney disease., Design, Setting, Participants, & Measurements: The relationship of systolic BP (SBP), diastolic BP (DBP), and pulse pressure (PP) with death, CVE, and progression to long-term dialysis was examined in 1099 patients with advanced CKD (eGFR≤30 ml/min per 1.7 3m(2); not receiving dialysis) who participated in the Homocysteine in Kidney and ESRD study. That study enrolled participants from 2001 to 2003. Cox proportional hazard models were used to examine the association between BP and adverse outcomes., Results: The mean±SD baseline eGFR was 18±7 ml/min per 1.73 m(2). During a median follow-up of 2.9 years, 453 patients died, 215 had a CVE, and 615 initiated long-term dialysis. After adjustment for demographic characteristics and confounders, SBP, DBP, and PP were not associated with a higher risk of death. SBP and DBP were also not associated with CVE. The highest quartile of PP was associated with a substantial higher risk of CVE compared with the lowest quartile (hazard ratio [HR], 1.67; 95% confidence interval [95% CI], 1.10 to 2.52). The highest quartiles of SBP (HR, 1.28; 95% CI, 1.01 to 1.61) and DBP (HR, 1.36; 95% CI, 1.07 to 1.73), but not PP, were associated with a higher risk of progression to long-term dialysis compared with the lowest quartile., Conclusions: In patients with advanced kidney disease not undergoing dialysis, higher PP was strongly associated with CVE whereas higher SBP and DBP were associated with progression to long-term dialysis. These results suggest that SBP and DBP should not be the only factors considered in determining antihypertensive therapy; elevated PP should also be considered., (Copyright © 2015 by the American Society of Nephrology.)

Background: Iron deficiency anemia and serum phosphate levels > 4.0mg/dL are relatively common in chronic kidney disease stages 3 to 5 and are associated with higher risks of progressive loss of kidney function, cardiovascular events, and mortality., Study Design: Double-blind, placebo-controlled, randomized trial., Setting & Participants: 149 patients with estimated glomerular filtration rates < 60 mL/min/1.73 m(2), iron deficiency anemia (hemoglobin, 9.0-12.0 g/dL; transferrin saturation [TSAT]≤ 30%, serum ferritin ≤ 300 ng/mL), and serum phosphate levels ≥ 4.0 to 6.0mg/dL. Use of intravenous iron or erythropoiesis-stimulating agents was prohibited., Intervention: Randomization to treatment for 12 weeks with ferric citrate coordination complex (ferric citrate) or placebo., Outcomes & Measurements: Coprimary end points were change in TSAT and serum phosphate level from baseline to end of study. Secondary outcomes included change from baseline to end of treatment in values for ferritin, hemoglobin, intact fibroblast growth factor 23 (FGF-23), urinary phosphate excretion, and estimated glomerular filtration rate., Results: Ferric citrate treatment increased mean TSAT from 22% ± 7% (SD) to 32% ± 14% and reduced serum phosphate levels from 4.5 ± 0.6 to 3.9 ± 0.6 mg/dL, while placebo exerted no effect on TSAT (21% ± 8% to 20% ± 8%) and less effect on serum phosphate level (4.7 ± 0.6 to 4.4 ± 0.8 mg/dL; between-group P<0.001 for each). Ferric citrate increased hemoglobin levels (from 10.5 ± 0.8 to 11.0 ± 1.0 g/dL; P<0.001 vs placebo), reduced urinary phosphate excretion 39% (P<0.001 vs placebo), and reduced serum intact FGF-23 levels from a median of 159 (IQR, 102-289) to 105 (IQR, 65-187) pg/mL (P=0.02 vs placebo). The incidence and severity of adverse effects were similar between treatment arms., Limitations: The study is limited by relatively small sample size and short duration and by having biochemical rather than clinical outcomes., Conclusions: Short-term use of ferric citrate repletes iron stores, increases hemoglobin levels, and reduces levels of serum phosphate, urinary phosphate excretion, and FGF-23 in patients with chronic kidney disease stages 3 to 5., (Copyright © 2015 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Evidence suggests that the renin-angiotensin-aldosterone system (RAAS) interacts with the vitamin D-fibroblast growth factor 23-Klotho axis. We investigated whether circulating mineral metabolism markers modify outcomes in response to RAAS inhibition in subjects with advanced chronic kidney disease (CKD)., Methods: In this retrospective cohort study, we analyzed the association of angiotensin-converting enzyme inhibitor (ACEI) and angiotensin receptor blocker (ARB) use with all-cause mortality and dialysis initiation among 1,753 subjects (1,099 CKD, estimated glomerular filtration rate 18 ± 6 ml/min/1.73 m(2) and 654 end-stage renal disease [ESRD]) from the Homocysteine in Kidney and End Stage Renal Disease (HOST) study. A propensity score analysis accounted for indication bias and Cox regression models adjusted for mineral metabolism markers., Results: Mean follow-up was 3.2 years; 714 (41%) subjects died and 615 (56%) initiated dialysis. In adjusted analyses, all subjects treated with ACEI/ARB had a significantly lower hazard of death (hazards ratio (HR) 0.81, 95% CI 0.70-0.95, p = 0.007). Those with CKD not on dialysis and treated with ACEI/ARB trended toward a lower hazard of dialysis initiation (HR 0.86, 95% CI 0.73-1.01, p = 0.06). The association with mortality did not differ by level of mineral metabolism marker (p for interaction >0.16); however, the relationship with dialysis initiation differed according to the median serum phosphorus level (p for interaction <0.001)., Conclusions: RAAS inhibition was associated with decreased all-cause mortality independent of disordered mineral metabolism among mostly male HOST subjects with advanced CKD and ESRD. However, among those with CKD not requiring dialysis, the renoprotection associated with RAAS inhibition was attenuated by higher serum phosphorus levels. Further studies are needed to confirm this association., (© 2015 S. Karger AG, Basel.)

Background: Previous trials of binders in chronic kidney disease (CKD) stages 3-5 have shown only modest changes in serum phosphate but evaluated morning phosphate. It is unknown whether a circadian pattern of phosphate concentrations exists in CKD and is modifiable by dietary manipulation., Objectives: We determined the circadian pattern of serum phosphate concentrations in CKD and whether it was modifiable by altering absorbable phosphate., Design: This was a crossover feeding study in 11 CKD participants (estimated glomerular filtration rate: 30-45 mL · min(-1) · 1.73 m(-2)) and 4 healthy control subjects. All subjects received high-phosphate (2500 mg/d), normal-phosphate (1500 mg/d), and low-phosphate (1000 mg/d plus 1000 mg lanthanum carbonate 3 times/d) diets for 5 d followed by a 10-d washout. After each 5-d feed, phosphate and other measurements were made every 4 h over 1 day., Results: In CKD participants who consumed the high-phosphate diet, there were circadian changes in phosphate with lowest concentrations (± SDs) at 0800 (4.2 ± 0.5 mg/dL) and 2 peaks at 1600 and 0400 (4.5 ± 0.8 and 4.4 ± 0.6 mg/dL, respectively), which were similar to those in healthy controls. Results with the normal-phosphate diet were similar. The low-phosphate diet altered the circadian rhythm (P = 0.02) such that 0400 and 1600 peaks were absent. Differences in phosphate for lowest- compared with highest-phosphate diets were smallest at 0800 and largest at 1600 (0.5 compared with 1.0 mg/dL) in CKD. Circadian changes in phosphate were not explained by urine phosphate excretion, parathyroid hormone, or fibroblast growth factor-23., Conclusions: A circadian pattern of serum phosphate is observed in CKD with lowest concentrations at 0800 and highest at 1600 and 0400. This circadian pattern is modifiable by phosphate intake and most evident at 1600. Future intervention studies targeting intestinal phosphate absorption should consider afternoon phosphate measurements., (© 2014 American Society for Nutrition.)

Importance: Little is known about the necessity of multiple same-day intraocular pressure (IOP) measurements in describing the effect of IOP-lowering surgical procedures, and such evidence could affect surgical trial recruitment and retention of participants., Objective: To determine whether a single IOP measurement might adequately approximate the mean of several measurements in glaucoma surgical trials., Design, Setting, and Participants: A prospective, multicenter, interventional cohort from the prerandomization phase of a randomized clinical trial evaluating use of a supraciliary implant for treatment of IOP was conducted at multiple ophthalmology clinics. A total of 609 patients (609 eyes) with primary open-angle glaucoma and cataract were included., Interventions: One IOP measurement was made while patients were receiving their usual medications to lower IOP, and 3 IOP measurements were made at 8 am, 12 pm, and 4 pm after patients underwent washout of all IOP-lowering eyedrops., Main Outcomes and Measures: The proportion of eyes in which the increase in IOP after washout, using the mean of the 3 measurements, differed by more than 0.5, 1.0, 1.5, or 2.0 mm Hg from the increase in IOP after washout using only 1 of the postwashout measurements. A proportion of 10% or less at the 1.5-mm Hg cutoff was considered clinically acceptable. The hypothesis was formulated after data collection but before the data were examined., Results: The mean (SD) IOP before washout was 18.5 (4.0) mm Hg. The mean increase in IOP after washout, using the mean of the 3 measurements, was 5.3 (4.2) mm Hg. The percentage of eyes in which the increase in IOP using a single postwashout IOP differed from the increase in IOP using the mean of 3 measurements by more than 1.5 mm Hg was 35.1%, 25.6%, 34.2%, 30.0%, and 31.4% when the single measurement was made at 8 am, 12 pm, 4 pm, a randomly chosen single measure of those 3 times, and the time closest to that of the prewashout IOP, respectively. By logistic regression, the 12 pm postwashout IOP had the lowest proportion of eyes differing from the mean (P < .001) and thus most closely approximated the mean diurnal IOP., Conclusions and Relevance: Although eliminating multiple IOP measurements would simplify the conduct of surgical trials in glaucoma, our data show that using a single IOP measurement after washout does not adequately approximate the mean of multiple IOP measurements.

Background: The management of hyperphosphatemia in patients with moderate to severe chronic kidney disease (CKD) includes dietary phosphate restriction and/or prescription of phosphate binders. Measuring phosphate intake in CKD is important for monitoring dietary adherence and for the effectiveness of therapeutic interventions. The 24-hour urine collection is the gold standard method for determining phosphate intake; however, timed urine collections are cumbersome and prone to error. We investigated the precision and accuracy of spot urine phosphate measurements, compared to 24-hour urine phosphate (24hUrP) collection., Study Design, Setting, and Participants: We evaluated simultaneous spot and 24hUrP measurements, collected on multiple occasions, from 143 participants in the Phosphate Normalization Trial, a randomized trial of phosphate binders versus placebo among persons with an estimated glomerular filtration rate between 20-45 mL/minute per 1.73 m2. We used residual analyses and graphical methods to model the functional relationship of spot urine phosphate and creatinine measurements with 24hUrP. We used multiple linear regression to test whether additional covariates improved model prediction, including treatment assignment, age, sex, height, weight, urine collection time, and last meal time. We internally validated results using leave-one-out cross-validation, and externally validated in an independent replication cohort., Results: A log-log relation between the spot urine phosphate-to-creatinine ratio and 24hUrP excretion yielded the best model fit. In addition to spot urine phosphate and creatinine concentrations, inclusion of age, sex, and weight significantly improved prediction of 24hUrP. Compared with a spot urine phosphate-to-creatinine ratio alone (r2 = 0.12, P < .001), the new equation more accurately predicted 24hUrP (leave-one-out validation r2 = 0.43, P < .001, independent validation r2 = 0.39, P < .001)., Conclusion: We describe a novel equation to predict 24hUrP excretion using spot urine phosphate and creatinine, age, sex, and weight. The equation is more accurate and precise than the urine phosphate-to-creatinine ratio alone, and it provides a simple method for estimating 24hUrP excretion in patients with nondialysis-requiring CKD., (Copyright © 2014 National Kidney Foundation, Inc. All rights reserved.)

Aims: The concentration of fibroblast growth factor 23 (FGF-23) is elevated in patients on dialysis. FGF receptors have been implicated in the pathogenesis of left ventricular (LV) hypertrophy. The objective of this study was to examine the associations between high plasma FGF-23 concentration and LV systolic dysfunction., Methods: We tested the hypothesis that high plasma FGF-23 concentration is associated with LV dysfunction in 110 chronic dialysis patients from the Homocysteine study who had paired echocardiograms performed for clinical indications. C-terminal FGF-23 concentrations were measured in stored plasma samples. Multivariate regression analyses were performed to evaluate the association of FGF-23 concentration with LV dysfunction., Results: Participants had a mean age of 60 ± 11 years. Median FGF-23 level and mean ejection fraction (EF) at baseline were 4,632 (1,384 - 14,997) RU/ml and 50 ± 13%, respectively. Median follow-up time was 1.9 years. Higher FGF-23 concentration was directly associated with decreases in EF during follow-up. After adjustment for demographics, baseline EF, hypertension, diabetes, cardiovascular disease, body mass index, systolic blood pressure, hemoglobin and markers of mineral metabolism, participants with FGF-23 in the highest tertile had an 8% decrease in EF compared to participants in the lowest tertile (β -8.0, 95% CI -15.5 to -0.53; p = 0.04). When FGF-23 was evaluated as a continuous variable, for every log10 increase in FGF-23, EF decreased during follow-up by 6.5% (β -6.5, 95% CI -11.3 to -1.73; p = 0.01)., Conclusion: In conclusion, higher FGF-23 concentration is independently associated with LV systolic dysfunction in chronic dialysis patients.

Background/aims: Serum phosphate (P) has been linked to adverse events in patients with chronic kidney disease. Salivary phosphate (Psal) has been proposed as a potential target of therapy with a chitosan-containing chewing gum., Methods: We conducted several pilot studies to characterize Psal and its relationship with kidney function and subsequently conducted two clinical efficacy studies: a double-blind placebo-controlled trial in patients with end-stage renal disease (ESRD) and an open-label trial in those with stage 3-4 CKD., Results: Pilot studies demonstrated no relationship between the level of kidney function and Psal. Mean Psal was approximately 6.46 mmol/l across the entire spectrum of kidney function. Passive saliva collection demonstrated higher Psal concentration as compared to active collection. There was no evidence of diurnal variation in Psal. Twice daily 20 mg chitosan gum over 4 weeks reduced serum P by 0.065 mmol/l in the double-blind, placebo-controlled trial in ESRD (p = NS vs. placebo). In an open-label extension in these subjects, 40 mg chitosan gum three times daily reduced serum P by 0.065 mmol/l (p = 0.03 vs. end of washout). In a 2-week open-label trial in patients with CKD not on dialysis, 20 mg chitosan gum given three times daily reduced serum P by 0.05 mmol/l (p = 0.003 vs. day 1). Neither trial demonstrated any significant change in Psal with chitosan gum., Conclusions: Psal concentration is approximately 4-5 times that of serum P and is not related to glomerular filtration rate. Chitosan chewing gum resulted in a reduction of serum P by approximately 0.05-0.065 mmol/l but had no effect on Psal concentration., (Copyright © 2013 S. Karger AG, Basel.)

Background: Fibroblast growth factor 23 (FGF23) has been associated with death in dialysis patients. Since FGF23 shares structural features with FGF19 subfamily members that exert hormonal control of fat mass, we hypothesized that high circulating FGF23 concentrations would be associated with the development of a uremic lipid profile and lower body mass index (BMI)., Methods: This study was conducted among 654 patients receiving chronic hemodialysis. C-terminal FGF23 concentrations were measured in stored plasma samples. Linear regression was used to examine the cross-sectional associations of plasma FGF23 concentrations with BMI, total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein-cholesterol (HDL-C) and triglycerides. Cox proportional hazard models were used to examine the association between FGF23 concentrations and all-cause mortality., Results: Participants had a mean age of 60 ± 11 years and a median (IQR) FGF23 concentration of 4,212 (1,411-13,816) RU/ml. An increase per SD in log10 FGF23 was associated with lower BMI (β = -1.11; p = 0.008), TC (β = -6.46; p = 0.02), LDL-C (β = -4.73; p = 0.04) and HDL-C (β = -2.14; p = 0.03); after adjusting for age, gender, race, cardiovascular risk factors, serum albumin, markers of mineral metabolism, and use of lipid-lowering drugs. The association of FGF23 with death was attenuated after adjustment for HDL-C (HR of highest quartile 1.53, 95% CI 1.06-2.20 compared to lowest quartile)., Conclusion: These results indicate that higher plasma FGF23 levels are associated with lower BMI and dyslipidemia in dialysis patients. The association between FGF23 and death may be mediated through unexplored metabolic risk factors unrelated to mineral metabolism., (Copyright © 2013 S. Karger AG, Basel.)

Background: Patients with chronic kidney disease (CKD) not requiring dialysis have a high prevalence of 25-hydroxyvitamin D (25(OH)D) deficiency but the relationship between 25(OH)D levels and metabolic syndrome is unknown in this population., Methods: This study analyzed stored plasma samples from 495 non-diabetic subjects with severe kidney disease, not yet on dialysis, who participated in the homocysteine in kidney and end stage renal disease study. Metabolic syndrome was defined as the presence of all three of the following: (1) Serum triglycerides ≥ 150 mg/dl or drug treatment for hypertriglyceridemia; (2) serum high density lipoprotein-cholesterol (HDL-C) < 50 mg/dl for women or < 40 mg/dl for men or drug treatment for dyslipidemia; and (3) blood pressure ≥ 130/85 mmHg or drug treatment for hypertension. Multivariate logistic regression models were used to evaluate the cross-sectional association between plasma 25(OH)D levels and metabolic syndrome., Results: The prevalence of metabolic syndrome increased as 25(OH)D levels declined, with the highest prevalence in participants with 25(OH)D levels < 20 ng/ ml. Participants with 25(OH)D levels < 20 ng/ml had a significantly increased risk of metabolic syndrome compared to subjects with levels > 30 ng/ml after adjustment for multiple confounders (OR 2.25, 95% CI 1.25 - 4.07). Plasma 25(OH)D levels were inversely associated with diastolic blood pressure (R = -0.10, p = 0.029) and serum triglyceride levels (R = -0.14, p = 0.002)., Conclusion: 25(OH)D deficiency is strongly associated with an increased risk of metabolic syndrome in non-diabetic patients with severe CKD not yet on dialysis, independent of cardiometabolic risk factors and other important regulators of mineral metabolism.

Longitudinal studies of the association of estimated glomerular filtration rate (eGFR) and albuminuria with coronary artery calcium (CAC), a measure of cardiovascular disease burden, are few and contradictory. In this study, 421 community-dwelling men and women (mean age 67 years) without known heart disease had eGFRs assessed using the Modification of Diet in Renal Disease (MDRD) equation and albuminuria assessed by urine albumin/creatinine ratio (ACR) from 1997 to 1999. The mean eGFR was 78 ml/min/1.73 m(2), and the median ACR was 10 mg/g. CAC was measured using electron-beam computed tomography from 2000 to 2001, when the median total Agatston CAC score was 77; 4.5 years later, 338 participants still without heart disease underwent repeat scans (median CAC score 112); 46% of participants showed CAC progression, defined as an increase ≥2.5 mm(3) in square root-transformed CAC volume score. Cross-sectional and longitudinal logistic regression analyses showed no separate or joint association between eGFR or ACR and CAC severity or progression. In conclusion, this study does not support the use of eGFR or ACR to identify asymptomatic older adults who should be screened for subclinical cardiovascular disease with initial or sequential scanning for CAC. In the elderly, kidney function and CAC may not progress together., (Published by Elsevier Inc.)

Purpose: To evaluate the effectiveness of glycerin 1% formulated with the novel and proprietary ophthalmic excipient poly(l-lysine)-graft-poly(ethylene glycol) (PLL-g-PEG) (Eyeon Particle Sciences LLC) in extending tear film break-up time (TFBUT) compared with a market-leading artificial tear formulation of propylene glycol (0.3%) and polyethylene glycol (0.4%) (Systane(®) Lubricant Eye Drops; Alcon, Fort Worth, TX)., Methods: This prospective single-center, single visit, randomized, double-masked exploratory trial compared the new formulation and Systane using TFBUT. Noninvasive break-up time (NIBUT) was measured in subjects with asymptomatic to mild (n=5), mild to moderate (n=5), and moderate to severe (n=6) dry eye disease using the TearscopePlus™ at pre-instillation and again at 15, 30, 60, and 120 min after instillation. Fluorescein break-up time (FBUT) was measured at 120 min after instillation., Results: At 15 min (N=16), the new formulation extended mean NIBUT by 14.67 s (P=0.05) compared with 7.40 s (P=0.34) by Systane. The new formulation had a mean FBUT of 4.92 s longer than Systane at 120 min (P=0.12). With outliers removed (N=13), the difference between the mean NIBUT change from baseline for the new formulation and Systane at 120 min was statistically significant (P=0.03)., Conclusions: This study demonstrates that PLL-g-PEG as a polymer excipient in artificial tears is effective in improving the performance of demulcents to significantly prolong NIBUT at 15 min, and that protective activity from this artificial tear product for 2 or more hours after eye drop instillation is possible.

Background: Low vitamin D concentrations are prevalent in patients with chronic kidney disease (CKD). We investigated the relationship between plasma 25-hydroxyvitamin D (25[OH]D) or 1,25-dihydroxyvitamin D (1,25[OH](2)D) concentrations with death, cardiovascular events, and dialysis therapy initiation in patients with advanced CKD., Study Design: The HOST (Homocysteinemia in Kidney and End Stage Renal Disease) Study was a randomized double-blind trial evaluating the effects of high doses of folic acid on death and long-term dialysis therapy initiation in patients with advanced CKD (stages 4 and 5 not yet on dialysis therapy). 25(OH)D and 1,25(OH)(2)D were measured in stored plasma samples obtained 3 months after trial initiation and evaluated at clinically defined cutoffs (<10, 10-30, and >30 ng/mL) and tertiles (<15, 15-22, and >22 pg/mL), respectively. Cox proportional hazard models were used to examine the association between vitamin D concentrations and clinical outcomes., Setting & Participants: 1,099 patients with advanced CKD from 36 Veteran Affairs Medical Centers., Predictors: 25(OH)D and 1,25(OH)(2)D concentrations., Outcomes: Death, cardiovascular events, and time to initiation of long-term dialysis therapy., Results: After a median follow-up of 2.9 years, 41% (n = 453) died, whereas 56% (n = 615) initiated dialysis therapy. Mean 25(OH)D and 1,25(OH)(2)D concentrations were 21 ± 10 ng/mL and 20 ± 11 pg/mL, respectively. After adjustment for potential confounders, the lowest tertile of 1,25(OH)(2)D was associated with death (HR, 1.33; 95% CI, 1.01-1.74) and initiation of long-term dialysis therapy (HR, 1.78; 95% CI, 1.40-2.26) compared with the highest tertile. The association with death and initiation of dialysis therapy was moderately attenuated after adjustment for plasma fibroblast growth factor 23 (FGF-23) concentrations (HRs of lower tertiles of 1.20 [95% CI, 0.91-1.58] and 1.56 [95% CI, 1.23-1.99], respectively, compared with highest tertile). There was no association between 25(OH)D concentrations and outcomes., Limitations: Participants were mostly men., Conclusions: Low plasma 1,25(OH)(2)D concentrations are associated with death and initiation of long-term dialysis therapy in patients with advanced CKD. FGF-23 level may attentuate this relationship., (Copyright © 2012 National Kidney Foundation, Inc. All rights reserved.)

Some propose using phosphate binders in the CKD population given the association between higher levels of phosphorus and mortality, but their safety and efficacy in this population are not well understood. Here, we aimed to determine the effects of phosphate binders on parameters of mineral metabolism and vascular calcification among patients with moderate to advanced CKD. We randomly assigned 148 patients with estimated GFR=20-45 ml/min per 1.73 m(2) to calcium acetate, lanthanum carbonate, sevelamer carbonate, or placebo. The primary endpoint was change in mean serum phosphorus from baseline to the average of months 3, 6, and 9. Serum phosphorus decreased from a baseline mean of 4.2 mg/dl in both active and placebo arms to 3.9 mg/dl with active therapy and 4.1 mg/dl with placebo (P=0.03). Phosphate binders, but not placebo, decreased mean 24-hour urine phosphorus by 22%. Median serum intact parathyroid hormone remained stable with active therapy and increased with placebo (P=0.002). Active therapy did not significantly affect plasma C-terminal fibroblast growth factor 23 levels. Active therapy did, however, significantly increase calcification of the coronary arteries and abdominal aorta (coronary: median increases of 18.1% versus 0.6%, P=0.05; abdominal aorta: median increases of 15.4% versus 3.4%, P=0.03). In conclusion, phosphate binders significantly lower serum and urinary phosphorus and attenuate progression of secondary hyperparathyroidism among patients with CKD who have normal or near-normal levels of serum phosphorus; however, they also promote the progression of vascular calcification. The safety and efficacy of phosphate binders in CKD remain uncertain.

Aims: To examine the effect of combined calcium and vitamin D3 supplementation on bone mineral density (BMD) inpatients with chronic kidney disease (CKD)., Methods: We performed a post-hoc analysis of the DECALYOS II, a 2-year randomized, double-blind, placebo-controlled study of 610 women randomized to: calcium-vitamin D3 fixed combination, calcium plus vitamin D3 separate combination, or placebo. Both active treatment groups received the same daily amount of calcium (1,200 mg) and vitamin D3 (800 IU). BMD of the distal radius was measured by single X-ray absorptiometry at baseline, 12 and 24 months., Results: At baseline 47.2%, 36.4% and 16.4% of the study population had an eGFR ≥ 60, 45 -59, and < 45 ml/min/1.73 m2, respectively. Both active regimens vs. placebo markedly increased serum 25-hydroxyvitamin D levels from baseline in all eGFR groups (p 0.22 for all time points)., Conclusion: Combined calcium and vitamin D3 supplementation was effective in reducing rate of BMD loss in women with moderate CKD.

Background and Objectives: This study examined differences in the concentration of markers of mineral metabolism across race in patients with advanced CKD not requiring dialysis and ESRD., Design, Setting, Participants, & Measurements: Concentrations of 25-hydroxyvitamin D (25(OH)D), 1,25-dihydroxyvitamin D (1,25(OH)(2)D), intact parathyroid hormone (iPTH), and fibroblast growth factor 23 (FGF-23) were measured in stored plasma samples of 1497 patients with advanced CKD not yet on dialysis and ESRD who participated in the Homocysteine in Kidney and End Stage Renal Disease study. Linear regression models were used to examine the relationship between race and 25(OH)D, 1,25(OH)(2)D, iPTH, and FGF-23 concentrations., Results: Non-Hispanic white patients comprised 58% of the cohort, whereas non-Hispanic blacks comprised 42%. Median (interquartile range) FGF-23 concentrations were lower in blacks compared with whites with CKD (323 [181-655] versus 431 [232-1026] RU/ml; P<0.001) but not in ESRD. In adjusted linear regression models, blacks with CKD not requiring dialysis had significantly lower plasma FGF-23 concentrations (difference, -159; 95% confidence interval, -205 to -106; P<0.001) compared with whites, independent of plasma 25(OH)D, 1,25(OH)(2)D, and iPTH concentrations. This difference was not observed in the ESRD group. The magnitude of correlation for the relationships between 1,25(OH)(2)D with iPTH, FGF-23 with 1,25(OH)(2)D, and FGF-23 with iPTH were stronger among blacks than whites with CKD not requiring dialysis., Conclusions: In advanced CKD not requiring dialysis, blacks have lower FGF-23 concentrations than whites. Blacks with CKD and ESRD have lower 25(OH)D and higher iPTH compared with whites, independent of FGF-23 concentrations.

Concentrations of the phosphate-regulating hormone fibroblast growth factor-23 (FGF-23) are elevated in patients with chronic kidney disease (CKD), but whether higher plasma FGF-23 concentrations associate with all-cause mortality, cardiovascular events, or initiation of chronic dialysis is not completely understood. Here, we measured FGF-23 concentration in stored plasma samples from 1099 patients with advanced CKD who participated in The Homocysteine in Kidney and End Stage Renal Disease study. Mean serum phosphorus concentration was 4.3 mg/dl, median FGF-23 concentration was 392 RU/ml, and mean GFR was 18 ml/min/1.73 m(2). During a median follow-up of 2.9 yr, 453 (41%) patients died from any cause, 215 (20%) had a cardiovascular event, and 615 (56%) initiated chronic dialysis. Compared with the lowest quartile of FGF-23, each subsequent quartile associated with a progressively higher risk for death, adjusted for confounders (HR [95% CI] of 1.24 [0.91 to 1.69], 1.76 [1.28 to 2.44], and 2.17 [1.56 to 3.08] for the second through fourth quartiles, respectively). In addition, compared with the lowest quartile, the two highest quartiles of FGF-23 also associated with a significantly elevated risk for cardiovascular events and initiation of chronic dialysis. In conclusion, in advanced CKD, FGF-23 strongly and independently associates with all-cause mortality, cardiovascular events, and initiation of chronic dialysis.

Background: recent systematic reviews have cast doubt on the association between vitamin D and cardiovascular disease. No prior studies have investigated the association between 25-hydroxyvitamin D (25[OH]D), 1,25-dihydroxyvitamin D (1,25[OH](2)D), or intact parathyroid hormone and cardiovascular mortality in a temperate climate., Methods: a total of 1073 community-dwelling older adults were evaluated in 1997-1999; serum levels of 25(OH)D (mean 42 ng/mL), 1,25(OH)(2)D (median 29 pg/mL), and intact parathyroid hormone (median 46 pg/mL) were measured; mean estimated glomerular filtration rate was 74 mL/min/1.73 m(2). Participants were followed up to 10.4 (mean 6.4) years with 111 cardiovascular deaths., Results: in unadjusted Cox proportional hazards models, higher levels of 1,25(OH)(2)D were protective against cardiovascular mortality, whereas higher levels of intact parathyroid hormone predicted increased risk of cardiovascular death. After adjusting for age alone or multiple covariates, there was no significant association between 25(OH)D, 1,25(OH)(2)D, or intact parathyroid hormone and cardiovascular mortality; results did not differ by an estimated glomerular filtration rate ≥ 60 mL/min/1.73 m(2) or<60 mL/min/1.73 m(2)., Conclusion: in this prospective study of Caucasian, middle-income, community-dwelling older adults living in sunny southern California, serum levels of 25(OH)D, 1,25(OH)(2)D, and intact parathyroid hormone were not independently associated with cardiovascular mortality., (Published by Elsevier Inc.)

Background: The degree to which recipient/donor (R/D) size mismatching leads to nephron underdosing and worse kidney allograft survival remains poorly defined, particularly in the setting of preexisting nephron loss such as the expanded criteria donor (ECD)., Methods: We performed a retrospective analysis of 69,737 deceased donor transplants followed by a subset analysis of ECD transplants using data from the Scientific Registry of Transplant Recipients from 1992 to 2005. Ratios of R/D body surface area (BSA) were used to estimate nephron disparity and segregate pairs., Results: In the entire cohort, severe BSA disparity (R/D BSA>1.38 m) was associated with slightly worse 10-year unadjusted graft survival (35% for severe BSA disparity vs. 39% in pairs of comparable size, P<0.0001). In multivariate analysis, BSA disparity was associated with a 15% increased risk of graft loss (hazard ratio 1.15, P<0.0001). Within ECD cohorts, severe BSA disparity was associated with a decrease in 10-year unadjusted graft survival of greater magnitude than the overall cohort (10% for severe BSA disparity vs. 22% in pairs of comparable size, P<0.0004). On multivariate analysis, severe R/D BSA disparity was associated with worse allograft survival similar to the entire cohort (hazard ratio 1.18, P=0.04)., Conclusions: Recipients receiving kidneys from substantially smaller donors have a statistically higher rate of graft loss that is more pronounced in ECD kidneys. Although severe R/D size disparity is an independent risk factor for graft loss, the magnitude of this risk requires consideration in the context of other risk factors for the graft loss and the hazards of dialysis.

Secondary hyperparathyroidism (SHPT) affects a significant number of hemodialysis patients, and metabolic disturbances associated with it may contribute to their high mortality rate. As patients with lower serum calcium, phosphorus, and parathyroid hormone are reported to have improved survival, we tested whether prescription of the calcimimetic cinacalcet to hemodialysis patients with SHPT improved their survival. We prospectively collected data on hemodialysis patients from a large provider beginning in 2004, a time coincident with the commercial availability of cinacalcet hydrochloride. This information was merged with data in the United States Renal Data System to determine all-cause and cardiovascular mortality. Patients included in the study received intravenous (i.v.) vitamin D therapy (a surrogate for the diagnosis of SHPT). Of 19,186 patients, 5976 received cinacalcet and all were followed from November 2004 for up to 26 months. Unadjusted and adjusted time-dependent Cox proportional hazards modeling found that all-cause and cardiovascular mortality rates were significantly lower for those treated with cinacalcet than for those without calcimimetic. Hence, this observational study found a significant survival benefit associated with cinacalcet prescription in patients receiving i.v. vitamin D. Definitive proof, however, of a survival advantage awaits the performance of randomized clinical trials.

The recent increase in fructose consumption in industrialized nations mirrors the rise in the prevalence of hypertension, but epidemiologic studies have inconsistently linked these observations. We investigated whether increased fructose intake from added sugars associates with an increased risk for higher BP levels in US adults without a history of hypertension. We conducted a cross-sectional analysis using the data collected from the National Health and Nutrition Examination Survey (NHANES 2003 to 2006) involving 4528 adults without a history of hypertension. Median fructose intake was 74 g/d, corresponding to 2.5 sugary soft drinks each day. After adjustment for demographics; comorbidities; physical activity; total kilocalorie intake; and dietary confounders such as total carbohydrate, alcohol, salt, and vitamin C intake, an increased fructose intake of > or =74 g/d independently and significantly associated with higher odds of elevated BP levels: It led to a 26, 30, and 77% higher risk for BP cutoffs of > or =135/85, > or =140/90, and > or =160/100 mmHg, respectively. These results suggest that high fructose intake, in the form of added sugar, independently associates with higher BP levels among US adults without a history of hypertension.

Higher levels of serum phosphorus that remain within the reference range are associated with increased risk of cardiovascular disease (CVD). However, the mechanisms by which higher serum phosphorus concentrations may contribute to the development of CVD remain unclear. Cross-sectional association between serum phosphorus levels and arterial stiffness as estimated by an ankle brachial pressure index (ABPI) >1.3 was examined in 581 participants in the Third National Health and Nutrition Examination Survey. Logistic regression analysis was performed to evaluate whether higher serum phosphorus levels were associated with high ABPI, independently of several potential confounders. Of 581 participants, 38% and 10% had a serum phosphorus levels >3.5 and >4.0 mg/dl, respectively. An ABPI >1.3 was present in 7.3% of participants. Higher quartiles of serum phosphorus levels were associated with a greater prevalence of high ABPI: 5.4%, 3.7%, 7.8%, and 12.9% for quartiles 1 (<3.1 mg/dl), 2 (3.1 to 3.4 mg/dl), 3 (3.4 to 3.7 mg/dl), and 4 (3.7 to 5.0 mg/dl), respectively. There was a strong, positive association between the highest quartile of serum phosphorus (3.7 to 5.0 mg/dl) and high ABPI compared to the reference group (3.1 to 3.4 mg/dl) after adjustment for demographics, traditional CVD risk factors, kidney function, C-reactive protein, serum calcium, and 25-hydroxyvitamin D levels (adjusted odds ratio 4.78, 95% confidence interval 1.73 to 13.2, p = 0.003). In conclusion, serum phosphorus levels, even within the reference range, are independently associated with high ABPI, a marker of arterial stiffness, in the US adult population.

Objective: Hypertension affects 73 million Americans and costs the US healthcare system over $73 billion annually. Despite increasing awareness of the consequences of uncontrolled hypertension, numerous antihypertensive pharmacologic clinical studies and consistent updates to hypertension guidelines, control rates are suboptimal and have not met national goals. Among treated hypertensives, only 45% of women and 51% of men have reached blood pressure (BP) levels below 140/90 mmHg. Individualization of antihypertensive regimens with hemodynamic information from impedance cardiography (ICG) has been advocated to further improve hypertension control rates. We therefore undertook a quantitative analysis of the trials evaluating the role of ICG as an adjunct to therapeutic decision-making in the treatment of hypertension and the attainment of BP control., Methods: Five studies comprising a total population of 759 patients met the inclusion criteria. Two randomized controlled trials (RCTs) involving a total of 268 patients and three single-arm prospective trials with 491 patients were evaluated using ICG data to guide therapeutic decision-making in the treatment of hypertensive patients., Results: Significant benefit was found in both RCTs for ICG-guided BP treatment. The combined odds ratio for the two trials was 2.41 (95% CI = 1.44-4.05, p = 0.0008), in favor of ICG treatment, meaning that it was more than twice as likely to achieve BP success when using ICG than if ICG was not used. Success attainment of goal BP of <140/90 mmHg was 67% in the ICG-guided arms of the combined randomized trials. Overall success in the single-arm prospective trials of ICG-guided BP treatment was a similar 68%., Conclusion: The results of this meta-analysis confirm the value of using ICG-derived hemodynamic data as an adjunct to therapeutic decision-making in the treatment of hypertension. The data reviewed here demonstrate that ICG-based approaches are in keeping with previously advocated strategies incorporating patient-individualized drug regimens, evidence-based medicine, and practical, easy to apply, cost-effective principles to further improve hypertension control rates.

Background: Organ donor characteristics can be used to predict outcomes in kidney transplantation. We hypothesized that pancreas donation status could reflect organ quality and be predictive of kidney graft outcomes following Standard Criteria Donor (SCD) kidney transplantation., Methods: We performed a retrospective analysis of deceased donor kidney alone (DD KA) transplants reported to SRTR from 1992 to 2005. Group 1 = kidney alone recipients from pancreas donors (KA, P+) and Group 2 = kidney alone recipients from non-pancreas donors (KA, P-). We compared patient and graft survival between groups at 10-yr post-transplant., Results: Group 1 (KA, P+) comprised 19 633 (20%) recipients and Group 2 (KA, P-) comprised 78 737 (80%) recipients. Ten-yr graft survival for Group 1 vs. Group 2 was 42.6% and 36.9% (p < 0.0001), respectively. Pancreas donation status (non-pancreas donor) was associated with a hazard ratio for graft loss of 1.23 on univariate analysis (p < 0.0001), and KA, P-remained an independent risk factor for graft failure at 10 yr, HR 1.09 (p < 0.0001)., Conclusion: Donor pancreas donation status is an independent predictor of improved outcomes of SCD kidney recipients. Further study of the pancreas organ donor pre-procurement is warranted to optimize not only pancreas utilization but also kidney graft outcomes.

Objective: Serum 25-hydroxyvitamin D [25(OH)D] levels are inversely associated with important cardiovascular disease (CVD) risk factors. However, the association between 25(OH)D levels and prevalent CVD has not been extensively examined in the general population., Methods: We performed a cross-sectional analysis of data from the Third National Health and Nutrition Examination Survey (1988-1994) and examined the association between serum 25(OH)D levels and prevalence of CVD in a representative population-based sample of 16,603 men and women aged 18 years or older. Prevalence of CVD was defined as a composite measure inclusive of self-reported angina, myocardial infarction or stroke., Results: In the whole population, there were 1308 (8%) subjects with self-reported CVD. Participants with CVD had a greater frequency of 25(OH)D deficiency [defined as serum 25(OH)D levels <20 ng/mL] than those without (29.3% vs. 21.4%; p<0.0001). After adjustment for age, gender, race/ethnicity, season of measurement, physical activity, body mass index, smoking status, hypertension, diabetes, elevated low-density lipoprotein cholesterol, hypertriglyceridemia, low high-density lipoprotein cholesterol, chronic kidney disease and vitamin D use, participants with 25(OH)D deficiency had an increased risk of prevalent CVD (odds ratio 1.20 [95% confidence interval (CI) 1.01-1.36; p=0.03])., Conclusions: These results indicate a strong and independent relationship of 25(OH)D deficiency with prevalent CVD in a large sample representative of the US adult population.

Background: Simultaneous pancreas-kidney transplantation (SPK) may provide superior patient and kidney graft survival compared with deceased donor kidney transplant alone (DD KA), not because of the addition of a pancreas transplant but because of differences in organ donor, recipient, and transplant characteristics., Methods: We performed a retrospective analysis from the scientific registry of transplant recipients database comparing patient and kidney graft survival of SPK and DD KA recipients from 1997 to 2005, segregating the DD KA recipients into (a) recipients of KA from pancreas donors (KA, P+) and (b) recipients of KA from non-pancreas donors to control for donor differences., Results: Of 8453 SPK waitlisted patients, 7952 received SPK, 101 received KA, P+, and 401 received KA from non-pancreas donors (KA, P-). Five-year kidney graft survival was not different in the SPK and KA, P+ groups (76.2% vs. 81.9%, P=0.15) and was significantly better than the KA, P- group (64.3%, SPK vs. KA, P-, P=0.002; KA, P+ vs. KA, P-, P=0.01). When controlling for recipient and transplant differences by multivariate analysis, KA, P+ transplant was associated with a 50% reduction in risk for kidney graft loss compared with SPK., Conclusions: Donor, recipient, and transplant differences exist when comparing SPK to DD KA that bias outcomes in favor of SPK and limit conclusions regarding superior graft and patient survival.

Background and Objectives: Simultaneous pancreas-kidney transplantation (SPK) is regarded as the treatment of choice for type 1 diabetes (T1DM) and kidney dysfunction, despite the morbidity associated with pancreas transplantation. These morbidities often influence selection of SPK versus living-donor kidney alone (LD KA) transplant. This study quantifies the impact of pancreas graft function on outcomes following SPK., Design, Setting, Participants, & Measurements: Using the SRTR database, SPK wait-listed patients transplanted from 1997 to 2005 were evaluated and segregated as: (1) SPK recipients with functioning pancreas graft 12 mo posttransplant (SPK, P+); (2) SPK recipients with loss of pancreas graft function within 12 mo posttransplant (SPK, P-); (3) recipients of deceased donor (DD) KA; (4) recipients of LD KA. The study compared patient and kidney graft survival to 84 mo posttransplant., Results: Patient survival for SPK, P+ was significantly better than the LD KA; SPK, P-; and DD KA cohorts (88.6% versus 80.0%, 73.9% and 64.8%, respectively [P < 0.001]), a finding confirmed by multivariate analysis and not influenced by pancreas-after-kidney transplantation (PAK) rates and outcomes. Unadjusted graft survival was also highest in the SPK, P+ cohort (72.0% versus 63.6%, 59.8%, 49.7%, P = 0.015 versus LD KA)., Conclusions: SPK recipients with functioning pancreas grafts have superior survival compared with LD KA and DD KA, including in the setting of PAK. Early pancreas graft failure results in kidney and patient survival rates similar to KA. These data help further clarify the decision-making of SPK versus KA transplant options for patients and providers.

Background: Studies addressing the effects of vitamin D(3) supplementation on secondary hyperparathyroidism in patients with moderate chronic kidney disease are scarce., Study Design: Post hoc analysis of the randomized clinical trial Vitamin D, Calcium, Lyon Study II (DECALYOS II) to assess effects according to baseline estimated glomerular filtration rate (eGFR)., Setting & Participants: Multicenter, randomized, double-blinded, placebo-controlled study of 639 elderly women randomly assigned to calcium-vitamin D(3) fixed combination; calcium plus vitamin D(3) separate combination, or placebo., Interventions: Placebo or calcium (1,200 mg) and vitamin D(3) (800 IU) in fixed or separate combination., Outcomes & Measurements: Proportion of participants with a mean decrease in intact parathyroid hormone (iPTH) level of 30% or greater. eGFR was calculated using the 4-variable Modification of Diet in Renal Disease (MDRD) Study equation and categorized as 60 or greater, 45 to 59, and less than 45 mL/min/1.73 m(2)., Results: 610 participants had an eGFR at baseline: 288 (47.2%), 222 (36.4%), and 100 (16.4%) were in each decreasing eGFR category. Across decreasing eGFR groups, 88%, 86%, and 89% had 25-hydroxyvitamin D (25[OH]D) levels less than 15 ng/mL at baseline. On treatment, similar improvements in the proportion of participants achieving 25(OH)D levels greater than 30 ng/mL at 6 months were seen in all kidney function groups (43%, 49%, and 41%, respectively). Active regimens versus placebo increased mean 25(OH)D levels from baseline in all eGFR groups at all times (P < 0.001 for all). The proportion with a 30% or greater decrease in iPTH level at 6 months was 50% in all eGFR groups on treatment versus 6% to 9% for placebo (P < 0.001 for all). The effects of the intervention on iPTH levels did not differ according to baseline eGFR (interaction P > 0.1 for all times)., Limitations: This study included only elderly white women., Conclusion: Vitamin D(3) was effective in increasing 25(OH)D and decreasing iPTH levels in patients with moderate chronic kidney disease.

Background: The association of serum bilirubin concentrations with kidney function and albuminuria has not been established in the US general population., Methods: We performed a cross-sectional analysis of data from the National Health and Nutrition Examination Survey (NHANES) 2001-2006 and examined the associations of serum total bilirubin concentrations with estimated glomerular filtration rate (eGFR) and albuminuria in a nationally representative sample of 13,184 adults aged 20 years or older. eGFR was estimated using the abbreviated Modification of Diet in Renal Disease equation. Urinary albumin excretion was measured using the albumin/creatinine ratio., Results: An eGFR < 60 mL/min/1.73 m(2) and urinary albumin/creatinine ratio > or = 30 mg/g were present in 8.1% (n=1072) and 10.6% (n=1402) of participants, respectively. A total of 427 (3.2%) individuals had a serum total bilirubin concentration >22.23 micromol/L. After adjustment for demographics, comorbidities, alcohol consumption, viral hepatitis status and other laboratory measures, serum bilirubin was negatively associated with eGFR, and positively with albuminuria both in the whole cohort and in the subgroup of non-diabetic individuals. In contrast, serum bilirubin was not significantly associated with eGFR or albuminuria in persons with diabetes (n=1253)., Conclusions: Increasing serum concentrations of total bilirubin are independently associated with decreasing eGFR and increasing albuminuria in the US adult population.

Introduction: Acute kidney injury (AKI) is associated with high mortality rates. New biomarkers that can identify subjects with early AKI (before the increase in serum creatinine) are needed to facilitate appropriate treatment. The purpose of this study was to test the role of serum cytokines as biomarkers for AKI and prolonged mechanical ventilation., Methods: This was a case-control study of children undergoing cardiac surgery. AKI was defined as a 50% increase in serum creatinine from baseline within 3 days. Levels of serum interleukin (IL)-1beta, IL-5, IL-6, IL-8, IL-10, IL-17, interferon (IFN)-gamma, tumor necrosis factor-alpha (TNF-alpha), granulocyte colony-stimulating factor (G-CSF), and granulocyte-macrophage colony-stimulating factor (GM-CSF) were measured using a bead-based multiplex cytokine kit in conjunction with flow-based protein detection and the Luminex LabMAP multiplex system in 18 cases and 21 controls. Levels of IL-6 and IL-8 were confirmed with single-analyte ELISA; IL-18 was also measured with single-analyte ELISA., Results: IL-6 levels at 2 and 12 hours after cardiopulmonary bypass (CPB) and IL-8 levels at 2, 12 and 24 hours were associated with the development of AKI using the Wilcoxon rank-sum test and after adjustment for age, gender, race, and prior cardiac surgery in multivariate logistic regression analysis. In patients with AKI, IL-6 levels at 2 hours had excellent predictive value for prolonged mechanical ventilation (defined as mechanical ventilation for more than 24 hours postoperatively) by receiver operator curve (ROC) analysis, with an area under the ROC curve of 0.95. IL-8 levels at 2 hours had excellent predictive value for prolonged mechanical ventilation in all patients. Serum IL-18 levels were not different between those with and without AKI., Conclusions: Serum IL-6 and IL-8 values identify AKI early in patients undergoing CPB surgery. Furthermore, among patients with AKI, high IL-6 levels are associated with prolonged mechanical ventilation, suggesting that circulating cytokines in patients with AKI may have deleterious effects on other organs, including the lungs.

Background/aims: There is limited information about the association of anemia with 25-hydroxyvitamin D [25(OH)D] deficiency and inflammation in the setting of decreased kidney function in the general population., Methods: We examined the association that anemia has with 25(OH)D deficiency and inflammation among 16,301 participants in the Third National Health and Nutrition Examination Survey (NHANES III). Measures of kidney function were estimated glomerular filtration rate (GFR) by using the Modification of Diet in Renal Disease equation., Results: The age-adjusted prevalence of anemia (hemoglobin <12 g/dl) at an estimated GFR of 59-30 ml/min/1.73 m(2) was 17% increasing to 56% for those participants with an estimated GFR <30 ml/min/1.73 m(2), while the age-adjusted prevalence of elevated C-reactive protein (CRP >0.21 mg/dl) and reduced 25(OH)D (<20 ng/ml) was 50 and 30%, respectively. After adjusting for demographics, comorbidities and laboratory results, 25(OH)D <20 ng/ml (OR: 1.17; 95% CI: 1.03-1.32; p = 0.014) and log CRP (OR: 3.63; 95% CI: 2.4-5.48 per unit increase of log CRP; p < 0.0001) were associated with hemoglobin levels <12 g/dl., Conclusion: This study provides evidence that lower 25(OH)D and higher CRP levels are independently associated with lower hemoglobin concentrations in kidney disease subjects not requiring dialysis.

Background: Patients receiving dialysis therapy for end-stage kidney failure have a high cardiovascular mortality that can only be partially explained by traditional risk factors., Methods: This study was a post hoc analysis of a prospectively gathered data set from a randomized trial comparing outcomes in new haemodialysis patients treated with sevelamer or calcium-containing phosphate binders. Patients were followed from the time of enrollment until death or censor on 31 December 2005. Median follow-up was 3.6 years. Demographics, cardiovascular risk factors, laboratory data, medication use and severity of vascular calcification were available at baseline and over the first 18 months of dialysis., Results: Baseline predictors of mortality included age, creatinine, heart rate, iPTH, C-reactive protein (CRP), coronary and aortic calcium scores and the presence of aortic valve calcification. Over the first 18 months, averages of diastolic blood pressure, BUN, creatinine, albumin, phosphorus, iPTH and CRP were all significantly different between survivors and non-survivors. A stepwise multivariable adjusted Cox regression model demonstrated that low BUN and albumin and high CRP along with the use of calcium-containing phosphate binders (rather than sevelamer) were the strongest predictors of mortality in patients new to haemodialysis., Conclusions: These findings suggest that non-traditional risk factors, such as inflammation and malnutrition measured during the first 18 months of dialysis, are important determinates of survival in new dialysis patients. In addition, the unique risk factor for dialysis patients, the use of calcium-containing phosphate binders, was associated with a higher mortality rate in patients new to dialysis.