Publications by authors named "Sharon M Moe"

173 Publications

Age and sex effects on FGF23-mediated response to mild phosphate challenge.

Bone 2021 May 19;146:115885. Epub 2021 Feb 19.

Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Medicine/Division of Nephrology, Indiana University School of Medicine, Indianapolis, IN 46202, USA. Electronic address:

Background: During aging, there is a normal and mild loss in kidney function that leads to abnormalities of the kidney-bone metabolic axis. In the setting of increased phosphorus intake, hyperphosphatemia can occur despite increased concentrations of the phosphaturic hormone FGF23. This is likely from decreased expression of the FGF23 co-receptor Klotho (KL) with age; however, the roles of age and sex in the homeostatic responses to mild phosphate challenges remain unclear.

Methods: Male and female 16-week and 78-week mice were placed on either normal grain-based chow or casein (higher bioavailable phosphate) diets for 8 weeks. Gene expression, serum biochemistries, micro-computed tomography, and skeletal mechanics were used to assess the impact of mild phosphate challenge on multiple organ systems. Cell culture of differentiated osteoblast/osteocytes was used to test mechanisms driving key outcomes.

Results: Aging female mice responded to phosphate challenge by significantly elevating serum intact FGF23 (iFGF23) versus control diet; males did not show this response. Male mice, regardless of age, exhibited higher kidney KL mRNA with similar phosphate levels across both sexes. However, males and females had similar blood phosphate, calcium, and creatinine levels irrespective of age, suggesting that female mice upregulated FGF23 to maintain blood phosphorus, and compromised renal function could not explain the increased serum iFGF23. The 17β-estradiol levels were not different between groups, and in vivo bone steroid receptor (estrogen receptor 1 [Esr1], estrogen receptor 2 [Esr2], androgen receptor [Ar]) expression was not different by age, sex, or diet. Trabecular bone volume was higher in males but decreased with both age and phosphate challenge in both sexes. Cortical porosity increased with age in males but not females. In vitro studies demonstrated that 17β-estradiol treatment upregulated FGF23 and Esr2 mRNAs in a dose-dependent manner.

Conclusions: Our study demonstrates that aging female mice upregulate FGF23 to a greater degree during a mild phosphate challenge to maintain blood phosphorus versus young female and young/old male mice, potentially due to direct estradiol effects on osteocytes. Thus, the control of phosphate intake during aging could have modifiable outcomes for FGF23-related phenotypes.
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http://dx.doi.org/10.1016/j.bone.2021.115885DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009839PMC
May 2021

Calciphylaxis or vascular oxalosis?

Clin Kidney J 2021 Jan 18;14(1):435-438. Epub 2020 Jan 18.

Division of Nephrology, Indiana University School of Medicine, Indianapolis, IN, USA.

We report the case of a 31-year-old female with primary hyperoxaluria type 1 with end-stage kidney disease who developed severe peripheral vascular disease leading to limb amputation initially thought to be secondary to calciphylaxis. However, polarized review of the pathologic specimen revealed calcium oxalate deposition in the lumen of blood vessels. This unusual presentation of systemic oxalosis demonstrates the adverse consequences of elevations of serum oxalate in patients with hyperoxaluria and that levels can acutely worsen with abrupt onset of kidney failure.
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http://dx.doi.org/10.1093/ckj/sfz190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7857799PMC
January 2021

Clinical, histopathologic and molecular features of idiopathic and diabetic nodular mesangial sclerosis in humans.

Nephrol Dial Transplant 2021 Feb 4. Epub 2021 Feb 4.

Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.

Background: Idiopathic nodular mesangial sclerosis, also called idiopathic nodular glomerulosclerosis (ING), is a rare clinical entity with an unclear pathogenesis. The hallmark of this disease is the presence of nodular mesangial sclerosis on histology without clinical evidence of diabetes mellitus or other predisposing diagnoses. To achieve insights into its pathogenesis, we queried the clinical, histopathologic and transcriptomic features of ING and nodular diabetic nephropathy (DN).

Methods: All renal biopsy reports accessioned at Indiana University Health from 2001 to 2016 were reviewed to identify 48 ING cases. Clinical and histopathologic features were compared between individuals with ING and DN (n = 751). Glomeruli of ING (n = 5), DN (n = 18) and reference (REF) nephrectomy (n = 9) samples were isolated by laser microdissection and RNA was sequenced. Immunohistochemistry of proline-rich 36 (PRR36) protein was performed.

Results: ING subjects were frequently hypertensive (95.8%) with a smoking history (66.7%). ING subjects were older, had lower proteinuria and had less hyaline arteriolosclerosis than DN subjects. Butanoate metabolism was an enriched pathway in ING samples compared with either REF or DN samples. The top differentially expressed gene, PRR36, had increased expression in glomeruli 248-fold [false discovery rate (FDR) P = 5.93 × 10-6] compared with the REF and increased 109-fold (FDR P = 1.85 × 10-6) compared with DN samples. Immunohistochemistry revealed a reduced proportion of cells with perinuclear reaction in ING samples as compared to DN.

Conclusions: Despite similar clinical and histopathologic characteristics in ING and DN, the uncovered transcriptomic signature suggests that ING has distinct molecular features from nodular DN. Further study is warranted to understand these relationships.
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http://dx.doi.org/10.1093/ndt/gfaa331DOI Listing
February 2021

The cardiovascular-dialysis nexus: the transition to dialysis is a treacherous time for the heart.

Eur Heart J 2021 Mar;42(13):1244-1253

Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 77 Ave. Louis Pasteur, NRB-741-G, Boston, MA 02115, USA.

Chronic kidney disease (CKD) patients require dialysis to manage the progressive complications of uraemia. Yet, many physicians and patients do not recognize that dialysis initiation, although often necessary, subjects patients to substantial risk for cardiovascular (CV) death. While most recognize CV mortality risk approximately doubles with CKD the new data presented here show that this risk spikes to >20 times higher than the US population average at the initiation of chronic renal replacement therapy, and this elevated CV risk continues through the first 4 months of dialysis. Moreover, this peak reflects how dialysis itself changes the pathophysiology of CV disease and transforms its presentation, progression, and prognosis. This article reviews how dialysis initiation modifies the interpretation of circulating biomarkers, alters the accuracy of CV imaging, and worsens prognosis. We advocate a multidisciplinary approach and outline the issues practitioners should consider to optimize CV care for this unique and vulnerable population during a perilous passage.
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http://dx.doi.org/10.1093/eurheartj/ehaa1049DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8014523PMC
March 2021

Spot Urine Samples to Estimate Na and K Intake in Patients With Chronic Kidney Disease and Healthy Adults: A Secondary Analysis From a Controlled Feeding Study.

J Ren Nutr 2020 Dec 9. Epub 2020 Dec 9.

Department of Nutrition Science, Purdue University, West Lafayette, IN; Department of Food Science and Nutrition, University of Minnesota, Minneapolis, MN.

Objective: The objective of this study was to assess the agreement between estimated 24-hour urinary sodium excretion (e24hUNa) and estimated 24-hour urinary potassium excretion (e24hUK), calculated from a spot urine sample using several available equations and actual sodium and potassium intake from a controlled diet in both healthy participants and those with chronic kidney disease (CKD).

Design And Methods: This study is a secondary analysis of a controlled feeding study in CKD patients matched to healthy controls. Participants (n = 16) consumed the controlled diet, which provided ∼2400 mg Na/day and ∼3000 mg K/day, for 8 days. On days 7 and 8, participants consumed all meals and collected all urine in an inpatient research setting, and they were discharged on day 9. The day 7 morning spot urine sample was used to calculate e24hUNa and e24hUK, which was compared with known sodium and potassium intake, respectively.

Results: Average e24hUNa from the INTERSALT and Tanaka-Na equations were higher than actual sodium intake by 373 mg and 559 mg, respectively, though the differences were not significant. e24hUNa from the Nerbass-SALTED equation in CKD participants was significantly higher than actual sodium intake by ∼2000 mg (P < .001), though e24hUNa from the Nerbass-RRID equation was not different from intake. e24hUK from the Tanaka-K equation was significantly lower than actual potassium intake (P < .001). For both e24hUNa and e24hUK for all participants, agreement with actual intake was poor, and e24hUNa and e24hUK were not correlated with actual sodium or potassium intake, respectively.

Conclusion: e24hUNa and e24hUK are poor indicators of true sodium and potassium intake, respectively, in both healthy and CKD participants. Findings should be confirmed in larger sample sizes with varying levels of dietary sodium and potassium.
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http://dx.doi.org/10.1053/j.jrn.2020.09.007DOI Listing
December 2020

EOS789, a broad-spectrum inhibitor of phosphate transport, is safe with an indication of efficacy in a phase 1b randomized crossover trial in hemodialysis patients.

Kidney Int 2020 Oct 31. Epub 2020 Oct 31.

Clinical Translational Sciences Institute, Indiana University School of Medicine, Indianapolis, Indiana, USA; Division of Nephrology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA. Electronic address:

The treatment of hyperphosphatemia remains challenging in patients receiving hemodialysis. This phase 1b study assessed safety and efficacy of EOS789, a novel pan-inhibitor of phosphate transport (NaPi-2b, PiT-1, PiT-2) on intestinal phosphate absorption in patients receiving intermittent hemodialysis therapy. Two cross-over, randomized order studies of identical design (ten patients each) compared daily EOS789 50 mg to placebo with meals and daily EOS789 100 mg vs EOS789 100 mg plus 1600 mg sevelamer with meals. Patients ate a controlled diet of 900 mg phosphate daily for two weeks and began EOS789 on day four. On day ten, a phosphate absorption testing protocol was performed during the intradialytic period. Intestinal fractional phosphate absorption was determined by kinetic modeling of serum data following oral and intravenous doses of Phosphate (P). The results demonstrated no study drug related serious adverse events. Fractional phosphate absorption was 0.53 (95% confidence interval: 0.39,0.67) for placebo vs. 0.49 (0.35,0.63) for 50 mg EOS789; and 0.40 (0.29,0.50) for 100 mg EOS789 vs. 0.36 (0.26,0.47) for 100 mg EOS789 plus 1600 mg sevelamer (all not significantly different). The fractional phosphate absorption trended lower in six patients who completed both studies with EOS789 100 mg compared with placebo. Thus, in this phase 1b study, EOS789 was safe and well tolerated. Importantly, the use of P as a sensitive and direct measure of intestinal phosphate absorption allows specific testing of drug efficacy. The effectiveness of EOS789 needs to be evaluated in future phase 2 and phase 3 studies.
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http://dx.doi.org/10.1016/j.kint.2020.09.035DOI Listing
October 2020

Cardiovascular Functional Changes in Chronic Kidney Disease: Integrative Physiology, Pathophysiology and Applications of Cardiopulmonary Exercise Testing.

Front Physiol 2020 15;11:572355. Epub 2020 Sep 15.

Division of Nephrology, Indiana University School of Medicine, Indianapolis, IN, United States.

The development of cardiovascular disease during renal impairment involves striking multi-tiered, multi-dimensional complex alterations encompassing the entire oxygen transport system. Complex interactions between target organ systems involving alterations of the heart, vascular, musculoskeletal and respiratory systems occur in Chronic Kidney Disease (CKD) and collectively contribute to impairment of cardiovascular function. These systemic changes have challenged our diagnostic and therapeutic efforts, particularly given that imaging cardiac structure at rest, rather than ascertainment under the stress of exercise, may not accurately reflect the risk of premature death in CKD. The multi-systemic nature of cardiovascular disease in CKD patients provides strong rationale for an integrated approach to the assessment of cardiovascular alterations in this population. State-of-the-art cardiopulmonary exercise testing (CPET) is a powerful, dynamic technology that enables the global assessment of cardiovascular functional alterations and reflects the integrative exercise response and complex machinery that form the oxygen transport system. CPET provides a wealth of data from a single assessment with mechanistic, physiological and prognostic utility. It is an underutilized technology in the care of patients with kidney disease with the potential to help advance the field of cardio-nephrology. This article reviews the integrative physiology and pathophysiology of cardio-renal impairment, critical new insights derived from CPET technology, and contemporary evidence for potential applications of CPET technology in patients with kidney disease.
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http://dx.doi.org/10.3389/fphys.2020.572355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7522507PMC
September 2020

Reversing cortical porosity: Cortical pore infilling in preclinical models of chronic kidney disease.

Bone 2021 Feb 11;143:115632. Epub 2020 Sep 11.

Department of Anatomy, Cell Biology, Physiology, Indiana University School of Medicine, Indianapolis, IN, United States; Department of Medicine - Division of Nephrology, Indiana University School of Medicine, Indianapolis, IN, United States; Department of Biomedical Engineering, Indiana University Purdue University of Indianapolis, Indianapolis, IN, United States; Roudebush Veterans Administration Medical Center, Indianapolis, IN, United States. Electronic address:

Purpose: Chronic kidney disease (CKD) patients have a high incidence of fracture due in part to cortical porosity. The goal of this study was to study cortical pore infilling utilizing two rodent models of progressive CKD.

Methods: Exp 1: Female C57Bl/6J mice (16-week-old) were given dietary adenine (0.2%) to induce CKD for 10 weeks after which calcium water supplementation (Ca-HO; 1.5% and 3%) was given to suppress PTH for another 4 weeks. Exp 2: Male Cy/+ rats were aged to ~30 weeks with baseline porosity assessed using in vivo μCT. A second in vivo scan followed 5-weeks of Ca-HO (3%) supplementation.

Results: Exp 1: Untreated adenine mice had elevated blood urea nitrogen (BUN), parathyroid hormone (PTH), and cortical porosity (~2.6% porosity) while Ca-HO lowered PTH and cortical porosity (0.5-0.8% porosity). Exp 2: Male Cy/+ rats at baseline had variable porosity (0.5%-10%), but after PTH suppression via Ca-HO, cortical porosity in all rats was lower than 0.5%. Individual pore dynamics measured via a custom MATLAB code demonstrated that 85% of pores infilled while 12% contracted in size.

Conclusion: Ca-HO supplementation causes net cortical pore infilling over time and imparted mechanical benefits. While calcium supplementation is not a viable clinical treatment for CKD, these data demonstrate pore infilling is possible and further research is required to examine clinically relevant therapeutics that may cause net pore infilling in CKD.
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http://dx.doi.org/10.1016/j.bone.2020.115632DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7770083PMC
February 2021

Mobility Impairment in Patients New to Dialysis.

Am J Nephrol 2020 11;51(9):705-714. Epub 2020 Aug 11.

Division of Nephrology, Indiana University School of Medicine, Indianapolis, Indiana, USA.

Background: Impaired mobility is associated with functional dependence, frailty, and mortality in prevalent patients undergoing dialysis. We investigated risk factors for mobility impairment, (poor gait speed) in patients incident to dialysis, and changes in gait speed over time in a 2-year longitudinal study.

Methods: One hundred eighty-three patients enrolled within 6 months of dialysis initiation were followed up 6, 12, and 24 months later. Grip strength, health-related quality of life, and comorbidities were assessed at baseline. Outcomes were (a) baseline gait speed and (b) change in gait speed over time. Gait speed was assessed by 4-meter walk. Multivariate linear regression was used to identify risk factors for low gait speed at baseline. For longitudinal analyses, linear mixed effects modeling with gait speed modeled over time was used as the outcome.

Results: Participants were 54.7 ± 12.8 years old, 52.5% men, 73.9% black with mean dialysis vintage of 100.1 ± 46.9 days and median gait speed 0.78 (0.64-0.094) m/s. Lower health utility and grip strength, diabetic nephropathy, and walking aids were associated with lower baseline gait speed. Loss of 0.1 m/s gait speed occurred in 24% of subjects at 1 year. In multivariate mixed effects models, only age, walking aid use, lower health utility, and lower handgrip strength were significantly associated with gait speed loss.

Conclusions: In our cohort of incident dialysis patients, overall gait speed is very low and 54.2% of the subjects continue to lose gait speed over 2 years. Older age, lower handgrip strength, and quality of life are risk factors for slowness. Patients at highest risk of poor gait speed can be identified at dialysis initiation to allow targeted implementation of therapeutic options.
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http://dx.doi.org/10.1159/000509225DOI Listing
August 2020

Plant-Based Diets, the Gut Microbiota, and Trimethylamine N-Oxide Production in Chronic Kidney Disease: Therapeutic Potential and Methodological Considerations.

J Ren Nutr 2021 Mar 29;31(2):121-131. Epub 2020 Jun 29.

Department of Nutrition Science, Purdue University, West Lafayette, Indiana; Division of Nephrology, Indiana University School of Medicine, Indianapolis, Indiana. Electronic address:

High circulating trimethylamine-N-oxide (TMAO) is associated with an increased risk of cardiovascular disease and mortality in people with chronic kidney disease (CKD). In individuals with CKD, reduced kidney function leads to decreased excretion of TMAO, which results in accumulation in the circulation. Higher circulating TMAO has been linked to higher intake of animal-based foods in omnivorous diets. Thus, plant-based diets have been suggested as an intervention to slow the progression of CKD and reduce cardiovascular risk, perhaps explained in part by reduced TMAO production. This article reviews the current evidence on plant-based diets as a dietary intervention to decrease gut-derived TMAO production in patients with CKD, while highlighting methodological issues that present challenges to advancing research and subsequent translation of this approach. Overall, we find that plant-based diets are promising for reducing gut-derived TMAO production in patients with CKD but that further interventional studies are warranted.
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http://dx.doi.org/10.1053/j.jrn.2020.04.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7770016PMC
March 2021

Prevalence and Persistence of Uremic Symptoms in Incident Dialysis Patients.

Kidney360 2020 Feb;1(2):86-92

Division of Nephrology, University of Mississippi Medical Center, Jackson, Mississippi.

Background: Uremic symptoms are major contributors to the poor quality of life among patients on dialysis, but whether their prevalence or intensity has changed over time is unknown.

Methods: We examined responses to validated questionnaires in two incident dialysis cohort studies, the Choices for Health Outcomes in Caring for ESRD (CHOICE) study (=926, 1995-1998) and the Longitudinal United States/Canada Incident Dialysis (LUCID) study (=428, 2011-2017). We determined the prevalence and severity of uremic symptoms-anorexia, nausea/vomiting, pruritus, sleepiness, difficulty concentrating, fatigue, and pain-in both cohorts.

Results: In CHOICE and LUCID, respectively, mean age of the participants was 58 and 60 years, 53% and 60% were male, and 28% and 32% were black. In both cohorts, 54% of the participants had diabetes. Median time from dialysis initiation to the symptoms questionnaires was 45 days for CHOICE and 77 days for LUCID. Uremic symptom prevalence in CHOICE did not change from baseline to 1-year follow-up and was similar across CHOICE and LUCID. Baseline symptom prevalence in CHOICE and LUCID was as follows: anorexia (44%, 44%, respectively), nausea/vomiting (36%, 43%), pruritus (72%, 63%), sleepiness (86%, 68%), difficulty concentrating (55%, 57%), fatigue (89%, 77%), and pain (82%, 79%). In both cohorts, >80% of patients had three or more symptoms and >50% had five or more symptoms. The correlation between individual symptoms was low (<0.5 for all comparisons). In CHOICE, no clinical or laboratory parameter was strongly associated with multiple symptoms.

Conclusions: The burden of uremic symptoms among patients on dialysis is substantial and has not changed in the past 15 years. Improving quality of life will require identification of the factors that underlie the pathogenesis of uremic symptoms and better ways of removing the toxins that are responsible.
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http://dx.doi.org/10.34067/kid.0000072019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7289028PMC
February 2020

Kidney Histopathology and Prediction of Kidney Failure: A Retrospective Cohort Study.

Am J Kidney Dis 2020 09 24;76(3):350-360. Epub 2020 Apr 24.

Division of Nephrology, Indiana University School of Medicine, Indianapolis, IN. Electronic address:

Rationale & Objective: The use of kidney histopathology for predicting kidney failure is not established. We hypothesized that the use of histopathologic features of kidney biopsy specimens would improve prediction of clinical outcomes made using demographic and clinical variables alone.

Study Design: Retrospective cohort study and development of a clinical prediction model.

Setting & Participants: All 2,720 individuals from the Biopsy Biobank Cohort of Indiana who underwent kidney biopsy between 2002 and 2015 and had at least 2 years of follow-up.

New Predictors & Established Predictors: Demographic variables, comorbid conditions, baseline clinical characteristics, and histopathologic features.

Outcomes: Time to kidney failure, defined as sustained estimated glomerular filtration rate ≤ 10mL/min/1.73m.

Analytical Approach: Multivariable Cox regression model with internal validation by bootstrapping. Models including clinical and demographic variables were fit with the addition of histopathologic features. To assess the impact of adding a histopathology variable, the amount of variance explained (r) and the C index were calculated. The impact on prediction was assessed by calculating the net reclassification index for each histopathologic variable and for all combined.

Results: Median follow-up was 3.1 years. Within 5 years of biopsy, 411 (15.1%) patients developed kidney failure. Multivariable analyses including demographic and clinical variables revealed that severe glomerular obsolescence (adjusted HR, 2.03; 95% CI, 1.51-2.03), severe interstitial fibrosis and tubular atrophy (adjusted HR, 1.99; 95% CI, 1.52-2.59), and severe arteriolar hyalinosis (adjusted HR, 1.53; 95% CI, 1.14-2.05) were independently associated with the primary outcome. The addition of all histopathologic variables to the clinical model yielded a net reclassification index for kidney failure of 5.1% (P < 0.001) with a full model C statistic of 0.915. Analyses addressing the competing risk for death, optimism, or shrinkage did not significantly change the results.

Limitations: Selection bias from the use of clinically indicated biopsies and exclusion of patients with less than 2 years of follow-up, as well as reliance on surrogate indicators of kidney failure onset.

Conclusions: A model incorporating histopathologic features from kidney biopsy specimens improved prediction of kidney failure and may be valuable clinically. Future studies will be needed to understand whether even more detailed characterization of kidney tissue may further improve prognostication about the future trajectory of estimated glomerular filtration rate.
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http://dx.doi.org/10.1053/j.ajkd.2019.12.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7483298PMC
September 2020

Implementation of a Renal Precision Medicine Program: Clinician Attitudes and Acceptance.

Life (Basel) 2020 Mar 26;10(4). Epub 2020 Mar 26.

Department of Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA.

A precision health initiative was implemented across a multi-hospital health system, wherein a panel of genetic variants was tested and utilized in the clinical care of chronic kidney disease (CKD) patients. Pharmacogenomic predictors of antihypertensive response and genomic predictors of CKD were provided to clinicians caring for nephrology patients. To assess clinician knowledge, attitudes, and willingness to act on genetic testing results, a Likert-scale survey was sent to and self-administered by these nephrology providers (N = 76). Most respondents agreed that utilizing pharmacogenomic-guided antihypertensive prescribing is valuable (4.0 ± 0.7 on a scale of 1 to 5, where 5 indicates strong agreement). However, the respondents also expressed reluctance to use genetic testing for CKD risk stratification due to a perceived lack of supporting evidence (3.2 ± 0.9). Exploratory sub-group analyses associated this reluctance with negative responses to both knowledge and attitude discipline questions, thus suggesting reduced exposure to and comfort with genetic information. Given the evolving nature of genomic implementation in clinical care, further education is warranted to help overcome these perception barriers.
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http://dx.doi.org/10.3390/life10040032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7235993PMC
March 2020

Adverse Effects of Autoclaved Diets on the Progression of Chronic Kidney Disease and Chronic Kidney Disease-Mineral Bone Disorder in Rats.

Am J Nephrol 2020 6;51(5):381-389. Epub 2020 Mar 6.

Division of Nephrology, Indiana University School of Medicine, Indianapolis, Indiana, USA,

Background: Autoclaving rodent diets is common in laboratory animals, but autoclaving increases the formation of dietary advanced glycation end-products (AGE). We studied the effect of autoclaved (AC) diet alone or in combination with a diet high in bioavailable phosphorus on biochemistries of chronic kidney disease-mineral and bone disorder (CKD-MBD), intestinal gene expression, and oxidative stress.

Methods: Male CKD rats (Cy/+) and normal littermates were fed 1 of 3 diets: AC 0.7% phosphorus grain-based diet for 28 weeks (AC); AC diet for 17 weeks followed by non-autoclaved (Non-AC) 0.7% phosphorus casein diet until 28 weeks (AC + Casein); or Non-AC diet for 16 weeks followed by a Non-AC purified diet until 30 weeks (Non-AC + Casein).

Results: AC diets contained ~3× higher AGEs and levels varied depending on the location within the autoclave. Rats fed the AC and AC + Casein diets had higher total AGEs and oxidative stress, irrespective of kidney function. Kidney function was more severely compromised in CKD rats fed AC or AC + Casein compared to Non-AC + Casein. There was a disease-by-diet interaction for plasma phosphorus, parathyroid hormone, and c-terminal fibroblast growth factor-23, driven by high values in the CKD rats fed the AC + Casein diet. Compared to Non-AC + Casein, AC and AC + Casein-fed groups had increased expression of receptor of AGEs and intestinal NADPH oxidase dual oxidase-2, independent of kidney function.

Conclusions: Autoclaving rodent diets impacts the progression of CKD and CKD-MBD, highlighting the critical importance of standardizing diets in experiments.
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http://dx.doi.org/10.1159/000506729DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7228841PMC
March 2020

Effects of etelcalcetide on fibroblast growth factor 23 in patients with secondary hyperparathyroidism receiving hemodialysis.

Clin Kidney J 2020 Feb 26;13(1):75-84. Epub 2019 Apr 26.

Department of Nephrology, Medical University of Vienna, Vienna, Austria.

Background: Etelcalcetide is an intravenous calcimimetic approved for treatment of secondary hyperparathyroidism (sHPT) in patients receiving hemodialysis. Besides lowering parathyroid hormone (PTH), etelcalcetide also significantly reduces fibroblast growth factor 23 (FGF23), but the mechanisms are unknown.

Methods: To investigate potential mediators of etelcalcetide-induced FGF23 reduction, we performed secondary analyses of the 26-week randomized trials that compared the effects on PTH of etelcalcetide ( = 509) versus placebo ( = 514) and etelcalcetide ( = 340) versus cinacalcet ( = 343) in adults with sHPT receiving hemodialysis. We analyzed changes in FGF23 in relation to changes in PTH, calcium, phosphate and bone turnover markers. We also investigated how concomitant treatments aimed at mitigating hypocalcemia altered the FGF23-lowering effects of etelcalcetide.

Results: Etelcalcetide reduced FGF23 [median % change (quartile 1-quartile 3)] from baseline to the end of the trial significantly more than placebo [-56% (-85 to -7) versus +2% (-40 to +65); P <0.001] and cinacalcet [-68% (-87 to -26) versus -41% (-76 to +25); P <0.001]. Reductions in FGF23 correlated strongly with reductions in calcium and phosphate, but not with PTH; correlations with bone turnover markers were inconsistent and of borderline significance. Increases in concomitant vitamin D administration partially attenuated the FGF23-lowering effect of etelcalcetide, but increased dialysate calcium concentration versus no increase and increased dose of calcium supplementation versus no increase did not attenuate the FGF23-lowering effects of etelcalcetide.

Conclusion: These data suggest that etelcalcetide potently lowers FGF23 in patients with sHPT receiving hemodialysis and that the effect remains detectable among patients who receive concomitant treatments aimed at mitigating treatment-associated decreases in serum calcium.
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http://dx.doi.org/10.1093/ckj/sfz034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7025329PMC
February 2020

Increasing Nephrologist Awareness of Symptom Burden in Older Hospitalized End-Stage Renal Disease Patients.

Am J Nephrol 2020 19;51(1):11-16. Epub 2019 Nov 19.

Division of Nephrology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA.

Background: End-stage renal disease (ESRD) patients have significant symptom burden. Reduced provider awareness of symptoms contributes to underutilization of symptom management resources.

Method: We hypothesized that improved nephrologist awareness of symptoms leads to symptom improvement. In this prospective, multicenter interventional study, 53 (age >65) ESRD inpatients underwent symptom assessment using the modified Edmonton Symptom Assessment System (ESAS) at admission and 1-week post-discharge. Physicians caring for the enrollees were asked if they felt their patients would die within the year, and then sequentially randomized to receive the results of the baseline survey (group 1) or to not receive the results (group 2).

Results: Fifty-two patients completed the study; 1 died. Baseline characteristics were compared. For 70% of the total cohort, physicians reported that they would not be surprised if their patient died within a year. There was no difference in baseline scores of the patients between the 2 physician groups. Severity ratings were compared between in-hospital and post discharge scores and between physicians who received the results versus those that did not. Total ESAS scores improved more in group 1 (12.9) than in group 2 (9.2; p = 0.04). Among individual symptoms, there was greater improvement in pain control (p = 0.02), and nominal improvement in itching (p = 0.03) in group 1 as compared to group 2. There were 3 palliative care consults.

Conclusions: Our findings reinforce the high symptom burden prevalent in older ESRD patients. The improvement in total scores, and individual symptoms of pain and itching in group 1 indicates better symptom control when physician awareness is increased. Residual symptoms post hospitalization and low utilization of palliative care resources are suggestive of a missed opportunity by nephrologists to address the high symptom burden at the inpatient encounter, which is selective for sick patients and/or indication of inadequacy of dialysis to control these symptoms.
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http://dx.doi.org/10.1159/000504333DOI Listing
February 2021

Effect of Advanced Glycation End-Products (AGE) Lowering Drug ALT-711 on Biochemical, Vascular, and Bone Parameters in a Rat Model of CKD-MBD.

J Bone Miner Res 2020 03 30;35(3):608-617. Epub 2019 Dec 30.

Division of Nephrology, Department of Medicine, Indiana University School of Medicine, Indianapolis, IN, USA.

Chronic kidney disease-mineral bone disorder (CKD-MBD) is a systemic disorder that affects blood measures of bone and mineral homeostasis, vascular calcification, and bone. We hypothesized that the accumulation of advanced glycation end-products (AGEs) in CKD may be responsible for the vascular and bone pathologies via alteration of collagen. We treated a naturally occurring model of CKD-MBD, the Cy/+ rat, with a normal and high dose of the AGE crosslink breaker alagebrium (ALT-711), or with calcium in the drinking water to mimic calcium phosphate binders for 10 weeks. These animals were compared to normal (NL) untreated animals. The results showed that CKD animals, compared to normal animals, had elevated blood urea nitrogen (BUN), PTH, FGF23 and phosphorus. Treatment with ALT-711 had no effect on kidney function or PTH, but 3 mg/kg lowered FGF23 whereas calcium lowered PTH. Vascular calcification of the aorta assessed biochemically was increased in CKD animals compared to NL, and decreased by the normal, but not high dose of ALT-711, with parallel decreases in left ventricular hypertrophy. ALT-711 (3 mg/kg) did not alter aorta AGE content, but reduced aorta expression of receptor for advanced glycation end products (RAGE) and NADPH oxidase 2 (NOX2), suggesting effects related to decreased oxidative stress at the cellular level. The elevated total bone AGE was decreased by 3 mg/kg ALT-711 and both bone AGE and cortical porosity were decreased by calcium treatment, but only calcium improved bone properties. In summary, treatment of CKD-MBD with an AGE breaker ALT-711, decreased FGF23, reduced aorta calcification, and reduced total bone AGE without improvement of bone mechanics. These results suggest little effect of ALT-711 on collagen, but potential cellular effects. The data also highlights the need to better measure specific types of AGE proteins at the tissue level in order to fully elucidate the impact of AGEs on CKD-MBD. © 2019 American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbmr.3925DOI Listing
March 2020

Kidney Disease Progression Does Not Decrease Intestinal Phosphorus Absorption in a Rat Model of Chronic Kidney Disease-Mineral Bone Disorder.

J Bone Miner Res 2020 02 15;35(2):333-342. Epub 2019 Nov 15.

Department of Nutrition Science, Purdue University, West Lafayette, IN, USA.

The Cy/+ rat has been characterized as a progressive model of chronic kidney disease-mineral bone disorder (CKD-MBD). We aimed to determine the effect of kidney disease progression on intestinal phosphorus absorption and whole-body phosphorus balance in this model. A total of 48 Cy/+ (CKD) and 48 normal littermates (NL) rats were studied at two ages: 20 weeks and 30 weeks, to model progressive kidney function decline at approximately 50% and 20% of normal kidney function. Sodium-dependent and sodium-independent intestinal phosphorus absorption efficiency were measured by the in situ jejunal ligated loop method using P radioisotope. Our results show that CKD rats had slightly higher sodium-dependent phosphorus absorption compared to NL rats, and absorption decreased from 20 to 30 weeks. These results are in contrast to plasma 1,25OH D, which was lower in CKD rats. Gene expression of the major intestinal phosphorus transporter, NaPi-2b, was not different between CKD and NL rats in the jejunum but was lower in CKD rats versus NL rats in the duodenum. Jejunal ligated loop phosphorus absorption results are consistent with percent net phosphorus absorption results obtained from metabolic balance: higher net percent phosphorus absorption values in CKD rats compared with NL, and lower values in 30-week-olds compared with 20-week-olds. Phosphorus balance was negative (below zero) in CKD rats, significantly lower in 30-week-old rats compared with 20-week-old rats, and lower in CKD rats compared with NL rats at both ages. These results demonstrate no reduction in intestinal phosphorus absorption with progression of CKD despite lower 1,25OH D status when assessed by an in situ ligated loop test, which is in contrast to the majority of in vitro studies, and if confirmed in further studies, could challenge the physiological relevance of in vitro findings. © 2019 American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbmr.3894DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7012714PMC
February 2020

Voluntary Wheel Running Has Beneficial Effects in a Rat Model of CKD-Mineral Bone Disorder (CKD-MBD).

J Am Soc Nephrol 2019 10 9;30(10):1898-1909. Epub 2019 Sep 9.

Division of Nephrology and.

Background: Reduced bone and muscle health in individuals with CKD contributes to their higher rates of morbidity and mortality.

Methods: We tested the hypothesis that voluntary wheel running would improve musculoskeletal health in a CKD rat model. Rats with spontaneous progressive cystic kidney disease (Cy/+ ) and normal littermates (NL) were given access to a voluntary running wheel or standard cage conditions for 10 weeks starting at 25 weeks of age when the rats with kidney disease had reached stage 2-3 of CKD. We then measured the effects of wheel running on serum biochemistry, tissue weight, voluntary grip strength, maximal aerobic capacity (VO), body composition and bone micro-CT and mechanics.

Results: Wheel running improved serum biochemistry with decreased creatinine, phosphorous, and parathyroid hormone in the rats with CKD. It improved muscle strength, increased time-to-fatigue (for VO), reduced cortical porosity and improved bone microarchitecture. The CKD rats with voluntary wheel access also had reduced kidney cystic weight and reduced left ventricular mass index.

Conclusions: Voluntary wheel running resulted in multiple beneficial systemic effects in rats with CKD and improved their physical function. Studies examining exercise interventions in patients with CKD are warranted.
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http://dx.doi.org/10.1681/ASN.2019040349DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6779348PMC
October 2019

Tester and testing procedure influence clinically determined gait speed.

Gait Posture 2019 10 28;74:83-86. Epub 2019 Aug 28.

Indiana Center for Musculoskeletal Health, Indiana University, Indianapolis, IN, United States; Division of Nephrology, Department of Medicine, School of Medicine, Indiana University, Indianapolis, IN, United States.

Background: There is a clinical need to be able to reliably detect meaningful changes (0.1 to 0.2 m/s) in usual gait speed (UGS) considering reduced gait speed is associated with morbidity and mortality.

Research Question: What is the impact of tester on UGS assessment, and the influence of test repetition (trial 1 vs. 2), timing method (manual stopwatch vs. automated timing), and starting condition (stationary vs. dynamic start) on the ability to detect changes in UGS and fast gait speed (FGS)?

Methods: UGS and FGS was assessed in 725 participants on a 8-m course with infrared timing gates positioned at 0, 2, 4 and 6 m. Testing was performed by one of 13 testers trained by a single researcher. Time to walk 4-m from a stationary start (i.e. from 0-m to 4-m) was measured manually using a stopwatch and automatically via the timing gates at 0-m and 4-m. Time taken to walk 4-m with a dynamic start was measured during the same trial by recording the time to walk between the timing gates at 2-m and 6-m (i.e. after 2-m acceleration).

Results: Testers differed for UGS measured using manual vs. automated timing (p = 0.02), with five and two testers recording slower and faster UGS using manual timing, respectively. 95% limits of agreement for trial 1 vs. 2, manual vs. automated timing, and dynamic vs. stationary start ranged from ±0.15 m/s to ±0.20 m/s, coinciding with the range for a clinically meaningful change. Limits of agreement for FGS were larger ranging from ±0.26 m/s to ±0.35 m/s.

Significance: Repeat testing of UGS should performed by the same tester or using an automated timing method to control for tester effects. Test protocol should remain constant both between and within participants as protocol deviations may result in detection of an artificial clinically meaningful change.
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http://dx.doi.org/10.1016/j.gaitpost.2019.08.020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6790294PMC
October 2019

Skeletal levels of bisphosphonate in the setting of chronic kidney disease are independent of remodeling rate and lower with fractionated dosing.

Bone 2019 10 9;127:419-426. Epub 2019 Jul 9.

Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, United States; Department of Medicine - Division of Nephrology, Indiana University School of Medicine, Indianapolis, IN, United States; Department of Biomedical Engineering, Indiana University Purdue University of Indianapolis, Indianapolis, IN, United States; Roudebush Veterans Administration Medical Center, Indianapolis, IN, United States. Electronic address:

Background: Chronic kidney disease (CKD) results in a dramatic increase in skeletal fracture risk. Bisphosphates (BP) are an effective treatment for reducing fracture risk but they are not recommended in advanced CKD. We have recently shown higher acute skeletal accumulation of fluorescently-tagged zoledronate (ZOL) in the setting of CKD but how this accumulation is retained/lost over time is unclear. Furthermore, it is unknown if alternative dosing approaches can modulate accumulation in the setting of CKD.

Methods: To address these two questions normal (NL) and Cy/+ (CKD) rats were divided into control groups (no dosing), a single dose of a fluorescent-tagged ZOL (FAM-ZOL), a single dose of non-labelled zoledronate (ZOL) or ten weekly doses of FAM-ZOL each at 1/10th the dose of the single dose group. Half of the CKD animals in each group were provided water with 3% calcium in drinking water (CKD + Ca) to suppress PTH and remodeling. At 30 or 35 weeks of age, serum, tibia, ulna, radius, vertebra, femora, and mandible were collected and subjected to assessment methods including biochemistry, dynamic histomorphometry and multi-spectral fluorescence levels (using IVIS SpectrumCT).

Results: FAM-ZOL did not significantly reduce bone remodeling in either NL or CKD animals while Ca supplementation in CKD produced remodeling levels comparable to NL. At five- and ten-weeks post-dosing, both CKD and CKD + Ca groups had higher levels of FAM-ZOL in most, but not all, skeletal sites compared to NL with no difference between the two CKD groups suggesting that the rate of remodeling did not affect skeletal retention of FAM-ZOL. Fractionating the FAM-ZOL into ten weekly doses led to 20-32% less (p < 0.05) accumulation/retention of compound in the vertebra, radius, and ulna compared to administration as a single dose.

Conclusions: The rate of bone turnover does not have significant effects on levels of FAM-ZOL accumulation/retention in animals with CKD. A lower dose/more frequent administration paradigm results in lower levels of accumulation/retention over time. These data provide information that could better inform the use of bisphosphonates in the setting of CKD in order to combat the dramatic increase in fracture risk.
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http://dx.doi.org/10.1016/j.bone.2019.07.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6708715PMC
October 2019

Effect of ovariectomy on the progression of chronic kidney disease-mineral bone disorder (CKD-MBD) in female Cy/+ rats.

Sci Rep 2019 05 28;9(1):7936. Epub 2019 May 28.

Department of Nutrition Science, Purdue University, West Lafayette, IN, 47907, USA.

Male Cy/+ rats have shown a relatively consistent pattern of progressive kidney disease development that displays multiple key features of late stage chronic kidney disease-mineral bone disorder (CKD-MBD), specifically the development of cortical bone porosity. However, progression of disease in female Cy/+ rats, assessed in limited studies, is more heterogeneous and to date has failed to show development of the CKD-MBD phenotype, thus limiting their use as a practical model of progressive CKD-MBD. Animal and human studies suggest that estrogen may be protective against kidney disease in addition to its established protective effect on bone. Therefore, in this study, we aimed to determine the effect of ovariectomy (OVX) on the biochemical and skeletal manifestations of CKD-MBD in Cy/+ female rats. We hypothesized that OVX would accelerate development of the biochemical and skeletal features of CKD-MBD in female Cy/+ rats, similar to those seen in male Cy/+ rats. Female Cy/+ rats underwent OVX (n = 8) or Sham (n = 8) surgery at 15 weeks of age. Blood was collected every 5 weeks post-surgery until 35 weeks of age, when the rats underwent a 4-day metabolic balance, and the tibia and final blood were collected at the time of sacrifice. OVX produced the expected changes in trabecular and cortical parameters consistent with post-menopausal disease, and negative phosphorus balance compared with Sham. However, indicators of CKD-MBD were similar between OVX and Sham (similar kidney weight, plasma blood urea nitrogen, creatinine, creatinine clearance, phosphorus, calcium, parathyroid hormone, and no cortical porosity). Contrary to our hypothesis, OVX did not produce evidence of development of the CKD-MBD phenotype in female Cy/+ rats.
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http://dx.doi.org/10.1038/s41598-019-44415-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6538713PMC
May 2019

Time course of rapid bone loss and cortical porosity formation observed by longitudinal μCT in a rat model of CKD.

Bone 2019 08 3;125:16-24. Epub 2019 May 3.

Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN, United States; Department of Medicine, Division of Nephrology, Indiana University School of Medicine, Indianapolis, IN, United States; Department of Biomedical Engineering, Indiana University Purdue University of Indianapolis, Indianapolis, IN, United States; Roudebush Veterans Administration Medical Center, Indianapolis, IN, United States. Electronic address:

Background: Rodent studies of bone in chronic kidney disease have primarily relied on end-point examinations of bone microarchitecture. This study used longitudinal in vivo microcomputed tomography (in vivo μCT) to characterize the onset and progression of bone loss, specifically cortical porosity, in the Cy/+ rat of model of CKD.

Methods: Male CKD rats and normal littermates were studied. In vivo μCT scans of the right distal tibia repeated at 25, 30, and 35 weeks were analyzed for longitudinal changes in cortical and trabecular bone morphometry. In vitro μCT scans of the tibia and femur identified spatial patterns of bone loss across distal, midshaft and proximal sites.

Results: CKD animals had reduced BV/TV and cortical BV at all time points but developed cortical porosity and thinning between 30 and 35 weeks. Cortical pore formation was localized near the endosteal surface. The severity of bone loss was variable across bone sites, but the distal tibia was representative of both cortical and trabecular changes.

Conclusions: The distal tibia was found to be a sensitive suitable site for longitudinal imaging of both cortical and trabecular bone changes in the CKD rat. CKD trabecular bone loss progressed through ~30 weeks followed by a sudden acceleration in cortical bone catabolism. These changes varied in timing and severity across individuals, and cortical bone loss and porosity progressed rapidly once initiated. The inclusion of longitudinal μCT in future studies will be important for both reducing the number of required animals and to track individual responses to treatment.
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http://dx.doi.org/10.1016/j.bone.2019.05.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6581598PMC
August 2019

Phosphate Binders and Nonphosphate Effects in the Gastrointestinal Tract.

J Ren Nutr 2020 01 4;30(1):4-10. Epub 2019 Mar 4.

Division of Nephrology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana; Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, Indiana; Department of Medicine, Roudebush Veterans Affairs Medical Center, Indianapolis, Indiana. Electronic address:

Phosphate binders are commonly prescribed in patients with end-stage kidney disease to prevent and treat hyperphosphatemia. These binders are usually associated with gastrointestinal distress, may bind molecules other than phosphate, and may alter the gut microbiota, altogether having systemic effects unrelated to phosphate control. Sevelamer is the most studied of the available binders for nonphosphate-related effects including binding to bile acids, endotoxins, gut microbiota-derived metabolites, and advanced glycation end products. Other binders (calcium- and noncalcium-based binders) may bind vitamins, such as vitamin K and folic acid. Moreover, the relatively new iron-based phosphate binders may alter the gut microbiota, as some of the iron or organic ligands may be used by the gastrointestinal bacteria. The objective of this narrative review is to provide the current evidence for the nonphosphate effects of phosphate binders on gastrointestinal function, nutrient and molecule binding, and the gut microbiome.
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http://dx.doi.org/10.1053/j.jrn.2019.01.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6722023PMC
January 2020

Increased FGF23 protects against detrimental cardio-renal consequences during elevated blood phosphate in CKD.

JCI Insight 2019 02 21;4(4). Epub 2019 Feb 21.

Department of Medical and Molecular Genetics.

The phosphaturic hormone FGF23 is elevated in chronic kidney disease (CKD). The risk of premature death is substantially higher in the CKD patient population, with cardiovascular disease (CVD) as the leading mortality cause at all stages of CKD. Elevated FGF23 in CKD has been associated with increased odds for all-cause mortality; however, whether FGF23 is associated with positive adaptation in CKD is unknown. To test the role of FGF23 in CKD phenotypes, a late osteoblast/osteocyte conditional flox-Fgf23 mouse (Fgf23fl/fl/Dmp1-Cre+/-) was placed on an adenine-containing diet to induce CKD. Serum analysis showed casein-fed Cre+ mice had significantly higher serum phosphate and blood urea nitrogen (BUN) versus casein diet and Cre- genotype controls. Adenine significantly induced serum intact FGF23 in the Cre- mice over casein-fed mice, whereas Cre+ mice on adenine had 90% reduction in serum intact FGF23 and C-terminal FGF23 as well as bone Fgf23 mRNA. Parathyroid hormone was significantly elevated in mice fed adenine diet regardless of genotype, which significantly enhanced midshaft cortical porosity. Echocardiographs of the adenine-fed Cre+ hearts revealed profound aortic calcification and cardiac hypertrophy versus diet and genotype controls. Thus, these studies demonstrate that increased bone FGF23, although associated with poor outcomes in CKD, is necessary to protect against the cardio-renal consequences of elevated tissue phosphate.
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http://dx.doi.org/10.1172/jci.insight.123817DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6478421PMC
February 2019

Comparison of Risk Factors for Pediatric Kidney Stone Formation: The Effects of Sex.

Front Pediatr 2019 12;7:32. Epub 2019 Feb 12.

Division of Nephrology, Akron Children's Hospital, Akron, OH, United States.

Urinary stones are affecting more children, and pediatric stone formers have unique pathophysiology compared to adults. While adult stone formers are most frequently male, children have an age dependent sex prevalence. Under 10 years, a majority of stone formers are boys; adolescent stone formers are mostly female. Previous adult studies have shown that stone composition is influenced by the sex and age of the stone former. Thus, we hypothesize that female and male stone forming children will also have sex and age specific stone phenotypes. Retrospective chart review of a large pediatric center's stone forming children 6/1/2009 to 6/1/2016. Patients were identified by ICD 9 codes: N20, N20.1, and N20.9. Charts were reviewed for radiographic evidence of stones or documented visualized stone passage. One hundred and thirty six subjects: 54 males and 82 females. Females were older, median age 14 years [interquartile range (IQR): 11, 15] vs. males' median age 12 years (IQR: 11, 14) ( < 0.01). Females had lower height -scores, median 0.2 (IQR: -0.8, 0.8) vs. males' median 0.8 (IQR: -0.2, 1.8) ( < 0.01). Presenting symptoms were similar except flank pain affecting 39% of females vs. 22% of males ( = 0.04). Leukocyte esterase was positive in more females than males (33 vs. 4%) ( < 0.001). Males had a higher BUN/Cr ratio, mean ± standard deviation of 19.8 ± 6.3 vs. 16.6 ± 6.5 in females ( = 0.01). Glomerular hyperfiltration was present in 9% of patients while 35% of patients had estimated glomerular filtration rate (eGFR) < 90 ml/min/1.73 m. Treatment strategies and clinical course were similar except females were told to increase dietary citrate more frequently than males (21 vs. 4%) ( < 0.01). We have provided a novel analysis and demonstrated that low height -score and pyuria are more common in female stone formers. We have also shown that 9% of pediatric stone formers have labs consistent with hyperfiltration. Whether high protein intake and/or chronic dehydration are associated with hyperfiltration and long-term renal function in children with kidney stones will be an area for future research.
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http://dx.doi.org/10.3389/fped.2019.00032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6379338PMC
February 2019

Fibroblast Growth Factor 23 Genotype and Cardiovascular Disease in Patients Undergoing Hemodialysis.

Am J Nephrol 2019 22;49(2):125-132. Epub 2019 Jan 22.

Division of Nephrology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA,

Background: Elevated serum concentrations of fibroblast growth factor 23 (FGF23) are associated with cardiovascular mortality in patients with chronic kidney disease and those undergoing dialysis.

Objectives: We tested the hypotheses that polymorphisms in FGF23, its co-receptor alpha-klotho (KL), and/or FGF23 receptors (FGFR) are associated with cardiovascular events and/or mortality.

Methods: We used 1,494 DNA samples collected at baseline from the Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events Trial, in which patients were randomized to the calcimimetic cinacalcet or placebo for the treatment of secondary hyperparathyroidism. We analyzed European and African Ancestry samples separately and then combined summary statistics to perform a meta-analysis. We evaluated single-nucleotide polymorphisms (SNPs) in FGF23, KL, and FGFR4 as the key exposures of interest in proportional hazards (Cox) regression models using adjudicated endpoints (all-cause and cardiovascular mortality, sudden cardiac death, and heart failure [HF]) as the outcomes of interest.

Results: rs11063112 in FGF23 was associated with cardiovascular mortality (risk allele = A, hazard ratio [HR] 1.32, meta-p value = 0.004) and HF (HR 1.40, meta-p value = 0.007). No statistically significant associations were observed between FGF23 rs13312789 and SNPs in FGFR4 or KL genes and the outcomes of interest.

Conclusions: rs11063112 was associated with HF and cardiovascular mortality in patients receiving dialysis with moderate to severe secondary hyperparathyroidism.
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http://dx.doi.org/10.1159/000496060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6473180PMC
April 2020

Characterizing Dysgeusia in Hemodialysis Patients.

Chem Senses 2019 03;44(3):165-171

Department of Nutrition Science, Purdue University, West Lafayette, IN, USA.

Dysgeusia (abnormal taste) is common in those with chronic kidney disease and contributes to poor nutritional intake. Previous sensory work has shown that taste improves after dialysis sessions. The goal of this pilot study was to characterize altered taste perceptions in patients on dialysis compared with healthy adults, and to evaluate relationships between serum parameters with taste perceptions. We hypothesized that patients undergoing dialysis would experience blunted taste intensities compared with controls, and that serum levels of potential tastants would be inversely related to taste perception of compounds. Using a cross-sectional design, we carried out suprathreshold sensory assessments (flavor intensity and liking) of tastants/flavors potentially influenced by kidney disease and/or the dialysis procedure. These included sodium chloride, potassium chloride, calcium chloride, sodium phosphate, phosphoric acid, urea, ferrous sulfate, and monosodium glutamate. Individuals on maintenance hemodialysis (n= 17, 10 males, range 23-87 years) were compared with controls with normal gustatory function (n=29, 13 males, range 21-61 years). Unadjusted values for intensity and liking for the solutions showed minimal differences. However, when values were adjusted for participants' perceptions of water (as a control for taste abnormalities), intensity of monosodium glutamate, sodium chloride, and sodium phosphate solutions were more intense for patients on dialysis compared with controls. Some significant correlations were also observed between serum parameters, particularly potassium, for dialysis patients and sensory ratings. These results suggest altered taste perception in patients during dialysis warrants further study.
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http://dx.doi.org/10.1093/chemse/bjz001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6594298PMC
March 2019

Effect of dietary phosphorus intake and age on intestinal phosphorus absorption efficiency and phosphorus balance in male rats.

PLoS One 2018 19;13(11):e0207601. Epub 2018 Nov 19.

Department of Nutrition Science, Purdue University, West Lafayette, IN, United States of America.

Intestinal phosphorus absorption is an important component of whole-body phosphorus metabolism, and limiting dietary phosphorus absorption is particularly of interest as a therapeutic target in patients with chronic kidney disease to manage mineral bone disorders. Yet, mechanisms and regulation of intestinal phosphorus absorption have not been adequately studied and discrepancies in findings exist based on the absorption assessment technique used. In vitro techniques show rather consistent effects of dietary phosphorus intake level and age on intestinal sodium-dependent phosphate transport. But, the few studies that have used in vivo techniques conflict with these in vitro studies. Therefore, we aimed to investigate the effects of dietary phosphorus intake level on phosphorus absorption using the in situ ligated loop technique in three different aged rats. Male Sprague-Dawley rats (n = 72), were studied at 10-, 20-, and 30-weeks-of-age on a low (0.1%), normal (0.6%), or high (1.2%) phosphorus diet in a 3x3 factorial design (n = 8/group). Rats were fed their assigned diet for 2-weeks prior to absorption testing by jejunal ligated loop as a non-survival procedure, utilizing 33P radioisotope. Metabolic cages were used for determination of calcium and phosphorus balance over the final four days prior to sacrifice, and blood was collected at the time of sacrifice for biochemistries. Our results show that phosphorus absorption was higher in 10-week-old rats compared with 20- and 30-week-olds and this corresponded to higher gene expression of the major phosphate transporter, NaPi-2b, as well as higher whole-body phosphorus balance and net phosphorus absorption. Dietary phosphorus intake level did not affect jejunal phosphorus absorption or NaPi-2b gene expression. Our results contrast with studies utilizing in vitro techniques, but corroborate results of other rodent studies utilizing in situ or in vivo methods. Thus, there is need for additional studies that employ more physiological methods of phosphorus absorption assessment.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0207601PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6242370PMC
April 2019

Sudden cardiac death in patients undergoing dialysis: More than a single toxin.

Authors:
Sharon M Moe

Heart Rhythm 2019 02 24;16(2):318-319. Epub 2018 Sep 24.

Division of Nephrology, Indiana University School of Medicine, Indianapolis, Indiana. Electronic address:

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http://dx.doi.org/10.1016/j.hrthm.2018.09.017DOI Listing
February 2019