Publications by authors named "Tamara Isakova"

117 Publications

Advance Care Planning in Older Adults with CKD: Patient, Care Partner, and Clinician Perspectives.

J Am Soc Nephrol 2021 Apr 7. Epub 2021 Apr 7.

William B Schwartz MD Division of Nephrology, Tufts Medical Center, Boston, Massachusetts.

Background: Older patients with advanced CKD are at high risk for serious complications and death, yet few discuss advance care planning (ACP) with their kidney clinicians. Examining barriers and facilitators to ACP among such patients might help identify patient-centered opportunities for improvement.

Methods: In semistructured interviews in March through August 2019 with purposively sampled patients (aged ≥70 years, CKD stages 4-5, nondialysis), care partners, and clinicians at clinics in across the United States, participants described discussions, factors contributing to ACP completion or avoidance, and perceived value of ACP. We used thematic analysis to analyze data.

Results: We conducted 68 semistructured interviews with 23 patients, 29 care partners, and 26 clinicians. Only seven of 26 (27%) clinicians routinely discussed ACP. About half of the patients had documented ACP, mostly outside the health care system. We found divergent ACP definitions and perspectives; kidney clinicians largely defined ACP as completion of formal documentation, whereas patients viewed it more holistically, wanting discussions about goals, prognosis, and disease trajectory. Clinicians avoided ACP with patients from minority groups, perceiving cultural or religious barriers. Four themes and subthemes informing variation in decisions to discuss ACP and approaches emerged: () role ambiguity and responsibility for ACP, () questioning the value of ACP, () confronting institutional barriers (time, training, reimbursement, and the electronic medical record, EMR), and () consequences of avoiding ACP (disparities in ACP access and overconfidence that patients' wishes are known).

Conclusions: Patients, care partners, and clinicians hold discordant views about the responsibility for discussing ACP and the scope for it. This presents critical barriers to the process, leaving ACP insufficiently discussed with older adults with advanced CKD.
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http://dx.doi.org/10.1681/ASN.2020091298DOI Listing
April 2021

Subtyping CKD Patients by Consensus Clustering: The Chronic Renal Insufficiency Cohort (CRIC) Study.

J Am Soc Nephrol 2021 Mar 18;32(3):639-653. Epub 2021 Jan 18.

Department of Biostatistics, Epidemiology and Informatics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.

Background: CKD is a heterogeneous condition with multiple underlying causes, risk factors, and outcomes. Subtyping CKD with multidimensional patient data holds the key to precision medicine. Consensus clustering may reveal CKD subgroups with different risk profiles of adverse outcomes.

Methods: We used unsupervised consensus clustering on 72 baseline characteristics among 2696 participants in the prospective Chronic Renal Insufficiency Cohort (CRIC) study to identify novel CKD subgroups that best represent the data pattern. Calculation of the standardized difference of each parameter used the cutoff of ±0.3 to show subgroup features. CKD subgroup associations were examined with the clinical end points of kidney failure, the composite outcome of cardiovascular diseases, and death.

Results: The algorithm revealed three unique CKD subgroups that best represented patients' baseline characteristics. Patients with relatively favorable levels of bone density and cardiac and kidney function markers, with lower prevalence of diabetes and obesity, and who used fewer medications formed cluster 1 (=1203). Patients with higher prevalence of diabetes and obesity and who used more medications formed cluster 2 (=1098). Patients with less favorable levels of bone mineral density, poor cardiac and kidney function markers, and inflammation delineated cluster 3 (=395). These three subgroups, when linked with future clinical end points, were associated with different risks of CKD progression, cardiovascular disease, and death. Furthermore, patient heterogeneity among predefined subgroups with similar baseline kidney function emerged.

Conclusions: Consensus clustering synthesized the patterns of baseline clinical and laboratory measures and revealed distinct CKD subgroups, which were associated with markedly different risks of important clinical outcomes. Further examination of patient subgroups and associated biomarkers may provide next steps toward precision medicine.
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http://dx.doi.org/10.1681/ASN.2020030239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7920178PMC
March 2021

Association of Educational Attainment With Incidence of CKD in Young Adults.

Kidney Int Rep 2020 Dec 19;5(12):2256-2263. Epub 2020 Sep 19.

Center for Translational Metabolism and Health, Institute for Public Health and Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.

Introduction: Chronic kidney disease (CKD) is greatly affected by social determinants of health. Whether low educational attainment is associated with incident CKD in young adults is unclear.

Methods: We evaluated the association of education with incident CKD in 3139 Coronary Artery Risk Development in Young Adults participants. We categorized education into low (high school and less), medium (college), and high (master's and professional studies) groups. Incident CKD was defined as new development of estimated glomerular filtration rate (eGFR) <60 ml/min per 1.73 m or urine albumin to creatinine ratio (ACR) ≥30 mg/g. Change in eGFR over 20 years was a secondary outcome.

Results: At baseline, mean age was 35.0 ± 3.6 years, 47% were Black, and 55% were women. Participants with lower educational attainment were less likely to have high income and health insurance and to engage in a healthy lifestyle. Over 20 years, 407 participants developed CKD (13%). Compared with individuals with low educational attainment, those with medium and high educational attainment had an unadjusted hazard ratios for CKD of 0.79 (95% confidence interval [CI] 0.65-0.97) and 0.44 (95% CI, 0.30-0.63), respectively. This association was no longer significant after adjusting for income, health insurance, lifestyle, and health status. Low educational attainment was significantly associated with a change in eGFR in crude and adjusted analyses, although the association was attenuated in the multivariable models (low: -0.83 [95% CI, -0.91 to -0.75], medium: -0.80 (95% CI, -0.95 to -0.64), and high: -0.70 (95% CI, -0.89 to -0.52) ml/min per 1.73 m per yr).

Conclusions: Health care access, lifestyle, and comorbid conditions likely help explain the association between low educational attainment and incident CKD in young adults.
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http://dx.doi.org/10.1016/j.ekir.2020.09.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7710886PMC
December 2020

Design and Rationale of HiLo: A Pragmatic, Randomized Trial of Phosphate Management for Patients Receiving Maintenance Hemodialysis.

Am J Kidney Dis 2020 Dec 3. Epub 2020 Dec 3.

Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, NC; Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC. Electronic address:

Rationale & Objective: Hyperphosphatemia is a risk factor for poor clinical outcomes in patients with kidney failure receiving maintenance dialysis. Opinion-based clinical practice guidelines recommend the use of phosphate binders and dietary phosphate restriction to lower serum phosphate levels toward the normal range in patients receiving maintenance dialysis, but the benefits of these approaches and the optimal serum phosphate target have not been tested in randomized trials. It is also unknown if aggressive treatment that achieves unnecessarily low serum phosphate levels worsens outcomes.

Study Design: Multicenter, pragmatic, cluster-randomized clinical trial.

Setting & Participants: HiLo will randomize 80-120 dialysis facilities operated by DaVita Inc and the University of Utah to enroll 4,400 patients undergoing 3-times-weekly, in-center hemodialysis.

Intervention: Phosphate binder prescriptions and dietary recommendations to achieve the "Hi" serum phosphate target (≥6.5 mg/dL) or the "Lo" serum phosphate target (<5.5 mg/dL).

Outcomes: Primary outcome: Hierarchical composite outcome of all-cause mortality and all-cause hospitalization. Main secondary outcomes: Individual components of the primary outcome.

Results: The trial is currently enrolling.

Limitations: HiLo will not adjudicate causes of hospitalizations or mortality and does not protocolize use of specific phosphate binder classes.

Conclusions: HiLo aims to address an important clinical question while more generally advancing methods for pragmatic clinical trials in nephrology by introducing multiple innovative features including stakeholder engagement in the study design, liberal eligibility criteria, use of electronic informed consent, engagement of dietitians to implement the interventions in real-world practice, leveraging electronic health records to eliminate dedicated study visits, remote monitoring of serum phosphate separation between trial arms, and use of a novel hierarchical composite outcome.

Trial Registration: Registered at ClinicalTrials.gov with study number NCT04095039.
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http://dx.doi.org/10.1053/j.ajkd.2020.10.008DOI Listing
December 2020

Variability in Kidney Function Estimates in Emerging Adults With Spina Bifida: Implications for Transitioning From Pediatric to Adult Care.

Urology 2021 Feb 24;148:306-313. Epub 2020 Nov 24.

Division of Urology, Department of Surgery, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL; Center for Health Services and Outcomes Research, Institute for Public Health and Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL.

Objective: To examine the variability of estimated glomerular filtration rate (eGFR) in emerging adults with spina bifida (SB) by comparing multiple equations across the transitional age period, hypothesizing that creatinine (Cr)-based equations show greater variability than cystatin-C (CysC)- or combination-based equations.

Methods: A retrospective cohort study was performed from 2012 to 2017 at a multidisciplinary SB clinic. Emerging adults were defined as patients ages 18-28 years old. Four pediatric, 3 adult, and 3 averaged eGFR equations were considered. Cross-sectional variability in eGFR data was assessed using coefficients of variation, chronic kidney disease (CKD) stage classification, and pairwise percent relative difference in eGFR between analogous pediatric and adult equations based on included lab values. Longitudinal changes in eGFR over time were compared across equations using a covariance pattern model accounting for repeated measures.

Results: Seventy-five emerging adults with SB (median age 21.8 years; 55% female; 83% with myelomeningocele) were included in cross-sectional analyses. Adult equations gave higher median eGFRs by 22%-27% and generally milder CKD stage classification than analogous pediatric equations. In longitudinal analyses (median follow-up of 22 months), all equations conferred negative eGFR changes over time (range -1.9 to -4.3 mL/min/1.73m per year) that were not significantly different.

Conclusion: In emerging adults with SB, adult equations demonstrated higher median eGFRs by 22%-27% compared to analogous pediatric equations, even with Cystatin-C, and generally downstaged CKD stage classification. The same eGFR equation should be used for serial kidney function monitoring in emerging adults with SB who transition care from pediatric to adult services.
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http://dx.doi.org/10.1016/j.urology.2020.10.050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7880582PMC
February 2021

Diagnostic Test Characteristics of Ultrasound Based Hydronephrosis in Identifying Low Kidney Function in Young Patients with Spina Bifida: A Retrospective Cohort Study.

J Urol 2021 04 18;205(4):1180-1188. Epub 2020 Nov 18.

Nephrology and Hypertension, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois.

Purpose: Kidney dysfunction in spina bifida is usually detected by low estimated glomerular filtration rate or ultrasound based hydronephrosis. We assessed the diagnostic test characteristics of hydronephrosis for detecting low estimated glomerular filtration rate, hypothesizing that hydronephrosis has low sensitivity compared to cystatin C based estimated glomerular filtration rate.

Materials And Methods: We conducted a single center, retrospective cohort study, including patients with spina bifida from 2012-2017 with 2 kidneys and complete data needed to calculate estimated glomerular filtration rate via multiple pediatric (age 1-17.9 years) or adult (age ≥18 years) estimating equations. We evaluated the association of hydronephrosis status (high grade, low grade or none) with estimated glomerular filtration rate, adjusting for small kidney size and scarring, and calculated diagnostic test characteristics of hydronephrosis for low estimated glomerular filtration rate.

Results: We analyzed 247 patients (176 children and 71 adults). Mean±SD age was 13.7±6.6 years, and 81% of patients had myelomeningocele. Hydronephrosis (77% low grade) was found in 35/176 children and 18/71 adults. Hydronephrosis was associated with low estimated glomerular filtration rate in stepwise fashion, independent of kidney size and scarring. However, across cystatin C based pediatric equations, any hydronephrosis (compared to none) had 23%-48% sensitivity, and high grade hydronephrosis (compared to none or low grade) had 4%-15% sensitivity for estimated glomerular filtration rate <90 ml/min/1.73 m, which remained unchanged after excluding small kidneys and scarring. Across cystatin C based adult equations, any and high grade hydronephrosis had 55%-75% and 40%-100% sensitivity, respectively, for estimated glomerular filtration rate <90 ml/min/1.73 m, although with wide confidence intervals. Specificity was higher with high grade vs any hydronephrosis. Sensitivities were higher for estimated glomerular filtration rate <60 ml/min/1.73 m.

Conclusions: Hydronephrosis was associated with low estimated glomerular filtration rate but had poor sensitivity for cystatin C based estimated glomerular filtration rate <90 ml/min/1.73 m, especially among children with spina bifida.
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http://dx.doi.org/10.1097/JU.0000000000001411DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7946739PMC
April 2021

Systematic integrated analysis of genetic and epigenetic variation in diabetic kidney disease.

Proc Natl Acad Sci U S A 2020 11 3;117(46):29013-29024. Epub 2020 Nov 3.

Department of Medicine, Renal Electrolyte and Hypertension Division, University of Pennsylvania, Philadelphia, PA 19104;

Poor metabolic control and host genetic predisposition are critical for diabetic kidney disease (DKD) development. The epigenome integrates information from sequence variations and metabolic alterations. Here, we performed a genome-wide methylome association analysis in 500 subjects with DKD from the Chronic Renal Insufficiency Cohort for DKD phenotypes, including glycemic control, albuminuria, kidney function, and kidney function decline. We show distinct methylation patterns associated with each phenotype. We define methylation variations that are associated with underlying nucleotide variations (methylation quantitative trait loci) and show that underlying genetic variations are important drivers of methylation changes. We implemented Bayesian multitrait colocalization analysis (moloc) and summary data-based Mendelian randomization to systematically annotate genomic regions that show association with kidney function, methylation, and gene expression. We prioritized 40 loci, where methylation and gene-expression changes likely mediate the genotype effect on kidney disease development. Functional annotation suggested the role of inflammation, specifically, apoptotic cell clearance and complement activation in kidney disease development. Our study defines methylation changes associated with DKD phenotypes, the key role of underlying genetic variations driving methylation variations, and prioritizes methylome and gene-expression changes that likely mediate the genotype effect on kidney disease pathogenesis.
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http://dx.doi.org/10.1073/pnas.2005905117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7682409PMC
November 2020

Fibroblast Growth Factor 23 and Exercise Capacity in Heart Failure with Preserved Ejection Fraction.

J Card Fail 2021 Mar 7;27(3):309-317. Epub 2020 Oct 7.

Center for Translational Metabolism and Health, Institute of Public Health and Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois; Division of Nephrology and Hypertension, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois; Division of Nephrology, Department of Medicine, Jesse Brown Veterans Affairs Medical Center, Chicago, Illinois. Electronic address:

Background: Heart failure with preserved ejection fraction (HFpEF) is characterized by left ventricular hypertrophy and decreased exercise capacity. Fibroblast growth factor 23 (FGF23), a hormone involved in phosphate, vitamin D, and iron homeostasis, is linked to left ventricular hypertrophy and HF. We measured c-terminal FGF23 (cFGF23) and intact FGF23 (iFGF23) levels and examined their associations with exercise capacity in patients with HFpEF.

Methods And Results: Using multivariable linear regression and linear mixed models, we studied the associations of cFGF23 and iFGF23 with baseline and mean weekly change over 24 weeks in peak oxygen consumption and 6-minute walk distance in individuals enrolled in the Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in HFpEF trial. Our study population included 172 individuals with available plasma for cFGF23 and iFGF23 measurements. Median (25th-75th percentile) baseline cFGF23 and iFGF23 levels were 208.7 RU/mL (132.1-379.5 RU/mL) and 90.3 pg/mL (68.6-128.5 pg/mL), respectively. After adjustment for cardiovascular disease and hematologic and kidney parameters, higher cFGF23 was independently associated with a lower peak oxygen consumption at baseline. Higher iFGF23 was independently associated with shorter 6-minute walk distance at baseline. No significant associations were appreciated with the longitudinal outcomes.

Conclusions: In patients with HFpEF, higher FGF23 levels are independently associated with decreased exercise capacity at baseline.
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http://dx.doi.org/10.1016/j.cardfail.2020.09.477DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7914143PMC
March 2021

Mineral bone disease in autosomal dominant polycystic kidney disease.

Kidney Int 2021 04 11;99(4):977-985. Epub 2020 Sep 11.

Division of Renal Diseases and Hypertension, University of Colorado Denver Anschutz Medical Campus, Aurora, Colorado, USA. Electronic address:

Mice with disruption of Pkd1 in osteoblasts demonstrate reduced bone mineral density, trabecular bone volume and cortical thickness. To date, the bone phenotype in adult patients with autosomal dominant polycystic kidney disease (ADPKD) with stage I and II chronic kidney disease has not been investigated. To examine this, we characterized biochemical markers of mineral metabolism, examined bone turnover and biology, and estimated risk of fracture in patients with ADPKD. Markers of mineral metabolism were measured in 944 patients with ADPKD and other causes of kidney disease. Histomorphometry and immunohistochemistry were compared on bone biopsies from 20 patients with ADPKD with a mean eGFR of 97 ml/min/1.73m and 17 healthy individuals. Furthermore, adults with end stage kidney disease (ESKD) initiating hemodialysis between 2002-2013 and estimated the risk of bone fracture associated with ADPKD as compared to other etiologies of kidney disease were examined. Intact fibroblast growth factor 23 was higher and total alkaline phosphatase lower in patients with compared to patients without ADPKD with chronic kidney disease. Compared to healthy individuals, patients with ADPKD demonstrated significantly lower osteoid volume/bone volume (0.61 vs. 1.21%) and bone formation rate/bone surface (0.012 vs. 0.026 μm/μm/day). ESKD due to ADPKD was not associated with a higher risk of fracture as compared to ESKD due to diabetes (age adjusted incidence rate ratio: 0.53 (95% confidence interval 0.31, 0.74) or compared to other etiologies of kidney disease. Thus, individuals with ADPKD have lower alkaline phosphatase, higher circulating intact fibroblast growth factor 23 and decreased bone formation rate. However, ADPKD is not associated with higher rates of bone fracture in ESKD.
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http://dx.doi.org/10.1016/j.kint.2020.07.041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7993988PMC
April 2021

Drug Development in Kidney Disease: Proceedings From a Multistakeholder Conference.

Am J Kidney Dis 2020 12 5;76(6):842-850. Epub 2020 Aug 5.

Division of Nephrology, Department of Medicine, Duke University School of Medicine, Durham, NC; Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC.

Occasional bursts of discovery and innovation have appeared during the otherwise stagnant past several decades of drug development in nephrology. Among other recent drug discoveries, the unexpected kidney benefits observed with sodium/glucose cotransporter 2 inhibitors may herald a renaissance of drug development in kidney disease. This recent progress highlights the need to further promote and stimulate research and development of promising therapies that may ameliorate the morbidity and mortality associated with kidney disease. To help identify and address barriers to drug development in nephrology, the Duke Clinical Research Institute convened a conference in April 2019 that included stakeholders from academia, industry, government agencies, and patient advocacy. From these discussions, several opportunities were identified to improve every stage of drug development for kidney disease from early discovery to implementation into practice. Key topics reviewed in this article are the utility of interconnected data and site research networks, surrogate end points, pragmatic and adaptive trial designs, the promising uses of real-world data, and methods to improve the generalizability of trial results and uptake of approved drugs for kidney-related diseases.
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http://dx.doi.org/10.1053/j.ajkd.2020.05.026DOI Listing
December 2020

Effects of ferric carboxymaltose on markers of mineral and bone metabolism: A single-center prospective observational study of women with iron deficiency.

Bone 2020 12 28;141:115559. Epub 2020 Jul 28.

Division of Nephrology and Hypertension, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA; Center for Translational Metabolism and Health, Institute for Public Health and Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA; Jesse Brown Veterans Administration Medical Center, Chicago, IL 60612, USA.

Background: Two weekly infusions of ferric carboxymaltose (FCM) are commonly prescribed for treatment of iron-deficiency anemia. However, administration of FCM increases intact levels of fibroblast growth factor 23 (FGF23), which causes hypophosphatemia due to renal phosphate wasting, calcitriol deficiency and secondary hyperparathyroidism. The adverse effects of FCM on mineral metabolism and bone health emerged from case reports and secondary analyses of trials. Data on these safety signals with FCM in clinical practice are limited because markers of mineral and bone metabolism are not routinely checked.

Methods: To obtain real-world experience with effects of FCM on mineral and bone metabolism, we conducted a prospective observational study of 16 women who were managed at a single-center hematology clinic for iron-deficiency anemia. From October 2016 to February 2018, all participants received two weekly infusions of FCM at a hematology infusion clinic. We hypothesized that FCM would decrease phosphate, increase intact FGF23 (iFGF23), and decrease c-terminal FGF23 (cFGF23). Secondary outcomes were changes in hemoglobin, iron indices, urine fractional excretion of phosphate (FePi), parathyroid hormone (PTH), calcitriol, calcium, osteocalcin, and bone-specific alkaline phosphatase (BAP). FCM was administered at weeks zero and one, and we measured laboratory values at weeks zero, one, two, and five of the study. We used linear mixed models to analyze the significance of the changes in laboratory values over time.

Results: After two FCM infusions, nearly all (14 of 16) participants developed hypophosphatemia. iFGF23 increased, cFGF23 decreased, and phosphate decreased significantly from week zero to week two (iFGF23 increased by +134.0% [40.6, 305.8], p < 0.001; cFGF23 decreased by -516.3% [-1332.7, -142.7], p = 0.002; phosphate decreased by -49.8 ± 15.4%, p < 0.001). There was also a significant increase in FePi, PTH, and BAP and a significant decrease in calcitriol and calcium from week zero to week two. There was no significant change in osteocalcin during this time period. iFGF23, but not PTH, was independently associated with decreased phosphate. iFGF23 was also significantly associated with decrease in calcitriol from week zero to week two. Elevation in BAP suggests disordered bone mineralization in response to FCM therapy.

Conclusion: In this prospective observational study of women with iron deficiency anemia, two FCM infusions significantly altered markers of bone mineralization and mineral metabolism. The results suggest that FCM should be used cautiously in the treatment of iron-deficiency anemia.
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http://dx.doi.org/10.1016/j.bone.2020.115559DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7680361PMC
December 2020

Fibroblast Growth Factor 23 and Risk of Hospitalization with Infection in Chronic Kidney Disease: The Chronic Renal Insufficiency Cohort (CRIC) Study.

J Am Soc Nephrol 2020 08 23;31(8):1836-1846. Epub 2020 Jun 23.

Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.

Background: Risk of infectious disease is increased among individuals with CKD. Fibroblast growth factor 23 (FGF23) is often elevated in CKD, and may impair immune function directly or indirectly through proinflammatory and vitamin D-suppressing pathways. Whether FGF23 is associated with risk of infection has not been evaluated in a CKD population.

Methods: In 3655 participants of the Chronic Renal Insufficiency Cohort study, we evaluated the association of baseline plasma levels of C-terminal FGF23 with time to first hospitalization with major infection, defined by hospital discharge with a diagnosis code for urinary tract infection, pneumonia, cellulitis/osteomyelitis, or bacteremia/septicemia. Multivariable Cox models were used to estimate hazard ratios (HRs) and adjust for confounding.

Results: During a median follow-up of 6.5 years, 1051 individuals (29%) were hospitalized with major infection. Multivariable Cox analysis indicated a graded increase in the risk of infection with higher levels of FGF23 (HR, 1.51; 95% CI, 1.23 to 1.85 with the highest quartile [≥235.9 RU/ml] versus lowest quartile [<95.3 RU/ml]; HR, 1.26; 95% CI, 1.18 to 1.35 per SD increment in log FGF23). The association was consistent across infection subtypes and demographic and clinical subgroups, and remained significant after additional adjustment for biomarkers of inflammation (IL-6, TNF-, high-sensitivity C-reactive protein, fibrinogen, and albumin), and bone mineral metabolism (25-hydroxyvitamin D, phosphorus, calcium, and parathyroid hormone). The association was consistent across infection subtypes of urinary tract infection (482 cases), cellulitis/osteomyelitis (422 cases), pneumonia (399 cases), and bacteremia/septicemia (280 cases).

Conclusions: Among individuals with CKD, higher FGF23 levels were independently and monotonically associated with an increased risk of hospitalization with infection.
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http://dx.doi.org/10.1681/ASN.2019101106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7460903PMC
August 2020

Editorial: New and repurposed therapeutics for mineral, stone and vascular disorders.

Curr Opin Nephrol Hypertens 2020 07;29(4):357-358

Division of Nephrology and Hypertension, Department of Medicine and Center for Translational Metabolism and Health, Institute for Public Health and Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA.

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http://dx.doi.org/10.1097/MNH.0000000000000620DOI Listing
July 2020

Kidney Functional Magnetic Resonance Imaging and Change in eGFR in Individuals with CKD.

Clin J Am Soc Nephrol 2020 06 28;15(6):776-783. Epub 2020 Apr 28.

Division of Nephrology and Hypertension, Center for Translational Metabolism and Health, Institute for Public Health and Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois.

Background And Objectives: Kidney functional magnetic resonance imaging (MRI) requires further investigation to enhance the noninvasive identification of patients at high risk of CKD progression.

Design, Setting, Participants, & Measurements: In this exploratory study, we obtained baseline diffusion-weighted and blood oxygen level-dependent MRI in 122 participants of the CKD Optimal Management with Binders and Nicotinamide trial, which was a multicenter, randomized, double-blinded, 12-month, four-group parallel trial of nicotinamide and lanthanum carbonate versus placebo conducted in individuals with eGFR 20-45 ml/min per 1.73 m. Lower values of apparent diffusion coefficient (ADC) on diffusion-weighted MRI may indicate increased fibrosis, and higher values of relaxation rate (R2*) on blood oxygen level-dependent MRI may represent decreased oxygenation. Because there was no effect of active treatment on eGFR over 12 months, we tested whether baseline kidney functional MRI biomarkers were associated with eGFR decline in all 122 participants. In a subset of 87 participants with 12-month follow-up MRI data, we evaluated whether kidney functional MRI biomarkers change over time.

Results: Mean baseline eGFR was 32±9 ml/min per 1.73 m, and mean annual eGFR slope was -2.3 (95% confidence interval [95% CI], -3.4 to -1.1) ml/min per 1.73 m per year. After adjustment for baseline covariates, baseline ADC was associated with change in eGFR over time (difference in annual eGFR slope per 1 SD increase in ADC: 1.3 [95% CI, 0.1 to 2.5] ml/min per 1.73 m per year, ADC×time interaction =0.04). This association was no longer significant after further adjustment for albuminuria (difference in annual eGFR slope per 1 SD increase in ADC: 1.0 (95% CI, -0.1 to 2.2) ml/min per 1.73 m per year, ADC×time interaction =0.08). There was no significant association between baseline R2* and change in eGFR over time. In 87 participants with follow-up functional MRI, ADC and R2* values remained stable over 12 months (intraclass correlation: 0.71 and 0.68, respectively).

Conclusions: Baseline cortical ADC was associated with change in eGFR over time, but this association was not independent of albuminuria. Kidney functional MRI biomarkers remained stable over 1 year.

Clinical Trial Registry Name And Registration Number: CKD Optimal Management with Binders and Nicotinamide (COMBINE), NCT02258074.
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http://dx.doi.org/10.2215/CJN.13201019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7274274PMC
June 2020

A Simple Equation to Estimate Urinary Flow Rate Using Urine Creatinine.

Am J Nephrol 2020 9;51(5):395-400. Epub 2020 Mar 9.

Division of Nephrology-Hypertension, Department of Medicine, University of California San Diego, San Diego, California, USA,

Background: Accurate assessment of urine flow remains challenging in both inpatient and outpatient settings. We hypothesized we could derive an equation that would accurately estimate urine flow rate (eV) through derivation from other existing equations commonly used in nephrology clinical practice.

Methods: The eV equation was derived using the Cockcroft-Gault and the measured creatinine clearance (CrCl = UCrV/PCr) equations. Within the African American Study of Kidney Disease and Hypertension (AASK; n = 570) and COMBINE (n = 133) clinical trials, we identified participants with concordant estimated and measured creatinine excretion rates to define a subset with highly accurate 24-h urine collections, to assure a reliable gold standard. We then compared eV to measured 24-h urine flow rates in these trials.

Results: In AASK, we found a high correlation between eV and measured urine flow rate (V; r = 0.91, p < 0.001); however, Bland-Altman plots showed that eV was 9.5 mL/h lower than V, on average. Thus, we added a correction factor to the eV equation and externally validated the new equation in COMBINE. eV and V were again highly correlated (r = 0.91, p < 0.001), and bias was improved (mean difference 5.3 mL/h). Overall, 80% of individuals had eV that was within 20% of V.

Conclusions: A simple equation using urine creatinine, demographics, and body weight can accurately predict urine flow rate and may have clinical utility in situations where it is difficult to accurately measure the urine flow rate.
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http://dx.doi.org/10.1159/000506728DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7228836PMC
March 2020

Racial Differences in the Associations Between Food Insecurity and Fibroblast Growth Factor 23 in the Coronary Artery Risk Development in Young Adults Study.

J Ren Nutr 2020 11 6;30(6):509-517. Epub 2020 Mar 6.

Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois.

Objective: Food insecurity is associated with consumption of phosphate additive-laden processed food and beverage products, which could result in higher levels of fibroblast growth factor 23 (FGF23) to compensate for the increased dietary phosphate load. We sought to determine whether food insecurity is associated with higher levels of FGF23. We stratified analyses by race since differences may occur between food insecurity and diet quality across races.

Design And Methods: The longitudinal community-based Coronary Artery Risk Development in Young Adults Study recruited from 4 US centers: Birmingham, AL; Chicago, IL; Minneapolis, MN; and Oakland, CA, during the cohort inception in 1985/1986. This analysis included 3,421 black and white participants from Coronary Artery Risk Development in Young Adults follow-up years 20, 25, and 30 who were enrolled in the study between the ages of 18 and 30 years. Econometric fixed effects models stratified by race that adjust by design for all time-invariant covariates were used to model the longitudinal association of food insecurity, defined as the self-reported ability to afford desired quantity and quality of food. The main outcome of interest was changing to the highest quartile of plasma FGF-23 concentrations.

Results: During follow-up, 29% of blacks and 14% of whites experienced change in food security. Developing food insecurity was associated with a 1.48 greater odds of increasing to the highest quartile of FGF23 (95% confidence interval 1.02-2.15) among blacks; however, there was no significant longitudinal association among whites (odds ratio = 1.14, 95% confidence interval 0.67-1.95).

Conclusions: Among blacks, food insecurity was associated with an increase in levels of FGF23. Although phosphate consumption was presumed to mediate the association between food insecurity and FGF23 levels, we were unable to directly test this pathway.
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http://dx.doi.org/10.1053/j.jrn.2020.01.020DOI Listing
November 2020

Kidney Function Surveillance in the National Spina Bifida Patient Registry: A Retrospective Cohort Study.

J Urol 2020 09 6;204(3):578-586. Epub 2020 Mar 6.

Center for Translational Metabolism and Health, Institute for Public Health and Medicine, Feinberg School of Medicine at Northwestern University, Chicago, Illinois.

Purpose: Chronic kidney disease affects 25% to 50% of patients with spina bifida. Guidelines recommend kidney function surveillance in these patients but practice patterns are unknown. Variations in kidney function surveillance were assessed in patients with spina bifida based on the hypothesis that the treating clinic and spina bifida type would be associated with kidney function surveillance.

Materials And Methods: A retrospective cohort study was conducted of U.S. patients in the National Spina Bifida Patient Registry from 2013 to 2018. Followup was anchored at the 2013 visit. Participants with either an outcome event within 2 years of followup or more than 2 years of followup without an outcome event were included. Primary outcome was kidney function surveillance, defined as at least 1 renal ultrasound and serum creatinine within 2 years of followup. Primary exposures were clinic and spina bifida type, which were analyzed with covariates including sociodemographic and clinical characteristics in logistic regression models for their association with the outcome. Sensitivity analyses were performed using different kidney function surveillance definitions.

Results: Of 8,351 patients 5,445 were included with a median followup of 3.0 years. Across 23 treating clinics kidney function surveillance rates averaged 62% (range 6% to 100%). In multivariable models kidney function surveillance was associated with treating clinic, younger patient age, functional lesion level, nonambulatory status and prior bladder augmentation. Treating clinic remained a significant predictor of kidney function surveillance in all sensitivity analyses.

Conclusions: Within the National Spina Bifida Patient Registry wide variation exists in practice of kidney function surveillance across treating clinics despite adjustment for key patient characteristics.
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http://dx.doi.org/10.1097/JU.0000000000001010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7415638PMC
September 2020

Identifying sub-phenotypes of acute kidney injury using structured and unstructured electronic health record data with memory networks.

J Biomed Inform 2020 02 3;102:103361. Epub 2020 Jan 3.

Weill Cornell Medicine, New York, NY, USA. Electronic address:

Acute Kidney Injury (AKI) is a common clinical syndrome characterized by the rapid loss of kidney excretory function, which aggravates the clinical severity of other diseases in a large number of hospitalized patients. Accurate early prediction of AKI can enable in-time interventions and treatments. However, AKI is highly heterogeneous, thus identification of AKI sub-phenotypes can lead to an improved understanding of the disease pathophysiology and development of more targeted clinical interventions. This study used a memory network-based deep learning approach to discover AKI sub-phenotypes using structured and unstructured electronic health record (EHR) data of patients before AKI diagnosis. We leveraged a real world critical care EHR corpus including 37,486 ICU stays. Our approach identified three distinct sub-phenotypes: sub-phenotype I is with an average age of 63.03±17.25 years, and is characterized by mild loss of kidney excretory function (Serum Creatinine (SCr) 1.55±0.34 mg/dL, estimated Glomerular Filtration Rate Test (eGFR) 107.65±54.98 mL/min/1.73 m). These patients are more likely to develop stage I AKI. Sub-phenotype II is with average age 66.81±10.43 years, and was characterized by severe loss of kidney excretory function (SCr 1.96±0.49 mg/dL, eGFR 82.19±55.92 mL/min/1.73 m). These patients are more likely to develop stage III AKI. Sub-phenotype III is with average age 65.07±11.32 years, and was characterized moderate loss of kidney excretory function and thus more likely to develop stage II AKI (SCr 1.69±0.32 mg/dL, eGFR 93.97±56.53 mL/min/1.73 m). Both SCr and eGFR are significantly different across the three sub-phenotypes with statistical testing plus postdoc analysis, and the conclusion still holds after age adjustment.
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http://dx.doi.org/10.1016/j.jbi.2019.103361DOI Listing
February 2020

Vitamin D Metabolic Ratio and Risks of Death and CKD Progression.

Kidney Int Rep 2019 Nov 30;4(11):1598-1607. Epub 2019 Aug 30.

Division of Nephrology, Department of Medicine, University of Washington, Seattle, Washington, USA.

Introduction: Assessment of impaired vitamin D metabolism is limited by lack of functional measures. CYP24A1-mediated vitamin D clearance, calculated as the ratio of serum 24,25-dihydroxyvitamin D3 to 25-hydroxyvitamin D3 (the vitamin D metabolic ratio, VDMR), is induced by 1,25-dihydroxyvitamin D and may assess tissue-level activity. We tested associations of the VDMR with risks of death and progression to end-stage renal disease (ESRD) in patients with chronic kidney disease (CKD).

Methods: We studied participants from the Chronic Renal Insufficiency Cohort (CRIC), which included a random subset of 1080 CRIC participants plus additional participants who experienced ESRD or died (case cohort study design). Serum 24,25-dihydroxyvitamin D3 and 25-hydroxyvitamin D3 was measured 1 year after enrollment. The primary outcomes included death and progression to ESRD. Using inverse probability weighting, we tested associations of VDMR (24,25[OH]D/25[OH]D) with risks of death and ESRD, adjusting for demographics, comorbidity, and kidney function (estimated glomerular filtration rate [eGFR] and urine protein-to-creatinine ratio [PCR]).

Results: There were a total of 708 ESRD events and 650 deaths events over mean (SD) follow-up periods of 4.9 (2.9) years and 6.5 (2.5) years, respectively. Lower VDMR was associated with increased risk of ESRD prior to adjusting for kidney function (hazard ratio [HR], 1.80 per 20 pg/ng lower VDMR; 95% confidence interval [CI], 1.56-2.08), but not with adjustment for kidney function (HR, 0.94 per 20 pg/ng; 95% CI, 0.81-1.10). Lower VDMR was associated with modestly increased mortality risk, including adjustment for kidney function (HR, 1.18 per 20 pg/ng; 95% CI, 1.02-1.36).

Conclusion: Lower VDMR, a measure of CYP24A1-mediated vitamin D clearance, was significantly associated with all-cause mortality but not with progression to ESRD in patients with CKD.
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http://dx.doi.org/10.1016/j.ekir.2019.08.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6933450PMC
November 2019

Serial Fibroblast Growth Factor 23 Measurements and Risk of Requirement for Kidney Replacement Therapy: The CRIC (Chronic Renal Insufficiency Cohort) Study.

Am J Kidney Dis 2020 06 19;75(6):908-918. Epub 2019 Dec 19.

Division of Nephrology and Hypertension, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL; Center for Translational Metabolism and Health, Institute of Public Health and Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL.

Rationale & Objective: Studies using a single measurement of fibroblast growth factor 23 (FGF-23) suggest that elevated FGF-23 levels are associated with increased risk for requirement for kidney replacement therapy (KRT) in patients with chronic kidney disease. However, the data do not account for changes in FGF-23 levels as kidney disease progresses.

Study Design: Case-cohort study.

Setting & Participants: To evaluate the association between serial FGF-23 levels and risk for requiring KRT, our primary analysis included 1,597 individuals in the Chronic Renal Insufficiency Cohort Study who had up to 5 annual measurements of carboxy-terminal FGF-23. There were 1,135 randomly selected individuals, of whom 266 initiated KRT, and 462 individuals who initiated KRT outside the random subcohort.

Exposure: Serial FGF-23 measurements and FGF-23 trajectory group membership.

Outcomes: Incident KRT.

Analytical Approach: To handle time-dependent confounding, our primary analysis of time-updated FGF-23 levels used time-varying inverse probability weighting in a discrete time failure model. To compare our results with prior data, we used baseline and time-updated FGF-23 values in weighted Cox regression models. To examine the association of FGF-23 trajectory subgroups with risk for incident KRT, we used weighted Cox models with FGF-23 trajectory groups derived from group-based trajectory modeling as the exposure.

Results: In our primary analysis, the HR for the KRT outcome per 1 SD increase in the mean of natural log-transformed (ln)FGF-23 in the past was 1.94 (95% CI, 1.51-2.49). In weighted Cox models using baseline and time-updated values, elevated FGF-23 level was associated with increased risk for incident KRT (HRs per 1 SD ln[FGF-23] of 1.18 [95% CI, 1.02-1.37] for baseline and 1.66 [95% CI, 1.49-1.86] for time-updated). Membership in the slowly and rapidly increasing FGF-23 trajectory groups was associated with ∼3- and ∼21-fold higher risk for incident KRT compared to membership in the stable FGF-23 trajectory group.

Limitations: Residual confounding and lack of intact FGF-23 values.

Conclusions: Increasing FGF-23 levels are independently associated with increased risk for incident KRT.
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http://dx.doi.org/10.1053/j.ajkd.2019.09.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7247939PMC
June 2020

A Randomized Trial Comparing the Safety, Adherence, and Pharmacodynamics Profiles of Two Doses of Sodium Bicarbonate in CKD: the BASE Pilot Trial.

J Am Soc Nephrol 2020 01 17;31(1):161-174. Epub 2019 Dec 17.

Department of Internal Medicine, University of Utah Health and Renal Section, Veterans Affairs Salt Lake City Health Care System, Salt Lake City, Utah.

Background: Oral sodium bicarbonate (NaHCO) may preserve kidney function in CKD, even if initiated when serum bicarbonate concentration is normal. Adequately powered trials testing this hypothesis have not been conducted, partly because the best dose for testing is unknown.

Methods: This multicenter pilot trial assessed the safety, tolerability, adherence, and pharmacodynamics of two doses of NaHCO over 28 weeks in adults with eGFR 20-44 or 45-59 ml/min per 1.73 m with urinary albumin/creatinine (ACR) ≥50 mg/g and serum bicarbonate 20-28 meq/L. We randomly assigned 194 participants from ten clinical sites to receive higher-dose (HD-NaHCO; 0.8 meq/kg of lean body wt per day; =90) or lower-dose (LD-NaHCO; 0.5 meq/kg of lean body wt per day; =52) NaHCO or matching placebo (=52). The dose was adjusted depending on side effects. The prescribed dose at week 28 was the primary outcome; a dose was considered acceptable for a full-scale trial if ≥67% of participants were on full-dose and ≥80% were on ≥25% of the per-protocol dose.

Results: Mean±SD baseline eGFR was 36±9 ml/min per 1.73 m, serum bicarbonate was 24±2 meq/L, and median (IQR) ACR was 181 (25-745) mg/g. Both doses were well tolerated without significant changes in BP, weight, or serum potassium. The proportions of adverse events and hospitalizations were similar across the groups. Consequently, 87% in HD-NaHCO, 96% in LD-NaHCO, and 87% in placebo were on full dose at week 28; and 91% in HD-NaHCO, 98% in LD-NaHCO, and 92% in placebo were on ≥25% of the per-protocol dose. Mean urinary ammonium excretion was 25% lower and serum bicarbonate concentration was 1.3 meq/L higher in HD-NaHCO compared with LD-NaHCO at week 28. However, mean ACR increased by 12% in the lower-dose group and 30% in the higher-dose group.

Conclusions: Both NaHCO doses were well tolerated over 28 weeks with no significant difference in adverse events or hospitalization compared with placebo. The higher dose lowered urinary ammonium excretion and increased serum bicarbonate more than the lower dose but was associated with a greater increase in ACR. The higher 0.8 meq/kg of lean body wt per day dose of NaHCO may be a reasonable choice for future trials.
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http://dx.doi.org/10.1681/ASN.2019030287DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6934992PMC
January 2020

Inflammatory Markers and Incidence of Hospitalization With Infection in Chronic Kidney Disease.

Am J Epidemiol 2020 05;189(5):433-444

Persons with chronic kidney disease (CKD) are at high risk of infection. While low-grade inflammation could impair immune response, it is unknown whether inflammatory markers are associated with infection risk in this clinical population. Using 2003-2013 data from the Chronic Renal Insufficiency Cohort Study (3,597 participants with CKD), we assessed the association of baseline plasma levels of 4 inflammatory markers (interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), interleukin-1 receptor antagonist (IL-1RA), and transforming growth factor-β (TGF-β)) with incident hospitalization with major infection (pneumonia, urinary tract infection, cellulitis and osteomyelitis, and bacteremia and sepsis). During follow-up (median 7.5 years), 36% (n = 1,290) had incident hospitalization with major infection. In multivariable Cox analyses with each inflammatory marker modeled as a restricted cubic spline, higher levels of IL-6 and TNF-α were monotonically associated with increased risk of hospitalization with major infection (for 95th vs. 5th percentile, hazard ratio = 2.11 (95% confidence interval: 1.68, 2.66) for IL-6 and 1.88 (95% confidence interval: 1.51, 2.33) for TNF-α), while corresponding associations for IL-1RA or TGF-β were nonsignificant. Thus, higher plasma levels of IL-6 and TNF-α, but not IL-1RA or TGF-β, were significantly associated with increased risk of hospitalization with major infection. Future studies should investigate whether inflammatory pathways that involve IL-6 and TNF-α increase susceptibility to infection among individuals with CKD.
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http://dx.doi.org/10.1093/aje/kwz246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7306687PMC
May 2020

Ferric citrate reduces fibroblast growth factor 23 levels and improves renal and cardiac function in a mouse model of chronic kidney disease.

Kidney Int 2019 12 30;96(6):1346-1358. Epub 2019 Aug 30.

Division of Nephrology and Hypertension, Department of Medicine, and Center for Translational Metabolism and Health, Institute for Public Health and Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, USA. Electronic address:

Iron deficiency, anemia, hyperphosphatemia, and increased fibroblast growth factor 23 (FGF23) are common and interrelated complications of chronic kidney disease (CKD) that are linked to CKD progression, cardiovascular disease and death. Ferric citrate is an oral phosphate binder that decreases dietary phosphate absorption and serum FGF23 concentrations while increasing iron stores and hemoglobin in patients with CKD. Here we compared the effects of ferric citrate administration versus a mineral sufficient control diet using the Col4a3 knockout mouse model of progressive CKD and age-matched wild-type mice. Ferric citrate was given to knockout mice for four weeks beginning at six weeks of age when they had overt CKD, or for six weeks beginning at four weeks of age when they had early CKD. Ten-week-old knockout mice on the control diet showed overt iron deficiency, anemia, hyperphosphatemia, increased serum FGF23, hypertension, decreased kidney function, and left ventricular systolic dysfunction. Ferric citrate rescued iron deficiency and anemia in knockout mice regardless of the timing of treatment initiation. Circulating levels and bone expression of FGF23 were reduced in knockout mice given ferric citrate with more pronounced reductions observed when ferric citrate was initiated in early CKD. Ferric citrate decreased serum phosphate only when it was initiated in early CKD. While ferric citrate mitigated systolic dysfunction in knockout mice regardless of timing of treatment initiation, early initiation of ferric citrate also reduced renal fibrosis and proteinuria, improved kidney function, and prolonged life span. Thus, initiation of ferric citrate treatment early in the course of murine CKD lowered FGF23, slowed CKD progression, improved cardiac function and significantly improved survival.
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http://dx.doi.org/10.1016/j.kint.2019.07.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6875640PMC
December 2019

Longitudinal Evolution of Markers of Mineral Metabolism in Patients With CKD: The Chronic Renal Insufficiency Cohort (CRIC) Study.

Am J Kidney Dis 2020 02 23;75(2):235-244. Epub 2019 Oct 23.

Division of Nephrology, Department of Medicine, and Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC.

Rationale & Objective: The pathogenesis of disordered mineral metabolism in chronic kidney disease (CKD) is largely informed by cross-sectional studies of humans and longitudinal animal studies. We sought to characterize the longitudinal evolution of disordered mineral metabolism during the course of CKD.

Study Design: Retrospective analysis nested in a cohort study.

Setting & Participants: Participants in the Chronic Renal Insufficiency Cohort (CRIC) Study who had up to 5 serial annual measurements of estimated glomerular filtration rate, fibroblast growth factor 23 (FGF-23), parathyroid hormone (PTH), serum phosphate, and serum calcium and who subsequently reached end-stage kidney disease (ESKD) during follow-up (n = 847).

Exposure: Years before ESKD.

Outcomes: Serial FGF-23, PTH, serum phosphate, and serum calcium levels.

Analytical Approach: To assess longitudinal dynamics of disordered mineral metabolism in human CKD, we used "ESKD-anchored longitudinal analyses" to express time as years before ESKD, enabling assessments of mineral metabolites spanning 8 years of CKD progression before ESKD.

Results: Mean FGF-23 levels increased markedly as time before ESKD decreased, while PTH and phosphate levels increased modestly and calcium levels declined minimally. Compared with other mineral metabolites, FGF-23 levels demonstrated the highest rate of change (velocity: first derivative of the function of concentration over time) and magnitude of acceleration (second derivative). These changes became evident approximately 5 years before ESKD and persisted without deceleration through ESKD onset. Rates of changes in PTH and phosphate levels increased modestly and without marked acceleration around the same time, with modest deceleration immediately before ESKD, when use of active vitamin D and phosphate binders increased.

Limitations: Individuals who entered the CRIC Study at early stages of CKD and who did not progress to ESKD were not studied.

Conclusions: Among patients with progressive CKD, FGF-23 levels begin to increase 5 years before ESKD and continue to rapidly accelerate until transition to ESKD.
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http://dx.doi.org/10.1053/j.ajkd.2019.07.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7012684PMC
February 2020

Serum Calcification Propensity and Clinical Events in CKD.

Clin J Am Soc Nephrol 2019 11 28;14(11):1562-1571. Epub 2019 Oct 28.

Center for Translational Metabolism and Health, Institute for Public Health and Medicine, and

Background And Objectives: Patients with CKD are at high risk for cardiovascular disease, ESKD, and mortality. Vascular calcification is one pathway through which cardiovascular disease risks are increased. We hypothesized that a novel measure of serum calcification propensity is associated with cardiovascular disease events, ESKD, and all-cause mortality among patients with CKD stages 2-4.

Design, Setting, Participants, & Measurements: Among 3404 participants from the prospective, longitudinal Chronic Renal Insufficiency Cohort Study, we quantified calcification propensity as the transformation time (T) from primary to secondary calciprotein particles, with lower T corresponding to higher calcification propensity. We used multivariable-adjusted Cox proportional hazards regression models to assess the associations of T with risks of adjudicated atherosclerotic cardiovascular disease events (myocardial infarction, stroke, and peripheral artery disease), adjudicated heart failure, ESKD, and mortality.

Results: The mean T was 313 (SD 79) minutes. Over an average 7.1 (SD 3.1) years of follow-up, we observed 571 atherosclerotic cardiovascular disease events, 633 heart failure events, 887 ESKD events, and 924 deaths. With adjustment for traditional cardiovascular disease risk factors, lower T was significantly associated with higher risk of atherosclerotic cardiovascular disease (hazard ratio [HR] per SD lower T, 1.14; 95% confidence interval [95% CI], 1.05 to 1.25), ESKD within 3 years from baseline (HR per SD lower T, 1.68; 95% CI, 1.52 to 1.86), and all-cause mortality (HR per SD lower T, 1.16; 95% CI, 1.09 to 1.24), but not heart failure (HR per SD lower T, 1.06; 95% CI, 0.97 to 1.15). After adjustment for eGFR and 24-hour urinary protein, T was not associated with risks of atherosclerotic cardiovascular disease, ESKD, and mortality.

Conclusions: Among patients with CKD stages 2-4, higher serum calcification propensity is associated with atherosclerotic cardiovascular disease events, ESKD, and all-cause mortality, but this association was not independent of kidney function.

Podcast: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2019_10_28_CJN04710419.mp3.
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http://dx.doi.org/10.2215/CJN.04710419DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6832040PMC
November 2019

Single Measurements of Carboxy-Terminal Fibroblast Growth Factor 23 and Clinical Risk Prediction of Adverse Outcomes in CKD.

Am J Kidney Dis 2019 12 21;74(6):771-781. Epub 2019 Aug 21.

Division of Nephrology, Department of Medicine, Durham, NC; Duke Clinical Research Institute, Duke University School of Medicine, Durham, NC. Electronic address:

Rationale & Objective: An elevated fibroblast growth factor 23 (FGF-23) level is independently associated with adverse outcomes in populations with chronic kidney disease, but it is unknown whether FGF-23 testing can improve clinical risk prediction in individuals.

Study Design: Prospective cohort study.

Setting & Participants: Participants in the Chronic Renal Insufficiency Cohort (CRIC) Study (n = 3,789).

Exposure: Baseline carboxy-terminal FGF-23 (cFGF-23) level.

Outcomes: All-cause and cardiovascular (CV) mortality, incident end-stage renal disease (ESRD), heart failure (HF) admission, and atherosclerotic events at 3, 5, and 8 years.

Analytical Approach: We assessed changes in model performance by change in area under the receiver operating characteristic curve (ΔAUC), integrated discrimination improvement (IDI), relative IDI, and net reclassification index (NRI) above standard clinical factors. We performed sensitivity analyses, including an additional model comparing the addition of phosphate rather than cFGF-23 level and repeating our analyses using an internal cross-validation cohort.

Results: Addition of a single baseline value of cFGF-23 to a base prediction model improved prediction of all-cause mortality (ΔAUC, 0.017 [95% CI, 0.001-0.033]; IDI, 0.021 [95% CI, 0.006-0.036]; relative IDI, 32.7% [95% CI, 8.5%-56.9%]), and HF admission (ΔAUC, 0.008 [95% CI, 0.0004-0.016]; IDI, 0.019 [95% CI, 0.004-0.034]; relative IDI, 10.0% [95% CI, 1.8%-18.3%]), but not CV mortality, ESRD, or atherosclerotic events at 3 years of follow-up. The NRI did not reach statistical significance for any of the 3-year outcomes. The incremental predictive utility of cFGF-23 level diminished in analyses of the 5- and 8-year outcomes. The cFGF-23 models outperformed the phosphate model for each outcome.

Limitations: Power to detect increased CV mortality likely limited by low event rate. The NRI is not generalizable without accepted prespecified risk thresholds.

Conclusions: Among individuals with CKD, single measurements of cFGF-23 improve prediction of risks for all-cause mortality and HF admission but not CV mortality, ESRD, or atherosclerotic events. Future studies should evaluate the predictive utility of repeated cFGF-23 testing.
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http://dx.doi.org/10.1053/j.ajkd.2019.05.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6875624PMC
December 2019

Early Prediction of Acute Kidney Injury in Critical Care Setting Using Clinical Notes and Structured Multivariate Physiological Measurements.

Stud Health Technol Inform 2019 Aug;264:368-372

Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.

The onset of acute kidney injury (AKI) during an intensive care unit (ICU) admission is associated with increased morbidity and mortality. Developing novel methods to identify early AKI onset is of critical importance in preventing or reducing AKI complications. We built and applied multiple machine learning models to integrate clinical notes and structured physiological measurements and estimate the risk of new AKI onset using the MIMIC-III database. From the clinical notes, we generated clinically meaningful word representations and embeddings. Four supervised learning classifiers and mixed-feature deep learning architecture were used to construct prediction models. The best configurations consistently utilized both structured and unstructured clinical features and yielded competitive AUCs above 0.83. Our work suggests that integrating structured and unstructured clinical features can be effectively applied to assist clinicians in identifying the risk of incident AKI onset in critically-ill patients upon admission to the ICU.
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http://dx.doi.org/10.3233/SHTI190245DOI Listing
August 2019

Estimated kidney function in children and young adults with spina bifida: A retrospective cohort study.

Neurourol Urodyn 2019 09 8;38(7):1907-1914. Epub 2019 Jul 8.

Division of Nephrology and Hypertension, Feinberg School of Medicine at Northwestern University, Chicago, Illinois.

Aims: Current estimated glomerular filtration rate (eGFR) equations may be inaccurate in patients with spina bifida (SB) because of reduced muscle mass and stature. Cross-sectional and longitudinal variability of eGFR were analyzed in these patients across multiple equations, hypothesizing greater variability in creatinine-based than cystatin-C (Cys-C)-based equations.

Methods: This retrospective cohort study included children (age, 1-17.9 years) and adults (≥18 years) with SB from 2002-2017 at a large SB clinic. Those without all data needed to calculate eGFR were excluded. Four pediatric and three adult eGFR equations were compared for cross-sectional outcomes of eGFR and elevated office blood pressures using chronic kidney disease (CKD) stage classification, and for longitudinal outcome of eGFR slope over time using covariance pattern models accounting for repeated measures.

Results: One hundred and eighty two children and 75 adults had greater than or equal to 1 set of data measurements; 118 and 52, respectively, had greater than or equal to 2 sets. The pediatric bedside Schwartz equation had the highest median eGFR and coefficient of variation. CKD stage classification by eGFR showed large differences across equations in children, with rates of eGFR < 60 and <90 ml/min/1.73 m ranging from 2%-9% and 5%-69%, respectively. Only one equation showed a significant inverse association between eGFR and blood pressure. Longitudinally, eGFR slopes over time were different across pediatric equations (P < .001) but not adult equations. The bedside Schwartz equation had a positive eGFR slope; the other Cys-C-containing equations had negative slopes.

Conclusions: Creatinine-based equations in children with SB vary considerably from cystatin-C-containing equations in calculating both single point-in-time eGFR values and eGFR trends over time.
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http://dx.doi.org/10.1002/nau.24092DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6706288PMC
September 2019

A Pilot Randomized Trial of Ferric Citrate Coordination Complex for the Treatment of Advanced CKD.

J Am Soc Nephrol 2019 08 5;30(8):1495-1504. Epub 2019 Jul 5.

Stanford University, Palo Alto, California.

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 2:1 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 (<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 (=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 (=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.
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http://dx.doi.org/10.1681/ASN.2018101016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6683712PMC
August 2019

Association of Fitness With Racial Differences in Chronic Kidney Disease.

Am J Prev Med 2019 07 21;57(1):68-76. Epub 2019 May 21.

Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois.

Introduction: Non-white minorities are at higher risk for chronic kidney disease than non-Hispanic whites. Better cardiorespiratory fitness is associated with slower declines in estimated glomerular filtration rate and a lower incidence of chronic kidney disease. Little is known regarding associations of fitness with racial disparities in chronic kidney disease.

Methods: A prospective cohort of 3,842 young adults without chronic kidney disease completed a maximal treadmill test at baseline in 1985-1986. Chronic kidney disease status was defined as estimated glomerular filtration rate of <60 mL/min/1.73 m during 10-, 15-, 20-, 25-, and 30-year follow-up assessments (through 2006). Analyses were completed in 2019. Multivariable Cox models were used to determine hazard ratios and 95% CI for incidence of chronic kidney disease. Multivariable models included race, gender, age, field center, education, baseline estimated glomerular filtration rate, and time-varying covariates of healthy diet index, smoking status, alcohol intake, BMI, systolic blood pressure, and fasting glucose. Percent attenuation quantified the association of fitness to racial disparities in chronic kidney disease.

Results: Chronic kidney disease incidence was higher among blacks (n=83/1,941, 1.61 per 1,000 person years) than whites (43/1,901, 0.82 per 1,000 person years). Every 1-minute shorter treadmill duration was associated with 1.14 (95% CI=1.04, 1.25) times higher risk of chronic kidney disease. Blacks were 1.72 (95% CI=1.13, 2.63) times more likely to develop chronic kidney disease compared with whites. The risk was reduced to 1.54 (95% CI=1.01, 2.39) with fitness added. This suggests that fitness is associated with 20.4% (95% CI=5.8, 43.0%) of the excess risk of chronic kidney disease attributable to race.

Conclusions: Low fitness is a modifiable factor that may contribute to the racial disparity in chronic kidney disease.
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http://dx.doi.org/10.1016/j.amepre.2019.02.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6589135PMC
July 2019