Publications by authors named "Joachim H Ix"

392 Publications

Kidney Tubulointerstitial Fibrosis and Tubular Secretion.

Am J Kidney Dis 2021 Sep 24. Epub 2021 Sep 24.

Rationale And Objectives: Tubular secretion plays an important role in the efficient elimination of endogenous solutes and medications, and lower secretory clearance is associated with risk of kidney function decline. We evaluated whether histopathologic quantification of interstitial fibrosis and tubular atrophy (IFTA) was associated with lower tubular secretory clearance in persons undergoing kidney biopsy.

Study Design: Cross sectional.

Settings And Participants: The Boston Kidney Biopsy Cohort is a study of persons undergoing native kidney biopsies for clinical indications.

Exposures: Semi-quantitive score of IFTA reported by two trained pathologists.

Outcomes: We measured plasma and urine concentrations of nine endogenous secretory solutes using a targeted liquid chromatography mass-spectroscopy assay. We used linear regression to test associations of urine to plasma ratios (UPR) of these solutes with IFTA score after controlling for estimated GFR (eGFR) and albuminuria.

Results: Among 418 persons, the mean age was 53 years, 51% were women, 64% were White and 18% were Black. The mean eGFR was 50 ml/min/1.73m2 and median albumin/creatinine ratio was 819 mg/g. Compared to individuals with <25% IFTA, those with >50% IFTA had 12 to 37% lower UPR for the all 9 secretory solutes. Adjusting for age, sex, race, eGFR and urinary albumin and creatinine attenuated the associations, yet trend of lower secretion across groups remained statistically significant (p for trend <0.05) for 7 of 9 solutes. A standardized composite secretory score incorporating UPR for all 9 secretory solutes using the min-max method showed similar results (p for trend <0.05).

Limitations: Single time point and spot measures of secretory solutes.

Conclusions: Greater IFTA severity is associated with lower clearance of endogenous secretory solutes even after adjusting for eGFR and albuminuria.
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http://dx.doi.org/10.1053/j.ajkd.2021.08.015DOI Listing
September 2021

Soluble Klotho and Incident Hypertension.

Clin J Am Soc Nephrol 2021 Oct 23;16(10):1502-1511. Epub 2021 Sep 23.

Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas

Background And Objectives: Hypertension is associated with significant morbidity and mortality despite effective antihypertensive therapies. Soluble klotho is a circulating protein that in preclinical studies is protective against the development of hypertension. There are limited studies of klotho and blood pressure in humans.

Design, Setting, Participants, & Measurements: Within the Health, Aging, and Body Composition Study, a cohort of well-functioning older adults, soluble klotho was measured in serum. We evaluated the cross-sectional and longitudinal association between klotho and blood pressure, prevalent hypertension, incident hypertension, and BP trajectories. Analyses were adjusted for demographics, cardiovascular disease and kidney disease risk factors, and measures of mineral metabolism including calcium, phosphate, parathyroid hormone, 25(OH) vitamin D, and fibroblast growth factor 23.

Results: The median klotho concentration was 630 pg/ml (478-816, 25th to 75th percentile). Within the cohort, 2093 (76%) of 2774 participants had prevalent hypertension and 476 (70%) of the remaining 681 developed incident hypertension. There was no association between klotho and prevalent hypertension or baseline systolic BP, but higher klotho was associated with higher baseline diastolic BP (fully adjusted =0.92 mmHg, 95% confidence interval, 0.24 to 1.60 mmHg, higher per two-fold higher klotho). Higher baseline serum klotho levels were significantly associated with a lower rate of incident hypertension (fully adjusted hazard ratio, 0.80; 95% confidence interval, 0.69 to 0.93 for every two-fold higher klotho). Higher klotho was also associated with lower subsequent systolic BP and diastolic BP (-0.16, 95% confidence interval, -0.31 to -0.01, mmHg lower systolic BP per year and -0.10, 95% confidence interval, -0.18 to -0.02, mmHg lower diastolic BP per year, for each two-fold higher klotho).

Conclusions: Higher klotho is associated with higher baseline diastolic but not systolic BP, a lower risk of incident hypertension, and lower BP trajectories during follow-up.
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http://dx.doi.org/10.2215/CJN.05020421DOI Listing
October 2021

Urine Biomarkers of Kidney Tubule Health, Injury, and Inflammation are Associated with Progression of CKD in Children.

J Am Soc Nephrol 2021 Oct 20;32(10):2664-2677. Epub 2021 Sep 20.

National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, Maryland.

Background: Novel urine biomarkers may improve identification of children at greater risk of rapid kidney function decline, and elucidate the pathophysiology of CKD progression.

Methods: We investigated the relationship between urine biomarkers of kidney tubular health (EGF and -1 microglobulin), tubular injury (kidney injury molecule-1; KIM-1), and inflammation (monocyte chemoattractant protein-1 [MCP-1] and YKL-40) and CKD progression. The prospective CKD in Children Study enrolled children aged 6 months to 16 years with an eGFR of 30-90ml/min per 1.73m. Urine biomarkers were assayed a median of 5 months [IQR: 4-7] after study enrollment. We indexed the biomarker to urine creatinine by dividing the urine biomarker concentration by the urine creatinine concentration to account for the concentration of the urine. The primary outcome was CKD progression (a composite of a 50% decline in eGFR or kidney failure) during the follow-up period.

Results: Overall, 252 of 665 children (38%) reached the composite outcome over a median follow-up of 6.5 years. After adjustment for covariates, children with urine EGF concentrations in the lowest quartile were at a seven-fold higher risk of CKD progression versus those with concentrations in the highest quartile (fully adjusted hazard ratio [aHR], 7.1; 95% confidence interval [95% CI], 3.9 to 20.0). Children with urine KIM-1, MCP-1, and -1 microglobulin concentrations in the highest quartile were also at significantly higher risk of CKD progression versus those with biomarker concentrations in the lowest quartile. Addition of the five biomarkers to a clinical model increased the discrimination and reclassification for CKD progression.

Conclusions: After multivariable adjustment, a lower urine EGF concentration and higher urine KIM-1, MCP-1, and -1 microglobulin concentrations were each associated with CKD progression in children.
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http://dx.doi.org/10.1681/ASN.2021010094DOI Listing
October 2021

Evaluating associations of joint swelling, joint stiffness and joint pain with physical activity in first-degree relatives of patients with rheumatoid arthritis: Studies of the Aetiology of Rheumatoid Arthritis (SERA), a prospective cohort study.

BMJ Open 2021 Sep 14;11(9):e050883. Epub 2021 Sep 14.

Department of Epidemiology, Colorado School of Public Health, University of Colorado - Anschutz Medical Campus, Aurora, Colorado, USA.

Objective: Physical activity (PA) in preclinical rheumatoid arthritis (RA) is associated with lower RA risk and disease severity. As joint signs and symptoms of inflammatory arthritis serve as a barrier to PA in RA, it is important to consider whether they affect PA in the time prior to RA. Therefore, we investigated whether joint swelling, stiffness or pain were associated with PA in first-degree relatives (FDRs) of patients with RA, a population at higher risk for future RA.

Design: Prospective study design.

Setting: We recruited FDRs of patients with RA from academic centres, Veterans' hospitals and rheumatology clinics or through responses to advertising from six sites across the USA.

Participants: We evaluated associations of joint stiffness, joint swelling and joint pain with PA time in 268 FDRs with ≥2 visits over an average 1.2 years. Clinicians confirmed joint swelling. Participants self-reported joint stiffness and/or pain.

Primary Outcome Measures: PA during a typical 24-hour day was quantified via questionnaire, weighted to reflect metabolic expenditure, where 24 hours was the minimum PA time. Linear mixed models evaluated associations between symptoms and change in PA over time, adjusting for age, sex, race, body mass index, smoking and RA-related autoantibodies.

Results: Average weighted PA time was 37±7 hours. In the cross-sectional analysis, PA time was 1.3±0.9 hours higher in FDRs reporting joint pain (p=0.15); and 0.8±1.6 and 0.4±1 hours lower in FDRs with joint swelling (p=0.60) and stiffness (p=0.69), respectively. Longitudinally, adjusting for baseline PA time, baseline symptoms were not significantly associated with changes in PA time. However, on average over time, joint stiffness and pain were associated with lower PA time (p=0.0002, p=0.002), and joint swelling was associated with higher PA time (p <0.0001).

Conclusion: Baseline symptoms did not predict future PA time, but on average over time, joint symptoms influenced PA time.
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http://dx.doi.org/10.1136/bmjopen-2021-050883DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8442039PMC
September 2021

Kidney tubule health, mineral metabolism, and adverse events in persons with CKD in SPRINT.

Nephrol Dial Transplant 2021 Sep 2. Epub 2021 Sep 2.

Kidney Health Research Collaborative, Department of Medicine, San Francisco Veterans Affairs Health Care System and University of California San Francisco, San Francisco, CA, USA.

Background: Measures of kidney tubule health are risk markers for acute kidney injury (AKI) in persons with chronic kidney disease (CKD) during hypertension treatment, but their associations with other adverse events (AEs) are unknown.

Methods: Among 2,377 Systolic Blood Pressure Intervention Trial (SPRINT) participants with CKD, we measured at baseline eight urine biomarkers of kidney tubule health and two serum biomarkers of mineral metabolism pathways that act on the kidney tubules. Cox proportional hazards models were used to evaluate biomarker associations with risk of a composite of pre-specified serious AEs (hypotension, syncope, electrolyte abnormalities, AKI, bradycardia, and injurious falls) and outpatient AEs (hyperkalemia and hypokalemia).

Results: At baseline, the mean age was 73 ±9 years and mean eGFR was 46 ±11 ml/min/1.73m2. During a median follow-up of 3.8 years, 716 (30%) participants experienced the composite AE. Higher urine interleukin-18, kidney injury molecule-1, neutrophil gelatinase-associated lipocalin (NGAL), and monocyte chemoattractant protein-1 (MCP-1), lower urine uromodulin (UMOD), and higher serum fibroblast growth factor-23 were individually associated with higher risk of the composite AE outcome in multivariable-adjusted models including eGFR and albuminuria. When modeling biomarkers in combination, higher NGAL (HR: 1.08 per 2-fold higher biomarker level, 95% CI: 1.03, 1.13), higher MCP-1 (HR: 1.11, 95% CI: 1.03, 1.19), and lower UMOD (HR: 0.91, 95% CI: 0.85, 0.97) were each associated with higher composite AE risk. Biomarker associations did not vary by intervention arm (P >0.10 for all interactions).

Conclusions: Among persons with CKD, several kidney tubule biomarkers are associated with higher risk of AEs during hypertension treatment, independent of eGFR and albuminuria.
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http://dx.doi.org/10.1093/ndt/gfab255DOI Listing
September 2021

Associations of CKD risk factors and longitudinal changes in urine biomarkers of kidney tubules among women living with HIV.

BMC Nephrol 2021 Aug 30;22(1):296. Epub 2021 Aug 30.

Kidney Health Research Collaborative, Department of Medicine, San Francisco Veterans Affairs Health Care System and University of California, San Francisco, CA, USA.

Background: Novel urine biomarkers have enabled the characterization of kidney tubular dysfunction and injury among persons living with HIV, a population at an increased risk of kidney disease. Even though several urine biomarkers predict progressive kidney function decline, antiretroviral toxicity, and mortality in the setting of HIV infection, the relationships among the risk factors for chronic kidney disease (CKD) and urine biomarkers are unclear.

Methods: We assessed traditional and infection-related CKD risk factors and measured 14 urine biomarkers at baseline and at follow-up among women living with HIV in the Women's Interagency Health Study (WIHS). We then used simultaneously adjusted multivariable linear regression models to evaluate the associations of CKD risk factors with longitudinal changes in biomarker levels.

Results: Of the 647 women living with HIV in this analysis, the majority (67%) were Black, the median age was 45 years and median follow-up time was 2.5 years. Each traditional and infection-related CKD risk factor was associated with a unique set of changes in urine biomarkers. For example, baseline hemoglobin a1c was associated with worse tubular injury (higher interleukin [IL]-18), proximal tubular reabsorptive dysfunction (higher α1-microglobulin), tubular reserve (lower uromodulin) and immune response to injury (higher chitinase-3-like protein-1 [YKL-40]). Furthermore, increasing hemoglobin a1c at follow-up was associated with further worsening of tubular injury (higher kidney injury molecule-1 [KIM-1] and IL-18), as well as higher YKL-40. HCV co-infection was associated with worsening proximal tubular reabsorptive dysfunction (higher β2-microglobulin [β2m]), and higher YKL-40, whereas HIV viremia was associated with worsening markers of tubular and glomerular injury (higher KIM-1 and albuminuria, respectively).

Conclusions: CKD risk factors are associated with unique patterns of biomarker changes among women living with HIV, suggesting that serial measurements of multiple biomarkers may help in detecting and monitoring kidney disease in this setting.
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http://dx.doi.org/10.1186/s12882-021-02508-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8406753PMC
August 2021

The Vitamin D Metabolite Ratio Is Associated With Changes in Bone Density and Fracture Risk in Older Adults.

J Bone Miner Res 2021 Aug 23. Epub 2021 Aug 23.

Departments of Laboratory Medicine and Medicine and the Kidney Research Institute, University of Washington, Seattle, WA, USA.

Recent studies have suggested that 25-hydroxyvitamin D (25(OH)D) may be a poor biomarker of bone health, in part because measured levels incorporate both protein-bound and free vitamin D. The ratio of its catabolic product (24,25-dihydroxyvitamin D [24,25(OH) D]) to 25(OH)D (the vitamin D metabolite ratio [VMR]) may provide more information on sufficient vitamin D stores and is not influenced by vitamin D-binding protein concentrations. We evaluated whether the VMR or 25(OH)D are more strongly associated with bone loss and fracture risk in older adults. We performed a retrospective cohort study of 786 community-dwelling adults aged 70 to 79 years who participated in the Health Aging and Body Composition study. Our primary outcomes were annual changes in bone density and incident fracture. The mean age of these participants was 75 ± 3 years, 49% were female, 42% were Black, and 23% had an estimated glomerular filtration rate (eGFR) <60 mL/mL/1.73m . In fully adjusted models, a 50% lower VMR was associated with 0.3% (0.2%, 0.6%) more rapid decline in total hip bone mineral density (BMD). We found similar relationships with thoracic and lumbar spine BMD. In contrast, 25(OH)D concentrations were not associated with longitudinal change in BMD. There were 178 fractures during a mean follow-up of 10 years. Each 50% lower VMR was associated with a 49% (95% confidence interval [CI] 1.06, 2.08) greater fracture risk, whereas lower 25(OH)D concentrations were not significantly associated with fracture risk (hazard ratio [HR] per 50% lower 1.07 [0.80, 1.43]). In conclusion, among a diverse cohort of community-dwelling older adults, a lower VMR was more strongly associated with both loss of BMD and fracture risk compared with 25(OH)D . Trials are needed to evaluate the VMR as a therapeutic target in persons at risk for worsening BMD and fracture. © 2021 American Society for Bone and Mineral Research (ASBMR).
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http://dx.doi.org/10.1002/jbmr.4426DOI Listing
August 2021

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

Am J Kidney Dis 2021 Aug 19. Epub 2021 Aug 19.

Division of Nephrology-Hypertension, Department of Medicine, University of California San Diego, San Diego, CA; Nephrology Section, Veterans Affairs San Diego Healthcare System, San Diego, CA.

Osteoporosis and fractures are common in persons with advanced chronic kidney disease (CKD) and on chronic dialysis. While the diagnosis of osteoporosis in this population can be difficult, imaging, especially with dual-energy X-Ray absorptiometry (DXA), is helpful in identifying persons with CKD at the highest risk of fracture. Although blood biomarkers including parathyroid hormone and bone-specific alkaline phosphatase concentrations can aid in assessing bone turnover state, bone biopsy remains the gold standard in determining bone turnover in persons with advanced kidney disease and osteoporosis. With the increasing armamentarium of osteoporosis drugs, it now may be possible to prevent many fractures t advanced CKD. Unfortunately, data on these drugs are limited in persons with advanced CKD. Clinicians, aided by advances in imaging, biomarkers and bone biopsy can now use these novel agents to target bone turnover abnormalities such as adynamic bone disease and high bone turnover disease. This review will discuss the most recent literature surrounding the diagnosis, management and monitoring of osteoporosis and fractures in persons with advanced CKD or on chronic dialysis.
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http://dx.doi.org/10.1053/j.ajkd.2021.06.031DOI Listing
August 2021

Urinary Biomarkers and Kidney Outcomes: Impact of Indexing Versus Adjusting for Urinary Creatinine.

Kidney Med 2021 Jul-Aug;3(4):546-554.e1. Epub 2021 Apr 30.

Kidney Health Research Collaborative, Department of Medicine, San Francisco VA Health Care System, University of California, San Francisco, CA.

Rationale & Objective: Urinary biomarker concentrations are frequently indexed to urinary creatinine (Ucr) concentration in spot samples to account for urine dilution; however, this may introduce biases. We evaluated whether indexing versus adjusting urinary biomarker concentrations for Ucr concentration altered their associations with outcomes.

Study Design: Observational cohort.

Setting & Participants: We analyzed data from 2,360 Systolic Blood Pressure Intervention Trial (SPRINT) participants with estimated glomerular filtration rates < 60 mL/min/1.73 m and urinary albumin (UAlb) and 8 urinary kidney tubule biomarkers measured at baseline.

Outcomes: The primary outcome was a composite of cardiovascular disease events; secondary outcomes were all-cause mortality and a composite of kidney outcomes (50% estimated glomerular filtration rate decline, end-stage kidney disease, or transplantation).

Analytical Approach: We used Cox proportional hazards regression to examine the associations of 1/Ucr with outcomes and compared the associations of UAlb and 8 individual urinary tubule biomarkers with outcomes, analyzed by indexing to Ucr, adjusting for 1/Ucr or the biomarker alone (without Ucr concentration).

Results: During a median follow-up of 3.3 years, 307 composite cardiovascular events, 166 deaths, and 34 composite kidney outcomes occurred. After multivariable adjustment, 1/Ucr was significantly associated with cardiovascular events (HR, 1.27 per 2-fold higher; 95% CI, 1.11-1.45), not associated with either mortality (HR, 1.06; 95% CI, 0.87-1.28) or kidney events (HR, 1.49; 95% CI, 0.95-2.35). For UAlb and urinary tubule biomarker concentrations, most risk estimates were not significantly different when indexed to Ucr concentration versus adjusted for 1/Ucr.

Limitations: Cohort excluded patients with diabetes and overall had low levels of albuminuria.

Conclusions: 1/Ucr is independently associated with cardiovascular events in trial participants with chronic kidney disease. Indexing versus adjusting for 1/Ucr does not significantly change the associations of most urinary biomarkers with clinical outcomes.
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http://dx.doi.org/10.1016/j.xkme.2021.02.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8350828PMC
April 2021

Commentary on the KDIGO 2021 Clinical Practice Guideline for the Management of Blood Pressure in CKD.

Curr Cardiol Rep 2021 08 16;23(9):132. Epub 2021 Aug 16.

University of Utah Health Center, Salt Lake City, UT, USA.

Purpose Of Review: To summarize and explain the new guideline on blood pressure (BP) management in chronic kidney disease (CKD) published by Kidney Disease: Improving Global Outcomes (KDIGO), an independent global nonprofit organization which develops and implements evidence-based clinical practice guidelines in kidney disease. KDIGO issued its first clinical practice guideline for the Management of Blood Pressure (BP) in Chronic Kidney Disease (CKD) for patients not receiving dialysis in 2012 and now updated the guideline in 2021.

Recent Findings: Recommendations in this update were developed based on systematic literature reviews and appraisal of the quality of the evidence and strength of recommendation following the "Grading of Recommendations Assessment, Development and Evaluation" (GRADE) approach. The updated guideline includes five chapters covering BP measurement techniques, lifestyle interventions for lowering BP, and management of BP in three target populations, namely adults (with and without diabetes), kidney transplant recipients, and children. A dedicated chapter on BP measurement emphasizing standardized preparation and measurement protocols for office BP measurement is a new addition, following protocols used in large randomized trials of BP targets with pivotal clinical outcomes. Based on the available evidence, and in particular in the CKD subgroup of the SPRINT trial, the 2021 guideline suggests a systolic BP target of <120 mm Hg, based on standardized measurements, for most individuals with CKD not receiving dialysis, with the exception of kidney transplant recipients and children. This recommendation is strictly contingent on the measurement of BP using standardized office readings and not routine office readings.
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http://dx.doi.org/10.1007/s11886-021-01559-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8366157PMC
August 2021

Urine creatinine concentration and clinical outcomes in older adults: The Cardiovascular Health Study.

J Am Geriatr Soc 2021 Aug 7. Epub 2021 Aug 7.

Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA.

Purpose: Loss of muscle mass and strength are associated with long-term adverse health outcomes in older adults. Urine creatinine concentrations (Ucr; mg/dl) are a measure of muscle tissue mass and turnover. This study assessed the associations of a spot Ucr level with muscle mass and with risk of hospitalization, mortality, and diabetes mellitus in older adults.

Methods: We examined 3424 participants from the Cardiovascular Health Study who provided spot urine samples in 1996-1997 and who were followed through June 2015. All participants underwent baseline measurement of grip strength. In a sub-cohort, 1331 participants underwent dual energy X-ray absorptiometry (DEXA) scans, from which lean muscle mass was derived. Participants were followed for a median of 10 years for hospitalizations and mortality, and 9 years for diabetes mellitus.

Results: In linear regression analysis, a one standard deviation higher Ucr concentration (64.6 mg/dl) was associated with greater grip strength (kg force) β = 0.44 [0.16, 0.72]; p = 0.002) and higher lean muscle mass (kg) (β = 0.43 [0.08, 0.78]; p = 0.02). In Cox regression analyses, each standard deviation greater Ucr concentration was associated with lower rates of hospitalizations (0.94 [95% confidence interval, 0.90, 0.98]; p < 0.001) and lower mortality risk (0.92 [0.88, 0.97]; p < 0.001), while a one standard deviation increase in muscle mass derived from DEXA had no such significant association. Ucr levels were not associated with incident diabetes mellitus risk (0.97 [0.85, 1.11]; p = 0.65).

Conclusion: A higher spot Ucr concentration was favorably associated with muscle mass and strength and with health outcomes in older community-living adults. The ease of obtaining a spot Ucr makes it an attractive analyte to use for gauging the health of older adults.
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http://dx.doi.org/10.1111/jgs.17388DOI Listing
August 2021

Management of Blood Pressure in Patients With Chronic Kidney Disease Not Receiving Dialysis: Synopsis of the 2021 KDIGO Clinical Practice Guideline.

Ann Intern Med 2021 09 22;174(9):1270-1281. Epub 2021 Jun 22.

Tufts University, Boston, Massachusetts (M.J.S.).

Description: The Kidney Disease: Improving Global Outcomes (KDIGO) 2021 clinical practice guideline for the management of blood pressure (BP) in patients with chronic kidney disease (CKD) not receiving dialysis is an update of the KDIGO 2012 guideline on the same topic and reflects new evidence on the risks and benefits of BP-lowering therapy among patients with CKD. It is intended to support shared decision making by health care professionals working with patients with CKD worldwide. This article is a synopsis of the full guideline.

Methods: The KDIGO leadership commissioned 2 co-chairs to convene an international Work Group of researchers and clinicians. After a Controversies Conference in September 2017, the Work Group defined the scope of the evidence review, which was undertaken by an evidence review team between October 2017 and April 2020. Evidence reviews were done according to the Cochrane Handbook. The GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach was used to guide the development of the recommendations and rate the strength and quality of the evidence. Practice points were included to provide guidance when evidence was insufficient to make a graded recommendation. The guideline was revised after public consultation between January and March 2020.

Recommendations: The updated guideline comprises 11 recommendations and 20 practice points. This synopsis summarizes key recommendations pertinent to the diagnosis and management of high BP in adults with CKD, excluding those receiving kidney replacement therapy. In particular, the synopsis focuses on recommendations for standardized BP measurement and a target systolic BP of less than 120 mm Hg, because these recommendations differ from some other guidelines.
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http://dx.doi.org/10.7326/M21-0834DOI Listing
September 2021

Urine Biomarkers of Kidney Tubule Health and Incident CKD Stage 3 in Women Living With HIV: A Repeated Measures Study.

Kidney Med 2021 May-Jun;3(3):395-404.e1. Epub 2021 Apr 17.

Kidney Health Research Collaborative, Department of Medicine, San Francisco Veterans Affairs Health Care System and University of California, San Francisco, San Francisco, CA.

Rationale & Objective: Single measurements of urinary biomarkers reflecting kidney tubule health are associated with chronic kidney disease (CKD) risk in HIV infection, but the prognostic value of repeat measurements over time is unknown.

Study Design: Cohort study.

Setting & Participants: 647 women living with HIV infection enrolled in the Women's Interagency Health Study.

Exposures: 14 urinary biomarkers of kidney tubule health measured at 2 visits over a 3-year period.

Outcome: Incident CKD, defined as estimated glomerular filtration rate (eGFR) < 60 mL/min/1.73 m at two 6-month visits and an average eGFR decline ≥ 3% per year.

Analytical Approach: We used multivariable generalized estimating equations adjusting for CKD risk factors to evaluate baseline, time-updated, and change-over-time biomarker associations with incident CKD. We compared CKD discrimination between models with and without a parsimoniously selected set of biomarkers.

Results: During a median 7 years of follow-up, 9.7% (63/647) developed CKD. In multivariable-adjusted analyses, 3 of 14 baseline biomarkers associated with incident CKD. In contrast, 10 of 14 time-updated biomarkers and 9 of 14 biomarkers modeled as change over time associated with incident CKD. Urinary epidermal growth factor (EGF), α-microglobulin (A1M), and albumin were selected using penalized regression methods. In the time-updated model, lower urinary EGF (risk ratio [RR] per 2-fold higher time-updated biomarker levels, 0.69; 95% CI, 0.58-0.81), higher urinary A1M (RR, 1.47; 95% CI, 1.25-1.73), and higher urinary albumin excretion (RR, 1.21; 95% CI, 1.03-1.42) were jointly associated with increased risk for CKD. Compared with a base model (C statistic, 0.75), CKD discrimination improved after adding urinary EGF, A1M, and albumin values across baseline (C = 0.81), time-updated (C = 0.83), and change-over-time (C = 0.83) models ( < 0.01 for all).

Limitations: Observational design, incident CKD definition limited to eGFR.

Conclusions: Repeat urinary biomarker measurements for kidney tubule health have stronger associations with incident CKD compared with baseline measurements and moderately improve CKD discrimination in women living with HIV infection.
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http://dx.doi.org/10.1016/j.xkme.2021.01.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8178470PMC
April 2021

Kidney Function Following Left Ventricular Assist Device Implantation: An Observational Cohort Study.

Kidney Med 2021 May-Jun;3(3):378-385.e1. Epub 2021 Apr 2.

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

Rationale & Objective: Nearly half the patients with heart failure have chronic kidney disease. Implantation of a left ventricular assist device (LVAD) improves kidney function in some but not all patients, and lack of improvement is associated with worse outcomes. Preimplantation factors that predict change in kidney function after LVAD placement are not well described.

Study Design: Single-center observational study.

Setting & Participants: Consecutive patients undergoing LVAD implantation.

Predictors: 48 diverse preimplantation variables including demographic, clinical, laboratory, hemodynamic, and echocardiographic variables.

Outcomes: The primary outcome was change in estimated glomerular filtration rate (eGFR) at 1 month after implantation. Secondary outcomes included eGFR changes at 3, 6, and 12 months.

Analytic Approach: Univariable and multivariable linear regression.

Results: Among 131 patients, average age was 60 ± 13 years, 83% were men, 47% had pre-existing chronic kidney disease, and mean preimplantation eGFR was 57 ± 23 mL/min/1.73 m. At 1-month following LVAD implantation, eGFR improved in 98 (75%) patients. Variables associated with 1-month increases in eGFR were younger age, absence of diabetes mellitus (DM), use of inotropes, lower implantation eGFR, and higher implantation serum urea nitrogen, alanine aminotransferase, bilirubin, and creatinine levels. In multivariable models, younger age (β = 7.14 mL/min/1.73 m per SD; 95% CI, 3.17-11.10), lower eGFR (β = 7.72 mL/min/1.73 m per SD; 95% CI, 3.10-12.34), and absence of DM (β = 10.36 mL/min/1.73 m; 95% CI, 2.99-17.74) were each independently associated with 1-month improvement in eGFR. Only younger age and lower eGFR were associated with improvements in eGFR at later months.

Limitations: Single-center study. Loss to follow-up from heart transplantation and death over duration of study.

Conclusions: Only younger age, lower eGFR, and absence of DM were associated with improvement in eGFR at 1 month. Thus, prediction of eGFR change at 1 month and beyond is limited by using preimplantation variables.
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http://dx.doi.org/10.1016/j.xkme.2021.01.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8178473PMC
April 2021

The Promise of Tubule Biomarkers in Kidney Disease: A Review.

Am J Kidney Dis 2021 May 27. Epub 2021 May 27.

Kidney Health Research Collaborative, San Francisco Veterans Affairs Medical Center and University of California, San Francisco, CA; Division of General Internal Medicine, San Francisco Veterans Affairs Medical Center, San Francisco, CA.

For over 70 years, serum creatinine has remained the primary index for detection and monitoring of kidney disease. Tubulointerstitial damage and fibrosis are highly prognostic for subsequent kidney failure in biopsy studies, yet this pathology is invisible to the clinician in the absence of a biopsy. Recent discovery of biomarkers that reflect distinct aspects of kidney tubule disease have led to investigations of whether these markers can provide additional information on risk of chronic kidney disease (CKD) progression and associated adverse clinical end points, above and beyond estimated glomerular filtration rate and albuminuria. These biomarkers can be loosely grouped into those that mark tubule cell injury (eg, kidney injury molecule 1, monocyte chemoattractant protein 1) and those that mark tubule cell dysfunction (eg, α-microglobulin, uromodulin). These kidney tubule biomarkers provide new opportunities to monitor response to therapeutics used to treat CKD patients. In this review, we describe results from some unique contributions in this area and discuss the current challenges and requirements in the field to bring these markers to clinical practice. We advocate for a broader assessment of kidney health that moves beyond a focus on the glomerulus, and we highlight how such tools can improve diagnostic accuracy and earlier assessment of therapeutic efficacy or harm in CKD patients.
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http://dx.doi.org/10.1053/j.ajkd.2021.03.026DOI Listing
May 2021

Sodium and Health Outcomes: Ascertaining Valid Estimates in Research Studies.

Curr Atheroscler Rep 2021 05 11;23(7):35. Epub 2021 May 11.

University of California San Diego School of Public Health and Human Longevity Science, 9500 Gilman Drive, MC 0628, La Jolla, CA, 92093-0628, USA.

Purpose Of Review: The dietary reference intake (DRI) for sodium has been highly debated with persuasive and elegant arguments made for both population sodium reduction and for maintenance of the status quo. After the 2015 Dietary Guidelines Advisory Committee (DGAC) report was published, controversy ensued, and by Congressional mandate, the sodium DRIs were updated in 2019. The 2019 DRIs defined adequate intake (AI) levels by age-sex groups that are largely consistent with the DRIs for sodium that were published in 2005. Given the overall similarities between the 2005 and 2019 DRIs, one may wonder how the recently published research on sodium and health outcomes was considered in determining the DRIs, particularly, the recent studies from very large observational cohort studies. We aim to address this concern and outline the major threats to ascertaining valid estimates of the relationship between dietary sodium and health outcomes in observational cohort studies. We use tools from modern epidemiology to demonstrate how unexpected and inconsistent findings in these relationships may emerge. We use directed acyclic graphs to illustrate specific examples in which biases may occur.

Recent Findings: We identified the following key threats to internal validity: poorly defined target intervention, poorly measured sodium exposure, unmeasured or residual confounding, reverse causality, and selection bias. Researchers should consider these threats to internal validity while developing research questions and throughout the research process. For the DRIs to inform real-world interventions relating to sodium reduction, it is recommended that more specific research questions be asked that can clearly define potential interventions of interest.
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http://dx.doi.org/10.1007/s11883-021-00909-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8113303PMC
May 2021

Biomarkers of Kidney Tubule Health, CKD Progression, and Acute Kidney Injury in SPRINT (Systolic Blood Pressure Intervention Trial) Participants.

Am J Kidney Dis 2021 09 20;78(3):361-368.e1. Epub 2021 Apr 20.

Nephrology Section, Veterans Affairs San Diego Healthcare System, La Jolla, CA; Division of Nephrology and Hypertension, Department of Medicine, University of California-San Diego, San Diego, CA; Division of Preventive Medicine, Department of Family Medicine and Public Health, University of California-San Diego, San Diego, CA. Electronic address:

Rationale & Objective: The Systolic Blood Pressure Intervention Trial (SPRINT) compared the effect of intensive versus standard systolic blood pressure targets on cardiovascular morbidity and mortality. In this ancillary study, we evaluated the use of exploratory factor analysis (EFA) to combine biomarkers of kidney tubule health in urine and plasma and then study their role in longitudinal estimated glomerular filtration rate (eGFR) change and risk of acute kidney injury (AKI).

Study Design: Observational cohort nested in a clinical trial.

Setting & Participants: 2,351 SPRINT participants with eGFR < 60 mL/min/1.73 m at baseline.

Exposure: Levels of neutrophil gelatinase-associated lipocalin (NGAL), interleukin 18 (IL-18), chitinase-3-like protein (YKL-40), kidney injury molecule 1 (KIM-1), monocyte chemoattractant protein 1 (MCP-1), α-microglobulin (A1M) and β-microglobulin (B2M), uromodulin (UMOD), fibroblast growth factor 23 (FGF-23), and intact parathyroid hormone (PTH).

Outcome: Longitudinal changes in eGFR and risk of AKI.

Analytical Approach: We performed EFA to capture different tubule pathophysiologic processes. We used linear mixed effects models to evaluate the association of each factor with longitudinal changes in eGFR. We evaluated the association of the tubular factors scores with AKI using Cox proportional hazards regression.

Results: From 10 biomarkers, EFA generated 4 factors reflecting tubule injury/repair (NGAL, IL-18, and YKL-40), tubule injury/fibrosis (KIM-1 and MCP-1), tubule reabsorption (A1M and B2M), and tubule reserve/mineral metabolism (UMOD, FGF-23, and PTH). Each 1-SD higher tubule reserve/mineral metabolism factor score was associated with a 0.58% (95% CI, 0.39%-0.67%) faster eGFR decline independent of baseline eGFR and albuminuria. Both the tubule injury/repair and tubule injury/fibrosis factors were independently associated with future risk of AKI (per 1 SD higher, HRs of 1.18 [95% CI, 1.10-1.37] and 1.23 [95% CI, 1.02-1.48], respectively).

Limitations: The factors require validation in other settings.

Conclusions: EFA allows parsimonious subgrouping of biomarkers into factors that are differentially associated with progressive eGFR decline and AKI. These subgroups may provide insights into the pathological processes driving adverse kidney outcomes.
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http://dx.doi.org/10.1053/j.ajkd.2021.01.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8384678PMC
September 2021

Decongestion discriminates risk for one-year mortality in patients with improving renal function in acute heart failure.

Eur J Heart Fail 2021 07 15;23(7):1122-1130. Epub 2021 Apr 15.

School of Medicine, University College Dublin, Dublin, Ireland.

Aims: Improving renal function (IRF) is paradoxically associated with worse outcomes in acute heart failure (AHF), but outcomes may differ based on response to decongestion. We explored if the relationship of IRF with mortality in hospitalized AHF patients differs based on successful decongestion.

Methods And Results: We evaluated 760 AHF patients from AKINESIS for the relationship between IRF, change in B-type natriuretic peptide (BNP), and 1-year mortality. IRF was defined as a ≥20% increase in estimated glomerular filtration rate (eGFR) relative to admission. Adequate decongestion was defined as a ≥40% decrease in last measured BNP relative to admission. IRF occurred in 22% of patients who had a mean age of 69 years, 58% were men, 72% were white, and median admission eGFR was 49 mL/min/1.73 m . IRF patients had more severe heart failure reflected by lower admission eGFR, higher blood urea nitrogen, lower systolic blood pressure, lower sodium, and higher use of inotropes. IRF patients had higher 1-year mortality (25%) than non-IRF patients (15%) (P < 0.01). However, this relationship differed by BNP trajectory (P-interaction = 0.03). When stratified by BNP change, non-IRF patients and IRF patients with decreasing BNP had lower 1-year mortality than either non-IRF and IRF patients without decreasing BNP. However, in multivariate analysis, IRF was not associated with mortality [adjusted hazard ratio (HR) 1.0, 95% confidence interval (CI) 0.7-1.5] while BNP was (adjusted HR 0.5, 95% CI 0.3-0.7). When IRF was evaluated as transiently occurring or persisting at discharge, again only BNP change was significantly associated with mortality.

Conclusion: Improving renal function is associated with mortality in AHF but not independent of other variables and congestion status. Achieving adequate decongestion, as reflected by lower BNP, in AHF is more strongly associated with mortality than IRF.
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http://dx.doi.org/10.1002/ejhf.2179DOI Listing
July 2021

UAB-UCSD O'Brien Center for Acute Kidney Injury Research.

Am J Physiol Renal Physiol 2021 05 29;320(5):F870-F882. Epub 2021 Mar 29.

Division of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama.

Acute kidney injury (AKI) remains a significant clinical problem through its diverse etiologies, the challenges of robust measurements of injury and recovery, and its progression to chronic kidney disease (CKD). Bridging the gap in our knowledge of this disorder requires bringing together not only the technical resources for research but also the investigators currently endeavoring to expand our knowledge and those who might bring novel ideas and expertise to this important challenge. The University of Alabama at Birmingham-University of California-San Diego O'Brien Center for Acute Kidney Injury Research brings together technical expertise and programmatic and educational efforts to advance our knowledge in these diverse issues and the required infrastructure to develop areas of novel exploration. Since its inception in 2008, this O'Brien Center has grown its impact by providing state-of-the-art resources in clinical and preclinical modeling of AKI, a bioanalytical core that facilitates measurement of critical biomarkers, including serum creatinine via LC-MS/MS among others, and a biostatistical resource that assists from design to analysis. Through these core resources and with additional educational efforts, our center has grown its investigator base to include >200 members from 51 institutions. Importantly, this center has translated its pilot and catalyst funding program with a $37 return per dollar invested. Over 500 publications have resulted from the support provided with a relative citation ratio of 2.18 ± 0.12 (iCite). Through its efforts, this disease-centric O'Brien Center is providing the infrastructure and focus to help the development of the next generation of researchers in the basic and clinical science of AKI. This center creates the promise of the application at the bedside of the advances in AKI made by current and future investigators.
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http://dx.doi.org/10.1152/ajprenal.00661.2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8424552PMC
May 2021

Physical activity in hemodialysis patients on nondialysis and dialysis days: Prospective observational study.

Hemodial Int 2021 04 1;25(2):240-248. Epub 2021 Mar 1.

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

Introduction: The physical decline in patients with end-stage kidney disease (ESKD) is associated with morbidity and mortality. Prior studies have attempted to promote physical activity at the time of dialysis; however, physical activity patterns on the nondialysis days are unknown. This study aimed to quantify physical activity on dialysis and nondialysis days in hemodialysis patients using a wearable actigraph.

Methods: In this prospective study, subjects receiving hemodialysis were recruited from two outpatient dialysis units in urban San Diego and rural Imperial County, CA, between March 2018 and April 2019. Key inclusion criteria included: (1) receiving thrice weekly hemodialysis for ≥3 months, (2) age ≥ 18 years, and (3) able to walk with or without assistive devices. All participants wore a Fitbit Charge 2 tracker for a minimum of 4 weeks. The primary outcome was the number of steps per day. Each participant completed the Physical Activity Questionnaire, the Patient Health Questionnaire (PHQ)-9, the PROMIS Short form Fatigue Questionnaire at baseline, and the Participant Technology Experience Questionnaire at day 7 after study enrolment.

Findings: Of the 52 recruited, 45 participants (urban = 25; rural = 20) completed the study. The mean age was 61 ± 15 years, 42% were women, 64% were Hispanic, and the mean dialysis vintage was 4.4 ± 3.0 years. For those with valid Fitbit data (defined as ≥10 hours of wear per day) for 28 days (n = 45), participants walked an average of 3688 steps per day, and 73% of participants were sedentary (<5000 steps/day). Participants aged >80 years were less active than younger (age < 65 years) participants (1232 vs. 4529 steps, P = 0.01). There were no statistical differences between the groups when stratified by gender (women vs. men [2817 vs. 4324 steps, respectively]), urbanicity (rural vs. urban dialysis unit [3141 vs. 4123 steps, respectively]), and dialysis/nondialysis day (3177 vs. 4133 steps, respectively). Due to the small sample size, we also calculated effect sizes. The effect size was medium for the gender differences (cohen's d = 0.57) and small to medium for urbanicity and dialysis/nondialysis day (d = 0.37 and d = 0.33, respectively). We found no association between physical activity and self-reported depression and fatigue scale. The majority of participants (62%, 28/45) found the Fitbit tracker easy to wear and comfortable.

Discussion: ESKD participants receiving hemodialysis are frequently sedentary, and differences appear more pronounced in older patients. These findings may assist in designing patient-centered interventions to increase physical activity among hemodialysis patients.
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http://dx.doi.org/10.1111/hdi.12913DOI Listing
April 2021

Association of Urine Biomarkers of Kidney Tubule Injury and Dysfunction With Frailty Index and Cognitive Function in Persons With CKD in SPRINT.

Am J Kidney Dis 2021 10 27;78(4):530-540.e1. Epub 2021 Feb 27.

Division of Nephrology-Hypertension, University of California-San Diego, San Diego, California; Veterans Affairs San Diego Healthcare System, San Diego, California.

Rationale & Objective: The associations of the glomerular markers of kidney disease, estimated glomerular filtration rate (eGFR) and albuminuria, with frailty and cognition are well established. However, the relationship of kidney tubule injury and dysfunction with frailty and cognition is unknown.

Study Design: Observational cross-sectional study.

Setting & Participants: 2,253 participants with eGFR<60mL/min/1.73m in the Systolic Blood Pressure Intervention Trial (SPRINT).

Exposure: Eight urine biomarkers: interleukin 18 (IL-18), kidney injury molecule 1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), chitinase-3-like protein 1 (YKL-40), monocyte chemoattractant protein 1 (MCP-1), α-microglobulin (A1M), β-microglobulin (B2M), and uromodulin (Umod).

Outcome: Frailty was measured using a previously validated frailty index (FI), categorized as fit (FI≤0.10), less fit (0.100.21). Cognitive function was assessed using the Montreal Cognitive Assessment (MoCA).

Analytical Approach: Associations between kidney tubule biomarkers with categorical FI were evaluated using multinomial logistic regression with the fit group as the reference. Cognitive function was evaluated using linear regression. Models were adjusted for demographic, behavioral, and clinical variables including eGFR and urine albumin.

Results: Three of the 8 urine biomarkers of tubule injury and dysfunction were independently associated with FI. Each 2-fold higher level of urine KIM-1, a marker of tubule injury, was associated with a 1.22 (95% CI, 1.01-1.49) greater odds of being in the frail group. MCP-1, a marker of tubulointerstitial fibrosis, was associated with a 1.30 (95% CI, 1.04-1.64) greater odds of being in the frail group, and A1M, a marker of tubule reabsorptive capacity, was associated with a 1.48 (95% CI, 1.11-1.96) greater odds of being in the frail group. These associations were independent of confounders including eGFR and urine albumin, and were stronger than those of urine albumin with FI (1.15 [95% CI, 0.99-1.34]). Higher urine B2M, another marker of tubule reabsorptive capacity, was associated with worse cognitive scores at baseline (β: -0.09 [95% CI, -0.17 to-0.01]). Urine albumin was not associated with cognitive function.

Limitations: Cross-sectional design, and FI may not be generalizable in other populations.

Conclusions: Urine biomarkers of tubule injury, fibrosis, and proximal tubule reabsorptive capacity are variably associated with FI and worse cognition, independent of glomerular markers of kidney health. Future studies are needed to validate these results among other patient populations.
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http://dx.doi.org/10.1053/j.ajkd.2021.01.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8390569PMC
October 2021

Executive summary of the KDIGO 2021 Clinical Practice Guideline for the Management of Blood Pressure in Chronic Kidney Disease.

Kidney Int 2021 03;99(3):559-569

KfH Kidney Center, Munich, Germany; Friedrich Alexander University of Erlangen-Nürnberg, Erlangen, Germany. Electronic address:

The Kidney Disease: Improving Global Outcomes (KDIGO) 2021 Clinical Practice Guideline for the Management of Blood Pressure in Chronic Kidney Disease for patients not receiving dialysis represents an update to the KDIGO 2012 guideline on this topic. Development of this guideline update followed a rigorous process of evidence review and appraisal. Guideline recommendations are based on systematic reviews of relevant studies and appraisal of the quality of the evidence. The strength of recommendations is based on the "Grading of Recommendations Assessment, Development and Evaluation" (GRADE) approach. The scope includes topics covered in the original guideline, such as optimal blood pressure targets, lifestyle interventions, antihypertensive medications, and specific management in kidney transplant recipients and children. Some aspects of general and cardiovascular health, such as lipid and smoking management, are excluded. This guideline also introduces a chapter dedicated to proper blood pressure measurement since all large randomized trials targeting blood pressure with pivotal outcomes used standardized preparation and measurement protocols adhered to by patients and clinicians. Based on previous and new evidence, in particular the Systolic Blood Pressure Intervention Trial (SPRINT) results, we propose a systolic blood pressure target of less than 120 mm Hg using standardized office reading for most people with chronic kidney disease (CKD) not receiving dialysis, the exception being children and kidney transplant recipients. The goal of this guideline is to provide clinicians and patients a useful resource with actionable recommendations supplemented with practice points. The burden of the recommendations on patients and resources, public policy implications, and limitations of the evidence are taken into consideration. Lastly, knowledge gaps and recommendations for future research are provided.
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http://dx.doi.org/10.1016/j.kint.2020.10.026DOI Listing
March 2021

Serum Individual Nonesterified Fatty Acids and Risk of Heart Failure in Older Adults.

Cardiology 2021;146(3):351-358. Epub 2021 Feb 25.

New York Academy of Medicine, New York, New York, USA.

Background: Heart failure (HF) is highly prevalent among older adults and is associated with high costs. Although serum total nonesterified fatty acids (NEFAs) have been positively associated with HF risk, the contribution of each individual NEFA to HF risk has not been examined.

Objective: The aim of this study was to examine the association of individual fasting NEFAs with HF risk in older adults.

Methods: In this prospective cohort study of older adults, we measured 35 individual NEFAs in 2,140 participants of the Cardiovascular Health Study using gas chromatography. HF was ascertained using review of medical records by an endpoint committee.

Results: The mean age was 77.7 ± 4.4 years, and 38.8% were male. During a median follow-up of 9.7 (maximum 19.0) years, 655 new cases of HF occurred. In a multivariable Cox regression model controlling for demographic and anthropometric variables, field center, education, serum albumin, glomerular filtration rate, physical activity, alcohol consumption, smoking, hormone replacement therapy, unintentional weight loss, and all other measured NEFAs, we observed inverse associations (HR [95% CI] per standard deviation) of nonesterified pentadecanoic (15:0) (0.73 [0.57-0.94]), γ-linolenic acid (GLA) (0.87 [0.75-1.00]), and docosahexaenoic acid (DHA) (0.73 [0.61-0.88]) acids with HF, and positive associations of nonesterified stearic (18:0) (1.30 [1.04-1.63]) and nervonic (24:1n-9) (1.17 [1.06-1.29]) acids with HF.

Conclusion: Our data are consistent with a higher risk of HF with nonesterified stearic and nervonic acids and a lower risk with nonesterified 15:0, GLA, and DHA in older adults. If confirmed in other studies, specific NEFAs may provide new targets for HF prevention.
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http://dx.doi.org/10.1159/000513917DOI Listing
August 2021

Editorial: From MACH15 to MACH0 - a missed opportunity to understand the health effects of moderate alcohol intake.

Eur J Prev Cardiol 2020 Feb 12. Epub 2020 Feb 12.

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

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http://dx.doi.org/10.1177/2047487320904230DOI Listing
February 2020

Nonesterified Fatty Acids and Kidney Function Decline in Older Adults: Findings From the Cardiovascular Health Study.

Am J Kidney Dis 2021 08 4;78(2):259-267. Epub 2021 Feb 4.

Division of General Medicine, Department of Medicine, Beth Israel Deaconess Medical Center, Boston, MA.

Rationale & Objective: Circulating nonesterified fatty acids (NEFAs) make up a small portion of circulating lipids but are a metabolically important energy source. Excessive circulating NEFAs may contribute to lipotoxicity in many tissues, including the kidneys. We investigated the relationship between total circulating NEFA concentration and kidney outcomes in older, community-dwelling adults.

Study Design: Prospective cohort study.

Setting & Participants: 4,698 participants≥65 years of age in the Cardiovascular Health Study who underwent total fasting serum NEFA concentration measurements in 1992-1993.

Exposure: Fasting serum NEFA concentration at one time point.

Outcome: Three primary outcomes: estimated glomerular filtration rate (eGFR) decline of≥30%, the composite of eGFR decline≥30% or kidney failure with replacement therapy, and change in eGFR. These outcomes were assessed over 4- and 13-year periods.

Analytical Approach: Logistic regression for the dichotomous outcomes and mixed effects models for the continuous outcome, with sequential adjustment for baseline covariates. Inverse probability of attrition weighting was implemented to account for informative attrition during the follow-up periods.

Results: Serum NEFA concentrations were not independently associated with kidney outcomes. In unadjusted and partially adjusted analyses, the highest quartile of serum NEFA concentration (compared with lowest) was associated with a higher risk of≥30% eGFR decline at 4 years and faster rate of decline of eGFR. No associations were evident after adjustment for comorbidities, lipid levels, insulin sensitivity, medications, and vital signs: the odds ratio for the eGFR decline outcome was 1.33 (95% CI, 0.83-2.13), and the difference in eGFR slope in the highest versus lowest quartile of serum NEFA concentration was-0.15 (95% CI, -0.36 to 0.06) mL/min/1.73m per year.

Limitations: Single NEFA measurements, no measurements of post-glucose load NEFA concentrations or individual NEFA species, no measurement of baseline urine albumin.

Conclusions: A single fasting serum NEFA concentration was not independently associated with long-term adverse kidney outcomes in a cohort of older community-living adults.
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http://dx.doi.org/10.1053/j.ajkd.2020.11.030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8316278PMC
August 2021

Proteinuria and nocturnal blood pressure dipping in hypertensive children and adolescents.

Pediatr Res 2021 Jan 27. Epub 2021 Jan 27.

Department of Medicine, Division of Nephrology and Hypertension, University of California San Diego, La Jolla, CA, USA.

Background: The absence of nocturnal blood pressure dipping is associated with adverse cardiovascular outcomes in adults, and proteinuria is a risk factor for non-dipping in this population. Risk factors for non-dipping in children are largely unknown.

Methods: We retrospectively identified patients aged 5-19 years who underwent 24-h ambulatory blood pressure monitoring (ABPM) from August 2018 to January 2019 and had a spot urine protein-to-creatinine ratio (PCR) within 1 year of their ABPM. Dipping was defined as ≥10% reduction in systolic and diastolic blood pressure from day to night. Multivariable logistic and linear regression models evaluated the association of proteinuria with non-dipping.

Results: Among 77 children identified, 27 (35.1%) were non-dippers. Each two-fold higher urine PCR was associated with 38% higher odds of non-dipping, after adjusting for body mass index (BMI). Higher urine PCR was also associated with a lower diastolic dipping percentage by 1.33 (95% confidence interval 0.31-2.34), after adjusting for BMI, age, and estimated glomerular filtration rate.

Conclusions: Limitations of this study include its retrospective design and the time lapse between urine PCR and ABPM. Proteinuria appears to be associated with blood pressure non-dipping in children. This finding needs to be confirmed in prospective studies.

Impact: Our study demonstrates the association of proteinuria with non-dipping of blood pressure in children. This association has been explored in adults, but to our knowledge, this is the first time it is evaluated in children referred for evaluation of elevated blood pressure. Non-dipping is a modifiable risk factor for kidney function decline and cardiovascular disease in adulthood, and thus early identification in children is important. The association between proteinuria and non-dipping in children will allow us to more readily identify those at risk, with a future focus on interventions to modify blood pressure dipping patterns.
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http://dx.doi.org/10.1038/s41390-020-01315-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8313642PMC
January 2021

Individual non-esterified fatty acids and incident atrial fibrillation late in life.

Heart 2021 Jan 22. Epub 2021 Jan 22.

Medical Service, San Francisco VA Medical Center, San Francisco, California, USA.

Objective: Obesity and dysmetabolism are major risk factors for atrial fibrillation (AF). Expansion of fat depots is associated with increased circulating total non-esterified fatty acids (NEFAs), elevated levels of which are associated with incident AF. We undertook comprehensive serum measurement of individual NEFA to identify specific associations with new-onset AF late in life.

Methods: The present study focused on participants with available serum and free of AF selected from the Cardiovascular Health Study, a community-based longitudinal investigation of older US adults. Thirty-five individual NEFAs were measured by gas chromatography. Cox regression was used to evaluate the association of individual NEFAs with incident AF.

Results: The study sample included 1872 participants (age 77.7±4.4). During median follow-up of 11.3 years, 715 cases of incident AF occurred. After concurrent adjustment of all NEFAs and full adjustment for potential confounders, higher serum concentration of nervonic acid (24:1 n-9), a long-chain monounsaturated fatty acid, was associated with higher risk of AF (HR per SD: 1.18, 95% CI 1.08 to 1.29; p<0.001). Conversely, higher serum concentration of gamma-linolenic acid (GLA) (18:3 n-6), a polyunsaturated n-6 fatty acid, was associated with lower risk of AF (HR per SD: 0.81, 95% CI 0.71 to 0.94; p=0.004). None of the remaining NEFAs was significantly associated with AF.

Conclusions: Among older adults, serum levels of non-esterified nervonic acid were positively associated, while serum levels of non-esterified GLA were inversely associated, with incident AF. If confirmed, these results could offer new strategies for AF prevention and early intervention in this segment of the population at highest risk.
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http://dx.doi.org/10.1136/heartjnl-2020-317929DOI Listing
January 2021

Effect of Lanthanum Carbonate on Blood Pressure in CKD.

Am J Kidney Dis 2021 08 9;78(2):312-314. Epub 2021 Jan 9.

Division of Nephrology-Hypertension, University of California San Diego, San Diego, CA.

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http://dx.doi.org/10.1053/j.ajkd.2020.12.012DOI Listing
August 2021

Estimated GFR Variability and Risk of Cardiovascular Events and Mortality in SPRINT (Systolic Blood Pressure Intervention Trial).

Am J Kidney Dis 2021 07 14;78(1):48-56. Epub 2020 Dec 14.

Division of Preventive Medicine, Department of Family Medicine and Public Health, University of California San Diego, San Diego, CA; Nephrology Section, Veterans Affairs San Diego Healthcare System, La Jolla, CA. Electronic address:

Rationale And Objective: Although low estimated glomerular filtration rate (eGFR) is associated with cardiovascular disease (CVD) events and mortality, the clinical significance of variability in eGFR over time is uncertain. This study aimed to evaluate the associations between variability in eGFR and the risk of CVD events and all-cause mortality.

Study Design: Longitudinal analysis of clinical trial participants.

Settings And Participants: 7,520 Systolic Blood Pressure Intervention Trial (SPRINT) participants ≥50 year of age with 1 or more CVD risk factors.

Predictors: eGFR variability, estimated by the coefficient of variation of eGFR assessments at the 6th, 12th, and 18-month study visits.

Outcomes: The SPRINT primary CVD composite outcome (myocardial infarction, acute coronary syndrome, stroke, heart failure, or CVD death) and all-cause mortality from month 18 to the end of follow-up.

Analytical Approach: Cox models were used to evaluate associations between eGFR variability and CVD outcomes and all-cause mortality. Models were adjusted for demographics, randomization arm, CVD risk factors, albuminuria, and eGFR at month 18.

Results: Mean age was 68 ± 9 years; 65% were men; and 58% were White. The mean eGFR was 73 ± 21 (SD) mL/min/1.73 m at 6 months. There were 370 CVD events and 154 deaths during a median follow-up of 2.4 years. Greater eGFR variability was associated with higher risk for all-cause mortality (hazard ratio [HR] per 1 SD greater variability, 1.29; 95% CI, 1.14-1.45) but not CVD events (HR, 1.05; 95% CI, 0.95-1.16) after adjusting for albuminuria, eGFR, and other CVD risk factors. Associations were similar when stratified by treatment arm and by baseline CKD status, when accounting for concurrent systolic blood pressure changes, use of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and diuretic medications during follow up.

Limitations: Persons with diabetes and proteinuria > 1 g/d were excluded.

Conclusions: In trial participants at high risk for CVD, greater eGFR variability was independently associated with all-cause mortality but not CVD events.
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http://dx.doi.org/10.1053/j.ajkd.2020.10.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8200370PMC
July 2021
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