Publications by authors named "Lawrence J Appel"

431 Publications

Potassium-enriched salt substitutes: benefits, risks, and a "trolley problem" in public health.

Am J Clin Nutr 2021 May 8. Epub 2021 May 8.

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

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http://dx.doi.org/10.1093/ajcn/nqab153DOI Listing
May 2021

Effects of Behavioral Weight Loss and Metformin on Insulin-like Growth Factors in Cancer Survivors: A Randomized Trial.

J Clin Endocrinol Metab 2021 Apr 22. Epub 2021 Apr 22.

Department of Medicine, Johns Hopkins University.

Context: Higher levels of insulin-like growth factor-1 (IGF-1) are associated with increased risk of cancers and higher mortality. Therapies that reduce IGF-1 have considerable appeal as means to prevent recurrence.

Design: Randomized, 3-parallel-arm controlled clinical trial.

Interventions And Outcomes: Cancer survivors with overweight or obesity were randomized to 1) self-directed weight loss (comparison), 2) coach-directed weight loss, or 3) metformin treatment. Main outcomes were changes in IGF-1 and IGF-1:IGFBP3 molar ratio at six months. The trial duration was 12 months.

Results: Of the 121 randomized participants, 79% were women, 46% were African Americans, and the mean age was 60 years. At baseline, the average BMI was 35 kg/m 2; mean IGF-1 was 72.9 (SD, 21.7) ng/ml; and mean IGF1:IGFBP3 molar ratio was 0.17 (SD, 0.05). At 6 months, weight changes were -1.0% (p=0.07), -4.2% (p<0.0001), and -2.8% (p<0.0001) in self-directed, coach-directed, and metformin groups, respectively. Compared to the self-directed group, participants in metformin had significant decreases on IGF-1 (mean difference in change: -5.50 ng/ml, p=0.02) and IGF1:IGFBP3 molar ratio (mean difference in change: -0.0119, p=0.011) at 3 months. The significant decrease of IGF-1 remained in participants with obesity at 6 months (mean difference in change: -7.2 ng/ml; 95% CI: -13.3 to -1.1), but not in participants with overweight (p-for interaction=0.045). There were no significant differences in changes between the coach-directed and self-directed groups. There were no differences in outcomes at 12 months.

Conclusions: In cancer survivors with obesity, metformin may have a short-term effect on IGF-1 reduction that wanes over time.
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http://dx.doi.org/10.1210/clinem/dgab266DOI Listing
April 2021

Use of Salt-Restriction Spoons and Its Associations with Urinary Sodium and Potassium in the Zhejiang Province of China: Results of a Population-Based Survey.

Nutrients 2021 Mar 24;13(4). Epub 2021 Mar 24.

Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University, No. 2024 E. Monument Street, Baltimore, MD 21287, USA.

In China, a major source of sodium is salt added during cooking. In this context, use of a salt-restriction spoon (SRS) has been promoted in public health campaigns and by health care providers. To describe use of and factors associated with SRS use, knowledge of correct use, and actual correct use. This study is a population-based, representative survey of 7512 residents, aged 18 to 69 years, of China's Zhejiang Province. The survey, which was conducted in 2017 using a multistage random sampling strategy, collected demographic information, SRS use, and physical measurements; a 24-h urine collection was obtained from 1,496 of the participants. The mean age of the participants was 44.8 years, 50.1% were females, and over 1/3 (35.3%) were classified as hypertensive. Mean 24-h urinary sodium and potassium excretions were 167.3(72.2) mmol/24 h and 38.2(18.2) mmol/24 h, respectively. Only 12.0% (899/7512) of participants once used or were currently using SRS; of the 899 users, 73.4% knew how to use the SRS correctly, and just 46.5% actually used it correctly. SRS use was more commonly associated with behavioral factors rather than socio-demographic factors. Initiation of SRS use by health care providers was associated with correct technical knowledge of SRS. Lower sodium-to-potassium ratio was associated with SRS use, while SRS use was not associated with urinary sodium and potassium excretion. Use of SRS was uncommon in Zhejiang Province of China. Given that a common source of sodium in China is salt added during cooking, use of SRS is an appealing strategy, ideally as part of a multi-component campaign.
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http://dx.doi.org/10.3390/nu13041047DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8063796PMC
March 2021

Effects of dietary macronutrients on serum urate: results from the OmniHeart trial.

Am J Clin Nutr 2021 Mar 1. Epub 2021 Mar 1.

Division of General Medicine, Beth Israel Deaconess Medical Center/Harvard Medical School, Boston, MA, USA.

Background: Dietary recommendations to prevent gout emphasize a low-purine diet. Recent evidence suggests that the Dietary Approaches to Stop Hypertension (DASH) diet reduces serum urate while also improving blood pressure and lipids.

Objective: To compare the effects of DASH-style diets emphasizing different macronutrient proportions on serum urate reduction.

Methods: We conducted a secondary analysis of the Optimal Macronutrient Intake Trial to Prevent Heart Disease feeding study, a 3-period, crossover design, randomized trial of adults with prehypertension or hypertension. Participants were provided with 3 DASH-style diets in random order, each for 6 wk. Each DASH-style diet emphasized different macronutrient proportions: a carbohydrate-rich (CARB) diet, a protein-rich (PROT) diet, and an unsaturated fat-rich (UNSAT) diet. In the PROT diet, approximately half of the protein came from plant sources. We compared the effects of these diets on serum urate at weeks 4 and 6 of each feeding period.

Results: Of the 163 individuals included in the final analysis, the mean serum urate at baseline was 5.1 mg/dL. Only the PROT diet reduced serum urate from baseline at the end of the 6-wk feeding period (-0.16 mg/dL; 95% CI: -0.28, -0.04; P = 0.007). Neither the CARB diet (-0.03 mg/dL; 95% CI: -0.14, 0.09; P = 0.66) nor the UNSAT diet (-0.01 mg/dL; 95% CI: -0.12, 0.09; P = 0.78) reduced serum urate from baseline. The PROT diet lowered serum urate by 0.12 mg/dL (95% CI: -0.20, -0.03; P = 0.006) compared with CARB and by 0.12 mg/dL (95% CI: -0.20, -0.05; P = 0.002) compared with UNSAT.

Conclusions: A DASH-style diet emphasizing plant-based protein lowered serum urate compared with those emphasizing carbohydrates or unsaturated fat. Future trials should test the ability of a DASH-style diet emphasizing plant-based protein to lower serum urate and prevent gout flares in patients with gout. This trial was registered at clinicaltrials.gov as NCT00051350.
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http://dx.doi.org/10.1093/ajcn/nqaa424DOI Listing
March 2021

Effects of Dietary Patterns on Serum Urate: Results From a Randomized Trial of the Effects of Diet on Hypertension.

Arthritis Rheumatol 2020 Dec 8. Epub 2020 Dec 8.

Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.

Objective: To determine whether the Dietary Approaches to Stop Hypertension (DASH) diet or an alternative, simplified diet, emphasizing high-fiber fruits and vegetables (the FV diet), lowers serum urate levels.

Methods: We conducted a secondary study of the DASH feeding study, a 3-arm, parallel-design, randomized trial of 459 adults with systolic blood pressure (BP) of <160 mm Hg and diastolic BP of 80-95 mm Hg, who were not receiving BP medications. Participants were randomized to receive 8 weeks of monitored feeding and ate 1 of 3 diets: 1) a typical American diet (control), 2) the FV diet, a diet rich in fruits and vegetables but otherwise similar to the control diet, or 3) the DASH diet, which was rich in fruits, vegetables, and low-fat dairy products, and reduced in fat, saturated fat, and cholesterol. Body weight was kept constant throughout the study. Serum urate levels were measured at baseline and after 8 weeks of feeding.

Results: For the 327 participants with available specimens (mean ± SD age 45.4 ± 11.0 years, 47% women, 50% African American), the mean ± SD baseline serum urate level was 5.7 ± 1.5 mg/dl. Compared to the control diet, the FV diet reduced the mean serum urate level by 0.17 mg/dl (95% confidence interval [95% CI] -0.34, 0.00; P = 0.051) and the DASH diet reduced the mean serum urate level by 0.25 mg/dl (95% CI -0.43, -0.08; P = 0.004). These effects increased with increasing baseline serum urate levels (<5, 5-5.9, 6-6.9, 7-7.9, and ≥8 mg/dl) for those receiving the DASH diet (a reduction of 0.08, 0.12, 0.42, 0.44, and 0.73 mg/dl, respectively; P for trend = 0.04), but not for those receiving the FV diet.

Conclusion: Our findings indicate that the DASH diet reduces serum urate levels, particularly among those with hyperuricemia. These findings support the growing need for a dedicated trial to test the DASH diet among patients with hyperuricemia and gout.
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http://dx.doi.org/10.1002/art.41614DOI Listing
December 2020

A Randomized Pilot Study of DASH Patterned Groceries on Serum Urate in Individuals with Gout.

Nutrients 2021 Feb 7;13(2). Epub 2021 Feb 7.

Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02215, USA.

The Dietary Approaches to Stop Hypertension (DASH) diet reduces serum urate (SU); however, the impact of the DASH diet has not been previously evaluated among patients with gout. We conducted a randomized, controlled, crossover pilot study to test the effects of ~$105/week ($15/day) of dietitian-directed groceries (DDG), patterned after the DASH diet, on SU, compared with self-directed grocery shopping (SDG). Participants had gout and were not taking urate lowering therapy. Each intervention period lasted 4 weeks; crossover occurred without a washout period. The primary endpoint was SU. Compliance was assessed by end-of-period fasting spot urine potassium and sodium measurements and self-reported consumption of daily servings of fruit and vegetables. We randomized 43 participants (19% women, 49% black, mean age 59 years) with 100% follow-up. Mean baseline SU was 8.1 mg/dL (SD, 0.8). During Period 1, DDG lowered SU by 0.55 mg/dL (95% CI: 0.07, 1.04) compared to SDG by 0.0 mg/dL (95% CI: -0.44, 0.44). However, after crossover (Period 2), the SU difference between groups was the opposite: SDG reduced SU by -0.48 mg/dL (95% CI: -0.98, 0.01) compared to DDG by -0.05 mg/dL (95% CI: -0.48, 0.38; P for interaction by period = 0.11). Nevertheless, DDG improved self-reported intake of fruit and vegetables (3.1 servings/day; 95% CI: 1.5, 4.8) and significantly reduced total spot urine sodium excretion by 22 percentage points (95% CI: -34.0, -8.6). Though relatively small in scale, this pilot study suggests that dietitian-directed, DASH-patterned groceries may lower SU among gout patients not on urate-lowering drugs. However, behavior intervention crossover trials without a washout period are likely vulnerable to strong carryover effects. Definitive evaluation of the DASH diet as a treatment for gout will require a controlled feeding trial, ideally with a parallel-design.
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http://dx.doi.org/10.3390/nu13020538DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7914968PMC
February 2021

Low-carbohydrate dietary pattern on glycemic outcomes trial (ADEPT) among individuals with elevated hemoglobin A1c: study protocol for a randomized controlled trial.

Trials 2021 Feb 1;22(1):108. Epub 2021 Feb 1.

Department of Epidemiology, Tulane University School of Public Health and Tropical Medicine, 1440 Canal St, Suite 2000, New Orleans, LA, 70112, USA.

Background: Type 2 diabetes mellitus (T2DM) is a major cause of morbidity and mortality globally. Strong evidence supports the importance of diet and other lifestyle factors in preventing T2DM. Among individuals with T2DM, low-carbohydrate diets lead to decreases in hemoglobin A1c (HbA1c). However, research on the effects of low-carbohydrate diets on glycemic outcomes among individuals not currently on glucose-lowering medications who have elevated HbA1c is limited.

Methods: The objective of this randomized controlled trial is to study the effect of a healthy low-carbohydrate diet achieved through behavioral intervention and key food supplementation compared with usual diet on HbA1c and other metabolic risk factors among individuals with HbA1c from 6.0 to 6.9% who are not on glucose-lowering medications. In this parallel trial, 150 participants will be randomized to the intervention or control group for 6 months. The healthy low-carbohydrate diet target is < 40 g of net carbohydrates during the first 3 months and < 40 to 60 net grams for months 3 to 6. This diet is characterized by abundant unsaturated fat and protein, high-fiber foods such as non-starchy vegetables and nuts, and minimal refined carbohydrates. The primary outcome is the difference in HbA1c change from baseline to 6 months in the intervention compared with usual diet group. Secondary outcomes include differences between groups in 6-month changes in fasting glucose, systolic blood pressure, total-to-high-density lipoprotein (HDL) cholesterol ratio, and body weight. Exploratory outcomes include differences in 6-month changes in fasting insulin, homeostasis model assessment of insulin resistance, diastolic blood pressure, waist circumference, and 10-year cardiovascular disease risk. An intention-to-treat analysis will be used.

Discussion: We expect that the results from this study will lead to new approaches for developing and implementing dietary approaches (other than the most commonly used reduced fat diet) that will substantially reduce risk of cardiometabolic disease among adults with or at high risk of T2DM. The study intervention involves behavioral counseling and promotes consumption of dietary components thought to reduce risk of cardiometabolic disease and has expected applicability in clinical practice.

Trial Registration: ClinicalTrials.gov NCT03675360 . Registered on September 18, 2018 (prior to enrolment of the first participant).
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http://dx.doi.org/10.1186/s13063-020-05001-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7848246PMC
February 2021

Vitamin D, Calcium Supplements, and Implications for Cardiovascular Health: JACC Focus Seminar.

J Am Coll Cardiol 2021 Feb;77(4):437-449

Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University, Baltimore, Maryland, USA; Division of General Internal Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.

Vitamin D and calcium supplements are commonly used, often together, to optimize bone health. Multiple observational studies have linked low serum 25-hydroxyvitamin D concentrations with increased cardiovascular risk. However, subsequent randomized controlled trials (RCTs) failed to demonstrate cardiovascular benefit with vitamin D supplementation. Although vitamin D supplements do not appear to be harmful for cardiovascular health, the lack of benefit in RCTs should discourage their use for this purpose, favoring optimizing vitamin D status through healthy lifestyles such as specific foods and modest sunlight exposure. Furthermore, some (but not all) observational and RCT studies of calcium supplementation have suggested potential for cardiovascular harm. Therefore, calcium supplementation should be used cautiously, striving for recommended intake of calcium predominantly from food sources. In this review, the authors examine the currently available evidence investigating whether vitamin D and calcium supplements are helpful, harmful, or neutral for cardiovascular health.
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http://dx.doi.org/10.1016/j.jacc.2020.09.617DOI Listing
February 2021

Biomarkers of Immune Activation and Incident Kidney Failure With Replacement Therapy: Findings From the African American Study of Kidney Disease and Hypertension.

Am J Kidney Dis 2021 Jan 1. Epub 2021 Jan 1.

Division of Nephrology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD; Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins Medical Institutions, Baltimore, MD; Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD.

Rationale & Objective: Immune activation is fundamental to the pathogenesis of many kidney diseases. Innate immune molecules such as soluble urokinase-type plasminogen activator receptor (suPAR) have been linked to the incidence and progression of chronic kidney disease (CKD). Whether other biomarkers of immune activation are associated with incident kidney failure with replacement therapy (KFRT) in African Americans with nondiabetic kidney disease is unclear.

Study Design: Prospective cohort.

Setting & Participants: African American Study of Kidney Disease and Hypertension (AASK) participants with available baseline serum samples for biomarker measurement.

Predictors: Baseline serum levels of soluble tumor necrosis factor receptor 1 (sTNFR1), sTNFR2, tumor necrosis factor α (TNF-α), and interferon γ (IFN-γ).

Outcomes: Incident KFRT, all-cause mortality.

Analytical Approach: Cox proportional hazards models.

Results: Among 500 participants with available samples, mean glomerular filtration rate was 44.7mL/min/1.73m, and median urinary protein-creatinine ratio was 0.09g/g at baseline. Over a median follow up of 9.6 years, there were 161 (32%) KFRT and 113 (23%) death events. In models adjusted for demographic and clinical factors and baseline kidney function, each 2-fold higher baseline level of sTNFR1, sTNFR2, and TNF-α was associated with 3.66-fold (95% CI, 2.31-5.80), 2.29-fold (95% CI, 1.60-3.29), and 1.35-fold (95% CI, 1.07-1.71) greater risks of KFRT, respectively; in comparison, each doubling of baseline suPAR concentration was associated with 1.39-fold (95% CI, 1.04-1.86) greater risk of KFRT. sTNFR1, sTNFR2, and TNF-α were also significantly associated with death (up to 2.2-fold higher risks per 2-fold higher baseline levels; P≤0.01). IFN-γ was not associated with either outcome. None of the biomarkers modified the association of APOL1 high-risk status (genetic risk factors for kidney disease among individuals of African ancestry) with KFRT (P>0.05 for interaction).

Limitations: Limited generalizability to other ethnic groups or causes of CKD.

Conclusions: Among African Americans with CKD attributed to hypertension, baseline levels of sTNFR1, sTNFR2, and TNF-α but not IFN-γ were associated with KFRT and mortality.
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http://dx.doi.org/10.1053/j.ajkd.2020.11.014DOI Listing
January 2021

Effects of the Dietary Approaches to Stop Hypertension Diet and Sodium Reduction on Blood Pressure in Persons With Diabetes.

Hypertension 2021 Feb 21;77(2):265-274. Epub 2020 Dec 21.

From the Division of General Internal Medicine, Johns Hopkins University School of Medicine, Baltimore, MD (E.T., L.J.A., H.-C.Y., S.J.P., E.R.M., N.M.M.).

Elevated blood pressure and blood pressure-related morbidity are extraordinarily common in persons with diabetes. The Dietary Approaches to Stop Hypertension dietary pattern and dietary sodium reduction are recommended as lifestyle interventions in individuals with diabetes. However, these recommendations have largely been based on studies conducted in persons without diabetes. In this review, we summarize available evidence from trials that tested the effects of these 2 dietary interventions on blood pressure in people with diabetes. Overall, of the 3 trials (total n=151) that tested the effects of the Dietary Approaches to Stop Hypertension dietary pattern in persons with diabetes, 2 trials documented that the Dietary Approaches to Stop Hypertension dietary pattern lowered blood pressure. While 16 trials (total n=445) tested the effects of sodium reduction in persons with diabetes, results were inconsistent, likely because of design limitations, for example, brief duration, small sample size, and low baseline blood pressure levels, as well as differences in the mode of intervention delivery (behavioral interventions, feeding studies, and sodium supplements). In conclusion, there is a substantial need for additional research on the blood pressure lowering effects of the Dietary Approaches to Stop Hypertension diet and sodium reduction in people with diabetes and hypertension, given the high prevalence of hypertension and the dearth of high-quality trials in this population.
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http://dx.doi.org/10.1161/HYPERTENSIONAHA.120.14584DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7810162PMC
February 2021

Clinical events and patient-reported outcome measures during CKD progression: findings from the CRIC study.

Nephrol Dial Transplant 2020 Dec 16. Epub 2020 Dec 16.

University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.

Background: Patients with chronic kidney disease (CKD) face risk of end-stage kidney disease (ESKD), cardiovascular disease (CVD), and death, but also decline in kidney function, quality of life (QOL), and mental and physical well-being. This study describes the multidimensional trajectories of CKD using clinical events, kidney function, and patient-reported outcome measures. We hypothesized that more advanced CKD stages would associate with more rapid decline in each outcome.

Methods: Among 3,939 participants enrolled in the Chronic Renal Insufficiency Cohort (CRIC) Study, we evaluated multidimensional disease trajectories by G- and A-stages of enrollment eGFR and albuminuria, respectively. These trajectories included clinical events (ESKD, CVD, heart failure, death), eGFR decline, and patient-reported outcome measures (kidney disease QOL [KDQOL] burden, effects, and symptoms questionnaires, as well as the short-form-12 mental and physical composite).We also evaluated a group-based multi-trajectory model to group participants on the basis of longitudinal patient-reported outcome measures and compared group assignments by enrollment G- and A-stage.

Results: Mean participant age was 58 years, 45% were women, mean baseline eGFR was 44 mL/min/1.73 m2, and median urine albumin-to-creatinine ratio was 52 mg/g. The incidence of all clinical events was greater and eGFR decline was faster with more advanced G- and A-stages. While baseline KDQOL and physical component measures were lower with more advanced G- and A-stage of CKD; changes in patient-reported outcome measures were inconsistently related to the baseline CKD stage. Groups formed on patient-reported outcome measure trajectories were fairly distinct from existing CKD staging (observed agreement, 60.6%) but also were associated with risk of ESKD, CVD, heart failure, and death.

Conclusions: More advanced baseline CKD stage was associated with higher risk of clinical events and faster eGFR decline, but was only weakly related to changes in patient-reported metrics over time.
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http://dx.doi.org/10.1093/ndt/gfaa364DOI Listing
December 2020

Urine Metabolites Associated with the Dietary Approaches to Stop Hypertension (DASH) Diet: Results from the DASH-Sodium Trial.

Mol Nutr Food Res 2021 02 28;65(3):e2000695. Epub 2020 Dec 28.

Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, 21205, USA.

Scope: Serum metabolomic markers of the Dietary Approaches to Stop Hypertension (DASH) diet are previously reported. In an independent study, the similarity of urine metabolomic markers are investigated.

Methods And Results: In the DASH-Sodium trial, participants are randomly assigned to the DASH diet or control diet, and received three sodium interventions (high, intermediate, low) within each randomized diet group in random order for 30 days each. Urine samples are collected at the end of each intervention period and analyzed for 938 metabolites. Two comparisons are conducted: 1) DASH-high sodium (n = 199) versus control-high sodium (n = 193), and 2) DASH-low sodium (n = 196) versus control-high sodium. Significant metabolites identified using multivariable linear regression are compared and the top 10 influential metabolites identified using partial least-squares discriminant analysis to the results from the DASH trial. Nine out of 10 predictive metabolites of the DASH-high sodium and DASH-low sodium diets are identical. Most candidate biomarkers from the DASH trial replicated. N-methylproline, chiro-inositol, stachydrine, and theobromine replicated as influential metabolites of DASH diets.

Conclusions: Candidate biomarkers of the DASH diet identified in serum replicated in urine. Replicated influential metabolites are likely to be objective biomarkers of the DASH diet.
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http://dx.doi.org/10.1002/mnfr.202000695DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7967699PMC
February 2021

The Effects of Four Doses of Vitamin D Supplements on Falls in Older Adults : A Response-Adaptive, Randomized Clinical Trial.

Ann Intern Med 2021 02 8;174(2):145-156. Epub 2020 Dec 8.

Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland (C.M.M., A.L.S., J.A.S., J.C., M.M., S.N.B., J.C., L.T.D., D.M.S., J.T.).

Background: Vitamin D supplementation may prevent falls in older persons, but evidence is inconsistent, possibly because of dosage differences.

Objective: To compare the effects of 4 doses of vitamin D supplements on falls.

Design: 2-stage Bayesian, response-adaptive, randomized trial. (ClinicalTrials.gov: NCT02166333).

Setting: 2 community-based research units.

Participants: 688 participants, aged 70 years and older, with elevated fall risk and a serum 25-hydroxyvitamin D [25-(OH)D] level of 25 to 72.5 nmol/L.

Intervention: 200 (control), 1000, 2000, or 4000 IU of vitamin D per day. During the dose-finding stage, participants were randomly assigned to 1 of the 4 vitamin D doses, and the best noncontrol dose for preventing falls was determined. After dose finding, participants previously assigned to receive noncontrol doses received the best dose, and new enrollees were randomly assigned to receive 200 IU/d or the best dose.

Measurements: Time to first fall or death over 2 years (primary outcome).

Results: During the dose-finding stage, the primary outcome rates were higher for the 2000- and 4000-IU/d doses than for the 1000-IU/d dose, which was selected as the best dose (posterior probability of being best, 0.90). In the confirmatory stage, event rates were not significantly different between participants with experience receiving the best dose (events and observation time limited to the period they were receiving 1000 IU/d;  = 308) and those randomly assigned to receive 200 IU/d ( = 339) (hazard ratio [HR], 0.94 [95% CI, 0.76 to 1.15];  = 0.54). Analysis of falls with adverse outcomes suggested greater risk in the experience-with-best-dose group versus the 200-IU/d group (serious fall: HR, 1.87 [CI, 1.03 to 3.41]; fall with hospitalization: HR, 2.48 [CI, 1.13 to 5.46]).

Limitations: The control group received 200 IU of vitamin D per day, not a placebo. Dose finding ended before the prespecified thresholds for dose suspension and dose selection were reached.

Conclusion: In older persons with elevated fall risk and low serum 25-(OH)D levels, vitamin D supplementation at doses of 1000 IU/d or higher did not prevent falls compared with 200 IU/d. Several analyses raised safety concerns about vitamin D doses of 1000 IU/d or higher.

Primary Funding Source: National Institute on Aging.
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http://dx.doi.org/10.7326/M20-3812DOI Listing
February 2021

Changes in hypertension control in a community-based population of older adults, 2011-2013 to 2016-2017.

Am J Hypertens 2020 Dec 5. Epub 2020 Dec 5.

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

Background: The 2014 hypertension guideline raised treatment goals in older adults. The study objective was to examine changes in blood pressure (BP) control (<140/90 mmHg) from 2011-2013 to 2016-2017 among Black and white older adults with treated hypertension.

Methods: Participants were 1600 white and 650 Black adults aged 71-90 years in the Atherosclerosis Risk in Communities (ARIC) Study with treated hypertension in 2011-2013 (baseline) who had BP measured in 2016-2017 (follow up). Factors associated with changes in BP control were examined by race.

Results: BP was controlled among 75.3% of white and 65.7% of Black participants at baseline and 59.0% of white and 56.5% of Black participants at follow up. Among those with controlled BP at baseline, risk factors for incident uncontrolled BP included age (RR 1.15 per 5 years, 95% CI 1.07-1.25), female sex (RR 1.36, 95% CI 1.16-1.60), and chronic kidney disease (CKD) (RR 1.19, 95% CI 1.01-1.40) among white participants, and hypertension duration (RR 1.14 per 5 years, 95% CI 1.03-1.27) and diabetes (RR 1.48, 95% CI 1.15-1.91) among Black participants. Among those with uncontrolled BP at baseline, white females vs males (RR 0.60, 95% CI 0.46-0.78) and Black participants with CKD vs without (RR 0.58, 95% CI 0.36-0.93) were less likely to have incident controlled BP.

Conclusions: BP control decreased among white and Black older adults. Black individuals with diabetes or CKD were less likely to have controlled BP at follow up. Higher treatment goals may have contributed to these findings and unintended differences by race.
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http://dx.doi.org/10.1093/ajh/hpaa206DOI Listing
December 2020

Digit Preference in Office Blood Pressure Measurements, United States 2015-2019.

Am J Hypertens 2020 Nov 27. Epub 2020 Nov 27.

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

Background: Blood pressure (BP) measurement error may lead to under- or overtreatment of hypertension. One common source of error is terminal digit preference, most often a terminal digit of '0'. The objective was to evaluate national trends in terminal digit preference in office BP measurements among adults with treated hypertension.

Methods: Data were from IQVIA's National Disease and Therapeutic Index, a nationally representative, serial cross-sectional survey of office-based physicians. The analysis included office visits from 2015 to 2019 among adults aged ≥18 years receiving antihypertensive treatment. Annual trends were examined in the percent of systolic and diastolic BP measurements ending in zero by patient sex, age, and race/ethnicity, physician specialty, and first or subsequent hypertension treatment visit.

Results: From 2015 to 2019, there were ~60 million hypertension treatment visits annually (unweighted N: 5,585-9,085). There was a decrease in the percent of visits with systolic (41.7% to 37.7%) or diastolic (42.7% to 37.8%) BP recordings ending in zero. Trends were similar by patient characteristics. However, a greater proportion of measurements ended in zero among patients aged ≥80 (vs 15-59 or 60-79) years, first (vs subsequent) treatment visits, visits to cardiologists (vs primary care physicians), and visits with systolic BP ≥140 or diastolic BP ≥90 (vs <140/90) mmHg.

Conclusions: Despite modest improvement, terminal digit preference remains a common problem in office BP measurement in the U.S. Without bias, 10-20% of measurements are expected to end in zero. Reducing digit preference is a priority for improving BP measurement accuracy and hypertension management.
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http://dx.doi.org/10.1093/ajh/hpaa196DOI Listing
November 2020

Serum levels of IL-6, IL-8 and IL-10 and risks of end-stage kidney disease and mortality.

Nephrol Dial Transplant 2021 02;36(3):561-563

Division of Nephrology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

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http://dx.doi.org/10.1093/ndt/gfaa260DOI Listing
February 2021

The Relationship of COVID-19 Severity with Cardiovascular Disease and Its Traditional Risk Factors: A Systematic Review and Meta-Analysis.

Glob Heart 2020 Sep 22;15(1):64. Epub 2020 Sep 22.

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

Background: Whether cardiovascular disease (CVD) and its traditional risk factors predict severe coronavirus disease 2019 (COVID-19) is uncertain, in part, because of potential confounding by age and sex.

Methods: We performed a systematic review of studies that explored pre-existing CVD and its traditional risk factors as risk factors of severe COVID-19 (defined as death, acute respiratory distress syndrome, mechanical ventilation, or intensive care unit admission). We searched PubMed and Embase for papers in English with original data (≥10 cases of severe COVID-19). Using random-effects models, we pooled relative risk (RR) estimates and conducted meta-regression analyses.

Results: Of the 661 publications identified in our search, 25 papers met our inclusion criteria, with 76,638 COVID-19 patients including 11,766 severe cases. Older age was consistently associated with severe COVID-19 in all eight eligible studies, with RR >~5 in >60-65 versus <50 years. Three studies showed no change in the RR of age after adjusting for covariate(s). In univariate analyses, factors robustly associated with severe COVID-19 were male sex (10 studies; pooled RR = 1.73, [95% CI 1.50-2.01]), hypertension (8 studies; 2.87 [2.09-3.93]), diabetes (9 studies; 3.20 [2.26-4.53]), and CVD (10 studies; 4.97 [3.76-6.58]). RR for male sex was likely to be independent of age. For the other three factors, meta-regression analyses suggested confounding by age. Only four studies reported multivariable analysis, but most of them showed adjusted RR ~2 for hypertension, diabetes, and CVD. No study explored renin-angiotensin system inhibitors as a risk factor for severe COVID-19.

Conclusions: Despite the potential for confounding, these results suggest that hypertension, diabetes, and CVD are independently associated with severe COVID-19 and, together with age and male sex, can be informative for predicting the risk of severe COVID-19.
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http://dx.doi.org/10.5334/gh.814DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7546112PMC
September 2020

Features of patient-education websites for patients with chronic kidney disease: an analysis of recommended websites.

BMC Nephrol 2020 11 3;21(1):457. Epub 2020 Nov 3.

Welch Center for Prevention, Epidemiology, and Clinical Research, The Johns Hopkins University, 2024 E. Monument St., Baltimore, MD, 21287, USA.

Background: Chronic kidney disease (CKD) requires lifelong self-management. With the rise in access to the Internet, many CKD patients and their caregivers increasingly use the internet for information on CKD self-management. A recent environmental scan by Smekal et al. identified 11 CKD-related websites that covered the greatest number of content areas. This paper aims to evaluate these 11 selected websites in order to identify those that most effectively address content areas relevant to patients with CKD.

Methods: Each website was assessed for information to 6 content areas: diet, physical activity, financial information, emotional support, general CKD information, and medication adherence. A three-tiered scoring metric was used in which a 0 was given if a content area was completely unaddressed, a (+) was given for a category that was generally addressed, and a (++) was given for a category that was addressed with actionable guidance.

Results: While CKD information and diet were very comprehensively covered with scores of 11 (++) and 8 (++), respectively; physical activity, emotional support and medication adherence received the fewest (++) scores (3 for physical activity and five for both emotional support and medication adherence). For each content area, recommendations are made for websites that are particularly useful. Common themes for these highlighted websites include specific instructions, multiple modalities of information, downloadable and printable resources, and contact references for personal inquiries.

Conclusion: The recommended websites can help CKD patients and caregivers utilize the most applicable information for their specific self-management needs. Website improvements related to physical activity, emotional support, and financial information for persons with CKD are warranted.
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http://dx.doi.org/10.1186/s12882-020-02128-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7607846PMC
November 2020

Dietary intake of adults with and without diabetes: results from NHANES 2013-2016.

BMJ Open Diabetes Res Care 2020 10;8(1)

Division of General Internal Medicine, Department of Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland, USA.

Introduction: Diet is a critical aspect of the management of adults with diabetes. This paper aims to compare dietary intakes of key macronutrients and micronutrients of US adults with and without diabetes and across the spectrum of diabetes.

Research Design And Methods: We compared absolute and energy-adjusted dietary intake of major macronutrients and micronutrients among those with and without diabetes and across the spectrum of glycemic control using a 24-hour dietary recall from a cross-sectional, nationally representative sample of 9939 US adults, 20+ years old (National Health and Nutrition Examination Survey 2013-2016). Diabetes was defined as an glycohemoglobin A1c (HbA1c)≥6.5%, fasting glucose ≥126 mg/dL, serum glucose at 2 hours following a 75 g glucose load (oral glucose tolerance test) ≥200 mg/dL, any diagnosis of diabetes or use of diabetes medication (self-reported).

Results: Percent of calories from macronutrients was similar for those with and without diabetes (p>0.05, energy adjusted and adjusted for age, race, and sex). In both groups, sugar accounted for about 20% of calories. Those with diabetes consumed about 7% more calcium (p=0.033), about 5% more sodium (p=0.026), and had lower diet quality (Healthy Eating Index-2015, p=0.021) than those without diabetes. Among those with diabetes, those with an HbA1c>9.0% consumed about 4% less magnesium (p-analysis of variance=0.007) than those with an HbA1c<6.5%. Results were similar within strata of age, race, and sex. Macronutrient intake did not vary consistently by HbA1c level.

Conclusions: In this nationally representative sample, there were no substantial or consistent differences in the dietary intake of macronutrients or micronutrients between US adults with and without diabetes. Improving the diets of those with diabetes will likely require enhanced targeted efforts to improve the dietary intake of persons with diabetes, as well as broad efforts to improve the dietary intake of the general population.
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http://dx.doi.org/10.1136/bmjdrc-2020-001681DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7590352PMC
October 2020

Simplified blood pressure measurement approaches and implications for hypertension screening: the Atherosclerosis Risk in Communities study.

J Hypertens 2021 Mar;39(3):447-452

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

Objectives: Averaging multiple blood pressure (BP) measurements is recommended for hypertension (HTN) screening but can be impractical, especially in resource-constrained settings. We aimed to explore the implications of fewer BP measurements on BP classification and subsequent cardiovascular disease (CVD) risk.

Methods: We studied 8905 middle-aged participants without diagnosed HTN and quantified misclassified HTN (≥140/90 mmHg) by simplified BP approaches (e.g. single 1st BP, single 2nd BP, mainly 1st but 2nd BP if 1st was in a certain range) vs. the reference standard of the average of 2nd and 3rd BP. We also assessed CVD risk related to HTN status.

Results: There were 823 participants classified as HTN by the standard approach. With single 1st BP, 2.8% of non-HTN were overidentified as HTN, and 18.3% of HTN were identified as not having HTN. The corresponding estimates with single 2nd BP were 2.1 and 6.4%. Similar estimates were seen when 2nd BP was used if 1st BP at least 130/80 (1.9 and 8.1%), with only 27.8% requiring 2nd BP. Two thousand, one hundred and seventy-eight CVD cases were documented in this population over 30 years. HTN by either the standard approach or any of the simplified approaches conferred higher CVD risk vs. consistent no HTN by both approaches.

Conclusion: In those without diagnosed HTN, a simplified BP measurement approach using the 2nd BP only when the 1st BP is at least 130/80 could reduce the total number of BP measurements by more than 50%, identify HTN with limited misclassification (2-8%), and predict CVD risks reasonably well.
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http://dx.doi.org/10.1097/HJH.0000000000002682DOI Listing
March 2021

Evidence-Based Policy Making for Public Health Interventions in Cardiovascular Diseases: Formally Assessing the Feasibility of Clinical Trials.

Circ Cardiovasc Qual Outcomes 2020 11 28;13(11):e006378. Epub 2020 Sep 28.

Welch Center for Prevention, Epidemiology, and Clinical Research, Baltimore, MD (K.F., L.J.A.).

Implementation of prevention policies has often been impeded or delayed due to the lack of randomized controlled trials (RCTs) with hard clinical outcomes (eg, incident disease, mortality). Despite the prominent role of RCTs in health care, it may not always be feasible to conduct RCTs of public health interventions with hard outcomes due to logistical and ethical considerations. RCTs may also lack external validity and have limited generalizability. Currently, there is insufficient guidance for policymakers charged with establishing evidence-based policy to determine whether an RCT with hard outcomes is needed before policy recommendations. In this context, the purpose of this article is to assess, in a case study, the feasibility of conducting an RCT of the oft-cited issue of sodium reduction on cardiovascular outcomes and then propose a framework for decision-making, which includes an assessment of the feasibility of conducting an RCT with hard clinical outcomes when such trials are unavailable. We designed and assessed the feasibility of potential individual- and cluster-randomized trials of sodium reduction on cardiovascular outcomes. Based on our assumptions, a trial using any of the designs considered would require tens of thousands of participants and cost hundreds of millions of dollars, which is prohibitively expensive. Our estimates may be conservative given several key challenges, such as the unknown costs of sustaining a long-term difference in sodium intake, the effect of differential cotreatment with antihypertensive medications, and long lag time to clinical outcomes. Thus, it would be extraordinarily difficult to conduct such a trial, and despite the high costs, would still be at substantial risk for a spuriously null result. A robust framework, such as the one we developed, should be used to guide policymakers when establishing evidence-based public health interventions in the absence of trials with hard clinical outcomes.
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http://dx.doi.org/10.1161/CIRCOUTCOMES.119.006378DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7674216PMC
November 2020

Use of electronic recruitment methods in a clinical trial of adults with gout.

Clin Trials 2021 Feb 15;18(1):92-103. Epub 2020 Sep 15.

Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.

Background/aims: Electronic-based recruitment methods are increasingly utilized in clinical trials to recruit and enroll research participants. The cost-effectiveness of electronic-based methods and impact on sample generalizability is unknown. We compared recruitment yields, cost-effectiveness, and demographic characteristics across several electronic and traditional recruitment methods.

Methods: We analyzed data from the diet gout trial recruitment campaign. The diet gout trial was a randomized, controlled, cross-over trial that examined the effects of a dietary approaches to stop hypertension (DASH)-like diet on uric acid levels in adults with gout. We used four electronic medical record and four non-electronic medical record-based recruitment methods to identify and recruit potentially eligible participants. We calculated the response rate, screening visit completion rate, and randomization rate for each method. We also determined cost per response, the screening, and randomization for each method. Finally, we compared the demographic characteristics among individuals who completed the screening visit by recruitment method.

Results: Of the 294 adults who responded to the recruitment campaign, 51% were identified from electronic medical record-based methods. Patient portal messaging, an electronic medical record-based method, resulted in the highest response rate (4%), screening visit completion rate (37%), and randomization rate (21%) among these eight methods. Electronic medical record-based methods ($60) were more cost-effective per response than non-electronic medical record-based methods ($107). Electronic-based methods, including patient portal messaging and Facebook, had the highest proportion of White individuals screened (52% and 60%). Direct mail to non-active patient portal increased enrollment of traditionally under-represented groups, including both women and African Americans.

Conclusion: An electronic medical record-based recruitment strategy that utilized the electronic medical record for participant identification and postal mailing for participant outreach was cost-effective and increased participation of under-represented groups. This hybrid strategy represents a promising approach to improve the timely execution and broad generalizability of future clinical trials.
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http://dx.doi.org/10.1177/1740774520956969DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7878277PMC
February 2021

Effects of Intensive Blood Pressure Treatment on Orthostatic Hypotension : A Systematic Review and Individual Participant-based Meta-analysis.

Ann Intern Med 2021 01 10;174(1):58-68. Epub 2020 Sep 10.

Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts (S.P.J., J.L.C., K.J.M.).

Background: Although intensive blood pressure (BP)-lowering treatment reduces risk for cardiovascular disease, there are concerns that it might cause orthostatic hypotension (OH).

Purpose: To examine the effects of intensive BP-lowering treatment on OH in hypertensive adults.

Data Sources: MEDLINE, EMBASE, and Cochrane CENTRAL from inception through 7 October 2019, without language restrictions.

Study Selection: Randomized trials of BP pharmacologic treatment (more intensive BP goal or active agent) that involved more than 500 adults with hypertension or elevated BP and that were 6 months or longer in duration. Trial comparisons were groups assigned to either less intensive BP goals or placebo, and the outcome was measured OH, defined as a decrease of 20 mm Hg or more in systolic BP or 10 mm Hg or more in diastolic BP after changing position from seated to standing.

Data Extraction: 2 investigators independently abstracted articles and rated risk of bias.

Data Synthesis: 5 trials examined BP treatment goals, and 4 examined active agents versus placebo. Trials examining BP treatment goals included 18 466 participants with 127 882 follow-up visits. Trials were open-label, with minimal heterogeneity of effects across trials. Intensive BP treatment lowered risk for OH (odds ratio, 0.93 [95% CI, 0.86 to 0.99]). Effects did not differ by prerandomization OH ( for interaction = 0.80). In sensitivity analyses that included 4 additional placebo-controlled trials, overall and subgroup findings were unchanged.

Limitations: Assessments of OH were done while participants were seated (not supine) and did not include the first minute after standing. Data on falls and syncope were not available.

Conclusion: Intensive BP-lowering treatment decreases risk for OH. Orthostatic hypotension, before or in the setting of more intensive BP treatment, should not be viewed as a reason to avoid or de-escalate treatment for hypertension.

Primary Funding Source: National Heart, Lung, and Blood Institute, National Institutes of Health. (PROSPERO: CRD42020153753).
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http://dx.doi.org/10.7326/M20-4298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855528PMC
January 2021

Interventions Made to Preserve Cognitive Function Trial (IMPCT) study protocol: a multi-dialysis center 2x2 factorial randomized controlled trial of intradialytic cognitive and exercise training to preserve cognitive function.

BMC Nephrol 2020 09 3;21(1):383. Epub 2020 Sep 3.

Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Background: Kidney disease and dialysis significantly impact cognitive function across the age spectrum. Cognitive training (CT) and/or exercise training (ET) are promising approaches to preserve cognitive function among community-dwelling older adults, but have not been tested for cognition preservation in hemodialysis patients of all ages. In this manuscript, we summarize the protocol for the Interventions Made to Preserve Cognitive Function Trial (IMPCT).

Methods: We will perform a 2 × 2 factorial randomized controlled trial (RCT) of eligible adult (≥18 years) hemodialysis initiates (n = 200) to test whether intradialytic CT (brain games on a tablet PC), ET (foot peddlers) and combined CT + ET while undergoing hemodialysis preserves executive function compared to standard of care (SC). Participants will engage in the interventions to which they are randomized for 6 months. The primary objective is to compare, among interventions, the 3-month change in executive function measured using the Trail Making Test A (TMTA) and B (TMTB); specifically, executive function is calculated as TMTB-TMTA to account for psychomotor speed. This primary outcome was selected based on findings from our pilot study. The secondary objectives are to compare the risk of secondary cognitive outcomes, ESKD-specific clinical outcomes, and patient-centered outcomes at 3-months and 6-months. All data collection and interventions are conducted in the dialysis center.

Discussion: We hypothesize that receiving intradialytic CT or ET will better preserve executive function than SC but receiving combined CT + ET, will be the most effective intervention. The current trial will be an important step in understanding how intradialytic interventions might preserve cognitive health.

Trial Registration: Clinicaltrials.Gov (Date: 8/6/18): # NCT03616535 . Protocol Version: 10 (April 2020).

Funding: NIDDK R01DK114074.
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http://dx.doi.org/10.1186/s12882-020-02041-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7469421PMC
September 2020

Effects of carbohydrate quality and amount on plasma lactate: results from the OmniCarb trial.

BMJ Open Diabetes Res Care 2020 08;8(1)

Division of General Medicine and Primary Care, Beth Israel Deaconess Medical Center, Boston, Massachusetts, USA

Introduction: Plasma lactate is a marker of non-oxidative glucose metabolism associated with progression to diabetes. We examined the effect of carbohydrate quality (glycemic index (GI)) and amount (%kcal) on plasma lactate. We hypothesized that low GI (≤45 (g)) versus high (≥65 (G)) and low %kcal from carbohydrate (40% kcal (c)) versus high (58% kcal (C)) each would reduce lactate levels.

Research Design And Methods: We measured lactate in OmniCarb, a randomized, cross-over trial of four diets in overweight/obese adults without diabetes or cardiovascular disease (N=163). The four diets were high carbohydrate+high GI (CG, reference), high carbohydrate+low GI (Cg), low carbohydrate+high GI (cG), and low carbohydrate+low GI (cg). Participants (N=163) consumed each of the four diets over a 5-week period, separated by 2-week washout periods. Plasma lactate levels were measured at baseline, during which the participants consumed their own diets, and after each 5-week period.

Results: Baseline plasma lactate was 1.2 mmol/L. In the setting of high carbohydrate amount, reducing GI lowered plasma lactate non-significantly by 0.08 mmol/L (Cg vs CG: 95% CI -0.16 to 0.00; p=0.06). In the setting of high GI, reducing carbohydrate amount lowered plasma lactate by 0.10 mmol/L (cG vs CG: 95% CI -0.19 to -0.02; p=0.02). The combined effect of reducing GI and carbohydrate proportion in the diet (cg vs CG) was similar (cg vs CG: -0.08; 95% CI -0.16 to 0.00; p=0.04). All four diets reduced plasma lactate compared with baseline.

Conclusions: Compared with a diet with high GI and high carbohydrate amount, diets with low GI and/or low carbohydrate amount reduced plasma lactate. Whether this change in lactate leads to long-term change in glucose metabolism needs to be examined.

Trial Registration Number: NCT00608049.
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http://dx.doi.org/10.1136/bmjdrc-2020-001457DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7462151PMC
August 2020

Novel Risk Factors for Progression of Diabetic and Nondiabetic CKD: Findings From the Chronic Renal Insufficiency Cohort (CRIC) Study.

Am J Kidney Dis 2021 01 28;77(1):56-73.e1. Epub 2020 Aug 28.

Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA; Renal, Electrolyte, and Hypertension Division, Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA; Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA.

Rationale & Objective: Identification of novel risk factors for chronic kidney disease (CKD) progression may inform mechanistic investigations and improve identification of high-risk subgroups. The current study aimed to characterize CKD progression across levels of numerous risk factors and identify independent risk factors for CKD progression among those with and without diabetes.

Study Design: The Chronic Renal Insufficiency Cohort (CRIC) Study is a prospective cohort study of adults with CKD conducted at 7 US clinical centers.

Setting & Participants: Participants (N=3,379) had up to 12.3 years of follow-up; 47% had diabetes.

Predictors: 30 risk factors for CKD progression across sociodemographic, behavioral, clinical, and biochemical domains at baseline.

Outcomes: Study outcomes were estimated glomerular filtration rate (eGFR) slope and the composite of halving of eGFR or initiation of kidney replacement therapy.

Analytical Approach: Stepwise selection of independent risk factors was performed stratified by diabetes status using linear mixed-effects and Cox proportional hazards models.

Results: Among those without and with diabetes, respectively, mean eGFR slope was-1.4±3.3 and-2.7±4.7mL/min/1.73m per year. Among participants with diabetes, multivariable-adjusted hazard of the composite outcome was approximately 2-fold or greater with higher levels of the inflammatory chemokine CXCL12, the cardiac marker N-terminal pro-B-type natriuretic peptide (NT-proBNP), and the kidney injury marker urinary neutrophil gelatinase-associated lipocalin (NGAL). Among those without diabetes, low serum bicarbonate and higher high-sensitivity troponin T, NT-proBNP, and urinary NGAL levels were all significantly associated with a 1.5-fold or greater rate of the composite outcome.

Limitations: The observational study design precludes causal inference.

Conclusions: Strong associations for cardiac markers, plasma CXCL12, and urinary NGAL are comparable to that of systolic blood pressure≥140mm Hg, a well-established risk factor for CKD progression. This warrants further investigation into the potential mechanisms that these markers indicate and opportunities to use them to improve risk stratification.
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http://dx.doi.org/10.1053/j.ajkd.2020.07.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7752839PMC
January 2021

No U-turn on sodium reduction.

J Clin Hypertens (Greenwich) 2020 11 29;22(11):2156-2160. Epub 2020 Aug 29.

Johns Hopkins University, Baltimore, MD, USA.

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http://dx.doi.org/10.1111/jch.14021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7754279PMC
November 2020

The Relationship Between Urine Uromodulin and Blood Pressure Changes: The DASH-Sodium Trial.

Am J Hypertens 2021 03;34(2):154-156

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

Background: Uromodulin modulates the sodium-potassium-two-chloride transporter in the thick ascending limb of the loop of Henle, and its overexpression in murine models leads to salt-induced hypertension. We hypothesized that individuals with higher baseline levels of urine uromodulin would have a greater increase in systolic blood pressure (SBP) for the same increase in sodium compared with those with lower uromodulin levels.

Methods: We used data from 157 subjects randomized to the control diet of the Dietary Approaches to Stop Hypertension (DASH)-Sodium trial who were assigned to 30 days of low (1,500 mg/d), medium (2,400 mg/d), and high salt (3,300 mg/d) diets in random order. Blood pressure was measured prerandomization and then weekly during each feeding period. We evaluated the association of prerandomization urine uromodulin with change in SBP between diets, as measured at the end of each feeding period, using multivariable linear regression.

Results: Baseline urine uromodulin stratified by tertiles was ≤17.64, 17.65-31.97, and ≥31.98 µg/ml. Across the tertiles, there were no significant differences in SBP at baseline, nor was there a differential effect of sodium diet on SBP across tertiles (low to high, P = 0.81). After adjusting for age, sex, body mass index, and race, uromodulin levels were not significantly associated with SBP change from low to high sodium diet (P = 0.42).

Conclusions: In a randomized trial of different levels of salt intake, higher urine uromodulin levels were not associated with a greater increase in blood pressure in response to high salt intake.
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http://dx.doi.org/10.1093/ajh/hpaa140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7951043PMC
March 2021

Adherence to Healthy Dietary Patterns and Risk of CKD Progression and All-Cause Mortality: Findings From the CRIC (Chronic Renal Insufficiency Cohort) Study.

Am J Kidney Dis 2021 02 5;77(2):235-244. Epub 2020 Aug 5.

Welch Center for Prevention, Epidemiology, and Clinical Research, Johns Hopkins University, Baltimore, MD; Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD. Electronic address:

Rationale & Objective: Current dietary guidelines recommend that patients with chronic kidney disease (CKD) restrict individual nutrients, such as sodium, potassium, phosphorus, and protein. This approach can be difficult for patients to implement and ignores important nutrient interactions. Dietary patterns are an alternative method to intervene on diet. Our objective was to define the associations of 4 healthy dietary patterns with risk for CKD progression and all-cause mortality among people with CKD.

Study Design: Prospective cohort study.

Setting & Participants: 2,403 participants aged 21 to 74 years with estimated glomerular filtration rates of 20 to 70mL/min/1.73m and dietary data in the Chronic Renal Insufficiency Cohort (CRIC) Study.

Exposures: Healthy Eating Index-2015, Alternative Healthy Eating Index-2010, alternate Mediterranean diet (aMed), and Dietary Approaches to Stop Hypertension (DASH) diet scores were calculated from food frequency questionnaires.

Outcomes: (1) CKD progression defined as≥50% estimated glomerular filtration rate decline, kidney transplantation, or dialysis and (2) all-cause mortality.

Analytical Approach: Cox proportional hazards regression models adjusted for demographic, lifestyle, and clinical covariates to estimate hazard ratios (HRs) and 95% CIs.

Results: There were 855 cases of CKD progression and 773 deaths during a maximum of 14 years. Compared with participants with the lowest adherence, the most highly adherent tertile of Alternative Healthy Eating Index-2010, aMed, and DASH had lower adjusted risk for CKD progression, with the strongest results for aMed (HR, 0.75; 95% CI, 0.62-0.90). Compared with participants with the lowest adherence, the highest adherence tertiles for all scores had lower adjusted risk for all-cause mortality for each index (24%-31% lower risk).

Limitations: Self-reported dietary intake.

Conclusions: Greater adherence to several healthy dietary patterns is associated with lower risk for CKD progression and all-cause mortality among people with CKD. Guidance to adopt healthy dietary patterns can be considered as a strategy for managing CKD.
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http://dx.doi.org/10.1053/j.ajkd.2020.04.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7855760PMC
February 2021

Dietary Sodium Intake and Sodium Density in the United States: Estimates From NHANES 2005-2006 and 2015-2016.

Am J Hypertens 2020 09;33(9):825-830

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

Background: In the United States, current guidelines recommend a total sodium intake <2,300 mg/day, a guideline which does not consider kilocalorie intake. However, kilocalorie intake varies substantially by age and sex. We hypothesized that compared with sodium density, total sodium intake overestimates adherence to sodium recommendations, especially in adults consuming fewer kilocalories.

Methods: In the National Health and Nutrition Examination Survey (NHANES), we estimated the prevalence of adherence to sodium intake recommendations (<2,300 mg/day) and corresponding sodium density intake (<1.1 mg/kcal = 2,300 mg at 2,100 kcal) by sex, age, race/ethnicity, and kilocalorie level. Adherence estimates were compared between the 2005-2006 (n = 5,060) and 2015-2016 (n = 5,266) survey periods.

Results: In 2005-2006, 23.1% (95% confidence interval [CI]: 21.5, 24.9) of the US population consumed <2,300 mg of sodium/day, but only 8.5% (CI: 7.6, 9.4) consumed <1.1 mg/kcal in sodium density. In 2015-2016, these figures were 20.9% (CI: 18.8, 23.2) and 5.1% (CI: 4.4, 6.0), respectively. In 2015-2016, compared with 2005-2006, adherence by sodium density decreased more substantially (odds ratio = 0.59; CI: 0.48, 0.72; P < 0.001) than adherence by total sodium consumption (odds ratio = 0.85; CI: 0.73, 0.98; P = 0.03). The difference in adherence between total sodium and sodium density goals was greater among those with lower kilocalorie intake, namely, older adults, women, and Hispanic adults.

Conclusions: Adherence estimated by sodium density is substantially less than adherence estimated by total sodium intake, especially among persons with lower kilocalorie intake. Further efforts to achieve population-wide reduction in sodium density intake are urgently needed.
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http://dx.doi.org/10.1093/ajh/hpaa104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7481988PMC
September 2020