Browsing by Author "Friedman, Allon N."

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    Association Between Early Treatment With Tocilizumab and Mortality Among Critically Ill Patients With COVID-19
    (American Medical Association, 2020-10-20) Gupta, Shruti; Wang, Wei; Hayek, Salim S.; Chan, Lili; Mathews, Kusum S.; Melamed, Michal L.; Brenner, Samantha K.; Leonberg-Yoo, Amanda; Schenck, Edward J.; Radbel, Jared; Reiser, Jochen; Bansal, Anip; Srivastava, Anand; Zhou, Yan; Finkel, Diana; Green, Adam; Mallappallil, Mary; Faugno, Anthony J.; Zhang, Jingjing; Velez, Juan Carlos Q.; Shaefi, Shahzad; Parikh, Chirag R.; Charytan, David M.; Athavale, Ambarish M.; Friedman, Allon N.; Redfern, Roberta E.; Short, Samuel A. P.; Correa, Simon; Pokharel, Kapil K.; Admon, Andrew J.; Donnelly, John P.; Gershengorn, Hayley B.; Douin, David J.; Semler, Matthew W.; Hernán, Miguel A.; Leaf, David E.; STOP-COVID Investigators; Medicine, School of Medicine
    Importance: Therapies that improve survival in critically ill patients with coronavirus disease 2019 (COVID-19) are needed. Tocilizumab, a monoclonal antibody against the interleukin 6 receptor, may counteract the inflammatory cytokine release syndrome in patients with severe COVID-19 illness. Objective: To test whether tocilizumab decreases mortality in this population. Design, Setting, and Participants: The data for this study were derived from a multicenter cohort study of 4485 adults with COVID-19 admitted to participating intensive care units (ICUs) at 68 hospitals across the US from March 4 to May 10, 2020. Critically ill adults with COVID-19 were categorized according to whether they received or did not receive tocilizumab in the first 2 days of admission to the ICU. Data were collected retrospectively until June 12, 2020. A Cox regression model with inverse probability weighting was used to adjust for confounding. Exposures: Treatment with tocilizumab in the first 2 days of ICU admission. Main Outcomes and Measures: Time to death, compared via hazard ratios (HRs), and 30-day mortality, compared via risk differences. Results: Among the 3924 patients included in the analysis (2464 male [62.8%]; median age, 62 [interquartile range {IQR}, 52-71] years), 433 (11.0%) received tocilizumab in the first 2 days of ICU admission. Patients treated with tocilizumab were younger (median age, 58 [IQR, 48-65] vs 63 [IQR, 52-72] years) and had a higher prevalence of hypoxemia on ICU admission (205 of 433 [47.3%] vs 1322 of 3491 [37.9%] with mechanical ventilation and a ratio of partial pressure of arterial oxygen to fraction of inspired oxygen of <200 mm Hg) than patients not treated with tocilizumab. After applying inverse probability weighting, baseline and severity-of-illness characteristics were well balanced between groups. A total of 1544 patients (39.3%) died, including 125 (28.9%) treated with tocilizumab and 1419 (40.6%) not treated with tocilizumab. In the primary analysis, during a median follow-up of 27 (IQR, 14-37) days, patients treated with tocilizumab had a lower risk of death compared with those not treated with tocilizumab (HR, 0.71; 95% CI, 0.56-0.92). The estimated 30-day mortality was 27.5% (95% CI, 21.2%-33.8%) in the tocilizumab-treated patients and 37.1% (95% CI, 35.5%-38.7%) in the non-tocilizumab–treated patients (risk difference, 9.6%; 95% CI, 3.1%-16.0%). Conclusions and Relevance: Among critically ill patients with COVID-19 in this cohort study, the risk of in-hospital mortality in this study was lower in patients treated with tocilizumab in the first 2 days of ICU admission compared with patients whose treatment did not include early use of tocilizumab. However, the findings may be susceptible to unmeasured confounding, and further research from randomized clinical trials is needed.
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    The Association Between Kidney Disease and Diabetes Remission in Bariatric Surgery Patients With Type 2 Diabetes
    (Elsevier, 2019-12) Friedman, Allon N.; Wang, Junyao; Wahed, Abdus S.; Docherty, Neil G.; Fennern, Erin; Pomp, Alfons; Purnell, Jonathan Q.; le Roux, Carel W.; Wolfe, Bruce; Medicine, School of Medicine
    Rationale & objective: The association between bariatric surgery, type 2 diabetes, and chronic kidney disease (CKD) is poorly understood. We studied whether remission of type 2 diabetes induced by bariatric surgery influences markers of kidney disease, if CKD is associated with remission of diabetes after bariatric surgery, and if baseline levels of gut hormones and peptides modify these associations. Study design: Prospective observational study. Study participants: 737 bariatric surgery patients with type 2 diabetes who participated in a multicenter cohort study for up to 5 years. Predictors: Demographics, blood pressure, medications, type of bariatric surgery, anthropometrics, markers of kidney disease, and circulating levels of gut hormones and peptides. Outcomes: Estimated glomerular filtration rate (eGFR), urinary albumin excretion, prognostic risk for CKD, and remission of diabetes. Analytical approach: Linear mixed models for eGFR; generalized linear mixed models with logit link for albuminuria, prognostic risk for CKD, and diabetes remission. Results: Remission of diabetes at 5 years post-bariatric surgery was not independently associated with eGFR but was associated with lower risk for moderate/severe increase in albuminuria (risk ratio, 0.66; 95% CI, 0.48-0.90) and stabilization in prognostic risk for CKD. These findings were modified by baseline ghrelin level. Lower preoperative eGFR and greater prognostic risk for CKD were independently associated with reduced likelihood of diabetes remission. The association with preoperative GFR was modified by C-peptide level. Higher baseline circulating ghrelin level was independently associated with a lower prognostic risk for CKD. Limitations: A minority of participants had baseline CKD; lack of comparison group; no information on duration of diabetes, other clinical end points, or kidney biopsy results. Conclusions: Remission of type 2 diabetes 5 years after bariatric surgery was associated with improvements in albuminuria and stabilized prognostic risk for CKD, but not with eGFR. Lower kidney function and greater prognostic risk at the time of bariatric surgery was linked to a lower likelihood of diabetes remission. These results highlight the need to identify the mechanisms through which bariatric surgery may delay the long-term progression of CKD in type 2 diabetes. Keywords: C-peptide; CKD risk; Obesity; Roux-en-Y gastric bypass (RYGB); albuminuria; bariatric surgery; chronic kidney disease (CKD); diabetes remission; estimated glomerular filtration rate (eGFR); ghrelin; gut peptides; insulin; laparoscopic adjustable gastric banding (LAGB); modifiable risk factor; type 2 diabetes mellitus (T2DM); urinary albumin-creatinine ratio (UACR); weight loss.
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    Association between plasma endocannabinoids and appetite in hemodialysis patients: A pilot study
    (Elsevier, 2016-07) Friedman, Allon N.; Kim, Jeffrey; Kaiser, Shaun; Pedersen, Theresa L.; Newman, John W.; Watkins, Bruce A.; Medicine, School of Medicine
    Uremia-associated anorexia may be related to altered levels of long chain n-6 and n-3 polyunsaturated fatty acid (PUFA) derived circulating endocannabinoids (EC) and EC-like compounds that are known to mediate appetite. Our study's hypothesis was that such molecules are associated with appetite in patients with end-stage renal disease. A cross-sectional observational study was performed in 20 chronic hemodialysis patients (9 females, 11 males) and 10 healthy female controls in whom appetite was assessed using the Simplified Nutritional Appetite Questionnaire (SNAQ) and blood drawn in the fasting (and when applicable) pre-dialysis state. Blood levels of PUFA and EC were also measured. Higher blood levels of the long chain n-6 fatty acid 20:4n6 (arachidonic acid) and lower levels of the long chain n-3 fatty acid 20:5n3 (eicosapentaenoic acid) were observed in female hemodialysis patients compared to controls. No differences were observed between male and female patients. In female study participants strong correlations between specific EC-like compounds and total SNAQ scores were noted, including with the n-6 PUFA derived linoleoyl ethanolamide (L-EA; ρ=-0.60, P<.01) and the n-3 PUFA derived docosahexaenoyl ethanolamide (DH-EA; ρ=0.63, P<.01). The L-EA:DH-EA ratio was most strongly associated with the SNAQ score (ρ=-0.74, P≤.001), and its questions associated with appetite (ρ=-0.69, P≤.01) and satiety (ρ=-0.81, P≤.001). These findings support a link between circulating EC and appetite in hemodialysis patients.
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    The Case for a Bariatric-Centered Approach to CKD Care
    (American Society of Nephrology, 2019-02-07) Friedman, Allon N.; Medicine, School of Medicine
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    Diagnosis and Management of Type 2 Diabetic Kidney Disease
    (American Society of Nephrology, 2017-08-07) Doshi, Simit M.; Friedman, Allon N.; Medicine, School of Medicine
    Type 2 diabetic kidney disease (DKD) is the most common cause of CKD and ESRD worldwide, and carries with it enormous human and societal costs. The goal of this review is to provide an update on the diagnosis and management of DKD based on a comprehensive review of the medical literature. Topics addressed include the evolving presentation of DKD, clinical differentiation of DKD from non-DKD, a state-of-the-art evaluation of current treatment strategies, and promising emerging treatments. It is expected that the review will help clinicians to diagnose and manage patients with DKD.
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    Effect of Bariatric Surgery on CKD Risk
    (American Society of Nephrology, 2018-04) Friedman, Allon N.; Wahed, Abdus S.; Wang, Junyao; Courcoulas, Anita P.; Dakin, Gregory; Hinojosa, Marcelo W.; Kimmel, Paul L.; Mitchell, James E.; Pomp, Alfons; Pories, Walter J.; Purnell, Jonathan Q.; le Roux, Carel; Spaniolas, Konstantinos; Steffen, Kristine J.; Thirlby, Richard; Wolfe, Bruce; Medicine, School of Medicine
    Obesity is linked to the development and progression of CKD, but whether bariatric surgery protects against CKD is poorly understood. We, therefore, examined whether bariatric surgery influences CKD risk. The study included 2144 adults who underwent bariatric surgery from March of 2006 to April of 2009 and participated in the Longitudinal Assessment of Bariatric Surgery-2 Study cohort. The primary outcome was CKD risk categories as assessed by the Kidney Disease Improving Global Outcomes (KDIGO) consortium criteria using a combination of eGFR and albuminuria. Patients were 79% women and 87% white, with a median age of 46 years old. Improvements were observed in CKD risk at 1 and 7 years after surgery in patients with moderate baseline CKD risk (63% and 53%, respectively), high baseline risk (78% and 56%, respectively), and very high baseline risk (59% and 23%, respectively). The proportion of patients whose CKD risk worsened was ≤10%; five patients developed ESRD. Sensitivity analyses using year 1 as baseline to minimize the effect of weight loss on serum creatinine and differing eGFR equations offered qualitatively similar results. Treatment with bariatric surgery associated with an improvement in CKD risk categories in a large proportion of patients for up to 7 years, especially in those with moderate and high baseline risk. These findings support consideration of CKD risk in evaluation for bariatric surgery and further study of bariatric surgery as a treatment for high-risk obese patients with CKD.
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    Factors Associated With Death in Critically Ill Patients With Coronavirus Disease 2019 in the US
    (American Medical Association, 2020-07-15) Gupta, Shruti; Hayek, Salim S.; Wang, Wei; Chan, Lili; Mathews, Kusum S.; Melamed, Michal L.; Brenner, Samantha K.; Leonberg-Yoo, Amanda; Schenck, Edward J.; Radbel, Jared; Reiser, Jochen; Bansal, Anip; Srivastava, Anand; Zhou, Yan; Sutherland, Anne; Green, Adam; Shehata, Alexandre M.; Goyal, Nitender; Vijayan, Anitha; Velez, Juan Carlos Q.; Shaefi, Shahzad; Parikh, Chirag R.; Arunthamakun, Justin; Athavale, Ambarish M.; Friedman, Allon N.; Short, Samuel A. P.; Kibbelaar, Zoe A.; Omar, Samah Abu; Admon, Andrew J.; Donnelly, John P.; Gershengorn, Hayley B.; Hernán, Miguel A.; Semler, Matthew W.; Leaf, David E.; Medicine, School of Medicine
    Importance: The US is currently an epicenter of the coronavirus disease 2019 (COVID-19) pandemic, yet few national data are available on patient characteristics, treatment, and outcomes of critical illness from COVID-19. Objectives: To assess factors associated with death and to examine interhospital variation in treatment and outcomes for patients with COVID-19. Design, Setting, and Participants: This multicenter cohort study assessed 2215 adults with laboratory-confirmed COVID-19 who were admitted to intensive care units (ICUs) at 65 hospitals across the US from March 4 to April 4, 2020. Exposures: Patient-level data, including demographics, comorbidities, and organ dysfunction, and hospital characteristics, including number of ICU beds. Main Outcomes and Measures: The primary outcome was 28-day in-hospital mortality. Multilevel logistic regression was used to evaluate factors associated with death and to examine interhospital variation in treatment and outcomes. Results: A total of 2215 patients (mean [SD] age, 60.5 [14.5] years; 1436 [64.8%] male; 1738 [78.5%] with at least 1 chronic comorbidity) were included in the study. At 28 days after ICU admission, 784 patients (35.4%) had died, 824 (37.2%) were discharged, and 607 (27.4%) remained hospitalized. At the end of study follow-up (median, 16 days; interquartile range, 8-28 days), 875 patients (39.5%) had died, 1203 (54.3%) were discharged, and 137 (6.2%) remained hospitalized. Factors independently associated with death included older age (≥80 vs <40 years of age: odds ratio [OR], 11.15; 95% CI, 6.19-20.06), male sex (OR, 1.50; 95% CI, 1.19-1.90), higher body mass index (≥40 vs <25: OR, 1.51; 95% CI, 1.01-2.25), coronary artery disease (OR, 1.47; 95% CI, 1.07-2.02), active cancer (OR, 2.15; 95% CI, 1.35-3.43), and the presence of hypoxemia (Pao2:Fio2<100 vs ≥300 mm Hg: OR, 2.94; 95% CI, 2.11-4.08), liver dysfunction (liver Sequential Organ Failure Assessment score of 2 vs 0: OR, 2.61; 95% CI, 1.30–5.25), and kidney dysfunction (renal Sequential Organ Failure Assessment score of 4 vs 0: OR, 2.43; 95% CI, 1.46–4.05) at ICU admission. Patients admitted to hospitals with fewer ICU beds had a higher risk of death (<50 vs ≥100 ICU beds: OR, 3.28; 95% CI, 2.16-4.99). Hospitals varied considerably in the risk-adjusted proportion of patients who died (range, 6.6%-80.8%) and in the percentage of patients who received hydroxychloroquine, tocilizumab, and other treatments and supportive therapies. Conclusions and Relevance: This study identified demographic, clinical, and hospital-level risk factors that may be associated with death in critically ill patients with COVID-19 and can facilitate the identification of medications and supportive therapies to improve outcomes.
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    Hypothesis: Potential Utility of Serum and Urine Uromodulin Measurement in Kidney Transplant Recipients?
    (Lippincott, Williams & Wilkins, 2017-10-06) Bostom, Andrew G.; Steubl, Dominik; Friedman, Allon N.; Medicine, School of Medicine
    Seventy years after its discovery, studies of the myriad properties, and potential disease associations of uromodulin are now burgeoning. Although normative ranges for serum/plasma uromodulin concentrations were established over 30 years ago, their external validation occurred only in very recent, larger studies. As tubular function indices, serum and urinary uromodulin may be more sensitive indicators of kidney graft dysfunction undetected by glomerular filtration markers, or proteinuria. Moreover, 2 sizable, just published longitudinal reports revealed that lower serum uromodulin levels were associated with cardiovascular disease (CVD) outcomes, total mortality, and infectious disease deaths, in patients with known or suspected coronary heart disease. Preliminary longitudinal studies have reported that reduced levels of plasma or serum uromodulin were linked to progression to end-stage renal disease in chronic kidney disease patients, and graft failure in kidney transplant recipients (KTRs). Conflicting data on the associations, or lack thereof, between lower urinary uromodulin concentrations and accelerated loss of renal function, or renal failure, in nontransplant chronic kidney disease patients, are perhaps due, in part, to analytical limitations in determining urine uromodulin. Potential longitudinal associations between serum and urinary uromodulin concentrations, and CVD outcomes, graft failure, and all-cause mortality, await validation in large, diverse cohorts of chronic KTRs. Taking advantage of an efficient case-cohort design scheme, we demonstrate how the completed FAVORIT clinical trial cohort might be ideally suited to evaluate these associations. Using available case-cohort sample data, statistical power simulations are provided to detect relative risk estimates of 1.50 for CVD (n = 309 events), 1.56 for graft failure (n = 223 events) or 1.50 for death from any cause (n = 320 events), comparing values below the median, to values equal to or above the median for serum uromodulin values. Edifying data such as these would advance our understanding of the hypothetical utility of uromodulin measurement in KTRs considerably.
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    Influence of dietary protein on glomerular filtration before and after bariatric surgery: a cohort study
    (Elsevier, 2014-04) Friedman, Allon N.; Quinney, Sara K.; Inman, Margaret; Mattar, Samer G.; Shihabi, Zak; Moe, Sharon; Department of Medicine, IU School of Medicine
    BACKGROUND: Obesity-associated elevations in glomerular filtration rate (GFR) are common and may play a role in the development of kidney disease, so identifying the underlying mechanism is important. We therefore studied whether reductions in dietary protein intake, which is known to modulate GFR, explain why GFR decreases after bariatric surgery-induced weight loss. STUDY DESIGN: Cohort study with participants as their own controls. SETTING & PARTICIPANTS: 8 severely obese patients with normal kidney function were recruited from bariatric surgery centers in Indianapolis, IN. All participants were placed on a fixed-protein (50-g/d) diet for 1 week before and after a minimum of a 20-kg weight loss by bariatric surgery and were followed up closely by dieticians for adherence. PREDICTOR: Ad lib versus low-protein diet before versus after bariatric surgery. OUTCOME: Measured GFR, using repeated-measures analysis, was used to estimate the independent effects of diet and surgery. MEASUREMENT: GFR was measured using plasma iohexol clearance. RESULTS: A median of 32.9 (range, 19.5-54.4)kg was lost between the first presurgery visit and first postsurgery visit. Dietetic evaluations and urinary urea excretion confirmed that patients generally adhered to the study diet. GFRs on an ad lib diet were significantly higher before compared to after surgery (GFR medians were 144 (range, 114-178) and 107 (range, 85-147) mL/min, respectively; P=0.01). Although bariatric surgery (-26mL/min; P=0.005) and dietary sodium intake (+7.5mL/min per 100mg of dietary sodium; P=0.001) both influenced GFR, consuming a low-protein diet did not (P=0.7). LIMITATIONS: Small sample size; mostly white women; possible lack of generalizability. CONCLUSIONS: The decrease in GFR observed after bariatric surgery is explained at least in part by the effects of surgery and/or dietary sodium intake, but not by low dietary protein consumption.
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    Inquiry into the short- and long-term effects of Roux-en-Y gastric bypass on the glomerular filtration rate
    (Taylor & Francis, 2020-07-13) Friedman, Allon N.; Considine, Robert V.; Quinney, Sara K.; Medicine, School of Medicine
    Bariatric surgery is known to attenuate glomerular hyperfiltration over the long term and thereby protect the kidney from mechanical damage. Whether this effect is directly related to weight loss or is independent of weight as are some of its other beneficial metabolic effects is not known. We explored this question in a preliminary study that directly measured glomerular filtration rate (GFR) before, immediately after, and again many months after Roux-en-Y gastric bypass after large weight loss had occurred. We simultaneously measured stimulated circulating glucagon-like peptide-1, which is upregulated after Roux-en-Y gastric bypass and is a putative mediator of GFR after bariatric surgery. We found no weight-independent effect of Roux-en-Y gastric bypass on GFR nor an association between circulating GLP-1 levels and GFR. These findings, if confirmed in larger studies, will help steer future enquiries in this area.