Author Interviews, Brigham & Women's - Harvard, Genetic Research, Kidney Disease, Surgical Research / 07.06.2016
Genetic Variant Highly Associated with Kidney Injury After Cardiac Surgery
MedicalResearch.com Interview with:
David E. Leaf, MD, MMSc, FASN
Instructor in Medicine, Harvard Medical School
Associate Physician, Renal Division, Brigham and Women's Hospital
MedicalResearch.com: What is the background for this study? What are the main findings?
Dr. Leaf: Heme oxygenase-1 (HO-1), the rate-limiting enzyme in the degradation of heme, has a central role in the pathophysiology of acute kidney injury (AKI) in animal models, but data on HO-1 in human AKI are sparse. Genetic polymorphisms in the number of guanosine thymidine dinucleotide [(GT)n] repeats in the promoter of the HO-1 gene are inversely associated with HO-1 expression, and longer (GT)n repeats are associated with increased cardiovascular events and mortality in a variety of clinical settings. However, no study has evaluated the association between number of (GT)n repeats and risk of AKI in a large cohort of patients. We analyzed the allelic frequencies of (GT)n repeats in the HO-1 gene promoter in 2377 Caucasian patients who underwent cardiopulmonary bypass surgery to evaluate their association with AKI. We categorized patients as having the short (S) or long (L) allele if they had.
Dr. Jiang He[/caption]
Jiang He, M.D., Ph.D.
Joseph S. Copes Chair and Professor
Department of Epidemiology
School of Public Health and Tropical Medicine
Tulane University, New Orleans
MedicalResearch: What is the background for this study?
Dr. Jiang He: Chronic kidney disease is associated with increased risk of end-stage renal disease, cardiovascular disease, and all-cause mortality. A positive association between sodium intake and blood pressure is well established in observational studies and clinical trials. However, the association between sodium intake and clinical cardiovascular disease remains less clear. Positive monotonic, J-shaped, and U-shaped associations have been reported. Methodologic limitations, including inconsistencies in dietary sodium measurement methods, could be contributing to these conflicting findings. Furthermore, no previous studies have examined the association between sodium intake and incident cardiovascular disease among patients with chronic kidney disease.
Dr. Laura E. Niklason[/caption]
Dr Laura E Niklason, MD PhD
Department of Anesthesia & Biomedical Engineering
Yale University, New Haven, CT
MedicalResearch.com: What is the background for this study? What are the main findings?
Dr. Niklason: For end stage renal disease patients who are not candidates for fistula, dialysis access grafts are the best option for chronic hemodialysis. However, polytetrafluoroethylene arteriovenous grafts suffer from high rates of thrombosis, infection and intimal hyperplasia at the venous anastomosis.
We are conducting two, single arm Phase II trials where a novel bioengineered human acellular vessel (HAV) was implanted into the arms of patients for hemodialysis access. Primary endpoints were safety (freedom from immune response/infection, aneurysm, or mechanical failure, and incidence of adverse events), and efficacy as assessed by primary, primary assisted and secondary patencies at 6 months. Secondary endpoints included patency and intervention rates at 12, 18 and 24 months, and changes in panel reactive antibodies following implantation. All patients were followed for at least one year, or had a censoring event.
Human acellular vessels were implanted into 60 patients at 6 centers in the US and Poland. The average duration of follow-up was 16 months (range 12 to 30); all patients have completed at least 12 months of follow-up (or been censored).
Dr. Ambay Pandey[/caption]
Ambarish Pandey, MD
Cardiology Fellow, PGY5
University of Texas Southwestern Medical Center
Dallas, Texas
MedicalResearch.com: What is the background for this study? What are the main findings?
Dr. Pandey: Previous studies have reported an underutilization of guideline based heart failure therapies among patients with heart failure (HF) and end-stage renal diseases. However, it is not known if the proportional use of these evidence-based medical therapies and associated clinical outcomes among these patients has changed over time. In this study, we observed a significant increase in adherence to heart failure process of care measures over time among dialysis patients with no significant change in clinical outcomes over time.
Dr. Hiten Patel[/caption]
Hiten D. Patel, MD, MPH
Resident, Urological Surgery
James Buchanan Brady Urological Institute
The Johns Hopkins Medical Institutions
Baltimore, Maryland 21287
MedicalResearch.com: What is the background for this study?
Dr. Patel: The study reports results of a systematic review contracted by the Agency for Healthcare Research and Quality based on input from stakeholders. Part of the motivation was due to the American Urological Association's desire to use the results as a basis to update relevant clinical guidelines.
There are four major management options for clinically localized small renal masses diagnosed on imaging including active surveillance, thermal ablation, partial nephrectomy, and radical nephrectomy. The body of research evaluating these management options is broad, but many of the studies performing comparative analyses have limitations. Therefore, the systematic review aimed to evaluate a number of outcomes (e.g. overall survival, cancer specific survival, local recurrence, metastasis, renal function, complications, and perioperative outcomes) based on available comparative studies in the literature.
Dr. Judith Lechner[/caption]
A.Univ.-Prof. Dr. Judith Lechner
Div. Physiology
Medical University of Innsbruck
Innsbruck Austria
MedicalResearch.com: What is the background for this study? What are the main findings?
Dr. Lechner: Women are not just small men. Sex differences affect most, if not all the organ systems in the body. Over the past decades biomedical researchers have been mainly using male models. Therefore, there is a significant gap in knowledge of female physiology except for organ functions involved in reproduction. While the necessity to fill in these gaps has been advocated, our understanding of sex and gender differences in human physiology and pathophysiology is still limited. This holds especially true for the kidneys, e.g. while international registries show that fewer women than men are in need of renal replacement therapy due to end stage renal disease, the potentially underlying causes are still not known.
The aim of our study was to find out, if hormone changes due to the female menstrual cycle would affect normal renal cells. For this purpose, urinary samples of healthy women of reproductive age were collected daily and analyzed for menstrual cycle-associated changes of marker proteins. Specifically, two enzymes (Fructose-1,6-bisphosphatase, Glutathione-S-transferase alpha) were measured, which are intracellular components of proximal tubular cells, a key population of renal cells. Upon cell damage, these enzymes are released into the urine, qualifying them as clinical markers for early detection of tubular injury. Since even in healthy persons low amounts of these enzymes can be detected in the urine, we used these marker proteins to analyze potential effects of the female hormone cycle on normal functioning of this cell population. As a result, we could detect transient increases of Fructose-1,6-bisphosphatase and Glutathione-S-transferase alpha correlating with specific phases of the female hormone cycle, namely ovulation and menses.
This finding suggests that cyclical changes of female hormones might affect renal cell homeostasis, potentially providing women with an increased resistance against kidney damages. Thus, recurring changes of sex hormone levels, as during the natural menstrual cycle, might be involved in periodic tissue re-modeling not only in reproductive organs, but to a certain extent in the kidneys as well.
Dr. Renato Lopes[/caption]
MedicalResearch.com Interview with:
Renato D. Lopes MD, MHS, PhD
Duke University Medical Center
Duke Clinical Research Institute
Durham, NC 27705
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Dr. Vavalle[/caption]
John P. Vavalle, MD, MHS
Assistant Professor of Medicine
Division of Cardiology
UNC Center for Heart & Vascular Care
Medical Research: What is the background for this study? What are the main findings?
Dr. Lopes: Patients with varying degrees of underlying renal failure who presented for primary percutaneous coronary intervention (PCI) for the treatment of ST-segment elevation myocardial infarction (STEMI) were studied as part of the APEX-AMI trial.
Baseline renal dysfunction portends a worse prognosis in patients undergoing PCI. However, the association between clinical outcomes and angiographic results with baseline renal function in this population of STEMI patients is not clearly defined. We report the results of a trial population with a full spectrum of underlying renal function (normal to dialysis dependent) and developed a prediction model for the development of acute kidney injury following primary percutaneous coronary intervention.
In summary, patients with worse underlying renal function had worse angiographic outcomes, higher mortality, and were less likely to be treated with evidence-based medications. The rate of acute kidney injury (AKI) after PCI appears to increase with worsening underlying renal function, except for those with Class IV chronic kidney disease where the rate of AKI was lowest. Our novel prediction model for the development of AKI found that the strongest predictors of AKI were age and presenting in Killip Class III or IV.
Dr. Daniel Friedman[/caption]
MedicalResearch.com Interview with:
Daniel Friedman, MD
Cardiology Fellow
Duke University Hospital
Durham, North Carolina
MedicalResearch: What is the background for this study? What are the main findings?
Dr. Friedman: Cardiac resynchronization therapy (CRT) has been demonstrated to reduce heart failure hospitalizations, heart failure symptoms, and mortality in randomized clinical trials. However, these well-known trials either formally excluded or did not report enrollment of patients with more advanced chronic kidney disease (CKD), which we defined as a glomerular filtration rate of <45ml/minute. Since advanced CKD has been associated with an increased risk of adverse outcomes among patients with a variety of pacemakers and defibrillators, many have questioned whether the risks of CRT may outweigh the benefits in this population. Furthermore, many have hypothesized that the competing causes of morbidity and mortality among advanced CKD patients who meet criteria for CRT may mitigate clinical response and net benefit.
Our study assessed the comparative effectiveness of CRT with defibrillator (CRT-D) versus defibrillator alone in CRT eligible patients with a glomerular filtration rate of <60ml/minute (Stage III-V CKD, including those on dialysis). We demonstrated that CRT-D use was associated with a significant reduction in heart failure hospitalization or death in the overall population and across the spectrum of CKD. The lower rates of heart failure hospitalization or death was apparent in all subgroups we tested except for those without a left bundle branch block. Importantly, we also demonstrated that complication rates did not increase with increasing severity of CKD.
Dr. Nakharni[/caption]
MedicalResearch.com Interview with:
Girish N. Nadkarni, MD, MPH
Division of Nephrology, Department of Medicine
Icahn School of Medicine at Mount Sinai
New York, New York
MedicalResearch.com: What is the background for this study? What are the main findings?
Dr. Nadkarni: Cardiovascular disease is one of the major causes of morbidity and mortality in patients with kidney disease. Moreover, there is a lack of good quality evidence in kidney disease patients. In addition, previous studies have shown that cardiovascular trials exclude patients with kidney disease. We wanted to analyze all of the clinical trials on acute myocardial infarctions and heart failure in the last decade and see if they continued excluding patients with kidney disease. We discovered that in 371 trials including close to six hundred thousand patients, the majority (57%) excluded patients with kidney disease. A large proportion of the trials excluded patients for non-specific reasons, rather than a prespecified threshold of kidney function and did not report kidney function at baseline. Finally, in trials that did include kidney patients and reported outcomes by 
Dr. Thakar[/caption]
MedicalResearch.com Interview with:
Charuhas Thakar, MD
Director, Division of Nephrology and Hypertension Professor of Medicine
University of Cincinnati
Medical Research: What is the background for this study? What are the main findings?
"Diabetes is the major contributor to the growing burden of end-stage renal disease,” says Charuhas Thakar, MD, professor and director of the Division of Nephrology and Hypertension at the UC College of Medicine.
"Acute kidney injury is a common problem among diabetic patients who require admissions to hospitals. Approximately one-third of patients who develop AKI also have diabetes mellitus.”
Dr. Thakar along with a team of researchers have looked at a cohort of about 3,700 patients with Type 2 diabetes longitudinally followed for a five-year period to determine AKI’s impact.
AKI is a rapid loss of kidney function, which is common in hospitalized patients.
It has many causes that include low blood volume, exposure to substances or interventions harmful to the kidney and
obstruction of the urinary tract.
Dr. Molnar[/caption]
MedicalResearch.com Interview with:
Miklos Z Molnar, MD, PhD, FEBTM, FERA, FASN
Associate Professor of Medicine
Division of Nephrology, Department of Medicine
University of Tennessee Health Science Center
Memphis, TN, 38163
Medical Research: What is the background for this study? What are the main findings?
Dr. Molnar: We examine the association between presence of depression and all-cause mortality; incident Coronary Heart Disease (CHD) (new onset AMI, CABG or PCI), incident ischemic stroke, slopes of eGFR (OLS, <-5 vs ≥-5 ml/min/1.73m2/yr) in 933,211 diabetic (based on ICD9, medication and HbA1c ≥ 6.5%) US Veterans with eGFR ≥ 60 ml/min/1.73m2 at baseline. We adjusted for independent covariates, collected from VA databases, such as age, gender, race, BMI, marital status, income, service connection, comorbid conditions (ICD9), baseline eGFR, serum albumin.
Mean age was 64±11 years, 97% were male and 18% African-American. Depression was present in 340,806 (37%) patients at enrollment. During a median follow-up of 7.3 years, 180,343 patients (19%) developed Chronic Kidney Disease (CKD).AS (adjusted hazard ratio [aHR] and 95% confidence interval [CI]: 1.20 (1.19-1.21)). Similarly, depression was associated with 35% higher risk of incident stroke (aHR and 95% CI: 1.35 (1.32-1.39), 24% higher risk of incident CHD (aHR and 95% CI: 1.24 (1.22-1.27) and 25% higher risk of all cause mortality (aHR and 95% CI: 1.25 (1.24-1.26) during the follow-up.
