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le Roux, Carel W.
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le Roux, Carel W.
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le Roux, Carel W.
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- PublicationThe Impact of CKD on Perioperative Risk and Mortality after Bariatric Surgery(American Society of Nephrology, 2021-02)
; ; ; ; Background Twenty percent of patients with CKD in the United States have a body mass index (BMI) ≥35 kg/m2. Bariatric surgery reduces progression of CKD to ESKD, but the risk of perioperative complications remains a concern. Methods The 24-month data spanning 2017–2018 were obtained from the Metabolic and Bariatric Surgery Quality Improvement Program (MBSAQIP) database and analyzed. Surgical complications were assessed on the basis of the length of hospital stay, mortality, reoperation, readmission, surgical site infection (SSI), and worsening of kidney function during the first 30 days after surgery. Results The 277,948 patients who had primary bariatric procedures were 44±11.9 (mean ± SD) years old, 79.6% were women, and 71.2% were White. Mean BMI was 45.7±7.6 kg/m2. Compared with patients with an eGFR≥90 ml/min per BSA, those with stage 5 CKD/ESKD were 1.91 times more likely to be readmitted within 30 days of a bariatric procedure (95% CI, 1.37 to 2.67; P<0.001). Similarly, length of hospital stay beyond 2 days was 2.05-fold (95% CI, 1.64 to 2.56; P<0.001) higher and risk of deep incisional SSI was 6.92-fold (95% CI, 1.62 to 29.52; P=0.009) higher for those with stage 5 CKD/ESKD. Risk of early postoperative mortality increased with declining preoperative eGFR, such that patients with stage 3b CKD were 3.27 (95% CI, 1.82 to 5.89; P<0.001) times more likely to die compared with those with normal kidney function. However, absolute mortality rates remained relatively low at 0.53% in those with stage 3b CKD. Furthermore, absolute mortality rates were <0.5% in those with stages 4 and 5 CKD, and these advanced CKD stages were not independently associated with an increased risk of early postoperative mortality. Conclusions Increased severity of kidney disease was associated with increased complications after bariatric surgery. However, even for the population with advanced CKD, the absolute rates of postoperative complications were low. The mounting evidence for bariatric surgery as a renoprotective intervention in people with and without established kidney disease suggests that bariatric surgery should be considered a safe and effective option for patients with CKD.50 - PublicationComment on: Metabolic surgery improves renal injury independent of weight loss: a meta-analysisDiabetic kidney disease (DKD) is the leading cause of end-stage renal disease and significantly elevates cardiovascular disease risk [1]. Persons with DKD accounted for 45.4% and 38.2% of incident and prevalent cases of end-stage renal disease in the United States in 2015, respectively [2]. Current management of DKD focuses on control of hyperglycemia and hypertension along with renin-angiotensin-aldosterone system blockade to minimize proteinuria. The most notable recent advances in DKD care include sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide-1 agonists, which reduce glycosylated hemoglobin (A1C), blood pressure, weight, cardiovascular mortality, and nephropathy progression [ 3]. Despite this, existing therapies for DKD slow the rate of renal functional decline rather than reversing it.
46Scopus© Citations 7 - PublicationMetabolic Surgery to Treat Obesity in Diabetic Kidney Disease, Chronic Kidney Disease, and End-Stage Kidney Disease; What Are the Unanswered Questions?(Frontiers, 2020-08-17)
; ; ; ; Obesity is a major factor in contemporary clinical practice in nephrology. Obesity accelerates the progression of both diabetic and non-diabetic chronic kidney disease and, in renal transplantation, both recipient and donor obesity increase the risk of allograft complications. Obesity is thus a major driver of renal disease progression and a barrier to deceased and living donor kidney transplantation. Large observational studies have highlighted that metabolic surgery reduces the incidence of albuminuria, slows chronic kidney disease progression, and reduces the incidence of end-stage kidney disease over extended follow-up in people with and without type 2 diabetes. The surgical treatment of obesity and its metabolic sequelae has therefore the potential to improve management of diabetic and non-diabetic chronic kidney disease and aid in the slowing of renal decline toward end-stage kidney disease. In the context of patients with end-stage kidney disease, although complications of metabolic surgery are higher, absolute event rates are low and it remains a safe intervention in this population. Pre-transplant metabolic surgery increases access to kidney transplantation in people with obesity and end-stage kidney disease. Metabolic surgery also improves management of metabolic complications post-kidney transplantation, including new-onset diabetes. Procedure selection may be critical to mitigate the risks of oxalate nephropathy and disruption to immunosuppressant pharmacokinetics. Metabolic surgery may also have a role in the treatment of donor obesity, which could increase the living kidney donor pool with potential downstream impact on kidney paired exchange programmes. The present paper provides a comprehensive coverage of the literature concerning renal outcomes in clinical studies of metabolic surgery and integrates findings from relevant mechanistic pre-clinical studies. In so doing the key unanswered questions for the field are brought to the fore for discussion.70Scopus© Citations 23 - PublicationParallel assessment of albuminuria and plasma sTNFR1 in people with type 2 diabetes and advanced chronic kidney disease provides accurate prognostication of the risks of renal decline and death(Springer, 2020-09-09)
; ; ; ; ; ; ; ; ; Identification of people with diabetes and chronic kidney disease at high-risk of early mortality is a priority to guide intensification of therapy. We aimed to investigate the complementary prognostic value of baseline urine albumin-to-creatinine ratio (uACR) and plasma soluble tumour necrosis factor receptor-1 (sTNFR1) with respect to early mortality and renal functional decline in a population with type 2 diabetes and advanced chronic kidney disease. We measured plasma sTNFR1 in people with type 2 diabetes (HbA1c ≥ 48 mmol/mol) at 2 hospital sites in Dublin between October 15th, 2014 and July 17th, 2015. In a subgroup of patients with advanced chronic kidney disease at baseline (estimated glomerular filtration rate (eGFR) ≤ 60 mL/min/BSA) (n = 118), we collected clinical and longitudinal laboratory data to investigate relationships between sTNFR1 and renal and mortality endpoints by multivariable linear mixed-effects models and Cox proportional hazards regression models. The cohort was 64% male and 97% Caucasian. Mean age was 74 years, with a median type 2 diabetes duration of 16 years. Mean CKD-EPI eGFR was 42 mL/min/BSA and median [IQR] uACR was 3 [11] mg/mmol. Twenty-three (39%) people in quartiles 3 and 4 for plasma sTNFR1 died over 4-year follow-up. After adjustment for clinical variables, annual CKD-EPI eGFR decreased by − 0.56 mL/min/BSA/year for each logarithm unit increase in baseline uACR, corresponding to an annual loss of renal function of 3% per year. Furthermore, elevated uACR, but not sTNFR1, increased the risk of ≥ 40% decline in CKD-EPI eGFR (HR 1.5, p = 0.001) and doubling of serum creatinine (HR 2.0, p < 0.001). Plasma sTNFR1 did not predict a more negative trajectory in eGFR slope. However, for those people in quartiles 3 and 4 for plasma sTNFR1, an increased risk of incident mortality was detected (HR 4.9, p = 0.02). No such association was detected for uACR. In this elderly cohort of patients with type 2 diabetes and chronic kidney disease, sTNFR1 predicted short-to-medium term mortality risk but not risk of progressive renal functional decline. In contrast, parallel assessment of uACR predicted renal functional decline but not mortality, highlighting the complementary prognostic information provided by both parameters.94Scopus© Citations 3 - PublicationComment on: Impact of serum uric acid on renal function after bariatric surgery: a retrospective studyObesity is an independent risk factor for renal functional decline in people with chronic kidney disease and is highly prevalent among people with the leading cause of chronic kidney disease, diabetic kidney disease [1]. Intentional weight loss strategies hold promise as a means of arresting progressive renal functional decline in diabetic kidney disease [2]. Optimization of renal outcomes after metabolic surgery centers on blood pressure and glycemic control, as well as addressing proteinuria. The role of uric acid–lowering in this setting is controversial. Purines (adenine, guanine) from nucleic acids (RNA, DNA) are metabolized to xanthine and hypoxanthine, and subsequently converted to uric acid by xanthine oxidase [3]. Uric acid is a nitrogenous waste product, which is excreted via the urine. Epidemiologic studies highlight a relationship between hyperuricemia and renal functional decline, proteinuria, and cardiovascular disease [4]. Whether serum uric acid plays a causal role in chronic kidney disease progression or is simply a biomarker of kidney function remains a controversial question, which is currently being addressed by placebo-controlled, randomized controlled studies, such as the PERL study in which people with diabetic kidney disease and hyperuricemia are randomized to uric acid–lowering therapy or placebo [5]. The present study by Hung et al. [6] adds to the observational evidence implicating uric acid as a marker of adverse renal outcomes and, importantly, is the first study to examine this phenomenon in patients with and without baseline chronic kidney disease after metabolic surgery.
44Scopus© Citations 1 - PublicationCharacterization of the renal cortical transcriptome following Roux-en-Y gastric bypass surgery in experimental diabetic kidney disease(BMJ, 2020-08-02)
; ; ; ; ; ; ; ; ; ; ; Introduction Roux-en-Y gastric bypass surgery (RYGB) reduces albuminuria and the long-term incidence of end-stage renal disease in patients with obesity and diabetes. Preclinical modeling in experimental diabetic kidney disease demonstrates that improvements in glomerular structure likely underpin these findings. Research design and methods In adult male Zucker diabetic fatty (ZDF) rats, we profiled the effect of RYGB on weight and metabolic control as well biochemical, structural and ultrastructural indices of diabetic renal injury. Furthermore, we sequenced the renal cortical transcriptome in these rats and used bioinformatic pathway analyses to characterize the transcriptional alterations governing the renal reparative response to RYGB. Results In parallel with improvements in weight and metabolic control, RYGB reduced albuminuria, glomerulomegaly, podocyte stress and podocyte foot process effacement. Pathway analysis of RYGB-induced transcriptomic changes in the renal cortex highlighted correction of disease-associated alterations in fibrosis, inflammation and biological oxidation pathways. RYGB reversed disease-associated changes in the expression of transforming growth factor (TGF)-β superfamily genes that strongly correlated with improvements in structural measures of glomerulopathy. Conclusions Improved glomerular structure in ZDF rats following RYGB is underpinned by pathway level changes, including interruption of the TGF-β-driven early profibrotic programme. Our data provide an important layer of experimental support for clinical evidence demonstrating that RYGB arrests renal damage in patients with obesity and type 2 diabetes.67Scopus© Citations 8 - PublicationValidating the association between plasma tumour necrosis factor receptor 1 levels and the presence of renal injury and functional decline in patients with Type 2 diabetes(Elsevier, 2017-09-18)
; ; ; ; ; ; AIMS: Elevated plasma soluble tumour necrosis factor receptor 1 (TNFR1) predicts long-term progression of chronic kidney disease. We investigated the association between elevated TNFR1 and the presence of renal disease in patients with Type 2 diabetes mellitus registering a haemoglobin A1c (HbA1c) >48mmol/mol despite medical therapy. METHODS: Using sensitivity, specificity and regression analyses we interrogated the association between plasma TNFR1 and presence of chronic kidney disease as assessed by the presence of microalbuminuria and/or an estimated glomerular filtration rate of less than 60ml/min/1.73m2 (stages 3-5 chronic kidney disease). The association of TNFR1 with C-reactive protein and leptin-adiponectin ratio as plasma markers of systemic inflammation and adipose stress respectively was also investigated. RESULTS: Upper quartile TNFR1 is independently associated with elevated urinary albumin-creatinine ratios, reductions in eGFR and strongly predicts the presence of stages 3-5 chronic kidney disease in regression modelling. Elevated TNFR1 levels are associated with increased plasma C-reactive protein and augmented leptin-adiponectin ratio. CONCLUSIONS: Our study confirms plasma TNFR1 as a surrogate of renal structural and functional impairment in patients with type 2 diabetes mellitus. Association of TNFR1 with markers of systemic inflammation and adipose stress indicates that TNFR1 may be a biomarker of these processes as components of the pathogenesis of diabetic kidney disease.343Scopus© Citations 11 - PublicationImpact of bariatric surgery on cardiovascular and renal complications of diabetes: a focus on clinical outcomes and putative mechanismsIntroduction: Cardiovascular and renal disease accounts for a substantial proportion of the morbidity and mortality associated with obesity and type 2 diabetes mellitus (T2DM). Bariatric surgery is associated with improved long-term cardiovascular and renal outcomes. Areas covered: All major case-control, cohort, and randomized controlled trial studies of bariatric surgery in adults with T2DM were screened and data on prespecified cardiovascular and renal outcomes collated. Bariatric surgery reduces all-cause mortality and risk of cardiovascular disease, albuminuria and progressive chronic kidney disease. Patients with poorer glycemic control and established microvascular disease preoperatively may stand to benefit the most from the surgical approach. Reduced sympathetic drive, remission of glomerular hypertension, enhanced natriuresis, gut microbiota shifts, reduced systemic and renal inflammation, improved lipoprotein profiles, and reductions in chronic cardiac remodeling may all be implicated. Expert commentary: Ongoing RCTs of bariatric surgery selectively recruiting patients with class 1 obesity and established microvascular complications of diabetes will help to better characterize which subgroups of patients benefit most from this effective therapy.
85Scopus© Citations 20 - PublicationMedications Activating Tubular Fatty Acid Oxidation Enhance the Protective Effects of Roux-en-Y Gastric Bypass Surgery in a Rat Model of Early Diabetic Kidney Disease(Frontiers Media, 2022-01-26)
; ; ; ; ; ; ; ; Background: Roux-en-Y gastric bypass surgery (RYGB) improves biochemical and histological parameters of diabetic kidney disease (DKD). Targeted adjunct medical therapy may enhance renoprotection following RYGB. Methods: The effects of RYGB and RYGB plus fenofibrate, metformin, ramipril, and rosuvastatin (RYGB-FMRR) on metabolic control and histological and ultrastructural indices of glomerular and proximal tubular injury were compared in the Zucker Diabetic Sprague Dawley (ZDSD) rat model of DKD. Renal cortical transcriptomic (RNA-sequencing) and urinary metabolomic (1H-NMR spectroscopy) responses were profiled and integrated. Transcripts were assigned to kidney cell types through in silico deconvolution in kidney single-nucleus RNA-sequencing and microdissected tubular epithelial cell proteomics datasets. Medication-specific transcriptomic responses following RYGB-FMRR were explored using a network pharmacology approach. Omic correlates of improvements in structural and ultrastructural indices of renal injury were defined using a molecular morphometric approach. Results: RYGB-FMRR was superior to RYGB alone with respect to metabolic control, albuminuria, and histological and ultrastructural indices of glomerular injury. RYGB-FMRR reversed DKD-associated changes in mitochondrial morphology in the proximal tubule to a greater extent than RYGB. Attenuation of transcriptomic pathway level activation of pro-fibrotic responses was greater after RYGB-FMRR than RYGB. Fenofibrate was found to be the principal medication effector of gene expression changes following RYGB-FMRR, which led to the transcriptional induction of PPARα-regulated genes that are predominantly expressed in the proximal tubule and which regulate peroxisomal and mitochondrial fatty acid oxidation (FAO). After omics integration, expression of these FAO transcripts positively correlated with urinary levels of PPARα-regulated nicotinamide metabolites and negatively correlated with urinary tricarboxylic acid (TCA) cycle intermediates. Changes in FAO transcripts and nicotinamide and TCA cycle metabolites following RYGB-FMRR correlated strongly with improvements in glomerular and proximal tubular injury. Conclusions: Integrative multi-omic analyses point to PPARα-stimulated FAO in the proximal tubule as a dominant effector of treatment response to combined surgical and medical therapy in experimental DKD. Synergism between RYGB and pharmacological stimulation of FAO represents a promising combinatorial approach to the treatment of DKD in the setting of obesity.99Scopus© Citations 3 - PublicationCan Metabolic Surgery Be Used to Improve Access to and Outcomes of Kidney Transplantation?Obesity is common in people with chronic kidney disease (CKD) (1) and associated with a higher risk of kidney allograft complications (2); thus, BMIs 35 kg/m2 and 40 kg/m2 are generally considered relative and absolute contraindications to kidney transplantation (2). Metabolic surgery improves renal outcomes in patients with type 2 diabetes (3) and diabetes is an important risk factor for renal functional decline after kidney transplantation, raising the possibility that metabolic surgery may improve graft survival and mortality in this setting (2). An understanding of the efficacy and safety of metabolic surgery in people with end-stage kidney disease (ESKD) and in kidney transplant recipients is required.
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