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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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- PublicationObesity is common in chronic kidney disease and associates with greater antihypertensive usage and proteinuria: evidence from a cross-sectional study in a tertiary nephrology centreObesity is a treatable risk factor for chronic kidney disease progression. We audited the reporting of body-mass index in nephrology outpatient clinics to establish the characteristics of individuals with obesity in nephrology practice. Body-mass index, clinical information and biochemical measures were recorded for patients attending clinics between 3rd August, 2018 and 18th January, 2019. Inferential statistics and Pearson correlations were used to investigate relationships between body-mass index, type 2 diabetes, hypertension and proteinuria. Mean ± SD BMI was 28.6 ± 5.8 kg/m2 (n = 374). Overweight and obesity class 1 were more common in males (P = .02). Amongst n = 123 individuals with obesity and chronic kidney disease, mean ± SD age, n (%) female and median[IQR] eGFR were 64.1 ± 14.2 years, 52 (42.3%) and 29.0[20.5] mL/min/BSA, respectively. A positive correlation between increasing body-mass index and proteinuria was observed in such patients (r = 0.21, P = .03), which was stronger in males and those with CKD stages 4 and 5. Mean body-mass index was 2.3 kg/m2 higher in those treated with 4-5 versus 0-1 antihypertensives (P = .03). Amongst n = 59 patients with obesity, chronic kidney disease and type 2 diabetes, 2 (3.5%) and 0 (0%) were prescribed a GLP-1 receptor analogue and SGLT2-inhibitor, respectively. Our data provides a strong rationale not only for measuring body-mass index but also for acting on the information in nephrology practice, although prospective studies are required to guide treatment decisions in people with obesity and chronic kidney disease.
349Scopus© Citations 16 - 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.159Scopus© Citations 5 - 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.155Scopus© Citations 6 - 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.
226Scopus© Citations 29 - PublicationUrinary Metabolomic Changes Accompanying Albuminuria Remission following Gastric Bypass Surgery for Type 2 Diabetic Kidney Disease(MDPI, 2022-02-02)
; ; ; ; ; ; In the Microvascular Outcomes after Metabolic Surgery randomised clinical trial (MOMS RCT, NCT01821508), combined metabolic surgery (gastric bypass) plus medical therapy (CSM) was superior to medical therapy alone (MTA) as a means of achieving albuminuria remission at 2-year follow-up in patients with obesity and early diabetic kidney disease (DKD). In the present study, we assessed the urinary 1H-NMR metabolome in a subgroup of patients from both arms of the MOMS RCT at baseline and 6-month follow-up. Whilst CSM and MTA both reduced the urinary excretion of sugars, CSM generated a distinctive urinary metabolomic profile characterised by increases in host–microbial co-metabolites (N-phenylacetylglycine, trimethylamine N-oxide, and 4-aminobutyrate (GABA)) and amino acids (arginine and glutamine). Furthermore, reductions in aromatic amino acids (phenylalanine and tyrosine), as well as branched-chain amino acids (BCAAs) and related catabolites (valine, leucine, 3-hydroxyisobutyrate, 3-hydroxyisovalerate, and 3-methyl-2-oxovalerate), were observed following CSM but not MTA. Improvements in BMI did not correlate with improvements in metabolic and renal indices following CSM. Conversely, urinary metabolites changed by CSM at 6 months were moderately to strongly correlated with improvements in blood pressure, glycaemia, triglycerides, and albuminuria up to 24 months following treatment initiation, highlighting the potential involvement of these shifts in the urinary metabolomic profile in the metabolic and renoprotective effects of CSM.313Scopus© Citations 6 - PublicationImpact of intentional weight loss on diabetic kidney diseaseType 2 diabetes mellitus (T2DM) and obesity constitute interwoven pandemics challenging healthcare systems in developed countries, where diabetic kidney disease (DKD) is the most common cause of end-stage renal disease. Obesity accelerates renal functional decline in people with T2DM. Intentional weight loss (IWL) strategies in this population hold promise as a means of arresting DKD progression. In the present paper, we summarize the impact of IWL strategies (stratified by lifestyle intervention, medications, and metabolic surgery) on renal outcomes in obese people with DKD. We reviewed the Medline, EMBASE and Cochrane databases for relevant randomized control trials and observational studies published between August 1, 2018 and April 15, 2019. We found that IWL improves renal outcomes in the setting of DKD and obesity. Rate of progression of DKD slows with IWL, but varying outcome measures among studies makes direct comparison difficult. Furthermore, established means of estimating renal function are imperfect owing to loss of lean muscle mass with IWL strategies. The choice of optimal IWL strategy needs to be individualized; future work should establish the comparative efficacy of IWL strategies in obese people with DKD to better inform such decisions.
Scopus© Citations 9 74 - PublicationImpact of Metabolic Surgery on Renal Injury in Pre-Clinical Models of Diabetic Kidney DiseaseBackground: Surgical approaches to the treatment of obesity and type 2 diabetes, most notably the Roux-en-Y gastric bypass (RYGB) procedure, have been shown to be renoprotective, reducing the incidence of albuminuria and end-stage kidney disease over 15- to 20-year follow-up in patients with obesity. The tissue level effects of metabolic surgery on the diabetic kidney are not easily interrogated in clinical samples. However, elucidation of the cellular and molecular basis for the renoprotective effects of metabolic surgery is now emerging from a body of pre-clinical work in rodent models of diabetic kidney disease (DKD). Summary: Experimental metabolic surgery (RYGB, sleeve gastrectomy [SG], Roux-en-Y oesophagojejunostomy, and duodenojejunal bypass) exerts a pronounced albuminuria-lowering effect in rat models of DKD. Following RYGB in the Zucker diabetic fatty rat, glomerular histology is improved as demonstrated by reductions in podocyte stress, glomerulomegaly, and glomerulosclerosis. Glomerular ultrastructure improves after RYGB and after SG, manifested by quantifiable reductions in podocyte foot process effacement. The transcriptional programme underpinning these structural improvements has been characterized at the pathway level using RNA sequencing and is associated with a significant reduction in the activation of inflammatory and fibrotic responses. Key Messages: Experimental metabolic surgery reduces biochemical, histological, and molecular indices of DKD. These pre-clinical data support a growing interest in the potential utility of metabolic surgery as a therapeutic approach to slow renal functional decline in patients with obesity and DKD.
258Scopus© Citations 3