Now showing 1 - 10 of 18
  • Publication
    Multi-Omic Characterisation of Renal Responses to Intentional Weight Loss in Diabetic Kidney Disease
    (University College Dublin. School of Medicine, 2022) ;
    0000-0001-7005-3966
    Metabolic/bariatric surgery reduces the incidence of albuminuria and slows chronic kidney disease progression over extended follow-up, and hence may have a potential role to play as a complement to medical therapy in the management of diabetic kidney disease (DKD). Enhanced understanding of the molecular underpinnings of surgery-associated renoprotection, its reliance on weight loss, and synergy with medical treatment may also identify new algorithms and treatment targets to improve control of DKD. In a sub-study of the Microvascular Outcomes after Metabolic Surgery randomised clinical trial, I characterised urinary metabolomic changes by proton nuclear magnetic resonance (1H-NMR) spectroscopy at baseline and six months following randomisation to medical therapy alone (MTA) and combined metabolic surgery plus medical therapy (CSM). Roux-en-Y gastric bypass (RYGB) was the metabolic surgery employed. Whilst CSM and MTA both reduced 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 and related catabolites (valine, leucine, 3-hydroxyisobutyrate, 3-hydroxyisovalerate, and 3-methyl-2-oxovalerate), were observed following CSM but not MTA. Urinary metabolites changed by CSM at six months were moderately-to-strongly correlated with improvements in cardiometabolic and renal indices up to 24 months following treatment initiation. In the Zucker Diabetic Sprague Dawley (ZDSD) rat model of DKD, I compared the effects of RYGB surgery alone and in combination with fenofibrate, metformin, ramipril, and rosuvastatin (RYGB-FMRR) on renal injury, the renal cortical transcriptome, and the urinary 1H-NMR metabolome. RYGB-FMRR was superior to RYGB alone with respect to metabolic control, albuminuria, and histological and ultrastructural indices of glomerular damage and mitochondrial injury in the proximal tubule. Fenofibrate exerted a dominant effect on gene expression changes following RYGB-FMRR, and led to the transcriptional induction of peroxisome proliferator-activated receptor-alpha (PPARa)-responsive genes that are predominantly expressed in the proximal tubule and which regulate peroxisomal and mitochondrial fatty acid oxidation (FAO). In the aforementioned ZDSD model as well as the Zucker Diabetic Fatty (ZDF) rat model, the effects on renal injury as well as the renal cortical transcriptome of a non-invasive intervention designed to mimic RYGB were explored. This intervention, entitled dietary restriction plus medical therapy (DMT), consisted of dietary restriction to 20% weight loss (comparable to RYGB surgery) plus treatment with fenofibrate, liraglutide, metformin, ramipril, and rosuvastatin. Changes in the urinary 1H-NMR metabolome were also profiled in the ZDSD model. DMT improved metabolic control, albuminuria, and histological and ultrastructural indices of glomerular injury in both animal models. Similar to changes observed after RYGB-FMRR, transcriptomic evidence of increased PPARa-regulated FAO was observed in both ZDF and ZDSD rats after DMT. PPARa-regulated renal FAO transcripts and related urinary nicotinamide metabolites and TCA cycle intermediates were moderately-to-strongly correlated with improvements in glomerular and proximal tubular injury following both RYGB-FMRR and DMT. Integrative multi-omic analyses point to PPARa-stimulated FAO in the proximal tubule as a dominant effector of treatment response when surgical or diet-induced weight loss is combined with medical therapy in experimental DKD. Synergism between intentional weight loss and pharmacological stimulation of FAO represents a promising combinatorial approach to the treatment of DKD in the setting of obesity.
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  • Publication
    Parallel 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
    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
  • Publication
    Obesity is common in chronic kidney disease and associates with greater antihypertensive usage and proteinuria: evidence from a cross-sectional study in a tertiary nephrology centre
    Obesity 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.
      152Scopus© Citations 8
  • Publication
    Medications 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
    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
  • Publication
    Influence of Referral to a Combined Diabetology and Nephrology Clinic on Renal Functional Trends and Metabolic Parameters in Adults With Diabetic Kidney Disease
    To examine the impact of a diabetes renal clinic (DRC) on renal functional and metabolic indices in adults who have diabetes mellitus (DM) and chronic kidney disease (CKD).All patients evaluated at a DRC in a single tertiary referral center from January 1, 2008, to December 31, 2012, were identified. Serial renal and metabolic indices from January 1, 2004, to December 31, 2014, were recorded, and trends over time were analyzed by linear mixed-effects models.A total of 200 patients who had DM and CKD were identified and subdivided into 3 categories based on presumptive CKD etiology: 43 (21.5%) with type 1 DM (T1D) only, 127 (63.5%) with type 2 DM (T2D) only, and 30 (15.0%) with DM and an additional CKD etiology. Average annual absolute (mL/min per body surface area per year) and percentage (%/year) changes, respectively, in Chronic Kidney Disease Epidemiology Collaboration estimated glomerular filtration rate before vs after first DRC attendance were: -1.59 vs -3.10 (P=.31) and -1.22 vs -9.39 (P=.06) for T1D; -5.64 vs -3.07 (P=.004) and -10.88 vs -9.94 (P=.70) for T2D; and -6.50 vs +0.91 (P<.001) and -13.28 vs -2.29 (P=.001) for DM with an additional CKD etiology. Glycemic control worsened in those who had T2D, whereas trends in total cholesterol levels improved in those who had T1D.After first DRC attendance, the absolute rate of estimated glomerular filtration rate decline remained similar for those who had T1D, but it slowed for those who had T2D or DM with additional CKD etiology. Thus, benefits of combined diabetology and nephrology consultation may vary for different diabetic subpopulations.
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  • Publication
    Bacterial Cholangitis in Autosomal Dominant Polycystic Kidney and Liver Disease
    To describe first episodes of bacterial cholangitis complicating autosomal dominant polycystic kidney disease (ADPKD) and autosomal dominant polycystic liver disease (ADPLD) and to identify risk factors for cholangitis episodes among patients with ADPKD-associated polycystic liver disease (PLD). We searched the electronic medical records at our tertiary referral center for episodes of cholangitis in patients with ADPKD or ADPLD from January 1, 1996, through June 30, 2017. Cases were categorized as suspected or definite cholangitis by expert review. Clinical, laboratory, and radiologic data were manually abstracted. A nested case-control study was conducted to investigate risk factors for cholangitis in patients with ADPKD. We identified 29 cases of definite or suspected cholangitis complicating PLD (24 with ADPKD-associated PLD and 5 with ADPLD). Among patients with definite cholangitis in ADPKD-associated PLD (n=19) vs ADPLD (n=4), the mean ± SD age was 62.4±12.2 vs 55.1±8.6 years, and 9 (47.4%) vs 0 (0%), respectively, were male. The odds of gallstones (odds ratio [OR], 21.6; 95% CI, 3.17-927; P<.001), prior cholecystectomy (OR, 12.2; 95% CI, 1.59-552; P=.008), duodenal diverticulum (OR, 13.5; 95% CI, 2.44 to not estimable; P=.004), type 2 diabetes mellitus (OR, 6.41; 95% CI, 1.01 to not estimable; P=.05), prior endoscopic retrograde cholangiopancreatography (OR, 14.0; 95% CI, 1.80-631; P=.005), and prior kidney transplant (OR, 8.06; 95% CI, 1.72-76.0; P=.004) were higher in patients with ADPKD-associated PLD with definite cholangitis compared to controls. Gallstones, prior cholecystectomy, duodenal diverticulosis, type 2 diabetes mellitus, prior endoscopic retrograde cholangiopancreatography, and prior kidney transplant constituted risk factors for cholangitis among patients with ADPKD-associated PLD.
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  • Publication
    The Impact of CKD on Perioperative Risk and Mortality after Bariatric Surgery
    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.
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  • Publication
    Multiplex Serum Biomarker Assays Improve Prediction of Renal and Mortality Outcomes in Chronic Kidney Disease
    (American Society of Nephrology, 2021-08-26) ; ; ;
    Background We investigated the predictive value of 11 serum biomarkers for renal and mortality end points in people with CKD. Methods Adults with CKD (n=139) were enrolled from outpatient clinics between February 2014 and November 2016. Biomarker quantification was performed using two multiplex arrays on a clinical-grade analyzer. Relationships between biomarkers and renal and mortality end points were investigated by random forests and Cox proportional hazards regression. Results The cohort was 56% male. The mean age was 63 years and median (IQR) CKD-EPI eGFR was 33 (24–51) ml/min per BSA. A total of 56 (40%) people developed a composite end point defined as ≥40% decline in eGFR, doubling of serum creatinine, RRT, or death over median (IQR) follow-up of 5.4 (4.7–5.7) years. Prediction of the composite end point was better with random forests trained on serum biomarkers compared with clinical variables (area under the curve of 0.81 versus 0.78). The predictive performance of biomarkers was further enhanced when considered alongside clinical variables (area under the curve of 0.83 versus 0.81 for biomarkers alone). Patients (n=27, 19%) with high soluble TNF receptor-1 (≥3 ng/ml) and neutrophil gelatinase-associated lipocalin (≥156 ng/ml), coupled with low complement 3a des-arginine (<2368 ng/ml), almost universally (96%) developed the composite renal and mortality end point. C-reactive protein (adjusted hazard ratio, 1.4; 95% CI, 1.1 to 1.8), neutrophil gelatinase-associated lipocalin (adjusted hazard ratio, 2.8; 95% CI, 1.3 to 6.1) and complement 3a des-arginine (adjusted hazard ratio, 0.6; 95% CI, 0.4 to 0.96) independently predicted time to the composite end point. Conclusions Outpatients with the triad of high soluble TNF receptor-1 and neutrophil gelatinase-associated lipocalin coupled with low complement 3a des-arginine had high adverse event rates over 5-year follow-up. Incorporation of serum biomarkers alongside clinical variables improved prediction of CKD progression and mortality. Our findings require confirmation in larger, more diverse patient cohorts.
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  • Publication
    Impact of Metabolic Surgery on Renal Injury in Pre-Clinical Models of Diabetic Kidney Disease
    Background: 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.
      100Scopus© Citations 3
  • Publication
    Comment on: Impact of serum uric acid on renal function after bariatric surgery: a retrospective study
    Obesity 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