Now showing 1 - 10 of 18
  • 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.
  • 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.
  • Publication
    Protocol for a preclinical systematic review and meta-analysis of pharmacological targeting of peroxisome proliferator-activated receptors in experimental renal injury
    Introduction Impaired lipid metabolism in the renal tubule plays a prominent role in the progression of renal fibrosis following acute kidney injury (AKI) and in chronic kidney disease (CKD). Peroxisome proliferator-activated receptors (PPARs) are promising druggable targets to mitigate renal fibrosis by redirecting metabolism, including restoration of fatty acid oxidation (FAO) capacity. We aim to synthesise evidence from preclinical studies of pharmacological PPAR targeting in experimental renal injury, and inform the design of future studies evaluating PPAR-mediated restoration of FAO in AKI and CKD.
    Scopus© Citations 2  101
  • Publication
    Metabolic Surgery to Treat Obesity in Diabetic Kidney Disease, Chronic Kidney Disease, and End-Stage Kidney Disease; What Are the Unanswered Questions?
    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.
      199Scopus© Citations 30
  • Publication
    Comment on: Metabolic surgery improves renal injury independent of weight loss: a meta-analysis
    (Elsevier, 2019-06-01) ;
    Diabetic 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.
    Scopus© Citations 7  91
  • Publication
    Characterization of the renal cortical transcriptome following Roux-en-Y gastric bypass surgery in experimental diabetic kidney disease
    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.
      141Scopus© Citations 10
  • 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.
      349Scopus© Citations 16
  • 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.
      258Scopus© Citations 3
  • Publication
    Impact of bariatric surgery on cardiovascular and renal complications of diabetes: a focus on clinical outcomes and putative mechanisms
    Introduction: 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
  • 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.
      166Scopus© Citations 8