Case Report: Diabetic ketoacidosis after co-administration of empagliflozin and probenecid.

Sodium-glucose cotransporter-2 (SGLT2) inhibitors are filtered and secreted to their primary site of action in the proximal tubule of the kidney. At this site, SGLT2 inhibitors also reduce renal elimination of ketone bodies, a finding implicated in their propensity to cause ketoacidosis. Many commonly used medications have potential to diminish renal elimination of SGLT2 inhibitors and to compound the effects of SGLT2 inhibitors on renal elimination of ketone bodies by inhibiting tubular secretion of the SGLT2 inhibitor itself and/or ketone bodies.

A Systems Nephrology Approach to Diabetic Kidney Disease Research and Practice.

Background: Diagnosis and staging of diabetic kidney disease (DKD) via the serial assessment of routine laboratory indices lacks the granularity required to resolve the heterogeneous disease mechanisms driving progression in the individual patient. A systems nephrology approach may help resolve mechanisms underlying this clinically apparent heterogeneity, paving a way for targeted treatment of DKD.

Summary: Given the limited access to kidney tissue in routine clinical care of patients with DKD, data derived from renal tissue in preclinical model systems, including animal and in vitro models, can play a central role in the development of a targeted systems-based approach to DKD.

Impact of time-restricted feeding on kidney injury in male rats with experimental metabolic syndrome.

Disruptions to circadian rhythm may be implicated in the pathogenesis of metabolic syndrome (Met-S). For example, eating during an extended period of the day may negatively impact the circadian rhythms governing metabolic control, contributing, therefore, to Met-S and associated end-organ damage. Accordingly, time-restricted eating (TRE)/feeding (TRF) is gaining popularity as a dietary intervention for the treatment and prevention of Met-S.

Dietary restriction and medical therapy drives PPARα-regulated improvements in early diabetic kidney disease in male rats.

The attenuation of diabetic kidney disease (DKD) by metabolic surgery is enhanced by pharmacotherapy promoting renal fatty acid oxidation (FAO). Using the Zucker Diabetic Fatty and Zucker Diabetic Sprague Dawley rat models of DKD, we conducted studies to determine if these effects could be replicated with a non-invasive bariatric mimetic intervention. Metabolic control and renal injury were compared in rats undergoing a dietary restriction plus medical therapy protocol (DMT; fenofibrate, liraglutide, metformin, ramipril, and rosuvastatin) and ad libitum-fed controls.

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.

Urinary Metabolomic Changes Accompanying Albuminuria Remission following Gastric Bypass Surgery for Type 2 Diabetic Kidney Disease.

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 H-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).

Multiplex Serum Biomarker Assays Improve Prediction of Renal and Mortality Outcomes in Chronic Kidney Disease.

Background: We investigated the predictive value of 11 serum biomarkers for renal and mortality end points in people with CKD.

Methods: Adults with CKD (=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.

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.

Liraglutide Does Not Adversely Impact Fat-Free Mass Loss.

Objectives: This study aimed to examine fat-free mass (FFM) loss between successful responders to lifestyle intervention alone compared with lifestyle intervention plus liraglutide 3.0 mg. An additional objective was to examine the effects of varying resistance training frequencies (days per week) on FFM retention.

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).

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.

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 (HbA ≥ 48 mmol/mol) at 2 hospital sites in Dublin between October 15th, 2014 and July 17th, 2015.

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 3 August, 2018 and 18 January, 2019.

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.

Improvements in diabetic albuminuria and podocyte differentiation following Roux-en-Y gastric bypass surgery.

Background: Multiple studies demonstrate an albuminuria-lowering impact of Roux-en-Y gastric bypass surgery, but neither evaluation of its penetrance across different baseline levels of albuminuria nor its association with alterations in podocyte phenotype has previously been reported.

Methods: We profiled changes in body weight, glycaemic control and urinary albumin excretion following Roux-en-Y gastric bypass surgery in 105 patients with type 2 diabetes, albuminuria of varying degrees of severity and classified as being at moderate or high risk of chronic kidney disease progression according to the Kidney Disease: Improving Global Outcomes 2012 criteria. In parallel pre-clinical studies, the impact of Roux-en-Y gastric bypass surgery on markers of podocyte injury was assessed in the Zucker diabetic fatty rat model of diabetic kidney disease.

Fat free mass is positively associated with hunger and energy intake at extremes of obesity.

Fat mass (FM) has been shown to be negatively associated with energy intake (EI) in lean individuals but in overweight and Class I obese individuals this relationship is poorly understood. Fat free mass (FFM) is positively associated with EI in lean, overweight and Class I obese individuals. To date, the relationships between FFM, FM, hunger and EI have not been investigated in patients with a body mass index (BMI) > 35 kg/m.

Impact of intentional weight loss on diabetic kidney disease.

Type 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.

Bacterial Cholangitis in Autosomal Dominant Polycystic Kidney and Liver Disease.

Objective: 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).

Patients And Methods: 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.

Effect of Macronutrient Type and Gastrointestinal Release Site on PYY Response in Normal Healthy Subjects.

Background And Aims: Enteroendocrine L cells release satiety inducing hormones in response to stimulation by luminal macronutrients. We sought to profile the differential effect of macronutrient type and site of release on circulating concentrations of the L cell-derived enteroendocrine hormone peptide tyrosine tyrosine (amino acids 1 to 36) (PYY).

Materials And Methods: Eight healthy volunteers were recruited to a randomized, double-blinded, six-way crossover study.