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. Multi-centre prospective cohort studies, including the Kidney Precision Medicine Project (KPMP) and the European Nephrectomy Biobank (ENBiBA) project, will improve access to human diabetic kidney tissue for research purposes. Integration of diverse data domains from such initiatives including clinical phenotypic data, renal and retinal imaging biomarkers, histopathological and ultrastructural data, and an array of molecular omics (transcriptomics, proteomics, etc.) alongside multi-dimensional data from preclinical modelling offers exciting opportunities to unravel individual-level mechanisms underlying progressive DKD. The application of machine and deep learning approaches may particularly enhance insights derived from imaging and histopathological/ultrastructural data domains. KEY MESSAGES: Integration of data from multiple model systems (in vitro, animal models, and patients) and from diverse domains (clinical phenotypic, imaging, histopathological/ultrastructural, and molecular omics) offers potential to create a precision medicine approach to DKD care wherein the right treatments are offered to the right patients at the right time.

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. To date, no studies have specifically examined the impact of TRE/TRF on the renal consequences of Met-S. The proposed study seeks to use a model of experimental Met-S-associated kidney disease to address this knowledge gap, disambiguating therein the effects of calorie restriction from the timing of food intake. Spontaneously hypertensive rats will consume a high-fat diet (HFD) for 8 weeks and then be allocated by stratified randomisation according to albuminuria to one of three groups. Rats will have free 24-h access to HFD (Group A), access to HFD during the scheduled hours of darkness (Group B) or access to HFD provided in the form of two rations, one provided during the light phase and one provided during the dark phase, equivalent overall in quantity to that consumed by rats in Group B (Group C). The primary outcome measure will be a change in albuminuria. Changes in food intake, body weight, blood pressure, glucose tolerance, fasting plasma insulin, urinary excretion of C-peptide and renal injury biomarkers, liver and kidney histopathology and inflammation, and fibrosis-related renal gene expression will be assessed as secondary outcomes.

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. The global renal cortical transcriptome and urinary 1H-NMR metabolomic profiles were also compared. Kidney cell type-specific and medication-specific transcriptomic responses were explored through in silico deconvolution. Transcriptomic and metabolomic correlates of improvements in kidney structure were defined using a molecular morphometric approach. The DMT protocol led to ∼20% weight loss, normalized metabolic parameters and was associated with reductions in indices of glomerular and proximal tubular injury. The transcriptomic response to DMT was dominated by changes in fenofibrate- and peroxisome proliferator-activated receptor-α (PPARα)-governed peroxisomal and mitochondrial FAO transcripts localizing to the proximal tubule. DMT induced urinary excretion of PPARα-regulated metabolites involved in nicotinamide metabolism and reversed DKD-associated changes in the urinary excretion of tricarboxylic acid (TCA) cycle intermediates. FAO transcripts and urinary nicotinamide and TCA cycle metabolites were moderately to strongly correlated with improvements in glomerular and proximal tubular injury. Weight loss plus pharmacological PPARα agonism is a promising means of attenuating 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 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.

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. METHODS AND ANALYSIS: Studies reporting on the impact of pharmacological PPAR modulation in animal models of renal injury will be collected from MEDLINE (Ovid), Embase and Web of Science databases. Predefined eligibility criteria will exclude studies testing medications which are not specific ligands of one or more PPARs and studies involving multimodal pharmacological treatment. The Systematic Review Centre for Laboratory Animal Experimentation risk of bias tool and Collaborative Approach to Meta-Analysis and Review of Animal Experimental Studies checklist will be used to assess quality of the included studies. Data extraction will be followed by a narrative synthesis of the data and meta-analysis where feasible. Analysis will be performed separately for AKI, CKD and renal transplant models. Subgroup analyses will be performed based on study design characteristics, PPAR isotype(s) targeted, and classes of PPAR-targeting medications used. Risk of publication bias will be assessed using funnel plotting, Egger's regression and trim-and-fill analysis. ETHICS AND DISSEMINATION: Ethical approval is not required. Findings will be published in a peer-reviewed journal and presented at scientific meetings. PROSPERO REGISTRATION NUMBER: CRD42021265550.

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 (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 desarginine (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.

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. METHODS: This prospective study examined patients with BMI ≥ 35 kg/m2 receiving treatment in a tertiary care obesity clinic. Body composition (dual-energy x-ray absorptiometry) was captured at baseline and after 16 weeks of treatment. Exercise-related data (aerobic minutes per week and resistance training frequency) were captured at week 16. A total of 78 individuals were examined in two groups, the first with lifestyle intervention alone (n = 19) and the second with lifestyle intervention plus liraglutide 3.0 mg (n = 59). Linear mixed-effects models were used to examine between-group differences. RESULTS: Compared with lifestyle intervention alone, participants on liraglutide lost more weight (-12.2 kg vs. -9.7 kg, P = 0.048) and FFM (-2.3 kg vs. -1.5 kg, P = 0.06). After controlling for weight loss, there was no difference in FFM loss between groups (0.14 kg/wk vs. -0.09 kg/wk, P = 0.12). Absolute weight loss (kilograms) was associated with FFM loss (kilograms) (ρ = 0.58, P < 0.0001). Exercise did not increase weight loss, and resistance training frequency (days per week) did not attenuate FFM loss. CONCLUSIONS: Liraglutide does not have effects on FFM beyond what can be expected from total weight loss. Resistance training did not attenuate FFM loss in the liraglutide or lifestyle-alone groups. To ameliorate FFM loss after liraglutide, a new strategy may be needed that may combine exercise with specific nutritional interventions.

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.

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.

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.

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.

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.

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.

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)-ß 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-ß-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.

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. RESULTS: At 12- to 18-month post-operative follow-up in patients at moderate or high risk of chronic kidney disease, significant reductions in albuminuria were observed across all tertiles of baseline albumin-creatinine ratio, with remission of albuminuria occurring in 78% of patients. Relative to sham-operated control animals, weight loss and improvements in glycaemia following Roux-en-Y gastric bypass surgery in Zucker diabetic fatty rats were paralleled by normalisation of glomerular tuft-size, reductions in podocyte expression of desmin, and preservation of podocyte foot process morphology. CONCLUSION: Improvements in podocyte differentiation likely underpin the reductions in albuminuria observed following Roux-en-Y gastric bypass surgery.

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/m2. The aim of the present study was to examine the associations between FFM, FM, BMI, hunger and EI in individuals with severe (BMI > 35 kg/m2) obesity. In total, 43 subjects (52% male) with a mean (±standard deviation) BMI of 44.5 ±â€¯6.2 kg/m2 were recruited for this cross-sectional analysis. Dual energy x-ray absorptiometry and an ad libitum food buffet were used to measure body composition and EI respectively, and hunger was measured using a visual analogue scale (0-100 mm). BMI (p = 0.02; p < 0.01) and FFM (p < 0.01; p = 0.02), but not FM (p = 0.18; p = 0.71), were positively associated with both EI and pre-buffet hunger, respectively, on multivariable regression using the general linear model. These findings suggest that in extremes of obesity FFM continues to promote hunger and EI, but the inhibitory effect of FM on EI that has been observed in lean populations was not present in this cohort suffering from severe obesity.

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. 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. RESULTS: 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. CONCLUSION: 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.

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. 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.