Association of Obesity With Kidney and Cardiac Outcomes Among Patients With Glomerular Disease: Findings From the Cure Glomerulonephropathy Network.

RATIONALE & OBJECTIVE: The influence of obesity on cardiorenal outcomes in individuals with glomerular disease is incompletely known. This study examined the association between obesity and kidney and cardiovascular outcomes in children and adults with glomerular kidney disease. STUDY DESIGN: Prospective, multicenter, observational study. SETTING & PARTICIPANTS: Participants in the Cure Glomerulonephropathy Network (CureGN) who were ≥5 years of age at enrollment. EXPOSURES: Adult body mass index (BMI) groups: 20-24 (healthy) vs 25-34 (overweight/class 1 obesity) vs ≥35 (class 2/3 obesity); and Pediatric BMI Percentiles: 5th - 84th (healthy) vs 85th - 94th (overweight) vs ≥95th (obese). OUTCOMES: A composite kidney outcome (40% eGFR decline or kidney failure) and a composite cardiovascular outcome (myocardial infarction, stroke, heart failure, or death) ANALYTICAL APPROACH: Time to composite primary outcomes by BMI strata were estimated using Kaplan-Meier analysis. The adjusted associations between BMI and outcomes were estimated using Cox proportional hazards analysis. RESULTS: The study included 2301 participants (1548 adults and 753 children). The incidence of the primary kidney endpoint was 90.8 per 1000 person-years in adults with class 2/3 obesity, compared with 58.0 in normal weight comparators. In the univariable analysis class 2/3 obesity was associated with the primary kidney outcome only in adults (HR 1.6, 95% CI 1.1-2.2, p = 0.006) compared to the healthy weight groups. In the multivariable adjusted analysis, class 2/3 obesity did not remain significant among adults when controlling for baseline eGFR and proteinuria. Adults with class 2/3 obesity had an incidence of 19.7 cardiovascular events per 1000 person-years, and greater cardiovascular risk (HR 3.9, 95%CI 1.4-10.7, p = 0.009) in the fully adjusted model. LIMITATIONS: BMI is an imperfect indicator of adiposity. Residual confounding may exist from socioeconomic factors. CONCLUSIONS: Among adult patients in CureGN, class 2/3 obesity is associated with cardiovascular but not kidney outcomes when adjusted for potential confounding factors.

Delayed Diagnosis of Ectopic Cushing Syndrome.

Here, we present the case of a 40-year-old man in whom the diagnosis of ectopic adrenocorticotropin (ACTH) syndrome went unrecognized despite evaluation by multiple providers until it was ultimately suspected by a nephrologist evaluating the patient for edema and weight gain. On urgent referral to endocrinology, screening for hypercortisolism was positive by both low-dose overnight dexamethasone suppression testing and 24-hour urinary free cortisol measurement. Plasma ACTH values confirmed ACTH-dependent Cushing syndrome. High-dose dexamethasone suppression testing was suggestive of ectopic ACTH syndrome. Inferior petrosal sinus sampling demonstrated no central-to-peripheral gradient, and 68Ga-DOTATATE scanning revealed an avid 1.2-cm left lung lesion. The suspected source of ectopic ACTH was resected and confirmed by histopathology, resulting in surgical cure. While many patients with Cushing syndrome have a delayed diagnosis, this case highlights the critical need to increase awareness of the signs and symptoms of hypercortisolism and to improve the understanding of appropriate screening tests among nonendocrine providers.

Characterizing the metabolic response of the zebrafish kidney to overfeeding.

Obesity is a global epidemic and risk factor for the development of chronic kidney disease. Obesity induces systemic changes in metabolism, but how it affects kidney metabolism specifically is not known. Zebrafish have previously been shown to develop obesity-related kidney pathology and dysfunction when fed hypercaloric diets. To understand the direct effects of obesity on kidney metabolic function, we treated zebrafish for 8 wk with a control and an overfeeding diet. At the end of treatment, we assessed changes in kidney and fish weights and used electron microscopy to evaluate cell ultrastructure. We then performed an untargeted metabolomic analysis on the kidney tissue of fish using ultra-high performance liquid chromatography coupled with high-resolution mass spectrometry and used mummichog and gene set enrichment analysis to uncover differentially affected metabolic pathways. Kidney metabolomes differed significantly and consistently between the control and overfed diets. Among 9,593 features, we identified 235 that were significantly different (P < 0.05) between groups (125 upregulated in overfed diet, 110 downregulated). Pathway analysis demonstrated perturbations in glycolysis and fatty acid synthesis pathways, and analysis of specific metabolites points to perturbations in tryptophan metabolism. Our key findings show that diet-induced obesity leads to metabolic changes in the kidney tissue itself and implicates specific metabolic pathways, including glycolysis and tryptophan metabolism in the pathogenesis of obesity-related kidney disease, demonstrating the power of untargeted metabolomics to identify pathways of interest by directly interrogating kidney tissue.NEW & NOTEWORTHY Obesity causes systemic metabolic dysfunction, but how this affects kidney metabolism is less understood. This study used ultra-high performance liquid chromatography coupled with high-resolution mass spectrometry to analyze the kidneys of overfed zebrafish. Metabolites in the kidneys of obese zebrafish revealed perturbations in metabolic pathways including glycolysis and tryptophan metabolism. These data suggest obesity alters metabolism within the kidney, which may play an important role in obesity-related kidney dysfunction.

Kidney Considerations in Pediatric Obesity.

PURPOSE OF REVIEW: Chronic kidney disease (CKD) is a common condition and a major cause of morbidity and mortality in adults, but children and adolescents are also at risk for early kidney injury and development of CKD. Obesity contributes both directly and indirectly to the development of CKD. The purpose of this review is to describe obesity-related kidney disease (ORKD) and diabetic kidney disease (DKD) and their impact in the pediatric population. RECENT FINDINGS: Although obesity-related CKD in childhood and adolescence is uncommon, nascent kidney damage may magnify the lifetime risk of CKD. Glomerular hyperfiltration is an early phenotype of both ORKD and DKD and typically manifests prior to albuminuria and progressive decline in GFR. Novel treatments for obesity and type 2 diabetes exerting protective effects on the kidneys are being investigated for use in the pediatric population. It is important to understand the impact of obesity on the kidneys more fully in the pediatric population to help detect injury earlier and intervene prior to the onset of irreversible progression of disease and to guide future research in this area.

Blockbuster Medications for Obesity: A Primer for Nephrologists.

The prevalence of obesity in the United States and across the world continues to climb, imparting increased risk of chronic disease. This impact is doubly felt in nephrology because obesity not only increases the risk of chronic kidney disease (CKD) but also exacerbates existing cardiovascular morbidity and mortality. The role of medical weight loss therapy in CKD has been debated, but increasing evidence suggests that intentional weight loss is protective against adverse kidney and cardiovascular outcomes. This may be particularly true with the advent of novel pharmacotherapies taking advantage of the incretin system, resulting in weight loss approaching that seen with surgical interventions. Moreover, these novel therapies have repeatedly demonstrated protective effects on the cardiovascular system. Here, we review the impact of obesity and weight loss on CKD, and the biological basis and clinical evidence for incretin therapy. This perspective provides recommended prescribing practices as a practical tool to engage nephrologists and patients with CKD in the treatment of obesity-related morbidity.

High-calorie diet results in reversible obesity-related glomerulopathy in adult zebrafish regardless of dietary fat.

Obesity is a risk factor for the development of kidney disease. The role of diet in this association remains undetermined, in part due to practical limitations in studying nutrition in humans. In particular, the relative importance of calorie excess versus dietary macronutrient content is poorly understood. For example, it is unknown if calorie restriction modulates obesity-related kidney pathology. To study the effects of diet-induced obesity in a novel animal model, we treated zebrafish for 8 wk with diets varied in both calorie and fat content. Kidneys were evaluated by light and electron microscopy. We evaluated glomerular filtration barrier function using a dextran permeability assay. We assessed the effect of diet on podocyte sensitivity to injury using an inducible podocyte injury model. We then tested the effect of calorie restriction on the defects caused by diet-induced obesity. Fish fed a high-calorie diet developed glomerulomegaly (mean: 1,211 vs. 1,010 µm2 in controls, P = 0.007), lower podocyte density, foot process effacement, glomerular basement membrane thickening, tubular enlargement (mean: 1,038 vs. 717 µm2 in controls, P < 0.0001), and ectopic lipid deposition. Glomerular filtration barrier dysfunction and increased susceptibility to podocyte injury were observed with high-calorie feeding regardless of dietary fat content. These pathological changes resolved with 4 wk of calorie restriction. Our findings suggest that calorie excess rather than dietary fat drives obesity-related kidney dysfunction and that inadequate podocyte proliferation in response to glomerular enlargement may cause podocyte dysfunction. We also demonstrate the value of zebrafish as a novel model for studying diet in obesity-related kidney disease.NEW & NOTEWORTHY Obesity is a risk factor for kidney disease. The role of diet in this association is difficult to study in humans. In this study, zebrafish fed a high-calorie diet, regardless of fat macronutrient composition, developed glomerulomegaly, foot process effacement, and filtration barrier dysfunction, recapitulating the changes seen in humans with obesity. Calorie restriction reversed the changes. This work suggests that macronutrient composition may be less important than total calories in the development of obesity-related kidney disease.

Environmental Exposures and Kidney Disease.

Accumulating evidence underscores the large role played by the environment in the health of communities and individuals. We review the currently known contribution of environmental exposures and pollutants on kidney disease and its associated morbidity. We review air pollutants, such as particulate matter; water pollutants, such as trace elements, per- and polyfluoroalkyl substances, and pesticides; and extreme weather events and natural disasters. We also discuss gaps in the evidence that presently relies heavily on observational studies and animal models, and propose using recently developed analytic methods to help bridge the gaps. With the expected increase in the intensity and frequency of many environmental exposures in the decades to come, an improved understanding of their potential effect on kidney disease is crucial to mitigate potential morbidity and mortality.

Targeting pro-inflammatory cytokines following joint injury: acute intra-articular inhibition of interleukin-1 following knee injury prevents post-traumatic arthritis.

INTRODUCTION: Post-traumatic arthritis (PTA) is a progressive, degenerative response to joint injury, such as articular fracture. The pro-inflammatory cytokines, interleukin 1(IL-1) and tumor necrosis factor alpha (TNF-α), are acutely elevated following joint injury and remain elevated for prolonged periods post-injury. To investigate the role of local and systemic inflammation in the development of post-traumatic arthritis, we targeted both the initial acute local inflammatory response and a prolonged 4 week systemic inflammatory response by inhibiting IL-1 or TNF-α following articular fracture in the mouse knee. METHODS: Anti-cytokine agents, IL-1 receptor antagonist (IL-1Ra) or soluble TNF receptor II (sTNFRII), were administered either locally via an acute intra-articular injection or systemically for a prolonged 4 week period following articular fracture of the knee in C57BL/6 mice. The severity of arthritis was then assessed at 8 weeks post-injury in joint tissues via histology and micro computed tomography, and systemic and local biomarkers were assessed in serum and synovial fluid. RESULTS: Intra-articular inhibition of IL-1 significantly reduced cartilage degeneration, synovial inflammation, and did not alter bone morphology following articular fracture. However, systemic inhibition of IL-1, and local or systemic inhibition of TNF provided no benefit or conversely led to increased arthritic changes in the joint tissues. CONCLUSION: These results show that intra-articular IL-1, rather than TNF-α, plays a critical role in the acute inflammatory phase of joint injury and can be inhibited locally to reduce post-traumatic arthritis following a closed articular fracture. Targeted local inhibition of IL-1 following joint injury may represent a novel treatment option for PTA.

Genetic and cellular evidence of decreased inflammation associated with reduced incidence of posttraumatic arthritis in MRL/MpJ mice.

OBJECTIVE: To examine the relationship between inflammation and posttraumatic arthritis (PTA) in a murine intraarticular fracture model. METHODS: Male C57BL/6 and MRL/MpJ "superhealer" mice received tibial plateau fractures using a previously established method. Mice were killed on day 0 (within 4 hours of fracture) and days 1, 3, 5, 7, 28, and 56 after fracture. Synovial tissue samples, obtained prior to fracture and on days 0, 1, 3, 5, and 7 after fracture, were examined by reverse transcription-polymerase chain reaction for gene expression of proinflammatory cytokines and chemokines. Synovial fluid and serum samples were collected to measure cytokine concentrations, using enzyme-linked immunosorbent assay. Whole joints were examined histologically for the extent of synovitis and cartilage degradation, and joint tissue samples from all time points were analyzed immunohistochemically to evaluate the distribution of interleukin-1 (IL-1). RESULTS: Compared to C57BL/6 mice, MRL/MpJ mice had less severe intraarticular and systemic inflammation following joint injury, as evidenced by lower gene expression of tumor necrosis factor α and IL-1ß in the synovial tissue and lower protein levels of IL-1α and IL-1ß in the synovial fluid, serum, and joint tissues. Furthermore, after joint injury, MRL/MpJ mice had lower gene expression of macrophage inflammatory proteins and macrophage-derived chemokine (CCL22) in the synovial tissue, and also had reduced acute and late-stage infiltration of synovial macrophages. CONCLUSION: C57BL/6 mice exhibited higher levels of inflammation than MRL/MpJ mice, indicating that MRL/MpJ mice are protected from PTA in this model. These data thus suggest an association between joint tissue inflammation and the development and progression of PTA in mice.