Diabetes-related Kidney Disease Research Articles

Association Between Microvascular Disease and Cardiorespiratory Fitness Among Adults With Type 2 Diabetes.

Little is known about the extent to which microvascular disease is associated with cardiorespiratory fitness (CRF) among individuals with type 2 diabetes. A total of 4,766 participants with type 2 diabetes underwent maximal exercise testing in the Look AHEAD (Action for Health in Diabetes) study at baseline. Low CRF was defined based on the Aerobics Center Longitudinal Study reference standards. Microvascular disease was defined as having one or more of diabetes-related kidney disease (DKD), retinopathy, and neuropathy. The burden of microvascular disease was defined as the number of microvascular beds affected. Of the 4,766 participants (mean age 58.9 ± 6.7 years, 58.5% women, 66.1% White individuals), 1,761 (37%) had microvascular disease. Participants with microvascular complications in three vascular territories had a lower CFR than those without any microvascular disease (mean adjusted metabolic equivalent of task [MET] 6.58 vs. 7.26, P = 0.001). Participants with any microvascular disease had higher odds of low CRF than those without microvascular disease (adjusted odds ratio [OR] 1.45, 95% CI 1.24-1.71). An increasing burden of microvascular disease was associated with higher odds of low CRF (for microvascular disease in three vascular territories, adjusted OR 2.82, 95% CI 1.36-5.85). Adjusted ORs for low CRF were 1.24 (95% CI 0.99-1.55), 1.34 (95% CI 1.02-1.76), and 1.44 (95% CI 1.20-1.73) for neuropathy, retinopathy, and DKD associations, respectively. In a large cohort of adults with type 2 diabetes, the presence of microvascular disease and its burden were independently associated with lower CRF.

Patients with diabetes in regions with population decline and likelihood of receiving diabetes management education and screenings for related complications in Korea

ObjectiveMany municipal districts in Korea face population decline owing to overall population decreases and aging. We investigated the association between geographic rurality and likelihood of receiving diabetes management education and diabetic retinopathy and diabetes-related kidney disease screenings among adults with diabetes. MethodsPatient data were obtained from the 2021 Korea Community Health Survey (27,391 individuals; aged ≥19 years and physician-diagnosed with diabetes mellitus). Geographic rurality was categorized based on population decline as follows: with, at risk of, or without population decline. The association between geographic rurality and likelihood of receiving diabetes management education and diabetic retinopathy and diabetes-related kidney disease screenings was examined using multilevel logistic regression analyses. ResultsAmong 27,391 patients with diabetes, 31.1% received diabetes education; 40.0% and 46.4% were screened for diabetic retinopathy and diabetes-related kidney disease, respectively. Individuals residing in regions with population decline were less likely to receive diabetes education (odds ratio [OR] 0.62, 95% CI 0.50–0.75) and diabetic retinopathy (OR 0.79, 95% CI 0.70–0.90) and diabetes-related kidney disease (OR 0.64, 95% CI 0.55–0.75) screenings, as compared with their counterparts. ConclusionsOur findings highlight the importance of increased monitoring and providing diabetes education and screenings for patients with diabetes living in rural areas.

The degradation of TGR5 mediated by Smurf1 contributes to diabetic nephropathy

The multiple roles of TGR5 in the regulation of glucose metabolism, inflammation, and oxidative stress have drawn attention as therapeutic candidates for diabetes-related kidney disease. However, diabetes induces downregulation of renal TGR5 protein expression, and the regulatory mechanisms have not been clarified. Here, we identify that Smurf1, an E3 ubiquitin ligase, is a critical interactor of TGR5 and mediates the ubiquitination and proteasomal degradation of TGR5 under high glucose stimulation in glomerular mesangial cells. Genetic deficiency of Smurf1 restores TGR5 protein expression and attenuates renal injuries in diabetic mice. Mechanistically, Smurf1 interacts with the TGR5 ICL2 region by its HECT domain and induces K11/K48-linked polyubiquitination of TGR5 at K306 residue. Moreover, restoration of TGR5 protects db/db mice from diabetic nephropathy. These observations elucidate the critical role of Smurf1 in regulating TGR5 stability, suggesting that pharmacological targeting of the interaction between Smurf1 and TGR5 could serve as a promising therapeutic strategy against diabetic nephropathy.

Understand How Diabetes Contributes to the Development of Kidney Disease: A Single Center Study

Background: This study investigates the relationship between Diabetes and renal disease. It will review the epidemiological patterns of diabetes-related kidney disease and how various treatment choices, lifestyle changes, and expanding preventative measures might lower the risk of kidney disease in diabetics. Additionally, it will go through the symptoms and effects of kidney disease on those with Diabetes and the likelihood of effective treatment and preservation of kidney function. We'll also discuss how this study may affect patients, healthcare professionals, and decision-makers. Methodology: From January 2022 to January 2023, this research was carried out in the nephrology department of the Miangul Abdul Haq Jahanzeb renal hospital in Swat. The study identified pertinent themes on how Diabetes leads to the development of kidney disease by using several sources, including medical papers, news articles, and web resources. The Cochrane Library and PubMed, and other pertinent research sources were examined. Additionally, qualitative interviews with healthcare experts were done, including endocrinologists, nephrologists, and other medical specialists with knowledge of Diabetes and kidney disease. Results: According to the findings, Diabetes considerably raises the risk of renal disease. Glomerulonephritis, diabetic nephropathy, and hypertension-related kidney disease accounted for most kidney conditions associated with Diabetes. Options for treatment exist to lower risk factors, control kidney disease complications, and enhance general health and well-being in people with Diabetes. The most significant lifestyle changes that people with Diabetes may do to lower their risk of kidney disease include weight reduction, regular exercise, a healthy diet, quitting smoking, and consuming less salt and alcohol. A further key role in lowering the risk of kidney disease and its development is the increased accessibility of preventative methods, such as good pre-diabetes and diabetes screening, optimal diabetes treatment, and vaccination against influenza and pneumococcal illness. Conclusion: Diabetes has a significant role in the development of renal disease. The increased accessibility of preventive screening, proper diabetes management, and immunization against infectious diseases play an important role in lowering the overall risk of developing kidney disease in people with Diabetes, even though treatment options and lifestyle changes exist to reduce risk factors for the disease's progression. Keywords: Epidemiology, risk factors, therapy, lifestyle changes, preventive, healthcare providers, pre-diabetes screening, diabetes management, vaccination, renal disease

Expression of Angiopoetin-Like Protein-4 and Kidney Injury Molecule-1 as Preliminary Diagnostic Markers for Diabetes-Related Kidney Disease: A Single Center-Based Cross-Sectional Study.

The purpose of the study was to examine the urinary levels of kidney injury molecule-1 (KIM-1) and angiopoietin-like protein-4 (ANGPTL-4) in individuals with diabetic kidney disease (DKD) and their association with established DKD diagnostic markers such as albuminuria and estimated glomerular filtration rate (eGFR). Levels of ANGPTL-4 and KIM-1 were estimated in urine samples. A total of 135 participants were recruited into three groups: 45 diabetes type 2 patients in the control group and 90 DKD patients in two disease groups. Concentrations of ANGPTL-4 and KIM-1 were conclusively related to the urinary albumin-creatinine ratio (UACR). Also, the levels of both ANGPTL-4 and KIM-1 were negatively associated with the eGFR. Multivariable Poisson regression analysis showed that urinary ANGPTL-4 (PR: 3.40; 95% CI: 2.32 to 4.98; p < 0.001) and KIM-1 (PR: 1.25; 95% CI: 1.14 to 1.38; p < 0.001) were prevalent in DKD patients. Receiver operating characteristic (ROC) analysis of urinary ANGPTL-4 and KIM-1 in the combined form resulted in an area under curve (AUC) of 0.967 (95%CI: 0.932-1.000; p < 0.0001) in the microalbuminuria group and 1 (95%CI: 1.000-1.000; p < 0.0001) in the macroalbuminuria group. The association of urinary levels of ANGPTL-4 and KIM-1 with UACR and eGFR and significant prevalence in the diabetic kidney disease population illustrates the diagnostic potential of these biomarkers.

Effect of crocin and losartan on biochemical parameters and genes expression of FRMD3 and BMP7 in diabetic rats.

Diabetes is a multifactorial and growing disease, one of the severe complications of which is diabetic nephropathy (DN), which is the most common cause of chronic renal failure. FERM domain containing 3 (FRMD3) is responsible for maintaining the shape and integrity of nephron cells, and bone morphogenetic protein 7 (BMP7) helps maintain function and reduce kidney damage. This study aimed to evaluate the effect of crocin and losartan on biochemical parameters and the expression of FRMD3 and BMP7 genes in streptozotocin (STZ)-induced diabetic rats. Forty male Wistar rats were randomly divided into five experimental groups as healthy, diabetic control (D), crocin, losartan, and diabetic rats treated with losartan-crocin (n = 8). A single dose of STZ (50 mg/kg intraperitoneally injection) was used to induce diabetes. Four weeks after induction of diabetes, rats received crocin (50 mg/kg) and losartan (25 mg/kg) daily for four weeks orally. Rats were sacrificed at the end of the intervention, and blood samples were taken to determine serum levels of glucose, urea, creatinine (Cr), malondialdehyde (MDA), and thiol. Real-time polymerase chain reaction (PCR) was used to assess the expression of the FRMD3 and BMP7 genes in the kidney samples. Diabetes induction increased serum levels of glucose, Cr, urea, MDA, and thiol, but decreased BMP7 and FRMD3 genes expression. Treatment with crocin and losartan decreased these biochemical parameters and increased the expression of the BMP7 and FRMD3 genes. Crocin may be a promising therapeutic agent for preventing and improving diabetes-related kidney disease due to its antidiabetic and antioxidant properties.

Retinopathy as an independent predictor of all-cause mortality in individuals with type 2 diabetes

AimsTo assess whether the presence and grade of diabetic retinopathy (DR) predict all-cause mortality, independent of risk factors for cardiovascular disease (CVD) and other complications, including diabetes-related kidney disease (DKD) and CVD, in individuals with type 2 diabetes mellitus. MethodsProspective cohort study that enroled 15,773 patients in 19 Italian centers in 2006–2008. DR ascertained by fundoscopy, DKD by albuminuria and estimated glomerular filtration rate, and prior CVD by hospital discharge records. All-cause mortality retrieved for 15,656 patients on 31 October 2015. ResultsThe adjusted risk of death was increased in patients with any DR (hazard ratio, 1.136 [95% confidence interval, 1.054;1.224] P < 0.0001), advanced DR, including severe non-proliferative and proliferative DR and diabetic macula edema (1.213 [1.097;1.340] P < 0.0001), and especially proliferative DR alone (1.381 [1.207;1.580] P < 0.0001), compared with those without DR. The impact of DR was more evident in patients without than in those with DKD or CVD. Mortality risk was increased in participants with DR alone, though much less than in those with DKD or CVD alone and particularly in those with both DR and DKD or CVD. DR grade was related to mortality in individuals without DKD or CVD, whereas it conferred no additional risk to those with albuminuric or nonalbuminuric DKD or established CVD. ConclusionsIn patients with type 2 diabetes mellitus, the excess mortality risk conferred by DR is relatively small and higher in those without DKD and CVD, suggesting that it may be mediated by the concurrent presence of these complications, even at a subclinical level.

The impact of prebiotic fructooligosaccharides on gut dysbiosis and inflammation in obesity and diabetes related kidney disease.

Obesity is an extensive health problem worldwide that is frequently associated with diabetes. It is a risk factor for the development of several diseases including diabetic nephropathy. Recent studies have reported that gut dysbiosis aggravates the progression of obesity and diabetes by increasing the production of uremic toxins in conjunction with gut barrier dysfunction which then leads to increased passage of lipopolysaccharides (LPS) into the blood circulatory system eventually causing systemic inflammation. Therefore, the modification of gut microbiota using a prebiotic supplement may assist in the restoration of gut barrier function and reduce any disturbance of the inflammatory response. In this review information has been compiled concerning the possible mechanisms involved in an increase in obesity, diabetes and kidney dysfunction via the exacerbation of the inflammatory response and its association with gut dysbiosis. In addition, the role of fructooligosaccharides (FOS), a source of prebiotic widely available commercially, on the improvement of gut dysbiosis and attenuation of inflammation on obese and diabetic conditions has been reviewed. The evidence confirms that FOS supplementation could improve the pathological changes associated with obesity and diabetes related kidney disease, however, knowledge concerning the mechanisms involved is still limited and needs further elucidation.

Integrated metabolomics coupled with pattern recognition and pathway analysis to reveal molecular mechanism of cadmium-induced diabetic nephropathy.

Diabetic nephropathy (DN) is becoming a worldwide public health problem and its pathophysiological mechanism is not well understood. Emerging evidences indicated that cadmium (Cd), an industrial material but also an environmental toxin, may be involved in the development and progression of diabetes and diabetes-related kidney disease. However, the underlying mechanism is still unclear. Herein, a DN animal model was constructed by exposing to Cd, the metabolomic profiling of DN mice were obtained by using ultra performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS), pattern recognition and pathway analysis were performed to screen potential biomarker. Moreover, western blotting was employed to verify the possible mechanism involved in the occurrence of Cd-induced DN. A total of 66 metabolites in serum have been screened out and identified as biomarkers, including free fatty acids, phospholipids, sphingomyelins, glycerides, and others. Significant differences were demonstrated between the metabolic profiles, including decreased levels of phospholipid and increased content of triglyceride, diacylglycerols, ceramide, lysophosphatidylcholine in Cd-induced DN mice compared with control. Protein expression level of p38 MAPK and Wnt/β-catenin were significantly increased. UPLC-Q-TOF/MS-based serum metabolomics coupled with pattern recognition methods and pathway analysis provide a powerful approach to identify potential biomarkers and is a new strategy to predict the underlying mechanism of disease caused by environmental toxicant.

Melatonin Improves Endoplasmic Reticulum Stress-Mediated IRE1α Pathway in Zücker Diabetic Fatty Rat.

Obesity and diabetes are linked to an increased prevalence of kidney disease. Endoplasmic reticulum stress has recently gained growing importance in the pathogenesis of obesity and diabetes-related kidney disease. Melatonin, is an important anti-obesogenic natural bioactive compound. Previously, our research group showed that the renoprotective effect of melatonin administration was associated with restoring mitochondrial fission/fusion balance and function in a rat model of diabesity-induced kidney injury. This study was carried out to further investigate whether melatonin could suppress renal endoplasmic reticulum (ER) stress response and the downstream unfolded protein response activation under obese and diabetic conditions. Zücker diabetic fatty (ZDF) rats and lean littermates (ZL) were orally supplemented either with melatonin (10 mg/kg body weight (BW)/day) (M–ZDF and M–ZL) or vehicle (C–ZDF and C–ZL) for 17 weeks. Western blot analysis of ER stress-related markers and renal morphology were assessed. Compared to C–ZL rats, higher ER stress response associated with impaired renal morphology was observed in C–ZDF rats. Melatonin supplementation alleviated renal ER stress response in ZDF rats, by decreasing glucose-regulated protein 78 (GRP78), phosphoinositol-requiring enzyme1α (IRE1α), and ATF6 levels but had no effect on phospho–protein kinase RNA–like endoplasmic reticulum kinase (PERK) level. In addition, melatonin supplementation also restrained the ER stress-mediated apoptotic pathway, as indicated by decreased pro-apoptotic proteins phospho–c–jun amino terminal kinase (JNK), Bax, and cleaved caspase-3, as well as by upregulation of B cell lymphoma (Bcl)-2 protein. These improvements were associated with renal structural recovery. Taken together, our findings revealed that melatonin play a renoprotective role, at least in part, by suppressing ER stress and related pro-apoptotic IRE1α/JNK signaling pathway.

The Antioxidative Role of Natural Compounds from a Green Coconut Mesocarp Undeniably Contributes to Control Diabetic Complications as Evidenced by the Associated Genes and Biochemical Indexes.

The purpose of this study was to look into the effects of green coconut mesocarp juice extract (CMJE) on diabetes-related problems in streptozotocin- (STZ-) induced type 2 diabetes, as well as the antioxidative functions of its natural compounds in regulating the associated genes and biochemical markers. CMJE's antioxidative properties were evaluated by the standard antioxidant assays of 1,1-diphenyl-2-picrylhydrazyl (DPPH), superoxide radical, nitric oxide, and ferrous ions along with the total phenolic and flavonoids content. The α-amylase inhibitory effect was measured by an established method. The antidiabetic effect of CMJE was assayed by fructose-fed STZ-induced diabetic models in albino rats. The obtained results were verified by bioinformatics-based network pharmacological tools: STITCH, STRING, GSEA, and Cytoscape plugin cytoHubba bioinformatics tools. The results showed that GC-MS-characterized compounds from CMJE displayed a very promising antioxidative potential. In an animal model study, CMJE significantly (P < 0.05) decreased blood glucose, serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine, uric acid, and lipid levels and increased glucose tolerance as well as glucose homeostasis (HOMA-IR and HOMA-b scores). The animal's body weights and relative organ weights were found to be partially restored. Tissue architectures of the pancreas and the kidney were remarkably improved by low doses of CMJE. Compound-protein interactions showed that thymine, catechol, and 5-hydroxymethylfurfural of CMJE interacted with 84 target proteins. Of the top 15 proteins found by Cytoscape 3.6.1, 8, CAT and OGG1 (downregulated) and CASP3, COMT, CYP1B1, DPYD, NQO1, and PTGS1 (upregulated), were dysregulated in diabetes-related kidney disease. The data demonstrate the highly prospective use of CMJE in the regulation of tubulointerstitial tissues of patients with diabetic nephropathy.

1488-P: Closing the Racial/Ethnic Disparity Gap in Kidney Failure from Diabetes in the United States, 2000-2016

Diabetes-related end-stage kidney disease (ESKD-D) disproportionately affects U.S. racial/ethnic minority populations compared with whites. With the recent plateau in diabetes prevalence, we assessed ESKD-D trends by race/ethnicity to determine if disparity gaps have changed. From the U.S. Renal Data System, we obtained the number of adults (whites, blacks, Hispanics, Asians, and Native Americans [NAs]) aged ≥18 years with newly treated ESKD-D (with diabetes listed as primary cause) between 2000 and 2016. ESKD-D incidence rates by race/ethnicity were calculated using Census population estimates and age-adjusted to the 2000 U.S. standard population. Average annual percentage change (AAPC) in rates was estimated using joinpoint regression. From 2000 to 2016, the age-adjusted ESKD-D rates decreased by 53% for NAs (66.7 to 31.2 per 100,000, AAPC= -4.5%, p&amp;lt;0.001); by 33% for Hispanics (50.0 to 33.3, AAPC= -2.1%, p&amp;lt;0.001); by 20% for blacks (56.2 to 44.7, AAPC= -1.6%, p=0.02), did not change for Asians, and increased by 10% for whites (15.4 to 17.0, AAPC= 0.6%, p=0.01) (Figure). ESKD-D incidence declined for NAs, Hispanics, and blacks, narrowing the gap with whites, with NAs having the largest decline. However, in 2016, ESKD-D incidence rates in NAs, Hispanics, and blacks were about 2.0-2.5 times higher than whites. Continued efforts might be considered to sustain and improve ESKD-D trends in these populations. Disclosure N. Burrows: None. Y. Zhang: None. I.A. Hora: None. M.E. Pavkov: None. G. Imperatore: None.

Chronic kidney disease in type 2 diabetes: Implications for managing glycaemic control, cardiovascular and renal risk.

This review examines the current literature relating to diabetes related kidney disease (DKD) and the optimal management of cardio-renal risk. DKD develops in approximately 40% of patients with type 2 diabetes mellitus. The mainstay of therapy is to reduce the progression of DKD by optimising hyperglycaemia, blood pressure, lipids and lifestyle. Evidence supports the role for renin-angiotensin system blockade in limiting the progression of DKD. Recent data from diabetes related cardiovascular outcome trials and renal specific trials have provided a novel insight on the additional benefits of sodium-glucose cotransporter-2 inhibitors (SGLT2i) in reducing the progression of DKD as well as cardiovascular risk. Lessons have been learnt from CREDENCE and there are expectations that DAPA-CKD and EMPA-KIDNEY will further support the benefits of SGLT2 inhibition in relation to DKD. As a consequence, international guidelines have been updated to reflect the positive benefits. In addition, novel steroidal mineralocorticoid receptor antagonists offer a potential role in future years. The review examines the current evidence and future approach to optimising outcomes for renal protection in patients with diabetes.

A physician-initiated double-blind, randomised, placebo-controlled, phase 2 study evaluating the efficacy and safety of inhibition of NADPH oxidase with the first-in-class Nox-1/4 inhibitor, GKT137831, in adults with type 1 diabetes and persistently elevated urinary albumin excretion: Protocol and statistical considerations

PurposeKidney disease caused by type 1 diabetes can progress to end stage renal disease and can increase mortality risk. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox) plays a major role in producing oxidative stress in the kidney in diabetes, and its activity is attenuated by GKT137831, an oral Nox inhibitor with predominant inhibitory action on Nox-1 and Nox − 4. Previous studies have demonstrated renoprotective effects with GKT137831 in various experimental models of type 1 diabetes-related kidney disease. This study will evaluate the effect of GKT137831 in treating clinical diabetic kidney disease. DesignThis is a multi-center, randomized, placebo-controlled trial, parallel arm study evaluating the effect on albuminuria of treatment with GKT137831 400 mg BID for 48 weeks. The study will randomize 142 participants who have persistent albuminuria and estimated glomerular filtration rate (eGFR) at baseline of at least 40 ml/min/1.73m2. Primary outcome measuresDifference between arms in urine albumin to creatinine ratio. Secondary outcome measures include eGFR. ConclusionThis study is important because it may identify a new way of slowing renal disease progression in people with type 1 diabetes and albuminuria already receiving standard of care treatment.

Diabetes-related kidney, eye, and foot disease in Taiwan: An analysis of nationwide data from 2005 to 2014

Patients with diabetes have a higher risk of developing chronic complications and cause a huge burden to the public health care system as well as on patients and their families. We studied these diabetic complications about kidney, eye and peripheral vascular diseases to understand their prevalence and distributions in a national survey. We analyzed diabetic complications using National-Health-Insurance claims filed from 2005 to 2014. We used this database to evaluate their developments of kidney, eye, and peripheral vascular diseases according to the International-Classification-of-Diseases, Ninth Revision using clinical modification diagnosis codes. The prevalence of diabetic kidney disease (DKD) significantly increased from 10.49% to 17.92% from 2005 to 2014. The prevalence rate of diabetic foot significantly decreased from 1.34% to 1.05% from 2005 to 2014, and the rate of severe infection also significantly decreased from 50.69% to 45.85%. The amputation rate significantly decreased from 24.91% to 17.47% among all patients with diabetic foot. In this study, the trends in DKD and dialysis prevalence were similar to those of the 2012 report. The rate of increase in dialysis prevalence is lower in this study than in the 2012 report. The prevalence of diabetic foot, severe infection, and amputation in this report exhibited significantly decreasing trends. This improvement may be attributable to care from multidisciplinary teams. We should dedicate more resources to our prevention program of DKD and retinopathy to further improve outcomes in the future.

Association of diabetes-related kidney disease with cardiovascular and non-cardiovascular outcomes: a retrospective cohort study

BackgroundDiabetes-related kidney disease is associated with end-stage renal disease and mortality, but opportunities remain to quantify its association with cardiovascular and non-cardiovascular morbidity outcomes.MethodsWe used the Truven Health MarketScan Commercial Claims and Encounters Database, 2010–2014, which includes specific health services records for employees and their dependents from a selection of large employers, health plans, and government and public organizations. We used administrative claims data to quantify the association between diabetes-related kidney disease and end-stage renal disease, myocardial infarction, congestive heart failure, stroke, and infections. Cox proportional hazard regression models were used to estimate adjusted hazard ratios of developing complications.ResultsAmong 2.2 million patients with diabetes, 7.1% had diabetes-related kidney disease: 13.5%, stage 1–2; 33.8%, stage 3; 13.2% stages 4–5; 39.5%, unknown stage. In multivariable Cox proportional hazard models adjusted for demographic characteristics, baseline comorbid conditions, and total hospital days during the baseline period, hazard ratios for each outcome increased with greater diabetes-related kidney disease severity (stage 1–2 vs. stage 4–5) compared with no diabetes-related kidney disease: myocardial infarction, 1.2 (95% confidence interval 1.1–1.4) and 3.1 (2.9–3.4); congestive heart failure, 1.7 (1.6–1.9) and 5.6 (5.3–5.8); stroke, 1.3 (1.2–1.5) and 2.3 (2.1–2.5); infection, 1.4 (1.3–1.5) and 2.9 (2.8–3.0). Among patients with stage 4–5 disease, 36-month cumulative incidence was nearly 22.8% for congestive heart failure, and 25.8% for infections.ConclusionsDiabetes-related kidney disease appears to be formally diagnosed at a more advanced stage than might be expected, given clinical practice guidelines. Risks of cardiovascular and non-cardiovascular outcomes are high.

PATOGENIA. FACTORES DE RIESGO EN DIABETES MELITUS

La interacción entre uroepitelio y uropatógeno, base de la patogenia de las infecciones del tracto urinario (ITUs), puede derivar en la eliminación bacteriana por parte de la célula huésped o la invasión y multiplicación bacteriana. Dentro de la célula huésped los uropatógenos pueden perturbar las defensas y resistir el tratamiento antibiótico. En pacientes con diabetes, especialmente con enfermedad renal por diabetes, se ha demostrado una reducción de la capacidad de inhibición de la adherencia bacteriana al uroepitelio, por ende mayor posibilidad de invasión bacteriana. La glicosilación de todos los elementos del sistema inmune, incluida la menor liberación de factores como las interleuquinas a nivel urinario y la alteración del vaciamiento vesical por neuropatía autonómica,favorecen el desarrollo de este tipo de infecciones.

Identifying Outcome Measures for Type 2 Diabetes Value-Based Contracting Using the Delphi Method.

Value-based contracts (VBCs) between payers and pharmaceutical manufacturers link drug payments to predefined performance measures and require shared risk between both entities. It is unclear how outcome measures were selected in previously reported VBCs, and many VBCs have focused on surrogate endpoints often used in the conduct of clinical trials, which may not be valued by or of importance to patients. To identify outcome measures that are meaningful to key stakeholders and feasibly measured to inform VBCs for diabetes medications. We conducted a modified Delphi survey to incorporate views from patients (n = 9), endocrinologists (n = 5), primary care physicians (n = 4), payers (n = 3), pharmacy benefit managers (n = 3), and pharmaceutical company representatives (n = 2). A list of 12 diabetes-related outcome measures was generated from the literature and consultations with subject matter experts. Participants rated the importance of each outcome on a 5-point Likert scale and selected the 3 most meaningful outcomes. Nonpatient participants then used a Likert scale to rate the feasibility of collecting each outcome. Consensus was defined as ≥ 75% agreement on the importance and feasibility of an outcome (Likert scores 4 or 5 or selection of an outcome as most meaningful). A 2-sample test of proportions was performed to examine differences between patient and nonpatient stakeholder rankings of outcomes. All 12 outcomes reached consensus for importance on the Likert scale. The measure "reducing risk of heart attacks" was the most meaningful outcome (84%), while "reducing A1c levels" ranked second (68%). The 2 measures rated as most feasibly collected were "reducing A1c levels" and "reducing risk of hospitalizations from diabetes" (93.8% each). The measures "weight loss," "reducing risk of diabetes-related kidney disease," "reducing risk of emergency room visits from diabetes," and "reducing risk of diabetes-related amputations and foot ulcers" also reached consensus for feasibility. There were statistically significant differences between patient and nonpatient stakeholders in the selection of "reducing A1c levels" (37.5% vs. 82.3%, respectively; P = 0.03) and "reducing risk of diabetes-related kidney disease" (50.0% vs. 11.8%, respectively; P = 0.03) as most meaningful outcomes. The measures "reducing risk of heart attacks" and "reducing A1c levels" were identified as top priority diabetes outcome measures. Express Scripts provided research funding for this study to the UPMC Center for Value-Based Pharmacy Initiatives. Henderson is employed by Express Scripts and was involved in the conception and design of the study and manuscript approval. The other authors are employed by the UPMC Center for Value-Based Pharmacy Initiatives and have nothing to disclose.

Characteristics of Adults With Type 2 Diabetes Mellitus by Category of Chronic Kidney Disease and Presence of Cardiovascular Disease in Alberta Canada: A Cross-Sectional Study.

Background:Type 2 diabetes mellitus (T2DM) is associated with an excess risk of cardiovascular disease (CVD) and chronic kidney disease (CKD). Although CVD, CKD, and use of antihyperglycemic treatments are all key drivers of the costs and consequences experienced by people with diabetes, no recent Canadian data describe these characteristics among adults with diabetes.Objective:To describe prevalence of CVD, CKD, and use of antihyperglycemic treatments among adults with diabetes.Design:Retrospective population-based, cross-sectional study.Setting:Alberta, Canada.Patients:All adults with T2DM as of March 31, 2017.Measurements:We described the demographic and clinical characteristics by CKD stage and CVD status and type. CKD stage was categorized according to international guidelines and based on estimated glomerular filtration rate (eGFR) and severity of albuminuria.Methods:Clinical and demographic characteristics were defined using provincial administrative data; medication use was based on data from the provincial drug plan. Additional analyses examined subgroups based on demographic characteristics, clinical characteristics, and medication use.Results:There were 260 903 participants, all of whom had T2DM. Median age was 64 years; 53.6% were male; and 10.9% lived in rural communities. Median duration of diabetes was 7.7 years. Half of the participants had A1C <7%. Overall, 33.0% had CKD; among these most had eGFR <60 mL/min/1.73 m2; 11.1%, 5.6%, and 2.9% had CKD stages 3a, 3b, and 4/5, respectively. The overall prevalence of CVD (prior myocardial infarction, stroke/transient ischemic attack, or peripheral artery disease) was 22.5%; prevalence increased in parallel with the presence of CKD: 14.4%, 28.8%, 35.7%, 44.3%, and 50.9% for stages 1, 2, 3a, 3b, and 4/5, respectively. Prescriptions for antihyperglycemic medications were more common in people with CKD as compared with those without. However, the use of all antihyperglycemic medications except insulin and meglitinide was progressively lower in the presence of more severe CKD.Limitations:The study is based on administrative data; therefore, the findings could be influenced by measurement error (eg, accuracy of diagnostic and procedural codes and prescription drug codes used).Conclusions:These findings will be useful to policy makers seeking to understand the burden of diabetes-related kidney disease as well as the potential budget implications and potential clinical benefits of expanded use of antihyperglycemic use in this population.

A novel rare CUBN variant and three additional genes identified in Europeans with and without diabetes: results from an exome-wide association study of albuminuria

Aims/hypothesisIdentifying rare coding variants associated with albuminuria may open new avenues for preventing chronic kidney disease and end-stage renal disease, which are highly prevalent in individuals with diabetes. Efforts to identify genetic susceptibility variants for albuminuria have so far been limited, with the majority of studies focusing on common variants.MethodsWe performed an exome-wide association study to identify coding variants in a two-stage (discovery and replication) approach. Data from 33,985 individuals of European ancestry (15,872 with and 18,113 without diabetes) and 2605 Greenlanders were included.ResultsWe identified a rare (minor allele frequency [MAF]: 0.8%) missense (A1690V) variant in CUBN (rs141640975, β = 0.27, p = 1.3 × 10−11) associated with albuminuria as a continuous measure in the combined European meta-analysis. The presence of each rare allele of the variant was associated with a 6.4% increase in albuminuria. The rare CUBN variant had an effect that was three times stronger in individuals with type 2 diabetes compared with those without (pinteraction = 7.0 × 10−4, β with diabetes = 0.69, β without diabetes = 0.20) in the discovery meta-analysis. Gene-aggregate tests based on rare and common variants identified three additional genes associated with albuminuria (HES1, CDC73 and GRM5) after multiple testing correction (pBonferroni < 2.7 × 10−6).Conclusions/interpretationThe current study identifies a rare coding variant in the CUBN locus and other potential genes associated with albuminuria in individuals with and without diabetes. These genes have been implicated in renal and cardiovascular dysfunction. The findings provide new insights into the genetic architecture of albuminuria and highlight target genes and pathways for the prevention of diabetes-related kidney disease.