Management Of Diabetic Kidney Disease Research Articles

Improving the Dysregulation of FoxO1 Activity Is a Potential Therapy for Alleviating Diabetic Kidney Disease.

A substantial proportion of patients with diabetes will develop kidney disease. Diabetic kidney disease (DKD) is one of the most serious complications in diabetic patients and the leading cause of end-stage kidney disease worldwide. Although some mechanisms have been revealed to contribute to the understanding of the pathogenesis of DKD and some drugs currently in use have been shown to be beneficial, prevention and management of DKD remain tricky and challenging. FoxO1 transcriptional factor is a crucial regulator of cellular homeostasis and posttranslational modification is a major mechanism to alter FoxO1 activity. There is increasing evidence that FoxO1 is involved in the regulation of various cellular processes such as stress resistance, autophagy, cell cycle arrest, and apoptosis, thereby playing an important role in the pathogenesis of DKD. Improving the dysregulation of FoxO1 activity by natural compounds, synthetic drugs, or manipulation of gene expression may attenuate renal cell injury and kidney lesion in the cells cultured under a high-glucose environment and in diabetic animal models. The available data imply that FoxO1 may be a potential clinical target for the prevention and treatment of DKD.

Update on diagnosis, pathophysiology, and management of diabetic kidney disease

Diabetic kidney disease (DKD) is a chronic complication of diabetes mellitus which may eventually lead to end-stage kidney disease (ESKD). Despite improvements in glycaemic control and blood pressure management with renin-angiotensin-aldosterone system (RAAS) blockade, the current therapy cannot completely halt DKD progression to ESKD in some patients. DKD is a heterogeneous disease entity in terms of its clinical manifestations, histopathology and the rate of progression, which makes it difficult to develop effective therapeutics. It was formerly considered that albuminuria preceded kidney function decline in DKD, but recent epidemiological studies revealed that a distinct group of patients presented kidney dysfunction without developing albuminuria. Other comorbidities, such as hypertension, obesity and gout, also affect the clinical course of DKD. The pathophysiology of DKD is complex and multifactorial, involving both metabolic and haemodynamic factors. These induce activation of intracellular signalling pathways, oxidative stress, hypoxia, dysregulated autophagy and epigenetic changes, which result in kidney inflammation and fibrosis. Recently, two groups of antidiabetic drugs, sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 (GLP-1) receptor agonists, were demonstrated to provide renoprotection on top of their glucose-lowering effects. Several other therapeutic agents are also being developed and evaluated in clinical trials.

Diabetic Nephropathy and Diabetic Kidney Disease

Diabetic kidney disease (DKD) is the leading cause of chronic kidney disease (CKD) and end-stage kidney disease (ESKD) in the United States and worldwide. Alterations in glomerular hemodynamics, inflammation, and fibrosis are primary mediators of kidney tissue damage, although the relative contribution of these mechanisms likely varies between individuals and over the course of the natural history of diabetic kidney disease. The presence of DKD is also strongly associated with cardiovascular morbidity/mortality and has a major influence on survival. Clinical presentation and prognosis of DKD are heterogeneous and vary between individuals, although the severity of albuminuria, particularly when combined with elevated blood pressure, remains an important marker of those at higher risk of progression. Management of DKD requires a holistic approach that combines cardiovascular risk reduction with elements to slow the progression of kidney disease, namely glycemic control, RAAS inhibition and blood pressure lowering. Effective delivery of these interventions in combination reduces the risks of DKD progression, as well as other microvascular complications, cardiovascular events, and mortality. Several international groups have issued clinical guidelines that largely agree on recommended targets, and in clinical practice these should be tailored for each individual patient. SGLT2 inhibitors are exciting new options now available to slow the progression of diabetic nephropathy.

Kidney Disease in Type 2 Diabetes Mellitus and Benefits of Sodium-Glucose Cotransporter 2 Inhibitors: A Consensus Statement.

Diabetic kidney disease (DKD) occurs in approximately 20–40% of patients with type 2 diabetes mellitus. Patients with DKD have a higher risk of cardiovascular and all-cause mortality. Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers and antihyperglycemic drugs form the mainstay of DKD management and aim to restrict progression to more severe stages of DKD. Sodium-glucose cotransporter 2 inhibitors (SGLT2i) control hyperglycemia by blocking renal glucose reabsorption in addition to preventing inflammation, thereby improving endothelial function and reducing oxidative stress; consequently, this class of prescription medicines is emerging as an important addition to the therapeutic armamentarium. The EMPA-REG OUTCOME, DECLARE TIMI 58, and CANVAS trials demonstrated the renoprotective effects of SGLT2i, such as restricting decline in glomerular filtration rate, in the progression of albuminuria, and in death due to renal causes. The renoprotection provided by SGLT2i was further confirmed in the CREDENCE study, which showed a 30% reduction in progression of chronic kidney disease, and in the DELIGHT study, which demonstrated a reduction in albuminuria with dapagliflozin compared with placebo (− 21.0%, confidence interval [CI] − 34.1 to − 5.2, p = 0.011). Furthermore, a meta-analysis demonstrated a reduced risk of dialysis, transplantation, or death due to kidney disease (relative risk 0.67; 95% CI 0.52–0.86; p = 0.0019) and a 45% risk reduction in worsening of renal function, end-stage renal disease, or renal death (hazard ratio 0.55, CI 0.48–0.64, p < 0.0001) with SGLT2i, irrespective of baseline estimated glomerular filtration rate. Thus, there is emerging evidence that SGLT2i may be used to curb the mortality and improve the quality of life in patients with DKD. However, clinicians need to effectively select candidates for SGLT2i therapy. In this consensus statement, we have qualitatively synthesized evidence demonstrating the renal effects of SGLT2i and proposed recommendations for optimal use of SGLT2i to effectively manage and delay progression of DKD.

Expert consensus on the diagnosis and management of diabetic kidney disease.

Expert consensus on the diagnosis and management of diabetic kidney disease.

ASIAN PACIFIC SOCIETY OF NEPHROLOGY CLINICAL PRACTICE GUIDELINE ON DIABETIC KIDNEY DISEASE - EXECUTIVE SUMMARY.

Introduction: COVID-19 is now a global pandemic affecting millions of people Patients on dialysis are at an increased risk to COVID-19 infection due to their exposure in the health care setting Strategies for infection control and prevention are also being implemented in the dialysis units because of the increased risk of virus transmission within the unit Objective: Describe the different measures and strategies done to mitigate the spread of COVID-19 outbreak in a hospital based dialysis centre Methods: Review of the epidemic course with contact tracing was done from March 14 to May 14, 2020 in the dialysis unit of a tertiary hospital Results: Of 167 haemodialysis patients, 20 were considered COVID-19 suspects Eight tested positive-2 were traced to be exposed with the first confirmed case, 2 were handled by a COVID-19 infected healthcare worker (HCW) who was asymptomatic at time of contact while 2 asymptomatic patients tested positive during mass screening Two of 67 HCWs tested positive were exposed to patients Key interventions during the course of the outbreak included: mass testing of patients and HCWs after identifying 6 patients and 2 HCWs infected with COVID-19 using nasopharyngeal/oropharyngeal swabs by RT-PCR;dialysis of COVID-19 confirmed and suspected cases in isolation rooms separate from the dialysis unit (instead of cohorting);provision of adequate protective personal equipment for HCWs and surgical masks for all patients, environmental disinfection especially in the waiting area with strict social distancing and screening for signs and symptoms at the entrance of the unit Conclusion: Infection control strategies are needed to manage the spread of COVID-19 in dialysis centres These infection prevention measures should be implemented at the first indication of transmission in the area and should be maintained for the duration of the pandemic and until the area show no more reports of transmission

SGLT2 Inhibitors: Slowing of Chronic Kidney Disease Progression in Type 2 Diabetes.

Diabetic kidney disease (DKD) is a topic of increasing concern among clinicians involved in the management of type 2 diabetes mellitus (T2DM). It is a progressive and costly complication associated with increased risk of adverse cardiovascular (CV) and renal outcomes and mortality. Ongoing monitoring of the estimated glomerular filtration (eGFR) rate alongside the urine albumin:creatinine ratio (ACR) is recommended during regular T2DM reviews to enable a prompt DKD diagnosis or to assess disease progression, providing an understanding of adverse risk for each individual. Many people with DKD will progress to end-stage kidney disease (ESKD), requiring renal replacement therapy (RRT), typically haemodialysis or kidney transplantation. A range of lifestyle and pharmacological interventions is recommended to help lower CV risk, slow the advancement of DKD and prevent or delay the need for RRT. Emerging evidence concerning sodium-glucose co-transporter-2 inhibitor (SGLT2i) agents suggests a role for these medicines in slowing eGFR decline, enabling regression of albuminuria and reducing progression to ESKD. Improvements in renal end points observed in SGLT2i CV outcome trials (CVOTs) highlighted the possible impact of these agents in the management of DKD. Data from the canagliflozin CREDENCE trial (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation) have since demonstrated the effectiveness of this medicine in reducing the risk of kidney failure and CV events in a population comprising individuals with T2DM and renal disease. CREDENCE was the first SGLT2i study to examine renal outcomes as the primary end point. Real-world studies have reaffirmed these outcomes in routine clinical practice. This article summarises the evidence regarding the use of SGLT2i medicines in slowing the progression of DKD and examines the possible mechanisms underpinning the renoprotective effects of these agents. The relevant national and international guidance for monitoring and treatment of DKD is also highlighted to help clinicians working to support this vulnerable group.Electronic supplementary materialThe online version of this article (10.1007/s13300-020-00930-x) contains supplementary material, which is available to authorized users.

Improving management of diabetic kidney disease: will GLP-1 receptor agonists have a role?

Kidney disease affects around 40% of people with type 2 diabetes and is a leading cause of morbidity and mortality.1 Management of diabetic kidney disease has traditionally focused on tight glycaemic control (in the early stages) and blood pressure control (with agents that inhibit the renin–angiotensin system).1 Despite this, most patients with diabetic kidney disease experience a gradual decline in kidney function, eventually progressing to end-stage kidney disease and an increased risk of cardiovascular events and mortality.

Managing diabetic kidney disease

Managing diabetic kidney disease Abstract. Diabetic kidney disease is a common complication of diabetes associated with an increased cardiovascular mortality and is the leading cause of end-stage renal disease. A heterogeneous set of pathological mechanisms drives the development and progression of diabetic kidney disease. A comprehensive diagnostic work-up and repeated reevaluation are needed since diabetic patients can suffer from other nephropathies with a clinical presentation similar to diabetic kidney disease. Screening, treatment of cardiovascular risk factors and the reduction of albuminuria, using renin-angiotensin-aldosterone system and sodium-dependent glucose transporter 2 inhibitors are crucial in the management of diabetic kidney disease.

Racial Differences in the Effectiveness of a Multifactorial Telehealth Intervention to Slow Diabetic Kidney Disease.

African Americans are significantly more likely than non-African Americans to have diabetes, chronic kidney disease, and uncontrolled hypertension, increasing their risk for kidney function decline. The objective of this study was to compare how African Americans and non-African Americans with diabetes responded to a multifactorial telehealth intervention designed to slow kidney function decline. Secondary analysis of a randomized trial. Primary care patients (N=281, 56% African American) were allocated to either: (1) a multifactorial, pharmacist-delivered phone-based telehealth intervention focused on behavioral and medication management of diabetic kidney disease; or (2) an education control. The primary study outcome was change in estimated glomerular filtration rate (eGFR). Linear mixed models were used to explore the moderating effect of race on the relationship between study arm and eGFR decline over time; the mean annual rate of eGFR decline was estimated by race and study arm. Findings demonstrated a differential intervention effect on kidney function over time by race (Pinteraction=0.005). Among African Americans, the intervention arm had significantly greater preservation of eGFR over time than the control arm (difference in the annual rate of eGFR decline=1.5 mL/min/1.73 m; 95% confidence interval: 0.04, 3.02). For non-African Americans, the intervention arm had a faster decline in eGFR over time than the control arm (difference in the annual rate of eGFR decline=-1.7 mL/min/1.73 m; 95% confidence interval: -3.3, -0.02). A multifactorial, pharmacist-delivered telehealth intervention for diabetic kidney disease may be more effective for slowing eGFR decline among African Americans than non-African Americans.

Time-series proteomic study of the response of HK-2 cells to hyperglycemic, hypoxic diabetic-like milieu.

During diabetes, renal proximal tubular cells (PTC) are exposed to a combination of high glucose and hypoxic conditions, which plays a relevant role in the development of diabetic kidney disease (DKD). In this work, a time-series proteomic study was performed to analyse the effect of a diabetic-like microenvironment induced changes on HK-2 cells, a human cell line derived from normal proximal tubular epithelial cells. Cells simultaneously exposed to high glucose (25 mM) and hypoxia (1% O2) were compared to cells in control conditions for up to 48 h. Diabetic conditions increased the percentage of death cells after 24 and 48 h, but no differences in the protein/cell ratio were found. The relative protein quantification using dimethyl-labeling and UHPLC-MS/MS analysis allowed the identification of 317, 296 and 259 proteins at 5, 24 and 48 h, respectively. The combination of statistical and time expression profile analyses indicated an increased expression of proteins involved in glycolysis, and a decrease of cytoskeletal-related proteins. The exposure of HK-2 cells to high glucose and hypoxia reproduces some of the effects of diabetes on PTC and, with the limitations inherent to in vitro studies, propose new mechanisms and targets to be considered in the management of DKD.

An updated overview of diabetic nephropathy: Diagnosis, prognosis, treatment goals and latest guidelines.

Diabetic nephropathy (DN) is a major healthcare challenge. It occurs in up to 50% of those living with diabetes, is a major cause of end-stage kidney disease (ESKD) that requires treatment with dialysis or renal transplantation, and is associated with significantly increased cardiovascular morbidity and mortality. DN is a clinical syndrome characterized by persistent albuminuria and a progressive decline in renal function, but it is increasingly recognized that the presentation and clinical course of kidney disease in diabetes is heterogeneous. The term diabetic kidney disease (DKD) is now commonly used to encompass the spectrum of people with diabetes who have either albuminuria or reductions in renal function. In this article, the clinical presentation and approach to diagnosis of DKD will be discussed, as will its prognosis. The general principles of management of DKD will also be reviewed with reference to current international guidelines.

The future of diabetic kidney disease management: what to expect from the experimental studies?

Diabetic kidney disease (DKD) is a major cause of end-stage renal disease. Intensive blood glucose and blood pressure control, particularly using inhibitors of the renin-angiotensin system, have long been mainstays of therapy in patients with DKD. Moreover, new anti-hyperglycemic drugs have recently shown renoprotective effects and this represents a major progress in the management of DKD. However, the risk of progression is still substantial and additional drugs are required. Recent preclinical studies have identified novel therapeutic targets that may optimize renoprotection in the near future. Besides strategies aimed to reduce oxidative stress and inflammation in the kidney, novel extra-renal approaches targeting stem cells, extracellular vesicles, and the microbiota are on the horizon with promising preclinical data. Herein, we will review these lines of research and discuss potential clinical applications. Given the poor yield of experimental studies in DKD in the past years, we will also discuss strategies to improve translation of preclinical research to humans.

Potential of Renin-Angiotensin-Aldosterone System Modulations in Diabetic Kidney Disease: Old Players to New Hope!

Due to a tragic increase in the incidences of diabetes globally, diabetic kidney disease (DKD) has emerged as one of the leading causes of end-stage renal diseases (ESRD). Hyperglycaemia-mediated overactivation of the renin-angiotensin-aldosterone system (RAAS) is key to the development and progression of DKD. Consequently, RAAS inhibition by angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARBs) is the first-line therapy for the clinical management of DKD. However, numerous clinical and preclinical evidences suggested that RAAS inhibition can only halt the progression of the DKD to a certain extent, and they are inadequate to cure DKD completely. Recent studies have improved understanding of the complexity of the RAAS. It consists of two counter-regulatory arms, the deleterious pressor arm (ACE/angiotensin II/AT1 receptor axis) and the beneficial depressor arm (ACE2/angiotensin-(1-7)/Mas receptor axis). These advances have paved the way for the development of new therapies targeting the RAAS for better treatment of DKD. In this review, we aimed to summarise the involvement of the depressor arm of the RAAS in DKD. Moreover, in modern drug discovery and development, an advance approach is the bispecific therapeutics, targeting two independent signalling pathways. Here, we discuss available reports of these bispecific drugs involving the RAAS as well as propose potential treatments based on neurohormonal balance as credible therapeutic strategies for DKD.

SGLT-2 inhibitors in Diabetic Kidney Disease: What Lies Behind their Renoprotective Properties?

Despite optimal management of diabetic kidney disease (DKD) with intensive glycemic control and administration of agents blocking the renin-angiotensinaldosterone- system, the residual risk for nephropathy progression to end-stage-renal-disease (ESRD) remains high. Sodium-glucose co-transporter type 2 (SGLT-2)-inhibitors represent a newly-introduced anti-diabetic drug class with pleiotropic actions extending above their glucose-lowering efficacy. Herein, we provide an overview of preclinical and clinical-trial evidence supporting a protective effect of SGLT-2 inhibitors on DKD. A systematic literature search of bibliographic databases was conducted to identify preclinical studies and randomized trials evaluating the effects SGLT-2 inhibitors on DKD. Preclinical studies performed in animal models of DKD support the renoprotective action of SGLT-2 inhibitors showing that these agents exert albuminuria-lowering effects and reverse glomerulosclerosis. The renoprotective action of SGLT-2 inhibitors is strongly supported by human studies showing that these agents prevent the progression of albuminuria and retard nephropathy progression to ESRD. This beneficial effect of SGLT-2 inhibitors is not fully explained by their glucose-lowering properties. Attenuation of glomerular hyperfiltration and improvement in a number of surrogate risk factors, including associated reduction in systemic blood pressure, body weight, and serum uric acid levels may represent plausible mechanistic explanations for the cardio-renal protection offered by SGLT-2 inhibitors. Furthermore, the tubular cell metabolism seems to be altered towards a ketone-prone pathway with protective activities. SGLT-2 inhibition emerges as a novel therapeutic approach of diabetic with anticipated benefits towards cardio-renal risk reduction. Additional research efforts are clearly warranted to elucidate this favorable effect in patients with overt DKD.

Management of Type 2 Diabetes and Chronic Kidney Disease in Fiji in 2018: Knowledge, Attitude, and Practice of Patients.

The aim was to identify the level of knowledge, attitude, and practice (KAP) in patients with type 2 diabetes (T2D) and chronic kidney disease (CKD) at Sigatoka Subdivisional Hospital (SSH) in 2018 since no studies have been done on this issue so far in Fiji. A quantitative, cross-sectional study including 225 patients was carried out July 1, 2018, through August 31, 2018, using a validated self-structured questionnaire. Fijians, aged 30 years or above, with confirmed T2D and CKD who were attending the Special Outpatient Department (SOPD) at SSH, were included in the study using a purposive sampling method to identify eligible participants. Data was gathered by a questionnaire that covered questions related to each aspect of KAP. The relation of native Fijians (i-Taukei) to Fijians of Indian descent (FID) was approximately 1:1. The majority of participants had high levels of knowledge, attitude, and practice (61.8%, 63.6%, and 88.4%, respectively). However, a few areas of low knowledge were evident, such as the relation between high blood pressure and renal status in people with diabetes and the need for renal transplant in end-stage kidney disease (ESKD) abroad. Low attitude was apparent for the impact and management of diabetic kidney disease (DKD). Low practice was evident regarding clinic attendance, self-monitoring, and opting for non-medical treatment. The majority of T2D patients with CKD had a high level of knowledge, but weaknesses were observed in the self-management of CKD and clinic attendance. This information should be considered by clinicians and policy-makers to improve management and treatment of CKD in T2D.

Glucomannans Alleviated the Progression of Diabetic Kidney Disease by Improving Kidney Metabolic Disturbance.

This study is aimed to investigate the kidney protective effects of glucomannans from Dendrobium officinale stem, konjac, and Aloe vera leaves on type 2 diabetic rats and explore its potential mechanisms. Pathological and metabolomics analysis methods are adopted in this study. Compared with the model group, lower levels of fasting blood glucose, serum insulin, and glycated serum protein are observed in glucomannan-treated groups. Concentrations of serum low-density lipoprotein cholesterol, total cholesterol, triacylglycerols, and nonesterified fatty acid are significantly decreased by glucomannan treatment. Furthermore, glucomannan treatment significantly decreased the levels of uric acid, creatinine, urea in serum, and glycosuria, ketone body, and protein in the urine. Histopathological analysis showed that glucomannan treatment normalized the architecture of glomerulus. Metabolomic analysis indicated glucomannan treatment could improve urea cycle, metabolism of lipid, glucose, and amino acids on diabetes. In particular, the konjac glucomannan treatment is more effective in lipid and glucose regulation. Glucomannan from D. officinale is more effective in balancing the urea cycle and amino acid metabolism. The disturbance of lipid, glucose, and amino acid metabolism is closely associated with the advancement of diabetic kidney disease, and glucomannan treatment could be efficient in the management of diabetic kidney disease.

Nephrology Referral in Diabetes Practice

AbstractDiabetic nephropathy, including diabetic kidney disease (DKD), is a major complication of diabetes. Appropriate management of DKD requires multispecialty intervention under the guidance of endocrinology and nephrology. However, delayed referral to specialized nephrology services usually occurs, and this leads to suboptimal outcomes. This multispecialty consensus suggests simple clinical and biochemical parameters that should prompt referral of DKD patients to nephrology. A checklist for physicians who manage DKD is also provided.

Erratum to: Multidisciplinary management of diabetic kidney disease: a systematic review and meta-analysis

Erratum to: Multidisciplinary management of diabetic kidney disease: a systematic review and meta-analysis

MDM2 controls NRF2 antioxidant activity in prevention of diabetic kidney disease

Oxidative stress and P53 contribute to the pathogenesis of diabetic kidney disease (DKD). Nuclear factor erythroid 2-related factor 2 (NRF2) is a master regulator of cellular antioxidant defense system, is negatively regulated by P53 and prevents DKD. Recent findings revealed an important role of mouse double minute 2 (MDM2) in protection against DKD. However, the mechanism remained unclear. We hypothesized that MDM2 enhances NRF2 antioxidant signaling in DKD given that MDM2 is a key negative regulator of P53. The MDM2 inhibitor nutlin3a elevated renal P53, inhibited NRF2 signaling and induced oxidative stress, inflammation, fibrosis, DKD-like renal pathology and albuminuria in the wild-type (WT) non-diabetic mice. These effects exhibited more prominently in nutlin3a-treated WT diabetic mice. Interestingly, nutlin3a failed to induce greater renal injuries in the Nrf2 knockout (KO) mice under both the diabetic and non-diabetic conditions, indicating that NRF2 predominantly mediates MDM2's action. On the contrary, P53 inhibition by pifithrin-α activated renal NRF2 signaling and the expression of Mdm2, and attenuated DKD in the WT diabetic mice, but not in the Nrf2 KO diabetic mice. In high glucose-treated mouse mesangial cells, P53 gene silencing completely abolished nutlin3a's inhibitory effect on NRF2 signaling. The present study demonstrates for the first time that MDM2 controls renal NRF2 antioxidant activity in DKD via inhibition of P53, providing MDM2 activation and P53 inhibition as novel strategies in the management of DKD.