Kidney Disease and Diabetes

Estimated Lifetime Benefit of Combined RAAS and SGLT2 Inhibitor Therapy in Patients with Albuminuric CKD without Diabetes

Vart, Priya — Tue, 22 Nov 2022 05:49:08 GMT-08:00

Development and Validation of a Lifetime Risk Model for Kidney Failure and Treatment Benefit in Type 2 Diabetes

Østergaard, Helena Bleken — Fri, 04 Nov 2022 07:10:25 GMT-07:00

Dynein-mediated trafficking, a new mechanism of diabetic podocytopathy

hua-sun@uiowa.edu — Tue, 06 Dec 2022 01:28:30 GMT-08:00

Background: Diabetic nephropathy (DN) is characterized by increased endocytosis and degradation of nephrin, a protein that comprises the molecular sieve of the glomerular filtration barrier. While nephrin internalization has been found activated in diabetes-stressed podocytes, the post-internalization trafficking steps that lead to the eventual depletion of nephrin and the development of DN are unclear. Our work on an inherited podocytopathy uncovered that dysregulated dynein could compromise nephrin trafficking, leading us to test whether and how dynein mediates the pathogenesis of DN. Methods: We analyzed the transcription of dynein components in public DN databases, using the Nephroseq platform. We verified altered dynein transcription in diabetic podocytopathy by quantitative PCR. Dynein-mediated trafficking and degradation of nephrin was investigated using an in vitro nephrin trafficking model and was demonstrated in a mouse model with streptozotocin (STZ)-induced DN, as well as in human kidney biopsy sections. Results: Our transcription analysis revealed increased expression of dynein in human DN and diabetic mouse kidney, correlated significantly with the severity of hyperglycemia and DN. In diabetic podocytopathy, we observed that dynein-mediated post-endocytic sorting of nephrin was upregulated, resulting in accelerated nephrin degradation and disrupted nephrin recycling. In hyperglycemia-stressed podocytes, Dynll1, one of the most upregulated dynein components, is required for the recruitment of dynein complex that mediates the post-endocytic sorting of nephrin. This was corroborated by observing enhanced Dynll1-nephrin colocalization in podocytes of diabetic patients, as well as dynein-mediated trafficking and degradation of nephrin in STZ-induced diabetic mice with hyperglycemia. Knockdown of Dynll1 attenuated lysosomal degradation of nephrin and promoted its recycling, suggesting the essential role of Dynll1 in dynein-mediated mistrafficking. Conclusion: Our studies show that hyperglycemia stimulates dynein-mediated trafficking of nephrin to lysosomes by inducing its expression. The decoding of dynein-driven pathogenesis of diabetic podocytopathy offers a spectrum of new dynein-related therapeutic targets for DN.

Designing Interventions Addressing Structural Racism to Reduce Kidney Health Disparities: A Report from a National Institute of Diabetes and Digestive and Kidney Diseases Workshop

Crews, Deidra C. — Wed, 19 Oct 2022 12:40:55 GMT-07:00

Structural racism embodies the many ways in which society fosters racial discrimination through “mutually reinforcing inequitable systems” that limit access to resources and opportunities that can promote health and well being among marginalized communities. To achieve health equity, and kidney health equity more specifically, structural racism must be eliminated. In February 2022, the National Institute of Diabetes and Digestive and Kidney Diseases convened the “Designing Interventions that Address Structural Racism to Reduce Kidney Health Disparities” workshop, which was aimed at describing the mechanisms through which structural racism contributes to health and health care disparities for people along the continuum of kidney disease and identifying actionable opportunities for interventional research focused on dismantling or addressing the effects of structural racism. Participants identified six domains as key targets for interventions and future research: (1) apply an antiracism lens, (2) promote structural interventions, (3) target multiple levels, (4) promote effective community and stakeholder engagement, (5) improve data collection, and (6) advance health equity through new health care models. There is an urgent need for research to develop, implement, and evaluate interventions that address the unjust systems, policies, and laws that generate and perpetuate inequities in kidney health.

Accepting Living Kidney Donors with Preexisting Diabetes Mellitus

Soliman, Karim M. — Tue, 11 Oct 2022 09:23:53 GMT-07:00

Effects of Dapagliflozin in People without Diabetes and with Microalbuminuria

Heerspink, Hiddo J.L. — Fri, 09 Sep 2022 01:31:57 GMT-07:00

The Association of Pre-Transplant C-Peptide Level with the Development of Post-Transplant Diabetes: A Cohort Study

Vinson, Amanda J. — Tue, 28 Jun 2022 11:23:09 GMT-07:00

Association of Pre-Transplant C-Peptide with Post-Transplant Diabetes: A New Approach to Identifying High-Risk Patients?

Joachim, Emily — Thu, 27 Oct 2022 08:30:18 GMT-07:00

Enhanced SHP-1 Expression in Podocyturia Is Associated with Kidney Dysfunction in Patients with Diabetes

Lizotte, Farah — Wed, 31 Aug 2022 12:01:56 GMT-07:00

The Integration of Diabetic Eye Screening into Hemodialysis Units in Northern Ireland

Cushley, Laura N. — Wed, 18 May 2022 01:30:25 GMT-07:00

A Post Hoc Analysis of KidneyIntelX and Cardiorenal Outcomes in Diabetic Kidney Disease

Nadkarni, Girish N. — Thu, 19 May 2022 08:54:56 GMT-07:00

The Next Frontier: Biomarkers and Artificial Intelligence Predicting Cardiorenal Outcomes in Diabetic Kidney Disease

Braden, Gregory L. — Thu, 29 Sep 2022 07:30:28 GMT-07:00

Seeing the Light: Improving Diabetic Retinopathy Outcomes by Bringing Screening to the Dialysis Clinic

Klein, Klara R. — Thu, 29 Sep 2022 07:30:28 GMT-07:00

Continuous Glucose Monitoring to Optimize Management of Diabetes in Patients with Advanced CKD

Galindo, Rodolfo J. — Wed, 31 Aug 2022 10:49:50 GMT-07:00

Treatment of patients with diabetes and CKD includes optimizing glycemic control using lifestyle modifications and drugs that safely control glycemia and improve clinical kidney and cardiovascular disease outcomes. However, patients with advanced CKD, defined as eGFR <30 ml/min per 1.73 m2 or kidney disease treated with dialysis, have limitations to the use of some preferred glucose-lowering medications, are often treated with insulin, and experience high rates of severe hypoglycemia. Moreover, hemoglobin A1c accuracy decreases as GFR deteriorates. Hence, there is a need for better glycemic monitoring tools. Continuous glucose monitoring allows for 24-hour glycemic monitoring to understand patterns and the effects of lifestyle and medications. Real-time continuous glucose monitoring can be used to guide the administration of insulin and noninsulin therapies. Continuous glucose monitoring can overcome the limitations of self-monitored capillary glucose testing and hemoglobin A1c and has been shown to prevent hypoglycemic excursions in some populations. More data are needed to understand whether similar benefits can be obtained for patients with diabetes and advanced CKD. This review provides an updated approach to management of glycemia in advanced CKD, focusing on the role of continuous glucose monitoring in this high-risk population.

Endothelial Cell-Specific Molecule-1 Inhibits Albuminuria in Diabetic Mice

vbhalla@stanford.edu — Tue, 19 Jul 2022 01:29:42 GMT-07:00

Background: Diabetic kidney disease (DKD) is the most common cause of kidney failure in the world, and novel predictive biomarkers and molecular mechanisms of disease are needed. Endothelial cell-specific molecule-1 (Esm-1) is a secreted proteoglycan that attenuates inflammation. We previously identified that a glomerular deficiency of Esm-1 associates with more pronounced albuminuria and glomerular inflammation in DKD-susceptible relative to DKD-resistant mice, but its contribution to DKD remains unexplored. Methods: Using hydrodynamic tail-vein injection, we over-express Esm-1 in DKD-susceptible DBA/2 mice and delete Esm-1 in DKD-resistant C57BL/6 mice to study the contribution of Esm-1 to DKD. We analyze clinical indices of DKD, leukocyte infiltration, podocytopenia, and extracellular matrix production. We also study transcriptomic changes to assess potential mechanisms of Esm-1 in glomeruli. Results: In DKD-susceptible mice, Esm-1 inversely correlates with albuminuria and glomerular leukocyte infiltration. We show that over-expression of Esm-1 reduces albuminuria and diabetes-induced podocyte injury independent of changes in leukocyte infiltration. Using a complementary approach, we find that constitutive deletion of Esm-1 in DKD-resistant mice modestly increases the degree of diabetes-induced albuminuria versus wild-type controls. By glomerular RNAseq, we identify that Esm-1 attenuates expression of kidney disease-promoting and interferon-related genes, including Ackr2 and Cxcl11. Conclusions: We demonstrate that in DKD-susceptible mice, Esm-1 protects against diabetes-induced albuminuria and podocytopathy, possibly through select interferon signaling. Companion studies in patients with diabetes suggest a role of Esm-1 in human DKD.

Moving from Evidence to Implementation of Breakthrough Therapies for Diabetic Kidney Disease

Tuttle, Katherine R. — Wed, 01 Jun 2022 11:56:25 GMT-07:00

Diabetic kidney disease is the most frequent cause of kidney failure, accounting for half of all cases worldwide. Moreover, deaths from diabetic kidney disease increased 106% between 1990 and 2013, with most attributed to cardiovascular disease. Recommended screening and monitoring for diabetic kidney disease are conducted in less than half of patients with diabetes. Standard-of-care treatment with an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker is correspondingly low. Sodium-glucose cotransporter 2 inhibitors, glucagon-like peptide 1 receptor agonists, and a nonsteroidal mineralocorticoid antagonist are highly effective therapies to reduce kidney and cardiovascular risks in diabetic kidney disease. However, <20% of eligible patients are receiving these agents. Critical barriers are high out-of-pocket drug costs and low reimbursement rates. Data demonstrating clinical and cost-effectiveness of diabetic kidney disease care are needed to garner payer and health care system support. The pharmaceutical industry should collaborate on value-based care by increasing access through affordable drug prices. Additionally, multidisciplinary models and communication technologies tailored to individual health care systems are needed to support optimal diabetic kidney disease care. Community outreach efforts are also central to make care accessible and equitable. Finally, it is imperative that patient preferences and priorities shape implementation strategies. Access to care and implementation of breakthrough therapies for diabetic kidney disease can save millions of lives by preventing kidney failure, cardiovascular events, and premature death. Coalitions composed of patients, families, community groups, health care professionals, health care systems, federal agencies, and payers are essential to develop collaborative models that successfully address this major public health challenge.

The Role of Glucagon-Like Peptide 1 (GLP-1) Receptor Agonists in the Prevention and Treatment of Diabetic Kidney Disease

Tommerdahl, Kalie L. — Fri, 08 Apr 2022 07:31:44 GMT-07:00

Intestinal Bacterial Translocation Contributes to Diabetic Kidney Disease

Linh, Hoang Thuy — Wed, 09 Mar 2022 07:41:00 GMT-08:00

Reduced Glomerular Filtration in Diabetes Is Attributable to Loss of Density and Increased Resistance of Glomerular Endothelial Cell Fenestrations

Finch, Natalie C. — Tue, 15 Mar 2022 08:38:02 GMT-07:00

Of Mice and MAVS–Diabetic Kidney Disease and the Leaky Gut

Farré, Ricard — Tue, 31 May 2022 10:00:28 GMT-07:00

SGLT2 Inhibition and Uric Acid Excretion in Patients with Type 2 Diabetes and Normal Kidney Function

Suijk, Danii L.S. — Wed, 23 Mar 2022 08:31:11 GMT-07:00

Perspective on Nonsteroidal Mineralocorticoid Receptor Antagonism in Diabetic Kidney Disease

Ghuman, Jasleen K. — Wed, 19 Jan 2022 01:30:01 GMT-08:00

Molecular Signatures of Diabetic Kidney Disease Hiding in a Patient with Hypertension-Related Kidney Disease

Patel, Jiten — Wed, 15 Dec 2021 10:07:40 GMT-08:00

The Kidney Precision Medicine Project (KPMP) seeks to establish a molecular atlas of the kidney in health and disease and improve our understanding of the molecular drivers of CKD and AKI. Herein, we describe the case of a 66-year-old woman with CKD who underwent a protocol KPMP kidney biopsy. Her clinical history included well-controlled diabetes mellitus, hypertension, and proteinuria. The patient’s histopathology was consistent with modest hypertension-related kidney injury, without overt diabetic kidney disease. Transcriptomic signatures of the glomerulus, interstitium, and tubular subsegments were obtained from laser microdissected tissue. The molecular signatures that were uncovered revealed evidence of early diabetic kidney disease adaptation and ongoing active tubular injury with enriched pathways related to mesangial cell hypertrophy, glycosaminoglycan biosynthesis, and apoptosis. Molecular evidence of diabetic kidney disease was found across the nephron. Novel molecular assays can supplement and enrich the histopathologic diagnosis obtained from a kidney biopsy.

Comparative Effects of Sodium-Glucose Cotransporter 2 Inhibitors on Serum Electrolyte Levels in Patients with Type 2 Diabetes: A Pairwise and Network Meta-Analysis of Randomized Controlled Trials

Zhang, Jingjing — Wed, 19 Jan 2022 11:33:25 GMT-08:00

Association between TNF Receptors and KIM-1 with Kidney Outcomes in Early-Stage Diabetic Kidney Disease

Waijer, Simke W. — Tue, 07 Dec 2021 07:23:50 GMT-08:00

Atrasentan: The Difficult Task of Integrating Endothelin A Receptor Antagonists into Current Treatment Paradigm for Diabetic Kidney Disease

Ortiz, Alberto — Wed, 01 Dec 2021 01:40:40 GMT-08:00

CHOP-ASO Ameliorates Glomerular and Tubular Damage on Top of ACE Inhibition in Diabetic Kidney Disease

Shahzad, Khurrum — Fri, 03 Sep 2021 09:49:58 GMT-07:00

Identification of Diabetic Nephropathy in Patients Undergoing Kidney Biopsy through Blood and Urinary Profiles of d-Serine

Iwata, Yukimasa — Thu, 09 Sep 2021 07:23:06 GMT-07:00

Kidney Effects of Empagliflozin in People with Type 1 Diabetes

Cherney, David Z.I. — Fri, 17 Sep 2021 10:39:07 GMT-07:00

Renal Histologic Analysis Provides Complementary Information to Kidney Function Measurement for Patients with Early Diabetic or Hypertensive Disease

Quinn, Ghazal Z. — Wed, 04 Aug 2021 12:11:01 GMT-07:00

Transforming the Care of Patients with Diabetic Kidney Disease

Brosius, Frank C. — Tue, 08 Jun 2021 06:52:50 GMT-07:00

Diabetes and its associated complications pose an immediate threat to humankind. Diabetic kidney disease is one of the most devastating complications, increasing the risk of death more than ten-fold over the general population. Until very recently, the only drugs proven and recommended to slow the progression of diabetic kidney disease were angiotensin-converting enzyme inhibitors and angiotensin II type 1 receptor blockers, which act by inhibiting the renin-angiotensin system. Despite their efficacy as kidney and cardiovascular protective therapies and as antihypertensive agents, renin-angiotensin system inhibitors have been grossly underutilized. Moreover, even when renin-angiotensin system inhibitors are used, patients still have a high residual risk of diabetic kidney disease progression. Finally, the kidney-protective effect of renin-angiotensin system inhibitors has been categorically demonstrated only in patients with macroalbuminuria included in the Irbesartan Diabetic Nephropathy Trial (IDNT) and Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) trials, not in other individuals. The lack of new therapies to treat diabetic kidney disease over the past 2 decades has therefore represented a tremendous challenge for patients and health care providers alike. In recent years, a number of powerful new therapies have emerged that promise to transform care of patients with diabetes and kidney disease. The challenge to the community is to ensure rapid implementation of these treatments. This white paper highlights advances in treatment, opportunities for patients, challenges, and possible solutions to advance kidney health, and introduces the launch of the Diabetic Kidney Disease Collaborative at the American Society of Nephrology, to aid in accomplishing these goals.

GLP-1 Receptor Agonists in Diabetic Kidney Disease

Michos, Erin D. — Tue, 13 Apr 2021 08:05:32 GMT-07:00

Correction: Pre-emptive Short-term Nicotinamide Mononucleotide Treatment in a Mouse Model of Diabetic Nephropathy

American Society of Nephrology — Fri, 01 Oct 2021 10:51:44 GMT-07:00

Association of Coding Variants in Hydroxysteroid 17-beta Dehydrogenase 14 (HSD17B14) with Reduced Progression to End Stage Kidney Disease in Type 1 Diabetes

Mychaleckyj, Josyf C. — Wed, 14 Jul 2021 09:30:46 GMT-07:00

Coding Variants in Susceptibility to Diabetic Kidney Disease

Liu, Lili — Fri, 01 Oct 2021 10:51:44 GMT-07:00

Patiromer to Enable Spironolactone in Patients with Resistant Hypertension and CKD (AMBER)

Agarwal, Rajiv — Wed, 23 Jun 2021 10:54:11 GMT-07:00

Comprehensive Search for Novel Circulating miRNAs and Axon Guidance Pathway Proteins Associated with Risk of ESKD in Diabetes

Satake, Eiichiro — Thu, 17 Jun 2021 07:41:24 GMT-07:00

Predictors of Kidney Disease Progression in Diabetes and Precision Medicine: Something Old, Something New, and Something Borrowed

Vasquez-Rios, George — Tue, 31 Aug 2021 11:00:30 GMT-07:00

Post-transplant Diabetes Mellitus in Kidney Transplant Recipients: A Multicenter Study

Malik, Rubab F. — Thu, 03 Jun 2021 06:17:21 GMT-07:00

New Onset Diabetes Mellitus after Transplant: The Challenge Continues

Aziz, Fahad — Thu, 26 Aug 2021 05:30:24 GMT-07:00

Prevention of Post-Transplantation Diabetes: Small Steps, Big Opportunities

Sharif, Adnan — Fri, 30 Jul 2021 11:00:32 GMT-07:00

Early Postoperative Basal Insulin Therapy versus Standard of Care for the Prevention of Diabetes Mellitus after Kidney Transplantation: A Multicenter Randomized Trial

Schwaiger, Elisabeth — Fri, 30 Jul 2021 11:00:32 GMT-07:00

The Patient Voice in Health Care Decision Making

Sadusky, Tami — Tue, 09 Mar 2021 06:42:55 GMT-08:00

Dysregulation of Principal Cell miRNAs Facilitates Epigenetic Regulation of AQP2 and Results in Nephrogenic Diabetes Insipidus

Petrillo, Federica — Tue, 16 Mar 2021 07:22:13 GMT-07:00

Could NAD+ Precursor Supplements Induce a Legacy of Protection against Diabetic Nephropathy?

Hyndman, Kelly A. — Wed, 14 Apr 2021 08:35:30 GMT-07:00

Pre-emptive Short-term Nicotinamide Mononucleotide Treatment in a Mouse Model of Diabetic Nephropathy

Yasuda, Itaru — Thu, 01 Apr 2021 09:56:37 GMT-07:00

Black Race Coefficient in GFR Estimation and Diabetes Medications in CKD: National Estimates

Walther, Carl P. — Thu, 08 Apr 2021 08:00:09 GMT-07:00

A Hyaluronan Synthesis Inhibitor Delays the Progression of Diabetic Kidney Disease in A Mouse Experimental Model

Selman, Guillermo — Tue, 02 Mar 2021 10:28:08 GMT-08:00

Effect of Apabetalone on Cardiovascular Events in Diabetes, CKD, and Recent Acute Coronary Syndrome

Kalantar-Zadeh, Kamyar — Tue, 27 Apr 2021 09:07:41 GMT-07:00

Opportunities To Improve Diabetes Care in the Hemodialysis Unit: A Cohort Study in Ontario, Canada

Clemens, Kristin K. — Fri, 19 Feb 2021 10:37:14 GMT-08:00

SGLT2 Inhibitors in Diabetic Kidney Disease

Zoungas, Sophia — Wed, 03 Feb 2021 11:29:56 GMT-08:00

Clinical Outcomes by Albuminuria Status with Dulaglutide versus Insulin Glargine in Participants with Diabetes and CKD: AWARD-7 Exploratory Analysis

Tuttle, Katherine R. — Tue, 08 Dec 2020 01:29:19 GMT-08:00

Effects of the Soluble Guanylate Cyclase Stimulator Praliciguat in Diabetic Kidney Disease

Hanrahan, John P. — Wed, 16 Dec 2020 08:21:00 GMT-08:00

Association of Multiple Plasma Biomarker Concentrations with Progression of Prevalent Diabetic Kidney Disease: Findings from the Chronic Renal Insufficiency Cohort (CRIC) Study

Schrauben, Sarah J. — Thu, 29 Oct 2020 09:51:16 GMT-07:00

The Relationship between AKI and CKD in Patients with Type 2 Diabetes: An Observational Cohort Study

Hapca, Simona — Fri, 18 Sep 2020 12:35:49 GMT-07:00

Esaxerenone (CS-3150) in Patients with Type 2 Diabetes and Microalbuminuria (ESAX-DN)

Ito, Sadayoshi — Wed, 25 Nov 2020 01:28:54 GMT-08:00

Mineralocorticoid Receptor Antagonists for Diabetic Kidney Disease

Rossing, Peter — Wed, 25 Nov 2020 01:28:54 GMT-08:00

Are SGLT2 Inhibitors Safe and Effective in Advanced Diabetic Kidney Disease?

Zoungas, Sophia — Thu, 19 Nov 2020 06:44:08 GMT-08:00

Histopathologic and Clinical Features in Patients with Diabetes and Kidney Disease

Sanghavi, Sarah F. — Fri, 11 Sep 2020 07:13:38 GMT-07:00

Decision Algorithm for Prescribing SGLT2 Inhibitors and GLP-1 Receptor Agonists for Diabetic Kidney Disease

Li, Jiahua — Tue, 09 Jun 2020 06:29:26 GMT-07:00

Diabetic kidney disease and its comorbid conditions, including atherosclerotic cardiovascular disease, heart failure, diabetes, and obesity, are interconnected conditions that compound the risk of kidney failure and cardiovascular mortality, and exponentiate health care costs. Sodium glucose cotransporter 2 inhibitor (SGLT2i) and glucagon-like peptide 1 receptor agonist (GLP-1 RA) are novel diabetes medications that prevent cardiovascular events and kidney failure. Clinical trials exploring the cardiovascular and kidney outcomes of SGLT2i and GLP-1 RA have fundamentally shifted the treatment paradigm of diabetes. Clinical guidelines for diabetes management recommend a more holistic approach beyond glycemic control and emphasize heart and kidney protection of SGLT2i and GLP-1 RA. However, the adoption of prescribing SGLT2i and GLP-1 RA for patients with diabetes and high cardiovascular and kidney risk has been slow. In this review, we provide a decision-making tool to help clinicians determine when to consider SGLT2i and GLP-1 RA for heart and kidney protection. First, we discuss a comprehensive risk assessment for patients with diabetic kidney disease. We compare the effectiveness of SGLT2i and GLP-1 RA for different risk categories. Then, we present a decision algorithm using cardiovascular and kidney failure risk stratification and the strength of current evidence for the use of SGLT2i and GLP-1 RA. Lastly, we review the adverse effects of SGLT2i and GLP-1 RA and propose mitigation strategies.

Abdominal Pain and Fever in an Elderly Patient with Diabetes Mellitus

Khetan, Prakash — Thu, 29 Oct 2020 05:30:23 GMT-07:00

Hypoglycemia in Patients with Type 2 Diabetes Mellitus and Chronic Kidney Disease: A Prospective Observational Study

Hong, Susana — Thu, 09 Jul 2020 10:01:15 GMT-07:00

Shaping Up Mitochondria in Diabetic Nephropathy

Mise, Koki — Thu, 30 Jul 2020 10:36:47 GMT-07:00

Mitochondrial medicine has experienced significant progress in recent years and is expected to grow significantly in the near future, yielding many opportunities to translate novel bench discoveries into clinical medicine. Multiple lines of evidence have linked mitochondrial dysfunction to a variety of metabolic diseases, including diabetic nephropathy (DN). Mitochondrial dysfunction presumably precedes the emergence of key histologic and biochemical features of DN, which provides the rationale to explore mitochondrial fitness as a novel therapeutic target in patients with DN. Ultimately, the success of mitochondrial medicine is dependent on a better understanding of the underlying biology of mitochondrial fitness and function. To this end, recent advances in mitochondrial biology have led to new understandings of the potential effect of mitochondrial dysfunction in a myriad of human pathologies. We have proposed that molecular mechanisms that modulate mitochondrial dynamics contribute to the alterations of mitochondrial fitness and progression of DN. In this comprehensive review, we highlight the possible effects of mitochondrial dysfunction in DN, with the hope that targeting specific mitochondrial signaling pathways may lead to the development of new drugs that mitigate DN progression. We will outline potential tools to improve mitochondrial fitness in DN as a novel therapeutic strategy. These emerging views suggest that the modulation of mitochondrial fitness could serve as a key target in ameliorating progression of kidney disease in patients with diabetes.

Podocyte Integrin-β3 and Activated Protein C Coordinately Restrict RhoA Signaling and Ameliorate Diabetic Nephropathy

Madhusudhan, Thati — Fri, 24 Jul 2020 07:43:53 GMT-07:00

Drug Testing for Residual Progression of Diabetic Kidney Disease in Mice Beyond Therapy with Metformin, Ramipril, and Empagliflozin

Motrapu, Manga — Tue, 23 Jun 2020 08:10:24 GMT-07:00

The Feasibility and Safety of Obtaining Research Kidney Biopsy Cores in Patients with Diabetes

Hogan, Jonathan J. — Mon, 27 Apr 2020 08:36:27 GMT-07:00

Endogenous miR-204 Protects the Kidney against Chronic Injury in Hypertension and Diabetes

Cheng, Yuan — Tue, 02 Jun 2020 09:18:12 GMT-07:00

Health Care Costs by Type of Expenditure across eGFR Stages among Patients with and without Diabetes, Cardiovascular Disease, and Heart Failure

Nichols, Gregory A. — Tue, 02 Jun 2020 09:18:14 GMT-07:00

Automated Image Analyses of Glomerular Hypertrophy in a Mouse Model of Diabetic Nephropathy

Østergaard, Mette V. — Fri, 01 May 2020 09:42:46 GMT-07:00

Dietary Fiber Protects against Diabetic Nephropathy through Short-Chain Fatty Acid–Mediated Activation of G Protein–Coupled Receptors GPR43 and GPR109A

Li, Yan Jun — Fri, 01 May 2020 07:53:51 GMT-07:00

Darbepoetin Alfa in Patients with Advanced CKD without Diabetes: Randomized, Controlled Trial

Hayashi, Terumasa — Fri, 03 Apr 2020 06:00:08 GMT-07:00

Role of Impaired Nutrient and Oxygen Deprivation Signaling and Deficient Autophagic Flux in Diabetic CKD Development: Implications for Understanding the Effects of Sodium-Glucose Cotransporter 2-Inhibitors

Packer, Milton — Fri, 10 Apr 2020 07:16:41 GMT-07:00

Growing evidence indicates that oxidative and endoplasmic reticular stress, which trigger changes in ion channels and inflammatory pathways that may undermine cellular homeostasis and survival, are critical determinants of injury in the diabetic kidney. Cells are normally able to mitigate these cellular stresses by maintaining high levels of autophagy, an intracellular lysosome-dependent degradative pathway that clears the cytoplasm of dysfunctional organelles. However, the capacity for autophagy in both podocytes and renal tubular cells is markedly impaired in type 2 diabetes, and this deficiency contributes importantly to the intensity of renal injury. The primary drivers of autophagy in states of nutrient and oxygen deprivation—sirtuin-1 (SIRT1), AMP-activated protein kinase (AMPK), and hypoxia-inducible factors (HIF-1α and HIF-2α)—can exert renoprotective effects by promoting autophagic flux and by exerting direct effects on sodium transport and inflammasome activation. Type 2 diabetes is characterized by marked suppression of SIRT1 and AMPK, leading to a diminution in autophagic flux in glomerular podocytes and renal tubules and markedly increasing their susceptibility to renal injury. Importantly, because insulin acts to depress autophagic flux, these derangements in nutrient deprivation signaling are not ameliorated by antihyperglycemic drugs that enhance insulin secretion or signaling. Metformin is an established AMPK agonist that can promote autophagy, but its effects on the course of CKD have been demonstrated only in the experimental setting. In contrast, the effects of sodium-glucose cotransporter–2 (SGLT2) inhibitors may be related primarily to enhanced SIRT1 and HIF-2α signaling; this can explain the effects of SGLT2 inhibitors to promote ketonemia and erythrocytosis and potentially underlies their actions to increase autophagy and mute inflammation in the diabetic kidney. These distinctions may contribute importantly to the consistent benefit of SGLT2 inhibitors to slow the deterioration in glomerular function and reduce the risk of ESKD in large-scale randomized clinical trials of patients with type 2 diabetes.

Targeting Inflammation in Diabetic Kidney Disease: Is There a Role for Pentoxifylline?

Leehey, David J. — Fri, 28 Feb 2020 05:30:09 GMT-08:00

Diabetic kidney disease (DKD) is the most common cause of ESKD in the United States and worldwide. Current treatment for DKD includes strict glycemic control and normalization of BP with renin-angiotensin-aldosterone system (RAAS) blockade. Although RAAS blockers slow progression of disease, they do not generally prevent ESKD and none of the studies with these agents in DKD included patients who were nonproteinuric, which make up an increasingly large percentage of patients with diabetes now seen in clinical practice. Recent studies with glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 (SGLT2) inhibitors have shown beneficial renal effects, and the benefits of SGLT2 inhibitors likely extend to patients who are nonproteinuric. However, there remains a need to develop new therapies for DKD, particularly in those patients with advanced disease. A role of chronic low-grade inflammation in microvascular complications in patients with diabetes has now been widely accepted. Large clinical trials are being carried out with experimental agents such as bardoxolone and selonsertib that target inflammation and oxidative stress. The Food and Drug Administration–approved, nonspecific phosphodiesterase inhibitor pentoxifylline (PTX) has been shown to have anti-inflammatory effects in both animal and human studies by inhibiting the production of proinflammatory cytokines. Small randomized clinical trials and meta-analyses indicate that PTX may have therapeutic benefits in DKD, raising the possibility that a clinically available drug may be able to be repurposed to treat this disease. A large, multicenter, randomized clinical trial to determine whether this agent can decrease time to ESKD or death is currently being conducted, but results will not be available for several years. At this time, the combination of RAAS blockade plus SGLT2 inhibition is considered standard of care for DKD, but it may be reasonable for clinicians to consider addition of PTX in patients whose disease continues to progress despite optimization of current standard-of-care therapies.

Safety of Liraglutide in Type 2 Diabetes and Chronic Kidney Disease

Mann, Johannes F.E. — Wed, 04 Mar 2020 07:23:06 GMT-08:00

Liraglutide for the Treatment of Type 2 Diabetes and Safety in Diabetic Kidney Disease

Cherney, David Z. — Wed, 04 Mar 2020 07:23:05 GMT-08:00

Glomerular Diseases in Patients with Diabetes Mellitus: An Underappreciated Epidemic

Freeman, Natasha S. — Thu, 06 Feb 2020 10:35:00 GMT-08:00

Carbamylated Lipoproteins and Progression of Diabetic Kidney Disease

Tan, Kathryn C.B. — Wed, 19 Feb 2020 08:33:16 GMT-08:00

Hypothesis as to How a Common Missense Mutation in COL4A3 May Confer Protection against Diabetic Kidney Disease

Pieri, Myrtani — Mon, 27 Jan 2020 06:13:17 GMT-08:00

Prolyl Hydroxylase Domain Inhibitor Protects against Metabolic Disorders and Associated Kidney Disease in Obese Type 2 Diabetic Mice

Sugahara, Mai — Wed, 29 Jan 2020 07:28:59 GMT-08:00

Sodium Bicarbonate Supplementation and Urinary TGF-β1 in Nonacidotic Diabetic Kidney Disease

Raphael, Kalani L. — Thu, 23 Jan 2020 07:59:43 GMT-08:00

Sodium Glucose Cotransporter 2 Inhibition Heralds a Call-to-Action for Diabetic Kidney Disease

Tuttle, Katherine R. — Mon, 18 Nov 2019 08:35:30 GMT-08:00

Whole-Genome Sequencing of Finnish Type 1 Diabetic Siblings Discordant for Kidney Disease Reveals DNA Variants associated with Diabetic Nephropathy

Guo, Jing — Thu, 09 Jan 2020 10:35:16 GMT-08:00

Identification of Acer2 as a First Susceptibility Gene for Lithium-Induced Nephrogenic Diabetes Insipidus in Mice

de Groot, Theun — Thu, 26 Sep 2019 05:53:58 GMT-07:00

Effects of Selonsertib in Patients with Diabetic Kidney Disease

Chertow, Glenn M. — Tue, 10 Sep 2019 06:48:08 GMT-07:00

Computational Segmentation and Classification of Diabetic Glomerulosclerosis

Ginley, Brandon — Thu, 05 Sep 2019 06:03:14 GMT-07:00

Genome-Wide Association Study of Diabetic Kidney Disease Highlights Biology Involved in Glomerular Basement Membrane Collagen

Salem, Rany M. — Thu, 19 Sep 2019 10:26:09 GMT-07:00

Biologic Underpinnings of Type 1 Diabetic Kidney Disease

Sedor, John R. — Thu, 19 Sep 2019 10:26:08 GMT-07:00

Efficacy and Safety of Esaxerenone (CS-3150) for the Treatment of Type 2 Diabetes with Microalbuminuria

Ito, Sadayoshi — Thu, 27 Jun 2019 06:22:24 GMT-07:00

Hypoglycemia in People with Type 2 Diabetes and CKD

Ahmad, Iram — Wed, 17 Apr 2019 05:03:09 GMT-07:00

Early Glomerular Hyperfiltration and Long-Term Kidney Outcomes in Type 1 Diabetes

Molitch, Mark E. — Thu, 23 May 2019 08:24:32 GMT-07:00

Proximal Tubule Autophagy Differs in Type 1 and 2 Diabetes

Sakai, Shinsuke — Tue, 30 Apr 2019 09:11:01 GMT-07:00

Changes in Albuminuria But Not GFR are Associated with Early Changes in Kidney Structure in Type 2 Diabetes

Looker, Helen C. — Fri, 31 May 2019 10:00:30 GMT-07:00

Protein O-GlcNAcylation Is Essential for the Maintenance of Renal Energy Homeostasis and Function via Lipolysis during Fasting and Diabetes

Sugahara, Sho — Wed, 01 May 2019 12:15:13 GMT-07:00

Inhibition of Sodium Glucose Cotransporter 2 Attenuates the Dysregulation of Kelch-Like 3 and NaCl Cotransporter in Obese Diabetic Mice

Ishizawa, Kenichi — Tue, 26 Mar 2019 06:34:53 GMT-07:00

Efficacy and Safety of Imarikiren in Patients with Type 2 Diabetes and Microalbuminuria

Ito, Sadayoshi — Tue, 12 Feb 2019 07:06:19 GMT-08:00

COL4A3 Gene Variants and Diabetic Kidney Disease in MODY

Wang, Yiting — Mon, 16 Jul 2018 07:44:52 GMT-07:00

Race in America

Tuttle, Katherine R. — Thu, 24 May 2018 06:17:07 GMT-07:00

Incidence and Progression of Chronic Kidney Disease in Black and White Individuals with Type 2 Diabetes

Gerber, Claire — Thu, 24 May 2018 06:17:08 GMT-07:00

Add-On Antihypertensive Medications to Angiotensin-Aldosterone System Blockers in Diabetes

Schroeder, Emily B. — Fri, 23 Mar 2018 05:56:14 GMT-07:00

Facility-Level Variations in Kidney Disease Care among Veterans with Diabetes and CKD

Navaneethan, Sankar D. — Thu, 29 Nov 2018 07:49:44 GMT-08:00

Kidney Biomarkers and Decline in eGFR in Patients with Type 2 Diabetes

Garlo, Katherine G. — Tue, 16 Jan 2018 06:07:31 GMT-08:00

Soluble Urokinase Plasminogen Activator Receptor and Outcomes in Patients with Diabetes on Hemodialysis

Drechsler, Christiane — Thu, 11 May 2017 07:12:37 GMT-07:00

SGLT2 Inhibition in the Diabetic Kidney—From Mechanisms to Clinical Outcome

van Bommel, Erik J.M. — Thu, 02 Mar 2017 09:14:16 GMT-08:00

Diabetic kidney disease not only has become the leading cause for ESRD worldwide but also, highly contributes to increased cardiovascular morbidity and mortality in type 2 diabetes. Despite increased efforts to optimize renal and cardiovascular risk factors, like hyperglycemia, hypertension, obesity, and dyslipidemia, they are often insufficiently controlled in clinical practice. Although current drug interventions mostly target a single risk factor, more substantial improvements of renal and cardiovascular outcomes can be expected when multiple factors are improved simultaneously. Sodium-glucose cotransporter type 2 in the renal proximal tubule reabsorbs approximately 90% of filtered glucose. In type 2 diabetes, the maladaptive upregulation of sodium-glucose cotransporter type 2 contributes to the maintenance of hyperglycemia. Inhibiting these transporters has been shown to effectively improve glycemic control through inducing glycosuria and is generally well tolerated, although patients experience more genital infections. In addition, sodium-glucose cotransporter type 2 inhibitors favorably affect body weight, BP, serum uric acid, and glomerular hyperfiltration. Interestingly, in the recently reported first cardiovascular safety trial with a sodium-glucose cotransporter type 2 inhibitor, empagliflozin improved both renal and cardiovascular outcomes in patients with type 2 diabetes and established cardiovascular disease. Because the benefits were seen rapidly after initiation of therapy and other glucose-lowering agents, with the exception of liraglutide and semaglutide, have not been able to improve cardiovascular outcome, these observations are most likely explained by effects beyond glucose lowering. In this mini review, we present the drug class of sodium-glucose cotransporter type 2 inhibitors, elaborate on currently available renal and cardiovascular outcome data, and discuss how the effects of these agents on renal physiology may explain the data.

Temporal Trends in the Epidemiology of Biopsy-Proven Glomerular Diseases: An Alarming Increase in Diabetic Glomerulosclerosis

Hou, Jean — Tue, 21 Mar 2017 08:44:16 GMT-07:00

Diabetes and CKD in the United States Population, 2009–2014

Zelnick, Leila R. — Fri, 20 Oct 2017 05:52:27 GMT-07:00

Burden of Proof—When Is Kidney Disease Attributable to Diabetes?

Saulnier, Pierre-Jean — Fri, 20 Oct 2017 05:52:28 GMT-07:00

Rates of Cardiac Rhythm Abnormalities in Patients with CKD and Diabetes

Akoum, Nazem — Tue, 19 Mar 2019 06:55:45 GMT-07:00

LRG1 Promotes Diabetic Kidney Disease Progression by Enhancing TGF-β–Induced Angiogenesis

Hong, Quan — Mon, 11 Mar 2019 07:58:43 GMT-07:00

Single-Cell RNA Profiling of Glomerular Cells Shows Dynamic Changes in Experimental Diabetic Kidney Disease

Fu, Jia — Thu, 07 Mar 2019 07:45:22 GMT-08:00

The Other Glucose Transporter, SGLT1 – Also a Potential Trouble Maker in Diabetes?

Carlström, Mattias — Wed, 13 Mar 2019 08:05:05 GMT-07:00

FXR/TGR5 Dual Agonist Prevents Progression of Nephropathy in Diabetes and Obesity

Wang, Xiaoxin X. — Tue, 31 Oct 2017 07:51:28 GMT-07:00

Bile acids are ligands for the nuclear hormone receptor farnesoid X receptor (FXR) and the G protein–coupled receptor TGR5. We have shown that FXR and TGR5 have renoprotective roles in diabetes- and obesity-related kidney disease. Here, we determined whether these effects are mediated through differential or synergistic signaling pathways. We administered the FXR/TGR5 dual agonist INT-767 to DBA/2J mice with streptozotocin-induced diabetes, db/db mice with type 2 diabetes, and C57BL/6J mice with high-fat diet-induced obesity. We also examined the individual effects of the selective FXR agonist obeticholic acid (OCA) and the TGR5 agonist INT-777 in diabetic mice. The FXR agonist OCA and the TGR5 agonist INT-777 modulated distinct renal signaling pathways involved in the pathogenesis and treatment of diabetic nephropathy. Treatment of diabetic DBA/2J and db/db mice with the dual FXR/TGR5 agonist INT-767 improved proteinuria and prevented podocyte injury, mesangial expansion, and tubulointerstitial fibrosis. INT-767 exerted coordinated effects on multiple pathways, including stimulation of a signaling cascade involving AMP-activated protein kinase, sirtuin 1, PGC-1α, sirtuin 3, estrogen-related receptor-α, and Nrf-1; inhibition of endoplasmic reticulum stress; and inhibition of enhanced renal fatty acid and cholesterol metabolism. Additionally, in mice with diet-induced obesity, INT-767 prevented mitochondrial dysfunction and oxidative stress determined by fluorescence lifetime imaging of NADH and kidney fibrosis determined by second harmonic imaging microscopy. These results identify the renal signaling pathways regulated by FXR and TGR5, which may be promising targets for the treatment of nephropathy in diabetes and obesity.

Empagliflozin and Kidney Function Decline in Patients with Type 2 Diabetes: A Slope Analysis from the EMPA-REG OUTCOME Trial

Wanner, Christoph — Fri, 12 Oct 2018 07:42:18 GMT-07:00

Platelet Microparticles Mediate Glomerular Endothelial Injury in Early Diabetic Nephropathy

Zhang, Yang — Fri, 19 Oct 2018 08:18:18 GMT-07:00

Genetic Contribution to Risk for Diabetic Kidney Disease

Rich, Stephen S. — Mon, 16 Jul 2018 07:44:51 GMT-07:00

Effects of Diabetes Medications Targeting the Incretin System on the Kidney

MacIsaac, Richard J. — Wed, 10 Jan 2018 06:47:57 GMT-08:00

The Absence of the ACE N-Domain Decreases Renal Inflammation and Facilitates Sodium Excretion during Diabetic Kidney Disease

Eriguchi, Masahiro — Wed, 05 Sep 2018 07:37:46 GMT-07:00

A NOX4/TRPC6 Pathway in Podocyte Calcium Regulation and Renal Damage in Diabetic Kidney Disease

Ilatovskaya, Daria V. — Wed, 23 May 2018 06:48:21 GMT-07:00

Background Loss of glomerular podocytes is an indicator of diabetic kidney disease (DKD). The damage to these cells has been attributed in part to elevated intrarenal oxidative stress. The primary source of the renal reactive oxygen species, particularly H2O2, is NADPH oxidase 4 (NOX4). We hypothesized that NOX4-derived H2O2 contributes to podocyte damage in DKD via elevation of podocyte calcium. Methods We used Dahl salt-sensitive (SS) rats with a null mutation for the Nox4 gene (SSNox4−/−) and mice with knockout of the nonselective calcium channel TRPC6 or double knockout of TRPC5 and TRPC6. We performed whole animal studies and used biosensor measurements, electron microscopy, electrophysiology, and live calcium imaging experiments to evaluate the contribution of this pathway to the physiology of the podocytes in freshly isolated glomeruli. Results Upon induction of type 1 diabetes with streptozotocin, SSNox4−/− rats exhibited significantly lower basal intracellular Ca2+ levels in podocytes and less DKD-associated damage than SS rats did. Furthermore, the angiotensin II–elicited calcium flux was blunted in glomeruli isolated from diabetic SSNox4−/− rats compared with that in glomeruli from diabetic SS rats. H2O2 stimulated TRPC-dependent calcium influx in podocytes from wild-type mice, but this influx was blunted in podocytes from Trpc6-knockout mice and, in a similar manner, in podocytes from Trpc5/6 double-knockout mice. Finally, electron microscopy revealed that podocytes of glomeruli isolated from Trpc6-knockout or Trpc5/6 double-knockout mice were protected from damage induced by H2O2 to the same extent. Conclusions These data reveal a novel signaling mechanism involving NOX4 and TRPC6 in podocytes that could be pharmacologically targeted to abate the development of DKD.

Protein S Protects against Podocyte Injury in Diabetic Nephropathy

Zhong, Fang — Tue, 06 Mar 2018 06:04:32 GMT-08:00

Background Diabetic nephropathy (DN) is a leading cause of ESRD in the United States, but the molecular mechanisms mediating the early stages of DN are unclear. Methods To assess global changes that occur in early diabetic kidneys and to identify proteins potentially involved in pathogenic pathways in DN progression, we performed proteomic analysis of diabetic and nondiabetic rat glomeruli. Protein S (PS) among the highly upregulated proteins in the diabetic glomeruli. PS exerts multiple biologic effects through the Tyro3, Axl, and Mer (TAM) receptors. Because increased activation of Axl by the PS homolog Gas6 has been implicated in DN progression, we further examined the role of PS in DN. Results In human kidneys, glomerular PS expression was elevated in early DN but suppressed in advanced DN. However, plasma PS concentrations did not differ between patients with DN and healthy controls. A prominent increase of PS expression also colocalized with the expression of podocyte markers in early diabetic kidneys. In cultured podocytes, high-glucose treatment elevated PS expression, and PS knockdown further enhanced the high-glucose–induced apoptosis. Conversely, PS overexpression in cultured podocytes dampened the high-glucose– and TNF-α–induced expression of proinflammatory mediators. Tyro3 receptor was upregulated in response to high glucose and mediated the anti-inflammatory response of PS. Podocyte-specific PS loss resulted in accelerated DN in streptozotocin-induced diabetic mice, whereas the transient induction of PS expression in glomerular cells in vivo attenuated albuminuria and podocyte loss in diabetic OVE26 mice. Conclusions Our results support a protective role of PS against glomerular injury in DN progression.

Lipoxins Regulate the Early Growth Response–1 Network and Reverse Diabetic Kidney Disease

Brennan, Eoin P. — Wed, 28 Feb 2018 07:19:10 GMT-08:00

Background The failure of spontaneous resolution underlies chronic inflammatory conditions, including microvascular complications of diabetes such as diabetic kidney disease. The identification of endogenously generated molecules that promote the physiologic resolution of inflammation suggests that these bioactions may have therapeutic potential in the context of chronic inflammation. Lipoxins (LXs) are lipid mediators that promote the resolution of inflammation. Methods We investigated the potential of LXA4 and a synthetic LX analog (Benzo-LXA4) as therapeutics in a murine model of diabetic kidney disease, ApoE−/− mice treated with streptozotocin. Results Intraperitoneal injection of LXs attenuated the development of diabetes-induced albuminuria, mesangial expansion, and collagen deposition. Notably, LXs administered 10 weeks after disease onset also attenuated established kidney disease, with evidence of preserved kidney function. Kidney transcriptome profiling defined a diabetic signature (725 genes; false discovery rate P≤0.05). Comparison of this murine gene signature with that of human diabetic kidney disease identified shared renal proinflammatory/profibrotic signals (TNF-α, IL-1β, NF-κB). In diabetic mice, we identified 20 and 51 transcripts regulated by LXA4 and Benzo-LXA4, respectively, and pathway analysis identified established (TGF-β1, PDGF, TNF-α, NF-κB) and novel (early growth response–1 [EGR-1]) networks activated in diabetes and regulated by LXs. In cultured human renal epithelial cells, treatment with LXs attenuated TNF-α–driven Egr-1 activation, and Egr-1 depletion prevented cellular responses to TGF-β1 and TNF-α. Conclusions These data demonstrate that LXs can reverse established diabetic complications and support a therapeutic paradigm to promote the resolution of inflammation.

Biomarkers Associated with Progression of Diabetic Kidney Disease: Do They Hold the Same Meaning for Blacks and Women?

Hickson, LaTonya J. — Fri, 20 Apr 2018 07:37:29 GMT-07:00

Depletion of Gprc5a Promotes Development of Diabetic Nephropathy

Ma, Xiaojie — Tue, 10 Apr 2018 08:02:07 GMT-07:00

Background Renal glomeruli are the primary target of injury in diabetic nephropathy (DN), and the glomerular podocyte has a key role in disease progression. Methods To identify potential novel therapeutic targets for DN, we performed high-throughput molecular profiling of G protein–coupled receptors (GPCRs) using human glomeruli. Results We identified an orphan GPCR, Gprc5a, as a highly podocyte-specific gene, the expression of which was significantly downregulated in glomeruli of patients with DN compared with those without DN. Inactivation of Gprc5a in mice resulted in thickening of the glomerular basement membrane and activation of mesangial cells, which are two hallmark features of DN in humans. Compared with wild-type mice, Gprc5a-deficient animals demonstrated increased albuminuria and more severe histologic changes after induction of diabetes with streptozotocin. Mechanistically, Gprc5a modulated TGF-β signaling and activation of the EGF receptor in cultured podocytes. Conclusions Gprc5a has an important role in the pathogenesis of DN, and further study of the podocyte-specific signaling activity of this protein is warranted.

Progressive Renal Disease Established by Renin-Coding Adeno-Associated Virus–Driven Hypertension in Diverse Diabetic Models

Harlan, Shannon M. — Mon, 23 Oct 2017 06:02:12 GMT-07:00

Progress in research and developing therapeutics to prevent diabetic kidney disease (DKD) is limited by a lack of animal models exhibiting progressive kidney disease. Chronic hypertension, a driving factor of disease progression in human patients, is lacking in most available models of diabetes. We hypothesized that superimposition of hypertension on diabetic mouse models would accelerate DKD. To test this possibility, we induced persistent hypertension in three mouse models of type 1 diabetes and two models of type 2 diabetes by adeno-associated virus delivery of renin (ReninAAV). Compared with LacZAAV-treated counterparts, ReninAAV-treated type 1 diabetic Akita/129 mice exhibited a substantial increase in albumin-to-creatinine ratio (ACR) and serum creatinine level and more severe renal lesions. In type 2 models of diabetes (C57BKLS db/db and BTBR ob/ob mice), compared with LacZAAV, ReninAAV induced significant elevations in ACR and increased the incidence and severity of histopathologic findings, with increased serum creatinine detected only in the ReninAAV-treated db/db mice. The uninephrectomized ReninAAV db/db model was the most progressive model examined and further characterized. In this model, separate treatment of hyperglycemia with rosiglitazone or hypertension with lisinopril partially reduced ACR, consistent with independent contributions of these disorders to renal disease. Microarray analysis and comparison with human DKD showed common pathways affected in human disease and this model. These results identify novel models of progressive DKD that provide researchers with a facile and reliable method to study disease pathogenesis and support the development of therapeutics.

Segmental Sclerosis and Extracapillary Hypercellularity Predict Diabetic ESRD

Mottl, Amy K. — Mon, 27 Nov 2017 06:42:39 GMT-08:00

Pathogenetic markers of diabetic kidney disease (DKD) progression to ESRD are lacking. We characterized the prognostic value of histologic findings in DKD for time to ESRD in native kidney specimens from biopsies performed from 1995 to 2011 with diabetic glomerulosclerosis as the only glomerular disease diagnosis (n=109). Biopsy specimens were analyzed according to standard methods, including determination of diabetic nephropathy class, as defined by the Renal Pathology Society. Clinical data were extracted from electronic medical records. We used competing risk models, with death as the competing risk, to estimate subdistribution hazard ratios (HRs) for ESRD. All multivariable models included age, sex, black race, baseline eGFR, and baseline proteinuria. Pathologic characteristics achieving P<0.1 were added into successively complex models. ESRD occurred in 56% of patients, and 26% of patients died before reaching ESRD. In univariate analyses, diabetic nephropathy class was not statistically significant in predicting time to ESRD. The final multivariable model (n=106) showed a borderline association between mild mesangial expansion and decreased risk for ESRD (subdistribution HR, 0.64; 95% confidence interval, 0.40 to 1.00). Poor prognostic factors in the final model included segmental sclerosis and extracapillary hypercellularity (subdistribution HR, 2.04; 95% confidence interval, 1.36 to 3.05; and subdistribution HR, 2.21; 95% confidence interval, 1.19 to 4.11, respectively). In conclusion, we identified segmental sclerosis and extracapillary hypercellularity as novel, poor prognostic indicators of time from DKD to ESRD. Whether these indicators represent a distinct pathogenetic phenotype of DKD will require a large study with a broad spectrum of disease severity.

Modulation of Renal GLUT2 by the Cannabinoid-1 Receptor: Implications for the Treatment of Diabetic Nephropathy

Hinden, Liad — Fri, 13 Oct 2017 06:12:18 GMT-07:00

Altered glucose reabsorption via the facilitative glucose transporter 2 (GLUT2) during diabetes may lead to renal proximal tubule cell (RPTC) injury, inflammation, and interstitial fibrosis. These pathologies are also triggered by activating the cannabinoid-1 receptor (CB1R), which contributes to the development of diabetic nephropathy (DN). However, the link between CB1R and GLUT2 remains to be determined. Here, we show that chronic peripheral CB1R blockade or genetically inactivating CB1Rs in the RPTCs ameliorated diabetes-induced renal structural and functional changes, kidney inflammation, and tubulointerstitial fibrosis in mice. Inhibition of CB1R also downregulated GLUT2 expression, affected the dynamic translocation of GLUT2 to the brush border membrane of RPTCs, and reduced glucose reabsorption. Thus, targeting peripheral CB1R or inhibiting GLUT2 dynamics in RPTCs has the potential to treat and ameliorate DN. These findings may support the rationale for the clinical testing of peripherally restricted CB1R antagonists or the development of novel renal-specific GLUT2 inhibitors against DN.

The Adiponectin Receptor Agonist AdipoRon Ameliorates Diabetic Nephropathy in a Model of Type 2 Diabetes

Kim, Yaeni — Fri, 12 Jan 2018 07:47:04 GMT-08:00

Adiponectin exerts renoprotective effects against diabetic nephropathy (DN) by activating the AMP-activated protein kinase (AMPK)/peroxisome proliferative-activated receptor–α (PPARα) pathway through adiponectin receptors (AdipoRs). AdipoRon is an orally active synthetic adiponectin receptor agonist. We investigated the expression of AdipoRs and the associated intracellular pathways in 27 patients with type 2 diabetes and examined the effects of AdipoRon on DN development in male C57BLKS/J db/db mice, glomerular endothelial cells (GECs), and podocytes. The extent of glomerulosclerosis and tubulointerstitial fibrosis correlated with renal function deterioration in human kidneys. Expression of AdipoR1, AdipoR2, and Ca2+/calmodulin-dependent protein kinase kinase–β (CaMKKβ) and numbers of phosphorylated liver kinase B1 (LKB1)– and AMPK-positive cells significantly decreased in the glomeruli of early stage human DN. AdipoRon treatment restored diabetes-induced renal alterations in db/db mice. AdipoRon exerted renoprotective effects by directly activating intrarenal AdipoR1 and AdipoR2, which increased CaMKKβ, phosphorylated Ser431LKB1, phosphorylated Thr172AMPK, and PPARα expression independently of the systemic effects of adiponectin. AdipoRon-induced improvement in diabetes-induced oxidative stress and inhibition of apoptosis in the kidneys ameliorated relevant intracellular pathways associated with lipid accumulation and endothelial dysfunction. In high-glucose–treated human GECs and murine podocytes, AdipoRon increased intracellular Ca2+ levels that activated a CaMKKβ/phosphorylated Ser431LKB1/phosphorylated Thr172AMPK/PPARα pathway and downstream signaling, thus decreasing high-glucose–induced oxidative stress and apoptosis and improving endothelial dysfunction. AdipoRon further produced cardioprotective effects through the same pathway demonstrated in the kidney. Our results show that AdipoRon ameliorates GEC and podocyte injury by activating the intracellular Ca2+/LKB1-AMPK/PPARα pathway, suggesting its efficacy for treating type 2 diabetes–associated DN.

Diabetic Kidney Disease

Tong, Lili — Wed, 18 Oct 2017 06:20:27 GMT-07:00

Diabetic Kidney Disease

Alicic, Radica Z. — Thu, 18 May 2017 11:07:35 GMT-07:00

Diabetic kidney disease develops in approximately 40% of patients who are diabetic and is the leading cause of CKD worldwide. Although ESRD may be the most recognizable consequence of diabetic kidney disease, the majority of patients actually die from cardiovascular diseases and infections before needing kidney replacement therapy. The natural history of diabetic kidney disease includes glomerular hyperfiltration, progressive albuminuria, declining GFR, and ultimately, ESRD. Metabolic changes associated with diabetes lead to glomerular hypertrophy, glomerulosclerosis, and tubulointerstitial inflammation and fibrosis. Despite current therapies, there is large residual risk of diabetic kidney disease onset and progression. Therefore, widespread innovation is urgently needed to improve health outcomes for patients with diabetic kidney disease. Achieving this goal will require characterization of new biomarkers, designing clinical trials that evaluate clinically pertinent end points, and development of therapeutic agents targeting kidney-specific disease mechanisms (e.g., glomerular hyperfiltration, inflammation, and fibrosis). Additionally, greater attention to dissemination and implementation of best practices is needed in both clinical and community settings.Introduction

Variations in MicroRNA-25 Expression Influence the Severity of Diabetic Kidney Disease

Liu, Yunshuang — Mon, 18 Sep 2017 09:48:20 GMT-07:00

Diabetic nephropathy is characterized by persistent albuminuria, progressive decline in GFR, and secondary hypertension. MicroRNAs are dysregulated in diabetic nephropathy, but identification of the specific microRNAs involved remains incomplete. Here, we show that the peripheral blood from patients with diabetes and the kidneys of animals with type 1 or 2 diabetes have low levels of microRNA-25 (miR-25) compared with those of their nondiabetic counterparts. Furthermore, treatment with high glucose decreased the expression of miR-25 in cultured kidney cells. In db/db mice, systemic administration of an miR-25 agomir repressed glomerular fibrosis and reduced high BP. Notably, knockdown of miR-25 in normal mice by systemic administration of an miR-25 antagomir resulted in increased proteinuria, extracellular matrix accumulation, podocyte foot process effacement, and hypertension with renin-angiotensin system activation. However, excessive miR-25 did not cause kidney dysfunction in wild-type mice. RNA sequencing showed the alteration of miR-25 target genes in antagomir-treated mice, including the Ras-related gene CDC42. In vitro, cotransfection with the miR-25 antagomir repressed luciferase activity from a reporter construct containing the CDC42 3′ untranslated region. In conclusion, these results reveal a role for miR-25 in diabetic nephropathy and indicate a potential novel therapeutic target for this disease.

Farnesoid X Receptor Agonism Protects against Diabetic Tubulopathy: Potential Add-On Therapy for Diabetic Nephropathy

Marquardt, Andi — Mon, 10 Jul 2017 11:39:50 GMT-07:00

Established therapies for diabetic nephropathy (dNP) delay but do not prevent its progression. The shortage of established therapies may reflect the inability to target the tubular compartment. The chemical chaperone tauroursodeoxycholic acid (TUDCA) ameliorates maladaptive endoplasmic reticulum (ER) stress signaling and experimental dNP. Additionally, TUDCA activates the farnesoid X receptor (FXR), which is highly expressed in tubular cells. We hypothesized that TUDCA ameliorates maladaptive ER signaling via FXR agonism specifically in tubular cells. Indeed, TUDCA induced expression of FXR-dependent genes (SOCS3 and DDAH1) in tubular cells but not in other renal cells. In vivo, TUDCA reduced glomerular and tubular injury in db/db and diabetic endothelial nitric oxide synthase–deficient mice. FXR inhibition with Z-guggulsterone or vivo-morpholino targeting of FXR diminished the ER-stabilizing and renoprotective effects of TUDCA. Notably, these in vivo approaches abolished tubular but not glomerular protection by TUDCA. Combined intervention with TUDCA and the angiotensin-converting enzyme inhibitor enalapril in 16-week-old db/db mice reduced albuminuria more efficiently than did either treatment alone. Although both therapies reduced glomerular damage, only TUDCA ameliorated tubular damage. Thus, interventions that specifically protect the tubular compartment in dNP, such as FXR agonism, may provide renoprotective effects on top of those achieved by inhibiting angiotensin-converting enzyme.

Lysophosphatidic Acid Receptor Antagonism Protects against Diabetic Nephropathy in a Type 2 Diabetic Model

Zhang, Ming-Zhi — Mon, 24 Jul 2017 06:14:25 GMT-07:00

Lysophosphatidic acid (LPA) functions through activation of LPA receptors (LPARs). LPA–LPAR signaling has been implicated in development of fibrosis. However, the role of LPA–LPAR signaling in development of diabetic nephropathy (DN) has not been studied. We examined whether BMS002, a novel dual LPAR1 and LPAR3 antagonist, affects development of DN in endothelial nitric oxide synthase-knockout db/db mice. Treatment of these mice with BMS002 from 8 to 20 weeks of age led to a significant reduction in albuminuria, similar to that observed with renin-angiotensin system inhibition (losartan plus enalapril). LPAR inhibition also prevented the decline in GFR observed in vehicle-treated mice, such that GFR at week 20 differed significantly between vehicle and LPAR inhibitor groups (P<0.05). LPAR inhibition also reduced histologic glomerular injury; decreased the expression of profibrotic and fibrotic components, including fibronectin, α-smooth muscle actin, connective tissue growth factor, collagen I, and TGF-β; and reduced renal macrophage infiltration and oxidative stress. Notably, LPAR inhibition slowed podocyte loss (podocytes per glomerulus ±SEM at 8 weeks: 667±40, n=4; at 20 weeks: 364±18 with vehicle, n=7, and 536±12 with LPAR inhibition, n=7; P<0.001 versus vehicle). Finally, LPAR inhibition minimized the production of 4-hydroxynonenal (4-HNE), a marker of oxidative stress, in podocytes and increased the phosphorylation of AKT2, an indicator of AKT2 activity, in kidneys. Thus, the LPAR antagonist BMS002 protects against GFR decline and attenuates development of DN through multiple mechanisms. LPAR antagonism might provide complementary beneficial effects to renin-angiotensin system inhibition to slow progression of DN.

Diagnosis and Management of Type 2 Diabetic Kidney Disease

Doshi, Simit M. — Thu, 09 Mar 2017 06:04:22 GMT-08:00

Type 2 diabetic kidney disease (DKD) is the most common cause of CKD and ESRD worldwide, and carries with it enormous human and societal costs. The goal of this review is to provide an update on the diagnosis and management of DKD based on a comprehensive review of the medical literature. Topics addressed include the evolving presentation of DKD, clinical differentiation of DKD from non-DKD, a state-of-the-art evaluation of current treatment strategies, and promising emerging treatments. It is expected that the review will help clinicians to diagnose and manage patients with DKD.

Plasma Biomarkers and Kidney Function Decline in Early and Established Diabetic Kidney Disease

Coca, Steven G. — Fri, 05 May 2017 06:28:24 GMT-07:00

Biomarkers of diverse pathophysiologic mechanisms may improve risk stratification for incident or progressive diabetic kidney disease (DKD) in persons with type 2 diabetes. To evaluate such biomarkers, we performed a nested case-control study (n=190 cases of incident DKD and 190 matched controls) and a prospective cohort study (n=1156) using banked baseline plasma samples from participants of randomized, controlled trials of early (ACCORD) and advanced (VA NEPHRON-D) DKD. We assessed the association and discrimination obtained with baseline levels of plasma TNF receptor–1 (TNFR-1), TNFR-2, and kidney injury molecule–1 (KIM-1) for the outcomes of incident DKD (ACCORD) and progressive DKD (VA-NEPHRON-D). At baseline, median concentrations of TNFR-1, TNFR-2, and KIM-1 were roughly two-fold higher in the advanced DKD population (NEPHRON-D) than in the early DKD population (ACCORD). In both cohorts, patients who reached the renal outcome had higher baseline levels than those who did not reach the outcome. Associations between doubling in TNFR-1, TNFR-2, and KIM-1 levels and risk of the renal outcomes were significant for both cohorts. Inclusion of these biomarkers in clinical models increased the area under the curve (SEM) for predicting the renal outcome from 0.68 (0.02) to 0.75 (0.02) in NEPHRON-D. Systematic review of the literature illustrated high consistency in the association between these biomarkers of inflammation and renal outcomes in DKD. In conclusion, TNFR-1, TNFR-2, and KIM-1 independently associated with higher risk of eGFR decline in persons with early or advanced DKD. Moreover, addition of these biomarkers to clinical prognostic models significantly improved discrimination for the renal outcome.

Therapeutic Considerations for Antihyperglycemic Agents in Diabetic Kidney Disease

Neumiller, Joshua J. — Tue, 02 May 2017 07:10:33 GMT-07:00

Diabetic kidney disease is among the most frequent complications of diabetes, with approximately 50% of patients with ESRD attributed to diabetes in developed countries. Although intensive glycemic management has been shown to delay the onset and progression of increased urinary albumin excretion and reduced GFR in patients with diabetes, conservative dose selection and adjustment of antihyperglycemic medications are necessary to balance glycemic control with safety. A growing body of literature is providing valuable insight into the cardiovascular and renal safety and efficacy of newer antihyperglycemic medications in the dipeptidyl peptidase-4 inhibitor, glucagon-like peptide-1 receptor agonist, and sodium-glucose cotransporter 2 inhibitor classes of medications. Ongoing studies will continue to inform future use of these agents in patients with diabetic kidney disease.

Survival Benefit of Transplantation with a Deceased Diabetic Donor Kidney Compared with Remaining on the Waitlist

Cohen, Jordana B. — Thu, 25 May 2017 07:13:48 GMT-07:00

Glomerular Hyperfiltration in Diabetes: Mechanisms, Clinical Significance, and Treatment

Tonneijck, Lennart — Tue, 31 Jan 2017 05:27:40 GMT-08:00

An absolute, supraphysiologic elevation in GFR is observed early in the natural history in 10%–67% and 6%–73% of patients with type 1 and type 2 diabetes, respectively. Moreover, at the single-nephron level, diabetes-related renal hemodynamic alterations—as an adaptation to reduction in functional nephron mass and/or in response to prevailing metabolic and (neuro)hormonal stimuli—increase glomerular hydraulic pressure and transcapillary convective flux of ultrafiltrate and macromolecules. This phenomenon, known as glomerular hyperfiltration, classically has been hypothesized to predispose to irreversible nephron damage, thereby contributing to initiation and progression of kidney disease in diabetes. However, dedicated studies with appropriate diagnostic measures and clinically relevant end points are warranted to confirm this assumption. In this review, we summarize the hitherto proposed mechanisms involved in diabetic hyperfiltration, focusing on ultrastructural, vascular, and tubular factors. Furthermore, we review available evidence on the clinical significance of hyperfiltration in diabetes and discuss currently available and emerging interventions that may attenuate this renal hemodynamic abnormality. The revived interest in glomerular hyperfiltration as a prognostic and pathophysiologic factor in diabetes may lead to improved and timely detection of (progressive) kidney disease, and could provide new therapeutic opportunities in alleviating the renal burden in this population.

Insights into Diabetic Kidney Disease Using Urinary Proteomics and Bioinformatics

Van, Julie A.D. — Fri, 03 Feb 2017 08:05:16 GMT-08:00

A number of proteomic and peptidomic analyses of urine from diabetic subjects have been published in the quest for a biomarker that predicts progression of nephropathy. Less attention has been paid to the relationships between urinary proteins and the underlying biological processes revealed by the analyses. In this review, we focus on the biological processes identified by studying urinary proteins and protein-protein interactions at each stage of diabetic nephropathy to provide an overview of the events underlying progression of kidney disease reflected in the urine. In uncomplicated diabetes, proteomic/peptidomic analyses indicate that early activation of fibrotic pathways in the kidney occurs before the onset of microalbuminuria. In incipient nephropathy, when albumin excretion rates are abnormal, proteomic/peptidomic analyses suggest that changes in glomerular permselectivity and tubular reabsorption account, at least in part, for the proteins and peptides that appear in the urine. Finally, overt nephropathy is characterized by proteins involved in wound healing, ongoing fibrosis, and inflammation. These findings suggest that there is a spectrum of biological processes in the diabetic kidney and that assessing protein networks may be more informative than individual markers with respect to the stage of disease and the risk of progression.

Anti–TGF-β1 Antibody Therapy in Patients with Diabetic Nephropathy

Voelker, James — Mon, 19 Sep 2016 10:04:57 GMT-07:00

TGF-β has been implicated as a major pathogenic factor in diabetic nephropathy. This randomized, double-blind, phase 2 study assessed whether modulating TGF-β1 activity with a TGF-β1–specific, humanized, neutralizing monoclonal antibody (TGF-β1 mAb) is safe and more effective than placebo in slowing renal function loss in patients with diabetic nephropathy on chronic stable renin-angiotensin system inhibitor treatment. We randomized 416 patients aged ≥25 years with type 1 or type 2 diabetes, a serum creatinine (SCr) level of 1.3–3.3 mg/dl for women and 1.5–3.5 mg/dl for men (or eGFR of 20–60 ml/min per 1.73 m2), and a 24-hour urine protein-to-creatinine ratio ≥800 mg/g to TGF-β1 mAb (2-, 10-, or 50-mg monthly subcutaneous dosing for 12 months) or placebo. We assessed a change in SCr from baseline to 12 months as the primary efficacy variable. Although the Data Monitoring Committee did not identify safety issues, we terminated the trial 4 months early for futility on the basis of their recommendation. The placebo group had a mean±SD change in SCr from baseline to end of treatment of 0.33±0.67 mg/dl. Least squares mean percentage change in SCr from baseline to end of treatment did not differ between placebo (14%; 95% confidence interval [95% CI], 9.7% to 18.2%) and TGF-β1 mAb treatments (20% [95% CI, 15.3% to 24.3%], 19% [95% CI, 14.2% to 23.0%], and 19% [95% CI, 14.0% to 23.3%] for 2-, 10-, and 50-mg doses, respectively). Thus, TGF-β1 mAb added to renin-angiotensin system inhibitors did not slow progression of diabetic nephropathy.

Genetics of Diabetic Kidney Disease—From the Worst of Nightmares to the Light of Dawn?

Ma, Ronald C.W. — Wed, 23 Nov 2016 09:30:59 GMT-08:00

Suppressor of Cytokine Signaling-1 Peptidomimetic Limits Progression of Diabetic Nephropathy

Recio, Carlota — Thu, 08 Sep 2016 07:50:41 GMT-07:00

Diabetes is the main cause of CKD and ESRD worldwide. Chronic activation of Janus kinase and signal transducer and activator of transcription (STAT) signaling contributes to diabetic nephropathy by inducing genes involved in leukocyte infiltration, cell proliferation, and extracellular matrix accumulation. This study examined whether a cell-permeable peptide mimicking the kinase-inhibitory region of suppressor of cytokine signaling-1 (SOCS1) regulatory protein protects against nephropathy by suppressing STAT-mediated cell responses to diabetic conditions. In a mouse model combining hyperglycemia and hypercholesterolemia (streptozotocin diabetic, apoE-deficient mice), renal STAT activation status correlated with the severity of nephropathy. Notably, compared with administration of vehicle or mutant inactive peptide, administration of the SOCS1 peptidomimetic at either early or advanced stages of diabetes ameliorated STAT activity and resulted in reduced serum creatinine level, albuminuria, and renal histologic changes (mesangial expansion, tubular injury, and fibrosis) over time. Mice treated with the SOCS1 peptidomimetic also exhibited reduced kidney leukocyte recruitment (T lymphocytes and classic M1 proinflammatory macrophages) and decreased expression levels of proinflammatory and profibrotic markers that were independent of glycemic and lipid changes. In vitro, internalized peptide suppressed STAT activation and target gene expression induced by inflammatory and hyperglycemic conditions, reduced migration and proliferation in mesangial and tubuloepithelial cells, and altered the expression of cytokine-induced macrophage polarization markers. In conclusion, our study identifies SOCS1 mimicking as a feasible therapeutic strategy to halt the onset and progression of renal inflammation and fibrosis in diabetic kidney disease.

The Genetic Landscape of Renal Complications in Type 1 Diabetes

Sandholm, Niina — Mon, 19 Sep 2016 10:04:56 GMT-07:00

Diabetes is the leading cause of ESRD. Despite evidence for a substantial heritability of diabetic kidney disease, efforts to identify genetic susceptibility variants have had limited success. We extended previous efforts in three dimensions, examining a more comprehensive set of genetic variants in larger numbers of subjects with type 1 diabetes characterized for a wider range of cross-sectional diabetic kidney disease phenotypes. In 2843 subjects, we estimated that the heritability of diabetic kidney disease was 35% (P=6.4×10−3). Genome-wide association analysis and replication in 12,540 individuals identified no single variants reaching stringent levels of significance and, despite excellent power, provided little independent confirmation of previously published associated variants. Whole-exome sequencing in 997 subjects failed to identify any large-effect coding alleles of lower frequency influencing the risk of diabetic kidney disease. However, sets of alleles increasing body mass index (P=2.2×10−5) and the risk of type 2 diabetes (P=6.1×10−4) associated with the risk of diabetic kidney disease. We also found genome-wide genetic correlation between diabetic kidney disease and failure at smoking cessation (P=1.1×10−4). Pathway analysis implicated ascorbate and aldarate metabolism (P=9.0×10−6), and pentose and glucuronate interconversions (P=3.0×10−6) in pathogenesis of diabetic kidney disease. These data provide further evidence for the role of genetic factors influencing diabetic kidney disease in those with type 1 diabetes and highlight some key pathways that may be responsible. Altogether these results reveal important biology behind the major cause of kidney disease.