Diabetes, Metabolism and The Kidney

The kidney has a key role in maintaining glucose homeostasis and is the site of action of SGLT2 inhibitors, which enhance glucose excretion to reduce plasma glucose levels. Here, Ralph DeFronzo and colleagues examine the role of the kidney in regulating glucose reabsorption and the effect of SGLT2 inhibition on renal function, glucose homeostasis, and cardiovascular disease.

Renal and vascular insulin resistance results in pathophysiological alterations including sodium retention, renal gluconeogenesis and podocyte dysfunction. Here, the authors discuss the mechanisms and effects of insulin resistance in the kidney and vasculature as well as therapeutic approaches to improve insulin sensitivity.

An increasing body of evidence points toward a role for the complement system in the pathogenesis of diabetic nephropathy. Here, Allan Flyvbjerg describes the underlying experimental and clinical evidence and discusses how the association between complement activation and diabetic nephropathy might facilitate the identification of new biomarkers of disease progression and targets for therapeutic intervention.

Nicotinamide adenine dinucleotide (NAD⁺) depletion contributes to the pathogenesis of cardiac and renal diseases. Here, the authors review the roles of NAD⁺ in the heart and kidney and discuss the mechanisms by which NAD⁺supplementation might have therapeutic efficacy, with a focus on the role of mitochondrial sirtuins.

Heparanase is an endoglycosidase that regulates numerous cell functions and is able to degrade the extracellular matrix component heparan sulfate, which has a key role in maintaining the integrity of the glomerular filtration barrier. In this Review, Rabelink and colleagues describe the biological regulation and functions of heparanase, including the role of this enzyme in the development of kidney disease.

Metabolomics has been instrumental for the identification of new biomarkers of chronic kidney disease (CKD). Here, the authors discuss metabolomics technologies and their application in renal disease, including the specificity and functional relevance of CKD-associated metabolic biomarkers.

Diabetic kidney disease is caused by microvascular damage sustained as a result of diabetes. Cooper et al. discuss current knowledge on this condition, arguing that novel strategies to halt and reverse disease progression are urgently needed.

Senescent cells, which accumulate with ageing, are also involved in organ development and disease. Here, the authors examine the beneficial and detrimental effects of chronic and acute senescent cells in kidney formation, repair, disease and ageing and how these can be therapeutically modulated.

Chronic kidney disease (CKD) is a common comorbidity in patients with type 2 diabetes mellitus (T2DM). In this Review, Paul Zimmet and colleagues discuss the changing epidemiology of T2DM and the effect of these changes on the prevalence of CKD. They indicate how the decreasing prevalence of cardiovascular disease in T2DM has resulted in an increased prevalence of CKD, outline differences in the prevalence and disease burden of T2DM and CKD in various populations worldwide, and describe the financial, societal, and clinical impact of these diseases.

Pattern recognition receptors and danger-associated molecular patterns of the innate immune system contribute to the initiation of an inflammatory response in diabetes mellitus and diabetic nephropathy. In this Review, Jun Wada and Hirofumi Makino discuss how these components of the innate immune system can lead to insulin resistance, diabetes mellitus, and renal failure and describe signalling mediators and pathways that could be targeted for treatment.

The mTOR pathway has a role in the development of renal disease, kidney transplant rejection and malignancies. Here, the authors discuss the mechanisms by which mTOR complexes drive the pathogenesis of these diseases as well as the therapeutic potential of mTOR inhibitors.

In diabetic patients undergoing maintenance haemodialysis, extremely high and low glycaemic levels are associated with increased morbidity and mortality owing to vascular and diabetic complications. The prevention of glycaemic disarrays in this population is challenging owing to factors including changes in the metabolism of glucose and drugs, malnutrition and insulin resistance. Here, the authors review the pathophysiology and management of haemodialysis-induced hypoglycaemia and hyperglycaemia in patients with diabetes.

Diabetes mellitus is often accompanied by numerous microvascular and/or macrovascular complications. Identification of risk alleles for diabetic complications could lead to improved understanding of the underlying mechanistic processes, but has so far been limited. Here, McCarthy and colleagues discuss the utility of human genetic studies in identifying novel risk variants for diabetic complications, the challenges faced in identifying robust genetic associations for diabetic kidney disease and the benefits that genome-wide association studies can offer.

Post-transplantation diabetes mellitus (PTDM) is a frequent complication among renal transplant recipients, and is associated with cardiovascular disease and reduced lifespan. In this Review, Jenssen and Hartmann discuss the diagnostic criteria for PTDM and evaluate available and emerging treatment options, highlighting the considerations that should be made when selecting an appropriate therapeutic regimen.

Albuminuria is used as a marker of kidney disease progression, but whether it has a role in the pathogenesis of kidney disease and the reasons for its association with cardiovascular disease are unclear. In this Review, Rabelink and de Zeeuw propose that degradation of the glycocalyx leads to albuminuria and that the filtered protein contributes to kidney disease pathogenesis. Furthermore, they discuss how systemic degradation of the gylcocalyx can lead to cardiovascular disease, providing an explanation for the association between these diseases and albuminuria.

A close relationship has been described between cardiometabolic disorders (CMDs) and the gut microbiota. In this Review, Judith Aron-Wisnewsky and Karine Clément outline the evidence supporting a link between the composition of the gut microbiota with cardiovascular and chronic kidney disease. They outline the methods used to study the microbiome, the effect of dietary intake patterns on microbiota composition and its derived metabolites, and possible areas for intervention to prevent or treat CMDs.

Regular physical activity is associated with reduced mortality in the general population and in patients with chronic kidney disease. Here, the authors discuss the importance of physical activity for patients with renal disease and patient-reported barriers and facilitators for physical activity.

The incidence of obesity-related glomerulopathy (ORG) — a distinct entity featuring proteinuria, glomerulomegaly, progressive glomerulosclerosis and renal functional decline — is increasing in parallel with the obesity epidemic. Here, Vivette D'Agati and colleagues review the pathology, clinical features, treatment and pathogenesis of ORG.

LncRNAs are important regulators of kidney and heart morphogenesis and contribute to the development of cardiac disease. Studies over the past 5 years have shown that lncRNAs are also involved in renal diseases such as acute kidney injury, glomerular diseases, acute allograft rejection and renal cell carcinoma. In this Review, Lorenzen and Thum describe current understanding of the function of lncRNAs in renal and cardiovascular diseases and how these non-coding RNAs might be targeted for therapeutic purposes.