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Diabetic Kidney Disease (c. 2018)

      Diabetes has become a global pandemic that rivals almost any other that has come before it. In the year 2015, 415 million people in the world were living with diabetes, and by the year 2040, that number is projected to rise to 642 million. Most of these people, 95%, have type 2 diabetes. More sobering, there is no evidence that the steadily upward trend in diabetes frequency will abate despite unequivocal evidence that type 2 diabetes is largely preventable, especially by healthy lifestyle choices. Along with diabetes, rates of diabetic complications including diabetic kidney disease (DKD) will inevitably increase. This has been clearly shown in the United States Renal Data System reports that demonstrate a progressively increasing prevalence of ESRD attributed to diabetes even while incidence rates have stabilized over the past 15 years. When greater numbers of people are alive with diabetes, incidence rates must fall in order to have a chance to stabilize or reduce DKD prevalence. Dr. Koye, Dr. Magliano, Dr. Nelson, and Dr. Pakov take us deep into the global epidemiology of diabetes and kidney disease with a call to the enormous unmet need for awareness, a first step toward problem-solving actions.
      Notably, the ESRD rates in DKD belie an unpleasant truth. Most people with DKD die without progressing to ESRD. Indeed, the ESRD population with diabetes represents a survivor cohort of just 10% of those who originally developed DKD. As a community concerned about DKD and kidney disease overall, it is imperative that we openly confront this enormous fatality risk by intentional steps to address the rates of death and ESRD. Dr. Jiang, Dr. Fine, and Dr. Mottl emphasize the importance of competing risks in studies with survival analyses given the high likelihood of death before ESRD in DKD. They demonstrate the use of methodology for analyzing survival data in the presence of the competing risks of death and ESRD, underscoring the large impact of a competing risk with high incidence, as is the case in progressive DKD.
      Diabetes per se is defined by the presence of persistent hyperglycemia, and there is no doubt that glycemic control is a pivotal determinant of complications including DKD. Dr. MacIsaac, Dr. Jerums, and Dr. Ekinci review the evidence from observational studies and clinical trials in both type 1 and 2 diabetes that link intensive glycemic control and the primary prevention of DKD with an emphasis on preventing early glomerular filtration rate loss as well as albuminuria. In a complementary piece, Dr. Cooper, Dr. De Vos, and Dr. Hettige inform about recent data from studies of the newer glucose-lowering agents, sodium glucose cotransporter-2 inhibitors, glucagon-like peptide-1 receptor agonists, and dipeptidyl peptidase-4 inhibitors. Early studies of glucagon-like peptide-1 receptor agonists and sodium glucose co-transporter-2 inhibitors have shown reduced DKD progression as well as cardiovascular events, the most common causes of death across the DKD spectrum.
      There is an unparalleled nexus of hypertension and the renin angiotensin system with DKD onset and progression. Lowering blood pressure with either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker has been at center for DKD treatment for more than 2 decades. Indeed, renin angiotensin system inhibition is the standard against which all other new treatments must surpass to meet regulatory requirements for new drug approvals for DKD. Dr. Patney, Dr. Chaudhary, and Dr. Whaley-Connell provide an up-to-date perspective from population-level studies and clinical trials that clearly show how control of hypertension reduces risk of DKD and cardiovascular disease in diabetes. They review the robust data indicating that targeting the renin angiotensin system improves clinical outcomes to a greater extent than any other classes of antihypertensive agents in DKD.
      Acute kidney injury is now recognized as a leading DKD accelerant beyond traditional risk factors of hyperglycemia and hypertension. In addition, the paradigm of glomerulus-centered pathophysiology has expanded to include the tubulointerstitium with major roles of immunity and inflammatory responses. Biomarkers of proximal tubule injury have been shown to associate with DKD progression independent of glomerular injury biomarkers such as albuminuria. Dr. Bonventre and Dr. Yu summarize the mechanisms of increased susceptibility to acute kidney injury in diabetes, and consequently, the roles played by various cell types in facilitating maladaptive responses that longitudinally contribute to DKD onset and progression.
      With the recognition of inflammation as a major mechanism of both glomerular and tubulointerstitial damage in diabetes, inflammatory mediators have emerged as potential biomarkers with corresponding therapeutic targets. Dr. Alicic, Dr. Johnson, and I discuss the innate immune response and associated effector cells along with their proinflammatory cytokines, chemokines, adhesion molecules, and signal transduction pathways involved in DKD. In particular, we focus on the promise of targeting inflammation for clinical translation by review of favorable results from recent phase 2 clinical trials, such as those testing inhibitors of monocyte-chemotactic protein-1/chemokine C–C motif-ligand 2 and the Janus kinase/signal transducer and activator of transcription pathways as new therapies for DKD.
      Conventional approaches to biomarker development in DKD are difficult due to the absence of trustworthy clinical end points before death or ESRD. However, there are well-characterized alterations in kidney structure that highly correlate with kidney function, precede clinical DKD, and predict progression. Dr. Looker, Dr. Mauer, and Dr. Nelson discuss how these structural parameters may serve as clinically useful end points for identifying new biomarkers, particularly in early disease. Dr. Brosius and Dr. Ju provide a corresponding overview of systems biological studies of kidney tissue that are ideally suited to identify key mechanisms responsible for DKD. As an example, the therapeutic target of Janus kinase/signal transducer and activator of transcription was derived from a transcriptomic investigation that examined an entire network of changes in mRNA expression that mapped to DKD. Importantly, unbiased systems biological studies for biomarker and therapeutic discovery can start with analysis of disease in humans rather than animal or cell culture models that often inadequately replicate clinical DKD.
      I hope you relish this comprehensive journey through our current understanding of DKD. It covers a vast expanse from the global epidemiology down to the molecular details provided by Systems Biology. DKD is a big problem that requires multidimensional solutions. Whether you are a clinician, a scientist, a patient, or anyone concerned about DKD, we invite you to join the quest and sincerely thank you for all you do every day to make lives better.