Diabetic kidney disease

Abstract

The kidney is arguably the most important target of microvascular damage in diabetes. A substantial proportion of individuals with diabetes will develop kidney disease owing to their disease and/or other co-morbidity, including hypertension and ageing-related nephron loss. The presence and severity of chronic kidney disease (CKD) identify individuals who are at increased risk of adverse health outcomes and premature mortality. Consequently, preventing and managing CKD in patients with diabetes is now a key aim of their overall management. Intensive management of patients with diabetes includes controlling blood glucose levels and blood pressure as well as blockade of the renin-angiotensin-aldosterone system; these approaches will reduce the incidence of diabetic kidney disease and slow its progression. Indeed, the major decline in the incidence of diabetic kidney disease (DKD) over the past 30 years and improved patient prognosis are largely attributable to improved diabetes care. However, there remains an unmet need for innovative treatment strategies to prevent, arrest, treat and reverse DKD. In this Primer, we summarize what is now known about the molecular pathogenesis of CKD in patients with diabetes and the key pathways and targets implicated in its progression. In addition, we discuss the current evidence for the prevention and management of DKD as well as the many controversies. Finally, we explore the opportunities to develop new interventions through urgently needed investment in dedicated and focused research. For an illustrated summary of this Primer, visit: http://go.nature.com/NKHDzg.

Figure 1.. The prevalence of CKD in different populations with type 2 diabetes.

Data from patients with type 2 diabetes surveyed in the DEMAND study, US NHANES III, the Australian NEFRON study and the Italian RIACE study. Yellow circle denotes the percentage with an eGFR of <60 ml/min/1.73 m². Blue circle denoted patients with albuminuria. The percentage not included in either circle denotes patients without CKD.

Figure 2.. The central role of ROS in diabetic complications.

Mitochondrial production of reactive oxygen species (ROS) accelerates in response to an increase in intracellular glucose. In addition, pathogenetic ROS are also generated through the ROS-induced uncoupling of nitric oxide synthase and inactivation of NADPH oxidases. ROS go on to mediate DNA damage, which in turn activates poly(ADP ribose) polymerase (PARP). PolyADP-ribosylation of glyceraldehyde-3-dehydrogenase by PARP leads to the inhibition of this key glycolytic enzyme and a subsequent bottleneck in glycolysis. As a result, early glycolytic intermediates accumulate and are then diverted into pathogenetic signalling pathways.

Figure 3.. Glomerulopathy in diabetes.

Morphological and functional alterations to renal glomeruli are one of the hallmarks of DKD.

Figure 4.. Cellular contributors to myofibroblast recruitment and subsequent tubulointerstitial fibrosis in DKD.

The myofibroblasts responsible for the matrix deposition that leads to tubulointerstitial fibrosis in DKD are derived from a variety of sources, with transformation of local resident fibroblasts, mesenchymal stem cells and bone marrow derived fibrocytes and the induction of endothelial to mesenchymal and tubuloepithelial to mesenchymal transitions the main contributors.

Figure 5.. The relationship between glycaemic control and the incidence of CKD.

The hazard for the development of an albumin excretion rate > 30mg/day in adults from the FinnDiane study of with type 1 diabetes and no CKD (orange), and the distribution of glycaemic control (histogram) in those patients with type 1 diabetes developing microalbuminuria (bars) (P.-H.G. and M.C.T, unpublished data).

Figure 6.. The incidence of ESRD in patients with type 2 diabetes from the ADVANCE-ON trial.

Incidence of end-stage renal disease (ESRD) stratified according to intervention arm, where patients were subjected to either blood pressure (BP) lowering or glucose lowering treatments. Data is presented for sites (n=144) that were able to follow the majority (≥85%) of patients surviving to participate in post-trial follow-up outlining the number of patients who progressed to ESRD and, of these, the number who were receiving renal replacement therapy (RRT) and the number who had died as a result of kidney disease (renal death). Neither treatment significantly reduced the incidence of ESRD..

Figure 7.. The strong association between chronic kidney disease (CKD) and increased incidence and prevalence of other diabetic complications.

The increased risk of diabetic complications for patients with CKD means that the management of CKD is never only focused on the kidney, but must also involve the pro-active prevention, early detection and effective treatment of all diabetic complications.