Diabetic kidney disease & glycemic control

Pathophysiology of DKD and Glycemic Goals in Patients with Low GFR

Presented by:
Bernard Zinman, CM, MD, FRCP, FACP
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital,
University of Toronto, Toronto, Canada

Diabetic kidney disease (DKD) is the most common cause of end-stage renal disease (ESRD) and has high morbidity and mortality rates. The natural history of DKD is modifiable and progress has been made in reducing the number of people who develop ESRD. However, more work still needs to be done.1 The pathogenesis of DKD has been well studied and is known to incorporate multiple pathways. These include metabolic, hemodynamic, and inflammatory pathways all of which may play a role in cell signaling pathways, transcription factors, and ultimately renal and structural changes, including pathological lesion formation consistent with DKD.2,3 Glomerular hypertension and single nephron hyperfiltration also appear to be key culprits in the progression of DKD as can be seen by the changes in glomerular filtration rate (GFR) in chronic kidney disease (CKD) stage 3 and 4.4

Results from the DCCT study were instrumental in providing information about the benefits of good glycemic control as well as primary prevention of nephropathy with decreased risk reductions of micro- and macroalbuminuria. When reviewing primary and secondary GFR outcomes in DCCT/EDIC on type 1 diabetes patients in 2011, intensively treated patients continued to have sustained effects on eGFR levels as well as fewer deaths.5,6 Interestingly, in the long-term follow-up of the conventional and intensified treatment patients, subjects in the conventional treatment group showed an increased risk of the development of micro- and macroalbuminuria for almost 10 years after despite maintaining glycemic control similar to that of the intensive treatment group.7 This finding is consistent with cardiovascular and eye complications as well.7 Ironically, it was only those patients that progressed to macroalbuminuria that developed a decreased estimated GFR over time suggesting that some cases of microalbuminuria may be benign.8

The ADVANCE study focused on type 2 diabetes and enrolled more than 11,000 patients who were randomized to intensive treatment (HbA1c 6.5%) or standard treatment per local guidelines. The primary outcome included cardiovascular disease death, nonfatal myocardial infarction, and nonfatal stroke. While there was no significant difference between either group for major adverse cardiac events (MACE) or death, the intensive group did show statistical significance for hypoglycemia episodes (more episodes compared to conventional therapy) and decreases for new or worsening nerphropathy.9 Not surprisingly, patients in the standard treated group were more likely to develop ESRD over the intensive group (HR 0.35, p = 0.01).10

As kidney failure worsens, anemia may develop. The red blood cells have a shortened survival and are increasingly younger, which may falsely decrease the HbA1c for the same mean level of glucose.11 This problem is exacerbated with the use of erythropoietin and iron.11 Glycated albumin results are not affected by anemia and its relationship with glycemic control is not affected by lowered GFR.11 However, severe proteinuria seen in nephrotic syndrome does shorten the exposure time of albumin to glucose and causes a lowering of glycated albumin for the same level of glucose.11

Continuous glucose monitoring (CGM) is a suitable and important option for evaluating glucose levels independent of HbA1c and should be strongly considered for efficacy.

There have been a number of observational studies that show a relatively consistent profile showing that a decreased HbA1c may improve renal outcomes, but as these are observational in nature, further evidence is needed.12-14 However, it is important to remember that it is the entire patient being treated, not just the kidney. As such, glycemic control will have a positive impact on quality of life, retinopathy progression, and neuropathy. Achieving the best HbA1c possible, without an unacceptable increase in the risk of hypoglycemia, is the goal.

Key Messages

  • DKD is the most common cause of ESRD and has a high morbidity and mortality rate.
  • Follow-up findings from the DCCT and EDIC studies demonstrate long-term benefits of intense glycemic control including reductions in micro- and macroalbuminuria, reduced nephropathy, and reduced deaths, even after glycemic control relaxed to match conventional treatment group levels.
  • Follow-up findings from the ADVANCE study demonstrated decreases in new or worsening nephropathy in patients previously treated with intensive glucose control.
  • HbA1c and glycated albumin levels are falsely decreased in patients with DKD.


Present disclosure: The presenter reported that he is a consultant and has received honoraria from Astra Zeneca, Abbott, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novo Nordisk, and Sanofi. He has also received grant support from Boehringer Ingelheim and Novo Nordisk.

Written by: Debbie Anderson, PhD

Reviewed by: Marco Gallo, MD


Diabetic kidney disease & glycemic control

Pathophysiology of DKD and Glycemic Goals in Patients with Low GFR