New Research Suggests Differences in Diabetic Kidney Disease Between T1 and T2D

New research suggests that there may be significant differences in kidney disease among individuals with type 1 diabetes (T1D) vs those with type 2 diabetes (T2D), potentially influencing the risk, progression, and treatment choices for diabetic kidney disease (DKD).

These studies were included in the session “Diabetes Kidney Disease in Type 1 and Type 2 Diabetes—The Same Disease?” at the American Diabetes Association (ADA) 83rd Scientific Sessions in San Diego, California. A short recap of the session was included in an ADA press release.

While DKD may appear similar clinically, histopathologic, molecular, and genetic features indicate distinct characteristics in the kidney disease associated with these 2 types of diabetes.

According to Viji Nair, PhD, MS, bioinformatics team leader of the George M. O'Brien Kidney Translational Core Center at the University of Michigan, the current understanding of the natural history of diabetes is primarily based on studies conducted in patients with T1D. However, serial biopsies suggest that T2D follows different trends and patterns in terms of disease progression, complications, and comorbidities.

The disparities between T1D and T2D are particularly evident among young patients, as youth with T2D exhibit a higher prevalence of DKD and a faster progression of albuminuria compared to youth with T1D. Moreover, youth-onset T2D carries a higher risk of end-stage kidney disease and all-cause mortality compared to diabetes onset at any age.

Morphometric analysis of kidney biopsies from young individuals with T1D and T2D reveals clear distinctions. In youth-onset T2D, glomerular tuft area, glomerular volume, mesangial matrix area, and mesangial volume are all significantly increased compared to T1D.

Furthermore, single-cell sequencing studies demonstrate shared and specific transcriptional alterations in patients with either T1D or T2D when compared with healthy controls. However, the gene expression patterns between the types are distinctly different. Nair expressed her team's interest in investigating molecular pathways and conducting direct comparisons between T1D and T2D to identify altered mechanisms.

The Kidney Precision Medicine Project (KPMP) is playing a pivotal role in redefining and reclassifying common kidney diseases. By combining deep molecular phenotyping of kidney biopsies with clinical characteristics, innovative digital pathology, and clinical outcomes, the project aims to uncover significant histologic differences between individuals with diabetes of over 25 years who do not have chronic kidney disease (CKD) and those who do.

“There are clear histologic differences between CKD patients and diabetes mellitus resilient (DMR) patients when examining glomerular, tubulointerstitial, and vascular compartments,” said Sylvia Rosas, MD, MSCE, associate professor of medicine at Joslin Diabetes Center, in a statement. “Histopathologic lesions are significantly associated with estimated glomerular filtration rate (eGFR), and proteinuria and chronic histopathologic lesions are associated with kidney disease progression.”

Additionally, single-cell RNA sequencing reveals different cell types in patients with DMR or DKD, although the clinical implications of these findings are still unclear.

Treatment approaches for the different diabetes types also differ, especially concerning angiotensin II receptor blockers (ARB), angiotensin-converting enzyme (ACE) inhibitors, sodium-glucose cotransporter-2 (SGLT2) inhibitors, non-steroidal mineralocorticoid receptor antagonists (nsMRA), and glucagon-like peptide-1 (GLP-1) receptor agonists.

“Intensive glycemic control helps in type 1 diabetes, but it is not enough,” said Anand Srivastava, MD, MPH, associate professor of nephrology at the University of Illinois Chicago. “A quarter of patients still develop microalbuminuria, and intensive glycemic control is associated with weight gain, worsening insulin resistance, central obesity, dyslipidemia, higher blood pressure, and worse inflammation.”

He also noted that there is a temptation to use the same agents for renal protection in T1D as those used in T2D. While some agents have promising results, others may not translate as effectively.

Clinical trials involving ARBs have shown up to a 20% reduction in the risk of doubling serum creatinine, end-stage kidney disease, or death in T2D. ACE inhibitor trials in T1D have yielded even better outcomes, with reductions of up to 50% in the risk of doubling serum creatinine, death, dialysis, or kidney transplant.

Regarding SGLT2 inhibitors, they have demonstrated similar effects on eGFR and albuminuria in both diabetes types. However, the class also carries a comparable risk of diabetic ketoacidosis in both types.

Data on nsMRA and GLP-1 receptor agonists in T1D are limited and conflicting. While both classes provide clear kidney benefits in T2D, their advantages for T1D are not as evident. Dr. Srivastava concluded that further trials targeting the reduction of adverse kidney outcomes in both T1D and T2D are necessary.

Reference

Studies indicate differences in diabetic kidney disease in type 1 and type 2 diabetes. News release. American Diabetes Association. Accessed June 30, 2023. https://www.adameetingnews.org/live-updates/session-coverage/studies-indicate-differences-in-diabetic-kidney-disease-in-type-1-and-type-2-diabetes/