Synergistic effect of chronic kidney disease, neuropathy, and retinopathy on all-cause mortality in type 1 and type 2 diabetes: a 21-year longitudinal study

Abstract

Background: The prognostic value of common and frequently associated diabetic microvascular complications (MVC), namely chronic kidney disease (CKD), cardiac autonomic neuropathy (CAN), peripheral neuropathy (DPN), and retinopathy (DR), is well established. However, the impact of their different combinations on long-term mortality has not been adequately assessed.

Methods: We retrospectively analyzed 21-year longitudinal data from 303 patients with long-standing type 1 (T1D) or type 2 diabetes (T2D), who were thoroughly characterized at baseline for the presence of MVC using ^99mTc-DTPA dynamic renal scintigraphy, overnight urine collection, cardiovascular autonomic tests, monofilament testing, and dilated fundus oculi examination.

Results: After a 5,244 person-years follow-up, a total of 133 (43.9%) deaths occurred. The presence of CKD and CAN, regardless of other MVC, increased the adjusted all-cause mortality risk by 117% (HR 2.17 [1.45-3.26]) and 54% (HR 1.54 [1.01-2.36]), respectively. Concomitant CKD&CAN at baseline were associated with the highest mortality risk (HR 5.08 [2.52-10.26]), followed by CKD&DR (HR 2.95 [1.63-5.32]), and CAN&DR (HR 2.07 [1.11-3.85]). Compared with patients free from MVC, the mortality risk was only numerically higher in those with any isolated MVC (HR 1.52 [0.87-2.67]), while increased by 203% (HR 3.03 [1.62-5.68]) and 692% (HR 7.92 [2.93-21.37]) in patients with two and three concomitant MVC, respectively.

Conclusions: Our study demonstrates the long-term, synergistic, negative effects of single and concomitant diabetic MVC on all-cause mortality, which should encourage comprehensive screenings for MCV in both T1D and T2D to improve risk stratification and treatment.

Keywords: Cardiac autonomic neuropathy; Diabetes mellitus; Diabetic kidney disease; Diabetic retinopathy; Microvascular complications; Renal dynamic scintigraphy.

Fig. 1

Flow diagram of patients’ selection

Fig. 2

Kaplan–Meier and model-predicted survival curves for single diabetic microvascular complications, including chronic kidney disease (A) and its components, namely reduced glomerular filtration rate (B) and albuminuria (C), cardiac autonomic neuropathy (D), diabetic peripheral neuropathy (E), and diabetic retinopathy (F)

Fig. 3

Kaplan–Meier and model-predicted survival curves for pairwise combinations of diabetic microvascular complications, including chronic kidney disease (CKD) and cardiac autonomic neuropathy (CAN) (A), CKD and diabetic retinopathy (DR) (B), and CAN&DR (C)

Fig. 4

Distribution of diabetic microvascular complications in patients characterized for the presence of chronic kidney disease (CKD), cardiac autonomic neuropathy (CAN), and diabetic retinopathy (DR) (A). Kaplan–Meier and model-predicted survival curves for the total number of concomitant diabetic microvascular complications among CKD, CAN, and DR (B)