Impairment of platelet mitochondrial respiration in patients with chronic kidney disease with and without diabetes

Abstract

Chronic kidney disease (CKD) and diabetic kidney disease (DKD) are major public health problems, and their burden is growing relentlessly with the aging of the global population. Their early recognition is now a public health priority, and there is an unmet need for the identification of specific biomarkers in minimally invasive or non-invasive samples. Mitochondrial dysfunction plays a pivotal role in the development and progression of both CKD and DKD and circulating platelets have emerged as an ideal candidate for the assessment of the respiratory function. The present study assessed mitochondrial respiration in platelets isolated from the peripheral blood of patients with DKD and CKD compared to healthy controls. The study included a total number of 89 subjects, as follows: 30 DKD patients divided into three subgroups based on the urinary albumin-to-creatinine ratio (uACR): 20 normoalbuminuric, 10 microalbuminuric, and 10 macroalbuminuric, 29 CKD patients (positive controls) and 20 healthy individuals (negative controls). Platelets were isolated by differential centrifugations and a high-resolution respirometry protocol was adapted to assess mitochondrial respiration dependent on complex I (CI) and complex II (CII). A significant reduction of the CI-supported active respiration was found in the normoalbuminuric DKD patients and further decreased in the microalbuminuric DKD subgroup. Both CI and CII-dependent coupled respiration and the maximal uncoupled respiration were significantly reduced in the macroalbuminuric DKD subgroup. In conclusion, mitochondrial respiration impairment in peripheral platelets is evident from the early stages of DKD. Moreover, platelet mitochondrial respiration was more severely impaired in patients with macroalbuminuric DKD as compared to those with CKD. Further, more extensive follow-up studies are warranted to determine whether platelet respiratory mitochondrial dysfunction could serve as a peripheral biomarker for kidney mitochondrial dysfunction and/or as a prognostic tool in DKD.

Keywords: Albuminuria; Chronic kidney disease; Diabetic kidney disease; Platelet mitochondrial respiration.

Fig. 1

Respiratory parameters measured in platelets isolated from DKD patients. CTRL control group, NA-DKD normoalbuminuric diabetic kidney disease, MicroA-DKD microalbuminuric diabetic kidney disease, MacroA-DKD macroalbuminuric diabetic kidney disease, ET electron transport, OXPHOS oxidative phosphorylation. One-way ANOVA with Bonferroni’s post hoc test was performed. *p < 0.05; **p < 0.01; ***p < 0.001; ****p < 0.0001

Fig. 2

Respiratory parameters measured in platelets isolated from non-diabetic CKD patients. CTRL control group, CKD chronic kidney disease, OXPHOS oxidative phosphorylation, ET electron transport. One-way ANOVA with Bonferroni’s post hoc test was performed. *p < 0.05; ** p < 0.01; *** p < 0.001; **** p < 0.0001

Fig. 3

Respiratory parameters measured in platelets isolated from CKD subgroups according to the eGFR. CTRL control group, P1 early CKD (eGFR > 60 mL/min/1.73 m²), P2 late CKD (eGFR ≤ 60 mL/min/1.73 m.²), OXPHOS oxidative phosphorylation, ET electron transport. One-way ANOVA with Bonferroni’s post hoc test was performed. *p < 0.05; **p < 0.01; ***p < 0.001; ****p < 0.0001

Fig. 4

Respiratory Parameters in Platelets Isolated from DKD vs CKD patients. CTRL control group, NA-DKD normoalbuminuric diabetic kidney disease, MicroA-DKD microalbuminuric diabetic kidney disease, MacroA-DKD macroalbuminuric diabetic kidney disease, ET electron transport, OXPHOS oxidative phosphorylation. One-way ANOVA with Bonferroni’s post hoc test was performed. *p < 0.05; **p < 0.01; ***p < 0.001; ****p < 0.0001