In the present study, we enrolled 218 T2DM patients with biopsy-proven DKD and without known CVD history. 10-year ASCVD risk score was calculated and compared between different eGFR categories, which showed that about 75.2% patients with DKD were at high risk of 10-year ASCVD event and comparable risk score was found among patients in different stages. DKD patients, even in CKD stage1, had comparable ASCVD risk score to patients in CKD stage 2, 3, and 4. Patients with higher risk (≥ 14.1%) for 10-year ASCVD event had an older age, higher SBP, more obvious male predominance, more smokers, higher triglyceride level, and lower HDL-C and eGFR level than those with lower risk. As for histological lesion, glomerular class, IFTA and arteriolar hyalinosis showed no statistical difference between two groups. However, interstitial inflammation was more severe in patients with higher ASCVD risk score than those with lower risk score. The renal survival rate was comparable between the two risk score groups.
ASCVD, a major kind of CVD, is the leading cause of morbidity and mortality worldwide[20]. In a prospective study of association between lipids and risk of ASCVD, higher triglyceride and lower HDL-C was associated with higher ASCVD event respectively[21], which was in accordance with our results. Smoking, DM, and hypertension were also regarded as risk factors of ASCVD in many studies[22–24]. Accumulated evidence suggested that CKD was an independent risk factor for ASCVD, and the interrelation becomes stronger in patients with declined eGFR[25, 26]. Among the placebo group of SHARP study, the rate of 4-point major atherosclerotic cardiovascular events distinguished between eGFR level: 6.8% for CKD stages 1 and 2,10.4% for CKD3,12.7% for CKD4,13.3% for CKD5 without dialysis and 16.5% for CKD5 on dialysis, respectively[27]. Recent published European Society of Cardiology (ESC) and European Atherosclerosis Society (EAS) guidelines for dyslipidemia classified patients with CKD3 as “high-risk population” of 10-year coronary heart disease, and patients with CKD4-5 as “very high-risk population”[28]. Besides CKD, the coexistence of T2DM, known as ASCVD equivalent, increases the risk and mortality of ASCVD as well. According to cardiovascular and diabetes mellitus section of American Heart Association in 2015, the risk of dying from CVD is 2 to 4-fold of diabetic patients compared with non-diabetic patients[29].The association between DKD and future ASCVD event hasn’t been well learned. Being different with general CKD patients, DKD patients in CKD stage 1 in our study were already at high risk of ASCVD with median ASCVD risk score of 10.9%, which should be classified as “high-risk population”.
The Pooled Cohort Equation, first published as a part of ACC/AHA guideline in 2013, has been well developed in estimating the future 10-year risk for ASCVD. PCE is subsequently validated in different populations and turned to have good discrimination and calibration[12, 30].Considering the poor CVD prognosis of patients with CKD, many studies were conducted to investigate the relation between PCE-estimated ASCVD risk and renal function. Tysonet al[31]conducted a second analysis of Exercise and Nutritional Interventions for Cardiovascular Health (ENCORE) trialin participants with eGFR ≥ 60 mL/min/1.73 m2. They found that the ASCVD risk(estimated using PCE) increased 2.7% with every decline of eGFR by 15 mL/min/1.73 m2. A Chinse epidemiological study enrolled 259657 patients to investigated the association of eGFR with 10-year ASCVD risk. Their data showed that patients with insufficient kidney function confronted higher 10-year ASCVD risk, compared with those with normal renal function[32]. However, the estimated 10-year ASCVD risk in DKD patients remained unclear. In our cohort, about 75.2% patients with DKD were at high risk of 10-year ASCVD event, and eGFR was negatively correlated with ASCVD risk, which was consistent with other studies on general chronic kidney diseases[31–33].However, there seemed to be no significant difference in ASCVD risk score among different CKD stages.This could because diabetes and kidney dysfunction were both strong indicators of ASCVD, which led to high ASCVD risk of DKD patients even in CKD stage 1. Considering comparable 10-year ASCVD risk score between different eGFR stages, ASCVD prevention in DKD patients deserves greater attention even at early stage of DKD than general CKD population.
Ample studies have investigated the interaction between kidney and CVD, while most of them are focusing on impaired kidney function increasing CVD risk and mortality, such as ACCORD, ALLHAT[34, 35]. However, the impact of CVD on renal function and possible mechanisms are rarely learned and less clear. Myocardial infarction(MI), a kind of ASCVD, is reported to cause renal function loss of about 3 ml/(min•year) to individuals with normal renal function[36]. In a rat model of CKD induced by unilateral nephrectomization, proteinuria and plasma creatinine increased in MI group significantly compared with control group. Renal interstitial damage and focal glomerulosclerosis were more severe in MI group than those in control group[37]. The number of macrophages in glomeruli was higher in MI group. A possible mechanism was related to the systemic or focal renal inflammation, which was derived from severe inflammation reaction in kidney after MI[37, 38]. Traditional risk factors of ASCVD, such as hypertension, dyslipidemia, obesity, and metabolic syndromes can damage the kidney directly and by promoting intrarenal atherogenesis, even in the absence of obstructive lesions in the renal artery. Logistic analysis in our study also showed that the higher ASCVD risk score was associated with renal dysfunction. Altough the estimated ASCVD risk score was negatively associated with baseline eGFR, the estimated ASCVD risk score was not an independent risk factor for progression to ESRD. Additionally, the presence of DR, lower serum albumin and eGFR were independently associated with renal outcotmes. This inconsistency could be due to different characteristics of our patients, such as race, baseline eGFR and medical complications. Our participants had DM and were diagnosed with DKD by renal biopsy. Considering DM as a proinflammatory disease and strong indicator of ASCVD, the inflammation reaction induced by CVD could add little extra damage to kidney.
Diabetes, a disorder of glucose metabolism, can lead to macrovascular complications, which are similar to atherosclerotic lesion both in morphology and function, and microvascular complications(retinopathy, nephropathy, etc.)[39]. Proper glycemic control was supposed to release the heavy burden of diabetic complications, and several trials of glucose control in diabetic patients were conducted. ADVANCE and VADT indicated the benefits of intensive glucose control to microvascular endpoints, but no significant improvement of macrovascular outcomes[40, 41].Why glucose control had this paradoxical effect on diabetic micro- and macro-vascular complications remained obscure. There were structural and functional differences between macro- and microvessels. Macrovessels mainly provided blood to organs, while microvessels, worked as the smallest function unit of cardiovascular system, delivered nutrients to local tissue and took part in blood pressure maintenance[42]. For diabetic microangiopathy, vascular damage induced by intracellular hyperglycemia occurred early in the diabetes course and finally led to typical pathological changes in the vasculature. The most common vasculature change was thickened basement membrane, which could be due to overproduction of extracellular matrix proteins[43].Several pathogenic theories of diabetic microvascular complications had been reported, including production of advanced glycation products, increased oxidative stress and reactive oxygen species, existence of low-grade inflammation and protein kinase C activation[43]. Macroangiopathy in diabetes was characterized by development of atherosclerosis. Several metabolic abnormalities, including hyperglycemia, insulin resistance and dyslipidemia, acted on different cells of macro-vasculature and platelets[44].Besides those pathogenetic mechanisms mentioned above in diabetic microangiopathy, platelet and coagulation system activation was also involved in diabetic macroangiopathy. Increased clotting factors and plasminogen activator inhibitor-Ⅰ, and decreased antithrombin III contribute to atherosclerosis. It could be the different pathogenic mechanism between micro- and macro-vascular complications, that explained non-predictable role of ASCVD risk for renal prognosis.
There are several limitations in our study. First, this is a retrospective study, which means that we can’t exclude some other factors that may influence analysis results, such as life style, eating habits, etc. Second, there is inevitable bias of selecting participants, because of the indications of renal biopsy for diabetic patients. Our renal biopsies for diabetic patients were mainly performed for those with a rapid declining eGFR or suddenly increased proteinuria, especially those without DR and/or long DM duration. Third, based on the strict application of the Pooled Cohort Equationused in this study, patients younger than 40 years or older than 79 years were not included in this study. Included patients also had to meet the restricted range for blood pressure, cholesterol and HDL-C level, which leads to amounts of data loss of ASCVD risk. Finally, this study is completed in a single center, causing limited sample size and unanalyzed racial and geographical differences.