Clinical features of and risk factors for normoalbuminuric diabetic kidney disease in hospitalized patients with type 2 diabetes mellitus: a retrospective cross-sectional study

A retrospective cross-sectional study was designed and implemented in patients with T2DM who were hospitalized in the Department of Endocrinology at the Eighth Affiliated Hospital of Sun Yat-sen University between August 2012 and January 2020. Inpatients with available details of serum creatinine (Scr) and UACR were enrolled in this study. For patients who met all selection criteria and had multiple hospitalization records, only the first hospitalization record was entered. Exclusion criteria were as follows: (1) patients with type 1 diabetes mellitus; (2) patients who had been rehospitalized; (3) patients with ketoacidosis, hyperosmolar coma, acute infection, pregnancy, acute cardiovascular and cerebrovascular diseases, and other stressors; and (4) patients with other types of nephropathy such as primary nephrotic syndrome and hypertensive nephropathy. A total of 1620 patients were ultimately enrolled in this study (Fig. 1). This study was examined and approved by the Ethics Committee of the Eighth Affiliated Hospital of Sun Yat-Sen University, and written informed consent was obtained from all participants.

We collected the following clinical data through face-to-face interviews: age, sex, smoking status, use of insulin, previous use of RASIs, previous treatments with lipid-lowering medication, histories of hypertension and diabetes, and adverse cardiovascular events.

Next, we physically examined all participants; height and weight, waist and hip circumferences, and BP were assessed. BMI was calculated as weight (kg) divided by height (m) squared (kg/m²) [11]. The difference between systolic BP (SBP) and diastolic BP (DBP) was pulse pressure (PP) [12].

Finally, imaging and laboratory test results were collected. Blood samples were obtained from patients after overnight fasting. Fasting plasma glucose (FPG), Scr, blood urea nitrogen, total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), apolipoprotein A (ApoAI), apolipoprotein B (ApoB), and serum uric acid (SUA) were directly measured using colorimetric and turbidimetric assays with the Beckman AU 5800 analyzer (Beckman Coulter, Shenzhen, China). Glycated hemoglobin (HbA1c) levels were examined using a fully automated glycosylated hemoglobin analyzer HLC-723 G7 (Tosoh, Shenzhen, China). Fasting morning urine samples were collected for the determination of albumin (UAlb) and creatinine (Ucr) using an A15 Automatic Biochemistry Analyzer (Biosystems, Shenzhen, China), and urinary albumin-to-creatinine ratio (UACR) was calculated as UAlb (mg) divided by Ucr (g). Ultrasonography of bilateral carotid and bilateral lower-extremity arteries were performed with a Sequoia 512 (Acuson, Shenzhen, China) for the evaluation of plaque and stenotic severity. We calculated the eGFR using the Chronic Kidney Disease Epidemiology Collaboration’s formula recommended in the ADA [3].

T2DM was diagnosed according to the 1999 World Health Organization diagnostic criteria [13]. DKD was defined as diabetes with UACR of ≥30 mg/g and/or eGFR of < 60 ml/min/1.73 m² in the absence of signs or symptoms of other primary causes of kidney damage according to the ADA guidelines and Chinese clinical practice guidelines [3, 4]. DR was diagnosed by ophthalmologists using standardized fundoscopic examination according to the International Clinical Diabetic Retinopathy Disease Severity Scale [14]. Diabetic peripheral neuropathy (DPN) was evaluated by electromyography. Hypertension was defined as taking medication for hypertension or SBP of ≥140 mmHg and/or a DBP of ≥90 mmHg according to the 2010 Chinese Guidelines for the Management of Hypertension [15]. The carotid plaque score was evaluated according to a semiquantitative scale score that included the following: one site with plaques having thickness of < 2 mm (score = 1), two sites with plaques having both thickness of ≤2 mm or one site with plaques having thickness of > 2 mm (score = 2), two sites with plaques including at least one plaque with thickness of > 2 mm (score = 3), and two sites with plaques having both thickness of > 2 mm or annular plaque (score = 4), with the final score being the sum of bilateral carotid plaque scores [16]. Peripheral arterial disease (PAD) was defined as ≥50% luminal narrowing of a lower-extremity artery [17]. Anemia was defined as the adult men with hemoglobin (Hb) level of <120  g/L and adult women with Hb of < 110 g/L according to the Chinese criteria [18]. Smoking history was defined by the World Health Organization (WHO) in 1997 as those who had smoked for at least 6 months or had smoked at least 100 cigarettes in their lifetime.

Reduced eGFR was defined as eGFR of < 60 ml/min/1.73 m²; albuminuria was defined as UACR of ≥30 mg/g; and normoalbuminuria was defined as UACR of < 30 mg/g [3]. We classified the T2DM patients into four groups on the basis of the presence or absence of albuminuria and reduced eGFR:

All statistical analyses were conducted using SPSS version 26.0. Continuous data with normal distribution are expressed as mean ± standard deviation (x̄ ± s), whereas non-normally distributed data are presented as median and interquartile interval [M(QL, QU)]. Count data are expressed as n (%), and comparisons among groups were performed using Pearson’s chi-square test. One-way analysis of variance with least significant difference was applied for intergroup comparisons when the data showed normal distribution and homogeneity of variance. The Kruskal−Wallis test was used to compare variables with skewed distribution. Variates with a p-value of < 0.1 in the univariate analysis and the risk factors reported in prior literature were included in the binary logistic regression analyses with forward stepwise method to define independent risk factors of NADKD. Significance level was set at p < 0.05, and confidence interval (CI) was 95%.

Of the 1620 eligible participants, 500 (30.9%) had DKD and 45 (2.8%) had NADKD, which accounted for 9.0% of all DKD. The characteristics of the participants are presented in Table 1. The average age of all participants was 57.0 ± 12.4 years, with 34.4% of them being female. In patients with normoalbuminuric T2DM, compared with the control group (non-DKD), NADKD was significantly associated with older age; female sex; higher prevalence and longer duration of diagnosed hypertension; higher PP, higher SUA; higher use of insulin before hospital admission; higher prevalence of anemia; higher prior use of antihypertensive drugs and lipid-lowering drugs; higher prior use of RASIs; and lower levels of DBP, HbA1c, TC, ApoB, and ApoB/ApoAI. In addition, patients with NADKD had a higher prevalence of macrovascular complications than did the control group, which was mainly manifested as a higher prevalence of stroke, adverse cardiovascular event, carotid plaque, and PAD. However, there were no significant differences in the prevalence of DR and DPN. The prevalence of diabetic complications in the four groups is presented in Fig. 2. Among patients with T2DM who had a reduced eGFR, those with NADKD had a shorter duration of diabetes and a lower level of SBP, DBP, PP, TC, ApoB, ApoB/ApoAI, and prevalence of anemia than patients with AGDKD (Table 1). Furthermore, patients with NADKD had a lower prevalence of PAD, DR, and DPN, except for the prevalence of stroke, adverse cardiovascular event, and carotid plaque (Fig. 2).

Normoalbuminuric T2DM patients were selected as the study population. Considering reduced eGFR as the dependent variable, the potential risk factors of univariate logistic regression analysis and previous research reports were entered into binary logistic regression analyses with forward stepwise method to define independent risk factors of NADKD. Ultimately, sex and age; duration of diabetes; BMI; hypertension; previous use of antihypertensive drugs, RASIs, and lipid-lowering drugs; smoking; PP; duration of hypertension; and FPG, HbA1c, TG, TC, HDL-C, LDL-C, and ApoB/ApoAI levels were considered as independent variables. Table 2 showed that age (95% CI: 1.055–1.123, p < 0.001), HbA1c level (95% CI: 0.716–0.983, p = 0.03), and previous use of RASIs (95% CI: 1.212–4.481, p = 0.011) were the significant factors that independently predicted NADKD.

All T2DM patients were selected as the study population. Considering reduced eGFR as the dependent variable, binary logistic regression analyses using forward stepwise method were performed. Results demonstrated that independent risk factors associated with reduced eGFR were age (95% CI: 1.041–1.081, p < 0.001), duration of diabetes (95% CI: 1.011–1.065, p < 0.01), hypertension (95% CI: 1.656–4.573, p < 0.001), and UACR (95% CI: 1.001–1.002, p < 0.001; Table 3).