BACKGROUND AND AIMS
Diabetes is an emerging public health problem because of the high mortality and morbidity rates associated with its serious complications. Among the most common microvascular complications, diabetic kidney disease (DKD) represents a leading cause of the development of end-stage renal disease (ESRD). Additionally, DKD is associated with a substantially increased burden of cardiovascular (CV) outcomes and all-cause mortality.1 Along with temporal changes in diabetes care, and in spite of stable overall prevalence of DKD, the frequency of increased albuminuria has declined, while that of low estimated glomerular filtration rate (eGFR) has increased.2 Thus, non-albuminuric DKD has become the prevailing phenotype (PH) in patients with Type 2 diabetes mellitus (T2DM);3 however, it remains unclear whether its prognosis is different from that of the other DKD PH.4 This study evaluated the relationship between different DKD PH and incidence of major vascular events and all-cause mortality in subjects with T2DM.
MATERIALS AND METHODS
This observational, prospective, single-centre, cohort study enrolled 986 adults with T2DM in 2002–2004; subjects were followed-up for a mean of 12.9±2.7 years. Based on albuminuria (Alb; measured by urine albumin-to-creatinine ratio) and eGFR (measured by Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI] equation), each subject was classified as: no-DKD (Alb-/eGFR-), albuminuria alone (urine albumin-to-creatinine ratio ≥30 mg/g; Alb+/eGFR-; DKD1–2), reduced eGFR alone (eGFR <60 mL/min/1.73 m2; Alb-/eGFR+; Alb-DKD), or both albuminuria and reduced eGFR (Alb+/eGFR+; Alb+DKD). Vital status was retrieved for all individuals on 31st December 2017 by interrogating the Italian Health Card Database; data for major vascular events were available for 972 participants (98.6%) and were obtained, to the same date, in collaboration with the Tuscany Regional Health Agency through hospital discharge registers (International Classification of Diseases, Ninth Revision, Clinical Modification codes). Subsequent to Kaplan–Meier (K–M) analyses, hazard ratios (HR; 95% Confidence Interval [CI]) for different outcomes associated with each DKD PH were assessed by unadjusted and adjusted Cox regressions.
Of 986 patients with T2DM, 779 (79.0%) had no-DKD, 144 had DKD1–2 (14.6%), 33 (3.3%) had Alb-DKD, and 30 (3.0%) had Alb+DKD PH; thus, Alb-DKD accounts for 15.9% of all DKD and for 52.4% of all DKD Stages ≥3. A gradually heavier CV risk profile, in terms of traditional and nontraditional risk factors, was distributed through the DKD PH. Death from all causes occurred in 230 individuals (23.3%; 18.0 per 1,000 patient-years [PY]): 19.1% in the no-DKD group, 33.3% in DKD1–2, 36.4% in Alb-DKD, and 70.0% in Alb+DKD (K–M log-rank 77.97; p<0.0001). After adjustment for confounders, HR for death were 1.47 (95% CI: 1.04–2.07) for DKD1–2, 1.22 (95% CI: 0.66–2.25) for Alb-DKD, and 2.43 (95% CI: 1.46–4.06) for Alb+DKD. Major CV events occurred in 276 out of 972 subjects (28.4%; 25.2 per 1,000 PY): 25.3, 38.5, 43.8, and 43.3% through each DKD PH, respectively (K–M; p<0.0001). Adjusted HR for major CV events were 1.37 (95% CI: 1.00–1.89) in DKD1–2, 1.73 (95% CI: 0.98–3.03) in Alb-DKD, to decrease to 1.11 (95% CI: 0.61–2.03) in Alb+DKD, due to competition with all-cause mortality. Coronary events occurred in 184 subjects (18.9%; 16.0 per 1,000 PY): 16.7, 25.9, 31.3, and 30.0% through DKD PH, respectively (K–M; p<0.0001). Adjusted HR for coronary events were 1.41 (95% CI: 0.96–2.07) in DKD1–2, 2.18 (95% CI: 1.11–4.30) in Alb-DKD, to decrease to 1.31 (95% CI: 0.46–3.70) in Alb+DKD. Hospitalisation for heart failure occurred in 84 subjects (8.6%; 6.8 per 1,000 PY): 6.8, 14.7, 21.9, and 13.3% through DKD PH (p<0.0001). Adjusted HR for hospitalisation for heart failure were 1.91 (95% CI: 1.14–3.19) in DKD1–2, 2.40 (95% CI: 1.07–5.38) in Alb-DKD, and 1.31 (95% CI: 0.46–3.70) in Alb+DKD. ESRD occurred in 71 individuals (7.3%; 5.7 per 1,000 PY): 5.7, 10.5, 9.4, and 30.0% through DKD PH (p<0.0001). Adjusted HR for ESRD were 1.79 (95% CI: 0.99–3.26) in DKD1–2, 1.28 (95% CI: 0.39–4.23) in Alb-DKD, and 5.37 (95% CI: 2.46–11.72) in Alb+DKD.
In the patient cohort of T2DM over a very long follow-up, the non-albuminuric DKD PH did not show a significantly greater risk of all-cause mortality; had a significant risk of CVD events, mainly coronary events; and had the highest risk of hospitalisation for heart failure, but a low risk of renal function decline to ESRD. Distribution of DKD PH and, in particular, the prevalence of the emerging Alb-DKD PH was similar to that reported in a larger Italian study, the RIACE multicentre study.1,4 Similar findings have emerged from cross-sectional observations in cohorts of T2DM from several countries, as well as in subjects enrolled in multinational interventional studies, as summarised in a recent review.3 A high prevalence of the Alb-DKD PH has also been observed in Type 1 diabetes mellitus.5,6 At variance with the present study, RIACE showed that risk of all-cause death in Alb-DKD was significantly increased and similar to that of the albuminuria-alone PH (DKD1–2); these differences are likely due to the larger population of the RIACE study, but also to the longer follow-up of the present cohort. Incidence of major CV events and coronary events, and of hospitalisation for heart failure, were significantly higher in Alb-DKD; these observations are consistent with cross-sectional data from RIACE where coronary events correlated more strongly with the Alb-DKD PH than with the albuminuric forms. Finally, as reported by others,7 the Alb-DKD PH was less prone to progress to ESRD.