Low-grade proteinuria and atherosclerotic cardiovascular disease: A transition study of patients with diabetic kidney disease

PLOS ONE RESEARCH ARTICLE Low-grade proteinuria and atherosclerotic cardiovascular disease: A transition study of patients with diabetic kidney disease Satoshi Yamaguchi1,2, Takayuki Hamano1,3*, Tatsufumi Oka1, Yohei Doi1, Sachio Kajimoto1, Yusuke Sakaguchi4, Akira Suzuki2, Yoshitaka Isaka1 a1111111111 a1111111111 a1111111111 a1111111111 a1111111111 1 Department of Nephrology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan, 2 Department of Internal Medicine, Japan Community Health Care Organization Osaka Hospital, Osaka, Osaka, Japan, 3 Department of Nephrology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Aichi, Japan, 4 Department of Inter-Organ Communication Research in Kidney Disease, Osaka University Graduate School of Medicine, Suita, Osaka, Japan * Abstract OPEN ACCESS Citation: Yamaguchi S, Hamano T, Oka T, Doi Y, Kajimoto S, Sakaguchi Y, et al. (2022) Low-grade proteinuria and atherosclerotic cardiovascular disease: A transition study of patients with diabetic kidney disease. PLoS ONE 17(2): e0264568. https://doi.org/10.1371/journal.pone.0264568 Editor: Emmanuel A. Burdmann, University of Sao Paulo Medical School, BRAZIL Received: September 15, 2021 Accepted: February 11, 2022 Published: February 25, 2022 Copyright: © 2022 Yamaguchi et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability Statement: Data cannot be shared publicly as data contain potentially identifying or sensitive patient information. The deidentified data are available upon request from Medical Center for Translational Research Osaka University Hospital (E-mail: . osaka-u.ac.jp). The data are available only after the approval of the Ethics Committee. Diabetic kidney disease (DKD) is heterogeneous in terms of proteinuria. Patients with DKD who present with low-grade proteinuria are more likely to have nephrosclerosis rather than traditional diabetic nephropathy. The amount of proteinuria might reflect the underlying pathology of renal failure and influence the prognosis after dialysis initiation. Clinical implications of proteinuria at the start of dialysis have not been confirmed, while greater proteinuria is associated with higher risk of cardiovascular disease (CVD) in the predialysis stages of chronic kidney disease. We performed a retrospective multicenter cohort study enrolling incident hemodialysis patients with diabetes. Patients were stratified using proteinuria quartiles. We examined the association of proteinuria quartiles with types of subsequent CVD. Among the enrolled 361 patients, the estimated mean glomerular filtration rate and proteinuria was 5.4 mL/min/1.73 m2 and 6.3 g/gCr, respectively. Lower quartile of proteinuria (cutoffs: 3.0, 5.4, and 8.8 g/gCr) was significantly associated with male, older age, and history of atherosclerotic CVD including coronary artery disease, peripheral arterial disease, and cerebral infarction (Ptrend<0.05). Kidney size was smaller in patients with lower levels of proteinuria. Patients with higher levels of proteinuria were more likely to have proliferative diabetic retinopathy (Ptrend<0.05). Multivariate competing risk analysis revealed that the first quartile of proteinuria was associated with a greater risk of atherosclerotic CVD than the third quartile (subhazard ratio [95% confidence interval]: 2.04 [1.00–4.14]). This association was attenuated after additional adjustments for history of atherosclerotic CVD. Furthermore, patients with lower quartiles of proteinuria were more likely to die of atherosclerotic CVD than those with non-atherosclerotic CVD (Ptrend = 0.01). Diabetic patients with lower proteinuria at dialysis initiation were characterized by severer macroangiopathy, as shown by a more atrophic kidney and higher prevalence of past atherosclerotic CVD. Hence, they are at a high risk of developing atherosclerotic CVD. Funding: The authors received no specific funding for this work. PLOS ONE | https://doi.org/10.1371/journal.pone.0264568 February 25, 2022 1 / 12 PLOS ONE Competing interests: The authors have declared that no competing interests exist. Low-grade proteinuria and atherosclerotic CVD among incident dialysis patients with diabetes Introduction Diabetic kidney disease is heterogeneous: patients with diabetes develop kidney disease due to diabetes per se and/or other comorbidities, including aging-related nephron loss and hypertension [1]. Among patients with classical diabetic nephropathy, macroalbuminuria usually precedes the decline of renal function (proteinuric pathway) [2, 3]. In contrast, some patients with diabetes develop renal insufficiency without albuminuria [4], similar to patients with nephrosclerosis. In fact, a previous study showed that most patients with diabetic nephropathy and estimated glomerular filtration rate (eGFR)<60 mL/min/1.73 m2 had concomitant macroalbuminuria, while a small proportion of patients with nephrosclerosis showed macroalbuminuria even when their eGFR reached 45 mL/min/1.73 m2 [5]. Furthermore, the populationbased National Health and Nutrition Examination Survey showed that the prevalence of albuminuria (albuminuria-to-creatinine ratio �30 mg/g) decreased progressively from 20.8% in 1988–1994 to 15.9% in 2009–2014, while the prevalence of reduced eGFR (<60 mL/min/1.73 m2) increased from 9.2% in 1988–1994 to 14.1% in 2009–2014 [6]. In patients with diabetes, non-proteinuric pathways, which include obesity, dyslipidemia, and hypertension, are also involved in the loss of renal function [3]. These non-proteinuric pathway components are risk factors for atherosclerosis [7, 8]. In a study enrolling patients with biopsy-proven diabetic nephropathy, patients with normoalbuminuria and eGFR<60 mL/min/1.73 m2 were reported to have pathologically more severe atherosclerosis (intimal thickening) in the kidney than patients with microalbuminuria or macroalbuminuria and eGFR<60 mL/min/1.73 m2 [9]. Intimal thickening suggests the involvement of hypertension [10]. In this context, non-proteinuric pathways may have contributed to atherosclerosis in patients with diabetes. Moreover, these patients with diabetes and low levels of proteinuria at dialysis initiation might have suffered from a more severe atherosclerosis during pre-dialysis chronic kidney disease (CKD). The deterioration of renal function might be attributed to non-proteinuric pathways rather than the proteinuric pathway. In addition, patients with diabetes and modest proteinuria might have smaller kidneys than patients with severe proteinuria, because atherosclerosis, accompanied with aging, accelerates kidney atrophy [11]. Supposing that moderate proteinuria at dialysis initiation reflects the severity of atherosclerosis, it might also predict future atherosclerotic cardiovascular (...truncated)