Peripheral perfusion, measured by perfusion index, is a novel indicator for renal events in patients with type 2 diabetes mellitus

www.nature.com/scientificreports OPEN Peripheral perfusion, measured by perfusion index, is a novel indicator for renal events in patients with type 2 diabetes mellitus Hiroshi Okada1*, Muhei Tanaka2, Takashi Yasuda3, Yuki Okada1, Hisahiro Norikae4, Tetsuya Fujita4, Takashi Nishi4, Hirokazu Oyamada5, Tetsuro Yamane6 & Michiaki Fukui2 Diabetic kidney disease (DKD) is one of the leading causes of end stage renal disease. Despite recent therapies, mortality due to DKD and resources spent on healthcare are important problems. Thus, appropriate markers are needed to predict renal outcomes. Therefore, we investigated the role of peripheral perfusion as an indicator for renal events in patients with type 2 diabetes mellitus. This retrospective cohort study included 566 patients who were admitted to Matsushita Memorial Hospital in Osaka, Japan for type 2 diabetes mellitus. Peripheral perfusion was assessed using perfusion index (PI), which represents the level of circulation through peripheral tissues and was measured on each toe using a Masimo SET Radical-7 (Masimo Corporation, Irvine, CA, USA) instrument. The duration of follow up was 3.0 years. The median age of patients was 70 years (IQR range: 61–77 years) and median PI value was 2.9% (IQR range: 1.8–4.8%). Multiple logistic regression analyses showed that PI (per 1% increase) was associated with an odds ratio of composite of end-stage renal disease (ESRD) and/or doubling of serum creatinine level; n = 40 (odds ratio 0.823 [95% CI: 0.680–0.970]), and composite of ESRD, doubling of serum creatinine level, and renal death and/or cardiovascular death; n = 44 (odds ratio 0.803 [95% CI: 0.665–0.944]). The factors which were statistically significant in univariate analysis and those known to be related factors for renal event were considered simultaneously as independent variables for multiple logistic regression analysis. PI can be a novel indicator for renal events in patients with type 2 diabetes mellitus. Despite the advances in renoprotective therapies, such as renin-angiotensin system blockade and sodium-glucose cotransporter-2 inhibitors1,2, the prevalence of diabetic kidney disease (DKD) and resources spent on healthcare due to DKD are increasing globally in patients with type 2 diabetes mellitus. DKD develops in approximately 40% of patients with diabetes and is one of the leading causes of end-stage renal disease3–5. DKD has been reported to be associated with the progression of cardiovascular diseases and increased risk of cardiovascular mortality6–8. Total deaths due to cardiovascular diseases and infections are highly prevalent in patients with end-stage renal disease (ESRD)9. The progression of DKD involves glomerular hyperfiltration, albuminuria, decline in estimated glomerular filtration rate (eGFR), and ESRD. Patients with type 2 diabetes mellitus present heterogeneous process of DKD10. Indeed, normoalbuminuric renal insufficiency is common in patients with type 2 diabetes mellitus11. Interstitial changes such as chronic renal hypoxia might precede glomerular disease without albuminuria, wherein, intrarenal arteriosclerosis might be a main factor for declining eGFR. Further, the peripheral perfusion index (PI) is the ratio of pulsatile blood flow to non-pulsatile blood flow in the monitored tissue and has been shown to reflect changes in peripheral perfusion12,13. We have recently demonstrated that a low PI value indicates atherosclerosis in clinical care setting14 and diabetic kidney disease in the patients with type 2 disease in the cross sectional 1 Department of Diabetes and Endocrinology, Matsushita Memorial Hospital, 5-55 Sotojima-cho, Moriguchi, 5708540, Japan. 2Department of Endocrinology and Metabolism, Kyoto Prefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan. 3Department of Nephrology, Matsushita Memorial Hospital, Moriguchi, Japan. 4Department of General Affairs, Matsushita Memorial Hospital, Moriguchi, Japan. 5Department of Gastroenterology, Matsushita Memorial Hospital, Moriguchi, Japan. 6Department of Surgery, Matsushita Memorial Hospital, Moriguchi, Japan. *email: Scientific Reports | (2020) 10:6054 | https://doi.org/10.1038/s41598-020-62926-8 1 www.nature.com/scientificreports www.nature.com/scientificreports/ All Patients with eGFR ≥ 60 ml/min/1.73 m2 n (male/female) 566 (332/234) 358 (214/144) Age (years) 70 (61–77) 67 (54–75) Duration of diabetes (years) 7.0 (4.0-14.0) 6.0 (4.0–13.0) Body mass index (kg/m2) 24.3 (21.54–27.8) 23.9 (20.9–27.3) Systolic blood pressure (mmHg) 129 (115–143) 129 (117–141) Diastolic blood pressure (mmHg) 75 (65–82) 76 (68–82) Heart rate (beat/min) 78 (70–90) 79 (71–88) Perfusion index (%) 2.9 (1.8–4.8) 3.2 (2.1–5) Hemoglobin A1c (%) 8.4 (7.3–9.9) 8.5 (7.4–10.0) Total cholesterol (mg/dl) 177 (155–209) 177 (157–210) Triglycerides (mg/dl) 126 (87.8–189.3) 123 (81–181) Uric acid (mg/dl) 5.0 (4.0–6.2) 4.5 (3.7–5.5) Creatinine (mg/dl) 0.8 (0.65–1.03) 0.69 (0.56–0.81) eGFR (ml/min/1.73 m2) 66.2 (51.1–81.3) 78.6 (67.8–93.7) UACR (mg/g Cr) 37.2 (9.5–138.5) 21.7 (8.7–58.2) Hypertension (−/+) 254/312 188/170 Smoking status (never/past/recent) 252/116/198 146/78/134 History of cardiovascular disease (−/+) 378/188 269/89 RAS inhibitor (−/+) 316/250 224/134 Incretin related therapies (−/+) 170/396 128/230 SGLT-2 inhibitor (−/+) 522/44 326/32 Statin (−/+) 336/230 232/126 Table 1. Characteristics of patients. Data are expressed as the median (interquartile range) or absolute number. eGFR, estimated glomerular filtration rate; UACR, urine albumin-to-creatinine ratio; RAS, renin-angiotensin system; SGLT, sodium-glucose cotransporter study15. However, the association of diminished PI with renal events in patients with type 2 diabetes mellitus has not been reported. Therefore, we aimed to clarify whether PI might be an indicator for renal events including decline in eGFR, cardiovascular death, and progression of albuminuria, in patients with type 2 diabetes mellitus. Results The characteristics of 566 patients enrolled in this study are shown in Table 1. The median age of patients was 70 years (IQR range: 61–77 years) and the median PI value was 2.9% (IQR range: 1.8–4.8%). The number of patients who developed ESRD, showed doubling of serum creatinine level, renal death and cardiovascular death, and the progression of albuminuria during the study period was 14 (2.5%), 38 (6.7%), 10 (1.8%), and 192 (33.9%), respectively. The number of patients who developed composite of ESRD, and/or doubling of serum creatinine level and composite of ESRD, doubling of serum creatinine level, renal death and/or cardiovascular death was 40 (7.1%) and 44 (7.8%), respectively. Table 2 shows correlation between PI values and other variables. BMI, total cholesterol, and logarithm of triglyceride level were positively correlated with PI. Age, creatinine level, and logarithm of UACR were negatively (...truncated)