Increased serum PCSK9 levels are associated with renal function impairment in patients with type 2 diabetes mellitus.

PURPOSE: The purpose of this study was to investigate the association between serum proprotein convertase subtilisin/kexin type 9 (PCSK9) levels and renal function impairment in type 2 diabetes mellitus (T2DM) patients. METHODS: PCSK9 levels were measured in T2DM patients, streptozotocin plus high-fat diet (STZ + HFD) mice, human proximal tubular epithelial (HK-2) cells treated with high glucose plus palmitic acid (HGPA) and the corresponding control groups. The T2DM patients were further divided into three groups according to serum PCSK9 levels. An analysis of clinical data was conducted, and a binary logistic regression model was used to test the relationship between potential predictors and urine albumin/urine creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR). RESULTS: PCSK9 levels were higher in the DM group than in the control group in humans, mice and HK-2 cells. The systolic blood pressure (SBP), serum creatinine (Scr), blood urea nitrogen (BUN), triglyceride (TG), and urine α1-MG/urine creatinine ratio (UαCR) values in PCSK9 tertile 3 were significantly higher than those in PCSK9 tertile 1 (p < 0.05). The DBP and UACR values were significantly higher in PCSK9 tertile 3 than in PCSK9 tertile 1 and PCSK9 tertile 2 (both p < 0.05). In addition, URCR values were significantly higher in PCSK9 tertile 3 and PCSK9 tertile 2 than in PCSK9 tertile 1 (both p < 0.05). Serum PCSK9 levels were positively correlated with SBP, Scr, BUN, TG, URCR, UαCR and UACR but inversely correlated with eGFR. In STZ + HFD mice, serum PCSK9 levels were positively correlated with Scr, BUN and UACR, which was consistent with the findings in the patients. A logistic regression model revealed that serum PCSK9 is an independent risk factor for UACR ≥30 mg/g and eGFR <60 mL/min/1.73 m2. The ROC curve showed that 170.53 ng/mL and 337.26 ng/mL PCSK9 were the best cutoff values for UACR ≥30 mg/g and eGFR <60 mL/min/1.73 m2, respectively. CONCLUSION: Serum PCSK9 levels are associated with renal function impairment in T2DM patients and in some patients lower PCSK9 may be helpful to decrease chronic kidney disease.

Prognostic Value of Serum Interleukin-6, NF-κB plus MCP-1 Assay in Patients with Diabetic Nephropathy.

Objective: To assess the prognostic value of serum interleukin-6 (IL-6), nuclear factor-κB (NF-κB), and monocyte chemoattractant protein 1(MCP-1) assay in patients with diabetic nephropathy. Methods: From May 2019 to March 2020, 104 patients with diabetic nephropathy treated in our institution assessed for eligibility were recruited and assigned at a ratio of 1 : 1 to either the observation group ([urinary albumin excretion rate (UAER)] of 30 mg-300 mg/24 h) or the research group ([UAER] >300 mg/24 h). IL-6, MCP-1, renal function indices, and NF-κB levels were determined, and their correlation with DN was analyzed. Logistic regression was used to analyze the influencing factors of end-stage renal disease in patients with diabetic nephropathy. The receiver operating characteristic (ROC) curve was drawn, and the area under the curve (AUC) was calculated to analyze the predictive value of combined detection of IL-6, MCP-1, and NF-κB in the prognosis of patients with diabetic nephropathy. Results: The eligible patients with UAER of 30 mg-300 mg/24 h were associated with significantly higher levels of IL-6, MCP-1, NF-κB, blood urea nitrogen (BUN), and serum creatinine (Scr) versus those with UAER >300 mg/24 h (P < 0.05). During the follow-up, a total of 38 patients progressed to end-stage renal diseases. Eligible patients with end-stage renal diseases showed significantly higher serum IL-6, MCP-1, and NF-κB levels versus those without end-stage renal diseases (P < 0.05). Serum IL-6, MCP-1, and NF-κB are independent risk factors for the occurrence of end-stage renal disease in patients with diabetic nephropathy. The AUCs of IL-6, MCP-1, and NF-κB for predicting the prognosis of patients with diabetic nephropathy were 0.562, 0.634, and 0.647, respectively, and the AUC of the three combined detection for predicting the prognosis of patients with diabetic nephropathy was 0.889. Conclusion: Serum IL-6, NF-κB, and MCP-1 levels are closely related to renal injury and poor prognosis in patients with diabetic nephropathy, and the combined assay is valuable for assessing patients' condition and prognosis.

Soluble tumor necrosis factor receptor 2 is associated with progressive diabetic kidney disease in patients with type 2 diabetes mellitus.

BACKGROUND: Chronic low-grade inflammation is considered one of the major mechanisms for the progression of diabetic kidney disease. We investigated the prognostic value of circulating soluble tumor necrosis factor receptor 2 (sTNFR2) for early nephropathy in patients with type 2 diabetes. MATERIALS AND METHODS: A total of 364 patients with type 2 diabetes and an estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73m2 were followed up for a median of 4 years. Renal outcomes were defined as a composite of either or both a >30% decline in the eGFR and/or albuminuria stage progression determined with consecutive tests. RESULTS: Seventy-three patients developed renal composite events. Serum concentrations of sTNFR2 were strongly associated with the risk of renal function decline and progressive changes in albuminuria. Through a receiver operating characteristic curve analysis, a serum sTNFR2 level of 1.608 ng/mL was adopted as the discriminator value for predicting renal outcomes (area under the curve 0.63, 95% confidence interval 0.57-0.70, p < 0.001), yielding a sensitivity of 75.3% and a specificity of 51.2%. The association of sTNFR2 levels ≥1.608 ng/mL to renal outcomes was significant after adjusting for relevant variables (hazard ratio 2.27, 95% confidence interval 1.23-4.20, p = 0.009) and remained consistent across subgroups stratified by age, sex, systolic blood pressure, eGFR, albuminuria, and the use of renin-angiotensin system blockers. CONCLUSIONS: Higher circulating levels of sTNFR2 are independently associated with an eGFR decline and progressive albuminuria in patients with type 2 diabetes.

Aldosterone-to-Renin Ratio Is Associated with Diabetic Nephropathy in Type 2 Diabetic Patients: A Single-Center Retrospective Study.

BACKGROUND It is well established that primary aldosteronism (PA) and aldosterone-to-renin ratio (ARR) are associated with kidney disease. The aim of this study was to retrospectively investigate the relationship between ARR, urinary albumin excretion (UAE), and estimated glomerular filtration rate (eGFR) in patients with type 2 diabetes from a single center. MATERIAL AND METHODS We included 70 patients with type 2 diabetes, UAE ≤100 mg/day, not taking renin-aldosterone system inhibitors, did not meet the diagnostic criteria for PA, and had an ARR <20. The patients were divided into 3 groups: the normal low (NL) group (33 patients) with a UAE <10 mg/day, the normal (N) group (22 patients) with a UAE of 10-29 mg/day, and the microalbuminuria (M) group (15 patients) with a UAE of 30-100 mg/day. The ARR, plasma renin activity (PRA), and plasma aldosterone (PAC) were compared among groups. RESULTS The ARR was highest in group M (10.1±4.6), 6.5±0.3 in group NL, and 7.0±2.7 in group N. The PRA and PAC were significantly lower in group M (P<0.001). The ARR showed a significant positive correlation with log UAE (r=0.37, P<0.001) and a significant negative correlation with eGFR (r=-0.33, P<0.01). CONCLUSIONS High levels of aldosterone relative to renin, which did not fulfill confirmatory criteria for PA, may be one of the risk factors for the development of diabetic nephropathy in patients with diabetes. The present results are supported by previous research showing that an increased ARR without PA was a risk factor for kidney disease.

A Retrospective Analysis of Hematologic Parameters in Patients with Early Diabetic Kidney Disease.

OBJECTIVE: To retrospectively analyze the hematologic parameters in patients with early Diabetic Kidney Disease (DKD) to define potential biomarkers that can be used to predict early DKD. METHODS: 134 diabetic patients without nephropathy and 49 patients with early DKD were enrolled for this study and the hematologic parameters were retrospectively analyzed. Paired comparison was conducted by T-test and the predicting value of any statistically different parameter was tested using the Receiver Operating Characteristic curve (ROC) analysis model. RESULTS: The number of Neutrophil (N) was higher (P <0.001) while monocyte (M) was lower (P <0.01) in the early DKD group than that of DM group without nephropathy. In addition, neutrophil to lymphocyte ratio (NLR) was higher while platelet to lymphocyte ratio (PLR) was significantly lower in the early DKD group(P <0.001). Results from ROC curve analysis showed the sensitivity and specificity of PLR to predict early DKD were 83.7% and 82.6%, respectively. CONCLUSIONS: PLR may be a potential hematologic parameter that can be used to predict early DKD.

Predictive Ability of Visit-to-Visit Variability of HbA1c Measurements for the Development of Diabetic Kidney Disease: A Retrospective Longitudinal Observational Study.

AIMS: This study is aimed at clarifying the relationship between visit-to-visit variability of glycated hemoglobin (HbA1c) and the risk of diabetic kidney disease (DKD) and to identifying the most useful index of visit-to-visit variability of HbA1c. METHODS: This clinic-based retrospective longitudinal study included 699 Japanese type 2 diabetes mellitus patients. Visit-to-visit variability of HbA1c was calculated as the internal standard deviation of HbA1c (HbA1c-SD), the coefficient of variation of HbA1c (HbA1c-CV), the HbA1c change score (HbA1c-HVS), and the area under the HbA1c curve (HbA1c-AUC) with 3-year serial HbA1c measurement data, and the associations between these indices and the development/progression of DKD were examined. RESULTS: Cox proportional hazards models showed that the HbA1c-SD and HbA1c-AUC were associated with the incidence of microalbuminuria, independently of the HbA1c level. These results were verified and replicated in propensity score (PS) matching and bootstrap analyses. Moreover, the HbA1c-SD and HbA1c-AUC were also associated with oxidized human serum albumin (HSA), an oxidative stress marker. CONCLUSIONS: Visit-to-visit variability of HbA1c was an independent risk factor of microalbuminuria in association with oxidative stress among type 2 diabetes mellitus patients. HbA1c-AUC, a novel index of HbA1c variability, may be a potent prognostic indicator in predicting the risk of microalbuminuria.

Association of significantly elevated plasma levels of NGAL and IGFBP4 in patients with diabetic nephropathy.

BACKGROUND: Diabetic nephropathy (DN) is a type of progressive kidney disease affecting approximately 40% of patients with diabetes. Current DN diagnostic criteria predominantly rely on albuminuria and serum creatinine (sCr) levels. However, the specificity and reliability of both markers are limited. Hence, reliable biomarkers are required for early diagnosis to effectively manage DN progression. METHODS: In this study, a cohort of 159 individuals were clinically evaluated and the plasma levels of NGAL, IGFBP-1, IGFBP-3, and IGFBP-4 were determined using Multiplexing Assays. Additionally, the association between the plasma levels of NGAL, IGFBP-1, IGFBP-3, and IGFBP-4 in patients with DN were compared to those in patients with T2D without kidney disease and control participants. RESULTS: Circulating level of NGAL were significantly higher in people with DN compared to people with T2D and non-diabetic groups (92.76 ± 7.5, 57.22 ± 8.7, and 52.47 ± 2.9 mg/L, respectively; p <  0.0001). IGFBP-4 showed a similar pattern, where it was highest in people with DN (795.61 ng/ml ±130.7) compared to T2D and non-diabetic people (374.56 ng/ml ±86.8, 273.06 ng/ml ±27.8 respectively, ANOVA p <  0.01). The data from this study shows a significant positive correlation between NGAL and IGFBP-4 in people with DN (ρ = .620, p <  0.005). IGFBP-4 also correlated positively with creatinine level and negatively with eGFR, in people with DN supporting its involvement in DN. CONCLUSION: The data from this study shows a parallel increase in the plasma levels of NGAL and IGFBP-4 in DN. This highlights the potential to use these markers for early diagnosis of DN.

d-allulose protects against diabetic nephropathy progression in Otsuka Long-Evans Tokushima Fatty rats with type 2 diabetes.

d-allulose is a rare sugar that has been reported to possess anti-hyperglycemic effects. In the present study, we hypothesized that d-allulose is effective in attenuating the progression of diabetic nephropathy in the Otsuka Long-Evans Tokushima Fatty (OLETF) rat model of type 2 diabetes mellitus. Drinking water with or without 3% d-allulose was administered to OLETF rats for 13 weeks. Long-Evans Tokushima Otsuka rats that received drinking water without d-allulose were used as non-diabetic control rats. d-allulose significantly attenuated the increase in blood glucose levels and progressive mesangial expansion in the glomerulus, which is regarded as a characteristic of diabetic nephropathy, in OLETF rats. d-allulose also attenuated the significant increases in renal IL-6 and tumor necrosis factor-α mRNA levels in OLETF rats, which is a proinflammatory parameter. Additionally, we showed that d-allulose suppresses mesangial matrix expansion, but its correlation with suppressing renal inflammation in OLETF rats should be investigated further. Collectively, our results support the hypothesis that d-allulose can prevent diabetic nephropathy in rats.

Serum chromogranin A correlated with albuminuria in diabetic patients and is associated with early diabetic nephropathy.

BACKGROUND: The kidney is the main site for the removal of chromogranin A (CgA). Previous studies have found that patients with renal impairment displayed elevated concentrations of CgA in plasma and that CgA concentrations reflect a deterioration of renal function. In this study, we aimed to estimate serum CgA levels and to evaluate the role of serum CgA in the early diagnosis of diabetic nephropathy (DN). METHODS: A total of 219 patients with type 2 diabetes mellitus (T2DM) were included in this cross-sectional study. These patients were classified into normoalbuminuria (n = 121), microalbuminuria (n = 73), or macroalbuminuria (n = 25) groups based on their urine albumin to creatinine ratios (UACRs). The degree of DN is reflected by UACR. A control group consisted of 45 healthy subjects. The serum CgA levels were measured by ELISA, and other key parameters were assayed. RESULTS: Serum CgA levels were higher in patients with T2DM than in control subjects, and a statistically significant difference among the studied subgroups regarding CgA was found (P < 0.05). The levels of serum CgA increased gradually with the degree of DN (P < 0.001). Serum CgA levels showed a moderate-intensity positive correlation with UACRs (P < 0.001). A cutoff level of 3.46 ng/ml CgA showed 69.86% sensitivity and 66.12% specificity to detect DN in the early stage. CONCLUSION: The levels of serum CgA increased gradually with the degree of DN and can be used as a biomarker in the early detection of DN.

The Association of Postprandial Triglyceride Variability with Renal Dysfunction and Microalbuminuria in Patients with Type 2 Diabetic Mellitus: A Retrospective and Observational Study.

OBJECTIVE: We examined whether or not day-to-day variations in lipid profiles, especially triglyceride (TG) variability, were associated with the exacerbation of diabetic kidney disease. METHODS: We conducted a retrospective and observational study. First, 527 patients with type 2 diabetes mellitus (DM) who had had their estimated glomerular filtration rate (eGFR) checked every 6 months since 2012 for over 5 years were registered. Variability in postprandial TG was determined using the standard deviation (SD), SD adjusted (Adj-SD) for the number of measurements, and maximum minus minimum difference (MMD) during the first three years of follow-up. The endpoint was a ≥40% decline from baseline in the eGFR, initiation of dialysis or death. Next, 181 patients who had no micro- or macroalbuminuria in February 2013 were selected from among the 527 patients for an analysis. The endpoint was the incidence of microalbuminuria, initiation of dialysis, or death. RESULTS: Among the 527 participants, 110 reached a ≥40% decline from baseline in the eGFR or death. The renal survival was lower in the higher-SD, higher-Adj-SD, and higher-MMD groups than in the lower-SD, lower-Adj-SD, and lower-MMD groups, respectively (log-rank test p = 0.0073, 0.0059, and 0.0195, respectively). A lower SD, lower Adj-SD, and lower MMD were significantly associated with the renal survival in the adjusted model (hazard ratio, 1.62, 1.66, 1.59; 95% confidence intervals, 1.05-2.53, 1.08-2.58, 1.04-2.47, respectively). Next, among 181 participants, 108 developed microalbuminuria or death. The nonincidence of microalbuminuria was lower in the higher-SD, higher-Adj-SD, and higher-MMD groups than in the lower-SD, lower-Adj-SD, and lower-MMD groups, respectively (log-rank test p = 0.0241, 0.0352, and 0.0474, respectively). CONCLUSIONS: Postprandial TG variability is a novel risk factor for eGFR decline and the incidence of microalbuminuria in patients with type 2 DM.

Hypoxia preconditioning increases the ability of healthy but not diabetic rat-derived adipose stromal/stem cells (ASC) to improve histological lesions of streptozotocin-induced diabetic nephropathy.

BACKGROUND: Mesenchymal stromal cells (MSC) have demonstrated ability to improve diabetic nephropathy (DN) in experimental models, as well as by improving kidney endogenous progenitor cells proliferation and differentiation. Many studies have demonstrated the effect of hypoxia on MSC improving their functionality but the potential enhancement of the nephroprotective properties of MSC cultured under low oxygen concentration has been explored in few studies, none of them in the context of DN. On the other hand, diabetes is associated with abnormalities in MSCs functionality. These findings related to the hypoxia preconditioning ability to enhance adipose-tissue derived-MSC (ASC) performance have led us to wonder if hypoxia could increase the known beneficial effect of normal ASC in DN and if it could correct the expected inability of diabetic rat-derived ASC to exert this effect in vivo. To answer these questions, in the present study we have used ASC from healthy and diabetic-induced rats, cultured under standard conditions or hypoxia preconditioned, in a DN rat model induced by streptozotocin (STZ). METHODS: Diabetes was induced in Wistar-rats by 60 mg/kg streptozotocin (STZ) intraperitoneal injection. Fifteen days thereafter, five diabetic-induced rats and five healthy, previously injected with saline, were sacrificed and used as ASC donors . Both healthy and diabetic rat-derived ASC (cASC and dASC, respectively) were cultured under standard conditions (21%O2)(N) or were subjected to a 48 h conditioning period in hypoxia (3%O2)(H). Thus, four types of cells were generated depending on their origin (healthy or diabetic-induced rats) and the culture conditions(N or H):cASC-N, cASC-H, dASC-N and dASC-H. DN experimental study were carried out fifteen days after STZ induction of diabetes in fifty-two healthy rats. DN-induced-animals were randomly assigned to be injected with 200 µL saline as placebo or with 3 × 106 cASC-N, cASC-H, dASC-N or dASC-H, according to the study group. Serum glucose, urea and creatinine, and urine albumin levels were measured at 2-weeks intervals until day+ 45 after ND-induction.Animals were sacrificed and kidneys extracted for histopathological and transmission electron microcopy analysis RESULTS: None of the four study groups that received cell treatment showed significant changes in serum glucose, urea and creatinine levels, urine albumin concentration and body weight compared to placebo ND-induced group. Interestingly, only the group that received cASC-H showed a reduction in glucose and creatinine levels although it did not reach statistical significance.All DN-induced groups treated with ASC reduced significantly renal lesions such as mesangial expansion, mesangiolysis, microaneurysms and acute tubular necrosis compared to ND-induced placebo group (p ≤ 0.05). Renal injuries such as clear tubular cell changes, thickening of tubular basement membrane, tubular cysts and interstitial fibrosis significantly showed reduction in ND-induced rats treated with cASC-H regarding to their received cASCN (p ≤ 0.05). Non statistical differences were observed in the improvement capacity of cASC and dASC culture under standard condition.However, hypoxia preconditioning reduces the presence of tubular cysts (p ≤ 0.01). CONCLUSIONS: Hypoxia preconditioning enhances the ability of healthy rat-derived ASC to improve kidney injury in a rat model of DN. Moreover, diabetic-derived ASC exhibits a similar ability to healthy ASC which is clearly more than expected, but it is not significantly modified by hypoxia preconditioning.

Significance of serum miR-29a in the occurrence and progression of diabetic nephropathy: A cross-sectional study.

BACKGROUND: Diabetic nephropathy (DN), a common microvascular complication of type 2 diabetes mellitus (T2DM), is an important factor causing chronic kidney disease. However, the relationship between miR-29a and DN remains unknown. Therefore, a cross-sectional study was conducted to identify a potential molecular biomarker for DN prevention and management by detecting the serum miR-29a levels. METHODS: The serum miR-29a levels were measured in 360 subjects (180 T2DM patients and 180 healthy controls) using quantitative reverse transcription PCR (qRT-PCR), and other conventional indicators were measured and analysed. A binary logistic regression was used to evaluate the DN risk factors; a receiver operating characteristic (ROC) curve was applied to analyse the diagnostic efficacy of miR-29a for DN, and a Spearman's rank correlation analysis was used to evaluate the correlation between serum miR-29a and cystatin C. RESULTS: The serum miR-29 levels in the T2DM patients were higher than those in the healthy subjects and significantly increased with the progression of DN (p < 0.05). Serum miR-29a and cystatin C are independent predictors of the occurrence of DN. Compared with a single indicator, the combination of serum miR-29a and cystatin C has better DN diagnostic performance. In addition, the serum miR-29a levels were positively correlated with cystatin C in the patients with DN (r = 0.521, p < 0.001). CONCLUSION: The expression of serum miR-29a was significantly associated with the occurrence and progression of DN and is expected to become a potential biomarker for the diagnosis of DN.

Cardiorenal protection with SGLT2 inhibitors in patients with diabetes mellitus: from biomarkers to clinical outcomes in heart failure and diabetic kidney disease.

Type 2 diabetes (T2D) is one of the most common causes of chronic kidney disease (CKD) and cardiovascular (CV) disease. Until recently, glycemic and BP control were the cornerstones for preventing progression of CKD and CV disease associated with T2D. However, there has been a paradigm shift in treatment since the publication of the first clinical trial demonstrating benefits of sodium glucose cotransporter 2 (SGLT2) inhibitors in 2015. SGLT2 inhibitors have been shown to reduce the risk of major adverse CV events and progression of kidney disease in the setting of T2D. However, the elucidation of mechanisms of underlying these clinical benefits is the subject of ongoing investigation. Experimental studies have shown that SGLT2 inhibitors have diverse pleiotropic effects such as modulation of neurohormones such as the renin-angiotensin-aldosterone system, increasing hematocrit, altering energy substrate use, and attenuating systemic inflammation and oxidative stress, all of which have been implicated in the CV and kidney protective effects of SGLT2 inhibitors. In this review, we highlight biomarkers linked with diabetic kidney disease and heart failure and discuss how SGLT2 inhibitor-associated changes potentially mediate the cardiorenal protection observed with these therapies.

Can Probiotics Supplementation Improve Glycemic and Renal Status in Diabetic Nephropathy? A Systematic Review and Meta-Analysis of Clinical Trials.

BACKGROUND & AIM: This meta-analysis was performed to quantify the effects of probiotics on renal and glycemic biomarkers among patients with Diabetic Nephropathy (DN). METHODS: Electronic databases were searched on May 10, 2020. All trials that investigated the effect of probiotics on serum glycemic markers (Fasting Plasma Glucose [FPG], Hemoglobin A1C, Insulin, Homeostatic Model Assessment-Insulin Resistance [HOMA-IR], and Quantitative Insulin Sensitivity Check Index [QUICKI]), and renal status markers (Creatinine [Cr], Blood Urea Nitrogen [BUN], and Glomerular Filtration Rate [GFR]) were included. RESULTS: Seven trials that included 340 patients were identified for analysis. The results indicated that probiotics significantly reduced FPG (WMD= -19.08 mg/dl; 95% CI= -32.16, -5.99; P=0.004), HOMA-IR (WMD= -1.88; 95% CI= -3.63, -0.12; P=0.036), and Cr (WMD= -0.18 mg/dl; 95% CI= -0.26, -0.09; P<0.001) levels in DN patients; however, there was no statistically significant change in Hemoglobin A1C, Insulin, QUICKI, BUN, and GFR. CONCLUSION: This meta-analysis supports the potential use of probiotics in the improvement of some glycemic and renal biomarkers in patients with DN.

Serum Vitamin D: Correlates of Baseline Concentration and Response to Supplementation in VITAL-DKD.

CONTEXT: The effect of daily vitamin D supplementation on the serum concentration of vitamin D (the parent compound) may offer insight into vitamin D disposition. OBJECTIVE: To assess the total serum vitamin D response to vitamin D3 supplementation and whether it varies according to participant characteristics. To compare results with corresponding results for total serum 25-hydroxyvitamin D [25(OH)D], which is used clinically and measured in supplementation trials. DESIGN: Exploratory study within a randomized trial. INTERVENTION: 2000 International Units of vitamin D3 per day (or matching placebo). SETTING: Community-based. PARTICIPANTS: 161 adults (mean ± SD age 70 ± 6 years; 66% males) with type 2 diabetes. MAIN OUTCOME MEASURES: Changes in total serum vitamin D and total serum 25(OH)D concentrations from baseline to year 2. RESULTS: At baseline, there was a positive, nonlinear relation between total serum vitamin D and total serum 25(OH)D concentrations. Adjusted effects of supplementation were a 29.2 (95% CI: 24.3, 34.1) nmol/L increase in serum vitamin D and a 33.4 (95% CI: 27.7, 39.2) nmol/L increase in serum 25(OH)D. Among those with baseline 25(OH)D < 50 compared with ≥ 50 nmol/L, the serum vitamin D response to supplementation was attenuated (15.7 vs 31.2 nmol/L; interaction P-value = 0.02), whereas the serum 25(OH)D response was augmented (47.9 vs 30.7 nmol/L; interaction P-value = 0.05). CONCLUSIONS: Vitamin D3 supplementation increases total serum vitamin D and 25(OH)D concentrations with variation according to baseline 25(OH)D, which suggests that 25-hydroxylation of vitamin D3 is more efficient when serum 25(OH)D concentration is low.

Nutritional Status, Selected Nutrients Intake and Their Relationship with the Concentration of Ghrelin and Adiponectin in Patients with Diabetic Nephropathy.

BACKGROUND: Overnutrition is one of the risk factors of chronic kidney disease (CKD). The factors related to both obesity and CKD are adiponectin and ghrelin. The aim of the study was to assess if there is a link of nutritional status and selected nutrients intake with adiponectin and ghrelin in patients with diabetic nephropathy (DN). METHODS: The study involved 55 patients diagnosed with DN in the pre-dialysis period (two groups: GFR < 30 and >30 mL/min/1.73 m2). In all participants standard blood tests, total ghrelin and total adiponectin plasma concentrations and anthropometric measurements (BMI, WHR- waist-hip ratio, body composition analysis) were performed. The evaluation of energy and nutrient intakes was made using the three-day food record method. RESULTS: Excessive body weight was found in 92.80% patients. The average daily energy intake was 1979.67 kcal/day (14.45% protein energy, 28.86% fat, and carbohydrates 56.89%). In the group with eGFR < 30 mL/min/1.73 m2 the analysis showed a negative relationship between ghrelin and WHR value, and the creatine and albumin concentrations. There was a positive correlation between ghrelin concentration and the consumption of carbohydrates and sucrose. In the group of patients with eGFR > 30 mL/min/1.73 m2, a positive correlation was found between the concentration of ghrelin and the consumption of vegetable protein, carbohydrates, and glucose. CONCLUSIONS: The study confirms the high prevalence of obesity in patients with DN-Excessive supply of protein was found in the patients' diets, which may contribute to the deterioration of the course of the disease and its prognosis. In patients with eGFR < 30 there was a negative correlation between ghrelin concentration and nutritional status, and in patents with eGFR > 30 between ghrelin concentration and some nutrients intake.

Blood and Urine Biomarkers Predicting Worsening Kidney Function in Patients with Type 2 Diabetes Post-Acute Coronary Syndrome: An Analysis from the EXAMINE Trial.

INTRODUCTION: Worsening kidney function (WKF) is frequent among patients with type 2 diabetes (T2D) and a recent acute coronary syndrome (ACS) and is associated with a poor prognosis. An accurate prediction of WKF is clinically important. AIMS: Using data from the Cardiovascular Outcomes Study of Alogliptin in Patients with Type 2 Diabetes and Acute Coronary Syndrome trial including patients with T2D and a recent ACS, and a large biomarker panel incorporating proteins measured both in blood and urine, we aim to determine those with best performance for WKF prediction. METHODS: WKF was defined as a ≥40% estimated glomerular filtration rate (eGFR) drop from baseline, eGFR <15 mL/min, or dialysis. Mixed-effects and time-updated Cox models were used. RESULTS: 5,131 patients were included from whom 222 (4.3%) developed at least one WKF episode over a median follow-up of 18 months. Patients who developed WKF were more frequently women, had longer diabetes duration, a more frequent heart failure history, higher anemia prevalence, and impaired kidney function. In multivariable models including all variables (clinical and biomarkers) independently associated with WKF with a p value ≤0.0001, blood kidney injury molecule 1 (KIM-1) was (by far) the variable with strongest WKF association, followed by anemia. KIM-1 alone provided good discrimination for WKF prediction (area under the curve = 0.73). Patients in the high KIM-1-derived risk tertile had a 6.7-fold higher risk of any WKF than patients classified as low risk. In time-updated Cox models, the occurrence of WKF was independently associated with a higher risk of death: adjusted hazard ratio = 4.93 (3.06-7.96), p value <0.0001. CONCLUSION: Blood KIM-1 was the biomarker with the strongest association with WKF. The occurrence of WKF was independently associated with a higher risk of subsequent cardiovascular events and mortality.

Lipidomics Reveals Serum Specific Lipid Alterations in Diabetic Nephropathy.

In diabetes mellitus (DM), disorders of glucose and lipid metabolism are significant causes of the onset and progression of diabetic nephropathy (DN). However, the exact roles of specific lipid molecules in the pathogenesis of DN remain unclear. This study recruited 577 participants, including healthy controls (HCs), type-2 DM (2-DM) patients, and DN patients, from the clinic. Serum samples were collected under fasting conditions. Liquid chromatography-mass spectrometry-based lipidomics methods were used to explore the lipid changes in the serum and identify potential lipid biomarkers for the diagnosis of DN. Lipidomics revealed that the combination of lysophosphatidylethanolamine (LPE) (16:0) and triacylglycerol (TAG) 54:2-FA18:1 was a biomarker panel for predicting DN. The receiver operating characteristic analysis showed that the panel had a sensitivity of 89.1% and 73.4% with a specificity of 88.1% and 76.7% for discriminating patients with DN from HCs and 2-DM patients. Then, we divided the DN patients in the validation cohort into microalbuminuria (diabetic nephropathy at an early stage, DNE) and macroalbuminuria (diabetic nephropathy at an advanced stage, DNA) groups and found that LPE(16:0), phosphatidylethanolamine (PE) (16:0/20:2), and TAG54:2-FA18:1 were tightly associated with the stages of DN. The sensitivity of the biomarker panel to distinguish between patients with DNE and 2-DM, DNA, and DNE patients was 65.6% and 85.9%, and the specificity was 76.7% and 75.0%, respectively. Our experiment showed that the combination of LPE(16:0), PE(16:0/20:2), and TAG54:2-FA18:1 exhibits excellent performance in the diagnosis of DN.

Serum Irisin and Diabetic Nephropathy in Patients with Diabetes Mellitus.

Dear Editor,I read the article by Wang et al., who conducted a meta-analysis to investigate the association between serum irisin levels and diabetic nephropathy (DN) in patients with type 2 diabetes mellitus (T2DM) 1. The mean serum irisin level in T2DM patients with microalbuminuria was significantly lower than that in T2DM patients with normoalbuminuria. In addition, the mean serum irisin level in T2DM patients with macroalbuminuria was significantly lower than that in T2DM patients with microalbuminuria. Furthermore, the mean serum irisin level in T2DM patients with estimated glomerular infiltration rate (eGFR)<60 ml/min 1.73 m2 was significantly lower than that in T2DM patients with eGFR≥60 ml/min 1.73 m2. The authors concluded that decreased serum irisin level was associated with albuminuria and reduced eGFR in T2DM patients. DN was significantly related to decreased serum irisin level in T2DM patients with dose-response manner. Progression of DN may be considered as advanced DM status, and serum irisin level would reflect glucose intolerance via insulin resistance. I have a comment about their study with special reference to the fundamental relationship between the types of DM and serum irisin levels.

Serum exosomes from diabetic kidney disease patients promote pyroptosis and oxidative stress through the miR-4449/HIC1 pathway.

BACKGROUND: Diabetic kidney disease (DKD) is a major contributor to end-stage renal disease. Several microRNAs (miRNAs) have been found to be enriched in exosomes of DKD patients, but it remains unclear if any of these miRNAs play an important role in the pathogenesis of DKD. METHODS: Exosomes from diabetic kidney disease (DKD) patients were isolated, and the expression of miR-4449 was measured by qRT-PCR. Reactive oxygen species (ROS) was determined by DCDFA assay kit, and pyroptosis was measured by quantifying the level of activated caspase 1. mRNA and protein levels were quantified by qRT-PCR and WB. RESULTS: In this study, we demonstrated that miR-4449 is enriched in the serum exosomes of DKD patients, and these exosomes regulate the expression of pro-inflammatory cytokines, ROS levels, and pyroptosis through miR-4449. CONCLUSIONS: Our study uncovered a novel mechanism for the progression of DKD that is mediated through miR-4449 in serum exosomes, which highlights an important role for exosomes in the pathogenesis of DKD.