Progression Of Diabetic Kidney Disease In Patients Research Articles

Plasma proteomics of diabetic kidney disease among Asians with younger-onset type 2 diabetes.

Patients with younger onset of type 2 diabetes (YT2D) have increased risk for kidney failure compared to those with late onset. However, the mechanism of diabetic kidney disease (DKD) progression in this high-risk group is poorly understood. To identify novel biomarkers and potential causal proteins associated with DKD progression in patients with YT2D. Among YT2D (T2D onset age ≤ 40 years), 144 DKD progressors (cases) were matched for T2D onset age, sex, and ethnicity with 292 non-progressors (controls) and divided into discovery and validation sets. DKD progression was defined as decline of estimated glomerular filtration rate (eGFR) of 3ml/min/1.73m2 or greater or 40% decline in eGFR from baseline. 1472 plasma proteins were measured through a multiplex immunoassay that uses a proximity extension assay technology. Multivariable logistic regression was used to identify proteins associated with DKD progression. Mendelian randomization (MR) was used to evaluate causal relationship between plasma proteins and DKD progression. 42 plasma proteins were associated with DKD progression, independent of traditional cardio-renal risk factors, baseline eGFR and urine albumin-to-creatinine ratio (uACR). The proteins identified were related to inflammatory and remodelling biological processes. Our findings suggested angiogenin as one of the top signals (odds ratio =5.29, 95% CI 2.39-11.73, P = 4.03 × 10-5). Furthermore, genetically determined plasma angiogenin level was associated with increased odds of DKD progression. Large-scale proteomic analysis identified novel proteomic biomarkers for DKD progression in YT2D. Genetic evidence suggest a causal role of plasma angiogenin in DKD progression.

Association Between Liver Fibrosis Score and Diabetic Kidney Disease: A Retrospective Cross-Sectional Study of Hospitalized Patients.

To investigate the association between liver fibrosis score and diabetic kidney disease (DKD) in type 2 diabetes mellitus (T2DM). A total of 897 hospitalized patients with T2DM were included in this study. Each patient completed DKD screening. Logistic regression analysis was used to assess the predictive value of non-alcoholic fatty liver disease fibrosis score (NAFLD-FS) and fibrosis-4 (FIB-4) for the occurrence of DKD and risk for DKD progression, respectively. The prevalence of DKD and risk for its progression significantly increased with increasing NAFLD-FS risk category. DKD prevalence also increased with increasing FIB-4 risk category. Multivariate logistic regression analysis showed that the "high-risk" NAFLD-FS had a significantly higher risk of DKD (odds ratio [OR]: 1.89, 95% confidence interval [CI]: 1.16-3.08) and risk for DKD progression (OR: 2.88, 95% CI: 1.23-6.78), and the "intermediate-risk" FIB-4 had a significantly higher risk of DKD (OR: 1.41, 95% CI: 1.00-1.98). Subgroup analysis showed that the association between NAFLD-FS and FIB-4 and DKD was significant in the female subgroup, whereas the association between the "high-risk" NAFLD-FS and risk for DKD progression was significant in the male subgroup. NAFLD-FS and FIB-4 are strongly associated with DKD and risk for DKD progression in patients with T2DM. Additionally, sexual dimorphism exists in this association.

Renoprotective Effects of Mineralocorticoid Receptor Antagonists Against Diabetic Kidney Disease.

Diabetic kidney disease (DKD) is a growing epidemic worldwide and a leading cause of end-stage kidney disease. Mineralocorticoid receptor (MR) blockade using Finerenone is a recently approved therapeutic approach to slow down the progression of DKD in patients with type 2 diabetes in addition to other therapies such as angiotensin-II converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), sodium-glucose co-transporter 2 (SGLT2) inhibitors, and glucagon-like peptide 1 (GLP-1) analogs. This review elaborates on the pathophysiologic pathways activated by aldosterone (the human mineralocorticoid) in DKD, the pharmacology of three different generations of mineralocorticoid receptor antagonists (MRAs), specifically, spironolactone, eplerenone, and finerenone, and the mechanisms by which these MRAs elicit their protective effects on the kidney under diabetic settings.

Diabetic kidney disease progression is associated with decreased lower-limb muscle mass and increased visceral fat area in T2DM patients.

AimThis study aimed to explore the relationship between lower-limb muscle mass/visceral fat area and diabetic kidney disease (DKD) progression in patients with type 2 diabetes mellitus (T2DM).MethodsA total of 879 participants with T2DM were divided into 4 groups according to the prognosis of CKD classification from Kidney Disease: Improving Global Outcomes (KDIGO). Rectus femoris cross-sectional area (RFCSA) was measured through ultrasound, and visceral fat area (VFA) was evaluated with bioelectric impedance analysis (BIA).ResultsT2DM patients with high to very high prognostic risk of DKD showed a reduced RFCSA (male P < 0.001; female P < 0.05), and an enlarged VFA (male P < 0.05; female P < 0.05). The prognostic risk of DKD was negatively correlated with RFCSA (P < 0.05), but positively correlated with VFA (P < 0.05). Receiver-operating characteristic analysis revealed that the cutoff points of T2DM duration combined with RFCSA and VFA were as follows: (male: 7 years, 6.60 cm2, and 111 cm2; AUC = 0.82; 95% CI: 0.78–0.88; sensitivity, 78.0%; specificity, 68.6%, P < 0.001) (female: 9 years, 5.05 cm2, and 91 cm2; AUC = 0.73; 95% CI: 0.66–0.81; sensitivity, 73.9%; specificity, 63.3%, P < 0.001).ConclusionA significant association was demonstrated between reduced RFCSA/increased VFA and high- to very high-prognostic risk of DKD. T2DM duration, RFCSA, and VFA may be valuable markers of DKD progression in patients with T2DM.Clinical trial registrationhttp://www.chictr.org.cn, identifier ChiCTR2100042214

Serum interleukin-6 levels predict kidney disease progression in diabetic nephropathy.

Inflammation is a main mechanism for the pathogenesis and progression of diabetic kidney disease (DKD). Interleukin-6 (IL-6) is an important inflammatory mediator that is suggested to be involved in the pathogenesis of DKD. The aim of our study was to evaluate the association between IL-6 levels and progression of DKD in patients with type 2 diabetes mellitus. Materials an methods: IL-6 levels were measured at baseline and after 4 and 12 months in 70 patients included in a multi-center, randomized controlled clinical trial designed to compare the effect of RAS blockers in monotherapy to dual blockade for slowing the progression of DKD. The primary composite endpoint was > 50% increase in baseline serum creatinine, end-stage kidney disease (ESKD), or death. The median follow-up was 36 months, during which 27 patients (38.6%) reached the primary endpoint. Baseline IL-6 levels correlated with TNF-α, C-reactive protein, and PTH levels. Survival analysis showed that patients with the highest IL-6 levels (> 4.84 pg/mL) reached the primary endpoint faster than the other two groups. Multivariate Cox regression analysis showed that baseline IL-6 levels > 4.84 pg/mL (HR 4.10, 95% CI 1.36 - 12.31) were a risk factor for reaching the primary endpoint adjusted for eGFR and proteinuria. Generalized linear mixed model analysis showed no effect on subsequent IL-6 levels either with RAS blockade monotherapy or dual blockade. These results suggest that treatment with RAS blockade does not influence IL-6 levels. IL-6 is independently associated with an increased risk for progression of DKD.

Factors predicting the progression of diabetic kidney disease in type 2 diabetic patients using continuous glucose monitoring

Background. An increase in the prevalence of type 2 diabetes mellitus (DM) is accompanied by an increase in the number of patients with severe chronic complications. Diabetic kidney disease (DKD) is the leading cause of death in these patients after cardiovascular diseases. The purpose was to predict the progression of DKD in patients with type 2 diabetes mellitus depending on the glucose variability (GV) measured by continuous glucose monitoring. Materials and methods. We examined 53 type 2 DM patients aged 57.0 (51.0; 64.0) years with an average disease duration of 9.0 (6.0; 13.0) years. The laboratory examination included determination of glycated hemoglobin, blood creatinine, albuminuria (AU), glomerular filtration rate (GFR) according to CKD-EPI equation. GV was measured by iPro2 GMS system. The maximum and minimum blood glucose levels and standard deviation (SD) of glycemia were considered. The role of GV in predicting DKD progression has been established using stepwise multiple regression analysis. Results. DKD was detected in 41.51% of patients. In regression analysis, we created a linear multiple regression equation to describe the dependence of AU on the GV, F=10.39 (p&lt;0.001). The variability of AU by 36.7% is due to the minimum level of glycemia and SD of glycemia— multiple correlation coefficient R is 0.6372, the coefficient of determination R2 is 0.4060, adjusted R2 is 0.3670. Partial coefficient of correlation between AU and SD of glycemia, r=0.25 (p=0.027); between AU and the minimum blood glucose level, r=0.31 (p=0.005). Conclusions. According to the results of correlation analysis, a significant effect of GV, as well as the value of minimum blood glucose level on AU was established. It is statistically proved that high fluctuations of glycemia (SD) should be considered as a factor predicting the progression of DKD in type 2 DM patients. Using regression analysis, a mathematical model of DKD progression in type 2 DM patients was developed based on GV parameters.

Особливості добового профілю артеріального тиску у хворих на цукровий діабет залежно від ендотеліальної дисфункції

Актуальність. Цукровий діабет (ЦД) — захворювання, що супроводжується оксидативним стресом, хронічним неспецифічним запаленням, пошкодженням судинної стінки, ендотеліальною дисфункцією. Особливістю перебігу артеріальної гіпертензії у хворих на ЦД є більш раннє формування діабетичної хвороби нирок (ДХН). Сьогодні здійснюється пошук маркерів ендотеліальної дисфункції, що дозволять виявляти ДХН на ранніх стадіях, коли зміни в нирках потенційно оборотні. Метою роботи було дослідити показники добового профілю артеріального тиску у хворих на ЦД та визначити їх взаємозв’язки з показниками швидкості клубочкової фільтрації й ендотеліальної функції за рівнем показників TGF-β1 (transforming growth factor beta-1 — трансформуючий фактор росту бета-1) та VCAM-1 (vascular cell adhesion molecule 1 — васкулярна молекула судинної адгезії 1). Матеріали та методи. У дослідження включені 124 хворі на ЦД, із них 66 пацієнтів із ЦД 1-го типу, 58 — із ЦД 2-го типу. Результати. Рівні показників ендотеліальної функції TGF-β1 та VCAM-1 у хворих на ЦД 1-го та 2-го типів кількісно залежали від показника швидкості клубочкової фільтрації. Між показниками ендотеліальної функції TGF-β1, VCAM-1 та показниками добового моніторування артеріального тиску виявлені сильні та середньої сили кореляційні зв’язки, у зв’язку з чим комплекс показників добового моніторування артеріального тиску та наявність ендотеліальної дисфункції можна вважати ранніми ознаками прогресування ДХН. Висновки. Для добового профілю артеріального тиску у хворих на ЦД на ранніх стадіях діабетичної нефропатії характерне вірогідне порушення циркадних ритмів. Недостатнє нічне зниження артеріального тиску у хворих на ЦД 1-го та 2-го типу характеризує наявність прогресування діабетичної нефропатії за показниками добового індексу артеріального тиску.

FC 085SERUM INTERLEUKIN-6 LEVELS PREDICT RENAL DISEASE PROGRESSION IN DIABETIC KIDNEY DISEASE

Abstract Background and Aims Inflammation is a main mechanism for the pathogenesis and progression of diabetic kidney disease (DKD). Interleukin-6 (IL-6) is an important inflammatory mediator and different studies have suggested its involvement in the pathogenesis of DKD. The aim of our study was to evaluate the association between IL-6 levels and progression of DKD in patients with type 2 diabetes. We also tested whether the use of optimal doses of RAS blockade in monotherapy had an influence on the levels of IL-6 in comparison with dual blockade. Method IL-6 levels were measured at baseline and after 4 and 12 months in 70 patients included in the PRONEDI trial (EUDRACT 2004-002470-31), a multicenter, randomized controlled clinical trial. The study included type 2 diabetes patients with a clinical diagnosis of DKD, stage 2 or 3 CKD, and a urinary protein/creatinine ratio (UPCR) &amp;gt;300 mg/g (morning urine spot) on 2 separate opportunities. The primary composite endpoint was a &amp;gt;50% increase in baseline serum creatinine, end stage kidney disease (ESKD) or death. Cox regression model was adjusted for potential confounders or modifiers including eGFR calculated using the CKD-EPI equation and UPCR. Mixed models were adjusted to study longitudinal data. Results The recruitment period was 18 months and the median follow-up was 36 (IQR: 20-48) months, after which 27 patients (38.6%) reached the primary endpoint. At baseline mean IL-6 levels in the whole cohort were 4.58 ± 2.90, at 4 months 4.61 ± 3.10 and at 12 months: 6.14 ± 4.97. Patients were further divided into three groups according to the tertiles of baseline IL-6 levels (tertile 1: 0.65–2.65 pg/mL; tertile 2: 2.66–4.83 pg/mL and tertile 3: 4.84–13.30 pg/mL). There were no differences among the groups in demographic characteristics, cardiovascular risk factors, serum creatinine or proteinuria among the groups. Correlation analyses for IL6 and other inflammatory parameters were carried out for all subjects. The results showed that inflammatory parameters had a significant correlation between them. IL-6 levels correlated with TNFα (r: 0.29; 95% CI: 0.05 - 0.49 p= 0.02), C-reactive protein (r= 0.61; 95%CI: 0.44 - 0.74 p&amp;lt;0.01), and PTH (r: 0.30, 95% CI: 0.03-0.54, p=0.03). However, in the univariate analysis only IL-6 tertiles were associated with the primary outcome (OR: 2.41; 95% CI 1.25-4.64, p=0.008). Patients with the highest IL-6 levels (&amp;gt;4.84 pg/ml) experienced a significantly faster evolution to endpoint (mean survival: 33.2 months, CI 95%: 25.2-41.3) than the other 2 groups. In the multivariate Cox regression analysis, the highest levels of IL-6 (Tertile 3) were significantly associated with the primary outcome (HR:3.86; 95%CI: 1.08-13.86) after being adjusted for baseline serum creatinine and proteinuria. The time-dependent area under the ROC curve at two years of follow-up was 0.88 (95% CI: 0.79 - 0.97). The best cut-off IL-6 level was found at 4.68 pg/ml (sensitivity: 100%, specificity: 78.7%) Generalized linear mixed model analysis showed no effect on subsequent IL-6 levels either with RAS blockade monotherapy or dual blockade. Conclusion In conclusion, our results show that higher levels of IL-6 are independently associated with progression of DKD in patients with type 2 diabetes, and that treatment with RAS blockade does not influence these levels. Serum IL-6 may be used as a noninvasive biomarker of progression to ESKD. Since our results show that higher IL-6 levels are associated with a worse renal prognosis, anti- inflammatory drugs that modulate IL-6 could be promising therapeutic agents to improve outcomes. Further studies focusing on the potential applications of anti-IL6 treatment in DKD are warranted.

Serum cell-free DNA and progression of diabetic kidney disease: a prospective study

AimsCell-free DNA (cfDNA) is associated with diabetes and cardiovascular diseases. Our study was to evaluate whether serum cfDNA could predict the progression of diabetic kidney disease (DKD).MethodsIn this prospective study,...

504-P: TGF-ß1 and VCAM-1 as Early Diagnostic Biomarkers of Diabetic Kidney Disease Progression

Aim: To evaluate the significance of using transforming growth factor beta 1 (TGF-β1) and vascular adhesion molecule -1 (VCAM-1) as early prognostic markers of diabetic kidney disease (DKD) progression in patients with DM type 1 and 2. Materials and Methods: The study included 66 patients with T1DM, 58 with T2DM and 20 healthy volunteers. Diabetic patients were divided into three groups depending on the estimated glomerular filtration rate. All patients were equal for age and sex. The endothelial function was determined by TGF-β1 and VCAM-1 levels. Recognitive Operating Characteristic - was used to assess the discrimination ability (diagnostic test value) to be a predictor of DKD progression. Results: Patients of all study groups had significantly higher (p˂0,05) levels of TGF-b1 and VCAM-1 versus control group. That’s present endothelial dysfunction in DM patients. The diagnostic value of TGF-b1 and VCAM-1 was compared with diagnostic value of AU. The highest test’s sensitivity and specificity has TGF-b1, its predictive ability concerning DKD progression can be assessed as “excellent” for both types of DM (Se = 100.0; Sr = 100.0; AUC = 1.000; p &amp;lt; 0.001). VCAM-1 has “excellent” operating characteristics for predicting DKD progression in T2DM (Se = 100,0; SP = 88,89; AUC = 0,923; p &amp;lt;0.001) and “very good” in T1DM (Se = 86,36; Sp = 90.48; AUC = 0.866; p &amp;lt;0.001). AU has “good” operating characteristics concerning DKD progression: Se = 57,50; Sd = 97.44; AUC = 0.785; p &amp;lt;0,001 for type1 and 2 DM. That’s shows us evaluation of AU in DM has a high specificity, but low sensitivity of the prognosis DKD progression for both types of DM. Conclusion: We provide evidences that TGF-β1 and VCAM-1 can be used for prediction of DKD progression in patients with type 1 and type 2 DM. Diagnostic capabilities of VCAM-1 and TGF-β1 significantly exceed the diagnostic capabilities of AU, which determines them as early markers. Disclosure C. Daria: None. N. Pertseva: None.

Risk factors in metabolic syndrome predict the progression of diabetic nephropathy in patients with type 2 diabetes

BackgroundWhile metabolic syndrome can independently predict the development of diabetic kidney disease (DKD) in patients with type 2 diabetes, the risk factors for DKD progression have rarely been discussed. The purpose of this study is to evaluate the association between metabolic syndrome and the progression of DKD in patients with type 2 diabetes. Material and methodsThis retrospective observational cohort study lasted approximately five years. We defined metabolic syndrome using the criteria of the National Cholesterol Education Program Adult Treatment Panel III with the Asian definition of obesity. The progression of DKD was demonstrated by either the progression of albuminuria or worsening renal function. Progression of albuminuria was defined by the transition from normoalbuminuria (<30 mg/g) to microalbuminuria (30–300 mg/g) or from micro- to macroalbuminuria (>300 mg/g). Worsening renal function was defined by a reduction of eGFR to 50% of the baseline or the doubling of serum creatinine. We adopted multivariate Cox-regression analysis to determine the risk factors associated with DKD progression. ResultsThis study consisted of 935 type 2 diabetic patients with a mean age of 64.62 years. We found progression of albuminuria in 172 patients (18.4%) and worsened renal function in 41 patients (4.4%). After Cox regression analysis, the multivariable-adjusted HR for the progression of albuminuria and worsened renal function was 1.65 (95% C.I.:1.07–2.53 P = 0.022) and 2.62 (95% C.I.:1.01–6.79 P = 0.047) respectively, for those with metabolic syndrome compared to those without metabolic syndrome. ConclusionThe presence of metabolic syndrome independently predicts DKD progression in patients with type 2 diabetes.

STC-1 ameliorates renal injury in diabetic nephropathy by inhibiting the expression of BNIP3 through the AMPK/SIRT3 pathway

Diabetic kidney disease (DKD) is the leading cause of morbidity and mortality in individuals with diabetes, and it is the leading cause of end-stage renal disease (ESRD) worldwide. Stanniocalcin-1 (STC-1) is present in various tissues, and it has antioxidant and anti-apoptotic activities, which play a role in kidney protection, including diabetic nephropathy (DN). However, the mechanism that underlies these effects remains unknown. This study suggests that STC-1 ameliorates oxidative stress and cell apoptosis in the kidneys of db/db mice and high glucose (HG)-treated BUMPT cells by inhibiting Bnip3 expression through AMPK/Sirt3 pathway activation. In the clinic, DKD patients with high levels of STC-1 have a better prognosis than patients with low STC-1 levels. Thus, we concluded that STC-1 ameliorates renal injury in DN by inhibiting the expression of Bnip3 through the AMPK/SIRT3 pathway and that serum STC-1 is independently associated with DKD progression in patients with type 2 diabetes. As high STC-1 levels indicate a better prognosis, synthetic STC-1 may become a potential drug for the treatment of DKD patients.

Mineralocorticoid Antagonism and Diabetic Kidney Disease.

Type 2 diabetes (T2D) is associated with an increased risk of diabetic kidney disease (DKD), cardiovascular disease, and heart failure, in part through activation of the renin-angiotensin-aldosterone system (RAAS). Although recent cardiovascular outcome trials have identified newer therapeutic agents such as sodium-glucose cotransporter-2 (SGLT-2) inhibitors and glucagon-like peptide-1 (GLP-1)-receptor agonists that reduce the risk of these complications, patients still exhibit residual cardiorenal morbidity and mortality. Accordingly, the identification of pharmacological agents that attenuate micro- and macrovascular complications related to T2D is a major priority. Our aim was to review evidence for the role of novel mineralocorticoid receptor antagonists (MRAs) that are being developed as adjunctive therapies to reduce the risk of DKD and cardiovascular disease in the setting of T2D. Dual RAAS blockade with angiotensin-converting enzyme (ACE) inhibitor plus angiotensin receptor blockade (ARB) or ARB plus renin inhibition increases serious adverse events such as acute kidney injury and stroke. Due to the potential for these serious side effects, more recent interest has focused on newer, more selective non-steroidal MRAs such as finerenone as cardiorenal protective therapies. Finerenone reduces albuminuria in the setting of DKD in patients with T2D and has a lower risk of hyperkalemia compared to currently available MRAs. Novel MRAs such as finerenone have the potential to reduce the risk of DKD progression in patients with T2D. The impact of finerenone on hard, long-term cardiorenal endpoints is being examined in the FIGARO and FIDELIO trials in patients with DKD.

Endothelial Dysfunction and 24-Hour Ambulatory Blood Pressure Monitoring in Patients with Diabetes

Abstract Arterial hypertension in patients with diabetes plays a main role in the earlier development of diabetic kidney disease (DKD), and endothelial dysfunction is considered to be a process involved in the development of diabetic complications. It is important to study the markers which gives the opportunity to identify DKD in early stage. In this article is presented a study of 24-hour Ambulatory Blood Pressure Monitoring (24hABPM) data in patients with diabetes and its interconnection with estimated glomerular filtration rate and endothelial dysfunction. The endothelial function was determined using the levels of TGF-b1(transforming growth factor-beta1) and VCAM-1 (vascular cell adhesion molecule-1). In our study, we obtained convincing results that complex including endothelial dysfunction and results of 24hABPM can be considered as early signs of DKD progression in patients with diabetes.