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    Association of HbA Variability and Renal Progression in Patients with Type 2 Diabetes with Chronic Kidney Disease Stages 3⁻4. Lee Mei-Yueh,Huang Jiun-Chi,Chen Szu-Chia,Chiou Hsin-Ying Clair,Wu Pei-Yu International journal of molecular sciences Little is known about the predictive value of glycosylated hemoglobin (HbA) variability in patients with advanced chronic kidney disease (CKD). The aim of this study was to investigate whether HbA variability is associated with progression to end-stage renal disease in diabetic patients with stages 3⁻5 CKD, and whether different stages of CKD affect these associations. Three hundred and eighty-eight patients with diabetes and stages 3⁻5 CKD were enrolled in this longitudinal study. Intra-individual HbA variability was defined as the standard deviation (SD) of HbA, and the renal endpoint was defined as commencing dialysis. The results indicated that, during a median follow-up period of 3.5 years, 108 patients started dialysis. Adjusted Cox analysis showed an association between the highest tertile of HbA SD (tertile 3 vs. tertile 1) and a lower risk of the renal endpoint (hazard ratio = 0.175; 95% confidence interval = 0.059⁻0.518; = 0.002) in the patients with an HbA level ≥ 7% and stages 3⁻4 CKD, but not in stage 5 CKD. Further subgroup analysis showed that the highest two tertiles of HbA SD were associated with a lower risk of the renal endpoint in the group with a decreasing trend of HbA. Our results demonstrated that greater HbA variability and a decreasing trend of HbA, which may be related to intensive diabetes control, was associated with a lower risk of progression to dialysis in the patients with stages 3⁻4 CKD and poor glycemic control (HbA1c ≥ 7%). 10.3390/ijms19124116
    Clinical utility of serum beta-2-microglobulin as a predictor of diabetic complications in patients with type 2 diabetes without renal impairment. Kim M K,Yun K-J,Chun H J,Jang E-H,Han K-D,Park Y-M,Baek K-H,Song K-H,Cha B-Y,Park C S,Kwon H-S Diabetes & metabolism AIM:As serum beta-2-microglobulin (B2M) levels are usually elevated in patients with renal failure, they have been suggested as a surrogate marker of cardiovascular mortality for patients with chronic kidney disease. Glycation of B2M is cytotoxic and may contribute to the risk of diabetic complications in patients with diabetes. Our objective was to evaluate the relationship between B2M and diabetic complications in patients with type 2 diabetes (T2D) and normal kidney function. METHODS:A total of 366 patients with T2D and preserved renal function with no clinical evidence of cardiovascular disease were enrolled consecutively into this study. High B2M was defined as a median serum B2M level ≥ 1.8 mg/L. Subclinical atherosclerosis was defined as a carotid artery intima-media thickness (C-IMT) ≥ 0.9 mm or the presence of carotid plaque. The definition of diabetic nephropathy was based on the presence of albuminuria (≥ 30 mg/g creatinine). RESULTS:Patients with high B2M were older, and had diabetes of longer duration, higher serum creatinine, microalbuminuria, and increased vascular stiffness and C-IMT compared with patients with low B2M. B2M levels were positively correlated with C-IMT and vascular stiffness, and these associations remained constant after adjusting for age. In addition, after adjusting for age, gender, body mass index, serum creatinine, hypertension, smoking and alcohol consumption, the adjusted odds ratio (OR) for atherosclerosis was 2.01 [95% confidence interval (CI): 1.02-3.94] per 1mg/L increase in B2M. The prevalences of diabetic retinopathy and nephropathy were significantly higher with a high B2M than with a low B2M. The multiple adjusted OR for diabetic nephropathy was 2.29 (95% CI: 1.11-4.72) per 1mg/L increase of B2M. CONCLUSION:Higher serum B2M was an independent risk factor for subclinical atherosclerosis and diabetic nephropathy in patients with T2D without renal impairment. 10.1016/j.diabet.2014.08.002
    Haemoglobin A1c variability is a strong, independent predictor of all-cause mortality in patients with type 2 diabetes. Orsi Emanuela,Solini Anna,Bonora Enzo,Fondelli Cecilia,Trevisan Roberto,Vedovato Monica,Cavalot Franco,Gruden Gabriella,Morano Susanna,Nicolucci Antonio,Penno Giuseppe,Pugliese Giuseppe, Diabetes, obesity & metabolism AIMS:To evaluate various measures of haemoglobin (Hb) A1c variability, compared with average HbA1c, as independent predictors of mortality. MATERIALS AND METHODS:The Renal Insufficiency And Cardiovascular Events Italian multicentre study enroled 15 733 patients with type 2 diabetes from 19 diabetes clinics during 2006-2008. A total of 3 to 5 HbA1c measures, obtained during the 2-year period before enrolment, were available from 9 centres (8290 patients) and were used to calculate average HbA1c (HbA1c -MEAN) and HbA1c variability, measured as intra-individual standard deviation (HbA1c-SD), SD adjusted for the number of HbA1c assessments (HbA1c-AdjSD) and coefficient of variation (HbA1c-CV), that is, the HbA1c-SD to HbA1c-MEAN ratio. Vital status on October 31, 2015 was retrieved for 8252 patients (99.5%). RESULTS:The measures of HbA1c variability increased according to quartiles of HbA1c-MEAN and vice versa. HbA1c-MEAN and measures of HbA1c variability were associated with all-cause mortality; however, the strength of association of HbA1c-MEAN was lower than that of HbA1c -SD, HbA1c-CV or HbA1c-AdjSD, and disappeared after adjusting for confounders and any of the measures of HbA1c variability. Mortality increased with quartiles of HbA1c-MEAN, HbA1c -SD, HbA1c-CV and HbA1c-AdjSD, but only the association with HbA1c variability measures remained after adjustment for confounders and/or each other measure. In the fully adjusted model, mortality risk was lower for HbA1c-SD below the median and higher for HbA1c-SD above the median, regardless of whether HbA1c-MEAN was below or above the median. Conclusions HbA1c variability is a strong, independent predictor of all-cause mortality in type 2 diabetes and appears to be even more powerful than average HbA1c in predicting mortality. 10.1111/dom.13306
    Nuclear factor κB-dependent anti-inflammatory effects of s-allyl cysteine and s-propyl cysteine in kidney of diabetic mice. Mong Mei-chin,Yin Mei-chin Journal of agricultural and food chemistry Renal protection of s-allyl cysteine (SAC) and s-propyl cysteine (SPC) in diabetic mice against inflammatory injury was examined. Each agent at 0.5 and 1 g/L was added to the drinking water for 10 weeks. SAC or SPC intake significantly reduced the plasma blood urea nitrogen level and increased creatinine clearance (P < 0.05). These treatments significantly lowered the renal level of reactive oxygen species, nitric oxide, interleukin-6, tumor necrosis factor-α, and prostaglandin E(2) in diabetic mice (P < 0.05). Renal mRNA expression of inducible nitric oxide synthase, cyclooxygenase-2, protein kinase C (PKC)-α, PKC-β, and PKC-γ was enhanced in diabetic mice (P < 0.05); however, SAC or SPC treatments dose dependently declined mRNA expression of these factors (P < 0.05). Nuclear factor κB (NF-κB) activity, mRNA expression, and protein production in kidney of diabetic mice were significantly increased (P < 0.05). SAC or SPC intake dose dependently suppressed NF-κB activity, NF-κB p65 mRNA expression, and protein level (P < 0.05). Diabetes also enhanced renal protein expression of mitogen-activated protein kinase (P < 0.05). SAC and SPC, only at a high dose, significantly suppressed protein production of p-p38 and p-ERK1/2 (P < 0.05). Renal mRNA expression and protein generation of peroxisome proliferator-activated receptor (PPAR)-α and PPAR-γ were significantly down-regulated in diabetic mice (P < 0.05), but the intake of SAC or SPC at high dose up-regulated PPAR-α and PPAR-γ (P < 0.05). These findings support that SAC and SPC are potent anti-inflammatory agents against diabetic kidney diseases. 10.1021/jf3002685
    Association of serum vaspin and adiponectin levels with renal function in patients with or without type 2 diabetes mellitus. Yan Meiyu,Su Bin,Peng Wenhui,Li Liang,Li Hailing,Zhuang Jianhui,Lu Yuyan,Jian Weixia,Wei Yidong,Li Weiming,Qu Shen,Xu Yawei Journal of diabetes research Vaspin and adiponectin are two adipocytokines with antidiabetic effects. Some studies reported that levels of adiponectin and vaspin were correlated with decreased glomerular filtration rate (FGR) and increased albuminuria. We therefore evaluated the vaspin and adiponectin levels in renal insufficiency (RI) patients with or without T2DM. Serum vaspin, adiponectin levels were measured in 416 subjects with or without T2DM. Analysis was made between groups divided by these subjects presence or absence of RI. We found that serum adiponectin level was significantly higher in nondiabetic patients with RI than in nondiabetic subjects without RI; however, there were no statistical differences between the diabetic patients with RI and without RI. In all the subjects, the serum adiponectin level was also higher in 50 individuals with RI than that in 366 subjects without RI. The serum vaspin levels showed no significant differences between the diabetic patients or nondiabetics subjects with RI and without RI. Contrary to adiponectin, the serum vaspin level was lower in 169 patients with T2DM than in 247 individuals without T2DM. Our data suggested that both of T2DM and renal insufficiency were correlated with the serum level of adiponectin. However, the serum vaspin levels showed no significant difference between the individuals with renal insufficiency and without renal insufficiency. 10.1155/2014/868732
    Urine metabolites are associated with glomerular lesions in type 2 diabetes. Saulnier Pierre-Jean,Darshi Manjula,Wheelock Kevin M,Looker Helen C,Fufaa Gudeta D,Knowler William C,Weil E Jennifer,Tanamas Stephanie K,Lemley Kevin V,Saito Rintaro,Natarajan Loki,Nelson Robert G,Sharma Kumar Metabolomics : Official journal of the Metabolomic Society INTRODUCTION:Little is known about the association of urine metabolites with structural lesions in persons with diabetes. OBJECTIVES:We examined the relationship between 12 urine metabolites and kidney structure in American Indians with type 2 diabetes. METHODS:Data were from a 6-year clinical trial that assessed renoprotective efficacy of losartan, and included a kidney biopsy at the end of the treatment period. Metabolites were measured in urine samples collected within a median of 6.5 months before the research biopsy. Associations of the creatinine-adjusted urine metabolites with kidney structural variables were examined by Pearson's correlations and multivariable linear regression after adjustment for age, sex, diabetes duration, hemoglobin A, mean arterial pressure, glomerular filtration rate (iothalamate), and losartan treatment. RESULTS:Participants (n = 62, mean age 45 ± 10 years) had mean ± standard deviation glomerular filtration rate of 137 ± 50 ml/min and median (interquartile range) urine albumin:creatinine ratio of 34 (14-85) mg/g near the time of the biopsy. Urine aconitic and glycolic acids correlated positively with glomerular filtration surface density (partial r = 0.29, P = 0.030 and r = 0.50, P < 0.001) and total filtration surface per glomerulus (partial r = 0.32, P = 0.019 and r = 0.43, P = 0.001). 2-ethyl 3-OH propionate correlated positively with the percentage of fenestrated endothelium (partial r = 0.32, P = 0.019). Citric acid correlated negatively with mesangial fractional volume (partial r=-0.36, P = 0.007), and homovanillic acid correlated negatively with podocyte foot process width (partial r=-0.31, P = 0.022). CONCLUSIONS:Alterations of urine metabolites may associate with early glomerular lesions in diabetic kidney disease. 10.1007/s11306-018-1380-6
    Plasma Leucine-Rich α-2-Glycoprotein 1 Predicts Rapid eGFR Decline and Albuminuria Progression in Type 2 Diabetes Mellitus. Liu Jian-Jun,Pek Sharon Li Ting,Ang Kevin,Tavintharan Subramaniam,Lim Su Chi, The Journal of clinical endocrinology and metabolism Context:Abnormal angiogenesis plays an important role in pathogenesis of diabetic kidney disease (DKD). Leucine-rich α-2 glycoprotein 1 (LRG1) is a newly identified angiogenic factor. Objective:To study whether plasma LRG1 may independently predict progression of DKD in individuals with type 2 diabetes mellitus (T2DM). Design and Setting:Prospective cohort study in a regional hospital. Patients:In total, 1226 T2DM participants were followed for a mean ± standard deviation (SD) of 3.1 ± 0.4 years. Main Outcomes:Albuminuria progression was defined as elevation in albuminuria level to a higher category. Chronic kidney disease (CKD) progression [rapid estimated glomerular filtration rate (eGFR) decline] was defined as a 40% or greater deterioration in eGFR in 3 years. Results:Both participants with albuminuria progression and those with CKD progression had higher plasma LRG1 levels at baseline. LRG1 independently predicted albuminuria progression above traditional risk factors, including baseline eGFR and urine albumin to creatinine ratio. A 1-SD increment in LRG1 was associated with a 1.26-fold [95% confidence interval (CI), 1.04 to 1.53, P = 0.018] higher adjusted risk for albuminuria progression. The association of LRG1 with microalbuminuria to macroalbuminuria progression was stronger than its association with normoalbuminuria to microalbuminuria progression [odds ratio (OR), 1.51; 95% CI, 1.04 to 2.18, P = 0.029 vs OR, 1.09; 95% CI, 0.86 to 1.37, P = 0.486, per 1-SD LRG1 increment]. Also, LRG1 independently predicted CKD progression above traditional risk factors. A 1-SD increment in LRG1 was associated with a 1.48-fold (95% CI, 1.04 to 2.11, P = 0.032) higher adjusted risk for CKD progression. Conclusions:Plasma LRG1 predicts both albuminuria and CKD progression beyond traditional risk factors. It may play a role in the pathologic pathway leading to progression of DKD in T2DM. 10.1210/jc.2017-00930
    HbA1c variability is associated with microalbuminuria development in type 2 diabetes: a 7-year prospective cohort study. Hsu C C,Chang H Y,Huang M C,Hwang S J,Yang Y C,Lee Y S,Shin S J,Tai T Y Diabetologia AIMS/HYPOTHESIS:HbA(1c) variability has been shown to be an independent risk factor for nephropathy in patients with type 1 diabetes. In this study, we aimed to explore the association between HbA(1c) variability and microalbuminuria development in patients with type 2 diabetes. We also intended to test the applicability of serially measured HbA(1c) over 2 years for this risk assessment. METHODS:Between 2003 and 2005, we recruited 821 middle-aged normoalbuminuric individuals with type 2 diabetes and followed them through to the end of 2010. The average follow-up time was 6.2 years. We defined microalbuminuria as a urine albumin to creatinine ratio of 30 mg/g (3.4 mg/mmol) or higher. HbA(1c) variability was calculated by the SD of serially measured HbA(1c). The Cox proportional hazards model was used to evaluate the association between HbA(1c) SD quartile and development of microalbuminuria. RESULTS:The incidence of microalbuminuria for the overall population was 58.4, 58.6, 60.8 and 91.9 per 1,000 person-years for Q1- to Q4-adjusted HbA(1c) SD, respectively (p for trend = 0.042). Compared with patients in Q1, those in Q4 were about 37% more likely to develop microalbuminuria. The HR derived from a series of 2 year HbA(1c) measurements was similar to that from data collection for longer than 4 years. CONCLUSIONS/INTERPRETATION:In addition to mean HbA(1c) values, HbA(1c) variability, even measured as early as 2 years, is independently associated with the development of microalbuminuria in patients with type 2 diabetes. 10.1007/s00125-012-2700-4
    The paradoxical association of adiponectin with mortality rate in patients with type 2 diabetes: evidence of synergism with kidney function. Ortega Moreno Lorena,Lamacchia Olga,Salvemini Lucia,De Bonis Concetta,De Cosmo Salvatore,Cignarelli Mauro,Trischitta Vincenzo,Menzaghi Claudia Atherosclerosis BACKGROUND:The paradoxical relationship between high adiponectin and increased mortality, described in several clinical subsets, has been reported only once in type 2 diabetes (T2D) and only in selected elderly patients. We investigated this relationship in unselected patients with T2D and, then, addressed its possible modulation by several demographic and clinical conditions, known to affect per se mortality rate. METHODS:Patients from the Gargano Mortality Study (GMS; N = 897, follow-up = 10.5 ± 3.7 years; 290 events) and the Foggia Mortality Study (FMS; N = 529, follow-up = 7.1 ± 2.5 years; 143 events), were investigated. RESULTS:For each SD adiponectin increase, HRs (95% CI) for all-cause mortality were 1.30 (1.19-1.43) in GMS, 1.43 (1.26-1.64) in FMS and 1.34 (1.24-1.45) in the combined studies. This association was independent of the possible confounding effect of demographics, adiposity measures, diabetes-related features, kidney function-related parameters and medications (p = 9.34 × 10(-9)). While no interaction was observed between adiponectin and sex, age, smoking habits, BMI, waist circumference, HbA1c, diabetes duration, micro-/macro-albuminuria and medications, a strong interaction was observed with GFR, with a significant adiponectin-mortality association observed in individuals with GFR ≥ but not those with GFR < 60 ml/min/1.73 m(2); p for adiponectin-by-GFR status interaction = 2.13 × 10(-6)). CONCLUSION:This is the first study reporting a paradoxical association of adiponectin with all-cause mortality in a large sample of unselected diabetic patients and indicating that such counterintuitive effect is observed only among patients with preserved kidney function. Further studies are needed to address if the strong interwoven effect of adiponectin and GFR turns to be useful in improving previously validated tools for predicting mortality in T2D. 10.1016/j.atherosclerosis.2015.12.026
    Filtration markers as predictors of ESRD and mortality in Southwestern American Indians with type 2 diabetes. Foster Meredith C,Inker Lesley A,Hsu Chi-Yuan,Eckfeldt John H,Levey Andrew S,Pavkov Meda E,Myers Bryan D,Bennett Peter H,Kimmel Paul L,Vasan Ramachandran S,Coresh Josef,Nelson Robert G, American journal of kidney diseases : the official journal of the National Kidney Foundation BACKGROUND:A growing number of serum filtration markers are associated with mortality and end-stage renal disease (ESRD) in adults. Whether β-trace protein (BTP) and β2-microglobulin (B2M) are associated with these outcomes in adults with type 2 diabetes is not known. STUDY DESIGN:Longitudinal cohort study. SETTING & PARTICIPANTS:250 Pima Indians with type 2 diabetes (69% women; mean age, 42 years; mean diabetes duration, 11 years). PREDICTORS:Serum BTP, B2M, and glomerular filtration rate measured by iothalamate clearance (mGFR) or estimated using creatinine (eGFRcr) or cystatin C level (eGFRcys). OUTCOMES & MEASUREMENTS:Incident ESRD and all-cause mortality through December 2013. HRs were reported per interquartile range decrease of the inverse of BTP and B2M (1/BTP and 1/B2M) using Cox regression. Improvement in risk prediction with the addition of BTP or B2M level to established markers (eGFRcys with mGFR or eGFRcr) was evaluated using C statistics, continuous net reclassification improvement, and relative integrated discrimination improvement (RIDI). RESULTS:During a median follow-up of 14 years, 69 participants developed ESRD and 95 died. Both novel markers were associated with ESRD in multivariable models. BTP level remained statistically significant after further adjustment for mGFR (1/BTP, 1.53 [95% CI, 1.01-2.30]; 1/B2M, 1.54 [95% CI, 0.98-2.42]). B2M level was associated with mortality in multivariable models and after further adjustment for mGFR (HR, 2.12; 95% CI, 1.38-3.26). The addition of B2M level to established markers increased the C statistic for mortality but only weakly when assessed by either continuous net reclassification improvement or RIDI; none was improved for ESRD by the addition of these markers. LIMITATIONS:Small sample size, single measurements of markers. CONCLUSIONS:In Pima Indians with type 2 diabetes, BTP and, to a lesser extent, B2M levels were associated with ESRD. B2M level was associated with mortality after adjustment for traditional risk factors and established filtration markers. Further studies are warranted to confirm whether inclusion of B2M level in a multimarker approach leads to improved risk prediction for mortality in this population. 10.1053/j.ajkd.2015.01.013
    Levels of Serum 25(OH)VD3, HIF-1α, VEGF, vWf, and IGF-1 and Their Correlation in Type 2 Diabetes Patients with Different Urine Albumin Creatinine Ratio. Shao Ying,Lv Chuan,Yuan Qin,Wang Qiuyue Journal of diabetes research OBJECTIVE:To investigate changes in serum 25(OH)VD3, HIF-1α, VEGF, vWf, IGF-1, and their correlation in type 2 diabetes patients at different stages of diabetic kidney disease (DKD). METHODS:502 type 2 diabetes patients were divided into three groups: Normoalbuminuric group (201 patients), Microalbuminuric group (171 patients), and Macroalbuminuric group (130 patients). Serum 25-hydroxyvitamin D3 [25(OH)VD3] was measured by chemiluminescence. Serum hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF), von Willebrand factor (vWf), and insulin-like growth factor-1 (IGF-1) were determined by enzyme-linked immunosorbent assay. We detected the aforementioned serum factors in all cases and 224 control subjects. RESULTS:Serum HIF-1α, VEGF, vWf, and IGF-1 in type 2 diabetes patients were significantly higher than those in the control group and increased with the increase of Ln(ACR), respectively (P < 0.001). Serum 25(OH)VD3 was significantly lower in type 2 diabetes patients and decreased with the increase of Ln(ACR) (P < 0.001). Ln(ACR) was positively correlated with duration, HbA1c, Scr, BUN, TC, LDL, TG, UA, HIF-1α, VEGF, IGF-1, vWf, and Fg and negatively correlated with 25(OH)VD3 and eGFR. CONCLUSION:Serum HIF-1α, VEGF, vWf, and IGF-1 may be involved in DKD process through inflammation, angiogenesis, and endothelial injury. Serum 25(OH)VD3 may have protective effects on DKD partly by inhibiting inflammation, abnormal angiogenesis, and vascular endothelial dysfunction. 10.1155/2016/1925424
    Evaluation of the diagnostic characteristics of urinary kidney injury molecule 1 (uKIM-1) and uKIM-1/creatinine ratio in the assessment of incipient diabetic kidney disease. De Carvalho José Antonio M,Tatsch Etiane,Hausen Bruna S,Bollick Yãnaí S,Torbitz Vanessa D,Guarda Naiara S,De Campos Luízi P,Duarte Thiago,Duarte Marta M M F,Londero Sílvia W K,Comim Fabio V,Moresco Rafael N Clinical chemistry and laboratory medicine 10.1515/cclm-2014-0655
    The synergistic relationship between estimated GFR and microalbuminuria in predicting long-term progression to ESRD or death in patients with diabetes: results from the Kidney Early Evaluation Program (KEEP). Amin Amit P,Whaley-Connell Adam T,Li Suying,Chen Shu-Cheng,McCullough Peter A,Kosiborod Mikhail N, American journal of kidney diseases : the official journal of the National Kidney Foundation INTRODUCTION:Chronic kidney disease may complicate diabetes, often manifesting with reduced glomerular filtration rate (GFR), albuminuria, or both. Although greater albuminuria and lower estimated GFR both predict adverse prognosis, whether a synergistic prognostic interaction occurs in patients with diabetes has not been defined in a large national cohort study. METHODS:We used 2000-2011 data from the National Kidney Foundation's Kidney Early Evaluation Program (KEEP) for 42,761 participants with diabetes. Kaplan-Meier survival analysis and multivariable Cox regression were used to ascertain the association of estimated GFR, albumin-creatinine ratio (ACR), and their interaction on all-cause mortality and progression to end-stage renal disease (ESRD) at a median 4 years of follow-up. RESULTS:Of 42,761 participants with diabetes, 8,618 (20.2%) had estimated GFR <60 mL/min/1.73 m(2), 7,715 (18.0%) had ACR >30 mg/g, and 2,641 (6.2%) had both. The unadjusted incidence (per 1,000 person-years) of all-cause mortality increased from 3.1 (95% CI, 2.4-3.8) in participants with estimated GFR ≥ 105 mL/min/1.73 m(2) and no albuminuria to 73.7 (95% CI, 54.9-92.5) in participants with estimated GFR <30 mL/min/1.73 m(2) and macroalbuminuria (P < 0.001). Progression to ESRD likewise increased from 0.2 (95% CI, 0-0.4) to 220.4 (95% CI, 177.2-263.6) per 1,000 person-years (P < 0.001). After adjustment for confounders, both estimated GFR and albuminuria were associated independently with mortality and progression to ESRD, with a strong synergistic interaction (P for interaction < 0.001); estimated GFR <30 mL/min/1.73 m(2) and macroalbuminuria together were associated with a 5-fold higher risk of mortality and a more than 1,000-fold higher risk of progression to ESRD (compared with patients with estimated GFR >60 mL/min/1.73 m(2) and ACR <30 mg/g; P < 0.001 for both outcomes). CONCLUSIONS:In this large cohort of diabetic KEEP participants with more than 170,000 person-years of follow-up, both estimated GFR and albuminuria were associated independently with mortality and progression to ESRD, with a strong synergistic interaction. 10.1053/j.ajkd.2013.01.005
    Toe-brachial index is associated more strongly with albuminuria or glomerular filtration rate than ankle-brachial index in patients with type 2 diabetes. Fukui Michiaki,Tanaka Muhei,Hamaguchi Masahide,Senmaru Takafumi,Sakabe Kazumi,Asano Mai,Yamazaki Masahiro,Hasegawa Goji,Imai Saeko,Nakamura Naoto Hypertension research : official journal of the Japanese Society of Hypertension The aim of this study was to investigate whether toe-brachial index (TBI) is more strongly associated with albuminuria or estimated glomerular filtration rate (eGFR) than ankle-brachial index (ABI), and thus is a more suitable tool for evaluating the association between peripheral artery disease (PAD) and diabetic nephropathy than ABI in patients with type 2 diabetes. We evaluated the relationships between ABI or TBI and the degree of urinary albumin excretion or eGFR, as well as the major cardiovascular risk factors, in 390 patients with type 2 diabetes. Furthermore, we compared the area under the receiver-operator characteristic curve (AUC) of TBI or ABI for albuminuria or chronic kidney disease (CKD). Low-density lipoprotein cholesterol was negatively associated with ABI. Age and duration of diabetes were negatively associated with TBI, and diastolic blood pressure and high-density lipoprotein cholesterol were positively associated with TBI. Log (urinary albumin excretion) was associated more strongly with TBI (r=-0.265, P<0.0001) than with ABI (r=-0.132, P=0.0111), and eGFR was positively associated with TBI (r=0.195, P=0.0002) but not with ABI (r=0.023, P=0.6571). The AUCs of TBI for albuminuria (P=0.0002) and CKD (P=0.0322) were significantly greater than those of ABI. In conclusion, TBI is associated more strongly with albuminuria and eGFR than ABI in patients with type 2 diabetes. Our study suggests that TBI may be a more suitable tool for evaluating the association between PAD and diabetic nephropathy than ABI in patients with type 2 diabetes. 10.1038/hr.2012.16
    Urinary monocyte chemotactic protein 1: marker of renal function decline in diabetic and nondiabetic proteinuric renal disease. Camilla Roberta,Brachemi Soumeya,Pichette Vincent,Cartier Pierre,Laforest-Renald Alexandra,MacRae Tara,Madore François,Troyanov Stéphan Journal of nephrology BACKGROUND:Reliable biomarkers are needed to identify patients with glomerular disease at risk of progression. Transforming growth factor beta 1 (TGF-β1) and monocyte chemotactic protein 1 (MCP-1) play key roles in promoting renal tissue injury. Whether their urinary measurement adds value to current predictors of progression is uncertain. METHODS:We enrolled patients with diabetic (n=53) and nondiabetic (n=47) proteinuric renal disease and retrospectively studied their rate of renal function decline over a defined period of 2 years. We simultaneously measured urinary protein, MCP-1 and TGF-β1, standardized to urinary creatinine. RESULTS:The initial estimated glomerular filtration rate, proteinuria and rate of renal function decline (slope) were 36 ml/min per 1.73 m2, 1.1 g/day and -4.0 ± 7.2 ml/ min per 1.73 m2 year. Median urinary TGF-β1 and MCP- 1 levels were 0.3 (range 0.0-28.1) and 18 (range 3-370) ng/mmol of creatinine, respectively. Urinary protein and MCP-1 to creatinine ratios were associated with slope, and this applied to both diabetic and nondiabetic patients separately. Urinary TGF-β1 showed no relation to slope. However, the majority of its measurements were below the suggested reproducibility threshold. Using linear regression, both normalized urinary protein and MCP-1 were independently associated with the slope. Adding urinary MCP-1 to the model statistically raised the adjusted R2 from 0.35 to 0.40, refining patient risk stratification. Using cutoffs for urinary protein and MCP-1 obtained by receiver operating characteristic curves, the risk of progression was confidently determined in 80% of patients. CONCLUSION:Urinary MCP-1 is a marker of renal function decline in diabetic and nondiabetic proteinuric renal disease, independent of and additive to proteinuria. 10.5301/jn.2010.1458
    Plasma triglycerides as a risk factor for chronic kidney disease in type 2 diabetes mellitus: Evidence from northeastern Thailand. Zaman Sojib Bin,Karim Mohd Anisul,Hossain Naznin,Al Kibria Gulam Muhammed,Islam Sheikh Mohammed Shariful Diabetes research and clinical practice AIMS:To investigate the observational association between plasma triglyceride and CKD in patients with T2DM. METHODS:A hospital-based retrospective registry was used to obtain data of 3,748 T2DM patients from May 2016 to October 2016. Anthropometric measurements and biochemical reports of T2DM patients with CKD were obtained by data extraction of medical records. CKD was defined according to the estimated glomerular filtration rate (eGFR< 60 mL/min/1.73 m). Multiple logistic regression was used to determine the association between plasma triglyceride and CKD. RESULTS:The mean age of the participants was 61.4 ± 11.0 years, and a majority of them was female (64%) with poor glycemic control (83%), increased plasma triglyceride (51%) and 27% of T2DM patients had CKD. There was a significant trend towards deteriorating renal function (lower eGFR) with categorically raised triglyceride levels. After controlling for age, sex and other confounders, 'borderline high' (adjusted odds ratio (OR): 1.24, 95% confidence interval (CI): 1.01-1.54), 'high' (adjusted OR: 1.52, 95% CI: 1.24-1.85) and 'very high' (adjusted OR: 3.40, 95% CI: 1.94-5.94) triglyceride level groups had higher likelihood to have CKD compared to normal triglyceride level. CONCLUSION:CKD was associated with a higher level of plasma triglyceride among patients with T2DM. These results support the rationale to screen and manage increased triglyceride in routine clinical practices among persons with diabetes to prevent CKD. 10.1016/j.diabres.2018.02.011
    Association between gain in adiposity and diabetic kidney disease worsening in type 2 diabetes is mediated by deteriorating glycaemic control: A 3-year follow-up analysis. Moh Angela Mei Chung,Wang Jiexun,Tan Clara,Ang Su Fen,Ang Keven,Subramaniam Tavintharan,Sum Chee Fang,Kwan Pek Yee,Lee Simon Biing Ming,Tang Wern Ee,Lim Su Chi Diabetes research and clinical practice AIMS:Increased adiposity confers elevated risk for diabetic kidney disease (DKD) progression in type 2 diabetes mellitus (T2DM). This 3-year prospective study examined whether worsening of metabolic control e.g. development of uncontrolled diabetes mediated the relationship between increased adiposity and DKD deterioration. METHODS:T2DM subjects who had adequately controlled diabetes (HbA1c < 8%) at initial recruitment were analysed (N = 853). HbA1c ≥ 8% at follow-up was classified as development of uncontrolled T2DM. Absolute changes in body weight (ΔWeight), body mass index (ΔBMI), and body fat mass (ΔBFM) were calculated by subtracting baseline from follow-up values. DKD deterioration (outcome) was defined as an increase in the composite ranking of relative risk by glomerular filtration rate and albuminuria levels (Kidney Disease: Improving Global Outcomes 2009). RESULTS:Subjects with deteriorated DKD displayed lower reduction in body composition at follow-up than those who remained stable or/improved (all P < 0.05). In separate regression models, ΔWeight (risk ratio (RR):1.04, 95% CI:1.01-1.06), ΔBMI (RR:1.07, 95% CI:1.01-1.13), and ΔBFM (RR:1.03, 95% CI:1.01-1.06) were independently associated with worsened DKD. The associations were attenuated after accounting for the loss of glycaemic control. Binary mediation analysis revealed that the development of uncontrolled diabetes explained 41.7%, 45.4% and 39.7%, respectively, of the effects of ΔWeight, ΔBMI and ΔBFM on the outcome. CONCLUSIONS:Among T2DM individuals who had adequately-controlled T2DM at initial recruitment, the relationship between gain in adiposity and DKD deterioration is mediated by the development of poor glycaemic control over time. Therefore, preventing worsening adiposity and hyperglycaemia is pivotal to impede DKD progression. 10.1016/j.diabres.2019.107812
    Cumulative risk, age at onset, and sex-specific differences for developing end-stage renal disease in young patients with type 1 diabetes: a nationwide population-based cohort study. Möllsten Anna,Svensson Maria,Waernbaum Ingeborg,Berhan Yonas,Schön Staffan,Nyström Lennarth,Arnqvist Hans J,Dahlquist Gisela, , , Diabetes OBJECTIVE:This study aimed to estimate the current cumulative risk of end-stage renal disease (ESRD) due to diabetic nephropathy in a large, nationwide, population-based prospective type 1 diabetes cohort and specifically study the effects of sex and age at onset. RESEARCH DESIGN AND METHODS:In Sweden, all incident cases of type 1 diabetes aged 0-14 years and 15-34 years are recorded in validated research registers since 1977 and 1983, respectively. These registers were linked to the Swedish Renal Registry, which, since 1991, collects data on patients who receive active uremia treatment. Patients with > or =13 years duration of type 1 diabetes were included (n = 11,681). RESULTS:During a median time of follow-up of 20 years, 127 patients had developed ESRD due to diabetic nephropathy. The cumulative incidence at 30 years of type 1 diabetes duration was low, with a male predominance (4.1% [95% CI 3.1-5.3] vs. 2.5% [1.7-3.5]). In both male and female subjects, onset of type 1 diabetes before 10 years of age was associated with the lowest risk of developing ESRD. The highest risk of ESRD was found in male subjects diagnosed at age 20-34 years (hazard ratio 3.0 [95% CI 1.5-5.7]). In female subjects with onset at age 20-34 years, the risk was similar to patients' diagnosed before age 10 years. CONCLUSIONS:The cumulative incidence of ESRD is exceptionally low in young type 1 diabetic patients in Sweden. There is a striking difference in risk for male compared with female patients. The different patterns of risk by age at onset and sex suggest a role for puberty and sex hormones. 10.2337/db09-1744
    Clinical predictive biomarkers for normoalbuminuric diabetic kidney disease. Gohda Tomohito,Nishizaki Yuji,Murakoshi Maki,Nojiri Shuko,Yanagisawa Naotake,Shibata Terumi,Yamashita Mami,Tanaka Kanako,Yamashita Yoshinori,Suzuki Yusuke,Kamei Nozomu Diabetes research and clinical practice AIMS:A portion of patients with diabetes mellitus follow the progression of a non-albuminuria-based pathway; i.e., normoalbuminuric diabetic kidney disease (NA-DKD). However, the risk factors which determine NA-DKD are not yet fully understood. This cross-sectional study was therefore aimed to investigate the association between various biomarker levels and estimated glomerular filtration rate (eGFR) in patients with type 2 diabetes mellitus and normoalbuminuria (T2D-NA). METHODS:We measured cardiovascular disease (CVD) [serum osteoprotegerin (OPG), plasma brain natriuretic peptide (BNP), cardio-ankle vascular index (CAVI)], tubular damage [urinary L-type fatty acid binding protein (L-FABP)], and inflammatory [serum tumornecrosis factor (TNF) α and its receptors (TNFRs)] biomarkers in 314 patients with T2D-NA. RESULTS:The biomarkers of CVD and inflammation showed a significant negative correlation with eGFR. In a logistic multivariate model, none of the biomarkers, except TNFα and TNFRs, were associated with reduced renal function (eGFR < 60 mL/min/1.73 m) after adjustment for possible biological and clinical covariates. However, the association observed in TNFα was lost after adjusting for TNFR and other covariates. CONCLUSIONS:In patients with T2D-NA, elevated levels of circulating TNFRs, but not of TNFα, were strongly associated with reduced renal function, independently of all relevant covariates. 10.1016/j.diabres.2018.04.026
    Urinary Fibrinogen as a Predictor of Progression of CKD. Wang Hongtian,Zheng Chunxia,Lu Yinghui,Jiang Qi,Yin Ru,Zhu Ping,Zhou Minlin,Liu Zhihong Clinical journal of the American Society of Nephrology : CJASN BACKGROUND AND OBJECTIVES:Fibrinogen has been reported to be involved in kidney tubulointerstitial fibrosis and podocyte injury in mouse models. However, the relationship between urinary fibrinogen and kidney outcomes has not been clarified in patients with CKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS:We evaluated 402 patients with CKD and kidney biopsies, including 101 with diabetic nephropathy, 94 with idiopathic membranous nephropathy, 55 with idiopathic FSGS, and 152 with IgA nephropathy. We quantified urinary fibrinogen by ELISA and tested associations with kidney histology and progression to ESRD. RESULTS:Median (interquartile range) urinary fibrinogen-to-creatinine ratio was 536 (191-1461) ng/mg for patients with CKD, significantly higher than 2 (2-3) ng/mg for healthy controls (<0.001). Urinary fibrinogen was positively correlated with urine protein (=0.64; <0.001) and interstitial fibrosis and tubular atrophy (=0.10; =0.04), and it was negatively correlated with eGFR (=-0.20; <0.001). Over a median follow-up period of 35 months (interquartile range, 24-78 months), 68 of 402 patients (17%) developed ESRD. Higher urinary fibrinogen level was associated with increased risk of ESRD (hazard ratio, 2.12; 95% confidence interval, 1.31 to 3.26) per log higher urinary fibrinogen-to-creatinine ratio (=0.003) adjusting for age, sex, BP, urine protein, disease type, eGFR, and interstitial fibrosis and tubular atrophy. For prediction of ESRD, the addition of urinary fibrinogen to eGFR, urine protein, and BP increased the area under the receiver operating curve from 0.73 to 0.76, and the Akaike information criterion improved from 333.6 to 327.0. CONCLUSIONS:Urinary fibrinogen correlated with interstitial fibrosis and tubular atrophy and was an independent risk factor for progression of CKD to ESRD. 10.2215/CJN.01360217
    Risk Prediction for Early CKD in Type 2 Diabetes. Dunkler Daniela,Gao Peggy,Lee Shun Fu,Heinze Georg,Clase Catherine M,Tobe Sheldon,Teo Koon K,Gerstein Hertzel,Mann Johannes F E,Oberbauer Rainer, Clinical journal of the American Society of Nephrology : CJASN BACKGROUND AND OBJECTIVES:Quantitative data for prediction of incidence and progression of early CKD are scarce in individuals with type 2 diabetes. Therefore, two risk prediction models were developed for incidence and progression of CKD after 5.5 years and the relative effect of predictors were ascertained. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS:Baseline and prospective follow-up data of two randomized clinical trials, ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial (ONTARGET) and Outcome Reduction with Initial Glargine Intervention (ORIGIN), were used as development and independent validation cohorts, respectively. Individuals aged ≥55 years with type 2 diabetes and normo- or microalbuminuria at baseline were included. Incidence or progression of CKD after 5.5 years was defined as new micro- or macroalbuminuria, doubling of creatinine, or ESRD. The competing risk of death was considered as an additional outcome state in the multinomial logistic models. RESULTS:Of the 6766 ONTARGET participants with diabetes, 1079 (15.9%) experienced incidence or progression of CKD, and 1032 (15.3%) died. The well calibrated, parsimonious laboratory prediction model incorporating only baseline albuminuria, eGFR, sex, and age exhibited an externally validated c-statistic of 0.68 and an R(2) value of 10.6%. Albuminuria, modeled to depict the difference between baseline urinary albumin/creatinine ratio and the threshold for micro- or macroalbuminuria, was mostly responsible for the predictive performance. Inclusion of clinical predictors, such as glucose control, diabetes duration, number of prescribed antihypertensive drugs, previous vascular events, or vascular comorbidities, increased the externally validated c-statistic and R(2) value only to 0.69 and 12.1%, respectively. Explained variation was largely driven by renal and not clinical predictors. CONCLUSIONS:Albuminuria and eGFR were the most important factors to predict onset and progression of early CKD in individuals with type 2 diabetes. However, their predictive ability is modest. Inclusion of demographic, clinical, and other laboratory predictors barely improved predictive performance. 10.2215/CJN.10321014
    Role of elevated serum uric acid levels at the onset of overt nephropathy in the risk for renal function decline in patients with type 2 diabetes. Tanaka Kentaro,Hara Shigeko,Hattori Masakazu,Sakai Ken,Onishi Yukiko,Yoshida Yoko,Kawazu Shoji,Kushiyama Akifumi Journal of diabetes investigation AIMS/INTRODUCTION:Despite the use of intensive therapies, declining renal function is often observed during the overt nephropathy stage of type 2 diabetes. We aimed at investigating the role of serum uric acid (SUA) levels at the onset of overt nephropathy in the risk of renal function decline in type 2 diabetes patients. MATERIALS AND METHODS:The present cohort study included 290 type 2 diabetes patients who were followed from the onset of overt nephropathy. The relationship between SUA and declining renal function was assessed using Cox regression models after adjusting for known risk factors. RESULTS:Over a median 4.8-year follow-up period, 85 patients (4.9/100 person-years) showed serum creatinine (Cr) doubling with a total cumulative incidence of 71.9% at 20 years of follow up. The highest SUA tertile resulted in significantly a higher incidence (7.7/100 person-years) and cumulative incidence at 20 years (85.7%) than the middle (3.9/100 person-years, 54.2%) and lowest (3.0/100 person-years, 55.5%) tertiles. The univariate Cox hazard model resulted in significant risks for Cr doubling related to female sex, short diabetes duration, smoking and elevated levels of low-density lipoprotein cholesterol (LDL-c), glycated hemoglobin and SUA tertiles. SUA tertiles remained statistically significant in the multivariate model (highest vs lowest hazard ratio 2.68, 95% confidence interval 1.48-5.00, P = 0.0009). CONCLUSIONS:Elevated SUA levels within the normal range (men >6.3 mg/dL, women >5.1) at the onset of overt nephropathy resulted in an increased risk for declining renal function in type 2 diabetes patients. 10.1111/jdi.12243
    Serum kidney injury molecule 1 and β-microglobulin perform as well as larger biomarker panels for prediction of rapid decline in renal function in type 2 diabetes. Colombo Marco,Looker Helen C,Farran Bassam,Hess Sibylle,Groop Leif,Palmer Colin N A,Brosnan Mary Julia,Dalton R Neil,Wong Max,Turner Charles,Ahlqvist Emma,Dunger David,Agakov Felix,Durrington Paul,Livingstone Shona,Betteridge John,McKeigue Paul M,Colhoun Helen M, Diabetologia AIMS/HYPOTHESIS:As part of the Surrogate Markers for Micro- and Macrovascular Hard Endpoints for Innovative Diabetes Tools (SUMMIT) programme we previously reported that large panels of biomarkers derived from three analytical platforms maximised prediction of progression of renal decline in type 2 diabetes. Here, we hypothesised that smaller (n ≤ 5), platform-specific combinations of biomarkers selected from these larger panels might achieve similar prediction performance when tested in three additional type 2 diabetes cohorts. METHODS:We used 657 serum samples, held under differing storage conditions, from the Scania Diabetes Registry (SDR) and Genetics of Diabetes Audit and Research Tayside (GoDARTS), and a further 183 nested case-control sample set from the Collaborative Atorvastatin in Diabetes Study (CARDS). We analysed 42 biomarkers measured on the SDR and GoDARTS samples by a variety of methods including standard ELISA, multiplexed ELISA (Luminex) and mass spectrometry. The subset of 21 Luminex biomarkers was also measured on the CARDS samples. We used the event definition of loss of >20% of baseline eGFR during follow-up from a baseline eGFR of 30-75 ml min [1.73 m]. A total of 403 individuals experienced an event during a median follow-up of 7 years. We used discrete-time logistic regression models with tenfold cross-validation to assess association of biomarker panels with loss of kidney function. RESULTS:Twelve biomarkers showed significant association with eGFR decline adjusted for covariates in one or more of the sample sets when evaluated singly. Kidney injury molecule 1 (KIM-1) and β-microglobulin (B2M) showed the most consistent effects, with standardised odds ratios for progression of at least 1.4 (p < 0.0003) in all cohorts. A combination of B2M and KIM-1 added to clinical covariates, including baseline eGFR and albuminuria, modestly improved prediction, increasing the area under the curve in the SDR, Go-DARTS and CARDS by 0.079, 0.073 and 0.239, respectively. Neither the inclusion of additional Luminex biomarkers on top of B2M and KIM-1 nor a sparse mass spectrometry panel, nor the larger multiplatform panels previously identified, consistently improved prediction further across all validation sets. CONCLUSIONS/INTERPRETATION:Serum KIM-1 and B2M independently improve prediction of renal decline from an eGFR of 30-75 ml min [1.73 m] in type 2 diabetes beyond clinical factors and prior eGFR and are robust to varying sample storage conditions. Larger panels of biomarkers did not improve prediction beyond these two biomarkers. 10.1007/s00125-018-4741-9
    Association of serum leptin levels with progression of diabetic kidney disease in patients with type 2 diabetes. Hanai Ko,Babazono Tetsuya,Mugishima Michino,Yoshida Naoshi,Nyumura Izumi,Toya Kiwako,Bouchi Ryotaro,Tanaka Nobue,Uchigata Yasuko Diabetes care OBJECTIVE:To clarify the association of serum leptin levels with progression of diabetic kidney disease in patients with type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS:This was an observational cohort study of 668 patients with T2D. Patients were classified into three groups by sex-specific tertile of leptin levels. Outcome measurements were the rate of change in estimated glomerular filtration rate (eGFR) and progression to a more advanced stage of albuminuria. RESULTS:Patients with low or high leptin levels had a steeper eGFR decline (-2.07 and -2.14 mL/min/1.73 m(2)/year) than those with midrange leptin levels (-0.82 mL/min/1.73 m(2)/year; P < 0.01), whereas patients with low leptin levels had an elevated risk of progression of albuminuria as compared with those with high leptin levels (hazard ratio 3.125 [95% CI 1.302-7.499]). CONCLUSIONS:Both low and high serum leptin levels were risk factors for kidney function decline. Meanwhile, lower serum leptin levels were associated with progression of albuminuria. 10.2337/dc11-1039
    The changes of serum sKlotho and NGAL levels and their correlation in type 2 diabetes mellitus patients with different stages of urinary albumin. Wu Can,Wang Qiuyue,Lv Chuan,Qin Ningning,Lei Sha,Yuan Qin,Wang Guan Diabetes research and clinical practice OBJECTIVE:To investigate the changes of serum anti-aging protein Klotho and neutrophil gelatinase-associated lipocalin (NGAL) levels and their correlation in type 2 diabetes mellitus (T2DM) patients at different stages of diabetic kidney disease (DKD) determined by urinary albuminuria. METHODS:462 cases with T2DM were divided into three groups: normoalbuminuric [N-UAlb; urinary albumin to creatinine ratio (UACR) < 30 mg/g, n=180], microalbuminuric [M-UAlb; UACR 30-300 mg/g, n = 158], macroalbuminuric [L-UAlb; UACR > 300 mg/g, n = 124]. The levels of serum soluble-Klotho (sKlotho), NGAL, 8-isoprostane prostaglandin F2α (8-iso-PGF2α), monocyte chemotactic protein-1 (MCP-1), tumor necrosis factor-α (TNF-α), transforming growth factor-β1 (TGF-β1) were determined by enzyme-linked immunosorbent assay (ELISA) in all cases and 160 control subjects. RESULTS:Compared with control, serum sKlotho levels were significantly decreased (P < 0.001), and serum NGAL levels increased significantly (P < 0.001) in T2DM patients. Furthermore, serum sKlotho and NGAL levels were significantly negatively correlated (P < 0.001). Serum sKlotho levels negatively correlated with UACR, TG, CHO, LDL, 8-Iso-PGF2α, MCP-1, TNF-α, TGF-β1 (P < 0.001), but positively correlated with LDL (P < 0.001). Serum NGAL levels positively correlated with UACR, 8-Iso-PGF2α, MCP-1, TNF-α, TGF-β1 (P < 0.001). In addition, serum NGAL levels and LDL were significantly positively correlated (P = 0.005), and HDL was significantly negatively correlated (P < 0.001). CONCLUSION:Serum Klotho and NGAL levels may become new biomarkers of the early diagnosis of DKD in T2DM. Klotho may participate in the development of DKD pathological mechanism such as oxidative stress related to inflammation, renal fibrosis, lipid metabolic disorders, modulating the pathological process of diabetic kidney tissue. NGAL may play a part in these mechanisms. 10.1016/j.diabres.2014.08.026
    Association of urinary KIM-1, L-FABP, NAG and NGAL with incident end-stage renal disease and mortality in American Indians with type 2 diabetes mellitus. Fufaa Gudeta D,Weil E Jennifer,Nelson Robert G,Hanson Robert L,Bonventre Joseph V,Sabbisetti Venkata,Waikar Sushrut S,Mifflin Theodore E,Zhang Xiaoming,Xie Dawei,Hsu Chi-Yuan,Feldman Harold I,Coresh Josef,Vasan Ramachandran S,Kimmel Paul L,Liu Kathleen D, Diabetologia AIMS/HYPOTHESIS:Kidney injury molecule 1 (KIM-1), liver fatty acid-binding protein (L-FABP), N-acetyl-β-D-glucosaminidase (NAG) and neutrophil gelatinase-associated lipocalin (NGAL) are urinary biomarkers of renal tubular injury. We examined their association with incident end-stage renal disease (ESRD) and all-cause mortality in American Indians with type 2 diabetes. METHODS:Biomarker concentrations were measured in baseline urine samples in 260 Pima Indians who were followed for a median of 14 years. HRs were reported per SD of creatinine (Cr)-normalised log-transformed KIM-1, NAG and NGAL, and for three categories of L-FABP. RESULTS:During follow-up, 74 participants developed ESRD and 101 died. Median concentrations of KIM-1/Cr, NAG/Cr and NGAL/Cr and the proportion of detectable L-FABP were highest in those with macroalbuminuria (p < 0.001 for KIM-1/Cr, NAG/Cr and L-FABP; p = 0.006 for NGAL/Cr). After multivariable adjustment, NGAL/Cr was positively associated with ESRD (HR 1.59, 95% CI 1.20, 2.11) and mortality (HR 1.39, 95% CI 1.06, 1.82); L-FABP/Cr was inversely associated with ESRD (HR [for highest vs lowest tertile] 0.40, 95% CI 0.19, 0.83). Addition of NGAL/Cr to models that included albuminuria and glomerular filtration rate increased the c-statistic for predicting ESRD from 0.828 to 0.833 (p = 0.001) and for death from 0.710 to 0.722 (p = 0.018). Addition of L-FABP/Cr increased the c-statistic for ESRD from 0.828 to 0.832 (p = 0.042). CONCLUSIONS/INTERPRETATION:In Pima Indians with type 2 diabetes, urinary concentrations of NGAL and L-FABP are associated with important health outcomes, but they are unlikely to add to risk prediction with standard markers in a clinically meaningful way given the small increase in the c-statistic. 10.1007/s00125-014-3389-3
    Glomerular hyperfiltration and renal disease progression in type 2 diabetes. Ruggenenti Piero,Porrini Esteban L,Gaspari Flavio,Motterlini Nicola,Cannata Antonio,Carrara Fabiola,Cella Claudia,Ferrari Silvia,Stucchi Nadia,Parvanova Aneliya,Iliev Ilian,Dodesini Alessandro Roberto,Trevisan Roberto,Bossi Antonio,Zaletel Jelka,Remuzzi Giuseppe, Diabetes care OBJECTIVE:To describe the prevalence and determinants of hyperfiltration (glomerular filtration rate [GFR] ≥120 mL/min/1.73 m(2)), GFR decline, and nephropathy onset or progression in type 2 diabetic patients with normo- or microalbuminuria. RESEARCH DESIGN AND METHODS:We longitudinally studied 600 hypertensive type 2 diabetic patients with albuminuria <200 μg/min and who were retrieved from two randomized trials testing the renal effect of trandolapril and delapril. Target blood pressure (BP) was <120/80 mmHg, and HbA(1c) was <7%. GFR, albuminuria, and glucose disposal rate (GDR) were centrally measured by iohexol plasma clearance, nephelometry in three consecutive overnight urine collections, and hyperinsulinemic euglycemic clamp, respectively. RESULTS:Over a median (range) follow-up of 4.0 (1.7-8.1) years, GFR declined by 3.37 (5.71-1.31) mL/min/1.73 m(2) per year. GFR change was bimodal over time: a larger reduction at 6 months significantly predicted slower subsequent decline (coefficient: -0.0054; SE: 0.0009), particularly among hyperfiltering patients. A total of 90 subjects (15%) were hyperfiltering at inclusion, and 11 of 47 (23.4%) patients with persistent hyperfiltration progressed to micro- or macroalbuminuria versus 53 (10.6%) of the 502 who had their hyperfiltration ameliorated at 6 months or were nonhyperfiltering since inclusion (hazard ratio 2.16 [95% CI 1.13-4.14]). Amelioration of hyperfiltration was independent of baseline characteristics or ACE inhibition. It was significantly associated with improved BP and metabolic control, amelioration of GDR, and slower long-term GFR decline on follow-up. CONCLUSIONS:Despite intensified treatment, patients with type 2 diabetes have a fast GFR decline. Hyperfiltration affects a subgroup of patients and may contribute to renal function loss and nephropathy onset or progression. Whether amelioration of hyperfiltration is renoprotective is worth investigating. 10.2337/dc11-2189
    Urinary type IV collagen excretion predicts subsequent declining renal function in type 2 diabetic patients with proteinuria. Katavetin Pisut,Katavetin Paravee,Susantitaphong Paweena,Townamchai Natavudh,Tiranathanagul Khajohn,Tungsanga Kriang,Eiam-Ong Somchai Diabetes research and clinical practice Baseline urinary type IV collagen excretion was negatively correlated with the subsequent GFR change (r(s)=-0.39, p=0.04) in our cohort of 30 type 2 diabetic patients with proteinuria. Therefore, it could be used to predict subsequent declining renal function in type 2 diabetic patients with proteinuria. 10.1016/j.diabres.2010.05.007
    Circulating vitamin D metabolites and kidney disease in type 1 diabetes. de Boer Ian H,Sachs Michael C,Cleary Patricia A,Hoofnagle Andrew N,Lachin John M,Molitch Mark E,Steffes Michael W,Sun Wanjie,Zinman Bernard,Brunzell John D, The Journal of clinical endocrinology and metabolism CONTEXT:Impaired vitamin D metabolism may contribute to the development and progression of diabetic kidney disease. OBJECTIVE:The aim of the study was to test associations of circulating vitamin D metabolites with risks of incident microalbuminuria, impaired glomerular filtration rate (GFR), and hypertension in type 1 diabetes. DESIGN:We performed a cohort study of 1193 participants in the Diabetes Control and Complications Trial (DCCT), a randomized clinical trial of intensive diabetes therapy, and its observational follow-up, the Epidemiology of Diabetes Interventions and Complications (EDIC) Study. We measured plasma concentrations of 25-hydroxyvitamin D [25(OH)D], 1,25-dihydroxyvitamin D, and 24,25-dihydroxyvitamin D by mass spectrometry at the end of the DCCT and tested associations with incident microalbuminuria, impaired GFR, and hypertension over up to 16 yr of EDIC follow-up. RESULTS:At the time metabolites were measured, mean age was 32.4 yr; mean duration of diabetes, 7.5 yr; mean iothalamate GFR, 132.9 ml/min/1.73 m(2); and geometric mean albumin excretion rate, 11.8 mg/24 h. Over follow-up, 166 cases of microalbuminuria, 54 cases of impaired GFR, and 541 cases of hypertension were observed. Compared with 25(OH)D of at least 30 ng/ml, 25(OH)D below 20 ng/ml was associated with a 65% higher risk of microalbuminuria (95% confidence interval, 7 to 154%) in adjusted analyses. Low concentrations of 24,25-dihydroxyvitamin D, but not 1,25-dihydroxyvitamin D, were also associated with increased risk of microalbuminuria. No circulating vitamin D metabolite was associated with risk of impaired GFR or hypertension. CONCLUSIONS:Low plasma concentrations of 25(OH)D and 24,25-dihydroxyvitamin D are associated with increased risk of microalbuminuria in type 1 diabetes. In contrast, we did not find evidence linking impaired vitamin D metabolism to early GFR loss or the development of hypertension. 10.1210/jc.2012-2852
    Uric Acid Is an Independent Risk Factor for Decline in Kidney Function, Cardiovascular Events, and Mortality in Patients With Type 1 Diabetes. Pilemann-Lyberg Sascha,Hansen Tine Willum,Tofte Nete,Winther Signe Abitz,Theilade Simone,Ahluwalia Tarunveer Singh,Rossing Peter Diabetes care OBJECTIVE:Previous studies have provided inconclusive results on the role of uric acid (UA) in risk prediction. Here we aimed to improve the power and precision of the predictive value of UA for the risk of decline in kidney function, cardiovascular events (CVEs), and mortality in patients with type 1 diabetes (T1D). RESEARCH DESIGN AND METHODS:Plasma UA was measured in 670 patients with T1D and various degrees of albuminuria, ranging from normoalbuminuria to macroalbuminuria. Associations of UA with an estimated glomerular filtration rate (eGFR) decline of ≥30%, CVEs, and mortality were analyzed. The median follow-up time was 5.3 years [interquartile range (IQR) 2.7-6.2 years] for a decline in eGFR of ≥30%, 5.8 years (2.5-6.4 years) for progression in albuminuria status, 5.1 years (4.7-5.6 years) for CVE, and 6.2 years (5.8-6.7 years) for mortality. Both univariable and multivariable associations of UA with relevant outcomes and variables were reported. Hazard ratios (HRs) were calculated per doubling of the UA level. RESULTS:A doubling in UA level was associated with a higher risk of decline in eGFR of ≥30% ( = 89) (HR 3.18 [IQR 1.71-5.93]; < 0.001), CVE ( = 94) (HR 2.25 [IQR 1.20-4.21]; = 0.011), and mortality ( = 58) (HR 2.58 [IQR 1.12-5.90]; = 0.025) in adjusted analyses. Adding UA to the adjusted model including conventional risk factors improved the relative integrated discrimination index by 12.6% for a decline in eGFR of ≥30% ( < 0.001), 6.5% for CVE ( = 0.010), and 11.8% ( = 0.003) for mortality. A doubling in UA level was also associated with a steeper decline in eGFR ( < 0.0026) and a steeper increase in urine albumin-to-creatinine ratio ( < 0.0027) in adjusted analysis. CONCLUSIONS:In individuals with T1D, a higher UA level is associated with a higher risk of decline in kidney function, CVE, and mortality, independently of other risk factors. Our results suggest that UA has a promising role in risk stratification among individuals with T1D. 10.2337/dc18-2173
    Effects of uric acid on kidney function decline differ depending on baseline kidney function in type 2 diabetic patients. Hanai Ko,Tauchi Eriko,Nishiwaki Yui,Mori Tomomi,Yokoyama Yoichi,Uchigata Yasuko,Babazono Tetsuya Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association BACKGROUND:Most existing data regarding effects of uric acid (UA) on diabetic kidney disease have considered patients with preserved kidney function. We examined a hypothesis that there are differences in the effects of serum UA levels on the decline in kidney function depending on baseline kidney function in diabetic patients. METHODS:In this historical cohort study, 7033 type 2 diabetic patients were analyzed and classified into two groups as follows: nonchronic kidney disease (non-CKD), with an estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2 (n = 4994), and CKD, with an eGFR <60 mL/min/1.73 m2 (n = 2039). The composite endpoint was a ≥30% decrease in eGFR from baseline or the initiation of renal replacement therapy. The hazard ratio (HR) of serum UA levels at baseline was estimated using multivariate Cox proportional hazards models. RESULTS:There was a significant interaction between UA levels and baseline eGFR with respect to the endpoint (P < 0.001). The HRs of 1 mg/dL increase in UA levels were 1.13 [95% confidence interval (CI) 1.05-1.22, P = 0.002] and 0.93 (95% CI 0.88-0.99, P = 0.02) in the non-CKD and CKD groups, respectively. When patients were classified by quintile of UA levels, the HRs of those in the 5th quintile (versus 1st quintile) were 1.64 (95% CI 1.23-2.18, P < 0.001) and 0.76 (95% CI 0.58-0.99, P = 0.05) in the non-CKD and CKD groups, respectively. CONCLUSIONS:The effects of UA on kidney function decline might differ depending on baseline kidney function in type 2 diabetic patients. High UA levels are the prognostic factor only in patients with preserved kidney function. 10.1093/ndt/gfy138
    The renal tubular damage marker urinary N-acetyl-β-D-glucosaminidase may be more closely associated with early detection of atherosclerosis than the glomerular damage marker albuminuria in patients with type 2 diabetes. Kim So Ra,Lee Yong-Ho,Lee Sang-Guk,Kang Eun Seok,Cha Bong-Soo,Lee Byung-Wan Cardiovascular diabetology BACKGROUND:To determine the association between urinary N-acetyl-β-D-glucosaminidase (NAG), a marker of renal tubulopathy, and carotid intima-media thickness (IMT) and plaques in patients with type 2 diabetes mellitus (T2D) and to compare the predictive value of NAG versus albuminuria, a marker of renal glomerulopathy. METHODS:A total of 343 participants were enrolled in this retrospective cross-sectional study. We recruited participants with T2D who were tested for blood glucose parameters, urinary NAG, and urinary albumin-to-creatinine ratio (ACR) and had been checked for carotid ultrasonography. RESULTS:We classified participants into a below-median urinary NAG group (Group I; n = 172) or an above-median group (Group II; n = 171). Mean, maximum, and mean of maximum carotid IMT and the proportion of patients with carotid plaques were significantly higher in Group II compared with Group I. In multiple linear regression analyses, high urinary NAG (Group II) was significantly associated with carotid IMT, independently of urinary ACR and other confounding factors. In terms of carotid plaques, both urinary NAG and ACR were significantly higher in participants with carotid plaques than in those without carotid plaques. After adjustment for confounding factors, both urinary NAG and ACR were significantly associated with the presence of carotid plaques. CONCLUSIONS:Elevated urinary NAG, a marker of renal tubular damage, was related to increased carotid IMT and the presence of carotid plaques in patients with T2D. Urinary NAG may be a more sensitive biomarker than urinary albumin for early detection of atherosclerosis. 10.1186/s12933-017-0497-7
    The early decline in renal function in patients with type 1 diabetes and proteinuria predicts the risk of end-stage renal disease. Skupien Jan,Warram James H,Smiles Adam M,Niewczas Monika A,Gohda Tomohito,Pezzolesi Marcus G,Cantarovich Diego,Stanton Robert,Krolewski Andrzej S Kidney international The risk of end-stage renal disease (ESRD) remains high in patients with type 1 diabetes and proteinuria; however, little is known about the rate of decline in their renal function. To help determine this, we enrolled patients with type 1 diabetes and proteinuria whose estimated glomerular filtration rate (eGFR) was normal (equal to or above 60 ml/min per 1.73 m(2)). Using a minimum of five serial measurements of serum creatinine for 161 patients, we determined individual trajectories of eGFR change and the occurrence of ESRD during 5-18 years of follow-up. The rates were linear for 110 patients, for 24 the nonlinear rate was mild enough to satisfy a linear model, and the rates were clearly nonlinear for only 27 patients. Overall, in more than one-third of patients, the eGFR decline was less than 3.5 ml/min per 1.73 m(2) per year and the lifetime risk of ESRD could be considered negligible. In the remainder of patients, eGFR declined with widely different slopes and ESRD developed within 2 to 18 years. Based on up to 5 years observation, when renal function was within the normal range, the estimates of early eGFR slope predicted the risk of ESRD during subsequent follow-up better than the baseline clinical characteristics of glycated hemoglobin, blood pressure, or the albumin to creatinine ratio. Thus, the early slope of eGFR decline in patients with type 1 diabetes and proteinuria can be used to predict the risk of ESRD. 10.1038/ki.2012.189
    Body mass index has no effect on rate of progression of chronic kidney disease in subjects with type 2 diabetes mellitus. Mohsen Ali,Brown Rebecca,Hoefield Richard,Kalra Philip A,O'Donoghue Donal,Middleton Rachel,New David Journal of nephrology BACKGROUND:The incidences of obesity and chronic kidney disease (CKD) are reaching epidemic levels. Recently obesity has been associated with the development of CKD. However, it is unclear whether obesity is a risk factor for the progression of CKD. This study investigated the effect of raised body mass index (BMI, calculated as kg/m2) on the rate of CKD progression in a group of patients with CKD and type 2 diabetes mellitus. METHODS:The Chronic Renal Insufficiency Standards Implementation Study (CRISIS) is a large epidemiological study conducted in Manchester, UK. From the CRISIS database, we assessed the rate of progression of CKD in 229 adults who met the inclusion criteria. Baseline measurements such as BMI, estimated glomerular filtration rate (eGFR) and systolic and diastolic blood pressure were collected. eGFR measurements were obtained during follow-up to calculate the rate of eGFR change (ΔeGFR). Linear regression analysis and independent sample t-test were used in data analysis. RESULTS:After a mean follow-up period of 31 months, linear regression analysis showed no relationship between ΔeGFR and BMI. Furthermore, independent sample t-test comparing the obese (BMI =30) and nonobese (BMI <30) groups' ΔeGFR showed no statistical significance (p=0.572). Similar results were observed after stratification according to CKD stages 3, 4 and 5. CONCLUSION:Raised BMI did not influence the rate of progression of chronic kidney disease in patients with type 2 diabetes mellitus. 10.5301/jn.5000062
    Predictors of Renal Function Decline in Chinese Patients with Type 2 Diabetes Mellitus and in a Subgroup of Normoalbuminuria: A Retrospective Cohort Study. Hu Ping,Zhou Xiang-Hai,Wen Xin,Ji Linong Diabetes technology & therapeutics BACKGROUND:Risk factors related to renal function decline in type 2 diabetes mellitus (T2DM) remain uncertain. This study aimed to investigate risk factors in relation to renal function decline in patients with T2DM and in a subgroup of patients with normoalbuminuria. METHODS:This study was a retrospective cohort study, which included 451 patients with T2DM aged 63 ± 14 years admitted to a tertiary hospital in Beijing, China, between April and December 2010 and followed up for 6-60 months. Endpoint was renal function decline, defined as estimated glomerular filtration rate less than 60 mL/min 1.73 m or at least twofold increase of serum creatinine. Cox proportional hazards analysis was used to estimate hazard ratios (HRs) for candidate risk factors of renal function decline. RESULTS:After a median follow-up of 3.3 years, 94 (20.8%) patients developed renal function decline. Increased age (HR, 1.045; 95% CI, 1.020-1.070), albuminuria (HR, 1.956; 95%CI, 1.271-3.011), mild renal dysfunction (HR, 4.521; 95%CI, 2.734-7.476), hyperfiltration (HR, 3.897; 95%CI, 1.572-9.663), and increased hemoglobin A1c (HR, 1.128; 95%CI, 1.020-1.249) were identified as major risk factors. Among a subgroup of 344 patients with normoalbuminuria at baseline, 53 (15.4%) patients developed renal function decline. Increased age (HR, 1.089; 95%CI, 1.050-1.129), mild renal dysfunction (HR, 4.667; 95%CI, 2.391-9.107), hyperfiltration (HR, 5.677; 95%CI, 1.544-20.872), smoking (HR, 2.886; 95%CI, 1.370-6.082), higher pulse pressure (HR, 1.022; 95%CI, 1.004-1.040), and increased fasting glucose (HR, 1.104; 95%CI, 1.020-1.194) were major risk factors. CONCLUSIONS:Risk factors of diabetic renal impairment in T2DM should be screened and evaluated at an early stage of diabetes. Albuminuria, mild renal dysfunction, hyperfiltration, increased blood glucose, increased pulse pressure, and smoking were all predictors for diabetic renal impairment and interventions that focus on these risk factors may reduce further decline in renal function. 10.1089/dia.2016.0115
    Serum haptoglobin levels are associated with renal function decline in type 2 diabetes mellitus patients in a Chinese Han population. Huang Yeping,Huang Yan,Zhang Rong,Jin Li,Zhang Hong,Hu Cheng Diabetes research and clinical practice AIMS:We investigated whether serum haptoglobin (Hp) levels play a role in the development and progression of diabetic kidney disease (DKD) in type 2 diabetes mellitus (T2DM) patients in a Chinese Han population, which has not been previously investigated. METHODS:We recruited 233 participants who had suffered from T2DM for more than 10 years, including 118 subjects with DKD (case) and 115 subjects without DKD (control). Serum Hp levels were measured by an enzyme-linked immunosorbent assay. RESULTS:Serum Hp levels were significantly higher (P = 0.0258) in case group (2.74 (1.77, 3.48) g/L) than control (2.29 (0.98, 3.48) g/L). The serum Hp level was significantly positively associated with both logarithmically transformed (log-transformed) serum creatinine (r = 0.1663, P = 0.011) and albuminuria levels (r = 0.1793, P = 0.0062) and was negatively associated with the log-transformed estimated glomerular filtration rate (r = -0.1482, P = 0.0237). Multiple linear regression analysis revealed that serum Hp levels were significantly correlated with serum creatinine levels (P = 0.0088) after adjusting for confounding risk factors. CONCLUSIONS:Our findings suggest that serum Hp levels may be used as a potential biomarker for the early diagnosis and monitoring of DKD in T2DM patients. 10.1016/j.diabres.2019.107865
    HbA(1c) variability and the development of microalbuminuria in type 2 diabetes: Tsukuba Kawai Diabetes Registry 2. Sugawara A,Kawai K,Motohashi S,Saito K,Kodama S,Yachi Y,Hirasawa R,Shimano H,Yamazaki K,Sone H Diabetologia AIMS/HYPOTHESIS:The aim of this study was to examine the association between HbA(1c) variability and the development of microalbuminuria as defined by an albumin/creatinine ratio ≥ 3.4 mg/mmol (≥ 30 mg/g) in at least two of three consecutive urine samples in Japanese patients with type 2 diabetes. METHODS:HbA(1c) level was measured in 812 serially registered normoalbuminuric adults aged 21-79 years with type 2 diabetes. After registration, a 1-year period to establish baseline values for mean HbA(1c) and HbA(1c) variability (measured as the intrapersonal SD of serially collected HbA(1c)) was decided upon. The association between HbA(1c) variability and the development of microalbuminuria was determined by Cox regression analysis after adjustment for other risk factors for microalbuminuria. RESULTS:Microalbuminuria occurred in 193 patients during the observation period of (mean ± SD) 4.3 ± 2.7 years. Even after adjustment for mean HbA(1c), HbA(1c) variability was a significant predictor of microalbuminuria independently of the mean HbA(1c); the HR for every 1% (95% CI) increase in mean HbA(1c) was 1.22 (1.06, 1.40) (p = 0.005), and that for HbA(1c) variability was 1.35 (1.05, 1.72) (p = 0.019). The effects of these two variables were quite similar when 1 SD was used; the HR for every 1 SD increase (95% CI) in HbA(1c) was 1.23 (1.07, 1.43) (p = 0.005), and that for HbA(1c) variability was 1.20 (1.03, 1.39) (p = 0.019). CONCLUSIONS/INTERPRETATION:HbA(1c) variability affects the development of microalbuminuria independently of mean HbA(1c) in type 2 diabetes. Further studies should be performed to evaluate the influence of HbA(1c) variability on other complications and in individuals of other ethnicities with type 2 diabetes. 10.1007/s00125-012-2572-7
    Association between the extent of urinary albumin excretion and glycaemic variability indices measured by continuous glucose monitoring. Jin S-M,Kim T-H,Oh S,Baek J,Joung J Y,Park S-M,Cho Y Y,Sohn S Y,Hur K Y,Lee M-S,Lee M-K,Kim J H Diabetic medicine : a journal of the British Diabetic Association AIMS:The contribution of glycaemic variability to the microvascular complication of diabetes has not been established. We examined whether there is an independent association between indices of glycaemic variability in continuous glucose monitoring and extent of albuminuria. METHODS:A total of 173 patients with Type 2 diabetes (without insulin therapy, n = 96; with insulin therapy, n = 77) who had unexplained large fluctuations in blood glucose values underwent three-day continuous glucose monitoring. We used a multinomial logistic regression model to determine whether the indices of glycaemic variability independently affected the odds of having a spot urine albumin/creatinine ratio of 30-299 mg/g and ≥ 300 mg/g. RESULTS:Higher standard deviation (P = 0.002), mean of daily differences (P = 0.023) and mean amplitude of glycaemic excursion (P = 0.043) significantly increased the odds of having a urine albumin/creatinine ratio of ≥ 300 mg/g. In multivariable analysis, only higher standard deviation, but not mean amplitude of glycaemic excursion and mean of daily differences, independently increased the odds of having a urine albumin/creatinine ratio of ≥ 300 mg/g (P = 0.025). Coefficient of variation (sd/mean) was not associated with the odds of having a urine albumin/creatinine ratio of 30-299 or ≥ 300 mg/g. CONCLUSIONS:The independent association between standard deviation and the extent of albuminuria was lost when the measures were normalized by mean glucose level. At least in terms of relative measures of glycaemic variability, we failed to demonstrate an independent association between glycaemic variability and albuminuria extent in patients with inadequately controlled Type 2 diabetes. 10.1111/dme.12607
    Simultaneous control of glycemic, blood pressure, and lipid significantly reduce the risk of renal progression in diabetes patients. Chang Po-Ya,Chien Li-Nien,Lin Yuh-Feng,Chiu Wen-Ta,Chiou Hung-Yi European journal of internal medicine BACKGROUND AND AIM:Hyperglycemic, hypertension, and lipid abnormalities are risk factors for diabetic kidney disease However, no study has discussed the association of the simultaneous control of glycemic, blood pressure, and lipids with renal function among diabetes patients. Thus, this study examined the interactive effects of the intensive control of all 3 conditions on the progression of renal function. MATERIALS AND METHODS:The study population was derived from eight hospitals in Taiwan from October 2008 to April 2015. Demographic characteristics were collected using structured questionnaires. Clinical variables were obtained from medical chart review. The renal progression was defined as a decline in the eGFR by more than 25% according to the baseline eGFR. RESULTS:Total of 1602 diabetes patients were included in the study analysis, the mean age was 63.03±10.98years, 55.56% were men. Compared to the simultaneous control of glycemic, blood pressure and lipid group, the poor control of all three diseases had the highest risk of renal progression, with an adjusted OR of 2.21 (95% CI, 1.26-3.86). Even if the patients with an intensive control of lipid, the result showed that the poor control of both glycemic and hypertension was associated with the increased risk of renal progression than the reference group. CONCLUSION:This study demonstrated that the simultaneous poor control of glycemic, blood pressure, and lipid had the highest risk of renal progression. Thus, patients with type 2 diabetes should not only control glycemic but also manage their blood pressure and lipid. 10.1016/j.ejim.2016.09.013
    Effects of smoking and its cessation on creatinine- and cystatin C-based estimated glomerular filtration rates and albuminuria in male patients with type 2 diabetes mellitus: the Fukuoka Diabetes Registry. Ohkuma Toshiaki,Nakamura Udai,Iwase Masanori,Ide Hitoshi,Fujii Hiroki,Jodai Tamaki,Kaizu Shinako,Kikuchi Yohei,Idewaki Yasuhiro,Sumi Akiko,Hirakawa Yoichiro,Kitazono Takanari Hypertension research : official journal of the Japanese Society of Hypertension Cigarette smoking is an important modifiable risk factor for lifestyle diseases. The smoking rate remains high, and the prevalence of diabetes mellitus is increasing in Asian countries; however, few studies have examined the effects of smoking on chronic kidney disease (CKD) in Asian diabetic patients. The aim of the present study was to investigate the association between smoking and its cessation with CKD and its components in patients with type 2 diabetes. A total of 2770 Japanese male patients with type 2 diabetes aged ⩾20 years were divided according to the amount of cigarette smoking and the years since cessation. The associations with CKD, the urinary albumin-creatinine ratio (UACR) and the estimated glomerular filtration rate (eGFR) were cross-sectionally examined. The proportions of CKD and the mean UACR dose-dependently increased with increases in both the number of cigarettes per day and the Brinkman index compared with the never smokers. The creatinine-based eGFR also increased with increases in the amount of smoking, whereas the cystatin C-based eGFR decreased, and their average did not significantly change. These parameters exhibited inverse associations with the years after smoking cessation compared with the association with the amount of smoking. A dose-dependent association of active smoking and a graded inverse association of the years since quitting with CKD enhance the merit of smoking cessation in patients with type 2 diabetes. 10.1038/hr.2016.51
    Joint relationship between renal function and proteinuria on mortality of patients with type 2 diabetes: the Taichung Diabetes Study. Lin Cheng-Chieh,Chen Ching-Chu,Kung Pei-Tseng,Li Chia-Ing,Yang Sing-Yu,Liu Chiu-Shong,Lin Wen-Yuan,Lee Cheng-Chun,Li Tsai-Chung,Kardia Sharon L R Cardiovascular diabetology BACKGROUND:Estimated glomerular filtration rate (eGFR) is a powerful predictor of mortality in diabetic patients with limited proteinuria data. In this study, we tested whether concomitant proteinuria increases the risk of mortality among patients with type 2 diabetes. METHODS:Participants included 6523 patients > 30 years with type 2 diabetes who were enrolled in a management program of a medical center before 2007. Renal function was assessed by eGFR according to the Modification of Diet in Renal Disease Study equation for Chinese. Proteinuria was assessed by urine dipstick. RESULTS:A total of 573 patients (8.8%) died over a median follow-up time of 4.91 years (ranging from 0.01 year to 6.42 years). The adjusted expanded cardiovascular disease (CVD)-related mortality rates among patients with proteinuria were more than three folds higher for those with an eGFR of 60 mL/min/1.73 m2 or less compared with those with an eGFR of 90 mL/min/1.73 m2 or greater [hazard ratio, HR, 3.15 (95% confidence interval, CI, 2.0-5.1)]. The magnitude of adjusted HR was smaller in patients without proteinuria [1.98 (95% CI, 1.1-3.7)]. An eGFR of 60 mL/min/1.73 m2 to 89 mL/min/1.73 m2 significantly affected all-cause mortality and mortality from expanded CVD-related causes only in patients with proteinuria. Similarly, proteinuria affected all outcomes only in patients with an eGFR of <60 mL/min/1.73 m2. CONCLUSION:The risks of all-cause mortality, as well as expanded and non-expanded mortality from CVD-related causes associated with proteinuria or an eGFR of 90 mL/min/1.73 m2 or greater are independently increased. Therefore, the use of proteinuria measurements with eGFR increases the precision of risk stratification for mortality. 10.1186/1475-2840-11-131
    Association of neutrophil-gelatinase-associated lipocalin with microvascular complications in patients with type 2 diabetes: a cross-sectional study. Aslanhan Erhan,Ojalvo David,Özsenel Ekmek Burak,Ucak Basat Sema,Borlu Fatih Cardiovascular endocrinology & metabolism Diabetic nephropathy and diabetic retinopathy are serious microvascular complications of diabetes mellitus. Recent studies have demonstrated that neutrophil-gelatinase-associated lipocalin (NGAL) may be accompanied by these complications during and before the appearance of microalbuminuria. In this study, we set out to research the role of NGAL in patients with diabetic nephropathy and diabetic retinopathy. Material and methods:Eighty-two patients with type 2 diabetes were enrolled in our study. Urinary microalbumine and NGAL levels were measured in urine samples over 24 hours. We also studied NGAL levels in serum. All patients went through an ophthalmologic examination. The results were evaluated based on the presence of microalbuminuria and retinopathy. Results:There were no significant differences in serum and urine NGAL levels between normoalbuminuric ( = 66) and microalbuminuric ( = 16) patients. We also did not find any significant difference in patients with retinopathy ( = 16) or without retinopathy ( = 66). Conclusion:There are controversial findings about the role of NGAL in diabetic patients in medical literature. Standard values of urine and serum NGAL levels have yet to be determined. Our study suggests that NGAL is not a useful marker to differentiate microalbuminuric patients from normoalbuminuric subjects. We also did not find a relationship between NGAL levels and the presence of retinopathy. Additional studies with larger sample sizes will be required to confirm or refute these findings. 10.1097/XCE.0000000000000180
    Impact of bariatric surgery on renal functions in patients with type 2 diabetes: systematic review of randomized trials and observational studies. Zhou Xu,Li Ling,Kwong Joey S W,Yu Jiajie,Li Youping,Sun Xin Surgery for obesity and related diseases : official journal of the American Society for Bariatric Surgery BACKGROUND:The impact of bariatric surgery on renal functions in patients with type 2 diabetes (T2D) remains uncertain. OBJECTIVES:To assess the impact of bariatric surgery on renal functions in patients with T2D. SETTING:Systemic review and meta-analysis of randomized trials and observational studies. METHODS:We searched PubMed, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) from inception to April 3, 2016. We included studies assessing bariatric surgery for renal functions in patients with T2D. We analyzed changes in renal functions before and after surgery and compared outcomes between surgeries versus nonsurgical treatments. RESULTS:Twenty-nine studies (4 randomized controlled trials, 5 cohort studies, 20 before-and-after studies; all at moderate to high risk of bias) were eligible, involving 18,172 patients. Analyses of changes before and after surgeries suggested a significantly lower proportion of albuminuria (difference -21.2%, 95% confidence interval [CI] -28.8% to -13.5%), 24-hour urine albumin excretion rate (weighted mean difference -48.78 mg/24 hr, 95% CI -75.32 to -22.24) and urine albumin-to-creatinine ratio (uACR) (weighted mean difference -16.10 mg/g, 95% CI -22.26 to -9.94) after surgery. Compared with nonsurgical treatment, bariatric surgery was associated with a statistically lower level of uACR and lower risk of new-onset albuminuria (odds ratio .18, 95% CI .03-.99 from randomized controlled trials). The effects on glomerular filtration rate, serum creatinine, creatinine clearance, and risk of end-stage renal disease were not statistically significant. CONCLUSIONS:Low-quality evidence suggests that bariatric surgery possibly improves albuminuria and uACR in patients with T2D; its effects on other outcomes were uncertain. Well-conducted, adequately powered, randomized controlled trials are warranted to examine the effect of bariatric surgery on renal functions in the T2D population. 10.1016/j.soard.2016.05.003
    Risk factors of chronic kidney diseases in Chinese adults with type 2 diabetes. Yang Lin,Chu Tsun Kit,Lian Jinxiao,Lo Cheuk Wai,Lau Pak Ki,Nan Hairong,Liang Jun Scientific reports In this study we conducted a cross sectional study to comprehensively evaluated the risk factors of chronic kidney disease (CKD) in a large sample of Chinese adults under primary care for type 2 diabetes mellitus (T2DM). We investigated the risk factors associated with the prevalence of CKD in adults with T2DM, who were enrolled in the Risk Factor Assessment and Management Programme for Patients with Diabetes Mellitus (RAMP-DM) of Hong Kong from July 2014 to June 2017. We collected the individual data of 31,574 subjects, with mean age of 63.0 (±10.8) years and mean DM duration of 7.4 (±6.4) years. Of them 9,386 (29.7%) had CKD and 7,452 (23.6%) had micro- or macro-albuminuria. After adjustment for multiple demographic and lifestyle confounders, we identified several modifiable risk factors associated with higher rate of CKD: obesity (OR = 1.54), current smoking (OR = 1.33), higher systolic blood pressure (OR = 1.01), dyslipidemia (OR = 1.32 and 0.61 for triglycerides (TG) and high-density lipoprotein cholesterol (HDL-C)), hyperglycemia (OR = 1.11 for HbA), diabetic retinopathy (OR = 1.36 and 2.60 for non-sight and sight threatening retinopathy), and stroke (OR = 1.43). The risk factors of lower dialytic blood pressure and coronary heart disease were identified only in men, whereas peripheral arterial disease only in women. In conclusion, several modifiable and gender specific risk factors were significantly associated with higher prevalence of CKD in Chinese adults with T2DM. The high-risk populations identified in this study shall receive regular screening for renal functions to achieve better patient management in primary care settings. 10.1038/s41598-018-32983-1
    Prognostic value of visit-to-visit systolic blood pressure variability related to diabetic kidney disease among patients with type 2 diabetes. Yu Zhe-Bin,Wang Jian-Bing,Li Die,Chen Xue-Yu,Lin Hong-Bo,Chen Kun Journal of hypertension BACKGROUND:This study aimed to evaluate the impact of visit-to-visit variability (VVV) of blood pressure on the risk of diabetic nephropathy and whether it provides additional predictive information among patients with type 2 diabetes mellitus (T2DM) in China. METHODS:We included 12 630 T2DM patients during January 2008-December 2012 using a retrospective cohort design. VVV of SBP was assessed as standard deviation, coefficient of variation and variation independent of mean of the blood pressure readings during the measurement period. Hazard ratios and 95% confidence intervals were estimated for the associations of variability in SBP with risk of diabetes nephropathy by using Cox proportional hazards regression models. Risk prediction ability was assessed using C statistic, integrated discrimination improvement (IDI) and net reclassification index (NRI). RESULTS:We found a dose-response relationship across quartiles of VVV SBP (P trend < 0.001). Hazard ratio in the highest quartile of SD SBP (≥9.2 mmHg) was 1.49 (1.16-1.93) as compared with the lowest quartile (<4.8 mmHg) after adjusted for mean SBP values, max SBP values and other covariates. Addition of SD SBP significantly improved risk prediction for diabetic kidney disease (DKD) [C statistic (from 0.664 to 0.673), IDI (0.0011, 95% CI: 0.0003-0.0104) and NRI (0.053, 95% CI: 0.0017-0.113)]. Results remained similar across different subgroups, sensitivity analyses or using coefficient of variation and variance independent of mean. CONCLUSION:VVV of SBP is a significant risk factor of DKD among T2DM patients on top of mean and max BP values, which provides additional significant predictive information. 10.1097/HJH.0000000000002038
    Risk factors for the development of albuminuria and renal impairment in type 2 diabetes--the Swedish National Diabetes Register (NDR). Afghahi Henri,Cederholm Jan,Eliasson Björn,Zethelius Björn,Gudbjörnsdottir Soffia,Hadimeri Henrik,Svensson Maria K Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association BACKGROUND:The aim of this study was to identify clinical risk factors associated with the development of albuminuria and renal impairment in patients with type 2 diabetes (T2D). In addition, we evaluated if different equations to estimate renal function had an impact on interpretation of data. This was done in a nationwide population-based study using data from the Swedish National Diabetes Register. METHODS:Three thousand and six hundred sixty-seven patients with T2D aged 30-74 years with no signs of renal dysfunction at baseline (no albuminuria and eGFR >60 mL/min/1.73 m(2) according to MDRD) were followed up for 5 years (2002-2007). Renal outcomes, development of albuminuria and/or renal impairment [eGFR < 60 mL/min/1.73 m(2) by MDRD or eCrCl > 60 mL/min by Cockgroft-Gault (C-G)] were assessed at follow-up. Univariate regression analyses and stepwise regression models were used to identify significant clinical risk factors for renal outcomes. RESULTS:Twenty percent of patients developed albuminuria, and 11% renal impairment; thus, ~6-7% of all patients developed non-albuminuric renal impairment. Development of albuminuria or renal impairment was independently associated with high age (all P < 0.001), high systolic BP (all P < 0.02) and elevated triglycerides (all P < 0.02). Additional independent risk factors for albuminuria were high BMI (P < 0.01), high HbA1c (P < 0.001), smoking (P < 0.001), HDL (P < 0.05) and male sex (P < 0.001), and for renal impairment elevated plasma creatinine at baseline and female sex (both P < 0.001). High BMI was an independent risk factor for renal impairment when defined by MDRD (P < 0.01), but low BMI was when defined by C-G (P <  0.001). Adverse effects of BMI on HbA1c, blood pressure and lipids accounted for ~50% of the increase risk for albuminuria, and for 41% of the increased risk for renal impairment (MDRD). CONCLUSIONS:Distinct sets of risk factors were associated with the development of albuminuria and renal impairment consistent with the concept that they are not entirely linked in patients with type 2 diabetes. Obesity and serum triglycerides are semi-novel risk factors for development of renal dysfunction and BMI accounted for a substantial proportion of the increased risk. The equations used to estimate renal function (MDRD vs. C-G) had an impact on interpretation of data, especially with regard to body composition and gender. 10.1093/ndt/gfq535
    Serum retinol binding protein 4 level is related with renal functions in Type 2 diabetes. Akbay E,Muslu N,Nayir E,Ozhan O,Kiykim A Journal of endocrinological investigation AIM:We aimed to evaluate the metabolic parameters and diabetes complications which would probably affect the serum retinol-binding protein 4 (RBP4) levels in Type 2 diabetic individuals. In addition to serum RBP4 concentration, the levels of its ligands, serum retinol and transthyretin (TTR) were also considered in this evaluation. SUBJECTS AND METHODS:Serum RBP4, retinol, and TTR levels were measured in 53 Type 2 diabetic subjects and 30 body mass index (BMI)- matched controls. The molar ratios of RBP4 to retinol and RBP4 to TTR were compared. RESULTS:While the RBP4 values were similar to those in the control group in Type 2 diabetic patients, the molar ratio of RBP4 to TTR was found to be higher than that of the control group. The serum RBP4 levels in patients who had retinopathy and macrovascular disease were similar to those in patients who did not. However, the RBP4 levels, molar ratios of RBP4 to retinol and RBP4 to TTR in micro- macroalbuminuric patients were found to be significantly higher than in normoalbuminuric subjects and controls. There was no correlation between the RBP4 levels and the patients' age, BMI, duration of diabetes, LDL, triglyceride, serum creatinine, and glycated hemoglobin values. Micro-macroalbuminuria and estimated glomerular filtration rate were independent determinants for increased serum RBP4 levels. CONCLUSION:According to the data obtained from this study, diabetic retinopathy and cardiovascular complications do not affect the serum RBP4 level in Type 2 diabetes. Renal functions rather than the metabolic factors of diabetes determine the RBP4 level and its relation with its ligands. 10.3275/7024
    Increasing Mortality in Adults With Diabetes and Low Estimated Glomerular Filtration Rate in the Absence of Albuminuria. Kramer Holly,Boucher Robert E,Leehey David,Fried Linda,Wei Guo,Greene Tom,Rosas Sylvia E,Cooper Richard,Cao Guichan,Beddhu Srinivasan Diabetes care OBJECTIVE:Improved blood pressure control and use of renin-angiotensin-aldosterone system blockers have altered the clinical presentation or phenotype of chronic kidney disease (CKD) in U.S. adults with diabetes. These changes may influence mortality. RESEARCH DESIGN AND METHODS:Data from the National Health and Nutrition Examination Surveys (NHANES) 1988-2006 were used to examine mortality trends in adults with diabetes, defined as physician diagnosis, fasting glucose ≥126 mg/dL, HbA >6.5% (48 mmol/mol), or use of glucose-lowering medications. Mortality trends by CKD phenotype (estimated glomerular filtration rate [eGFR] and urine albumin-to-creatinine ratio [ACR] level) were obtained via linkage with the National Death Index through 31 December 2011 while accounting for the complex survey design. RESULTS:From 1988 to 2006, adults with an eGFR <60 mL/min/1.73 m and an ACR <30 mg/g increased from ∼0.9 million (95% CI 0.7, 1.1) or 6.6% of the total population with diabetes during years 1988-1994 to 2.4 million (95% CI 1.9, 2.9) or 10.1% of the total population with diabetes during years 2007-2010. Mortality rates generally trended downward for adults with diabetes and an ACR ≥30 mg/g but increased in those with eGFR <60 mL/min/1.73 m and an ACR <30 mg/g from 35 deaths per 1,000 person-years (95% CI 22, 55) during years 1988-1994 to 51 deaths per 1,000 person-years (95% CI 33, 83) during years 2003-2006. CONCLUSIONS:ACR values are decreasing in U.S. adults with diabetes, but optimal management strategies are needed to reduce mortality in those with a low eGFR and an ACR <30 mg/g. 10.2337/dc17-1954
    The effect of uric acid lowering treatment on albuminuria and renal function in Type 1 diabetes: a randomized clinical trial. Pilemann-Lyberg S,Persson F,Frystyk J,Rossing P Diabetic medicine : a journal of the British Diabetic Association 10.1111/dme.13577
    Glycated albumin and continuous glucose monitoring to replace glycated haemoglobin in patients with diabetes treated with haemodialysis. Meyer L,Chantrel F,Imhoff O,Sissoko A,Serb L,Dorey F,Fleury D,Smagala A,Kepenekian L,Krummel T,Le Floch J-P,Kessler L Diabetic medicine : a journal of the British Diabetic Association 10.1111/dme.12294
    Glycated hemoglobin and the risk of kidney disease and retinopathy in adults with and without diabetes. Selvin Elizabeth,Ning Yang,Steffes Michael W,Bash Lori D,Klein Ronald,Wong Tien Y,Astor Brad C,Sharrett A Richey,Brancati Frederick L,Coresh Josef Diabetes OBJECTIVE:Glycated hemoglobin was recently recommended for use as a diagnostic test for diabetes. We examined the association between 2010 American Diabetes Association diagnostic cut points for glycated hemoglobin and microvascular outcomes (chronic kidney disease, end-stage renal disease [ESRD], and retinopathy) and formally tested for the presence of risk thresholds in the relationships of glycated hemoglobin with these outcomes. RESEARCH DESIGN AND METHODS:Prospective cohort and cross-sectional analyses of 11,357 participants (773 with a history of diagnosed diabetes) from the Atherosclerosis Risk in Communities (ARIC) Study. RESULTS:During a median of 14 years of follow-up of individuals without diagnosed diabetes at baseline, clinical categories of glycated hemoglobin were associated with risk of chronic kidney disease, with adjusted hazard ratios (HRs) of 1.12 (0.94-1.34) and 1.39 (1.04-1.85) for glycated hemoglobin 5.7-6.4% and ≥6.5%, respectively, as compared with <5.7% (P trend = 0.002). The corresponding HRs for ESRD were 1.51 (0.82-2.76) and 1.98 (0.83-4.73), respectively (P trend = 0.047). In the absence of diagnosed diabetes, glycated hemoglobin was cross sectionally associated with the presence of moderate/severe retinopathy, with adjusted odds ratios of 1.42 (0.69-2.92) and 2.91 (1.19-7.11) for glycated hemoglobin 5.7-<6.5% and ≥6.5%, respectively, compared with <5.7% (P trend = 0.011). Risk associations were stronger among individuals with a history of diabetes. We did not observe significant thresholds in the associations of glycated hemoglobin with kidney disease risk or retinopathy. CONCLUSIONS:These data from a community-based, biracial population support the use of new 2010 American Diabetes Association glycated hemoglobin cut points for the diagnosis of diabetes. 10.2337/db10-1198
    The coefficient variation of home blood pressure is a novel factor associated with macroalbuminuria in type 2 diabetes mellitus. Ushigome Emi,Fukui Michiaki,Hamaguchi Masahide,Senmaru Takafumi,Sakabe Kazumi,Tanaka Muhei,Yamazaki Masahiro,Hasegawa Goji,Nakamura Naoto Hypertension research : official journal of the Japanese Society of Hypertension The purpose of this study was to investigate the association between day-by-day variability in home blood pressure (HBP) on 14 consecutive days and macroalbuminuria in patients with type 2 diabetes. We compared the coefficient of variation (CV) of HBP in 858 Japanese patients with and without macroalbuminuria. Next, we analyzed the relationship between the logarithm of urinary albumin excretion (UAE) and the CV of HBP using linear regression analysis. Then, we evaluated the association between the CV of HBP and macroalbuminuria, defined as UAE ≥300 mg g(-1) creatinine, using logistic regression analysis. The CVs of morning and evening systolic blood pressure (SBP) were significantly greater in patients with macroalbuminuria than in those without (8.08±3.35 vs. 7.19±2.25%, P<0.05 and 9.01±3.58 vs. 7.98±2.57%, P<0.05, respectively). Multivariate linear regression analyses indicated that the CVs of morning SBP (P<0.05) and diastolic blood pressure (DBP; P<0.05), and those of evening SBP (P<0.05) were the independent explanatory variables for the logarithm of UAE. Multivariate logistic regression analyses also demonstrated that the odds ratio for the CVs of morning SBP, morning DBP and evening SBP for macroalbuminuria were 1.35 (P<0.05), 1.29 (P<0.05) and 1.44 (P<0.05), respectively. We conclude that the CV of HBP is correlated with macroalbuminuria, independent of the known risk factors, in Japanese patients with type 2 diabetes. 10.1038/hr.2011.128
    Association between serum 25-hydroxyvitamin D and glycated hemoglobin levels in type 2 diabetes patients with chronic kidney disease. Lim Lee Ling,Ng Yong Muh,Kang Pei San,Lim Soo Kun Journal of diabetes investigation AIMS/INTRODUCTION:Vitamin D is suggested to influence glucose homeostasis. An inverse relationship between serum 25-hydroxyvitamin D (25[OH]D) and glycemic control in non-chronic kidney disease (CKD) patients with type 2 diabetes was reported. We aimed to examine this association among type 2 diabetes patients with CKD. MATERIALS AND METHODS:A total of 100 type 2 diabetes participants with stage 3-4 CKD were recruited. Blood for glycated hemoglobin (HbA ), serum 25(OH)D, renal and lipid profiles were drawn at enrollment. Correlation and regression analyses were carried out to assess the relationship of serum 25(OH)D, HbA and other metabolic traits. RESULTS:A total of 30, 42, and 28% of participants were in CKD stage 3a, 3b and 4, respectively. The proportions of participants based on ethnicity were 51% Malay, 24% Chinese and 25% Indian. The mean (±SD) age and body mass index were 60.5 ± 9.0 years and 28.3 ± 5.9 kg/m , whereas mean HbA and serum 25(OH)D were 7.9 ± 1.6% and 37.1 ± 22.2 nmol/L. HbA was negatively correlated with serum 25(OH)D (r = -0.314, P = 0.002), but positively correlated with body mass index (r = 0.272, P = 0.006) and serum low-density lipoprotein cholesterol (P = 0.006). There was a significant negative correlation between serum 25(OH)D and total daily dose of insulin prescribed (r = -0.257, P = 0.042). Regression analyses showed that every 10-nmol/L decline in serum 25(OH)D was associated with a 0.2% increase in HbA . CONCLUSIONS:Lower serum 25(OH)D was associated with poorer glycemic control and higher insulin use among multi-ethnic Asians with type 2 diabetes and stage 3-4 CKD. 10.1111/jdi.12696
    Urinary NGAL and RBP Are Biomarkers of Normoalbuminuric Renal Insufficiency in Type 2 Diabetes Mellitus. Li Aimei,Yi Bin,Liu Yan,Wang Jianwen,Dai Qing,Huang Yuxi,Li Yan Chun,Zhang Hao Journal of immunology research Objectives:As a screening index of diabetic kidney disease (DKD), urinary albumin/creatine ratio (UACR) is commonly used. However, approximately 23.3%-56.6% of DKD patients with estimated glomerular filtration rate (eGFR) < 60 ml/min per 1.73 m are normoalbuminuric. Thus, urinary biomarkers of nonalbuminuric renal insufficiency in type 2 diabetes mellitus (T2DM) patients are urgently needed. Methods:This cross-sectional study enrolled 209 T2DM patients with normoalbuminuria whose diabetes duration was more than 5 years. The patients were classified into two groups, NO-CKD (eGFR ≥ 60 ml/min per 1.73 m, = 165) and NA-DKD (eGFR < 60 ml/min per 1.73 m, = 44). Levels of urinary neutrophil gelatinase-associated lipocalin (NGAL), retinol-binding protein (RBP), plasminogen activator inhibitor-1 (PAI-1), vascular cell adhesion molecule-1 (VCAM-1), and E-cadherin were detected, and their correlations with eGFR, plasma TNF-, IL-6, endothelin-1 (ET-1), and 8-hydroxydeoxyguanosine (8-OHdG) were assessed. Results:Among patients with renal insufficiency, 26.0% was normoalbuminuric. Compared to the NO-CKD group, the NA-DKD group was older with lower hemoglobin (HB) levels and higher systolic blood pressure (SBP), plasma TNF-, IL-6, and 8-OHdG levels. Logistic regression analysis suggested that age, TNF-, and 8-OHdG were independent risk factors for nonalbuminuric renal insufficiency. Compared to the NO-CKD group, the NA-DKD group exhibited significant increases in urinary NGAL and RBP levels but not PAI-1, VCAM-1, and E-cadherin. Urinary NGAL and RBP both correlated negatively with eGFR and positively with plasma IL-6 and 8-OHdG. Multiple linear regression indicated NGAL ( = -0.287, = 0.008) and RBP ( = -44.545, < 0.001) were independently correlated with eGFR. Conclusion:Age, plasma TNF-, and 8-OHdG are independent risk factors for renal insufficiency in T2DM patients with normoalbuminuria. Urinary NGAL and RBP can serve as noninvasive biomarkers of normoalbuminuric renal insufficiency in T2DM. 10.1155/2019/5063089
    Low 25-hydroxyvitamin D levels and mortality in non-dialysis-dependent CKD. Navaneethan Sankar D,Schold Jesse D,Arrigain Susana,Jolly Stacey E,Jain Anil,Schreiber Martin J,Simon James F,Srinivas Titte R,Nally Joseph V American journal of kidney diseases : the official journal of the National Kidney Foundation BACKGROUND:Low 25-hydroxyvitamin D (25[OH]D) levels are common in patients with non-dialysis-dependent chronic kidney disease (CKD). The associations between low 25(OH)D levels and mortality in non-dialysis-dependent patients with CKD are unclear. STUDY DESIGN:Retrospective cohort study. SETTING & PARTICIPANTS:Patients with stages 3-4 CKD (estimated glomerular filtration rate, 15-59 mL/min/1.73 m(2); n = 12,673) who had 25(OH)D levels measured after the diagnosis of CKD in the Cleveland Clinic Health System. PREDICTOR:25(OH)D levels categorized into 3 groups: <15, 15-29, and ≥30 ng/mL. OUTCOMES:We examined factors associated with low 25(OH)D levels and associations between low 25(OH)D levels and all-cause mortality (ascertained using the Social Security Death Index and our electronic medical record) using logistic regression, Cox proportional hazard models, and Kaplan-Meier survival curves. MEASUREMENTS:25(OH)D was measured using chemiluminescence immunoassay. RESULTS:Of 12,763 patients with CKD, 15% (n = 1,970) had 25(OH)D levels <15 ng/mL, whereas 45% (n = 5,749) had 25(OH)D levels of 15-29 ng/mL. Male sex, African American race, diabetes, coronary artery disease, and lower estimated glomerular filtration rate were associated significantly with 25(OH)D level <30 ng/mL. A graded increase in risk of 25(OH)D level <30 ng/mL was evident across increasing body mass index levels. Patients who had 25(OH)D levels measured in fall through spring had higher odds for 25(OH)D levels <30 ng/mL. After covariate adjustment, patients with CKD with 25(OH)D levels <15 ng/mL had a 33% increased risk of mortality (95% CI, 1.07-1.65). The group with 25(OH)D levels of 15-29 ng/mL did not show a significantly increased risk of mortality (HR, 1.03; 95% CI, 0.86-1.22) compared with patients with 25(OH)D levels ≥30 ng/mL. LIMITATIONS:Single-center observational study, lack of data for albuminuria and other markers of bone and mineral disorders, and attrition bias. CONCLUSIONS:25(OH)D level <15 ng/mL was associated independently with all-cause mortality in non-dialysis-dependent patients with CKD. 10.1053/j.ajkd.2011.04.028
    Intensive glucose control improves kidney outcomes in patients with type 2 diabetes. Perkovic Vlado,Heerspink Hiddo Lambers,Chalmers John,Woodward Mark,Jun Min,Li Qiang,MacMahon Stephen,Cooper Mark E,Hamet Pavel,Marre Michel,Mogensen Carl Erik,Poulter Neil,Mancia Giuseppe,Cass Alan,Patel Anushka,Zoungas Sophia, Kidney international The effect of intensive glucose control on major kidney outcomes in type 2 diabetes remains unclear. To study this, the ADVANCE trial randomly assigned 11,140 participants to an intensive glucose-lowering strategy (hemoglobin A1c target 6.5% or less) or standard glucose control. Treatment effects on end-stage renal disease ((ESRD), requirement for dialysis or renal transplantation), total kidney events, renal death, doubling of creatinine to above 200 μmol/l, new-onset macroalbuminuria or microalbuminuria, and progression or regression of albuminuria, were then assessed. After a median of 5 years, the mean hemoglobin A1c level was 6.5% in the intensive group, and 7.3% in the standard group. Intensive glucose control significantly reduced the risk of ESRD by 65% (20 compared to 7 events), microalbuminuria by 9% (1298 compared to 1410 patients), and macroalbuminuria by 30% (162 compared to 231 patients). The progression of albuminuria was significantly reduced by 10% and its regression significantly increased by 15%. The results were almost identical in analyses taking account of potential competing risks. The number of participants needed to treat over 5 years to prevent one ESRD event ranged from 410 in the overall study to 41 participants with macroalbuminuria at baseline. Thus, improved glucose control will improve major kidney outcomes in patients with type 2 diabetes. 10.1038/ki.2012.401
    Novel Tubular Biomarkers Predict Renal Progression in Type 2 Diabetes Mellitus: A Prospective Cohort Study. Satirapoj Bancha,Aramsaowapak Kasemsan,Tangwonglert Theerasak,Supasyndh Ouppatham Journal of diabetes research Tubulointerstitial injury is both a key feature of diabetic nephropathy and an important predictor of renal dysfunction. Novel tubular biomarkers related to renal injury in diabetic nephropathy could improve risk stratification and prediction. A total of 303 type 2 diabetic patients were followed up. The baseline urine values of cystatin-C to creatinine ratio (UCCR), angiotensinogen to creatinine ratio (UANG), NGAL to creatinine ratio (UNGAL), and KIM-1 to creatinine ratio (UKIM-1) were measured. The primary outcome was a decline in estimated GFR of ≥25% yearly from baseline. Urine tubular biomarkers of UCCR, UANG, UNGAL, and UKIM-1 were significantly higher according to the degree of albuminuria and all were significantly higher among patients with rapid decline in estimated GFR of ≥25% yearly from baseline. All biomarkers predicted primary outcomes with ROC for UCCR of 0.72; 95% CI 0.64-0.79, for UANG of 0.71; 95% CI 0.63-0.79, for UNGAL of 0.64; 95% CI 0.56-0.72, and for UKIM-1 of 0.71; 95% CI 0.63-0.79. Using multivariate Cox regression analysis, the number of patients with rapid renal progression was higher among those in the upper quartiles of all biomarkers than in those in the lower quartiles. . Type 2 diabetic patients with high levels of urine tubular biomarkers had a more rapid decline in renal function. 10.1155/2016/3102962
    Urinary α -microglobulin and albumin excretion in children and adolescents with type 1 diabetes. Saif Aasem,Soliman Neveen Journal of diabetes BACKGROUND:The present study investigated the correlation between urinary α -microglobulin as a marker of tubular dysfunction and albumin excretion in children and adolescents with type 1 diabetes (T1D). METHODS:Ninety-two Egyptian patients with T1D were included in the study (mean [± SD] age 14.14 ± 5.13 years). The duration of diabetes in all patients was >5 years (mean [± SD] duration 8.28 ± 2.62 years) and all had normal renal function. Forty healthy subjects were also included as a control group. Urinary albumin excretion was assessed in all patients and urinary α -microglobulin was measured in both patients and control in the morning urine specimen. RESULTS:Analysis of the results showed that patients had significantly higher levels of urinary α -microglobulin than the controls (P < 0.01). Among the patients, there was a strong positive correlation between urinary α -microglobulin and urinary albumin excretion (P < 0.01). Positive correlations were also found between urinary α -microglobulin and duration of diabetes (P < 0.01), HbA1c (P < 0.05), and fasting and postprandial blood glucose (P < 0.05 for both). CONCLUSION:The present study shows that urinary α -microglobulin is strongly correlated with urinary albumin excretion in children and adolescents with T1D. In addition, it demonstrates the importance of tubular dysfunction as an early and integral component of diabetic nephropathy syndrome in these patients. The results of the present study emphasize the value of tight glycemic control in slowing the progression of tubular dysfunction, especially in patients with a longer duration of diabetes. 10.1111/1753-0407.12383
    Proteome analysis of acute kidney injury - Discovery of new predominantly renal candidates for biomarker of kidney disease. Malagrino Pamella Araujo,Venturini Gabriela,Yogi Patrícia Schneider,Dariolli Rafael,Padilha Kallyandra,Kiers Bianca,Gois Tamiris Carneiro,Cardozo Karina Helena Morais,Carvalho Valdemir Melechco,Salgueiro Jéssica Silva,Girardi Adriana Castello Costa,Titan Silvia Maria de Oliveira,Krieger José Eduardo,Pereira Alexandre Costa Journal of proteomics The main bottleneck in studies aiming to identify novel biomarkers in acute kidney injury (AKI) has been the identification of markers that are organ and process specific. Here, we have used different tissues from a controlled porcine renal ischemia/reperfusion (I/R) model to identify new, predominantly renal biomarker candidates for kidney disease. Urine and serum samples were analyzed in pre-ischemia, ischemia (60min) and 4, 11 and 16h post-reperfusion, and renal cortex samples after 24h of reperfusion. Peptides were analyzed on the Q-Exactive™. In renal cortex proteome, we observed an increase in the synthesis of proteins in the ischemic kidney compared to the contralateral, highlighted by transcription factors and epithelial adherens junction proteins. Intersecting the set of proteins up- or down-regulated in the ischemic tissue with both serum and urine proteomes, we identified 6 proteins in the serum that may provide a set of targets for kidney injury. Additionally, we identified 49, being 4 predominantly renal, proteins in urine. As prove of concept, we validated one of the identified biomarkers, dipeptidyl peptidase IV, in a set of patients with diabetic nephropathy. In conclusion, we identified 55 systemic proteins, some of them predominantly renal, candidates for biomarkers of renal disease. BIOLOGICAL SIGNIFICANCE:The main bottleneck in studies aiming to identify novel biomarkers in acute kidney injury (AKI) has been the identification of markers that are predominantly renal. In fact, putative biomarkers for this condition have also been identified in a number of other clinical scenarios, such as cardiovascular diseases, chronic kidney failure or in patients being treated in intensive care units from a number of conditions. Here we propose a comprehensive, sequential screening procedure able to identify and validate potential biomarkers for kidney disease, using kidney ischemia/reperfusion as a paradigm for a kidney pathological event. 10.1016/j.jprot.2016.07.019
    Levels of albuminuria and risk of developing macroalbuminuria in type 2 diabetes: historical cohort study. Chida Shoma,Fujita Yoshikuni,Ogawa Akifumi,Hayashi Akinori,Ichikawa Raishi,Kamata Yuji,Takeuchi Akihiro,Takano Koji,Shichiri Masayoshi Scientific reports Although increased urinary albumin excretion may increase the risk of adverse renal outcomes in patients with diabetes, it remains unclear whether microalbuminuria is associated with a higher incidence of macroalbuminuria in the absence of non-diabetic kidney events that frequently develop during the long-term course of type 2 diabetes. This historical cohort study included patients with type 2 diabetes, spot urine albumin:creatinine ratio (ACR) <300 mg/gCr and normal serum creatinine concentrations treated between August 1988 and April 2015. Patients with any evidence suggesting non-diabetic kidney diseases at baseline were excluded. Over a median follow-up of 50 months, 70 of the 1760 included patients developed macroalbuminuria. Twenty-one of these patients were diagnosed with non-diabetic renal events. The five-year cumulative incidence of macroalbuminuria in patients with ACRs of 0-7.5 mg/gCr, 7.5-30 mg/gCr, 30-150 mg/gCr, and 150-300 mg/gCr were 0%, 0.53%, 3.5%, and 36.0%, respectively, with significant differences between each pair of ACR categories. In type 2 diabetes, higher urinary ACR, even within a level of normoalbuminuria, was associated with a greater incidence of macroalbuminuria when non-diabetic renal events were excluded. These results conflict with findings suggesting that microalbuminuria is a poor indicator for the progression of diabetic nephropathy. 10.1038/srep26380
    Comments on 'in patients with type 1 diabetes and new-onset microalbuminuria the development of advanced chronic kidney disease may not require progression to proteinuria'. Mitrovic Jelena S,Lezaic Visnja Kidney international 10.1038/ki.2010.300
    Reproducibility of albuminuria in type 2 diabetic subjects. Findings from the Renal Insufficiency And Cardiovascular Events (RIACE) study. Pugliese Giuseppe,Solini Anna,Fondelli Cecilia,Trevisan Roberto,Vedovato Monica,Nicolucci Antonio,Penno Giuseppe, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association BACKGROUND:Measurement of urinary albumin excretion (UAE) shows important intra-individual variability suggesting the need for multiple assessments. This study aimed at investigating the reproducibility of UAE in type 2 diabetes. METHODS:UAE was obtained from two to three samples collected in a 3- to 6-month period from 4062 of the 15 773 type 2 diabetic subjects participating in the Renal Insufficiency And Cardiovascular Events (RIACE) Italian Multicentre Study in 2007-08. UAE was assessed as albumin excretion rate (AER) in 24-h urine collections from 833 subjects and albumin:creatinine ratio (A/C) in early-morning urine samples from 3229 patients. Albuminuria was measured by immunonephelometry or immunoturbidimetry. RESULTS:The median coefficient of variation (CV) was 32.5% (interquartile range: 14.3-58.9). Concordance rate between a single UAE and the geometric mean of multiple measurements was 94.6% for normoalbuminuria, 83.5% for microalbuminuria, 91.1% for macroalbuminuria and 90.6% for albuminuria (micro + macro). CV was significantly higher (P < 0.01) for AER measurement than for A/C and with immunoturbidimetry than with immunonephelometry, whereas concordance rates were similar between the two modalities of urine collection and the two assay methods. Receiver-operating characteristic (ROC) plots demonstrated a good performance of single UAE in predicting the geometric mean of multiple measures at the cut-off level of both microalbuminuria (ROC(AUC) 0.926; 95% confidence interval: 0.915-0.937) and macroalbuminuria (ROC(AUC) 0.950; 95% confidence interval: 0.927-0.973). CONCLUSIONS:Data from this large cohort indicate that, in type 2 diabetic subjects, a single UAE value, thought to be encumbered with high intra-individual variability, is an accurate predictor of nephropathy stage for clinical and epidemiological purposes. 10.1093/ndt/gfr140
    Sustained kidney biochemical derangement in treated experimental diabetes: a clue to metabolic memory. de Oliveira Antonio Anax F,de Oliveira Tiago F,Bobadilla Larissa L,Garcia Camila C M,Berra Carolina Maria,de Souza-Pinto Nadja C,Medeiros Marisa H G,Di Mascio Paolo,Zatz Roberto,de M Loureiro Ana Paula Scientific reports The occurrence of biochemical alterations that last for a long period of time in diabetic individuals even after adequate handling of glycemia is an intriguing phenomenon named metabolic memory. In this study, we show that a kidney pathway is gradually altered during the course of diabetes and remains persistently changed after late glycemic control in streptozotocin-induced diabetic rats. This pathway comprises an early decline of uric acid clearance and pAMPK expression followed by fumarate accumulation, increased TGF-β expression, reduced PGC-1α expression, and downregulation of methylation and hydroxymethylation of mitochondrial DNA. The sustained decrease of uric acid clearance in treated diabetes may support the prolonged kidney biochemical alterations observed after tight glycemic control, and this regulation is likely mediated by the sustained decrease of AMPK activity and the induction of inflammation. This manuscript proposes the first consideration of the possible role of hyperuricemia and the underlying biochemical changes as part of metabolic memory in diabetic nephropathy development after glycemic control. 10.1038/srep40544
    Effects of Intensive Control of Glycemia on Clinical Kidney Outcomes in Type 2 Diabetes Patients Compared with Standard Control: A Meta-Analysis. Herrera-Gómez Francisco,Asensio-González María,González-López Anunciación,Álvarez F Javier Frontiers in pharmacology Association between poor control of glycemia and the onset of microvascular complications in type 2 diabetes mellitus (T2DM) patients is a hard issue. However, it seems that the impact of pharmacological treatment is important only in early stages of diabetic nephropathy. We sought to examine whether intensive glycemic control is associated with improvement of clinical Chronic Kidney Disease (CKD) outcomes compared to standard glycemic control. Meta-analysis of published and unpublished randomized controlled trials (RCT) and analysis of RCTs comparing anti-diabetic drugs and/or insulin (intensive control) vs. dietary measures (standard control) for relevant outcomes related to progression of CKD clinically manifest was undertaken. Summary estimates obtained by random effects model and funnel plots for assessing reporting bias are presented. Our analysis was based on four RCTs representing 27,391 adult T2DM patients with CKD from around the world. The pooled OR for the outcomes of doubling of serum creatinine and need of dialysis were, respectively, of 0.98 with 95% confidence interval (95% CI) 0.81-1.19, and 0.84 with 95% CI 0.69-1.02. The pooled OR for the outcome of death from kidney failure was 0.62 with 95% CI 0.39-0.98. Clinical differences between studies were not translated in statistical heterogeneity. Reporting bias may be present. Intensive glycemic control has an effect on death from kidney failure compared to standard glycemic control. Better comprehension of glycemic control effects on both T2DM patients with and without CKD is important for individualization of these two treatment modalities. 10.3389/fphar.2017.00845
    The role of adiponectin in renal physiology and development of albuminuria. Christou Georgios A,Kiortsis Dimitrios N The Journal of endocrinology Adiponectin is secreted by the adipose tissue and is downregulated in states of obesity and insulin resistance. There is a growing body of evidence indicating that adiponectin has renoprotective effects and protects against the development of albuminuria in rodent experiments. Adiponectin crossing the glomerular filtration barrier possibly inhibits inflammation, fibrosis and oxidative stress in kidneys through activation of AMP-activated protein kinase. Moreover, microalbuminuria is a well established early sign of progressive cardiovascular and renal disease, even in subjects with preserved glomerular filtration rate. Studies investigating the relationship between serum adiponectin levels and urinary albumin excretion rate (UAE) have yielded conflicting data and the mechanisms underlying the interplay between adiponectin and albuminuria remain to be elucidated. This article constitutes a critical review attempting to clarify any remaining confusion about this matter. Furthermore, this article examines the clinical significance of adiponectin-albuminuria interplay, suggesting that adiponectin is possibly involved in the development of albuminuria that is associated with obesity, diabetes and cardiovascular disease and may mediate, at least in part, the actions of medical treatments that influence UAE, such as angiotensin-converting-enzyme inhibitors, angiotensin II receptor blockers, thiazolidinediones, fenofibrate and diet. Further studies to investigate more thoroughly the renoprotective role of adiponectin in the human setting should be carefully planned, focusing on causality and the possible influence of adiponectin on the development of albuminuria in specific clinical settings. 10.1530/JOE-13-0578
    Serum Uric Acid and Risk of CKD in Type 2 Diabetes. De Cosmo Salvatore,Viazzi Francesca,Pacilli Antonio,Giorda Carlo,Ceriello Antonio,Gentile Sandro,Russo Giuseppina,Rossi Maria C,Nicolucci Antonio,Guida Pietro,Feig Daniel,Johnson Richard J,Pontremoli Roberto, Clinical journal of the American Society of Nephrology : CJASN BACKGROUND AND OBJECTIVE:Serum uric acid may predict the onset and progression of kidney disease, but it is unclear whether uric acid is an independent risk factor for diabetic nephropathy. Our aim was to study the relationship between uric acid levels and the development of CKD components in patients with type 2 diabetes. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS:Longitudinal study of a cohort of patients with type 2 diabetes from the database of the Italian Association of Clinical Diabetologists network. From a total of 62,830 patients attending the diabetes centers between January 1, 2004, and June 30, 2008, we considered those with baseline eGFR values ≥60 ml/min per 1.73 m2 and normal albumin excretion (n=20,142). Urinary albumin excretion, GFR, and serum uric acid were available in 13,964 patients. We assessed the association of serum uric acid quintiles with onset of CKD components by multinomial logistic regression model adjusting for potential confounders. We calculated the relative risk ratios (RRRs) for eGFR <60 ml/min per 1.73 m2, albuminuria, and their combination at 4 years. RESULTS:At 4-year follow-up, 1109 (7.9%) patients developed GFR <60 ml/min per 1.73 m2 with normoalbuminuria, 1968 (14.1%) had albuminuria with eGFR ≥60 ml/min per 1.73 m2, and 286 (2.0%) had albuminuria with eGFR <60 ml/min per 1.73 m2. The incidence of eGFR <60 ml/min per 1.73 m2 increased in parallel with uric acid quintiles: Compared with the lowest quintile, RRRs were 1.46 (95% confidence interval [CI], 1.14 to 1.88; P=0.003), 1.44 (95% CI, 1.11 to 1.87; P=0.006), 1.95 (95% CI, 1.48 to 2.58; P<0.001), and 2.61 (95% CI, 1.98 to 3.42; P<0.001) for second, third, fourth, and fifth quintiles, respectively. Serum uric acid was significantly associated with albuminuria only in presence of eGFR <60 ml/min per 1.73 m2. CONCLUSIONS:Mild hyperuricemia is strongly associated with the risk of CKD in patients with type 2 diabetes. 10.2215/CJN.03140315
    Albuminuria Reduction after High Dose of Vitamin D in Patients with Type 1 Diabetes Mellitus: A Pilot Study. Felício João Soares,de Oliveira Alana Ferreira,Peixoto Amanda Soares,de Souza Ana Carolina Contente Braga,Abrahão Neto João Felício,de Melo Franciane Trindade Cunha,Carvalho Carolina Tavares,de Lemos Manuela Nascimento,Cavalcante Sávio Diego Nascimento,Resende Fabricio de Souza,Dos Santos Márcia Costa,Motta Ana Regina,Janaú Luísa Corrêa,Yamada Elizabeth Sumi,Felício Karem Miléo Frontiers in endocrinology BACKGROUND:Some studies suggest an association between diabetic kidney disease (DKD) and vitamin D (VD), but there is no data about the effect of high dose of VD on DKD in type 1 diabetes mellitus (T1DM). Our pilot study aims to evaluate albuminuria reduction in patients with T1DM supplemented with high dose of VD. METHODS:22 patients received doses of 4,000 and 10,000 IU/day of cholecalciferol for 12 weeks according to patient's previous VD levels. They were submitted to continuous glucose monitoring system, 24 hours ambulatory blood pressure monitoring and urine albumin-to-creatinine ratio before and after VD supplementation. RESULTS:There was a reduction of DKD prevalence at the end of the study (68 vs 32%;  = 0.05), with no changes on insulin doses, glycated hemoglobin, glycemic variability and blood pressure values. A correlation between percentage variation of VD levels (ΔVD) and albuminuria at the end of the study was presented ( = -0.5;  < 0.05). Among T1DM patients with DKD at the beginning of the study, 8/13 (62%) had their DKD stage improved, while the other five ones (38%) showed no changes ( < 0.05). CONCLUSION:Our pilot study suggests an association between VD high dose supplementation, lower prevalence and improvement in stages of DKD in T1DM. 10.3389/fendo.2017.00199
    Short-term blood pressure variability in nondialysis chronic kidney disease patients: correlates and prognostic role on the progression of renal disease. Borrelli Silvio,Garofalo Carlo,Mallamaci Francesca,Tripepi Giovanni,Stanzione Giovanna,Provenzano Michele,Conte Giuseppe,De Nicola Luca,Zoccali Carmine,Minutolo Roberto Journal of hypertension OBJECTIVE:In chronic kidney disease (CKD), few cross-sectional studies evidenced an association between short-term BP variability (BPV) derived from ambulatory blood pressure (ABP) monitoring and renal damage. However, no study has evaluated the association of short-term BPV with the risk of CKD progression. METHODS:We performed a cohort study to assess the correlates and the predictive value for incident renal outcomes of short-term BPV in hypertensive patients with CKD stage G1-5. As measures of short-term BPV, we considered the weighted SD (W-SD), and the coefficient of variation of SBP (CV-24-h SBP). Primary outcome was a composite endpoint of ESRD (chronic dialysis or transplantation) or GFR decline of at least 50%. RESULTS:We included 465 patients (63.5 ± 14.2 years; 54.7% men; eGFR: 44 ± 22 ml/min per 1.73 m; proteinuria: 0.2 [0.1-0.9] g/day); W-SD, CV-24-h SBP and 24 h SBP were 12.5 ± 3.3 mmHg, 11.1 ± 2.8% and 127 ± 16 mmHg, respectively. W-SD was independently associated with older age, history of cardiovascular disease, diagnosis of diabetic, hypertensive and polycystic nephropathy, and higher 24 h SBP whereas no association with eGFR and proteinuria was found. During follow-up (median, 6.4 years), 130 patients reached the renal outcome (107 ESRD and 23 GFR decline of ≥50%). Higher 24 h, daytime and night-time SBP robustly predicted the composite renal endpoint [1.18 (1.10-1.25) for 5 mmHg], whereas BPV as measured by the W-SD did not either when expressed as a continuous variable [hazard ratio 0.97 (95% CI 0.91-1.04)] or when categorized into tertiles [1.16 (0.70-1.92) and 0.95 (0.54-1.68) in II and III tertiles, respectively]. Similar findings were found with CV-24-h SBP. CONCLUSION:In CKD patients, short-term BPV is strongly associated with 24 h, night-time and daytime BP but is independent from the eGFR and proteinuria and does not predict CKD progression. 10.1097/HJH.0000000000001825
    Intercellular adhesion molecule, plasma adiponectin and albuminuria in type 2 diabetic patients. Lenghel Alina Ramona,Kacso Ina Maria,Bondor Cosmina Ioana,Rusu Crina,Rahaian Rodica,Gherman Caprioara Mirela Diabetes research and clinical practice AIMS:Our study addressed the influence of early inflammatory stages of diabetic kidney disease: leukocyte adhesion and monocyte activation (as assessed by intercellular leukocyte adhesion molecule-ICAM-1 and monocyte chemoatractant protein-MCP-1) on the degree of albuminuria. Plasma levels of adiponectin, a possible anti-inflammatory counteracting mechanism, were also studied in correlation to the above-mentioned cytokines. METHODS:79 consecutive type 2 diabetic outpatients and 46 controls were included. Routine laboratory analysis, urinary albumin to creatinine ratio (uACR), plasma adiponectin, plasma ICAM-1 and urinary MPC-1 were assessed. RESULTS:In multiple regression ICAM-1 (p=0.004) and adiponectin (p=0.04) were the main determinants of uACR. Plasma adiponectin positively correlated to ICAM-1 (p=0.03, r=0.24). In albuminuric patients (uACR ≥30 mg/g) plasma adiponectin was significantly higher compared to normoalbuminuric ones (uACR <30 mg/g). In albuminuric patients the main determinants of uACR were plasma ICAM-1 and adiponectin. In multiple regression ICAM-1 is the only one that retains statistical significance (p=0.02). Urinary MCP-1 did not correlate to uACR. CONCLUSIONS:In our type 2 diabetic patients, plasma levels of ICAM-1 and adiponectin are predictive for albuminuria. Urinary MCP-1 does not correlated to uACR. Plasma adiponectin positively correlates to adhesion molecule ICAM-1 in our cohort. 10.1016/j.diabres.2011.08.028
    Serum Angptl2 levels are independently associated with albuminuria in type 2 diabetes. Li Qin,Gong Wei,Yang Zhihong,Lu Bin,Yang Yehong,Zhao Weiwei,Hu Renming Diabetes research and clinical practice BACKGROUND:Elevated serum Angptl2 levels are positively associated with the development of type 2 diabetes. We investigated whether serum Angptl2 levels are associated with diabetic nephropathy in patients with type 2 diabetes. METHODS:Two hundred and thirty patients with type 2 diabetes and 63 healthy controls participated in this cross-sectional study. Subjects with type 2 diabetes were divided into three groups using urinary albumin-to-creatinine ratio (ACR): a normoalbuminuric group (n=57), a microalbuminuric group (n=130) and a macroalbuminuria group (n=43). Serum Angptl2 concentrations were measured by enzyme-linked immunosorbent assay. RESULTS:Median serum (interquartile range) Angptl2 levels in control subjects and patients with type 2 diabetes with normoalbuminuria, microalbuminuria and macroalbuminuria were 24.03 (16.3-33.45), 36.14 (27.91-43.07), 44.6 (37.47-49.92), 50.19 (45.95-60.13)ng/ml (p<0.01) respectively. Angptl2 levels correlated with urinary ACR in participants with type 2 diabetes (r=0.38, p<0.01). Significant intercorrelations of Angptl2 were found with age, duration of diabetes, and fasting plasma glucose. After adjustment for significant covariates, albuminuria was still significantly associated with Angptl2 levels in type 2 diabetes (r=0.31, p<0.01). CONCLUSIONS:Angptl2 levels are elevated in patients with type 2 diabetes with an independent association between increasing Angptl2 levels and increasing levels of albuminuria. This suggests a possible role of Angptl2 in progressive nephropathy in patients with type 2 diabetes. 10.1016/j.diabres.2013.03.028
    Blood pressure status and the incidence of diabetic kidney disease in patients with hypertension and type 2 diabetes. De Cosmo Salvatore,Viazzi Francesca,Piscitelli Pamela,Giorda Carlo,Ceriello Antonio,Genovese Stefano,Russo Giuseppina,Guida Pietro,Fioretto Paola,Pontremoli Roberto, Journal of hypertension OBJECTIVE:Antihypertensive treatment and blood pressure (BP) reduction are known to retard the progression of diabetic kidney disease (DKD) in type 2 diabetes mellitus (T2DM) but long-term real-life clinical data on the incidence of DKD are lacking. In this observational, prospective cohort study, we investigated the association between achievement and maintenance of recommended BP values and the incidence of DKD and its components over a 4-year follow-up in patients with T2DM and hypertension from the Italian Medical Diabetologists registry. METHODS:Clinical records from a total of 12 995 patients with normal renal function and urine albumin excretion at baseline and regular visits during a 4-year follow-up were retrieved and analyzed. The association between recommended, time-updated BP control (BPC) (i.e. ≥75% of visits with SBP and DBP <140/85 mmHg) and the occurrence of renal outcomes was evaluated. RESULTS:At baseline, 28% of patients (n = 3612) had recommended BP values. Over the 4-year follow-up, 37% (n = 4845) developed DKD, 16% (n = 2061) low glomerular filtration rate and 27% (n = 3487) albuminuria. Patients who failed to achieve and maintain BPC over the study period showed an increased risk of developing DKD [odds ratio (OR) 1.38, P < 0.001], low glomerular filtration rate (OR 1.18, P = 0.03) and albuminuria (OR 1.47, P < 0.001) as compared with those with persistent BPC. These results were consistent after adjustment for covariates and in different subgroups. CONCLUSION:Long-term BPC is associated with a reduction in the incidence of DKD and its components in patients with hypertension and T2DM. 10.1097/HJH.0000000000001045
    Albuminuria and estimated glomerular filtration rate as predictors of diabetic end-stage renal disease and death. Berhane Abeba M,Weil E Jennifer,Knowler William C,Nelson Robert G,Hanson Robert L Clinical journal of the American Society of Nephrology : CJASN BACKGROUND AND OBJECTIVES:We investigated predictive value of albuminuria and estimated GFR (eGFR) for ESRD in Pima Indians with type 2 diabetes. DESIGN, SETTING, PARTICIPANTS AND MEASUREMENTS:Beginning in 1982, 2420 diabetic Pima Indians ≥18 years old were followed until they developed ESRD or died or until December 31, 2005. Individuals were classified at baseline by urinary albumin-to-creatinine ratio (ACR) and by eGFR, calculated by the Chronic Kidney Disease Epidemiology Collaboration equation. Predictors of ESRD and mortality were examined by proportional hazards regression. RESULTS:During a mean follow-up of 10.2 years, 287 individuals developed ESRD. Incidence of ESRD among individuals with macroalbuminuria (ACR ≥ 300 mg/g) was 9.3 times that of those with normoalbuminuria (ACR < 30 mg/g), controlled for age, gender, and duration of diabetes. Incidence among individuals with eGFR 15 to 29 ml/min per 1.73 m(2) was 81.9 times that of those with eGFR 90 to 119 ml/min per 1.73 m(2). Models that combined albuminuria and eGFR added significant predictive information about risk of ESRD or death compared with models containing eGFR or albuminuria alone. The hazard ratio for ESRD associated with a 10-ml/min per 1.73 m(2) lower eGFR was 1.36, whereas that associated with an increase in albuminuria category was 2.69; corresponding hazard ratios for death were 1.15 and 1.37. CONCLUSIONS:These results suggest that incorporation of quantitative information about albuminuria into staging systems based on eGFR adds significant prognostic information about risk for diabetic ESRD and death. 10.2215/CJN.00580111
    Gender differences in the association between HDL cholesterol and the progression of diabetic kidney disease in type 2 diabetic patients. Hanai Ko,Babazono Tetsuya,Yoshida Naoshi,Nyumura Izumi,Toya Kiwako,Hayashi Toshihide,Bouchi Ryotaro,Tanaka Nobue,Ishii Akiko,Iwamoto Yasuhiko Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association BACKGROUND:The impact of serum lipid abnormalities on the progression of diabetic kidney disease (DKD) remains conflicting. Furthermore, gender differences in the association between dyslipidaemia and outcome of DKD are largely unknown. We therefore conducted this single-centre observational cohort study to clarify gender differences in the association between serum lipid profiles and the progression of DKD. METHODS:Seven hundred and twenty-three Japanese type 2 diabetes mellitus (T2DM) patients with normoalbuminuria or microalbuminuria, 280 women and 443 men, with a mean (± SD) age of 63 ± 11 years were studied. The endpoint was the progression to a more advanced stage of albuminuria. For statistical analyses, Cox proportional hazard model analyses were conducted. RESULTS:During the mean follow-up period of 4.3 years, 62 of 477 patients with normoalbuminuria and 69 of 246 patients with microalbuminuria reached the endpoint. A significant interaction between high-density lipoprotein (HDL) cholesterol and gender was detected (P(interaction) = 0.04); therefore, separate analyses were conducted for men and women. Overall, in men, the univariate Cox proportional hazard model revealed that higher triglycerides and lower HDL cholesterol levels were significantly associated with higher risk of reaching the endpoint. In the multivariate Cox proportional hazard model, only HDL cholesterol levels remained as an independent predictor of the endpoint (hazard ratio 0.391, P = 0.01). In women, no serum lipid parameters were associated with the endpoint. CONCLUSIONS:Lower HDL cholesterol levels seem to be associated with the progression of DKD in men but not in women. 10.1093/ndt/gfr417
    Smoking cessation predicts amelioration of microalbuminuria in newly diagnosed type 2 diabetes mellitus: a 1-year prospective study. Voulgari Christina,Katsilambros Nicholas,Tentolouris Nicholas Metabolism: clinical and experimental The objective of the study was to assess the effect of smoking cessation on microalbuminuria in subjects with newly diagnosed type 2 diabetes mellitus (DM). From 500 smokers newly diagnosed with type 2 DM and microalbuminuria, only 193 (96 men/97 women; age, 56.4 ± 7.8 years) agreed to participate and were educated on smoking cessation, diet, and exercise. Pharmacological interventions were not different among the studied groups. All subjects were contacted by phone monthly with emphasis on smoking cessation. Anthropometric, biochemical parameters and urine specimens were obtained at baseline and at 12-month follow-up. Microalbuminuria was defined as an albumin to creatinine ratio of 30 to 299.9 μg/mg creatinine. Ankle brachial pressure index was determined by ultrasound. A total of 120 (62.2%) subjects quit smoking. Prevalence of microalbuminuria was reduced at 1 year to 72.6% in the subjects who quit smoking and to 22.5% in those who continued smoking (P = .015). Multivariate logistic regression analysis demonstrated that independently associated with the reduction in albumin to creatinine ratio (84.8 vs 28.7 μg/mg creatinine) were amelioration of glycemic control (P < .001), blood pressure (P = .02), dyslipidemia (P = .02), and insulin resistance (P = .05). Smoking cessation also reduced the prevalence of peripheral vascular disease (P = .03) and neuropathy (P = .04). From the pharmacological and lifestyle interventions, smoking cessation had the highest and an independent contribution to the reduction of microalbuminuria (P < .001). Smoking cessation in newly diagnosed type 2 DM patients is associated with amelioration of metabolic parameters, blood pressure, and the reduction of microalbuminuria. Stricter counseling about the importance of quitting smoking upon type 2 DM diagnosis is necessary to protect against the development of diabetic nephropathy and vascular complications. 10.1016/j.metabol.2011.02.014
    Plasma biomarkers improve prediction of diabetic kidney disease in adults with type 1 diabetes over a 12-year follow-up: CACTI study. Bjornstad Petter,Pyle Laura,Cherney David Z I,Johnson Richard J,Sippl Rachel,Wong Randy,Rewers Marian,Snell-Bergeon Janet K Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association Background:The objective of the study was to determine whether plasma biomarkers of kidney injury improve the prediction of diabetic kidney disease (DKD) in adults with type 1 diabetes (T1D) over a period of 12 years. Methods:Participants (n = 527, 53% females) in the Coronary Artery Calcification in T1D (CACTI) Study were examined during 2002-04, at a mean (± standard deviation) age of 39.6 ± 9.0 years with 24.8 years as the median duration of diabetes. Urine albumin-to-creatinine (ACR) and estimated glomerular filtration rate (eGFR) by CKD-EPI (chronic kidney disease epidemiology collaboration) creatinine were measured at the baseline and after mean follow-up of 12.1 ± 1.5 years. Albuminuria was defined as ACR ≥30 mg/g and impaired GFR as eGFR <60 mL/min/1.73 m2. Kidney injury biomarkers (Meso Scale Diagnostics) were measured on stored baseline plasma samples. A principal component analysis (PCA) identified two components: (i) kidney injury molecule-1, calbindin, osteoactivin, trefoil factor 3 and vascular endothelial growth factor; and (ii) β-2 microglobulin, cystatin C, neutrophil gelatinase-associated lipocalin and osteopontin that were used in the multivariable regression analyses. Results:Component 2 of the PCA was associated with increase in log modulus ACR [β ± standard error (SE): 0.16 ± 0.07, P = 0.02] and eGFR (β ± SE: -2.56 ± 0.97, P = 0.009) over a period of 12 years after adjusting for traditional risk factors (age, sex, HbA1c, low-density lipoprotein cholesterol and systolic blood pressure and baseline eGFR/baseline ACR). Only Component 2 of the PCA was associated with incident-impaired GFR (odds ratio 2.08, 95% confidence interval 1.18-3.67, P = 0.01), adjusting for traditional risk factors. The addition of Component 2 to traditional risk factors significantly improved C-statistics and net-reclassification improvement for incident-impaired GFR (ΔAUC: 0.02 ± 0.01, P = 0.049, and 29% non-events correctly reclassified, P < 0.0001). Conclusions:Plasma kidney injury biomarkers can help predict development of DKD in T1D. 10.1093/ndt/gfx255
    Glycated Hemoglobin and Outcomes in Patients with Advanced Diabetic Chronic Kidney Disease. Kuo I-Ching,Lin Hugo You-Hsien,Niu Sheng-Wen,Hwang Daw-Yang,Lee Jia-Jung,Tsai Jer-Chia,Hung Chi-Chih,Hwang Shang-Jyh,Chen Hung-Chun Scientific reports Diabetes is the major risk factor for end-stage renal disease (ESRD) worldwide. In advanced chronic kidney disease (CKD), less is known about the predictive value of HbA1c. We enrolled 2401 diabetic patients with stage 3-4 and stage 5 CKD, who were classified into 4 groups according to their baseline HbA1c values (<6%, 6%-7%, 7%-9%, and >9%). During the median follow-up of 3 years, 895 patients developed ESRD, and 530 died. In linear regression analysis, higher HbA1c correlated with higher eGFR in patients with stage 5 CKD but not in stage 3-4 CKD. In Cox regression analysis, a trend toward worse clinical outcomes existed when the HbA1c level exceeded 6% in stage 3-4 CKD, but the significance was only observed for >9%. The hazard ratios (HRs) for ESRD, all-cause mortality and combined CV events with mortality in the group of HbA1c >9% were 1.6 (95% CI, 1.07 to 2.38), 1.52 (95% CI, 0.97 to 2.38) and 1.46 (95% CI, 1.02 to 2.09), respectively. This study demonstrates that the higher HbA1c level is associated higher risks for clinical outcomes in diabetic patients with stage 3-4 CKD but not in stage 5 CKD. 10.1038/srep20028
    Intrapersonal HbA(1c) variability and the risk of progression of nephropathy in patients with Type 2 diabetes. Rodríguez-Segade S,Rodríguez J,García López J M,Casanueva F F,Camiña F Diabetic medicine : a journal of the British Diabetic Association AIM:To investigate the association between nephropathy and HbA(1c) variability (assessed as the standard deviation of each patient's HbA(1c) measurements) among patients with Type 2 diabetes. METHODS:Albumin excretion rate and HbA(1c) were measured in 2103 patients followed up for a mean 6.6 years. Multivariate Cox regression analysis was used to determine the influence of HbA(1c) variability on the risk of progression of nephropathy after adjustment for age, sex, duration of diabetes, baseline condition (two cohorts defined by duration of diabetes, retinopathy and albumin excretion rate), baseline HbA(1c) , insulin use, BMI, use of anti-hypertensive agents, smoking, lipid status, retinopathy, updated mean HbA(1c) and number of HbA(1c) measurements. RESULTS:Nephropathy progressed in 18.3% of subjects. HbA(1c) variability was significantly greater among progressors than among non-progressors (12 vs. 10 mmol/mol; 1.12 vs. 0.90%; P < 0.0001) and was a significant predictor of progression of nephropathy even after adjustment for updated mean HbA(1c) and other risk factors (hazard ratio 1.37, 95% CI 1.12-1.69). CONCLUSION:In patients with Type 2 diabetes, the risk of progression of nephropathy increases significantly with HbA(1c) variability, independently of the influence of updated mean HbA(1c) . 10.1111/j.1464-5491.2012.03767.x
    Plasma Triglycerides and HDL-C Levels Predict the Development of Diabetic Kidney Disease in Subjects With Type 2 Diabetes: The AMD Annals Initiative. Russo Giuseppina T,De Cosmo Salvatore,Viazzi Francesca,Pacilli Antonio,Ceriello Antonio,Genovese Stefano,Guida Pietro,Giorda Carlo,Cucinotta Domenico,Pontremoli Roberto,Fioretto Paola, Diabetes care OBJECTIVE:Despite the achievement of blood glucose, blood pressure, and LDL cholesterol (LDL-C) targets, the risk for diabetic kidney disease (DKD) remains high among patients with type 2 diabetes. This observational retrospective study investigated whether diabetic dyslipidemia-that is, high triglyceride (TG) and/or low HDL cholesterol (HDL-C) levels-contributes to this high residual risk for DKD. RESEARCH DESIGN AND METHODS:Among a total of 47,177 patients attending Italian diabetes centers, 15,362 patients with a baseline estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m, normoalbuminuria, and LDL-C ≤130 mg/dL completing a 4-year follow-up were analyzed. The primary outcome was the incidence of DKD, defined as either low eGFR (<60 mL/min/1.73 m) or an eGFR reduction >30% and/or albuminuria. RESULTS:Overall, 12.8% developed low eGFR, 7.6% an eGFR reduction >30%, 23.2% albuminuria, and 4% albuminuria and either eGFR <60 mL/min/1.73 m or an eGFR reduction >30%. TG ≥150 mg/dL increased the risk of low eGFR by 26%, of an eGFR reduction >30% by 29%, of albuminuria by 19%, and of developing one abnormality by 35%. HDL-C <40 mg/dL in men and <50 mg/dL in women were associated with a 27% higher risk of low eGFR and a 28% risk of an eGFR reduction >30%, with a 24% higher risk of developing albuminuria and a 44% risk of developing one abnormality. These associations remained significant when TG and HDL-C concentrations were examined as continuous variables and were only attenuated by multivariate adjustment for numerous confounders. CONCLUSIONS:In a large population of outpatients with diabetes, low HDL-C and high TG levels were independent risk factors for the development of DKD over 4 years. 10.2337/dc16-1246
    Diabetes Control and the Risks of ESRD and Mortality in Patients With CKD. Navaneethan Sankar D,Schold Jesse D,Jolly Stacey E,Arrigain Susana,Winkelmayer Wolfgang C,Nally Joseph V American journal of kidney diseases : the official journal of the National Kidney Foundation BACKGROUND:Diabetes is the leading cause of end-stage renal disease (ESRD) and a significant contributor to mortality in the general population. We examined the associations of hemoglobin A (HbA) levels with ESRD and death in a population with diabetes and chronic kidney disease (CKD). STUDY DESIGN:Cohort study. SETTING & PARTICIPANTS:6,165 patients with diabetes (treated with oral hypoglycemic agents and/or insulin) and CKD stages 1 to 5 at a large health care system. PREDICTOR:HbA level (examined as a categorical and continuous measure). OUTCOMES:All-cause and cause-specific mortality ascertained from the Ohio Department of Health mortality files and ESRD ascertained from the US Renal Data System. RESULTS:During a median 2.3 years of follow-up, 957 patients died (887 pre-ESRD deaths) and 205 patients reached ESRD. In a Cox proportional hazards model, after multivariable adjustment including for kidney function, HbA level < 6% was associated with higher risk for death when compared with HbA levels of 6% to 6.9% (HR, 1.23; 95% CI, 1.01-1.50). Similarly, HbA level ≥ 9% was associated with higher risk for all-cause death (HR, 1.34; 95% CI, 1.06-1.69). In competing-risk models, baseline HbA level was not associated with ESRD. For cause-specific mortality, diabetes accounted for >12% of deaths overall and >19% of deaths among those with HbA levels > 9%. LIMITATIONS:Small proportion of participants with advanced kidney disease; single-center population. CONCLUSIONS:In this cohort of patients with CKD with diabetes, HbA levels < 6% and ≥9% were associated with higher risk for death. HbA levels were not associated with ESRD in this specific CKD population. Diabetes-related deaths increased with higher HbA levels. 10.1053/j.ajkd.2016.11.018
    Rapid GFR decline is associated with renal hyperfiltration and impaired GFR in adults with Type 1 diabetes. Bjornstad Petter,Cherney David Z,Snell-Bergeon Janet K,Pyle Laura,Rewers Marian,Johnson Richard J,Maahs David M Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association BACKGROUND:Rapid glomerular filtration rate (GFR) decline (>3 mL/min/1.73 m(2)) is an increasingly recognized high-risk diabetic nephropathy (DN) phenotype in Type 1 diabetes. Rapid GFR decline is a recognized predictor of impaired GFR (<60 mL/min/1.73 m(2)). However, the association between rapid GFR decline and renal hyperfiltration is not well described in Type 1 diabetes. We hypothesized that renal hyperfiltration (estimated glomerular filtration rate, eGFR ≥ 120 mL/min/1.73 m(2)) would predict rapid GFR decline over 6 years and that rapid GFR decline would predict impaired GFR at 6 years in adults with Type 1 diabetes. METHODS:GFR was calculated by chronic kidney disease epidemiology (CKD-EPI) creatinine in 646 adults with Type 1 diabetes in the coronary artery calcification in Type 1 diabetes study. Logistic multivariable models were employed to investigate the relationships between renal hyperfiltration and rapid GFR decline, and rapid GFR decline and incident impaired GFR over 6 years. RESULTS:Renal hyperfiltration predicted greater odds of rapid GFR decline over 6 years [odds ratio (OR): 5.00, 95% confidence interval (CI): 3.03-8.25, P < 0.0001] adjusting for hemoglobin A1c (HbA1c), systolic blood pressure (SBP), low-density lipoprotein cholesterol (LDL-C), sex, duration, log of albumin/creatinine ratio and estimated insulin sensitivity. Furthermore, rapid GFR decline predicted greater odds of incident impaired eGFR (OR: 15.99, 95% CI 2.34-114.37, P = 0.006) in a similarly adjusted model. Sensitivity analyses with GFR calculated by CKD-EPI combined creatinine and cystatin C, and renal hyperfiltration defined as ≥135 mL/min/1.73 m(2) yielded similar results. CONCLUSIONS:In adults with Type 1 diabetes, rapid GFR decline over 6 years was associated with baseline renal hyperfiltration and incident GFR impairment. These observations may suggest an intermediate and predictive role of rapid GFR decline in the progression of DN. 10.1093/ndt/gfv121
    TNF-α and microalbuminuria in patients with type 2 diabetes mellitus. Lampropoulou I-Th,Stangou M,Papagianni A,Didangelos T,Iliadis F,Efstratiadis G Journal of diabetes research AIM:Recent evidence suggests that chronic subclinical inflammation plays a key role in the pathogenesis and progression of diabetic nephropathy. Aim of the present study was to investigate possible correlation between the presence and degree of microalbuminuria and markers of inflammation in patients with type 2 diabetes mellitus (DM). PATIENTS-METHODS:Eighty patients were enrolled and clinical and laboratory data were recorded. Albumin-creatinine ratio (ACR) was calculated in first-morning urine samples. Serum and urinary tumor necrosis factor-α (TNF-α) levels were determined by ELISA. RESULTS:Forty-five patients had normoalbuminuria, 33 microalbuminuria, and 2 macroalbuminuria. Patients with microalbuminuria were older, with higher glycosylated hemoglobin levels (HbA1c) and they more frequently had diabetic retinopathy, neuropathy, and cardiovascular disease and were on treatment with angiotensin converting enzyme inhibitors (ACEi) and/or angiotensin receptor blockers (ARBs). ACR was significantly correlated with the presence of cardiovascular disease, hypertension, and HbA1c levels and the administration of clopidogrel and ACEi or ARBs. ACR was not correlated with C-reactive protein, fibrinogen, or serum TNF-α levels but had a strong correlation with urinary TNF-α levels. CONCLUSIONS:In patients with type 2 DM, urinary, but not serum, TNF-α levels are associated with the presence and severity of microalbuminuria. 10.1155/2014/394206
    Urinary proteomics for prediction of mortality in patients with type 2 diabetes and microalbuminuria. Currie Gemma E,von Scholten Bernt Johan,Mary Sheon,Flores Guerrero Jose-Luis,Lindhardt Morten,Reinhard Henrik,Jacobsen Peter K,Mullen William,Parving Hans-Henrik,Mischak Harald,Rossing Peter,Delles Christian Cardiovascular diabetology BACKGROUND:The urinary proteomic classifier CKD273 has shown promise for prediction of progressive diabetic nephropathy (DN). Whether it is also a determinant of mortality and cardiovascular disease in patients with microalbuminuria (MA) is unknown. METHODS:Urine samples were obtained from 155 patients with type 2 diabetes and confirmed microalbuminuria. Proteomic analysis was undertaken using capillary electrophoresis coupled to mass spectrometry to determine the CKD273 classifier score. A previously defined CKD273 threshold of 0.343 for identification of DN was used to categorise the cohort in Kaplan-Meier and Cox regression models with all-cause mortality as the primary endpoint. Outcomes were traced through national health registers after 6 years. RESULTS:CKD273 correlated with urine albumin excretion rate (UAER) (r = 0.481, p = <0.001), age (r = 0.238, p = 0.003), coronary artery calcium (CAC) score (r = 0.236, p = 0.003), N-terminal pro-brain natriuretic peptide (NT-proBNP) (r = 0.190, p = 0.018) and estimated glomerular filtration rate (eGFR) (r = 0.265, p = 0.001). On multivariate analysis only UAER (β = 0.402, p < 0.001) and eGFR (β = - 0.184, p = 0.039) were statistically significant determinants of CKD273. Twenty participants died during follow-up. CKD273 was a determinant of mortality (log rank [Mantel-Cox] p = 0.004), and retained significance (p = 0.048) after adjustment for age, sex, blood pressure, NT-proBNP and CAC score in a Cox regression model. CONCLUSION:A multidimensional biomarker can provide information on outcomes associated with its primary diagnostic purpose. Here we demonstrate that the urinary proteomic classifier CKD273 is associated with mortality in individuals with type 2 diabetes and MA even when adjusted for other established cardiovascular and renal biomarkers. 10.1186/s12933-018-0697-9
    Progression of nephropathy in type 2 diabetes: the glycation gap is a significant predictor after adjustment for glycohemoglobin (Hb A1c). Rodríguez-Segade Santiago,Rodríguez Javier,Cabezas-Agricola Jose M,Casanueva Felipe F,Camiña Félix Clinical chemistry BACKGROUND:The glycation gap has been proposed as an index of nonglycemic determinants of glycated hemoglobin (Hb A(1c)). We investigated whether it predicts progression of nephropathy in type 2 diabetic patients. METHODS:We recorded albumin excretion rate, Hb A(1c), and serum fructosamine in 2314 patients over an average of 6.5 years. Hb A(1c) was regressed on fructosamine by using a repeated-measures longitudinal regression model and data for all visits of all patients; the raw glycation gap gg was calculated at each visit, as measured by Hb A(1c) minus the value predicted by the regression; and the mean glycation gap (GG) was defined for each patient as the mean of the values for the raw glycation gap (gg) calculated at each visit. The study group was divided into high-, medium- and low-GG groups of equal sizes, which were compared for progression of nephropathy by Cox regression analyses controlling for age, sex, duration of diabetes, initial nephropathy status, therapy, baseline Hb A(1c), mean Hb A(1c), and mean fructosamine. The design of the study was a retrospective cohort study with follow-up for 6.5 (SD 4.2) years. RESULTS:The gg exhibited considerable stability over time. In the high- and medium-GG groups, the risk of progression of nephropathy was respectively 2.5 and 1.6 times that of the low-GG group (P < 0.0001 and P = 0.001, respectively) after adjustment as described above. CONCLUSIONS:GG predicts the progression of nephropathy in type 2 diabetic patients independently of fructosamine and even after adjustment for Hb A(1c). The joint use of the glycation gap and fructosamine as measures of nonglycemic and glycemic determinants of glycation, respectively, may improve evaluation of the risk of nephropathy and of the glycemic control desirable for the individual patient. 10.1373/clinchem.2010.144949
    Renal and Cardiovascular Risk According to Tertiles of Urinary Albumin-to-Creatinine Ratio: The Adolescent Type 1 Diabetes Cardio-Renal Intervention Trial (AdDIT). Marcovecchio M Loredana,Chiesa Scott T,Armitage Jane,Daneman Denis,Donaghue Kim C,Jones Timothy W,Mahmud Farid H,Marshall Sally M,Neil H Andrew W,Dalton R Neil,Deanfield John,Dunger David B, Diabetes care OBJECTIVE:Baseline data from the Adolescent Type 1 Diabetes Cardio-Renal Intervention Trial (AdDIT) indicated that tertiles of urinary albumin-to-creatinine ratios (ACRs) in the normal range at age 10-16 years are associated with risk markers for diabetic nephropathy (DN) and cardiovascular disease (CVD). We aimed to determine whether the top ACR tertile remained associated with DN and CVD risk over the 2-4-year AdDIT study. RESEARCH DESIGN AND METHODS:One hundred fifty adolescents (mean age 14.1 years [SD 1.6]) with baseline ACR in the upper tertile (high-ACR group) recruited to the AdDIT trial, who remained untreated, and 396 (age 14.3 years [1.6]) with ACR in the middle and lower tertiles (low-ACR group), who completed the parallel AdDIT observational study, were evaluated prospectively with assessments of ACR and renal and CVD markers, combined with carotid intima-media thickness (cIMT) at baseline and end of study. RESULTS:After a median follow-up of 3.9 years, the cumulative incidence of microalbuminuria was 16.3% in the high-ACR versus 5.5% in the low-ACR group (log-rank < 0.001). Cox models showed independent contributions of the high-ACR group (hazard ratio 4.29 [95% CI 2.08-8.85]) and HbA (1.37 [1.10-1.72]) to microalbuminuria risk. cIMT change from baseline was significantly greater in the high- versus low-ACR group (mean difference 0.010 mm [0.079], = 0.006). Changes in estimated glomerular filtration rate, systolic blood pressure, and hs-CRP were also significantly greater in the high-ACR group ( < 0.05). CONCLUSIONS:ACR at the higher end of the normal range at the age of 10-16 years is associated with an increased risk of progression to microalbuminuria and future CVD risk, independently of HbA. 10.2337/dc18-1125
    Urinary neutrophil gelatinase-associated lipocalin and progression of diabetic nephropathy in type 1 diabetic patients in a four-year follow-up study. Nielsen Stine Elkjaer,Hansen Henrik Post,Jensen Berit Ruud,Parving Hans-Henrik,Rossing Peter Nephron. Clinical practice BACKGROUND:Neutrophil gelatinase-associated lipocalin (NGAL), a marker of renal tubular damage, predicts progression in non-diabetic chronic kidney. We evaluated urinary (u)-NGAL as a predictor of progression in diabetic nephropathy in type 1 diabetic (T1D) patients. METHODS:As a substudy of a 4-year randomized, intervention study evaluating low-protein diet in T1D patients with diabetic nephropathy, 78 patients were studied with yearly measurements of u-NGAL (ELISA, BioPorto). OUTCOME:Decline in glomerular filtration rate (GFR) ((51)Cr-EDTA), and end-stage renal disease (ESRD) or death. RESULTS:Mean age 40.7 (8.2) years and 50 men. 13 patients developed ESRD or died. Baseline GFR (mean, SD): 68 (31) ml/min/1.73 m(2). Baseline u-NGAL [geometric mean (95% CI)] and GFR were 15.6 ng/24 h (11.8-20.7) and 68 (31) ml/min/1.73 m(2). During follow-up, an increase in u-NGAL [geometric mean (95% CI)] of 15%/year (4-27) and a decline in GFR of 3.7 (3.0) ml/min/year were observed. Baseline u-NGAL was not associated with the decline in GFR. Elevated u-NGAL at baseline (log-transformed) predicted death and ESRD (HR 3.8, 95% CI 1.04-14.0), however not after adjustment for known progression promoters (HR 2.0, p = 0.6). CONCLUSION:Elevated u-NGAL was not related to decline in GFR during a 4-year follow-up. Elevated u-NGAL was associated with the development of ESRD and death, but not after adjustment. 10.1159/000320615
    BP and Renal Outcomes in Diabetic Kidney Disease: The Veterans Affairs Nephropathy in Diabetes Trial. Leehey David J,Zhang Jane H,Emanuele Nicholas V,Whaley-Connell Adam,Palevsky Paul M,Reilly Robert F,Guarino Peter,Fried Linda F, Clinical journal of the American Society of Nephrology : CJASN BACKGROUND AND OBJECTIVES:Proteinuric diabetic kidney disease frequently progresses to ESRD. Control of BP delays progression, but the optimal BP to improve outcomes remains unclear. The objective of this analysis was to evaluate the relationship between BP and renal outcomes in proteinuric diabetic kidney disease. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS:BP data from all 1448 randomized participants in the Veterans Affairs Nephropathy in Diabetes Trial were included in a post hoc analysis. The associations of mean on-treatment BP with the primary end point (decline in eGFR, ESRD, or death), renal end point (decline in eGFR or ESRD), rate of eGFR decline, and mortality were measured. RESULTS:The median (25th, 75th percentile) follow-up time was 2.2 (1.2, 3.0) years. There were 284 primary end points. In univariate analyses, both mean systolic and mean diastolic BPs were strongly associated (P<0.001) with the primary end point. After multivariate adjustment, the hazard of developing the primary end point became progressively higher as mean systolic BP rose from <120 to ≥ 150 mmHg (P=0.02), with a significantly higher hazard ratio for 140-149 versus 120-129 mmHg (1.51 [1.06, 2.15]; P=0.02). There was also a significant association of mean diastolic BP with the hazard of developing the primary end point (P<0.01), with a significantly higher hazard ratio when mean diastolic BP was 80-89 versus 70-79 mmHg (1.54 [1.05, 2.25]; P=0.03); there was also a strong trend when mean diastolic BP was <60 mmHg. Associations between BP and both renal end point and rate of eGFR decline were similar to those with the primary end point. No association of BP with mortality was observed, possibly because of the limited number of mortality events. CONCLUSIONS:In patients with proteinuric diabetic kidney disease, mean systolic BP ≥ 140 mmHg and mean diastolic BP ≥ 80 mmHg were associated with worse renal outcomes. 10.2215/CJN.02850315
    Hypomagnesaemia: a modifiable risk factor of diabetic nephropathy. Bherwani Sonny,Jibhkate Srushtee Bipin,Saumya A S,Patel Sitendu Kumar,Singh Ritu,Ghotekar L H Hormone molecular biology and clinical investigation BACKGROUND:Diabetes mellitus (DM) is a heterogeneous disease characterised by an absolute or relative deficiency of insulin and insulin resistance. Diabetes is occurring at younger age in India. It is estimated that 20% of the type 2 DM patients reach end-stage renal disease (ESRD) during their lifetime. Recently, it has been proposed that hypomagnesaemia is a novel factor implicated in the pathogenesis of diabetic complications. Considering this, a study was designed to estimate the prevalence and association of hypomagnesaemia with diabetic nephropathy in North Indian population. MATERIALS AND METHODS:The investigated clinical group composed of 100 type 2 diabetics, grouped into two, on the basis of presence or absence of diabetic nephropathy with n=50 each. Biochemical investigations including fasting blood sugar (BS-F), blood urea, creatinine, magnesium (Mg), urinary albumin-creatinine ratio (U-A/C ratio) were carried out. Descriptive statistics was applied to described frequency and means. χ2-Test and Student's t-tests were used to analyze associations between categorical and continuous variables, respectively. Pearson's correlation was done to find the association of nephropathy with hypomagnesaemia. RESULTS:We observed that 37% of diabetic patients had hypomagnesaemia (mean=1.40±0.16 mg/dL). There was also a significantly higher prevalence of hypomagnesaemia (52%) in DM nephropathy patients (mean=1.62±0.31 mg/dL) compared to without nephropathy patients (22%, mean=1.86±0.28 mg/dL). Serum magnesium levels were significantly inversely correlated with serum creatinine (r=-0.222, p=0.026) and U-A/C ratio (r=-0.352, p=0.000), and positively correlated with glomerular filtration rate (GFR) (r=0.304, p=0.002). CONCLUSION:We concluded that hypomagnesaemia was significantly associated with higher prevalence of diabetic nephropathy and can be used as a marker for the risk of development of diabetic nephropathy. 10.1515/hmbci-2016-0024