HbA1C Variability Is Strongly Associated with Development of Macroalbuminuria in Normal or Microalbuminuria in Patients with Type 2 Diabetes Mellitus: A Six-Year Follow-Up Study.
BioMed research international
BACKGROUND:Glycemic variability is associated with higher risk of microvascular complications in patients with type 2 diabetes. AIM:To test the hypothesis that glycemic variability can contribute to progression to macroalbuminuria in normal or microalbuminuria in patients with type 2 diabetes. DESIGN:This prospective study enrolled 193 patients with type 2 diabetes at a tertiary medical center. METHODS:For each patient, the intrapersonal glycemic variability (mean, SD, and coefficient of variation of HbA1c) was calculated using all measurements obtained three years before the study. Patients were divided into four groups stratified by both urine albumin/creatinine ratio and HbA1c-SD. The presence of macroalbuminuria was assessed with Kaplan-Meier plots and compared by log-rank test. RESULTS:Of the 193 patients, 83 patients were in the macroalbuminuria state. Patients in the initial macroalbuminuria group after enrollment had the highest diabetes duration, mean, CV-HbA1c and HbA1c-SD, and uric acid level, and the lowest estimate glomerular filtration rate, followed by subsequent macroalbuminuria and without macroalbuminuria groups. Patients with microalbuminuria and high HbA1c-SD showed the highest progression rate to macroalbuminuria, after a six-year follow-up study by Kaplan-Meier Plots and compared by log-rank test. CONCLUSIONS:Higher HbA1C variability is more likely to progress to macroalbuminuria in those patients who are already in a microalbuminuria state. We recommend that clinicians should aggressively control blood glucose to an acceptable range and avoid blood glucose fluctuations by individualized treatment to prevent renal status progression.
10.1155/2020/7462158
Differential metabolic profile associated with the condition of normoalbuminuria in the hypertensive population.
Santiago-Hernandez Aranzazu,Martinez Paula J,Martin-Lorenzo Marta,Ruiz-Hurtado Gema,G Barderas Maria,Segura Julian,Ruilope Luis M,Alvarez-Llamas Gloria
Nefrologia
BACKGROUND AND AIM:Albuminuria is an indicator of sub-clinical organ damage and a marker of cardiovascular risk and renal disease. A percentage of hypertensive patients develop albuminuria despite being under chronic suppression of the renin-angiotensin system (RAS). We previously identified urinary metabolites associated with the development of albuminuria. In this study, we searched for metabolic alterations which reflect different levels within the condition of normoalbuminuria. PATIENTS, MATERIALS AND METHODS:Urine from 48 hypertensive patients under chronic RAS suppression was analysed. They were classified according to the albumin/creatinine ratio (ACR) into 3groups: Normoalbuminuria (<10mg/g); high-normal (10-30mg/g in men, or 20-40mg/g in women); and moderately high albuminuria (microalbuminuria, 30-200mg/g or 40-300mg/g, respectively). The metabolome was analysed by mass spectrometry and a correlation analysis was performed between altered metabolite levels and ACR. RESULTS:Oxaloacetate, 3-ureidopropionate, guanidoacetate and malate show significant variation between the normo and micro groups. Additionally, these metabolites are able to differentiate between patients in the normo and high-normal range. A significant correlation between metabolites and ACR was found. Observed variations point to alterations in the energy metabolism already in patients with albuminuria in the high-normal range. CONCLUSIONS:The association between the molecular panel consisting of 3-ureidopropionate, oxaloacetate, malate and guanidoacetate and different levels of albuminuria is confirmed. A metabolic fingerprint was also identified showing variations within the condition of normoalbuminuria allowing an earlier molecular stratification of patients.
10.1016/j.nefro.2019.10.007
Gender Differences in Genetic Associations of RAB38 with Urinary Protein-to-Creatinine Ratio (UPCR) Levels in Diabetic Nephropathy Patients.
Yu Zhi-Lei,Wong Chung-Shun,Lai Yi Ting,Chou Wan-Hsuan,Faridah Imaniar Noor,Kao Chih-Chin,Lin Yuh-Feng,Chang Wei-Chiao
Journal of personalized medicine
Renal dysfunction is common in patients with diabetes mellitus (DM). Previous findings from a meta-analysis of GWAS indicated that the variation of is highly associated with the urinary albumin-to-creatinine ratio (UACR) in European populations. In addition, knockout rats showed an increase in urinary albumins. Although the prevalence of chronic kidney disease is high in Taiwan, the role of genetic variants in diabetic renal function is still unclear. In the current study, 275 diabetic nephropathy (DN) patients were recruited to perform a genetic association study. Our results indicated that rs1027027, rs302647, and rs302646 in were significantly associated with urinary protein-to-creatinine ratio (UPCR) levels in DN patients. Importantly, after analysis stratified by gender, a significant genetic influence on UPCR levels was observed in the male population. The findings confirmed the roles of gender and variants of in the risk of UPCR in Diabetic Nephropathy patients.
10.3390/jpm10040184
Relation of short-term blood pressure variability to early renal effects in hypertensive patients with controlled blood pressure.
Farrag Hazem M A,Amin Amr S,Abdel-Rheim Alaa-Eddin R
Blood pressure monitoring
INTRODUCTION:Microalbuminuria is a common early hypertension-mediated organ damage, which correlates with the overall cardiovascular risk and development of end-stage renal damage. Lately, blood pressure variability has shown an additive value over traditional BP measurement in prediction of cardiovascular and renal involvement. AIM:Investigate the relation between short-term blood pressure variability and microalbuminuria in controlled hypertensive patients. PATIENTS AND METHODS:Ninety non-diabetic hypertensive patients with controlled blood pressure and normal estimated glomerular filtration rate had 24-hour ambulatory blood pressure monitoring with calculation of short-term blood pressure variability indices (SD, coefficient of variation and average reading variability of systolic and diastolic blood pressure for 24-hour, daytime and nighttime], and measurement of the albumin/creatinine ratio. RESULTS:Patients were classified into group 1 (61 patients without microalbuminuria) and group 2 (29 patients with microalbuminuria). No significant difference was observed between both groups regarding age, sex, body mass index, office blood pressure, average 24-hour ambulatory blood pressure monitoring readings and dipping status, but significantly longer duration of hypertension in group 2. All blood pressure variability indices were significantly higher in group 2, which showed strong positive correlations with microalbuminuria level. Multivariate analysis represented an average reading variability of 24-hour systolic blood pressure as the most powerful independent predictor for microalbuminuria (r = 0.516, P = 0.001). Receiver operating characteristic curve analysis revealed that average reading variability of 24-hour systolic blood pressure (>12.55) could predict microalbuminuria (sensitivity = 89.7%, specificity = 88.5%, area under curve = 0.949, P = 0.001). CONCLUSION:Short-term blood pressure variability correlated well with early renal effects in controlled hypertensive patients. Average reading variability of 24-hour systolic blood pressure was the strongest predictor for microalbuminuria in such patients.
10.1097/MBP.0000000000000383
Association of Albuminuria With Intraglomerular Hydrostatic Pressure and Insulin Resistance in Subjects With Impaired Fasting Glucose and/or Impaired Glucose Tolerance.
Tsuda Akihiro,Ishimura Eiji,Uedono Hideki,Ochi Akinobu,Nakatani Shinya,Morioka Tomoaki,Mori Katsuhito,Uchida Junji,Emoto Masanori,Nakatani Tatsuya,Inaba Masaaki
Diabetes care
OBJECTIVE:Little is known about the relationships between insulin resistance, intrarenal hemodynamics, and urinary albumin excretion (UAE) in humans with impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT). The aim of the current study was to examine intrarenal hemodynamic abnormalities, insulin resistance, and UAE in subjects with IFG or IGT. We hypothesized that intrarenal hemodynamic abnormalities would be associated with insulin resistance. RESEARCH DESIGN AND METHODS:Fifty-four kidney donors underwent 75-g oral glucose tolerance and inulin and para-aminohippuric acid clearance testing. Insulin sensitivity index (ISI) was evaluated by the Matsuda index. Intrarenal hemodynamic parameters were calculated by the Gomez formulae. RESULTS:Of the 54 subjects, 33 exhibited IFG or IGT and 31 exhibited normal glucose tolerance (NGT). Glomerular hydrostatic pressure (P) and UAE were significantly higher in the IFG or IGT subjects with obesity ( = 0.015 and 0.0001, respectively). Log ISI correlated significantly and negatively with P ( = -0.351, = 0.009) in all subjects. In multiple regression analyses among all subjects, log ISI was associated significantly and independently with P (β = -0.316, = 0.015), after adjustment for age, sex, and systolic blood pressure. Further, BMI (β = 0.517, = 0.0004), P (β = 0.420, = 0.004), and log ISI (β = -0.366, = 0.008) were each associated significantly and independently with UAE after adjustment. CONCLUSIONS:We demonstrated that increased insulin resistance is associated with increased P and UAE in IFG or IGT subjects. These hemodynamic burdens and insulin resistance may cause injury to the glomeruli even in subjects with IFG or IGT.
10.2337/dc18-0718
Gestational Diabetes Mellitus and Renal Function: A Prospective Study With 9- to 16-Year Follow-up After Pregnancy.
Diabetes care
OBJECTIVE:To examine whether gestational diabetes mellitus (GDM), independent of subsequent diabetes, is an early risk factor for renal impairment long term after the index pregnancy. RESEARCH DESIGN AND METHODS:In the Diabetes & Women's Health (DWH) study (2012-2016), we examined the independent and joint associations of GDM and subsequent diabetes with long-term renal function among 607 women with and 619 women without GDM in the Danish National Birth Cohort (DNBC) index pregnancy (1996-2002). At median follow-up of 13 years after the index pregnancy, serum creatinine (mg/dL) and urinary albumin (mg/L) and creatinine (mg/dL) were measured, from which estimated glomerular filtration rate (eGFR) (mL/min/1.73 m) and urinary albumin-to-creatinine ratio (UACR) (mg/g) were derived. RESULTS:Compared with women without GDM or subsequent diabetes, women with a GDM history had significantly higher eGFR even if they had not subsequently developed diabetes (adjusted β-coefficient [95% CI] = 3.3 [1.7, 5.0]). Women who had a GDM history and later developed diabetes ( = 183) also had significantly higher UACR [exponent β = 1.3 [95% CI 1.1, 1.6]) and an increased risk of elevated UACR (≥20 mg/g) [adjusted relative risk [95% CI] = 2.3 [1.1, 5.9]) compared with women with neither. After adjusting for potential confounders including prepregnancy BMI and hypertension, GDM without subsequent diabetes was not related to UACR. CONCLUSIONS:Women who develop GDM in pregnancy were more likely to show increased eGFR levels 9-16 years postpartum, which could indicate early stages of glomerular hyperfiltration and renal damage. However, only those who subsequently developed diabetes showed overt renal damage as evidenced by elevated UACR.
10.2337/dc17-2629
Early atherosclerosis relates to urinary albumin excretion and cardiovascular risk factors in adolescents with type 1 diabetes: Adolescent type 1 Diabetes cardio-renal Intervention Trial (AdDIT).
Maftei Oana,Pena Alexia S,Sullivan Thomas,Jones Timothy W,Donaghue Kim C,Cameron Fergus J,Davis Elizabeth,Cotterill Andrew,Craig Maria E,Gent Roger,Dalton Neil,Daneman Denis,Dunger David,Deanfield John,Couper Jenny J,
Diabetes care
OBJECTIVE:The origins of cardiovascular and renal disease in type 1 diabetes begin during childhood. We aimed to evaluate carotid (cIMT) and aortic intima-media thickness (aIMT) and their relationship with cardiovascular risk factors and urinary albumin excretion in adolescents with type 1 diabetes in the Adolescent Type 1 Diabetes cardio-renal Intervention Trial (AdDIT). RESEARCH DESIGN AND METHODS:A total of 406 adolescents with type 1 diabetes, who were 14.1 ± 1.9 years old with type 1 diabetes duration of 6.7 ± 3.7 years, and 57 age-matched control subjects provided clinical and biochemical data and ultrasound measurements of vascular structure (cIMT and aIMT). Vascular endothelial and smooth muscle function was also measured in 123 of 406 with type 1 diabetes and all control subjects. RESULTS:In type 1 diabetic subjects, mean/maximal aIMT (P < 0.006; <0.008), but not mean/maximal cIMT, was greater than in control subjects. Mean/maximal aIMT related to urinary albumin-to-creatinine ratio (multiple regression coefficient [SE], 0.013 [0.006], P = 0.03; 0.023 [0.007], P = 0.002), LDL cholesterol (0.019 [0.008], P = 0.02; 0.025 [0.011], P = 0.02), and age (0.010 [0.004], P = 0.004; 0.012 [0.005], P = 0.01), independent of other variables. Mean/maximal cIMT was greater in males (0.023 [0.006], P = 0.02; 0.029 [0.007], P < 0.0001), and mean cIMT related independently to systolic blood pressure (0.001 [0.001], P = 0.04). Vascular smooth muscle function related to aIMT and cIMT but not to urinary albumin excretion. CONCLUSIONS:aIMT may be a more sensitive marker of atherosclerosis than cIMT in type 1 diabetes during mid-adolescence. Higher urinary albumin excretion, even within the normal range, is associated with early atherosclerosis and should direct clinical attention to modifiable cardiovascular risk factors.
10.2337/dc14-0700
Diagnostic performance of random urine samples using albumin concentration vs ratio of albumin to creatinine for microalbuminuria screening in patients with diabetes mellitus: a systematic review and meta-analysis.
Wu Hon-Yen,Peng Yu-Sen,Chiang Chih-Kang,Huang Jenq-Wen,Hung Kuan-Yu,Wu Kwan-Dun,Tu Yu-Kang,Chien Kuo-Liong
JAMA internal medicine
IMPORTANCE:A random urine sample measuring the albumin concentration (UAC) without simultaneously measuring the urinary creatinine is less expensive than measuring the ratio of albumin to creatinine (ACR), but comparisons of their diagnostic performance for microalbuminuria screening among patients with diabetes mellitus (DM) have not been undertaken in previous meta-analyses. OBJECTIVE:To compare the diagnostic performance of the UAC vs the ACR in random urine samples for microalbuminuria screening among patients with DM. DATA SOURCES:Electronic literature searches of PubMed, MEDLINE, and Scopus for English-language publications from the earliest available date of indexing through July 31, 2012. STUDY SELECTION:Clinical studies assessing the UAC or the ACR of random urine samples in detecting the presence of microalbuminuria among patients with DM using a urinary albumin excretion rate of 30 to 300 mg/d in 24-hour timed urine collections as the criterion standard. DATA EXTRACTION AND SYNTHESIS:Bivariate random-effects models for analysis and pooling of the diagnostic performance measures across studies, as well as comparisons between different screening tests. MAIN OUTCOMES AND MEASURES:The primary end point was the diagnostic performance measures of the UAC or the ACR in random urine samples, as well as comparisons between them. RESULTS:We identified 14 studies, with a total of 2078 patients; 9 studies reported on the UAC, and 12 studies reported on the ACR. Meta-analysis showed pooled sensitivities of 0.85 and 0.87 for the UAC and the ACR, respectively, and pooled specificities of 0.88 and 0.88, respectively. No differences in sensitivity (P = .70), specificity (P = .63), or diagnostic odds ratios (P = .59) between the UAC and the ACR were found. The time point of urine collection did not affect the diagnostic performance of either test. CONCLUSIONS AND RELEVANCE:The UAC and the ACR yielded high sensitivity and specificity for the detection of microalbuminuria. Because the diagnostic performance of the UAC is comparable to that of the ACR, our findings indicate that the UAC of random urine samples may become the screening tool of choice for the population with DM, considering the rising incidence of DM and the constrained health care resources in many countries.
10.1001/jamainternmed.2014.1363
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
Effects of the SGLT-2 inhibitor dapagliflozin on glomerular and tubular injury markers.
Dekkers Claire C J,Petrykiv Sergei,Laverman Gozewijn D,Cherney David Z,Gansevoort Ron T,Heerspink Hiddo J L
Diabetes, obesity & metabolism
The mechanisms by which SGLT-2 inhibitors lower albuminuria are incompletely understood. We assessed in a post-hoc analysis of a cross-over trial the effects of the SGLT2 inhibitor dapagliflozin on glomerular markers (IgG to IgG4 and IgG to albumin), tubular markers (urinary KIM-1, NGAL and LFABP) and inflammatory markers (urinary MCP-1 and IL-6) to provide more insight into kidney protective effects. Dapagliflozin decreased albuminuria by 43.9% (95% CI, 30.3%-54.8%) and eGFR by 5.1 (2.0-8.1) mL/min/1.73m compared to placebo. Dapagliflozin did not change glomerular charge or size selectivity index compared to placebo. Dapagliflozin decreased urinary KIM-1 excretion by 22.6% (0.3%-39.8%; P = .05) and IL-6 excretion by 23.5% (1.4%-40.6%; P = .04) compared to placebo, whereas no changes in NGAL, LFABP and MCP-1 were observed. During dapagliflozin treatment, changes in albuminuria correlated with changes in eGFR (r = 0.36; P = .05) and KIM-1 (r = 0.39; P = .05). In conclusion, the albuminuria-lowering effect of 6 weeks of dapagliflozin therapy may be the result of decreased intraglomerular pressure or reduced tubular cell injury.
10.1111/dom.13301
Kidney Injury Molecule-1 Enhances Endocytosis of Albumin in Renal Proximal Tubular Cells.
Zhao Xueying,Jiang Chen,Olufade Rebecca,Liu Dong,Emmett Nerimiah
Journal of cellular physiology
Receptor-mediated endocytosis plays an important role in albumin reabsorption by renal proximal tubule epithelial cells. Kidney injury molecule-1 (KIM-1) is a scavenger receptor that is upregulated on the apical membrane of proximal tubules in proteinuric kidney disease. In this study, we examined the cellular localization and functional role of KIM-1 in cultured renal tubule epithelial cells (TECs). Confocal immunofluorescence microscopy reveals intracellular and cell surface localization of KIM-1 in primary renal TECs. Albumin stimulation resulted in a redistribution of KIM-1 and tight junction protein zonula occludens-1 in primary TEC monolayer. An increase in albumin internalization was observed in both primary TECs expressing endogenous KIM-1 and rat kidney cell line (NRK-52E) overexpressing exogenous KIM-1. KIM-1-induced albumin accumulation was abolished by its specific antibody. Moreover, endocytosed KIM-1 and its cargo proteins were delivered from endosomes to lysosomes for degradation in a clathrin-dependent pathway. Supportive evidence includes (1) detection of KIM-1 in Rab5-positive early endosomes, Rab7-positive late endosomes/multivesicular bodies, and LAMP1-positive lysosomes, (2) colocalization of KIM-1 and clathrin in the intracellular vesicles, and (3) blockade of KIM-1-mediated albumin internalization by chlorpromazine, an inhibitor of clathrin-dependent endocytosis. KIM-1 expression was upregulated by albumin but downregulated by transforming growth factor-β1. Taken together, our data indicate that KIM-1 increases albumin endocytosis in renal tubule epithelial cells, at least partially via a clathrin-dependent mechanism. J. Cell. Physiol. 231: 896-907, 2016. © 2015 Wiley Periodicals, Inc.
10.1002/jcp.25181
Generation of urinary albumin fragments does not require proximal tubular uptake.
Weyer Kathrin,Nielsen Rikke,Christensen Erik I,Birn Henrik
Journal of the American Society of Nephrology : JASN
Urinary albumin excretion is an important diagnostic and prognostic marker of renal function. Both animal and human urine contain large amounts of albumin fragments, but whether these fragments originate from renal tubular degradation of filtered albumin is unknown. Here, we used mice with kidneys lacking megalin and cubilin, the coreceptors that mediate proximal tubular endocytosis of albumin, to determine whether proximal tubular degradation of albumin forms the detectable urinary albumin fragments. After intravenous administration of (125)I-labeled mouse albumin to knockout and control mice, we examined kidney uptake of albumin and urinary excretion of both intact albumin and its fragments using size exclusion chromatography. In control mice, all labeled albumin eluted as albumin fragments in the urine. In megalin/cubilin-deficient mice, we observed decreased uptake and degradation of albumin and increased urinary excretion of intact albumin; we did not, however, detect a decrease in the excretion of albumin fragments. These results show that the generation of urinary albumin fragments occurs independently of renal tubular uptake and degradation of albumin, suggesting that the pathophysiological implications of changes in urinary albumin fragments require reevaluation.
10.1681/ASN.2011101034
Albumin impairs renal tubular tight junctions via targeting the NLRP3 inflammasome.
Zhuang Yibo,Hu Caiyu,Ding Guixia,Zhang Yue,Huang Songming,Jia Zhanjun,Zhang Aihua
American journal of physiology. Renal physiology
Proteinuria is, not only a hallmark of glomerular disease, but also a contributor to kidney injury. However, its pathogenic mechanism is still elusive. In the present study, the effects of albumin on renal tubular tight junctions and the potential molecular mechanisms of those effects were investigated. In mouse proximal tubular cells (mPTCs), albumin treatment resulted in a significant loss of the cellular tight junction proteins zonula occludens-1 (ZO-1) and claudin-1 in a time- and dose-dependent manner, indicating a severe impairment of the tight junctions. On the basis of our previous study showing that albumin stimulated NLRP3 [neuronal apoptosis inhibitor protein, major histocompatibility complex class 2 transcription activator, incompatibility locus protein from Podospora anserina, and telomerase-associated protein (NACHT); leucine-rich repeat (LRR); and pyrin domain (PYD) domains-containing protein 3] inflammasome activation in mPTCs, we pretreated mPTCs with NLRP3 siRNA (siNLRP3) and found that NLRP3 knockdown significantly blocked the downregulation of ZO-1 and claudin-1 induced by albumin. Similarly, in albumin-overloaded wild-type mice, both ZO-1 and claudin-1 were downregulated at the protein and mRNA levels in parallel with the impaired formation of the tight junctions on transmission electron microscopy and the abnormal renal tubular morphology on periodic acid-Schiff staining, which contrasted with the stimulation of NLRP3 in the renal tubules. In contrast, NLRP3 knockout (NLRP3(-/-)) mice preserved normal ZO-1 and claudin-1 expression as well as largely normal tight junctions and tubular morphology. More importantly, deletion of the NLRP3 pathway downstream component caspase-1 similarly blocked the albumin overload-induced downregulation of ZO-1 and claudin-1. Taken together, these findings demonstrated an important role of the albumin-NLRP3 inflammasome axis in mediating the impairment of renal tubular tight junctions and integrity.
10.1152/ajprenal.00509.2014