Renal Function Decline In Type Research Articles

Rs4862705 in the melatonin receptor 1A gene is associated with renal function decline in type 1 diabetes individuals.

The pathogenesis of chronic diabetes complications has oxidative stress as one of the major elements, and single-nucleotide polymorphisms (SNPs) in genes belonging to antioxidant pathways modulate susceptibility to these complications. Considering that melatonin is a powerful antioxidant compound, our aim was to explore, in a longitudinal cohort study of type 1 diabetes (T1D) individuals, the association of microvascular complications and SNPs in the gene encoding melatonin receptor 1A (MTNR1A). Eight SNPs in MTNR1A were genotyped in 489 T1D individuals. Besides cross-sectional analyses of SNPs with each one of the microvascular complications (distal polyneuropathy, cardiovascular autonomic neuropathy, retinopathy, and diabetic kidney disease), a longitudinal analysis evaluated the associations of SNPs with renal function decline in 411 individuals followed up for a median of 8 years. In a subgroup of participants, the association of complications with urinary 6-sulfatoxymelatonin (aMT6s) concentration was investigated. The group of individuals with a renal function decline ≥ 5 mL min-1 1.73 m-2 year-1 presented a higher frequency of the A allele of rs4862705 in comparison with nondecliners, even after adjustment for confounding variables (OR = 1.84, 95% CI = 1.20-2.82; p = 0.0046). No other significant associations were found. This is the first study showing an association between a variant in a gene belonging to the melatonin system and renal function decline in the diabetic setting.

The usefulness of serum beta-2 microglobulin as a biomarker for evaluating renal function decline in type II diabetes mellitus

Background and objective: Serum beta-2 microglobulin (β2M) has been used as a useful clinical marker of chronic kidney dysfunction. The current study aims to evaluate the diagnostic accuracy of β2M for the early detection of diabetic nephropathy among Iraqi patients with type II diabetes mellitus. Methods: The study included 84 participants divided into four groups, three of them were type II diabetics and the fourth is the healthy individuals’ (control) group. The diabetic’ subgroups were named according to the Micral test as: normoalbuminuria (21 patients), microalbuminuria (21 patients), and macroalbuminuria group (21 patients). The control group included 21, age- and sex-matched, healthy participants. Biochemical markers for diabetes mellitus as well as β2M were determined for each participant and then were analyzed statistically. Results: The serum β2M of normoalbuminuria group was (2.86±0.95 µg/mL), microalbuminuria group was (5.06±1.97 µg/mL) and macroalbuminuria group (3.6±1.59 µg/mL). The results showed significant increase (p˂0.05) in the β2M level of microalbuminuria group when compared with that of normoalbuminuria and macroalbuminuria groups. In addition, a highly significant increase (p˂0.01) in β2M concentration was observed in microalbuminuria group when compared with that of the control group. Conclusions: β2M can be used as a useful biomarker for the early detection of diabetic nephropathy.

Hyperglycemia Regulated Circulating MicroRNAs and Their Effects on Renal Function Decline in Type 2 Diabetes

Background: It has been reported that microRNAs (miRNAs) play an important role in the pathogenesis of diabetic complications. We aimed to search for circulating miRNA that were associated with hyperglycemia in type 2 diabetes and examine their effects on renal function decline. Methods: Using the next-generation sequencing-based HTG EdgeSeq miRNA platform, a total of 2,083 miRNAswere measured in baseline plasma specimens obtained from73 subjects with type 2 diabetes (T2D) and normal renal function (discovery panel) and 136 subjects with T2D and impaired renal function (replication panel). Subjects in both panels were followed for 6–12 years to determine eGFR decline. Results: We identified 11 candidate miRNAsthat were strongly associated with elevated levels of glycated hemoglobin (HbA1c) in both screening and replication panels. Using bioinformatics analyses, we found that the candidate miRNAs targeted proteins of 6 pathways (the Ras signaling pathway, Signaling pathways regulating pluripotency of stem cells, the MAPK pathway, Glutamatergic synapse, the Rap 1 signaling pathway, and the AMPK signaling pathway). Importantly, 4 of these 11 miRNAs were significantly associated with risk of renal function decline. Conclusion: There were few previous reports about the association between circulating miRNAs, hyperglycemia, and diabetic kidney disease in T2D. The present study comprehensively examined and identified hyperglycemia-regulated miRNAs in human samples. Our finding are novel in that circulatingmiRNAsregulated by hyperglycemia are associated with risk of eGFR decline in T2D.

Low HDL cholesterol and the risk of rapid renal function decline in type 2 diabetes

Background and Aims: Low HDL-cholesterol (HDL-C) is associated with a higher risk of chronic kidney disease (CKD) in epidemiological studies and a recent Mendelian randomization study has suggested that genetically higher HDL-C concentration is causally associated with better kidney function. We therefore aim to determine whether HDL-C is associated with rapid kidney function decline in type 2 diabetic patients without overt nephropathy.

Quantitative levels of serum N-glycans in type 1 diabetes and their association with kidney disease.

We investigated associations of quantitative levels of N-glycans with hemoglobin A1c (HbA1c), renal function and renal function decline in type 1 diabetes. We measured 46 total N-glycan peaks (GPs) on 1565 serum samples from the Scottish Diabetes Research Network Type 1 Bioresource Study (SDRNT1BIO) and a pool of healthy donors. Quantitation of absolute abundance of each GP used 2AB-labeled mannose-3 as a standard. We studied cross-sectional associations of GPs and derived measures with HbA1c, albumin/creatinine ratio (ACR) and estimated glomerular filtration rate (eGFR), and prospective associations with incident albuminuria and final eGFR. All GPs were 1.4 to 3.2 times more abundant in SDRTN1BIO than in the healthy samples. Absolute levels of all GPs were slightly higher with higher HbA1c, with strongest associations for triantennary trigalactosylated disialylated, triantennary trigalactosylated trisialylated structures with core or outer arm fucose, and tetraantennary tetragalactosylated trisialylated glycans. Most GPs showed increased abundance with worsening ACR. Lower eGFR was associated with higher absolute GP levels, most significantly with biantennary digalactosylated disialylated glycans with and without bisect, triantennary trigalactosylated trisialylated glycans with and without outer arm fucose, and core fucosylated biantennary monogalactosylated monosialylated glycans. Although several GPs were inversely associated prospectively with final eGFR, cross-validated multivariable models did not improve prediction beyond clinical covariates. Elevated HbA1c is associated with an altered N-glycan profile in type 1 diabetes. Although we could not establish GPs to be prognostic of future renal function decline independently of HbA1c, further studies to evaluate their impact in the pathogenesis of diabetic kidney disease are warranted.

Circulating MicroRNAs Associated with Hyperglycemia and Their Effects on Renal Function Decline in Type 2 Diabetes: Global miRNome Analysis

Circulating MicroRNAs Associated with Hyperglycemia and Their Effects on Renal Function Decline in Type 2 Diabetes: Global miRNome Analysis

517-P: Serum Galectin-3 and the Risk of Rapid Renal Function Decline in Type 2 Diabetes

Background and Aims: Galectin-3 is a broad-spectrum biological response modifier and belongs to the multifunctional galectin family. It is involved in tissue fibrosis, immunity, and inflammatory response and recent evidence suggests that galectin-3 is associated with chronic kidney disease (CKD) in both diabetic and nondiabetic populations. We therefore aim to determine whether serum galectin-3 level is associated with rapid kidney function decline in type 2 diabetic individuals without overt nephropathy. Methods: Galectin-3 was measured in the baseline samples by ELISA in 998 type 2 diabetic patients with estimated glomerular filtration rate (eGFR) ≥60 ml/min/1.73m2 and no macroalbuminuria. Rapid renal progression during follow up was defined as a rate of eGFR decline >5 ml/min/year according to Kidney Disease Improving Global Outcomes (KDIGO) Guideline. Results: Over a median follow up of 12 years, 91 subjects had eGFR decline >5 ml/min/year and they had significantly higher serum galectin-3 level than those with more stable renal function (8.52 ± 2.20 ng/ml vs. 7.58 ± 2.38 respectively, p<0.01). In an unadjusted model, serum galectin-3 was associated with rapid decline in kidney function [hazard ratio (HR) 1.16, 95% CI 1.07-1.26, p<0.001]. Serum galectin-3 remained a significant independent predictor even after adjustment for age, gender, body mass index, smoking, baseline eGFR, systolic blood pressure, HbA1c and duration of diabetes, the presence of microalbuminuria and renin-angiotensin system blockers therapy (p=0.004). Conclusion: In type 2 diabetic subjects without overt nephropathy, serum galectin-3 was a significant independent risk factor for rapid decline in kidney function. Disclosure K.C.B. Tan: None. C. Lee: None. Y. Wong: None. S. Shiu: None.

Comparison of serum and urinary biomarker panels with albumin/creatinine ratio in the prediction of renal function decline in type 1 diabetes

Aims/hypothesisWe examined whether candidate biomarkers in serum or urine can improve the prediction of renal disease progression in type 1 diabetes beyond prior eGFR, comparing their performance with urinary albumin/creatinine ratio (ACR).MethodsFrom the population-representative Scottish Diabetes Research Network Type 1 Bioresource (SDRNT1BIO) we sampled 50% and 25% of those with starting eGFR below and above 75 ml min−1 [1.73 m]−2, respectively (N = 1629), and with median 5.1 years of follow-up. Multiplexed ELISAs and single molecule array technology were used to measure nine serum biomarkers and 13 urine biomarkers based on our and others’ prior work using large discovery and candidate studies. Associations with final eGFR and with progression to <30 ml min−1 [1.73] m−2, both adjusted for baseline eGFR, were tested using linear and logistic regression models. Parsimonious biomarker panels were identified using a penalised Bayesian approach, and their performance was evaluated through tenfold cross-validation and compared with using urinary ACR and other clinical record data.ResultsSeven serum and seven urine biomarkers were strongly associated with either final eGFR or progression to <30 ml min−1 [1.73 m]−2, adjusting for baseline eGFR and other covariates (all at p<2.3 × 10−3). Of these, associations of four serum biomarkers were independent of ACR for both outcomes. The strongest associations with both final eGFR and progression to <30 ml min−1 [1.73 m]−2 were for serum TNF receptor 1, kidney injury molecule 1, CD27 antigen, α-1-microglobulin and syndecan-1. These serum associations were also significant in normoalbuminuric participants for both outcomes. On top of baseline covariates, the r2 for prediction of final eGFR increased from 0.702 to 0.743 for serum biomarkers, and from 0.702 to 0.721 for ACR alone. The area under the receiver operating characteristic curve for progression to <30 ml min−1 [1.73 m]−2 increased from 0.876 to 0.953 for serum biomarkers, and to 0.911 for ACR alone. Other urinary biomarkers did not outperform ACR.Conclusions/interpretationA parsimonious panel of serum biomarkers easily measurable along with serum creatinine may outperform ACR for predicting renal disease progression in type 1 diabetes, potentially obviating the need for urine testing.

MicroRNAs 1915–3p, 2861, and 4532 Are Associated with Long-Term Renal Function Decline in Type 1 Diabetes

To the Editor: Diabetic kidney disease (DKD)1 is the leading cause of end-stage renal disease worldwide (1). Microalbuminuria is the earliest indicator of DKD in diabetes mellitus (DM). Microalbuminuria is clinically sensitive but not specific to this disease, which in some patients progresses with rapid glomerular filtration rate (GFR) decline (2). Research on new urinary biomarkers had demonstrated the ability of microRNAs (miRNAs) to discriminate between individuals with DKD and either healthy or non-DKD individuals (3). In an article published in Clinical Chemistry , Cardenas-Gonzalez et al. identified miRNAs miR-1915-3p, miR-2861, and miR-4532 as novel urinary miRNA biomarkers in DKD (3). Despite validating the results in different DM cohorts, the study's cross-sectional design was unable to address causality or prediction of subsequent outcomes. To further evaluate the prognostic potential of these new biomarkers, we tested the correlation between the expression of the 3 miRNAs and long-term estimated GFR (eGFR) decline in a cohort of 113 individuals with type 1 diabetes (T1D) who were recruited from 2013 to 2017 at the Diabetes Outpatient Clinic, Hospital das Clinicas. At the time of recruitment, spot urine samples were collected in sterile RNase-free flasks, centrifuged for 10 min, 3000 g at 4 °C, and frozen at −80 °C without additives or protease inhibitors within 4 h from collection. Clinical and demographic data [sex, age, T1D duration, use of angiotensin-converting …

Serum haptoglobin levels are associated with renal function decline in type 2 diabetes mellitus patients in a Chinese Han population

AimsWe 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. MethodsWe 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. ResultsSerum 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. ConclusionsOur findings suggest that serum Hp levels may be used as a potential biomarker for the early diagnosis and monitoring of DKD in T2DM patients.

Comparison of Insulin, Sulfonylurea and Sulfonylureas-Metformin Combination on HbA1c and eGFR Level on Age-, Sex- and BMI-Matched Groups of Indonesian Type 2 DM Patients

Objective: This study aimed to evaluate efficacy of insulin, sulfonylurea, and sulfonylureas-metformin combination in reducing the HbA1c level and preventing renal function decline in type 2 diabetes mellitus (DM) patients in Indonesia. Methods: A cross-sectional study was conducted at Dr. Sitanala Hospital involving 105 patients who were taking: insulin (30), sulfonylureas (30) and sulfonylureas-metformin combination (45). The subjects were classified into age-, sex- and BMI-matched groups. We measured their HbA1c level and serum creatinine to calculate eGFR level. Results: There were no differences among the three groups in term of age, sex, BMI, occupation and exercise habit. However, diet and family history of DM were different between the three groups. The average of HbA1c levels in the sulfonylureas-metformin group was 7.46±1.81 and showed a significant difference compared to the insulin group (8.27±1.74) with p=0.042. No significant difference existed in eGFR in the three groups (p=0.476). Subjects with obesity or BMI >30 kg/m2 had 3.268 times probability (p= 0.001) of having HbA1c >7 relative to underweight (BMI 7%, compared to those without diabetic family history (p = 0.002). Conclusion: We found in this study site that sulfonylureas-metformin combination was more efficient in decreasing HbA1c level in type 2 DM patients compared to insulin or sulfonylureas monotherapy. Family history of DM and overweight had considerable effect on uncontrolled HbA1c. Meanwhile, there was no significant difference among the three groups in preventing the decline of eGFR. Key words: Diabetes Mellitus, HbA1c, Insulin, Sulfonylureas, Metformin.

Serum Adipocyte Fatty Acid-Binding Protein Levels Are Linked to Rapid Renal Function Decline in Patients with Type 2 Diabetes and Normal Renal Function

Background: Rapid renal function decline has been recognized as an important predictor for diabetic nephropathy (DN). Adipocyte fatty acid-binding protein (A-FABP) is a major cytoplasmic protein in adipocytes and is closely associated with metabolic syndrome and type 2 diabetes. We aim to investigate the role of adipokines including A-FABP and inflammatory cytokines in the development of rapid renal function decline in type 2 diabetes and normal renal function. Methods: A total of 456 subjects with type 2 diabetes with normal renal function were recruited from an outpatient clinic at the Diabetes Center of Inha University Hospital and were followed up for 6 years with serial glomerular filtration rate (GFR) measurements. The serum levels of tumor necrosis factor (TNF)-a, and interleukin (IL)-6, high molecular weight (HMW) adiponectin, endogenous secretory receptor for advanced glycation end products (esRAGE), A-FABP and pentraxin-related protein (PTX3) were measured at baseline. Rapid renal function decline was defined as an eGFR decline &amp;gt;3.3% per year. Results: During follow-up, 120 participants (26.3%) developed rapid renal function decline and mean annual eGFR decline was -5.4 ± 2.7% and -0.6 ± 2.4% in decliners and non-decliners, respectively. Median A-FABP levels were significantly higher in patients with rapid decliners than in non-decliners (19.1 vs. 16.8 ng/ml, p=0.011). No significant difference of three cytokines levels were observed between groups. Each log unit increase of A-FABP was independently associated with greater risk of rapid renal function decline (odds ratio [OR] = 3.60; 95% confidence interval [CI] 1.95-6.66; p &amp;lt; 0.001) after adjustments for sex, BMI, A1C, GFR, hypertension, presence of carotid artery plaque and urine albumin creatinine ratio. Conclusions: High plasma A-FABP was an independent risk factor for rapid renal function decline in type 2 diabetes and normal renal function. Disclosure D. Seo: None. S. Kim: None. S. Ahn: None. S. Hong: None. M. Nam: None.

Reduced Levels of Anti-Ageing Hormone Klotho Predict Renal Function Decline in Type 2 Diabetes

Soluble Klotho (sKlotho) is a circulating hormone with cardiovascular-renal protective effects. Whether sKlotho predicts estimated glomerular filtration rate (eGFR) decline in patients with type 2 diabetes mellitus (T2DM) with relatively preserved renal function is unknown. Single-center observational follow-up study of 101 patients with T2DM and eGFR >45 mL/min [91% on renin angiotensin system (RAS) blockade] followed for a median of 9 years (range, 2 to 13 years). Primary outcome was a >50% decline in eGFR. sKlotho, serum phosphorus, serum calcium, and fibroblast growth factor-23 levels were measured from stored samples collected at baseline. Patients were followed up with standardized clinical and biochemical measurements. Patients with residual microalbuminuria (MA) despite RAS blockade (n = 53) had significantly lower levels of sKlotho [median, 184.7 pg/mL; interquartile range (IQR), 130.5 to 271.8 pg/mL) compared with patients without MA (n = 39; median, 235.2 pg/mL; IQR, 172.0 to 289.4 pg/mL; P = 0.03). Of the cohort, 21% reached the primary outcome. In a competing risk analysis, a 10% higher sKlotho level reduced the incidence of the primary outcome by 12% (hazard ratio, 0.27; 95% confidence interval, 0.15 to 0.52; P < 0.001] independent of traditional risk factors. Patients with sKlotho below the median of 204.4 pg/mL had nearly a fourfold higher cumulative incidence of the primary outcome compared with those above the median (24% vs 6.2%; P = 0.01). In patients with T2DM with relatively preserved eGFR, reduced levels of sKlotho predict renal function decline independent of traditional risk markers. sKlotho is a biomarker of renal dysfunction and a potential treatment target for renoprotection in T2DM.

Systems Biology-Derived Biomarkers to Predict Progression of Renal Function Decline in Type 2 Diabetes.

Chronic kidney disease (CKD) in diabetes has a complex molecular and likely multifaceted pathophysiology. We aimed to validate a panel of biomarkers identified using a systems biology approach to predict the individual decline of estimated glomerular filtration rate (eGFR) in a large group of patients with type 2 diabetes and CKD at various stages. We used publicly available "omics" data to develop a molecular process model of CKD in diabetes and identified a representative parsimonious set of nine molecular biomarkers: chitinase 3-like protein 1, growth hormone 1, hepatocyte growth factor, matrix metalloproteinase (MMP) 2, MMP7, MMP8, MMP13, tyrosine kinase, and tumor necrosis factor receptor-1. These biomarkers were measured in baseline serum samples from 1,765 patients recruited into two large clinical trials. eGFR decline was predicted based on molecular markers, clinical risk factors (including baseline eGFR and albuminuria), and both combined, and these predictions were evaluated using mixed linear regression models for longitudinal data. The variability of annual eGFR loss explained by the biomarkers, indicated by the adjusted R2 value, was 15% and 34% for patients with eGFR ≥60 and <60 mL/min/1.73 m2, respectively; variability explained by clinical predictors was 20% and 31%, respectively. A combination of molecular and clinical predictors increased the adjusted R2 to 35% and 64%, respectively. Calibration analysis of marker models showed significant (all P < 0.0001) but largely irrelevant deviations from optimal calibration (calibration-in-the-large: -1.125 and 0.95; calibration slopes: 1.07 and 1.13 in the two groups, respectively). A small set of serum protein biomarkers identified using a systems biology approach, combined with clinical variables, enhances the prediction of renal function loss over a wide range of baseline eGFR values in patients with type 2 diabetes and CKD.

Predictors of Renal Function Decline in Chinese Patients with Type 2 Diabetes Mellitus and in a Subgroup of Normoalbuminuria: A Retrospective Cohort Study.

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. 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 m2 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. 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. 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.

Type 2 diabetic patients with diabetic retinopathy and concomitant microalbuminuria showed typical diabetic glomerulosclerosis and progressive renal dysfunction

AimsTo determine whether or not diabetic retinopathy (DR) in type 2 diabetic patients can predict the renal functional decline. MethodsWe examined 32 normo-microalbuminuric type 2 diabetic patients by renal biopsy (23 men, age 49±10yrs) divided into two groups according to the presence (n=19) or absence (n=13) of DR. Electron microscopic morphometry including mesangial fractional volume [Vv(Mes/glom)] were performed and light microscopic tissues were categorized as: C1, normal/near normal renal structure; C2, typical diabetic glomerulopathy; C3, atypical injury patterns. Patients were followed up for 7.1±3.8years, and glomerular filtration rate (GFR) and urinary albumin excretion (UAE) measurements were taken annually. ResultsVv(Mes/glom) was larger in DR+ than that in DR–. Vv(Mes/glom) positively correlated with the UAE if patients had DR. The patients with DR had a significant higher rate of C2 pattern compared to those in DR–. Among patients with DR and C2, GFR in microalbuminuria (n=7) decreased while GFR in normoalbuminuria (n=5) did not change during the observation. ConclusionsType 2 diabetic patients with DR and C2 showed progressive renal dysfunction after they had microalbuminuria. DR and albuminuria should be considered to determine renal function decline in type 2 diabetic patients.

Thioredoxin interacting protein expression in the urinary sediment associates with renal function decline in type 1 diabetes

ABSTRACTAims: Thioredoxin interacting protein (TXNIP), an inhibitor of antioxidant thioredoxin (Trx), is upregulated by hyperglycemia and implicated in pathogenesis of diabetes complications. We evaluated mRNA expressions of genes encoding TXNIP and Trx (TXN) in urinary sediment and peripheral blood mononuclear cells (PBMC) of type 1 diabetes (T1D) patients with different degrees of chronic complications. Methods: qPCR was employed to quantify target genes in urinary sediment (n = 55) and PBMC (n = 161) from patients sorted by presence or absence of diabetic nephropathy (DN), retinopathy, peripheral and cardiovascular neuropathy; 26 healthy controls and 13 patients presenting non-diabetic nephropathy (focal and segmental glomerulosclerosis, FSGS) were also included. Results: Regarding the urinary sediment, TXNIP (but not TXN) expression was higher in T1D (p = 0.0023) and FSGS (p = 0.0027) patients versus controls. Expressions of TXNIP and TXN were higher, respectively, in T1D patients with versus without DN (p = 0.032) and in those with estimated glomerular filtration rate (eGFR) < 60 versus ≥60 mL/min/1.73 m2 (p = 0.008). eGFR negatively correlated with TXNIP (p = 0.04, r = −0.28) and TXN (p = 0.04, r = −0.30) expressions. T1D patients who lost ≥5 mL/min/1.73 m2 yearly of eGFR presented higher basal TXNIP expression than those who lost <5 mL/min/1.73 m2 yearly after median follow-up of 24 months. TXNIP (p < 0.0001) and TXN (p = 0.002) expressions in PBMC of T1D patients were significantly higher than in controls but no differences were observed between patients with or without chronic complications. Conclusions: TXNIP and TXN are upregulated in urinary sediment of T1D patients with diabetic kidney disease (DKD), but only TXNIP expression is associated with magnitude of eGFR decline.

A panel of novel biomarkers representing different disease pathways improves prediction of renal function decline in type 2 diabetes.

ObjectiveWe aimed to identify a novel panel of biomarkers predicting renal function decline in type 2 diabetes, using biomarkers representing different disease pathways speculated to contribute to the progression of diabetic nephropathy.Research Design and MethodsA systematic data integration approach was used to select biomarkers representing different disease pathways. Twenty-eight biomarkers were measured in 82 patients seen at an outpatient diabetes center in The Netherlands. Median follow-up was 4.0 years. We compared the cross-validated explained variation (R2) of two models to predict eGFR decline, one including only established risk markers, the other adding a novel panel of biomarkers. Least absolute shrinkage and selection operator (LASSO) was used for model estimation. The C-index was calculated to assess improvement in prediction of accelerated eGFR decline defined as <-3.0 mL/min/1.73m2/year.ResultsPatients’ average age was 63.5 years and baseline eGFR was 77.9 mL/min/1.73m2. The average rate of eGFR decline was -2.0 ± 4.7 mL/min/1.73m2/year. When modeled on top of established risk markers, the biomarker panel including matrix metallopeptidases, tyrosine kinase, podocin, CTGF, TNF-receptor-1, sclerostin, CCL2, YKL-40, and NT-proCNP improved the explained variability of eGFR decline (R2 increase from 37.7% to 54.6%; p=0.018) and improved prediction of accelerated eGFR decline (C-index increase from 0.835 to 0.896; p=0.008).ConclusionsA novel panel of biomarkers representing different pathways of renal disease progression including inflammation, fibrosis, angiogenesis, and endothelial function improved prediction of eGFR decline on top of established risk markers in type 2 diabetes. These results need to be confirmed in a large prospective cohort.

Systolic blood pressure as a predictor of incident albuminuria and rapid renal function decline in type 2 diabetic patients

AimsAlbuminuria and a reduced estimated glomerular filtration rate (eGFR) are known risk factors of poor cardiovascular outcomes in diabetic patients. We here aimed to investigate the determinants of incident albuminuria and rapid progression of renal dysfunction in patients with type 2 diabetes. MethodsType 2 diabetic outpatients (n=215) with a mean baseline eGFR of 87±20 mLmin−11.73 m−2 were followed for 12 months. Urinary albuminuria was defined according to the urine albumin-to-creatinine ratio (UACR). ResultsAmong 132 patients with normoalbuminuria at baseline, 20 (15.2%) progressed to a more advanced stage of albuminuria within 1 year, and 20.5% of the 215 patients experienced a rapid decline in eGFR (eGFR reduction >5 mLmin−11.73 m−2year−1). After adjusting for potential confounders, both baseline UACR and systolic blood pressure (SBP) were found to be significant independent factors for incident albuminuria and a rapid decline of eGFR in separate models. Using receiver operating characteristic curves, systolic blood pressures of 132 and 138 mmHg were found to predict incident albuminuria and a rapid decline of eGFR, respectively. ConclusionsIn addition to baseline UACR, SBP is one of the most powerful modifiable independent risk factors for incident albuminuria and a rapid renal function decline in type 2 diabetic patients without symptomatic cardiovascular disease.

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

Aims/IntroductionDespite 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 MethodsThe 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.ResultsOver 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).ConclusionsElevated 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.