Urinary Albumin-to-creatinine Ratio Research Articles

Deletion, but Not Heterozygosity, of eNOS Raises Blood Pressure and Aggravates Nephropathy in BTBR ob/ob Mice

Introduction: ob/ob mice are a leptin-deficient type 2 diabetes mellitus model, which, on a BTBR background, mimics the glomerular pathophysiology of diabetic nephropathy (DN). Since leptin deficiency reduces blood pressure (BP) and endothelial nitric oxide synthase (eNOS) lowers BP and is kidney protective, we attempted to develop a more robust DN model by introducing eNOS deficiency in BTBR ob/ob mice. Methods: Six experimental groups included littermate male and female BTBR ob/ob or wild-type for ob (control) as well as wild-type (WT), heterozygote (HET), or knockout (KO) for eNOS. Systolic BP (by automated tail-cuff) and GFR (by FITC-sinistrin plasma kinetics) were determined in awake mice at 27–30 weeks of age, followed by molecular and histological kidney analyses. Results: Male and female ob/ob WT presented hyperglycemia and larger body and kidney weight, GFR, glomerular injury, and urine albumin to creatinine ratio (UACR) despite modestly lower BP versus control WT. These effects were associated with a higher tubular injury score and renal mRNA expression of NGAL only in males, whereas female ob/ob WT unexpectedly had lower KIM-1 and COL1A1 expression versus control WT, indicating sex differences. HET for eNOS did not consistently alter BP or renal outcome in control or ob/ob. In comparison, eNOS KO increased BP (15–25 mm Hg) and worsened renal markers of injury, inflammation and fibrosis, GFR, UACR, and survival rates, as observed in control and, more pronouncedly, in ob/ob mice and independent of sex. Conclusions: Deletion, but not heterozygosity, of eNOS raises blood pressure and aggravates nephropathy in BTBR ob/ob mice.

Effects of Dapagliflozin in Patients with Membranous Nephropathy.

Despite the provision of renin-angiotensin-aldosterone-system inhibitors and immunosuppressive therapies, membranous nephropathy often progresses to end-stage kidney disease (ESKD). The objective of this prespecified analysis was to assess the safety and efficacy of dapagliflozin in patients with membranous nephropathy enrolled in the DAPA-CKD trial. Patients with an estimated glomerular filtration rate (eGFR) of 25-75 mL/min/1.73 m2 and urinary albumin-to-creatinine ratio (UACR) 200-5,000 mg/g were randomized to dapagliflozin 10 mg once daily or placebo, along with standard-of-care and followed for median 2.4 years. The primary endpoint was a composite of ≥50% sustained decline in eGFR, ESKD, or kidney or cardiovascular death. Exploratory efficacy endpoints included eGFR slope and UACR. Among DAPA-CKD participants with membranous nephropathy, 19 were randomized to dapagliflozin and 24 to placebo. The mean (SD) age was 59.9 ± 12.1 years, the mean eGFR was 45.7 ± 12.1 mL/min/1.73 m2, and the median UACR was 1,694.5 (25%, 75% range 891-2,582.5) mg/g. Two of 19 (11%) patients randomized to dapagliflozin and five of 24 (21%) randomized to placebo experienced the primary composite endpoint. Total and chronic mean eGFR slopes for dapagliflozin and placebo were -3.87 and -4.29 and -2.66 and -4.22 mL/min/1.73 m2/year, respectively; corresponding between-group mean differences were 0.42 and 1.57 mL/min/1.73 m2/year. Dapagliflozin reduced geometric mean (SEM) UACR relative to placebo (-29.3% ± 1.2% vs. -3.6% ± 1.1%; between-group mean difference [95% CI] -26.7 [-50.4, 8.3]). Four (21%) patients randomized to dapagliflozin and seven (29%) randomized to placebo experienced a serious adverse event. In membranous nephropathy, the effects of dapagliflozin on kidney disease progression and albuminuria were generally favorable; there was insufficient power to justify formal inference testing.

Plausible prediction of renoprotective effects of sodium-glucose cotransporter-2 inhibitors in patients with chronic kidney diseases.

This narrative review was conducted due to uncertainty in predicting the beneficial impact of sodium-glucose cotransporter-2 (SGLT2) inhibitors on a dip of estimated glomerular filtration rate (eGFR), regardless of albuminuria presence, with the aim of elucidating plausible predictors of kidney function outcome among patients treated with SGLT2 inhibitors. The PubMed and Web of Science databases were searched in May 2023 for relevant articles published in English between 2013 and 2023. A total of 25 full-length scientific publications (comprising 11 large randomized trials and two cohort studies) were included for analysis. The majority of studies demonstrated a limited value of conventional biomarkers, such as initial decline in eGFR, a trajectory of eGFR during SGLT2 inhibitor administration, and urine albumin-to-creatinine ratio (UACR), in prediction of renoprotection. Included studies showed that the tendency to decreased eGFR, UACR, hemoglobin, glycosylated hemoglobin, lipid profile, serum uric acid, inflammatory biomarkers and natriuretic peptides did not predict clinical outcomes in groups without heart failure (HF) treated with SGLT2 inhibitors. In HF groups, biomarkers of inflammation, kidney injury, oxidative stress, mitochondrial dysfunction, ketogenesis, energy metabolism, and adipose tissue dysfunction (adropin and irisin), were detected with the aim of finding potential biomarkers. Biomarkers of adipose tissue dysfunction and inflammation may be promising for predicting SGLT2 inhibitor benefit compared with N-terminal pro-B-type natriuretic peptide and energy metabolism indicators.

Long-term impacts of endocrine-disrupting chemicals exposure on kidney function: A community-based cohort study

This study explores the extended renal effects of endocrine-disrupting chemicals (EDCs) exposure, a linkage already established with adverse health outcomes, notably chronic kidney disease. To delve deeper, the Chang Gung Community Research Center conducted a longitudinal study with 887 participants. Among them, 120 individuals were scrutinized based on EDC scores, analyzing 17 urinary EDCs and renal function. Findings revealed elevated mono-(2-ethylhexyl) phthalate (MEHP) and bisphenol A levels in higher EDC exposure cases. MEHP notably correlated with increased urinary albumin-to-creatinine ratio (UACR), predicting a > 15% decline in estimated glomerular filtration rate. Higher MEHP levels also hinted at declining renal function. UACR escalation linked significantly with specific EDCs: MEHP, methylparaben, nonylphenol, and 4-tert-octylphenol. This research underscores enduring renal hazards tied to environmental EDC exposure, particularly MEHP, emphasizing the urgent call for robust preventive public health strategies.

The impact of weekly semaglutide, a glucagon-like peptide-1 agonist, on kidney outcomes in adults with type 2 diabetes mellitus.

Type 2 diabetes mellitus (T2DM) is a chronic metabolic disorder associated with kidney complications. This study aims to investigate the effects of weekly subcutaneous semaglutide, a GLP-1 agonist, on kidney outcomes. This retrospective cohort study was conducted in nephrology and endocrinology clinics at KFAFH from March 2022 to February 2023. The sample size was determined based on hospital records, and randomly selected patients who met the inclusion criteria were included. The inclusion criteria included adults with T2DM who were on weekly subcutaneous semaglutide for 6 months or longer. Patients with type 1 diabetes mellitus, pregnant or gestational diabetes patients, individuals who added other antidiabetic medications during the study period, and participants who refused to be involved were excluded from the study. The study included participants aged between 42 and 85 years, with a mean age of 65.38 years, and the majority (58.7%) were males. There was a significant weight and BMI reduction observed in all patients, with P values <0.001 for both. The average weight reduction was 2.97 kg (SD = 2.34, 95% CI 1.65-3.30), and the average Body (BMI) reduction was 1.16 (SD = 0.91, 95% CI 1.03-1.29). A vast majority of participants (98.5%) reported a weight loss of at least 1 kg, and 13.8% of participants experienced a change in BMI category from higher to lower. No patients reported an increase in the BMI category. There was a significant reduction in glycohemoglobin (HbA1c) measurements from 9.18 pretreatment to 8.13 posttreatment, with an average reduction of 1.05 units (SD = 1.84, 95% CI 0.79-1.31). The majority of participants (70.9%) reported a reduction in HbA1c of at least 0.1 unit. Although there was a slight decrease in estimated glomerular filtration rate (eGFR) values on average (1.35 units), the change was not statistically significant (P = 0.059). More than half of the participants (51.5%) reported an increase in eGFR, 45.4% reported a decrease, and 3.1% reported no change. There was a statistically significant reduction in urinary albumin-to-creatinine ratio (UACR) values from a median of 5.97 pretreatment to a median of 5.60 post-treatment. The median decrease was 0.72 units, with one-third (33.3%) reporting an increase and two-thirds (66.7%) reporting a decrease in values. The correlation analysis revealed no significant association between the total quantity of semaglutide taken and the magnitude of changes. Our study on the impact of weekly semaglutide in adults with T2DM reveals positive effects on kidney outcomes, including weight loss, glycemic control and improved urine albumin creatine ratio, and a reduced risk of nephropathy. These findings highlight the potential of semaglutide as a safe and effective treatment option for improving renal health in individuals with T2DM.

Relationship Between Lipoprotein(a), Renal Function Indicators, and Chronic Kidney Disease: Evidence From a Large Prospective Cohort Study.

Chronic kidney disease (CKD) poses a significant global public health challenge. While lipoprotein(a) (Lp[a]) has been established as a significant factor in cardiovascular disease, its connection to CKD risk remains a topic of debate. Existing evidence indicates diverse risks of kidney disease among individuals with various renal function indicators, even when within the normal range. This study aims to investigate the joint associations between different renal function indicators and Lp(a) regarding the risks of incident CKD in the general population. The analysis involved a cohort of 329,415 participants without prior CKD who were enrolled in the UK Biobank between 2006 and 2010. The participants, with an average age of 56 (SD 8.1) years, included 154,298/329,415 (46.84%) males. At baseline, Lp(a) levels were measured using an immunoturbidimetric assay and classified into 2 groups: low (<75 nmol/L) and high (≥75 nmol/L). To assess participants' baseline renal function, we used the baseline urine albumin-to-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR). The relationship between Lp(a), renal function indicators, and the risk of CKD was evaluated using multivariable Cox regression models. These models were adjusted for various factors, including sociodemographic variables, lifestyle factors, comorbidities, and laboratory measures. A total of 6003 incident CKD events were documented over a median follow-up period of 12.5 years. The association between elevated Lp(a) levels and CKD risk did not achieve statistical significance among all participants, with a hazard ratio (HR) of 1.05 and a 95% CI ranging from 0.98 to 1.13 (P=.16). However, a notable interaction was identified between Lp(a) and UACR in relation to CKD risk (P for interaction=.04), whereas no significant interaction was observed between Lp(a) and eGFR (P for interaction=.96). When compared with the reference group with low Lp(a) and low-normal UACR (<10 mg/g), the group with high Lp(a) and low-normal UACR exhibited a nonsignificant association with CKD risk (HR 0.98, 95% CI 0.90-1.08; P=.74). By contrast, both the low Lp(a) and high-normal UACR (≥10 mg/g) group (HR 1.16, 95% CI 1.08-1.24; P<.001) and the high Lp(a) and high-normal UACR group (HR 1.32, 95% CI 1.19-1.46; P<.001) demonstrated significant associations with increased CKD risks. In individuals with high-normal UACR, elevated Lp(a) was linked to a significant increase in CKD risk, with an HR of 1.14 and a 95% CI ranging from 1.03 to 1.26 (P=.01). Subgroup analyses and sensitivity analyses consistently produced results that were largely in line with the main findings. The analysis revealed a significant interaction between Lp(a) and UACR in relation to CKD risk. This implies that Lp(a) may act as a risk factor for CKD even when considering UACR. Our findings have the potential to provide valuable insights into the assessment and prevention of CKD, emphasizing the combined impact of Lp(a) and UACR from a public health perspective within the general population. This could contribute to enhancing public awareness regarding the management of Lp(a) for the prevention of CKD.

The Use of Canagliflozin in Diabetes Mellitus Type 2 on Renal Outcome: A Systematic Review

Introduction: One of the leading causes of death in patients with diabetes mellitus is Diabetic Kidney Disease (DKD). Canagliflozin is one of the therapeutic options that can be used to mitigate the progression of DKD. However, the limited existing studies have left the data regarding the effects of canagliflozin on the progression of DKD still unclear. Therefore, a comprehensive study on the efficacy and safety of using canagliflozin in patients with DKD is warranted.Methods: We performed a systematic search in the PubMed, Cochrane Library, ResearchGate, and Springer for randomized, placebo-controlled trials of the treatment of type 2 diabetes mellitus (T2DM) with canagliflozin that were published. A total of 25 journals were identified, and after excluding irrelevant studies, eighteen studies were ultimately included in this systematic review with total participants of 20,047.Results: Canagliflozin reduces the rate of estimated glomerular filtration rate (eGFR) decline in patients with diabetes mellitus. The reduction of urinary albumin-to-creatinine ratio (UACR) level was greater in canagliflozin group than in the control group, and the progression of albuminuria was slower in the canagliflozin group than in the control group.Conclusion: The use of Canagliflozin is considered to be one of the effective therapeutic options for kidney protection in patients with diabetes mellitus who are at risk of chronic kidney disease (CKD).

Longitudinal Pilot Evaluation of the Gut Microbiota Comparing Patients With and Without Chronic Kidney Disease

ObjectiveThe gut microbiota contributes to metabolic diseases, such as diabetes and hypertension, but is poorly characterized in chronic kidney disease (CKD). Design and methodsWe enrolled 24 adults within household pairs, in which at least one member had self-reported kidney disease, diabetes, or hypertension. CKD was classified based on estimated glomerular filtration rate (eGFR) <60 ml/min/1.73m2 or urine-albumin-to-creatinine ratio (UACR) of ≥30 mg/g. Participants collected stool and dietary recalls seasonally over a year. Gut microbiota was characterized using 16s rRNA and metagenomic sequencing. Results10 participants had CKD (42%) with a median (IQR) eGFR of 49 (44, 54) ml/min/1.73 m2. By 16s rRNA sequencing, there was moderate to high intra-class correlation (ICC=0.6) for seasonal alpha diversity (Shannon index) within-individuals and modest differences by season (p<0.01). ICC was lower with metagenomics, which has resolution at the species level (ICC=0.2). There were no differences in alpha or beta diversity by CKD with either method. Among 79 genera, Frisingicoccus, Tuzzerella, Faecalitalea, and Lachnoclostridium had lower abundance in CKD, while Collinsella, Lachnospiraceae_ND3007, Veillonella, and Erysipelotrichaceae_UCG_003 were more abundant in CKD (each nominal p<0.05) using 16s rRNA sequencing. Higher Collinsella and Veillonella and lower Lachnoclostridium in CKD were also identified by metagenomics. By metagenomics, Coprococcus catus and Bacteroides stercoris were more and less abundant in CKD, respectively, at false discovery rate corrected p=0.02. ConclusionsWe identified candidate taxa in the gut microbiota associated with CKD. High ICC in individuals with modest seasonal impacts imply that follow up studies may use less frequent sampling.

Association between Psoriasis and Renal Functions: An Integration Study of Observational Study and Mendelian Randomization.

Psoriasis is an autoimmune-mediated disease with several comorbidities in addition to typical skin lesions. Increasing evidence shows the relationships between psoriasis and renal functions, but the relationship and causality remain unclear. We aimed to investigate the associations and causality between psoriasis and four renal functions, including the estimated glomerular filtration rate (eGFR), blood urea nitrogen (BUN), urine albumin to creatinine ratio (UACR), and chronic kidney disease (CKD). For the population-based study, we analyzed the National Health and Nutrition Examination Survey (NHANES) data from five cycles (2003-2006 and 2009-2014) on psoriasis and renal functions. Subgroup analyses were conducted among different categories of participants. Meanwhile, a bidirectional two-sample Mendelian randomization (TSMR) study in European populations was also performed using summary-level genetic datasets. Causal effects were derived by conducting an inverse-variance weighted (MR-IVW) method. A series of pleiotropy-robust MR methods was employed to validate the robustness. Multivariable MR (MVMR) was conducted to complement the result when five competing risk factors were considered. A total of 20,244 participants were enrolled in the cross-sectional study, where 2.6% of them had psoriasis. In the fully adjusted model, participants with psoriasis had significantly lower eGFR (p = 0.025) compared with the healthy group. Individuals who are nonoverweight are more likely to be affected by psoriasis, leading to an elevation of BUN (Pint = 0.018). In the same line, TSMR showed a negative association between psoriasis and eGFR (p = 0.016), and sensitive analysis also consolidated the finding. No causality was identified between psoriasis and other renal functions, as well as the inverse causality (p > 0.05). The MVMR method further provided quite consistent results when adjusting five confounders (p = 0.042). We detected a significant negative effect of psoriasis on eGFR, with marginal association between BUN, UACR, and CKD. The adverse of psoriasis on the renal should merit further attention in clinical cares.

Urine albumin-to-creatinine ratio diurnal variation rate predicts outcomes in idiopathic membranous nephropathy

BackgroundIdiopathic membranous nephropathy (IMN) is a leading cause of end-stage renal disease (ESRD). The purpose of this study was to evaluate whether urinary albumin-to-creatinine ratio (UACR) diurnal variation rate calculated by spot urinary protein test predicts 1-year nephrotic outcomes as a biomarker of proteinuria severity in patients with IMN.MethodsPatients’ baseline demographics, blood and urinary biomarkers, and clinical and pathological characteristics were collected retrospectively. Urine samples were collected at 7:00 (before breakfast) and 19:00 (after dinner) to calculate the UACR diurnal variation rate. A prediction model for no remission (NR) was developed statistically based on differences between prognosis groups. Receiver operating characteristic curve (ROC) analysis was performed to evaluate prediction abilities and determine optimal cut-off points of the model and UACR diurnal variation rate alone.ResultsThe formula for calculating the probability of NR was exp(L)/(1 + exp(L)), where the linear predictor L = – 22.038 + 0.134 × Age (years) + 0.457 × 24-h urinary protein + 0.511 × blood urea nitrogen (BUN) + 0.014 × serum uric acid (SUA) + 2.411 if glomerular sclerosis + 0.816 × fasting blood glucose (FBG)-0.039 × UACR diurnal variation rate (%). Optimal cut-off points for NR prediction by the final model and UACR diurnal variation rate alone were 0.331 and 58.5%, respectively. Sensitivity and specificity were 0.889 and 0.859 for the final model, and 0.926 and 0.676 for UACR diurnal variation rate alone.ConclusionUACR diurnal variation using spot urinary protein is a simpler way to predict nephrotic outcomes and is a highly sensitive screening tool for identifying patients who should undergo further comprehensive risk assessment.

CCDC92 promotes podocyte injury by regulating PA28α/ABCA1/cholesterol efflux axis in type 2 diabetic mice.

Podocyte lipotoxicity mediated by impaired cellular cholesterol efflux plays a crucial role in the development of diabetic kidney disease (DKD), and the identification of potential therapeutic targets that regulate podocyte cholesterol homeostasis has clinical significance. Coiled-coil domain containing 92 (CCDC92) is a novel molecule related to metabolic disorders and insulin resistance. However, whether the expression level of CCDC92 is changed in kidney parenchymal cells and the role of CCDC92 in podocytes remain unclear. In this study, we found that Ccdc92 was significantly induced in glomeruli from type 2 diabetic mice, especially in podocytes. Importantly, upregulation of Ccdc92 in glomeruli was positively correlated with an increased urine albumin-to-creatinine ratio (UACR) and podocyte loss. Functionally, podocyte-specific deletion of Ccdc92 attenuated proteinuria, glomerular expansion and podocyte injury in mice with DKD. We further demonstrated that Ccdc92 contributed to lipid accumulation by inhibiting cholesterol efflux, finally promoting podocyte injury. Mechanistically, Ccdc92 promoted the degradation of ABCA1 by regulating PA28α-mediated proteasome activity and then reduced cholesterol efflux. Thus, our studies indicate that Ccdc92 contributes to podocyte injury by regulating the PA28α/ABCA1/cholesterol efflux axis in DKD.

Urinary exosomal microRNA-145-5p and microRNA-27a-3p act as noninvasive diagnostic biomarkers for diabetic kidney disease.

Diabetic kidney disease (DKD), characterized by increased urinary microalbumin levels and decreased renal function, is the primary cause of end-stage renal disease. Its pathological mechanisms are complicated and multifactorial; Therefore, sensitive and specific biomarkers are needed. Urinary exosome originate from diverse renal cells in nephron segments and partially mirror the pathological changes in the kidney. The microRNAs (miRNAs) in urinary exosome are remarkably stable and highly tissue-specific for the kidney. To determine if urinary exosomal miRNAs from diabetic patients can serve as noninvasive biomarkers for early DKD diagnosis. Type 2 diabetic mellitus (T2DM) patients were recruited from the Second Hospital of Hebei Medical University and were divided into two groups: DM, diabetic patients without albuminuria [urinary albumin to creatinine ratio (UACR) < 30 mg/g] and DKD, diabetic patients with albuminuria (UACR ≥ 30 mg/g). Healthy subjects were the normal control (NC) group. Urinary exosomal miR-145-5p, miR-27a-3p, and miR-29c-3p, were detected using real-time quantitative polymerase chain reaction. The correlation between exosomal miRNAs and the clinical indexes was evaluated. The diagnostic values of exosomal miR-145-5p and miR-27a-3p in DKD were determined using receiver operating characteristic (ROC) analysis. Biological functions of miR-145-5p were investigated by performing Gene Ontology analysis and Kyoto Encyclopedia of Genes and Genomes pathway enrichment. Urinary exosomal expression of miR-145-5p and miR-27a-3p was more upregulated in the DKD group than in the DM group (miR-145-5p: 4.54 ± 1.45 vs 1.95 ± 0.93, P < 0.001; miR-27a-3p: 2.33 ± 0.79 vs 1.71 ± 0.76, P < 0.05) and the NC group (miR-145-5p: 4.54 ± 1.45 vs 1.55 ± 0.83, P < 0.001; miR-27a-3p: 2.33 ± 0.79 vs 1.10 ± 0.51, P < 0.001). The exosomal miR-145-5p and miR-27a-3p positively correlated with albuminuria and serum creatinine and negatively correlated with the estimated glomerular filtration rate. miR-27a-3p was also closely related to blood glucose, glycosylated hemoglobin A1c, and low-density lipoprotein cholesterol. ROC analysis revealed that miR-145-5p had a better area under the curve of 0.88 [95% confidence interval (CI): 0.784-0.985, P < 0.0001] in diagnosing DKD than miR-27a-3p with 0.71 (95%CI: 0.547-0.871, P = 0.0239). Bioinformatics analysis revealed that the target genes of miR-145-5p were located in the actin filament, cytoskeleton, and extracellular exosome and were involved in the pathological processes of DKD, including apoptosis, inflammation, and fibrosis. Urinary exosomal miR-145-5p and miR-27a-3p may serve as novel noninvasive diagnostic biomarkers or promising therapeutic targets for DKD.

Causal effects of human serum metabolites on occurrence and progress indicators of chronic kidney disease: a two-sample Mendelian randomization study.

Chronic kidney disease (CKD) is often accompanied by alterations in the metabolic profile of the body, yet the causative role of these metabolic changes in the onset of CKD remains a subject of ongoing debate. This study investigates the causative links between metabolites and CKD by leveraging the results of genomewide association study (GWAS) from 486 blood metabolites, employing bulk two-sample Mendelian randomization (MR) analyses. Building on the metabolites that exhibit a causal relationship with CKD, we delve deeper using enrichment analysis to identify the metabolic pathways that may contribute to the development and progression of CKD. In conducting the Mendelian randomization analysis, we treated the GWAS data for 486 metabolic traits as exposure variables while using GWAS data for estimated glomerular filtration rate based on serum creatinine (eGFRcrea), microalbuminuria, and the urinary albumin-to-creatinine ratio (UACR) sourced from the CKDGen consortium as the outcome variables. Inverse-variance weighting (IVW) analysis was used to identify metabolites with a causal relationship to outcome. Using Bonferroni correction, metabolites with more robust causal relationships are screened. Additionally, the IVW-positive results were supplemented with the weighted median, MR-Egger, weighted mode, and simple mode. Furthermore, we performed sensitivity analyses using the Cochran Q test, MR-Egger intercept test, MR-PRESSO, and leave-one-out (LOO) test. Pathway enrichment analysis was conducted using two databases, KEGG and SMPDB, for eligible metabolites. During the batch Mendelian randomization (MR) analyses, upon completion of the inverse-variance weighted (IVW) approach, sensitivity analysis, and directional consistency checks, 78 metabolites were found to meet the criteria. The following four metabolites satisfy Bonferroni correction: mannose, N-acetylornithine, glycine, and bilirubin (Z, Z), and mannose is causally related to all outcomes of CKD. By pathway enrichment analysis, we identified eight metabolic pathways that contribute to CKD occurrence and progression. Based on the present analysis, mannose met Bonferroni correction and had causal associations with CKD, eGFRcrea, microalbuminuria, and UACR. As a potential target for CKD diagnosis and treatment, mannose is believed to play an important role in the occurrence and development of CKD.

The Effect of Sodium-Glucose Cotransporter Inhibitors on Renal Function as Adjunctive to Insulin in Adults with Type1 Diabetes: An Updated Multilevel Meta-analysis of Randomized Controlled Trials.

This systematic review aimed to summarize the existing evidence from published randomized controlled trials (RCTs) on the impact of sodium-glucose cotransporter (SGLT) inhibitors on albuminuria levels and renal function in patients with type1 diabetes mellitus (T1D). The literature search was performed through Medline (via PubMed), Cochrane Library, and Scopus until November11, 2023. Double-independent study selection, data extraction, and quality assessment were performed. Evidence was pooled with three-level mixed-effects meta-analysis. In total, 5221 participants with T1D among 11 RCTs were analyzed. All RCTs had low risk of bias according to the Cochrane Collaboration tool (RoB2). SGLT inhibitors were associated with a significantly greater reduction in urine albumin-to-creatinine ratio (UACR) compared to controls (MD = - 23.13%; 95%CI = [- 33.69, - 12.57]; P < 0.001; level of evidence high). On the basis of subgroup analysis, this effect was consistent across all available SGLT inhibitors, irrespective of the dosage. Finally, a neutral class effect was observed on the estimated glomerular filtration rate (eGFR, MD = - 1.03mL/min/1.73m2; 95%CI = [- 2.26, 0.19]; P = 0.1; level of evidence moderate). Only empagliflozin was associated with a significant reduction in eGFR compared to placebo (MD = - 2.23mL/min/1.73m2; 95%CI = [- 3.62, - 0.84]; P = 0.002). Our findings suggest that adjunctive therapy with SGLT inhibitors results in a significant reduction in albuminuria, while their use is associated with a neutral effect on creatinine clearance, as a measure of renal function. Future renal outcome trials are needed to assess SGLT inhibitors' role in the pharmacological armamentarium against diabetic nephropathy in T1D.

Association of systemic immune-inflammation index with diabetic kidney disease in patients with type 2 diabetes: a cross-sectional study in Chinese population.

Systemic immune-inflammation index (SII), a novel inflammatory marker, has been reported to be associated with diabetic kidney disease (DKD) in the U.S., however, such a close relationship with DKD in other countries, including China, has not been never determined. We aimed to explore the association between SII and DKD in Chinese population. A total of 1922 hospitalized patients with type 2 diabetes mellitus (T2DM) included in this cross-sectional study were divided into three groups based on estimated glomerular filtration rate (eGFR) and urinary albumin-to-creatinine ratio (ACR): non-DKD group, DKD stages 1-2 Alb group, and DKD-non-Alb+DKD stage 3 Alb group. The possible association of SII with DKD was investigated by correlation and multivariate logistic regression analysis, and receiver-operating characteristic (ROC) curves analysis. Moving from the non-DKD group to the DKD-non-Alb+DKD stage 3 Alb group, SII level was gradually increased (P for trend <0.01). Partial correlation analysis revealed that SII was positively associated with urinary ACR and prevalence of DKD, and negatively with eGFR (all P<0.01). Multivariate logistic regression analysis showed that SII remained independently significantly associated with the presence of DKD after adjustment for all confounding factors [(odds ratio (OR), 2.735; 95% confidence interval (CI), 1.840-4.063; P < 0.01)]. Moreover, compared with subjects in the lowest quartile of SII (Q1), the fully adjusted OR for presence of DKD was 1.060 (95% CI 0.773-1.455) in Q2, 1.167 (95% CI 0.995-1.368) in Q3, 1.266 (95% CI 1.129-1.420) in the highest quartile (Q4) (P for trend <0.01). Similar results were observed in presence of DKD stages 1-2 Alb or presence of DKD-non- Alb+DKD stage 3 Alb among SII quartiles. Last, the analysis of ROC curves revealed that the best cutoff values for SII to predict DKD, Alb DKD stages 1- 2, and DKD-non-Alb+ DKD stage 3 Alb were 609.85 (sensitivity: 48.3%; specificity: 72.8%), 601.71 (sensitivity: 43.9%; specificity: 72.3%), and 589.27 (sensitivity: 61.1%; specificity: 71.1%), respectively. Higher SII is independently associated with an increased risk of the presence and severity of DKD, and SII might be a promising biomarker for DKD and its distinct phenotypes in Chinese population.

Correlation between Neutrophil to Lymphocyte Ratio and Urine Albumin to Creatinine Ratio in Diabetic Nephropathy Patients: A Cross-sectional Study

Introduction: One of the microvascular complications of diabetes is known as Diabetic Nephropathy (DN). The clinical manifestation of DN is an increase in the amount of albumin excreted in the urine. Albuminuria is the inflammatory process that occurs before end-stage renal failure and is a diagnostic marker. The total White Blood Cell (WBC) count is a crude but sensitive measure of inflammation. It is examined as an inflammatory marker in various cardiac and non cardiac disorders, such as acute Myocardial Infarction (MI), stroke, and heart failure. Aim: To find a correlation between Neutrophil to Lymphocyte Ratio (NLR) and Urine Albumin to Creatinine Ratio (UACR) in DN patients. Materials and Methods: This was an analytical cross-sectional study done over a period of 18 months from January 2018 to June 2019 at Vydehi Institute of Medical Sciences and Research Centre in Bengaluru, Karnataka, India. on 104 subjects diagnosed with type 2 Diabetes Mellitus (DM) registered in present study. Spot albuminuria was tested by immune turbidimetry method. Urine creatinine was tested using Jaffe’s kinetic method, from which spot UACR was calculated. The patients with albuminuria and without albuminuria were grouped into cases and controls, respectively. NLR was calculated using complete blood count and correlated with UACR. The estimated Glomerulus Filtration Rate (eGFR) was calculated using the Modification of Diet in Renal Disease (MDRD) equation and correlated with UACR. Cases were further subgrouped into moderately increased albuminuria and severely increased albuminuria groups. Mean and standard deviation, independent sample t-test, Chi-square test, Odds Ratio (OR) were applied to find significance. A p-value of &lt;0.05 was considered statistically significant, and an OR more than one suggests a positive association. Results: A total of 104 diabetic subjects were registered, with 52 subjects having DN and 52 having normal urine albumin. The mean age was 56±11.3 years and 50.6±11.8 years in the case and control groups, respectively. Among the 52 subjects in the case group, 12 (23.1%) were female and 40 (76.9%) were male. In the 52 control group, 30.8% (n=16) were female, and 69.2% (n=36) were male. The mean urine albumin was 75.5±121.2 mg/dL and 1.2±1.2 mg/dL in the case and control groups, respectively (p&lt;0.001). A correlation was calculated between UACR and NLR, with a cut-off value for NLR of 2.92. The cutoff value for NLR was calculated using the Receivers Operating Curve (ROC). The Chi-square test was applied, showing statistical significance (p&lt;0.001), with an OR calculated at 4.34 (OR &gt;1). Conclusion: The present study showed a significant positive correlation between NLR and UACR. Therefore, NLR may be considered a novel surrogate marker of DN, as an alternative to UACR, which is expensive and requires special equipment.

Correlations of Serum Retinol-Binding Protein and Stromal Cell-Derived Factor-1 with Renal Function in Patients with Diabetic Kidney Disease.

The aim is to investigate the correlations of serum retinol-binding protein (RBP) and stromal cell-derived factor-1 (SDF-1) with renal function in patients with diabetic kidney disease (DKD). A total of 438 patients with type 2 diabetes mellitus (T2DM) treated from October 2017 to October 2020 were enrolled in this prospective study and divided into simple T2DM and DKD groups. According to urinary albumin-to-creatinine ratio (UACR), DKD patients were divided into moderate, severe, and nephrotic groups. They were assigned to one of the following categories of estimated glomerular filtration rate (eGFR): G1, G2, G3a, G3b, G4, and G5 stages. The correlations of RBP and SDF-1 with renal function were analyzed. The DKD group had a longer T2DM course and higher RBP, uric acid (UA), blood urea nitrogen (BUN), β2-microglobulin (β2-MG), serum creatinine (Scr) levels and UACR, and lower SDF-1 level and eGFR than those of simple T2DM group (p < 0.05). The areas under the receiver operating characteristic curves of RBP and SDF-1 for identifying DKD were 0.903 and 0.868, and the optimal cutoff values were 70.71 mg/L and 5.69 ng/mL, respectively. With increasing urinary albumin and clinical stage, RBP, UA, BUN, β2-MG and Scr levels and UACR significantly rose, while SDF-1 level and eGFR declined (p < 0.05). In patients with DKD, RBP was correlated positively with UACR, UA, BUN, β2-MG, and Scr (r = 0.764/0.787/0.693/0.577/0.801, p < 0.0001), and negatively with eGFR (r = -0.782, p < 0.0001). SDF-1 was correlated negatively with UACR, UA, BUN, β2-MG and Scr (r = -0.744/-0.794/-0.666/-0.605/-0.820, p < 0.0001), and positively with eGFR (r = 0.767, p < 0.0001). The multiple linear regression equation was RBP = 29.852 + 0.007 x UACR + 0.101 x UA + 0.497 x BUN + 0.034 x Scr-0.083 x eGFR (p < 0.001). RBP and SDF-1 can identify DKD in patients with T2DM, and the degree of renal function damage is correlated positively with RBP and negatively with SDF-1. Elevated levels of UA, BUN, Scr and UACR as well as reduced eGFR are risk factors for evaluating RBP.

Genetic Evidence for the Causal Relationship Between Gut Microbiota and Diabetic Kidney Disease: A Bidirectional, Two-Sample Mendelian Randomisation Study.

Aims: According to the gut-kidney axis theory, gut microbiota (GM) has bidirectional crosstalk with the development of diabetic kidney disease (DKD). However, empirical results have been inconsistent, and the causal associations remain unclear. This study was aimed at exploring the causal relationship between GM and DKD as well as the glomerular filtration rate (GFR) and urinary albumin-to-creatinine ratio (UACR). Materials and Methods: Two-sample Mendelian randomisation (MR) analysis was performed with inverse-variance weighting as the primary method, together with four additional modes (MR-Egger regression, simple mode, weighted mode, and weighted median). We utilised summary-level genome-wide association study statistics from public databases for this MR analysis. Genetic associations with DKD were downloaded from the IEU Open GWAS project or CKDGen consortium, and associations with GM (196 taxa from five levels) were downloaded from the MiBioGen repository. Results: In forward MR analysis, we identified 13 taxa associated with DKD, most of which were duplicated in Type 2 diabetes with renal complications but not in Type 1 diabetes. We observed a causal association between genetic signature contributing to the relative abundance of Erysipelotrichaceae UCG003 and that for both DKD and GFR. Similarly, host genetic signature defining the abundance of Ruminococcaceae UCG014 was found to be simultaneously associated with DKD and UACR. In reverse MR analysis, the abundance of 14 other GM taxa was affected by DKD, including the phylum Proteobacteria, which remained significant after false discovery rate correction. Sensitivity analyses revealed no evidence of outliers, heterogeneity, or horizontal pleiotropy. Conclusion: Our findings provide compelling causal genetic evidence for the bidirectional crosstalk between specific GM taxa and DKD development, contributing valuable insights for a comprehensive understanding of the pathological mechanisms of DKD and highlighting the possibility of prevention and management of DKD by targeting GM.

Clinical metabolomics of Zicuiyin in treatment of diabetic kidney disease

This study aimed to analyze the therapeutic effect of Zicuiyin on diabetic kidney disease(DKD) and explore the possible targets of this formula. Eighteen DKD patients treated in the endocrine department or nephrology department of Second Affilia-ted Hospital of Tianjin University of Traditional Chinese Medicine from January to December in 2019 were enrolled and assigned into a test group(n=10) and a control group(n=8). Both groups received routine chemical medicine treatment. In addition, the test group was treated with Zicuiyin and the control group with Huangkui Capsules for 8 weeks. The clinical trial was approved by the Ethics Committee of Second Affiliated Hospital of Tianjin University of Traditional Chinese Medicine, with the ethical approval No. 2017-023-01, and all the patients signed the informed consent form. The results showed that the 8-week treatment with Zicuiyin lowered the level of glycosylated hemoglobin(HbA1c) and recovered the 24 h urinary protein(24hUP), 24 h urinary microalbumin(24hmAlb), urine albumin-to-creatinine ratio(UACR), and estimated glomerular filtration rate(eGFR) of the patients with 24hUP&lt;3.5 g. According to the different levels in 24hUP, all the patients were divided into two subgroups(subgroup A with 24hUP&lt;3.5 g and subgroup B with 24hUP≥3.5 g). The ultra-high performance liquid chromatography-quadrupole-time-of-flight tandem mass spectrometry(UPLC-Q-TOF-MS/MS)-based non-targeted metabolomics analysis was conducted on the baseline serum samples from diffe-rent subgroups of patients. Nineteen biomarker candidates were identified to distinguish the metabolic differences between the two subgroups, and their correlations with clinical indicators were analyzed. Zicuiyin lowered the levels of phenylalanine, pseudouridine, and adenosine [fold change(FC)&lt;0.5, P&lt;0.05] in subgroup A. The results indicated that Zicuiyin was more effective on the DKD patients with low urinary protein levels, and its targets were involved in phenylalanine metabolism and nucleoside metabolism.

Urinary Nephrin: A Potential Biomarker of Early Glomerular Injury in a Cohort of Pregnant Women Attending Routine Antenatal Care Services.

Introduction: Glomerular injury may occur during pregnancy as a consequence of systemic disease and pregnancy-related medical complications. While urinary nephrin has been shown to provide early identification of preeclampsia (PE) in high-risk pregnancies, the role of urinary nephrin in determining glomerular injury in pregnant women is yet to be explored. This study aimed to investigate the use of urinary nephrin as a predictor for early glomerular injury in a study conducted at the Townville University Hospital. Methods and Materials: A cross-sectional study was conducted. All pregnant women with a full dataset (n = 273) were classified into three categories according to their urinary albumin-to-creatinine ratio (ACR): normoalbuminuria, microalbuminuria and macroalbuminuria. Continuous variables were compared between groups, and the cut-off value for the urinary nephrin-to-creatinine ratio (NCR) was determined to predict albuminuria as an indirect indicator of early glomerular injury. The percentages of pregnant women who had elevated nephrinuria were calculated for each of the ACR categories. Results: Urinary NCR positively correlated with urinary ACR (r = 0.29, p < 0.0001). Urinary NCR increased comparably in women with normoalbuminuria, microalbuminuria and macroalbuminuria. Using a cut-off value of 14 ng/mg, nephrinuria was detected in 65% of women with normoalbuminuria, 95% with microalbuminuria and 100% with macroalbuminuria. Of the normoalbuminuric women who had an elevated urinary NCR (> 14 ng/mg), 78% were diagnosed with a hypertensive disorder and 63% were diagnosed with diabetes in pregnancy. In women with PE, urinary NCR and ACR were significantly higher when compared to women who did not develop PE. The AUC of the ROC for urinary NCR was 0.74 (95% CI: 0.650-0.824), with a sensitivity of 97% and a specificity of 36% to predict glomerular injury and a sensitivity of 93% and specificity of 42% to predict glomerular injury of PE. Conclusion: The study found that urinary NCR were elevated not only in women with micro- and macroalbuminuria but also in pregnant women with normoalbuminuria. Increased urinary NCR without increased urinary albumin may be associated with early glomerular injury. Urinary NCR may be a more sensitive marker than microalbuminuria to detect early glomerular injury in women with systemic disease and adverse pregnancy outcomes.