Gut microbial products valerate and caproate predict renal outcome among the patients with biopsy-confirmed diabetic nephropathy.

AIMS: Valerate and caproate are two subtypes of short-chain fatty acids produced by gut microbiota. We aimed to measure the serum valerate and caproate levels and analyze the associations between them and renal prognosis of diabetic nephropathy (DN). METHODS: The serum samples of patients with biopsy-confirmed diagnosis of DN were collected in the First Affiliated Hospital of Zhejiang University, from April 1, 2013, to March 31, 2018. One hundred patients were included and divided into an early DN group (eGFR ≥ 60 ml/min, n = 42) and an advanced DN group (eGFR < 60 ml/min, n = 58). The valerate and caproate were measured using gas chromatography-mass spectrometry. Participants were followed up until the cutoff date of August 31, 2018, or if they met the primary endpoint of end-stage renal disease (ESRD). RESULTS: There were 71 males and 29 females in this study, and 29 patients developed ESRD. We observed a significant lower concentration of valerate and caproate in the advanced DN group. There were negative correlations between valerate and glomerular classification (r = - 0.20, P = 0.03) and between caproate and interstitial fibrosis and tubular atrophy (IFTA) (r = - 0.24, P = 0.01). And there were positive correlations between valerate or caproate and eGFR (r = 0.22, P = 0.02; r = 0.38, P < 0.01). Multivariate Cox analysis revealed higher levels of valerate and caproate were negatively related to progression to ESRD (HR = 0.024, P = 0.016; HR = 0.543, P = 0.030). The area under the curve values of valerate and caproate levels were 0.66 and 0.63, respectively, in predicting progression to ESRD. CONCLUSION: This study showed alterations in serum valerate and caproate in DN and demonstrates lower valerate and caproate levels with progression of DN to ESRD.

Mannose-binding lectin activates the nuclear factor-κB and renal inflammation in the progression of diabetic nephropathy.

Increased serum mannose-binding lectin (MBL) level has been proven to correlate with the development of diabetic nephropathy (DN). Here, we aim to find the role and mechanism of MBL involved in the progression of DN. Patients with DN were recruited and divided into two groups according to different rs1800450 genotypes of the MBL2 gene, and inflammatory profiles in monocytes/macrophages were compared between the two groups. MBL was given to treat macrophages, HK2, and HMC, and a co-culture transwell system was then employed. Renal inflammation and fibrosis parameters were measured after knocking down or overexpressing MBL genes in mice. Proinflammatory profile, manifesting as enhanced IL-1ß production and M1 polarization, was found in monocytes/macrophages from DN with a rs1800450 GG genotype of MBL2 gene who had higher MBL level, compared with those with a rs1800450 GA genotype. In mechanism, MBL directly induced inflammatory responses in macrophages, which promoted inflammatory and fibrotic markers in HK2 and HMCs during co-culture. Further experiments showed that MBL can promote macrophages transforming to the M1 subset mainly by activating the nuclear factor-κB pathway. After downregulation of MBL, the blood glucose, triglyceride, urine protein, injuries of glomerulus and tubules, and the degree of renal inflammation and fibrosis were ameliorated in db/db mice treated with AAV-MBL1/2-shRNA. Overexpression of MBL promoted macrophage infiltration in the kidney. In conclusion, MBL is a crucial mediator in the progression of DN via activating the nuclear factor-κB pathway in macrophages. This will serve as a genetic base for some patients with DN who have poor outcomes and provide a direction for the screening.

Relationship between blood neutrophil-lymphocyte ratio and renal tubular atrophy/interstitial fibrosis in IgA nephropathy patients.

BACKGROUND: The study aimed to explore the relationship between neutrophil-lymphocyte ratio(NLR) in peripheral blood and renal tubular atrophy/interstitial fibrosis and to evaluate the clinical significance of NLR in IgA nephropathy (IgAN) patients. METHODS: A Total of 263 IgAN patients were included. The participants were categorized into four groups based on quartile of NLR. The clinical data, pathological features, and 2-year renal survival rates were compared among the four groups. The independent factors affecting renal tubular atrophy/interstitial fibrosis in IgAN were determined by multivariate linear regression analysis. RESULTS: The percentage of renal tubular atrophy/interstitial fibrosis increased with the increase of NLR level (p=0.003). The tubular atrophy/interstitial fibrosis score T1 and T2 in Group Q4 was 40%, which was higher than that of other groups, especially Group Q1 (22.73%, p=0.033) and Group Q3 (22.39%, p=0.029). NLR [ß=1.230, 95%CI (0.081, 2.379), p=0.036] might be an independent factor affecting renal tubular atrophy/interstitial fibrosis in IgAN. The area under curve predicted by NLR was 0.596 (95%CI 0.534~0.656, p=0.007) with the specificity 88.24% and the optimal critical value of NLR 3.25. Fourteen patients progressed to end-stage renal disease within 2 years, and the 2-year survival rate of kidney was 93.49%. The renal survival rate in Group Q4 was 87.04%, lower than that in other three groups, especially Group Q1 (98.11%, p=0.029). CONCLUSION: NLR was correlated with the level of renal tubular atrophy/interstitial fibrosis and might be a significant factor for predicting the prognosis in the IgAN. BACKGROUND: IgA nephropathy (IgAN) is an important cause of the end stage renal disease (ESRD). The study aimed to explore the relationship between neutrophil-lymphocyte ratio (NLR) in peripheral blood and renal tubular atrophy/interstitial fibrosis, and to evaluate the clinical significance of NLR in IgA nephropathy (IgAN) patients. METHODS: Total 263 IgAN patients confirmed by renal biopsy pathology were included from January 2013 to May 2018 in Ningbo Hwamei Hospital, University of Chinese Academy of Sciences. The peripheral blood samples were taken from these participants and the NLR was analyzed. The participants were categorized into four groups based on the median and upper and lower quartile of NLR, which were Group Q1 (NLR<1.64), Group Q2 (1.64≤NLR<2.19), Group Q3 (2.19≤NLR<3.00), and Group Q4 (NLR≥3.00), respectively. The clinical data and pathological features were compared among four groups. The independent factors affecting renal tubular atrophy/interstitial fibrosis in IgAN were determined by multivariate linear regression analysis. The diagnostic ability of NLR for renal tubular atrophy/interstitial fibrosis was evaluated by the area under receiver operating characteristic curve (AUC). The 2-year renal survival rates were compared among the four groups. RESULTS: The levels of white blood cell count, neutrophil count, highly sensitive C-reactive protein, and the percentage of renal tubular atrophy/interstitial fibrosis were increased while lymphocyte count and estimated glomerular filtration rate were decreased with the increase of NLR level (P < 0.05). The percentage of tubular atrophy/interstitial fibrosis 26%-50% (T1) and >50% (T2) in Group Q4 was 40%, which was higher than that of other groups, especially Group Q1 (22.73%) and Group Q3 (22.39%), with significant difference (P < 0.05). NLR [ß = 1.230, 95%CI (0.081, 2.379), P = 0.036] might be an independent factor affecting renal tubular atrophy/interstitial fibrosis in IgAN according to multivariate linear regression analysis results. The AUC predicted by NLR was 0.596 (95%CI 0.534~0.656, P = 0.007) with the specificity 88.24%, the sensitivity 30.00% and the optimal critical value of NLR 3.25. Fourteen patients progressed to end-stage renal disease within 2 years; and the 2-year survival rate of kidney was 93.49%. The renal survival rate in Group Q4 was 87.04%, lower than that in other three groups, especially Group Q1 (98.11%), with significant difference (P < 0.05). CONCLUSION: NLR was correlated with the level of renal tubular atrophy/interstitial fibrosis and might be an significant factor for predicting the prognosis in IgAN.

Mannose-binding lectin activation is associated with the progression of diabetic nephropathy in type 2 diabetes mellitus patients.

BACKGROUND: We aimed to investigate whether mannose-binding lectin (MBL) activation contributed to the progression of diabetic nephropathy (DN), and its role in predicting the renal prognosis of DN. METHODS: Seventy-seven patients who received renal biopsy in the First Affiliated Hospital, College of Medicine, Zhejiang University between August 2013 and September 2016 were enrolled in the study. These patients were followed up until the endpoint of end-stage renal disease (ESRD) or the last follow-up time of August 31, 2018. They were divided into ESRD group (33 patients) and non-ESRD group (44 patients). Their baseline characteristics and MBL levels (serum and urine) were compared between groups. The correlation between single nucleotide polymorphisms (SNPs) of the MBL2 gene and renal outcomes was also analyzed. RESULTS: The median (interquartile ranges) of serum and urine MBL levels were significantly higher in ESRD group than those in non-ESRD group [2,783.75 (1,244.28, 3,837.07) vs. 1,141.60 (652.67, 3,188.44) ng/mL, P=0.016; 1.02 (0.43, 2.05) vs. 0.27 (0.04, 0.58) ng/mg, P<0.01, respectively]. Both univariate and multivariate Cox analysis showed that serum MBL >1,108.75 ng/mL (stratified by maximum Youden index) was an independent predictor for ESRD [hazard ratio (HR) =4.164, 95% confidence interval (CI): 1.601-10.833, P=0.003; HR =4.644, 95% CI: 1.320-16.337, P=0.017; respectively]. For the patients with rs1800450 SNPs of MBL2 gene, patients with homozygous genotype (GG) had higher serum MBL level (median 2,963.52 ng/mL) compared with those with heterozygous genotype (GA) (median 665.38 ng/mL) (P<0.001). MBL2 rs1800450 GA genotype was an independent protective factor for ESRD with a HR of 0.485 (95% CI: 0.237-0.991; P=0.047). CONCLUSIONS: Activation of MBL contributed to the progression of DN. The rs1800450 SNP of the MBL2 gene may be of value in predicting the progression to ESRD in DN patients.

Association between coffee consumption and risk of bladder cancer in a meta-analysis of 16 prospective studies.

BACKGROUND: Current evidence remains equivocal as to whether and how consumption of coffee may be associated with risk of bladder cancer, and potential influence of confounding by smoking on this association is yet to be elucidated. We conducted an updated meta-analysis of prospective studies to address these issues. METHODS: Relevant studies were identified by searching PubMed and EMBASE databases from inception to April 2019. A random-effects model was used to estimate summary relative risk (RR) with corresponding 95% confidence interval (CI) of bladder cancer associated with coffee consumption. RESULTS: The final analysis included 16 prospective studies comprising 2,122,816 participants and 11,848 bladder cancer cases. Overall, coffee consumption was not associated with risk of bladder cancer (RR high-vs-low = 1.07, 95% CI: 0.96-1.20). The lack of association persisted in the strata defined by sex or participants' smoking status. Meta-regression analyses identified the number cases (P difference = 0.06) and the degree of adjustment for smoking (P difference = 0.04) as potential sources of heterogeneity. There was an increased risk of bladder cancer related to higher coffee consumption among studies with fewer cases (RR high-vs-low = 1.38, 95% CI: 1.05-1.81) and among those with poorer adjustment for smoking (RR high-vs-low = 1.48, 95% CI: 1.14-1.93). Results were similar in the dose-response analyses (RR 1 cup/d = 1.01, 95% CI: 0.98-1.03). CONCLUSION: Best evidence available to date does not support an independent association between coffee consumption and bladder cancer risk. Some direct associations observed in individual studies may be a result of residual confounding by smoking. SUPPLEMENTARY INFORMATION: Supplementary information accompanies this paper at 10.1186/s12986-019-0390-3.