Prognostic Value of Hemoglobin Concentration on Renal Outcomes with Diabetic Kidney Disease: A Retrospective Cohort Study.

Objective: Diabetic kidney disease (DKD) patients with anemia face an elevated risk of glomerular filtration rate decline. However, the association between hemoglobin and estimated Glomerular Filtration Rate (eGFR) progression remains to be elucidated. Methods: A retrospective cohort of 815 subjects with DKD was followed from January 2010 to January 2023. A Cox proportional hazard regression model was utilized to explore the predictive role of hemoglobin in renal outcomes. Renal outcomes were defined as a composite endpoint, including a 50% decline in eGFR from baseline or progression to End-Stage Renal Disease (ESRD). To unveil any nonlinear relationship between hemoglobin and renal outcomes, Cox proportional hazard regression with cubic spline functions and smooth curve fitting was conducted. Additionally, subgroup analyses were performed to identify specific patient populations that might derive greater benefits from higher hemoglobin. Results: Among the 815 DKD subjects, the mean age was 56.482 ± 9.924 years old, and 533 (65.4%) were male. The mean hemoglobin was 121.521±22.960 g/L. The median follow-up time was 21.103±18.335 months. A total of 182 (22.33%) individuals reached the renal composite endpoint during the study period. After adjusting for covariates, hemoglobin was found to exert a negative impact on the renal composite endpoint in patients with DKD (HR 0.975, 95% CI [0.966, 0.984]). A nonlinear relationship between hemoglobin and the renal composite endpoint was identified with an inflection point at 109 g/L. Subgroup analysis unveiled a more pronounced association between hemoglobin and renal prognosis in males. Conclusion: Hemoglobin emerges as a predictive indicator for the renal prognosis of diabetic kidney disease in China. This study reveals a negative and non-linear relationship between hemoglobin levels and the renal composite endpoint. A substantial association is noted when hemoglobin surpasses 109 g/L in relation to the renal composite endpoint.

Linc279227 contributes to mitochondrial dysfunction in high glucose-treated mouse renal tubular epithelial cells.

BACKGROUND: The aberrant expression of long noncoding RNAs (lncRNAs) has been associated with diabetic nephropathy (DN), a major complication of diabetes mellitus (DM). This study investigated the differential expression of lncRNAs in DM without renal damage and DM with renal damage, known as DN, and elucidated the functions of a pathogenic lncRNA. METHODS: High-throughput sequencing was performed on the kidneys of male db/db mice with kidney injury, db/db mice without kidney involvement and db/m control littermates. Linc279227 expression was confirmed by RT‒qPCR and fluorescence in situ hybridization. The effects of linc279227 on high glucose (HG)-treated renal tubular epithelial cells (RTECs) were evaluated by autophagy flux monitoring, Western blot determination and mitochondrial morphological detection. RESULTS: With high-throughput sequencing, we identified a 1024 nt long intergenic noncoding RNA, TCONS_00279227 (linc279227), whose expression was markedly increased in the kidneys of db/db mice with kidney injury compared to db/db mice without kidney injury and db/m control littermates. Fluorescence in situ hybridization confirmed that linc279227 was mainly located in the renal tubules of mice with DN. In vitro, linc279227 expression was found to be significantly increased in RTECs treated with high glucose (HG) for 48 h. Silencing linc279227 markedly restored the levels of autophagy-/mitophagy-associated proteins in HG-stimulated RTECs. Furthermore, silencing linc279227 reduced phosphorylated Drp1 expression and increased Mfn2 expression in RTECs exposed to HG. CONCLUSION: Our data suggest that linc279227 plays an important role in mitochondrial dysfunction in HG-treated RTECs and that silencing linc279227 rescues RTECs exposed to HG.

Clinical Relevance of Body Fluid Volume Status in Diabetic Patients With Macular Edema.

Objective: To investigate body fluid status in diabetic macular edema (DME) patients and the extent to which it is affected by renal function. Methods: One hundred and thirty-two eyes from 132 patients with diabetes mellitus (DM) were prospectively collected in this cross-sectional, observational study. Thirty-five were DM patients without diabetic retinopathy (DR), 31 were DR patients without DME, and 66 were DME patients. The fluid status of each participant was quantified with extracellular water-to-total body water ratio (ECW/TBW) using a body composition monitor. Central subfield thickness (CST) and macular volume (MV) were obtained using optical coherence tomography (OCT). Urine albumin-to-creatinine ratio (UACR), estimated glomerular filtration rate (eGFR), and albumin was obtained using serum and urine laboratory data. Results: ECW/TBW was significantly increased in DME patients (39.2 ± 0.9, %) compared to DM (38.1 ± 0.7, %, P = 0.003) and DR patients without DME (38.7 ± 0.9, %, P < 0.001). In multilinear regression, fluid overload was positively related to DME and UACR (DME vs. DM: ß = 2.418, P < 0.001; DME vs. DR: ß = 1.641, P = 0.001; UACR, per 102, ß = 1.017, P = 0.01). In the binary logistic regression for DME risk, the area under the receiver operating characteristic curve (AUROC) increased significantly by adding ECW/TBW along with UACR and age (AUC: 0.826 vs. 0.768). Conclusion: DME patients had elevated body fluid volume independent of kidney functions. The assessment of extracellular fluid status may help in the management of DME.

Development and validation of a simple equation to evaluate dietary protein intake using the blood urea nitrogen/serum creatinine ratio in patients with stage 3 chronic kidney disease.

PURPOSE: The aim of this research was to develop a simple equation to evaluate dietary protein intake (DPI) in patients with stage 3 chronic kidney disease (CKD) using the blood urea nitrogen (BUN)/serum creatinine (SCr) ratio (BUN/SCr). METHODS: In a prospective cohort of 136 inpatients with stage 3 CKD from 2 centres, the estimated dietary protein intake (DPI) was calculated using Maroni's formula after the patients implemented a 7 day protein-restricted diet. We developed estimation equations based on BUN/SCr and the spot urinary urea nitrogen (UUN)/urinary creatinine (UCr) ratio (UUN/UCr) in combination with sex and body mass index (BMI). These equations were then internally and externally validated. RESULTS: The following candidate parameters were derived from univariate regression analysis for 5 established models: sex, BMI, BUN/SCr, UUN and UUN/UCr. Sex and BMI were included in all models after variable evaluation using multiple regression analysis. UUN, UUN/UCr and BUN/SCr were included in model 3, model 4 and model 5, respectively. Both internal and external validation indicated that model 5 resulted in the lowest values for bias and root mean square error and the highest P30 compared with model 3 and model 4. Therefore, the model 5 equation, DPI = - 5.18 (- 14.49 if the patient is female) + 1.89 × BMI + 1.38 × BUN/SCr, was selected because of the higher correlation (r = 0.498) between the estimated DPI and predicted DPI. CONCLUSION: The DPI equation developed using BUN/SCr, sex and BMI may be used to estimate protein intake for patients with stage 3 CKD. TRIAL REGISTRATION: Chinese Clinical Trial Registry Center (ChiCTR-ROC-17011363). Registered on 11 May 2017, Retrospectively registered, http://www.chictr.org.cn/index.aspx .

Modified arteriosclerosis score predicts the outcomes of diabetic kidney disease.

BACKGROUND: The significance of renal arteriosclerosis in the prediction of the renal outcomes of diabetic kidney disease (DKD) remains undetermined. METHODS: We enrolled 174 patients with DKD from three centres from January 2010 to July 2017. The severity and extent of arteriosclerosis were analysed on sections based on dual immunohistochemical staining of CD31 and α-smooth muscle actin. An X-tile plot was used to determine the optimal cut-off value. The primary endpoint was renal survival (RS), defined as the duration from renal biopsy to end-stage renal disease or death. RESULTS: The baseline estimated glomerular filtration rate (eGFR) of 135 qualified patients was 45 (29 ~ 70) ml/min per 1.73 m2, and the average 24-h urine protein was 4.52 (2.45 ~ 7.66) g/24 h. The number of glomeruli in the biopsy specimens was 21.07 ± 9.7. The proportion of severe arteriosclerosis in the kidney positively correlated with the Renal Pathology Society glomerular classification (r = 0.28, P < 0.012), interstitial fibrosis and tubular atrophy (IFTA) (r = 0.39, P < 0.001), urine protein (r = 0.213, P = 0.013), systolic BP (r = 0.305, P = 0.000), and age (r = 0.220, P = 0.010) and significantly negatively correlated with baseline eGFR (r = - 0.285, P = 0.001). In the multivariable model, the primary outcomes were significantly correlated with glomerular class (HR: 1.72, CI: 1.15 ~ 2.57), IFTA (HR: 1.96, CI: 1.26 ~ 3.06) and the modified arteriosclerosis score (HR: 2.21, CI: 1.18 ~ 4.13). After risk adjustment, RS was independently associated with the baseline eGFR (HR: 0.97, CI: 0.96 ~ 0.98), urine proteinuria (HR: 1.10, CI: 1.04 ~ 1.17) and the modified arteriosclerosis score (HR: 2.01, CI: 1.10 ~ 3.67), and the nomogram exhibited good calibration and acceptable discrimination (C-index = 0.82, CI: 0.75 ~ 0.87). CONCLUSIONS: The severity and proportion of arteriosclerosis may be helpful prognostic indicators for DKD.

Integrin ß3 overexpression contributes to podocyte injury through inhibiting RhoA/YAP signaling pathway.

Axis formed by integrin ß3 (ITGß3)-Ras homolog gene family, member A (RhoA), and Yes-associated protein (YAP) plays an important role in atherosclerosis. In addition, ITGß3 overexpression was noted in high-glucose (HG) exposure podocytes. However, the ITGß3-RhoA-YAP axis on HG-induced podocyte injury remains unclear. This study aimed to investigate whether ITGß3 regulates podocyte injury by regulating the RhoA-YAP axis. The function and potential mechanism of ITGß3 were observed through in vitro wound-healing assays, flow cytometry, reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and western blot assay. Results showed that HG treatment increased the ability of wound closure and apoptosis; however, in spite of HG treatment, ITGß3 inhibition mitigated the ability of wound closure and apoptosis in podocytes. By contrast, overexpression of ITGß3 increased the wound closure and apoptosis abilities of podocytes. Under HG treatment, ITGß3 knockdown is associated with upregulation of RhoA, total YAP1, and nucleus YAP1, whereas ITGß3 overexpression has opposite effect. In addition, RhoA overexpression in podocytes reverses the effect of ITGß3 overexpression on the wound closure and apoptosis abilities of podocytes, rescue the expression of YAP in ITGß3 overexpression podocytes. Taken together, ITGß3 overexpression promotes podocytes injury by inhibiting RhoA-YAP axis. This will provide a new clue for preventing podocyte from damage.

Diabetic Kidney Disease Benefits from Intensive Low-Protein Diet: Updated Systematic Review and Meta-analysis.

A dietary protein intake (DPI) of between 0.6 and 0.8 g protein per kilogram body weight per day (g/kg/day) is frequently recommended for adults with moderate-to-advanced chronic kidney disease (CKD). However, evidence on whether patients with diabetic kidney disease (DKD) actually benefit from a DPI of ≤ 0.8 g/kg/day and from a low-protein diet (LPD) at CKD stages 1-3 has not been consistent. We systematically searched MEDLINE, EMBASE, Cochrane Library, Web of Knowledge, as well as the bibliographies of articles identified in the search, for eligible randomized controlled trials that had investigated the effects of LPD (prescribed DPI < 0.8 g/kg/day) versus control diet on the progression of DKD. Nine trials that included 506 participants and follow-up periods varying from 4.5 to 60 months were included in the subsequent systematic review and meta-analysis. The data showed that patients with DKD who consumed < 0.8 g protein/kg/day had a significantly reduced decline in glomerular filtration rate (GFR) (mean difference [MD] 22.31 mL/min/1.73 m2, 95% confidence interval [CI] 17.19, 27.42; P < 0.01) and a significant decrease in proteinuria (standard mean difference [SMD] - 2.26 units, 95% CI - 2.99, - 1.52; P < 0.001) versus those on the control diet. The benefits of LPD to patients with DKD at CKD stages 1-3 were a markedly decreased proteinuria (SMD - 0.96 units, 95% CI - 1.81, - 0.11; P = 0.03) and slight but significant decreases in glycated hemoglobin (- 0.42%) and cholesterol levels (- 0.22 mmol/L). Our meta-analysis indicated that a DPI of < 0.8 g/kg/day was strongly associated with a slow decline in GFR and decreased proteinuria in the patients with DKD. Patients with CKD stages CKD 1-3 benefited from LPD in terms of a marked decrease of proteinuria and slight but significant improvements in lipid and glucose control.

HDAC6-mediated α-tubulin deacetylation suppresses autophagy and enhances motility of podocytes in diabetic nephropathy.

Histone deacetylase 6 (HDAC6) is the specific subtype of HDACs which preferentially located in the cytoplasm, and is crucial in insulin signalling. However, the role of HDAC6 in type 2 diabetic nephropathy (DN) remains undefined. In current study, we observed that HDAC6 was markedly activated in the kidneys of type 2 diabetic patients and db/db mice with albuminuria, along with the advanced glycation end products (AGE)-treated podocytes. Selective inhibition of HDAC6 activity protected kidneys from hyperglycaemia in db/db mice. Notably, overexpressing HDAC6 inhibited autophagy and promoted motility aside from the apoptosis of podocytes exposed to AGE. We further determined that HDAC6 regulated the autophagy partially by decreasing the acetylation of α-tubulin at the residue of lysine 40. In contrast, we confirmed that there was no interaction of HDAC6 with α-tubulin at the sites of lysine 112 and lysine 352. Consistently, inhibiting HDAC6 by siRNA or the selective inhibitor, tubacin, restored the autophagy level and motility of podocytes and rescued podocytes from AGE stimulation. We provide strong evidence of an unexpected role of HDAC6 in the cascade that modulates podocytes autophagy and motility, enlightening that HDAC6 may be a promising therapeutic target for DN treatment.

Associations between retinal microvasculature/microstructure and renal function in type 2 diabetes patients with early chronic kidney disease.

AIMS: To explore the associations between the microvascular/microstructural changes in the retina measured by optical coherence tomography angiography (OCTA) and renal function in type 2 diabetes patients with early chronic kidney disease (CKD). METHODS: This cross-sectional study, including 150 type 2 diabetes patients, was conducted from July 2017 to January 2019. We obtained retinal vessel density (VD) and retinal thickness using OCTA. The correlations between OCTA-derived parameters and CKD-related systemic data were assessed by multiple regression analyses. RESULTS: We found a significant decrease of VD in patients with CKD. Multiple regression analyses showed that: a) decreased eGFR (estimated glomerular filtration rate) was significantly correlated with decreased VD of superficial vascular complex (SVC) in macular area; b) increased UACR (urine albumin to creatinine ratio) was significantly associated with increased macular thickness; c) decreased HGB/HCT (Hemoglobin or Hematocrit) was significantly correlated with both decreased VD of SVC and increased retinal thickness in macular area. CONCLUSIONS: Decrease in the microcirculation of the retina and thickening of the macula associated with impaired renal function in type 2 diabetes. Our finding encourages the application of OCTA-derived metrics in diabetic eyes to monitor the progression of CKD.

Clinical value of renal phospholipase A2 receptor deposit in the prognosis evaluation and treatment options of idiopathic membranous nephropathy: A retrospective cohort study.

AIM: Phospholipase A2 receptor (PLA2R) is a target antigen for idiopathic membranous nephropathy (IMN). However, the association between renal PLA2R antigen and disease prognosis had not been fully investigated. In addition, there was a paucity of studies investigating the difference of therapeutic effects between cyclophosphamide and cyclosporine A in PLA2R-associated IMN. METHODS: This retrospective cohort study recruited 300 eligible patients diagnosed with biopsy-proven IMN between September 2015 and July 2018 in Guangdong Provincial People's Hospital. The remission of proteinuria was compared between PLA2R-associated and non-PLA2R-associated IMN. The difference of therapeutic effects between cyclophosphamide and cyclosporine A were also investigated in PLA2R-associated IMN. RESULTS: The positive rate of renal PLA2R antigen in recruited IMN patients was 82.3%. Non-PLA2R-associated IMN patients had a higher probability to achieve remission than PLA2R-associated IMN patients (Log-rank test, P = .013). Multivariate COX analysis showed that renal PLA2R antigen was an independent risk factor for not achieving remission in IMN patients (Hazard Ratio: 1.619; 95% confidence interval: 1.133 to 2.313; P = .008). In PLA2R-associated IMN, patients receiving cyclophosphamide had a higher probability to achieve remission compared with those receiving cyclosporine A (Log-rank test, P = .018) while there was no difference in renal survival. Multivariate COX regression analysis showed that compared with cyclosporine A, patients receiving cyclophosphamide had a higher probability to achieve remission. CONCLUSION: Phospholipase A2 receptor -associated IMN patients had a lower probability to achieve remission compared with non-PLA2R-associated IMN. Compared with cyclosporine A, cyclophosphamide exerted better therapeutic effects in remission of proteinuria and may be the preferred immunosuppressant for PLA2R-associated IMN. SUMMARY AT A GLANCE This article highlighted the prognostic value of intra-renal phospholipase A2 receptor deposition in idiopathic membranous nephropathy (IMN). Renal phospholipase A2 receptor (PLA2R)-associated IMN patients had a lower probability to achieve remission compared with non-PLA2R-associated IMN.

Association of diabetic retinopathy and diabetic macular oedema with renal function in southern Chinese patients with type 2 diabetes mellitus: a single-centre observational study.

BACKGROUND AND OBJECTIVES: The association of diabetic retinopathy (DR) and diabetic macular oedema (DME) with renal function in southern Chinese patients with diabetes is poorly understood. So we aimed to study the correlation between stage of DR and DME with stage of estimated glomerular filtration rate (eGFR) and stage of urine albumin-to-creatinine ratio (UACR), and to explore the systemic risk factors for DR and DME. DESIGN AND SETTING: This single-centre retrospective observational study was conducted from December 2017 to November 2018. PARTICIPANTS: 413 southern Chinese patients with type 2 diabetes mellitus. OUTCOME MEASURES: The correlations between stage of DR and DME with stage of eGFR/UACR were assessed by Spearman's or χ² analyses and represented with histograms. Risk factors associated with the occurrence of DR and DME were performed by logistic regression and represented with nomograms. RESULTS: Stage of DR had a positive correlation with stage of eGFR (r=0.264, p<0.001) and stage of UACR (r=0.542, p<0.001). With the stage of eGFR/UACR being more severe, the prevalence of DME became higher as well (both p<0.001). The risk factors for DR were DM duration (OR 1.072; 95% CI 1.032 to 1.114; p<0.001), stage of UACR (OR 2.001; 95% CI 1.567 to 2.555; p<0.001) and low-density lipoprotein (LDL) (OR 1.301; 95% CI 1.139 to 1.485; p<0.001), while risk factors for DME were stage of UACR (OR 2.308; 95% CI 1.815 to 2.934; p<0.001) and LDL (OR 1.460; 95% CI 1.123 to 1.875; p=0.008). CONCLUSIONS: Among southern Chinese patients, stage of DR and DME were positively correlated with renal function, while stage of UACR performed a better relevance than stage of eGFR.

Macular Capillary Perfusion in Chinese Patients With Diabetic Retinopathy Obtained With Optical Coherence Tomography Angiography.

BACKGROUND AND OBJECTIVE: To compare the macular perfusion in the retina and choroidal layer between control subjects and Chinese patients with diabetic retinopathy (DR) using optical coherence tomography angiography (OCTA) and to evaluate the association of OCTA characteristics with the stage of DR. PATIENTS AND METHODS: A total of 200 eyes (normal controls = 40; mild non-proliferative diabetic retinopathy [NPDR] = 40; moderate NPDR = 40; severe NPDR = 40; and PDR [proliferative diabetic retinopathy] = 40) underwent OCTA imaging. OCTA parameters were vessel densities in the superficial capillary plexus (SCP), deep capillary plexus (DCP), and choriocapillaris, as well as foveal avascular zone (FAZ) area (mm2) in the SCP. RESULTS: The reduction of macular perfusion in the SCP, DCP, and choriocapillaris was correlated with increasing severity of DR. Vessel density in the SCP, DCP, and choriocapillaris was 55.31% ± 2.56%, 62.40% ± 2.46%, and 66.87% ± 1.30%, respectively, in control subjects; 50.58% ± 3.14%, 56.31% ± 4.24%, and 66.20% ± 1.69%, respectively, in mild NPDR; 46.46% ± 3.09%, 49.40% ± 5.68%, and 64.39% ± 1.94%, respectively, in moderate NPDR; 45.61% ± 3.81%, 49.33% ± 6.14%, and 63.75% ± 2.21%, respectively, in severe NPDR; and 43.78% ± 3.71%, 44.78% ± 6.36%, and 61.32% ± 6.29%, respectively, in PDR. Vessel density in DR groups decreased compared with normal controls (P < .001). FAZ area in the SCP was 0.34 ± 0.09 mm2 in control subjects compared with 0.48 ± 0.17 mm2 (mild NPDR), 0.52 ± 0.13 mm2 (moderate NPDR), 0.62 ± 0.24 mm2 (severe NPDR), and 0.75 ± 0.30 mm2 (PDR). FAZ in the SCP of patients with DR was greater than that in control subjects (P < .001). Vessel density in the DCP shows better ability to identify the severity of DR (area under the curve, sensitivity, and specificity of 0.967, 92.5%, and 93.1%, respectively) than vessel density in the SCP and choriocapillaris. CONCLUSION: OCTA might be clinically useful to evaluate different stages of DR in a noninvasive manner. Vessel density in DCP could be an objective and reliable indicator for monitoring progression of DR. [Ophthalmic Surg Lasers Imaging Retina. 2019;50:e88-e95.].

Low-Volume Tidal Peritoneal Dialysis Is a Preferable Mode in Patients Initiating Urgent-Start Automated Peritoneal Dialysis: A Randomized, Open-Label, Prospective Control Study.

The aim of this study is to evaluate the safety of low-volume tidal peritoneal dialysis (TPD) and intermittent peritoneal dialysis (IPD) in ESRD patients initiating automated peritoneal dialysis (APD) after an acute catheter insertion. Clinical outcomes of patients who received either TPD or IPD using an APD system were compared in a randomized, open-label, prospective control study in a single-center setting. From May 2011 to May 2013, 49 patients were enrolled and 27 patients received low-volume TPD treatment, whereas 22 patients underwent low-volume IPD right after Tenckhoff catheter insertion. The incidence of complications during the 14-day APD treatment were observed. After APD treatment, all the patients were transferred to continuous ambulatory peritoneal dialysis and followed up for 2 years. The IPD group demonstrated a significantly higher incidence of catheter-related complications (omental wrapping 27.3% vs. 0% and suction pain 18.2% vs. 0%) than the TPD group after adjusting for age, gender, baseline diabetes, systolic blood pressure, BMI, and the experience of the operators. However, the short duration of APD treatment with either IPD or TPD mode did not affect the long-time technical survival. In patients immediately after catheter insertion, low-volume TPD mode demonstrated a lower incidence of catheter-related complications compared to IPD. Although our results provided evidence that TPD is a preferable APD mode for this specific population, definitive conclusions about TPD benefit cannot be made, owing to early termination of the trial.

Optic nerve head perfusion changes preceding peripapillary retinal nerve fibre layer thinning in preclinical diabetic retinopathy.

IMPORTANCE: Whether neural or vascular defects occur first in the early onset of diabetic retinopathy (DR) is undetermined. BACKGROUND: To investigate microcirculation and microstructure differences of optic nerve head (ONH) between diabetic eyes without clinically evident retinopathy and healthy controls using optical coherence tomography angiography (OCTA). DESIGN: Cross-sectional observational study. PARTICIPANTS: Sixty eyes of 60 patients with type 2 diabetes and without clinically evident retinopathy and 60 eyes of 60 age-matched healthy controls were included in this study. METHODS: All participants underwent 4.5 × 4.5-mm rectangle scans centred on the ONH using OCTA (RTVue-XR Avanti; Optovue, Fremont, CA). MAIN OUTCOME MEASURES: Peripapillary retinal nerve fibre layer (RNFL) thickness and capillary perfusion density inside the ONH and in the peripapillary region were compared between the two groups. RESULTS: Vessel density values in both peripapillary and inside the disc were significantly lower in diabetic patients without DR compared to normal controls. The reduction of vessel density was prominent in all eight peripapillary sectors in diabetic eyes (all P < 0.05). Thinning of RNFL thickness was significant in the nasal superior (P < 0.001), inferior nasal (P = 0.023) and superior nasal quadrant (P < 0.001) in diabetic eyes in comparison to normal controls. CONCLUSIONS AND RELEVANCE: ONH perfusion and peripapillary RNFL thickness were significantly decreased in preclinical DR patients compared to normal controls. Microvascular alterations in ONH may occur earlier than peripapillary RNFL defect in the course of DR.

Podocyte-specific knockin of PTEN protects kidney from hyperglycemia.

Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) has proven to be downregulated in podocytes challenged with high glucose (HG), and knockout of PTEN in podocytes aggravated the progression of diabetic kidney disease (DKD). However, whether podocyte-specific knockin of PTEN protects the kidney against hyperglycemia in vivo remains unknown. The inducible podocyte-specific PTEN knockin (PPKI) mice were generated by crossing newly created transgenic loxP-stop- loxP-PTEN mice with podocin-iCreERT2 mice. Diabetes mellitus was induced in mice by intraperitoneal injection of streptozotocin at a dose of 150 mg/kg. In vitro, small interfering RNA and adenovirus interference were used to observe the role of PTEN in HG-treated podocytes. Our data demonstrated that PTEN was markedly reduced in the podocytes of patients with DKD and focal segmental glomerulosclerosis, as well as in those of db/db mice. Interestingly, podocyte-specific knockin of PTEN significantly alleviated albuminuria, mesangial matrix expansion, effacement of podocyte foot processes, and incrassation of glomerular basement membrane in diabetic PPKI mice compared with wild-type diabetic mice, whereas no alteration was observed in the level of blood glucose. The potential renal protection of overexpressed PTEN in podocytes was partly attributed with an improvement in autophagy and motility and the inhibition of apoptosis. Our results showed that podocyte-specific knockin of PTEN protected the kidney against hyperglycemia in vivo , suggesting that targeting PTEN might be a novel and promising therapeutic strategy against DKD.

Peripheral kynurenine/tryptophan ratio is not a reliable marker of systemic indoleamine 2,3-dioxygenase: A lesson drawn from patients on hemodialysis.

Indoleamine 2,3-dioxygenase (IDO) has emerged as a pivotal enzyme for mediating immune tolerance. Because IDO metabolizes tryptophan into kynurenine, the plasma kynurenine/tryptophan (Kyn/Trp) ratio has been widely used as a marker of systemic IDO. Here, we evaluated the clinical value of using the plasma Kyn/Trp ratio to estimate cell-mediated immune responses to tuberculin skin testing and risk of new bacterial infection. We also compared the Kyn/Trp ratio to a novel IDO marker, the IDO median fluorescence index (MFI) of peripheral blood mononuclear cells, which was determined by flow cytometry. In 228 patients from two hemodialysis centers, the two IDO markers were higher in patients than in healthy controls but were not correlated with each other. In vitro experiments demonstrated that peripheral blood mononuclear cells could not metabolize tryptophan into kynurenine, indicating that the increased Kyn/Trp ratio was IDO-independent. Skin induration diameters of tuberculin skin testing were correlated with the IDO MFI (negatively), but not the Kyn/Trp ratio. Further, in a 24-month prospective cohort, the Kyn/Trp ratio was not correlated with clinical infection. Alternatively, patients with a higher IDO MFI had a lower accumulative infection-free survival rate. Using a Cox proportional hazard model, it was also revealed that a higher IDO MFI was significantly associated with new bacterial infection. Taken together, these results indicate that the Kyn/Trp ratio is not a reliable circulating IDO marker in hemodialysis patients. However, the IDO MFI reflects an immunocompromised state and thus might be a potential clinical marker of bacterial infection.

Time-averaged serum potassium levels and its fluctuation associate with 5-year survival of peritoneal dialysis patients: two-center based study.

The time-averaged serum potassium was more comprehensive to reflect the all-time changes of serum potassium levels during peritoneal dialysis (PD). However, the association of fluctuation of time-averaged serum potassium level with long-time survival of PD patients remains unknown. In this retrospective study, we included 357 incident PD patients in 2 centers from January 1, 2007 to October 31, 2012 with follow-up through October 31, 2014. Our data demonstrated that it was the lower time-averaged serum potassium level rather than baseline of serum potassium level that was associated with high risk of death. Patients with higher standard deviation (SD) had significantly poorer all-cause (p = 0.016) and cardiovascular mortality (p = 0.041). Among the patients with time-averaged serum potassium levels below 4.0 mEq/L, a lower mean value was more important than its SD to predict death risk. In contrast, the patients with time-averaged serum potassium levels above 4.0 mEq/L, those with serum potassium SD < 0.54 mEq/L, exhibited a higher 3-year and 5-year survival rate for both all-cause and cardiovascular mortality compared to the control groups. Our data clearly suggested both time-averaged serum potassium and its fluctuation contributed disproportionately to the high death risk in PD patients.