A pedigree with COL4A5 mutation presenting with Alport syndrome and focal segmental glomerulosclerosis lesions: a case report.

Alport syndrome (AS) is a heterogeneous hereditary nephropathy which can be caused by the COL4A3/COL4A4/COL4A5 gene. Patients with AS present with many phenotypes associated with kidney defects, and commonly develop secondary focal segmental glomerulosclerosis (FSGS) late in the course of AS. Evidence supports the pathogenic role of COL4A3/COL4A4/COL4A5 mutations in FSGS. We report a familial hematuria pedigree with two members that have AS and FSGS, respectively. The proband presented with microhematuria, proteinuria, renal dysfunction and sensorineural hearing loss. Pathological examination of his renal biopsy samples revealed FSGS lesions and massive foam cells by light microscopy, irregular GBM, and focal podocyte foot process effacement under electron microscopy, as well as negative α5 (IV) staining by immunofluorescence detection so he was diagnosed as AS. The proband's younger brother had only renal manifestations without obvious extrarenal lesions. Light microscopy examination of renal biopsy samples showed only FSGS lesion without foam cells. Electron microscopy and α5 (IV) staining were not performed and he was diagnosed with FSGS. Using whole-exome sequencing, we identified a novel COL4A5 mutation (c.4456G>A:p.G1486S) in this pedigree, which affected two males (the proband and his brother) and three female family members. The three female family members were heterozygous or the COL4A5 mutation and only presented with microhematuria. Our findings suggest importance of electron microscopy analysis and COL4A3/COL4A4/COL4A5 mutation screening in patients with FSGS lesions under light microscopy.

Effectiveness and safety of cyclophosphamide or tacrolimus therapy for idiopathic membranous nephropathy.

BACKGROUND: Guidelines recommend classical combined therapy of steroid and cyclophosphamide (CYC) for patients with idiopathic membranous nephropathy (IMN), while it is associated with severe adverse effects. AIMS: We conducted an observational and retrospective study to evaluate the effectiveness and safety of steroids plus tacrolimus (TAC) versus steroids plus CYC for IMN. METHODS: A total of 203 kidney-biopsy-proven IMN patients was enrolled in this study. One group (n = 142) received steroid combined with intravenous CYC (750 mg/m2 body surface) and the other group (n = 61) received steroid combined with oral TAC (target blood concentration of 4-8 ng/mL). The primary outcomes were achievement of remission. The secondary end-points included incidence of adverse events, relapse rates, 24 h urinary protein (UP), serum albumin, serum creatinine and estimated glomerular filtration rate. RESULTS: Over the 18-month observation period, the study suggested that the remission rates at the first 3 months were significantly higher in TAC group than in CYC group (72.1% vs 54.9%, P < 0.05). Although the cumulative incidence of serious and non-serious adverse events was not different significantly between the two groups, the incidence after first 3 months was lower in TAC group. Levels of 24-h UP and serum albumin improved in the TAC group more than in the CYC group (P < 0.05) over the observed period. CONCLUSIONS: Because of its short-term effectiveness and long-term safety profile, steroid plus TAC might be a better option for IMN.

Management of anticoagulation and antiplatelet therapy in patients with primary membranous nephropathy.

BACKGROUND: It has been recognized that primary membranous nephropathy (MN) is related to an increased risk for thromboembolic complications. However, the current evidence supporting prophylactic and therapeutic anticoagulation is too weak to better meet the clinical needs of this patient population. The present review provides some suggestions to guide the decision on anticoagulant management in primary MN patients with a high risk of thrombosis or with thromboembolic complication. MATERIALS AND METHODS: We extracted relevant studies by searching the published literature using the Cochrane Library, Medline, PubMed and Web of Science from March 1968 to March 2018. Eligible publications included guidelines, reviews, case reports, and clinical trial studies that concerned the rational management of anticoagulation therapy in the primary MN population. The evidence was thematically synthesized to contextualize implementation issues. RESULTS: It was helpful for clinicians to make a decision for personalized prophylactic aspirin or warfarin in primary MN patients when serum albumin was < 3.2 g/dl to prevent arterial and venous thromboembolic events (VTEs). The treatment regimen for thromboembolic complications (VTEs, acute coronary syndrome and ischemic stroke) in primary MN was almost similar to that for the general population with thromboembolic events. It is noteworthy that patients should continue the previous primary MN treatment protocol during the entire treatment period until they achieve remission, the protocol is complete and the underlying diseases resolve. CONCLUSION: The utility of prophylactic aspirin or warfarin may have clinical benefits for the primary prevention of thromboembolic events in primary MN with hypoalbuminemia. It is necessary to perform large randomized controlled trials and to formulate relevant guidelines to support the present review.

Effectiveness and safety of cyclophosphamide or tacrolimus therapy for idiopathic membranous nephropathy.

Background: Guidelines recommend combined therapy of glucocorticoid and cyclophosphamide (CYC) for patients with idiopathic membranous nephropathy (IMN), while it is associated with severe adverse effects. We conducted a retrospective study to evaluate the effectiveness and safety of glucocorticoid plus tacrolimus (TAC) for IMN. Methods: Two hundred and three kidney-biopsy-proven IMN patients were enrolled in this study. One group (n = 142) received glucocorticoid combined with intravenous CYC (750 mg/m2 body surface) and the other group (n = 61) received glucocorticoid combined with oral TAC (target blood concentration of 4-8 ng/mL). The primary outcomes were achievement of remission and incidence of adverse events. The secondary end points included relapse rates, 24 h urinary protein (UP), serum albumin, serum creatinine and estimated glomerular filtration rate. Results: Over the 18-month observation period, the study suggested that the remission rates at the first 3 months were significantly higher in TAC group than in CYC group (72.1% versus 54.9%, p < .05). Although the cumulative incidence of serious and non-serious adverse events was not different significantly between the two groups, the incidence after first 3 months was lower in TAC group. 24hUP and serum albumin improved in TAC group more than the CYC group (p < .05) over the observed period. Conclusion: Because of its short-term effectiveness and long-term safety profile, glucocorticoid plus TAC might be a better option for IMN.

Correction to: Early versus late initiation of renal replacement therapy impacts mortality in patients with acute kidney injury post cardiac surgery: a meta-analysis.

After publication of this article [1], it was noticed that the affiliations of Honghong Zhou were incorrect. The sole affiliation should be, "Department of Nephrology, the Second Affiliated Hospital of Nanchang University, China" and can be seen in the author details of this correction.

Endothelial cells secreted endothelin-1 augments diabetic nephropathy via inducing extracellular matrix accumulation of mesangial cells in ETBR-/- mice.

Endothelin B receptor (ETBR) deficiency may contribute to the progression of diabetic nephropathy (DN) in a streptozotocin (STZ) model, but the underlying mechanism is not fully revealed. In this study, STZ-diabetic ETBR-/- mice was characterized by increased serum creatinine and urinary albumin, enhanced glomerulosclerosis, and upregulated ET-1 expression compared with STZ-diabetic WT mice. In vitro, HG conditioned media (CM) of ETBR-/- GENs promoted mesangial cell proliferation and upregulated ECM-related proteins, and ET-1 knockout in GENs or inhibition of ET-1/ETAR in mesangial cell suppressed mesangial cell proliferation and collagen IV formation. In addition, ET-1 was over-expressed in ETBR-/- GENs and was regulated by NF-kapapB pathway. ET-1/ETBR suppressed NF-kappaB to modulate ET-1 in GENs. Furthermore, ET-1/ETAR promoted RhoA/ROCK pathway in mesangial cells, and accelerated mesangial cell proliferation and ECM accumulation. Finally, in vivo experiments proved inhibition of NF-kappaB pathway ameliorated DN in ETBR-/- mice. These results suggest that in HG-exposed ETBR-/- GENs, suppression of ET-1 binding to ETBR activated NF-kappaB pathway, thus to secrete large amount of ET-1. Due to the communication between GENs and mesangial cells in diabetes, ET-1 binding to ETAR in mesangial cell promoted RhoA/ROCK pathway, thus to accelerate mesangial cell proliferation and ECM accumulation.

Comparative Efficacy and Safety of Therapies in IgA Nephropathy: A Network Meta-analysis of Randomized Controlled Trials.

The present study aims to compare the relative efficacy and safety of different interventions for IgA nephropathy (IgAN) with proteinuria more than 1 g/d by using network meta-analysis. We searched PubMed, Embase, and the Cochrane Library for studies compared the rate of clinical remission and/or end-stage renal disease (ESRD) and/or serious adverse events in IgAN patients with proteinuria (>1 g/d). The surface under the cumulative ranking area (SUCRA) was calculated to rank the interventions. A total of 21 randomized controlled trials with 1822 participants were included for the comparisons of 7 interventions. The rank of the most effective treatments to induce clinical remission was renin-angiotensin system inhibitors (RASi) plus urokinase, steroid plus tonsillectomy, and RASi plus steroid with a SUCRA of 0.912, 0.710, and 0.583, respectively. As for the prevention of ESRD or doubling of serum creatinine, RASi plus steroid (SUCRA 0.012) was the most effective, followed by RASi (SUCRA 0.282) and steroid (SUCRA 0.494), leaving mycophenolate mofetil as the least effective (SUCRA 0.644). There was no statistical difference among all interventions in the occurrence of serious adverse events. The current network meta-analysis demonstrated for the first time that RASi plus steroid is probably the best therapeutic choice, not only for reducing proteinuria but also for maintaining long-term renal protection.

Correction to: SGLT2 inhibitors: a novel choice for the combination therapy in diabetic kidney disease.

Following publication of the original article [1] the authors reported that the first affiliation ("Medical Center of the Graduate School, Nanchang University, China") had been added in error, and that the correct author information is as given in this erratum.

Author Correction: PLK2 Plays an Essential Role in High D-Glucose-Induced Apoptosis, ROS Generation and Inflammation in Podocytes.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

Early versus late initiation of renal replacement therapy impacts mortality in patients with acute kidney injury post cardiac surgery: a meta-analysis.

BACKGROUND: Acute kidney injury (AKI) is a common clinical complication of cardiac surgery and increases mortality and hospitalization. We aimed to explore and perform an updated meta-analysis of qualitative and quantitative evaluations of the relationship between early renal replacement therapy (RRT) and mortality. METHODS: We searched the Chinese Biomedical Database, the Cochrane Library, EMBASE, Global Health, MEDLINE and PubMed. RESULTS: Fifteen studies (five randomized controlled trials (RCTs), one prospective cohort and nine retrospective cohorts) including 1479 patients were identified for detailed evaluation. The meta-analysis suggested that early RRT initiation reduced 28-day mortality (odds ratio (OR) 0.36; 95% confidence interval (CI) 0.23 to 0.57; I 2 60%), and shortened intensive care unit (ICU) length of stay (LOS) (mean difference (MD) -2.50; 95% CI -3.53 to -1.47; I 2 88%) and hospital LOS (MD -0.69; 95% CI -1.13 to -0.25; I 2 88%), and also reduced the duration of RRT (MD -1.18; 95% CI -2.26 to -0.11; I 2 69%), especially when RRT was initiated early within 12 hours (OR 0.23; 95% CI 0.08 to 0.63; I 2 73%) and within 24 hours (OR 0.52; 95% CI 0.28 to 0.95; I 2 58%) in patients with AKI after cardiac surgery. CONCLUSIONS: Early RRT initiation decreased 28-day mortality, especially when it was started within 24 hours after cardiac surgery in patients with AKI.

PLK2 Plays an Essential Role in High D-Glucose-Induced Apoptosis, ROS Generation and Inflammation in Podocytes.

Diabetic kidney disease (DKD) is a serious complication of hyperglycemia. Currently, there is no effective therapeutic intervention for DKD. In this study, we sought to provide a set of gene profile in diabetic kidneys. We identified 338 genes altered in diabetes-induced DKD glomeruli, and PLK2 exhibited the most dramatic change. Gene set enrichment analysis (GSEA) indicated multiple signaling pathways are involved DKD pathogenesis. Here, we investigated whether PLK2 contributes to podocyte dysfunction, a characteristic change in the development of DKD. High D-glucose (HDG) significantly increased PLK2 expression in mouse podocytes. Suppressing PLK2 attenuated HDG-induced apoptosis and inflammatory responses both in vitro and in vivo. NAC, an antioxidant reagent, rescued HDG and PLK2 overexpression-induced kidney injuries. In summary, we demonstrated that silencing PLK2 attenuates HDG-induced podocyte apoptosis and inflammation, which may serve as a future therapeutic target in DKD.

SGLT2 inhibitors: a novel choice for the combination therapy in diabetic kidney disease.

Diabetic kidney disease (DKD) is the most common cause of end stage renal disease. The comprehensive management of DKD depends on combined target-therapies for hyperglycemia, hypertension, albuminuria, and hyperlipaemia, etc. Sodium-glucose co-transporter 2 (SGLT2) inhibitors, the most recently developed oral hypoglycemic agents acted on renal proximal tubules, suppress glucose reabsorption and increase urinary glucose excretion. Besides improvements in glycemic control, they presented excellent performances in direct renoprotective effects and the cardiovascular (CV) safety by decreasing albuminuria and the independent CV risk factors such as body weight and blood pressure, etc. Simultaneous use of SGLT-2 inhibitors and renin-angiotensin-aldosterone system (RAAS) blockers are novel strategies to slow the progression of DKD via reducing inflammatory and fibrotic markers induced by hyperglycaemia more than either drug alone. The available population and animal based studies have described SGLT2 inhibitors plus RAAS blockers. The present review was to systematically review the potential renal benefits of SGLT2 inhibitors combined with dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists, mineralocorticoid receptor antagonists, and especially the angiotensin-converting enzyme inhibitors/angiotensin receptor blockers.

Relationship of angiotensin I-converting enzyme (ACE) and bradykinin B2 receptor (BDKRB2) polymorphism with diabetic nephropathy.

PURPOSE: To determine whether ACE2 I/D and BDKRB23 +9/-9 polymorphism causatively affect diabetic nephropathy progression RESULTS: STZ-induced metabolic disorder, as well as inflammatory responses, was significantly aggravated in ACE II-B2R4+9bp, ACE DD-B2R+9bp, or ACE DD-B2R-9bp diabetic mice but not ACE II-B2R-9bp, indicating the genetic susceptibility of ACE DD or B2R+9bp to diabetic nephropathy. Furthermore, ACE II-B2R+9bp, ACE DD-B2R+9bp, or ACE DD-B2R-9bp rather than ACE II-B2R-9bp, worsened renal performance and enhanced pathological alterations induced by STZ. Markedly elevated monocyte chemoattractant protein-1(MCP-1), podocin, osteopontin (OPN), transforming growth factor-ß1 (TGF-ß1), and reduced nephrin, podocin were also detected both in diabetic mice and podocytes under hyperglycemic conditions in response to ACE II-B2R+9bp, ACE DD-B2R+9bp, or ACE DD-B2R-9bp, versus ACE II-B2R-9bp. In addition, high glucose-induced mitochondrial oxidative stress and cell apoptosis were observably increased in response to ACE II-B2R+9bp, ACE DD-B2R+9bp, or ACE DD-B2R-9bp but not ACE II-B2R-9bp. CONCLUSIONS: We provide first evidence indicating the causation between ACE DD or B2R+9bp genotype and the increased risk for diabetic nephropathy, broadening our horizon about the role of genetic modulators in this disease.

Clinical Utility of Serum Cystatin C in Predicting Diabetic Nephropathy Among Patients with Diabetes Mellitus: a Meta-Analysis.

BACKGROUND/AIMS: Clinically, there is lack of predictors for diabetic nephropathy (DN) in diabetes mellitus (DM) without microalbuminuria, macroalbuminuria or retinopathy. METHODS: PubMed, Chinese Biomedical Database, Cochrane Library, EMBASE and Elsevier Database were searched from inception to August 13, 2016. Studies involving patients with DM and containing data on cystatin C measurements and the measured glomerular filtration rate (mGFR) were included. Pooled sensitivity, specificity, positive predictive value, negative predictive value and other diagnostic indices were evaluated using a random effect model. RESULTS: The meta-analysis enrolled 9 studies with 1417 patients. The pooled sensitivity and specificity of serum cystatin C for predicting DN were 0.88 (95% CI 0.85 - 0.91) and 0.85 (95% CI 0.82 - 0.87), respectively. The pooled positive and negative predictive values of serum cystatin C for predicting DN were 7.04 (95% CI 4.33 - 11.43) and 0.13 (95% CI 0.09 - 0.20), respectively. The area under the summary receiver operating characteristic (SROC) curve was 0.9549, and the diagnostic odds ratio was 66.80 (95% CI 27.92 - 159.86). CONCLUSION: Serum cystatin C is an early predictor of DN among patients with DM.

The prevention of statins against AKI and mortality following cardiac surgery: A meta-analysis.

OBJECTIVE: It is universally acknowledged that acute kidney injury (AKI) often comes following cardiac surgery with severe morbidity and mortality. The impact of statins on the incidence of AKI and mortality after cardiac surgery are controversial, therefore, it is urgent to explore the source of heterogeneity via the subgroup analysis. METHODS: We searched PubMed, ISI and Elsevier to May 31st 2016 for studies which investigated the effects of statins relevant to this theme. Statistical analysis was using RevMan5.2 and Stata12.0. The outcomes were the occurrence of AKI and the mortality after cardiac surgery. For the first time, we discussed the source of heterogeneity on the basis of the characters of patients in the following subgroup analysis. RESULTS: A total of 17 studies with 18,684 statins and 24,033 non-statin users were included. The meta-analysis suggested that statins not only reduced the occurrence of AKI [Odds Ratio (OR) 0.72, 95% Confidence Interval (CI) 0.55-0.94)] in the subjects without high risk factors, also decreased the mortality of the patients suffering AKI (OR 0.40, 95% CI 0.22-0.72). CONCLUSION: Patients undergoing cardiac surgery might benefit from statins by reducing the occurrence of AKI and the mortality of the patients suffering AKI.