Hong Ren

Mycophenolate mofetil or tacrolimus compared with intravenous cyclophosphamide in the induction treatment for active lupus nephritis

BACKGROUNDnAlthough the use of aggressive immunosuppression has improved both patient and renal survival of patients with lupus nephritis (LN), the optimal treatment of LN remains challenging. The objective of this study is to assess the efficacy and safety of mycophenolate mofetil (MMF) and tacrolimus compared with intravenous cyclophosphamide (IVC) as induction therapies for active lupus nephritis (ALN).nnnMETHODSnIn this open-label, 24-week prospective study, 60 patients with biopsy-proven ALN (Classes III, IV, V or combination) were randomly assigned to receive MMF, tacrolimus or IVC in combination with corticosteroids. The remission of proteinuria, systemic lupus erythematosus disease active index and adverse events were compared.nnnRESULTSnThe response rates at 24 weeks were 70% (14/20) in the MMF group, 75% (15/20) in the tacrolimus group and 60% (12/20) in the IVC group (P>0.05). The complete remission rates were also similar in the three groups (40, 45 and 30%, respectively; P>0.05). There were more cases of infection in the IVC group (8/20) and the MMF group (8/20) than the tacrolimus group (3/20) and more hyperglycemia in the tacrolimus group (5/20) than the other two groups (2 or 3/20), but the results were not statistically significant among the three groups. Proteinuria decreased and serum albumin increased more quickly in the patients treated with tacrolimus (P=0.0051 and P=0.048).nnnCONCLUSIONSnThis pilot study suggests that both MMF and tacrolimus are possible alternatives to IVC as induction therapies for ALN in Chinese patients. Tacrolimus possibly results in a faster resolution of proteinuria and hypoalbuminemia. Further studies are necessary to determine the optimal dosage and duration of the therapies.

Predicting Progression of IgA Nephropathy: New Clinical Progression Risk Score

IgA nephropathy (IgAN) is a common cause of end-stage renal disease (ESRD) in Asia. In this study, based on a large cohort of Chinese patients with IgAN, we aim to identify independent predictive factors associated with disease progression to ESRD. We collected retrospective clinical data and renal outcomes on 619 biopsy-diagnosed IgAN patients with a mean follow-up time of 41.3 months. In total, 67 individuals reached the study endpoint defined by occurrence of ESRD necessitating renal replacement therapy. In the fully adjusted Cox proportional hazards model, there were four baseline variables with a significant independent effect on the risk of ESRD. These included: eGFR [HRu200a=u200a0.96(0.95–0.97)], serum albumin [HRu200a=u200a0.47(0.32–0.68)], hemoglobin [HRu200a=u200a0.79(0.72–0.88)], and SBP [HRu200a=u200a1.02(1.00–1.03)]. Based on these observations, we developed a 4-variable equation of a clinical risk score for disease progression. Our risk score explained nearly 22% of the total variance in the primary outcome. Survival ROC curves revealed that the risk score provided improved prediction of ESRD at 24th, 60th and 120th month of follow-up compared to the three previously proposed risk scores. In summary, our data indicate that IgAN patients with higher systolic blood pressure, lower eGFR, hemoglobin, and albumin levels at baseline are at a greatest risk of progression to ESRD. The new progression risk score calculated based on these four baseline variables offers a simple clinical tool for risk stratification.

Functional analysis of promoter mutations in the ACTN4 and SYNPO genes in focal segmental glomerulosclerosis

BACKGROUNDnTo investigate the promoter mutations of ACTN4 and SYNPO genes in patients with idiopathic focal segmental glomerulosclerosis (FSGS), and to provide functional analysis of these mutations in the role of FSGS occurrence.nnnMETHODSnThe study consisted of 82 Chinese idiopathic FSGS patients (55 patients had nephrotic syndrome: NS) and 90 healthy individuals. Genomic DNA extracted from peripheral leukocytes of patients of healthy individuals were used to analyse the ACTN4 and SYNPO gene promoter mutations by polymerase chain reaction (PCR) and direct sequencing. Mutations were matched with GenBank and TRANSFAC software database (www.genometix.de; www.gene-regulation.com). A dual luciferase assay system was used to analyse the effects of mutations based on PGL3-Basic vector, pRL-SV40 vector, a PC12 cell line and podocytes in vitro. Kidney alpha-actinin-4 and synaptopodin expression of mutated patients and genomic DNA of their parents were investigated.nnnRESULTSnThe study detected the ACTN4 gene promoter 1-34C>T, 1-590delA and (1-1044delT)+(1-797T>C)+(1-769A>G) heterozygous mutations in three patients, respectively, and the SYNPO gene promoter 1-24G>A and 1-851C>T heterozygous mutations in two patients, respectively (with adenine of translation start site ATG naming +1). The same mutations were not found in the control group of 90 healthy people. Excepting one patient with an ACTN4 gene promoter mutation who inherited her parents 1-1044delT and 1-797T>C mutated chromosome, respectively, the same mutations were not found in patients parents. Alpha-actinin-4 and synaptopodin protein expression are reduced in mutated patients kidneys. Dual luciferase assays show that compared to the normal group (with the exception of the 1-1044delT group), luciferase activity in mutated groups decreased for the most part. (1-1044delT)+(1-797T>C)+(1-769A>G) mutations are associated with poor clinical outcomes, and patients with these mutations progress to end-stage renal failure.nnnCONCLUSIONnThe study detected heterozygous mutations in the promoters of the ACTN4 and SYNPO genes in patients with idiopathic FSGS. These mutations affected gene transcription in vitro and may affect protein translation in vivo. So we presumed that the ACTN4 and SYNPO promoter mutations might also contribute to pathophysiology of idiopathic FSGS.

Coiled Versus Straight Peritoneal Dialysis Catheters: A Randomized Controlled Trial and Meta-analysis

BACKGROUNDnVariations in peritoneal dialysis catheter design include differences in numbers of cuffs, shapes of subcutaneous paths (swan neck vs Tenckhoff), and shapes of intra-abdominal segments (straight vs coiled). The relative benefits of these designs have not been studied adequately. The objective of this study is to compare the clinical outcomes of coiled- versus straight-end swan neck peritoneal dialysis catheters.nnnSTUDY DESIGNnProspective randomized controlled trial (RCT); results were meta-analyzed with other RCTs of coiled versus straight catheters.nnnSETTING & PARTICIPANTSn80 consecutive continuous ambulatory peritoneal dialysis patients were enrolled in the RCT. The meta-analysis considers data for 242 patients with coiled and 251 patients with straight catheters.nnnINTERVENTIONnPatients were randomly assigned to a coiled-end swan neck catheter (n = 40) or a straight-end swan neck catheter (n = 40) group.nnnOUTCOMESnCatheter tip migration with dysfunction (primary outcome) and catheter failure, catheter-related infection, technique failure, and all-cause mortality (secondary outcomes).nnnRESULTSnThe primary outcome occurred in 18 patients in the coiled group and 9 in the straight group. This difference was not statistically significant (HR, 1.96; 95% CI, 0.88-4.37; P = 0.09). Although rates of early (<8 weeks) catheter tip migration were similar between the 2 groups, we detected a significant association of the coiled design with increased risk of late (>8 weeks) catheter tip migration (HR, 6.43; 95% CI, 1.45-28.6; P = 0.005). The increased risk of overall catheter failure in the coiled group was not statistically significant (P = 0.06). In the meta-analysis, coiled catheters were associated significantly with increased risk of catheter tip migration (based on 4 trials: RR, 2.08; 95% CI, 1.30-3.33; P = 0.002).nnnLIMITATIONSnSingle-center open-label experimental study powered to detect differences in only the most common complication of catheter tip migration with dysfunction. Our RCT examines only swan neck catheters, whereas the meta-analysis considers both swan neck and Tenckhoff designs.nnnCONCLUSIONSnAlthough we were unable to show statistically significant differences in the primary outcome in our RCT, pooled meta-analysis results suggest that coiled catheters may be more prone to migration and resultant dysfunction.

Diuretics associated acute kidney injury: clinical and pathological analysis

Abstract Objective: In order to evaluate the clinical and pathological characteristics of diuretics associated acute kidney injury (AKI) and its management. Methods: We performed a retrospective study including 131 cases that diagnosed as diuretics associated AKI from 1 January 1999 to 1 January 2010 in Ruijin Hospital affiliated to Shanghai Jiao Tong University. Drug applications and its related clinical, laboratory and histological data were collected. Results: The male to female ratio was 2:1. The proportion of ages <20 years, 20–40 years, 40–60 years and ≥60 years were 6.9%, 17.6%, 27.5% and 48.1% respectively. Most patients (96.2%) had at least one complication of which chronic kidney disease (CKD) occurred most frequently (72 in 131, 55.0%). We divided all the patients to diuretic group (Nu2009=u2009131) and non-diuretic group (Nu2009=u2009185) based on diuretics history. We found patients in diuretic group had higher rates of CVD (38.9% vs. 18.4%), hypertension (42.0% vs. 29.2%), CKD (55.0% vs. 27.0%) and DM (17.6% vs. 4.3%) than non-diuretic group. Of 131 diuretics associated AKI, 36 cases (27.5%) were caused by diuretics only, 39 cases (29.8%) were caused by the combination of diuretics and other drugs like antibiotics, contrast media, ACEI or NSAIDs, and 56 cases (42.7%) had other AKI risk factors such as operation, infection, acute heart failure or hepatorenal syndrome. In addition, our data suggested the severity of RIFLE classification and pathological injury of glomerular basement membrane was higher in large-dosage furosemide group (>u2009=u2009120u2009mg/d) than in low-dosage group (<120u2009mg/d). The most common lesion induced by diuretics was vacuolar degeneration of tubular epithelial cell. Logistic regression analysis showed predictors of all-cause mortality were age, gender, RIFLE classification when AKI onset. Age and RIFLE classification were predictive factor of non-complete recovery. Conclusion: This article firstly focuses on diuretics associated AKI, whose onset was related to aging, primary diseases and diuretic dosage. The combination of diuretics with other drugs such as antibiotics, contrast media, ACEI, NSAIDs, etc. would synergistically induced AKI. The pathological lesion of diuretics associated AKI may be mostly manifested vacuolar degeneration of tubular epithelial cell. Aging, gender, severity of RIFLE classification may be predictive factors of all-cause mortality of diuretics associated AKI.

Distinct metabolic profile of primary focal segmental glomerulosclerosis revealed by NMR-based metabolomics.

Background Primary focal segmental glomerulosclerosis (FSGS) is pathological entity which is characterized by idiopathic steroid-resistant nephrotic syndrome (SRNS) and progression to end-stage renal disease (ESRD) in the majority of affected individuals. Currently, there is no practical noninvasive technique to predict different pathological types of glomerulopathies. In this study, the role of urinary metabolomics in the diagnosis and pathogenesis of FSGS was investigated. Methods NMR-based metabolomics was applied for the urinary metabolic profile in the patients with FSGS (nu200a=u200a25), membranous nephropathy (MN, nu200a=u200a24), minimal change disease (MCD, nu200a=u200a14) and IgA nephropathy (IgAN, nu200a=u200a26), and healthy controls (CON, nu200a=u200a35). The acquired data were analyzed using principal component analysis (PCA) followed by orthogonal projections to latent structure discriminant analysis (OPLS-DA). Model validity was verified using permutation tests. Results FSGS patients were clearly distinguished from healthy controls and other three types of glomerulopathies with good sensitivity and specificity based on their global urinary metabolic profiles. In FSGS patients, urinary levels of glucose, dimethylamine and trimethylamine increased compared with healthy controls, while pyruvate, valine, hippurate, isoleucine, phenylacetylglycine, citrate, tyrosine, 3-methylhistidine and β-hydroxyisovalerate decreased. Additionally, FSGS patients had lower urine N-methylnicotinamide levels compared with other glomerulopathies. Conclusions NMR-based metabonomic approach is amenable for the noninvasive diagnosis and differential diagnosis of FSGS as well as other glomerulopathies, and it could indicate the possible mechanisms of primary FSGS.

Fine Mapping Implicates a Deletion of CFHR1 and CFHR3 in Protection from IgA Nephropathy in Han Chinese

An intronic variant at the complement factor H (CFH) gene on chromosome 1q32 (rs6677604) associates with risk of IgA nephropathy (IgAN), but the association signal has not been uniformly replicated in Han Chinese populations. We investigated whether the causal sequence variant resides in the CFH gene or the neighboring complement factor H-related 1 (CFHR1) gene and CFHR3, which harbor an 84-kb combined deletion (CFHR3,1Δ) in linkage disequilibrium with rs6677604. Imputation of 1000 Genomes Project data did not suggest new causal single-nucleotide variants within the CFH cluster. We next performed copy number analysis across the CFH locus in two independent Han Chinese case-control cohorts (combined n=3581). The CFHR3,1Δ and rs6677604-A alleles were rare (4.4% in patients and 7.1% in controls) and in strong linkage disequilibrium with each other (r2=0.95); of these alleles, CFHR3,1Δ associated more significantly with decreased risk of IgAN (odds ratio [OR], 0.56; 95% confidence interval [95% CI], 0.46 to 0.70; P=8.5 × 10-8 versus OR, 0.61; 95% CI, 0.50 to 0.75; P=1.6 × 10-6 for rs6677604-A). Moreover, CFHR3,1Δ explained all of the association signal at rs6677604 and remained significant after conditioning on rs6677604 genotype (P=0.01). Exploratory analyses of clinical and histopathologic parameters using the Oxford classification criteria revealed a suggestive association of CFHR3,1Δ with reduced tubulointerstitial injury (OR, 0.46; 95% CI, 0.25 to 0.79). These data indicate that dysregulated activity of the alternative complement pathway contributes to IgAN pathogenesis in both Asians and Europeans and implicate CFHR3,1Δ as the functional allele at this locus.

Impact of Rapamycin on Peritoneal Fibrosis and Transport Function

Objectives: To observe the impact of rapamycin on peritoneal fibrosis and peritoneal transport function in a rat model of peritoneal fibrosis. Methods: A total of 40 male SD rats were randomly divided into five groups, with 8 rats in each group. Group N was the normal control. In group NS, the rats were injected daily with 20 ml of saline intraperitoneally. In groups GLU, L-RAPA and H-RAPA, rats were injected daily with 20 ml of 4.25% peritoneal dialysis solution intraperitoneally, together with 150 µg of lipopolysaccharide on days 1, 3, 5 and 7. Rapamycin was administered to groups L-RAPA (250 µg/day) and H-RAPA (500 µg/day) intragastrically. On days 21 and 35, 4 rats from each group were selected to evaluate their peritoneal transport function (ultrafiltration volume, D2/D₀ ratio). The parietal peritoneal membrane from the rats was used for pathological study. Light microscopy (HE staining and VG staining) was used to assess the morphological changes. The expression levels of Col I, α-SMA, TGF-β1, Reca and Ki67 in the parietal peritoneal membrane were observed by immunohistochemistry. Results: The ultrafiltration volume and D2/D₀ ratio decreased in group GLU compared with group N on day 21 (p < 0.05) and further decreased on day 35 (p < 0.01), whereas such a significant change was not observed in group L-RAPA or H-RAPA. Furthermore, severe loss of the peritoneal mesothelial cells, exposure of the collagen matrix under the mesothelial cells, and infiltration of fibroblasts and various inflammatory cells were detected in group GLU on days 21 and 35. The thickness of the submesothelial compact zone significantly increased in group GLU compared with group N (p < 0.01). However, in groups L-RAPA and H-RAPA, the morphological changes were clearly alleviated, and the submesothelial compact zone was thinner than in group GLU (p < 0.01). The expression levels of Col I, α-SMA, TGF-β1, Ki67 and Reca in the peritoneal membrane were significantly increased in group GLU compared with group N on days 21 and 35 (p < 0.01), whereas these changes were significantly attenuated in groups L-RAPA and H-RAPA compared with group GLU (p < 0.01). Conclusions: Rapamycin had an obvious effect in inhibiting peritoneal fibrosis and improving peritoneal membrane transport function.

Novel mutations in the inverted formin 2 gene of Chinese families contribute to focal segmental glomerulosclerosis

Here, we report a genetic study of an extended family of Chinese ancestry with focal segmental glomerulosclerosis (FSGS), with one of the affected members also concurrently diagnosed with IgA nephropathy (IgAN). By genome-wide linkage analysis and subsequent sequencing, we identified an S85W mutation in the inverted formin 2 (INF2) gene that perfectly cosegregated with the kidney disease phenotype. The entire INF2 coding region was sequenced in 200 healthy controls, 55 families with FSGS, and 34 families with IgAN. This analysis identified a novel insertion, S129_Q130insVRQLS, in another FSGS pedigree. In vitro studies found that α-actinin 4 expression was decreased and INF2 showed perinuclear localization in S85W-transfected podocytes. Phosphorylation of serum response factor, and that its nuclear translation was decreased in S85W podocytes, indicated decreased activation in mutants. Abnormal actin organization was also found in S85W podocytes, while no change of microtubule structure was observed. Co-immunoprecipitation and immunofluorescence found decreased interaction between INF2 and Cdc42 in S85W podocytes. However, all these changes were not found in S129_Q130insVRQLS podocytes. The overall frequency of INF2 mutations was ~3.6% among Chinese familial FSGS, which was considerably lower than that from studies of European FSGS families. Thus, S85W but not the S129_Q130insVRQLS variant leads to podocyte cytoskeletal abnormalities, probably by impaired serum response factor phosphorylation.

Underweight Is an Independent Risk Factor for Renal Function Deterioration in Patients with IgA Nephropathy.

Studies on the relationship between body mass index (BMI) and renal progression in IgA Nephropathy (IgAN) were limited, especially for underweight patients with IgAN. To elucidate the clinical features and effect of underweight on renal function deterioration in this disease, we recruited IgAN patients with diagnostic age ≥18 years old and a baseline estimated glomerular filtration rate (eGFR) ≥15 ml/min/1.73m2 from our center between 1985 and 2014. Patients secondary to systemic diseases or follow-up less than 6 months were excluded. All patients’ clinical data at renal biopsy and during follow-up were recorded. Renal outcome was defined as end-stage kidney disease (ESRD). Baseline body mass index (BMI) was calculated by weight (kg) over squared height (m2). According to WHO Asian guideline, BMI was categorized as follows: <18.5kg/m2 (underweight), 18.5–22.99kg/m2 (normal weight), 23–27.49kg/m2 (overweight) and obese (≥27.5 kg/m2). Of 930 primary IgAN patients enrolled in this study, mean age at renal biopsy was 37.6 years and 49.2% were men. Totally, 114 (12.3%) ESRD occurred after a mean follow-up of 47.1 months. More ESRD happened in underweight patients (17.3%) compared to patients with normal weight (13.2%), overweight (11.0%) or obesity (9.5%). By multivariate Cox regression analysis, underweight was independently associated with a higher risk of ESRD after adjustment for demographic characteristics and clinical variables (HR: 3.5, 95% CI: 1.3–9.5, P = 0.01) comparing to normal weight. Underweight patients had lower hemoglobin, serum uric acid, triglycerides, cholesterol and lymphocyte counts than patients with normal weight. Furthermore, BMI was positively correlated with serum C3 (r = 0.25, p <0.001). Our research finds that underweight is an independent risk factor for kidney disease progression in IgAN, which might be associated with malnutrition status and decreased C3 levels.