Regulon analysis identifies protective FXR and CREB5 in proximal tubules in early diabetic kidney disease.

Diabetic kidney disease (DKD) is the most common complication of diabetes mellitus and a leading cause of kidney failure worldwide. Despite its prevalence, the mechanisms underlying early kidney damage in DKD remain poorly understood. In this study, we used single nucleus RNA-seq to construct gene regulatory networks (GRNs) in the kidney cortex of patients with early DKD. By comparing these networks with those of healthy controls, we identify cell type-specific changes in genetic regulation associated with diabetic status. The regulon activities of FXR (NR1H4) and CREB5 were found to be upregulated in kidney proximal convoluted tubule epithelial cells (PCTs), which were validated using immunofluorescence staining in kidney biopsies from DKD patients. In vitro experiments using cultured HK2 cells showed that FXR and CREB5 protected cells from apoptosis and epithelial-mesenchymal transition. Our findings suggest that FXR and CREB5 may be promising targets for early intervention in patients with DKD.

Clinical features of anemia in membranous nephropathy patients: a Chinese cohort study.

BACKGROUND: Anemia is a common complication in patients with progressive chronic kidney disease. This cohort study evaluated the prevalence, clinical features and prognosis of membranous nephropathy (MN) with anemia. METHODS: We retrospectively analyzed a cohort of MN patients diagnosed using renal biopsy between February 2012 and February 2018. The clinical and pathological characteristics at baseline were recorded, and the outcomes (hemoglobin, proteinuria and renal function) during follow-ups were also evaluated. Univariate and multivariate logistic regression analyses were performed to identify the independent risk factors for anemia in MN patients. The MN patients were divided according to the therapeutic effect they experienced as follows: without-anemia, completely corrected anemia, standard anemia treatment and nonstandard anemia treatment groups. We compared the rate of complete remission of MN and renal end-point events among the four groups. RESULTS: The median age of 483 patients was 42.43 (26.59, 50.20) years at the time of MN diagnosis. The prevalence of anemia at baseline was 23.81%, and the cumulative prevalence was 50.72%. There were 133 cases of mild anemia, 103 cases of moderate anemia and 9 cases of severe anemia; in addition, there were 228 cases of normocytic anemia and 17 cases of microcytic hypochromic anemia. Multivariate logistic regression indicated that acute renal tubule injury >5% (OR = 1.634, 95% CI 1.034, 2.581; p = 0.035), total protein level (OR = 0.949, 95% CI 0.923, 0.975; p < 0.001), cholesterol level (OR = 0.833, 95% CI 0.749, 0.926, p = 0.001), hypokalemia (OR = 2.612, 95% CI 1.227, 5.560, p = 0.013) and hypophosphatemia (OR = 2.653, 95% CI 1.303, 5.403, p = 0.007) were independent risk factors for anemia in MN patients. The complete remission rate of MN patients without anemia was significantly higher than that of anemia patients who exhibited treatment failure. The incidence of renal endpoint events was different among the four groups. CONCLUSION: The anemia experienced by MN patients is mainly mild and moderate, normocytic anemia. The pathological features of acute renal tubular injury and clinical nutritional status are independent risk factors for anemia. There were differences in renal prognosis among anemia patients with different treatment outcomes.

Relationship between anti-GBM antibodies and kidney outcomes in patients with anti-GBM disease.

INTRODUCTION: Animal experiments have shown that anti-GBM antibodies play a pathogenic role in anti-GBM disease. However, the relationship between anti-GBM antibody levels and kidney outcomes in patients with anti-GBM disease is unclear. METHODS: We performed a retrospective analysis of 110 patients diagnosed with anti-GBM disease. We compared their baseline characteristics stratifying on different anti-GBM antibody levels, and used Cox regression analysis to analyze the correlation between antibody levels and kidney survival. We further selected 69 patients to evaluate the modification of antibody titers over 14 days of treatment, then compared kidney survival of patients in the group with antibody level decrease < 48% to those with antibody decrease ≥ 48%. RESULTS: The 110 patients had a median follow-up of 27.1 (Q1-Q3: 7.9-80.1) months, and among them 90 (81.8%) developed kidney failure. Multivariate analysis suggested that anti-GBM antibody level was an independent risk factor for progression to kidney failure in patients with anti-GBM disease (HR 1.08, 95% CI 1.01-1.16). The patients who reduced the antibodies levels quickly had better kidney survival than those who did not, and multivariate analysis also indicated that antibody decrease rate was related to kidney outcomes. CONCLUSIONS: Anti-GBM antibody level is closely related to kidney outcomes in patients with anti-GBM disease, and short-term reduction of antibodies can be beneficial to improving kidney outcomes.

Efficacy of long-term repeated rituximab treatment in refractory phospholipase A2 receptor-antibody-related membranous nephropathy.

Aims: To evaluate the efficacy of long-term repeated rituximab treatment in refractory PLA2R-Ab-related membranous nephropathy (MN). Materials & methods: Rituximab was administered at a single dose of 375 mg/m2 and repeated if peripheral B-cell levels were >5/ul in 46 patients with refractory PLA2R-Ab-related MN. Results: The median frequency of rituximab treatment was 3 (IQR 2.0-4.0). A total of 32 (32/46) patients achieved remission (completed remission [CR] or partial remission [PR]) over a median time of 17.0 months, and 10 patients eventually progressed to CR. The proportion of serum PLA2R-Ab depletion was 73.91% (34/46) over a median time of 9 months. Antibody depletion preceded proteinuria remission. Conclusions: Long-term repeated rituximab treatment achieved high kidney and immunological response rates in refractory PLA2R-Ab related MN, and antibody depletion was a prerequisite for proteinuria remission.

Membranous nephropathy (MN) is the leading cause of proteinuria in adults and is mainly manifested as edema. Phospholipase 2 receptor (PLA2R) antibody is detected in 70­80% of patients with MN. Its main treatments are immunosuppressive therapies. The efficacy of traditional immunosuppressant drugs including steroids and alkylating and calcineurin inhibitors in reducing proteinuria have been confirmed; however, several adverse events such as diabetes mellitus, infections, cancer and kidney injury have been reported. Rituximab, a monoclonal antibody against CD20 on B cells, has been verified to be effective, safer and better tolerated in MN. However, the optimal rituximab regimen for MN has not yet been established. Here, we use B-cell-driven long-term repeated rituximab regimen and determine its exciting efficacy for refractory MN.

Relationship Between Serum Complement C3 Levels and Outcomes Among Patients With Anti-GBM Disease.

Background: IgG and complement 3 (C3) are generally found to be deposited along the glomerular basement membrane (GBM) in human anti-GBM disease. The pathogenic role of complement activation in kidney damage of anti-GBM disease has been explored in recent years. Therefore, we investigated the relationship between serum C3 and outcomes among patients with anti-GBM disease in this study. Methods: Ninety-four anti-GBM disease patients between January 2004 and December 2020 at the National Clinical Research Center of Kidney Diseases Jinling Hospital were retrospectively analyzed, and were divided into the low C3 group and the normal C3 group according to serum C3 levels at diagnosis. Fifty-six patients had undergone renal biopsy. We analyzed the clinical manifestations, laboratory tests, kidney pathology, treatment, and outcomes between the two groups. The primary endpoint was kidney failure. Cox regression and smooth curve fitting of generalized additive mixed model analysis were used to explore the correlation between serum C3 and kidney failure. The outcomes of the two groups were compared by the Kaplan-Meier curve. Results: A total of 94 patients (aged 43.6 ± 16.2; male patients, 46%) with anti-GBM disease were enrolled. There were 26 patients with low C3 levels and 68 patients with normal C3 levels. Compared with the normal C3 group, patients in the low C3 group have a higher proportion of glomerular sclerosis progressing to kidney failure. Multivariate Cox regression analysis suggested that C3 is associated with kidney outcomes in patients with anti-GBM disease (HR = 0.782, 95% CI = 0.673-0.907, p = 0.001). Smooth curve fitting of generalized additive mixed model analysis indicated that the level of C3 had a linear relationship with the changing trend of kidney failure. The Kaplan-Meier curve showed that there was a statistical difference between the two groups in terms of kidney failure (p = 0.033). Conclusion: The kidney outcomes of anti-GBM disease in the low C3 group were poorer than those in the normal C3 group. The influence of C3 on the kidney outcomes of patients with anti-GBM disease may be of clinical relevance.

Non-diabetic urine glucose in idiopathic membranous nephropathy.

This study aims to analyze the characteristics of idiopathic membranous nephropathy (iMN) with nondiabetic urine glucose during the follow-up. We retrospectively analyzed the data of 1313 patients who were diagnosed iMN. The prevalence of nondiabetic urine glucose during follow-up was 10.89%. There were significant differences between the patients with nondiabetic urine glucose and those without urine glucose in gender, hypertension ratio, proteinuria, N-acetyl-ß-glucosaminidase, retinol binding protein, serum albumin, serum creatinine (Scr), cholesterol, triglyceride and positive anti-phospholipase A2 receptor antibody ratio, glomerular sclerosis ratio, acute and chronic tubular injury lesion at baseline. To exclude the influence of the baseline proteinuria and Scr, case control sampling of urine glucose negative patients was applied according to gender, baseline proteinuria and Scr. The proteinuria nonremission (NR) ratio was 45.83 versus 12.50% of the urine glucose positive group and case control group. Partial remission (PR) ratio of the two groups was 36.46 versus 23.96% and complete remission (CR) ratio was 19.79% versus 63.54%, respectively. Patients with urine glucose had higher risk of 50% estimated glomerular filtration rate (eGFR) reduction. Cox regression showed that urine glucose and baseline Scr were risk factors of 50% reduction of eGFR. Urine glucose remission ratio of the patients with proteinuria NR, PR, and CR was 13.33, 56.25, and 94.73% (p < 0.005). Patients who got urine glucose remission also had better renal survival. In conclusion, non-diabetic urine glucose was closely related to proteinuria. It could be applied as a tubular injury marker to predict renal function.

Effectiveness and safety of KunXian capsule for the treatment of IgA nephropathy.

BACKGROUND: Tripterygium Wilfordii Hook F (TwHF) preparation has been widely used in the treatments of IgA nephropathy (IgAN) in China. However, the effectiveness and safety of the new generation of TwHF preparation, KuxXian capsule, on the treatment of IgAN remains unknown. METHODS: Here, we retrospectively describe our experience treating 55 consecutive IgAN patients with KunXian. We defined complete remission as proteinuria < 0.5 g/24 h and partial remission as proteinuria < 1 g/24 h, each also having > 50% reduction in proteinuria from baseline. RESULTS: At first follow-up after KunXian treatment (5.7 weeks, IQR 4.7-7.9), all but two patients (96%) showed a reduction in proteinuria. The overall median proteinuria decreased from 2.23 g/day at baseline to 0.94 g/day (P < 0.001) at the first follow-up. During a median follow-up of 28 weeks after KunXian administration, 25(45.5%) patients achieved complete remission, 34 (61.8%) patients achieved complete/partial remission. Of the 12 patients discontinued KunXian treatment during the follow-up, the median proteinuria was increased from 0.97 g/24 h to 2.74 g/24 h after a median of 10.9 weeks (P = 0.004). Multivariable Cox models showed that female, treatment switching from previous generation of TwHF preparation, lower initial KunXian dosage, and higher proteinuria at baseline were independently associated proteinuria remission. Of the 20 pre-menopausal females, 12 of them developed oligomenorrhea or menstrual irregularity and ten of them developed amenorrhea. CONCLUSION: KunXian is effectiveness and safety for the treatment of IgA nephropathy. Woman of childbearing age to be informed of the risk of ovarian failure after being treated with TwHF preparations.

An equation to estimate 24-hour total urine protein excretion rate in patients who underwent urine protein testing.

BACKGROUND: The urine protein-creatinine ratio (UPCR) in a spot first-morning urine sample is used to estimate 24-h urine proteinuria (24hUP) in patients who underwent urine protein testing. UPCR cannot be directly compared with 24-h proteinuria. Thus, an equation to estimate 24-h total protein excretion rate, using age, gender, and the UPCR may improve its bias and accuracy in patients who underwent urine protein testing. METHODS: We simultaneously measured 24-h urine protein and the same day's first-morning spot urine from patients with kidney disease. Generalized linear and no-linear models, using age, gender, and UPCR, were constructed to estimate for 24-h urine protein and the best model (NJ equation) was selected to estimated 24 hUP (e24hUP). RESULTS: A total of 5435 paired samples (including a training cohort of 3803 patients and a validation cohort of 1632 patients) were simultaneously measured for UPCR and 24-h urine protein. In the training cohort, the unadjusted UPCR obviously underestimated 24-h urine protein when UPCR ≤1.2 g/g (median bias - 0.17 g/24 h) and overestimated 24-h urine protein when UPCR > 1.2 g/g (median bias 0.53 g/24 h). In the validation cohort, the NJ equation performed better than the unadjusted UPCR, with lower root mean square error (0.81 vs. 1.02, P < 0.001), less bias (median difference between measured and estimated urine protein, - 0.008 vs. 0.12), improved precision (interquartile range of the differences, 0.34 vs. 0.50), and greater accuracy (percentage of estimated urine protein within 30% of measured urine protein, 53.4% vs. 32.2%). Bland-Altman plot indicated that the agreement of spot and daily estimates was less pronounced with 24 hUP > 2 g than lower values. CONCLUSIONS: The NJ e24hUP equation is more accurate than unadjusted UPCR to estimate 24 hUP in patients with kidney disease and could be used for laboratory application.

HLA Alleles and Prognosis of PLA2R-Related Membranous Nephropathy.

BACKGROUND AND OBJECTIVES: Associations between HLA alleles and susceptibility to M-type phospholipase A2 receptor (PLA2R)-related membranous nephropathy have been well defined previously in Chinese patients. However, the relationships between HLA alleles and kidney outcome remain unclear. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Five HLA genes (DRB1, DQA1, DQB1, DRB3, and DRB5) were genotyped in a prospective cohort of 392 patients with PLA2R-related membranous nephropathy. The associations between HLA alleles and kidney outcomes were studied. RESULTS: A total of 79 HLA alleles were identified in this study. Four HLA alleles, DRB1*13:01 (n=12; hazard ratio, 3.7; 95% confidence interval, 1.8 to 7.8; P<0.001), DQB1*06:03 (n=12; hazard ratio, 3.7; 95% confidence interval, 1.8 to 7.8; P<0.001), DRB1*04:05 (n=12; hazard ratio, 3.8; 95% confidence interval, 1.5 to 9.5; P=0.004), and DQB1*03:02 (n=21; hazard ratio, 3.1; 95% confidence interval, 1.4 to 6.7; P=0.005), were associated with a ≥40% eGFR decline during follow-up. DRB1*13:01 and DQB1*06:03 were tightly linked with each other. Forty-four of the 392 patients (11%) carried at least one of the four identified risk HLA alleles in this study. Compared with patients who were negative for all risk HLA alleles, those carrying at least one risk HLA allele had a significant risk of a ≥40% eGFR decline during follow-up (hazard ratio, 3.9; 95% confidence interval, 2.3 to 6.7; P<0.001). After adjusting for age, sex, proteinuria, albumin, eGFR, and anti-PLA2R antibody levels, multivariable Cox analysis showed that patients carrying any of the four risk HLA alleles remained associated with a higher risk of a ≥40% decline in eGFR (hazard ratio, 4.1; 95% confidence interval, 2.3 to 7.1; P<0.001). CONCLUSIONS: Carrying any of the HLA alleles, DRB1*13:01/DQB1*06:03, DRB1*04:05, and DQB1*03:02, was independently associated with poor prognosis in Chinese patients with PLA2R-related membranous nephropathy.

Nuclear Receptor Interacting Protein-2 Mediates the Stabilization and Activation of ß-Catenin During Podocyte Injury.

Objective: Activation of ß-catenin causes podocyte injury and proteinuria, but how ß-catenin signalling is regulated during podocyte injury remains elusive. Nuclear receptor interacting protein 2 (NRIP2) modulates the Wnt pathway in colorectal cancer-initiating cells, but the role of NRIP2 in podocyte injury has not yet been investigated. We aimed to examine the interaction between NRIP2 and ß-catenin signalling. Materials and Methods: Knockdown or overexpression of NRIP2 and ß-catenin and chemical treatments were performed in cultured human podocytes. Immunoprecipitation, immunoblotting and immunofluorescence assays were used to assess protein interactions and expression. Data from the GEO dataset and kidney tissues from patients with focal segmental glomerulosclerosis (FSGS) and surgical nephrectomy were examined. An adriamycin (ADR) nephropathy model was established in NRIP2 knockout mice. Results: NRIP2 knockdown accelerated ß-catenin degradation, which was reversed by MG132; specifically, NRIP2 bound ß-catenin and stabilized it to prevent its degradation through the ubiquitin proteasomal pathway. Overexpression of NRIP2 led to ß-catenin activation and Snail1 induction, and these effects were attenuated by ß-catenin knockdown. NRIP2 knockdown blocked ADR-stimulated ß-catenin activation. In ADR mice, genetic knockout of Nrip2 ameliorated podocyte injury and loss, glomerulosclerosis, and proteinuria by inhibiting ß-catenin activation. Moreover, NRIP2 was significantly upregulated in podocytes of FSGS patients and colocalized with nuclear ß-catenin. Conclusion: These results established NRIP2 as a stabilizer of ß-catenin activation through the ubiquitin proteasomal pathway in podocyte injury.

Characterization of thromboelastography of patients with different pathological types of nephrotic syndrome.

To investigate the changes in blood coagulability as measured by thromboelastography (TEG) in patients with nephrotic syndrome of different etiologies as well as in patients with venous thromboembolic events (VTE).From January 2013 to October 2017, patients who were diagnosed as idiopathic membranous nephropathy (IMN), minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) were enrolled into this retrospective study in which their clinical characteristics, including TEG variables, were investigated. According to the presence or absence of VTE, the patients with IMN were divided into 2 groups of VTE and non-VTE. The risk factors of VTE were analyzed with logistic regression.Significant differences in TEG parameters were found among the 3 groups of patients with R and K values lower, while the α-angle, maximum amplitude (MA) and confidence interval (CI) values higher, in the IMN group than those in the MCD and FSGS groups (P < .01). Multiple linear regression analysis indicated that the histologic subtype was an independent relevant factor of K time, angle, MA, and CI values. Multivariate logistic regression analysis revealed that serum albumin and CI value were independent risk factors of VTE (P < .05).The results showed that IMN patients may have higher whole blood coagulability than MCD and FSGS patients. The hypercoagulability in IMN patients may be attributed to platelet hyperactivity and the accelerated fibrin-platelet interaction. Hypoproteinemia and increased CI value were independent risk factors of VTE in IMN.

Renal Prognosis and Related Risk Factors for Henoch-Schönlein Purpura Nephritis: A Chinese Adult Patient Cohort.

This study investigated the clinicopathological characteristics of Henoch-Schönlein purpura nephritis (HSPN) in Chinese adult patients and analyzed the renal outcomes and prognostic risk factors for progression to end-stage renal disease (ESRD). Adult patients who had biopsy-proven HSPN were studied. Their clinicopathological data, renal prognoses and related risk factors were assessed. A total of 698 patients were studied, including 363 men (52.0%) and 335 women (48.0%). Most of the patients had hematuria (85.8%) and/or proteinuria (82.1%). During a median follow-up of 54.0 months, 32 patients (4.6%) progressed to ESRD. The 5- and 10-year cumulative renal survival rates from ESRD were 96.4% and 88.6%, respectively. Baseline urinary protein, renal insufficiency, glomerular sclerosis and tubular atrophy/interstitial fibrosis were independent predictors of renal outcomes. Both the time-average mean arterial pressure and proteinuria during follow-up also influenced the renal prognosis. The patients with a time-average proteinuria <0.4 g/day had the lowest rates of ESRD or a 50% decline in renal function. In conclusion, identifying of clinical and histological prognostic factors may permit the prediction of renal outcomes. The optimal goal of therapy for HSPN patients may be to lower proteinuria to <0.4 g/day and control hypertension to achieve an ideal renal outcome.

Changes in the Spectrum of Kidney Diseases: An Analysis of 40,759 Biopsy-Proven Cases from 2003 to 2014 in China.

OBJECTIVES: To evaluate the changing spectrum of kidney diseases over time in China using renal biopsy-proven cases. METHODS: All patients over the age of 14 years who were diagnosed with a kidney disease by renal biopsy in the Renal Biopsy Registry of the National Clinical Research Center of Kidney Diseases in Jinling Hospital, Nanjing, from 2003 to 2014 were included. RESULTS: In total, 40,759 cases of renal biopsy were analyzed. The mean age of the patients was 36.59 ± 14.12 years. 52.0$ of the patients were male. Primary glomerulonephritis (PGN), secondary glomerulonephritis, tubulointerstitial disease, and hereditary renal diseases accounted for 67.1, 26.4, 2.9, and 2.5$, respectively. IgA nephropathy (IgAN), membranous nephropathy (MN), minimal change disease, and focal segmental glomerulosclerosis were the leading PGN diagnoses. The frequency of MN increased significantly (p < 0.001) by doubling from 2003 to 2014. An analysis by age category indicated that the frequency of MN increased significantly over time (p < 0.001) in all age categories and increased by more than 2 times in the 14-24 age category. Lupus nephritis (LN) and Henoch-Schönlein purpura nephritis (HSPN) decreased significantly (p < 0.001), diabetic nephropathy (DN) increased nearly twice (p < 0.001), monoclonal immunoglobulin deposition disease (MIDD) tripled (p < 0.001), and hypertensive nephropathy (HT) (p < 0.001) and renal amyloidosis (AMY) (p < 0.05) showed an upward trend. An analysis by age category showed that hepatitis B-related nephritis has significantly decreased in the 14-24 age category (p < 0.001). CONCLUSION: PGN continued to be the predominant kidney disease in China with IgAN being the most common PGN. The frequency of MN increased significantly, with a maximum increase in young adults. LN and HSPN decreased significantly, DN and MIDD increased significantly, and HT and AMY also showed an increasing trend. The kidney disease trends presented in this study serve as a reference point for patient care, disease prevention, and public health interventions.

Mycophenolate Mofetil Combined With Prednisone Versus Full-Dose Prednisone in IgA Nephropathy With Active Proliferative Lesions: A Randomized Controlled Trial.

BACKGROUND: Observational studies suggest that patients with immunoglobulin A nephropathy (IgAN) with active proliferative lesions show a good response to immunosuppressive treatment. STUDY DESIGN: Multicenter, prospective, randomized, controlled trial. SETTING & PARTICIPANTS: 176 patients with IgAN with active proliferative lesions (cellular and fibrocellular crescents, endocapillary hypercellularity, or necrosis), proteinuria with protein excretion ≥ 1.0g/24h, and estimated glomerular filtration rate > 30mL/min/1.73m2. INTERVENTION: Mycophenolate mofetil (MMF) group: MMF, 1.5g/d, for 6 months and prednisone, 0.4 to 0.6mg/kg/d, for 2 months and then tapered by 20% per month for the next 4 months; prednisone group: prednisone, 0.8 to 1.0mg/kg/d, for 2 months and then tapered by 20% per month for the next 4 months. All patients were followed up for another 6 months. OUTCOMES: The primary end point was complete remission rate at 6 and 12 months. RESULTS: At baseline, median estimated glomerular filtration rates were 90.2 and 94.3mL/min/1.73m2 and mean proteinuria was protein excretion of 2.37 and 2.47g/24h in the MMF and prednisone groups, respectively. At 6 months, complete remission rates were 37% (32 of 86 patients) and 38% (33 of 88 patients); the between-group difference was not statistically significant (P=0.9). At 12 months, complete remission rates were 48% (35 of 73 patients) and 53% (38 of 72 patients) in the MMF and prednisone groups, respectively; the between-group difference was not statistically significant (P=0.6). Incidences of Cushing syndrome and newly diagnosed diabetes mellitus were lower in the MMF group than in the prednisone group. LIMITATIONS: Not all participants were treated with renin-angiotensin system blockers, relatively short follow-up. CONCLUSIONS: MMF plus prednisone versus full-dose prednisone did not differ in reducing proteinuria, but patients treated with the former had fewer adverse events in patients with IgAN with active proliferative lesions.

Evaluating tacrolimus treatment in idiopathic membranous nephropathy in a cohort of 408 patients.

BACKGROUND: The KDIGO Clinical Practice Guidelines for Glomerulonephritis recommended tacrolimus as an alternative regimen for the initial therapy for Idiopathic membranous nephropathy (IMN), however, large observational studies evaluating tacrolimus treatment in IMN remains rare. METHODS: A total of 408 consecutive IMN patients with nephrotic syndrome who were treated with tacrolimus in Jinling Hospital were included. The effectiveness and safety of tacrolimus treatment in IMN were analyzed in this study. RESULTS: The cumulative partial or complete remission after tacrolimus therapy were 50%, 63% and 67% at 6, 12 and 24 months, respectively, and the cumulative complete remission rates were 4%, 13% and 23%, respectively. Multivariate logistic analysis showed that higher tacrolimus exposure during induction treatment, female gender, higher eGFR and no history of previous immunosuppressive therapy were independently associated with higher probability of remission. A relapse occurred in 101 of the 271 (37.3%) patients with partial or complete remission, and 18 of the 95 (18.9%) patients with complete remission. Tapering duration of tacrolimus and complete remission versus partial remission status were independent factors associated with risk of relapse. A decline in eGFR was the most frequent adverse event during tacrolimus treatment. During tacrolimus treatment, a ≥40% decrease in eGFR was observed in 43 (10.5%) patients. CONCLUSIONS: Low dose tacrolimus is effective for IMN, with a total remission rate of 66% whereas with a rather high rate of relapse. However, the safety of tacrolimus treatment needs to be further validated in large randomized clinical trials.

HLA-DRB1*15:01 and HLA-DRB3*02:02 in PLA2R-Related Membranous Nephropathy.

Idiopathic membranous nephropathy (MN) is associated with HLA; however, the HLA allele involved remains unknown. To identify the HLA risk alleles associated with phospholipase A2 receptor (PLA2R)-related MN in the Chinese population, we sequenced the entire MHC region in DNA samples from 99 patients with PLA2R-related MN, 50 patients with PLA2R-unrelated MN, and 100 healthy subjects. Two HLA risk alleles, HLA-DRB1*15:01 and HLA-DRB3*02:02, independently and strongly associated with an increased risk of PLA2R-related MN. After adjusting for HLA-DRB1*15:01 and HLA-DRB3*02:02, no other alleles showed significant association with PLA2R-related MN. A replication study in an independent cohort of 293 participants with PLA2R-related MN and 285 healthy controls validated these findings. In a joint analysis, a multivariate logistic regression model confirmed that HLA-DRB1*15:01 (odds ratio [OR], 24.9; 95% confidence interval [95% CI], 15.3 to 42.6; P=2.3×10-35) and HLA-DRB3*02:02 (OR, 17.7; 95% CI, 11.0 to 30.3; P=8.0×10-29) independently and strongly associated with PLA2R-related MN. As many as 98.7% of patients with PLA2R-related MN, compared with 43.9% of control subjects, carried at least one HLA risk allele. Subjects with either risk allele had higher odds of developing PLA2R-related MN than those without a risk allele (OR, 98.9; 95% CI, 44.4 to 281.7; P=2.5×10-23). These HLA risk alleles also associated with the age at disease onset in patients with PLA2R-related MN. In conclusion, our findings provide clear evidence that the HLA-DRB1*15:01 and HLA-DRB3*02:02 alleles independently and strongly associate with PLA2R-related MN in the Chinese population.

PLA2R antibodies and PLA2R glomerular deposits in psoriasis patients with membranous nephropathy.

BACKGROUND: The association between psoriasis and membranous nephropathy (MN) remains largely unclear. We examined the prevalence of serum PLA2R antibody and characterized the expression of PLA2R and THSD7A in glomeruli in patients with MN and psoriasis. METHODS: A total of 24 patients with MN without evidence of a secondary cause except psoriasis were enrolled. The clinical and pathological features were retrospectively analyzed. Serum anti-PLA2R antibody was measured using IFA Mosaic. Renal tissue samples stored in the laboratory bio-bank were used for PLA2R staining under immunofluorescence microscopy and THSD7A immunohistochemical analysis. RESULTS: Twenty-four patients (21 male and 3 female) with a mean age of 43.6 ± 15.7 years old were enrolled. Serum anti-PLA2R antibody was positive in 7 patients, which was significantly lower than the positivity observed in idiopathic MN (29.2% vs. 81.7%, P < 0.001). Glomerular PLA2R staining was positive in 7 patients with positive serum anti-PLA2R antibody. THSD7A staining was negative in all 24 patients. During the follow-up visits, 13 patients with negative serum PLA2R antibody achieved CR. In contrast, CR was only achieved in 1 patient with positive serum PLA2R antibody, PR was achieved in 2 patients. CONCLUSIONS: The prevalence of serum anti-PLA2R antibody and glomerular expression of PLA2R was significantly lower in patients with psoriasis and MN than in those with idiopathic MN, and THSD7A staining was negative, suggesting that MN is associated with psoriasis in the majority of patients. However, idiopathic MN might also accompany psoriasis in a minority of psoriatic patients with positive serum anti-PLA2R antibody.

Rapid Identification of Potential Drugs for Diabetic Nephropathy Using Whole-Genome Expression Profiles of Glomeruli.

OBJECTIVE: To investigate potential drugs for diabetic nephropathy (DN) using whole-genome expression profiles and the Connectivity Map (CMAP). METHODOLOGY: Eighteen Chinese Han DN patients and six normal controls were included in this study. Whole-genome expression profiles of microdissected glomeruli were measured using the Affymetrix human U133 plus 2.0 chip. Differentially expressed genes (DEGs) between late stage and early stage DN samples and the CMAP database were used to identify potential drugs for DN using bioinformatics methods. RESULTS: (1) A total of 1065 DEGs (FDR < 0.05 and fold change > 1.5) were found in late stage DN patients compared with early stage DN patients. (2) Piperlongumine, 15d-PGJ2 (15-delta prostaglandin J2), vorinostat, and trichostatin A were predicted to be the most promising potential drugs for DN, acting as NF-κB inhibitors, histone deacetylase inhibitors (HDACIs), PI3K pathway inhibitors, or PPARγ agonists, respectively. CONCLUSION: Using whole-genome expression profiles and the CMAP database, we rapidly predicted potential DN drugs, and therapeutic potential was confirmed by previously published studies. Animal experiments and clinical trials are needed to confirm both the safety and efficacy of these drugs in the treatment of DN.

Clinico-pathological characteristics and outcomes of patients with biopsy-proven hypertensive nephrosclerosis: a retrospective cohort study.

BACKGROUND: This study aimed to investigate renal outcomes and their predictors in biopsy-proven hypertensive nephrosclerosis (HN) patients and to compare clinico-pathological characteristics and prognoses between benign nephrosclerosis (BN) and malignant nephrosclerosis (MN) patients. METHODS: Data for biopsy-proven HN patients were retrospectively analyzed. Renal survival rates and relationships between clinico-pathological characteristics and outcomes were assessed. RESULTS: A total of 194 patients were enrolled; the mean age at biopsy was 43.8 years, and male gender predominated (82.5 %). The median duration of hypertension was 5.0 years, and the mean systolic and diastolic blood pressures were 195 ± 37 and 126 ± 26 mmHg, respectively. The median serum creatinine (Scr) level, estimated glomerular filtration rate (eGFR), and proteinuria level were 1.61 mg/dl, 49.6 ml/min/1.73 m(2), and 0.80 g/24 h, respectively. BN and MN were found by renal biopsy in 55.2 % and 44.8 % of patients, respectively. At biopsy, MN patients were younger, and had higher median Scr and proteinuria levels, higher incidences of anemia, hypertensive heart disease and hypertensive retinopathy, and worse renal outcomes than BN patients. During a median follow-up period of 3.0 years, 36 patients (18.6 %) reached end-stage renal disease (ESRD), and the 5- and 10-year cumulative renal survival rates for HN patients were 84.5 % and 48.9 %, respectively. A decreased baseline eGFR, an increased baseline proteinuria level, anemia, increased percentage of global glomerulosclerosis and tubular atrophy and interstitial fibrosis (TAIF) were independent predictors of future ESRD. CONCLUSIONS: The clinico-pathological characteristics and prognoses were significantly different between the MN and BN patients. The renal outcomes of HN patients were independently associated with the baseline eGFR and proteinuria level, anemia, percentage of global glomerulosclerosis and TAIF.