Assessment of right ventricular dysfunction and its association with excess risk of cardiovascular events in patients undergoing maintenance hemodialysis.

AIMS: Recent accumulating evidence has recently documented a significant prevalence of right ventricular dysfunction (RVD) in end-stage renal disease (ESRD) patients. Tricuspid annular plane systolic excursion (TAPSE)/pulmonary-artery systolic pressure (PASP) ratio assessed with echocardiography might be a useful clinical index of right ventricular (RV) -pulmonary arterial (PA) coupling. The current study aimed to investigate the value of the TAPSE/PASP ratios in patients on maintenance hemodialysis (MHD). METHODS: We studied 83 times echocardiographic tests from 68 patients with MHD. The associations of TAPSE/PASP ratios with echocardiography variables, clinical characteristics, and biochemical parameters were analyzed, as well as the associations of TAPSE/PASP ratios with odds of all-cause mortality, cardiovascular disease (CVD) events and frequent intermittent dialysis hypotension (IDH). RESULTS: Correlation analysis showed TAPSE/PASP ratios positively correlated with LVEF and negatively correlated with E/A and E/e' values. For clinical and biochemical parameters, TAPSE/PASP ratios negatively correlated with BNP, NT-proBNP, age, CRP, and average interdialysis weight gain (ΔBW) and positively correlated with albumin. Logistic regression analysis, which induced the TAPSE/PASP ratio as a continuous variable (per 0.1 mm/mmHg increase), identified that the TAPSE/PASP ratio was associated with decreased CVD events (OR 0.386 [95% CI 0.231-0.645], p < 0.001) and frequent IDH odds (OR 0.571 [95% CI 0.397-0.820], p = 0.002). Moreover, the TAPSE/PASP ratio independently predicted CVD events (adjusted HR 0.539 [95% CI 0.391-0.743], p < 0.001) during a follow-up period of 12 months. CONCLUSIONS: RVD, assessed by echocardiography TAPSE/PASP ratio, was found to be associated with increased risks of CVD events and frequent IDH in patients with MHD.

Patients with primary focal segmental glomerulosclerosis with detectable urinary CD80 are more similar to patients with minimal change disease in clinicopathological features.

BACKGROUND: Focal segmental glomerulosclerosis (FSGS) is an important cause of refractory nephrotic syndrome (NS) in children and adults. Urinary CD80 is elevated in some patients with primary FSGS, however, its clinical value is not fully clarified. This study aims to evaluate the clinical and pathological significance of urinary CD80 in patients with primary FSGS. METHODS: Sixty-one adult patients with biopsy-proven primary FSGS, with standard treatment and long-term follow up, were enrolled retrospectively. Urinary CD80, on the day of kidney biopsy, was measured using commercial ELISA kits and adjusted by urinary creatinine excretion. Their associations with clinical and pathological parameters were investigated. RESULTS: Urinary CD80 was detectable in 30/61 (49.2%) patients, who presented with a higher level of proteinuria (10.7 vs. 5.8 g/24h; p = 0.01), a lower level of serum albumin (19.3 ± 3.9 vs. 24.2 ± 8.2 g/L; p = 0.005), a higher prevalence of hematuria (70.0 vs. 38.7%; p = 0.01), and showed a lower percentage of segmental glomerulosclerosis lesion [4.8 (3.7-14.0) vs. 9.1 (5.6-21.1) %; p = 0.06]. The cumulative relapse rate was remarkably high in these patients (log-rank, p = 0.001). Multivariate analysis identified that the elevated urinary CD80 was an independent risk factor for steroid-dependent NS (OR 8.81, 95% CI 1.41-54.89; p = 0.02) and relapse (HR, 2.87; 95% CI 1.29-6.38; p = 0.01). CONCLUSIONS: The elevated urinary CD80 is associated with mild pathological change and steroid-dependent cases of primary FSGS adults, which indicates these patients are more similar to minimal change disease (MCD) in clinicopathological features.

Long-term visit-to-visit variability in low-density lipoprotein cholesterol is associated with poor cardiovascular and kidney outcomes in patients with primary nephrotic syndrome.

PURPOSE: It is unclear whether long-term variability in low-density lipoprotein cholesterol (LDL-C) is associated with clinical outcomes in patients with nephrotic syndrome (NS). METHODS: A large cohort of 1100 patients with primary NS underwent treatment and regular follow-up. Long-term variability in LDL-C was assessed by calculating its weighted standard deviation (w-SD). The primary endpoints of this study were the occurrence of arteriosclerotic cardiovascular disease (ASCVD) or kidney dysfunction. Factors associated with the w-SD of LDL-C were evaluated by linear regression. Associations of the w-SD of LDL-C with clinical outcomes were evaluated by Cox proportional hazards regression. RESULTS: Over a median follow-up of 44.8 (interquartile range, 26.8, 70.1) months, 198 patients developed ASCVD (45.9 cases per 1,000 patient-years), and 84 patients developed kidney dysfunction (17.6 cases per 1,000 patient-years). The incidence rates of the primary outcomes increased across the quartiles of the w-SD of LDL-C (log-rank, P < 0.001). Multivariate Cox regression analysis showed that higher LDL-C variability was associated with an increased risk of ASCVD [hazard ratio (HR), 2.236; 95% confidence interval (CI), 1.684-2.969, P < 0.001] and an increased risk of kidney dysfunction (HR, 3.047; 95% CI 2.240-4.144, P < 0.001). The results were similar after adjusting the w-SD of LDL-C by its related parameters (baseline and mean LDL-C as well as mean total cholesterol), although the mean LDL-C was also an independent risk factor for ASCVD and kidney dysfunction. CONCLUSION: Long-term variability in LDL-C was independently associated with the risk of ASCVD and kidney dysfunction in NS patients.

The quantifying relationship between the remission duration and the cardiovascular and kidney outcomes in the patients with primary nephrotic syndrome.

BACKGROUND: Patients with persistent nephrotic-range proteinuria have a high risk of kidney dysfunction and cardiovascular events. Recently, the maintenance of proteinuria remission has been demonstrated to reduce the risk of kidney endpoint. However, the effect of remission duration on cardiovascular outcomes remains unclear. METHODS: This study enrolled 982 patients with primary nephrotic syndrome who had achieved clinical remission. Remission duration was defined as the maintenance time (months) of the first remission. Arteriosclerotic cardiovascular disease (ASCVD) and kidney dysfunction (ESKD or eGFR reduction >50%) were the endpoints. Survival curves, Cox regression models, restricted cubic spline analysis were used and the cutoff time points were determined. RESULTS: During the 38.3 months of follow-up, 161 (16.4%) patients developed ASCVD (51.3 per 1000 patient-years) and 52 (5.3%) patients developed kidney dysfunction (15.3 per 1000 patient-years). Multivariate analysis showed that remission duration was an independently protective factor to ASCVD, in which each one-year extension associated with a 15% reduction of the risk (HR, 0.854; 95% CI, 0.776 ∼ 0.940, p = .001). The initial time point was seven months for remission to present the protective effect to ASCVD and the maximum time point was 36 months. Remission duration was also an independently protective factor to kidney dysfunction. This effect was shown from the beginning of remission and reached the maximum at 26 months. CONCLUSIONS: The maintenance of proteinuria remission was crucial for the improvement of cardiovascular and kidney outcomes in nephrotic syndrome patients.

Effects of hydroxychloroquine on proteinuria in membranous nephropathy.

BACKGROUND: Many patients with primary membranous nephropathy have severe proteinuria unresponsive to optimized renin-angiotensin-aldosterone system inhibitors (RAASi). We evaluated the efficacy and safety of hydroxychloroquine as an adjunctive agent in membranous nephropathy (MN) treatments. METHODS: We prospectively recruited 126 patients with biopsy-proven primary membranous nephropathy and urinary protein 1-8 g/day while receiving optimized RAASi treatment for ≥ 3 months and well-controlled blood pressure. Forty-three patients received hydroxychloroquine and RAASi (hydroxychloroquine-RAASi group), and 83 patients received RAASi alone (RAASi group). Treatment responses, including proteinuria reduction, complete and partial remission rates, and autoantibody against phospholipase A2 receptor (anti-PLA2R) levels, were compared between the two groups at 6 months and over the long term. RESULTS: At 6 months, the effective response rate (proteinuria reduction > 30%) (57.5% vs. 28.9%, P = 0.002), clinical remission rate (35.0% vs. 15.7%, P = 0.015), and percentage change in proteinuria (- 51.7% vs. - 21.9%, P < 0.001) were higher, and the rate of switching to immunosuppressants (25.0% vs. 45.8%, P = 0.027) was lower in the hydroxychloroquine-RAASi group than in the RAASi group. Hydroxychloroquine administration was an independent protective factor with an effective response (OR 0.37, P = 0.021). In the long term, the clinical remission rate was higher in the HCQ-RAASi group (62.5% vs. 38.6%, P = 0.013). Hydroxychloroquine therapy was associated with a higher rate of anti-PLA2R reduction (< 20 U/ml) (HR 0.28, P = 0.031). We observed no serious adverse events associated with hydroxychloroquine. CONCLUSIONS: Hydroxychloroquine could be an option for patients with membranous nephropathy seeking to achieve proteinuria reduction and anti-PLA2R antibody reduction in addition to optimized RAASi. Randomized controlled trials are needed to confirm these findings. TRIAL REGISTRATION: ChiCTR2100045947, 20210430, retrospectively registered.

Rituximab Therapy for Primary Membranous Nephropathy in a Chinese Cohort.

Background: Rituximab has become one of the first-line therapies for the treatment of moderate and high-risk primary membranous nephropathy (pMN). We retrospectively reviewed 95 patients with pMN who received rituximab therapy and focused on the therapeutic effects and safety of this therapy in a Chinese cohort. Methods: Ninety-five consecutive patients with pMN diagnosed by kidney biopsy received rituximab and were followed up for >6 months. Four weekly doses of rituximab (375 mg/m2) was adopted as the initial administration. Repeated single infusions were administrated to maintain B cell depletion levels of <5 cells/mL. Results: A total of 91 patients completed rituximab therapy with the total dose of 2.4 (2.0, 3.0) g; 64/78 (82.1%) patients achieved anti-PLA2R antibody depletion in 6.0 (1.0, 12.0) months; 53/91 (58.2%) patients achieved clinical remission in 12.0 (6.0, 24.0) months, including complete remission in 18.7% of patients and partial remission in 39.6% of patients. Multivariate logistic regression analysis showed that severe proteinuria (OR = 1.22, P = 0.006) and the persistent positivity of anti-PLA2R antibodies (OR = 9.00, P = 0.002) were independent risk factors for no-remission. The remission rate of rituximab as an initial therapy was higher than rituximab as an alternative therapy (73.1 vs. 52.3%, P = 0.038). Lastly, 45 adverse events occurred in 37 patients, but only one patient withdrew from treatment due to severe pulmonary infection. Conclusion: Rituximab is a safe and effective treatment option for Chinese patients with pMN, especially as an initial therapy.

Complement activation profile of patients with primary focal segmental glomerulosclerosis.

BACKGROUND: Studies on adriamycin mice model suggest complement system is activated and together with IgM contributes to the glomerular injury of primary focal segmental glomerulosclerosis (FSGS). We recently reported primary FSGS patients with IgM and C3 deposition showed unfavorable therapeutic responses and worse renal outcomes. Here we examined the plasma and urinary complement profile of patients with primary FSGS, aiming to investigate the complement participation in FSGS pathogenesis. METHODS: Seventy patients with biopsy-proven primary FSGS were enrolled. The plasma and urinary levels of C3a, C5a, soluble C5b-9, C4d, C1q, MBL, and Bb were determined by commercial ELISA kits. RESULTS: The levels of C3a, C5a and C5b-9 in plasma and urine of FSGS patients were significantly higher than those in normal controls. The plasma and urinary levels of C5b-9 were positively correlated with urinary protein, renal dysfunction and interstitial fibrosis. The plasma C5a levels were positively correlated with the proportion of segmental sclerotic glomeruli. The urinary levels of Bb were elevated, positively correlated with C3a and C5b-9 levels, renal dysfunction, and interstitial fibrosis. The plasma C1q level was significantly decreased, and negatively correlated with urinary protein excretion. Urinary Bb level was a risk factor for no remission (HR = 3.348, 95% CI 1.264-8.870, P = 0.015) and ESRD (HR = 2.323, 95% CI 1.222-4.418, P = 0.010). CONCLUSION: In conclusion, our results identified the systemic activation of complement in human primary FSGS, possibly via the classical and alternative pathway. The activation of complement system was partly associated with the clinical manifestations, kidney pathological damage, and renal outcomes.

Membranous Nephropathy in Pregnancy.

BACKGROUND: Primary membranous nephropathy (pMN) is less common in women of child-bearing age. The kidney risk factors to adverse maternal-fetal outcomes and the effects of pregnancy on pMN process need to be investigated. METHODS: We retrospectively screened all the patients with biopsy-proven pMN from 2008 to 2018. Any cases of pregnancy that occurred at the time of pMN diagnosis or during follow-up were included in the study. Clinical and pathological data were collected from all patients at the time of kidney biopsy and their gestational results were recorded. RESULTS: Of the 27 pregnancies with gestational time of 35.9 ± 4.5 weeks, 10 adverse maternal-fetal events occurred, including fetal loss (11%), preterm delivery (26%), and severe preeclampsia (15%). The kidney parameters were relatively stable with all preserved kidney function. Time-averaged urinary protein (p < 0.001) and serum albumin (p < 0.001), maximum urinary protein (p = 0.001) and minimum serum albumin (p = 0.01) before week 20, anti-phospholipase A2 receptor (PLA2R) positivity (p = 0.03), and no remission during pregnancy (p = 0.004) were risk factors to adverse maternal-fetal outcomes. Time-averaged urinary protein and serum albumin correlated with the birth weight percentile of neonates. CONCLUSIONS: Pregnancy in pMN patients showed risks to adverse maternal-fetal events. Heavy proteinuria, especially before week 20 of gestation, severe hypoalbuminemia, positive anti-PLA2R, and no remission were risk factors to worse outcomes.

Complement activation products in the circulation and urine of primary membranous nephropathy.

BACKGROUND: Complement activation plays a substantial role in the pathogenesis of primary membranous nephropathy (pMN). C5b-9, C3c, MBL, and factor B have been documented in the subepithelial immune deposits. However, the changing of complement activation products in circulation and urine is not clear. METHODS: We measured the circulating and urinary levels of C1q, MBL, C4d, Bb, properdin, C3a, C5a, and sC5b-9, in 134 patients with biopsy-proven pMN, by enzyme-linked immunosorbent assay. All the plasma values were corrected by eGFR and all the urinary values were corrected by urinary creatinine and urinary protein excretion. Anti-PLA2R antibodies were measured in all patients. RESULTS: The plasma complement activation products were elevated both in the patients with and without anti-PLA2R antibodies. C3a levels were remarkably increased in the circulation and urine, much higher than the elevated levels of C5a. C5b-9 was in normal range in plasma, but significantly higher in urine. The urinary C5a had a positive correlation with anti-PLA2R antibody levels and urinary protein. The plasma level of C4d was elevated, but C1q and MBL were comparable to healthy controls. Positive correlations were observed between plasma C4d/MBL and urinary protein, only in the patients with positive anti-PLA2R antibodies but not in those without. The plasma level of Bb was elevated and had positive correlation with urinary protein only in the patients without anti-PLA2R antibodies. CONCLUSION: Complement activation products were remarkable increased in pMN and may serve as sensitive biomarkers of disease activity. The complement may be activated through lectin pathway with the existence of anti-PLA2R antibodies, while through alternative pathway in the absence of antibody.

Plasma Complement Protein C3a Level Was Associated with Abdominal Aortic Calcification in Patients on Hemodialysis.

The complement system plays an important role in cardiovascular disease in patients on hemodialysis. Vascular calcification is also one of the major causes of cardiovascular disease. We want to investigate the relationship between complement activation and vascular calcification in dialyzed patients. One hundred eight hemodialysis patients and 65 heathy controls were enrolled prospectively. Plasma C3a, C5a, mannose-binding lectin (MBL), and membrane attack complex (MAC or C5b-9) levels were detected using ELISA. Plasma C3c, fB, fH, C1q, and C4 levels were measured by immunity transmission turbidity. Abdominal aortic calcification (AAC) was measured by abdomen lateral plain radiograph, and the AAC score was calculated. We identified increased level of MBL and decreased level of C3c and complement factor B compared with normal control. However, C1q, complement factor H, and C4 levels remained at a similar level compared with individuals with normal renal function. The C3a and C5a levels increased, without change of MAC. Forty two of 108 HD patients had the AAC score. C3a levels were correlated with AAC score (r = 0.461, p = 0.002). The median C3a concentration was 238.72 (196.96, 323.41) ng/mL. When evaluated as AAC categories (≤ 4, > 5) with ordinal logistic regression, univariate analyses revealed that higher C3a levels were associated with severe AAC, while multivariate analyses adjusted for age, sex, and calcium level showed that higher C3a levels (OR, 6.28 (1.25-31.69); p = 0.03) were associated with severe AAC. The areas under the curve (AUC) for C3a to diagnose severe abdominal aortic calcification were 0.75(0.58-0.92, 0.01). The complement system was activated in patients on hemodialysis. Higher C3a levels are independently associated with severe AAC. Plasma C3a might have a diagnostic value for the severe AAC in HD patients.

Antibodies against M-Type Phospholipase A2 Receptor May Predict Treatment Response and Outcome in Membranous Nephropathy.

BACKGROUND: Anti-phospholipase A2 receptor (PLA2R) antibodies are specific to the diagnosis of primary membranous nephropathy (pMN). The prevalence of positive antibodies varies among different cohorts. Still there is discrepancy in regard to the association between antibody levels and clinical courses, and the prognostic value of antibodies to treatment responses and kidney outcomes. METHODS: Three hundred fifty-nine consecutive kidney biopsy-proven pMN patients were enrolled. Anti-PLA2R antibodies were detected by immunofluorescence assay (IFA) and enzyme-linked immunosorbent assay (ELISA). RESULTS: The positive rate of anti-PLA2R antibodies in pMN was 65.2% (234/359) by IFA and 56.3% (202/359) by ELISA. The antibody level presented positive correlation with urinary protein excretion (r = 0.164, p = 0.002). Detectable antibodies and a higher level of proteinuria were independent risk factors to no-remission after treatments (OR 3.15, p = 0.004; OR 1.11, p = 0.006) and were independent risk factors to no-spontaneous remission (OR 2.20, p = 0.011; OR 1.36, p < 0.001). A higher level of antibodies (hazard ratio 1.002, p = 0.019) was the independent risk factor to kidney dysfunction during follow-up. The antibodies turned negative in 42 out of 52 (80.8%) patients who achieved clinical remission, while they remained positive in all patients of the no-response category (p < 0.001). CONCLUSION: We documented correlations between anti-PLA2R antibody levels and clinical severity in this large Chinese pMN cohort. Antibody positivity and higher antibody level might predict treatment responses and kidney outcomes of pMN.

HLA class II alleles differing by a single amino acid associate with clinical phenotype and outcome in patients with primary membranous nephropathy.

Genome-wide associations and HLA genotyping have revealed associations between HLA alleles and susceptibility to primary membranous nephropathy. However, associations with clinical phenotypes and kidney outcome are poorly defined. We previously identified DRB1*1501 and DRB1*0301 as independent risk alleles for primary membranous nephropathy. Here, we investigated HLA associations with demographic characteristics, anti-phospholipase A2 receptor (PLA2R) antibody, treatment response and kidney outcome after a median follow-up of 52 months in 258 patients. DRB1*0301, but not DRB1*1501, was associated with a significantly higher level of PLA2R antibody (odds ratio 1.58, 95% confidence interval 1.13-2.22). Although DRB1*1502, which differs from DRB1*1501 by a single amino acid, was not a risk allele for primary membranous nephropathy (odds ratio 1.01), it was associated with significantly lower estimated glomerular filtration rates both at baseline (1.79, 1.18-2.72) and at last follow-up (1.72, 1.17-2.53), a significantly worse renal outcome by Kaplan-Meier analysis and a significantly higher risk of end-stage renal disease by Cox regression analysis (hazard ratio 4.52, 1.22-16.74). Nevertheless, the absence of remission remained the only independent risk factor for end-stage renal disease by multivariate analysis. DRB1*1502 was also associated with a significantly higher median PLA2R antibody level [161.4 vs. 36.3 U/mL] and showed interaction with DRB1*0301 for this variable. Thus, HLA genes control PLA2R antibody production and primary membranous nephropathy severity and outcome. Additionally, DRB1*1502 behaves like a modifier gene with a strong predictor value when associated with HLA risk alleles. Other modifier genes need further investigations in larger cohorts.

Clinical implications of pathological features of primary membranous nephropathy.

BACKGROUND: The clinical outcome varies considerably in primary membranous nephropathy (pMN). Risk factors for kidney prognosis include ageing, male gender, persistent heavy proteinuria, decreased eGFR at presentation, persistent elevation of anti-PLA2R antibodies, no remission, and so on. It was controversial whether the histopathological features of pMN could predict treatment response and kidney outcome. METHODS: A retrospective study was conducted in 371 patients with biopsy-proven pMN. Pathological parameters included immunofluorescence staining, membranous Churg's stages, sclerosis, crescent, focal segmental sclerosis lesion, chronic and acute tubulointerstitial injury. The fluorescence intensity was determined: 0, negative; 1, weak; 2, moderate; 3, strong; 4, glaring. Chronic tubulointerstitial injury was graded by the involved area: 0, 0-5%; 1, 6-25%; 2, 26-50%; 3, > 50%. RESULTS: We found that patients with higher intensity of C3 staining, advanced membranous stage, and more severe chronic tubulointerstitial injury presented with higher positivity rate of anti-PLA2R antibodies, higher levels of urinary protein excretion and serum creatinine, and lower level of serum albumin. Univariate Cox regression analysis showed that severe (grade = 3) chronic tubulointerstitial injury was a risk factor to the kidney outcome of ESKD (HR = 61.02, 95%CI, 7.75-480.57, P < 0.001) and over 50% reduction of eGFR (HR = 4.43, 95%CI, 1.26-15.6, P = 0.021). Multivariate analysis demonstrated it as an independent risk factor to ESKD (HR = 25.77, 95% CI, 1.27-523.91, P = 0.035). None of the pathological parameters exerted any influence on treatment response (P > 0.05). CONCLUSIONS: We found the prognostic role of chronic tubulointerstitial injury to the kidney outcome of pMN. This study highlighted the value of kidney biopsy under the widespread usage of anti-PLA2R antibodies for diagnosis and prognosis.

Clinical and prognostic significance of glomerular C1q deposits in primary MN.

BACKGROUND: Although complement activation is believed to be important in mediating PMN, the pathways involved and clinical consequences remain controversial. Many cases of idiopathic or primary membranous nephropathy (PMN) present with subepithelial C1q deposits along with IgG and C3 on glomerular capillary walls but without deposits of IgA or IgM ("full house") by immunofluorescence or any causes of secondary MN. We sought to define the clinical and pathological significance of these C1q deposits in PMN by comparing a variety of clinical parameters, outcomes and other serum and urine factors in patients with and without significant glomerular C1q deposits. METHODS: Two-hundred eighty-eight patients with biopsy-proven PMN were enrolled. We compared the clinical and pathological features, treatment responses and kidney outcomes, between patients with and without C1q deposition. Circulating anti-PLA2R antibodies and complement components in plasma and urine were detected by ELISA. RESULTS: Glomerular C1q deposition was detected on capillary walls by immunofluorescence in 66/288 (22.9%) patients. C1q-positive patients presented with lower concentrations of serum IgG (5.3 ±â€¯3.1 vs. 6.6 ±â€¯3.5 g/l, p = 0.008), a higher frequency of IgA (37.9% vs. 15.8%, p < 0.001), IgM (48.5% vs. 31.5%, p = 0.011) and C3c (100% vs. 88.3%, p = 0.004) deposits in glomeruli and more stage III of MN (24.2% vs. 11.7%, p < 0.001) by pathologic criteria. Other features, including gender, age, anti-PLA2R antibody positivity and concentrations, proteinuria, albumin and serum creatinine, were not different between the patients with and without C1q deposition (p > 0.05). The IgG subclasses of anti-PLA2R antibodies in circulation or in glomeruli showed no difference (p > 0.05). C1q deposition, and C1q concentrations in circulation and urine had no apparent effect on the treatment responses or kidney outcomes (p > 0.05). CONCLUSION: The classical pathway of complement is activated in some patients with PMN, but may not play an essential role in mediating the kidney injury seen in this disease.

Prevalence and risk factors for vascular calcification in Chinese patients receiving dialysis: baseline results from a prospective cohort study.

OBJECTIVE: With limited data available on calcification prevalence in chronic kidney disease (CKD) patients on dialysis, the China Dialysis Calcification Study (CDCS) determined the prevalence of vascular/valvular calcification (VC) and association of risk factors in Chinese patients with prevalent hemodialysis (HD) or peritoneal dialysis (PD). METHODS: CKD patients undergoing HD/PD for ≥6 months were enrolled. Prevalence data for calcification and medical history were documented at baseline. Coronary artery calcification (CAC) was assessed by electron beam or multi-slice computed tomography (EBCT/MSCT), abdominal aortic calcification (AAC) by lateral lumbar radiography, and cardiac valvular calcification (ValvC) by echocardiography. Serum phosphorus, calcium, intact parathyroid hormone (iPTH), and 25-hydroxyvitamin D and FGF-23 were evaluated. A logistic regression model was used to evaluate the association between risk factors and VC. RESULTS: Of 1,497 patients, 1,493 (78.3% HD, 21.7% PD) had ≥1 baseline calcification image (final analysis cohort, FAC) and 1,423 (78.8% HD, 21.2% PD) had baseline calcification data complete (BCDC). Prevalence of VC was 77.4% in FAC (80.8% HD, 65.1% PD, p < .001) and 77.5% in BCDC (80.7% HD, 65.8% PD). The proportion of BCDC patients with single-site calcification were 20% for CAC, 4.3% for AAC, and 4.3% for cardiac valvular calcification (ValvC), respectively. Double site calcifications were 23.4% for CAC and AAC, 6.5% for CAC and ValvC, and 1.1% for AAC and ValvC, respectively. In total, 17.9% patients had calcification at all three sites. CONCLUSIONS: High prevalence of total VC in Chinese CKD patients will supplement current knowledge, which is mostly limited, contributing in creating awareness and optimizing VC management.

T cell responses to peptides of Goodpasture autoantigen in patients with anti-glomerular basement membrane disease.

AIM: Cell-mediated autoimmunity, especially autoreactive T cells, is crucial in the initiation of anti-glomerular membrane (GBM) disease. Epitopes for T cells on Goodpasture autoantigen are not fully defined. This study investigated T cell epitopes in anti-GBM patients, aiming to identify the epitopes and their clinical significance. METHODS: Peripheral blood mononuclear cells (PBMC) were collected from 13 patients with anti-GBM disease. Twenty-four overlapping linear peptides were synthesized covering the whole sequence of human α3(IV)NC1. PBMC response to each peptide was detected by proliferation assay. Their associations with clinical features were further analyzed. RESULTS: Peripheral blood mononuclear cells proliferative responses to linear peptides on α3(IV)NC1 could be detected in all patients. Five major epitopes were identified as stimulatory in over half of the patients: α3(IV)NC1127-148 (P14) (69.2%), α3(IV)NC1159-178 (77.8%), α3(IV)NC1179-198 (55.6%), α3(IV)NC1189-208 (P19) (75.0%) and α3(IV)NC1141-154 (57.1%). P14 and P19 were highly recognized in patients comparing with healthy controls (69.2% vs. 0.0%, P = 0.011; 75.0% vs. 0.0%, P = 0.021, respectively). CONCLUSION: T cell proliferation to linear epitopes was detected in human anti-GBM disease. α3127-148 was a mutual T and B cell epitope, implying its initial role in epitope spreading process.

Rituximab for non-responsive idiopathic membranous nephropathy in a Chinese cohort.

Background: Rituximab had been shown to be effective in inducing remission of nephrotic syndrome in patients with idiopathic membranous nephropathy (iMN). This study applied rituximab therapy for 36 non-responsive iMN patients to investigate its effects and safety. Methods: Thirty-six iMN patients who were non-responsive to prior immunosuppression were enrolled. Rituximab was used for B-cell depletion in patients, with a goal of <5 B cells/mm3 in the circulation. After completing the study, patients were monitored for a median of 12.0 months [interquartile range (IQR) 9.0-19.3]. Results: Fifteen of the 36 (41.7%) patients achieved partial (n = 13) or complete (n = 2) response to the rituximab treatment. The median time for achieving partial response was 4.0 months (IQR 3.0-6.0). The responders had relatively lower levels (118 ± 112 U/mL versus 345 ± 357 U/mL, P = 0.03) of anti-phospholipase 2 receptor (PLA2R) antibodies before the rituximab treatment, and all of them achieved antibody depletion or reduction. B-cell depletion was achieved in all patients. Renal function remained stable in the responders [estimated glomerular filtration rate (eGFR) 53.3 ± 40.5 versus 55.6 ± 33.2 mL/min/1.73 m2, P = 0.67] but deteriorated in the non-responders (eGFR 57.5 ± 29.3 versus 45.3 ± 32.8 mL/min/1.73 m2, P = 0.02) with two patients reaching end-stage kidney disease. Two of the 15 patients relapsed during the follow-up period with anti-PLA2R antibody reoccurrence and B-cell reconstitution. The second course of rituximab combined with tacrolimus induced a faster partial response again in one patient. Conclusion: Rituximab therapy could induce remission of proteinuria and stabilization of renal function in non-responsive iMN patients, even those with damaged renal function. Anti-PLA2R antibodies may be used as a marker for individualized rituximab dosage and treatment monitoring.

Circulating Antibodies against Thrombospondin Type-I Domain-Containing 7A in Chinese Patients with Idiopathic Membranous Nephropathy.

BACKGROUND AND OBJECTIVES: Thrombospondin type-I domain-containing 7A (THSD7A) was recently identified as the target antigen in about 10% of patients with M-type phospholipase A2 receptor (PLA2R)-negative membranous nephropathy in European and North American populations. The prevalence of THSD7A in other populations and their clinical associations deserve further clarification. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Immunofluorescence assay was performed to investigate anti-THSD7A antibodies in 578 consecutive patients with biopsy-proven idiopathic membranous nephropathy, 114 patients with secondary membranous nephropathy, 64 disease controls, and 20 healthy controls. Glomerular expression of THSD7A antigen was examined by immunohistochemistry. Anti-PLA2R antibodies and glomerular PLA2R expression were also screened. RESULTS: Among the 578 patients with idiopathic membranous nephropathy, 12 (2%) patients were identified as THSD7A-positive: ten patients were THSD7A-positive alone, which accounted for 16% (ten of 64) of PLA2R-negative patients; two patients were dual-positive for both anti-THSD7A and anti-PLA2R antibodies and showed enhanced expression of both antigens colocalized in glomeruli. Among the 114 patients with secondary membranous nephropathy, one among 44 (2%) patients with cancer had anti-THSD7A antibodies, whereas 18 of 44 (41%) had anti-PLA2R antibodies. No anti-THSD7A antibody was detected in other disease controls or healthy individuals. Clinical features were comparable between the patients with and without THSD7A. During follow-up, two patients who achieved remission had a clearance of circulating antibodies against THSD7A, whereas antibodies increased in parallel with proteinuria in a patient with a relapse. CONCLUSIONS: THSD7A-associated membranous nephropathy has a low prevalence in Chinese patients. The double-positive patients suggest dual autoimmune responses.

Comparison of bioimpedance and clinical methods for dry weight prediction in maintenance hemodialysis patients.

BACKGROUND: Bioelectrical impedance analysis (BIA) is a promising technique to evaluate dry weight. We compared the dry weight calculated by the three BIA equations Carlo Basile (CB) , Yanna Dou (YD) and the body composition spectroscopy (BCS) with clinical evaluation in maintenance hemodialysis (MHD) patients. METHODS: The dry weight of enrolled MHD patients (DWClin) was evaluated under strict clinical surveillance. The whole-body resistances at 50 kHz, intra- and extracellular resistances were measured to calculate the dry weight (DWCB, DWYD and DWBCS) using each of the three equations. RESULTS: Neither DWCB nor DWBCS were statistically different compared to DWClin (DWCB 63.2 ± 17.2 vs. 63.1 ± 16.1 kg; DWBCS 62.8 ± 16.8 vs. 63.1 ± 16.1 kg, p > 0.05). DWYD was significantly lower than DWClin (DWYD 62.0 ± 16.1 vs. 63.1 ± 16.1 kg, p < 0.05). The bias between DWCB and DWClin was the smallest among these three methods (ΔDWCB -0.1 ± 1.4 kg; ΔDWYD 1.1 ± 2.9 kg; ΔDWBCS 0.3 ± 1.8 kg). CONCLUSION: The CB equations have better consistency with clinical dry weight in MHD patients.