CD206+CD68+ mono-macrophages and serum soluble CD206 level are increased in antineutrophil cytoplasmic antibodies associated glomerulonephritis.

BACKGROUND: Antineutrophil Cytoplasmic Antibodies (ANCA) associated glomerulonephritis (AGN) is a group of autoimmune diseases and mono-macrophages are involved in its glomerular injuries. In this study, we aim to investigate the role of CD206+ mono-macrophages in AGN. METHODS: 27 AGN patients (14 active AGN, 13 remissive AGN) together with healthy controls (n = 9), disease controls (n = 6) and kidney function adjusted controls (n = 9) from Department of Nephrology, Ruijin hospital were recruited. Flow cytometry was used to study proportion of CD206+ cells in peripheral blood. Immunohistochemistry for CD206 staining was performed and CD206 expression was scored in different kidney regions. Serum soluble CD206 (sCD206) was measured by enzyme-linked immunosorbent assay (ELISA). We also generated murine myeloperoxidase (MPO) (muMPO) ANCA by immunizing Mpo-/- mice. Mouse bone marrow-derived macrophages (BMDMs) from wild C57BL/6 mice and peripheral blood mononuclear cell (PBMC) derived macrophages from healthy donors were treated with MPO ANCA with or without its inhibitor AZD5904 to investigate the effects of MPO-ANCA on CD206 expression. RESULTS: The proportion of peripheral CD206+CD68+ cells in active AGN patients were significantly higher than that in remissive patients (p < 0.001), healthy controls (p < 0.001) and kidney function adjusted controls (p < 0.001). Serum sCD206 level in active AGN patients was higher than that in healthy controls (p < 0.05) and remissive patients (p < 0.01). Immunohistochemistry showed CD206 was highly expressed in different kidney regions including fibrinoid necrosis or crescent formation, glomeruli, periglomerular and tubulointerstitial compartment in active AGN patients in comparison with disease controls. Further studies showed MPO ANCA could induce CD206 expression in BMDMs and PBMC derived macrophages and such effects could be reversed by its inhibitor AZD5904. CONCLUSION: ANCA could induce CD206 expression on mono-macrophages and CD206+ mono-macrophages are activated in AGN. CD206 might be involved in the pathogenesis of AAV and may be a potential target for the disease.

Evaluating renal outcome of ANCA-associated renal vasculitis: comparative study of two histopathological scoring systems.

OBJECTIVES: Renal risk score (RRS) and chronicity score (CS) are both newly proposed tools to predict end stage renal disease (ESRD) which could be applicable in antineutrophil cytoplasmic antibody (ANCA)-associated renal vasculitis patients. Their predictive value has not been fully studied and compared. METHODS: 252 patients with newly biopsy-proven ANCA-associated renal vasculitis were retrospectively studied at the Department of Nephrology, Ruijin Hospital, China. Patients were evaluated with RRS and CS for clinical factors, pathological lesions and outcome. Their predictive value of renal survival was also compared. RESULTS: The median RRS score point at diagnosis was 6 (interquartile range [IQR] 0-9) and CS score point was 4 (IQR 3-7). In accordance with severity of RRS category and CS grade, percentage of hypertensive patients, dialysis dependency, and level of proteinuria increased accordingly. Significant differences were found regarding dialysis dependency within RRS and CS groups (p<0.001 and p<0.01 respectively). The addition of RRS or CS scoring scheme to the base model of dialysis dependency significantly improved discrimination. The C statistic, integrated discrimination improvement and net reclassification improvement were significantly increased by adding either RRS/CS or both. Furthermore, RRS had better ROC. CONCLUSIONS: Among ANCA associated renal vasculitis patients, RRS and CS achieved similar discrimination, but the discrimination of RRS was superior.

A regulatory role for CD72 expression on B cells and increased soluble CD72 in primary Sjogren's syndrome.

BACKGROUND: CD72, a co-receptor of B cell receptor (BCR), has been reported to have both positive and negative effects on B cell functions in several immunological diseases. The B cell plays an important role in the pathogenesis of primary Sjogren's syndrome (pSS). However, whether CD72 is involved in the process remains unknown. This study aimed to observe the possible role of CD72 in the pathogenesis of pSS. RESULTS: A total of 60 cases who fulfilled the American-European Consensus Group (AECG) criteria for the diagnosis of pSS and 61 gender and age-matched healthy controls were recruited in this study. The percentage of CD72+ B cells was 85.31 ± 8.37% in pSS patients and 76.91 ± 8.50% in healthy controls(p < 0.001). The percentage of CD72+ B cells was correlated to serum IgG levels in patients [ß = 0.018(0.001-0.036), p = 0.034]. The level of serum soluble CD72 was significantly higher in pSS patients than the one in healthy controls (0.41 (0.29) vs 0.07 (0.08) ng/mL, p < 0.001). CONCLUSIONS: The percentage of CD72+ B cells was upregulated in pSS patients and was correlated to the serum IgG level, which revealed the hyperactivity of B cells in this disease. The serum soluble CD72 level was also increased in pSS patients. These results indicated a potential role of CD72 in the pathogenesis of pSS.

Acute Kidney Disease Increases the Risk of Post-Kidney Biopsy Bleeding Complications.

INTRODUCTION: Kidney biopsy, providing the insightful information for most kidney diseases, is an invasive diagnostic tool with certain risks ranging from the least severe macroscopic hematuria to the most severe life-threatening bleeding necessitating renal artery embolization. We aimed to compare the postbiopsy bleeding complications between 2 common methods and to further explore the risk factors of bleeding complications in patients using the negative pressure suction puncture (NPS) method. METHODS: We retrospectively collected the data from percutaneous native kidney biopsies in 2016. The clinical, laboratory tests, pathological findings, and the occurrence of bleeding complications following kidney biopsy were analyzed. The kidney biopsy was performed in our center by experienced nephrologists with 2 different methods, namely, NPS method and real-time ultrasound-guided needle (RTU) method. We compared rates of complications between 2 methods and evaluated univariate and multivariate association of risk factors with bleeding complications in the NPS group. RESULTS: 626 kidney biopsies were performed between January 2016 and December 2016. There were 83.2% (521/626) participants in the NPS group and 16.8% (105/626) in the RTU group. There were more participants in the RTU group needing >1 needle pass during biopsy than those in the NPS group (61.0 vs. 14.7%, p < 0.001). Acute kidney disease (AKD) occurred before the procedure of kidney biopsy accounted for 13.8% (72/521) in the NPS group and 1.9% (2/105) in the RTU group. The renal pathological findings revealed higher number of glomeruli in the NPS group than in the RTU group (26.8 ± 13.0 vs. 17.2 ± 8.6, p < 0.001). The incidence of bleeding complications in the NPS group was lower than that in the RTU group (9.2 vs. 21.9%, p < 0.01). Logistic multivariate regression showed that AKD was independently associated with bleeding complications after kidney biopsy in the NPS group. CONCLUSION: Regarding the bleeding risk, there was noninferiority of NPS over RTU. AKD contributes to higher risks of bleeding complications after kidney biopsy.

Serum pre-albumin is prognostic for all-cause mortality in patients with community-acquired and post-operative acute kidney injury.

BACKGROUND: Acute kidney injury (AKI) is a critical clinical syndrome characterised by a rapid decrease in renal filtration, with the accumulation of products of metabolism such as creatinine and urea. In recent years, the incidence of AKI has increased not only in critically ill hospitalised patients but also in community patients. Also, the prognosis of AKI is poor and treatment is limited in these populations. The increasing incidence and poor prognosis may be the reasons why more investigators are involved in epidemiological and risk factor analysis of AKI. AIMS: To investigate the effects of these risk factors on outcomes in both community-acquired and hospitalised AKI populations to provide certain guidance for clinics and to explore the prognostic value of prealbumin on all-cause mortality in patients with community-acquired and post-operative AKI. METHODS: From 2000 to 2010, 477 patients diagnosed with AKI and treated in the Department of Nephrology, Ruijin Hospital, Shanghai Jiaotong University, were enrolled in the community-acquired AKI (CA-AKI) group and 138 patients diagnosed with AKI after an operation were enrolled in the post-operative AKI (PO-AKI) group. Data were collected at AKI onset and 1 year after discharge and analysed retrospectively. RESULTS: Compared with PO-AKI patients, more patients in CA-AKI group had chronic kidney disease, obesity and hyperlipidaemia, and fewer patients had cerebrovascular disease (CVD), anaemia, shock or arrhythmia. Risks for CA-AKI were atherosclerosis, CVD, arrhythmia, multiple organ dysfunction syndrome and usage of vasoactive agents, and risks for PO-AKI were elderly, arrhythmia and requirement of renal replacement therapy. A higher level of serum PA was associated with a better outcome in the CA-AKI group (hazard ratio 0.92, 95% confidence interval 0.85-0.996) and PO-AKI group (hazard ratio 0.91, 95% confidence interval 0.84-0.99). In the CA-AKI group, the cumulative survival rate of patients with a normal PA level (PA >20 mg/dL) was higher than that among patients with a lower PA (PA ≤20 mg/dL; 95.4% vs 88.3%, P = 0.031). Similarly, in the PO-AKI group, a normal PA level was associated with a higher survival rate (74.1% vs 47.6%, P = 0.019). CONCLUSION: Serum PA may serve as a prognostic marker for CA-AKI and PO-AKI, and further research is warranted to confirm this finding.

A validation study of crescents in predicting ESRD in patients with IgA nephropathy.

BACKGROUND: A working group on the Oxford classification of IgA nephropathy (IgAN) recently reported that crescents detected in kidney tissue predicted a worse renal outcome. However, this finding must be validated in independent cohorts before it can be widely applied to clinical practice. METHODS: Biopsy-proven IgAN patients were continuously recruited from two large renal centers in China from 1989 to 2014. All patients were followed for more than 1 year unless end stage renal disease (ESRD) occurred within 12 months. Crescents were defined as focal cellular or fibrocellular crescent formations. IgAN patients without detectable crescents were recruited to the C0 group. Patients with crescents in less than or more than 1/4 of all glomeruli were recruited to the C1 or C2 group, respectively. Primary outcome was defined as the time to ESRD, and the secondary outcome was defined as the time to an estimated glomerular filtration rate (eGFR) decline equal to or greater than 50% or to ESRD. RESULTS: In total, 1152 IgAN patients were recruited in this study. Among all patients, 53.7% were in the C0 group, 38.8% were in the C1 group, and 7.5% were in the C2 group. Compared to patients in the C0 group, patients in the C1 or C2 group were younger, had more urinary protein excretion and lower eGFR, and presented with more severe mesangial hypercellularity, endocapillary proliferation or tubular atrophy/interstitial fibrosis. After 45 months of follow-up, ESRD had occurred in 80 (12.9%), 46 (10.3%) and 18 (20.9%) of patients in the C0, C1 and C2 groups, respectively. By multivariable Cox regression analysis, inclusion in the C1 (HR = 1.07, 95% CI 0.71-1.63), C2 (HR = 0.84, 95% CI 0.41-1.73), or C1 or C2 group (HR = 1.02, 95% CI 0.68-1.52) was not associated with a higher rate of ESRD than inclusion in the C0 group after adjusting for age, gender, eGFR, mean arterial pressure (MAP), MEST scores, and immunosuppressive treatment. However, in patients with nephrotic-range proteinuria, patients in either the C1 or C2 group had a higher rate of the primary outcome, ESRD (HR = 2.54, 95% CI 1.14-5.66) after adjusting for age, gender, eGFR, MAP, MEST scores, and immunosuppressive treatment. Similar results were found when we evaluated the association between crescents and the secondary outcome. CONCLUSIONS: IgAN patients with crescents had more severe clinical and pathological manifestations than those without crescents. However, we failed to replicate the association between crescents and renal function progression in Chinese IgAN patients followed for more than 1 year.

Glucocorticoids in the treatment of patients with primary focal segmental glomerulosclerosis and moderate proteinuria.

BACKGROUND: To compare the efficacy of glucocorticoids in primary focal segmental glomerulosclerosis (pFSGS) patients with moderate proteinuria. Registered at http://www.chictr.org.cn/ , study No. ChiCTR-OPN-17012789. METHODS: pFSGS patients with urine protein between 1.0 and 3.5 g/24 h were recruited from 2006 to 2016. No decline in urine protein > 50% was observed after 2 months of run-in angiotensin-converting enzyme inhibitors/angiotensin-receptor blockers (ACEI/ARB) treatment. Patients were assigned to study group (glucocorticoids with ACEI/ARB) or control group (ACEI/ARB without glucocorticoids). Variables including 24-h urinary protein, serum albumin and serum creatinine during the trial were recorded. Remission was defined as proteinuria < 0.3 g/24 h or declined > 50%, and our composite end point as > 30% decrease of eGFR or eGFR < 30 ml/min. RESULTS: A total of 102 patients were enrolled (study group N = 52, control group N = 50), and the median follow-up time was 36 (12-117) months without significant difference between groups. During the 12-month follow-up, the remission rate was significantly higher in study group [73.1 vs 50.0% (P = 0.01)], and the initial median response time was 3 months in the study group while 6 in the control group. The end point was reached by 22.2% cases in study group, and 42.0% in control. The medium survival times were study group 72 months and control 57 (P = 0.03). Minor adverse reactions were observed in 10 patients (study group N = 8, control group N = 2). CONCLUSIONS: Additional glucocorticoids therapy is more efficacious compared to ACEI/ARB alone in the treatment of patients with pFSGS and moderate proteinuria.

Combination Cyclophosphamide/Glucocorticoids Provide Better Tolerability and Outcomes versus Glucocorticoids Alone in Patients with Sjogren's Associated Chronic Interstitial Nephritis.

BACKGROUND: Steroid therapy has become an effective option for patients with primary Sjogren's syndrome with tubulointerstitial nephritis (TIN), while the use of cytotoxic agents is still debated. Our study aimed to compare the clinical outcomes of patients treated with cyclophosphamide (CTX) combined with glucocorticoids with those of patients treated with glucocorticoids alone. METHODS: All patients with primary Sjogren's syndrome with chronic TIN admitted to the Division of Nephrology, Ruijin Hospital, from January 1, 2002, to April 30, 2016, and treated with steroids alone or combined with CTX were included. The immunological prognosis, improvements of renal function, and acquired tubular defects of the patients were retrospectively compared between the 2 therapeutic groups. RESULTS: A total of 70 cases were included. Of these, 36 were diagnosed by renal biopsy. A total of 56 patients were treated with glucocorticoids alone, while 14 patients received glucocorticoids combined with CTX. There were no significant differences in clinical characteristics and laboratory parameters between the 2 therapeutic groups at baseline. Compared with patients in the steroid group, patients in the CTX group showed better estimated glomerular filtration rate (eGFR) improvement (21.35 ± 19.63 vs. 2.72 ± 19.11 mL/min/1.73 m2, p = 0.006) but a similar decline in immunoglobulin G (IgG; 450 [interquartile range, IQR 910] vs.176 [IQR 1,910] mg/dL, p = 0.93) at 12 months of follow-up. CTX therapy was associated with better eGFR improvement (ß = 12.96 [2.95-22.97]) even after adjusting for dry mouth, anti-Sjögren's-syndrome-related antigen A and anti-Sjögren's-syndrome-related antigen B positivity, hemoglobin, initial steroid dose, and baseline eGFR by linear regression analyses. Subgroup analyses revealed that the beneficial effects of CTX therapy on renal function were only observed in patients with baseline IgG ≥1,560 mg/dL or eGFR <90 mL/min/1.73 m2. The urine α1-microglobulin improvement was better in the CTX group than in the steroid group at 12 months of follow-up (ß = 1.29, 95% CI 0.56-2.02, p = 0.001). CONCLUSIONS: CTX therapy is suggested for primary Sjogren's syndrome patients with chronic TIN, especially those with higher IgG levels and abnormal renal function at baseline.

Genetic Features of Chinese Patients with Gitelman Syndrome: Sixteen Novel SLC12A3 Mutations Identified in a New Cohort.

BACKGROUND: Gitelman syndrome (GS) is an autosomal recessive renal tubulopathy caused by inactivating mutations in the SLC12A3 gene. Although hundreds of different mutations across the SLC12A3 gene have been reported worldwide, data from mainland China are limited. We investigated the clinical manifestations and genetic features of Chinese patients with GS. METHODS: Fifty-four unrelated Chinese patients with clinically diagnosed GS were included. Clinical manifestations and biochemical parameters were collected and analyzed. All exons and flanking regions of the SLC12A3 and CLCNKB genes were screened by direct sequencing. RESULTS: Weakness was the most commonly reported symptom in this cohort of patients with GS. In gender-based analyses, higher systolic blood pressure and urine protein excretion were observed in male patients. For genetic screening, 2 pathogenic SLC12A3 mutations were identified in 38 patients (70.4%), 1 mutation in 11 patients (20.4%) and no mutation in 5 patients (9.3%). In total, 42 distinct pathogenic mutations throughout SLC12A3 were identified; 16 were novel, including 9 missense, 1 deletion, 1 insertion, 3 splice site and 2 nonsense mutations. Eleven mutations were recurrently found in different patients. Among them, T60M and D486N were identified in 11 individuals. No CLCNKB mutations were found. CONCLUSION: Sixteen novel SLC12A3 pathogenic mutations were identified in a cohort of Chinese patients with GS. T60M and D486N were most frequent and appear to be important candidate alleles in Chinese patients with GS.

The importance of sensitive screening for abnormal glucose metabolism in patients with IgA nephropathy.

AIM: To investigate the prevalence of abnormal glucose metabolism, insulin resistance (IR) and the related risk factors in IgA nephropathy (IgAN) patients. METHODS: We analyzed oral glucose tolerance test (OGTT) and clinical data of 107 IgAN patients and 106 healthy controls. Glucose metabolism, homeostasis model assessment of insulin resistance (HOMA-IR) and the insulin sensitivity index (ISI) of both groups were evaluated. RESULTS: The prevalence of abnormal glucose metabolism was significantly higher in the IgAN group than in the control group (41.12% vs. 9.43%, p < 0.001), while the prevalence of IR between the two groups was not significantly different. IgAN patients have significantly higher fasting blood glucose, fasting insulin, OGTT 2-hour blood glucose, OGTT 2-hour insulin, HOMA-IR, and lower ISI than healthy controls. Triglyceride (OR = 2.55), 24-hour urine protein excretion (OR = 1.39), and age (OR = 1.06) were independent risk factors for abnormal glucose metabolism in IgAN patients. BMI, eGFR, 24-hour urine protein excretion, triglyceride, fasting blood glucose, fasting insulin, OGTT 2-hour blood glucose, and OGTT 2-hour insulin were significantly higher in IgAN patients with IR than in IgAN patients without IR, while HDL and ISI were significantly lower. BMI, serum albumin, and 24-hour urine protein excretion were correlated factors of IR in IgAN patients. CONCLUSIONS: Our study highlighted that abnormal glucose metabolism was common in IgAN patients. Triglyceride and 24-hour urine protein excretion were significant risk factors for abnormal glucose metabolism. Therefore, sensitive screening for glucose metabolism status and timely intervention should be carried out in clinical work.

Clinical and pathological study on patients with primary antineutrophil cytoplasmic autoantibody-associated vasculitis with renal immune complex deposition.

BACKGROUND: Traditionally, antineutrophil cytoplasmic autoantibody-associated vasculitis (AAV) is histologically characterized by pauci-immune glomerulonephritis. However, more and more literature has reported immune complex (IC) deposits to be found in renal specimen from patients with AAV. The role that these IC deposits play in the development of AAV, as well as their clinical and pathological significance, is worthy of studying. OBJECTIVES: The objective of this study was to analyze the clinical and pathological characteristics of Chinese patients with AAV having renal IC deposition. METHODS: A retrospective study was performed on 34 patients with AAV in Shanghai Ruijin Hospital with renal IC deposition. Clinical and pathological data were collected and studied and compared with other 76 AAV patients having classic pauci-immune glomerulonephritis. RESULTS: Thirty-four patients were enrolled in this study, with a mean age of 56.4 ± 16.4 years and a male-female ratio of 1:1.3 (19/15). Twenty-seven patients (79.4%) had impaired renal function, with an average serum creatinine of 4.4 ± 3.2 mg/dL. C3 (82.4%) and immunoglobulin M (50%) were the most common IC deposits observed in the kidneys. During the follow-up (median, 39 months), 6 patients (17.7%) died, and 11 (32.4%) finally progressed to end-stage renal disease despite immunosuppressive therapy. Compared with patients having classic pauci-immune glomerulonephritis, patients with renal IC deposits had similar clinical and laboratory features except for more proteinuria (2374 ± 2221 vs 1444 ± 1956 mg/24 h, P = 0.002), a higher prevalence of nephrotic syndrome (30.3% vs 9.6%, P = 0.007) and hypocomplementemia (86.8 ± 33.1 vs 110 ± 45.5 mg/dL, P = 0.029), and also a higher risk for progressing to end-stage renal disease (32.4% vs 13.1%, P = 0.018). CONCLUSIONS: Patients with AAV with renal IC deposition might have a worse renal prognosis than those having classic pauci-immune glomerulonephritis.

Clinical analysis of ANCA-associated renal vasculitis patients with chronic dialysis.

OBJECTIVE: Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) constitute a subgroup of life-threatening diseases which affects the kidney in more than half of the patients at diagnosis. Currently, little has been published focusing on AAV patients with dialysis. We analysed AAV patients with chronic dialysis to provide more detailed information. METHODS: From 1997 to 2011, AAV patients complicated by renal involvement resulting in end-stage renal disease (ESRD) and had undergone haemodialysis (HD) or peritoneal dialysis (PD) for at least 3 months in Shanghai Ruijin hospital were retrospectively analysed in this study. Their data were also compared to those without dialysis at the same time. RESULTS: We enrolled 49 AAV patients with chronic dialysis. 41 required dialysis at initial presentation and rest 8 progressed to ESRD during follow-up. 19 HD patients died and 6 PD patients died during follow-up, and infection was the most common cause among the patients. There was no significant difference regarding survival between HD patients and PD patients (p>0.05). However anaemia and level of triglyceride was more significantly improved in HD patients at the end of observation (p<0.05, p<0.05 respectively). Compared with patients without dialysis dependency, dialysis patients presented higher percentage of hypertension (p<0.01), more severe renal involvement and higher BVAS (p<0.01). For the outcome, survival was significantly higher in non-dialysis patients (p<0.05). CONCLUSIONS: Patients with AAV experienced a high rate of renal failure and dialysis dependence. Our study suggests that haemodialysis and peritoneal dialysis are two comparable dialysis modalities for AAV patients with ESRD. However, AAV patients with dialysis dependency had worse outcome in comparison with those without dialysis.

Risk evaluation for diabetic retinopathy in Chinese renal-biopsied type 2 diabetes mellitus patients.

AIM: To investigate diabetic retinopathy (DR) prevalence in Chinese renal-biopsied type 2 diabetes mellitus (T2DM) patients with kidney dysfunction, and to further evaluate its relationship with diabetic nephropathy (DN) incidence and the risk factors for DR development in this population. METHODS: A total of 84 renal-biopsied T2DM patients were included. Fundus and imaging examinations were employed for DR diagnosis. Demographic information and clinical measures along with renal histopathology were analyzed for comparisons between the DR and non-DR groups. Risk factors on DR development were analyzed with multiple logistic regression. RESULTS: DR prevalence was 50% in total. The incidences of DN, non-diabetic renal disease (NDRD) and mixed-type pathology were 47.6%, 19.0% and 33.3% in the DR group respectively, while 11.9%, 83.3% and 4.8% in the non-DR group. Systolic blood pressure, ratio of urinary albumin to creatine ratio, urinary albumin, 24-hours urinary protein, the incidence and severity of DN histopathology were found statistically increased in the DR group. Multiple logistic regression analysis showed histopathological DN incidence significantly increased the risk of DR development [odds ratio (OR)=21.664, 95% confidential interval (CI) 5.588 to 83.991, P<0.001 for DN, and OR=45.475, 95%CI 6.949 to 297.611, P<0.001 for mixed-type, respectively, in reference to NDRD)], wherein DN severity positively correlated. CONCLUSION: Renal histopathological evidence indicates DN incidence and severity increases the risk of DR development in Chinese T2DM patients inexperienced of regular fundus examinations.

Persistently elevated sFlt-1 and recovery of reduced ADAMTS13 activity in malignant hypertension.

BACKGROUND AND OBJECTIVES: Malignant hypertension (MHT) characterized by acute hypertension with retinopathy or multiorgan damage, is a severe form of hypertensive emergency and associated with target organ involvement and poor kidney outcome. However, the underlying mechanisms are unclear. METHODS: Eighty-four patients with acute severe hypertension from the Nephrology Department and Emergency Department in a single center during January 2016 and December 2017 were prospectively enrolled and divided into MHT ( n  = 48) and non-MHT ( n  = 36) subgroups according to target organ evaluation. Forty healthy controls were recruited. Serum soluble Fms-like tyrosine kinase-1 (sFlt-1) levels and plasma ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 motif, member 13) activity were examined at baseline and 12-month follow-up. Renal endpoints were defined as a significant decrease in the estimated glomerular filtration rate (eGFR) of more than 40% or the occurrence of end-stage renal disease. RESULTS: Serum sFlt-1 levels were persistently elevated in MHT. Baseline serum sFLT-1 levels were correlated with plasma ADAMTS13 activity and markers of target organ damage. Plasma ADAMTS13 activity was reduced in both MHT and non-MHT patients and recovered to the normal range at 12-month follow-up. During an average follow-up time of 53 ±â€Š13 months, the restoration of reduced ADAMTS13 activity was correlated with the improvement of kidney function and independently reduced the risk of renal endpoints. CONCLUSIONS: Abnormal angiogenesis and endothelial damage are involved in the pathophysiology of hypertensive emergency. Evaluation of ADAMTS13 and sFlt-1 may help in the diagnosis and assessment of MHT. Recovery of ADAMTS13 predicts better renal outcome in patients with hypertensive emergencies.

Globotriaosylsphingosine improves risk stratification of kidney progression in Fabry disease patients.

BACKGROUND: Kidney damage is common in patients with Fabry disease (FD), but more accurate information about the risk of progression to kidney failure is needed for clinical decision-making. In particular, FD patients with mild renal involvement often lack timely intervention and treatment. We aimed to utilize a model to predict the risk of renal progression in FD patients. METHODS: Between November 2011 and November 2019, ERT-naive patients with FD were recruited from three medical centers in China. To assess the risk of a 50% decline in the estimated glomerular filtration rate (eGFR) or end-stage kidney disease (ESKD), Cox proportional hazards models were utilized. The performance of these models was assessed using discrimination, calibration, and reclassification. RESULTS: A total of 117 individuals were enrolled. The mean follow-up time was 4.8 years, during which 35 patients (29.9 %) progressed to the composite renal outcomes. Male sex, baseline proteinuria, eGFR and globotriaosylsphingosine (Lyso-Gb3) were found to be independent risk factors for kidney progression by the Cox model, based on which a combined model containing those clinical variables and Lyso-Gb3 and clinical models including only clinical indicators were constructed. The two prediction models had relatively good performance, with similar model fit measured by R2 (59.8 % vs. 61.1 %) and AIC (51.54 vs. 50.08) and a slight increase in the C statistic (0.949 vs. 0.951). Calibration curves indicated closer alignment between predicted and actual renal outcomes in the combined model. Furthermore, subgroup analysis revealed that Lyso-Gb3 significantly improved the predictive performance of the combined model for kidney prognosis in low-risk patients with a baseline eGFR over 60 ml/min/1.73 m2 or proteinuria levels less than 1 g/d when compared to the clinical model. CONCLUSIONS: Lyso-Gb3 improves the prediction of kidney outcomes in FD patients with a low risk of progression, suggesting that these patients may benefit from early intervention to assist in clinical management. These findings need to be externally validated.

Tacrolimus versus cyclophosphamide in steroid-dependent or steroid-resistant focal segmental glomerulosclerosis: a randomized controlled trial.

BACKGROUND: The efficacy and safety of tacrolimus (TAC) and cyclophosphamide (CTX) were prospectively examined in steroid-dependent or steroid-resistant primary focal segmental glomerulosclerosis (FSGS). METHODS: Patients with biopsy-proven FSGS were enrolled and randomly divided into two groups: CTX and TAC. Patients treated with CTX (0.5-0.75 g/m(2)·month, i.v.) received prednisone at 0.8 mg/kg·day, while patients treated with TAC (0.1 mg/kg·day) received prednisone at 0.5 mg/kg·day. The plasma concentration of TAC was monitored and maintained at 5-10 ng/ml. After a 6-month treatment the patients were evaluated. Patients with complete remission (CR) and partial remission (PR) continued the treatment for 12 months with the dose tapered, whereas the patients with no response were excluded from the study and underwent an alternative treatment. RESULTS: A total of 33 patients were recruited and 27 completed the 12-month follow-up. The TAC-treated patients (n = 15) showed a quick remission. The initial remission time averaged 1.23 ± 0.21 versus 2.21 ± 0.77 months in the CTX group (n = 18), but no significant difference was achieved (p > 0.05). At 6 months, the two groups showed a similar outcome. Ten patients from each group showed remission (7 CR and 3 PR). At 12 months, the CTX group had 9 CR and 3 PR while the TAC group had 6 CR and 5 PR. Remission rates in TAC tended to be higher than that in CTX, but there was no difference. CTX patients had a high prevalence of infections (50.0 vs. 13.3% in TAC, p < 0.05). In contrast, TAC-treated patients showed a high incidence of hyperglycemia (26.7 vs. 0.0% in CTX, p < 0.05). CONCLUSION: These results suggest that CTX and TAC had a similar efficacy in steroid-dependent and steroid-resistant FSGS as manifested by reduced proteinuria, improved serum albumin level and renal function.

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

BACKGROUND: Although 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). METHODS: In 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. RESULTS: The 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). CONCLUSIONS: This 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.

Mycophenolate mofetil or tacrolimus compared with azathioprine in long-term maintenance treatment for active lupus nephritis.

This study aimed to evaluate the efficacy and safety of mycophenolate mofetil (MMF) or tacrolimus (TAC) compared with azathioprine (AZA) as maintenance therapy for active lupus nephritis (ALN). Patients with ALN who responded to 24 weeks of induction treatment were enrolled. Patients who received MMF or TAC as induction therapy continued MMF or TAC treatment during the maintenance period, whereas those who received intravenous cyclophosphamide were subjected to AZA treatment. The primary endpoint was the incidence of renal relapse. Secondary endpoints included extrarenal flares and composite endpoints (deaths, end-stage renal disease, or doubling of serum creatinine levels). A total of 123 ALN patients (47 in the MMF group, 37 in the TAC group, and 39 in the AZA group) were enrolled. The median follow-up time was 60 months. Ten MMF-treated patients, ten TAC-treated patients, and eight AZA-treated patients experienced renal relapses (P = 0.844). The cumulative renal relapse rates in the MMF group (P = 0.934) and TAC group (P = 0.673) were similar to the renal relapse rate in the AZA group. No significant difference in the incidence of severe adverse event was observed among the groups. Long-term maintenance therapies with MMF or TAC might have similarly low rates of renal relapse and similar safety profiles compared with AZA.

Association Between NPHS2 p.R229Q and Focal Segmental Glomerular Sclerosis/Steroid-Resistant Nephrotic Syndrome.

Aim: NPHS2 is the coding gene of podocin. This study aims to investigate the association between NPHS2 p.R229Q (rs61747728), the most frequently reported missense variant of NPHS2, and focal segmental glomerular sclerosis (FSGS) or steroid-resistant nephrotic syndrome (SRNS) based on typing the variant in a Chinese FSGS/SRNS cohort and conducting a meta-analysis. Method: We recruited patients with FSGS or SRNS and healthy individuals. To conduct a meta-analysis, all studies on p.R229Q and FSGS/SRNS were searched from public databases. Results: In total, we enrolled 204 patients with FSGS, 61 patients with SRNS [46 with FSGS, 9 with minimal change disease (MCD), and six patients with IgA nephropathy (IgAN)], and 100 healthy controls. Unexpectedly, p.R229Q was absent in the patients from our cohort. By meta-analysis of 21 studies including 2,489 patients with FSGS/SRNS and 6,004 healthy controls, we confirmed that the A allele of p.R229Q was significantly associated with increased risk of FSGS/SRNS (allelic OR = 1.9, 95% CI = 1.44-2.52, P < 0.001). However, the subgroup analysis showed that the association between p.R229Q and FSGS/SRNS was true only in Caucasians (allelic OR = 2.14, 95%CI = 1.54-2.98, P < 0.001) and in early-onset patients (allelic OR: 2.13, 95% CI = 1.21-3.76, P = 0.009). Conclusion: NPHS2 p.R229Q may play an important role in enhancing the susceptibility of FSGS/SRNS, especially in ethnicity of Caucasian and age of early-onset patients.

Coiled versus straight peritoneal dialysis catheters: a randomized controlled trial and meta-analysis.

BACKGROUND: Variations 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. STUDY DESIGN: Prospective randomized controlled trial (RCT); results were meta-analyzed with other RCTs of coiled versus straight catheters. SETTING & PARTICIPANTS: 80 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. INTERVENTION: Patients were randomly assigned to a coiled-end swan neck catheter (n = 40) or a straight-end swan neck catheter (n = 40) group. OUTCOMES: Catheter tip migration with dysfunction (primary outcome) and catheter failure, catheter-related infection, technique failure, and all-cause mortality (secondary outcomes). RESULTS: The 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). LIMITATIONS: Single-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. CONCLUSIONS: Although 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.