C5b-9 and adhesion molecules in human idiopathic membranous nephropathy.

BACKGROUND: Cellular immune responses and C5b-9 seem to play an important role in the pathogenesis and progression of idiopathic membranous nephropathy (IMN). The aim of the study was to investigate the role of C5b-9 and adhesion molecules in the pathogenesis of the disease. METHODS: The clinical and pathological data of 35 patients with biopsy-proven IMN were correlated with immunohistochemical findings using monoclonal antibodies against T lymphocytes, monocytes/macrophages (MM), HLA-DR antigens, C5b-9, and adhesion molecules such as alpha3beta1, LFA-1beta, and ICAM-1. RESULTS: In the glomeruli, C5b-9 deposits showed a significant correlation with the intensity of IgG and C3 deposition. The stage of the disease had a significant negative relationship with the glomerular alpha3beta1 expression. In the tubulointerstitium (TIN), the number of HLA-DR(+) cells was highly correlated with the numbers of total T lymphocytes, MM, and LFA-1beta(+) cells, as well as with the percentage of tubules with C5b-9 deposits. The extent of ICAM-1 expression in the TIN was significantly correlated with the numbers of interstitial MM, HLA-DR(+), and LFA-1beta(+) cells, as well as with the extent of tubular C5b-9 deposition. The severity of tubular atrophy and interstitial fibrosis had a relationship with the numbers of total T lymphocytes, MM, HLA-DR(+), and LFA-1beta(+) cells and with the extent of tubular C5b-9 deposition and ICAM-1 expression in the TIN. Serum creatinine (Scr) was highly correlated with the numbers of interstitial total T lymphocytes, MM, HLA-DR(+), and LFA-1beta(+) cells. Moreover, Scr had a significant relationship with the severity of tubular atrophy and interstitial fibrosis, as well as with the extent of tubular C5b-9 deposition and ICAM-1 expression in the TIN. Proteinuria was significantly correlated with the extent of tubular alpha3beta1 expression. CONCLUSIONS: In IMN, C5b-9 formation may be secondary to IgG and C3 deposition. Proteinuria may contribute to the TIN damage by altering the expression of alpha3beta1 integrins in tubular cells. De novo ICAM-1 and C5b-9 expression within the TIN as well as the activated interstitial cells may be important factors leading to renal damage and renal function impairment.     

Urinary C3dg and C5b-9 indicate active immune disease in human membranous nephropathy.

We have measured complement activation markers, C3dg and C5b-9 in plasma and urine from patients with idiopathic membranous nephropathy and IgA nephropathy. There was no significant difference in levels of plasma C5b-9 between the patient groups. However, high plasma concentrations of C3dg were associated significantly with IgA nephropathy with 45% of patients having levels over 25 U/ml (P less than 0.001). High concentrations of urinary C3dg and C5b-9 were associated significantly with membranous nephropathy (43% and 43% of the patient group, respectively) compared to patients with IgA nephropathy (10% and 0%, respectively, P less than 0.001). In a retrospective analysis of 31 patients with membranous nephropathy, 66% of patients with high initial urinary C5b-9 showed an unstable clinical course compared to 18% of patients with initially absent or low C5b-9 (P less than 0.001). We suggest that high urinary C5b-9 identifies those patients with a membranous lesion which retains an active immunological component contributing to the pathology of progressive glomerular damage.     

Urinary excretion of cytokines and complement SC5b-9 in idiopathic membranous glomerulonephritis

Idiopathic membranous glomerulonephritis (iMGN) has previouslybeen shown to be associated with urinary excretion of terminalcomplement complexes while increased urinary levels of cytokineshave been reported in mesangial proliferative glomerulonephritis.In the present cross-sectional study urinary excretion of IL-1ßTNF-, IL-6;, and soluble C5b-9 (SC5b-9) was examined for 23patients with iMGN, 16 patients with diabetic nephropathy (DNP),and 17 healthy subjects. IL-1ß excretion (pg/mg crea)was significantly higher in iMGN patients (375, range 162–11000) than in DNP patients (39, range 22–59, P<0.001)or healthy controls (151, range 23–481, P<0.00l). TNF-excretion rate (pg/mg crea) was clearly higher (38, range 21–700)in iMGN patients than in DNP patients (14, range 8–52,P< 0.001) or healthy subjects (11, range 7–26, P<0.001).Median IL-6 excretion (pg/mg crea) was only marginally higherin iMGN patients (73, range 0–850) than in healthy subjects(64, range 3–158, P=0.02) but significantly higher thanin DNP patients (29, range 17–47, P<0.001). No significantcorrelation with corresponding serum values was observed forurinary IL-6 or TNF- excretion. Urinary IL-1/ß andTNF- correlated with decreased renal function. Five of 23 patientsshowed progression of iMGN over a follow-up of 6 months. Theexcretion of all cytokines, TNF- in particular, was significantlyhigher in patients with a progressive disease than in the otherpatients. High TNF- excretion (>57 pg/mg crea) was detectedin 4/5 patients with progression but in none of the stable patients(P<0.001). Seventy-seven per cent of the iMGN patients and94% of DNP patients, but none of the healthy subjects had detectableSC5b-9 excretion. In DNP patients the urinary SC5b-9 levelscorrelated with proteinuria whereas in iMGN the SC5b-9 excretioncould not be accounted for by proteinuria alone. Urinary excretionof SC5b-9 correlated with decreased renal function and had arelationship to urinary IL-1/ß and TNF- excretionin iMGN patients. Moreover the median excretion rate of SC5b-9was higher in patients with than in those without progressionof iMGN. The results suggest that increased urinary IL-1ß,TNF-, and SC5b-9 excretion are detected in patients having iMGN.They may be indicators of a progressive renal disease in iMGN.     

Association of serum mannose-binding lectin,anti-phospholipase A2 receptor antibody and renal outcomes in idiopathic membranous nephropathy and atypical membranous nephropathy: a single center retrospective cohort study

ObjectivesIdiopathic membranous nephropathy (iMN) is a major cause of nephrotic syndrome. Atypical membranous nephropathy (aMN) is a new type of nephropathy in China, characterized by a ‘full-house’ on immunofluorescent examination, that is IgG, IgA, IgM, C3, C1q positive, but without clinical evidence of a secondary cause. Phospholipase A2 receptor (PLA2R) was the major target antigens in iMN patients. Activation of the mannose-binding lectin (MBL) pathway plays a vital role in the development of MN. Our objective was to investigate the role of PLA2R and MBL in the pathogenesis of iMN and aMN.MethodsWe conducted a retrospective observational study using propensity score matching by age, gender, and eGFR. All clinical, laboratory data, and follow-up data of the patients were collected. Serum levels of anti-PLA2R antibodies and MBL were tested.ResultsFinally, 30 iMN patients and 30 aMN patients were included, and 20 healthy controls were retrospectively collected in this study. The 24 h proteinuria level was higher and serum albumin was lower in anti-PLA2R (+) patients than in anti-PLA2R (−) patients in both iMN and aMN groups. In aMN patients, MBL levels were significantly higher in anti-PLA2R (+) patients than in anti-PLA2R (−) patients (p = .045). The serum level of anti-PLA2R positively correlated with no-remission in both iMN and aMN groups.ConclusionsThe complement lectin pathway has an association with the development of MN, especially in patients with positive anti-PLA2R antibodies. Serum MBL cannot differentiate between the two diseases. Serum MBL levels are not associated with clinical manifestations, nor with prognosis.     

Renal C3 synthesis in idiopathic membranous nephropathy: correlation to urinary C5b-9 excretion

Renal C3 synthesis in idiopathic membranous nephropathy: Correlation to urinary C5b-9 excretion. BACKGROUND: Complement activation plays a central pathogenetic role in idiopathic membranous nephropathy (IMN). Urinary excretion of C5b-9 correlates to the immunologic activity of this disease. Recently, renal cortical C3 gene expression has been described in several nephropathies. METHODS: The aim of this study was to investigate the renal C3 gene expression by in situ hybridization in IMN and to correlate it with histopathologic, pathophysiologic, and immunologic (urinary C5b-9) indices of disease activity. RESULTS: C3 was expressed in 77% of 22 renal biopsies of IMN patients, mainly at the cortical tubular and glomerular parietal epithelial cell levels. C3 protein synthesis by tubular cells was demonstrated by immunofluorescence. The intensity of C3 gene expression by both glomerular and tubulointerstitial compartments correlated with the glomerular stage of disease (P = 0. 0023 and P = 0.0214, respectively). Although no correlation was found with proteinuria, serum creatinine at renal biopsy time was strongly associated with renal C3 expression. IMN patients showed a trend of increased urinary C5b-9 levels, which correlated to C3 at the tubulointerstitial level (P = 0.0143). CONCLUSION: Renal C3 production, mainly at the tubular level, may be induced by urinary excretion of C5b-9 in IMN and may have a pathogenetic role in the tubulointerstitial damage that can be associated with this disease.     

Elevated urinary excretion of the C5b-9 complex in membranous nephropathy.

In experimental membranous nephropathy, antibody binding to glomerular epithelial cell membrane antigens results in complement activation and formation of complement C5b-9 membrane attack complexes in glomeruli. During active disease, the C5b-9 complexes are shed into the urine. To test the hypothesis that a similar mechanism might be operative in human membranous nephropathy, we measured urinary excretion of C5b-9 and C5 in 146 proteinuric patients with biopsy-proven glomerular diseases or diabetes mellitus. Urinary excretion of C5b-9 relative to C5 excretion was higher in 40 patients with membranous nephropathy than in 106 patients with proteinuria due to non-membranous glomerulonephritis when analyzed by covariance analysis (P less than 0.0002). Urinary C5b-9 excretion was higher in membranous nephropathy than in membranoproliferative glomerulonephritis (N = 13, P less than 0.05), minimal change-focal sclerosis (N = 33, P less than 0.001), mesangial proliferative glomerulonephritis (N = 9, P less than 0.02) and IgA nephropathy (N = 7, P less than 0.025). Urinary C5b-9 excretion was also higher in patients with lupus nephritis (N = 18, P less than 0.02) compared to those with non-membranous glomerulonephritis. The lupus patients with the highest excretion had clinical or pathological features of membranous nephropathy. Nine patients with membranous nephropathy and elevated urinary C5b-9 excretion had a shorter duration of disease (P less than 0.05), lower serum creatinine levels (P less than 0.05) and more proteinuria (P less than 0.02) than the 31 membranous nephropathy patients with normal values.(ABSTRACT TRUNCATED AT 250 WORDS)     

The pathogenetic significance of C5b-9 in IgA nephropathy

Renal biopsies from 20 patients with IgAN were retrospectivelystudied using monoclonal antibodies against T cells, monocytes/macrophages(MM), HLA-DR-related antigen and the C5b-9 neoantigen. GlomerularC5b-9 deposits were mainly found in the mesangial areas andshowed an association with IgA (P<0.005) and C3 deposits(P<0.001). Interstitial T cells and MM were highly correlatedwith the interstitial DR+ve cells (P<0.001 and P<0.0005respectively). Tubular C5b-9 deposition was observed on thetubular basement membranes and related to the numbers of interstitialT cells (P<0.005), MM (P<0.005) and DR+ve cells (P<0.01)as well as to the tubular DR expression (P <0.025). The severityof tubular atrophy and interstitial fibrosis showed a positivecorrelation with the interstitial T cells, MM and DR+ve cells,as well as with the intensity of tubular C5b-9 deposition (P<0.05and P<0.05 respectively). Plasma creatinine on presentationwas correlated with the numbers of interstitial T cells (P<0.05),MM (P<0.01), interstitial DR+ve cells (P<0.005), and tubularC5b-9 deposits (P<0.005). No correlation between glomerularT cells, MM, and C5b-9 deposits with plasma creatinine was seen.During follow-up, renal function deteriorated in those patientswith the more extensive tubular C5b-9 deposits In conclusion, glomerular C5b-9 deposition seems to be secondaryto the IgA and C3 deposition. In contrast, tubular C5b-9 isrelated to the numbers of interstitial T cells and MM. Activatedinterstitial mononuclear cells may lead to the tubular depositionof C5b-9, which eventually might contribute to the developmentof tubulointerstitial lesions (TIL) and renal function impairment     

氯沙坦对特发性膜性肾病患者尿蛋白谱的影响

目的观察氯沙坦对特发性膜性肾病(idiopathic membranous nephropathy,IMN)患者尿蛋白谱的影响,以期阐明其部分治疗机制。方法将79例IMN患者随机分为观察组(42例)及对照组(37例),所有患者在纳入实验前均常规治疗1个月。观察组在常规治疗基础上服用氯沙坦(100mg/d)治疗3个月,对照组继续给予常规治疗3个月。治疗前后分别进行尿β2-微球蛋白肌酐比值(urinaryβ2-microglobulin to creatinine ratio,β2-MG/Cr)、视黄醇结合蛋白肌酐比值(retinol binding protein to creatinine ratio,RBP/Cr)、蛋白肌酐比值(urinary protein to creatinine ratio,PRO/Cr),足细胞顶端膜性蛋白肌酐比值(Podocalyxin to creatinine ratio,PCX/Cr)、白蛋白肌酐比值(albumin to creatinine ratio,Alb/Cr)、免疫球蛋白G肌酐比值(immunoglobulin G to creatinine ratio,IgG/Cr)测定,然后对治疗前后结果进行分析评价。结果观察组氯沙坦治疗后尿PCX/Cr、Alb/Cr、PRO/Cr较治疗前有明显降低(P0.01),但尿β2-MG/Cr、RBP/Cr、IgG/Cr治疗前后比较无明显差异(P0.05);对照组尿PRO/Cr、ALB/Cr治疗后有所下降(P0.05),其余比值治疗前后无明显差异(P0.05)。观察组治疗后较对照组治疗后尿PCX/Cr、ALB/Cr、PRO/Cr有所降低(P0.05),β2-MG/Cr、RBP/Cr、IgG/Cr无明显差异(P0.05)。结论氯沙坦可明显减少IMN患者尿蛋白排泄,其机制可能与肾小球基底膜电荷屏障的修复有关,对肾小球基底膜的结构损伤无修复作用,也未发现对损伤肾小管明显的保护作用。     

Relationship between interstitial infiltrates and steroid responsiveness of proteinuria in membranous nephropathy

Mononuclear inflammatory cells were retrospectively analysedusing monoclonal antibodies in the interstitium and glomeruliof 16 renal biopsy specimens from patients with nephrotic syndromedue to idio-pathic membranous nephropathy (IMN). The aim ofthe study was to determine the composition of the infiltrateand to assess the ability to predict the response of proteinuriato corticosteroids. All patients had received prednisolone asa sole treatment. Nine patients had shown a complete or partialremission of proteinuria (group A) and seven did not respondat all (group B). Both groups were matched for age and degreeof proteinuria; also both groups had normal renal function atthe time of biopsy. Very few intraglomerular leukocytes, mostlymonocytes/ macrophages (MM) were found. The majority of interstitialcells were T lymphocytes and MM. CD4+ve T helper/inducer cellspredominated among the interstitial T cell population and Bcells were a minor component. No significant differences werefound between the two groups regarding the types of the intraglomerularcells. However, interstitial T-cells, CD4 + ve T helper/inducercells, CD8+ve T cytotoxic/suppressor cells and MM were significantlyhigher in group A than in group B. Also HLA-DR expressing interstitialcells were much in excess in group A. In addition patients with complete remission of proteinuriahad higher numbers of interstitial cells compared to those withpartial response. There was no correlation between the numbersof types of intraglomerular and interstitial cells and the degreeof proteinuria at presentation. Also no association was foundbetween intraglomerular or interstitial cell population andsubsequent relapse of proteinuria. In conclusion, interstitial but not intraglomerular mononuclearcells seem to determine the initial response of proteinuriato corticosteroids in patients with IMN.     

Urinary protein and renal prognosis in idiopathic membranous nephropathy: a multicenter retrospective cohort study in Japan

Background: Several studies have revealed a relationship between proteinuria and renal prognosis in idiopathic membranous nephropathy (IMN). The benefit of achieving subnephrotic proteinuria (<3.5?g/day), however, has not been well described.

Methods: This multicenter, retrospective cohort study included 171 patients with IMN from 10 nephrology centers in Japan. The relationship between urinary protein over time and a decrease of 30% in estimated glomerular filtration rate (eGFR) was assessed using time-dependent multivariate Cox regression models adjusted for clinically relevant factors.

Results: During the observation period (median, 37?months; interquartile range, 16–71?months), 37 (21.6%) patients developed a 30% decline in eGFR, and 2 (1.2%) progressed to end-stage renal disease. Time-dependent multivariate Cox regression models revealed that lower proteinuria over time were significantly associated with a lower risk for a decrease of 30% in eGFR (primary outcome), adjusted for clinically relevant factors. Complete remission (adjusted hazard ratio [HR], 0.005 [95%CI, 0.0–0.09], p?p?=?.002), and 1.0 to 3.5?g/day (ICR II) (adjusted HR, 0.12 [95%CI, 0.02–0.64], p?=?.013) were significantly associated with avoiding a 30% decrease in eGFR, compared to that at no remission.

Conclusions: Attaining lower proteinuria predicts good renal survival in Japanese patients with IMN. This study quantifies the impact of proteinuria reduction in IMN and the clinical relevance of achieving subnephrotic proteinuria in IMN as a valuable prognostic indicator for both the clinician and patient.     

The short- and long-term outcomes of membranous nephropathy treated with intravenous immune globulin therapy. Kanazawa Study Group for Renal Diseases and Hypertension.

BACKGROUND: A considerable diversity in prognosis is seen with membranous nephropathy (MN). A recent report showed beneficial effects of immune globulin (Glb) therapy in Heymann nephritis, a rat model of MN. However, the early and late clinical effects of Glb in human MN have remained unclear. METHODS: We studied retrospectively 86 patients with primary MN from 1965 to 1988 who were followed for at least 5 years, or until renal or actual death. Thirty patients were non-randomly treated with 1-3 courses of intravenous immune globulin, 5-10 g/day (100-150 mg/kg/day) for 6 consecutive days. Based on electron microscopic (EM) findings, the patients were divided into two subtypes, i.e. homogeneous type with synchronous electron-dense deposits, and heterogeneous type with various stages of dense deposits, due to their different clinical outcomes. RESULTS: There was no difference in the initial clinicopathological states between Glb (n = 30) and non-Glb group (n = 56) (70 vs. 68% in nephrotic state; 37 vs. 39% in female, 50 vs. 52% in homogeneous type, 50 vs. 48% in heterogeneous type respectively). For the homogeneous type, at 6 months post-treatment, Glb therapy had induced earlier remission as compared to non-Glb treatments with corticosteroid alone or together with cyclophosphamide (57 vs. 10% respectively, P = 0.006). However, there was no significant difference in the early therapeutic effect for the heterogeneous type (13% for Glb vs. 5% for non-Glb in remission after 6 months), or in the final outcome for all groups (18% for Glb vs. 10% for non-Glb in renal death after 15 years). No adverse effects were recorded during or after Glb therapy. CONCLUSIONS: Our results suggest that short-term relatively low-dose intravenous Glb therapy has a beneficial effect in the earlier induction of remission in a subgroup of MN, the homogeneous type with EM findings of synchronous electron-dense deposits, but does not alter the long-term outcome of human MN.     

The clinical outcome and risk factors of phospholipase A2 receptor-associated idiopathic membranous nephropathy in adults

Objective To report the spontaneous remission and induced remission of phospholipase A2 receptor (PLA2R)-associated idiopathic membranous nephropathy (IMN) in adults, as well as to explore the potential prognostic factors. Methods A total of 120 patients with IMN in Huashan Hospital during 2012 and 2017 were enrolled and their clinical data were collected. Results PLA2R-associated IMN patients accounted for 89.2% of the IMN patients. Spontaneous remission occurred in 35.5% of PLA2R-associated IMN patients. The patients with higher serum albumin and lower level of PLA2R antibody were more likely to achieve spontaneous remission (both P＜0.05). Multivariate logistic regression analysis showed that male was an independent risk factor for spontaneous remission in PLA2R-associated IMN patients (OR=0.060, 95%CI 0.007-0.493, P=0.009), while higher serum albumin at baseline (OR=1.480, 95%CI 1.144-1.932, P=0.004) and the improvement of serum albumin after 3 months' non-immunosuppressive treatment (OR=2.040, 95%CI 1.322-3.151, P=0.001) were independent protective factors for spontaneous remission. About 42.1% PLA2R-associated IMN patients had received immunosuppressive therapy, with induced remission rate being 70.7%. High serum albumin before treatment was an independent protective factor for induced remission (OR=1.268, 95%CI 1.014-1.585, P=0.038). Conclusions PLA2R-associated IMN accounts for most of the IMN patients, with a spontaneous remission rate of 35.5%, during the follow-up period, which is even higher in patients with higher baseline serum albumin and lower PLA2R antibody titer. Induced remission rate is 70.7% in patients in need of immunosuppresants. The serum albumin level may be helpful in predicting spontaneous remission and response to immunosuppressive therapy.     

Insidious transmission of membranous nephropathy from kidney donor with no clinical manifestations before and after transplantation

Abstract:  Live kidney donors are supposed to have no clinical kidney disease. Here, we present a unique case of subclinical membranous nephropathy (MN) from a living donor, who had urinalysis-free stable kidney function pre- and post-transplant. A 39-yr-old Asian woman received a second kidney graft from her spouse whose urinalysis and blood chemistry were stable and normal. Her intraoperative one-h core biopsy revealed thick glomerular basement membrane (GBM) and a bubbly type appearance, compatible with stage II MN on Churg's classification. According to two other protocol biopsies, GBM thickening persisted until month six post-transplant. Interestingly, both the donor and the recipient had stable kidney function without overt proteinuria at each monthly visit until one yr post-transplant. Taken together, we speculate that "silent" MN may exist in certain healthy individuals, who present only with histopathologically compatible MN and no other findings.     

Antiproteinuric effect of angiotensin-converting enzyme inhibition and C5b-9 urinary excretion in membranous glomerulonephritis

Background: Angiotensin-converting enzyme (ACE) inhibitors have an antiproteinuric effect in membranous glomerulonephritis (MGN). However, no studies hae investigated whether this antiproteinuric effect is influenced by urinary C5b-9 excretion, a marker of immunological activity in this disease. Methods: Eleven patients with biopsy-proven MGN were treated with captopril for 8 weeks. The evolution of several clinical and biochemical parameters, including 24-h urinary protein excretion was evaluated every 4 weeks. Urinary C5b-9 excretion was measured at the onset and at the end of captopril treatment. Results: Patients with MGN had significantly higher C5b-9 excretions than a group of 14 healthy controls (89±23 vs 3.7±1.4 ng/mg UCr; P<0.001). A significant correlation was found between urinary C5b-9 and the magnitude of proteinuria, both at the onset and at the end of treatment. After 8 weeks of captopril treatment, proteinuria had decreased from 8±1.8 to 5.2±1.3 g/day (P<0.05). Four weeks after captopril discontinuation, proteinuria rose to 7.3±1.7 g/day (P<0.05). A marked variability in the antiproteinuric response was observed, ranging from 0 to 85% with respect to baseline values. No correlation between decrease in proteinuria and baseline urinary C5b-9 levels was observed. Several patients with elevated urinary C5b-9 levels had captopril-induced decrease in proteinuria. Conclusions: ACE inhibition induces an antiproteinuric effect in patients with MGN. The urinary C5b-9 excretion does not predict the magnitude of this response.     

The pathology and clinical features of early recurrent membranous glomerulonephritis

We assessed the earliest manifestations of recurrent membranous glomerulonephritis (MGN) in renal allografts. Clinical, laboratory and pathologic data were reviewed in 21 patients at the initial biopsy within 4 months post-transplant with evidence of MGN and on follow-up biopsies, compared to a biopsy control group of eight transplants without recurrent MGN. The mean time of first biopsy with pathologic changes was 2.7 months. In each earliest biopsy, immunofluorescence (IF) showed granular glomerular basement membrane (GBM) staining for C4d, IgG, kappa and lambda. IF for C3 was negative or showed trace staining in 16/21. On each MGN biopsy positive by IF, 14/19 showed absence of deposits or rare tiny subepithelial deposits by electron microscopy (EM). At the earliest biopsy, the mean proteinuria was 1.1 g/day; 16 patients had <1 g/day proteinuria. Follow-up was available in all patients (mean 35 months posttransplant). A total of 13 patients developed >1 g/day proteinuria; 12 were treated with: rituximab (n = 8), ACEI and increased prednisone dose (n = 2), ACEI or ARB only (n = 2). All patients showed reduction in proteinuria after treatment. A total of 11/16 patients showed progression of disease by EM on follow-up biopsy. Recognition of early allograft biopsy features aids in diagnosis of recurrent MGN before patients develop significant proteinuria.     

Immunosuppressive therapy with cyclophosphamide and prednisolone in severe idiopathic membranous nephropathy

In idiopathic membranous nephropathy (IMN) immunosuppressivetherapy should be reserved for patients with potential riskfactors at baseline or who show a progressive course. Cyclophosphamidepulse therapy (CPT) in IMN is not yet widely tested. We carriedout a trial of CPT combined with conventional treatment in agroup of patients with IMN at a greater risk. The study group consisted of 36 nephrotic adult IMN patients(M, 26; F, 10) with various combinations of risk factors. Meanproteinuria was 11.3 g/day, 47.% patients were hypertensive,78% had tubular changes, and 36% had focal glomerulosclerosis.They were treated with CPT and/or conventional low-dose cyclophosphamideand prednisolone. Median duration of immunosuppression was 14months and median total cumulative dose of cyclophosphamide172mg/kg body weight. At 6 months (6m) remission was achieved in 44% cases and atthe 36th month in 73%. None of the patients developed moderateor severe renal failure. Side-effects were minimal. Multivariateanalysis of baseline data and the changing course of the diseaseduring therapy showed that tubular changes (P = 0.0025), creatinineclearance at baseline (P = 0.04) and at 6m (P = 0.02), and proteinuriaat 6m (P<0.0001) significantly influenced the therapeuticeffect. We conclude that cyclophosphamide (including pulse) and prednisolonecan bring significant remission and maintain renal functionin IMN with potential risk factors.     

Relationship between renal phospholipase A2 receptor expression and clinical characteristics,prognosis in idiopathic membranous nephropathy patients

Objective To explore the relationship of phospholipase A2 receptor (PLA2R) expression in renal tissue with clinical characteristics, prognosis of idiopathic membranous nephropathy(IMN) patients. Methods 134 patients diagnosed as nephropathy proven by biopsy was selected as subjects of this research, including 98 patients with IMN patients, 10 patients with secondary membranous nephropathy and 26 patients with other renal glomerular diseases. The expression of PLA2R antigen in renal tissue was detected by immuno-fluorescence chemistry staining. Results The positive rate of renal PLA2R expression in IMN patients was higher than that in SMN patients (91.84% vs 40.00%, P＜0.01), whereas there is no expression in other glomerular diseases. The PLA2R negative group were mainly stage I membranous nephropathy, and positive group was mainly in stage II. The distribution of pathological stage between the two groups was statistically significant (P＜0.01). Compared with the positive group, the negative group was manifested with higher eGFR[(115.91±23.32) ml?min-1?(1.73 m2)-1 vs (94.06±27.38) ml?min-1?(1.73 m2)-1, P=0.031], associated with the higher 12-month complete remission rate (87.50% vs 44.07%, P=0.021). Conclusions The expression of PLA2R antigen in renal tissue plays an important role in the diagnosis, disease evaluation and prognosis of IMN. The negative PLA2R in kidney tissue of IMN may indicate a good clinical prognosis.     

Pathological study on the relationship between C4d, CD59 and C5b-9 in acute renal allograft rejection

Abstract:  In order to evaluate the activation or inhibition of the later phases of classical complement cascade in renal allograft presenting with acute rejection, particularly with C4d deposition on the peritubular capillary (PTC), we observed the expression of CD59 and C5b-9 on the PTC. Subjective cases were divided into two groups, an acute rejection group, of 4 males and 6 females, and a normal donor group, of 5 males and 5 females. Renal biopsies were performed at the onset of acute rejection and at the transplant operation, before reperfusion. C4d deposition on PTC was found in three of 10 cases (30%) with biopsy proven acute rejection, whereas CD59 on PTC was positively expressed in all of the rejection cases. Although C5b-9 was not observed on PTC in the acute rejection group, it was intensively deposited on the tubular basement membrane (TBM) in five cases, including the three with positive C4d on PTC. In the normal donor group, CD59 on PTC was intensively observed, whereas C5b-9 was weakly expressed on TBM. CD59, a complement regulatory factor, works as an inhibitory factor against the formation of C5b-9, a membrane attack complex. From our data, we noted the dissociation between the depositions of C4d and C5b-9 on PTC. The substantially expressed CD59 on PTC may affect this dissociation between C4d and C5b-9 on PTC. The intensive deposition of C5b-9 on TBM in acute rejection cases may suggest an independent immunological injury attacking tubular cells.