T cell subsets in glomerulonephritis

Abnormal lymphocyte function has been postulated to have a pathogenetic role in nephrotic syndrome. In an attempt to investigate the pathogenetic role of lymphocyte subsets in human glomerular disease, we studied 110 children suffering from nephritis during the acute nephrotic phase or nephritis without steroid treatment, 4 weeks later after steroid treatment, in remission and relapse. These patients included minimal change nephrotic syndrome (MCNS) 15 cases, focal segmental glomerular sclerosis (FGS) 6 cases, mesangial cell proliferative nephropathy (MesPGN) 42 cases, membranoproliferative glomerulonephritis (MPGN) 2 cases, hepatitis B surface antigenemia associated with membranous nephropathy (HBVMN) 10 cases, IgA mesangial nephropathy (IgAN) without nephrotic syndrome 7 cases, poststreptococcal glomerulonephritis (PSGN) 24 cases and chronic glomerulonephritis (CGN) 4 cases. There was no significant difference in the total lymphocyte count of each different pathological group of nephritis except that lymphopenia was noted in the CGN patients. When the lymphocyte phenotypic profile was examined, OKT8 cells were significantly increased in the MesPGN patients and both OKT4 and OKT8 cells were significantly increased in HBVMN. Comparison of MCNS and MesPGN during the acute nephrotic phase showed the OKT4/OKT8 ratio decreased significantly in MesPGN. Four weeks after steroid treatment, OKT4 cells decreased both in MCNS and MesPGN being pronounced in MCNS. In the remission stage with steroid treatment the OKT4/OKT8 ratio decreased in MCNS and was mildly elevated in MesPGN. In relapse, the OKT4/OKT8 ratio was the same as it was during the onset of nephrotic phase. MCNS cases were steroid responsive whereas in MesPGN there were frequent relapses or partial steroid response.(ABSTRACT TRUNCATED AT 250 WORDS)     

Current issues in pediatric lupus nephritis: role of revised histopathological classification

Childhood-onset systemic lupus erythematosus (SLE) has an unpredictable natural history with variable clinical manifestations. The prognosis of SLE is linked closely to renal involvement with lupus nephritis (LN), which is more severe in patients with childhood-onset compared with adult-onset disease. The histopathological classification of LN facilitates treatment decisions, protocols, and clinical research. After the World Health Organization and modified WHO classifications of LN from 1974 to 1995, the International Society of Nephrology and Renal Pathology Society Working Group revised the histopathological classification of LN. The reclassification was published in 2004 after their consensus conference held at Columbia University in New York in May 2002. The aims of the reclassification were to standardize definitions, emphasize clinically relevant lesions, and encourage uniform and reproducible reporting among centers. Although the revised classification is time-consuming, it is important for future international collaboration on multicenter trials of disease-modifying agents. The prognosis of SLE and LN is linked to the histopathology of the renal lesion, but the clinical manifestations of LN, including nephrotic syndrome and hypertension, cannot predict the degree of renal involvement. However, we are many years away from completely understanding the etiopathogenesis of LN and the predictive role of the revised histological classification for direction of patient management.     

A chemotactic inhibitory factor in the minimal change nephrotic syndrome

This study attempts to investigate the role of neutrophil in the increased incidence of infection in nephrotic syndrome. We investigated the function of neutrophils in the various categories of nephritis and the relationship to the response of steroid therapy in the nephrotic syndrome. We used peripheral blood for the study of chemotaxis in 62 children suffering from nephritis in the acute phase and in remission. These patients included minimal change nephrotic syndrome (9 cases), focal segmental glomerular sclerosis (3 cases), mesangial cell proliferative nephropathy (23 cases), Hepatitis B antigenemia associated membranous glomerulonephropathy (4 cases), poststreptococcal glomerulonephritis (20 cases) and chronic glomerulonephritis (3 cases). The chemotactic index was significantly increased in normal range in the remission stage. The molecular weight of the chemotactic inhibitory factor was estimated to be about 89,000 using Sephacryl S-200 column. All cases of mesangial proliferative nephropathy had nephrotic syndrome with frequent relapses or steroid resistance. These results suggest that the chemotactic index may serve as an important parameter between steroid responsive and non-responsive nephrotic syndrome.     

Hepatitis B-associated nephrotic syndrome in Jamaican children

Between December 1984 and November 1996, 171 children under 12 years old presented to the University Hospital of the West Indies with nephrotic syndrome. Hepatitis B surface antigen (HBsAg) was found in ten (6%) of these children, eight of whom had membranous nephropathy (MN), and one each had mesangial proliferative glomerulonephritis (MesN) and minimal change nephrotic syndrome (MCNS). Only those children with MesN and MCNS were steroid-sensitive. The HBsAg-positive status was identified incidentally on screening. At a mean follow-up of 34 months, seven of ten children had experienced complete or partial remission and three had persistent nephrotic syndrome, although none was in renal failure. Six of the ten had biochemical hepatitis. All the children were still HBsAg-positive. Hepatitis B virus (HBV) is a factor contributory to nephrotic syndrome in Jamaican children. As diagnostic clinical markers for HBV-associated nephropathy are usually absent, all children presenting with nephrotic syndrome should be screened for HBsAg. A policy should be implemented in Jamaica for screening pregnant women and at-risk groups for HBsAg, as well as for immunising susceptible neonates, in order to reduce the incidence of HBV-associated pathology.     

他克莫司在儿童肾脏疾病中的临床应用及作用机制

儿童肾小球疾病的发病机制中免疫因素是主要致病因素之一。他克莫司作为继环孢菌素A之后临床应用的一种强而有效的免疫抑制剂,近年来在儿童肾脏疾病治疗中的地位与作用日渐被重视。他克莫司在针对难治性肾病综合征包括激素依赖型、激素耐药型和频繁复发型等肾小球疾病治疗中取得了良好的效果。该文从作用机制入手,综述他克莫司在肾病综合征、局灶节段性肾小球硬化、系膜增生性肾小球肾炎、膜性肾病、狼疮性肾炎等儿童肾脏疾病中的应用。     

Immunological Profile in Children with Minimal Change Nephrotic Syndrome

ABSTRACT. Peripheral blood from patients with active stage of minimal change nephrotic syndrome (MCNS) was examined for concanavalin A (ConA)-inducible suppressor T cell activity, proliferative response to phytohemagglutinin (PHA) and in the autologous (AMLR) and allogeneic (MLR) mixed lymphocyte reaction, proportions of T cells with receptors for IgM (Tu) or IgG (Tγ) and the levels of serum immunoglobulin M, G and A. Six of 9 patients with MCNS studies showed deficiency of ConA-induced suppressor cell activity. In the AMLR, only one of 9 patients with MCNS demonstrated depressed proliferative response (p<0.05). In the allogeneic MLR, T cells from 5 of 9 patients with MCNS demonstrated poor proliferative response when stimulated with normal control non-T cells. Five of 9 patients with MCNS had depressed proliferative response to PHA. The proportion of total T cells, Tu cells and Ty cells in the patient group were comparable to healthy control group. Serum IgG was significantly decreased in 7 of 11 patients. This study demonstrates multiple immunological abnormalities in patients with MCNS that might play a role in its pathogenesis.     

Immunological profile in children with minimal change nephrotic syndrome

Peripheral blood from patients with active stage of minimal change nephrotic syndrome (MCNS) was examined for concanavalin A (ConA)-inducible suppressor T cell activity, proliferative response to phytohemagglutinin (PHA) and in the autologous (AMLR) and allogeneic (MLR) mixed lymphocyte reaction, proportions of T cells with receptors for IgM (Tu) or IgG (T gamma) and the levels of serum immunoglobulin M, G and A. Six of 9 patients with MCNS studies showed deficiency of ConA-induced suppressor cell activity. In the AMLR, only one of 9 patients with MCNS demonstrated depressed proliferative response (p less than 0.05). In the allogeneic MLR, T cells from 5 of 9 patients with MCNS demonstrated poor proliferative response when stimulated with normal control non-T cells. Five of 9 patients with MCNS had depressed proliferative response to PHA. The proportion of total T cells, Tu cells and T gamma cells in the patient group were comparable to healthy control group. Serum IgG was significantly decreased in 7 of 11 patients. This study demonstrates multiple immunological abnormalities in patients with MCNS that might play a role in its pathogenesis.     

Apoptosis in renal disease: a brief review of the literature and report of preliminary findings in childhood lupus nephritis.

Apoptosis, a programmed form of cell death, is an important mechanism that maintains cellular homeostasis. The cellular content of tissues is regulated by a balance between cell proliferation and cell loss. Apoptosis is important not only in physiological conditions but in pathological processes as well. Apoptosis has been implicated in the pathogenesis of certain renal diseases. In human models, systemic lupus erythematosus (SLE) and IgA nephropathy have been the main interests. These studies have mainly shown that apoptosis is important in the control of mesangial cell population. We have attempted to define the role of apoptosis in a cohort of childhood lupus nephritis. We have analyzed apoptosis by the terminal deoxynucleotidyl transferase (Tdt)-mediated dUTP-biotin nick end-labeling (TUNEL) method in eight SLE pediatric patients, two of whom had hereditary deficiencies of complement components. Although the sample size was small because of the rarity of hereditary complement deficiencies, we have shown that apoptotic activity was the greatest among these pediatric patients. It has been previously suggested that in lupus, autoimmunity develops as a result of inadequate clearance of apoptotic blebs containing nuclear elements; complement deficiencies are the most important hereditary factors predisposing to the inadequate clearance of apoptotic particles. This is the first time this hypothesis has been evaluated in the tissue samples of hereditary complement deficiency-related proliferative lupus nephritis. On the other hand, apoptosis was not different from the other mesangial proliferative glomerulopathies in the lupus nephritis samples. Further studies are needed to confirm our preliminary findings. Apoptosis has been implicated in other renal diseases as well, such as autosomal polycystic kidney disease, and in experimental models. A short review of the relevant literature is presented highlighting the role of apoptosis in the pathogenesis and prognosis of certain renal diseases.     

Autoantibodies in minimal change nephrotic syndrome

The presence of low level antibody (AAb) activity and circulating immune complexes (CIC) were studied in 17 patients with minimal change nephrotic syndrome (MCNS). Study groups include 12 MCNS without mesangial deposits (Group I) and 5 MCNS with mesangial deposits (Group II). In Group I reactivity against normal tissue antigens was demonstrated (kidney tubular microsomal antigen - 8, smooth muscle - 5, gastric cell - 5). In Group II reactivity against kidney basement membrane was demonstrated in all five patients. CIC were detected in eight (Group I - 6, Group II - 2). Dissociation of the CIC showed that they all contained antibodies with a corresponding autoantibody activity which could be removed by prior incubation with their complexed antigen. The presence of these AAb's and their formation of CIC may indicate their role in initiating a primary immunological insult to the kidney.     

Failure of clinical and laboratory characteristics to differentiate mesangial proliferative from minimal-change nephrotic syndrome

Twelve clinical and laboratory characteristics of nephrotic syndrome were compared in 24 children with biopsy-proven mesangial proliferative glomerulonephritis (MesPGN) and 17 children with biopsy-proven minimal-change nephropathy (MCNS). The objective of the study was to determine if these characteristics alone, without renal biopsy, could be used to differentiate the two histopathologic entities. Sex, urinary protein level and IgM immunofluorescence were found to be significantly different in the two groups. Discriminant analysis produced two formulae which gave a discriminant rate of 79% for MesPGN and 76% for MCNS. We conclude that the clinical and laboratory characteristics studied could not differentiate MesPGN from MCNS.     

Clinicopathological features of childhood nephrotic syndrome in Saudi Arabia.

The clinicopathological features are described in 119 Arab children in Saudi Arabia with the nephrotic syndrome. The clinical and laboratory data are similar to those described in other parts of the world. However, mesangial proliferative glomerulonephritis (MesPGN) was found in 21 of 66 biopsies (31.8%), giving a frequency of 17.6% of all children with the nephrotic syndrome. Minimal-change nephrotic syndrome (MCNS) was diagnosed in 17 biopsies (25.8%) and in 58 patients (48.7%). Onset of the nephrotic syndrome was at less than 1 year of age in 17 patients (14.3%). Seven children had 11 episodes of peritonitis. Seven children had positive hepatitis B surface antigen (HBsAg) in their serum: renal biopsy carried out on four of them showed membranous glomerulonephritis (MGN) in three, and four of the seven patients developed end-stage renal disease (ESRD). There were nine deaths, all in patients with end-stage renal disease: six of the deaths occurred in infants. The pattern of childhood nephrotic syndrome in Saudi Arabia is different from the pattern in tropical countries.     

Clinicl Significance of Mesangial IgM Deposits in Minimal Change Nephrotic Syndrome

The clinicopathologic features and the response to corticosteroid therapy were compared in 9 patients with minimal change nephrotic syndrome (MCNS) and diffuse mesangial IgM deposits (Group I) and in 32 of those without IgM deposits (Group II). However, serum IgM levels in Group I in both relapse and remission were significantly higher than those of Group II and controls (p<0.001). In Group I mesangial IgM deposits were diffuse in 9 (100%), mesangial C_1q was present in 4, IgA and fibrinogen were each observed in 1, respectively. Electron dense deposits in the mesangium were also present in 2 to 5 patients in Group I. No significant differences were found between the two groups in age of onset, sex ratio, laboratory data except for serum IgM level, duration before biopsy, follow-up periods, outcome, and response to steroid therapy. Our data suggest that a more severe degree of either impairment of mesangial clearance of IgM or overproduction of IgM may be involved in patients with MCNS and mesangial IgM deposits but that these patients could not be considered a distinct group of patients.     

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目的总结对系统性红斑狼疮(SLE)并发乳糜性腹水的诊断及治疗经验。方法报道中山大学附属第一医院儿科首例SLE并发乳糜性腹水患儿的诊治经过并进行文献复习。结果患儿诊断为SLE、狼疮性肾炎(LN)、溶血性贫血。LN表现为肾病综合征型,肾穿刺活检示LNV+III(A/C),伴有持续严重腹水,腹水检查提示为乳糜性腹水,先后给予甲泼尼龙(MP)、环磷酰胺(CTX)冲击及饮食治疗,狼疮指标好转,腹水消退。查阅相关文献,其发病机制可能与SLE对淋巴网状系统的影响,低蛋白血症致肠壁水肿,淋巴管通透性增加,脂质代谢异常等因素有关。结论 SLE并发乳糜性腹水属罕见病例,对SLE合并难治性腹水,建议行腹腔穿刺腹水检查排除乳糜腹。治疗原则是以原发病变的治疗为主,配合饮食控制等保守治疗。     

Lupic nephropathy in childhood: morphologic analysis of 18 cases

The present study describes 21 cases (17 females and 01 male) of 12 year old patients, or younger, with diagnosis of SLE, that were submitted to renal biopsy. The histologic study demonstrated 10 cases of membranoproliferative glomerulonephritis (Class IV-WHO); 4 cases of focal proliferative glomerulonephritis (Class III-WHO; 2 cases of mesangial proliferative glomerulonephritis (Class II-WHO) and 2 cases of membranous glomerulonephritis (Class V-WHO). Three cases were excluded. In this study the incidence of lupus nephritis in children was small, similar to what has been described by other authors, and presenting unfavorable histologic patterns.     

Lupus nephritis in children

Systemic lupus erythematosus (SLE) is an autoimmune disease with varied clinical manifestations. Children and adolescents comprise one-fourth of affected patients with SLE and 40–80% of them have renal involvement. Lupus nephritis (LN) may present with mild urinary abnormalities or fulminant acute nephritis and renal failure. Diffuse proliferative glomerulonephritis (WHO class IV) is the predominant histological presentation in children and more common in boys than girls. This probably is one of the main reasons for the high mortality reported in the initial studies. Early diagnosis and aggressive treatment have led to improvement prognosis in these children. Cytotoxic therapy including intravenous cyclophosphamide has a definite role in the management WHO class IV and occasionally class III lupus nephritis. Prolonged steroid and cytotoxic therapy may lead to significant toxicity.     

Pilot study comparing the childhood arthritis and rheumatology research alliance consensus treatment plans for induction therapy of juvenile proliferative lupus nephritis

Background

To reduce treatment variability and facilitate comparative effectiveness studies, the Childhood Arthritis and Rheumatology Research Alliance (CARRA) published consensus treatment plans (CTPs) including one for juvenile proliferative lupus nephritis (LN). Induction immunosuppression CTPs outline treatment with either monthly intravenous (IV) cyclophosphamide (CYC) or mycophenolate mofetil (MMF) in conjunction with one of three corticosteroid (steroid) CTPs: primarily oral, primarily IV or mixed oral/IV. The acceptability and in-practice use of these CTPs are unknown. Therefore, the primary aims of the pilot study were to demonstrate feasibility of adhering to the LN CTPs and delineate barriers to implementation in clinical care in the US. Further, we aimed to explore the safety and effectiveness of the treatments for induction therapy.

Methods

Forty-one patients were enrolled from 10 CARRA sites. Patients had new-onset biopsy proven ISN/RPS class III or IV proliferative LN, were starting induction therapy with MMF or IV CYC and high-dose steroids and were followed for up to 24 months. Routine clinical data were collected at each visit. Provider reasons for CTP selection were assessed at baseline. Adherence to the CTPs was evaluated by provider survey and medication logs. Complete and partial renal responses were reported at 6 months.

Results

The majority of patients were female (83%) with a mean age of 14.7 years, SD 2.8. CYC was used more commonly than MMF for patients with ISN/RPS class IV LN (vs. class III), those who had hematuria, and those with adherence concerns. Overall adherence to the immunosuppression induction CTPs was acceptable with a majority of patients receiving the target MMF (86%) or CYC (63%) dose. However, adherence to the steroid CTPs was poor (37%) with large variability in dosing. Renal response endpoints were exploratory and did not show a significant difference between CYC and MMF.

Conclusions

Overall, the immunosuppression CTPs were followed as intended in the majority of patients however, adherence to the steroid CTPs was poor indicating revision is necessary. In addition, our pilot study revealed several sources of treatment selection bias that will need to be addressed in for future comparative effectiveness research.

     

Lupus nephritis. Collaborative study by the French Society of Paediatric Nephrology.

Sixty two children were included in a collaborative study to determine the prognosis for lupus nephritis. Renal involvement was confirmed by histologic study of renal biopsy specimens which were classified into five categories: minimal lesions (11 cases, 18%); focal segmental glomerulonephritis (15, 24%); diffuse proliferative glomerulonephritis (30, 48%); membranous nephropathy (5, 8%); and glomerular sclerosis (1,2%). That the predictive value of the early biopsy is limited was indicated by the most recent status of 37 patients five years after onset--total remission (13, 35%); urinary abnormalities or nephrotic syndrome (7, 19%); moderate renal failure (4, 11%); chronic renal failure (7, 19%); and hypertension (6, 16%). Treatment did not always prevent the development of severe renal failure; in particular, plasmapheresis failed to avert the death of one patient and the development of chronic renal failure in two others.     

The number of podocyte slit diaphragms is decreased in minimal change nephrotic syndrome

The pathophysiology of proteinuria in acquired kidney diseases is mostly unknown. Recent findings in genetic renal diseases suggest that glomerular epithelial cells (podocytes) and the slit diaphragm connecting the podocyte foot processes play an important role in the development of proteinuria. In this work we systematically evaluated the podocyte slit pores by transmission electron microscopy in two important nephrotic diseases, minimal change nephrotic syndrome (MCNS) and membranous nephropathy (MN). As controls, we used kidneys with tubulointerstitial nephritis (TIN). Effacement of podocyte foot processes was evident in proteinuric kidneys. However, quite normal looking foot processes and slit pores with varying width were also observed. Careful analysis of slit pores revealed, that the proportion of the pores spanned by the linear image of slit diaphragm, was reduced by 39% in kidneys from MCNS patients (1265 pores analyzed) compared with TIN samples (902 pores analyzed, p = 0.0003). To enhance the detection rate of the slit diaphragms, the "empty" podocyte pores were further analyzed with tilting series from -45 to +45. This revealed the linear diaphragm image in 71% and 26% of the slits in TIN and MCNS kidneys, respectively (p = 0.0003). In contrast to findings in MCNS, no significant reduction of the slit diaphragms were seen in MN kidneys compared with the controls. The results suggest that MCNS is associated with disruption of glomerular slit diaphragms.     

Cyclosporine in steroid dependent and resistant childhood nephrotic syndrome

OBJECTIVE: To evaluate the efficacy of cyclosporine (CyA) monotherapy in steroid resistant (SRNS) and steroid dependent (SDNS) nephrotic syndrome in children. DESIGN: A retrospective study. SETTING: Tertiary kidney care center for children at Bangalore. METHODS: Forty-one children with SDNS and SRNS with normal renal functions were treated with CyA at a dose of 6 mg/kg/day initially and maintained at 3 to 4 mg/kg/day if remission was sustained. The dosage was adjusted according to the CyA blood levels in non-responders. RESULTS: The median age of patients was 93 months (range 48-936) months. Thirteen children had minimal change disease (MCNS), 10 had mesangial proliferative glomerulonephritis (GN). Ten had membrano-proliferative (GN) (MPGN) and 8 had focal segmental glomerulosclerosis (FSGS). Median age at onset of disease and median time for CyA usage from disease onset was 22 months and 16 months respectively. Median duration of CyA therapy was 24 months (range 6-72) months. The data was analyzed to determine significance of variables on the outcome. Median follow up was 71 months (range 20-205) months. Eleven children were CyA resistant. Of the remaining 30 who were CyA responders, 22 (73.33%) were CyA dependent. Seven children developed chronic renal failure (CRF). CONCLUSIONS: The predictors for CyA non-responsiveness were steroid resistance, non MCNS on biopsy and longer duration between onset of nephrotic syndrome and CyA usage, irrespective of the age of onset of the disease. There was a higher incidence of CyA dependence among young responders. Patients with CyA resistance are at high risk for significant infections and CRF.     

婴幼儿期肾病综合征临床特点分析

目的　探讨婴幼儿期原发性肾病综合征 (简称婴幼儿肾病 )的临床特点 ;分析婴幼儿肾病临床特点、免疫功能、病理分型和糖皮质激素 (简称激素 )疗效的关系。方法　对 31例婴幼儿肾病患儿进行临床观察 ;进行体液免疫和细胞免疫功能测定 ;14例接受肾穿刺活检 ;31例均采用激素中长程疗法 ,18例予以免疫抑制剂如环磷酰胺 (CTX)等联合治疗。结果　婴幼儿肾病临床以肾炎型肾病为主 ;体液免疫和细胞免疫功能下降 ;病理以非微小病变型为主 ;约 6 0 %患儿对激素治疗不敏感 ,需用激素与免疫抑制剂联合治疗。结论　婴幼儿肾病具有与其它儿童肾病综合征不同的特点 ,应当引起临床重视。