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The histologic diagnosis and clinical findings of glomerulonephritis are very important for determining the treatment strategies. Contrary to expectation, some patients with glomerulonephritis get worse and progress into endstage renal disease. Renal deposition of C3 cleavage products are significant in the pathogenesis and development of glomerulonephritis. Recently, some investigators have reported local C3 synthesis in human renal tissue, and have suggested that it contributes to local inflammatory disorders. The purpose of this study was to explore further the clinicopathologic significance of renal C3 mRNA expression. We examined C3 mRNA expression in kidney tissues (2 normal and 18 diseased) by using nonradioactive, in situ hybridization, and compared results with clinicopathologic findings. In all diseased kidney specimens, proximal tubules had C3 mRNA-positive cells. In some cases of minimal-change nephrotic syndrome, lupus nephritis, and membranoproliferative glomerulonephritis, C3 mRNA-positive cells were found in the glomerulus. Specimens from patients with lupus nephritis showed C3 mRNA expression not only in in their tubules and glomeruli, but also in invasive, inflammatory cells. However, no signal was observed in the normal kidney specimens Cases with severe nephrotic conditions and/or with tubular injury showed strong expression. These data indicate that renal C3 mRNA that could not been detected by routine immunohistologic methods is, in fact, detectable during the active stage of disease. Therefore detection of renal C3 mRNA may give us new information for assessing pathologic activities, and may be an effective means for determining the prognosis of patients with glomerulonephritis.

慢性維持透析を受けているC1 inhibitor (C1 INH) 欠損症2症例で, 良好なシャントにもかかわらず頻回にシャント閉塞が発生した. 一例は遺伝性血管性浮腫でループス腎炎を合併して維持透析となっている. 他の一例は糖尿病性腎症から腎不全となり維持透析を受けていたが, 精査の結果, 後天性のC1 INH欠損症と診断された. 2症例とも血管性浮腫の発作とともにシャント閉塞を計5回起こした. C1 INHは補体C1のみならず凝固系のXII因子, プラスミン, カリクレイン-キニン系にも作用を及ぼすことより, これら2症例の補体系の検討とともに, 凝固線溶系, カリクレイン-キニン系への影響を調べた. また, 血栓症の既往がなく, 良好なシャントを持つ慢性維持透析患者29名の凝固, 線溶系も検討した. 維持透析患者の透析前の凝固線溶系はほぼ正常と考えられた. シャント閉塞時のthrombin-antithrombin III complex (TAT), bradykinin値は高値であった. 一例ではシャント閉塞には至らない発作時にもこれらの高値が確認された.一般に, 血管性浮腫症例で血栓症が多く起こることは報告されていないが, シャントという非生理的な血行動態下では, 発作時に凝固線溶系, カリクレイン-キニン系の異常によりシャント閉塞が起こることが考えられた.

It has been proposed that a vascular permeability factor (VPF) is involved in the pathogenesis of lipoid nephrosis (LN). There is now increasing evidence that interleukin 10 (IL-10) and interleukin 13 (IL-13) have regulatory effects on cytokine production by activated macrophages. These results prompted us to study the effects of recombinant human IL-10 and IL-13 on VPF secretion in LN. In the present study, we demonstrate that the regulatory cytokines IL-10 and IL-13 are potent inhibitors of the VPF activity of activated peripheral blood mononuclear cells. Each cytokine was found to suppress VPF secretion in a dose-dependent fashion. More importantly, the combination of the cytokines was found to give a potent synergistic suppression of VPF by concanavalin A activated peripheral blood mononuclear cells from patients with LN. When both anti-IL-10 and anti-IL-13 antibodies were added together to the peripheral blood mononuclear cells, a further increase of concanavalin A enhanced secretion of VPF occurred. These data establish IL-10 and IL-13 as potent inhibitors of VPF activity and suggest their utility in controlling deleterious VPF-mediated responses such as occur in LN patients with nephrotic syndrome.

A 47-year old man presented with atrial fibrillation, weight loss, hand tremor, and hyperperspiration concurrent with the reactivation of the disease activity of myeloperoxidase antineutrophil cytoplasmic antibody (MPO-ANCA)-associated glomerulonephritis. Laboratory findings indicated that the hyperthyroidism had already existed when glomerulonephritis was detected, and Graves' disease became evident while decreasing the dose of prednisolone. Although the levels of thyroid-stimulating hormone receptor antibody, antithyroid peroxidase antibody, and myeloperoxidase antibody increased, both disease activities were suppressed by increasing the dose of prednisolone. This case indicates that MPO-ANCA-associated glomerulonephritis and Graves' disease may share a common pathogenesis.

Background The diagnosis of hereditary angioedema (HAE) is often delayed due to the low awareness of this condition. In patients with undiagnosed HAE, abdominal symptoms often create the risk of unnecessary surgical operation and/or drug therapy. To explore the cause of misdiagnosis, we compared the laboratory findings of HAE patients under normal conditions with those during abdominal attacks. Methods Patient medical histories were analyzed and laboratory data at the first consultation with no symptoms and no medication were compared with those at visits to the emergency department during severe attacks. Results Fourteen HAE patients were enrolled. Initial HAE symptoms occurred at 20.2 ± 9.4 years of age. The correct diagnosis of HAE was made 22.7 ± 14.2 years after the initial symptoms. A common site of angioedema was the extremities. Half of the patients experienced a life-threatening laryngeal attack and/or severe abdominal pain. In the patients with severe abdominal pain, significant leukocytosis with neutrophilia along with increased levels of hematocrit were observed while levels of C-reactive protein (CRP) remained low. All severe attacks were alleviated with an infusion of C1-inhibitor concentrate. Conclusions Consideration of the likelihood of a HAE attack is important when patients present with acute abdominal pain and leukocytosis without elevation of CRP.

BACKGROUND We focused on the fluctuations of serum C3 levels throughout the clinical course of patients and investigated the relationship between these fluctuations and clinical findings. METHODS IgA nephropathy patients (n = 122) were enrolled in the present study. Serum C3 and other clinical markers were compared at the time of renal biopsy and at last follow-up (6.67 ± 2.07 years). Patients were divided into 3 groups based on serum C3 levels: Group I with first C3 levels below the mean -1 SD, which turned into an increase at last observation; group II with first C3 levels more than the mean +1 SD, which turned into a decrease at last observation; and group III, with first C3 levels more than the mean +1 SD, which turned into an increase at last observation. First and last levels of clinical markers were compared among the 3 groups. RESULTS Serum C3 levels of the patients whose renal symptoms, including hematuria, proteinuria and estimated glomerular filtration rate (eGFR), were improved, were significantly increased at last observation (p

Background The patient-rated elbow evaluation (PREE) is a joint-specific, self-administered questionnaire consisting of a pain scale (PREE-P) and a functional scale (PREE-F), the latter consisting of specific function (PREE-SF) and usual function (PREE-UF). The purpose of this study was to cross-culturally adapt the PREE into Japanese (PREE-J) and to test its reliability, validity, and responsiveness. Methods A consecutive series of 74 patients with elbow disorder completed the PREE-J, the Japanese version of the disabilities of the arm, shoulder, and hand (DASH–JSSH) questionnaire, and the official Japanese version of the 36-Item Short-Form Health Survey (SF-36). Of the 74 patients, 53 were reassessed for test–retest reliability 1 or 2 weeks later. Reliability was investigated in terms of reproducibility and internal consistency. The validity of the PREE-J was examined by factor analysis, and correlation coefficients were obtained using the PREE-J, DASH-JSSH, and SF-36. Responsiveness was examined by calculating the standardized response mean (SRM) and effect size after elbow surgery in 53 patients. Results Cronbach’s α coefficients for PREE-P, PREE-F, and PREE were 0.92, 0.97, and 0.97, respectively, and the corresponding intraclass correlation coefficients were 0.92, 0.93, and 0.94, respectively. Unidimensionality of PREE-P and PREE-F was confirmed by factor analysis. The coefficients of correlation between PREE-P and PREE-F or DASH–JSSH were 0.81 and 0.74, respectively; that between PREE-F and DASH–JSSH was 0.86, and those between DASH–JSSH and PREE-SF or PREE-UF were 0.85 and 0.82, respectively. Moderate correlation was observed in “physical functioning” for SF-36 and PREE-F (r = −0.69) or PREE (r = −0.68). The SRMs/effect sizes of PREE-P (1.31/1.32) or PREE (1.28/1.12) were more responsive than the DASH–JSSH (0.99/0.85), “bodily pain” (−1.15/−1.43), and “physical functioning” (−0.70/−0.44) in SF-36. Conclusion The PREE-J represents a reliable, valid, and responsive instrument and has evaluation capacities equivalent to those of the original PREE.

We herein present the case of a 56-year-old Japanese woman who developed purulent pericarditis after undergoing chemoradiotherapy for esophageal cancer. She developed epigastralgia and a fever and was admitted to our hospital. A physical examination revealed hypotension, tachycardia and pericardial friction rub. Echocardiography revealed moderate pericardial effusion. Based on these observations, the patient was diagnosed with cardiac tamponade. Computed tomography confirmed the presence of an esophagopericardial fistula. Treatment with pericardiocentesis, drainage and short-term intrapericardial administration of antibiotics relieved the patient's symptoms. Daily rinsing through a catheter with normal saline prevented relapse of the purulent pericarditis. Esophagopericardial fistulas are so rare that their treatment is not well-established. We herein report successful palliative care of a malignant esophagopericardial fistula associated with purulent pericarditis.

Although it has been 45 years since membranoproliferative glomerulonephritis (MPGN) and C3 nephritic factor (3NeF) were first reported, the pathophysiology of MPGN is not fully understood at present. Careful analysis of previous case reports of MPGN has been the key to developing approaches to study the mechanisms of MPGN pathophysiology. In this review, previous studies on MPGN, mainly on its association with C3NeF, are discussed and important issues on MPGN as yet unknown are stated. Complements play important roles in MPGN. Studies on complements, particularly C3NeF, advanced as studies on pathophysiology of MPGN progressed and consequently, complement activation alternative pathways were clarified. Important, although not well-known research subjects on MPGN, include characteristics of several kinds of NeF and type I, III and dense deposit disease (DDD). Detailed reading of case reports often yields new research ideas and study directions of the disease and its treatment. The present review demonstrates that reviewing previous case reports is one approach to further advancing our understanding of the complicated disease of MPGN.

Background/Aims: Mannose-binding lectin (MBL), a liver-derived C-type serum lectin, activates the complement cascade through the lectin pathway. Since the complement system contributes to the host defense against infections and mediates inflammatory processes including atherosclerosis, and since chronic renal failure (CRF) patients are prone to the development of infectious complications and cardiovascular disease, we focused on serum MBL levels in CRF patients who were either uremic, or who were receiving hemodialysis treatment. Methods: MBL levels were measured in the sera of subjects with CRF before they began dialysis treatment (pre-HD patients; n = 23) and in the sera of subjects who were receiving maintenance hemodialysis (HD patients; n = 178), by ELISA using polyclonal anti-rabbit IgG and a monoclonal antibody directed against MBL (3E7). Results: Mean levels (± SD) of serum MBL were significantly higher in pre-HD subjects (4.343 ± 2.533 µg/ml, p < 0.05) and in HD subjects (8.897 ± 4.920 µg/ml, p < 0.05), than in healthy controls (1.452 ± 0.692 µg/ml). Levels were also significantly higher in HD subjects than in pre-HD subjects (p < 0.05). Conclusions: Elevated serum MBL levels in patients with CRF might have significantly influence pathologic conditions such as alterations of the immune system and acceleration of atherogenesis.

Background Glomerular damage in IgA nephropathy (IgAN) is mediated by complement activation via the alternative and lectin pathways. Therefore, we focused on molecules stabilizing and regulating the alternative pathway C3 convertase in urine which might be associated with IgAN pathogenesis. Methods Membrane attack complex (MAC), properdin (P), factor H (fH) and Complement receptor type 1 (CR1) were quantified in urine samples from 71 patients with IgAN and 72 healthy controls. Glomerular deposition of C5, fH and P was assessed using an immunofluorescence technique and correlated with histological severity of IgAN and clinical parameters. Fibrotic changes and glomerular sclerosis were evaluated in renal biopsy specimens. Results Immunofluorescence studies revealed glomerular depositions of C5, fH and P in patients with IgAN. Urinary MAC, fH and P levels in IgAN patients were significantly higher than those in healthy controls (p < 0.001), but CR1 was significantly lower than that in healthy controls (p < 0.001). Urinary MAC and fH levels were positively correlated with serum creatinine (sCr), urinary N-acetyl-β-D-glucosaminidase (u-NAG), urinary β2 microglobulin (u-Bm), urinary protein (p < 0.001), interstitial fibrosis (MAC: p < 0.01, fH: p < 0.05) and the percentage of global glomerular sclerosis (p < 0.01). Urinary P was positively correlated with u-NAG, u-Bm, and urinary protein (p < 0.01). Conclusions Complement activation occurs in the urinary space in IgAN and the measurement of levels of MAC and fH in the urine could be a useful indicator of renal injury in patients with IgAN.

Mannose-binding lectin (MBL), L-ficolin and MBL associated serine protease-2 (MASP-2) are molecules involved in initiation of the lectin pathway (LP) in the complement system. Although MBL deficiency is observed in almost 10% of healthy people, studies of associations between MBL deficiency and end-stage renal disease (ESRD) remain rare. The objective of the present study is to clarify the significance of the LP in maintenance hemodialysis (HD) patients, especially in terms of MBL levels. Two hundred and forty-four HD patients who had been followed up for 74±84months and 199 healthy controls were included in this study. Measurements of serum concentrations of MBL, L-ficolin, and MASP-2 were performed. Low serum MBL levels (0.1µg/mL) in the patients were confirmed by examination of a point mutation in the Mbl-2 gene. Seventeen HD patients (7%) and 20 healthy controls (10%) had MBL deficiency. During the follow-up period, 99 patients died. There was no significant difference in the frequency of deaths by infectious diseases between MBL deficient and non-deficient patients. In both patients and healthy controls with MBL deficiency, the serum concentration of L-ficolin tended to be high, and that of MASP-2 was significantly high (P0.05). MBL deficiency is not a risk factor for HD induction or life-threatening infections. It is postulated that the elevation of concentration of the two components of the LP, L-ficolin and MASP-2, may compensate for the insufficient activity of the LP in MBL deficiency.

Background The complement system is vital for innate immunity and is implicated in the pathogenesis of inflammatory diseases and the mechanism of host defense. Complement deficiencies occasionally cause life-threatening diseases. In hemodialysis (HD) patients, profiles on complement functional activity and deficiency are still obscure. The objectives of the present study were to measure the functional complement activities of the classical pathway (CP), lectin pathway (LP) and alternative pathway (AP) using a novel method and consequently to elucidate the rates of deficiencies among HD patients. Methods In the present study, 244 HD patients at one dialysis center and 204 healthy controls were enrolled. Functional complement activities were measured simultaneously using the Wielisa®-kit. The combination of the results of these three pathway activities allows us to speculate which candidate complement is deficient; subsequently, the deficient complement was determined. Results All three functional complement activities were significantly higher in the HD patients than in the control group (P < 0.01 for all cases). After identifying candidates in both groups with complement deficiencies using the Wielisa®-kit, 16 sera (8.8%) with mannose-binding lectin (MBL) deficiency, 1 serum (0.4%) with C4 deficiency, 1 serum (0.4%) with C9 deficiency, and 1 serum (0.4%) with B deficiency were observed in the HD group, and 18 sera (8.8%) with MBL deficiency and 1 serum (0.5%) with B deficiency were observed in the control group. There were no significant differences in the 5-year mortality rate between each complement-deficient group and the complement-sufficient group among the HD patients. Conclusion This is the first report that profiles complement deficiencies by simultaneous measurement of functional activities of the three complement pathways in HD patients. Hemodialysis patients frequently suffer from infections or malignancies, but functional complement deficiencies do not confer additional risk of mortality.

Immunoglobulin A nephropathy (IgAN) is characterized by mesangial cell proliferation and mesangial expansion with mesangial depositions of IgA. We have found that electron-dense deposits (EDD) are often observed in areas other than paramesangial areas in glomeruli. To compare electron microscopic findings with light microscopic findings and clinical data, we examined the biopsies from 178 patients with IgAN. Patients were divided into two groups: group A had only paramesangial deposits and group B had deposits not only in paramesangial areas but also in other areas. All patients examined in this study had EDD in glomerular paramesangial areas. Thirty-six patients were included in group B. Cellular crescent formation in glomeruli and urinary protein in group B were significantly higher than those in group A (P < 0.01). Serum albumin and estimated glomerular filtration rate (eGFR) in group B were significantly lower than those in group A (P < 0.05). Group B showed a significant positive correlation with histological severity, which is defined in the Japanese Clinical Guidelines on IgAN. In patients with broad distribution of EDD, urinary protein was significantly increased (P < 0.05). Detailed observation of EDD distribution has an impact on evaluation of the disease activity of IgAN.

Hamatometacarpal fracture–dislocation is a rare injury that consists of a fourth metacarpal fracture and a fifth carpometacarpal joint injury. We present the case of a 21-year-old man with a divergent hamatometacarpal fracture–dislocation that consisted of a combination of dorsal intra-articular fracture–dislocation of the fourth carpometacarpal joint, palmar dislocation of the fifth carpometacarpal joint, and fracture of the hook of the hamate. The mechanism of palmar dislocation of the fifth metacarpal base and fracture of the hook of the hamate involved extension of the fifth metacarpal and ulnopalmar load transmission.

A 77-year-old diabetic man newly contracted pulmonary mucormycosis. A rapidly progressing clinical course including severe worsening of pneumonia and renal failure culminated in death. This patient presented with hypocomplementemia and dermal vasculitis. Autopsied organs were examined by histological technique. Lung tissues showed pulmonary artery thrombosis and extensive alveolar invasion by Mucor hyphae with depositions of immunoglobulins, mannose-binding lectin (MBL) and C1q. The right internal jugular vein was occluded by thrombi containing numerous hyphae. The glomerular change was a hallmark of extra-capillary proliferative glomerulonephritis, which was overlying diabetic nephropathy. Depositions of IgM, C3 and C4 on glomeruli were also detected. Electron microscopy showed electron-dense deposits in the mesangial area and the wall of the afferent arteriole. This report shows evidence of complement opsonization of Mucor hyphae and refers to mucormycosis that developed small-sized vasculitis with complement activation.

Bcl11b+/- heterozygous mice and Bcl11b+/-p53+/- doubly heterozygous mice showed more susceptibility to γ-ray-induced thymic lymphomas than Bcl11b wild-type mice and p53+/- mice, respectively. Most of the thymic lymphomas developed in irradiated Bcl11b+/-p53+/- mice retained the Bcl11b wild-type allele, indicating that Bcl11b is a haploinsuffi cient tumor suppressor gene. Of interest is the high retention of the wild-type Bcl11b allele in those radiation-induced tumors, and this leads to the implication that the main contribution of irradiation in the Bcl11b+/-p53+/- mice is not to tumor initiation, by inducing allelic losses, but to the promotion of thymic lymphoma development. Although the reason for this unexpected high retention is unclear, an explanation might be the apoptosis given by loss of Bcl11b in the Jurkat T-cell line, because apoptosis appears to contradict the predicted property of tumor suppressors. Our chapter also shows the presence of clonally growing large thymocytes in atrophic thymuses at 40 days after irradiation. Those cells are probably prelymphoma cells because of the genetic alteration detected. However, the cell number was low, and therefore abrogation of the hindrance in cell proliferation through additional genetic and/or epigenetic changes may be a prerequisite for lymphoma development.

A 57-year-old-woman, who was treated with regular maintenance hemodialysis (HD), newly contracted rheumatoid arthritis (RA). Oral predonisolone was effective for alleviating her arthralgia but the RA activity became steroid-dependent. For treatment of poorly controlled synovitis leukocytapheresis (LCAP) showed excellent efficacy in the treatment of her joint pain. No serious adverse effects were observed. Serological markers such as CRP, serum amyloid A, matrix metalloproteinase 3 and peripheral blood lymphocyte count fluctuated with her clinical symptoms. We recommend LCAP as candidate therapy for steroid-dependent patients with RA who are on maintenance HD.

The complement system plays an important role in renal pathogenesis, and C5b-9, a terminal complement complex, is regarded as the principal mediator of proteinuria in idiopathic membranous nephropathy(MN). Since factor H regulates complement activation at the C3 step and is a crucial factor in complement-mediated tissue injury, the urinary excretion of factor H in patients with idiopathic MN was investigated.Seven patients with biopsy-proven idiopathic MN were studied for twenty-four weeks. Urinary factor H levels were measured by ELISA from regularly collected urine samples, and then evaluated and compared with assays of urinary protein and C5b-9 excretion.During the study, five patients were treated with steroid therapy. All seven patients maintained stable renal function and showed a decline in urinary protein excretion. The mean level of urinary factor H was markedly elevated (156.1 +/- 47.1 U/mg U-Cr) before treatment (0 week), and gradually declined to 127.2 +/- 43.5 U/mg U-Cr at 12 weeks, and to 64.7 +/- 26.9 U/mg U-Cr) at 24 weeks. This followed decreases in urinary protein and urinary C5b-9 excretion. Percent change in urinary factor H level significantly decreased 24 weeks after treatment without affecting the plasma factor H level.These results suggest that factor H contributes to the regulatory mechanism of in situ complement activation, and thus the study of urinary factor H levels, as well as urinary C5b-9, may be significant in idiopathic MN.

Recurrent chromosomal rearrangements at BCL11B are found in human hematopoietic malignancies mostly of T-cell origin. However, it is unclear how this disruption contributes to oncogenesis, because the majority of leukemias express BCL11B from an undisrupted allele. Here, we show that Bcl11b +/− p53 +/− mice exhibited greater susceptibility to lymphomas than Bcl11b +/+ p53 +/− mice but most lymphomas retained and expressed the wild-type Bcl11b allele. This strongly suggests that Bcl11b is haploinsufficient for suppression of thymic lymphoma development in mice of the p53 +/− background, a situation in which functional loss of only one allele confers a selective advantage for tumor growth. The haploinsufficiency is further supported by that Bcl11b +/− mouse embryos were impaired in thymocyte development and survival. These results indicate relevance of BCL11B aberration to human leukemogenesis.

Mouse thymic lymphomas induced by gamma-irradiation exhibited homozygous deletions of the Rit1/Bcl11b tumor suppressor gene on chromosome 12 at high frequencies. Internal deletions of one allele were frequently accompanied by loss of the other allele. In order to elucidate the mechanism of these internal deletions, the sites of breakage and rejoining were examined by PCR mapping and sequencing. The 5' site of the deletions clustered within an approximately 5 kb region of intron 1 and the 3' site was confined to a site in intron 3. These sites contained P and/or N nucleotides and cryptic sequences recognizable by the RAG1/2 recombinase in the vicinity. This suggests that the Rit1 intragenic deletions were generated by endogenous illegitimate V(D)J recombinase activity and such aberrant recombination was also detected by nested PCR of DNA from the thymus of unirradiated mice but not of RAG2-deficient mice. A rough estimate indicated that there reside as many as 10(3)-10(4) thymocytes having Rit1 deletions, assuming the presence of 10(8) thymocytes in the thymus of unirradiated mice. Moreover, the recombination frequency was not affected by gamma-irradiation. These results show no effect of radiation on Rit1 mutations and suggest an indirect mechanism for its role in lymphomagenesis.

Background/Aims: The complement system plays an important role in the pathogenesis of membranous nephropathy (MN). In order to elucidate the regulatory mechanism of complement activation, we demonstrated glomerular deposition and urinary excretion of complement factor H, which controls the alternative pathway and the amplification loop at the C3 step, in patients with idiopathic MN. Methods: Renal biopsy specimens from 20 patients with idiopathic MN were studied immunohistochemically using monoclonal antibodies against complement components including factor H. SDS-PAGE and Western blotting analysis of urine samples were performed, and the urinary excretion of factor H and C5b-9 were measured by quantitative sandwich ELISA. Results: Intense glomerular deposition of factor H was observed with C3b·C3c and C5b-9 at an early stage of the disease. Factor H was detected in Western blots of urine samples, but factor H-like protein 1 (FHL-1) was not. The mean level of urinary factor H was elevated (86.30 ± 21.93 U/mg urinary creatinine) in comparison to that of normal controls (4.76 ± 1.03 U/mg urinary creatinine). Urinary factor H level exhibited no correlation with clinical parameters; however, a negative correlation was found between urinary C5b-9/factor H and creatinine clearance (r = 0.662, p < 0.01). Conclusion: The source of glomerular and urinary factor H is supposedly a 150-kD protein. There was no evidence to suggest that FHL-1 is synthesized at the site of inflammation. The urinary C5b-9 to urinary factor H ratio is indicative of the degree of ongoing complement activation in the glomeruli and complement-mediated renal injury. These findings suggest that factor H contributes to the control mechanism of in situ complement activation and prevents renal damage in idiopathic MN.

Thromboembolism is known as a major complication of nephrotic syndrome, but only 4 cases of portal vein thrombosis have been reported as a complication of nephrotic syndrome. All of these 4 cases had acute symptoms, and 3 of 4 were in relapsing phase of nephrotic syndrome when thrombi were found. We describe here a case of 51-year-old woman with fresh nephrotic syndrome that was asymptomatically complicated by portal, splenic and renal vein thrombosis.In the presence of fresh nephrotic syndrome of minimal change, asymptomatic and widely distributed, including portal vein, thrombus formation occurred. If the clinical course shows resistance to therapy, we must consider the complication of venous thrombosis. Anticoagulant therapy with heparin and warfarin was effective and all thrombi disappeared without any other complications.

Background: Complement factor H (hCFH) plays a key inhibitory role in the control of the alternative complement pathway. We examined whether urinary hCFH (U-hCFH) levels is useful as an indirect indicator of renal damage. Methods: Urine samples were obtained from 104 patients with renal disease. Urine was collected with 10 mM EDTA and U-hCFH levels were measured using the BTA TRAK Assay Kit. Results: In the 62 patients with nephritis, the levels of U-hCFH were elevated (range 15–52,198 U/ml) over the normal range (0–14 U/ml). U-hCFH levels of patients with chronic renal failure, lupus nephritis, membranoproliferative glomerulonephritis, focal glomerulosclerosis were higher than that of IgA nephropathy patients (p < 0.05). In the patients with minimal change disease, showed high levels of U-hCFH during the nephrotic syndrome. U-hCFH was correlated significantly with urinary protein and urinary N-acetyl-β-D-glucosaminidase. Conclusion: We demonstrated that U-hCFH was detected in the urine of nephritis patients.

Renal blood flow decreases with the progression of chronic glomerulonephritis (CGN). This disease induces medullary ischemia and further renal dysfunction in patients with chronic renal insufficiency (CRI). Prostacyclin (PGI2), with its vasodilative action, increases renal blood flow (RBF) without increasing glomerular filtration rate (GFR). We therefore examined the possibility that PGI2 would mitigate the progression of renal dysfunction by increasing RBF in patients with CRI. Sixteen patients with progressive renal insufficiency (serum creatinine: 2.14+/-0.89 mg/dl) due to CGN were prospectively chosen for this study. The blood pressure was already under control using calcium channel blockers before and during this study in nine hypertensive patients. In the first 6 months the patients received a low-protein (0.6 g/kg/day) and low-salt (5.0 g/day) diet. In the next 6 months they received 60 microg/day of PGI2 analogue (Beraprost sodium) orally. GFR was determined by 24-hour creatinine clearance, and effective renal plasma flow (ERPF) was determined by 99mTc-MAG3 scintigraphy. Glomerular capillary pressure, the resistance ratio of afferent and efferent arterioles (R(A)/R(E)), and the other hemodynamic parameters from Gomez's estimation equation were determined at the start of this study, just before the administration of Beraprost and at the end of the study. The levels of GFR and ERPF were 34.6+/-12.4 and 140.6+/-52.1 ml/min at the start of this study respectively, and decreased to 28.0+/- 12.0 and 115.6+/-45.3 ml/min after the first 6 months without Beraprost. The levels of GFR and ERPF stayed at 28.1+/-15.7 and 119.2+/-57.6 ml/min after the next 6 months with Beraprost in the same patients. R(A)/R(E) increased in the first 6 months from 7.9+/-3.6 to 10.8+/-8.6, but remained constant during 6 months of Beraprost administration, at 10.5+/-8.0. These data indicate that PGI2 analogue diminishes the vascular resistance of glomerular afferent and efferent arterioles regulating the decrease of renal blood flow without glomerular hyperfiltration, thus mitigating the progression rate of renal dysfunction.

Membranes used for dialysis therapy activate complement. Complement activation is maximal after initiating dialysis and returns to predialysis values by the end of dialysis. No changes in C3 levels have been detected after dialysis. We hypothesized that although C3 levels were unchanged, C3 activity could be altered by dialysis. We measured complement activation in vitro in serum from patients randomized to dialysis treatments using different types of membranes. The classical pathway was activated with aggregated immunoglobulin G (IgG), and the alternative pathway was activated with inulin. Both the classical and alternative pathways were suppressed after dialysis using cellulose membranes (aggregate IgG, P [lt ] 0.01; inulin, P [lt ] 0.001). When polyacrylonitrile (PAN) or polyethylene glycol grafted cellulose membranes were used for dialysis, only minor suppression of complement pathways was measured. Levels of the control factor SP-40,40 increased at later times for dialysis using cellulose membranes ( P [lt ] 0.05). Factor H levels were also greater after dialysis using cellulose membranes compared with PAN membranes ( P [lt ] 0.05). In summary, cellulose membranes suppress complement activation in serum. One suppressing factor may be the complement control factor SP-40,40. [copy ] 2001 by the National Kidney Foundation, Inc.

A 24-year-old woman presented with renal insufficiency, macrohematuria, and mild urinary protein. Polyclonal hypergamma-globulinemia, thrombocytosis, increased concentration of serum, and urinary interleukin (IL)-6 all indicated persistent immune activation caused by a Chlamydia trachomatis infection of the fallopian tube. Gynecological treatment with levofloxacin was effective both for the renal symptoms and other immunological parameters. First and second renal biopsy specimens showed an immune-complex glomerulopathy with extensive interstitial infiltration of many types of inflammatory cells, including plasma cells. Thus, we conclude that chlamydial salpingitis must be considered as one causative disease factor for renal involvement by means of its persistent immune activation effects.

It has been proposed that immune responses in mammalian normal pregnancy are Th2-like, thereby protecting the fetus and placenta from being rejected. Administration of exogenous Th1 cytokines into pregnant mice is reported to induce feto-placental resorption. However, the effects of exogenous Th2 cytokines and Th2 directed responses in pregnant animals have not been well studied. In this study, we examined IL-4 and IL-12, which play decisive roles in the development of Th2 and Th1 responses, respectively, in the induction of fetal resorption and development of experimental pre-eclampsia. Transfer of either IL-4 and/or IL-12 stimulated splenocytes from BALB/C virgin female mice into BALB/C pregnant mice mated with either C57BL/6 or BALB/C male mice resulted in fetal resorption and glomerular nephritis associated with hypertension and proteinuria. In mice treated with IL-12 stimulated splenocytes, fatty liver degeneration associated with bile retention was observed. These results indicate that both excessive Th1 and Th2 activation contribute to the development of fetal resorption and pre-eclampsia, but that Th1 is critical to the development of liver degeneration.

The role of free sialic acid on complement activation was investigated. The serum levels of free sialic acid and total sialic acid were measured by previously described methods in 16 patients with acute post‐infectious glomerulonephritis (AGN), 27 patients with systemic lupus erythematosus (SLE), 15 patients with persistent hypocomplementemic membranoproliferative glomerulonephritis (MPGN), and 13 healthy controls. A statistical study demonstrated an increased level of free sialic acid in patients with AGN and SLE in which the hypocomplementemia improved throughout the course and a decreased level of free sialic acid in patients with MPGN and SLE in which hypocomplementemia continued throughout the course. The levels of total sialic acid were significantly increased in patients with AGN and SLE and were significantly decreased in patients with MPGN. There was no correlation between the levels of free sialic acid and total sialic acid in patients with AGN, in whom the levels of both total and free sialic acids were increased. To examine the effect of free sialic acid on the complement cascade, lipopolysaccharide (LPS) was incubated with normal human serum (NHS) in the various concentrations of N‐acetyl neuraminic acid (NANA), a member of the sialic acid group. The incubation mixtures were examined by enzyme immunoassay using monoclonal anti‐iC3b antibody or anti‐Bb antibody. Native C3 or Factor B in NHS broke down less following the addition of NANA. To elucidate the role of NANA on the hemolytic function of C3, a rabbit erythrocyte (Ra E) hemolytic assay was carried out. Ra E lysed completely in the presence of R3 with native C3. However, hemolysis occurred to a lesser degree in C3‐depleted serum (R3) or R3 with NANA‐treated C3. To investigate the influence of NANA on complement components, the levels of complement components were measured in the incubation mixture with various doses of NANA and NHS. The levels of C3 and C5 were significantly decreased after the addition of NANA, even though the levels of Factor H and Factor I were not markedly changed. These data indicate that NANA exerts an influence on the complement components even though it has no effect on the regulatory proteins of complement. Our in vitro findings, together with the in vivo data, suggest that free sialic acid might have an inhibitory effect on the activation of C3 and the following complement cascade, and might also have been responsible for the improvement of hypocomplementemia. J. Clin. Lab. Anal. 13:173–179, 1999. © 1999 Wiley‐Liss, Inc.

The role of sialidase in complement activation and in development of hypocomplementemia in patients with postinfectious acute glomerulonephritis (AGN) was investigated. In sera from 17 patients with AGN and 14 healthy controls, sialidase activity and serum levels of free and total sialic acid were measured by previously established methods. Circulating sialidase activity and serum levels of free and total sialic acid and haptoglobin were increased, and the C3 level was decreased in the acute phase of AGN. There was no correlation between free sialic acid and total sialic acid, which increased in parallel with serum levels of haptoglobin, one of the acute-phase reactants. A follow-up study of these parameters in a typical case reflected this tendency and suggested that increased sialidase after infection, in addition to complement activation by the infectious substance, could play a role in development of hypocomplementemia. To clarify this mechanism, purified neuraminidase was incubated with normal human serum under various conditions. Complement breakdown products were measured in the incubation mixture by enzyme-linked immunosorbent assay using monoclonal antibodies against iC3b, Bb, and C4d neoantigens. iC3b was generated dose-dependently in the presence of neuraminidase. Further examination revealed that iC3b and Bb were generated in the incubation mixture with neuraminidase and NHS and that C4d was not detected in the same mixture. These findings indicate that neuraminidase activates the alternative complement pathway. These in vitro data, together with the former in vivo data led us to conclude that increased sialidase after infection could accelerate the complement amplification system, resulting in hypocomplementemia in the acute phase of postinfectious AGN.

The characteristic function of interleukin (IL)-15 appears to be its ability to mimic the stimulatory action of IL-2 on lymphocytes by utilizing part of the IL-2 receptor complex. To gain insight into the immunoregulatory properties of this cytokine in patients with minimal-change nephrotic syndrome (MCNS), we analyzed effects of IL-15 on vascular permeability factor (VPF) release in vitro. Peripheral blood mononuclear cells (PBMC) were isolated from 16 patients with MCNS, 16 patients with IgA nephropathy (IgAN) and 16 healthy controls. Cells were stimulated with concanavalin A (Con A) and the VPF was assessed using the method of Lagrue with minor modifications. PBMC secreted significantly increased amounts of VPF under stimulation with Con A in patients with MCNS and IgAN patients with the nephrotic syndrome as compared with normal controls. Here we have demonstrated, for the first time, that addition of IL-15 to PBMC obtained from nephrotic patients as well as from normal controls increased Con A-induced release of VPF by 250%. This stimulatory effect was found highly significant and was dose-dependent. The effect of IL-15 on the secretion of VPF was specific, since a complete reversion was obtained with a neutralizing antibody to human IL-15. Our findings reveal that IL-15 has the potential to function as an immunoregulatory molecule of PBMC VPF release. In addition, IL-15 had similar effects to IL-2 in terms of its capacity to upregulate VPF release. Taken together, our data emphasize a positive regulatory role for IL-15 in inducing the release of VPF when present at optimal levels. Therefore, IL-15 antagonists may provide a basis for immune intervention in the pathophysiology of VPF.

Increased production of a vascular permeability factor (VPF) from peripheral blood mononuclear cells (PBMC) in patients with minimal-change nephrotic syndrome (MCNS) has been reported. Interleukin-4 (IL-4) and interleukin-10 (IL-10), both produced by T-helper type-2 cells, are cytokines with the capacity to downregulate proinflammatory responses. To gain insight into the immunoregulatory properties of these cytokines, we analyzed the effects of recombinant human IL-4 and IL-10 on VPF release in MCNS patients. In the present study we show that the regulatory cytokines IL-4 and IL-10 are potent inhibitors of the VPF activity of concanavalin A-activated MCNS PBMC. Each cytokine was found to suppress VPF release in a dose-dependent manner. Moreover, when used at suboptimal concentrations, a combination of the two cytokines resulted in enhanced suppression of VPF release. Neutralization of endogenously produced IL-4 and IL-10 by both anti-IL-4 and anti-IL-10 antibodies resulted in an increased release of VPF. These data demonstrate that IL-4 acts in concert with IL-10 to inhibit VPF release and suggest that they are effective biologic regulators of the VPF responses in vitro.

A known inhibitor of the complement cascade (K-76 COONa) was administered to an inbred diabetic rat model to investigate whether the complement system may play a role in the progression of diabetic glomerulosclerosis. Drinking water containing K-76 COONa was available continuously to inbred diabetic rats (Otsuka Long-Evans Tokushima Fatty, OLETF) from the age of 25 to 55 weeks (Group L). Drinking water without K-76 COONa was similarly available to OLETF rats (Group H) and nondiabetic control rats (Long-Evans Tokushima Otsuka, LETO) (Group C). The levels of plasma glucose (mg/dl) at the 55th week were 156 ± 16 in Group C, 252 ± 18 in Group L and 349 ± 93 in Group H. There was no significant difference in the degree of diabetes between Group L and Group H. The levels of urinary protein at 55 weeks of age (mg/day) were 2.1 ± 0.4 in Group C, 11.6 ± 1.5 in Group L and 18.0 ± 2.8 in Group H. The level of urinary protein was significantly decreased by the administration of K-76 COONa. Histological examination of renal specimens from the sacrificed rats at 55 weeks of age revealed diffuse mesangial expansion in almost all glomeruli in Group H, exudative lesions in 30% of glomeruli in Group H, and only mild mesangial expansion was recognized in Group L. Immunofluorescence study revealed brilliant staining of C3 and immunoglobulins (Ig) in Group H; trace staining of Ig and no staining of C3 were recognized in Group L. The incubation study with guinea pig serum and glomeruli from rats revealed that Ig and complement components also bound to injured glomeruli in vitro. These data indicate that the complement cascade is activated by injured glomeruli and this activation exacerbates diabetic glomerulosclerosis.

The vascular permeability factor (VPF) is a lymphokine that has been shown to play a role in lipoid nephrosis (LN). Prior studies have shown that interleukin (IL) 12 promotes T helper type 1 differentiation and enhances production of T helper type 1 cytokines such as gamma interferon and IL-2. We, therefore, investigated the effects of recombinant human IL-12 on the release of VPF by peripheral blood mononuclear cells (PBMC) from LN patients. The VPF activity was measured according to the method of Ovary, with minor modifications. The goal of the present study was to examine the importance of IL-12 in concanavalin A induced VPF release in vitro. The levels of VPF were measured in a group of healthy subjects, LN patients with or without the nephrotic syndrome, and patients suffering from IgA nephropathy. There was a significantly increased concanavalin A induced release of VPF in LN and IgA nephropathy patients with nephrotic syndrome as compared with normal controls. Recombinant human IL-12 was found to enhance VPF release in a dose-dependent manner. Neutralization of endogenously produced IL-12 by anti-IL-12 antibody resulted in a decreased release of VPF by LN PBMC. These data indicate that endogenously produced IL-12 functions as a costimulatory molecule in vitro. Our data show that IL-12 can upregulate the release of VPF derived from LN PBMC. Thus IL-12 might be a potent adjuvant for inducing VPF. Therefore, IL-12 antagonists may interfere with newly initiated and ongoing VPF release associated with nephrotic syndrome.

Serum from patients with membranoproliferative glomerulonephritis (MPGN) and acute poststreptococcal glomerulonephritis (APSGN) accelerated the decay of the cell bound C4b2a (C42) and C4b hemolytic activity relative to pooled normal human serum (pNHS) after 5 min incubation at 30 degrees C in EDTA-GVB. The accelerated decay of the C42 hemolytic activity was heat stable (56 degrees C 30 min) and was inhibited by monoclonal antibody against human C4 binding protein (MoAb:C4BP) or C4 binding protein (C4BP) depleted serum. C4 nephritic factor (C4NeF) was employed to stabilize the labile classical pathway C3 convertase C42 complex. Serum from patients with MPGN and APSGN reduced the C4NeF stabilizing activity. Sera from 32 of 46 patients with MPGN and all of 7 patients with APSGN reduced the C42 hemolytic activity relative to 50 normal human serum (NHS) after 5 min incubation at 30 degrees C in EDTA-GVB, and there was no relationship with the serum concentration of C4BP. In vivo, accelerated decay of C42 convertase might interfere with the clearing and processing mechanism of circulating immune complexes (IC) by reducing deposition of C3b on the IC lattice.