T cell cytokine polarity as a determinant of immunoglobulin A (IgA) glycosylation and the severity of experimental IgA nephropathy

Immunoglobulin A (IgA) glycosylation, recognized as an important pathogenic factor in IgA nephropathy (IgAN), is apparently controlled by the polarity of T helper (Th) cytokine responses. To examine the role of cytokine polarity in IgAN, inbred mice were immunized by intraperitoneal priming with inactivated Sendai virus (SeV) emulsified in either complete Freund's adjuvant (CFA) or incomplete Freund's adjuvant (IFA), which promote Th1- or Th2-immune response, respectively, and then boosted identically twice orally with aqueous suspensions of inactivated virus. Next, some mice were challenged intranasally with infectious SeV. Mice primed with CFA or IFA had equal reductions in nasal viral titre relative to non-immune controls, and equally increased serum levels of SeV-specific IgA antibody. Mice primed with CFA showed higher SeV-specific IgG than those with IFA. Splenocytes from mice primed with IFA produced copious amounts of interleukin (IL)-4 and IL-5, but little interferon-gamma and IL-2; those primed with CFA had reciprocal cytokine recall responses. Total serum IgA and especially SeV-specific IgA from mice primed with IFA showed a selective defect in sialylation and galactosylation. Although the frequency and intensity of glomerular deposits and haematuria did not differ, glomerulonephritis in mice primed with IFA and challenged with infectious virus was more severe than in those given CFA, as judged by serum creatinine level. We conclude that the polarity of T cell cytokines controls the pattern of IgA glycosylation and exerts direct or indirect effects on functional glomerular responses to immune complex deposition.     

Abnormalities of the IgA immune system in members of unrelated pedigrees from patients with IgA nephropathy.

In the last few years many investigators have reported the recurrence of primary IgA nephropathy (IgAN) or the presence of persistent microhaematuria and/or proteinuria in family members of patients with IgAN. Our study was undertaken to investigate the relevance of abnormalities in the regulation of the IgA and IgM immune system in microhaematuric and asymptomatic family members of IgAN patients. Fifty-four out of 120 members of nine unrelated pedigrees were examined by urinalysis; polymeric IgA (pIgA), IgA rheumatoid factor (IgARF), IgA1-IgG immune complexes (IgA 1-IgG IC) and IgA 1-IgM IC, and other immunoglobulins were measured in serum samples. Moreover, we studied the production of immunoglobulins, pIgA and IgARF by peripheral blood mononuclear cells (PBMC) in basal conditions and after pokeweed mitogen (PWM) stimulation. Our data demonstrate that persistent microhaematuria was present in 24% of relatives. High serum levels of IgA, mainly pIgA and IgARF, IgA 1-IgG IC and IgA 1-IgM IC occurred in 66% of relatives. Abnormal spontaneous production of IgA by PBMC and after PWM stimulation was present in 64% of family members. Interestingly, high serum levels of IgM and abnormal production of this immunoglobulin by PBMC were observed in relatives. However, the immunological abnormalities did not correlate in any way with the presence of urinary abnormalities such as microhaematuria, which was most likely determined by an underlying glomerular alteration.     

IgA-containing immune complexes after challenge with food antigens in patients with IgA nephropathy.

The possibility that patients with IgA nephropathy (IgAN) might have abnormal IgA immune responses to immunogens commonly encountered at mucosal surfaces, resulting in the formation of circulating immune complexes (CIC), was examined. Since it is generally held that such increased IgA responses are characterized by detectable aberrancies in handling of IgA-containing CIC, IgAN patients and controls were given a large volume of bovine milk (after dietary deprivation of bovine antigens) and immune complex levels were measured over a period of 12 h. An assay based on binding of CIC containing C3 to solid-phase anti-C3 and subsequent development with isotype-specific antibody revealed no differences in responses of patients and controls with respect to IgG- and IgM-containing CIC. Although IgAN patients tended to have higher levels of IgA-containing CIC, there were no differences in response patterns when IgA CIC levels after ingestion of the milk stimulus were related to baseline levels. Polymorphonuclear leucocytes (PMNC), which bear surface receptors for IgA, were isolated from some subjects at the same times as the samples for CIC levels and examined by two-colour immunofluorescence for the coincident presence of IgA and milk antigens. In contrast to the data obtained in the CIC assays, these experiments revealed the simultaneous presence of IgA and two of three milk proteins in PMNC of IgAN patients but not controls. Follow-up experiments designed to assess more quantitatively the coincidental presence of IgA and milk antigens indicated no significant differences between patients and controls. However, milk proteins seemed to be more commonly associated with IgA in PMNC of IgAN patients, suggesting the presence of non-complement-fixing IgA/antigen CIC after mucosal challenge of some IgAN patients.     

Antibodies to polyclonal IgA,IgA1, and IgA2 and isotype-specific immune complexes in IgA nephropathy

The concentrations of serum IgG and IgM antibodies to polyclonal IgA (IgA_p), IgA₁, and IgA₂ were determined by enzyme immunoassay in 31 patients with IgA nephropathy and 30 healthy controls. Patients with IgA nephropathy had significantly raised concentrations of serum IgA compared to controls (Mann-WhitneyU test,P=0.001) and increased concentrations of conglutinin-binding IgA immune complexes (P=0.024). No differences in the median concentrations of IgG and IgM anti-IgA antibodies were found between the patients and the controls. In serum samples from healthy controls there was a significant positive correlation between IgM anti-IgA_p and IgA immune complex concentrations (P=0.05), which contrasted with the finding of an inverse correlation between IgM anti-IgA_p and IgA immune complex concentrations in patients with IgA nephropathy (P<0.05). In addition, the concentrations of conglutinin binding IgM immune complexes in serum were found to correlate with the concentration of IgM anti-IgA_p (0.010<P<0.025), IgM anti-IgA₁, and IgM anti-IgA₂ (P«0.005 for both) in patients with IgA nephropathy but not in controls. IgM anti-IgA antibodies may be important in augmenting the clearance of IgA immune complexes from the serum of patients with IgA nephropathy.     

Association of single-nucleotide polymorphisms in the polymeric immunoglobulin receptor gene with immunoglobulin A nephropathy (IgAN) in Japanese patients

Immunoglobulin A nephropathy (IgAN) is a primary glomerulonephritis of common incidence world-wide whose etiology and pathogenesis remain unresolved, although genetic factors are assumed to be involved in the development and progression of this disease. To identify genetic variations that might confer susceptibility to IgAN, we performed a case-control association study involving 389 Japanese IgAN patients and 465 controls. Genome-wide analysis of approximately 80,000 single-nucleotide polymorphisms (SNPs) identified a significant association between IgAN and six SNPs located in the PIGR (polymeric immuoglobulin receptor) gene at chromosome 1q31-q41. One of them, PIGR-17, caused an amino-acid substitution from alanine to valine at codon 580 (χ²=13.05, P=0.0003, odds ratio [OR] =1.59, 95% confidence interval [95% CI] =1.24–2.05); the OR of minor homozygotes to others was 2.71 (95% CI=1.31–5.61). Another SNP, PIGR-2, could affect promoter activity (χ²=11.95, P=0.00055, OR=1.60, 95% CI=1.22–2.08); the OR of minor homozygotes to others was 2.08 (95% CI=0.94–4.60). Pairwise analyses demonstrated that all six SNPs were in almost complete linkage disequilibrium. Biopsy specimens from IgAN patients were positively stained by antibody against the secretory component of PIGR, but corresponding tissues from non-IgAN patients were not. Our results suggest that a gene associated with susceptibility to IgAN lies within or close to the PIGR gene locus on chromosome 1q in the Japanese population. Electronic database information: URLs for the data in this article are as follows: Online Mendelian Inheritance in Man (for IgAN, MIM161950): JSNP (for SNPs and primers):     

Three SNPs of FCRL3 and one SNP of MTMR3 are associated with immunoglobulin A nephropathy risk

PurposeImmunoglobulin A nephropathy (IgAN) is determined by a combination of multiple genetic and environmental factors, but its etiology and pathogenesis are not well understood. We aim to determine whether variations in FCRL3 and MTMR3 correlate with IgAN risk indices in Chinese Han people.MethodsEight single nucleotide polymorphisms (SNPs) of FCRL3 and MTMR3 were genotyped, and association analysis was performed. A total of 426 patients with IgAN and 498 healthy individuals, serving as the control group, were recruited for this association study.ResultsThere were significant associations between FCRL3 rs11264793 (OR = 0.78; 95 % CI = 0.63-0.98; p = 0.029), rs11264794 (OR = 0.81; 95 % CI = 0.67-0.98; p = 0.026) and rs7522061 (OR = 0.79; 95 % CI = 0.65-0.95; p = 0.012) and decreased risk of IgAN according to allele model results. Under genetic models, FCRL3 and MTMR3 were associated with the risk of IgAN. Interestingly, FCRL3 reduced the IgAN susceptibility only in females, while MTMR3 was a risk factor for IgAN only in males. In addition, FCRL3 rs11264793 and rs7522061 were significantly associated with a decreased risk of IgAN in different disease grades. Moreover, the haplotypes ACC (p = 0.02) and CTC (p = 0.017) of LD block rs11264794/rs7522061/rs11264799 in the FCRL3 gene were significantly associated with a decreased risk of IgAN.ConclusionsWe suggest that three SNPs of FCRL3 were associated with a decreased risk of IgAN, while one SNP of MTMR3 was associated with an increased risk of IgAN in Chinese Han populations. These findings may be useful in the development of early prognostics for IgAN.     

High-dose intravenous immunoglobulin pulse therapy in patients with progressive immunoglobulin A nephropathy: a long-term follow-up

In progressive immunoglobulin A nephropathy (IgAN), intravenous immunoglobulin (IVIg) treatment has been used to delay disease progression, but the long-term efficacy is largely unknown. We report the clinical outcomes after IVIg therapy in six male patients with progressive IgAN [median glomerular filtration rate (GFR) 31 ml/min per 1.73 m(2)] followed for a median observation period of 8 years. In this single-arm, non-randomized study, IVIg was given monthly at a dose of 2 g/kg body weight for 6 months. The course of renal function was assessed by linear regression analysis of GFR and proteinuria, and was compared to eight patients with IgAN (median GFR 29 ml/min per 1.73 m(2)) without IVIg as a contemporaneous control group. IgAN disease progression was delayed after IVIg therapy on average for 3 years. The mean loss of renal function decreased from -1.05 ml/min per month to -0.15 ml/min per month (P = 0.024) and proteinuria decreased from 2.4 g/l to 1.0 g/l (P = 0.015). The primary end-point (GFR < 10 ml/min or relapse) occurred 5.2 years (median; range 0.4-8.8) after the first IVIg pulse, and after 1.3 years (median; range 0.8-2.4) in the control group (P = 0.043). In Kaplan-Meier analysis, the median renal survival time with IVIg was prolonged by 3.5 years (IVIg 4.7 years versus control 1.2 years; P = 0.006). IVIg pulse therapy may be considered as a treatment option to reduce the loss of renal function and improve proteinuria in patients with progressive IgAN.     

IgA nephropathy with subendothelial deposits

Summary IgA nephropathy with subendothelial deposits in the capillary walls of the glomeruli (IgA type 2) was compared histometrically and clinically with IgA nephropathy without subendothelial deposits (IgA type 1) and membranoproliferative glomerulonephritis with subendothelial deposits (MPGN). Study cases consisted of 32 biopsies from 26 patients of IgA type 1, 25 biopsies from 20 patients of IgA type 2 and 31 biopsies from 27 patients of MPGN. Histological changes of the glomeruli consisted of an increase in the mesangial matrix and hypercellularity in the mesangium in both types of IgA nephropathy, and the degree of the changes was a little higher in IgA type 2 than in IgA type 1 (0.02<P<0.05). Mesangial changes of MPGN were marked as compared with IgA type 1 and IgA type 2 (P< 0.001). Histometry of the mesangium on the cases followed up showed that the degree of mesangial thickening increased with lapse of time in IgA type 2 and MPGN, whereas it remained unchanged up to 13 years in IgA type 1. Proteinuria tended to be mild in IgA type 1, moderate in IgA type 2, and marked in MPGN. The impairment of renal function was observed in 21.9% of IgA type 1, in 36.0% of IgA type 2 and in 58.1% of MPGN. IgA type 2 has been shown to be pathologically and clinically intermediate between IgA type 1 and MPGN. These results suggest that there is a clinicopathological overlap between IgA nephropathy and MPGN with IgA deposition.     

Secretory immunoglobulin A (IgA) responses in IgA nephropathy patients after mucosal immunization, as part of a polymeric IgA response

Secretory immunoglobulin A (SIgA), although generated at mucosal surfaces, is also found in low concentrations in the circulation. Recently, SIgA was demonstrated in mesangial deposits of patients with immunoglobulin A nephropathy (IgAN), suggesting a role in the pathogenesis. This finding is in line with the belief that high molecular weight (HMW) immunoglobulin A (IgA) is deposited in the kidney. However, there is little information on the size distribution of antigen-specific IgA in circulation upon mucosal challenge. In this study we measured antigen-specific IgA, including SIgA, in serum following challenge of IgAN patients and controls via intranasal vaccination with a neoantigen, cholera toxin subunit B (CTB). We size-fractionated serum and nasal washes to study the size distribution of total IgA, SIgA and CTB-specific IgA. Finally, we compared the size distribution of antigen-specific IgA after mucosal immunization with the distribution upon systemic immunization. A significant induction of antigen-specific SIgA was detectable in serum of both patients with IgAN and controls after mucosal immunization with CTB. Independent of the route of immunization, in both groups the antigen-specific IgA response was predominantly in the polymeric IgA fractions. This is in contrast to total IgA levels in serum that are predominantly monomeric. We conclude that mucosal challenge results in antigen-specific SIgA in the circulation, and that the antigen-specific IgA response in both IgAN patients and in controls is of predominantly HMW in nature. No differences between IgAN patients and controls were detected, suggesting that the size distribution of antigen-specific IgA in the circulation is not disturbed specifically in IgAN patients.     

The level of urinary secretory immunoglobulin A (sIgA) of patients with IgA nephropathy is elevated and associated with pathological phenotypes

Recent studies have demonstrated deposition of secretory immunoglobulin A (sIgA) in glomeruli of some patients with IgA nephropathy (IgAN). The aim of this study is to investigate the levels of urinary sIgA in IgAN patients with different pathological phenotypes and whether it could be used as a non‐invasive biomarker for assessment of kidney injury in IgAN. Urine samples from 202 patients with IgAN were collected on the day of renal biopsy. Forty‐eight fulfilled the histopathological criteria of Haas‐I or II (group 1), 60 fulfilled Haas‐III (group 2) and 94 patients fulfilled Haas‐IV or V (group 3). Urine samples from 60 healthy sex‐ and age‐matched volunteers with negative urinalysis were collected as normal controls. Urinary sIgA was detected by sandwich enzyme‐linked immunosorbent assay and was corrected by urinary creatinine. In comparison with normal controls, the levels of urinary sIgA were significantly higher in IgAN [2·22 (0–43·82) μg/mg Cr versus 1·08 (0–16·49) μg/mg Cr, P < 0·001]. The levels of urinary sIgA were significantly higher in group 3 than that in group 2 and group 1 [3·54 (0–43·82) μg/mg Cr versus 1·63 (0–15·88) μg/mg Cr versus 0·91 (0–11·79), P < 0·001], and group 2 than group 1 (P = 0·014). The levels of urinary sIgA were associated positively with proteinuria (r = 0·443, P < 0·001), serum creatinine (r = 0·376, P < 0·001) and histopathological parameters, such as ratio of global sclerosis (r = 0·356, P < 0·001), ratio of total crescents (r = 0·339, P < 0·001) and ratios of cellular crescents (r = 0·231, P < 0·001). The levels of urinary sIgA were associated closely with histopathological phenotypes of IgAN and might be used as a non‐invasive biomarker to evaluate kidney injury in IgAN.     

Glomerular electron-dense deposits in childhood IgA nephropathy

Summary An electron-microscopic study of the glomeruli was made on 154 children with IgA nephropathy and no evidence of systemic disease, in whom immunofluorescence microscopy had shown diffuse mesangial deposition of IgA. Mesangial deposits were observed in all but eight children. Subepithelial deposits were observed in 40 children and were almost always accompanied by both mesangial and subendothelial deposits. Subepithelial deposits were significantly associated with more severe clinical presentations, a worse outcome and more severe light microscopic glomerular changes. These observations support the concept that IgA nephropathy is an immune complex disease.     

Etiology of IgA nephropathy syndrome

Since Berger's original paper on mesangial IgA-IgG deposition with hematuria, there have been a number of clinical and pathological studies regarding IgA immune complexes, the mechanisms of glomerular IgA deposition leading to glomerular injury and animal models of IgA nephropathy. During the last quarter of this century, glomerular changes such as IgA nephropathy have also been observed in cases associated with other diseases, such as systemic lupus erythematosus, Schoenlein-Henoch purpura, liver cirrhosis and chronic inflammatory diseases of the lung. This evidence supports the idea of an IgA nephropathy syndrome. On the other hand, IgA is thought to be an important humoral factor at the mucosal immune system and appears to have an antibody function against various etiologic candidates of extrinsic or intrinsic substances at the mucosal and systemic immune system. Glomerular IgA deposition in IgA nephropathy syndrome is thought to result from elevated levels of circulating immune complexes or aggregated IgA due to an overproduction of polymeric IgA as antibodies in the serum and due to the clearance impairment of IgA immune complexes in the hepatic and splenic phagocytic system. The glomerular IgA subclass is not one-sided, but should be evaluated in comparison with the age of patients at renal biopsy; this indicates the approximate age of onset. Cirrhotic IgA glomerulonephritis is not related to Hepatitis B or C virus infection, but to the pathophysiologic condition of liver cirrhosis. Various etiologic candidates such as viral, microbial, dietary antigens or auto-antigens have been listed and experimental models of IgA nephropathy syndrome have provided some clues in understanding the etiology of primary IgA nephropathy. However much still remains to be clarified and some specific epitopes common among these etiologic candidates will have to be identified.     

Identification of mannose-binding lectin as a mechanism in progressive immunoglobulin A nephropathy

Immunoglobulin A nephropathy (IgAN), the pathogenesis of which remained still unclear is one of the leading courses of end-stage renal disease in approximately 50% affected patients. On the basis of several researches, the activation of complement mannose-binding lectin (MBL) pathway might be the underlying mechanism in disease progress. In order to investigate the relationship between MBL pathway and IgAN, we discussed the MBL gene polymorphism as well as its expressed level in serum, urine and renal parenchymal, with renal outcome in IgAN patients. The significantly down-regulated expression of MBL was discovered, which may serve as a potential urinary biomarker in progressive IgAN according to the results of difference in gel electrophoresis and matrix-assisted laser desorption/ionization time of flight mass spectrometry. The single nucleotide polymorphisms of MBL gene in promoter and exon region were found and confirmed relating with the poor prognosis of progressive IgAN patients. As a result, the deficient activation of MBL pathway caused by the mutation of MBL accompanied with low expressed level of MBL in serum might be the potential inspiring regulation in IgAN, and will attract a promising insight in remedy of IgAN to inhibit further progress.     

Detection of IgA class circulating immune complexes bound to anti-C3d antibody in patients with IgA nephropathy

IgA class circulating immune complexes (CIC) were detected by solid-phase fluorescent enzyme immunoassay of F(ab')2 anti-C3d antibody in the serum of 52 patients with IgA nephropathy. Conglutinin (Kg) binding IgA class CIC were also measured, and results by these assays were compared. Kg binding IgA class CIC and anti-C3d binding IgA class CIC were detected in 27% and 44%, respectively, of the patients with IgA nephropathy. Either or both of the two were found in 65% of the patients. There was no significant correlation between IgA class CIC detected by these methods and serum IgA. Although all samples with a very high level of anti-C3d binding IgA class CIC did not also have a very high level of Kg binding IgA class CIC, there was a slight quantitative correlation between the 2 assays. Ultracentrifugation analysis showed that anti-C3d binding IgA class CIC were of various sizes between polymeric (21 S) and monomeric IgA (7 S), whereas Kg binding IgA class CIC were mostly monomeric IgA (8 S) with a minor component of heavy fractions (14 S). Both IgA class CIC fixed iC3b and IgA class CIC fixed C3d are present in IgA nephropathy. These observations suggest that the different types of complement bound to IgA class CIC have different roles in IgA nephropathy.     

The glycans deficiencies of macromolecular IgA1 is a contributory factor of variable pathological phenotypes of IgA nephropathy

Recent evidence has suggested that IgA1-containing macromolecules and the glycosylation of IgA1 in sera from patients with IgAN might involve the pathogenesis of IgAN. However, whether the different histological phenotypes can be attributed or not to the aberrant glycosylation of macromolecular IgA1 has not yet been elucidated. The aim of the current study is to investigate the glycosylation of IgA1 molecules in serum IgA1-containing macromolecules and their association with pathological phenotypes of IgAN. Sera was collected from 40 patients with IgAN and 20 donors. Twenty patients had mild mesangial proliferative IgAN, the remaining 20 had focal proliferative sclerosing IgAN. Polyethylene glycol 6000 was used to precipitate the macromolecules from sera of patients and controls. Biotinylated lectins were used in an enzyme-linked immunosorbent assay (ELISA) to examine different glycans on IgA1 molecules. The alpha2,6 sialic acid was detected by elderberry bark lectin (SNA) and the exposure of terminal galactose (Gal) and N-acetylgalactosamine (GalNAc) were detected by Arachis hypogaea (PNA) and Vilsa villosa lectin (VVL), respectively. The IgA1 glycans levels corrected by IgA1 concentrations were compared between patients and controls. Reduced terminal alpha2,6 sialic acid of IgA1 (79.89 +/- 25.17 versus 62.12 +/- 24.50, P = 0.034) was demonstrated only in precipitates from sera of patients with focal proliferative sclerosing IgAN, compared with those from controls. Reduced galactosylation of IgA1 molecules in precipitates was demonstrated in patients with both mild mesangial proliferative IgAN and focal proliferative sclerosing IgAN compared with normal controls (24.52 +/- 18.71 versus 76.84 +/- 32.59 P = 0.000 and 33.48 +/- 25.36 versus 76.84 +/- 32.59 P = 0.000). However, no significant difference was found in IgA1 glycosylation in the supernatant between patients and normal controls (P > 0.05). The glycosylation deficiency of IgA1 existed only in serum IgA1-containing macromolecules of patients with IgAN, and was associated with the renal pathological phenotypes. This suggests that aberrant glycosylation of IgA1 in serum macromolecules might be a contributory factor in the pathogenesis of IgAN.     

Progress in Molecular and Genetic Studies of IgA Nephropathy

Several new findings emerged recently from biochemical, genetic, and molecular studies of patients with IgA nephropathy. It appears that immunoglobulin A1-secreting cells of IgA nephropathy patients produce increased amounts of aberrantly glycosylated IgA1 in which the O-linked glycans in the hinge region are deficient in the content of galactose. The galactose-deficient IgA1 in the circulation is recognized by naturally occurring antibodies with anti-glycan specificity, and immune complexes are formed. These circulating immune complexes escape hepatic degradation and eventually are deposited in the kidney mesangium. Resident mesangial cells bind the IgA-containing immune complexes with the involvement of a novel IgA receptor and become activated. A familial form of IgA nephropathy has been linked to chromosome 6q22-23. Recent progress in molecular analyses of IgA nephropathy thus defines this disease as an autoimmune process with a novel IgA mesangial receptor and certain genetically determined traits.     

健康人IgA特异性激活补体类循环免疫复合物的研究

本文建立了检测IgA 特异性激活补体类循环免疫复合物(IgA/C3-CIC)的捕捉法ELISA,用于检测404例健康人血清标本,发现除脐血外的各个体均存在这类免疫复合物。其含量与年龄和性别有关,而与ABO 血型无明显关系。这与健康人血清IgA 水平的年龄和性别差异相似。提示健康人IgA/C_3—CIC的含量变化主要取决于血清IgA 水平,确定其正常值时应考虑到这些因素。同时也说明,对健康人这类免疫复合物的检测可以反映正常免疫反应的若干特点。     

Induction of unresponsiveness against IgA in IgA-deficient patients on subcutaneous immunoglobulin infusion therapy

Patients with IgA deficiency often demonstrate circulating antibodies against IgA, which have been suggested to be associated with transfusion reactions. Sera from three patients with common variable immunodeficiency (CVID) and one with a selective IgA deficiency with anti-IgA antibodies receiving subcutaneous gammaglobulin replacement therapy were analysed for serum levels of IgG, IgA and anti-IgA before and during a treatment period of 4–7 years. Treatment with gammaglobulin preparations containing significant amounts of IgA (< 5 mg/ml) resulted in a decrease or disappearance of the anti-IgA antibodies. Analysis of serum fractions, however, revealed anti-IgA activity in the complex-containing fractions. In vitro experiments gave similar results with a shift of anti-IgA activity from the monomeric to the complex-containing fractions (that could not be detected in whole serum). When the patients were subsequently switched to treatment with a preparation containing less IgA (< 80 μg/ml) or made an interruption in the treatment schedule, the anti-IgA antibodies reappeared. Importantly, however, one of the patients lost his anti-IgA activity during a 3-month period on the preparation containing the higher IgA levels, and these antibodies did not reappear after switching to the low IgA-containing preparation. After 5 years on this preparation, anti-IgA can still not be detected, suggesting induction of unresponsiveness.     

炎症介质在IgA肾病中的临床应用价值探讨

目的探讨hs-CRP、IL-6、IL-18、TNF-α和TGF-β1在Ig A肾病中的临床应用价值。方法选取2010年6月至2013年11月肾穿刺活检确诊的Ig A肾病患者71例,根据病理Lee氏分级的结果将Ig A肾病组分为3个亚组,轻度组(Ⅰ级+Ⅱ级)32例,中度组(Ⅲ级)17例,重度组(Ⅳ级+Ⅴ级)22例;同时选取35例健康对照。检测各组血清Scr、Urea、CysC和尿UTP水平及血清炎症因子hs-CRP、IL-6、IL-18、TNF-α和TGF-β1水平,并比较各炎症因子与Scr、Urea、CysC和尿UTP的相关性。结果 Ig A肾病患者各组血清hs-CRP、IL-6、IL-18、TNF-α和TGF-β1水平逐渐增高,与健康对照组有显著性差异(P<0.05);随着疾病进展,重度组各炎症因子水平与轻度组和中度组比较有显著性差异(P<0.05);各炎症因子与Scr、Urea、CysC和尿UTP呈正相关(P<0.05)。结论炎症介质可以监测肾损伤程度,炎症损伤与Ig A肾病进展有密切关系。     

IgA肾病联合诊断数学模型的建立与验证

目的 建立并评价实验室检验指标联合诊断IgA肾病(IgA nephropathy,IgAN)数学模型,探索无创性诊断IgA肾病的方法.方法 采集并分析解放军总医院2013年至2015年行肾活检病理学检查的588例住院患者(200例IgAN,388例Non-IgAN)的实验室检查数据.结果 t检验或Mann-Whitney U秩和检验分析表明,在31项实验室检查指标中有23项在IgAN与Non-IgAN中差异具有统计学意义(P＜0.05).多参数Logistic回归分析表明,血清白蛋白(ALB)、血清肌酐(CREA)、血清总胆固醇(CHO)、血清纤维蛋白(FIB)、血清D-二聚体(D-D)、血清IgA (sIgA)、血清IgG (sIgG)7项实验室检查指标对IgAN的诊断具有意义.用这7项指标建立联合诊断数学模型,该模型诊断将单一指标诊断IgAN的ROC曲线下面积(AUC)从0.747从提高到0.890.模型验证结果表明,诊断IgAN与Non-IgAN的总准确度、灵敏度、特异性、阳性预测值、阴性预测值分别为0.813、0.737、0.849、0.700、0.871.结论 实验室检查项目ALB、CREA、CHO、FIB、D-D、IgA和IgG具有联合诊断IgAN的能力,基于多项实验室检查、联合诊断和数据分析的方法可用于IgAN的诊断,具有较好的临床应用价值.