Predictors for progression in immunoglobulin A nephropathy with significant proteinuria

Aim: Proteinuria is a primary factor requiring treatment in immunoglobulin (Ig)A nephropathy. The purpose of this study was to assess the relevance of treatment response and relapse of proteinuria with renal function decline. Methods: One hundred and twenty‐five biopsy‐proven primary IgA nephropathy patients who had more than 1.0 g/day proteinuria at the first assessment were studied. All patients underwent anti‐proteinuric treatment, and the association of the rate of renal function decline with treatment responsiveness, clinical and laboratory data was investigated. Results: The treatment response of the patients was: 30.4% complete response (<0.3 g/day proteinuria), 32.8% partial response (0.3–1.0 g/day), 23.2% minimal response (decrement but not reduced to <1 g/day) and 13.6% no response (no decrement of proteinuria). The slope of renal function decline (?1.06 vs?1.24 mL/min per 1.73 m²/year, P = 0.580) was comparable between complete and partial response groups, but they were slower than those of minimal or non‐response groups (P < 0.001). In multivariate analysis including other parameters, mean arterial pressure (MAP; β = –0.240, P = 0.004) during follow up, minimal (β = –0.393, P < 0.001) and non‐response (β = –0.403, P < 0.001) were significant predictors. In further investigation of complete and partial response groups, MAP (β = –0.332, P = 0.001) and relapse of proteinuria (β = –0.329, P = 0.001) were independently associated with slope of renal decline. Conclusion: Achievement of less than 1.0 g/day proteinuria and MAP were important for limiting the loss of renal function, and relapse of proteinuria should be closely monitored in proteinuric IgA nephropathy.     

Association of angiotensinogen gene M235T polymorphism with the risk of IgA nephropathy: a meta-analysis

The association between angiotensinogen (AGT) M235T gene polymorphism and IgA nephropathy (IgAN) risk remains elusive. Our aim was to evaluate the association between AGT M235T gene polymorphism and IgAN susceptibility by performing a meta-analysis. Eligible studies were searched according to predefined criteria using electronic databases. Eight studies were identified for the analysis of the association between AGT M235T gene polymorphism and IgAN risk. M allele/MM genotype were not associated with IgAN risk in overall populations, Caucasians and Asians (overall populations: p?=?0.448 and 0.861, Caucasians: p?=?0.618 and 0.886, Asians: p?=?0.566 and 0.652). TT/MT genotype were not associated with IgAN risk in overall populations, Caucasians and Asians (overall populations: p?=?0.703 and 0.454, Caucasians: p?=?0.975 and 0.946, Asians: p?=?0.697 and 0.353). No evidence of publication bias was observed. In conclusion, AGT M235T gene polymorphism may not be correlated with IgAN susceptibility in overall populations, Caucasians and Asians. However, more studies should be performed in the future.     

Steroid and cyclophosphamide in IgA nephropathy.

BACKGROUND: IgA nephropathy is associated with a wide spectrum of possible lesions. Therefore, different responses to anti-inflammatory or immunosuppressive therapies should be expected with acute inflammatory changes, which are predominantly reversible, and with prevalently sclerotic lesions. METHODS: The effects of a combined schedule of prednisone and cyclophosphamide was analysed in the specific subset of IgA nephropathy patients with acute inflammatory histologic changes associated with haematuria and proteinuria. Two groups of patients, with similar histologic lesions and clinical presentation, were considered. The first group (12 patients) was treated within 1 week after renal biopsy; starting with three pulses of methylprednisolone (1 g) followed by oral prednisone (0.8 mg/kg body weight for 2 weeks, 0.6 mg/kg for another 2 weeks, 0.4 mg/kg for an additional 4 weeks, then slowly tapered by 5 mg each month until discontinuation) and 1.5 mg/kg cyclophosphamide for 2 months. A second sample of eight untreated patients served as a control group. Treated and untreated patients had diffuse mesangial proliferation with florid crescents (8-60% in treated and 10-40% in untreated patients) with mild degree of glomerular sclerosis and interstitial changes. Basal creatinine (167 micromol/l, range 79-371 vs 132 micromol/l, range 79-256) and proteinuria (3.0 g/24 h, 1.0-4.9 vs 3.3 g/24 h, 1.0-13.7) were not statistically different between treated and untreated patients respectively. Nine treated and six untreated patients were hypertensive. Blood pressure treatment did not include ACE-inhibitors. RESULTS: Untreated patients' 5-year renal survival, as assessed by the Kaplan-Meier method, was found to be significantly lower than treated patients (37.5 vs 91.6%, log-rank P=0.01 and Breslow test P=0.008; relative risk to reach the endpoint of a 100% increase in serum creatinine=3.58, P=0.03). CONCLUSION: This short course of therapy with prednisone and cyclophosphamide has been effective in a subset of IgA nephropathy patients with florid glomerular changes and major urinary abnormalities, turning off phlogistic activity and preventing subsequent progression toward renal failure.     

Angiotensin-Converting Enzyme Gene Polymorphism Is Correlated to the Progression of Disease in Patients with IgA Nephropathy: A Metaanalysis

Angiotensin-converting enzyme (ACE) displays potent vasoconstrictive effects, attenuation of fibrinolysis, and platelet activation and aggregation. Recently it was mentioned that the insertion/deletion polymorphism of the ACE gene is associated with ESRD. The lengthy course of IgA Nephropathy (IgAN) and the possibility of good outcomes without therapy suggest nontoxic therapies such as ACE inhibitors and angiotensin receptor blockers (ARBs). However, the correlation between the ACE gene polymorphism and progression of IgAN still requires further approval. Here, the author performs a summative analysis on the recent previous reports on the ACE gene polymorphism and its correlation to progression of IgAN. The meta-analysis was performed to assess the correlation between the pattern of ACE gene polymorphism and progression of IgAN. From five available studies, 346 and 555 patients with (group 1) and without (group 2) the progression of disease are evaluated. According to this study, the frequency of DD genotype in group 1 is significant higher than group 2 (p < 0.05). In addition, the author first reports a non-significant correlation between the ethnicity and the ACE gene polymorphism.     

An increased polymeric IgA level is not a prognostic marker for progressive IgA nephropathy.

BACKGROUND: Elution of IgA from renal biopsies of patients with primary IgA nephropathy (IgAN) has suggested that mesangial IgA deposits are mainly multimeric in nature. This macromolecular IgA consists of dimeric and polymeric IgA and may be derived from the circulation. In children with IgAN, circulating macromolecular IgA levels correlate with bouts of macroscopic haematuria, but in adults a correlation with disease activity is less clear. Therefore, we have designed a novel method to assess the levels of polymeric IgA (pIgA) in sera from patients and controls. METHODS: A novel precipitation assay using recombinant CD89 was developed to measure pIgA. Polymeric IgA levels were measured in serum samples obtained from healthy volunteers (n = 21) and patients with IgAN (n = 51). Subsequently, serum pIgA levels were correlated with clinical parameters of disease. RESULTS: Serum pIgA levels were significantly increased in patients with IgAN. However, pIgA concentrations relative to total IgA were significantly lower in sera of patients with IgAN. No correlation was found between serum pIgA levels and clinical parameters of IgAN, such as decline of glomerular filtration rate, haematuria or proteinuria. CONCLUSIONS: Although absolute levels of serum pIgA are increased in patients with IgAN as compared with controls, levels of pIgA relative to total serum IgA are lower. No significant correlation was found between serum concentrations of pIgA and clinical parameters of disease. These data support the notion that it is not the size alone, but the physicochemical composition of the macromolecular IgA that is the key factor leading to mesangial deposition.     

Presentation, prognosis and outcome of IgA nephropathy in Indian adults

BACKGROUND: IgA nephropathy (IgAN) is not well characterized in India. This retrospective study of 478 patients with IgAN was performed to clarify the presenting features, prognostic factors and the renal survival rates of the disease. METHODS: Three hundred and forty-seven patients who had been followed on average for 27 months after diagnosis were divided into two groups based on renal function at diagnosis. In group 1 (229 patients), the creatinine clearance estimated by the Modification of Diet in Renal Disease formula was <85 mL/min and in group 2 (118 patients) it was >/=85 mL/min. RESULTS: The predominant modes of presentation were nephrotic syndrome, hypertension and renal failure. Twenty-nine percent of patients had more than a 20% decline in renal function at the last follow up. Multivariate analyses with stepwise logistic regression identified hypertension (odds ratio (OR) 3.5), nephrotic range proteinuria (OR 3.4) and sclerosed glomeruli on biopsy (OR 4.1) to be independently associated with progression in group 1 and hypertension (OR 2.3) in group 2. Seventeen percent of patients progressed to end-stage renal disease (ESRD). Using multivariate analysis by the Cox model, four risk factors for developing ESRD were identified: hypertension (hazard ratio (HR) 3.1); nephrotic proteinuria (HR 1.9); interstitial fibrosis (HR 2.5); and sclerosed glomeruli (HR 1.8). The renal survival rates at 1, 5 and 10 years were 84, 55 and 33%, respectively, with a median renal survival of 61 months from the time of biopsy. CONCLUSION: The relatively rapid rate of progression of IgAN in India is suggestive towards a 'malignant' nature of the disease in this country.     

The ACACB gene rs2268388 polymorphism is associated with nephropathy in Caucasian patients with diabetes: a meta-analysis

Abstract

To date, case–control studies on the association between a single-nucleotide polymorphism (SNP), rs2268388, in the acetyl-coenzyme A carboxylase beta (ACACB) gene and diabetic nephropathy have provided controversial results. To clarify the effect of rs2268388 on the risk of diabetic nephropathy, a meta-analysis of all case–control studies was performed. The fixed effects and random effects models showed that the C allele was associated with a decreased susceptibility risk of diabetic nephropathy compared with the T allele among Caucasian patients with diabetes. The contrast of the recessive model produced the same pattern of results as the allele contrast. Our pooled data suggest a significant association exists between rs2268388 and diabetic nephropathy among Caucasian patients with diabetes.     

Immunological studies of IgA nephropathy in blacks reveal elevations of serum IgA2 as well as IgA1

Although IgA nephropathy (IgAN) is recognized worldwide as themost common primary glomerulonephritis, the prevalence of thisdisease among American blacks is strikingly low despite thefrequency of other renal disorders. We have previously describedthe clinical features of 27 black patients enrolled in a multicentreIgAN database; in this paper we report several immunologicalparameters of the disease in this population. Quantificationof serum immunoglobulins revealed significantly higher concentrationsof total IgA, IgAl and IgA2 (P=0.0001, 0.002 and 0.005 respectively)in the patients, but no significant increases in IgG or IgM.Examination of immunoglobulin synthesis by peripheral bloodlymphocytes indicated relatively few differences in the secretionof immunoglobulins by patients compared to healthy Americanblacks. The spontaneous production of total IgA, IgA1, and IgA2in patients was depressed compared to the control subjects (P=0.02,0.04, 0.03,), yet the ratio of IgA1:IgA2 was normal. Stimulationwith poke-weed mitogen enhanced secretion of immunoglobulinin both subject groups. However, a significantly greater IgA1:IgA2ratio was noted in the patients (P=0.002). Circulating immunecomplexes containing C3 and IgA as well as C3 and IgM were elevatedin the patients (P=0.0006, 0.0003 and 0.02, respectively). Theseimmunological aberrancies did not correlate with clinical manifestationsof disease. These data suggest the immune abnormalities of blackIgAN patients are similar to, but not identical with, thoseof white patients.     

Genetic Polymorphism of Vascular Endothelial Growth Factor: Impact on Progression of IgA Nephropathy

Background. Vascular endothelial growth factor (VEGF) plays a pivotal role in the capillary endothelial cell growth and proliferation and has known effects on glomerular microvascular permeability. Because certain VEGF polymorphisms are correlated with alterations in VEGF expression, we hypothesized that VEGF genetic polymorphisms may affect the renal survival and progression of primary IgA nephropathy. Methods. The study population consisted of 195 biopsy-proven IgA nephropathy patients at our center between 1984 and 2004. VEGF genotype polymorphism at ?2578 positions was determined from peripheral blood leukocytes DNA using polymerase chain reaction methodologies. The primary end point was kidney survival as measured by the time interval from renal biopsy to end-stage renal disease or the requirement of renal replacement therapy. Results. In total, we studied 119 women (61%) and 76 men (39%), with a mean age of 35 ± 10 yr at the time of renal biopsy. Observed genotype frequency was 55.6%, 38.8%, and 5.1% for CC, CA, and AA genotypes respectively. Baseline characteristics did not differ significantly between three genotype groups for patient age, sex, prevalence of hypertension, degree of proteinuria, initial serum creatinine concentration, and the histological grading. After a median follow-up period of 11 yr, doubling of the baseline serum creatinine occurred in 107 of them; 99 patients reached end-stage renal disease requiring renal replacement therapy with a median renal survival of 88 months. The kidney survival in the CC genotype subgroup was similar to that of the CA/AA genotype subgroup during the first 2 yr but became worse than the latter thereafter (log-rank test P = 0.023). The kidney survival rates at the end of 6 yr were 76.8% in the CA genotype, 67.0% in the CC, and 50.0% in the AA genotype groups. Unadjusted hazard ratio of developing end-stage renal disease was 2.65 (95% CI, 1.16 to 6.06) for the CC group as compared to the CA/AA group. The influence of VEGF genotype upon renal survival, however, was not significant after multivariate Cox regression analysis. Conclusion. Our preliminary results raise the concern that the CC genotype of the VEGF promoter at ?2578 position might be associated with increased risk of renal progression in patients with IgA nephropathy.     

Immunoglobulin A1 protease: A new therapeutic candidate for immunoglobulin A nephropathy

Immunoglobulin A nephropathy (IgAN), characterized by predominant or exclusive deposition of IgA1 in glomerular mesangium, is the most common primary glomerulonephritis worldwide. At present, the treatment is always limited due to the incomplete understanding of the pathogenesis of IgAN. Mesangial deposited IgA1 is the common final pathway leading to glomerulonephritis and renal injury. IgA1 protease, a proteolytic enzyme with strict substrate specificity for human IgA1, may be an effective therapeutic candidate for IgAN by removing the mesangial deposited IgA1.     

Effect of aggregated immunoglobulin A1 from immunoglobulin A nephropathy patients on nephrin expression in podocytes

Aim: Abnormal immunoglobulin (Ig)A1 is considered to play a pivotal role in IgA nephropathy. We used mouse podocytes as the experimental model to investigate the effect of aggregated IgA1 (aIgA1) isolated from IgA nephropathy (IgAN) patients on nephrin expression in podocytes through direct and indirect pathways. Methods: Jacalin affinity chromatography and Sephacryl S‐200 molecular sieve chromatography were used to isolate IgA1 from blood of IgAN patients which was therefore became aIgA1. Podocytes were incubated with aIgA1 or special mesangial medium. Nephrin expression in podocytes was measured by real‐time polymerase chain reaction and western blot analysis. Results: Aggregated IgA1 from IgAN patients and healthy controls reduced nephrin expression in podocytes at mRNA and protein levels when compared with podocytes incubated with control medium (RPMI‐1640 with 0.5% foetal bovine serum) (P < 0.05). While medium from mesangial cells incubated with aIgA1 from IgAN inhibited nephrin expression in podocytes at mRNA and protein levels when compared with podocytes incubated with medium from mesangial cells with aIgA1 from healthy controls (P < 0.05). Conclusion: Our findings implicate that aIgA1 from IgAN patients could inhibit nephrin expression through direct and indirect pathways, although these mechanisms remain to be clarified.     

Prediction of early progression in recently diagnosed IgA nephropathy.

BACKGROUND: Most studies of prognosis in IgA nephropathy (IgAN) have tried to predict dichotomous outcomes based on a small number of clinical or semi-quantitative histological variables in large numbers of patients. METHODS: We pursued a quite different approach. We measured GFR annually for 4-5 years in 22 adult patients with recently diagnosed IgAN. Quantitative morphology was performed on the diagnostic biopsy specimens and baseline glomerular filtration dynamics were performed at study entry. An initial set of 30 plausible predictor variables (half demographic or physiological, half structural) was reduced to 22 using phylogenetic trees. Least-angle regression (LARS) was used to predict the rate of GFR change from these variables RESULTS: The rate of GFR change ranged from a loss of 41 ml/min/year to a gain of 8.6 ml/min/year. We found an optimum predictor set of five baseline variables: the percentage of glomeruli with global sclerosis, the fractional interstitial area, the serum creatinine, the average tuft volume of non-sclerotic glomeruli and the renal plasma flow. CONCLUSIONS: The strong predictive relationship of the three structural variables with the slope of GFR in our subjects suggests that even at the time of their initial diagnosis many patients with IgAN already manifest a 'remnant kidney' phenomenon. The distinctive pathophysiological insights derived from this study suggest some of the advantages of intense quantitative investigations applied to a small number of subjects.     

A tricontinental view of IgA nephropathy.

BACKGROUND: The purpose of this retrospective study was to analyse patients from four centres in three continents to determine if differences in long-term outcome of IgA nephropathy (IgAN) are explained by clinical and laboratory features at presentation. METHODS: The study included 711 adults with biopsy-proven IgAN from Glasgow, UK (n = 112), Helsinki, Finland (n = 204), Sydney, Australia (n = 121) and Toronto, Canada (n = 274). Data collected from time of presentation to a nephrologist were age, gender, 24-h urine protein excretion (UP(0)), mean arterial pressure (MAP(0)) and creatinine clearance (CrCl(0)). Outcomes were slope of creatinine clearance (CrCl) and renal survival. RESULTS: At presentation there was significant vari-ability in baseline clinical features with patients from Helsinki having the lowest median UP(0), lowest MAP(0) and highest CrCl(0), all suggesting milder disease. There was significant variability in renal survival between centres with 10-year actuarial survival of 95.7, 87.0, 63.9 and 61.6% in Helsinki, Sydney, Glasgow and Toronto, respectively (P < 0.0001; log rank). Cox proportional hazards model revealed lower age(0) and lower CrCl(0) were significant independent predictors of reduced renal survival. In addition, patients from Helsinki and Sydney but not Glasgow had significantly longer renal survival than patients from Toronto. Median slope of CrCl varied by region from -1.24 ml/min/year in Helsinki, to -3.99 ml/min/year in Toronto (Kruskal-Wallis H test P < 0.0001). By multivariate analysis older age(0), higher CrCl(0) and lower UP(0) were independently associated with slower progression. Subjects from Helsinki had a significantly slower deterioration independent of the other clinical parameters at presentation. When the 269 patients presenting with CrCl(0) <75 ml/min were analysed separately there was no independent centre effect. CONCLUSIONS: The findings are consistent with the hypothesis that geographical variability in long-term outcome of IgAN is explained by lead-time bias and inclusion of milder cases in centres with apparent good outcome, but do not exclude the possibility that some of the variability is due to other factors such as genetics, diet or treatment.     

脓毒症的基因多态性研究

尽管脓毒症的诊断和治疗取得了长足进步,但严重脓毒症和脓毒性休克的病死率仍居高不下.社会人口统计学和临床风险因素预测模型不能完全解释为什么在遭受相似程度打击后,有些人群易于发生脓毒症和多器官功能障碍综合征,有的患者却病情较轻而易于恢复.近年来,人们认识到遗传因素会影响脓毒症的易感性和预后.随着人类基因组计划和国际人类基因组单体型图计划的完成,脓毒症的遗传易感基因研究成为当前国内外研究的热点和焦点.基因多态性研究可以加深对脓毒症的发生、发展机制的认识,提供更精确的个体化靶向治疗措施.本文就基因多态性研究的相关概念、方法和在脓毒症基因关联研究中的策略及存在的问题作简要概述.     

Anomalous kinetics of galactose-deficient IgA incurring nephropathy revealed by cross-scale optical imaging

1. Download : Download high-res image (453KB)
2. Download : Download full-size image

     

Relationship between methylenetetrahydrofolate reductase (MTHFR) A1298C gene polymorphism and type 2 diabetic nephropathy risk: a meta-analysis

Relationship between methylenetetrahydrofolate reductase (MTHFR) A1298C gene polymorphism and type 2 diabetic nephropathy (T2DN) risk is still unclear. This study was performed to evaluate if there is an association between the MTHFR A1298C gene polymorphism and T2DN risk using meta-analysis. The relevant reports were searched and identified from PubMed, Cochrane Library on 1 October 2013, and eligible studies were included and synthesized. Eight reports were recruited into this meta-analysis for the association of the MTHFR A1298C gene polymorphism with T2DN risk. The MTHFR A1298C C allele or CC genotype was shown to be not associated with T2DN risk (C allele: OR?=?0.76, 95% CI: 0.43–1.34, p?=?0.34; CC genotype: OR?=?1.18, 95% CI: 0.63–2.22, p?=?0.60). Interestingly, AA genotype was associated with the T2DN risk (OR?=?0.68, 95% CI: 0.49–0.96, p?=?0.03). In the sensitivity analysis according to the Hardy–Weinberg equilibrium (HWE), the results were consistent with those in non-sensitivity analysis. However, in the sensitivity analysis according to the control source from hospital, sample size of case (≥100), sample size of case (<100), the MTHFR A1298C gene polymorphism was not associated with T2DN risk. In conclusion, the MTHFR A1298C gene polymorphism was not associated with T2DN risk. However, additional studies are required to firmly establish a correlation between the MTHFR A1298C gene polymorphism and T2DN risk.     

基于GEO数据库的IgA肾病基因的筛选和生物信息学分析

目的 通过生物信息学分析鉴定IgA肾病的生物标志物,旨在阐明IgA肾病疾病进展的可能分子机制.方法 从GEO数据库下载包含IgA肾病患者和健康对照的微阵列数据集GSE104948、GSE93798和GSE37460数据集,并使用limma R包进行分析,以获得差异表达基因.然后进行GO分析和KEGG通路富集分析,运用S...     

Randomised controlled trial of leflunomide in the treatment of immunoglobulin A nephropathy

AIM: To investigate the effect of leflunomide for treatment of immunoglobulin A (IgA) nephropathy. METHODS: Sixty IgA nephropathy patients were divided into two groups at random. Patients in the test group received leflunomide and patients in the control group received fosinopril. Clinical data were obtained at weeks 2, 4, 6, 8, 12, 16, 20, 24 and 28. RESULTS: The complete remission rate was 62.1% and the total effectiveness rate was 72.4%. In the leflunomide group, proteinuria significantly decreased from 1.66 +/- 0.42 g to 0.60 +/- 0.68 g (P < 0.05). The efficacy rate of leflunomide compared with fosinopril in treating IgA nephropathy was not statistically different (P > 0.05). Side-effects were mild in both treatment groups. CONCLUSION: These preliminary results are encouraging, but further randomised studies are required before leflunomide can be recommended for the treatment of IgA nephropathy.