Multivariate analysis of prognostic factors and effect of treatment in patients with IgA nephropathy

BACKGROUND: Although the clinical and histological prognostic factors of IgA nephropathy have been investigated in detail, the value of treatment in terms of renal outcome is not well understood. METHODS: The authors examined data from 237 patients with IgA nephropathy (age 31.4+/-13.5 years, mean+/-SD) who had been followed-up for at least six months (follow-up periods, 62.3+/-45.5 months). The authors initially tested the significance of prognostic factors (age, sex, systolic blood pressure, proteinuria, serum creatinine, and histological severity) and treatment strategies (steroid therapy, renin-angiotensin system inhibitors and tonsillectomy) on renal outcome with univariate analysis, then evaluated the findings using the Cox proportional hazards model. RESULTS: Univariate and multivariate analyses showed that among the prognostic variables, a high level of serum creatinine at renal biopsy, large amounts of proteinuria, and extensive histological injury were significant risk factors for end-stage renal failure. Kaplan-Meier analysis showed that the renal survival rates associated with these factors were significantly poorer depending on their severity. Univariate analysis revealed that tonsillectomy was the only significant treatment that contributes to the maintenance of renal survival. Moreover, urinary abnormalities disappeared at a significantly higher frequency when patients were treated by tonsillectomy. The Cox proportional hazards model showed that steroid therapy independently contributed to improve renal prognosis in addition to tonsillectomy, and the hazard ratios were 0.26 (95% CI, 0.07 to 0.93) and 0.37 (95% CI, 0.14 to 0.99), respectively. CONCLUSION: Steroid therapy and tonsillectomy can independently improve renal outcome in patients with IgA nephropathy.     

Clinicopathological and prognostic analysis of IgA nephropathy patients with anemia

Objective To analyze the clinicopathological features of IgA nephropathy (IgAN) patients with anemia and the influencing factors of prognosis. Methods The clinical and pathological data of patients diagnosed with primary IgAN at the First Affiliated Hospital of Fujian Medical University from January 1, 2006 to December 31, 2016 were retrospectively analyzed. The patients were divided into anemia group and non-anemia group according to whether the patient was anemia or not. The clinical and pathological data of the two groups were collected. All of them were followed up from the date of renal biopsy to January 1, 2018. Survival curves of the two groups were drawn by Kaplan-Meier method, and compared by Log-rank test. Multivariate Cox proportional hazards regression model was adopted to explore the influencing factors of prognosis in IgAN patients. Results A total of 231 subjects were enrolled, including 122 males (52.8%), and the male-female ratio was 1.12∶1. Their age was (34.8±10.1) years (15-68 years). There were 70 patients (30.3%) in anemia group, 161 cases (69.7%) in non-anemic group. Compared with non-anemia group, anemia group had higher proportion of females, lower serum albumin, higher proportion of tubular atrophy/interstitial fibrosis (T1/2), endothelial cell proliferation (E1) and crescent formation (C1/2), which were statistically significant (all P＜0.05). The patients had a median follow-up time as 6.3 years (0.3-12.9 years). Survival analysis showed that patients in anemia group had lower cumulative renal survival rate than that in non-anemia group ( χ2=15.234, P＜0.001). Multivariate Cox hazards regression analysis revealed that anemia (HR=3.820, 95%CI 1.674-8.719, P=0.001), tubular atrophy/interstitial fibrosis (T1/2) (HR=3.770, 95%CI 1.026-13.852, P=0.046), glomerular segmental sclerosis/adhesion (S1) (HR=4.211, 95%CI 1.139-15.576, P=0.031), hypertension (HR=2.988, 95%CI 1.276-6.999, P=0.012), increased 24 h urinary protein (HR=1.103, 95%CI 1.046-1.163, P＜0.001) and estimated glomerular filtration (eGFR)＜60 ml?min-1?(1.73 m2)-1 (HR=3.725, 95%CI 1.639-8.462, P=0.002) were the independent risk factors for poor renal prognosis in patients with IgAN. Conclusions The clinicopathological features of IgAN patients with anemia are relatively serious, and the renal cumulative survival rate is lower. Anemia, tubular atrophy/interstitial fibrosis (T1/2), glomerular segmental sclerosis/adhesion (S1), hypertension, increased urinary protein and eGFR＜60 ml?min-1?(1.73 m2)-1 are the independent risk factors for poor renal prognosis in patients with IgAN.     

IgA肾病患者高血压的相关因素分析

目的探讨IgA肾病患者高血压的相关因素。方法经肾脏活体组织检查确诊的IgA肾病患者120例,采用单因素和多因素Logistic回归分析IgA肾病患者高血压发生的相关因素。结果120例IgA肾病患者中伴有高血压患者39例（占32．5％）。单因素分析发现,24h尿蛋白定量≥2．0g、尿素氮（BUN）≥8mmol／L、血肌酐（SCr）≥133μmol／L、肾小球率过滤（GFR）〈60ml·min^-1·（1．73m^2）^-1、高尿酸血症、贫血、肾小球慢性病变指数≥4分、肾间质炎症细胞侵润〉25％、肾小管萎缩和问质纤维化〉25％、肾小动脉管壁增厚、Lee分级Ⅳ～Ⅴ级与IgA肾病患者高血压相关。多因素Logistic回归结果显示,蛋白尿程度、GFR水平为IgA肾病高血压发生的独立危险因素。结论32．5％的IgA肾病患者伴有高血压,蛋白尿程度、GFR水平是高血压的独立危险因素。     

Related factors of hyperuricemia in IgA nephropathy patients

Objective To investigate the influencing factors of hyperuricemia in patients with IgA nephropathy (IgAN). Methods A retrospective study was performed in patients with renal biopsy diagnosed as IgAN in the Department of Nephrology, Provincial Hospital of Anhui Medical University from January 2016 to October 2018. According to the blood uric acid level, they were divided into two groups: patients with hyperuricemia and patients without hyperuricemia. The general clinical indicators and renal pathological data were compared between the two groups. Logistic regression model was used to analyze the influencing factors of hyperuricemia in IgAN patients. Results A total of 125 IgAN patients with age of (35.70±11.16) years old were enrolled, including 63 males and 62 females. The morbidity of hyperuricemia was 44.0%(55/125). Compared with the normal blood uric acid group, the blood urea nitrogen, serum creatinine and the proportion of chronic kidney disease (CKD) stage 3-5, small arterial wall thickening, fibrous crescents/globules, renal interstitial fibrosis, renal tubular atrophy, glomerular sclerosis and inflammatory cell infiltration in the hyperuric acid group were higher, while the level of estimated glomerular filtration rate (eGFR) was lower. And the differences were statistically significant (all P＜0.05). Multivariate logistic regression analysis showed that the level of serum creatinine was an independent related factor of hyperuricemia in IgAN patients (OR=1.034, 95%CI 1.005-1.064, P=0.021). Conclusions IgAN patients with hyperuricemia presented more severe glomerular, tubular and interstitial lesions, and the level of serum creatinine is an independent related factor of hyperuricemia in IgAN patients. High uric acid level may have an important influence on the progression of IgAN, so good control of serum uric acid may improve the prognosis of patients with IgAN.     

IgA肾病患者高尿酸血症患病率及其相关危险因素分析

目的 探讨IgA肾病患者高尿酸血症的患病率及其临床、病理危险因素.方法 回顾性分析1996年1月至2012年12月于中山大学附属第一医院行肾穿刺活检确诊为IgA肾病的2566例患者的临床及病理特征,行多因素Logistic回归分析IgA肾病患者高尿酸血症发生的影响因素.结果 2566例IgA肾病患者中,高尿酸血症的患病率为36.6％,其中CKD 1～5期各期患者高尿酸血症的患病率分别为16.2％、37.4％、66.4％、87.7％和76.4％.IgA肾病患者伴发高尿酸血症的相关危险因素包括:男性、CKD分期高、肾活检病理球性硬化比例高.肾功能正常(CKD 1～2期)IgA肾病患者伴发高尿酸血症的相关危险因素包括:男性、CKD分期高、血胆固醇水平升高及肾活检病理球性硬化比例高.肾功能受损(CKD 3～5期)IgA肾病患者伴发高尿酸血症的相关危险因素包括:CKD分期高及肾活检病理球性硬化比例高.结论 IgA肾病患者高尿酸血症的患病率为36.6％,明确IgA肾病肾功能正常及受损患者发生高尿酸血症的相关危险因素有利于本病的综合防治.     

Thin basement membrane disease in patients with familial IgA nephropathy

BACKGROUND: Immunoglobulin A nephropathy (IgAN) can exist as a primary glomerulonephritis (GN) or in association with various clinical conditions, suggesting that it could include several heterogeneous disorders. The familial form of IgAN has been increasingly recognized, supporting the suggestion that genetic factors could be involved in the disease pathogenesis, although it remains unclear whether the familial form is itself heterogeneous. METHODS: This study included 24 patients with a biopsy-proven IgAN from 11 unrelated families coming from five geographically distinct regions of Italy, and 90 of their relatives investigated for the presence of nephritis. Families were included in a genome-wide linkage analysis to identify loci responsible for the disease. RESULTS: Liver or systemic disease was not found in any case, and no hearing loss or ocular alterations were detected. Renal biopsy showed mesangial expansion at light microscopy, with glomerular sclerosis involving from 11 to 35% of glomeruli in eight patients. Ultrastructural examination revealed mesangial electron dense deposits along with a diffuse glomerular basement membrane (GBM) thinning typical of thin basement membrane disease (TBMD) in eight patients belonging to six families. Of the 90 relatives, 12 had "suspected IgAN", 73 were defined as "unaffected" and five as "probably unaffected". Families with co-existent TBMD failed to link to the IGAN1 locus. After a follow-up of 3-19 yrs, nine patients (37%) showed a progressive reduction in renal function and five of them reached end-stage renal disease (ESRD). CONCLUSION: These data demonstrate that familial IgAN is present outside geographically confined regions of Italy. Co-aggregation of IgAN with TBMD suggests that familial IgAN itself is a heterogeneous disorder and that inherited GBM abnormalities could be the first alteration, in some cases.     

Characteristics and risk factors of intrarenal arterial lesions in patients with IgA nephropathy.

BACKGROUND: Although the clinical importance of immunoglobulin-A nephropathy (IgAN) is widely recognized, the characteristics of intrarenal arterial lesions in this disease and the main factors associated with them have not been studied extensively, and a large-scale analysis of intrarenal arterial lesions in IgAN has not been performed. METHODS: To clarify these issues, we investigated the prevalence, underlying factors and significance of intrarenal arterial lesions in 1005 patients with IgAN. We distinguished different degrees of severity of small artery and arteriolar lesions (mild, moderate and severe), using a semi-quantitative scoring system. We compared the arterial lesions of IgAN patients with those of 627 non-IgAN patients, who had mesangial proliferating glomerulonephritis without IgA deposits, and of 221 patients with membranous nephropathy (MN). RESULTS: The IgAN patients with arterial lesions were significantly younger than the non-IgAN and MN patients (mean ages 34.6 vs 40.4 and 47.7 years, respectively). The prevalence of intrarenal small artery and arteriolar lesions was 54.6% in IgAN patients, compared with 26.6 and 47.1% in non-IgAN and MN patients, respectively; the percentages of moderate/severe arterial lesions were 37.0 vs 21.6 and 23.1%, respectively; and the percentages of hyaline changes were 43.7 vs 16.8 and 21.2%, respectively. The differences in the prevalence of lesions between IgAN patients and the two other groups were statistically significant for all three parameters. Our search for possible relationships between arterial-arteriolar lesions and various indirect outcome markers disclosed significant associations with hypertension, higher serum creatinine and uric acid, high urinary protein excretion, glomerulosclerosis, tubular atrophy and interstitial fibrosis. Furthermore, these parameters were changed more markedly in IgAN patients with moderate/severe arterial lesions and hyaline changes than in IgAN patients who had mild arterial lesions and wall thickening alone. CONCLUSIONS: The prevalence of small intrarenal arterial-arteriolar lesions was higher in IgAN patients than in non-IgAN and MN patients; moreover, the lesions in IgAN patients were associated with younger age, were more severe and exhibited a higher degree of hyaline changes. Finally, the severity of small arterial- arteriolar lesions was linked to several markers of adverse outcome.     

Demonstration of secretory IgA in kidneys of patients with IgA nephropathy.

BACKGROUND: Recently we reported a possible role for secretory IgA (SIgA) in IgA nephropathy (IgAN), as suggested by increased serum levels in patients with active disease and accumulation of SIgA in a glomerular eluate. Therefore, we attempted to find support for these findings by analysis of the presence of SIgA in biopsies of IgAN patients. METHODS: Renal biopsies of 26 patients with biopsy-proven IgAN were analysed for the presence of SIgA and complement proteins. RESULTS: In 15% mesangial deposition of SIgA was demonstrated, using a specific staining for secretory component (SC) and colocalization with IgA. The presence of SIgA in these biopsies showed a strong correlation with deposition of mannose-binding lectin (MBL) and C4d. Moreover, we observed a strong colocalization between SIgA and MBL or C4d. This local complement activation has previously been linked to more severe renal disease. CONCLUSIONS: Therefore, these data provide additional evidence for a pathogenic role for SIgA in IgA nephropathy.     

Specificity of IgA antibodies in sera from patients with IgA nephropathy.

A study was undertaken on the specificity of circulating IgA antibodies in patients with IgA nephropathy detected by immunofluorescence using avidin-biotin complexes. Renal biopsy specimens and serum samples were obtained from 33 patients with IgA nephropathy, 14 other glomerular diseases and 3 normal renal tissues. These renal specimens were treated with citrate buffer (pH 3.2), and then incubated with serum samples obtained from the same and other patients with IgA nephropathy, other glomerular diseases or healthy adults at 37 degrees C for 30 min. The specimens were incubated with biotin conjugated gout F(ab')2 anti-human IgA antiserum at 37 degrees C for 30 min, and then with fluorescein-labeled avidin at 37 degrees C for 30 min. It was found that IgA antibodies in the sera from patients with IgA nephropathy specifically combined with the autologous glomerular mesangial areas, but only 25.7% of them combined with allogeneic renal tissues of IgA nephropathy patients. Confirmatory findings were obtained using an automatic image analyzer. However, these IgA antibodies did not combine with the renal tissues from patients with other glomerular diseases or normal renal tissues. In parallel studies, in order to distinguish IgA nephropathy from other glomerular diseases before renal biopsy, the renal specimens from patients with IgA nephropathy were also incubated with serum samples obtained from 42 patients with proteinuria and/or hematuria before renal biopsy. It was demonstrated that the incidence of IgA binding in IgA nephropathy was significantly higher than that in other glomerular diseases prior to renal biopsy.(ABSTRACT TRUNCATED AT 250 WORDS)     

Evaluation of tonsillectomy before kidney transplantation in patients with IgA nephropathy

The effectiveness of a tonsillectomy before kidney transplantation (KTx) in suppressing the recurrence of IgA nephropathy (IgAN) has never been studied. The aim of this study was to analyze the effectiveness of a preoperative tonsillectomy for preventing IgAN recurrence and to identify predictive risk factors for IgAN recurrence. Of the 462 recipients who underwent a KTx between 2006 and 2011, a total of 78 patients had biopsy-proven IgAN as their primary disease. Among these 78 patients, 28 patients (group 1) underwent a tonsillectomy and 50 patients (group 2) did not undergo a tonsillectomy before KTx. The time to recurrence was 15.5 ± 8.7 months, in group 1 and 20.2 ± 18.6 months in group 2. No significant difference was observed between the two groups (P = 0.63). Using a multivariate Cox regression analysis, ABO incompatible KTx and acute rejection were associated with a lower incidence of recurrence (P = 0.02 and 0.002 respectively). These results suggested that a preoperative tonsillectomy might not affect the recurrence of IgAN during a short-term follow-up period, whereas preoperative desensitization and the use of a higher steroid dose were effective for suppressing the recurrence of IgAN.     

Serum IgA/C3 ratio may predict diagnosis and prognostic grading in patients with IgA nephropathy

Recently, the authors reported that the ratio of serum IgA to C3 (serum IgA/C3 ratio) is a good marker to distinguish patients with IgA nephropathy from non-IgA nephropathy patients together with serum IgA levels using an international reference preparation (IFCC/CRM470). In this study, the authors investigated whether the serum IgA/C3 ratio might be an indicator of prognostic grading in patients with IgA nephropathy. Two hundred and thirteen patients with IgA nephropathy and 96 other glomerular diseases including diffuse or focal mesangial proliferative glomerulonephritis without mesangial IgA deposition (non-IgA PGN), membranous nephropathy and thin basement membrane syndrome were examined. The levels of serum IgA and C3 in these patients were adjusted by the specified formula to those using international standard serum (IFCC/CRM470) in this study. The results of this study showed the highest levels of IgA/C3 ratio in patients with IgA nephropathy. The serum IgA/C3 ratio appears to gradually increase according to the prognostic grading of this disease. Therefore, measurement of the serum IgA/C3 ratio may be useful for prediction of diagnosis and prognostic grading in patients with IgA nephropathy.     

Elevated serum secretory IgA in patients with IgA nephropathy

Serum secretory IgA was measured to elucidate the significance of secretory IgA in patients with IgA nephropathy. The levels of serum secretory IgA and IgA were, respectively, 6.8 +/- 3.5 micrograms/ml and 231.0 +/- 69.2 mg/dl in the controls and 11.8 +/- 3.2 micrograms/ml and 385.3 +/- 78.7 mg/dl in the patients. The levels of serum secretory IgA and IgA in the patients were significantly higher than those in controls (p less than 0.01). Elevated serum secretory IgA may reflect the excessive state of the IgA-secreting system in IgA nephropathy patients.     

Neuropeptide Y Y1 receptor polymorphism as a prognostic predictor in Japanese patients with IgA nephropathy.

BACKGROUND: Neuropeptide Y exhibits a vasoconstricting action and regulates systemic blood pressure as well as noradrenalin. There are 5 types of NPY receptors, Y1 - Y5, which were introduced by pharmacological differences. Recently, a single point mutation in the first intron of the NPY Y1 receptor (NPYY1R) was reported. SUBJECTS AND METHODS: In this study, we investigated the relationship between NPYY1R gene polymorphism and clinical characteristics in patients with IgA nephropathy using polymerase chain reaction and restriction fragment length polymorphism analysis. RESULTS: Distribution of the NPYY1R genotypes which were defined as YY, Yy and yy genotypes, did not differ between 60 normal control subjects and 68 patients with IgA nephropathy (15 : 36 : 9 versus 21 : 40 : 7, respectively). In IgA nephropathy patients, the incidence of hypertension and the rate of urinary protein excretion were slightly higher in the non-YY genotype than in the YY genotype group (23% versus 5% and 1.1 +/- 1.2 versus 0.6 +/- 0.4 g/24 h, p = 0.09 and p = 0.05, respectively). The reciprocal of the serum creatinine level was estimated to determine the deterioration in renal function during follow-up after the renal biopsy. The level was lower in the non-YY genotype than in the YY genotype group (-0.002 +/- 0.064 vs 0.033 +/- 0.053/month, respectively, p < 0.01). Multiple regression analysis for the reciprocal of the serum creatinine level revealed that the NPYY1R genotype was an effective variable (p < 0.01). CONCLUSION: In conclusion, we propose that the NPYY1R gene polymorphism may be a novel prognostic predictor in patients with IgA nephropathy.     

Clinicopathological characteristics and risk factors in elderly patients with biopsy-proven IgA nephropathy

BackgroundImmunoglobulin A nephropathy (IgAN) has been well studied among young people, but few data on clinicopathological characteristics, treatment response and outcomes for elderly IgAN patients are available.MethodsA cohort study of elderly IgAN patients was performed. The combined endpoints of renal outcome were a 50% decline in eGFR compared with the time of renal biopsy, end-stage kidney disease and/or death. Risk factors associated with poor renal outcomes were then determined. The benefits of immunosuppressant therapies were also evaluated by Kaplan-Meier survival curve analysis.ResultsThis study ultimately included 126 elderly patients with IgAN. Comparison between the endpoint and non-endpoint groups indicated that patients with poor outcomes had more severe clinical features, such as worse kidney function, severe hematuria and lower albumin levels. Cox regression analysis indicated that age (HR 1.15, 95% CI 1.02–1.29, p = 0.021), male gender (HR 9.71, 95% CI 1.00–97.56, p = 0.050), and urine red blood cells (HR 1.003, 95% CI 1.000–1.006, p = 0.029) were independent risk factors for poor renal outcome in elderly IgAN patients. To explore possible reasons accounting for the predictive value of age and sex, patients were divided into two groups based on these two variables. Patients in the geriatric group had lower serum albumin, estimated glomerular filtration rate, hemoglobin and aspartate aminotransferase levels than those in the quinquagenarian group. Male patients tended to have higher hemoglobin, higher alanine aminotransferase, and lower triglycerides and cholesterol levels than female patients. To investigate different treatment responses, patients were classified into two groups depending on treatment strategies (renin-angiotensin system inhibitors and immunosuppressive therapy), and the survival analysis indicated no significant difference in kidney outcome between the two groups (p > 0.05). This result still holds after adjusting for age, sex, eGFR, hematuria, and proteinuria.ConclusionAdvanced age, male, and hematuria might be independently associated with poor kidney outcomes in elderly patients with IgAN. Immunosuppressive therapy might confer no overall benefit to older IgAN patients.