Mycophenolate mofetil in IgA nephropathy: results of a 3-year prospective placebo-controlled randomized study

BACKGROUND: Because humoral immunity is believed to play a pivotal role in the pathogenesis of IgA nephropathy (IgAN), a prospective placebo-controlled randomized study was started in patients with IgAN using mycophenolate mofetil (MMF). METHODS: A total of 34 patients with IgAN were treated with salt intake restriction, angiotensin-converting enzyme (ACE) inhibition and MMF 2 g per day (N= 21) or placebo (N= 13). After 36 months of follow-up clinical, biochemical, and radiologic data were analyzed using linear mixed models for longitudinal data and Kaplan-Meier survival analysis. RESULTS: Therapy had to be stopped prematurely in five patients. Two patients (MMF group) evolved to end-stage renal disease (ESRD). There was no difference between groups in the percentage of patients with a decrease of 25% or more in the inulin clearance or with a serum creatinine increase of 50% or more over 3 years. There was also no significant difference between groups in annualized rate of change of serum creatinine, computed by linear regression analysis. No significant difference was noted between groups for inulin clearance, serum creatinine, proteinuria, blood pressure, or other parameters of renal function. Hemoglobin and C-reactive protein were significantly lower in the MMF group compared with the placebo group. As a function of time, a significant decline in both groups was noted of proteinuria, parenchymal thickness of the kidneys and C3d. CONCLUSION: In patients with IgAN at risk for progressive disease, no beneficial effect of 3-year treatment with MMF 2 g per day could be demonstrated on renal function/outcome or proteinuria. However, larger randomized studies are needed to confirm or reject these results.     

Mycophenolate mofetil (MMF) vs placebo in patients with moderately advanced IgA nephropathy: a double-blind randomized controlled trial.

BACKGROUND: IgA nephropathy (IgAN) is the most common form of glomerulonephritis worldwide. Up to 40% progress to end-stage renal disease (ESRD) over 10-20 years. Currently, treatment is limited. We studied the use of mycophenolate mofetil (MMF) vs placebo in a group of North American IgAN patients at high risk for progressive disease. METHODS: Included were 32 patients aged 18-75 years from multiple centres who had their biopsies read at Columbia and who had at least 1 g of proteinuria per day plus at least two of the following risk factors: (i) male sex; (ii) hypertension >150/90 mmHg or requiring antihypertensive medications; (iii) creatinine clearance, measured by 24 h urine collection, <80 and >20 ml/min at time of enrolment; and (iv) presence of glomerulosclerosis or tubulointerstitial atrophy and fibrosis on renal biopsy. Patients were randomized to either 1 year of MMF, titrated up to a dose of 1000 mg bid, or placebo. Total follow-up was 2 years. All patients received angiotensin inhibition medication. The primary outcome was a 50% increase in baseline serum creatinine (SCr). Secondary outcomes were an increase of 0.5 mg/dl SCr, ESRD and a 50% reduction in proteinuria. RESULTS: The mean baseline SCr was 2.4 mg/dl. No statistically significant differences were observed for any outcome. Five of 17 who received MMF vs two of 15 patients in the placebo group reached a 50% increase in SCr (P = 0.4). In both groups, all patients who reached the primary outcome also reached ESRD. Ten who received MMF vs seven who received placebo had a 0.5 mg/dl increase in SCr (P = 0.7) Only three MMF and two placebo patients had a 50% reduction in 24 h proteinuria. No serious adverse events occurred in either group. CONCLUSION: No benefit was seen in patients who received MMF in this high risk group, probably reflecting the relatively advanced stage of disease of our population. We conclude that MMF is probably not effective in patients with IgAN who already have moderate renal insufficiency.     

IgA肾病患者糖代谢异常和胰岛素抵抗的研究

目的:研究原发性IgA肾病(IgA nephropathy,IgAN)患者中糖代谢异常及胰岛素抵抗(insulin resistance,IR)的发生率及相关危险因素。方法:回顾性分析107例IgAN患者(IgAN组)和106例健康对照者(对照组)的口服葡萄糖耐量试验(oral glucose tolerance test,OGTT)结果,并收集一般临床及实验室资料,计算胰岛素抵抗指数(HOMA-IR)和胰岛素敏感性指数(ISI),评估糖代谢异常及胰岛素抵抗发生率。结果:IgAN组糖代谢异常的发生率高于对照组;IgAN组血压、血清肌酐、尿酸、三酰甘油、胆固醇、低密度脂蛋白、血糖(空腹及OGTT2h)、血清胰岛素(空腹及OGTT2h)、HOMA-IR均高于对照组,血清白蛋白、高密度脂蛋白、ISI低于对照组,差异均有统计学意义(P<0.05)。年龄(OR=1.061)、24h尿蛋白定量(OR=1.387)、三酰甘油(OR=2.553)是IgAN患者发生糖代谢异常的独立危险因素。与糖代谢正常的IgAN患者相比,合并糖代谢异常的IgAN患者年龄、BMI、24h尿蛋白定量、三酰甘油、空腹血糖、OGTT2h血糖及血清胰岛素、HOMA-IR均较高(P<0.05),而高密度脂蛋白、ISI较低(P<0.05)。IgAN合并IR的患者BMI、24h尿蛋白定量、三酰甘油、空腹血糖、空腹血胰岛素、OGTT2h血糖及血清胰岛素水平均显著高于不伴IR的IgAN患者(P<0.05),血肌酐、高密度脂蛋白、ISI则较低(P<0.05);BMI(OR=0.059,P<0.05)、血清白蛋白(OR=0.033,P<0.01)、24h尿蛋白定量(OR=0.077,P<0.05)为IgAN患者发生胰岛素抵抗的独立危险因素。结论:IgAN患者糖代谢异常的发生率高于正常人,存在明显的高胰岛素血症及胰岛素抵抗;年龄、24h尿蛋白定量、三酰甘油是IgAN患者发生糖代谢异常的独立危险因素;BMI、血清白蛋白、24h尿蛋白定量为IgAN患者发生胰岛素抵抗的独立危险因素。     

Role of proteinuria reduction in the progression of IgA nephropathy

Proteinuria has been shown to play a causal role in the progression towards ESRD of IgA nephropathy (IgAN). We demonstrated that steroids are effective in reducing proteinuria and preserving renal function. AIM: to evaluate the long-term effect of steroids in IgAN patients (6th year evaluation) and better clarify the role of proteinuria reduction in slowing down the progression. METHODS: multicenter randomized controlled trial of 86 adult IgAN patients with serum creatinine < or = 1.5 mg/ dL and moderate proteinuria. They received either supportive therapy or methylprednisolone 1-g i.v. for three days at months 1, 3, and 5, plus oral prednisone (0.5 mg/kg every other day for six months). RESULTS: Proteinuria significantly decreased in the treated patients (from 2.0+/-0.60 g/24 h at baseline to 1.0+/-0.68 g/24 h at six months) and remained stable till the 6th year (0.67+/-0.5 g/24 h), it slightly decreased in the control group. Six-year renal survival was significantly better in the steroid than in the control group: 9 patient (20.9%) in the steroid group and 15 (34.8%) in the control group reached the primary end-point of a 50% increase in serum creatinine from baseline. Five controls and none of the steroid-treated patients started dialysis. Steroid-treated patients did not experience any major side effects during follow-up. CONCLUSIONS: Steroids significantly reduce proteinuria and protect against renal function deterioration in IgAN patients. Early reduction of proteinuria could also be marker of a persistent reduction in its levels over time and of a better outcome in the long term.     

ROLE OF PROTEINURIA REDUCTION IN THE PROGRESSION OF IgA NEPHROPATHY

Proteinuria has been shown to play a causal role in the progression towards ESRD of IgA nephropathy (IgAN). We demonstrated that steroids are effective in reducing proteinuria and preserving renal function. Aim: to evaluate the long-term effect of steroids in IgAN patients (6th year evaluation) and better clarify the role of proteinuria reduction in slowing down the progression. Methods: multicenter randomized controlled trial of 86 adult IgAN patients with serum creatinine ≤1.5 mg/dL and moderate proteinuria. They received either supportive therapy or methylprednisolone 1-gi.v. for three days at months 1, 3, and 5, plus oral prednisone (0.5 mg/kg every other day for six months). Results: Proteinuria significantly decreased in the treated patients (from 2.0 ± 0.60 g/24 h at baseline to 1.0 ± 0.68 g/24 h at six months) and remained stable till the 6th year (0.67 ± 0.5 g/24 h); it slightly decreased in the control group. Six-year renal survival was significantly better in the steroid than in the control group: 9 patient (20.9%) in the steroid group and 15 (34.8%) in the control group reached the primary end point of a 50% increase in serum creatinine from baseline. Five controls and none of the steroid-treated patients started dialysis. Steroid-treated patients did not experience any major side effects during follow- up. Conclusions: Steroids significantly reduce proteinuria and protect against renal function deterioration in IgAN patients. Early reduction of proteinuria could also be marker of a persistent reduction in its levels over time and of a better outcome in the long term.     

Treatment of IgA nephropathy with ACE inhibitors: a randomized and controlled trial

Some retrospective studies have suggested a beneficial influence of angiotensin-converting enzyme (ACE) inhibitors on the progression of IgA nephropathy (IgAN), but prospective and controlled studies demonstrating this effect are lacking. Forty-four patients with biopsy-proven IgAN, proteinuria > or = 0.5 g/d, and serum creatinine (SCr) < or = 1.5 mg/dl were randomly assigned either to receive enalapril (n = 23) or to a control group (n = 21) in whom BP was controlled with antihypertensives other than ACE inhibitors. Primary outcome was renal survival estimated by a 50% increase in baseline SCr. Secondary outcomes were the presence of a SCr > 1.5 mg/dl at the last visit and the evolution of proteinuria. Baseline clinical findings were similar at baseline between enalapril-treated and control group, and there were no differences in BP control during follow-up. Mean follow-up was 78 +/- 37 mo in the enalapril group and 74 +/- 36 mo in the control group. Three patients (13%) in the enalapril group and 12 (57%) in the control group reached the primary end point (P < 0.05). Kaplan-Meier renal survival was significantly better in enalapril group than in control group: 100% versus 70% after 4 yr and 92% versus 55% after 7 yr (P < 0.05). Three patients in the enalapril group (13%) and 11 (52%) in the control group showed SCr > 1.5 mg/dl at the last visit (P < 0.05). Proteinuria significantly decreased in the enalapril group, whereas it tended to increase in the control group (P < 0.001 between groups). In conclusion, ACE inhibitors significantly improve renal survival in proteinuric IgAN with normal or moderately reduced renal function.     

Mycophenolate mofetil treatment for therapy-resistant glomerulopathies

BACKGROUND: The management of steroid-resistant glomerulopathies remains a clinical problem. In this trial, we report a clinical observation of 43 patients treated with mycophenolate mofetil (MMF) for steroid-resistant glomerulopathies. METHODS: All patients underwent renal biopsies, and immunofluorescence and light microscopy examinations were conducted in all cases. All patients had been treated with prednisone at a dose of 1 mg/kg per day for at least 8 weeks. Of the 43 patients, 16 were treated with cyclophosphamide and five were treated with cyclosporine A before MMF started. The primary study outcomes were the change in the urinary protein excretion, serum creatinine, comparing the levels at the start of MMF treatment with those at the end of the MMF treatment period. Changes in renal function were also estimated with Modification of Diet in Renal Failure calculation. Wilcoxon signed-ranks test was used as appropriate to compare data from the start with data at the end of the treatment period. RESULTS: The primary glomerular diseases represented included membranoproliferative glomerulonephritis in 23.2%, membranous glomerulonephritis in 18.6%, IgA nephropathy in 13.9%, focal segmental glomerulosclerosis in 9.3%, lupus nephritis (systemic lupus erythematosus) in 25.6% and pauci-immune glomerulopathy in 9.3% of patients. The mean follow-up time was 28.9+/-12 months. Before MMF treatment, 16 patients (37%) had nephrotic range proteinuria and 11 (26%) had renal insufficiency. The urinary protein before MMF treatment was 3.3+/-2.6 g/dL (0.6-9.6) and decreased significantly to 0.87+/-1.1 g/dL (0-5.5) at the end of the MMF treatment period (P=0.02). During treatment, complete remission was seen in 27 patients, partial remission in 10 patients and MMF failure in six patients. The serum creatinine level decreased significantly from 1.29+/-0.55 mg/dL (0.6-3.0) to 1.14+/-0.38 mg/dL (0.5-2.4) post MMF therapy (P=0.046). Using the four-variable Modification of Diet in Renal Failure formula, the glomerular filtration rate increased from 71.5+/-28 mL/min per 1.73 m2 to 78.1+/-27 mL/min per 1.73 m2 (P=0.021). Renal insufficiency resolved in seven of the 11 (63.6%) patients with renal insufficiency initially, two with membranoproliferative glomerulonephritis, two with membranous glomerulonephritis, one with focal segmental glomerulosclerosis, four with pauci-immune glomerulopathy, two with systemic lupus erythematosus nephritis, and in two patients de novo renal insufficiency developed. CONCLUSION: In general, MMF was well tolerated, and most of the patients achieved remission and improvement of renal functions. MMF treatment appeared to offer benefits to problematic patients refractory to conventional therapies for glomerulopathies.     

Prospective study on renal outcome of IgA nephropathy superimposed on diabetic glomerulosclerosis in type 2 diabetic patients.

BACKGROUND AND METHODS: In order to examine the clinical outcome of IgA nephropathy (IgAN) superimposed on diabetic glomerulosclerosis in type 2 patients we studied 36 Chinese patients (26 men, 10 women), who were recruited for renal biopsy when they had proteinuria of more than 1 g/day. Twenty-seven had isolated diabetic glomerulosclerosis and nine had IgAN superimposed on diabetic glomerulosclerosis (combined). Renal function was assessed by serial serum creatinine, 24-h urine protein and creatinine measurements. Patient survival rate, incidence of end-stage renal disease (ESRD), blood pressure, and glycaemic control status were determined. RESULTS: The age at the time of renal biopsy was younger for the combined group when compared with the diabetic glomerulosclerosis group (44+/-3.6 vs 58+/-2.1 years, P=0.006). The duration of diabetes was, however, similar for the two groups (8.0+/-2.3 vs 6.7+/-1.2 years, P=NS). After a mean follow-up of 31.6+/-15.3 months, 15 patients (one in the combined group and 14 in the diabetic glomerulosclerosis group) developed ESRD. Nine patients (all in the diabetic glomerulosclerosis group) died during follow-up. With similar glycaemic and blood pressure control, the two groups had comparable rate of decline of creatinine clearance (CrCl) (-0.73+/-0.26 vs -0.73+/- 0.18 ml/min/1.73 m(2)/month, P=NS), final serum creatinine (363+/-134 vs 426+/-52 micromol/l, P=NS) and proteinuria levels (4.3+/-0.9 vs 4.4+/-0.6 g/day, P=NS), as well as CrCl (44.1+/-19.0 vs 33.4+/-6.9 ml/min/ 1.73 m(2), P=NS). CONCLUSION: It is concluded that the superimposed IgAN does not significantly alter the medium-term clinical outcome of patients with diabetic glomerulosclerosis.     

Clinicopathological features and outcomes of primary IgA nephropathy patients with chronic tonsillitis

Objective To explore the clinicopathological features and renal outcomes of primary IgA nephropathy (IgAN) patients with chronic tonsillitis. Methods Patients with biopsy-proven primary IgAN admitted to The First Affiliated Hospital, Sun Yat-sen University from January 2006 to December 2011 were enrolled. The clinicopathological features and renal outcomes of patients with and without chronic tonsillitis were retrospectively compared. The primary outcome was progression to end stage renal diseases and/or doubling of serum creatinine. Results A total of 981 primary IgAN patients were enrolled and 98 patients (9.99%) had a history of chronic tonsillitis. Compared with patients without chronic tonsillitis, IgAN patients with chronic tonsillitis exhibited significantly higher prevalence of acute episodes of tonsillitis as a predisposition (P＜0.001), higher serum IgA levels (P=0.012), and higher prevalence of macrohematuria (P=0.006). No significant difference in renal pathological features was observed in patients with and without chronic tonsillitis. Moreover, the renal outcomes were similar as regards IgAN patients with and without chronic tonsillitis. Conclusion IgAN patients with chronic tonsillitis had higher prevalence of acute episodes of tonsillitis and macrohematuria as well as higher serum IgA levels. However, IgAN patients with and without chronic tonsillitis showed no significant difference in renal pathological features and renal outcomes.     

针灸治疗IgA肾病的作用

目的观察针灸治疗对IgA肾病患者蛋白尿、血肌酐（SCr）、血浆内皮素（ET）的影响,探讨针灸对IgA肾病的治疗作用。方法IgA肾病患者30例,随机分为两组,针灸联合激素组15例,接受针灸联合口服泼尼松龙治疗;针灸组15例仅接受针灸治疗,疗程均为2个月。测定治疗前、后24h尿蛋白定量、SCr、血浆ET浓度。结果治疗后两组患者24h尿蛋白定量、SCr、血浆ET浓度均较治疗前显著降低,针灸联合激素组降低的幅度显著高于单纯针灸治疗组（P〈0．01）。结论针灸治疗IgA肾病有减少蛋白尿、保护肾功能的作用,此可能与降低血浆ET水平有一定关系,针灸联合激素治疗IgA肾病的效果优于单纯使用针灸。     

Treatment of idiopathic membranoproliferative glomerulonephritis with mycophenolate mofetil and steroids.

BACKGROUND: Treatment of adults with idiopathic membranoproliferative glomerulonephritis (IMPGN) is often unrewarding with approximately 60% of patients progressing to end-stage renal failure within 10 years. Although children with IMPGN may respond to steroid therapy, there is no significant benefit to treating adult IMPGN patients with immunosuppression. METHODS: Outcome measures in five patients with IMPGN who were treated with oral prednisolone and mycophenolate mofetil (MMF) (treatment group) were compared with six patients with IMPGN who did not receive immunosuppression (control group). RESULTS: There was no significant difference between either group in baseline clinical characteristics or systolic and diastolic blood pressure during observation. In the treatment group, there was a significant reduction in proteinuria from a baseline of 5.09 to 1.97 g/24 h (P = 0.003) at 6 months, 1.96 g/24 h (P = 0.003) at 12 months and 2.59 g/24 h (P = 0.015) at 18 months. There was no significant change in proteinuria over 18 months in the control group. Serum creatinine concentration and creatinine clearance did not change significantly over 18 months in the treatment group. In the control group, there were significant changes in serum creatinine and creatinine clearance over 18 months [baseline 103 to 159 micromol/l (P = 0.004) and baseline 108 to 67 ml/min (P > 0.001), respectively] when compared to baseline, although the differences were not significant when the two groups were compared directly. CONCLUSIONS: This preliminary study suggests that in the short term, the combination of MMF and prednisolone can significantly reduce proteinuria and may preserve renal function in patients with IMPGN.     

Association of interleukin-10 gene G-1082A polymorphism with the progression of primary glomerulonephritis

BACKGROUND: Interleukin-10 (IL-10) is a cytokine with immunosuppressive properties. We evaluated the influence of G-1082A polymorphism in the IL-10 gene promoter, which has been associated with modified IL-10 production, on the two most common forms of primary glomerulonephritis: IgA nephropathy (IgAN) and focal segmental glomerulosclerosis (FSGS). METHODS: We studied Caucasian patients (N= 191) with biopsy-proven glomerulonephritis (IgAN: N= 123, FSGS: N= 68) followed-up for 6.5 +/- 5.5 years. Patients were classified according to the slope of reciprocal serum creatinine (>/= or <-0.1 dL(*)mg(-1) (*)year(-1)) into group A (slow progressors, IgAN: N= 75, FSGS: N= 47) and group B (fast progressors, IgAN: N= 48, FSGS: N= 21). One hundred healthy volunteers were analyzed as control patients. G-1082A polymorphism was determined by polymerase chain reaction (PCR) amplification. RESULTS: The allele frequencies were similar in patients and control group (NS). Initial renal function, proteinuria, and blood pressure did not differ significantly between patients with different genotypes. G-1082A polymorphism was associated with the progression of both IgAN and FSGS: GA/AA genotypes were more frequent in group B (fast progressors) than in group A (slow progressors; P= 0.012 for IgAN, P < 0.05 for FSGS). Patients with the GA/AA genotypes showed a worse outcome in the Kaplan-Meier analysis of renal survival (P < 0.05 for both IgAN and FSGS). The IL-10 polymorphism remained an independent risk factor for progression in multivariate analysis (Cox regression model, P < 0.05 for IgAN and FSGS). CONCLUSION: Our results suggest that IL-10 gene G-1082A polymorphism is an important marker of progression in patients with IgAN and FSGS.     

The level of serum secretory IgA of patients with IgA nephropathy is elevated and associated with pathological phenotypes.

BACKGROUND: Mucosal infection associated episodic macroscopic haematuria is observed in many patients with IgA nephropathy (IgAN), however, the mechanism has not been elucidated. Recent study suggested that secretory IgA (SIgA) might play an important role in the pathogenesis of IgAN. The aim of this study is to investigate the level of serum SIgA and the deposition of SIgA in glomeruli in IgAN patients with different pathological phenotypes. METHODS: The levels of serum SIgA were detected in 57 patients with IgAN and 48 normal controls. The associations between the levels of SIgA and the pathological phenotypes of IgAN as well as clinical parameters were investigated. Frozen renal sections from 34 of the 57 patients without IgM deposition were immunofluorescence stained and examined by confocal microscopy to detect the co-deposition of IgA and secretory component (SC). The association between deposition of SIgA and the level of serum SIgA was analysed. RESULTS: The level of serum SIgA in patients with IgAN was significantly higher than that of normal controls. The level of serum SIgA in patients with focal proliferative sclerosing IgAN (fpsIgAN) was much higher than that in patients with mild mesangial proliferative IgAN (mIgAN) (P<0.001). The level of serum SIgA correlated with the level of serum creatinine (R=0.509, P<0.001), degree of proteinuria (R=0.643, P<0.001) and creatinine clearance (R= -0.454, P=0.002) in patients with IgAN. Significant co-deposition of SC and IgA were found in 11 of the 34 patients. Although the level of serum SIgA in patients with SC deposits was higher than those without SC deposits, the difference was not significant. CONCLUSIONS: It was concluded that mesangial IgA, at least partly, was originated from mucosal immune sites. The levels of serum SIgA were significantly increased in patients with IgAN and were closely associated with pathological phenotypes.     

Angiotensin-converting enzyme insertion/deletion polymorphism and prognosis of IgA nephropathy

BACKGROUND/AIM: Well-known factors for a poor prognosis in IgA nephropathy (IgAN) are hypertension, proteinuria, and renal insufficiency at the time of diagnosis. Also hypertriglyceridemia and hyperuricemia seem to play a role in the progression of IgAN. Angiotensin-converting enzyme (ACE) gene I/D polymorphism has been associated with cardiovascular diseases and with progression of IgAN. We, therefore, investigated the contribution of ACE gene I/D polymorphism in the prognosis of IgAN and its association with the other risk factors affecting the prognosis. METHODS: A total of 168 patients with IgAN were followed up for 6-17 (median 11) years from renal biopsy with respect to progression of renal disease defined as elevation of serum creatinine above 125 microM (1.4 mg/dl) in men or 105 microM (1.2 mg/dl) in women and over 20% from the baseline level. In addition to serum creatinine, the urinary protein excretion was evaluated at the time of renal biopsy and at the assessment visit at the end of the follow-up period. RESULTS: During the follow-up period, 26 (15%) patients showed progression of renal disease. Patients with ACE genotype II had a more favorable course than those with genotypes ID or DD. Although there were no significant differences among the ACE genotypes with respect to proteinuria > or =1 g/24 h at the time of renal biopsy, proteinuria > or =1 g/24 h was more frequent in patients with genotypes ID or DD than in those with genotype II at the end of the follow-up period. No associations were found between hypertension, serum lipids or serum urate, and ACE genotypes. CONCLUSIONS: Our results show that patients with ACE genotype II have a more favorable prognosis than those with genotypes ID/DD. Secondly, proteinuria (> or =1 g/24 h) found in patients with genotype II at diagnosis may improve, while in patients with genotypes ID/DD it is a more constant feature.     

他克莫司与霉酚酸酯治疗儿童难治性IgA肾病的疗效比较

目的比较他克莫司(tacrolimus,TAC)与霉酚酸酯(mycophenolate mofetil,MMF)在难治性IgA肾病(IgA nephropathy,IgAN)患儿的临床疗效。方法难治性IgAN的诊断定义为:在联合肾素-血管紧张素系统(RAS)阻断剂及糖皮质激素序贯治疗后,仍表现为大量蛋白尿(≥50 mg·kg-1·d-1)。遵循病例对照匹配方法,回顾性选取2012年1月1日至2016年12月31日在东部战区总医院行肾活检确诊为难治性IgAN的患儿76例,根据治疗方案将患儿分为TAC组(38例)和MMF组(38例),比较两组24 h尿蛋白量(24hUP)、血清白蛋白(Alb)、血清肌酐(Scr)、血清尿酸(UA)、血糖(Glu)、不良反应发生情况以及疗效等。结果两组患者间年龄、性别比、血压、估算肾小球滤过率(eGFR)、24hUP、尿红细胞计数(U-RBC)、Scr、Alb、BUN、天门冬氨酸转氨酶(AST)、丙氨酸转氨酶(ALT)、Glu及病理牛津分型、加用免疫抑制剂前行大剂量甲泼尼龙冲击治疗比例差异均无统计学意义(均P>0.05),两组患者具有可比性。用药3个月起,两组患儿24hUP均较基线值明显降低,差异有统计学意义(均P<0.05),且在3、6、12个月时TAC组24hUP均显著低于MMF组(均P<0.05)。TAC组Alb在用药1个月后即较基线值明显升高(P<0.05),而MMF组在用药3个月后明显升高(P<0.05),其中TAC组Alb在1、3、6个月时均高于MMF组(均P<0.05),在12个月时两组Alb差异无统计学意义。TAC组的总有效率、完全缓解率及无效率自用药3个月起与MMF组差异均有统计学意义(均P<0.05),但随访期间部分缓解率、随访时点复发率及累计复发率两组间差异无统计学意义(均P>0.05)。其中TAC组在6个月时达到最大有效率(94.7%),而MMF组在12个月时达到最大有效率(68.4%),差异有统计学意义(χ2=8.756,P=0.003)。两组不良反应发生率比较差异无统计学意义(15.8%比21.1%,χ2=0.350,P=0.554)。但TAC组在治疗3个月时血糖高于MMF组,差异有统计学意义[5.02(4.72,5.22)mmol/L比4.42(4.19,5.07)mmol/L,Z=-2.745,P=0.006]。结论TAC与MMF治疗难治性IgAN均取得良好的治疗效果,但TAC组更快达到缓解水平,且缓解率更高。     

Low doses of drugs able to alter intestinal mucosal permeability to food antigens (5-aminosalicylic acid and sodium cromoglycate) do not reduce proteinuria in patients with IgA nephropathy: a preliminary noncontrolled trial.

In an uncontrolled trial, patients with IgA nephropathy (IgAN) were treated with drugs that can alter the intestinal mucosal permeability to food antigens. These drugs are known to ameliorate urinary abnormalities and histological lesions of IgAN associated with ulcerative colitis or Crohn's disease [5-aminosalicylic acid (5-ASA)] or to prevent, in mice, the induction of IgAN-like disease by oral immunization [disodium cromoglycate (SCG)]. Nine patients [serum creatinine (s-Cr) less than 2 mg/dl; 24-hour proteinuria higher than 1.5 g, but not nephrotic) were treated with 5-ASA (2.4 g/day for 6 months); 9 similar patients were treated with SCG (400 mg/day for 6 months); the follow-up extended to 6 months after stopping therapy. The 5-ASA group showed a slight but not significant decrease in s-Cr, 24-hour/proteinuria, IgA circulating immune complexes (IgA-CIC) and IgA rheumatoid factor (IgA-RF); serum beta 2-microglobulin and serum IgA were unchanged; 2 of 9 treated patients showed, after 6 months of therapy, a reduction in proteinuria of more than 50% that lasted for the subsequent 18 months. The SCG-treated group showed a slight but not significant increase in 24-hour proteinuria and a significant decrease in serum IgA; unchanged were s-Cr, IgA-CIC, IgA-RF, serum beta 2-microglobulin; no patient treated with SCG showed a reduction in proteinuria of more than 50%. At the dosages and for the periods used, 5-ASA and SCG did not show a significant influence on clinical and laboratory parameters of disease in IgAN; other trials with increased dosages are warranted to definitely ascertain the possible therapeutic role of these drugs in IgAN.     

Histological grading of IgA nephropathy predicting renal outcome: revisiting H. S. Lee's glomerular grading system.

BACKGROUND: The glomerular grading system is useful to compare biopsy specimens and to predict the natural course of disease in IgA nephropathy (IgAN), although no grading system can be perfect. METHODS: H. S. Lee's grading system for IgAN was refined as follows: grade I, normal or focal mesangial cell proliferation; grade II, diffuse mesangial cell proliferation, or <25% of glomeruli with crescent (Cr)/segmental sclerosis (SS)/global sclerosis (GS); grade III, 25-49% of glomeruli with Cr/SS/GS; grade IV, 50-75% of glomeruli with Cr/SS/GS; grade V, >75% of glomeruli with Cr/SS/GS. This refined H. S. Lee grading system was then tested for clinical relevance on 187 patients with IgAN followed up for an average of 6.5 years (minimum, 3 years). In the survival analysis, a modified primary end-point (progressive renal disease) was used. RESULTS: The glomerular grades were significantly related to hypertension, serum creatinine levels and the amounts of proteinuria at time of biopsy. By univariate analysis, glomerular grades, hypertension, renal insufficiency and significant proteinuria (> or =1 g/day) were significantly associated with progressive renal disease. By multivariate analysis using the Cox regression model, glomerular grades, renal insufficiency and significant proteinuria were independent prognostic factors for progressive renal disease. At the end of follow-up, glomerular grades were significantly related to serum creatinine levels, amounts of proteinuria, hypertension and progressive renal disease. CONCLUSIONS: These findings indicate that the refined H. S. Lee grading system for IgAN is useful in assessing the patients' clinical outcome and is sufficiently simple and easy to reproduce as to be universally applicable in prognostic work.     

Early prediction of IgA nephropathy progression: proteinuria and AOPP are strong prognostic markers

BACKGROUND: Inflammation and oxidative stress have been incriminated in the pathogenesis of IgA nephropathy (IgAN). The aim of the present study was to assess whether markers reflecting these pathophysiologic processes, namely C-reactive protein (CRP) and advanced oxidation protein products (AOPP), would allow-in conjunction with clinical and histopathologic parameters-to predict disease progression. METHODS: Between 1994 and 1997, 120 adult patients with biopsy-proven IgAN were included in a prospective cohort study, and followed until the end of 2002 or start of dialysis. In every patient, we determined plasma levels of CRP and AOPP. These parameters were included, together with clinical data, in a multivariate Cox proportional hazard regression analysis, with halving of baseline creatinine clearance as the primary renal end point. RESULTS: A total of 51 patients reached the renal end point, including 30 who had to start dialysis. With multivariate analysis, the most potent independent risk factors of poor renal outcome were proteinuria > or =1 g/day [proportional hazard risk (HR) = 23.7, P= 0.0001], hypertension (HR = 8.13, P= 0.008), and AOPP plasma level (HR = 1.09 per 10 micromol/L, P= 0.042), whereas angiotensin II inhibitors were protective (HR = 0.19, P= 0.001). CONCLUSION: Our data support the role of oxidative stress in the pathogenesis of IgAN and suggest that patients with proteinuria > or =1 g/day should be eligible for early implemented antioxidant and/or anti-inflammatory therapeutic strategies, with AOPP plasma level as a surrogate marker to evaluate their effects.     

Clinicopathological features and renal outcomes of IgA nephropathy with acute tubulointerstitial nephropathy

Objective To evaluate the clinicopathological characteristics and outcomes of IgA nephropathy (IgAN) with acute tubulointerstitial nephropathy (ATIN). Methods Patients who were diagnosed as IgAN with ATIN and IgAN without ATIN by renal biopsy in Peking University First Hospital were enrolled. There were 74 cases of IgAN with ATIN, and seventy-four cases of IgAN without ATIN were enrolled based on stratified sampling (chosen by 1∶1). The two groups were well matched with age, gender, follow-up time, mesangial hypercellularity(M), endocapillaryhypercellularity(E), segmental glomerulosclerosis(S), tubular atrophy/interstitial fibrosis(T) and cellular/fibrocellular crescent(C). The clinicopathological characteristics and outcomes of two groups were retrospectively analyzed. A composite end point, defined as 30% or 50% estimated glomerular filtration rate (eGFR) decline and end stage renal disease (ESRD) was used. Renal function and proteinuria during follow-up were observed. Renal survival was calculated by Kaplan-Meier survival analysis and risk factors of progression were analyzed by using univariate and multivariate Cox regression models. Results Seventy-four cases of IgAN with ATIN and seventy-four cases of IgAN without ATIN were enrolled. Serum creatinine [(185.6±83.2) μmol/L vs (146.3±69.2) μmol/L, P=0.010] and incidence of acute kidney disease (AKD) (31.1% vs 5.4%, P＜0.001) were higher in IgAN with ATIN group than those in IgAN without ATIN group. Patients in ATIN group received more immunosuppressive treatment (86.5% vs 58.1%, P＜0.001). During 1 year after biopsy, mean eGFR increased significantly in IgAN with ATIN group [(39.7±14.6) ml?min-1?(1.73 m2)-1 vs (47.2±19.9) ml?min-1?(1.73 m2)-1, P=0.017], but mean eGFR was not statistic different in IgAN without ATIN group [(60.0±30.5) ml?min-1?(1.73 m2)-1 vs (59.0±31.7) ml?min-1?(1.73 m2)-1, P=0.567]. Median follow-up was 23.0 months in IgAN with ATIN group, and Median follow-up was 30.0 months in IgAN without ATIN group. Incidence of composite end point had no significant differences between two groups. IgAN with ATIN was not the independent risk factor for end point. IgAN patients with ATIN were divided into two groups (with AKD and without AKD), then renal survival rate was higher (Log-rank test, χ2=5.293, P=0.021) and the risk for composite end point decreased by 79.2% (HR=0.208, 95%CI 0.046-0.939, P=0.041) in the group with AKD. Conclusions In IgAN, there is a subgroup of patients with the specific pathological phenotype combined with ATIN. Compared with those without AKD, the risk for composite end point of IgAN patients with ATIN and AKD showed a 79.2% decrease.     

Clinical and pathological features of hyperuricemia in children with IgA nephropathy at a single center

Objective To investigate the clinical, pathological features and risk factors of hyperuricemia in children with IgA nephropathy (IgAN). Methods A retrospective study of 269 primary IgAN children diagnosed between January 1, 2006 to December 31, 2017 at the Children Kidney Disease Center, the First Affiliated Hospital of Sun Yat-sen University, was performed in the hyperuricemia group (uric acid＞350 μmol/L) and the normal uric acid group. The clinical and pathological characteristics were analyzed, and the risk factors of hyperuricemia were analyzed by using multivariate logistic regression analysis. Results There were 185 males and 84 females in the 269 IgAN children with age of (9.2±3.1) years old, among whom there were 70 patients (26.0%) accompanied by hyperuricemia. Clinical indicators such as hypertension, urea nitrogen, serum creatinine, blood lipids, urinary protein in hyperuricemia group were higher than those in normal uric acid group (all P＜0.05), while estimated glomerular filtration rate, serum total protein and albumin were less (all P＜0.05). There were 58 patients (23.0%) and 12 patients (70.5%) associated with hyperuricemia among IgAN children with CKD 1-2 and CKD 3-5. The proportion of hyperuricemia in CKD stage 3-5 IgAN children was statistically higher than that in normal uric acid group (P＜0.01). The hyperuricemia group had a higher proportion of Lee IV and V grade, and a lower proportion of the Lee III grade than the normal uric acid group (all P＜0.05). According to the Oxford pathological classification score, there was no significant difference in total scores of renal lesions, glomerular score, and tubulointerstitial score between the two groups (all P＞0.05). According to the Katafuchi semi-quantitative score, there was no significant difference in the total scores of renal lesions, glomeruli, and tubulointerstitial scores (all P＞0.05), while the hyperuricemia group had higher renal vascular scores than the normal uric acid group (P＜0.01). Multivariate logistic regression analysis showed that hypertension (OR=12.596, 95%CI 1.778-89.243, P=0.011), higher total cholesterol (OR=1.192, 95%CI 1.064-1.336, P=0.002), higher urea nitrogen (OR=1.273, 95%CI 1.104-1.468, P=0.001), proteinuria 3+(OR=1.875, 95%CI 1.309-2.684, P=0.001), proteinuria 4+(OR=1.627, 95%CI 1.241-2.134, P＜0.001) and CKD stage 3 (OR=3.355, 95%CI 1.376-8.181, P=0.008) were the risk factors of hyperuricemia in children with IgAN. Conclusions Twenty-six percent IgAN children patients are accompanied by hyperuricemia, and their clinical parameters and pathological changes are more severe than those in normal uric acid group. Hypertension, higher total cholesterol, higher urea nitrogen, proteinuria 3+/4+ and CKD stage 3 are the risk factors of hyperuricemia in children with IgAN.