Combination therapy using prednisolone and cyclophosphamide slows the progression of moderately advanced IgA nephropathy

AIM: We retrospectively examined the effect of combination therapy using prednisolone (PSL) and cyclophosphamide (CPA) on the progression of IgA nephropathy (IgAN) in 45 patients with moderate to severe histological changes. PATIENTS AND METHODS: Patients were recruited from 129 consecutive patients with IgAN seen over 10 years based on semiquantitative histological grading. They were divided into two groups: PSL+CPA group (n = 26, male/female = 11/15, age 40+/-3 years (SEM)) or control group undergone conventional therapy with or without antiplatelet agents (n = 19, male/female = 10/9, age 41+/-3). In PSL+CPA group, PSL and CPA treatment commenced using a dose of 30 and 50 mg/day, respectively. PSL was reduced by 5 mg every month. RESULTS: The clinical parameters at the start of treatment such as age, gender, histological score, blood pressure, urinary protein excretion and serum creatinine concentration (SCr) were not different between the groups. The mean observation period in PSL+CPA group (3.3+/-0.3 years) was not different from the control group (4.0+/-0.7 years). In PSL+CPA group, urinary protein excretion, defined as the ratio of urinary protein to creatinine concentration (UP/UCr), significantly decreased from 3.9+/-0.4 to 1.3 +/-0.2 (p<0.01), whereas it remained high in the control group (3.8+/-0.7 to 2.7+/-0.8). The progression rate (PR), which was determined by the slope of the correlation between time after renal biopsy and reciprocal SCr, was significantly lower in PSL+CPA (0.054+/-0.014) than in the control group (0.172+/-0.032 dl/mg/year, p<0.001). Our results indicated that PSL+CPA combination therapy was effective in slowing the progression of moderately advanced IgAN. CONCLUSION: We suggest that the immunosuppressive treatment with CPA is sometimes necessary to preserve renal function in patients with histologically advanced IgAN.     

The product of duration and amount of proteinuria (proteinuria index) is a possible marker for glomerular and tubulointerstitial damage in IgA nephropathy

BACKGROUND/AIMS: IgA nephropathy (IgAN) is one of the major causes for chronic renal failure (CRF). Presence of massive proteinuria, hypertension, increased serum creatinine level and sclerotic histopathological changes of the glomerulus are known to be determinants for the progression of CRF. However, the relationships between duration of proteinuria/hematuria and histopathological changes, which may be correlated with the renal prognosis, have not been clarified. METHODS: A cross-sectional, univariate analysis of clinical parameters on the four glomerular and three tubulointerstitial histopathological grades in 57 untreated biopsy-proven IgAN patients (M/F = 32/25) was performed. RESULTS: The age at the time of renal biopsy (35.2 +/- 13.0 years; mean +/- SD), average duration of proteinuria (5.3 +/- 5.8 years), mean urinary protein excretion (0.99 +/- 1.22 g/day), serum creatinine (Cr 0.97 +/- 0.28 mg/dl), Cr clearance (Ccr 75.5 +/- 29.4 ml/min), and blood urea nitrogen (BUN 15.4 +/- 3.9 mg/dl) were well correlated with both histopathological grades. The product of duration (years) and urinary protein excretion (g/day) at the time of renal biopsy was more significantly correlated with glomerular and tubulointerstitial histopathological grades and serum Cr. CONCLUSION: The natural course of IgAN is steadily progressive depending on the duration and amount of proteinuria. The product of these two factors (proteinuria index) may be a useful predictor for glomerular and interstitial histopathological changes and the fate of renal function in IgAN.     

Prospective randomized controlled multicenter trial on steroids plus ramipril in proteinuric IgA nephropathy

Recent studies have shown that steroids improve renal survival and reduce proteinuria in IgA nephropathy (IgAN) patients with moderate urinary protein excretion and normal renal function. However, this effect seems to diminish over time. Moreover, it has been demonstrated that long-term use of ramipril reduces the risk of end-stage renal disease in proteinuric diabetic and non-diabetic chronic nephropathies. We have planned a long-term unblinded, prospective, centrally randomized, controlled, multicentric trial to assess whether combined treatment of steroids and ramipril is superior to ramipril alone in patients with progressive IgAN disease. A minimum of 134 patients with biopsy-proven IgAN, grade G3 or G4, daily proteinuria > 1.0 g and creatinine clearance > 50 mL/min will be enrolled during a 2-year recruitment period. The patients will be allocated randomly to receive a six-month course of oral prednisone (1.0 mg/Kg/day for 2 months, tapered by 0.2 mg/Kg/day every month) plus ramipril (2.5 mg/day for one month, increased by 1.25 mg/day every month to achieve and maintain a blood pressure less than 120-80 mm Hg and/or to reduce daily proteinuria to 1.0 g or less or by at least 50%) in the experimental group or ramipril alone in the control group. Ramipril will be administered during the whole 5-year follow-up period in both groups. The primary endpoint will be renal survival estimated by 50% increase in baseline serum creatinine; the secondary endpoints will be urinary protein and cytokine excretion and side-effects. Analyses will be done by intention to treat. A p <0.05 will be taken as significant.     

骨形成蛋白7和转化生长因子β1在不同病理类型IgA肾病的变化

目的 观察转化生长因子β1（TGF-β1）和骨形成蛋白7（BMP-7）在不同病理类型IgA肾病的变化,并探讨其意义。方法 89例IgA肾病患者分成3组：A组为47例轻度系膜增生性IgA肾病;B组为29例中重度系膜增生性IgA肾病;C组为13例增生硬化或硬化性IgA肾病。检测患者的血压、尿蛋白量（24 h）、Scr和Ccr。免疫组化和ELISA方法测定患者肾组织冰冻切片及其血、尿中TGF-β1和BMP-7水平。计算患者病理切片硬化肾小球数、新月体数和间质纤维化面积百分比。结果 随着IgA肾病患者肾小球病变的加重,肾小管萎缩和肾间质纤维化增多,其血压、尿蛋白量（24 h）、Scr逐渐增加,除B、C两组间尿蛋白量（24 h）无显著差异外,其余各组间差异均有统计学意义（P＜0．05）。与A组比较,B组肾组织及血、尿TGF-β1明显增多,C组显著降低（P＜0．01）。肾组织冰冻切片及血、尿BMP-7随着肾脏病变的加重,水平逐渐下降（P＜0．01）;而且与Ccr呈正相关;与血压、Scr、尿蛋白量（24 h）、硬化肾小球数、新月体数、肾间质纤维化面积呈负相关。结论 TGF-β1在IgA肾病系膜增生严重时明显增加,肾脏广泛纤维化时明显降低,可能参与了IgA肾病肾间质纤维化的发生。BMP-7随肾脏病变的加重而明显降低,可能导致其抗肾纤维化作用减弱。     

Clinical assessment of low-dose steroid therapy for patients with IgA nephropathy: a prospective study in a single center

BACKGROUND/AIM: No accepted therapy has been established for progressive IgA nephropathy (IgAN). The purpose of the present study was to assess low-dose steroid therapy in the treatment of patients with IgAN. METHODS: A prospective trial of low-dose steroid therapy was performed in patients with IgAN with mild histological activities. Twenty-four patients in the steroid group and 24 patients in the control group were included in this study. The initial dose of prednisolone was 0.4 mg/kgBW/day (20-30 mg/day), gradually tapered to 5-10 mg/day over 24 months. The patients with mild active inflammatory lesions were treated with prednisolone. The patients assigned to the control group were treated with dipyridamole or zilazep hydrochloride in a dose of 150 or 300 mg/day. RESULTS: In all of the patients studied, serum creatinine levels did not significantly change over 24 months. However, daily proteinuria significantly reduced after 24 months of steroid therapy (0.97 +/- 0.75 vs. 0.31 +/- 0.51 g/day, P = 0.0012), even if did not change after 24 months of anti-platelet drugs (0.89 +/- 0.49 vs. 0.68 +/- 0.69 g/day, P = 0.2289), respectively. In addition, the grade of hematuria significantly reduced after 24 months of steroid therapy (35.6 +/- 36.3 RBC/HPF vs. 13.7 +/- 28.4 RBC/HPF, P = 0.0249) and 24 months of anti-platelet drugs (30.1 +/- 37.1 RBC/HPF vs. 12.4 +/- 20.3 RBC/HPF, P = 0.0465), respectively. Systolic and diastolic blood pressures did not significantly change during treatment with steroid or anti-platelet drugs. Vascular changes (0.63 +/- 0.73) in the steroid group were lower than those (1.08 +/- 0.88) in the control group (P = 0.008). CONCLUSION: Our data suggested that low-dose steroid therapy for IgAN patients with mild inflammatory lesions could reduce the amount of urinary protein excretion and prevent deterioration of renal function, provided the histological findings in the renal biopsies showed mild vascular lesions.     

伴足细胞尿的IgA肾病的临床病理特征

目的 探讨伴足细胞尿的IgA肾病（IgAN）患者的临床病理特点。方法 入选IgAN患者36例,其中男性20例,女性16例,平均年龄（34．1±12．2）岁。10例健康志愿者为健康对照。足细胞排泄的定量检测采用尿沉渣涂片免疫组化染色直接计数。进行尿液足细胞排泄与肾脏病理的相关分析。结果 （1）IgAN患者尿细胞podocalyxin阳性率为61%,健康对照组为0（P＜0．05）。（2）与非大量蛋白尿（＜3．0 g/24 h）IgAN患者比较,大量蛋白尿（≥3．0 g/24 h）IgAN患者的尿液足细胞检测阳性率、尿液足细胞排泄数、足细胞与尿肌酐的比值以及足细胞占尿液小管上皮细胞的百分数均显著增高（P＜0．05）。IgAN患者足细胞排泄水平与蛋白尿水平呈正相关（r=0．446,P=0．007）。（3）与无足细胞尿的患者比较,伴足细胞尿的IgAN患者的蛋白尿水平显著增高,血浆白蛋白水平显著降低,肾小管上皮细胞与尿肌酐的比值亦显著增高（P＜0．05）。但伴与不伴足细胞尿的2组IgAN患者在年龄、性别、血压、Scr、血红蛋白水平以及血浆脂质代谢等方面差异均无统计学意义（P＞0．05）。（4）尿足细胞的排泄与细胞新月体或细胞纤维性新月体、小球血管襻腔狭窄和足突广泛融合病变有关,而与系膜、内皮细胞病变及局灶基底膜增厚无关。伴足细胞尿的患者肾小球和肾小管间质纤维化更明显（P＜0．05）。伴有新月体的患者其尿液足细胞排泄水平、尿液上皮细胞和管型的排泄均增加（P＜0．05）。结论 足细胞尿不仅是IgAN患者肾小球损伤的结果,也是IgAN患者活动性损伤的指标。足细胞尿排泄的水平与蛋门尿水平呈正相关,与肾脏病理类型也有一定的关系。     

Severity of nephrotic IgA nephropathy according to the Oxford classification

Background

IgA nephropathy with nephrotic syndrome (nephrotic IgAN) is a rare form of IgAN. Its prognosis and response to steroid therapy are still controversial because the differential diagnosis between nephrotic IgAN and minimal change nephrotic syndrome with IgA depositions is sometimes confused.

Methods

In this retrospective cohort analysis, we accurately diagnosed 42 cases of nephrotic IgAN (4.4%) from 954 IgAN patients, according to the Oxford classification. We analyzed the clinical and histological data, prognosis, and response to steroid therapy.

Results

In nephrotic IgAN, mean estimated glomerular filtration rate (eGFR) was 51.1?±?24.6?ml/min, proteinuria was 5.71?±?2.56?g/day, and urinary red blood cells were 51.0?±?37.8 high power field. Both active and chronic histological lesions were observed. Cumulative renal survival rate was significantly lower in nephrotic IgAN than in non-nephrotic IgAN (the control group consisted of 47 non-nephrotic IgAN patients diagnosed between 1995 and 1996) (log-rank test: P?Conclusion Nephrotic IgAN is a very severe form of IgAN, with renal dysfunction, massive hematuria, and active and chronic histopathological lesions. Renal outcome is severe; however, steroid therapy can improve prognosis in cases with higher eGFR and lower T-grade, according to the Oxford classification.     

Does circulating erythropoietin reflect progression of IgA nephropathy? Comparison with urinary N-acetyl-beta-D-glucosaminidase.

BACKGROUND: Recent reports describe that erythropoietin (Epo) is produced by peritubular interstitial fibroblast-like cells in response to a hypoxic stimulus. We studied serum Epo levels as a possible marker of tubulointerstitial damage in the progression of IgA nephropathy (IgAN), in comparison with urinary (u-) levels of N-acetyl-beta-D-glucosaminidase (NAG), which is mainly derived from proximal tubular cells and is used as a marker of tubular damage. METHODS: Thirty-eight patients with IgA nephropathy (IgAN) with relatively preserved renal function (serum creatinine: sCr, 0.5-2.2 mg/dl) were examined. The severity of glomerulosclerosis and interstitial fibrosis of the renal biopsy tissue was expressed by semiquantitative grading scores. Clinical parameters including serum creatinine (sCr), blood pressures, and 24-h proteinuria levels were obtained at the renal biopsy. Epo was measured by a radioimmunoassay (RIA) of sera obtained in the morning and u-NAG was measured by colorimetric method of 24-h urine samples. RESULTS: The mean Epo level of the patients (17.7+/-6.3 mU/ml) was not different from the control level (19.3+/-3.7 mU/ml). There were no significant correlations between Epo levels and red blood cell (RBC) counts, haematocrit (Hct), or haemoglobin (Hb) levels. The mean u-NAG level of the patients (6.7+/-6.2 U/gCr) was significantly higher than the control level (1.9+/-0.5 U/gCr). There was an inverse quantitative correlation between Epo and u-NAG levels in the patients (P<0.02). The u-NAG levels showed quantitative positive correlations with sCr (P<0.001), u-proteins (P<0.001), systolic (SBP) (P<0.001), and diastolic blood pressures (DBP) (P<0.05). Conversely, Epo levels were inversely correlated with sCr, SBP and DBP (each P<0.05). The patients with higher u-proteins (>2.0 g/day) showed significantly decreased Epo levels (P<0.05) than those with lower u-proteins (<2.0 g/day). The both scores of glomerulosclerosis and interstitial fibrosis were positively correlated with the u-NAG levels (each P<0.001), but were not correlated with the Epo levels. CONCLUSIONS: The significant correlation between u-NAG and serum Epo levels suggests that tubular damage and interstitial cell dysfunction are associated each other in the progression of IgAN. Serum Epo levels bearing inverse correlations with sCr, blood pressure levels and heavy proteinuria seem to reflect clinical severity of IgAN, whereas u-NAG can be more useful progression marker of IgAN bearing correlations with both clinical and histological findings.     

The effects of dual blockade of the renin-angiotensin system on urinary protein and transforming growth factor-beta excretion in 2 groups of patients with IgA and diabetic nephropathy

AIMS: The therapeutic benefits of dual blockade of the renin-angiotensin system (RAS) have been inconsistent on renal function and proteinuria. To know the contribution of the heterogeneity of study subjects to such inconsistency, we evaluated the effects of dual blockade of RAS in 2 groups of selected renal diseases, IgA and diabetic nephropathy. To avoid confounding by the blood pressure-reducing effects, angiotensin II receptor antagonists (ATRAs) were added on the patients with long-term, optimally controlled blood pressure taking ACE inhibitors. Twenty-four-hour urinary protein excretion rate and urinary TGF-beta1 level were measured as surrogate markers of renal injury. METHODS: We conducted a prospective crossover trial with 14 IgA and 18 type-2-diabetic nephropathy patients showing moderate degree of proteinuria (> or = 1.0 g/day) and renal dysfunction (creatinine clearance 25 - 75/ml/min). Four to 8 mg once-daily dose of candesartan and placebo were alternatively added on ramipril dose of 5 - 7.5 mg/day for 16 weeks. RESULTS: All baseline data except for the age factor were statistically the same between the 2 disease groups. Twenty-four-hour mean arterial blood pressures were 91.2 +/- 1.6 and 92.3 +/- 1.8 mmHg in IgA and diabetic nephropathy patients respectively at baseline (p = NS). Mean arterial pressure did not change by the addition of candesartan or placebo in both groups. The addition of candesartan (combination) reduced 24-hour urinary protein excretion rate in IgA nephropathy patients with a mean change of -12.3 +/- 4.5%, which is significantly greater compared to a mean change of -0.1 +/- 3.3% after the addition of placebo (placebo) (mean difference 12.4 +/- 5.0, 95% CI 1.2 - 23.5; p < 0.05). Urinary TGF-beta1 level was reduced considerably by the combination therapy, with a -28.9 +/- 6.0% decrease, which was significantly different to that by the placebo, with +4.3 +/- 12.4% (33.3 +/- 13.5, 3.2 - 63.3; p < 0.05). In diabetic nephropathy patients, the addition of candesartan did not reduce 24-hour urinary protein excretion rate. Mean changes of 24-hour urinary protein excretion rate were -0.8 +/- 4.7% by the combination therapy and +0.5 +/- 6.1% by placebo (mean difference 1.3 +/- 4.7, 95% CI -6.8 - 13.5; p < NS). The level of urinary TGF-beta1 was reduced by the combination therapy, with -14.3 +/- 9.5% decrease, but it did not reach statistical significance compared to placebo of +0.7 +/- 15.5% (15.0 +/- 13.5, -14.4 - 44.5; p < NS). The changes in 24-hour urinary protein excretion rate and urinary TGF-beta1 level were neither correlated with each other, nor with the change in mean arterial pressure. Significant changes in the renal function were not detected during the study period. CONCLUSION: Definite beneficial effects of dual blockade of RAS on proteinuria and TGF-beta1 excretion were found in IgA nephropathy patients, which was independent of blood pressure-reducing effect. With our 16-week trial, such benefits were not observed in type 2 diabetic nephropathy. The reduction in urinary TGF-beta1 level suggests that the combination therapy may provide additional renoprotection through the antisclerosing effects. Based on our results, for a proper interpretation the therapeutic effects of the combination therapy should be evaluated separately according to the underlying renal disease.     

Treatment of IgA nephropathy with eicosapentanoic acid (EPA): a two-year prospective trial

Thirty-seven patients with biopsy proven mesangial IgA nephropathy were prospectively allocated to either two years of treatment with eicosapentanoic acid (EPA) 10 g per day or no treatment. At entry treated and untreated patients with renal dysfunction (Group A) or patients with normal serum creatinine less than 0.12 mmol/l (Group B) did not differ in serum creatinine, creatinine clearance, urinary protein excretion, or quantitative urinary red cell counts. Compliance with EPA therapy was excellent as assessed by plasma fatty acid profiles. At the end of the trial creatinine clearance in treated patients had gone from 80 +/- 16 to 57 +/- 17 ml/min (p less than 0.05) and in untreated patients from 76 +/- 18 to 55 +/- 14 (p less than 0.05). There were no beneficial effects in either Group A or Group B patients. The only two patients who had improvement in renal function were in the EPA treatment group. Although no side effects of treatment were noted, EPA does not alter the course of established mesangial IgA nephropathy.     

Predictors of poor outcomes in steroid therapy for immunoglobulin A nephropathy

Background: Steroid therapy appears to be beneficial in patients of immunoglobulin A nephropathy (IgAN), as it causes a reduction in the proteinuria and improves the renal survival. Methods: A retrospective review of the 5 year follow‐up data of 60 patients with IgAN who were treated with steroids was conducted. Steroid non‐responders were defined as patients in whom the primary end‐point of a 30% decrease of the estimated glomerular filtration rate from baseline was reached. The patients were divided into two groups, namely, the steroid responder group (n = 47) and the steroid non‐responder group (n = 13), and the clinicopathophysiological characteristics were compared between the two groups. Results: Significant decrease of the proteinuria was observed in the responder group over the 5 year follow‐up period, whereas no significant change of the urinary protein excretion was observed in the non‐responder group during the same period. In regard to the pathological findings, significantly higher ratios of glomerular obsolescence and glomerular tuft adhesion to the Bowman's capsule, and significantly higher severity of interstitial fibrosis at the time of diagnosis in the non‐responder group than in the responder group were found. The rates of glomerular obsolescence and glomerular tuft adhesion to the Bowman's capsule, the severity of interstitial fibrosis, serum albumin and urinary protein excretion were identified as independent risk factors influencing the rate of renal function deterioration. Conclusion: To develop effective therapeutic modalities, it is important to have a thorough understanding of the clinicopathophysiological characteristics of IgAN patients showing poor treatment response to steroids (non‐responder group in this study).     

ACE gene polymorphism in childhood IgA nephropathy: Association with clinicopathologic findings

A deletion polymorphism in the angiotensin-converting enzyme (ACE) gene has been reported to be a risk factor for progression to chronic renal failure in immunoglobulin A nephropathy (IgAN). In this study, we investigated the association between ACE gene polymorphism and clinical findings, early biopsy findings such as the extent of mesangial proliferation, focal lesions (capsular adhesions, glomerulosclerosis, and crescents), and the glomerular area in childhood IgAN. Genomic DNA was obtained from 97 patients and control subjects. Gene polymorphisms, consisting of an insertion (I) or deletion (D) of the 287-base pair Alu sequence, were detected using the polymerase chain reaction. The extent of capsular adhesions and glomerulosclerosis was significantly higher in patients with the ID/DD genotypes than in those with the II genotype (ID/DD v II: 8.0%+/-1.4% v 2.5%+/-0.8% [P = 0.017] and 5.1%+/-1.3% v 1.4%+/-0.6% [P = 0.028], respectively). Whereas there was no difference in the extent of mesangial proliferation and crescents between the ID/DD genotypes and the II genotype. Urinary protein excretion at the time of biopsy was significantly greater in patients with the ID/DD genotypes than in those with the II genotype (1.02+/-0.15 g/d/m2 body surface area v 0.56+/-0.13 g/d/m2 body surface area; P = 0.012). These results indicate that ACE gene polymorphism may not influence the extent of mesangial proliferation and crescents that are acute lesions. However, the ID/DD genotypes are associated with chronic lesions, such as capsular adhesions or glomerulosclerosis and urinary protein excretion in childhood IgAN. (Am J Kidney Dis 1998 May;31(5):774-9)     

The treatment of mesangial IgA nephropathy with cyclophosphamide, dipyridamole and warfarin: a two-year prospective trial

Of 52 patients with mesangial IgA nephropathy, 25 were allocated to treatment with cyclophosphamide (6 months), and dipyridamole and warfarin (2 years) and 27 to no treatment in a randomized prospective 2-year study. At entry, the treated and untreated groups of patients did not differ in mean serum creatinines, urinary protein excretions, quantitative urinary erythrocyte counts or blood pressure readings. At the end of the trial mean (+/- SEM) serum creatinine values had gone from 0.12 +/- 0.01 to 0.13 +/- 0.01 mmol/l (p less than 0.05) in untreated patients and from 0.10 +/- 0.01 to 0.12 +/- 0.01 mmol/l (p less than 0.05) in treated patients. Mean (+/- SEM) log values of urinary erythrocyte (rbc) counts had not changed significantly from 5.47 +/- 0.09 to 5.21 +/- 0.14 log rbc/ml in untreated patients, from 5.45 +/- 0.11 to 5.49 +/- 0.19 log rbc/ml in treated patients. However, in treated patients, mean (+/- SEM) urinary protein excretions decreased from 1.67 +/- 0.35 to 1.15 +/- 0.31 g/24 h (p less than 0.01) whereas in untreated patients urinary protein was unchanged between initial values of 1.76 +/- 0.34 and follow-up at 1.89 +/- 0.45 g/24 h. No significant changes in blood pressure occurred in either group. This study supports the observation that treatment of IgA nephropathy with cyclophosphamide, dipyridamole and warfarin is associated with a reduction of urinary protein excretion but a significant effect on preservation of renal function, at least as determined by serum creatinine values, could not be confirmed over this two-year study.     

IgA肾病患者血与尿血管内皮生长因子水平变化的临床意义

目的 :探讨IgA肾病患者血、尿血管内皮生长因子 (VEGF)水平的临床意义。 方法 :IgA肾病患者2 0例和健康对照 14例 ,留取空腹血清和晨起清洁中段尿 ,采用抗体夹心ELISA方法测定血、尿VEGF水平。详细收集IgA肾病患者的血压、肾功能、2 4h尿蛋白定量和血尿程度等资料 ,与血、尿VEGF对比分析其临床意义。结果 :IgA肾病患者血、尿VEGF水平均高于健康对照组 (P <0 .0 1或P <0 .0 5 ) ;IgA肾病患者血、尿VEGF水平与 2 4h尿蛋白定量呈正相关 (P <0 .0 1或P <0 .0 5 ) ,2 4h尿蛋白定量 <1.5g的患者血、尿VEGF水平明显低于尿蛋白定量 >1.5 g的患者 (P <0 .0 1或P <0 .0 5 ) ;与患者血尿程度、血压无相关性。结论 :IgA肾病患者血、尿VEGF水平与IgA肾病尿蛋白排出量呈正相关     

Supplementation with a low dose of L-arginine reduces blood pressure and endothelin-1 production in hypertensive uraemic rats.

BACKGROUND: We documented recently that increased endothelin-1 (ET-1) production in blood vessels and glomeruli of uraemic rats plays a crucial role in the development of hypertension and the progression of chronic renal failure. Normally, biological effects and local production of ET-1 are attenuated by the immediate release of nitric oxide (NO). Increasing evidence suggest, however, that NO release is impaired in chronic renal failure. We investigated whether supplementation with L-arginine, the natural precursor of NO, improves NO synthesis in uraemic rats with reduced renal mass and modulates vascular and renal ET-1 production as well as blood pressure and renal failure progression. METHODS: One week after surgical renal mass reduction, the uraemic and sham-operated animals received either no treatment or 0.1% L-arginine in drinking water for 5 weeks. In another series of experiments, uraemic rats received 1% L-arginine for 5 weeks. Immunoreactive-ET-1 (ir-ET-1) levels in plasma, urine, and vascular and renal tissue preparations was measured by radioimmunoassay after sample extraction and purification. RESULTS: Before treatment, systolic blood pressure was significantly elevated in uraemic animals compared to sham-operated controls (156+/-7 vs 111+/-3 mmHg, respectively; P<0.01). Thereafter, systolic blood pressure increased further in uraemic-untreated rats (systolic blood pressure at week 5; 199+/-9 mmHg, P<0.01), whereas it remained similar in uraemic rats supplemented with 0.1% L-arginine (171+/-9 mmHg, NS). At the end of the study, serum creatinine and urea, proteinuria and ir-ET-1 excretion were significantly augmented, while creatinine clearance was reduced in uraemic animals compared to the controls. Ir-ET-1 level was also increased in glomeruli as well as in thoracic aorta, mesenteric arterial bed, and pre-glomerular arteries, and was associated with vascular hypertrophy as assessed by tissue weight. In contrast, ir-ET-1 level was diminished in the renal papilla of uraemic rats. Treatment with 0.1% L-arginine significantly reduced proteinuria and urinary ir-ET-1 excretion (P<0.05) as well as ir-ET-1 level in glomeruli (P<0.01) and in thoracic aorta (P<0.05). These changes were associated with increased plasma NO metabolites NO2/NO3 levels in L-arginine-treated animals (P<0.01) and reduced aortic hypertrophy (P<0.05). In contrast, supplementation with 1% L-arginine had no effect on systolic blood pressure in uraemic rats, but exacerbated proteinuria and urinary ir-ET-1 excretion and increased serum urea (P<0.05) were observed. CONCLUSIONS: These results indicate that improvement of NO release with a low dose but not with a high dose of L-arginine significantly attenuates the development of hypertension and the progression of renal insufficiency in rats with reduced renal mass. These protective effects may be mediated in part by the reduction of vascular and renal ET-1 production.     

Urinary secretory immunoglobulin A in acute renal allograft rejection

Periodical determinations of the urinary secretory immunoglobulin A (S-IgA) excretion rate were performed in 12 cadaveric graft recipients. In five patients with primary functioning grafts the S-IgA excretion on the first postoperative day was 4.2 +/- 2.6 mg/g creatinine, decreasing to 1.8 +/- 1.2 mg/g creatinine (P less than 0.05) at the day of discharge. Acute tubular necrosis developed in the seven remaining patients. In this group the initial S-IgA excretion was 12.6 +/- 7.5 mg/g creatinine (P less than 0.05 compared to the former group), decreasing to 2.0 +/- 0.9 mg/g creatinine (P less than 0.05) at discharge. An acute rejection episode was observed in six patients. The S-IgA excretion increased from 3.0 +/- 1.5 mg/g creatinine 3-4 days before rejection to 6.4 +/- 3.1 mg/g creatinine (P less than 0.05) 1-2 days before rejection, and peaked at 14.0 +/- 8.6 mg/g creatinine (P less than 0.05) when the diagnosis of rejection was established and anti-rejection treatment was started. In three patients the initial steroid pulse therapy was not successful and S-IgA excretion further increased to 29.0 +/- 15.6 mg/g creatinine. After successful anti-rejection treatment, using steroids and OKT3, the S-IgA excretion decreased to 3.4 +/- 2.6 mg/g creatinine. In acute graft rejection, the elevated globulin synthesis by infiltrating plasma cells. In the early phase of rejection, dimeric IgA is the only immunoglobulin able to penetrate into the urine by transepithelial transport after binding to secretory component expressed on tubular epithelial cells.(ABSTRACT TRUNCATED AT 250 WORDS)     

Efficacy and safety of 'rescue therapy' with mycophenolate mofetil in resistant primary glomerulonephritis--a multicenter study.

BACKGROUND: Studies of mycophenolate mofetil (MMF) in primary glomerulonephritis have varied in their inclusion criteria, regimen and follow-up compromising assessments of efficacy and optimal dose. METHOD: This multicentre study analysed the safety and efficacy of MMF monotherapy in a large cohort with primary glomerulonephritis that was resistant to other conventional therapies. A total of 98 patients with biopsy-proven primary glomerulonephritis resistant to other drugs received MMF monotherapy for 1 year. Primary outcome measures were urinary protein excretion and the number of patients with complete or partial remission of proteinuria. Secondary analyses were time to remission and changes in the slope of creatinine clearance. RESULTS: Fifty-four percent of the patients achieved either complete or partial remission of proteinuria with no significant differences between glomerulonephritis types. Median (range) dose of MMF was 2 g/day (1.5-2 g/day) Mean (SD) treatment time to remission was 141.5 (+/-61.1) days with no significant differences between glomerulonephritis types. Serum albumin increased (P<0.01), whereas proteinuria (P<0.01) serum LDL-cholesterol (P<0.01) and mean blood pressure (P<0.05) decreased post-treatment. No significant changes were observed in glomerular filtration rate (GFR), serum creatinine or slopes of GFR. The reduction of urinary protein excretion was significantly higher in patients with basal nephrotic proteinuria and preserved renal function; it did not arise from an increased dose of angiotensin-converting enzyme inhibitors or angiotensin II receptor antagonists, since, among responders, mean blood pressure significantly decreased and the number of anti-hypertensive drugs could be reduced. CONCLUSIONS: MMF monotherapy causes a moderate decrease in proteinuria in >50% of the patients who do not have other treatment options. The response to therapy is largely influenced by a preserved renal function and requires sustained MMF treatment.     

Urinary excretion rate of guanidinoacetic acid as a new marker in hypertensive renal damage

This study was undertaken to evaluate the relation between the urinary excretion of guanidinoacetic acid (GAA) and other substances in hypertensive patients (6 with borderline hypertension and 29 with hypertension) and 12 normal controls. In 10 of the hypertensive patients, GAA was measured before and after 4 weeks of treatment with calcium entry blocker. In hypertensive patients the rate of GAA urinary excretion was 43.5 +/- 17-4 micrograms/min, which was much lower than in the controls (77.2 +/- 35.9 micrograms/min) (p less than 0.01). There was no significant difference among these groups in creatinine clearance (CCr), serum creatinine (Cr), beta 2-microglobulin (BMG) or in the urinary excretion of BMG, N-acetyl-D-glucosaminidase (NAG) or radiosensitive microalbumin (mAlb). The urinary excretion rate of GAA was positively correlated with CCr (r = 0.62; p less than 0.01), and negatively correlated with mean blood pressure (r = -0.49; p less than 0.01). Finally, the GAA excretion was significantly correlated with urinary NAG (r = 0.24; p less than 0.05) and serum BMG (r = -0.31; p less than 0.05), but not with urinary mAlb (r = 0.12; p less than 0.05). Ten hypertensive patients followed for 4 weeks attained their ultimate mean blood pressure reduction after treatment (from 119.3 +/- 8.0 to 101.7 +/- 13.5 mm Hg; p less than 0.001), but the GAA/Cr ratio in the urinary excretion was significantly elevated (from 0.054 +/- 0.016 to 0.070 +/- 0.02; p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Transforming growth factor-beta(1) in the kidney and urine of patients with glomerular disease and proteinuria.

BACKGROUND: Transforming growth factor-beta(1) (TGF-beta(1)) is the major fibrogenic growth factor implicated in the pathogenesis of renal scarring. Proteinuria is a poor prognostic feature for various types of glomerular disease and its toxic action may be related to the activation of tubular epithelial cells towards increased production of cytokines and chemoattractant peptides. In this work we studied the site of synthesis and expression profile of TGF-beta(1) in the renal tissue of patients with heavy proteinuria and examined the relation of this expression with the urinary excretion of TGF-beta(1). METHODS: Twenty-five patients with heavy proteinuria (8.4+/-3.0 g/24 h) were included in the study. All patients underwent a diagnostic kidney biopsy and were commenced on immunosuppressive therapy with corticosteroids and cyclosporin. The sites of synthesis and expression profile of TGF-beta(1) mRNA and protein in the kidney were examined by in situ hybridization and immunohistochemistry. Urinary and plasma TGF-beta(1) levels were determined by ELISA before the initiation of treatment and 6 months later and compared with those of normal subjects and of patients with IgA nephropathy and normal urinary protein excretion. RESULTS: The site of synthesis and expression of TGF-beta(1) in the renal tissue of patients with heavy proteinuria was mainly localized within the cytoplasm of tubular epithelial cells. Interstitial expression was also present but glomerular TGF-beta(1) expression was found only in patients with mesangial proliferation. Urinary TGF-beta(1) excretion was significantly higher in nephrotic patients compared with normal subjects and with patients with IgA nephropathy and normal urinary protein excretion (783+/-280 vs 310+/-140 and 375+/-90 ng/24 h, respectively; P<0.01). In patients with remission of proteinuria after immunosuppressive therapy, urinary TGF-beta(1) excretion was significantly reduced (from 749+/-290 to 495+/-130 ng/24 h; P<0.01), while in patients with persistent nephrotic syndrome, it remained elevated. CONCLUSIONS: The localization of TGF-beta(1) mRNA and protein within tubular epithelial cells, along with its increased urinary excretion in patients with nephrotic syndrome, suggest the activation of these cells by filtered protein towards increased TGF-beta(1) production.     

Mycophenolate mofetil alleviates persistent proteinuria in IgA nephropathy

BACKGROUND: Mycophenolate mofetil (MMF) is increasingly used to treat primary glomerulopathies. Its effectiveness in IgA nephropathy (IgAN) remains unclear. METHODS: Forty IgAN patients with persistent proteinuria (>1 g/24 hours) despite conventional treatment with blockers of the renin-angiotensin system were randomized to receive MMF for 24 weeks (group 1) or continue conventional therapy (group 2), and followed for 72 weeks. The primary end point was reduction of proteinuria by 50% or more over entry level. RESULTS: Sixteen patients (80%) in group 1 versus six patients (30%) in group 2 reached the primary end point (P= 0.0019). Time-averaged change in proteinuria showed a significant decline in group 1, while control subjects displayed a modest rise (P= 0.003). By 72 weeks, the mean proteinuria was 62.0 +/- 7.7% (P= 0.003) and 120.5 +/- 14.1% (P= 0.351) that of the corresponding baseline value in group 1 and group 2, respectively. There was concomitant increase in serum albumin and decrease in serum IgA levels in group 1 but not group 2 patients. Baseline histologic grades, blood pressure control, and the rates of change in serum creatinine and creatinine clearance were not different between the two groups. Normalization in binding of polymeric IgA to cultured mesangial cells and serum interleukin-6 (IL-6) levels, which sustained to study end, was observed in group 1 but not group 2 subjects. CONCLUSION: In selected patients with IgAN, MMF is effective in lowering proteinuria and ameliorating some of the putative pathogenetic abnormalities.