Corticosteroid therapy in IgA nephropathy with nephrotic syndrome: a long-term controlled trial

A randomized prospective study of 34 patients with IgA nephropathy and nephrotic syndrome was conducted to determine the therapeutic value of corticosteroid therapy. The patients were divided into two groups: Group A, 17 patients receiving oral prednisolone/prednisone for four months; and Group B, 17 patients receiving no corticosteroid therapy and acting as controls. The groups are comparable in age of presentation, sex ratio, and duration of study. No difference in serum creatinine levels, creatinine clearance, serum IgA levels, severity of renal histopathological changes, incidence of hypertension or incidence of impaired renal function could be demonstrated but the Group A patients had significantly heavier proteinuria. During the mean study period of 38 months (range 12-106), no significant difference in serum creatinine levels and creatinine clearance was demonstrated between the two groups. Forty percent of the Group A patients developed complications related to steroid therapy. Despite the overall lack of therapeutic value in IgA nephropathy with nephrotic syndrome as reflected by change in renal function, corticosteroid treatment resulted in excellent remission of nephrotic syndrome in 80% of patients with mild glomerular histopathological changes. Our findings suggest that corticosteroid therapy is only beneficial to selected groups of patients with IgA nephropathy and nephrotic syndrome but its indiscriminate use should be discouraged.     

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.     

Corticosteroid therapy in IgA nephropathy

The benefits and risks of steroids for the treatment of IgA nephropathy remain uncertain. We systematically searched MEDLINE, EMBASE, and the Cochrane Library for randomized, controlled trials of corticosteroid therapy for IgA nephropathy published between 1966 and March 2011. We identified nine relevant trials that included 536 patients who had urinary protein excretion >1 g/d and normal renal function. Forty-six (8.6%) of these patients developed a kidney failure event, defined as doubling of the serum creatinine/halving of the GFR or ESRD. Overall, steroid therapy was associated with a lower risk for kidney failure (relative risk, 0.32 [95% confidence interval [CI], 0.15-0.67]; P=0.002) and a reduction in proteinuria (weighted mean difference, -0.46 g/d [95% CI, -0.63 to -0.29 g/d]), with no evidence of heterogeneity in these outcomes. Subgroup analysis suggested that the dose modifies the effect of steroids for renal protection (P for heterogeneity=0.030): Relatively high-dose and short-term therapy (prednisone >30 mg/d or high-dose pulse intravenous methylprednisolone with duration ≤1 year) produced significant renal protection, whereas low-dose, long-term steroid use did not. Steroid therapy was associated with a 55% higher risk for adverse events. The quality of included studies was low, however, limiting the generalizability of the results. In conclusion, steroids appear to provide renal protection in patients with IgA nephropathy but increase the risk for adverse events. Reliably defining the efficacy and safety of steroids in IgA nephropathy requires a high-quality trial with a large sample size.     

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.     

Tacrolimus monotherapy in membranous nephropathy: a randomized controlled trial

Membranous nephropathy is a common cause of nephrotic syndrome in adults. Although some patients with membranous nephropathy achieve a spontaneous remission, renal function continues to deteriorate in others. We conducted a prospective randomized trial evaluating monotherapy with tacrolimus to achieve complete or partial remission in patients with biopsy-proven membranous nephropathy. Twenty-five patients received tacrolimus (0.05 mg/kg/day) over 12 months with a 6-month taper, whereas 23 patients were in the control group. The probability of remission in the treatment group was 58, 82, and 94% after 6, 12, and 18 months but only 10, 24, and 35%, respectively in the control group. The decrease in proteinuria was significantly greater in the treatment group. Notably, six patients in the control group and only one in the treatment group reached the secondary end point of a 50% increase in their serum creatinine. No patient in the tacrolimus group showed a relapse during the taper period. Nephrotic syndrome reappeared in almost half of the patients who were in remission by the 18th month after tacrolimus withdrawal. We conclude that tacrolimus is a very useful therapeutic option for patients with membranous nephropathy and preserved renal function. The majority of patients experienced remission with a significant reduction in the risk for deteriorating renal function.     

Leflunomide plus low-dose prednisone in patients with progressive IgA nephropathy: a multicenter,prospective, randomized,open-labeled,and controlled trial

BackgroundImmunoglobulin A nephropathy (IgAN) is the most common cause of glomerulonephritis worldwide, and the optimal approach to its treatment remains a significant challenge.MethodsWe did a prospective, randomized, open-labeled, multicenter, controlled trial, comprised of 3-month run-in, 12-month treatment, and 12-month follow-up phases. After 3-month run-in phase, patients with biopsy-confirmed IgAN at risk of progression were randomly allocated to LEF plus low-dose prednisone (LEF + prednisone group) or conventionally accepted-dose prednisone [prednisone(alone) group] Our primary outcome was 24-h urine protein excretion (UPE) and secondary outcomes were serum albumin (sALB), serum creatinine (Scr), and eGFR. Safety was evaluated in all patients who received the trial medications.ResultsOne hundred and eight patients [59 in LEF + prednisone group, 49 in prednisone (alone) group]were enrolled and finished their treatment and follow-up periods. There is no significant difference in the baseline level between the two groups. Compared with baseline, both groups showed a significant decrease in 24-h UPE (p < 0.01) and increase in sALB (p < 0.01), with stable Scr and eGFR throughout the 12-month treatment period. What’s more, these effects were sustained through the 12-month follow-up period. However, there was no difference in 24-h UPE, sALB, Scr, and eGFR between the two groups (p > 0.05). At 12 months, a difference in overall response rate, relapsing rate, and incidence of adverse events between the two groups was not significant.ConclusionsThe efficacy and safety of LEF plus low-dose prednisone and conventionally accepted-dose prednisone in the treatment of progressive IgAN are comparable.     

The efficacy of tonsillectomy on clinical remission and relapse in patients with IgA nephropathy: a randomized controlled trial

Background The efficacy of tonsillectomy in immunoglobulin A nephropathy (IgAN) remains controversial. The aim of the study was to conduct a randomized controlled trial to evaluate the effect of tonsillectomy in patients with IgAN. Methods We randomly selected 98 patients with biopsy-proven IgA nephropathy and randomly allocated to receive tonsillectomy combined with drug therapy (Group A) or drug therapy alone (Group B). The participating patients were entered into a 4-year single-center study. Remission and relapse rate were calculated for hematuria and proteinuria using the Kaplan–Meier method. Results No differences were found between the two groups in their baseline clinical and histological characteristics. Patients with tonsillectomy exhibited considerable improvement in the following aspects compared to those patients who did not undergo tonsillectomy: time to reach first remission (3.1 vs. 24.9 months, p?p?p?p?p?=?0.0047) for hematuria and (23.5 vs. 10.5 months, p?=?0.0012) for proteinuria, as well as lower relapse rate for hematuria and proteinuria in Group A. Conclusion Our clinical data demonstrated that tonsillectomy could be beneficial for IgAN patients, particularly by contributing to faster and longer remission, as well as reducing the frequency of possible future relapses.     

Prophylactic sclerotherapy in children with esophageal varices: long-term results of a controlled prospective randomized trial

BACKGROUND/PURPOSE: Experience using endoscopic prophylactic sclerotherapy (PS) is restricted to adult patients and has led to conflicting results. There has not been a randomized, controlled study on the use of PS in children. The purpose of this study is to evaluate prospectively the value of PS to prevent the first hemorrhage from esophageal varices in children with portal hypertension and to assess the effect of PS on survival rate. METHODS: In a controlled, prospective, computer-based randomized trial, the effectiveness of PS was analyzed in 100 consecutive children allocated to a group receiving sclerotherapy (n = 50) or to a control group (n = 50) subjected only to regular clinical and endoscopic examinations. Clinical characteristics in both groups were similar. The minimum follow-up period was at least 18 months after the cessation of the sessions of sclerotherapy. RESULTS: After a median follow-up of 4.5 years, PS eliminated the esophageal varices in 47 of 50 (94%) patients but only 38 (76%) of them do not present upper digestive hemorrhage. Before complete obliteration of the varices, upper gastrointestinal bleeding occurred in 12 patients (24%). Six children (12%) had gastric varices, 3 of 6 of whom (50%) bled. Congestive hypertensive gastropathy was observed to occur in 8 (16%) patients, 4 of 8 of which (50%) had hemorrhagic episodes. Two patients bled from undetermined cause. In the control group, only 29 (58%) children remained free from esophageal variceal bleeding and 26 (52%) from any upper gastrointestinal bleeding (P<.05). During the follow-up period, the development of gastric varices was observed in 5 (10%) patients (P>.05) and of congestive hypertensive gastropathy in only 3 (6%) patients (P<.05), but none of them bled. PS does not improve survival rate. CONCLUSIONS: In children with cirrhotic and noncirrhotic portal hypertension, PS reduces the overall incidence of bleeding from esophageal varices that were eradicated in 94% of cases. The source of bleeding has been different in each group, being predominantly from esophageal varices in the control group and from the stomach in the prophylaxis group. When applied with appropriate technique, PS is a safe procedure with a low incidence of minor complications. PS does not change the incidence of gastric varices but increases the development of congestive hypertensive gastropathy. PS increases the risk of bleeding from the naturally formed gastric varices and from congestive hypertensive gastropathy. PS does not affect survival rate.     

Combined treatment with renin-angiotensin system blockers and polyunsaturated fatty acids in proteinuric IgA nephropathy: a randomized controlled trial

Background. Currently, several therapeutic protocols exist forIgA nephropathy (IgAN); results in slowing the progression toend-stage renal disease (ESRD) are variable, but 30–40%of patients require replacement therapy (dialysis or renal transplantation)by 20 years from the onset. The adverse effects brought by thechronic assumption of drugs can be a potential limit. Actually,the most used therapies for IgAN are renin–angiotensinsystem blockers (RASB), glucocorticoids and immunosuppressiveagents. Trials with polyunsaturated fatty acids (PUFA) in IgANhave been done since the first successful attempt by Hamazakiin 1984, resulting in alternate answers, but no trials haveever been done testing the efficacy of combined therapy withRASB and PUFA. Methods. We tested the effect of a 6-month course of PUFA (3grams/day) in a group of 30 patients with biopsy-proven IgANand proteinuria already treated with RASB randomized to receivePUFA supplementation or to continue their standard therapy.The primary end-point was the percent reduction of proteinuriafrom the baseline. Secondary end-points were modifications inglomerular filtration rate (GFR), blood pressure, serum triglyceridesand erythrocyturia. Results. At the end of the 6-month trial, the percent reductionof proteinuria was 72.9% in the PUFA group and 11.3% in theRASB group (P < 0.001). A reduction of 50% of baseline proteinuriawas achieved in 80.0% of PUFA patients and 20.0% of RASB patients(P = 0.002). Erythrocyturia was significantly lower in the PUFAgroup (P = 0.031). No significant changes in renal function,blood pressure and triglycerides were observed. Conclusions. PUFA associated with RASB reduced proteinuria inpatients with IgAN more than RASB alone.     

Three-year randomized controlled trial of dipyridamole and low-dose warfarin in patients with IgA nephropathy and renal impairment

Summary: Activation of platelets and the coagulation pathway are factors which may contribute to the progression of renal disease in IgA nephropathy (IgAN). Of 21 patients with IgAN and serum creatinines between 1.6 and 3.0 mg/dL, 10 were assigned to treatment with dipyridamole and low-dose warfarin (keeping the thrombotest between 30 and 50%) and 11 to no treatment in a prospective randomized 3-year study. At entry into the trial, patients in the treatment group were younger (35 ± 6 years vs 42 ± 9 years) and had worse histological scores for tubular atrophy (1.7 ± 0.7 vs 1.1 ± 0.5) and arteriolar hyperplasia (1.4 ± 0.7 vs 0.7 ± 0.8) than those in the non-treatment group. There were no differences in serum creatinine values, creatinine clearances, urinary protein excretions, serum albumins or urinary erythrocyte counts. At the end of the trial, patients on treatment did not experience a significant increase in serum creatinine values (1.9 ± 0.3 mg/dL to 2.5 ± 1.2) or reduction in creatinine clearances (52 ± 20mL/min to 52 ± 27). Untreated patients, however, experienced a significant rise in serum creatinine values (2.1 ± 0.5 mg/dL to 3.3 ± 1.1, P < 0.01) and a fall in creatinine clearances (51 ± 26 mL/min to 31 ± 22, P = 0.06). There was no significant change in the proteinuria in either group (treatment group: 1.2 ± 1.2 g/day to 1.3 ± 1.1, non-treatment group: 1.9 ± 1.4 to 1.5 ± 1.1) and there was also no change in serum albumins and urinary erythrocyte counts. Four untreated and one treated patient developed end-stage renal failure during the course of the trial. This study suggests that treatment of patients with IgAN and renal impairment with dipyridamole and low-dose warfarin retards the deterioration of renal function, as measured by the serum creatinine and creatinine clearance.     

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.     

他克莫司治疗乙型肝炎病毒相关性膜性肾病的随机对照临床试验

目的 进行前瞻性、随机、对照临床试验,评估他克莫司联合恩替卡韦和小剂量糖皮质激素治疗乙型肝炎病毒相关性膜性肾病(Hepatitis B virus-associated membrane nephropathy,HBV-MN)的临床疗效.方法 入组患者38例,按随机数字表法分为试验组19例和对照组19例,试验组给予他克莫司(0.05 mg· kg-1·d-1)、小剂量激素(醋酸泼尼松,0.5 mg·kg-1·d-1)及恩替卡韦(0.5 mg/d)联合治疗,对照组接受恩替卡韦(0.5 mg/d)单一疗法,以完全缓解率及部分缓解率来评估患者疗效.结果 在治疗第6个月及12个月试验组总缓解率分别为88.89％、94.44％,但在对照组仅38.89％、58.82％,试验组观察到尿蛋白缓解更加明显.恩替卡韦可减少乙型肝炎病毒DNA(HBV-DNA)滴度,在治疗第3个月,入组患者肝功能均恢复正常.试验组有1例、对照组有2例因达到次要终点而退出本次试验.试验组有1例在他克莫司减量过程中尿蛋白复发.结论 他克莫司联合恩替卡韦和小剂量糖皮质激素治疗HBV-MN,能显著降低蛋白尿、保护肾功能,并能控制HBV-DNA的复制,是HBV-MN有效的治疗模式之一.     

Sustainable effect of skin stretching for burn scar excision: long-term results of a multicenter randomized controlled trial

Purpose

Primary wound closure of large defects after burn scar excision may be facilitated by intraoperative stretching of the adjacent skin. In a randomized controlled trial (RCT), the effect of skin stretching for wound closure after scar excision (SS) was compared to scar excision without additional techniques (SE). Short-term results already showed that in the SS group larger scars could be excised in a one-step procedure. In this paper, the long-term scar outcome using reliable and valid measurement tools was evaluated.

Basic procedures

The percentage of total remaining scar area (i.e. remaining scar compared to preoperative scar), the percentage of linear scarring (i.e. surface area of linear scar compared to excised scar) and scar hypertrophy was measured at 3 and 12 months postoperatively.

Main findings

At 12 months postoperatively, the percentage of total remaining scar area was significantly lower in the SS group (26%) compared to the SE group (43%). The percentage of linear scarring (SS: 21%, SE: 25%) and the incidence of hypertrophy (SS: 29%, SE: 40%) were not significantly different between the treatment groups.

Conclusions

This RCT demonstrates the long-term beneficial and sustainable effect skin stretching for wound closure after scar excision without leading to wider linear scars or more scar hypertrophy.     

外科术后患者允许性摄入不足的前瞻、随机、对照临床研究

目的评价术后早期允许性低热量摄入的临床效果。方法42例术后患者按能量摄入水平随机分为实验组(75kJ·kg-1·d-1)和对照组(117kJ·kg-1·d-1),于术前及术后分别监测血常规、肝肾功能、输液后血糖及胰岛素干预情况,并观察感染指标、住院时间和相关住院费用。结果两组患者术后4d血红蛋白及肝功能等指标差异无统计学意义;对照组空腹血糖及输液后血糖有显著增高(P<0.05);胰岛素干预量为实验组的4倍;平均住院时间实验组(10d)较对照组(11d)短,但是两组差异无统计学意义(P=0.5);实验组相关治疗费用明显降低。结论本研究提示术后短期内适度的低热量补给不影响患者的营养状态,却可避免高血糖,住院费用也较低。     

Peri-apatite coating decreases uncemented tibial component migration: long-term RSA results of a randomized controlled trial and limitations of short-term results

Background and purpose — Biological fixation of uncemented knee prostheses can be improved by applying hydroxyapatite coating around the porous surface via a solution deposition technique called Peri-Apatite (PA). The 2-year results of a randomized controlled trial, evaluating the effect of PA, revealed several components with continuous migration in the second postoperative year, particularly in the uncoated group. To evaluate whether absence of early stabilization is diagnostic of loosening, we now present long-term follow-up results.

Patients and methods — 60 patients were randomized to PA-coated or uncoated (porous only) total knee arthroplasty of which 58 were evaluated with radiostereometric analysis (RSA) performed at baseline, at 3 months postoperatively and at 1, 2, 5, 7, and 10 years. A linear mixed-effects model was used to analyze the repeated measurements.

Results — PA-coated components had a statistically significantly lower mean migration at 10 years of 0.94?mm (95% CI 0.72–1.2) compared with the uncoated group showing a mean migration of 1.72?mm (95% CI 1.4–2.1). Continuous migration in the second postoperative year was seen in 7 uncoated components and in 1?PA-coated component. All of these implants stabilized after 2 years except for 2 uncoated components.

Interpretation — Peri-apatite enhances stabilization of uncemented components. The number of components that stabilized after 2 years emphasizes the importance of longer follow-up to determine full stabilization and risk of loosening in uncemented components with biphasic migration profiles.