Efficacy of immunosuppressive therapy in IgA nephropathy presenting with isolated hematuria. Randomized prospective trial of early steroid withdrawal compared with low-dose steroids in renal transplant recipients using serial protocol biopsies to assess efficacy and safety. Prospective, randomized trial of steroid withdrawal in kidney recipients treated with mycophenolate mofetil and cyclosporine. Controlled prospective trial of prednisolone and cytotoxics in progressive IgA nephropathy. Controlled, prospective trial of steroid treatment in IgA nephropathy: a limitation of low-dose prednisolone therapy. Corticosteroids in IgA nephropathy: a randomised controlled trial. Evidence of improving quality of reporting of randomized controlled trials in subfertility. Randomised controlled trial of steroid withdrawal in renal transplant recipients receiving triple immunosuppression. Steroid avoidance in renal transplantation using basiliximab induction, cyclosporine-based immunosuppression and protocol biopsies. Withdrawal of steroids from triple-drug therapy in kidney transplant patients. Multicenter randomized prospective trial of steroid withdrawal in renal transplant recipients receiving basiliximab, cyclosporine microemulsion and mycophenolate mofetil. Quality of reporting of randomized controlled trials in general endocrinology literature. Steroid-withdrawal at 3 days after renal transplantation with anti-IL-2 receptor alpha therapy: a prospective, randomized, multicenter study.
The role of immunosuppressive therapy in the management of IgA nephropathy (IgAN) remains controversial. No consensus has yet emerged on the specific treatment of IgAN and this is mostly related to the lack of complete understanding of the multifactorial pathogenesis of the disease. Choice of appropriate therapeutic agents is further limited by the difficulty in identifying patients who would most likely benefit from therapy. Immunosuppressive therapy has not been recommended in patients with isolated hematuria and well preserved renal function because of their generally favourable prognosis and there are no clinical trials in this area. Considering that mild IgAN may be an early stage of the disease and can be reversed by immunosuppressive agents we have used prednisolone and azathioprine in patients with isolated hematuria in a prospective, randomized, controlled study since 1988. In this prospective study we have evaluated the effect of prednisolone with azathioprine on the clinical course of IgAN and its impact on histologic parameters and prevention of progression in patients with isolated hematuria. We studied 43 biopsy-proven IgAN patients (29 males and 14 females, aged between 13-63 years, mean age 28+/-6) with isolated hematuria and well-preserved renal function (Ccr 89.2+/-10.2 ml/min). The patients were assigned to two groups: 21 patients received prednisolone (40 mg/day) and azathioprine (100 mg/day) orally for four months (group A) and 22 patients received no specific treatment for IgAN and served as a control group (group B). In Group A prednisolone was reduced to 20 mg/day at the end of the second month, then slowly tapered over a two-month period and stopped. The median duration of follow-up was 60 months (range 12-120 months). At the end of the therapy hematuria disappeared in 17 patients. In three patients who did not respond to therapy, microscopic hematuria persisted. Of the 22 patients of group B, three had episodes of gross hematuria and proteinuria >500 mg/day. No significant changes in biochemical profile were observed in either group. Thirteen patients (eight from the treated, five from the untreated group) underwent a repeat biopsy after 12+/-6 months (range 10-25). An improvement of histopathological features was noted in Group A, while deterioration was noted in Group B. We conclude that early treatment with prednisolone and azathioprine appears to be beneficial in preventing the progression of immunologic renal injury and in improving histopathological features in IgAN patients with isolated hematuria. Corticosteroid therapy after renal transplantation is associated with many adverse effects. Newer immunosuppressive agents may allow for safe and effective reductions in dose or early steroid withdrawal.
                In this prospective, single-center clinical trial, 60 patients were randomized into 2 groups: control patients (n = 28), who received low doses of prednisone throughout, and study patients (n = 32), who were withdrawn from steroids 7 days posttransplant. Patients received a limited course of rabbit antilymphocyte globulin (rALG) induction therapy, tacrolimus (TAC), and mycophenolate mofetil (MMF). Patients were followed for clinical outcomes and renal function. Protocol biopsies were performed at 1, 6, and 12 months.
                Clinical rejections occurred in 11% of controls and 13% of study patients. Renal function was well maintained and equivalent in both groups. In all, 111 protocol biopsies were performed without complications. Subclinical rejection was noted in only 2 protocol biopsies, and borderline changes were seen in 12 biopsies, all of which were distributed equally between both groups. Unsuspected acute TAC toxicity was seen in 8 biopsies. Protocol biopsies led to changes in therapy in 10% of patients. In both groups, serial protocol biopsies demonstrated increased allograft fibrosis over time, which was significant at 1 year in the steroid withdrawal group.
                The immunosuppressive combination of rALG, TAC, and MMF prevents subclinical rejection and the need for high doses of steroids after transplantation. However, continual low-dose steroid therapy may aid in preventing chronic allograft fibrosis. Protocol biopsies help define the short-term and long-term risks of steroid withdrawal therapy. Our transplant centre began a prospective, randomized trial of steroid withdrawal in low risk renal transplant recipients on triple immunosuppression consisting of mycophenolate mofetil (MMF), microemulsion cyclosporine (CSA), and prednisone. One hundred and twenty patients were randomized either to discontinue or remain on steroids (60 patients per group). Study design consisted of analyses of 1-yr outcomes after study entry. This report includes the 1-yr results plus results at last follow-up (mean follow-up 3.7 yr). There were no significant differences in rates of patient and graft survival at 1 yr or at last follow-up. Additionally, the incidences of acute and chronic rejection as well as graft function were the same at 1 yr and at last follow-up. Significant improvement was noted in total serum cholesterol and bone density at 1 yr and last follow-up. Initial improvement in patient weight at 1 yr was not sustained at last follow-up. No significant impact of steroid withdrawal on serum triglycerides, blood pressure, or post-transplant diabetes mellitus was observed. To date, we have observed no immunologic risk, and some significant benefit in regards to side effects, of steroid withdrawal between 6 and 36 months after transplantation in low risk renal transplant recipients maintained on prednisone, MMF, and microemulsion CSA.
                Steroid withdrawal in low risk kidney transplant recipients is safe and ameliorates many of the unwanted sides effects of steroid use. In a single-center, multiple-referral source study, 38 patients with progressive IgA nephropathy and controlled hypertension were randomized to treatment with prednisolone and cytotoxic agents, to therapy with low-dose cyclophosphamide then azathioprine, and to control groups. The follow-up period lasted 2 to 6 yr. Renal survival, as assessed by Kaplan-Meier analysis annually to 5 yr, showed significant preservation of function from 3 yr in the treatment group and 82, 82, 72, and 72% for 2, 3, 4, and 5 yr, respectively, compared with 68, 47, 26, and 6% in controls. Rate of loss of renal function, evaluated objectively by least-squares analyses of reciprocal serum creatinine, was reduced-and in one-third of the patients, arrested-during immunosuppressive treatment. Proteinuria, present in all patients at the time of entry into the trial, was reduced by treatment from 12 mo, compared with pretreatment levels or controls; erythrocyturia was reduced from 6 mo. Histologic activity and chronicity indexes were determined in renal biopsies performed at trial entry. Multivariate analysis demonstrated that mesangial cell proliferation and matrix scores were highest in those patients with more rapidly progressive disease. No morphologic variable or residual renal function predicted response to immunosuppressive therapy at entry. Mean arterial pressures did not differ significantly between treatment and control groups. There was thus no explanation other than treatment for the improved outcome in patients who received immunosuppressive therapy. Morbidity attributable to treatment or to renal failure occurred in both groups; an audit showed that benefits of therapy outweighed expected or minor side effects of drugs in this population at risk of end-stage renal failure. Patients selected for moderately progressive IgA nephropathy benefit from treatment with prednisolone and cytotoxic agents; results are consistent with modulation of systemic immune response or nephritic injury, thus explaining improved outcome, and indicate that this therapy has an acceptably low risk of side effects. No accepted therapy has been established for progressive immunoglobulin A (IgA) nephropathy.
                A prospective, randomized, controlled trial of low-dose prednisolone therapy was performed in patients with IgA nephropathy with moderate histological characteristics. Forty-three patients in the steroid group and 47 patients in the control group were included in the study. The initial dose of prednisolone was 20 mg/d, gradually tapered to 5 mg/d during 2 years.
                Baseline urine protein-creatinine ratio (UP-UCR) was significantly greater in the steroid group than in controls. Follow-up duration was 65 +/- 25 months in the steroid group and 64 +/- 23 months in controls. Changes in UP-UCR from baseline, ie, UP-UCR at last follow-up minus UP-UCR at baseline, were significantly lower in the steroid group than in controls (steroid group, -0.84 +/- 1.78; controls, 0.26 +/- 1.65; P = 0.0034). Kidney survival was similar in both groups. Patients were divided into two subgroups according to clinical course. There were 28 improved patients and 15 unimproved patients in the steroid group and 27 improved patients and 20 unimproved patients in the control group. In the steroid group, UP-UCR was significantly greater in the unimproved than improved subgroup (3.1 +/- 2.6 versus 1.8 +/- 1.5).
                These data suggest that our protocol had an antiproteinuric effect, but could not improve kidney survival. Because the effect of steroid therapy to prevent the progression of IgA nephropathy is believed to be linked closely to reduction in urinary protein, an insufficient dose of prednisolone in our protocol may be the reason for the discrepancy between the effect on proteinuria and kidney survival. IgA nephropathy is progressive in most cases and has no established therapy. In this randomised trial, we assessed the efficacy and safety of a 6-month course of steroids in this disorder.
                Between July, 1987, and September, 1995, we enrolled 86 consecutive patients from seven renal units in Italy. Eligible patients had biopsy-proven IgA nephropathy, urine protein excretion of 1.0-3.5 g daily, and plasma creatinine concentrations of 133 micromol/L (1.5 mg/dL) or less. Patients were randomly assigned either supportive therapy alone or steroid treatment (intravenous methylprednisolone 1 g per day for 3 consecutive days at the beginning of months 1, 3, and 5, plus oral prednisone 0.5 mg/kg on alternate days for 6 months). The primary endpoint was deterioration in renal function defined as a 50% or 100% increase in plasma creatinine concentration from baseline. Analyses were by intention to treat.
                Nine of 43 patients in the steroid group and 14 of 43 in the control group reached the primary endpoint (a 50% increase in plasma creatinine) by year 5 of follow-up (p<0.048). Factors influencing renal survival were vascular sclerosis (relative risk for 1-point increase in score 1.53, p=0.0347), female sex (0.22, p=0.0163), and steroid therapy (0.41, p=0.0439). All 43 patients assigned steroids completed the treatment without experiencing any important side-effects.
                A 6-month course of steroid treatment protected against deterioration in renal function in IgA nephropathy with no notable adverse effects during follow-up. An increase in urinary protein excretion could be a marker indicating the need for a second course of steroid therapy. The quality of randomized controlled trials (RCTs) in subfertility and their suitability for inclusion in meta-analyses have been assessed in the past and found to be insufficient. Our aim was to assess whether this quality has improved over time, particularly since the publication of the Consolidated Standards of Reporting Trials (CONSORT) statement, and to assess what proportion of trials could be included in the meta-analyses of pregnancy outcomes such as those included in Cochrane Reviews.
                A selection of subfertility trials published in 1990, 1996 and 2002 was collected from the Cochrane Menstrual Disorder and Subfertility Group (MDSG) database. Only trials published in English as full journal articles, claiming to be randomized and reporting on pregnancy outcomes, were included.
                One hundred and sixty-four trials met our inclusion criteria. Twenty-four (15%) were found not to be randomized, despite claims, and only 10 trials (6%) provided adequate details on the methods of randomization and allocation concealment. Of these, only three had sufficient details extractable to allow for an intention-to-treat analysis of the outcome 'live birth'.
                Although an improvement in some subfertility-specific issues was observed, the quality of reporting of RCTs still needs to improve to make them suitable for inclusion in meta-analyses such as those in the Cochrane Library. The combination of cyclosporin, azathioprine, and prednisolone (triple immunosuppression) is the most commonly used immunosuppressive regimen early after renal transplantation, but the risks and benefits of maintaining the steroid component of this regimen in the long term are uncertain.
                A randomised controlled trial of steroid withdrawal was conducted among renal transplant patients receiving triple immunosuppression. Between one and six years after transplantation, 100 such patients were randomised either to reduce prednisolone treatment to zero over about four months or to maintain their triple immunosuppression unchanged. Outcome was analysed according to "Intention-to-treat".
                In 42 (86%) of 49 patients allocated to steroid withdrawal, complete steroid withdrawal was achieved. Although these patients did not experience defined acute rejection episodes, insidious increases in plasma creatinine were observed more frequently in this group than in the controls. In 97 patients surviving one year after trial entry, plasma creatinine exceeded the baseline by more than 25% at some time in the first year in 25 (53%) of 47 in the steroid withdrawal group compared with 9 (18%) of 50 in the control group (p < 0.001, chi-square test). In some cases these increases were transient. However, when corrected for the baseline (entry) value significant differences between groups were apparent in both mean plasma creatinine and mean creatinine clearance; mean (SD) plasma creatinine values at entry, immediately after withdrawal, and at one year were 138 (27), 151 (36), and 150 (36) mumol/L in the steroid withdrawal group versus 138 (34), 140 (51), and 139 (47) mumol/L in the control group (p = 0.017, analysis of covariance). Steroid withdrawal patients showed a further rise in mean plasma creatinine to 160 (44) and 161 (65) mumol/L at two and three years from trial entry. Changes in several clinical and metabolic indices were also observed in association with steroid withdrawal. Blood pressure declined but the reduction was incompletely sustained, being more evident immediately after steroid withdrawal than at one year. Total cholesterol declined about 1 mmol/L in the steroid withdrawal group. Other changes associated with steroid withdrawal were reductions in white cell count and haemoglobin and increases in plasma phosphate and alkaline phosphatase.
                Late steroid withdrawal is feasible in most patients with stable graft function on triple immunosuppression and has potentially beneficial metabolic effects. However, a substantial proportion of patients show a reduction in graft function, indicating a need for caution in considering the long term outcome. Reducing chronic steroid exposure is important to minimize steroid-related morbidity, particularly for susceptible renal transplant recipients. Steroid-free and steroid-sparing protocols have shown benefits, but safety has not been established for all populations. We investigated the safety of steroid avoidance (SA) in a population including African-Americans, using modern immunosuppression with protocol biopsy monitoring.
                A randomized-controlled SA trial (early discontinuation, days 2-7) was conducted in a population (n = 77) including African-Americans and cadaveric kidney recipients. Patients received basiliximab, cyclosporine (CsA), and mycophenolate mofetil (MMF). In controls, steroids were tapered to 5 mg prednisone/d by day 30. Protocol biopsies were performed (1, 6, 12 and 24 months) to evaluate subclinical acute rejection (SCAR) and chronic allograft nephropathy (CAN).
                The SA did not result in significantly higher incidences of graft loss, AR, SCAR, CAN, or renal fibrosis. SA patients experienced similar renal function, comparable serum lipid levels, and a trend toward fewer cases of new-onset diabetes. Clinical outcomes of African-American and non-African-American patients did not significantly differ.
                The SA is safe in the context of basiliximab induction and CsA-based immunosuppression. This protocol could minimize steroid-related side effects in susceptible groups, including African-Americans, without increasing the risk of AR or graft failure. In renal transplant patients with stable graft function, triple-drug immunosuppression may not be necessary, while withdrawal of steroids may eliminate side effects. The primary aim of this study was to assess the risk of rejection after steroid withdrawal.
                A total of 88 patients with stable graft function and serum creatinine <160 micromol/l, treated with cyclosporin A, azathioprine and prednisone were randomized into group A (n=46) with a gradual prednisone reduction to zero in the course of 6 months, and group B (n=42) on triple-drug therapy without change. At the time of randomization, fine-needle aspiration biopsy (FNAB) was carried out in all of the patients. After stopping steroids, the patients were followed up for a period of 12 months.
                Four patients failed to complete steroid withdrawal, three due to rejection, and one due to leukopenia. The proportion of rejection in three patients in group A (6.6%) was not significantly different from rejection in two patients in group B (4.8%). The mean value of serum creatinine was not significantly different in both groups in the course of follow-up. A finding of some degree of immunological activity in FNAB was made in four patients in each group, but none of these patients developed rejection. Compared with group B, significant decreases in serum cholesterol and blood leukocytes were observed in group A. Prednisone withdrawal did not have any influence on hypertension and serum triglycerides.
                Gradual withdrawal of steroids is not associated with a higher risk for rejection and has a beneficial effect on serum total cholesterol levels. FNAB was not a useful tool for predicting rejection. Corticosteroids withdrawal from immunosuppressive regimens has thus far been associated with increased risk of acute rejection episodes. In this study, basiliximab, a chimeric monoclonal interleukin-2 receptor antagonist, added to a maintenance regimen consisting of cyclosporine microemulsion and mycophenolate mofetil was studied for its effectiveness in allowing early corticosteroid withdrawal in de novo renal allograft recipients. Primary renal transplant recipients receiving basiliximab, cyclosporine-microemulsion, and mycophenolate mofetil, were randomized to either corticosteroid withdrawal at day four post-transplantation (n = 40) or standard steroid therapy (n = 43). The primary endpoint was the incidence of biopsy-proven acute rejection episodes. Randomized subjects who underwent transplantation and received at least one dose of basiliximab were analyzed in an intent-to-treat fashion. The incidence of biopsy-proven acute rejection at 12 months was not significantly different between the steroid withdrawal group (20%) and the standard treatment group (16%). Patient and graft survival was 100% in the steroid withdrawal group while one death in a patient with a functioning graft occurred in the standard steroid group. Seventy-two percent of the steroid withdrawal group remained off steroids at 6 months post-transplant. Allograft function and incidence of adverse events and infections were similar between the two groups. Rapid and early corticosteroid withdrawal among renal transplant recipients receiving basiliximab induction and daily therapy with cyclosporine-microemulsion and mycophenolate mofetil was not associated with an increased risk of acute rejection. The reporting quality of randomized controlled trials (RCTs) is poor in general medicine and several areas of specialization but unknown in endocrinology.
                Our aim was to assess the reporting quality of RCTs in general endocrinology. A secondary objective was to identify predictors for better reporting quality.
                We systematically reviewed RCTs published in three general endocrinology journals between January 2005 and December 2006.
                We included parallel-design RCTs that addressed a question of treatment or prevention. Article selection and data abstraction were conducted by two reviewers independently, and disagreements were resolved by consensus.
                There were two main outcomes: 1) a 15-point overall reporting quality score (OQS) based on the Consolidated Standards for Reporting Trials (CONSORT); and 2) a 3-point key score, based on allocation concealment, blinding, and use of intention-to-treat analysis.
                Eighty nine RCTs were included. The median OQS was 10 (interquartile range = 2). Allocation concealment, blinding, and analysis by intention to treat were reported in 10, 20, and 16 of the 89 RCTs, respectively. A multivariable regression analysis showed that complete industrial funding [incidence rate ratio (IRR) = 1.014; 95% confidence interval (CI), 1.010-1.018], journal of publication (IRR = 1.068; 95% CI, 1.007-1.132), and sample size (IRR = 1.048; 95% CI, 1.026-1.070) were significantly associated with a slightly better OQS.
                The quality of RCT reporting in general endocrine literature is suboptimal. We discuss our results, highlight the areas where improvements are needed, and provide some recommendations. Steroids have been included in most immunosuppressive regimens after renal transplantation, but are feared for their side-effects. We conducted a prospective multicenter study to investigate whether it is feasible to withdraw steroids early after transplantation with the use of anti-IL-2Ralpha induction, tacrolimus and mycophenolate mofetil (MMF). A total of 364 patients were randomized to receive either two doses of daclizumab (1 mg/kg) and, for the first 3 days, 100 mg of prednisolone (daclizumab group n = 186), or steroids (tapered to 0 mg at week 16; controls n = 178). All patients received tacrolimus and MMF. The incidence of biopsy-confirmed acute rejection at 12 months was not different between the daclizumab group (15%) and the controls (14%) (95% confidence interval of difference: -6 to + 8%, NS). Graft survival at 12 months was comparable in the two groups (daclizumab group: 91%; controls: 90%). Mean arterial blood pressure, serum lipids, and incidence of patients with hyperglycemia were temporary lower in the daclizumab group compared with controls. The immunosuppressive regimen of the daclizumab group was associated with increased costs. In conclusion, with the use of anti-IL-2Ra induction and daily therapy with tacrolimus and MMF it is feasible to withdraw steroids at 3 days after renal transplantation.
The optimal management of IgAN remains uncertain. The RCTs identified were small, of sub-optimal methodological quality and tended to only report favorable and surrogate outcomes without a thorough reporting of treatment harms. All outcomes favor the use of immunosuppressive interventions, with steroids appearing to be the most promising. Further study, in the form of RCTs, is necessary to ascertain which patients would benefit from these interventions, whether they are the ones with early signs of renal dysfunction or those with more advanced renal impairment.