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.     

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.     

Supportive Versus Immunosuppressive Therapy of Progressive IgA nephropathy (STOP) IgAN trial: rationale and study protocol

Introduction: The best treatment of IgA nephropathy (IgAN) is currently not well defined. The Supportive Versus Immunosuppressive Therapy of Progressive IgA Nephropathy (STOP IgAN) trial aims to answer if, in IgAN patients, an immunosuppressive treatment is more effective than a supportive treatment. Methods: In a randomized prospective multicenter study (www.clinicaltrials.gov, NCT00554502), we will treat 148 patients at risk for progressive IgA nephropathy following a 6-month run-in phase, in 2 groups: (group a) supportive treatment: patients with a persistent proteinuria >0.75 g/day will receive a maximized therapy to reduce blood pressure and urinary protein loss using angiotensin-converting enzyme inhibitors and AT1 blockers, statins, dietary counseling for a low-sodium and low-protein diet and education/intervention programs to stop smoking. (group b) immunosuppressive treatment: in addition to the identical treatment of group a, patients will receive treatment with steroids (glomerular filtration rate [GFR] > or =60 ml/min) or steroids plus cyclophosphamide/azathioprine (GFR <60 ml/min). Study end points are the complete remission of the disease and the individual degree of renal functional loss. If the immunosuppressive therapy shows a superior efficacy with respect to prevention of renal failure, the potentially higher therapy cost and risk might be justified. Finally, our trial can serve as a model for various other types of glomerulonephritis, for which such trials are very difficult to perform, given their infrequency.     

Corticosteroid effectiveness in IgA nephropathy: long-term results of a randomized, controlled trial

Proteinuria plays a causal role in the progression of IgA nephropathy (IgAN). A previous controlled trial showed that steroids are effective in reducing proteinuria and preserving renal function in patients with IgAN. The objective of this study was to evaluate the long-term effectiveness of steroids in IgAN, examine the trend of proteinuria during follow-up (starting from the hypothesis that the degree of reduction in proteinuria may influence IgAN outcome), and evaluate how histologic scores can influence steroid response. A secondary analysis of a multicenter, randomized, controlled trial of 86 adult IgAN patients who were receiving supportive therapy or intravenous methylprednisolone plus oral prednisone for 6 mo was conducted. Ten-year renal survival was significantly better in the steroid than in the control group (97% versus 53%; log rank test P = 0.0003). In the 72 patients who did not reach the end point (doubling in baseline serum creatinine), median proteinuria significantly decreased (1.9 g/24 h at baseline, 1.1 g/24 h after 6 mo, and 0.6 g/24 h after a median of 7 yr). In the 14 progressive patients, proteinuria increased from a median of 1.7 g/24 h at baseline to 2.0 g/24 h after 6 mo and 3.3 g/24 h after a median of 5 yr. Steroids were effective in every histologic class. Cox multivariate regression analyses showed that, in addition to steroids, a low baseline histologic score, a reduction in proteinuria after 6 mo, and no increase in proteinuria during follow-up all were independent predictors of a beneficial outcome. Steroids significantly reduce proteinuria and protect against renal function deterioration in IgAN. The histologic picture and proteinuria during early and late follow-up improve the prediction of outcome, but considerable variability remains outside the model.     

Addition of Azathioprine to Corticosteroids Does Not Benefit Patients with IgA Nephropathy

The optimal treatment for IgA nephropathy (IgAN) remains unknown. Some patients respond to corticosteroids, suggesting that more aggressive treatment may provide additional benefit. We performed a randomized, multicenter, controlled trial to determine whether adding azathioprine to steroids improves renal outcome. We randomly assigned 207 IgAN patients with creatinine ≤2.0 mg/dl and proteinuria ≥1.0 g/d to either (1) a 3-day pulse of methylprednisolone in months 1, 3, and 5 in addition to both oral prednisone 0.5 mg/kg every other day and azathioprine 1.5 mg/kg per day for 6 months (n = 101, group 1) or (2) steroids alone on the same schedule (n = 106, group 2). The primary outcome was renal survival (time to 50% increase in plasma creatinine from baseline); secondary outcomes were changes in proteinuria over time and safety. After a median follow-up of 4.9 years, the primary endpoint occurred in 13 patients in group 1 (12.9%, 95% CI 7.5 to 20.9%) and 12 patients in group 2 (11.3%, CI 6.5 to 18.9%) (P = 0.83). Five-year cumulative renal survival was similar between groups (88 versus 89%; P = 0.83). Multivariate Cox regression analysis revealed that female gender, systolic BP, number of antihypertensive drugs, ACE inhibitor use, and proteinuria during follow-up predicted the risk of reaching the primary endpoint. Treatment significantly decreased proteinuria from 2.00 to 1.07 g/d during follow-up (P < 0.001) on average, with no difference between groups. Treatment-related adverse events were more frequent among those receiving azathioprine. In summary, adding low-dose azathioprine to corticosteroids for 6 months does not provide additional benefit to patients with IgAN and may increase the risk for adverse events.IgA nephropathy (IgAN) causes ESRD in a significant percentage of patients.^1–3 None of the treatment strategies currently used in clinical practice have proved to be more effective than another, although corticosteroids give some results.^4–6In 1999, we found that a 6-month steroid course significantly decreased the risk of a 50% increase in plasma creatinine from baseline at 5 years in comparison with supportive therapy; proteinuria also decreased.⁷ However, 6 months of steroid therapy may not be enough to ensure stable remission in some patients. Thus, we hypothesized that more aggressive treatment may lead to better results, especially in the long term. Previous studies have suggested the possibility that adding immunosuppressants (particularly azathioprine) to corticosteroids may be more effective in preserving renal function^8,9 and reducing proteinuria.¹⁰ However, azathioprine has mainly been given in combination with other drugs.⁸ Moreover, the sample size⁸ and study design⁹ were inadequate in two of three studies.The aim of this trial was to assess the efficacy and safety of adding low-dose azathioprine for 6 months to steroids in adult IgAN patients.¹¹ We decided to use azathioprine at low dose and for a relatively short period to decrease the risk of serious side effects of this immunosuppressant in relatively young and healthy subjects.     

Critical threshold of azathioprine dosage for maintenance immunosuppression in kidney graft recipients. Collaborative Transplant Study

BACKGROUND: There are conflicting reports in the literature concerning the efficacy of maintenance immunosuppression in renal transplantation with a regimen of azathioprine and steroids. METHODS: The daily dosage (mg/kg) of azathioprine administered 1 year after transplantation was analyzed in relation to subsequent long-term graft outcome. Transplants performed from 1985 to 1996 and reported to the Collaborative Transplant Study were analyzed. RESULTS: In patients on maintenance immunosuppression without cyclosporine, the daily dosage of azathioprine had a highly significant influence on long-term graft outcome. Patients who received > 1.5 mg/kg/ day of azathioprine had a 69% graft survival rate at 7 years, compared with a 55% rate in patients receiving 1.01-1.5 mg/kg/day (P<0.0001) and a 45% rate in patients receiving < or = 1.00 mg/kg/day (P<0.0001). This observation was valid for patients who were taken off cyclosporine during the first year as well as for patients who were treated with azathioprine and steroids (without cyclosporine) from the beginning. CONCLUSION: Maintenance immunosuppression with azathioprine and steroids results in good long-term kidney graft survival, provided azathioprine is administered at a daily dose of >1.5 mg/kg.     

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.     

Treatment of IgA nephropathy with angiotensin converting enzyme inhibitors: design of a prospective randomized multicenter trial.

Although several in vitro studies and clinical observations suggest that ACE-inhibitors (ACE-I) are a promising treatment for IgA nephropathy (IgAN), meta-analysis of published data is not yet conclusive. Therefore, a European double-blinded, prospective, randomized therapeutic trial was designed to evaluate ACE-I treatment benefits in young IgAN patients (<35 years old) with persistent moderate proteinuria (>1<3.5 g/day/1.73 m2) and fair renal function (creatinine clearance >50 mL/min/1.73 m2). Patients enrolled are randomly assigned to benazepril (0.2 mg/kg/day) or placebo. Patients should be enrolled within a five year recruitment period (end on December 2003) for a total duration of follow-up of six years (end on December 2004). Hypertension and some genetic, histological and immunological factors will be evaluated to clarify their eventual role in the final response to ACE-I treatment.     

A prospective randomized trial of low-dose versus high-dose steroids in cadaveric renal transplantation

Low-dose steroid regimens, in combination with azathioprine, have become increasingly common for immunosuppression of renal transplant recipients. The change from conventional high-dose steroid regimens was prompted by the results of several prospective trials that showed similar graft survivals with high-dose and low-dose steroids, but a lower incidence of steroid-induced complications in low-dose-steroid--treated patients. However, the number of patients entered into the trials was small, and consequently there remained a possibility that a clinically relevant difference in graft survival could have remained undetected. A multi-center prospective trial was performed to compare graft survival with high-dose (91 patients) and low-dose (98 patients) oral steroids in combination with azathioprine. There was significantly worse graft survival in the low-dose group. The difference was largely due to a poor graft survival in patients receiving low-dose steroids and azathioprine less than 1.75 mg/kg/day. Graft survivals were similar in the high-dose and low-dose steroid patients who received azathioprine doses of greater than 1.75 mg/kg/day. The results indicate that the combination of low doses of both steroids and azathioprine provides inadequate immunosuppression in renal transplantation, although higher doses of azathioprine allow the use of low-dose steroids without significantly more graft losses than with high-dose steroids.     

Prednisone monotherapy induced remission in a group of patients with membranous lupus nephritis

The treatment of membranous lupus nephritis (MLN) is still controversial in the literature. We conducted a retrospective analysis of patients in two medical centers of S?o Paulo-Brazil in order to evaluate the clinical response in patients submitted to either a regimen with prednisone alone or to a double immunosuppressive regimen (prednisone plus cyclophosphamide or prednisone plus azathioprine). Methods: MLN female patients were enrolled in this retrospective study conducted from February 1999 to June 2007. Data were collected from the patients' medical charts. Race distribution was similar in both groups: Caucasian (72.3%) and Afro-Latin-American (27.7%). The prednisone regimen consisted of 1 mg/kg/day for 8 weeks and tapering until 0.1 mg/kg/day (n = 29). The double immunosuppressive treatment consisted of the same doses of prednisone plus monthly intravenous cyclophosphamide or azathioprine for 6 months (n = 24). Criteria for remission (complete and partial) and renal function loss as well as flare criteria followed those used in the literature. Results: There was no difference between the prednisone group and the double immunosuppressive group regarding age (33.2 ± 9.4 vs. 29.1 ± 9.1 y), estimated GFR (76.5 ± 26.6 vs. 74.1 ± 39.6 ml/min/1.73 m2), serum albumin (2.8 ± 0.7 vs. 2.6 ± 0.3 g/dl), positive ANA (87.5 vs. 90.0%), positive anti- dsDNA (47.6 vs. 44.0%), renal SLEDAI indices (6.6 ± 2.6 vs. 7.0 ± 3.1), follow-up time (71 ± 46 vs. 62 ± 45 months), as well as proteinuria (3.1 ± 1.9 vs. 4.8 ± 2.4 g/day) and number of non-nephrotic patients (6 in the prednisone group vs. 3 in the double immunosuppressive group). The prednisone group presented higher C3 values (85.2 ± 31.5 vs. 62.3 ± 41.6 U/ml, p = 0.04). Clinical and laboratory characteristics at 6 months and at last follow-up did not reveal any differences between treatment regimens. Renal survival after an 8-year follow-up did not differ in both groups (prednisone group 86.2% vs. double immunosuppressive group 75%), and patients in both groups showed a high rate of renal flares (prednisone group 51.7% vs. double immunosuppressive group 62.5%). Univariate analysis showed that only patient age predicted flares (r = -0.048, p = 0.04). Borderline significance was obtained for proteinuria analysis (p = 0.07). Adverse effects did not differ between the groups. Conclusions: A regimen of corticosteroids in MLN induced a high remission rate after 6 months. Both treatment regimens showed a high flare rate and age was the only predictive parameter (r = -0.048, p = 0.04). Renal survival after 8 years did not differ between the groups.     

Crescentic, proliferative IgA nephropathy: clinical and histological response to methylprednisolone and intravenous cyclophosphamide.

BACKGROUND: IgA nephropathy is an immune-complex glomerulopathy that can result in capillary or extra-capillary proliferation. Previous attempts to correlate specific histological findings including cellular crescents or endocapillary proliferation, with clinical outcomes, have produced conflicting results. METHODS: We conducted a prospective open-labelled trial of 12 patients with crescentic, proliferative IgA nephropathy and clinically progressive disease and treated them with pulse steroids and intravenous cyclophosphamide. Therapy included pulse solumedrol at 15 mg/kg/day for 3 days, followed by monthly intravenous cyclophosphamide at 0.5 g/m(2) body surface area for 6 months. Clinically significant proteinuria (>1.0 g/24 h) was present in all patients, while nephrotic-range proteinuria (>3.0 g/24 h) was observed in eight of 12 patients. All patients were hypertensive (BP >140/90 mmHg). RESULTS: After 6 months of treatment, the mean serum creatinine was reduced from a maximum of 2.65+/-0.39 to 1.51+/-0.10 mg/dl (P<0.03), while proteinuria was reduced from 4.04 to 1.35 g/24 h (P<0.01). The mean slope of 1/serum creatinine increased from -0.0398+/-0.02 to 0.0076+/-0.01 after 6 months of therapy, but this trend did not reach statistical significance (P<0.08). A repeat kidney biopsy was performed in all treated patients. Endocapillary proliferation, cellular crescents and karyorrhexis were eliminated in all 12 patients after 6 months of therapy, while interstitial fibrosis and tubule dropout remained unchanged. To determine the long-term efficacy of the treatment, treated patients were compared to 12 historical controls matched for severity of IgA on initial biopsy. After 36 months, the rate of end-stage renal disease in the treated group was lower (1/12) than in the historical controls (5/12). CONCLUSIONS: We conclude that steroids and intravenous cyclophosphamide reduce proliferative lesions, reduce proteinuria and stabilize renal function in patients with crescentic IgA nephropathy.     

Efficacy of immunosuppressive therapy in IgA nephropathy presenting with isolated hematuria

The role of immunosuppressive therapy in the management of IgA nephropathy (IgAN) remains controversial. No consensushas yet emerged on the specific treatment of IgAN and this ismostly related to the lack of complete understanding of themultifactorial pathogenesis of the disease. Choice of appropriatetherapeutic agents is further limited by the difficulty inidentifying patients who would most likely benefit from therapy.Immunosuppressive therapy has not been recommended in patientswith isolated hematuria and well preserved renal function becauseof their generally favourable prognosis and there are no clinicaltrials in this area. Considering that mild IgAN may be an earlystage of the disease and can be reversed by immunosuppressiveagents we have used prednisolone and azathioprine in patientswith isolated hematuria in a prospective, randomized, controlledstudy since 1988. In this prospective study we have evaluated theeffect of prednisolone with azathioprine on the clinical courseof IgAN and its impact on histologic parameters and preventionof progression in patients with isolated hematuria. We studied 43biopsy-proven IgAN patients (29 males and 14 females, agedbetween 13–63 years, mean age 28 ± 6) with isolated hematuria andwell-preserved renal function (C_cr 89.2 ± 10.2 ml/min). Thepatients were assigned to two groups: 21 patients receivedprednisolone (40 mg/day) and azathioprine (100 mg/day) orally forfour months (group A) and 22 patients received no specifictreatment for IgAN and served as a control group (group B). InGroup A prednisolone was reduced to 20 mg/day at the end of thesecond month, then slowly tapered over a two-month period andstopped. The median duration of follow-up was 60 months (range12–120 months). At the end of the therapy hematuria disappearedin 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 >500mg/day. No significant changes in biochemical profile wereobserved in either group. Thirteen patients (eight from thetreated, five from the untreated group) underwent a repeat biopsyafter 12 ± 6 months (range 10–25). An improvement ofhistopathological features was noted in Group A, whiledeterioration was noted in Group B. We conclude that earlytreatment with prednisolone and azathioprine appears to bebeneficial in preventing the progression of immunologic renalinjury and in improving histopathological features in IgANpatients with isolated hematuria.     

Effectiveness of steroid therapy in different stages of membranous nephropathy

The published studies on histological staging and response to steroid therapy of membranous glomerulonephritis are not consistent. We analysed data from 25 adult patients with stage I (group 1, n = 7) and stage II (group 2, n = 18) disease. The interval between clinical onset and admission was similar in the two groups. At admission all patients had normal creatinine clearance; proteinuria averaged 5.4 +/- 4.0 in group 1 and 9.0 +/- 4.0 in group 2 (g/day per 100 ml GFR). All patients received 6 months steroid therapy (months 1-2, 1 mg/kg b.w. per day; month 3-5: 0.65 mg/kg b.w. e.o.d.; month 6, tapering). After this cycle of steroid therapy, proteinuria declined by 84% in group 1 (five patients being in partial remission, i.e. 0.4-2 g/day, and two patients in complete remission, i.e. less than or equal to 0.3 g/day) and by 47% in group 2 (two patients being in complete remission and six in partial remission). Only 1 patient in group 1 relapsed with nephrotic proteinuria after 36 months, and renal function was still normal in all patients at the most recent follow-up (59 +/- 32 months). In contrast, 14 patients in group 2 had nephrotic syndrome and seven renal insufficiency at the most recent follow-up. We conclude that short-term steroid therapy is effective only in patients with early membranous changes.     

Combined therapy of tacrolimus and corticosteroids in cyclosporin-resistant or -dependent idiopathic focal glomerulosclerosis: a preliminary uncontrolled study with prospective follow-up.

BACKGROUND: Cyclosporin has improved the outcome for steroid-resistant patients with focal glomerulosclerosis, but there is a proportion of patients that are either cyclosporin-resistant or suffer relapses, needing long-term therapy to sustain the remission. In these cases, preliminary reports suggest that tacrolimus could be an alternative therapy, but to date the evidence is limited to small series of patients with no long-term follow-up. METHODS: In this study we analysed the efficacy and safety of a combined therapy of tacrolimus and steroids in 25 patients (mean serum creatinine= 1.24+/-0.49 mg/dl; mean proteinuria=10.2+/-9.5 g/day; mean serum albumin=2.4+/-0.58 g/dl) with idiopathic primary focal glomerulosclerosis and proven resistance to or dependence on cyclosporin A. RESULTS: After a 6 months trial of tacrolimus and steroids, proteinuria decreased in 17 patients (68%) (complete remission in 10 patients (40%), partial remission in two patients (8%) and a moderate reduction in proteinuria to levels <3 g/day was seen in five additional patients (20%)). The only predictor of response to tacrolimus was a previous response to cyclosporin and prednisone, either as a complete or partial remission (remission rate 75% vs 15.3; P=0.036). Mean time to remission was 112+/-24 days. After tacrolimus discontinuation, 13/17 patients (76%) relapsed and were treated with a second trial of tacrolimus for 1 year, achieving complete remission in five patients (38.4%), partial remission in four patients (30.7%) and reduction of proteinuria <3 g/day in four patients (30.7%). After 2 years of follow-up, 12 patients (48%) were on sustained remission. The main side effect was acute reversible nephrotoxicity (40%). Predictors of renal toxicity were age (P=0.037), baseline creatinine (P=0.046) and tacrolimus trough level (P=0.001). CONCLUSIONS: We conclude that combined therapy of tacrolimus and steroids induce sustained remission of proteinuria in a significant number of patients with idiopathic focal glomerulosclerosis whose disease was not controlled by the standard therapy of steroids and cyclosporin A.     

Mycophenolic acid therapy after cyclophosphamide pulses in progressive IgA nephropathy

BACKGROUND: In progressive IgA nephropathy (IgAN), cyclophosphamide or steroids have been used to reduce the loss of renal function, but disease progression may occur after the end of treatment. The value of mycophenolic acid (MPA) maintenance therapy following initial immunosuppression in progressive IgAN is largely unknown. METHODS: In a prospective single-center trial, 20 patients with advanced IgAN (median glomerular filtration rate [GFR], 22 ml/min) and disease progression after cyclophosphamide pulse (CyP; n=18) or steroid pulse therapy (n=2) were treated with MPA for a median of 27 months. MPA dosages (initially mycophenolate mofetil 500 mg twice daily) were adjusted according to predose plasma concentrations (target concentrations 1.5 to 4 microg/mL). The course of renal function was assessed by linear regression of glomerular filtration rates. RESULTS: Median loss of renal function per month was significantly reduced from -0.8 ml/min to -0.03 ml/min per month after 6 months, to -0.05 ml/min per month after 12 months, and to -0.12 ml/min per month at the end of the study after median 27 months (p<0.05). An improved or stable GFR was observed in 16 of 20 patients during the first 12 months, and sustained in 10 patients during 24 months of follow-up. Proteinuria decreased significantly from 1.1 g/L to 0.4 g/L during MPA treatment (p=0.018). CONCLUSION: Our results indicate that MPA may be beneficial to slow down the loss of renal function in patients with progressive IgAN after previous immunosuppressive treatment.     

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.     

Long term treatment of IgA nephropathy with cyclosporine A

20-50% of patients with IgA nephropathy (IgAN) reach end-stage renal failure. Yet a standard treatment for those with progressive course and/or great proteinuria is lacking. We treated 6 patients with biopsy proven IgAN, proteinuria over 3.5 g/24 h and S-creatinine less than 200 micromol/L non-responding to corticosteroids administered for 3 months. They were given cyclosporine A (CsA) 5 mg/kg bw/day then titrated aiming at a serum concentration of 70-150 ng/mL for one year tapered to discontinuation in 9 months. Prednisone 5-10 mg on alternate days was given with CsA. Proteinuria (g/day) decreased from 4.66 +/- 0.43 to 1.38 +/- 0.29 (p < 0.01) after 1 month and to 0.59 +/- 0.14 (p < 0.001) after 1 year of treatment and remained lower than baseline 2 years from the beginning (1.44 +/- 0.27, p < 0.001). GFR (creatinine clearance) did not change during the first month (1.25 +/- 0.21 mL/s vs 1.38 +/- 0.29 mL/s), but decreased after 1 year (1.05 +/- 0.14 mL/s, p < 0.05). After two years it increased to 1.17 +/- 0.16, NS from baseline. We also calculated the ratio of proteinuria to the GFR (mg/L) to assess the role of hemodynamic changes in the decrease of proteinuria. This ratio was 53.80 + 6.47 before therapy, it decreased after 1 month (11.56 +/- 1.7, p < 0.05) and further after 1 year (6.78 + 1.45, p < 0.01). Three months after discontinuation it was still 14.32 +/- 1.00, p < 0.05 from baseline. In conclusion, CsA significantly lowered moderate to high proteinuria in 6 patients with IgAN. Significant decrease of the proteinuria/GFR ratio suggests some non-hemodynamic mechanism of CsA action. The therapy was well tolerated and side-effects were not so severe as to require CsA withdrawal.     

Misoprostol in renal transplant recipients: a prospective, randomized, controlled study on the prevention of acute rejection episodes and cyclosporin A nephrotoxicity

The aim of this prospective and randomized study was to determinewhether misoprostol, an analogue of PGE1, could decrease theincidence and the number of rejection episodes and could improvethe renal function over a 12-month follow-up, when given at400 µg/day for 12 months in renal transplant patients.Given the known side-effects and the additive cost of misoprostol,a benefit of the therapy should be a decrease of at least 50%in the incidence of rejection episodes in the treated group.Therefore, 60 consecutive renal transplant patients were randomizedto receive misoprostol or to receive aluminium and magnesiumhydroxide. Patients received steroids, azathioprine, antithymocyteglobulins, and cyclosporin A (CsA). CsA was randomly startedon day 0 or on day 8. At 12 months, no difference in the incidenceof rejection episodes was observed: 63.3% in the 30 patientsof the misoprostol + group versus 70.0% in the misoprostol-group(P=0.558 Mantel-Cox). The renal function, assessed by plasmacreatinine, inulin, and para-aminohippuric acid clearances,was not significantly different between misoprostol + and misoprostol-groups.No episode of CsA nephrotoxicity was observed in any patientof group one or group two. At 12 months, the mean dosage ofCsA was 4.9±0.28 mg/kg/day in the misoprostol+group versus4.52 ± 0.23 mg/kg/day in the misoprostol - group andthe trough level was not significantly different between thetwo groups. The graft survival rate at 12 months was 86.7% inthe Misoprostol+ group and 83.33% in the misoprostol- group.The trial failed to demonstrate a significant beneficial effectof misoprostol on the decrease of acute rejection episodes,on the prevention of CsA nephrotoxicity, or on the improvementof renal function over a 12-month period.     

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.