Prednisolone co-administered with losartan confers renoprotection in patients with IgA nephropathy

BACKGROUND: Treatment options for progressive IgA nephropathy are limited. METHODS: We performed a small, randomized controlled trial to evaluate the effects of prednisolone (PSL, 30 mg/dL, gradually tapered to 5 mg/dL over two years) plus 50 mg/day of losartan (LST, an angiotensin II receptor blocker) or PSL alone on IgA nephropathy. We separated 38 patients (age, 33 +/- 11 years; creatinine clearance, 103 +/- 31 mL/min; proteinuria, 1.6 +/- 0.5 g/day) into two groups that were treated with either PSL plus LST or PSL alone, and compared the proteinuria and creatinine clearance after two years. Baseline and histopathological data did not significantly differ between the two groups. RESULTS: Two years of treatment in both groups significantly decreased proteinuria compared with baseline, and PSL plus LST (from 1.6 +/- 0.6 to 0.3 +/- 0.1 g/day, p < 0.05) was more effective than PSL alone (from 1.6 +/- 0.3 to 0.5 +/- 0.1 g/day, p < 0.05). Creatinine clearance in both groups was similar at the start of study but significantly differed at the end of the study (PSL plus LST, 104.3 +/- 36.4 to 100.4 +/- 38.9 mL/min; PSL alone, 103.4 +/- 28.5 to 84.8 +/- 34.3 mL/min, p < 0.05). CONCLUSIONS: Combined therapy with PSL plus LST appears to be more effective than PSL alone in reducing proteinuria and protecting renal function in patients with IgA nephropathy.     

Prednisolone Co-Administered with Losartan Confers Renoprotection in Patients with IgA Nephropathy

Background.Treatment options for progressive IgA nephropathy are limited. Methods. We performed a small, randomized controlled trial to evaluate the effects of prednisolone (PSL, 30 mg/dL, gradually tapered to 5 mg/dL over two years) plus 50 mg/day of losartan (LST, an angiotensin II receptor blocker) or PSL alone on IgA nephropathy. We separated 38 patients (age, 33 ± 11 years; creatinine clearance, 103 ± 31 mL/min; proteinuria, 1.6 ± 0.5 g/day) into two groups that were treated with either PSL plus LST or PSL alone, and compared the proteinuria and creatinine clearance after two years. Baseline and histopathological data did not significantly differ between the two groups. Results. Two years of treatment in both groups significantly decreased proteinuria compared with baseline, and PSL plus LST (from 1.6 ± 0.6 to 0.3 ± 0.1 g/day, p < 0.05) was more effective than PSL alone (from 1.6 ± 0.3 to 0.5 ± 0.1 g/day, p < 0.05). Creatinine clearance in both groups was similar at the start of study but significantly differed at the end of the study (PSL plus LST, 104.3 ± 36.4 to 100.4 ± 38.9 mL/min; PSL alone, 103.4 ± 28.5 to 84.8 ± 34.3 mL/min, p < 0.05). Conclusions. Combined therapy with PSL plus LST appears to be more effective than PSL alone in reducing proteinuria and protecting renal function in patients with IgA nephropathy.     

Effects of long-term treatment with mizoribine in patients with proliferative lupus nephritis

AIM: Mizoribine (MZR) is a purine antimetabolic immunosuppressant agent that has few little severe adverse events. We studied whether maintenance therapy with MZR and prednisolone (PSL) in severe proliferative lupus nephritis patients could improve immunity, reduce proteinuria, prevent renal relapse, and reduce steroid dose. METHOD: Long-term maintenance therapy with MZR and PSL was evaluated in ten patients with biopsy-proven proliferative lupus nephritis. Patients with severe lupus nephritis, who had proteinuria of 0.5 g or more even after treatments with plasma exchange and/or pulse methyl prednisolone, were recruited. MZR at an average dose of 140 +/- 10 (100 - 200) mg was administered two to three times/day in combination with PSL. The average period for the MZR maintenance therapy was 89.7 +/- 5.5 (70 - 126) months. Urine protein excretion, serum hemolytic complement activity (CH50), C3, serum creatinine, general and biochemical blood examinations, anti-ds-DNA antibody were collected at each monthly medical examination. RESULTS: All patients were females, mean age 43.0 +/- 3.3 years. A significant decrease in proteinuria was noted two years after the combination therapy (p = 0.0016). Five patients experienced lupus nephritis relapse. Patients who did not experience relapses had their MZR combination therapy initiated earlier (p = 0.037) when compared with the patients who experienced relapses. Serum creatinine levels remained unchanged in all patients throughout treatment and follow-up, even during renal relapses. Levels of C3 and CH50 normalized as proteinuria decreased. None of the patients developed serious side effects during MZR treatment. A significant steroid-sparing effect was observed three years after initiating MZR (p = 0.0025). CONCLUSION: From our long-term observation, maintenance therapy with low-dose PSL combined with MZR can eliminate proteinuria and have steroid-sparing effect. Early initiation of the therapy can protect against renal relapses among severe proliferative lupus nephritis patients without serious side effects.     

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.     

Efficacy and safety of lisinopril for mild childhood IgA nephropathy: a pilot study

Even in children with mild immunoglobulin (Ig)A nephropathy (IgA-N) showing minimal/focal mesangial proliferation, persistent proteinuria seems to be a risk factor for progression of the disease, indicating the need for an effective and safe treatment even in such cases. Studies carried out to date have indicated that angiotensin-converting enzyme inhibitors (ACEIs) reduce urinary protein excretion and preserve renal function in adult IgA-N. However, no prospective study of ACEI only for childhood IgA-N has yet been carried out. In this prospective single-arm pilot trial, we administered lisinopril (0.4 mg/kg per day) as therapeutic treatment to 40 children with mild IgA-N with proteinuria [morning urinary protein/creatinine ratio (uP/Cr) ≥ 0.2 g/g]. Thirty-three patients reached the primary endpoint (uP/Cr < 0.2) during the 2-year treatment period. The cumulative disappearance rate of proteinuria determined by the Kaplan–Meier method was 80.9%. Mean uP excretion was reduced from 0.40 to 0.18 g/m²/day (p < 0.0001). Of the 40 patients treated, five (12.5%) showed dizziness, and four of these five needed the lisinopril dose reduced. However, lisinopril therapy was continued in all patients during the 2-year treatment period. No other side effect, such as cough, was observed. We conclude that the efficacy and safety of lisinopril is seemingly acceptable for the treatment of children with mild IgA-N. The participants in the Japanese Pediatric IgA Nephropathy Treatment Study Group are listed in the Appendix.     

The pathology and clinical features of early recurrent membranous glomerulonephritis

We assessed the earliest manifestations of recurrent membranous glomerulonephritis (MGN) in renal allografts. Clinical, laboratory and pathologic data were reviewed in 21 patients at the initial biopsy within 4 months post-transplant with evidence of MGN and on follow-up biopsies, compared to a biopsy control group of eight transplants without recurrent MGN. The mean time of first biopsy with pathologic changes was 2.7 months. In each earliest biopsy, immunofluorescence (IF) showed granular glomerular basement membrane (GBM) staining for C4d, IgG, kappa and lambda. IF for C3 was negative or showed trace staining in 16/21. On each MGN biopsy positive by IF, 14/19 showed absence of deposits or rare tiny subepithelial deposits by electron microscopy (EM). At the earliest biopsy, the mean proteinuria was 1.1 g/day; 16 patients had <1 g/day proteinuria. Follow-up was available in all patients (mean 35 months posttransplant). A total of 13 patients developed >1 g/day proteinuria; 12 were treated with: rituximab (n = 8), ACEI and increased prednisone dose (n = 2), ACEI or ARB only (n = 2). All patients showed reduction in proteinuria after treatment. A total of 11/16 patients showed progression of disease by EM on follow-up biopsy. Recognition of early allograft biopsy features aids in diagnosis of recurrent MGN before patients develop significant proteinuria.     

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.     

Restricted protein diet is associated with decrease in proteinuria: consequences on the progression of renal failure.

OBJECTIVE: Reduction of proteinuria is associated with a slower progression of renal failure. We questioned whether the change in proteinuria in response to a supplemented very low protein diet (SVLPD), which is known to reduce proteinuria, could function as a marker of the potential renoprotective effect of an SVLPD. DESIGN AND PATIENTS: In the 220 consecutive patients of our previously published cohort, the glomerular filtration rate (GFR) was assessed every 3 months using the (51)Cr-EDTA method. Seventy-eight patients (mean age 52 +/- 17 years, body mass index 23 +/- 3 kg/m(2), GFR 15 +/- 6 mL/min) exhibited a proteinuria more than 1 g per day at the start of the regimen. Mean protein intake assessed by urinary nitrogen appearance was 0.42 +/- 0.24 g/kg per day at 4 months. The median follow-up was 24 months. RESULTS: Proteinuria decreased significantly after patients were treated with an SVLPD. The maximum mean percent reduction was attained at 3 months (47% +/- 27%), was not influenced by the levels of baseline proteinuria, and was similar in patients receiving or not receiving angiotensin-converting enzyme inhibition at the start of the study. The percent reduction and the residual proteinuria at 3 months predicted the rate of the later GFR decline. GFR decline was significantly lower in patients whose reduction in proteinuria at 3 months was higher than 50% (0.42 +/- 0.37 mL/min/mo vs. 0.10 +/- 0.15 mL/min/mo and 1.0 +/- 0.6 mL/min/mo vs. 0.15 +/- 0.19 mL/min/mo, P < .001 in patients with proteinuria higher or lesser than 3 g/d at start, respectively). CONCLUSION: These results do not differ from those reported with therapies antagonizing angiotensin II formation and/or activity aiming at reducing proteinuria in chronic renal diseases.     

The Combination of Mycophenolate Mofetil with Corticosteroids Induces Remission of Henoch-Schönlein Purpura Nephritis

Background: Henoch-Sch?nlein purpura (HSP) is a form of systemic vasculitis that can progress to Henoch-Sch?nlein purpura nephritis (HSPN), and the most effective treatment remains controversial. Our aim was to compare the effects of oral mycophenolate mofetil (MMF) with low-dose prednisone and the full-dose corticosteroids (CS; prednisone) for the induction therapy of HSPN with large proteinuria. Methods: Fifty-three patients with biopsy-proved HSPN with large proteinuria (>2.0 g/24 h) were divided into two groups: the MMF group (n = 27) who received oral MMF 1.0 g/day (1.5 g/day for patients with a body weight >70 kg) combined with low-dose prednisone (0.4-0.5 mg/kg/day), and the CS group (n = 26) who received the full-dose prednisone (0.8-1.0 mg/kg/day). We compared the effects of inducing remission at 6-month follow-up and the overall remission rate at the end of the follow-up between the two groups. Results: At 6 months, the estimated glomerular filtration rate level remained stable, while the urine protein decreased significantly in both groups, and the remission rate was 76.9% in the CS group and 55.5% in the MMF group (p = 0.101). With a median follow-up of 28.8 months in the CS group and 28.2 months in the MMF group, the overall remission rate was 80.8% in the CS group and 77.8% in the MMF group (p = 0.788). The MMF group had less side effects than the CS group (48.1 vs. 76.9%, p = 0.031). The relapse was 4/21 (19.0%) in the CS group and 0/21 in the MMF group (p = 0.115). Conclusion: MMF is useful for inducing remission and maintaining remission in Chinese HSPN, and may be used as a steroid-sparing agent in the treatment of HSPN.     

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.     

Clinical Implications of Proteinuria in Renal Transplant Recipients Switching to Rapamycin for Chronic Allograft Dysfunction

There is evidence that treatment with m-TOR inhibitors can be beneficial in cases of chronic renal allograft dysfunction. However, some authors have reported poor outcomes of renal function if the switch to m-TOR inhibitors is made in the presence proteinuria > 0.8 g/d. The present study sought to provide a retrospective analysis of the clinical outcome of 63 kidney recipients diagnosed with chronic allograft dysfunction whose therapy was converted to rapamycin including 35 subjects with renal biopsy-proven chronic allograft nephropathy. At the time of conversion, patients were divided into three groups: group I (negative proteinuria), group II (proteinuria between 0.3 and 0.8 g/d), and group III (proteinuria > 0.8 g/d). On conversion, 21 recipients had no proteinuria (group I). After a follow-up of 24.6 ± 12.8 months, they showed a significant improvement in renal function (previous MDRD4 = 39.9 ± 11.5 mL/m/1.73 m², current MDRD4 50.3 ± 13.3 mL/m/1.73 m², P < .05). Fifteen patients (71.4%) developed proteinuria, which was generally mild (0.8 ± 0.7 g/d) and controlled with angiotensin-converting enzyme inhibitors (42.8%). In group II (n = 18), renal function clearly stabilized after a follow-up of 23.2 ± 14.4 months (previous MDRD4 = 30 ± 8.8 mL/m/1.73 m², current MDRD4 = 37 ± 12.2 mL/m/1.73 m², NS), although there was a progressive deterioration of previous proteinuria levels (previous proteinuria 0.4 ± 0.15 g/d, current proteinuria 1.2 ± 2 g/d, P < .05), which was more frequent and intense in patients whose treatment with calcineurin inhibitors (CNIs) was suspended (with CNI 0.9 ± 1.7 g/d, without CNI 1.6 ± 2.2 g/d, P < .05). Group III (n = 24) had a greater degree of renal insufficiency and a worse outcome after 25.9 ± 18 months of follow-up, with a frank and progressive deterioration in renal function (previous MDRD4 = 38 ± 17 mL/m/1.73 m², current MDRD4 = 32.5 ± 19.2 mL/m/1.73 m², P < .05) and proteinuria (previous proteinuria = 1.5 ± 0.7 g/d, current proteinuria = 2.5 ± 2.2 g/d, P < .05) after conversion. Again, the deterioration in proteinuria was more intense in the patients whose previous CNIs were suspended (with CNI = 1.1 ± 0.9 g/d, without CNI = 4.2 ± 2.3 g/d, P < .05). In conclusion, for patients with chronic allograft dysfunction who do not present with proteinuria or whose proteinuria is less than 0.8 mg/d, switching to rapamycin is useful, since it clearly improves or stabilizes renal function, although there may be a discrete increase in proteinuria in the second case. However, among patients with proteinuria greater than 0.8 mg/d accompanied by a greater degree of renal insufficiency, conversion to rapamycin leads to deterioration of proteinuria levels and renal function. These data show that conversion to rapamycin in cases of chronic allograft dysfunction must be made early when there is no proteinuria or it is minimal, and that proteinuria is a predictor of the outcome of allograft function.     

Combined treatment with steroids and azathioprine in IgA nephropathy: design of a prospective randomised multicentre trial

Corticosteroids have had variable success in IgA nephropathy (IgAN). Our previous trial with a six-month course of steroids in IgAN patients showed they were effective in reducing the risk of renal function deterioration and proteinuria, but this effect seemed to decrease in the long term. This new randomised trial was designed to prospectively evaluate whether adding low-dose azathioprine to steroids improves long-term renal survival in adult biopsy-proven IgAN patients with proteinuria > or = 1 g/24 h and plasma creatinine < or = 2.0 mg/dl. The patients will be treated with steroids (methylprednisolone 1 g i.v. for three consecutive days at months 1, 3 and 5, plus oral prednisone 0.5 mg/kg every other day for six months) plus azathioprine 1.5 mg/kg/day for six months or steroids alone with the same schedule. Altogether a minimum of 346 patients should be enrolled within a four-year recruitment period. The planned duration of follow-up is five years.     

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.     

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.     

Prednisone-induced fluctuations of proteinuria in patients with a nephrotic syndrome

We studied the effect of prednisone on urinary protein excretion in 19 patients with a nephrotic syndrome, who were treated with prednisone (125-150 mg) on alternate days. We found a typical, fluctuating pattern of proteinuria resulting from an increased protein excretion rate on prednisone days and a decreased protein excretion rate on nonprednisone days. The urinary protein excretion on prednisone days was 9.9 +/- 3.3 g/24 h, as compared to 5.7 +/- 3.8 g/24 h on nonprednisone days (mean +/- SD). In the whole group of patients the percentual change in proteinuria was significantly correlated with the endogenous creatinine clearance. However, systematic differences between creatinine excretion rates on prednisone and nonprednisone days were not found in individual patients. In 6 patients, renal hemodynamics were studied more precisely, using a single injection technique. Only a slight and nonsignificant decrease in glomerular filtration rate was found on nonprednisone days (delta = -9.6 +/- 16.3%; mean +/- SD). Filtration fraction remained unchanged. It is therefore suggested that the effects of prednisone on proteinuria are not simply mediated by overall changes in renal hemodynamics.     

Prognosis and treatment of membranous glomerulonephritis-a 5-year prospective study

The aims of the study were to describe the clinical, pathological and biological features of membranous GN and to prospectively evaluate the relationships between individual negative prognostic factors--type of therapy and outcome. Between 1993-1998, 13/150 (8.7%) consecutive patients with renal biopsy had membranous GN (M = 62%, age = 42.5 +/- 14.5 years). Main (major) findings in these patients were: asymptomatic proteinuria--23.1%, heavy proteinuria (> 10 g/day)--33.3%, microscopic hematuria--53.8%, increased plasma creatinine levels--33.3%, hypertension--23.1% cases. 60% of the patients with nephrotic proteinuria had an underlying cause (infection, malignancy, immune-mediated systemic diseases). 40% of the patients with nephrotic proteinuria had 0 or less than 2 negative prognostic factors (without any of the recognized severe morphological changes). The following differentiated treatment protocols were applied: no treatment for asymptomatic proteinuria (group A), i.v. methyl-prednisolone boluses + prednisone 1 mg/kgc/day 3 months for those patients with few negative prognostic factors (group B), and steroids (as above) + cyclophosphamide (2 mg/kgc/day 3 months) or the Ponticelli regime in patients with important risk factors (group C). Outcome after a median follow-up period of 24 months was: complete remission in all cases from groups A + B (with only one exception were the underlying cause was breast malignancy); in group C in 75% of the subjects a complete or partial remission (proteinuria < 1 g/day) was obtained. Only one case progressed to chronic renal failure. There were no secondary effects from corticoids or immunosuppressive therapy. CONCLUSIONS: In membranous GN treatment should be tailored to the presence and type of negative prognostic factors. Even in high-risk patients combined steroids and immunosuppressive therapy determines a favorable outcome in 75% of the cases, without severe adverse effects.     

Development of Proteinuria After Switch to Sirolimus-Based Immunosuppression in Long-Term Cardiac Transplant Patients

Calcineurin-inhibitor therapy can lead to renal dysfunction in heart transplantation patients. The novel immunosuppressive (IS) drug sirolmus (Srl) lacks nephrotoxic effects; however, proteinuria associated with Srl has been reported following renal transplantation. In cardiac transplantation, the incidence of proteinuria associated with Srl is unknown. In this study, long-term cardiac transplant patients were switched from cyclosporine to Srl-based IS. Concomitant IS consisted of mycophenolate mofetil ± steroids. Proteinuria increased significantly from a median of 0.13 g/day (range 0–5.7) preswitch to 0.23 g/day (0–9.88) at 24 months postswitch (p = 0.0024). Before the switch, 11.5% of patients had high-grade proteinuria (>1.0 g/day); this increased to 22.9% postswitch (p = 0.006). ACE inhibitor and angiotensin-releasing blocker (ARB) therapy reduced proteinuria development. Patients without proteinuria had increased renal function (median 42.5 vs. 64.1, p = 0.25), whereas patients who developed high-grade proteinuria showed decreased renal function at the end of follow-up (median 39.6 vs. 29.2, p = 0.125). Thus, proteinuria may develop in cardiac transplant patients after switch to Srl, which may have an adverse effect on renal function in these patients. Srl should be used with ACEi/ARB therapy and patients monitored for proteinuria and increased renal dysfunction.     

Treatment of mesangiocapillary glomerulonephritis with alternate-day prednisone —a report of The International Study of Kidney Disease in Children

It has been claimed that long-term prednisone treatment ameliorates the course of children with mesangiocapillary glomerulonephritis (MCGN). The International Study of Kidney Disease in Children conducted a randomized, double-blinded, placebo-controlled clinical trial in 80 children with idiopathic MCGN, including 42 patients with type I disease, 14 with type II disease, 17 with type III disease, and 7 with nontypable disease. Criteria for admission included heavy proteinuria and a glomerular filtration rate of greater than or equal to 70 ml/min per 1.73 m². Prednisone or lactose, 40 mg/m², was given every other day as a single morning dose. The mean duration of treatment was 41 months, renal failure being the most common reason for termination of therapy. Treatment failure was defined as an increase from baseline of 30% or more in serum creatinine, or more than 35 mol/l. Overall, treatment failure occurred in 55% of patients treated with lactose, compared with 40% in the prednisone group. Life-table analysis showed a renal survival rate (i.e., stable renal function) at 130 months of 61% among patients receiving prednisone and 12% among patients receiving lactose (P=0.07). Of patients with type I or III MCGN, 33% treated with prednisone were treatment failures, compared with 58% in the lactose group. Long-term treatment with prednisone appears to improve the outcome of children with MCGN.     

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.     

Relationship of renal lesions with urinary protein excretion in patients with overt diabetic nephropathy]

We investigated the relationship of renal lesions with the degrees of proteinuria in 57 type 2 diabetic patients with overt proteinuria (urinary protein excretion rate (UP) > 0.5 g/day). Creatinine clearance (Ccr) ranged from 25.4 to 131.0 ml/min/1.73 m2. Kidney specimens were obtained and the diagnosis of diabetic nephropathy was made in all patients. The degree of each of the following histologic changes were evaluated: diffuse or nodular lesion, the type of nodular change, mesangiolysis, arteriolar hyalinosis and interstitial damage. We divided the patients into the following 4 groups according to Ccr and UP: group A with Ccr > 60 and UP > 3 g/day (n = 10), group B with Ccr > 60 and UP < 3 g/day (n = 10), group C with Ccr < 60 and UP > 3 g/day (n = 23) and group D with Ccr < 60 and UP < 3 g/day (n = 14), and compared the histologic parameters among the 4 groups. Diffuse index in group A was greater than those in group B (p = 0.05), while those in groups C and D were not different. Nodular index, percentage of patients with nodular lesion did not differ among the 4 groups, however the percentage of glomeruli with complicated nodules (nodular lesion with mesangiolysis and/or microaneurysm) in group C was greater than those in group D (p < 0.05). Hyalinosis index did not differ between group A and B, nor between group C and D, respectively. Interstitial index in group A and B did not differ, however that in group C was greater than in group D (p < 0.05). In addition, the rate of Ccr decrease between renal biopsy and after 12 months was significantly greater in group A and C than in group B and D, respectively (both p < 0.01). These results suggest that 1) mesangial expansion was associated with the degree of proteinuria in patients with slight impaired renal function, 2) tubulointerstitial involvement was associated with the degree of proteinuria in patients with advanced impaired renal function, and 3) these structural changes might be associated with decrease in renal function in diabetic nephropathy.