Immunosuppressive Agents In The Treatment Of IgA Nephropathy

PART1 Comparison of single glucocorticoid therapy and combined therapy with cyclosporine A in treating IgA nephropathy and the diagnostic significance of mesangial C4d depositionBACKGROUNDIgA nephropathy (IgAN) is the most common form glomerulonephritis in worldwide. Approximately 30% of patients will progress to end-stage renal disease (ESRD) after 10-20 years. CyclosporinA (CsA) is a potent immunosuppressive drug.Long-term treatment with cyclosporin A has been successful in other nephropathies but its use in IgAN is controversial. Early small sample, prospective randomized controlled trial reported that high dose cyclosporine A can reduce proteinuria but have no renal protective effect; however some case reports and retrospectively researches demonstrated CsA can treatment IgAN effectively. Whether medium dose CsA dose combined with glucocorticoid therapy is more effective and safer in IgAN therapy? In this study, we aim to evaluate the effects of a combined therapy with medium dose of CsA and methprednisolone on clinic outcomes.METHODSProspective randomized controlled tria1.43 IgAN patients aged 18-70 years with proteinuria> 1.0g/24hours and estimated glomerular filtration rate(eGFR)>30ml/min.1.73m2.Patients was divided randomly into two groups:(1) full dose of glucocorticoid treatment group (methprednisolone 0.8mg/kg for 8 weeks then gradually reduced to maintenance doses 4mg/d), and(2) combined therapy group(methprednisolone 0.5mg/kg and CsA 3mg/kg/d as the initial dosages, then maintained with 4mg/d and 25-50mg/d, respectively). The primary end point was reduction of proteinuria by 50% or more over entry level. Secondary end point was a 50% increase in baseline serum creatinine level or 25%eGFR decrease in baseline eGFR. RESULTSAfter 12 months'treatment,24 hr urinary protein excretion declined from 3.23±3.31g to 0.37±0.23g (P=0.002) in combined therapy group. Patients in the glucocorticoid group also had a significantly remission on proteinuria (0.38±0.27g/24h vs 2.87±2.20 g/24,P=0.0001). The complete remission rate of both groups was 52.63% and 47.37% respectively. Patients undertook combined therapy achieved significantly improvement on eGFR after 9 months (91.0±32.02 vs 78.75±23.12ml/min.1.73m2,P=0.02)while the glucocorticoid group patients achieved significantly increased of eGFR after 3 months(100.10±28.10 to 86.46±26.12 ml/min.1.73m2 (P=0.011). The incidence of a transient drop of eGFR (<25%) was 27.27% in combined therapy group and 4.76% in glucocorticoid group.CONCLUSIONSFull dose of glucocorticoid treatment and the combined therapy with medium dose of CsA and glucocorticoid both can remarkably reduce proteinuria and ameliorate renal function in patients with lgAN patients without severe adverse events. The combined therapy is as effective as full dose glucocorticoid treatment and in some cases is a more viable option than full dose glucocorticoid. PART 2 Glucocorticoid therapy and combined therapy with mycophenolate mofetil in treating IgA nephropathy:Prospective randomized controlled trialBACKGROUNDIgA nephropathy is the most common form glomerulonephritis in worldwide. In China,40%-50% primary glomerulonephritis patients are IgA nephritis. The course of IgAN is variable, approximately20%-50%of adult patients with IgAN develop progressive renal failure, even end-stage renal disease (ESRD) after 10-20 years. The pathogenesis of the disease is not fully understood,there is to date no curative therapy for patients with IgAN.Since the pathogenesis of IgAN may involve abnormal production, glycosylation and removal of IgA with subsequent immune complex deposition and inflammation in glomeruli, many treatments have targeted the immune system. Mycophenolate mofetil is a prodrug of MPA that selectively suppresses the proliferation of T and B lymphocytes, antibody formation, glycosylation of adhesion molecules and the mesangial proliferation through inhibition of de novo guanine nucleotide synthesis.MMF is widely used to preventing allograft rejection after renal transplant and also proved to be efficacious for the treatment severe lupus nephritis.But the results from four controlled trials of MMF treatment IgAN varied greatly. Two researchs from China showed that MMF is effective in lowering proteinuria and ameliorating patient's renal fuction, but other two randomized, placebo-controlled studies with MMF/ACEI did not find any significant differences between the placebo and MMF groups. In this study, we aim to evaluate the effects of a combined therapy with MMF and methprednisolone on clinic outcomes.METHODSProspective randomized controlled trial.86 IgAN patients aged 18-70 years with proteinuria> 1.0g/24hours and estimated glomerular filtration rate(eGFR)>30ml/min.1.73m2.Patients was divided randomly into two groups:(1) full dose of steroid treatment group (methprednisolone 0.8mg/kg for 8 weeks then gradually reduced to maintenance doses 4mg/d), and(2) combined therapy group(methprednisolone 0.4mg/kg for 8weeks, slowly tapped to 4mg/d;and MMF 0.75 bid as the initial dosages,24weeeks later reduced to 0.5 bid. The primary end point was reduction of proteinuria by 50% or more over entry level. Secondary end point was a 50% increase in baseline serum creatinine level or 25%eGFR decrease in baseline eGFR.RESULTSAfter 24 weeks treatment,24 hr urinary protein excretion declined from2.26±1.24 g/24h to 0.52±0.40g/24h (P＜0.01) in combined therapy group. Patients in the steroid group also had a significantly remission on proteinuria 0.59±0.39 g/24h vs 2.79±2.89 g/24h, P＜0.01).93.33% in combine group and 88.11% in steroid patients reached primary outcome. The complete remission rate of both groups was 26.67% and 41.67% respectively (P=0.21). The mean eGFR was 80.07±30.13ml/min.1.73m2 (P<0.05) and 95.64±23.95 ml/min.1.73m2 (P<0.05) that of the corresponding baseline value in combined group and steoid group, respectively. No patients reached 50% increase in Serum creatinine.2 of 30(6.67%) in combine group vs 5 of 36 (13.89%) patients in the stroid group reached a transiently 25% decrease in eGFR (P=0.34). The compliance in steroid group was inferior to combine group (P=0.053).Both groups has the risk of infection. Before treatment,serum IL-6 and MCP-1 levels were increased significantly in IgAN patients compared to controls(IL-6:66.57±36.1 lpg/ml vs 17.12±8.0pg/ml, P＜0.001; MCP-1: 487.23±267.37pg/ml vs181.22±59.70pg/ml, P＜0.001) and decreased significantly after steroid and MMF treatment for 24 weeks(IL-6,posttherapy vs pretherapy:full dose steroid treatment group:50.84±30.50 vs 72.14±43.37pg/ml, P=0.002; combined therapy group:39.87±12.62 vs 59.54±29.26pg/ml, P=0.001; posttherapy vs pretherapy:full dose steroid group 342.39±28.27 vs 501.20±313.29pg/ml,P=0.041; combined therapy group:353.15±32.67vs 483.81±226.11, P=0.025).Serum MCP-1 levels showed significant positive correlation with active histological lesions and macroscopic hematuria.CONCLUSIONFull dose of steroid treatment and the combined therapy with medium dose of steroid and MMF both can remarkably reduce proteinuria and ameliorate renal function in patients with IgAN patients without severe adverse events. The combined therapy is as effective as full dose steroid treatment and in some cases is a more viable option as full dose steroid.Steroid and MMF can significantly suppress serum IL-6, MCP-1 of IgAN patients and thus may exert their efficacy on IgAN. Serum MCP-1 levels may represent active lesions in IgAN. PART 3 Clinical and Pathologic Patterns Based on 2444 Native Kidney BiopsiesBACKGROUNDPercutaneous renal biopsy is the most important method to assessment of kidney diseases. It can provide diagnostic precision, especially in glomerular diseases, and also provides important information of prognostic value and about treatment options. The prevalence of biopsy-proven glomerulonephritis varies according to geographic area, socioeconomic condition, race, age, and indications for renal biopsy. In this study, we retrospectively analyze the pathologic patterns of native kidney biopsies based on a five-year overview and to identify the age-specific pathologic features.METHODSRetrospectively review the reports of 2444 native kidney biopsies whose renal biopsies were performed in Zhongshan Hospital, Fudan University, from Jan 2005 to Dec 2009. Patients were divided into 4 groups according to age, and the pathologic entities based on age distribution were analyzed. RESULTSPrimary glomerulonephritis remained the most common (79.58%) pathologic pattern in our unit. IgA nephritis, holding a 47.97 percentage, was the most common type of primary glumerulonephritis, which kept a steady incidence, but the yearly incidence of focal segmentalglomerulonephritis varied a lot. The prevalence of mesangial proliferative glomerulonephritis decreased every year(P<0.001) while membranous nephropathy were presented with an increase tendency. As for secondary kidney diseases, diabetic nephropathy and hypertensive nephropathy occurred more frequently year after year(All P<0.001).There was an age-specific impact on the constitution of histopathology types.97% patients of aged between 18-45 years old and minimal changes diseases were prevalent in patients under 18 years old. Membraneous nephropathies (33.59%) were most frequent primary glomerulonephritis over 65 years old. Of patients under 18 years old, the most frequent secondary kidney disease was Henoch-Schonlein Purpura Nephritis. Lupus nephritis was responsible for most cases which etiology was determined (65.42%) in young and middle-aged adults.CONCLUSIONThe constituent ratio of histopathology types varie yearly with age specific characteristics.