Cyclosporine A Combined With Medium/low Dose Of Prednisone On Progressive IgA Nephropathy

BackgroundPrimary IgA nephropathy (IgA nephropathy, IgAN) is an immune pathology diagnosis.It was denied as a kind of glomerulonephritis characterized immune complex deposition based on IgA in the glomerular mesangial area.The main clinical manifestations of IgAN were hematuria, microscopic hematuria with/without asymptomatic proteinuria, proteinuria, rapidly progressive nephritis syndrome.There is different incidence of IgAN in different area. For example, the incidence rate is as high as30-40%in the Asian and Pacific area, but about10-20%in the Europe and America.Especially in recent years, IgAN has become the most common form of glomerulonephritis worldwide. It is consistent with the data from some Chinese hospitals. Up to40%progress to end-stage renal disease over10-20years. IgAN has been the most common disease lead to chronic renal failure. Therefore, early diagnosis and intervention are important for IgAN treatment.The patho genesis of IgAN is unkown. Many factors, including the abnormal immune response or immune dysfunction have been recognized as the main cause of desease. In addition, cytokines, inflammatory mediator, hemodynamic abnormalities and genetic factors are believed to play a certain role in the promotion and progress of the disease.Because the pathogenesis of IgA nephropathy is not clear, there is not consistent therapy on IgAN up to now. In rencent years, some literatures has been published in domestic and foreign journals, presenting the application of corticosteroids, cytotoxic agents such as cyclophosphamide, and some non immunosuppressive drugs such as angiotensin-converting enzyme inhibitors, statins, cod-liver oil on IgAN and achieve a significant effect. However, there are also some test draw the opposite conclusion.Progressive IgAN is described as significant proteinuria(>1g/d), hypertension, impaired renal function.The pathological changes in these patients is general heavier, more performance, interstitial fibrosis and vascular sclerosis.The patients with progressive IgAN are not insensitive to glucocorticoid.They often suffered from proteinuria(>1g/d)or less than25%of reduction of proteinuria after the application of glucocorticoid for more than12weeks. Therefore, for these patients, application of ACEI and (or) ARB and glucocorticoid combined with an immunosuppressant in advocated.Cyclosporine A,a potent, highly selective immunosuppressant,has been widely used to treat patients with organ transplantation and autoimmune diseases.Compared with other immunosuppressive agents, CsA selectively acts on T lymphocytes without affecting bone marrow myeloid and erythoid cells. Many clinical studies have indicated tha CsA has good clinical efficacy in the treatment of minimal change nephrosis, focal segmental glomerulosclerosis,as well as idiopathic membranous nephropathy induced nephrotic syndrome. However, its application in the treatment of progressive IgAN is rarely reported.Based on the present status of the research, we designed the prospective, controlled clinical studies to explore the clinical efficacy and safety of joint treatment with CsA and medium/low-dose prednisone in patients with progressive IgAN in order to provide a theroretical evidence for clinical treatment on the progressive IgAN.Objective:1. To explore the clinical efficancy of small dose of CsA and prednisone on pressive IgAN.2. To explore the clinical efficancy of prednisone alone on pressive IgAN.3. To compare the difference of clinical efficancy between CsA combined with medium/low dose of prednisone and big dosage of prednisone alone.on pressive IgAN. Methods:Subject:The study sample was drawn from the inpatients in Department of Nephrology in Taian Central Hospital from June2010to May2012who were proved to be IgAN by renal biopsy with Lee’s Grade III-V.96patients including44females and52males were enrolled in the present study.Methods:A total of96inpatients who met the criteria were enrolled in a prospective controlled clinical study.They were assigned into two groups,CsA group and steroid group.Patients in the CsA group were initially given either0.6-0.8mg/kg/day prednisone(maximum40mg/day) plus3mg/kg/day CsA.Other patients in the steroid group were given lmg/kg/day prednisone(maximum60mg/day) alone. During the therapy,the dose of prednisone was reduced in both groups and the dose of CsA was gradually tailed off over the first3months and maintained at2mg/kg/day in the CsA group. Prednisone was given to patients in the CsA group every moring (0.6-0.8mg/kg/day, maximum40mg/day) for6-8weeks. The dose was the reduced by5mg every2weeks to10mg/day. Patients in the steroid group were given prednisone (1.0mg/kg/day maximum,60mg/day) every morning for8-12weeks. The dose was then gradually reduced by5mg every2weeks to20mg/day, and then by2.5mg every2weeks to10mg/day. This was the maintenance dose for1year. The plasma levels of urinary protein excretion(24hUPr), fasting blood glucose(FBG),total cholesterol(TC), triglyceride(TG), serum creatinine(Scr), blood uric acid (UC) were detected by automatic biochemical analyzer (OlympusAU5400), respectively. The glomerular filtration rate (eGFR) was detected by MDRD fomula. And the clinical efficacy and side effects of CsA were assayed.Results1.The characteristics of the participants.Patients in the two groups had similar baseline demographic,clinical, and laboratory characteristics (Table1). Their baseline sex and age distributions were similar. Their systolic, diastolic, and mean blood pressure showed no significant differences. The number of patients with blood pressure higher than140/90mmHg at baseline was also similar in the two groups:10(20.8%) in the steroid group and12(25%) in the CsA group (p>0.05). The mean proteinuria values at baseline were2.01±0.8g/day (range:1.03-3.47g/day) in the steroid group and2.07±0.9g/day (range:1.11-3.36g/day) in the CsA group(p>0.05). Lee’s classification at the time of biopsy was III, IV, and V in36patients, eight patients, and four patients, respectively, in the steroid group and in32patients,10patients, and six patients, respectively, in the CsA group.Renal function, estimated by Scr and eGFR, was similar in the two groups. Information in Table1also suggested no significant differences in serum albumin, uric acid,cholesterol, triglyceride, and fasting blood glucose between the two groups.2.Primary outcomes1) Compariation of the biochemical index after treatment between the two groups There was a marked difference in urinary protein excretion and serum albumin between different times and groups by repeated measure with analysis of variance. However, as shown in Table2, Scr, serum uric acid, mean arterial pressure, serum cholesterol, serum triglyceride, fasting blood glucose, and eGFR did not change significantly from baseline to the end of the study in both groups. For patients in the CsA group, urinary protein excretion decreased significantly from2.07±0.9g/day to1.22±0.5g/day after1month of treatment, and proteinuria was reduced to0.53±0.4g/day (p<0.01) after12months of follow-up. Similar outcomes were also observed in patients in the steroid group. In addition, proteinuria differed significantly between the two groups after2months and6months of therapy (p<0.05), but not after12months of therapy. Serum albumin concentration increased significantly after2months of treatment with CsA combined with prednisone. Compared with the steroid group, serum albumin increased significantly after2el2months of combined therapy, and these changes were more significant after12months of therapy. Although serum albumin level also increased in patients treated with prednisone alone, this increase did not reach statistical significance. The time of action time for CsA was21.3±6.7days. Serum CsA concentration was102.5±55.1ng/mL in patients who reached complete remission and had an average CsA dose of2.64±0.57 mg/kg/day. Despite the satisfactory changes in serum albumin concentration and urinary protein excretion, we noticed no improvement of renal function or alteration in renal creatinine concentration during combined treatment with CsA and steroid.2) the clinical efficacy of the two treatmentsComplete remission occurred in12.5%,37.5%,41.7%, and52.1%patients after1month,2months,6months, and12months of combined treatment with CsA and steroid, respectively. Although the efficacy of the two treatments did not differ significantly after6months, it differed significantly after12months. In addition, the complete remission rate of patients in the CsA group was significantly higher than that of patients in the steroid group after2months of treatment (p<0.05or p<0.01).3) the clinical efficacy of the two treatments for IgAN patients with different Lee’s GradePatients with Lee’s Grade III in the CsA group had a CR rate of56.25%and PR+CR rate of100%, which were significantly higher than those of patients with Lee’s Grade III in the steroid group (p<0.05). The remission rates of patients with Lee’s Grade IV and V IgAN were similar between the two groups (p>0.05). In addition, the remission rate of patients with Lee’s Grade III IgAN in the CsA group was significantly higher than that of patients with Lee’s Grades IV and V in the same group (p<0.05).4) ComplicationsSeveral complications were observed in patients in the CsA group.(1) Hypertension was found in four patients, who were treated with antihypertensive therapy.(2) Liver damage was found in three patients, who were successfully managed by adjusting blood CsA concentration.(3) Overgrowth of body hair and gingiva were observed in nine patients and five patients, respectively. These symptoms disappeared after tapering off the CsA dose. No infection, leukopenia, renal impairment, hair loss, or other adverse reactions were found. In the steroid group, six patients had infection, five patients had hypertension, and eight patients had abnormal blood glucose. They all recovered after appropriate therapies. All patients in the steroid group completed the trial. Two patients were lost to follow-up after3months and4months treatment, respectively, and two participants stopped using CsA after6months of follow-up due to no clinical improvement.Conclusion1. CsA combined with medium/low dose of prednisone can be effective in reducing the level of urinary protein excretion and increase the level of serum albumin.2. Compared with prednisone alone,the therapy of combination of CsA and prednisone will more effectively relieve the progress of IgAN.3. To Lee’s Grade III of IgAN, higher clinial remission will be got in the combination of CsA and prednisone than prednisone alone.4. There is no difference of clinical remission in Lee’s Grade IV and V of IgAN compared the combination therapy with prednisone alone. BackgroundIgA nephropathy is the most common type of primary glomerular disease in the world[1]. It was also the the most common type of the glomerularnephritis in China. The incidence is about20-45%. It has been believed to be a kind of disease with a good progress and a good prognosis.But after about forty years of clinical observation, people gradually realize that it is no longer a benign disease it has been believed. IgA nephropathy has been recognized not only to be the most common type of the primary glomerular disease but also the most common reason that leading to renal failure.Some data showed that about a half patients progress into ESRD.Diagnosis of IgA nephropathy relies on renal biopsy. It was comfirmed by immunofluorescence. As to monitor the pathological changes, patients need accept repeated renal biopsy. The renal biopsy is a risk of invasive examination. The patient is not consent to accept repeated renal biopsy. Therefore it is a goal to doctors to look for a reliable method without traumatic to monitor the renal pathological changes. In recent years, the level of some cytokines or inflammatory factors changed in the blood or urine during the process of the renal disease.The monocytechemotactic protein in the urine (MCP-1), interleukin-6(IL-6)/endothelialcell growth factor, kidney injury molecule (KM)-1, interleukin-8(IL-8) and transforming growth factor beta1(TGF-beta1) played an important role in the assessment of tubule interstitial injury, pathological grading, kidney damage, prognosis and the effect of the medicine in IgA nephropathy. But the study is not comprehensive and meticulous. Further study is needed to looking for one or several kinds of cytokines which can comprehensively assess the condition and progress of IgA nephropathy and sensitivity to drugs.IL-18is a new kind of proinflammatory cytokine discovered in recent years. It was produced produced by the activated of monocyte macrophages.It stimulate the body to produce TNF-a,IL-8, NO and many kinds of inflammatory factors which directly involved in the occurrence of immune renal injury[7]. Domestic and foreign scholars put forward the IL-18play a decisive role in the pathogenesis and disease progression of kidney disease such as lupus nephritis and nephrotic syndrome, et al. However, few data showed the changes of the level of IL-18in IgA nephropathy.Cell adhesion molecules (inter cellular cell adhesion molecule-1ICAM-1)is a member of the immunoglobulin super family. When the body is subjected to external stimuli or stress response, some inflammatory factors including IL-1, TNF-a and IFN-r can up regulate ICAM-1. White cells are activated, morphological changes, enhancement and the binding capacity of ICAM-1. At the same time, ICAM-1binding with corresponding receptors, the endothelial cell activation, so as to promote white blood cells, inflammatory cells, tumor cells and endothelial cellsadhesion to move. And then stimulate a series of reaction such as intercellular signal transduction, inflammation, immune response, angiogenesis, tumor metastasis and other pathological and physiological process. Up to date, few research about ICAM-1on progressive IgA nephropathy was done.In our study, we took a method of enzyme linked immunosorbent assay(ELISA) to determine the serum levels of IL-18, ICAM-1at the beginning and the end of the experiment to explore the significance of the two factors on IgA nephropathy and the mechanisms of CsA.Objective:1,To explore the effect of cyclosporine A combined medium/lowdose of prednisone on IL-18and ICAM-1of progressive IgA nephropathy.2, To explore the effect of prednisone on IL-18and ICAM-1of progressive IgA nephropathy;3,To compare the difference of IL-18and ICAM-1in two groups4,To explore the possible mechanism of medicine on progressive IgA nephropathy;Method:All patients in cyclosporine A group and the steroid group were selected as the objects.46healthy person were seleted as the normal control group.All objects were informed consent and signed the consent form. ELISA was use to detect the serum level of ICAM-1, IL-18in all objects at the beginning of the study and at the end of 12months of the experiment. The same method of the therapy to the patients is as before that was in the first section.Results:Compared with the control group,the serum level of IL-18and ICAM-1in CsA group and in steroid group is higer obveriously. The level of the factors decrease significantly after the therapy, but still higher than that in the control group(P<0.05). Compared with the steroid group, the level of the factors in the CsA group was decreased significantly. The level of IL-18and ICAM-1of patients in complete remission group was significantly lower than that in the partial remission group and invalid group. Furthermore, compared with the invalid group, the level in partial remission group was decreased significantly((P<0.05). Through the analysis of correlation showed that IL-18was positively associated with urinary protein, serum creatinine level, and negatively correlated with serum albumin and glomerular filtration rate. A positive relation between ICAM-1and urine protein, serum creatinine and negative relation with glomerular filtration rate.Conclusion:1. The serum IL-18and ICAM-1in progressive IgA nephropathy were significantly higher than those of healthy person. IL-18concentration were positively correlated with urinary protein, serum creatinine but negatively correlated with serum albumin and eGFR. ICAM-1concentration werepositively correlated with urinary protein and serum creatinine but negatively correlated with eGFR.2. The heavier the pathological changes,the higher the serum IL-18、ICAM-1were.3. The possible mechanism of the cyclosporine A combined with prednisone on progresssiv IgA nephropathy may be achieved by lowering the serum levels of IL-18and ICAM-1.4. IL-18, ICAM-1can be used as the evaluation of the condition assessment and the therapeutic effect and prognosis.