The Clinical And Pathological Characteristics Of Renal Small Artery Remodeling In IgA Nephropathy And The Effect Of Mycophenolate Mofetil

Background and Objective IgA nephropathy(IgAN)is the most common primary glomerulonephritis worldwide.During the past 40 years,nephrologists around the world have conducted extensive research and numerous reports,but the mechanism of pathogenesis and progression of IgAN is not yet fully understood.IgAN still remains a major cause of end-stage renal disease.Past researches have focused on the glomerular and tubulointerstitial lesions,which have made important progress. However,a very important aspect of the renal disease that compensated and decompensated remodeling may occur in the renal small arteries and arterioles,has long been neglected.The renal artery remodeling is common pathological change of IgAN,and is closely related to glomerulosclerosis and renal fibrosis.This study was to investigate the clinical and pathological features of renal small artery-arteriole (RA)remodeling of IgAN by morphological methods and the efficacy and safety of Mycophenolate Mofetil in the treatment of IgAN combined with RA lesions.Methods 1)From April 1997 to May 2007,firstly we screened renal biopsy confirmed IgAN patients and selected 29 cases of IgAN combined with malignant hypertension(IgAN-MHT);then screened 108 patients of essential malignant hypertension(E-MHT)with renal damage and selected 23 cases of E-MHT.We evaluated 785 afferent arteries,211 interlobar arteries and 11 arcuate arteries. According to the diameter of the vessel cross section and involvement of vascular smooth muscle layers,the affected arteries were divided into small arteries and arterioles.According to the pathological characteristics,RA changes were divided into four types:vascular occlusion,proliferative endarteritis,media thickening and hyalinosis/fibrinoid necrosis.Then a semi-quantitative scoring system of RA remodeling was established.Firstly,the clinical,pathological and prognostic features of RA were evaluated based on IgAN-MHT,which was followed by a comparative study of IgAN-MHT and E-MHT to establish a differential diagnosis formula and a prognosis formula for clinical guide.2)The clinical and pathological data of 757 cases with IgA nephropathy between January 2003 and December 2006 were analyzed.Glomerular,tubulointerstitial,renal arteriosclerosis(RAS)lesions were scored by semi-quantitative evaluation.3)A randomized controlled clinical trial was conducted in 120 patients with IgAN diagnosed by renal biopsy as Lee SMK's gradeⅢ～Ⅴwith area of interstitial inflammation over 25%.After 3 months of run-in phase,109 patients with 24h proteinuria excretion of 1.0 to 3.5g/d and serum creatine level(Scr)less than 300umol/L were randomly assigned to receive conventional therapy with MMF (MMF group,55 patients)or without MMF(Control group,54 patients).Among these 109 cases there were 96 patients with RAS.Renal survival was calculated by Kaplan-Meier survival analysis and risk factors of progression were analyzed by using univariate and multi-variate Cox regression models.The endpoint was doubling the baseline serum creatinine or the incidence of end-stage renal disease.Results 1)1.4%of all the IgA nephropathy patients presented malignant hypertension.The common clinical features were renal failure(100%), hyperuricacidemia(62.7%),and hypertriglyceridemia(51.7%).The average amount of urine protein excretion was 2.8g/d.The most common pathological changes were moderate mesangial proliferation,severe global sclerosis,severe interstitial inflammation and severe interstitial-tubular fibrosis.The small arteries(arcuate arteries and interlobular arteries)and arterioles(afferent arterioles)were both involved in IgAN-MHT.The characteristic lesions of RA included vascular occlusion, media thickening,proliferative endarteritis(onionskin lesion,musculomucoid intimal hyperplasia),hyaline arteriosclerosis,but mainly vascular occlusion(86.2%).The analysis of relationships among vascular lesions and clinical parameters showed that arteriole lesions were negatively related with age and total protein level;vascular occlusion was positively related with uric acid level.The average follow-up period was 21.1 moths.14 patients reached the endpoint.The arteriole lesions were the main independent risk factors for the progression of IgAN-MHT(RR=10.21, 95%CI=1.16～89.67).2)IgAN-MHT and E-MHT may both affect the renal artery(arcuate artery and interlobular artery)and arterioles(mainly afferent artery),but the proliferative endarteritis and hyalinosis of E-MHT were more serious.By the application of multiple linear regression analysis,serum IgG,IgA,24-hour urine protein can be used as the basis for the differential diagnosis of the two groups.The following was the formula for the differential diagnosis:Y=-1.129-0.005*IgG(mg/dl)+0.017*IgA(mg/dl)+0.968*urine protein excretion(g/d). IgAN-MHT group had a worse outcome than E-MHT group.3)IgAN had a higher incidence of RAS.Age,body mass index,history,the incidence of hypertension,renal failure,serum triglycerides,uric acid,proteinuria were all related to RAS.With the degree of RAS worsing,the Lee SMK grade increased,the scores of hypercellularity,glomerularsclerosis,interstitial and tubular lesions all increased gradually.RAS,fibrosis,glomerularsclerosis,interstitial infiltration of inflammatory cells were all independent risk factors of GFR＜60ml/min/1.73m2.Age, hypertension,glomerularsclerosis,interstitial infiltration of inflammatory cells are the relevant factors of RAS lesions.4)For the IgAN patients combined with RA lesions,MMF group has a better outome than control group.24-hour urine protein and serum creatinine level were associated with poor prognosis of IgAN with RA lesions,but MMF treatment was protective factors with good tolerance.The outcome of IgAN combined with the worst RA lesions was worst.Conclusions 1)Intrarenal artery occlusion was the most common lesions of vascular remodeling in IgAN-MHT.Intrarenal arterioles lesions were major risk factors of IgAN-MHT.2)The IRV of E-MHT Group was more serious.IgAN-MHT group had a worse renal outcome than E-MHT.3)RAS had a high incidence in IgAN and were closely related to a number of clinical,pathological and prognostic indicators.4)MMF treatment can effectively improve the outcome of IgAN associated with IRV and were well tolerated.