| Transplant glomerulopathy(TG)is a group of disorders that are characterized histopathologically by glomerular capillary loop duplication with pauci-immunocomplex deposition.Cardinal clinical symptoms of TG included proteinuria,serum creatinine elevation and hypertension.It is the leading cause of long-term allograft failure.Although chronic and repetitive endothelial injury is conceived to be the contributing factor,the exact pathomechanisms of TG remains elusive.Chronic active antibody-mediated rejection(cABMR)is the predominant etiology for TG,with alloantibody,T cell-mediated rejection(TCMR),thrombotic microangiopathy(TMA)and hepatitis C virus(HCV)infection have all been reported to cause TG.Domestic and exotic studies regarding TG are scarce,with limitations of small sample size and short follow-up time.We,in the present study,investigated the clinicopathologic features and factors associated with TG to elucidate independent predisposing factors that affect TG survival by taking advantage of large sample size of TG in our center.Urinary retinol-binding protein(urRBP)is a non-invasive biomarker of proximal tubular injury and associated with the prognoses of a variety of glomerular diseases.Routinely measured urRBP in our center could enable us to analyze its association with TG survival,with the aim of clarifying the predictive value of urRBP.TG frequently co-existed with Immunoglobulin A nephrology(IgAN)clinically,which could possibly attributed to the fact that both presented long after kidney transplantation.To the best of my knowledge,coexistence of TG and IgAN have not been previously reported.This study explored the clinicopathologic features and prognosis of patients with both TG and IgAN to improve the diagnosis and treatment.Bortezomib is the primary treatment for TG,given that cABMR accounts for the majority of TG.Although several studies reported promising treatment efficacy of bortezomib for early allograft antibody-mediated rejection(ABMR),it remains controversial regarding the effect of bortezomib for late cABMR.Therefore,we studied the efficacy and safety of bortezomib for cABMR in the present investigation.Part 1.Clinicopathological features and renal prognosis of transplant glomerulopathy in a Chinese CohortObjective:TG represents a major cause of long-term allograft failure and is the leading cause of overall post-transplant proteinuria.The extent to which histopathologic features predicts prognostication is uncertain.Methods:A single-center retrospective cohort with biopsy-proven TG was investigated.Renal biopsies were scored according to Banff 2017.The primary outcome was death-censored graft failure defined as return to dialysis or estimated glomerular filtration rate decreased to<15 mlˇmin-1(1.73m2)-1.The prognostic significance of clinical and histopathologic parameters were determined using Cox proportional hazards models.Results:Data from 180 cases were available for analysis with a median follow-up of 5.0(2.6-8.2)years.In multivariable models,ci+ct score(hazard ratio[HR]3.1;95%confidence interval[CI]2.0 to 4.9),cg score(HR 1.7;95%CI 1.1 to 2.8),eGFR(HR 2.1;95%CI 1.4 to 3.2)and proteinuria(HR 2.4;95%CI 1.6 to 3.7)were independent predictors of the primary outcome.The only significant pathologic factors for the severity of proteinuria were cg and g+ptc(adjusted R2=0.46)as determined by multivariable stepwise linear regression analysis.Conclusions:Severe ci+ct and cg at biopsy were predictors of unfavorable allograft prognosis in TG patients even after taking into consideration clinical characteristics.Histologic severity of cg and g+ptc were significantly associated with clinical proteinuria.Part 2.Urinary retinol-binding protein as clinical predictors of long-term allograft outcomes in transplant glomerulopathyObjective:We aimed to explored the associations between clinical parameters and long-term allograft outcomes in TG in a large retrospective cohort with long follow-up.Methods:Clinical and laboratory data at biopsy from 180 cases of TG with an eGFR>15 mlˇmin-1ˇ(1.73m2)-1 from January 2004 to December 2016 at our center were retrospectively analyzed.The main outcome of this study was initiation of replacement therapy or an eGFR declined to<15 mlˇmin-1ˇ(1.73m2)-1.Results:During a median follow-up of 5 years(interquartile range 2.6-8.2 years),117 cases(65.0%)achieved the combined event.In the Cox regression,urinary RBP,and urinary NAG were positively related to the risk of the main outcome.However,after adjustments for eGFR,proteinuria,anemia,and HCV infection,only urinary RBP(?2.85 vs.<2.85mg/L)(OR 2.13;95%CI 1.21-3.75,P=0.0091)remained as significant independent predictors of the main outcome.In addition,correlation analysis between urRBP and urNAG and interstitial fibrosis/tubule atrophy(Banff ci+ct)revealed that urRBP was significantly associated with ci+ct(p=0.61,P<0.001),while urNAG was not(?=0.24,P=0.06).Conclusion:Urinary RBP is independently related to the risk of allograft progression in TG patients.Whether this biomarker has a role in the setting of TG should be further investigated.Part 3.Clinicopathologic features and prognosis of patients with IgA nephropathy superimposed on transplant glomerulopathyObjective:To observe the clinicopathologic features and prognostic of patients with IgAN superimposed on TG(TG+IgAN).Methods:Electronic medical records of Jinling Hospital were searched for TG+IgAN that was diagnosed during January 2004 to December 2016.Clinicopathologic features and prognoses information were retrieved and analyzed.The primary outcome was initiation of replacement therapy or an eGFR declined to<15 ml min-1ˇ(1.73m2)-1.Results:A total of 49 patients with pathologically confirmed TG+IgAN were enrolled in this study.The median time from renal transplantation to allograft biopsy was 85 months.There were 131 patients with TG in the control group.There was no statistical difference in the age,gender,and immunosuppressive regimen during renal biopsy in the two groups.In TG+IgAN patients,the median serum creatinine level was 1.98 mg/dl,the median urinary protein was 1.45 g/24h,and 16.3%of the patients had nephrotic range proteinuria(proteinuriria?3.5),the incidence of microscopic hematuria was 40.8%,and the average hemoglobin was 10.5 g/dl.In terms of pathology,the degree of glomerular mesangial matrix hyperplasia in the TG+IgAN group was significantly heavier compared with TG group(P=0.004),and the degree of hyaline degeneration of the small arteries was lighter(P=0.043).There was no significant difference in the of interstitial inflammation(i),tubulitis(t),glomerulitis(g),peritubular capillaritis(ptc)and intimal arteritis(v).Calculated by Kaplan-Meier method,the median survival time of 49 patients with TG+IgAN was 36.9 months,and there was no difference in survival rate of allografts compared with TG group.Conclusions:Compared with TG patients without IgA,TG+IgAN patients had higher incidence of microscopic hematuria,more severe glomerular mesangial matrix hyperplasia,and no significant differences in other clinicopathological features.The prognosis of TG+IgAN patients was not significantly different from those without IgAN.Part 4.Bortezomib in chronic active antibody-mediated rejection:a single center experienceObjective:To evaluate the efficacy and safety of bortezomib in kidney transplant recipients with cABMR.Methods:A retrospective study wad conducted in patients who met the Banff 2017 criteria for cABMR from January 2004 to July 2017 in Jinling Hospital.Identified cABMR patients were dichotomized to bortezomib group and control group with a 1:1 match using the propensity score matching method.The primary outcome was initiation of replacement therapy or an eGFR declined to<15 ml min-1ˇ(1.73m2)-1.The prognosis and adverse reactions of the two groups were analyzed and evaluated.Results:A total of 136 patients with cABMR were included in the study,including 29 patients in bortezomib group and 97 patients in control group.There were no significant differences with regard to clinical data such as age,sex ratio,immunosuppressive regimen,allograft age,serum creatinine,eGFR,urine protein,serum albumin,hemoglobin,and HCV positive rate between the two groups(all P>0.05).There were no significant differences in Banff scores between the two groups(g,i,t,v,ah,mm,ci,ct,cv,ptc,c4d)(all P>0.05).The median survival for bortezomib group and control group was 40.7 months and 36.9 months respectively.No statistically significant difference in graft survival between the two groups was observed(P=0.83),even after propensity score adjustment(P=0.29).The incidence of nausea,diarrhea and thrombocytopenia in bortezomib group was higher than those in control group(P<0.05).Conclusions:Bortezomib does not seem to improve the prognosis of cABMR while is associated with higher incidence of adverse reactions. |
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