Qiquan Sun

De novo development of circulating anti-endothelial cell antibodies rather than pre-existing antibodies is associated with post-transplant allograft rejection

Anti-endothelial cell antibodies (AECAs) are thought to be involved in the development of renal allograft rejection. To explore this further, we determine whether AECAs play a role both in predicting the incidence of allograft rejection and long-term outcomes by analysis of serum samples from 226 renal allograft recipients for AECAs pre- and post-transplant. Surprisingly, the presence of pre-existing AECAs was not associated with either an increased risk of rejection or a detrimental impact on recipient/graft survival. Subsequent de novo AECAs, however, were associated with a significantly increased risk of early acute rejection. Moreover, these rejections tended to be more severe with a significantly increased incidence of both steroid-resistant and multiple episodes of acute rejection. The acute rejections associated with de novo AECAs did not correlate with C4d deposition at the time of renal biopsy, but did demonstrate an association with the presence of glomerulitis and peritubular capillary inflammation. Significantly more patients with de novo AECAs developed graft dysfunction. Thus, our prospective study suggests the emergence of de novo AECAs is associated with transplant rejection that may lead to allograft dysfunction.

Effect of CYP3A5 Genotype on Renal Allograft Recipients Treated With Tacrolimus

OBJECTIVE Tacrolimus concentrations are associated with CYP3A5 genotype. The purpose of this study was to evaluate the outcomes and drug concentrations/doses among a posttransplant population with various CYP3A5 genotypes within 12 months. METHODS Sixty seven kidney recipients receiving immunosuppression with tacrolimus + mycophenolate mofetil + prednisolone were grouped according to their CYP3A5 genotypes (*1/*1; *1/*3; *3/*3). The initial dose of tacrolimus (0.15 mg/kg/d) was adjusted according to achieve a target therapeutic window. All patients underwent a protocol biopsy at 1 month posttransplantation. We assayed serum creatinine and tacrolimus blood trough concentrations to calculate the concentration per dosage during follow-up. We also investigated the incidence of acute rejection episodes and the nephrotoxicity of tacrolimus according to the renal biopsy. RESULTS There was no significant difference among serum creatinine concentrations. Tracrolimus blood concentrations showed a significant difference at day 7 and 1 month with no significant difference at 3, 6, or 12 months among the three groups. The CYP3A5*3/*3 group showed the largest concentration per dosage (C/D) and CYP3A5*1/*1, the smallest C/D. There was a significant difference among the three groups. The occurrence of an acute rejection episode within 3 months showed a significant difference among the three groups but not from 3 to 12 months after transplantation. Nephrotoxicity was greatest among the CYP3A5*3/*3 group. CONCLUSION CYP3A5 influenced the blood concentrations of tacrolimus. Our study suggested to choose the initial dosage according to the CYP3A5 genotype to obtain a better outcome and reduce the incidences of acute rejection episodes and nephrotoxicity.

Circulating Anti-endothelial Cell Antibodies Are Associated with Poor Outcome in Renal Allograft Recipients with Acute Rejection

BACKGROUND AND OBJECTIVES Anti-endothelial cell antibody (AECA) can cause hyperacute rejection and immediate graft loss after renal transplantation; however, its prevalence and significance during acute rejection are unknown. Previous studies suggested that AECA may be detected in recipients with acute vascular rejection (AVR). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We retrospectively analyzed 653 cadaveric renal transplant recipients; circulating AECA was positive in 13 of 47 cases of AVR; another two cases of hyperacute rejection also had detectable AECA. Twenty-six cases of AVR without circulating AECA were selected as controls. RESULTS AECA-positive AVR usually occurred within 1 yr after transplantation and mostly was resistant to steroid treatment. Compared with the control group, the AECA-positive group was associated with a significantly lower 1-yr graft survival rate (46.7 versus 80.5%; P = 0.038), and more patients had histologic interstitial plasma cell infiltration (53.8 versus 11.5%; P = 0.005). More patients with AECA-positive AVR experienced another one or more episodes of acute rejection during 1 yr of follow-up (75.0 versus 13.0%; P = 0.003). AECA-positive AVR with C4d deposition in peri-tubular capillaries had the worst outcome in this cohort, and it accounted for 38.5% graft loss in AVR. AECA in turn accounted for 71.4% of graft loss in C4d(+) AVR. CONCLUSIONS Circulating AECA is associated with poor outcome in renal allograft recipients with acute rejection and should be monitored regularly.

An aggressive systematic strategy for acute respiratory distress syndrome caused by severe pneumonia after renal transplantation

Acute respiratory distress syndrome (ARDS) caused by pneumonia after renal transplantation was usually associated with overimmunosuppression and high mortality rate. We evaluated the efficacy of an aggressive systemic protocol including strategies improving bodys immune function. Twenty‐one recipients were enrolled in this study. Patients were subjected to a protocol including (i) withdrawal of most immunosuppressants, (ii) early use of immunoenhancers and continuous renal replacement therapy (CRRT), (iii) reasonable administration of antibiotic regimen, (iv) prompt mechanical ventilating strategy, and (v) adequate nutrition. Immunosuppressants were adjusted according to the value of CD4+, CD8+T lymphocytes in peripheral blood. CRRT was conducted at once when patients were admitted to the intensive care unit (ICU), regardless the graft function. Thirteen (62%) survived and eight died finally. This is a high survival rate for this kind of patients. Eighteen patients had received thymosin treatment. All patients who survived experienced renal allograft dysfunction during CRRT, but when CRRT stopped, the function of all grafts gradually recovered. No acute rejection episodes were documented during the treatment. The aggressive systemic protocol including strategies improving the bodys immune function and CRRT can improve the outcome of patients with ARDS after renal transplantation. The count of CD4+, CD8+T lymphocytes of peripheral blood is useful in the adjustment of immunosuppressants and the prediction of patient outcome.

Detectable circulating antiendothelial cell antibodies in renal allograft recipients with C4d-positive acute rejection: a report of three cases.

It is suggested that non-HLA endothelial antigens may also cause C4d-positive acute rejection, but this is very rare. We report on three renal allograft recipients who developed C4d-positive acute rejection with detectable circulating antiendothelial cell antibodies (AECAs). All patients had severe dialysis-dependent graft dysfunction. Histologic manifestations include neutrophils infiltration on peritubular capillaries and glomeruli. Endoarteritis can be seen in all the patients. Two patients lost grafts after the rescue therapy including immunoadsorption, mycophenolate mofetil with or without tacrolimus. The titer variation of AECAs might be associated with the graft outcome. In patients those who lost grafts, AECAs titer increased from 1:10 to 1:80 in one patient, and was kept positive during the treatment in the other patient. In the recovered patient, however, the titer became negative from 1:40. From our report, it appears that persisting circulating AECAs during the rescue treatment of C4d-positive acute rejection may be associated with a poor outcome.

Predominance of Intraglomerular T-bet or GATA3 May Determine Mechanism of Transplant Rejection

The transcription factors T-bet and GATA3 determine the differentiation of helper T cells into Th1 or Th2 cells, respectively. An altered ratio of their relative expression promotes the pathogenesis of certain immunological diseases, but whether this may also contribute to the pathogenesis of antibody-mediated rejection (ABMR) versus T cell-mediated rejection (TCMR) is unknown. Here, we characterized the intragraft expression of T-bet and GATA3 and determined the correlation of their levels with the presence of typical lesions of ABMR and TCMR. We found a predominant intraglomerular expression of T-bet in patients with ABMR, which was distinct from that in patients with TCMR. In ABMR, interstitial T-bet expression was typically located in peritubular capillaries, although the overall quantity of interstitial T-bet was less than that observed in TCMR. The expression of intraglomerular T-bet correlated with infiltration of CD4+ and CD8+ lymphocytes, which express T-bet, as well as intraglomerular CD68+ monocyte/macrophages, which do not express T-bet. The predominance of intraglomerular T-bet expression relative to GATA3 expression associated with poor response to treatment with bolus steroid. In summary, predominance of intraglomerular T-bet expression correlates with antibody-mediated rejection and resistance to steroid treatment.

Endothelial injury in transplant glomerulopathy is correlated with transcription factor T-bet expression

Transplant glomerulopathy is an important cause of late graft loss. Inflammatory lesions including glomerulitis and peritubular capillaritis, suggestive of endothelial injury, are prominent in this condition but the mechanism underlying this inflammation remains unclear. Here we measured the expression of T-bet (a member of the T-box family of transcription factors regulating Th1 lineage commitment) and its relationship with inflammation in 70 patients with transplant glomerulopathy. Within this cohort, 32 patients were diagnosed with transplant glomerulopathy, 23 with interstitial fibrosis/tubular atrophy, and 15 with stable grafts. There was a significant increase in T-bet expression in both glomerular and peritubular capillaries of the transplant glomerulopathy group. This expression was strongly correlated with CD4(+), CD8(+), and CD68(+) cell infiltration within glomerular and peritubular capillaries. The expression of GATA3, a Th2 regulator, was rarely found in the transplant glomerulopathy group. Transplant glomerulopathy was associated with diffuse peritubular capillary dilation without reduced capillary density. Moreover, the degree of capillary dilation was significantly correlated with the number of infiltrating CD68(+) cells. Since endothelial injury is a typical lesion that follows alloantibody reactivity, our results suggest that T-bet is involved in the pathogenesis of this glomerulopathy.

Capillary Dilation and Rarefaction Are Correlated with Intracapillary Inflammation in Antibody-Mediated Rejection

Antibody-mediated rejection (ABMR) remains one of the major causes of graft loss after renal transplantation. It is dominated by endothelial damage in microcirculation. Clarifying the mechanism of microcirculating damage is obviously a key step to understand the pathogenesis of ABMR. Here we characterized capillary variation in ABMR and its possible mechanisms. Compared with T cell-mediated rejection and stable grafts, there was a significant dilation and rarefaction in peritubular capillaries (PTCs) of the ABMR group; Image-Pro Plus revealed a significantly larger intra-PTC area. Interestingly, the dilation of PTCs was strongly correlated with the intra-PTC cell counting. Moreover, peritubular capillary inflammation is correlated with in situ T-bet expression, and there was a good correlation between the intra-PTC expression of T-bet and the PTC diameter. HIF-1α up-regulation could be observed in ABMR but it was not necessary for capillary dilation. In general, ABMR is characterized with early capillary dilation and rarefaction; our data confirmed that the dilation is strongly correlated with intracapillary inflammation, which in turn is correlated with in situ T-bet expression. T-bet plays an important role in the development of microcirculating injury, and thus it is a potential target for the treatment of ABMR.

The Prevalence of Immunologic Injury in Renal Allograft Recipients with De Novo Proteinuria

Post-transplant proteinuria is a common complication after renal transplantation; it is associated with reduced graft and recipient survival. However, the prevalence of histological causes has been reported with considerable variation. A clinico-pathological re-evaluation of post-transplant proteinuria is necessary, especially after dismissal of the term “chronic allograft nephropathy,” which had been considered to be an important cause of proteinuria. Moreover, urinary protein can promote interstitial inflammation in native kidney, whether this occurs in renal allograft remains unknown. Factors that affect the graft outcome in patients with proteinuria also remain unclear. Here we collected 98 cases of renal allograft recipients who developed proteinuria after transplant, histological features were characterized using Banff scoring system. Cox proportional hazard regression models were used for graft survival predictors. We found that transplant glomerulopathy was the leading (40.8%) cause of post-transplant proteinuria. Immunological causes, including transplant glomerulopathy, acute rejection, and chronic rejection accounted for the majority of all pathological causes of proteinuria. Nevertheless, almost all patients that developed proteinuria had immunological lesions in the graft, especially for interstitial inflammation. Intraglomerular C3 deposition was unexpectedly correlated with the severity of proteinuria. Moreover, the severity of interstitial inflammation was an independent risk factor for graft loss, while high level of hemoglobin was a protective factor for graft survival. This study revealed a predominance of immunological parameters in renal allografts with post-transplant proteinuria. These parameters not only correlate with the severity of proteinuria, but also with the outcome of the graft.

Observation of Efficacy and Safety of Converting the Calcineurin Inhibitor to Sirolimus in Renal Transplant Recipients With Chronic Allograft Nephropathy

OBJECTIVE The objective of this study was to evaluate the efficacy and safety of converting from a calcineurin inhibitor (CNI) to sirolimus among renal transplant recipients with chronic allograft nephropathy (CAN). METHODS In 16 patients with CAN, substituted sirolimus for CsA or FK506 and observed the incidence of acute rejection and changes in serum creatinine, triglycerides, cholesterol, blood uric acid, and peripheral blood leukocyte/platelet counts within 12 months. All recipients underwent an allograft biopsy before conversion. The targeted sirolimus level was 4-8 ug/L. RESULTS After conversion to sirolimus, the creatinine level of 7 cases decreased and the efficacy rate was (43.8%). No acute rejection occurred during the follow-up. The cases with hypercholesteremia increased from 3 to 7 after conversion; hypertriglyceridemia increased from 3 to 5; leukopenia occurred in 2; subnormal platelet counts increased from 2 to 3; and hyperuricemia increased from 6 to 7. Meanwhile, the average level of peripheral blood leukocytes obviously decreased in the first month, the average peripheral blood cholesterol increased over 12 months, but the average content of peripheral blood platelets, triglyceride and blood uric acid failed to display as statistic difference. Eight patients showed C4d deposition in peritubular capillary in graft tissue before conversion, 7 cases of whom showed no improvement in renal function. In 6 cases there was no C4d deposition in peritubular capillary in graft tissue. Only 2 of 6 cases showed no improvement in renal function. There were 6 patients whose creatinine level was <2.48 mg/dL before conversion, and renal function in 5 of them improved in a year after conversion. In contrast, among 10 patients whose blood creatinine level was >2.48 mg/dL, only 2 cases improved. CONCLUSION It is safe for patients with CAN to use substitute sirolimus for CNI; the incidence of acute rejection did not increase. In this study, 43.8% of patients showed improved renal function. The main adverse reactions after conversion to sirolimus were hypercholesteremia and decreased peripheral blood leukocytes. The serum creatinine level and the deposition of C4d in peritubular capillary were important factors influencing therapeutic efficacy.