Xiaoguang Xu

De novo urothelial carcinoma in kidney transplantation patients with end-stage aristolochic acid nephropathy in China.

Introduction: Aristolochic acid contained in Chinese herbs has been proved to be nephrotoxic and carcinogenic. Immunosuppression is associated with an increased risk of developing malignancies. What will be the result if these two significant risk factors are concomitantly present in transplanted patients with aristolochic acid nephropathy (AAN)? Patients and Methods: A 2-center cohort of 1,612 renal transplant recipients was studied retrospectively from January 1998 to December 2006. We performed an evaluation of the database and review of the charts and pathology reports of these recipients. Results: Kidney transplantations were performed in 17 patients with AAN. Nine (52.9%) of these recipients developed urothelial carcinoma (UC), compared with a 0.46% prevalence of urinary tract tumors among kidney-transplanted patients in China. Eight cases (88.9%) involved the upper urinary tract (bilateral, 3 cases, 37.5%; unilateral, 5 cases, 62.5%). All patients underwent surgical treatment. Six patients (75%) had recurrence during the follow-up period. Three patients died within a mean of 20 months after tumor excision. Conclusions: The risk for UC is distinctly increased in patients with AAN after transplantation. Regular screening for early detection of malignancy is mandatory.

Characterisation of Tertiary Lymphoid Organs in Explanted Rejected Donor Kidneys

ABSTRACT Purpose: Tertiary lymphoid organs (TLOs) have been described within organ allografts, but whether they promote destructive or beneficial alloimmune responses remains controversial. This study aimed to characterize TLO distribution in human chronically rejected renal allografts and to explore their functions. Methods: A total of 29 explanted chronically rejected and 12 acutely rejected renal allografts were analyzed by immunohistochemistry. The distribution of TLOs, T cells, follicular dendritic cells, B cells, and follicular regulatory T (Tfr) cells, as well as Ki67, peripheral lymph node addressin (PNAd), podoplanin, AID, IL-17, IL-21, IL-10, and C4d expression were detected by immunohistochemistry. Correlations between lymphoid neogenesis and the expression of IL-17, IL-21, C4d, podoplanin, IL-10, and Foxp3 were evaluated. In addition, the duration of graft function was compared between allografts that harbored or lacked TLOs. Results: TLOs were detected in 27.6% of chronically rejected renal grafts, but they rarely had germinal centers. Lymphoid neogenesis negatively correlated with CXCR5 expression, and almost completely correlated with IL-17 expression. Those grafts that harbored a TLO functioned for an average of 5.98 years and those without a TLO lasted only about half as long with an average of 2.91 years. However, in grafts that harbored a TLO, Foxp3+ cells were comparitively less than those without a TLO. Foxp3+CXCR5+ Tfr cells and IL-10+ cells were rare in grafts, irrespective of the presence of a TLO. Conclusion: TLOs in chronically rejected kidney allografts may be an epiphenomenon of the inflammatory process that is related to graft duration.

Serum hematopoietic growth factors as diagnostic and prognostic markers of acute renal allograft rejection: A potential role for serum stem cell factor

OBJECTIVES Hematopoietic growth factors (HGFs) are proliferative and chemotactic agents for hematopoietic stem cells, although their functions on renal transplantation are rarely reported. This study aimed to investigate the association of HGFs with acute T cell-mediated renal rejection. EXPERIMENTAL DESIGN A cytokine bead array was used to analyze 10 HGFs in the sera of 32 patients with acute T cell-mediated renal allograft rejection before and during rejection and after rejection reversal. Stable renal allograft recipients (n=38) were also investigated. RESULTS Serum levels of stem cell factor (SCF), IL-3, flt3 ligand, G-CSF, M-CSF and GM-CSF were elevated during episodes of rejection compared with before and after rejection. Serum concentrations of SCF, G-CSF, flt3 ligand and IL-3 were significantly higher than in the absence of rejection. Moreover, serum SCF levels were significantly higher in patients before rejection versus stable controls. CONCLUSIONS HGFs are reported to be involved in acute T cell-mediated renal allograft rejection. A direct correlation was observed between SCF levels and the occurrence of acute renal allograft rejection which may represent an effective diagnostic and predictive biomarker for acute cellular renal allograft rejection.

IFN-γ-producing Th1-like regulatory T cells may limit acute cellular renal allograft rejection: Paradoxical post-transplantation effects of IFN-γ

PURPOSE IFN-γ is a protypical proinflammatory cytokine that plays a central role in inflammation and acute graft rejection. Accumulating evidence indicates that IFN-γ can exert previously unexpected immunoregulatory activities. However, little is known about the role of IFN-γ secreted by Th1-like regulatory T cells in human kidney transplantation. METHODS To determine the function of IFN-γ in acute T cell-mediated renal allograft rejection (ACR), we examined serum cytokine expression profiles in ACR patients by human cytokine multiplex immunoassay and analyzed the cellular origins of IFN-γ in peripheral blood and renal allograft biopsies from ACR cases and controls by flow cytometry and immunohistochemistry, respectively. RESULTS The results showed significant reduction in serum concentrations of Th1-inducing cytokines IL-12p70 and IFN-γ as well as Th2-related cytokine IL-4 in ACR patients compared with stable controls. However, levels of several Th1-, Th2- and Th17-related cytokines, such as IL-2, TNF-α, TNF-β, IL-12 (p40), IL-10, IL-15, IL-17, IL-21, and IL-23, as well as the frequencies of Th1 and Th17 cell, did not differ between ACR cases and stable controls. Moreover, we found the levels of IFN-γ were correlated with those of the anti-inflammatory factor, IL-1 receptor antagonist (IL-1Ra) in ACR. Notably, the Th1-like Treg cell-to-Foxp3- Th1 cell ratio was significantly lower in ACR patients compared with that in stable controls. In graft biopsies from ACR patients, Treg cells and Th1-like Treg cells were less abundant than those without ACR. CONCLUSIONS Our study indicates that IFN-γ secreted from Th1-like Treg cells negatively modulates ACR.

CD20 Expression in the Transplanted Kidney of Patients with Graft Loss and Transient Allograft Dysfunction

CD20 Expression in the Transplanted Kidney of Patients with Graft Loss and Transient Allograft Dysfunction This study aimed to explore the relationship between the infiltration of CD20+ B cells and the survival time of a renal allograft and to investigate the role of infiltrated B cells in the rejection of the renal allograft. A total of 40 patients with renal allograft loss due to refractory rejection and 20 patients with transient renal allograft dysfunction were recruited. Renal biopsy was done and CD20 expression was detected by immunohistochemistry. In addition, the survival time of the renal allograft was also obtained. The relationships between the CD20 expression and the survival time of the renal allograft and graft loss due to rejection were analyzed. The associations of gender, age and clinicopathogical types with the CD20 expression were also investigated. The proportion of patients positive for CD20 in the transplanted kidney was higher in patients receiving nephrectomy of the allograft due to rejection than in those with transient allograft dysfunction. The diffuse infiltration of CD20+ B cells was considered as positive staining. In 40 samples from patients with graft loss, 19 had diffuse infiltration of CD20+ B cells (47.5%). In 19 patients positive for CD20, hyperacute rejection was found in 1 patient, acute rejection in 5 and chronic rejection in 13. Statistical analysis showed the CD20 expression was not associated with the age and gender of donors and recipients, regimen for immunosuppressive treatment, cold/warm ischemia time and secondary transplantation. CD20+ B cell infiltration predicts a poor prognosis of patients with kidney transplantation and is one of the risk factors of graft loss. Ekspresija CD20 u Presałenom Bubregu Kod Pacijenata sa Gubitkom Grafta i Prolaznom Disfunkcijom Alografta Cilj ove studije bio je da se ispita odnos između infiltracije CD20+ B ćelija i vremena preživljavanja bubrežnog alografta, kao i da se istraži uloga infiltriranih B ćelija u odbacivanju bubrežnog alografta. Obuhvaćeno je ukupno 40 pacijenata sa gubitkom bubrežnog alografta usled refraktornog odbacivanja i 20 pacijenata sa prolaznom disfunkcijom bubrežnog alografta. Izvršena je biopsija bubrega a ekspresija CD20 detektovana je imunohistohemijski. Pored toga, utvrđeno je vreme preživljavanja bubrežnog alografta. Analizirani su odnosi između ekspresije CD20 i vremena preživljavanja bubrežnog alografta i gubitka grafta usled odbacivanja. Takođe je ispitana povezanost pola, uzrasta i kliničko-patoloških tipova i ekspresije CD20. Proporcionalno više pacijenata kod kojih je nađena ekspresija CD20 u presađenom bubregu bilo je među pacijentima podvrgnutim nefrektomiji alografta usled odbacivanja nego među onima sa prolaznom disfunkcijom alografta. Difuzna infiltracija CD20+ B ćelija označena je kao pozitivno bojenje. Od 40 uzoraka od pacijenata sa gubitkom grafta, kod 19 je otkrivena difuzna infiltracija CD20+ B ćelija (47,5 %). Od 19 pacijenata pozitivnih na CD20, kod 1 je pronađeno hiperakutno odbacivanje, kod 5 akutno odbacivanje a hronično odbacivanje kod 13 subjekata. Statistička analiza je pokazala da ekspresija CD20 nije povezana sa uzrastom niti sa polom davalaca i primalaca, režimom imunosupresivne terapije, vremenom hladne/tople ishemije i sekundarnom transplantacijom. Infiltracija CD20+ B ćelija daje lošu prognozu kod pacijenata posle presađivanja bubrega i predstavlja jedan od faktora rizika za gubitak grafta.