The Banff Working Group on Liver Allograft Pathology reviewed and discussed literature evidence regarding antibody-mediated liver allograft rejection at the 11th (Paris, France, June 5-10, 2011), 12th (Comandatuba, Brazil, August 19-23, 2013), and 13th (Vancouver, British Columbia, Canada, October 5-10, 2015) meetings of the Banff Conference on Allograft Pathology. Discussion continued online. The primary goal was to introduce guidelines and consensus criteria for the diagnosis of liver allograft antibody-mediated rejection and provide a comprehensive update of all Banff Schema recommendations. Included are new recommendations for complement component 4d tissue staining and interpretation, staging liver allograft fibrosis, and findings related to immunosuppression minimization. In an effort to create a single reference document, previous unchanged criteria are also included.
BackgroundIn vivo models of uremia are important tools to study numerous aspects of acute and chronic kidney disease. Mouse models are pivotal because most genetically engineered animal models are mice, which allow dissecting the impact of selected target genes in renal failure. Adenine-based protocols to induce renal failure are available in rats, but have not been adapted in mice due to their reluctance to consume adenine. In the current paper we developed a novel method for induction of renal failure through dietary delivery of adenine mixed in a casein-based diet.ResultsAfter an induction phase, a stable model of renal impairment was obtained (target urea range 80–100 mg/dL), mimicking several aspects of chronic kidney disease - mineral and bone disorder including secondary hyperparathyroidism, bone abnormalities and pathological elevation of FGF23. No deaths occurred and the level of uremia was adaptable through adjustments of the adenine content, providing significant advantages compared to existing models. In an 8-week proof-of-concept study, renal histology showed mainly a tubulointerstitial damage with infiltrating leukocytes, interstitial edema and widening of the Bownman's space. Fibrosis was present in most animals as defined by histology and gene expression changes of fibrosis markers. Parathyroid cell proliferation was markedly increased but without signs of glandular hypertrophy. Skeletal histology showed increased trabecular bone and bone marrow adiposity whereas bone biomarkers (CTX and PINP) suggested higher bone formation, but surprisingly, lower bone resorption and perturbations in mineral metabolism.ConclusionsWe present a novel, non-surgical method for induction of renal failure in mice. This is an important complement to existing uremic models for pathophysiological studies in acute and chronic kidney disease, especially in terms of tubulointerstitial lesions.
The anti-CD20 antibody rituximab has recently gained interest as a B-cell depleting agent in renal transplantation. However, little is known about the pharmacodynamics of rituximab in renal transplant recipients.We have therefore studied the effect of single-dose rituximab in combination with conventional triple immunosuppressive therapy on the B-cell population in peripheral blood as well as in tissues.A total of 49 renal transplant recipients received singledose rituximab, as induction therapy (n = 36) or as anti-rejection therapy (n = 13). We counted B cells in peripheral blood and performed immunohistochemical staining on lymph nodes and kidney transplant tissue samples to assess the prevalence of B cells. In all but 6 patients (88%) complete depletion of B cells in peripheral blood was achieved. In adults, 15 months after treatment the CD19+ and CD20+ cell counts were still below 5 cells/lL in the majority of patients (78%). The immunohistochemical staining showed a complete elimination of B cells in kidney tissue and a reduction of B cells in lymph nodes.In conclusion, single-dose rituximab in kidney transplant recipients evokes a long-term elimination of B cells in peripheral blood as well as within the kidney transplant. The effect seems to extend beyond the expected 3-12 months observed in lymphoma patients.
Renal Klotho controls mineral metabolism by directly modulating tubular reabsorption of phosphate and calcium and by acting as a co-receptor for the phosphaturic and vitamin D-regulating hormone fibroblast growth factor-23 (FGF23). Klotho null mice have a markedly abnormal phenotype. We sought to determine effects of renal-specific and partial deletion of Klotho to facilitate investigation of its roles in health and disease. We generated a mouse model with partial deletion of Klotho in distal tubular segments (Ksp-KL 2/2 ).In contrast to Klotho null mice, Ksp-KL 2/2 mice were fertile, had a normal gross phenotype, and did not have vascular or tubular calcification on renal histology. However, Ksp-KL 2/2 mice were hyperphosphatemic with elevated FGF23 levels and abundant expression of the sodium-phosphate cotransporter Npt2a at the brush border membrane. Serum calcium and 1,25-dihydroxyvitamin D 3 levels were normal but parathyroid hormone levels were decreased. TRPV5 protein was reduced with a parallel mild increase in urinary calcium excretion. Renal expression of vitamin D regulatory enzymes and vitamin D receptor was higher in Ksp-KL 2/2 mice than controls, suggesting increased turnover of vitamin D metabolites and a functional increase in vitamin D signaling. There was a threshold effect of residual renal Klotho expression on FGF23: deletion of .70% of Klotho resulted in FGF23 levels 30-250 times higher than in wild-type mice. A subgroup of Ksp-KL 2/2 mice with normal phosphate levels had elevated FGF23, suggesting a Klothoderived renal-bone feedback loop. Taken together, renal FGF23-Klotho signaling, which is disrupted in CKD, is essential for homeostatic control of mineral metabolism.
Summary:We have evaluated whether allogeneic hematopoietic stem cell transplantation (HSCT) could induce an antitumor effect in patients with metastatic solid tumors. A total of 12 HLA-identical siblings and 6 HLA-A-, -B-and -DRb1-compatible unrelated grafts were used. Diagnoses were adenocarcinoma of kidney (n ¼ 10), colon (n ¼ 6), breast (n ¼ 1) and cholangiocarcinoma (n ¼ 1). Conditioning was fludarabine 30 mg/m 2 /day for 3 days and 2 Gy of total body irradiation. Recipients of unrelated HSCT were also given thymoglobuline and two additional days of fludarabine. The median CD34+ cell dose was 7.5 Â 10 6 / kg. Immunosuppression was mycophenolate mofetil and cyclosporin. Among all, 12 patients became complete donor chimeras within a median of 28, 29 and 65 days for B, myeloid and T cells, respectively. Two patients rejected the grafts, one developed marrow aplasia and three were mixed chimeras. The probability of grades II-IV acute graft-versus-host-disease (GVHD) was 57%. Regression of all tumor metastases was seen in one patient with colon carcinoma. Another patient with colon and two with renal carcinoma had regression of lung metastases, but progression of metastases in the liver and/or bone. Necrosis of lung metastasis was found in one further patient with renal carcinoma who died of graft-versushost-disease (GVHD). In all, 10 patients died; four of transplant-related complications, one of trauma and five of progressive disease. Thus, progression was common after allogeneic HSCT in unselected patients with advanced solid tumors. However, the regression of some metastases associated with GVHD provides suggestive evidence that the GVHD effect may occur in renal and colon adenocarcinoma using reduced intensity conditioning. The immune system is known to induce tumor regression. 1 Following allogeneic hematopoietic stem cell transplantation (HSCT), graft-versus-host disease (GVHD) has been found to contribute to an antileukemic effect. 2,3 An alloresponse of donor T lymphocytes is most probably the cause of GVHD and the graft-versus-leukemia (GVL) effect. 4 An allogeneic graft-versus-tumor (GVT) effect has also been reported in breast and renal metastatic carcinoma. [5][6][7][8][9] When performing HSCT, lethal myeloablative conditioning to eradicate leukemia and induce marked immunosuppression to pave the way for the donor immunohematopoietic system has been the routine for several decades 10À13 . However, this approach has been challenged by using lower doses and less toxic conditioning to induce immunosuppression and take advantage of the GVT effect later rather than the antitumor effect of chemoradiotherapy. [14][15][16][17][18][19]
We analyzed the outcome of allogeneic hematopoietic stem cell transplantation (HSCT) over the past 2 decades. Between 1992 and 2009, 953 patients were treated with HSCT, mainly for a hematologic malignancy. They were divided according to 4 different time periods of treatment: 1992 to 1995, 1996 to 2000, 2001 to 2005, and 2006 to 2009. Over the years, many factors have changed considerably regarding patient age, diagnosis, disease stage, type of donor, stem cell source, genomic HLA typing, cell dose, type of conditioning, treatment of infections, use of granulocyte-colony stimulating factor (G-CSF), use of mesenchymal stem cells, use of cytotoxic T cells, and home care. When we compared the last period (2006-2009) with earlier periods, we found slower neutrophil engraftment, a higher incidence of acute graft-versus-host disease (aGVHD) of grades II-IV, and less chronic GVHD (cGHVD). The incidence of relapse was unchanged over the 4 periods (22%-25%). Overall survival (OS) and transplant-related mortality (TRM) improved significantly in the more recent periods, with the best results during the last period (2006-2009) and a 100-day TRM of 5.5%. This improvement was also apparent in a multivariate analysis. When correcting for differences between the 4 groups, the hazard ratio for mortality in the last period was 0.59 (95% confidence interval [CI]: 0.44-0.79; P < .001) and for TRM it was 0.63 (CI: 0.43-0.92; P = .02). This study shows that the combined efforts to improve outcome after HSCT have been very effective. Even though we now treat older patients with more advanced disease and use more alternative HLA nonidentical donors, OS and TRM have improved. The problem of relapse still has to be remedied. Thus, several different developments together have resulted in significantly lower TRM and improved survival after HSCT over the last few years.
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