Isogeneic MSC application in a rat model of acute renal allograft rejection modulates immune response but does not prolong allograft survival.

Application of mesenchymal stromal cells (MSCs) has been proposed for solid organ transplantation based on their potent immuno-modulatory effects in vitro and in vivo. We investigated the potential of MSCs to improve acceptance of kidney transplants in an MHC-incompatible rat model including isogeneic kidney transplantation (RTx) as control. MSCs were administered i.v. or i.a. at time of transplantation. No immunosuppression was applied. Renal function was monitored by serum-creatinine, histopathology, immunochemistry for graft infiltrating cells and expressions of inflammatory genes. We demonstrated the short-term beneficial effects of MSC injection. In the long term, however, MSC-related life-threatening/shortening events (thrombotic microangiopathy, infarctions, infections) were evident despite decreased T- and B-cell infiltration, lower interstitial inflammation and downregulated inflammatory genes particularly after i.a. MSC injection. We conclude that i.a. MSC administration provides efficient immunomodulation after allogeneic RTx, although timing and co-treatment strategies need further fine-tuning to develop the full potential of powerful cell therapy in solid organ transplantation.

Renal comorbidity after solid organ and stem cell transplantation.

After transplantation of solid organs or hematopoietic stem cells, a significant acute decrease in renal function occurs in the majority of patients. Depending on the degree of kidney injury, a large number of patients develop chronic kidney disease (CKD) and some develop end-stage renal disease requiring renal replacement therapy. The incidence varies depending on the transplanted organ, but important risk factors for the development of CKD are preexisting renal disease, hepatitis C, diabetes, hypertension, age, sex, posttransplant acute kidney injury and thrombotic microangiopathy. This review article focuses on the risk factors of posttransplant chronic kidney disease after organ transplantation, considering the current literature and integrates the incidence and the associated mortality rates of acute and chronic kidney disease. Furthermore, we introduce the RECAST (REnal Comorbidity After Solid organ and hematopoietic stem cell Transplantation) registry.

[BK virus nephropathy after kidney transplantation]. / BK-Virusnephropathie nach Nierentransplantation.

JC and BK viruses are strains of the polyomavirus group with pathogenic potential in humans. BK is the most frequent pathogenic agent of polyomavirus nephropathy (BKVN) in kidney transplant patients, which is only exceptionally caused by JC virus. Asymptomatic BK virus infection is often acquired in childhood and the virus persists in urothelium and kidneys of healthy individuals, where it can be reactivated under immunosuppression. Up to 10% of transplanted kidneys are affected by BKVN, while the risk of transplant failure due to BKVN exceeds 50% in some publications. In kidney biopsies BKVN leads to tubulointerstitial nephritis, which may be difficult to distinguish from acute cellular rejection without additional use of immunohistochemistry for a polyomavirus antigen. Typical hallmarks of BKVN include cytopathic effects caused by the virus with cell lysis, denudation of tubular basement membranes and nuclear inclusion bodies. An early diagnosis is essential for transplant survival, making screening of blood and urine for BK virus after kidney transplantation part of the standard care of renal transplant patients today. In the case of significant viremia or biopsy-proven BKVN immunosuppression is reduced to allow clearing of the virus.

Pathological characteristics of a series of rare chronic histiocytic intervillositis of the placenta.

Chronic histiocytic intervillositis of the placenta (CHI) is a rare and poorly understood pathology which may occur in all trimesters. The most conspicuous feature is a histiocytic infiltration of the intervillous space without involvement of the villous parenchyma. In this report on CHI, we re-evaluate a series of four cases and focus on histological, immunohistological and fluorescence in situ hybridisation-derived findings, fetal status and clinical data for previously unrecognised CHI-associated features. Our approach revealed that assisted reproduction-induced pregnancy had been performed in 2 of 4 CHI cases, but other factors and comorbidities are likely to contribute to CHI.

[Current problems of kidney transplantation]. / Aktuelle Probleme der Nierentransplantation.

The long-term problems after kidney transplantation have changed considerably in recent years. While formerly immunosuppression and prevention of acute rejection were of prime concern, now attention focuses on chronic alterations of the transplanted organ and long-term survival of the patients. The transplantation procedure itself has evolved into a standardized technique with a high level of surgical quality. Problems involving organ preservation and ischemia/reperfusion damage also play a role, especially in view of chronic aspects. Monitoring of long-term complications should follow a program for the transplanted organ as well as a program for the patient. Monitoring kidney function should address the organ more precisely than has previously been the case. Serum creatinine level and proteinuria alone provide insufficient information and only change long after cellular deterioration has begun. Hence it is imperative that new testing methods be developed. One possibility is offered by protocol biopsies that allow histological and molecular analysis of the kidney at regular intervals. The patient programs concentrate on diagnostics and treatment of the cardiovascular diseases. Furthermore, the patients must be screened for occurrence of neoplasia. There are no prospective studies covering all cardiovascular risk factors after kidney transplantation. This pertains particularly to the subject of hypertension.

The Tie2 receptor antagonist angiopoietin 2 facilitates vascular inflammation in systemic lupus erythematosus.

OBJECTIVE: To investigate the role of the angiopoietin-tyrosine kinase with Ig-like and epidermal growth factor-like domains (Ang-Tie) system in systemic lupus erythematosus (SLE). Endothelial activation is emerging as a key event for leukocyte recruitment and accelerated atherosclerosis in SLE. Recently, the endothelial-specific Ang-Tie ligand-receptor system has been identified as a major regulator of vascular responsiveness to inflammatory stimuli. METHODS: Ang1 (by immunoradiometric sandwich assay (IRMA)) and Ang2 (by ELISA) were measured in sera of 43 patients with SLE and 30 healthy controls. Expression of Ang2 was studied by immunohistochemistry in biopsies of human lupus nephritis. RESULTS: Circulating Ang2 concentrations were increased and concentrations of Ang1 decreased in patients with active SLE compared to healthy controls. This tendency was still present in inactive SLE, although less pronounced. Individual Ang2 concentrations correlated well with SLE Disease Activity Index (SLEDAI) score, proteinuria, double-stranded DNA (dsDNA) titre and soluble vascular cell adhesion molecule 1 (sVCAM-1). In a multivariate regression analysis, renal involvement was the only independent predictor for elevated Ang2. Serum Ang2 was identified as a strong predictor for disease activity by receiver operating characteristic (ROC) procedures and regression tree models. Protein expression of Ang2 was upregulated in glomeruli of patients with lupus nephritis. CONCLUSIONS: These data indicate that Ang2-mediated disruption of protective Ang1/Tie2 signalling is operational in SLE. Ang2 might facilitate endothelial inflammation, permeability and contribute to premature atherosclerosis. Furthermore, circulating Ang2 may be a valuable new biomarker for disease activity in SLE. Strategies to control the deleterious effects of Ang2 may open new perspectives to prevent endothelial inflammation in SLE.

Peritubular capillaritis in renal allografts: prevalence, scoring system, reproducibility and clinicopathological correlates.

While glomerulitis is graded according to the Banff classification, no criteria for scoring peritubular capillaritis (PTC) have been established. We retrospectively applied PTC-scoring criteria to 688 renal allograft (46 preimplantation, 461 protocol, 181 indication) biopsies. A total of 26.3% of all analyzed biopsies had peritubular capillaritis (implant 0%, protocol 17.6%, indication 45.5%; p < 0.0001). The most common capillaritis pattern was of moderate severity (5-10 luminal cells), focal in extent (10-50% of PTC), with a minority of neutrophils. A total of 24% of C4d- compared with 75% of C4d+ biopsies showed capillaritis (p < 0.0001). More than 80% of biopsies with glomerulitis had peritubular capillaritis. A total of 50.4% of biopsies with borderline or T-cell mediated rejection (TCMR) and 14.1% of biopsies without TCMR or antibody-mediated rejection (ABMR) showed capillaritis (p < 0.0001). The inter-observer reproducibility of the PTC-scoring features was fair to moderate. Diffuse capillaritis detected in early protocol biopsies had significant negative prognostic impact in terms of glomerular filtration rate 2 years posttransplantation. Indication biopsies show a significantly higher prevalence of capillaritis than protocol biopsies (45.5% vs. 17.6%; p < 0.0001). Capillaritis is more frequent and pronounced in ABMR, but can be observed in TCMR cases. Thus, scoring of peritubular capillaritis is feasible and can provide prognostic and diagnostic information in renal allograft biopsies.

Infiltrates in protocol biopsies from renal allografts.

In renal transplantation, clinical decisions are based primarily on the Banff classification of biopsies. However, the incorporation of 'minor or nonspecific' cellular infiltrates into the Banff classification and their interpretation is uncertain. We analyzed 833 protocol and 306 indicated biopsies to test whether such infiltrates are harmless or whether they have a bearing on outcomes. We characterized morphology, localization and cellular composition of infiltrates, and correlated these findings to the Banff classification and allograft outcome. We found that protocol biopsies had the same prevalence of infiltrates as indication biopsies (87% vs. 87%). Diffuse cortical infiltrates, the hallmark of cellular rejection were more common in indication biopsies and related to tubulitis and a rise in serum creatinine. However, in biopsies with cellular rejection according to Banff criteria, we observed an increase in all infiltrate types (specific and nonspecific) and all cell types (T cells, B cells, histiocytes). The only predictor of allograft function outcome was persistent inflammation in sequential biopsies, irrespective of type, localization and composition of the cellular infiltrates. As detected by sequential biopsies, persistence of any inflammation including those infiltrates currently not considered by the Banff classification should be regarded as a morphological correlate of ongoing allograft damage.

Allelic loss is often the first hit in the biallelic inactivation of the p53 and DPC4 genes during pancreatic carcinogenesis.

The presumed precursor lesions of pancreatic ductal adenocarcinoma were recently classified according to their increasing grade of dysplasia and were designated as pancreatic intraepithelial neoplasia (PanIN) 1 through 3. In this study, we tested whether molecular genetic alterations can be correlated with this classification and may help to further categorize the various PanIN grades. We determined the frequencies of allelic loss at chromosomal arms 9p, 17p, and 18q in 81 microdissected duct lesions of various PanIN grades, using a combination of whole genome amplification and microsatellite analysis. In addition we examined the p53 and Dpc4 protein expression patterns by immunohistochemical analysis. In PanIN-1, we did not detect allelic losses. In PanIN-2, allelic losses were found in increasing frequency, and were particularly high in those lesions with moderate-grade dysplasia (low grade, 20, 33, and 17%, loss at 9p, 17p, and 18q, respectively; moderate grade, 46, 77, and 58%). PanIN-3 and invasive carcinomas exhibited abundant losses. Abnormal p53 and Dpc4 protein expression was only rarely identified in PanIN-2 lesions, but occurred frequently in PanIN-3 lesions and invasive carcinomas. The combined genetic and protein expression data support a model in which allelic loss is the first hit in the biallelic inactivation of the p53 and DPC4 tumor suppressor genes. In addition, our data indicate that allelic loss analysis may be useful in separating PanIN-2 lesions with low-grade dysplasia from those PanIN-2 lesions with moderate-grade dysplasia, each potentially representing a distinct progression step toward invasive carcinoma.