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Epoxy-fatty-acids (EpFAs), cytochrome P450 dependent arachidonic acid derivatives, have been suggested to have anti-inflammatory properties, though their effects on autoimmune diseases like systemic lupus erythematosus (SLE) have yet to be investigated. We assessed the influence of EpFAs and their metabolites in lupus prone NZB/W F1 mice by pharmacological inhibition of soluble epoxide hydrolase (sEH, EPHX2). The sEH inhibitor 1770 was administered to lupus prone NZB/W F1 mice in a prophylactic and a therapeutic setting. Prophylactic inhibition of sEH significantly improved survival and reduced proteinuria. By contrast, sEH inhibitor-treated nephritic mice had no survival benefit; however, histological changes were reduced when compared to controls. In humans, urinary EpFA levels were significantly different in 47 SLE patients when compared to 10 healthy controls. Gene expression of EPHX2 was significantly reduced in the kidneys of both NZB/W F1 mice and lupus nephritis (LN) patients. Correlation of EpFAs with SLE disease activity and reduced renal EPHX gene expression in LN suggest roles for these components in human disease.

Background: The use of mammalian target of rapamycin inhibitors (mTORis) in kidney transplantation increases the risk of donor-specific human leukocyte antigen (HLA) antibody formation and rejection. Here, we investigated the long-term consequences of early mTORi treatment compared to calcineurin inhibitor (CNI) treatment. Methods: In this retrospective single-center analysis, key outcome parameters were compared between patients participating in randomized controlled immunosuppression trials between 1998 and 2011, with complete follow-up until 2018. The outcomes of eligible patients on a CNI-based regimen (n = 384) were compared with those of patients randomized to a CNI-free mTORi-based regimen (n = 81) and 76 patients randomized to a combination of CNI and mTORi treatments. All data were analyzed according to the intention-to-treat (ITT) principle. Results: Deviation from randomized immunosuppression for clinical reasons occurred significantly more often and much earlier in both mTORi-containing regimens than in the CNI treatment. Overall patient survival, graft survival, and death-censored graft survival did not differ between the treatment groups. Donor-specific HLA antibody formation and BPARs were significantly more common in both mTORi regimens than in the CNI-based immunosuppression. Conclusions: The tolerability and efficacy of the mTORi treatment in kidney graft recipients are inferior to those of CNI-based immunosuppression, while the long-term patient and graft survival rates were similar. [ABSTRACT FROM AUTHOR]

Summary: Antibody‐mediated rejection (ABMR) is a major cause of graft loss in renal transplantation. We assessed the predictive value of clinical, pathological, and immunological parameters at diagnosis for graft survival. We investigated 54 consecutive patients with biopsy‐proven ABMR. Patients were treated according to our current standard regimen followed by triple maintenance immunosuppression. Patient characteristics, renal function, and HLA antibody status at diagnosis, baseline biopsy results, and immunosuppressive treatment were recorded. The risk of graft loss at 24 months after diagnosis and the eGFR slope were assessed. Multivariate analysis showed that eGFR at diagnosis and chronic glomerulopathy independently predict graft loss (HR 0.94; P = 0.018 and HR 1.57; P = 0.045) and eGFR slope (beta 0.46; P < 0.001 and beta −5.47; P < 0.001). Cyclophosphamide treatment (6× 15 mg/m2) plus high‐dose intravenous immunoglobulins (IVIG) (1.5 g/kg) was superior compared with single‐dose rituximab (1× 500 mg) plus low‐dose IVIG (30 g) (HR 0.10; P = 0.008 and beta 10.70; P = 0.017) and one cycle of bortezomib (4× 1.3 mg/m2) plus low‐dose IVIG (HR 0.16; P = 0.049 and beta 11.21; P = 0.010) regarding the risk of graft loss and the eGFR slope. In conclusion, renal function at diagnosis and histopathological signs of chronic ABMR seem to predict graft survival independent of the applied treatment regimen. Stepwise modifications of the treatment regimen may help to improve outcome. [ABSTRACT FROM AUTHOR]

Antineutrophil cytoplasmic antibodies-associated vasculitis (AAV) is a well-described cause of multiple organ involvement including rapidly progressive pauci-immune crescentic glomerulonephritis. Kidney transplantation (KTx) is considered the treatment of choice in patients with end-stage renal disease (ESRD) due to AAV. Patient and graft survival in AAV after KTx is favourable and comparable with other non-diabetic causes of ESRD. While relapse of AAV is high in dialysis patients (up to 50%), it decreases after KTx (8.6–22.2%). Yet, relapse may occur at any time after KTx and transplant involvement has been documented in at least 25 cases. Therapeutic guidelines for the management of AAV after KTx do not exist and clinical management is a controversial discussion. We present two unusual cases of young males with smouldering AAV who recently underwent KTx at our hospital. Case 1 experienced repeated relapses after KTx and was finally successfully treated with rituximab. Case 2 received rituximab pre-emptively before living kidney donation and remained free of flairs. Prompted by theses two cases, we reviewed the literature focusing on the right point of time for transplantation, risk assessment, role of antineutrophil cytoplasmic antibodies, clinical presentation of flairs and immunosuppression in smouldering Wegener's granulomatosis (WG) and in relapse, including individualized treatment with rituximab. [ABSTRACT FROM PUBLISHER]

The Banff 2017 report permits the diagnosis of pure chronic antibody-mediated rejection (cAMR) in absence of microcirculation inflammation. We retrospectively investigated renal allograft function and long-term outcomes of 67 patients with cAMR, and compared patients who received antihumoral therapy (cAMR-AHT, n = 21) with patients without treatment (cAMRwo, n = 46). At baseline, the cAMR-AHT group had more concomitant T-cell-mediated rejection (9/46 (19.2%) vs. 10/21 (47.6%); p = 0.04), a higher g-lesion score (0.4 ± 0.5 versus 0.1 ± 0.3; p = 0.01) and a higher median eGFR decline in the six months prior to biopsy (6.6 vs. 3.0 mL/min; p = 0.04). The median eGFR decline six months after biopsy was comparable (2.6 vs. 4.9 mL/min, p = 0.61) between both groups, and three-year graft survival after biopsy was statistically lower in the cAMR-AHT group (35.0% vs. 61.0%, p = 0.03). Patients who received AHT had more infections (0.38 vs. 0.20 infections/patient; p = 0.04). Currently, antihumoral therapy is more often administered to patients with cAMR and rapidly deteriorating renal function or concomitant TCMR. However, long-term graft outcomes remain poor, despite treatment. [ABSTRACT FROM AUTHOR]

The article presents a study of a 42-year-old man diagnosed with peripheral oedema after being conducted with deceased-donor kidney transplantation. His abdominal examination indicated a loud systolic-diastolic murmur, in which the authors suspected him for acute renal allograft. He was performed with magnetic resonance imaging and magnetic resonance angiography. It mentions that both examination indicated arteriovenous malformation (AVM).

Objectives: Whether T-cell-mediated rejection Banff classification type Ib (severe tubulointerstitial rejection) and type IIa (mild vascular rejection) are associated with responses to antirejection therapy and long-term graft survival are unclear., Materials and Methods: One hundred ten patients were enrolled who had at least 1 episode of T-cell-mediated rejection and whose highest T-cell-mediated rejection severity was T-cell-mediated rejection type Ib or IIa., Results: T-cell-mediated rejection Ib occurred significantly later than T-cell-mediated rejection IIa (P < .001). The proportion of partial/no response to antirejection therapy was comparable between the 2 groups (P = .83). Up to 8-year posttransplant, death-censored graft survival rate of the T-cell-mediated rejection Ib group was similar to that of the T-cell-mediated rejection IIa group (P = .51). Early T-cell-mediated rejection IIa had a statistically higher death-censored graft survival rate than did late T-cell-mediated rejection IIa (P < .001), while no significant difference in the death-censored graft survival was found between early and late T-cell-mediated rejection Ib (P = .11) or between early T-cell-mediated rejection Ib and early T-cell-mediated rejection IIa (P = .11) or between late T-cell-mediated rejection Ib and late T-cell-mediated rejection IIa (P = .07). Furthermore, the T-cell-mediated rejection IIa with isolated v1 lesion (v1, i0-1, t0-1) showed a similar death-censored graft survival rate compared to T-cell-mediated rejection IIa with intensive tubulointerstitial inflammation (v1, i2-3, t2-3). The timing of rejection, graft number, the number of indicated biopsies and the presence of ci/ct lesions were associated with long-term graft loss., Conclusions: The designation of T-cell-mediated rejection type Ib and IIa reflects the different type rather than the distinct severity of rejection and has no independent prognostic significance.

Objectives: To determine the pathologic features of early- and late-onset acute cellular rejection that may contribute to graft loss after kidney transplant., Materials and Methods: There were 247 patients who had acute cellular rejection included in the study. The biopsy that showed the highest acute cellular rejection severity was evaluated for each patient (total, 247 biopsies) and classified as early (time of biopsy, ≤ 6 mo) or late (time of biopsy, > 6 mo) acute cellular rejection., Results: The mean scores of interstitial inflammation (interstitial inflammation and tubulitis), scarring (interstitial fibrosis/tubular atrophy), and vascular disorders (arteriolar hyaline thickening and vascular intimal fibrosis) were significantly higher in late than early acute cellular rejection. Death-censored graft survival at 8 years after kidney transplant was higher in patients who had early (88%) than late acute cellular rejection (66%; P ≤ .001). Early and late acute cellular rejection with either low- or high-grade interstitial fibrosis/tubular atrophy had similar death-censored graft survival. In patients who had late acute cellular rejection, death-censored graft survival was significantly higher when there was low- (survival, 79%) than high-grade vascular intimal fibrosis (survival, 48%; P ≤ .006). Long-term graft loss was significantly associated with the number of biopsies, intimal arteritis, and tubulitis in patients who had early acute cellular rejection, and vascular intimal fibrosis in patients who had late acute cellular rejection., Conclusions: High-grade vascular intimal fibrosis was a risk factor for poor long-term graft survival in late acute cellular rejection after kidney transplant.

We present the case of a 48-year-old otherwise healthy man who required an urgent liver transplant owing to acute liver failure after flupirtine treatment. After 3 months of daily flupirtine intake as treatment for pseudoradicular pain syndrome, he presented at our institution with signs of jaundice and hepatic encephalopathy. Laboratory results showed elevated liver transaminases, and the liver histopathology supported the assumed drug-induced liver injury. After listing him for an urgent liver transplant, he was given a liver graft from a 21-year-old man. Despite a rejection episode on day 11 after the surgery (which was successfully treated by steroid pulse therapy), the postoperative course was uneventful and the patient recovered completely. To the best of our knowledge, this is the first report of a liver transplant for acute liver failure after taking flupirtine.

Background: We assessed the predictive value of TP53 mutations and prostate-specific antigen (PSA) for tumor progression in prostate cancer (PCa) patients., Materials and Methods: Ninety tumor tissue samples of patients with PCa from radical prostatectomy were used. Tumor progression was estimated biochemically by the PSA level (> 0.2 microg/l) or by detection of metastases. Screening for TP53 mutations was performed by temperature gradient gel electrophoresis (TGGE) in exon-specific manner. Follow-up data were collected from medical protocols. Statistical analysis was performed by uni- and multivariate techniques., Results: In 32 out of 90 patients (35.6%), TP53 mutations were detected. Thirteen out of 32 patients (40.6%) with TP53 mutations and nine out of 58 patients (15.5%) with TP53 wild-type showed tumor progression after 25 and 45 months, respectively., Conclusion: TP53 mutations in exon 7 and exon 8 are factors of tumor progression in PCa. Their contribution to tumor recurrence is more significant than tumor stage and pretherapeutic PSA level.

Background: The predictive value of TP53 mutations and prostate-specific antigen (PSA) was assessed in prostate needle biopsies of samples without signs of malignancy for later affliction by prostate cancer (PCa). Comparison of mutation frequency and PSA level in prostate needle biopsies with data of patients with benign prostate hyperplasia (BPH) treated by transurethral resection (TURP), patients with prostatic intraepithelial neoplasia (PIN), and patients with PCa, was made., Materials and Methods: A total of 466 samples were analysed from patients with benign and malignant diseases of the prostate, including 52 samples of needle biopsies of the prostate with repeated benign histopathological diagnosis. Analysis of TP53 state by temperature gradient gel electrophoresis of TP53 exon-specific PCR products of exons 5, 6, 7 and 8 was performed. Clinical follow-up of 100 patients with benign diseases of the prostate and with PIN was available., Results: Needle biopsy samples with repeated benign diagnosis resemble BPH specimens taken by TURP in TP53 mutation frequency (TURP: 16.1%, needle biopsy: 21.2%) and later affliction by PCa (TURP: 3/32 = 9.4%, needle biopsy: 8/51 = 15.7%, p = 0.409). Patients with TP53 mutations in needle biopsy samples showed a significantly reduced disease-free survival time for affliction by PCa (log rank: p = 0.0149). This significance is raised by computing exon 6 mutations only with respect to affection by PCa (p = 0.0002). In TURP patients, exon 7-mutations were also significant (p = 0.0086). Needle biopsy TP53 mutations (p = 0.029) had significant predictive values for later affliction by PCa in multivariate analysis. PSA level and patient age had no predictive value for PCa., Conclusion: TP53 mutations reduce the PCa-free survival time in patients with needle biopsy of the prostate and primary benign diagnosis. Exon 6 mutations enhance the risk of being affected by PCa 32-fold.

To alert clinicians to a potential novel adverse drug effect of interferon beta 1a, we herein report a patient with relapsing-remitting multiple sclerosis who developed ulcerative colitis following treatment with interferon beta 1a. Ulcerative colitis persisted despite discontinuation of interferon beta 1a treatment and switching the patient to glatiramer acetate. Tacrolimus (FK506), 6-mercaptopurine, and prednisolone were required to induce remission. Both ulcerative colitis and multiple sclerosis were eventually well controlled using this regimen. Our report underscores that caution should be exercised when prescribing immunostimulatory agents in patients with inflammatory bowel disease (IBD) and challenges current efforts to stimulate innate immunity as a novel therapeutic concept for IBD.

Osteoclast-like giant cell tumors (OGCT) are rare abdominal tumors, which mainly occur in the pancreas. The neoplasms are composed of two distinct cell populations and frequently show an inhomogenous appearance with cystic structures. However, due to the rarity of these tumors, only very limited clinical data are available. Imaging features and sonographic appearance have hardly been characterized. Here we report on two cases of osteoclast-like giant cell tumors, one located within the pancreas, the other within the liver, in which OGCTs are extremely rare. Both patients were investigated by contrast sonography, which demonstrated a complex, partly cystic and strongly vascularized tumor within the head of the pancreas in the first patient and a large, hypervascularized neoplasm with calcifications within the liver in the second patient. The liver OGCT responded well to a combination of carboplatin, etoposide and paclitaxel. With a combination of surgical resection, radiofrequency ablation and chemotherapy, the patient's survival is currently more than 15 mo, making him the longest survivor with an OGCT of the liver to date.