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Acute kidney injury (AKI) is frequent after liver transplantation (LT), with impact on graft function, morbidity and mortality. Although multifactorial, the pathophysiology of perioperative kidney injury remains unclear. Our aims were to analyze the frequency, evolution and risk factors for kidney impairment during the peri- and early post-operative period.In a prospective, single-center study of 27 adult patients undergoing first single-organ LT, we analyzed measured glomerular filtration rate (mGFR) pre-transplant, at post-operative day (POD) 10, and at 1, 3, 12 and 36 months. Kidney and liver graft biopsies were performed during LT.A median mGFR decline of 45% was detected from pre-transplant to POD 10, correlating strongly with the mGFR evolution from baseline to 12 months (rs = 0.80,The greatest decline in mGFR was evident within 10 days and AKI within hours of LT, irrespective of baseline mGFR and before introduction of calcineurin inhibitors. Very early post-LT kidney injury has substantial consequences for long-term kidney function.

The first live birth after uterus transplantation occurred in Sweden in 2014. Uterus transplantation has repeatedly, and at many centers worldwide, proven to be a feasible treatment for absolute uterine factor infertility. Hysterectomy in live donors and transplantation are well described in numerous reports. However, there are no reports of hysterectomy in the recipient after uterus transplantation, which will occur at either graft failure, after childbirth, or after numerous failed pregnancy attempts. We present the first report of hysterectomy in recipients after uterus transplantation with detailed analyses of findings in conjunction with graft failures.An analysis of recipient hysterectomies (n = 10), performed in 2012-2020, was conducted. Data from the international uterus transplantation registry (ISUTx registry) were extracted, and medical records were systematically reviewed, to collect and compile characteristics of recipients and donors, as well as pre-, per-, and postoperative data, including clinical course of graft failures.Hysterectomy in recipients was performed in conjunction with cesarean section (n = 3), 3-6 months after cesarean section (n = 3), or after failed pregnancy attempts (n = 1) or graft failure (n = 3). The durations of anesthesia (2 h 36 min to 7 h 35 min) and hysterectomy surgery (1 h 42 min to 5 h 52 min) ranged widely, with long perioperative interruptions for insertion of ureteral catheters in two cases. Adhesions to the uterus were abundant, the majority being mild. Three uteri that subsequently showed graft failure (hysterectomy at 1, 3, and 8 months post transplantation) showed histological signs of ischemia in biopsies taken 1-week post-transplant and early signs of central hypoperfusion by Doppler ultrasound. In these graft failure explants, there were no epithelial linings in the uterine cavity or in the cervix. The inner uterine wall was severely ischemic and/or necrotic, whereas outer parts were partly viable. There were signs of moderate atherosclerosis of uterine arteries but no rejection. Mild postoperative complications were frequent (6/10), with one supravaginal hematoma requiring surgical drainage.Hysterectomy after uterus transplantation is a complex and time-consuming procedure, and perioperative ureteral catheters may be helpful. Histopathology of early cervical biopsies showing ischemic signs may indicate subsequent irreversible damage, leading to graft failure.

Background Immunoglobulin A nephropathy (IgAN) and its systemic variant IgA vasculitis (IgAV) damage the glomeruli, resulting in proteinuria, hematuria and kidney impairment. Dendrin is a podocyte-specific protein suggested to be involved in the pathogenesis of IgAN. Upon cell injury, dendrin translocates from the slit diaphragm to the nucleus, where it is suggested to induce apoptosis and cytoskeletal changes, resulting in proteinuria and accelerated disease progression in mice. Here we investigated gene and protein expression of dendrin in relation to clinical and histopathological findings to further elucidate its role in IgAN/IgAV. Methods Glomerular gene expression was measured using microarray on 30 IgAN/IgAV patients, 5 patients with membranous nephropathy (MN) and 20 deceased kidney donors. Dendrin was spatially evaluated on kidney tissue sections by immunofluorescence (IF) staining (IgAN patients, n = 4; nephrectomized kidneys, n = 3) and semi-quantified by immunogold electron microscopy (IgAN/IgAV patients, n = 21; MN, n = 5; living kidney donors, n = 6). Histopathological grading was performed according to the Oxford and Banff classifications. Clinical data were collected at the time of biopsy and follow-up. Results Dendrin mRNA levels were higher (P = .01) in IgAN patients compared with MN patients and controls and most prominently in patients with preserved kidney function and fewer chronic histopathological changes. Whereas IF staining did not differ between groups, immunoelectron microscopy revealed that a higher relative nuclear dendrin concentration in IgAN patients was associated with a slower annual progression rate and milder histopathological changes. Conclusion Dendrin messenger RNA levels and relative nuclear protein concentrations are increased and associated with a more benign phenotype and progression in IgAN/IgAV patients.

Background: Macrophages in renal transplants have been shown to participate in antibody-mediated rejection and are associated with impaired renal function. We calculated the glomerular macrophage index (GMI) in a large transplant biopsy cohort, studied its quantity in different diagnostic groups, to clarify its possible impact on graft survival. Methods: GMI, defined as the mean number of macrophages in 10 glomeruli, was prospectively quantified in 1440 renal transplant biopsies over a 10-year period. The main histopathological diagnoses were grouped into eight disease entities, and GMI was compared to normal transplant biopsies as the reference group. The impact of GMI on graft survival was analyzed. Results: GMI was highest in chronic (mean 9.4) and active (9.7) antibody mediated rejections (ABMR), mixed rejections (7.6), and recurrent or de novo glomerulonephritis (7.5) and differed significantly from normal transplants (1.3) in almost all diagnostic groups. Hazard ratios for graft loss were significantly increased for all biopsies with GMI ≥1.9 compared to GMI 80% with GMI ≤ 1.8. Conclusion: GMI levels were predictive of graft loss independent of histological diagnoses and may guide clinicians to decide follow-up and therapy.

Introduction The proof-of-concept of uterus transplantation, as a treatment for absolute uterine factor infertility, came with the first live birth after uterus transplantation, which took place in Sweden in 2014. This was after a live donor procedure, with laparotomy in both donor and recipient. In our second, ongoing trial we introduced a robotic-assisted laparoscopic surgery of the donor to develop minimal invasive surgery for this procedure. Here, we report the surgery and pregnancy behind the first live birth from that trial. Material and methods In the present study, within a prospective observational study, a 62-year-old mother was the uterus donor and her 33-year-old daughter with uterine absence as part of the Mayer-Rokitansky-Kuster-Hauser syndrome, was the recipient. Donor surgery was mainly done by robotic-assisted laparoscopy, involving dissections of the utero-vaginal fossa, arteries and ureters. The last part of surgery was by laparotomy. Recipient laparotomy included vascular anastomoses to the external iliac vessels. Data relating to in vitro fertilization, surgery, follow up, obstetrics and postnatal growth are presented. Results Three in vitro fertilization cycles prior to transplantation gave 12 cryopreserved embryos. The surgical time of the donor in the robot was 360 minutes, according to protocol. The durations for robotic surgery for dissections of the utero-vaginal fossa, arteries and ureters were 30, 160 and 84 minutes, respectively. The remainder of donor surgery was by laparotomy. Recipient surgery included preparations of the vaginal vault, three end-to-side anastomoses (one arterial, two venous) on each side to the external iliacs and fixation of the uterus. Ten months after transplantation, one blastocyst was transferred and resulted in pregnancy, which proceeded uneventfully until elective cesarean section in week 36+1 . A healthy boy (Apgar 9-10-10) was delivered. Follow up of child has been uneventful for 12 months. Conclusions This is the first report of a live birth after use of robotic-assisted laparoscopy in uterus transplantation and is thereby a proof-of-concept of use of minimal invasive surgery in this new type of transplantation.

BACKGROUND: The prognosis for kidney survival is poor in patients presenting with circulating anti–glomerular basement membrane (GBM) antibodies and severe kidney injury. It is unknown if treatment with an endopeptidase that cleaves circulating and kidney bound IgG can alter the prognosis. METHODS: An investigator-driven phase 2a one-arm study (EudraCT 2016–004082–39) was performed in 17 hospitals in five European countries. A single dose of 0.25 mg/kg of imlifidase was given to 15 adults with circulating anti-GBM antibodies and an eGFR

Extracellular matrix fibril components, such as collagen, are crucial for the structural properties of several tissues and organs. Tunicate-derived cellulose nanofibrils (TNC) combined with living cells could become the next gold standard for cartilage and soft-tissue repair, as TNC fibrils present similar dimensions to collagen, feasible industrial production, and chemically straightforward and cost-efficient extraction procedures. In this study, we characterized the physical properties of TNC derived from aquaculture production in Norwegian fjords and evaluated its biocompatibility regarding induction of an inflammatory response and foreign-body reactions in a Wistar rat model. Additionally, histologic and immunohistochemical analyses were performed for comparison with expanded polytetrafluoroethylene (ePTFE) as a control. The average length of the TNC as determined by atomic force microscopy was tunable from 3 μm to 2.4 μm via selection of a various number of passages through a microfluidizer, and rheologic analysis showed that the TNC hydrogels were highly shear-thinning and with a viscosity dependent on fibril length and concentration. As a bioink, TNC exhibited excellent rheological and printability properties, with constructs capable of being printed with high resolution and fidelity. We found that post-print cross-linking with alginate stabilized the construct shape and texture, which increased its ease of handling during surgery. Moreover, after 30 days in vivo, the constructs showed a highly-preserved shape and fidelity of the grid holes, with these characteristics preserved after 90 days and with no signs of necrosis, infection, acute inflammation, invasion of neutrophil granulocytes, or extensive fibrosis. Furthermore, we observed a moderate foreign-body reaction involving macrophages, lymphocytes, and giant cells in both the TNC constructs and PTFE controls, although TNC was considered a non-irritant biomaterial according to ISO 10993-6 as compared with ePTFE. These findings represent a milestone for future clinical application of TNC scaffolds for tissue repair. One sentence summary: In this study, the mechanical properties of tunicate nanocellulose are superior to nanocellulose extracted from other sources, and the biocompatibility is comparable to that of ePTFE.

Aim: The primary aim of this study was to in depth examine if the histological findings in a transplanted kidney biopsy can predict the prognosis for the graft and the patient. The secondary aim was to extend knowledge of the impact of time elapsed on biopsy findings. Methods: Data from 1462 patients were merged from a kidney transplantation registry and a biopsy registry during 1 January 2007 and 30 September 2017. Kaplan–Meier analysis and multivariate Cox-regression analysis were performed and hazard ratios (HR) with 95% confidence intervals (CI) were presented. Results: Compared to normal biopsy findings, graft survival after biopsy (gsaBiopsy) was shorter for patients with glomerular diseases (HR 8.2, CI:3.2–21.1), rejections (HR 4.2, CI:1.7–10.3), chronic changes including IFTA (HR 3.2, CI:1.3–8.0), acute tubular injuries (HR 3.0, CI:1.2–7.8), and borderline changes (HR 2.9, CI:1.1–7.6). Sub-analysis of rejections showed shorter gsaBiopsy for chronic TCMR (HR 4.7, CI:1.9–11.3), active ABMR (HR 3.6, CI:1.7–7.7) and chronic ABMR (HR 3.5, CI:2.0–6.0). Patients with TCMR Banff grade II (HR 0.35, CI:0.20–0.63) and grade I (HR 0.52, CI:0.29–0.93) had a better gsaBiopsy compared to all other types of rejections. Conclusion: Shorter gsaBiopsy was noted in kidneys with glomerular diseases, rejections, acute tubular injuries and borderline changes. TCMR Banff rejections grade I and II were associated with a better prognosis.

Lead (Pb), cadmium (Cd) and mercury (Hg) are all nephrotoxic metals, and a large part of the body burden of Cd and Hg is found in the kidneys. There are, however, few studies on associations between exposure to these toxic metals and renal biopsy findings, and none at low-level exposure.To examine the hypothesis that low-level concentration of Pb, Cd or Hg in the kidneys is associated with histopathological changes in the kidneys.We determined concentrations of Pb, Cd and Hg in kidney, blood and urine in 109 healthy kidney donors, aged 24-70 years. The renal biopsies were scored according to the Banff classification regarding tubular atrophy, interstitial fibrosis, glomerulosclerosis, arteriosclerosis, and arteriolohyalinosis. Kidney function was assessed based on glomerular filtration rate (GFR) as well as urinary excretion of albumin, low molecular weight proteins, kidney injury molecule 1 and N-acetylglucose aminidase. Associations between metal concentrations and histopathological changes, were assessed in models also including age, sex and smoking.The median kidney concentrations of Pb, Cd and Hg were 0.08, 13 and 0.21 μg/g, respectively. There were signs of tubular atrophy in 63%, interstitial fibrosis in 21%, glomerulosclerosis in 71%, arteriosclerosis in 47%, and arteriolohyalinosis in 36% of the donors, but, as could be expected, the histopathological findings were limited, mostly Banff grade 1. In models adjusted for age, sex and smoking, kidney Cd was positively associated with tubular atrophy (p = 0.03) and possibly with arteriolohyalinosis (p = 0.06). Kidney Hg was associated with arteriosclerosis (p = 0.004).The results suggest that even low levels of Cd in the kidney can induce a mild degree of tubular atrophy. This is in line with previous findings at high-level Cd exposure. The association between kidney Hg and renal arteriosclerosis was unexpected, and may be a chance finding.

To evaluate reproductive, obstetric, and long-term health of the first completed study of uterus transplantation (UTx).Prospective.University hospital.Nine live donor UTx procedures were conducted and seven were successful. Donors, recipients, and children born were observed.In vitro fertilization was performed with embryo transfer (ET) of day 2 or day 5 embryos in natural cycles. Pregnancies and growth trajectory of the children born were observed. Health-related quality of life, psychosocial outcome, and medical health of donors and recipients were evaluated by questionnaires.The results of in vitro fertilization, pregnancies, growth of children, and long-term health of patients were reported.Six women delivered nine infants, with three women giving birth twice (cumulative birth rates of 86% and 67% in surgically successful and performed transplants, respectively). The overall clinical pregnancy rate (CPR) and live birth rate (LBR) per ET were 32.6% and 19.6%, respectively. For day 2 embryos, the CPR and LBR per ET were 12.5% and 8.6%, respectively. For day 5 embryos, the CPR and LBR per ET were 81.8% and 45.4%, respectively. Fetal growth and blood flow were normal in all pregnancies. Time of delivery (median in full pregnancy weeks + days [ranges]) by cesarean section and weight deviations was 35 + 3 (31 + 6 to 38 + 0) and -1% (-13% to 23%), respectively. Three women developed preeclampsia and four neonates acquired respiratory distress syndrome. All children were healthy and followed a normal growth trajectory. Measures of long-term health in both donors and recipients were noted to be favorable. When UTx resulted in a birth, scores for anxiety, depression, and relationship satisfaction were reassuring for both the donors and recipients.The results of this first complete UTx trial show that this is an effective infertility treatment, resulting in births of healthy children and associated with only minor psychological and medical long-term effects for donors and recipients.NCT02987023.

BACKGROUND The acceptance of ABO-incompatible (ABOi) liver grafts will expand the donor pool for a patient in urgent need for a liver transplantation (LT). Here we report our results with emergency ABOi DD (deceased donor) LT using rituximab and antigen specific immunoadsorption. PATIENTS AND METHODS 2009 to 2019 we performed 20 ABOi DD LTs (adults n = 17, children n = 3) for patients in urgent need for a LT. Immunosuppression consisted of rituximab (n = 20) and basiliximab (n = 15) or anti-thymocyte globuline (n = 4), intravenous immunoglobulin (IVIG; n = 6), tacrolimus, prednisolone and mycophenolate mofetil. Fifteen patients were treated with IA (n = 14) or both IA and plasmapheresis (PP; n = 1) pre-transplant and 18 patients were treated with IA (n = 15) or both IA and PP (n = 3) post-transplant. The median pre-transplant MELD- score was 40 (range 18-40). Patient and graft survival and complications were compared to a 1:4 case matched control group of ABO-identical or compatible (ABOid/c) DDLT. RESULTS The 1-, 3- and 5-year patient and graft survival rates were 85, 85 and 78% for the ABOi recipients and not significantly different compared to ABOid/c controls. Only one ABOi patient developed antibody-mediated rejection. CONCLUSION Patient and graft survival after emergency ABOi DDLT using rituximab and immunoadorption was equal to ABOid/DDLT. ABOi DD LT was a successful approach to expand the donor pool for patients in urgent need for a liver graft.

Summary Background Late radiation cystitis is an adverse effect of cancer treatment with radiotherapy in the pelvic region. Symptoms of late radiation cystitis can be assessed with the Expanded Prostate Index Composite Score (EPIC). Previous reports indicate that hyperbaric oxygen therapy reduces symptoms from late radiation cystitis, but the evidence is predominantly based on non-randomised and retrospective studies. We aimed to assess whether hyperbaric oxygen therapy would mitigate symptoms of late radiation cystitis. Methods We did a randomised, controlled, phase 2–3 trial (RICH-ART [Radiation Induced Cystitis treated with Hyperbaric oxygen—A Randomised controlled Trial]) at five Nordic university hospitals. All patients aged 18–80 years, with pelvic radiotherapy completed at least 6 months previously, a score of less than 80 in the urinary domain of the Expanded Prostate Index Composite Score (EPIC), and referred to participating hyperbaric clinics due to symptoms of late radiation cystitis, were eligible for inclusion. Exclusion criteria were ongoing bleeding requiring blood transfusion exceeding 500 mL in the past 4 weeks, permanent urinary catheter, bladder capacity less than 100 mL, fistula in the urinary bladder, previous treatment with hyperbaric oxygen therapy for late radiation injuries, and contraindications to hyperbaric oxygen therapy. After computer-generated 1:1 randomisation with block sizes of four for each stratification group (sex, time from radiotherapy to inclusion, and previous invasive surgery in the pelvic area), patients received hyperbaric oxygen therapy (30–40 sessions, 100% oxygen, breathed at a pressure of 240–250 kPa, for 80–90 min daily) or standard care with no restrictions for other medications or interventions. No masking was applied. The primary outcome was change in patient-perceived urinary symptoms assessed with EPIC from inclusion to follow-up at visit 4 (6–8 months later), measured as absolute change in EPIC urinary total score. RICH-ART closed enrolment on Dec 31, 2017; the last follow-up data will be compiled in 2023. RICH-ART is registered with ClinicalTrials.gov , number NCT01659723 , and with the European Medicines Agency, number EudraCT 2012-001381-15. Findings Of 223 patients screened between May 9, 2012, and Dec 20, 2017, 87 patients were enrolled and randomly assigned to either hyperbaric oxygen therapy (n=42) or standard care (n=45). After excluding eight patients who withdrew consent directly after randomisation (one in the hyperbaric oxygen therapy group and seven in the standard care group), 79 were included in the intention-to-treat analyses (n=41 in the hyperbaric oxygen therapy group, n=38 in the standard care group). Median time from randomisation to visit 4 was 234 days (IQR 210–262) in the hyperbaric oxygen therapy group and 217 days (195–237) in the standard care group. The difference between change in group mean of EPIC urinary total score at visit 4 was 10·1 points (95% CI 2·2–18·1; p=0·013; 17·8 points [SD 18·4] in the hyperbaric oxygen therapy group vs 7·7 points [15·5] in the standard care group). 17 (41%) of 41 patients in the hyperbaric oxygen therapy group experienced transient grade 1–2 adverse events, related to sight and hearing, during the period of hyperbaric oxygen therapy. Interpretation Our results suggest that hyperbaric oxygen therapy relieves symptoms of late radiation cystitis. We conclude that hyperbaric oxygen therapy is a safe and well tolerated treatment. Funding The regional research fund of Region Vastra Gotaland, Sweden, the regional Health Technology Assessment Centre at Sahlgrenska University Hospital, Sweden, and Lions Cancer Research Fund of Western Sweden.

In anti-glomerular basement membrane (anti-GBM) disease, IgG class autoantibodies induce rapidly progressive glomerulonephritis. Regrettably, many patients are diagnosed at a late stage when even intensive conventional treatment fails to restore renal function The endopeptidase IdeS (Immunoglobulin G degrading enzyme of Streptococcus pyogenes) (imliflidase) rapidly cleaves all human IgG subclasses into F(ab′)2 and Fc fragments. We received permission to treat three patients with refractory anti-GBM nephritis without pulmonary involvement on a compassionate basis. All patients were dialysis-dependent for days or weeks when treated, and all had high levels of circulating anti-GBM despite plasma exchange. A single dose of IdeS led to complete clearance of circulating anti-GBM antibodies in all three patients. After about a week, all rebounded but the rebounds were easily managed by plasma exchange in two of three cases. Renal histology demonstrated severe crescentic glomerulonephritis with acute but mainly chronic changes. Staining for the Fc fragment was negative in all while Fab was positive in two patients. Unfortunately, none of the patients regained independent renal function. Thus, treatment with IdeS led to rapid clearance of circulating and kidney bound anti-GBM antibodies. The clinical utility, dosing and usage to preserve renal function remain to be determined.

Acute kidney injury (AKI) is frequent after liver transplantation (LT) and correlates with later development of chronic kidney disease. Its etiology is multifactorial and combines pre-, intra-, and postoperative factors. Additionally, the liver graft itself seems an important element in the development of AKI, yet the detailed mechanisms remain unclear. We hypothesized that grafts of LT recipients developing significant early AKI may show distinct proteomic alterations, and we set out to identify proteome differences between LT recipients developing moderate or severe AKI (n = 7) and LT recipients without early renal injury (n = 7). Liver biopsies obtained one hour after reperfusion were assessed histologically and using quantitative proteomics. Several cytokines and serum amyloid A2 (SAA2) were analyzed in serum samples obtained preoperatively, 2–4 h, and 20–24 h after graft reperfusion, respectively. LT induced mild histological alterations without significant differences between groups but uniformly altered liver function tests peaking on postoperative day 1, with a trend towards more severe alterations in patients developing AKI. Global quantitative proteomic analysis revealed 136 proteins differing significantly in their expression levels (p < 0.05, FC 20%): 80 proteins had higher and 56 had lower levels in the AKI group. Most of these proteins were related to immune and inflammatory responses, host defense, and neutrophil degranulation. No differences between the studied pro- and anti-inflammatory cytokines or SAA2 between groups were found at any moment. Our results suggest that grafts of LT patients who develop early AKI reveal a distinct proteome dominated by an early yet prominent activation of the innate immunity. These findings support the hypothesis that AKI after LT may be favored by certain graft characteristics.

Background and Aims Kidney transplantation is frequently used as a treatment in uremic patients. However, long term function is not easily predicted. The aim of this study was to investigate to what extent histological diagnosis in the first registered transplant kidney biopsy is related to clinical outcome. Method Included were data of 1463 patients (36.6 % women, 63.4 % men) that were merged from a kidney transplantation register and a biopsy register. These patients obtained their first registered transplant biopsy during the period January 1, 2007 until July 30, 2017. Fisher’s exact test and χ-2 analyses were used for cross-tabulation of data. Graft- and patient-survival analysis was performed by Kaplan-Meier analysis with log-rank tests comparing different groups and in next step age and gender adjusted analysis were performed by multivariate Cox-regression-analysis. Data are presented as Hazard Ratio (HR) and 95% Confidence Intervals (CI). A two-sided p-value of Results The graft-survival was shorter for patients with biopsy-proven glomerular diseases (HR 8.1, CI 3.1-20.7) and rejections (HR 4.3, CI 1.7 -10.5) compared to normal biopsy findings. Further, there was a shorter graft-survival for those with chronic damages (HR 3.2, CI 1.3-8.0), acute tubular injuries (HR 3.0, CI 1.2-7.8), and borderline changes (HR 2.9, CI 1.1-7.6). The patient-survival was reduced for patients with biopsy-proven hematological diseases (HR 9.6, CI 2.1-44.0). Sub analysis of all types of rejections showed shorter graft-survival for chronic T-cell-mediated rejection (TCMR) (HR 4.8, CI 2.1-11.7), active antibody-mediated rejection (ABMR) (HR 4.4, CI 2.1-9.3), chronic ABMR (HR 3.8, CI 2.2-6.7), combined chronic ABMR and TCMR (HR 4.0, CI 2.4-6.9) and other rejections (HR 3.3, CI 1.1-9.6) compared to acute TCMR. Patients with TCMR Banff grade II rejection had a better graft-survival (HR 0.35, CI 0.20-0.63) compared to other rejections as well as patients with TCMR Banff grade I (HR 0.52, CI 0.29-0.93). 265 patients had graft-loss and 42 of those patients died afterwards (15.8%). Of the 42 who died after graft-loss 9 patients died within 30 days after transplant failure (21.4%). Conclusion A shorter graft-survival was found in kidneys with glomerular diseases, rejections, acute tubular injuries, borderline changes and chronic damages. A shorter patient-survival was noted for patients with transplant kidney biopsies with hematological diseases. Patients with Banff grade II rejection had a better graft-survival compared to all other diagnosis and other rejections. Further, awareness should be given to patients the first month after graft-loss.

Historically, secondary amyloidosis has been a feared complication of chronic inflammatory conditions. The fibril protein AA derives from the acute phase reactant serum amyloid A (SAA). Long-term elevation of SAA levels remains a major risk factor for the development of AA amyloidosis in rheumatic diseases, and the prognosis may be unpredictable. Nowadays, with increased availability of effective biological agents, the incidence of AA amyloidosis seems to be declining. Still, genetically predisposed subjects with slowly progressive disease and mild symptoms combined with ongoing systemic inflammation may be at risk. Interleukin-6 (IL-6) is one of the drivers of SAA release and effectiveness of the humanized anti-IL-6 receptor antibody tocilizumab (TCZ) for the treatment of AA amyloidosis has been observed in some rheumatic conditions. Herein, we report two male subjects with longstanding ankylosing spondylitis (AS) complicated by renal amyloidosis who received TCZ with rapid and beneficial effects regarding inflammation and proteinuria. To the best of our knowledge, the use of TCZ in AS patients with this extra-articular manifestation has not previously been described. The paper includes histopathology, clinical follow-up, and longitudinal data of the two cases along with a comprehensive review of relevant literature. Mechanisms behind amyloid-mediated tissue damage and organ dysfunction are discussed. Altogether, our data highlight that blocking IL-6 signaling may represent a promising therapeutic option in patients with renal AA amyloidosis. Funding Agencies|King Gustaf V and Queen Victorias Freemasons Foundation; Region Ostergotland (ALF grants); Swedish Rheumatism Association

International audience; Uveal melanoma is a malignant tumor of the eye that often metastasizes to the liver conferring poor prognosis. When comparing immune profiles in peripheral blood of untreated patients with uveal melanoma liver metastasis and healthy blood donors, it was observed that immune cells of uveal melanoma patients carried immunosuppressive features. Patient blood contained an increased content of CD14+HLA-DR−/low M-MDSCs and inflammatory CD16+ monocytes, while their dendritic cells expressed lower levels of activation markers. Melanoma patients also harbored an enhanced fraction of CD4+Foxp3+ regulatory T cells, while their effector T cells expressed lower levels of the activation marker HLA-DR. Biopsies from liver metastases were obtained from patients with uveal melanoma that subsequently underwent hyperthermic isolated hepatic perfusion (IHP) with melphalan. There were trends indicating a positive correlation between a high infiltration of CD8+ T cells in metastases and an activated immune cell profile in blood. High metastatic infiltration of CD8+ T cells and CD68+ macrophages, but not of immunosuppressive CD163+ macrophages, correlated to a longer overall survival in patients treated with IHP. Hence, while the immune system of patients with uveal melanoma shows signs of immunosuppression, the presence of activated immune cells may correlate to a longer survival, at least following IHP treatment.

Lentigo maligna (LM) represents an overgrowth of atypical melanocytes at the dermal-epidermal junction of chronically sun-damaged skin. The presence of LM on sun-damaged skin poses a diagnostic challenge because the solar-induced melanocytic hyperplasia makes it difficult to assess the LM margins. Melanocytic density can be used to discriminate sun-damaged skin from LM. The aim of this study was to quantify the melanocytic density at the surgical margins of scanned whole-slide images of LM comparing sections stained with H&E and SOX10. Twenty-six surgically excised LM diagnosed at the Department of Pathology at Sahlgrenska University Hospital were collected. The slides that contained the closest surgical margin or harbored the highest density of melanocytes at the margin were selected for serial sectioning using H&E and SOX10. Whole-slide imaging at ×40 magnification was used, and a circular field with a diameter of 0.5 mm at the surgical margin was superimposed on the image. Five blinded pathologists reviewed the slides in a randomized order. In the majority of the cases (24/26), the pathologists identified more melanocytes on the SOX10 slides than those on the H&E slides. On average, 2.5 times more melanocytes were counted using SOX10 compared with H&E (P < 0.05). Furthermore, the average group SD on the H&E slides was 4.12 compared with 2.83 on the SOX10 slides (P = 0.004). Thus, the use of SOX10 staining leads to higher melanocytic density counts compared with H&E staining when assessing the surgical margins of LM. The use of SOX10 staining also significantly decreased the interobserver variability between pathologists.

Uterus transplantation has proved to be a feasible treatment for uterine factor infertility. Herein, we report on recipient outcome in the robotic uterus transplantation trial of 2017&ndash, 2019. The eight recipients had congenital uterine aplasia. The donors were six mothers, one sister, and one family friend. Donor surgery was by robotic-assisted laparoscopy. Recipient surgery was by laparotomy and vascular anastomoses to the external iliacs. The duration (median (ranges)) of recipient surgery, blood loss, measured (left/right) uterine artery blood flow after reperfusion, and length of hospital stay were 5.15 h (4.5&ndash, 6.6), 300 mL (150&ndash, 600), 43.5 mL/min (20&ndash, 125)/37.5 mL/min (10&ndash, 98), and 6 days (5&ndash, 9), respectively. Postoperative uterine perfusion evaluated by color Doppler showed open anastomoses but restricted blood distribution in two cases. Repeated cervical biopsies in these two cases initially showed ischemia and, later, necrosis. Endometrial growth was not seen, and hysterectomy was later performed, with pathology showing partly viable myometrium and fibrosis but necrosis towards the cavity. The other six patients acquired regular menstrual cyclicity. Surgery was performed in two patients to correct vaginal stenosis. Reversible rejection episodes were seen in two patients. In conclusion, the rate of viable uterine grafts during the initial 6-months of the present study (75%) leaves room for improvement in the inclusion/exclusion criteria of donors and in surgical techniques. Initial low blood flow may indicate subsequent graft failure.

Background and Aims Kidney transplantation is a frequent treatment in uremic patients. However, long term patency is limited. The aim of this study was to investigate the histological findings in transplant biopsies in relation to clinical outcome in patients. Method 1542 patients (36.4 % women) were included if they had a first kidney transplant registered in a quality assessment registry (period October 24, 1968 and August 28, 2017) and also had registered a first transplant kidney biopsy during the period January 1, 2007 until Mars 2, 2018. Graft- and patient-survival analysis was performed by Kaplan-Meier- and Cox-regression-analysis (adjusted for age and gender). Data are presented as Hazard Ratio (HR) and 95% Confidence Intervals (CI). A two-sided p-value of Results Patients with primary and recurrent glomerulonephritis (GN) found in the biopsy had a worse graft- (70% at 5-year) and patient-survival (85% at 5-year) compared to all other diagnoses (p Conclusion Patients with GN and patients with TGP had a worse outcome in both graft- and patient-survival. Awareness should focus on the patients who die soon after graft-loss.

Uterus transplantation has enabled women with absolute uterine factor infertility to carry a pregnancy. The first human uterus transplantation trial was initiated in 2013 in Gothenburg, Sweden. It was completed with 7 transplantations with long-term allograft survival and 9 children born from 6 women. In the present study we describe the histopathology of these 7 allografts, which were removed at 22-83 months after transplantation, and compare findings to control cases. Morphological findings in a subset of explants included linear subepithelial inflammation and perivascular stromal inflammation in the cervix, small inflammatory foci in the myometrium, and intimal inflammation in larger arteries. The average number of T cells, B cells, and macrophages was higher in transplants compared to normal controls, but variability was high among transplants. Chronic-active vascular rejection was seen in 2 of 7 transplants, both showed also inflammation in the cervix. Further, the inflammation seen in the cervix reflected the inflammation in the myometrium, suggesting that cervical biopsies are suitable to monitor rejection. However, the degree of inflammation and signs of rejection in explants did not reflect on the possibility to become pregnant in this limited series.

Background: Oral implants have displayed clinical survival results at the 95%-99% level for over 10 years of follow up. Nevertheless, some clinical researchers see implant disease as a most common phenomenon. Oral implants are regarded to display disease in the form of mucositis or peri-implantitis. One purpose of the present article is to investigate whether a state of disease is necessarily occurring when implants display soft tissue inflammation or partially lose their bony attachment. Another purpose of this article is to analyze the mode of defense for implants that are placed in a bacteria rich environment and to analyze when an obtained steady state between tissue and the foreign materials is disturbed. Materials and Methods: The present article is authored as a narrative review contribution. Results: Evidence is presented that further documents the fact that implants are but foreign bodies that elicit a foreign body response when placed in bone tissue. The foreign body response is characterized by a bony demarcation of implants in combination with a chronic inflammation in soft tissues. Oral implants survive in the bacteria-rich environments where they are placed due to a dual defense system in form of chronic inflammation coupled to immunological cellular actions. Clear evidence is presented that questions the automatic diagnostics of an oral implant disease based on the finding of so called mucositis that in many instances represents but a normal tissue response to foreign body implants instead of disease. Furthermore, neither is marginal bone loss around implants necessarily indicative of a disease; the challenge to the implant represented by bone resorption may be successfully counteracted by local defense mechanisms and a new tissue-implant steady state may evolve. Similar reactions including chronic inflammation occur in the interface of orthopedic implants that display similarly good long-term results as do oral implants, if mainly evaluated based on revision surgery in orthopedic cases. The most common mode of failure of orthopedic implants is aseptic loosening which has been found coupled to a reactivation of the inflammatory- immune system. Conclusions: Implants survive in the body due to balanced defense reactions in form of chronic inflammation and activation of the innate immune system. Ten year results of oral and hip /knee implants are hence in the 90+ percentage region. Clinical problems may occur with bone resorption that in most cases is successfully counterbalanced by the defense/healing systems. However, in certain instances implant failure will ensue characterized by bacterial attacks and/or by reactivation of the immune system that now will act to remove the foreign bodies from the tissues.

Uterus transplantation (UTx) has been successfully introduced as a treatment option for women with absolute uterine factor infertility (AUFI). AUFI representing approximately 3% to 5% of the female general population is linked to either congenital uterine agenesis (Mayer-Rokitansky-Küster-Hauser syndrome), major congenital uterine malformation (hypoplastic uterus, fraction of bicornuate/unicornuate uterus), a surgically absent uterus, or an acquired condition (intrauterine adhesions, leiomyoma) linked to uterine malfunction that causes implantation failure or defect placentation. The world's first clinical uterus transplant was performed in 2000. However, a hysterectomy became necessary shortly after the surgery due to uterine necrosis. In 2011, a group in Turkey reported on a surgically successful deceased donor transplant; however, this procedure has, to date, not resulted in a healthy live birth, the ultimate goal of UTx. Building on an extensive experimental background in various animal models, including primates, the Gothenburg group led by Brännström reported on the first delivery of a healthy baby in a recipient of a live donor UTx in 2014. This event did not only show the feasibility of UTx, it also helped defining relevant areas of clinical and basic research. Use of a gestational surrogate carrier, is, at least in theory, an alternative for a woman with AUFI seeking genetic motherhood. However, in the clear majority of countries worldwide, gestational surrogacy is not practiced based on legal, ethical, or religious concerns. Of note, the overwhelming majority of surveyed women in the United Kingdom, a country which permits surrogacy, preferred UTx over gestational surrogacy and adoption. Moreover, randomly selected women of fertile age in Sweden preferred UTx over gestational surrogacy. A recent large survey in Japan with more than 3000 participants revealed that UTx had a twofold higher acceptance rate compared with gestational surrogacy. In a recent US survey exploring the potential of donating vascularized composite allografts, uterus donation achieved the highest priority. Thus, the acceptance of UTx as infertility treatment for women with AUFI is high, although the procedure remains in its infancy. Here, we provide an update of clinical activities, summarize achievements and challenges, and submit areas of research interests.

AIM: To evaluate if the administration of desmopressin alters the risk for renal biopsy complications.METHODS: A multicenter registry containing 576 native kidney biopsies (NKb) with a serum creati ...

Histopathology is currently the gold standard to diagnose rejection in transplanted organs. In contrast to other solid transplants, there is yet no knowledge about laboratory parameters or early clinical signs that may indicate rejection after uterus transplantation. However, the graft after uterus transplantation can be monitored by histological analysis of ectocervical biopsies. These biopsies are easily accessible at a standard gynecological examination, without putting the patient or graft at risk. Protocol biopsies are taken at regular time intervals after transplantation with subsequent follow-up biopsies in case of rejection to monitor treatment. We have developed and published a grading system for diagnosis of rejection on uterus transplantation biopsies, and this has been successfully applied during the initial Swedish trial with live donor transplantation and during the ongoing robotic-assisted uterus transplantation trial.

BACKGROUND Marginal bone resorption has by some been identified as a "disease" whereas in reality it generally represents a condition. PURPOSE The present article is a comparison between oral and orthopedic implants, as previously preferred comparisons between oral implants and teeth seem meaningless. MATERIALS AND METHODS The article is a narrative review on reasons for marginal bone loss. RESULTS AND CONCLUSIONS The pathology of an oral implant is as little related to a tooth as is pathology of a hip arthroplasty to a normally functioning, pristine hip joint. Oral as well as orthopedic implants are recognized as foreign bodies by the immune system and bone is formed, either in contact or distance osteogenesis, to shield off the foreign materials from remaining tissues. A mild immune reaction coupled to a chronic state of inflammation around the implant serve to protect implants from bacterial attacks. Having said this, an overreaction of the immune system may lead to clinical problems. Marginal bone loss around oral and orthopedic implants is generally not dependent on disease, but represents an immunologically driven rejection mechanism that, if continuous, will threaten implant survival. The immune system may be activated by various combined patient and clinical factors or, if rarely, by microbes. However, the great majority of cases with marginal bone loss represents a temporary immune overreaction only and will not lead to implant failure due to various defense mechanisms.

BK-virus (BKV) associated nephropathy (BKVAN) and BKV associated haemorrhagic cystitis (HC) are complications of BKV infection/reactivation in renal and allogeneic haematopoietic stem cell transplantation (HSCT) patients, respectively. The task of how to manage these diseases was given to the chair by the Swedish Reference Group for Antiviral Therapy (RAV). After individual contributions by members of the working group, consensus discussions were held in a meeting on 23 January 2018 arranged by RAV. Thereafter, the recommendations were published in Swedish on November 2018. The current translation to English has been approved by all co-authors. High BKV serum levels suggest an increased risk for BKVAN and potential graft failure. For detection of BKVAN, careful monitoring of BKV DNA levels in serum or plasma is recommended the first year after renal transplantation and when increased creatinine serum levels of unknown cause are observed. Notably, a renal biopsy is mandatory for diagnosis. To reduce the risk for progression of BKVAN, there is no specific treatment, and tailored individual decrease of immunosuppression is recommended. For BKV-HC, BKV monitoring is not recommended, since BK-viruria frequently occurs in HSCT patients and the predictive value of BKV in plasma/serum has not been determined. However, the risk for BKV-HC is higher for patients undergoing myeloablative conditioning, having an unrelated, HLA-mismatched, or a cord blood donor, and awareness of the increased risk and early intervention may benefit the patients. Also for BKV-HC, no specific therapy is available. Symptomatic treatment, e.g. forced diuresis and analgesics could be of use.

Purpose Radiotherapy is effective in the treatment of tumors in the pelvic area but is associated with side effects such as cystitis and proctitis. Hyperbaric Oxygen Therapy (HBOT) has emerged as a treatment modality for radiation-induced side effects. In a rat model for radiation cystitis, we studied the effects of HBOT on oxidative stress and pro-fibrotic factors. Materials and methods Sedated Sprague-Dawley rats underwent bladder irradiation of 20 Gy with and without 20 sessions of HBOT during a fortnight. Control animals were treated with and without HBOT. All four groups of animals were euthanized 28 days later. Histopathological examinations, immunohistochemistry and quantitative polymerase chain reaction (qPCR) were used to analyze changes in oxidative stress (8-OHdG), anti-oxidative responses (SOD-1, SOD2, HO-1 and NRFα) and a panel of Th1-type and Th2-type cytokines (IL-1β, IL-4, IL-5, IL-6, IL-10, IL-13, TNF-α, TGF-β, IFN-γ) in the urinary bladder. Results Bladder irradiation increased the expression of 8-OHdG, SOD2, HO-1, NRFα, IL-10, TNF-α and tended to increase TGF-β. These changes were completely reversed by HBOT while HBOT in control animals had no effects on the studied markers for oxidative stress, anti-oxidative responses and Th1-type and Th2-type cytokines. Conclusions Radiation induced a significant elevation of oxidative stress, antioxidants and pro-fibrotic factors in our animal model for radiation cystitis that were completely reversed and normalized by HBOT. Our findings indicate that HBOT may prevent radiation-induced changes by affecting oxidative stress and inflammatory cascades induced by radiation. Summary Radiotherapy may cause the development of chronic inflammation and fibrosis, significantly impairing organ function. We hypothesized that bladder irradiation induces an oxidative stress reaction, thereby triggering the redox system and thus initiating an inflammatory and pro-fibrotic response. We aimed to assess whether these changes would be reversed by hyperbaric oxygen using an animal model for radiation cystitis. Our study show that hyperbaric oxygen therapy may reverse oxidative stress and pro-inflammatory factors induced by radiation.

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.

Objective To determine whether a uterus from the mother of a woman with absolute uterine factor infertility can be transplanted to daughter and carry a pregnancy with delivery of a healthy child. Design Part of an observational study. Setting University teaching hospital. Patient(s) Twenty eight-year-old woman with uterine agenesis, her male partner, and her 50-year-old mother. Intervention(s) In vitro fertilization with embryo cryopreservation before live donor uterus transplantation (UTx). Induction immunosuppression. Embryo transfer 12 months after UTx, pregnancy controls, delivery, and hysterectomy. Main Outcome Measure(s) Results of IVF-ET, parameters of pregnancy/birth, and surgical data of transplantation/cesarean section/hysterectomy. Result(s) Two IVF cycles before UTx resulted in 10 cryopreserved embryos. Donor surgery included hysterectomy with vascular pedicles of uterine vessels and proximal vessels up to and including parts of internal iliacs. Recipient surgery was by bilateral vascular connections to external iliacs, vaginal–vaginal anastomosis, and uterine fixation. Pregnancy occurred at the first single ET, and the pregnancy proceeded uneventfully until gestational week 34, when the patient developed cholestasis with intense pruritus. Cesarean section was performed at 34+6, with delivery of a healthy boy (weight 2,335 g). Hysterectomy was performed 3.5 months after delivery. The weight of the healthy child at 12 months was 9.3 kg. Grandmother (uterus donor) and mother are in good health 3 years after UTx. Conclusion(s) This is the first report of a live birth after mother-to-daughter UTx, and it also represents the second birth ever after human UTx. Clinical Trial Registration NCT01844362.

The pathophysiology behind radiation cystitis is poorly understood. Here we investigated whether bladder irradiation affects the immune system of the rat urinary bladder. Female rats were sedated and exposed to one single radiation dose of 20 Gy or only sedated (controls) and killed 16 h to 14 days later. Rats were placed in a metabolic cage at 16 h, 3 days, 7 days and 14 days following bladder irradiation. The urinary bladders were harvested and analysed with qPCR, immunohistochemistry and/or Western blot for the expression of interferon (IFN)-γ, interleukin (IL)-1β, IL-2, IL-4, IL-5, IL-6, IL-10, IL-13, nitric oxide synthases (eNOS, iNOS and nNOS), tumour necrosis factor (TNF)-α and toll-like receptor 4 (TLR4). Urine was collected and analysed for IL-6 and nitrite (reflecting nitric oxide activity) with ELISA and the Griess reaction, respectively. Irradiation increased bladder frequency and decreased voiding volumes 14 days following bladder irradiation. Bladder irradiation increased the expression of IL-10 and collagen in the bladder, while TLR4 and IL-6 expressions were decreased in the urothelium concomitantly with a decrease in mast cells in the submucosa and urine levels of IL-6 and nitrite. The present findings show that bladder irradiation leads to urodynamic changes in the bladder and may suppress important immunoregulatory pathways in the urinary bladder.

To describe general observations of immunological reactions to foreign materials and to realize that CP titanium gives rise to a foreign body reaction with subsequent bone embedment when placed as oral implants. To analyse the possibility of titanium allergy.The present paper is of a narrative review type. Hand and Medline searches were performed to evaluate marginal bone loss of oral implants and the potential of titanium allergy.Immunological reactions to foreign substances include Type I hypersensitivity reactions such as allergy, Type II hypersensitivity reactions characterised by IgM or IgG antibodies that may react with blood group antigens at transfusion, and Type III hypersensitivity caused by antigen-antibody immune complexes exemplified by acute serum sickness. There is also Type IV hypersensitivity, or delayed hypersensitivity, which is typically found in drug and foreign body reactions. It proved very difficult to find a universally acceptable definition of reasons for marginal bone loss around oral implants, which lead to most varying figures of so-called peri-implantitis being 1% to 2% in some 10-year follow-up papers to between 28% and 56% of all placed implants in other papers. It was recognised that bone resorption to oral as well as orthopaedic implants may be due to immunological reactions. Today, osseointegration is seen as an immune-modulated inflammatory process where the immune system is locally either up- or downregulated. Titanium implant allergy is a rare condition, if it exists. The authors found only two papers presenting strong evidence of allergy to CP titanium, but with the lack of universally accepted and tested patch tests, the precise diagnosis is difficult.CP titanium acts as a foreign body when placed in live tissues. There may be immunological reasons behind marginal bone loss. Titanium allergy may exist in rare cases, but there is a lack of properly designed and analysed patch tests at present.

Background: Idiopathic membranous nephropathy (MN) is one of the leading causes of nephrotic syndrome in adults and may result in end-stage renal disease (ESRD). In this retrospective study, we describe the outcomes and treatment patterns of patients with idiopathic MN in six nephrology clinics in the western part of Sweden. Methods: Seventy-three consecutive patients with biopsy-proven MN in the years 2000–12 were classified as idiopathic, i.e. secondary forms were excluded. The patients were followed retrospectively for a mean period of 83 months and clinical data were collected through the medical files. Results: A high proportion (88%) of the patients received supportive treatment with angiotensin-converting enzyme inhibition, angiotensin receptor blockade and/or statins. At the end of follow-up, 43 patients were in complete remission, 12 in partial remission, 10 patients had developed ESRD and 8 patients had on-going proteinuria. Fifty-one per cent of the patients received immunosuppressive therapy and the choice of therapy varied between and within the clinics. There was a tendency to initiate specific treatment at an early point instead of awaiting a possible spontaneous remission (21% of the patients), and nonrecommended therapy such as corticosteroids only was used in a high proportion of these cases (47%). Conclusions: Even though the treatment recommendations in idiopathic MN have not changed the last decade, the question of whom and when to treat seems to lead to uncertainty. Recent studies have presented promising results supporting the PLA2R antibody the predictive marker needed for this patient group. The diverse treatment approach presented in this study might have resulted in a worse outcome than expected. Hopefully, unnecessary exposure to immunosuppressive therapy or delayed treatment can be avoided through better support, education and treatment forums, and thus result in an improved outcome.

BACKGROUND: In idiopathic membranous nephropathy (MN), antibodies directed towards the glomerular phospholipase A2 receptor (PLA2R) have mainly been reported to be of IgG4 subclass. However, the role of the different IgG subclasses in the pathogenesis of MN, both in idiopathic MN and in secondary cases, is still unclear. In this retrospective study, we test the hypothesis that the absence of glomerular IgG4 and PLA2R in patients with MN indicates malignant disease. METHODS: The distribution pattern of glomerular IgG subclasses and PLA2R was studied in 69 patients with idiopathic MN and 16 patients with malignancy-associated MN who were followed up for a mean of 83 months. RESULTS: A significant correlation between the absence of IgG4 and PLA2R and malignancy-associated MN was found. Thus, IgG4 was positive in 45 of 69 patients (65%) with idiopathic MN but only in 5 of 16 patients (31%) with malignancy-associated MN. The other IgG subclasses did not differ statistically between the groups, IgG2-positivity being present in more than 94% of patients in both groups. Thirty-five of 63 patients (56%) with idiopathic MN and 3 of 16 (19%) patients with malignancy-associated MN had glomerular deposits of PLA2R. CONCLUSIONS: We have found that the absence of glomerular IgG4 and PLA2R is common in patients with malignancy-associated MN. In our material, IgG2 could not be used as a marker of underlying malignant disease. Finally, neither IgG1 nor IgG3 seems to be involved in the pathogenesis of MN.

The aim of this study was to investigate if specific clinical and histological findings can be related to biopsy complications to enable more closely monitoring patients at high risk.Results from 1081 biopsies (994 patients, median age 54.5 years; 896 native and 185 transplant kidney biopsies) were included. Diagnostic quality, morphology, clinical data and complications were prospectively registered.In native kidney biopsies, the most common diagnosis was IgA-nephritis, while in transplant kidney biopsies it was rejection. Patients with IgA-nephritis had a higher risk of major complications (11.7 versus 6.4 %, Odds Ratio (OR) 1.8, Confidence Interval (CI) 1.1-3.2) when compared to patients with other diseases. In native kidney biopsies, patients who experienced major complications had higher degrees of glomerulosclerosis (31 versus 20 %, p = 0.008), whereas in transplant kidney biopsies, patients had higher degrees of interstitial fibrosis (82 versus 33 %, p0.001) when compared to patients without major complications. IgA-nephritis-patients had a higher risk of re-biopsies (4.7 versus 1.3 %, OR 4, CI 1.5-11) than patients with other diseases. Patients with native kidneys who needed re-biopsies were younger (42.6 versus 52.3 years, p = 0.031) and had a higher degree of interstitial fibrosis (63 versus 34 %, p = 0.046).Patients with IgA-nephritis have an increased risk of major biopsy complications. The risk of re-biopsies was higher in younger individuals and in patients with IgA-nephritis.

Objective To report the 12-month outcome of seven patients with viable uteri after uterus transplantation (UTx). Design Prospective observational study. Setting University hospital. Patient(s) Seven patients with absolute uterine infertility and viable uteri for 12 months after live-donor UTx. Intervention(s) Predetermined immunosuppression was with tacrolimus and mychophenolate mofetil (MMF) during 6 months, whereupon MMF should be withdrawn. Frequent ultrasound examinations were performed to assess uterine appearance and uterine artery blood flow. Cervical biopsies (for histological detection of rejection) were obtained at preset time points, with temporary adjustments of immunosuppression if there were signs of rejection. Menstruations were systematically recorded. Main Outcome Measure(s) Menstruation, uterine artery blood flow, histology of cervical biopsies, and blood levels of tacrolimus. Result(s) All patients showed regular menses after 1–2 months. Uterine artery blood flow was unchanged, with a median pulsatility index of 1.9 (range, 0.5–5.4). Blood levels of tacrolimus were approximately 10, 9, and 8 (μg/L) during months 2, 9, and 12, respectively. Four recipients showed mild inflammation in biopsies after MMF withdrawal and were treated with corticosteroids and azathioprine during the remainder of the 12 months. Subclinical rejection episodes were detected on ectocervical biopsies in five recipients. Histology showed apoptotic bodies and occasional spongiosis in the squamous epithelium. Moderate infiltration of lymphocytes and neutrophils was seen in the epithelial/stromal interface. All rejection episodes were successfully treated for 2 weeks with corticosteroids or dose increments of tacrolimus. Conclusion(s) We demonstrate long-term uterine viability after UTx, with continued menstruation and unaltered uterine artery blood flow. Subclinical rejection episodes were effectively reversed by temporary increase of immunosuppression. Clinical Trial Registration Number NCT01844362.

One prerequisite for a successful clinical outcome of human pluripotent stem cell (hPSC) based therapies is immune compatibility between grafted cells/tissue and recipient. This study explores immune determinants of human embryonic stem cell lines (hESC) and induced human pluripotent stem cell (hiPSC) lines and hepatocyte- and cardiomyocyte-like cells derived from these cells. HLA class I was expressed on all pluripotent hPSC lines which upon differentiation into hepatocyte-like cells was considerably reduced in contrast to cardiomyocyte-like cells which retained class I antigens. No HLA class II antigens were found in the pluripotent or differentiated cells. Histo-blood group carbohydrate antigens SSEA-3/SSEA-4/SSEA-5, Globo H, A, Lex/Ley and sialyl-lactotetra were expressed on all hPSC lines. Blood group AB(O)H antigen expression was in accordance with ABO genotype. Interestingly, only a subpopulation of A1O1 cells expressed A. During differentiation of hPSC, some histo-blood group antigens showed congruent alteration patterns while expression of other antigens differed between the cell lines. No systematic difference in the hPSC cell surface tissue antigen expression was detected. In conclusion, hPSC and their derivatives express cell surface antigens that may cause an immune rejection. Furthermore, tissue antigen expression must be established for each individual stem cell line prior to clinical application.