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Objective To investigate whether post-transplantation immunosuppression negatively affects prostate cancer outcomes in male kidney transplant recipients. Patients and methods We used the Swedish Renal Register and the National Prostate Cancer Register to identify all kidney transplantation recipients diagnosed with prostate cancer in Sweden 1998-2016. After linking these registers with Prostate Cancer Database Sweden (PCBaSe), a case-control study was designed to compare time period and risk category-specific probabilities of a prostate cancer diagnosis amongst kidney transplantation recipients versus the male general population. The registers did not include information about the specific immunosuppression agent used in all transplantation recipients. Data from PCBaSe were used to compare prostate cancer characteristics at diagnosis and survival for patients with prostate cancer with versus without a kidney transplant. Propensity score matching, Cox regression analysis and Fisher's exact test were used and 95% confidence intervals (CIs) calculated. Results Almost half of the 133 kidney transplantation recipients were transplanted before the mid-1990s, when PSA testing became common. The transplant recipients were not more likely than age-matched control men to be diagnosed with any (odds ratio [OR] 0.84, 95% CI 0.70-0.99) or high-risk or metastatic prostate cancer (OR 0.84, 95% CI 0.62-1.13). None of the ORs for the different categories of prostate cancer increased with time since transplantation. Cancer characteristics at the time of diagnosis and cancer-specific survival were similar amongst transplant recipients and the control group of 665 men diagnosed with prostate cancer without a kidney transplant. Conclusions This Swedish nationwide, register-based study gave no indication that immunosuppression after kidney transplantation increases the risk of prostate cancer or adversely affects prostate cancer outcomes. The study suggests that men with untreated low-grade prostate cancer can be accepted for transplantation.

Kidney transplantation (Ktx) in elderly has become increasingly accepted worldwide despite their higher burden of comorbidities. We investigated important risk factors affecting long-term patient and graft survival. We included all (n = 747) Ktx patients >60 years from 2000 to 2012 in Sweden. Patients were age-stratified, 60-64, 65-69 and >70 years. Follow-up time was up to 10 years (median 7.9 years, 75% percentile >10 years). Primary outcome was 10-year patient survival in age-stratified groups. Secondary outcomes were 5-year patient and graft survival in age-stratified groups and the impact of risk factors including Charlson comorbidity index (CCI) on patient and graft survival. Mortality was higher in patients >70 years, after 10 years (HR 1.94; 95% CI 1.24-3.04; P = 0.004). Males had a higher 10-year risk of death (HR 1.39; CI 95% 1.04-1.86; P = 0.024). Five-year patient survival did not differ between age groups. In multivariate Cox analysis (n = 500), hazard ratio for 10-year mortality was 4.6 in patients with CCI >= 7 vs. Funding Agencies|ChiesiChiesi Pharmaceuticals Inc; Stiftelsen for njursjuka and Njurforbundet

BACKGROUND Living anonymous donation (LAD) of kidneys was introduced in Sweden in 2004. This study reports on outcomes of Swedish LAD experiences from 2004 to 2016, focusing on donors' motives, the care they received, psychosocial aspects, and medical status at follow-up. MATERIAL AND METHODS Donor data were collected through a physician interview, medical check-up, review of medical charts, the Hospital Anxiety Depression Scale (HADS), and a routine national questionnaire. Of the 26 LADs during the study period, 1 donor died and 1 declined to participate, leaving a study population of 24. RESULTS Half of the donors were male, which is a higher proportion than for directed living donors. The major motive detected was altruism. Of the 24 LADs, 96% were very satisfied and would donate again if possible, 46% noted increased self-esteem, and a third were happier after the donation. Sixty-two percent received anonymous information about the recipient and 40% would have liked to meet the recipient. HADS scores were normal. Two donors had antidepressant treatment, 1 of whom had received treatment before donation. Half mentioned that the pre-donation assessment took too long. At follow-up, mean eGFR was 62±12 mL/min/1.73 m², of which 16 were in CKD II and 8 were in CKD III. Four donors had developed hypertension, 1 of whom also developed type 2 diabetes. CONCLUSIONS Swedish LADs are very satisfied and medical outcomes are acceptable. We propose that the transplant community and the National Board of Health and Welfare take a more active approach to informing the general public about LAD.

Background and Aims Chronic kidney disease (CKD) shares important features of a dysregulated ageing process with other common “burden of lifestyle” diseases, which aggregates into the diseasome of ageing. Typically, this is hallmarked by an acceleration of epigenetic (DNA methylation-based) clocks. It remains to be determined if current therapeutic interventions, such as renal transplantation or dialysis, can slow this clock, and thus the rate of biological ageing, in CKD. We therefore assessed the rate of biological ageing in CKD patients and whether these therapies impact on it, by measuring epigenetic age before and 1 year after treatment. Methods Whole blood samples were taken from CKD 5 patients at baseline and 1 year after renal transplantation (n=12) or dialysis (n=11; peritoneal dialysis n=7, haemodialysis n=4) as well as from age and sex-matched population-based controls (n=24). DNA methylation was measured using the Illumina Infinium Human Methylation 450K BeadChip and epigenetic age was calculated using three independent DNA methylation clocks: the Horvath, Hannum, and PhenoAge clocks. Additionally, a novel composite clock incorporating these three clocks was evaluated. We then calculated the age acceleration (difference between epigenetic and chronological age) for each clock and compared average age acceleration between groups and across time points. Results Incident dialysis patients displayed accelerated ageing versus chronologically age-matched controls (p Conclusion CKD 5 patients display an increased biological (i.e. epigenetic) age. This age acceleration is mitigated one year after renal transplantation, but not in patients undergoing dialysis. Neither therapy reverses high biological age.

(1) Background: Post-transplant lymphoproliferative disease (PTLD) is a significant complication of solid organ transplantation (SOT). However, there is lack of consensus in PTLD management. Our aim was to establish a present benchmark for comparison between international centers and between various organ transplant systems and modalities, (2) Methods: A cross-sectional questionnaire of relevant PTLD practices in pediatric transplantation was sent to multidisciplinary teams from 17 European center members of ERN TransplantChild to evaluate the centers’ approach strategies for diagnosis and treatment and how current practices impact a cross-sectional series of PTLD cases, (3) Results: A total of 34 SOT programs from 13 European centers participated. The decision to start preemptive treatment and its guidance was based on both EBV viremia monitoring plus additional laboratory methods and clinical assessment (61%). Among treatment modalities the most common initial practice at diagnosis was to reduce the immunosuppression (61%). A total of 126 PTLD cases were reported during the period 2012–2016. According to their histopathological classification, monomorphic lesions were the most frequent (46%). Graft rejection after PTLD remission was 33%. Of the total cases diagnosed with PTLD, 88% survived, (4) Conclusions: There is still no consensus on prevention and treatment of PTLD, which implies the need to generate evidence. This might successively allow the development of clinical guidelines.

Background and Aims The genome of every cell accumulates somatic mutations while aging. Somatic mutation data can be used to track a cell´s exposure to mutagens, thereby allowing the discovery of cell types that are more susceptible to mutate and become cancer and the underling mechanisms. Method To detect somatic mutations in healthy, human kidney, we set up a protocol for whole genome DNA sequencing of single non-cancer cells. The protocol requires in vitro clonal expansion prior to sequencing, a step that restricts the analysis to cells able to proliferate in vitro (progenitors), but allows a gene expression analysis in addition to genome sequencing. Cells were obtained from six living kidney donors undergoing surgery. In addition to the kidney cortex biopsy, multiple control tissues (skin, subcutaneous fata and visceral fat) were obtained from each donor, allowing a well-controlled comparison of mutation landscapes in different cell types. Donors´ age spanned from 30 to 69. Results Somatic mutation and gene expression data showed that we were able to culture two different populations of CD133/CD24 positive, tubular cells. One population showed a low amount of somatic mutations and a mutation profile similar to progenitors from other tissues (fat, skeletal muscle and blood), consistent with a lack of exposure to mutagens. Conversely, the other population showed high mutation burden and a unique mutation landscape, characterized by mutation enrichment in active chromatin, regulatory, and transcribed regions. Accumulation of potential, cancer-driver mutations was 6-fold faster in these compared to control cells. The mutation profile was similar to that of the most common kidney cancer subtypes (clear cell- and papillary cell-carcinoma) and indicated that these cells originated from the proximal tubule, in agreement with gene expression data. Conclusion Our somatic mutation data from single genomes support the existence of two different populations of proliferating tubule cells in healthy, human kidney. One is protected from mutagen exposure, similar to stem cells from other organs. The other population is derived from damaged proximal tubule cells and shows a high mutation rate between 30 and 70 years of age. Mutations are enriched in transcribed genes and regulatory regions, thus enhancing the chances of tumorigenic transformation and suggesting conditions that predispose to cancer in the kidney proximal tubule.

The current pandemic SARS-CoV-2 has required an unusual allocation of resources that can negatively impact chronically ill patients and high-complexity procedures. Across the European Reference Network on Pediatric Transplantation (ERN TransplantChild), we conducted a survey to investigate the impact of the COVID-19 outbreak on pediatric transplant activity and healthcare practices in both solid organ transplantation (SOT) and hematopoietic stem cell transplantation (HSCT). The replies of 30 professionals from 18 centers in Europe were collected. Twelve of 18 centers (67%) showed a reduction in their usual transplant activity. Additionally, outpatient visits have been modified and restricted to selected ones, and the use of telemedicine tools has increased. Additionally, a total of 14 COVID-19 pediatric transplanted patients were identified at the time of the survey, including eight transplant recipients and six candidates for transplantation. Only two moderate-severe cases were reported, both in HSCT setting. These survey results demonstrate the limitations in healthcare resources for pediatric transplantation patients during early stages of this pandemic. COVID-19 disease is a major worldwide challenge for the field of pediatric transplantation, where there will be a need for systematic data collection, encouraging regular discussions to address the long-term consequences for pediatric transplantation candidates, recipients, and their families. info:eu-repo/semantics/publishedVersion

BACKGROUND: The concept of organ transplantation as treatment for complex genetic conditions, including Wolcott-Rallison syndrome (WRS), continues to show promise. Liver transplantation is essential for survival of patients with WRS, and pancreas transplantation cures their type I diabetes mellitus. METHODS: The recipient, a 3-year-old girl weighing 14 kg at the time of transplantation, suffered from major complications of WRS, including repetitive liver failure episodes and poorly controlled diabetes. The patient underwent a nonacute, combined, simultaneous liver and pancreas transplantation from a pediatric donor without using the en bloc technique. RESULTS: Well-preserved graft functions at 2-year follow-up with normal liver and pancreas function. CONCLUSIONS: This is the first case report of simultaneous liver and pancreas transplantation as treatment of WRS in a small child in Europe. Two-year follow-up demonstrates that organ transplantation can halt life-threating recurrent liver failure episodes and cure type 1 diabetes. (Less)

Background Patients with chronic kidney disease stage 5 (CKD5) are predisposed to vascular calcification (VC), but the combined effect of factors associated with VC was sparsely investigated. We applied the relaxed linear separability (RLS) feature selection model to identify features that concomitantly associate with VC in CKD5 patients. Methods Epigastric arteries collected during surgery from living donor kidney transplant recipients were examined to score the histological extent of medial VC. Sixty-two phenotypic features in 152 patients were entered into RLS model to differentiate between no-minimal VC (n = 93; score 0-1) and moderate-extensive VC (n = 59; score 2-3). The subset of features associated with VC was selected on the basis of cross-validation procedure. The strength of association of the selected features with VC was expressed by the absolute value of 'RLS factor'. Results Among 62 features, a subset of 17 features provided optimal prediction of VC with 89% of patients correctly classified into their groups. The 17 features included traditional risk factors (diabetes, age, cholesterol, BMI and male sex) and markers of bone metabolism, endothelial function, metabolites, serum antibodies and mitochondrial-derived peptide. Positive RLS factors range from 1.26 to 4.05 indicating features associated with increased risk of VC, and negative RLS factors range from -0.95 to -1.83 indicating features associated with reduced risk of VC. Conclusion The RLS model identified 17 features including novel biomarkers and traditional risk factors that together concomitantly associated with medial VC. These results may inform further investigations of factors promoting VC in CKD5 patients.

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.

Objective Chronic kidney disease-mineral bone disorder (CKD-MBD) is a major complication of end-stage renal disease (ESRD). Reduced bone mineral density (BMD) is associated with vascular calcification. Here we investigated associations between vertebral bone density (VBD) and coronary artery calcification (CAC), quantified by cardiac computed tomography (CT), and BMD quantified by dual-energy X-ray absorptiometry (DXA), and their relations with mortality. Methods In 231 ESRD patients (median age 56 years, 63% males) comprising incident dialysis patients, prevalent peritoneal dialysis patients and recipients of living donor kidney transplant, VBD (Hounsfield units, HUs) and CAC scores (Agatston units, AUs) were quantified by cardiac CT, and, in 143 of the patients, BMD was measured by DXA of total body. Metabolic and inflammation biomarkers potentially linked to CKD-MBD were also analysed. Results Patients with low tertile of VBD were older and had more often cardiovascular disease (CVD), and higher HbA1c (non-diabetics), interleukin-6 and CAC score. Low VBD was independently associated with higher CAC score (> 100 AUs) after adjustment for age, gender, diabetes, CVD, inflammation and cohorts. In Cox proportional hazards analysis, low VBD was independently associated with all-cause mortality after adjustment for age, gender, diabetes, CVD, inflammation and subjective global assessment (SGA). The root mean-squared error of prediction (RMSE) showed a good degree of association between VBD and BMD evaluated from DXA. In receiver-operator characteristics curve (ROC) analysis, lower VBD was more strongly associated with higher CAC score and all-cause mortality than BMD evaluated from DXA. Conclusions While assessments of BMD by DXA and CT showed good degree of agreement, associations of high CAC, and mortality, with low VBD were stronger than those based on low BMD by DXA. The strong independent associations of low VBD with high CAC score and increased mortality risk suggest that VBD may serve as an important prognosticator in ESRD patients.

The NPRTSG has collected data on pediatric KTx since 1994. The registry archives information from all centers that perform pediatric KTx in Denmark, Finland, Norway, and Sweden and has 100% coverage. The first NPRTSG report was published in 1998 and was based on data collected in the 1982─1996 period. The present report provides data on 602 pediatric KTx in the Nordic countries from 1997 to 2012. Comparison of the patient demographics and one- and three-yr graft survivals between the two time cohorts revealed no significant change in the recipient and donor demographics. The number of transplantations increased by approximately 30%, doubling the recipients below the age of two yr. The use of Tac and mycophenolate as primary immunosuppression increased from practically 0% to 50% and 40%, respectively. The one- and three-yr graft survivals improved significantly (p < 0.001), especially among the youngest recipients with transplant from DD. In these patients, the one-yr survival improved from 70% to 94.6% and the three-yr graft survival from 60% to 94.6%, respectively. The improved graft survival may be at least partly due to changes in immunosuppression strategies, but also greater experience may also be of importance.

BACKGROUND Donor-specific antibodies create an immunologic barrier to transplantation. Current therapies to modify donor-specific antibodies are limited and ineffective in the most highly HLA-sensitized patients. The IgG-degrading enzyme derived from Streptococcus pyogenes (IdeS), an endopeptidase, cleaves human IgG into F(ab′)2 and Fc fragments inhibiting complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity, which suggests that IdeS might be useful for desensitization. We report on the combined experience of two independently performed open-label, phase 1–2 trials (conducted in Sweden and the United States) that assessed the efficacy of IdeS with regard to desensitization and transplantation of a kidney from an HLA-incompatible donor. METHODS We administered IdeS to 25 highly HLA-sensitized patients (11 patients in Uppsala or Stockholm, Sweden, and 14 in Los Angeles) before the transplantation of a kidney from an HLA-incompatible donor. Frequent monitoring for adverse events, outcomes, donor-specific antibodies, and renal function was performed, as were renal biopsies. Immunosuppression after transplantation consisted of tacrolimus, mycophenolate mofetil, and glucocorticoids. Patients in the U.S. study also received intravenous immune globulin and rituximab after transplantation to prevent antibody rebound. RESULTS Recipients in the U.S. study had a significantly longer cold ischemia time (the time elapsed between procurement of the organ and transplantation), a significantly higher rate of delayed graft function, and significantly higher levels of class I donor-specific antibodies than those in the Swedish study. A total of 38 serious adverse events occurred in 15 patients (5 events were adjudicated as being possibly related to IdeS). At transplantation, total IgG and HLA antibodies were eliminated. A total of 24 of 25 patients had perfusion of allografts after transplantation. Antibody-mediated rejection occurred in 10 patients (7 patients in the U.S. study and 3 in the Swedish study) at 2 weeks to 5 months after transplantation; all these patients had a response to treatment. One graft loss, mediated by non-HLA IgM and IgA antibodies, occurred. CONCLUSIONS IdeS reduced or eliminated donor-specific antibodies and permitted HLA-incompatible transplantation in 24 of 25 patients.

Background. Tacrolimus (Prograf ® ) is a key drug in the immunosuppressive treatment of renal transplant patients. Since the expiration of the patent for Prograf ® , generic preparations have been approved in Europe as bioequivalence has been shown in healthy volunteers. However, few studies have investigated whether patients can be successfully converted from Prograf ® to generic tacrolimus. Tacrolimus drug costs are by far the largest single item in the total drug expenditure for patients with renal disease in the Stockholm area. Considerable reductions in drug costs could be achieved if generic tacrolimus were to be used. The aim of this quality assurance study was to evaluate whether a switch from Prograf ® to generic tacrolimus (Tacrolimus Sandoz ® ) could be safely performed in renal transplant patients. It further aimed to investigate changes of renal function (measured in estimated glomerular filtration rate, eGFR), need for dose changes and to calculate potential drug cost savings as a result of the conversion. Methods. We planned to recruit at least 50 patients. Plasma creatinine levels and trough concentrations of tacrolimus were collected from patients with renal transplants at three occasions during treatment with Prograf ® and three times after conversion to Tacrolimus Sandoz ® . The eGFR was calculated before and after the conversion. Results. Sixty-three of 67 enrolled patients (69% males, age 28–80 years) are included in this analysis. The ratio of mean trough concentrations of tacrolimus after comparison with before conversion was 1.02 (90% confidence interval 0.95–1.09). Fourteen patients experienced a change in tacrolimus levels >20% compared with baseline, no patients changed >20% in eGFR. The drug cost saving per daily dose was 33.40 SEK (∼E3.60, −23%). Conclusions. Stable kidney transplant patients treated with Prograf ® can be converted to Tacrolimus Sandoz ® if trough concentrations of tacrolimus and plasma creatinine levels are closely monitored. The conversion brought savings, despite costs for extra monitoring.

ABO-incompatible (ABOi) kidney transplantation has become an established strategy to increase the number of available living donors. At our center, the conditioning protocol for ABOi patients is based on anti-A/B antibody removal and depletion of B cells with the anti-CD20 mAb rituximab (Mabthera®). It is known that even low amounts of remaining rituximab in serum of patients results in false positive B cell cross match results, masking detection of potentially harmful donor human leukocyte antigen (HLA) specific antibodies. Treatment of donor cells with high concentrations (>1 mg/mL) of pronase is currently standard procedure for elimination of rituximab (RIT) interference. It is, however, troublesome that recent reports indicate that pronase treatment per se can induce incorrect flow cytometry cross match (FCXM) results. The aim of this study was to evaluate an alternative pronase-free FCXM for crossmatching of patients treated with rituximab. FCXM with an anti-RIT monoclonal antibody (mAb) pre-blocking step were evaluated on normal human sera (NHS) and patient sera supplemented with RIT. NHS supplemented with RIT or patient sera, without donor specific antibodies (DSA), resulted in high B cell median channel shift (>200 IgG) above background. This shift was eliminated by a serum pre-blocking step with 2-fold excess of anti-RIT (clone MB2A4). Blocking with anti-RIT did not influence the T cells crossmatch results. We present data supporting proof-of-concept that blocking with anti-RIT antibody prior to XM can enable reliable detection of anti-HLA class I and II donor specific antibodies without use of pronase treated donor cells.

Chronic kidney disease (CKD) mineral and bone disorders (CKD-MBD) may lead to low bone mineral density (BMD) and vascular calcification (VC), but links to the latter are unclear. Here we investigated associations between BMD, coronary artery calcium (CAC) scores, and histological signs of VC in end-stage renal disease (ESRD) patients undergoing living-donor kidney transplantation (LD-Rtx). In 66 ESRD patients (median age 45 years, 68% males), BMD (by dual-energy X-ray absorptiometry, DXA), CAC score (by computed tomography, CT; n = 54), and degree of VC score (graded by histological examination of epigastric artery specimens collected at LD-Rtx; n = 55) were assessed at the time of LD-Rtx. Of the patients, 26% had osteopenia and 7% had osteoporosis. Of those undergoing artery biopsy, 16% had extensive VC, and of those undergoing CT 28% had high CAC score (>100 Agatston units). CAC scores correlated with BMD of legs and pelvis. BMDs of leg and pelvic sub-regions were significantly lower in patients with extensive VC. In multivariate regression analysis adjusted for age and gender, lower BMD of leg sub-region was associated with CAC score >100 AUs and extensive VC, and patients with extensive VC had significantly higher CAC score. Both high CAC and extensive VC were independently predicted by low BMD of legs. Low BMD has the potential to identify ESRD patients at risk of vascular calcification.

Background. As antigen-specific immunoadsorption (IA) using the Glycosorb-ABO columns is becoming increasingly popular in ABO-incompatible (ABOi) transplantation, in this study, we retrospectively investigated the efficacy of Glycosorb-ABO IA in vivo and ex vivo .W e also assessed the risk of anti-A/B antibody (ABab) rebound before and after ABOi kidney transplantation. Methods. A protocol for ABOi living donor kidney transplantation was used, combining four preoperative and three preemptive postoperative Glycosorb-ABO IAs with rituximab and maintenance immunosuppression. ABabs were determined by a haemagglutination titration technique. Results. ABOi kidney transplantation was attempted 45 times and 43 transplantations were performed. Overall patient survival was 93% and graft survival was 91%. Mean followup was 4.5 years. Glycosorb-ABO IA significantly reduced the ABabs in the majority of patients (P < 0.0001). However, in three patients (6.8%), the antibody elimination was incomplete. Inadequate adsorption of core-chain-dependent ABabs may explain this finding, but further studies are needed. In five patients, the preconditioning was interrupted before transplantation, resulting in ABab rebound. Yet, when preconditioning was restarted, the antibodies could be removed as planned. After ABOi transplantation, rebound of ABabs was seen in two patients (5%). Conclusions. Glycosorb-ABO IA in combination with rituximab effectively depletes ABabs in most patients, but owing to core-chain-dependent ABabs, GlycosorbABO IA may be less effective than nonspecific techniques for antibody removal in some patients. Rebound before transplantation subsequent to interrupted preconditioning does not hamper a successful ABOi transplantation. Postoperatively, when this protocol for ABOi transplantation is followed, the risk of ABab rebound is small.

As the demand for kidney transplantation is constantly growing methods to expand the donor pool have become increasingly important. ABO-incompatibility has hitherto been regarded as an absolute contraindication to living donor donation. However, as ABO-incompatibility has accounted for the majority of living donor exclusions, efforts have been made to overcome this immunologic barrier. Successful desensitization protocols thus far, have combined plasmapheresis for antibody removal with splenectomy to reduce the antibody producing B-cell pool, in addition to quadruple immunosuppression. Although good graft function has been achieved, the high risks involved have been deterrent. We have developed a protocol for ABO-incompatible kidney transplantation based on antigen-specific immunoadsorption and rituximab, in combination with standard maintenance immunosuppression (tacrolimus, mycophenolate mofetil and corticosteroids). We hypothesized that the anti-A/B antibodies could be effectively eliminated and good graft function achieved, without the complications of coagulopathy and transfusion reactions associated with plasmapheresis. Furthermore, we hypothesized that the substitution of splenectomy with a single dose of the anti-CD20 antibody rituximab would further reduce surgical risk as well as the risk of infectious complications. In 2001 the program for ABO-incompatible kidney transplantation was started at our center. To date 50 ABO-incompatible kidney transplantations have been performed according to the protocol based on antigen-specific immunoadsorption and rituximab. Safety and efficacy of the protocol has been evaluated in several studies, all showing that the antigen-specific immunoadsorption is well tolerated and without any serious side effects. Patient and graft survival as well as kidney function have been comparable to that of ABO-compatible living donor kidney transplantation and the incidence of antibody-mediated rejection 0%. We conclude that AB0-incompatible kidney transplantation using a protocol based on antigen-specific immunoadsorption and rituximab, in combination with triple immunosuppressive therapy is safe and effective. ABO-incompatibility following this protocol does not have a negative impact on graft function. ABO-incompatible kidney transplantation is equivalent to standard ABO-compatible living donor kidney transplantation.

ABO-incompatible (ABOi) kidney transplantation has gained a renewed interest during the past years. In 2001, a protocol for ABOi kidney transplantation based on antigen-specific immunoadsorption and rituximab was introduced at our center. In this study long-term graft function using this protocol was assessed. All ABOi kidney recipients with >1-year follow-up (n=15) were compared with all ABO-compatible (ABOc) living donor kidney recipients maintained on the same basic immunosuppression (n=27). Patient and graft survival as well as rejections and calculated glomerular filtration rate were analyzed. Mean follow-up was 3 years. There was no significant difference in patient and graft survival nor in rejection episodes. Mean glomerular filtration rate (79-83 ml/min) was equivalent at 1, 2, and 3 years in both groups. We conclude that ABOi kidney transplantation using antigen-specific immunoadsorption and rituximab is equivalent to standard ABOc living donor kidney transplantation. ABOi transplantation following this protocol does not have a negative impact on graft function long-term.

Sclerostin, an osteocyte-derived inhibitor of bone formation, is linked to mineral bone disorder. In order to validate its potential as a predictor of vascular calcification, we explored associations of circulating sclerostin with measures of calcification in 89 epigastric artery biopsies from patients with end-stage renal disease. Significantly higher sclerostin levels were found in the serum of patients with epigastric and coronary artery calcification (calcification score 100 or more). In Spearman's rank correlations, sclerostin levels significantly associated with age, intact parathyroid hormone, bone-specific alkaline phosphatase, and percent calcification. Multivariable regression showed that age, male gender, and sclerostin each significantly associated with the presence of medial vascular calcification. Receiver operating characteristic curve analysis showed that sclerostin (AUC 0.68) predicted vascular calcification. Vascular sclerostin mRNA and protein expressions were low or absent, and did not differ between calcified and non-calcified vessels, suggesting that the vasculature is not a major contributor to circulating levels. Thus, high serum sclerostin levels associate with the extent of vascular calcification as evaluated both by coronary artery CT and scoring of epigastric artery calcification. Among circulating biomarkers of mineral bone disorder, only sclerostin predicted vascular calcification.

The aim of the present study was to evaluate the immunosuppressive effect of tacrolimus (TAC) in discordant islet xenotransplantation. Fetal porcine islet-like cell clusters (ICCs) were transplanted under the kidney capsule in normoglycemic rats treated with TAC monotherapy, TAC plus other immunosuppressive drugs or cyclosporin A (CsA) monotherapy. Twelve or 24 days after transplantation, the extent of a cellular infiltration in the xenografts was evaluated using immunohistochemistry. In some animals, the grafts were examined for antibody and complement deposition and the levels of xenoreactive antibodies in serum were determined. In untreated rats, the xenografts were completely rejected after 12 days and no intact ICCs remained. TAC monotherapy (at 0.5 and 1.0 mg/kg b.w.) almost completely inhibited rejection for up to 12 days. In animals treated with TAC monotherapy (at 0.5 mg/kg b.w.), rejection was markedly inhibited for up to 24 days. However, the effect after 24 days was not consistent and in some grafts there were signs of rejection. The protective effect of TAC observed in this study is in contrast to the findings in rats given CsA monotherapy in which no or only a marginal effect on islet xenograft rejection was observed. Only when CsA was given at 20 mg/kg b.w., an inhibitory effect could be observed. Immunosuppression with TAC at a suboptimal dose (0.3 mg/kg b.w.) plus 15-deoxyspergualin or brequinar also had an inhibitory effect on the rejection. In animals given TAC plus mycophenolate mofetil, a protective effect was observed as well; however, this effect was not consistent.

Background: The uremic milieu exposes chronic kidney disease (CKD) patients to premature ageing processes. The impact of renal replacement therapy (dialysis and renal transplantation [RTx]) or immunosuppressive treatment regimens on ageing biomarkers has scarcely been studied. Methods: In this study telomere length in whole blood cells was measured in 49 dialysis patients and 47 RTx patients close to therapy initiation and again after 12 months. Forty-three non-CKD patients were included as controls. Results: Non-CKD patients had significantly (P

In 1990-1993, eight diabetic renal transplant patients had porcine fetal islets injected intraportally at Huddinge Hospital in Stockholm. Four of the patients had evidence of xenograft function reflected in the excretion of small amounts of porcine C-peptide. Two patients had the porcine fetal islets placed under the capsule of a simultaneously transplanted kidney. In one of these patients, a graft biopsy specimen taken 3 weeks after transplantation revealed morphologically intact epithelial cells staining positively for insulin and glucagon. The insulin production was in all instances insufficient to affect the patient's insulin requirements. All patients formed specific xenoantibodies (mostly anti-Gal); presumably, most of the xenoislets were destroyed by rejection. On follow-up studies carried out 6-8 years after xenotransplantation, most patients still had higher-than-pretransplant levels of xenoantibodies. There was no evidence of transmission of porcine endogeneous retroviruses to the patients. All patients expressed a positive attitude toward the use of animal tissue for treatment of disease, and none of the patients regretted participating in the trial. Cell transplantation is leading the way at present for clinical xenotransplantation. The finding that complement inhibition protects intraportally injected porcine islets from an injurious incompatibility reaction holds promise for future clinical application. A similar protective effect might be achievable with the use of islets from transgenic pigs expressing human complement receptors.

The purpose of this study was to investigate the effect of macrophage depletion, using liposome-encapsulated dichloromethylene diphosphonate (Lip-Cl2MDP), on delayed xenograft rejection (DXR) in the guinea pig-to-C6-deficient rat heart transplantation model. In this model, hyperacute rejection does not occur, but, in untreated recipients, xenografts are still destroyed by DXR within 1-2 days. Graft survival was 68 +/- 8.4 h in splenectomized control rats, 77 +/- 16.3 h with Lip-Cl2MDP alone, 99 +/- 10.4 h with deoxysperguarlin (DSG; P < 0.01 vs. controls), and 127 +/- 19.4 h with Lip-Cl2MDP plus DSG (P < 0.01 vs. DSG alone). Treatment with DSG alone or in combination with Lip-Cl2MDP resulted in significant reductions in serum IgM levels at rejection. Immunohistological studies showed that Lip-Cl2MDP alone or in combination with DSG reduced infiltration of grafts by both EDI + and ED2 + macrophages. These experiments support the concept that macrophages play an important role in DXR and suggest that strategies targeting macrophages may be useful in controlling DXR.

Islet transplantation offers an attractive future means to treat diabetes as long as prevention of xenograft rejection can be accomplished. This review analyses the role of 5 new immunosuppressive drugs [tacrolimus, sirolimus, mycophenolate mofetil, gusperimus (15-deoxyspergualin) and leflunomide] in the context of islet xenotransplantation. Although cytotoxic T cells are the major effector cells in allogeneic islet rejection, macrophages serve as important contributing effector cells in xenogeneic islet rejection. All the drugs discussed in this review inhibit T cell activation, and several of them also inhibit B cells. In addition, gusperimus has been found to inhibit macrophages. All the drugs have, at least in some animal model, delayed islet xenograft rejection. Synergistic, or at least additive, protective effects have been observed when 2 or more of the drugs have been used in combination. Assessment of the relative efficacy of the various drugs is made difficult by the use of different models in the various studies performed. In the future, several drugs should be examined in a single model. The efficacy of the various drugs in controlling autoimmune beta cell damage after transplantation remains poorly known. One of the drugs, tacrolimus, has the disadvantage of being diabetogenic in animals and humans. The other drugs do not disturb glucose homeostasis, at least in humans. Mycophenolate mofetil and leflunomide are antiproliferative drugs, a feature that might be disadvantageous in fetal endocrine pancreas transplantation. Although several of the newly available drugs show considerable promise in the prevention of islet xenograft rejection, the search for even better immunosuppressive drugs must continue.

Background. Morphological characteristics of islet xenograft rejection differ from those of islet allograft rejection. Therefore, prevention of islet xenograft rejection probably requires a different type of immunosuppression from that used in allogeneic transplantation. Methods. Fetal porcine islet-like cell clusters (ICC) were transplanted into the renal subcapsular space of rats treated with different immunosuppressive protocols. The existence of a cellular infiltrate or deposits of antibodies and complement in the grafts was evaluated at different times after transplantation using immunohistochemistry. Results. Treatment with leflunomide (LEF), cyclosporine (CsA), mycophenolate mofetil (MMF), 15-deoxyspergualin, and rapamycin alone or in combination had an insufficient inhibitory effect on ICC xenograft rejection. However, in animals treated with LEF+CsA, the rejection process was markedly inhibited. However, some macrophages and T cells were still present, and at 24 days, the xenografts were destroyed. In LEF+CsA-treated animals that were given sera containing an excessive amount of rat anti-porcine xenoreactive antibodies, marked deposits of IgG, and to some extent C3 as well, were detected along the border between intact ICC, and the xenografts were surrounded by macrophages. However, almost no cells infiltrated the grafts, and there were many intact ICC. In animals treated with LEF+CsA+MMF, only occasional infiltrating cells were seen at 12 and 24 days after transplantation, and the endocrine tissue was completely intact. Conclusions. LEF+CsA+MMF prevented rejection of porcine ICC xenografts in the rat for up to 24 days after transplantation.

Proper revascularization after transplantation is assumed to be crucial for appropriate islet graft function. We developed a novel noninvasive imaging method, based on adenoviral transduction of islets with a hypoxia responsive reporter gene, for continuous in vivo monitoring of hypoxia in islet grafts in a mouse model. In addition, morphological data were obtained from a deceased patient previously subject to intraportal transplantation. We detected only transient hypoxia in a minority of the animals transplanted. Importantly, a clear response to hypoxia was observed in vitro after removal of the islet grafts on day 28 after transplantation. Also, the morphological data from the deceased patient demonstrated an extensive revascularization of the transplanted islets. In fact, no differences could be seen between native islets, in pancreas biopsies taken prior to islet isolation, and transplanted islets regarding the number, distribution, and shape of the blood vessels. However, fewer small islets (diameter

Efficacy of immunosuppressive drugs in islet xenotransplantation: A study in the pig to rat model.

Background: Prolonged cold ischemia is frequently associated with a greater risk of delayed graft function and enhanced graft failure. We hypothesized that media, combining a high oxygen-dissolving capacity with specific qualities of organ preservation solutions, would be more efficient in reducing immediate ischemia-reperfusion injury from organs stored long term compared with standard preservation media. Methods: Kidneys retrieved from brain-dead pigs were flushed using either cold histidine-tryptophan-ketoglutarate (HTK) or oxygen-precharged emulsion composed of 75% HTK and 25% perfluorohexyloctane. After 18 h of cold ischemia the kidneys were transplanted into allogeneic recipients and assessed for adenosine triphosphate content, morphology, and expression of genes related to hypoxia, environmental stress, inflammation, and apoptosis. Results: Compared with HTK-flushed kidneys, organs preserved using oxygen-precharged HTK-perfluorohexyloctane emulsion had increased elevated adenosine triphosphate content and a significantly lower gene expression of hypoxia inducible factor-1α, vascular endothelial growth factor, interleukin-1α, tumor necrosis factor-α, interferon-α, JNK-1, p38, cytochrome-c, Bax, caspase-8, and caspase-3 at all time points assessed. In contrast, the mRNA expression of Bcl-2 was significantly increased. Conclusions: The present study has demonstrated that in brain-dead pigs the perfusion of kidneys with oxygen-precharged HTK-perfluorohexyloctane emulsion results in significantly reduced inflammation, hypoxic injury, and apoptosis and cellular integrity and energy content are well maintained. Histologic examination revealed less tubular, vascular, and glomerular changes in the emulsion-perfused tissue compared with the HTK-perfused counterparts. The concept of perfusing organs with oxygen-precharged emulsion based on organ preservation media represents an efficient alternative for improved organ preservation. © 2012 Elsevier Inc. All rights reserved.

Organs from deceased donors after brain death (BD) remain the major source of organs for transplantation. The catastrophic event of BD and the inevitable consequences of ischemia reperfusion injury (IRI) are linked to impaired graft quality and transplantation outcome. The aim of this thesis was to create a BD model in pigs to assess early effects on IRI in kidneys preserved with an oxygenated solution and to evaluate the protective effects of coating the renal vessel walls with a heparin conjugate during hypothermic machine perfusion (HMP).Brain death was achieved by raising the intracranial pressure (ICP) through stepwise increasing the volume of an epidurally placed balloon to the point of exceeding the mean arterial pressure (MAP) creating a negative cerebral perfusion pressure (CPP). This reproducible, clinically relevant experimental model makes evaluation of potential targeted methods to protect the organs possible. Kidneys retrieved from brain-dead pigs were preserved either in an oxygenated emulsion composed of 75% histidine-tryptophan-ketoglutarate (HTK) and 25% perfluorohexyloctane F6H8 or HTK alone. After 18h of cold storage the kidneys were transplanted into allogeneic pigs. F6H8 was associated with replenishment of adenosine triphosphate and lower gene expression of hypoxia inducible factor (HIF)-1a, vascular endothelial growth factor (VEGF), interleukin (IL)-1α and tumour necrosis factor (TNF)-α. F6H8 reduced early IRI at both the cellular and molecular level.Kidneys from BD pigs were evaluated for the feasibility of coating the vessel walls with the heparin conjugate CHC (Corline Systems AB, Uppsala, Sweden) to restore glycocalyx. Porcine kidneys were preserved by HMP for 20h with 50 mg biotinylated CHC added to the perfusion solution. CHC was detected on the inner surface of the kidney vessels by immunofluorescence, and its uptake in kidneys was confirmed by reduced content in the perfusate. An ex vivo normothermic perfusion circuit was developed to assess kidney function. Perfusion with CHC during HMP was associated with lower creatinine levels, increased urine volume and reduced tubular injury. Modifying renal vessels walls using CHC during HMP improved early graft function. Preservation with the oxygenated F6H8 solution or CHC could be used to improve graft quality and ameliorate IRI in kidneys retrieved from deceased donors.

Benchmarking and comparisons between transplantation centers are becoming more common. A crude comparison indicated a 50% difference in patient survival between centers in Sweden. A 'task group' was formed to refute or confirm and learn from this observation. Patient survival and graft survival of 5 933 patients transplanted at three different transplantation centers in Sweden (Stockholm, Goteborg, and Malmo) were followed up until February 2007. Patient survival and graft survival were compared between the centers with and without consideration being given to important covariates such as time period, type of donation (living or deceased donor), gender, and age. A refined cohort of 2,956 adult patients that had been transplanted for the first time between 1991 and 2007 was assessed in more detail using Cox regression analysis. The difference in patient and transplant outcome observed in the crude comparison diminished considerably after adjustment for differences in case mix and time period of transplantation, and was neither evident nor significant after 1999. Patient survival and graft survival have improved considerably during the time period since 1991. The adjusted hazards ratio for mortality was 0.39 (95% CI 0.29-0.53) for patients who were transplanted after 1999 when compared with those transplanted between 1991 and 1994. Crude comparisons between results from transplantation centers may be severely confounded not only by case mix but also by differences in the proportion of patients transplanted during different time periods. Patient outcome and graft outcome have improved considerably since 1991, and after 1999 center effects were no longer apparent in Sweden.

Background. In 2001 a protocol for ABO-incompatible (ABOi) kidney transplantation based on antigen-specific immunoadsorption and rituximab was introduced at our center, short-term results being comparable with those of ABO-compatible (ABOc) living donor kidney transplantation. Of greater importance, however, is long-term graft function, thus far not evaluated. The aim of this study was therefore to assess long-term results of this protocol. Methods. Twenty ABOi kidney recipients with more than 12-month follow-up were included in the study: all adult crossmatch negative ABOi kidney recipients (n15) were compared with an adult ABOc living donor recipient control group (n30), and all pediatric ABOi kidney recipients (16 years of age) (n5) were compared with a group of pediatric ABOc kidney recipients (n18). Results. Mean follow-up was three years. There was no significant difference in patient survival, nor in graft survival or in the incidence of acute rejection in any of the groups. In the adult kidney recipients mean glomerular filtration rate was equivalent at all time points (79 – 83 mL/min), as was s-creatinine. In the pediatric groups, s-creatinine was similar but glomerular filtration rate lower among the ABOi kidney recipients. There was a significant reduction (P0.0001) without rebound in A/B antibody titers after transplantation (median IgG 1:2 and median IgM 1:11 year posttransplant) compared with pretransplant levels (median IgG 1:32 and IgM 1:16). Conclusion. We conclude that ABOi kidney transplantation using antigen-specific immunoadsorption and rituximab is equivalent to ABOc living donor kidney transplantation. ABOi transplantation after this protocol does not have a negative impact on long-term graft function.

The B-cell depleting anti-CD20 antibody rituximab has become a therapeutic alternative in renal transplantation. However, understanding of the pharmacodynamics is limited. We have therefore studied the effect of single-dose rituximab, in combination with conventional triple immunosuppressive therapy, on the B-cell population in peripheral blood as well as in tissues, in kidney transplant recipients. Forty-nine kidney recipients received single-dose rituximab. The prevalence of B cells was assessed in peripheral blood, kidney transplant tissue, and in lymph nodes. In 88%, complete depletion of B cells in peripheral blood was observed and, 15 months after treatment, B cells were still undetectable in the majority of patients. In kidney tissue, B cells were also completely eliminated. In contrast, the B cells were not eliminated in lymph nodes, although a reduction was observed. In conclusion, single-dose rituximab in kidney transplant recipients evokes a long-term elimination of B-cells in peripheral blood as well as within the kidney transplant.

In ABO-incompatible kidney transplantation, only a few studies have addressed the necessity, duration, and content of immunosuppressive induction therapy. At our center (Karolinska Institute, Stockholm, Sweden), using a preconditioning regimen consisting of 13 days of tacrolimus, mycophenolate mofetil, and prednisolone, we have investigated both short- and long-term renal allograft function (up to 28 days and 1 year after transplantation, respectively) and correlated them to tacrolimus 12-hr trough levels. In summary, during the first 28 days after transplantation, renal allograft function in the ABO-incompatible group was impaired when compared with that observed in the ABO-compatible group. One possible explanation for this finding is the prolonged pretransplantation exposure to tacrolimus in the ABO-incompatible group, resulting in tacrolimus-associated renal toxicity, which slows the reduction in plasma creatinine. In fact, the day before, and also immediately after, the transplantation (for the first 3-4 postoperative days), the tacrolimus 12-hr trough levels in the ABO-incompatible group were greater than in the ABO-compatible group. Possibly, a shorter pretreatment period with tacrolimus or a reduced target tacrolimus trough level could eliminate this difference in postoperative renal allograft function. However, 1 year after transplantation, kidney allograft function in the two study groups was similar.

Background: The aim of this study was to investigate whether transmission of porcine endogenous retrovirus (PERV) occurs in a model of diabetes reversal by the xenotransplantation of adult porcine islets (APIs) into immunoincompetent diabetic rodents. Methods: Black-6 nu/nu mice and Lewis rats were immunosuppressed with cyclosporin A (CsA) and FTY 720, and rendered diabetic with streptozotocin. Purified APIs were transplanted into the renal subcapsular space; 5000 islet equivalents (IEQs) were used in the nude mice (n = 4) and 40 000 IEQs in the rats (n = 4). The nude mice were sacrificed at 75 days after transplantation. In order to confirm chronic xenograft function, the graft-bearing kidney was removed prior to sacrifice. The rats were followed until xenograft rejection, at which time they were sacrificed. Immediately after sacrifice, tissue samples (liver, spleen, and small intestine) were taken for analysis. Quantitative polymerase chain reaction (PCR) was used to assess evidence of PERV transmission, and porcine cell chimerism. Results: All animals became normoglycemic within 48 h of transplantation. The nude mice remained normoglycemic during the 75-day study period, with removal of the graft-bearing kidney resulting in prompt hyperglycemia. The rats remained normoglycemic until xenograft rejection, which occurred at 66 ± 28 days. Despite the evidence of porcine cell microchimerism in recipients, real-time PCR detected no evidence of PERV transmission in any of the tissue specimens tested. Conclusions: There was no evidence of PERV transmission following transplantation of pig islets into diabetic nude mice and immunosuppressed rats.

Our aim was to evaluate the effect of FTY720 in discordant islet xenotransplantation.Fetal porcine islet-like cell clusters (ICCs) were transplanted into normoglycemic rats that were either left untreated or treated with FTY720 only, with FTY720 plus cyclosporine A (CsA) or with CsA only. Twelve or 24 days after transplantation, graft morphology was evaluated immunohistochemically. Furthermore, adult porcine islets (APIs) were transplanted into diabetic rats immunosuppressed with FTY720 plus CsA. Blood glucose and porcine C-peptide levels were monitored.In untreated rats, the ICC xenografts were completely rejected after 12 days. Treatment with CsA had only a marginal effect on the rejection. In animals given FTY720, only the number of infiltrating cells was somewhat reduced. However, at 12 days, no intact ICCs remained. Immunosuppression with FTY720 plus CsA had a marked inhibitory effect on islet xenograft rejection and plentiful morphologically intact ICCs remained. Twelve days after transplantation, only occasional macrophages and T cells could be detected. At 24 days after transplantation, the findings were similar. Furthermore, diabetic rats transplanted with APIs and immunosuppressed with FTY720 plus CsA remained normoglycemic for 53.0+/-15.8 days. In fact, one animal remained normoglycemic for more than 100 days. Serum levels of porcine C-peptide remained at levels similar to those for human C-peptide in healthy individuals.Immunosuppression with FTY720 plus CsA inhibited almost all morphological signs of pig-to-rat islet xenograft rejection for up to 24 days after transplantation. Diabetic rats transplanted with APIs and immunosuppressed with FTY720 plus CsA remained normoglycemic for 53.0+/-15.8 days.

Protective effect of FK-506 in pig-to-rat islet xenotransplantation isabrogated by prednisolone.

This study aimed to investigate the effects of 15-deoxyspergualin (DSG), tacrolimus (FK 506) and cyclosporin A (CyA), alone or in combination, on delayed xenograft rejection (DXR). We used the guinea-pig-to-C6-deficient (C6-)-PVG-rat heart transplantation model, since in this strain combination, hyperacute rejection is avoided. In C6- control rats, the guinea pig xenografts survived for 39.2 +/- 6.3 h (mean +/- SD). Splenectomy alone resulted in a xenograft survival of 71.8 +/- 7.8 h, but the addition of CyA or FK 506 did not further improve graft survival (73.6 +/- 3.0 h and 72.0 +/- 17.6 h, respectively). In contrast, DSG treatment increased graft survival to a mean of 99.8 +/- 9.2 h. When CyA or FK 506 was combined with DSG, no additional effects were observed (105 +/- 24.3 h and 95.1 +/- 5.6 h, respectively). DSG alone or in combination with FK 506 or CyA resulted in a significant reduction in the serum IgM levels and reduced the deposits of IgM and IgG in rejected grafts. However, all xenografts were still heavily infiltrated by ED1 + macrophages, regardless of the treatment used. Thus, DSG treatment resulted in moderate prolongation of xenograft survival in C6- rats. The effect seems to be related to suppression of xenoreactive antibody production. To prolong xenograft survival further, strategies that inhibit macrophage infiltration seem required.

THE CONCEPT of pig-to-man islet transplantation is based on the facts that porcine insulin can serve as a substitute for human insulin, that the regulation of insulin release from β-cells in pigs resembles that in humans and that pigs, without major ethical restraints, are readily available in large numbers. It is also assumed that primarily nonvascularized xenografts, such as islets, should escape hyperacute rejection. 1 However, islets and other primarily nonvascularized xenografts are rapidly destroyed by vigorous cellular rejection and we have recently shown that the characteristics of this rejection fundamentally differ from those of allogeneic rejection. 2 If pig-to-man islet transplantation is to succeed, the means of preventing such rejection must be found.

A logical method to cure insulin-dependent diabetes would be to transplant insulin-producing islets to the patient. For 20 years, considerable efforts have been invested into making such transplantations feasible. If this procedure is to be widely used, the supply of human islet tissue will not be sufficient. Animal tissue would then have to be relied upon. There are good reasons to believe that islets from animals can perform their physiological function in humans. Also, at this stage, islet transplantation is clearly the safest means of performing clinical trials in xenotransplantation.