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Publisher Copyright: © 2022 International Society of Nephrology Introduction: The genomic mismatch level between donor and recipient may be associated with the risk of rejection and graft survival. We determined the association of genome-level matching with acute rejection in deceased-donor kidney transplantation. Methods: The study cohort consists of 1025 recipient-donor pairs transplanted in a single center from 2007 to 2017 in Helsinki. The associations between the sums of whole-genome missense variant mismatches and missense mismatches in transmembrane, secretory, and kidney-related proteins, with acute rejection were estimated using Cox model. In addition, we analyzed 40 deletion-tagging variants using Cox model. Results: The association analysis between mismatch sums of kidney-related proteins and acute rejection resulted in an unadjusted hazard ratio (HR) of 1.15 (95% confidence interval [CI], 1.01–1.30; P = 0.029) and adjusted HR of 1.13 (95% CI, 0.99–1.28; P = 0.071). In deletion analysis, a mismatch in rs7542235 genotype GG tagging a homozygous deletion at the complement factor H-related (CFHR), proteins locus, predisposed to acute rejection with an unadjusted HR of 3.10 (95% CI, 1.53–6.29; P = 0.002) and adjusted HR of 2.97 (95% CI, 1.46–6.05; P = 0.003). Conclusion: In conclusion, analyses of genome-level mismatches may be useful tools in prediction of transplantation outcome. The relative importance differs between populations, because we found evidence for CFHR deletion but could not replicate the finding of previously reported LIMS1 deletion.

Background and objectives Increased donor age is one of the most important risk factors for delayed graft function (DGF), and previous studies suggest that the harmful effect of cold ischemia time is increased in kidneys from older donors. Our aim was to study the association of increased donor age and cold ischemia time with the risk of delayed graft function in a large cohort kidney transplants from the current era. Design, setting, participants, & measurements The Scientific Registry of Transplant Recipients was used for this observational, retrospective registry analysis to identify all deceased donor kidney transplantations in the United States between 2010 and September 2018, who were on dialysis pretransplantation (n=90,810). The association of donor age and cold ischemia time with the risk of DGF was analyzed in multivariable models adjusted for recipient characteristics (age, race, sex, diabetes, calculated panel-reactive antibodies, pretransplant dialysis duration) and donor characteristics (cause of death, sex, race, body mass index, creatinine, donation after circulatory death status, history of hypertension, and HLA mismatch). Results Cold ischemia time and donor age were independently associated with the risk of DGF, but the risk of DGF was not statistically significantly lower in donor age categories between 50 and 64 years, compared with donors ?65 years. The harmful association of cold ischemia time was not higher in kidneys from older donors in any age category, not even among donation after circulatory death donors. When donor risk was assessed with kidney donor profile index, although a statistically significant interaction with cold ischemia time was found, no practically meaningful increase in cold-ischemia susceptibility of kidneys with a high kidney donor profile index was found. Conclusions We were unable to demonstrate an association between donor age and DGF. The association of longer cold ischemia time with the risk of DGF was not magnified in older or more marginal donors.

Background. Long cold ischemia time (CIT) is the most important factor contributing to delayed graft function (DGF) after kidney transplant. Improvements in pretransplant procedures may reduce CIT and improve clinical outcome. Materials and Methods. Pretransplant histocompatibility tests were modernized at our laboratory in 2015, leading to significant decrease of time consumed for these enabling earlier surgery. The effects of this on kidney transplant CIT, DGF, and other clinical outcomes were studied. The study population consisted of 896 consecutive deceased donor kidney recipients, of which 442 patients received a transplant with the old crossmatch and 454 received a transplant with the new crossmatch. Results. CIT shortened from mean 20 hours 6 minutes to 15 hours 52 minutes (P

BackgroundThe genomic mismatch level between donor and recipient is associated with the risk of acute rejection and long-term graft survival. In the present study, we determined the association of genome-level matching with acute rejection in a single-center kidney transplantation cohort.MethodsAltogether, 1025 pairs of deceased donors and kidney transplant recipients transplanted in 2007–2017 were genotyped. The associations between the sums of whole genome missense variant mismatches and missense mismatches in transmembrane, secretory, and kidney-related proteins, with acute rejection were estimated using Cox proportional hazards model. Additionally, we analyzed 40 common deletion-tagging variants using Cox model.ResultsThe increasing mismatch sum in kidney-related proteins associated with acute rejection with an unadjusted HR of 1.15 (95% CI, 1.01–1.30; P=0.029) when dividing the sum into quartiles. The sums of other mismatches were not associated with acute rejection. In deletion analysis, a mismatch in rs7542235 (NC_000001.11:g.196854483A>G), genotype GG tagging a homozygous deletion at the complement Factor H-related (CFHR) proteins locus, predisposed to acute rejection with adjusted HR of 2.97 (95% CI, 1.46–6.05; P=0.003).ConclusionsThe present study supports that mismatches in gene deletions and kidney-related proteins are novel histocompatibility factors in kidney transplantation. The relative importance of different gene deletions varies between populations, as we found evidence for CFH-related gene deletion but not for the previously reported LIMS1 deletion.SIGNIFICANCE STATEMENTThe first genome-wide association studies have not identified strong candidate genes for complication risks of kidney transplantation whereas matching of non-HLA genes may be promising. The current study determined the association of genome-level matching with acute rejection among 1025 kidney transplant pairs. The increasing mismatch sum in kidney-related proteins was associated with acute allograft rejection. Also, an association between acute allograft rejection and rs7542235 genotype GG, tagging a homozygous deletion at the complement factor H-related (CFHR) loci on chr 1 was found. The present study suggests that mismatches in gene deletions and kidney-related proteins are important novel histocompatibility factors in kidney transplantation.

The burden of sexually transmitted infections (STI) among solid-organ transplant recipients is currently unknown. We studied the risk of STIs among kidney transplant recipients compared with the general population in a nationwide cohort.Between 2002 and 2019, all microbiological findings of Chlamydia trachomatis, Neisseria gonorrhoeae, Treponema pallidum (syphilis), and human immunodeficiency virus among kidney transplant recipients65 years and transplanted between 1995 and 2017 in our country were captured from statutory national registries. Data from the general population of Finland, population 5.5 million, were used for comparisons. Incidence of STIs and age and sex-adjusted standardized incidence ratios (SIR) were calculated.Altogether 3612 transplantations, with a total follow-up of 27 069 person-years were included. A total of 30 STIs microbiological findings of STI were confirmed in 25 patients: C. trachomatis (N = 27), N. gonorrhoeae (N = 2), and syphilis (N = 1). No hospitalizations associated with STIs were detected. The risk of STI after kidney transplantation was significantly lower compared to the general population (SIR, 0.57, 95% CI 0.39-0.80). The lower risk of STIs was more pronounced in female patients (SIR 0.40, 95% CI 0.20-0.74), whereas in male patients the difference was statistically not significant (SIR 0.69, 95% CI 0.44-1.04). Of the confirmed STI cases, 30% were detected in patients who received their transplants during adolescence.Within the Finnish kidney transplant population, the age and sex-adjusted incidence of sexually transmitted infections is not higher compared to the general population. Highest frequency of infections was seen among patients transplanted during adolescence.

Cytomegalovirus (CMV) infection remains a major challenge in solid organ transplantation. Ganciclovir has changed the prognosis, but with the expense of possible viral resistance. New antiviral drugs, such as letermovir, have not been studied sufficiently in kidney and pancreas transplant recipients. We reviewed abdominal organ transplants recipients with CMV infection from the national transplant registry and identified patients treated with letermovir from electronic medical records. We report on letermovir treatment in one kidney and three simultaneous pancreas and kidney (SPK) transplant patients with refractory or ganciclovir-resistant CMV infection (UL54/ UL97 mutation). In SPK patients, persistent leukopenia undermined immunosuppressive and antiviral treatment, favoring life-threatening bacterial infections or ganciclovir resistance. All patients achieved viral clearance after letermovir monotherapy of 1.5 to 6 months. Letermovir was well tolerated and leukopenia resolved. Adjustments of calcineurin inhibitor doses were challenging. One acute rejection occurred because of under immunosuppression. After the end of treatment, recurrent low-grade CMV-DNAemia was common requiring reinitiating antiviral therapy to achieve viral clearance. To conclude, letermovir was a well-tolerated valuable option for the treatment of refractory or resistant CMV infection in kidney and pancreas transplantation. This article is protected by copyright. All rights reserved.

BACKGROUND Kidney transplantation is reported to save costs compared to maintenance dialysis. We analyzed the current actual costs of kidney transplantation compared to dialysis, and analyzed risk factors for higher costs after transplantation. MATERIAL AND METHODS Altogether, 338 kidney transplant recipients between 2009 and 2014 were included in this study. All individual-level cost data from specialized health care and data from all reimbursed medication and travel costs were acquired from official records. Cost data were compared before and after transplantation within the same patients starting from dialysis initiation and continued until the end of follow-up at the end of 2015. RESULTS Total annual costs were median 53 275 EUR per patient in dialysis, 59 583 EUR for the first post-transplantation year (P

Background: Pretransplant dialysis modality may affect outcome after simultaneous pancreas-kidney transplantation (SPKT), and it has been suspected that peritoneal dialysis (PD) is associated with more postoperative complications compared to hemodialysis (HD). The aim of this study was to evaluate whether pretransplant dialysis modality affects the risk for postoperative complications in SPKT recipients. Material/ Methods: This was a retrospective longitudinal cohort study of all patients undergoing SPKT from 2010 to 2017, during which 99 simultaneous pancreas-kidney transplantations were performed. Three pre-emptive transplantations were excluded. Patient groups receiving PD (n=59) or HD (n=37) were similar regarding baseline characteristics. All complications occurring during the first 3 months after transplantation, as well as patient and graft survival, were analyzed. Results: There were no significant differences in postoperative complications between groups, with similar rates of intraabdominal infections (8% in HD vs. 10% in PD), pancreatitis (16% in HD vs. 17% in PD), gastrointestinal bleedings (22% in HD vs. 10% in PD), and relaparotomies (27% in HD vs. 24% in PD). None of the patients had venous graft thrombosis. Past peritonitis was not associated with increased risk for postoperative complications in PD patients. Patient and graft survival were similar between PD and HD groups. Conclusions: Peritoneal dialysis is not a risk factor for postoperative complications after SPKT.

Background Simultaneous pancreas-kidney transplantation (SPK) carries a high risk of major postoperative complications, but knowledge on early warning signs and surrogate markers for postoperative complications is scarce. Aims Our aim was to analyze the complication-predictive value of different laboratory tests in pancreas transplantation. Materials & Methods All SPKs in Finland between January 2010 and February 2020 were retrospectively analyzed. Levels of first three-day plasma amylase, drain fluid amylase, C-reactive protein, C-peptide, plasma trypsinogen, and white blood cell count were assessed for their performance predicting cumulative postoperative complications (assessed using the Comprehensive Complication Index) within 90 days from transplantation by using ROC analyses. Results Of the 164 SPK patients included, 39 suffered at least one complication requiring laparotomy. First-day plasma amylase had the best value in predicting complications based on its high AUC value and easy clinical applicability, with an optimum cutoff of six times the upper normal limit. Negative predictive values (NPVs) and positive predictive values of this cutoff were 0.81 and 0.71 for any relaparotomy, and 0.91 and 0.71 for the Comprehensive Complication Index >47.7 (which equals the morbidity of two relaparotomies), respectively. Conclusion In conclusion, first-day plasma amylase could be able to detect patients at risk of complications after SPK.

Cytomegalovirus continues to be a concern after transplantation despite prophylaxis regimens. Our aim was to analyse post-prophylaxis primary cytomegalovirus infections among kidney transplant recipients after 6-month valganciclovir prophylaxis and to determine the usefulness of surveillance after prophylaxis. Data from all cytomegalovirus D+/R- kidney transplant recipients from January 2004 to October 2018 at our center who received 6-month prophylaxis with valganciclovir were retrospectively analysed (N = 481). Detailed analyses were performed for 136 patients who were monitored every 2-4 weeks for DNAemia after the discontinuation of prophylaxis. Post-prophylaxis primary cytomegalovirus infection occurred in 182/481 (38%) patients median 264 days after transplantation (IQR: 226-367) and median 84 days after the end of prophylaxis (IQR: 46-187). In 49% patients, cytomegalovirus infection occurred over 3 months after the end of prophylaxis. Cytomegalovirus infection was not associated with lower patient or graft survival and no independent risk factors for infection were found. From patients monitored closely, 71/136 (52%) patients developed post-prophylaxis primary cytomegalovirus infection. Altogether, 52/136 (38%) patients were diagnosed with probable post-prophylaxis cytomegalovirus disease and 19/136 (14%) patients had asymptomatic CMV infection. Recurrent infection occurred in 38/71 (39%) patients. The incidence of post-prophylaxis primary cytomegalovirus infection among D+/R- kidney transplant recipients remains high despite 6-month prophylaxis. Surveillance after prophylaxis was challenging as a considerable portion of the infections occurred late and already symptomatic.

Kidney transplant recipients (KTRs) have an increased cancer risk compared to the general population, but absolute risks that better reflect the clinical impact of cancer are seldom estimated. All KTRs in Sweden, Norway, Denmark, and Finland, with a first transplantation between 1995 and 2011, were identified through national registries. Post-transplantation cancer occurrence was assessed through linkage with cancer registries. We estimated standardized incidence ratios (SIR), absolute excess risks (AER), and cumulative incidence of cancer in the presence of competing risks. Overall, 12 984 KTRs developed 2215 cancers. The incidence rate of cancer overall was threefold increased (SIR 3.3, 95% confidence interval [CI]: 3.2–3.4). The AER of any cancer was 1560 cases (95% CI: 1468–1656) per 100 000 person-years. The highest AERs were observed for nonmelanoma skin cancer (838, 95% CI: 778–901), non-Hodgkin lymphoma (145, 95% CI: 119–174), lung cancer (126, 95% CI: 98.2–149), and kidney cancer (122, 95% CI: 98.0–149). The five- and ten-year cumulative incidence of any cancer was 8.1% (95% CI: 7.6–8.6%) and 16.8% (95% CI: 16.0–17.6%), respectively. Excess cancer risks were observed among Nordic KTRs for a wide range of cancers. Overall, 1 in 6 patients developed cancer within ten years, supporting extensive post-transplantation cancer vigilance. publishedVersion

IntroductionRemote ischaemic preconditioning (RIPC) using a non-invasive pneumatic tourniquet is a potential method for reducing ischaemia-reperfusion injury. RIPC has been extensively studied in animal models and cardiac surgery, but scarcely in solid organ transplantation. RIPC could be an inexpensive and simple method to improve function of transplanted organs. Accordingly, we aim to study whether RIPC performed in brain-dead organ donors improves function and longevity of transplanted organs.Methods and analysesRIPTRANS is a multicentre, sham-controlled, parallel group, randomised superiority trial comparing RIPC intervention versus sham-intervention in brain-dead organ donors scheduled to donate at least one kidney. Recipients of the organs (kidney, liver, pancreas, heart, lungs) from a randomised donor will be included provided that they give written informed consent. The RIPC intervention is performed by inflating a thigh tourniquet to 300 mm Hg 4 times for 5 min. The intervention is done two times: first right after the declaration of brain death and second immediately before transferring the donor to the operating theatre. The sham group receives the tourniquet, but it is not inflated. The primary endpoint is delayed graft function (DGF) in kidney allografts. Secondary endpoints include short-term functional outcomes of transplanted organs, rejections and graft survival in various time points up to 20 years. We aim to show that RIPC reduces the incidence of DGF from 25% to 15%. According to this, the sample size is set to 500 kidney transplant recipients.Ethics and disseminationThis study has been approved by Helsinki University Hospital Ethics Committee and Helsinki University Hospital’s Institutional Review Board. The study protocol was be presented at the European Society of Organ Transplantation congress in Copenhagen 14−15 September 2019. The study results will be submitted to an international peer-reviewed scientific journal for publication.Trial registration numberNCT03855722.

Background and objectives Transplant centers in Europe aim to minimize the time from brain death to organ procurement (procurement delay), but evidence to justify this is scarce. In the United States, procurement times are significantly longer. Our objective was to analyze how procurement delay associates with kidney allograft outcomes. Design, setting, participants, & measurements Kidney transplantations from brain-dead donors were retrospectively analyzed from the Finnish Kidney Transplant Registry and the Scientific Registry of Transplant Recipients in the United States. Multivariable models were adjusted with donor and recipient characteristics, and the relationship between procurement delay and outcomes was modeled with cubic spline functions. Results In total, 2388 and 101,474 kidney transplantations in Finland and the United States were included, respectively. The median procurement delay was 9.8 hours (interquartile range, 7.8-12.4) in Finland and 34.8 hours (interquartile range, 26.3-46.3) in the United States. A nonlinear association was observed between procurement delay and the risk of delayed graft function, with highest risk seen in short and very long procurement delays. In multivariable models, the lowest risk of delayed graft function was associated with procurement delay between 20 and 50 hours. In multivariable models, longer procurement delay was linearly associated with lower risk of graft loss (hazard ratio, 0.90/1 h longer; 95% confidence interval, 0.88 to 0.92; P Conclusions Longer procurement delay was associated with noninferior or even better kidney allograft outcomes.

OBJECTIVE To examine time trends in mortality rates and causes of death in patients with type 1 diabetes and end-stage renal disease on dialysis and after kidney transplantation. RESEARCH DESIGN AND METHODS In a nationwide retrospective cohort analysis, all patients with type 1 diabetes in Finland who received a kidney transplant alone were compared with patients who remained on dialysis. The main outcome was patient survival after starting dialysis. The cohort was divided into dialysis, functioning kidney transplant, and dialysis after transplant loss. Causes of death were retrieved and standardized mortality ratios calculated. RESULTS We studied 2,383 patients. Patients survived a median of 15.9 years after a successful transplant, 11.2 years if transplant function was lost, and 2.9 years if they remained on chronic dialysis. Standardized mortality ratio decreased in all subgroups during the past four decades: from 2005 onwards, it was 3.9 in patients receiving a kidney transplant, 11.5 in patients with graft loss, and 32.5 in patients on dialysis. The most common cause of death in all patients was ischemic heart disease (45%) followed by infection (18%), which was more common in patients on dialysis. CONCLUSIONS Kidney transplantation is the treatment of choice for patients with type 1 diabetes and end-stage renal disease because it substantially reduces the excess death risk when compared with dialysis. Even when kidney graft function is lost, the excess death risk is still considerably lower. Although overall mortality has decreased over the years, premature death due to ischemic heart disease remains high.

Parainfluenza virus (PIV) can cause serious infections after hematopoietic stem cell or lung transplantation. Limited data exist about PIV infections after kidney transplantation. We describe an outbreak of PIV-3 in a transplant unit. During the outbreak, 45 patients were treated on the ward for postoperative care after kidney or simultaneous pancreas-kidney (SPK) transplantation. Overall, 29 patients were tested for respiratory viruses (12 patients with respiratory symptoms, 17 asymptomatic exposed patients) from nasopharyngeal swabs using polymerase chain reaction. PIV-3 infection was confirmed in 12 patients. One patient remained asymptomatic. In others, symptoms were mostly mild upper respiratory tract symptoms and subsided within a few days with symptomatic treatment. Two patients suffered from lower respiratory tract symptoms (dyspnea, hypoxemia, pulmonary infiltrates in chest computed tomography) and required supplemental oxygen. Four of six SPK patients and eight of 39 of kidney transplant patients were infected with PIV (p = 0.04). In patients with follow-up tests, PIV-3 shedding was still detected 11-16 days after diagnosis. Despite rapid isolation of symptomatic patients, PIV-3 findings were diagnosed within 24 days, and the outbreak ceased only after closing the transplant ward temporarily. In conclusion, PIV-3 infections early after kidney or SPK transplantation were mostly mild. PIV-3 easily infected immunosuppressed transplant recipients, with prolonged viral shedding.

Background:Effective digestive enzymes are crucial for successful islet isolation. Supplemental proteases are essential because they synergize with collagenase for effective pancreatic digestion. The activity of these enzymes is critically dependent on the presence of Ca2+ions at a concentration of 5–10 mM. The present study aimed to determine the Ca2+concentration during human islet isolation and to ascertain whether the addition of supplementary Ca2+is required to maintain an optimal Ca2+concentration during the various phases of the islet isolation process.Methods:Human islets were isolated according to standard methods and isolation parameters. Islet quality control and the number of isolations fulfilling standard transplantation criteria were evaluated. Ca2+was determined by using standard clinical chemistry routines. Islet isolation was performed with or without addition of supplementary Ca2+to reach a Ca2+of 5 mM.Results:Ca2+concentration was markedly reduced in bicarbonate-based buffers, especially if additional bicarbonate was used to adjust the pH as recommended by the Clinical Islet Transplantation Consortium. A major reduction in Ca2+concentration was also observed during pancreatic enzyme perfusion, digestion, and harvest. Additional Ca2+supplementation of media used for dissolving the enzymes and during digestion, perfusion, and harvest was necessary in order to obtain the concentration recommended for optimal enzyme activity and efficient liberation of a large number of islets from the human pancreas.Conclusions:Ca2+is to a large extent consumed during clinical islet isolation, and in the absence of supplementation, the concentration fell below that recommended for optimal enzyme activity. Ca2+supplementation of the media used during human pancreas digestion is necessary to maintain the concentration recommended for optimal enzyme activity. Addition of Ca2+to the enzyme blend has been implemented in the standard isolation protocols in the Nordic Network for Clinical Islet Transplantation.

As the median age of deceased kidney donors rises, updated knowledge of transplant outcomes from older deceased donors in differing donor-recipient age groups is required. Using ERA-EDTA Registry data we determined survival outcomes of kidney allografts donated from the same older deceased donor (55-70 years), and transplanted into one recipient younger and one recipient of similar age to the donor. The recipient pairs were divided into two groups: group 1; younger (median age: 52 years) and older (60 years) and group 2; younger (41 years) and older (60 years). A total of 1410 adults were transplanted during 2000-2007. Compared to the older recipients, the mean number of functioning graft years at 10 years was 6 months longer in the group 1 and group 2 younger recipients (P

Background Updated survival outcomes of young recipients receiving young or old deceased donor kidneys are required when considering accepting a deceased donor kidney. Methods We examined outcomes in 6448 European kidney allografts donated from younger (≥20– Results The 10-year cumulative incidence of graft failure was lowest in very young {22.0% [95% confidence interval (95% CI) 19.1–24.9]} and young [15.3% (95% CI 13.7–16.9)] recipients of younger donor kidneys and highest in very young [36.7% (95% CI 31.9–41.5)] and young [29.2% (95% CI 25.1–33.2)] recipients of older donor kidneys. At the 10-year follow-up, younger donor kidneys had a 1 year (very young) or 9 months (young) longer mean graft survival time compared with older donor kidneys. Graft failure risk in younger donor kidneys was 45% [very young adjusted hazard ratio (aHR) 0.55 (95% CI 0.44–0.68)] and 40% [young aHR 0.60 (95% CI 0.53–0.67)] lower compared with older donor kidneys. A 1-year increase in donor age resulted in a 2% [very young aHR 1.02 (95% CI 1.00–1.04)] or 1% [young aHR 1.01 (95% CI 1.00–1.01)] increase in the 10-year risk of death. Conclusions Younger donor kidneys show survival benefits over older donor kidneys in adult recipients ages 20–50 years. Updated survival outcomes from older deceased donors are necessary due to advances in transplantation medicine and the increasing role these donors play in organ transplantation.

Liver metastases of colorectal cancer can be operated with a curative intent in selected cases. However, more than half of the patients have a recurrence. The aim of this study was to evaluate the prognostic and predictive value of carcinoembryonic antigen (CEA), carbohydrate antigen 19-9 (CA19-9), human chorionic gonadotropin β (hCGβ) and tumour-associated trypsin-inhibitor (TATI) in colorectal cancer patients before and 3 months after resection of liver metastases. Marker concentrations were determined in blood samples from 168 colorectal cancer patients, who underwent liver resection between the years 1998 and 2007 at Helsinki University Hospital, Finland. The samples were taken before and 3 months after curative resection. Increased concentrations of CEA (>5 µg/L) and hCGβ (>1 pmol/L) 3 months after liver resection correlated with recurrence and impaired overall survival and increased CA19-9 (>26 kU/L) with impaired overall survival, but postoperative TATI was not prognostic. Preoperatively elevated CEA and CA19-9 correlated with impaired overall survival, but not with recurrence. Neither preoperative hCGβ nor TATI was prognostic. In conclusion, CEA is a useful prognostic marker, when measured 3 months after resection of colorectal liver metastases. CA19-9 also has prognostic significance and may have additional value.

Supplemental digital content is available in the text., Background Effective digestive enzymes are crucial for successful islet isolation. Supplemental proteases are essential as they synergize with collagenase for effective pancreas digestion. The presence of tryptic-like activity has been implicated in efficient enzyme blends and the present study aimed to evaluate if addition of clostripain, an enzyme with tryptic-like activity, could improve efficacy of the islet isolation procedure. Methods Clostripain was added to the enzyme blend just before pancreas perfusion. Islets were isolated per standard method and numerous isolation parameters, islet quality control, and the number of isolations fulfilling standard transplantation criteria were evaluated. Two control organs per clostripain organ were chosen by blindly matching against body mass index, cold ischemia time, hemoglobin A1c, donor sex, and donor age. Results There were no differences in pancreas weight, dissection time, digestion time, harvest time, percent digested pancreas, or total pellet volume before islet purification between control or clostripain pancreases. Glucose-stimulated insulin release results were similar between groups. Total isolation islet equivalents, purified tissue volume and islet equivalents/g pancreas as well as fulfillment of transplantation criteria favored clostripain processed pancreases. Conclusions The addition of clostripain to the enzyme blend soundly improved islet yields and transplantation rates. It gently aided pancreas digestion and maintained proper islet functionality. The addition of clostripain to the enzyme blend has now been implemented into standard isolation protocols at the isolation centers in Uppsala and in Oslo.

Background and Aims: The aim of the study was to clarify the frequency and the sequel of surgical complications occurring within 1 year after renal transplantation. Patients and Methods: Surgical complications after 1670 consecutive adult kidney transplantations performed between 2000 and 2009 were retrospectively analyzed. In 2%, a living-related allograft was used, and 10% were retransplantations. An intravesical technique without stenting was used for the ureteric implantation. Results: There were 282 surgical complications occurring in 259 (15.5%) transplantations. Ureteral obstruction occurred in 53 (3.1%), lymphoceles in 39 (1.5%), postoperative hemorrhage in 36 (2.1%), and renal vein thrombosis in 22 (1.3%) patients, respectively. Out of the 17 lung emboli, 4 were fatal. Male recipients had twice as much ureteral stenosis as female (2.4 vs 1.2%, p Conclusion: Surgical complications impair patient and graft survival after kidney transplantation.

While the majority of kidney transplantations in Finland have been traditionally performed from deceased donors, the frequency of living donors should be increased. Kidney donation is a safe procedure for a carefully examined donor, and for the recipient living donation enables elective surgery and preemptive transplantation. Potential risks for the donor must be minimized, but according to current recommendations, mild hypertension or obesity are not absolute contraindications for donation. Guidelines for donor selection and examination have been updated to simplify the process for all parties. Legislation in Finland requires changes to optimize the use of all potential living donors.

Although short-term outcome after kidney transplantation has improved, a small proportion of grafts are lost during the first year. We characterize in detail all early graft losses in the current era in a nationwide cohort of kidney transplant recipients. Altogether 2447 kidney transplantations, performed between June 2004 and October 2016, were included. All graft losses (return to dialysis or patient death) occurring during the first post-transplant year were characterized. During the first post-tranplant year, altogether 109 grafts were lost, 67 grafts failed, and 42 patients died. Fifty-five per cent of the deaths were due to cardiovascular causes, and 29% due to infectious causes. Twenty-one per cent of the failed grafts were primary nonfunction of unknown reason, 34% were lost due to venous thrombosis and 9% due to arterial thrombosis, but only 10 (15%) patients lost a graft due to acute cellular or humoral rejection. Independent risk factors for death included diabetes, and longer duration of pretransplant dialysis treatment, whereas risk factors for graft failure included increased level of panel-reactive antibodies and increased cold ischaemia time. Kidney allografts are rarely lost due to immunological reasons during the first post-transplant year. The most common causes of early death after transplantation are cardiovascular and infectious causes.

Kidney outcomes in early post-liver transplantation (LT) are crucial for long-term prognosis, but difficult to predict. Among 203 adult LT patients, we studied the value of plasma neutrophil gelatinase-associated lipocalin (NGAL) measured pre-LT for predicting acute kidney injury (AKI), kidney-replacement therapy within three months, and kidney dysfunction at three months post-LT. Glomerular filtration rate (GFR) was estimated by creatinine-based and cystatin C-based equations. Highest NGAL levels were among patients on pre-LT kidney-replacement therapy, whereas NGAL exceeded 200 μg/L in only three (2%) patients with pre-LT GFR60 mL/min. Pre-LT NGAL260 μg/L predicted GFR60 mL/min at three months post-LT (OR 17.8, 95% CI 2.1-153) independently of 19 other variables reflecting recipient characteristics, liver and kidney function, perioperative hemodynamic stress, and immunosuppression. Of 81 patients with pre-LT GFR60 mL/min, 48% had GFR60 mL/min at three months, and an NGAL level260 μg/L predicted this outcome with 90% specificity and 46% sensitivity. NGAL failed to predict post-LT AKI or need for temporary kidney-replacement therapy. In conclusion, NGAL independently predicted irreversibility of pre-LT kidney dysfunction and could thus help in optimizing patient care and in the decision to perform combined liver-kidney transplantation. Pre-LT NGAL was not useful in patients with preserved pre-LT kidney function or in predicting post-LT AKI.

It has been proposed that the liver protects the kidney in CLKT. However, few studies have examined long-term renal function after CLKT and contrasted renal function of CLKT patients to KT patients beyond one year after transplantation. We studied long-term renal function of CLKT patients and compared renal function of CLKT patients to KT patients between one and five years after transplantation. Patients who underwent CLKT between 1993 and 2011 were included (n = 34; 11 children and 23 adults). Ninety-six (27 children and 69 adults) KT patients were selected as controls. GFR was estimated (eGFR) and measured (mGFR) with Cr-51-EDTA clearance. Mean mGFR was 63 at one and 70 at ten years after pediatric CLKT. Mean eGFR was 75 at one and 50 at ten years after adult CLKT. Difference in mean mGFR between pediatric CLKT and KT patients was 8 (95% CI -7 to 23) and 11 (95% CI -4 to 26) at one and five years after transplantation, respectively. Difference in mean eGFR between adult CLKT and KT patients was 8 (95% CI -5 to 20) and 1 (95% CI -10 to 12) at one and five years after transplantation, respectively. Longitudinal changes in GFRs were somewhat similar in CLKT and KT patients in both age-groups but pediatric CLKT patients had on average higher GFRs than pediatric KT patients. In long-term follow-up, renal function remains stable in pediatric CLKT patients but declines in adult CLKT patients.

Prediction of prognosis in hepatocellular carcinoma (HCC) is difficult. The aim of this study was to evaluate the prognostic value of serum MMP-8, -9, -13, and TIMP-1 in patients with HCC.Pre-treatment serum samples from 134 patients with HCC were retrospectively analyzed. The serum concentration of MMP-8 was analyzed with immunofluorometric assay (IFMA), and those of MMP-9, MMP-13, and TIMP-1 were determined by enzyme-linked immunosorbent assays (ELISA). Clinical data were retrieved from patient records and survival data obtained from Statistics Finland.The overall cumulative disease-specific survival was 69% at 1 year, 50% at 2 years, and 33% at 5 years. Kaplan-Meier overall survival analysis showed that patients with low concentrations of serum MMP-8 or TIMP-1 had a statistically significantly better overall survival than patients with high concentrations of serum MMP-8 or TIMP-1 (P=0.013 and P=0.003). Interestingly, the overall survival in patients with high MMP-9/TIMP-1 ratio was statistically significantly better than in those patients with low MMP-9/TIMP-1 ratio (P=0.004).Our results suggest that serum MMP-8, TIMP-1, and the ratio of MMP-9/TIMP-1 might be useful adjuncts as predictors of prognosis in patients with HCC.

Hepatocellular carcinoma (HCC) is the sixth most common cancer and the third most frequent cause of cancer death worldwide. The aim of this study was to evaluate the prognostic value of serum tumor-associated trypsin inhibitor (TATI) and the free β subunit of human chorionic gonadotropin (hCGβ) in patients with HCC.The serum concentrations of TATI and hCGβ were determined by time-resolved immunofluorometric assays (IFMA) in pretreatment serum samples from 144 patients with HCC. Clinical data were retrieved from patient records and survival data obtained from Statistics Finland.The overall cumulative disease-specific survival was 69% at 1 year, 50% at 2 years and 33% at 5 years. Disease-specific median survival time was 26 months. The overall survival in patients with low serum concentrations of TATI or hCGβ was statistically significantly better than in patients with elevated concentrations (p = 0.003 and 0.003, respectively). In multivariate analysis, both serum TATI and serum hCGβ were independent prognostic markers.The results imply that elevated serum concentrations of TATI and hCGβ are predictors of adverse prognosis in patients with HCC and appear to be useful adjuncts in predicting prognosis in patients with HCC.

Aims Oxidative stress may contribute to the development of chronic pancreatitis (CP). The enzymes manganese superoxide dismutase 2 (MnSOD, SOD2) and catalase (CAT) counteract free radical activity within the mitochondria and the cytosol. Moreover, CAT activity contributes to the transformation of ethanol to acetaldehyde, a toxic intermediate product of ethanol metabolism, which has been associated with pancreatic damage. Common functional polymorphisms have been described in the MnSOD gene [rs4880, NM_000636.3:c.47 T > C, alanine (ALA) to valine (Val)] and in the CAT promoter region [rs1001179, NG_013339.1:g.4760 C > T]. We investigated whether these polymorphisms are associated with alcoholic CP. Methods We genotyped 470 patients with alcoholic CP for these MnSOD and CAT polymorphisms. We also analysed these variants in 357 healthy control subjects, and in an additional control group of 113 individuals with non-alcoholic CP. We used the age at onset of CP as marker of disease severity and investigated whether different genotypes are associated with different ages at onset. In patients with alcoholic CP, we investigated whether an interaction exists between smoking behaviour and genotypes by comparing genotype distributions in smokers and non-smokers. Results We did not observe significant differences of genotype frequencies between patient groups and controls. In patient groups, we did not find significant differences in the ages at onset between different genotypes. We did not observe an interaction between these polymorphisms. We did not find an association of these variants with smoking behaviour. Conclusions The investigated MnSOD and CAT polymorphisms do not predispose to the development of alcoholic CP. Short summary Patients with alcoholic pancreatitis and controls were genotyped for polymorphisms in oxidative stress genes. There were no significant differences of genotype frequencies between patients and controls, and no association with the age at onset of disease was observed. The polymorphisms are not associated with the development of alcoholic pancreatitis.

Nicotine intoxication is a rare cause of death and can lead to brain death after respiratory arrest and hypoxic-ischemic encephalopathy. To our knowledge, no previous reports regarding organ donation after nicotine intoxication have been described. We present a successful case of kidney donation after brain death caused by subcutaneous nicotine overdose from liquid nicotine from an e-cigarette cartridge in an attempted suicide. Both kidneys were transplanted successfully with immediate graft function, and both recipients were discharged at postoperative day 9 with normal plasma creatinine levels. Graft function has remained excellent in follow-up. This case suggests that kidneys from a donor with fatal nicotine intoxication may be successfully used for kidney transplantation in the absence of other contraindications for donation.

Background:The significance of JC polyomavirus (JCPyV) after kidney transplantation ranges from irrelevant to full-blown nephropathy or PML. Objectives: To investigate the clinical significance of high-level JCPyV viruria and JCPyV primary infections after kidney transplantation. Study design: JCPyV viruria was detected in routine screening by quantitative real-time PCR in 40/238 kidney transplant recipients and was high-level (> 10(7)copies/ml) in 17 patients. A protocol biopsy at the time of JCPyV viruria was available from 10 patients. Results: Peak urine viral loads were 1.0 x 10(7)-2.5 x 10(9)copies/ml in the 17 high-level viruria patients. 6/15 (40%) patients with high-level JCPyV viruria with pretransplant sera available were JCPyV IgG negative suggesting that JCPyV viruria resulted from the donor graft in most cases. No acute graft dysfunction was associated with JCPyV viruria. No positive SV40 staining was detected in protocol biopsies, and nospecific histopathology was associated with high-level viruria; JCPyV nephropathy was not found. No differences were seen in histopathology or graft function at 3 years in patients with high-level viruria compared to non-JCPyV viruric patients transplanted during the same time period, and outcome was similar in patients with presumably primary and reactivated JCPyV. The mean estimated GFR at last follow-up was 44 ml/min (range 12-60 ml/min). One graft with high-level viruria was lost 9 years posttransplant due to recurrent IgA nephropathy Conclusions: High-level JCPyV viruria seems to be associated with primary JCPyV infection reflecting the average seroprevalence of 60%, but is not stringently associated with inferior graft function or survival, or histopathological changes. c 2016 Elsevier B.V. All rights reserved.

BK polyomavirus (BKPyV) commonly reactivates after kidney transplantation, and can cause polyomavirus-associated nephropathy (PyVAN), whereas after allogeneic stem cell transplantation the most frequent manifestation of BKPyV is polyomavirus-associated hemorrhagic cystitis (PyVHC). Despite high-level BKPyV replication in both, the pathogenesis and manifestation of both BKPyV entities appears to differ substantially. We describe an unusual case of simultaneous PyVAN and PyVHC presenting with acute symptoms in a BKPyV-IgG positive recipient eight months after kidney transplantation from a haploidentical living donor, who was BKPyV-IgG negative. Symptoms of cystitis and viremia subsided rapidly after reduction of immunosuppression. (C) 2015 Elsevier B.V. All rights reserved.

This study aimed to evaluate a 50:50 mix of perfluorohexyloctane/polydimethylsiloxane 5 (F6H8S5) preservation of pancreases in a clinical setting compared with standard solutions for 1) cold ischemia time (CIT) 20 h. Procured clinical-grade pancreases were shipped in either F6H8S5 or in standard preservation solutions, that is, University of Wisconsin (UW) or Custodiol. F6H5S5 was preoxygenated for at least 15 min. Included clinical-grade pancreases were procured in UW or Custodiol. Upon arrival at the islet isolation laboratory, the duodenum was removed followed by rough trimming while F6H8S5 was oxygenated for 15-20 min. Trimmed pancreases were immersed into oxygenated F6H8S5 and stored at 4°C overnight followed by subsequent islet isolation. Pancreas preservation using F6H8S5 proved as effective as UW and Custadiol when used within CIT up to 10 h, in terms of both isolation outcome and islet functionality. Preservation in F6H8S5 of pancreases with extended CIT gave results similar to controls with CIT

In immunosuppressed patients human herpesvirus 6 (HHV-6) reactivations are common. The aim of the study was to determine to which extent HHV-6 can be found in the gastrointestinal tract in kidney transplant recipients and in patients on chronic dialysis. The HHV-6 and cytomegalovirus (CMV) examinations were performed on gastro duodenal and colon biopsy specimens obtained from 81 kidney transplant recipients and on 46 chronic dialysis patients. The HHV-6 and CMV were demonstrated by immunohistochemistry detecting both HHV-6A and HHV-6B, and CMV-specific antigens. The HHV-6B-positive cells, were found in gastroduodenal biopsy specimens from 34% of the transplant recipients and 28% of the patients on chronic dialysis, CMV-positive cells were found in specimens from 53% of the transplant recipients and 28% of the patients on chronic dialysis. The HHV-6B positive cells were found in the colonic mucosa specimens from 36% of the transplant recipients and 22% of the patients on chronic dialysis, CMV-positive cells were found in specimens from 36% of the transplant recipients and 17% of the patients on chronic dialysis. The HHV-6B positive cells were found equally often in the gastroduodenal as in the colorectal mucosa. The HHV-6B positive cells as well as CMV positive cells were simultaneously found in every fifth of transplant recipients.

The prevalence and significance of cytomegalovirus (CMV) detected in biopsy specimens from the gastroduodenal mucosa of liver transplant patients, patients with chronic or acute liver failure and immunocompetent patients with dyspeptic symptoms were evaluated. 80 liver transplant patients with upper gastrointestinal symptoms, 132 patients with chronic and 25 with acute liver failure, and 33 immunocompetent, dyspeptic patients underwent oesophagogastroduodenoscopies, with biopsies from the duodenum and stomach. CMV was demonstrated by immunohistochemistry in frozen sections, using a monoclonal antibody against CMV-specific antigens (pp65 matrix protein), and in paraffin sections by a monoclonal antibody against delayed early protein (p52). 71% of the liver transplant patients, 45% of the patients with chronic liver disease, 20% with acute liver failure, and 45% of the immunocompetent, dyspeptic patients had CMV-positive findings in the gastroduodenal mucosa (liver transplant patients vs other groups, p

Purpose: The homozygous p.C282Y variant of the HFE gene is a major risk factor for hereditary hemochromatosis, a disorder of iron metabolism resulting in progressive iron accumulation in a variety of organs including the pancreas. Heterozygosity of p.C282Y and p.H63D may increase susceptibility to chronic liver and pancreatic disease. This study determines the frequencies of p.C282Y and p.H63D alterations in patients with chronic pancreatitis and pancreatic adenocarcinoma. Methods: In total, 958 patients (349 with alcoholic pancreatitis, 343 with idiopathic pancreatitis, 64 with familial chronic pancreatitis, 34 with acute pancreatitis, and 168 with pancreatic adenocarcinoma) were enrolled and compared with 681 healthy and 100 alcoholic controls. Furthermore, 45 parent–offspring trios were included for segregation analysis. Genotyping of p.C282Y and p.H63D was performed by restriction fragment length polymorphism or melting curve analyses. Results: No significant differences were found in heterozygosity for p.C282Y and p.H63D when patients with alcoholic (8.0/21.5%), idiopathic (7.3/24.5%), or familial (9.8/23.0%) pancreatitis, or pancreatic adenocarcinoma (5.4/28.6%) were compared with healthy (6.2/24.8%) and alcoholic (7.0/25.0%) controls. Neither genotype was associated with the presence of secondary diabetes mellitus in patients with chronic pancreatitis. Conclusion: Although hemochromatosis is associated with pancreatic pathology, the p.C282Y and p.H63D variants do not play a significant role in the pathogenesis of chronic pancreatitis or pancreatic adenocarcinoma.

The first simultaneous pancreas-kidney transplantation in Finland was performed in 2010. On a global scale, already more than 45,000 pancreatic transplantations have been performed. Pancreatic transplantation restores the blood glucose level to normal, but only at the cost of possible adverse effects due to surgery and anti-rejection drugs. Based on our experience with 24 patients, this operation has met the expectations and shown that simultaneous pancreas-kidney transplantation is a good alternative for selected type 1 diabetics instead of mere kidney transplantation. In the future we aim to conduct approximately 15 combined transplantations per year.