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  • Kettunen, Jarno L. T.; Parviainen, Helka; Miettinen, Päivi J.; Färkkilä, Martti; Tamminen, Marjo; Salonen, Pia; Lantto, Eila; Tuomi, Tiinamaija (2017)
    Context: The clinical spectrum of organogenetic anomalies associated with HNF1B mutations is heterogeneous. Besides cystic kidney disease, diabetes, and various other manifestations, odd cases of mainly neonatal and posttransplantation cholestasis have been described. The biliary phenotype is incompletely defined. Objective: To systematically characterize HNF1B-related anomalies in the bile ducts by imaging with magnetic resonance imaging (MRI) or magnetic resonance cholangiopancreatography (MRCP). Setting and Patients: Fourteen patients with HNF1B mutations in the catchment area of the Helsinki University Hospital were evaluated with upper abdominal MRI and MRCP. Blood samples and clinical history provided supplemental data on the individual phenotype. Main Outcome Measure(s): Structural anomalies in the biliary system, medical history of cholestasis, other findings in abdominal organs, diabetes and antihyperglycemic treatment, hypomagnesemia, and hyperuricemia. Results: Structural anomalies of the bile ducts were found in seven of 14 patients (50%). Six patients had choledochal cysts, which are generally considered premalignant. Conclusions: Structural anomalies of the biliary system were common in HNF1B mutation carriers. The malignant potential of HNF1B-associated choledochal cysts warrants further studies.
  • Virtanen, Elina; Seppälä, Hanna; Helanterä, Ilkka; Laine, Pia; Lautenschlager, Irmeli; Paulin, Lars; Mannonen, Laura; Auvinen, Petri; Auvinen, Eeva (2018)
    Background: BK polyomavirus (BKPyV) infection is a common asymptomatic viral infection in the general population. Severe complications are seen in immunocompromised individuals, such as polyomavirus-associated nephropathy (PyVAN) in renal transplant recipients. Information on BKPyV microRNA expressions is scarce, although polyomavirus-encoded microRNAs have been shown to control viral replication and assist in immune evasion. Whereas the pathogenic role of rearrangements in JC polyomavirus has been well established, little is known about BKPyV rearrangements in PyVAN. Objectives: To assess viral microRNA expression and transcriptional control region (TCR) sequence variation in PyVAN patients. Study design: bkv-miR-B1-3p and bkv-miR-B1-5p microRNA expression was quantified in 55 plasma samples from 9 PyVAN patients and 2 controls using specific miRNA assays. TCR architectures among the viral populations in each patient were characterized by massive parallel sequencing. Results: bkv-miR-B1-3p and bkv-miR-B1-5p miRNA expression was established in 85.5% and 98.2% of samples, respectively. On average, an 8.9-fold (bkv-miR-B1-3p) and 8.7-fold (bkv-miR-B1-5p) higher expression levels were detected in PyVAN patients as compared to controls. Rearranged BKPyV strains with duplications and deletions were detected in 7/9 PyVAN patients, but 77.6-99.9% of all sequence reads in all samples represented archetype strains. Conclusions: The frequent detection and increased expression of miRNAs suggest involvement in PyVAN pathogenesis. Despite the predominance of archetype BKPyV strains, the frequent detection of minor rearranged viral populations urges further study on their role in severe kidney disease. Our results suggest that miRNA expression is increased in PyVAN patients, as well as in the presence of rearranged viral strains.
  • Keronen, Satu; Martola, Leena; Finne, Patrik; Burton, Inari S.; Kröger, Heikki; Honkanen, Eero (2019)
    Background and objectives Over the past decade, the management of CKD-mineral and bone disorder has changed substantially, altering the pattern of bone disease in CKD. We aimed to evaluate the natural history of kidney bone disease in contemporary kidney transplant recipients and patients on dialysis. Design, settings, participants, & measurements Sixty one patients on dialysis who were referred to kidney transplantation participated in this prospective cohort study during November 2009 and December 2010. We performedbaseline bone biopsieswhile thepatientswere ondialysis andrepeatedthe procedure in 56 patients at 2 years after kidney transplantation or 2 years after baseline if transplantationwas not performed. Measurements of mineral metabolism and bone turnover, as well as dual energy x-ray absorptiometry scans, were obtained concurrently. Results A total of 37 out of 56 participants received a kidney transplant, of which 27 underwent successful repeat bone biopsy. The proportion of patients with high bone turnover declined from 63% at baseline to 19% at 2 years after kidney transplantation, whereas the proportion of thosewith lowbone turnover increased from26% to 52%. Of 19 participants remaining on dialysis after 2 years, 13 underwent successful repeat biopsy. The proportion of patients remaining on dialysis with high bone turnover decreased from 69% to 31%, and low bone turnover increased from8% to 38%. Abnormal bonemineralization increased in transplant recipients from33% to 44%, but decreased in patients remaining on dialysis from 46% to 15%. Trabecular bone volume showed little change after transplantation, but low bone volume increased in patients remaining on dialysis. Bone mineral density did not correlate with histomorphometric findings. Conclusions Bone turnover decreased over time both in patients remaining on dialysis and in kidney transplant recipients. Bone mineral density and bone biomarkers were not associated with bone metabolism changes detected in bone biopsy specimens.
  • Keronen, Satu M.; Martola, Leena A.L.; Finne, Patrik; Burton, Inari S.; Tong, Xiaoyu F.; Kröger, Heikki P.; Honkanen, Eero O. (2022)
    Bone histomorphometric analysis is the most accurate method for the evaluation of bone turnover, but non-invasive tools are also required. We studied whether bone biomarkers can predict high bone turnover determined by bone histomorphometry after kidney transplantation. We retrospectively evaluated the results of bone biopsy specimens obtained from kidney transplant recipients due to the clinical suspicion of high bone turnover between 2000 and 2015. Bone biomarkers were acquired concurrently. Of 813 kidney transplant recipients, 154 (19%) biopsies were taken at a median of 28 (interquartile range, 18–70) months after engraftment. Of 114 patients included in the statistical analysis, 80 (70%) presented with high bone turnover. Normal or low bone turnover was detected in 34 patients (30%). For discriminating high bone turnover from non-high, alkaline phosphatase, parathyroid hormone, and ionized calcium had the areas under the receiver operating characteristic curve (AUCs) of 0.704, 0.661, and 0.619, respectively. The combination of these markers performed better with an AUC of 0.775. The positive predictive value for high turnover at a predicted probability cutoff of 90% was 95% while the negative predictive value was 35%. This study concurs with previous observations that hyperparathyroidism with or without hypercalcemia does not necessarily imply high bone turnover in kidney transplant recipients. The prediction of high bone turnover can be improved by considering alkaline phosphatase levels, as presented in the logistic regression model. If bone biopsy is not readily available, this model may serve as clinically available tool in recognizing high turnover after engraftment.
  • Zhang, Luyao; Hemminki, Otto; Zheng, Guoqiao; Försti, Asta; Sundquist, Kristina; Sundquist, Jan; Hemminki, Kari (2019)
    Literature on familial risk of carcinomas in situ (CISs) is limited because many cancer registries do not collect information on CIS. In Sweden CISs are collected, and we used these data to analyze familial relative risks (RRs) for concordant (CIS-CIS) types of anogenital (cervical, other female and male genital and anal) and skin squamous cell CIS; additionally RRs were assessed between CIS types and between CIS and invasive forms. RRs were calculated for the offspring generations when family members were diagnosed CIS. Case numbers for CIS ranged from 330 in anal to 177,285 in cervical CIS. Significant concordant CIS-CIS RRs were 2.74 for female genital, 1.77 for cervical and 2.29 for SCC skin CISs. The CIS forms associated also with each other, except for cervical and skin CIS types. RRs for concordant CIS-invasive cancer associations were lower than CIS-CIS associations. Cervical CIS associated with non-Hodgkin CIS which may suggest immune dysfunction as a contributing factors. The results for anogenital CIS types suggest that life style related human papilloma virus infections contributed to the observed familial associations. Lower risks for CIS-invasive cancer than CIS-CIS suggest that CIS and invasive cancers share only partially risk factors that underlie familial clustering.
  • Hölttä, Tuula; Jalanko, Hannu (2020)
    Congenital nephrotic syndrome (CNS) was primarily considered one disease entity. Hence, one treatment protocol was proposed in the beginning to all CNS patients. Today, with the help of gene diagnostics, we know that CNS is a heterogeneous group of disorders and therefore, different treatment protocols are needed. The most important gene defects causing CNS are NPHS1, NPHS2, WT1, LAMB2, and PLCE1. Before active treatment, all infants with CNS died. It was stated already in the mid-1980s that intensive medical therapy followed by kidney transplantation (KTx) should be the choice of treatment for infants with severe CNS. In Finland, early aggressive treatment protocol was adopted from the USA and further developed for treatment of children with the Finnish type of CNS. The aim of this review is to state reasons for "early aggressive treatment" including daily albumin infusions, intensified nutrition, and timely bilateral nephrectomy followed by KTx at the age of 1-2 years.
  • Peräsaari, J. P.; Jaatinen, T.; Merenmies, J. (2018)
    The virtual crossmatch, which is based on single antigen bead technology, is used in the prediction of crossmatch results. However, this assay differs in sensitivity and specificity from crossmatch methods. In our study, the results of physical crossmatches, performed with three different methods, were assessed against virtual cross match results. The aim was to determine the potential cut-off values for donor specific antibodies (DSA) that would predict the crossmatch results obtained by different methods. The results of different crossmatch techniques were correlated with the virtual crossmatch. The receiver operating characteristic (ROC) analysis revealed the Flow cytometric crossmatch (FCXM) and Luminex crossmatch (LXM) to be the most accurate, with area under curve (AUC) values of 0.861 and 0.805, respectively. While we found that the virtual crossmatch correlated well with all the crossmatch results, FCXM produced the best results (83% of the DSA detected). LXM outperformed the other tests in terms of the accuracy in separating class II DSA.
  • Zhang, Luyao; Hemminki, Otto; Chen, Tianhui; Zheng, Guoqiao; Försti, Asta; Sundquist, Kristina; Sundquist, Jan; Hemminki, Kari (2019)
    Data on familial risks in penile and vulvar/vaginal cancers and in second primary cancers (SPCs) following these cancers are limited. We used the Swedish Family-Cancer Database from years 1958 through 2015 to identify 3641 penile and 8856 vulvar/vaginal cancers and to calculate relative risks (RRs) and 95% confidence intervals (CIs) for these cancers according to site-specific cancer in family members; additionally risk for SPCs was calculated. The familial RR for concordant (same) penile cancer was 3.22 (1.34-7.74), and it was 2.72 (1.69-4.39) for vulvar/vaginal cancer; RRs were increased for vulvar/vaginal cancer in families of anal cancer patients. RR for second penile cancer after penile cancers was 11.68 (7.95-17.18), while that for concordant vulvar/vaginal cancer was 9.03 (7.31-11.15). SPCs were diagnosed in 16.8% of penile cancer patients and in them 45.9% of deaths were caused by SPC (other than penile cancer). In vulvar/vaginal cancer patients with SPC, 36.4% of deaths were due to SPC. The results showed that these genital cancers might run in families and as SPCs are associated with human papilloma virus and smoking related cancers. Risk for these genital and anal SPCs are high and a follow-up plan should be agreed at diagnosis of these cancers.
  • Limnell, Niko; Schramko, Alexey A. (2018)
    Objectives: Fluid therapy is required to maintain perfusion to donor organs. Recent reviews on the choices of fluids have emphasized the safety of using crystalloids, as opposed to fluid therapy with colloids, which has been reported to be either unequivocally or potentially harmful in a number of studies on various patient populations. We aimed to analyze whether the type of fluid administered to donors is connected with kidney transplant outcomes. Materials and Methods: A total of 100 consecutive brain-dead multiorgan donors and their respective 181 kidney recipients were studied retrospectively. Data concerning donor fluid therapy, the characteristics of the donors and the recipients, and outcomes after kidney transplant were extracted from organ retrieval and patient records. Cases with early graft function were compared with cases with delayed graft function. Results: Donors had received both crystalloids and colloids in most cases (84%). Fluid therapy with crystalloids alone was more common among the 40 recipients with delayed (30%) than in the 103 recipients with early graft function (11%) (P = .005). Donor age, time on renal replacement therapy before transplant, and donor fluid therapy with crystalloids alone were independent risk factors for delayed graft function in multivariate analysis. Conclusions: Our results suggest that donor fluid therapy including colloids could be beneficial instead of harmful compared with treatment with crystalloids alone. This finding needs to be evaluated in prospective studies.
  • Benoni, Henrik; Eloranta, Sandra; Dahle, Dag O.; Svensson, My H. S.; Nordin, Arno; Carstens, Jan; Mjoen, Geir; Helanterä, Ilkka; Hellstrom, Vivan; Enblad, Gunilla; Pukkala, Eero; Sorensen, Soren S.; Lempinen, Marko; Smedby, Karin E. (2020)
    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.
  • Zheng, Guoqiao; Sundquist, Kristina; Sundquist, Jan; Chen, Tianhui; Foersti, Asta; Hemminki, Akseli; Hemminki, Kari (2021)
    Background: Second primary cancers (SPCs) are increasing, which may negatively influ-ence patient survival. Gastric cancer (GC) has poor survival and when it is diagnosed as SPC it is often the cause of death. We wanted to analyze the risk of SPCs after GC and the risk of GC as SPC after any cancer. Such bidirectional analysis is important in relation to fatal cancers because SPCs may be under-reported in the short-term survival period. Methods: Cancers were obtained from the Swedish Cancer Registry from years 1990 through 2015. Standardized incidence ratios (SIRs) were used to estimate bidirectional relative. Results: We identified 23,137 GC patients who developed 1042 SPCs (4.5%); 2158 patients had GC as SPC. While the risk for three SPCs was increased after GC, seven first primary cancers were followed by an increased risk of GC as SPC, including esophageal, colorectal, bladder, squamous cell skin and breast cancers and non-Hodgkin lymphoma. Breast cancer, which was followed by a diagnosis of second GC, showed an excess of lobular histology. Conclusion: Multiple primary cancers in the same individuals may signal genetic predis-position. Accordingly, the association of GC with breast cancer may be related to mutations in the CDH1 gene, and clustering of colorectal, small intestinal and bladder cancers could be related to Lynch syndrome. The third line of findings supports a contribution of immune dysfunction on the increased risk of GC as SPC after skin cancer and non-Hodgkin lymphoma. Early detection of GC in the risk groups could save lives.
  • Zheng, Guoqiao; Sundquist, Kristina; Sundquist, Jan; Chen, Tianhui; Forsti, Asta; Hemminki, Akseli; Liska, Vaclav; Hemminki, Kari (2021)
    Background: Second primary cancers (SPCs) are important clinically as they may negatively influence patient survival and they may tell about therapeutic side effects and general causes of cancer. Population-based literature concerning SPCs after hepatobiliary cancers is limited and here we assess risks of SPCs after hepatocellular cancer (HCC), and cancers of the gallbladder, bile ducts and ampulla of Vater. In reverse order, we consider the risk of hepatobiliary cancers as SPCs after any cancer. Methods: We used standardized incidence ratios (SIRs) to estimate bidirectional relative risks of subsequent cancers associated with hepatobiliary cancers. Cancer diagnoses were obtained from the Swedish Cancer Registry from years 1990 through 2015. Results: We identified 9997 primary HCCs, 1365 gallbladder cancers and 4721 bile duct cancers. After HCC, risks of four SPCs were increased: gallbladder (SIR = 4.38; 95% confidence interval 1.87-8.67), thyroid (4.13; 1.30-9.70), kidney (2.92; 1.66-4.47) and squamous cell skin (1.55; 1.02-2.26) cancers. In reverse order, HCC as SPC, in addition to the above cancers, associations included upper aerodigestive tract, esophageal, small intestinal and bladder cancers and non-Hodgkin lymphoma. For gallbladder and bile duct cancers, associations were found with small intestinal and pancreatic cancers. Conclusion: The results suggested that HCC is associated with two types of SPC, one related to shared environmental risk factors, such as alcohol, exemplified by upper aerodigestive tract and esophageal cancer, and the other related to immune dysfunction, exemplified by squamous cell skin cancer. SPCs associated with gallbladder and bile duct cancers suggest predisposition to mutations in the mismatch repair gene MLH1.
  • Zheng, Guoqiao; Chattopadhyay, Subhayan; Sud, Amit; Sundquist, Kristina; Sundquist, Jan; Försti, Asta; Houlston, Richard; Hemminki, Akseli; Hemminki, Kari (2019)
    Improvement of survival in lymphocytic leukaemia has been accompanied by the occurrence of second primary cancer (SPCs). Based on Swedish Family Cancer Database, we applied bi-directional analyses in which relative risks (RRs) were calculated for any SPCs in patients with chronic lymphocytic leukaemia (CLL), acute lymphoblastic leukaemia (ALL) and hairy cell leukaemia (HCL) and the risks of these leukaemias as SPCs. After CLL, RRs were significant for 20 SPCs, and high for skin squamous cell cancer (2458 for insitu and 763 for invasive), Merkel cell carcinoma (1436), Hodgkin lymphoma (716) and Kaposi sarcoma (676). Conversely, 15 CLL cancer pairs were reciprocally increased. The increased risks were reciprocal for ALL and four cancers. RR for ALL was 1535 after myeloid neoplasia. HCL showed reciprocally increased RRs with non-Hodgkin lymphoma and melanoma. The concordance between RRs for bi-directional associations between CLL and different cancers, and HCL and different cancers was highly significant. For CLL (also for HCL), the bi-directional risks with skin cancers and other immune-related cancers suggest the probable involvement of immune dysfunction. For ALL, treatment may contribute to risks of multiple SPCs. Increased risk of ALL after haematological neoplasms may indicate bone marrow dysfunction. These findings may help guide treatment decisions and prognostic assessment.
  • Chattopadhyay, Subhayan; Hemminki, Akseli; Försti, Asta; Sundquist, Kristina; Sundquist, Jan; Hemminki, Kari (2020)
    Second primary cancers (SPCs) are becoming a common cancer entity, which may interfere with survival in relatively benign first primary cancers. We examined the hypothesis that immune dysfunction may contribute to SPCs by assessing SPCs associated with known immune responsive skin cancers, invasive and in situ squamous cell carcinoma, Kaposi sarcoma, and Merkel cell carcinoma. Cancers were identified from the Swedish Cancer Registry from the year 1958 to 2015. Standardized relative risks were calculated bidirectionally for any SPC after skin cancer and for skin cancer as SPC. Over 80,000 first primary cancers were identified for each invasive and in situ squamous cell carcinoma of the skin. Bidirectional increased risks were observed for 26 cancers associated with invasive skin cancer; the Spearman rank correlation was 0.72 (P = 4.6 x 10(-5)). The highest bidirectional relative risks were for invasive and in situ skin cancer as SPCs (14.59 and 16.71, respectively). Remarkably high risks for second in situ squamous cell carcinoma of the skin were found after Kaposi sarcoma (685.68) and Merkel cell carcinoma (117.23). The high systematic bidirectional risks between immune responsive skin cancers and most other cancers suggest that immune suppression is a key mechanism contributing to an increased risk of SPCs.
  • Klein, H. J.; Schanz, U.; Hivelin, M.; Waldner, M.; Koljonen, V.; Guggenheim, M.; Giovanoli, P.; Gorantla, V. S.; Fehr, T.; Plock, J. A. (2016)
    Sensitization describes the acquired ability of the immune system to react to foreign human leukocyte antigens (HLA) by producing antibodies and developing memory cells. In the field of transplantation, recipient preformed HLA antibodies due to previous sensitization have been identified - beneath ABO incompatibility - as a major factor for acute graft rejection. Several reasons for sensitization have largely been studied, such as previous blood transfusions, pregnancies or former transplants. Recent studies indicate that the use of assist devices (e.g. ECMO) or cadaveric skin allotransplantation providing temporary coverage in burn patients may lead to additional sensitization. As vascularized composite allotransplantation (VCA) has become a rapidly advancing therapeutic option for reconstruction of complex tissue defects in burns, it seems even more important to become familiar with immunological principles and to be cautiously aware of both sources of sensitization and therapeutic concepts in burns avoiding sensitization. This may also include emergency VCAs in burn patients as potential strategy for early definitive reconstruction avoiding procedures triggering HLA antibody formation. We hereby provide an overview on current evidence in the field of pre- and peritrans-plant sensitization, followed by posttransplant strategies of desensitization and their potential impact on future treatments of burn patients. (C) 2015 Elsevier Ltd and ISBI. All rights reserved.
  • Abd ElHafeez, Samar; Noordzij, Marlies; Kramer, Anneke; Bell, Samira; Savoye, Emilie; Abad Diez, Jose Maria; Lundgren, Torbjorn; Reisater, Anna Varberg; Kerschbaum, Julia; Santiuste de Pablos, Carmen; Ortiz, Fernanda; Collart, Frederic; Palsson, Runolfur; Arici, Mustafa; Heaf, James G.; Massy, Ziad A.; Jager, Kitty J. (2021)
    In this study we aimed to compare patient and graft survival of kidney transplant recipients who received a kidney from a living-related donor (LRD) or living-unrelated donor (LUD). Adult patients in the ERA-EDTA Registry who received their first kidney transplant in 1998-2017 were included. Ten-year patient and graft survival were compared between LRD and LUD transplants using Cox regression analysis. In total, 14 370 patients received a kidney from a living donor. Of those, 9212 (64.1%) grafts were from a LRD, 5063 (35.2%) from a LUD and for 95 (0.7%), the donor type was unknown. Unadjusted five-year risks of death and graft failure (including death as event) were lower for LRD transplants than for LUD grafts: 4.2% (95% confidence interval [CI]: 3.7-4.6) and 10.8% (95% CI: 10.1-11.5) versus 6.5% (95% CI: 5.7-7.4) and 12.2% (95% CI: 11.2-13.3), respectively. However, after adjusting for potential confounders, associations disappeared with hazard ratios of 0.99 (95% CI: 0.87-1.13) for patient survival and 1.03 (95% CI: 0.94-1.14) for graft survival. Unadjusted risk of death-censored graft failure was similar, but after adjustment, it was higher for LUD transplants (1.19; 95% CI: 1.04-1.35). In conclusion, patient and graft survival of LRD and LUD kidney transplant recipients was similar, whereas death-censored graft failure was higher in LUD. These findings confirm the importance of both living kidney donor types.