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Larsson, Erik
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Publications (10 of 64) Show all publications
Sedigh, A., Nordling, S., Carlsson, F., Larsson, E., Norlin, B., Lubenow, N., . . . Lorant, T. (2019). Perfusion of Porcine Kidneys With Macromolecular Heparin Reduces Early Ischemia Reperfusion Injury. Transplantation, 103(2), 420-427
Open this publication in new window or tab >>Perfusion of Porcine Kidneys With Macromolecular Heparin Reduces Early Ischemia Reperfusion Injury
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2019 (English)In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 103, no 2, p. 420-427Article in journal (Refereed) Published
Abstract [en]

Background: Previously, we have been able to demonstrate the possibility of coating the inner surface of the renal arteries in porcine kidneys with a heparin conjugate during hypothermic machine perfusion (HMP). The purpose of this study was to assess the efficacy of this treatment in reducing early ischemia-reperfusion injury.

Method: Brain death was induced in male landrace pigs by stepwise volume expansion of an epidural balloon catheter until negative cerebral perfusion pressure (CPP) was obtained. Both kidneys (matched pairs; n = 6 + 6) were preserved for 20 hours byHMP during which 50mg heparin conjugate was added to one of the HMP systems (treated group). A customized ex vivo normothermic oxygenated perfusion (NP) system with added exogenous creatinine was used to evaluate early kidney function. Blood, urine and histological samples were collected during the subsequent 3 hours of NP.

Results: Kidney weight was lower at the end of NP (P = 0.017) in the treated group compared with control kidneys. The rate of decline in creatinine level was faster (P = 0.024), total urinary volume was higher (P = 0.031), and the level of urine neutrophil gelatinase-associated lipocalin (NGAL) was lower (P = 0.031) in the treated group. Histologically, less tubular changes were seen (P = 0.046). During NP intrarenal resistance remained lower (P < 0.0001) in the treated group.

Conclusions: Perfusion of porcine kidneys with heparin conjugate during HMP reduces preservation injury and improves organ function shortly after reperfusion. No increased risk of bleeding was seen in this setup. This protective strategy may potentially improve the quality of transplanted kidneys in the clinical setting.

Place, publisher, year, edition, pages
LIPPINCOTT WILLIAMS & WILKINS, 2019
National Category
Surgery
Identifiers
urn:nbn:se:uu:diva-377674 (URN)10.1097/TP.0000000000002469 (DOI)000457576600035 ()30299374 (PubMedID)
Funder
VINNOVA
Available from: 2019-02-25 Created: 2019-02-25 Last updated: 2019-02-25Bibliographically approved
Holanda, D., Drachenberg, C. B., Minervini, M. I., Papadimitriou, J. C., Arend, L. J., Odorico, J. S., . . . Torrealba, J. (2018). Allograft Duodenal Cuff Biopsy as Surrogate in Evaluation of Pancreatic Transplant Rejection - A Multicenter Data Effort. Paper presented at 14th World Congress of the International-Pancreas-and-Islet-Transplant-Association (IPITA), SEP 24-27, 2013, Monterey, CA. Transplantation, 102, S447-S447
Open this publication in new window or tab >>Allograft Duodenal Cuff Biopsy as Surrogate in Evaluation of Pancreatic Transplant Rejection - A Multicenter Data Effort
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2018 (English)In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 102, p. S447-S447Article in journal, Meeting abstract (Other academic) Published
Place, publisher, year, edition, pages
Lippincott Williams & Wilkins, 2018
National Category
Surgery
Identifiers
urn:nbn:se:uu:diva-368382 (URN)10.1097/01.tp.0000543236.47060.ec (DOI)000444541200705 ()
Conference
14th World Congress of the International-Pancreas-and-Islet-Transplant-Association (IPITA), SEP 24-27, 2013, Monterey, CA
Available from: 2018-12-05 Created: 2018-12-05 Last updated: 2018-12-05Bibliographically approved
Lorant, T., Bengtsson, M., Eich, T., Eriksson, B.-M., Winstedt, L., Järnum, S., . . . Kjellman, C. (2018). Safety, immunogenicity, pharmacokinetics, and efficacy of degradation of anti-HLA antibodies by IdeS (imlifidase) in chronic kidney disease patients.. American Journal of Transplantation, 18(11), 2752-2762
Open this publication in new window or tab >>Safety, immunogenicity, pharmacokinetics, and efficacy of degradation of anti-HLA antibodies by IdeS (imlifidase) in chronic kidney disease patients.
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2018 (English)In: American Journal of Transplantation, ISSN 1600-6135, E-ISSN 1600-6143, Vol. 18, no 11, p. 2752-2762Article in journal (Refereed) Published
Abstract [en]

Safety, immunogenicity, pharmacokinetics, and efficacy of the IgG-degrading enzyme of Streptococcus pyogenes (IdeS [imlifidase]) were assessed in a single-center, open-label ascending-dose study in highly sensitized patients with chronic kidney disease. Eight patients with cytotoxic PRAs (median cytotoxic PRAs of 64%) at enrollment received 1 or 2 intravenous infusions of IdeS on consecutive days (0.12 mg/kg body weight ×2 [n = 3]; 0.25 mg/kg ×1 [n = 3], or 0.25 mg/kg ×2 [n = 2]). IgG degradation was observed in all subjects after IdeS treatment, with <1% plasma IgG remaining within 48 hours and remaining low up to 7 days. Mean fluorescence intensity values of HLA class I and II reactivity were substantially reduced in all patients, and C1q binding to anti-HLA was abolished. IdeS also cleaved the IgG-type B cell receptor on CD19+ memory B cells. Anti-IdeS antibodies developed 1 week after treatment, peaking at 2 weeks. A few hours after the second IdeS infusion, 1 patient received a deceased donor kidney offer. At enrollment, the patient had a positive serum crossmatch (HLA-B7), detected by complement-dependent cytotoxicity, flow cytometry, and multiplex bead assays. After IdeS infusion (0.12 mg/kg ×2) and when the HLA-incompatible donor (HLA-B7+ ) kidney was offered, the HLA antibody profile was negative. The kidney was transplanted successfully.

Keywords
clinical research/practice, clinical trial, crossmatch, desensitization, histocompatibility, kidney transplantation/nephrology, kidney transplantation: living donor, pharmacokinetics/pharmacodynamics
National Category
Urology and Nephrology
Identifiers
urn:nbn:se:uu:diva-366863 (URN)10.1111/ajt.14733 (DOI)000449512400020 ()29561066 (PubMedID)
Available from: 2018-11-26 Created: 2018-11-26 Last updated: 2019-06-26Bibliographically approved
Yang, T., Zhang, X.-M., Tarnawski, L., Peleli, M., Zhuge, Z., Terrando, N., . . . Carlström, M. (2017). Dietary nitrate attenuates renal ischemia-reperfusion injuries by modulation of immune responses and reduction of oxidative stress. Redox Biology, 13, 320-330
Open this publication in new window or tab >>Dietary nitrate attenuates renal ischemia-reperfusion injuries by modulation of immune responses and reduction of oxidative stress
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2017 (English)In: Redox Biology, ISSN 0090-7324, E-ISSN 2213-2317, Vol. 13, p. 320-330Article in journal (Refereed) Published
Abstract [en]

Ischemia-reperfusion (IR) injury involves complex pathological processes in which reduction of nitric oxide (NO) bioavailability is suggested as a key factor. Inorganic nitrate can form NO in vivo via NO synthase-independent pathways and may thus provide beneficial effects during IR. Herein we evaluated the effects of dietary nitrate supplementation in a renal IR model. Male mice (C57BL/6J) were fed nitrate-supplemented chow (1.0 mmol/kg/day) or standard chow for two weeks prior to 30 min ischemia and during the reperfusion period. Unilateral renal IR caused profound tubular and glomerular damage in the ischemic kidney. Renal function, assessed by plasma creatinine levels, glomerular filtration rate and renal plasma flow, was also impaired after IR. All these pathologies were significantly improved by nitrate. Mechanistically, nitrate treatment reduced renal superoxide generation, pro-inflammatory cytokines (IL-1 beta, IL-6 and IL-12 p70) and macrophage infiltration in the kidney. Moreover, nitrate reduced mRNA expression of pro-inflammatory cytokines and chemo attractors, while increasing anti-inflammatory cytokines in the injured kidney. In another cohort of mice, two weeks of nitrate supplementation lowered superoxide generation and IL-6 expression in bone marrow-derived macrophages. Our study demonstrates protective effect of dietary nitrate in renal IR injury that may be mediated via modulation of oxidative stress and inflammatory responses. These novel findings suggest that nitrate supplementation deserve further exploration as a potential treatment in patients at high risk of renal IR injury.

Place, publisher, year, edition, pages
ELSEVIER SCIENCE BV, 2017
Keywords
Acute kidney injury, Inflammation, Inorganic nitrate, NADPH oxidase, Nitric oxide, Oxidative stress
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-335128 (URN)10.1016/j.redox.2017.06.002 (DOI)000410470000025 ()28623824 (PubMedID)
Funder
Swedish Heart Lung Foundation, 20140448Swedish Research Council, 2016-01381The Karolinska Institutet's Research Foundation, 2415/2012-225, 2-3707/2013
Available from: 2017-12-04 Created: 2017-12-04 Last updated: 2017-12-04Bibliographically approved
Hellström, V., Tufveson, G., Wallgren, A., Loskog, A., Larsson, E., Tötterman, T., . . . Lorant, T. (2017). Donor Derived and BK Virus Positive Urologic Cancers After Renal Transplantation. Paper presented at American Transplant Congress, APR 29-MAY 03, 2017, Chicago, IL. American Journal of Transplantation, 17(S3), 472-472, Article ID A188.
Open this publication in new window or tab >>Donor Derived and BK Virus Positive Urologic Cancers After Renal Transplantation
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2017 (English)In: American Journal of Transplantation, ISSN 1600-6135, E-ISSN 1600-6143, Vol. 17, no S3, p. 472-472, article id A188Article in journal, Meeting abstract (Other academic) Published
National Category
Surgery
Identifiers
urn:nbn:se:uu:diva-335823 (URN)10.1111/ajt.14306 (DOI)000404515703188 ()
Conference
American Transplant Congress, APR 29-MAY 03, 2017, Chicago, IL
Available from: 2018-01-15 Created: 2018-01-15 Last updated: 2018-01-15Bibliographically approved
Jordan, S. C., Lorant, T., Choi, J., Kjellman, C., Winstedt, L., Bengtsson, M., . . . Tufveson, G. (2017). IgG Endopeptidase in Highly Sensitized Patients Undergoing Transplantation.. New England Journal of Medicine, 377(5), 442-453
Open this publication in new window or tab >>IgG Endopeptidase in Highly Sensitized Patients Undergoing Transplantation.
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2017 (English)In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 377, no 5, p. 442-453Article in journal (Refereed) Published
Abstract [en]

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. (Funded by Hansa Medical; ClinicalTrials.gov numbers, NCT02224820 , NCT02426684 , and NCT02475551 .).

Place, publisher, year, edition, pages
Massachusetts Medical Society, 2017
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-333282 (URN)10.1056/NEJMoa1612567 (DOI)000406747100006 ()28767349 (PubMedID)
Note

Drs. Jordan and Lorant, and Drs. Vo and Tufveson, contributed equally to this article. 

Available from: 2017-11-09 Created: 2017-11-09 Last updated: 2017-11-23Bibliographically approved
Cedervall, J., Dragomir, A., Saupe, F., Zhang, Y., Ärnlöv, J., Larsson, E., . . . Olsson, A.-K. (2017). Pharmacological targeting of peptidylarginine deiminase 4 prevents cancer-associated kidney injury in mice.. Oncoimmunology, 6(8), Article ID e1320009.
Open this publication in new window or tab >>Pharmacological targeting of peptidylarginine deiminase 4 prevents cancer-associated kidney injury in mice.
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2017 (English)In: Oncoimmunology, ISSN 2162-4011, E-ISSN 2162-402X, Vol. 6, no 8, article id e1320009Article in journal (Refereed) Published
Abstract [en]

Renal insufficiency is a frequent cancer-associated problem affecting more than half of all cancer patients at the time of diagnosis. To minimize nephrotoxic effects the dosage of anticancer drugs are reduced in these patients, leading to sub-optimal treatment efficacy. Despite the severity of this cancer-associated pathology, the molecular mechanisms, as well as therapeutic options, are still largely lacking. We here show that formation of intravascular tumor-induced neutrophil extracellular traps (NETs) is a cause of kidney injury in tumor-bearing mice. Analysis of clinical biomarkers for kidney function revealed impaired creatinine clearance and elevated total protein levels in urine from tumor-bearing mice. Electron microscopy analysis of the kidneys from mice with cancer showed reversible pathological signs such as mesangial hypercellularity, while permanent damage such as fibrosis or necrosis was not observed. Removal of NETs by treatment with DNase I, or pharmacological inhibition of the enzyme peptidylarginine deiminase 4 (PAD4), was sufficient to restore renal function in mice with cancer. Tumor-induced systemic inflammation and impaired perfusion of peripheral vessels could be reverted by the PAD4 inhibitor. In conclusion, the current study identifies NETosis as a previously unknown cause of cancer-associated renal dysfunction and describes a novel promising approach to prevent renal failure in individuals with cancer.

Keywords
Cancer, DNase I, GSK484, kidney injury, neutrophil extracellular traps
National Category
Cancer and Oncology Clinical Laboratory Medicine
Research subject
Pathology
Identifiers
urn:nbn:se:uu:diva-329754 (URN)10.1080/2162402X.2017.1320009 (DOI)000408961700006 ()28919990 (PubMedID)
Available from: 2017-09-20 Created: 2017-09-20 Last updated: 2019-04-02Bibliographically approved
Larsson, E. & Ulvestad, E. (2016). Human endogenous retroviruses Foreword. Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), 124(1-2), 3-3
Open this publication in new window or tab >>Human endogenous retroviruses Foreword
2016 (English)In: Acta Pathologica, Microbiologica et Immunologica Scandinavica (APMIS), ISSN 0903-4641, E-ISSN 1600-0463, Vol. 124, no 1-2, p. 3-3Article in journal, Editorial material (Other academic) Published
National Category
Immunology in the medical area
Identifiers
urn:nbn:se:uu:diva-282991 (URN)10.1111/apm.12508 (DOI)000370081300001 ()26818256 (PubMedID)
Available from: 2016-04-13 Created: 2016-04-08 Last updated: 2018-01-10Bibliographically approved
Krogvold, L., Wiberg, A., Edwin, B., Buanes, T., Jahnsen, F. L., Hanssen, K. F., . . . Dahl-Jørgensen, K. (2016). Insulitis and characterisation of infiltrating T cells in surgical pancreatic tail resections from patients at onset of type 1 diabetes. Diabetologia, 59(3), 492-501
Open this publication in new window or tab >>Insulitis and characterisation of infiltrating T cells in surgical pancreatic tail resections from patients at onset of type 1 diabetes
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2016 (English)In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 59, no 3, p. 492-501Article in journal (Refereed) Published
Abstract [en]

Aims/hypothesis

It is thought that T cells play a major role in the immune-mediated destruction of beta cells in type 1 diabetes, causing inflammation of the islets of Langerhans (insulitis). The significance of insulitis at the onset of type 1 diabetes is debated, and the role of the T cells poorly understood.

Methods

In the Diabetes Virus Detection (DiViD) study, pancreatic tissue from six living patients with recent-onset type 1 diabetes was collected. The insulitis was characterised quantitatively by counting CD3+ T cells, and qualitatively by transcriptome analysis targeting 84 T and B lymphocyte genes of laser-captured microdissected islets. The findings were compared with gene expression in T cells collected from kidney biopsies from allografts with ongoing cellular rejection. Cytokine and chemokine release from isolated islets was characterised and compared with that from islets from non-diabetic organ donors.

Results

All six patients fulfilled the criteria for insulitis (5–58% of the insulin-containing islets in the six patients had ≥ 15 T cells/islet). Of all the islets, 36% contained insulin, with several resembling completely normal islets. The majority (61–83%) of T cells were found as peri-insulitis rather than within the islet parenchyma. The expression pattern of T cell genes was found to be markedly different in islets compared with the rejected kidneys. The islet-infiltrating T cells showed only background levels of cytokine/chemokine release in vitro.

Conclusions/interpretation

Insulitis and a significant reserve reservoir for insulin production were present in all six cases of recent-onset type 1 diabetes. Furthermore, the expression patterns and levels of cytokines argue for a different role of the T cells in type 1 diabetes when compared with allograft rejection.

Keywords
Gene expression; Inflammation; Insulin; Insulitis; Pancreas; T cells; Type 1 diabetes
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-274977 (URN)10.1007/s00125-015-3820-4 (DOI)000377302900012 ()26602422 (PubMedID)
Funder
Novo NordiskSwedish Child Diabetes FoundationSwedish Diabetes Association
Note

De två första författarna delar förstaförfattarskapet.

De två sista författarna delar sistaförfattarskapet.

Available from: 2016-01-27 Created: 2016-01-27 Last updated: 2017-11-30Bibliographically approved
Porpino, S. K. P., Zollbrecht, C., Peleli, M., Montenegro, M. F., Brandao, M. C. R., Athayde-Filho, P. F., . . . Carlstrom, M. (2016). Nitric oxide generation by the organic nitrate NDBP attenuates oxidative stress and angiotensin II-mediated hypertension. British Journal of Pharmacology, 173(14), 2290-2302
Open this publication in new window or tab >>Nitric oxide generation by the organic nitrate NDBP attenuates oxidative stress and angiotensin II-mediated hypertension
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2016 (English)In: British Journal of Pharmacology, ISSN 0007-1188, E-ISSN 1476-5381, Vol. 173, no 14, p. 2290-2302Article in journal (Refereed) Published
Abstract [en]

Background and PurposeNO deficiency and oxidative stress are crucially involved in the development or progression of cardiovascular disease, including hypertension and stroke. We have previously demonstrated that acute treatment with the newly discovered organic nitrate, 2-nitrate-1,3-dibuthoxypropan (NDBP), is associated with NO-like effects in the vasculature. This study aimed to further characterize the mechanism(s) and to elucidate the therapeutic potential in a model of hypertension and oxidative stress. Experimental ApproachA combination of ex vivo, in vitro and in vivo approaches was used to assess the effects of NDBP on vascular reactivity, NO release, NADPH oxidase activity and in a model of hypertension. Key ResultsEx vivo vascular studies demonstrated NDBP-mediated vasorelaxation in mesenteric resistance arteries, which was devoid of tolerance. In vitro studies using liver and kidney homogenates revealed dose-dependent and sustained NO generation by NDBP, which was attenuated by the xanthine oxidase inhibitor febuxostat. In addition, NDBP reduced NADPH oxidase activity in the liver and prevented angiotensin II-induced activation of NADPH oxidase in the kidney. In vivo studies showed that NDBP halted the progression of hypertension in mice with chronic angiotensin II infusion. This was associated with attenuated cardiac hypertrophy, and reduced NADPH oxidase-derived oxidative stress and fibrosis in the kidney and heart. Conclusion and ImplicationsThe novel organic nitrate NDBP halts the progression of angiotensin II-mediated hypertension. Mechanistically, our findings suggest that NDBP treatment is associated with sustained NO release and attenuated activity of NADPH oxidase, which to some extent requires functional xanthine oxidase.

National Category
Pharmaceutical Sciences
Identifiers
urn:nbn:se:uu:diva-300542 (URN)10.1111/bph.13511 (DOI)000379675900010 ()27160064 (PubMedID)
Funder
Swedish Research Council, 521-2011-2639Swedish Heart Lung Foundation, 20140448Stockholm County CouncilThe Karolinska Institutet's Research Foundation
Available from: 2016-08-10 Created: 2016-08-09 Last updated: 2018-01-10Bibliographically approved
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