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- Friman, Styrbjörn, 1948, et al.
(author)
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Long-term, Prolonged-release Tacrolimus-based Immunosuppression in De Novo Liver Transplant Recipients: 5-year Prospective Follow-up of Patients in the DIAMOND Study
- 2021
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In: Transplantation Direct. - : Ovid Technologies (Wolters Kluwer Health). - 2373-8731. ; 7:8
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Journal article (peer-reviewed)abstract
- Background. Immunosuppression with calcineurin inhibitors (CNIs) is reportedly associated with risk of renal impairment in liver transplant recipients. It is believed that this can be mitigated by decreasing initial exposure to CNIs or delaying CNI introduction until 3-4 d posttransplantation. The ADVAGRAF studied in combination with mycophenolate mofetil and basili ximab in liver transplantation (DIAMOND) trial evaluated different administration strategies for prolonged-release tacrolimus (PR-T). Methods. DIAMOND was a 24-wk, open-label, phase 3b trial in de novo liver transplant recipients randomized to: PR-T 0.2 mg/kg/d (Arm 1); PR-T 0.15-0.175 mg/kg/d plus basiliximab (Arm 2); or PR-T 0.2 mg/kg/d delayed until day 5 posttransplant plus basiliximab (Arm 3). In a 5-y follow-up, patients were maintained on an immunosuppressive regimen according to standard clinical practice (NCT02057484). Primary endpoint: graft survival (Kaplan-Meier analysis). Results. Follow-up study included 856 patients. Overall graft survival was 84.6% and 73.5% at 1 and 5 y post transplant, respectively. Five-year rates for Arms 1, 2, and 3 were 74.7%, 71.5%, and 74.5%, respectively. At 5 y, death-censored graft survival in the entire cohort was 74,7%. Overall graft survival in patients remaining on PR-T for z30 d was 79.1%. Graft survival in patients who remained on PR-T at 5 y was 87.3%. Patient survival was 86.6% at 1 y and 76.3% at 5 y, with survival rates similar in the 3 treatment arms at 5 y. Estimated glomerular filtration rate at the end of the 24-wk initial study and 5 y posttransplant was 62.1 and 61.5 mi./min/1.73 m(2), respectively, and was similar between the 3 treatment arms at 5 y. Overall, 18 (2.9%) patients had z1 adverse drug reaction, considered possibly related to PR-T in 6 patients. Conclusions. In the DIAMOND study patient cohort, renal function, graft survival, and patient survival were similar between treatment arms at 5 y posttransplant.
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| 2. |
- Norén, Åsa, et al.
(author)
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Liver Graft Proteomics Reveals Potential Incipient Mechanisms behind Early Renal Dysfunction after Liver Transplantation
- 2022
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In: International Journal of Molecular Sciences. - : MDPI AG. - 1422-0067. ; 23:19
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Journal article (peer-reviewed)abstract
- Acute kidney injury (AKI) is frequent after liver transplantation (LT) and correlates with later development of chronic kidney disease. Its etiology is multifactorial and combines pre-, intra-, and postoperative factors. Additionally, the liver graft itself seems an important element in the development of AKI, yet the detailed mechanisms remain unclear. We hypothesized that grafts of LT recipients developing significant early AKI may show distinct proteomic alterations, and we set out to identify proteome differences between LT recipients developing moderate or severe AKI (n = 7) and LT recipients without early renal injury (n = 7). Liver biopsies obtained one hour after reperfusion were assessed histologically and using quantitative proteomics. Several cytokines and serum amyloid A2 (SAA2) were analyzed in serum samples obtained preoperatively, 2-4 h, and 20-24 h after graft reperfusion, respectively. LT induced mild histological alterations without significant differences between groups but uniformly altered liver function tests peaking on postoperative day 1, with a trend towards more severe alterations in patients developing AKI. Global quantitative proteomic analysis revealed 136 proteins differing significantly in their expression levels (p < 0.05, FC 20%): 80 proteins had higher and 56 had lower levels in the AKI group. Most of these proteins were related to immune and inflammatory responses, host defense, and neutrophil degranulation. No differences between the studied pro- and anti-inflammatory cytokines or SAA2 between groups were found at any moment. Our results suggest that grafts of LT patients who develop early AKI reveal a distinct proteome dominated by an early yet prominent activation of the innate immunity. These findings support the hypothesis that AKI after LT may be favored by certain graft characteristics.
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| 3. |
- Norén, Åsa, et al.
(author)
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Perioperative kidney injury in liver transplantation: a prospective study with renal histology and measured glomerular filtration rates
- 2022
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In: Scandinavian Journal of Gastroenterology. - : Informa UK Limited. - 0036-5521 .- 1502-7708. ; 57:5, s. 595-602
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Journal article (peer-reviewed)abstract
- Background Acute kidney injury (AKI) is frequent after liver transplantation (LT), with impact on graft function, morbidity and mortality. Although multifactorial, the pathophysiology of perioperative kidney injury remains unclear. Our aims were to analyze the frequency, evolution and risk factors for kidney impairment during the peri- and early post-operative period. Methods In a prospective, single-center study of 27 adult patients undergoing first single-organ LT, we analyzed measured glomerular filtration rate (mGFR) pre-transplant, at post-operative day (POD) 10, and at 1, 3, 12 and 36 months. Kidney and liver graft biopsies were performed during LT. Results A median mGFR decline of 45% was detected from pre-transplant to POD 10, correlating strongly with the mGFR evolution from baseline to 12 months (rs = 0.80, p<.001) and baseline to 36 months (rs = 0.82, p<.001). AKI occurred in 59% of recipients within 48 h of LT, notably before the introduction of calcineurin inhibitors on POD 3. AKI was strongly associated with mGFR at 12 and 36 months. Kidney and liver graft biopsies showed only minor histological changes. Donor and recipient body mass index, recipient age, model of end-stage liver disease score, diagnosis of hepatitis C, donor cause of death, as well as bleeding, transfusions and duration of the anhepatic phase correlated with early kidney dysfunction. Conclusion The greatest decline in mGFR was evident within 10 days and AKI within hours of LT, irrespective of baseline mGFR and before introduction of calcineurin inhibitors. Very early post-LT kidney injury has substantial consequences for long-term kidney function.
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