Circulatory death donor (DCD) kidney transplantations are steadily increasing. Consensus reports recommend limiting donor warm ischemia time (DWIT) in DCD donation, although an independent effect on ...graft outcome has not been demonstrated. We investigated death‐censored graft survival in 18 065 recipients of deceased‐donor kidney transplants in the Eurotransplant region: 1059 DCD and 17 006 brain‐dead donor (DBD) kidney recipients. DWIT was defined as time from circulatory arrest until cold flush. DCD donation was an independent risk factor for graft failure (adjusted hazard ratio HR 1.28, 95% CI 1.10‐1.46), due to an increased risk of primary nonfunction (62/1059 vs 560/17 006; P < .0001). With DWIT in the model, DCD donation was no longer a risk factor, demonstrating that DWIT explains the inferior graft survival of DCD kidneys. Indeed, DCD transplants with short DWIT have graft survival comparable to that of standard‐criteria DBD transplants (P = .59). DWIT also associated with graft failure in DCDs (adjusted HR 1.20 per 10‐minute increase, 95% CI 1.03‐1.42). At 5 years after transplantation, graft failure occurred in 14 of 133 recipients (10.5%) with DWIT <10 minutes, 139 of 555 recipients (25.0%) with DWIT between 10 and 19 minutes, and 117 of 371 recipients (31.5%) with DWIT ≥20 minutes. These findings support the expert opinion–based guidelines to limit DWIT.
Asystolic donor warm ischemia time determines graft survival after circulatory‐dead donor kidney transplantation.
Recent studies raised the concern that warm ischemia during completion of vascular anastomoses in kidney implantation harms the transplant, but its precise impact on outcome and its interaction with ...other risk factors remain to be established. We investigated the relationship between anastomosis time and graft survival at 5 years after transplantation in 13 964 recipients of deceased donor solitary kidney transplants in the Eurotransplant region. Anastomosis time was independently associated with graft loss after adjusting for other risk factors (adjusted hazard ratio HR 1.10 for every 10‐min increase, 95% confidence interval CI 1.06–1.14; p < 0.0001), whereas it did not influence recipient survival (HR 1.00, 95% CI 0.97–1.02). Kidneys from donation after circulatory death (DCD) were less tolerant of prolonged anastomosis time than kidneys from donation after brain death (p = 0.02 for interaction). The additive effect of anastomosis time with donor warm ischemia time (WIT) explains this observation because DCD status was no longer associated with graft survival when adjusted for this summed WIT, and there was no interaction between DCD status and summed WIT. Time to create the vascular anastomoses in kidney transplantation is associated with inferior transplant outcome, especially in recipients of DCD kidneys.
In this study on the Eurotransplant registry, anastomosis time is associated with worse renal graft survival, and is more detrimental in donation after circulatory death kidneys compared to donation after brain death kidneys due to the additive effect with donor warm ischemia time.
Vascular renal resistance (RR) during hypothermic machine perfusion (HMP) is frequently used in kidney graft quality assessment. However, the association between RR and outcome has never been ...prospectively validated. Prospectively collected RR values of 302 machine‐perfused deceased donor kidneys of all types (standard and extended criteria donor kidneys and kidneys donated after cardiac death), transplanted without prior knowledge of these RR values, were studied. In this cohort, we determined the association between RR and delayed graft function (DGF) and 1‐year graft survival. The RR (mmHg/mL/min) at the end of HMP was an independent risk factor for DGF (odds ratio 21.12 1.03–435.0; p = 0.048) but the predictive value of RR was low, reflected by a c‐statistic of the receiver operator characteristic curve of 0.58. The RR was also found to be an independent risk factor for 1‐year graft failure (hazard ratio 12.33 1.11–136.85; p = 0.004). Determinants of transplant outcome are multifactorial in nature and this study identifies RR as an additional parameter to take into account when evaluating graft quality and estimating the likelihood of successful outcome. However, RR as a stand‐alone quality assessment tool cannot be used to predict outcome with sufficient precision.
Increased renal resistance during hypothermic machine perfusion of deceased donor kidneys associates with the development of delayed graft function and 1‐year graft survival, but cannot be used exclusively in the process of accepting a kidney graft.
Aims: Cytokeratin (CK) 7 and CK19 expression, present in hepatic progenitor cells (HPCs) and in cholangiocytes but not in normal hepatocytes, has been reported in some hepatocellular carcinomas ...(HCCs); however, the incidence and relevance of this expression in HCC in Caucasians is not known. Therefore, our aim was to study the occurrence and clinicopathological characteristics of HCC expressing CK7 and/or CK19 in 109 Caucasian patients.
Methods and results: The expression of hepatocellular differentiation markers (Hepar, canalicular polyclonal carcinoembryonic antigen), biliary/progenitor cell markers (CK7, CK19), α‐fetoprotein (AFP), p53 and β‐catenin in HCC was semiquantitatively assessed by immunohistochemistry. Of 109 HCCs, 78 were CK7–/CK19– (72%), 13 CK7+/CK19– (12%), seven CK7–/CK19+ (6%), 11 CK7+/CK19+ (10%). CK19 expression was significantly associated with elevated serum AFP (400 ng/ml) (P = 0.023), tumour AFP expression (P < 0.0001), presence in serum of anti‐hepatitis B core (P = 0.016), less fibrosis in non‐neoplastic parenchyma (P = 0.009) and less nuclear β‐catenin expression (P = 0.021). CK7 expression was significantly associated with elevated serum bilirubin (> 2 mg/dl) (P = 0.0005) and less nuclear β‐catenin expression (P = 0.003). HCC expressing CK19 had a higher rate of recurrence (P = 0.009, hazard ratio 12.5, n = 31) after liver transplantation compared with CK19– tumours.
Conclusions: In our series, 28% of HCCs contained cells expressing CK7 and/or CK19. They potentially derive from HPCs. The higher recurrence rate of CK19+ HCC after transplantation suggests a worse prognosis for these HCCs compared with CK19– HCC.
DIAMOND: multicenter, 24‐week, randomized trial investigating the effect of different once‐daily, prolonged‐release tacrolimus dosing regimens on renal function after de novo liver transplantation. ...Arm 1: prolonged‐release tacrolimus (initial dose 0.2mg/kg/day); Arm 2: prolonged‐release tacrolimus (0.15–0.175mg/kg/day) plus basiliximab; Arm 3: prolonged‐release tacrolimus (0.2mg/kg/day delayed until Day 5) plus basiliximab. All patients received MMF plus a bolus of corticosteroid (no maintenance steroids). Primary endpoint: eGFR (MDRD4) at Week 24. Secondary endpoints: composite efficacy failure, BCAR and AEs. Baseline characteristics were comparable. Tacrolimus trough levels were readily achieved posttransplant; initially lower in Arm 2 versus 1 with delayed initiation in Arm 3. eGFR (MDRD4) was higher in Arms 2 and 3 versus 1 (p = 0.001, p = 0.047). Kaplan–Meier estimates of composite efficacy failure‐free survival were 72.0%, 77.6%, 73.9% in Arms 1–3. BCAR incidence was significantly lower in Arm 2 versus 1 and 3 (p = 0.016, p = 0.039). AEs were comparable. Prolonged‐release tacrolimus (0.15–0.175mg/kg/day) immediately posttransplant plus basiliximab and MMF (without maintenance corticosteroids) was associated with lower tacrolimus exposure, and significantly reduced renal function impairment and BCAR incidence versus prolonged‐release tacrolimus (0.2mg/kg/day) administered immediately posttransplant. Delayed higher‐dose prolonged‐release tacrolimus initiation significantly reduced renal function impairment compared with immediate posttransplant administration, but BCAR incidence was comparable.
The DIAMOND study demonstrates that an initial lower dose or a delayed higher dose of prolonged‐release tacrolimus significantly reduces renal function impairment versus a higher initial dose of prolonged‐release tacrolimus administered immediately posttransplant, over 24 weeks of treatment in de novo liver transplant recipients.
Between 2003 and 2012, 42 869 first liver transplantations performed in Europe with the use of either University of Wisconsin solution (UW; N = 24 562), histidine‐tryptophan‐ketoglutarate(HTK; N = ...8696), Celsior solution (CE; N = 7756) or Institute Georges Lopez preservation solution (IGL‐1; N = 1855) preserved grafts. Alternative solutions to the UW were increasingly used during the last decade. Overall, 3‐year graft survival was higher with UW, IGL‐1 and CE (75%, 75% and 73%, respectively), compared to the HTK (69%) (p < 0.0001). The same trend was observed with a total ischemia time (TIT) >12 h or grafts used for patients with cancer (p < 0.0001). For partial grafts, 3‐year graft survival was 89% for IGL‐1, 67% for UW, 68% for CE and 64% for HTK (p = 0.009). Multivariate analysis identified HTK as an independent factor of graft loss, with recipient HIV (+), donor age ≥65 years, recipient HCV (+), main disease acute hepatic failure, use of a partial liver graft, recipient age ≥60 years, no identical ABO compatibility, recipient hepatitis B surface antigen (−), TIT ≥ 12 h, male recipient and main disease other than cirrhosis. HTK appears to be an independent risk factor of graft loss. Both UW and IGL‐1, and CE to a lesser extent, provides similar results for full size grafts. For partial deceased donor liver grafts, IGL‐1 tends to offer the best graft outcome.
In a retrospective review of over 42,000 liver transplants perf ormed in Europe between 2003 and 2012 examining the use of either University of Wisconsin, histidine‐ tryptophan‐ketoglutarate (HTK), Celsior, or Institut Georges Lopez solution, the authors show that the use of HTK solution is an independent risk factor of graft loss. See editorial by Stewart on page 295.
We report a multicenter, prospective, randomized, open‐label trial investigating the effect of lower levels and delayed introduction of tacrolimus on renal function in liver transplant recipients. ...Adult patients with good renal function undergoing primary liver transplant were randomized to either: group A (standard‐dose tacrolimus target trough levels >10 ng/mL and corticosteroids; n = 183); group B (mycophenolate mofetil MMF 2g/day, reduced‐dose tacrolimus target trough levels ≤8 ng/mL, and corticosteroids; n = 170); group C (daclizumab induction, MMF, reduced‐dose tacrolimus delayed until the fifth day posttransplant and corticosteroids, n = 172). The primary endpoint was change from baseline in estimated glomerular filtration rate (eGFR) at 52 weeks. The eGFR decreased by 23.61, 21.22 and 13.63 mL/min in groups A, B and C, respectively (A vs C, p = 0.012; A vs B, p = 0.199). Renal dialysis was required less frequently in group C versus group A (4.2% vs. 9.9%; p = 0.037). Biopsy‐proven acute rejection rates were 27.6%, 29.2% and 19.0%, respectively. Patient and graft survival was similar. In conclusion, daclizumab induction, MMF, corticosteroids and delayed reduced‐dose tacrolimus was associated with less nephrotoxicity than therapy with standard‐dose tacrolimus and corticosteroids without compromising efficacy or tolerability.
In patients with good renal function prior to liver transplant, delayed introduction and lower dose tacrolimus in the peri‐operative period is associated with less renal impairment at one year than standard treatment.
Background
When the blood supply ceases in a deceased organ donor, ischaemic injury starts. Kidneys are cooled to reduce cellular metabolism and minimize ischaemic injury. This cooling is slow and ...kidneys are lukewarm during nephrectomy. Smaller single‐centre studies have shown that prolonged donor nephrectomy time decreases early kidney transplant function, but the effect on long‐term outcome has never been investigated in large multicentre cohort studies.
Methods
The relationship between donor nephrectomy time and death‐censored graft survival was evaluated in recipients of single adult‐to‐adult, first‐time deceased‐donor kidneys transplanted in the Eurotransplant region between 2004 and 2013.
Results
A total of 13 914 recipients were included. Median donor nephrectomy time was 51 (i.q.r. 39–65) min. Kidneys donated after circulatory death had longer nephrectomy times than those from brain‐dead donors: median 57 (43–78) versus 50 (39–64) min respectively (P < 0·001). Donor nephrectomy time was independently associated with graft loss when kidneys were donated after circulatory death: adjusted hazard ratio (HR) 1·05 (95 per cent c.i. 1·01 to 1·09) per 10‐min increase (P = 0·026). The magnitude of this effect was comparable to the effect of each hour of additional cold ischaemia: HR 1·04 (1·01 to 1·07) per h (P = 0·004). For kidneys donated after brain death, there was no effect of nephrectomy time on graft survival: adjusted HR 1·01 (0·98 to 1·04) per 10 min (P = 0·464).
Conclusion
Prolonged donor nephrectomy time impairs graft outcome in kidneys donated after circulatory death. Keeping this short, together with efficient cooling during nephrectomy, might improve outcome.
Antecedentes
La lesión por isquemia empieza en el momento que cesa la irrigación sanguínea del órgano donante. Para reducir el metabolismo celular y la lesión isquémica se reduce la temperatura de los riñones. Este enfriamiento es lento y los riñones se mantienen tibios durante la nefrectomía. Estudios unicéntricos con muestras pequeñas han demostrado que el tiempo de la nefrectomía del donante disminuye la función precoz del injerto renal, pero nunca se ha analizado su repercusión a largo plazo en grandes estudios multicéntricos.
Métodos
Se analizó la relación entre la duración de la nefrectomía del donante y la supervivencia del injerto en 13.914 adultos receptores de un primer riñón procedente de donante cadavérico adulto en la región de Eurotransplant entre los años 2004 y 2013.
Resultados
La mediana de duración de la nefrectomía del donante fue de 51 minutos (rango intercuartílico 39‐65). En los riñones obtenidos en donantes a corazón parado la duración de la nefrectomía fue más prolongada que en los donantes en muerte cerebral (mediana 57 min (43‐78 min) versus 50 min (39‐64 min), P < 0,001). La duración de la nefrectomía en el donante se asoció de forma independiente con la pérdida del injerto (cociente de riesgos instantáneos, hazard ratio, HR, ajustado 1,05 por cada incremento de 10 minutos, i.c. del 95%: 1,01 a 1,09; P = 0,026) cuando los riñones se obtuvieron en donantes en parada cardíaca. La magnitud de este efecto fue comparable al efecto de cada hora adicional de isquemia fría (1,04, i.c. 95% 1,01‐1,07, P = 0,004). En los riñones obtenidos de donantes en muerte cerebral, la duración de la nefrectomía no influyó en la supervivencia del injerto (HR ajustada 1,01 por aumento de 10 min, i.c. del 95%: 0,98 a 1,04).
Conclusión
La duración de la nefrectomía en donantes a corazón parado afecta la función de los injertos trasplantados. Reducir esta duración y disponer de un sistema de enfriamiento eficiente durante la nefrectomía podría mejorar los resultados.
This study of the Eurotransplant registry covering 13 914 kidney transplants demonstrated that donor nephrectomy time impairs graft outcome in kidneys donated after circulatory death, but not in kidneys donated after brain death.
Quicker the better
Summary
Bone loss and vascular calcification coincide in patients with end-stage renal disease, similar as to what is observed in the general population. In the present bone biopsy study, we provide ...further evidence that (micro-)inflammation may represent a common soil for both diseases.
Introduction
Vascular calcification is a common complication of end-stage renal disease (ESRD) and is predictive of subsequent cardiovascular disease and mortality. Mounting evidence linking bone disorders with vascular calcification has contributed to the development of the concept of the bone-vascular axis. Inflammation is involved in the pathogenesis of both disorders. The aim of the present study was to evaluate the relationship between aortic calcification, inflammation, and bone histomorphometry in patients with ESRD.
Methods
Parameters of inflammation and mineral metabolism were assessed in 81 ESRD patients (55 ± 13 year, 68 % male) referred for renal transplantation. Static bone histomorphometry parameters were determined on transiliac bone biopsies performed during the transplant procedure. Aortic calcification was quantified on lateral lumbar X-rays using the Kauppila method.
Results
Aortic calcification, low bone turnover, and low bone area were observed in 53, 37, and 21 % of patients respectively. Inflammatory markers were found to be independently associated with aortic calcification (hsIL-6) and low bone area (TNF-α). Low bone area associated with aortic calcification, independent of age, diabetes, and inflammation.
Conclusions
Low bone area and inflammation associates with aortic calcification, independent of each other and traditional risk factors. Our data emphasize the role of (micro-)inflammation in the bone-vascular axis in CKD.
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