Impact of Extraction Time During Donation After Circulatory Death Organ Procurement on Kidney Function After Transplantation in The Netherlands.

Background: In The Netherlands, 60% of deceased-donor kidney offers are after donation after circulatory death. Cold and warm ischemia times are known risk factors for delayed graft function (DGF) and inferior allograft survival. Extraction time is a relatively new ischemia time. During procurement, cooling of the kidneys is suboptimal with ongoing ischemia. However, evidence is lacking on whether extraction time has an impact on DGF if all ischemic periods are included. Methods: Between 2012 and 2018, 1524 donation after circulatory death kidneys were procured and transplanted in The Netherlands. Donation and transplantation-related data were obtained from the database of the Dutch Transplant Foundation. The primary outcome parameter was the incidence of DGF. Results: In our cohort, extraction time ranged from 14 to 237 min, with a mean of 62 min (SD 32). In multivariate logistic regression analysis, extraction time was an independent risk factor for incidence of DGF (odds ratio per minute increase 1.008; 95% confidence interval, 1.003-1.013; P = 0.001). The agonal phase, hypoperfusion time, and anastomosis time were not independent risk factors for incidence of DGF. Conclusions: Considering all known ischemic periods during the donation after the circulatory death process, prolonged kidney extraction time increased the risk of DGF after kidney transplantation.

Human Transplant Kidneys on Normothermic Machine Perfusion Display Endocrine Activity.

Normothermic machine perfusion (NMP) is an alternative to hypothermic machine perfusion (HMP) for donor kidney preservation before transplantation. Contrary to HMP, NMP allows for functional assessment of donor kidneys because normothermic conditions allow for metabolic activity. The kidneys are key producers of hormones. Yet, it remains unknown whether donor kidneys during NMP display endocrine functions. Methods: Fifteen donor kidneys were subjected to HMP followed by 2 h of NMP before transplantation. NMP perfusate was collected at 3 time points (0, 1, 2 h) for the measurements of prorenin/renin, erythropoietin (EPO), and vitamin D, and urine samples were collected at 1 h and 2 h for urodilatin measurement. Fifteen HMP perfusate samples were collected for the same measurements. Results: Kidneys on NMP secreted significantly more prorenin, renin, EPO, and active vitamin D than during HMP. EPO and vitamin D secretion remained stable during 2 h of NMP, whereas the prorenin release rate increased and renin release rate decreased after 1 h. Donation after brain death kidneys secreted more vitamin D and less EPO during NMP than donation after circulatory death kidneys. Twelve donor kidneys produced urine during NMP and released detectable levels of urodilatin. Kidneys exhibited a large variation in hormone release rates. No significant differences were found in hormone release capacity between delayed graft function (DGF) and non-DGF kidneys, and no significant correlations were found between hormone release rates and the duration of DGF or 1-mo posttransplant serum creatinine levels. Conclusions: Human transplant kidneys display endocrine activity during NMP. To explore whether correlations exist between hormone release rates and posttransplant kidney function, large numbers of kidneys are required.

The Effect of Recipient Back-Table Duration on Graft Outcome of Deceased Donor Kidneys: A Single-Center Prospective Cohort Study.

BACKGROUND: Little is known about the influence of the duration of the kidney back-table preparation period and kidney temperature on graft outcomes after transplantation. The aim of this study is to investigate the back-table duration and its relation to graft outcome and the relation between kidney temperature and graft outcome. METHODS: In this prospective cohort study, deceased donor kidney temperature is measured at fixed time points using an infrared thermometer during back-table preparation and transplantation. Additionally, the back-table duration is measured using a timer. RESULTS: Between September 2020 and July 2021, 49 kidneys were prospectively included in this study. Median back-table duration was 33.7 (standard deviation ± 14.1) min and donor kidney temperature increased up to 14.9 °C (±2.8) after 60 min of back-table preparation. Mean implantation time was 24.9 (±7.6) min and kidney temperature increased up to 25.9 °C (±2.4) after 30 min of implantation time. Longer back-table duration was significantly associated with higher rates of delayed graft function (p = 0.037). However, this observation did not sustain at 3 and 6-months post-transplantation. No association was found between kidney temperature and graft outcomes. CONCLUSION: Longer back-table duration is significantly associated with DGF after deceased donor kidney transplantation. No association was observed between kidney temperature and graft outcomes of deceased donor kidneys.

Ipsilateral Aorto-Iliac Calcification is Not Directly Associated With eGFR After Kidney Transplantation: A Prospective Cohort Study Analyzed Using a Linear Mixed Model.

Aorto-iliac calcification (AIC) is a well-studied risk factor for post-transplant cardiovascular events and mortality. Its effect on graft function remains unknown. The primary aim of this prospective cohort study was to assess the association between AIC and estimated glomerular filtration rate (eGFR) in the first year post-transplant. Eligibility criteria were: ≥50 years of age or ≥30 years with at least one risk factor for vascular disease. A non-contrast-enhanced CT-scan was performed with quantification of AIC using the modified Agatston score. The association between AIC and eGFR was investigated with a linear mixed model adjusted for predefined variables. One-hundred-and-forty patients were included with a median of 31 (interquartile range 26-39) eGFR measurements per patient. No direct association between AIC and eGFR was found. We observed a significant interaction between follow-up time and ipsilateral AIC, indicating that patients with higher AIC scores had lower eGFR trajectory over time starting 100 days after transplant (p = 0.014). To conclude, severe AIC is not directly associated with lower post-transplant eGFR. The significant interaction indicates that patients with more severe AIC have a lower eGFR trajectory after 100 days in the first year post-transplant.

Screening, Management, and Acceptance of Patients with Aorto-Iliac Vascular Disease for Kidney Transplantation: A Survey among 161 Transplant Surgeons.

INTRODUCTION: Aorto-iliac vascular disease (AVD) is frequently found during the workup for kidney transplantation. However, recommendations on screening and management are lacking. We aimed to assess differences in screening, management, and acceptance of these patients for transplantation by performing a survey among transplant surgeons. Second, we aimed to identify center- and surgeon-related factors associated with decline or acceptance of kidney transplant candidates with AVD. METHODS: A survey was sent to transplant surgeons and urologists. The survey contained general questions (part I) and 2 patient-based cases (part II) with Trans-Atlantic Inter-Society Consensus (TASC) D and B AVD supported with videos of their CT scans. RESULTS: One hundred ninety-one (20.3%) participants responded; 171 were currently involved in kidney transplantation: 161 (94.2%) completed part I and 145 (84.8%) part II. Screening for AVD was often (38.5%) restricted to high-risk patients. The majority of respondents (67.7%) rated "technical problems" as the most important concern in case of AVD, followed by "increased mortality risk because of cardiovascular comorbidity" (29.8%). Pretransplant vascular interventions to facilitate transplantation were infrequently performed (71.4% mentioned <10 per year). Ninety (64.3%) respondents answered that an open vascular procedure should preferably be performed prior to kidney transplantation while 42 (30.0%) respondents preferred a simultaneous open vascular procedure. The decline rate was higher in the TASC D case compared to the TASC B case (26.9% and 9.7%, respectively). Respondents from centers with expertise in pretransplant vascular interventions were more likely to accept both patients with TASC D and B for transplantation. CONCLUSION: There is no uniformity in the screening, management, and acceptance of patients with AVD for transplantation. If a center declines a patient with AVD because of technical concerns, the patient should be referred for a second opinion to a tertiary center with expertise in pretransplant vascular interventions. Multidisciplinary meetings including a vascular surgeon and a cardiologist could help optimize these patients for transplantation.

Risk of post-transplant cardiovascular events in kidney transplant recipients with preexisting aortoiliac stenosis.

Prediction of the risk of cardiovascular events (CVE's) is important to optimize outcomes after kidney transplantation. Aortoiliac stenosis is frequently observed during pre-transplant screening. We hypothesized that these patients are at higher risk of post-transplant CVE's due to the joint underlying atherosclerotic disease. Therefore, we aimed to assess whether aortoiliac stenosis was associated with post-transplant CVE's. This retrospective, single-center cohort study included adult kidney transplant recipients, transplanted between 2000 and 2016, with contrast-enhanced imaging available. Aortoiliac stenosis was classified according to the Trans-Atlantic Inter-Society Consensus (TASC) II classification and was defined as significant in case of ≥50% lumen narrowing. The primary outcome was CVE-free survival. Eighty-nine of 367 patients had significant aortoiliac stenosis and were found to have worse CVE-free survival (median CVE-free survival: stenosis 4.5 years (95% confidence interval (CI) 2.8-6.2), controls 8.9 years (95% CI 6.8-11.0); log-rank test P < .001). TASC II C and D lesions were independent risk factors for a post-transplant CVE with a hazard ratio of 2.15 (95% CI 1.05-4.38) and 6.56 (95% CI 2.74-15.70), respectively. Thus, kidney transplant recipients with TASC II C and D aortoiliac stenosis require extensive cardiovascular risk management pre-, peri,- and post-transplantation.

Additional Normothermic Machine Perfusion Versus Hypothermic Machine Perfusion in Suboptimal Donor Kidney Transplantation: Protocol of a Randomized, Controlled, Open-Label Trial.

INTRODUCTION: Ageing of the general population has led to an increase in the use of suboptimal kidneys from expanded criteria donation after brain death (ECD-DBD) and donation after circulatory death (DCD) donors. However, these kidneys have inferior graft outcomes and lower rates of immediate function. Normothermic machine perfusion (NMP) may improve outcomes of these suboptimal donor kidneys. Previous non-randomized studies have shown the safety of this technique and suggested its efficacy in improving the proportion of immediate functioning kidneys compared to static cold storage (SCS). However, its additional value to hypothermic machine perfusion (HMP), which has already been proved superior to SCS, has not yet been established. METHODS AND ANALYSIS: This single-center, open-label, randomized controlled trial aims to assess immediate kidney function after 120 minutes additional, end-ischemic NMP compared to HMP alone. Immediate kidney function is defined as no dialysis treatment in the first week after transplant. Eighty recipients on dialysis at the time of transplant who receive an ECD-DBD or DCD kidney graft are eligible for inclusion. In the NMP group, the donor kidney is taken of HMP upon arrival in the recipient hospital and thereafter put on NMP for 120 minutes at 37 degrees Celsius followed by transplantation. In the control group, donor kidneys stay on HMP until transplantation. The primary outcome is immediate kidney function. ETHICS AND DISSEMINATION: The protocol has been approved by the Medical Ethical Committee of Erasmus Medical Center (2020-0366). Results of this study will be submitted to peer-reviewed journals. REGISTRATION: registered in clinicaltrials.gov (NCT04882254). HIGHLIGHTS: This is the first RCT to compare additional NMP to HMP alone.Extensive sampling will offer in-depth analysis of kidney physiology during NMP.This RCT may help identify biomarkers to predict clinical outcomes during NMP.Biomarkers can help develop NMP as assessment tool for declined kidneys.

To screen or not to screen? The development of a prediction model for aorto-iliac stenosis in kidney transplant candidates.

Screening for aorto-iliac stenosis is important in kidney transplant candidates as its presence affects pre-transplantation decisions regarding side of implantation and the need for an additional vascular procedure. Reliable imaging techniques to identify this condition require contrast fluid, which can be harmful in these patients. To guide patient selection for these imaging techniques, we aimed to develop a prediction model for the presence of aorto-iliac stenosis. Patients with contrast-enhanced imaging available in the pre-transplant screening between January 1st, 2000 and December 31st, 2018 were included. A prediction model was developed using multivariable logistic regression analysis and internally validated using bootstrap resampling. Model performance was assessed with the concordance index and calibration slope. Three hundred and seventy-three patients were included, 90 patients (24.1%) had imaging-proven aorto-iliac stenosis. Our final model included age, smoking, peripheral arterial disease, coronary artery disease, a previous transplant, intermittent claudication and the presence of a femoral artery murmur. The model yielded excellent discrimination (optimism-corrected concordance index: 0.83) and calibration (optimism-corrected calibration slope: 0.91). In conclusion, this prediction model can guide the development of standardized protocols to decide which patients should receive vascular screening to identify aorto-iliac stenosis. External validation is needed before this model can be implemented in patient care.

Implementation of donation after circulatory death kidney transplantation can safely enlarge the donor pool: A systematic review and meta-analysis.

BACKGROUND: Donation after circulatory death (DCD) kidney transplantation has been introduced to address organ shortage. However, DCD kidneys are not accepted worldwide due to concerns about inferior quality. To investigate whether these concerns are justified, we performed a systematic review and meta-analysis to investigate DCD graft outcomes compared to donation after brain death (DBD). MATERIALS AND METHODS: EMBASE, Medline, Cochrane, Web of Science and Google Scholar were searched from database inception until September 2020. Exclusion criteria were studies reporting on pediatric/dual kidney transplants, multi-organ transplants or studies including normothermic perfusion techniques. The primary outcome was graft survival. Secondary outcomes were primary non-function (PNF), delayed graft function (DGF), 3-months biopsy-proven acute rejection (BPAR), 1-year estimated Glomerular Filtration Rate (eGFR), patient survival, and urologic complications. A random-effects model was used for meta-analysis. Meta-regression analysis was performed in case of high between-study heterogeneity. RESULTS: Fifty-one studies were included, comprising 73,454 DCD and 518,229 DBD recipients. One-year graft loss was increased in DCD recipients (death-censored: risk ratio (RR) 1.10 (95%-confidence interval (CI) 1.04-1.16), all-cause: RR 1.13 (95%-CI 1.08-1.19)). Ten-year graft loss was similar to DBD (death-censored: RR 1.02 (95%-CI 0.92-1.13), all-cause: RR 1.03 (95%-CI 0.94-1.13)). DCD recipients had an increased risk of PNF (RR 1.43 (95%-CI 1.26-1.62)), DGF (RR 2.02 (95%-CI 1.88-2.16)), and 1-year mortality (RR 1.10 (95%-CI 1.01-1.21)). No differences were observed for 3-months BPAR, ureter stenosis/leakage, 1-year eGFR and 10-year mortality. CONCLUSION: Long-term DCD kidney transplant outcomes are similar to DBD despite a higher risk of PNF, DGF, and a 13% increased risk of graft loss in the first year after transplantation. These results should encourage implementation of DCD programs.

A comparison between combined liver kidney transplants to liver transplants alone: A systematic review and meta-analysis.

BACKGROUND: Since the introduction of the Model for End-stage Liver disease criteria in 2002, more combined liver kidney transplants are performed. Until 2017, no standard allocation policy for combined liver kidney transplant (CLKT) was available and each transplant center decided eligibility for CLKT or liver transplant alone (LTA) on a case-by-case basis. The aim of this systematic review was to compare the clinical outcomes of CLKT compared to LTA in patients with renal dysfunction. METHODS: Databases were systematically searched for studies published between January 2010 and March 2021. Outcomes were expressed as risk ratios and pooled with a random-effects model. The primary outcome was patient survival. RESULTS: Four studies were included. No differences were observed for mortality risk at 1 year (risk ratio (RR) 1.03 [confidence interval (CI) 0.97-1.09], 3 years (RR 1.06 [CI 0.99-1.13]) and 5 years (RR 1.08 [CI 0.98-1.19]). The risk of graft loss was similar in the first year (RR 1.10 [CI 0.93-1.30], while 3-year risk of graft loss was significantly lower in CLKT patients (RR 1.15 [CI 1.08-1.24]). CONCLUSIONS: CLKT has similar short-term graft and patient survival as LTA in patients with renal dysfunction. More data is needed to decide from which KDIGO stage patients benefit the most from CLKT.

Aorto-Iliac Artery Calcification and Graft Outcomes in Kidney Transplant Recipients.

While the association of vascular calcification with inferior patient outcomes in kidney transplant recipients is well-established, the association with graft outcomes has received less attention. With this dual-centre cohort study, we aimed to determine the clinical impact of recipient pre-transplant aorto-iliac calcification, measured on non-contrast enhanced computed tomography (CT)-imaging within three years prior to transplantation (2005-2018). We included 547 patients (61.4% male, age 60 (interquartile range 51-68) years), with a median follow-up of 3.1 (1.4-5.2) years after transplantation. The aorto-iliac calcification score (CaScore) was inversely associated with one-year estimated-glomerular filtration rate (eGFR) in univariate linear regression analysis (standard ß -3.3 (95% CI -5.1 to -1.5, p < 0.0001), but not after adjustment for potential confounders, including donor and recipient age (p = 0.077). In multivariable Cox regression analyses, a high CaScore was associated with overall graft failure (p = 0.004) and death with a functioning graft (p = 0.002), but not with death-censored graft failure and graft function decline. This study demonstrated that pre-transplant aorto-iliac calcification is associated with one-year eGFR in univariate, but not in multivariable linear regression analyses. Moreover, this study underlines that transplantation in patients with a high CaScore does not result in earlier transplant function decline or worse death censored graft survival, although ongoing efforts for the prevention of death with a functioning graft remain essential.

Postoperative Ultrasound in Kidney Transplant Recipients: Association Between Intrarenal Resistance Index and Cardiovascular Events.

Doppler ultrasound, including intrarenal resistance index (RI) measurement, is a widely used modality to assess kidney transplantation (KTx) vascularization. The aim of this study is to gain insight in the associations between early postoperative RI measurements and cardiovascular events (CVEs), all-cause mortality, and death-censored graft survival. METHODS: From 2015 to 2017, a prospective cohort study was conducted in patients in which RI measurement was performed immediately after KTx. The RI was calculated as (peak systolic velocity-end-diastolic velocity)/peak systolic velocity. End points were CVEs, all-cause mortality, and graft failure. Kaplan-Meier analyses (logrank test) were used for differences in end points. Univariate and multivariate associations were investigated by means of Cox regression analyses. RESULTS: RI cutoff of 0.70 was used. We included 339 recipients, of which 271 (80%) had an RI ≤ 0.70 and 68 (20%) had an RI > 0.70. CVEs were observed in 27 (8%) patients, 27 (8%) patients died, and 17 (5%) patients had graft failure during a median follow-up of 37 months (interquartile range, 33-43). Kaplan-Meier analyses and univariate Cox regression indicated a significant association with overall CVE-free survival (hazard ratios [HR], 2.79; P = 0.011; logrank test, P = 0.008) and all-cause mortality (HR, 2.59; P = 0.017; logrank test, P = 0.013) for patients with an RI above and below 0.70. An independent association was shown between an RI > 0.70 and CVE-free survival (HR, 2.48; P = 0.042) when deceased donation was not included in the model. CONCLUSIONS: In the early postoperative period, a high RI showed to be associated with CVEs after adjustment for cardiovascular risk factors, whereas no independent association was found with overall survival and graft failure. For the interpretation of RI measurements after KTx surgery, patients' cardiovascular state should be taken into consideration.

Aorto-Iliac Artery Calcification Prior to Kidney Transplantation.

As vascular calcification is common in kidney transplant candidates, aorto-iliac vessel imaging is performed for surgical planning. The aim of the present study was to investigate whether a novel non-contrast enhanced computed tomography-based quantification technique for aorto-iliac calcification can be used for cardiovascular risk stratification prior to kidney transplantation. In this dual-center cohort study, we measured the aorto-iliac calcium score (CaScore) of 547 patients within three years prior to transplantation (2005-2018). During a median (interquartile range) follow-up of 3.1 (1.4, 5.2) years after transplantation, 80 (14.7%) patients died, of which 32 (40.0%) died due to cardiovascular causes, and 84 (15.5%) patients had a cardiovascular event. Kaplan-Meier survival curves showed significant differences between the CaScore tertiles for cumulative overall-survival (Log-rank test p < 0.0001), cardiovascular survival (p < 0.0001), and cardiovascular event-free survival (p < 0.001). In multivariable Cox regression, the aorto-iliac CaScore was associated with all-cause mortality (hazard ratio 1.53, 95%CI 1.14-2.06, p = 0.005), cardiovascular mortality (2.04, 1.20-3.45, p = 0.008), and cardiovascular events (1.35, 1.01-1.80, p = 0.042). These independent associations of the aorto-iliac CaScore with the outcome measures can improve the identification of patients at risk for (cardiovascular) death and those who could potentially benefit from stringent cardiovascular monitoring to improve their prognosis after transplantation.

Machine perfusion in abdominal organ transplantation: Current use in the Netherlands.

Scarcity of donor organs and the increment in patients awaiting a transplant increased the use of organs from expanded criteria donors or donation after circulatory death. Due to the suboptimal outcomes of these donor organs, there is an increased interest in better preservation methods, such as ex vivo machine perfusion or abdominal regional perfusion to improve outcomes. This state-of-the-art review aims to discuss the available types of perfusion techniques, its potential benefits and the available evidence in kidney, liver and pancreas transplantation. Additionally, translational steps from animal models towards clinical studies will be described, as well as its application to clinical practice, with the focus on the Netherlands. Despite the lack of evidence from randomized controlled trials, currently available data suggest especially beneficial effects of normothermic regional perfusion on biliary complications and ischemic cholangiopathy after liver transplantation. For ex vivo machine perfusion in kidney transplantation, hypothermic machine perfusion has proven to be beneficial over static cold storage in a randomized controlled trial, while normothermic machine perfusion is currently under investigation. For ex vivo machine perfusion in liver transplantation, normothermic machine perfusion has proven to reduce discard rates and early allograft dysfunction. In response to clinical studies, hypothermic machine perfusion for deceased donor kidneys has already been implemented as standard of care in the Netherlands.

The prognosis of kidney transplant recipients with aorto-iliac calcification: a systematic review and meta-analysis.

The prognosis of kidney transplant recipients (KTR) with vascular calcification (VC) in the aorto-iliac arteries is unclear. We performed a systematic review and meta-analysis to investigate their survival outcomes. Studies from January 1st, 2000 until March 5th, 2019 were included. Outcomes for meta-analysis were patient survival, (death-censored) graft survival and delayed graft function (DGF). Twenty-one studies were identified, eight provided data for meta-analysis. KTR with VC had a significantly increased mortality risk [1-year: risk ratio (RR) 2.19 (1.39-3.44), 5-year: RR 2.28 (1.86-2.79)]. The risk of 1-year graft loss was three times higher in recipients with VC [RR 3.15 (1.30-7.64)]. The risk of graft loss censored for death [1-year: RR 2.26 (0.58-2.73), 3-year: RR 2.19 (0.49-9.82)] and the risk of DGF (RR 1.24, 95% CI 0.98-1.58) were not statistically different. The quality of the evidence was rated as very low. To conclude, the presence of VC was associated with an increased mortality risk and risk of graft loss. In this small sample size, no statistical significant association between VC and DGF or risk of death-censored graft loss could be demonstrated. For interpretation of the outcomes, the quality and sample size of the evidence should be taken into consideration.

Impact of Aortoiliac Stenosis on Graft and Patient Survival in Kidney Transplant Recipients Using the TASC II Classification.

BACKGROUND: Patients with end-stage renal disease and aortoiliac stenosis are often considered ineligible for kidney transplantation, although kidney transplantation has been acknowledged as the best therapy for end-stage renal disease. The clinical outcomes of kidney transplantation in patients with aortoiliac stenosis are not well-studied. This study aimed to assess the impact of aortoiliac stenosis on graft and patient survival. METHODS: This retrospective, single-center study included kidney transplant recipients transplanted between January 1, 2000, and December 31, 2016, who received contrast-enhanced imaging. Patients with aortoiliac stenosis were classified using the Trans-Atlantic Inter-Society Consensus (TASC) II classification and categorized as having TASC II A/B lesions or having TASC II C/D lesions. Patients without aortoiliac stenosis were functioning as controls. RESULTS: A total number of 374 patients was included in this study (n = 88 with TASC II lesions, n = 286 as controls). Death-censored graft survival was similar to the controls. Patient and uncensored graft survival was decreased in patients with TASC II C/D lesions (log-rank test P < 0.001). Patients with TASC II C/D lesions had a higher risk of 90-day mortality (hazard ratio, 3.96; 95% confidence interval, 1.12-14.04). In multivariable analysis, having a TASC II C/D lesion was an independent risk factor for mortality (hazard ratio, 3.25; 95% confidence interval, 1.87-5.67; P < 0.001). Having any TASC II lesion was not a risk factor for graft loss (overall P = 0.282). CONCLUSIONS: Kidney transplantation in patients with TASC II A/B is feasible and safe without increased risk of perioperative mortality. TASC II C/D decreases patient survival. Death-censored graft survival is unaffected.