Suboptimal Graft Function Research Articles

Clinical Outcomes and Donor-specific Antibody Rebound 5 y After Kidney Transplant Enabled by Imlifidase Desensitization.

Imlifidase is an IgG-cleaving endopeptidase conditionally approved in Europe for desensitization of highly sensitized patients before kidney transplantation. We present 5-y outcomes and donor-specific antibody (DSA) levels for clinical trial participants from a single site who received imlifidase for desensitization before incompatible transplantation (NCT02790437). Imlifidase was administered up to 24 h before living or deceased donor kidney transplantation. DSAs were monitored before transplantation, at days 7 and 28, and at 5 y posttransplant. At 5 y, 7 of 8 participants were alive. One of these 7 had suboptimal graft function secondary to donor-derived disease but remained dialysis independent. Three participants had antibody-mediated rejection (AMR), which occurred in the first 30 d in all cases and was successfully treated. No new episodes of suspected or biopsy-proven AMR occurred after 30 d posttransplant. Seven participants had DSA rebound. DSAs commonly persisted 5 y posttransplant, although they were generally lower strength compared with pre-imlifidase. Dilution studies of sensitized serum enabled the identification of lower AMR risk phenotypes for persisting DSAs. Severe and/or opportunistic infections were not observed at greater than expected frequency. Five-year outcomes of imlifidase-enabled incompatible transplants are overall favorable. DSA rebound is common, but antibody strength lessens in the long term, and longitudinally persisting DSAs did not lead to premature graft failure.

407.5: Long-term outcome of recipients with suboptimal graft function at 1 month after deceased-donor kidney transplantation.

407.5: Long-term outcome of recipients with suboptimal graft function at 1 month after deceased-donor kidney transplantation.

#2986 Patiromer for hyperkalemia in the early post-transplant period

Abstract Background and Aims Hyperkalemia is a serious condition among kidney transplant (KT) recipients, which can lead to life-threatening complications such as cardiac arrhythmias. Following kidney transplantation, the causes of hyperkalemia are multifactorial owing to graft function, excess potassium repletion, comorbidities, and medications used in the peri- and post-operative setting. The risk for hyperkalemia is increased immediately post-transplantation, particularly in those with suboptimal graft function and higher calcineurin inhibitors levels. A rapidly rising potassium refractory to medical therapy can be an indication for dialysis. Managing hyperkalemia after kidney transplantation is associated with increased morbidity and healthcare costs. In that manner, newer alternatives such as patiromer and sodium zirconium cyclosilicate have emerged due to their potentially superior efficacy and safety profiles. Method This is an observational, retrospective, single-center study aimed to evaluate the efficacy and safety of patiromer for hyperkalemia management in adult transplant recipients over the first 3 months post-transplant period, between January and December 2022 (since patiromer is available in our hospital pharmacy). We included all the kidney transplant recipients of our hospital, with the exception of those with primary graft failure. Information concerning the donor, recipient, graft, drugs pre and post-transplant, fluid therapy, transfusions, and blood tests (ions, blood gases, glycemia, kidney function measurements, anticalcineurin inhibitors levels) were collected. Patiromer was administered in a single-daily dose, diluted in 250 cc of water, in the afternoon, at least 2 hours separated of other drugs. Results In total, 69 recipients were included in the analysis. 94% were from deceased donors and 54% from donation after cardiac death. The average age of the entire cohort was 55 years and 66% were male. Medical history of each KT recipients reveal that 89% has hypertension, 32% diabetes, and 35% previous cardiopathy. Hypertension treatment before the KT included beta-blockers (39%) and angiotensin-converting enzyme inhibitors (37%). The incidence of hyperkalemia (K ≥ 5.5 mmol/L) was 29.7% in the first three months, mostly in the first week (21.6%). Patiromer was administered to 37% of them. For the 88.5% an initial dose of 8.4 g/day was enough. Although, 27% required an increase of the dose to 16.8 g/day and 8% to 25.2 g/day. The changes in serum potassium levels following the first patiromer dose are shown in Graphic 1. The mean time duration of the patiromer treatment was 14.5 days (3.7-36.7). However, 27% continue with patiromer beyond three months. There was no significant difference in the dose/levels of tacrolimus neither in the serum magnesium levels between patients with or without patiromer. No gastrointestinal complications were observed following the use of patiromer. Conclusion Patiromer may play an important role in the management of hyperkalemia over the first weeks after KT, allowing a significant and sustained reduction of the serum potassium levels, although additional long-term studies are necessary to confirm these effects.

#1645 The role of donor Cystatin-C in posttransplant outcomes in kidney transplantation

Abstract Background and Aims Cystatin-C is an established marker of glomerular filtration rate in kidney disease. High levels of cystatin-C have been associated with unfavorable outcomes (acute kidney injury, cardiovascular morbidity) in critically ill patients. The aim of this study was to evaluate the levels of Cystatin-C in donors after brain (DBD) and circulatory death (DCD) and investigate its association with posttransplant graft function. Method Plasma samples from 303 donors (283 deceased, 20 living donors; LD) were obtained from the Quality in Organ Donation (QUOD) and the Oxford Transplant (OTB) biobanks. QUOD is a national multi-center UK wide bioresource of deceased donor clinical samples collected during donor management and organ procurement. OTB is a living donor biobank established to obtain clinical samples as control cohorts. Only deceased donors with both grafts transplanted were included in the study. Plasma Cystatin-C from LD samples as assessed as an optimal control group. The samples were linked to donor and recipient metadata obtained from the National Transplant Registry (NHSBT). Using Luminex assays, plasma Cystatin-C was quantified in samples collected during donor management (prior to cross clamp in DBDs and LDs and at withdrawal of support in DCDs). We performed descriptive statistics and multivariate linear and logistic analysis to determine the association between Cystatin-C, primary non-function (PNF), delayed graft function (DGF), acute rejection (AR) and 12-month posttransplant graft function. Results Among 303 donors (median age: 50 years), 126 were DCDs, 157 DBDs (20.1% of them were expanded criteria donors, ECD) and 20 LDs. ECDs and DCDs had significantly higher levels of Cystatin-C, compared to DBDs. In a total of 606 recipients, 11 (1.9%) developed PNF, and 128 (21%) developed DGF (24 as pairs, 80 non-pairs). Forty-six recipients (7.6%) experienced at least one AR episode and 60 (10%) donors had lost the graft during follow-up. Donor levels of Cystatin-C were associated with DGF and were further elevated in donors of kidneys which developed PNF (P-value < .0001, Fig. 1). Grafts with acute rejections were retrieved from donors with higher levels of Cystatin-C, but the difference did not meet statistical significance. Cystatin-C levels were significantly lower (P-value < .0001) in donors who offered concordant grafts with optimal 12-month post-transplant function (eGFR >60 ml/min), compared with grafts with intermediate function (GFR 30-60 ml/min) or eGFR <30ml/min (Fig. 2). LDs had significantly lower levels of Cystatin-C compared to deceased donors in all studied outcomes (Figs 1 and 2). Cystatin-C during donor management was an independent risk factor for inferior 12-month paired graft function, after the implementation of three different multivariate models, including donor (β-coef = −11.3, P-value = .001), recipient (β-coef = −16, P-value < .001) and post-transplant characteristics (β-coef = −13.1, P-value = .002). Conclusion In a large cohort of deceased and living donors, we were able to evaluate the circulating levels of Cystatin-C during donor management with the use of high-end performance technology. The concentration of Cystatin-C was notably different among donor types and was significantly higher in donors with kidneys that developed PNF or had suboptimal graft function 12-month posttransplant. Our findings suggest that Cystatin-C may have a role in identifying higher-risk donors during donor management and offers the opportunity for granular assessment of donor kidney quality prior to transplantation.

#2403 Impact of pregnancy on kidney transplant recipients

Abstract Background and Aims Kidney transplantation (KT) provides an opportunity to increase fertility in women with chronic kidney disease and gestational desire. Lack of knowledge about obstetric complications and implications for the graft may lead to discourage pregnancy for these women. Although the incidence of pregnancy is rising in women receiving KT, the impact that it may have on the graft function is unknown. Method We conducted an observational, retrospective, single-centre study of a cohort of kidney transplant recipients (KTR) who became pregnant between 2007 and 2022. Clinical and analytical parameters were evaluated before, during and after pregnancy. The main aim was to assess the long-term impact of pregnancy on the graft by analysing renal function 3 years after pregnancy. Results We included 25 women receiving a KT between 1990 and 2018, among which 72% (n = 18) were transplanted from a deceased donor. 2 women (8%) received a combined liver-kidney transplant and 2 women (8%) a simultaneous pancreas-kidney transplant. Maintenance immunosuppression before conception included teratogenic drugs in 68% of cases [12 of them (48%) received mycophenolate mofetil and 5 of them (20%), mTOR inhibitors]. Planned withdrawal was only applied in 50.0% of pregnancies (n = 15). 30 pregnancies were identified (5 patients had 2 post-transplant pregnancies). Median age at gestation was 35 years [interquartile range (IQR) 33-39]. 5 conceptions required assisted reproductive technology. The main complications were gestational hypertension in 4 KTR (13.3%) and preeclampsia in 7 pregnancies (23.3%). 60% of neonates (n = 18) were preterm births (36 [IQR 34-37] weeks of pregnancy at birth) and 44% (n = 12) had low birth weight (2530 [IQR 2283-2950] grams). No foetal malformations were described. Due to physiological changes, a significant increase in estimated glomerular filtration rate (eGFR) was observed in the first and the second trimester of pregnancy (61 [IQR 50-91] ml/min and 70 [IQR 50-90] ml/min, respectively vs. baseline eGFR 59 [IQR 47-77] ml/min; p 0.001]. However, eGFR was equal to the previous one in the third trimester of pregnancy (60 [IQR 44-69] ml/min vs. 59 [IQR 47-77] ml/min; p 0.322). Median proteinuria remained below 0.5 g/day throughout pregnancy, without significant variation. Immunosuppression regimen during pregnancy was mainly based on a combined therapy of steroids, calcineurin inhibitors and azathioprine (21 KTR, 70%). Tacrolimus dose increase (median 63.6% [IQR 33.3-90.0%]) was necessary to maintain proper drug levels throughout gestation. Kidney graft function showed a decline in the first and second year after pregnancy compared to baseline function (54 [IQR 35-77] ml/min and 55 [IQR 36-75] ml/min vs. 59 [IQR 47-77] ml/min; p 0.018 and p 0.021, respectively]. Nevertheless, by the third year post-pregnancy, eGFR was similar to the baseline function (62 [IQR 43-73] ml/min vs. 59 [IQR 47-77] ml/min; p 0.365]. Likewise, annual eGFR variation was comparable during 3 years before (+1.0 ml/min/year) and 3 years after pregnancy (−0.9 ml/min/year), hence no worsening was observed after gestation (p 0.78). No differences were observed in proteinuria either (baseline proteinuria 0.17 [IQR 0.13-0.3] g/day vs. third-year proteinuria 0.21 [IQR 0.15-0.34] g/day; p 0.938). Only 5 women had a baseline serum creatinine above current recommendations for pregnancy (>1.5 mg/dl) and only 3 women presented baseline proteinuria > 0.5 g/day. In this group (n = 7), pregnancy occurred later after KT (96.0 [IQR 80.9-213.0] vs. 46.0 [IQR 16.0-67.5] months; p 0.024). The only 2 graft losses in the cohort were in this group. Both were attributed to transplant glomerulopathy, and they occurred at years 3 and 5 after pregnancy. On the other side, in this group there were no other baseline differences or obstetrical complications [Table 1]. Conclusion Pregnancy does not normally affect graft function and it stabilises within 3 years after gestation. It is important to increase data on women with suboptimal graft function to determine the direct implications that pregnancy may have on these KTRs.

Assessment of biological organ age using molecular pathology in pre-transplant kidney biopsies

Organ shortage is a major challenge in kidney transplantation but the use of older donors, often with co-morbidities, is hampered by inconsistent outcomes. Methods of accurately stratifying marginal donor organs by clinical and histological assessment are lacking. To better understand organ variability, we profiled the transcriptomes of 271 kidneys from deceased donors at retrieval. Following correction for biopsy composition, we assessed molecular pathways that associated with delayed, and sub-optimal one-year graft function. Analysis of cortical biopsies identified an adaptive immune gene-rich module that significantly associated with increasing age and worse outcomes. Cellular deconvolution using human kidney reference single cell transcriptomes confirmed an increase in kidney-specific B and T cell signatures, as well as kidney macrophage, myofibroblast and fibroblast gene sets in this module. Surprisingly, innate immune pathway and neutrophil gene signature enrichment was associated with better outcomes. Thus, our work uncovers cellular molecular features of pathological organ ageing, identifiable at kidney retrieval, with translational potential.

Trends in pediatric donor heart discard rates and the potential use of unallocated hearts for allogeneic valve transplantation

ObjectivesAllogeneic valve transplantation is an emerging therapy that delivers a living valve from a donor heart. We reviewed the national discard rate of pediatric and young adult (aged 25 years or younger) donor grafts to estimate the number of hearts potentially available to source valve allotransplantation. MethodsWe queried the United Network for Organ Sharing database to identify pediatric and young adult heart donors from 1987 to 2022. Donor heart discard was defined as nontransplantation of the allograft. ResultsOf 72,460 pediatric/young adult heart donations, 41,065 (56.7%) were transplanted and 31,395 (43.3%) were unutilized. The average annual number of discarded hearts in era 1 (1987-2000), era 2 (2000-2010), and era 3 (2010-2022) was 791 (42.8%), 1035 (46.3%), and 843 (41.2%), respectively. From 2017 to 2021, the average annual number of discards by age was: 39 (31.8%) neonates/infants, 78 (38.0%) toddlers, 41 (49.4%) young children, 240 (38.0%) adolescents, and 498 (40.1%) young adults. High-volume procurement regions had the greatest proportion of nonutilization, with the national average discard rate ranging from 39% to 49%. The most frequently documented reasons for nonallocation were distribution to the heart valve industry (26.5%), presumably due to suboptimal graft function, poor organ function (22.7%), and logistical challenges (10.8%). ConclusionsWith ∼900 pediatric/young adult donor hearts discarded annually, unutilized grafts represent a potential source of valves for allogeneic valve transplant to supplement current conduit and valve replacement surgery. The limited availability of neonatal and infant hearts may limit this technique in the youngest patients, for whom cryopreserved homografts or xenografts will likely remain the primary valve substitute.

Generation of Insulin-Producing Multicellular Organoids.

Clinical islet transplantation (CIT) is an established noninvasive treatment for type I diabetes (T1D) and has demonstrated improved glycemic control, preventing the occurrence of severe hypoglycemia. However, CIT has several limitations, such as the need for multiple donors, lifelong immunosuppression, and suboptimal long-term graft function. Most of the transplanted islets are lost due to inflammation, ischemic damage, and delayed revascularization.Generation of organoids have gained increasing interest in regenerative medicine in recent years. In the context of beta-cell replacement, it offers a possibility to address limitations of CIT by allowing to produce uniform organoids from single or multiple cell types facilitating revascularization and anti-inflammatory and/or immunomodulatory protection. We have previously generated multicellular insulin-secreting organoids composed of islet cells and the human amniotic epithelial cells (hAECs). These 3D insulin-secreting structures demonstrated improved viability and function both in vitro and in vivo. Here we detail a stepwise methodology to generate insulin-secreting organoids using two different methods. In addition, quality assessment in vitro tests are also described.

Successful surgical correction of ascending aortic dissection in a kidney transplant patient

Cardiovascular disease is the leading cause of death in patients with a transplanted kidney and in graft loss. We present the first clinical case of successful surgical correction of ascending aortic dissection (DeBakey type I) in a young patient with a functioning kidney graft. The patient underwent the first cadaveric kidney transplantation (KTx), which was complicated by acute humoral rejection and suboptimal graft function. High blood pressure, anemia, elevated blood levels of triglycerides, phosphorus, parathyroid hormone, and uric acid were recorded. A repeat KTx was performed five years later; the patient’s condition and kidney function were satisfactory. Three years later,the patient started experiencing severe pain along the thoracic and lumbar spine; his blood creatinine level was 408 μmol/L. Computed tomography and echocardiography diagnosed DeBakey type I aortic dissection (AD) with critical narrowing of the true aortic lumen at certain levels, dissection of aortic branches. Aortic resection surgery with prosthetic replacement of the ascending aorta according to David procedure with reimplantation of coronary artery orifices according to Kouchoukos technique, prosthetic replacement of the aortic arch with debranching of brachiocephalic artery and left common carotid artery were successfully performed as planned under endotracheal anesthesia, cardiopulmonary bypass and selective pharmacological cold cardioplegia. The peculiarities of the course, possible causes and outcomes of surgical correction of thoracic AD in the patient are discussed.

Robotic Versus Open Kidney Transplantation from Deceased Donors: A Prospective Observational Study

BackgroundWhile robot-assisted kidney transplantation (RAKT) from living donors has been shown to achieve favourable outcomes, there is a lack of evidence on the safety and efficacy of RAKT as compared with the gold standard open kidney transplantation (OKT) in the setting of deceased donors, who represent the source of most grafts worldwide. ObjectiveTo compare the intraoperative, perioperative, and midterm outcomes of RAKT versus OKT from donors after brain death (DBDs). Design, setting, and participantsData from consecutive patients undergoing RAKT or OKT from DBDs at a single academic centre between October 2017 and December 2020 were prospectively collected. InterventionRAKT or OKT. Outcome measurements and statistical analysisThe primary outcomes were intraoperative adverse events, postoperative surgical complications, delayed graft function (DGF), and midterm functional outcomes. A multivariable logistic regression analysis assessed the independent predictors of DGF, trifecta, and suboptimal graft function (estimated glomerular filtration rate [eGFR] <45 ml/min/1.73 m2) at the last follow-up. Results and limitationsOverall, 138 patients were included (117 [84.7%] OKTs and 21 [15.3%] RAKTs). The yearly proportion of RAKT ranged between 10% and 18% during the study period. The OKT and RAKT cohorts were comparable regarding all graft-related characteristics, while they differed regarding a few donor- and recipient-related factors. The median second warm ischaemic time, ureterovesical anastomosis time, postoperative complication rate, and eGFR trajectories did not differ significantly between the groups. A higher proportion of patients undergoing OKT experienced DGF; yet, at a median follow-up of 31 mo (interquartile range 19–44), there was no difference between the groups regarding the dialysis-free and overall survival. At the multivariable analysis, donor- and/or recipient-related factors, but not the surgical approach, were independent predictors of DGF, trifecta, and suboptimal graft function at the last follow-up. The study is limited by its nonrandomised nature and the small sample size. ConclusionsOur study provides preliminary evidence supporting the noninferiority of RAKT from DBDs as compared with the gold standard OKT in carefully selected recipients. Patient summaryKidney transplantation using kidneys from deceased donors is still being performed with an open surgical approach in most transplant centres worldwide. In fact, no study has compared the outcomes of open and minimally invasive (robotic) kidney transplantation from deceased donors. In this study, we evaluated whether robotic kidney transplantation using grafts from deceased donors was not inferior to open kidney transplantation regarding the intraoperative, postoperative, and midterm functional outcomes. We found that, in experienced hands and provided that there was a time-efficient organisation of the transplantation pathway, robotic kidney transplantation from deceased donors was feasible and achieved noninferior outcomes as compared with open kidney transplantation.

Intraoperative transit time flow measurement in patients with diffuse coronary artery disease in the prevention of aortocoronary bypass graft occlusion

Aim. To study the parameters of transit time flow measurement (TTFM) for coronary bypass grafts in patients with diffuse lesions with different diameter of target coronary arteries.Material and methods. The study included 150 patients with diffuse coronary artery disease. All patients underwent microscope-assisted coronary artery bypass grafting (CABG), during which the TTFM parameters were evaluated. Depending on the diameter of target coronary arteries, patients were divided into 3 groups: group 1 included grafts to arteries ≤1 mm (n=101), group 2 — 1-1,5 mm (n=138), group 3 — ≥1,5 mm (n=308). Comparative analysis of TTFM parameters was performed.Results. Mostly participants were male (76%); mean age was 62,9±7,6 years. During hospitalization, we recorded 1 death, 2 perioperative myocardial infarctions (1,3%) and 1 cerebrovascular accident (0,7%). TTFM analysis showed the worst hemodynamic parameters and a higher rate of suboptimal function in group 1; blood flow parameters were comparable in groups 2 and 3. The additional analysis in group 1 and combined groups 2 and 3 allows us to make an opinion about the negative impact of coronary artery diameter less than 1 mm on optimal blood flow through the grafts (odds ratio=2,1, 95% confidence interval, 1,2-3,8, p=0,011).Conclusion. Diffuse coronary atherosclerosis with a diameter of target coronary arteries less than 1 mm significantly increase the risk of suboptimal graft function that requires considering more aggressive secondary prevention. TTFM demonstrate high effectiveness of microscope-assisted CABG in target coronary artery diameter of 1-1,5 mm and higher.

MO952EFFECT OF KIDNEY TRANSPLANTATION ON PARATHYROID GLANDS FUNCTION

Abstract Background and Aims The normalization of the function of the parathyroid glands after successful kidney transplantation does not occur in all patients. The aim of our study was to determine of parathyroid function, patient factors that would be predictive of achieving a normal serum PTH in the first months after surgery and prevalence of hyperparathyroidism (HPT) in patients after kidney transplantation (KT) at various stages of the post-transplant period. Method The observational cross-retrospective study included 230 kidney graft recipients. Inclusion criteria: the duration of the post-transplant period is more than 12 months and stable kidney transplant function for 6 months. The median of the pre-transplant stage was 18 months (Q1-Q3: 9; 35), post-transplant period - 42 months (Q1-Q3: 21; 73). Serum concentrations of parathyroid hormone (PTH), calcium, phosphorus, total alkaline phosphatase activity, albumin, and creatinine were determined using standard methods. HPT was diagnosed with PTH&amp;gt;130 pg/ml. Retrospective analysis of parameters in three months after surgery it was performed in 197 patients. Estimated glomerular filtration rate (eGFR) was calculated using the CKD-EPI formula, stratification of chronic kidney disease (CKD) stages was carried out according to the eGFR. Results Patients had different kidney transplant function: eGFR 117-15 ml/min, median 51 (Q1-Q3: 39;65): CKD 1(КT) st. was in 3.5%, CKD 2(КT) st. - in 33.9%, CKD 3(КT) st. - in 49.1% and CKD 4(КT) st. – in 13.5% patients. Serum PTH levels were 27-670 pg/ml, median 120 pg/ml (Q1-Q3: 87; 182). The median PTH of blood in patients was 99 pg/ml (Q1-Q3: 76; 120), 98 pg/ml (Q1-Q3: 79; 123), 120 pg/ml (Q1-Q3: 89; 180) and 267 pg/ml (Q1-Q3: 170; 328), respectively, with CKD 1(КT), CKD 2(КT), CKD 3(T) and CKD 4(КT) st. The frequency of HPT was 38.7%: 19.8% in patients with eGFR≥60 ml/min, 38.1% and 93.5% in patients with CKD 3(КT) and CKD 4(КT) st. (p&amp;lt;0.001) (Fig. 1). HPT was equally frequently diagnosed in the second, third, fourth and fifth years after kidney transplantation and amounted to 30.3% in the first five years. In patients with a post-transplant period of more than 5 years, HPT was 54.7% (p&amp;lt;0.001). In the same group, the proportion of patients with eGFR&amp;lt;60 ml/min was also higher - 55.5% (p=0.002) (Fig. 2). An inverse relationship was established between serum PTH and eGFR and a direct relationship between serum PTH and serum creatinine (p&amp;lt;0.001). A retrospective analysis showed that 3 months after kidney transplantation, the median PTH was 178 pg/ml (Q1-Q3: 120; 250), HPT was recorded in 65.5% of patients. Serum PTH decreased by 6-92%, median 50%. Kidney graft function was worse in patients with a decrease in serum PTH ≤50% (n = 100) versus patients with a decrease in serum PTH &amp;gt;50% (n = 97). Minimal blood creatinine was recorded in the early postoperative period, respectively, on (median) 7 and 5 days (p = 0.015), the median eGFR by the end of the third month was 59 and 63 ml/min, respectively (p=0.044). We found that preoperative PTH&amp;gt;585 pg/ml (p&amp;lt;0.0001 OR 2.93 95% CI 1.78; 5.05), delayed kidney graft function (p=0.005 OR 1.57 95% CI 1.58; 9.87), and eGFR&amp;lt;60 ml/min (p&amp;lt;0.0005 OR 2.01 95% CI 1.36; 3.09) were predictive of HPT in patients in the early stages after kidney transplantation. Conclusion Hyperparathyroidism in patients after kidney transplantation continues to be an ongoing problem. It occurs in a third of patients in the first five postoperative years and in half patients in subsequent years. Preoperative secondary hyperparathyroidism, delayed and suboptimal kidney graft function prevent the restoration of parathyroid glands function after kidney transplantation.

Offspring to Parent LDLT: Narrowing the Gap Between Theory and Evidence.

To the Editor, We are encouraged by the renewed interest in regard to the topic of offspring donation in the setting of living donor liver transplantation (LDLT). We reviewed the comments from Ho et al with great interest. Their comments demonstrate the need for validation of the findings of Dagan et al across a broad range of demographic groups.1 Of note, Ho et al reviewed their institution’s (National Taiwan University Hospital) LDLT experience and found no significant difference in long-term patient survival between recipients who received their grafts from offspring or nonoffspring donors. And furthermore, the gender of the donor also did not seem to influence survival. As suggested by Cohen et al, fetal alloimmunity during pregnancy may create an immune environment, which leads to suboptimal graft function in the setting of offspring organ donation.2 In our study, of the organ procurement and transplantation network/scientific registry of transplant recipients (OPTN/SRTR) database from 1998 to 2018, offspring donation was only found to be inferior to nonoffspring donation in a subgroup analysis of recipient gender, when the recipient was female (mother), with male offspring paradoxically associated with inferior outcomes. No difference was observed with male recipients or in aggregate (male and female). As pregnancy would be the precipitating event to induce alloimmunity, only maternal recipients would be expected to experience inferior outcomes following offspring donation. This result was significant even after adjustment for relevant covariates, including donor age, graft type, so on. It would be interesting to observe whether this phenomenon is also present in Ho et al’s patient cohort after an adjusted analysis with particular focus of the outcomes of the offspring to female parent recipient subgroup. As Dagan et al utilized OPTN/SRTR, several database-related constraints (missingness, lack of vascular anatomy detail of grafts, postop immunosuppression dosages, etc.) were placed on the study, which now requires validation in broader, more granular datasets like that of The National University. The implications of the findings of Dagan et al have wide-ranging impacts on the future of donor selection and management in the setting of LDLT (ie, counseling and the need to crossmatch). As such, we encourage continued debate and free inquiry into the matter. Sincerely,

222-OR: BETA-2 Calculated Based on Single Fasting Blood Sample Allows to Define and Discriminate between Optimal and Suboptimal Islet Allograft Function Prior to the Clinical Need for Insulin Support

Introduction: The goal of the study was using BETA-2 to define suboptimal islet allograft function, which precedes clinical need of the insulin support and to discriminate it from the optimal function which allows for persistent insulin independence after islet allotransplantation. Material: Thirty five islet transplants were performed in 16 patients with T1DM. BETA-2 trends over the time were assessed in 3 transplant groups depending on the clinical outcome: Group 1 (N=9) persistent insulin independence; Group 2 (N=13) insulin independence loss preceded by the gradual islet graft decline; Group 3 (N=13) no insulin independence. Day 75 was a surrogate day of accomplished islet engraftment. Results: None of the transplants with BETA-2 &amp;lt; 17.4 on Day 75 resulted in persistent insulin independence (ROC AUC=17.4 for BETA-2 Group 1 vs. Group 2+ Group 3 with 100% sensitivity). Moreover, afterwards BETA-2 always oscillated above 17.4 and never dropped below after each transplant from Group 1 with up to 12 years follow-up. In contrast BETA-2 dropped below 17.4 in every case from Group 2, 9 months (3-24) prior to the loss of insulin independence (Kaplan-Meyer, p=0.03). Based on above, we defined that optimal islet function at any time point was represented by BETA-2 &amp;gt;=17.4, whereas suboptimal when BETA-2 was below that. Once BETA-2 dropped below 17.4 at any time point, islet function never recovered, instead gradually deteriorated with subsequent need for insulin support in every patient from group 2. Optimal vs. suboptimal islet graft function could be also discriminated based on individual fasting glucose, c-peptide or A1c values but with lower sensitivity and specificity. BETA-2 values never reached 17.4 at any time point after each transplant from Group 3. Conclusion: BETA-2 with cut off 17.4 allowed to define and discriminate optimal vs. suboptimal islet allograft function before need for insulin support. Disclosure P.J. Bachul: None. J.E. Golebiewska: None. F. Antic: None. M. Para: None. L. Basto: None. K. Golab: None. L. Perea: None. L. Wang: None. M.L. Tibudan: None. C.C. Thomas: None. P. Witkowski: None. Funding State of Illinois; Dompé

Robot-assisted Kidney Transplantation with Regional Hypothermia Using Grafts with Multiple Vessels After Extracorporeal Vascular Reconstruction: Results from the European Association of Urology Robotic Urology Section Working Group

BackgroundKidney transplantation using grafts with multiple vessels (GMVs) is technically demanding and may be associated with increased risk of complications or suboptimal graft function. To date, no studies have reported on robot-assisted kidney transplantation (RAKT) using GMVs. ObjectiveTo report our experience with RAKT using GMVs from living donors, focusing on technical feasibility and early postoperative outcomes. Design, setting, and participantsWe reviewed the multi-institutional, prospectively collected European Association of Urology (EAU) Robotic Urology Section (ERUS)-RAKT database to select consecutive patients undergoing RAKT from living donors using GMVs between July 2015 and January 2018. Patients undergoing RAKT using grafts with single vessels (GSVs) served as controls. In case of GMVs, ex vivo vascular reconstruction techniques were performed during bench surgery according to the case-specific anatomy. InterventionRAKT with regional hypothermia. Outcome measurements and statistical analysisIntraoperative outcomes and early (30 d) postoperative complications and functional results were the main study endpoints. Multivariable logistic regression analysis evaluated potential predictors of suboptimal renal function at 1 mo. Results and limitationsOverall, 148 RAKTs were performed during the study period. Of these, 21/148 (14.2%) used GMVs; in all cases, single arterial and venous anastomoses could be performed after vascular reconstruction. Median anastomoses and rewarming times did not differ significantly between the GMV and GSV groups. Total and cold ischemia times were significantly higher in the GMV cohort (112 vs 88min, p=0.004 and 50 vs 34min, p=0.003, respectively). Overall complication rate and early functional outcomes were similar among the two groups. No major intra- or postoperative complications were recorded in the GMV cohort. At multivariable analysis, use of GMVs was not significantly associated with suboptimal renal function at 1 mo. Small sample size and short follow-up represent the main study limitations. ConclusionsRAKT using GMVs from living donors is technically feasible and achieved favorable perioperative and short-term functional outcomes. Larger studies with longer follow-up are needed to confirm our findings. Patient summaryIn this study, we evaluated for the first time in literature the results of RAKT from living donors using kidneys with multiple arteries and veins. We found that, in experienced centers, RAKT using kidneys with multiple vessels is feasible and achieves optimal results in terms of postoperative kidney function with a low number of postoperative complications.

Chemical Control of Grafted Human PSC-Derived Neurons in a Mouse Model of Parkinson’s Disease

Transplantation of human pluripotent stem cell (hPSC)-derived neurons is a promising avenue for treating disorders including Parkinson's disease (PD). Precise control over engrafted cell activity is highly desired, as cells do not always integrate properly into host circuitry and can cause suboptimal graft function or undesired outcomes. Here, we show tunable rescue of motor function in a mouse model of PD, following transplantation of human midbrain dopaminergic (mDA) neurons differentiated from hPSCs engineered to express DREADDs (designer receptors exclusively activated by designer drug). Administering clozapine-N-oxide (CNO) enabled precise DREADD-dependent stimulation or inhibition of engrafted neurons, revealing D1 receptor-dependent regulation of host neuronal circuitry by engrafted cells. Transplanted cells rescued motor defects, which could be reversed or enhanced by CNO-based control of graft function, and activating engrafted cells drives behavioral changes in transplanted mice. These results highlight the ability to exogenously and noninvasively control and refine therapeutic outcomes following cell transplantation.

CT-based renal volume and graft function after living-donor kidney transplantation: Is there a volume threshold to avoid?

Donated kidney volume influences post-transplant outcomes and graft survival. We evaluated the relationship between living-donor kidney volume and recipient graft function at 12 months post-transplantation, exploring a volume threshold for a suboptimal graft function, and compared two different formulas of volume estimation. A retrospective analysis of 82 pairs of living-donor kidney transplants was conducted. Donor renal volumes were estimated from computerized tomography scans using the ellipsoid formula and the voxel counting technique. Linear and restricted cubic regression spline was used to analyze the association of volume with graft function. Additionally, we determined the correlation between the two volume estimation formulas and established a correction factor for the ellipsoid formula. Renal volume (adjusted to recipient BSA) had the strongest independent effect (B = 1.65 per 10 ml/m(2) increase, p value <0.001) on graft function at 12 months. The eGFR at 12 months was 52.5, 63.6 and 67.6 ml/min/1.73 m(2) for the low, medium and high volume ratio terciles, respectively (p value <0.001). The odds of a GFR <50 ml/min became significantly reduced with volumes above 145 cc/1.73 m(2). A strong positive correlation between the two formulas was identified (R(2) = 0.705), but the optimal correction factor for our cohort was 0.566. In a Caucasian population, higher donor kidney volumes estimated from preoperative CT scans are associated with higher recipient eGFRs at 12 months after live-donor transplantation. Using this criterion, transplant teams can potentially improve selection of living donors if multiple donors are available. However, the need for precise estimation of donor kidney volumes should not be overlooked.

Looking Behind the Curtain: Pre-Transplant Mismatched Eplet Load May Better Predict Increases in Post-Transplant DSA.

Purpose: Patients receiving renal transplants in the presence of donor specific HLA antibodies (DSA) are at increased risk for antibody mediated rejection (AMR) as well as decreased graft survival. For highly sensitized patients, transplanting in the presence of low/moderate DSA may be the only viable option. We looked at which characteristics of pre-existing DSA are associated with poor post-transplant(tx) outcomes. Methods: We identified 11 patients (mean cPRA=87+7%) with DSAs from a cohort of 165 consecutive renal txs performed between 10/2012 and 12/2013. Patients were desensitized using plasmapheresis(PP) and IVIg and received standard induction and maintenance therapy post-tx. DSA titers and MFI were determined by solid phase assays (pre-Tx, day 3, weekly 1-4, months 2, 3, 6, 9, 12). Donor-recipient eplet mismatches (MM) in the DSA-associated HLA antigens were determined using HLA Matchmaker. Results: Post-tx, 5 of the 11 (45.5%) desensitized patients no longer had clinically significant DSA. Increased DSA were found in the remaining 6 (55.5%) within 2 weeks (MFI=3469-15000, titers 1:16->1:1024) and 5 developed de novo DSA. No association between pre-tx MFI values, positive xmatch (T or B), or previous tx and increased post-tx DSA was found. In contrast, patients with negative DSA post-tx averaged 6.4+3.6 eplet MM in pertinent HLA antigen, whereas those with increasing DSA post-tx averaged 16.8+5.6 MM eplets.Expression of Cytosolic DoubleFigure: No Caption available.Increased DSA were successfully reversed in 2 patients with PP and IVIg and in 1 with increased basal immunosuppression. The remaining 3, after treatment, have DSA levels that are stable or slightly lower with surviving but sub-optimal graft function. Conclusions: Renal transplants may be performed successfully in presence of DSA, but remain at increased risk for graft failure or poor function. Our data suggest that mismatched eplet load is predictive of clinically significant post-tx DSA and may identify patients in need of frequent monitoring and aggressive early intervention to minimize DSA load and improve outcomes.

172-P: MYSTERIOUS “SUBOPTIMAL” FUNCTION OF A DECEASED DONOR (DD) RENAL ALLOGRAFT

Aim To determine the role of alloimmune status of a deceased donor renal allograft with suboptimal graft function. Methods HLA typing was done by rSSOP and antibody assays were done by LabScreen mixed (LSM), LabScreen ID/Flow PRA, Luminex Single Antigen Bead assays (SAB), and by DSA assay using beads coated with donor lymphocyte lysates (GenProbe). Crossmatches were done by Flow cytometry (FC). Biopsy was assessed by histology and C4d staining. Results The recipient had no Class I, II or MICA antibodies from Feb ‘08 till Feb ‘12 when B∗44:02 and A80 antibodies were detected by SAB. Serum from Mar ‘12 was negative for HLA Class I, II, and MICA by SAB. Quarterly sera from April ‘12 till Feb ‘13 had no HLA or MICA antibodies using LSM and or LabScreen ID and transplant was done from a DD in April’13 based on negative T-B FC using mouse monoclonal antihuman-IgG FITC using Feb’13 serum. The recipient had suboptimal graft function. Retro crossmatches and antibody assays with Mar and April ‘13 sera showed B∗44:02 DSA and both sera were T-B FC positive using splenocytes from the DD and blood lymphocytes from surrogate donor with Goat Antihuman IgG FITC. Using beads coated with lymphocyte lysates from the DD and surrogate, both sera had Class I DSA. The patient was treated based on DSA but the creatinine level remained abnormal. A biopsy ruled out immune mediated rejection. The DSA persists and the creatinine remains abnormal. In comparison, a living donor transplant (LD) recipient with no DSA, negative FC at the time of transplant, developed an A2, B∗44:03, DR7 and DR15 (recall DSAs) 7 days post transplant and suffered a C4d positive AMR. Conclusions The suboptimal graft function remains unclear in the DD case. The DSA assay with cell lysates might be useful to assess “actual DSA”. Both DD and LD cases show relevance of historic antibodies. The DD case needs follow-up to understand if alloimmunity is associated with the observed sub-optimal graft function.

Does Cardiopulmonary Arrest and Resuscitation of Heart Donors Portend Inferior Outcomes in Heart Transplantation Recipients?

Purpose Myocardial ischemia sustained during cardiopulmonary arrest and resuscitation of a heart donor (CPR+) is thought to be associated with suboptimal graft function and poor outcomes in recipients. We examined graft and recipient survival in patients receiving heart transplantation from CPR+ donors and compared them to recipients whose heart donors did not sustain cardiac arrest (CPR-). Methods and Materials Retrospective analysis of UNOS adult heart transplantation data from May 1994 through July 2012 was performed. Discrete variables were compared using the Chi-Square test. Continuous variables were compared using t test. Patient and graft survivals were calculated using actuarial method and compared using Wilcoxon test. Results Of the 29,242 adult heart transplantations performed in North America during study period, 1,396 (4.7%) received hearts from CPR+ donors. More number of young 25.5±15yrs vs. 28.5±14yrs P figure 1 ] Graft survival mirrored recipient survival in both groups. Conclusions A large multicenter adult heart transplant data from across North America did not show inferior outcomes in recipients of heart transplantation from selected CPR+ donors. Recipient and graft survival were similar over five years of follow-up.