Challenges, highlights, and opportunities in cellular transplantation: A white paper of the current landscape.

Although cellular transplantation remains a relatively small field compared to solid organ transplantation, the prospects for advancement in basic science and clinical care remain bountiful. In this review, notable historical events and the current landscape of the field of cellular transplantation are reviewed with an emphasis on islets (allo- and xeno-), hepatocytes (including bioartificial liver), adoptive regulatory immunotherapy, and stem cells (SCs, specifically endogenous organ-specific and mesenchymal). Also, the nascent but rapidly evolving field of three-dimensional bioprinting is highlighted, including its major processing steps and latest achievements. To reach its full potential where cellular transplants are a more viable alternative than solid organ transplants, fundamental change in how the field is regulated and advanced is needed. Greater public and private investment in the development of cellular transplantation is required. Furthermore, consistent with the call of multiple national transplant societies for allo-islet transplants, the oversight of cellular transplants should mirror that of solid organ transplants and not be classified under the unsustainable, outdated model that requires licensing as a drug with the Food and Drug Administration. Cellular transplantation has the potential to bring profound benefit through progress in bioengineering and regenerative medicine, limiting immunosuppression-related toxicity, and providing markedly reduced surgical morbidity.

Association of balanced abdominal organ transplant center volumes with patient outcomes.

BACKGROUND: The volume-outcome relationship for organ-specific transplantation is well-described; it is unknown if the relative balance of kidney compared with liver volumes within an institution relates to organ-specific outcomes. We assessed the association between relative balance within a transplant center and outcomes. METHODS: National retrospective analysis of isolated kidney and liver transplants in United States 2005-2014 followed through 2019. Latent class analysis defined transplant center phenotypes. Multivariate Cox models estimated death-censored graft loss and mortality. RESULTS: Latent class analysis identified four phenotypes: kidney only (n = 117), kidney dominant (n = 36), mixed/balanced (n = 90), and liver dominant (n = 13). Compared to mixed centers, the risk of kidney graft loss was higher at kidney-dominant (HR 1.07, p < .001) and liver-dominant (HR 1.10, p < .001) centers, while kidney-only (HR 1.06, p = .01) centers had higher mortality. Liver graft loss was not associated with phenotype, but risk of patient death was lower (HR 0.93, p = .02) at liver dominant and higher (HR 1.06, p = .02) at kidney-dominant centers. CONCLUSIONS: A mixed phenotype was associated with improved kidney transplant outcomes, whereas liver transplant outcomes were best at liver-dominant centers. While these findings need to be verified with center-level resources, optimization of shared resources could improve patient and organ outcomes.

Noncirrhotic hyperammonemia after deceased donor kidney transplantation: A case report.

A 72-year-old woman with end-stage kidney disease due to recurrent urinary tract infections and obstructive uropathy of a solitary kidney presented to our hospital for renal transplantation. She underwent successful transplantation of a deceased donor allograft, but developed acute mental status deterioration on the fifth postoperative day. Her serum ammonia was found to be markedly elevated to 447 µmol/L in the setting of normal hepatic function. She was treated with emergent dialysis and empiric antibiotics targeting urea-splitting organisms, and ultimately made a full neurologic recovery with stable renal allograft function. Noncirrhotic hyperammonemia (NCH) is an exceedingly rare clinical entity but seems to have a predilection for patients who have undergone solid organ transplantation. This report emphasizes the importance of rapid diagnosis and initiation of treatment for NCH, which is associated with a high rate of mortality and irreversible neurological morbidity. We outline the successful workup and management approach for this patient.

Hand-assisted laparoscopic retroperitoneal donor nephrectomy: A single-institution experience of over 500 cases-Operative technique and clinical outcomes.

OBJECTIVE: Although there are several variations of laparoscopic living-donor nephrectomies, there is no consensus as to the best technique. Our objective was to describe our technique and assess the outcomes of our approach to hand-assisted laparoscopic retroperitoneal donor nephrectomies. METHODS: From July 2001 to October 2015, 507 consecutive hand-assisted laparoscopic retroperitoneal donor nephrectomies were performed. Their clinical information was retrospectively reviewed including warm ischemia time, skin incision to kidney ready time, estimated blood loss, adverse intraoperative events, and postoperative complications. RESULTS: Mean incision time to kidney removal was 135 minutes (55-260), mean warm ischemia time was 125 seconds (30-390), and mean blood loss was 83 mL (20-500). Average length of stay was 3 days (1-6). There were no significant differences between left and right kidney donors based on demographics, length of hospital stay, or warm ischemia time. There were no conversions to open surgery. Complications occurred in 4.9% of patients (25/507), including 4 cases of perioperative bleeding. CONCLUSIONS: This is a single-center series describing the safety and efficacy of the hand-assisted laparoscopic retroperitoneal donor nephrectomy for both right and left sides. It does not require intraperitoneal manipulation and allows for safe extraction of either kidney with minimal warm ischemia time.

Human vascular progenitor cells derived from renal arteries are endothelial-like and assist in the repair of injured renal capillary networks.

Vascular progenitor cells show promise for the treatment of microvasculature endothelial injury. We investigated the function of renal artery progenitor cells derived from radical nephrectomy patients, in animal models of acute ischemic and hyperperfusion injuries. Present in human adventitia, CD34positive/CD105negative cells were clonal and expressed transcription factors Sox2/Oct4 as well as surface markers CXCR4 (CD184)/KDR(CD309) consistent with endothelial progenitor cells. Termed renal artery-derived vascular progenitor cells (RAPC), injected cells were associated with decreased serum creatinine after ischemia/reperfusion, reduced albuminuria after hyperperfusion, and improved blood flow in both models. A small population of RAPC integrated with the renal microvasculature following either experimental injury. At a cellular level, RAPC promoted local endothelial migration in co-culture. Profiling of RAPC microRNA identified high levels of miRNA 218; also found at high levels in exosomes isolated from RAPC conditioned media after cell contact for 24 hours. After hydrogen peroxide-induced endothelial injury, RAPC exosomes harbored Robo-1 transcript; a gene known to be regulated by mir218. Such exosomes enhanced endothelial cell migration in culture in the absence of RAPC. Thus, our work shows the feasibility of pre-emptive pro-angiogenic progenitor cell procurement from a targeted patient population and potential therapeutic use in the form of autologous cell transplantation.

Ferumoxytol-Enhanced Magnetic Resonance Imaging in Late-Stage CKD.

Ferumoxytol is a superparamagnetic iron oxide particle encapsulated by a semisynthetic carbohydrate with properties that can be used by the nephrologist for diagnosis and therapy. Ferumoxytol is approved by the US Food and Drug Administration for treating iron deficiency anemia in the setting of chronic kidney disease, but not for clinical diagnostic imaging. It has gained appeal as a magnetic resonance imaging contrast agent in patients with estimated glomerular filtration rates < 30mL/min/1.73m(2) in whom gadolinium-based contrast magnetic resonance imaging agents are relatively contraindicated because of the association with gadolinium deposition and nephrogenic systemic fibrosis. Ferumoxytol metabolism is not dependent on kidney function, but rather is removed from the circulation by the reticuloendothelial system of the liver, spleen, and bone marrow. Additionally, the prolonged intravascular half-life (>14 hours) of ferumoxytol allows for longer image acquisition and repeat imaging, if necessary. In patients with contraindications for gadolinium contrast agents, ferumoxytol is an alternative agent for vascular assessment, including patency and course.

Comprehensive comparative study of computed tomography-based estimates of split renal function for potential renal donors: modified ellipsoid method and other CT-based methods.

OBJECTIVE: To investigate a new modified computed tomographic (CT) ellipsoid method of split renal function and to compare results from this method with other CT-derived metrics. METHODS: Thirty-eight potential renal donors with both CT and nuclear renography were retrospectively evaluated for estimated split function using 6 CT methods to determine accuracy. For the CT methods, correlation, reproducibility, ease in image post-processing, and the ability of CT-derived methods to determine the dominant kidney before renal transplantation were evaluated using a nuclear renography reference standard. RESULTS: Four of the 6 CT methods (split renal volume, modified ellipsoid method, parenchymal area, attenuation capacity) showed similar strong correlation (r = 0.84-0.79). Bland-Altman analysis revealed similar performance in differences (SDs <3.0%) between those CT measures and reference standard, as well as good interobserver agreement for the modified ellipsoid and parenchymal area methods. The technically simpler methods had inferior performance. Post-processing time for the modified ellipsoid method was significantly shorter than semiautomated split renal volume or parenchymal area method (P < 0.01). Each CT-based method showed excellent agreement (100% or 97.4%) with renography regarding the determination of dominant kidney. CONCLUSIONS: Excellent correlation with nuclear split renal function supports the use of CT alone for the imaging assessment for many potential renal donors, including the decision of which kidney to harvest. Among the CT-based methods, the modified ellipsoid method can be performed rapidly with high accuracy and reproducibility.

Racial and ethnic disparities in kidney transplantation.

Success of renal transplantation, as a viable alternative to dialysis, has been tempered by long-standing racial disparities. Ethnic minorities have less access to transplantation, are less likely to be listed for transplantation, and experience a higher rate of graft failure. Reasons for the existing racial disparities at various stages of the transplantation process are complex and multi-factorial. They include a combination of behavioral, social, environmental, and occupational factors, as well as potential intended or unintended discrimination within the healthcare system. Immunologic factors such as human leukocyte antigen matching, composition of the organ donor pool, and patient immune response, all of which affect post-transplantation graft rejection rates and patient survival, also contribute to health disparities between ethnic groups.

Single graft loss in dual renal transplant recipients: impact of graft placement on recipient outcomes.

We aimed to assess the impact of graft placement in dual renal transplantation on the risk for single graft loss and to report recipient outcomes. Between 2004 and 2007, 55 dual renal transplants were performed at our institution. Allografts were placed bilaterally (one in each iliac fossa) in 42 patients and unilaterally (both in the same iliac fossa) in 14 patients. Nine recipients (16.4%) underwent explantation of a single graft as a consequence of vascular thrombosis designated as the SINGLE group, whereas 46 had two functional allografts (DUAL group). There was a higher rate of graft loss in case of unilateral placement (n = 5/14) compared with bilateral placement (n = 4/41) (35.7% vs. 9.8%, P = 0.035). One-year glomerular filtration rate was significantly lower in the SINGLE group (29.4 ml/min/1.73 m(2) vs. 49.4 ml/min/1.73 m(2) in the DUAL group, P < 0.05). Significantly, none of the nine recipients of the SINGLE group returned to dialysis with a mean follow-up of 34.1 months. Graft survival at 1 year was 100% and 97.9% in SINGLE and DUAL groups, respectively. Unilateral placement of both allografts is associated with an increased risk of single graft loss and therefore lower renal function at 1 year. However, this strategy is safe in selected indications.

The combination of donor and recipient age is critical in determining host immunoresponsiveness and renal transplant outcome.

OBJECTIVE: To evaluate the interaction of donor and recipient age on transplant outcome and immune response. SUMMARY BACKGROUND DATA: The age of donor and recipient is becoming increasingly important in organ transplantation. We tested the relevance and consequences of recipient and donor age on immunoresponsiveness and transplant outcome in a uni- and multilateral cohort analysis. METHODS: We obtained and analyzed data from 108,188 recipients of deceased donor kidneys of the United Network for Organ Sharing database transplanted between 1995 and 2008. Univariate analysis of allograft and patient survival was calculated by Kaplan Meyer. Multivariate analyses were performed using the Cox Proportional Hazards method. Data were assessed and compared by decades of increasing donor and recipient age with and without censoring transplant loss for death with a functioning graft. This approach allowed a detailed analysis of interacting factors. RESULTS: Transplant survival was lowest in elderly recipients. However, when the analysis was censored for patient's death with a functioning kidney transplant, survival improved incrementally with each decade of increasing recipient age. This was even more surprising as older recipients had received less well-matched organs of poorer quality. The frequency of acute rejection decreased dramatically with increasing age, emphasizing the effect of age on the vigor of the recipient's immune responses. In contrast, increasing donor age was associated with more frequent acute rejection rates. The effects of donor and recipient age in combination demonstrated that grafts of older donors fared significantly better in older recipients. CONCLUSIONS: Our results show that increasing recipient age is associated with an improved transplant survival, lower rates of rejection, and superior outcome of older donor organs. Physiological and/or immunologic aspects of organ and recipient age seem to determine, at least in part, the success of renal transplantation.

Analysis of infusion-site reactions in renal transplant recipients receiving peripherally administered rabbit antithymocyte globulin as compared with basiliximab.

Antithymocyte globulin rabbit (r-ATG) has been used for the treatment and prevention of acute rejection in renal transplant recipients (RTR). Current manufacturer recommendations for r-ATG dictate the need for administration through a high-flow vein (central line). Previous studies have shown peripheral administration of r-ATG to be safe; however, these studies suggest the co-administration of heparin and hydrocortisone and did not compare the infusion-site reaction rates to a control group. A retrospective analysis was conducted of adult RTR receiving r-ATG or basiliximab between January 2004 and October 2006. Each agent was administered through a dedicated peripheral line. The primary endpoint was the incidence of infusion-site reactions. Other endpoints included the need to replace the intravenous catheter and the incidence of systemic thrombosis within 1 month of transplantation. During the study period, 152 peripheral infusions of r-ATG and 92 peripheral infusions of basiliximab were administered. No difference in infusion-site reactions was noted between the groups. There was also no difference either in the need for peripheral line replacement or the rates of systemic thrombosis. Peripheral administration of r-ATG is safe and can be infused without concomitant heparin and hydrocortisone. This method of r-ATG infusion was shown to be as safe as peripherally administered basiliximab.

Renal transplantation in patients with positive lymphocytotoxicity crossmatches: one center's experience.

BACKGROUND: Sensitization to human leukocyte antigens remains an important barrier to successful renal transplantation. MATERIALS AND METHODS: Herein we describe our center's experience with a plasmapheresis-based desensitization protocol for highly sensitized patients. Twenty-nine patients had a positive T-cell or positive B-cell lymphocytotoxicity crossmatch against their donors. In some cases, baseline crossmatches were of high titer (e.g., 11 had baseline titers > or =1:32). RESULTS: Twenty-eight of 29 patients were rendered T-cell crossmatch negative and B-cell crossmatch negative/low positive and transplanted. None had hyperacute rejection but 11 (39%) had acute antibody mediated rejection. Median follow-up is 22 months: 25 of the 28 (89%) of allografts are still functioning with mean plasma creatinine 1.5 mg/dL. There was one death because of the transplant or immunsuppression, one case of cytomegalovirus disease and no cases of lymphoproliferative disease. CONCLUSION: This series provides further evidence of the high efficacy of plasmapheresis-based desensitization protocols. Even patients with high baseline crossmatch titers can be successfully desensitized and transplanted. Short- and medium-term outcomes are encouraging but longer-term data are needed.

Donor postextubation hypotension and age correlate with outcome after donation after cardiac death transplantation.

BACKGROUND: Compared with standard donors, kidneys recovered from donors after cardiac death (DCD) exhibit higher rates of delayed graft function (DGF), and DCD livers demonstrate higher rates of biliary ischemia, graft loss, and worse patient survival. Current practice limits the use of these organs based on time from donor extubation to asystole, but data to support this is incomplete. We hypothesized that donor postextubation parameters, including duration and severity of hemodynamic instability or hypoxia might be a better predictor of subsequent graft function. METHODS: We performed a retrospective examination of the New England Organ Bank DCD database, concentrating on donor factors including vital signs after withdrawal of support. RESULTS: Prolonged, severe hypotension in the postextubation period was a better predictor of subsequent organ function that time from extubation to asystole. For DCD kidneys, this manifested as a trend toward increased DGF. For DCD livers, this manifested as increased rates of poor outcomes. Maximizing the predictive value of this test in the liver cohort suggested that greater than 15 min between the time when the donor systolic blood pressure drops below 50 mm Hg and flush correlates with increased rates of diffuse biliary ischemia, graft loss, or death. Donor age also correlated with worse outcome. CONCLUSIONS: Time between profound instability and cold perfusion is a better predictor of outcome than time from extubation to asystole. If validated, this information could be used to predict DGF after DCD renal transplant and improve outcomes after DCD liver transplant.

C4d positivity is often associated with acute cellular rejection in renal transplant biopsies following Campath-1H (Alemtuzumab) induction.

Peritubular capillary C4d positivity, a marker for antibody-mediated rejection, is observed in approximately 20-50% of indicated renal transplant biopsies and in just 2% of unremarkable protocol biopsies. However, C4d staining has not been evaluated in protocol renal biopsies from patients with Campath-1H induction treatment, and the association between various types of inflammatory cells and acute antibody-mediated rejection is unclear. This study investigated the rates of C4d positivity in unremarkable protocol renal biopsies, biopsies with acute tubular necrosis (ATN), and biopsies with acute cellular rejection (ACR), all following Campath-1H treatment and post-operative immunosuppression. There was low positivity of C4d staining in both the protocol and ATN groups, but the ACR group had a 47.2% rate of positivity (combining focal and diffuse positive cases). Since Campath-1H treatment caused significant depletion of circulating lymphocytes but not circulating monocytes in renal recipients, this study also investigated the role of monocytes in humoral rejection. In ACR cases, CD68 positive monocytes were composed of 59.4 +/- 4.69% inflammatory cells, which was significantly higher than CD3 positive lymphocytes (38.9 +/- 4.4%). Co-localization of positive C4d staining in endothelium and marginating CD68 positive monocytes was illustrated by double staining. Our data indicate that acute antibody-mediated rejection occurs much more frequently in renal transplants with ACR. Moreover, the high percentage of monocytes observed in ACR cases (due to monocytes being less sensitive to Campath-1H depletion) suggests that monocytes are involved in antibody-mediated rejection.

Campath-1H induction and the incidence of infectious complications in adult renal transplantation.

BACKGROUND: The purpose of this study was to evaluate adult renal transplantation patients who received a alemtuzumab (Campath-1H)-based induction protocol for the incidence of infectious complications. METHODS: We began using 30 mg Campath-1H intravenously for induction therapy in May 2003. The patients were treated with a maintenance regimen of tacrolimus or mycophenolate mofetil (MMF), and rapidly tapered prednisone; valganciclovir was used for CMV prophylaxis. Forty-nine adult patients who received renal transplants between May 1, 2003 and June 7, 2004 were included. The mean follow-up time was 13.7 months with a range of 10-24 months. Data were collected via a retrospective chart review. RESULTS: The infectious complications noted in the Campath-1H group were compared with a historical group of 56 patients receiving conventional immunosuppression. There was one case of cytomegalovirus (CMV) viremia and two cases of CMV disease (one pneumonitis and one enteritis). There were four cases of urinary tract infection and one extremity cellulitis. One patient developed Cryptococcal meningitis. Eight of the 49 (16%) patients in the Campath group had an infectious complication, compared to 18 out of 56 (32%) in the historical group. CONCLUSION: Campath-1H induction for renal transplantation appears to have a low incidence of associated infectious complications when compared to historical regimens.

Chronic active thrombotic microangiopathy in native and transplanted kidneys.

We report 2 complicated cases of thrombotic microangiopathy with chronic features and active components. The first case was a 36-yr-old woman with positive anti-DNA antibody and possible lupus cerebritis, who developed thrombotic microangiopathy secondary to a series of syndromes, including preeclampsia and anti-phospholipid antibody syndrome. Renal biopsy revealed no evidence of lupus nephritis and her renal function returned to normal 1 week after the biopsy. The second case was a 46-yr-old man who developed thrombotic microangiopathy of unknown etiology, which led to end-stage renal disease within 6 mo. The patient received a living related-donor transplant, but thrombotic microangiopathy recurred in the donor kidney only 40 days after the renal transplantation.

Monocyte-mediated acute renal rejection after combined treatment with preoperative Campath-1H (alemtuzumab) and postoperative immunosuppression.

Campath-1H (alemtuzumab), a humanized monoclonal antibody against CD52, can cause more profound depletion of lymphocytes than monocytes. The resultant imbalance of lymphocytes and monocytes after Campath-1H treatment of a renal-transplant recipient may lead to an acute rejection dominated by monocytes. We report such a case of acute transplant rejection in a 49-yr-old man who received a living non-related kidney transplant and was treated with preoperative Campath-1H and postoperative immunosuppression. An initial post-transplant renal biopsy showed diffuse mild acute rejection with 95% CD68-positive monocytes, but only 5% CD3-positive T lymphocytes. Inflammatory cells in the renal biopsy were negative for CD34 and CD1a stains, suggesting non-involvement of CD34-derived dendritic cells in the acute rejection. After steroid treatment for 2 wk, the patient's serum creatinine concentration diminished to 1.5 mg/dl. The histopathological features of acute rejection were absent in a second biopsy of the transplanted kidney. In summary, this case is an instance of monocyte-mediated acute rejection of a transplanted kidney.

The combined risk of donor quality and recipient age: higher-quality kidneys may not always improve patient and graft survival.

BACKGROUND: The Kidney Donor Profile Index (KDPI) is a more precise donor organ quality metric replacing age-based characterization of donor risk. Little prior attention has been paid on the outcomes of lower-quality kidneys transplanted into elderly recipients. Although we have previously shown that immunological risks associated with older organs are attenuated by advanced recipient age, it remains unknown whether risks associated with lower-quality KDPI organs are similarly reduced in older recipients. METHODS: Donor organ quality as measured by the KDPI was divided into quintiles (very high, high, medium, low, and very low quality), and Cox proportional hazards was used to assess graft and recipient survival in first-time adult deceased donor transplant recipients by recipient age. RESULTS: In uncensored graft survival analysis, recipients older than 69 years had demonstrated comparable outcomes if they received low-quality kidneys compared to medium-quality kidneys. Death-censored analysis demonstrated no increased relative risk when low-quality kidneys were transplanted into recipients aged 70 to 79 years (hazard ratio [HR], 1.11; P=0.19) or older than 79 years (HR, 1.08; P=0.59). In overall survival analysis, elderly recipients gained no relative benefit from medium-quality kidneys over low-quality kidneys (70-79 years: HR, 1.03, P=0.51; >79 years: HR, 1.08; P=0.32). CONCLUSION: Our analysis demonstrates that transplanting medium-quality kidneys into elderly recipients does not provide significant advantage over low-quality kidneys.