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of cellular transplants should mirror that of solid organ transplants and not be classified under the unsustainable, outdated model that requires licensing as a drug with the Food and Drug Administration.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.

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.

Expansion and somatic hypermutation of B-cell clones in rejected human kidney grafts.

BACKGROUND: B-cell infiltrates are common in rejected kidney allografts, yet their composition is still unclear. The aim of our study was to characterize the clonal composition of B-cell infiltrates of rejected human kidney grafts. METHODS: We used a molecular approach to characterize the partial B-cell repertoires of 5 failed human kidney grafts with detectable B-cell infiltrates. A comparison between the intragraft and blood repertoire was also conducted for 1 case. RESULTS: Redundant sequences were observed in both blood and graft, although the level of clonal amplification was significantly higher for the graft. Somatic hypermutations (SHMs) were also more frequent in sequences found in the graft compared to the blood. The rate of nonsilent mutations was significantly higher in complementarity determining regions (CDRs) compared to framework regions in blood sequences as well as in graft sequences found at low frequency. In contrast, this preferential distribution was lost in sequences found at high frequency in the graft, suggesting a lack of affinity maturation in situ. Lastly, follicular dendritic cells were undetectable in CD20 infiltrates in all samples examined. CONCLUSIONS: We provide here evidence that B-cell clones expand and undergo SHMs in situ. However, the even distribution of nonsilent SHM in high-frequency graft sequences together with the absence of follicular dendritic cells do not support the view that infiltrating B cells are part of functional germinal centers.

Long-term outcomes of kidney transplantation across a positive complement-dependent cytotoxicity crossmatch.

BACKGROUND: More than 30% of potential kidney transplant recipients have pre-existing anti-human leukocyte antigen antibodies. This subgroup has significantly lower transplant rates and increased mortality. Desensitization has become an important tool to overcome this immunological barrier. However, limited data is available regarding long-term outcomes, in particular for the highest risk group with a positive complement-dependent cytotoxicity crossmatch (CDC XM) before desensitization. METHODS: Between 2002 and 2010, 39 patients underwent living-kidney transplantation across a positive CDC XM against their donors at our center. The desensitization protocol involved pretransplant immunosuppression, plasmapheresis, and low-dose intravenous immunoglobulin±rituximab. Measured outcomes included patient survival, graft survival, renal function, rates of rejection, infection, and malignancy. RESULTS: The mean and median follow-up was 5.2 years. Patient survival was 95% at 1 year, 95% at 3 years, and 86% at 5 years. Death-censored graft survival was 94% at 1 year, 88% at 3 years, and 84% at 5 years. Uncensored graft survival was 87% at 1 year, 79% at 3 years, and 72% at 5 years. Twenty-four subjects (61%) developed acute antibody-mediated rejection of the allograft and one patient lost her graft because of hyperacute rejection. Infectious complications included pneumonia (17%), BK nephropathy (10%), and CMV disease (5%). Skin cancer was the most prevalent malignancy in 10% of patients. There were no cases of lymphoproliferative disorder. Mean serum creatinine was 1.7±1 mg/dL in functioning grafts at 5 years after transplantation. CONCLUSION: Despite high rates of early rejection, desensitization in living-kidney transplantation results in acceptable 5-year patient and graft survival rates.

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.

Induction treatment with rabbit antithymocyte globulin versus basiliximab in renal transplant recipients with planned early steroid withdrawal.

STUDY OBJECTIVE: To compare the safety and efficacy of rabbit antithymocyte globulin (r-ATG) with basiliximab in renal transplant recipients for whom an early steroid withdrawal (ESW) regimen was planned. DESIGN: Single-center, retrospective, cohort study. SETTING: Tertiary care medical center, including inpatient hospital stays and outpatient nephrology clinics. PATIENTS: Ninety-nine consecutive adult recipients of living- or deceased-donor renal transplants between January 1, 2004, and December 31, 2007, in whom ESW was planned and who received either r-ATG or basiliximab; patients receiving an extended-criteria kidney donation or a donation after cardiac death were excluded. MEASUREMENTS AND MAIN RESULTS: All patients received mycophenolate mofetil and tacrolimus as maintenance therapy with planned ESW. Induction therapy was either r-ATG 1.5 mg/kg/day for 4 days (68 patients) or basiliximab 20 mg on postoperative days 0 and 4 (31 patients). The primary composite end point of biopsy-proven acute rejection (BPAR), graft loss, and death occurred in 6 patients (9%) and 9 patients (29%) in the r-ATG and basiliximab groups at 1 year after transplantation, respectively (p=0.01), with rates of 7% (5/68 patients) and 26% (8/31 patients) for BPAR (p=0.02), 0% and 3% (1/31 patients) for graft loss (p=0.31), and 2% (1/68 patients) and 0% for patient death (p>0.99). Average time to first BPAR was significantly longer in the r-ATG group (mean ± SD 151.4 ± 82.9 vs 53.6 ± 68.4 days, p<0.01). Kidney function at 12 months was similar between the two groups. CONCLUSION: Rabbit-ATG was associated with a lower frequency and delayed onset of BPAR compared with basiliximab in renal transplant recipients who received an ESW regimen.

Longitudinal trends and influence of BMI mismatch in living kidney donors and their recipients.

BACKGROUND AND OBJECTIVES: Age and body mass index (BMI) of kidney donors and recipients affect kidney allograft outcomes. Moreover, while deceased donor and recipient body size mismatch have been reported to influence allograft outcomes, how BMI mismatch in living kidney donor-recipient pairs affect graft survival is not well defined. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: We investigated trends in characteristics of 90,815 US. living kidney donors and their recipients between 1987 and 2008. RESULTS: Median ages of donors and their recipients have risen over time, and the proportion of living donors age ≥ 50 years increased from 11 to 25%. Median BMI of recipients increased from 22.6 to 26.6 kg/m(2); median BMI of kidney donors for the past 5 years has been 26.4 kg/m(2). Only 35% of living donor-recipient pairs were in the same BMI category (<25, 25-29.9, 30-34.9, or ≥ 35 kg/m(2)). BMI mismatch where the living donor was three categories heavier than the recipient was associated with a significant adjusted risk for death-censored allograft loss (HR 2.31, 95% CI 1.05-5.08). CONCLUSIONS: Living kidney donors are donating at more advanced ages, and the majority are overweight or obese in recent years. In summary: (1) previous longitudinal studies of living kidney donor outcomes may not be generalizable to recent donors, and studies of contemporary living kidney donor cohorts may be informative, (2) the majority of living donor-recipient pairs have BMI mismatch, and (3) extreme BMI mismatch where the living donor is heavier may confer an independent risk for allograft loss.

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.

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.

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.

Evaluation of fluoroquinolones for the prevention of BK viremia after renal transplantation.

BACKGROUND AND OBJECTIVES: Nearly 30% of renal transplant recipients develops BK viremia, a prerequisite for BK nephropathy. Case reports have evaluated treatment options for BK virus, but no controlled studies have assessed prophylactic therapies. Fluoroquinolone antibiotics were studied for prevention of BK viremia after renal transplantation. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This retrospective analysis evaluated adult renal transplant recipients with at least one BK viral load (blood) between 90 and 400 days after transplantation. Six to 12 months of co-trimoxazole was used for Pneumocystis prophylaxis. In sulfa-allergic/-intolerant patients, 6 to 12 months of atovaquone with 1 month of a fluoroquinolone was used. Fluoroquinolones can inhibit BK DNA topoisomerase. The two groups studied were those that received 30 days of levofloxacin or ciprofloxacin after transplantation and those that did not. The primary endpoint was BK viremia rates at 1 year. Of note, of the 160 patients not receiving fluoroquinolone prophylaxis, 40 received a fluoroquinolone for treatment of a bacterial infection within 3 months after transplantation. Subgroup analysis evaluating these 40 patients against the 120 who had no exposure to fluoroquinolones was completed. RESULTS: A 1-month fluoroquinolone course after transplantation was associated with significantly lower rates of BK viremia at 1 year compared with those with no fluoroquinolone. In the subgroup analysis, exposure to fluoroquinolone for treatment of bacterial infections within 3 months after transplantation was associated with significantly lower 1-year rates of BK viremia. CONCLUSIONS: This analysis demonstrates that fluoroquinolones are effective at preventing BK viremia after renal transplantation.