Dual kidney transplants from adult marginal donors successfully expand the limited deceased donor organ pool.

BACKGROUND: The need to expand the organ donor pool remains a formidable challenge in kidney transplantation (KT). The use of expanded criteria donors (ECDs) represents one approach, but kidney discard rates are high because of concerns regarding overall quality. Dual KT (DKT) may reduce organ discard and optimize the use of kidneys from marginal donors. STUDY DESIGN: We conducted a single-center retrospective review of outcomes in adult recipients of DKTs from adult marginal deceased donors (DD) defined by limited renal functional capacity. If the calculated creatinine clearance in an adult DD was <65 mL/min, then the kidneys were transplanted as a DKT. RESULTS: Over 11.5 yr, 72 DKTS were performed including 45 from ECDs, 17 from donation after cardiac death (DCD) donors, and 10 from standard criteria donors (SCD). Mean adult DD and recipient ages were both 60 yr, including 29 DDs and 26 recipients ≥65 yr of age. Mean pre-DKT waiting and dialysis vintage times were 12 months and 25 months, respectively. Actual patient and graft survival rates were 84.7% and 70.8%, respectively, with a mean follow-up of 58 months. One yr and death-censored graft survival rates were 90% and 80%, respectively. Outcomes did not differ by DD category, recipient age, or presence of delayed graft function (DGF). Eleven patients died at a mean of 32 months post-DKT (eight with functioning grafts) and 13 other patients experienced graft losses at a mean of 33 months. The incidence of DGF was 25%; there were two cases (2.8%) of primary non-function. Mean length of initial hospital stay was 7.2 d. Mean serum creatinine and glomerular filtration rate levels at 12 and 24 months were 1.5 and 53 and 1.5 mg/dL and 51 mL/min/1.73 m(2) , respectively. DKT graft survival and function were superior to concurrent single ECD and similar to concurrent SCD KTs. Two patients underwent successful kidney retransplantation, so the dialysis-free rate in surviving patients was 87%. The proportion of total renal function transplanted from adult DD to DKT recipients was 77% compared to 56% for patients receiving single KTs. CONCLUSIONS: Dual kidney transplantation using kidneys from adult marginal DDs that otherwise might be discarded offer a viable option to counteract the growing shortage of acceptable single kidneys. Excellent medium-term outcomes can be achieved and waiting times can be reduced in a predominantly older recipient population.

Pancreas transplantation with portal venous drainage with an emphasis on technical aspects.

Advances in surgical techniques and clinical immunosuppression have led to improving results in vascularized pancreas transplantation. Most pancreas transplants are performed with enteric exocrine drainage and systemic venous delivery of insulin (systemic-enteric technique) although bladder drainage (systemic-bladder technique) remains a viable option. To improve the physiology of pancreas transplantation, an innovative technique of portal venous delivery of insulin and enteric drainage of the exocrine secretions (portal-enteric technique) was developed and refined over the past 27 yr. However, the potential of portal-enteric pancreas transplantation has never been fully realized as it is currently performed in only 18% of simultaneous pancreas-kidney/sequential pancreas after kidney and 10% of pancreas-alone transplants with enteric drainage. A number of studies have demonstrated no major or consistent differences in outcomes for bladder-drained or enteric-drained pancreas transplants with either portal or systemic venous drainage although some studies suggest purported metabolic and immunologic advantages associated with portal venous delivery of insulin. The purpose of this study is to review the existing literature on portal-enteric pancreas transplantation with an emphasis on surgical aspects and technical modifications/nuances that have been introduced with time and experience.

Influence of recipient age on deceased donor kidney transplant outcomes in the expanded criteria donor era.

METHODS: We performed a retrospective single-center review of 884 deceased donor (DD) kidney transplants (KTs) in patients (pts) aged ≥40 yr. RESULTS: One hundred and four (11.8%) pts were ≥70 (mean 74), 286 (32.3%) were 60-69 (mean 64), and 494 (55.9%) were 40-59 (mean 51) yr of age; the proportion receiving expanded criteria donor (ECD) kidneys were 66%, 49%, and 30%, respectively (p < 0.001). Mean waiting time (15 months) was shorter for pts ≥70 yr compared to the other two groups combined (23 months, p = 0.002). With mean follow-up ranging from 54 to 70 months, actual pt (81% vs. 72%, p = 0.002) and graft (66% vs. 58.5%, p = 0.03) survival rates were higher in the younger compared to the two older groups, whereas death-censored graft survival was similar (76% vs. 73%, p = NS). The incidence of death with a functioning graft correlated with older recipient age group, increasing from 13% to 18% to 23% (p = 0.01). The incidence of delayed graft function was similar (31.8% overall), and renal function, morbidity, and resource utilization were similar among groups. CONCLUSIONS: By directing ECD kidneys to selected older pts, waiting times are reduced and censored survival outcomes are similar to middle-aged patients, suggesting that matching strategies for graft and patient lifespan are warranted.

Extramedullary Waldenström Macroglobulinemia Presenting as a Subcutaneous Penile Mass.

Primary penile malignancy is a rare occurrence in the United States, with squamous carcinoma being the most common aetiology. Non-squamous penile cancers are scarcely reported in the literature. We present a unique case of a 65-year-old male with a history of Waldenström macroglobulinemia (WM) previously in remission complaining of a painless subcutaneous bump on the base of the penis. Biopsy with histological and immunohistochemical analysis confirmed the recurrence of WM. This novel case illustrates an unusual presentation of the disease after being successfully managed with chemotherapy and immunotherapy in an asymptomatic individual. There is only another reported case in the literature of a patient with a similar presentation. We highlight the clinical features and presentation of this condition, including a consensus for the approach and management of non-Hodgkin's lymphomas of the penis.

Modeling African American prostate adenocarcinoma by inducing defined genetic alterations in organoids.

Genomic studies are rapidly identifying genetic alterations in human cancer, but functional validation of such alterations has been slow. Here, using human prostate cancer as a model, we have assessed the feasibility of engineering defined genetic alterations in well-known cancer driver genes to transform benign prostate epithelial organoids derived from African American men. Benign human prostate organoids were transduced with lentiviruses expressing MYC, shPTEN, shTP53 and AR, alone and in various combinations, to recapitulate prostate cancer development. Organoids expressing MYC, shPTEN, shTP53 and AR (denoted MPPA); MYC, shPTEN and shTP53 (MPP); or MYC (M) were significantly larger, had higher proliferation rates and demonstrated pathologically transformed morphology compared to organoids transduced with control lentivirus. Alterations in MYC, PTEN and TP53 also affected the rate of organoid basal-to-luminal differentiation in vitro. MPPA and MPP organoids expressed the clinical prostate cancer marker AMACR and developed prostate adenocarcinoma when grafted under the renal capsule in mice. These data indicate that genetic alterations commonly observed in human prostate cancer can be rapidly modeled in human organoid culture. Prostate cancer organoids provide a useful pre-clinical model for the evaluation of new candidate cancer genes, cancer disparities, and potentially for testing of novel therapeutic agents.

Single vs dual (en bloc) kidney transplants from donors ≤ 5 years of age: A single center experience.

AIM: To compare outcomes between single and dual en bloc (EB) kidney transplants (KT) from small pediatric donors. METHODS: Monocentric nonprospective review of KTs from pediatric donors ≤ 5 years of age. Dual EB KT was defined as keeping both donor kidneys attached to the inferior vena cava and aorta, which were then used as venous and arterial conduits for the subsequent transplant into a single recipient. Donor age was less useful than either donor weight or kidney size in decision-making for kidney utilization as kidneys from donors < 8 kg or kidneys < 6 cm in length were not transplanted. Post-transplant management strategies were standardized in all patients. RESULTS: From 2002-2015, 59 KTs were performed including 34 dual EB and 25 single KTs. Mean age of donors (17 mo vs 38 mo, P < 0.001), mean weight (11.0 kg vs 17.4 kg, P = 0.046) and male donors (50% vs 84%, P = 0.01) were lower in the dual EB compared to the single KT group, respectively. Mean cold ischemia time (21 h), kidney donor profile index (KDPI; 73% vs 62%) and levels of serum creatinine (SCr, 0.37 mg/dL vs 0.49 mg/dL, all P = NS) were comparable in the dual EB and single KT groups, respectively. Actuarial graft and patient survival rates at 5-years follow-up were comparable. There was one case of thrombosis resulting in graft loss in each group. Delayed graft function incidence (12% dual EB vs 20% single KT, P = NS) was slightly lower in dual EB KT recipients. Initial duration of hospital stay (mean 5.4 d vs 5.6 d) and the one-year incidences of acute rejection (6% vs 16%), operative complications (3% vs 4%), and major infection were comparable in the dual EB and single KT groups, respectively (all P = NS). Mean 12 mo SCr and abbreviated MDRD levels were 1.17 mg/dL vs 1.35 mg/dL and 72.5 mL/min per 1.73 m(2) vs 60.5 mL/min per 1.73 m(2) (both P = NS) in the dual EB and single KT groups, respectively. CONCLUSION: By transplanting kidneys from young pediatric donors into adult recipients, one can effectively expand the limited donor pool and achieve excellent medium-term outcomes.

Depleting antibody induction in simultaneous pancreas-kidney transplantation: a prospective single-center comparison of alemtuzumab versus rabbit anti-thymocyte globulin.

BACKGROUND: The study purpose was to analyze midterm outcomes in a prospective trial of alemtuzumab (Alem) versus rabbit anti-thymocyte globulin (rATG) induction in simultaneous pancreas-kidney transplantation (SPKT). METHODS: From February 2005 to October 2008, 46 SPKTs (45 portal-enteric drainage) were prospectively randomized as part of a larger kidney transplant study to receive either single-dose Alem (30 mg intraoperatively) or multiple-dose rATG antibody induction (starting intraoperatively, minimum three doses administered) with tacrolimus/mycophenolate ± steroids. RESULTS: Of 222 kidney transplant patients enrolled in the study, 46 received SPKTs; 28 (61%) received Alem and 18 (39%) rATG induction. Follow-up ranged from 67 to 111 months (mean 80 months). There were no significant differences between the two groups in 5 years actual patient (86% Alem vs 89% rATG), kidney (82% Alem vs 61% rATG, p = 0.17) or pancreas (68% Alem vs 56% rATG) graft survival rates. Five years death-censored kidney (92% Alem vs 69% rATG, p = 0.09) and pancreas (76% Alem vs 56% rATG, p = 0.198) graft survival rates were slightly higher in patients receiving Alem. Acute rejection (21% Alem vs 44% rATG, p = 0.12) and major infection (39% Alem vs 67% rATG, p = 0.13) rates were slightly lower in the Alem group; cytomegalovirus infections were significantly lower (0 Alem vs 17% rATG, p = 0.05). The incidence of late acute rejection was low in both groups. There were no differences in early pancreas thrombosis (3.6% Alem vs 11% rATG), postoperative bleeding (11% Alem vs 0 rATG), other surgical complications, readmissions or freedom from steroids between groups. In patients with functioning grafts, 5 years mean serum creatinine (1.4 Alem vs 1.6 mg/dl rATG), calculated abbreviated modification of diet in renal disease glomerular filtration rate (55 Alem vs 52 ml/min/1.73 m(2) rATG), hemoglobin A1c (both 5.4%) and C-peptide (2.6 Alem vs 2.3 ng/ml rATG) levels were similar. CONCLUSIONS: Single-dose Alem and multiple-dose rATG induction provide similar midterm patient survival and graft functional outcomes with no major differences in morbidity or resource utilization.

Evolving experience using kidneys from deceased donors with terminal acute kidney injury.

BACKGROUND: Kidney transplantation from deceased donors with terminal acute kidney injury (AKI) is not widely accepted. STUDY DESIGN: Acute kidney injury donor kidneys were defined by a doubling of the donor's admission serum creatinine (SCr) level and a terminal SCr level >2.0 mg/dL before organ recovery. RESULTS: Over 5.5 years, we transplanted 84 AKI donor kidneys, including 64 kidneys from standard criteria donors (SCD), 11 from expanded criteria donors (ECD), and 9 from donation after cardiac death (DCD) donors. Mean donor age was 36 years (range 15 to 68 years); mean admission and terminal donor SCr levels were 1.25 mg/dL and 3.2 mg/dL, respectively (mean terminal estimated glomerular filtration rate 25.5 mL/minute). With a mean follow-up of 35 months (range 6 to 70 months), actual patient and graft survival rates are 98% and 89%, respectively, which are numerically, but not statistically, higher than concurrent kidney transplants from brain-dead (non-AKI) SCDs at our center. Delayed graft function (DGF) occurred in 34 patients (40%). Mean 1-, 12-, and 24-month SCr levels were 1.8, 1.6, and 1.7 mg/dL, respectively. Delayed graft function was associated with lower 3-year graft survival for non-AKI SCD transplants (68% vs 90%, with and without DGF), but there was no impact of DGF on graft survival for AKI donor kidneys (89% vs 91%). CONCLUSIONS: Although AKI donor kidneys more commonly have DGF, the higher rate of DGF does not worsen graft outcomes. Kidneys from deceased donors with terminal AKI transplanted into appropriately selected patients have excellent medium-term outcomes and represent a method to safely expand the donor pool.

Regeneration and bioengineering of transplantable abdominal organs: current status and future challenges.

INTRODUCTION: The most critical issue to organ transplantation is the identification of new sources of organs. The present manuscript illustrates the state-of-the-art regenerative medicine (RM) investigations aiming to manufacturing abdominal organs for transplant purposes. AREAS COVERED: This manuscript focuses on research in the bioengineering and regeneration of kidneys, insulin-producing cells, livers and small bowel. The main technology currently under development exploits the seeding of cells on supporting scaffolding material. Despite favorable preliminary results obtained with relatively simple, hollow organs, when more complex organs are considered, the scenario changes dramatically. Investigations are still in early stages, and clinical translation is not yet foreseeable based on current knowledge and information. Obstacles are numerous but we believe the critical factor hampering success is lack of in-depth understanding of the extracellular matrix (ECM) and cell-ECM interactions, as well as the mechanisms with which organs develop in utero. EXPERT OPINION: The success of RM to generate transplantable abdominal organs relies heavily on progress in (stem) cell therapies, developmental and ECM biology, and in the thorough understanding of the intricate relationship and interplay between cells and the ECM. This will require enormous investments in financial and medical resources, which ideally should be embarked upon by governments, the private sector and academia.

Discarded human kidneys as a source of ECM scaffold for kidney regeneration technologies.

In the United States, more than 2600 kidneys are discarded annually, from the total number of kidneys procured for transplant. We hypothesized that this organ pool may be used as a platform for renal bioengineering and regeneration research. We previously showed that decellularization of porcine kidneys yields renal extracellular matrix (ECM) scaffolds that maintain their basic components, support cell growth and welfare in vitro and in vivo, and show an intact vasculature that, when such scaffolds are implanted in vivo, is able to sustain physiological blood pressure. The purpose of the current study was to test if the same strategy can be applied to discarded human kidneys in order to obtain human renal ECM scaffolds. The results show that the sodium dodecylsulfate-based decellularization protocol completely cleared the cellular compartment in these kidneys, while the innate ECM framework retained its architecture and biochemical properties. Samples of human renal ECM scaffolds stimulated angiogenesis in a chick chorioallantoic membrane assay. Importantly, the innate vascular network in the human renal ECM scaffolds retained its compliance. Collectively, these results indicate that discarded human kidneys are a suitable source of renal scaffolds and their use for tissue engineering applications may be more clinically applicable than kidneys derived from animals.