Umar Farooq

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.

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 donors 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.

Liver bioengineering: Current status and future perspectives

The present review aims to illustrate the strategies that are being implemented to regenerate or bioengineer livers for clinical purposes. There are two general pathways to liver bioengineering and regeneration. The first consists of creating a supporting scaffold, either synthetically or by decellularization of human or animal organs, and seeding cells on the scaffold, where they will mature either in bioreactors or in vivo. This strategy seems to offer the quickest route to clinical translation, as demonstrated by the development of liver organoids from rodent livers which were repopulated with organ specific cells of animal and/or human origin. Liver bioengineering has potential for transplantation and for toxicity testing during preclinical drug development. The second possibility is to induce liver regeneration of dead or resected tissue by manipulating cell pathways. In fact, it is well known that the liver has peculiar regenerative potential which allows hepatocyte hyperplasia after amputation of liver volume. Infusion of autologous bone marrow cells, which aids in liver regeneration, into patients was shown to be safe and to improve their clinical condition, but the specific cells responsible for liver regeneration have not yet been determined and the underlying mechanisms remain largely unknown. A complete understanding of the cell pathways and dynamics and of the functioning of liver stem cell niche is necessary for the clinical translation of regenerative medicine strategies. As well, it will be crucial to elucidate the mechanisms through which cells interact with the extracellular matrix, and how this latter supports and drives cell fate.

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.

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 m2 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.

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

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.

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

We performed a retrospective single‐center review of 884 deceased donor (DD) kidney transplants (KTs) in patients (pts) aged ≥40 yr.