Tayyab S. Diwan

Terminal complement inhibition decreases antibody-mediated rejection in sensitized renal transplant recipients.

Sensitized renal transplant recipients with high levels of donor‐specific alloantibody (DSA) commonly develop antibody‐mediated rejection (AMR), which may cause acute graft loss or shorten allograft survival. We examined the efficacy of terminal complement inhibition with the humanized anti‐C5 antibody, eculizumab, in the prevention AMR in renal transplant recipients with a positive crossmatch against their living donor. The incidence of biopsy‐proven AMR in the first 3 months posttransplant in 26 highly sensitized recipients of living donor renal transplants who received eculizumab posttransplant was compared to a historical control group of 51 sensitized patients treated with a similar plasma exchange (PE)‐based protocol without eculizumab. The incidence of AMR was 7.7% (2/26) in the eculizumab group compared to 41.2% (21/51) in the control group (p = 0.0031). Eculizumab also decreased AMR in patients who developed high levels of DSA early after transplantation that caused proximal complement activation. With eculizumab, AMR episodes were easily treated with PE reducing the need for splenectomy. On 1‐year protocol biopsy, transplant glomerulopathy was found to be present in 6.7% (1/15) eculizumab‐treated recipients and in 35.7% (15/42) of control patients (p = 0.044). Inhibition of terminal complement activation with eculizumab decreases the incidence of early AMR in sensitized renal transplant recipients (ClincalTrials.gov number NCT006707).

The impact of proteasome inhibition on alloantibody-producing plasma cells in vivo.

Background. Donor specific alloantibody producing plasma cells (DSA-PCs) appear resistant to conventional immunosuppressive agents. This study aimed to determine the impact of pretransplant monotherapy with the proteasome inhibitor bortezomib on DSA-PCs in sensitized renal allograft candidates and to assess if DSA-PC depletion would enhance the efficacy of DSA removal using plasma exchange (PE). Methods. Only patients with DSA levels considered too high to successfully undergo transplantation with PE alone were included in this study: i.e. those with a baseline B flow cytometric crossmatch (BFXM) >450 against a potential living donor. Four sensitized patients received 4 doses (1.3 mg/m2/dose) of bortezomib and 4 received 16 doses. The number of DSA-PCs was determined pre and post-treatment using an ELISPOT assay. Five of these patients underwent post-treatment PE and their response was compared to 8 highly-sensitized patients (BFXM >450) who underwent PE alone. Results. When considering all 8 patients as one group, bortezomib treatment decreased DSA-PCs in the marrow (mean±SD=16.7±14.5 DSA-PCs/ml pre-treatment vs. 6.2±3.6 DSA-PCs/ml after treatment, P=0.048). In the time frame of the study, bortezomib alone did not decrease serum DSA levels. However, five bortezomib treated patients underwent PE and showed a greater decease in DSA compared to the historical control group of 8 sensitized patients who underwent PE alone (mean decrease in BFXM channel shift=272.6±92.1 with bortezomib vs 95.4±72.2 in PE alone P=0.008). Conclusions. Bortezomib depletes DSA-PCs and appears to potentiate DSA removal by PE in sensitized renal transplant recipients.

Impact of recipient morbid obesity on outcomes after liver transplantation

The aim of this study was to analyze the impact of morbid obesity in recipients on peritransplant resource utilization and survival outcomes. Using a linkage between the University HealthSystem Consortium and Scientific Registry of Transplant Recipients databases, we identified 12 445 patients who underwent liver transplantation (LT) between 2007 and 2011 and divided them into two cohorts based on recipient body mass index (BMI; <40 vs. ≥40 kg/m²). Recipients with BMI ≥40 comprised 3.3% (n = 416) of all LTs in the studied population. There were no significant differences in donor characteristics between two groups. Recipients with BMI ≥40 were significant for being female, diabetic, and with NASH cirrhosis. Patients with a BMI ≥40 had a higher median MELD score, limited physical capacity, and were more likely to be hospitalized at LT. BMI ≥40 recipients had higher post‐LT length of stay and were less often discharged to home. With a median follow‐up of 2 years, patient and graft survival were equivalent between the two groups. In conclusion, morbidly obese LT recipients appear sicker at time of LT with an increase in resource utilization but have similar short‐term outcomes.

Addressing Morbid Obesity as a Barrier to Renal Transplantation With Laparoscopic Sleeve Gastrectomy

Morbid obesity is a barrier to renal transplantation and is inadequately addressed by medical therapy. We present results of a prospective evaluation of laparoscopic sleeve gastrectomy (LSG) for patients failing to achieve significant weight loss with medical therapy. Over a 25‐month period, 52 obese renal transplant candidates meeting NIH guidelines for metabolic surgery underwent LSG. Mean age was 50.0 ± 10.0 years with an average preoperative BMI of 43.0 ± 5.4 kg/m2 (range 35.8–67.7 kg/m2). Follow‐up after LSG was 220 ± 152 days (range 26–733 days) with last BMI of 36.3 ± 5.3 kg/m2 (range 29.2–49.8 kg/m2) with 29 (55.8%) patients achieving goal BMI of <35 kg/m2 at 92 ± 92 days (range 13–420 days). The mean percentage of excess weight loss (%EWL) was 32.1 ± 17.6% (range 6.7–93.8%). A segmented regression model was used to compare medical therapy versus LSG. This revealed a statistically significant increase in the BMI reduction rate (0.3 kg/m2/month versus 1.1 kg/m2/month, p < 0.0001). Patients also experienced a 40.9% decrease in anti‐hypertensive medications (p < 0.001) and a 49.7% decrease in total daily insulin dose (p < 0.001). LSG is a safe and effective means for addressing obesity in kidney transplant candidates in the context of a multidisciplinary approach.

Natural orifice translumenal endoscopic surgery (NOTES): creation of a gastric valve for safe and effective transgastric surgery in humans

IntroductionNOTES has become a clinical reality. There remain, however, many challenges that need to be addressed in order to refine the technique. One of the most feared potential complications of transgastric surgery is a leak from the port of entry into the peritoneum. When withdrawing the endoscope into the gastric lumen it is difficult to make a secure closure due to the loss of pneumogastrium. We present a novel and safe technique for creating a gastrotomy developed in our animal laboratory and applied in all of our human NOTES cholecystectomies.MethodsUsing an aggressive grasping and needle-delivery device, full-thickness bites create an imbricated ridge of tissue that acts as a valve, allowing visualization while maintaining pneumogastrium when the endoscope is withdrawn from the peritoneum into the lumen. At closure, full-thickness serosa-to-serosa approximation is easily achieved due to excellent visualization.ResultsWith this technique we have been able to accomplish consistent results in ten pig models. In our series of five patients who have undergone NOTES transgastric cholecystectomy, there have been no leaks to date using the same technique. Video footage presents this technique performed on humans.ConclusionsCreation of a gastric valve during transgastric surgery has proved to be a safe approach. This technique allows maintenance of insufflation and visualization during the procedure and provides a feasible and safe means of closure at the end of the procedure.

Laparoscopic radiofrequency ablation for the management of colorectal liver metastases: 10-year experience.

Published results addressing the treatment of colorectal liver metastases (CRLM) with radiofrequency ablation (RFA) vary widely with local recurrence rates of 2–40% and 5‐year survival of 14–55%. The goal of this study was to analyze our 10‐year experience with laparoscopic RFA.

Hepatitis C transmission from seropositive, nonviremic donors to non–hepatitis C liver transplant recipients

Breakthroughs in hepatitis C virus (HCV) treatment and rising rates of intravenous drug use have led to an increase in the number of organ donors who are HCV antibody–positive but serum nucleic acid test (NAT)–negative. The risk of HCV transmission from the liver grafts of these donors to recipients is unknown. To estimate the incidence of HCV transmission, we prospectively followed 26 consecutive HCV antibody–negative (n = 25) or NAT‐negative (n = 1) transplant recipients who received a liver graft from donors who were HCV antibody–positive but serum NAT‐negative between March 2016 and March 2017. HCV transmission was considered to have occurred if recipients exhibited a positive HCV PCR test by 3 months following transplantation. Drug overdose was listed as the cause of death in 15 (60%) of the donors. One recipient died 18 days after transplantation from primary graft nonfunction and was excluded. Of the remaining 25 recipients, HCV transmission occurred in 4 (16%), at a median follow‐up of 11 months, all from donors who died of drug overdose. Three of these patients were treated with direct‐acting antiviral therapy, with two achieving a sustained virologic response and one an end‐of‐treatment response. One patient with HCV transmission died after a complicated postoperative course and did not receive antiviral therapy. Conclusion: In this prospective cohort of non‐HCV liver recipients receiving grafts from HCV antibody–positive/NAT‐negative donors, the incidence of HCV transmission was 16%, with the highest risk conferred by donors who died of drug overdose; given the availability of safe and highly effective antiviral therapies, use of such organs could be considered to expand the donor pool. (Hepatology 2018;67:1673‐1682).

Using implantation biopsies as a surrogate to evaluate selection criteria for living kidney donors

Background The acceptance criteria used for living kidney donors are largely theoretical, as they are not clearly linked to outcomes. The goal of this study was to use implantation biopsies as a surrogate outcome marker to evaluate our living kidney donor selection criteria. Methods One thousand six hundred sequential living kidney donor biopsies were performed between 2001 and 2011. Implantation biopsies were assessed by dedicated renal pathologists according to the Banff criteria. Biopsies with any chronic score of 2 or higher were deemed to have moderate to severe changes (MSC). Results MSC was present in 4% (n=65) of implantation biopsies and occurred across a wide range of age and other demographics. By multivariate analysis, donor age (odds ratio [95% confidence interval], 1.060 [1.035–1.086]; P<0.0001) and donor systolic blood pressure (SBP) (odds ratio [95% confidence interval], 1.022 [1.006–1.037]; P=0.0060) were associated with MSC. Donor gender, body mass index, diastolic blood pressure, glomerular filtration rate, and urinary microalbuminuria were not. MSC was further increased in donors older than 60 years with SBP>140 (30% [7 of 23]) and donors older than 60 years with SBP>140 and glomerular filtration rate above the 25th percentile (42.8% [3 of 7]). In donors younger than 60 years, combining factors did not show an increased prevalence of MSC. At follow-up, renal function was similar in donors with and without MSC. Conclusions MSC occurred sporadically in donors with varied characteristics. Although we did not detect patterns to support specific changes in our acceptance criteria, certain subgroups of donors might benefit from close follow-up.

Use of Elderly Allografts in Liver Transplantation.

Introduction The use of liver allografts from elderly donors (≥70 years) has increased because of organ shortage and increased life expectancy. The aim of this study is to evaluate the current utilization of elderly donors in United States, recipient selection, and their posttransplant outcomes. Methods A linkage between Scientific Registry of Transplant Recipients and University HealthSystem Consortium databases was performed. Between January 2007 and December 2011, 12,445 liver transplant (LT) recipients were identified and divided into 2 cohorts based on donor age: 70 years or older (n = 540) and younger than 60 years (n = 10,473). Results Elderly donors accounted for 4.3% of all donors used in the 5-year period. When compared to younger donors, elderly donors were more likely to be women, shared regionally or nationally, and used at higher volume centers. Elderly donor allografts were less likely to be used in recipients with model of end-stage liver disease score higher than 27 (13.2% vs 23.0%, P < 0.001), hospitalized (16.8% vs 21.7%, P = 0.03), or on hemodialysis at time of transplant (2.6% vs 8.2%, P < 0.001). Both recipient groups had similar perioperative mortality, 30-day readmission rates, and short-term patient survival. In the multivariate analysis, including recipient, donor, center and regional factors, donor age 70 years or older was associated with slightly increased risk of graft loss (hazard ratio, 1.3; 95% confidence interval, 1.08–1.56; P = 0.005). Conclusions The current trend toward the use of elderly donors in liver transplant recipients with low model of end-stage liver disease scores (<27), without hepatitis C, not hospitalized and not on dialysis, is associated with acceptable perioperative outcomes, patient survival, and slightly worse graft survival.

Biomesh Placement in Laparoscopic Repair of Paraesophageal Hernias

The placement of mesh in the crural closure of paraesophageal hiatal hernia repairs has been shown to decrease hernia recurrence rates. Typical synthetic mesh are easy to use but have high rate of erosion into the esophagus. Alternatively, biologic mesh decrease the risk of erosion, but are more difficult to manipulate, and there is currently no well-described method for securing them. Current fixation techniques of mesh are difficult, cumbersome, incur extra expense, and are not without complications. A method that requires no additional sutures or staples and achieves excellent contact and reinforcement of the crural closure is presented.