Adel Bozorgzadeh

TLR-dependent cross talk between human Kupffer cells and NK cells

The liver protects the host from gut-derived pathogens yet is tolerant of antigenic challenge from food and commensal sources. Innate responses involving liver macrophages (Kupffer cells) and effector liver natural killer (NK) cells form the first line in this defense. We address the impact of Toll-like receptor (TLR) signaling on the cross talk between these two cells, and reveal how the liver displays a down-regulated inflammatory response to constitutive bacterial elements through the secretion of interleukin (IL) 10 yet retains a vigorous response to viral challenge. The data support the model that (a) human liver Kupffer cells respond to TLR ligands and indirectly activate NK cells; (b) the activation depends on cell–cell contact; (c) the Kupffer cells synthesize NK cell activating signals, among which IL-18 is critical, and NK cell inhibitory factors, including IL-10; (d) ligands that signal via myeloid differentiation factor 88 induce IL-10, giving a blunted response in the NK cells; and (e) ligands that signal via the Toll–IL-1 receptor domain–containing adaptor inducing interferon (IFN) β–IFN regulatory factor 3 pathway induce less IL-10, and also directly potentiate the stimulatory effect of IL-18 on NK cells, resulting in enhanced activation. Subversion of cellular mechanisms of innate immune response against viruses may be important for hepatotropic viruses (e.g., hepatitis B and C) to develop persistence.

Nephrogenic Systemic Fibrosis Among Liver Transplant Recipients: A Single Institution Experience and Topic Update

Nephrogenic systemic fibrosis (NSF) is a recently characterized systemic fibrosing disorder developing in the setting of renal insufficiency. NSFs rapidly progressive nature resulting in disability within weeks of onset makes early diagnosis important. Two reports of NSF after liver transplantation are known of. We present three cases of NSF developing within a few months after liver transplantation and review the current literature. Loss of regulatory control of the circulating fibrocyte, its aberrant recruitment, in a milieu of renal failure and a recent vascular procedure appear important in its development. Known current therapies lack consistent efficacy. Only an improvement in renal function has the greatest likelihood of NSFs resolution. Delayed recognition may pose a significant barrier to functional recovery in the ubiquitously deconditioned liver transplant patient. Early recognition and implementation of aggressive physical therapy appear to have the greatest impact on halting its progression.

Survival Benefit with Kidney Transplants from HLA-Incompatible Live Donors

BACKGROUND A report from a high-volume single center indicated a survival benefit of receiving a kidney transplant from an HLA-incompatible live donor as compared with remaining on the waiting list, whether or not a kidney from a deceased donor was received. The generalizability of that finding is unclear. METHODS In a 22-center study, we estimated the survival benefit for 1025 recipients of kidney transplants from HLA-incompatible live donors who were matched with controls who remained on the waiting list or received a transplant from a deceased donor (waiting-list-or-transplant control group) and controls who remained on the waiting list but did not receive a transplant (waiting-list-only control group). We analyzed the data with and without patients from the highest-volume center in the study. RESULTS Recipients of kidney transplants from incompatible live donors had a higher survival rate than either control group at 1 year (95.0%, vs. 94.0% for the waiting-list-or-transplant control group and 89.6% for the waiting-list-only control group), 3 years (91.7% vs. 83.6% and 72.7%, respectively), 5 years (86.0% vs. 74.4% and 59.2%), and 8 years (76.5% vs. 62.9% and 43.9%) (P<0.001 for all comparisons with the two control groups). The survival benefit was significant at 8 years across all levels of donor-specific antibody: 89.2% for recipients of kidney transplants from incompatible live donors who had a positive Luminex assay for anti-HLA antibody but a negative flow-cytometric cross-match versus 65.0% for the waiting-list-or-transplant control group and 47.1% for the waiting-list-only control group; 76.3% for recipients with a positive flow-cytometric cross-match but a negative cytotoxic cross-match versus 63.3% and 43.0% in the two control groups, respectively; and 71.0% for recipients with a positive cytotoxic cross-match versus 61.5% and 43.7%, respectively. The findings did not change when patients from the highest-volume center were excluded. CONCLUSIONS This multicenter study validated single-center evidence that patients who received kidney transplants from HLA-incompatible live donors had a substantial survival benefit as compared with patients who did not undergo transplantation and those who waited for transplants from deceased donors. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases.).

Quantifying the Risk of Incompatible Kidney Transplantation: A Multicenter Study

Incompatible live donor kidney transplantation (ILDKT) offers a survival advantage over dialysis to patients with anti‐HLA donor‐specific antibody (DSA). Program‐specific reports (PSRs) fail to account for ILDKT, placing this practice at regulatory risk. We collected DSA data, categorized as positive Luminex, negative flow crossmatch (PLNF) (n = 185), positive flow, negative cytotoxic crossmatch (PFNC) (n = 536) or positive cytotoxic crossmatch (PCC) (n = 304), from 22 centers. We tested associations between DSA, graft loss and mortality after adjusting for PSR model factors, using 9669 compatible patients as a comparison. PLNF patients had similar graft loss; however, PFNC (adjusted hazard ratio [aHR] = 1.64, 95% confidence interval [CI]: 1.15–2.23, p = 0.007) and PCC (aHR = 5.01, 95% CI: 3.71–6.77, p < 0.001) were associated with increased graft loss in the first year. PLNF patients had similar mortality; however, PFNC (aHR = 2.04; 95% CI: 1.28–3.26; p = 0.003) and PCC (aHR = 4.59; 95% CI: 2.98–7.07; p < 0.001) were associated with increased mortality. We simulated Centers for Medicare & Medicaid Services flagging to examine ILDKTs effect on the risk of being flagged. Compared to equal‐quality centers performing no ILDKT, centers performing 5%, 10% or 20% PFNC had a 1.19‐, 1.33‐ and 1.73‐fold higher odds of being flagged. Centers performing 5%, 10% or 20% PCC had a 2.22‐, 4.09‐ and 10.72‐fold higher odds. Failure to account for ILDKTs increased risk places centers providing this life‐saving treatment in jeopardy of regulatory intervention.

Living-Donor Liver Transplantation in the United States: Identifying Donors at Risk for Perioperative Complications

Donor safety has been scrutinized by both the medical community and the media. Variability exists in reported donor complications and associated risk factors are ill defined. Use of administrative data can overcome the bias of single‐center studies and explore variables associated with untoward events. A retrospective cohort study identifying living liver donors in two large healthcare registries yielded 433 right and left lobe donors from 13 centers between 2001 and 2005. Perioperative complications were identified using International Classification of Diseases, 9th Revision (ICD‐9) coding data and classified according to the Clavien system. Logistic regression models identified factors associated with complications. There was one perioperative death (0.23%). The overall complication rate was 29.1% and major complication rate defined by a Clavien grade ≥3 was 3.5%. Center living‐donor volume (OR = 0.97, 95% CI = 0.95–0.99) and the ratio of living‐donors to all donors (living and deceased) (OR = 0.94, 95% CI = 0.92–0.96) were associated with a lower risk of all complications. Donor age >50 years (OR = 4.25, 95% CI = 1.22–14.87) was associated with a higher risk of major complications. Living liver donation is currently performed with a low risk of major morbidity. Use of administrative data represents an important tool to facilitate a better understanding of donor risk factors.

The duration of antibiotic administration in penetrating abdominal trauma

BACKGROUND The epidemiology of penetrating abdominal trauma is changing to reflect an increasing incidence of multiple injuries. Not only do multiple injuries increase the risk of infection, a very high risk of serious infection is conferred by immunosuppression from hemorrhage and transfusion and the high likelihood of intestinal injury, especially to the colon. Optimal timing and choice of presumptive antibiotic therapy has been established for penetrating trauma, but duration has not been studied extensively in such seriously injured patients. The purpose of this study was to test the hypothesis that 24 hours of antibiotic therapy remains sufficient to reduce the incidence of infection in penetrating abdominal trauma. METHODS Three hundred fourteen consecutive patients with penetrating abdominal trauma were prospectively randomized into two groups: Group I received 24 hours of intravenous cefoxitin (1 g q6h) and group II received 5 days of intravenous cefoxitin. The development of a deep surgical site (intra-abdominal) infection as well as any type of nosocomial infection, as defined by the Centers for Disease Control and Prevention, (ie, surgical site infections, catheter-related infections, urinary tract, pneumonia), was recorded. Hospital length of stay was a secondary endpoint. Statistical analysis included chi-square tests for coordinate variables and two-tailed unpaired t tests for continuous variables. The independence of risk factors for the development of infection was assessed by multivariate analysis of variance. Significance was determined when P <0.05. RESULTS Three hundred patients were evaluable. There was no postoperative mortality, and no differences in overall length of hospitalization between groups. The duration of antibiotic treatment had no influence on the development of any infection (P = 0.136) or an intraabdominal infection (P = 0.336). Only colon injury was an independent predictor of the development of an intraabdominal infection (P = 0.0031). However, the overall infection incidence was affected by preoperative shock (P = 0.003), colon (P = 0.0004), central nervous system (CNS) injuries (P = 0.031), and the number of injured organs (P = 0.026). Several factors, including intraoperative shock (P = 0.021) and injuries to the colon (P = 0.0008), CNS (P = 0.0001), and chest (P = 0.0006), were independent contributors to prolongation of the hospital stay. CONCLUSIONS Twenty-four hours of presumptive intravenous cefoxitin versus 5 days of therapy made no difference in the prevention of postoperative infection or length of hospitalization. Infection was associated with shock on admission to the emergency department, the number of intra-abdominal organs injured, colon injury specifically, and injury to the central nervous system. Intra-abdominal infection was predicted only by colon injury. Prolonged hospitalization was associated with intraoperative shock and injuries to the chest, colon, or central nervous system.

The activation state of human intrahepatic lymphocytes

The immune tolerance induced by the liver as an allograft is difficult to reconcile with the evidence that the liver selectively accumulates activated T cells from the circulation. However, much of this information is based on murine liver lymphocytes that were isolated using enzymatic digestion. In the present study we made use of a novel resource, the lymphocytes isolated during the perfusion of living donor liver lobe prior to transplantation. These healthy human liver lymphocytes displayed surface markers indicating a high degree of activation of natural killer cells, CD56+ T cells, CD4+ T cells and CD8+ T cells. These properties were independent of enzymatic treatment or the details of cell isolation. We conclude that the healthy human liver is a site of intense immunological activity.

Survival outcomes in liver transplantation for hepatocellular carcinoma, comparing impact of hepatitis C versus other etiology of cirrhosis

The incidence of hepatocellular carcinoma (HCC) is on the rise worldwide as the most common primary hepatic malignancy. In the US approximately one half of all HCC is related to Hepatitis C virus (HCV) infection. The relationship between the primary disease and HCC recurrence after liver transplantation is unknown. We hypothesized that the primary hepatic disease underlying the development of cirrhosis and HCC would be associated with the risk of recurrent HCC after transplantation. A retrospective review was conducted of all primary liver transplants performed at the University of Rochester Medical Center from May 1995 through June 2004. The pathology reports from the native livers of 727 recipients were examined for the presence of HCC. There were 71 liver transplant recipients with histopathological evidence of HCC. These patients were divided in two groups on the basis of HCV status. Group 1 consisted of 37 patients that were both HCV and HCC positive, and Group 2 consisted of 34 patients that were HCC positive but HCV negative. Patient characteristics were analyzed, as well as number of tumors, tumor size, presence of vascular invasion, lobe involvement, recipient demographics, donor factors, pretransplantation HCC therapy, rejection episodes, and documented HCC recurrence and treatment. There were no statistically significant differences between the 2 groups, with the exception of recipient age and the presence of hepatitis B coinfection. The tumor characteristics of both groups were similar in numbers of tumors, Milan criteria status, vascular invasion, incidental HCC differentiation, and largest tumor size. The HCV positive population had a far lower patient survival rate with patient survival in Group 1 at 1, 3, and 5 years being 81.1%, 57.4%, and 49.3% respectively, compared with 94.1%, 82.8%, and 76.4% in Group 2 (p = 0.049). Tumor‐free survival in Group 1 at 1, 3, and 5 years was 70.3%, 43%, and 36.8% respectively, vs. 88.1%, 73%, and 60.8% in Group 2. In a subgroup analysis, tumor‐free survival was further examined by stratifying the patients on the basis of Milan criteria. Group 1 patients outside of Milan criteria had a statistically lower tumor‐free survival. By contrast, there was no statistical difference in tumor‐free survival in Group 2 patients stratified according to Milan criteria. Cox regression analysis identified HCV and vascular invasion as significant independent predictors of tumor‐free survival. Our results suggest that Milan selection criteria may be too limiting and lose their predictive power when applied to patients without HCV infection. Liver Transpl 13:807–813, 2007.

Minimizing Morbidity of Organ Donation: Analysis of Factors for Perioperative Complications After Living-Donor Nephrectomy in the United States

Background. Expansion of living kidney donation through liberalizing acceptance criteria invites a renewed focus on safety and outcomes. Wide variability exists in reported donor complications, and associated risk factors are ill defined. Use of administrative data can overcome the bias of single-center studies and identify variables associated with untoward events. Methods. The study population consisted of 3074 living kidney donors from 28 centers during 2004 and 2005. Data from a large healthcare registry were used to retrospectively identify the study cohort. Perioperative complications were identified using ICD-9-CM coding and classified according to the Clavien system. Logistic regression models were constructed to identify donor and center factors associated with complications. Results. There were no perioperative deaths. The overall complication rate was 10.6% and major complications defined by Clavien grade ≥3 was 4.2%. The prevalence of tobacco use, obesity, and hypertension, was 7.8%, 2.4%, and 2.3%, respectively. Age >50 (odds ratio [OR]=1.81, 95% confidence interval [95% CI]=1.25–2.61), tobacco use (OR=1.41, 95% CI=1.02–1.94), obesity (OR=1.92, 95% CI=1.06–3.46), and annual center volume ≤50 (OR=2.28, 95% CI=1.68–3.09), were significantly associated with overall morbidity, however only annual center volume ≤50 (OR=2.07, 95% CI=1.27–3.37) was significantly associated with a risk of major complications. Conclusions. The inclusion of donors with tobacco abuse, obesity, and age >50 increases complications; however, the risk of major morbidity is small. Use of administrative data represents an important tool to facilitate the reconciliation of an increased need for organ donors with the concern for donor safety.

Impact of center volume on outcomes of increased-risk liver transplants.

The use of high‐risk donor livers, which is reflective of the gross national shortage of organs available for transplantation, has gained momentum. Despite the demand, many marginal livers are discarded annually. We evaluated the impact of center volume on survival outcomes associated with liver transplantation using high–donor risk index (DRI) allografts. We queried the Scientific Registry of Transplant Recipients database for deceased donor liver transplants (n = 31,576) performed between 2002 and 2008 for patients who were 18 years old or older, and we excluded partial and multiple liver transplants. A high‐DRI cohort (n = 15,668), which was composed of patients receiving grafts with DRIs > 1.90, was analyzed separately. Transplant centers (n = 102) were categorized into tertiles by their annual procedure volumes: high‐volume centers (HVCs; 78‐215 cases per year), medium‐volume centers (MVCs; 49‐77 cases per year), and low‐volume centers (LVCs; 5‐48 cases per year). The endpoints were allograft survival and recipient survival. In comparison with their lower volume counterparts, HVCs used donors with higher mean DRIs (2.07 for HVCs, 2.01 for MVCs, and 1.91 for LVCs), more donors who were 60 years old or older (18.02% for HVCs, 16.85% for MVCs, and 12.39% for LVCs), more donors who died after a stroke (46.52% for HVCs, 43.71% for MVCs, and 43.36% for LVCs), and more donation after cardiac death organs (5.04% for HVCs, 4.45% for MVCs, and 3.51% for LVCs, all P values < 0.001). Multivariate risk‐adjusted frailty models showed that increased procedure volume at a transplant center led to decreased risks of allograft failure [hazard ratio (HR) = 0.93, 95% confidence interval (CI) = 0.89‐0.98, P = 0.002] and recipient death (HR = 0.90, 95% CI = 0.83‐0.97, P = 0.004) for high‐DRI liver transplants. In conclusion, HVCs more frequently used higher DRI livers and achieved better risk‐adjusted allograft and recipient survival. A greater understanding of the outcomes of transplantation with high‐DRI livers may improve their utilization, the postoperative outcomes, and future allocation practices. Liver Transpl 17:1191–1199, 2011.