Adyr A. Moss

Treatment of recurrent hepatitis C infection after liver transplantation with combination of pegylated interferon α2b and ribavirin: An open-label series

Background. Hepatitis C virus (HCV) recurrence after orthotopic liver transplantation (OLT) is universal. We aimed to evaluate the efficacy and safety of pegylated interferon (PEG-IFN) and ribavirin (RIB) in the treatment of post-OLT HCV recurrence. Methods. Thirty-seven patients with recurrent HCV after OLT were screened and began treatment. Nineteen patients have completed therapy. PEG-IFN was started at a dose of 0.5 &mgr;g/kg per week and titrated toward a maximum dose of 1.5 &mgr;g/kg per week. RIB was started at a dose of 400 mg per day and titrated toward a maximum of 1000 mg per day, as tolerated. Therapy continued for 1 year after HCV replication was undetectable by reverse transcriptase-polymerase chain reaction and was discontinued if there was no virologic clearance at 48 weeks. Results. Twelve patients (63%) completed the combination regimen. Therapy was discontinued in seven (37%) patients. Seven patients (37%) had undetectable viral load at the end of treatment. Of those, five patients (26%) had sustained viral response 6 months after discontinuation of therapy. Five patients (26%) had no virologic response. Necro-inflammatory score declined from 5.22 to 2.89 (P =0.05) in nonresponders versus 6.8 to 2.6 (P <0.01) in responders. Fibrosis stage did not change in either group. Genotype 1-infected patients had a lower likelihood of attaining end of treatment or sustained viral response (P <0.05 for both). Conclusions. Post-OLT HCV recurrence can be safely treated with PEG-IFN and RIB. Bone marrow toxicity, depression, and rejection are limiting factors that require aggressive management. There was short-term histologic benefit to the use of this regimen, even in those patients without viral clearance.

Natural History of Post-Liver Transplantation Hepatitis C: A Review of Factors That May Influence Its Course

Our aim was to assess long‐term survival in patients transplanted for HCV‐related end‐stage liver disease (ESLD) and evaluate potentially modifiable predictors of survival. We performed a retrospective analysis of adult liver transplants (LT) at our institution for HCV‐related ESLD since the programs inception. Pertinent demographic, clinical, and biochemical information was retrieved from electronic medical records and histological data from 990 per‐protocol liver biopsies were collected. Three hundred eighty LT were performed at our institution during the study period, 206 patients were transplanted for HCV‐related ESLD; 6 died within 30 days of transplantation and were not included. The remaining 200 recipients (DDLT 168 LDLT 32) constituted the evaluable population. The demographics were as follows: 150 males, median age 53 years; median donor age 39 years; hepatocellular carcinoma (HCC) in 26%. Overall 1‐, 5‐, and 7‐year survival: 95%, 81%, and 79%; median survival 43 months, mortality 15%. Significant HCV recurrence (HAI ≥6 and/or fibrosis ≥2) was present in 49%, “early recurrence” (within 1 year of LT) in 30.5% and biopsy‐proven acute rejection was present in 27%. Factors with a significant negative impact on patient survival included: fibrosis stage ≥2 at 12‐month biopsy, advanced donor age, history of HCC and early acute rejection. Survival was similar regardless of the donor type (DDLT vs. LDLT). Early and aggressive HCV recurrence has a very heavy toll on patient survival. Prompt recognition and treatment of “rapid fibrosers” may impart benefit. As has been described before, avoidance of rejection and selection of young donors for HCV‐positive recipients will also improve survival in this population. On the basis of our findings, LDLT is a good option for HCV‐positive recipients. Liver Transpl 15:1872–1881, 2009.

Pre-emptive transplants for patients with renal failure: an argument against waiting until dialysis.

Background. Pre-emptive kidney transplants have not been favored in some centers because of concern about possible increased noncompliance and allegedly inferior long-term results. We analyzed our experience with pre-emptive kidney transplants to determine whether such concerns are justified. Patients and Methods. Between January 1, 1984, and June 30, 1998, we performed 1849 adult primary kidney transplants: 385 pre-emptive (recipients not undergoing dialysis, ND) and 1464 non-pre-emptive (recipients undergoing dialysis, D). Results were subdivided by donor source: cadaver (CAD) and living donor (LD). ND recipients tended to be younger, but otherwise, the two groups were similar. Posttransplantation quality of life in recipients was evaluated using the nationally standardized Short Form Health Survey (SF-36). The posttransplantation employment status of the recipients was also evaluated. Results. The patient survival rate 5 years posttransplantation was significantly better for ND (vs. D) recipients for both CAD (92.6% vs. 76.6%, P =0.001) and LD (93.3% vs. 89.5%, P =0.02) transplants. The 5-year patient survival rate was significantly higher for ND recipients compared with recipients undergoing dialysis for < 1, 1–2, and > 2 years pretransplantation for both CAD (P =0.0005) and LD (P =0.0001) transplants. The graft survival rate 5 years posttransplantation was similar between ND and D recipients for CAD transplants, but significantly better for ND (vs. D) recipients of LD transplants (92.3% vs. 84.8%, P =0.006). For CAD transplants, the 5-year graft survival rate was not different when ND recipients were compared with recipients undergoing dialysis for < 1, 1–2, and > 2 years pretransplantation; for LD transplants it was significantly higher for ND recipients compared with recipients undergoing dialysis for < 1, 1–2, and > 2 years pretransplantation (P =0.04). The incidence of acute and chronic rejection was no different between ND and D recipients for either CAD or LD transplants, and it was also not affected by the pretransplantation time undergoing dialysis. Graft loss secondary to the recipient’s discontinuation of immunosuppressive therapy (a crude estimate of compliance) was similar between ND and D recipients. Five years posttransplantation, the SF-36 scores regarding the recipient’s quality of life and the employment status were similar for ND compared with D recipients, regardless of donor source. Conclusions. ND recipients do not seem to have higher rates of noncompliance than D recipients. Results for ND recipients seem to be superior than for D recipients, supporting the contention that renal failure patients should, if possible, undergo transplantation before dialysis.

Impact of Subclinical Inflammation on the Development of Interstitial Fibrosis and Tubular Atrophy in Kidney Transplant Recipients

Our aim was to study the impact of subclinical inflammation on the development of interstitial fibrosis and tubular atrophy (IF/TA) on a 1‐year protocol biopsy in patients on rapid steroid withdrawal (RSW). A total of 256 patients were classified based on protocol biopsy findings at months 1 or 4. Group 1 is 172 patients with no inflammation, group 2 is 50 patients with subclinical inflammation (SCI), group 3 is 19 patients with subclinical acute rejection (SAR) and group 4 is 15 patients with clinical acute rejection (CAR). On the 1‐year biopsy, more patients in group 2 (SCI) (34%, p = 0.004) and group 3 (SAR) (53%, p = 0.0002), had an IF/TA score > 2 compared to group 1 (control) (15%). IF/TA was not increased in group 4 (CAR) (20%). The percent with IF/TA score > 2 and interstitial inflammation (Banff i score > 0) was higher in group 2 (16%, p = 0.004) and group 3 (37%, p < 0.0001) compared to group 1 (3%). In a multivariate analysis, patients in groups 2 or 3 had a higher risk of IF/TA score > 2 on the 1‐year biopsy (OR 6.62, 95% CI 2.68–16.3). We conclude that SCI and SAR increase the risk of developing IF/TA in patient on RSW.

Relationship between Inpatient Hyperglycemia and Insulin Treatment after Kidney Transplantation and Future New Onset Diabetes Mellitus

BACKGROUND AND OBJECTIVES Approximately two-thirds of kidney transplant recipients with no previous history of diabetes experience inpatient hyperglycemia immediately after kidney transplant surgery; whether inpatient hyperglycemia predicts future new onset diabetes after transplant (NODAT) is not established. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS A retrospective study was conducted to determine the risk conferred by inpatient hyperglycemia on development of NODAT within 1 year posttransplant. All adult nondiabetic kidney transplant recipients between June 1999 and January 2008 were included. Posttransplant inpatient hyperglycemia was defined as any bedside capillary blood glucose > or = 200 mg/dl or insulin therapy during hospitalization. NODAT was defined as HbA1C > or = 6.5%, fasting venous serum glucose > or = 126 mg/dl, or prescribed diet or medical therapy for diabetes mellitus. RESULTS The study cohort included 377 patients. NODAT developed in 1 (4%) of the 28 patients without inpatient hyperglycemia, 4 (18%) of the 22 patients with inpatient hyperglycemia but not treated with insulin, and in 98 (30%) of the 327 of the patients who were diagnosed with inpatient hyperglycemia and were treated with insulin. In adjusted analyses, requirement of insulin therapy during hospitalization posttransplant was associated with a 4-fold increase in NODAT (relative risk 4.01; confidence interval, 1.49 to 10.7; P = 0.006). CONCLUSION Development of inpatient hyperglycemia after kidney transplantation in nondiabetic patients significantly increased the risk of NODAT. Additionally, we observed a significantly increased risk of cardiovascular events in patients who developed NODAT.

Hyperglycemia during the Immediate Period after Kidney Transplantation

BACKGROUND AND OBJECTIVES Hyperglycemia and new-onset diabetes occurs frequently after kidney transplantation. The stress of surgery and exposure to immunosuppression medications have metabolic effects and can cause or worsen preexisting hyperglycemia. To our knowledge, hyperglycemia in the immediate posttransplantation period has not been studied. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS We conducted a retrospective, observational study to characterize the prevalence and assess the pharmacologic management of hyperglycemia in kidney transplant recipients who underwent transplantation at our center between June 1999 and December 2006. Data were abstracted from electronic and pharmacy databases. RESULTS The study cohort included 424 patients (mean age 51 yr; 58% men; 25% with pretransplantation diabetes). All patients with and 87% without pretransplantation diabetes had evidence of hyperglycemia (bedside glucose >or=200 mg/dl or physician-instituted insulin therapy), whereas the prevalence of hypoglycemia was low (4.5%). Hyperglycemia was sustained throughout hospitalization. All patients with and 66% without pretransplantation diabetes required insulin at hospital discharge. Patients with pretransplantation diabetes were treated primarily with short-acting insulin during the first 24 h after transplantation but were transitioned to long-acting insulin as the hospital stay progressed. CONCLUSIONS Investigators have historically attempted to identify hyperglycemia after hospital discharge. Our data indicate that a substantial number of patients without pretransplantation diabetes develop hyperglycemia and require insulin during the hospital phase of their care immediately after kidney transplantation. Prospective studies are needed to delineate factors that contribute to development of new-onset diabetes after transplantation among patients with transient hyperglycemia.

Pretransplant risk score for new-onset diabetes after kidney transplantation

OBJECTIVE New-onset diabetes after kidney transplantation (NODAT) has adverse clinical and economic implications. A risk score for NODAT could help identify research subjects for intervention studies. RESEARCH DESIGN AND METHODS We conducted a single-center retrospective cohort study using pretransplant clinical and laboratory measurements to construct a risk score for NODAT. NODAT was defined by hemoglobin A1c (HbA1c) ≥6.5%, fasting serum glucose ≥126 mg/dL, or prescribed therapy for diabetes within 1 year posttransplant. Three multivariate logistic regression models were constructed: 1) standard model, with both continuous and discrete variables; 2) dichotomous model, with continuous variables dichotomized at clinically relevant cut points; and 3) summary score defined as the sum of the points accrued using the terms from the dichotomous model. RESULTS A total of 316 subjects had seven pretransplant variables with P < 0.10 in univariate logistic regression analyses (age, planned corticosteroid therapy posttransplant, prescription for gout medicine, BMI, fasting glucose and triglycerides, and family history of type 2 diabetes) that were selected for multivariate models. Areas under receiver operating curves for all three models were similar (0.72, 0.71, and 0.70). A simple risk score calculated as the sum of points from the seven variables performed as well as the other two models in identifying risk of NODAT. CONCLUSIONS A risk score computed from seven simple pretransplant variables can identify risk of NODAT.

Hepatitis C virus recurrence in living donor liver transplant recipients.

Recurrence of hepatitis C virus (HCV) after liver transplantation (LT) is a universal phenomenon. Recent reports have suggested an earlier and more aggressive recurrence in the living donor liver transplant (LDLT) population. The aim of this study was to compare the histological recurrence of HCV after LDLT versus deceased donor transplantation (DDT). Twenty-nine patients underwent LT for HCV-related end-stage liver disease at our institution between April 2001 and March 2003 (42 months). Twenty patients underwent DDT, and nine patients LDLT. Laboratory data were collected on a weekly to biweekly basis and HCV PCR was performed before LT and 3–4 months and yearly post-LT. Liver biopsies were performed as needed and per institutional protocol at 7 days, at 4 months, and yearly thereafter. All biopsies were evaluated by a single pathologist and scored for rejection (Banff score) and chronic hepatitis (Ishak score system). The predominant genotype in the DDT and LDLT groups was genotype 1 (DDT=70%, LDLT=79%). HCV RNA titers pre-LT and 3–4 months after LT did not differ. The incidence of rejection was higher in the DDT group (P < 0.05). There was a trend toward improved lshak stage and grade in the LDLT group at 4 and 12 months post-LT, however, this trend did not reach statistical significance. No histological difference in the recurrence or severity rate was observed at 4 or 12 months post-LT in the DDT group vs. the LDLT group.

Regional Variations in Peer Reviewed Liver Allocation Under the MELD System

The Model for End‐Stage Liver Disease (MELD) is used to assign priority for liver transplantation candidates. The Organ Procurement and Transplantation Network (OPTN) approved recognized exceptional diagnoses (REDs) for which MELD fails to accurately measure priority. Centers can request increased MELD points in cases not recognized by this policy (non‐REDs). Our aim was to compare regional practices to justify non‐RED requests for MELD adjustments. The UNOS/OPTN database was queried to extract all adult cases for which a non‐RED MELD adjustment was requested from 2/27/02 until 8/27/03. The data were stratified by region and justification. Data for 29 510 listings were available. 26 947 had complete diagnosis information. There were 827 non‐RED requests of which 477 (57.7%) petitions were approved by the regional review boards (RRBs). The approval rate varied significantly among regions (range: 28–75%, p < 0.0001). The most common non‐REDs were complications of portal hypertension (48%). The percentage of patients listed with non‐REDs varied significantly among regions (0.7–8.3 %, p < 0.0001), as did the proportion of patients transplanted with non‐REDs (2.1–31.9%, p < 0.0001). Demographics did not differ among regions requesting non‐REDs.Widespread regional variations exist in the handling of requests for non‐REDs. These variations point to the need for reform to standard exception criteria.

Transplanting Kidneys from Deceased Donors With Severe Acute Kidney Injury

Our aim was to determine outcomes with transplanting kidneys from deceased donors with acute kidney injury, defined as a donor with terminal serum creatinine ≥2.0 mg/dL, or a donor requiring acute renal replacement therapy. We included all patients who received deceased donor kidney transplant from June 2004 to October 2013. There were 162 AKI donor transplant recipients (21% of deceased donor transplants): 139 in the standard criteria donor (SCD) and 23 in the expanded criteria donor (ECD) cohort. 71% of the AKI donors had stage 3 (severe AKI), based on acute kidney injury network (AKIN) staging. Protocol biopsies were done at 1, 4, and 12 months posttransplant. One and four month formalin‐fixed paraffin embedded (FFPE) biopsies from 48 patients (24 AKI donors, 24 non‐AKI) underwent global gene expression profiling using DNA microarrays (96 arrays). DGF was more common in the AKI group but eGFR, graft survival at 1 year and proportion with IF/TA>2 at 1 year were similar for the two groups. At 1 month, there were 898 differentially expressed genes in the AKI group (p‐value <0.005; FDR <10%), but by 4 months there were no differences. Transplanting selected kidneys from deceased donors with AKI is safe and has excellent outcomes.