Dilip Moonka

Calcineurin inhibitor-free mycophenolate mofetil/sirolimus maintenance in liver transplantation: the randomized spare-the-nephron trial.

Mycophenolate mofetil (MMF) and sirolimus (SRL) have been used for calcineurin inhibitor (CNI) minimization to reduce nephrotoxicity following liver transplantation. In this prospective, open‐label, multicenter study, patients undergoing transplantation from July 2005 to June 2007 who were maintained on MMF/CNI were randomized 4 to 12 weeks after transplantation to receive MMF/SRL (n = 148) or continue MMF/CNI (n = 145) and included in the intent‐to‐treat population. The primary efficacy endpoints were the mean percentage change in the calculated glomerular filtration rate (GFR) and a composite of biopsy‐proven acute rejection (BPAR), graft lost, death, and lost to follow‐up 12 months after transplantation. Patients were followed for a median of 519 days after randomization. MMF/SRL was associated with a significantly greater renal function improvement from baseline with a mean percentage change in GFR of 19.7 ± 40.6 (versus 1.2 ± 39.9 for MMF/CNI, P = 0.0012). The composite endpoint demonstrated the noninferiority of MMF/SRL versus MMF/CNI (16.4% versus 15.4%, 90% confidence interval = −7.1% to 9.0%). The incidence of BPAR was significantly greater with MMF/SRL (12.2%) versus MMF/CNI (4.1%, P = 0.02). Graft loss (including death) occurred in 3.4% of the MMF/SRL‐treated patients and in 8.3% of the MMF/CNI‐treated patients (P = 0.04). Malignancy‐related deaths were less frequent with MMF/SRL. Adverse events caused withdrawal for 34.2% of the MMF/SRL‐treated patients and for 24.1% of the MMF/CNI‐treated patients (P = 0.06). The use of MMF/SRL is an option for liver transplant recipients who can benefit from improved renal function but is associated with an increased risk of rejection (but not graft loss). Liver Transpl 19:675–689, 2013..

Risk for renal cell carcinoma in chronic hepatitis C infection.

Background: Chronic infection with hepatitis C virus (HCV) confers increased risk for chronic renal disease, and numerous reports suggest an association with renal cell carcinoma (RCC), a cancer with rapidly rising global incidence. We sought to determine whether HCV infection confers an increased risk for developing RCC. Methods: With the use of administrative data from a large, integrated, and ethnically diverse healthcare system, we did a cohort study of 67,063 HCV-tested patients between 1997 and 2006 who were followed for the development of RCC until April 2008. Results: A search of the health system cancer registry for patients with the diagnosis of kidney cancer showed that RCC was diagnosed in 0.6% (17 of 3,057) of HCV-positive patients versus 0.3% (177 of 64,006) of HCV-negative patients. The mean age at RCC diagnosis was much younger in HCV-positive individuals (54 versus 63; P < 0.001). The univariate hazard ratio for RCC among HCV patients was 2.20 (95% confidence interval, 1.32-3.67; P = 0.0025). In a multivariate model that included the risk factors age, African-American race, male gender, and chronic kidney disease, the overall hazard ratio for RCC among HCV patients was 1.77 (95% confidence interval, 1.05-2.98; P = 0.0313). Conclusion: Chronic HCV infection confers a risk for the development of RCC. Impact: Clinicians should consider newly identified renal lesions in patients with chronic HCV infection with a heightened suspicion for neoplasm, and newly diagnosed cases of RCC may require more careful surveillance for the presence of HCV infection. Additional studies are required to confirm these findings and to explore potential mechanisms of oncogenesis. Cancer Epidemiol Biomarkers Prev; 19(4); 1066–73. ©2010 AACR.

Peritransplant absolute lymphocyte count as a predictive factor for advanced recurrence of hepatitis C after liver transplantation.

Lymphocytes play an active role in natural immunity against hepatitis C virus (HCV). We hypothesized that a lower absolute lymphocyte count (ALC) may alter HCV outcome after liver transplantation (LT). The aim of this study was to investigate the impact of peritransplant ALC on HCV recurrence following LT. A total of 289 LT patients between 2005 and 2011 were evaluated. Peritransplant ALC (pre‐LT, 2‐week, and 1‐month post‐LT) and immunosuppression were analyzed along with recipient and donor factors in order to determine risk factors for HCV recurrence based on METAVIR fibrosis score. When stratifying patients according to pre‐ and post‐LT ALC (<500/μL versus 500‐1,000/μL versus >1,000/μL), lymphopenia was significantly associated with higher rates of HCV recurrence with fibrosis (F2‐4). Multivariate Cox regression analysis showed posttransplant ALC at 1 month remained an independent predictive factor for recurrence (P = 0.02, hazard ratio [HR] = 2.47 for <500/μL). When peritransplant ALC was persistently low (<500/μL pre‐LT, 2‐week, and 1‐month post‐LT), patients were at significant risk of developing early advanced fibrosis secondary to HCV recurrence (F3‐4 within 2 years) (P = 0.02, HR = 3.16). Furthermore, severe pretransplant lymphopenia (<500/μL) was an independent prognostic factor for overall survival (P = 0.01, HR = 3.01). The use of rabbit anti‐thymocyte globulin induction (RATG) had a remarkable protective effect on HCV recurrence (P = 0.02, HR = 0.6) despite its potential to induce lymphopenia. Subgroup analysis indicated that negative effects of posttransplant lymphopenia at 1 month (<1,000/μL) were significant regardless of RATG use and the protective effects of RATG were independent of posttransplant lymphopenia. Conclusion: Peritransplant ALC is a novel and useful surrogate marker for prediction of HCV recurrence and patient survival. Immunosuppression protocols and peritransplant management should be scrutinized depending on peritransplant ALC. (Hepatology 2014;58:35–45)

Renal insufficiency after liver transplantation in the MELD era compared to the pre-MELD era

Abstract:  Because the model for end‐stage liver disease (MELD) system for liver allocation gives priority to patients with a higher creatinine, and because pre‐transplant renal function is one determinant of post‐transplant renal function, this study compares the burden of renal insufficiency in the pre‐MELD and MELD eras. Two hundred and elven patients, at our institution, transplanted in the pre‐MELD era, were compared to 143 in the MELD era. The GFR (mL/min/1.73 m2) was significantly higher in the MELD cohort than the pre‐MELD cohort at time of transplant, discharge, and 12 months post‐transplant (95.5 vs. 85.3, p = 0.039; 90.4 vs. 77.4, p = 0.002; 66.8 vs. 60.3, p = 0.026). There was no difference between the two groups in time to renal failure. There was a higher rate of sirolimus use in the MELD era (27% vs. 18%: p = 0.042) and a slightly higher use of kidney–liver transplant in the MELD era (p = 0.056). We did not identify greater renal insufficiency in the MELD era. There was greater renal function in the MELD era at time of transplant, discharge and month 12. Potential explanations include: absence of an increase in renal insufficiency prior to transplant in the MELD era, greater use of renal sparing immunotherapy and growing use of kidney–liver transplant.

Novel intraoperative management in the model for end‐stage liver disease–sodium era: Continuous venovenous hemofiltration for severe hyponatremia in liver transplantation

The Organ Procurement and Transplant Network/ United Organ Sharing Network introduced the Model for End-Stage Liver Disease–sodium (MELD-Na) score for the allocation of liver grafts in 2016. As a result, the number of liver transplantation (LT) recipients who suffer from severe hyponatremia (<125 mEq/L) may increase. A rapid change in serum sodium can lead to osmotic demyelination syndrome (ODS). Patients undergoing LT with hyponatremia are at risk of developing complications of rapid sodium correction due to significant sodium loads received from intraoperative fluids and administered blood and blood products. Our center previously considered a serum sodium level of <125 mEq/L to be a relative contraindication to LT surgery. However, we acknowledged that these patients may subsequently become too ill and lose their transplant opportunity while waiting for a sodium correction. In the setting of severe hyponatremia, the benefit of proceeding with lifesaving LT surgery might outweigh the risk of posttransplant neurological complications. Therefore, intraoperative management should be fine-tuned to minimize rapid changes in serum sodium levels. Recently, continuous venovenous hemofiltration (CVVH) with dilutional methods of sodium correction has been described as an effective modality to manage severe hyponatremia, that allows for a gradual correction of hyponatremia. We attempted to use intraoperative CVVH to maintain a target serum sodium level by using diluted replacement fluid in 3 LT patients who had severe hyponatremia (<125 mEq/L) at the time of LT. In these 3 patients, we successfully managed serum sodium levels intraoperatively and postoperatively and prevented neurological complications and other significant postoperative morbidity. Retrospective collection and analysis of the transplant database were approved by the institutional review board at Henry Ford Hospital.