Roy D. Bloom

Proceedings of Consensus Conference on Simultaneous Liver Kidney Transplantation (SLK)

A consensus conference sponsored by the American Society of Transplant Surgeons (ASTS), American Society of Transplantation (AST), United Network for Organ Sharing (UNOS) and American Society of Nephrology (ASN) convened to examine simultaneous liver‐kidney transplantation (SLK). Directors from the 25 largest liver transplant programs along with speakers with recognized expertise attended. The purposes of this conference were to propose indications for SLK, to establish a prospective data registry and, most importantly, to recommend standard listing criteria for these patients. Scientific registry of transplant recipients data, and single center data regarding chronic kidney disease (CKD) and acute kidney injury (AKI) in conjunction with liver failure as a basis for SLK was presented and discussed. The consensus was that Regional Review Boards (RRB) should determine listing for SLK, as with other MELD exceptions, with automatic approval for: (i) End‐stage renal disease with cirrhosis and symptomatic portal hypertension or hepatic vein wedge pressure gradient ≥ 10 mm Hg (ii) Liver failure and CKD with GFR ≤ 30 mL/min (iii) AKI or hepatorenal syndrome with creatinine ≥ 2.0 mg/dL and dialysis ≥ 8 weeks (iv) Liver failure and CKD and biopsy demonstrating > 30% glomerulosclerosis or 30% fibrosis. The RRB would evaluate all other requests to determine appropriateness.

Association of Hepatitis C with Posttransplant Diabetes in Renal Transplant Patients on Tacrolimus

Posttransplant diabetes mellitus (PTDM) remains a common complication of immunosuppression. Although multiple risk factors have been implicated, none have been clearly identified as predisposing to the increased PTDM frequency observed in patients on tacrolimus. Hepatitis C virus (HCV) has been associated with diabetes and is a significant renal transplant comorbidity. In this study, records of 427 kidney recipients who had no known diabetes before transplantation were retrospectively examined. A multivariate logistic regression model was fit with covariates that had unadjusted relationships with PTDM to examine the independent relationship of HCV and the odds of development of PTDM by 12 mo posttransplant. A potential interaction between HCV and the use of tacrolimus as maintenance therapy on the odds of the development of PTDM was examined. Overall, PTDM occurred more frequently in HCV(+) than HCV(-) patients (39.4% versus 9.8%; P = 0.0005). By multivariate logistic regression, HCV (adjusted odds ratio [OR], 5.58; 95% confidence interval [CI], 2.63 to 11.83; P = 0.0001), weight at transplantation (adjusted OR 1.028; 95% CI, 1.00 to 1.05; P = 0.001), and tacrolimus (adjusted OR, 2.85; 95% CI, 1.01 to 5.28; P = 0.047) were associated with PTDM. A significant interaction (P = 0.0001) was detected between HCV status and tacrolimus use for the odds of PTDM. Among the HCV(+) cohort, PTDM occurred more often in tacrolimus-treated than cyclosporine A-treated patients (57.8% versus 7.7%; P < 0.0001). PTDM rates in HCV(-) patients were similar between the two calcineurin inhibitors (10.0% versus 9.4%; P = 0.521, tacrolimus versus cyclosporine A). In conclusion, HCV is strongly associated with PTDM in renal transplant recipients and appears to account for the increased diabetogenicity observed with tacrolimus.

Mycophenolic acid pharmacodynamics and pharmacokinetics provide a basis for rational monitoring strategies.

Mycophenolic acid (MPA), the active immunosuppressant form of the pro-drug mycophenolate mofetil (MMF), is a widely used component of immunosuppressive regimens in organ transplantation. This immunosuppressant is commonly administered in combination with a calcineurin inhibitor (CIN)+ corticosteroid with or without induction therapy in the form of a polyclonal anti-T lymphocyte preparation or one of the available humanized monoclonal interleukin 2 inhibitors. There is strong evidence that maintenance CIN-MMFsteroid-based triple therapy, initiated in the early posttransplant period significantly reduces the risk of acute rejection in the first post-transplant year, when compared to double therapy regimens comprising CIN and steroids alone. After the initial phase of graft stabilization, there are several therapeuticapproachescurrentlyemployed in transplantpractice, including: (1) maintenance of a three-drug regimen, at reduced doses compared to the early post-transplant period; (2) elimination of corticosteroid; (3) reduction or elimination of CIN; (4) replacement of CIN with sirolimus in patients who are especially sensitive to the nephrotoxic effects of these agents; or (5) reduction or discontinuation of MMF, while retaining full-dose CIN or sirolimus and maintenance corticosteroids are among the other therapeutic options under investigation. Dose individualization of CIN is facilitated by target drug concentration monitoring, whereas for MMF, empiric dosing is most commonly practiced.

Treatment of PTLD with Rituximab or Chemotherapy

Information regarding treatment of post‐transplant lymphoproliferative disease (PTLD) beyond reduction in immunosuppression (RI) is limited. We retrospectively evaluated patients receiving rituximab and/or chemotherapy for PTLD for response, time to treatment failure (TTF) and overall survival (OS). Thirty‐five patients met inclusion criteria. Twenty‐two underwent rituximab treatment, with overall response rate (ORR) 68%. Median TTF was not reached at 19 months and estimated OS was 31 months. In univariable analysis, Epstein‐Barr virus (EBV) positivity predicted response and TTF. LDH elevation predicted shorter OS. No patient died of rituximab toxicity and all patients who progressed underwent further treatment with chemotherapy. Twenty‐three patients received chemotherapy. ORR was 74%, median TTF was 10.5 months and estimated OS was 42 months. Prognostic factors for response included stage, LDH and allograft involvement by tumor. These factors and lack of complete response (CR) predicted poor survival. Twenty‐six percent of the patients receiving chemotherapy died of toxicity. Rituximab and chemotherapy are effective in patients with PTLD who fail or do not tolerate RI. While rituximab is well tolerated, toxicity of chemotherapy is marked. PTLD patients requiring therapy beyond RI should be considered for rituximab, especially with EBV‐positive disease. Chemotherapy should be reserved for patients who fail rituximab, have EBV‐negative tumors or need a rapid response.

Renal function after orthotopic liver transplantation is predicted by duration of pretransplantation creatinine elevation

In patients with recent onset renal insufficiency, the decision to perform combined kidney/liver transplantation (CKLT) vs. orthotopic liver transplantation alone (OLTa) can be difficult. We hypothesized that duration of renal dysfunction may correlate with creatinine elevation after liver transplantation. We retrospectively identified 69 liver transplantation patients with pretransplantation creatinine ≥1.5 mg/dL (53 OLTa, 13 CKLT). Variables analyzed were presence of hepatorenal syndrome, creatinine, Model for End‐Stage Liver Disease score, albumin, age, race, gender, cause of liver disease, diabetes mellitus, hypertension, and history of ascites, spontaneous bacterial peritonitis, variceal bleeding, hepatic encephalopathy, renal replacement therapy (RRT), and transjugular intrahepatic portosystemic shunting. Duration of pretransplantation renal dysfunction was predictive of 6‐ and 12‐month creatinine post‐OLTa. Area under the receiver operating characteristic (ROC) curve for prediction of 12‐month renal insufficiency by renal dysfunction duration was 0.71; optimal duration cutoff was 3.6 weeks. We applied a multivariable model, derived from OLTa patients, to CKLT subjects with definite or possible hepatorenal syndrome. Predicted 12‐month creatinine without renal transplantation was >2.0 mg/dL for each patient. CKLT patients as opposed to OLTa patients had longer duration of renal dysfunction (median, 18.1 vs. 2.7 weeks, P < 0.001), higher creatinine (median 4.0 versus 1.7 mg/dL, P < 0.001), and higher rate of pretransplantation RRT (62% vs. 7%, P < 0.001). Adjusting for baseline characteristics, CKLT patients had lower creatinine than OLTa patients at 6 months (P =0.15) and 12 months (P =0.01) after transplantation. In conclusion, duration, but not cause, of renal dysfunction predicts renal outcome in OLTa recipients. Prospective studies may use duration of renal dysfunction to help identify CKLT candidates. (Liver Transpl 2005;11:1048–1055.)

Fixed- or Controlled-Dose Mycophenolate Mofetil with Standard- or Reduced-Dose Calcineurin Inhibitors: The Opticept Trial

Mycophenolate mofetil (MMF) was developed with cyclosporine as a fixed‐dose immunosuppressant. More recent data indicate a relationship between mycophenolic acid (MPA) exposure in individuals and clinical endpoints of rejection and toxicity. This 2‐year, open‐label, randomized, multicenter trial compared the efficacy and safety of concentration‐controlled MMF (MMFCC) dosing with a fixed‐dose regimen in 720 kidney recipients. Patients received either (A) MMFCC and reduced‐level calcineurin inhibitor (MMFCC/CNIRL); (B) MMFCC and standard‐level CNI (MMFCC/CNISL); or (C) fixed‐dose MMF and CNISL (MMFFD/CNISL). Antibody induction and steroid use were according to center practice. The primary endpoint was noninferiority (α= 0.05) of group A versus group C for treatment failure (including biopsy‐proven acute rejection [BPAR], graft loss and death) at 1 year. Although mean CNI trough levels in group A did not reach the prespecified targets, they were statistically lower than those in groups B and C (p ≤ 0.01 for each comparison). BPAR rates (8.5%) were low across groups. Group A had 19% fewer treatment failures (23% vs. 28%, p = 0.18). MMF doses were highest (p < 0.05), with withdrawals for adverse events the fewest (p = 0.02), in group A. Of the 80% of subjects taking tacrolimus (Tac), those with higher MPA exposure had significantly less rejection (p < 0.001) and diarrhea correlated with Tac, but not with MPA levels. Thus, MMFCC with low‐dose CNI resulted in outcomes not inferior to those with standard CNI exposure and MMFFD, indicating potential utility of MMFCC in CNI‐sparing regimens.

Kidney and Pancreas Transplantation in the United States, 1995–2004

This article examines OPTN/SRTR data on kidney and pancreas transplantation for 2004 and the previous decade, and discusses recent changes in kidney‐pancreas (KP) allocation policy and emerging issues in kidney donation after cardiac death (DCD). Although the number of kidney donors continues to increase, new waiting list registrations again outpaced the number of kidney transplants performed, rising by 11% between 2003 and 2004 and contributing to a 1‐year increase of 8% in the number of patients active on the waiting list. DCD has increased steadily since 2000; 39% more DCD transplants were performed in 2004 than 2003. Both deceased donor and living donor kidney graft survival rates remain excellent and are improving. The number of people living with a functioning kidney transplant doubled between 1995 and 2004, to 101 440 with a functioning kidney‐alone and 7213 with a functioning KP. Health care providers in all settings are more likely to be exposed to these transplant recipients. Patient survival following simultaneous pancreas‐kidney (SPK) transplantation is excellent and has improved incrementally since 1995; death rates in the first year fell from 60 per 1000 patient‐years at risk in 2001 to 45 in 2003. The number of solitary pancreas transplants increased dramatically in 2004.

Chronic Kidney Disease after Nonrenal Solid-Organ Transplantation

Chronic kidney disease (CKD) is a common complication after nonrenal solid-organ transplantation. The risk for CKD is influenced by many factors, some of which have a direct impact on how such patients are treated in the pre-, peri-, and posttransplantation settings. This review describes hazards for acute and chronic kidney injury, with particular emphasis on calcineurin inhibitor-mediated nephrotoxicity. Rather than a detailed description of management issues that are common to the general CKD population, highlighted are aspects that are more specific to nonrenal solid-organ transplant recipients with a focus on liver, heart, and lung recipients. Strategies to minimize nephrotoxic insults and retard progressive renal injury are discussed, as are issues that are pertinent to dialysis and transplantation. Finally, future approaches to prevent and treat CKD without compromising function of the transplanted organ are addressed.

Comparison of open, laparoscopic, and hand-assisted approaches to live-donor nephrectomy

Background. Minimally invasive donor nephrectomy has become a favored procedure for the procurement of kidneys from live donors. The optimal minimally invasive surgical approach has not been determined. In the current work, we compared the outcome of kidneys procured using the traditional open approach with two minimally invasive techniques: the standard laparoscopic procedure and a hand-assist procedure. Methods. The function of live-donor kidneys procured by open versus minimally invasive procedures was compared (procedures compared were the traditional open donor nephrectomy [ODN], the standard laparoscopic [LAP] approach, and the hand-assisted [HA] laparoscopic technique). The length of donor operation, donor length of stay in the hospital, surgical complications, and cost of hospitalization for three groups of patients were assessed in a series of 150 live-donor nephrectomies. Results. We found that both minimally invasive procedures yielded kidney allografts with excellent early function and a minimum of complications in the donor. The open procedure was associated with a reduced operative time but increased donor length of stay in the hospital. Resource utilization analysis revealed that both minimally invasive techniques were associated with a slight increase in costs compared with the open procedure, despite a shorter hospital stay. Conclusions. Minimally invasive donor nephrectomy is safe and effective for procuring normally functioning organs for live-donor transplantation. Of the two minimally invasive approaches examined, the hand-assisted technique was found to afford a number of important advantages, including facilitating teaching of residents and students, that it is more readily mastered by transplant surgeons, and that it may provide an additional margin of safety for the donor.

Successful Treatment of Hepatitis C in Renal Transplant Recipients With Direct-Acting Antiviral Agents.

The direct‐acting antivirals (DAAs) constitute an emerging group of small molecule inhibitors that effectively treat hepatitis C virus (HCV) infection, a common comorbidity in end‐stage renal disease patients. To date, there are no data to guide use of these agents in kidney transplant patients. The authors collected data from 20 consecutive kidney recipients treated with interferon‐free treatment regimens for HCV at their center: 88% were infected with genotype 1; 50% had biopsy‐proved advanced hepatic fibrosis on their most recent liver biopsy preceding treatment (Metavir stage 3 fibrosis [F3] or F4); and 60% had failed treatment pretransplantation with interferon‐based therapy. DAA treatment was initiated a median of 888 days after renal transplantation. All patients cleared the virus while on therapy, and 100% have achieved a sustained virologic response at 12 weeks after completion of DAA therapy. The most commonly used regimen was sofosbuvir 400 mg daily in combination with simeprevir 150 mg daily. However, four different treatment approaches were used, with comparable results. The DAAs were well tolerated, and less than half of patients required calcineurin inhibitor dose adjustment during treatment. Eradication of HCV infection with DAAs is feasible after kidney transplantation with few treatment‐related side effects.