Larry Melton

End-stage renal disease (ESRD) after orthotopic liver transplantation (OLTX) using calcineurin-based immunotherapy: risk of development and treatment.

BACKGROUND The calcineurin inhibitors cyclosporine and tacrolimus are both known to be nephrotoxic. Their use in orthotopic liver transplantation (OLTX) has dramatically improved success rates. Recently, however, we have had an increase of patients who are presenting after OLTX with end-stage renal disease (ESRD). This retrospective study examines the incidence and treatment of ESRD and chronic renal failure (CRF) in OLTX patients. METHODS Patients receiving an OLTX only from June 1985 through December of 1994 who survived 6 months postoperatively were studied (n=834). Our prospectively collected database was the source of information. Patients were divided into three groups: Controls, no CRF or ESRD, n=748; CRF, sustained serum creatinine >2.5 mg/dl, n=41; and ESRD, n=45. Groups were compared for preoperative laboratory variables, diagnosis, postoperative variables, survival, type of ESRD therapy, and survival from onset of ESRD. RESULTS At 13 years after OLTX, the incidence of severe renal dysfunction was 18.1% (CRF 8.6% and ESRD 9.5%). Compared with control patients, CRF and ESRD patients had higher preoperative serum creatinine levels, a greater percentage of patients with hepatorenal syndrome, higher percentage requirement for dialysis in the first 3 months postoperatively, and a higher 1-year serum creatinine. Multivariate stepwise logistic regression analysis using preoperative and postoperative variables identified that an increase of serum creatinine compared with average at 1 year, 3 months, and 4 weeks postoperatively were independent risk factors for the development of CRF or ESRD with odds ratios of 2.6, 2.2, and 1.6, respectively. Overall survival from the time of OLTX was not significantly different among groups, but by year 13, the survival of the patients who had ESRD was only 28.2% compared with 54.6% in the control group. Patients developing ESRD had a 6-year survival after onset of ESRD of 27% for the patients receiving hemodialysis versus 71.4% for the patients developing ESRD who subsequently received kidney transplants. CONCLUSIONS Patients who are more than 10 years post-OLTX have CRF and ESRD at a high rate. The development of ESRD decreases survival, particularly in those patients treated with dialysis only. Patients who develop ESRD have a higher preoperative and 1-year serum creatinine and are more likely to have hepatorenal syndrome. However, an increase of serum creatinine at various times postoperatively is more predictive of the development of CRF or ESRD. New strategies for long-term immunosuppression may be needed to decrease this complication.

Simultaneous liver-kidney transplantation: evaluation to decision making.

Questions about appropriate allocation of simultaneous liver and kidney transplants (SLK) are being asked because kidney dysfunction in the context of liver failure enhances access to deceased donor organs. There is specific concern that some patients who undergo combined liver and kidney transplantation may have reversible renal failure. There is also concern that liver transplants are placed prematurely in those with end‐stage renal disease. Thus to assure allocation of transplants only to those truly in need, the transplant community met in March 2006 to review post‐MELD (model for end‐stage liver disease) data on the impact of renal function on liver waitlist and transplant outcomes and the results of SLK.

Renal replacement therapy and orthotopic liver transplantation: The role of continuous veno-venous hemodialysis

BACKGROUND The need for renal replacement therapy (RRT) either before or after orthotopic liver transplant (OLTX) has been reported to be a poor prognostic indicator for survival. Use of continuous veno-venous hemodialysis (CVVHD) for RRT has been reported in three series of OLTX patients with high 90-day mortality rates of 57-60%. We have examined our patient population to determine the effect of necessity and type of RRT on patient survival after OLTX. METHODS We analyzed 1535 OLTX that were performed at our institution from 1985 through 1999, 1037 from 1985 to 1995 (period I) and 498 from 1996 to 1999 (period II). Combined liver-kidney transplants were excluded from analysis. Hospital dialysis unit records and a prospectively maintained database on all OLTX patients served as the source of data. Patients were classified into groups defined on whether or not they received RRT, when they received RRT, and the type of RRT. Groups were compared for preoperative intensive care unit status, time on the waiting list, laboratory variables, 90-day postoperative mortality, 1-year patient survival, and absolute survival. RESULTS Use of RRT increased from 8.29% in period I to 12.45% in period II, along with increased median waiting times. In period I, patients receiving preoperative RRT had a 90-day mortality (0%) and a 1-year survival (89.5%) almost identical to those patients who never required RRT (1.7% and 90.6%). Patients who developed acute renal failure postoperatively requiring RRT, however, had a 90-day mortality of 28.6% and a 1-year survival of 55%. In period II, patients requiring RRT had a 90-day mortality of 39.7% and a 1-year actuarial survival of 54.5% compared with 6.9% and 88.6% in patients never requiring RRT. Patients treated with CVVHD had a 90-day mortality of 42% compared with 25% in patients treated with hemodialysis alone. However, patients receiving CVVHD both pre- and postoperatively had a 90-day mortality of 27.7% vs. 50% in those patients who only received CVVHD postoperatively. Patients who developed acute renal failure postoperatively, which required RRT, regardless of therapy, had a 1-year survival of only 41.0% compared with a 1-year survival of 73.6% in those patients started on RRT preoperatively, P=0.03. CONCLUSIONS The need for RRT has increased along with waiting time in OLTX patients. Patients developing the need for RRT postoperatively have an increased 90-day mortality and lower 1-year survival with the highest being present in patients receiving CVVHD, which was started postoperatively. These findings may reflect a trend toward a sicker population awaiting OLTX and emphasize the negative impact of renal failure on survival after OLTX.

Simultaneous Liver-Kidney Transplantation Summit: Current State and Future Directions

Although previous consensus recommendations have helped define patients who would benefit from simultaneous liver–kidney transplantation (SLK), there is a current need to reassess published guidelines for SLK because of continuing increase in proportion of liver transplant candidates with renal dysfunction and ongoing donor organ shortage. The purpose of this consensus meeting was to critically evaluate published and registry data regarding patient and renal outcomes following liver transplantation alone or SLK in liver transplant recipients with renal dysfunction. Modifications to the current guidelines for SLK and a research agenda were proposed.

Acute kidney injury following liver transplantation: Definition and outcome

The incidence of acute kidney injury (AKI) has been reported to vary between 17% and 95% post–orthotopic liver transplantation. This variability may be related to the absence of a uniform definition of AKI in this setting. The purpose of this study was to identify the degree of AKI that is associated with long‐term adverse outcome. Furthermore, to determine the best definition (for use in future studies) of AKI not requiring dialysis in post–liver transplant patients, we retrospectively reviewed the effect of 3 definitions of AKI post–orthotopic liver transplantation on renal and patient outcome between 1997 and 2005. We compared patients with AKI to a control group without AKI by each definition. AKI was defined in 3 groups as an acute rise in serum creatinine, from the pretransplant baseline, of >0.5 mg/dL, >1.0 mg/dL, or >50% above baseline to a value above 2 mg/dL. In all groups, the glomerular filtration rate was significantly lower at both 1 and 2 years post‐transplant. Patient survival was worse in all groups. Graft survival was worse in all groups. The incidence of AKI was highest in the group with a rise in creatinine of >0.5 mg/dL (78%) and lowest in patients with a rise in creatinine of >50% above 2.0 mg/dL (14%). Even mild AKI, defined as a rise in serum creatinine of >0.5 mg/dL, was associated with reduced patient and graft survival. However, in comparison with the other definitions, the definition of AKI with the greatest impact on patients outcome post–liver transplant was a rise in serum creatinine of >50% above baseline to >2 mg/dL. Liver Transpl 15:475–483, 2009.

Preoperative and perioperative predictors of the need for renal replacement therapy after orthotopic liver transplantation

Background. Acute renal failure developing after orthotopic liver transplantation (OLTx) requiring renal replacement heralds a poor prognosis. Our center has previously reported a 1-year survival of only 41.8%. We undertook this study to determine whether we could identify preoperative and perioperative factors that would predict which patients are at risk. Methods. OLTxs performed between January 1, 1996, and December 31, 2001, were included in our retrospective database review. Combined kidney-liver transplants or patients with preoperative renal replacement therapy (RRT) were excluded. A total of 724 OLTxs were studied, which were divided into group I: no RRT, n=637; group II: hemodialysis only post-OLTx, n=17; and group III: continuous RRT post-OLTx, n=70. Univariate and stepwise logistic multivariate analyses were performed. Results. Preoperative serum creatinine greater than 1.9 mg/dL (odds ratio [OR] 3.57), preoperative blood urea nitrogen greater than 27 mg/dL (OR 2.68), intensive care unit stay more than 3 days (OR 10.23), and Model for End-Stage Liver Disease score greater than 21 (OR 2.5) were significant. A clinical prediction model was constructed: probability of requiring dialysis posttransplant=(−2.4586+1.2726 [creatinine >1.9] + 0.9858 [blood urea nitrogen >27] + 0.4574 [Model for End-Stage Liver Disease score >21] + 1.1625 [intensive care unit days >3]). A clinical prediction rule for patients with a score greater than 0.12 was applied to OLTx recipients who underwent transplantation in 2002. A total of 15 of 20 patients who received RRT and 111 of 121 who did not were correctly classified with the model. Conclusions. This model allowed us to identify patients at high risk for developing the need for RRT postoperatively. Strategies for these patients to prevent or ameliorate acute renal failure and reduce the need for RRT postoperatively are needed.

Equivalent pharmacokinetics of mycophenolate mofetil in African-American and Caucasian male and female stable renal allograft recipients.

African‐American (AA) renal transplant recipients require higher doses of mycophenolate mofetil (MMF) than Caucasians. A hypothesized pharmacokinetic (PK) difference was tested in stable renal transplant recipients. Whole blood was collected before, and 20, 40 and 75 min, and 2, 3, 4, 6, 8 and 12 h after the MMF dose. Mycophenolic acid (MPA) and its glucuronide metabolite (MPAG) were analyzed using HPLC. Analysis of variance was performed for the primary end‐points of dose‐adjusted PK parameters AUC0–12 and Cmax of MPA using log‐transformed values. Differences between races and genders were estimated: 90% confidence intervals (CI) were calculated. Back‐transformation gave estimates of the race and gender ratio and their CI. Equivalence of the groups was determined if the 90% confidence limits were included in the interval (0.80, 1.25). The calculated PK parameters were comparable among the four subgroups (Caucasian, AA, Male, Female). The 90% CIs for the ratio of dose‐adjusted AUC0–12 of MPA between races were between 89.7 and 112.9%. There were no race, gender or race‐by‐gender effects (p‐values = 0.196) nor differences between diabetics and nondiabetics. This study demonstrates that dosing requirement for MMF in AA and Caucasians is unlikely to be related to different exposures to MPA.

Predicting renal failure after liver transplantation from measured glomerular filtration rate: review of up to 15 years of follow-up.

Background. The immunosuppressive medications that have contributed greatly to the success of liver transplantation are also associated with posttransplant renal dysfunction. We reviewed measured glomerular filtration rate (GFR) data from patients who underwent transplantation more than 10 years ago to assess whether results from specific time points can predict renal failure. Methods. The GFR data were obtained at initial evaluation (IE), at month 3, and at years 1, 2, 5, 10, and 15. Two groupings were compared, one based on GFR at IE and the other at month 3. Patients were further stratified into three GFR (mL/min/1.73 m2) groups: G1, GFR more than 80; G2, GFR 60 to 80; and G3, GFR less than 60. Results. A total of 592 liver transplant recipients met the inclusion criteria; 114 had paired GFR data from IE to year 15. Analysis of paired and censored data based on IE GFR showed that 62.2% of G3 patients developed renal failure by year 5; another 6.7% did so by year 10 (P=0.027). The month 3 GFR data showed that 56.3% of G3 patients developed renal failure by year 5; another 15.6% did so by year 10. Surprisingly, 37.0% of G2 patients experienced renal failure by year 5; another 11.1% did so by year 10 (P=0.0024). Conclusions. The month 3 data indicate a slow but steady decline in GFR over years. The lower the initial GFR is after transplant, the sooner renal failure develops. Patients with GFR less than 60 mL/min per 1.73 m2 at month 3 have a higher risk of renal failure; however, those who avoid renal failure seem to maintain renal function long term.

Disseminated adenovirus infection in renal transplant recipients: the role of cidofovir and intravenous immunoglobulin

R. Saquib, L.B. Melton, A. Chandrakantan, K.M. Rice, C.W. Spak, R.D. Saad, A.Z. Fenves, Y.M. Barri. Disseminated adenovirus infection in renal transplant recipients: the role of cidofovir and intravenous immunoglobulin.
Transpl Infect Dis 2010: 12: 77–83. All rights reserved

West Nile virus infection in kidney and pancreas transplant recipients in the Dallas-Fort Worth Metroplex during the 2012 Texas epidemic.

BACKGROUND In 2012, the United States experienced one of its worst West Nile virus (WNV) epidemics, reporting 5,387 human cases and final death toll of 243. Texas was at the epicenter of the outbreak, with 1,875 reported cases and 89 deaths that year. The Texas outbreak centered mainly in the Dallas-Fort Worth area where 30 deaths were reported. We report three cases of severe WNV infection complicated by meningoencephalitis in our organ transplant population. METHODS Clinical data were collected from chart review. Therapy and outcomes on three identified patients were reviewed and compared with previously reported cases of WNV infection in kidney/pancreas transplant recipients and the general population. RESULTS Two recipients of kidney and one recipient of a combined kidney and pancreas transplant were treated at our center for WNV infection. All three patients presented with a rapid decline in mental status within 24 hours of admission consistent with meningoencephalitis. Diagnosis was made based on detection of WNV IgM in the serum. All patients received intravenous immunoglobulin (IVIG) therapy at 400 mg/kg × 3 to 4 doses. As a result, two patients had a full recovery, and one patient died. CONCLUSION Transplant recipients have a higher risk of neurologic complications from WNV infection. In areas where WNV is endemic, clinicians must have a high index of suspicion when treating patients presenting with fever, headache, and confusion. Full recovery in two of three patients suggests a potential role of IVIG therapy in controlling active WNV infection, particularly in immunosuppressed patients.