Limiting hepatitis C virus progression in liver transplant recipients using sirolimus-based immunosuppression.

Hepatitis C virus (HCV) causes progressive liver fibrosis in liver transplant recipients and is the principal cause of long-term allograft failure. The antifibrotic effects of sirolimus are seen in animal models but have not been described in liver transplant recipients. We reviewed 1274 liver recipients from 2002 to 2010 and identified a cohort of HCV recipients exposed to sirolimus as primary immunosuppression (SRL Cohort) and an HCV Control Group of recipients who had never received sirolimus. Yearly protocol biopsies were done recording fibrosis stage (METAVIR score) with biopsy compliance of >80% at both year one and two. In an intent-to-treat analysis, the SRL Cohort had significantly less advanced fibrosis (stage ≥2) compared to the HCV Control Group at year one (15.3% vs. 36.2%, p < 0.0001) and year two (30.1% vs. 50.5%, p = 0.001). Because sirolimus is sometimes discontinued for side effects, the SRL Cohort was subgroup stratified for sirolimus duration, showing progressively less fibrosis with longer sirolimus duration. Multivariate analysis demonstrated sirolimus as an independent predictor of minimal fibrosis at year one, and year two. This is the first study among liver transplant recipients with recurrent HCV to describe the positive impact of sirolimus in respect of reduced fibrosis extent and rate of progression.

Superior conjunction of pioneer 6.

Spectrograms of the radio signals from Pioneer 6 were taken as the spacecraft was occulted by the sun. The spectral bandwidths increased slowly at first, then very rapidly at 1 degree from the sun. In addition, six solar "events" produced marked increases of bandwidth lasting for several hours. The received signal power seemed unaffected by the solar corona.

Pulsars: observations of spectra.

Dynamic spectrograms of two of the recently discovered pulsating radio sources have been obtained. The data provide the instantaneous spectrum and the time-frequency history of the signals over a bandwidth of 3 megahertz.

Radar observations of icarus.

Radar observations of Icarus were made in mid-June 1968, at the time of closest approach. From the data, it is estimated that the radius is between 0.3 and 0.6 kilometer and the rotation period between 1.5 and 3.3 hours. A set of round-trip Doppler shift measurements is given.

Mercury: Surface Features Observed during Radar Studies.

Radar studies of Mercury have shown the presence of several large, rough surface features and of one smooth area.

A radar snapshot of venus.

A radar brightness map of Venus has been obtain d. It reveals interesting surface features and much structure over a large area.

Ganymede: observations by radar.

Radar cross-section measurements indicate that Ganymede scatters to Earth 12 percent of the power expected from a conducting sphere of the same size and distance. This compares with 8 percent for Mars, 12 percent for Venus, 6 percent for Mercury, and about 8 percent for the asteroid Toro. Furthermore, Ganymede is considerably rougher (to the scale of the wavelength used, 12.6 centimeters) than Mars, Venus, or Mercury. Roughness is made evident in this experiment by the presence of echoes away from the center of the disk. A perfectly smooth target would reflect only a glint from the center, whereas a very rough target would reflect power from over the entire disk.

Ganymede: radar surface characteristics.

Radar observations of Ganymede, at X-band, show that the surface is unusually bright and has unusual polarization properties. A model of the surface based on large numbers of random ice facets (hence vacuum-ice interfaces) is able to account for these characteristics.

Satellite radar interferometry for monitoring ice sheet motion: application to an antarctic ice stream.

Satellite radar interferometry (SRI) provides a sensitive means of monitoring the flow velocities and grounding-line positions of ice streams, which are indicators of response of the ice sheets to climatic change or internal instability. The detection limit is about 1.5 millimeters for vertical motions and about 4 millimeters for horizontal motions in the radar beam direction. The grounding line, detected by tidal motions where the ice goes afloat, can be mapped at a resolution of approximately 0.5 kilometer. The SRI velocities and grounding line of the Rutford Ice Stream, Antarctica, agree fairly well with earlier ground-based data. The combined use of SRI and other satellite methods is expected to provide data that will enhance the understanding of ice stream mechanics and help make possible the prediction of ice sheet behavior.

Remote sensing of ocean currents.

A method of remotely measuring near-surface ocean currents with a synthetic aperture radar (SAR) is described. The apparatus consists of a single SAR transmitter and two receiving antennas. The phase difference between SAR image scenes obtained from the antennas forms an interferogram that is directly proportional to the surface current. The first field test of this technique against conventional measurements gives estimates of mean currents accurate to order 20 percent, that is, root-mean-square errors of 5 to 10 centimeters per second in mean flows of 27 to 56 centimeters per second. If the full potential of the method could be realized with spacecraft, then it might be possible to routinely monitor the surface currents of the world's oceans.

Mars radar observations, a preliminary report.

Radar observations of a narrow belt of the surface of Mars, centered at 16 degrees south latitude, show a very rugged terrain, with elevation differences greater than 13 kilometers from peak to valley. For nearby points, the relative altitude is measured to 40 meters at best; the precision is worse for points at different latitudes, or widely separated in longitude, because of orbital uncertainties. Some of the larger craters have been resolved, and their depth and, in some cases, the height of the raised rim have been measured. Where high resolution photographs, are available, the correlation is excellent.

Quasars: Millisecond-of-Arc Structure Revealed by Very-Long-Baseline Interferometry.

Observations with the Goldstone-Haystack radio interferometer of the quasars 3C 279 and 3C 273 have disclosed the presence of fine structure in their radio emissions. Although the interpretation is not unique, the fringe-amplitude data for quasar 3C 279 are quite consistent with emissions from two points, each contributing equally to the correlated flux. The separation of the two points is estimated to be (1.55 +/- 0.05) x 10(-3) arc second, or about 20 light years at the distance of 3 x 10(9) light years inferred from optical red-shift data. The formal uncertainty in the right-ascension component of the separation is about 6 x 10(-6) arc second; differential proper motion in this direction at half the speed of light could be discerned within a year. The fringe-amplitude data of quasar 3C 273 allow similar, but less definitive, interpretations.

Quasars revisited: rapid time variations observed via very-long-baseline interferometry.

Recent Goldstone-Haystack radio interferometric observations of the quasars 3C 279 and 3C 273 reveal rapid variations in their fine structure. Most notably, the data for 3C 279, interpreted in terms of a symmetric double-source model and the accepted red-shift distance, indicate differential proper motion corresponding to an apparent speed about ten times that of light. A number of possible mechanisms that might give rise to such an apparent speed are considered; although several may be plausible, no definitive choice can be made on the basis of present evidence. More interferometric observations of quasars are clearly needed to clarify their structure and internal kinematics.

MELD scores do not predict patient morbidity while on the liver transplant waiting list.

The goals of this study were to assess waitlist morbidity in terms of the frequency of health care services utilized by patients while on the liver transplant (LTX) waiting list and to determine whether that utilization can be predicted by the Model for End-Stage Liver Disease (MELD). Sixty-three noncomatose subjects were followed from waitlist placement until death, change in status, LTX, or study discontinuance. Health care events included doctor/clinic visits, labs, outpatient/inpatient tests and procedures, and hospital/intensive care unit days. Listing MELD scores and LTX MELD scores were examined against the number of health care event occurrences within 60 days of listing and 60 days of LTX, respectively, as were changes in MELD scores between listing and LTX and differences in the number of occurrences between the two time points. The only significant correlations noted were between LTX MELD scores and number of hospital days near LTX (r = .360, P = .046) and between LTX MELD scores and the sum total number of occurrences near LTX (r = .370, P = .044). These results suggest that MELD scores do not appear to predict morbidity in terms of health care utilization in patients awaiting LTX. Developing a system capable of predicting waitlist morbidity may lead to the implementation of medical interventions aimed at circumventing foreseeable complications and/or crises in patients awaiting LTX.

Sirolimus conversion after liver transplantation: improvement in measured glomerular filtration rate after 2 years.

METHODS: We reviewed our prospectively maintained database of 2005 liver transplantations. Therapy was either started de novo or converted from calcineurin inhibitors (CNIs) to sirolimus as the main immunosuppressive agent for nephrotoxicity or rejection. Glomerular filtration rate (GFR) was determined with iodine 125-labeled sodium isthalamate (Glofil-125), and serum creatinine concentration was obtained before and 3 months after transplantation, and yearly in both groups. Sirolimus levels were 10 to 15 ng/mL in patients at less than 3 months after transplantations and 5 to 10 ng/mL in the remaining patients. All patients received mycophenolate mofetil as maintenance therapy. RESULTS: Data for 29 patients in the de novo group and 35 in the conversion group were reviewed. Patients in the de novo group demonstrated an acute cellular rejection rate of 17.2%, 40% of which were steroid resistant. In this group, 48.2% discontinuation of sirolimus was necessary because of adverse effects. Patients in the conversion group demonstrated an acute cellular rejection rate of 2.8% and a 34.3% rate of sirolimus discontinuation. Seventeen (56.7%) patients at 1 year and 8 (44.4%) patients at 2 years demonstrated continued improvement in GFR. In the conversion group, case-control analysis did not demonstrate a significant difference in GFR and serum creatinine concentration (P > .05) at 1 and 2 years after conversion. At the time of review, no patients in the conversion group required hemodialysis. CONCLUSIONS: Conversion to sirolimus therapy is an effective strategy in improving renal function in patients with CNI-induced nephrotoxicity and can be done without increased rejection. Most of our patients (65.7%) tolerated sirolimus conversion. Of these, 56.7% and 44.4% demonstrated continued increase in GFR with the CNI-free regimen at 1 and 2 years, respectively. Long-term, large-population, prospective, randomized, controlled studies should further validate these results.

Late-onset acute rejection in orthotopic liver transplantation--associated risk factors and outcome.

A retrospective review of 375 consecutive orthotopic liver transplants was performed to determine the incidence and outcome of late rejection episodes ([LR] rejection occurring more than 6 months following transplant). A total of 31 episodes in 26 patients were identified. Eighteen of these episodes were associated with subtherapeutic levels of cyclosporine. Of these, 7 were due to noncompliance, 2 were due to biliary strictures, and 1 was due to malabsorption in a cystic fibrosis patient. All 31 episodes were treated initially with steroids, and 22 had a complete response, although one progressed to chronic rejection over a year later. Of the remaining 9, 1 received FK506 with a complete response, and 8 received OKT3. Of the 8 patients who received OKT3, 5 had a complete response, 1 received RS61443 following OKT3 and progressed to chronic rejection, and the remaining 2 received further steroids. Of these 2, 1 had a complete response following the steroids while the second was converted to FK506 with a complete response. Compared with 315 acute rejection episodes ([AR] occurring less than 6 months posttransplant), patients with late rejection episodes had an equivalent response to steroids (63.2% AR reversed vs. 71% LR reversed) but a lower response rate to OKT3 (91.5% AR reversed vs. 62.5% LR reversed). There was, therefore, a higher rate of persistent rejection (61% AR episodes vs. 15.4% LR episodes) but no increase in the incidence of chronic rejection (7% AR episodes vs. 7.7% LR episodes). We conclude that LR is a relatively common occurrence following liver transplant, which is most often associated with low cyclosporine levels. Many of these episodes are due to noncompliance, but biliary problems must also be investigated. The incidence of resistant rejection is higher in this group of patients but is not associated with a concurrent increase in chronic rejection.

Long-term survival and renal function following liver transplantation in patients with and without hepatorenal syndrome--experience in 300 patients.

We have retrospectively reviewed the first 308 patients undergoing orthotopic liver transplantation (OLTX) at our institution to determine the following: 1) To what extent does renal function deteriorate postoperatively? 2) To what extent does renal function recover after OLTX for hepatorenal syndrome (HRS)? 3) What is the survival rate of patients with HRS compared with those without HRS? In non-HRS patients, GFR declined from 97.1 +/- 2.9 cc/min to 56.6 +/- 2.4 cc/min at 6 weeks postoperative, 62.6 +/- 2.6 cc/min at 1 year, and 58.3 +/- 3.5 cc/min at 2 years. In HRS patients, GFR increased from 19.9 +/- 3.6 cc/min to 32.5 +/- 3.1 cc/min at 6 weeks, 45.9 +/- 5.5 cc/min at 1 year, and 37.9 +/- 5.9 cc/min at 2 years. Dosages of cyclosporine were comparable in both groups. There was no difference in perioperative (90-day) mortality. One- and 2-year actuarial survival rates in the non-HRS patients were 87.2% and 82.1%, respectively. The actuarial 1- and 2-year survival rate for the HRS patients was 76.6% (P = NS). Ten percent of HRS patients developed ESRD posttransplant compared with 0.8% of non-HRS patients (P less than 0.005). We conclude that patients with HRS can safely undergo OLTX with acceptable perioperative mortality and good long-term survival. Most HRS patients have return of acceptable renal function. Patients without HRS have a severe decline in GFR posttransplant, which is stable up to 3 years posttransplant.

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.

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.

Hepatic artery stenosis after liver transplantation--incidence, presentation, treatment, and long term outcome.

Little is known about hepatic artery (HA) patency and patient clinical course when the nonthrombosed HA has been revised. We undertook this study to evaluate the risk factors in the development of HA stenosis and to assess the impact of HA revision on the outcome. A total of 857 adult consecutive OLT in 780 patients performed over a 6-year period were studied. Patients who underwent revision of their nonthrombosed but stenotic HA were reviewed for patient/graft survival, method of HA revision, incidence of biliary strictures, and long-term HA patency. Overall 39 patients (5%) with 41 allografts underwent HA revision for stenosis. Median time to diagnosis was 100 days posttransplant (range 1-1220 days). HA flow at the time of OLT was found to be the only significant variable of an anastomotic stenosis. No risk factor could be identified for the graft HA stenosis. Treatment methods included resection of the stenotic segment with primary reanastomosis (n = 17), aortohepatic iliac artery graft (n = 11), interposition vein graft (n = 4), vein patch angioplasty (n = 2), interposition artery graft (n = 1), and percutaneous transluminal balloon angioplasty (n = 6). Postrevisional HA patency was demonstrated in 32 (78%) cases. At a median follow-up of 25 months, 26 patients (67%) were asymptomatic with good liver function. Nine patients had developed biliary strictures. Seven patients had undergone retransplantation and 8 patients had died. The actuarial patient and graft survivals at 4 years in the patients with revised HA were 65% and 56%, respectively. HA stenosis requiring revision is an infrequent occurrence after OLT. Long-term patency of the revised HA is good. Revision of the HA may help prevent biliary strictures and allow for good long-term graft function in the majority of patients.