Laparoscopic Liver Resection: A South American Experience with 2887 Cases.

BACKGROUND: Laparoscopic liver resections (LLR) have been increasingly performed in recent years. Most of the available evidence, however, comes from specialized centers in Asia, Europe and USA. Data from South America are limited and based on single-center experiences. To date, no multicenter studies evaluated the results of LLR in South America. The aim of this study was to evaluate the experience and results with LLR in South American centers. METHODS: From February to November 2019, a survey about LLR was conducted in 61 hepatobiliary centers in South America, composed by 20 questions concerning demographic characteristics, surgical data, and perioperative results. RESULTS: Fifty-one (83.6%) centers from seven different countries answered the survey. A total of 2887 LLR were performed, as follows: Argentina (928), Brazil (1326), Chile (322), Colombia (210), Paraguay (9), Peru (75), and Uruguay (8). The first program began in 1997; however, the majority (60.7%) started after 2010. The percentage of LLR over open resections was 28.4% (4.4-84%). Of the total, 76.5% were minor hepatectomies and 23.5% major, including 266 right hepatectomies and 343 left hepatectomies. The conversion rate was 9.7%, overall morbidity 13%, and mortality 0.7%. CONCLUSIONS: This is the largest study assessing the dissemination and results of LLR in South America. It showed an increasing number of centers performing LLR with the promising perioperative results, aligned with other worldwide excellence centers.

Metabolic changes following conversion from an anticalcineurin-based therapy to an everolimus-based one: a single-center experience.

Everolimus (EVL), an antagonist of mammalian target of rapamycin, has been recently introduced into solid organ transplantation either associated with low dose of anticalcineurins (CNI) or replacing them in an attempt to avoid nephrotoxicity and chronic allograft nephropathy. Due to the molecular similarities with sirolimus, it has been expected that there would be the same incidence of metabolic changes and adverse events. We retrospectively studied kidney allograft recipients converted from CNI to EVL during a 12-month period. Patients received a standard dose of EVL starting at 1.5 mg/d and thereafter titrating to achieve trough levels in the range of 3 to 5 ng/mL. Patients achieved mean EVL trough levels of 5.2, 4.0 and 4.5 ng/mL at 1, 6, and 12 months, respectively. One year following conversion, the calculated creatinine clearance increased from 57 to 63 mL/min and proteinuria did not change. Fasting blood glucose levels decreased significantly following conversion to EVL. During the same time, no significant changes were observed in body weight, body mass index, albumin, cholesterol, triglyceride, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, lipid-lowering medication requirements, blood magnesium, and uric acid. We concluded that EVL did not negatively influence various nutritional parameters.

Living donor liver transplantation in pediatric patients with acute liver failure: safe and effective alternative.

UNLABELLED: Living donor liver transplantation (LDLT) for patients with acute liver failure (ALF) is still controversial. To be considered a feasible alternative, this therapeutic option should offer similar results to transplants performed with cadaveric grafts, without significant risks for donors. The aim of this study was to compare the outcomes of pediatric patients with ALF who were transplanted with either cadaveric or living donor grafts. PATIENTS AND METHODS: Between March 1994 and February 2007, 149 patients under 18 years were transplanted, including 43 (28.8%) with ALF. We reviewed the demography, etiology, surgical technique, complications, and long-term results in this group. Patient actuarial survival was determined by Kaplan-Meier analysis. RESULTS: The median age of the recipients was 4.8 years (range 1.2 to 18) including 26 boys and 17 girls. Sixteen (37.2%) underwent LDLT. Three patients in the living donor group needed a second graft (18.7%) versus 7 (26%) among the cadaveric group. No mortality or serious morbidity was observed in living donors. Fifteen patients died. Septic and neurologic complications, and primary graft non-function were the most frequent causes of death. All patients died during the first year after liver transplant. Actuarial 1- and 5-year survivals were 65% without a significant difference between the groups. CONCLUSION: Considering that patients with ALF have no chance of survival without transplantation and that cadaveric grafts remain a limited resource, especially in our country, these results showed that LDLT was a valid option for these patients, as well as a secure procedure for the donors.

Alemtuzumab induction in kidney transplantation: clinical results and impact on T-regulatory cells.

Alemtuzumab (ALT), a humanized monoclonal anti-CD52 antibody, was introduced in solid organ transplantation as an induction agent. ALT associated with anticalcineurins has provided a low incidence of acute rejection episodes (ARE) and potential tolerogenic properties. We analyzed the clinical outcomes and effects on peripheral Treg of renal transplant recipients treated with ALT. Six-month data on kidney alone or kidney combined with pancreas or liver patients treated with ALT and tacrolimus (TAC) in standard doses were compared with those on renal transplant recipients of similar demography who were not treated with ALT. We evaluated patient and graft survivals, ARE incidence, hematological parameters, renal function, adverse events, and CD4+CD25+FoxP3+ T cells in peripheral blood. Demographics of recipients, donors, and transplants were similar in both groups. Mean HLA mismatch was slightly greater among ALT-treated patients (3.5 vs 2.5). No combined transplantation was performed in the ALT-untreated group. Patient and graft survivals were 100% without rejection or serious infections in both groups. ALT-treated recipients showed anemia and leukopenia in 3 patients as well as severe lymphopenia in 5 recipients, who partially recovered on day 90. Final mean plasma creatinine was 1.4 mg/dL, while calculated creatinine clearance was approximately 65 mL/min in both groups. Mean Treg cell percentage was higher among ALT-treated recipients than the comparative group or healthy controls (P < .05). In conclusion, renal transplantation results obtained using ALT with rigorous immunosuppressive therapy were excellent; serious adverse events and acute rejection were absent. The effect of the increased proportion of Treg cells must be evaluated with longer observation.

Conversion from a calcineurin inhibitor-based immunosuppressive regimen to everolimus in renal transplant recipients: effect on renal function and proteinuria.

New immunosuppressive agents are being actively researched to avoid complications of chronic allograft nephropathy (CAN), calcineurin inhibitor (CNI) nephrotoxicity, and posttransplantation cancer. The family of mTOR inhibitors offers a unique immunosuppressive opportunity to avoid CNI toxicity and reduce the incidence of malignancy. Nevertheless, increasing data have demonstrated that sirolimus (SRL), the first mTOR introduced in the treatment of solid organ transplant recipients, induces proteinuria, an adverse event that could produce deterioration of long-term renal function. In this short-term study of patients followed for 1 to 16 months, we examined changes in renal function and proteinuria among renal transplant recipients converted from a CNI-based regimen to an everolimus (EVL)-based one, a recently introduced mTOR inhibitor. Our data showed that renal function can be optimized after conversion to EVL by up to 42% in recipients showing CAN grade 1 or 2, or CNI nephrotoxicity. Importantly, patients who improved their creatinine clearance did not show increased proteinuria measured in a voided specimen as the ratio of urinary protein and creatinine concentration (P/C). These results, if confirmed with long-term follow-up and a larger number of patients, would allow us to consider EVL as a promising agent for maintenance immunosuppressive regimens in kidney transplantation.

Pediatric liver retransplantation: indications and outcome.

INTRODUCTION: Liver transplantation is the only treatment for end-stage liver disease. Not all patients have a favorable outcome. Graft failure secondary to primary nonfunction, vascular complications, or chronic rejection among other problems may lead to retransplantation. Retransplantation represents 8% to 29% of liver transplantations in the pediatric population. The aim of this study was to present our experience with retransplanted children by analyzing the indications and the results. METHODS: All patients were prospectively included in our database, including 125 children. We included the indications for retransplantation, complications, and mortality. Kaplan-Meier curves were used for survival analysis. RESULTS: Since 1994, 125 patients were transplanted and 25 were retransplanted (20%), including 5 who received a third graft. Primary nonfunction represented 30% of the indications for retransplantation and hepatic artery thrombosis, 20%. Six of 25 patients who received a first retransplantation and 2 of 5 who received a second retransplantation died. The most frequent cause of death was multiorgans failure. The survivals at 1 and 5 years were 82% and 76% for children receiving a first retransplantation, and 60% at 1 and 5 years for those who received a second retransplantation. CONCLUSIONS: Organ failure after liver transplantation was a common event in pediatric transplantation. Survival was similar between patients transplanted once and those who received one retransplantation. Survival decreased among patients who received a third graft but was maintained at 60%, which is better than most published results for first retransplanted patients. Retransplantation is a valid option with good results for selected pediatric cases.

Pediatric liver transplantation: ten years of experience in a multicentric program in Chile.

Liver transplantation is the only treatment for patients with terminal acute and chronic diseases. Liver transplantation was started in Chile in 1985; our pediatric program began in 1993. The aim of this paper work was to present our experience from 1993 through 2004. One hundred and thirty two orthotopic liver transplants (OLT) were performed in children of mean age 5 years and median age 4 years (8 months to 15 years). The most frequent indications were biliary atresia, (43.1%) and acute liver failure (ALF; 20.4%), whose frequent cause was unknown but viral hepatitis A was the second one. A complete liver was transplanted in 59 patients, reduced in 39, split in one, and as an auxiliary liver in another one. Living related liver transplantation was performed in 32 cases (24.2%), of which thirty included segments II and III, and two, a right liver. A terminal arterial anastomosis was performed in 102 (77.2%) recipients and a graft interposition in 32 patients (24.2%). In 16 cases, biliary reconstruction was performed through an enterobiliary anastomosis. Immunosuppression included cyclosporine (Neoral), steroids, and azathioprine with conversion to tacrolimus (Prograf) as indicated. Rejection episodes, which were always biopsy-proven, were treated either with methylprednisolone or with antibodies. Biliary complications were the most frequent (21.4%) and the second cause was vascular complications (13%). Sixty-six patients suffered an acute rejection episode. Actuarial graft survival was 81.3% at 1 year and 72% at 5 years, while actuarial graft survival for ALF was 75.9% at 1 year and 67.8% at 5 years. Our results are comparable to those reported by most international groups.

Living related liver transplantation. Why this option has been discarded in a pediatric liver transplant program in Chile.

Living related living transplantation (LRLT) has opened new possibilities for planning transplantation in better conditions for children with emergency situations and chronic liver diseases. Since we began the LRLT program in 1999, we have performed 57 pediatric liver transplants, 17 (29.8%) using living related donors (LRD). The aim of this study was to analyze the reasons why LRD were discarded as a therapeutic option. All pediatric patients were prospectively included in our Microsoft Excel database that was reviewed for obtaining information about causes why the LRLT could not be done. LRLT was proposed in 28 cases and performed in 17 (60.7%). The reasons for LRD rejection were: parent's fear of surgical complications in four cases; drug abuse in two; a mother without family support; medical reasons in two; and only one, due to anatomical reasons and in one case, cadaveric graft transplantation was performed while completing the father's evaluation. From these eleven cases, the indications for liver transplant were acute liver failure (ALF) in seven, biliary atresia in three, and Alagille syndrome in one. Nine were transplanted with cadaveric organs, but two patients with ALF died awaiting a liver. Efforts should be made to clarify the advantages and the disadvantages of LRD in each case, allowing parents to make a free, well-informed decision.

Combined liver and kidney transplantation in a multicenter transplantation program in Chile.

INTRODUCTION: Combined liver and kidney transplantation (CLKT) is an exceptional therapeutic procedure limited to a few diseases with advanced compromise of these organs. Hyperoxaluria type I and polycystic disease are the most frequent indications. The aim of this article was to report our indications and results of CLKT in a multicenter transplantation program in Chile. MATERIAL AND METHODS: Our Excel database was reviewed to select patients who were treated with CLKT between 1993 and July 2004. RESULTS: Among 242 liver transplantations (LT) and 48 kidney transplantations (KT), 7 were CLKT, representing 2.8% of LT and 14.5% of KT. Four patients were women and 3 were male of average age 46.8 years. One patient was a child. Most frequent indications were chronic renal failure associated with terminal liver disease and polycystic disease. One patient needed liver retransplantation due to hepatic vein thrombosis. One patient had a biliary fistula and another had a urinary fistula, treated conservatively. Acute liver rejection took place in 3 cases, 1 of which required antibodies. Two patients died, 1 due to aspergillosis and the other due to vascular complications in the transplanted liver. Actuarial survival rates were 71.4% at 1 and 5 years. Chronic renal failure is not a contraindication to LT. CONCLUSION: CLKT is an acceptable option for these patients.

ABO-incompatible liver transplantation: a new therapeutic option for patients with acute liver failure in Chile.

Different ways have been suggested to expand donor numbers for liver transplantation. Transplantation using ABO-incompatible hepatic grafts has recently been a controversial issue due to the high risk of hyperacute rejection mediated by preformed anti-ABO antibodies. We report three patients with acute liver failure who were transplanted with ABO-incompatible livers: A to O in two patients and A to B in one case. We used pre- and posttransplant total plasma exchange, splenectomy, and triple immunosuppression. All three patients are alive; one graft was lost, probably secondary to thrombotic microangiopathy with low isohemagglutinin titers of 1:8. One patient developed acute cellular rejection that was reversed with a bolus of methylprednisolone. No antibody-mediated rejection occurred. Financial and infectious considerations have to be considered. In our series, the final liver transplantation cost was higher than average for acute liver failure. Plasmapheresis has the highest cost of all the additional procedures. ABO-incompatible liver transplantation, because of the splenectomy it requires, has been associated with more infections due to encapsulated organisms. However, with splenectomy in our three patients, none had infections due to these bacteria. In our country, we do not consider ABO-incompatible liver transplantation as a first-line option, except for highly selected patients.

Basiliximab: efficacy and tolerability in adults and children.

UNLABELLED: An open, single arm, prospective clinical trial to assess the efficacy and safety of basiliximab (Simulect) combined with cyclosporine microemulsion (Neoral), steroids, and azathioprine was performed in four centers in Chile, two adult and two pediatric. The 23 patients who were enrolled were followed for 12 months. There were four acute rejection episodes (three adults and one child) and three graft losses (two adults and one child) during the study. Renal function in both adult and pediatric patients at 6 and 12 months was good. Basiliximab was well tolerated. The incidence of infections was low, with only one CMV infection. There were no deaths. CONCLUSIONS: The incidence of acute rejection episodes among renal allograft recipients treated with basiliximab is low, showing that the drug is well tolerated. In particular the number of CMV infections is extremely low.

Outcomes of orthotopic liver transplantation in Chile.

Our liver transplant program was started in 1993 in a private clinic and a public hospital. Thereafter, a rapid increase in adults and pediatric candidates for this therapeutic option lead to this analysis of results in 165 orthotopic liver transplants (OLT) in 143 patients between November 1993 and December 2002. Seventy-four OLT were performed in 66 adult patients and 91 in the pediatric group. Liver grafts came from cadaveric donors in 145 cases (74 adults and 71 children). The technique of living-related donor was utilized in 20 pediatric cases. Main indications for OLT in the adult group were HCV cirrhosis, primary biliary cirrhosis; biliary atresia and acute liver failure were the indications in pediatric patients. Retransplantation was needed for 23 patients, including 9 adults and 14 children. The most frequent causes of death were sepsis, graft primary nonfunction, and vascular complications. Actuarial survivals at 1 and 5 years were 80.7% and 72.6% for the adult group and 82% and 74.8% for the pediatric group, respectively. Our results are comparable to those published by large, experienced, international centers, with much better financial support.

Epidemiology and results of liver transplantation for acute liver failure in Chile.

Acute liver failure (ALF) is a severe, life-threatening condition associated with a high mortality rate. The objective of this study is to present the experience of a Chilean liver transplant program with orthotopic liver transplantation (OLT) for ALF. All patients with the diagnosis of ALF evaluated in our program between January 1995 and May 2003 were included in the analyses of etiology and outcomes. Candidates for OLT activated on a national waiting list were transplanted with cadaveric or living-related donor (LRD) organs. Twenty-seven patients age 1 to 19 years (median, 7.4 years) were transplanted at a median weight of 30.7 kg including 17 cadaveric and 10 with LRD livers. Most frequent etiologies were hepatitis A in 10 cases (37%) and unknown in 12 (48.1%). One donor experienced superficial phlebitis. Four patients were retransplanted (14.8%). Twenty patients are alive with 1- and 5-year survival rates of 74.1% At a median follow up of 34 months (range = 2 to 120). Seven patients died due to sepsis, multiorganic failure, graft primary nonfunction, intracranial hemorrhage, and intraoperative cardiac arrest. This experience revealed results comparable to international reports, allowing survival of patients destined to die.

Results in laparoscopic living donor nephrectomy: a multicentric experience.

OBJECTIVE: Renal transplantation is the most successful therapy to improve survival and quality of life for patients with end-stage renal disease. Living donors have been used as an alternative to reduce the stay on the waiting list. Laparoscopic living donor nephrectomy has become the standard procedure for renal transplantation. Minimally invasive surgery involves less postoperative pain with less analgesic requirements allowing shorter hospital stay for the donor. MATERIAL AND METHODS: We retrospectively analyzed demographic and intraoperative data and surgical complications for 46 patients who underwent laparoscopic living donor nephrectomy between March 2001 and March 2011. RESULTS: Mean donor age was 41 years. Mean operative time was 170 ± 45 minutes. The average cold ischemic time was 40 minutes and warm ischemic time was 26 minutes. Twenty-one patients were donors for pediatric receptors. Fourty patients underwent left laparoscopic nephrectomy, the other 6 patients underwent right laparoscopic nephrectomy due to vascular anatomic variant. Right laparoscopic nephrectomy was converted in 1 case (2.2%) due to renal vein laceration without donor morbidity and without compromise of graft function. Renal function at the second day post donor nephrectomy was measured using serum creatinine averaged 1.2 mg/dL with a mean increase of 0.4 mg/dL from baseline, with normalization after 30 days. No patient required blood transfusion, and there were no immediate surgical complications, infections, or mortality. One patient developed an incisional hernia in relation to the site of kidney removal. The mean hospital stay was 5 ± 1 days. CONCLUSIONS: Laparoscopic nephrectomy in our experience is a safe technique without postoperative morbidity or mortality. It is associated with low levels of pain, early discharge and early return to physical activity and work, good sense of aesthetic results, and long-term graft function comparable to traditional nephrectomy and cadaveric grafts.

Liver transplantation in children weighing less than 10 kg: Chilean experience.

BACKGROUND: Orthotopic liver transplantation is the treatment of choice for most terminal liver diseases in children. In small children (≤ 10 kg), this procedure is challenging and has special considerations. The aim of this study is to describe the experience of a Chilean liver transplantation program in this subgroup of patients. METHODS: The liver transplant database of Hospital Luis Calvo Mackenna and Clinica Las Condes was reviewed. All children less than 10 kg undergoing liver transplantation between January 1994 and July 2011 were included. Patient and graft outcomes and main complications were analyzed. RESULTS: We have performed 230 pediatric liver transplantations, 49 of them in 41 patients weighing less than 10 kg. The first indication for transplantation was biliary atresia in 25 patients (61%). A living related donor was used in 23 cases (51%). Actuarial survival was 75.7% at 1 year and 67.1% at 5 years. The main cause of death was infection, and the leading cause of graft loss was vascular complication. DISCUSSION: Our transplant program includes 2 centers that perform more than 90% of pediatric liver transplantations in Chile, including public health pediatric patients from all around the country. Patients weighing less than 10 kg represent the most challenging group in pediatric liver transplantation due to higher rates of vascular and biliary complications and postoperative infections.

Pediatric liver transplantation experience and outcome in Chile.

INTRODUCTION: In 1994 our group began its experience with pediatric liver transplantation. The experience gained during this period is the largest in the country, positioning the Hospital Luis Calvo Mackenna and Clinica Las Condes as major referral centers in the public and private sectors. The aim of this study was to report our experience of our pediatric liver transplantation program during this period. METHODS: The liver transplantation database of Hospital Luis Calvo Mackenna and Clinica Las Condes between January 1994 and July 2011 was reviewed recording age, gender, indications for transplantation, surgical technique, complications, and survival. Survival rates were calculated using Kaplan-Meier analysis. RESULTS: During the period described 230 transplantations were performed in 189 pediatric patients. Fifty-five percent were male patients. The average age was 5 years. The main causes of transplantation were biliary atresia (50%), fulminant hepatic failure (25%), and other cholestatic diseases by 10%. Vascular and biliary complications were the leading cause of graft loss and retransplantation. The overall rate of retransplantation at 5 years was 20%. The technique of living donor was used in 28% of the cases. The 1-year patient actuarial survival rate was 80%, 73% at 5 years, and 68% at 10 years. In the last 3 years the survival rate at 1 year exceeds 90%. DISCUSSION: Our program includes more than 90% of the national liver experience. The incorporation of living donor is a milestone that has enabled us to save many patients who previously died while waiting for an organ. Its use in cases of full acute liver failure has allowed us to dramatically reduce mortality on the waiting list. Our results in the last 3 years reflect the experience that results in a significant decrease in mortality, comparing favorably to other series published in the international literature.

Alloantigen-specific response is preserved and autoimmunity is maintained in an HIV-positive patient with immunoglobulin A nephropathy undergoing renal transplantation: a warning about long-term reduction in immunosuppression--a case report.

We report the case of a 43-year-old patient with HIV infection treated with antiretroviral therapy, which was complicated by immunoglobulin A (IgA) nephropathy and renal failure, who subsequently was transplanted using a deceased donor kidney transplant. During the late posttransplant period we detected specific anti-donor HLA antibodies showing a preserved alloantigen response. A renal biopsy showed no acute cellular or humoral rejection, an absence of pericapillary C4d deposits or SV40 infected cells, but demonstrated IgA mesangial deposits and mild interstitial fibrosis probably related to calcineurin inhibitor toxicity. This case shows that allo- and autoimmune responses are preserved despite immunosuppressive treatment and original HIV disease. It warns of the importance of maintaining optimal monitoring and immunosuppressive strategies among HIV-positive recipients who become solid organ transplant recipients.

Late acute humoral rejection in low-risk renal transplant recipients induced with an interleukin-2 receptor antagonist and maintained with standard therapy: preliminary communication.

Low-risk renal transplant recipients treated with standard immunosuppressive therapy including interleukin-2 receptor (IL-2R) antagonist show a low incidence of early rejection episodes but few reports have examined the incidence and severity of late rejection processes. This study evaluated retrospectively cellular and antibody-mediated rejection (AMR) among 42 recipients selected because they showed low panel-reactive-antibodies, short cold ischemia time, no delayed graft function, and therapy including basiliximab (Simulect) induction. The mean observation time was 6.6 years. Sixty-seven percent of donors were deceased. Ten-year patient and death-censored graft survivals were 81% and 78%, respectively. Seven patients lost their kidneys due to nonimmunologic events. The seven recipients who experienced cellular rejection episodes during the first posttransplant year had them reversed with steroids. Five patients displayed late acute AMR causing functional deterioration in four cases including 1 graft loss. De novo sensitization occurred in 48% of recipients including patients without clinical rejection. In conclusion, long-term follow-up of kidney transplant recipients selected by a low immunologic risk showed a persistent risk of de novo sensitization evolving to acute AMR in 11% of cases. Although immunologic events were related to late immunosuppressive reduction, most graft losses were due to nonimmunologic factors.

Evaluation of late immunologic parameters among renal transplant recipients induced with Campath-1H.

Organ transplantation success depends principally on avoiding rejection, a purpose almost accomplished with immunosuppressant therapy. Nevertheless, drug side effects have promoted the search for other mechanisms to restrain alloresponses. T-regulatory cells (Treg) might exert that function. Campath 1H (C1H) induces Treg proliferation in the period subsequent to T-cell depletion following C1H administration. In the present study, the status of Treg and de novo HLA antibody production was determined posttransplantation when T-cell repopulation had been completed. In 14 patients, the following parameters were analyzed: renal function, rejection, Treg, panel-reactive antibody (PRA), and HLA antibodies. Patient and graft survivals were 100%. At the moment of Treg determination (20 months following transplant) the mean tacrolimus level was 8.4 ng/mL. One patient experienced an antibody-mediated rejection at 15 months after transplantation while having 3.2% Treg, with excellent treatment responses. Mean leukocyte and lymphocyte counts were 5752 and 1183 cells/mm(3); the mean peripheral blood percentage of Treg of 7.1% +/- 5.9% was not different from that observed in subjects without induction (mean 5.5% +/- 2.5%). Three patients (21%) showed Treg greater than 8.0%. In seven patients, we compared Treg at 4 and 20 months posttransplant, observing a decline from a mean of 19.9% to 5.9% (P = .05). In seven recipients, posttransplant PRA was determined; five of them became "de novo" sensitized, three with a mean class I PRA of 16% and two with a mean class II PRA of 37%. In conclusion, patient and graft survivals were excellent, mean Treg percentage was not elevated with results lower than in the early posttransplant period. Rejection incidence was negligible. Late "de novo" sensitization occurred in 70% showing that B cell-mediated alloresponses were only partially controlled among recipients induced with C1H even when associated with sustained anticalcineurin treatment.