Mycophenolate mofetil decreases rejection in simultaneous pancreas-kidney transplantation when combined with tacrolimus or cyclosporine

BACKGROUND: Historically, the acute rejection rates in simultaneous pancreas-kidney (SPK) recipients have been extremely high (50-80%), with many second and third rejection episodes despite the use of quadruple immunosuppression (antibody induction and cyclosporine [CsA]-azathioprine [AZA]-based maintenance immunosuppression). Although this acute rejection has rarely led to graft loss, it has been a great cause of morbidity and of significantly increased cost. In an attempt to decrease the acute rejection rate and related morbidity in SPK transplant recipients, we compared two "state-of-the-art" immunosuppression regimens in a prospective, randomized, single-center study. METHODS: Patients who received SPK transplants were randomized to receive either tacrolimus (TAC) and mycophenolate mofetil (MMF, n=18) or CsA (Neoral formulation) and MMF (n=18). All patients received OKT3 induction and prednisone, which was tapered to 5 mg/day by 6 months after transplantation. All rejection episodes were biopsy proven. In addition, metabolic control (HgbA1C, hypertension, serum cholesterol), drug toxicity, and infection also were measured. Data were compared with that of a historical group (n=18) who received conventional CsA (Sandimmune formulation) and AZA-based immunosuppression. RESULTS: The incidence of biopsy-proven acute rejection was 11% in both the TAC-MMF and CsA-MMF groups with only two patients in each group experiencing a rejection episode. This rejection rate was significantly decreased from that of the CsA-AZA historical group (77%, P<0.01). There were no significant differences in infection rates, including cytomegalovirus, or in metabolic control (HgbA1C, hypertension, and cholesterol levels). All patients remained on their initial immunosuppression regimen for the first 3 months after transplantation. Between 3 and 6 months after transplantation, three patients were switched from TAC to CsA for recurrent migraine headaches, posttransplant diabetes, and chronic cytomegalovirus infection. Two patients in the CsA-MMF group died of nonimmunologic causes (aspiration pneumonia and arrhythmia) between 3 and 6 months after transplantation. CONCLUSIONS: The data from this study show that MMF treatment significantly decreases the incidence of biopsy-proven acute rejection in SPK transplant recipients compared with AZA-treated historical controls. In addition, we conclude that TAC and CsA (Neoral), when combined with MMF, yield similar, low acute rejection rates with similar graft function and metabolic control.     

Nicardipine as antihypertensive therapy in liver transplant recipients: results of long-term use

Arterial hypertension is frequent in liver transplant recipients on cyclosporine A (CsA). Nicardipine is a calcium channel blocker (CCB) that has been shown to be efficient in controlling postoperative hypertension. However, its use has been limited in organ recipients because of its reported interaction with CsA metabolism. In this report, we studied the results of the long-term use of nicardipine after liver transplantation. Forty-nine consecutive liver transplant recipients with a follow-up longer than 2 years were studied. Immunosuppressive regimen was based on CsA and prednisone. Patients with immediate postoperative hypertension received intravenous nicardipine, secondarily switched to oral nicardipine (group 1, n = 27). Patients with delayed hypertension (i.e., >2 weeks posttransplant) received other antihypertensive drugs which did not interact with CsA metabolism. These patients and those without hypertension formed group 2 (n = 22). The two groups were similar for age, sex, body weight, and transplantation indications. Interaction of nicardipine with CsA metabolism was confirmed. Whereas cyclosporine blood levels were similar in both groups at any time during the study, the mean cyclosporine daily dose required to achieve such levels was 30% lower in group 1 compared with group 2 (P < .01). This resulted in a significant cost-containment. The use of nicardipine was not associated with an increased incidence of graft rejection or CsA toxicity episodes. The results in liver transplant recipients showed that nicardipine interacts with CsA metabolism, leading to a 30% reduction in CsA dose and does not increase the risk of CsA toxicity or graft rejection. Nicardipine can be used safely for the treatment of arterial hypertension after liver transplantation with a potential cost-containment.     

CsA levels in the early posttransplant period--predictive of chronic rejection in liver transplantation?

The increasing success of clinical liver transplantation has brought rejection to the forefront as a cause of morbidity and graft loss. The relationship of immunosuppressive drug doses and levels to acute and chronic rejection remains a matter of debate. The effect of blood CsA levels and drug doses on the incidence of acute and chronic rejection and the impact of acute rejection episodes on the occurrence of chronic rejection were studied in 146 grafts in 132 patients. These patients were transplanted in the 4-year period from June 1989 using CsA-based immunosuppression (CsA, azathioprine, prednisolone). Liver grafts in patients maintained on median CsA levels (whole blood, trough level) of > or = 175 micrograms/L in the first 28 days posttransplant had a significantly lower incidence of chronic rejection (2 out of 49 vs. 22 out of 97; P = 0.002). There was no significant difference in incidence of graft loss due to fatal sepsis (6% vs. 5%) or nephrotoxicity between the high and low CsA level groups. The overall graft loss rate was lower in the higher CsA level group (22% vs. 37%). The total doses of the individual drugs did not correlate with the incidence of acute or chronic rejection. Although the occurrence of acute rejection itself did not determine later chronic rejection, late occurrence (P < 0.00001) and multiple episodes (two or more; P = 0.0002) of acute rejection were significant risk factors for the occurrence of chronic rejection. We conclude that to minimize graft loss to rejection, CsA levels should be maintained at greater than 175 micrograms/L in the early posttransplant period, and late and recurrent episodes of acute rejection should be prevented.     

A comparison of tacrolimus (FK506) and cyclosporine for immunosuppression after cadaveric renal transplantation. FK506 Kidney Transplant Study Group

BACKGROUND: Tacrolimus (FK506), a macrolide molecule that potently inhibits the expression of interleukin 2 by T lymphocytes, represents a potential major advance in the management of rejection following solid-organ transplantation. This randomized, open-label study compared the efficacy and safety of tacrolimus-based versus cyclosporine-based immunosuppression in patients receiving cadaveric kidney transplants. METHODS: A total of 412 patients were randomized to tacrolimus (n=205) or cyclosporine (n=207) after cadaveric renal transplantation and were followed for 1 year for patient and graft survival and the incidence of acute rejection. RESULTS: One-year patient survival rates were 95.6% for tacrolimus and 96.6% for cyclosporine (P=0.576). Corresponding 1-year graft survival rates were 91.2% and 87.9% (P=0.289). There was a significant reduction in the incidence of biopsy-confirmed acute rejection in the tacrolimus group (30.7%) compared with the cyclosporine group (46.4%, P=0.001), which was confirmed by blinded review, and in the use of antilymphocyte therapy for rejection (10.7% and 25.1%, respectively; P<0.001). Impaired renal function, gastrointestinal disorders, and neurological complications were commonly reported in both treatment groups, but tremor and paresthesia were more frequent in the tacrolimus group. The incidence of posttransplant diabetes mellitus was 19.9% in the tacrolimus group and 4.0% in the cyclosporine group (P<0.001), and was reversible in some patients. CONCLUSIONS: Tacrolimus is more effective than cyclosporine in preventing acute rejection in cadaveric renal allograft recipients, and significantly reduces the use of antilymphocyte antibody preparations. Tacrolimus was associated with a higher incidence of neurologic events, which were rarely treatment limiting, and with posttransplant diabetes mellitus, which was reversible in some patients.     

Primary immunosuppression with mycophenolate mofetil and antithymocyte globulin for kidney transplant recipients of a suboptimal graft

BACKGROUND: In renal transplantation the beneficial immunosuppressive effects of cyclosporin (CsA) may be curtailed by its nephrotoxicity, specially in patients receiving a cadaveric allograft from suboptimal donors or at risk of delayed graft function. Mycophenolate mofetil (MMF) and antithymocyte globulin (ATG) have each demonstrated to be potent immunosuppressants in renal transplantation. In a prospective analysis we have studied the results at 6 months of the combination of MMF, ATG and low-dose steroids in patients with low immunological risk receiving a first cadaveric renal allograft from a suboptimal donor or at risk of delayed graft function. METHODS: Patients with preformed reactive antibodies < 500% receiving a first graft from a suboptimal donor (age > or = 40 years, non-heart-beating, acute renal failure, arterial hypertension) or at risk of delayed graft function (cold ischaemia time > or = 24 h) were eligible for this open single-arm pilot trial. From September 1996 to March 1997 we recruited 17 patients. They were treated with MMF 2 g p.o. preoperatively, and after transplantation at 3 g/day; rabbit ATG i.v. at 2 mg/kg preoperatively, and 1.5 mg/kg/day the first day after transplantation, followed by four doses of 1 mg/kg on alternate days; prednisone was given at 0.25 mg/kg/day and reduced progressively to 0.1 mg/kg/day at 3 months. Primary outcomes were incidence of biopsy-proven acute rejection, delayed graft function, opportunistic infections, graft and patient survival, and the need for introduction of CsA treatment. RESULTS: delayed graft function occurred in two cases (12%). Four of 17 patients (24%) had a biopsy-proven acute rejection (2 grade I and 2 grade II) within the first 3 months after transplantation. CsA was added in two cases with grade II biopsy-proven acute rejection, and in one with grade I biopsy-proven acute rejection. In one patient MMF was replaced by CsA because of gastrointestinal intolerance. Mean serum creatinine 6 months after transplantation was 159+/-59 micromol/1. Cytomegalovirus tissue invasive disease occurred in one patient (6%). At 6 months follow-up all patients are alive with functioning allografts. CONCLUSIONS: These preliminary results suggest that in low-immunological-risk patients who receive a suboptimal renal allograft or at risk of delayed graft function, the combination of MMF, ATG, and steroids is an efficient immunosuppressive regime that may avoid the use of CsA in 70% of the recipients.     

Steroid withdrawal from long-term immunosuppression in liver allograft recipients

Corticosteroids were withdrawn from the immunosuppressive regimen of 168/197 (85%) of liver transplant patients who survived for more than three months. In 14, steroids were restarted for reasons other than rejection. The remaining 154 patients were evaluated for the occurrence of rejection and graft loss. Risk factors for the development of rejection after steroid withdrawal were assessed. There were 13 episodes of rejection in 12 (7.8%) grafts; 7 (4.5%) experienced acute cellular rejection, and 6 (3.9%) developed chronic ductopenic rejection. All cases of acute rejection resolved with high-dose steroids. Graft and patient loss due to chronic rejection was 3 (1.9%) and 2 (1.3%), respectively. Chronic rejection resolved in 1 patient, 1 was successfully retransplanted, and in the other 2 the principal cause of death was recurrent tumor. None of the risk factors examined (primary indication for transplant, severity of previous acute rejection, use of OKT3, retransplantation, ABO blood group donor/recipient match, CMV infection, and CsA mono versus CsA and AZA double therapy) were associated with the development of chronic rejection poststeroid withdrawal. The prevalence of side effects, after steroid withdrawal, was low; 66% of patients never required antihypertensive medication; 14% experienced a significant septic episode, and only 4 died with sepsis as the major factor. There were no fungal sepsis and no new cases of diabetes. Withdrawal of corticosteroids after 3 months can be successfully achieved in the majority of liver allograft recipients and is associated with a low rate of rejection, graft loss, and complications attributable to immunosuppressive medication.     

Study of the beta -delayed neutron decay of 18N

The shortage of suitable liver donors for children has motivated the use of ABO-incompatible (ABO-I) grafts for transplantation in urgent situations. However, survival after ABO-I liver grafts has been reported at about 30% as compared with 80% in cases of ABO-identical or -compatible liver grafts. This difference has been attributed to antibody-mediated, hyperacute or chronic liver rejection, due to preformed ABO antibodies (alloantibodies). In this study, we report our results with ABO-I livers in children without alloantibodies at the time of transplantation. From January 1988 to June 1993, 143 OLT were performed in 122 children. Eight children received 8 ABO-I liver grafts. Of these, 7 patients were included in the study. All 7 were alloantibody free before OLT. Five children were spontaneously alloantibody free, while in 2 children, the plasma alloantibodies were eliminated before and after transplantation using intravenous infusion of specific blood group antigens of the donor blood group (soluble antigens). Immunosuppression consisted of a triple-drug treatment combining CsA, AZA, and steroids. The follow-up period was between 10 and 48 months. One child died from a surgical complication. Six children survived, but 1 died 10 months later from intestinal obstruction. There were no graft losses and no episodes of hyperacute or chronic rejection. The graft and patient survival rate was 71%. There was a 28% incidence of rejection, but all were mild (requiring steroid boluses only). Our results suggest that the absence of ABO alloantibodies at the time of and after transplantation can protect ABO-I liver grafts against antibody-mediated rejection, whether hyperacute or chronic, and that soluble antigens are effective in eliminating alloantibodies in children.     

Long-term outcome of a prospective randomized trial of conversion from cyclosporine to azathioprine treatment one year after renal transplantation

BACKGROUND: Since the introduction of cyclosporine (CsA), 1-year renal allograft survival has improved, but concern persists about the long-term adverse effects of CsA, especially with respect to renal function and blood pressure. This randomized controlled trial was set up to establish whether withdrawal of CsA would alter long-term outcome. METHODS: Adult patients who, at 1 year after renal transplantation, had a stable serum creatinine of less than 300 micromol/L and who had not had acute rejection within the last 6 months were eligible for entry. Patients were randomized either to continue on CsA (n=114) or to stop CsA and start azathioprine (Aza, n=102). All patients remained on prednisolone. Median follow-up was 93 months after transplantation (range: 52-133 months). RESULTS: There was no significant difference in actuarial 10-year patient or graft survival (Kaplan-Meier), despite an increased incidence of acute rejection within the first few months after conversion. Median serum creatinine was lower in the Aza group (Aza: 119 micromol/L; CsA. 153 micromol/L at 5 years after randomization, P=0.0002). The requirement for antihypertensive treatment was also reduced after conversion to Aza; 75% of patients required antihypertensive treatment at the start of the study, decreasing to 55% from 1 year after randomization in the Aza group and increasing to >80% in the CsA group (55% (Aza) and 84% (CsA) at 5 years after randomization, P<0.005). CONCLUSIONS: Conversion from CsA to Aza at 1 year after renal transplantation results in improvement in both blood pressure control and renal allograft function, and is not associated with significant adverse effects on long-term patient or graft survival.     

The Nordic multicenter double-blind randomized controlled trial of prophylactic ursodeoxycholic acid in liver transplant patients

BACKGROUND: Prophylactic treatment with ursodeoxycholic acid (UDCA) has been reported to reduce the incidence of acute rejection after liver transplantation compared with historical controls. We investigated this in a prospective, randomized, placebo-controlled multicenter study. METHODS: Fifty-four liver transplant patients were allocated to the UDCA treatment group (15 mg/kg/day), and 48 patients were allocated to the placebo group. Trial medicine was started on the first postoperative day and was given for 3 months. Follow-up was for 12 months. Treatment was stratified for adults with chronic liver disease (n=77), adults with acute liver failure (n=10), and children (n=15). RESULTS: The frequency of patients with acute rejection was 65% in the UDCA treatment group and 68% in the placebo group. The frequency of steroid-resistant rejection was similar in both groups. The probability of acute rejection, analyzed according to the intention-to-treat policy with Kaplan-Meier analysis, was similar in both treatment groups. No significant differences were found in patient survival and graft survival probabilities. For the biochemical markers of cholestasis, only gamma-glutamyltransferase was significantly improved after 2 months of UDCA treatment. CONCLUSIONS: The initial optimistic report of a beneficial effect of prophylactic treatment with UDCA on acute rejection after liver transplantation was not confirmed in this controlled study.     

Ten years of liver transplantation: an evolving understanding of late graft loss

BACKGROUND: We undertook this study to understand the causes of late graft loss and long-term outcome in orthotopic liver transplantation (OLT) recipients. METHODS: Prospectively collected data of 1174 consecutive OLT in 1045 adult patients who received liver grafts between April 1985 and August 1995 were reviewed. The causes of graft loss, pretransplant patient characteristics, and posttransplant events were analyzed in patients who survived at least 1 year after OLT, in an attempt to establish a link between these factors and graft loss. RESULTS: One hundred fifty-nine (17.9%) grafts were lost after the first year. Of these, 132 grafts were lost by death and 27 by retransplantation. Recipients who survived the first year (n=884) had 5- and 10-year survivals of 81.4% and 67.2%, respectively. Death with a functioning graft occurred in 97 (61%) patients. The main causes of late graft loss were recurrent disease (n=48), cardiovascular and cerebral vascular accidents (n=28), infections (n=24), and chronic rejection (n = 15). Pretransplant heart disease and diabetes were found to be significant risk factors for late graft loss due to cardiovascular diseases and cerebral vascular accidents. CONCLUSIONS: Survival of OLT patients who live beyond the first posttransplant year is excellent. Some patient characteristics may be associated with late graft loss. Compared with previous reports, this study shows an increased incidence of late graft loss secondary to recurrent diseases, de novo malignancies, cardiovascular diseases, and cerebral vascular accidents. Chronic rejection seems to be a less frequent cause of late graft loss. The prevention of recurrent disease and better immunosuppression may further improve these results.     

Gastric bypass in morbidly obese kidney transplant recipients

Severe post-transplant obesity has previously been shown to have a negative impact on graft survival following kidney transplantation. It also contributes to late patient mortality and is associated with hypertension, diabetes and hyperlipidemia. We undertook Roux-en-Y gastric bypass (GBP) in three morbidly obese (200-260% ideal body weight) (IBW) patients 6-8 yr following kidney transplantation. Roux-en-Y gastrojejunostomy to a 30 ml stapled gastric pouch was created with the jejunojejunostomy (both loops) 80-120 cm from the ligament of Treitz. By 12 months post-GBP, weight loss plateaued at 100-150% IBW. Both patients that had developed post-transplant diabetes mellitus (PTDM) had complete resolution within 9 months following GBP. On average the patients required 3 less hypertension (HTN) medications after GBP; 2 of the 3 patients are now normotensive off medication. Improvements in hyperlipidemia were also shown. The absolute cyclosporine (CsA) requirement (mg/d) increased by approximately 33% (p = NS), and there was also a significant increase in the weight adjusted CsA requirement from 1.8 to 3.5 mg/kg/d (p = 0.02, ANOVA) following GBP in order to maintain similar TDX trough CsA levels. GBP offers significant reduction in weight, HTN, PTDM and hyperlipidemia in morbidly obese kidney transplant recipients. However, CsA dose requirements may increase after GBP as a consequence of the defunctionalized intestine.     

The significance of citrate, uromucoid and GAG for diagnosis of renal tubular acidosis in patients with urinary calculi]

BACKGROUND: The purpose of this study was to determine the effects of early postoperative tube feeding on outcomes of liver transplant recipients. METHODS: Fifty transplant patients were randomized prospectively to receive enteral formula via nasointestinal feeding tubes (tube-feeding [TF] group) or maintenance i.v. fluid until oral diets were initiated (control group). Thirty-one patients completed the study. Resting energy expenditure, nitrogen balance, and grip strength were measured on days 2, 4, 7, and 12 after liver transplantation. Calorie and protein intakes were calculated for 12 days posttransplant. RESULTS: Tube feeding was tolerated in the TF group (n = 14). The TF patients had greater cumulative 12-day nutrient intakes (22,464 +/- 3554 kcal, 927 +/- 122 g protein) than did the control patients (15,474 +/- 5265 kcal, 637 +/- 248 g protein) (p < .002). Nitrogen balance was better in the TF group on posttransplant day 4 than in the control group (p < .03). There was a rise in the overall mean resting energy expenditure in the first two posttransplant weeks from 1487 +/- 338 to 1990 +/- 367 kcal (p = .0002). Viral infections occurred in 17.7% of control patients compared with 0% of TF patients (p = .05). Although other infections tended to occur more frequently in the control group vs the TF group (bacterial, 29.4% vs 14.3%; overall infections, 47.1% vs 21.4%), these differences were not statistically significant. Early posttransplant tube feeding did not influence hospitalization costs, hours on the ventilator, lengths of stay in the intensive care unit and hospital, rehospitalizations, or rejection during the first 21 posttransplant days. CONCLUSIONS: Early posttransplant tube feeding was tolerated and promoted improvements in some outcomes and should be considered for all liver transplant patients.     

National Transplantation Pregnancy Registry: analysis of pregnancy outcomes in female liver transplant recipients

Outcomes from 48 pregnancies in 34 female liver transplant recipients were analyzed. Data were collected via interviews, questionnaires, and hospital records. All recipients were treated with cyclosporine-based immunosuppression except 2 patients treated with FK506 and 2 treated with no immunosuppression. The age at conception was 26.1 +/- 5.9 years (mean +/- SD) with a transplant interval (time from transplantation to conception) of 2.9 +/- 2.5 years. There were 49 outcomes (1 set of twins): miscarriage 9 (18%), therapeutic abortion 4 (8%), and live birth 36 (74%). No stillbirths or ectopic pregnancies were reported. Of the 36 live births, the gestational age was 36.9 +/- 3.5 weeks, the birthweight was 2,604 +/- 698 grams, 39% were premature (< 37 weeks), and 31% had low birthweight (< 2,500 grams). No birth defects or neonatal deaths (< 28 days) were reported. The newborn complication rate was 17% (n = 6), 5% in premature infants. The incidence of drug-treated hypertension was 46%; pre-eclampsia 21%; infectious complications 26%; and Caesarean section 47%. Recipients with hypertension had a higher proportion of premature infants (71%) than normotensive patients (38%) (P = .04 by Fisher's exact test). Acute rejection was diagnosed in 6 pregnancies, 2 of which were ended by therapeutic abortion. Four recipients who continued their pregnancies were treated with increased immunosuppression for rejection, and all delivered livebirths. There were two grafts lost within 6 months of pregnancy. The only maternal death occurred in a patient who required retransplantation for recurrent C hepatitis 3 months afte therapeutic abortion and died 6 months later. The other recipient with graft loss was successfully retransplanted for chronic rejection 6 months after delivery. We draw the following conclusions: (1) female liver transplant recipients can safely undergo pregnancy, although there is a high rate of premature and low birthweight infants; (2) pregnancies in this population should be considered high-risk and require close monitoring of liver function; and (3) altered graft function during pregnancy should be thoroughly investigated.     

Emergency medicine: the Italian experience

BACKGROUND: Studies using tacrolimus and corticosteroids or the combination of cyclosporine, mycophenolate mofetil, and corticosteroids have been shown to reduce the incidence of biopsy-proven acute rejection episodes in cadaveric kidney recipients compared with cyclosporine-based immunosuppression. The current study is a retrospective analysis of our experience with tacrolimus combined with mycophenolate mofetil and steroids as primary immunosuppression for kidney transplant recipients. METHODS: In a retrospective analysis, 72 patients who received primary therapy with tacrolimus, mycophenolate mofetil, and corticosteroids (triple therapy) were compared with a control group of 98 kidney recipients who received tacrolimus and corticosteroids (double therapy). RESULTS: There was a significant reduction in the incidence of biopsy-confirmed acute rejection in the triple therapy group (8.2%) compared with the double therapy group (21%; P=0.003). One-year patient and graft survival did not differ between groups. The incidence of posttransplant diabetes mellitus was 18% and 21% in the triple and double therapy groups, respectively. Leukopenia and gastrointestinal side effects were the most common cause for discontinuation of mycophenolate mofetil. CONCLUSIONS: The combination of tacrolimus with mycophenolate mofetil and corticosteroids is more effective at preventing early acute rejection than tacrolimus and corticosteroids alone. The use of mycophenolate mofetil was associated with a higher incidence of leukopenia and diarrhea, often leading to discontinuation of the drug.     

Long-term improvement in renal function after cyclosporine reduction in renal transplant recipients with histologically proven chronic cyclosporine nephropathy

BACKGROUND: Chronic cyclosporine (CsA) nephropathy, which has been unequivocally documented in recipients of heart, heart-lung, liver, or bone marrow transplants, as well as in nontransplant situations, usually results in a progressive deterioration of renal function. In this study, we assessed the potential reversibility of chronic CsA nephropathy in renal transplant recipients. PATIENTS AND METHODS: Twenty-three renal transplant patients with biopsy-proven CsA nephropathy associated with long-term CsA administration (27+/-4 months) were followed up for more than 2 years after CsA reduction (18/23 patients) or withdrawal (5/23 patients) and addition of azathioprine. Changes in effective renal plasma flow and glomerular filtration rate were assessed before and 2 years after CsA reduction, whereas serum creatinine, proteinuria, blood pressure, and CsA concentrations were monitored up to 5 years. RESULTS: At 2-year follow-up, glomerular filtration rate increased from 40+/-3 to 47+/-4 (P<0.05) and effective renal plasma flow from 217+/-23 to 244+/-24 ml/min/1.73 m2 (NS). Mean arterial pressure significantly decreased from 98.7+/-2.9 to 93.1+/-2.7 mmHg (P<0.05). There was no significant change in renal vascular resistance, filtration fraction, or albumin excretion. A significant decrease in serum creatinine was also observed during the whole follow-up (73+/-6.5 months). CsA reduction was followed by only one episode of acute reversible rejection; chronic rejection developed in three patients 2 years or later after CsA reduction. CONCLUSIONS: These data suggest that CsA nephropathy participates in graft dysfunction in a small group of renal transplant recipients. In addition, graft dysfunction may be reversible when CsA dosage is reduced early after diagnosis of chronic CsA nephropathy.     

Hypertension two years after renal transplantation: causes and consequences

The incidence of hypertension 2 years after renal transplantation and the possible causes of hypertension were studied retrospectively. A group of 93 patients treated with cyclosporin (CyA), azathioprine (Aza), and/or prednisolone (Pred) were compared to a group of 31 patients treated with Aza and Pred. There were more patients with hypertension in the CyA group (73%) than in the Aza group (58%). Hypertension before transplantation predisposed to hypertension after transplantation. After transplantation, hypertension was most common among patients with polycystic kidney disease (46%), chronic glomerulonephritis (67%), and diabetes (71%). The accumulated immunosuppressive medication (CyA/Pred) did not affect the occurrence of hypertension. Hypertensive patients had significantly poorer graft function than did normotensive patients (serum creatinine level 229 mumol/l vs 162 mumol/l, P < 0.01). The 10-year graft survival was markedly impaired in the group with hypertension (42% vs 65% for normotensives, P < 0.05). The 10-year patient survival was 59% vs 79% (P = NS). The study further confirms the frequent finding that hypertension has a negative effect on graft and patient survival rates.     

Toxicities of tacrolimus and cyclosporin A after allogeneic blood stem cell transplantation

To determine how well tacrolimus (FK506) and cyclosporin A (CsA) are tolerated after HLA-identical blood stem cell transplantation, we performed a retrospective review of 87 adults transplanted consecutively who received FK506 (n = 40) or CsA (n = 47) in a nonrandomized fashion in combination with methylprednisolone for graft-versus-host disease (GVHD) prophylaxis and compared the incidences of complications potentially related to the immunosuppressive agents. Pre-transplant demographic characteristics, drug compliance and rates of acute GVHD were comparable for the two groups. Following first discharge, fewer patients in the FK506 group required antihypertensive therapy (32 vs 59%, P = 0.022), but more required insulin (34 vs 10%, P = 0.014). There was also a trend for more hyperkalemia and less moderate-to-severe venoocclusive disease in the FK506 group. However, nephrotoxicity, neurotoxicity, hemolytic-uremic syndrome, and cytomegaloviral or fungal infections through the first 100 days post-transplant did not differ significantly between the two groups. We conclude that for allogeneic blood stem cell transplant recipients, the incidence of complications related to FK506 and CsA in equally effective dose schedules in combination with methylprednisolone are similar with the exception of the risks of hypertension and hyperglycemia.     

Impact of Sandimmune, Neoral, and Prograf on rejection incidence and renal function in primary liver transplant recipients

Following primary liver transplantation, immunosuppressive efficacy of Neoral and Prograf was similar and superior to that of Sandimmune. Rejection incidence was statistically increased with Sandimmune therapy. Incidence of hypertension, posttransplant diabetes mellitus, and infectious complications was not statistically different. Although early compromise in renal function was associated with Sandimmune, Neoral, and Prograf immunosuppression, no progressive renal dysfunction was identified.     

Risks of subsequent pregnancies on mother and newborn in female heart transplant recipients

BACKGROUND: Female heart transplant recipients are able to carry pregnancies successfully. This study evaluates the effect of subsequent pregnancies on newborn and maternal outcomes and graft survival. METHODS: Subjects were identified through a previously reported multicenter study, case reports from literature review, and recipients entered in the National Transplantation Pregnancy Registry. A retrospective analysis was completed of 35 heart transplant recipients with first pregnancies (FP) and 12 who had one or two additional pregnancies (P>1). Newborns were assessed for gestational age, neonatal birth weight, and complications. Maternal data included pregnancy outcome, peripartum complications, including infection and rejection, current graft function, and recipient survival. RESULTS: Forty-seven pregnancies (35 FP and 12 P>1) from 35 heart transplant recipients were studied. FP outcomes included 26 live births (one set of twins), four miscarriages, and six therapeutic abortions, whereas P>1 outcomes included 11 live births (one set of twins), and two miscarriages. There was no significant difference between mean birth weights (2353+/-986 gm vs 2588+/-521 g, P>1 vs FP; mean+/-SD; p=NS) or prematurity incidence (<37 weeks; 50% vs 40%; p=NS) for the live-born infants. Compared with the FP group, there was a trend toward increased neonatal complications in P>1 (40% vs 12%; p=NS). Complications were significantly more common in premature newborns compared with full-term newborns (33% vs 5%; p < 0.05). No structural malformations were identified in the live-born infants. Maternal complication rates were the same in both groups (40%). Of 28 recipients available for follow-up, the maternal survival rate was 75% for the FP group and 89% for the P> group. Mean rejection rate per year was slightly increased after pregnancy in the P>1 group. Surviving recipients had similar graft function by echocardiographic left ventricular ejection fraction. CONCLUSIONS: Post-heart transplantation pregnancies often have successful outcomes, but there is a high incidence of prematurity and low birth weight. Subsequent pregnancies do not seem to significantly increase the incidence of complications in either the newborn or mother or increase graft rejection or failure. Larger studies of posttransplantation pregnancies may provide more definitive information.     

Circulating ICAM-1, E-selectin, IL-2 receptor, and HLA class I in human small bowel, liver, and small bowel-plus-liver transplant recipients

Recently, soluble(s) circulating isoforms of intercellular adhesion molecule-1 (sICAM-1) and sE-selectin (formerly endothelial leukocyte adhesion molecule-1) have been described in normal human serum. Elevated levels have been reported in acute and chronic inflammatory disorders, including allograft rejection. In this study, plasma levels of sICAM-1 and sE-selectin were determined in groups of tacrolimus (FK 506)-treated adult patients following either isolated small bowel (SB), liver, or combined SB plus liver (SB/L) transplantation. Each molecule was measured at 1, 2, 4, 6, 8, and 12 weeks (all patients) and at 6, 9, and 12 months after transplantation (SB and SB/L only) by enzyme linked immunosorbent assay. Levels were compared with those of soluble interleukin-2 receptor (sIL-2R; a marker of lymphocyte activation) and soluble HLA class I (which has been reported to be elevated in liver transplant-related complications). Elevations above normal in mean plasma levels of sICAM-1 (2.4-fold), sE-selectin (1.8-fold), sIL-2R (10.6-fold), and sHLA class I (1.3-fold) were found in patients with stable isolated SB grafts during the first 12 weeks posttransplant. Except for sHLA class I, levels of each protein were subsequently reduced, up to 1 year posttransplant. However, further increases in sICAM-1 and in sIL-2R and sE-selectin levels were observed during episodes of SB rejection compared with stable grafts. Mean levels of all molecules were higher in patients with isolated SB grafts compared with those given liver or combined (SB/L) transplants, either during stable SB graft function (up to 12 weeks posttransplant) or rejection. The data demonstrate increased adhesion molecule production/shedding following SB transplantation and are suggestive of a reduced overall level of immune activation in liver and SB/L compared with isolated SB transplantation.