Renal function outcome in pediatric liver transplant recipients

The orthotopic liver transplantation (OLT) allows survival of children followed for severe hepatic injury, provided that the immunosuppressive treatment is prolonged. The nephrotoxicity of cyclosporine predicts the long-term outcome of the adult patients receiving a liver transplant. The aim of this study was to determine the long-term outcome of renal function in children receiving OLT. This study included 12 children, with a median for age of 7.1 yr (2-15 yr) at the time of OLT. The duration of follow-up was at least 4 yr, being 7 yr in 10 patients and more than 10 yr in seven. Renal function was evaluated with the serum level of creatinine, calculated glomerular filtration rate (cGFR), and measurement of glomerular filtration rate using chrome 51 ethylenediaminetetraacetate ((51)Cr EDTA) clearance performed at least once during follow-up. The doses and the serum concentrations (C(0)) of cyclosporine were reported at each study time. The cGFR decreased significantly 2 yr after the OLT [median (range): 106 mL/min/1.73 m(2) (71-150) at the time of OLT vs. 85 mL/min/1.73 m(2) (57-128) 2 yr after the OLT, p = 0.03], and decreased again between 7 and 10 yr after OLT [median (range): 99 mL/min/1.73 m(2) (76-125) 7 yr after OLT vs. 81 mL/min/1.73 m(2) (66-140) 10 yr after OLT, p = 0.04]. Six patients developed chronic renal failure (cGFR from 57 to 80 mL/min/1.73 m(2)) 2 yr after OLT associated with high doses of cyclosporine [median (range): 8.8 mg/kg/day (3.5-13)]. The cGFR overestimated renal function by 16% compared with the isotopic measurement of GFR (p = 0.03). Using the (51)Cr EDTA measurement, six of seven patients followed up more than 10 yr after OLT presented mild (n = 3) or moderate (n = 3) chronic renal failure. In our study, the majority of OLT recipients developed a chronic renal failure 10 yr after transplantation. Cyclosporine seems to be the most important factor responsible for the impairment of renal function. The use of the mycophenolate mofetil, a new immunosuppressive agent, allowing a reduction in the dose of cyclosporine, could minimize renal dysfunction. While awaiting the results of a prospective long-term study, close drug monitoring is advised.     

Fading renal hyperfiltration in children following liver transplantation

In a prospective longitudinal study, we investigated the renal function (RF) of 23 children before and after orthotopic liver transplantation (OLT). The aim was to assess both the outcome of pretransplant hyperfiltration and the clinical nephrotoxic effects of cyclosporin A (CsA); children with decreased RF prior to OLT were therefore excluded. The RF study of the 13 remaining patients included glomerular filtration rate (GFR) and effective renal plasma flow (RPF) measured by inulin (Cin: mL/min/1.73 m2) and para-amino hippurate (Cpah: mL/min/1.73 m2) clearances, respectively. Hyperfiltration prior to OLT was observed in six children, i.e. Cin>170 [range 172-230] and Cpah>800 [808-1,133]. A significant decrease in RF was noted as soon as 6 months after OLT: Cin (mean+/-SD)=107+/-23 vs. 158+/-46 (p<0.003); Cpah=583+/-119 vs. 791+/-243 (p<0.004). This was due to loss of hyperfiltration in the six children, as there was no significant difference in RF before and 6 months after OLT in the other seven children. With a 36-month follow-up, there was no correlation between CsA trough blood level and RF. In conclusion, following OLT, RF underwent early changes owing to loss of prior hyperfiltration in children without impaired RF before OLT. In addition, no evidence of CsA nephrotoxicity was found and RF remained stable during follow-up.     

Improved long-term allograft function in pediatric renal transplantation with mycophenolate mofetil

MMF has been shown to decrease the incidence of acute rejection in children and adults at 1 and 3 yr. Other beneficial effects of MMF have been more difficult to demonstrate. Our open-labeled study presents a 5-yr data for patients and graft survival, allograft function, and growth in MMF-treated patients. The trial included 29 patients who were treated with MMF in combination with cyclosporine and methylprednisone. Patients were compared with a preceding group of 29 patients treated with AZA instead of MMF. Patient and graft survival rate 5 yr after transplantation were 97 and 90% in the MMF group vs. 93 and 83% in the AZA group (p: NS). Acute rejection was 20.6% in the MMF group vs. 58.6% in the AZA group (p < 0.01). Chronic rejection was 10.3% in the MMF group and 25% in the AZA group (p: NS). The changes in the creatinine clearance from baseline to 5 yr (Delta) were different between groups (-6.0 +/- 5.1 mL/min/1.73 m(2) in the MMF group vs. -22.2 +/- 7.6 mL/min/1.73 m(2) in the AZA group, p < 0.05). Also, the slope of 1/Scr showed a significant lower incidence of worsening renal function after the second year of renal transplantation (p < 0.0001) in the MMF group compared with the AZA group. Delta Height SDS in prepubertal patients was 0.3 +/- 0.4 SDS in the MMF group vs. -0.8 +/- 0.2 SDS in the AZA group (p < 0.05). This study shows that long-term MMF therapy has resulted in a decrease in acute rejection and was associated with a protection against renal function deterioration. The use of MMF enables a reduction in the dose of steroids and leads to a linear growth improvement of children after renal transplantation.     

Cardiac function in children post-orthotopic liver transplantation: echocardiographic parameters and biochemical markers of subclinical cardiovascular damage

Tacrolimus and cyclosporin A (CsA), the mainstay of preventive therapy for solid organ rejection, may cause various side-effects, such as hypertension and nephrotoxicity. Furthermore, tacrolimus is associated with cardiac hypertrophy. In the immediate post-transplant period, both drugs raise the levels of Endothelin-1 (ET), a potent vasoconstrictor; and of B-type Natriuretic Peptide (BNP), a sensitive marker of left ventricular volume overload, which may precede echocardiographic changes of cardiac dysfunction. The aim of the study was to investigate the presence of cardiac damage, by echocardiography and by the biochemical markers BNP and ET, in post-orthotopic liver transplantation (OLT) children, receiving long-term immunosuppressive therapy. ET (ELISA) and BNP (RIA) were measured in plasma of 18 children, post-OLT and 18 healthy controls. Children post-OLT were echocardiographically assessed for left ventricular mass (interventricular septum and posterior wall dimensions), systolic function (ejection fraction, fractional shortening) and diastolic parameters (mitral valve E and A waves, deceleration time, isovolumic relaxation time). None of the post-transplant recipients had a history or physical examination consistent with cardiac disease and all recipients were normotensive. Echocardiography revealed no systolic or diastolic dysfunction in any of the recipients. The mean ET and BNP levels tended to be higher among children post-liver transplant, compared with healthy controls (ET: 4.22 +/- 5.35 pg/mL vs. 2.1 +/- 2.0 pg/mL; BNP: 7.05 +/- 4.4 pg/mL vs. 5.87 +/- 2.0 pg/mL, respectively, mean +/- s.d.) although differences did not reach statistical significance. Three children (17%) had elevated BNP and/or ET levels. A strong correlation was observed between ET and BNP levels in post-OLT children (r = 0.79, p < or = 0.05). No correlation was found between ET or BNP levels and echocardiographic findings. In children receiving long-term immunosuppressive therapy post-OLT, although cardiac function is grossly preserved, ET and BNP levels tend to be higher than in healthy, age-matched children. Thus, elevated levels of BNP and/or ET may identify patients with early cardiac damage.     

Glomerular and tubular function following orthotopic liver transplantation in children

Since its advent, cyclosporine nephrotoxicity has been a major concern to pediatricians attending to liver transplant recipients. The aims of this study were to examine glomerular and tubular function after orthotopic liver transplantation (OLT) in children, their correlation to CsA, and how they differed according to the underlying disease. Patients and methods: Glomerular and tubular function was examined in 28 patients aged 7 months to 14 yr at the time of transplantation (mean 4.0 +/- 3.6), retrospectively examining creatinine clearance, tubular phosphate reabsorption (TRP), calcium/creatinine ratio, sodium excretion fraction, and protein/creatinine ratio. The group with metabolic disease and an underlying tubulopathy was compared with the group with liver disease only. The effect of CsA trough levels and cumulated dose on these indices was examined, as was the effect of antihypertensives on creatinine clearance. Both glomerular and tubular functions improved significantly following liver transplantation. In patients on CsA (n = 21), CrCl decreased significantly at 1 month post-OLT (42.6 +/- 26.6 mL/min/1.73 m(2)) when compared with pretransplantation, and 3, 12 and 60 months post-OLT (p < 0.05). It improved between 12 and 60 months post-OLT (p < 0.05). It was correlated with cyclosporine trough levels (p < 0.03), and with total dose of CsA at 12 months. This was not true for patients on tacrolimus (n = 7). Overall pretransplant TRP was below normal (73.7% +/- 19.6), which was significantly lower than the values at years 2, 3, and 5 post-OLT (p < 0.05), owing mainly to the metabolic group which recovered normal proximal tubular function by the end of the second week post-OLT. Calcium/creatinine ratio was significantly worse in the group with liver disease only (p < 0.01). Protein/creatinine ratio normalized rapidly in both groups. Urinary sodium excretion fraction (FENa) was very abnormal in the early postoperative phase, normalizing thereafter in both groups. Kidney function improved after liver transplantation in patients with and without pre-existing kidney dysfunction. Overall, creatinine clearance was correlated to CsA trough levels suggesting CsA did not have an irreversible 'sclerosing' effect in the medium term. Combined antihypertensive therapy using nifedipine and enalapril may be the optimal choice for patients requiring medical management of their hypertension, although the observed effect on creatinine clearance did not reach statistical significance in this study. Tubular dysfunction is frequent in both groups of patients, pre- and post-transplant, and may contribute to bone mineral density as well as to metabolic disturbances in this population.     

Mycophenolate mofetil without antibody induction in cadaver vs. living donor pediatric renal transplantation

Mycophenolate mofetil (MMF) is a new immunosuppressive agent that blocks de novo purine synthesis in T and B lymphocytes via a potent selective inhibition of inosine monophosphate dehydrogenase. MMF has been shown to significantly reduce the incidence of acute rejection in both adult and pediatric renal transplantation. The impact of MMF on routine antibody induction therapy in pediatric renal transplantation has not been defined. Remarkably, a recent North American Pediatric Transplant Cooperative Study concluded that T-cell antibody induction therapy was deleterious for patients who received MMF. Our study examines the use of MMF in an evolving immunosuppressive strategy to avoid antibody induction in both living (LD) and cadaver (CAD) donor pediatric renal transplantation. We retrospectively analyzed the records of 43 pediatric renal transplants that received MMF-based triple therapy without antibody induction therapy between November 1996 and April 2000. We compared CAD (n = 17) with LD (n = 26). The two groups were similar demographically except that CAD had significantly younger donors than LD, 26.1 +/- 13.7 vs. 36.2 +/- 9.2 yr (p = 0.006). All the patients received MMF at 600 mg/m2/b.i.d. (maximum dose of 2 g/d) and prednisone with cyclosporine (86%) or tacrolimus (14%). Mean follow-up was >36 months for each group. Acute rejection rate at 6 months was 11.8% (CAD) vs. 15.4% (LD) (p = 0.999) and at 1 yr was 23.5% (CAD) vs. 26.9% (LD) (p = 0.999). Mean estimated glomerular filtration rate (ml/min/1.73 m2) at 6 months was 73.3 +/- 15.3 (CAD) vs. 87.6 +/- 24.2 (LD) (p = 0.068). Patient survival at 1, 2, and 3 yr was 100, 100, and 100% for CAD vs. 100, 96, and 96% for LD, respectively. Graft survival at 1, 2, and 3 yr was 100, 100, and 94% for CAD vs. 96, 88, and 71% for LD, respectively. Graft loss in CAD was because of chronic rejection (n = 2) while in LD it was because of non-compliance (n = 6), post-transplant lymphoproliferative disorder (n = 1), and sepsis (n = 1). In conclusion, MMF without antibody induction in both CAD and LD pediatric renal transplantation provides statistically similar and effective prophylaxis against acute rejection at 6 months and 1 yr post-transplant. The short-term patient and graft survival rates are excellent, however, non-compliance remains a serious challenge to long-term graft survival. Additional controlled studies are needed to define the role of MMF without antibody induction therapy in pediatric renal transplantation.     

Conversion from calcineurin inhibitor to sirolimus in pediatric chronic allograft nephropathy

CAN is a major cause for allograft loss in renal transplantation. Sirolimus was recently introduced as a potent non-nephrotoxic alternative to CNIs. In the present study, effects of a conversion protocol were investigated in pediatric CAN with declining GFR, defined by a Schwartz formula clearance below 60 mL/1.73 m2/min, steadily increasing SCr and allograft biopsy. In eight children with a median age of 12.8 yr, sirolimus was started at median 32 months after transplantation with a loading dose of 0.24 mg/kgBW, followed by 0.2 mg/kgBW/day, aimed at trough levels of 15-20 ng/mL. CNIs were reduced to 50% at start of sirolimus and discontinued at median seven days when target levels of sirolimus were reached. Following conversion, changes of GFR significantly stabilized (-2.9 vs. +0.4 mL/min/1.73 m2/month, p = 0.025). Individual GFR increased in five of eight patients (p = 0.026), only one child exhibited unaltered progression of graft failure. In the responders, mean SCr improved by 0.3 mg/dL (p = 0.043). Effects were not dependent on GFR at conversion, nor time post-transplantation. Blood pressure, hematological parameters and proteinuria remained stable during the observation period, serum lipids transiently increased. About half of the children suffered from infectious complications. No child had to be taken off sirolimus; there was no graft loss during the observation period. In conclusion, conversion from CNIs to sirolimus is an effective protocol with tolerable side effects to stabilize renal graft function for at least one yr in the majority of children with biopsy proven CAN.     

Increase in de novo food allergies after pediatric liver transplantation: Tacrolimus vs. cyclosporine immunosuppression

Post‐TAFA is an uncommon but serious complication of organ transplantation. This study aimed to compare the incidence of FA in CsA and tacrolimus‐treated children following OLT and identify risk factors. The medical charts of all patients who underwent OLT at our institution were reviewed. Between 1985 and 2010, 218 OLTs were performed on 188 pediatric recipients, of which 154 were included in the study. Three patients (3%) of the 102 receiving CsA developed FA, compared with nine (17%) in the 52 tacrolimus‐treated patients, the latter exceeding general population reported FA prevalence (RR 5.88; 95% CI: 1.66–20.81). All TAFA cases underwent transplantation before the age of three with an incidence of 29% (9/31) in the tacrolimus‐treated children in comparison with 7% (3/41) in the CsA group (RR 3.97; 95% CI: 1.17–13.45). Eosinophilia was present in 81% of children receiving tacrolimus compared with 54% in the CsA group (p = 0.002). We observed a statistically significant increase incidence of FA in tacrolimus‐treated children following an OLT and those under the age of three are particularly vulnerable. The underlying process is still unknown and probably multifactorial.     

Tacrolimus vs. cyclosporine A as primary immunosuppression in pediatric renal transplantation: a NAPRTCS study

Using the North American Renal Transplant Cooperative Study (NAPRTCS) database, we performed a retrospective cohort study of 986 pediatric renal transplant recipients (index transplant 1997-2000) who were treated either with Cyclosporine A (CSA), Mycophenolate Mofetil (MMF) and steroids (n = 766) or tacrolimus (TAC), MMF and steroids (n = 220) to examine potential difference in clinical outcomes between these two groups. In the first year post-transplant, time to first rejection (29.1% vs. 29%, p = 0.840), risk for rejection [Adjusted Relative Risk (aRR) 1.01, 95% Confidence Interval (CI) 0.77, 1.323], graft survival (96.8% vs. 97.9%, p = 0.607) and risk for graft failure (aRR 0.988, 95% CI 0.64, 1.928) were not significantly different in TAC and CSA-treated patients. At 2 yr post-transplant, there was also no difference in risk for rejection (aRR 0.918, 95% CI 0.669, 1.259), graft survival (91.4% vs. 95.1%, p = 0.152) and risk for graft failure (aRR 0.702, 95% CI 0.461, 1.762) in the subset of 391 CSA-treated patients and 77 TAC-treated patients on whom 2 yr follow data were available in the database. TAC-treated patients were significantly less likely to require antihypertensive medication at 1 yr [aRR 0.74 (95% CI 0.454, 0.637)] and 2 yr post-transplant [aRR 0.67 (95% CI 0.56, 0.793)]. At 1 yr post-transplant, TAC-treated patients enjoyed a higher mean GFR as estimated by the Schwartz formula [89.1 mL/min/1.73 m(2) (SE 2.64) vs. 78.6 mL/min/1.73 m(2) (SE 1.07), p = 0.0003]. In addition, in the subset of patients with 2 yr of follow-up, TAC patients had a higher mean GFR at both 1 yr [98.6 mL/min/1.73 m(2) (SE 3.83) vs. 78.0 mL/min/1.73 m(2) (SE 1.44), p = 0.0003] and 2 yr post-transplant [96.7 mL/min/1.73 m(2) (SE 3.33) vs. 73.2 mL/min/1.73 m(2) (SE 1.48), p < 0.0001]. In summary, TAC and CSA, in combination with MMF and steroids, produce similar rejection rates and graft survival in pediatric renal transplant recipients. However, TAC is associated with improved graft function at 1 and 2 yr post-transplant. Further analysis as more patient data are obtained will be necessary to determine if this difference in graft function persists and translates into improved graft survival.     

Early discontinuation of steroids is safe and effective in pediatric kidney transplant recipients

In pediatric kidney transplantation, steroid induced growth retardation and cushingoid features are of particular concern. In children, gradual steroid withdrawal late after kidney transplantation increases the risk of rejection. In this pilot study, we investigated the outcome of pediatric renal transplantation with an early steroid withdrawal protocol. This is a retrospective case-control study of pediatric renal transplants with age-matched historical control. Groups were comparable in terms of HLA matching, donor type and graft ischemia time. In the steroid withdrawal group (SWG, n = 13), induction therapy included mycophenolate mofetil (MMF) and a 5-day course of steroids with Thymoglobulin in 11 and basiliximab in two other patients. In the steroid group (SG, n = 13), in addition to steroids, four patients were given basiliximab, eight were given Thymoglobulin, and one OKT3. Maintenance therapy included tacrolimus (SWG n = 11, SG n = 3) or cyclosporine (SWG n = 2, SG n = 10). Azathioprine was given to all the patients in the SG, except the last two patients of this series who were prescribed MMF. MMF was given to all in the SWG. Patient and graft survival rates were 100% in both groups. In the SWG, no acute rejection episode was detected. In the steroid group, three patients (25%) presented with an acute rejection episode. All but one patient in either group showed immediate graft function. Patients in the steroid-withdrawal group exhibited a significantly higher creatinine clearance at 6 and 12 months post-transplant (95.8 +/- 23.3 vs. 71.3 +/- 21.9, p = 0.03; and 91.3 +/- 21.6 vs. 69.6 +/- 28.6, p = 0.04). In the SWG delta BMI was significantly lower and delta height Z score was significantly higher, and we observed significantly less hyperlipidemia, body disfigurement, and need for anti-hypertensive medication. Early steroid withdrawal in pediatric renal transplant recipients is efficacious and safe and does not increase risk of rejection, preserving optimal growth and renal function, and reducing cardiovascular risk factors.     

Limited surgical interventions in children with posterior urethral valves can lead to better outcomes following renal transplantation

There is currently no consensus as to the most appropriate means by which children with posterior urethral valves (PUV) are to be managed prior to transplantation. We compared (i) renal allograft survival and function in patients with PUV vs. those with non-obstructive causes of ESRD and (ii) graft outcomes in children who had limited interventions (Group 1) vs. those with more extensive urologic surgeries to decompress the urinary tract (Group 2). Twenty-six pediatric renal transplant recipients had ESRD due to PUV (Group 1, n = 16; Group 2, n = 10). The study group was compared to 23 matched controls with ESRD due to non-obstructive causes. Five yr patient and graft survival was similar in all patients with PUV (Groups 1 and 2) when compared to all other kidney recipients in the transplant program, 96.2% vs. 98.0% and 87.5% vs. 87.0%, respectively. Although calculated creatinine clearance (Ccr), was similar between the PUV group and controls for the first 4 yr, the 5 yr graft function was significantly lower in the PUV group. (53.7 +/- 15.7 vs. 70.2 +/- 21.0 mL/min/1.73 m2; p = 0.03). When the two PUV groups were compared, graft survival was equivalent, but graft function was significantly better at 5 yr in Group 1(60.4 +/- 10.8 vs. 33.8 +/- 9.3 mL/min/1.73 m2; p = 0.02). Thus, patients with PUV managed by a limited intervention approach of vesicostomy with delayed valve ablation or primary valve ablation, had better outcomes. When ESRD is virtually certain, additional pre-transplant surgeries affecting the urinary tract should be avoided.     

Better renal function with enhanced immunosuppression and protocol biopsies after kidney transplantation in children

Subclinical rejection may be associated with decreased graft function after renal transplantation (Tx). Detection by protocol biopsies and treatment could thus be important for the long-term prognosis. We have earlier discovered that glomerular filtration rate (GFR) declined in young children during the first 18 months. Consequently, we slightly enhanced and individualized each patient's immunosuppression. This was a retrospective study of 59 pediatric renal Tx patients between 1995 and 2001. The 35 historical controls received triple-therapy of azathioprine, methylprednisolone and cyclosporine. GFR was measured by protocol at discharge, 6 and 18 months, and a core biopsy was obtained at 18 months. The 24 study patients in addition received basiliximab, had GFR measured at 3 and 12 months, and a biopsy taken at 3 months. Based on histology and function, immunosuppression was individually adjusted. The groups were compared for GFR and histology at 18 months after Tx. There were less acute rejection episodes in the study group (0.38 vs. 1.23 per patient) and serum creatinine concentrations were lower. Subclinical rejection was detected and treated in 39% at 3 months. There were more chronic changes in the control (47%) than in the study group (29%) at 18 months. GFR was significantly higher in the study group at 18 months (87 vs. 68 mL/min/1.73 m(2)), most remarkably in patients < or =2 yr of age (99 vs. 68 mL/min/1.73 m(2)). Detection of subclinical rejection and slightly enhanced and individualized immunosuppression improved GFR 18 months after renal Tx, especially in the youngest patients.     

Sirolimus in chronic allograft nephropathy in pediatric recipients

CAN is a common cause of late graft loss. Nephrotoxicity due to CNIs is known to contribute to CAN. We retrospectively evaluated the efficacy and safety of SRL in pediatric renal Tx recipients showing CAN in their allograft biopsy. Twenty-one patients aged 10.4 +/- 4.6 yr at Tx time receiving CNIs as primary immunosuppression were converted to SRL at 58.9 +/- 49.1 months after Tx, due to progressive decline of renal function and biopsy proven CAN. Mean follow-up after switch was 19.7 +/- 9.5 months. All patients received CsA as part of the immunosuppressive regimen, at a mean dose 4.4 +/- 1.2 mg/kg/day. Mean daily dose of SRL three month after conversion was 2.6 +/- 0.8 mg/body surface area/day and the mean through levels where 6.9 +/- 2.5 ng/mL. Graft biopsies showed Grade I CAN in 12 children and Grade II CAN in nine. After SRL introduction, there were neither acute rejection episodes nor graft losses. GFR improved at three months and was sustained thereafter only in children with Grade I CAN. Post-Tx time at conversion was the only significant variable between patients who had Grade I CAN and Grade II CAN (33.6 +/- 33.3 vs. 92.7 +/- 47.5 months, p = 0.003). Nine patients had no AEs, six patients had nine SAE: five diarrhea, one herpes zoster, one pancreatic pseudo cyst, one pneumonia, and one Influenza A infection; 11 patients had 13 AEs: six oral aphthous ulcers, three urinary tract infections, two herpes simplex, one lymphedema, and one nephrotic proteinuria. Significant improvement of GFR occurred in Grade I CAN group at three months from conversion and was sustained during follow-up. Those who had Grade II CAN experienced no change in GFR. The incidence of AEs and SAE is of concern and further studies are necessary to assess their relevance.     

Comparison of outcomes with low-dose anti-thymocyte globulin, basiliximab or no induction therapy in pediatric kidney transplant recipients: a retrospective study

It is unclear which induction therapy yields the best outcomes in pediatric kidney transplantation. Retrospective data of 88 children receiving a renal allograft between November 1996 and October 2003 were analyzed. Patients received ATGI (n = 12), BI (n = 29), or NAI (n = 47). The mean ATG dose was 5.1 +/- 2.1 mg/kg. At 12 months, graft survival rates were 91.7%, 100%, and 97.9% for ATGI, BI, and NAI groups, respectively. Acute rejection rates at 12 months were 0 (ATGI), 20.6% (BI), and 10.7% (NAI). The mean GFR for ATGI (42.4 +/- 25.9 mL/min) was lower than for BI (78.3 +/- 27.2 mL/min), and NAI (66 +/- 28.3 mL/min) at 12 months (p < 0.05). One ATGI patient developed CMV pneumonia but none developed post-transplant lymphoproliferative disorder. Although there was no renal allograft survival benefit with either ATGI or BI, relative to NAI, the absence of acute rejection and equivalent rates of viral infections in the higher-risk ATGI recipient group suggests that the treatment strategy is promising. A large prospective study is needed to better define the role of ATGI in pediatric kidney transplantation.     

Use of anti-hypertensive medications and post-transplant renal allograft function in children

Post-transplant hypertension is a common occurrence in children. The relative effect of this hypertension on renal allograft function is uncertain. Examining the accumulated data for pediatric renal transplant recipients at our institution from monthly visits for up to three years, we determined whether the use of anti-hypertensive medications (anti-HTN medications) was associated with allograft dysfunction. Monthly clinical data included height, weight, serum creatinine, cyclosporin A (CsA) trough levels, number of acute rejection episodes, and number of anti-HTN medications. Estimated glomerular filtration rate (eGFR) was calculated monthly for each patient using the Schwartz formula. Time post-transplant was grouped into 6-month intervals. One thousand three hundred and sixty-three monthly data sets from 6 months (n = 76 patients) to 3 yr post-transplant (n = 47 patients) were analyzed. Overall mean eGFR was 75 mL/min/1.73 m2 at 6 months and 54 mL/min/1.73 m2 at 3 yr. A lower eGFR was found at all post-transplant time intervals for patients receiving anti-HTN medications compared with those who were not (p < 0.01). This lower eGFR was found at some but not all times post-transplant when patients were grouped by donor type or history of acute rejection episodes and analyzed separately. Mean CsA trough levels were higher at all post-transplant time intervals in patients receiving anti-HTN medications (p < 0.05). While a causal relationship between post-transplant hypertension and graft dysfunction cannot be established from this study, we conclude that the need for anti-HTN medications is associated with worse allograft function.     

Long‐term outcomes in pediatric liver recipients: Comparison between cyclosporin A and tacrolimus

In recent years, tacrolimus (FK506, TAC) has been increasingly utilized in liver transplantation. However, long-term risks and benefits as compared with conventional cyclosporin A (CsA) have not been fully elucidated. This retrospective study examined the potential outcome differences between TAC- and CsA-based immunosuppressive therapy in pediatric liver transplant recipients. From March 1988 to December 1996, 218 children (aged 0.1-17 yr) underwent 238 orthotopic liver transplantations; 58.7% (128/218) were under 2 yr of age at time of transplant. Initially, the maintenance immunosuppressive regimen consisted of CsA and prednisone, with antilymphocytic preparations (MALG, ATGAM, and OKT3) as induction therapy. Subsequently, TAC was used first as rescue therapy for steroid refractory rejection in CsA patients and then as maintenance immunosuppression. Fifty-seven out of the 147 CsA patients were converted to TAC for various reasons while 71 patients were placed on TAC as primary maintenance immunosuppression. 62.6 per cent (92/147) of liver recipients on CsA experienced at least one biopsy-proven acute rejection episode as compared to 50.7% (36/71) for TAC patients (p = 0.09); likewise, 34% (50/147) of CsA patients had more than one episode of rejection vs. 18.3% (13/71) for patients on TAC (p < 0.02). Rejection was the reason for conversion from CsA to TAC in 29 of 57 patients. Conversely, 19.0% (28/147) of CsA patients had to be switched to TAC for reasons not related to rejection (i.e. side-effects). The overall incidence of histologically proven chronic rejection was 7.8% (17/218). 10.9 per cent (16/147) of the children who were on CsA initially developed chronic rejection, which was significantly higher compared with one of 71 TAC recipients (p < 0.02). Of these 16 CsA patients with chronic rejection, 50.0% (8/16) underwent retransplantation for graft failure (mean interval from time of diagnosis of chronic rejection to re-transplant, 4.0 months; range 1-8 months), whereas the TAC patient has remained clinically stable with normal liver function tests after 23 months of follow-up. One year after liver transplantation, 72.8% (107/147) of CsA patients were still on steroids (mean dosage 0.20 mg/kg/d), as compared to 42.3% (30/71) of the TAC patients (mean dosage 0.14 mg/kg/d). The incidence of post-transplant lymphoproliferative disorder (PTLD) in Epstein-Barr virus (EBV)-infected patients was 2.2% (2/90), 7.0% (5/71) and 12.3% (7/57) for CsA, primary and TAC-converted groups, respectively. The overall incidence of PTLD was 6.9% (15/218). In summary, pediatric liver transplant recipients treated with TAC as primary maintenance immunosuppressive medication experienced significantly fewer episodes of rejection; especially chronic rejection, which lead to graft loss. However, the trade-off is a potential increased incidence of EBV-related PTLD in these patients.     

Tacrolimus-induced cholestatic syndrome following pediatric liver transplantation and steroid-resistant graft rejection

Several factors may contribute to post-transplant cholestatic complications after liver transplantation. These include ischemic reperfusion injury, hypoperfusion, bile duct strictures, and hepatotoxic drugs. Up to now, there have been no publications on tacrolimus cholestatic toxicity in clinical transplantation when the drug was used in therapeutic doses. We describe six pediatric liver graft recipients in whom cholestatic complications developed under a tacrolimus-based immunosuppression following liver transplantation and all of them suffered from previous steroid-resistant graft rejection. The overall incidence of cholestatic syndrome was 5.4% in children receiving tacrolimus. The immunosuppression was switched back to cyclosporine and prednisolone in all six patients resulting in completely resolved clinical signs and laboratory findings. We conclude from our observations that a cholestatic syndrome following pediatric liver transplantation may be caused by tacrolimus therapy following steroid-resistant graft rejection, even if given in therapeutic doses.     

Treatment strategies in pediatric solid organ transplant recipients with calcineurin inhibitor-induced nephrotoxicity

Although short-term kidney allograft survival has improved significantly since the introduction of the calcineurin inhibitors (CNI) cyclosporine A (CsA) and tacrolimus, long-term transplant survival remains a major concern, chronic allograft nephropathy (CAN) being the principal reason for graft loss after the first post-transplant year. This is particularly major for pediatric renal transplant recipients because of their higher life expectancy compared with adults. The mechanisms leading to CAN are multiple, including acute and chronic alloimmune responses and nephrotoxicity of CNIs. CNI-induced nephrotoxicity is also a long-term concern in other pediatric solid organ transplant recipients, such as liver and heart. Prevention of allograft nephropathy requires a balance of maintaining adequate immunosuppression, while avoiding the toxic effects of CNIs. Regimens that are based on mycophenolate mofetil (MMF) alone or in combination with newer agents may allow for reduced reliance on CNIs and thus may represent an effective treatment paradigm for long-term maintenance of a renal allograft. From the available data it appears that the currently safest treatment strategy in pediatric renal and heart transplant recipients with CNI toxicity is an MMF-based therapy with low-dose CNIs +/- low-dose steroids, while in pediatric liver transplant recipients, CNI-free MMF-based immunosuppressive therapy with or without steroids appears feasible in a significant subset of patients. In renal transplant recipients, the benefit of a CNI-free MMF/steroid therapy on renal function is gained at the cost of increased rejection in a subset of patients, although the relative importance of rejection vs. overall renal function requires further clinical investigation. The introduction of mammalian target of rapamycin (mTOR) inhibitors provides an opportunity for unique CNI-sparing regimens that combine two antiproliferative agents (MMF and TOR inhibitors). It is possible that a sirolimus-based CNI-free immunosuppressive regimen in terms of renal transplant survival is superior to CNI minimization, where the detrimental effects of CNIs on allograft function and structure are still operative, albeit to a lesser degree. Substitution of CNIs by mTOR inhibitors is therefore promising, but requires validation in long-term studies in large cohorts.     

Frequency of hyperuricemia and effect of calcineurin inhibitors on serum uric acid levels in liver transplanted children

Hyperuricemia is common after renal and cardiac transplantations, but it is rarely reported after liver transplantations. The aim of this study is to determine the frequency of hyperuricemia in children following orthotopic liver transplantation and the effects of calcineurin inhibitors tacrolimus and cyclosporine) on blood uric acid levels. Between September 1997 to January 2004, 76 liver transplantations were performed in 70 children (male/female; 39/31) at Ege University, Organ Transplantation Center (37 deceased donation and 39 live donors). Patients who had been transplanted within the last three months and patients who died within six months after liver transplantation were excluded from the study. Finally 59 patients were included in this study. Uric acid levels were measured before transplantation and after transplantation within six months intervals for two yr. In these series 17 cases had increased uric acid levels after liver transplantation (28.8%). Serum uric acid levels in both groups (tacrolimus or cyclosporine) were detected to be significantly higher than initial values at 12th months (p < 0.05). Hyperuricemia developed in eight patients receiving cyclosporine (eight of 11; 72%) whereas nine patients receiving tacrolimus developed hyperuricemia (nine of 48; 18%). However, the rate of having high uric acid levels was significantly higher in cyclosporine group compared tacrolimus group (p = 0.001, OR: 11.5, CI 95% 2.5-52.4). Uric acid levels were also significantly higher in cyclosporine group in 12th and 18th months (respectively, p = 0.003 and p = 0.003). Serum creatinine levels at 12th, 18th and 24th months were significantly higher in cyclosporine group than tacrolimus group (respectively, p = 0.009, p = 0.04 and p = 0.02). Hyperuricemia is a common complication after liver transplantation in children. Cyclosporine may cause hyperuricemia more often in respect to tacrolimus and this may be related to the impairment of renal functions. Complications developing because of hyperuricemia such as gout disease or renal calculi are quite rare in children.     

Outcome after kidney transplantation in children with thrombotic risk factors

BACKGROUND: According to the data from the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS), vascular thrombosis accounts for 11.6% of graft losses in pediatric renal transplantation. In adults, inherited and acquired thrombophilic risk factors, e.g. factor V Leiden mutation, have been associated with early graft loss and increased rejection episodes. Data on the impact of these factors on the outcome of children after renal transplantation are rare. METHODS/PATIENTS: Sixty-six pediatric patients awaiting renal transplantation (mean age 10.1 yr) were screened for inherited and acquired risk factors for hypercoagulable disorders (protein C, S, and antithrombin III deficiency, antiphospholipid antibodies, factor V Leiden, prothrombin, and MTHFR mutation) in order to intensify anticoagulation in those with an increased risk for thrombophilia: intravenous heparin was administered with a partial prothrombin time (PTT) prolongation of 50 s for 14 days and switched to low-molecular-weight heparin for another 8 wk before aspirin was introduced for the first year. Patients without hypercoagulable risk factors were treated with heparin without PTT prolongation for 14 days and switched to aspirin immediately afterwards. The results on graft survival, incidence of acute rejection episodes, and long-term renal graft function were analyzed between recipients with and without hypercoagulable risk factors. RESULTS: Thrombophilic risk factors were identified in 27.3% of our patients. No thrombosis occurred. One serious bleeding complication led to a second surgical intervention. The rate of acute rejection episodes was not increased in patients with and without thrombotic risk factors after 90 days (16.7 vs. 25%), 1 yr (22.2 vs. 33.3%), and 3 yr (38.9 vs. 41.7%) of follow-up, respectively (p = n.s.). After a mean follow-up of 3 yr the kidney function was comparable in both groups, with 63.1 in recipients with and 69.8 mL/min/1.73 m(2) in recipients without hypercoagulable risk (p = n.s.). At latest follow-up, three graft losses were found not to be attributed to thrombotic risk factors. INTERPRETATION: Children with thrombophilic risk factors were identified and treated with an intensified anticoagulation regimen after renal transplantation. An increased risk for graft failure, acute rejection episodes, or impaired renal function for pediatric renal transplant recipients with hypercoagulable status was not found.