Rapid discontinuation of corticosteroids in pediatric renal transplantation

Abstract:  Corticosteroid immunosuppression has permitted the development of successful allotransplantation; however, corticosteroids are associated significant post-transplant complications. To circumvent these problems, we implemented a protocol of rapid discontinuation of corticosteroids in 19 consecutive pediatric primary kidney transplant recipients. Mean age at time of transplant was 13.4 (±4.5) yr, 52.6% were male, 63.2% underwent living donor transplantation. All patients were administered Thymoglobulin^® [anti-thymocyte globulin (rabbit)] as induction immunosuppression with a rapid tapering dose of corticosteroids (total of five daily doses), and maintained on mycophenolate mofetil and tacrolimus. Two patients had immediate recurrence of primary disease (FSGS), requiring further corticosteroid therapy. Otherwise, remaining 17 patients were maintained off corticosteroids, with excellent graft function; mean baseline eGFR of 112 mL/min/1.73 m² (±19) at 28 months (±14) post-transplantation. There was 100% patient and rejection-free graft survival at 27 months (range 5–58 months) post-transplantation; 47% underwent renal transplant biopsy secondary to acute rise in serum creatinine with or without worsening hypertension. All biopsies had no evidence of acute rejection; 62.5% had findings consistent with tacrolimus toxicity. Renal transplantation utilizing a rapid discontinuation of corticosteroid protocol in pediatric patients appears to be safe and effective, without increasing the risk of acute rejection or graft loss.     

Outcome of living donor renal allograft survival in children with focal segmental glomerulosclerosis

Abstract:  FSGS is the most frequent GN that may recur in a renal allograft. Compared with adults, the impact of FSGS on graft survival appears to be more significant in children. Thus we decided to assess graft survival and complications after renal transplantation in children with FSGS. Outcome of renal transplantation in 25 children with FSGS who received a renal transplant at Labafi Nejad Hospital was studied and compared with 75 patients as a control group. The mean follow-up duration was 68.16 (s.d. = 41.93) months. Other than demographics, variables such as DGF, acute rejection, number of acute rejection episodes, and graft failure in both groups were evaluated. Acute rejection was seen in 22/25 (88%) of FSGS group, compared to 40/75 (53.3%) in the control group. This difference was statistically significant (p = 0.001). DGF was seen in 4/25 (16%) and 13/75 (17.3%) in the FSGS and control groups, respectively (p = N.S.). The mean graft survival time was 115.61 (s.e.m. = 12.56) and 155.56 (s.e.m. = 7.16) month in FSGS and control group, respectively (p = N.S.). We demonstrated that graft function and survival were not significantly different in the FSGS and control patients. However, acute rejection episodes were more common in FSGS patients but without a significant impact on graft survival.     

Association of mast cells and liver allograft rejection

Abstract:  MCs are important effector cells in a broad range of immune responses. Their role in liver allograft rejection is not clear. Twenty-one liver transplant recipients (mean age ± s.d.; 10.2 ± 4.1 yr) who experienced a rejection episode are included in this study. Biopsy specimens from normal livers (allograft biopsy with normal histopathology n = 5 and naïve livers n = 6), transplanted livers with CR (n = 5), and transplanted livers with ACR (n = 26) were studied. The total number of PT in each biopsy specimen was documented, and the number of PT that contained MCs was expressed as a percentage of the total number of PT. MCs, percentage of PT containing MCs and the average number of MCs/PT was significantly higher in rejection specimens than in control biopsy samples. All parameters were significantly higher in CR group than AR groups. Increasing grades of rejection was also associated with progressively more MCs and MC/PT ( r  = 0.68 p = 0.000; r  = 0.58 p = 0.002). Only serum bilirubin level was related to the MCs in AR group. Only MC/PT was detected as an independent predictor of graft survival (p = 0.011, RR 2.87 95% CI 1.3–6.5). Despite the fact that the role of MCs in liver allograft rejection is still unknown; they exist in inflammatory infiltrates during pediatric liver allograft rejection. MC-rich portal infiltrates may distinguish chronic liver rejection from other inflammatory states such as AR, hepatitis and biliary obstruction.     

A prospective study of dobutamine stress echocardiography for the assessment of cardiac allograft vasculopathy in pediatric heart transplant recipients

Abstract:  Transplant CAV is the leading cause of graft loss beyond one yr post-heart transplant. Diagnosis can be challenging and the previous "gold standard," coronary ANG, tends to underestimate disease. The purpose of this study was to relate DSE to ANG for the diagnosis of CAV. Prospective annual DSE at a single centre on all heart transplant patients (1999–2006) were compared with results from routine coronary angiograms. Progression of CAV over time as determined by DSE and ANG and associated factors were sought through logistic regression models adjusted for repeated measures. There were 102 heart transplant patients (54 males) transplanted between 1989 and 2006. Median age at transplant was 17 months (0–16.6 yr). The initial DSE was at a median of 10-months post-transplantation. There was a high correlation between an abnormal DSE and an abnormality on ANG (p = 0.002). There was an increased probability of an abnormal DSE with increasing grade of CAV as assessed by ANG (p < 0.001). Factors associated with an abnormal DSE included older age at transplant (p = 0.04), higher grade of rejection (p = 0.002), higher total cholesterol (p = 0.04), higher LDL (p < 0.05), and older age at the time of DSE (p = 0.002). DSE result was not related to HDL, triglyceride or homocysteine levels, or to steroid or statin use. The probability of an abnormal DSE result increases with increasing angiographic grade of CAV, and thus DSE may be used for initial screening for CAV with ANG reserved for confirmation and grading. Patients transplanted at an older age and those with a greater history of rejection were at higher risk of a positive DSE and may require increased surveillance for CAV.     

Acute rejection episodes in pediatric renal transplant recipients with cytomegalovirus infection

Abstract:  CMV infection is the most important opportunistic virus infection after renal transplantation leading to increased patient mortality, graft loss, risk for acute rejection episodes and impaired renal function. The potential impact of prophylactic anti-viral therapy on long-term graft outcome is relevant. The aim of this study was to evaluate the incidence of CMV infection, its risk factors and long-term outcome in children after renal transplantation. 103 children (mean age 10.6 ± 5.3, range 1.6–22.0 yr) were monitored weekly for pp65 for the first 6–8 wk after renal transplantation, followed by a monthly monitoring for the first year. CMV infection occurred in 23/103 children (21.1%) with 10 patients (9.7%) developing CMV disease characterized by positive pp65 in the presence of organ involvement. The CMV R−/D+ and R+/D+ serostatus was significantly associated with an increased risk of CMV infection (p < 0.0001 and p = 0.009). 14/28 R−/D+ patients developed CMV infection despite prophylactic treatment with CMV hyperimmune globulin. The incidence of acute rejection episodes after or during CMV infection was significantly increased (p = 0.003) and the D+ serostatus was significantly associated with acute rejection episodes within the first year after transplantation (p = 0.006). In summary the overall incidence of CMV infection in this single center experience is 21.1%. The D+ serostatus represents a serious risk factor for both CMV infection and acute rejection episodes. In future the potential impact of different modalities of prophylactic anti-viral therapy on the prevention of acute rejection should be considered.     

Non-adherence to post-transplant care: prevalence, risk factors and outcomes in adolescent liver transplant recipients

Abstract:  This study examined the prevalence, demographic variables and adverse outcomes associated with non-adherence to post-transplant care in adolescent liver transplant recipients. We conducted a retrospective chart review of 111 adolescent patients (age 12–21 yr) greater than six months post-transplantation and defined non-adherence as not taking the immunosuppressive(s) or not attending any clinic visit in 2005. Fifty subjects (45.0%) were non-adherent and 61 (55.0%) were adherent. Twenty percent of the subjects did not attend clinic and 10.9% did not complete laboratory tests. Non-adherence was significantly associated with fewer completed laboratory tests (p < 0.0001), single parent status (p < 0.0186), and older age and greater years post-transplantation by both univariate and multivariate analyses (p < 0.008, p < 0.0141 and p < 0.0012, p < 0.0174, respectively). Non-adherence to medication was significantly associated with a rejection episode in 31 patients (p < 0.0069) but not in the subgroup of seven patients who stopped their immunosuppression completely. Non-adherence to post-transplant care is a prevalent problem in adolescents particularly of an older age and greater years post-transplantation. Rejection was a significant consequence of medication non-adherence except in a subgroup with presumed graft tolerance who discontinued their immunosuppression. These results emphasize the need for strict monitoring of adherence to post-transplant care to improve long-term survival and quality of life in adolescent transplant patients.     

Decreases in circulating CD4+CD25hiFOXP3+ cells and increases in intragraft FOXP3+ cells accompany allograft rejection in pediatric liver allograft recipients

Abstract:  We examined CD4⁺CD25^hiFOXP3⁺ cells Treg in children following liver transplantation and determined the relationship between Treg cell levels in the blood and in the graft. Peripheral blood was obtained from pediatric liver transplant patients at sequential time points: pre-transplant, one month, 3–4 months, 6–7 months, and 11–12 months post-transplant. PBMC were isolated, labeled for CD4, CD25 and FOXP3 expression and analyzed by flow cytometry for CD4⁺CD25^hiFOXP3⁺ cells. Sorted CD4⁺CD25^hi cells were assessed for functional activity. Pretransplant blood levels of CD4⁺CD25^hiFOXP3⁺ Treg cells were not significantly different from post-transplant blood levels of CD4⁺CD25^hiFOXP3⁺ Treg cells. However, the blood levels of CD4⁺CD25^hiFOXP3⁺ Treg cells were significantly decreased during acute rejection compared with levels when graft function was stable. Immunohistochemistry revealed that FOXP3⁺ cells were increased in the portal region of livers with histopathologic evidence of acute graft rejection compared with livers without evidence of rejection and were localized primarily within the inflammatory infiltrate. These data indicate that Treg cells are found at the site of allograft rejection and may play a role in regulation of alloreactivity. Moreover, monitoring peripheral CD4⁺CD25^hiFOXP3⁺ Treg cell levels may be useful in improving the post-transplant management of pediatric liver allograft recipients.     

Potential influence of tacrolimus and steroid avoidance on early graft function in pediatric renal transplantation

Abstract:  With the increasing adoption of steroid-sparing immunosuppression protocols in renal transplantation, it is important to evaluate any adverse effects of steroid avoidance on graft function. Early graft function, measured by CrCl was retrospectively studied in 158 consecutive pediatric renal transplant recipients from 1996 to 2005, receiving either steroid-free or steroid-based immunosuppression. Patients receiving steroid-free immunosuppression vs. steroid-based immunosuppression had no difference change in CrCl (ΔCrCl) in the first week post-transplantation (p = 0.12). When stratified by corticosteroid usage, patients with higher tacrolimus trough levels (≥14 ng/mL) had slower graft function recovery in the first week post-transplantation than those with lower tacrolimus trough levels (p = 0.008) in the steroid-free group only. Despite initial slower graft function recovery in this subgroup, there was no negative impact on graft function in the steroid-free group; in fact steroid-free patients trended towards better CrCl at six months (p = 0.047) and 12 months (p < 0.001) post-transplant than the steroid-based group. With the improved immunological outcomes with steroid avoidance, close surveillance should be performed of tacrolimus levels to avoid levels >14 ng/mL. In patients with slow recovery of early graft function, short-term perioperative steroids may be considered.     

An unusual case of fatal pulmonary allograft rejection

This case report describes an atypical form of acute pulmonary allograft rejection that was refractory to conventional therapy. The rejection manifested primarily as interstitial lymphocytic infiltrates with little perivascular involvement. Despite aggressive therapy the patient died within 7 months of transplant. The timely recognition and treatment of unusual forms of allograft rejection is vital in the management of pulmonary transplant patients.     

The relationship of donor source and age on short- and long-term allograft survival in pediatric renal transplantation

Abstract:  Limited pediatric data on allograft survival from advanced aged kidney donors exist. To determine the influence of donor source and age on allograft survival in pediatric renal transplant recipients, we analyzed the OPTN database. Allograft survival for 7291 pediatric renal transplants was evaluated. Up to five yr post-transplantation, graft survival was higher for LD vs. DD recipients. At seven yr, allograft survival was 71% in 18–54 yr-old LD recipients, 59.1% in ≥55 yr-old LD, and 45.1% in ≥50 yr-old DD recipients. An approximate 35% improvement in allograft survival in 18–54 yr-old LD recipients was observed. Multivariate results showed that recipients of LD 35–49 (aRR 0.66, 95% CI 0.55–0.80) and LD 50–54 (aRR 0.65, 95% CI 0.45–0.94) have a graft survival advantage over the ideal DD. In LD ≥55 yr, no improvement in graft survival was observed when compared with the 18–34 yr-old DD. In summary, we observed in a pediatric population, <55 yr-old LD kidneys afford improved long-term allograft survival when compared with DD kidney recipients. Increasing awareness of the long-term graft survival advantage for children receiving an LD kidney, even from older donors, should be a priority.     

Urinary tract infections in pediatric renal transplant recipients – a two center risk factors study

Abstract:  UTI are common in renal Tx recipients and may significantly impact on the graft function. The aim of our study was to evaluate the prevalence, risk factors, and significance of UTI in Tx children. We performed a retrospective cross-sectional study of 76 Tx patients, median age at Tx was 13.4 yr. Twenty-one of 76 (28%) patients developed at least one UTI during the mean follow-up time of 3.3 ± 2.0 yr post-Tx. The first UTI occurred at a median of 160 days post-Tx. The RR of having UTI was significantly higher in patients with the primary diagnosis of obstructive uropathy (RR = 2.6, 95th CI = 1.1–6.0, p = 0.032), history of PN pre Tx (RR = 2.7, 95th CI = 1.3–5.4, p = 0.009) and pre Tx VUR (RR = 2.2, 95th CI = 1.1–4.5, p = 0.045). These three factors also significantly decreased the infection-free survival time to the first UTI. Most UTI caused reversible acute allograft dysfunction, but the long-term graft function could not be reliably assessed with SCr. In conclusion, UTI occurred in 28% of pediatric Tx recipients, mostly during the first year post-Tx despite antibiotic prophylaxis. The diagnosis of obstructive uropathy, history of UTI and VUR prior to Tx were significant risk factors.     

Extended daclizumab monotherapy for rejection-free survival in non-adherent adolescent recipients of renal allografts

Abstract:  Acute rejection episodes are almost inevitable in the face of immunosuppression non-adherence and a known risk factor for developing chronic allograft nephropathy and accelerated graft loss. Daclizumab, a humanized monoclonal antibody directed against the alpha chain of the IL-2 receptor, is an important advance for induction therapy in renal transplant immunosuppression, reducing early acute graft rejection without affecting the tolerability of standard immunosuppression, for both steroid-based and steroid-free immunosuppressive protocols, in children and adults. In the absence of depot immunosuppression for maintenance therapy, we explored extended daclizumab therapy as temporary maintenance immunosuppression for acute rejection prophylaxis in two patients with recalcitrant immunosuppression non-adherence. Both patients had prior episodes of aggressive acute rejection associated with their non-adherence but achieved stable and rejection-free renal allograft function with daclizumab monotherapy in the presence of documented non-adherence thus providing an effective bridge for up to 12 months until immunosuppression adherence was re-established with ongoing psychosocial support. This report suggests that daclizumab monotherapy over an extended period of time during the period of non-adherence in the post transplant period could be a rescue modality to avoid immune activation and thereby prevent acute rejection in the face of erratic maintenance immunosuppression.     

Calcineurin-inhibitor free immunosuppression with mycophenolate mofetil and corticosteroids in paediatric renal transplantation improves renal allograft function without increasing acute rejection

Abstract:  The aim of this study was to determine whether CNIs can be safely withdrawn in paediatric patients with declining renal allograft function receiving MMF and corticosteroids for long-term immunosuppression following renal transplantation. We performed a retrospective review of paediatric renal transplant recipients who received MMF with corticosteroids at least three months after transplantation with or without CNI in a single centre. Thirty-eight children (71% male), mean age 7.2 ± 3.7 yr received MMF and corticosteroids, with 29 (76%) receiving a CNI. Mean follow-up was 59.2 ± 42 months post-MMF commencement and 109 ± 98.8 months post-transplantation. Patient and renal allograft survival were 100% and 94%, respectively. There was a significant improvement in eGFR after MMF introduction both in children on a CNI and those where the CNI was withdrawn, with stabilisation of eGFR after two yr. There was no significant difference in the number of acute rejection episodes prior to or following introduction of MMF between the groups. MMF in combination with corticosteroids is a safe and effective immunosuppressive regimen in paediatric renal transplantation. Complete withdrawal of CNIs after conversion to MMF should be considered in all patients, to preserve renal function as evidenced by improved eGFR.     

Standardizing resistive indices in healthy pediatric transplant recipients of adult-sized kidneys

Gholami S, Sarwal MM, Naesens M, Ringertz HG, Barth RA, Balise RR, Salvatierra O. Standardizing resistive indices in healthy pediatric transplant recipients of adult-sized kidneys.
Pediatr Transplantation 2010: 14: 126–131. © 2009 John Wiley & Sons A/S.
Abstract:  Small pediatric recipients of an adult-sized kidney have insufficient renal blood flow early after transplantation, with secondary chronic hypoperfusion and irreversible histological damage of the tubulo-interstitial compartment. It is unknown whether this is reflected by renal resistive indices. We measured renal graft resistive indices and volumes of 47 healthy pediatric kidney transplant recipients of an adult-sized kidney in a prospective study for six months post-transplant. A total of 205 measurements were performed. The smallest recipients (BSA ≤0.75 m²) had higher resistive indices compared to recipients with a BSA between 0.75 and 1.5 m² (p < 0.0001) and to recipients with a BSA ≥ 1.5 m² (p < 0.0001). Resistive indices increased during the first six months in the smallest recipients (p = 0.02), but not in the two larger recipient groups (BSA 0.75–1.5 m² and ≥1.5 m²). All three BSA groups showed a reduction in renal volume after transplantation, with the greatest reduction occurring in the smallest recipients. In conclusion, renal transplant resistive indices reflect pediatric recipient BSA dependency. The higher resistance to intra-renal vascular flow and significant decrease in renal volume in the smallest group likely reflect accommodation of the size discrepant transplanted adult-sized kidney to the smaller pediatric recipient vasculature with associated lower renal artery flow.     

Kidney transplantation in children with posterior urethral valves

Abstract:  There is controversy about the outcome of renal transplantation in patients with PUV. The objective of this study was to analyze the outcome of renal transplantation in children with PUV. Fifteen patients had a history of PUV as the etiology of their ESRD. Forty-five patients comprised a control group without lower urinary tract anomalies. Mean age and follow-up duration were not significantly different between the case and the control group (p = 0.1). The immunosuppressive protocol and the year of transplantation were similar in these two groups (p = 0.2, 0.4, respectively). Among patients with PUV, 37.5% had acute rejection; and 56.2% had chronic rejection. Among the controls, 22.2% had acute rejection and 28.8% had chronic rejection. None of these differences was significant. Mean survival time was seven yr in affected patients and 6.2 yr in the control group (p = 0.9). Among patients with PUV, the rate of graft survival in the first year after transplantation was 95%; and those in the third, fifth, and seventh yr, 91%, 65%, and 50%, respectively. For the controls, the graft survival was 83% at one yr; 80% at three yr; 71% at five yr; and 60% at seven yr after transplantation (p = 0.9). Conclusively, this study showed that a history of PUV had no effect on graft function. Graft survival was not different among these patients compared with patients free of these anomalies. We also showed that urological complications were few in these patients.     

Reversible acute anuric kidney injury after surgical evacuation of perinephric hematomas as a complication of renal transplant biopsies

Percutaneous renal transplant biopsy is the gold standard investigation to diagnose the cause of renal allograft dysfunction. There are inherent risks to this investigation, despite the procedure becoming safer due to the increased utilization of ultrasound‐guided techniques. These biopsy risks can be increased when there is acute rejection present with a swollen transplanted kidney. Subcapsular hematomas are not uncommon after percutaneous renal transplant biopsies, but we describe two cases of post‐biopsy subcapsular hematoma which were associated with acute renal allograft dysfunction in pediatric renal transplant recipients who did not have acute rejection.     

Multicenter trial of everolimus in pediatric renal transplant recipients: results at three year

Abstract:  There are few prospective clinical trials of mTOR inhibitors (or proliferation signal inhibitors) combined with CNI inhibitors in de novo pediatric renal transplantation. Results reported here are from a multicenter, open-label study in de novo pediatric renal transplant patients (≤16 yr), in which patients received everolimus with cyclosporine and corticosteroids for one yr, then entered an extension study for a further two yr. Nineteen patients completed the one-yr study, of whom three discontinued study medication. Fifteen of the remaining 16 patients entered the extension study, eight of whom were aged <10 yr (Group 1) and seven were aged 10–16 yr (Group 2). Mean daily dose of everolimus during the first 36 months was 1.53 mg/m² BSA. Biopsy-proven acute rejection occurred in three patients in Group 2 and in one patient in Group 1. Biopsy-proven chronic allograft rejection was reported in four patients (two in each age group). Graft survival at one yr was 100%; one patient in Group 2 lost their graft subsequently during the extension. For patients entering the extension, patient survival at three yr was 100%. There were three cases of viral infection, including one case of cytomegalovirus infection. At three yr, mean total cholesterol was 5.5 ± 0.8 m m /L (213 ± 31 mg/dL) and four patients received statin therapy. Mean serum creatinine at 36 months was 96 ± 36 μ m /L (1.1 ± 0.4 mg/dL). This is the first long-term prospective study to demonstrate that a regimen of everolimus, cyclosporine, and corticosteroids provides good efficacy, tolerability, and safety in de novo pediatric renal transplant patients.     

Chronic kidney disease in children following lung and heart–lung transplantation

Abstract:  CKD is a major co-morbidity in pediatric lung transplant recipients. We report the prevalence of renal impairment post-lung transplant at a single center, using a modified, age-adjusted eGFR for the best approximation of true GFR, and investigated associations and possible predictors of decline in renal function post-transplant. Renal function was assessed by eGFR pre-transplant, three and 12 months post-transplant, and at last follow-up. Decline in renal function was analyzed as percentage fall in eGFR in two phases (0–3 and 3–12). Furthermore, we investigated impact of gender, age, pre-transplant diagnosis and renal function, transplant type, early post-transplant dialysis, and tacrolimus trough levels on decline in eGFR using multivariate analysis. Over a five-yr period, 30 transplants were performed. Mean eGFR pretransplant was 117 mL/min/1.73 m² (s.d. 35) with mean decline in eGFR during the first three months post-transplant of 33% (s.d. 31, p < 0.001). Thereafter, mean decline in eGFR was 8% (s.d. 18, p = 0.02). None of the factors assessed were significantly associated with decline in eGFR post-transplant. In conclusion, many children have decline in renal function following lung transplantation, particularly early post-transplant. Unlike in adults, we were unable to detect any predictors of renal impairment in pediatric lung transplant recipients.     

Effect of donor pneumoperitoneum on early allograft perfusion following renal transplantation in pediatric patients: an intraoperative Doppler ultrasound study

Abstract:  Decreased perfusion and trauma during laparoscopic harvesting are proposed causative factors for DGF and rejection in children following renal transplantation with laparoscopic donor nephrectomy (LDN) allograft. We performed a retrospective review of 11 children who underwent LDN transplant and 11 preceding patients who underwent ODN transplant. Intraoperative DUS findings, creatinine values and clearance, time to nadir creatinine and AR episodes were compared. There were no significant differences in the BMI, vascular anatomy, side of nephrectomy, or warm ischemia time in the two groups. Mean follow-up duration was 11.4 and 30.4 months in LDN and ODN groups. DUS showed initial turbulent flow in five of the LDN and four of the ODN group with an average RI of 0.59 and 0.66 in the ODN and LDN groups, respectively (NS). Three patients in the ODN group had an abnormal RI compared to none in the LDN group (p = 0.034). The creatinine values, creatinine clearances (at 24 h, one, four wk and last follow-up) and AR episodes were similar in both groups. Pneumoperitoneum during LDN does not appear to have an adverse impact on early graft reperfusion.