Anti-lymphocyte antibodies late in the course of pediatric renal transplantation.

Beyond the immediate post-transplant period, physicians are often reluctant to use anti-lymphocyte preparations to treat episodes of acute renal functional deterioration attributable to acute rejection. This is due to the perception that such episodes are less likely to be reversible, and to concern regarding the potential adverse effects of anti-lymphocyte antibodies, including opportunistic infections, lymphoproliferative disorders, and the development of human anti-mouse antibodies. Records were reviewed for all 365 renal transplants performed in 267 patients at our center from 1971 to 1996. Anti-lymphocyte antibodies were used in an attempt to reverse 6 episodes of corticosteroid-resistant acute rejection in 5 children at a mean interval of 24.5 months following transplantation. The mean serum creatinine at initiation of therapy with the anti-lymphocyte agents was 2.9 mg/dl. Following treatment, the mean serum creatinine decreased to 1.3 mg/dl (P=0.03, Student's t-test). Two patients developed uncomplicated opportunistic infections after completion of anti-lymphocyte therapy; none have developed lymphoproliferative disorders or antibodies to OKT3. We conclude that in the correct clinical setting with corticosteroid-resistant acute rejection, the use of anti-lymphocyte antibodies should not be withheld solely on the basis of length of time since transplantation.

Predictive value of race in post-transplantation recurrence of focal segmental glomerulosclerosis in children.

BACKGROUND: Focal segmental glomerulosclerosis (FSGS) is a leading cause of end-stage renal disease (ESRD) in children, and one of the most difficult to manage because of its high recurrence rate post-transplantation (Tx). Several predictive factors have been associated with disease recurrence (DR) although one in particular, the role of recipient race, has not been adequately evaluated. Herein we report our experience with DR in the post-Tx period in eight patients. METHODS: Records were reviewed for all renal transplants performed at St Christopher's Hospital for Children from 1971 to 1997. RESULTS: Twenty patients received 27 allografts for ESRD due to FSGS. Ten (37%) grafts went to African-American (AA) children, and 16 (59%) to those of Caucasian (C) origin. DR was observed in eight (30%) grafts after Tx. No differences were noted between the patients who developed DR and those who did not, with respect to age at diagnosis or time to ESRD. DR was observed in one (10%) of 10 grafts in AA, compared to seven (41%) of 17 grafts in the other (O) racial groups (P=0.19). At last follow-up, the only AA recipient with DR has maintained stable renal function, while three (43%) of seven in O have lost their grafts. CONCLUSION: In conclusion, in our population post-Tx recurrence of FSGS occurred more frequently and represented a greater threat to graft survival in O recipients than in those of AA descent. Recipient race should therefore be taken into consideration during pre-Tx counselling of families of children with FSGS.

Pleural effusion complicating acute peritoneal dialysis in hemolytic uremic syndrome.

Hemolytic uremic syndrome (HUS) is a leading cause of acute renal failure (ARF) in children, and one for which treatment with peritoneal dialysis (PD) is often necessary. Between January 1982 and December 1996, 176 children received PD for ARF at St. Christopher's Hospital for Children; 34 (19%) of whom had HUS. Of these 34, 7 (20%) developed pleural effusions (PE) while receiving PD, whereas none of the remaining 142 children with other causes of ARF did so. The mean age of the 7 affected children was 5.2 (range 0.4-17) years; none had heart failure or nephrotic syndrome, nor had any of them undergone thoracic surgery. PE were diagnosed by chest radiograph at an interval of 2 (range 1-3) days after starting PD. Thereafter, 4 (57%) patients were successfully maintained on a modified PD prescription; 2 others were converted to hemodialysis and 1 to continuous venovenous hemodiafiltration. Although PE are a known complication of PD, none of the patients so treated for non-HUS related ARF developed them. Whether they represent a purely mechanical complication of PD, or are in some way attributable to HUS itself, is not entirely clear. Regardless, when children with HUS require PD, physicians should monitor for the development of this potential complication to minimize the risk of serious respiratory compromise.

Calcineurin activity in children with renal transplants receiving cyclosporine.

BACKGROUND: The major immunosuppressive effect of cyclosporine is through the inhibition of calcineurin, an enzyme important in the activation of T lymphocytes. In children, neither calcineurin activity nor its inhibition by cyclosporine (CsA) has been investigated. METHODS: Calcineurin activity, was measured in stable pediatric renal transplant patients, with healthy children used as controls. Whole blood CsA concentrations were measured by monoclonal radioimmunoassay. Simultaneous calcineurin and CsA levels were measured before and 1, 2, 3.5, 5, and 12 hr after their routine morning CsA dose. RESULTS: Calcineurin activity was approximately 50% inhibited at trough blood concentrations (148 microg/L); moreover, inhibition increased as CsA concentrations rose and declined as concentrations fell. Maximum calcineurin inhibition was about 70% at concentrations of about 431 microg/L. Linear regression analysis revealed a significant correlation between mean CsA blood concentration and the mean degree of inhibition of calcineurin activity (P=0.005, one-tailed). CONCLUSION: We conclude that inhibition of calcineurin activity by CsA in pediatric renal transplant recipients correlates with CsA blood concentrations.

Response to the varicella vaccine in children with nephrotic syndrome.

Varicella vaccine was administered to seven children with corticosteroid-sensitive nephrotic syndrome. Immunization was not associated with any significant reactions or with increased frequency of relapse. The antibody response was, however, variable and a second dose was necessary before seroconversion was achieved in four patients. The findings indicate that immunization with varicella vaccine is safe in children with nephrotic syndrome in remission, but that a two-dose vaccine schedule should be considered.

Comparison and validation of limited sampling equations for cyclosporine area-under-the-curve monitoring calculations in pediatric renal transplant recipients.

Therapeutic monitoring of cyclosporine (CsA) by using area-under-the-concentration-time-curve (AUC) values in renal transplant recipients has been previously demonstrated to predict posttransplant clinical outcome. Two previous studies also reported that limited sampling equations could accurately determine the AUC of CsA using one to six blood concentration determinations in adults. The purpose of this study was to validate the accuracy of these equations in a pediatric population. In 18 pediatric patients who received renal allografts, three limited sampling equations, which used one, four, or five concentration time points, accurately estimated CsA AUC when compared with an actual 7- to 9-point curve. An equation that used a single concentration time point at 5 hours was unbiased and provided the best precision in calculating a 12-hour interval AUC. This equation had a mean absolute percentage error of 5.8% (95% confidence interval, 3.3 to 8.3). Equations using four or five concentration time points were found to provide estimates of AUC for a 24-hour interval AUC, with less than 10% error. These findings suggest that limited sampling models using as few as one to four concentration time points provide accurate estimations of CsA AUC in pediatric patients. The use of these limited sampling models provides the clinical advantage of lower blood sampling requirements and reduced costs associated with the monitoring of cyclosporine.

Intravenous immunoglobulin prophylaxis of cytomegalovirus infection in pediatric renal transplant recipients.

Cytomegalovirus (CMV), the most significant infectious cause of morbidity following renal transplantation, may be a greater problem for children than for adults due to their relative lack of experience with this virus. Therefore, we prospectively gave Gammagard as prophylaxis to CMV-negative children who received CMV-positive allografts and compared the results to our experience with similar high-risk recipients transplanted prior to our use of intravenous immunoglobulin G (IvIgG). Symptomatic CMV disease developed in 17% of the IvIgG recipients as compared with 71% of the untreated patients (p = 0.01). The CMV infections that did occur in IvIgG recipients developed significantly later than in untreated children (median time of onset after transplantation 2.60 vs. 1.35 months; p < 0.05) and generally were less severe, although 1 IvIgG recipient died despite prophylaxis. IvIgG administration did not affect the frequency of rejection or graft or patient survival. We conclude that IvIgG administration to high-risk pediatric renal transplant recipients may protect against posttransplantation CMV disease and may lessen the severity of infections that do develop in patients who receive it.

Effective immunization against influenza in pediatric renal transplant recipients.

Viral infections such as influenza are an important cause of morbidity following organ transplantation. We evaluated the immunogenicity of a commercially available influenza vaccine in pediatric renal transplant recipients in a two-phase, prospective study. In phase one, 47 transplant patients and seven control subjects with bronchopulmonary dysplasia received influenza vaccine. Sera were collected at the time of vaccination and 6 wk later. In phase two, sera from 18 transplant recipients and 47 healthy adults who had received the same vaccine were collected 6-12 months after vaccination. Antibody titers to the A/Taiwan/1/86 antigen were measured with hemagglutination inhibition assay in both phases of the study. Vaccine was well tolerated in all subjects. No vaccinated patient required hospitalization for complications of influenza infection. Vaccination did not increase the frequency of acute allograft rejection. In phase one, 43 patients (91%) and 5 controls (71%) either seroconverted (developed a fourfold or greater rise in titer), or developed post-vaccination titers > or = 1:160 (p = NS). Among the transplant recipients, non-seroconverters had a higher pre-vaccination geometric mean antibody titer (GMT) than those who seroconverted. Seroconversion developed independently of whether patients received double or triple immunosuppression. In phase two, post-vaccination GMT were similar for patients and control subjects at 11.5 and 8 months post-vaccination, respectively. In our study, influenza vaccination produced equivalent humoral immunity in transplant recipients and normal subjects. Routine influenza vaccination should be performed annually in this high-risk population.

Pharmacokinetics of cyclosporine after renal transplant in children.

The pharmacokinetics of cyclosporine and the relationship between blood levels and average drug concentration were prospectively evaluated in 18 children 1 month after renal transplantation. All children had normal renal function and no hepatic or gastrointestinal dysfunction. Cyclosporine was administered after an overnight fast, and serial blood samples were drawn over a 24-hour period. Analysis of cyclosporine levels was performed by means of monoclonal radio immunoassay on whole blood. Children were divided into three age groups for comparison: 2-5 years, 5-10 years, and > 10 years. There were no differences between age groups in serum protein, serum lipids, or hemoglobin levels, or in the pharmacokinetic parameters of cyclosporine except as follows: significant differences were noted in cyclosporine dose based on body weight, apparent steady-state volume of distribution, and apparent blood clearance, with the youngest children (2-5) requiring higher doses, a relative greater distribution, and exhibiting more rapid drug clearance than those > 10 years of age. In addition, we observed diurnal variation in trough levels, with morning levels (0 hr) significantly higher than those obtained in the evening (12 hours after administration of cyclosporine). Trough levels demonstrated a fair correlation with area under the concentration-time curve (AUC) and average concentration (Cav), but an abbreviated kinetic profile using cyclosporine levels 1 and 3.5 hours after administration accurately predicted AUC.

Fusarium peritonitis in a child on peritoneal dialysis: case report and review of the literature.

OBJECTIVE: To review various aspects of the management of peritonitis due to Fusarium, a soil mold which infrequently causes infections in humans. DATA SOURCES: A case of Fusarium peritonitis in a child on chronic peritoneal dialysis (PD) is presented. The child developed Fusarium peritonitis 2 weeks after an episode of bacterial peritonitis. His Tenckhoff catheter was removed, and he was maintained on hemodialysis while receiving intravenous amphotericin. Following 2 weeks of treatment with amphotericin, he was successfully returned to PD. A literature review of all previously reported cases of Fusarium peritonitis was then conducted to determine features common to infections caused by Fusarium. Emphasis was also placed on unique characteristics of the organism that may affect patient management, as well as patient characteristics that may increase the risk for infection by Fusarium. RESULTS: Fusarium may cause infection in immunosuppressed individuals, such as cancer patients or patients on chronic PD. The organism has a propensity to attach to foreign bodies such as intravascular and intraperitoneal catheters. Therefore, successful treatment of infections caused by Fusarium may require catheter removal in addition to systemic antifungal therapy. CONCLUSIONS: This report presents the first known case of Fusarium peritonitis in a child. In view of the difficulties posed by this unusual organism, optimal therapy of Fusarium peritonitis should consist of immediate catheter removal and treatment with systemic antifungal drugs.

Natural history and etiology of hyperuricemia following pediatric renal transplantation.

A retrospective review was conducted to determine the incidence, etiology, natural history and complications of hyperuricemia after pediatric renal transplantation. Of 81 active transplant recipients aged 10.1 +/- 4.8 (mean +/- SD) years being followed by St. Christopher's Hospital for Children, 57 (70%) were males and 59 (73%) Caucasian. Their immunosuppression consisted of azathioprine, cyclosporine A and prednisone. Mean serum uric acid concentrations peaked at 6 months post transplantation (6.2 +/- 2.6 mg/dl), when 39% of the patients had hyperuricemia and 60% were receiving diuretics, and decreased thereafter. At 30 months, 23% of the patients had hyperuricemia and 17% required diuretics. When we compared 42 normouricemic (group A) with 24 hyperuricemic (group B) patients at 18 months post transplantation, we found that patients in group B were older (11.6 +/- 4.2 vs. 8.6 +/- 5.2 years, P = 0.01), had worse renal function (77 +/- 25 vs. 96 +/- 36 ml/min per 1.73 m2, P = 0.03) and required diuretics more frequently (63% vs. 21%, P = 0.001), but had identical blood levels of cyclosporine A (82 +/- 28 vs. 84 +/- 35 ng/ml, P = 0.78). A family history of gout did not affect the prevalence of hyperuricemia after transplantation. Asymptomatic hyperuricemia is common following pediatric renal transplantation and is more likely attributable to reduced renal function and diuretic therapy than to the known hyperuricemic effect of cyclosporine A. Of these variables, only diuretic therapy is readily controllable and should be closely regulated following pediatric renal transplantation.

Peritoneal dialysis catheter infections in children after renal transplantation: choosing the time of removal.

As a foreign body, the peritoneal dialysis (PD) catheter represents a potential source of infection, particularly for immunosuppressed renal transplant patients. A retrospective study was therefore undertaken to compare the risks and benefits of our policy of removing PD catheters at 3 months following renal transplant, which was established to allow for early re-initiation of dialysis. Between 1984 and 1990, 43 renal transplants were performed in 35 children who had been receiving maintenance PD. During the 1st month post transplantation, the PD catheter was used in 25 patients (58%) because of acute rejection or primary allograft non-function. Thirty-one patients were eventually discharged with functioning allografts and a PD catheter in place. Of them, 43% developed a catheter-related infection within the next 2 months, a period during which PD was not performed. Potential contributing factors included a history of catheter-related infection prior to transplantation, use of high-dose methylprednisolone to treat acute rejection, and the type of maintenance immunosuppression prescribed; conversely, the use of prophylactic antibiotics appeared to decrease this risk. This study established the potential need for the catheter during the first few weeks, but because of the infection risk of 43% by 3 months post transplantation, our protocol was revised to include catheter removal at the time of hospital discharge. From 1990 until the end of 1992, an additional 19 PD recipients underwent transplantation. In this group, catheters were used during the 1st month in 6 children (32%). Fifteen patients were discharged with a functioning allograft and only 1 patient returned to PD at 12 months post transplant. It is concluded that PD catheters represent an additional source of infection following transplantation and should be removed at the time of hospital discharge, after which the likelihood of use is low.

Growth of children following the initiation of dialysis: a comparison of three dialysis modalities.

Maintenance dialysis usually serves as an interim treatment for children with end-stage renal disease (ESRD) until transplantation can take place. Some children, however, may require dialytic support for an extended period of time. Although dialysis improves some of the problems associated with growth failure in ESRD (acidosis, uremia, calcium, and phosphorus imbalance), many children continue to grow poorly. Therefore, three different dialysis modalities, continuous ambulatory peritoneal dialysis (CAPD), cycler/intermittent peritoneal dialysis (CPD), and hemodialysis (HD), were evaluated with regard to their effects on the growth of children initiating dialysis and remaining on that modality for 6-12 months. Growth was best for children undergoing CAPD when compared with the other two modalities with regard to the following growth parameters: incremental height standard deviation score for chronological age [-0.55 +/- 2.06 vs. -1.69 +/- 1.22 for CPD (P < 0.05) and -1.80 +/- 1.13 for HD (P < 0.05)]; incremental height standard deviation score for bone age [-1.68 +/- 1.71 vs. -2.45 +/- 1.43 for CPD (P = NS) and -2.03 +/- 1.28 for HD (P = NS)]; change in height standard deviation score during the dialysis period [0.00 +/- 0.67 vs. -0.15 +/- .29 for CPD (P = NS) and -0.23 +/- .23 for HD (P = NS)]. The reasons why growth appears to be best in children receiving CAPD may be related to its metabolic benefits: lower levels of uremia, as reflected by the blood urea nitrogen [50 +/- 12 vs. 69 +/- 16 mg/dl for CPD (P < 0.5) and 89 +/- 17 for HD (P < 0.05)], improved metabolic acidosis, as indicated by a higher serum bicarbonate concentration [24 +/- 2 mEq/l vs. 22 +/- 2 for CPD (P < 0.05) and 21 +/- 2 for HD (P < 0.05)]. In addition, children undergoing CAPD receive significant supplemental calories from the glucose absorbed during dialysis. CAPD, and possibly, other types of prolonged-dwell daily peritoneal dialysis appear to be most beneficial for growth, which may be of particular importance for the smaller child undergoing dialysis while awaiting transplantation.

Growth after conversion to alternate-day corticosteroids in children with renal transplants: a single-center study.

During the 1980s all children with growth potential and stable/adequate renal function at 6-9 months after kidney transplantation underwent conversion to alternate-day corticosteroids in an attempt to maximize growth. Conversion was attempted in 79 of 160 children who received allografts during this decade and was considered successful if they remained on alternate-day prednisone for more than 1 year, with a calculated creatinine clearance of at least 75% of the pre-conversion baseline value. Conversion succeeded in 55 children but failed in 24. Growth was markedly improved among those successfully converted when compared with the failure group, as measured by standard deviation score for growth velocity based on chronological age (+0.94 +/- 1.58 vs. -0.86 +/- 1.53, P < 0.001) and bone age (+0.49 +/- 0.61 vs. -1.24 +/- 1.47, P < 0.001). The improved growth among the successfully converted patients is believed to have been related to the combined effects of lower corticosteroid dose (0.36 +/- 0.16 vs. 0.48 +/- 0.21 mg/kg per day, P < 0.02) and better renal function (calculated creatinine clearance 87 +/- 32 vs. 47 +/- 21 ml/min per 1.73 m2, P < 0.001) at 1 year post conversion. Two factors appeared to improve the likelihood of successful conversion: the use of cyclosporine and receiving a live-related rather than cadaver transplant. Cyclosporine was associated with improvement in the overall rate for successful conversion in all recipients, from 59% to 83% (P < 0.05). Recipients of allografts from live-related donors underwent successful conversion in 90% of cases compared with 58% receiving cadaver allografts (P < 0.05). (ABSTRACT TRUNCATED AT 250 WORDS)

Urinary tract infections in children with posterior urethral valves after kidney transplantation.

The records of 14 boys with posterior urethral valves who had renal failure and subsequently underwent renal transplantation were reviewed to determine the postoperative incidence of urinary tract infection relative to that of 29 male transplant children without valves, who served as controls. There were no significant differences between the posterior urethral valve patients and controls with regard to age, donor source, immunosuppression, followup after transplantation or mean calculated creatinine clearance. Vesicoureteral reflux was found in 1 child with posterior urethral valves and 3 of the children in the control group (p not significant). A total of 15 urinary tract infections occurred in 5 children (36%) with posterior urethral valves, for a rate of 1 per 30 patient-months of followup, and 6 urinary tract infections occurred in 2 controls (7%), for a rate of 1 per 216 patient-months of followup (p < 0.05). However, only 1 of 26 controls (4%) without vesicoureteral reflux had urinary tract infection, for a rate 1 per 1,144 patient-months (p < 0.01). Conversely, the rate of urinary tract infections in controls with vesicoureteral reflux was similar to that of children with posterior urethral valves. Of the 5 children with posterior urethral valves 4 had the initial urinary tract infection within 2 months of transplantation and 10 of 15 episodes occurred within the first 4 months. Antimicrobial prophylaxis did not appear to decrease the rate of infection in children with posterior urethral valves. A history of posterior urethral valves increases the frequency of urinary tract infection after renal transplantation but the usefulness of antimicrobial prophylaxis and the relationship to long-term graft function remain to be determined. Urinary tract infection rarely develops in other transplanted boys without vesicoureteral reflux.

Cerebral infarct with recurrence of hemolytic-uremic syndrome in a child following renal transplantation.

A white girl with a history of atypical hemolytic-uremic syndrome (HUS) and persistent microangiopathic anemia, and thrombocytopenia for 2 months after the initial presentation at age 7 months, received her first cadaveric renal transplant at age 3 years. During the first 2.5 days post transplant, she developed progressive thrombocytopenia and anemia followed by tonic-clonic seizures and loss of consciousness, secondary to a diffuse cerebral infarction of the left hemisphere. Renal histology showed evidence of glomerular microthrombi and microangiopathy. A large cerebral infarct, previously described in patients during their initial presentation with HUS, presented in our patient as part of the recurrence of the disease post renal transplantation.

Treatment of steroid-resistant post-transplant nephrotic syndrome with cyclophosphamide in a child with congenital nephrotic syndrome.

A child with congenital nephrotic syndrome underwent renal transplantation, was treated for acute rejection, and then developed nephrotic syndrome and renal failure. He was felt to have minimal change disease on allograft biopsy, but failed to respond to therapy with corticosteroids. Cyclophosphamide was substituted for cyclosporine and rapidly induced a complete remission of his nephrotic syndrome. We feel that this case not only represents an important example of a useful therapeutic approach to the child with congenital nephrotic syndrome who develops nephrotic syndrome post transplantation, and also raises questions concerning the pathogenesis of congenital nephrotic syndrome.