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To determine whether steroid avoidance in pediatric kidney transplantation is safe and efficacious, a randomized, multicenter trial was performed in 12 pediatric kidney transplant centers. One hundred thirty children receiving primary kidney transplants were randomized to steroid-free (SF) or steroid-based (SB) immunosuppression, with concomitant tacrolimus, mycophenolate and standard dose daclizumab (SB group) or extended dose daclizumab (SF group). Follow-up was 3 years posttransplant. Standardized height Z-score change after 3 years follow-up was -0.99 ± 2.20 in SF versus -0.93 ± 1.11 in SB; p = 0.825. In subgroup analysis, recipients under 5 years of age showed improved linear growth with SF compared to SB treatment (change in standardized height Z-score at 3 years -0.43 ± 1.15 vs. -1.07 ± 1.14; p = 0.019). There were no differences in the rates of biopsy-proven acute rejection at 3 years after transplantation (16.7% in SF vs. 17.1% in SB; p = 0.94). Patient survival was 100% in both arms; graft survival was 95% in the SF and 90% in the SB arms (p = 0.30) at 3 years follow-up. Over the 3 year follow-up period, the SF group showed lower systolic BP (p = 0.017) and lower cholesterol levels (p = 0.034). In conclusion, complete steroid avoidance is safe and effective in unsensitized children receiving primary kidney transplants.

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.

Nutritional data compiled during the Growth Failure in Children with Renal Diseases Clinical Trial were analyzed to determine the relationship between the dietary intake of divalent minerals and sodium, nutritional status, and serum calcium, phosphorus, and parathyroid hormone (PTH) concentrations and blood pressure in black versus white children. One hundred eighteen patients are included in this report; 25 were black (21%) and 93 were white (79%). Although more of the blacks were male, the age distribution, midarm circumference, midarm muscle circumference, blood pressure, and serum calcium, phosphorus, and PTH concentrations were comparable in the two groups. Phosphorus intake was within the recommended daily allowance in both groups; in contrast, calcium intake was inadequate in all patients: 81% of the recommended daily allowance in whites, and 74% in blacks. Sixteen children were noted to be hypertensive during the observation period; six patients were receiving a variety of antihypertensive medications, including diuretics in two children. Linear regression analysis revealed that systolic and diastolic blood pressures were directly related to calcium and phosphorus intake in black patients. In white children, only dietary phosphorus intake and diastolic blood pressure were directly related. There was no relationship between sodium intake or GFR and blood pressure in the white or black children. PTH levels were directly correlated with systolic and diastolic blood pressure in all children. The correlations between PTH and blood pressure were stronger in white versus black patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Monitoring of renal graft status through peripheral blood (PB) rather than invasive biopsy is important as it will lessen the risk of infection and other stresses, while reducing the costs of rejection diagnosis. Blood gene biomarker panels were discovered by microarrays at a single center and subsequently validated and cross-validated by QPCR in the NIH SNSO1 randomized study from 12 US pediatric transplant programs. A total of 367 unique human PB samples, each paired with a graft biopsy for centralized, blinded phenotype classification, were analyzed (115 acute rejection (AR), 180 stable and 72 other causes of graft injury). Of the differentially expressed genes by microarray, Q-PCR analysis of a five gene-set (DUSP1, PBEF1, PSEN1, MAPK9 and NKTR) classified AR with high accuracy. A logistic regression model was built on independent training-set (n = 47) and validated on independent test-set (n = 198)samples, discriminating AR from STA with 91% sensitivity and 94% specificity and AR from all other non-AR phenotypes with 91% sensitivity and 90% specificity. The 5-gene set can diagnose AR potentially avoiding the need for invasive renal biopsy. These data support the conduct of a prospective study to validate the clinical predictive utility of this diagnostic tool.

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.

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.

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.

The efficacy of rifampin in eliminating Staphylococcus aureus colonization was evaluated in a pediatric peritoneal dialysis population. Six children with documented nasal colonization were treated for 7 days with rifampin and cloxacillin. Although antimicrobial therapy eliminated nasal carriage in all patients, recolonization occurred in 66%. Exit site colonization proved difficult to eradicate with negative cultures documented in only 3 of 5 children after rifampin/cloxacillin therapy. Although S. aureus carriage is a risk factor for S. aureus infections, efforts to eradicate carriage with rifampin are hindered by rapid recolonization.

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.

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.

Hyperlipidemia (HL) is a common problem in adult renal transplant (TP) recipients, contributing to an increased risk of cardiovascular disease and chronic TP nephropathy. There are multiple causes of HL post renal TP in adult patients, including pre TP HL, immunosuppressive agents, renal dysfunction, hypoalbuminemia secondary to nephrotic syndrome, obesity, and conditions that lead to end-stage renal disease (ESRD). We evaluated the incidence and risk factors of HL in 62 pediatric renal TP recipients (15.4+/-4.2 years, range-3.0-22.3 years) with long-term (6.7+/-3.1 years) functioning [glomerular filtration rate (GFR) 66.7+/-23.2 ml/min per 1.73 m(2)] allografts. The mean serum cholesterol (C) level was 205. 5+/-43.6 mg/dl. Thirty-two patients (51.6%) exhibited elevated serum C levels. The mean serum triglyceride (TG) level was 157.3+/-88.4 mg/dl. Serum TG levels were elevated in 32 patients (51.6%). In patients with elevated serum levels of either C or TG, the mean low-density lipoprotein level (LDL) was 138.6+/-44.1 mg/dl (normal130 mg/dl) and the high-density lipoprotein (HDL) level 54.6+/-15.9 mg/dl (normal34 mg/dl). Of those patients studied, 45.5% had high LDL levels, whereas 9.1% exhibited low HDL levels. The two risk factors for elevated serum C levels in our patient population were pre-TP HL and increased years since TP. The only risk factor for elevated serum TG levels was reduced GFR. A family history of HL had a significant deleterious impact upon serum levels of C (P=0.01), but did not affect serum TG levels (P=0.7). Years on dialysis prior to TP, history of prior TP, gender, body mass index, and disease leading to ESRD had no influence upon the development of post-TP HL. We conclude that post-renal TP HL is a significant problem in pediatric renal TP recipients.

A 3.5-year-old boy presented with end-stage renal disease and bilateral nephrocalcinosis. Renal biopsy demonstrated marked parenchymal calcium oxalate deposition and a diagnosis of primary hyperoxaluria (PH) was made. Following 2 years of hemodialysis he received two renal allografts which were lost at 7 and 11 months, respectively, due to biopsy-proven recurrent oxalosis. Combined liver-kidney transplantation was then performed, after which renal and hepatic function initially stabilized. The patient died on the 28th postoperative day, of in fectious complications and progressive respiratory insufficiency. However, comparisons between the patterns of urinary oxalate excretion noted after the isolated renal and liver-kidney transplants indicated that, following the latter, successful biochemical correction of the enzyme defect responsible for type 1 PH had occurred.

Hypertension (HTN) is a significant problem in pediatric renal transplant (TP) recipients, predisposing the individuals to the development of cardiovascular disease and graft dysfunction. Calcium channel blockers (CCB) are considered excellent agents to treat post-TP HTN. We compared the efficacy and adverse effects of the two most commonly prescribed CCBs in our pediatric renal TP population: nifedipine (Procardia, or P) and amlodipine (Norvasc, or N). All patients (n = 24) had been started on a CCB for systolic (SBP) and/or diastolic BP (DBP) > 95%. There were no other changes in adjunctive antihypertensive medications or doses during the cross-over period. Post-TP, pretreatment (pretx) SBP was 137.6 +/- 10.9 mmHg. The post-treatment SBP were (in mmHg): 128.5 +/- 11.9 (all patients, n = 24) (p = 0.009 vs. pretx); 126.4 +/- 10.0 (P alone, n = 15) (p = 0.007 vs. pretx); 132.8 +/- 14.4 (P + other antihypertensive(s), n = 9) (p = 0.331, NS vs. pretx). The post-TP, pretreatment DBP was 88.2 +/- 11.1 mmHg. The post-treatment DBP were (in mmHg): 78.5 +/- 6.9 (all patients, n = 24) (p = 0.03 vs. pretx); 77.2 +/- 7.4 (P alone, n = 15) (p = 0.008 vs. pretx); 80.7 +/- 6.1 (P + other antihypertensive(s), n = 9) (p = 0.063, NS vs. pretx). P and N were equally effective in reducing SBP (p = 0.843, NS) and DBP (p = 0.612, NS). Cyclosporin A (CyA) dose (p = 0.81) and trough levels (p = 0.19) were similar in P- and N-treated patients. Calculated GFR was virtually identical in P- and N-treated patients (p = 0.89). Patients (or parents of) reported a higher incidence of various side-effects while receiving P, including headache, flushing, dizziness and leg cramps. Furthermore, 22/24 (91.7%) reported some degree of gingival hyperplasia during treatment with P, and all these patients reported a stabilization or reduction of hypertrophy after the switch from P to N. We conclude that CCBs (N) are efficacious drugs for the purpose of BP control and renal protection in pediatric renal TP recipients.

nephrotic syndrome in children, approximately oneBackground. Focal segmental glomerulosclerosis third of whom progress to ESRD [2]. In a substantial (FSGS ) is a leading cause of end-stage renal disease proportion, FSGS recurs following Tx, resulting in ( ESRD) in children, and one of the most diYcult to graft loss in about one-half [3‐7]. Predictive factors manage because of its high recurrence rate post- that have been associated with a high risk of DR are transplantation ( Tx). Several predictive factors have a younger age at presentation [6‐8], progression to been associated with disease recurrence (DR) although ESRD within 3 years of disease onset [6,8], and in one in particular, the role of recipient race, has not some reports the identification of mesangial proliferabeen adequately evaluated. Herein we report our tion on native kidney biopsy [3,6,8,9]. The predictive experience with DR in the post-Tx period in eight role of recipient race in recurrence of FSGS has been patients. inadequately addressed. To date, this issue has been Methods. Records were reviewed for all renal trans- investigated in only one report, in which a reduced plants performed at St Christopher’s Hospital for risk of DR was demonstrated in AA [9]. Children from 1971 to 1997. Results. Twenty patients received 27 allografts for ESRD due to FSGS. Ten (37%) grafts went to African- Subjects and methods American (AA) children, and 16 (59%) to those of Caucasian (C ) origin. DR was observed in eight (30%) Records were reviewed for all renal transplants performed grafts after Tx. No diVerences were noted between the at St Christopher’s Hospital for Children from 1971 to 1997. patients who developed DR and those who did not, Children whose native kidney biopsy showed clear evidence with respect to age at diagnosis or time to ESRD. DR of FSGS were identified, and their charts reviewed to obtain was observed in one (10%) of 10 grafts in AA, com- demographic information and data relating to their post-Tx pared to seven (41%) of 17 grafts in the other (O) clinical course. Patients with a histological diagnosis of FSGS racial groups (P=0.19). At last follow-up, the only who presented with ESRD, but without a preceding history AA recipient with DR has maintained stable renal of clinical nephrosis, were excluded from the analysis. DR function, while three (43%) of seven in O have lost was defined as the appearance of nephrotic-range proteinuria their grafts. (>40 mg/h/m2) in the absence of acute or chronic rejection, Conclusion. In conclusion, in our population post-Tx and was confirmed by allograft biopsy. Fisher’s two-tailed recurrence of FSGS occurred more frequently and exact test was used for statistical analysis of diVerences between the cohort of patients with and without DR. 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 Results pre-Tx counselling of families of children with FSGS.

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.

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.

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 titersor = 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.

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.

We reviewed the effectiveness of Muromonab-CD3 (OKT3) and anti-thymocyte globulin (ATG) in the treatment of corticosteroid-resistant acute renal allograft rejection in 49 transplanted children. Reversal of rejection was successful in 22 of 23 patients (96%) treated with OKT3 and 21 of 26 (81%) treated with ATG (P = NS). Re-rejection episodes occurred within 1 month of cessation of therapy in 9 of 22 patients treated with OKT3 but only in 2 of 21 who received ATG (P0.05). In the patients with re-rejection, 7 of the 9 patients originally given OKT3 and 1 of the 2 who received ATG responded to a repeat course of high-dose corticosteroids; thus, at 1 month post treatment, the incidence of graft loss due to initial rejection or re-rejection was 13% for the OKT3 and 23% for the ATG group (P = NS). Graft survival was similar at 6 months: 82% for OKT3- and 73% for ATG-treated patients (P = NS); 100% patient survival was noted in both groups. Mean calculated creatinine clearance prior to, during, and at 1 and 6 months post rejection was similar in the OKT3- and ATG-treated groups. Neutropenia and thrombocytopenia occurred more frequently in the ATG group, but there was no significant difference in infectious complications. Two patients developed high (or = 1:1,000) OKT3 antibody titers. In our experience, children with corticosteroid-resistant acute renal allograft rejection treated with OKT3 and ATG had similar allograft survival and level of renal function at 1 and 6 months, and number of infectious complications post therapy.

One hundred twenty-seven children (83 males, 44 females, 86 white, 41 nonwhite; mean age 12.1 years) who received 160 renal transplants between 1980 and 1989 were retrospectively studied. Variables such as age, sex, primary diagnosis, type, HLA-DR mismatching, and repeated transplants were compared between races and found not to be significant. However, HLA-A and -B cadaveric-graft mismatching, which was equivalent between whites and nonwhites prior to 1985 (pre-cyclosporine A era), has significantly favored whites (49% with 0 to 2 HLA-A and -B mismatch vs 16% in nonwhites) since 1985 (P less than .05), and a significantly higher proportion of nonwhite patients (59%) were receiving medical assistance (P less than .0001). Graft survival was evaluated with significantly poorer results in nonwhites as compared to whites (P less than .05). Although no difference was found between white and nonwhite cadaveric-graft survival before 1985, nonwhites had significantly worse graft survival since 1985 (72% vs 59% for 1 year and 61% vs 24% for 3 years in whites and nonwhites, respectively; P less than .05). Subpopulations such as nonwhite adolescents, nonwhite females, nonwhites with repeated transplants, and all low socioeconomic patients were identified as high-risk children with poor long-term survival. It is concluded that secondary to poorer matching since 1985 there has been decreased graft survival in nonwhites despite cyclosporine A. Attempts to improve matching and attention to high-risk groups are needed for equivalent survival.

The efficacy of recombinant human growth hormone (rGH) was assessed in five pediatric allograft recipients with severe growth retardation despite successful renal transplants. rGH 0.05 mg/kg per dose was given six times weekly by subcutaneous injection to five prepubertal children (mean age 15.2±2.0 years) all of whom had bone ages less than or equal to 12 years (10.0±1.4 years), a height standard deviation score of less than −2.5 (−4.9±1.5), no evidence of catch-up growth, a calculated glomerular filtration rate (GFR) of more than 40ml/min per 1.73 m2 (51±6.8 ml/min per 1.73 m2), and stable renal function on alternate-day prednisone (16.7±2.6 mg/m2 per dose). Growth hormone profiles were abnormal in all children before treatment. rGH administration led to a significant increase in both growth rate (3.5±1.6 cm/year pre therapy, 8.5±1.4 cm/year post therapy,P

OKT3 has become one of the more effective antirejection therapies for patients receiving kidney transplants. However, its usefulness is diminished or blocked by the development of antimouse/anti-OKT3 antibodies. We evaluated 17 children receiving OKT3 for steroid-resistant acute rejection for the development and persistence of antibodies after therapy. OKT3 was successful in reversing acute rejection in 14 of 17 patients. Eight children developed antimouse antibodies, 7 at a low titer (1:100). The retesting of all children 6 months later showed no detectable antibodies. Children develop anti-OKT3 antibodies at a rate similar to adults and with time lose detectable levels which may have significance if a subsequent course of OKT3 is needed.

SAFETY AND IMMUNOGENECITY OF THE VARICELLA VACCINE(VARIVAX®) IN CHILDREN WITH NEPHROTIC SYNDROME (NS). 2190

Criteria to categorize children as having hypertension associated with high, low or normal PRA as determined by the technique of renin sodium indexing; or with PRA responsiveness which was normal, suppressed or excessive after acute volume depletion induced by a loop diuretic were established in 30 normotensive adolescents. Four hour upright PRA corrected for daily sodium excretion was elevated in 16% of 43 and 84% of 25 children with essential and renal related hypertension. Low PRA was found in 5 of 43 and 0 of 25 children. In 36 children with essential hypertension evaluated after acute volume depletion, 4 and 5 had hyper- and hypo- responsive PRA compared to the 30 normotensive children. The application of these two approaches enables the renin angiotensin system to be systematically categorized in hypertensive children.

Although cyclosporine has improved allograft survival in renal transplant patients, problems with drug toxicity remain, raising the question whether cyclosporine should be stopped at some point post-transplant. However, the relative safety of converting from cyclosporine to another immunosuppressive agent, or simply stopping cyclosporine remains an issue of debate and has not been evaluated in children. We have developed a protocol to convert children, who are 6 months post-transplant and have stable kidney function, from cyclosporine and prednisone to azathioprine and prednisone. Eleven children have undergone conversion because of suspected/potential nephrotoxicity or because of other difficulties with cyclosporine (expense, hirsutism). These children were compared with a control group of 12 children who met all criteria for conversion at 6 months but remained on cyclosporine. Allograft survival was similar in both groups but the children converted from cyclosporine experienced an improvement in renal function as measured by calculated creatinine clearance. There were no episodes of rejection for a period of 4 months post-conversion and all rejection episodes that developed subsequently occurred during or after the change from daily to alternate-day prednisone. We believe that conversion from cyclosporine to azathioprine can be accomplished safely in children with stable allograft function but long-term risks and benefits need further evaluation.

Histologic patterns in the glomerular tufts in "Glomerulonephritis with many crescents" take three main forms: (1) compression and sclerosis of glomeruli, (2) necrotizing glomerulitis, and (3) proliferation with or without exudation. In the third group, histologic differentiation between patients with poststreptococcal glomerulonephritis with many crescents (AGN) and those with nonstreptococcal rapidly progressive glomerulonephritis (RPGN) may be impossible. In a retrospective study, quantitative morphometry of glomeruli effectively separated three patients with AGN from two patients with RPGN after the usual histologic and electron microscopic observations had failed. Parameters studied were areas of tufts and crescents and total number of cells and granulocytes in tufts and crescents. Surface areas of tufts and crescents were separately determined by photographing glomeruli, projecting and tracing outlines of tufts and crescents, and cutting out and weighing the tracings. The cell density of glomerular tufts (cell per 1000-sq. mum. area) was significantly greater in AGN than in RPGN when either total cell densities (17.64 plus or minus 0.41 versus 13.63 plus or minus 0.30) or total cells minus granulocytes (16.39 plus or minus 0.50 versus 12.99 plus or minus 0.52) were compared. The cell density in the tufts was 120 and 70 per cent greater than controls in AGN and RPGN, respectively. Exudation of inflammatory cells is contributory but not the major cause of hypercellularity in AGN. Follow-up studies with biopsies showed marked resolution in two of three patients with AGN, with normal blood urea nitrogen levels and focal scarring in the third, whereas the two patients with RPGN had either extensive scarring and reduced renal function or required chronic hemodialysis.

The progressive encephalopathy observed in 5 children with chronic renal failure was clinically similar to the so-called dialysis encephalopathy of adults, except that it was not related to dialysis therapy. Renal osteodystrophy is more prevalent in children than in adults and often more severe. The attempt to control the crippling deformities of renal osteodystrophy in growing children with renal insufficiency has led to the use of large quantities of aluminum containing antacids. The encephalopathy observed in children with chronic renal failure may be related to the oral ingestion of aluminum containing compounds in the presence of persistent secondary hyperparathyroidism. We suggest that alternative methods for the adequate control of serum phosphorus levels should be sought and indications for parathyroidectomy in children reevaluated. During the past 18 mos we have lowered the dose of aluminum containing compounds to 50 to 100 mg/Kg/day in our patients with progressive renal failure and recommend parathyroidectomy. No new cases of the encephalopathy have occurred.

Several reports of neonatal hypertension, once regarded as a rarity, have been published (Bauer et al. 1975; Plummer et al. 1976; Adelman 1978). With the availability of accurate instruments for measurement, blood pressure monitoring in newborns has become routine. Furthermore, with the introduction of indwelling umbilical artery catheters, the incidence of hypertension due to renal artery thrombosis has risen sharply.

The use of the peritoneal membrane for removing uremic solutes was first reported in 1923 (1). Since then many investigators have contributed to bringing peritoneal dialysis (P.D.) from an experimental technique conducted in animals to its present state of clinical prominence. Although the technique of peritoneal dialysis is being used with increased frequency in children, relatively few studies dealing with dialysis kinetics have been performed in children and/or the developing animal.

In an attempt to reduce corticosteroid toxicity and to induce long-term remission, immunosuppressive agents such as cyclophosphamide and chlorambucil have been used in combination with corticosteroids to treat the frequently relapsing and steroid resistant nephrotic syndrome.(1–5) The effectiveness of cyclophosphamide has been established and its long-term results have been reviewed by Rance and co-workers.(6) These studies indicate that the duration of remission following a course of cyclophosphamide is approximately proportional to the length of the course. When low doses of the drug were given for sufficiently short periods of time to reduce toxic side effects, relapse subsequently occurred in as many as 48% of the patients during the first 12 to 26 months after therapy. Data from Grupe and co-workers (7) indicate that the combination of prednisone and chlorambucil, produces a longer remission than steroids alone, and that this combination also alters the subsequent course of relapses. In a more recent publication (8) by the same authors, a life table analysis of two dosage schedules of chlorambucil at four years shows that 91% of patients on low doses and 80% of those on high doses are still in remission.

In those children with thoracic asphyxiant dystrophy, a genetically determined disorder, who survive infancy, the development of renal disease may be life-threatening. This report will present data obtained in six patients from three families which deals with the renal abnormalities in thoracic asphyxiant dystrophy. Both functional and anatomic abnormalities are described. Abnormalities in solute transport in the proximal tubule may be the earliest sign of renal dysfunction in this syndrome. Early glomerular changes may be more important than previously recognized. Finally, the various phenotypic expressions of this disorder are considered.

The perirenal and pelvic accumulation of loculated lymphatic fluid following kidney transplantation surgery is a recognized but infrequent complication. We have observed such lymphoceles in association with 5 of 108 renal allografts in children. 2/5 lymphoceles occurred with cadeveric allografts and 3/5 with live related kidneys. Fever, renal insufficiency, and oligo-anuria were present in all 5 patients. Lower abdominal pain (4/5) and leg swelling (3/5) were findings not typical of rejection. Occurrence ranged between 1 and 9 weeks post-transplantation. The combination of renal scintigraphy and ultrasonography was successful in differentiating the lymphoceles from extravasated urine, hemorrhage and inflammatory collections. Lymphatic collections were seen as persistent photon deficient areas on scintigraphic flow and static images. Contact B-scan ultrasonograms showed them as anechoic collections with strong through transmission. Both modalities detected kidney obstruction secondary to the lymphocele. All patients required surgical drainage because the lymphocele obstructed the transplanted kidney or pelvic lymphatics. All patients have retained their allografts which are functioning satisfactorily.

Maintenance IHPD has been made possible in recent years by the development of automatic dialysis systems and permanent peritoneal catheter. We have used IHPD in our ESRD program because of geographic factors, technical difficulties encountered with hemodialysis due to Inappropriate size of the existing dlalyzers,and the lack of suitable vessels for an adequate vascular assess. Our experience involves 9 children maintained on chronic IHPD for 3-30 mos. Ages ranged from 6-13 years, 2 were anephric, 4 were oliguric, 3 had polyuria. Medical problems encountered included: growth failure, hypertension, anemia, renal osteodystrophy and peritonitis. Inadequate growth was a significant complication In 7/9 patients. Hypertension was adequately controlled In 7/8. The mean Interval between blood transfusions was 6.8 wks and progression of renal osteodystrophy was observed In 3/9 patients. Five patients had a total of 8 episodes of peritonitis during 101.5 dialysis-month, an incidence of I episode/12.6 patient-month,or 0.55% of all 1440 dialysis. Eight are alive, I died following a cadaveric kidney transplant and 3 remain on IHPD. Three underwent a successful live-related transplant, 5 patients underwent a cadaveric kidney transplant, 2 have good functioning grafts and 3 had irreversible acute rejection. Although no form of dialysis is optimal,IHPD can be as effective as hemodialysis and offers certain psychosocial and medical advantages.

A distinct neurologic syndrome characterized by varying degrees of myoclonus, dysarthria, seizures, dementia, coma, and abnormal EEG occurred in 6 children with chronic renal failure. EEG findings were similar to those described in adults with dialysis dementia and consisted of diffuse slowing with bursts of 2-4 hz polyspike wave discharges. The children (4 male and 2 female) had congenital renal disorders. The encephalopathy could not be attributed to hypertension or known metabolic disturbances due to uremia. Encephalopathy occurred between the ages ot 26 months and 10 years, when renal failure was advanced (GFR 5-10 ml/min/ 1.73 m2). All had received high doses (340-800 mg/kg/day) of aluminum containing phosphate binding gels for periods of 9 months to 5 years prior to the onset of their encephalopathy. Dialysis and successful renal transplantation did not significantly alter the clinical course. The encephalopathy may be related to aluminum intoxication. However, these children differ from previously described adults with dialysis related encephalopathy attributed to aluminum toxicity in that they had not been dialyzed prior to the onset of neurologic signs. Perhaps the nervous system of growing children is more susceptible to trace metal intoxication. These observations suggest that the use of large quantities of aluminum containing gels needs reevaluation in children with renal failure. Supported by NIH grants KR-75 and RR 5624.

Renal blood flow has been measured in children of age 1½ to 16 years, by injecting 133Xe into the renal artery at the time of aortography or surgery. The rate of washout of radioactivity was monitored on magnetic tape and the resultant data analyzed by graphic analysis using a semi-automatic method of plotting and computing the rates and fraction of blood flow perfusing the outer and inner cortical regions of the kidney. The number, type, and results of the studies follows: 1) In 8 normal kidneys, RBF's were similar to adult values. 2) In 53 studies of RBF in children with congenital heart disease, RBF's were reduced in both cyanotic and acyanotic heart disease, were further reduced when heart failure was present (8 patients) and fell after angiography (19 patients). 3) Following renal biopsy drops in RBF may occur in intact kidneys, but not in the transplanted kidney (4 patients). 4)In chronic renal disease outer cortical blood flow is diminished. 5) 31 measurements of RBF in donor kidneys upon insertion and/or following transplantation suggest that this technique may have some value in predicting both the immediate and subsequent function of the graft. 6)In 5 patients with renal vascular hypertension, 133Xe measurements of RBF were helpful in determining secretory rates of renin in both kidneys. Supported NIH grants RR-75, RR-5624 and HE-12651.

Recent epidemiologic data suggest that DE may affect as many as 5.3% of adults receiving maintenance dialysis. To determine the magnitude and geographic distribution of this problem in childhood a questionnaire survey of 96 pediatric end-stage renal disease (ESRD)centers was conducted. 14/61 responding centers (23.0%) caring for 728 ESRD patients responded affirmatively to the questionnaire. 24 patients(3. 3%) were reported to have developed unexplained encephalopathy: the geographic distribution of cases was worldwide. 73.9% of patients had congenital renal disease. Personality changes, dementia and regression of developmental milestones were noted in patients from all 14 centers. Seizures were noted in patients from 9/14 centers and an abnormal EEG in those from 10/13. Speech disturbances were seen in cases from 11/14 centers. 13/13 reported patients were receiving aluminum-containing. compounds prior to or at the time of appearance of symptoms. Secondary hyperparathyroidism affected patients from 12/13 centers. Children from 9/13 centers had been dialyzed prior to appearance of neurologic symptoms. Symptoms occurred in 9 children who had not been dialyzed. A syndrome of unexplained progressive neurologic deterioration occurs in children with ESRD and appears to be clinically indistinguishable from that of adult DE. The implications of the above findings are discussed.

The efficacy of ATG (ATGAMR-Upjohn Co.) in prolonging patient + cadaver renal allograft survival was studied in 21 patients,age 5 to 19 yrs receiving transplants from May 1977 to Oct.1979. Of the 9 patients randomly selected to receive ATG, 3 were given a fixed dose for the 28 day period of therapy; the daily doses of 3 were altered in relation to the percentage of rosette forming cells. Six of the selected patients received the full course of therapy; 1 patient had a positive skin test to ATG; 2 had untoward reactions to the first (and only) administered dose. Of those receiving ATG 1 had irreversible rejection 1 mo after transplantation, and 1 kidney was rejected after 3 mo. Three control patients experienced irreversible rejection within 1 mo, + 2 kidneys were rejected after 3 mos. All patients except 1 experienced threatened rejection episodes during the first mo. One patient died at 2 wks and 2 died within 1 yr after transplantation. All 3 were controls. The 5 treated patients with functioning allografts 4 mos to 2 yrs after surgery had creatinine clearances from 42 to 91 m1/min/1.73M2; 7 controls had clearances from 22 to 120 m1/min/1.73M2. Conclusions: Although the number of patients was very small, there appeared to be no correlation between patient and graft survival and ATG therapy. There was a correlation between graft survival and HLA matching.