The pharmacokinetics and immunosuppressive response of tacrolimus in paediatric renal transplant recipients

The aims of our trial were to study the pharmacokinetics of tacrolimus in paediatric kidney transplant recipients. The study comprised 25 patients (median age 13 years, range 2–20 years) followed for 12 months; five pharmacokinetics profiles (within the first and second week and after 1 month, 6 months and 12 months) were obtained. Patients were divided into two groups: six children <6 years old and 19 older children. Tacrolimus was given at an initial dose of 0.15 mg/kg twice a day. Blood samples were drawn before and 1 h, 2 h, 3 h, 4 h, 6 h, 9 h and 12 h after drug administration. Patient and kidney survival rates were 100% at 1 year. At 6 months and 12 months creatinine clearance was 68.5±16.3 ml/min per 1.73 m² and 64.0±15.2 ml/min per 1.73 m² body surface area, respectively. Tacrolimus trough levels were 7.8±1.9 ng/ml and 7.3±2.5 ng/ml. The area under the concentration–time curve for 0 h to 12 h (AUC_0–12) normalised to a dose of 0.15 mg/kg, increased with time from the kidney transplantation and stabilised after the 6th month post-transplantation. During the first month after transplantation the normalised tacrolimus concentration–time profiles were significantly greater in the older children (P<0.05); the actual doses were significantly greater in the younger children (P<0.05). In conclusion, initial doses of 0.15 mg/kg twice a day orally are safe and guarantee a satisfactory degree of immunosuppression, with our therapeutic regimen. Children <6 years old need to start with a 50% higher tacrolimus dose to achieve the same pharmacokinetic and immunosuppressive results.     

Chronic allograft nephropathy and mycophenolate mofetil introduction in paediatric renal recipients

Mycophenolate mofetil (MMF) introduction with concurrent reduction in calcineurin inhibitors has been shown to be beneficial in chronic allograft nephropathy (CAN) in adults. MMF was introduced to 19 children with CAN 26.3±5.8 (range 3.1–82.6) months after transplantation. Patients were followed up for a mean of 13.2±2.9 (range 1.2–51.1) months. The mean initial MMF dose was 660±56 mg/m² per day, increased to 1,042±73 mg/m² per day a year later. Cyclosporin was reduced from 138±10 mg/m² per day at MMF introduction, to 116±15 mg/m² per day at 6 months and 107±24 mg/m² per day at 1 year. Six months prior to MMF introduction GFR deteriorated by –32.7±7.3 ml/min per 1.73m² per year. Six months after the introduction of MMF, GFR improved by +26.2±7.1 ml/min per 1.73m² per year (P <0.001). The introduction of MMF significantly reduced both the graft rejection rate (P=0.01) and systolic blood pressure (P=0.01), without a significant change in antihypertensive treatment. Haematological parameters did not significantly differ before and after MMF introduction. The introduction of MMF in paediatric renal transplant recipients with CAN may cause a significant improvement in GFR in both the short-term and the long-term and may well have a beneficial effect on systolic blood pressure. MMF has the potential to enable CNI-sparing protocols to be adopted.Preliminary results of this study were presented at the 7th Annual Congress of the British Transplantation Society, 2004, Birmingham, UK, and at the 13th Congress of the Internal Pediatric Nephrology Association, 2004, Adelaide, Australia     

Advantages of cyclosporin A using 2-h levels in pediatric kidney transplantation

Clinical trials in adult liver and heart recipients have shown that management of cyclosporine (CsA) dose with 2-h levels (C2) leads to lower rejection rates and serum creatinine levels compared with C0 monitoring. Therefore, we investigated whether C2 monitoring might also improve late graft survival after kidney transplantation in children. To date, no results in adult renal transplantation and in pediatric transplantation have been published. Forty-nine stable pediatric kidney recipients with a minimum time of 1 year after transplantation (mean=7±5 years) entered the study. None of the patients had experienced an acute rejection up to 6 months before entering the study. CsA dosing was based on C0 monitoring for the first 6 months and then based on C2 monitoring for the following 6 months. C0 and C2 levels were measured at 4-weekly intervals. Percentage decline in glomerular filtration rate (GFR) and mean coefficients of variation of CsA levels (C_var) were calculated and compared during the 6-months periods. At the beginning of the study, the mean calculated GFR was 53±15 ml/min per 1.73 m². During the 6 months of C0 monitoring, the mean GFR decreased to 49±12 m/min per 1.73 m² (P=0.001, paired t-test). Six months after switching to C2 monitoring, the mean GFR remained stable, at 49±15 ml/min per 1.73 m² (P=0.3 paired t-test). The largest increase in GFR (3.9±7.9%) was found in patients with a decrease of their CsA dose of more than 5% under C2 monitoring. C_var was significantly lower under C2 than under C0 monitoring (0.24±0.10 vs. 0.30±0.15, P=0.02, unpaired t-test). We conclude that the switch to C2 monitoring helped to identify patients with CsA overdosing as well as to reduce variation in CsA level, which resulted in a halt in GFR decline.     

Recombinant human growth hormone in infants and young children with chronic renal insufficiency

Children with chronic renal insufficiency (CRI) secondary to congenital structural abnormalities frequently have significant growth retardation by 2 years of age. In a multicenter placebo-controlled study of the use of recombinant human growth hormone (rhGH), 30 of 125 (24%) participants were<2.5 years of age at enrollment. Since the treatment arms of the study were balanced for age at randomization, data for these patients were examined for efficacy and safety. During the first 2 years of the study, approximately two-thirds of the patients (n=19) received rhGH 0.05 mg/kg per day subcutaneously and one-third (n=11) received placebo injections. At entry into the study, the mean (± SD) calculated creatinine clearance was 29.2±14.3 (range 12.0–63.7) ml/min per 1.73 m² in the rhGH-treated group and 23.3±15.1 (range 8.0–59.4) ml/min per 1.73 m² in the placebo-treated group. The 1st year growth rate was 14.1±2.6 cm/year for the rhGH-treated group and 9.3±1.5 cm/year in the placebo-treated group (P<0.00005). During the 2nd year of the study, the growth rate was 8.6±1.2 cm/year in the rhGH-treated group compared with 6.9±1.0 in the placebo groupP=0.025). The height standard deviation score was +2.0±0.7 for the rhGH-treated group compared with –0.2±1.1 in the placebo-treated group (P<0.00005) during the 2 years of the study. Minor adverse events occurred with similar frequency in both groups. These data suggest that rhGH is efficacious and safe in children with CRI under age 2.5 years. rhGH therapy may correct significant loss of growth at this age when used in conjunction with optimal medical management.     

Differential effects of recombinant human growth hormone on glomerular filtration rate and renal plasma flow in chronic renal failure

In normal subjects recombinant human growth hormone (rhGH) increases glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) through the action of insulin-like growth factor-I (IGF-I). We have measured clearance of inulin and para-aminohippuric acid in 18 children with chronic renal failure (CRF) during their 1st year of rhGH treatment to look at the immediate (first 3 h), short-term (1 week) and long-term (1 year) effects of treatment. On day 1 mean (range) age was 9.1 (4.9–13.9) years, GFR 19 (9–58) and ERPF 77 (34–271) ml/min per 1.73 m². During treatment height velocity increased from 4.5 (1.7–6.5) to 9.5 (4.8–12.7) cm/year (P<0.0001). Two children required dialysis after 0.75 years and 1 child was electively transplanted after 0.5 years. There were no other serious adverse events. GFR and ERPF were unchanged in the 3 h following rhGH. GFR remained constant on day 8, 22 (6–56) and after 1 year, 20 (9–59) ml/min per 1.73 m². ERPF increased to 96 (33–276) ml/min per 1.73 m² on day 8P=0.005), and remained elevated, but not significantly so, at 99 (24–428) ml/min per 1.73 m² at 1 year. Fasting IGF-I increased from 147 (46–315) ng/ml to 291 (61–673) by day 8P<0.003), and to 341 (101–786) ng/ml at 1 year. There was no correlation between the change in IGF-I and renal function. Blood pressure, albumin excretion and dietary protein intake were unchanged by treatment. The significance of increased ERPF after 1 week of rhGH in CRF is unclear, but long-term follow-up of renal function is indicated.     

Effect of cyclosporin a on proteinuria in patients with Alport's syndrome

Eight patients with Alport's syndrome and massive proteinuria (129±60.57 mg/m² per hour) were treated with cyclosporin A (CyA) for 8 months. The average dose of CyA administered to all patients was 4.21±0.26 mg/kg per day and blood CyA levels of 63.4±4.1 ng/ml were attained. In five patients, proteinuria abated during the 3rd week of treatment. In the remaining three, all of whom had low creatinine clearance (82.0, 46.0 and 43.2 ml/min per 1.73 m² respectively), proteinuria persisted but at levels lower than before treatment: 32.5±15.9 mg/m² per hour versus 183.3±29.7 mg/m² per hour. No permanent decrease in creatinine clearance was observed in any of these patients throughout treatment. In those patients in whom proteinuria abated, it reappeared 2 weeks after discontinuation of CyA treatment. We observed no significant increases in angiotensin II plasma levels in our patients during CyA administration. Although we have shown that CyA will reduce massive proteinuria in patients with Alport's syndrome, we cannot yet recommend its use as a therapeutic measure.     

Effect of malnutrition on serum creatinine and cystatin C levels

The concentration of cystatin C has been shown to be independent of age, gender and height, but the effect of malnutrition has not been studied. Levels of serum creatinine and cystatin C were estimated in 77 malnourished and 77 normally nourished boys between 2 years and 6 years of age without evidence of renal disease. The mean (95% confidence interval) serum creatinine level in the malnourished boys was significantly lower than that in the normally nourished boys [0.42 (0.38–0.45) mg/dl and 0.51 (0.48–0.55)] mg/dl, respectively, (P < 0.01)]. The mean level of serum cystatin C was 1.05 (0.94–1.17) mg/l and 1.12 (1.01–1.24) mg/l, respectively, in normally nourished and malnourished boys (P = 0.35). Mean glomerular filtration rate (GFR) estimated by the Schwartz equation in the malnourished boys was significantly higher than that in normally nourished children [141.8 (123.3–160.2) ml/min per 1.73 m² body surface area and 119.4 (109.3–129.5) ml/min per 1.73 m² body surface area], respectively (P = 0.04). However, the mean cystatin C-derived GFR was similar in the malnourished and normally nourished boys [99.70 (85.8–113.5) ml/min per 1.73 m² and 109.2 (94.4–124.0) ml/min per 1.73 m²], respectively (P = 0.35). The mean bias between GFR estimates using Bland and Altman analysis was greater in the malnourished children than in the normally nourished children (32.3% and 17.6%, respectively) (P = 0.15). Serum creatinine levels are lower in malnourished children and lead to overestimation of GFR, while cystatin C levels are unaffected.     

Renal function in Laron syndrome patients treated by insulin-like growth factor-I

Eight children with Laron syndrome (5 males, 3 females) aged 3–14.5 years received daily subcutaneous injections of 150 g/kg recombinant insulin-like growth factor-I (IGF-I) for 5 months. The children were examined weekly for the 1st month and then once monthly. At each visit, overnight fasting blood was drawn for serum IGF-I and blood chemistry measurements and a 24-h urine collection was performed for the determination of calcium, phosphorus, creatinine and nitrogen. The main effects related to kidney function were: an initial weight gain with a mild transitory reduction in the urinary volume, an increase in serum electrolyte concentrations and a decrease in urinary electrolyte excretion. The lower than normal mean (± SEM) basal creatinine clearance (76.7±15.8 ml/min per 1.73 m²) increased towards the normal range during treatment to 124.9±13 ml/min per 1.73 m², with a mean increment of 73.4±28% (P<0.02) from basal values after 2 months of treatment, without changes in the serum creatinine. Initially an increase in blood urea nitrogen was observed together with a reduction in urinary nitrogen excretion. During the IGF-I therapy the urinary calcium excretion increased from 0.7±0.2 nmol/day to 1.5±0.3 nmol/day and the tubular reabsorption of phosphate increased from 1.24±0.06 to more than 1.38±0.04 nmol/l (P<0.002), resulting in a significant increase in serum phosphate levels from 1.51±0.06 to more than 1.63±0.04 nmol/l (P<0.005). The present study shows for the first time that long-term IGF-I deficiency in man results in a subnormal glomerular filtration rate and that chronic substitution therapy with IGF-I has marked renotropic effects identical to those ascribed to growth hormone.     

Effects of growth hormone administration in pediatric renal allograft recipients

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<0.001) and percentage of expected growth velocity for bone age (67±31% pre therapy, 163±27% post therapy,P<0.001) with evidence of true catch-up growth. During the study period, three children had the appearance of secondary sexual characteristics, and one had premature advancement of his bone age. GFR decreased in three children, and in one rGH was discontinued due to a steady rise in serum creatinine. No significant changes were seen in serum calcium, phosphorus, cholesterol, triglycerides, glucose, or thyroid function, although a significant increase in alkaline phosphatase was found. In summary, growth-retarded pediatric renal allograft recipients may have abnormal endogenous GH production and respond favorably to rGH. The potential risk of deterioration in renal function due to rGH-induced hyperfiltration must be investigated.     

Short-term outcomes of severe lupus nephritis in a cohort of predominantly African–American children

Renal involvement is one of the major determinants of the outcome in patients with systemic lupus erythematosus. Although African–American ethnicity has been suggested to be a poor prognostic factor in severe lupus nephritis in adult patients, information on outcomes of African–American children with this disease is still very limited. We retrospectively studied the patients diagnosed with severe lupus nephritis by renal biopsy at Le Bonheur Children’s Medical Center from January 1990 to December 2003. All patients were below the age of 18 years at the time of biopsy. Clinical features assessed included age, gender, race, estimated glomerular filtration rate (GFR), presence of hypertension, gross hematuria, degree of proteinuria, complement 3 and 4 levels, serum albumin, renal histology and dose of oral prednisone. Forty-four patients were studied: 82% were African–American and 89% were female. Mean age at biopsy was 14.2±3 years (median 15.0 years; range 4.7 years to 17.0 years). Renal biopsies were assessed according to the WHO classification. Twenty-seven percent, 43%, and 30% were in class III, IV and V, respectively. At presentation, 55% had hypertension and 23% had a history of macroscopic hematuria. The patients had varying degrees of proteinuria, including 18% with nephrotic syndrome. Eighteen percent had moderate renal insufficiency with estimated GFRs less than 50 ml/1.73m² body surface area per minute. All the patients were treated with corticosteroids. Sixty-eight percent also received cyclophosphamide and 20% received either mycophenolate mofetil (MMF) or azathioprine (AZA). Two patients developed end stage renal disease and required chronic dialysis within 12 months of biopsy. At the 12-month follow-up visit, 23% of patients had complete remission and 48% had partial remission. The mean estimated GFR had increased from 96.0 ml/1.73m² per minute to 124 ml/1.73m² per minute (P=0.03). Mean serum creatinine levels decreased from 1.62 mg/dl to 0.91 mg/dl (P=0.03). Complement 3 levels increased from 54.3 mg/dl to 90.3 mg/dl (P<0.01). Mean serum albumin levels also increased from 2.8 mg/dl to 3.6 mg/dl (P<0.01) and urine protein-to-creatinine ratio decreased from 5.8 to 1.0 (P<0.01). The average prednisone dose decreased from 0.96 mg/kg per day to 0.41 mg/kg per day (P=0.64). In our center, with predominantly African–American children, patients with lupus nephritis presented similarly to those in other studies with predominantly Caucasian patients, and short-term renal outcomes were not different.     

Frequently relapsing nephrotic syndrome: treatment with mycophenolate mofetil

Long-term treatment with cyclosporin A (CyA) of children with frequently relapsing steroid-sensitive nephrotic syndrome (SSNS) carries the risk of nephrotoxicity. We have analyzed renal function in 23 children with SSNS during CyA therapy. Repeated measurements of glomerular filtration rate (single-shot ⁵¹Cr-EDTA clearance) showed a decline from 131±21 ml/min per 1.73 m² to 116±27 ml/min per 1.73 m² at last follow-up. Similarly, effective renal plasma flow (simultaneous ¹²³I-hippurate clearance) was correlated with duration of CyA treatment, and showed a decline from 980±318 ml/min per 1.73 m² to 724±242 ml/min per 1.73 m². In a pilot study we investigated the effect of mycofenolate mofetil (MMF) in 7 children with a median age of 12.7 years [6 with minimal change nephrotic syndrome (MCNS), 1 with focal segmental glomerulosclerosis (FSGS)] with signs of nephrotoxicity because of long-term CyA therapy. Only 1 patient with SSNS showed a relapse during MMF therapy. In the patient with FSGS, MMF was started in addition to CyA, resulting in complete remission for a follow-up of 28 months. This preliminary study demonstrates that children with MCNS treated with CyA may be successfully converted to MMF without major side effects. In all cases, including FSGS, MMF had a beneficial effect on renal function. These data should be confirmed by a prospective randomized clinical trial.     

Anaphylactoid purpura: Characteristics of 16 patients who progressed to renal failure

Renal insufficiency occurs in at least 1.5% of children with anaphylactoid purpura (AP). We reviewed the records of 16 children who developed end-stage renal disease (ESRD group) secondary to AP and matched them for age, era of onset, renal histology, and clinical severity at onset with 16 children who has AP but whose creatinine clearance returned to and remained normal (recovery group). We reviewed creatinine clearances at 1, 3, 5, and 10 years after onset. A creatinine clearance >70 ml/min per 1.73 m² was present in 50% of the patients in the ESRD group at 3 years and in 25% at 5 years after onset. In contrast, all patients in the recovery group had a creatinine clearance >70 ml/min per 1.73 m² by 3 years (7 of 16 had a creatinine clearance >125 ml/min per 1.73 m²) and all were normal 95–125 ml/min per 1.73 m²) by 5 years. Thus, the presence of an increased creatinine clearance (>125 ml/min per 1.73 m²) at 3 years predicted recovery, while failure to reach a creatinine clearance of >70 ml/min per 1.73 m² at 3 years predicted progression to ESRD. There was no evidence of recurrent systemic AP or nephritis in the 14 patients who underwent renal allograft transplantation. We conclude that long-term evaluation of patients over many years is required to identify those who will progress to ESRD from AP and that recurrence of AP in the renal transplant is uncommon.     

Serum cystatin C levels in children with sickle cell disease

Patients with sickle cell disease (SCD) may develop kidney dysfunction from childhood. The purpose of this study was to examine the value of serum cystatin C as a marker for glomerular filtration rate (GFR) in children with SCD, as compared to serum creatinine and creatinine clearance (CrCl). Twenty children (ages 9–21, ten males) with SCD with and without albuminuria were studied. The mean serum cystatin for the whole group was 0.89 mg/l (0.5–1.7 mg/l). Mean serum cystatin C was significantly different among the children with proteinuria (n=4), microalbuminuria (n=5), and without albuminuria (n=11) (1.25 mg/l, 0.84 mg/l, and 0.78 mg/l, respectively). The mean GFR derived from serum cystatin was significantly different among these subgroups, becoming abnormal in the proteinuric cohort (63 ml/min per 1.73 m²), in contrast to 94 for the microalbuminuric, and 103 for the normal subgroups. Serum creatinine (mean: 0.58 mg/dl, range: 0.3–1.1) did not change significantly with the level of albuminuria. Mean CrCl remained normal to increased within the subgroups, (133 ml/min per 1.73 m² for those with proteinuria, 144 for those with microalbuminuria, and 163 for the normal subgroup). We conclude that serum cystatin C correlates with the level of albuminuria and may be a reliable method to measure renal function in SCD. An erratum to this article can be found at     

FK506 in pediatric kidney transplantation—Primary and rescue experience

Between 14 December 1989 and 17 December 1993, 43 patients undergoing kidney transplantation alone at the Children's Hospital of Pittsburgh received FK506 as the primary immunosuppressive agent. The mean recipient age was 10.2±4.8 years (range 0.7–17.4 years), with 7 (16%) children under 5 years of age and 2 (5%) under 2 years of age. Fifteen (35%) children underwent retransplantation, and 5 (12%) had a panel-reactive antibody level greater than 40%. Twenty-two (51%) transplants were with cadaveric donors and 21 (49%) were with living donors. The mean follow-up was 25±14 months; there were no deaths; 1- and 3-year actuarial graft survival was 98% and 85%. The mean serum creatinine and blood urea nitrogen were 1.2±0.6 mg/dl and 26±11 mg/dl; the calculated creatinine clearance was 75±23 ml/min per 1.73 m². Twenty-four (62%) patients have been successfully with-drawn from steroids and 24 (62%) require no anti-hypertensive medication. Improved growth was seen, particularly in pre-adolescent children off steroids. Between 28 July 1990 and 2 December 1993, 24 children were referred for rescue therapy with FK506, 14.6±16.4 months (range 1.1–53.2 months) after transplantation. Nineteen (79%) were referred because of resistant rejection; 4 (17%) were referred because of proteinuria; 1 (4%) was switched because of steroid-related obesity. There were no deaths; 1-and 2-year graft survival was 75% and 68%; 17 (71%) patients were successfully rescued, including 1 of 2 patients who arrived on dialysis; 4 (24%) of the successfully rescued patients were weaned off steroids. While not without side effects, which include nephrotoxicity, neurotoxicity, diabetogenicity, and viral complications, FK506 appears to be an effective immunosuppressive agent for both primary and rescue therapy after kidney transplantation. Its steroid-sparing qualities may be of particular importance in the pediatric population.     

Prophylactic oral ganciclovir after renal transplantation-dosing and pharmacokinetics

Ganciclovir alone or in combination with hyperimmunoglobulin is replacing other treatment modalities for the prophylactic treatment of cytomegalovirus (CMV) infections. No dose recommendations are available for oral ganciclovir therapy in children with impaired renal function after renal transplantation of a kidney from a CMV IgG-positive donor. We undertook a pharmacokinetic study in 14 pediatric renal transplant recipients who were CMV IgG negative and had received a graft from a CMV IgG-positive donor. We estimated the daily dosage of oral ganciclovir in relation to the glomerular filtration rate (GFR). Oral ganciclovir was administered at a starting dose of 3 × 1 g for children with a weight above 50 kg, 3 × 750 mg for children between 50 and 37.5 kg, and 3 × 500 mg for children between 37.5 and 24 kg. The starting dose was reduced by 50% for GFR values ≤50 ml/min per 1.73 m² and by 75% for GFR values ≤25 ml/min per 1.73 m². The daily dose was divided into three daily doses unless GFR was <40 ml/min per 1.73 m², when only two daily doses were given. Doses were adjusted according to the measured plasma trough concentrations (c) using the simple formula: c _ganciclovir(measured)/c _ganciclovir(desired) = dosage rate(used)/dosage rate(adjusted). Mean stable plasma trough concentration was 0.91±0.68 μg/ml. The dosage rate, adjusted to a trough concentration of 1.0 μg/ml, correlated with the GFR. The dose per day could be calculated according to a simple equation for a GFR <100 ml/min per 1.73 m²: dosage per day (mg/kg per day) = GFR. No CMV disease developed in any of the patients during oral ganciclovir, but 1 patient developed an acute rejection episode and a positive pp65 antigen 5 weeks after discontinuation of ganciclovir. The drug was well tolerated and without side effects. Received March 3, 1997; received in revised form July 25, 1997; accepted July 30, 1997     

Antithymocyte treatment of steroid-resistant acute rejection in renal transplantation

To evaluate the outcome of early (ER <3 months) and late (LR >3 months) episodes of corticosteroid resistant acute allograft rejection (CRR) treated with anti-thymocyte globulin (ATG) in pediatric renal allograft recipients. Retrospective study of 15 children, mean age 13.2y, who received ATG for the treatment of biopsy proven CRR over a 15 year period. Seven children received ATG for ER (median 26 days post transplantation) and 8 for LR (median 763 days). There was a significant improvement in the 3 month eGFR (70.3 ml/min/1.73m², SD 22.3, p = 0.018) when compared with the value prior to ATG treatment (23.3 ml/min/1.73m², SD 10.2) in the ER group. In the LR group (4 DSA positive) there was no improvement in the eGFR at 3 months (42 ml/min/1.73m², SD 10.5, p = 0.32) when compared with the value prior to ATG (38 ml/min/1.73m², SD 9.7). At final review, eGFR in the ER group was 72.3 ml/min/1.73m² (SD 33) vs. 37.7 ml/min/1.73m² (SD 17.9) in the LR group after a mean follow up of 10.4y and 1.2y, respectively. ATG therapy in CRR is associated with reversal of rejection and excellent graft outcome in children with ER. The benefits remain uncertain in LR, the etiology of which is multifactorial.     

Pulse methylprednisolone treatment of idiopathic steroid-resistant nephrotic syndrome

Although much of the interest in pulse methylprednisolone therapy (PMT) has centered around its use in children with focal segmental glomerulosclerosis, PMT has also been shown to be effective in the treatment of other proteinuric renal diseases. We hypothesized that a PMT-based treatment protocol, derived from the Tune-Mendoza protocol, would effectively induce a more rapid remission in young children with idiopathic steroid-resistant nephrotic syndrome (SRNS). A retrospective analysis was conducted of 11 consecutive SRNS patients (mean age 3.6±1.5 years) that received PMT between 1 August 1992 and 1 May 1998. The initial mean urinary protein/urinary creatinine ratio (UP/UC, mg/mg) was 8.3±9.7 and mean estimated creatinine clearance (C _Cr) 137.7±47.0 ml/min per 1.73 m². An average of 24.8±10.5 PMT doses were given. The mean duration of PMT therapy until remission was 23.4±29.9 days (median 12 days). Cyclosporine and cyclophosphamide were used to maintain and extend remissions in 5 and 4 patients, respectively. At the conclusion of the study, the mean UP/UC was 0.12±0.22 and mean C _Cr 151.8± 39.8 ml/min per 1.73 m² (no C _Cr≤100 ml/min per 1.73 m²). Of the 11 patients, 9 attained complete remission. Adverse effects were mild and infrequent. This PMT protocol appears to safely and effectively induce remission in young children with SRNS. A future prospective trial that evaluates the efficacy of PMT in young children with SRNS is warranted. Received: 15 March 2000 / Revised: 14 August 2000 / Accepted: 18 August 2000     

Etiology of chronic renal failure in Turkish children

The etiology of chronic renal failure (CRF) was studied in 459 Turkish children (205 girls, 254 boys) for the period January 1979-December 1993. Their mean age at onset of CRF was 9.5±4.2 years (range 1–16 years); CRF was defined as a glomerular filtration rate (GFR) below 50 ml/min per 1.73 m² for at least 6 months. When a GFR determination was not available, the serum creatinine concentration was used: greater than 1 mg/dl for children aged 1–3 years, greater than 1.5 mg/dl for those 3–10 years and greater than 2 mg/dl for those 10–16 years. Primary renal disorders were as follows: reflux nephropathy 32.4% glomerular diseases 22.2%, hereditary renal disorders 11.4%, amyloidosis 10.6%, urinary stones 8% and other renal disorders 15.4%. Twenty-three cases of reflux nephropathy (15.4%) were associated with neural tube defects (NTD) and 20 (13.4%) were caused by infravesical obstruction. CRF caused vesicoureteral reflux associated with NTD and amyloidosis are more frequent in our series compared with west European and Nordic countries.     

The immune status of uraemic children/adolescents with chronic renal failure and renal replacement therapy

In adults with chronic renal failure (CRF) and/or renal replacement therapy (RRT) various immunological abnormalities have been described, but few data are available for the paediatric age group. We performed basic in vitro immunological studies in 26 patients 10 months–19 years of age with advanced renal failure, 11 with CRF (creatinine clearance 16.8±5.2 ml/min per 1.73 m²), 15 on RRT with haemodialysis (HD;n=9) and continuous ambulatory peritoneal dialysis (CAPD;n=6) as well as in 16 healthy controls. None had clinical evidence of deranged immune function. No significant differences were found in the percentages of B- and T-cells, T-cell subsets CD3, CD4, CD8 and mitogenic responses to phytohaemagglutinin and concanavalin A (Con A) between RRT patients (HD=CAPD) and control children. Most parameters in CRF patients were also normal, although they had a low percentage of B-cells (12.1±4.1; RRT: 19.7±6.5; controls: 18.5±7.1;P<0.01), relatively low levels of serum immunoglobulin G (948.4±209.4 mg/dl; HD: 1374.7±235.2 mg/dl;P<0.01; CAPD: 966.3±430.2 mg/dl, NS) and a high normal response to Con A (34.3±13.6 cpm ×10^–3; RRT: 34.5±11.3 cpm ×10^–3; controls: 23.4±9.9 cpm ×10^–3,P<0.01). All these values were, however, well within the normal accepted range. These data indicate that children/adolescents with CRF and/or RRT have no significant basic in vitro immunological defects. This study did not test the functional immune status of the young uraemic patients.     

Cyclosporine-A-induced nephrotoxicity in children with minimal-change nephrotic syndrome: long-term treatment up to 10 years

The impact of cyclosporine A (CsA) therapy in patients with steroid-dependent nephrotic-syndrome (SDNS) on long-term renal function is controversial. Data beyond 5 years are rare. Long-term renal function was evaluated in children with SDNS with and without CsA therapy, especially beyond 5 years. Twenty children were treated with CsA (study group) for a mean of 5.4 ± 2.2 years (ten patients for 5–11 years). Glomerular filtration rate (GFR) was calculated before and after 3 and 12 months and at latest follow-up of therapy. Fifteen children with cyclophosphamide-treated SDNS without CsA served as controls. In the study group, GFR decreased within 12 months from 136 ± 19 to 120 ± 31, to 114 ± 14 ml/min per 1.73 m² at latest follow-up (p < 0.0001). Patients with CsA > 5 years had a GFR of 111 ± 14 ml/min per 1.73 m² at latest follow-up without a GFR below 90 ml/min per 1.73 m². No CsA toxicity was found in biopsies. In the control group, GFR dropped within 3 months, from 137 ± 27 to 130 ± 24, to 126 ± 19 ml/min per 1.73 m² at latest follow-up (p = 0.1). Patients with and without nephrotoxic CsA therapy showed a drop in GFR. In CsA-treated patients, GFR was about 12% lower at latest follow-up compared with patients without nephrotoxic therapy but always remained within normal range. CsA seems to be safe, even in long-term treatment for more than 5 years.