Rowan G. Walker

The use of mycophenolate mofetil suspension in pediatric renal allograft recipients.

Abstract. Mycophenolate mofetil (MMF) is widely used to prevent acute rejection in adults after renal, cardiac, and liver transplantation. This study investigated the safety, tolerability, and pharmacokinetics of MMF suspension in pediatric renal allograft recipients. One hundred renal allograft recipients were enrolled into three age groups (33 patients, 3 months to <6 years; 34 patients, 6 to <12 years; 33 patients, 12 to 18 years). Patients received MMF 600 mg/m2 b.i.d. concomitantly with cyclosporine and corticosteroids with or without antilymphocyte antibody induction. One year after transplantation, patient and graft survival (including death) were 98% and 93%, respectively. Twenty-five patients (25%) experienced a biopsy-proven (Banff grade borderline or higher) or presumptive acute rejection within the first 6 months post-transplantation. Analysis of pharmacokinetic parameters for mycophenolic acid (MPA) and mycophenolic acid glucuronide showed no clinically significant differences among the age groups. The dosing regimen of MMF 600 mg/m2 b.i.d. achieved the targeted early post-transplantation MPA 12-h area under concentration-time curve (AUC0–12) of 27.2 µg h per ml. Adverse events had similar frequencies among the age groups (with the exception of diarrhea, leukopenia, sepsis, and anemia, which were more frequent in the <6 years age group) and led to withdrawal of MMF in about 10% of patients. Administration of MMF 600 mg/m2 b.i.d. is effective in prevention of acute rejection, provides predictable pharmacokinetics, and is associated with an acceptable safety profile in pediatric renal transplant recipients.

Evaluation and long-term outcome of pediatric renovascular hypertension

Abstractu2002Seventeen children with renovascular hypertension were managed at the Royal Childrens Hospital, Melbourne, over the 20-year period from 1975 to 1996. The age at presentation ranged from 10 days to 18 years. All children presented with severe hypertension with mean systolic blood pressure 7 standard deviations above age-matched averages and mean diastolic blood pressure 5.5 standard deviations above age-matched averages. Neurofibromatosis was the most common etiology (58% of patients) and there were no cases of Takayasus arteritis. Patients underwent a variety of biochemical and imaging investigations but in all cases renal angiography was necessary for definitive diagnosis and for planning therapy. Ten of the 17 patients had surgical procedures performed. Percutaneous transluminal angioplasty was performed in four patients but led to cure in only one patient following thrombosis of the affected artery producing segmental renal infarction. Other vascular reconstructive procedures, including the use of autologous or synthetic bypass grafts and autotransplantation, produced cure of hypertension in 50% of children with improvement in a further 30%. The long-term outlook for children treated with surgical reconstructive procedures was excellent. One patient underwent surgery for avulsion of an arterial graft following a pubertal growth spurt. No other patient originally cured by surgery has required reoperation with no cases of restenosis at a mean follow-up of 11 years 3 months.

Triple immunosuppression with subsequent prednisolone withdrawal: 6 years' experience in paediatric renal allograft recipients

Thirty-four children (≤15 years of age) with end-stage renal failure received 39 renal allografts between 1985 and 1991 and were treated with cyclosporin A (CyA), azathioprine and low-dose prednisolone (PNL). We aimed to withdraw PNL by 6 months after transplantation. Median duration of follow-up was 2 years 4 months (range 0.1 month to 6 years, 4 months). There were no deaths. Crude graft survival for living-related grafts (n=9) was 100%, although only 1 patient has been followed for >2 years. For cadaveric grafts (n=30), 1- and 5-year actuarial graft survivals were 90% and 79% respectively. At 12 months posttransplant, the median (range) glomerular filtration rate for all patients was 63 (19–109) ml/min per 1.73 m2 (n=25) and at 5 years was 48 (17–64) ml/min per 1.73 m2 (n=9). Complications observed included rejection episodes which occurred after discontinuation of PNL. Long-term (after 12 months), 28% of patients remain on PNL. Hypertension was present in more than 50% of patients. Severe CyA nephrotoxicity was not seen. Catch-up growth as determined by the change (Δ) in mean height standard deviation score (Ht-SDS) was noted at 1 year [ΔSDS/year=+0.60;P<0.001 (n=18)] and at 2 years [ΔSDS/year=+0.27;P<0.01 (n=16)] in pre-pubertal patients. The median Ht-SDS at 2 years for pre-pubertal children was −0.71 SD and growth velocity did not improve thereafter. In pubertal patients, the mean ΔSDS per year at 1 year (n=7) was +0.43 and at 2 years (n=4) was +0.17. The catch-up growth in pubertal patients did not reach statistical significance. It was concluded that the use of this immunosuppression regime was associated with an excellent patient and graft survival. Catch-up growth is especially encouraging in pre-pubertal patients. However routine discontinuation of PNL may require review.

Factors influencing growth and final height after renal transplantation

Abstract: Growth retardation occurs commonly in children and adolescents with chronic renal insufficiency. While some children exhibit catch‐up growth following renal transplantation, for many children growth remains sub‐optimal. The aim of the current study was to review the factors influencing growth and final height following renal transplantation. Data from all children who had a renal transplant performed between 1985 and 1998 at the Royal Melbourne and Royal Childrens Hospitals, Melbourne (nu2003=u200385), were examined retrospectively. Two children who died in the first year post‐transplant and one patient lost to follow‐up within 6u2003months of their transplant were excluded. Children with multiple grafts had only growth following their most recent graft analyzed. The mean height standard deviation score (Ht‐SDS) at the time of transplantation was −2.11 (range: −5.05 to 0.27), improving to −1.50 (range: −3.67 to 1.27) at 7u2003yr post‐transplant. On univariate analysis, the dose of cyclosporin at 6u2003months and at 1 and 3u2003yr, and the graft function at 1u2003yr, had a significant positive correlation with the change in Ht‐SDS (ΔHt‐SDS) at each of those time‐points post‐transplant. At all time‐points there was a strong correlation between pretransplant height and subsequent growth. A sub‐group of children who were 16u2003yr of age or older at December 1999, and who were considered to have reached their final height, were examined to determine predictors of final height. Multiple regression analysis of clinical and laboratory parameters from the sub‐group of patients ≥ 16u2003yr of age showed that height at the time of transplant, age at the time of transplant, and final glomerular filtration rate, were significant independent predictors of growth (r2u2003=u20030.82, p = 0.01). In addition, the immunosuppressive regimen at 1, 3, and 5u2003yr post‐transplant had a significant effect on growth. This study confirms the importance of each of these factors for post‐transplant growth.

Anti-neutrophil cytoplasmic antibody-associated glomerulonephritis in children

Two cases of anti-neutrophil cytoplasmic antibody (ANCA)-associated necrotizing and crescentic glomerulonephritis are reported. A 12-year-old girl and a 10-year-old boy presented with polyarthritis, anaemia, haematuria, proteinuria, impaired renal function, anorexia, nausea, marked loss of weight and lethargy. The boy also had a vasculitic rash and anterior uveitis. Both children had diffuse cytoplasmic ANCA identified by indirect immunofluorescence and confirmed by specific enzyme-linked immunosorbent assay. Renal biopsies showed severe focal and segmental necrotizing glomerulonephritis with 100% crescents. They were treated with plasma exchange, prednisolone, cyclophosphamide and heparin. Within 1 month of commencing treatment, both had normal serum creatinine concentrations and ANCA was not detectable. Renal biopsies 6 weeks following commencement of treatment revealed quiescent disease, although up to 40% of glomeruli were sclerosed or had fibrous crescents. Following cessation of cyclophosphamide and heparin after 7 months and reduction in steroid dose, a biopsy at 10 months in the boy revealed quiescent disease, but the girl had recurrent disease associated with reappearance of a low titre of ANCA and small cellular crescents in 20% of the glomeruli. These cases reflect the potential usefulnes of ANCA determination for categorizing paediatric patients, helping in the selection of therapy and as a possible marker of disease activity, similar to the experience in adults.

An extreme example of the neonatal form of Bartter’s syndrome

Abstract. A male infant is described who had polyuria over the 4 months of his life with urine volumes exceeding 1,000 ml/kg per day, severe serum electrolyte losses, metabolic alkalosis and increased plasma renin activity (56 ng/ml per hour). He had a normal blood pressure and glomerular filtration rate when fluid replete. The urine flow rate was about 25% of the glomerular filtration rate. Renal histology showed hyperplasia of the juxtaglomerular apparatus and abnormalities of the proximal tubules. The features of this case suggest an extreme form of Bartter’s syndrome presenting from the first days of life.

Stent-related ureteric obstruction in paediatric renal transplantation.

The rates of ureteric obstruction and complications for use of externally draining uretero-vesico-cutaneous (external) stents (Group 1: n=39) and the use of internal uretero-vesical (double-J) stents (Group 2: n=16), in 55 of 64 consecutive paediatric renal-transplant recipients, performed at our institution between January 1996 and December 2003, have been compared. Serum creatinine levels pre and post-operatively and pre and post-stent removal were recorded. The diagnosis of ureteric obstruction was based on an increase in serum creatinine of ≥20%, in conjunction with ultrasound evidence of hydronephrosis or hydroureter, where other causes of renal dysfunction were excluded. Ureteric obstruction occurred in 13 of the 39 patients (33.3%) in Group 1, compared with only one case of ureteric obstruction in the 16 patients (6.25%) in Group 2 (OR=7.5, 95% CI=0.8–70, P=0.038). There was no evidence of a difference in the number of urinary tract infections (9/39 in Group 1, 6/16 in Group 2, OR=0.5, 95% CI=0.14 to 1.8, P=0.275) or the mean length of hospital stay (10.9 days in Group 1, 10.1 days in Group 2, 95% CI=−2.3 to 4 days, P=0.565) between the two groups. Glomerular filtration rate (GFR) improved in the week after stent removal in Group 2, but deteriorated in Group 1 (P=0.07). This non-randomised comparison of stent types supports the use of prophylactic double-J stents in paediatric renal transplantation- in terms of decreased ureteric complications and improved renal function post-stent removal.

Grandparent donors in paediatric renal transplantation

The outcome of transplantation from grandparent donors in comparison with parental donors in paediatric renal transplantation was evaluated in 53 living related donor (LRD) transplantations performed between January 1996 and August 2003. The donor in 13 cases (25%) was a grandparent (Gpar group), and the remaining donors formed the parent group (Par group). The median age of recipients in the Gpar group was 2.75 (1.7–10.6) years and in the Par group was 12.75 (2.4–22) years (P<0.0001). There was no evidence of a difference in patient and graft survival, glomerular filtration rate (GFR) after transplantation, or the number of biopsy proven episodes of rejection between the groups. Doses of prednisolone in the first year following transplantation were greater in recipients from Gpar donors, but the other immunosuppression doses were similar. The median age of donors in the Gpar group was 56 (50–67) years and in the Par group was 41 (27–58) years (P<0.0001). There was no evidence of a difference between the two donor groups in mean creatinine clearance at last follow-up. There were two major donor complications in the Gpar group and one in the Par group. There was no evidence that the length of stay differed between the two groups in either the donors or recipients. These results support the use of carefully selected healthy grandparents as LRDs in children. This option potentially allows for the use of parent donors for a subsequent transplantation.

Recent advances in the management of vesico-ureteric reflux.

Recent studies have demonstrated that both congenital hypoplasia and acquired scarring are involved in the parenchymal lesions associated with reflux nephropathy. Medical therapy can prevent symptomatic infection. While there is no proof that either medical or antireflux surgery prevents acquired scarring, paradoxically there is evidence that surgery adds no benefit to medical therapy, and that the results of medical therapy and surgical therapy are similar in children with isolated severe reflux. The group at most severe risk of renal scarring is infants and the effects of medical and surgical therapy in preventing acquired renal injury in this group have not been sufficiently investigated. On the basis of this information it has been our practice to maintain urine sterility using continuous antibiotic prophylaxis throughout infancy and early childhood. Following the development of reliable urine toilet habit and the ability to collect midstream urine specimens, antibiotics are given according to the frequency of urine infection, and weekly testing of morning urine with nitrite strips at home is used for early detection of infection and prevention of symptomatic infection. Antireflux surgery is mandatory for those children with complicated VUR (such as urinary tract obstruction) and should otherwise be reserved for those having persistent breakthrough infections in infancy and early childhood.

Tamm-Horsfall protein: are serum levels a marker for urinary tract obstruction?

Tamm-Horsfall protein (THP) has been found in the renal interstitium in patients with obstructive uropathy. The aim of this study was to investigate whether serum concentrations of THP could serve as a screening test for urinary tract obstruction. The presence of THP in normal human serum was confirmed by sodium dodecyl sulphate polyacrylamide gel electrophoresis and Western blotting. A specific enzyme immunoassay was then used to measure the serum concentration of THP. Serum THP concentrations were estimated in a cross-sectional study of a group of 23 patients who had technetium-99m-diethylenetriaminepenta-acetic acid (DTPA) nuclear urinary excretion studies to define urinary tract obstruction, and in longitudinal studies in 2 patients who developed acute bilateral ureteric obstruction following operations for ureteric reimplantation. The subjects with DTPA-proven urinary tract obstruction had higher concentrations of serum THP (n=10, median = 43.9 ng/ml, range 10.4–152.1 ng/ml) than those who did not have obstruction (n=13, median = 9.6 ng/ml, range 1.26–61.9 ng/ml). While this difference was significant (P<0.01, Mann-Whitney U test), 6 of the 10 patients with obstruction had serum THP concentrations within the range of those patients without obstruction. The patients who developed acute bilateral ureteric obstruction both had increases in serum THP concentrations with obstruction and decreases in serum THP concentrations following relief of obstruction. These changes paralleled those in serum creatinine. The studies indicate that urinary tract obstruction results in increases in serum THP concentrations but these changes are not sufficient in magnitude to allow screening of children for urinary tract obstruction.