Paediatric nephrology: the last 50 years.

In 1965, the specialty of paediatric nephrology was in its infancy. Following the development of a landmark collaborative research study, the International Study of Kidney Disease in Childhood in the mid-1960s, the first specialist societies were formed: the European Society of Pediatric Nephrology in 1967 and the American Society of Pediatric Nephrology in 1969. The extraordinary improvements in care delivered to children with kidney disease over the past 50 years are too broad to cover in any one paper. They traverse the spectrum of diagnosis, classification, therapeutics, social well-being and transition to adult care. We have selected four case scenarios to highlight these changes in key areas of paediatric nephrology: post-streptococcal glomerulonephritis, nephrotic syndrome, haemolytic uraemic syndrome and neonatal dialysis and childhood transplantation.

Early experience with conversion to sirolimus in a pediatric renal transplant population.

Sirolimus is an immunosuppressive agent that offers potentially significant benefits for young transplant patients facing life-long treatment. Its action of reducing cell proliferation may reduce the risk of chronic allograft nephropathy and posttransplant neoplasia. Twenty-nine children were converted from calcineurin inhibitors to sirolimus after renal transplantation and followed for a minimum of 12 months. Glomerular filtration increased transiently in those converted before 12 months after transplantation but not in those converted later, when chronic histological changes had developed. Mild acute rejection occurred after conversion in 10%, and side effects led to cessation of sirolimus in 31%. Anemia occurred in 55% of patients and responded well to darbepoetin. Most side effects (anemia, hypercholesterolemia, mouth ulcers, and myalgias) became less severe with time. The number of antihypertensive drugs required decreased significantly on sirolimus. Although side effects are frequent on sirolimus, in the majority of children, they are mild enough to allow the patient to continue taking the drug, and for these children the long-term benefits are potentially valuable.

Persistent familial hematuria in children and the locus for thin basement membrane nephropathy.

This study examined how often children with persistent familial hematuria were from families where hematuria segregated with the known genetic locus for the condition known as benign familial hematuria or thin basement membrane nephropathy (TBMN) at COL4A3/COL4A4. Twenty-one unrelated children with persistent familial hematuria as well as their families were studied for segregation of hematuria with haplotypes at the COL4A3/COL4A4 locus for benign familial hematuria and at the COL4A5 locus for X-linked Alport syndrome. Eight families (38%) had hematuria that segregated with COL4A3/COL4A4, and four (19%) had hematuria that segregated with COL4A5. At most, eight of the other nine families could be explained by disease at the COL4A3/COL4A4 locus if de novo mutations, non-penetrant hematuria or coincidental hematuria in unaffected family members was present individually or in combination. This study confirms that persistent familial hematuria is not always linked to COL4A3/COL4A4 (or COL4A5) and suggests the possibility of a further genetic locus for benign familial hematuria. This study also highlights the risk of excluding X-linked Alport syndrome on the basis of the absence of a family history or of kidney failure.

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.

Vincristine treatment in steroid-dependent nephrotic syndrome.

Treatment of children with steroid-dependent nephrotic syndrome (SDNS) continues to be a challenge when relapses recur after treatment with cyclophosphamide and side effects or non-compliance make steroids and cyclosporin unsatisfactory. We treated 12 patients with intravenous vincristine for SDNS in a regime of 1-1.5 mg/m2 weekly for 4 weeks then monthly for 4 months. Four of the 5 patients in relapse when commencing vincristine remitted within 2 doses. Comparing relapse frequency in the 12 months before and after vincristine, there was a reduction from 4 to 1.5 (p=0.004) relapses per year. Median sustained remission was 5 months, but 1 frequently relapsing patient remains in remission 4 years after vincristine. Vincristine was also successfully used in 1 or 2 doses at weekly intervals for subsequent relapses in 5 patients. Side effects were minimal in most cases. Abdominal pain occurred in 2 patients who commenced vincristine at 1.5 mg/m2, but resolved when continued at 1 mg/m2. We felt vincristine had a role in a subset of children with challenging SDNS administered as 1 mg/m2 weekly for 4 weeks then 1.5 mg/m2 monthly for 4 months. Vincristine allowed steroid- and cyclosporin-sparing, contributed to long-term remission in some patients, and was especially valuable in children with poor compliance with oral medication. Many patients expressed a preference for a few doses of vincristine rather than a standard course of oral prednisolone or cyclosporin.

Vincristine treatment of nephrotic syndrome complicated by Kimura disease.

Kimura disease is a rare inflammatory condition of unknown aetiology. It typically presents in young Asian males with the triad of non-tender subcutaneous swellings in the head and neck region, peripheral eosinophilia and raised serum IgE. About 16% of cases have associated renal disease. We present the case of a 10-year-old boy with a past history of steroid responsive, frequently relapsing nephrotic syndrome who developed a right submandibular swelling and eosinophilia. Kimura disease was diagnosed on the basis of clinical and histological findings. The condition recurred during relapses of nephrotic syndrome. Because of poor adherence with oral medication, our patient was treated with intravenous vincristine with synchronous remissions of his nephrotic syndrome and Kimura swellings on each occasion.

Persistent renal cortical scintigram defects in children 2 years after urinary tract infection.

BACKGROUND: Renal cortical scintigraphic studies challenge the role of vesicoureteric reflux in renal scar development, emphasizing instead the part played by acute pyelonephritis. OBJECTIVE: To determine the prevalence of renal cortical defects in a child cohort 2 years after the child's first diagnosed urinary tract infection and to analyze the relationship of these defects with acute illness variables, primary vesicoureteric reflux and recurrent infections. MATERIALS AND METHODS: In a prospective cohort study, 193 children younger than 5 years with their first proven urinary tract infection underwent renal sonography, voiding cystourethrogram, and renal cortical scintigraphy within 15 days of diagnosis. Two years later, 150 of the 193 children, or 77.7%, had a further renal cortical scintigram, including 75, or 86.2%, of the 87 children who had acute scintigraphic defects. The relationship of cortical defects to age, gender, pre-treatment symptom duration, hospitalization, presence and grade of vesicoureteric reflux, and recurrent urinary tract infections was evaluated. RESULTS: Overall, 20 of the 150 (13.3%; 95% confidence interval (CI) 8.3, 19.8) children had persistent defects 2 years after infection. This included 20 of 75 (26.7%; 95% CI 17.1, 38.1) with initially abnormal scintigrams. No new defects were detected. Although acute defects were more common in the young, those with persistent defects were older (median ages 16.4 vs. 6.8 months, P=0.004) than those with transient abnormalities. After adjustment for age, persistent defects were no longer associated with gender and were not predicted by acute illness variables, primary vesicoureteric reflux or recurrent infections. CONCLUSIONS: Renal cortical scintigraphic defects persisted in approximately one-quarter of young children after their first proven urinary tract infection. The associated clinical features, however, failed to predict scar formation. It is possible that some of the scintigraphic defects preceded the infection by arising from either previously undiagnosed acute pyelonephritis or from underlying congenital dysplasia. The etiology of scars may be best addressed by determining whether prevention of urinary tract infections from birth avoids post-natal scar acquisition or extension.

Anemia in pediatric renal transplant recipients.

The aim of this study was to establish the prevalence of anemia in stable pediatric renal transplant recipients and to examine the association of anemia with renal function, immunosuppressants, angiotensin converting enzyme inhibitors, and growth, as well as iron, vitamin B(12), and folate stores. This is a cross-sectional study of the 50 renal transplant recipients currently followed at our center. Patient data were collected regarding hematological parameters, growth, medications, renal function, underlying renal disease, delayed graft function, episodes of rejection, and iron or erythropoietin therapy post transplantation. The mean hemoglobin level (Hb) was 110 g/l and the overall prevalence of anemia was 60%, including 30% who were severely anemic (Hb<100 g/l). There was a high rate of iron deficiency (34%) and serum iron was the parameter of iron metabolism most closely associated with anemia. Hb in patients with low serum iron was 90.7 g/l versus 114.4 g/l in those with normal serum iron ( P<0.01). Both univariate and multiple linear regression determined tacrolimus dose and creatinine clearance to be significant factors associated with anemia. Tacrolimus dose correlated with a 10 g/l reduction in Hb for every increase of tacrolimus dose of 0.054 mg/kg per day ( P=0.001). The dose of mycophenolate was positively correlated with Hb, but this was likely to be confounded by our practice of dose reduction in the setting of anemia. Angiotensin converting enzyme inhibitor use was not associated with anemia. Severely anemic patients tended to be shorter, with a mean Z-score for height of -1.8 compared with -0.9 for those with normal Hb ( P=0.02). Anemia is a significant and common problem in pediatric renal transplant patients. Deteriorating renal function is an important cause, but other factors like iron deficiency and immunosuppression are involved. Definition of iron deficiency is difficult and serum iron may be a valuable indicator. Medication doses, nutritional status, need for erythropoietin and iron, as well as poor graft function and growth require systematic scrutiny in the care of the anemic renal transplant recipient.

Time course of transient cortical scintigraphic defects associated with acute pyelonephritis.

BACKGROUND: Acute pyelonephritis is distinguished from renal scarring using repeat cortical scintigraphy. The defects of acute pyelonephritis resolve, while those of scars persist. OBJECTIVE: To determine the duration of reversible cortical defects following acute pyelonephritis and the time interval required to differentiate infection from scars. MATERIALS AND METHODS: An observational prospective study of 193 children (386 kidneys) aged less than 5 years following their first proven urinary tract infection (UTI). Renal cortical scintigraphic defects were detected in 112 (29%) kidneys within 15 days of diagnosis. Of these, 95 underwent repeat renal cortical scans 2 years after the UTI, including 50 with additional scans performed within 2-6 months of infection. RESULTS: Of the 50 kidneys undergoing a second renal cortical scan within 2-6 months of the first UTI, 22 (44%) had persistent defects. A third scan was performed on 17 (77%) kidneys after 2 years, by which time defects had resolved in another 8 (47%) kidneys. The predictive value of defects detected within 2-6 months of UTI representing scars is 53% (95% CI 28, 77). Overall, nine (18%) kidneys with initial renal cortical abnormalities had permanent defects. In the 45 kidneys undergoing a second cortical scan more than 6 months after the UTI, 11 (24%) had persistent defects. None of the 95 kidneys undergoing serial scans developed new or larger defects. CONCLUSIONS: Renal scars may not be reliably diagnosed by cortical scintigraphy performed within 6 months of UTI because the inflammatory lesions may not have fully resolved.