Quantitative viral load monitoring and cidofovir therapy for the management of BK virus-associated nephropathy in children and adults.

BACKGROUND: BK virus (BKV)-associated nephropathy (BKVAN) has been increasingly recognized as an important cause of renal transplant dysfunction. We report the role of quantitative viral load monitoring in the management of BKVAN. METHODS: We developed a real-time quantitative polymerase chain reaction (PCR) assay for BKV detection in urine and plasma. Four renal allograft recipients, including two children, with BKVAN were treated with low-dose cidofovir and followed prospectively. RESULTS: The PCR assay showed a detection limit of 10 viral copies with an intra-assay coefficient of variation of 19%. All four patients with BKVAN demonstrated intranuclear inclusions on allograft biopsy and a progressive rise in serum creatinine; three patients underwent multiple biopsies before the diagnosis of BKVAN was made. Three of the patients experienced a "viral syndrome" before the onset of renal dysfunction. One child also demonstrated an echogenic renal mass. All of the patients demonstrated strongly positive urinary PCR values (>100,000 copies/microL). BKV DNA was also detected in the plasma of three patients. All the patients were treated with intravenous low-dose cidofovir (0.25-1 mg/kg per dose, every 2-3 weeks, without probenecid). BK viruria resolved within 4 to 12 weeks (after 1-4 doses) of the cidofovir therapy, and all patients remain with stable renal function 6 to 26 months posttherapy. CONCLUSIONS: Quantitative PCR for BKV is a sensitive and reliable method for following the course of the infection in renal transplant patients. In addition, cidofovir therapy may be useful in the treatment of some of these patients, and its role needs to be investigated further.

Early volume expansion during diarrhea and relative nephroprotection during subsequent hemolytic uremic syndrome.

OBJECTIVES: To determine if interventions during the pre-hemolytic uremic syndrome (HUS) diarrhea phase are associated with maintenance of urine output during HUS. DESIGN: Prospective observational cohort study. SETTINGS: Eleven pediatric hospitals in the United States and Scotland. PARTICIPANTS: Children younger than 18 years with diarrhea-associated HUS (hematocrit level <30% with smear evidence of intravascular erythrocyte destruction), thrombocytopenia (platelet count <150 × 10³/mm³), and impaired renal function (serum creatinine concentration > upper limit of reference range for age). INTERVENTIONS: Intravenous fluid was given within the first 4 days of the onset of diarrhea. OUTCOME MEASURE: Presence or absence of oligoanuria (urine output ≤ 0.5 mL/kg/h for >1 day). RESULTS: The overall oligoanuric rate of the 50 participants was 68%, but was 84% among those who received no intravenous fluids in the first 4 days of illness. The relative risk of oligoanuria when fluids were not given in this interval was 1.6 (95% confidence interval, 1.1-2.4; P = .02). Children with oligoanuric HUS were given less total intravenous fluid (r = -0.32; P = .02) and sodium (r = -0.27; P = .05) in the first 4 days of illness than those without oligoanuria. In multivariable analysis, the most significant covariate was volume infused, but volume and sodium strongly covaried. CONCLUSIONS: Intravenous volume expansion is an underused intervention that could decrease the frequency of oligoanuric renal failure in patients at risk of HUS.

Renal transplant biopsy specimen adequacy in a paediatric population.

Updated guidelines on the diagnosis of acute allograft rejection including criteria for biopsy specimen adequacy were published in 1999. We sought to determine the adequacy of specimens in paediatric transplant patients and identify factors influencing adequacy. All renal transplant biopsies performed between 1998 and 2003 were classified as adequate (n =25), minimal (n =19) or inadequate (n =27) in accordance with the Banff 97 criteria, and the histological diagnoses were documented. The effect on specimen adequacy of grade of operator, method of sedation, age of child, needle gauge, number of cores and total core length was then investigated. Overall, a minimal or adequate specimen was obtained in 62% of cases. No histological diagnosis could be made in 30% of all specimens, just over half of which were inadequate. Higher rates of rejection were found in adequate (52%) than inadequate (33%) samples. The grade of operator (p =0.498), the age of the child at the time of biopsy (p =0.815) and type of sedation (p =0.188) did not affect adequacy. More than one core was obtained in 38 (54%) cases, and this was significantly associated with specimen adequacy (p <0.0005) as was longer total core length (p =0.002). Clinical features in isolation are not sufficient for the diagnosis of acute allograft rejection. Renal biopsy remains the gold standard and relies on adequate specimen collection. Our data shows that specimen adequacy according to the Banff 97 guidelines is achievable in children and that more than one core at the time of sampling significantly improves this achievement. Adequate sampling reduces the risk of an inconclusive histological diagnosis.

Body composition and nutritional intake in children with chronic kidney disease.

The aim of this study was to assess body composition in children with chronic renal failure (CRF) and post renal transplantation (Tx), and to compare it to body mass index (BMI) and nutritional intake. Dietary assessment using 3-day diaries, total and regional body composition assessment by dual x-ray energy absorptiometry of 50 CRF children (29M, 21F), median age 8.9 yrs and 50 Tx children (32M, 18F), median age 12.9 yrs. BMI, percentage fat mass (%FM) and lean mass (LM) were corrected for height and expressed as SDS (HSDS). In both groups, BMIHSDS was lower than %FMHSDS and higher than LMHSDS (p<0.05). In the Tx group, there were associations on bivariate analysis between energy & protein intake and BMIHSDS & %FMHSDS (r,0.5, p<0.05), and between LMHSDS and protein intake (r,0.5, p<0.05). On multivariate analysis, there was an association between LMHSDS and time since transplantation (r,-0.4, p<0.05). Children in the CRF and Tx groups had a high percentage predicted trunk:leg FM ratio of 148% and 157%, respectively. Children with CRF and Tx have discordant body composition with a relatively high FM and low LM, which is not reflected by BMI. In addition, they appear to have an increased level of central adiposity that may predispose them to increased morbidity in later life.

Bone mineral content, corrected for height or bone area, measured by DXA is not reduced in children with chronic renal disease or in hypoparathyroidism.

The combination of poor growth and parathyroid and mineral disorders complicates the diagnosis of renal bone disease in children with chronic renal insufficiency (CRI), and the role of dual X-ray absorptiometry (DXA) is unclear. We aimed to examine the role of DXA in assessing variation in size-adjusted bone mineral content (BMC) in children with CRI and compare it with a cohort with hypoparathyroidism (HPT) and pseudo-hypoparathyroidism (PHPIa). In 29 patients with CRI (21 male) with a median age of 11 years (10th, 90th centiles 4.4, 14.6) and 10 patients with HPT and PHPIa (three male), with a median age of 13.7 years (7, 16) lumbar spine (LS) and total body (TB) BMC were measured by DXA. Age-, gender- and height-matched data allowed calculation of percentage predicted bone area for age and gender (pBAr) and percentage predicted BMC for bone area and height. In the CRI group, the median glomerular filtration rate (GFR) was 27.4 ml/min per 1.73 m2 (7.1, 69.5), and the median duration of illness was 9.3 years (2.1, 12.1). Median height standard deviation score (Ht SDS) was -1.6 (-3.0, 0.3), and, as expected, median LS and TB pBAr were low at 82% (68, 974) and 76% (63, 92), respectively. LS and TB predicted BMC (pBMC) SDS (corrected for bone size) were generally high, with a median value of 0.4 (-0.9, 1.4) and 0.4 (-0.1,0.9), respectively. Analysis of the prepubertal subset of children (n=15) showed that median percentage predicted LS BMC for height was 104% (80, 116), whereas the median TB BMC for height was 96% (74, 108). Median Ht SDS of the HPT and PHPIa cohort was -0.3 (-2.9, 0.3) and median LS and TB pBAr were 90% (66, 100) and 91% (76, 98), respectively. Median LS and TB pBMC SDS were 0.6 (-0.4, 1.8) and 0.7 (0.3, 1.1), respectively. Median percentage predicted LS and TB BMC for height were 102% (82, 114) and 102% (92, 122). There was no relationship between pBMC SDS and duration of illness, GFR, vitamin D dose, serum intact parathyroid hormone (PTH), serum calcium/phosphate product or serum total alkaline phosphatase (ALP) in the CRI or the HPT cohort. However, one of the highest pBMC SDSs was recorded in a child with PHPIa before she started on any treatment. In children with CRI, BMC, when adjusted for co-existing growth retardation, is similar to that observed in children with hypoparathyroidism. The correct reading of BMC needs a correction for bone size.

Urinary excretion of calcium and phosphate in preterm infants.

The aims of this study were to determine reference ranges for the urinary calcium (UCa/Cr) and phosphate (UPO(4)/Cr) creatinine ratios and to study factors influencing these ratios in a representative population of preterm infants managed according to current nutritional guidelines. Spot urine samples were obtained from 186 preterm infants (gestation 24-34 weeks) for measurement of UCa/Cr and UPO(4)/Cr ratios as part of a routine metabolic bone screening program, once every 2-4 weeks from the 3rd to the 18th week of life. Data were also collected on gender, appropriate or small for gestational age (SGA), nutrition [total parenteral nutrition (TPN), preterm or term formula, and breast milk], plasma Ca, P0(4), urea, and electrolytes and on the use of drugs (frusemide, dexamethasone, and theophylline). Data from infants treated with any of these three drugs were analyzed separately and not included in establishing the reference ranges for UCa/Cr and UPO(4)/Cr. The mean gestational age of the study population was 28 weeks (range 24-34 weeks). The 95th percentile for UCa/Cr at 3 weeks of age was 3.8 mmol/mmol and decreased significantly with increasing postnatal age (P<0.001). The 95th per-centile for UPO(4)/Cr was 26.69 mmol/mmol at 3 weeks of age, but this did not change significantly with increasing postnatal age (P=0.296). On univariate analysis there was no significant association of UCa/Cr and UPO(4)/Cr with gender and type of enteral nutrition. The UCa/Cr was lower in infants who were SGA (P=0.013) and with low plasma Ca (P=0.008). Infants on TPN had significantly higher UCa/Cr (P =0.019) and lower UPO(4)/Cr ratios(P<0.001). Multivariate analysis confirmed the decrease in UCa/Cr ratio with increasing postnatal age, but the SGA effect was eliminated. The use of furosemide(P<0.001) and theophylline (P=0.003) was associated with a significant increase in the UCa/Cr ratio. The use of dexamethasone was also associated with an increase in UCa/Cr ratio, but this did not achieve statistical significance (P=0.339). The use of furosemide, theophylline,and dexamethasone had no effect on UPO(4)/Cr. We report a reference range for UCa/Cr and UPO(4)/Cr ratios and factors influencing these ratios in a representative population of preterm infants between 24 and 34 weeks gestation, managed according to current nutritional guide-lines.

Glomerular basement membrane thickness in children: a stereologic assessment.

BACKGROUND: Stereologic methods have emerged as the technique of choice in assessing glomerular basement membrane (GBM) thickness, following conceptual modeling comparing the stereologic technique of harmonic mean of the orthogonal intercept estimation (Th) with the model based method of arithmetic mean estimation (ATH), with no direct comparison undertaken. We undertook to establish the gold standard for GBM estimation and use this technique to establish a range for GBM thickness in children. METHODS: Intra-observer and inter-glomerular variation was estimated in 34 cases with (presumed) normal GBM thickness, using Th, ATH and a rapid direct measurement technique, with intra-observer variation measured in 35 cases with GBM attenuation. A total of 34,011 measurements were undertaken to establish a range for Th in children on 212 biopsies from 199 patients (127 male) demonstrating minimal change nephropathy (N = 153), focal segmental glomerulosclerosis (24), no abnormality (24), and acute tubular necrosis (8), which were used as surrogates for normals. RESULTS: Th demonstrated less variation than ATH in both the normal and attenuated groups. GBM thickness increased throughout childhood, from 194 +/- 6.5 nm (mean +/- SE) at one year to 297 +/- 6.0 nm at 11 years, with a reduced rate of increase after age 11 years. CONCLUSION: Stereologic methods are superior to model based techniques in estimating GBM thickness and should be regarded as the technique of choice in this area. GBM thickness was observed to increase during childhood with no gender effect demonstrable as a main effect or interaction.

Skeletal disproportion in children with chronic renal disease.

OBJECTIVES: To assess stature and skeletal disproportion in children with chronic renal disease. METHODS: Cross-sectional study of height (HT), sitting height (SH), subischial leg length (SILL), sitting height/height ratio (SH:HT) and disproportion score (SH SDS minus SILL SDS) in 56 children (M:35) with median age 11.4 years (range 4.5,18.7) with chronic renal disease. RESULTS: There were 19 children with chronic renal insufficiency, 6 receiving peritoneal dialysis and 31 after renal transplant. The median HTSDS for the whole group was -1.21 (-2.8, 0.35). The median SH:HT ratio in non-transplanted children and renal transplant were 0.51 (0.49, 0.53) and 0.50 (0.48, 0.53), respectively (p = 0.02). The median disproportion score of the whole group was -3.2 (-4.8, -1.8). There was a significant correlation between disproportion score and SH:HT (r = 0.5, p = 0.005). SH:HT ratio was negatively related to duration of illness (r = 0.4, p = 0.005). CONCLUSION: Children with chronic renal disease have significant body disproportion and this may be due to a disproportionately greater effect of disease and treatment on spinal growth.