The true distribution volume and bioavailability of mizoribine in children with chronic kidney disease.

BACKGROUND: Mizoribine (MZR) is used kidney transplant and various kidney diseases. However, few studies reported the association between pharmacokinetics and pharmacodynamics. The Pharmacokinetics Study Group for Pediatric Kidney Disease (PSPKD) used population pharmacokinetics (PPK) analysis and Bayesian analysis to investigate the usefulness of MZR. In this study, the fact that almost all MZR are excreted unchanged in urine was used to calculate its bioavailability (F) and true distribution volume (V d), and analyzed these correlation with age. METHODS: Ishida et al. reported a PPK analysis by the PSPKD. In the present study, 71 samples extracted from their study population of 105 pediatric chronic kidney disease patients aged between 1 and 20 years were investigated. The bioavailability was calculated by measuring total excreted MZR in 24 h urine samples, and this was compared to the oral dosage. The apparent distribution volume (V d/F) obtained from Bayesian analysis was then used to calculate true distribution volume (V d), and the correlation of each parameter with age was investigated. RESULTS: The median dose of MZR per weight was 5.17 mg/kg/day. Median bioavailability was 32.02%. Median V d per weight was 0.46 L/kg. There was a significant, weakly positive correlation between bioavailability and age (p = 0.026). There was also a significant, weakly negative correlation between V d per weight and age (p = 0.003). CONCLUSION: Bioavailability and V d per weight tended to decrease depending on age. The younger patient required larger dose required to obtain the maximum effect from MZR, and this is important for immunosuppressive therapy.

Population pharmacokinetics of mizoribine in pediatric patients with kidney disease.

BACKGROUND: The present study aimed to obtain information enabling optimisation of the clinical effect of mizoribine (MZR) in pediatric patients with kidney disease. METHODS: A total of 105 pediatric patients with kidney disease treated at our institutions were enrolled. Kidney transplant patients were excluded. Population pharmacokinetic analysis of MZR was performed based on serum concentration data. Area under the curve from time zero to infinity (AUC∞) and maximal concentration (C max) were calculated by Bayesian analysis. RESULTS: In children, the appearance of MZR in the blood tended to be slower and the subsequent rise in blood concentration tended to be more sluggish, compared to healthy adults. Apparent volume of distribution and oral clearance were also higher in children compared to adults. A significant positive correlation was observed between patient age and AUC∞. There were significant differences of AUC∞ and C max by age group. No relationship was observed between the administration method of MZR and serum concentration. CONCLUSION: The pharmacokinetics of MZR was different in children compared to adults. To obtain the expected clinical efficacy, the regular MZR dosage schedule (2-3 mg/kg/day) might be insufficient for pediatric patients. In particular, younger patients might require a higher dosage of MZR per unit body weight.

Three infants with rotavirus gastroenteritis complicated by severe gastrointestinal bleeding.

Rotavirus gastroenteritis causes substantial morbidity and mortality worldwide in children. We report three infants with rotavirus gastroenteritis complicated by various severity of gastrointestinal bleeding. Two patients (cases 1 and 2) recovered completely without any specific treatments. One patient (case 3) died despite extensive treatments including a red blood cell transfusion and endoscopic hemostatic therapy. Rotavirus genotypes G1P[8] and G9P[8] were detected in cases 2 and 3, respectively. Rotavirus antigenemia levels were not high at the onset of melena, suggesting that systemic rotaviral infection does not play an important role in causing melena.

The kinetics of urinary shedding of BK virus in children with renal disease.

Children with renal diseases are typically treated with immunosuppressive drugs, which place them at high risk of reactivation of the BK virus (BKV). Currently, little is known about the impact of immunosuppressive drugs on the kinetics of urinary shedding of BKV and viral reactivation in pediatric patients with renal diseases. Urine samples were collected monthly for 1 year from 20 children (median age, 9 years; range, 4-15 years) with renal diseases and subjected to real-time PCR. Urinary shedding of BKV was detected in 35% (7/20) of the patients, three of these patients having persistent viral DNA excretion (two cases, twelve times; one case, four times) and four having intermittent viral DNA excretion. Thirty-four of the 240 urine samples contained BKV DNA (median copy numbers, 5.66 log copies/mL; range, 2.45-7.69 log copies/mL). In two of the cases with persistent viral shedding, high copy numbers (range, 4.57-7.69 log copies/mL) of BKV DNA were detected in all 12 urine samples collected. In the other case with persistent viral excretion, a range of 2.45-3.98 log copies/mL of BKV DNA was detected in the four urine samples collected between the 9th and 12th sampling time points. Additionally, high copy numbers (range, 3.12-4.36 log copies/mL) of BKV DNA were detected intermittently in the urine samples of the other four cases. No remarkable correlations were found between the kinetics of BKV DNA loads and urinary findings such as proteinuria and hematuria. The present data demonstrate the kinetics of urinary BKV shedding in pediatric patients with renal diseases. Additionally, no pathogenic role for BKV infection was identified.

Analysis of the shedding of three ß-herpesviruses in urine and saliva of children with renal disease.

Cytomegalovirus (CMV), human herpesvirus 6 (HHV-6) and 7 (HHV-7) are important pathogens in immunocompromised patients. To elucidate the kinetics of the three ß-herpesviruses in saliva and urine samples were collected serially from children with renal diseases. Twenty children with renal diseases were enrolled in this study. A total of 240 saliva and urine samples were collected monthly from the patients over a 1-year period. Viral DNAs loads were measured by real-time PCR. In 10 CMV seropositive patients CMV DNA was detected rarely in saliva and CMV DNA load was lower than the other two ß-herpesviruses DNA loads. All patients were seropositive for HHV-6B and the virus was detected frequently in saliva. Two of 20 patients were HHV-7 seronegative. High copies of viral DNA were detected continuously in saliva of the HHV-7 seropositive patients. Although neither CMV nor HHV-6B DNA load was different among the three renal diseases, HHV-7 DNA load was different among the diseases (P = 0.039). HHV-6B DNA loads were significantly higher in patients with immunosuppressive treatment compared to those without treatment (P = 0.013). Although CMV DNA was detected in urine samples collected from 5 of 10 CMV seropositive patients, HHV-6B and HHV-7 DNA were detected at relatively low frequencies in urine. No remarkable temporal associations between viral DNA excretion and proteinuria or immunosuppressive treatment were demonstrated. The pattern of viral DNA excretion in saliva and urine were different among the three viruses. No temporal correlation was observed between viral infection and renal diseases.

Evaluation of limited sampling designs to estimate maximal concentration and area under the curve of mizoribine in pediatric patients with renal disease.

The aim of this study was to evaluate limited sampling designs to estimate the maximal concentration (C(max)) and area under the curve (AUC) of mizoribine in pediatric patients with renal disease. We utilized 48 serum mizoribine concentration profiles obtained from the full (6-point) sampling pharmacokinetic test, and estimated 48 individual C(max) and AUC values accurately with Bayesian analysis using the full sampling data. We then developed limited sampling models (LSM) for C(max) and AUC using 1-4 serum mizoribine concentration data points. The C(max) and AUC estimation performance of the Bayesian and LSM analysis was fairly good in the 3-point (2, 3, and 6 hr after the dose) sampling design. In addition, the C(max) estimation performance of the Bayesian and LSM analysis deteriorated only marginally even in the 1-point (3 hr) sampling design. On the other hand, the AUC estimation performance seemed to be inadequate in the 1-point (3 hr) sampling design; however, it improved markedly in the 2-point (3 and 6 hr) sampling design. These findings suggested that the 1-point (3 hr) sampling design is promising for approximate C(max) estimation, but that the 2-point (3 and 6 hr) sampling design is preferable to estimate the AUC of mizoribine.

Urinary neutrophil-gelatinase associated lipocalin is a potential noninvasive marker for renal scarring in patients with vesicoureteral reflux.

PURPOSE: Renal scarring is a serious complication that often occurs with chronic pyelonephritis in the presence of vesicoureteral reflux. In a previous study we established a rat model of renal scarring in which we found the up-regulation of neutrophil-gelatinase associated lipocalin at the mRNA and protein levels. In this study we evaluated urinary neutrophil-gelatinase associated lipocalin as a potential biomarker for progression of renal scarring in patients with vesicoureteral reflux. MATERIALS AND METHODS: A total of 34 patients diagnosed with vesicoureteral reflux without evidence of current urinary tract infection and 28 normal healthy children were enrolled in this study. Renal scars were evaluated by (99m)technetium dimercapto-succinic acid renal scan in 24 of the reflux cases. Urinary neutrophil-gelatinase associated lipocalin levels were monitored by ELISA. RESULTS: In normal subjects urinary neutrophil-gelatinase associated lipocalin was high during infancy, decreased rapidly within the following year and reached a low stable level from age 3 years onward. Urinary neutrophil-gelatinase associated lipocalin levels, normalized to age matched standards, were significantly increased in patients with vesicoureteral reflux compared to controls. These levels did not correlate with reflux grade, but were significantly higher in patients with radiological evidence of renal scarring irrespective of reflux grade. CONCLUSIONS: Estimation of urinary neutrophil-gelatinase associated lipocalin may be useful as a noninvasive diagnostic or prognostic biomarker for renal scarring.

Evaluation of active human herpesvirus 6 infection by reverse transcription-PCR.

Monitoring of active human herpesvirus 6 (HHV-6) infection is important for distinguishing between reactivation and latency of the virus. The reverse transcription polymerase chain reaction (RT-PCR) may be a useful tool in order to distinguish active and latent HHV-6 infection. An RT-PCR assay detecting 4 different HHV-6 gene transcripts was established. Samples of peripheral blood mononuclear cells (PBMCs) were collected from patients with exanthem subitum and used to evaluate the reliability of the assay. After confirming the reliability of the assay, RT-PCR was used to determine whether HHV-6 reactivation occurs in children with hypercytokinemia. Three gene transcripts (U31, U39, and U94) were detected in 90-100% of the PBMC samples collected from febrile period of exanthem subitum patients, from which HHV-6 was isolated. The two gene transcripts encoding the late proteins U31 and U39, however, were not detected in samples collected during the convalescent period that contained no infectious virus. The putative latency associated gene transcript, U94, was detected in 2 (10%) of the 20 convalescent samples, and another immediate early gene transcript, U90, was also detected in 3 (15%) of the 20 convalescent samples. The frequency of HHV-6 reactivation in patients with hypercytokinemia, suggesting monocyte/macrophage activation, was studied. Only 9 of 17 patients diagnosed with Kawasaki disease and 1 patient diagnosed with juvenile rheumatoid arthritis were positive for HHV-6 DNA in their PBMCs samples. Neither the U31 gene nor the U94 gene transcript was detected in any of the 10 samples. An RT-PCR assay screening for both immediate early and late genes may be useful for monitoring active HHV-6 infection. No HHV-6 reactivation was found in patients with hypercytokinemia using the RT-PCR assay.