The effect of vascular access location and size on circuit survival in pediatric continuous renal replacement therapy: a report from the PPCRRT registry.

PURPOSE: Well-functioning vascular access is essential for the provision of adequate CRRT. However, few data exist to describe the effect of catheter size or location on CRRT performance in the pediatric population. METHODS: Data for vascular access site, size, and location, as well as type of anticoagulant used and patient demographic data were gathered from the ppCRRT registry. Kaplan-Meier curves were generated and then analyzed by log-rank test or Cox Proportional Hazards model. RESULTS: Access diameter was found to significantly affect circuit survival. None of the 5 French catheters lasted longer than 20 hours. Seven and 9 French, but not 8 French, catheters fared worse than larger diameter catheters (p=0.002). Circuits associated with internal jugular access survived longer than subclavian or femoral access associated circuits (p<0.05). Circuit survival was also found to be favorably associated with the CVVHD modality (p<0.001). CONCLUSIONS: Functional CRRT circuit survival in children is favored by larger catheter diameter, internal jugular vein insertion site and CVVHD. For patients requiring catheter diameters less than 10 French, CRRT circuit survival might be optimized if internal jugular vein insertion is feasible. Conversely, when a vascular access site other than the internal jugular vein is most prudent, consideration should be given to using the largest diameter catheter appropriate for the size of the child. The CVVHD modality was associated with longer circuit survival, but the mechanism by which this occurs is unclear.

Evaluation of the PRISMA M10 circuit in critically ill infants with acute kidney injury: A report from the Prospective Pediatric CRRT Registry Group.

Currently available extracorporeal circuits in the US often require blood priming to prevent hypotension/anemia in smaller pediatric patients. The PRISMA M10 circuit, available in other countries has not received extensive study and has not been cleared for use in the US. We performed an FDA mandated study of the M10 circuit in the US for use in critically ill pediatric patients with acute kidney injury <15 kg in size. FDA guidelines allowed for maximal blood pump flow of 20 ml/min. Fifteen pts (9 M, 6 F, mean size 5.8+/-2.8 kg, range 2.6-12.5 kg, age 4 d - 13 mo, mean creatinine =1.2+/-0.7 mg/dL) were studied at 4 ppCRRT centers. Sixty-one filters (range 1-4 circuits per pt) were used (mean circuit life 28.6+/-22.5 h, range 1 to 74.5 h, 55%>24 h). No blood leaks occurred. All circuits achieved Qb 20 ml/min. Forty-two out of 61 filters clotted and mean circuit life was lower for these filters than those changed for other reasons (23+/-17 vs. 41+/-28 h, <0.005). Circuits using larger access demonstrated significantly longer survival. We conclude that the M10 filter can serve well for CRRT in small pediatric patients. Further study is needed to determine in higher blood flow rates would decrease clotting rates and increase filter life span and ultrafiltration rates.

The Prospective Pediatric Continuous Renal Replacement Therapy (ppCRRT) Registry: design, development and data assessed.

Many issues plague the pediatric ARF outcome literature, which include data only from single center sources, a relative lack of prospective study, mixture within studies of renal replacement therapy modality without stratification and inconsistent use of methods to control for patient illness severity in outcome analysis. Since January 2001, the Prospective Pediatric CRRT (ppCRRT) Registry Group has been collecting data from multiple United States pediatric centers to obtain demographic data regarding pediatric patients who receive CRRT, assess the effect of different CRRT prescriptions on circuit function and evaluate the impact of clinical variables on patient outcome. The aim of the current paper is to describe the ppCRRT Registry design, review the decision process and rationale for the options chosen for the ppCRRT format and discuss the analysis plan and future projects envisioned for the ppCRRT Registry.

The pharmacokinetics of enalapril in children and infants with hypertension.

Forty children with hypertension between the age of 2 months and 15 years received 0.07 to 0.14 mg/kg of enalapril as a single daily dose. Enalapril was administered orally as a novel extemporaneous suspension in children younger than 6 years of age and as tablets in older children. First-dose and steady-state pharmacokinetics were estimated in children ages 1 to 24 months, 25 months to < 6 years, 6 to < 12 years, and 12 to < 16 years. Maximum serum concentrations for enalapril occurred approximately 1 hour after administration. Serum concentrations of enalaprilat, the active metabolite of enalapril, peaked between 4 and 6 hours after the first dose and 3 and 4 hours after multiple doses. The area under the concentration versus time curve (AUC), adjusted for body surface area, did not differ between age groups. Based on comparison of first-dose and steady-state AUCs, the accumulation of enalaprilat in children ranged from 1.13- to 1.45-fold. For children ages 2 to 15 years, mean urinary recovery of total enalaprilat ranged from 58.3% in children ages 6 to < 12 years to 71.4% in children ages 12 to < 16 years. Urinary recovery for children ages 2 to < 6 years was 66.8%. The mean percentage conversion of enalapril to enalaprilat ranged from 64.7% for children ages 1 to 24 months to 74.6% for children ages 6 to < 12 years. The median effective half-life for accumulation ranged from 14.6 hours in children ages 12 to < 16 years to 16.3 hours in children ages 6 to < 12 years. There were two serious adverse events, neither of which was attributed to enalapril or resulted in discontinuation of the study drug. The extemporaneous suspension used in this study was tolerated well. The pharmacokinetics of enalapril and enalaprilat in hypertensive children ages 2 months to 15 years with normal renal function appears to be similar to that previously observed in healthy adults.

Proteinuria and focal segmental glomerulosclerosis in severely obese adolescents.

OBJECTIVE: To describe the clinical and laboratory features of obesity associated proteinuria and focal segmental glomerulosclerosis. STUDY DESIGN: The patients were seen over a 12-year period at two large children's hospitals. Renal biopsies, performed for the diagnosis of unexplained heavy proteinuria and prepared for light, immunofluorescent, and electron microscopy, were read independently by two pediatric pathologists. Blood pressure, body mass index, serum levels of creatinine, albumin, and cholesterol, and 24-hour urinary protein were measured. RESULTS: Seven African American adolescents were identified with obesity-associated proteinuria, which was characterized by severe obesity (120 +/- 30 kg), markedly elevated body mass index (46 +/- 11), mild hypertension (134/74 +/- 10/18 mm Hg), slightly low to normal serum albumin levels (3.6 +/- 0.2 g/dL), moderately elevated serum cholesterol levels (196 +/- 60 mg/dL), and elevated 24-hour protein excretion (3.1 +/- 1.3 g/dL). Calculated creatinine clearance was normal in 6 patients and decreased in one. Typical renal histologic features included glomerular hypertrophy, focal segmental glomerulosclerosis, increased mesangial matrix and cellularity, relative preservation of foot process morphology, and absence of evidence of inflammatory or immune-mediated pathogenesis. One patient showed a dramatic reduction in proteinuria in response to weight reduction. Three patients who were given angiotensin-converting enzyme inhibitors had reduced urinary protein losses from 2.9 g to 0.7 g per day. One patient developed end-stage renal disease. CONCLUSION: Obese adolescents should be monitored for proteinuria, which has distinct clinical and pathologic features and may be associated with significant renal sequelae. Such proteinuria may respond to weight reduction and/or treatment with angiotensin-converting enzyme inhibitors.

Is growth a valid outcome measure of dialysis clearance in children undergoing peritoneal dialysis?

OBJECTIVE: Our study evaluated growth as a clinical outcome measure of peritoneal dialysis (PD) adequacy in children with end-stage renal disease (ESRD). DESIGN: This retrospective single-center study was carried out in our tertiary-care medical center. PATIENTS: The study enrolled 24 patients who initiated dialysis after January 1, 1995, and who had been on dialysis for a minimum of 1 year. RESULTS: The weekly mean total [PD + residual renal function (RRF)] creatinine clearance (C(Cr)) and Kt/V(urea) were 70.3 +/- 18 L per 1.73 m2 and 3.45 +/- 0.73, respectively. Of the 24 patients, 12 (50%) were anuric. The mean height standard deviation score (SDS) changed to -1.78 at the end of 1 year from -1.58 at baseline. Catch-up growth (positive delta height SDS) was observed in 9 patients (37%), 7 of whom (78%) had residual renal function (RRF). In contrast, only 5 of 15 patients (33%) with a negative deltaSDS for height had RRF (p < 0.025). The mean height SDS in patients with RRF improved to -1.64 from -1.78; in patients without RRF, it worsened to -1.90 from -1.37 (p = 0.01). While the weekly total Kt/V(urea) in patients with RRF (3.53) was similar to that in patients without RRF (3.37, p = 0.6), only the native Kt/V(urea) had a significant (but weak) positive correlation with delta height SDS (r2 = 0.17, p = 0.04). In contrast, the total weekly C(Cr) was significantly higher (p = 0.001) in patients with RRF (81.1 L/1.73 m2) as compared with those without RRF (59.5 L/1.73 m2). However, only the native C(Cr)--and not the dialysis C(Cr)--had a significant (but weak) positive correlation with delta height SDS (r2 = 0.17, p = 0.04). CONCLUSIONS: These preliminary data provide evidence for a correlation between solute clearance and growth, with RRF exerting a significant influence on that outcome. The Kt/V(urea) data also appear to contradict the presumed equivalence of PD and native clearance in children with ESRD.

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

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 microg 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.

A randomized prospective crossover trial of amlodipine in pediatric hypertension.

Amlodipine has potential advantages in children since it can be dissolved into a liquid preparation and has a long elimination half-life, allowing for once-daily administration. The objective of this study was to compare the efficacy and compliance of amlodipine with that of standard long-acting calcium channel blockers (felodipine or nifedipine) in hypertensive children. A randomized, prospective, crossover study of 11 hypertensive children (9-17 years of age, 10 renal transplant patients) was performed with electronic monitoring of compliance. Each treatment arm was 30 days. No significant differences were observed in mean systolic (SBP) and diastolic blood pressures (DBP) between amlodipine and the other calcium channel blockers. Using 24-h blood pressure monitoring there were no significant differences over each drug treatment period in both mean day-time and night-time SBP and DBP. Patient compliance was similar in both the amlodipine and the nifedipine/felodipine treatment periods. These data suggest that amlodipine is as effective in pediatric nephrology patients as nifedipine and felodipine. Amlodipine may be optimally suited for treatment of young children because at present it is the only calcium channel blocker which can be administered once daily as a liquid preparation.

Success and safety of same-day kidney biopsy in children and adolescents.

Renal biopsy is crucial for the diagnosis, management, and monitoring of many kidney diseases. Although percutaneous renal biopsy is considered a routine safe procedure in children, the optimal length of in-hospital observation following the procedure is not yet known. We prospectively studied two comparable groups of children to compare the success and safety of performing native renal biopsy as an outpatient procedure versus keeping the children hospitalized post biopsy. Doppler ultrasonography of the biopsied kidney was performed approximately 2 weeks after the procedure. For 40 children the biopsy was performed on a same-day basis (study group) and another 15 children were kept for overnight observation (control group). All biopsies yielded adequate tissue for histopathological diagnosis. There was no difference between the two groups in the amount of reported pain and analgesics used after the procedure. Only 1 child in the study group was readmitted 5 days after the biopsy for 48 h, but no major complications were detected. The incidence of post-biopsy intra- or perirenal hematoma detection by sonography was not statistically different between the two groups (39% study group, 43% control group). Follow-up imaging studies were performed on 10 of the 20 children who had an early post-biopsy hematoma and all were completely normal. Patients and their families appreciated being discharged home the same day. In addition, total charges for hospitalization were significantly less for the study group than the control group. We conclude that in selected patients, same-day discharge after renal biopsy may be performed safely without an increased risk of complications.

Tenckhoff catheters prove superior to cook catheters in pediatric acute peritoneal dialysis.

Peritoneal dialysis (PD) is the most common form of renal replacement therapy in infants and young children with acute renal failure (ARF). The two most commonly used catheters for performing acute PD are the Cook catheter (CC), placed at the bedside, and the surgically placed Tenckhoff catheter (TC). In the present study, we compared the complications and survival rates of the two catheters. The records of 59 children (age, 1 day to 16.7 years) who underwent PD for ARF from March 1989 through June 1999 in our hospital were reviewed. The initial (primary) catheter was a TC in 22 patients and a CC in 37 patients. The age of the patients who received a primary TC (2.8 +/- 4.5 years) was no different than the age of those with a primary CC (1.4 +/- 2.0 years; P = not significant). The duration of use (mean +/- SD) of TCs (16.5 +/- 14.2 days) was significantly greater than the duration of CC use (4.9 +/- 4.2 days; P < 0.001). Only two patients with a TC (9%) developed complications, whereas 18 patients with a CC (49%) developed complications, 13 of whom required catheter replacement (P < 0.01). Thirty-five patients (59%) recovered renal function after undergoing dialysis for 11.5 +/- 8.0 days. Twenty-three of those patients (66%) required dialysis for more than 5 days. Only 4 patients with a primary CC had successful completion of dialysis without catheter-associated complications compared with 15 patients with a primary TC. Kaplan-Meier survival analysis showed that by day 6 of dialysis, only 46% of primary CCs were functioning without complications compared with 90% of TCs that were free of complications. We conclude that the use of a CC is associated with significantly more complications than a TC, and nearly one half of the CCs are likely to be nonfunctional beyond 5 days of dialysis, at a time when two thirds of the patients are still expected to be undergoing dialysis. Therefore, when possible, a TC should be the catheter of choice when initiating acute PD in children. In those patients for whom a CC is chosen as the initial catheter, an elective change to a TC should be considered once dialysis is expected to extend beyond 5 days.

Single-dose pharmacokinetics of a pleconaril (VP63843) oral solution in children and adolescents. Pediatric Pharmacology Research Unit Network.

Pleconaril is an orally active, broad-spectrum antipicornaviral agent which demonstrates excellent penetration into the central nervous system, liver, and nasal epithelium. In view of the potential pediatric use of pleconaril, we conducted a single-dose, open-label study to characterize the pharmacokinetics of this antiviral agent in pediatric patients. Following an 8- to 10-h period of fasting, 18 children ranging in age from 2 to 12 years (7.5 +/- 3.1 years) received a single 5-mg/kg of body weight oral dose of pleconaril solution administered with a breakfast of age-appropriate composition. Repeated blood samples (n = 10) were obtained over 24 h postdose, and pleconaril was quantified from plasma by gas chromatography. Plasma drug concentration-time data for each subject were fitted to the curve by using a nonlinear, weighted (weight = 1/Ycalc) least-squares algorithm, and model-dependent pharmacokinetic parameters were determined from the polyexponential parameter estimates. Pleconaril was well tolerated by all subjects. A one-compartment open-model with first-order absorption best described the plasma pleconaril concentration-time profile in 13 of the subjects over a 24-h postdose period. Pleconaril pharmacokinetic parameters (means +/- standard deviations) for these 13 patients were as follows. The maximum concentration of the drug in serum (Cmax) was 1,272.5 +/- 622.1 ng/ml. The time to Cmax was 4.1 +/- 1.5 h, and the lag time was 0.75 +/- 0.56 h. The apparent absorption rate constant was 0.75 +/- 0.48 1/h, and the elimination rate constant was 0.16 +/- 0.07 1/h. The area under the concentration-time curve from 0 to 24 h was 8,131.15 +/- 3,411.82 ng.h/ml. The apparent total plasma clearance was 0.81 +/- 0.86 liters/h/kg, and the apparent steady-state volume of distribution was 4.68 +/- 2.02 liters/kg. The mean elimination half-life of pleconaril was 5.7 h. The mean plasma pleconaril concentrations at both 12 h (250.4 +/- 148.2 ng/ml) and 24 h (137.9 +/- 92.2 ng/ml) after the single 5-mg/kg oral dose in children were higher than that from in vitro studies reported to inhibit > 90% of nonpolio enterovirus serotypes (i.e., 70 ng/ml). Thus, our data support the evaluation of a 5-mg/kg twice-daily oral dose of pleconaril for therapeutic trials in pediatric patients with enteroviral infections.

Neonatal outcome in pregnancies associated with renal replacement therapy.

Pregnancy in women receiving renal replacement therapy is not without risk to the mother and fetus. This article reviews the information on fetal outcome in pregnancies associated with renal transplantation and dialysis. The incidence of neonatal mortality, prematurity, and small-for-gestational-age infants is increased in pregnancies associated with maternal renal replacement therapy. Conversely, there does not appear to be a significant increase in the rate of congenital malformations. Whereas the fetal risk for inheritable renal disease is clearly defined in most cases, the risk associated with a host of new immunosuppressive medications is poorly understood. In addition, the newborn may be at risk for abnormalities in water homeostasis caused by the large solute load transferred from the mother receiving dialysis and requires close observation. Continued accumulation of clinical data will permit women receiving dialysis or with a kidney transplant to make informed decisions about current or future pregnancies.

Hypothetical framework for enhanced renal tubular secretion of drugs in cystic fibrosis.

Several clinical studies demonstrate reduced serum concentrations of renally excreted drugs in patients with cystic fibrosis (CF). To explain this phenomenon, we propose a model supporting increased proximal tubular secretion of certain drugs in individuals with CF. We hypothesize that the chloride channel located on the apical surface of renal proximal tubular cells and controlled by the cystic fibrosis transmembrane conductance regulator (CFTR) operates suboptimally in CF patients, and that the abnormal CFTR decreases Cl- reabsorption, resulting in an increased concentration of Cl- in the tubular lumen. We postulate that, in an effort to maintain homeostasis, luminal Cl- moves intracellularly in exchange for organic anions. The result of stimulating this anion exchanger is an increased rate of organic anion secretion by the renal tubule. Hence, due to enhanced tubular secretion, individuals with CF demonstrate increased tubular clearance of organic anion drugs, resulting in lower steady state serum concentrations.

Peritoneal penetration of amphotericin B lipid complex and fluconazole in a pediatric patient with fungal peritonitis.

Fungal peritonitis is a rare event in patients receiving peritoneal dialysis. This case report describes the blood and dialysate concentrations of fluconazole and amphotericin B following intravenous administration in a 5-month-old infant with Candida albicans peritonitis receiving continuous cyclic peritoneal dialysis. Fluconazole rapidly and efficiently penetrated the peritoneal fluid achieving concentrations that exceed the minimal inhibitory concentration (MIC) for most Candida species. In contrast, the amount of amphotericin B in the dialysate was below the limit of quantification despite measurable blood concentrations. This suggests that fluconazole represents a better choice for antifungal therapy because of its excellent peritoneal penetration.

Compliance with cyclosporine in adolescent renal transplant recipients.

Inadequate compliance with prescribed medication regimens in children is complex and poorly understood. We measured the extent and pattern of noncompliance with cyclosporine in our adolescent renal transplant population and attempted to determine factors associated with poor compliance. After informed consent, each patient was provided cyclosporine capsules in a medication bottle equipped with an electronic monitoring device (MEMS-4) in the lid. Of the 24 patients eligible, 19 patients (8 female, 11 male) completed the study. Four (21%) patients took less than 80% of the prescribed cyclosporine doses. Five (26%) patients took drug holidays involving > or = consecutive doses. There was a trend towards improved compliance with the evening dose (88.5% vs. 93.4%, P = 0.09) and a downward trend in compliance over the course of the study (P = 0.17). None of the variables tested were found to be associated with noncompliance. Experienced physicians and nurses were able to identify 2 of the 4 individuals who were identified by MEMS as noncompliant. Additionally, 2 of the 4 noncompliance patients demonstrated low cyclosporine trough levels (< 50 ng/ml). Noncompliance with cyclosporine regimens occurs commonly in adolescent renal transplant recipients. Unexpectedly low cyclosporine levels are strongly suggestive of noncompliance, whereas other variables, including prediction by physicians and nurses intimately involved in the care, were not reflective of noncompliance.

Nephrotic syndrome associated with an Epstein-Barr virus infection.

A 19-month-old child developed the nephrotic syndrome coincident with an Epstein-Barr virus (EBV) infection. This rare association was confirmed by EBV titers. There was a spontaneous resolution of the nephrotic syndrome temporally related to the abatement of the EBV infection.

Midodrine efficacy and pharmacokinetics in a patient with recurrent intradialytic hypotension.

Recurrent intradialytic hypotension, a complication of hemodialysis, is a consequence of an inadequate compensatory response or a paradoxic response to ultrafiltration-induced volume reduction. We report the use of midodrine, an alpha agonist, in an 18-year-old man with Bardet-Biedl syndrome and recurrent intradialytic hypotension. The clinical features of the intradialytic hypotensive spells are consistent with a paradoxic withdrawal of sympathetic activity, although an underlying abnormality in autonomic dysfunction cannot be excluded. Midodrine significantly increased the intradialytic blood pressure and decreased the intradialytic hypotensive episodes requiring intervention. The pharmacokinetic characteristics of the prodrug midodrine and the active metabolite de-glymidodrine in this patient with end-stage renal disease approximate those reported for patients with normal renal function. However, the prolonged terminal half-life for the active metabolite, de-glymidodrine, warrants careful administration in patients with renal failure.