Use of opportunistic clinical data and a population pharmacokinetic model to support dosing of clindamycin for premature infants to adolescents.

Clindamycin is commonly prescribed to treat children with skin and skin-structure infections (including those caused by community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA)), yet little is known about its pharmacokinetics (PK) across pediatric age groups. A population PK analysis was performed in NONMEM using samples collected in an opportunistic study from children receiving i.v. clindamycin per standard of care. The final model was used to optimize pediatric dosing to match adult exposure proven effective against CA-MRSA. A total of 194 plasma PK samples collected from 125 children were included in the analysis. A one-compartment model described the data well. The final model included body weight and a sigmoidal maturation relationship between postmenstrual age (PMA) and clearance (CL): CL (l/h) = 13.7 × (weight/70)(0.75) × (PMA(3.1)/(43.6(3.1) + PMA(3.1))); V (l) = 61.8 × (weight/70). Maturation reached 50% of adult CL values at ~44 weeks PMA. Our findings support age-based dosing.

Urea and nitrogen excretion in pediatric peritoneal dialysis patients.

BACKGROUND: Adequate nutrition is critical to the care of children with end-stage renal disease, and failure to reach the target dietary intake is associated with growth failure. Prospective studies of urea and nitrogen output in adults have led to the derivation of quantitative relationships, which allow assessment of dietary protein intake when only urea appearance is known. Such a clinically useful relationship has not been defined in children receiving chronic peritoneal dialysis (PD). METHODS: We studied 18 pediatric PD patients (ages 0.8 to 14.3 years) on 132 occasions and determined norms of urea nitrogen appearance (UNA), total nitrogen appearance (TNA), and nonurea nitrogen appearance (NUNA). We stratified data on UNA, TNA, NUNA, nonprotein nitrogen appearance, and the protein equivalent of nitrogen appearance by age groups (0 to 5, 6 to 10, and 11 to 15 years of age) and demonstrated significant differences. In addition, dietary protein and energy intake were measured in the outpatient setting with food scales and dietitian interviews, and the results were stratified by age, presence of residual renal function, and recombinant human growth hormone (rhGH) therapy. RESULTS: UNA (3.05 +/- 1.38 g/day, 103 +/- 42 mg/kg/day) and TNA (4.67 +/- 1.86 g/day, 159 +/- 52 mg/kg/day) varied significantly between different age groups. NUNA in pediatric subjects (56 +/- 24 mg/kg/day) was significantly greater than previously published adult norms. A linear relationship was defined between UNA and TNA that was specific to pediatric PD patients [TNA (g/day) = 1.26(UNA) + 0.83]. When the relationship was scaled to body mass, the y intercept was significantly different in the youngest subjects [TNA = 1.03 (UNA) + 0.02 (weight in kg) + 0.56 (for subjects age 0 to 5) or 0.98 (for subjects age 11 to 15 or 6 to 10), r2 = 0.91]. Dietary protein intake was significantly greater in subjects receiving rhGH therapy, although nitrogen excretion was unchanged. CONCLUSIONS: Markers of protein metabolism in pediatric PD patients are age dependent and differ from adult values. An age-specific relationship between TNA and UNA is defined for pediatric subjects; it does not vary with rhGH or the presence of residual renal function.

Improvement in specific aspects of neurocognitive performance in children after renal transplantation.

BACKGROUND: Chronic renal failure in childhood is considered to affect neurocognitive function adversely, and kidney transplantation may ameliorate the deficits. However, previous studies have suffered from the use of poorly matched control groups, comparison of transplant with uncorrected uremia, lack of standardization of dialysis, and insufficiently sensitive neuropsychological tests. METHODS: We studied nine medically stable children and adolescents age 14.2 +/- 3.5 years with end-stage renal disease prior to and again one year after successful renal transplant. At baseline, the Wechsler Intelligence Scale for Children-III (WISC-III) or the Wechsler Adult Intelligence Scale-Revised (WAIS-R) was performed. Repeatable tests used before and after transplant included the Paced Auditory Serial Addition Test (PASAT) or the Children's Paced Auditory Serial Addition Test (CHIPASAT), the Stroop Color-Word Naming Test, the Buschke Selective Reminding Test, the Meier Visual Discrimination Test, the Grooved Pegboard Test, the WISC-III or the WAIS-R Coding subtests and the Trailmaking Test. Computer-based measures of mental processing speed, reaction time, and discrimination sensitivity included the Cognitive Abilities Test (CAT) and the Connors Continuous Performance Test (CPT). Formal kinetic modeling of dialysis delivery ensured adequate renal replacement therapy. Transplant function was good on stable doses of immunosuppressives, without recent rejections at the time of testing. RESULTS: Within-subject comparison showed statistically significant improvement in mental processing speed by CAT, reaction time and discrimination sensitivity by CPT, and working memory by PASAT/CHIPASAT after renal transplant. Other measures were unchanged. CONCLUSION: Mental processing speed and sustained attention improved in children after renal transplantation in a carefully controlled prospective cross-over study.

Simultaneous removal and replacement of infected peritoneal dialysis catheters.

Infection is an important complication of peritoneal dialysis that often limits technique survival. Recurrent episodes of peritonitis caused by the same organism may be the result of catheter infection, necessitating removal. We performed 34 single-step catheter replacement procedures in children and young adults for recurrent peritonitis or refractory exit site and tunnel infections. The success rate of the procedure was high (85%), with rare instances of intraoperative contamination. The presence of Staphylococcus aureus infection or exit site and tunnel infection were not risk factors for worse outcome. All patients continued on peritoneal dialysis through catheter change without requiring interval hemodialysis. Eighteen peritoneal dialysis catheters were replaced in a staged procedure with an interval off peritoneal dialysis. There was one early reinfection of the new catheter. Patients with Pseudomonas sp infections were more likely to be treated with a staged procedure; S aureus infections were equally likely to be managed by staged or simultaneous catheter removals. Simultaneous removal and replacement of infected peritoneal dialysis catheters is an effective management strategy when compared with two-step catheter replacements.

Acute renal failure in the pediatric patient.

Acute renal failure (ARF) in children, which occurs in a variety of settings and whose differential diagnosis is best approached by age of the patient, presents a unique challenge to even the experienced pediatric nephrologist, with respect to proper diagnosis and adequate therapy. Efficient dialytic clearance, if warranted, is possible in virtually all children, using peritoneal dialysis (PD), hemodialysis (HD), continuous arteriovenous hemofiltration (CAVH), or continuous venovenous hemofiltration (CVVH), with or without dialysate. The choice of modality employed is most often guided by the child's clinical condition, and experience locally with the particular modalities. Clearly, HD, CAVH, and continuous arteriovenous hemofiltration with dialysis (CAVHD) require greater technical expertise, most often from a pediatric nephrologist. Maximum achievable clearances differ for each age-group and need to be considered when prescribing such therapies for ARF. Careful attention to the unique catabolic needs of the acutely uremic child is warranted as well. Technical advances will facilitate renal replacement therapies in the smallest of pediatric patients with ARF. It is hoped that with an enhanced understanding of the unique needs of children with ARF, both of the disease processes and their therapies, the disappointing outcome of ARF in children will be reversed.

Peritoneal equilibration test results are different in infants, children, and adults.

Peritoneal equilibration test (PET) curves have been standardized in adult peritoneal dialysis (PD) patients. However, it appears that norms for pediatric PD patients may be different. A series of PET in 29 stable, chronic PD patients < or = 14 yr old performed at dwell volumes of 33 +/- 6 mL/kg with 2.5% Dianeal is reported. PET results for glucose and creatinine transport were compared between patients age < or = 2 and those 3 to 14 and published adult values by analysis of variance. Children < or = 2 transport glucose and creatinine more rapidly than do children 3 to 14 and adults. Children 3 to 14 transport glucose more rapidly than do adults; creatinine transport is not significantly different. These data demonstrate that transport characteristics differ between very young children, older children, and adults. Because PET are usually performed to plan mode of therapy, to address inadequate ultrafiltration, or to increase clearance, awareness of these results should assist in the clinical care of children on PD.

Hereditary sclerosing glomerulopathy in the conorenal syndrome.

Kidney failure is recognized to occur in association with bone malformations, yet the renal disease often is incompletely characterized. In the syndrome of cone-shaped epiphyses of the phalanges and renal failure (conorenal syndrome), the kidney disease has been previously labeled "nephronophthisis" (now termed "medullary cystic disease"). We report two siblings with the conorenal syndrome in whom longitudinal clinical study has been possible and from whom kidney biopsy specimens were obtained prior to renal failure; their renal disease is incompatible with medullary cystic disease. The variable clinical course and nephropathology of this syndrome are characterized. These results call into question the association of medullary cystic disease of the kidney with other syndromes of bone dysplasia with renal failure.

Measurement of peritoneal dialysis delivery in children.

We measured urea [weekly urea clearance/total body water (KT/Vurea)] and creatinine (CCr) clearances on 35 occasions in 15 stable chronic peritoneal dialysis patients to determine the feasibility and reproducibility of such measurements in children. In addition, we performed peritoneal equilibration tests (PETs) to characterize our patients' peritoneal membranes and to estimate weekly clearances. We demonstrated that dialysis delivery can be quantified by these standard measurements in children of widely varying size. Further, we found that clearances predicted from PET data were similar to measured values in all patients. However, predicted and measured values were most significantly correlated in patients with high and high-average peritoneal membrane permeability. KT/Vurea and CCr were correlated overall, but differences in scaling affected the validity of the relationship. When both clearances were scaled to weight, the correlation was closer, but still differed between PET-determined peritoneal membrane types.

Estimation of urea and creatinine clearance in peritoneal dialysis.

The authors performed peritoneal equilibration tests (PET) in children and young adults of widely varying sizes to characterize membrane transport type, and used data (D/P ratios) obtained to predict clearances of urea (KT/Vurea) and creatinine (CrCl). Overall, PET predicted and measured values for KT/Vurea and CrCl were not significantly different. KT/Vurea could be reliably predicted from PET data for all membrane transport types. However, the relationship between predicted and measured CrCl was only significant for patients with high and high average membrane transport. In addition, the relationship between KT/Vurea and CrCl was significant only in patients with high and high average membrane transport.

Kidney epithelial cells release growth factors in response to extracellular signals.

The growth of nontransformed monkey kidney epithelial cells in culture appears to be regulated by the interplay of positive and negative autocrine growth factors. Reduction of the potassium or sodium concentration of the medium induces rapid release of novel growth-promoting activities, whereas addition of the mitogen adenosine diphosphate stimulates the appearance of a platelet-derived growth factor-like protein which could function in a paracrine manner. These observations suggest that autocrine and paracrine growth factors could play an important role in physiological and pathological states in the kidney.