Rita D. Swinford

Chronic rejection and chronic cyclosporin toxicity in renal allografts

Recent evidence indicates that growth factors are critically important in both chronic rejection and chronic cyclosporin A toxicity, suggesting that these two entities share a common pathophysiological pathway, leading to progressive allograft failure. Here, Manuel Pascual and colleagues discuss the relevance of growth factors to chronic allograft nephropathy, and the implications for therapy in view of the great choice of immunosuppressive drugs now available.

A limited sampling strategy for the estimation of Neoral AUCs in pediatric patients

Abstract The improved pharmacokinetics of Neoral allows the development of an accurate estimate of the full area under the concentration time curve (AUC) from a limited sampling strategy. As no such strategy has been derived from pharmacokinetic data obtained from children on 12-hourly dosing, and as patient convenience demands shorter sampling times, we derived a limited sampling strategy from 45 AUCs obtained from 19 pediatric renal transplant patients by stepwise forward multiple regression, and prospectively tested them on a separate group of 49 AUCs obtained from 18 pediatric renal transplant patients. Full cyclosporine (CsA) AUCs were obtained from samples drawn pre dose (C0) and at 2, 4, 6, 8 and 12 h post dose (C2, C4, C6, C8, and C12). High-precision predictions of full AUC were obtained based on the formula: AUC = 444 + 3.69 × C0 + 1.77 × C2 + 4.1 × C4 (mean prediction error ± SD = 0.3 ± 6.4%, 95% confidence interval=–1.7% to 1.9%.) In conclusion, CsA exposure in pediatric renal transplant patients on 12-hourly Neoral dosing can be reliably predicted by an early time point-based limited sampling strategy in children. This formula has the advantage of obtaining trough as well as AUC from one brief, convenient sampling period.

Evaluation of serum creatinine concentration-based glomerular filtration rate equations in pediatric patients with chronic kidney disease.

To evaluate the accuracy of four equations based on serum creatinine concentration—the original Schwartz equation and the Leger, Bedside Chronic Kidney Disease in Children (CKiD), and Counahan‐Barratt equations—for determining glomerular filtration rate (GFR) in pediatric patients with chronic kidney disease.

Reduced variability of neoral pharmacokinetic studies in pediatric renal transplantation.

Abstract In adult renal transplant recipients the Neoral area under the curve (AUC) displays less inter- and intra- individual variability than Sandimmune, and those renal transplant recipients with reduced intra-individual variability of the AUC have a lower risk for chronic rejection. As variability of Neoral pharmacokinetic (Pk) parameters has not been investigated in pediatric renal transplant recipients, we retrospectively analyzed 453 Pk profiles in 14 pediatric patients who were switched from Sandimmune to Neoral and compared the inter- and intra-individual variability of the Pk profiles on both formulations. After the switch, we observed less inter- and intra-individual variability of AUC, the 2-h concentration, and the oral clearance. As clearance with both formulations is supposedly equal, the significantly lower intra-individual variability of oral clearance is most likely an effect of less variable absorption. While the lower inter-individual variability of the Pk parameters suggests increased success in keeping cyclosporine concentrations on target, the lower intra-individual variability leads to the hypothesis that with Neoral, a lower incidence of chronic rejection might be achieved.

First-year response to rhGH therapy in children with CKD: a National Cooperative Growth Study Report

A clear definition of the appropriate growth response during recombinant human growth hormone (rhGH) treatment has never been established in the pediatric chronic kidney disease (CKD) population. We present here data from Genentech’s National Cooperative Growth Study (NCGS) on the first-year growth response in prepubertal children with CKD. Using NCGS data, we constructed response curves for the first year of rhGH therapy in 270 (186 males, 84 females) naïve-to-treatment, prepubertal children with CKD prior to transplant or dialysis. Data from both genders were combined because gender was not significantly related to height velocity (p = 0.51). Response to rhGH was expressed as height velocity (HV) in cm/year. Mean, mean ± 1SD, and mean − 2SD for HV during the first year of rhGH treatment as well as pretreatment HV were plotted versus age. Age-specific HV plots for rhGH-treated children with CKD are presented. At all ages, the first-year mean HV was greater than the mean pretreatment HV. The mean − 2SD for HV in children on rhGH treatment was similar to the mean pretreatment HV. These growth plots will be useful to clinicians for assessing a patient’s first-year growth response. We propose that a HV below the mean − 1SD is an inadequate response. These curves may help identify patients with a suboptimal growth response due to confounding medical factors and/or non-compliance.

Diagnostic Evaluation of Pediatric Hypertension

A clinical challenge to the successful treatment of children with hypertension (HTN) is in the identification and evaluation of those children who will benefit from antihypertensive therapy (1). Additionally, consideration must be given to the causative spectrum of HTN in pediatric patients, as it is broad and changes with age. Most infants, toddlers, and school-aged children must be presumed to have secondary HTN. Essential HTN is most prevalent in adolescence and not dissimilar from that found in adults. For children with severe HTN—those above the 99th percentile—careful, comprehensive and immediate evaluation is required. A general rule for the identification of children at higher risk for secondary HTN is: the younger the child and the more severe the HTN, the more likely it is that a secondary cause will be found. Nontheless, older pediatric patients are still at risk and evaluation is important. The cause(s) of the child’s HTN may be remediable and may benefit from pharmacologic therapy. Also important to consider are children with diabetes and/or chronic kidney disease (CKD). Recent recommendations for these children include beginning therapy with antihypertensive medications, although the patient may be normotensive. Another recommendation for kidney and cardiovascular protection is that blood pressure (BP) be lowered to below the 90th percentile in children and <130/80 mmHg in older adolescents and adults (2). This chapter has been organized as a guideline for the clinician evaluating a new pediatric patient with HTN, with references to other chapters in this book for more detailed information of secondary HTN in children.

Evaluation of the Hypertensive Pediatric Patient

A clinical challenge to the successful treatment of children with hypertension is in the identification and then thorough evaluation of children with elevated blood pressure (BP) (1). In this light, consideration must be given to the causative spectrum of hypertension in pediatric patients as it is broad and changes with age. Most infants, toddlers, and school-aged children must be presumed to have secondary hypertension, with primary hypertension most prevalent in adolescence. For children with severe hypertension, those above the 99th percentile, careful, comprehensive, and immediate evaluation is required. A rule of thumb for the identification of children with secondary hypertension is when the hypertension is severe and the child is young, with the highest sensitivity found in the youngest and most severely hypertensive. However, this may not always be the case, and therefore evaluation is important as the cause may be remediable and benefit from pharmacologic therapy. Recommendations for pharmacologic treatment are based on the presence of symptomatic hypertension, evidence of end-organ damage and/or stage 2 hypertension, or stage 1 hypertension unresponsive to lifestyle modification (2). Not to be discounted are children in high-risk diagnostic groups, e.g., diabetes mellitus and chronic kidney disease (CKD), whose onset of premature atherosclerosis leads to early cardiovascular disease. Recent recommendations for treatment based on risk stratification by disease process are now available (3).

Management of Hypertension in Children and Adolescents

Hypertension in children and adolescents is becoming a greater problem in the developed world. Although traditionally thought of as usually secondary to renal, vascular, or endocrine causes, primary hypertension is becoming the most common form seen in childhood. This changing epidemiology is related to the recent obesity epidemic. The evaluation of high blood pressure in children is more involved than in adults and is aimed both at identifying secondary causes and to identify other co-morbidities of cardiovascular risk. Treatment of hypertension in childhood and adolescence is aimed at reducing cardiovascular risk. While there are a growing number of antihypertensive agents with FDA labeling for children, there remain far fewer options than for adults. This paper reviews the epidemiology, definitions, evaluations, and management of elevated blood pressure in children and adolescents.

Evaluation of Hypertension in Pediatric Patients

The management of hypertension in the pediatric population begins with a thorough diagnostic evaluation which can be tailored to the individual patient based on age, symptoms, and severity of hypertension. We outline four phases of evaluation which are integral to the optimal management of hypertension in children. The first phase seeks to answer whether the patient is truly hypertensive in the nonmedical setting. This can be confirmed with either ambulatory blood pressure monitoring or self-monitored blood pressure monitoring. Once it is determined that the patient is truly hypertensive, the second phase provides screening for etiology of hypertension, hypertensive end-organ damage, and comorbidities. The third phase of evaluation defines the underlying abnormality which could be causing the hypertension, and the fourth phase determines the significance and remediability of the abnormality. By systematically using the four phases outlined in this chapter, the clinician can conduct a thorough evaluation of the hypertensive patient.

The Safety and Efficacy of the Calcium Channel Blocker (CCB) Amlodipine in the Treatment of Secondary Hypertension in Children † 1806

The Safety and Efficacy of the Calcium Channel Blocker (CCB) Amlodipine in the Treatment of Secondary Hypertension in Children † 1806