Angela Delucchi

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.

Early steroid withdrawal in pediatric renal transplant on newer immunosuppressive drugs.

Abstract:  Steroids have been a cornerstone in renal transplant immunosuppression. New immunosuppressive drugs have led to protocols using early steroid withdrawal or complete avoidance. A prospective protocol in 23 pediatric renal transplant (ages 2–14 yr) who received decreasing steroid doses stopping at day 7 post‐Tx, FK, and MMF were compared with a CsA, AZT, historically matched steroid‐based control group. Basiliximab was used in two doses. Anthropometric, biochemical variables, AR rates, and CMV infection were evaluated and compared using Student’s t‐test and regression analysis. A better growth pattern was seen in steroid withdrawal group. GFR rate and serum glucose were similar in both groups. Total serum cholesterol levels were significantly lower in steroid withdrawal group. The incidence of AR at 12 months was 4.3% in steroid withdrawal group vs. 8.6% in steroid‐based group (p = ns). No difference in CMV infection was observed. Hemoglobin levels were low during the first months in both groups; reached normal values after six months. SBP became higher at 12 months in steroid‐based group. Patient and graft survival was 98% in both groups at one‐yr post‐transplant. Early steroid withdrawal was efficacious, safe, and did not increase risk of rejection, preserving optimal growth, renal function, and reducing cardiovascular risk factors.

Enalapril and prednisone in children with nephrotic-range proteinuria

Abstract The effect of enalapril and low prednisone doses on the urinary protein electrophoretic pattern was studied in 13 pediatric patients with glomerular diseases and steroid-resistant nephrotic syndrome. Enalapril was administred at doses of 0.2–0.6 mg/kg per day for 24–84 months, and prednisone was introduced 2 months later in 11 patients at doses of 30 mg/m2 on alternate days. The urine protein electrophoretic pattern showed a reduction of 80% and 70% in the total protein and albumin, respectively, after enalapril. Total urinary protein decreased from 5.46 to 1.1 g/m2 per day (P<0.001). A marked change from a pattern of non-selective urinary protein loss to an albumin-selective proteinuria was observed. Mean total plasma proteins increased from 4.7 to 5.43 g/dl (P<0.001). Four patients became free of proteinuria 24 months after enalapril was started, but only 2 remained free of proteinuria at 48 months of follow-up. The other 11 patients had persistent albuminuria of between 0.5 and 2.6 g/m2 per day with a selective urinary electrophoretic pattern. No additional decrease was observed after steroids were introduced. A clinical improvement in edema was observed in all children. Three patients developed transient acute renal failure, during the course of an infectious disease; 2 developed peritonitis and 1 pneumopathy. In these patients withdrawal of enalapril was necessary until a complete recovery of renal function was observed. Four patients were hypertensive on admission, achieving normal blood pressure 1 month after enalapril was started. No episodes of systemic arterial hypotension were seen. Creatinine clearance and serum potassium showed no statistically significant change.

Steroid Withdrawal in Pediatric Kidney Transplant Allows Better Growth, Lipids and Body Composition: A Randomized Controlled Trial

Background: Glucocorticoid immunosuppressant therapy in pediatric kidney transplant (Tx) recipients does not allow the improvement of growth after Tx. Objective: To determine the effect of early steroid withdrawal (SW) on longitudinal growth, insulin sensitivity (IS), and body composition (BC). Methods: This was a prospective, randomized, multicenter study in Tx. Insulin-like growth factor (IGF)-I, IGF-binding protein 3 (IGFBP3), IS, and BC (DEXA/pQCT) were determined at baseline and up to 12 months after Tx. Results: A total of 30 patients were examined; 14 patients were assigned to the SW group (7 male, 7 female; 12 in Tanner stage I) and 16 patients were assigned to the steroid control (SC) group (10 male, 6 female;12 in Tanner stage I). Their chronological age was 7.8 ± 4.3 years, height was -2.3 ± 0.99 SD scores (SDS), and body mass index -0.3 ± 1.2 SDS. After 1 year, the SW group showed an increase in height SDS (+1.2 ± 0.22 vs. +0.60 ± 0.13 SDS in the SC group, p < 0.02), lower IGFBP3 (p < 0.05), cholesterol (p < 0.05), and higher high-density lipoprotein cholesterol (p < 0.05). SW patients had lower trunk fat with no differences in IS. Only in prepubertal patients, the SW group had lower glycemia (p < 0.05), very low-density lipoprotein cholesterol (p < 0.01), triglycerides (p < 0.05), triglycerides/glycemia index (TyG; p < 0.02), and better lean mass. Both groups showed an improvement in lean mass after kidney Tx. Conclusions: SW improved longitudinal growth, lipid profile, and trunk and lean fat in Tx patients. In prepubertal recipients, the decrease in TyG suggests better IS.

Latin American Registry of Pediatric Renal Transplantation 2004-2008

Latin American Pediatric Nephrology Association (ALANEPE) and Latin American Pediatric Renal Transplant Cooperative Study. Latin American Registry of Pediatric Renal Transplantation 2004–2008.
Pediatr Transplantation 2010: 14:701–708.

Focal segmental glomerulosclerosis relapse after transplantation: treatment with high cyclosporine doses and a short plasmaphaeresis course

Ginevri et al. point out a number of similarities and discrepancies in our data when compared with their previous publication [1]. The conclusion of their study, restated in their correspondence, is that vesicoureteric reflux (VUR) is the important determinant of urinary retinol-binding protein (RBP) excretion. However, we found no significant difference in RBP excretion in children with VUR but no scarring compared with controls. Although the upper limit of our normal range is higher than that used by Ginevri et al. [1] it is specific to our in-house assay. Our paper attempts to explore the inter-relationship between RBP excretion, glomerular filtration rate (GFR) and renal scarring [2]. We believe that the exclusion of subjects with low GFR is inappropriate in this analysis. Whilst overload of low molecular weight protein reabsorptive mechanisms has been postulated at low GFR, the renal thresholds of both RBP and ~2-microglobulin are not reached until the GFR is 30 ml/min per 1.73 m 2 [3]. When the GFR was greater than 80 ml/min per 1.73 m:, we found 0 of 14 children with unilateral renal scarring, 2 of 12 children with minimum type A renal scarring and 3 of 7 children with minimum type B scarring had abnormal RBP excretion (X 2 = 6.7, P <0.05, unpublished data). We believe that the degree of scarring is the important determinant of RBP excretion in children with VUR, for either normal or low GFR. Finally, we agree with Ginevri et al. [1] that long-term follow-up studies will be useful in determining the value of RBP measurement in children with VUR and renal scarfing.

Kidney transplant in pediatric patients with severe bladder pathology

The aim of the current study was to compare results in pediatric renal transplantation of patients with and without SBP. Between 2001 and 2013, a total of 168 kidney transplants were performed at our center. A retrospective analysis was performed and recipients were divided into two groups: NB and SBP. Incidence of surgical complications after procedure, and graft and patient survival were evaluated. A total of 155 recipients (92%) with complete data were analyzed, and 13 recipients that had had previous bladder surgeries were excluded (11 with VUR surgery and two with previous kidney transplants), of the 155 recipients: 123 (79%) patients had NB, and 32 (21%) patients had SBP, with a median follow‐up of 60 (1–137) and 52 (1–144) months, respectively. Among post‐transplant complications, UTI (68.8% vs. 23%, p < 0.0001) and symptomatic VUR to the graft (40.6% vs. 7.3%, p < 0.0001) were significantly higher in the SBP group. There was no significant difference in overall graft and patient survival between groups. Renal transplantation is safe in pediatric recipients with SBP; however, urologic complications such as UTI and VUR were significantly higher in this group. Graft and patient survival was similar in SBP and NB groups.

THE PLASMA PERMEABILITY FACTOR IN NEPHROTIC SYNDROME: INDIRECT EVIDENCE IN PEDIATRIC PERITONEAL DIALYSIS

♦ Background: Nephrotic syndrome (NS) in children has been associated with a systemic circulating permeability factor. Therefore, once peritoneal dialysis (PD) has been started, peritoneal protein losses should be higher in the nephrotic than in the non-nephrotic population. ♦ Objective: We compared peritoneal protein losses in children with and without NS on PD. ♦ Methods: Our retrospective 4-year study analyzed Hispanic patients with NS under PD. Data at dialysis entry and 6 months later were compared. Nutritional support was given according to recommended dietary allowances and recommendations from the Kidney Disease Outcomes Quality Initiative. Clinical and biochemical data were obtained, and 24-hour dialysate and urine samples were collected to measure protein losses. Dialysis dose (Kt/V), daily protein intake (DPI), normalized protein equivalent of nitrogen appearance (nPNA), peritoneal equilibration test (PET), and peritonitis rate were determined. All measurements took place at least 4 weeks after resolution of a peritonitis episode. All patients received automated PD using a HomeChoice PD System cycler (Baxter Healthcare Corporation, Deerfield, IL, USA), with an exchange volume of 1100 mL/m2 and a dextrose concentration of 1.5% - 2.5%. A control group of non-NS children on PD matched by age and sex were also studied. Data are reported as mean ± standard deviation. Differences between groups were calculated using the Mann-Whitney U-test, and p < 0.05 was considered significant. ♦ Results: Each study group consisted of 10 patients [NS patients: 4 boys, mean age of 7.3 ± 4.1 years; control patients: 6 boys, mean age of 7.2 ± 4.7 years (p = nonsignificant)]. In the group with NS, 8 patients were diagnosed by biopsy as having focal segmental glomerulosclerosis, and 2 as having minimal-change disease. At study entry, patients with NS had hourly urinary protein losses of 398 ± 313 mg/m2 and daily peritoneal protein losses of 3.4 ± 1.9 g/m2, compared with 29.9 ± 31 mg/m2 and 1.5 ± 1.1 g/m2 respectively in the control group (p < 0.05). The same statistical difference was found 6 months later. We observed no statistical differences in PET results, daily exchange volume, and mean dextrose concentration of dialysate. Similarly, no significant between-group differences were observed for Kt/V, DPI, nPNA, and biochemical parameters. ♦ Conclusions: Hispanic children with NS on PD show higher peritoneal protein losses than do their control counterparts. Such differences could be secondary to increased peritoneal permeability caused by a systemic permeability factor.

Hipovitaminosis D en pacientes pediátricos en terapia de sustitución renal

Background: Hypovitaminosis D has a high prevalence among patients with chronic kidney disease (CKD). Aim: To determine the prevalence of 25 hydroxy vitamin D (25(OH) D) insufficiency and deficiency in pediatric patients on dialysis and kidney transplantation. Material and Methods: Serum calcium and phosphorus, parathormone (PTH), alkaline phosphatases and 25 (OH)D were measured in 13 children on hemodialysis (HD), 18 on peritoneal dialysis (PD) and 53 that received an allograft (Tx), aged 9.8 ± 4.6 years (51% females). Results: Fifty four percent of patients had height Z score less than -1.88. Patients on HD had the lowest values. The average time of replacement therapy was 2.9 ± 2.8 years. Mean 25(OH)D levels in all was 18.7 ± 10.7ng/ml (HD: 21 ± 16.8, PD: 18.9 ± 8.5, Tx: 18.1 ± 9.72 ng/ml). Eighty eight percent of patients had levels below 30 ng/ml. Mean of serum calcium was 9.5 ± 0.64 mg/dl, serum phosphorus 5.03 ± 1.02 mg/dl, calcium-phosphorus product 48 ± 11.8 mg/dl and alkaline phosphatases 300.5 ± 171.3 IU/L. Average PTH values in dialyzed and Tx patients were 724.6 ± 640.5 and 107.7 ± 56.2 pg/ml, respectively (p < 0.001). A positive correlation between 25 (OH) D and calcium levels among PD patients was observed (r = 0.490, p = 0.04). Conclusions: Hypovitaminosis D is highly prevalent among children on renal substitution therapy, regardless of the type of therapy used and the stage of renal failure.