Isosorbide dinitrate in nephronophthisis treatment.

Nephronophthisis is a progressive disease that affects development of the renal tubules and leads to end stage renal disease. Many affected children have isolated renal disease; however, there can be additional manifestations including heart defects, liver fibrosis, brain malformations, and situs inversus. There is no way to slow or modify the disease. We describe a patient who presented at birth with cholestatic jaundice and decreased kidney function, found by exome sequencing to have two NPHP3 variants. Her clinical status deteriorated rapidly, and two disease-modifying agents were given in hopes of slowing disease progression, the arginine vasopressin type II receptor antagonist tolvaptan to stabilize her renal function and isosorbide dinitrate to manage her poorly controlled hypertension. Tolvaptan therapy initiated at 82 days of life had limited effect on the rate of decline in renal function and was insufficient to abrogate the need for dialysis; however, isosorbide dinitrate therapy led to a dramatic improvement in blood pressure control and allowed for the discontinuation of multiple anti-hypertensive agents. This is the first report of the use of tolvaptan and isosorbide dinitrate for nephronophthisis management. We suggest that isosorbide dinitrate may represent a disease-modifying agent in nephronophthisis treatment.

Therapeutic Drug Monitoring of Continuous Infusion Doripenem in a Pediatric Patient on Continuous Renal Replacement Therapy.

An 11-year-old African American male with severe combined immunodeficiency variant, non-cystic fibrosis bronchiectasis, pancreatic insufficiency, chronic mycobacterium avium-intracellulare infection, chronic sinusitis, and malnutrition presented with a 1-week history of fevers. He subsequently developed respiratory decompensation and cefepime was discontinued and doripenem was initiated. Doripenem was the carbapenem used due to a national shortage of meropenem. By day 7 the patient (24.7 kg) had a positive fluid balance of 6925 mL (28% FO), and on days 7 into 8 developed acute kidney injury evidenced by an elevated serum creatinine of 0.68 mg/dL, an increase from the baseline of 0.28 mg/dL. On day 9, the patient was initiated on continuous renal replacement therapy (CRRT) and the doripenem dosing was changed to a continuous infusion of 2.5 mg/kg/hr (60 mg/kg/day). Approximately 12.5 hours after the start of the doripenem a serum concentration was obtained, which was 4.01 mg/L corresponding to a clearance of 10.5 mL/min/kg. The pediatric dosing and pharmacokinetic data available for doripenem suggest a clearance estimate of 4.4 to 4.8 mL/min/kg, and the adult clearance estimate is 2.4 to 3.78 mL/min/kg. The calculated clearance in our patient of 10.5 mL/min/kg is over double the highest clearance estimate in the pediatric literature. This case demonstrates that doripenem clearance is significantly increased with CRRT in comparison with the published pediatric and adult data. An appropriate pharmacodynamic outcome (time that free drug concentration > minimum inhibitory concentration) can be achieved by continuous infusion doripenem with concurrent therapeutic drug monitoring.

Pharmacokinetics of Continuous Infusion Meropenem With Concurrent Extracorporeal Life Support and Continuous Renal Replacement Therapy: A Case Report.

Pharmacokinetic parameters can be significantly altered for both extracorporeal life support (ECLS) and continuous renal replacement therapy (CRRT). This case report describes the pharmacokinetics of continuous-infusion meropenem in a patient on ECLS with concurrent CRRT. A 2.8-kg, 10-day-old, full-term neonate born via spontaneous vaginal delivery presented with hypothermia, lethargy, and a ~500-g weight loss from birth. She progressed to respiratory failure on hospital day 2 (HD 2) and developed sepsis, disseminated intravascular coagulation, and liver failure as a result of disseminated adenoviral infection. By HD 6, acute kidney injury was evident, with progressive fluid overload >1500 mL (+) for the admission. On HD 6 venoarterial ECLS was instituted for lung protection and fluid removal. On HD 7 she was initiated on CRRT. On HD 12, a blood culture returned positive and subsequently grew Pseudomonas aeruginosa with a minimum inhibitory concentration (MIC) for meropenem of 0.25 mg/L. She was started on vancomycin, meropenem, and amikacin. A meropenem bolus of 40 mg/kg was given, followed by a continuous infusion of 10 mg/kg/hr (240 mg/kg/day). On HD 15 (ECLS day 9) a meropenem serum concentration of 21 mcg/mL was obtained, corresponding to a clearance of 7.9 mL/kg/min. Repeat cultures from HDs 13 to 15 (ECLS days 7-9) were sterile. This meropenem regimen was successful in providing a target attainment of 100% for serum concentrations above the MIC for ≥40% of the dosing interval and was associated with a sterilization of blood in this complex patient on concurrent ECLS and CRRT circuits.

Continuous Infusion Vancomycin Through the Addition of Vancomycin to the Continuous Renal Replacement Therapy Solution in the PICU: A Case Series.

OBJECTIVES: To describe our experience with achieving therapeutic serum vancomycin concentrations in pediatric continuous renal replacement therapy by using continuous infusion vancomycin by mixing vancomycin into the continuous renal replacement therapy solution. DESIGN: Retrospective chart review. SETTING: A 189-bed, freestanding children's tertiary care teaching hospital in Philadelphia, PA. PATIENTS: Pediatric patients receiving continuous renal replacement therapy from April 1, 2009, through December 31, 2014. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: There were a total of 21 patients who received continuous renal replacement therapy during the study period. Of these, 11 (52.3%) received vancomycin in the continuous renal replacement therapy solution. The median (range) concentration of vancomycin added to the continuous renal replacement therapy solution was 25 mg/L (18-35 mg/L). The mean vancomycin plateau level was 22.8 ± 3.3 mg/L. All patients achieved a serum vancomycin plateau level that was greater than 15 mg/L. There were no adverse events related to the addition of vancomycin to the continuous renal replacement therapy solution. CONCLUSIONS: The addition of vancomycin to the continuous renal replacement therapy solution(s) is an effective modality that is used for delivering vancomycin continuous infusion and for ensuring therapeutic vancomycin serum plateau levels in the setting of pediatric continuous renal replacement therapy. Further studies are required to evaluate whether this delivery method can lead to improved patient outcomes.

Domino as a bridge to definitive liver transplantation in a neonate.

An interim liver transplant was used to extend survival in a neonate. This was accomplished by the initial transplant of a left-lateral segment of a metabolically abnormal liver obtained from a 7-yr-old patient with primary oxalosis. This bridging strategy was required because our neonatal patient was dying of fulminant hepatic failure caused by hepatic vein thrombosis and a small liver or liver segment could not be found. Although problems with hyperoxaluria were encountered in the neonate post-transplant, the interim liver transplant enabled the baby to survive and grow until the age of 4 months. At that time, a definitive transplant was performed using the left-lateral segment of his mother's liver. This case represents the first reported use of a pediatric domino transplant where a metabolically abnormal liver was used to allow sufficient growth to permit a definitive liver transplantation.