Cefepime pharmacokinetics in critically ill children and young adults undergoing continuous kidney replacement therapy.

OBJECTIVES: Cefepime is an antibiotic commonly used to treat sepsis and is cleared by renal excretion. Cefepime dosing requires adjustment in patients with decreased kidney function and in those receiving continuous kidney replacement therapy (CKRT). We aimed to characterize cefepime PK in a diverse cohort of critically ill paediatric patients on CKRT. METHODS: Patients were identified from an ongoing pharmacokinetic/pharmacodynamic (PK/PD) study of beta-lactam antibiotics, and were included if they had received at least two cefepime doses in the ICU and were on CKRT for at least 24 h. PK parameters were estimated using MwPharm++ with Bayesian estimation and a paediatric population PK model. Target attainment was assessed as time of free cefepime concentrations above minimum inhibitory concentration (fT > 1× or 4 × MIC). RESULTS: Seven patients were included in the study (ages 2 to 20 years). CKRT indications included liver failure (n = 1), renal failure (n = 4) and fluid overload (n = 2). Total effluent flow rates ranged from 1833 to 3115 (mean 2603) mL/1.73 m2/h, while clearance was 2.11-3.70 (mean 3.0) L/h/70 kg. Effluent flows were lower, but clearance and fT > MIC were similar to paediatric data published previously. Using Pseudomonas aeruginosa MIC breakpoints, all patients had 100% of dosing interval above MIC, but only one had 100% of dosing interval above 4× MIC. CONCLUSIONS: Since most patients failed to attain stringent targets of 100% fT > 4×  MIC, model-informed precision dosing may benefit such patients.

Choline supplementation attenuates experimental sepsis-associated acute kidney injury.

Acute kidney injury (AKI) is common in critically ill patients, and sepsis is its leading cause. Sepsis-associated AKI (SA-AKI) causes greater morbidity and mortality than other AKI etiologies, yet the underlying mechanisms are incompletely understood. Metabolomic technologies can characterize cellular energy derangements, but few discovery analyses have evaluated the metabolomic profile of SA-AKI. To identify metabolic derangements amenable to therapeutic intervention, we assessed plasma and urine metabolites in septic mice and critically ill children and compared them by AKI status. Metabolites related to choline and central carbon metabolism were differentially abundant in SA-AKI in both mice and humans. Gene expression of enzymes related to choline metabolism was altered in the kidneys and liver of mice with SA-AKI. Treatment with intraperitoneal choline improved renal function in septic mice. Because pediatric patients with sepsis displayed similar metabolomic profiles to septic mice, choline supplementation may attenuate pediatric septic AKI.NEW & NOTEWORTHY Altered choline metabolism plays a role in both human and murine sepsis-associated acute kidney injury (SA-AKI), and choline administration in experimental SA-AKI improved renal function. These findings indicate that 1) mouse models can help interrogate clinically relevant mechanisms and 2) choline supplementation may ameliorate human SA-AKI. Future research will investigate clinically the impact of choline supplementation on human renal function in sepsis and, using model systems, how choline mediates its effects.

Recovery after Critical Illness and Acute Kidney Injury.

AKI is a common complication in hospitalized and critically ill patients. Its incidence has steadily increased over the past decade. Whether transient or prolonged, AKI is an independent risk factor associated with poor short- and long-term outcomes, even if patients do not require KRT. Most patients with early AKI improve with conservative management; however, some will require dialysis for a few days, a few weeks, or even months. Approximately 10%-30% of AKI survivors may still need dialysis after hospital discharge. These patients have a higher associated risk of death, rehospitalization, recurrent AKI, and CKD, and a lower quality of life. Survivors of critical illness may also suffer from cognitive dysfunction, muscle weakness, prolonged ventilator dependence, malnutrition, infections, chronic pain, and poor wound healing. Collaboration and communication among nephrologists, primary care physicians, rehabilitation providers, physical therapists, nutritionists, nurses, pharmacists, and other members of the health care team are essential to create a holistic and patient-centric care plan for overall recovery. Integration of the patient and family members in health care decisions, and ongoing education throughout the process, are vital to improve patient well-being. From the nephrologist standpoint, assessing and promoting recovery of kidney function, and providing appropriate short- and long-term follow-up, are crucial to prevent rehospitalizations and to reduce complications. Return to baseline functional status is the ultimate goal for most patients, and dialysis independence is an important part of that goal. In this review, we seek to highlight the varying aspects and stages of recovery from AKI complicating critical illness, and propose viable strategies to promote recovery of kidney function and dialysis independence. We also emphasize the need for ongoing research and multidisciplinary collaboration to improve outcomes in this vulnerable population.

Pharmacokinetics of meropenem in children receiving continuous renal replacement therapy: Validation of clinical trial simulations.

Meropenem is frequently prescribed in critically ill children receiving continuous renal replacement therapy (CRRT). We previously used clinical trial simulations to evaluate dosing regimens of meropenem in this population and reported that a dose of 20 mg/kg every 12 hours optimizes target attainment. Meropenem pharmacokinetics were investigated in this prospective, open-label study to validate our previous in silico predictions. Seven patients received meropenem (13.8-22 mg/kg) administered intravenously every 12 hours as part of standard care. A mean dose of 18.6 mg/kg of meropenem was administered, resulting in a mean peak concentration of 80.1 µg/mL. Meropenem volume of distribution was 0.35 ± 0.085 L/kg. CRRT clearance was 40.2 ± 6.6 mL/(min · 1.73 m(2) ) and accounted for 63.4% of the total clearance of 74.8 ± 36.9 mL/(min · 1.73 m(2) ). Simulations demonstrated that a dose of 20 mg/kg every 12 hours resulted in a time above the minimum inhibitory concentration (%fT > MIC) of 100% in 5 out of 7 subjects, with a %fT > MIC of 93% and 43% in the remaining 2 subjects. We conclude that CRRT contributed significantly to the total clearance of meropenem. A dosing regimen of 20 mg/kg achieved good target attainment in critically ill children receiving CRRT, which is consistent with our previously published in silico predictions.

Cardiac calcifications are more prevalent in children receiving hemodialysis than peritoneal dialysis.

BACKGROUND: Children receiving maintenance dialysis exhibit high cardiovascular (CV) associated mortality. We and others have shown high prevalence of cardiac calcifications (CC) in children with endstage renal disease (ESRD). However, no pediatric study has examined modality difference in CC prevalence. The current study was conducted to assess for a difference in CC prevalence between hemodialysis (HD) and peritoneal dialysis (PD) in children with ESRD. METHODS: 38 patients (19 female, 19 male; mean age 15.5 ± 4.1 years) receiving dialysis (21 HD, 17 PD) were included in the study. CC were assessed by ultrafast gated CT and quantified by Agatston score. Patients received thrice weekly HD for 3 - 3.5 hours or daily continuous cycler PD (CCPD). FGF 23, IL-6, IL-8, and CRP levels were obtained at time of CT. Time-averaged (6 months prior to CT) serum Ca, P, Alb, iPTH, and cholesterol levels were obtained. Patients on aspirin, with evidence of infection, underlying collagen vascular disease were excluded. RESULTS: CC were present in 11/38 patients, but more prevalent in HD vs. PD (9/21 vs. 2/17, p = 0.04). Subjects with CC were older (p = 0.0003), had longer dialysis vintage (p = 0.02) and higher serum phosphorus (p = 0.02) and FGF 23 levels (p = 0.03). HD patients also had significantly higher phosphorus (p = 0.02), FGF 23 (p = 0.009), and IL-8 levels (p = 0.02) when compared to PD patients. Residual renal function was not different between modalities or patients with CC. On a multinomial regression model, modality, and age remained independent associations for CC prevalence. CONCLUSION: We have shown that pediatric patients receiving CCPD have lower CC prevalence conferring lower CV risk. The better control of mineral imbalance in patients receiving PD may play an important role in lower CC prevalence.

High serum phosphorus and FGF 23 levels are associated with progression of coronary calcifications.

BACKGROUND: Coronary calcifications (CC) portend increased mortality in adults receiving hemodialysis (HD), however the risk factors associated with CC progression are not well known in pediatric patients. Our previous cross-sectional studies demonstrated high CC prevalence (31 %) in pediatric patients, which were significantly associated with high serum phosphorus (P), fibroblast growth factor 23 (FGF) levels, dialysis vintage, and low cholesterol. The current study was undertaken to determine and elucidate CC progression in pediatric HD patients. METHODS: A 1-year prospective longitudinal study of 16 pediatric patients (ten male; mean age, 16.9 ± 3 years; range, 10.1-20.4 years) receiving chronic HD was conducted. RESULTS: CC were observed in five of 16 (31.3 %) patients on baseline computed tomogram (CT) scan; 14/16 patients underwent 1-year CT. All patients with initial CC who completed CT at 1 year (3/5) progressed; one patient had new CC and none of the patients had resolved CC. Mean Agatston score increased from 23.4 ± 18.06 HU (baseline) to 169 ± 298.9 HU. Patients with CC progression had higher mean serum P (8.6 ± 1.8 mg/dl vs. 6.3 ± 1.1 mg/dl, p = 0.015) and FGF 23 levels (3,994 ± 860.5 pg/ml vs. 2,327 ± 1,206.4 pg/ml, p = 0.028). Serum P and FGF 23 levels were positively correlated with final Agatston scores (R = 0.65, p = 0.01 for serum P and R = 0.54, p = 0.045 for FGF 23) and change in Agatston scores (R = 0.65, p = 0.01 for serum P and R = 0.52, p = 0.048 for FGF 23). CONCLUSIONS: Our study shows that CC is progressive in pediatric patients receiving HD and that increased serum P and FGF 23 levels are associated with this progression.

Elevated FGF 23 and phosphorus are associated with coronary calcification in hemodialysis patients.

Increased mortality of adult chronic hemodialysis (HD) patients is associated with coronary calcifications (CC), increased serum phosphorus (P), use of calcium (Ca)-containing P-binders, and vitamin D deficiency. Serum concentration of fibroblast growth factor 23 (FGF 23) is markedly elevated in adults receiving dialysis and is independently associated with increased mortality. Although coronary calcifications have been described in pediatric and adult HD patients, no significant association between serum FGF 23 and CC has been reported. In our study, 5/16 patients had CC. Patients with CC were older, had longer dialysis vintage and higher serum P. Serum Ca, total PTH, elemental Ca intake, and calcitriol doses were not different for CC patients. Serum FGF 23 levels were markedly elevated in all patients (mean 4,024, range 874-8,253), but significantly higher in patients with CC (4,247 ± 10,35 vs 2,427 ± 11,92, p = 0.01) and positively correlated with Agatston calcification score (r = 0.69, p = 0.003) and serum P (r = 0.49, p = 0.05). Using multivariate analysis, serum FGF 23 and serum P remained the most significant factors associated with Agatston score. This study confirms the occurrence of CC in pediatric HD patients and is the first to show a significant association between CC and elevated serum FGF 23 in children.

Intravenous paricalcitol for treatment of secondary hyperparathyroidism in children on hemodialysis.

BACKGROUND: Secondary hyperparathyroidism is a common complication in children receiving hemodialysis. Active vitamin D is an effective therapy, but its use is often limited by hypercalcemia and increased calcium x phosphorus (Ca x P) product. Paricalcitol, a selective vitamin D receptor activator, causes less sustained hypercalcemia and increase in Ca x P product than calcitriol and has been used effectively in adult hemodialysis patients. STUDY DESIGN: Double blind, placebo-controlled. SETTING & PARTICIPANTS: Hemodialysis units and pediatric subjects receiving hemodialysis. INTERVENTION: After a washout period of 2 to 6 weeks, 29 subjects aged 5 to 19 years received either paricalcitol or placebo for up to 12 weeks (0.04 mug/kg if initial intact parathyroid hormone [iPTH] level < 500 pg/mL [ng/L]; 0.08 mug/kg if initial iPTH level > 500 pg/mL [ng/L]). The dose was increased by 0.04 mug/kg every 2 weeks until there was a 30% decrease in iPTH level from baseline or calcium level greater than 11 mg/dL (>2.74 mmol/L) or Ca x P product greater than 75 mg(2)/dL(2) (>6.04 mmol(2)/L(2)). OUTCOMES & MEASUREMENTS: Two consecutive 30% decreases from baseline in iPTH levels and safety of paricalcitol, including hypercalcemia and increase in Ca x P product. RESULTS: 60% of the paricalcitol group had 2 consecutive 30% decreases from baseline iPTH levels compared with 21% in the placebo group (P = 0.06). The paricalcitol group had a mean decrease in iPTH level of 164 pg/mL (ng/L), whereas the placebo group had a mean increase of 238 pg/mL (ng/L; P = 0.03). There was no difference from baseline to final visit in calcium, phosphorus, or Ca x P product values in either group. LIMITATIONS: Low power to detect differences in safety between groups and a short-term study. CONCLUSION: Paricalcitol decreased iPTH levels in children receiving hemodialysis with no significant changes in serum calcium, phosphorus, or Ca x P product values during the course of the study.

Intradialytic parenteral nutrition treatment and biochemical marker assessment for malnutrition in adolescent maintenance hemodialysis patients.

Protein-energy malnutrition (PEM) is a significant cause of morbidity and mortality for patients receiving maintenance hemodialysis. Minimal study has evaluated therapeutic options for and biochemical marker assessment of pediatric patient PEM. In 2001, we expanded the indications for intradialytic parenteral nutrition (IDPN) treatment of PEM to all maintenance hemodialysis patients, regardless of etiology, who had a >10% weight loss and were at less than the 90th percentile of ideal body weight. Nine patients received thrice weekly IDPN from 3 to 22 months with minimal side effects. Six patients had weight and body mass index increase, 1 patient stopped losing weight, and 2 patients continued to lose weight during the initial 5 months of IDPN therapy. Cohort subanalysis showed that all patients with organic PEM responded to IDPN therapy, whereas patients with psychosocial causes of PEM did not. The normalized protein catabolic rate increased significantly for patients whose condition responded to IDPN therapy, whereas serum albumin did not change. The current study suggests that IDPN is effective treatment of organic causes of PEM in pediatric patients receiving maintenance hemodialysis and that normalized protein catabolic rate may be superior to serum albumin as a marker of nutrition status. The observation that IDPN was not sufficient to reverse PEM in patients with psychosocial PEM causes should direct caregivers to address the relevant underlying causes as well as to provide intensive nutrition therapy.