e1 References 1 Dharnidharka VR, Fiorina P, Harmon WE Kidney transplantation in children N Engl J Med 2014;371(6) 549 558 2 Israni AK, Salkowski N, Gustafson S, et al New national allocation policy fo[.]
e1 References Dharnidharka VR, Fiorina P, Harmon WE Kidney transplantation in children N Engl J Med 2014;371(6):549-558 Israni AK, Salkowski N, Gustafson S, et al New national allocation policy for deceased donor kidneys in the United States and possible effect on patient outcomes J Am Soc Nephrol 2014;25(8):1842-1848 Hart A, Smith JM, Skeans MA, et al OPTN/SRTR 2017 annual data report: kidney Am J Transplant 2019;19(suppl 2):S19-S123 Smith JM, Martz K, Blydt-Hansen TD Pediatric kidney transplant practice patterns and outcome benchmarks, 1987-2010: A report of the North American Pediatric Renal Trials and Collaborative Studies Pediatr Transplant 2013;17:149-157 Rodrigue JR, Schold JD, Mandelbrot DA The decline in living kidney donation in the United States: Random variation or cause for concern? Transplantation 2013;9:767-773 Axelrod DA, McCullough KP, Brewer ED, Becker BN, Segev DL, Rao PS Kidney and pancreas transplantation in the United States 199-2008: the changing face of living donation Am J Transplant 2010;10:987-1002 Hooper DK, Fukuda T, Gardiner R, et al Risk of tacrolimus toxicity in CYP3A5 nonexpressors treated with intravenous nicardipine after kidney transplantation Transplantation 2012;93(8):806-812 Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group KDIGO clinical practice guideline for the care of kidney transplant recipients Am J Transplant 2009;9(suppl 3):S1– S157 Rosenberg AZ, Kopp JB Focal segmental glomerulosclerosis Clin J Am Soc Nephrol 2017;12(3):502-517 10 Trachtman R, Sran SS, Trachtman H Recurrent focal segmental glomerulosclerosis after kidney transplantation Pediatr Nephrol 2015;30(10):1793-1802 e2 Abstract: Transplantation is the treatment of choice in children with end-stage renal disease due to the beneficial impact on growth and development and quality of life The early posttransplantation phase requires close monitoring by a combined surgical and medical transplant team Key Words: Kidney transplantation, immunosuppression, delayed graft function 77 Renal Pharmacology JENNA R NICKLESS, VICTORIA CHADWICK, AND HEIDI YU PEARLS • • • The kidney is the primary elimination pathway for the majority of medications Thus, understanding appropriate dosing for patients in acute and chronic renal impairment is imperative to avoid adverse events and therapeutic failure Kidney disease not only affects renal elimination of medications but can also affect absorption, metabolism, and protein binding in acute and chronic kidney disease Intravenous fluid therapy to maintain adequate urine output has been shown to be effective for the prevention of acute kidney injury but not for treatment The kidney is an important target for drug therapy in the critically ill child and plays a central role in many physiologic processes that have a direct impact on drug action and disposition Key functions of the kidney include elimination of endogenous and exogenous substances from the body, including drugs and drug metabolites, as well as the maintenance of body fluid composition and volume There are complex glomerular and tubular mechanisms affecting these key functions that are directly and indirectly influenced by the function of other organs As one of the primary routes of medication and metabolic waste elimination, the kidneys are highly susceptible to toxicity and insult leading to renal failure The inability of the kidney to perform such key functions in renal failure may have deleterious effects on the function of other vital organs and physiologic systems Alteration in kidney function significantly affects drug disposition—including changes in absorption, distribution, metabolism, and elimination.1–4 With a significant number of renally cleared medications being used in the intensive care unit (ICU), special attention must be paid to kidney function and the effect of impaired renal function on drug elimination and metabolism in order to avoid medication toxicities or therapeutic failure Kidney Function and Drug Disposition Renal function in neonates, infants, and children is affected by a multitude of factors, including—but not limited to—development and maturation, underlying kidney disease and comorbidities, medications, and renal replacement therapy (RRT).4 Neonates have decreased renal function at birth, with the glomerular filtration rate (GFR) increasing to 20 to 30 mL/min per m2 in term • • • Medication dosing in renal replacement therapy is dependent on the medication properties, intrinsic renal clearance, and the renal replacement prescription Loop diuretics are dose dependent More diuresis is achieved at higher doses until the “ceiling dose” is reached Continuous infusion of loop diuretics can result in a steadier diuretic effect than intermittent high doses while also avoiding the high and low serum concentrations associated with toxicity and resistance neonates at approximately weeks of life and reaching adult levels at about months of age.5 Critically ill pediatric patients are at an increased risk of altered renal function Thus, it is important to understand how renal failure affects medication pharmacokinetics Renal elimination of medications is achieved through glomerular filtration, tubular secretion, reabsorption, and characterization of transporters on the renal tubule epithelium.3 GFR is estimated with the measurement of the rate that the kidney removes a substance from the blood (i.e., renal clearance) For drugs and drug metabolites that are primarily eliminated by glomerular filtration, such as gentamicin, the rate of elimination mirrors kidney function As such, when kidney function declines, the reduced drug elimination results in drug accumulation in the body (Fig 77.1) Decreased GFR is a hallmark feature of both chronic kidney disease (CKD) and acute kidney injury (AKI); it is important to identify the most accurate measurement of GFR in pediatric patients to appropriately adjust medication dosing (see Chapter 71).5–7 Although GFR is the most commonly used marker of renal function for medication dosing, renal transporters also play an important role in elimination of drugs and their metabolites.3 Albumin and other large molecules not pass through the glomeruli Thus, in general, drugs with high molecular weight and drugs bound to plasma proteins (e.g., furosemide) are not effectively removed by glomerular filtration but may be efficiently eliminated by the kidney through renal tubular secretion Active transport of drugs cleared by secretion or reabsorption (e.g., ganciclovir and famotidine) also decreases in acute and chronic renal impairment It is important to assess dosing of medications that are eliminated not only through filtration but also through secretion or reabsorption in patients with impaired renal function.2,3 937 938 S E C T I O N V I I Pediatric Critical Care: Renal Serum gentamicin concentration (µg/mL) 16 14.1 µg/mL 14 12 7.4 µg/mL 10 Drug Dosing in Kidney Disease 6.5 µg/mL 0.5 µg/mL 0 10 20 30 Time (h) 40 50 60 • Fig 77.1 Gentamicin time-concentration profile in a 5-year-old child receiving 2.5 mg/kg intravenously every hours The solid line represents the plasma concentration-time profile in a child with normal kidney function (e.g., 120 mL/min/1.73 m2), and the dashed line represents the plasma concentration-time profile in a child with a creatinine clearance of 30 mL/min/1.73 m2 Decreased renal elimination of drugs and drug metabolites is the most obvious consequence of altered renal function However, renal failure and associated coexisting conditions may also affect drug absorption, distribution, and metabolism (Table 77.1).1–4 Delayed gastric emptying, changes in gut motility, and modifications in gastric pH found in patients with renal disease can alter absorption and bioavailability of drugs.2 CKD has been shown to decrease plasma protein binding due to hypoalbuminemia, leading to increased free unbound fraction of drug and, ultimately, increasing patients’ drug exposure.2 Hydrophilic drugs may be affected in patients in renal failure due to edema, increased total body water, and an increase in volume of distribution—thus, decreasing drug exposure.4 Renal failure is also associated with decreased activity of hepatic and gastrointestinal drug-metabolizing TABLE Potential Alterations of Drug Distribution 77.1 in Kidney Failure PK Parameter Effect Proposed Mechanism Absorption g Edema of GI tract, uremic N/V, delayed gastric emptying Drug interaction: phosphate binders, H2 blockers Altered GI pH Distribution h Increased unbound drug fraction Hypoalbuminemia (nephrosis, malnutrition) Uremic changes in albumin structure Metabolism g h Inhibition of CYP-450 metabolism (liver, intestine, kidney) Drug interaction Direct inhibition by “uremic” milieu Induced CYP-450 metabolism Excretion enzymes and transporters, leading to decreased clearance of nonrenally eliminated drugs.3 Considering that renal failure can influence medication distribution in a multitude of ways, it is important to review all medications, including those not cleared renally, for safety and efficacy in pediatric patients with renal failure g Decreased GFR Decreased tubular secretion Increased tubular reabsorption CYP-450, Cytochrome P-450; GFR, glomerular filtration rate; GI, gastrointestinal; N/V, nausea and vomiting; PK, pharmacokinetic Determining safe and effective individualized dosing regimens for critically ill children begins with an estimation of the child’s kidney function with measurement of serum creatinine, calculating the eGFR, and monitoring urine output The next step is to evaluate the effect of kidney failure on the drug disposition characteristics for all of the drugs prescribed to the child A systematic approach to individualized drug therapy in children with kidney failure will maximize therapeutic efficacy and minimize toxicity (Box 77.1) Available literature for drug dosing in pediatric kidney failure is limited; thus, the majority of dose recommendations are extrapolated from adult literature Tertiary drug dosing references—such as Lexicomp, Micromedex, and Drug Prescribing in Renal Failure—can be a starting point to determine the optimal dose for patients Due to pediatric and critically ill patients’ changes in pharmacokinetics and pharmacodynamics, critically ill children with impaired kidney function are at an increased risk of under- or overdosing medications.9,10 It is important to recognize that pharmacokinetics and pharmacodynamics are different in patients with CKD versus those with AKI Patients with AKI may not show renal failure through endogenous biomarkers during the initial stages Thus, other signs of AKI are important to assess (e.g., urine output and organ perfusion) Endogenous biomarkers such as serum creatinine and cystatin C are good biomarkers when at steady state, such as in CKD However, they are not as reliable in AKI when renal function is dynamic (see also Chapter 71).10 When drugs are adjusted for renal impairment, they should always be adjusted based on renal and nonrenal clearance of the drug, the degree of renal impairment, and the potential nephrotoxicity risk of the drug.9 The development of drug dosage adjustments for patients in CKD is based on the desired exposure goal at steady state for the specific medication.11 Certain drugs are dosed based on a goal to keep an average steady state of drug concentration above the minimum inhibitory concentration (MIC; e.g., cephalosporin antibiotics) and others are dosed based on the relationship of peak drug concentration to effect (e.g., gentamicin).11,12 In medications that are dependent on time above MIC, the dose may be decreased but dosing frequency kept the same depending on the degree of renal failure For medications that are dependent on peak drug concentration effect, the dose may stay similar but the dosing interval will be lengthened to keep the peak concentration similar and avoid accumulation • BOX 77.1 Guidelines for Drug Dosing in Kidney Failure 3 4 5 Estimate the glomerular filtration rate Determine the percentage of drug eliminated by the kidney Adjust the medication dose or frequency of the dosing interval Monitor therapeutic response and adverse reactions Perform therapeutic drug monitoring when available CHAPTER 77 Renal Pharmacology Drug Dosing in Dialysis Gentamicin serum concentration (µg/mL) 939 7.3 µg/mL 3.6 µg/mL 1.9 µg/mL 0.5 mcg/mL 0 10 20 30 40 50 60 Time (h) 70 80 90 100 • Fig 77.2 Gentamicin concentration-time profile in a child with a creatinine clearance of 30 mL/min/1.73 m2 receiving intravenous gentamicin The dashed line represents the plasma concentration-time profile when the dose remains unchanged (2.5 mg/kg), and the dosing interval is adjusted to 32 hours (normal dosing interval [8-hour] dosing adjustment factor [0.3]) The solid line represents the plasma concentration-time profile if the dosing interval remains unchanged (8 hours) and the dose is adjusted to 0.625 mg/kg (normal dose [2.5 mg/kg] dosing adjustment factor [0.3]) Therapeutic drug monitoring should be used when able to ensure therapeutic efficacy and decrease toxicity For example, when assessing gentamicin dosing, the dosing interval is increased and the size of the drug dose remains unchanged (Fig 77.2, dashed line); the steady-state peak and trough drug concentration are similar to those seen in children with normal renal function However, there is a prolonged period when the serum gentamicin concentration is above and below the average steady-state concentration This dosing regimen may be inappropriate for drugs that should be maintained at a relatively stable serum concentration, such as cephalosporins or antihypertensive medications When the goal is maintenance of a serum concentration close to the steady-state level throughout the dosing interval, decreasing the size of the dose while maintaining the normal dosing interval will decrease the variation between the serum drug concentration peak and trough (see Fig 77.2, solid line) Critically ill children with AKI pose different challenges to medication dosing Patients with AKI commonly have an increase in volume of distribution (Vd) due to a positive fluid balance in the initial stages Knowing whether the drug is hydrophilic or lipophilic and knowing the drug-specific Vd is important to understanding whether a loading dose may be required.9 Hydrophilic drugs have a higher Vd in patients who are fluid positive in the early stages of AKI and thus may require higher initial dosing but will eventually have slower clearance Protein binding can also be variable in patients with renal dysfunction; thus, it is important to know whether a medication is highly protein bound For medications that are highly protein bound, patients will have an increase in unbound or free drug due to decreased albumin binding, leading to a higher overall exposure to the medication.9 Critically ill pediatric patients in renal failure are at increased risk of therapeutic failure or medication toxicity Therefore, close attention to patient clinical status and medication pharmacokinetics is essential when dosing medications RRT is used in approximately 5% of pediatric intensive care unit (PICU) patients.13 Predominant diagnoses necessitating RRT are AKI, electrolyte abnormalities, volume overload, and toxin removal.14,15 The most common modality of RRT used in the ICU setting is continuous renal replacement therapy (CRRT), followed by intermittent hemodialysis (IHD), and, to a lesser extent, peritoneal dialysis (PD) Refer to Chapter 75 for more complete information on dialysis modalities and indications Drug elimination in children receiving dialysis is a composite of nonrenal drug elimination, residual kidney elimination, and extracorporeal removal by dialysis Efficiency of a given dialysis modality to eliminate a drug depends on the physiochemical characteristics of the drug and the form and characteristics of the dialysis procedure Less than 20% of medications frequently used in children requiring CRRT have dosing guidance across all age groups.16 Most dosing is extrapolated from adult literature or studied in select age groups in the pediatric population In general, highly protein-bound drugs and drugs with a large Vd are not removed well by dialysis There are three primary types of CRRT used in the ICU: continuous venovenous hemofiltration (CVVH), continuous venovenous hemodialysis (CVVHD), and continuous venovenous hemodiafiltration (CVVHDF) It is important to distinguish among CRRT therapies, as the effect on medication clearance varies between each type CVVH relies on convection to remove medications, allowing clearance of larger drug molecules (#30,000 Da).17 CVVHD uses diffusion to clear medications, which only allows for clearance of small drug molecules (#500 Da).17 CVVHDF uses a combination of both convection and diffusion Correct dosing of medications in ICU patients on CRRT can be extremely challenging due to the combination of altered pharmacokinetics of critical illness, the dynamic nature of a CRRT prescription, and the variability found in medication dosing resources.13 Many tertiary medication dosing resources not specify the CRRT modality in their dosing recommendation and instead use the umbrella term CRRT These resources not account for the modality-specific differences in drug clearance, range of dialysis prescription, or intrinsic renal clearance of the patient With sepsis being a major reason for AKI in the ICU, many recent studies have highlighted the risks of underdosing antimicrobials when using tertiary medication dosing resources.11,13,15,18 One study found subtherapeutic antibiotic dosing rates as high as 60%.18 For example, per Pediatric Lexicomp, CRRT dosing for cefepime is 50 mg/kg per dose every 12 hours regardless of age.19 Recently, Stitt et al published a small study of four pediatric patients receiving CVVHDF who received cefepime monitoring levels The cefepime dose was fairly consistent around 50 mg/kg per dose but the frequency of administration varied from every hours to every 12 hours.15 Only one patient in their study reached the pharmacodynamic goal of percent of free drug greater than times the minimum inhibitory concentration (% fT MIC) This study highlights the variability of CRRT prescriptions on medication clearance and, while this study was not large enough to recommend a clear dosing regimen, it also highlights the importance of individualizing drug dosing based on the pharmacokinetic and pharmacodynamic properties of the medication as well as the dialysis prescription.15 In order to accurately dose a medication in CRRT, a practitioner must understand the physicochemical characteristics of ... the minimum inhibitory concentration (% fT MIC) This study highlights the variability of CRRT prescriptions on medication clearance and, while this study was not large enough to recommend a clear... when the serum gentamicin concentration is above and below the average steady-state concentration This dosing regimen may be inappropriate for drugs that should be maintained at a relatively stable