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Kidney Diseases in Infants and Children
Kidney Development and Maturation
Nephrogenesis begins in utero at approximately 5 to 6 weeks’ gestation and continues until nephron formation is complete at approximately 35 weeks’ gestation, although significant functional changes continue in the postnatal period. Fetal urine production commences prior to the end of the first trimester, and by the third trimester becomes the primary component of the amniotic fluid, which is essential for normal pulmonary development. Although the full-term newborn has the same number of nephrons per kidney as an adult (approximately 1 million), the glomeruli and tubules of the infant kidney are relatively immature. Key molecular transcription factors involved with kidney embryogenesis include the Wilms tumor suppressor gene 1 (WT1), fibroblast growth factor 2 (FGF2), vascular endothelial growth factor (VEGF), bone morphogenetic protein 7 (Bmp7), paired-box gene 2 (pax2), and wingless-related (WNT4).
The GFR of a newborn is only around 20 mL/min/1.73 m 2 in the first few days after birth, rising to approximately 40 mL/min/1.73 m 2 near the end of the first week of life, and gradually reaching adult levels of 100 to 130 mL/min/1.73 m 2 by 2 years of age. The changes in GFR that occur after birth are the result of increased cardiac output and mean arterial blood pressure, a decrease in renal vascular resistance, and an increased surface area available for glomerular filtration. Renal blood flow is only 3%–7% of the cardiac output in the fetus, eventually increasing to 25% of cardiac output by 2 years old. Concomitantly, blood flow is redistributed from the cortical-juxtamedullary glomeruli, which are larger but fewer in number than the more numerous glomeruli in the cortex.
In term neonates, the low GFR results in a serum creatinine (sCr) level that reflects the maternal serum creatinine value for the first 24 to 48 hours of life and gradually settles to approximately 0.4 mg/dL at the fifth to seventh day of life. The GFR in preterm infants is significantly lower than in term infants ( Table 46.1 ). The full-term newborn kidney measures 4 to 5 cm in length and continues to grow until reaching 10 to 12 cm by adolescence. Although the glomeruli do grow in size, most of this renal parenchymal expansion results from tubular growth and maturation and from an increased volume of the tubulointerstitial compartment.
TABLE 46.1
Normal GFR in Premature and Full-Term Neonates, Children, and Adolescents
| Age | Mean GFR ± SD (mL/min/1.73 m 2 ) |
| 1 week old | Preterm: 15 ± 6Term: 41 ± 15 |
| 2–8 weeks old | Term: 66 ± 25Preterm: 28.7 ± 14 |
| >8 weeks old | Term: 96 ± 22Preterm: 51.4 ± 16 |
| 2–12 years old | 133 ± 27 |
| 13–21 years old | Male: 140 ± 30Female: 126 ± 22 |
Preterm includes 29–34 WGA (weeks gestational age).
Adapted from Denis F. Geary DF, Schaefer F. Comprehensive Pediatric Nephrology. Philadelphia, Elsevier, 2008.
The neonatal renal tubules have a limited ability to concentrate or dilute the urine in response to different environmental or dietary conditions. Growing term infants maintain a positive sodium balance; in contrast, preterm infants tend to have a negative sodium balance in the first few weeks after birth due to immature reabsorption capacity in the distal tubules and intestines, and they require 3–5 mEq of sodium/kg/day for the first several weeks of life. The fractional excretion of sodium (FeNa) is highest during the first week of life, decreasing to adult ranges of <0.4% by 1 month of age. Additionally, the ability of the neonatal proximal tubule to reabsorb filtered HCO−3
Acute Kidney Injury
Introduction
Information specifically pertaining to pediatric acute kidney injury (AKI) is included in this section; AKI is covered in greater detail in Chapter 31. Despite its widespread use, serum creatinine is a poor marker of kidney function, particularly in the setting of pediatric AKI, as a consequence of its variability due to the influence of age, gender, body habitus, and nutritional status on the level. The use of serum creatinine as a biomarker reflective of kidney function remains particularly challenging in the setting of neonatal AKI, due to the dynamic nature of serum creatinine as a result of physiological changes and the higher prevalence of AKI due to nephrotoxic drug exposures, which tend to manifest as changes in urine output before changes in serum creatinine occur. An ongoing area of research is the study of novel biomarkers useful in the prediction of AKI.
Diagnosis
Substantial variability exists in the reported incidence, morbidity, and mortality estimates for pediatric AKI due to the use of multiple definitions. Significant effort has been made to standardize and validate pediatric AKI consensus definitions, and the most widely used are the Pediatric Risk, Injury, Failure, Loss and End-stage Renal Disease (pRIFLE) and the Kidney Disease: Improving Global Outcomes (KDIGO) consensus classifications ( Table 46.2 ). The RIFLE criteria were developed in 2004 in critically ill adults. RIFLE classifies AKI into five distinct categories based upon the magnitude and direction of change in creatinine, urine output, and duration of kidney replacement therapy (KRT). This classification system was subsequently modified for the pediatric population (pRIFLE) by the use of an estimated creatinine clearance based on the original Schwartz formula to quantify the change in GFR (rather than absolute changes in serum creatinine used in the adult version). Notably, the original Schwartz formula was derived based on serum creatinine assayed using the modified Jaffe method rather than the preferred enzymatic methodology, and this definition may also be problematic if a baseline creatinine clearance is unknown. In addition, all children with an estimated creatinine clearance less than 35 mL/min/1.73 m 2 are placed in the “pRIFLE-F” category (kidney failure class) instead of waiting for the serum creatinine concentration to reach 4 mg/dL, as in adults.
TABLE 46.2
Acute Kidney Injury Definitions in Children
| pRIFLE | KDIGO | nKDIGO a | |||
| Stage | Criteria | Stage | Criteria | Stage | Criteria |
| Risk (R) | eCrCl ↓ 25%UOP <0.5 mL/kg/h × 8 h | 1 | ↑ SCr ≥0.3 mg/dL b or ↑ SCr ≥1.5–2 × c UOP <0.5 mL/kg/h × 8 h | 1 | SCr rise ≥0.3 mg/dL b |
| Injury (I) | eCrCl ↓ 50%UOP <0.5 mL/kg/h × 16 h | 2 | ↑ SCr ≥2–3 ×UOP <0.5 mL/kg/h × 16 h | 2 | Increase in SCr by 150% to <200% from previous trough level d |
| Failure (F) | eCrCl ↓ 75% or CrCl<35 mL/min/1.73 m 2 UOP <0.5 mL/kg/h × 24 h or anuria for 12 h | 3 | ↑ SCr ≥3–4 × or SCr >4 (and meets criteria for AKI) or RRT initiated or eGFR <35 in patients <18 yoUOP <0.5 mL/kg/h × 24 h or anuria × 12 h | 3 | Increase in SCr by 200% to <300% from previous trough level or SCr ≥ 2.5 mg/dL |
| Loss (L) | Failure >4 weeks | N/A | NA | ||
| End-stage kidney disease (E) | Failure >3 months | N/A | NA | ||
a Should be used in children <120 days
d Reference Scr defined as the lowest previous SCr value AKI , Acute kidney injury; CrCl , creatinine clearance; KDIGO , Kidney Disease: Improving Global Outcomes; RRT , renal replacement therapy; SCr , serum creatinine; UOP , urine output. Adapted from Akcan-Arikan A, Zappitelli M, Loftis LL, et al. Modified RIFLE criteria in critically ill children with acute kidney injury. Kidney Int . 2007;71:1028–1035; Mehta R, Kellum J, Shah S, et al: Acute Kidney Injury Network: report of an initiative to improve outcomes in acute kidney injury. Crit Care . 2007;22:R31; Kidney Disease: Improving Global Outcomes (KDIGO) Acute Kidney Injury Work Group. KDIGO clinical practice guideline for acute kidney injury. Kidney Int Suppl . 2012;2:1–138, and Jetton JG, Ashkenazi DJ . Curr Opin Pediatr . 2012;24(2):191.
The 2012 KDIGO AKI Consensus Conference definition is recommended for the definition and staging of pediatric AKI and to guide clinical care. The KDIGO definition includes a 0.3 mg/dL increase in serum creatinine over 48 hours or a urine volume ≤0.5 mg/kg/hr for 6 hours. The diagnostic inclusion criteria of a serum creatinine elevation ≥1.5 times baseline within the prior 7 days allows for the inclusion of patients with late-onset AKI. Similarly, interest in standardizing the definition for neonatal AKI has expanded in the last few years, although, as of yet, there remains no accepted consensus definition for AKI in this patient population. However, modified KDIGO criteria (nKDIGO) for the diagnosis of AKI in neonates have been introduced and are based on increases in the serum creatinine concentration (see Table 46.2 ). Although epidemiological data vary widely, as discussed above, there is growing awareness that the incidence of pediatric AKI is increasing, particularly in cohorts of critically ill children in the intensive care unit or in those children with comorbid conditions, such as congenital heart disease, cancer, and hematopoietic stem cell transplantation. In all instances, the development of AKI is associated with an increased risk for mortality and adverse outcomes.
At the time of an acute clinical presentation, it may be difficult to distinguish AKI from CKD without imaging studies, evaluation of and laboratory testing for associated complications that are more common in CKD than AKI, or possibly a kidney biopsy. Urine volume in AKI is variable; patients may be anuric, oliguric, or polyuric (especially in neonates). Short stature, CKD-mineral bone disorder (CKD-MBD), delayed puberty, normocytic anemia, and hyperparathyroidism all suggest long-standing CKD rather than AKI.
Kidney function declines when adequate blood supply and oxygenation, parenchymal integrity, and/or patency of the urinary collecting system are interrupted. Consequently, AKI can be viewed as being caused by prerenal, intrinsic kidney, or postrenal factors, although substantial overlap and multifactorial etiologies can exist, particularly in hospitalized children. The most common etiologies of AKI in children are listed in Table 46.3 . The likelihood of recovery from AKI depends, in part, on the presence or absence of urine output, the quantity of urine output, the duration of anuria, and the underlying cause and severity of kidney injury. Quantifying the urine output is essential, as this predicts the clinical course and may aid in identifying the underlying insult. Oliguria is defined as a urine output less than 1 mL/kg/hr in infants and young children and less than 0.5 mL/kg/hr for 6 hours in older children. Children with nonoliguric AKI have lower complication rates and higher survival rates than those with anuric or oliguric AKI.
TABLE 46.3
Most Common Etiologies of AKI in Children
| Prerenal AKI | Intrinsic AKI | Postrenal AKI * |
Intravascular volume contraction
|
Prolonged prerenal AKIVascular disease
Glomerular disease
Tubulointerstitial disease
|
Much rarer cause of AKI (unless patient has a solitary kidney either from renal agenesis, nephrectomy, or transplantation)Complete urethral or bladder neck obstruction or bilateral ureteral obstruction
|
Decreased effective circulating blood volume
Altered intrarenal hemodynamics
|
||
* Postrenal conditions are very rare causes of AKI in children unless the child has a solitary kidney, either from renal agenesis, nephrectomy or transplantation.
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