Acute Kidney Injury and Chronic Kidney Disease

90 

Acute Kidney Injury and Chronic Kidney Disease DAVID ASKENAZI, DAVID SELEWSKI, LAUREL WILLIG, AND BRADLEY A. WARADY

KEY POINTS • Acute kidney injury (AKI) is common in critically ill neonates. AKI affects survival, hospital expenditures, and long-term outcomes, independent of severity of illness and comorbidities. • Renal development continues until 34 weeks’ gestation. Neonatal intensive care unit graduates, especially those with AKI, premature infants, and those with intrauterine growth retardation, are at risk for long-term chronic kidney disease (CKD). • Clinical sequelae of CKD include anemia, acidosis, electrolyte abnormality, growth restriction, renal osteodystrophy, fluid overload, hypertension, and uremia. Attention to these complications is critical to optimizing long-term outcomes. • Long-term survival of neonates with end-stage renal disease (ESRD) appears to be approaching that of older infants and young children, but they continue to have higher morbidity and mortality due to infectious and cardiovascular complications. • Renal replacement therapy can be performed in neonatal patients and is likely to improve outcomes in children with AKI and those with ESRD.

Acute Kidney Injury Acute kidney injuey (AKI) is characterized by a sudden impairment in kidney function, which may result in dysregulation of fluid balance, acid–base, electrolytes, and nitrogenous waste products. AKI has supplanted the term acute renal failure as the accepted terminology to describe acute changes in renal function across medicine, including neonatology (Mehta et al., 2007; Selewski et al., 2015). The term injury highlights the spectrum of organ injury and differentiates a damaged organ from an organ that has dysfunction. The main impetus to change the terminology was to highlight early detection, as even small changes in kidney function (rise of serum creatinine [SCr] by 0.3 mg/dL) can be associated with adverse outcomes. AKI is now staged into mild, moderate, and severe, based on either the most severe oliguria or rise in SCr. In 2005, the introduction of an empiric, categorical staged AKI defintion for adults dramatically changed the field of AKI as it brought consensus and enabled comparison between studies (Hoste and Kellum, 2006). In 2007, modifications were made based on improved understanding from observational data (Mehta et al., 2007). Additional modificatons occurred in 2012, and currently Kidney Diseases: Improving Global Outcomes (KDIGO) defines 1280

AKI when there is a rise in SCr of 0.3 mg/dL over 48 hours or a decrease in urine output (UOP) occurs. The development and utilization of standardized definitions of AKI have created commonality in defining AKI and clearly show that incremental degrees of AKI independently impact survival after correcting for comorbidities, complications, and severity of illness in neonatal (Selewski et al., 2015), pediatric (Akcan-Arikan et al., 2007), and adult studies (Hoste and Kellum, 2006). A neonatal classification of AKI used to define AKI in critically ill neonates (Table 90.1) parallels the KDIGO adult defintion and uses the lowest SCr as a baseline for subsequent SCr values. In April 2013, neonatologists and pediatric nephrologists participating in the NIDDK workshop carefully scrutinized this definition. They concluded that, at that time, this definition offered a reasonable starting point and would allow for consistency throughout studies yet warned that rigorous evaluation of the definition was necessary. Importantly, SCr-based AKI definitions do not detect kidney damage; instead they document changes in kidney function. Although SCr is the most common method of documenting changes in kidney function, it has significant shortcomings, including: • SCr does not change until 25%–50% of the kidney function has been lost, and thus it may take 48–72 hours for SCr levels to rise after an insult (Brion et al., 1986). • At a lower glomerular filtration rate (GFR), SCr will overestimate renal function due to tubular secretion (Brion et al., 1986). • SCr varies by muscle mass, hydration status, sex, age, and gender. • Different measurement methods (Jaffee reaction vs enzymatic) produce different values, and medications and bilirubin can affect SCr measured by the Jaffee method (Rajs and Mayer, 1992; Lolekha et al., 2001). • Once a patient receives dialysis, SCr can no longer be used to assess kidney function, since SCr is easily dialyzed. Additional problems specific to neonates with using SCr as a measure of AKI include: • SCr measurements in the first few days of life reflect the mother’s levels; thereafter, the distribution of normal SCr values varies greatly, dependent on level of prematurity and age (Gallini et al., 2000) (Fig. 90.1). • Normal nephronogenesis in the healthy fetus continues until 34 weeks of gestation when the number of nephrons, 1.6 to 2.4 million, approximates that of an adult (Abrahamson, 1991).

CHAPTER 90  Acute Kidney Injury and Chronic Kidney Disease  1281



Dependent on degree of prematurity, GFR steadily improves from 10–20 mL/min per 1.73 m2 during the first week of life to 30–40 mL/min per 1.73 m2 by 2 weeks after birth, concomitant with alterations in renal blood flow. GFR improves steadily over the first few months of life (Brion et al., 1986) (Table 90.2). An alternative to SCr is the measurement of serum cystatin C levels. Cystatin C is a low-molecular-weight protein that is freely filtered in the glomerulus and not resorbed. Cystatin C is a member of the cystatin superfamily of cysteine protease inhibitors, and is made by all nucleated cells within the body at a relatively constant rate. Cystatin C does not cross the placental barrier and, as a result of this, does not reflect maternal values. Serum cystatin C remains a functional biomarker that has shown promise in neonates but warrants further study. As a functional biomarker serum, cystatin C has been shown to provide more accurate assessments of neonatal renal function than SCr. Studies evaluating the potential role of cystatin C in neonates have been recently extensively reviewed (Filler and Lepage, 2013). TABLE 90.1 

As mentioned previously, SCr, UOP, and cystatin C are markers of kidney function, not damage. Over the last decade, there has been a significant amount of work to identify urine and serum biomarkers of AKI. Such biomarkers include urine and serum neutrophil gelatinase-associated lipocalin (NGAL), urine interleukin-18, kidney injury marker-1, and liver fatty acid-binding protein, originally identified and studied in neonates undergoing cardiopulmonary bypass (Mishra et al., 2005; Parikh et al., 2006) (Fig. 90.2). These markers will ideally show acute damage hours after an insult, distinguish between different causes and locations of tissue injury, and prognosticate clinical outcomes. In neonates, it is important to note these urine biomarkers will vary based on gestational age (GA), day of life, and gender (Saeidi et al., 2015). Urine biomarkers of AKI have been tested and show promise in the ability to predict AKI in very low birth weight (VLBW) (Askenazi et al., 2011) and near-term/term neonates (Tanigasalam et al., 2016). Future work is needed before these biomarkers can be used at the bedside. Once we can reliably identify AKI early in the disease process, preventive/therapeutic interventions can be studied to improve outcomes in neonates with AKI.

Definition of Neonatal Acute Kidney Injury

Stage

Serum Creatinine

Urine Output/24 Hours

0

No change in serum creatinine or rise <0.3 mg/dL

>1 mL/kg per hour

1

SCr rise ≥0.3 mg/dL rise from baseline or SCr rise ≥1.5–1.9 mg/dL × baseline SCra

>0.5 and ≤1 mL/kg per hour

2

SCr rise ≥2.0–2.9 mg/dL × baseline SCra

>0.3 and ≤0.5 mL/kg per hour

3

SCr rise ≥3 × baseline SCra or SCr ≥2.5 mg/dLa or Receipt of dialysis

≤0.3 mL/kg per hour

TABLE 90.2 

Baseline SCr = lowest SCr prior to measurement. SCr, Serum creatinine. a

Insulin Clearance Glomerular Filtration Rate in Healthy Premature Infants

Age

mL/min per 1.73 m2

1–3 days

14.0 ± 5.0 (Brion et al., 1986)

1–7 days

18.7 ± 5.5 (Guignard et al., 1975)

4–8 days

44.3 ± 9.3 (Barnett et al., 1948)

3–13 days

47.8 ± 10.7 (Barnett et al., 1948)

1.5–4 months

67.4 ± 16.6 (Barnett et al., 1948)

8 years

103 ± 12 (Vanpee et al., 1992)

Adapted from Schwartz GJ, Furth SL. Glomerular filtration rate measurement and estimation in chronic kidney disease. Pediatr Nephrol. 2007;22:1839–1848.

150.0 140.0 GA <27 wk GA 27–28 wk GA 29–30 wk GA 31–32 wk

Serum creatinine (µM/L)

130.0 120.0 110.0 100.0 90.0 80.0 70.0 60.0 50.0 40.0 30.0

• Fig. 90.1

0

1

2

3

4

5

6

7 10 Days of life

17

24

31

38

45

52

  Serum creatinine concentrations (µM/L) during the first days of life, with values given as means and standard error for infants born at different gestational ages. GA, Gestational age.

1282 PART XV I I  Renal and Genitourinary Systems

Epidemiology

250 IL-18 (pg/mL) AKI

Mean biomarker level

200

150

100

NGAL (ng/mL) AKI

50 IL-18 (pg/mL) no AKI NGAL (ng/mL) no AKI

2

0

4

6

12

24

48

Time after cardiopulmonary bypass (h)

• Fig. 90.2

  Mean values of urine interleukin-18 (pg/mL) and neutrophil gelatinase-associated lipocalin (ng/mL) over the first hours after cardiopulmonary bypass in infants who develop acute kidney injury (50% increase in serum creatinine) compared with those who did not develop acute kidney injury. AKI, Acute kidney injury; IL-18, interleukin-18; NGAL, neutrophil gelatinase-associated lipocalin.

TABLE 90.3 

Critically ill neonates experience multiple risks for the development of AKI during their hospitalization, including infections, nephrotoxic medications, and hypotension. The exact incidence of neonatal AKI is difficult to quantify because infants commonly have nonoliguric renal failure and may therefore may not be screened with SCr for AKI. Utilizing legacy definitions of AKI, such as SCr greater than 1.5 mg/dL or initiation of renal replacement therapy (RRT), previous studies had estimated the incidence of neonatal AKI to be 8%–24% with associated mortality rates between 10%–61% (Andreoli, 2004). Over the past decade there has been a significant amount of research utilizing modern staged definitions of AKI to evaluate the incidence and impact of AKI in a number of high-risk patient populations, including neonates with perinatal asphyxia or necrotizing enterocolitis (NEC), those undergoing cardiac surgery or receiving extracorporeal membrane oxygen (ECMO), sick term/premature infants, low birth weight babies, and general neonatal populations (Table 90.3).

Infants With Perinatal Asphyxia Infants with perinatal asphyxia represent a population known to be at high risk for the development of AKI. Recently there have been several single-center studies evaluating the incidence of AKI, utilizing modern AKI definitions in neonates with perinatal asphyxia. Selewski et al. (2013) evaluated 96 newborns undergoing therapeutic hypothermia for perinatal asphyxia and found that 38% had AKI. In this cohort, AKI was associated with adverse outcomes, with

Neonatal Acute Kidney Injury Studies

Study

Population

Definition

Incidence of AKI

Findings

Askenazi et al. 2009

Very low birth weight infants (n = 195)

AKIN criteria

Matched case– control study

AKI is associated with increased mortality after adjustment for confounders.

Gadepalli et al. 2011

Congenital diaphragmatic hernia on extracorporeal membrane oxygenation (n = 68)

RIFLE criteria

71%

Increased risk of mortality at highest level of AKI (failure)

Kaur et al. 2011

Perinatal asphyxia (n = 36)

AKIN criteria

41.7%

Modern staging systems (AKIN) capture AKI previously missed by previous standard of SCr >1.5 mg/dl.

Koralkar et al. 2011

Very low birth weight infants (n = 229)

Neonatal modified KDIGO criteria

18%

Adjusting for severity of illness AKI was associated with increased mortality.

Askenazi et al. 2013

Sick near-term neonates (n = 58)

Neonatal modified KDIGO criteria

15.6%

AKI associated with increased mortality and positive fluid balance

Alabbas et al. 2013

Cardiac surgery <28 days (n = 122)

AKIN criteria

62%

Severe AKI (stage III) was associated with increased mortality and length of stay after adjusting for severity of illness.

Selewski et al. 2013

Perinatal asphyxia (n = 96)

Neonatal modified KDIGO criteria

38%

AKI predicted prolonged mechanical ventilation, length of stay, and abnormal brain MRI findings at 7–10 days of life.

Zwiers et al. 2013

Extracorporeal membrane oxygenation <28 days (n = 242)

RIFLE criteria

64%

Increased risk of mortality at highest level of AKI (failure)

Rhone et al. 2013

Very low birth weight infants (n = 107)

Neonatal modified KDIGO criteria

26.2%

AKI is associated with nephrotoxic medication exposure.

AKI, Acute kidney injury; AKIN, acute kidney injury network; KDIGO, kidney disease improving global outcomes; MRI, magnetic resonance imaging; RIFLE, risk, injury, failure, loss, end-stage; SCr, serum creatinine.



CHAPTER 90  Acute Kidney Injury and Chronic Kidney Disease  1283

prolonged mechanical ventilation by a mean of 4 days (P < .001) and prolonged hospitalization by 3.4 days (P < .03). In the same cohort, those with AKI were more likely to have abnormal brain magnetic resonance imaging (MRI) findings at 7 to 10 days of life, implicating AKI as a potential marker and/or mediator of poor neurologic outcomes in infants with perinatal asphyxia (Sarkar et al., 2014). Recently, in a randomized controlled trial of 120 term neonates with perinatal asphyxia, those randomized to therapeutic hypothermia had lower rates of AKI compared with those who received standard care only (32% vs 60%, P < .05), suggesting therapeutic hypothermia may protect against the development of AKI (Tanigasalam et al., 2016).

Infants Undergoing Cardiac Pulmonary Bypass Surgery Several factors contribute to the risk of postoperative AKI in neonates undergoing cardiac pulmonary bypass (CPB) surgery, including prematurity, cardiopulmonary bypass characteristics and duration, surgical complexity, perioperative morbidities, hypotension, deep hypothermic circulatory arrest, and hypoxia (Blinder et al., 2011). The renal outcomes associated with cardiac surgery in pediatric patients have been well studied, and the association of AKI with adverse outcomes is clear. Alabbas et al. (2013) reported an incidence of AKI in 62% of 122 neonates (<28 days) following CPB. Stage 3 AKI was associated with increased mortality and prolonged length of stay. In a multicenter cohort of 264 babies younger than or 6 weeks of age undergoing CPB, Morgan et al. (2013) reported an incidence of AKI of 64%; those with AKI had longer duration of intubation and length of stay, after adjusting for covariates. In a study of 430 infants (≤90 days old) Blinder et al. (2011) reported an incidence of CPB–AKI of 52%. After correcting for severity of illness, AKI stage II and III were associated with increased hospital mortality (stage II odds ratio [OR] 5.1, 95% confidence interval [CI] 1.7–15.2; P = .004; stage III OR 9.46, 95% CI 2.9–30.7; P = .0002). Infants Requiring Extracorporeal Membrane Oxygenation Neonates on ECMO are predisposed to AKI for a number of reasons, including those inherent to their underlying critical illness (sepsis, ischemia, respiratory failure, cardiac failure, hypotension, nephrotoxic medications) and elements associated with ECMO (hemodynamic fluctuations, hemolysis, systemic inflammation). Several early studies of infants and children (Sell et al., 1987; Weber et al., 1990; Meyer et al., 2001; Cavagnaro et al., 2007; Shaheen et al., 2007) who receive ECMO suggest both AKI and RRT are associated with mortality. In a retrospective cohort study of 7941 neonates in the extracorporeal life support organization registry, where AKI was defined as infants in the registry who had an SCr greater than 1.5 mg/dL or an ICD-9 code for acute renal failure, neonatal mortality was 2175/7941 (27.4%). Nonsurvivors experienced more AKI than survivors (413/2175 [19.0%] vs 225/5766 [3.9%]; P < .0001), and more received RRT (863/2175 [39.7%] vs. 923/5766 [16.0%]; P < .0001). After adjusting for confounding variables, the adjusted OR for mortality was 3.2 (P < .0001) following AKI and 1.9 (P < .0001) for those given RRT. Zwiers et al. (2013) evaluated AKI in 242 neonates on ECMO, reporting an AKI incidence of 64% and a mortality of 65% when AKI progressed to the highest stage. These findings are similar to those reported by Gadepalli et al. (2011) in their evaluation of 68 neonates with congenital diaphragmatic hernia on ECMO, where AKI occurred in 71% of neonates, and those with the highest stage of AKI had a significantly increased mortality of 73%.

Very Low Birth Weight and Extremely Low Birth Weight Neonates There are now several single-center studies describing the epidemiology of AKI in premature infants. Askenazi et al. performed a case–control study matching premature infants by GA and birthweight and found that for every 1 mg/dL increase in SCr, the odds of death doubled (OR 1.94, 95% CI 1.13–3.32). The odds of death increased when confounding variables were adjusted (adjusted OR 3.44, 95% CI 1.23–9.61). In 2011, Koralkar et al. (2011) reported an 18% incidence of AKI in 229 VLBW infants and showed that infants with AKI had significantly higher mortality than those without AKI (42% vs 5%; P < .001), which persisted after adjusting for confounding variables (hazard ratio [HR] 2.4, 95% CI 0.95–6.00; P = .06). Viswanathan et al. (2012) reported an incidence of AKI of 12.5% in 472 extremely low birth weight (ELBW) infants in a single-center retrospective study. In this case–control study, those with AKI had significantly increased mortality (70% vs 22%; P < .001). Carmody et al. (2014) reported a higher incidence of AKI of 39.8% in a retrospective study of 455 VLBW infants. In this study, AKI was independently associated with increased mortality (OR 4.0, 95% CI 1.4–11.5) and length of stay (11.7 hospital days, 95% CI 5.1–18.4). Large prospective multicenter cohort studies with contemporary definitions of AKI are currently under way. One of the most common morbidities of prematurity is bronchopulmonary dysplasia (BPD), affecting 10% and 40% of surviving VLBW and ELBW infants, respectively (Eichenwald and Stark, 2008). The pathophysiology of this chronic lung condition involves elevated levels of proinflammatory interleukins, tumor necrosis factor-α (TNF-α), leukotrienes, and increased pulmonary vasculature permeability, which culminate in abnormal lung development and fibrosis. Not only does AKI cause pulmonary edema secondary to volume overload, but evidence in ischemic, nephrotoxic, and bilaterally nephrectomized animal models shows that AKI induces a proinflammatory process highlighted by increased levels of neutrophils, TNF-α, interleukins, free radicals, endothelial growth factors, and granulocyte colony-stimulating factor (G-CSF) (Kim et al., 2006; Hoke et al., 2007; Faubel, 2008). In 2015, Askenazi et al. showed an association between AKI and BPD in premature infants. Those with AKI had a 70% higher risk of oxygen requirement/death at 28 days old (risk ratio [RR] 1.71, 95% CI 1.22–2.39; P < .002). This association remained after controlling for GA, preeclampsia, 5-minute Apgar score, and maximum percentage weight change in the first 4 days (RR 1.45, 95% CI 1.07–1.97; P < .02). Those without AKI were 2.5 times more likely to come off oxygen (HR 1.3–5.0; P < .02) than those with AKI, even when controlling for GA, preeclampsia, 5-minute Apgar, and maximum percentage weight change (multivariate HR 2.0, 95% CI 0.9–4.0; P < .06) (Askenazi et al., 2015).

Pathophysiology of Neonatal Acute Kidney Injury Prerenal Prerenal azotemia occurs in response to decreased renal blood flow (RBF). Causes of prerenal azotemia in neonates include loss of effective circulating blood volume (perinatal blood loss, hemorrhage), dehydration (diarrhea, transepidermal free water losses, poor intake, gastric or chest tube losses), capillary leak (hydrops, infection, or hypoalbuminemia), increased abdominal pressures (NEC, repair or reduction of gastroschisis, omphalocoele,

1284 PART XV I I  Renal and Genitourinary Systems

TABLE 90.4 

Causes of Acute Kidney Injury in the Newborn

Prenatal Azotemia

Intrinsic Acute Kidney Injury

Obstructive Renal Failure

Loss of effective blood volume Absolute loss Hemorrhage Dehydration Relative loss: ↑ capillary leak Sepsis NEC RDS ECMO Hypoalbuminemia Renal hypoperfusion Congestive heart failure Pharmacologic agents Indomethacin Tolazoline ACE inhibitors

Acute tubular necrosis Severe renal ischemia Nephrotoxins Infections Congenital infections Pyelonephritis Bacterial endocarditis Renal vascular causes Renal artery thrombosis Renal vein thrombosis DIC Nephrotoxins Aminoglycosides Indomethacin Amphotericin B Radiocontrast dyes Acyclovir Intrarenal obstruction Uric acid nephropathy Myoglobinuria Hemoglobinuria Congenital malformations Bilateral renal agenesis Renal dysplasia Polycystic kidneys

Congenital malformations Imperforate prepuce Urethral stricture PUV Urethral diverticulum Ureterocele Megaureter UPJ obstruction Extrinsic compression Sacrococcygeal teratoma Hematocolpos Intrinsic obstruction Renal calculi Fungus balls Neurogenic bladder

DIC, Disseminated intravascular coagulation; ECMO, extracorporeal membrane oxygenation; NEC, necrotizing enterocolitis; PUV, posterior urethral valve; RDS, respiratory distress syndrome; UPJ, ureteropelvic junction.

congenital diaphragmatic hernia, ascites), and decreased cardiac output (cardiac surgery, heart failure, or use of ECMO), which results in a lack of pulsatile flow (Liem et al., 1995). Nonsteroidal antiinflammatory drugs (NSAIDs) such as indomethacin and angiotensin-converting enzyme inhibitors (ACE-Is) can also decrease RBF (Table 90.4). When low RBF occurs, renal autoregulation preserves GFR by increasing renal sympathetic tone, activation of the renin– angiotensin–aldosterone system, and increased activation of hormones such as vasopressin and endothelin. Increase in filtration fraction (GFR/RBF × 100) increases peritubular oncotic pressure, resulting in enhanced proximal tubular sodium and water reabsorption (Feld et al., 1986) in those with intact tubular function. These renal hemodynamic changes lead to a decrease in water and sodium losses, to maintain systemic volume expansion and blood pressure. In some newborns, oliguria does not develop because of poor vasopressin secretion, weak renal responsiveness to vasopressin (Dixon and Anderson, 1985), poor tubular function in underdeveloped tubular cells, or prolonged/severe hypoperfusion. In the context of renal hypoperfusion, correction of the underlying condition restores normal renal function unless renal hypoperfusion has been so severe or prolonged that renal parenchymal damage has already developed. Once parenchymal damage occurs, renal tubular cell damage (acute tubular necrosis) occurs even if renal perfusion is restored.

Intrinsic Acute Kidney Injury Prolonged or severe hypoperfusion is the most common cause of intrinsic AKI. Other causes of intrinsic AKI include nephrotoxic

medications and sepsis, which can cause AKI with either hypodynamic or hyperdynamic blood flow. Other rare causes of AKI include renal vein thrombosis, renal artery thrombosis, uric acid nephropathy, hemoglobinuria, and myoglobinuria (Table 90.4). Congenital abnormalities of kidneys and urinary tract are discussed further in the section under chronic kidney disease (CKD) of the newborn.

Ischemic Acute Kidney Injury The presentation and course of the renal damage after hypoxic ischemic injury depends on the severity and duration of the insult. In contrast to prerenal azotemia, renal function abnormalities in intrinsic AKI are not immediately reversible. The severity of intrinsic AKI ranges from mild tubular dysfunction, to acute tubular necrosis, to renal infarction and corticomedullary necrosis with irreversible renal damage (Feld et al., 1986). Prerenal azotemia and ischemic AKI are a continuum of physiologic responses. The main difference between prerenal AKI and ischemic AKI is that in the latter, hypoperfusion induces renal parenchymal cell injury, particularly to the tubular epithelium of the terminal medullary portion of the proximal tubule (S3 segment) and of the medullary portion of the thick ascending limb of the loop of Henle. The course of ischemic AKI may be subdivided into the prerenal, initiation, extension, maintenance, and recovery phases (Sutton et al., 2002) (Fig. 90.3). If, during prerenal azotemia, restoration of RBF occurs, GFR can return promptly to normal. The initiation phase includes the original insult and the associated events resulting in a drop in GFR. Tubular dysfunction with low GFR represents

CHAPTER 90  Acute Kidney Injury and Chronic Kidney Disease  1285



Pr

er

100

TABLE 90.5 

en

al

A Initiation

GFR (%)

Nephrotoxic Medications

Drug

Mechanism

Acyclovir

Urinary precipitation, especially with low flow and hypovolemia, with renal tubular obstruction and damage and decreased GFR. May cause direct tubular toxicity (metabolites)

Angiotensin-converting enzyme inhibitors

Decreased angiotensin II production inhibiting compensatory constriction of the efferent arteriole to maintain GFR

Aminoglycosides

Toxic to the proximal tubules (transport in the tubule, accumulate in lysosome, intracellular rise in reactive oxygen species and phospholipidosis, cell death); intrarenal vasoconstriction and local glomerular/mesangial cell contraction

Amphotericin B

Distal tubular toxicity, vasoconstriction, and decreased GFR

Nonsteroidal antiinflammatory drugs

Decreased afferent arteriole dilatation as a result of inhibiting prostaglandin production resulting in reduced GFR

Radiocontrast agents

Renal tubular toxicity secondary to increase in reactive oxygen species; intrarenal vasoconstriction may play a role

Vancomycin

Mechanism of AKI unclear, possible mechanism includes proximal tubular injury with generation of reactive oxygen species

B n sio ten Ex

y

er

v co

C Maintenance

Re

0 0

1

2

3

4

5

6

7

Days

• Fig. 90.3

Schematic representation of stages of the progression in acute kidney injury. GFR, Glomerular filtration rate.  

the maintenance phase. The duration of the maintenance phase depends, at least in part, on the severity and duration of the initial insult. The recovery phase is characterized by the gradual restoration of GFR and tubular functions, which can take months to occur. During the maintenance and recovery phase of AKI, the kidney is susceptible to further damage from additional insults. Recognition of the different phases of intrinsic AKI is helpful in the diagnosis, clinical management, and prognostication of the disorder. The histologic hallmark of severe ischemic AKI is damage to epithelial tubular cells with characteristic bleb formation and loss of brush border in the apical portion of the cell cytoskeleton dysruption and loss of tight junctions between cells. If injury is severe enough, apoptosis and necrosis will occur with resultant desquamation of cells, which lead to tubular obstruction. Not only are tubular epithelial cells critical in the pathophysiology of ischemic AKI, but damage to the innermost lining of the renal vascular system, the endothlial cells, has a critical role in the initiation, extension, maintenance, and recovery phases of ischemic AKI (Basile, 2007). When endothelial cell damage occurs, activation of vasocontriction, impaired vasodilation, and impaired leukocyte adhesion result in capillary obstruction and distorted peritubular capillary morphology. Capillary obstruction and impaired morphology lead to a cycle of increasing ischemia and vascular inflammation. The loss of endothelial cell function may represent an important therapeutic target in which vascular support and/or endothelial regeneration by progenitor cell may impact the short- and long-term consequences of AKI (Liu and Brakeman, 2008). Damaged endothelial and tubular cells not only lead to dysfunction within the kidney, but they produce a systemic inflammatory response, which leads to significant distant organ dysfunction. The inflammatory dysregulation is due (at least in part) to dysfunctional immune, inflammatory, and soluble mediator metabolism. AKI also has been shown to directly affect brain, lung, heart, liver, bone marrow, and gastrointestinal tract (Awad and Okusa, 2007). Mice with AKI (induced by bilateral renal ischemia for 60 minutes) had increased levels of the proinflammatory chemokines keratinocytederived chemoattractant and G-CSF in the cerebral cortex and hippocampus, which resulted in increased neuronal pyknosis and microgliosis in the brain (Liu et al., 2008; Liu and Brakeman, 2008). In the lung, mechanistic studies demonstrate that AKI induces increased pulmonary vascular permeability, soluble and cellular inflammation, and dysregulated salt and water channels.

AKI, Acute kidney injury; GFR, glomerular filtration rate.

Because neurologic and pulmonary morbidity are very high in the critically ill neonatal population, the potential deleterious effects of AKI on these organs need to be explored. In many cases, a combination of several causative factors contributes to the development of acute renal failure. For instance, absolute hypovolemia, increased capillary leak-induced loss of effective circulating blood volume, and reflex renal vasoconstriction all may contribute to renal hypoperfusion and ensuing renal injury in newborns with severe forms of shock.

Nephrotoxic Acute Kidney Injury Exposure to nephrotoxic medications is a potentially modifiable risk factor for intrinsic AKI in critically ill children and neonates. Table 90.5 lists commonly used nephrotoxic medications in the neonatal intensive care unit (NICU) and their mechanism of nephrotoxicity. Until recently the epidemiology and burden of nephrotoxic medication exposure in neonates were unknown. Rhone et al. (2014) recently evaluated the cumulative nephrotoxic medication exposure of a cohort of 107 VLBW neonates. In this study, 87% of the cohort was exposed to at least one nephrotoxic medication, and on average these neonates were exposed to over 14 days of nephrotoxic medications. In a number of pediatric patient populations, nephrotoxinassociated AKI has been linked to adverse outcomes including increased length of stay and cost (Zappitelli et al., 2011).

1286 PART XV I I  Renal and Genitourinary Systems

In the NICU, nephrotoxins can cause AKI by decreasing renal perfusion (NSAIDs, diuretics, ACE-Is), direct tubular injury (aminoglycocides, cephalosporins, amphotericin B, rifampin, vancomycin, NSAIDs, contrast media, myoglobin/hemoglobin [Hgb]), interstitial nephritis, and tubular obstruction (acyclovir). Although not a comprehensive review, some of the most common nephrotoxic medications in neonates are described. Indomethacin, a prostaglandin inhibitor used to treat patent ductus arteriosus in premature infants, is one of the most commonly used medications in the NICU. Severe, although usually transient, nephrotoxicity can occur with indomethacin administration. The potentiation of the vasoconstrictive and sodium- and water-retaining effects of angiotensin II, norepinephrine, and vasopressin by the indomethacin-induced inhibition of renal prostaglandin production is the primary mechanism of the renal actions of the drug. Because neonatal renal function is more dependent on local prostaglandin production (especially when intravascular volume is decreased as a result of fluid restriction, increased capillary leak, and transepidermal water losses in the preterm infant with patent ductus arteriosus), indomethacin administration is commonly associated with elevated SCr concentrations, decreased urine output, and hyponatremia (Cifuentes et al., 1979). Amphotericin B alters renal function by directly affecting tubular function, resulting in renal tubular acidosis and increased urinary potassium excretion. Although these nephrotoxic effects are most often reversible, cases of fatal neonatal renal failure caused by amphotericin B toxicity have been reported (Baley et al., 1984). Amphotericin B lipid complex (ABLC), liposomal amphotericin, and other lipid formulations of this drug consist of nonliposomal lipid bilayers complexed with amphotericin B. This lipid bilayer results in a higher affinity to fungal rather than mammalian cellular membranes and therefore is less nephrotoxic (Wurthwein et al., 2005). Auron et al. (2007) recently showed no differences in blood urea nitrogen or SCr, serum sodium, or serum potassium in 35 premature infants (average birthweight 764 ± 196 g) treated with ABLC compared with similar infants (controlling for GA and birthweight). Thus a 2-week course of ABLC is likely safe in premature infants, although studies to explore longer-term use of ABLC are needed. Aminoglycosides are one of the most commonly used medications used in the treatment of suspected or proven neonatal sepsis. Aminoglycosides inhibit lysosomal phospholipases, leading to primary proximal tubule cell damage (Giuliano et al., 1984), although changes in the ultrastructure of the glomerulus also occur (Ojala et al., 2001). A metaanalysis of 11 studies in septic neonates showed that both once-a-day and multiple-dose regimens showed adequate clearance of sepsis. Even though rates of ototoxicity or nephrotoxicity were not different among the two groups, pharmacokinetic studies revealed that once-a-day dosing caused less drug accumulation in the kidney’s proximal cells and more commonly achieved adequate peak concentrations (>5.0 mcg/dL) while avoiding toxic trough levels (<2 mcg/dL) (Rao et al., 2006). Aminoglycosides should be used with caution in any person with renal dysfuction, concomitant nephrotoxic medication use or poor renal perfusion (due to volume, hypoalbuminuria, heart failure). In those with renal dysfunction, serial monitoring to assure proper clearance of the medication is needed to prevent AKI. Because aminoglycoside toxicity is usually nonoliguric, serial monitoring of SCr values is necessary, especially during prolonged administration of these antibiotics, to detect their potential nephrotoxicity in the newborn. Acyclovir has replaced vidarabine for treatment of infection with herpes symplex virus (HSV) because of its ease of use and

more favorable side effect profile. High-dose acyclovir (60 mg/kg per day for 21 days) decreased the mortality of neonatal HSV sepsis and central nervous system disease to 29% and 4%, respectively (Kimberlin et al., 2001). Acyclovir is an antiviral agent that is eliminated rapidly in the urine through glomerular filtration and tubular secretion. It is nearly insoluble in the urine and may precipitate, particularly in the distal tubular lumen. Intravenous high-dose acyclovir treatment may lead to intratubular crystal precipitation and renal failure. Acyclovir-related nephrotoxicity can be limited by avoiding its use in those with renal insufficiency or intravascular volume depletion, infusing the drug slowly (over several hours), and by assuring adequate hydration to maintain high urinary flow rate, which will reduce the likelihood of crystal deposition in the tubules (Izzedine et al., 2005). Finally, medications given to pregnant women may cause combined ischemic and nephrotoxic renal injury in the fetus, resulting in the clinical presentation of AKI after birth. A frequently used class of medications that falls into this category is the NSAIDs prescribed for tocolysis—both nonselective and selective cyclooxygenase inhibitors such as indomethacin or ketoprofen (Bannwarth et al., 1999; Peruzzi et al., 1999), which can lead to severe AKI in the newborn.

Postrenal Acute Kidney Injury The most common causes of obstructive kidney dysfunction in the newborn are congenital malformations, including imperforate prepuce, urethral stricture, prune belly syndrome, and posterior urethral valves. Other causes of acute obstruction include neurogenic bladder, extrinsic compression (e.g., hematocolpos, sacrococcygeal teratoma), and intrinsic obstruction from renal calculi or fungal balls. Depending on the cause and associated damage to the kidneys, relief of the obstruction will markedly improve renal function.

Evaluation and Management of Neonatal Acute Kidney Injury There are three main goals in the care of neonates with AKI. First is to understand the cause of the problem. Second is to take steps to intervene to prevent further deterioration in kidney function. Third is to provide renal support to the patient by helping achieve proper homeostasis and blood pressure control, provide the synthetic substance that the failed kidney lacks, and assist in toxic clearance. Similar steps parallel proper care for the newborn with CKD.

Step 1: Understand the Cause of Acute Kidney Injury The pregnancy history, findings on prenatal tests, vital signs, changes in weight, physical examination, interventions, and medications prescribed provide important clues about the cause of neonatal AKI. SCr often does not rise for days after an injury, thus monitoring these values for several days after the inciting event is necessary to determine if AKI occurred. If urine is available, a urinalysis, urine culture, and a spot urine sample for sodium, creatinine, and osmolality can help differentiate the cause. Serum laboratory values can help understand the cause of AKI and should be monitored sequentially. These include serum sodium, potassium, chloride, bicarbonate, calcium, phosphorus, magnesium, urea, creatinine, uric acid, glucose, blood gases, Hgb, and platelets. One of the major goals in the initial evaluation of neonatal AKI is to determine if the kidney is hypoperfused. Several laboratory, clinical, and therapeutic interventions can help delineate prerenal azotemia from intrinsic AKI (Table 90.6). Decrease in body weight, tachycardia, dry mucous membranes, poor skin turgor, flattened

CHAPTER 90  Acute Kidney Injury and Chronic Kidney Disease  1287



TABLE 90.6 

Diagnostic Indices Suggestive of Prerenal Azotemia Versus Intrinsic Acute Kidney Injury in the Newborn Prerenal Azotemia

Intrinsic Acute Kidney Injury

Urine flow rate (mL/kg per hour)

Variable

Variable

Urine osmolality (mOsm/L)

>400

≤400

Urine-to-plasma osmolar ratio

>1.3

≤1.0

Urine-to-plasma creatinine ratio

29.2 ± 1.6c

9.7 ± 3.6c

Urine [Na+] (mEq/L)

10–50

a

30–90

FENa (%)

<0.3 (0.9 ± 0.6)

>3.0 (4.3 ± 2.2)c

Renal failure indexa,b

<3.0 (1.3 ± 0.8)c

>3.0 (11.6 ± 9.5)c

Response to fluid challenge

Improved tachycardia Increased UOP

No effect on tachycardia or UOP

c

Fractional excretion of sodium (FENa) = (urine [Na+]/serum [Na+])/(urine [Cr]/serum [Cr]) × 100. b Renal failure index = urine [Na+]/(urine [Cr]/serum [Cr]). c Mean ± standard deviation. UOP, Urine output. Data from Feld at al., 1986; Karlowicz and Adelman, 1992; and Mathew et al., 1980. See text for details. a

anterior fontanel, and elevation of serum sodium can be seen in those with low intravascular volumes. When the kidney is hypoperfused, the kidney will avidly retain sodium and water to preserve overall intravascular volume. Laboratory markers of prerenal azotemia include low urinary sodium excretion, low fractional excretion of sodium (FENa), low renal failure index, and high blood urea nitrogen:SCr ratio. However, it is important to recognize that preservation of urine sodium and water is dependent on intact tubular function; therefore disturbances of tubular function (from diuretic use, tubular injury, or primary tubular diseases) can affect the tests. As premature infants have poor tubular function, these studies have important limitations. Normal FENa in preterm infants born at less than 32 weeks of gestation is usually higher than 3% (Ellis and Arnold, 1982). Additionally, because of the developmentally regulated limitation of their concentrating capacity and the effects of low protein intake and urea excretion on urine osmolality, the urine-to-plasma creatinine ratio instead of the urine-to-plasma osmolar ratio should be used in newborns to evaluate their renal tubular reabsorptive capacity (Feld et al., 1986). If the suspicion of renal hypoperfusion is high, an appropriate fluid challenge with 10–20 mL/kg of isotonic fluids (usually normal saline) over 30 minutes should be given. Close observation of vital signs and UOP may serve to delineate if intravascular hypoperfusion is present. Several boluses may be necessary with careful prescription of fluid volume for the next 24 hours. Care to avoid fluid challenges is advised in those with suspected urinary outlet obstruction, lung pathology such as BPD, or congestive heart failure. Another important part of the evaluation of AKI is to assure that there is no obstruction to urine flow. A renal and bladder

ultrasound should be performed without delay if an obstructive process is suspected and to determine if congenital renal abnormalities are present. If hematuria or hypertension (or both) are present, the possibility of renal vascular disease should also be considered. Doppler ultrasound of the renal vessels can be performed if renal vascular thrombosis is suspected.

Step 2: Intervene to Preserve or Prevent Further Acute Kidney Injury The approach using provision of fluid boluses (if appropriate) as part of the evaluation of prerenal azotemia also serves as the initial management of AKI. Careful evaluation of any potentially nephrotoxic medications to determine if they are necessary, and/or if alternatives are available, is crucial. Clearly the clinican can reverse or prevent further damage by maintaining adequate renal perfusion, relieving abdominal compartment syndrome if present, assuring adequate oncotic pressure (keeping a serum albumin of 2.5 mg/dL or higher) and, if obstruction of the urinary outflow is discovered, provide interventions to elimate the obstruction. If systemic hypotension develops despite adequate volume administration, early initiation of blood pressure support often establishes appropriate renal perfusion (Seri et al., 1993; Seri et al., 1998). In cases of pressor/inotrope-resistant hypotension and shock, a brief course of low-dose hydrocortisone can be effective in restoring systemic perfusion and renal function in preterm neonates (Seri, 2001). Other management goals include the maintenance of blood oxygen content, provision of blood products for specific indexes, limiting severe acidosis, and maintenance of normal serum albuminemia (at least 2.5 mg/dL preferably). If abdominal compartment syndrome is noted, the kidney will need higher blood pressure or relief of abdominal pressure with a drain to maintain perfusion. Several therapies are commonly employed in AKI; however, little, if any, data are available to support the use of low-dose dopamine, fenoldapam (a selective dopamine-1 receptor agonist), or diuretics for the treatment or prevention of AKI. Low-dose dopamine can increase renal perfusion in the sick preterm and term infant with prerenal azotemia caused by hypoxemia, acidosis, or indomethacin administration (Seri, 1995; Seri et al., 1998; Seri et al., 2002). Although low-dose dopamine increases renal perfusion, well-powered randomized controlled studies (Bellomo et al., 2000) and several metaanalyses in adults with AKI have come to the same conclusion: compared with placebo, low-dose dopamine does not improve survival, shorten hospital stay, or limit dialysis use (Marik, 2002; Friedrich et al., 2005; Hoste et al., 2006). Similar studies have not been performed in children or neonates. Fenoldepam is a selective dopamine-1-receptor agonist the effects of which include vasodilation of renal and splanchnic vasculature, increased RBF, and increased GFR. It is approved in adults for treatment of severe hypertension but is not approved for the treatment of AKI. Nonetheless, its use in neonates with AKI has been explored in several single-center analyses, with conflicting results. Two retrospective single-center analyses (Moffett et al., 2008; Yoder and Yoder, 2009) found increased urine output in a select group of neonates with oliguria. In contrast, in a prospective placebocontrolled trial of low-dose fenoldepam (0.1 mcg/kg per min) in infants undergoing cardiac surgery with cardiopulmonary bypass (Ricci et al., 2008), low-dose fenoldepam did not show beneficial effects on AKI incidence, fluid balance control, time to sternal closure, time to extubation, or time to intensive care discharge. Diuretics are commonly used to induce diuresis in critically ill neonates; however, no studies in neonates, children, or adults have

1288 PART XV I I  Renal and Genitourinary Systems

shown that diuretics are effective in preventing AKI or improving outcomes once AKI occurs (Bellomo et al., 2000). The mannitol test (used to test if a patient has renal hypoperfusion) is contraindicated in newborns with a predisposition to the development of intraventricular hemorrhage or periventricular leukomalacia, because of the drug-induced sudden increase in serum osmolality.

Step 3: Provide Renal Support The clinician has an important role in helping to achieve homeostasis, and careful attention to what fluid/electrolytes are being delivered to the patient is critical. Managing fluids in the critically ill neonate with AKI can be very difficult. These infants may require large volumes of fluid to maintain adequate nutrition and hematologic indices and to provide appropriate medications. However, in an oliguric/anuric child these fluids can be detrimental as they can cause congestive heart failure, chest wall edema, and pulmonary failure. Therefore once adequate intravascular volume has been restored, prevention of severe fluid overload (by limiting crystalloid infusions) and the maximization of nutritional supplement concentration should be undertaken. Severe fluid restriction, limiting intake to insensible, gastrointestinal, and renal losses, is sometimes required but is performed at the heavy price of inadequate nutrition. Decisions on placement of dialysis access should be considered early in the course of AKI before severe fluid overload has occurred, because once severe fluid overload occurs, placement of a peritoneal dialysis (PD) or a hemodialysis (HD) catheter can be significantly more difficult, as is support of the infant with severe pulmonary edema. Although diuretics do not impact the course of AKI, they can be used to assist in maintaining fluid homeostasis. If an adequate dose of a loop diuretic (i.e., 1 mg/kg of furosemide intravenously) does not improve UOP, it is unlikely that higher doses, changing diuretic, and/or changing to continous dose will benefit the infant, and their use could have important side effects. In cardiac surgery patients, continuous doses were shown to be as effective with smaller total quantities of medication required and may provide less risk for nephrotoxicity or ototoxicity than larger intermittent dosing (Luciani et al., 1997). The potential toxicity of long-term and aggressive furosemide therapy, including ototoxicity, interstitial nephritis, osteopenia, nephrocalcinosis, hypotension, and persistence of patent ductus arteriosus, should be taken into consideration, especially in the preterm newborn (Karlowicz and Adelman, 1992). Hypertension is common in neonates with AKI. It can be due to increased renin release in malformed/damaged kidneys or secondary to increased intravascular volume from a lack of free water clearance. If hypertension is due to fluid overload, inducing free water clearance with diuretics or fluid removal with dialysis will address its cause. Calcium-channel blockers work by selectively causing vasodilation of the venous system. Short-acting calciumchannel blockers (isradipine for example) are reliable, have a quick onset of response, and are well-tolerated medications. Long-acting calcium-channel blockers (amlodipine for example) take longer to take effect but provide less lability with longer dosing intervals. β-Blockers (propranolol or labetolol) are also commonly used to treat hypertension in neonates. Use of ACE-Is in children with ischemic AKI should be avoided as they can produce further renal hypoperfusion and alter intrarenal hemodynamics in an already injured kidney. See Chapter 93 for more information on neonatal hypertension. Electrolyte abnormalities can vary depending on the cause of AKI. For example, aminoglycoside toxicity is commonly nonoliguric

with ongoing potassium and magnesium losses. Alternativly, ischemic AKI causes oliguira/anuria hyponatremia, hyperkalemia, hyperphosphatemia, and hypocalcemia. Polyuria with electrolyte (especially bicarbonate) losses may occur following the relief of a urinary obstruction. Management of electrolyte disorders can usually be managed by attention to electrolyte intake during intial course of AKI, frequent evalution, and specific therapies. Most cases of hyponatremia are due to water overload and, less commonly, low total sodium body composition. Attention to fluid status is critical to determine the cause and proper therapy of hyponatremia. In cases of nonsymptomatic hypervolemic hyponatremia (serum sodium concentrations usually between 120 and 130 milliequivalent [mEq]/L), restriction of free water intake is recommended. If hyponatremia at this level results in clinical signs and symptoms (lethargy, seizures) or serum sodium concentration falls below 120 mEq/L, use of 3% sodium chloride over 2 hours according to the following formula should be considered, but caution should be used to assure that the sodium (Na) is not corrected too quickly. Possible complications of hypertonic saline administration include congestive heart failure, pulmonary edema, hypertension, intraventricular hemorrhage, and periventricular leukomalacia. Care should be taken not to increase serum sodium concentration more rapidly than 0.5 mEq/hour. Severe hyperkalemia is a life-threatening medical emergency. Signs of progressive hyperkalemia on the electrocardiogram, in order of severity, consist of tall peaked T waves, heart block with widened QRS complexes, U wave formation, the development of sine waves, and finally cardiac arrest. Medications used to manage hyperkalemia, with their dose, onset, and duration of action, are listed in Table 90.7. Measures to remove potassium from the body

TABLE 90.7 

Medical Management of Hyperkalemia in the Newborn Onset of Action

Duration of Action

1–5 min

15–60 min

Sodium bicarbonate 1–2 mEq/kg (IV over (3.75% solution) 10 min)

5–10 min

2–6 hr

Insulin

1 IU/5 g glucose (IV bolus or continuous infusion)

15–30 min 4–6 hr

Glucose

≤14 mg/kg per min (IV 15–30 min 4–6 hr bolus or continuous infusion)

Furosemide

1 mg/kg dose or as continuous infusion

Drug

Dose

Calcium gluconate (10%)

0.5–1 mL/kg (IV over 10 min)

5–10 min

2–3 hr

Sodium polystyrene 1 g/kg dose q6h as sulfonate needed (orally/ rectally)

1–2 hra

4–6 hr

Dialysis

Immediate

Duration of therapy

As per nephrology

a Onset of action may take up to 6 hours, and the drug may be ineffective in preterm infants born at less than 29 weeks of gestation. See text for details. IU, International unit; IV, intravenous.



CHAPTER 90  Acute Kidney Injury and Chronic Kidney Disease  1289

include oral or rectal sodium polystyrene powder (Kayexalate), loop diureteics to enhance potassium excretion (if not anuric), and dialysis. Several methods to move potassium from the extracellular to the intracellular compartment are available including albuterol inhalation, sodium bicarbonate, and insulin/glucose. Adequate ionized calcium levels for cardioprotection should be sought in context of hyperkalemia. In 2007, Vemgal and Olhson performed a metaanalysis of studies on the management of hyperkalemia in premature infants. Given the limited data available, no firm clinical practice recommendations on which treatment modality was best for the treatment of infants with hyperkalemia were able to be made except that insulin/glucose may be better in premature infants (Vemgal and Ohlsson, 2007). Hyperphosphatemia is common in AKI and should be treated with low phosphorus intake. Breast milk and Similac 60/40 both contain low phosphorous and low potassium in comparison with other neonatal infant formulas. Significant elevations in serum phosphate represent a risk of development of extraskeletal calcifications of the heart, blood vessels, and kidneys in the newborn, especially when the calcium–phosphorus product exceeds 70 (Sell et al., 1987). Calcium carbonate may be used as a phosphate-binding agent in those whose phosphorous intake exceeds excretion. Although rarely an indication for dialysis without fluid overload or hyperkalemia, severe hyperphosphatemia is best treated with dialysis. Hypocalcemia is low in neonates with severe and prolonged AKI, especially those who develop an inablility to convert 25-hydroxy-vitamin D to 1-25-hydroxy vitamin D. Ionized calcium should be measured in those with low total calcium levels as concurrent hypoalbuminemia can affect total calcium levels. If ionized calcium is decreased and the newborn is symptomatic, 100–200 mg/kg of calcium gluconate should be infused over 10 to 20 minutes and repeated every 4 to 8 hours as necessary. Oral or intravenous calcitriol may be administered to increase intestinal reabsorption of calcium. Normal acid–base homeostasis depends on the kidneys’ ability to reabsorb bicarbonate. Thus infants with AKI commonly have a nonanion gap metabolic acidosis. Replacement with bicarbonate or acetate as a base is indicated in those with AKI to avoid or treat metabolic acidosis. In infants with severe respiratory failure, large doses of bicarbonate should be avoided as this can result in respiratory acidosis with increased carbon dioxide retention. Nutritional goals in infants with AKI are similar to those of infants without AKI. Commonly, parental nutrition and/or feeds will need to be concentrated to avoid excessive fluid gains. If nutritional goals are unable to be achieved due to oliguria/ongoing fluid overload, the potential risks of dialysis therapy versus the potential risks associated with inadequate caloric and protein needs should be discussed. If a neonate is on continuous peritoneal or HD, an additional 1 g/kg per day of protein is needed to supplement the protein losses that occur with this form of dialysis (Zappitelli et al., 2008, 2009). In a neonate with AKI, careful assessment of medication dosing is imperative. Because many drugs are excreted in the urine, impaired metabolism or clearance from the kidneys can cause drug accumulation and adverse side effects. In those on dialysis, pharmacokinetic properties (volume of distribution, protein binding, size, charge) of drugs, dialysis modality (peritoneal vs HD), and interval of dialysis (intermittent vs continous) will affect drug availablity (Churchwell and Mueller, 2009). Consultation with pharmacists and nephrologists familiar with drug dosing in renal failure is invaluable for neonates with AKI.

Renal Support Therapy With Dialysis Renal support therapy, either through the use of the peritoneal membrane or with the extracorporeal blood system, does not prevent or treat AKI or CKD; it is used solely to support the infant who lacks adequate kidney function. The decision to initiate dialysis (especially in those infants with severe congenital malformations of the kidney and urinary tract) is complex and requires a multidisciplinary approach to guide the family as they consider very difficult decisions (see later on decisions to initiate RRT). Access placement and some techinical challenges make neonatal dialysis more difficult than in older children, but this therapy is feasible in experienced programs with dedicated pediatric nephrologists, neonatologists, dialysis nurses, and surgeons.

Indications for Dialysis Initiation Absolute indications to initiate dialysis include severe electrolyte abnormalities that are not correctable with medical interventions, life-threatening intoxications of medications that can be cleared with dialysis, inborn errors of metabolism, fluid overload that leads to pulmonary edema or other organ dysfunction, inability to provide adequate nutritional requirements because of renal compromise, and uremia. If renal dysfunction and/or fluid overload occurs, discussions about dialysis initiation should occur early because prolonged fluid overload/uremia can worsen pulmonary edema and cardiopulmonary instability and make placement of access for dialysis very difficult. The timing of initiation of dialysis for those with AKI is controversial. Several observational studies show a clear advantage in adults who are dialyzed early versus late (Ronco et al., 1986; Liu et al., 2006), and pediatric studies have begun to show similar findings. The impact of fluid overload on outcomes in critically ill patients has been a hot topic across medicine. Pediatricians have been at the forefront of identifying the degree of fluid overload at the initiation of renal replacement as an independent risk factor for survival in critically ill children (Goldstein et al., 2001; Gillespie et al., 2004; Symons et al., 2007). Further studies evaluating the impact of fluid overload on outcomes in neonates need to be performed. Advocates for early initiation of renal support argue that critically ill patients benefit from early dialysis because they can remove excess fluid sooner, gain metabolic control faster, and provide renal support to allow for provision of maximal nutrition without progressive fluid overload. As technical access and machine advances have made neonatal dialysis safer and technically possible, early initiation of dialysis may improve outcomes in critically ill neonates with AKI. Further studies are needed before recommendations on timing of dialysis can be made. Access The limiting factor in performing dialysis in the smallest of babies is access to the peritoneal space or the vascular space for dialysis. The ideal acute PD access is a noncuff or single-cuff coiled catheter specifically designed for neonates undergoing PD. If this is not available, the use of a catheter that is used for chest tube drainage, or other catheters that may be available, can be lifesaving. The advantage to the straight uncuffed catheter is that it can be placed at the bedside and can be used soon after insertion. However, these catheters are more likely to become infected and/or develop leakage of fluids around the insertion site. For the patient who requires chronic dialysis, a catheter with two subcutaneous cuffs and the use of a downfacing exit site away from the diaper area and away from a gastrostomy tube are recommended (Auron et al.,

1290 PART XV I I  Renal and Genitourinary Systems

2007). As with all pediatric surgery procedures, the exact type of catheter and the timing and location of catheter insertion need to be tailored to the individual patient (Shaheen et al., 2007). Repair of hernia (if present) should be performed at the time of catheter insertion. Vascular access for HD requires a large (at least 7 French [F] but preferably an 8F) double lumen catheter that can be placed in the femoral or internal jugular vein. Double lumen catheters that are smaller than 7F are much more likley to develop problems during the dialysis procedure (Symons et al., 2007). Standard intravenous catheters are too flexible and too small to maintain patency with high blood flows. The use of 7F or 8F catheters is ideal; two 5F catheters in different sites can be lifesaving. If the need for dialysis is likely to last more than 1 week, a cuffed catheter is preferred to decrease the likelihood of infection. The length of the catheter should be chosen so that the tip of the catheter resides in the right atrium for internal jugular catheters and in the inferior vena cava for femoral catheters. Unless no other choices are available, the subclavian artery should not be used in infants who are likely to require long-term RRT because future forearm fistula of the ipsilateral arm can fail with “mild stenosis” of the subclavian vein.

Peritoneal Dialysis Once PD access is placed and the decision to start dialysis has occurred, small volume continuous cycles (10 cc/kg) are performed. The dialysate solution is left dwelling in the peritoneal cavity, during which time solute and fluid removal takes place and is then drained. Continuous cycles are performed with each cycle lasting about an hour. The dextrose concentration in the fluid will determine the amount of net water loss (ultrafiltration). Complications associated with PD include peritonitis, leakage around catheter exit site, tunnel infection, catheter malfunction, and obstruction by omentum (Coulthard and Vernon, 1995). Leakage of fluid into other compartments (including the chest in patients without an intact diaphragm) can occur, and, if suspected, the fluid composition will reveal high glucose levels if a leak is indeed present. Absolute or relative contraindications to PD include NEC, abdominal wall defects, and the presence of an intra-abdominal foreign body, such as a ventriculoperitoneal shunt or diaphragmatic patch. Hemodialysis Once reliable access to the vascular space is achieved, the HD procedure can be performed. The two types of HD, intermittent HD and continuous RRT (CRRT), differ mainly by the duration of the procedure. Intermittent HD is significantly more efficient than CRRT. The blood flow and time on therapy are the limiting factors for solute clearance on HD. Even with the smallest dialyzers and neonatal tubing, most infants need blood priming of the extracorporeal circuit for the therapy. Skilled pediatric HD nurses are required at the bedside during the entire procedure, which typically lasts 3–4 hours. Achieving the adequate fluid removal necessary for the entire day can be difficult to achieve in the few hours on dialysis, especially in hemodynamically unstable infants. This technique usually requires systemic heparinization, with activated clotting time usually kept at 180 to 200 seconds, rendering the technique risky in preterm newborns and others at high risk for intracranial bleeding. The main advantage to a continous modality is that lower blood flow and fluid removal rates can be used to accomplish the desired ultrafiltration and clearance goals. Ronco et al. (1986) described

the use of CRRT in a critically ill newborn. CRRT requires a double lumen venous catheter whereby the CRRT pump pulls blood from one port of the catheter and returns the blood via the other side of the catheter. This is now a relatively common procedure in level IV NICUs. Anticoagulation with CRRT is achieved with either systemic heparin or regional citrate anticoagulation. The advantage of regional citrate anticoagulation is that the patient is not systemically anticoagulated; however, this approach has the added risk of hypocalcemia caused from citrate excess (especially in those with impaired liver metabolism) and metabolic alkalosis (Tolwani and Wille, 2009). Because citrate is metabolized by the liver, caution must be exercised when dialyzing premature infants or newborns with multiorgan failure who may have impaired liver function. Outcome data in neonates who require CRRT are scarce. Symons et al. (2003) reported a survival rate of 32/85 (37.6%) in neonates who received CRRT in five large children’s hospitals in the United States. Between 2001 and 2007, the prospective pediatric CRRT group, a multicenter registry of 14 pediatric CRRT programs, reported outcomes for neonates in whom CRRT was initiated before 1 month of age (Symons et al., 2007). About 8% (35 neonates) in the registry were dialyzed in the first month of life. In this group, the median age was 8 days old; the median weight was 3.2 kg with the smallest infant weighing 1.3 kg. Of the 35 infants in the registry, 24 were dialyzed for either fluid overload, electrolyte imbalance, or both, and 11/35 were dialyzed for inborn errors of metabolism. Overall survival was 43%. Infants dialyzed for inborn errors had a better survival rate (73%) than the others (30%). Several technical issues specific to infants arise when using CRRT for dialysis. The extracorporeal volume can incorporate greater than 50% of the infants’ blood volume. For example, a 2.5-kg baby has a blood volume of 80 mL/kg (200 mL); the smallest circuit volume available on the most commonly used machine in the United States has an extracorporeal volume of around 100 mL, about 50% of infants’ blood volume. Priming the blood circuit with blood will minimize the risks of hypotension during circuit initiation, but additonal complications (acidosis, hypocalcemia, thrombocytopenia, and dilution of coagulation factors) make initiation of CRRT challenging. The risk for the bradykinin reaction that can occur at the initiation of CRRT with AN69 dialyzer (Baxter, Chicago, IL) membranes can be reduced using several techniques that minimize exposure of acidotic blood to the membrane (Brophy et al., 2001; Hackbarth et al., 2005).

Acute Kidney Injury as a Cause of Long-Term Chronic Kidney Disease Total GFR is determined by the filtration rate of single nephrons and the number of nephrons present. When the number of nephrons is diminished, single nephron GFR increases as the kidney works to compensate for low nephron numbers. This compensatory hypertrophy causes glomeruli to function under increased intracapillary hydraulic pressure, which, over time, causes damage to capillary walls. This abnormal process leads to progressive glomerulosclerosis, proteinuria, hypertension, and CKD (Brenner et al., 1996). The hyperfiltration hypothesis has been applied and confirmed in autopsy data of hypertensive patients (Ohishi et al., 1995; Keller et al., 2003) and has been written about at length regarding infants with intrauterine growth restriction (Wadsworth et al., 1985; Barker and Osmond, 1988; Barker et al., 1989; Manalich et al., 2000;



CHAPTER 90  Acute Kidney Injury and Chronic Kidney Disease  1291

White et al., 2009). A systematic review and metaanalysis in 2009 concluded that low birth weight babies (≤5.5 lbs) were 70% more likely to develop CKD later in life compared with individuals with normal birthweight (White et al., 2009). Nephrogenesis continues through 34 weeks’ gestation. Premature infants (even those born appropriate for GA) are therefore born with low nephron numbers compared with term infants. Using computer-assisted morphometry, Rodriguez et al. (2004) showed that premature infants who survived to at least 36 weeks’ postconception had nephron numbers similar to premature infants with short survival, suggesting that the extrauterine environment does not support normal neoglomerulogenesis. In addition, preterm infants with AKI had fewer nephrons than similar infants without AKI. Recent animal and epidemiology data suggest that AKI leads to CKD. As discussed in the section on the pathophysiology of ischemic AKI, tubular and vascular endothelial cellular damage occur with prolonged hypoperfusion. Animal models suggest that although tubular recovery occurs, damage to the vascular endothelial cells remains and can lead to interstitial fibrosis and progressive kidney dysfunction (Basile et al., 2001). Studies of children with AKI show that over 50% have at least one sign of CKD 3–5 years after the inciting event. Large adult studies suggest that after AKI, rates of CKD (low GFR) are 5%–10%, with about 3%–5% developing ESRD. The exact prevalence of CKD after neonatal AKI is unknown. Stapleton et al. (1987) reviewed the published single-center data and reported a 40%–88% prevalence of long-term CKD after oliguric renal failure. Since then, other retrospective small singlecenter studies describe similar tubular/glomerular dysfunction and hypertension in survivors of neonatal AKI (Chevalier et al., 1984; Polito et al., 1998; Abitbol et al., 2003). Outcome data on premature infants after AKI are scarce. Rodriguez et al. performed a cross-sectional study on premature infants during childhood born weighing less than 1000 grams and found that estimated GFR and tubular function were lower than in term-born children. Despite the limitations of these single-center studies, these data suggest that prematurity, intrauterine growth restriction, and AKI lead to a lower number of nephrons and/or endothelium dysfunction and an increased risk of long-term renal dysfunction. To further delineate the likelihood and extent that AKI causes CKD, and to provide guidelines for long-term follow-up, a prospective study is greatly needed. Future studies of interventions (such as ACE-Is) to decrease the rate of CKD progression in this growing population should be explored.

Renal Vascular Disease in the Newborn Thromboembolic events in neonates usually result from an imbalance of the delicate homeostasis between bleeding and thrombosis. Some may be of genetic origin, some may relate to underlying stresses during pathologic processes, and some may relate to treatments for the pathologic processes.

Renal Arterial Thrombus Incidence and Etiology Renal artery thrombosis in the neonate is far less common than renal vein thrombosis. A major risk factor for renal arterial obstruction is umbilical artery catheterization. Other significant risk factors are shock, coagulopathy, and congestive heart failure. The reported incidence of umbilical artery-related thromboembolism reflects, in large part, the diagnostic test chosen. Doppler ultrasonography

estimates the incidence of umbilical artery-related thromboembolism from 14%–35%, whereas studies using angiography document incidences up to 64%. Autopsy studies have shown an incidence of umbilical artery-related thromboembolism between 9% and 28%, although major clinical symptoms of umbilical artery-related thromboembolism occur in 1%–3% of infants (Andrew et al., 2001). Trauma (endothelial injury) at the time of insertion of an umbilical artery catheter is postulated to be the cause of aortic thrombus formation, which then leads to thrombosis of one or both renal arteries. High umbilical artery catheters, placed at the T6 to T10 vertebral level, have been associated with a decreased incidence of clinical vascular complications without a statistically significant increase in any adverse effects (Barrington, 2000b). The chances of umbilical artery catheter occlusion can be decreased by adding heparin to the infusing fluid at a concentration as low as 0.25 unit/mL (Barrington, 2000a).

Clinical Presentation Clinical presentation varies with the extent and severity of thrombosis. Thrombosis of the abdominal aorta or renal arteries can manifest in any of the following ways: signs of congestive heart failure, hypertension, oliguria, renal failure, decreased femoral pulses with lower limb ischemia, or bowel ischemia/frank NEC secondary to superior or inferior mesenteric artery thrombosis. Symptoms of renal arterial thrombosis manifest within the first few postnatal days in a term neonate, compared with a median age of 8 days in a preterm neonate. The symptoms can be classified based on clinical severity; minor thrombosis with mildly decreased limb perfusion, hypertension, and hematuria; moderate thrombosis with decreased limb perfusion, hypertension, oliguria, and congestive heart failure; and major thrombosis with hypertension and multiorgan failure. Laboratory findings associated with renal arterial thrombosis are thrombocytopenia, hypofibrinogenemia, elevated fibrin split products, variable prothrombin and thromboplastin times, conjugated hyperbilirubinemia, elevated blood urea nitrogen and creatinine, hyperreninemia, and hematuria. Diagnosis Doppler ultrasonography is used as the first line of imaging for diagnosing neonatal thrombosis although it usually fails to detect smaller intra-arterial thrombi and some larger asymptomatic venous thrombi (Roy et al., 2002). If ultrasonography is inconclusive, radionuclide imaging can be used. Angiography is the standard diagnostic modality and should be performed through the umbilical artery line if surgical intervention or fibrinolytic therapy is being considered. Treatment For asymptomatic or minimally symptomatic newborns, only supportive care is recommended, such as removal of the umbilical artery catheter and close ultrasonographic monitoring. Most of these thrombi resolve spontaneously. In newborns with mild signs of organ dysfunction and stable aortic and renal arterial thrombosis, management of hypertension, transient renal insufficiency, and mild congestive heart failure is recommended. Systemic heparin is given for anticoagulation. Close laboratory monitoring is done to avoid excessive heparinization, and clinical response is monitored by Doppler ultrasonography. The best method for monitoring heparinization remains controversial. (McDonald et al., 1981; Ignjatovic et al., 2006; Monagle et al., 2008; Newall et al., 2009).

1292 PART XV I I  Renal and Genitourinary Systems

Low molecular weight heparins (LMWHs) have some advantages over unfractionated heparin, thereby making them safe and efficacious alternatives to unfractionated heparin therapy. LMWHs have superior bioavailability, a longer half-life, and dose-independent clearance, which give a more predictable anticoagulant response. The incidences of heparin-induced thrombocytopenia and osteoporosis are rare with LMWHs; they can be used in neonates with poor venous access because they are administered subcutaneously. LMWHs also do not need frequent laboratory monitoring and dose adjustment (Albisetti and Andrew, 2002). In case of potential life-threatening complications of aortic or renal thrombosis, fibrinolytic therapy (systemic or intrathrombotic) along with supportive care is indicated. There are limited data on efficacy, dose, and safety of fibrinolytic agents in infants (MancoJohnson et al., 2002; Monagle et al., 2008). The intrathrombotic infusion of fibrinolytic agent reduces the cumulative dose and possible systemic adverse effects. Close monitoring by ultrasonography or angiography should be done to evaluate the response to this therapy. Fibrinolytic agents act by catalyzing the conversion of endogenous plasminogen to plasmin. The most commonly used agent is recombinant tissue plasminogen activator (tPA). The major complication of tPA therapy is bleeding. Thrombocytopenia and vitamin K deficiency, if present, should be corrected before the start of treatment. Development of intraventricular hemorrhage or cerebral edema should be monitored closely. Mild bleeding secondary to fibrinolytic therapy can be stopped with local pressure. In the event of major bleeding, tPA should be stopped and intravenous fresh frozen plasma or cryoprecipitate should be given. The antifibrinolytic agent aminocaproic acid (Amicar) should be considered if the bleeding is life threatening.

Prognosis The overall mortality rate with aortic and renal arterial thrombosis is between 9% and 20%, with mortality being higher with major aortic and renal arterial thrombosis (Nowak-Gottl et al., 1997). Renovascular hypertension is the most common long-term complication of renal arterial thrombosis. In most cases, these infants eventually are weaned from antihypertensive medications and remain normotensive. Another consequence of renal arterial thrombosis is chronic renal insufficiency caused by irreversible renal parenchymal damage; this is seen less frequently but always in cases with severe aortic and bilateral renal arterial thrombosis.

Renal Vein Thrombosis Incidence and Etiology Renal vein thrombosis (RVT) is the most common thrombosis in infancy and occurs primarily in the newborn period. It has an incidence of 2.2 cases per 100,000 live births (Bokenkamp et al., 2000). RVT has a male predominance of approximately 67%; it is unilateral in more than 70% of patients and more prevalent on the left side (approximately 63%). The thrombus also involved the inferior vena cava in approximately 43% of the cases, and it was associated with adrenal hemorrhage in approximately 15% (Dauger et al., 2009; Lau et al., 2007). The cause of RVT is unknown, although a number of factors are associated with this disorder. Prothrombotic factors—including lupus anticoagulant, protein C, protein S, plasma antithrombin III activity, lipoprotein (a), factor V Leiden mutation, prothrombin gene mutation, and methylenetetrahydrofolate (MTHFR) thermolabile mutation—have a significant role in the pathogenesis of neonatal RVT (Kosch et al., 2004; Marks et al., 2005; Lau et al.,

2007). Other associated factors are maternal diabetes, traumatic delivery, prematurity, hyperviscosity, hypovolemia, hemoconcentration, sepsis, birth asphyxia, cyanotic congenital cardiac disease, congenital renal vein defects, and an indwelling umbilical venous catheter (Nowak-Gottl et al., 1997; Bokenkamp et al., 2000; Proesmans et al., 2005; Lau et al., 2007).

Clinical Presentation There are three cardinal signs of RVT: macroscopic hematuria, palpable abdominal mass, and thrombocytopenia; these signs have been found in approximately 56%, 45%, and 47% of cases, respectively (Lau et al., 2007). Other signs and laboratory findings associated with RVT are oliguria or anuria, hemolytic anemia, metabolic acidosis, azotemia, and variable prothrombin and partial thromboplastin times. Diagnosis Renal ultrasonography is a useful and convenient way of diagnosing RVT. It shows unilaterally or bilaterally enlarged and echogenic kidneys with attenuation or loss of corticomedullary differentiation and little blood flow. In many cases, calcification and thrombus may be seen extending into the inferior vena cava (Proesmans et al., 2005). Doppler studies are useful for detecting resistance or absence of flow in renal venous branches and collateral vessels. Thrombosis in small intrarenal veins can cause increased resistance in renal arteries, even when blood flow in the main renal vein and its branches is normal (Lau et al., 2007). Length of the kidney has been reported to correlate negatively with renal outcomes (Winyard et al., 2006). Ultrasonography may also be used as a prognostic tool. Although renal ultrasonography is the most commonly used imaging modality for diagnosing RVT, contrast angiography is considered the gold standard. Angiography, however, is invasive and requires exposure to ionizing radiation and can be performed only in a neonate in a stable condition. MRI has also been reported to give excellent diagnostic findings in RVT, although it should be reserved for those cases in which Doppler findings are inconclusive (Basterrechea Iriarte et al., 2008). Treatment Treatment of neonatal RVT remains controversial because there is not enough literature to compare supportive therapy with anticoagulation, fibrinolysis, or both. Supportive therapy should be provided to all affected infants in an attempt to correct any abnormalities in fluid, electrolyte, and acid–base balance. Hypertonic solutions, nephrotoxic medications, hyperosmotic radiographic contrast agents, and unnecessary use of diuretics should be avoided. Prophylactic heparin therapy has been recommended in a majority of cases to prevent thrombus extension by some authors (Dauger et al., 2009), whereas others report similar renal outcomes between supportive treatment and heparin therapies, including a similar proportion of atrophic kidneys secondary to RVT in neonates whether they were managed supportively or with heparin (Lau et al., 2007). LMWH is being used more frequently than unfractionated heparin for anticoagulation. Fibrinolysis is usually reserved for more severe cases, such as bilateral thrombosis and systemic effects (Dauger et al., 2009). Whichever the treatment approach, affected neonates must be followed closely for renal complications such as hypertension, chronic renal insufficiency, and renal atrophy. Surgical interventions such as thrombectomy or nephrectomy have not shown any benefit. Thrombectomy prevents the main



CHAPTER 90  Acute Kidney Injury and Chronic Kidney Disease  1293

thrombus from extending into the inferior vena cava or contralateral kidney, but it does not prevent renal infarction because smaller intrarenal veins are almost always involved.

Prognosis Renal scarring and atrophy are well-recognized complications of RVT in the affected kidney, which can be assessed with a radionuclide scan. Approximately 19% of patients have persistent elevation of blood pressure, which has been shown to be slightly higher—at 21% for those with bilateral RVT. The mortality rate for neonates with RVT is approximately 3% (Lau et al., 2007). Most of the deaths are due to underlying disease and not RVT or secondary renal dysfunction. Because more than 80% of neonates with RVT have shown persistent abnormalities on renal imaging and there are not enough data on long-term outcome of such neonates, continued follow-up is strongly recommended.

Renal Cortical and Medullary Necrosis Incidence and Etiology Renal cortical and medullary necrosis is uncommon in newborns and usually encountered in critically ill newborns as a manifestation of perinatal and postnatal stress leading to end-organ injury. It is usually diagnosed on autopsy or manifested as elevated and persistent kidney dysfunction. The incidence is 5% in infants who die at less than 3 months of age (Lerner et al., 1992). Risk factors associated with renal cortical and medullary necrosis are congenital heart disease, perinatal anoxia, placenta abruption, twin–twin or twin–maternal transfusions, sepsis, infectious myocarditis, vascular malformations, dehydration, prematurity, respiratory distress syndrome, bleeding diathesis, cardiac catheterization, and intravenous contrast agents (Nygren et al., 1988; Lerner et al., 1992). Pathophysiology Medication administration, blood loss, and ischemia can interfere with compensatory mechanisms to maintain renal perfusion and can lead to acute tubular necrosis that, depending on the severity of the insult, then may lead to vasculature injury and microthrombi formation with subsequent renal cortical and medullary necrosis. Administration of ACE-Is in the context of hypoperfusion can decrease the perfusion pressure in the glomerulus and can precipitate acute renal failure and, eventually, renal cortical necrosis. Clinical Presentation The clinical manifestations include hematuria, oliguria, rising SCr, and renal enlargement, which are nondiagnostic and associated with many other common neonatal renal abnormalities. Because renal cortical and medullary necrosis usually develops in critically ill newborns in the setting of shock, this needs to be explored in all critically ill neonates with abnormal renal function. Diagnosis In renal cortical and medullary necrosis, laboratory features may be present, such as hematuria, elevated blood urea nitrogen and creatinine, and thrombocytopenia. Renal ultrasound examination results are normal initially but may show small kidneys that are hyperechoic for age, loss of corticomedullary differentiation, and progressive decreased kidney size. A radionucleotide renal scan shows decreased to no perfusion with delayed or no function (Andreoli., 2004).

Management and Prognosis Infants with cortical necrosis may have partial recovery or no recovery at all. Typically they need RRT, short-term or long-term, but those who recover enough renal function to be managed without dialysis are at risk for late development of chronic renal failure.

Chronic Kidney Disease Neonatal CKD is diagnosed when sustained derangements of glomerular filtration or tubular function occur with minimal to no resolution over time. In many cases, CKD follows AKI, and in others the acute phase of the renal compromise has not been detected or has occurred in utero, often as a result of anatomic abnormalities (e.g., hypoplasia, dysplasia, malformations). In that setting, the diagnosis of CKD is established without documented evidence of preexisting AKI. According to guidelines published by the Kidney Disease Outcomes Quality Initiative (KDOQI), CKD is present if there is evidence of kidney damage for more than 3 months, as defined by structural or functional abnormalities, with or without decreased GFR, or a GFR less than 60 mL/min per 1.73 m2 for more than 3 months in children older than 2 years with or without kidney damage. These guidelines do not apply to infants less than 2 years of age, as a result of ongoing maturation of the kidney and improvement in GFR over the first 2 years of life. In turn, the KDIGO guidelines from 2012 recommend that for the classification of CKD in neonates and infants, available normative values and conventionally accepted equations should be used to classify neonatal CKD into one of three categories: normal (GFR <1 standard deviation [SD] below the mean); moderately reduced (GFR >1 SD to ≤2 SD below the mean); or severely reduced (GFR >2 SD below the mean) (Zaritsky and Warady, 2014). Currently, the updated Schwartz formula derived using iohexol clearance and enzymatically measured creatinine is the most commonly used equation to estimate GFR using SCr; however, that equation is based on data derived from children greater than 1 year of age (Schwartz et al., 2009). Recent studies suggest that equations incorporating the use of cystatin C, renal mass, and body surface area may provide a more accurate assessment of GFR, at least for neonates (Treiber et al., 2015). ESRD, the point at which dialysis or kidney transplantation is necessary to ameliorate the physiologic complications of uremia owing to kidney failure, represents the most severe stage of CKD. The pathophysiologic mechanisms leading to the progression of AKI to CKD and ESRD are discussed earlier in this chapter.

Epidemiology There is little information on the incidence and prevalence of CKD in neonates and infants, due to the lack of a uniform definition. In one small study, the estimated incidence of CKD was 1 : 10,000 live births with a male to female ratio of 2.8 : 1. The most common causes of CKD in neonates are renal dysplasia and obstructive uropathy (Wedekin et al., 2008; Mekahli et al., 2010; Harambat et al., 2012; Carey et al., 2015). The male predominance results from the finding that posterior urethral valves are the most frequent congenital obstructive disorder. In a small German study, 53% of children with CKD were premature, a figure significantly higher than the rate experienced by the total infant population of Germany (Wedekin et al., 2008). A publication from the Chronic

1294 PART XV I I  Renal and Genitourinary Systems

Kidney Disease in Children (CKiD) cohort also revealed a high prevalence of children with CKD who had an abnormal birth history as defined by low birth weight (17%), small for GA (14%), or prematurity defined as GA less than 36 weeks (12%) (Greenbaum et al., 2011). In a study of more severe CKD, 35% of affected patients were born prematurely, and approximately 50% had a comorbidity, such as cardiopulmonary and/or neurologic involvement (Mekahli et al., 2010). Most epidemiologic reports focus on the development of ESRD in this age group. These studies demonstrate a varying regional incidence of ESRD, and the worldwide incidence is unknown. In one study, the estimated incidence of neonatal ESRD in the United States and Canada was 0.32 in 100,000 live births (Carey et al., 2007). The European Registry for Children on Renal Replacement Therapy collects data from many countries across Europe and recently reported the incidence of ESRD in children aged 0–4 years to be around 5.2 per million children (Chesnaye et al., 2015). The incidence in the 0–4 years age group as reported by the United States Renal Data System was 10.3 per million US population in this age group. This age group makes up between 10%–20% of all children who receive RRT (dialysis and transplantation) (Assadi, 2013; Borzych-Duzalka et al., 2013). Studies show that wealthier countries, those that spend more on health care, and countries where patients pay less out of pocket expenses have higher rates of RRT initiation. Thus much of the variability is likely explained by socioeconomic factors and less by genetic susceptibility to renal disease (Chesnaye et al., 2015).

Clinical Sequelae Pathophysiology of Anemia Anemia is a frequent complication of CKD in infants and children, and the prevalence of anemia increases with worsening stages of CKD. Recently, a study by Atkinson et al. (2010) revealed that 73% of pediatric patients with CKD stage 3 (GFR 30–59 mL/ min per 1.73 m2) were anemic. This percentage increased to 93% of those with CKD stage 5 (GFR <15 mL/min per 1.73 m2 or dialysis). The anemia of CKD is an important predictor of patient morbidity and mortality. It is associated with a number of physiologic abnormalities, including decreased tissue oxygen delivery, increased cardiac output, cardiac enlargement, ventricular hypertrophy, congestive heart failure, and impaired immune responsiveness (Gafter et al., 1994; Mitsnefes et al., 2000; Borzych-Duzalka et al., 2013). There is also evidence to suggest that the presence of anemia is associated with an increased risk of hospitalization in children with CKD (Staples et al., 2009). The pathophysiology of anemia in infants and young children with CKD is primarily the result of a decrease in the renal production of erythropoietin, iron deficiency, or both (Koshy and Geary, 2008). Other potential contributing factors include a shortened red blood cell life span, secondary hyperparathyroidism, hypothyroidism, folate and vitamin B12 deficiency, chronic inflammation, and hemoglobinopathies. In the early stages of CKD, iron deficiency tends to be common, and in one study of pediatric CKD patients, Baracco et al. (2011) found that 25% of patients with CKD stage 2 and 55% of patients with stage 3 CKD had iron deficiency. The cause of absolute iron deficiency is multifactorial and can be related to poor intake, gastrointestinal blood loss, and repeated phlebotomies for laboratory tests. Erythropoietin deficiency becomes more prevalent in the later stages of CKD. Children may also be particularly prone to factors that contribute to relative erythropoietin resistance including

hyperparathyroidism, aluminum toxicity, and hemolysis (Bamgbola 2011). The decreased erythropoietin production from the kidney ultimately leads to anemia through increased apoptosis of red blood cell precursors in the bone marrow, often accompanied by iron deficiency related to the factors listed above, as well as an increased production and decreased excretion of hepcidin (Atkinson and Furth, 2011; Ganz and Nemeth, 2016).

Management of Anemia According to the KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Anemia in Chronic Kidney Disease produced by the National Kidney Foundation, anemia is defined as an Hgb concentration less than the fifth percentile of normal for age and sex (Table 90.8) (KDOQI, 2007). The normative values used to define anemia in children older than 1 year are taken from the third National Health and Nutrition Examination Survey (Astor et al., 2002) database, whereas the norms for infants younger than 1 year are derived from other reference sources (Nathan, Orkin, 2003). Recently, KDIGO released recommendations for the diagnosis of anemia in CKD that defined anemia as Hgb less than 11.0 g/dL in children 0.5–5 years (KDIGO Group, 2012). The KDOQI guidelines recommend checking Hgb in all patients with CKD at least annually. In those children found to be anemic, the initial work-up should include red blood cell indices, reticulocyte count, white blood cell count with differential and platelet count, and iron parameters (serum iron, total iron binding capacity, and serum ferritin). These guidelines also recommend targeting an Hgb level between 11.0 and 13.0 g/dL as part of anemia management in pediatric patients with CKD (KDOQI and National Kidney Foundation, 2006; KDOQI, 2007). Erythropoiesisstimulating agents (ESAs) such as recombinant erythropoietin-alfa (EPO) and darbepoetin, an analogue of erythropoietin with a longer half-life, along with iron supplements, are the key elements of anemia management in CKD. Both ESAs appear to have equal efficacy and similar safety profile (Hattori et al., 2014; Schaefer et al., 2016) and have been studied in premature infants (Ohls et al., 2013). When treated with an ESA, infants and young children

TABLE 90.8 

Hemoglobin Levels in Children Between Birth and 24 Months for Initiation of Anemia Work-Up Mean Hb (gm/dL)

–2 SDa

Term (cord blood)

16.5

13.5

1–3 days

18.5

14.5

1 week

17.5

13.5

2 weeks

16.5

12.5

1 month

14.0

10.0

2 months

11.5

9.0

3–6 months

11.5

9.5

6–24 months

12.0

10.5

Age

a Values two standard deviations below the mean are equivalent to less than 2.5th percentile. Data taken from normal reference values. From National Kidney Foundation. KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Anemia in Chronic Kidney Disease. Am J Kidney Dis. 2006;47:S88.



CHAPTER 90  Acute Kidney Injury and Chronic Kidney Disease  1295

generally require larger doses than older children and adults, despite having a higher capacity for hematopoiesis. Whereas the average dose of EPO for children with CKD is 200–250 units/kg per week given by the subcutaneous route, younger children (<1 year) often require doses as high as 400 units/kg three times per week. This dose discrepancy holds true for patients receiving dialysis as well. Infants on dialysis have required doses averaging from 300–350 units/kg per week compared with those patients greater than 12 years whose dose averages around 200 units/kg per week. Children receiving HD typically require more EPO than patients receiving PD, as a result of the blood loss that routinely occurs with HD. Iron therapy typically consists of the provision of oral elemental iron in doses ranging from 2 to 3 mg/kg per day up to 6 mg/kg per day in two to three divided doses (KDOQI and National Kidney Foundation, 2006). Iron should be taken 2 hours before or 1 hour after all calcium-containing phosphate binders in patients with CKD and a history of hyperphosphatemia to maximize gastrointestinal absorption. In HD patients, intravenous iron administration is often recommended because of inadequate iron absorption after oral administration coupled with increased losses of blood and iron during the HD treatments. Levels of serum ferritin greater than 100 ng/mL and transferrin saturation values greater than 20% are believed to reflect adequate iron stores in patients with CKD (KDOQI and National Kidney Foundation, 2006).

Growth and Development Children with CKD often experience some degree of growth failure, which may start as early as CKD stage 3 (Hamasaki et al., 2015). The cause of the disordered growth in patients with CKD is a multifactorial process. Protein-calorie malnutrition, metabolic acidosis, electrolyte disarray, renal osteodystrophy, changes in the gonadotropic hormone axis in the face of uremia, and corticosteroid treatment are all factors that contribute to this challenging problem (Haffner, 2008). The growth failure that exists is especially concerning when CKD occurs in infancy, a time that is normally characterized by rapid growth. Many studies have demonstrated already delayed growth at the time of dialysis initiation that has persisted through at least the first year following dialysis initiation (van Stralen, 2011; Borzych-Duzalka et al., 2014). Young children on dialysis have historically often failed to grow normally, despite meeting 100% of the recommended daily allowance of caloric and protein intake (Shroff et al., 2003; Stańczyk et al., 2016). Thankfully, growth outcomes of infants with ESRD have improved over time, possibly because of advances in medical, nutritional, and surgical therapies (Ledermann et al., 1999; Hijazi et al., 2009). Recent reports have also described improved longitudinal growth and sustained catch-up growth in infants with CKD in whom recombinant growth hormone treatment was initiated in the first year of life. Similar results have also been obtained with intensive nutritional regimens (Fine et al.,1995; Maxwell, 1996; Mencarelli et al., 2009; Santos et al., 2010; Rees, 2015). Finally, growth outcomes regularly improve after transplantation in young patients in whom accelerated growth may occur (Fine et al., 2010; NAPRTCS, 2014). Renal impairment in infancy, a crucial time of neural development, raises concerns regarding the neurodevelopmental outcomes in children with ESRD. Advanced CKD has been linked to poor neurocognitive function in the areas of attention, memory, and inhibitory control (Hooper et al., 2011; Ruebner et al., 2015). Recently, small studies examining the effect of ESRD during infancy on neurocognitive development have suggested that there may be minor delays in intellectual and metacognitive function but that

most children without other comorbidities do not experience significant developmental delay (Johnson and Warady, 2013). Other comorbidities of CKD (e.g., anemia, iron deficiency, hypertension, cerebral vascular accidents, adverse effects of therapy) have been implicated in the neurodevelopmental impairments in many patients, and these comorbidities may explain the association between duration of CKD and impaired executive function (Geary, 1998; Lande et al., 2011; Johnson and Warady, 2013; Mendley et al., 2015). Genetic syndromes involving the central nervous system may also influence neurocognitive outcomes for these patients (Verbitsky et al., 2015). While larger studies are needed to provide additional data, it is clear that neurocognitive outcomes have improved for infants with ESRD over the past two decades, likely related to improved dialysis techniques, better nutrition, and avoidance of exposure to aluminum (Andreoli et al., 1984; Freundlich et al., 1985).

Nutrition Nutritional Assessment The origin of malnutrition in children with CKD is multifactorial; however, an inadequate voluntary intake is considered a major contributing factor, especially in infants. Nausea and vomiting are common in infants and children with CKD, with delayed gastric emptying and gastroesophageal reflux detected in as many as 75% of patients with these problems (Ruley et al., 1989). Protein energy wasting (PEW) is a common problem in patients with CKD and may be another major contributor to poor growth in the first few years of life. The International Society of Renal Nutrition and Management has identified specific biochemical evidence (i.e., low albumin, cholesterol, or transthyretin), reduced body mass index, and reduced muscle mass as the primary characteristics of PEW in adults (Fouque et al., 2008; Ingulli and Mak, 2014). Additional studies specific to the pediatric CKD and dialysis population have confirmed the importance of these factors, along with short stature as features characterizing PEW. Whereas few body composition studies of very young CKD patients have been performed, weightfor-length is often below average for infants with CKD who have not received calorie supplements, and small studies suggest that infants with CKD may have lean muscle mass deficits (Foster et al., 2012). However, the most prominent feature of inadequate nutrition in this population is linear growth restriction (KDIGO, 2009). Modified PEW scores as a reflection of poor nutrition in pediatric patients have also been associated with an increased risk for hospitalization, disease progression, and neurocognitive complications (Abraham et al., 2014). In view of the importance of nutritional status to the outcome of the infant and young child with CKD, frequent monitoring of the patient is mandatory. Collaboration with a pediatric renal dietician is beneficial to assist in the nutritional evaluation and treatment strategy. An age-related schema for parameters and frequency of nutritional assessment for patients with CKD has recently been published (Table 90.9) (KDIGO, 2009). The World Health Organization Growth Standards of length-for-age, weightfor-age, weight-for-length, body mass index–for-age, and head circumference–for-age should be used as the reference for children from birth to 2 years (WHO, 2006). Nutritional intervention is indicated in children with CKD when there are findings that include an impaired ability to ingest or tolerate oral feedings, a body mass index value less than the fifth percentile of height-for-age, an acute weight loss of 10% or more, or a length/height ratio more than two SDs less than the mean. However, neonates with

1296 PART XV I I  Renal and Genitourinary Systems

TABLE 90.9 

Recommended Parameters and Frequency of Nutritional Assessments for Children With Chronic Kidney Disease Stages 2 to 5 and 5d MINIMUM INTERVAL (MONTHS) AGE 0 TO <1 YEAR

Measure

CKD 2–3

CKD 4–5

AGE 1 TO 3 YEARS

CKD 5D

CKD 2–3

CKD 4–5

CKD 5D

Dietary intake

0.5–3

0.5–3

0.5–2

1–3

1–3

1–3

Height or length-for-age percentile or SDS

0.5–1.5

0.5–1.5

0.5–1

1–3

1–2

1

Height or length velocity–for-age percentile or SDS

0.5–2

0.5–2

0.5–1

1–6

1–3

1–2

Estimated dry weight and weight-for-age percentile or SDS

0.5–1.5

0.5–1.5

0.25–1

1–3

1–2

0.5–1

BMI-for-height-age percentile or SDS

0.5–1.5

0.5–1.5

0.5–1

1–3

1–2

1

Head circumference–for-age percentile or SDS

0.5–1.5

0.5–1.5

0.5–1

1–3

1–2

1–2

BMI, Body mass index; CKD, chronic kidney disease; SDS, standard deviation score. Modified from National Kidney Foundation. KDOQI Clinical Practice Guideline for Nutrition in Children with CKD: 2008 Update. Am J Kidney Dis. 2009;53:S16.

TABLE 90.10 

Equations to Estimate Energy Requirements for Children at Healthy Weights

Age (months)

EER (kcal/d) = Total Energy Expenditure + Energy Deposition

0–3

EER = [89 × weight (kg) – 100] + 175

4–6

EER = [89 × weight (kg) – 100] + 56

7–12

EER = [89 × weight (kg) – 100] + 22

13–35

EER = [89 × weight (kg) – 100] +20

EER, Estimated energy requirement. Modified from National Kidney Foundation. KDOQI Clinical Practice Guideline for Nutrition in Children with CKD: 2008 Update. Am J Kidney Dis. 2009;53:S36.

CKD should be considered to be at nutritional risk if they are preterm or are characterized by any of the following: • Low birth weight (<2500 g) • A birthweight z score less than –2 SD for GA • Polyuria and associated renal salt wasting

Nutritional Management In children with CKD, the spontaneous energy intake decreases with deteriorating kidney function. Energy intake is the principal determinate of growth during infancy. Energy requirements should, in turn, be considered to be 100% of the estimated energy requirement for chronologic age (Table 90.10) (Ruley et al., 1989; National Academies Press, 2002; KDOQI, 2009; Foster et al., 2012). Malnutrition has the most marked negative effect on the growth of children with congenital disorders leading to CKD. Supplemental nutritional support is indicated when the voluntary intake by the child fails to meet energy requirements and the child is not achieving expected rates of weight gain or growth for age. In infants requiring fluid restriction because of their impaired kidney function, oral intake of an energy-dense diet with a milk formula that has a caloric density greater than 20 kcal/oz and the appropriate phosphorus content for CKD stage is preferred. If poor appetite or vomiting preclude an adequate oral intake, tube feedings (e.g., nasogastric, gastrostomy, gastrojejunostomy) should be considered

and provided by either bolus or continuous infusion. The development of repeated emesis in children fed per nasogastric tube has prompted the use of gastrostomy as the preferred route of therapy (Warady et al., 1996). In infants younger than 1 year, an initial infusion rate of 10 to 20 mL/hour or 1 to 2 mL/kg per hour is generally well tolerated, to be followed by a daily increase of 5 to 10 mL per 8 hours or 1 mL/kg per hour toward achieving the treatment goal. It is imperative that tube-fed infants be encouraged to continue some oral intake or have oral stimulation (e.g., pacifier) if persistent feeding dysfunction is to be prevented. Whereas the spontaneous dietary protein intake (DPI) is reduced in progressive CKD in a manner similar to that of energy intake, the DPI of the patient with CKD is typically far in excess of the average requirements. At the same time, there is no evidence that strict dietary protein restriction has any nephroprotective effect (Chaturvedi and Jones, 2007), whereas aggressive restriction has been noted to compromise the growth of infants with CKD (Uauy et al., 1994). Because moderate dietary protein restriction reduces the accumulation of nitrogenous waste products, decreases acid load, and helps to lower dietary phosphorus intake (which helps preclude bone-mineral and cardiovascular complications), it is appropriate to gradually lower the DPI toward 100% of the dietary reference intake (DRI) as CKD progresses toward the need for dialysis (Ruley et al., 1989). More specifically, a DPI of 100%–140% DRI for CKD stage 3, 100%–120% DRI for CKD stage 4 to 5, and 100% DRI for CKD stage 5D (dialysis) have been proposed (Table 90.11) (KDOQI, 2009). In patients receiving dialysis, the dietary protein requirements are increased to account for dialysisrelated protein losses.

Acid–Base and Electrolytes Fluid and electrolyte requirements of children with CKD vary according to their primary kidney disorder and the degree of residual kidney function. Infants and children normally have a relatively larger endogenous hydrogen ion load (2–3 mEq/kg) than adults, resulting in metabolic acidosis as a common manifestation of CKD in children and an important negative influence on growth. Metabolic acidosis leads to changes in bone composition and decreases in 1,25-(OH)2D synthesis, in addition to endogenous growth hormone and recombinant growth hormone resistance (de-Brito Ashurst et al., 2015). Based on the experience of successfully

CHAPTER 90  Acute Kidney Injury and Chronic Kidney Disease  1297



TABLE 90.11 

Recommended Dietary Protein Intake for Children with Chronic Kidney Disease Stages 3 to 5 and 5d DRI

DRI (g/kg per day)

Recommended for CKD Stage 3 (g/kg per day) (100%–140% DRI)

Recommended for CKD Stages 4–5 (g/kg per day) (100%–120% DRI)

Recommended for HD (g/kg per day)a

Recommended for PD (g/kg per day)b

0–6 months

1.5

1.5–2.1

1.5–1.8

1.6

1.8

7–12 months

1.2

1.2–1.7

1.2–1.5

1.3

1.5

1–3 years

1.05

1.05–1.5

1.05–1.25

1.15

1.3

Age

DRI + 0.1 g/kg per day to compensate for dialytic losses. DRI + 0.15–0.3 g/kg per day depending on patient age, to compensate for peritoneal losses. CKD, Chronic kidney disease; DRI, dietary reference intake; HD, hemodialysis; PD, peritoneal dialysis. Modified from National Kidney Foundation. KDOQI Clinical Practice Guideline for Nutrition in Children with CKD: 2008 Update. Am J Kidney Dis. 2009;53:S49. a

b

enhancing the growth of infants and children with isolated renal tubular acidosis with alkali therapy (McSherry and Morris, 1978), it is recommended that children with CKD be treated to achieve a serum bicarbonate level of at least 22 mmol/L (KDOQI, 2009). A recent publication from the CKiD study revealed that a serum bicarbonate less than 18 mmol/L was a risk factor for poor growth. The fact that a minority of the children with a low bicarbonate level were receiving supplemental bicarbonate therapy emphasizes the importance of being vigilant with respect to evaluation and treatment (Rodig et al., 2014). In recent studies in adults with CKD, correction of metabolic acidosis led to a decreased rate of CKD progression (de Brito-Ashurst et al., 2009; Mahajan et al., 2010; Phisitkul et al., 2010). This finding may translate to the pediatric population as well, but further studies are required. Whereas restriction of sodium and water is often indicated in children with CKD complicated by sodium and fluid retention and systemic hypertension, infants and children with CKD secondary to obstructive uropathy or renal dysplasia are often polyuric and may experience substantial urinary sodium and water losses despite experiencing advanced stages of CKD. Infants and children with salt-wasting forms of CKD who do not receive salt supplementation may in turn experience extracellular volume contraction, vomiting, constipation, and significant growth retardation (Parekh et al., 2001). The same holds true for infants receiving PD, with or without polyuria, as most patients lose significant quantities of sodium in the dialysate. Sodium depletion in the infant PD population has resulted in hypotension, cerebral edema, and blindness (Lapeyraque et al., 2003). Individualized therapy can, in turn, be achieved by first prescribing at least the age-related DRI of sodium and chloride (Table 90.12), with subsequent modification of therapy based on regular assessment of clinical and laboratory data. In PD patients, a dialysis sodium balance study may be performed to formally assess sodium losses through dialysis to help guide sodium supplementation (Foster et al., 2012). Close monitoring of blood pressure is imperative because, as noted previously, episodes of severe hypotension in young infants on PD have been associated with tragic neurologic complications. Potassium homeostasis in children with CKD is usually unaffected until the GFR falls to less than 10% of normal. However, infants and children with disorders such as renal dysplasia and reflux nephropathy often demonstrate renal tubular resistance to aldosterone and may experience hyperkalemia, even when the GFR

TABLE 90.12 

Dietary Reference Intake for Healthy Children for Sodium, Chloride, and Potassium SODIUM (mg/d)

Age

AI

Upper Limit

CHLORIDE (mg/d)

AI

Upper Limit

POTASSIUM (mg/d)

AI

Upper Limit

0–6 months

120

ND

180

ND

400

ND

7–12 months

370

ND

570

ND

700

ND

3000

ND

1–3 years

1000

1500

1500

2300

AI, Adequate intake. Modified from National Kidney Foundation. KDOQI Clinical Practice Guideline for Nutrition in Children with CKD: 2008 Update. Am J Kidney Dis. 2009;53:S49.

is preserved. The hyperkalemia can be exacerbated by volume contraction, as can be seen in patients with salt-wasting forms of CKD. In patients who remain hyperkalemic despite repletion of salt and water, restriction of dietary potassium intake is critical. For infants and young children, the provision of 40 to 120 mg (1–3 mmol/kg per day) of potassium may be a reasonable place to start. Breast milk has a lower potassium content (546 mg/L; 14 mmol/L) than commercial milk-based infant formula (700–740 mg/L; 18–19 mmol/L) and may be preferred (KPOQI, 2009). Pretreatment of infant formula with a potassium binder such as sodium polystyrene sulfonate may also help address hyperkalemia in infants. Typically, 0.5 to 1.5 g of sodium polystyrene sulfonate is added to every 100 mL of formula or expressed breast milk. Recent studies suggest that this therapy significantly alters the composition of other electrolytes in a formula-dependent manner and mandates close monitoring. Calcium supplementation and sodium restriction may be required (Thompson et al., 2013). The powdered form of sodium polystyrene sulfonate is also recommended due to the presence of a high aluminum concentration in liquid preparations (Taylor et al., 2015). Constipation and certain medications (e.g., potassium-sparing diuretics, ACE-Is, angiotensin-receptor blockers) may exacerbate hyperkalemia in infants with CKD and should be addressed. Finally, the use of potassium-wasting diuretics

1298 PART XV I I  Renal and Genitourinary Systems

(e.g., furosemide) may also be utilized for the treatment of hyperkalemia in those patients who have urine output (Bunchman et al., 1991; Fassinger et al., 1998).

Renal Osteodystrophy Infants with CKD and secondary hyperparathyroidism may experience improvement subsequent to the initiation of RRT. One study followed 17 patients initiating HD between birth and 2 years of age and found that the percentage of patients with intact parathyroid hormone (iPTH) concentrations less than twice the upper limit of normal increased after 3 months of HD (41% at initiation vs 69% after 3 months) (Shroff et al., 2003). Another study of 20 infants on long-term PD revealed similar results (58% after 6 months of PD vs. 100% after 1 year of PD) (Ledermann, 2000). Further study regarding the prevalence of renal osteodystrophy in this population is needed.

Renal Replacement Therapy ESRD is an uncommon disorder in children less than 4 years of age, with an incidence of 5.2–10.3 per million age-related population (Chesnaye et al., 2015). Neonatal ESRD is even less common with an incidence of approximately 0.32 per 100,000 live births (Carey et al., 2007). A large international registry study of neonates on RRT showed that they made up between 6.8% and 18.3% of all infants less than 2 years of age on dialysis. Major causes of ESRD in the 0 to 2-year age group include congenital anomalies of the kidney and urinary tract and cystic kidney disease (van Stralen et al., 2014). Although kidney transplantation is the nearly universal goal for children who develop ESRD, data from the most recent North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) annual report revealed that 80% of children under 2 years old who received a renal transplant also received chronic dialysis before transplantation (NAPRTCS, 2014).

Peritoneal Dialysis PD is the preferred chronic dialysis modality for infants with ESRD. A recent publication from NAPRTCS has shown that greater than 90% of patients 0 to 1-year-old receiving dialysis were receiving PD at dialysis initiation (NAPRTCS 2011; Carey et al., 2015). The mechanics of chronic PD (CPD) are similar to those discussed above for acute PD. While the CPD prescription initially mirrors that of acute PD, the fill volume is subsequently titrated upwards during CPD to a goal of 600 to 800 mL/m2 body surface area in infants during each exchange; the duration of the dwell is adjusted to reach predefined adequacy metrics in terms of solute and fluid removal (National Kidney Foundation, 2006). The complications of PD are similar for acute and chronic PD. The single most serious complication is peritonitis, which occurs more frequently in infants than older children (NAPRTCS, 2011; Sethna et al., 2016). Some data suggest that peritonitis is increased in infants with oligoanuria (Vidal et al., 2012). Whereas grampositive organisms account for the majority of infections, gramnegative episodes of peritonitis are common in infants and young children (Zurowska et al., 2008), and the percentage of gramnegative and polymicrobial peritonitis episodes may be on the rise (Hijazi et al., 2009). Empiric therapy for peritonitis should, in turn, always provide coverage for gram-positive and gram-negative organisms (Warady et al., 2012). Other CPD-related complications that occur most frequently during infancy include anterior ischemic

optic neuropathy and sudden blindness secondary to hypovolemia, excessive loss of protein across the peritoneal membrane, and hernia formation (Quan and Baum, 1996; Lapeyraque et al., 2003; Hijazi et al., 2009).

Hemodialysis The use of HD during infancy is most often dictated by the presence of a medical condition (e.g., omphalocele, gastroschisis, diaphragmatic hernia, bladder exstrophy) that compromises the ability to use the peritoneal membrane as a dialyzing membrane. The HD procedure during infancy is complicated, and limited clinical experience has revealed a high incidence of patient morbidity (Al-Hermi et al., 1999; Shroff et al., 2003; Kovalski et al., 2007). As noted above, the complicated nature of the HD procedure mandates that it is performed only in highly qualified centers with access to pediatric dialysis expertise. Recent studies of complications for infants on chronic HD reveal improvement in central venous catheter life in recent years but continued high rates of hypertension, psychomotor retardation, and hospitalization (Feinstein et al., 2008; Quinlan et al., 2013; Pollack et al., 2016).

Transplantation The topic of kidney transplantation in patients who develop ESRD as neonates or young infants is complicated, and a lengthy discussion is beyond the scope of this chapter. In short, however, transplantation is a viable alternative for these young patients and is their best hope for long-term survival. In a review of NAPRTCS data, 20% of 0 to 1-year-olds and 24% of 2 to 5-year-olds with ESRD received a preemptive (e.g., no prior dialysis) transplant. Only eight infant transplants (<1 year of age) have been performed and entered into the NAPRTCS registry since 2008 (NAPRTCS, 2014). The overall transplant rates and graft survival rates for some of the largest and most recent studies of outcomes in neonates or young children with ESRD are listed in Table 90.13. Graft survival in patients who developed ESRD as neonates or infants has improved (Carey et al., 2015), and the rates of graft survival for the two groups are similar. These improvements in transplant rates and graft survival likely contribute to the improved overall survival of these patients and likely will improve further as outcomes in regards to other comorbidities, such as cardiovascular disease and growth, also improve. What is often most important for the neonatologist is recognition of the need to develop a collaborative strategy with members of the pediatric nephrology, surgery, and urology teams for management of congenital structural abnormalities of the urinary tract that are present in the patient with severe CKD/ESRD, the majority of whom will ultimately require dialysis and transplantation (Sarwal, Salvatierra, 2004).

Outcomes Hospitalization There is emerging evidence to support the clinical expectation that a majority of neonates and infants with CKD or ESRD require frequent hospitalization throughout childhood. In one study of 18 children requiring chronic HD by 2 years of age, the median number of hospital admissions while receiving dialysis was 6 (range 3 to 16). Of those hospitalized, the median hospitalization rate per patient was 8.2 admissions per year with the duration of hospitalization ranging from 63 to 399 days (Shroff et al., 2003).

CHAPTER 90  Acute Kidney Injury and Chronic Kidney Disease  1299



TABLE 90.13 

Outcomes of Large Studies of Neonates and Infants With Severe Chronic Kidney Disease

Study Age Range

Carey et al. 2007 <2 years

Hijazi et al. 2009 <1 year

Mekahli et al. 2010 ≤2 years

Van Stralen et al. 2014 ≤1 month

Carey et al. 2015 <1 year

Population

ESRD n = 193 neonates n = 505 infants EC = 1992–1998 LC = 1999–2005

ESRD n = 52

GFR <20 mL/min per 1.73 m2 or requiring dialysis n = 101

ESRD n = 264

PD n = 241(neonates) n = 387 (infants) EC = 1992–1999 LC = 2000–2012

Database(s)

NAPRTCS

Single center

Single center

ESPN/ERA-EDTA, IPPN, Japanese, ANZDATA

NAPRTCS

Comorbidities

NR

48.1% overall

50.4% overall • 24% NDD • 4% pulmonary • 10% CV

73% overall • 20% NDD • 12% pulmonary • 18% CV

NR

Growth

NR

Height SD: Z = −3.0 ± 1.5 (EC) Z = −1.4 ± 0.9 (LC)

<3rd% adult height M: 42% F: 63%

63% GR

NR

Survival and hospital rate

Survival • 76% neonates • 80% infants Hospitalization • 80% neonates • 73% infants

Survival • 62% (1, 3 year) • 87% (5 year) If survived first year

w/out comorbidity 83.5% (2 year) 81.3% (5 year) w/comorbidity 78.4% (2 year) 72.3% (5 year)

Survival 81% (2 year) 76% (5 year)

73% overall Neonates 70.0% (EC) 91% (LC) Infants 75.8% (EC) 84.6% (LC)

Transplant rates

Neonates 60% (EC) 80% (LC)

75%

70%

21.9% (2 year) 54.9% (5 year)

Neonates 39% (EC) 68% (LC) Infants 53% (EC) 65% (LC)

Graft survival

NR

79% (1 year) 68% (5 year)

75% (10 year) 55% (15 year)

84.2% (5 year)

3-year survival Neonates 86.3% (EC) 84.2% (LC) Infants ~80% (EC) 92.1% (LC)

ANZDATA, Australian and New Zealand Dialysis and Transplantation; Cr-EDTA GFR, chromimium-51-EDTA glomerular filtration rate; CV, cardiovascular; EC, early cohort; ESRD, end-stage renal disease; ESPN/ERA-EDTA, European Society of Paediatric Nephrology/European Renal Association-European Dialysis and Transplant Association; F, female; GR, growth retardation; IPPN, International Pediatric Peritoneal Dialysis; LC, late cohort; M, male; NDD, neurodevelopmental delay; NR, not reported; PD, peritoneal dialysis; SD, standard deviation; Z, zone.

Another study divided 698 children requiring chronic dialysis within the first 2 years of life into those initiating dialysis by 1 month of age and those initiating dialysis between 1 month and 24 months of age. Approximately 80% of children in both groups required hospitalization at some point in the 13-year follow-up period. Among children ever hospitalized, those initiating dialysis as neonates were hospitalized more frequently than were children starting dialysis later (mean number of hospitalizations 54 vs 39; P < .001) and experienced longer hospital stays (Carey et al., 2007).

Survival Long-term survival of neonates with ESRD appears to be approaching that of older infants and young children. In several recent studies examining medium-term survival of neonates, infants, or

young children who started dialysis, the overall survival rates ranged from 70%–87% (Table 90.13) (Carey et al., 2007; Hijazi et al., 2009; Mekahli et al., 2010; van Stralen et al., 2014; Carey et al., 2015). Neonates on dialysis had only slightly lower survival rates compared with older infants and children (Carey et al., 2007; Carey et al., 2015). The main reasons for death included infection and cardiovascular disease. Concomitant neurologic disease and other comorbidities were associated with increased mortality (Mekahli et al., 2010; van Stralen et al., 2014). Studies that examined multiple time periods showed improved survival for neonates and infants in more recent years (Carey et al., 2007; Carey et al., 2015). Although the recent large studies suggest a good medium-term survival and support the recommendation for RRT in these complex patients, more long-term data are clearly needed.

1300 PART XV I I  Renal and Genitourinary Systems

Ethics of Initiating or Withdrawing Renal Replacement Therapy Decisions to withdraw or withhold treatment have to be made for many patients in neonatology units and for as many as 30%–58% of patients in pediatric intensive care units. The conceptual framework for medical decision making in seriously ill newborns attempts first to classify the anticipated therapy and outcomes as clearly beneficial, clearly futile, or of uncertain benefit. While families should be active participants in medical decision making, physicians may override a family’s wishes in situations deemed clearly beneficial or clearly futile. RRT for neonates and very young infants has long been considered of uncertain benefit due to unclear long-term outcomes. In turn, medical providers have often deferred to family members with regards to decisions about dialysis initiation and withdrawal in young patients. However, as dialysis has become more routinely offered to neonates and infants with ESRD and more published data on improved medium-term and long-term outcomes have become available, consideration has been given to classifying this therapy as clearly beneficial (Lantos and Warady, 2013). Nevertheless, few studies have directly examined the changing attitudes of medical providers on this issue. Geary and colleagues initially conducted an international survey on the attitudes of pediatric nephrologists regarding the management of ESRD during infancy nearly two decades ago (Geary, 1998). More than 200 physicians from eight countries replied to a series of questions pertaining to the provision of RRT to neonates younger than 1 month of age versus those 1 to 12 months old. At that time, 93% of respondents stated that they would offer dialysis to some patients less than 1 month of age, 41% would offer it to all patients less than one month of age, and 50% believed it was usually ethical for families to withhold RRT. In a follow-up study conducted by the same group using an almost identical survey 10 years later, 98% of pediatric nephrologists responded that they would offer dialysis to some patients less than 1 month of age, although only 30% of pediatric nephrologists would offer it to all patients less than one month of age. Additionally, there was a 25% increase compared with the earlier survey in those who thought it was the parents right to “usually” refuse RRT in neonates (Teh et al., 2011). In both studies, physicians responded that they more routinely provided dialysis to the older than 1-month to 12-month age group and thought it was less acceptable for families to refuse dialysis initiation for children of this age (Geary, 1998; Teh et al., 2011). The factors that most often influenced the decision to initiate or withhold RRT were the presence of coexistent serious medical disorders and the anticipation of significant morbidity for the child (Geary, 1998; Teh et al., 2011). Evidence for this age-related variation in

philosophy and practice has been seen in other surveys as well (Fauriel et al., 2004). Most clinicians agree that there is more to their skill than the indiscriminant application of technology. Factors to consider when making the decision regarding initiation or withdrawal of RRT during infancy include quality of life concerns, allocation of resources, legal issues, and, most importantly, the opinions of the hospital team and the parents. Future research into the ethical issues surrounding infant dialysis requires separation of isolated renal failure from renal failure in the setting of comorbid conditions, the cost financially, socially, and emotionally, and research into the informed consent around the initiation of chronic dialysis (Lantos and Warady, 2013). The role of hospital ethics committees in the process remains extremely variable. In the end, clinicians and parents often struggle bravely to reach a compassionate decision with as much agreement as possible. Principles of practice that may provide valuable assistance in this process have been published (Watson, 2004).

Suggested Readings Abdu AT, Kriss VM, Bada HS, Reynolds EW. Adrenal hemorrhage in a newborn. Am J Perinatol. 2009;26:553-557. Andreoli SP. Acute renal failure in the newborn. Semin Perinatol. 2004;28:112-123. Andrew ME, Monagle P, deVeber G, Chan AK. Thromboembolic disease and antithrombotic therapy in newborns. Hematology Am Soc Hematol Educ Program. 2001;358-374. Barrington KJ. Umbilical artery catheters in the newborn: effects of heparin. Cochrane Database Syst. 2000;(Rev 2):CD000507. Flynn JT. Neonatal hypertension: diagnosis and management. Pediatr Nephrol. 2000;14:332-341. Kent AL, Kecskes Z, Shadbolt B, Falk MC. Normative blood pressure data in the early neonatal period. Pediatr Nephrol. 2007;22:1335-1341. Lau KK, Stoffman JM, Williams S, et al. Neonatal renal vein thrombosis: review of the English-language literature between 1992 and 2006. Pediatrics. 2007;120:e1278-e1284. Monagle P, Chalmers E, Chan A, et al. Antithrombotic therapy in neonates and children: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest. 2008;133(suppl 6):887S-968S. Proesmans W, van de Wijdeven P, Van Geet C. Thrombophilia in neonatal renal venous and arterial thrombosis. Pediatr Nephrol. 2005;20:241-242. Seliem WA, Falk MC, Shadbolt B, Kent AL. Antenatal and postnatal risk factors for neonatal hypertension and infant follow-up. Pediatr Nephrol. 2007;22:2081-2087. Complete references used in this text can be found online at www .expertconsult.com



CHAPTER 90  Acute Kidney Injury and Chronic Kidney Disease 

References Abitbol CL, Bauer CR, Montané B, Chandar J, Duara S, Zilleruelo G. Long-term follow-up of extremely low birth weight infants with neonatal renal failure. Pediatr Nephrol. 2003;18(9):887-893. Abraham AG, Mak RH, Mitsnefes M, et al. Protein energy wasting in children with chronic kidney disease. Pediatr Nephrol. 2014;29(7):1231-1238. Abrahamson DR. Glomerulogenesis in the developing kidney. Semin Nephrol. 1991;11(4):375-389. Akcan-Arikan A, Zappitelli M, Loftis LL, Washburn KK, Jefferson LS, Goldstein SL. Modified RIFLE criteria in critically ill children with acute kidney injury. Kidney Int. 2007;71(10):1028-1035. Al-Hermi BE, Al-Saran K, Secker D, Geary DF. Hemodialysis for end-stage renal disease in children weighing less than 10 kg. Pediatr Nephrol. 1999;13(5):401-403. Alabbas A, Campbell A, Skippen P, Human D, Matsell D, Mammen C. Epidemiology of cardiac surgery-associated acute kidney injury in neonates: a retrospective study. Pediatr Nephrol. 2013;7:1127-1134. Albisetti M, Andrew M. Low molecular weight heparin in children. Eur J Pediatr. 2002;161:71-77. Andreoli SP. Acute renal failure in the newborn. Semin Perinatol. 2004;28(2):112-123. Andreoli SP, Bergstein JM, Sherrard DJ. Aluminum intoxication from aluminum-containing phosphate binders in children with azotemia not undergoing dialysis. N Engl J Med. 1984;310(17):1079-1084. Andrew ME, Monagle P, deVeber G, et al. Thromboembolic disease and antithrombotic therapy in newborns. Hematology Am Soc Hematol Educ Program. 2001;358-374. Askenazi DJ, Hunley H, Koralkar R, et al. Urine biomarkers predict acute kidney injury and mortality in very low birth weight infants. J Pediatr. 2011;159:907-912. Askenazi DJ, Patil NR, Ambalavanan N, et al. Acute kidney injury is associated with bronchopulmonary dysplasia/mortality in premature infants. Pediatr Nephrol. 2015;30(9):1511-1518. Assadi F. Strategies to reduce the incidence of chronic kidney disease in children: time for action. J Nephrol. 2013;26(1):41-47. Astor BC, Muntner P, Levin A, Eustace JA, Coresh J. Association of kidney function with anemia: the Third National Health and Nutrition Examination Survey (1988-1994). Arch Intern Med. 2002;162(12): 1401-1408. Atkinson MA, Furth SL. Anemia in children with chronic kidney disease. Nat Rev Nephrol. 2011;7(11):635-641. Atkinson MA, Martz K, Warady BA, Neu AM. Risk for anemia in pediatric chronic kidney disease patients: a report of NAPRTCS. Pediatr Nephrol. 2010;25(9):1699-1706. Auron A, Simon S, Andrews W, et al. Prevention of peritonitis in children receiving peritoneal dialysis. Pediatr Nephrol. 2007;22(4):578-585. Awad AS, Okusa MD. Distant organ injury following acute kidney injury. Am J Physiol Renal Physiol. 2007;293(1):F28-F29. Baley JE, Kliegman RM, Fanaroff AA. Disseminated fungal infections in very low-birth-weight infants: therapeutic toxicity. Pediatrics. 1984;73(2):153-157. Bamgbola OF. Pattern of resistance to erythropoietin-stimulating agents in chronic kidney disease. Kidney Int. 2011;80(5):464-474. Bannwarth B, Lagrange F, Péhourcq F, Llanas B, Demarquez JL. (S)ketoprofen accumulation in premature neonates with renal failure who were exposed to the racemate during pregnancy. Br J Clin Pharmacol. 1999;47(4):459-460. Baracco R, Saadeh S, Valentini R, Kapur G, Jain A, Mattoo TK. Iron deficiency in children with early chronic kidney disease. Pediatr Nephrol. 2011;26(11):2077-2080. Barker DJ, Osmond C. Low birth weight and hypertension. BMJ. 1988;297(6641):134-135. Barker DJ, Osmond C, Golding J, Kuh D, Wadsworth ME. Growth in utero, blood pressure in childhood and adult life, and mortality from cardiovascular disease. BMJ. 1989;298(6673):564-567. Barnett HL, Hare K, McNamara H, Hare R. Measurement of glomerular filtration rate in premature infants. J Clin Invest. 1948;27(6):691-699.

1300.e1

Barrington KJ. Umbilical artery catheters in the newborn: effects of position of the catheter tip. Cochrane Database Syst Rev. 2000a;(2):CD000505. Barrington KJ. Umbilical artery catheters in the newborn: effects of heparin. Cochrane Database Syst Rev. 2000b;(2):CD000507. Basile DP. The endothelial cell in ischemic acute kidney injury: implications for acute and chronic function. Kidney Int. 2007;72(2):151-156. Basile DP, Donohoe D, Roethe K, Osborn JL. Renal ischemic injury results in permanent damage to peritubular capillaries and influences long-term function. Am J Physiol Renal Physiol. 2001;281(5):F887-F899. Basterrechea Iriarte F, Sota Busselo I, Nogués Pérez A. Evolution of imaging in renal vein thrombosis in the newborn. An Pediatr (Barc). 2008;69:442-445. Bellomo R, Chapman M, Finfer S, Hickling K, Myburgh J. Low-dose dopamine in patients with early renal dysfunction: a placebo-controlled randomised trial. Australian and New Zealand Intensive Care Society (ANZICS) Clinical Trials Group. Lancet. 2000;356(9248):2139-2143. Blinder JJ, Goldstein SL, Lee VV, et al. Congenital heart surgery in infants: Effects of acute kidney injury on outcomes. J Thorac Cardiovasc Surg. 2011;143:368-374. Bokenkamp A, von Kries R, Nowak-Göttl U, et al. Neonatal renal venous thrombosis in Germany between 1992 and 1994: epidemiology, treatment and outcome. Eur J Pediatr. 2000;159:44-48. Borzych-Duzalka D, Bilginer Y, Ha IS, et al. Management of anemia in children receiving chronic peritoneal dialysis. J Am Soc Nephrol. 2013;24(4):665-676. Brenner BM, Lawler EV, Mackenzie HS. The hyperfiltration theory: a paradigm shift in nephrology. Kidney Int. 1996;49(6):1774-1777. Brion LP, Fleischman AR, McCarton C, Schwartz GJ. A simple estimate of glomerular filtration rate in low birth weight infants during the first year of life: noninvasive assessment of body composition and growth. J Pediatr. 1986;109(4):698-707. Brophy PD, Mottes TA, Kudelka TL, et al. AN-69 membrane reactions are pH-dependent and preventable. Am J Kidney Dis. 2001;38(1):173-178. Bunchman TE, Wood EG, Schenck MH, Weaver KA, Klein BL, Lynch RE. Pretreatment of formula with sodium polystyrene sulfonate to reduce dietary potassium intake. Pediatr Nephrol. 1991;5(1): 29-32. Carey WA, Martz KL, Warady BA. Outcome of patients initiating chronic peritoneal dialysis during the first year of life. Pediatrics. 2015;136(3):e615-e622. Carey WA, Talley LI, Sehring SA, Jaskula JM, Mathias RS. Outcomes of dialysis initiated during the neonatal period for treatment of end-stage renal disease: a North American Pediatric Renal Trials and Collaborative Studies special analysis. Pediatrics. 2007;119(2):e468-e473. Carmody JB, Swanson JR, Rhone ET, Charlton JR. Recognition and reporting of AKI in very low birth weight infants. Clin J Am Soc Nephrol. 2014;9(12):2036-2043. Cavagnaro F, Kattan J, Godoy L, et al. Continuous renal replacement therapy in neonates and young infants during extracorporeal membrane oxygenation. Int J Artif Organs. 2007;30(3):220-226. Chaturvedi S, Jones C. Protein restriction for children with chronic renal failure. Cochrane Database Syst Rev. 2007;(4):CD006863. Chesnaye NC, Schaefer F, Groothoff JW, et al. Disparities in treatment rates of paediatric end-stage renal disease across Europe: insights from the ESPN/ERA-EDTA registry. Nephrol Dial Transplant. 2015;30(8):1377-1385. Chevalier RL, Campbell F, Brenbridge AN. Prognostic factors in neonatal acute renal failure. Pediatrics. 1984;74(2):265-272. Churchwell MD, Mueller BA. Drug dosing during continuous renal replacement therapy. Semin Dial. 2009;22(2):185-188. Cifuentes RF, Olley PM, Balfe JW, Radde IC, Soldin SJ. Indomethacin and renal function in premature infants with persistent patent ductus arteriosus. J Pediatr. 1979;95(4):583-587. Coulthard MG, Vernon B. Managing acute renal failure in very low birthweight infants. Arch Dis Child Fetal Neonatal Ed. 1995;73(3): F187-F192. Dauger S, Michot C, Garnier A, et al. Neonatal renal venous thrombosis in 2008. Arch Pediatr. 2009;16:132-141.

1300.e2

PART XV I I  Renal and Genitourinary Systems

de-Brito Ashurst I, O’Lone E, Kaushik T, McCafferty K, Yaqoob MM. Acidosis: progression of chronic kidney disease and quality of life. Pediatr Nephrol. 2015;30(6):873-879. de Brito-Ashurst I, Varagunam M, Raftery MJ, Yaqoob MM. Bicarbonate supplementation slows progression of CKD and improves nutritional status. J Am Soc Nephrol. 2009;20(9):2075-2084. Dixon BS, Anderson RJ. Nonoliguric acute renal failure. Am J Kidney Dis. 1985;6(2):71-80. Eichenwald EC, Stark AR. Management and outcomes of very low birth weight. N Engl J Med. 2008;358(16):1700-1711. Ellis EN, Arnold WC. Use of urinary indexes in renal failure in the newborn. Am J Dis Child. 1982;136(7):615-617. Fassinger N, Dabbagh S, Mukhopadhyay S, Lee DY. Mineral content of infant formula after treatment with sodium polystyrene sulfonate or calcium polystyrene sulfonate. Adv Perit Dial. 1998;14:274-277. Faubel S. Pulmonary complications after acute kidney injury. Adv Chronic Kidney Dis. 2008;15(3):284-296. Fauriel I, Moutel G, Moutard ML, et al. Decisions concerning potentially life-sustaining treatments in paediatric nephrology: a multicentre study in French-speaking countries. Nephrol Dial Transplant. 2004;19(5):12521257. [Epub 2004 Feb 19]. Feinstein S, Rinat C, Becker-Cohen R, Ben-Shalom E, Schwartz SB, Frishberg Y. The outcome of chronic dialysis in infants and toddlers— advantages and drawbacks of haemodialysis. Nephrol Dial Transplant. 2008;23(4):1336-1345. Feld LG, Springate JE, Fildes RD. Acute renal failure. I. Pathophysiology and diagnosis. J Pediatr. 1986;109(3):401-408. Filler G, Lepage N. Cystatin C adaptation in the first month of life. Pediatr Nephrol. 2013;28(7):991-994. Fine RN, Attie KM, Kuntze J, Brown DF, Kohaut EC. Recombinant human growth hormone in infants and young children with chronic renal insufficiency. Genentech Collaborative Study Group. Pediatr Nephrol. 1995;9(4):451-457. Fine RN, Martz K, Stablein D. What have 20 years of data from the North American Pediatric Renal Transplant Cooperative Study taught us about growth following renal transplantation in infants, children, and adolescents with end-stage renal disease? Pediatr Nephrol. 2010;25(4):739-746. Foster BJ, McCauley L, Mak RH. Nutrition in infants and very young children with chronic kidney disease. Pediatr Nephrol. 2012;27(9):1427- 1439. Fouque D, Kalantar-Zadeh K, Kopple J, et al. A proposed nomenclature and diagnostic criteria for protein-energy wasting in acute and chronic kidney disease. Kidney Int. 2008;73(4):391-398. Freundlich M, Zilleruelo G, Abitbol C, Strauss J, Faugere MC, Malluche HH. Infant formula as a cause of aluminium toxicity in neonatal uraemia. Lancet. 1985;2(8454):527-529. Friedrich JO, Adhikari N, Herridge MS, Beyene J. Meta-analysis: low-dose dopamine increases urine output but does not prevent renal dysfunction or death. Ann Intern Med. 2005;142(7):510-524. Gadepalli SK, Selewski DT, Drongowski RA, Mychaliska GB. Acute kidney injury in congenital diaphragmatic hernia requiring extracorporeal life support: an insidious problem. J Pediatr Surg. 2011;46(4):630- 635. Gafter U, Kalechman Y, Orlin JB, Levi J, Sredni B. Anemia of uremia is associated with reduced in vitro cytokine secretion: immunopotentiating activity of red blood cells. Kidney Int. 1994;45(1):224-231. Gallini F, Maggio L, Romagnoli C, Marrocco G, Tortorolo G. Progression of renal function in preterm neonates with gestational age < or = 32 weeks. Pediatr Nephrol. 2000;15(1–2):119-124. Ganz T, Nemeth E. Iron balance and the role of hepcidin in chronic kidney disease. Semin Nephrol. 2016;36(2):87-93. Geary DF. Attitudes of pediatric nephrologists to management of end-stage renal disease in infants. J Pediatr. 1998;133(1):154-156. Gillespie RS, Seidel K, Symons JM. Effect of fluid overload and dose of replacement fluid on survival in hemofiltration. Pediatr Nephrol. 2004;19(12):1394-1399.

Giuliano RA, Paulus GJ, Verpooten GA, et al. Recovery of cortical phospholipidosis and necrosis after acute gentamicin loading in rats. Kidney Int. 1984;26(6):838-847. Goldstein SL, Currier H, Graf C, Cosio CC, Brewer ED, Sachdeva R. Outcome in children receiving continuous venovenous hemofiltration. Pediatrics. 2001;107(6):1309-1312. Greenbaum LA, Muñoz A, Schneider MF, et al. The association between abnormal birth history and growth in children with CKD. Clin J Am Soc Nephrol. 2011;6(1):14-21. Guignard JP, Torrado A, Da Cunha O, Gautier E. Glomerular filtration rate in the first three weeks of life. J Pediatr. 1975;87(2):268-272. Hackbarth RM, Eding D, Gianoli Smith C, Koch A, Sanfilippo DJ, Bunchman TE. Zero balance ultrafiltration (Z-BUF) in blood-primed CRRT circuits achieves electrolyte and acid-base homeostasis prior to patient connection. Pediatr Nephrol. 2005;20(9):1328-1333. Haffner D, Nissel RN. Growth and puberty in chronic kidney disease. In: Geary D, Schaefer F, eds. Comprehensive Pediatric Nephrology. Philadelphia, PA: Mosby; 2008:709-732. Hamasaki Y, Ishikura K, Uemura O, et al. Growth impairment in children with pre-dialysis chronic kidney disease in Japan. Clin Exp Nephrol. 2015;19(6):1142-1148. Harambat J, van Stralen KJ, Kim JJ, Tizard EJ. Epidemiology of chronic kidney disease in children. Pediatr Nephrol. 2012;27(3):363-373. Hattori M, Uemura O, Hataya H, et al. Efficacy and safety of darbepoetin alfa for anemia in children with chronic kidney disease: a multicenter prospective study in Japan. Clin Exp Nephrol. 2014;18(4):634-641. Hijazi R, Abitbol CL, Chandar J, Seeherunvong W, Freundlich M, Zilleruelo G. Twenty-five years of infant dialysis: a single center experience. J Pediatr. 2009;155(1):111-117. Hoke TS, Douglas IS, Klein CL, et al. Acute renal failure after bilateral nephrectomy is associated with cytokine-mediated pulmonary injury. J Am Soc Nephrol. 2007;18(1):155-164. Hooper SR, Gerson AC, Butler RW, et al. Neurocognitive functioning of children and adolescents with mild-to-moderate chronic kidney disease. Clin J Am Soc Nephrol. 2011;6(8):1824-1830. Hoste EA, Clermont G, Kersten A, et al. RIFLE criteria for acute kidney injury are associated with hospital mortality in critically ill patients: a cohort analysis. Crit Care. 2006;10(3):R73. Hoste EA, Kellum JA. Acute kidney injury: epidemiology and diagnostic criteria. Curr Opin Crit Care. 2006;12(6):531-537. Ignjatovic V, Summerhayes R, Than J, et al. Therapeutic range for unfractionated heparin therapy: age-related differences in response in children. J Thromb Haemost. 2006;4:2280-2282. Ingulli EG, Mak RH. Growth in children with chronic kidney disease: role of nutrition, growth hormone, dialysis, and steroids. Curr Opin Pediatr. 2014;26(2):187-192. Izzedine H, Launay-Vacher V, Deray G. Antiviral drug-induced nephrotoxicity. Am J Kidney Dis. 2005;45(5):804-817. Johnson RJ, Warady BA. Long-term neurocognitive outcomes of patients with end-stage renal disease during infancy. Pediatr Nephrol. 2013;28(8):1283-1291. Karlowicz MG, Adelman RD. Acute renal failure in the neonate. Clin Perinatol. 1992;19(1):139-158. KDIGO Group. KDIGO Clinical Practice Guideline for Anemia in Chronic Kidney Disease. Kidney Int Suppl. 2012;2:279-335. KDOQI. KDOQI Clinical Practice Guideline and Clinical Practice Recommendations for anemia in chronic kidney disease: 2007 update of hemoglobin target. Am J Kidney Dis. 2007;50(3):471-530. KDOQI Work Group. KDOQI Clinical Practice Guideline for Nutrition in Children with CKD: 2008 update. Executive summary. Am J Kidney Dis. 2009;53(3 suppl 2):S11-S104. KDOQI. KDOQI Clinical Practice Guideline for Nutrition in Children with CKD: 2008 update. Executive summary. Am J Kidney Dis. 2009;53(3 suppl 2):S11-S104. KDOQI and National Kidney Foundation. III. Clinical practice recommendations for anemia in chronic kidney disease in children. Am J Kidney Dis. 2006;47(5 suppl 3):S86-S108.



CHAPTER 90  Acute Kidney Injury and Chronic Kidney Disease  1300.e3

KDOQI, National Kidney Foundation. III. Clinical practice recommendations for anemia in chronic kidney disease in children. Am J Kidney Dis. 2006;47(5 suppl 3):S86-S108. Keller G, Zimmer G, Mall G, Ritz E, Amann K. Nephron number in patients with primary hypertension. N Engl J Med. 2003;348(2):101-108. Kim DH, Park SH, Sheen MR, et al. Comparison of experimental lung injury from acute renal failure with injury due to sepsis. Respiration. 2006;73(6):815-824. Kimberlin DW, Lin CY, Jacobs RF, et al. Safety and efficacy of high-dose intravenous acyclovir in the management of neonatal herpes simplex virus infections. Pediatrics. 2001;108(2):230- 238. Koralkar R, Ambalavanan N, Levitan EB, McGwin G, Goldstein S, Askenazi D. Acute kidney injury reduces survival in very low birth weight infants. Pediatr Res. 2011;69(4):354-358. Kosch A, Kuwertz-Broking E, Heller C, et al. Renal venous thrombosis in neonates: prothrombotic risk factors and long-term follow-up. Blood. 2004;104:1356-1360. Koshy SM, Geary DF. Anemia in children with chronic kidney disease. Pediatr Nephrol. 2008;23(2):209-219. Kovalski Y, Cleper R, Krause I, Davidovits M. Hemodialysis in children weighing less than 15 kg: a single-center experience. Pediatr Nephrol. 2007;22(12):2105-2110. Lande MB, Gerson AC, Hooper SR, et al. Casual blood pressure and neurocognitive function in children with chronic kidney disease: a report of the children with chronic kidney disease cohort study. Clin J Am Soc Nephrol. 2011;6(8):1831-1837. Lantos JD, Warady BA. The evolving ethics of infant dialysis. Pediatr Nephrol. 2013;28(10):1943-1947. Lapeyraque AL, Haddad E, André JL, et al. Sudden blindness caused by anterior ischemic optic neuropathy in 5 children on continuous peritoneal dialysis. Am J Kidney Dis. 2003;42(5): E3-E9. Lau KK, Stoffman JM, Williams S, et al. Neonatal renal vein thrombosis: review of the English-language literature between 1992 and 2006. Pediatrics. 2007;120:e1278-e1284. Ledermann SE, Shaw V, Trompeter RS. Long-term enteral nutrition in infants and young children with chronic renal failure. Pediatr Nephrol. 1999;13(9):870-875. Lerner GR, Kurnetz R, Bernstein J, et al. Renal cortical and renal medullary necrosis in the first 3 months of life. Pediatr Nephrol. 1992;6: 516-518. Liem KD, Hopman JC, Oeseburg B, de Haan AF, Festen C, Kollée LA. Cerebral oxygenation and hemodynamics during induction of extracorporeal membrane oxygenation as investigated by near infrared spectrophotometry. Pediatrics. 1995;95(4):555-561. Liu KD, Brakeman PR. Renal repair and recovery. Crit Care Med. 2008;36(suppl 4):S187-S192. Liu KD, Himmelfarb J, Paganini E, et al. Timing of initiation of dialysis in critically ill patients with acute kidney injury. Clin J Am Soc Nephrol. 2006;1(5):915-919. Liu J, Yin XJ, Feng ZC. [Research advance on periventricular intraventricular hemorrhage in premature infants: a review]. Zhongguo Dang Dai Er Ke Za Zhi. 2008;10(3):435-440. Lolekha PH, Jaruthunyaluck S, Srisawasdi P. Deproteinization of serum: another best approach to eliminate all forms of bilirubin interference on serum creatinine by the kinetic Jaffe reaction. J Clin Lab Anal. 2001;15(3):116-121. Luciani GB, Nichani S, Chang AC, Wells WJ, Newth CJ, Starnes VA. Continuous versus intermittent furosemide infusion in critically ill infants after open heart operations. Ann Thorac Surg. 1997;64(4):1133- 1139. Mahajan A, Simoni J, Sheather SJ, Broglio KR, Rajab MH, Wesson DE. Daily oral sodium bicarbonate preserves glomerular filtration rate by slowing its decline in early hypertensive nephropathy. Kidney Int. 2010;78(3):303-309.

Manalich R, Reyes L, Herrera M, Melendi C, Fundora I. Relationship between weight at birth and the number and size of renal glomeruli in humans: a histomorphometric study. Kidney Int. 2000;58(2): 770-773. Manco-Johnson MJ, Grabowski EF, Hellgreen M, et al. Recommendations for tPA thrombolysis in children. On behalf of the Scientific Subcommittee on Perinatal and Pediatric Thrombosis of the Scientific and Standardization Committee of the International Society of Thrombosis and Haemostasis. Thromb Haemost. 2002;88:157-158. Marik PE. Low-dose dopamine: a systematic review. Intensive Care Med. 2002;28(7):877-883. Marks SD, Massicotte MP, Steele BT, et al. Neonatal renal venous thrombosis: clinical outcomes and prevalence of prothrombotic disorders. J Pediatr. 2005;146:811-816. Maxwell H. Recombinant human growth hormone (rhGH) treatment of infants and young children with chronic renal failure. Br J Clin Pract Suppl. 1996;85:64-65. McDonald MM, Jacobson LJ, Hay WW Jr, et al. Heparin clearance in the newborn. Pediatr Res. 1981;15:1015-1018. McSherry E, Morris RC Jr. Attainment and maintenance of normal stature with alkali therapy in infants and children with classic renal tubular acidosis. J Clin Invest. 1978;61(2):509-527. Mehta RL, Kellum JA, Shah SV, et al. Acute Kidney Injury Network (AKIN): report of an initiative to improve outcomes in acute kidney injury. Crit Care. 2007;11(2):R31. Mekahli D, Shaw V, Ledermann SE, Rees L. Long-term outcome of infants with severe chronic kidney disease. Clin J Am Soc Nephrol. 2010;5(1):10-17. Mencarelli F, Kiepe D, Leozappa G, Stringini G, Cappa M, Emma F. Growth hormone treatment started in the first year of life in infants with chronic renal failure. Pediatr Nephrol. 2009;24(5):1039-1046. Mendley SR, Matheson MB, Shinnar S, et al. Duration of chronic kidney disease reduces attention and executive function in pediatric patients. Kidney Int. 2015;87(4):800-806. Meyer RJ, Brophy PD, Bunchman TE, et al. Survival and renal function in pediatric patients following extracorporeal life support with hemofiltration. Pediatr Crit Care Med. 2001;2(3):238-242. Mishra J, Dent C, Tarabishi R, et al. Neutrophil gelatinase-associated lipocalin (NGAL) as a biomarker for acute renal injury after cardiac surgery. Lancet. 2005;365(9466):1231-1238. Mitsnefes MM, Daniels SR, Schwartz SM, Meyer RA, Khoury P, Strife CF. Severe left ventricular hypertrophy in pediatric dialysis: prevalence and predictors. Pediatr Nephrol. 2000;14(10–11):898-902. Moffett BS, Mott AR, Nelson DP, Goldstein SL, Jefferies JL. Renal effects of fenoldopam in critically ill pediatric patients: A retrospective review. Pediatr Crit Care Med. 2008;9(4):403-406. Monagle P, Chalmers E, Chan A, et al. Antithrombotic therapy in neonates and children: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2008;133(suppl 6):887S-968S. 8th Edition. Morgan CJ, Zappitelli M, Robertson CM, et al. Risk factors for and outcomes of acute kidney injury in neonates undergoing complex cardiac surgery. J Pediatr. 2013;162(1):120-127 e121. NAPRTCS (North American Pediatric Renal Trials and Collaborative Studies). 2008 Annual Report—Dialysis. http://www.naprtcs.org. 2008. NAPRTCS (North American Pediatric Renal Trials and Collaborative Studies). 2011 Annual Dialysis Report. http://www.naprtcs.org. 2011. NAPRTCS (North American Pediatric Renal Trials and Collaborative Studies). 2014 Annual Transplant Report. http://www.naprtcs.org. 2014. Nathan D, Orkin SH. Appendix 11. Normal hematologic values in children. In: S. N. Orkin DG, Ginsburg D, Look AT, Fisher DE, Lux SE, eds. Nathan and Oski’s Hematology of Infancy and Childhood. Philadelphia, PA: Saunders; 2003:1841. National Kidney Foundation. KDOQI clinical practice guideline and clinical practice recommendations for 2006 updates: hemodialysis adequacy, peritoneal dialysis adequacy and vascular access. Am J Kidney Dis. 2006;48(suppl 1):S1-S322.

1300.e4

PART XV I I  Renal and Genitourinary Systems

Newall F, Johnston L, Ignjatovic V, et al. Unfractionated heparin therapy in infants and children. Pediatrics. 2009;123:e510-e518. Nowak-Gottl U, von Kries R, Göbel U, et al. Neonatal symptomatic thromboembolism in Germany: two year survey. Arch Dis Child Fetal Neonatal Ed. 1997;76:F163-F167. Nygren A, Ulfendahl HR, Hansell P, et al. Effects of intravenous contrast media on cortical and medullary blood flow in the rat kidney. Invest Radiol. 1988;23:753-761. Ohishi A, Suzuki H, Nakamoto H, et al. Status of patients who underwent uninephrectomy in adulthood more than 20 years ago. Am J Kidney Dis. 1995;26(6):889-897. Ohls RK, Christensen RD, Kamath-Rayne BD, et al. A randomized, masked, placebo-controlled study of darbepoetin alfa in preterm infants. Pediatrics. 2013;132(1):e119-e127. Ojala R, Ala-Houhala M, Ahonen S, et al. Renal follow up of premature infants with and without perinatal indomethacin exposure. Arch Dis Child Fetal Neonatal Ed. 2001;84(1):F28-F33. Panel on Macronutrients; Subcommittees on Upper Reference Levels of Nutrients and Interpretation and Uses of Dietary Reference Intakes; Standing Committee on the Scientific Evaluation of Dietary Reference Intakes; Food and Nutrition Board; Institute of Medicine. Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein and Amino Acids (Macronutrients). The National Academies Press. 2005. Parekh RS, Flynn JT, Smoyer WE, et al. Improved growth in young children with severe chronic renal insufficiency who use specified nutritional therapy. J Am Soc Nephrol. 2001;12(11):2418-2426. Parikh CR, Mishra J, Thiessen-Philbrook H, et al. Urinary IL-18 is an early predictive biomarker of acute kidney injury after cardiac surgery. Kidney Int. 2006;70(1):199-203. Peruzzi L, Gianoglio B, Porcellini MG, Coppo R. Neonatal end-stage renal failure associated with maternal ingestion of cyclo-oxygenase-type-1 selective inhibitor nimesulide as tocolytic. Lancet. 1999;354(9190):1615. Phisitkul S, Khanna A, Simoni J, et al. Amelioration of metabolic acidosis in patients with low GFR reduced kidney endothelin production and kidney injury, and better preserved GFR. Kidney Int. 2010;77(7):617-623. Polito C, Papale MR, La Manna A. Long-term prognosis of acute renal failure in the full-term neonate. Clin Pediatr (Phila). 1998;37(6):381- 385. Pollack S, Eisenstein I, Tarabeih M, Shasha-Lavski H, Magen D, Zelikovic I. Long-term hemodialysis therapy in neonates and infants with endstage renal disease: a 16-year experience and outcome. Pediatr Nephrol. 2016;31(2):305-313. Proesmans W, van de Wijdeven P, Van Geet C. Thrombophilia in neonatal renal venous and arterial thrombosis. Pediatr Nephrol. 2005;20:241-242. Quan A, Baum M. Protein losses in children on continuous cycler peritoneal dialysis. Pediatr Nephrol. 1996;10(6):728-731. Quinlan C, Bates M, Sheils A, Dolan N, Riordan M, Awan A. Chronic hemodialysis in children weighing less than 10 kg. Pediatr Nephrol. 2013;28(5):803-809. Rajs G, Mayer M. Oxidation markedly reduces bilirubin interference in the Jaffe creatinine assay. Clin Chem. 1992;38(12):2411-2413. Rao SC, Ahmed M, Hagan R. One dose per day compared to multiple doses per day of gentamicin for treatment of suspected or proven sepsis in neonates. Cochrane Database Syst Rev. 2006;(1):CD005091. Rees L. Growth hormone therapy in children with CKD after more than two decades of practice. Pediatr Nephrol. 2015;31:1421-1435. Rhone ET, Carmody JB, Swanson JR, Charlton JR. Nephrotoxic medication exposure in very low birth weight infants. J Matern Fetal Neonatal Med. 2014;27(14):1485-1490. Ricci Z, Stazi GV, Di Chiara L, et al. Fenoldopam in newborn patients undergoing cardiopulmonary bypass: controlled clinical trial. Interact Cardiovasc Thorac Surg. 2008;7(6):1049-1053. Rodig NM, McDermott KC, Schneider MF, et al. Growth in children with chronic kidney disease: a report from the Chronic Kidney Disease in Children Study. Pediatr Nephrol. 2014;29(10):1987-1995. Rodriguez MM, Gómez AH, Abitbol CL, Chandar JJ, Duara S, Zilleruelo GE. Histomorphometric analysis of postnatal

glomerulogenesis in extremely preterm infants. Pediatr Dev Pathol. 2004;7(1): 17-25. Ronco C, Brendolan A, Bragantini L, et al. Treatment of acute renal failure in newborns by continuous arterio-venous hemofiltration. Kidney Int. 1986;29(4):908-915. Roy M, Turner-Gomes S, Gill G, et al. Accuracy of Doppler echocardiography for the diagnosis of thrombosis associated with umbilical venous catheters. J Pediatr. 2002;140:131-134. Ruebner RL, Laney N, Kim JY, et al. Neurocognitive dysfunction in children, adolescents, and young adults with CKD. Am J Kidney Dis. 2015. Ruley EJ, Bock GH, Kerzner B, Abbott AW, Majd M, Chatoor I. Feeding disorders and gastroesophageal reflux in infants with chronic renal failure. Pediatr Nephrol. 1989;3(4):424-429. Saeidi B, Koralkar R, Griffin RL, Halloran B, Ambalavanan N, Askenazi DJ. Impact of gestational age, sex, and postnatal age on urine biomarkers in premature neonates. Pediatr Nephrol. 2015;11:2037-2044. Santos F, Moreno ML, Neto A, et al. Improvement in growth after 1 year of growth hormone therapy in well-nourished infants with growth retardation secondary to chronic renal failure: results of a multicenter, controlled, randomized, open clinical trial. Clin J Am Soc Nephrol. 2010;5(7):1190-1197. Sarkar S, Askenazi DJ, Jordan BK, et al. Relationship between acute kidney injury and brain MRI findings in asphyxiated newborns after therapeutic hypothermia. Pediatr Res. 2014;75(3):431-435. Sarwal M, Salvatierra O. Preparing the pediatric dialysis patient for transplantation. In: Warady BA, Schaefer FS, Fine RN, Alexander SR, eds. Pediatric Dialysis. Dordrecht, the Netherlands: Kluwer Academic Publishers; 2004:525. Schaefer F, Hoppe B, Jungraithmayr T, et al. Safety and usage of darbepoetin alfa in children with chronic kidney disease: prospective registry study. Pediatr Nephrol. 2016;31(3):443-453. Schwartz GJ, Muñoz A, Schneider MF, et al. New equations to estimate GFR in children with CKD. J Am Soc Nephrol. 2009;20(3):629-637. Selewski DT, Charlton JR, Jetton JG, et al. Neonatal acute kidney injury. Pediatrics. 2015;136(2):e463-e473. Selewski DT, Jordan BK, Askenazi DJ, Dechert RE, Sarkar S. Acute kidney injury in asphyxiated newborns treated with therapeutic hypothermia. J Pediatr. 2013;162:725-729. Sell LL, Cullen ML, Whittlesey GC, Lerner GR, Klein MD. Experience with renal failure during extracorporeal membrane oxygenation: treatment with continuous hemofiltration. J Pediatr Surg. 1987;22(7):600-602. Seri I. Cardiovascular, renal, and endocrine actions of dopamine in neonates and children. J Pediatr. 1995;126(3):333-344. Seri I. Circulatory support of the sick preterm infant. Semin Neonatol. 2001;6(1):85-95. Seri I, Abbasi S, Wood DC, Gerdes JS. Regional hemodynamic effects of dopamine in the sick preterm neonate. J Pediatr. 1998;133(6):728-734. Seri I, Abbasi S, Wood DC, Gerdes JS. Regional hemodynamic effects of dopamine in the indomethacin-treated preterm infant. J Perinatol. 2002;22(4):300-305. Seri I, Rudas G, Bors Z, Kanyicska B, Tulassay T. Effects of low-dose dopamine infusion on cardiovascular and renal functions, cerebral blood flow, and plasma catecholamine levels in sick preterm neonates. Pediatr Res. 1993;34(6):742-749. Sethna CB, Bryant K, Munshi R, et al. Risk factors for and outcomes of catheter-associated peritonitis in children: the SCOPE collaborative. Clin J Am Soc Nephrol. 2016;9:1590-1596. Shaheen IS, Harvey B, Watson AR, Pandya HC, Mayer A, Thomas D. Continuous venovenous hemofiltration with or without extracorporeal membrane oxygenation in children. Pediatr Crit Care Med. 2007;8(4):362-365. Shroff R, Wright E, Ledermann S, Hutchinson C, Rees L. Chronic hemodialysis in infants and children under 2 years of age. Pediatr Nephrol. 2003;18(4):378-383. Stańczyk M, Miklaszewska M, Zachwieja K, et al. Growth and nutritional status in children with chronic kidney disease on maintenance dialysis in Poland. Adv Med Sci. 2016;61(1):46-51.



CHAPTER 90  Acute Kidney Injury and Chronic Kidney Disease  1300.e5

Staples AO, Wong CS, Smith JM, et al. Anemia and risk of hospitalization in pediatric chronic kidney disease. Clin J Am Soc Nephrol. 2009;4(1):48-56. Stapleton FB, Jones DP, Green RS. Acute renal failure in neonates: incidence, etiology and outcome. Pediatr Nephrol. 1987;1(3):314-320. Sutton TA, Fisher CJ, Molitoris BA. Microvascular endothelial injury and dysfunction during ischemic acute renal failure. Kidney Int. 2002;62(5):1539-1549. Symons JM, Brophy PD, Gregory MJ, et al. Continuous renal replacement therapy in children up to 10 kg. Am J Kidney Dis. 2003;41(5):984-989. Symons JM, Chua AN, Somers MJ, et al. Demographic characteristics of pediatric continuous renal replacement therapy: a report of the prospective pediatric continuous renal replacement therapy registry. Clin J Am Soc Nephrol. 2007;2(4):732-738. Tanigasalam V, Bhat BV, Adhisivam B, Sridhar MG, Harichandrakumar KT. Predicting severity of acute kidney injury in term neonates with perinatal asphyxia using urinary neutrophil gelatinase associated lipocalin. Indian J Pediatr. 2016;83(12–13):1374-1378. Tanigasalam V, Bhat V, Adhisivam B, Sridhar MG. Does therapeutic hypothermia reduce acute kidney injury among term neonates with perinatal asphyxia? - a randomized controlled trial. J Matern Fetal Neonatal Med. 2016;29(15):2544-2547. Taylor JM, Oladitan L, Carlson S, Hamilton-Reeves JM. Renal formulas pretreated with medications alters the nutrient profile. Pediatr Nephrol. 2015;30(10):1815-1823. Teh JC, Frieling ML, Sienna JL, Geary DF. Attitudes of caregivers to management of end-stage renal disease in infants. Perit Dial Int. 2011;31(4):459-465. Thompson K, Flynn J, Okamura D, Zhou L. Pretreatment of formula or expressed breast milk with sodium polystyrene sulfonate (Kayexalate (®) as a treatment for hyperkalemia in infants with acute or chronic renal insufficiency. J Ren Nutr. 2013;23(5):333-339. Tolwani AJ, Wille KM. Anticoagulation for continuous renal replacement therapy. Semin Dial. 2009;22(2):141-145. Treiber M, Pečovnik Balon B, Gorenjak M. A new serum cystatin C formula for estimating glomerular filtration rate in newborns. Pediatr Nephrol. 2015;30(8):1297-1305. Uauy RD, Hogg RJ, Brewer ED, Reisch JS, Cunningham C, Holliday MA. Dietary protein and growth in infants with chronic renal insufficiency: a report from the Southwest Pediatric Nephrology Study Group and the University of California, San Francisco. Pediatr Nephrol. 1994;8(1):45-50. van Stralen KJ, Borzych-Dużalka D, Hataya H. Survival and clinical outcomes of children starting renal replacement therapy in the neonatal period. Kidney Int. 2014;86(1):168-174. Vanpée M, Blennow M, Linné T, Herin P, Aperia A. Renal function in very low birth weight infants: normal maturity reached during early childhood. J Pediatr. 1992;121(5 Pt 1):784-788. Vemgal P, Ohlsson A. Interventions for non-oliguric hyperkalaemia in preterm neonates. Cochrane Database Syst Rev. 2007;(1):CD005257. Verbitsky M, Sanna-Cherchi S, Fasel DA, et al. Genomic imbalances in pediatric patients with chronic kidney disease. J Clin Invest. 2015;125(5):2171-2178. Vidal E, Edefonti A, Murer L, et al. Peritoneal dialysis in infants: the experience of the Italian Registry of Paediatric Chronic Dialysis. Nephrol Dial Transplant. 2012;27(1):388-395. Viswanathan S, Manyam B, Azhibekov T, Mhanna MJ. Risk factors associated with acute kidney injury in extremely low birth weight (ELBW) infants. Pediatr Nephrol. 2012;27(2):303-311.

Wadsworth ME, Cripps HA, Midwinter RE, Colley JR. Blood pressure in a national birth cohort at the age of 36 related to social and familial factors, smoking, and body mass. Br Med J (Clin Res Ed). 1985;291(6508):1534-1538. Warady BA, Bakkaloglu S, Newland J, et al. Consensus guidelines for the prevention and treatment of catheter-related infections and peritonitis in pediatric patients receiving peritoneal dialysis: 2012 update. Perit Dial Int. 2012;32(suppl 2):S32-S86. Warady BA, Weis L, Johnson L. Nasogastric tube feeding in infants on peritoneal dialysis. Perit Dial Int. 1996;16(suppl 1):S521-S525. Watson AR, Shooter M. The ethics of withholding and withdrawing dialysis in children. In: Warady BA, Schaefer FS, Fine RN, Alexander SR, eds. Pediatric Dialysis. Dordrecht, the Netherlands: Kluwer Academic Publishers; 2004:501. Weber TR, Connors RH, Tracy TF Jr, Bailey PV, Stephens C, Keenan W. Prognostic determinants in extracorporeal membrane oxygenation for respiratory failure in newborns. Ann Thorac Surg. 1990;50(5):720-723. Wedekin M, Ehrich JH, Offner G, Pape L. Aetiology and outcome of acute and chronic renal failure in infants. Nephrol Dial Transplant. 2008;23(5):1575-1580. White SL, Perkovic V, Cass A, et al. Is low birth weight an antecedent of CKD in later life? A systematic review of observational studies. Am J Kidney Dis. 2009;54(2):248-261. WHO Multicentre Growth Reference Study Group. WHO Child Growth Standards: Length/height-for-age, weight-for-age, weight-for-length, weight-for-height and body mass index-for-age: Methods and development. Geneva: World Health Organization; 2006. Winyard PJ, Bharucha T, De Bruyn R, et al. Perinatal renal venous thrombosis: presenting renal length predicts outcome. Arch Dis Child Fetal Neonatal Ed. 2006;91:F273-F278. Wurthwein G, Groll AH, Hempel G, Adler-Shohet FC, Lieberman JM, Walsh TJ. Population pharmacokinetics of amphotericin B lipid complex in neonates. Antimicrob Agents Chemother. 2005;49(12):5092-5098. Yoder SE, Yoder BA. An evaluation of off-label fenoldopam use in the neonatal intensive care unit. Am J Perinatol. 2009;26(10):745-750. Zappitelli M, Goldstein SL, Symons JM, et al. Protein and calorie prescription for children and young adults receiving continuous renal replacement therapy: a report from the Prospective Pediatric Continuous Renal Replacement Therapy Registry Group. Crit Care Med. 2008;36(12):3239-3245. Zappitelli M, Juarez M, Castillo L, Coss-Bu J, Goldstein SL. Continuous renal replacement therapy amino acid, trace metal and folate clearance in critically ill children. Intensive Care Med. 2009;35(4):698-706. Zappitelli M, Moffett BS, Hyder A, Goldstein SL. Acute kidney injury in non-critically ill children treated with aminoglycoside antibiotics in a tertiary healthcare centre: a retrospective cohort study. Nephrol Dial Transplant. 2011;26(1):144-150. Zaritsky JJ, Warady BA. Chronic kidney disease in the neonate. Clin Perinatol. 2014;41(3):503-515. Zurowska A, Feneberg R, Warady BA, et al. Gram-negative peritonitis in children undergoing long-term peritoneal dialysis. Am J Kidney Dis. 2008;51(3):455-462. Zwiers AJ, de Wildt SN, Hop WC, et al. Acute kidney injury is a frequent complication in critically ill neonates receiving extracorporeal membrane oxygenation: a 14-year cohort study. Crit Care. 2013;17(4):R151.