C h ro n i c K i d n e y D i s e a s e i n the Neonate Joshua J. Zaritsky,

MD, PhD

a,

*, Bradley A. Warady,

MD

b

KEYWORDS  Chronic kidney disease  Neonate  Dialysis  Nutrition KEY POINTS  The definition of chronic kidney disease (CKD) in neonates differs from that of children older than 2 years. In addition, kidney function during the neonatal period is characterized as normal, moderately reduced, or severely reduced, based on the age-adjusted glomerular filtration rate (GFR).  Nutritional management is a key component of the care provided to the neonate with CKD. Optimal nutrition is mandatory if the best possible outcomes in terms of height, weight, and brain development are to be achieved by the neonate or young infant experiencing impaired kidney function.  Historically, the morbidity and mortality rates of neonates with CKD have been poor, with the presence of nonrenal disease being the most important predictor of mortality. Over the last decade, however, there has been steady improvement in patient survival, even in those patients initiated on chronic dialysis as neonates.

DEFINING CKD IN THE NEONATE

Although the diagnosis of chronic kidney disease (CKD) is applicable to patients of all ages, its definition in neonates has some clear distinctions from that made in older children and adults. Specifically, the criterion established by KDOQI (Kidney Disease Outcomes Quality Initiative)1 and expanded by KDIGO (Kidney Disease: Improving Global Outcomes)2 that the duration of kidney disease be longer than 3 months does not apply to neonates. Instead, it is recognized that many of the developmental renal abnormalities that can account for decreased kidney function (see the next section) have lifelong consequences. Thus, it is possible to classify many children as having CKD within the first few days of life. The diagnosis of CKD in the neonatal period is typically made a priori after a renal ultrasonogram, first performed in the prenatal period and repeated soon after birth,

Disclosures: None. a Department of Pediatrics, Nemours/A.I. duPont Hospital for Children, 1600 Rockland Road, Wilmington, DE 19803, USA; b Department of Pediatrics, Children’s Mercy Hospital, 2401 Gillham Road, Kansas City, MO 64108, USA * Corresponding author. E-mail address: [email protected] Clin Perinatol - (2014) -–http://dx.doi.org/10.1016/j.clp.2014.05.002 perinatology.theclinics.com 0095-5108/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.

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reveals disorganized renal architecture or a significant urologic abnormality accompanied by abnormal kidney function; this is in stark contrast to adult CKD, which is usually the result of an episode of acute kidney injury (AKI) or a long-standing metabolic (ie, diabetes) or cardiovascular (ie, hypertension) condition. Clearly some neonates who suffer AKI shortly after birth as a result of perinatal asphyxia, hypoxia, sepsis, or hypovolemia will also go on to have long-standing kidney damage and CKD, although the time period that passes before the diagnosis can be made remains variable.3 It is important to recognize that the additional diagnostic criterion for CKD as per KDOQI of a glomerular filtration rate (GFR) of less than 60 mL/min/1.73 m2 does not apply until age greater than 2 years when the body surface area–adjusted GFR is comparable with values achieved by older children and adults. The normal GFR in the newborn period is significantly less than 60 mL/min/1.73 m2, and increases rapidly owing to enhancement of renal perfusion via a combination of increased mean arterial pressure accompanied by a decrease in renal vascular resistance.4 Increases in glomerular size and capillary permeability coupled with a redistribution of intrarenal blow flow to more superficial cortical nephrons also contribute to the characteristic increase in GFR that occurs throughout the neonatal period and early infancy.5 Thus, the definition of normal kidney function in the neonatal period (and conversely CKD) must take into account age-appropriate values of GFR. There are several published references for normative GFR values in both preterm infants6,7 and neonates4,8,9 (Table 1). GFR approximation is often made based on serum creatinine levels via a GFR-estimating equation for clinical care. At present the updated Schwarz equation, derived using iohexol clearance and enzymatically measured creatinine, appears to be the most robust,10 although none of the data that formed the basis for this equation were derived from neonates. In addition, estimated GFRs cannot be used in the setting of AKI when the serum creatinine is rapidly changing. Given these limitations, attempting to classify a neonate based on the traditional 5 KDOQI stages of CKD is potentially misleading and, therefore, not recommended. Table 1 Glomerular filtration rate (GFR) in healthy infants as assessed by inulin clearance Age

Mean GFR ± SD (mL/min/1.73 m2)

Preterm babies 1–3 d

14.0  5

1–7 d

18.7  5.5

4–8 d

44.3  9.3

3–13 d

47.8  10.7

8–14 d

35.4  13.4

1.5–4 mo

67.4  16.6

Term babies 1–3 d

20.8  5.0

3–4 d

39.0  15.1

4–14 d

36.8  7.2

6–14 d

54.6  7.6

15–19 d

46.9  12.5

1–3 mo

85.3  35.1

Abbreviation: SD, standard deviation. Adapted from Schwartz GJ, Furth SL. Glomerular filtration rate measurement and estimation in chronic kidney disease. Pediatr Nephrol 2007;22(11):1840.

Chronic Kidney Disease in the Neonate

Instead, the KDIGO guidelines2 recommend a CKD classification scheme for patients younger than 2 years, which takes into consideration normative data and the inherent variation associated with the GFR measurement method (ie, urine collection, clearance of exogenous marker). In turn, the kidney function of neonates can be classified as normal, moderately reduced, or severely reduced based on the age-adjusted GFR (Table 2). INCIDENCE AND COMMON CAUSES

Despite an increased awareness of the capacity to care for neonates with CKD, and a significant increase in the frequency of detection of the at-risk and affected population with prenatal ultrasonography,11,12 data regarding the incidence of CKD in neonates are limited. Much of the published data have examined the incidence and management of infants with end-stage renal disease (ESRD), in contrast to less severe CKD, and has considered a much broader age range of birth to 24 months. Wedekin and colleagues13 estimated a CKD incidence of 1:10,000 in a single-center retrospective analysis of infants younger than 1 year with a serum creatinine level greater than 1.13 mg/dL (100 mmol/L). The gender distribution (male-to-female ratio of 2.8:1) was expected as a result of the male-dominated contribution of obstructive uropathy (eg, posterior urethral valves) as a frequent cause of CKD. More than 50% of the infants with CKD were premature, a figure significantly higher than in the study’s total infant population. More recently, Greenbaum and colleagues14 reported that 17% of children enrolled in the Chronic Kidney Disease in Children (CKiD) study had a low birth weight compared with an overall rate of approximately 8% in the general United States population. Carey and colleagues,15 using data from the dialysis registry of the North American Pediatric Renal Trials and Collaborative Studies (NAPTRCS), estimated the incidence of ESRD in neonates to be only 0.045 cases per million population per year, or 0.32 cases per 100,000 live births. This rate is roughly comparable with that seen in the United Kingdom, where the annual infant incidence is estimated at 3 cases per million population.16 The incidence rate for neonates is substantially lower than the overall incidence of ESRD during the first 4 years of life based on data from the United States Renal Data System (USRDS), which reported an incidence of approximately 10 cases per million population in the 0- to 4-year age group over the last decade.17 This difference is likely a result of the fact that one of the most common causes of CKD in the neonatal period (see later discussion), congenital renal dysplasia, does not typically compromise kidney function so severely that dialysis is required in the newborn period. With the growing awareness of the frequent occurrence of AKI in this population, it must be noted that although the exact incidence of CKD after AKI remains unknown, it is likely substantial and parallels that seen in adults.18 In a retrospective study of Table 2 KDIGO classification schemata for CKD for ages less than 2 years Neonatal CKD Classification

GFR

Normal GFR

GFR 1 SD below the mean

Moderately reduced GFR

GFR >1 SD to 2 SD below the mean

Severely reduced GFR

GFR >2 SD below the mean

Abbreviations: KDIGO, Kidney Disease: Improving Global Outcomes; SD, standard deviation. Adapted from Kidney Disease: Improving Global Outcomes (KDIGO) 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney International Supplements 2013;3(1). Jan 1; with permission.

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older children who suffered from AKI (median age of 6.5 years at AKI event), Askenazi and colleagues19 found that more than 50% developed some form of CKD 3 to 5 years later. A variety of kidney disorders can result in neonatal CKD (Box 1). However, most studies examining the frequency of these disorders have focused on those that result in the need for chronic renal replacement therapy. In the cohort of neonatal patients needing dialysis (N 5 193) examined by Carey and colleagues,15 the most frequent renal disorders were congenital renal hypoplasia/dysplasia and obstructive uropathy (eg, posterior urethral valves) (Table 3).20 Similarly, Warady and Martz21 reviewed the causes of ESRD in 85 neonates who were entered into the NAPRTCS database from 2000 to 2010, and found the same 2 diagnoses predominant. These and other structural abnormalities of the urinary tract account for nearly 60.0% of cases of chronic dialysis in neonates, with the next most common diagnosis being polycystic kidney disease (PKD). In an Italian registry including 20 infants who began peritoneal dialysis (PD) during the first month of life, congenital anomalies of the kidney and urinary tract (CAKUT) accounted for half of the cases, followed by autosomal recessive PKD.22 Finally, recent data from 4 separate registries on a combined total of 264 neonates from 32 countries who received dialysis during the first month of life showed that CAKUT was the most common cause of ESRD (54.6%), followed by cystic kidneys (13.2%) and cortical necrosis (11.4%).23 ETHICAL CONSIDERATIONS

One of the most difficult issues that families and health care providers are confronted with is the decision regarding when and if chronic dialysis therapy should be initiated for the neonate with ESRD. Despite advances in dialysis technology and clinical expertise that now makes it possible to provide dialysis to this patient population safely and effectively, the concept of proceeding with a lifetime of ESRD care is unavoidably complex. Comorbidities such as neurocognitive delay, growth delay, and the almost universal need for supplemental tube feeding and multiple hospitalizations contribute to the ethical dilemma experienced by many. Often complicating the situation is the presence of significant nonrenal abnormalities, such as pulmonary hypoplasia, which are present in up to one-third of infants with ESRD and are Box 1 Disorders resulting in neonatal CKD Aplastic/hypoplastic/dysplastic kidneysa Autosomal dominant polycystic kidney disease Autosomal recessive polycystic kidney diseasea Obstructive uropathy (posterior urethral valves)a Pyelonephritis Reflux nephropathy Renal infarcta Syndrome of agenesis of abdominal musculaturea a

May result in need for dialysis in neonatal period. Adapted from Flynn JT, Mitsnefes M, Pierce C, et al. Blood pressure in children with chronic kidney disease: a report from the Chronic Kidney Disease in Children study. Hypertension 2008;52(4):631–7.

Chronic Kidney Disease in the Neonate

Table 3 Diagnosis of neonates with end-stage renal disease Diagnosis

n (%)

Renal dysplasia

72 (37.3)

Obstructive uropathy

39 (20.2)

ARPKD

23 (11.9)

Congenital nephrotic syndrome

3 (1.5)

Other

56 (29)

Abbreviation: ARPKD, autosomal recessive polycystic kidney disease. Adapted from Carey WA, Talley LI, Sehring SA, et al. 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):e470.

associated with an increased risk for mortality.24 In fact, the mortality rate of the youngest infants (0–2 years) who have received chronic dialysis has historically been poor, with 2-year mortality rates as high as 30%, although recent data have revealed somewhat better outcomes (see later discussion).15,25 In adult patients the 4 principles of medical ethics, namely autonomy, beneficence, nonmaleficence, and justice, are characteristically applied to decisions on whether to withhold or withdraw dialysis.26 In the case of neonates and young infants, the wishes of the parents, who are entitled to make decisions regarding the medical care their children receive, must also be taken into account. This type of ethical dilemma is not all that uncommon in the neonatal intensive care unit and occurs in other situations as well, such as in the case of the neonate with hypoplastic left heart syndrome.27,28 Ideally the decision of whether to provide dialysis represents a consensus opinion of the parents, nephrologist, neonatologist, and other members of a multidisciplinary team. The decision should be made only after a thorough review of the patient’s clinical status and the family’s desires is conducted, along with a review of the limited data that exist within the medical literature on the outcome of young infants with ESRD. Despite the best efforts to this end, there remains the substantial potential for disagreement regarding the best course of action to take because of the multiple patient and social factors that often exist, along with the different prior experiences of health care team members with similar patient scenarios. All of this can result in an emotionally charged environment. Nonetheless, it is most desirable for all nephrology team members who are involved in the patient’s care to have the opportunity to weigh in on the decision process. Although the nephrology team and family members most often come to a conclusion that is agreeable to all, on occasion a hospital ethics committee may be consulted for their opinion. More than a decade ago, Geary29 surveyed the opinions of pediatric caregivers from around the globe regarding the decision process surrounding the initiation of chronic dialysis in infants younger than 1 year. In that survey, a substantial percentage (50%) of physicians responded that it was usually acceptable for parents to refuse dialysis for children younger than 1 month, in contrast to the situation when children were 1 to 12 months of age at presentation, at which time dialysis refusal was less acceptable. Factors thought to be most influential by the physicians with respect to their opinions regarding withholding dialysis were the presence of “coexistent serious medical abnormalities” and the “anticipated morbidity for the child.” As a follow-up to this survey, Teh and colleagues30 and many of the same investigators recently reported on the results of a similar multination survey of both nephrologists and nurses on this topic. The survey was conducted to determine whether the perspectives of

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health care providers had changed over the subsequent decade in association with the advances in care that had taken place, and additional personal and published experiences. Of note, only 30% of the 270 nephrologists who responded indicated that they offer chronic dialysis to all children younger than 1 month, whereas 50% stated that they recommend the therapy to all children aged 1 to 12 months. The figure of 30% was decreased from the 41% figure reported in the prior survey. Ninety-eight percent of physicians responding to the recent survey stated they would offer dialysis to some infants younger than 1 month, compared with 93% 10 years ago. In the recent assessment, a minority of physicians (27%) believed that the parents should not be given the option to refuse dialysis for infants younger than 1 month, a figure that increased to 50% for children aged 1 to 12 months. Not surprisingly, and as was reported in the initial survey, the most influential factor contributing to a decision not to offer dialysis was the presence of a coexisting nonrenal abnormality. One additional and potentially troubling finding in terms of generating the all-important consensus within the health care team was the presence of significant differences in the responses of physicians and nurses with respect to dialysis initiation in the neonate. Specifically, nurses were more likely to consider the presence of oliguria or anuria as a contraindication to initiating dialysis, and placed more emphasis on the parent’s right to decide. The topic of ethics is undoubtedly in need of additional study, supported by the accumulation of data from clinicians and affected family members. The influence of advances in dialysis care, more recent data on short-term and long-term patient outcomes, and cultural differences must be considered in any future analysis.23 NUTRITIONAL MANAGEMENT

In the setting of neonatal CKD, the provision of adequate nutrition takes on particular importance because the neonatal period is typically characterized by accelerated brain growth and a linear growth rate of nearly 25 cm per year. Remarkably, approximately half of postnatal brain growth takes place in the first year of life, and one-third of the normal final adult height is achieved during the initial 2 years of life.31,32 Infants with severe CKD can lose more than 2 standard deviations of height and forever affect their final height if their clinical status is compromised by suboptimal care and/or complications of their disorder.33,34 One single-center retrospective study by Karlberg and colleagues34 of 71 children with early-onset ESRD found that one-third of the reduction in height occurred during the first postnatal months. There are also data linking poor growth with mortality in children with ESRD. Both Wong and colleagues35 and Furth and colleagues36 demonstrated an independent association between a decrease in height standard deviation score (SDS) and an increased risk of death, with impaired growth likely serving as a surrogate of overall well-being. Most noteworthy is that this early period of linear growth primarily depends on the provision of optimal nutrition, with the growth hormone/insulin-like growth factor (IGF) axis having less importance in comparison with its role later in life. Updated KDOQI pediatric nutrition guidelines have recently been published that provide recommendations for the parameters of growth and nutritional status to be monitored in infants and young children with CKD, and how frequently the monitoring should take place (Table 4). The guidelines addressing dietary intake include recommendations for 100% of the estimated energy requirements for chronologic age, with adjustments based on changes in either weight or linear growth,1,37 and 100% to 140% of the dietary reference intake (DRI) for protein in those patients with CKD and not yet on dialysis.1

Chronic Kidney Disease in the Neonate

Table 4 Recommended parameters and frequency of nutritional assessment for neonates with CKD Minimal Interval (mo) Measure

Normal GFR

Moderately Reduced GFR

Severely Reduced GFR

Dietary intake

0.5–3

0.5–3

0.5–2

Height or length velocityfor-age percentile or SDS

0.5–1.5

0.5–1.5

0.5–1

Height or length-for-age percentile or SDS

0.5–2

0.5–2

0.5–1

Estimated dry weight and weight-for-age

0.5–1.5

0.5–1.5

0.25–1

BMI-for-height-age percentile or SDS

0.5–1.5

0.5–1.5

0.5–1

Head circumference-forage percentile or SDS

0.5–1.5

0.5–1.5

0.5–1

Abbreviations: BMI, body mass index; SDS, standard deviation score. Adapted from KDOQI clinical practice guideline for nutrition in children with CKD: 2008 update. Executive summary. Am J Kidney Dis 2009;53(3 Suppl 2):S16; with permission.

There are several additional nutritional considerations that need to be addressed when PD is conducted. Specifically, neonates and infants can experience excessive losses of protein across the peritoneal membrane, with studies demonstrating average losses of 250 mg of protein per kilogram of body weight per day.38 To avoid the negative consequences of protein depletion, current guidelines recommend a dietary protein intake of 1.8 g/kg/d for the first 6 months of life, a value that takes into account the DRI and peritoneal losses.1 Neonates and infants who receive PD also experience excessive sodium losses across the peritoneal membrane because of the need for high ultrafiltration rates in relation to body weight. Both breast milk and standard formulas contain 7 to 8 mmol of sodium per liter, which is inadequate for the replacement of ongoing losses. Without adequate supplementation (w3–5 mEq/kg/d), the consequences of the resultant hyponatremia and low intravascular volume can be catastrophic, and include both blindness caused by anterior ischemic optic neuropathy and cerebral edema.39,40 In most cases, the nutritional targets for neonates with moderately to severely reduced GFR are not achievable without the implementation of either nasogastric (NG) or gastrostomy tube feeding. Children with advanced CKD suffer from poor appetite and early satiety that, in part, may be due to elevated circulating cytokines.41,42 Compounding the problem is the frequent presence of poor gastrointestinal motility and gastroesophageal reflux, which can lead to the loss of up to one-third of feedings via emesis.42–45 In turn, the provision of nocturnal feedings by slow, continuous drip, along with intermittent bolus feedings during the day, is often required to meet the nutritional goals (Table 5). Historically, NG tubes were preferentially used because of the simplicity of placement (although not necessarily simple from the perspective of the parent and patient) with no disruption of any ongoing PD. However, frequently associated complications of this approach to therapy (in addition to the unsightly appearance) include recurrent emesis, nasal trauma associated with tube replacement, and inhibition of the normal development of oral motor skills.46 The latter problem needs to be addressed with oral and occupational therapy. On the other hand, gastrostomy tubes and buttons, which were championed early on by Watson and Coleman, are not

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Table 5 Suggested rates for initiating and advancing tube feedings for neonates with CKD Method

Initial Hourly Infusion

Daily Increases

Goal

Continuous feedings

1–2 mL/kg/h

1 mL/kg/h

6 mL/kg/h

Bolus feedings

10–15 mL/kg/feed

20–40 mL every 4 h

20–30 mL/kg/feed

Adapted from KDOQI clinical practice guideline for nutrition in children with CKD: 2008 update. Executive summary. Am J Kidney Dis 2009;53(3 Suppl 2):S91; with permission.

associated with the development of altered oral motor skills, are not regularly associated with emesis, are not visible, and offer the additional advantage of being available for prolonged use during the postrenal transplant period when they can help ensure proper hydration and medication administration.47 It is for these reasons that gastrostomy tubes and buttons have supplanted NG tubes as the preferred route of enteral tube support in many centers. Data from single-center studies have repeatedly shown that the provision of tube feedings facilitates both height and weight gain. Kari and colleagues,33 in a review of 81 tube-fed infants with a GFR less than 20 mL/min/1.73 m2 during the first 6 months of life or placed on dialysis during the first 2 years of life, found that 81% of subjects achieved a normal height SDS after 1 year of follow-up. Subsequent evaluation of this same cohort 10 years later revealed that the intensive feeding regimen combined with early transplantation resulted in a normal mean adult height in those patients without comorbidities.48 Ramage and colleagues49 demonstrated that the use of enteral feedings in 8 infants receiving PD arrested the decline in height SDS traditionally reported, while Ledermann and colleagues50 demonstrated that enteral feeding resulted in significant improvements in weight, height, and head circumference SDS at both 1 and 2 years of age in 12 infants receiving PD. The most recent data are derived from the International Pediatric Peritoneal Dialysis Network (IPPN), which has provided further evidence of the benefit of supplemental tube feedings in terms of height and weight gain in children younger than 2 years and on PD, with marked global variation in the use of tube feedings during infancy.51 OUTCOMES

Published data on the outcomes of neonates with CKD are sparse. In a retrospective analysis of 1461 preterm infants that included 2-year follow-up data, Bruel and colleagues52 found that creatinine values greater than 1.6, 1.1, and 1.0 mg/dL at 24 to 27, 28 to 29, and 30 to 32 weeks of gestation, respectively, after adjustment for gestational age, birth weight, sex, and other renal failure risk factors, were significantly associated with neonatal mortality (odds ratio of 8.55 [95% confidence interval 4.23–17.28], P

Chronic kidney disease in the neonate.

An increased emphasis has been placed on the early identification of chronic kidney disease (CKD) in the neonatal population, given the long-term heal...
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