Adolescents with Chronic Kidney Disease: From Diagnosis to End-Stage Disease

By Stephanie Nguyen

End-stage renal disease is a devastating diagnosis to the patient, family and their care provider. This book covers all aspects of chronic kidney disease from a general description to its psychological impact on the adolescent and lastly its progression to end-stage and dialysis. It details the important aspects of the patient’s journey from diagnosis to their final destination including transplant and discussion of the medications used. It includes chapters on important etiologies of chronic kidney disease in adolescence, addressing the particular challenges a provider may be faced with in caring for this age group, and finally transition of their care to adult care providers.

 Written by experts in the field of pediatrics and nephrology Adolescents with Chronic Kidney Disease is the definitive resource in diagnosing and transitioning patients with chronic kidney disease.

• Language: English
• Publisher: Springer
• Release date: Oct 5, 2018
• ISBN: 9783319972206

Book preview

© Springer Nature Switzerland AG 2019

Maha N. Haddad, Erica Winnicki and Stephanie Nguyen (eds.)Adolescents with Chronic Kidney Diseasehttps://doi.org/10.1007/978-3-319-97220-6_1

1. Complications of Chronic Kidney Disease in Adolescents

Elaine Ku¹   and Jonas Kwok²  

(1)

Department of Medicine and Pediatrics, University of California San Francisco, San Francisco, CA, USA

(2)

College of Medicine, SUNY Downstate Medical Center, Brooklyn, NY, USA

Elaine Ku (Corresponding author)

Email: [e-mail]

Jonas Kwok

Email: [e-mail]

Keywords

CKDAdolescent medicinePediatric nephrologyTransitional care

Introduction

Definition of CKD

The Kidney Disease Improving Global Outcomes (KDIGO) defines chronic kidney disease (CKD) as abnormalities of kidney structure or function, present for 3 months, with implications for health, and is classified based on cause, glomerular filtration (GFR) category, and albuminuria (or proteinuria in children) category [1]. Thus, presence of structural abnormalities, persistently low GFR, or persistent proteinuria for more than 3 months is consistent with a diagnosis of CKD. GFR may be determined by a variety of methods, the most common employed equations of which are based on serum creatinine (SCr). The recommended equation for pediatric patients is the Schwartz bedside formula [2], which provides an estimate of the level of kidney function or GFR and is determined by taking 41.3*(height(m)/SCr (mg/dL)). The stages of CKD are shown in Table 1.1.

Table 1.1

KDIGO stages of chronic kidney disease by eGFR [1]

CKD During Adolescence

Adolescence is a high-risk period for patients with chronic kidney disease (CKD). While the probability of developing end-stage renal disease (ESRD) gradually increases with age in pediatric-onset CKD, a notable decline in survival occurs in puberty and early post-puberty [3]. Mechanisms contributing to the higher rate of progression of CKD in adolescence include higher blood pressures, risk for an imbalance between nephron mass and the filtration demands of growth, and alterations in hormone levels [4].

Adolescence is also unique because patients move from largely passive to more active roles in the management of their care. This period is critical for the development of self-management skills and transition readiness as adolescents prepare for young adulthood. It is not surprising, given the burden of stress on adolescents, that patients 14–16 years old have the highest rates of graft loss among all patients ≤55 years old [5, 6].

A major goal of CKD management in children and adolescents is to delay the onset of ESRD. Children, adolescents, and young adults constitute less than 5% of the ESRD population, and while 10-year survival is 75–80% in pediatric ESRD, the mortality rate is still 30 times higher than their age-matched peers [7]. Given the known average rate of decline in kidney function (approximately 4.3 and 1.5 ml/min per 1.73m² per year for glomerular and non-glomerular diagnoses, respectively), many adolescents are likely to see their CKD progress to ESRD during adolescence or young adulthood [3, 8, 9]. In fact, nearly 40% of all pediatric kidney transplants occur in adolescents aged 13–17.

Medical Complications

Growth and Puberty

Puberty is initiated by the gonadotropic hormone axis, which stimulates rapid linear growth, and is characterized clinically by the development of secondary sex characteristics including increased breast size in girls and testicular volume in boys. However, approximately 80% of growth is already complete by puberty in children [10]. Thus, while compromised accrual of height velocity is most apparent during puberty, prepubertal growth stunting also has a major impact on final height achievement. For children reaching ESRD before or during puberty, the onset of puberty may be delayed by up to 2–2.5 years, and the magnitude of the growth spurt that occurs may be substantially reduced [11]. Medications such as steroids that are used to treat the underlying kidney disease can also cause pubertal delay, as it disrupts the hormonal axis for growth [10]. Fortunately, normal onset of puberty is seen in children who are transplanted before 5 years of age [12].

Growth failure in children with CKD is a consequence of a variety of factors, most notably mineral and bone metabolism disorders that occur with CKD [13]. KDIGO guidelines recommend that providers monitor three aspects of bone disease in CKD patients: turnover, mineralization, and volume [14]. Both abnormalities of bone turnover and mineralization increase in prevalence as renal function declines, as measured by GFR. Disruption of the growth hormone-insulin-like growth factor axis, including resistance to growth hormone, also contributes to decreased linear growth [15].

Approximately 45–60% of adults with childhood-onset CKD have short stature [16]. Over one-third of children with CKD were below the 3rd percentile for height upon entry to the North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) registry [17]. For children with congenital CKD, growth velocity after 2 years of age can normalize to parallel the expected growth velocity, but patients do not necessarily experience catch-up growth and may remain persistently shorter than their peers [15, 17, 18]. Findings from the CKiD (Chronic Kidney Disease in Children) study suggest that girls with non-glomerular etiologies of CKD may experience the greatest growth impairment [19]. For adolescents who develop ESRD, this growth failure is associated with higher 5-year mortality [20].

Medical management for growth retardation in adolescents with CKD should focus on the early identification and correction of metabolic derangements, nutritional deficiencies, and hormonal abnormalities [15, 17, 19]. Recombinant human growth hormone (rhGH) has proven to be safe and efficacious, though it is more effective in prepubertal children and during earlier stages of CKD [21, 22]. However, growth hormone is underutilized in the treatment of children with CKD-related growth impairment, in part because patients may be deterred by the prospect of frequent injections [15, 19, 21]. A review of rhGH use in pediatric CKD found that side effects were uncommon in general, although elevated fasting glucose, glucose intolerance, granuloma formation, claudication, hypertension, and worsening of scoliosis are some potential adverse effects [15]. Other adverse effects associated with growth hormone use include decreased kidney function, papilledema with benign intracranial hypertension, or acute rejection in the setting of transplantation [15].

Catch-up growth for children with ESRD is not seen as often in patients on dialysis, but occurs with transplantation, though this growth is attenuated among those who are older at time of transplant and those receiving steroids after transplantation [15, 17].

Adolescence is a critical period for attaining peak bone mass, with 25% of skeletal mass being deposited within the 2 years of peak height velocity [23]. Adolescents are therefore vulnerable to decreased levels of nutritional vitamin D, mineral abnormalities, and alterations in bone accrual, as well as a higher risk of fracture due to relative under-mineralization of bones during this period [24, 25]. Risk of fracture is increased by 2.4- and 3-fold for boys and girls, respectively, compared to their age-matched healthy peers, with boys over 14 years old having the highest incidence of fractures [26]. Advanced pubertal stage, taller stature, and higher serum levels of parathyroid hormone were also associated with greater risk of fractures in the CKiD cohort of children with mild to moderate CKD [26].

Cardiovascular Disease

Traditional risk factors for cardiovascular disease (CVD), including obesity (15%), hypertension (54%), dyslipidemia (45%), and insulin abnormalities (9–19%), all occur at high rates in children and adolescents with CKD [27–29]. Children with CKD are also subject to nontraditional risk factors for CKD, including abnormal mineral metabolism, anemia, chronic inflammation, uremia, and fluid overload [28]. The relationship between disordered mineral metabolism and cardiovascular disease has been described by CKD-MBD (mineral and bone disorder) since the KDIGO consensus in 2009 [14]. Findings such as left ventricular hypertrophy (17–49%), increased carotid intima-media thickness, and vascular calcifications are more prevalent in children with even mild CKD, with still higher rates among those treated with dialysis [28, 30]. Cardiovascular disease still remains the leading cause of death, although this high mortality rate is lower after kidney transplantation [31].

Hypertension , along with albuminuria and low nephron mass, is a major risk factor for the progression of CKD [32]. Hypertension and CKD are intrinsically linked, with worsening of one condition exacerbating the other [28]. Hypertension secondary to increasing intravascular volume and peripheral vascular resistance causes a decline in renal function through intrinsic renal tissue damage and hypoperfusion, thereby triggering renin-angiotensin-aldosterone-system (RAAS) activation, increased salt and volume retention, vasoconstriction, and sympathetic upregulation, resulting in exacerbation of hypertension [32].

Hypertension is extremely common among children with CKD. In CKiD, 54% of the cohort was hypertensive at enrollment, while the NAPRTCS registry found a prevalence of 76.6% [32–34]. Hypertension is associated with the development of target-organ damage in children, and studies suggest the potential for regression of left ventricular hypertrophy through antihypertensive control in children with CKD [35]. In accordance with findings from the CKiD study, KDIGO guidelines recommend pharmacologic antihypertensive treatment for patients with systolic blood pressures above the 90th percentile for age, sex, and height [36]. The 2017 American Academy of Pediatric guidelines, in accordance with results of the ESCAPE trial, recommend hypertensive children with CKD be treated with ACE inhibitors or ARBs – especially in patients with proteinuria [37, 38]. Blood pressure targets in children with CKD are <90th percentile for age, sex, and height or <130/80 mmHg, whichever is lower among adolescents age 13 or older [37]. Ideally, blood pressure should be treated to a mean arterial pressure of <50th percentile on 24-h ambulatory blood pressure monitoring if available [37, 38]. Reduction of salt intake is recommended in the management of hypertension in children with CKD, as decreased intake is associated with reduction in proteinuria and blood pressure [32].

An up to 700-fold increased risk of cardiovascular mortality has been reported for children with ESRD compared to their healthy peers [39]. The US Renal Data System showed that 23% of mortality in children and young adults with childhood-onset ESRD was due to cardiovascular causes and that adolescents with CKD were at higher risk for arrhythmias than younger children [31]. These risk factors have prompted the American Heart Association (AHA) to place pediatric CKD patients in the highest category of cardiovascular risk [40]. However, adolescents with CKD who enter young adulthood may often receive suboptimal preventative CVD care, as measured by cardiovascular risk factor screening and guideline-directed treatment, in spite of the elevated CV risk in this population [41]. The American Heart Association cardiovascular risk management guidelines recommend screening and monitoring of blood pressure, lipids, and glucose, providing dietary counseling, and encouraging smoking cessation and physical activity [40].

Anemia

Anemia is common in childhood CKD, with over 30% of patients meeting National Kidney Foundation Disease Outcomes Quality Initiative criteria [42]. In a recent study, adolescents aged 10–18 in the United States had a high prevalence of anemia. Anemia was especially common among adolescents with long-standing CKD from congenital urological abnormalities [43]. Data from NAPRTCS indicated that the prevalence of anemia increases with progressive CKD stages [44]. The consequences of anemia in adolescents with CKD are numerous, as anemia has been linked to fatigue, depression, sleep disturbances, impaired cognitive function, loss of appetite, decreased exercise tolerance, decreased health-related quality of life in multiple domains, and increased mortality [23, 28, 43, 45].

The etiologies of anemia in CKD are multifactorial, including erythropoietin deficiency, iron deficiency, nutritional deficits, inflammation, hyperparathyroidism, and side effects of medications [23]. For adolescent girls, menstruation may also contribute to anemia. Treatment of anemia in CKD primarily consists of iron supplementation and erythropoietin-stimulating agents (ESAs), as well as management of non-renal complications if present. The 2012 KDIGO guidelines recommend targeting hemoglobin levels of 11–12 g/dl in children receiving ESA therapy [46]. Interestingly, adolescents exhibit the lowest rate of nonadherence (4%) to erythropoietin-stimulating agents among CKD medications [47].

Neurocognition

Adolescents with CKD are at increased risk for neurocognitive deficits compared to their healthy peers. CKD-specific comorbidities that may contribute to neurocognitive sequelae of CKD include anemia, hypertension, and cardiovascular disease [48–50]. While findings have not always been consistent, most of the available literature note either significantly decreased or low-normal scores for academic achievement, executive function, attention regulation, language acquisition, visual-spatial ability, memory, and inhibitory control [48, 49, 51, 52]. These impairments are correlated with worsening disease severity, longer duration of disease, and younger age of onset [53].

Between 21% and 40% of children and adolescents (6–17 years old) with mild to moderate CKD score one or more standard deviations below the average for IQ, academic achievement, attention, or executive functioning [51]. In older children and young adults (8–25 years old), declining renal function is associated with decreased attention, visual-spatial ability, and worse memory [49].

Patients reaching ESRD during childhood have lower IQs compared to their siblings and healthy controls [54]. However, the mode of renal replacement therapy may have different effects on neurocognition. Compared to patients on dialysis, children with renal transplants exhibit comparatively better academic performance and may even achieve normal attention, language, and visual-spatial test scores, with lasting impacts on IQ and educational attainment into adult life [48, 54, 55]. However, the prevalence of patients with CKD who receive special education services in the United States is comparable to the general population [48]. Academic achievement may be further impaired due to frequent absenteeism secondary to outpatient medical visits, hospitalizations, and hemodialysis sessions [48, 55].

In addition to school attainment and performance, neurocognitive deficits in adolescents are also concerning due to their potential influence on work attainment and earning potential. One study found that only 50–75% of adults with pediatric renal transplants were employed as adults [56].

Psychosocial Complications

Quality of Life

The disease burden of CKD is extensive, from systemic consequences and comorbidities, such as disordered bone mineral metabolism and anemia, to its impact on physical and psychosocial development [57]. Similar to adolescents with other chronic diseases, those with CKD often have more behavioral problems, hyperactivity, aggression, anxiety, worry, and depressive symptoms compared to their age-matched peers [57, 58].

A variety of tools have been used to assess health-related quality of life (HRQoL) in adolescents with CKD , and all indicate decreased HRQoL across multiple domains – social, physical, emotional, school function, cognition, pain, and disease-specific (disease burden, symptoms, pain, daily functioning) [45, 59, 60]. Evidence that adolescents and young adults with CKD are willing to trade considerable life expectancy for perfect health demonstrates the extent to which CKD disrupts patients’ daily lives [59]. Ideally, providers should identify HRQoL issues early in order to improve the social, emotional, and functional outcomes of adolescents with CKD.

Decreased HRQOL has been reported to be associated with changes in physical appearance related to CKD progression and its treatment (stunted growth, edema, and altered body fat distribution from corticosteroid treatment) [57]. Short stature is oft-cited as a major contributor to adolescents’ poor quality of life [42, 61]. Delayed puberty in children with CKD also delays adolescents’ sexual development, which may influence their self-concept and ability to fit in with their peers. Patients may also feel a lack of normalcy, independence, and ability to socialize and integrate themselves in society [59]. Children on dialysis have been reported to have still lower functional health status than patients who are pre-dialysis [62].

CKD also impacts adolescents’ quality of life via its impacts on sleep. The prevalence of sleep disorders in pre-dialysis children and adolescents with CKD is 40–50% and is associated with behavioral deficits, school performance, and decreased HRQoL when present [63]. Data from CKiD indicate that older age, shorter duration of CKD, and glomerular disease are associated with increased daytime sleepiness [63]. Adolescents over 14 years old with measured GFR <50 reported falling asleep two to three times more often during the day than younger children with higher GFRs, and adolescents with CKD also have higher prevalence of restless legs syndrome [42, 61]. Due to disordered hormonal balances and comorbidities, children and adolescents are also at risk for increased body mass index, which is associated with sleep-disordered breathing [63]. Urinary incontinence (mostly bedwetting) in children between 5 and 16 years old is also more common in the presence of CKD and may have lasting effects on adolescents due to the incontinence-related social stigma and lowered self-esteem [64].

Behavioral and emotional disorders in children and adolescents with CKD are common [60]. Depression is more common in children aged 9–18 with CKD stages 1–3 compared to their age-matched peers, with even greater likelihood in adolescents above age 13 [58, 65].

Family and Psychosocial Factors

Compounding patients’ personal challenges of living with CKD, patients’ families are also at risk for a variety of stressors. Having a child with chronic illness may affect the patient’s siblings who may often feel neglected, increase the psychological distress of caretakers by challenging the ability for caretakers to maintain employment, and also contribute to marital strain [53, 66]. Lower socioeconomic status, large families, lack of familial support, and younger patient age are risk factors for poorer psychosocial adjustment and quality of life in the parents of children with CKD [23, 67].

In contrast to patients’ self-reported quality of life, which improves with aging, parents tend to report worsening quality of life for their child with increasing age of the patient. While well-adjusted and supportive families can provide a buffer against the negative stressors on the patient and support the transition of patients to adult healthcare systems, low levels of family support are not uncommon and are correlated with worse patient adherence and overall outcomes [57, 68].

Studies have shown that CKD patients with household incomes <$75,000 were more likely to be younger and minorities, lack private insurance, and have mothers with lower education, abnormal birth history, and at least one clinical comorbidity [69]. Patients of low-income families are at higher risk for short stature compared to those with household incomes >$30,000 [69]. Lower maternal education has been associated with lower HRQoL in children with CKD [45]. Socioeconomic factors associated with poorer transition readiness and healthcare utilization in adolescents include younger age, public instead of private insurance, and lack of an individualized education plan (IEP) or 504 plan [70].

Duration of CKD and Its Influence on Quality of Life

Adolescents with CKD can be subdivided into two broad groups. In the first group, adolescents will have onset of their kidney disease during adolescence, often presenting for the first time during their teenage years. Compared to younger children with CKD, these adolescents have a higher incidence of glomerular disease, which is associated with more rapid progression of renal disease [71]. The second group includes adolescent-age patients who have been living with a renal diagnosis for years, often since birth as a result of congenital anomalies of the kidney and urinary tract (CAKUT) [72]. These patients have a much higher incidence of structural urological abnormalities and tend to be anemic and more severely affected by poor growth [17, 43].

CKiD data shows that children who have been living with CKD for a longer duration of time have better physical and emotional functioning compared to those with newer diagnoses [45]. This suggests that adolescents with congenital etiologies of their CKD may be able to better cope with the stressors of CKD, a phenomenon termed response shift [45].

Earlier diagnosis does not necessarily mean a more benign patient experience, however. Roumelioti et al. reported that children with long-standing CKD have less energy compared to those who had CKD for less than a quarter of their lives [61]. Children with later onset of CKD, as in adolescence, may have a higher likelihood of achieving normal growth and psychosocial development as a result of having had good health before their CKD diagnosis [53].

The rate of progression of CKD and severity of disease is inversely correlated with self-management ability [23]. Nevertheless, all pediatric CKD patients, regardless of disease severity, report decreased health-related quality of life across physical, social, emotional, and school function domains as assessed by the Pediatric Quality of Life Inventory (PedsQL) and Kidney Disease Quality of Life Instrument (KDQOL) [45, 59, 60].

Transition of Care

Adolescents are at higher risk for complications related to poor self-management and nonadherence [68, 73]. Compared to patients of other age groups with CKD and ESRD, adolescents may struggle with a number of challenges, including the need to fit in with peers, concerns surrounding body and self-image, school or work obligations, and poor recognition of the long-term consequences of their actions, including nonadherence to therapy [23, 74, 75]. Nonadherence in children with CKD has been reported to range from 4% to 22% and is associated with the frequency of medication dosing [47, 76]. As such, healthcare providers should dedicate extra time to adolescents with CKD to ensure that patients are prepared for medical self-management, adherent to therapy, and developing skills needed to navigate their way through adult healthcare systems.

Management of CKD involves keeping track of a list of appointments with nephrologists and other specialists depending on comorbidities, adherence to multiple medications on different dosing schedules, financial and insurance considerations, dietary restrictions, and frequent laboratory monitoring. While the bulk of this responsibility is shouldered by parents in earlier childhood, adolescents around 18–21 years of age are expected to be more self-reliant as they transition to adult care [23, 77]. This transition, compounded by the need to maintain age-appropriate activities and mature physically, sexually, cognitively, and socially, can be challenging in the life of young patients [78]. Ferris and colleagues cite a number of obstacles and challenges faced by adolescents with CKD, including [79]:

Slower maturation of cognitive function

Depression, lower socialization skills and self-esteem, and slower achievement of milestones

Adoption of high-risk behaviors including use of drugs and alcohol and nonadherence to treatment

Development of personal identity and need for peer recognition

Overcoming differences in physical appearance including shorter stature and scars from prior surgeries

Performing school-/work-related tasks in the setting of potential cognitive impairment

Learning to self-manage medications and appointments

Transitioning out of the home/loss of parental supervision

A consensus statement endorsed by both the International Society of Nephrology (ISN) and the International Pediatric Nephrology Association (IPNA) states that the transitional years span roughly from 14 to 24 years [78]. This age span underscores the recognition that transitional care should be individualized – not every patient may be ready for transition by 18 or 21 years of age [75, 80]. Transition requires long-term planning, with frequent assessments of readiness beginning as early as ages 12–14, and should involve pediatric and adult physicians, the family, and the patient [75, 81]. Successful transitions between pediatric and adult care may require holistic assessments of patients’ ability to self-manage, adhere to medications, and effectively utilize the healthcare system [70].

Ideally, dedicated transition clinics or youth workers should be available to facilitate transitions of care, though most facilities do not have such services [75]. Individualized care based on routine assessments of transition readiness – including emotional maturity, illness stability, availability of developmentally appropriate services, and emotional, physical, and psychological attainment – is essential for optimal transition and transfer of care [78, 79, 80]. Unfortunately, the transition of care from pediatric to adult nephrology is often fragmented, and not all patients may have access to a pediatric nephrologist in the United States [75, 82].

Concluding Thoughts

Chronic kidney disease and its complications have many implications for adolescents. Adolescence is an especially vulnerable stage of life for patients with CKD physically, emotionally, and socially. As a consequence, patients have higher mortality risk, have decreased quality of life, and are subject to the negative consequences of CKD on their growth and neurocognitive outcomes compared to both healthy peers and other CKD age groups. Transition preparation should begin early in adolescence, given the potential for the severe and lasting consequences of inappropriate disease management.

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