Chronic Kidney Disease in Children

Chronic kidney disease (CKD) and renal failure (RF) have been recognized as significant medical problems for most of the last 2 centuries and, until relatively recently, were uniformly fatal. Scientific and technologic improvements during the second half of the 20th century provided renal replacement therapy as a life-sustaining option for many individuals who otherwise may have died. The impact of these medical advancements has been remarkable.

Chronic kidney disease is characterized by an irreversible deterioration of renal function that gradually progresses to end-stage renal disease (ESRD). Chronic kidney disease has emerged as a serious public health problem. Data from the United States Renal Data System (USRDS) show that incidence of kidney failure is rising among adults and is commonly associated with poor outcomes and high cost. ^[1]  Moreover, in the past 2 decades, the incidence of chronic kidney disease in children has steadily increased, with poor and ethnic minority children disproportionately affected. ^[1]

Children, adolescents, and young adults constitute less than 5% of the end-stage kidney disease (ESKD) population, and their 10-year survival ranges from 70% to 85%. ^{[1, 2]}  Although children represent only a small proportion of all patients with CKD, affected children pose unique challenges to the health care system and to their providers, who must address not only the primary renal disorder, but the many extrarenal manifestations of CKD that complicate management. ^{[3, 4]}  Most importantly, the development of ESRD compromises the life expectancy of affected patients, with an age-specific mortality rate for children receiving dialysis that is 30 to 150 times higher than for healthy peers. 

The major health consequences of chronic kidney disease include not only progression to kidney failure but also an increased risk of cardiovascular disease. Evidence-based clinical practice guidelines support early recognition and treatment of chronic kidney disease–related complications to improve growth and development and, ultimately, the quality of life in children with this chronic condition. Appropriate pediatric care may reduce the prevalence of this complex and expensive condition.

Definition of chronic renal disease

The definition and classification of chronic renal disease may help identify affected individuals, possibly resulting in the early institution of effective therapy. To achieve this goal, the Kidney Disease Outcomes Quality Initiative (KDOQI) working group of the National Kidney Foundation (NKF) defined chronic kidney disease as "evidence of structural or functional kidney abnormalities (abnormal urinalysis, imaging studies, or histology) that persist for at least 3 months, with or without a decreased glomerular filtration rate (GFR), as defined by a GFR of less than 60 mL/min per 1.73 m²." ^{[2, 3, 4]}

Note, however, that the above definition is not applicable to children younger than 2 years, because they normally have a low GFR, even when corrected for body surface area. In these patients, calculated GFR based on serum creatinine can be compared with normative age-appropriate values to detect renal impairment.

See also Chronic Renal Failure, Renal Failure, Chronic and Dialysis Complications,Dermatologic Manifestations of Renal Disease, Renal Transplantation (Medical), and Perioperative Management of the Patient With Chronic Renal Failure.

The chief causes of chronic kidney disease (CKD) in children include the following:

• Obstructive uropathy

• Hypoplastic or dysplastic kidneys

• Reflux nephropathy

• Focal segmental glomerulosclerosis as a variant of childhood nephritic syndrome

• Polycystic kidney disease, autosomal-recessive and autosomal-dominant varieties

The distribution of causes varies with age. Whereas congenital anomalies of the kidney and urinary tract predominate in younger patients, glomerulonephritis is the leading cause in children older than 12 years of age. 

Despite the diverse etiologies, once chronic kidney disease develops, the subsequent response of the failing kidney is similar. The kidney initially adapts to damage by increasing the filtration rate in the remaining normal nephrons, a process called adaptive hyperfiltration. As a result, patients with mild chronic kidney disease often have a normal or near-normal serum creatinine concentration. Additional homeostatic mechanisms (most frequently occurring within the renal tubules) permit the serum concentrations of sodium, potassium, calcium, and phosphorous and total body water to also remain within the reference range, particularly among those with mild to moderate stages of chronic kidney disease.

Adaptive hyperfiltration, although initially beneficial, appears to result in long-term damage to the glomeruli of the remaining nephrons, which is manifested by pathologic proteinuria and progressive kidney insufficiency. This irreversibility appears to be responsible for the development of end-stage kidney failure among persons in whom the original illness is either inactive or cured.

Although the underlying problem that initiated chronic kidney disease often cannot be treated primarily, extensive studies in experimental animals and preliminary studies in humans suggest that progression in chronic renal disease may be largely due to secondary factors that are unrelated to the activity of the initial disease. These include anemia, osteodystrophy, systemic and intraglomerular hypertension, glomerular hypertrophy, proteinuria, metabolic acidosis, hyperlipidemia, tubulointerstitial disease, systemic inflammation, and altered prostanoid metabolism. This common sequence of events in diverse types of chronic kidney disease is the basis for the common management plan for children with chronic kidney disease, irrespective of the etiology.

A prospective multicenter cohort study by Greenberg et al that assessed long-term kidney outcomes after pediatric cardiac surgery (between one and 18 months of age) reported that at follow-up after cardiopulmonary bypass, 17% of the 131 children in the study (22 children) had hypertension and 18% (21 children) had chronic kidney disease. ^[5]  

United States statistics

Based on data from the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) chronic renal insufficiency (CRI) database, 5651 patients aged 2-17 years were entered into this voluntary listing and had an estimated glomerular filtration rate (eGFR) of less than 75 mL/min per 1.73 m². ^[6] In the past 2 decades, the incidence of the disease has steadily increased among all ethnic groups.

In a National Health and Nutrition Examination Survey (NHANES) on the prevalence of chronic kidney disease (CKD) in adolescents aged 12-18 years, the authors observed that the prevalence of persistent albuminuria was similar between 1988 and 2014 and ranged from 3.29% to 3.26%. However the prevalence of both reduced and low eGFRs was higher in the most recent study period. ^[7]  

International statistics

Globally, the prevalence of CKD stage II or lower in children is reported to be approximately 18.5-58.3 per million children. Disease prevalence is much lower than that in adults; in a study from India, children constituted 5.3% of all patients with chronic kidney disease seen in a referral hospital. ^[8] Data from the ItalKid study reported a mean incidence of 12.1 cases per year per million in the age-related population (age range, 8.8-13.9 y) and a prevalence of 74.7 per million in this population. ^[9] However, underreporting due to lack of recognition may suggest an even higher prevalence in children.

Sexual, racial, and age differences in incidence

In the United States, the incidence and rate of progression to end-stage renal disease (ESRD) are equal in both sexes, although obstructive uropathies are more common in males.

ESRD rates in Black individuals are 2.7 times higher than in White individuals, which may be due to genetic susceptibility; other factors may include socioeconomic problems and limited access to medical care. Such factors may result in the delivery of excessive numbers of low birth weight (LBW) babies, partially accounting for the observed increased incidence of ESRD, because chronic kidney disease is more common with increasing prematurity and survivorship.

Choi et al found that rates of ESRD among Black patients exceeded those among White patients at all levels of baseline eGFR. ^[10] Similarly, mortality rates among Black patients were equal to or higher than those among White patients at all levels of eGFR. Risk of ESRD among Black patients was highest at an eGFR of 45-59 mL/min/1.73 m², as was the risk of mortality. ^[1]

The frequency of chronic kidney disease increases with age and is much more common in adults than children. Among children, chronic kidney disease is more common in children older than 6 years than in those younger than 6 years. The percentages in the NAPRTCS cohort were 19% in children aged 0-1 years; 17% in those aged 6-12 years; 33% in children aged 2-5 years; and 31% in those older than 12 years. ^[6]

Chronic kidney disease (CKD) is a heterogeneous disease, with possibly both genomic and environmental contributory factors. Various studies have shown a high CKD heritability (30-75%).

Genome-wide association studies (GWAS) and GWAS meta-analyses have identified several genetic loci, including variants in UMOD, SHROOM3, solute carriers, and E3 ubiquitin ligases. However, these genetic markers do not account for all the susceptibility to CKD, and other factors must contribute to the missing heritability.

A shorter telomere length has been associated with renal dysfunction and CKD progression, although most studies include small numbers of cases with variable findings. Copy number variants (CNVs) have been linked to congenital anomalies of the kidney and urinary tract, posterior urethral valves, nephronophthisis, and immunoglobulin A nephropathy. The A3243G mutation in the MT-TL1 gene has been associated with focal segmental glomerulosclerosis.

Only one GWAS has found associations between X chromosome and renal function (rs12845465 and rs5987107). No loci in the Y chromosome have reached genome-wide significance. Although additional biomarkers have been investigated in less common suspects such as telomeres, CNVs, mitochondrial DNA, and sex chromosomes, hidden heritability in CKD remains unexplained. ^[11]

Once chronic kidney disease (CKD) occurs, progression to end-stage renal disease (ESRD) appears certain. In a study by Warady et al, hypoalbuminemia, hypertension, dyslipidemia, male gender, anemia, nephrotic range proteinuria, dyslipidemia at baseline, hyperphosphatemia,   and lower values for glomerular filtration rate (GFR) at baseline were predictors of rapid progression. ^[12]  However, the rate of progression depends on the underlying diagnosis, on the successful implementation of secondary preventive measures, and on the individual patient.

About 70% of children with chronic kidney disease develop ESRD by age 20 years. Children with ESRD have a 10-year survival rate of about 80% and an age-specific mortality rate of about 30 times that seen in children without ESRD. The most common cause of death in these children is cardiovascular disease, followed by infection. Of the deaths due to cardiovascular causes, 25% were attributed to cardiac arrest (cause uncertain), 16% to stroke, 14% to myocardial ischemia, 12% to pulmonary edema, 11% to hyperkalemia, and 22% to other cardiovascular causes, including arrhythmia. Data from the Australia and New Zealand (ANZ) registry revealed that the risk of death was associated with the year in which renal replacement therapy was initiated, the age of patients at the start of that therapy, and the type of dialysis used. ^[13]

Once the estimated glomerular filtration rate (eGFR) declines to less than 30 mL/min per 1.73 m² and the child has stage IV chronic kidney disease, the child and the family should be prepared for renal replacement therapy. The family should be provided with information related to preemptive kidney transplantation, peritoneal dialysis, and hemodialysis. When preemptive transplantation is not an option, the choice between the 2 forms of dialysis is generally dictated by technical, social, and compliance issues, as well as family preference. Peritoneal dialysis is much more common in infants and younger children.

Patients on long-term dialysis have a high incidence of morbidity and mortality. Preemptive renal transplantation should be the goal of management in these children.

Children with chronic kidney disease and their families should receive education about the importance of compliance with secondary preventative measures, natural disease progression, prescribed medications (highlighting their potential benefits and adverse effects), diet, and types of long-term renal replacement modalities.

Information related to preemptive kidney transplantation, peritoneal dialysis, and hemodialysis should be provided to the family once the child's estimated glomerular filtration rate (eGFR) declines to less than 30 mL/min per 1.73 m² and the child has stage IV chronic kidney disease.

For patient education information, see Chronic Kidney Disease and Kidney Transplant.