Chronic kidney disease in children: Epidemiology, etiology, and course

INTRODUCTION — 

Chronic kidney disease (CKD) is a state of irreversible and progressive kidney damage and/or reduction of kidney function for at least three months. The diagnosis can be based on decreased glomerular filtration rate (GFR) or markers reflecting structural abnormalities, such as proteinuria, abnormalities in urine sediment or electrolytes, or pathologic abnormalities on kidney biopsy or kidney imaging. (See "Chronic kidney disease in children: Clinical manifestations, evaluation, and diagnosis", section on 'Diagnostic criteria'.)

The rate of CKD progression depends on the underlying disorder and its treatment, genetic predisposition, and management of hypertension and proteinuria.

Kidney failure is defined as a GFR <15 mL/min/1.73 m² or treatment by dialysis. This is the preferred nomenclature rather than the previously used terms "end-stage renal disease" or "end-stage kidney disease." Kidney replacement therapy (KRT) is the appropriate terminology for the treatment of kidney failure by dialysis or transplant.

The etiology, epidemiology, and progression of CKD in children will be reviewed here. Other aspects of CKD in children are discussed in separate topic reviews:

●(See "Chronic kidney disease in children: Clinical manifestations, evaluation, and diagnosis".)

●(See "Chronic kidney disease in children: Overview of management".)

●(See "Chronic kidney disease in children: Complications".)

●(See "Growth failure in children with chronic kidney disease: Prevention and management".)

●(See "Pediatric chronic kidney disease-mineral and bone disorder (CKD-MBD)".)

EPIDEMIOLOGY

Incidence and prevalence — Obtaining accurate data on the epidemiology of pediatric CKD is challenging. The reported number of children with pediatric CKD is likely underestimated because earlier stages of CKD are usually asymptomatic, leading to underdiagnosis. Moreover, it is difficult to compare prevalence estimates for childhood CKD throughout the world due to the variability of available health resources for diagnosis and tracking of CKD and the use of different definitions [1,2]. Furthermore, published information is often based on reports from major referral centers and it is uncertain whether these data truly reflect population-based risks. Recognizing these limitations, available data provide the following estimates:

●Moderate to severe CKD – In a review of global data from 2008, the estimated median annual incidence of moderate to severe pediatric CKD cases per million of age-related population (pmarp) varied as follows [1]:

•Europe – 11.9

•Latin America – Rates ranged from 2.8 to 15.8

•Sub-Saharan Africa – Rates ranged from 1 to 3, based on single-center studies

In low-resource settings, reports of relatively low rates of CKD are most likely related to the limited health resources available for case detection and reporting.

For the United States, estimates of the prevalence of pediatric CKD come from the following analyses of data from the National Health and Nutrition Examination Survey (NHANES):

•Low glomerular filtration rate (GFR) – An analysis by the USRDS estimated the prevalence of low estimated GFR (<60 mL/min/1.73 m²) at 0.51 percent among adolescents 12 to 17 years old, using the "bedside Schwartz" equation and NHANES data collected from 2005 to 2020 [3]. A limitation of this report is that the racial and ethnic data from USRDS are from a relatively small cohort of children on Medicaid from 17 states.

•Moderate to severe CKD – An analysis by the Kidney Disease Surveillance System estimated a prevalence of CKD stage G3 to G5 of <1 percent among adolescents (figure 1), based on NHANES data from 2001 to 2020 and using the Chronic Kidney Disease in Children (CKiD) U25 equation [4]. There was a general downward trend, reaching 0.1 percent in the 2017 to 2020 cycle.

●Kidney replacement therapy (KRT) – In the same review of 2008 data, the annual incidence of pediatric kidney failure requiring KRT (cases pmarp) also varied substantially, most likely because of variation in the availability of KRT for children in the reporting countries [1]:

•New Zealand – 18

•United States – 15.5

•Western Europe and Australia – 9.5

•Russia – <4

The number of children with incident kidney failure requiring KRT in the United States decreased slightly from 916 children in 2011 to 815 children in 2021, based on data from the United States Renal Data System (USRDS) [5]. This corresponds to an adjusted annual incidence decline from 12.4 to 11.1 cases pmarp.

Associated risk factors — The prevalence of CKD varies with:

●Ancestry and race or ethnicity – Registry data suggest higher prevalence of CKD in some subpopulations defined by racial or ethnic identities:

•In North America, the prevalence of CKD is approximately twofold higher in Black children compared with White children [5].

•In Australia and New Zealand, children with indigenous ethnicity (eg, Aboriginal Australian and Maori children) have a higher risk for acute kidney injury and certain types of CKD. In indigenous populations, the prevalence of kidney failure is similar to that in nonindigenous populations before age 14 years but increases significantly after 15 years of age [6].

In the children with West African ancestry, the genotype of apolipoprotein L1 (APOL1) might explain the increased risk for CKD. The high-risk genotype for APOL1 (homozygous for the risk alleles "G1" or "G2" or G1G2 compound heterozygosity) is associated with an increased risk for the development of glomerular disease, particularly focal segmental glomerulosclerosis (FSGS), compared with those with a low-risk genotype (having no or one risk allele) [7]. In a combined analysis of the CKiD study and Nephrotic Syndrome Study Network (NEPTUNE) of 104 Black children with glomerular disease, children with the high-risk genotype experienced a faster decline in kidney function over time compared with children with the low-risk genotype [7]. (See "Epidemiology of chronic kidney disease", section on 'Apolipoprotein L1 in African Americans'.)

●Sex – Pediatric CKD is more common in males than in females [5,8-10]. The increased prevalence in males is due to their higher incidence of congenital anomalies of the kidney and urinary tract (CAKUT), including obstructive uropathy (posterior urethral valves), kidney dysplasia, kidney hypoplasia, and prune-belly syndrome.

●Age – Patients present with CKD throughout childhood. In the North American Pediatric Renal Trials and Collaborative Studies CKD registry report database, which contains over 7000 patients with CKD, the age distribution at presentation of CKD was as follows [8]:

•<12 months – 15 percent

•12 to 23 months – 5.2 percent

•2 to <6 years – 15.7 percent

•6 to <13 years – 32.1 percent

•13 to <18 years – 28.3 percent

•18 to 21 years – 3.7 percent

ETIOLOGY

Chronic kidney disease — The distribution of causes of pediatric CKD varies by age [8,9]. Congenital causes of CKD are typically diagnosed during infancy or childhood, although a growing percentage are diagnosed by antenatal screening [11]. Acquired causes of CKD are more commonly diagnosed in later childhood and adolescence.

The main categories are:

●Congenital anomalies of the kidney and urinary tract (CAKUT) – Most CKD registries and trials find that CAKUT accounts for approximately 60 percent of cases of pediatric CKD [1,3,8], with a higher preponderance in younger patients. In the most recent United States Renal Data System (USRDS) report, CAKUT accounted for 86 percent of all pediatric CKD; this estimate was based on a limited claims-based dataset in only 17 states, which likely accounts for the discrepancy. CAKUT includes kidney aplasia/hypoplasia/dysplasia, reflux nephropathy, obstructive uropathy anomalies (eg, posterior urethral valves), and polycystic kidney disease.

●Glomerular diseases – Glomerular diseases account for 10 to 20 percent of children with CKD [8,9]. A glomerular etiology is more common in older children, accounting for approximately 45 percent of cases in patients older than 12 years of age in the United States.

In the United States, focal segmental glomerulosclerosis (FSGS) was the most common glomerular disorder, occurring in 9 percent of all pediatric CKD cases. Black children were approximately twice as likely to develop FSGS than White children, and FSGS was the cause of CKD in one-third of the Black adolescents. (See 'Epidemiology' above.)

Other glomerular causes of CKD in children include hemolytic uremic syndrome and secondary glomerular disease (eg, systemic lupus nephritis). Unlike in adults, diabetic nephropathy and hypertension are rare causes of CKD in children.

●Other – Other disorders account for 20 to 30 percent of pediatric CKD cases and include:

•Genetic disorders such as Alport syndrome (also known as hereditary nephritis), cystinosis, and oxalosis

•Interstitial nephritis

•Unidentified or unknown primary underlying etiology

Kidney failure — A larger proportion of children with glomerular diseases develop kidney failure before adulthood compared with children with nonglomerular disease, due to more rapid CKD progression [12]. In the 2023 report from the USRDS, the following distribution of causes of kidney failure in children (ages 0 to 17 years) was reported for 2017 to 2021, although the specific percentages also vary by age (figure 2) [5]. Note that glomerular disease (primary and secondary) accounted for approximately one-third of children with kidney failure. In the Chronic Kidney Disease in Children (CKiD) study, the estimated duration of time to kidney replacement therapy (KRT) after disease onset was 42.5 years (95% CI 31.0-54.1) for nonglomerular disease and 25.4 years (95% CI 14.9-36.0) for glomerular disease [13].

●Glomerular disease:

•Primary glomerular disease – 21.2 percent

•Secondary glomerular disease/vasculitis – 8.3 percent

●CAKUT – 28.3 percent

●Cystic/hereditary/congenital diseases – 12.2 percent

●Interstitial nephritis/pyelonephritis – 4.7 percent

●Transplant complications – 1.5 percent

●Diabetes – 0 percent

●Neoplasms/tumors – 0.8 percent

●Miscellaneous conditions – 12.8 percent

●Etiology uncertain – 6.2 percent

RISK STRATIFICATION — 

Key predictors of risk for CKD progression are estimated glomerular filtration rate (GFR) at the time of diagnosis and proteinuria:

●Estimated GFR – CKD is categorized by stages based on the estimated GFR. Stages for children ≥2 years are outlined in the table (table 1). For children <2 years, age-specific standards for GFR are used to categorize the degree of kidney function impairment. (See "Chronic kidney disease in children: Clinical manifestations, evaluation, and diagnosis", section on 'Staging' and "Chronic kidney disease in children: Clinical manifestations, evaluation, and diagnosis", section on 'Estimation of glomerular filtration rate'.)

●Proteinuria – In children, the presence and severity of proteinuria (as measured by urinary protein-to-creatinine ratio) predict declining kidney function [12,14-17]. Measurement of urinary proteinuria rather than albuminuria is generally preferred for children with CKD because the majority have nonglomerular conditions and a relatively higher preponderance of tubular proteinuria, which may be missed if only albuminuria is assessed [12,14-16]. In adults with CKD, both proteinuria and albuminuria are important predictors of mortality and kidney outcomes. (See 'Progression of chronic kidney disease' below and "Definition and staging of chronic kidney disease in adults", section on 'Albuminuria'.)

Methods and standards for assessing proteinuria are discussed separately. (See "Evaluation of proteinuria in children" and "Chronic kidney disease in children: Clinical manifestations, evaluation, and diagnosis", section on 'Other diagnostic laboratory tests'.)

PROGRESSION OF CHRONIC KIDNEY DISEASE — 

CKD often leads to progressive loss of kidney function independent of the initiating cause of CKD. Management of CKD includes treating modifiable risk factors to prevent or slow disease progression. Management also includes treatment of CKD complications and comorbidities, including delayed growth and development, bone disease, and cardiovascular disease. (See "Chronic kidney disease in children: Overview of management", section on 'Prevent or slow progression of kidney disease'.)

Factors in all age groups — The progression of CKD to kidney failure is largely due to secondary factors that are unrelated to the initial disease. Key factors that mediate progression include:

●Hypertension – Elevated blood pressure (BP) is an important risk factor for CKD progression [12]. Elevated BP is associated with decline in glomerular filtration rate (GFR), independent of proteinuria [14]. Longitudinal data from the Chronic Kidney Disease in Children (CKiD) study demonstrated that elevated awake or sleep mean arterial pressures on 24-hour ambulatory blood pressure monitoring were associated with faster kidney function decline, particularly in children with glomerular disease [18].

The mechanism for the effect of systemic hypertension is that elevated BP leads to intrarenal hypertension, which causes increased glomerular stress and increased activation of the renin-angiotensin system (RAAS). This leads to a subsequent vicious cycle of damaged nephrons causing worsened BP control and increased intraglomerular hypertension, which accelerates the decline of kidney function. Accordingly, interruption of this cycle with RAAS blockade is a cornerstone of CKD management [19].

●Proteinuria – In children, elevated urinary protein excretion (urinary protein-to-creatinine ratio >2 mg/mg) and hypoalbuminemia are markers for CKD progression, reflecting glomerular injury, glomerular permeability, or tubular injury [12,20]. The rate of CKD progression increases with the level of proteinuria even among patients who are normotensive [14].

●Genetic predisposition – As an example, the APOL1 high-risk genotype (which is more common among people of West African descent) increases the susceptibility to CKD and may contribute to a faster rate of CKD progression compared with individuals without this genotype [21]. (See "Gene test interpretation: APOL1 (chronic kidney disease gene)".)

Other genetic causes of CKD, such as Alport syndrome and cystinosis, are responsible for a higher proportion of CKD in children compared with adults.

●Recurrent pyelonephritis – Recurrent pyelonephritis is a risk factor for CKD, particularly in children with congenital anomalies of the kidney and urinary tract (CAKUT).

Other markers for CKD progression include anemia, metabolic acidosis, hypovitaminosis D, hyperphosphatemia, hypocalcemia, compensatory glomerular hypertrophy, hyperlipidemia, intrarenal precipitation of calcium phosphate, and altered prostanoid metabolism.

CKD progression is characterized histologically by glomerulosclerosis, interstitial fibrosis, peritubular capillary rarefaction, and inflammation [22]. Thus, even if the initial injury is treated or attenuated, the parenchymal scarring of CKD may progress. The pathophysiologic mechanisms causing CKD progression is an area of active research, and proposed mechanisms are discussed separately. (See "Secondary factors and progression of chronic kidney disease".)

Additional factors relevant to children — In children, the following factors are associated with CKD progression, in addition to those that are commonly observed in all age groups [12,17,23-28].

●Neonatal factors – The long-term effects on kidney function need to be elucidated when kidney injury occurs in the neonatal period. Prematurity and fetal growth restriction are both risk factors for CKD as injury occurs during the time period of continued nephron development, which is completed at 35 to 36 weeks gestation [29,30].

●Growth – CKD usually accelerates during the periods of rapid growth, particularly in puberty, when the sudden increase in body mass increases the filtration demands for the remaining nephrons [31]. As a result, children with CKD should be closely monitored during adolescence for accelerated progression of CKD. In addition to the increase in body mass, hormonal changes during puberty may also contribute to the rapid decline in kidney function seen in adolescence [32]. It remains to be seen if effective interventions can be identified to modify the acceleration of CKD decline during these periods of rapid growth.

●Underlying primary disease – More rapid CKD progression is observed in children with glomerular disease versus those with nonglomerular disease [12,16]. Glomerular disease is often associated with proteinuria and elevated BP, which are important risk factors for CKD progression [12].

Among children with nonglomerular causes of CKD, proteinuria and elevated BP are somewhat less common but are still important predictors of CKD progression. In one study, elevated BP predicted a decline in GFR, independent of proteinuria. However, among children with normal BP, proteinuria was an independent predictor of more rapid GFR decline (figure 3) [14]. Additional risk factors associated with significant CKD progression included dyslipidemia, male sex, and anemia [33].

●Novel biomarkers – Several urinary and plasma proteins or metabolites are under active study to identify novel biomarkers that more accurately predict CKD progression in children [20,34,35]. These biomarkers, many of which have been identified from metabolomic and proteomic screening studies, are associated with tubulointerstitial injury, fibrosis, or inflammatory pathways. Promising biomarkers may eventually serve to better understand the etiology of CKD progression, improve diagnosis, and refine prognostication and may ultimately serve as therapeutic targets.

Despite identifying the above risk factors for pediatric CKD, large knowledge gaps remain in understanding pediatric CKD progression. Several multicenter pediatric CKD trials and cohort studies have been established to improve our understanding of pediatric CKD progression and hopefully identify predictive markers for CKD progression that will be helpful in slowing the CKD progression. An adaptive clinical web-based prediction tool using the CKiD cohort and externally validated by the ESCAPE cohort was released for clinicians and may be useful for clinical discussions regarding individual progression risk [36].

Interventions — Strict BP control and measures to reduce proteinuria are standard of care for children with CKD because they are likely to slow disease progression [12,37]. (See "Chronic kidney disease in children: Overview of management", section on 'Slow progression of chronic kidney disease'.)

SOCIETY GUIDELINE LINKS — 

Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Chronic kidney disease in children".)

INFORMATION FOR PATIENTS — 

UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Chronic kidney disease (The Basics)" and "Patient education: Medicines for chronic kidney disease (The Basics)" and "Patient education: Bone problems caused by kidney disease (The Basics)")

●Beyond the Basics topic (see "Patient education: Chronic kidney disease (Beyond the Basics)")

SUMMARY

●Definition and staging – Chronic kidney disease (CKD) refers to a state of irreversible and progressive reduction of kidney function and/or markers of kidney damage that persist for at least three months. It is categorized by stages based on the estimated glomerular filtration rate (GFR); stages for children ≥2 years are outlined in the table (table 1). For children <2 years, age-specific standards for GFR can be used to categorize the degree of kidney function impairment. (See "Chronic kidney disease in children: Clinical manifestations, evaluation, and diagnosis", section on 'Staging'.)

●Incidence and prevalence – In children, the incidence of CKD is likely underreported due to the asymptomatic nature of the early stages of CKD. Moreover, in some regions, the prevalence is further underestimated due to limited available health resources for systematic diagnosis and tracking of CKD. In settings with abundant health care resources, the incidence of moderate to severe CKD is generally between 10 and 20 cases per million of age-related population (pmarp). (See 'Epidemiology' above.)

●Etiology – Congenital disease accounts for approximately two-thirds of CKD cases in children and includes obstructive uropathy, kidney hypoplasia, and kidney dysplasia. Glomerular disorders are the second largest cause of childhood CKD and are more common in children older than 12 years of age (figure 2). (See 'Etiology' above.)

●CKD progression – In children, CKD is usually characterized by a progressive deterioration of kidney function, leading to kidney failure. However, the rate of CKD progression is variable and often unpredictable. Risk factors associated with an increased risk of progression of CKD include primary glomerular disease, hypertension, and proteinuria. (See 'Progression of chronic kidney disease' above.)

Strict blood pressure (BP) control has been the only intervention that has a demonstrated beneficial effect on slowing CKD progression in children. Interventions focused on reducing proteinuria are less well proven but are also a standard component of care. (See "Chronic kidney disease in children: Overview of management", section on 'Strict blood pressure control'.)