Chronic kidney disease in children: Definition, epidemiology, etiology, and course

INTRODUCTION — Chronic kidney disease (CKD) refers to a state of irreversible kidney damage and/or reduction of kidney function that is associated with a progressive loss of kidney function over time.

The etiology, epidemiology, and progression of CKD in children will be reviewed here. The clinical presentation, evaluation, management, and complications of CKD in children are discussed separately. (See "Chronic kidney disease in children: Clinical manifestations and evaluation" and "Chronic kidney disease in children: Overview of management" and "Chronic kidney disease in children: Complications".)

DEFINITIONS AND DIAGNOSIS — Chronic kidney disease (CKD) is defined as the presence of structural or functional kidney damage that persists over a minimum of three months. Functional damage is typically characterized by a sustained reduction of estimated glomerular filtration rate (eGFR), a persistent elevation of urinary protein excretion, or both.

This broad definition was used by the 2012 Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guidelines to define the diagnostic criteria and classification of pediatric CKD [1]. The KDIGO diagnosis criteria and classification are the standard used in clinical practice, research, and public health in the care of children with CKD and will be used throughout this topic.

The diagnosis of pediatric CKD is based on fulfilling one of the following criteria [1]:

●GFR of less than 60 mL/min per 1.73 m² for greater than three months with implications for health regardless of whether other CKD markers are present.

●GFR greater than 60 mL/min per 1.73 m² that is accompanied by evidence of structural damage or other markers of kidney function abnormalities, including proteinuria, albuminuria, renal tubular disorders, or pathologic abnormalities detected by histology or inferred by imaging. This category also includes patients with functioning kidney transplants.

STAGING: RISK STRATIFICATION — CKD staging guides management by stratifying the risk for progression and complications of CKD. Risk stratification guides the recommended intensity of monitoring and management for CKD progression and comorbid conditions associated with CKD. In adults, staging is based on the cause of the disease, glomerular filtration rate (GFR), and degree of albuminuria (see "Definition and staging of chronic kidney disease in adults"). However, staging for clinical care of children with CKD is primarily based on estimated (eGFR). Ongoing research is focused on developing comparable information to adult data to incorporate the degree of proteinuria and etiology to improve risk stratification for pediatric CKD. (See 'Evaluation of proteinuria' below.)

Glomerular filtration rate — GFR represents the sum of the filtration rates of all of the functioning nephrons. A reduction in GFR implies a decrease in the number of functioning nephrons due to underlying disease/injury or initial reduction due to congenital disorder [2]. For patients two years of age and older, the severity of CKD is categorized by the KDIGO clinical practice guidelines into stages based on estimated GFR (table 1) (see 'Estimated glomerular filtration rate' below) [1]:

●G1 – Normal GFR (≥90 mL/min per 1.73 m²)

●G2 – GFR between 60 and 89 mL/min per 1.73 m²

●G3a – GFR between 45 and 59 mL/min per 1.73 m²

●G3b – GFR between 30 and 44 mL/min per 1.73 m²

●G4 – GFR between 15 and 29 mL/min per 1.73 m²

●G5 – GFR <15 mL/min per 1.73 m² (kidney failure)

End-stage kidney disease defines a state of permanent loss of kidney function, generally requiring long-term dialysis or kidney transplant to sustain life and is categorized as stage G5 with a GFR below 15 mL/min per 1.73 m². (See "Overview of kidney replacement therapy for children with chronic kidney disease".)

Children less than two years of age — Normal levels of GFR vary with age, sex, and body size. GFR increases with maturation from infancy and approaches the adult mean value by two years of age (table 2) [3,4]. As a result, the above classification is not applicable to children less than two years of age, because their GFR is normally lower than the values of GFR of older individuals and would incorrectly place them in a stage of disease characterized by greater kidney impairment than their actual kidney function [5]. As an example, a six-month-old infant with normal kidney function would be incorrectly classified as having GFR category G2 disease because the mean GFR for this age is normally below 89 mL/min per 1.73 m².

Although the above schema cannot be used, an estimated GFR based on serum creatinine can be compared with normative age-appropriate values to detect kidney impairment in toddlers and infants with CKD (table 3). Values more than 1 standard deviation (SD) below the mean should raise concern and prompt continued monitoring of kidney function [5]:

●Moderate reduction is defined as an age-specific GFR value between 1 to 2 SD below the mean

●Severe reduction is defined as an age-specific GFR value >2 SD below the mean

Estimated glomerular filtration rate — Clinically, an estimated GFR is used as a measure of kidney function. The GFR is typically calculated from an individual's serum creatinine level and height and is a more accurate assessment of function than using serum creatinine alone. Using formulas to determine GFR is also easier in a clinical setting compared with assessing GFR by clearance of a urinary marker.

Calculated glomerular filtration rate — Serum creatinine-based formulas are generally used to estimate GFR in children with CKD and are typically calculated using the child's height, serum creatinine, and a constant "k" that is based on the creatinine assay used by the clinical laboratory performing the test (calculator 1):

The constant "k" used in the pediatric equation is dependent on the laboratory assay that measures serum creatinine:

●If the Jaffe method for creatinine is used, the value of "k" is directly proportional to the muscle component of body and varies with age and, in adolescents, with the sex of the patient [6-8]:

•Preterm infants up to one year of age – The value for "k" is 0.33

•Term infants up to one year of age – The value for "k" is 0.45

•Children of both sexes and adolescent females – The value for "k" is 0.55

•Adolescent males – The value for "k" is 0.77

●If the enzymatic method for creatinine is used, the value of "k" is equal to 0.413 for serum creatinine units in mg/dL and 36.52 for serum creatinine units in mcmol/L. [9]. This formula has only been validated for a range of GFR between 15 and 75 mL/min per 1.73 m² in children <18 years of age.

●The measurement of serum cystatin C is clinically available and standardized against International Federation of Clinical Chemistry (IFCC)-approved reference material. Newer and more precise GFR-estimating equations based on enzymatic creatinine and IFCC-standardized cystatin C have been published by the Chronic Kidney Disease in Children Study (CKiD study) [10]. These newer equations developed by CKiD include age- and sex-dependent values for "k" for children and young adults with CKD up to age 25 years old.

The use of the creatinine-based GFR estimating formulas is limited in patients with an unusual dietary intake (eg, vegetarian diet or creatinine supplements) or in those with decreased muscle mass (eg, amputation, malnutrition, or muscle wasting) [11]. In these circumstances, determining the GFR using a serum creatinine measurement in conjunction with a timed urine collection, as discussed below, or the use of serum cystatin C may be more appropriate [12].

Other methods — The following methods used to measure GFR are based on determining the clearance of a filtration marker and are not practical for routine clinical use. (See "Assessment of kidney function".)

●Inulin, a physiologically inert substance that is freely filtered at the glomerulus, has been the gold standard of marker. However, it requires continuous intravenous infusion, multiple blood samples, and, at times, bladder catheterization.

●Creatinine clearance is determined by serum creatinine and a timed urine collection for creatinine clearance; however, the collection is often inconvenient for families and inaccurate due to missed samples, episodes of incontinence, or voiding problems.

●Other methods include single-injection techniques for plasma disappearance of iohexol, inulin, and other exogenous filtration markers.

Evaluation of proteinuria — The KDIGO guidelines use the level of albuminuria to predict mortality and kidney outcomes in adults with CKD (see "Definition and staging of chronic kidney disease in adults", section on 'Albuminuria'). Although similar direct data in children are lacking, there is good evidence that the presence and severity of proteinuria (as measured by urinary protein-to-creatinine ratio) are predictive of declining kidney function in children [13-16]. In children >2 years old, a normal value for urinary protein-to-creatinine ratio is no more than 0.2 mg/mg [17]. In term infants, reported urinary protein-to-creatinine values are higher with values up to 1.4 mg/mg but more data are needed to confirm the normal values for infants [18]. Urinary albumin excretion is similar to urine protein-to-creatinine ratio in its capacity to predict CKD progression in children [15].

Urinary protein excretion (as measured by urinary protein-to-creatinine ratio) is used more frequently than albuminuria in pediatric CKD because the majority of children with CKD have nonglomerular congenital kidney conditions where albuminuria testing does not identify high levels of urine total protein loss due to tubular proteinuria and diabetic nephropathy, a major etiology for CKD in adults characterized by albuminuria, is uncommon in children. Based on published pediatric data, there is increasing evidence that the presence and severity of proteinuria (rather than albuminuria) are predictive of declining kidney function in children [13-16,19]. However, one study from the CKiD study reported urinary albumin excretion was similar to urine protein-to-creatinine ratio in its capacity to predict CKD progression in children [15]. (See 'Progression of chronic kidney disease' below.)

EPIDEMIOLOGY

Reported global incidence — 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 and lead to underdiagnosis. Additionally, there may be under-reporting due to inadequate health services in resource-limited areas. As a result, it is difficult to compare rates of childhood CKD throughout the world due to the variability of available health resources, both for the care of children with CKD as well as for tracking and collecting accurate population-based data and the use of different definitions [20,21]. Furthermore, published information is often based on reports from major referral centers, and it is uncertain whether these data truly reflect population-based risks.

These limitations were noted in a review article that provided the following population-based estimates of moderate to severe CKD or end-stage kidney disease (ESKD) in children defined as requiring kidney replacement therapy (KRT) [20]:

●Moderate to severe CKD – Estimated median annual incidence of per million of age-related population (pmarp) varied as follows:

•Europe – 11.9 cases pmarp.

•Latin America – Rates ranged from 2.8 to 15.8 cases pmarp.

•Sub-Saharan Africa, which has the most limited health resources, the lowest published rate of CKD was noted from single-center studies and ranged from 1 to 3 cases pmarp.

●KRT – The annual incidence of ESKD requiring KRT varied and is most likely directly related to the availability of KRT for children in the reporting countries:

•New Zealand – 18 cases pmarp

•United States – 15.5 cases pmarp

•Western Europe and Australia – 9.5 pmarp

•Russia – <4 cases pmarp

Race and genetics — Registry data from the North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) and the Australia and New Zealand Dialysis and Transplant Registry reported an increased risk for CKD in ethnic minority populations.

●In North America, the rate of CKD is two to three times higher in Black compared with White children [22].

●In Australia and New Zealand, children with indigenous ethnicity (eg, Aborigines and Maoris) have a higher risk for acute kidney injury and certain types of CKD. The rates of ESKD in the indigenous populations compared with the nonindigenous populations are similar under age 14 years but increase significantly after 15 years of age [23].

In the Black population, 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 0 or 1 risk alleles) [24]. In a combined analysis of the Chronic Kidney Disease in Children (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 [24].

Sex — The incidence and prevalence of pediatric CKD are greater in males than females [22,25,26]. The increased risk of CKD in males is due to their higher incidence of congenital anomalies of the kidney and urinary tract (CAKUT), including obstructive uropathy, kidney dysplasia, kidney hypoplasia, and prune-belly syndrome.

Age — Patients present with CKD throughout childhood. In the NAPRTCS chronic renal insufficiency (CRI) database, which contains over 7000 patients with CKD, the age distribution at presentation of CKD was as follows [22]:

●Below 12 months of age – 15 percent

●12 to 23 months – 5.2 percent

●2 years of age to below 6 years of age – 15.7 percent

●6 years of age to below 13 years of age – 32.1 percent

●13 years of age to below 18 years of age – 28.3 percent

●18 to 21 years of age – 3.7 percent

ETIOLOGY

Chronic kidney disease — The distribution of causes of pediatric CKD varies by age [22,25]. Congenital causes of kidney disease present and are typically diagnosed during infancy or childhood, although a growing percentage are diagnosed by antenatal detection [27]. The diagnosis of CKD due to acquired kidney disease tends to be more common in later childhood and adolescence.

●Congenital anomalies of the kidney and urology tract (CAKUT) account for 60 percent of pediatric CKD cases and are more prevalent in younger patients. These disorders include kidney aplasia/hypoplasia/dysplasia, reflux nephropathy, obstructive uropathy anomalies (eg, posterior urethral valves) and polycystic kidney disease.

●Glomerular causes account for 10 to 20 percent of children with CKD [22,25]. A glomerular etiology is more common in older children, accounting for approximately 45 percent of cases in patients greater 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 three times more likely to develop FSGS than White patients, and FSGS was the cause of CKD in one-third of Black adolescent patients. (See 'Race and genetics' 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 disorders account for 20 to 30 percent of pediatric CKD cases and include:

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

•Interstitial nephritis

•Unidentified or unknown primary underlying etiology

End-stage kidney disease — Although glomerular disease represents a smaller percentage of the etiology of overall CKD, these disorders account for a larger proportion of the underlying cause for pediatric end-stage kidney disease (ESKD) patients. This is due to the rapid rate of CKD progression in patients with these disorders compared with patients with nonglomerular causes of CKD [13].

In the 2023 report from the United States Renal Data System (USRDS), the following distribution of causes of ESKD in children (ages 0 to 17 years) was reported for 2017 to 2021 [28]. Note that primary and secondary glomerular diseases accounted for approximately one-third of children with ESKD.

●Primary glomerular disease – 21.2 percent

●Congenital anomalies of the kidney and urinary tract (CAKUT) – 28.3 percent

●Cystic/hereditary/congenital diseases – 12.2 percent

●Secondary glomerular disease/vasculitis – 8.3 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

PROGRESSION OF CHRONIC KIDNEY DISEASE

Overview — Acquired or congenital reduction in nephron number results in CKD. The progression of CKD is characterized by the progressive loss of kidney function independent of the initiating cause of CKD. It is important to understand the factors associated with progression of CKD to identify management strategies to prevent or slow the decline of kidney function to end-stage kidney disease (ESKD). Furthermore, it is essential to treat comorbid complications and to recognize the effect of CKD on growth and development and other chronic conditions such as cardiovascular disease. (See "Chronic kidney disease in children: Overview of management", section on 'Prevent or slow progression of kidney disease'.)

Proposed mechanisms — The progression of CKD to ESKD is largely due to secondary factors that are unrelated to the initial disease. These include systemic and intraglomerular hypertension, glomerular hypertrophy, the intrarenal precipitation of calcium phosphate, hyperlipidemia, and altered prostanoid metabolism. CKD progression is characterized histopathologically by focal segmental glomerulosclerosis (FSGS), which is called secondary FSGS, interstitial fibrosis, peritubular capillary rarefaction, and inflammation [29]. Thus, despite the initial injury being ameliorated or treated, the parenchymal scarring of CKD is progressive. 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".)

Pediatric factors — In children, multiple factors, in addition to those that are commonly observed in adults with CKD (systemic hypertension, proteinuria, anemia, hyperphosphatemia, hypocalcemia, and hypovitaminosis-D), are associated with CKD progression [13,30-34].

●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 weeks gestation [35,36].

●Growth – The rate of CKD progression is usually greatest during the periods of rapid growth, particularly in puberty, when the sudden increase in body mass results in a rise in the filtration demands of the remaining nephrons [37]. As a result, children with CKD should be closely monitored during adolescence for an 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. 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 [13,16]. Data from the Chronic Kidney Disease in Children (CKiD) cohort identified elevated urinary protein excretion (urinary protein-to-creatinine ratio >2 mg/mg), hypoalbuminemia, and elevated blood pressure (BP), which are more commonly seen in children with glomerular disease, as risk factors for CKD progression [13]. Of note, the rate of CKD progression increased with the level of proteinuria in patients who were normotensive; however, a decline in GFR was noted irrespective of the level of proteinuria among children with an elevated systolic BP.

For children with nonglomerular etiology, additional risk factors associated with significant CKD progression included dyslipidemia, male sex, anemia, proteinuria, and systolic BP level (figure 1) [14].

●Genetic factors – As noted above, genetic and ethnic predisposition may influence the rate of kidney function decline. As an example, the APOL1 high-risk genotype among Black patients increases the susceptibility to CKD and may contribute to a faster rate of CKD progression compared with groups of other ancestry. (See "Secondary factors and progression of chronic kidney disease", section on 'Genetic factors'.)

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.

Interventions — Interventions to slow CKD progression that are generally accepted standard of care include BP control and measures to reduce proteinuria [13]. (See "Chronic kidney disease in children: Overview of management", section on 'Slow progression of chronic kidney disease'.)

Blood pressure control — Although some of the risk factors noted above might be amenable to intervention, BP control in children has been the only risk factor that has been assessed in the setting of a randomized controlled trial.

The effect of high BP on progression of CKD is illustrated by the following:

●In the Effect of Strict Blood Pressure Control and ACE Inhibition on CRF Progression in Pediatric Patients (ESCAPE) trial of 468 pediatric patients with CKD stages 2 to 4 conducted from 1998 to 2001 across the European Union, CKD progression was slower in children who received intensified BP treatment to maintain a 24-hour mean arterial pressure below the 50^th age-related percentile compared with those in whom treatment was targeted to maintain BP levels between the 50^th and 90^th percentile [38]. All patients in this trial received the same fixed dose of an ACE inhibitor, with the addition of other BP medications as needed to achieve target BP levels.

●Longitudinal data from the CKiD study of 679 children with moderate CKD revealed that patients with 24-hour ambulatory blood pressures in the highest MAP category (>90^th percentile) experienced the fastest CKD progression as compared with individuals with blood pressures in the lowest MAP category (<50^th percentile) [39]. The effect of higher BP on the composite outcome of renal replacement therapy or 50 percent decline in renal function appeared to be greater for children with glomerular disease (hazard ratio [HR] 3.23 95% CI, 1.34-7.79) than for those with non-glomerular disease (HR 1.88, 95% CI, 1.03-3.44) [39].

SUMMARY

●Definition – Chronic kidney disease (CKD) refers to a state of irreversible kidney damage and/or reduction of kidney function that generally continues to progress over time. It is defined as the presence of structural or functional kidney damage that persists over a minimum of three months. (See 'Definitions and diagnosis' above.)

●Diagnostic criteria – In our practice, the diagnostic criteria that are used is based on the Kidney Disease: Improving Global Outcomes (KDIGO) 2012 clinical practice guidelines that require fulfilling one of the following clinical criteria (see 'Definitions and diagnosis' above):

•Glomerular filtration rate (GFR) of less than 60 mL/min per 1.73 m² for greater than three months with implications for health regardless of whether other CKD markers are present.

•GFR greater than 60 mL/min per 1.73 m² that is accompanied by evidence of structural damage or other markers of functional kidney abnormalities including proteinuria, albuminuria, renal tubular disorders, or pathologic abnormalities detected by histology or inferred by imaging.

●CKD stages – CKD staging guides management by stratifying the risk for progression and complications of CKD.

•Staging for children between 2 and 18 years of age – In our practice, we stage patients by their level of GFR for children between 2 and 18 years of age (calculator 1) (table 1). Clinically, the assessment of proteinuria is an important consideration in the management of a child with CKD. However, further work is needed to validate the inclusion of proteinuria for staging in a non-study cohort of pediatric patients with CKD. (See 'Staging: Risk stratification' above and 'Estimated glomerular filtration rate' above and 'Evaluation of proteinuria' above.)

•Staging for children <2 years of age – Children under two years of age do not fit within the KDIGO classification system, because they normally have a lower GFR even when corrected for body surface area. In these patients, an estimated GFR (eGFR) based on serum creatinine can be compared with normative age-appropriate values. A value >1 standard deviation (SD) below the mean should raise concern and prompt more intensive monitoring. (See 'Children less than two years of age' above.)

●Incidence – In children, the incidence of CKD is underreported due to the asymptomatic nature of the early stages of CKD. In some countries, the data may also be compromised by limited health resources that can systematically diagnose children with CKD. As a result, the reported incidence of CKD is widely variable. (See 'Epidemiology' above.)

●Etiology – CKD in children is the result of a heterogeneous group of disorders. Congenital disease accounts for 60 percent of CKD cases 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 greater 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 end-stage kidney disease (ESKD). 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, proteinuria, and hypertension. (See 'Progression of chronic kidney disease' above.)

Blood pressure (BP) control has been the only intervention that has been shown to have a beneficial effect on slowing CKD progression in children. (See 'Blood pressure control' above.)