Epidemiology of Pediatric Chronic Kidney Disease

Information on the incidence and prevalence of pediatric CKD is limited and imprecise; early CKD is often asymptomatic, so estimates of CKD in children often represent those with moderate or severe CKD or ESKD. Epidemiological information is often limited, and caution must be used when extrapolating data from small reference populations in the few well-designed studies. This study bias is important to recognize, as earlier stages of CKD are often more amenable to therapeutic interventions that can slow the rate of progression.

Small, international studies provide the most comprehensive data regarding incidence and prevalence of pediatric CKD. The ItalKid project, a prospective population-based registry that includes 20 years of Italian pediatric cases of CKD, as defined by a glomerular filtration rate (GFR) <75 mL/min/1.73 m ² , reported a yearly incidence and prevalence of CKD of 12.1 and 74.7 cases per million children and adolescents per year. Studies that have focused on severe CKD (e.g., GFR <30 mL/min/1.73 m ² ) in Sweden and Chile also report similar rates but are limited by small reference population size.

In contrast to adult CKD, where hypertension and diabetes are the most common etiologies, the majority of CKD in pediatric patients is due to congenital renal disorders, including dysplasia, hypoplasia, and aplasia as well as obstructive uropathy. In the United States the North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) registry has collected data on children with CKD since 1994 ; however, it does not provide information on incidence and prevalence rates. Of the 11,186 patients represented in the 2014 NAPRTCS data, almost half of the cases are due to congenital anomalies of the kidney and urinary tract (CAKUT), with aplasia/hypoplasia/dysplasia (15.8%), obstructive uropathy (15.3%), and reflux nephropathy (5%). Although CAKUT represents the majority of causes of CKD in younger children, glomerular diseases resulting in CKD increase in those older than 12 years of age with focal segmental glomerulosclerosis (FSGS), the third most common diagnosis (11.7%) and the most prevalent acquired renal disease. Other glomerulonephritis (e.g., immunoglobulin [Ig]A nephritis, membranoproliferative glomerulonephritis) make up less than 10% of the causes of pediatric CKD. Similar trends are reported in the Chronic Kidney Disease in Children (CKiD) study, an ongoing prospective study of children with CKD. In their initial cohort of 587 children, nonglomerular disease was the underlying cause of the majority of CKD (78%), with obstructive uropathy being the most common diagnosis. Of those children with glomerular disease as the cause of their CKD, FSGS was the most common diagnosis (7%). For reasons that remain incompletely understood but may partially be due to genetic polymorphisms, FSGS is more than three times more common in blacks (22.6%) than in whites (9.0%) and is especially prevalent among black adolescents (35%).

Due to a lack of data from low- and middle-income countries, it is difficult to estimate the causes of pediatric CKD, although more registry-based data has been published in recent years. A similar distribution for the etiology of CKD has been reported in Europe by the Italian and Belgian registries. The slightly higher proportions of hereditary nephropathy (15% to 19%) may be due to differences in cohorts racial or ethnic distribution. However, there are significant geographic and cultural differences in epidemiological trends of pediatric CKD due to genetic, environmental, and racial factors. For example, heritable causes of CKD (e.g., cystinosis, Alport syndrome, congenital nephrotic syndrome) are more common in areas of the world where consanguinity is more frequent, such as in Iran and Jordan. In Japan, a high percentage of pediatric CKD is due to glomerulonephritis, such as FSGS and IgA nephropathy. In less-developed areas of the world, glomerulonephritis continues to represent a significant percentage of kidney disease, suggesting the ongoing burden of infectious causes of CKD, including hepatitis, malaria, schistosomiasis, tuberculosis, and HIV.

Defining Chronic Kidney Disease

The effort to standardize the definitions of CKD has led to the Kidney Disease: Improving Global Outcomes (KDIGO) 2012 Clinical Practice Guideline (CPG) for Evaluation and Management of Chronic Kidney Disease, which includes kidney function based on GFR and the presence of urinary albumin and excretion rate. There are five stages of CKD, with lower stages (e.g., stage 1) representing higher GFR ( Table 6.1 ). The diagnosis of CKD in pediatric patients requires fulfilling one of the criteria:

• 1.
  

  GFR of less than 60 mL/min/1.73 m ² for greater than 3 months regardless of whether other CKD markers are present

  
  
• 2.
  

  GFR greater than 60 mL/min/1.73 m ² accompanied by markers of functional kidney abnormalities such as proteinuria, albuminuria, renal tubular disorders, or pathological abnormalities, or evidence of structural damage based on imaging or history

This classification has been widely adopted since its introduction; however, it does have significant limitations in pediatric patients. Although GFR is the primary criteria used to define and stage CKD, its use is challenging in younger children. In pediatric populations, the normal level of GFR varies depending on body size, age, and gender. Although normal GFR in adolescents and adults is approximately 120 mL/min/1.73 m ² , the norms are much lower in early childhood, even when adjusted for body surface area. GFR slowly increases to adult levels over the first year or two of life before reaching normal levels ( Table 6.2 ).

A gold standard measurement of GFR can be estimated from clearance of a filtration marker, either inulin or iohexol, in serum or blood at set time points after infusion. These studies can be challenging to perform for routine clinical use in children. Creatinine clearance can also be determined by 24-hour urine collection; however, this can often be compromised by incomplete collection and tends to overestimate GFR in advancing CKD due to enhanced renal tubular creatinine secretion. There has been growing evidence that cystatin C may be a more accurate marker of kidney function because it has less intrapatient variability and, in patients over 2 years old, levels are inversely associated with kidney function independent of body composition, age, gender, and height.

Given these limitations, GFR is often estimated by equations based on endogenous markers. The Schwartz formula, used since the 1980s, is based on serum creatinine as determined by the Jaffe technique. The Schwartz formula is the most widely used formula in pediatric practice, with GFR calculated as:

Of note, the constant is 0.45 for infants <1 year and 0.7 for adolescent boys. Despite its simplicity, with the introduction of enzymatic creatinine measurement the equation has become imprecise. Investigators have developed more accurate GFR-estimating equations using enzymatically determined creatinine, which can be used for children with CKD and which have been validated for children with an estimated GFR between 15 and 75 mL/min/1.73 m ² .

Natural History and Progression of Chronic Kidney Disease

The progression of CKD to ESKD results in many of the health consequences of this disease; however, the natural history and the rate of progression are both highly variable and unpredictable. Pediatric data suggest that there is a slower progression of disease in those with congenital renal disorders compared with those with glomerular etiologies of their CKD. Studies have demonstrated that the progression of CKD can be influenced by multiple factors, many of which are not modifiable (e.g., underlying renal pathology, genetics, race, age, and gender). However, some risk factors can be modified, such as obesity, hypertension, and proteinuria. There is evidence in both adult and pediatric studies that hypertension and proteinuria are the most significant risk factors for CKD progression; minimizing proteinuria and maximizing blood pressure control can slow progression of CKD.

It is postulated that proteinuria contributes to CKD progression due to tubular damage resulting in interstitial inflammation, fibrosis, and subsequent apoptosis of proximal tubular cells. In adult studies, both microalbuminuria and overt proteinuria are independent risk factors for CKD progression. Results from several pediatric cohort studies demonstrate similar trends, with an analysis of 202 patients in the CKiD cohort finding that those with proteinuria had mean eGFR that was 16 mL/min/1.73 m ² lower than those without proteinuria. In children with CKD stage 3 and 4 in the European Study Group for Nutritional Treatment of Chronic Renal Failure in Childhood, both proteinuria and hypertension were major independent risk factors for progression of CKD. Finally, a secondary analysis from the Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness (ESCAPE) trial found that residual urinary protein excretion during ACE inhibition therapy was associated with CKD progression.

Although proteinuria is a well-established biomarker in the progression of CKD, it does appear to have some limitations and some investigators suggest that urinary tubular proteins, such as β 2-microglobulin, may better predict the clinical course and progression of CKD. Other biomarkers, previously used in acute kidney injury, such as neutrophil gelatinase-associated lipocalin (NGAL), also show promise in pediatric CKD. Children with kidney disease resulting in a high load of tubular protein excretion are not commonly associated with renal insufficiency or rapid progression of CKD.

There is clear and consistent evidence from large trials that hypertension is a modifiable risk factor for CKD progression. Although data was primarily from adult populations, within the last 10 years several large studies have provided consistent evidence that, among children with CKD, uncontrolled hypertension is associated with significantly faster declines in GFR. Results from the ESCAPE trial show that intensified blood pressure control, defined as 24-hour mean arterial pressure below the 50th percentile for age, in children aged 3 to 18 with CKD (GFR between 15 and 80 mL/min/1.73 m ² ) was beneficial. Primary analysis showed that fewer patients in the intensified blood pressure control group reached the primary end point of 50% decline in GFR or progression to ESKD (29.9% vs. 41.7%).

Other factors contribute to the progression of pediatric CKD. Obesity and metabolic syndrome are associated with dyslipidemia, hypertension, and albuminuria, all of which may influence the progression of kidney disease. Although the mechanisms by which obesity potentiates and exacerbates CKD are largely speculative, studies suggest that a combination of lipotoxicity, a proinflammatory state, glomerular hyperfiltration, and resultant hemodynamic disturbances may all play a role. Race and genetics are two nonmodifiable risk factors for CKD progression. There is strong concordance of kidney disease in African American families, and African Americans have a faster rate of progression compared with all other populations after controlling for other factors. In the CKiD cohort, among 419 children with CKD, Caucasian children had significantly less proteinuria than other ethnicities at any GFR, regardless of underlying renal disease. The clustering of CKD in families suggests genetic and/or familial predisposition in some cases. In addition, several studies demonstrate links between CKD and various polymorphisms in genes encoding mediators of CKD (such as the renin-angiotensin system [RAS]) and an increased susceptibility to progression in disease such as IgA nephropathy.

Low birth weight (LBW) is another nonmodifiable factor associated with a reduction in the number of nephrons and a subsequent predisposition to CKD and hypertension in later life. In a cross-sectional analysis of the fourth National Health and Nutritional Examination cohort, adolescents (aged 12 to 15) who were born at LBW (<2500 g) were more likely to have a decreased GFR (OR = 1.49, P = 0.02) than those in the normal weight cohort. Using a cross-sectional national survey linked to birth records in Japan, investigators found that the risk ratio for CKD was significantly higher in the LBW group and those born prematurely. Finally, regardless of the degree of CKD, puberty appears to be associated with a steep decline in kidney function. This progression pattern may be due to an adolescent-specific pathophysiological mechanism: either the result of an imbalance between rapidly growing body size and residual nephron mass or related to sex hormones. Data pertaining to a variety of risk factors potentially associated with the progression of CKD, including those discussed in this section, are currently being collected by the CKiD study.

Prevention of Progression

Although many of the risk factors that potentiate progression of pediatric CKD are nonmodifiable, several antiproteinuric and antihypertensive therapies have demonstrated promising results in slowing the progression of CKD. Three large adult studies—the Appropriate Blood Pressure Control in Diabetes (ABCD) study, the African American Study of Kidney Disease and Hypertension (AASK), and the Modification of Diet in Renal Disease (MDRD) study—found that blood pressure control also decreases proteinuria. Although large pediatric studies are limited, results from the ESCAPE trial and CKiD cohort suggest that antiproteinuric treatment is protective in pediatric CKD patients. The goal of antiproteinuric treatment is to reduce proteinuria to <300 mg/m ² /day, a value that appears to be associated with the maximal renoprotective effect in adult studies.

Treatment with either angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II type I receptor blockers (ARBs) has been shown to be more effective for both blood pressure control and reduction in proteinuria compared with other agents currently available. By decreasing either angiotensin II tone (ACEI) or action (ARB), these agents reduce pressure within the glomerulus and decrease proteinuria, downregulate activation of inflammatory pathways, and attenuate local release of cytokines and chemokines. These changes appear to attenuate glomerular hypertrophy and sclerosis, tubulointerstitial inflammation, and fibrosis.

Well-matched studies assessing the efficacy of RAS antagonists for renoprotection in children with CKD are limited. Small uncontrolled studies in children with CKD provide evidence of stable kidney function and proteinuria in those treated with losartan for 2.5 years. A recent randomized controlled trial of ARB therapy in pediatric CKD patients found that ARB therapy significantly reduced proteinuria (35.8%) compared with the amlodipine/placebo (1.4%) group independent of blood pressure control. Similarly, in the CKiD cohort, Wong et al. observed an antiproteinuric effect of renin-angiotensin-aldosterone system blockade in those with glomerular diseases as a cause of their CKD. In the ESCAPE study, treatment with ACE inhibition lead to a 50% reduction in proteinuria in hypertensive children and a 2.2 mmHg decrease in mean arterial blood pressure (BP) in children with CKD, with similar efficacy in patients with hypo/dysplastic kidneys and glomerular disease.

Intensive blood pressure control, in addition to proteinuria, is also associated with significant risk reduction. The recently concluded ESCAPE trial found that fewer patients in the intensified-control group (blood pressure target below the 50th age-related percentile of 24-hour mean arterial pressure) than in the conventional-control group (target of 50th to 95th percentile) reached the composite primary end point of doubling serum creatinine, GFR deterioration to less than 10 mL/min/1.73 m ² , or need for renal replacement therapy (29.9% vs. 41.7%; hazard ratio, 0.65; 95% confidence interval [CI], 0.44 to 0.94; P = 0.02). This corresponds to a risk reduction of 35% and suggests that controlling blood pressure to reach a target of less than the 50th percentile may improve outcomes.

Finally, existing studies do not support the use of a low-protein diet to protect from CKD progression. One of the largest trials in adults, the MDRD trial, did not show an effect of a low-protein diet on CKD progression in patients with nondiabetic kidney disease. In children, data do not show a clear benefit, either. In a 2-year prospective, randomized multicenter study of 191 children with CKD, the use of a low-protein diet (0.8 to 1.1 g/kg) failed to affect the decline in creatinine clearance. Furthermore, a low-protein diet with intake below the Dietary Reference Intake (DRI) may have an adverse effect on growth. The current consensus is to provide children with CKD the age-appropriate recommended daily allowance for protein.

Growth Failure

Growth impairment is one of the most visible complications for children with CKD and is associated with significant morbidity and mortality. Pediatric CKD patients often fail to reach an adult height equivalent to either their genetic potential or population norms. Growth impairment is common in children with CKD, with data from NAPRTCS showing more than 35% of children had impaired growth with height less than third percentile (standard deviation score [SDS] of −1.88). On average, patients with CKD are 1.44 SD below sex- and age-specific norms for height, with the youngest patients (those under 1 year) having the most severe growth failure with a mean SDS of −2.34. Because one-third of postnatal stature is obtained in the first 2 years of life, this may have a profound effect on adult height. There is an increased risk for poor growth with decreasing renal function; however, growth failure is seen at all stages of CKD. Approximately one-fifth of patients in the 2008 NAPRTCS registry with an estimated CrCl <60 mL/min/1.73 m ² had an SDS of −1.85. The CKiD study estimates that for each decline of 10 mL/min/1.73 m ² in GFR, there is a corresponding decrease in height SDS by 0.12 to 0.16. Additionally, as puberty is both delayed and shortened in CKD, the height growth during puberty in children with CKD is only half that in children with normal kidney function.

Poor growth is also associated with an increased risk of both morbidity and mortality, with each SDS decrease in height associated with a 14% increased risk of death. Analysis of data from the United States Renal Data System (USRDS) found that children with ESKD on dialysis with growth failure had a threefold increased risk of death. Results from the NAPRTCS cohort also demonstrate that children with growth failure (height SDS <−2.5 at time of dialysis initiation) had a significantly higher risk of hospitalization and twice the risk of death compared with children with normal growth. In addition, severe growth impairment is associated with more complex clinical courses and with more hospitalizations, both of which affect health-related quality of life for these children and families. Short stature is associated with poor physical functioning and may affect the psychological development of patients. Short children are often treated as younger than their chronological age and may have lower expectations set for them compared with their average height peers.

Growth failure in children with CKD is multifactorial, but disturbances in growth hormone (GH) and insulin-like growth factor-1 (IGF-1) appear to be the primary contributing factors. Other risk factors for poor growth in children with CKD include secondary hyperparathyroidism, metabolic acidosis, inadequate nutrition, anemia, and disturbances of water and electrolyte balance. In normal growth, GH is released by the anterior pituitary in a pulsatile manner under the stimulation of growth hormone–releasing hormone (GHRH) and is then bound by GH receptors in the liver, resulting in the production of insulin growth factor (IGF)-1. A majority of IGF-1 is bound to insulin growth factor–binding protein 3 (IGFBP-3), and the remaining free (unbound) IGF-1 stimulates growth by acting on cartilaginous receptors in bone. In CKD, levels of GH are increased due to a decrease in metabolic clearance and IGF-1 feedback is attenuated, leading to amplified pulsatile release of GH. However, despite these increases in GH concentrations, there is a downregulation of IGF-1 synthesis in the liver as well as decreased bioavailability. In some patients with CKD, GH secretion is decreased as metabolic acidosis inhibits GH action on peripheral tissue and steroid therapy reduces GH pulsatility.

In pediatric CKD patients with persistent growth impairment, recombinant human GH (rhGH) is the standard therapy to correct and prevent the growth failure associated with CKD and ESKD. Recommendations of the 2008 KDOQI Clinical Practice Guideline suggest considering rhGH therapy for pediatric CKD stages 2 through 5 with short stature (defined as height SDS less than −1.88 ) and linear growth potential after metabolic abnormalities have been corrected and nutritional issues addressed. The treatment dose of rhGH is 0.05 mg/kg daily given via subcutaneous injection. Of note, the amount of rhGH given to pediatric CKD patients is higher than those with GH deficiency because CKD causes GH insensitivity and pharmacologic rather than replacement dosing is required in this population. rhGH is beneficial for children with CKD throughout the continuum of disease from mild CKD to ESKD to post–renal transplantation. Studies have demonstrated that improved clinical response to GH treatment is seen in patients with initiation in younger children (prepubertal), the degree of bone age delay, extent of height SDS gain within first year of treatment, and renal dysplasia as the primary renal disease. Cumulative height gain is predicted based on the height deficit at therapy initiation and the duration of treatment, suggesting that rhGH may help “unlock” growth potential. The largest response to rhGH treatment is seen within the first year of therapy, with less effect after 1 year; however, sustained use may allow achievement of a final adult height within the normal range.

Before the initiation of rhGH therapy, evaluation should include assessment of concomitant metabolic bone disease, including a serum parathyroid hormone (PTH) level as well as baseline hip x-rays due to the theoretical increased risk of femoral head avascular necrosis and slipped capital femoral epiphysis (SCFE). Evidence is mixed on obtaining bone age with x-ray imaging; however, many providers do obtain a bone age in older children and adolescents before initiation of rhGH. Despite initial concern that it may contribute to advancing CKD via induction of glomerular hyperfiltration, there is no evidence that rhGH accelerates progression of CKD. Ongoing monitoring is required to adjust treatment dose for changes in weight, to detect adverse effects, and to evaluate the response to rhGH, with an adequate response defined as a growth velocity greater than 2 cm/year. Adverse effects are rare in children undergoing rhGH treatment, but there may be a slightly higher risk of developing idiopathic intracranial hypertension, SCFE, or worsening of existing scoliosis. Treatment with rhGH should be stopped when epiphyses are closed, the patient has achieved target height, and/or when adverse events occur. Studies suggest that discontinuation of therapy at the time of kidney transplant did not adversely affect growth velocity. A simple approach to the use of rhGH is provided in Fig. 6.1 .

Management of GH therapy.

There is good evidence that the adult height of pediatric patients with CKD has improved significantly over the last several decades and, though multifactorial, rhGH had a primary role in this change. Long-term follow-up of a cohort of German children showed that patients with CKD who received rhGH grew significantly better than patients who did not, without differences in the duration of the pubertal growth spurt. Despite these findings, however, a significant percentage of pediatric CKD patients do not receive treatment. In the 2008 NAPRTCS report, only 11.1% of pediatric patients with CKD received rhGH at baseline and only 22.1% by the end of their first year. Although multiple factors appear to contribute, psychosocial concerns (including family refusal and/or noncompliance) were the ascribed cause in 30% of patients not receiving rhGH therapy, and waiting for insurance company approval delayed initiation of treatment in 18% of children. Additionally, there is substantial variation in nephrologist utilization of rhGH. These findings suggest an opportunity for improvement in our care of children with CKD.

Nutritional Issues and Metabolic Concerns

In children with CKD, protein energy malnutrition (PEM) is a common and important complication. PEM has a significant effect on linear growth and neurocognitive development and is particularly important in infants and young children, where deficits in linear growth and neurocognitive development may not be fully correctable. Although PEM is a well-known complication of CKD, the published prevalence rates range from 6% to 65%. The wide range is due to use of varying diagnostic criteria for PEM among studies. Given the obesity epidemic, it is important to balance concerns for PEM with avoidance of excessive nutrition, given its role in potentiating GFR decline in patients with CKD. Recent data from the CKiD cohort found that children with CKD consumed more sodium, protein, and calories than recommended by guidelines and that this intake was heavily driven by consumption of milk and fast food. In childhood CKD, the focus of nutritional care should be on maintenance of optimal nutritional status, avoidance of metabolic abnormalities, and reduction in the risk of associated morbidity and mortality in adulthood. A collaborative effort involving all members of the multidisciplinary care team is essential in nutritional management.

Malnutrition in children with CKD is often multifactorial; however, inadequate intake is often a major contributing factor ( Box 6.1 ). In infants, vomiting and delayed gastric emptying are common and may be worsened by gastroesophageal reflux. When these issues limit nutritional intake, medical management (e.g., antireflux measures with proton pump inhibition or H2-blockers) or surgical intervention (e.g., gastrostomy tube placement) may be required. Adolescents and older children may be at increased risk of malnutrition due to poor dietary habits, as well as alterations in smell and taste, which can have an effect on food intake.

BOX 6.1

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