Abbreviation: GFR, glomerular filtration rate.

In newborns, normal GFR is less than 60 mL/min/1.73 m², and body surface area-adjusted GFR values do not reach adult levels until 2 years of age. Thus, GFR threshold values used to stage CKD are not applicable to children younger than 2 years. Many references exist for normal GFR in preterm and term neonates; among the most comprehensive tables is included in a 2007 review article (see Selected References). Glomerular filtration rate values between 1 and 2 standard deviations below the mean should be considered moderately reduced, and GFR values at least 2 standard deviations below the mean should be considered severely reduced.

Studies of adult patients with CKD have found that morbidity and mortality associates not only with GFR level but also with degree of albuminuria; thus, the 2012 KDIGO guidelines recommend classifying adult CKD by GFR and albuminuria category. Although similar large-scale trials assessing albuminuria severity and clinical outcomes in pediatric patients with CKD are currently lacking, prospective studies are ongoing. As such, albuminuria is not currently used to classify pediatric CKD, although it may be used in future, pending further clinical data accumulation.

Epidemiology

The incidence of CKD in children is unknown. Current estimates are based on the number of children accepted for dialysis and renal transplantation; however, some children do not require dialysis or transplantation until adulthood. In 2008, the North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS) reported 7,037 patients with an estimated GFR of less than or equal to 75 mL/min/1.73 m². The causes of CKD can be broadly categorized into 2 main groups: congenital and acquired. Congenital conditions, such as obstructive uropathy, aplasia/hypoplasia/ dysplasia, reflux nephropathy, and prune-belly syndrome accounted for most of the diagnoses (53%) reported in 2008 and are referred to by the acronym CAKUT (congenital abnormalities of the kidney and urinary tract). Among the acquired conditions, focal segmental glomerulosclerosis is the most prevalent diagnosis at 9%. Overall, males are more often affected by CKD (64%). Age at registry entry varies, with 20% of children entered into the registry before 2 years of age, 16% between 2 and 5 years of age, 32% between 6 and 12 years of age, 28% between 13 and 17 years of age, and 4% after the age of 17 years; however, time at registry entry does not strictly correspond to age at time of CKD diagnosis.

Clinical and Biologic Presentation

The child with CKD often is asymptomatic or presents with nonspecific symptoms, and abnormal renal function is detected during a routine health examination or screening. For a small percentage of these patients, CKD is incidentally discovered when the patient presents with other illness, such as diarrhea and dehydration. Before receiving a diagnosis of CKD, a patient may also be referred to a specialty physician for the evaluation of growth retardation, hypertension, or anemia (Box 153.2). Occasionally, a history of recurrent episodes of fever without a source or partially treated urinary tract infection (UTI) secondary to undiagnosed vesicoureteral reflux is uncovered. A child may also report vague generalized symptoms, including malaise, anorexia, and vomiting, which may be associated with advanced renal failure.

Metabolic and Water/Electrolyte Abnormalities

The child with a congenital abnormality, such as obstructive uropathy or renal dysplasia, may develop polyuria resulting from an inability to concentrate urine, and salt wasting and polydipsia may become prominent features of the patient’s disease. In such cases, blood pressure is usually normal. A history of bed-wetting may therefore be a clue to CKD. In contrast, the child with advanced CKD may have impaired sodium excretion, resulting in water retention and, consequently, fluid overload and secondary hypertension. Hyperkalemia is not an uncommon component of CKD, and it becomes evident when the GFR falls below 10 mL/min/1.73 m². Hypokalemia is a less common problem and may be secondary to excessive diuretic use or strict dietary restriction; it may also be the hallmark of tubulointerstitial disease (eg, proximal tubulopathy) during the early stages of CKD.

Metabolic acidosis is mainly caused by the overall decrease in ammonium excretion from a reduced number of nephrons. Decreased excretion of titratable acid, as well as bicarbonate wasting in cases of proximal renal tubular acidosis, may also play a role.

Glucose intolerance may occur in some children with CKD despite elevated insulin levels. This may occur independently or in association with genetic diseases, such as hepatocyte nuclear factor-1β mutations, which induce renal cysts and atypical diabetes mellitus. The linear correlation between a decline in renal function and insulin resistance even at the early stages of CKD has been shown in adults. More than 50% of children develop hyperlipidemia by the time they reach ESRD. The characteristic plasma lipid abnormality is a moderate hypertriglyceridemia. A high prevalence of hypercholesterolemia and low levels of high-density lipids and albumin are characteristic as well. These derangements have a role in the manifestation of cardiovascular disease.

Growth Failure

Failure to thrive is the hallmark of CKD in children, and the degree of growth retardation varies according to the age of presentation. Because maximal growth occurs during the first few years after birth, children with congenital renal problems are the most affected. In the NAPRTCS, height deficits were greatest for children younger than 5 years, with nearly 50% below the third percentile for age and sex. Growth failure occurs early in the course of CKD and affects up to 35% of this population; by the time of renal transplantation, many children have severe short stature. Moreover, children with more severely impaired renal function tend to have more severe height deficits as well. Sexual development and bone age often are delayed in affected patients. Uremia, anorexia, and frequent vomiting contribute to the protein and calorie malnutrition frequently observed in younger children with CKD. Early, intensive management often is required to maximize nutritional status and optimize growth.

Mineral and Bone Disorders Associated With Chronic Kidney Disease

The effect of CKD on mineral and bone disorders (MBD) may be immediate (eg, biologic disequilibrium of calcium, phosphate, vitamin D, and parathyroid hormone [PTH]) or delayed (eg, growth retardation, bone pain, fractures, bone deformities, extraskeletal and vascular calcifications, increased morbidity and mortality). The development of CKD-MBD begins early in the course of CKD; clinical manifestations include growth retardation and skeletal deformities, such as genu valgum, ulnar deviation of the hands, pes varus, and slipped capital femoral epiphysis. Whereas the term renal osteodystrophy refers specifically to different bone lesions as defined by bone histomorphometry, the term CKD-MBD is used to define clinical and biochemical abnormalities as well as the long-term consequences of alterations in bone and mineral metabolism associated with CKD. Thus, CKD-MBD is manifested by 1 or a combination of the following abnormalities: abnormalities of calcium, phosphorus, PTH, or vitamin D metabolism; abnormalities in bone histology, linear growth, or strength; and vascular or other soft tissue calcification.

Anemia

The anemia of CKD is normochromic and normocytic. Insufficient EPO production occurs in the setting of GFR less than 30 mL/min/ 1.73 m². Anemia is frequently accompanied by decreased serum iron levels, increased total iron-binding capacity, and low reticulocyte counts. The patient undergoing dialysis is predisposed to develop bleeding tendencies secondary to platelet dysfunction and mechanical hemolysis.

Hypertension

The rate of hypertension in children with CKD varies from 38% to 78%. Prolonged hypertension may accelerate deterioration of renal function. An acute rise in blood pressure may cause seizure in a child with CKD. Other manifestations include headache, epistaxis, congestive heart failure, nerve palsies, and cerebral hemorrhage. Hypertension is a frequent finding in children with CKD secondary to polycystic kidney disease or chronic glomerulonephritis.

Cardiac Dysfunction

The patient with CKD is at increased risk for left ventricular hypertrophy (LVH), vascular calcification, and congestive heart failure. Left ventricular hypertrophy, as diagnosed on echocardiography, is present in 75% of adults with CKD; hypertension and anemia are important contributing factors. Left ventricular hypertrophy also occurs in pediatric patients with CKD, with a prevalence of 10% to 20% in CKD stages 3 and 4. Fluid overload, refractory hypertension, severe anemia, and uremic cardiomyopathy may contribute to congestive heart failure.

Neurologic Dysfunction

The child with CKD may have impaired neurodevelopment related to the age of presentation. Memory deficits, lack of concentration, depression, and weakness may occur. Children younger than 5 years are more affected because significant brain growth and maturation occur during the early years. The child with severe uremia may experience global developmental delay and seizures. Unless neurodevelopmental delays are recognized promptly and early intervention is instituted, neurologic dysfunction is often progressive. Some genetic diseases involving cerebral and renal development may play a role in developmental delay.

Pathophysiology

The Final Common Pathways in Nephron Loss

Regardless of the type of initial injury to the kidney, glomerular hyperfiltration and tubulointerstitial damage are the final common pathways of glomerular destruction. Hyperfiltration occurs as a response by the residual glomeruli to compensate for the loss of nephrons, as summarized in Figure 153.1. Reduced filtration results in increased production of renin and angiotensin-converting enzyme (ACE). The consequent vasoconstriction of the efferent arteriole increases the hydrostatic pressure on the capillary wall, resulting in a compensatory higher filtration rate per nephron but also increased protein transit across the wall. Proteinuria involves recruitment of inflammatory cells and upregulation of proinflammatory and profibrotic genes. Protein overload in tubular cells stimulates their differentiation into myofibroblasts, thus promoting fibrosis. Concurrently, the inflammatory cascade activates the complement system, resulting in additional damage to the kidney. Interstitial fibrosis impairs oxygenation of the tubular cells, and the resulting chronic hypoxia further activates the renin-angiotensin system. Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers have antihypertensive properties; additionally, they may reduce intraglomerular pressure, proteinuria, and the consequent tubulointerstitial fibrosis, thus potentially slowing the rate of CKD progression.

Growth Failure

Multiple factors are involved in the pathogenesis of growth retardation in children with CKD, including deficient calorie and protein intake, decreased EPO production resulting in anemia, metabolic acidosis, drug toxicity (from corticosteroids) and alterations in the growth hormone (GH)-insulinlike growth factor (IGF)-1 axis. Growth hormone-IGF-1 alterations are characterized by peripheral resistance to GH secondary to decreased expression of GH receptors and decreased levels of the bioactive IGF-1, the primary mediator of somatic growth. This decrease in bioactivity results from the retention of IGF-1 binding proteins (BPs), which worsens as GFR declines. Additionally, renal osteodystrophy in children involves alteration of the growth plate-cartilage architecture, which further contributes to growth failure. Adynamic bone growth (ie, low bone turnover) and severe hyperparathyroidism increase the severity of growth retardation. Also contributing to growth failure is the hypogonadism associated with CKD. In teenagers with CKD, the loss of pulsatile secretion of gonadotropin-releasing hormone contributes to shortening of the pubertal growth spurt and reduced growth velocity.

Figure 153.1. The consequences of reduction in nephron number in the pediatric patient.

Abbreviations: CKD, chronic kidney disease; GF, glomerular filtration.

Mineral and Bone Disorders Associated With Chronic Kidney Disease

The development of renal osteodystrophy is multifactorial. Reduced renal mass results in decreased synthesis of 1,25-dihydroxycholecalcif-erol; in turn, the stimulus to absorb calcium from the gut is decreased. The resultant hypocalcemia and lack of vitamin D feedback on the parathyroid glands stimulate the production of PTH, facilitating rapid mobilization of calcium from the skeleton, thus normalizing serum calcium at the expense of bone. With advancing CKD, skeletal resistance to PTH occurs, and circulating levels of PTH increase.

Hyperparathyroidism and the resultant high bone remodeling produces fibrosis in bone, a condition termed osteitis fibrosa. Administration of exogenous vitamin D and its derivatives can suppress such bone remodeling; however, without adequate monitoring, such administration can cause low bone turnover. The physician can monitor for adynamic bone by monitoring serum PTH and alkaline phosphatase levels, which usually are lower in these patients than in patients with secondary hyperparathyroidism and high bone turnover.

Hyperphosphatemia occurs when the few remaining nephrons lose the ability to excrete the daily load of phosphorus from the diet; it is a late phenomenon, usually occurring in CKD stages 4 and 5. Historically, aluminum-containing phosphate binders contributed to the pathogenesis of osteomalacia, a state characterized by poorly min-eralized osteoid, and adynamic bone disease; currently, the use of large doses of calcium-based phosphate binders and active vitamin D sterols are implicated in the pathogenesis of osteomalacia. Biochemical abnormalities present in CKD-MBD, including abnormal calcium-phosphate metabolism, hyperparathyroidism, and increased levels of fibroblast growth factor 23 (FGF23), in association with traditional cardiovascular disease risk factors, such as hypertension, hyperlipidemia, hyperhomocysteinemia, anemia, and oxidative stress, contribute significantly to the development of cardiovascular disease, which is the leading cause of death in individuals with ESRD. In young adults with childhood-onset CKD, the prevalence of coronary artery calcification can be as high as 92% when evaluated by sequential computed tomography (CT) with electrocardiogram gating.

In the early 2000s, FGF23 was identified as the pathogenic hormone in various forms of hypophosphatemic rickets and tumor-induced osteomalacia. Secreted by osteocytes, FGF23 functions as a phosphaturic hormone and as a suppressor of renal 1-α-hydroxylase. Circulating FGF23 levels have been observed to increase early in the course of CKD. Contributing to these elevated levels may be decreased FGF23 clearance, increased synthesis by osteocytes (a compensatory mechanism attempting to maintain normal phosphate levels) or an unintended response to treatment with active vitamin D analogs. In individuals with CKD, elevated FGF23 levels are associated with renal disease progression, cardiovascular morbidity, cardiovascular mortality, and all-cause mortality. In vitro and animal studies have shown that FGF23 may directly induce LVH.

Abbreviations: CAKUT, congenital abnormalities of kidney and urinary tract; GN, glomerulonephritis;

MPGN, membranoproliferative glomerulonephritis.

^a Total exceeds 100 because of rounding.

Anemia

Chronic kidney disease anemia begins when the GFR falls below 30 mL/min/1.73 m² and is the result of multiple factors, including decreased EPO production, decreased red cell survival, bone marrow inhibition, iron deficiency, vitamin B₁₂ and folate deficiency, inflammation, and osteitis fibrosa. Historically, aluminum toxicity was also implicated in CKD anemia. Blood loss during hemodialysis sessions may be contributory, as well. Recently, hepcidin, a hormone synthesized in the liver, was found to be central to the pathogenesis of CKD-associated anemia. Hepcidin causes the internalization of ferroportin, a protein that exports iron from the intracellular space to the extracellular compartment. Decreased hepcidin activity results in iron overload, whereas increased hepcidin activity is associated with anemia. Iron loading and inflammation increase hepcidin levels, and EPO treatment decreases hepcidin levels. As GFR decreases, hepcidin levels increase, resulting in ferroportin internalization, intracellular iron sequestration, and functional iron deficiency, thereby contributing to the anemia of CKD.

Differential Diagnosis

Initially, the main challenge for the physician is not determining a differential diagnosis but instead determining whether renal impairment is acute or chronic and, if chronic, the etiology. A variety of kidney problems, whether congenital, hereditary, acquired, or metabolic, may result in CKD. Although specific cures are not available for most of these renal conditions, a complete diagnostic workup is essential to determine the etiology of the renal disease. Such information may identify the presence of an inherited problem that may require genetic counseling and, in some cases, may aid in antici-pating problems associated with renal transplantation. Some renal diseases, such as focal segmental glomerulosclerosis and atypical hemolytic uremic syndrome, may recur after renal transplantation, and the patient and family must be informed early about this possibility in preparation for renal transplantation. The different etiologies of CKD, as well as their prevalence in the 2008 NAPRTCS registry, are summarized in Table 153.2.

At initial presentation, it is necessary to distinguish acute from chronic renal failure because therapeutic strategies may differ and long-term renal prognoses can be quite different as well. Hereditary diseases commonly encountered include hereditary nephritis (eg, Alport syndrome), branchio-oto-renal syndrome, and juvenile nephronophthisis. Acquired diseases, such as chronic glomerulonephritis,

membranoproliferative glomerulonephritis, and focal and segmental glomerulosclerosis, affect a large percentage of older children who progress to CKD. Whereas anemia, hypertension, and fluid and electrolyte abnormalities often are associated with both chronic and acute renal failure, suboptimal linear growth and signs and symptoms of renal osteodystrophy manifest over time and occur in patients with chronic renal impairment.

Evaluation

A complete evaluation of the child presenting with renal failure must be performed, including careful history and physical examination, along with laboratory tests and appropriate imaging studies.

History

A thorough history must be obtained, including a complete and detailed family history, because this may aid in diagnosis (Box 153.3). A prenatal history, including possible drug exposures and results of antenatal imaging, may also provide useful information.

Physical Examination

A complete physical examination is required. Height and weight must be measured accurately, and the results should be plotted on the same growth curves used for healthy children. Weight may be overestimated if fluid retention is present. Blood pressure must be taken, using an appropriately sized cuff. Blood pressure measurements should be compared to the 50th percentile for age, sex, and height. The presence of tachycardia, heart murmurs, or adventitious heart sounds that may be indicative either of uncompensated anemia or of cardiac or pericardial involvement must be noted. Gross eye examination should be performed, including fundal examination, to assess for evidence of chronic hypertension. Macular abnormalities or hearing problems may be indicative of a heritable disease, such as Alport syndrome. Ear abnormalities (eg, preauricular pits, ear tags) accompanied by hearing deficits may be associated with renal disease (eg, branchio-oto-renal syndrome). Undescended testes may be evident in some children with urogenital problems.

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