Part 3: Chronic Kidney Disease

INTRODUCTION

Chronic kidney disease (CKD) is defined as abnormalities of kidney structure or function present for ≥ 3 months. The chief markers of kidney damage include either decreased glomerular filtration rate (GFR) < 60 mL/min/1.73 m² or albuminuria. Additional markers are the presence of urine sediment abnormalities, electrolyte disturbances due to tubular disorder, abnormalities detected either by imaging or kidney biopsy, or a history of kidney transplantation. In addition, a defined staging system has evolved to classify the severity of CKD and guide clinical management, as certain manifestations and complications of CKD arise at specific GFR levels irrespective of the etiology of CKD. In 2012, Kidney Disease Improving Global Outcome (KDIGO) guidelines modified this staging system to include albuminuria, as the relative risk of mortality, cardiovascular complications, and disease progression is influenced independently by both GFR and albuminuria (Table 473-1). There are a number of caveats with respect to applying this classification system to pediatrics. First, the staging of CKD excludes patients younger than 2 years whose renal function improves markedly in the first 2 years of life; therefore, a GFR < 90 mL/min/1.73 m² in a 6-month-old child may not represent any abnormality of renal function. Second, the duration of ≥ 3 months to define CKD cannot be applied to newborns and infants younger than 3 months of age. Finally, in children, urinary protein excretion can be used instead of albumin excretion.

CAUSES OF CHRONIC KIDNEY DISEASE IN CHILDREN

The causes of CKD in children are very different from those in adults. In younger children, the most common causes are congenital abnormalities of the kidney and urinary tract (CAKUT) such as renal hypodysplasia and/or obstructive uropathy. The most common obstructive lesions are posterior urethral valves and prune belly syndrome, both of which occur only in boys (see Chapter 472). Renal cystic diseases, including cystic renal dysplasia, juvenile nephronophthisis, and autosomal recessive polycystic kidney disease, may cause significant loss of renal function during childhood (see Chapter 466). Glomerular diseases are an unusual cause of significant CKD in early childhood but can include congenital nephrotic syndrome or, more commonly, focal segmental glomerulosclerosis or hemolytic-uremic syndrome (see Chapter 468). In teenage years, membranoproliferative glomerulonephritis and membranous nephropathy may be seen, and CKD may be seen in association with systemic lupus erythematosus. However, if causes of end-stage renal disease in children are analyzed, there is a much greater proportion of glomerular diseases, implying greater progression of CKD in glomerular diseases compared with CAKUT.

INCIDENCE AND PREVALENCE

Obtaining a true population estimate is hampered by the nature of CKD, which often is asymptomatic, and a lack of agreement on a definition of CKD. The European Registry estimates the incidence of pediatric CKD to be 11 to 12 per million of the age-related population and the prevalence to be 55 to 60 per million of the age-related population. Although no incidence or prevalence data for pediatric CKD are available from North American registries, the US Renal Data Systems reported 1470 incident patients age 0 to 21 years with end-stage renal disease or renal transplants treated in 2013, with a prevalent population, including renal transplant patients, of 9979 (104 per million population). More detailed information is available in the Italian registry. For the period 1990 to 2000, the Italian registry identified 1197 children younger than 20 years with a creatinine clearance < 75 mL/min/1.73 m² body surface area before dialysis at the time of entry into the registry, with a mean incidence of 12.1 cases per million (range 8.8–13.9), and the prevalence was 74.7 per million of the age-related population.

It is clear that expanding the diagnosis of CKD to include patients with normal renal function but abnormal urinalysis or radiologic appearance (as recommended by KDIGO) greatly increases both the incidence and prevalence data. However, many of these patients have very minor renal disease.

COMPLICATIONS

The complications that should be anticipated in children with CKD are listed in Table 473-2. The frequency and severity of these complications increase as the stage of CKD increases. Consensus management recommendations for the complications of CKD have been provided by the Kidney Disease Outcomes Quality Initiative (KDOQI) and KDIGO guidelines and by groups of European expert panels, as summarized in this section.

Nutritional Disorders

Although protein-energy malnutrition is often seen in adults with CKD, the incidence of protein-energy malnutrition is approximately 7% to 20% in children with CKD, with a significantly increased frequency in both advanced CKD and in infants and young children with CKD. In young children, the key factor contributing to malnutrition is inadequate intake. Additional factors that can contribute to the development of protein-energy wasting include anorexia, nonspecific inflammation, transient infections, chronic acidemia, resistance to insulin, growth hormone resistance, increased glucagon levels, hyperparathyroidism, and blood loss through dialysis or frequent phlebotomy. Although the underlying cause of malnutrition in children with CKD often is multifactorial, it is extremely important that it be recognized and treated promptly and aggressively, as malnutrition has been strongly associated with mortality. Nutritional assessment should include measurement of height, weight, body mass index (weight/height²), head circumference in infants, skinfold thickness, mid-arm circumference, serum albumin, and cholesterol. No single 1 of these measures will define malnutrition, but in a child with CKD in whom 2 or more measures are abnormal, attention should focus on his or her nutritional state. Nutritional support from a specialized dietitian is necessary to optimize caloric intake, which is the overriding goal of treatment for malnutrition in children with CKD.

Achieving adequate caloric intake may be difficult. Children with CKD often have an impaired appetite, possibly associated with impaired taste and sometimes with nausea and vomiting. They may also require the restriction of specific dietary components, especially potassium and phosphate. Polyuria may also inhibit intake of other calorically dense liquids in children with congenital renal disease that require increased water intake due to the inability of the kidney to concentrate urine. Breast milk can be used, but specialized infant formulas designed for children with CKD often are required. Compared to other infant and pediatric formulas, these formulas have lower sodium, potassium, and phosphorus concentrations, as well as a lower renal solute load. In North America, they include PM 60/40 and Good Start. Infants with CKD due to renal dysplasia may waste sodium and require sodium supplementation to improve growth.

If additional caloric density is required, it is preferable to add modular commercial components rather than simply to concentrate the formula because concentrating commercial formulas will also result in increases in electrolyte and mineral content. Modular nutritional components include a variety of protein powder (Beneprotein powder, Resource), carbohydrate (Polycose, Benecalorie), and fat (vegetable oil, medium-chain triglyceride oil, Microlipid) products. Specific adult “renal formulas” that are high calorie with low electrolytes and phosphorus are not recommended for use in children younger than 2 years due to their high osmolality and inappropriate mineral content, especially their higher magnesium content. Due to the child’s poor appetite and high-volume fluid requirements, it can be unrealistic to expect an infant or child to achieve adequate nutrient intake by mouth. In these circumstances, it may be necessary to provide enteral nutrition (nasogastric or gastrostomy) or parenteral nutrition.

Consultation with a specialized dietitian with expertise in the management of children with CKD often is necessary. Psychological consultation may also be necessary to assure continued dietary compliance in older children, in whom difficulty in compliance with the required restricted diet is common.

Growth Impairment

Impaired growth is a common complication of CKD; it can have a profound psychological impact on a child and adversely affect his or her quality of life. Population studies show increased mortality rates in children with CKD and severe growth delay. Children with CKD are approximately 1.5 standard deviations below normal for height, and this height deficit is greatest in the youngest children, despite improved efforts to sustain growth. Approximately one-third of all children with CKD and approximately one-fifth of those with GFR > 50 mL/min/1.73 m² have a height below the third percentile for age. The maximal deterioration in height seems to occur in the first several months of life or prior to referral to a pediatric nephrologist; there is a high prevalence of low birth weight in children with CKD, which also contributes to poor growth. Once appropriate treatment of their undernutrition and renal osteodystrophy ensues, a normal growth pattern usually is established until at least stage 5 CKD (dialysis) is reached. However, growth lost in these first months of life may be very difficult to restore.

The causes of growth delay in children with CKD are numerous and include malnutrition/protein-energy wasting, chronic acidosis, severe renal osteodystrophy, sodium depletion, and growth hormone (GH) resistance. If possible, treatment should be directed to correction of these metabolic disturbances prior to introduction of GH.

GH is not deficient in children with CKD, and, in fact, plasma GH levels may be elevated. However, a number of abnormalities have been demonstrated in the steps required for activation for GH. These abnormal steps in the GH metabolic pathway include abnormal actions of GH directly on bone, defective conversion of GH to insulin-like growth factor 1 (IGF-1) in the liver, and accumulation of IGF-binding proteins in the serum, some of which interfere with the action or IGF-1 on bone. CKD can be thought of as a condition associated with partial GH resistance, which can be overcome by GH treatment.

Randomized controlled trials show that GH treatment can promote short-term growth in children with CKD. Previous concerns about the potential adverse effects of GH therapy and the possibility of a diminishing effect with prolonged usage have not been substantiated by long-term usage studies. Occasional complications of GH use include pseudotumor cerebri, worsening renal osteodystrophy, and slipped capital femoral epiphysis, but their incidence probably is no different from that in children with CKD who are not treated with GH. Therefore, current consensus recommendations are that children with growth impairment and CKD, for whom no other cause is apparent, be treated with GH. Despite this recommendation, only approximately 1 in 4 children with a height less than the fifth percentile are prescribed GH.

CKD Mineral Bone Disorder

CKD mineral bone disorder (MBD) is a systemic disorder characterized by alterations in mineral metabolism and bone and calcific cardiovascular abnormalities in CKD. In its severe form, bone disease deformities associated with rickets will impair growth. The pathogenesis of CKD MBD has become more complex with discovery of fibroblast growth factor 23 (FGF23), which is a hormone secreted by osteocytes in response to increased dietary phosphorus load; it acts with its obligatory cofactor klotho and causes phosphaturia. In addition, it decreases 1α-hydroxylase activity, thereby decreasing the level of 1,25-(OH)₂-vitamin D. Elevations in FGF23 are the earliest abnormality in mineral metabolism seen in children with CKD. The insufficiency of 1,25-(OH)₂-vitamin D in CKD can be a result of deficient activation of cholecalciferol to the active form of 1,25-dihydrocholecalciferol in the kidney or due to low cholecalciferol levels as a result of dietary insufficiency. In later stages of CKD, retention of phosphate worsens as renal function declines. Both the elevation of phosphate levels in plasma and a fall in plasma calcium values stimulate parathyroid hormone (PTH) secretion; PTH then increases phosphate excretion by suppression of tubular phosphate reabsorption, thereby returning phosphate values to normal, but at the expense of persisting elevation of PTH values. These mechanisms are illustrated in Figure 473-1.

Bone biopsy remains the gold standard for diagnosing bone abnormalities, although it is not done thereby because of its invasive nature. Traditionally, bone disease was classified as either a state of high bone turnover with osteitis fibrosa due to hyperparathyroidism or low turnover (adynamic) bone disease, which has been ascribed to oversuppressed PTH levels. Although high turnover is more common, low turnover disease has also been described in children. Recently, KDIGO proposed that bone biopsy be interpreted in terms of bone turnover, mineralization, and volume (TMV classification) because previous interpretations focused mainly on turnover; however, other abnormalities are also common in pediatric patients with CKD. It has been shown that skeletal mineralization defects start in pediatric patients as early as stage 2CKD, even before defects of bone turnover or any biochemical abnormality, except an increase in circulating FGF23 levels.

The effects of metabolic bone disease on the epiphysis are unique to children with CKD and may include growth failure, slipped epiphysis, and rickets. The effects of low-turnover bone disease, which leads to increased fractures in adults, are less clear in children but may adversely affect growth. Both low- and high-turnover bone disease may impair mineralization of bone and contribute to calcification of vessels.

Because expertise is not available to evaluate bone histomorphometry in most pediatric hospitals, recognition of metabolic bone disease in CKD relies on numerous surrogate markers and imaging techniques. Historically, x-rays of the knees, wrist/hand, and hips have been used and may demonstrate changes of rickets or subperiosteal resorption caused by hyperparathyroidism, but the sensitivity for detection of mild disease is poor. Also, radiologic techniques will not distinguish high-turnover from low-turnover states. Dual-energy x-ray absorptiometry (DXA) is of limited value to evaluate renal osteodystrophy because (1) it measures bone mineral density as total bone mass in a given area and may not detect structural alterations in trabecular and cortical bone density and architecture, (2) DXA does not distinguish the effects of PTH on cortical and trabecular bone, and (3) interpretation of results is confounded by impaired growth and whether comparison should be with height or chronologic age as well as pubertal stage. Therefore, great reliance is placed on surrogate biochemical markers to detect and treat renal osteodystrophy.

Whereas consensus exists regarding maintaining serum calcium and phosphorus in the normal range, there is divergence regarding PTH target, particularly in children receiving dialysis. Whereas expert panels have recommended maintaining PTH values in the normal range for children with stage 2 to 4 CKD, for children receiving dialysis, PTH ranges are recommended to be between 2 and 4 times the upper limit of normal and 2 to 9 times the upper limit of normal as suggested by National Kidney Foundation KDOQI and KDIGO guidelines, respectively (Table 473-3). This wide range is because of variability of different assays in measuring PTH as well as the bio-inactive PTH fragments that accumulate in patients on dialysis.

There are 4 classes of therapeutic agents that are used to prevent and treat renal bone disease. The first agent is vitamin D₃ (cholecalciferol). If plasma levels of 25-OH vitamin D are subnormal, supplementation with vitamin D₃ should be provided. If metabolic acidosis is present, it should be corrected with either oral sodium bicarbonate or sodium citrate supplements. Activated vitamin D analogs should be prescribed if the calcium level is not high and the PTH exceeds the recommended limits. The most commonly used analog in North America is calcitriol (Rocaltrol), but alfacalcidol, doxercalciferol, and paricalcitol may work equally well. In the presence of elevated plasma phosphate values, if dietary phosphate restriction is ineffective, phosphate binders such as calcium carbonate, calcium acetate, or sevelamer should be prescribed. Calcium-containing compounds are available in liquid formulations and, therefore, are most easily used in young children. However, excessive total calcium ingestion may lead to hypercalcemia, which has been associated with vascular calcification even in children.

Developmental Delay and Quality of Life

Children with CKD are at risk for developmental delay. It has been attributed to a variety of causes, including aluminum intoxication associated with the use of aluminum-containing phosphate binders and malnutrition. Improved nutritional management and discontinuation of aluminum-containing medications has reduced the severity of developmental delay, although with more precise testing, it also became apparent that developmental problems of some degree occur in many children with CKD, including those not receiving dialysis.

Developmental issues are most evident when renal failure occurs in infancy, when developmental problems occur in as many as 25% of patients, and severity correlates with the severity of renal dysfunction. Cognitive deficits are also noted in older children, and the overall IQ of school-age children with CKD is lower than that of the normal population. These delays often persist over time, and some cross-sectional studies have shown little difference between children on dialysis and those after transplantation. However, other longitudinal studies have demonstrated improvement in specific developmental deficits following renal transplant.

The Chronic Kidney Disease in Children (CKiD) study, which is an ongoing prospective, multicenter, observational cohort study from North America, has shown that approximately a third (21–40%) of patients even with mild to moderate CKD have impairment in measures of IQ, academic achievement, and attention regulation, with elevated blood pressure and lower GFR associated with lower scores. Specific deficits in language abilities have been observed, and in such cases, it is important to ensure that hearing is not impaired. Some children demonstrate improvement after transplantation, but this finding is inconsistent. In some patients, concurrent extrarenal morbidity may impact cognitive and motor abilities. These morbidities may be due to lower birth weight, seizure disorder, or congenital abnormalities, but they may also result from acquired complications of their renal disease such as severe renal osteodystrophy, adverse medication effects (particularly steroids), and marked growth impairment. Irrespective of the underlying cause, only half of children starting hemodialysis and three-fourths of those beginning home peritoneal dialysis attend school full time. Therefore, it is hardly surprising that these children have difficulty achieving normal educational standards and are at risk of social isolation from their peers. This combination of factors has an impact on their quality of life. In addition to growth impairment and the other issues outlined previously, anemia has been reported to adversely affect quality of life scores.

Numerous studies have evaluated quality of life and social behavior in children with CKD and shown lower health-related quality of life scores when compared to healthy controls, as well as more sleep- and fatigue-related symptoms. These studies seem to indicate that children receiving dialysis have lower scores than those who do not. Following renal transplant, quality of life improves compared to dialysis but may not achieve predisease scoring. This improvement is not surprising because patients who undergo transplantation are a heterogeneous group, whose quality of life may be substantially influenced by medication side effects and their level of renal dysfunction. Despite the documentation that quality of life may be reduced in children with CKD, children’s perception of their quality of life is considerably better than their parents’ perception of their quality of life.

Anemia

Anemia is defined as having a hemoglobin level of less than the fifth percentile of normal, which is adjusted for age and gender (Table 473-4). The definition as per KDIGO guidelines uses such a cutoff derived from National Health and Nutrition Examination Survey II data. The CKiD study has shown that below a measured GFR of 43 mL/min/1.73 m², there is a near linear relationship with a drop of 0.3 mg/dL of hemoglobin for every 5 mL/min/1.73 m² drop in GFR. Anemia is nearly universal in advanced CKD, and despite the nearly universal use of erythropoiesis-stimulating agents (ESAs) in children receiving dialysis, nearly half are below target as per data collected by US and European registries.

The most common cause of anemia with CKD is a deficiency of erythropoietin (EPO). EPO normally is produced in the peritubular interstitial cells of the kidneys and regulates bone marrow erythroid cell proliferation, differentiation, and survival. However, EPO deficiency in CKD often is aggravated by other causes of anemia. They include iron deficiency that may be due to a reduction in transferrin (the iron carrier protein) in CKD, increased blood loss associated with surgical procedures, and frequent phlebotomy; furthermore, increased hepcidin levels seen in CKD can cause functional iron deficiency because increased hepcidin levels prevent the release of iron from macrophages and inhibit intestinal iron absorption. Less common contributing factors include carnitine, folate, and vitamin B₁₂ deficiencies; severe hyperparathyroidism; and aluminum toxicity.

Investigation of anemia in children with CKD should routinely include measurement of complete blood count, serum iron, total iron-binding capacity, ferritin, and reticulocyte count. Less frequently, or when treatment with ESA and iron is ineffective, haptoglobin, lactate dehydrogenase, folate, vitamin B₁₂, carnitine, and aluminum values should be checked. In addition, severe hyperparathyroidism (PTH values), inflammation (C-reactive protein [CRP] values), and stool blood loss should be considered. However, in the usual circumstance, investigation is focused on the distinction between iron deficiency and inadequate ESA dosing. In isolation, no single one of the previously noted tests will identify iron deficiency. Transferrin saturation is the most helpful, but it may be falsely increased in patients with CKD and proteinuria caused by loss of transferrin in the urine; in such patients, this test is not useful. The evaluation of anemia is further discussed in Chapter 426. A low reticulocyte count may indicate insufficient ESA effect; iron, folate, or vitamin B₁₂ deficiency; or bone marrow unresponsiveness, whereas a high value may indicate an appropriately responsive bone marrow or the presence of covert hemolysis.

Anemia in children has been associated with increased hospitalization rates and increased mortality rates. It could be related to adverse cardiovascular outcome; indeed, increased left ventricular mass index has been associated with anemia in pediatric CKD and dialysis populations. The health-related quality of life of children with CKD appears to be lessened by anemia. Growth impairment may also be due to anemia because administration of ESA to children with CKD appears to promote catch-up growth prior to dialysis. Analysis of a large cohort of children in the North American Pediatric Renal Transplant Cooperative Study (NAPRTCS) database demonstrated that a hematocrit less than 33% is an independent risk factor for short stature in children with CKD.

ESAs revolutionized the management of anemia and are the cornerstone of treatment for anemia in pediatric patients with CKD. They can be administered either subcutaneously or intravenously (particularly in patients receiving hemodialysis). Whereas dosing was originally prescribed thrice weekly, for most children, hemoglobin is maintained in the normal range with epoetin alfa (Epogen) 150 U/kg/wk administered once or twice weekly. Although some disagreement exists as to the dose required for treatment of younger children, observational data from the NAPRTCS database show that younger children commonly receive higher doses, and in infants, the recommended dose is 200 to 300 U/kg/wk. An alternative ESA, darbepoetin, has a slightly altered molecule compared to epoetin alfa. A weekly starting dose of approximately 0.5 μg/kg is suggested. Although it is administered less frequently, increased pain at the injection site compared to epoetin alfa has been reported. Either epoetin alfa or darbepoetin can be used to successfully treat anemia in the vast majority of children with CKD.

Iron therapy is required for nearly all children with CKD to prevent and treat anemia. KDOQI guidelines suggest that oral iron can be administered at a dose of up to 6 mg/kg/d of elemental iron in 2 to 3 divided doses. Oral iron is hampered by gastrointestinal side effects and decreased absorption with concomitant use of phosphate-binding agents or proton pump inhibitors. As intestinal absorption is also hampered by elevated hepcidin levels in CKD, intravenous iron has been used in patients with CKD, particularly in patients on hemodialysis, because it can be administered during the hemodialysis treatment. Iron sucrose or sodium ferric gluconate is associated with a reduced incidence of anaphylactic reactions compared to the previously recommended iron dextran and has been studied in children for both treatment of iron deficiency and maintenance therapy. Obviously, the use of intravenous iron on a regular basis is not suited for the majority of patients with CKD unless they have some form of vascular access; intravenous iron also is considerably more expensive than the oral variety.

Cardiovascular Disease and Hypertension

Based on large registries from the United States, Europe, and Australia and New Zealand, children with CKD are classified as having the highest risk category for cardiovascular disease by the American Heart Association. Each of these studies has shown that cardiovascular disease accounts for 30% to 45% of all deaths in children receiving dialysis.

Contributing factors include both traditional factors, such as chronic hypertension and dyslipidemia, and nontraditional factors, such as abnormal mineral metabolism, arterial calcification, and likely anemia and inflammation. Hyperlipidemia is discussed in the next section. Hypertension, defined as a blood pressure greater than or equal to age, gender, and height-specific 90th percentiles, has been reported in more than half of children with CKD, and even with medications, only 48% were well controlled. More concerning is the finding that nearly one-third of patients with CKD have masked hypertension (normal office blood pressure but elevated blood pressure on ambulatory blood pressure monitoring), and thus hypertension may remain unrecognized and untreated in this population.

Left ventricular hypertrophy (LVH) is the most common cardiac abnormality in children with CKD. The CKiD study has shown the presence of LVH even with mild CKD. This prevalence increases as kidney function worsens, with nearly 60% to 80% of children initiating dialysis having LVH. Hypertension seems to be one of the main causes of LVH, although other factors such as anemia and abnormal mineral metabolism also likely contribute.

Excessive coronary artery calcification has been shown in children and young adults with end-stage renal disease using computed tomography screening. Arterial calcification is now known to infer substantial risk for cardiovascular disease in CKD, likely contributed to by chronic hyperphosphatemia, hypercalcemia, and an increased calcium-phosphate product. In adults, use of sevelamer, a non–calcium-containing phosphate binder, has been shown to decrease coronary artery calcification; however, this has not been studied in children.

Hyperlipidemia

Children with CKD are at substantial risk (39–65%) for development of dyslipidemia. Patients with glomerular diseases are at higher risk of developing dyslipidemia than are those with CKD due to CAKUT. The most common abnormality seen in children with CKD is hypertriglyceridemia. Other abnormalities seen are elevated non–high-density lipoprotein (HDL) cholesterol levels and lower HDL cholesterol levels. In addition, approximately a fourth of children had more than 1 lipid abnormality. KDIGO guidelines state that children with CKD should have lipid levels checked upon diagnosis and monitored annually.

The first line of therapy is therapeutic lifestyle change, which includes nutrition and dietary recommendations. Statins are the primary drug class recommended for treatment of increased cholesterol values. In adults, KDIGO guidelines clearly recommend using statin therapy for CKD for patients with elevated cholesterol or at high risk for a coronary event. The data on use of statins in children are primarily extrapolated from adults, although few studies in children have shown good safety profiles with short-term use. As a result, the KDIGO guidelines recommend not initiating statins in children with dyslipidemia. Similarly, the lack of long-term safety data precludes recommending pharmacologic therapy for treatment of hypertriglyceridemia in children. However, both of these recommendations from KDIGO are weak guidelines that have been formulated because of lack of long-term safety data.

Metabolic Acidosis and Electrolyte Imbalance

Numerous electrolyte derangements may be seen in children with CKD. Metabolic acidosis in renal failure may occur as a result of primary renal tubular damage, in which case a normal serum anion gap will be present, or as a result of increasing uremia when retention of phosphate or sulfate as acids may lead to an increased anion gap metabolic acidosis. The cardinal feature of metabolic acidosis is a reduction of bicarbonate on blood gases or carbon dioxide on serum electrolytes measurement. Treatment consists primarily of supplemental bicarbonate or citrate solutions. Treatment of metabolic acidosis in children is particularly important for ensuring growth and bone health.

Hyponatremia may occur as a reflection of urinary sodium wasting, which is common with congenital high urine output causes of CKD associated with CAKUT; treatment may require salt supplementation. Caution must be exercised to ensure that the child is not volume overloaded with dilutional hyponatremia. Hyperkalemia frequently results from impaired potassium excretion and may be aggravated by metabolic acidosis. Treatment may require potassium restriction in the diet. Chronic treatment with potassium-binding resins also may be required (eg, Kayexalate or calcium resonium). In association with disorders causing CKD as a result of proximal tubular defects (Fanconi syndrome), hypophosphatemia may be noted and may require supplemental phosphate. However, for most children with CKD, phosphate retention is more common and should be treated with a low-phosphorus diet and phosphate binders.

PROGRESSION

The natural course of CKD is that after the initial inciting event or injury, gradual deterioration of kidney function occurs. This decline does not occur in a linear fashion. The initial decline is somewhat slow, whereas later stages of CKD are associated with more persistent decline with rapid progression near stage 5 CKD. A number of important risk factors for progression have been identified, including the following: (1) the underlying disease, such that glomerular causes of CKD are associated with greater risk of progression; (2) genetic predisposition, such as the APOL1 allele, which is associated with greater risk of progression; (3) the severity at the time of diagnosis, as reflected by presenting GFR; (4) the degree of baseline proteinuria both in glomerular and in nonglomerular causes of CKD, with a graded increase in risk for progression that starts even with a less severe degree of proteinuria (urine protein/creatinine ratio 0.5–1 mg/mg); (5) growth, as the Italikid study has shown worsening of renal function with the pubertal growth spurt; (6) episodes of acute kidney injury, which accelerate the progression of CKD; (7) urinary tract infections (although the development of an occasional infection in children with obstructive uropathy or reflux nephropathy will not influence progression of end-stage renal disease, more frequent infections may be associated with an increased rate of deterioration in renal function); (8) hypertension (the ESCAPE study, which randomized children with CKD to either control to 50th percentile or traditional 90th percentile, showed that strict control of blood pressure resulted in slower decline of renal function); and (9) other factors, such as uric acid and bone mineral metabolism factors such as FGF23, serum phosphorus, and PTH. Although these are intriguing abnormalities that have been associated with CKD progression, most of these abnormalities also occur as a result of CKD. So it is difficult to determine the precise individual contribution and effect of these factors on CKD progression.

PREVENTING PROGRESSION

Dietary Protein Intake

In adults, a reduced-protein diet may reduce proteinuria and slow the decline of kidney function. This finding has been corroborated in studies of rats following subtotal nephrectomy. A 2-year prospective study randomized children to receive a restricted protein diet (125% of World Health Organization [WHO]–recommended protein intake) or a controlled diet (181% of WHO-recommended protein intake). The lower protein intake did not provide any benefit as measured by the rate of decline in creatinine clearance over a 2-year period, and growth occurred independent of protein intake. In addition, concern exists about implementation of a low-protein diet in children, for whom growth is essential. Therefore, it is not recommended to restrict protein intake in pediatric patients with CKD unless evaluation of an individual’s diet or laboratory values suggests that their protein intake is clearly excessive.

Hypertension Control

Strict blood pressure control is the only intervention that has been shown to decrease progression of CKD in children. The ESCAPE trial conducted in children showed that control of blood pressure to a target of the 50th percentile by ambulatory blood pressure monitoring was associated with a 35% risk reduction in progression. Based on this finding, KDIGO guidelines suggest that the target blood pressure for children should be 50th percentile for age, gender, and height, particularly in children with proteinuria. However, the caveat is that the ESCAPE trial used ambulatory blood pressure monitoring assessment of blood pressure, whereas KDIGO guidelines do not specify the method for measuring blood pressure. Since the ESCAPE trial used an angiotensin-converting enzyme inhibitor (ACE-I) in both arms and with the added benefit of antiproteinuric effect, agents such as ACE-Is or angiotensin receptor blockers are to be used as preferred agents in children with CKD and hypertension. Side effects from these medications in children with CKD include hyperkalemia and hypotension, particularly during volume depletion. Therefore, electrolytes should be monitored within a week of starting treatment, and extra attention should be paid during times of volume depletion such as diarrhea or vomiting. Teenage girls who are sexually active should also be advised to practice contraception or to notify their doctor in the event of a suspected pregnancy because these agents are associated with fetopathy. Calcium channel blockers also are widely used for blood pressure control in children, but the most commonly used dihydropyridine group of calcium channel blockers, specifically amlodipine and nifedipine, do not effectively reduce proteinuria.

Nonspecific Therapies

Therapies aimed at prevention or treatment of renal bone disease and cardiovascular disease associated with CKD also may indirectly impact the rate of progression of CKD. For example, although phosphate control is important and commonly requires the use of calcium-containing phosphate binders, caution must be employed to ensure that hypercalcemia, which might produce vascular and/or renal interstitial calcification, does not result.

For children with obstructive uropathies, particularly those with incomplete control of bladder emptying or those who require intermittent catheterization, increasing hydronephrosis, which may indicate partial lower tract obstruction, should be dealt with promptly by a pediatric urologist. Similarly, for those with repeated urinary tract infections, efforts should be focused on prevention either by assuring appropriate bladder drainage or by using prophylactic antibiotics.

Finally, although malnutrition is clearly a feature that is commonly seen in children with CKD, development of obesity must also be prevented. This is particularly important for the teenage patients, in whom participation in normal social and sporting activities must be encouraged.

PREPARATION FOR RENAL REPLACEMENT THERAPY

Management of children with stage 2+ CKD must include the recognition that the majority of these children progress to end-stage renal disease. Families should be counseled regarding this eventuality and provided with appropriate emotional supports to prepare. Discussion concerning the appropriate modality of renal replacement should be started when stage 3 CKD is reached so that families are appropriately educated about the relative benefits and adverse effects of each.

Discussions with the family should include the relative merits of a period of dialysis or the possibility of preemptive transplantation prior to the need for dialysis. Such preemptive transplantation is now the preferred treatment for many children with progressive CKD, with longer graft function and reduced mortality rates observed with preemptive transplantation when compared to children who have received chronic dialysis prior to undergoing transplantation. Preemptive transplantation is relatively easily arranged for patients with a prospective matched living donor. For patients in whom a living donor is not available, preemptive transplantation should still be considered; however, in this situation, a patient must be placed on the transplant list at an appropriate time, which by definition is prior to his or her development of end-stage renal disease requiring dialysis.

For patients in whom hemodialysis is the anticipated treatment for end-stage renal disease and who have a long wait time on dialysis, consideration should be given to placement of arteriovenous fistula a few months before it is expected that end-stage renal disease will develop. For patients on peritoneal dialysis, it is preferable that the catheter be inserted approximately 2 weeks prior to its anticipated use to allow for appropriate healing of the exit site wound, thereby reducing the likelihood of future peritonitis.

SUGGESTED READINGS

INTRODUCTION

End-stage renal disease (ESRD) is characterized by kidney failure that requires either chronic dialysis or kidney transplant. According to the US Renal Data System (USRDS) 2016 Annual Report, at the end of December 2014, 9721 children were receiving care for management of ESRD; of these, 1398 children represented incident cases of ESRD. Etiologies of pediatric ESRD can be divided into 4 main categories: congenital abnormalities of the kidney and urinary tract (CAKUT), primary glomerular diseases, secondary glomerular diseases, and hereditary/cystic kidney disease (Table 474-1). The degree of renal failure is characterized along a continuum and defined by chronic kidney disease (CKD) staging. The Kidney Disease Outcomes Quality Initiative (KDOQI) provides recommendations for follow-up and management based on CKD staging.

Renal transplantation is recognized as the better form of treatment for pediatric ESRD when compared to chronic dialysis as it offers the possibility of restoring normal kidney function, eliminating morbidity associated with renal impairment, and allowing for maximal cognitive, psychomotor, and physical development. However, preemptive transplantation is not always an option, and dialytic therapy often needs to be initiated. Timing of initiation of chronic dialysis therapy typically involves integration of laboratory data, clinical parameters, and psychosocial issues. There is no defined blood urea nitrogen (BUN) or creatinine value that serves as an absolute indication for the initiation of dialysis. Dialysis should be considered in children who are CKD stage 5 (glomerular filtration rate [GFR] < 15 mL/min/1.73 m²) and should be initiated in children who have uncontrolled hypertension, volume overload, metabolic derangements (hyperkalemia, acidosis, or hyperphosphatemia), malnutrition or poor growth, or uremic symptoms despite medical therapy with appropriate medication management and dietary modifications. There are 2 main modalities available in a dialysis program for infants, children, and adolescents: peritoneal dialysis (PD) and hemodialysis (HD). Selection of the appropriate modality is individualized to the needs of each patient and family. Patient size, age, lifestyle choices, parental preferences, and psychosocial assessments all play key roles in evaluating the choice of modality for chronic renal replacement therapy. Hence, the need for dialysis care should be anticipated as CKD progresses to allow for proper education of the patient and family, selection of modality, and planning for access.

PERITONEAL DIALYSIS

PD is the preferred modality for smaller patients and infants with ESRD. It is the most common initial modality for children younger than 9 years of age and weighing less than 20 kg, as the treatment is provided without an extracorporeal blood circuit or need for large-bore venous access. For school-age children, it offers the advantage of greater flexibility in the timing of treatment, allowing for less frequent interruptions in school schedules. It can be successfully performed in patients with cutaneous ureterostomies, vescicostomies, prune belly syndrome, posterior urethral valves, and polycystic kidney diseases. There are, however, several absolute contraindications to PD, which include extensive peritoneal adhesions that obstruct the flow of dialysate, mechanical defects (eg, omphalocele, gastroschisis, diaphragmatic hernia, bladder exstrophy), peritoneal-membrane failure, and psychosocial issues such as the lack of a care provider. Relative contraindications to PD include the presence of ventricular peritoneal shunts, peritoneal leaks, body size (severe malnutrition or obesity), and inflammatory or ischemic bowel disease. As a home-based therapy, PD requires a structured program to prepare the caregivers with an adequate knowledge base to understand and participate in PD care while providing support to reduce anxiety and stress associated with providing a life-sustaining therapy at home.

PD is performed via a process of repeated instillation and drainage of dialysate into, and out of, the peritoneal space through a PD catheter. It is implemented without an extracorporeal blood circuit and works via a complex physiology based on the capillary permeability of the peritoneal membrane lining the surface of the abdominal wall reflecting over the visceral organs. The dialysate solutions contain electrolytes additives, except for potassium and phosphorus, in physiologic concentrations to facilitate correction of electrolyte abnormalities and acid–base abnormalities. The dialysate solutions have different glucose contents ranging from 1.5% to 4.25%. This glucose concentration creates an osmotic gradient that facilitates net movement of water into the peritoneal cavity, which is referred to as ultrafiltration. In PD, solute clearance occurs via a process of diffusion, whereby solutes move from a compartment of higher concentration to a compartment of lower concentration across the peritoneal membrane, and by convection, whereby solutes move via solvent drag with the movement of fluid between the blood and dialysate compartments. As fluid is also reabsorbed by the lymphatic system, the net fluid removal achieved by PD is a reflection of differences between ultrafiltration and lymphatic resorption.

The PD catheter is made of a silicone rubber or polyurethane and is either straight or curled in configuration, with 1 or 2 Dacron cuffs to prevent dislocation, fluid leak, and bacterial migration. It is placed surgically with the intra-abdominal portion positioned in the pelvis slightly lateral to midline and tunneling of the catheter up through the skin to form the exit site (Fig. 474-1). One cuff is placed between the anterior and posterior fascia of the rectus sheath and the other 1.5 to 2 cm from the exit site to prevent cuff extrusion and infection. The exit site is positioned away from vesicostomies, gastrostomies, and ureterostomies in a lateral or down-facing orientation in order to reduce risk of development of infection. Ideally, use of the PD catheter is delayed for 2 weeks to allow for healing.

PD usually is performed daily and thus achieves more steady biochemical and blood pressure control with fewer dietary and fluid restrictions than occur with HD. PD is delivered continuously either manually (continuous ambulatory PD [CAPD]) or with an automated machine via continuous cycling PD (CCPD). CAPD is performed as 3 to 4 exchanges during the day and 1 longer exchange overnight. In comparison, CCPD usually is performed nightly by the patient or caregiver as 5 to 10 exchanges over a 10- to 12-hour period overnight with a long dwell during the day. This technique is performed for the majority of pediatric patients in the Unites States. The PD prescription subsequently is tailored to the child’s age, body size, metabolic control, peritoneal membrane transporter characteristics, and residual renal function to achieve goals as outline by the evidence-based clinical practice guidelines defined by KDOQI.

COMPLICATIONS OF PERITONEAL DIALYSIS

The most common complications of PD are infection-related: peritonitis and catheter-related exit-site or tunnel infections. Peritonitis occurs more frequently in younger children. A diagnosis of peritonitis needs to be considered in the setting of abdominal pain and cloudy PD effluent. The diagnosis is based on an effluent white blood cell count > 100/μL with at least 50% neutrophils. Gram-positive peritonitis, followed by culture-negative and then gram-negative peritonitis, are the more common causes of peritonitis. Fungal peritonitis occurs infrequently but is difficult to treat and often requires catheter removal. Peritonitis is a cause of significant morbidity and hospitalizations which can lead to the development of intra-abdominal adhesions and, ultimately, peritoneal membrane failure. PD catheter exit-site and tunnel infections are important risk factors for peritonitis and can require removal of the catheter if persistent or recurrent. Hence, regular monitoring of the exit site and prompt diagnosis of infection are important aspects of PD care. The diagnosis of a catheter exit-site or tunnel infection is made by the presence of purulent drainage, pericatheter swelling, redness, and/or tenderness. Routine care of the exit site followed by application of topical antibiotics (mupirocin or gentamicin) to the exit site reduces the incidence of exit-site infections and peritonitis.

Some of the noninfectious complications of PD include the development of dialysate leak, abdominal hernias, hydrothorax, and hemoperitoneum. Dialysate leaks more often occur in the postoperative period following placement of the catheter, with early manipulation of the catheter. Immobilizing the catheter after placement with healing for at least 2 weeks prior to use allows the exit site to seal and is critical to obtaining a functional catheter. Leakage that occurs later, after the PD catheter maturation, occurs in the abdominal wall and often is due to anatomical defects. The incidence of abdominal hernias is higher in young children and is inversely related to age. Hernias can be incisional, at the site of catheter placement, or midline, umbilical, or inguinal in origin. Inguinal hernias are more common in boys and are frequently bilateral in newborns because 80% to 90% have a patent processus vaginalis, which in the setting of PD can progress to a hernia. Hernias can interfere with ability to perform adequate PD by limiting exchange volume due to increasing hernia size. Because untreated hernias increase risk for bowel entrapment and/or strangulation, evaluation for the presence of hernias with placement of a PD catheter is now considered standard of care. Hydrothorax (Fig. 474-2) is a leakage of dialysate into the pleural space and occurs in approximately 3% of children on PD. Pleural effusions usually are unilateral and occur more commonly on the right side. A hydrothorax can develop after initiating PD, several months after initiation, or after surgery; the diagnosis is confirmed with an elevated pleural fluid-to-serum glucose concentration gradient of > 50 mg/dL. Management involves stopping PD temporarily; however, if fluid accumulation recurs, it may force transition to HD. Hemoperitoneum is observed primarily in adolescent females, usually 2 to 3 days prior to onset of menses or midcycle at time of ovulation. Hemoperitoneum can also be seen in the setting of abdominal or catheter trauma or, more rarely, in the setting of pancreatitis. Frequently, it can be managed conservatively with observation and instillation of intraperitoneal heparin to prevent obstruction of the catheter.

HEMODIALYSIS

HD is the predominant initial dialysis modality in children older than age 10 years. According to the USRDS 2016 Annual Report, approximately 50% of incident pediatric ESRD patients initiate HD once renal replacement therapy is needed, and 18% of prevalent children with ESRD are maintained on HD. According to data from the North American Pediatric Renal Trials and Collaborative Studies (NAPRTCS), it is not uncommon for children on PD to transition to HD as a result of recurrent infections, peritoneal membrane failure, family choice, or dialysis-access failure. The rationale for selection of HD as an initial modality includes psychosocial concerns, patient/family freedom from dialysis treatment responsibility, and overall shorter treatment times. Capability to provide HD is dependent on ability to place and maintain vascular access. In younger children, HD is more challenging due to the patient’s size, high rates of vascular-access failure, and need for expertise in pediatric dialysis.

HD mimics the function of the normal kidney by removing the waste products, solutes, and excess fluid via diffusion, convection, and ultrafiltration. Diffusion refers to the transmembrane solute movement across a semipermeable membrane in response to a concentration gradient. Convection, on the other hand, is transmembrane solute movement in association with plasma water and is determined by the ultrafiltration rate and membrane pore sizes. Ultrafiltration describes the movement of water across the membrane by convective flow down a pressure or osmotic gradient. In HD, there are 2 separate circuits, the blood circuit and the dialysate circuit, which run in opposite directions. The dialyzer provides the interface between the 2 circuits. The dialyzer has a hollow fiber configuration, which increases its surface area. During HD, the blood leaves the patient through the blood lines, passes through a dialyzer in an extracorporeal circuit as dialysate fluid runs countercurrent, and returns to the patient. The countercurrent flow maintains the gradient between the 2 compartments, thereby facilitating diffusion-based clearance. The clearance of different solutes is determined by the specific properties of dialyzer and the solute sizes. Fluid removal is regulated by the pressure gradient across the membrane (transmembrane pressure) and the permeability of the membrane to water (ultrafiltration coefficient of the dialyzer). Dialyzer selection is based on dialyzer properties and patient size. The dialysate fluid contains electrolytes in physiologic concentrations to normalize electrolyte and acid–base abnormalities. Potassium content is adjusted based on serum potassium concentrations. Bicarbonate is used as a buffer.

Pediatric dialysis programs in the United States offer conventional HD typically 3 times per week for 3 to 4 hours. A few centers in the United States offer more frequent HD, either as 4 days per week or as home HD 5 to 6 times per week for 2 to 3 hours. More intensified regimens with increases in session length and/or frequency have been developed in pediatric dialysis centers in Canada, France, the United Kingdom, and Germany. An intensified dialysis regimen can be delivered as an overnight treatment ranging from 6 to 8 hours, 3 to 7 times per week, or as shorter more frequent HD for 2 to 3 hours, 5 to 7 times per week, in a center or at home. Conventional HD can easily provide adequate dialysis as defined by KDOQI guidelines; however, there is increasing evidence that a more intensified regimen results in better blood pressure and phosphate control with decreased medication burden and improved appetite and growth.

Vascular access is the backbone of HD. For children with ESRD, focus should be on vein preservation. Good vascular access is needed to accommodate the necessary blood flow to provide adequate clearance during the HD treatment. There are several options for HD access. Arteriovenous fistulas (AVFs) are considered the best option even in pediatric patients. AVFs have superior access survival rates with less rates of infection compared to catheters. KDOQI guidelines recommend creation of AVF in children greater than 20 kg for whom transplant is not imminent. AVFs are created surgically by anastomosis of an artery to a vein. They can be created at the wrist using the radial artery and cephalic vein or radial artery and basilic vein, or at the elbow using the brachial artery and cephalic vein or brachial artery and basilic vein. Ideally AVF should be created at least 6 weeks prior to the expected need for dialysis in order to allow time for maturation of the fistula and to avoid the need for urgent catheter placement. Prior to AVF creation, vein mapping is recommended to identify acceptable access sites and areas of venous occlusion, stenosis, or outflow obstruction. However, AVFs are not always possible. In younger children, children in whom transplant is anticipated within 1 year, or children with poor anatomy for an AVF, a catheter may be necessary. Catheters should be placed in the internal jugular vein with the distal tip in the proximal atrium (Fig. 474-3). Placement in the subclavian vein should be avoided due to risk of developing subclavian stenosis, which could preclude placement of an AVF in the future. Arteriovenous grafts (AVGs) are another option for vascular access. AVGs may be an option for children who have poor anatomy for an AVF. With an AVG, an artificial conduit using a synthetic material is looped between the artery and vein. AVGs are used less frequently in children and are at higher risk than AVFs for infection due to the presence of synthetic material.

COMPLICATIONS OF HEMODIALYSIS

Access-related complications are associated with significant morbidity for children maintained on HD. Access dysfunction occurs in children with AVFs, AVGs, or catheters. Venous stenosis occurs not infrequently. Severe venous stenosis in children with an AVF or AVG is associated with increased risk for thrombosis. Monitoring with noninvasive ultrasound dilution flow can identify stenosis early, allowing for timely intervention with angioplasty or surgical revision. Catheter dysfunction can be due to thrombosis or a fibrin sheath. Thrombosis can be treated with thrombin plasminogen activator, but persistent dysfunction may require catheter replacement.

HD catheter infections may develop at the exit site, along the subcutaneous catheter, or in the catheter. Line sepsis typically presents with fever and/or chills while on HD. The presence of an exit site or tunnel infection increases the risk of catheter-associated sepsis. If signs of infection develop, the site should be cultured and broad-spectrum antibiotics initiated while awaiting culture results. If an exit site or tunnel infection is not improving, there are recurrent positive blood cultures, or septic shock occurs despite appropriate antibiotics, catheter removal may be needed with line replacement in 24 to 48 hours if possible. Infection rates are significantly lower in AVFs. If there is persistent bacteremia in a patient with an AVG, surgical revision may be required due to a nidus of infection within the synthetic component of the AVG.

The most common complication of HD is hypotension. Intradialytic hypotension is usually multifactorial in etiology, associated with fluid shifts from the extracellular to intracellular space, impaired sympathetic activity, and vasodilation in response to warmed dialysate. Hypotension can also be associated with excessive ultrafiltration requirements due to high interdialytic fluid gains. During hypotensive episodes, children can experience nausea, vomiting, cramping, dizziness, and headaches. There is also increasing evidence that children experience HD-associated reversible myocardial dysfunction or myocardial stunning in the setting of intradialytic blood pressure changes. Frequent reassessment of fluid goals, use of noninvasive monitoring of hematocrit changes, ultrafiltration modeling, and frequent reevaluation of dry weight help guide ultrafiltration goals, decrease symptoms of hypovolemia, and improve blood pressure profiles. If persistent hypotension prohibits ultrafiltration, an adrenergic agonist such as midodrine and dialysate cooling may be necessary in order to meet treatment ultrafiltration goals.

PEDIATRIC ESRD INTERDISCIPLINARY TEAM

Irrespective of the dialysis modality used, ESRD care requires an interdisciplinary team approach, which includes participation of not only the pediatric nephrologists but also the dialysis nurses, dietitian, social worker, child life specialist, school teachers, child psychologist, other subspecialty services (pediatric surgeons, vascular surgeons, interventional radiologists, and urologists), and family. The dietitian, for example, assists with manipulation of different formulas and nutritional supplements to enhance caloric density and protein content while balancing nutritional requirements with volume restrictions to promote growth. The social worker provides knowledge of available local, regional, state, and national resources and helps to assess the impact of ESRD on the family unit. Children with ESRD have lower health-related quality of life scores compared to healthy children; these scores are associated with frequent hospitalizations, procedures, and medical visits; school absences; disruption to home life; and restrictions on activities. The quality of life team, in conjunction with the child life specialist, school teachers, psychologist, and social worker, helps with this adjustment and assists with the development of coping strategies to address the stressors associated with need for renal replacement therapy. Together, each participant of the interdisciplinary team helps to address specific areas of care required to promote growth and development, provides psychosocial support, and addresses health-related quality of life with the goal to successfully nurture the child with ESRD and bridge the child to renal transplantation.

KIDNEY TRANSPLANTATION

Because all renal allografts eventually lose function, transplantation must be considered a treatment and not a cure for ESRD. By providing good renal function, a transplant not only improves physical and cognitive development in the affected child but also enhances the quality of life experienced by children and families dealing with pediatric ESRD. In comparison to renal replacement therapy with chronic dialysis, transplantation also increases life expectancy by decades and is a more cost-effective therapy. As such, the optimal treatment for the vast majority of children with ESRD is transplantation.

EPIDEMIOLOGY AND OUTCOMES

Because pediatric ESRD is rare, transplantation involving a child accounts for fewer than 5% of the kidney transplants done in the United States, averaging approximately 800 procedures annually. During the last several decades, just over a third of transplants in children have come from living donors, with parents serving as the most frequent source.

Outcomes have shown consistent improvement in long-term graft survival, with these better statistics arising as a result of disparate advances including more centers acquiring longitudinal experience with pediatric transplantation, a better understanding of technical surgical issues with renal transplantation in small children, enhanced approaches to prophylaxis or treating transplant-associated infections, and a better understanding of the pharmacokinetics of immunosuppressant medications in pediatric patients.

As a result, children younger than 10 years of age, who once represented the group with the worst long-term renal allograft survival, now hold the best allograft outcomes across all ages. With current approaches to pediatric kidney transplant across all pediatric patients with ESRD in North America, 50% of deceased donor transplants are still functioning after 12.5 years and 50% of living donor kidney transplants are still functioning approaching 20 years after transplant.

Only 20% of pediatric kidney transplantations are done in children 5 years of age or younger, and expertise in transplantation for very small children is more limited than in older and larger children. In preadolescent children who require transplantation, congenital anomalies of the kidneys and urinary tract such as dysplasia, hypoplasia, and urologic anomalies are the most common ESRD etiologies. By adolescence, an increasing number of transplanted children have reached ESRD because of acquired kidney disease such as focal segmental glomerulosclerosis (FSGS). Among African-American children, FSGS represents the most frequent reason for ESRD (Table 474-2).

CONTRAINDICATIONS TO TRANSPLANTATION

Almost all children with ESRD will be considered transplant candidates. There are relatively few absolute contraindications, but they include active malignancy or uncontrolled infection. Data from children with Wilms tumor suggest that those treated can undergo successful transplantation after being in remission and off treatment for 2 years, and, as a result, most pediatric transplant centers will wait 1 to 2 years before transplanting children who have overcome other malignancies.

Neurodevelopmental disability may be considered in the broad discussion of factors that may have an impact on a child’s candidacy for receiving a transplant, but there is general consensus in the transplant community that cognitive impairment or intellectual disability should not be a factor that automatically excludes transplant candidacy. In fact, data from the United Network for Organ Sharing (UNOS) show that approximately 15% of recent first renal transplantations in the United States have been performed in children with intellectual disabilities.

FACTORS DELAYING TRANSPLANTATION

Some temporary conditions may delay transplantation once ESRD has been reached. In infants, there is a significantly increased risk of graft thrombosis if small kidneys are transplanted, and babies generally need to grow to a weight between 6.5 and 10 kg and a length exceeding 65 cm before centers with expertise transplanting infants will go forward. Children of any age may have associated congenital anomalies that need to be medically or surgically addressed to optimize transplant outcomes as well, especially as it pertains to the need for urinary tract repair or reconstruction in children with urologic etiologies of ESRD. Proceeding to transplantation without such urologic repairs having been done places the allograft at risk for dysfunction related to infection or obstruction. In children with aggressive glomerulonephritis related to autoimmune or systemic immunologic factors, the renal disease generally must be quiescent without active systemic disease that could negatively impact the transplanted kidney or the posttransplant course. Finally, given chronic immunosuppression and the risk for infection after transplantation, it is crucial for transplant recipients to be adequately immunized prior to undergoing the procedure.

Certain conditions may mandate native nephrectomies prior to or at the time of transplantation to prevent posttransplant complications or potential risk to the transplanted allograft. They include transplantation in children smaller than 20 kg in whom blood flow to native kidneys may represent a vascular steal from the transplanted allograft. Children with recurrently infected native kidneys will benefit from nephrectomy to reduce the likelihood of a posttransplant episode of bacteremia or urosepsis from a pyelonephritis. Children with uncontrolled renal hypertension may need nephrectomies, given the potential for additional posttransplant hypertension related to medications such as calcineurin inhibitors. Children with urinary concentrating defects and pretransplant daily urine volumes exceeding 1 L/m² of body surface area may also benefit from a native nephrectomy to prevent the need for posttransplant daily hydration at volumes that may be problematic to maintain or that induce satiety and complicate long-term nutrition. Similarly, in children with ongoing nephrotic syndrome and heavy proteinuria despite ESRD, native nephrectomy will reduce the risk of nephrosis-related loss of proteins that place these children at higher risk for infection, thrombosis, and nutritional deficiency.

In pediatric patients who have been previously transfused or transplanted or who have received tissue allografts or in adolescents who have previously been pregnant, there is the additional risk of immune sensitization to human leukocyte antigen (HLA) or non-HLA antigens that mediates an immune response by the recipient against an allograft. This sensitization reduces the potential to find a compatible kidney transplant and may require desensitization to proceed to transplantation. The desensitization process generally involves combination therapy that may include intravenous immunoglobulin, rituximab, apheresis, and systemic immunosuppression.

LIVING DONOR TRANSPLANTS

Living donor transplantation is the preferred transplant modality. With living transplantation, there is increased likelihood of performing a preemptive transplant prior to the need for dialysis. There is also better long-term renal allograft function and survival, related in part to lower rates of delayed graft function after transplantation and fewer acute rejection episodes. Although children with ESRD are more likely to receive a living donor transplant than are adults, only approximately 35% of pediatric patients currently receive a living donor, and efforts to expand living donation remain a focus of the pediatric transplant community. Donor exchange or donor “swap” is a strategy that has also been used by some pediatric kidney transplant programs. In these programs, living donor/recipient pairs who have been found to be incompatible with each other are matched with other incompatible pairs to find new pairs who may then be compatible.

The precept underlying living donation is that the donor cannot be put at any physical or psychological risk through the act of donation. The donor evaluation is focused on assessing the prospective donor for overall medical and emotional fitness for the process and is overseen by a donor team that is independent of the patient’s transplant team. In addition to having no chronic medical problems that may be exacerbated by surgery or the loss of renal reserve that comes with a nephrectomy, to be considered as a successful donor for a pediatric patient, the candidate must have a compatible blood type (the Rh factor is of no concern) and no immunologic contraindications based on histocompatibility testing and cross-matching. Moreover, the donor must be at least 18 years of age to be able to give legal consent and, for most pediatric transplant recipients, be no older than approximately 60 years to allow for good nephron mass in the donated kidney. Because all nephrons have an element of natural obsolescence, even the healthiest adult loses a significant number of nephrons over time, resulting in a kidney from the average donor of 60 years or more possessing fewer nephrons than a kidney from a younger adult, which places the transplanted kidney at risk for a shorter duration of effective function.

The costs of a donor evaluation and the hospitalization and immediate outpatient surgical follow-up care for donation are covered by the recipient’s insurance. Despite the widespread application of laparoscopic techniques to perform the donor nephrectomy, the donor’s surgical procedure is more complex than is the recipient’s and often results in a more uncomfortable recovery. Most donors require at least a month of recovery prior to returning to work, with some individuals who perform more physically challenging employment requiring even longer periods of recovery. In the United States, a small number of employers, most notably certain government and military agencies and some healthcare facilities, provide paid leave for organ donation, but to date, there is no widespread mandated paid leave, and many donors face financial constraints to become a donor. Following donation, it is recommended that donors have ready access to medical care for acute problems and that they seek ongoing maintenance and preventative care to be monitored for the evolution of any unexpected renal sequelae of their organ donation such as proteinuria, hypertension, or progressive loss of GFR.

DECEASED DONOR TRANSPLANTS

If there is no living donor, then most children requiring kidney transplant will get listed for a deceased donor kidney. With deceased donor transplants in children, there is generally less HLA matching than seen with living donation in children. Although improved immunosuppression renders such matching less important than at one point in time, more matched allografts do tend to function longer. Nonetheless, the benefits of receiving a functioning renal allograft regardless of matching far outweigh the health disadvantages of remaining on dialysis awaiting a better-matched allograft.

Given the effect that transplantation has on improving growth, development, and quality of life in pediatric patients with ESRD, deceased donor kidney allocation schemes have been constructed to give advantage to those listed prior to 18 years of age so that they receive a kidney sooner than the average adult listed for a transplant. Children on the list are also preferentially allotted kidneys from younger donors to minimize the effects of natural nephron obsolescence with aging.

TRANSPLANT SURGERY

The actual surgical procedure varies depending on the size of the recipient. For most younger and smaller children weighing less than 20 kg, a midline transperitoneal approach is considered, with the allograft placed intra-abdominally and anastomosed to the aorta and the inferior vena cava. For children weighing more than 20 kg, a retroperitoneal approach is used with the allograft placed in the iliac fossa and vascular anastomoses to the common or external iliac vessels.

During the surgical procedure, there is ongoing attention given to the child’s effective volume and adequacy of perfusion of the kidney once transplanted. Ischemic injury to the transplant can occur after the kidney is removed from the donor and placed on ice prior to its placement in the donor. This so-called “cold ischemia” is generally more of a concern with deceased donor kidneys and places the donated graft at risk for acute kidney injury immediately after transplant, but cold ischemia times up to a day are used by many pediatric kidney transplant programs to allow for placement of deceased donor organs over large distances. Warm ischemia time refers to the period the organ is at body temperature but not being adequately perfused. It is largely a factor of the length of time it required for the kidney to be placed and vessels re-anastomosed into the recipient after the kidney is removed from the ice.

During the transplant surgery, the ureter from the transplanted kidney is implanted into the recipient’s bladder. An anti-refluxing anastomosis is optimal because it will prevent vesicoureteral reflux into the renal transplant and reduce the risk of infection from urinary stasis. Some transplant programs routinely leave a ureteral stent in place for several weeks to prevent any ureteral obstruction while the anastomosis heals.

IMMEDIATE TRANSPLANT OUTCOMES

Immediate outcomes after transplantation tend to be good in most children. With advances in histocompatibility testing and cross-matching, hyperacute antibody-mediated rejection rarely is encountered. Primary graft dysfunction with ongoing absence of any renal function whatsoever for other reasons occurs in fewer than 3% of pediatric kidney transplants. Although varying degrees of acute kidney injury are seen frequently, actual delayed graft function requiring dialysis while awaiting better allograft function occurs in only 5% of pediatric living donor and 15% of pediatric deceased donor kidney transplants. Such delayed graft function is a risk factor for poorer long-term transplant function.

IMMUNOSUPPRESSION STRATEGIES

Most transplanted children require some degree of initial and ongoing immunosuppression to allow long-term function of the allograft (Table 474-3). During the last 3 decades, approaches to immunosuppression in children receiving kidney transplants have evolved with the introduction of new immunosuppressive agents and a focus on trying to reduce overall immunosuppression burden but maintain highly efficacious results. Many pediatric transplant programs now use induction therapy just prior to the transplantation with an agent such as thymoglobulin, alemtuzumab, or basiliximab that depletes lymphocytes or reduces their ability to activate, replicate, or recruit other immune cells. The rationale behind induction therapy is to provide intense initial immunosuppression to minimize the likelihood for early acute rejection of the transplant. After induction, most children are then maintained on chronic immunosuppression with a calcineurin inhibitor such as tacrolimus and an antiproliferative agent such as mycophenolate mofetil. Although many children receive oral steroids as the third leg of chronic immunosuppression, there is increasing adoption of steroid-free regimens with good graft survival outcomes in children considered at lower immunologic risk for rejection. There is also pediatric experience with the mammalian target of rapamycin (mTOR) inhibitor sirolimus as a way to provide effective immunosuppression while reducing exposure to calcineurin inhibitors given their nephrotoxicity. Some pediatric programs transition from a calcineurin inhibitor to sirolimus within a few months after transplantation, whereas others will use it once there is concern for calcineurin nephrotoxicity.

COMPLICATIONS OF IMMUNOSUPPRESSION

With chronic immunosuppression comes concern for infection, especially in the initial 6 to 12 months after the procedure, when immunosuppression may be more intense. This is particularly true in younger children who may not yet have acquired native immunity to certain opportunistic viral infections such as cytomegalovirus (CMV), Ebstein-Barr virus (EBV), or the BK polyomavirus and who then encounter these viruses through direct infection from the transplanted organ or from exposure in the community. Most transplant programs will prescribe some period of valganciclovir prophylaxis to reduce the risk of acquiring CMV disease, especially in patients who have negative CMV serologies going into transplant and receive a kidney from a CMV-positive donor. Trimethoprim-sulfamethoxazole or atovaquone often is used for prophylaxis against Pneumocystis carinii pneumonia during the first year. In many transplant programs, there is often interval laboratory surveillance for evidence of viral infection with CMV, EBV, or BK virus using polymerase chain reaction (PCR). Infection is often considered an indication of excess ongoing immunosuppression in the transplanted patient, and maintenance immunosuppressive medications may be reduced to allow for a native immune response to be mounted, although a concern is reducing the immunosuppression excessively and putting the allograft at risk of rejection.

Another consequence of immunosuppression is a predisposition to the development of posttransplant lymphoproliferative disorder (PTLD). PTLD often is suspected in transplanted children who manifest tonsillar enlargement, lymphadenopathy, or hepatosplenomegaly or who have unexplained persistent fever or the onset of constitutional symptoms such as weight loss. Histologically, PTLD can range from reactive plasmacytic hyperplasia to polymorphic disease of either monoclonal or polyclonal etiology to monomorphic disease that is generally of B-cell origin. In children, a large number of cases are associated with EBV infection, and the increased likelihood for a transplanted child to be immunologically EBV naïve versus a transplanted adult accounts for the increased concern for EBV infection in transplanted children. Depending on its underlying histology, ‘cell markers’ and whether there is an association with an EBV infection, PTLD can be treated by a variety of approaches including reduction in immunosuppression alone, use of the anti–B-cell antibody rituximab, or the use of chemotherapy regimens similar to those employed with aggressive lymphomas. The development of PTLD does increase the likelihood for early graft loss.

Over time, chronic immunosuppression also increases risk of development of non-PTLD malignancy in transplanted children versus the general pediatric population by nearly 7-fold. Renal cell carcinoma, thyroid carcinoma, and skin malignancies such as melanoma are the most frequent cancers seen in children enrolled in the NAPRTCS transplant registry.

TRANSPLANT REJECTION

With advances in immunosuppression and increased familiarity with its provision in pediatric transplant recipients, rates of acute rejection episodes have fallen. Recent data suggest that the risk for acute rejection is less than 10% in the first year following a living donor kidney transplant and about 15% in a deceased donor transplant, with acute rejection rates falling subsequently over the life of a renal allograft. A rejection episode does tend to reduce long-term graft function, although the overwhelming majority of acute rejection episodes can be acutely reversed by intensification of immunosuppression. Steroids remain the mainstay of antirejection therapy, especially when cellular rejection is diagnosed.

Non-hyperacute antibody-mediated rejection is increasingly being recognized as a cause of allograft dysfunction. There is ongoing focus on the role of donor-specific antibody (DSA) mediating such rejection, especially given that contemporary approaches to cross-matching and histocompatibility testing generally detect problematic antibody that would have existed before transplantation. Optimal strategies as to monitoring for DSA and then reacting to its detection remain unclear in children. Similarly, there is a lack of clarity as to the best treatment for antibody-mediated rejection in children, with most approaches now using a combination of therapies including enhanced immunosuppression, intravenous immunoglobulin G, rituximab, and apheresis.

RECURRENT DISEASE IN THE TRANSPLANTED KIDNEY

Depending on the original etiology of the transplanted child’s ESRD, recurrent disease may complicate the posttransplant course. Historically, this has most frequently been encountered in children with FSGS, atypical hemolytic-uremic syndrome (aHUS), membranoproliferative glomerulonephritis (MPGN), and primary hyperoxaluria (PH). With the advent of eculizumab therapy to block the terminal complement cascade, many cases of recurrent aHUS can be prevented or successfully reversed. With the increased use of liver-kidney transplant in children with PH unresponsive to pyridoxine therapy, the concern for recurrent PH affecting a renal allograft has fallen as well. Recurrent FSGS remains very problematic, however, occurring in as many as 50% of children initially transplanted and upward of 80% of children with prior graft recurrence who are transplanted again. Techniques to reverse recurrence have focused on immunosuppression intensification and apheresis, and although many cases of recurrence are reversed, the renal allograft injury that ensues does place that graft at risk for earlier functional impairment over time. In fact, the usual allograft survival advantage seen with living donation is lost in children with FSGS who suffer a recurrence, with their long-term allograft outcomes similar to those of deceased donor kidneys.

CHRONIC ALLOGRAFT NEPHROPATHY

Eventually, all transplants lose substantial function as result of a process labeled chronic allograft nephropathy. On histologic review, these kidneys demonstrate significant interstitial fibrosis and tubular atrophy of the renal parenchyma with associated glomerulosclerosis. Both immunologic and nonimmune factors are thought to play roles in the development of these chronic changes, and advances in the prevention and management of pertinent factors such as acute cellular and antibody-mediated rejection, recurrent disease, nephrotoxin exposure, and posttransplant infection may allow for successful strategies to stave off these changes and preserve allograft function longer.

For the pediatric patient with ESRD, the advantages of having a functioning kidney transplant throughout childhood and adolescence lie with optimizing normal growth and development, enhancing educational and vocational training opportunities, and maximizing psychosocial health. Hence, increasing transplantation in children with ESRD, minimizing transplant-related medical complications, and improving long-term allograft outcomes remain overarching goals of the pediatric nephrology community and drive most of the research that is ongoing focused on pediatric ESRD.

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INTRODUCTION

Systemic hypertension occurs in approximately 3% to 4% of the pediatric population, and there is ample evidence that the roots of adult primary hypertension extend back to childhood. In young children, hypertension is often secondary to an underlying renal or cardiac disease, but with the rise in childhood obesity, primary hypertension is now recognized as the most frequent cause of hypertension in adolescents. Perhaps more concerning, blood pressure (BP) problems among children seem to be more common in recent cohorts than among historical populations. Management of systemic hypertension in the pediatric population begins with correct BP measurement using a standardized technique, categorization of BP using current normative standards, appropriate evaluation of the etiology of the hypertension, assessment of end-organ damage, and control of BP using both nonpharmacologic and pharmacologic means as appropriate.

EPIDEMIOLOGY

Although the prevalence of hypertension in children (3–4%) is much lower than in adults, recent data suggest that BP has risen among children and adolescents over recent decades. Much of the increase is thought to be attributable to an increase in weight in the pediatric population. Longitudinal studies begun in the 1970s in Muscatine, Iowa, and Bogalusa, Louisiana, established a relationship between body size and BP. Although height relates strongly to BP, weight remains a major determinant of BP even after adjustment for height. BP increases with age throughout childhood. Beginning with puberty, it is greater in boys than in girls. Ethnic differences in BP have also been described in some studies.

Longitudinal studies have established that the pattern of BP tracks over time. Systolic BP levels track from childhood better than diastolic BP levels. In the Bogalusa study, 40% of those with systolic BP and 37% of those with diastolic BP in the upper 20% in childhood continued to have BP above the 80th percentile 15 years later. Children in Muscatine, Iowa, with systolic BP levels above the 90th percentile for age and gender were at 2.5 times the risk for high adult BP than children with levels at the 50th percentile. Initial BP levels are the most predictive measure of the follow-up level, especially when combined with change in weight. In an illustrative BP screening study, children with even just 1 day of elevated BP at screening were subsequently found 2 years later to have a much higher risk of sustained hypertension.

Obesity has risen dramatically in the United States. Among children and adolescents, rates of overweight have increased from 13.9% from 1999 to 2000 to 16% from 2003 to 2004. In a more recent study, it was projected that the increase in childhood obesity in the United States will result in a significant increase in obesity among 35-year-olds by 2020, which could then translate into a significant increase in adult coronary heart disease. Although only future investigation will reveal the true trend, it appears that the obesity epidemic in the United States may be plateauing.

Weight-related disorders such as hypertension, type II diabetes mellitus, dyslipidemia, sleep disorders, and orthopedic problems are now commonly identified in pediatric patients. National survey data show a rise in the prevalence of hypertension from 2.7% from 1988 to 1994 to 3.7% from 1999 to 2002. Prehypertension is now reported to be present in approximately 10% of children and adolescents. National surveys have relied, however, on measurements of BP on a single occasion. More recent data from school-based screening in Houston confirm an approximate 3% prevalence of hypertension after measurement on 3 occasions and report a prevalence of 4% to 5% among obese children.

MEASUREMENT OF BLOOD PRESSURE

Accurate measurement of BP is required to make any diagnosis. BP is a constantly changing parameter with many factors influencing results (mental and physical activity, random and systematic error[s] in measurement, and a diurnal pattern for BP). This variability points out the need for standardization in the BP measurement technique. Although over a dozen years old, the “Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and Adolescents” still provides the most current US guidelines regarding BP measurement techniques. Although many practices are using automated oscillometric devices, auscultation remains the recommended technique for BP assessment because current normative data were collected by this technique. The measures are not always comparable. An elevated measurement by an automated monitor using the oscillometric technique should be verified by an auscultatory measurement.

It is recommended that all children beginning at age 3 years have their BP measured with each medical encounter. Younger children also require BP measurement if they have a history of prematurity, heart or kidney disease, or other conditions that could potentially alter BP. Correct BP measurement requires an occluding cuff that is appropriate to the size of the child’s upper arm. The cuff should have an inflatable bladder width at least 40% of the mid-arm circumference and a cuff length that covers 80% to 100% of the arm circumference. At least 7 different-size cuffs are needed to appropriately fit the range of arm sizes in the pediatric population. The child needs to be cooperative with BP measurement and, if possible, not agitated or crying. Five minutes of rest are recommended prior to BP measurement; the child should be seated with both feet on the floor and the back supported. Systolic BP is noted by the onset of the “tapping” Korotkoff sounds (K1). The disappearance of the Korotkoff sounds (K5) is now used as the definition of diastolic BP. BP sounds are often more difficult to hear in infants and young children. This may require that automated (oscillometric) BP measurement devices or the Doppler technique be used to determine BP in children younger than 3 years. More recent normative BP data by oscillometry for term infants in the first 12 months of life have been published. Whenever an automated device is used, several BP measurements should be averaged to obtain a more accurate estimate.

BLOOD PRESSURE STANDARDS AND DEFINITIONS

The “Fourth Report on the Diagnosis, Evaluation, and Treatment of High Blood Pressure in Children and Adolescents” lists the most current normative BP values from ages 1 to 17 years (Figs. 475-1, 475-2, 475-3, 475-4). In addition to age and gender, height is used to define normal BP because taller children normally have higher average BP values than shorter children of the same age. A child’s height percentile, as ascertained from standard Centers for Disease Control and Prevention growth curves, along with his or her age and gender are used to determine the 90th and 95th percentile values to classify the BP into the following 3 groups:

• Normal BP is defined as a systolic and diastolic BP below the 90th percentile for age, gender, and height AND below 120/80 mm Hg.

• Prehypertension is an average systolic and/or diastolic BP between the 90th and 95th percentiles for age, gender, and height. As with adults, adolescents with BP > 120 mm Hg systolic or 80 mm Hg diastolic are considered prehypertensive.

• Hypertension is defined as an average systolic and/or diastolic BP greater than the 95th percentile for age, sex, and height across 3 separate visits. In asymptomatic children, it is recommended that elevated BP readings be documented on at least 3 occasions before labeling someone as hypertensive.

Staging of hypertension can assist in identifying children who require more immediate attention and can predict the presence of hypertensive end-organ damage. Stage 1 hypertension is defined as BP levels that range from the 95th percentile to 5 mm Hg above the 99th percentile. If asymptomatic, these patients should undergo repeat BP measurement within 1 to 2 weeks at their source of primary care to confirm sustained elevations in BP. Stage 2 hypertension, with BP levels more than 5 mm Hg above the 99th percentile, requires prompt evaluation, and if persistent, is considered to be an indication for institution of antihypertensive therapy. Incorporation of BP staging in the evaluation of the child or adolescent with high BP is essential (Table 475-1 and Fig. 475-5).

Not every child with elevated BP in the office will have truly sustained hypertension. “White coat” hypertension is the name given to children and adults who exhibit a persistently elevated BP in the clinic but who have normal BP at other times. To evaluate children for this problem and avoid incorrectly labeling them as having hypertension, it is extremely helpful to evaluate BP with out-of-office readings. Three types of “out-of-office” readings include taking BP at school, at home, or with a 24-hour ambulatory BP monitor. The advantage of each method in comparison to clinic or office readings is that it allows for multiple readings over an extended period of time. There has been little formal evaluation, however, of the accuracy of home or school BP readings in the diagnosis of hypertension in pediatrics. Attention should be paid to the equipment and training of the BP observer and circumstances surrounding the measurement. Home or school BP readings are often helpful in the day-to-day management of hypertension in children receiving antihypertensive medications to provide high and low limits for their BP on therapy.

Ambulatory BP monitoring (ABPM) uses an automated device to obtain multiple (generally ∼70) BP readings over a 24-hour period. ABPM has been shown to correlate more closely than office BP readings with measures of hypertension end-organ damage in children such as left ventricular mass or progression of chronic kidney disease. ABPM can help evaluate the child’s “usual” BP and avoid overdiagnosis due to the “white coat” effect of in-office readings. Ambulatory monitoring has proven to be an extremely useful tool for the study of BP in children and adults. ABPM is now available at many pediatric referral centers and can be helpful in evaluating selected pediatric patients. Norms are available for children with this technique, and the American Heart Association has specific guidelines regarding pediatric usage. Potential clinical uses for this technique in pediatrics would include (1) evaluation for “white coat” hypertension or to determine disparities in clinic and home BP readings; (2) to evaluate hypertension resistant to antihypertensive medication; (3) to assess for intermittent symptoms possibly related to BP; (4) to assess for masked hypertension, a condition with normal pressures in the office but uncontrolled out-of-office BP; and (5) to assess for episodic hypertension.

ETIOLOGIES OF HYPERTENSION

The etiologies of hypertension are typically classified into primary (essential with no identified cause) and secondary (where a specific cause is identified). The most common causes vary with age, as shown in Table 475-2. Coarctation of the aorta or renovascular disease may be present in over 50% of hypertensive infants younger than 1 year and is frequently diagnosed later in childhood. Renal parenchymal disease is historically the most common cause of hypertension in school-age children, whereas adolescents with high BP are most likely to have primary hypertension. One of the most pronounced recent changes in the epidemiology of childhood BP problems is the increase in primary hypertension.

Primary Hypertension

The mechanisms that result in the development of primary hypertension have been the source of extensive research and controversy. Genetic and environmental factors play a role in the development of this disorder, and primary hypertension is more common among children of hypertensive than normotensive parents. Differences have been noted even in normotensive children with a positive versus negative family history of hypertension in carotid artery stiffness, BP reactivity to mental stress, and change in BP with exercise. Twin and adoption studies have helped characterize the role of various factors on the variability of BP. Height and body mass may relate not only to genetic influence, but also to nutrition and genetic influences. High dietary sodium intake, low potassium intake, low birth weight, and serum uric acid levels may also influence risk for development of high BP. The more recent rise in obesity, however, has been the primary factor influencing the increase in this condition among adolescents.

Renovascular and Renal Parenchymal Disease

Renovascular hypertension results from narrowing of the arteries to 1 or both kidneys. This narrowing leads to relative hypoperfusion of downstream kidney tissue, resulting in activation of the renin–angiotensin system. Renovascular hypertension may be present at any age but, as shown in Table 475-2, is more common in younger children than adolescents. Causes of renovascular hypertension include fibromuscular dysplasia, inflammatory diseases such as Takayasu arteritis, and vascular malformations. In the neonatal period, thromboembolism from an umbilical artery catheter has been an important cause of hypertension, but the frequency of this complication may have decreased in more recent years with lower (below the level of the renal arteries) placement of umbilical artery catheters. Renal artery stenosis may also develop in renal transplant recipients. Williams syndrome and neurofibromatosis are 2 inherited conditions with specific predisposition to renovascular hypertension.

Renal parenchymal disorders are commonly associated with high BP. Hypertension may develop in acute conditions, such as hemolytic-uremic syndrome and acute poststreptococcal glomerulonephritis, or chronic conditions, such as polycystic kidney disease, congenital anomalies of the kidney, or tuberous sclerosis complex. The mechanism of hypertension is often volume mediated when renal function is reduced, but may be renin mediated in conditions such as reflux nephropathy. Children with glomerular forms of chronic kidney diseases (CKDs) in particular are at high risk for development of hypertension. Up to 80% of patients with stage 4 or 5 CKD (glomerular filtration rate < 30 mL/min/1.73 m²) have been reported to have hypertension in some pediatric centers.

Severe Hypertension

Acute severe hypertension occurs when the BP is significantly elevated above the normal range, usually well above BPs that would be categorized as stage 2 hypertension, and there are concurrent symptoms of hypertension. In a hypertensive emergency, the patient has end-organ injury related to very high BP (eg, encephalopathy, pulmonary edema, cerebral hemorrhage). The patient usually has symptoms associated with high BP (eg, blurred vision, headache, nausea). The BP needs to be reduced quickly to a safer level. In hypertensive urgency, the BP may be rising or elevated, but there is no evidence of end-organ involvement. The patient may have symptoms similar to those seen in a hypertensive emergency or may be asymptomatic. The BP needs to be reduced to prevent it from continuing to rise or causing later injury (ie, becoming a hypertensive emergency). Due to confusion regarding this nomenclature, some clinicians prefer the term acute severe hypertension and then comment on the presence or absence of end-organ injury. Fortunately, these conditions are relatively rare in children, and the BP elevations are almost always secondary to some underlying medical condition. These etiologies are most commonly renal (renovascular or renal parenchymal) or cardiac (coarctation of the aorta). Although primary hypertension can present at diagnosis with severe (stage 2) BP elevation, this is more likely in a known hypertensive adolescent who has stopped taking antihypertensive medication. Acute cessation of clonidine and β-blockers, in particular, has been associated with precipitation of a hypertensive crisis. Additional causes of severe hypertension may include use of illicit drugs such as cocaine and amphetamines. Rare endocrine causes such as pheochromocytoma may also cause severe hypertension.

DIAGNOSTIC EVALUATION

Although primary hypertension is becoming more common in the pediatric age range, the differential diagnosis of childhood hypertension is extensive. It is therefore important to develop some idea of likely causes before initiating diagnostic testing. Important clues in the initial stage include the age of the child, the history, and the physical findings, especially the BP values themselves.

Hypertension in infants is nearly always related to an underlying cause (see Table 475-2), which in many cases will be obvious once the history has been obtained and the physical examination completed. Secondary causes also account for much hypertension in preadolescent children, with renal disease being the most common. Primary hypertension is increasing in prevalence, even in young children, primarily due to the obesity epidemic. Therefore, the extensive evaluation once recommended for this age group may not be necessary if the child is significantly obese and if other findings such as a family history of hypertension are present. In adolescents, hypertension is almost always primary in origin, so a more limited diagnostic workup should be undertaken in most cases. Those teenagers with secondary causes usually have some clue to the presence of an underlying disorder in their history or physical examination (Table 475-3).

Except in infants, the history should begin by asking whether any symptoms suggestive of hypertension are present, such as headaches, dizziness, diplopia, vomiting, or epistaxis. The interviewer should then focus on eliciting symptoms of other underlying disorders, including symptoms of possible renal disease, heart disease, or diseases affecting other organ systems (see Table 475-3). The past medical history should include questions about recent as well as chronic illnesses, prior hospitalizations or episodes of trauma, recurrent urinary tract infections or unexplained fevers, and neonatal history. Many maternal factors have been linked to later BP. Family history of hypertension, diabetes, kidney disease, and other cardiovascular disease (hyperlipidemia, myocardial infarction at an early age) should be elicited. Finally, it is important to ask about over-the-counter, prescription, and illicit drug use because many substances can either cause or exacerbate hypertension (Table 475-4).

The first step in the physical examination is to obtain the patient’s weight and height so that growth percentiles can be plotted and body mass index (BMI) calculated. BPs should be obtained in both upper extremities in the seated position and in at least 1 arm and 1 leg in the supine position. If initial BPs are obtained using an automated oscillometric device, they should be confirmed by auscultation using an aneroid sphygmomanometer. Cuff sizes should be chosen in accordance with the recommendations of the National High Blood Pressure Education Program (NHBPEP) Task Force. Given the high prevalence of white coat hypertension reported in more recent studies, ABPM should be obtained if possible to confirm the diagnosis of hypertension. In addition to detecting white coat hypertension, ABPM has been shown to correlate with the presence of hypertensive target-organ damage and can also be used to help differentiate between primary and secondary hypertension. When used as an initial diagnostic test, ABPM may save significant time and expense of further workup.

The remainder of the physical examination should focus on uncovering signs of specific underlying disorders that may be causing the elevated BP (see Table 475-3). In obese children, there may be signs of insulin resistance such as acanthosis nigricans, or in older females, findings suggestive of polycystic ovarian syndrome such as hirsutism. The physical examination may also provide clues as to the severity/chronicity of the patient’s hypertension, such as left ventricular hypertrophy (signified by an apical heave) or hypertensive retinopathy.

Patients with confirmed hypertension should then undergo diagnostic testing to follow up on findings from the history and physical examination and to assess for other coexisting cardiovascular risk factors. As outlined in Table 475-5, it is customary to obtain a basic set of screening studies in all patients, which should also serve to screen for other coexisting conditions such as impaired glucose tolerance or dyslipidemia. The extent of further evaluation depends on the likelihood of secondary hypertension and should be tailored based on clinical assessment. Plasma renin activity and aldosterone are occasionally included in this initial set of studies, especially when the patient’s hypertension is severe or if both systolic and diastolic hypertension are present. Renin and aldosterone levels might also be obtained if there is hypokalemia on the screening electrolytes, as a suppressed renin in conjunction with hypokalemia strongly suggests a single-gene disorder such as Liddle syndrome.

A renal ultrasound examination, which should be routinely obtained in all hypertensive preadolescent patients, may be omitted in adolescents and some older preadolescent children with stage 1 hypertension if the screening studies are normal and other features of primary hypertension are present, including obesity, positive family history, and isolated systolic hypertension. Those with stage 2 hypertension, with abnormal screening studies, or with diastolic hypertension should get an ultrasound. As recommended by consensus organizations, additional imaging studies, including renal angiography, nuclear renal scans, and voiding cystourethrograms, should only be obtained as indicated based on the results of the history, physical examination, and initial diagnostic studies.

Given the high prevalence of left ventricular hypertrophy in hypertensive children, 2-dimensional and M-mode echocardiography should be obtained to assess for the presence of hypertensive target-organ damage in patients with confirmed hypertension. Left ventricular mass should be indexed to height in meters to correct for the effect of obesity. Ophthalmologic exams should be obtained, but should be performed by an experienced pediatric ophthalmologist because hypertensive retinal changes are likely to be subtle in the young. At some point, pulse wave velocity, carotid imaging, and urine microalbumin testing may also find roles in the assessment of childhood hypertension, but more data are needed before these studies should be obtained routinely.

TREATMENT OF HYPERTENSION

Nonpharmacologic Therapy

Therapeutic lifestyle changes (TLC) are currently recommended as the initial management for children and adolescents with less severe hypertension, or those with primary hypertension and no hypertensive target-organ disease (see Fig. 475-5). Although the magnitude of change in BP may be modest, dietary modification, weight loss, and exercise have all been shown to successfully reduce BP in children and adolescents.

Although it is controversial whether excessive sodium intake may cause hypertension, once hypertension has been established, “salt sensitivity” becomes more common, and reduction in sodium intake is likely to be of benefit. Other nutrients that have been examined in patients with hypertension include potassium and calcium, both of which have been shown to have antihypertensive effects. Therefore, a diet that is low in sodium and enriched in potassium and calcium may be more effective in reducing BP than a diet that restricts sodium only. An example of such a diet is the so-called DASH (Dietary Approaches to Stop Hypertension) diet, which has been shown to have an antihypertensive effect in adults with hypertension, even in those receiving antihypertensive medication. Studies of sodium intake in children do show relationship to BP, and the DASH diet has been systematically studied in selected pediatric groups. Use of the DASH diet, particularly for adults with hypertension, has shown substantial reduction of BP with few, if any, adverse effects. Given these benefits, it is reasonable to recommend a similar diet for hypertensive children and adolescents.

Several studies have demonstrated that weight loss in obese adolescents can lower BP. Weight loss not only decreases BP but also improves other cardiovascular risk factors such as dyslipidemia and insulin resistance. In studies where a reduction in BMI of about 10% was achieved, short-term reductions in BP were in the range of 8 to 12 mm Hg. Unfortunately, weight loss is notoriously difficult to achieve and usually unsuccessful, especially in the primary care setting. However, identifying a medical complication of obesity such as hypertension can perhaps provide the necessary motivation for patients and families to institute appropriate lifestyle changes.

Increasing physical activity also has beneficial effects, particularly for children who are overweight and need to reduce their BMI. Increased physical activity may have a number of other beneficial effects, such as improvement in vascular function, and should be recommended for children with hypertension. In addition to increasing physical activity, children should have limitations placed on their sedentary time, with < 2 hours per day spent on television, computers, video games, and other sedentary pursuits. More recent studies have demonstrated that short-term dietary and exercise interventions can result in weight loss, reduced BP, and improvements in laboratory abnormalities associated with the metabolic syndrome in overweight children and adolescents. Furthermore, exercise was proven to be more beneficial than metformin in preventing the development of type II diabetes in high-risk adults. These studies support the recommendation made by the NHBPEP Working Group that therapeutic lifestyle changes should be considered primary therapy for obesity-related hypertension in children and adolescents. These measures should be incorporated into the treatment plan of all hypertensive children and adolescents, even those who require antihypertensive medications.

Pharmacologic Therapy

The long-term adverse consequences of untreated or undertreated hypertension, specifically the development of cardiovascular disease and CKD, have long been established in adults. To date, however, the long-term consequences of untreated hypertension in an asymptomatic, otherwise healthy child or adolescent remain unknown. Therefore, the decision to initiate pharmacologic therapy in the first or second decade of life can be anxiety-provoking for the pediatrician, child, and family. Lack of data on the benefits of therapy in the pediatric age group, as well as on the long-term effects of antihypertensive medications on growth and development, add further uncertainty to the decision to initiate drug treatment.

For these reasons, consensus statements issued by the NHBPEP have emphasized that a definite indication for initiating pharmacologic therapy should be ascertained before medication is prescribed in a child or adolescent. These are generally self-explanatory:

• Stage 2 hypertension

• Symptomatic hypertension

• Secondary hypertension

• Hypertensive target-organ damage

• Diabetes (types I and II)

• Persistent hypertension despite nonpharmacologic measures after at least 6 months

Most of the indicators represent situations in which BP reduction is likely to be beneficial in the treatment of another condition; for example, reduction of BP in patients with diabetes is an important strategy to prevent the development of diabetic nephropathy, and reduction of BP in patients with CKD will likely slow its rate of progression.

Another area of clinical uncertainty in use of antihypertensive medications in youth is the choice of an initial agent. In adults, studies such as ALLHAT (Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial) have provided evidence that a diuretic or a β-blocking agent should be the first choice of medication. No such evidence base exists for hypertensive children and adolescents, although a study has been initiated. In addition, it should not necessarily be assumed that what works well for adults will also work well for children and adolescents. The pharmacokinetics of medications may vary by age, and the mechanism of BP elevation may also differ with age. This may lead to different classes of agents being chosen for pediatric patients. Until good data are available to discern one class of medication from another in the young, it is probably advisable to consider several classes of agents, including diuretics, angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blocker (ARB) agents, and calcium channel blockers as potentially acceptable first-line agents. Although efficacy data exist, β-blockers are becoming less commonly used as first-line treatment in children due to their side effect profile compared to other agents.

Some authors have advocated a pathophysiologic approach to the choice of initial agent, for example, based on measurement of plasma renin. Those with high renin would be believed to have hypertension from renin-mediated vasoconstriction and should therefore be prescribed an antirenin agent, whereas those with low renin would be believed to have a volume overload–mediated hypertension and should be prescribed a diuretic. In secondary hypertension, the presence of underlying renal, cardiac, or endocrine disease can guide the choice of initial agent. Drugs affecting the renin–angiotensin system are clearly preferred in those with glomerulonephritis and other forms of CKD due to their benefit in preventing the progression to renal failure. In children with coarctation of the aorta, β-blockade has been suggested as the appropriate choice when hypertension persists following surgical correction. Hypertensive adolescents with type I or II diabetes should be treated with renin–angiotensin–aldosterone system blockade (an ACE inhibitor or ARB) because these agents may slow or prevent the development of diabetic nephropathy.

Other issues to consider in the choice of initial agent include the presence of another condition such as asthma or migraine and the likelihood of adherence to treatment. Adherence may be especially important in the treatment of hypertension in children and adolescents because most patients have so few symptoms. If BP control can be achieved with a single drug that is taken once a day, this will improve compliance and should be taken into consideration when the initial agent is chosen. Adverse effects of the agent should also be considered. Some classes of antihypertensive agents, particularly newer ones such as ACE inhibitors and ARBs, have a lower incidence of adverse effects and may be preferable.

An individualized stepped-care approach (Fig. 475-6) to the use of antihypertensive medications in children has been recommended by the NHBPEP since publication of the Second Task Force Report and continues to be advocated. Stepped-care allows for the individualization of therapy according to the needs of the patient and also facilitates detection of adverse effects as drug doses are increased or new agents added. In this approach, initial treatment consists of adding a monotherapy drug regimen to nonpharmacologic measures. The initial agent is begun at the recommended starting dose (Table 475-6). Increases in the dose of the initial medication should then be made to achieve BP control if necessary. Both efficacy and adverse effects should be monitored during titration; if significant adverse effects appear, the dose should be reduced or another agent chosen. If BP control is still not achieved, proceed to combination treatment by adding a low dose of another drug with a complementary mechanism of action. Alternatively, switching to a drug from a different class could be considered. If BP control is still not achieved, a third antihypertensive drug, usually a vasodilator or renin–angiotensin inhibitor, can be added, or the patient should be referred to an expert on childhood and adolescent hypertension. Poor compliance should always be considered throughout this process if the desired BP goal is not attained.

As with choice of agent, no evidence exists to guide treatment goals for children and adolescents with hypertension. However, based on data in adults and in children with CKD demonstrating benefits with lower BPs in those with secondary or complicated hypertension, the NHBPEP issued new guidelines in the Fourth Report. For children with uncomplicated primary hypertension and no hypertensive target-organ damage, the goal should be to normalize the pressure to < 120/80 mm Hg and < 90th percentile for age, gender, and height. Although not addressed in current US guidelines, children with secondary hypertension, diabetes, or hypertensive target-organ damage might benefit from even lower BP goals; European guidelines do call for lower thresholds in this high-risk population.

If pharmacologic treatment is needed, therapy should be monitored closely both for efficacy and for potential adverse effects. BP should be measured in the office every 2 to 4 weeks until control is achieved. Once control is achieved, then office visits every 3 to 4 months are appropriate. Home BP measurement should also be incorporated into the treatment plan because this may help improve compliance with treatment, as well as achievement of goal BP. Occasional repeat ABPM to assess circadian BP control is gaining support. Evaluation of adverse effects of medication will depend on the class of drug prescribed. Patients and their parents should be counseled proactively regarding potential class-specific, drug-related symptoms (eg, ACE inhibitor–related cough). Periodic laboratory monitoring may also be required, particularly if a diuretic or agent affecting the renin–angiotensin system is prescribed or if the hypertensive child or adolescent has underlying renal disease as the cause of hypertension. Females of childbearing potential should be counseled regarding the need to use an effective method of contraception if treatment with an ACE inhibitor or ARB is indicated because exposure to these drugs, even in the first trimester, may adversely affect fetal development.

PREVENTION

At this time, no studies of hypertension prevention have been conducted in the pediatric age group. However, the potential that future hypertension can be indeed be prevented is suggested by 3 types of data: studies of BP tracking, studies of lifestyle measures, and a more recent clinical trial of hypertension prevention in adults.

Many studies have documented the phenomenon of BP tracking, which refers to whether current BP is predictive of future BP. Data from large-scale pediatric population studies such as Muscatine and from adult studies such as Framingham have demonstrated that individuals with elevated BP at a young age are more likely to develop hypertension at a later point compared to those with a normal baseline BP. In many of these studies, the likelihood of BP tracking was greater when there was an accompanying increase in obesity. It follows that efforts to prevent and/or reverse obesity, regardless of whether an elevated BP has been documented, may result in prevention of future hypertension.

Similarly, cross-sectional data and interventional trials have demonstrated strong associations between body habitus and level of physical activity and elevated BP, as well as with hypertensive target-organ damage. For example, studies in both children and adults have established relationships between dietary sodium intake, fitness, and body mass with the development of left ventricular hypertrophy. There are also ample data that lifestyle changes can reverse left ventricular hypertrophy in hypertensive individuals, independent of the effects of antihypertensive medications. In a more recent study, the effects of a high-fiber, low-fat diet and 2 to 2.5 hours of supervised aerobic exercise daily were studied in a small group of overweight children. Two weeks of this intervention resulted in improvements in multiple components of the metabolic syndrome, including weight, waist circumference, BP, lipid profile, serum glucose and insulin, and calculated measures of insulin resistance. These data support the concept that adoption of a healthy lifestyle can prevent future hypertension and cardiovascular disease.

A more provocative concept is the use of antihypertensive medications to prevent hypertension. The Trial of Preventing Hypertension (TROPHY) demonstrated that treatment of prehypertensive adults with a low-dose angiotensin receptor blocker for 2 years significantly reduced the incidence of hypertension; furthermore, the reduction in the incidence of hypertension remained statistically significant 2 years after the discontinuation of treatment in those who received the angiotensin blocker compared to placebo recipients. The scientific basis for conducting the TROPHY trial came from studies showing a reduction in medial hypertrophy of resistance vessels in both hypertensive animals and humans who received antihypertensive drug treatment. Given that vascular changes begin early in the hypertensive disease process, extension of the TROPHY trial concepts to adolescents is currently being conducted as the SHIP-AHOY study (Systolic Hypertension in Pediatrics: Adult Hypertension Onset in Youth). That study will compare vascular and cognitive assessments of adolescents among 3 groups: those with normal, prehypertensive, and hypertensive BP. It may be that in the future, just as pediatricians use vaccines to prevent infectious diseases, it may be possible to use antihypertensive drugs in high-risk children and adolescents as one part of a strategy to prevent adult cardiovascular disease.

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