Rudolph's Pediatrics, 22nd Ed.

CHAPTER 477. Chronic Kidney Disease

Denis F. Geary

The definition of chronic kidney disease (CKD) and its different stages are outlined in Table 477-1. The term chronic kidney disease has been introduced to ensure consistency of terminology in relation to patients with sustained renal disorders, and to replace the terms chronic renal insufficiency and chronic renal failure.1 The definition of CKD excludes patients younger than 2 years whose renal function improves markedly in the first 2 years of life; therefore, a glomerular filtration rate (GFR) < 90 mL/min/1.73 m2 in a 6-month-old child may not represent any abnormality of renal function.

 CAUSES OF CHRONIC KIDNEY DISEASE IN CHILDREN

Causes of chronic kidney disease (CKD) in children do not vary substantially between disease registries from a variety of countries.2,3 In younger children, the most common causes are congenital abnormalities of the genitourinary system that are accompanied by vesicoureteric reflux or obstruction to urinary outflow leading to renal hypoplasia or dysplasia. The most common obstructive lesions are posterior urethral valves and prune belly syndrome, both of which only occur in boys (see Chapter 476). Renal cystic diseases, including multicystic kidneys, cystic renal dysplasia, juvenile nephronophthisis, and autosomal-recessive polycystic kidney disease, may cause significant loss of renal function during childhood (see Chapter 470). Glomerular diseases causing significant renal disease in early childhood rarely include congenital nephrotic syndrome, or more commonly, focal segmental glomerulosclerosis or hemolytic uremic syndrome (see Chapter 472). In teenage years, membranous nephropathy and membranoproliferative glomerulonephritis may be seen, and CKD may be seen in association with systemic lupus erythematosus.

 INCIDENCE AND PREVALENCE

According to the US Renal Data Systems report, there were 1325 incident patients ages 0 to 19 years with end-stage renal disease or renal transplants treated in 2005, with a prevalent population, including renal transplant patients, of 7362.4 The prevalence is too low to provide accurate estimates of prevalence of each chronic kidney disease (CKD) stage. However, more detailed information is available in the Italian registry from 1990 to 2000, including 1197 children with a creatinine clearance < 75 mL/min/1.73 m2 body surface area (BSA) (predialysis) and age younger than 20 years at the time of registration. This registry reported 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.3

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 the National Kidney Foundation Kidney Disease Outcomes Quality Initiative [NKF KDOQI]) 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 chronic kidney disease (CKD) are listed in Table 477-2. Including stage 1 CKD, an overall complication rate of 70% hypertension, 37% anemia, 17% metabolic bone disease, and 12% growth failure has been observed.5 The frequency and severity of these complications of CKD 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) guidelines and by groups of European expert panels, as summarized in this section.

Nutritional Disorders

Malnutrition in children with chronic kidney disease (CKD) is often accompanied by protein-energy wasting, which is characterized by decreased body stores of protein and energy fuels (fat mass).6 In CKD, additional factors that contribute to development of protein-energy wasting may include nonspecific inflammation, transient infections, chronic acidemia, resistance to insulin, growth hormone resistance, increased glucagon levels, hyperparathyroidism, and blood loss through dialysis or from frequent phlebotomy.6 Although the underlying cause of malnutrition in children with CKD is often multifactorial, it is extremely important that it be recognized and treated promptly. Nutritional assessment should include measurement of height, weight, body mass index (BMI; weight/height2), head circumference in infants, skinfold thickness, mid-arm circumference, serum albumin, cholesterol, and C-reactive protein (as a marker of nonspecific inflammation). No single one of these measures will define malnutrition, but in a child with CKD, where two or more are abnormal, attention should focus on his or her nutritional state (see Chapter 28). 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.

Table 477-1. Stages of Chronic Kidney Disease

Table 477-2. Complications of Chronic Kidney Disease in Children

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, and of the renal solute load. 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. Thus, administration of a formula with a low renal solute load (low protein, sodium, and potassium) is often necessary. Breast milk can be used, but specialized infant formulas designed for children with CKD are often required. These have lower sodium, potassium, and phosphorus, as well as a lower renal solute load, than other infant and pediatric formulas. In North America, these include PM 60/40 and Good Start.

If additional caloric density is required, it is preferable to add modular commercial components rather than to simply concentrate the formula because concentration increases electrolyte and mineral content. These include a variety of protein powder (Beneprotein powder, Resource), carbohydrate (Polycose, Bene-calorie), and fat (vegetable 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 higher magnesium content. Due to the child’s poor appetite, and sometimes unpalatable formula and 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. Approaches to the administration of enteral and enteral nutrition are discussed in Chapter 28. Percutaneous gastrostomy placement is contraindicated if peritoneal dialysis is likely.

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

Growth Impairment

Impaired growth is a common complication of chronic kidney disease (CKD); it can have a profound psychologic impact on a child and adversely affect his or her quality of life. Population studies show increased mortality in children with CKD and severe growth delay.7 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.2 About one third of all children with CKD and about one fifth of those with glomerular filtration rate > 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 nephrolo-gist; once appropriate treatment of their undernutrition and renal osteodystrophy ensues, a normal growth pattern is usually 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 chronic kidney disease are numerous, and include malnutrition/protein-energy wasting, chronic acidosis, severe renal osteodystrophy, sodium depletion, and growth hormone (GH) resistance. Where possible, treatment should be directed to correction of these metabolic disturbances prior to introduction of GH.

GH is not deficient in children with chronic kidney disease, 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 the bone.

Randomized controlled trials show that growth hormone (GH) treatment can promote short-term growth in children with chronic kidney disease (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.8 Occasional complications of GH use include pseudotumor cerebri, worsening renal osteodystrophy, and slipped capital femoral epiphysis, but the incidence of these is probably no different than children with CKD who are not treated with GH.9 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 about one in five children with a height less than the fifth percentile are prescribed GH.2

Metabolic Bone Disease

Metabolic bone disease affects many children with chronic kidney disease (CKD), and in its severe form deformities associated with rickets will impair growth. The exact cause of the bone abnormalities seen in children with CKD is not clear, but two pathogenetic mechanisms are recognized: (1) insufficiency of vitamin D from 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; and (2) retention of phosphate as renal function declines. Elevation of phosphate levels in plasma produces a reciprocal fall in plasma calcium values, which in turn stimulates 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 477-1.

Over the past two decades, renal bone disease has been classified according to the findings on histomorphometry of tetracycline-labeled bone tissue. Hyperparathyroidism produces a state of high bone turnover with osteitis fibrosa and thickened irregularly shaped trabeculae with initially increased, but later reduced, bone volume; increased resorption of cortical bone also produces decrease in cortical bone volume.10 More recently, low turnover (adynamic) bone disease has been reported in almost one third of children, and may result from attempts to treat hyperparathyroidism with activated vitamin D compounds and calcium-containing phosphate binders.10

The effects of metabolic bone disease on the epiphysis are unique to children with chronic kidney disease, and may include growth failure, slipped epiphysis, and, as mentioned previously, 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. As shown in Figure 477-2, both low and high turnover bone disease may impair mineralization of bone and contribute to calcification of vessels.

FIGURE 477-1. Schematic representation of the factors involved in the pathogenesis of secondary hyperparathyroidism. PTH, parathyroid hormone.

Because expertise is not available to evaluate bone histomorphometry in most pediatric hospitals, recognition of metabolic bone disease in chronic kidney disease relies on a number of 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 due to 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.10

FIGURE 477-2. Bone turnover in chronic kidney disease. Low and high turnover bone disease may impair mineralization of bone and contribute to calcification of vessels. X indicates entry into bone is blocked.

Two major expert panels have proposed guidelines for prevention and management of renal osteodystrophy in children with chronic kidney disease: one in the United States11 and one in Europe.12 The plasma levels for calcium, phosphate, calcium × phosphate product, and parathyroid hormone (PTH) values that they recommend are outlined in Table 477-3. Whereas there is a great deal of symmetry in these recommendations, there is divergence concerning the appropriate range to maintain PTH values, with a higher range recommended by the Kidney Disease Outcomes Quality Initiative (KDOQI) panel, based on a fear of developing low turnover bone disease with lower PTH values. Despite this disagreement, it is reasonable to suggest that for children with chronic kidney disease stages 2 and 3, PTH values should approximate or slightly exceed the upper limit of normal, and that this suggested level should increase somewhat as renal function worsens.

Table 477-3. National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF KDOQI) Recommended Values for Plasma Calcium (Ca), Phosphate (PO4), Ca × PO4, and Parathyroid Hormone (PTH) in Children with Chronic Kidney Disease Stages 2 to 4

There are four groups of therapeutic agents that are used to prevent and treat renal bone disease. (1) The first agent is vitamin D3 (cholecalciferol). If plasma levels of 25-OH vitamin D are subnormal, supplementation with vitamin D3 400 to 800 U/day should be provided. (2) If metabolic acidosis is present, this should be corrected with either oral sodium bicarbonate or sodium citrate supplements. (3) Activated vitamin D analogs should be prescribed if the calcium level is low 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. (4) 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 and increased calcium phosphate product, which in turn has been associated with vascular calcification. Therefore, the total (dietary and pharmacologic) intake of calcium daily should not exceed two times the daily recommended intake for calcium based on age or 2500 mg/day.

Developmental Delay and Quality of Life

Children with chronic kidney disease (CKD) are at risk for developmental delay. This 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, where developmental problems occur in as many as 25%, and severity correlates with the severity of renal dysfunction.13-17Cognitive deficits are also noted in older children, and the overall IQ of school-age children with CKD is lower than the normal population. These delays often persist over time, and some cross-sectional studies have shown little difference between children on dialysis or after transplantation. However, some longitudinal studies have demonstrated improvement in specific developmental deficits following renal transplant.

Specific deficits in language abilities have been observed, and in such cases, it is important to ensure that hearing is not impaired. Similarly, visual-motor constructive or perceptive abilities, impaired memory, and attention deficits have been reported in isolation, as combined disorders in children with CKD, and following transplantation; some children demonstrate improvement after, as compared to prior to, transplantation, but this is inconsistent. The factors causing these developmental or school problems for children with CKD are unclear. Chronic hospitalization may contribute. In some, coexistent extrarenal morbid conditions may impact cognitive and motor abilities. These morbidities may be due to congenital abnormalities, but 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.2 It is therefore 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 of a relatively mild nature has been reported to adversely affect quality of life scores.

Multiple studies have evaluated quality of life and social behavior in children with CKD, and despite shortcomings in design, the studies indicate that children with CKD prior to dialysis have a better quality of life than those on dialysis. Following renal transplant, quality of life improves compared to dialysis but does not achieve pretransplant quality. This is not surprising because transplant patients 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 the quality of life is considerably better than their parents’ perception of their quality of life.

Anemia

The lower limit of acceptable hemoglobin (Hb) in children with chronic kidney disease (CKD) has been defined by the KDOQI workgroup as < 11 g/dL, suggesting that a level below that threshold be considered anemia.14 This rather arbitrary definition includes a caveat that consideration should be given to the normal variation of Hb levels at different ages. Using a cut-off value of 12 g/dL, it has been reported that anemia is present in 36% of all children with CKD, and the prevalence increases to 93% in stages 4 and 5 CKD.5 Using the KDOQI value of 11 g/dL as the lower limit of acceptable Hb, 54% of children on hemodialysis and 70% on peritoneal dialysis were anemic, despite treatment with erythropoietin (EPO).15 However, improved hematocrit (Hct) counts have been noted more recently with the increased use of EPO.2

The most common cause of anemia with CKD is a deficiency of EPO. EPO is normally produced in the peritubular interstitial cells of the kidneys, and regulates bone marrow erythroid cell proliferation, differentiation, and survival. However, EPO deficiency in CKD is often aggravated by a number of other causes of anemia. These include chronic inflammation associated with “anemia of chronic disease”—possibly due to increased hepcidin production with inflammation, which prevents release of iron from macrophages and may inhibit intestinal iron absorption—iron deficiency that may be due to a reduction in transferring (the iron carrier protein) in CKD, increased blood loss associated with surgical procedures, and frequent phlebotomy. Less common contributing factors include carnitine, folate, and vitamin B12deficiencies; severe hyperparathyroidism; and aluminum toxicity.

Investigation of anemia in children with CKD should routinely include measurement of serum iron, transferrin, ferritin, reticulocyte count, and, where available, red blood cell (RBC) transferrin receptor. Less frequently, or when treatment with EPO and iron is ineffective, haptoglobin, lactic dehydrogenase (LDH), folate, vitamin B12, carnitine, and aluminum values should be checked. Also, severe hyperparathyroidism (parathyroid hormone [PTH] values), inflammation (C-reactive protein [CRP] values), and stool blood loss should be considered. However, in the usual circumstance, investigation is focused on distinction between iron deficiency and inadequate EPO dosing. In isolation, no single one of the previous tests will identify iron deficiency. Transferrin saturation is the most helpful, but it may be falsely increased in CKD patients with proteinuria, in which case this test is not useful. The evaluation of anemia is further discussed in Chapter 430. A low reticulocyte count may indicate insufficient EPO 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.

Consequences of anemia for children with chronic kidney disease (CKD) are not as well studied as in adults with CKD. It would be impractical and unethical to compare outcomes for children with hemoglobin values in the normal range versus very low hemoglobin values. Nonetheless, a number of studies have demonstrated some adverse affects of anemia. 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 EPO to children with CKD appears to promote catch-up growth prior to dialysis; as hemoglobin values increase,16 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.17 Regardless of whether anemia is related to reduced cognitive abilities in children with CKD is unclear, and it will be difficult to clarify this relationship in the future because of the widespread use of EPO-stimulating agents (ESAs).

The most serious potential complication of anemia in children with CKD is the enhanced risk of cardiovascular disease. In a 2-year prospective study of children with CKD prior to dialysis, 19% had left ventricular hypertrophy (LVH) when first evaluated, but this increased to 39% during the 2-year follow-up period. A lower hemoglobin value was associated with LVH at baseline and also independently predicted interval increase in left ventricular mass index.18 These same investigators confirmed an association between the presence of anemia and increased left ventricular mass index in children with CKD stages 2 to 4.

ESAs are the cornerstone of treatment for anemia in pediatric chronic kidney disease patients. EPO can be administered either subcutaneously or intravenously (although the latter may require increased dosing). Whereas dosing was originally prescribed thrice weekly, for most children hemoglobin is maintained in the normal range with EPO 150 U/kg/week administered once or twice weekly. Although there is some disagreement as to the dose required for treatment of younger children, observational data from the NAPRTCS database show that younger children receive higher doses, and in infants, the recommended dose is 200 to 300 U/kg/week. An alternative ESA, darbepoetin, has a slightly altered molecule compared to EPO. A weekly starting dose of approximately 0.5 μg/kg is suggested. Although it is administered less frequently, some report increased pain at the injection site compared to EPO. Either EPO or darbepoetin can be used to successfully treat anemia in the vast majority of children with chronic kidney disease.

Iron therapy is required for almost all children with chronic kidney disease to prevent and treat anemia. KDOQI guidelines suggest that oral iron can be administered at a dose of up to 6 mg/kg/day of elemental iron in two to three divided doses. The problem with oral iron in this patient population is that the majority of these patients take phosphate-binding agents, which cannot be given at the same time, thereby increasing the complexity of administering multiple medications each day. Also, because hydrochloric acid is required for absorption of oral iron, the concomitant use of proton pump inhibitors may interfere with its efficacy.

Intravenous iron in the form of iron sucrose or sodium ferric gluconate is associated with a greatly reduced incidence of anaphylactic reactions compared to the previously recommended iron dextran. Weekly maintenance therapy with a dose of 2 mg/kg to a maximum of 100 mg is effective, or intermittent administration to patients with documented iron deficiency, with a dose of 7 mg/kg (maximum dose 200 mg), is effective. Obviously, the use of intravenous (IV) iron on a regular basis is not suited for the majority of chronic kidney disease patients unless they have some form of vascular access; IV iron is also considerably more expensive than the oral variety.

Cardiovascular Disease and Hypertension

Two studies have shown dramatically increased risk for cardiovascular disease in children with chronic kidney disease (CKD). One reported that from 1990 to 1996 almost one fourth of the deaths of US children with end-stage renal disease requiring dialysis was due to cardiac causes, with a cardiovascular mortality rate 100 times higher than the general population in the 25- to 34-year-old age group.19Analysis of data from Australia and New Zealand on children requiring renal replacement therapy showed a 20-year survival rate of 66%, being 30 times higher than those with end-stage renal disease, with 45% of deaths due to cardiovascular disease.20

Contributing factors likely include chronic hypertension, hyperlipidemia, and arterial calcification. Hyperlipidemia is discussed in the next section. Hypertension, defined as blood pressure greater than or equal to age-, sex-, and height-specific 95th percentiles, has been reported in more than three fourths of children starting dialysis, with it being poorly controlled in half.21 Another study confirmed these prevalence rates for hypertension in children with CKD of all stages, and of particular concern was an incidence of 63%, even with stage 1 CKD.5 The prevalence of hypertension was less in children with congenital or obstructive uropathy than in those in whom renal disease was acquired from or related to an immunologic cause.21

Excessive coronary artery calcification has been shown in young adults with end-stage renal disease using electron-beam computerized tomography screening of the coronary arteries.22 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. This concern has led to the KDOQI guidelines for normalization phosphate, calcium, and calcium-phosphate product, and to the use of calcium-containing phosphate binders when possible, so that calcium intake will not exceed a total of 2500 mg daily, including dietary calcium.11

Hyperlipidemia

The KDOQI guidelines for management and prevention of dyslipidemias, states that patients ages 18 to 20 years should be considered at increased risk of atherosclerotic cardiovascular disease similarly to all adults with chronic kidney disease (CKD).23 Pubertal children younger than 18 years are also included in the KDOQI guidelines, whereas prepubertal children should follow the guidelines of the National Cholesterol Education Program (NCEP) Expert Panel on Children. The recommendations from and differences between the NCEP and KDOQI are outlined in Table 477-3.23 It is important to include patients with persistent nephrotic syndrome, which is not responsive to steroid therapy, among those with CKD who should be considered for lipid-lowering treatment, despite apparently normal renal function.

Statins are the primary drug class recommended for treatment of increased cholesterol values. However, neither NCEP nor KDOQI guidelines are of much value to assist with management of hypertriglyceridemia in children, which is equally common as elevation of low-density lipoprotein (LDL) cholesterol, but which is poorly responsive to treatment with statins. The fibrate class of drugs has been recommended for adults, but there is little experience with these drugs in children with CKD. Use of omega-3 fatty acids 3 to 8 g/d provided as fish oil supplements may reduce serum triglyceride levels in children on dialysis and might be considered as a safer alternative to fibrates. The problem is that many fish oil supplement products are unregulated; therefore, the omega-3 content may be unreliable.

Metabolic Acidosis and Electrolyte Imbalance

A number of electrolyte derangements may be seen in children with chronic kidney disease (CKD). Metabolic acidosis 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 sulphate 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 tCO2 on serum electrolytes. Treatment consists primarily of supplemental bicarbonate or citrate solutions.

Hyponatremia may occur as a reflection of urinary sodium wasting, which is common with congenital high-output causes of CKD, and treatment may require salt supplementation. Caution must be exercised to ensure that the child is not volume overloaded with dilutional hyponatremia. Hyperkalemia commonly 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 may also be required (eg, Kayexalate or calcium resonium). In association to 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 phosphate binders.

 PROGRESSION

Most important, the rate of progression of chronic kidney disease (CKD) is dependent on the underlying disease and the severity of CKD at the time of diagnosis, as reflected by their presenting glomerular filtration rate (GFR) and degree of proteinuria. However, the natural history appears to be affected by other factors. A detailed review of 176 children with renal hypo/dysplasia treated at Great Ormond Street Hospital in London indicated that 82% of children showed substantial early improvement in their GFR during the first 3 years of life (Fig. 477-3), although about half of the children then deteriorate to end-stage renal disease over the next 3 to 4 years.24 The other half stabilize until early puberty when half show another fairly rapid decline in kidney function, and the remainder remain stable throughout the remaining childhood years or progress to end-stage renal disease more slowly during puberty. Prospective data obtained by the Italian Kidney Registry also shows that the probability of kidney survival does not decrease linearly with age but shows a sharp decline during puberty and early postpuberty.3 If the renal dysfunction was mild (creatinine clearance 51–75 mL/min), 37% of the children had developed end-stage renal disease by 20 years of age; however, for those with moderate renal failure (creatinine clearance 25–50 mL/min) at registration, 70% had progressed to end-stage renal disease. Other studies have shown a significant association between the rate of deterioration of renal function and the severity of proteinuria in children with various causes of renal disease, including glomerular diseases, uropathies (including hypo/dysplastic kidneys), and congenital and hereditary nephropathies.24

FIGURE 477-3. Course of renal function in children with renal hypo/dysplasia at Great Ormond Street Hospital. (Source: Modified from Gonsalez Celedon C, Bitsori M, Tullus K. Progression of chronic renal failure in children with dysplastic kidneys. Pediatr Nephrol 2007;22(7):1014-1020.)

The occurrence of febrile urinary tract infections is not uncommon in children with hypo/dysplasia of the kidneys that may be associated with obstructive uropathies or vesicoureteric reflux. An increased rate of deterioration in renal function is only shown in those children that had more than two febrile urinary tract infections, suggesting that the development of an occasional infection will not influence progression of end-stage renal disease.24

A large number of studies in adults have clearly documented that hypertension is a risk factor for progression of CKD. Children with a systolic blood pressure > 120 mm Hg have a much more rapid deterioration in kidney function than those with lower blood pressures.24

 PREVENTING PROGRESSION

Dietary Protein Intake

In adults, intake of a reduced protein intake may reduce proteinuria and slow the decline of kidney function. This has been corroborated in studies of rats following subtotal nephrectomy. However, concern exists about implementation of a low protein diet in children, for whom growth is essential. A 2-year prospective study randomized children to receive a restricted protein diet (125% World Health Organization [WHO]-recommended protein intake) or a controlled diet (181% 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.24 Therefore, it is not recommended to restrict protein intake in patients with chronic kidney disease (CKD) unless evaluation of an individual’s diet or laboratory values suggests that their protein intake is clearly excessive.

Hypertension Control

Improved blood pressure control is associated with a slowing in the rate of deterioration of chronic kidney disease (CKD) in adults, leading to recommendations that in adults with CKD blood pressure optimally be less than 120/80 mm Hg and that any blood pressure greater than 130/80 mm Hg should be treated. The translation of these data to children implies that blood pressures should be maintained around the 75th percentile for age, which is clearly much more rigorous than generally applied in current clinical practice. This is best achieved by use of angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blocking (ARB) agents, either alone or in combination. These have the added benefit of reducing proteinuria, and because the severity of proteinuria is a concomitant risk factor for progression of CKD, it makes sense to improve blood pressure control and reduce proteinuria with the same medication whenever possible. To maximize the antiproteinuric effect of these agents, large doses may be required. Side effects from these medications in children with CKD include hyperkalemia and volume depletion. Therefore, electrolytes should be monitored within a week of starting treatment, and children should be advised about the risk of acute dizziness or syncope with vigorous exercise or activities such as roller coaster rides. 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. The efficacy of ACE inhibitors for blood pressure and proteinuria control in children has been demonstrated in the ESCAPE trial, which studied 400 children with CKD in Europe.25 Calcium channel blockers are also 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.

Table 477-4. Key Features of the NKF KDOQI Guidelines That Differ from Those of the National Cholesterol Expert Panel on Children.

Nonspecific Therapies

Therapies aimed at prevention or treatment of renal bone disease and cardiovascular disease associated with chronic kidney disease (CKD) may also 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 and/or an elevated calcium phosphate product, which might produce vascular and/or renal interstitial calcification, do not result. Similarly, whereas statin agents are recommended for control of LDL cholesterol, they may also have an indirect beneficial effect to produce some slight reduction in proteinuria.

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 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, where participation in normal social and sporting activities must be encouraged.

 PREPARATION FOR RENAL REPLACEMENT THERAPY

Management of children with chronic kidney disease (CKD) stages 2+ must recognize that for the majority of these children progression to end-stage renal disease is to be expected. Families should be counseled regarding this eventuality and provided with appropriate emotional supports to prepare for it. Discussion concerning the appropriate choice of renal replacement modality should be started when CKD stage 3 is reached so that the families are appropriately educated about the relative benefits and adverse effects of each.

For patients in whom hemodialysis is the anticipated treatment for end-stage renal disease, consideration should be given to placement of arteriovenous fistula a few months before it is expected that end-stage renal disease will develop. For peritoneal dialysis patients, 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.

Finally, 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, and results of transplantation in such patients are at least as good as those who have received prior dialysis. 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 may also 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.

Kidney transplantation is discussed in Chapter 129.