Chronic Kidney Disease in Children

Abstract

After completing this article, readers should be able to: Prior to 2002, the term chronic renal insufficiency was used to characterize patients who had progressive decline in renal function, defined as a glomerular filtration rate (GFR) of less than 75 mL/min per 1.73 m2 body surface area. Chronic kidney disease (CKD) is the new term defined by the National Kidney Foundation Kidney Disease and Outcome Quality Initiative (KDOQI) Group to classify any patient who has kidney damage lasting for at least 3 months with or without a decreased GFR or any patient who has a GFR of less than 60 mL/min per 1.73 m2 lasting for 3 months with or without kidney damage. The KDOQI Group also classified CKD into five stages: GFR values for CKD staging are for children older than 2 years of age because the GFR values for younger children are low due to ongoing renal maturation. Children who have CKD may present to clinicians with a combination of problems involving growth, nutrition, electrolyte disturbances, renal osteodystrophy, anemia, immunizations, hypertension, and renal transplantation. CKD has a prevalence of 1.5 to 3.0 per 1,000,000 among children younger than the age of 16 years. The most common causes of CKD in children are urologic abnormalities (∼30% to 33%) and glomerulopathies (∼25% to 27%). These two abnormalities account for more than 50% of the reported causes of end-stage renal disease in children. The other major causes are hereditary nephropathies (∼16%) and renal hypoplasia and dysplasia (∼11%). Data from the North American Pediatric Renal Trial and Collaborative Studies 2006 demonstrate very similar information (Table 1). Histologic similarities among the various causes of CKD are many, and possible common mechanisms accounting for similarities include cell-specific damage, the role of growth factors, and the effects of metabolic factors. Ultimately, these mechanisms could lead to some degree of healing or to additional sclerosis (scarring). Growth retardation is one of the major complications of a child who has CKD. The degree of growth failure has been correlated with age of onset of CKD. The cause of growth failure is believed to be multifactorial, including growth hormone (GH) and insulin-like growth factor-I (IGF-I) function, nutritional status, acid-base balance, and bone mineralization.The age of CKD onset is correlated with the degree of growth retardation because children who have normal renal function achieve one third of their final adult height during the first 2 years after birth. Data support current treatments for achieving accelerated growth in infants and young children who have CKD, but most children still do not reach their genetic height potential despite optimal management.GH is released from the anterior pituitary and is regulated by GH-releasing factor and somatostatin. The negative feedback mechanisms involve circulating GH and IGF-I concentrations. Most of IGF-I is bound to IGF-binding proteins, but it has been demonstrated that free IGF-I mediates many GH functions, including the stimulus for linear height of bone as well as some renal hemodynamic effects. GH has direct effects, not only on bone, but on other body tissues. When renal function is reduced, GH is increased because of decreased clearance by the kidneys despite the normal pulsatile release of the hormone, which continues despite the increased GH concentrations.Resistance to GH and to IGF-I also is believed to lead to growth reduction. GH resistance most likely is due to several causes. In some studies, serum GH concentrations are increased in patients who have CKD, but the concentrations of GH receptors are reduced. Another cause may be the upregulation of intracellular inhibitors, labeled suppressors of cytokine signaling (SOCS). The SOCS proteins can alter the phosphorylation of GH receptors and may cause GH resistance.Similarly, IGF-1 resistance probably is due to several causes. Total immunoreactive IGF concentrations in those who have CKD are normal, but the bioactive IGF is reduced by approximately 50%. IGF-binding proteins, of which six are now identified, increase with renal failure and most likely inhibit the actions of IGF-1 by binding with it, thereby preventing IGF-1 from binding to its receptor. In addition, some postreceptor IGF-1 signaling defects in renal failure may add to IGF-1 resistance.Other hormones that play a role in pubertal growth and development have been found to be reduced in children who have CKD, including luteinizing hormone, plasma testosterone, and free testosterone. These hormones play crucial roles in the pubertal development and pubertal growth spurt of children.Treatment of growth failure initially involves resolving nutritional deficiencies and improving the acid-base balance of children who have CKD. Once these tasks are accomplished, affected children begin GH therapy if growth retardation persists. The use of GH has been demonstrated to produce some catch-up growth, and many patients who have CKD attain a final height considered normal for their age range. Most patients who have CKD grow when given the recommended starting dose of 0.05 mg/kg per day, administered subcutaneously daily. Whether patients in the pubertal age group require additional GH needs additional investigation.Children who have CKD have nutrition and protein deficiencies for several reasons, including anorexia, nausea and vomiting from the uremia, and an abnormal sense of taste. Young children, in particular, need sufficient caloric intake to grow. Protein intake should be optimized to allow for maintenance of nitrogen balance and preservation of lean body mass. Some patients may require supplemental nasogastric or gastrotomy tube feeding if they cannot maintain optimal height and weight gain by oral feeding. However, if protein intake is excessive, hyperfiltration may occur, leading to increased damage to the renal parenchyma. Micropuncture studies demonstrate an increase in the GFR (hyperfiltration) after an amino acid load due to reduction in afferent arteriolar resistance.Prostaglandins, which can alter vascular tone and increase the GFR, recently have been implicated in the development of hyperfiltration because prostaglandin values have been noted to increase in response to an increased amino acid load. Protein restriction was believed to slow the progression of renal disease, but this effect has not been verified in children. Reducing protein intake to 0.8 to 1.1 g/kg per day has not been shown to affect linear growth negatively.Because many vitamins are lost during dialysis, pediatric patients undergoing this therapy should supplement their diets with vitamins, especially folic acid, trace minerals, and B complexes.Specialized formulas that have high energy contents and lower electrolyte contents have been developed for infants and children who have CKD. These are reasonable formulas for an older child already on dialysis who may be not be meeting his or her nutritional goal or who is experiencing poor weight gain or growth.Metabolic acidosis develops in patients who have CKD because of abnormally decreased bicarbonate reabsorption of filtered bicarbonate, reduction of renal ammonia synthesis, decreased acidified tubular fluid, and decreased titratable acid excretion. Decline in GFR below 50% of normal is accompanied by a decline in bicarbonate reabsorption. Reduced bicarbonate reabsorption leads to systemic acidosis, which causes protein degradation and efflux of calcium from bone. Such factors play a role in the poor linear growth observed in children who have CKD.Therapy should target maintaining a serum bicarbonate concentration of 20 to 22 mEq/L (20 to 22 mmol/L). Bicarbonate replacement consists of administering sodium bicarbonate supplements or phosphate binders. Most available binders have a base component such as calcium carbonate.Hyperkalemia is a complication of CKD. In the healthy kidney, potassium reabsorption occurs in the proximal tubules and the loop of Henle, and secretion of up to 90% of the daily intake of potassium occurs in the distal tubules. As renal disease progresses, the distal tubules of the remaining nephrons continue to secrete potassium. Increased aldosterone also enhances potassium secretion by stimulating sodium-potassium exchange in the kidneys and the colon. However, hyperkalemia develops from an increase in dietary potassium that overwhelms the compensatory mechanisms or by use of medications that alter potassium secretion (spironolactone, amiloride, or angiotensin converting enzyme inhibitors). Table 2lists approaches to treating hyperkalemia.Hypokalemia also can occur in children who have CKD but tends to develop in patients who have tubular defects such as seen with Fanconi syndrome.Calcium, phosphorus, and magnesium balance are maintained by the kidney when people have normal renal function. In CKD, hypocalcemia and hyperphosphatemia occur. The normal kidney converts 25-dihydroxyvitamin D3 into 1,25-dihydroxyvitamin D3 when stimulated by hypocalcemia, parathyroid hormone (PTH) release, and decreased dietary intake of phosphate. PTH is degraded and removed by the kidney.In renal disease, 1,25-dihydroxyvitamin D3 production decreases, intestinal absorption of calcium decreases, and hypocalcemia develops. This series of events, in turn, causes an increase in PTH formation. However, PTH has little effect due to low vitamin D and high serum phosphate concentrations (phosphorus cannot be secreted by the diseased kidneys) as well as downregulation of PTH receptors. Abnormal bone mineralization with resultant fractures and osteitis fibrosa can occur (FigureF1).Linear growth also can be affected by secondary hyperparathyroidism, with renal osteodystrophy possibly leading to alterations in the normal growth plate cartilage architecture due to abnormal bone mineralization and fibrosis of the endochondral bones.For children who have CKD, bone pathology must be treated aggressively. Available forms of vitamin D supplementation are dihydrotachysterol (DHT), 25-hydroxyvitamin D3 (calcifediol), 1-alpha-hydroxyvitamin D3, and 1,25-dihydroxyvitamin D3 (calcitriol) (Table 3). Paricalcitol, a newer intravenous form of vitamin D, is administered to children who have CKD and are receiving hemodialysis. When choosing a vitamin D preparation, the age of the patient, the ability to swallow pills, and whether the patient is on hemodialysis or peritoneal dialysis are important issues to consider. DHT can be formulated into a solution that is easy for infants to take orally, as can calcitriol, which also can be given to infants. Intravenous forms of vitamin D such as paricalcitol and doxercalciferol (doxercalciferol also has an oral formulation) usually are given to patients undergoing hemodialysis to ensure compliance and to reduce the number of necessary oral medications. Vitamin D treatment typically is started once a child develops stage 3 CKD. Dosing is titrated according to the serum phosphorus concentration returning to normal values for age and the PTH values returning to the upper limits of normal for age. Hyperphosphatemia is treated with administration of a phosphate binder with meals to facilitate bonding of phosphorus within the gastrointestinal tract, thereby increasing phosphate elimination. Commonly used binders are calcium-containing agents such as calcium carbonate and calcium acetate and other noncalcium-containing binders. Aluminum-containing phosphate binders should be avoided in children because of the risk of aluminum toxicity, which can occur in renal failure. Children who have CKD also should be following low-phosphate diets.Anemia in CKD is caused by either an insufficient production of erythropoietin by the diseased kidneys or by iron deficiency. Anemia is defined as a reduction in red blood cell volume or hemoglobin concentration below the normal range for a healthy person. Morbidity, mortality, and quality of life data from the KDOQI guidelines suggest that maintaining the hematocrit in the range of 33% to 36% (0.33 to 0.36) and the hemoglobin at 11.0 to 12.0 g/dL (110.0 to 120.0 g/L) is important for children who have CKD.Prior to the development of recombinant human erythropoietin, patients who had CKD had to undergo transfusions to increase their hematocrit values. Transfusions not only exposed patients to various infectious agents but exposed and sensitized them to human lymphocyte antigens, putting them at increased risk for rejection should they undergo renal transplantation. With improvement of anemia, children demonstrate improvement in cognitive development, cardiac function, and exercise tolerance, as well as decreased mortality.As stated, anemia is caused by either an insufficient production of erythropoietin by the diseased kidneys or by iron deficiency. Due to decreased appetites, children who have CKD cannot increase their iron stores adequately through an oral diet. Oral iron therapy should be administered at a dose of 2 to 3 mg/kg per day of elemental iron in two or three divided doses. Iron should be consumed on an empty stomach and not concomitantly with phosphate binders because iron binds to the phosphate binders.Parenteral iron can be provided to those who continue to lose blood or who cannot tolerate oral iron. Parenteral iron can be administered easily to patients receiving hemodialysis because they already have vascular access. Intravenous iron also can be used for the peritoneal dialysis patient who is resistant to oral iron or is noncompliant in taking oral iron. Erythropoietin can be administered subcutaneously to children who have CKD, including those undergoing peritoneal dialysis, or intravenously for those receiving hemodialysis. Erythropoietin can be given one, two, or three times per week. The initial dose ranges between 30 and 300 units/kg per week, with the usual maintenance dosage between 60 and 600 units/kg per week. The maintenance dose is determined and adjusted based on monthly hemoglobin values. A new form of erythropoietin, darbepoetin alfa, which has a longer half-life and requires dosing once every 2 weeks to once monthly, is being investigated for use in children. Hypertension is diagnosed in children who have CKD by finding an elevated blood pressure reading on three or more separate office visits at least 1 week apart. The diagnosis is based on the child's age, sex, and height percentile. Grades of hypertension are as follows, based on tables or graphs of normal values: (1) In addition to determining the underlying cause of the hypertension, clinicians should monitor patients at least annually with echocardiography to assess function and left ventricular status. Medications are adjusted to improve cardiac function. Those children who fall into the hypertensive urgency and emergency category require intravenous medications or a rapid-acting oral medication (nifedipine or minoxidil) to reduce blood pressure. (See Feld and Corey (1)) for information on antihypertensive medication choices.)Children who have CKD should be kept as medically stable as possible to prepare them for renal transplantation. Immunizations are important to reduce the risk of morbidity and mortality from vaccine-preventable infections. Although complete vaccination should be accomplished prior to renal transplantation, various transplant centers report that 20% to 30% of children do not complete their series of immunizations prior to transplantation. Because live vaccines are not recommended after transplantation, children who have received renal transplants and have not completed their live vaccine series prior to transplantation are at increased risk for developing varicella, measles, mumps, and rubella.Unfortunately, vaccine immunogenicity in children who have CKD may be altered due to underlying conditions that may impair immune function. Dialysis (peritoneal and hemodialysis), nephrosis, and uremia affect the immune system adversely. Hepatitis B antibodies can be removed by dialysis, so children undergoing dialysis require frequent measurement of hepatitis B antibody titers.The waiting time for a renal transplant can affect the vaccine schedule adversely. Prior to being placed on the deceased donor list, children may need to undergo an accelerated immunization schedule to provide some immunity before transplantation. For example, a child may receive the initial measles-mumps-rubella-varicella vaccine at 9 months of age prior to a planned transplantation scheduled in 2 to 3 months.All children who have CKD should receive all routine immunizations, including those against diphtheria, tetanus, polio, Haemophilus influenzae type b, and measles-mumps-rubella. They also should receive influenza vaccine annually, and if the 7-antigen pneumococcal vaccine has not been administered prior to 2 years of age, it should be given to children 2 years of age or older who have CKD. Responsiveness to immunizations varies from child to child. Occasionally, booster vaccines are necessary, and measuring antibody titers should be routine. The meningococcal vaccine is recommended for adolescents who have CKD.As stated, immune response to hepatitis B vaccine requires frequent evaluation, and children should receive a booster series if antibody titers become negative. Hepatitis B immunization is a challenge in children who have CKD because the individual may not follow the vaccination schedule, may have antibodies removed during dialysis, or may be taking medications that interfere with antibody response.Contraindications to vaccinations are few. The immunization schedule can be delayed if the patient is acutely and severely ill, but vaccination should proceed once the patient's condition has improved. Live vaccines should not be given if the patient recently was given intravenous immune globulin or other antibody-containing products to help improve immune impairment.Successful completion of pretransplantation immunization series in children who have CKD requires frequent communication among the pediatric nephrologist, pediatric transplantation team, and the primary general pediatrician.Once a child progresses to end-stage renal disease, the ultimate treatment is renal transplantation. The donor kidney can come from a living related, living unrelated, or deceased donor. Children are given priority for a deceased donor kidney when placed on the United Network for Organ Sharing (UNOS) waiting list. UNOS, originally established in 1968 as a professional organization, formed a Kidney Center in 1977 that developed computer-based matching of organs to facilitate transplants. Today, the UNOS organ center is open 365 days per year, 24 hours per day to facilitate organ procurement and organ sharing across the United States.Based on information from the North American Pediatric Renal Trials and Collaborative Studies, the 1-year rate among living donor is and the rate is The 1-year deceased donor rate is with the rate being The current for transplantation in the pediatric is end-stage renal disease, but many children receive kidney transplants without undergoing dialysis due to and on the of data that renal transplant do than those who receive dialysis prior to transplantation. 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