Version May 2024
INTRODUCTION — Chronic kidney disease (CKD) refers to a state of irreversible kidney damage and/or reduction of glomerular filtration rate (GFR) that is associated with progressive loss of kidney function over time. The loss of kidney function leads to a wide range of complications, which become more prevalent with progressive kidney function decline (table 1).
Complications of pediatric CKD and their management are discussed here. The etiology, epidemiology, progression, clinical manifestations, and overview of management of CKD in children are discussed separately. (See "Chronic kidney disease in children: Definition, epidemiology, etiology, and course" and "Chronic kidney disease in children: Clinical manifestations and evaluation" and "Chronic kidney disease in children: Overview of management".)
DEFINITIONS — CKD is defined as the presence of structural or functional kidney damage that persists over a minimum period of three months. Functional damage is characterized by sustained reduction of estimated glomerular filtration rate (eGFR), persistent elevation of urinary protein excretion, or both.
Based on this definition, clinical practice guidelines from the Kidney Disease: Improving Global Outcomes (KDIGO) in 2012 published criteria for diagnosis and staging of pediatric CKD [1]. The KDIGO staging classification is the standard used in clinical practice, research, and public health in the care of children with CKD greater than two years of age based on GFR and will be used throughout this topic (table 1). This classification system defines pediatric CKD as follows:
●Children ≥2 years:
•GFR <60 mL/min per 1.73 m2 for more than 3 months, or
•GFR >60 mL/min per 1.73 m2 that is also accompanied by evidence of structural damage or other markers of functional kidney abnormalities including proteinuria, albuminuria, renal tubular disorders, or pathologic abnormalities detected by histology or inferred by imaging. This category also includes patients with solitary kidney or functioning kidney transplants.
●Children <2 years – Children under two years of age do not fit within the above classification system, because they physiologically have an inherently lower GFR even when corrected for body surface area. In these patients, abnormal kidney function based on serum creatinine can be compared with age-appropriate normative values to detect kidney impairment (table 2). The KDIGO guideline suggests that a serum creatinine value more than one standard deviation above the mean should raise concern and prompt additional ongoing monitoring.
Additionally, the Chronic Kidney Disease in Children Under 25 GFR-estimating equation (U25 equation) has been validated in children with CKD as young as one year old [2] and online calculators are available for use. (See "Chronic kidney disease in children: Definition, epidemiology, etiology, and course", section on 'Staging: Risk stratification'.)
OVERVIEW AND EPIDEMIOLOGY — Moderate to severe loss of glomerular filtration rate (GFR; ie, GFR <45 mL/min per 1.73 m2 G3b to G5) (table 1) may result in a number of complications due to kidney function impairment [3]. These complications include:
●Disorders of fluid and electrolytes
●CKD-mineral and bone disorder (CKD-MBD)
●Anemia
●Hypertension
●Dyslipidemia
●Malnutrition and poor growth
●Endocrine abnormalities
●Neurodevelopmental impairment
●Uremia
It is challenging to determine the prevalence of these complications as published data are observational in nature and vary regarding the severity of CKD and whether interventions have been instituted.
●In a single center retrospective study, the following prevalence rate of associated complications in 366 children with CKD were reported [3]. In this cohort, 57 percent of patients were in CKD stage G1, 29 percent in G2, 10 percent in G3a-b, and 4 percent were in stages G4 or G5.
•Hypertension – 70 percent
•Anemia – 37 percent
•CKD-MBD – 17 percent
•Growth failure – 12 percent
•Electrolyte disorder or metabolic acidosis requiring intervention – 12 percent
●In the multicenter prospective Chronic Kidney Disease in Children study, the following prevalence was reported based on data from 586 participants with moderate to severe CKD (median GFR = 43 mL/min/1.73 m2) [4].
•Anemia (hemoglobin [Hb] <5th percentile or the use of erythropoietin) – 38 percent
•Growth failure (height <3rd percentile) – 16 percent
•Uncontrolled systolic hypertension – 14 percent
•Uncontrolled diastolic hypertension – 13 percent
FLUID AND ELECTROLYTE ABNORMALITIES
Sodium and water homeostasis — Kidneys normally can adapt to a wide range of sodium and water intake. Sodium and intravascular volume balance are usually maintained via homeostatic mechanisms until the glomerular filtration rate (GFR) falls below 15 mL/min per 1.73 m2; however, some children with milder CKD may not adequately respond to acute intravascular volume depletion.
●Salt wasting and poor urinary concentration – Salt-wasting and the inability to appropriately concentrate urine are often observed in children with obstructive uropathy and/or dysplastic kidneys. These children are at risk for clinically significant hypovolemia due to their inability to respond appropriately to acute intravascular volume depletion. Despite fluid losses that occur during episodes of vomiting and/or diarrhea, these patients may continue to have substantial and falsely reassuring urine output and/or isosthenuria noted on urine-specific gravity (SG; ie, urine SG that reflects SG of protein free plasma, usually 1.010 to 1.015). This increases the risk of hypovolemia, with a potential decrease in perfusion to the kidneys and prerenal acute kidney injury. Small children and infants are especially vulnerable as they are unable to independently access or indicate the need for fluids and are totally dependent on caretakers for fluid replacement. The perpetual need for access to free water should be emphasized to the caretakers, especially when the child has an intercurrent illness that increases volume losses (eg, vomiting or diarrhea) or decreased fluid intake. Salt supplementation is also frequently required in infants and younger children, who may require an additional 1 to 5 mEq/kg of sodium supplementation daily [5,6]. Hyponatremia is frequently observed during periods of salt depletion but also may be noted in the setting of excess free water administration. (See "Chronic kidney disease in children: Overview of management", section on 'Avoid subsequent kidney injury'.)
●Salt and fluid overload – As the kidney function becomes severely compromised (GFR <15 mL/min per 1.73 m2, stage G5), sodium and water retention may result in chronic intravascular volume overload. In general, a combination of dietary sodium restriction and diuretic therapy is used to prevent fluid overload:
•Sodium restriction – We recommend sodium intake of less than 1500 to 2400 mg/day for children who require sodium restriction, consistent with guidelines from the Kidney Disease Outcomes Quality Initiative [5].
This sodium restriction is often a difficult task given the sodium content of the favorite foods of children. Although the recommended daily sodium intake in healthy children is only 1.2 g/day for four- to eight-year-old children and 1.5 g/day for older children, this is substantially lower than the average intake in a healthy child in the United States [7,8].
•Diuretics – Diuretic therapy includes either loop diuretics such as furosemide given at a dose of 0.5 to 2 mg/kg per day or thiazide diuretics such as hydrochlorothiazide at 1 to 3 mg/kg per day. At our center, we typically use a thiazide diuretic in the early stages of CKD and a loop diuretic in the more advanced stages of disease when thiazide therapy may be less effective. Both classes of diuretics become less effective with decreasing GFR and may require higher mg/kg dosing to maintain desired effects on electrolyte stability and/or fluid balance.
Hyperkalemia — Hyperkalemia develops primarily because of inadequate potassium excretion due to a reduced GFR. Other factors that can contribute to elevated potassium levels include a high dietary potassium intake; increased tissue breakdown (rhabdomyolysis); hemolysis; metabolic acidosis; hypoaldosteronism (due in some cases to administration of an angiotensin-converting enzyme [ACE] inhibitor or an angiotensin II receptor blocker [ARB]); medication side effect (beta blockers, potassium-sparing diuretics, nonsteroidal antiinflammatory drugs); or impaired cellular uptake of potassium. Elevated serum potassium may also be due to voltage-dependent distal renal tubular acidosis, as may occur in children with obstructive uropathy [9]. (See "Hypokalemia in children", section on 'Increased urinary losses' and "Causes, clinical manifestations, diagnosis, and evaluation of hyperkalemia in children", section on 'Abnormalities in renal excretion'.)
Management to prevent hyperkalemia in children with CKD consists of the following and is consistent with the practice recommendations from the Pediatric Renal Nutrition Taskforce [10]. Specific interventions are presented separately in greater detail. (See "Management of hyperkalemia in children".)
●Low-potassium diet – For infants taking a formula or children taking nutritional supplements, select a product that is low in potassium. Breast milk has low potassium content and should generally be encouraged for infants with CKD [11]. For formula-fed infants, formulas that are extremely low in potassium are commercially available (ie, Renastart or Renastep for older children) [12]. Since they are extremely low in other electrolytes except sodium, they are often combined with other nutritional formulas in children who require a potassium-restricted diet. The use of these formulas requires close medical supervision, ideally by a multidisciplinary team including a pediatric renal dietician.
●Potassium binders:
•Cation-exchange resins (eg, sodium polystyrene sulfonate [SPS] or calcium polystyrene sulfonate), are used to decrease the absorption of dietary potassium in children. Their use in children should be directed by a clinician with expertise in managing pediatric hyperkalemia. In the United States, calcium polystyrene sulfonate is not available. As a result, our center uses SPS in the following manner:
-For formula-fed infants, the formula can be mixed with SPS and decanted to decrease the potassium content of the formula prior to feeding [13]. Direct oral administration of cation-exchange resins has been associated with intestinal necrosis, and its use is contraindicated in neonates, especially premature infants. Use of SPS results in a decrease in calcium, magnesium, and copper and an increase in the iron, sodium, and aluminum content of the nutritional formula [14]. Due to the increased availability of multiple low-potassium nutritional products, in our experience, SPS-decanting is used primarily for infants who require a hydrolyzed or non-cow's protein-based formula.
-For older children, SPS is available as an oral suspension or rectal enema. When administered into the intestinal tract, approximately 1 mEq of potassium is exchanged per g of SPS, which also delivers 4.1 mEq of sodium per g of drug to the patient. Long-term use of SPS is limited due to poor patient tolerability, as a result of both the poor palatability and associated diarrhea.
•Patiromer, a potassium-binding polymer, has been studied in adults with CKD stage G3 or greater with hyperkalemia, but similar pediatric data are not available. In adults, patiromer decreased serum potassium level after four weeks of treatment compared with placebo and remained efficacious throughout the study period of 52 weeks with lower potassium levels and a reduction in recurrent episodes of hyperkalemia. Clinical trials are underway in children to determine if patiromer has similar beneficial effects without serious adverse effects. (See "Treatment and prevention of hyperkalemia in adults", section on 'Patiromer'.) [13,14]
●Correction of metabolic acidosis – Oral sodium bicarbonate therapy can transiently improve hyperkalemia by inducing transcellular movement of potassium intracellularly. However, this is only a temporizing measure as it does not affect the overall body potassium load. (See 'Metabolic acidosis' below and "Management of hyperkalemia in children", section on 'Sodium bicarbonate'.)
●Correction of salt depletion – In children with obstructive uropathy or renal dysplasia, salt or volume depletion can result in hyperkalemia due to impaired distal sodium-potassium exchange in the distal tubule and cortical collecting ducts. This is best addressed with sodium supplementation and adequate fluid repletion. (See 'Sodium and water homeostasis' above.)
●Diuretics – Administration of a thiazide or loop diuretic to increase urinary potassium loss. Thiazide diuretics may be most useful in the setting of mild hyperkalemia and/or in the setting of mildly impaired GFR. Loop diuretics, which have more potent diuretic and kaliuretic effects, may be most useful in CKD patients who experience significant concomitant extracellular volume expansion or who have more advanced CKD.
●Kidney replacement therapy – Kidney replacement therapy may be necessary if conservative management fails to control severe symptomatic hyperkalemia, which may be associated with potentially life-threatening arrhythmias. (See "Management of hyperkalemia in children", section on 'Dialysis'.)
Hypokalemia — Hypokalemia is less frequently observed in children with CKD but may occur in the following scenarios:
●Children with polyuria (eg, those with congenital anomalies of the kidney and urinary tract [CAKUT]) with chronic intravascular volume depletion, which may cause increased renin and aldosterone activity, which enhances urinary potassium losses and leads to hypokalemia.
●Children with genetic tubular abnormalities resulting in increased urinary potassium loss, such as type II (proximal) renal tubular acidosis and Bartter syndrome.
●Aggressive diuretic therapy (eg, for fluid retention or edema).
●Severe acute malnutrition.
(See "Hypokalemia in children" and "Etiology and clinical manifestations of renal tubular acidosis in infants and children" and "Inherited hypokalemic salt-losing tubulopathies: Pathophysiology and overview of clinical manifestations".)
Metabolic acidosis — The cause of metabolic acidosis with advanced kidney disease is related to the fall in total ammonium excretion that occurs when the GFR decreases to below 40 to 50 mL/min per 1.73 m2 (stage G3). It is associated with an increased anion gap, which helps differentiate it from normal anion-gap metabolic acidosis that may occur in some patients with early CKD due to conditions of obstructive uropathy. In addition, there is a reduction in both titratable acid excretion (primarily as phosphate) and bicarbonate reabsorption. As the patient approaches CKD stage G5 (end-stage kidney disease), the serum bicarbonate concentration tends to stabilize between 12 and 20 mEq/L. A level below 10 mEq/L is unusual as buffering of the retained hydrogen ions by various body buffers prevents a progressive fall in the bicarbonate concentration. Acidosis is associated with growth impairment because the body utilizes bone buffering to bind some of the excess hydrogen ions. (See "Growth failure in children with chronic kidney disease: Risk factors, evaluation, and diagnosis", section on 'Metabolic acidosis'.)
We suggest providing enteral sodium bicarbonate therapy in patients with metabolic acidosis to maintain the serum bicarbonate level at or above 22 mEq/L consistent with the Kidney Disease Outcomes Quality Initiative and Kidney Disease: Improving Global Outcomes (KDIGO) guidelines [1,15]. Sodium bicarbonate therapy is started at 1 to 2 mEq/kg per day in two to three divided doses, and the dose is titrated to reach the clinical target. Citrate preparations should generally be avoided in children with CKD as these preparations enhance aluminum absorption from the intestine and increase the risk of aluminum toxicity. (See "Approach to the child with metabolic acidosis", section on 'Chronic metabolic acidosis' and "Aluminum toxicity in chronic kidney disease".)
CHRONIC KIDNEY DISEASE-MINERAL AND BONE DISORDER — CKD-mineral and bone disorder (CKD-MBD) presents as a clinical spectrum, encompassing abnormalities in mineral metabolism, bone structure, and extraskeletal calcifications that are found with progressive CKD. CKD-MBD, when untreated, can first be detected in children with glomerular filtration rate (GFR) stage G2, who are typically asymptomatic but have abnormal laboratory findings (eg, decreased serum calcidiol and/or calcitriol levels and elevated serum parathyroid hormone and fibroblast growth factor 23 levels (figure 1)) [16-18]. Patients with more advanced CKD, if untreated, may have bone pain, difficulty in walking, skeletal deformities including rickets, growth impairment, avascular necrosis, vascular calcifications, and an increased risk of fractures [19-23]. (See "Chronic kidney disease in children: Clinical manifestations and evaluation", section on 'Physical examination'.)
CKD-MBD in children, including its management, is discussed in greater detail separately. (See "Pediatric chronic kidney disease-mineral and bone disorder (CKD-MBD)".)
ANEMIA — Anemia due to reduced kidney erythropoietin production generally develops when the glomerular filtration rate (GFR) is below 40 mL/min per 1.73 m² [24]. At the onset of dialysis, the presence of anemia in children is very common and has been associated with excessive morbidity and an increased mortality risk [25]. If left untreated, the anemia of CKD is associated with fatigue, weakness, decreased executive function, increased somnolence, poor exercise tolerance, and growth impairment [19,26-31].
Because anemia occurs in all children with severe CKD (ie, stages G4 and G5) if untreated, guidelines have been developed for the early identification, evaluation, and treatment of anemia in children at all stages of CKD [1,32]. The recommendations for the management of anemia presented here are based on these sets of guidelines (algorithm 1).
Screening and evaluation of anemia — Annual testing of hemoglobin (Hb) should be performed in children with CKD, regardless of stage or cause. A diagnosis of anemia is made when the observed Hb result is below the 2.5th percentile of normal, adjusted for age and sex (table 3). (See "Approach to the child with anemia", section on 'Definition of anemia'.)
In any child with CKD and anemia, we perform the following evaluation, which is focused on identifying other potentially treatable causes of anemia (eg, iron deficiency) (algorithm 1) [33]. The anemia of CKD is principally normocytic and normochromic. The finding of microcytosis may reflect iron deficiency or aluminum excess, and macrocytosis may be associated with vitamin B12 or folate deficiency.
●Red blood cell indices
●Reticulocyte count
●Iron parameters (serum iron, total iron-binding capacity, percent transferrin saturation [TSAT], serum ferritin)
●Test for occult blood in stool
Interpretation of the results of these tests is discussed separately. (See "Approach to the child with anemia", section on 'Diagnostic approach'.) Evaluation for aluminum toxicity in CKD is discussed separately. (See "Aluminum toxicity in chronic kidney disease".)
Treatment of anemia — After eliminating other causes of anemia, treatment of anemia due to CKD includes iron supplementation (when indicated) and use of erythropoiesis-stimulating agents (ESA).
Target hemoglobin — We suggest a target Hb between 11 and 12 g/dL be maintained, which is consistent with published guidelines that are based on consensus expert opinion [32,34,35].
This target is supported by the following data:
●Hb levels below 10 and 11 g/dL are associated with increased mortality and morbidity in infants and children with CKD [32,36].
●Hb levels above 13 g/dL in adults are associated with an increased risk of cardiovascular-related events. As a result, there is a general consensus among experts in the field that adult targeted Hb levels should not exceed 13 g/dL in patients treated with an ESA (see "Treatment of anemia in nondialysis chronic kidney disease", section on 'Target hemoglobin value'). Limited retrospective data found that an Hb value >12 g/dL was not associated with increased cardiovascular morbidity or mortality in pediatric hemodialysis patients [37].
●Hb Z-scores of less than -1.0 were independently associated with growth impairment at the subsequent study visit, and one-half of these participants corresponded to Hb values higher than the threshold guidelines used as anemia cutoffs in the Kidney Disease: Improving Global Outcomes (KDIGO) clinical practice guidelines for anemia in CKD [31]. (See "Treatment of anemia in patients on dialysis".)
Iron — Iron therapy (elemental iron 2 to 6 mg/kg per day in two to three divided doses) should be initiated if iron deficiency is detected (microcytic anemia and low serum ferritin level). In our practice, which is consistent with published guidelines, iron supplementation is targeted to maintain a TSAT ≥20 percent and a serum ferritin ≥100 ng/dL in children with CKD [33]. We treat children with CKD who are not receiving hemodialysis with oral iron therapy. Intravenous iron therapy is reserved for children receiving hemodialysis or if the child not on dialysis is intolerant of oral iron or target Hb levels are not achieved with oral therapy.
Iron therapy should be given to all patients receiving therapy with an ESA to prevent the development of iron deficiency. Once the iron status is normal, iron parameters should be monitored at least every three months or monthly following the initiation of and/or increase in ESA dosing. (See "Diagnosis of iron deficiency in chronic kidney disease".)
Erythropoiesis-stimulating agents — Although primarily used in patients with end-stage kidney disease, ESAs (eg, recombinant human erythropoietin [rHuEPO], darbepoetin alfa, or continuous erythropoietin receptor activator [CERA], methoxy polyethylene glycol-epoetin beta) are also used to correct the anemia in some children at earlier CKD stages [38,39].
Increasing the Hb into an acceptable range in pediatric patients with anemia may ameliorate anemia-induced symptoms (eg, fatigue and exercise intolerance), result in cardiovascular improvement, and possibly delay progression of CKD and decrease mortality [40]. We suggest initiating ESAs when the Hb level is <10 g/dL, provided that iron stores are replete with a TSAT >25 percent and serum ferritin >200 ng/mL. Iron supplementation is initially provided until iron stores are complete repleted to this level prior to ESA administration. (See "Treatment of anemia in nondialysis chronic kidney disease".)
●Formulations and dosing – Initial dosing varies based on the choice of ESA, age of the patient, and severity of CKD. In our practice, the preferred ESAs are rHuEPO and darbepoetin alfa. CERA is a longer-acting ESA with the potential benefit of improved adherence with less frequent dosing and reduced pain associated with the subcutaneous injection compared with darbepoetin.
•rHuEPO (epoetin alfa) is administered:
-In children not receiving dialysis and those receiving peritoneal dialysis, by subcutaneous administration with rotation of the site of injection.
-In patients who receive hemodialysis, intravenously through their vascular access.
-The range of dosing is based on age and severity of CKD. For example, initial dosing for children ≥5 years of age not receiving dialysis is 80 to 120 units/kg per week, administered in two to three divided doses. Children younger than five years of age or children receiving dialysis typically require higher doses (as much as 300 units/kg per week).
•Darbepoetin alfa is a long-acting erythropoietic agent and may be a preferred ESA for adolescents to improve compliance. Its threefold longer half-life and greater biologic activity compared with epoetin-alfa or epoetin-beta allows for less frequent dosing to effectively maintain a target Hb. Based on limited pediatric data, darbepoetin alfa can be given at a dose of 0.25 to 0.75 mcg/kg no more frequently than once weekly [41-43]. In a randomized controlled trial, darbepoetin alfa was shown to be effective and safe in 116 children with CKD-related anemia when administered either weekly or every two weeks to achieve Hb targets of 10 to 12 g/dL [38]. Similar to rHuEPO, darbepoetin is administered subcutaneously for patients not receiving dialysis or those on peritoneal dialysis, while intravenous administration is used for children on hemodialysis through their vascular access.
•CERA (methoxy polyethylene glycol-epoetin beta), an ESA with a longer half-life compared with other ESAs, allows for once-monthly dosing. In the open-label multicenter DOLPHIN study of 64 children between 6 and 17 years of age undergoing hemodialysis, intravenous CERA was able to maintain stable Hb levels when patients were switched to CERA from either rHuEPO or darbepoetin alfa using a conversion factor of 4 mcg every four weeks for each weekly dose of 125 international units epoetin alfa/beta or 0.55 mcg darbepoetin [44]. Adverse side effects were similar to those reported in studies of CERA in adults and include hypertension and vascular access thrombosis, which are also observed with other ESAs. Intravenously administered CERA may be considered for use in children on hemodialysis. The SKIPPER multicenter randomized clinical trial determined that subcutaneous CERA was safe and efficacious for pediatric patients with dialysis-dependent and nondialysis-dependent CKD [39].
●Monitoring response – The response to ESA is monitored by measurement of the Hb every one to two weeks following the initiation of treatment or following a dose change regardless of which formulation is chosen. The expected increase in Hb after the initiation of rHuEPO therapy or after a dose change is between 1 to 2 g/dL over a two- to four-week period. Once a stable target Hb and ESA dose have been achieved, Hb measurement may be performed every four weeks.
The most common cause of an incomplete response to an ESA is iron deficiency. However, other conditions in the iron replete patient may cause an inadequate response to an ESA as well and include:
•Infection or inflammation (see "Inflammation in patients with kidney function impairment")
•Chronic blood loss (see "Approach to the child with anemia")
•CKD-mineral and bone disorder (CKD-MBD) [45] (see "Overview of chronic kidney disease-mineral and bone disorder (CKD-MBD)")
•Aluminum toxicity (see "Aluminum toxicity in chronic kidney disease")
•Folate or vitamin B12 deficiency (see "Treatment of vitamin B12 and folate deficiencies")
•Malnutrition
•Hemoglobinopathies
•Hemolysis (see "Overview of hemolytic anemias in children")
•Rare causes, including carnitine and copper deficiencies
●Dose adjustment – For children who develop acquired ESA hyporesponsiveness, avoid repeated escalations in ESA dose beyond double the dose at which the Hb had been stable because of concern for direct toxicity related to the elevated ESA dosages [35]. A dose of ESA >6000 international units/m2 per week in children on peritoneal dialysis was associated with an increased mortality risk [36], although it is uncertain if the excess mortality risk was due to the ESA or rather to a comorbid condition associated with ESA resistance.
●Adverse effects – The adverse effects of ESAs is covered in detail elsewhere (see "Treatment of anemia in patients on dialysis", section on 'Adverse effects of ESAs')," although it should be noted that the data remains scarce and of very low quality in children.
RISK FOR CARDIOVASCULAR DISEASE — Children with CKD are at risk for cardiovascular disease (CVD) [46]. CVD is the leading cause of death in children and young adults with CKD. Cardiac arrest is the most common cause, followed by arrhythmia, cardiomyopathy, and cerebrovascular disease; myocardial infarction is rarely reported in this population. Young adults (25 to 34 years) with CKD have at least a 100-fold higher risk for CVD-related mortality compared with the general population [47]. As a result, CKD in children is one of the chronic diseases associated with an increased risk for accelerated atherosclerosis and early CVD (algorithm 2). (See "Overview of risk factors for development of atherosclerosis and early cardiovascular disease in childhood", section on 'Chronic kidney disease'.)
The increased incidence of premature CVD is due to the high prevalence of the following CVD risk factors in children with CKD [48]:
●Hypertension
●Left ventricular hypertrophy (LVH)
●Obesity [49]
●Dyslipidemia
●Abnormal glucose metabolism
●Metabolic bone disease (see "Pediatric chronic kidney disease-mineral and bone disorder (CKD-MBD)", section on 'Complications')
Hypertension — Strict blood pressure (BP) control that adheres to targeted BP goals (table 4) is one of the most important modifiable risk factors proven to be effective in slowing the progression of CKD in children [50]. (See "Chronic kidney disease in children: Overview of management", section on 'Blood pressure and targeted goals' and "Chronic kidney disease in children: Overview of management", section on 'Slow progression of chronic kidney disease'.)
Hypertension, defined as BP greater than the BP targeted goal on three separate occasions, is common in children with CKD, ranging from 54 to 70 percent of patients [51-55]. Unlike many of the complications of CKD, hypertension can be present in the earliest stages of CKD, although its prevalence increases with progressive declines in glomerular filtration rate (GFR) (table 1) [3]. Hypertension is usually due to volume expansion and/or activation of the renin-angiotensin-aldosterone system (eg, glomerular disease). In some cases, hypertension may be due, in part, to concurrent medications (eg, corticosteroids or calcineurin inhibitors [eg, cyclosporine or tacrolimus]) that are used to treat the underlying kidney disease.
Guidelines from the American Academy of Pediatrics and American Heart Association call for an expanded role of the use of ambulatory BP monitoring (ABPM), particularly in the setting of high-risk conditions like CKD [56,57]. It is recommended that children with CKD and hypertension should have at least yearly ABPM when available, both to screen for masked hypertension and to monitor treatment efficacy [56]. A 2012 study of children enrolled in the Chronic Kidney Disease in Children study found a strikingly high proportion (35 percent) of children with CKD who exhibited masked hypertension (eg, normal clinic BP but abnormal 24-hour ABPM) [58]. Target-organ changes such as LVH appear to be more closely correlated with ABPM-based readings than office-based readings [52]. Participants with the highest mean arterial pressures on sleep and wake ABPM studies demonstrate an increased risk of CKD progression over time [59,60], identifying uncontrolled hypertension as an important modifiable risk factor for CKD progression.
Treatment of hypertension includes both pharmacologic and nonpharmacologic therapy:
Nonpharmacologic therapy — For all children with CKD and hypertension, nonpharmacologic treatment should be initiated with lifestyle changes, including weight reduction for children who are overweight, regular aerobic exercise regimen, dietary measures (eg, diet rich in fruit/vegetables and reduced fat and salt), stress reduction, and avoidance of excess alcohol consumption, caffeine, energy drinks, and smoke or vaping exposure. (See "Nonemergent treatment of hypertension in children and adolescents", section on 'Nonpharmacologic therapy'.)
Pharmacologic therapy — Pharmacologic therapy is indicated in children with CKD at the time hypertension is diagnosed. Although lifestyle factors are important adjunctive treatment strategies, the treatment of hypertension in children with CKD differs from children without CKD in whom a three- to six-month trial of lifestyle modifications may be an appropriate initial treatment strategy.
●Target BP goals – We use the following target BP goals for office measurements (table 4). These targets represent the thresholds for normal BP for pediatric patients with CKD, as defined by the 2017 American Academy of Pediatrics and American Heart Association guidelines [56]:
•For children with CKD (<13 years of age), target systolic and diastolic BPs are <90th percentile of normative data for age, gender, and height (table 5 and table 6 and figure 2)
•For adolescents with CKD (≥13 years of age), target BP is ≤120/80 mmHg
We also use ABPM annually to target strict BP control with a target goal of a 24-hour mean arterial BP below the 50th percentile based on pediatric ABPM normative data for gender and height, as recommended by the 2017 American Academy of Pediatrics guidelines (table 7 and table 8 and table 9 and table 10) [56].
●Choice of drugs
•Renin-angiotensin-aldosterone system inhibitors – When pharmacologic therapy is initiated, the preferred choice of an antihypertensive agent is one that targets the renin-angiotensin system (angiotensin-converting enzyme [ACE] inhibitor or angiotensin II receptor blockers [ARBs]) as it provides the added benefit of reducing proteinuria [1,50,61-66]. ACE inhibitors or ARBs appear to be more beneficial in slowing the progression of CKD compared with other agents in patients with CKD [66]. (See "Chronic kidney disease in children: Overview of management", section on 'Slow progression of chronic kidney disease' and "Overview of hypertension in acute and chronic kidney disease", section on 'Choice of antihypertensive therapy'.)
In our practice, we prefer to initiate therapy with an ACE inhibitor as there are more data on the safety and efficacy of this class of drugs in children compared with ARBs. We start with an initial dose of enalapril of 0.08 mg/kg per day (maximum of 5 mg/day), which is titrated to a maximum dose of 0.6 mg/kg per day (maximum of 40 mg/day) based on the response of the patient's BP and results of lab tests (eg, serum potassium). We use enalapril because its long half-life allows once a day dosing. Alternative long-acting ACE inhibitors commonly used in children are lisinopril and ramipril, which are also administered once a day. (See "Nonemergent treatment of hypertension in children and adolescents", section on 'ACE inhibitors'.)
In patients who develop a cough with an ACE inhibitor, we use the ARB drug losartan at an initial dose of 0.7 mg/kg per day (maximum of 50 mg/day), which is titrated to a maximum dose of 1.4 mg/kg per day (maximum of 100 mg/day). ARBs may induce a more complete inhibition of the renin-angiotensin-aldosterone system but do not affect bradykinin and thereby have a lower risk of cough and angioedema than ACE inhibitors. We typically avoid combination therapy of ACE inhibitors and ARBs as data from adults suggest an increased likelihood of adverse events. (See "Major side effects of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers", section on 'Combination of ACE inhibitors and ARBs'.)
Both ACE inhibitors and ARBs should be used cautiously if the GFR is less than 60 mL/min per 1.73 m² [64,66]. Of note, discontinuation of ACE inhibitor/ARB in children with advanced CKD has been associated with more rapid CKD progression [66]. Since the decline in GFR induced by an ACE inhibitor/ARB typically occurs within the first few days after the onset of therapy, the serum creatinine and potassium concentrations should be remeasured within 7 to 10 days after the institution of therapy or dose titration to ensure that the therapy has not adversely affected the GFR, resulting in a significant elevation of serum creatinine and/or hyperkalemia.
The teratogenic potential of these drugs in women of childbearing age also should be discussed with any pubertal adolescent female when administration of either an ACE inhibitor or ARB is being considered. (See "Major side effects of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers" and "Adverse effects of angiotensin converting enzyme inhibitors and receptor blockers in pregnancy".)
•Diuretics – A diuretic may be used for patients with hypertension and edema. For patients in early stages of CKD (estimated GFR [eGFR] ≥45 mL/min per 1.73 m2), a thiazide diuretic such as hydrochlorothiazide (1 to 3 mg/kg per day to a maximum of 50 mg/day) is often effective. For patients with more advanced CKD, a loop diuretic is recommended, because thiazides become less effective as monotherapy as the GFR declines. In our practice, we use the loop diuretic furosemide at a dose of 0.5 to 2 mg/kg per day in one to two divided doses.
Left ventricular hypertrophy — LVH is a common finding in patients with CKD and occurs as a response to mechanical or hemodynamic overload [46]. There are two different patterns of LVH: concentric LVH, which occurs in the presence of hypertension, and eccentric LVH, which is associated with volume overload and anemia [67]. Preventive measures to reduce the risk of LVH include strict BP control, maintenance of a healthy body weight, and avoidance of volume overload and anemia. (See 'Hypertension' above and 'Sodium and water homeostasis' above and 'Anemia' above.)
In a study of 366 children with CKD stage G2 through G4, 17 percent of the cohort had LVH detected by echocardiography [52]. LVH was more common in children with confirmed and masked hypertension compared with those with normal BP measurements (34, 20, and 8 percent, respectively). A subsequent analysis of 725 children enrolled in the Chronic Kidney Disease in Children study found that adiposity was independently associated with markers of cardiac damage, LV mass index, Z-score, and LVH, particularly in girls, suggesting that obesity is a potentially modifiable risk factor for CVD [68].
Dyslipidemia — Abnormal lipid metabolism is common in patients with CKD and is one of the primary factors that increase the risk for CVD [69]. Children greater than two years of age with CKD (a known associated atherosclerotic condition) should be screened for dyslipidemia annually (algorithm 2), consistent with guidelines from the American Academy of Pediatrics, American Heart Association, Kidney Disease: Improving Global Outcomes (KDIGO), and an expert panel sponsored by the United States National Heart, Lung, and Blood Institute [70]. (See "Society guideline links: Lipid disorders and atherosclerosis in children".)
Observational data in children have shown that the risk of dyslipidemia (eg, abnormally high triglyceride and non-high-density lipid cholesterol [non-HDL-C] levels and decreasing HDL-C level) is high in children with CKD and increases as the GFR declines, with the highest risk for those with end-stage kidney disease and following kidney transplantation (algorithm 2) [48,70-77].
Our approach — In our practice, children greater than two years of age with CKD (including dialysis patients and those with kidney transplant) are evaluated with a fasting lipid profile (algorithm 2) [15,70,78]. If a lipid abnormality is detected, management consists of therapeutic lifestyle changes with dietary recommendations (table 11) based on the severity of CKD and made in concert with our pediatric renal dietitian. We consider the use of statins only in older children in whom the magnitude of dyslipidemia remains severe (eg, low-density lipoprotein cholesterol [LDL] >130 mg/dL) despite dietary management. (See "Society guideline links: Lipid disorders and atherosclerosis in children".)
●In children with CKD stage G5 (end-stage kidney disease), a very restrictive diet is prescribed (table 12) [15].
●In children with CKD with hypertriglyceridemia (fasting level >500 mg/dL [>5.65 mmol/L]), a very low-fat diet (fat content less than 15 percent of the total caloric intake) with substitution of medium-chain triglycerides and fish oil instead of long-chain triglycerides is prescribed [78]. However, in children who are malnourished, dietary changes should be made judiciously, if at all.
●Statin therapy may be considered only in older patients (males ≥10 years of age and postmenarchal female patients) with severely elevated LDL-C levels despite nonpharmacologic therapy. The decision is made jointly with the family and patient (if appropriate) after considering the currently available evidence and the potential for adverse effects of statin therapy. (See "Dyslipidemia in children and adolescents: Management", section on 'Statin therapy'.)
●Fibric acid derivatives or niacin should not be used as there is a paucity of evidence regarding their safety and efficacy [78].
The screening and management of pediatric dyslipidemia are discussed in greater detail separately. (See "Dyslipidemia in children and adolescents: Definition, screening, and diagnosis" and "Dyslipidemia in children and adolescents: Management".)
MALNUTRITION AND POOR GROWTH — Children with CKD require special considerations with regards to dietary requirements [11]. Although caloric and energy needs are similar to age-appropriate healthy children, children with CKD who have growth faltering often require 100 to 120 percent of Daily Recommended Intake for calories to achieve optimal growth. Additionally, protein restriction is not typically advised, with recommendations of 100 to 140 percent of Daily Recommended Intake for protein for CKD and 100 to 120 percent for end-stage kidney disease patients [11]. Careful management of the nutritional status of children with CKD, ideally under the supervision of a dietician, is recommended to provide adequate energy, protein, and electrolytes to optimize growth. Supplemental tube feedings through a gastrostomy or nasogastric tube are often required in infants and young children with more advanced kidney disease.
Growth failure is frequently a hallmark of pediatric CKD. The etiology of growth failure is multifactorial (metabolic acidosis, decreased caloric intake, CKD-mineral and bone disorder [CKD-MBD], sodium depletion, and alterations in the function of the growth hormone [GH] and insulin-like growth factor axis), and early preventive measures are undertaken to avoid these contributing factors. Growth failure is typically most profound in younger children with moderate to severe CKD. Recombinant human GH (rhGH) therapy may be appropriate for children with impaired linear growth and adequate energy consumption and can have a beneficial effect on the height velocity of children with CKD who are growing poorly [79].
The prevention and management of growth failure, including the use of rhGH, are discussed in greater detail separately. (See "Growth failure in children with chronic kidney disease: Prevention and management" and "Growth failure in children with chronic kidney disease: Treatment with growth hormone" and "Growth failure in children with chronic kidney disease: Risk factors, evaluation, and diagnosis".)
ENDOCRINE DYSFUNCTION — In patients with CKD, the following endocrine systems become dysfunctional as kidney function progressively deteriorates. Each of these is discussed in greater detail separately.
●Growth hormone (GH) function – CKD is associated with a variety of abnormalities in GH homeostasis including changes in the plasma concentration of GH, its release, and its end-organ responsiveness. In particular, end-organ resistance to GH due to increased levels of insulin growth factor binding proteins appears to play a major role in growth impairment in children with CKD [80]. (See "Growth failure in children with chronic kidney disease: Risk factors, evaluation, and diagnosis", section on 'Pathogenesis: Disturbance of growth hormone/IGF-1 axis'.)
●Thyroid function – In patients with CKD, alterations in the production, distribution, and excretion of thyroid hormones occur with increasing kidney dysfunction. These abnormalities are generally characterized by low total and free T4 and T3, a normal thyroid-stimulating hormone level, and normal or decreased thyroid hormone-binding globulin levels or thyrotropin-releasing hormone stimulation test results. These findings are consistent with the "sick euthyroid syndrome" seen in other chronic diseases. (See "Thyroid function in chronic kidney disease".)
●Gonadal hormone function – There are abnormalities in gonadal hormones in both male and female patients, which result in delayed puberty in two-thirds of adolescents with end-stage kidney disease [81]. Although the onset of puberty is frequently delayed, progression through the pubertal stages appears to be normal or only slightly delayed [6].
•In males, abnormalities include reduced levels of serum free testosterone, dihydrotestosterone, and adrenal androgens and increases in serum luteinizing hormone (LH) and follicle-stimulating hormone (FSH). (See "Causes of primary hypogonadism in males", section on 'Chronic kidney disease'.)
•Postpubertal females with CKD have reduced serum estrogen, elevated LH and FSH, and loss of the LH pulsatile pattern. These disturbances result in anovulation. In a study of 287 females with CKD, the median age at menarche was similar between females with CKD and healthy normal females [82]. However, 10 percent of this cohort had delayed menarche, which appeared to be associated with short stature.
NEURODEVELOPMENTAL IMPAIRMENT — CKD is associated with neurological comorbidities ranging from seizures and severe intellectual disability to more subtle deficits resulting in poor school performance [83,84]. Children with CKD have lower scores for executive function, memory (verbal and visual), mathematics, reading, and spelling compared with the general population [85]. In addition, poor academic performance may be related to school absenteeism, a common problem for children with CKD [84,86]. Other reported factors associated with cognitive impairment in children with CKD include high blood lead level [87] and changes in regional cerebral blood flow [88]. In addition, daytime sleepiness and fatigue are commonly seen in children with CKD and may impact their school performance [89,90].
Children on dialysis have lower scores on cognitive testing than those with milder CKD [91,92]. This association may be explained in part by effects of uremia on cognition and neurodevelopment. Children with mild CKD may display normal cognitive function on intellectual testing; however, these children remain at risk for neurocognitive dysfunction and may have poorer scores on testing for adaptive behavior and attention [91,93].
Because of the risk of neurodevelopmental impairment, early developmental surveillance and screening are important components of routine health care for children with CKD to identify children with or at-risk for neurodevelopmental delay. (See "Chronic kidney disease in children: Overview of management", section on 'Neurodevelopment assessment'.)
UREMIA — With CKD progression, a constellation of signs and symptoms referred to as uremia develops. Manifestations, which can be observed even in children with mild to moderate CKD and increase in prevalence with decreasing kidney function, include fatigue; anorexia; nausea; vomiting; growth retardation; pruritus; peripheral neuropathy; and central nervous system abnormalities ranging from loss of concentration and lethargy to seizures, coma, and death [4].
Other complications of uremia include the following:
●Platelet dysfunction – Patients who are uremic also have an increased tendency to bleed secondary to abnormal platelet adhesion and aggregation properties
●Pericardial disease – Pericardial disease (pericarditis and pericardial effusion) is an indication to institute dialysis in children with CKD
Uremic bleeding — An increased tendency for bleeding is present in patients with severe CKD due primarily to abnormalities in platelet adhesion and aggregation properties. In asymptomatic patients, no specific therapy is required. However, in patients who are actively bleeding or who are about to undergo a surgical or invasive procedure (such as kidney biopsy), the platelet abnormality should be addressed by consideration of the following preventative treatment options. (See "Uremic platelet dysfunction".)
●Desmopressin (dDAVP), an analog of antidiuretic hormone that is the simplest and least toxic acute treatment – In our practice, dDAVP is often given to children with uremia prior to invasive procedures deemed high risk for bleeding. It is administered intravenously or subcutaneously at a dose of 0.3 mcg/kg with an onset of effect within one hour of administration; the effect lasts for six to eight hours.
●Cryoprecipitate (1 to 2 units/10 kg) – The effect lasts for 24 to 36 hours, but there is an increased risk of transmitted infectious diseases. Therefore, this is not considered routinely for prophylaxis but reserved for use in the setting of active bleeding.
●Estrogen (0.6 mg/kg per day for five days) – The onset of effect is over 6 to 24 hours, but the effect lasts for two to three weeks.
●Correction of anemia – An improved hemoglobin (Hb; hematocrit) is believed to facilitate increased interaction between platelets and blood vessels.
Uremic pericarditis — Uremic pericardial disease (pericarditis and pericardial effusion) is seen only in the late stages of CKD and is an indication to institute dialysis. Most patients with uremic pericarditis respond rapidly to dialysis, with resolution of chest pain as well as a decrease in the size of the pericardial effusion.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Chronic kidney disease-mineral and bone disorder".)
SUMMARY AND RECOMMENDATIONS
●Definition – Chronic kidney disease (CKD) refers to a state of irreversible kidney damage and/or reduction of kidney function that is associated with a wide range of complications. Complications begin to be observed with moderate to severe loss of loss of glomerular filtration rate (GFR; ie, GFR <45 mL/min per 1.73 m2) (table 1). (See 'Definitions' above.)
●Fluid and electrolyte abnormalities:
•Salt wasting and hypovolemia – Salt wasting and poor urinary concentrating ability are often seen in children with obstructive uropathy and/or dysplastic kidneys. These children are at risk for clinically significant hypovolemia as they are unable to respond appropriately to acute intravascular volume depletion that can occur with episodes of vomiting and diarrhea. (See 'Sodium and water homeostasis' above.)
•Salt and fluid overload – As kidney function becomes severely compromised (GFR <15 mL/min per 1.73 m2), sodium and water retention may result in chronic intravascular volume overload. In children with CKD and volume overload, we suggest a combination trial of dietary sodium restriction and diuretic therapy (Grade 2C). In our practice, we limit the sodium intake to 1.5 to 2.4 g/day. Thiazide diuretics (eg, hydrochlorothiazide) are preferred in the early stages of CKD, while furosemide or another loop diuretic is used in more advanced stages of CKD. (See 'Sodium and water homeostasis' above.)
•Hyperkalemia – In children with moderate to severe CKD, we recommend a low-potassium diet to prevent hyperkalemia (Grade 1C). Other interventions include the use of loop diuretics (eg, furosemide) and correction of metabolic acidosis. (See 'Hyperkalemia' above.)
•Metabolic acidosis – In children with CKD and metabolic acidosis, we suggest administering enteral sodium bicarbonate to maintain a serum bicarbonate level ≥22 mEq/L (Grade 2C). Citrate preparations should be avoided as these preparations enhance aluminum absorption. (See 'Metabolic acidosis' above.)
●CKD-mineral and bone disorder (CKD-MBD) – Management of CKD-MBD includes ongoing monitoring of bone metabolism (measurements of serum concentrations of calcium, phosphorus, parathyroid hormone, and alkaline phosphatase levels) and appropriate therapeutic interventions including dietary phosphate restriction, phosphate binders, vitamin D replacement therapy, active vitamin D analogs, and calcimimetic drugs. (See "Pediatric chronic kidney disease-mineral and bone disorder (CKD-MBD)".)
●Anemia – In children with CKD, hemoglobin (Hb) testing should be performed at least yearly. Anemia is defined as an Hb below the 2.5th percentile of normal adjusted for age and sex (table 3). After eliminating other causes of anemia (algorithm 1), treatment of anemia due to CKD includes iron supplementation and, in patients with severe CKD, erythropoietin therapy. We suggest administrating an erythropoiesis-stimulating agent (ESA) when the Hb level is <10 g/dL, provided that there is no evidence of iron deficiency or other cause of anemia (Grade 2C). When ESA is used in children with CKD, we suggest maintaining the Hb value between 11 and 12 g/dL (Grade 2C). (See 'Anemia' above.)
●Hypertension – In children with CKD and hypertension, we suggest that an angiotensin-converting enzyme (ACE) inhibitor or an angiotensin II receptor blocker (ARB) be used rather than other classes of antihypertensive agents to maintain targeted blood pressure (BP) goals (table 4) (Grade 2C). (See 'Hypertension' above.)
●Dyslipidemia – In children with CKD, screening for dyslipidemia is performed by obtaining fasting lipid profiles on an annual basis. In patients with CKD and dyslipidemia, we suggest an initial trial of nonpharmacologic therapy that includes diet (table 12 and table 11) and daily exercise (Grade 2C). We suggest statin therapy be considered in patients greater than 10 years old with a persistently elevated low-density lipoprotein cholesterol (LDL-C) level despite dietary measures (Grade 2C). (See 'Dyslipidemia' above.)
●Malnutrition and growth failure – In children with CKD, growth failure is a long-recognized complication and may be multifactorial (eg, metabolic acidosis, decreased caloric intake, CKD-MBD, and dysfunction of the growth hormone [GH] and insulin-like growth factor axis). However, poor growth may persist despite measures focused on modifying causal factors. Careful management of the nutritional status of children with CKD, ideally under the supervision of a dietician, is recommended to provide adequate energy, protein, and electrolytes to optimize growth. For these patients with persistent growth impairment, recombinant human GH (rhGH) is an option to improve linear growth. (See "Growth failure in children with chronic kidney disease: Treatment with growth hormone" and 'Malnutrition and poor growth' above.)
●Neurodevelopmental impairment – Children with CKD are at risk for neurocognitive dysfunction, particularly in executive functioning and attention. Ongoing and early neurodevelopmental assessment is necessary to determine whether early intervention or educational support is needed. (See 'Neurodevelopmental impairment' above.)
●Uremia – With progression of CKD, a constellation of signs and symptoms referred to as uremia develops with manifestations of anorexia, nausea, vomiting, growth retardation, peripheral neuropathy, central nervous system abnormalities, increased tendency for bleeding due to platelet dysfunction (uremic bleeding), and pericarditis. In affected children, uremic pericarditis resolves with the successful initiation of kidney replacement therapy. (See 'Uremia' above.)
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