Chronic Kidney Disease in Children and Adolescents Susan F. Massengill and Maria Ferris Pediatrics in Review 2014;35;16 DOI: 10.1542/pir.35-1-16

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Pediatrics in Review is the official journal of the American Academy of Pediatrics. A monthly publication, it has been published continuously since 1979. Pediatrics in Review is owned, published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2014 by the American Academy of Pediatrics. All rights reserved. Print ISSN: 0191-9601.

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Chronic Kidney Disease in Children and Adolescents Susan F. Massengill, MD,* Maria Ferris, MD, MPH, PhD†

Author Disclosure Drs Massengill and Ferris have disclosed

Educational Gap Chronic kidney disease (CKD) is a devastating diagnosis with many co-morbidities, increasing the risk of mortality 30 to 150 times that of the general pediatric population. Recognition of at-risk children can lead to earlier screening and risk reduction. Primary care clinicians are often unaware of the comorbid conditions and long-term consequences of CKD, particularly with respect to cardiovascular disease, nutrition and growth, neurocognitive development, and burden of disease.

no financial relationships relevant to this article. This commentary does not contain a discussion of an unapproved/ investigative use of

Objectives 1. 2. 3. 4.

a commercial product/ device.

After completing this article, readers should be able to:

Be aware of the life course of CKD and its co-morbidities. Recall the risk factors and complications of pediatric CKD. Discuss measures to prevent or delay the progression of pediatric CKD. Optimize the communication between the primary care clinician and nephrologist in treating children, adolescents, and young adults with CKD.

Case 1 A 13-month-old toddler new to your practice presents for his 1-year health maintenance visit with poor growth and developmental delay. He is just now sitting without support and appears to have occasional leg pain. He is pale, weighs 7.9 kg, and has a normal blood pressure. The results of laboratory studies are remarkable for anemia (hemoglobin, 9 g/dL [90 g/L]), profound acidosis (carbon dioxide, 12 mEq/L [12 mmol/L]), azotemia (urea nitrogen, 117 mg/dL [41.8 mmol/L]; creatinine, 2.44 mg/dL [216 mmol/L]), and profound hypocalcemia (calcium, 5.6 mg/dL [1.40 mmol/L]), prompting further evaluation where hypocalcemia was confirmed. Urinalysis revealed a specific gravity of 1.005 and proteinuria (1þ). Renal ultrasonography revealed bilateral renal hypoplasia. Renal replacement therapy was initiated with peritoneal dialysis, and the patient is on the renal transplantation waiting list.

Case 2 Abbreviations 1,25(OH)2 D: 1,25-dihydroxyvitamin D ACE: angiotensin-converting enzyme CKD: chronic kidney disease CKiD: Chronic Kidney Disease in Children CVD: cardiovascular disease eGFR: estimated glomerular filtration rate ESKD: end-stage kidney disease GFR: glomerular filtration rate HCT: health care transition MBD: metabolic bone disease

A previously healthy, 14-year-old, African American girl presents with a 3-month history of facial and lower-extremity rash and a 4.5-kg weight loss. Her medical history is unremarkable for contributing conditions. She denies sexual activity, travel, pet ownership, or tick exposure. Her family history is positive for type 1 diabetes mellitus in a younger brother and hypothyroidism in her mother. On physical examination, she is hypertensive (blood pressure, 150/90 mm Hg), with a malar erythematous rash and palpable purpura on the lower extremities. Laboratory studies reveal the following: serum creatinine, 2.5 mg/dL (221 mmol/L); estimated glomerular filtration rate (eGFR), 34 mL/min/1.73 m2; urea nitrogen, 75 mg/dL (26.8 mmol/L); and positive

*Director, Pediatric Nephrology, Levine Children’s Hospital, Adjunct Associate Professor of Pediatrics, University of North Carolina School of Medicine, Charlotte, NC. † Director, Pediatric Dialysis and Transplant Programs, UNC Kidney Center, Founder and Director, The UNC Children’s Hospital TRxANSITION Program, University of North Carolina at Chapel Hill, Chapel Hill, NC. 16 Pediatrics in Review Vol.35 No.1 January 2014

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antinuclear antibody and anti–double-stranded DNA results. Urinalysis reveals blood (3þ), proteinuria (4þ), 10 to 20 red blood cells per high-power field, and 1 red blood cell cast. Urine protein to creatinine ratio is 2.5 (reference range, 90 mL/min/1.73 m2) Mild reduction in the GFR (60-89 mL/min/1.73 m2) Moderate reduction in the GFR (30-59 mL/min/1.73 m2) Severe reduction in the GFR (15-29 mL/min/1.73 m2) Kidney failure GFR (90) 2 (GFR 60-89) 3 (GFR 30-59) 4 (GFR 15-29)

Urinalysis and BP measurement If low birth weight or other factors for Y renal mass BP measurement

5 (Transplant)

Growth, nutrition Urinalysis and BP measurement Exercise Encourage adherence and hydration

Peritoneal dialysis

Growth, nutrition


Growth, maintain fluid restriction

Selective conditions or psychosocial issues Congenital anomalies of the kidney and urinary tract

Acute kidney injury recovery


Universal medical services, universal literacy and numeracy appropriate services

Universal Psychosocial Services

Diagnosis and Treatment of Comorbid Conditions

Reduce Negative Effect of Comorbid Conditions and Treat Complications

Monitor growth

Modify CVD risk factors

Monitor for proteinuria Normalize BP Monitor growth Growth hormone as Monitor proteinuria, needed, modify normalize BP CVD risk factors Rapid fluid resuscitation Viral infection in dehydration surveillance (CMV, EBV): lymphadenopathy, enlarged tonsils, fever, bone marrow suppression Monitor for signs of Encourage living donor peritonitis, optimize transplantation protein intake High index of suspicion for infection

Teratogen avoidance and prenatal vitamins in future pregnancies

Postnatal ultrasonography, high index of suspicion for UTI

Urinalysis and BP measurement Serum chemical analyses Monitor growth Encourage healthy diet and exercise

Encourage hydration, avoid nephrotoxic agents

Surgical correction as needed, healthy toilet habits Psychosocial support of long-term enuresis Voiding history not reliable during dehydration (poor ADH response) Nephrology referral for abnormal growth or laboratory values

Monitor serial BP

Annual echocardiogram, urinalysis, eye examination; modify CVD risk factors Screen for modifiable CVD factors: normal BP, hyperlipidemia, exercise, and healthy weight and diet Provide immunizations Assume low functional and health literacy and numeracy and provide patient education and counseling at a fourth grade or below level. Monitor parent and patient’s ability to read prescription and food labels. Use teach-back method to ensure comprehension of education sessions and material. Monitor: psychosocial evaluation, health-related quality of life, individualized education plan Encourage: therapeutic camp participation Continued Pediatrics in Review Vol.35 No.1 January 2014 25

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chronic kidney disease

Table 4. (Continued)

Conditions Health care transition and treatment adherence

Reduce Negative Effect of Diagnosis and Comorbid Conditions and Treatment of Surveillance and Treat Complications Comorbid Conditions Risk Reduction Assess patient and parent literacy to customize patient and family education efforts; Monitor ability to read prescriptions and food labels; prescription refill rate or drug levels (when applicable) and support the health care transition process; adherence and successful disease self-management

ADH¼antidiuretic hormone; BP¼blood pressure; CKD¼chronic kidney disease; CMV¼cytomegalovirus; CVD¼cardiovascular disease; EBV¼Epstein-Barr virus; ESKD¼end-stage kidney disease; UTI¼urinary tract infections.

Case 2 This patient has been diagnosed as having CKD at a crucial developmental age. She is at risk for psychological distress and must adjust to her life-changing diagnosis and the medical treatment. This form of nephritis will need aggressive immunosuppression (corticosteroids and cyclophosphamide), which has many adverse effects, some of which can affect appearance, placing her at risk for treatment nonadherence. Her hypertension with proteinuria will require the use of ACE inhibitors or angiotensinreceptor blockers for their renoprotective effect. She needs to know that if she becomes pregnant the fetus is at risk for ACE fetopathy, affecting the fetal kidneys.

Cases 1 and 2 Both patients are at risk for early cardiovascular events during young adulthood. They would benefit from participating in therapeutic camps and psychosocial services. Both families will need to receive counseling and support to optimize family function. Living kidney donation for transplantation by family members of friends needs to be encouraged because this type of donation has better outcomes. The HCT preparation will need to start between ages 12 and 14 years to ensure successful disease self-management when they transfer to adult-focused health care clinicians. Both patients are at greater risk of nonadherence during the adolescent years, and prescription refill rate or therapeutic drug levels will assist the primary care clinician’s team to counsel these patients and encourage treatment concordance.

Primary Care Clinician Activities to Overcome the Challenges in the Diagnosis and Management of Pediatric-Onset CKD The 2 major barriers for early diagnosis and treatment of CKD are low awareness by the patient, family, and health care clinicians of risk factors for this condition and the silent nature of this condition in its initial stages. Early

identification of pediatric CKD in patients at risk is paramount to optimize patient outcomes. We suggest activities to achieve this goal in Table 3. Patients often present to emergency departments with CKD or ESKD in its late stages, and adjustment to the diagnosis is a major challenge for both the patients and their families. Regular screening for CKD factors as suggested in Table 3 and Table 4 will ensure early diagnosis and referral for prevention of unnecessary complications. As soon as CKD is diagnosed, referrals for psychosocial and educationalrelated services will help with adjustment to this condition. We find that if we refer all patients and families with a new diagnosis of CKD to obtain a baseline psychological evaluation there is less resistance by these families when a future need for these services arise. Establishing a relationship between the psychology team and the patient and family decreases the anxiety and stigma effect that this type of referral may create. Starting HCT-related activities in the early stages of adolescence will ensure successful disease self-management on transferring to adult-focused health care clinicians. Monitoring and encouraging adherence to treatment and medical appointments prevents CKD complications (transplant rejection, volume overload, and hypertensive crisis) along with optimizing the longevity of renal transplants. Once the diagnosis of CKD or ESKD is established, finding a living donor among the family members or friends is difficult in part due to public misconceptions about donation. The primary care clinician can assist with patient education and identification of potential donors. Ensuring close collaboration between the medical home (primary care clinicians) and medical neighbors (subspecialty clinicians, educators, community workers, and agencies) can be difficult given that electronic medical records are not readily available to all, but close communication among health care clinicians that includes the patient and family will positively affect the long-term outcomes of youth with pediatric-onset CKD.

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ACKNOWLEDGMENTS. We thank Wallace Brown, MD, Andrew Wallace, MS4, William Primack, MD, and Keisha Gibson, MD, MPH, from the University of North Carolina School of Medicine and Donald Jack Weaver, MD, PhD, and Charles McKay, MD, from Levine Children’s Hospital for their insightful comments.

Summary On the basis of evidence, children, adolescents, and young adults with chronic kidney disease or end-stage kidney disease may have: • Great morbidity in other organ systems, affecting their long-term survival. (1)(2)(3)(5)(6)(7)(8) • Lower immunization rates, placing them at risk for preventable conditions. (4) • Psychosocial and neurocognitive issues, affecting their self-esteem and school or job performance. (1) (8)(10)(11) • Psychiatric conditions, such as depression, anxiety, attention-deficit/hyperactivity disorder, maladjustment, and posttraumatic stress disorder. (1) (10)(11) • Nonadherence (14) and great treatment burden, (9) particularly in adolescence and young adulthood, placing these patients at risk for transplant loss and hospitalizations.

On the basis of research evidence and expert consensus, health care transition preparation to self-manage their condition will ensure successful outcomes and improved health-related quality of life. (12)(14)

References 1. Copelovitch L, Warady BA, Furth SL. Insights from the Chronic Kidney Disease in Children (CKiD) study. Clin J Am Soc Nephrol. 2011;6(8):2047–2053

chronic kidney disease

2. Ferris ME, Gipson DS, Kimmel PL, Eggers PW. Trends in treatment and outcomes of survival of adolescents initiating endstage renal disease care in the United States of America. Pediatr Nephrol. 2006;21(7):1020–1026 3. Wühl E, Trivelli A, Picca S, et al; ESCAPE Trial Group. Strict blood-pressure control and progression of renal failure in children. N Engl J Med. 2009;361(17):1639–1650 4. Neu AM. Immunizations in children with chronic kidney disease. Pediatr Nephrol. 2012;27(8):1257–1263 5. Shroff R, Weaver DJ Jr, Mitsnefes MM. Cardiovascular complications in children with chronic kidney disease. Nat Rev Nephrol. 2011;7(11):642–649 6. Mak RH, Cheung WW, Zhan J-Y, Shen Q, Foster BJ. Cachexia and protein-energy wasting in children with chronic kidney disease. Pediatr Nephrol. 2012;27(2):173–181 7. Foster BJ, McCauley L, Mak RH. Nutrition in infants and very young children with chronic kidney disease. Pediatr Nephrol. 2012; 27(9):1427–1439 8. Lande MB, Gerson AC, Hooper SR, et al. Casual blood pressure and neurocognitive function in children with chronic kidney disease: a report of the children with chronic kidney disease cohort study. Clin J Am Soc Nephrol. 2011;6(8): 1831–1837 9. So TY, Layton JB, Bozik K, et al. Cognitive pharmacy services at a pediatric nephrology and hypertension clinic. Ren Fail. 2011;33 (1):19–25 10. Sinha R, Davis ID, Matsuda-Abedini M. Sleep disturbances in children and adolescents with non-dialysis-dependent chronic kidney disease. Arch Pediatr Adolesc Med. 2009;163 (9):850–855 11. Davis ID, Greenbaum LA, Gipson D, et al. Prevalence of sleep disturbances in children and adolescents with chronic kidney disease. Pediatr Nephrol. 2012;27(3):451–459 12. Ferris ME, Mahan JD. Pediatric chronic kidney disease and the process of health care transition. Semin Nephrol. 2009;29(4): 435–444 13. Ferris ME, Harward DH, Bickford K, et al. A clinical tool to measure the components of health-care transition from pediatric care to adult care: the UNC TR(x)ANSITION scale. Ren Fail. 2012;34(6):744–753 14. Kiley DJ, Lam CS, Pollak R. A study of treatment compliance following kidney transplantation. Transplantation. 1993;55(1): 51–56

Parent Resources From the AAP at • English:

Pediatric-Nephrologist.aspx • Spanish:

pediatric-nephrologist.aspx • English:


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PIR Quiz Requirements To successfully complete 2014 Pediatrics in Review articles for AMA PRA Category 1 CreditTM, learners must demonstrate a minimum performance level of 60% or higher on this assessment, which measures achievement of the educational purpose and/or objectives of this activity. If you score less than 60% on the assessment, you will be given additional opportunities to answer questions until an overall 60% or greater score is achieved. NOTE: Learners can take Pediatrics in Review quizzes and claim credit online only at:

1. A 5-year-old child presents with short stature and anemia. Growth parameters have indicated that he has a downward trend on his percentile curves for age from the 25th percentile for weight and height at age 1 year to below the third percentile at present. He weighs 14 kg, and his height is 100 cm. Physical examination reveals heart rate of 100/min, respiratory rate of 26/min, and blood pressure of 120/80 mm Hg. Laboratory studies are as follows: hemoglobin, 9 g/dL; hematocrit, 27; serum sodium, 134 mEq/L; serum potassium, 4.2 mEq/L; serum chloride, 104 mEq/L; serum bicarbonate, 18 mEq/L; serum calcium, 7.0 mg/dL; serum phosphorous, 6.8 mg/dL; serum creatinine, 1.1 mg/dL; and blood urea nitrogen, 22 mg/dL. Abdominal ultrasonography reveals small kidneys bilaterally. In addition to his serum creatinine concentration which of the following is most helpful in determining his estimated glomerular filtration rate? A. Blood urea nitrogen. B. Fractional excretion of phosphorous. C. Height. D. Mean blood pressure. E. Weight. 2. A 13-year-old boy with reflux nephropathy and hypertension has been treated since age 5 years with an angiotensin-converting enzyme (ACE) inhibitor and dietary salt restriction. His vesicoureteral reflux was successfully repaired surgically. He is being followed up regularly by his pediatrician in consultation with a pediatric nephrologist. His blood pressure has been well controlled in the past. He has been in the 50th percentile for height and weight. Two years ago his serum calcium and phosphorous levels were normal, and his serum creatinine level was 1.1 mg/dL. On his visit today, he says that he has been tired and not able to sleep well at night. He also has had a runny nose and sore throat for the last 2 days. He has gained 10 cm in height and 10 kg in weight in the last 2 years and he remains in the 50th percentile for his age. His blood pressure and other vital signs are normal. Physical examination reveals pubic hair and genital development consistent with Tanner stage IV. His serum creatinine level is 1.7 mg/dL. Which of the following is the most likely reason for increase in his serum creatinine? A. B. C. D. E.

ACE inhibitor nephropathy. Expected increase according to age. Growth spurt. Intercurrent infection. Recurrence of vesicoureteral reflux.

3. A 9-year-old girl presents with fever, facial rash, and joint pains. On examination she appears ill, with a heart rate of 124/min, axillary temperature of 39˚C, respiratory rate of 28/min, and blood pressure of 146/90 mm Hg. Physical examination reveals erythematous rash in the malar area and petechial rash on extremities. Spleen is enlarged 2 cm below the costal margin. Laboratory studies are remarkable for the following: platelets, 70 3 103/mL (70 3 109/L); serum creatinine, 2.5 mg/dL; urea nitrogen, 54 mg/dL; and positive antinuclear antibody and anti–double-stranded DNA. Urinalysis reveals 3D blood, proteinuria (4D), and 20 red blood cells per high-power field. The urine protein to creatinine ratio is 2.5. Renal biopsy specimen reveals crescentic proliferative glomerulonephritis. The patient responds favorably to appropriate treatment with corticosteroids and cyclophosphamide. Which of the following antihypertensive medication for strict control of blood pressure will result in maximum protection from progression of chronic renal failure? A. B. C. D. E.

Darusentan (endothelin receptor antagonist). Hydralazine (vasodilator). Nifedipine (calcium channel blocker). Propranolol (b blocker). Ramipril (ACE inhibitor).

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4. A 5-year-old girl who underwent renal transplantation a year ago for dysplastic kidneys is under your care as her primary pediatrician. She is receiving corticosteroids and cyclosporine to prevent graft rejection. She is doing well and now is scheduled to enter kindergarten. If administered, which of the following vaccines poses the greatest risk to her health? A. B. C. D. E.

Diphtheria, tetanus, and acellular pertussis. Hepatitis B. Inactivated influenza. 23-valent polysaccharide pneumococcal vaccine. Varicella zoster.

5. A 14-year-old girl is awaiting renal transplantation for end-stage renal disease from focal segmental glomerulosclerosis. She is receiving hemodialysis 3 times a week and is taking multiple medications to control her hypertension. She was doing well until 6 months ago, when she started to feel constantly tired and was not able to sleep well at night. She has daytime somnolence and loss of appetite. She complains of frontal headaches in the morning and often refuses to go to school. Her school grades have fallen from A’s and B’s to mostly D’s. Last week her mother caught her smoking marijuana in her bedroom. Evaluation by a neurologist has revealed no abnormality. Referral to psychology services is required to evaluate her for which of the following conditions? A. Chemical dependency. B. Childhood-onset schizophrenia. C. Depression. D. Munchausen syndrome. E. Oppositional defiant disorder.

Corrections In the November 2013 article ”Cephem Antibiotics: Wise Use Today Preserves Cure for Tomorrow“ Parker S, Mitchell M, Child J. Pediatr Rev. 2013;34(11):510–524, doi: 10.1542/pir.34-11–510), in Table 3, under the Cefotaxime column, in the Escherichia coli row, the missing value should be S: £1. Also, in the print version of that article, in the Selected References introduction, the link to the complete reference list should be: The link is correct in the online version of the journal. In the October 2013 article ”Pneumonia“ (Gereige, RS, Laufer, PM. Pediatr Rev. 2013;34(10):438–456), ampicillin dosing in the first paragraph of ”Empiric Therapy“ should read, ”If this dose is desired, a combination of ampicillin-sulbactam at 300 mg/kg daily (dosing ampicillin at 200 mg/kg daily) and regular ampicillin at 100 to 200 mg/kg daily is a recommended regimen.“ The online version of the article was resupplied with correct dosage. The journal regrets this errors.

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Chronic Kidney Disease in Children and Adolescents Susan F. Massengill and Maria Ferris Pediatrics in Review 2014;35;16 DOI: 10.1542/pir.35-1-16

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