An 8-year-old male with a history of bilateral ptosis and narrow external auditory canals presented to his pediatrician with a 5-month history of decreased appetite and weight loss. He also complained of fatigue, polyuria, and polydipsia. He was on no medications, and there was no significant family history. One year prior, his weight and height were at the 10th percentile for age. On presentation, his weight and height had both fallen below the 5th percentile. He had normal blood pressure. Urinalysis had a specific gravity of 1.005 with no blood, protein, or glucose. Metabolic panel was significant for sodium 142 mmol/L, potassium 3.9 mmol/L, chloride 102 mmol/L, bicarbonate 21 mmol/L, BUN 94 mg/dL, creatinine 5.4 mg/dL, calcium 7.9 mg/dL, and phosphorous 8.2 mg/dL. Additional labs included hemoglobin 7.4 g/dL with normal mean corpuscular volume and parathyroid hormone level 1289 pg/ mL. Renal ultrasound showed normal size kidneys with increased echogenicity bilaterally.
Discussion: This patient was found to have kidney failure due to juvenile nephronophthisis. Given his history of poor growth, fatigue, and polyuria/polydipsia, chronic kidney disease (CKD) is more likely than an acute kidney injury (AKI). The presence of normocytic anemia (from impaired renal production of erythropoietin) and hyperparathyroidism (from hyperphosphatemia and impaired renal activation of vitamin D) also support an underlying chronic kidney disease process. The creatinine of 5.4 mg/dL corresponds to an estimated glomerular filtration rate of <10 mL/min/1.73 m2, classifying him as end-stage kidney disease (ESKD). His primary care practice promptly referred him to CHOP Nephrology.
Causes of CKD in children include congenital and acquired disorders. In this case, congenital anomalies are ruled out by a normal kidney ultrasound. The history of polyuria/polydipsia and the low urine specific gravity suggest impaired renal concentrating ability. The dilute urine without hematuria or proteinuria is consistent with a “bland urine” typical for tubulointerstitial nephritis (TIN) rather than an underlying glomerular disorder. As the underlying process appears to be both chronic and a tubulointerstitial process, one must consider the causes of chronic TIN in the different diagnosis. Chronic TIN can be secondary to inflammatory, autoimmune, and genetic conditions, including a group of disorders known as nephronophthisis (NPHP). NPHP is an autosomal recessive disorder affecting proteins involved in primary cilia function and is characterized by early onset CKD with progression to ESKD by 20 years of age. Extrarenal manifestations are present in 10% to 20% of patients, and include retinitis pigmentosa, hepatic fibrosis, neurologic abnormalities, and skeletal defects. NPHP can occur as an isolated kidney process, or as part of Joubert, Meckel-Gruber, Senior-Loken, and Cogan syndromes.
A kidney biopsy showed chronic interstitial fibrosis. An ophthalmologic examination ruled out entities like cystinosis or the syndrome of TIN and uveitis. Genetic testing identified a homozygous deletion in NPHP1, confirming the final diagnosis of juvenile nephronophthisis.
Next, the CHOP Nephrology team, including physicians, nurse practitioners, social workers, psychologists, pharmacists, and dialysis nurses, and the patient’s caregivers had extensive discussions to review renal replacement therapy treatment options, namely dialysis vs. transplant.
Physician-scientists at CHOP participate in a number of clinical studies that can help families assess the long-term outcomes of kidney disease, and which form of renal replacement therapy is best for their children. One recent study explored how outcomes have changed for children with ESKD over the last two decades. Despite improvements in overall mortality rates for children with kidney failure on dialysis in the United States, children on dialysis experience mortality rates at least 30 times higher than healthy children. Dialysis is associated with an increased risk for infection, anemia, impaired growth, and cardiovascular disease. For all these reasons, early kidney transplantation is the preferred renal replacement therapy for most children. Children who are transplanted grow better, learn better, and can lead more normal lives compared with children on dialysis.
The evaluation of a potential kidney transplant recipient and identification of a suitable donor take time. Thus, prompt recognition of disease and early referral to pediatric nephrology are crucial. First, transplant candidates must be evaluated by a multidisciplinary team and often must undergo special laboratory studies and imaging to complete their work-up. The ability of the patient and/or caregiver to adhere to the medical regimen of life-long immunosuppressive medications is an important consideration. Vaccinations must also be up to date. Second, we explore potential living kidney donors or the necessity of being placed on the waiting list for a deceased donor. When possible, living related donation is preferred as it generally permits better immunocompatibility. However, children who are placed on the national deceased donor waiting list do receive pediatric priority for kidney donors younger than 35 years of age.
This patient was promptly evaluated for transplant eligibility. His mother was found to be an excellent, healthy, and immunocompatible donor. The child received a preemptive kidney transplant within a few months of his diagnosis. He is now thriving, playing baseball, and enjoying his new “gift of life.”
Mitsnefes MM, Laskin BL, Dahhou M, Zhang X, Foster BJ. Mortality risk among children initially treated with dialysis for end-stage kidney disease, 1990-2010. JAMA. 2013;309(18):1921-1929.
A 4-year-old boy presented to the Hypertension and Vascular Evaluation (HAVE) Program for a second opinion regarding hypertension. At his 3-year well-child visit, his blood pressure (BP) was 130-140/80 mmHg (stage II hypertension), and he was started on amlodipine. Renal ultrasound, echocardiogram, abdominal MRI, bilateral renal, and aortic arteriogram were all normal. Labs on amlodipine showed: Na 136 mEq/L (low normal), K 3.1 mEq/L (low), Cl 92 mEq/L (low), and bicarbonate 33 mEq/L (high), indicative of a hypochloremic hypokalemic metabolic alkalosis. The BUN was 8 mg/dL and serum creatinine concentration 0.3 mg/ dL, indicating normal renal function. Plasma renin activity level was 51.86 ng/mL (normal <5.82), and serum aldosterone level was 4 ng/ mL (normal).
His BP control was not optimal on amlodipine, and when seen he was on labetalol, enalapril, and HCTZ. He had no headaches, dizziness, leg pain with exercise, abdominal pain after eating, excessive sweating, or facial flushing. The paternal grandfather and several distant relatives have essential hypertension; otherwise there is no significant family history of kidney or cardiovascular disease.
On physical examination, height was 81st percentile and weight 90th percentile. His BP was 113/42 mmHg in the right upper extremity. He had no features of Williams syndrome or of neurofibromatosis I. There was a soft grade 1/6 SEM with regular cardiac rhythm. Femoral pulses were well felt. There was a soft bruit over the left renal artery; no other bruits were present.
A 24-hour ambulatory blood pressure monitoring (ABPM) study was done (Figure 1) at home. This showed elevated daytime and nighttime SBP with an inadequate nocturnal SBP dip. Because of the pattern of the abnormal initial lab results, the abnormal ABPM study, and the bruit heard over the left renal artery, an abdominal aortic angiogram was repeated. This showed severe stenosis (>80%) in a third order branch vessel to the inferior pole of the left kidney with delayed perfusion to the segment supplied by this vessel. This was successfully treated using percutaneous transluminal balloon angioplasty. There was minimal post-dilatation residual narrowing (Figure 2). The right renal artery, abdominal aorta, celiac axis, and mesenteric arteries were normal.
Results showing elevated daytime and nighttime systolic pressures with an inadequate nocturnal systolic dip.
A: White arrow shows the stenosis; note the peripheral perfusion defect. B and C: Balloon dilatation of the artery with near normal caliber shown at conclusion of the procedure.
He was discharged the day after his procedure on enalapril 5 mg given twice daily, from which he was weaned off as an outpatient. As fibromuscular dysplasia (FMD) was the presumed diagnosis, he had an MRI of the neck and brain. Although the imaged vessels were normal, a large Chiari I malformation was found. He subsequently had this anomaly surgically corrected.
Discussion: Renal artery stenosis (RAS) accounts for up to 15% of hypertension diagnosed in prepubertal children. Findings that most suggest a diagnosis of RAS include stage 2 hypertension, an abdominal aortic or renal artery bruit, biochemical evidence of RAAS activation (hypokalemia, metabolic alkalosis, hyponatremia), and, in some instances, stigmata of specific syndromes associated with RAS (see Table 1).
In this child ABPM helped establish the severity of the hypertension while he was taking 3 anti-hypertensive medications. ABPM, a non-invasive technique for measuring multiple BP readings over a 24-hour period during regular activities and during sleep, has emerged as an increasingly important tool in the diagnosis and management of children with hypertension. ABPM is performed using an oscillometric Spacelab 90217 monitor. An appropriate-sized BP cuff is placed on the non-dominant arm and attached to a small monitor. For 24 hours, BP recordings are taken every 20 minutes while the patient is awake and every 30 minutes while he’s asleep. ABPM is considered satisfactory if there is a minimum of 40 readings during the 24 hours with at least 6 “sleep” readings.
Advantages of ABPM include the fact that measurements are made outside of the healthcare environment and the multiple parameters of BP assessed (mean 24-hour, daytime, and night-time SBP and DBP, BP load, nocturnal dipping, and BP variability). In the general adult population, nocturnal nondipping, nocturnal hypertension, and increased BP variability are predictive of cardiovascular morbidity and mortality. ABPM also permits diagnosis of masked hypertension (normal casual BP but ambulatory BP >95th percentile for sex and height). In adults, masked HTN has been associated with an increase in risk of sustained hypertension and cardiovascular morbidity. Children with chronic kidney disease (CKD) have a significant incidence of masked hypertension. Children should undergo ABPM if they have any of the following: persistent pre-hypertension, especially with comorbid cardiovascular risk factors; multiple providers report elevated BP readings but resting BP is normal in the clinic setting; solid organ transplant; or evidence of end-organ damage such as left ventricular hypertrophy.
Flynn JT, Urbina EM. Pediatric ambulatory blood pressure monitoring: indications and interpretations. J Clin Hypertens (Greenwich). 2012;14(6):372-382.
Urbina E, Alpert B, Flynn J, et.al; American Heart Association Atherosclerosis, Hypertension, and Obesity in Youth Committee. Ambulatory blood pressure monitoring in children and adolescents: recommendations for standard assessment: a scientific statement from the American Heart Association Atherosclerosis, Hypertension, and Obesity in Youth Committee of the council on cardiovascular disease in the young and the council for high blood pressure research. Hypertension. 2008;52(3):433-451.
Wilson AC, Schneider MF, Cox C, et al. Prevalence and correlates of multiple cardiovascular risk factors in children with chronic kidney disease. Clin J Am Soc Nephrol. 2011;6(12):2759-2765.
Lawrence Copelovitch, MD
CC, born with a single functional kidney, was referred to CHOP at 1 year of age with an obstruction in his ureter. He underwent robotic surgery to repair the obstruction, and a stent was placed to help maintain patency of the repaired ureter and minimize leakage during healing. Shortly thereafter, he developed multiple kidney stones in the area of the stent. He had a second surgery to remove the stones and was referred to Nephrology. The removed stones were analyzed and found to be 90% calcium phosphate and 10% calcium oxalate. Multiple urinalyses showed a high urinary concentrate of calcium, and CC was put on chlorothiazide to decrease his chance of developing urolithiasis in the future. He continued to be followed closely by his nephrologist, who advised drinking more fluids, and increased CC’s dose of chlorothiazide in response to continued high calcium-to-creatinine ratios—3.5 times normal. CC, now 7 years old, has remained stone-free and continues to have a normal functioning single kidney.
Discussion: One in 750 people are born with a single kidney, and 10% to 20% of people will develop a kidney stone during their lifetime. While for most kidney stone patients, a stone is a painful inconvenience, for those with one kidney, prompt recognition of urolithiasis is critical to prevent irreversible kidney damage or even kidney failure.
CC received follow-up care with Nephrology initially every 3 months for blood and urine tests and renal ultrasound. He is now seen every 6 months. As fluid intake is a critical component of stone prevention by effectively reducing the concentration of lithogenic factors, including calcium, oxalate, uric acid, and cysteine, we recommended CC drink an amount at least equal to calculated maintenance rates for his size plus 50%. Because he had very alkaline urine, which could predispose him to calcium phosphate stones (instead of the more common calcium oxalate stones), we advised giving him cranberry juice, which may have mildly acidified his urine and reduced the chance of forming new stones. We advised CC consume the recommended daily allowance for age of calcium to promote normal bone health and development.
Lifestyle changes are the suspected culprits in the 5-fold increase in pediatric kidney stones over the last decade. For otherwise healthy patients, the best predictor of kidney stones is a careful family history. Those with a family history of kidney stones are at 2.5 times greater risk of developing stones. Other conditions and medications that can increase risk are shown in Table 2.
When urinary calculi develop during childhood, the risk of lifelong stone formation is significant, with approximately 20% having recurrences within 10 years. Children with an identifiable metabolic abnormality also need to be followed closely as they have an up to 5-fold increased risk of recurrence compared with children without metabolic disorders. Given the high risk of recurrences in children with idiopathic hypercalciuria and hypocitraturia and the importance of excluding rare but treatable conditions such as primary hyperoxaluria and cystinuria, a comprehensive metabolic evaluation is indicated in all children.
CC’s medical history makes him a perfect candidate for treatment in CHOP’s multidisciplinary Pediatric Stone Center, where specialists from Surgery, Urology and Nephrology deliver care in concert for complex patients. The center makes visits easier for families that no longer need to schedule separate appointments with those specialists to obtain the full range of treatment options. During appointments, the child can also see a nutritionist to get advice on changes in diet that can help prevent future stones.
The Pediatric Stone Center was created to treat medically complex patients, such as those who have spina bifida or other chronic conditions that restrict movement, and patients without underlying conditions but who have suffered from recurring kidney stones.
To help primary care pedestrians know when referral to specialists is appropriate, CHOP has posted Pathway for the Outpatient Evaluation/Treatment of the Child with Urolithiasis at bit.ly/stonepathway. This clinical template outlines guidelines for kidney stone patients, including blood, urine, and imaging tests.
Copelovitch L. Urolithiasis in children: medical approach. Pediatr Clin North Am. 2012;59(4):881-896.
VanDervoort K, Wiesen J, Frank R, et al. Urolithiasis in pediatric patients: a single center study of incidence, clinical presentation and outcome. J Urol. 2007;177(6):2300-2305.
Pietrow PK, Pope JC IV, Adams MC, et al. Clinical outcome of pediatric stone disease. J Urol. 2002;167:670-673.
Diamond DA, Menon M, Lee PH, et al. Etiological factors in pediatric stone recurrence. J Urol. 1989;142(2):606-608.
To make a referral to or learn more about to Nephrology, the Pediatric Stone Center and the Hypertension and Vascular Evaluation (HAVE) Program at CHOP, call 215-590-2449 or visit www.chop.edu/nephrology.
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