085-Pediatric Nephrology


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085-Pediatric Nephrology

  1. 1. Focus on CME at the University of Calgary Common and Important Pediatric Nephrology Problems There are often non-specific results from laboratory investigations that may be due to serious disease, but these may be transient findings not requiring further investigation. Distinguishing the unimportant from the significant is essential for appropriate referral. By Julian Midgley, BM Bch, MRCP(UK), FRCPCH, DCH, CCH Presented at the University of Calgary General Practitioner Update Course, Calgary, Alberta, November 2000. W hat is common and what is important in pedi- atric nephrology? This depends on your point of view and the easiest vantage point is probably a Detecting what is important among common symp- toms or complaints might be the hardest task in medicine. Treatment may be difficult or straightfor- specialist’s since, often, problems are identified by ward, but management cannot begin until the prob- referral from family physicians or pediatricians. lem is defined. This article is intended to offer fam- ily physicians a guide to evaluate four common and important pediatric nephrology problems, and Dr. Midgley is assistant professor, enable them to interpret laboratory investigations for University of Calgary and chief of pediatric nephrology patients. nephrology, Alberta Children’s Hospital, Calgary, Alberta. His special areas of interest are clinical epidemiology, childhood Hematuria nephrotic syndrome and hemolytic Asymptomatic urinary abnormalities, including uremic syndrome. hematuria, are commonly detected by a routine uri- nalysis. Hematuria is typically defined as the pres- The Canadian Journal of CME / October 2001 85
  2. 2. Pediatric Nephrology ence of more than two red blood cells (RBC) per symptoms, a routine urinalysis that detects micro- high-powered field (hpf) in a spun urine. Many scopic hematuria should prompt a repeat investiga- laboratories, however, report 0 to 5 RBC/hpf and, tion, preferably on a first morning void, to detect therefore, > 5 RBC/hpf is often used as the actual persistent hematuria. A first morning void mini- definition of hematuria. Dipsticks for hemoglobin mizes the effect of activity, although it may yield a commonly detect 1 to 2 RBC/hpf, although the relatively concentrated specimen. Urine with a spe- sensitivity depends on the degree of hemolysis cific gravity of ≥ 1030 may yield a false-positive since the sticks actually detect free hemoglobin. result, because of a reduced amount of water These dipsticks are at least as sensitive as urine increasing the concentration of RBCs. The corollary sediment examination, but result in more false- is dilute urine that is positive for blood is unlikely to positive tests. In comparison, false-negative tests be a false-positive result. Asymptomatic, isolated are unusual. As a result, a negative dipstick reli- hematuria, without associated proteinuria or casts on ably excludes hematuria. microscopy, is rarely pathological in children. For Hematuria may be of benign etiology or, in rare example, in a review of 325 children referred for cases in children, indicative of a more serious under- evaluation of microscopic hematuria, and, therefore, lying disease. Clearly, macroscopic hematuria is perhaps more likely to have significant disease, likely to be more significant than microscopic hema- none had abnormal creatinine and electrolyte values, turia, and persisting hematuria more significant than while only 29 (8.9%) had hypercalciuria.1 A renal transient. Childhood physical activity, or even inter- ultrasound, voiding cystourethrogram, cystoscopy current illnesses, such as a viral upper respiratory or renal biopsy were rarely indicated for the investi- tract infection, can cause hematuria. In absence of gation of microscopic hematuria in otherwise Summary Common & Important Pediatric Nephrology Problems • Hematuria may be of benign etiology or, in rare cases in children, indicative of a more serious underlying disease. After urinary tract infections, idiopathic hypercalciuria is the second most common cause of childhood hematuria. • In general, proteinuria is more significant than hematuria. Like hematuria, proteinuria can be transient, and this may be due to exercise or intercurrent illness. • Urinary tract infections (UTIs) in children are relatively common with an annual incidence of about 1 in 1,000 children. Accurate diagnosis of UTIs in children is essential for proper evaluation and management (Figure 3). Although the gold standard is a urine culture, this result is usually not available for one to two days. • As many as 1% of newborn infants have a prenatal diagnosis of hydronephrosis or significant renal pelvic dilation. • In children, assessment of renal function may be difficult because some laboratories use reference ranges designed for adults, even when reporting children’s results. 86 The Canadian Journal of CME / October 2001
  3. 3. Pediatric Nephrology Figure 1 Schema for Evaluating Hematuria Associated symptoms? yes no Proteinuria or systemic Recurrent macroscopic disease? hematuria? no yes yes no Referral to a pediatrician or yes Persistent microscopic Investigate as appropriate pediatric nephrologist > 6 months Abdominal Dysuria etc. no flank pain Urine Urinalysis and Urinalysis and culture Ca/Creatinine culture ratio healthy children.1 Even for macroscopic hematuria, Proteinuria a lack of symptoms and lack of persistence, (as with microscopic hematuria), or lack of recurrence, like- In general, proteinuria is more significant than ly means there is no serious disease. If, however, hematuria. Like hematuria, proteinuria can be tran- there is recurrent macroscopic hematuria, other sient, and this may be due to exercise or intercurrent symptoms or persistence of microscopic hematuria illness. Persistent proteinuria can be the first sign of for more than six months, referral for assessment is kidney disease, although a child with it presents with warranted (Figure 1). periorbital edema, and should have a urinalysis fol- After urinary tract infections, idiopathic hyper- lowed by a prescription of antihistamines before calciuria is the second most common cause of being assumed to have an “allergic reaction.”3 childhood hematuria. A calcium-to-creatinine ratio Significant proteinuria for children is defined as > 5 of > 0.67 mmol/mmol is a useful screening test for mg/kg/day or > 4 mg/m2/hour. The gold standard for hypercalciuria. A timed urine collection showing quantifying the rate of protein excretion is generally an excretion rate of > 0.1 mmol/kg/day confirms a 24-hour urine collection, but this may not be prac- the diagnosis. Hypercalciuria should be screened tical, even in older children. Alternatively, a rela- for in children with dysuria (with or without hema- tively accurate estimate can be more simply and turia), who have negative urine cultures and in quickly obtained by calculating the total protein-to- children with recurrent abdominal/flank pain, espe- creatinine ratio (mg/mmol) on a random urine spec- cially with a family history of nephrolithiasis. imen. The laboratory may require reassurance that Unfortunately, the absence of hematuria does not the result is clinically useful, as laboratories often exclude hypercalciuria.2 contend that a random urine is not the “correct” 88 The Canadian Journal of CME / October 2001
  4. 4. Pediatric Nephrology Figure 2 Schema for Evaluating Proteinuria Associated Edema? yes no Referral to a yes Associated Hematuria? pediatrician or pediatric nephrologist no Persistent? yes no no No follow-up Teenager? needed yes yes Significant no Yearly follow-up nocturnal (see text) proteinuria? sample. Alternatively, the laboratory substitutes an 2+, 3+ or 4+ may be preferred (Table 1). albumin-to-creatinine ratio, since assessment of Postural or orthostatic proteinuria may explain microalbuminuria is a more commonly recognized apparently significant proteinuria in teenagers. A test used for assessing early nephropathy in diabetic routine urine check commonly will show 2+ or 3+ patients. A protein-to-creatinine ratio of ≥ 25 proteinuria by dipstick with no hematuria in a mg/mmol signifies significant proteinuria, and ≥ teenager who presented with fatigue. Orthostatic 250 mg/mmol proteinuria is more common in relatively tall and indicates “nephrotic range” proteinuria (Table 1). thin females, but males also can be affected. A repeat The dipstick, in comparison, is less predictive urinalysis during the day often seems to confirm because it reflects the urine protein concentration persistent proteinuria. The diagnosis of orthostatic that is also influenced by the urine volume. Highly proteinuria may be confirmed by a “split-24-hour concentrated urine, for example, may have a 3+ urine” test with a daytime collection and a nighttime response on the dipstick, but may not be indica- collection, which is often just the first morning void. tive of heavy proteinuria. The use of “mg/dL” or The 24-hour protein excretion may be up to 1,000 “g/L” for dipstick results implies a certain a mg (about 20 mg/kg/day), but normal excretion degree of certainty, and specifying results as 1+, rates are found in the nighttime collection. 90 The Canadian Journal of CME / October 2001
  5. 5. Pediatric Nephrology Table 1 Comparison of Various Methods of Assessing Proteinuria Proteinuria Method Insignificant Significant “Nephrotic Range” Units Semi- Dipstick Negative or 1+ 2+ 3+ 4+ quantitative trace 30 100 300 ≥ 2000 mg/dL 0.3 1.0 3.0 ≥ 20 g/L Quantitative Prot/Creat < 25 ≥ 25 to < 250 ≥ 250 mg/mmol Ratio Timed <5 ≥ 5 to < 50 ≥ 50 mg/kg/day Collection <4 ≥ 4 to < 40 ≥ 40 mg/m2/hr Prot = total protein; Creat = creatinine Alternatively, if a first voided urine shows an urinalysis and microscopy provides useful informa- insignificant protein-to-creatinine ratio, orthostatic tion in a more timely fashion. The detection of proteinuria is confirmed. Orthostatic proteinuria is pyuria by either leukocyte esterase detection (sensi- benign, but it may be prudent to follow with yearly tivity of the test is trace = 5 white blood cells urinalysis and blood pressure measurements. If sig- (WBC)/hpf to 15 WBC/hpf) by dipstick or by nificant, persistent, non-orthostatic proteinuria is microscopy (defined as 2 to 5 WBC/hpf of cen- detected, referral for further assessment will be trifuged urine) suggests the need for a UTI. Many required (Figure 2).4 laboratories report 0 to 5 WBC/hpf as normal and ≥ 5 to 10 WBC/hpf as abnormal. The finding of nitrite positivity by dipstick testing Urinary Tract Infections is an indirect method of detecting bacteriuria. A pos- Urinary tract infections (UTIs) in children are rela- itive test is specific, but a negative test may be a tively common with an annual incidence of about false-negative for several reasons. If urine has been one in 1,000 children. During childhood, 1% to 2% in the bladder a short time, there may have been of boys and 5% of girls will have at least one UTI. insufficient time for reduction of nitrate to nitrite by Urinary tract infections are important because of the the bacteria’s reductase enzymes. Only about 75% illness and symptoms they cause, parental concern of Escherichia coli and only about 20% of they engender and the need for radiological investi- Klebsiella and Enterobacter have the reductase gations of the renal tract. A relatively small number enzyme. of children will have serious complications, such as If there is evidence of both pyuria and bacteri- chronic renal insufficiency or hypertension. uria by urinalysis, the positive predictive value for Accurate diagnosis of UTIs in children is essen- a UTI is substantially increased, and empirical tial for proper evaluation and management (Figure treatment with oral cotrimoxazole or nitrofuran- 3). Although the gold standard is a urine culture, this toin is probably justified, especially if there are result is usually not available for one to two days. A symptoms. Oral cefixime also may be a reason- 92 The Canadian Journal of CME / October 2001
  6. 6. Pediatric Nephrology Figure 3 Schema for Evaluating Results of Urinalysis and Urine Culture Symptoms of UTI? yes no Nitrites or pyuria? Nitrites and pyuria? yes (or both) neither yes Consider repeating Empirical Rx Consider repeating urine or urine urine if either just Ca/Creat ratio pyuria or nitrites Culture Result positive negative Consider repeating Ensure treating with urine or urine appropriate antibiotic Ca/Creat ratio Ca = calcium; Creat = creatinine able choice for empiric treatment.5 Short-course cific symptoms may be absent, despite treatment (three to five days) is sufficient for chil- pyelonephritis. dren with acute, uncomplicated lower UTIs. Children with well-documented UTIs should be Children with acute pyelonephritis require 10 to investigated based on their age and presenting 14 days of antibiotics, which can be administered symptoms.6 All infants, regardless of age, require on an outpatient basis in older infants and children imaging, usually with a voiding cystourethrogram who are not toxic, providing good compliance is (VCUG) and ultrasound of the kidneys and bladder. expected. Children aged one to five years with febrile UTIs Urine cultures with multiple organisms or and boys at any age also should be considered for colony counts of less than 108 colony forming urinary tract imaging. Children with an ultrasound unites (cfu)/L should be considered suspect and suggesting scarring or at least grade 3 vesico- require confirmation, particularly with clean-catch ureteric reflux, or those who have upper tract symp- specimens, in asymptomatic children or in those toms, should have renal cortical scintigraphy with no evidence of pyuria. A simple scoring sys- (nuclear medicine renal scan) with 99mTc-DMSA tem to evaluate urine culture, pyuria and symp- or glucoheptonate to detect, or, just as importantly, toms may aid in the interpretation of laboratory exclude, renal scarring. Patients with first-time UTIs data (Table 2). In younger children, however, spe- who require imaging should be maintained on low- 94 The Canadian Journal of CME / October 2001
  7. 7. Pediatric Nephrology Table 2 Interpretation of a Urinalysis and Urine Culture Score cfu/L WBC/hpf Symptoms 0 < 106 or 0 to 5 None no growth 1 106 to 107 5 to 10 Lower tract 2 ≥ 108 >10 Pyelonephritis Total Score Interpretation 0 to 1 No UTI 2 Possible UTI: repeat urine 3 to 6 UTI dose antibiotic prophylaxis until their workup is completed.7 Delaying a VCUG, however, until at least one month after a UTI is prob- ably not necessary, and the duration of pro- phylaxis may be shortened by earlier Shouldn’t the first depression investigation. For children older than five be the last depression? years of age with a lower tract UTI, a renal tract ultrasound should suffice. Treatment of asymptomatic bacteriuria is not necessary, especially if the urinary tract is normal. Long-term antibiotic pro- phylaxis is indicated for children with fre- quent symptomatic recurrences of UTI and for those with known vesicouterine reflux (VUR). Prophylactic antibiotics should probably be given as a single nightly dose, equal to about one-quarter to one-half of the usual treatment dose. Whether antibiotic prophylaxis should be used for management of VUR and the duration of such treatment is becoming less certain.8,9 It may be reasonable to dis- continue prophylaxis in older children who are able verbalize the symptoms of a UTI, have a normal voiding pattern, a minor his-
  8. 8. Pediatric Nephrology Figure 4 experimental technique and early delivery is seldom justified.11 Persistent early onset oligohydramnios, Schema for Managing Fetal implying poor renal function, is the best predictor of Hydronephrosis poor neonatal outcome, but is uncommon. As many as 1% of newborn infants have a prena- tal diagnosis of hydronephrosis or significant renal Persistence in pelvic dilation.12 The likelihood of significant third trimester? pathology is related to the size of the fetal renal yes no pelvis. An anteroposterior diameter of the fetal renal pelvis of more than 2 cm predicts a high likelihood Consider referral to No follow-up of significant pathology.12 Significant dilatation plan postnatal required may not always imply pelviureteric junction investigations obstruction, since vesico-ureteric reflux or obstruc- no tion may be the cause. Antenatal counselling is often useful, especially from the parent’s point of view ≥ moderate Persistence of and, depending on the availability of specialists and hydronephrosis no hydronehprosis patterns of care, may be provided by obstetricians, at postnatal at 6 months? ultrasound? neonatologists, pediatricians, pediatric urologists or pediatric nephrologists (Figure 4). In general, con- yes yes servative management, rather than surgical interven- tion in the neonatal period, is indicated.13 More than Referral to a pediatrician mild, antenatally detected hydronephrosis should be or pediatric nephrologist investigated postnatally. Following delivery, antibi- otic prophylaxis should be prescribed. Trimethoprim (as a single agent, not as cotrimoxa- zole) at a dose of 1 mg/kg (practically a single 5 mg tory of infections and minimal or no renal scar- dose daily) should be used. An ultrasound of the kid- ring.10 neys and renal tract should be obtained. This should not occur in the first 48 hours after delivery because of a likelihood of a low urine flow rate, causing Antenatally Detected false-negative results. If at least moderate Hydronephrosis hydronephrosis is confirmed, referral for further investigation is recommended. If there is evidence The widespread use of antenatal ultrasound has of ureteric dilatation that may be identifiable ante- resulted in an increased recognition of fetal natally, a voiding cystourethrogram (VCUG) should hydronephrosis, although the vast majority of ante- be obtained. natal scans are not performed for the purpose of Alternatively, if there is significant hydronephro- screening for fetal renal tract abnormalities. sis without ureteric dilatation, a nuclear medicine Fortunately, about 50% of antenatally detected cases renal scan (Mag 3 preferred over diethylenetriamine of renal tract dilatation resolve before delivery. pentaacetic acid [DTPA]) may suffice, if it demon- Prenatal intervention for hydronephrosis remains an strates significant pelviureteric obstruction. 96 The Canadian Journal of CME / October 2001
  9. 9. Pediatric Nephrology Table 3 Table 4 Constants for Age Groups Reference Ranges for Timed Urine Collection for 2 to 11 yrs Constants (k) for the Equation: GFR(mL/min/1.73m2) = k x Height (cm)/Creatinine (umol/L) Investigation Reference Range Protein <4 mg/kg/day <5 mg/m2/day Age Group Constant (k) Creatinine 125-175 umol/kg/day Pre-term babies 29 Calcium < 0.1 mmol/kg/day Term babies 40 Oxalate 0.14-0.46 mmol/1.73m2/day Children & Adolescent girls 48 20-50 mg/1.73m2/day Adolescent boys 62 be crucial to ensure appropriate management. Most Radiologists may recommend a renal scan be per- laboratories provide reference ranges for investiga- formed at least one month after delivery, however, tions, which help physicians assess the significance especially in experienced pediatric centers, an earli- of the result. In children, assessment of renal func- er scan may be indicated if there is severe tion may be difficult, because some laboratories use hydronephrosis and/or cortical thinning.14 reference ranges designed for adults, even when reporting children’s results. Since the normal creati- nine for a five-year-old may be around 35 umol/L, Laboratory Investigations significant loss of renal function may still produce a The interpretation of laboratory investigations may result that is within a reference range for an adult
  10. 10. Pediatric Nephrology (typically 70 umol/L to 120 umol/L). Even when In pediatric nephrology, there are often non-spe- reference ranges for children are given, this may be cific results from laboratory investigations that for relatively wide age ranges. A reference range may be due to serious disease, but often are tran- might be 40 to 90 umol/L, and it is possible to have sient findings that do not require further investiga- CME a doubling of creatinine, and therefore, halving of tion. Distinguishing the unimportant from the sig- renal function, but still remain within the reference nificant is essential for appropriate referral of range. It is well recognized that creatinine values in patients. The approach to common problems dis- children are inversely proportional to height.15 cussed in this article will hopefully help the gen- Calculation of the glomerular filtration rate (GFR) eralist investigate or initiate a referral when it is is, therefore, possible, and can be compared to nor- required, but not when a conservative approach is mal GFR of 80 to 120 mL/min/1.73m2 (Table 3). indicated. Another laboratory investigation that common- ly has reference ranges that may not change with References 1. Feld LG, Meyers KE, Kaplan BS, et al: Limited evaluation of age is a timed-urine collection. Adequate instruc- microscopic hematuria in pediatrics. Pediatrics 1998; 102:E42. tion is required, and should emphasize the impor- www.pediatrics.org/cgi/content/full/102/4/e42. tance of discarding the urine voided at the start 2. Polito C, La Manna A, Cioce F, et al: Clinical presentation and time and including the urine voided at the stop natural course of idiopathic hypercalciuria in children. Pediatr. Nephrol 2000; 15:211-4. time. A timed-urine collection has conventionally 3. Bergstein JM: A practical approach to proteinuria. Pediatr. been taken over a 24-hour period and, although Nephrol 1999; 13:697-700. accuracy may be lower with shorter collection 4. Hogg RJ, Portman RJ, Milliner D, et al: Evaluation and man- agement of proteinuria and nephrotic syndrome in children: times, younger children may only be able to pro- Recommendations from a pediatric nephrology panel estab- vide a daytime collection. Unfortunately, some lished at the National Kidney Foundation conference on pro- laboratories reject collections for time periods teinuria, albuminuria, risk, assessment, detection, and elimina- other than 24 hours ± 0.5 hours, and may round to tion (PARADE). Pediatrics 2000; 105:1242-9. 5. Hoberman A, Wald ER: Treatment of urinary tract infections. 24 hours, rather than use the actual collection Pediatr. Infect. Dis J 1999; 18:1020-1. time. The most common reasons for a 24-hour 6. Guidelines for the management of acute urinary tract infection urine collection is the evaluation of creatinine in childhood. J R Coll Phys Lond 1991; 25:36-42. clearance and protein excretion. After the first 7. Rushton HG: Urinary tract infections in children. Epidemiology, evaluation, and management. Pediatr Clin. year of life, the reference range for creatinine North Am 1997; 44:1133-69. clearance does not change substantially during 8. Bollgren I: Antibacterial prophylaxis in children with urinary childhood. The creatinine excretion rate is lower, tract infection. Acta Paediatr Scand Suppl 1999; 88:48-52. 9. Linshaw MA: Controversies in childhood urinary tract infec- however, with younger age. Reference ranges on tions. World J Urol 1999; 17:383-95. laboratory reports for creatinine excretion rarely 10. Cooper CS, Chung BI, Kirsch AJ, et al: The outcome of stop- change with age. This may result in a comment on ping prophylactic antibiotics in older children with vesi- the laboratory report that implies an inadequate coureteral reflux. J Urol 2000; 163:269-72. 11. Coplen DE: Prenatal intervention for hydronephrosis. J Urol. urine collection when a low number, as compared 1997; 157:2270-7. to the adult reference range, is actually expected. 12. Elder JS: Antenatal hydronephrosis. Fetal and neonatal man- This applies to other, less commonly ordered agement. Pediatr.Clin.North Am 1997; 44:1299-321. investigations (Table 4). 13. Koff SA: Neonatal management of unilateral hydronephrosis: Role for delayed intervention. Urol Clin. North Am 1998; 25:181-6. 14. Conway JJ, Maizels M: The “well tempered” diuretic Conclusion renogram: a standard method to examine the asymptomatic neonate with hydronephrosis or hydroureteronephrosis. A 98 The Canadian Journal of CME / October 2001