Elaine S. Kamil, MD
A 14-year-old boy is brought to the office for a sports-related preparticipation physical examination. He has been previously healthy but had 1 hospital admission at age 2 years for management of a fractured humerus. He has no acute concerns. The family history is positive for diabetes mellitus in the paternal grandfather and lung cancer in the maternal grandfather. It is negative for renal disease and hypertension. The boy’s height and weight are at the 75th percentile for age, and his blood pressure is 110/70 mm Hg.
On physical examination the boy is a well-developed, well-nourished, athletic teenager. No abnormal findings are present. The complete blood cell count reveals a hemoglobin of 14.8 g/dL, a hematocrit of 48.3%, and a white blood cell count of 8,400 cells/mm3 with a normal differential. The urine has a pH of 5, a specific gravity of 1.025, and 3+ protein on urine dipstick test. The rest of the dipstick test is negative. Microscopic examination shows 0 to 1 white blood cell count per high-power field and 0 to 2 hyaline casts per low-power field.
1. What conditions cause proteinuria?
2. When should the child with proteinuria undergo further evaluation?
3. What type of evaluation should be carried out to assess proteinuria?
4. When should the child with proteinuria be referred to a pediatric nephrologist?
A small amount of protein is normally present in the urine. In children, normal urine protein excretion is less than 100 mg/m2 per 24-hour period or 4 mg/m2 per hour. Urine protein levels increase somewhat under certain conditions, such as vigorous exercise, febrile illness, accidental trauma, and congestive heart failure (CHF). Urinary protein excretion in children is also affected by age, sex, and body habitus. Normally the filtered proteins are of small- to medium-size molecular weights, whereas albumin and other larger molecules mostly are not filtered because of their size. Albumin accounts for less than 30% of the proteins in the urine. Most of the protein in the glomerular filtrate is reabsorbed by the tubular cells. Pathologic amounts of protein are present in the urine when the glomerular leak of protein is increased, when the tubules fail to reabsorb the protein filtered by the glomerulus, or if inflammation in the renal interstitium results in the addition of tubular proteins to the urine.
Urinary protein is initially detected by the urine dipstick; however, this method may produce false-positive results in alkaline or highly concentrated urine. A dipstick test that is positive for protein of 1+ in concentrated urine may not correlate with an abnormal 24-hour urinary protein excretion, whereas a dipstick test result of 1+ in very dilute urine may be associated with an abnormal 24-hour urinary protein excretion. Proteinuria is more accurately determined by performing a timed urine collection or a random sample for chemical determination of the ratio of urinary total protein concentration divided by the urinary creatinine concentration (ie, urine TP/Cr).
The prevalence of proteinuria depends on how the condition is defined. In a Texas study, 10 mg/dL of proteinuria was found consistently in the urine of 2% to 3% of children in 3 consecutive urine samples. When 50 mg/dL was used as the cutoff for proteinuria, however, only 0.4% to 0.7% of boys and 0.4% to 2.5% of girls had proteinuria in 2 of 3 consecutive samples. The prevalence of proteinuria increased with age. In Finland, approximately 11% of school-age children had at least 1 episode of proteinuria of 25 mg/dL on urine dipstick testing when the urine was tested 4 times. Approximately 2.5% of the children had proteinuria on 2 of 4 occasions.
Proteinuria is a laboratory finding that may present incidentally on a screening urinalysis or be detected during the evaluation of a complaint, such as edema, that may be caused by kidney disease. When proteinuria is detected as an incidental finding in the otherwise normal child, the laboratory evaluation of the proteinuria should be delayed until its persistence is confirmed on repeat urine dipstick testing, preferably on a first morning urine sample (Box 110.1). The child with edema and proteinuria most likely has renal lesions or, more rarely, CHF. Additional findings on examination could include the presence of hypertension, ascites, pleural effusions, or the rash of systemic lupus erythematosus or anaphylactoid purpura.
Box 110.1. Diagnosis of Proteinuria
•Presence of proteinuria on dipstick urinalysis (≥1+ confirmed on 3 occasions)
•Random urine TP/Cr >0.2 or 24-hour urine protein >4 mg/m2/hour
•Orthostatic proteinuria (assessed through separate measurement of afternoon and first morning urine for TP/Cr)
Edema in the absence of significant proteinuria can occur in conditions that cause hypoproteinemia (eg, liver or inflammatory bowel disease) or during allergic reactions.
The glomerular capillaries are adapted to permit the filtration of minimal amounts of plasma proteins, particularly those with a small molecular radius. Approximately 320 mg of albumin and 360 mg of low-molecular-weight proteins are filtered by the glomerular capillaries each day. Ninety-five percent of this material is reabsorbed by the proximal tubular cells. Normally, a child may excrete up to 100 mg/m2 per day of protein. Urinary protein excretion is increased in newborns to approximately 240 mg/m2 per day and in adolescents to approximately 300 mg/m2 per day. Adults may normally excrete up to 150 mg/m2 of protein per day. Only 10% to 15% of this is albumin; the rest of the proteins are other plasma proteins and urinary glycoproteins, such as Tamm-Horsfall protein.
In cases in which increased proteinuria results from glomerular disease, higher than normal levels of urinary proteins are primarily caused by the enhanced filtration of albumin. Abnormal urinary protein excretion is a marker of chronic kidney disease, and attempts to improve proteinuria with angiotensin-converting enzyme inhibitors or angiotensin receptor blockade in this setting have been shown to slow the progression of glomerular diseases. Protein excretion may be increased transiently by any condition that raises intra-glomerular capillary pressure, such as CHF, strenuous exercise, epinephrine use, fever, urinary infection, and surgery. The child or adult with very early diabetic nephropathy or early end-organ damage from hypertension exhibits an elevated urinary microalbumin-creatinine ratio. The child with diabetes or hypertension should undergo regular testing for the urinary microalbumin-creatinine ratio to detect early, reversible glomerular damage.
Individuals with orthostatic proteinuria excrete pathologic amounts of protein in their urine while they are upright, but their urinary protein excretion returns to normal when they are recumbent. Some children are affected by this poorly understood, benign condition. Orthostatic proteinuria seems to be more common in athletic adolescent individuals. Normal children exhibit a diurnal variation in urinary protein excretion, but that variation is exaggerated in children with orthostatic proteinuria. A recent careful study of 91 healthy Hispanic and non-Hispanic white children age 6 to 19 years and living in a city in the American Southwest showed that 19.8% of those children had orthostatic proteinuria. It was more common in boys older than 10 years and in those with a body mass index above the 85th percentile for age. Orthostatic proteinuria may be caused by increased pressure in the renal vasculature while the patient is upright. Several investigators have shown that patients with orthostatic proteinuria have partial obstruction of the left renal vein by entrapment between the aorta and superior mesenteric artery while standing.
The proteinuria may be physiological (ie, secondary to fever or CHF), transient, orthostatic, tubular (as seen in allergic interstitial nephritis), or glomerular. Aminoaciduria as a form of tubular proteinuria may occur, as occurs in certain inborn errors of metabolism.
It is important to elicit a complete history in the child with proteinuria (Box 110.2). When asking about a history of swelling, the physician should note that subtle periorbital edema may be present only in the early morning hours. If the proteinuria is detected at a routine screening examination, the conditions under which the urine was obtained should be determined. The child may have been ill with a high fever or have just participated in an athletic event, such as a track meet.
The physical examination should include a determination of blood pressure and measurement of height and weight. A careful assessment for edema should be made. The skin should be examined for signs of rash, such as that seen in Henoch-Schönlein purpura or healing impetigo. The joints should be inspected for any sign of swelling or joint inflammation. The abdominal examination should include a careful search for ascites or organomegaly.
Box 110.2. What to Ask
•Was the mother’s pregnancy remarkable in any way? What was the child’s birth like?
•Did the child have any neonatal problems that may indicate possible renal damage? Was the child born preterm? Did the child have intrauterine growth restriction?
•Is any swelling apparent in areas such as the ankles, abdomen, or periorbital region?
•Has the child had any recent illnesses, particularly pharyngitis or impetigo?
•Does the child have a history of joint pains and skin rashes? (The adolescent with such history may be at increased risk of having a collagen vascular disease.)
•Has the child had any previous urinary tract infections, urinary abnormalities, or dark urine?
•Does the child have a history of hypertension or weight loss or gain?
•Is the family history positive for renal disease?
•Does the child have diabetes mellitus?