Proteinuria can be detected by various means, and the most common is the dipstick test, a calorimetric assay that spots only albumin and not low-molecular-weight proteins. In addition, alkaline urine and the presence of contrast media in urine can lead to false dipstick positivity. Though 24-hour urine collection is the gold standard to quantify the proteinuria, spot urine protein-to-creatinine ratio can be used for initial confirmation after a positive screen with dipstick or to trend proteinuria ( Table 19.1 ). A ratio below 0.2 protein mg/creatinine mg is considered normal in children older than 2 years of age and a ratio less than 0.5 mg/mg is considered normal in younger children between 6 months and 2 years of age. In timed collection, protein excretion greater than 100 mg/m 2 in 24 hours or 4 mg/m 2 /hour is considered abnormal, and over 40 mg/m 2 /hr is considered nephrotic range. Qualitative analysis of protein in urine by immunonephelometry helps distinguish glomerular from tubular proteinuria.
| Method | Abnormal Proteinuria | Precautions |
|---|---|---|
| Urine dipstick | 1+ or more in a concentrated urine specimen (specific gravity ≥1.020) | False positive if urine pH >8.0 or specific gravity >1.025 or tested within 24 hr of a radiocontrast study |
| Sulfosalicylic acid test | 1+ or more | False-positive with iodinated radiocontrast agents |
| Urine protein/creatinine ratio (U p /U Cr ratio) in spot urine | >0.02 g/mmol or >0.2 mg/mg in children >2 yr | Protein excretion varies with child’s age |
| >0.06 g/mmol or >0.6 mg/mg in children 6 mo-2 yr | ||
| Nephrotic range: | ||
| >0.2 g/mmol or >2 mg/mg | ||
| Timed urine protein excretion rate | >4 mg/m 2 /hr or >150 mg/1.73 m 2 /24 hr | In an accurately collected 24-hr urine specimen, urine creatinine should be in the range of 0.13-0.20 mmol/kg or 16-24 mg/kg ideal body weight for females, and 0.18-0.23 mmol/kg or 21-27 mg/kg ideal body weight for males |
| Nephrotic range: | ||
| >40 mg/m 2 /hr or >3 g/1.73 m 2 /24 hr |
(See Nelson Textbook of Pediatrics, p. 2517.)
Proteinuria in children can be transient, orthostatic, or persistent. Transient and orthostatic proteinuria are benign conditions and require no treatment. Several factors including fever, stress, hypovolemia, exercise, and seizures can lead to transient proteinuria ( Table 19.2 ). Orthostatic proteinuria is defined as increased protein in urine only when upright. In this condition, absence of proteinuria when horizontal and resting can be confirmed by documenting absence of protein in a 1st morning void. Split day/night urine collection is the gold standard to diagnose orthostatic proteinuria, which is a common benign cause of proteinuria, especially in adolescents. Persistent proteinuria requires meticulous evaluation to rule out renal pathology.
| Transient Proteinuria |
|
| Orthostatic (Postural) Proteinuria |
| Glomerular Diseases Characterized by Isolated Proteinuria |
|
| Glomerular Diseases with Proteinuria as a Prominent Feature |
|
| Tubular Diseases |
|
Evaluation of proteinuria begins with a detailed history and physical examination. Pertinent histories that help distinguish pathologic from benign proteinuria include history of respiratory symptoms concurrent with or preceding the proteinuria, presence of red urine, edema, positive family history of kidney disease, or hearing loss. Findings of edema and hypertension suggest pathologic proteinuria. Repeating urine dipstick in asymptomatic children with a negative history can eliminate unnecessary further testing for transient proteinuria. If still positive, spot urine protein-to-creatinine ratio can help confirm the presence of proteinuria. If confirmed, a 1st morning void protein-to-creatinine ratio can then identify orthostatic proteinuria. Once the benign conditions are ruled out in asymptomatic children, further testing is similar to that of symptomatic children and these children should be referred to nephrologists. This more detailed evaluation begins with 24-hour urine collection where possible, complete urinalysis, and sediment evaluation looking for glomerular or other parenchymal pathology that could be causing the proteinuria ( Fig. 19.1 ). Positive leukocyte esterase, nitrite, and presence of pyuria or bacteriuria suggest a urinary tract infection. If not resolved with treatment of infection, proteinuria will need further evaluation. Low molecular proteins, such as β2-microglobulin, α1-microglobulin, lysozyme, and retinol-binding protein are found in tubular proteinuria as is seen in Fanconi syndrome or Dent disease. Red blood cell (RBC) cast is pathognomonic of glomerulonephritis . Serum chemistry including creatinine, BUN, electrolytes, albumin, and cholesterol will also help separate proteinuria secondary to glomerulonephritis or nephrotic syndrome. Lupus antibody studies, streptococcal infection, and complement C3 and C4 levels along with viral studies can help delineate the various causes of glomerulonephritis and nephrotic syndrome. Renal ultrasound should be considered to rule out any gross parenchymal etiology for the proteinuria, such as dysplastic kidney and cystic kidney disease. Renal biopsy may be indicated if there is evidence for worsening of proteinuria, hypoalbuminemia, deteriorating renal function, or a poor response to the initial therapy.
Differential diagnoses for proteinuria are extensive, as described in Table 19.2 . The initial evaluation of a patient with proteinuria is presented in Table 19.3 . Indications for a referral to a pediatric nephrologist are described in Table 19.4 . If there is obvious edema with proteinuria, the diagnostic evaluation noted in Table 19.3 advances directly to the 2nd phase and, if necessary, to the 3rd phase.
| Pediatrician’s Work-up: Phase I |
|
| Pediatrician’s Work-up: Phase II |
|
| Pediatric Nephrologist’s Work-up: Phase III |
|
|
The combination of proteinuria, hypoalbuminemia, edema, and hyperlipidemia are the defining features of nephrotic syndrome. Nephrotic syndrome may be a result of many primary etiologic factors, with varying renal pathologic processes and long-term consequences. Proteinuria that causes edema is always clinically significant, although not all edema is secondary to proteinuria ( Table 19.5 ). All children with nephrotic syndrome invariably have “nephrotic-range” proteinuria, necessitating detailed evaluation, and most require treatment. In rare cases, a child with asymptomatic proteinuria has nephrotic-range proteinuria. If there is concomitant hypoalbuminemia and hyperlipidemia, the work-up proceeds as if the child presented with nephrotic syndrome, despite the absence of edema. Even without hypoalbuminemia and hyperlipidemia, nephrotic-range proteinuria is less likely to be benign than is less marked asymptomatic proteinuria.
| Kidney Diseases |
|
| Heart Failure |
| Liver Failure |
| Nutritional and Gastrointestinal Disorders |
|
| Endocrine Disorders |
|
| Miscellaneous |
|
Nephrotic Syndrome in Young Children
(See Nelson Textbook of Pediatrics, p. 2571.)
Differential Diagnosis
Three diseases constitute all cases of isolated nephrotic syndrome: minimal change disease (the most common); focal segmental sclerosis (also called focal glomerular sclerosis); and membranous glomerulopathy. These classifications are based on pathologic findings. Thus these presentations could be primary or secondary due to other causes. In addition, nephrotic syndrome can be present along with glomerulonephritis (GN), such as postinfectious GN, IgA GN, or membranoproliferative GN. Systemic diseases also cause childhood nephrotic syndrome, accounting for 10% of cases. The three foremost considerations include SLE, anaphylactoid purpura (Henoch-Schönlein purpura), and hemolytic uremic syndrome. These diseases have extra-renal manifestations in addition to the proteinuria and must be considered in any child who presents with systemic illness and significant proteinuria. Hereditary forms of nephrotic syndrome are a genetically heterogeneous group of disorders representing a spectrum of hereditary renal diseases. There are 13 subtypes of hereditary nephrotic syndrome associated with 35 genes. Several of the more common disorders along with other causes of nephrotic syndrome are noted in Tables 19.6 and 19.7 .
| Idiopathic Nephrotic Syndrome |
|
| Genetic Disorders Associated with Proteinuria or Nephrotic Syndrome |
|
| Nephrotic Syndrome (Typical) |
|
| Proteinuria With or Without Nephrotic Syndrome |
|
| Multisystem Syndromes With or Without Nephrotic Syndrome |
|
| Metabolic Disorders With or Without Nephrotic Syndrome |
|
| Secondary Causes of Nephrotic Syndrome |
| Infections |
|
| Drugs |
|
| Immunologic or Allergic Disorders |
|
| Associated with Malignant Disease |
|
| Glomerular Hyperfiltration |
|
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