Proteinuria in Children: Evaluation and Differential Diagnosis ALEXANDER K.C. LEUNG, MD; ALEX H.C. WONG, MD, MPH; and STEFANI S.N. BARG, MD University of Calgary, Calgary, Alberta, Canada Although proteinuria is usually benign in the form of transient or orthostatic proteinuria, persistent proteinuria may be associated with more serious renal diseases. Proteinuria may be an independent risk factor for the progression of chronic kidney disease in children. Mechanisms of proteinuria can be categorized as glomerular, tubular, secretory, or overflow. A history, a physical examination, and laboratory tests help determine the cause. Transient (functional) proteinuria is temporary. It can occur with fever, exercise, stress, or cold exposure, and it resolves when the inciting factor is removed. Orthostatic proteinuria is the most common type in children, especially in adolescent males. It is a benign condition without clinical significance. Persistent proteinuria can be glomerular or tubulointerstitial in ori- gin. The urine dipstick test is the most widely used screening method. Although a 24-hour urine protein excretion test is usually recommended for quantitation of the amount of protein excreted in the urine, it may be impractical in chil- dren. A spot, first-morning urine test for a protein-to-creatinine or protein-to-osmolality ratio is a reliable substitute. Treatment of proteinuria should be directed at the underlying cause. Patients with active urinary sediments, hematu- ria, hypertension, hypocomplementemia, renal insufficiency with depressed glomerular filtration rate, or signs and symptoms suggestive of vasculitic disease may require referral to a pediatric nephrologist and a renal biopsy. (Am Fam Physician. 2017;95(4):248-254. Copyright © 2017 American Academy of Family Physicians.) CME This clinical content he presence of protein in urine is a with age, peaks during adolescence, and is conforms to AAFP criteria common laboratory finding in chil- higher in girls.11 for continuing medical education (CME). See dren. Although proteinuria is usu- CME Quiz Questions on ally benign, it can be a marker of a Mechanisms of Proteinuria page 220. Tserious underlying renal disease or systemic Mechanisms of proteinuria can be catego- 1-3 Author disclosure: No rel- disorder. When proteinuria coexists with rized as glomerular, tubular, secretory, or evant financial affiliations. hematuria, the likelihood of clinically signifi- overflow.1,2,12,13 Glomerular proteinuria is ▲ 1,2 Patient information: cant renal disease is higher. Further, pro- due to increased filtration of macromole- A handout on this topic is teinuria represents an independent risk factor cules, particularly albumin, across the glo- available at http://www. for the progression of nonglomerular or glo- merular capillary wall. This may be a result aafp.org/afp/2010/0915/ merular chronic kidney disease in children.4-9 of increased permeability of the glomerular p652.html. The Chronic Kidney Disease in Children basement membrane because of structural study demonstrated that persistent protein- defects of the membrane, loss of its negative uria with a high urine protein-to-creatinine charges, or direct damage by immune com- (UPr/Cr) ratio (more than 2 in patients with plexes.1,2,12 Glomerular proteinuria can also nonglomerular disease and more than 0.5 in occur when a reduced number of function- patients with glomerular disease) predicts ing nephrons leads to increased diffusion significant chronic kidney disease progres- of protein across the remaining glomeruli. sion.7 The challenge for the primary care Tubular proteinuria occurs when there is physician is to separate benign forms of pro- an increased excretion of normally filtered teinuria from those with clinical significance. low-molecular-weight proteins because of impaired reabsorption by the proximal Epidemiology tubules.12 Secretory proteinuria results Proteinuria is present in up to 10% of from oversecretion of certain proteins routine urine testing in school-aged chil- in the tubules, most notably the Tamm- dren, although this decreases to 0.1% with Horsfall proteins in interstitial nephri- repeated testing.10 The prevalence increases tis. Overflow proteinuria occurs when the 248Downloaded American from the Family American Physician Family Physician website at www.aafp.org/afp.www.aafp.org/afp Copyright © 2017 American AcademyVolume of Family 95, Physicians.Number 4 For ◆ theFebruary private, 15,noncom 2017- mercial use of one individual user of the website. All other rights reserved. Contact [email protected] for copyright questions and/or permission requests. Proteinuria in Children Table 1. Causes of Proteinuria in Children Transient (functional) proteinuria Idiopathic plasma concentrations of low-molecular-weight pro- Related to a medical condition (e.g., fever, seizure) teins exceed the capacity of the tubules to reabsorb the Unrelated to a medical condition (e.g., exercise, stress, filtered protein. dehydration, cold exposure) Orthostatic proteinuria Etiology Persistent proteinuria Table 1 summarizes the diverse etiologies of proteinuria Glomerular in children.1 Adaptation (hyperfiltration) because of nephron loss (e.g., reflux nephropathy secondary to vesicoureteric reflux) TRANSIENT PROTEINURIA Alport syndrome Collagen vascular disease or vasculitis: Henoch-Schönlein Transient (functional) proteinuria is temporary and purpura, systemic lupus erythematosus resolves when the inciting factor remits or is removed. Diabetes mellitus Transient proteinuria can occur with a medical condi- Glomerulopathy: congenital nephrotic syndrome, focal tion (e.g., fever, seizure) or another trigger, such as exer- segmental glomerulosclerosis, immunoglobulin A cise, stress, dehydration, or cold exposure. It can also be nephropathy, membranoproliferative glomerulonephritis, idiopathic. mesangial proliferative glomerulonephritis, minimal change glomerulopathy ORTHOSTATIC PROTEINURIA Infections: group A beta-hemolytic streptococcus infection, viral infection (hepatitis B and C, human immunodeficiency Orthostatic proteinuria is the most common cause of pro- virus, infectious mononucleosis), other infections (malaria, teinuria in children, especially in adolescent males.1,14,15 syphilis) It is a benign condition without clinical significance.1,15 Malignancies (lymphoma, solid tumors) The diagnosis is suggested with normal protein excre- Toxin (mercury) tion (i.e., negative urine dipstick test result, or a UPr/Cr Tubulointerstitial ratio of 0.2 or less) in a spot, first-morning urine sample Acute tubular necrosis: aminoglycosides, amphotericin B, cisplatin, nonsteroidal anti-inflammatory after the patient has been supine for the entire night, but drugs, radiocontrast media increased protein excretion (i.e., positive urine dipstick Acute tubulointerstitial nephritis: nonsteroidal anti- test result, or a UPr/Cr ratio of more than 0.2) at least inflammatory drugs, penicillin, cephalosporins, quinolones, four to six hours after the patient has been upright.1-3 The sulfonamides, cimetidine (Tagamet), allopurinol cause of orthostatic proteinuria is not clear; however, the Polycystic kidney disease anatomic compression of the left renal vein has been Proximal renal tubular acidosis: Fanconi syndrome (global proximal tubule dysfunction), cystinosis, Lowe syndrome, suggested. galactosemia, Wilson disease Pyelonephritis PERSISTENT PROTEINURIA Toxins (lead, copper, mercury) Persistent proteinuria can be tubulointerstitial or more commonly glomerular in origin.1-3 Albumin and immu- Adapted with permission from Leung AK, Wong AH. Proteinuria in noglobulin G in the urine are the usual indicators for children. Am Fam Physician. 2010 ;82( 6 ):647. glomerular diseases. Glomerular diseases can have nephrotic and/or nephritic features, and distinguishing these features can help narrow the differential diagnosis. Clinical Evaluation Nephrotic syndrome is characterized by heavy protein- Table 2 lists clinical clues to the underlying cause of per- uria (more than 1,000 mg per m2 per day or a UPr/Cr sistent proteinuria.1 ratio of more than 2), edema, hypoalbuminemia (less than 2.5 g per dL [25 g per L]), and hyperlipidemia.16 Diagnostic Evaluation Nephritic features include hematuria; hypertension; oli- Proteinuria is often an incidental finding on urine dip- guria; and active urinary sediments, such as red blood stick testing or urinalysis. Children with asymptomatic cells, white blood cells, and cellular casts. proteinuria usually have the transient or orthostatic Tubulointerstitial diseases usually involve low- form. Figure 1 is an algorithm for the evaluation of molecular-weight proteins. Proteinuria associated with asymptomatic proteinuria in children.1-3 renal tubular disorders is generally mild. Tubular pro- If a urine dipstick test shows trace amounts of protein, teinuria rarely presents a diagnostic dilemma because the test should be repeated with first-morning urine. If the underlying disease is usually detected before the the first-morning test shows a trace or negative amount proteinuria.17 of protein, it should be repeated in one year to ensure February 15, 2017 ◆ Volume 95, Number 4 www.aafp.org/afp American Family Physician 249 Proteinuria in Children Table 2. Clinical Clues to the Cause of Persistent Proteinuria in Children Cause of proteinuria Clinical features Laboratory findings* Glomerular Adaptation to nephron History of vesicoureteric reflux or recurrent urinary tract Elevated serum creatinine or blood urea loss infection nitrogen