Asymptomatic hematuria and proteinuria in children: Causes and appropriate diagnostic studies

T H E J O U R N A L OF

PEDIATRIC S AUGUST

MEDICAL

1976

V o l u m e 89

Number 2

PROGRESS

Asymptomatic hematuria and proteinuria in children: Causes and appropriate diagnostic studies Clark D. West, M . D . , Cincinnati, O h i o

SINCE THE ADVENT of simple dipstick methods for the detection of urinary abnormalities, children with blood in their urine without other symptoms or signs of disease have been encountered with increasing frequency. Proteinuria without other evidence of disease is also not uncommon. A recent study 1 indicates that the incidence of hematuria in school girls, ages 6 to 12 years, is 340/ 100,000 and in school boys, 120/100,000. Proteinuria in girls has an incidence about three times that Of hematuria; in boys it is about one-third of that of hematuria. The observations of that study also indicated that m a n y of the children who have only hematuria or 0nly proteinuria do not have serious disease. On the other hand, when these urinary abnormalities are encountered it is important that diagnostic steps be instituted to determine their cause. This communication is concerned with causes of hematuria and of proteinuria in children who are otherwise From The Children "s Hospital Research Foundation and The Department of Pediatrics, University of Cincinnati College of Medicine. Presented in part as the Eleventh Annual Waldo E. Nelson Lecture, St. Christopher's Hospital for Children and Temple University, Health Sciences Center, Philadelphia, Pa., March 24, 1976. Reprint address: Children's Hospital Research Foundation, Elland Ave. and Bethesda, CincinnatL Ohio, 45229.

well, i.e., asymptomatic proteinuria and hematuria; the diagnostic studies which are reasonable in such children are also outlined. Children with these urinary abnormalities can usually be placed in one of the following three categories: 1. Hematuria with no or minimal proteinuria: This is the abnormality most frequently encountered. The hematuria may be gross and later microscopic, or consistently microscopic. Less commonly, gross hematuria ceases and is followed by completely normal urine. In those with microscopic hematuria, the detection by ordinary methods of even trace amounts of protein* in the urine is an important clinical sign. Proteinuria in the presence of gross hematuria has little significance. Thus, in the child with hematuria, it is important to test at intervals yellow urine specimens for protein; the detection of even small amounts, and not necessarily in every specimen, usually means that the patient actually falls in category 3 and that a renal biopsy should be performed. 2. Proteinuria unaccompanied by hematuria: This abnormality is most frequently seen in older children and *In this paper, urine protein is consider*~dto be present in trace amounts when the concentrationis 10 to 20 mg/dll~This is approximatelythe limit of detection by precipitation with sui~bsalicylicacid. Since dipstick methods may,on occasion,detect lowerconcentrations,urines recorded as containinga trace by dipstick should be checked by the sulfosalicylicacid method.

Vol. 89, No. 2, pp. 173-182

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Table I. Causes of asymptomatic hematuria with no or minimal proteinuria Nonrenal bleeding Urinary tract infection Renal calculi Foreign body in urethra or bladder Extraglomerular renal bleeding Hydronephrosis Polycystic disease of kidney Sickle cell trait Essential hematuria Renal hemangioma Renal neoplasm Renal tuberculosis Glomerular bleeding Acute postinfectious glomerulonephritis Alport syndrome (hereditary nephritis) Membranoproliferative glomerulonephritis Sequela of Henoch-Schrnlein purpura IgA-IgG mesangial nephropathy Familial hematuria Benign hematuria

Table II. Historical information and diagnostic studies of value in determining cause of asymptomatic hematuria Historical information Family history of renal disease History of recent respiratory infection History of illness resembling Henoch-Schrnlein purpura If hematuria is gross, events associated with it: Trauma Concurrent respiratory or other infection Exercise Urine culture Tuberculin test Tests for sickle hemoglobinopathy, if appropriate Serum C3 or total complement level Tests 0f family members for hematuria Tests for low-grade proteinuria with microhematuria Intravenous pyelography Cystourethrogram With gross extraglomerular bleeding, cystoscopy to lateralize bleeding

adolescents? The presence of even small amounts of blood in the urine in association with protein is an important sign and may place the patient in category 3. 3. Both protein and blood detectable in the urine: To fall into this category, the patient must have proteinuria in the absence of gross hematuria; i.e., proteinuria with microscopic hematuria must be present. Patients in this group almost invariably have some form of glomerulonephritis and, if the urinary abnormality is persistent, a renal biopsy is indicated. Outlined below are the diseases which could be consid-

The Journal of Pediatrics August 1976

ered in patients falling into categories 1 and 2, above, and the diagnostic studies which should be carried out. The glomerulonephritides of childhood, which produce the urinary abnormalities present in patients falling into the third category, will be discussed in a subsequent re ~w. ASYMPTOMATIC HEMATURIA WITH NO, OR MINIMAL, PROTEINURIA Microhematuria in the essentially healthy child is in some instances found by chance on routine urinalysis or in the course of diagnostic studies for transient, unrelated illness. Other patients come to the attention of the physician because of the presence of gross hematuria manifested by brown or red urine. It is assumed in this discussion that the hematuria is truly asymptomatic and that the physician has ruled out by history and physical examination such conditions as drug ingestion, disease of the coagulation system, and systemic disease which might produce hematuria, and that symptoms of bladder irritation are not present. Drugs causing hematuria have been enUmerated previously. 2 Rare causes of hematuria such as Rendu-Osler-Weber disease or chronic bacteremia, as occurs in subacute bacterial endocarditis or in patients with infected atrioventricular shunts, should be suspected by history and physical examination and are not considered here. Symptoms of bladder irritation would suggest that the hematurin is the result of a viral cystitis or of a bacterial urinary tract infection of sufficient severity to produce hematuria. Bladder tumors, very rare in children, would also, in all likelihood, first be manifest by signs of vesical irritation; usually hematuria is a late event occurring when the tumor ulcerates? In Table I are listed some of the causes of asymptomatic hematuria. For convenience, the diseases are divided into three groups according to the source of the bleeding. The diagnostic procedures which are reasonable to perform in such patients to determine the cause of the hematuria are listed in Table II. As noted in Table II, there are a number of items in the history which may aid in determining the cause of the hematuria. Among these are a family history suggestive of Alport syndrome (hereditary nephritis), of an infection which might be the antecedent of acute postinfectious giomerulonephritis, or of an illness in the past suggestive of Henoch-Schrnlein purpura. If the hematuria is gross, it is of value to determine the events associated with it, particularly minor trauma, concurrent respiratory or other infection, or exercise. Whereas the diagnosis cannot be directly made from the answers to these questions, they do give leads suggestive of certain diagnoses as will be noted in the following discussion of the diseases producing asymptomatic hematuria.

Volume 89 Number 2

Nonrenal bleeding. Urinary tract infection is stated by some authors to be one of the most common causes of hematuria in children.:' Our experience would indicate that in this condition, the hematuria is rarely asymptomatic. Usually if the virulence of the organism and the severity of the infection are sufficient to produce hematuria, other symptoms pointing to urinary tract infection will be obvious. Nevertheless, the urine of the child with asymptomatic hematuria should be cultured to rule out urinary tract infection. This is particularly indicated in girls. Renal calculi would be a rare cause of asymptomatic hematuria in children. Not only is the incidence of calculi very low in children in the United States but also other symptoms, overshadowing the hematuria in their severity, would usually bring the child to the attention of the physician. Foreign bodies in the urethra or bladder may be manifest by hematuria although, as in other conditions causing nonrenal bleeding, the hematuria is rarely asymptomatic. There are usually, in addition, symptoms of bladder irritation or of a vesical calculus, :~especially when the foreign body has been present for a long time. Foreign bodies in the vagina may also produce bleeding which is mistaken for hematuria. Extraglomerular renal bleeding. With profuse bleeding from renal tissue other than the glomeruli, the urine is usually red rather than brown and may.contain clots; red cell casts should not be present. Hematuria occurs transiently in about 15% of patients with hydronephrosis. 3 It may be instigated by infection or by a stone; in either case it would, as a rule, not be asymptomatic. With hydronephrosis, asymptomatic gross hematuria can occur after relatively minor trauma; in the white child this chain Of events is virtually pathognomonic of hydronephrosis, but in the black child bleeding as a consequence of sickle cell trait is ~lso a possibility. Hydronephrosis is, of course, revealed by intravenous pyelography. Hematuria occurs with high frequency in polycystic disease of the kidney when cases of adults and children are considered together. In children, 20% of the cases have this manifestation. :~Very often proteinuria is also present so that the urinary abnormality is similar to that of glomerulonephritis. The diagnosis can be made in most patients by intravenous pyelography but, in a few, arteriography or tomography may be necessary. Sickle cell trait and sickle cell-hemoglobin C disease predispose to episodic gross h e m a t u r i a Y For reasons not understood, it is an uncommon complication of sickle cell disease?. 6 Children are less often affected than adults; males four times as frequently as females. There may be a

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1 75

history of antecedent minor trauma. "~ Bleeding most frequently occurs from the left kidney. Unless clots obstruct the ureter, the bleeding is usually painless. Bleeding often ceases spontaneously, but tends to recur; microhematuria is usually not present in the intervening period. The reason for the preponderance of bleeding from the left kidney is not clear; some authorities 4 feel that it is because blood flow in the left renal vein is impeded as compared with that in the right because it is longer and because the left spermatic, inferior phrenic, and adrenal veins drain into it. The exact site of the bleeding is not clear. Some kidneys removed to control bleeding have shown small vessels packed with sickle cells, and there may be extensive hemorrhage in the renal paranchyma and edema of the papillae. Other kidneys have shown little abnormality and the bleeding site may be in the ureter.' Tests for this hemoglobinopathy should always be performed in the black child with gross hematuria. Cystoscopy may lateralize the source of the bleeding. So-called essential hematuria is found with greater frequency in adults than in children. The bleeding is severe, and clots may cause renal colic. Blood replacement by transfusion may be required. By cystoscopy, the bleeding can usually be lateralized. Bleeding apparently occurs as the result of communicating channels developing between the pericalyceal venous plexus and the lumen of the calyx2 The bleeding may be episodic and difficult to control. When nephrectomy has been resorted to for control, bleeding has at times developed from the remaining kidney. The diagnosis is usually made on the basis that the bleeding is usually unilateral, and other conditions producing unilateral bleeding are excluded. A picture very like essential hematuria may be produced by a renal hemangioma. 8. 9 The gross hematuria may spontaneously disappear and later reappear. It is a rare cause of hematuria in adults and still rarer in children. Renal hemangiomas are usually not associated with hemangiomas elsewhere. If intravenous pyelography is performed during or shortly after severe gross extraglomerular renal bleeding from any cause, clots may be visualized in the pelvis and calyces, which give the appearance of a hemangioma or of a tumor. Extraglomerular renal bleeding, usually gross, can occur with Wilms tumor. Usually the most severe bleeding occurs late, and, therefore, it is often not asymptomatic, a Nevertheless, it is one of the prime duties of the physician to rule out, insofar as is possible, this cause of hematuria by intravenous pyr and, in the absence of evidence of neoplasm, to reassure the parents. Renal tuberculosis as the cause of bleeding is now

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rarely observed in the United States but the possibility should always be borne in mind. Gross hematuria was the presenting symptom in 20% of adults with this disease and occurred before symptoms of bladder irritation developed? ~ Microhematuria may also occur as a result of tuberculous cystitis,3 but this would usually not be asymptomatic. Pyuria is often present with the hematuria and yet by the usual methods, bacteruria cannot be demonstrated (amicrobic pyuria). A negative tuberculin test is strong evidence against renal tuberculosis. Glomerular bleeding. As a general rule, gross hematuria as the result of glomerular bleeding results in urine which is brown (color of tea or Coca-Cola), or reddish brown, and red blood cell casts may be present. Acute postinfectious glomerulonephritis, commonly poststreptococcal, is the disease usually first thought of by the pediatrician in encountering the patient with microhematuria or with brown urine indicating gross hematuria. Transient hematuria as the only symptom or sign may occur in the child with a mild form of this disease of which there are apparently many. ~ Yet experience would indicate that in the absence of an epidemic, most children with asymptomatic hematuria do not have acute glomerulonephritis. It is especially unlikely if the urinary abnormalities persist for more than two weeks and usually the duration is even shorter. Nevertheless, ancillary signs of acute glomerulonephritis (edema, hypertension, malaise, history of antecedent infection) should always be sought when a child with hematuria is first seen, and appropriate laboratory tests directed by making this diagnosis should be carried out. The tests would include measurement in the serum of the titer of antibody to streptococcal enzymes and of total complement or of the concentration of C3. As is well known, the results of these tests must be interpreted with (eservations. Elevated antistreptolysin O titers may be present in 30% of normal children, and elevated titers are not found in every patient with acute glomerulonephritis. Likewise, the serum level of C3 is normal in 11% of patients with overt acute glomerulonephritis, 1~ and Sagel and associates ~ found a number of children with hematuria a n d / o r proteinuria as the result of mild acute poststreptococcal glomerulonephritis who had no depression of serum complement levels. As will be noted below, the serum C3 concentration also may be persistently low when the hematuria is the result of membranoproliferative glomerulonephritis. Other uncommon causes of asymptomatic hematuria are Alport disease or hereditary nephritis, membranoproliferative glomerulonephritis in the "silent" phase, and the residual nephritis after an episode of Henoch-Sch6nlein purpura. Alport syndrome may be manifest only as hematuria in

The Journal of Pediatrics August 1976

early stages but usually at least traces of proteinuria are present. 13 Deafness in the patient and a history of hematuria, proteinuria, and renal insufficiency, with or without deafness, in family members would alert the physician to this disease as the possible cause of the hematuria. In its "silent" phase, membranoproliferative glomerulonephritis may be manifest solely by transient episodes of hematuria. TM Usually the hematuria is present only at the time of an intercurrent infection, and there is often a history of gross hematuria in the past. To rule out, insofar as is possible, this diagnosis, the serum C3 concentration should be measured in all patients with asymptomatic hematuria. A normal level is not infallible evidence against the diagnosis. TM 16 Whereas al ! reported cases 14 of "silent" membranoproliferative glomerulonephritis have had depressed serum concentrations of C3, we have encountered patients with the disease in this stage in whom the level has been transiently in the normal range. Asymptomatic hematuria as a sequela of undiagnosed Henoch-Sch6nlein purpura is of more academic than of practical interest. The undiagnosed case would be one in which the rash was absent or atypical and the manifestations were abdominal or joint pain and perhaps hematochezia with the urinary abnormalities not noted during the acute phase and asymptomatic hematuria discovered later. If this were accompanied by a low-grade proteinuria, a renal biopsy would be indicated. The biopsy would reveal the presence of a mild glomerulonephritis but by fight and immunofluorescence microscopy it is often difficult to distinguish this disease from IgA-IgG mesangial nephropathy discussed below. Failure to recognize this etiology of the hematuria would not be of great consequence, since there is no therapy and the prognosis, according to current thinking, would be good in that the patients with this disease who progress to end-stage renal failure are those who have severe renal disease at the onset characterized by nephrotic syndrome and glomerular insufficiency?7 More frequently encountered as the cause of hematuria is a form of glomerulonephritis known as IgA-IgG mesangial nephropathy, or Berger disease. ~8-2~In our experience, this disease in the child usually has a rather typical clinical course. The patient suddenly developS gross hematuria concurrent with infection, usually of the respiratory tract. As the infection subsides, the gross hematuria disappears to be replaced by microhematuria which may be constantly or intermittently present. It is our impression that respiratory infections are more frequent and severe in patients with this disease, particularly early in the course, than they are in other family members. Usually with subsequent respiratory infections, gross hematuria

Volume 89 Number 2

returns. To this point, the disease is not readily distinguishable from hematuria from many other causes, and a clue to its presence is the development of a trace or 1 + proteinuria with the microhematuria, i.e., in yellow urine specimens. Since the proteinuria may not be constantly present, a number of urine specimens, collected at intervals in the absence of gross hematuria, should be carefully tested for protein. If small amounts of protein are found, a renal biopsy should be performed. The glomerular abnormalities, as revealed by light and immunofluorescence microscopy; may not be sufficiently distinctive that residual nephritis as a sequella of Henoch-Sch6nlein purpura can be ruled out. Also encountered relatively frequently is familial hematuria, a benign condition in which hematuria is inherited as an autosomal dominant. 21 Microhematuria is usually constantly present and gross hematuria can occur in association with infection. Proteinuria is not present unless the hematuria is macroscopic. Examination of family members indicates that microhematuria is also present in a parent and often in siblings. It has been traced back through three generations. ~1 The family members affected would not have proteinuria (evidence of glomernlonephritis) as would be the case with hereditary nephritis or Alport disease. Family members are most expeditiously tested for hematuria by supplying the parents with appropriate dipsticks and instructing them to test the urine in the home rather than by bringing specimens to the physician. Although microhematuria from this cause is usually demonstrable in every urine specimen, we usually recommend that each family member be tested three to five times. Females should be warned against testing during menstrual periods. Persons with positive tests should be questioned and examined to make sure they do not have signs o f hereditary nephritis, renal calculi, or other causes for hematuria. If one p a r e n t has consistent asymptomatic hematuria without proteinuria and no cause for it can be found, familial hematuria should be strongly considered as the diagnosis. The diagnosis is strengthened by the detection of asymptomatic hematnria in siblings and other relatives. When there is evidence for this diagnosis, rel~al biopsy is not necessary. Light microscopy and immunohistologic studies usually show no glomerular abnormality. In the majority of cases of asymptomatic hematuria, no cause can be found. The condition has, therefore, to be regarded as idiopathic and has been designated benign, or benign recurrent, hematuria. Children with this abnormality have been described in a number of publications. ~2-2~ Although patients with low-grade but definite glomerulonephritis have often been included in these reports, few have developed serious illness and none with

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17 7

normal or near normal glomerular morphology on renal biopsy have developed significant disease. Thus, when proteinuria is not detectable on multiple yellow urine specimens by ordinary methods and the causes of hematuria described above have been eliminated, the diagnosis remaining, and which must be made at least tentatively, is benign hematuria. Renal biopsies in patients falling into this group have in our experience shown either normal glomeruli or very slight and equivocal proliferation of mesangial cells. The condition may have multiple causes but none have been found. It may manifest as gross hematuria followed by microhematuria or as microhematuria only. Microhematuria may be present in every urine specimen or episodically. In some cases, gross hematuria recurs, often in association with intercurrent infection. Some of the patients experience exacerbations of gross hematuria with exercise; in such patients the urine may be completely normal when the patient is sedentary. Perhaps some patients whose hematuria is more severe in the evening and minimal or absent on arising belong in this category. In these cases one may postulate an exaggeration of the mechanism producing exercise hematuria? 6 Usually the hematuria disappears within months, although occasionally it may persist for a longer time. When the diagnosis of benign hematuria has been made by elimination, it seems reasonable not to subject the child repetitively to more diagnostic procedures. On the other hand, the child should be examined at intervals, since the diagnostic studies described above are not infallible. To obtain information about the severity and frequency of the hematuria, the conditions with which it is associated (infection, exercise) and its duration, we have found it helpful to supply the parents with dipsticks and instructions to test the urine at intervals for blood and record the results. In addition, small aliquots of yellow urine specimens obtained randomly at home can be stored in the frozen state and brought to the physician to be tested carefully for protein. The advent of proteinuria would suggest progression of hereditary nephritis, IgA-IgG mesangial nephropathy, or membranoproliferative glomerulonephritis not detected previously by the presence of hypocomplementemia. A later fall in the serum level of C3 would also suggest membranoproliferative glomerulonephritis. The advent of either proteinuria or hypocomplementemia would be cause for performing a renal biopsy. The possibility of polycystic disease or a renal neoplasm undetectable by intravenous pyelography is remote but should be borne in':mind. Because of this possibility it seems wise, if the bleeding continues unabated after one year, to repeat the intravenous pyelography. If the bleeding continues for two years, a renal

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Table IlL Causes of asymptomatic proteinuria without hematuria Orthostatic, or postural, proteinuria Idiopathic nephrotic syndrome-subclinical Benign persistent proteinuria Membranous glomerulopathy Membranoproliferative glomerulonephritis Chronic pyelonephritis Congenital renal anomaly 9Polycystic disease Renal hypoplasia

biopsy may relieve the minds of the parents and the physician.

Summary of diagnostic approach to asymptomatic hematuria. The overall approach to the diagnosis of the cause of asymptomatic hematuria can be summarized as follows. When first seen, tests to rule out urinary tract infection and to give evidence for or against the diagnosis of acute poststreptococcal glomerulonephritis may be performed. These include culture of urine and measurement of the titers of antibody to streptococcal enzymes and of the serum level of C3. If the anti-enzyme titer and the C3 level are normal, acute glomerulonephritis is not entirely ruled out. If, however, acute glomerulonephritis is present, the urinary abnormality should be transient. A normal C3 level is also~evidence against membranoproliferative glomerulonephritis in the "silent" phase. If the hematuria is not transient, a number of other studies should be performed. Intravenous pyelography is always indicated to rule out neoplasm, hydronephrosis, or polycystic disease. A negative tuberculin test contributes evidence against renal tuberculosis. The parents should be instructed on, and provided with materials for, testing the urine of family members for hematuria. It is important that the physician satisfy himself that the microhematuria is not accompanied by a low-grade proteinuria by testing a number of yellow urine specimens obtained at various times for protein. If even small amounts of protein are detected by ordinary tests, a renal biopsy is indicated. If the bleeding is gross and the child is black, tests for sickle cell anemia should be performed. If cystoscopy performed when the urine is bloody indicates that the bleeding is unilateral, it is obviously of extraglomerular origin; the possibilities are sickle cell anemia, essential hematuria, or a renal hemangioma. Hydronephrosis and polycystic disease would have been previously ruled out by intravenous pyelography. In the absence of red urine due to profuse bleeding, cystoscopy is rarely necessary unless a foreign body in the bladder is suspected; the incidence of bladder tumor is very low in children and, as

The Journal of Pediatrics August 1976

noted previously, the hematuria is rarely asymptomatic. Nevertheless, the physician may elect to have cystoscopy performed to reassure himself and the parents that the bladder is not the site of the bleeding. If after these procedures, no cause for the hematuria is found, the diagnosis of benign hematuria is reasonable. Once this diagnosis is made by elimination, diagnostic studies should, for the time being, cease and the child should be followed at intervals as noted above. ASYMPTOMATIC

PROTEINURIA

The causes of proteinuria in the otherwise well child are listed in Table III. The commonest causes are orthostatic or postural proteinuria, occurring most commonly in the older child, and subclinical idiopathic nephrotic syndrome, usually seen in young children. In these conditions, hematuria would be uncommon. In the two glomerulonephritides listed in Table III, membranous and membranoproliferative, proteinuria alone is rare and most often the proteinuria is accompanied by hematuria. In addition, serious renal anomalies and chronic pyelonephritis may on occasion present as asymptomatic proteinuria, but signs and symptoms other than proteinuria would be apt to bring the child to the physician's attention. It should always be remembered that transient proteinuria can occur in the otherwise well child with exposure to cold or with severe exercise. Orthostatic proteinuria. In the older child and young adult, the most frequent cause of asymptomatic proteinuria without hematuria is postural Or orthostatic proteinuria. Random urine specimens contain protein in trace to 2 + concentrations. Occasionally the concentration of urine protein can be graded 4 + . It has been reported that hematuria, pyuria, and cylindruria can also be present but this is unusual in our experience. Although there has been considerable debate about the prognosis of this disease and some have felt that serious renal disease can later develop in patients with orthostatic proteinuria, it is now generally regarded a~ a benign condition 27~1 in which protein is not detectable by ordinary methods in urine formed when the patient is recumbent but is easily detected in urine formed while the patient is upright. It is now recognized that normal persons have increased albuminuria when in the upright position, although the amount excreted is too small to be detected by ordinary tests. Also excretion of albumin by patients with orthostatic proteinuria is greater than normal when they are in the recumbent position, but.. again the amount is not great enough to be detected by ordinary tests? 2 These observations would suggest that orthostatic proteinuria is an exaggeration of a normal physiologic phenomenon. Two types of postural proteinuria have been recog-

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nized?~. 29 In the "transient" type the proteinuria is inconsistently present in the upright position whereas in the "fixed and reproduceable" type, proteinuria can be consistently demonstrated when the patient is upright. The difference between these two types may be of no consequence but they should be carefully distinguished from "constant" proteinuria in which protein is present in urine formed in the recumbent as well as the upright position. Careful tests to determine whether the proteinuria is truly orthostatic are therefore important. Patients with a renal abnormality such as glomerulonephritis often exhibit distinctly lower rates of protein excretion when recumbent. In some cases, only traces of protein are present in urine formed when the child is recumbent, but this is a significant observation. Patients with "constant" proteinuria may have some depression of the levels of total serum protein and of serum albumin; serum cholesterol levels may be somewhat elevated. With orthostatic proteinuria, these serum constituents are in normal concentration. Measurement of these serum constituents together with those of creatinine and. urea and assessment of urine concentrating ability are always indicated in the patient with proteinuria when first seen. Also indicated is a careful history and physical examination, including measurement of blood pressure. Tests for orthostatic proteinuria are usually more accurately and expeditiously performed in the home than in the hospital. The patient or his parents are informed of the purpose of the test. The subject is instructed to void immediately before retiring. Some authorities recommend that the bladder be emptied one hour after retiring so that the urine in the upper tracts, formed when standing, is evacuated. A sample of urine voided in the morning while still in bed, or immediately upon arising, and a second, voided after being up and about, are placed in properly labeled containers. The test is repeated at least three times. The urine may be stored in thee frozen state until brought to the physician. Assuming that the test is properly performed, protein in trace amounts or greater in the specimen first voided in the morning constitutes evidence against orthostatic proteinuria. Consistent and complete absence of protein in the first voided morning urine indicates, if one or more of the second specimens contain protein, the presence of orthostatic proteinuria. Patients w i t h this abnormality produce urine with a higher protein concentration when in a lordotic position, as occurs when standing at attention or sitting on the knees on the bed or floor, than when walking about. The effect of lordosis on protein excretion can be strikingly demonstrated by having the subject void and then stand with his back to the wall, heels one to two inches from the wall and only the back of his head resting against the wall.

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The protein concentration of urine formed while the subject is in this position is usually very high and it may contain abundant casts and a few red blood cells. When the diagnosis of orthostatic proteinuria is made, the child and his parents should be reassured that there is no evidence of serious disease. Despite the apparently benign nature of the condition, it is nevertheless felt by many that re-examination of the patient at infrequent intervals is indicated, at least until further information is accumulated indicating that the abnormality is truly benign. Usually orthostatic proteinuria ceases as adulthood is attained, in which case follow-up examination would no longer be necessary. Idiopathic nephrotic syndrome. This disease may manifest as proteinuria only, many weeks before the development of edema brings the patient to the physician and is the most frequent cause of asymptomatic proteinuria in the younger child. Orthostatic proteinuria is rare before the age of six years. Usually red blood cells are not found in the urine with idiopathic nephrotic syndrome, but cylindruria may be present. Many children with proteinuria from this cause will have reduced levels of total serum protein, albumin, and IgG, and some elevation of the serum cholesterol concentration. When the child between one and six years of age has the combination of proteinuria without hematuria, hypoproteinemia, and hypercholesterolemia, the cause is usually idiopathic nephrotic syndrome and renal biopsy is not necessary. Instead, treatment with a corticosteroid in a regimen appropriate for idiopathic nephrotic syndrome should be instituted; if the proteinuria does not disappear, a renal biopsy is indicated. If the child with these abnormalities is under one year of age, it is possible that congenital nephrotic syndrome is present and a renal biopsy may be indicated. Usually children with this disease are brought to the physician because of edema. Onset of idiopathic nephrotic syndrome over the age of six years is less common; in this age range proteinuria without hematuria and evidence of a nephrotic syndrome by blood chemical studies would be an indication for renal biopsy. Benign persistent asymptomatic proteinuria. Persistent benign proteinuria has been described by McLaine and Drummond a3 in six patients, ages two to 13 years. The proteinuria was asymptomatic and the serum chemical values were normal in all except one who had mild hypoproteinemia and hypercholesterolemia. The average urinary excretion of protein varied from 0.5 to 1.8 gm/24 hours, but in individual collections could be considerably greater. Examination by light imd immunofluorescence microscopy of renal biopsy tissues showed no abnormality in five patients; one had slight focal mesangial proliferation which persisted unchanged in subsequent biopsies.

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Table IV. Diagnostic studies in asymptomatic proteinuria (history and physical examination give no evidence for the cause of the proteinuria)

Laboratory studies to detect: Impaired renal function Hypoproteinemia and hypercholesterolemia

Hypoproteinemia

Impaired function

I

Persistent hypocomplementemia

Laboratory tests negative

I

Appropriate radiographic studies

Age I to 6 years

Age >~ 6 years

Corticosteriod therapy

Renal biopsy

Remission

I

Manage as for idiopathic nephrotic syndrome

No remission

I

Renal biopsy

Renal biopsy

Age < 6 years

Age>~6 years

I

Test for orthostatic

Radiographic studies

I

if negative, renal biopsy or frequent re-examination

Positive

I

Reassurance bUttocontinUefollow

Negative

I

Radiographic stuiies If negative, renal biopsy

Over observation periods of up to eight years the patients developed no additional abnormalities suggestive of renal disease. The proteinuria in three patients was not responsive to therapy with a corticosteroid. The diagnosis of benign asymptomatic proteinuria sl~ould be considered if a child with "constant" proteinuria with normal serum protein and cholesterol values has no abnormality detectable by intravenous pyelography. The diagnosis, as that of benign hematuria, is made only by exclusion, and, for the patient suspected of having benign proteinuria, several directions are open for the course of further diagnostic studies. One approach would be to perform a renal biopsy to seek evidence for glomerulonephritis; in the absence of hypoproteinemia and hypercholesterolemia the likelihood of glomerulonephritis being present is not great. Another approach would be to follow the patient with blood tests at intervals to detect the advent of hypoproteinemia and hypercholesterolemia and, in the patient less than six years of age, treat as for idiopathic nephrotic syndrome should these abnormalities appear. With appearance of these abnormalities in the older child, renal biopsy should be performed before treatment is initiated.

Glomerulonephritis as the cause of asymptomatic proteinuria. Of the various forms of glomerulonephritis,

membranous and membranoproliferative are the two which can present as asymptomatic proteinuria. More commonly, in both diseases, red blood cells, as well as protein, are present in the urine. In Habib and associate's ~ series of 50 children with membranous glomerulonephritis, 85% had hematuria with the proteinuria when the urine was first tested. The diagnosis of membranous glomerulonephritis ean be made only by renal biopsy. By immunofluorescence, deposits of IgG and C3 in a granular pattern are present throughout the glomeruli. The diagnosis is confirmed by visualizing extensions of the glomerular basement membrane, or spikes, between subepithelial deposits in sections stained by the silver methenamine method. In the early stages of the disease, the silver-stained specimen may have to be examined under oil immersion to detect spiking of the basement membrane or, alternatively, electron microscopy may be necessary. Patients with membranoproliferative glomerulonephritis even less commonly have only asymptomatic proteinuria when they first come to the attention of the physician.

Volume 89 Number 2

Of the large number of patients with this disease studied by Cameron and associates, :'5 2% presented with proteinuria only. A low serum level of C3 would be highly suggestive of membranoprotiferative glomerui0nephritis and would indicate the need for a renal biopsy. A normal level of C3, on the other hand, would not rule out the diagnosis. In the event of a normal value, the disease might only be detected by renal biopsy performed because of mild hypoproteinemia in the child with "constant" proteinuria. Both light microscopy and immunohistologic studies show a distinctive pattern in this disease but diagnosis of the exact type present usually requires study by electron microscopy. Other possible causes of asymptomatic proteinuria. Chronic pyelonephritis or congenital anomalies of the kidney such as renal hypoplasia or polycystic disease may be manifest only as proteinuria. In patients with these diseases, serum chemical values might give evidence of renal impairment. The diagnosis would be made by intravenous pyelography performed because of "constant" proteinuria in the child who had normal serum concentrations of protein and cholesterol. There are other rarer causes of asymptomatic proteinuria. We have seen a child with proteinuria and mild hypoproteinemia without hematuria who had a family history on the maternal side of two uncles who died in early adulthood of chronic glomerulonephritis. The child's mother also had proteinuria without hematuria. Evidently this was a form of familial nephritis which is unusual in that hematuria was absent. Diagnostic studies indicated in asymptomatic proteinuria. A suggested scheme for diagnostic studies for the child with asymptomatic proteinuria is shown in Table IV. At the time of the initial examination, blood chemical studies appropriate to detect impairment of renal function, hypoproteinemia, hypercholesterolemia, and hypocomplementemia are performed. Wdth evidence only of renal impairment, appropriate radiographic studies should be performed to detect congenital renal anomalies or chronic pyelonephritis. If hypocomplementemia is present, a renal biopsy should be performed, if the proteinuria and hypocomplementem~a are persistent. If they are transient, acute postinfectious glomerulonephritis would be the more likely diagnosis. If hypoproteinemia, usually accompanied by hypercholesterolemia, is the only abnormality in the child age one to six years with proteinuria, a trial of corticosteroid therapy would be indicated on the assumption that the disease is idiopathic nephrotic syndrome. If a remission is not achieved by this therapy, a renal biopsy should be performed. Hypoproteinemia in the older child would immediately indicate the need for a renal biopsy. In the

Asymptornatic hematuria and proteinuria

18 1

child under the age of one year, congenital nephrotic syndrome would be a possibility. If, on the initial examination, serum chemical values are normal, the child six or more years of age should be tested for orthostatic proteinuria. If present, follow-up at infrequent intervals is indicated. If, instead, the proteinuria is found to be constant, radiographic studies should be performed and, if these are unrevealing, a renal biopsy. Children under age six rarely have postural proteinuria, and, if proteinuria with normal serum chemical values is present, radiographic studies are indicated. If these give no evidence of renal disease, a renal biopsy may be performed or, alternatively, the child may be tentatively considered to have benign proteinuria, and the physician may temporize, re-examining the child at intervals for signs of renal disease including chemical evidence of a nephrotic syndrome occurring before edema becomes apparent.

REFERENCES 1. Dodge WF, West EF, Smith EH, and Bunce H: Proteinuria and hematuria in school children: Epidemiology and natural history, J PEDIATR88:327, 1976. 2. Northway JD: Hematuria in children, J PEDIATR78:381, 1971. 3. Campbell M: Clinical pediatric urology, Philadelphia, 1951, WB Saunders Company. 4. Lucas WM, and Bullock WH: Hematuria in sickle cell disease, J Urol 83:733, 1960. 5. Schlitt LE, and Keitel HG: Renal manifestations of sickle cell disease: A review, Am J Med Sci 239:773, 1960. 6. Chapman AZ, Reeder PS, Friedman IA, and Baker LA: Gross hematuria in sickle cell trait and sickle ceil hemoglobin-C disease, Am J Med 19:773, 1955. 7. MacMahon HE, and Latorraca R: Essential renal hematuria, J Urol 71:667, 1954. 8. Hagen A: Renal angioma. Four cases of angioma of the renal pelvis, Acta Chir Scand 126:657, 1963. 9. Salm R, and Vickery CM: "Essential" hematuria due to a renal hemangioma, Br J Urol 41:267, 1969. 10. Wechsler H, Westhall M, and Lattimer JK: The earliest signs and symptoms in 127 male patients with genitourinary tuberculosis, J Urol 83:801, 1960. I1. Sagel I, Treser G, Ty A, Yoshizawa N, Kleinberger H, Yuceoglu AM, Wasserman E, and Lange K: Occurrence and nature of glomerular lesions after group A streptococci infections in children, Ann Intern Med 79:492, 1973. 12. Strife CF, McAdams AJ, McEnery P, Bove KE, and West CD: Hypocomplementemic and normocomplementemic acute nephritis in children: a comparison with respect to etiology, clinical manifestations and glomerular morphology, J PEDIATR84:29, 1974. 13. Goensch E, and Lytle JD: Kidney disease in the young, Philadelphia, 1971, WB Saui~iders Company, pp 249-256. 14. Northway JD, McAdams AJ~ Forristal J, and West CD: A "silent" phase of hypocomplementemic persistent nephritis detectable by reduced serum/~lC-globnlin levels, J PEDIATR 74:28, 1969.

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15. West CD, and McAdams AJ: Serum fllC globulin levels in persistent glomerulonephritis with low serum complement: variability unrelated to clinical course, Nephron 7:193, 1970. 16. Cameron JS, Ogg CS, White RHR, and Glasgow EF: The clinical features and prognosis of patients with normocomplementemic mesangio-capillary glomerulonephritis, Clin Nephrol 1:8, 1973. 17. Meadow SR, Glasgow EF, White RHR, Moncrieff MW, Cameron JS, and Ogg CS: Sch6nlein-Henoch nephritis, Q J Med 41:241, 1972. 18. Berger J: IgA glomerular deposits in renal disease, Transplant Proc 1:939, 1969. 19. McEnery PT, McAdams AJ, and West CD: Glomerular morphology, natural history and treatment of children and IgA-IgG mesangial nephropathy, in Kincaid-Smith P, Mathews TH, and Becker EL, editors: Glomerulonephritis, morphology, natural history and treatment, New York, 1973, John Wiley & Sons, pp 305-320. 20. Morel-Maroger L, Mery JP, Robert CL, and Richet G: Mesangial IgA deposits, in Kincaid-Smith P, Mathews TH and Becker EL, editors: Glomerulonephritis, morphology, natural history and treatment, New York, 1973, John Wiley & Sons, p 301. 5A. McConville JM, West CD, and McAdams AJ: Familial and nonfamilial benign hematuria, J PEDIATR69:207, 1966. 22. Arneil GC, Lain CN, McDonald AM, and McDonald, M: Recurrent haematuria in 17 children, Br Med J 2:233, 1969. 23. Glasgow EF, Moncrief MW, and White RHR: Symptomless haematuria in childhood; Br Med J 2:687, 1970. 24. Ayoub EM, and Vernier RL: Benign recurrent hematuria, Am J Dis Child 109:217, 1965.

The Journal of Pediatrics August 1976

25. Van de Putte LB, de la Rivere GB, and Vriesman PJC: Recurrent or persistent hematuria. Sign of mesangial immune complex deposition, N Engl J Med 290:1165, 1974. 26. Alyea EP, and Parish HH: Renal response to exerciseurinary findings, JAMA 167:807, 1958. 27. Fishberg AM: Hypertension and nephritis, ed 5, Philadelphia, 1954, Lea & Febiger, Publishers, pp 396-408. 28. Robinson RR: Orthostatic proteinuria: definition and prognosis, The Kidney (published by the National Kidney Foundation) 4: May, 1971. 29. Robinson RR: Idiopathic proteinuria (editorial), Ann Intern Med 71:1019, 1969. 30. Ruckley VA, MacDonald MK, MacLean PR, and Robson JS: Glomerular ultrastructure and function in postural proteinuria, Nephron 3:153, 1966. 31. Levitt JI: The prognostic significance df proteinuria in young college students, Ann Intern Med 66:685, 1967. 32. Robinson RR, and Glenn WG: Fixed and reproducible orthostatic proteinuria. IV. Urinary albumin excretion by healthy human subjects in the recumbent and upright postures, J Lab Clin Med 64:717, 1964. 33. McLaine PN, and Drummond KN: Benign persistent asymptomatic proteinuria in childhood, Pediatrics 46:548, 1970. 34. Habib R, Kleinknecht C, and Gubler M-C: Extramembranous glomerulonephritis in children: Report of 50 cases, J PEDIATR82:754, 1973. 35. Cameron JS, Glasgow EF, Ogg CS, and White RHR: Membranoproliferative glomerulonephritis with persistent hypocomplementemia, Br Med J 4:7, 1970.