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Hematuria, Proteinuria, and Urinary Tract Infections
Symposium on Persistent Signs and Symptoms
Hematuria, Proteinuria, and Urinary Tract Infections
Jerry M. Bergstein, M.D.*
In the area of renal disease, the most common persistent problems facing the practitioner are hematuria, proteinuria, and urinary tract infections. The purpose of this review is to provide guidelines to the etiology, diagnosis, and treatment of these problems.
HEMATURIA The causes of hematuria are listed in Table 1. Any of these may present as gross or microscopic hematuria. Glomerular lesions are the most common cause of gross hematuria. Acute poststreptococcal glomerulonephritis is the classic example of the acute nephritic syndrome (ANS) - the sudden onset of gross hematuria, edema, hypertension, and mild to severe azotemia. The syndrome commonly follows infection, the most frequent organisms being the nephritogenic strains of group A beta-hemolytic streptococci. However, other bacterial and viral agents may be etiologic. Acute poststreptococcal glomerulonephritis (AGN) is most common between three and seven years of age and is rare in children younger than age two years. The acute nephritic syndrome begins approximately 10 days after streptococcal throat or skin infection. Urinalysis reveals red blood cells (frequently with red blood cell casts), white blood cells, and protein. Although cultures of the skin or throat may be helpful, diagnosis requires evidence of streptococcal infection (rather than the carrier state) as demonstrated by elevated streptococcal antibody titers. The majority of children will have a depressed serum complement (C 3 ) level. The combination of an acute nephritic syndrome associated with evidence of streptococcal infection and hypocolllplementemia strongly suggests the diagnosis of acute glomerulonephritis, and renal biopsy is not indicated. The acute phase of the disease may persist for one to two weeks; the serum complement level usually returns to normal within two months. Although the hematuria may not resolve for
*Associate Professor and Director, Section of Nephrology, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana
Pediatric Clinics of North America-Vol. 29, No. 1, February 1982
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56
JERHY
Table 1.
M.
Etiology of a Chronic Cough by Age
I:\ FA:\ C)'
SCHOOL AGE TO ADOLESCENCE
1. Congenital anomalies
1. Reactive
Malformation of the aitway Tracheoesophageal fistula VasCular ring 2. Infections Viral - Respiratory syncytial virus
Asthma Postnasal drip 2. Infections Mycoplasma pneumonia 3. Irritative Cigarette smoking Environmetal pollution Psychogenic cough
Cytome~alovirus
Bacterial Chlamydia 3. Cystic fibrosis
BEHGSTEIN
pertussis
PRESCHOOL
1. Foreign body 2. Infections Viral Mycoplasmal Bacterial - Bronchiectasis Acute pneumonia 3. Reactive Asthma Postnasal drip Cystic fibrosis Passive smokin~ 4. Cystic fibrosis 5. Passive smoking
several months, the ultimate prognosis in children is excellent. No specific therapy exists; the management is that of acute renal failure. The most common cause of gross hematuria in our Clinic is the recurrent hematuria syndrome. In this syndrome painless gross hematuria develops one to two days after the onset of an apparent viral upper respiratory infection; occasionally, the hematuria may not be preceded by infection. The disease can be distinguished from acute glomerulonephritis by the short latent period between the infection and the onset of hematuria and by the normal serum complement level. Gross hematuria may persist for several days; hypertension and edema are rare, renal function approximates normal, and proteinuria is mild. Microscopic he1i1aturia may pPrsist between episodes of gross hematuria; this is of no consequence. The pen,istence of proteinuria or decreased renal function between episodes of gross hematuria or the presence of lgA in the mesangium (IgA nephropathy) on renal biopsy indicate the need for ongoing observation for evidence of deteriorating renal function. We recommend renal biopsy after a second episode of gross hematuria. Biopsy in the majority of patients will show minimal changes, suggesting a benign course despite further episodes of gross hematuria. Rarely, renal involvement may be the only manifestation of systemic lupus enthematosus. The best screening test for lupus is the demonstration of circulatint! antittll('lt·ar antibodies (A~A test).
\lemhranoproliferative glomerulonephritis is a common cause of chronic glomerulonephritis in older children and young adults. Although the majority present with nephrotic syndrome, approximately one third have an acute nephritic s\'lldronw. The diagnosis may be suspected by the age of onset (second decade) a.nd pnsistcnt ll\·pertension. The diagnosis may be confused with acute .duttlt'I'Ulolll·phrilts as coincidental eYidcncc of recent streptococcal infection may
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HEMATURIA. PROTEINURIA. AND URINARY TRACT INFECTIONS
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be present and both diseases are associated with hypocomplementemia. Lack of improvement after two to three months will lead to renal biopsy and the diagnosis of membranoproliferative glomerulonephritis. No· definitive therapy exists for membranoproliferative glomerulonephritis and many children will progress to end-stage renal failure. Although a common cause of nephrotic syndrome in adults, membranous glomerulonephritis is uncommon in children. The disease usually presents as asymptomatic proteinuria or nephrotic syndrome in the second decade of life. Although microscopic hematuria is common, gross hematuria is rare. The diagnosis is confirmed by renal biopsy. In children, the disease generally resolves after several years. Salt restriction and diuretics are used to control edema; no Specific therapy exists. Glomerulonephritis may be associated with several forms of chronic infection such as bacterial endocarditis, infected ventriculoatrial shunts, syphilis, malaria, hepatitis, and mononucleosis. Patients with these diseases may present with an acute nephritic syndrome or a nephrotic syndrome with microscopic hematuria. The diagnosis is suggested by the clinical picture and confirmed by renal biopsy; hypocomplementemia is common. Treatment of the underlying infection usually results in resolution of the glomerulonephritis. Antibodies directed against the glomerular basement membrane generally produce severe glomerulonephritis associated with crescent formation (idiopathic rapidly progressive glomerulonephritis). When these antibodies also react with pulmonary basement membrane, resulting in hemoptysis, the disease is called Goodpasture's syndrome. The diagnosis is confirmed by renal biopsy with the immunofluorescent demonstration of linear staining of the basement membrane for IgG and by the demonstration of antiglomerular basement membrane antibody in the circulation. Fortunately, these diseases are rare in childhood, as the prognosis is very poor and no definitive therapy exists. The syndrome of anaphylactoid (Henoch-Schonlein) purpura consists of the characteristic rash primarily involving the lower extremities, arthritis, abdominal pain, and, in approximately 50 per cent of patients, renal involvement. The large majority of those with renal involvement have a mild focal nephritis characterized clinically by hematuria, low-grade proteinuria, and relatively normal function. This form of the disease resolves spontaneously over several months; renal biopsy is not indicated. A small percentage of those with renal involvement will have severe glomerulonephritis with crescent formation. This should be suspected if the patient shows markedly diminished renal function or heavy proteinuria (nephrotic syndrome). The diagnosis is confirmed by biopsy. In an uncontrolled manner, certain investigators have shown beneficial effects with prednisone and azathioprine therapy. The hemolytic-uremic syndrome is the most common cause of acute renal failure in young children. Following an antecedent (presumably viral) gastroenteritis or pharyngitis, acute renal failure, microangiopathic hemolytic anemia, and thrombocytopenia develop. The diagnosis is suggested by the clinical picture in association with hematuria, proteinuria, azotemia, thrombocytopenia, and fragmented red blood cells in the blood smear. As no specific therapy exists, the management is that of acute renal failure; most patients recover. Certain patients with persistent asymptomatic microscopic hematuria have been described as having "benign hematuria." That this condition is truly "heuigu·· can only be confirmed by following the natural history as dcscriht·d lwhm.
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jERRY .\1. BERGSTEIN
Alport' s syndrome is the most common of several forms of hereditary nephritis. In most families, this disease is transmitted in an autosomal dominant manner; linkage with the X chromosome has been described. The clinical manifestations include renal disease, sensorineural deafuess, and occasionally ocular abnormalities. In males, the course is one of progressive renal failure leading to transplantation at the end of the second decade of life. Women have a milder course, frequently with a normal life span, although renal failure has been described. Since the disease may present as asymptomatic microscopic or recurrent gross hematuria, it is commonly confused with "benign hematuria" or the recurrent hematuria syndrome. Because of the high spontaneous mutation rate in Alport' s syndrome, a positive family history may be lacking. The diagnosis will eventually be confirmed when recurrent episodes of gross hematuria or the development of hematuria and proteinuria lead to renal biopsy. There are two major forms of polycystic kidneys. The infantile form is inherited in an autosomal recessive manner. It presents at birth with bilateral flank masses, microscopic hematuria, and hypertension; hepatomegaly may occur. The prognosis is poor although some children may grow to a size that permits transplantation. Adult polycystic disease has occasionally been detected in childhood. This autosomal dominant disease presents in a manner similar to the infantile form. Typically, the disease eventuates in renal failure in the third or fourth decade of life. Both forms of polycystic disease may be suspected on intravenous pyelography. The diagnosis is confirmed by renal biopsy. "Benign hematuria" may be familial although the precise mode of inheritance remains to be determined. Evaluation is similar to the nonfamilial form. Gross or microscopic hematuria may occur after sustained exercise. Although the precise mechanism of the hematuria has not been defined, the process is thought to be benign. Gross or more commonly microscopic hematuria may be a initial manifestation of urinary tract infection. The management of bacterial infections is described below. Hematuria may be associated with both inherited and acquired forms of coagulation factor deficiencies or thrombocytopenia, but this is rarely of clinical significance. An important cause of hematuria in the black population is sickle cell nephropathy. Gross or microscopic hematuria may occur in both sickle cell disease and trait, presumably owing to sickling of the red blood cells in the renal medulla; this may lead to scarring and atrophy. Glomerular lesions have also been described. Renal vein thrombosis is most common in young children with severe dehydration, asphyxia, shock, sepsis, cyanotic heart disease, or nephrotic syndrome and in infants of a diabetic mother. The disease presents with gross hematuria and oligoanuria if bilateral. The involved kidney(s) will be enlarged. Since the disease may be accompanied by a microangiopathic hemolytic anemia and thrombocytopenia, it may be difficult to distinguish from the hemolytic-uremic syndrome; isotopic or radiologic studies may be required to distinguish between these two entities. Treatment includes correction of dehydration and management of the acute renal failure. Anticoagulants are indicated oJ;J.ly in the presence of disseminated intravascular coagulation. Thrombectomy should be attempted only in the presence of severe bilateral disease. Anatomic abnormalities of the kidney may be associated with gross or microscopic hematuria. Except for vascular abnormalities, hematuria is rarely the pre-
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HEMATURIA, PROTEINURIA, AND URINARY TRACT INFECTIO:>IS
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senting complaint. Several medications and chemicals can cause hematuria, and certain food can color the urine red; comprehensive reviews are available. 2 .4 Hematuria is most commonly detected in a routine urinalysis obtained from an apparently healthy child. Although a thorough history and physical examination can be unrewarding, certain clues to the etiology may be obtained. For example, a recent history of upper respiratory, skin, or gastrointestinal infection might suggest glomerulonephritis or hemolytic-uremic syndrome. Frequency, dysuria, unexplained fevers and, in certain cases, an abdominal mass suggest urinary tract infection with or without urinary tract anomalies. A history of recurrent episodes of gross hematuria suggests the recurrent hematuria syndrome, IgA nephropathy, benign hematuria, or Alport's syndrome. Rash, joint pains, and melena point towards lupus or anaphylactoid purpura. A history of trauma, bleeding difficulties, and drug usage might be important. A family history of hematuria, hearing loss, or eye abnormalities could indicate an hereditary disorder. Although microscopic hematuria should be evaluated on an outpatient basis, the acute onset of gross hematuria warrants hospitalization of the child for two reasons. First, the child may have acute nephritis that rapidly leads to renal failure. Second, and perhaps more importantly, hospitalization of the child relieves parental anxiety which may be severe following the onset of gross hematuria. Evaluation of the child with hematuria is performed in steps, beginning with studies most likely to reveal the etiology (Table 2). Depending on the results of the initial group of studies, additional tests may be indicated to confirm the diagnosis. Laboratory evaluation should begin with a fi·esh urine specimen for urinalysis and culture. The presence of red blood cells casts in the urine sediment indicates that the hematuria originates in the kidney (e.g., glomerulonephritis); the absence of these casts does not exclude this diagnosis. Although pyuria, especially in the presence of bacteriuria, suggests bacterial infection, other causes of pyuria should be considered. These include: tuberculosis, mycoplasma, viruses, urethritis, vaginitis, foreign body, tumor, interstitial nephritis, glomerulonephritis, acute tubular n~crosis, nephrosclerosis, diabetes mellitus, amyloidosis, and homograft rejection.
Table 2.
Laboratory Evaluation of Hematuria
Step 1. Performed in all patients 1. Urinalysis and culture 2. Complete blood count 3. 24 hour creatinine clearance and protein excretion 4. Streptozyme, C 3 complement level 5. Intravenous pyelogram Step 2. When indicated 1. Coagulation studies, platelet count, Coombs' test 2. Sickle cell screen 3.
ANA
4.
Voiding cystourethrogram
Step 3. When indicated 1. Renal biopsy Step 4. When indicated l. Cystoscopy
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JERRY
.\1. BERGSTEIN
The diagnosis of bacterial infection must be confirmed by a quantitative urine culture. The detection of certain hematologic abnormalities may narrow the differential diagnosis of hematuria. Anemia may be dilutional (i.e., the result of fluid overload in acute renal failure) or hemolytic in nature. Confirmation of an hemolytic state (elevated reticulocyte count and plasma free hemoglobin, depressed haptoglobin level) necessitates further studies. Observation of the blood film may reveal a microangiopathic process, most commonly seen in hemolytic-uremic syndrome and renal vein thrombosis. A Coombs' positive hemolytic anemia or leukopenia suggests systemic lupus erythematosus. All black children with hematuria should be screened for sickle cell trait or disease. Thrombocytopenia (as determined by the platelet estimate) may result from decreased production of platelets (malignancies) or increased consumption (systemic lupus erythematosus, idiopathic thrombocytopenic purpura, hemolytic-uremic syndrome, renal vein thrombosis; the latter two diseases are associated with a microangiopathic anemia). The. best screening test for a bleeding diathesis is a good history; coagulation studies and a platelet count are not routinely obtained unless indicated by the history. Some estimate of renal function and degree of proteinuria is required in all patients with hematuria. If a timed urine collection cannot be obtained, then the urinalysis and serum creatinine are sufficient. To seek evidence of antecedent streptococcal infection, serum should be obtained for appropriate antibody titers. Because the ASO titer rarely rises after streptococcal skin infections, an anti-DNAse B titer or streptozyme test is preferred. The detection of a low C 3 complement level narrows the differential diagnosis of hematuria to certain forms of glomerulonephritis: poststreptococcal, systemic lupus erythematosus, membranoproliferative, and chronic infection. Unless a clear-cut diagnosis of glomerulonephritis is obtained, an intravenous pyelogram is indicated in all patients with hematuria to exclude polycystic kidney disease and anatomic abnormalities. Cystograms are performed only in certain patients with bacterial infections (see section on Urinary Tract Infections) and in patients with dysuria and hematuria who have sterile urine cultures. The performance of all Step 1 and the appropriate Step 2 studies listed in Table 2 will frequently reveal the etiology of the hematuria. In certain patients, all Step 1 and 2 studies will be normal (except for the hematuria) and no diagnosis will be found. Despite the lack of a diagnosis, no further studies need be performed. The parents should be reassured that the child does not at present have a serious problem. Because it remains possible that a significant problem could be detected in the future, the child with persistent microscopic hematuria must be committed to long-term follow-up. We recommend an annual reevaluation consisting of a history, physical examination, and blood pressure determination, urinalysis, creatinine clearance, and 24 hour protein determination. Renal biopsy is rarely rewarding in children with unexplained hematuria. 6 •8 Indications for biopsy include a second episode of unexplained gross hematuria (usually caused by recurrent hematuria syndrome, IgA nephropathy, benign hematuria, or Alport' s syndrome) or, in the patient with persistent microscopic hematuria, the development of decreased renal function, proteinuria, or hypertension. Cystoscopy should not be part of the routine evaluation of hematuria in
HEMATURIA, PROTEINURIA, AND URINARY TRACT bFECTIONS
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children. In the face of normal radiologic studies, we have found cystoscopy helpful primarily in boys with bright red hematuria, dysuria, and sterile urine cultures. These children were found to have an hemorrhagic urethritis, probably the result of local trauma.
PROTEINURIA Protein is present in the urine of healthy individuals. Although estimates vary, a reasonable upper limit of normal protein excretion in normal individuals is 150 mg per day. As proteinuria of this level may be detected by urine protein dipsticks, we consider a reading of trace on the dipstick as normal; + 1 may also fall within the normal range. It should be noted that urine protein dipsticks detect albumin and, thus, may miss other forms of proteinuria (e.g., low molecular weight proteins, Bence-Janes protein, gamma globulins). On the other hand, the sulfosalicylic acid method detects all forms of proteinuria. Although dipsticks react in a semiquantitative manner with increasing urinary albumin concentrations, the reaction is not sufficiently accurate to calculate protein excretion. Thus, significant proteinuria detected by dipstick ( +1 or greater) should be quantitated by the sulfosalicylic acid method in a timed (preferably 24 hour) urine collection. Sixty per cent of the proteins found in the urine of healthy individuals are derived from the plasma pool, albumin representing the largest fraction. The remaining 40 per cent consists of Tamm-Horsfall protein, a mucoprotein produced in the distal tubule, the function of which in the urine is unknown. Proteinuria in excess of 150 mg per day may be divided into two categories (Table 3). In the first category, nonpathologic proteinuria, the excessive proteinuria does not appear to be associated with a disease state. The level of proteinuria in this category is less than 2 gm per 24 hours and is never associated with edema. Orthostatic (postural) proteinuria probably falls into this category. Individuals with this condition excrete abnormal amounts of protein in both the supine and upright positions, the abnormal excretion being magnified in the upright position. The mechanism of the proteinuria is unknown. Although studies in adults 5 suggest that orthostatic proteinuria is a benign process, similar long-
Table 3.
Classification of Proteinuria
A. Nonpathologic proteinuria l. Orthostatic 2. Exercise 3. Febrile B. Pathologic proteinuria l. Tubular a. Hereditary b. Acquired 2. Glomerular a. Glomerulonephritis b. Idiopathic nephrotic syndrome of childhood c. Hereditary disorders d. Anatomical defects e. Drugs and chemicals
f.
Persistent asymptomatic proteinuria
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jERRY
M.
BERGSTEIN
term follow-up data do not exist in children. Since we cannot be certain that this condition in children is benign, we no longer obtain postural urine collections in children with persistent asymptomatic proteinuria (see below). Proteinuria, like hematuria, may occur after exercise. Although mechanisms are not understood, the degree of hematuria or proteinuria seems to correlate with the duration and severity of the exercise. The degree of proteinuria should not exceed +2 on the dipstick. Both exercise hematuria and proteinuria can be considered benign disorders as long as the urine returns to normal between bouts of exercise. Transient proteinuria may be detected in patients with fever in excess of 38° C. The proteinuria should not exceed +2 on the dipstick and may be considered benign as long as the urine returns to normal after recovery from the febrile illness. The second category of proteinuria, pathologic proteinuria, may result from glomerular or tubular abnormalities. Tubular proteinuria rarely exceeds 2 gm per 24 hours and does not cause edema. Healthy individuals filter large amounts of low molecular weight proteins smaller than albumin (e.g., lysozyme, light chains of immunoglobulin, beta2 -microglobulin, insulin, growth hormone) across the glomerular capillary wall. There are normally reabsorbed in the proximal tubule. Injury to the tubules may result in diminished reabsorptive capacity and wasting of these proteins in the urine. Tubular proteinuria may be seen in acquired (cadmium poisoning, analgesic abuse, vitamin D intoxication, hypokalemia, pyelonephritis, acute tubular necrosis, sarcoidosis, cystic disease, homograft rejection) and inherited disorders (cystinosis, Wilson's disease, Lowe's syndrome, renal tubular acidosis, galactosemia) and may be associated with other defects of proximal tubular function, such as glucosuria, phosphaturia, amino aciduria, and bicarbonaturia. Tubular proteinuria is rarely a diagnostic problem because the underlying disease is usually detected before the proteinuria. Asymptomatic patients with isolated proteinuria generally have glomerular rather than tubular proteinuria. In occult cases, the two forms of proteinuria can be distinguished by electrophoresis of the urine. The lower molecular weight proteins of tubular proteinuria migrate in the alpha and beta regions; little albumin will be present, whereas in glomerular proteinuria, the albumin peak will be prominent. The major cause of proteinuria is increased permeability of the glomerular capillary wall. Discussion of the mechanisms of glomerular filtration and proteinuria is beyond the scope of this review; excellent summaries are available. 1 •7 The level of glomerular proteinuria may range from less than I to more than 30 gm per 24 hours. Glomerular proteinuria may be termed selective (loss of plasma proteins of a molecular weight up to and including albumin) or nonselective (loss of albumin and larger molecular weight proteins such as lgG). Most forms of glomerulonephritis, including those with a secondary nephrotic syndrome, are accompanied by nonselective proteinuria. Selective proteinuria is seen primarily in minimal-change nephrosis and, in that disease, the presence of selective proteinuria correlates with a positive response to corticosteroids. However, determination of urinary protein selectivity is of limited clinical value owing to considerable overlap of selectivities in various forms of renal disease. Persistent asymptomatic proteinuria is defined as proteinuria ( +2 or greater) detected by routine urinalysis in an apparently healthy child. Causes include orthostatic proteinuria, "benign" proteinuria, membranous and membranoproliferative glomerulonephritis, pyelonephritis, hereditary nephritis, and develop-
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HEMATURIA, PROTEINURIA, AND URINARY TRAer INFEGnONS
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mental anomalies. The level of proteinuria is generally less than 2 gm per 24 hours and it is, of course, never associated with edema. Evaluation of the child with persistent asymptomatic proteinuria should include urine culture, creatinine clearance, 24 hour protein excretion, serum albumin, c3 complement level, cholesterol, streptozyme, and intravenous pyelogram. In patients with proteinuria of less than l gm per 24 hours and the remaining studies normal, renal biopsy is not indicated. However, these patients must be committed to an annual reevaluation consisting of urinalysis, creatinine clearance, and 24 hour protein determination. Indications for renal biopsy include persistent proteinuria in excess of l gm per 24 hours, the combination of hematuria and proteinuria (excepting the presence of a positive streptozyme test and a low C 3 suggesting poststreptococcal glomerulonephritis), persistently low C 3 , or the development of decreased renal function or hypertension. Nephrotic syndrome is defined as proteinuria in excess of 2 gm per m 2 per 24 hours, hypoalbuminemia (serum albumin less than 2.5 gm per 100 ml), edema, and hyperlipidemia. In the first decade of life, steroid-responsive (minimalchange) nephrosis is the most common type of nephrosis. In this age group, corticosteroid therapy is indicated without renal biopsy; biopsy should be performed in patients who fail to respond to steroids (persistent proteinuria after four weeks of prednisone) or prior to initiation of cytotoxic (cyclophosphamide) therapy. Although steroid-responsive nephrosis may occur in the second decade of life, membranoproliferative and membranous glomerulonephritis become increasingly frequent. To avoid steroid toxicity in these steroid-resistant forms of glomerulonephritis, renal biopsy is recommended in all children who present with nephrosis in the second decade prior to initiating corticosteroid therapy. In minimal-change nephrosis, remission is induced with prednisone, 60 mg per m 2 per day (maximum daily dose 60 mg) divided into three or four doses over the day. The mean response time is two weeks. Until the patient responds (loss of proteinuria) to prednisone, edema is controlled by salt and water restriction and diuretics (chlorothiazide, 20 to 40 mg per kg per day, and spironolactone, 3 to 5 mg per kg per day) as needed. After the urine is free of protein (negative, trace or + l on the dipstick) for five days, the dose of prednisone is switched to 60 mg per m 2 (maximum daily dose 60 mg) taken every other day as a single morning dose for breakfast. The alternate day therapy is continued for a total duration of six months, then abruptly stopped without tapering. Up to one year after completing corticosteroid therapy, the child will require corticosteroid supplementation for severe illness or surgery. Each relapse is treated in a similar manner. A relapse is defined as the recurrence of edema and not simple proteinuria. Many children with this disease will have intermittent proteinuria but the proteinuria may clear spontaneously. The large majority of children with steroid-responsive nephrosis will outgrow the disease toward the end of the second decade of life. It is important to indicate to the family that the child will have no residual renal dysfunction, that the disease is generally not hereditary, and that the child will be able to have children. To minimize the psychological effects of nephrosis, we emphasize that when in remission, the child is totally normal and may have unrestricted diet and activity. While the child is in remission, we ask the parents not to check the urine for protein. Since we are treating edema and not proteinuria, we recommend testing the urine only when edema develops. If proteinuria is confirmed, the physician is contacted and therapy commenced.
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BERGSTEIN
URINARY TRACT INFECTIONS Recurrent urinary tract infections in girls is one of the most common problems seen in our Clinic. Before dealing with this problem, I should like to review some basic concepts regarding urinary tract infections in childhood. In infancy, urinary tract infections are equally common in boys and girls and may arise from organisms ascending the urethra or from bacteremia. Beyond the first year of life, urinary tract infections are more common in girls and are almost exclusively the result of organisms ascending the urethra. It is important to recognize that the signs and symptoms of urinary tract infections in childhood rarely point to the urinary tract as the source of the illness. In newborn infants, the most common findings are fever, jaundice, weight loss, cyanosis, vomiting, irritability, or the clinical picture of sepsis. Infants and toddlers may present with unexplained fever, abdominal pain, diaper rash, diarrhea, or irritability. It is only in older children that we begin to elicit the classical symptoms of urinary tract infections, the most common being urgency, abdominal pain, and enuresis. Thus, in the face of persistent fever, unexplained by physical examination, think urinary tract infection. The diagnosis of urinary tract infection must be confirmed by a quantitative urine culture! Urinalysis demonstrating pyuria and/or bacteriuria suggests but does not confirm the diagnosis. Pyuria may exist in the absence of bacterial infection and infection may exist without pyuria. Bacteria detected in the urinalysis may be due to improper cleaning of the perineum prior to obtaining the specimen. In a child with symptoms suggesting urinary tract infection, the presence of white blood cells and/or bacteria in the urine supports the diagnosis and therapy may be initiated on this basis-but first send the culture. The proper techniques for collecting urine for culture (clean-catch, urethral catheterization, bag devices, suprapubic needle aspiration) have been well described by Kunin. 3 Excepting specimens obtained by a bag device, a culture revealing 100,000 or more colonies per ml of a single organism strongly suggests infection; two organisms in any number suggest contamination of the specimen. Urine obtained by bag device can be used for screening for infection only. If the bag device urine is sterile, infection is absent. As bags are easily contaminated, any growth, even greater than 100,000 colonies per ml of a single organism, must be confirmed by catheterization or needle aspiration. Clean-catch cultures revealing less than 10,000 colonies per ml generally indicate contamination of the specimen and the absence of infection. Clean-catch cultures yielding intermediate colony counts of 10,000 to 100,000 colonies per ml are difficult to interpret. These may represent a contaminated specimen or true infection with decreased bacterial growth due to urinary dilution, high acid and/or ammonia content. If therapy has not been initiated, urine cultures yielding intermediate colony counts should be repeated. If therapy has been initiated, the patient should be considered infected and the course of therapy completed. Colony counts exceeding 1000 per ml of urine from specimens obtained by catheterization or needle aspiration suggest infection. The significance of counts less than 1000 per ml in urine obtained by these techniques is unclear. Recent evidence suggests that organisms frequently ascend the urethra to the bladder; infection is prevented by washout from the bladder during voiding. Either technique of collecting urine for culture could obtain some of these organisms, resulting in a colony count of less than 1000 per ml. Additionally, catheterization
HEMATURIA, PROTEINURIA, AND URINARY TRACT INFECTIONS
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may introduce organisms into the bladder; collection of these could also result in a similar colony count. Optimally, colony counts in this range should he repeated. If this is not possible, then counts less than 1000 per ml are assumed to represent contaminated specimens. The majority of urinary tract infections are bladder infections and most of these are caused by E. coli. Because disc sensitivities to sulfonamides may be unreliable, our drug of choice for apparently uncomplicated cystitis is nitrofurantoin. Although recent studies suggest that as few as three days of therapy may be adequate, until further data are obtained we continue to recommend a 10 day course of therapy. As long as the sensitivity results indicate that the organism is sensitive to the therapeutic agent chosen, no studies are necessary during the course of therapy. The urine culture should he repeated three days after completing therapy to be certain the infection has been eliminated. Because of the high frequency of underlying obstructive uropathy and/or reflux, all males should undergo radiologic evaluation (intravenous pyelogram and voiding cystourethrogram) following their first urinary tract infection at any age. Debate continues regarding the need for radiologic evaluation of girls following first infections. As the frequency of anatomic abnormalities in girls seems inversely proportional to age, we recommend radiologic evaluation following first infections in girls below the age of 10 years. Above this age, radiologic evaluation may be delayed until the second infection. Despite normal radiographic studies, certain girls will have recurrent urinary tract infections. The definition of "recurrent urinary tract infections" is three separate symptomatic culture-proven infections in a 12 month period. Although several factors, such as the shorter female urethra, elevated vaginal pH, increased bacterial adherence to periurethral and vaginal epithelium, diminished cervicovaginal antibody production, pinworms, constipation and fecal soiling, tub baths, bubble baths, and swimming have been suggested as factors predisposing to recurrent urinary tract infections, the precise role of each of these is unknown. In girls with recurrent urinary tract infections and normal radiographic studies, we have found further urologic evaluation (cystoscopy) to be unrewarding and do not recommend it on a routine basis. Treatment of these patients involves long-term (one year) prophylaxis after eradication of existing infection. The organisms causing recurrent urinary tract infections derive from the fecal flora. The purpose of prophylaxis is to keep an agent in the urine to which these organisms will remain susceptible such that they will be eliminated should they enter the urinary tract. Although E. coli is the most common offending organism, sulfonamides are not appropriate agents for prophylaxis because of the development of resistant organisms in the fecal reservoir. Our first choice for prophylactic therapy is nitrofurantoin. For the first three months of prophylaxis, we recommend the same dosage as that used to treat infection (i.e., 5 to 7 mg per kg per day divided four times per day). After three months of prophylaxis, a urine culture is obtained. If this culture is sterile, the total daily dose of nitrofurantoin is cut in half and given only at breakfast and before bed. The reduced dosage is continued for the remainder of the year of prophylaxis. Cultures are repeated at three month intervals until six months after completion of prophylaxis. If the urine remains sterile to that point, then only periodic surveillance is necessary. A minority of girls will continue to suffer recurrent urinary tract infections after completion of one year of prophylaxis; a second year of prophylaxis is indicated.
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Certain patients will continue to have recurrent urinary tract infections while taking nitrofurantoin. These patients should be switched to the combination product of trimethoprim and sulfamethoxazole. Although it appears that this combination is the most effective prophylactic agent, we prefer to save it for problem patients in hopes of avoiding bacterial resistance. As with nitrofurantoin, a therapeutic dosage is used for the first three months; after a sterile culture is obtained, a half-therapeutic dose is continued for the remainder of the year of prophylaxis.
REFERENCES 1. Brenner, B.M., Hostetter, T.H., and Humes, H. D.: Molecular basis of proteinuria of glomerular origin. N. Engl. J. Med., 298:826, 1978. 2. Cone, T.E., Jr.: Diagnosis and treatment: Some syndromes, diseases, and conditions associated with abnormal coloration of the urine or diaper. Pediatrics, 41:654, 1968. 3. Kunin, C.M.: Detection, Prevention, and Management of Urinary Tract Infections. Philadelphia, Lea and Febiger, 1972, p. 27. 4. Northway, J.D.: Hematuria in children, J. Pediatr., 78:381, 1971. 5. Robinson, R.R.: Isolated proteinuria in asymptomatic patients. Kidney Int., 18:395, 1980. 6. Vehaskari, V.M., Rapola, J., Koskimies, 0., et al.: Microscopic hematuria in schoolchildren: epidemiology and clinicopathologic evaluation. J. Pediatr., 95:676, 1979. 7. Venkatachalam, M.A., and Rennke, H. G.: The structural and molecular basis of glomerular filtration. Circ. Res., 43:337, 1978. 8. West, C.D.: Asymptomatic hematuria and proteinuria in children: causes and appropriate diagnostic studies. J. Pediatr., 89:173, 1976. James Whitcomb Riley Hospital for Children 1100 West Michigan Street Indianapolis, Indiana 46223
Hematuria, Proteinuria, and Urinary Tract Infections
Jerry M. Bergstein, M.D.*
In the area of renal disease, the most common persistent problems facing the practitioner are hematuria, proteinuria, and urinary tract infections. The purpose of this review is to provide guidelines to the etiology, diagnosis, and treatment of these problems.
HEMATURIA The causes of hematuria are listed in Table 1. Any of these may present as gross or microscopic hematuria. Glomerular lesions are the most common cause of gross hematuria. Acute poststreptococcal glomerulonephritis is the classic example of the acute nephritic syndrome (ANS) - the sudden onset of gross hematuria, edema, hypertension, and mild to severe azotemia. The syndrome commonly follows infection, the most frequent organisms being the nephritogenic strains of group A beta-hemolytic streptococci. However, other bacterial and viral agents may be etiologic. Acute poststreptococcal glomerulonephritis (AGN) is most common between three and seven years of age and is rare in children younger than age two years. The acute nephritic syndrome begins approximately 10 days after streptococcal throat or skin infection. Urinalysis reveals red blood cells (frequently with red blood cell casts), white blood cells, and protein. Although cultures of the skin or throat may be helpful, diagnosis requires evidence of streptococcal infection (rather than the carrier state) as demonstrated by elevated streptococcal antibody titers. The majority of children will have a depressed serum complement (C 3 ) level. The combination of an acute nephritic syndrome associated with evidence of streptococcal infection and hypocolllplementemia strongly suggests the diagnosis of acute glomerulonephritis, and renal biopsy is not indicated. The acute phase of the disease may persist for one to two weeks; the serum complement level usually returns to normal within two months. Although the hematuria may not resolve for
*Associate Professor and Director, Section of Nephrology, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, Indiana
Pediatric Clinics of North America-Vol. 29, No. 1, February 1982
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56
JERHY
Table 1.
M.
Etiology of a Chronic Cough by Age
I:\ FA:\ C)'
SCHOOL AGE TO ADOLESCENCE
1. Congenital anomalies
1. Reactive
Malformation of the aitway Tracheoesophageal fistula VasCular ring 2. Infections Viral - Respiratory syncytial virus
Asthma Postnasal drip 2. Infections Mycoplasma pneumonia 3. Irritative Cigarette smoking Environmetal pollution Psychogenic cough
Cytome~alovirus
Bacterial Chlamydia 3. Cystic fibrosis
BEHGSTEIN
pertussis
PRESCHOOL
1. Foreign body 2. Infections Viral Mycoplasmal Bacterial - Bronchiectasis Acute pneumonia 3. Reactive Asthma Postnasal drip Cystic fibrosis Passive smokin~ 4. Cystic fibrosis 5. Passive smoking
several months, the ultimate prognosis in children is excellent. No specific therapy exists; the management is that of acute renal failure. The most common cause of gross hematuria in our Clinic is the recurrent hematuria syndrome. In this syndrome painless gross hematuria develops one to two days after the onset of an apparent viral upper respiratory infection; occasionally, the hematuria may not be preceded by infection. The disease can be distinguished from acute glomerulonephritis by the short latent period between the infection and the onset of hematuria and by the normal serum complement level. Gross hematuria may persist for several days; hypertension and edema are rare, renal function approximates normal, and proteinuria is mild. Microscopic he1i1aturia may pPrsist between episodes of gross hematuria; this is of no consequence. The pen,istence of proteinuria or decreased renal function between episodes of gross hematuria or the presence of lgA in the mesangium (IgA nephropathy) on renal biopsy indicate the need for ongoing observation for evidence of deteriorating renal function. We recommend renal biopsy after a second episode of gross hematuria. Biopsy in the majority of patients will show minimal changes, suggesting a benign course despite further episodes of gross hematuria. Rarely, renal involvement may be the only manifestation of systemic lupus enthematosus. The best screening test for lupus is the demonstration of circulatint! antittll('lt·ar antibodies (A~A test).
\lemhranoproliferative glomerulonephritis is a common cause of chronic glomerulonephritis in older children and young adults. Although the majority present with nephrotic syndrome, approximately one third have an acute nephritic s\'lldronw. The diagnosis may be suspected by the age of onset (second decade) a.nd pnsistcnt ll\·pertension. The diagnosis may be confused with acute .duttlt'I'Ulolll·phrilts as coincidental eYidcncc of recent streptococcal infection may
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HEMATURIA. PROTEINURIA. AND URINARY TRACT INFECTIONS
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be present and both diseases are associated with hypocomplementemia. Lack of improvement after two to three months will lead to renal biopsy and the diagnosis of membranoproliferative glomerulonephritis. No· definitive therapy exists for membranoproliferative glomerulonephritis and many children will progress to end-stage renal failure. Although a common cause of nephrotic syndrome in adults, membranous glomerulonephritis is uncommon in children. The disease usually presents as asymptomatic proteinuria or nephrotic syndrome in the second decade of life. Although microscopic hematuria is common, gross hematuria is rare. The diagnosis is confirmed by renal biopsy. In children, the disease generally resolves after several years. Salt restriction and diuretics are used to control edema; no Specific therapy exists. Glomerulonephritis may be associated with several forms of chronic infection such as bacterial endocarditis, infected ventriculoatrial shunts, syphilis, malaria, hepatitis, and mononucleosis. Patients with these diseases may present with an acute nephritic syndrome or a nephrotic syndrome with microscopic hematuria. The diagnosis is suggested by the clinical picture and confirmed by renal biopsy; hypocomplementemia is common. Treatment of the underlying infection usually results in resolution of the glomerulonephritis. Antibodies directed against the glomerular basement membrane generally produce severe glomerulonephritis associated with crescent formation (idiopathic rapidly progressive glomerulonephritis). When these antibodies also react with pulmonary basement membrane, resulting in hemoptysis, the disease is called Goodpasture's syndrome. The diagnosis is confirmed by renal biopsy with the immunofluorescent demonstration of linear staining of the basement membrane for IgG and by the demonstration of antiglomerular basement membrane antibody in the circulation. Fortunately, these diseases are rare in childhood, as the prognosis is very poor and no definitive therapy exists. The syndrome of anaphylactoid (Henoch-Schonlein) purpura consists of the characteristic rash primarily involving the lower extremities, arthritis, abdominal pain, and, in approximately 50 per cent of patients, renal involvement. The large majority of those with renal involvement have a mild focal nephritis characterized clinically by hematuria, low-grade proteinuria, and relatively normal function. This form of the disease resolves spontaneously over several months; renal biopsy is not indicated. A small percentage of those with renal involvement will have severe glomerulonephritis with crescent formation. This should be suspected if the patient shows markedly diminished renal function or heavy proteinuria (nephrotic syndrome). The diagnosis is confirmed by biopsy. In an uncontrolled manner, certain investigators have shown beneficial effects with prednisone and azathioprine therapy. The hemolytic-uremic syndrome is the most common cause of acute renal failure in young children. Following an antecedent (presumably viral) gastroenteritis or pharyngitis, acute renal failure, microangiopathic hemolytic anemia, and thrombocytopenia develop. The diagnosis is suggested by the clinical picture in association with hematuria, proteinuria, azotemia, thrombocytopenia, and fragmented red blood cells in the blood smear. As no specific therapy exists, the management is that of acute renal failure; most patients recover. Certain patients with persistent asymptomatic microscopic hematuria have been described as having "benign hematuria." That this condition is truly "heuigu·· can only be confirmed by following the natural history as dcscriht·d lwhm.
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jERRY .\1. BERGSTEIN
Alport' s syndrome is the most common of several forms of hereditary nephritis. In most families, this disease is transmitted in an autosomal dominant manner; linkage with the X chromosome has been described. The clinical manifestations include renal disease, sensorineural deafuess, and occasionally ocular abnormalities. In males, the course is one of progressive renal failure leading to transplantation at the end of the second decade of life. Women have a milder course, frequently with a normal life span, although renal failure has been described. Since the disease may present as asymptomatic microscopic or recurrent gross hematuria, it is commonly confused with "benign hematuria" or the recurrent hematuria syndrome. Because of the high spontaneous mutation rate in Alport' s syndrome, a positive family history may be lacking. The diagnosis will eventually be confirmed when recurrent episodes of gross hematuria or the development of hematuria and proteinuria lead to renal biopsy. There are two major forms of polycystic kidneys. The infantile form is inherited in an autosomal recessive manner. It presents at birth with bilateral flank masses, microscopic hematuria, and hypertension; hepatomegaly may occur. The prognosis is poor although some children may grow to a size that permits transplantation. Adult polycystic disease has occasionally been detected in childhood. This autosomal dominant disease presents in a manner similar to the infantile form. Typically, the disease eventuates in renal failure in the third or fourth decade of life. Both forms of polycystic disease may be suspected on intravenous pyelography. The diagnosis is confirmed by renal biopsy. "Benign hematuria" may be familial although the precise mode of inheritance remains to be determined. Evaluation is similar to the nonfamilial form. Gross or microscopic hematuria may occur after sustained exercise. Although the precise mechanism of the hematuria has not been defined, the process is thought to be benign. Gross or more commonly microscopic hematuria may be a initial manifestation of urinary tract infection. The management of bacterial infections is described below. Hematuria may be associated with both inherited and acquired forms of coagulation factor deficiencies or thrombocytopenia, but this is rarely of clinical significance. An important cause of hematuria in the black population is sickle cell nephropathy. Gross or microscopic hematuria may occur in both sickle cell disease and trait, presumably owing to sickling of the red blood cells in the renal medulla; this may lead to scarring and atrophy. Glomerular lesions have also been described. Renal vein thrombosis is most common in young children with severe dehydration, asphyxia, shock, sepsis, cyanotic heart disease, or nephrotic syndrome and in infants of a diabetic mother. The disease presents with gross hematuria and oligoanuria if bilateral. The involved kidney(s) will be enlarged. Since the disease may be accompanied by a microangiopathic hemolytic anemia and thrombocytopenia, it may be difficult to distinguish from the hemolytic-uremic syndrome; isotopic or radiologic studies may be required to distinguish between these two entities. Treatment includes correction of dehydration and management of the acute renal failure. Anticoagulants are indicated oJ;J.ly in the presence of disseminated intravascular coagulation. Thrombectomy should be attempted only in the presence of severe bilateral disease. Anatomic abnormalities of the kidney may be associated with gross or microscopic hematuria. Except for vascular abnormalities, hematuria is rarely the pre-
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HEMATURIA, PROTEINURIA, AND URINARY TRACT INFECTIO:>IS
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senting complaint. Several medications and chemicals can cause hematuria, and certain food can color the urine red; comprehensive reviews are available. 2 .4 Hematuria is most commonly detected in a routine urinalysis obtained from an apparently healthy child. Although a thorough history and physical examination can be unrewarding, certain clues to the etiology may be obtained. For example, a recent history of upper respiratory, skin, or gastrointestinal infection might suggest glomerulonephritis or hemolytic-uremic syndrome. Frequency, dysuria, unexplained fevers and, in certain cases, an abdominal mass suggest urinary tract infection with or without urinary tract anomalies. A history of recurrent episodes of gross hematuria suggests the recurrent hematuria syndrome, IgA nephropathy, benign hematuria, or Alport's syndrome. Rash, joint pains, and melena point towards lupus or anaphylactoid purpura. A history of trauma, bleeding difficulties, and drug usage might be important. A family history of hematuria, hearing loss, or eye abnormalities could indicate an hereditary disorder. Although microscopic hematuria should be evaluated on an outpatient basis, the acute onset of gross hematuria warrants hospitalization of the child for two reasons. First, the child may have acute nephritis that rapidly leads to renal failure. Second, and perhaps more importantly, hospitalization of the child relieves parental anxiety which may be severe following the onset of gross hematuria. Evaluation of the child with hematuria is performed in steps, beginning with studies most likely to reveal the etiology (Table 2). Depending on the results of the initial group of studies, additional tests may be indicated to confirm the diagnosis. Laboratory evaluation should begin with a fi·esh urine specimen for urinalysis and culture. The presence of red blood cells casts in the urine sediment indicates that the hematuria originates in the kidney (e.g., glomerulonephritis); the absence of these casts does not exclude this diagnosis. Although pyuria, especially in the presence of bacteriuria, suggests bacterial infection, other causes of pyuria should be considered. These include: tuberculosis, mycoplasma, viruses, urethritis, vaginitis, foreign body, tumor, interstitial nephritis, glomerulonephritis, acute tubular n~crosis, nephrosclerosis, diabetes mellitus, amyloidosis, and homograft rejection.
Table 2.
Laboratory Evaluation of Hematuria
Step 1. Performed in all patients 1. Urinalysis and culture 2. Complete blood count 3. 24 hour creatinine clearance and protein excretion 4. Streptozyme, C 3 complement level 5. Intravenous pyelogram Step 2. When indicated 1. Coagulation studies, platelet count, Coombs' test 2. Sickle cell screen 3.
ANA
4.
Voiding cystourethrogram
Step 3. When indicated 1. Renal biopsy Step 4. When indicated l. Cystoscopy
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JERRY
.\1. BERGSTEIN
The diagnosis of bacterial infection must be confirmed by a quantitative urine culture. The detection of certain hematologic abnormalities may narrow the differential diagnosis of hematuria. Anemia may be dilutional (i.e., the result of fluid overload in acute renal failure) or hemolytic in nature. Confirmation of an hemolytic state (elevated reticulocyte count and plasma free hemoglobin, depressed haptoglobin level) necessitates further studies. Observation of the blood film may reveal a microangiopathic process, most commonly seen in hemolytic-uremic syndrome and renal vein thrombosis. A Coombs' positive hemolytic anemia or leukopenia suggests systemic lupus erythematosus. All black children with hematuria should be screened for sickle cell trait or disease. Thrombocytopenia (as determined by the platelet estimate) may result from decreased production of platelets (malignancies) or increased consumption (systemic lupus erythematosus, idiopathic thrombocytopenic purpura, hemolytic-uremic syndrome, renal vein thrombosis; the latter two diseases are associated with a microangiopathic anemia). The. best screening test for a bleeding diathesis is a good history; coagulation studies and a platelet count are not routinely obtained unless indicated by the history. Some estimate of renal function and degree of proteinuria is required in all patients with hematuria. If a timed urine collection cannot be obtained, then the urinalysis and serum creatinine are sufficient. To seek evidence of antecedent streptococcal infection, serum should be obtained for appropriate antibody titers. Because the ASO titer rarely rises after streptococcal skin infections, an anti-DNAse B titer or streptozyme test is preferred. The detection of a low C 3 complement level narrows the differential diagnosis of hematuria to certain forms of glomerulonephritis: poststreptococcal, systemic lupus erythematosus, membranoproliferative, and chronic infection. Unless a clear-cut diagnosis of glomerulonephritis is obtained, an intravenous pyelogram is indicated in all patients with hematuria to exclude polycystic kidney disease and anatomic abnormalities. Cystograms are performed only in certain patients with bacterial infections (see section on Urinary Tract Infections) and in patients with dysuria and hematuria who have sterile urine cultures. The performance of all Step 1 and the appropriate Step 2 studies listed in Table 2 will frequently reveal the etiology of the hematuria. In certain patients, all Step 1 and 2 studies will be normal (except for the hematuria) and no diagnosis will be found. Despite the lack of a diagnosis, no further studies need be performed. The parents should be reassured that the child does not at present have a serious problem. Because it remains possible that a significant problem could be detected in the future, the child with persistent microscopic hematuria must be committed to long-term follow-up. We recommend an annual reevaluation consisting of a history, physical examination, and blood pressure determination, urinalysis, creatinine clearance, and 24 hour protein determination. Renal biopsy is rarely rewarding in children with unexplained hematuria. 6 •8 Indications for biopsy include a second episode of unexplained gross hematuria (usually caused by recurrent hematuria syndrome, IgA nephropathy, benign hematuria, or Alport' s syndrome) or, in the patient with persistent microscopic hematuria, the development of decreased renal function, proteinuria, or hypertension. Cystoscopy should not be part of the routine evaluation of hematuria in
HEMATURIA, PROTEINURIA, AND URINARY TRACT bFECTIONS
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children. In the face of normal radiologic studies, we have found cystoscopy helpful primarily in boys with bright red hematuria, dysuria, and sterile urine cultures. These children were found to have an hemorrhagic urethritis, probably the result of local trauma.
PROTEINURIA Protein is present in the urine of healthy individuals. Although estimates vary, a reasonable upper limit of normal protein excretion in normal individuals is 150 mg per day. As proteinuria of this level may be detected by urine protein dipsticks, we consider a reading of trace on the dipstick as normal; + 1 may also fall within the normal range. It should be noted that urine protein dipsticks detect albumin and, thus, may miss other forms of proteinuria (e.g., low molecular weight proteins, Bence-Janes protein, gamma globulins). On the other hand, the sulfosalicylic acid method detects all forms of proteinuria. Although dipsticks react in a semiquantitative manner with increasing urinary albumin concentrations, the reaction is not sufficiently accurate to calculate protein excretion. Thus, significant proteinuria detected by dipstick ( +1 or greater) should be quantitated by the sulfosalicylic acid method in a timed (preferably 24 hour) urine collection. Sixty per cent of the proteins found in the urine of healthy individuals are derived from the plasma pool, albumin representing the largest fraction. The remaining 40 per cent consists of Tamm-Horsfall protein, a mucoprotein produced in the distal tubule, the function of which in the urine is unknown. Proteinuria in excess of 150 mg per day may be divided into two categories (Table 3). In the first category, nonpathologic proteinuria, the excessive proteinuria does not appear to be associated with a disease state. The level of proteinuria in this category is less than 2 gm per 24 hours and is never associated with edema. Orthostatic (postural) proteinuria probably falls into this category. Individuals with this condition excrete abnormal amounts of protein in both the supine and upright positions, the abnormal excretion being magnified in the upright position. The mechanism of the proteinuria is unknown. Although studies in adults 5 suggest that orthostatic proteinuria is a benign process, similar long-
Table 3.
Classification of Proteinuria
A. Nonpathologic proteinuria l. Orthostatic 2. Exercise 3. Febrile B. Pathologic proteinuria l. Tubular a. Hereditary b. Acquired 2. Glomerular a. Glomerulonephritis b. Idiopathic nephrotic syndrome of childhood c. Hereditary disorders d. Anatomical defects e. Drugs and chemicals
f.
Persistent asymptomatic proteinuria
62
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BERGSTEIN
term follow-up data do not exist in children. Since we cannot be certain that this condition in children is benign, we no longer obtain postural urine collections in children with persistent asymptomatic proteinuria (see below). Proteinuria, like hematuria, may occur after exercise. Although mechanisms are not understood, the degree of hematuria or proteinuria seems to correlate with the duration and severity of the exercise. The degree of proteinuria should not exceed +2 on the dipstick. Both exercise hematuria and proteinuria can be considered benign disorders as long as the urine returns to normal between bouts of exercise. Transient proteinuria may be detected in patients with fever in excess of 38° C. The proteinuria should not exceed +2 on the dipstick and may be considered benign as long as the urine returns to normal after recovery from the febrile illness. The second category of proteinuria, pathologic proteinuria, may result from glomerular or tubular abnormalities. Tubular proteinuria rarely exceeds 2 gm per 24 hours and does not cause edema. Healthy individuals filter large amounts of low molecular weight proteins smaller than albumin (e.g., lysozyme, light chains of immunoglobulin, beta2 -microglobulin, insulin, growth hormone) across the glomerular capillary wall. There are normally reabsorbed in the proximal tubule. Injury to the tubules may result in diminished reabsorptive capacity and wasting of these proteins in the urine. Tubular proteinuria may be seen in acquired (cadmium poisoning, analgesic abuse, vitamin D intoxication, hypokalemia, pyelonephritis, acute tubular necrosis, sarcoidosis, cystic disease, homograft rejection) and inherited disorders (cystinosis, Wilson's disease, Lowe's syndrome, renal tubular acidosis, galactosemia) and may be associated with other defects of proximal tubular function, such as glucosuria, phosphaturia, amino aciduria, and bicarbonaturia. Tubular proteinuria is rarely a diagnostic problem because the underlying disease is usually detected before the proteinuria. Asymptomatic patients with isolated proteinuria generally have glomerular rather than tubular proteinuria. In occult cases, the two forms of proteinuria can be distinguished by electrophoresis of the urine. The lower molecular weight proteins of tubular proteinuria migrate in the alpha and beta regions; little albumin will be present, whereas in glomerular proteinuria, the albumin peak will be prominent. The major cause of proteinuria is increased permeability of the glomerular capillary wall. Discussion of the mechanisms of glomerular filtration and proteinuria is beyond the scope of this review; excellent summaries are available. 1 •7 The level of glomerular proteinuria may range from less than I to more than 30 gm per 24 hours. Glomerular proteinuria may be termed selective (loss of plasma proteins of a molecular weight up to and including albumin) or nonselective (loss of albumin and larger molecular weight proteins such as lgG). Most forms of glomerulonephritis, including those with a secondary nephrotic syndrome, are accompanied by nonselective proteinuria. Selective proteinuria is seen primarily in minimal-change nephrosis and, in that disease, the presence of selective proteinuria correlates with a positive response to corticosteroids. However, determination of urinary protein selectivity is of limited clinical value owing to considerable overlap of selectivities in various forms of renal disease. Persistent asymptomatic proteinuria is defined as proteinuria ( +2 or greater) detected by routine urinalysis in an apparently healthy child. Causes include orthostatic proteinuria, "benign" proteinuria, membranous and membranoproliferative glomerulonephritis, pyelonephritis, hereditary nephritis, and develop-
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HEMATURIA, PROTEINURIA, AND URINARY TRAer INFEGnONS
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mental anomalies. The level of proteinuria is generally less than 2 gm per 24 hours and it is, of course, never associated with edema. Evaluation of the child with persistent asymptomatic proteinuria should include urine culture, creatinine clearance, 24 hour protein excretion, serum albumin, c3 complement level, cholesterol, streptozyme, and intravenous pyelogram. In patients with proteinuria of less than l gm per 24 hours and the remaining studies normal, renal biopsy is not indicated. However, these patients must be committed to an annual reevaluation consisting of urinalysis, creatinine clearance, and 24 hour protein determination. Indications for renal biopsy include persistent proteinuria in excess of l gm per 24 hours, the combination of hematuria and proteinuria (excepting the presence of a positive streptozyme test and a low C 3 suggesting poststreptococcal glomerulonephritis), persistently low C 3 , or the development of decreased renal function or hypertension. Nephrotic syndrome is defined as proteinuria in excess of 2 gm per m 2 per 24 hours, hypoalbuminemia (serum albumin less than 2.5 gm per 100 ml), edema, and hyperlipidemia. In the first decade of life, steroid-responsive (minimalchange) nephrosis is the most common type of nephrosis. In this age group, corticosteroid therapy is indicated without renal biopsy; biopsy should be performed in patients who fail to respond to steroids (persistent proteinuria after four weeks of prednisone) or prior to initiation of cytotoxic (cyclophosphamide) therapy. Although steroid-responsive nephrosis may occur in the second decade of life, membranoproliferative and membranous glomerulonephritis become increasingly frequent. To avoid steroid toxicity in these steroid-resistant forms of glomerulonephritis, renal biopsy is recommended in all children who present with nephrosis in the second decade prior to initiating corticosteroid therapy. In minimal-change nephrosis, remission is induced with prednisone, 60 mg per m 2 per day (maximum daily dose 60 mg) divided into three or four doses over the day. The mean response time is two weeks. Until the patient responds (loss of proteinuria) to prednisone, edema is controlled by salt and water restriction and diuretics (chlorothiazide, 20 to 40 mg per kg per day, and spironolactone, 3 to 5 mg per kg per day) as needed. After the urine is free of protein (negative, trace or + l on the dipstick) for five days, the dose of prednisone is switched to 60 mg per m 2 (maximum daily dose 60 mg) taken every other day as a single morning dose for breakfast. The alternate day therapy is continued for a total duration of six months, then abruptly stopped without tapering. Up to one year after completing corticosteroid therapy, the child will require corticosteroid supplementation for severe illness or surgery. Each relapse is treated in a similar manner. A relapse is defined as the recurrence of edema and not simple proteinuria. Many children with this disease will have intermittent proteinuria but the proteinuria may clear spontaneously. The large majority of children with steroid-responsive nephrosis will outgrow the disease toward the end of the second decade of life. It is important to indicate to the family that the child will have no residual renal dysfunction, that the disease is generally not hereditary, and that the child will be able to have children. To minimize the psychological effects of nephrosis, we emphasize that when in remission, the child is totally normal and may have unrestricted diet and activity. While the child is in remission, we ask the parents not to check the urine for protein. Since we are treating edema and not proteinuria, we recommend testing the urine only when edema develops. If proteinuria is confirmed, the physician is contacted and therapy commenced.
64
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BERGSTEIN
URINARY TRACT INFECTIONS Recurrent urinary tract infections in girls is one of the most common problems seen in our Clinic. Before dealing with this problem, I should like to review some basic concepts regarding urinary tract infections in childhood. In infancy, urinary tract infections are equally common in boys and girls and may arise from organisms ascending the urethra or from bacteremia. Beyond the first year of life, urinary tract infections are more common in girls and are almost exclusively the result of organisms ascending the urethra. It is important to recognize that the signs and symptoms of urinary tract infections in childhood rarely point to the urinary tract as the source of the illness. In newborn infants, the most common findings are fever, jaundice, weight loss, cyanosis, vomiting, irritability, or the clinical picture of sepsis. Infants and toddlers may present with unexplained fever, abdominal pain, diaper rash, diarrhea, or irritability. It is only in older children that we begin to elicit the classical symptoms of urinary tract infections, the most common being urgency, abdominal pain, and enuresis. Thus, in the face of persistent fever, unexplained by physical examination, think urinary tract infection. The diagnosis of urinary tract infection must be confirmed by a quantitative urine culture! Urinalysis demonstrating pyuria and/or bacteriuria suggests but does not confirm the diagnosis. Pyuria may exist in the absence of bacterial infection and infection may exist without pyuria. Bacteria detected in the urinalysis may be due to improper cleaning of the perineum prior to obtaining the specimen. In a child with symptoms suggesting urinary tract infection, the presence of white blood cells and/or bacteria in the urine supports the diagnosis and therapy may be initiated on this basis-but first send the culture. The proper techniques for collecting urine for culture (clean-catch, urethral catheterization, bag devices, suprapubic needle aspiration) have been well described by Kunin. 3 Excepting specimens obtained by a bag device, a culture revealing 100,000 or more colonies per ml of a single organism strongly suggests infection; two organisms in any number suggest contamination of the specimen. Urine obtained by bag device can be used for screening for infection only. If the bag device urine is sterile, infection is absent. As bags are easily contaminated, any growth, even greater than 100,000 colonies per ml of a single organism, must be confirmed by catheterization or needle aspiration. Clean-catch cultures revealing less than 10,000 colonies per ml generally indicate contamination of the specimen and the absence of infection. Clean-catch cultures yielding intermediate colony counts of 10,000 to 100,000 colonies per ml are difficult to interpret. These may represent a contaminated specimen or true infection with decreased bacterial growth due to urinary dilution, high acid and/or ammonia content. If therapy has not been initiated, urine cultures yielding intermediate colony counts should be repeated. If therapy has been initiated, the patient should be considered infected and the course of therapy completed. Colony counts exceeding 1000 per ml of urine from specimens obtained by catheterization or needle aspiration suggest infection. The significance of counts less than 1000 per ml in urine obtained by these techniques is unclear. Recent evidence suggests that organisms frequently ascend the urethra to the bladder; infection is prevented by washout from the bladder during voiding. Either technique of collecting urine for culture could obtain some of these organisms, resulting in a colony count of less than 1000 per ml. Additionally, catheterization
HEMATURIA, PROTEINURIA, AND URINARY TRACT INFECTIONS
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may introduce organisms into the bladder; collection of these could also result in a similar colony count. Optimally, colony counts in this range should he repeated. If this is not possible, then counts less than 1000 per ml are assumed to represent contaminated specimens. The majority of urinary tract infections are bladder infections and most of these are caused by E. coli. Because disc sensitivities to sulfonamides may be unreliable, our drug of choice for apparently uncomplicated cystitis is nitrofurantoin. Although recent studies suggest that as few as three days of therapy may be adequate, until further data are obtained we continue to recommend a 10 day course of therapy. As long as the sensitivity results indicate that the organism is sensitive to the therapeutic agent chosen, no studies are necessary during the course of therapy. The urine culture should he repeated three days after completing therapy to be certain the infection has been eliminated. Because of the high frequency of underlying obstructive uropathy and/or reflux, all males should undergo radiologic evaluation (intravenous pyelogram and voiding cystourethrogram) following their first urinary tract infection at any age. Debate continues regarding the need for radiologic evaluation of girls following first infections. As the frequency of anatomic abnormalities in girls seems inversely proportional to age, we recommend radiologic evaluation following first infections in girls below the age of 10 years. Above this age, radiologic evaluation may be delayed until the second infection. Despite normal radiographic studies, certain girls will have recurrent urinary tract infections. The definition of "recurrent urinary tract infections" is three separate symptomatic culture-proven infections in a 12 month period. Although several factors, such as the shorter female urethra, elevated vaginal pH, increased bacterial adherence to periurethral and vaginal epithelium, diminished cervicovaginal antibody production, pinworms, constipation and fecal soiling, tub baths, bubble baths, and swimming have been suggested as factors predisposing to recurrent urinary tract infections, the precise role of each of these is unknown. In girls with recurrent urinary tract infections and normal radiographic studies, we have found further urologic evaluation (cystoscopy) to be unrewarding and do not recommend it on a routine basis. Treatment of these patients involves long-term (one year) prophylaxis after eradication of existing infection. The organisms causing recurrent urinary tract infections derive from the fecal flora. The purpose of prophylaxis is to keep an agent in the urine to which these organisms will remain susceptible such that they will be eliminated should they enter the urinary tract. Although E. coli is the most common offending organism, sulfonamides are not appropriate agents for prophylaxis because of the development of resistant organisms in the fecal reservoir. Our first choice for prophylactic therapy is nitrofurantoin. For the first three months of prophylaxis, we recommend the same dosage as that used to treat infection (i.e., 5 to 7 mg per kg per day divided four times per day). After three months of prophylaxis, a urine culture is obtained. If this culture is sterile, the total daily dose of nitrofurantoin is cut in half and given only at breakfast and before bed. The reduced dosage is continued for the remainder of the year of prophylaxis. Cultures are repeated at three month intervals until six months after completion of prophylaxis. If the urine remains sterile to that point, then only periodic surveillance is necessary. A minority of girls will continue to suffer recurrent urinary tract infections after completion of one year of prophylaxis; a second year of prophylaxis is indicated.
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Certain patients will continue to have recurrent urinary tract infections while taking nitrofurantoin. These patients should be switched to the combination product of trimethoprim and sulfamethoxazole. Although it appears that this combination is the most effective prophylactic agent, we prefer to save it for problem patients in hopes of avoiding bacterial resistance. As with nitrofurantoin, a therapeutic dosage is used for the first three months; after a sterile culture is obtained, a half-therapeutic dose is continued for the remainder of the year of prophylaxis.
REFERENCES 1. Brenner, B.M., Hostetter, T.H., and Humes, H. D.: Molecular basis of proteinuria of glomerular origin. N. Engl. J. Med., 298:826, 1978. 2. Cone, T.E., Jr.: Diagnosis and treatment: Some syndromes, diseases, and conditions associated with abnormal coloration of the urine or diaper. Pediatrics, 41:654, 1968. 3. Kunin, C.M.: Detection, Prevention, and Management of Urinary Tract Infections. Philadelphia, Lea and Febiger, 1972, p. 27. 4. Northway, J.D.: Hematuria in children, J. Pediatr., 78:381, 1971. 5. Robinson, R.R.: Isolated proteinuria in asymptomatic patients. Kidney Int., 18:395, 1980. 6. Vehaskari, V.M., Rapola, J., Koskimies, 0., et al.: Microscopic hematuria in schoolchildren: epidemiology and clinicopathologic evaluation. J. Pediatr., 95:676, 1979. 7. Venkatachalam, M.A., and Rennke, H. G.: The structural and molecular basis of glomerular filtration. Circ. Res., 43:337, 1978. 8. West, C.D.: Asymptomatic hematuria and proteinuria in children: causes and appropriate diagnostic studies. J. Pediatr., 89:173, 1976. James Whitcomb Riley Hospital for Children 1100 West Michigan Street Indianapolis, Indiana 46223