Adolescents With Proteinuria and/or the Nephrotic Syndrome
Although there is little information in the literature regarding adolescents with persistent proteinuria or the nephrotic syndrome (NS) [1-6], patients in this age group appear to demonstrate a variety of histopathologic lesions that are not typical for young children or mature adults. This article comments in detail on the evaluation of adolescents with normal and abnormal levels of proteinuria, including those with nephrotic ranges of proteinuria. Specific attention is given to determining which adolescents with proteinuria need to be sent to a specialist for consultation.
Protein handling by the kidneys in normal adolescents and those with kidney disease
Under normal circumstances, the glomeruli restrict the passage of large serum proteins, such as albumin. Relatively low-molecular- weight (LMW) proteins may be filtered by the glomeruli but are reabsorbed in the proximal tubules. The normal rate of protein excretion is considered to be less than 4 mg/m^sup 2^/h or less than 100 mg/m^sup 2^/d throughout adolescence. This rate equates to a urine protein-to-creatinine ratio of approximately 0.2 mg/mg, or urine albumin-to-creatinine ratio of 30 mg/g creatinine.
Excess urinary protein losses may be caused by increased passage of large serum proteins across the glomeruli or decreased reabsorption of LMW proteins by the renal tubules. The finding of increased urinary protein excretion on routine screening of adolescents is fairly common. A recent report describing a high prevalence was based on the findings of the Third National Health and Nutritional Examination Study . The study included 4088 children aged 8 to 18 years, who were evaluated as part of a nationally representative cross-sectional sample of apparently healthy individuals in the United States between 1988 and 1994. The method used to define abnormal proteinuria was an albumin-to- creatinine ratio (>30 mg/g) on a random urine specimen. The authors reported that 12% of the population sampled had albumin excretion of greater than 30 mg/g creatinine. Notably, the highest rates were found in adolescents in the later stages of puberty, with the highest level occurring in Tanner Stage 4 individuals, particularly girls, and in those who had a low or normal body mass index. However, it is likely that many of the subjects had transient or orthostatic proteinuria, as described in the next two sections. This caveat significantly decreases the potential health consequences of the high rates of proteinuria in adolescents that were described by Mueller et al .
When abnormal levels of proteinuria are found, the first step is to determine whether it is transient, orthostatic, or persistent in type. Transient proteinuria, which may be defined as proteinuria that is noted on one or two occasions but is not present on subsequent testing, is not considered to be indicative of underlying renal disease. Large-scale studies reporting the prevalence of proteinuria in groups of children describe much lower rates when the positive cases are defined as children with three or more consecutive urines showing proteinuria. Therefore, the finding of abnormal proteinuria in an adolescent should be confirmed on at least one additional urine, preferably a first morning urine, before additional studies are ordered.
Orthostatic proteinuria, which may be defined as protein excretion that is elevated when the subject is upright but resolves during recumbency, occurs most commonly in adolescents and young adults. This proteinuria may result in 3+ to 4+ protein on a random dipstick but rarely exceeds 1 g/m^sup 2^/d in a 24-hour urine specimen. Long-term follow-up studies have shown that this condition is benign in most affected individuals.
Persistent proteinuria, defined as proteinuria of 1+ or greater by dipstick or a urine protein-to-creatinine ratio of more than 0.2 on multiple first morning urine samples, is of more concern, especially if the urinalysis shows other abnormalities, such as hematuria (not associated with menses in adolescent females), glycosuria, or casts in the urinary sediment.
Methods of testing for proteinuria
The most frequently used screening method for proteinuria is the urinary dipstick. It is important to note that false-positive results may occur when the dipstick is used to assess proteinuria in very alkaline urine (pH ≥8), in concentrated urine specimens (specific gravity (SG) >1.025), or after the administration of radiographic dyes. Although protein excretion in adolescents has been measured traditionally using 24-hour urine collections, accurately timed urine collections of any duration are often difficult to obtain (particularly in this age group). As a result, the protein-to-creatinine (UP/C) ratio of an untimed (“spot”) urine specimen (preferably a first morning specimen) is recommended to estimate protein excretion in adolescents. The normal UP/C in adolescents is less than 0.2. This approach has been endorsed by a panel of pediatric nephrologists assembled by the National Kidney Foundation, as described in detail in a recent publication in Pediatrics . An alternative approach is to measure the urine albumin-to-creatinine ratio, although this will not detect LMW globulins.
Fig. 1. Evaluation of proteinuria in adolescents. ANA, antinuclear antibody; Hep, hepatitis; P/C, protein/creatininc; U/A, urine albumin; U/S, ultrasonography.
Evaluating adolescents with proteinuria
The first step in the evaluation of an adolescent with persistent dipstick proteinuria (≥1+) is to obtain a complete urinalysis and a first morning “spot” urine for UP/C ratio (Fig. 1). The physician should stress the importance of the patient’s voiding just before going to bed and remaining recumbent until just before obtaining this specimen. If the urinalysis is normal and the UP/C ratio on the first morning urine sample is less than 0.2, a diagnosis of orthostatic proteinuria may be made, and no additional studies are necessary. However, if the urinalysis shows other abnormalities or the first morning UP/C ratio is greater than 0.2, blood should be sent for total serum protein, albumin, creatinine, cholesterol, and electrolytes. In addition, measurement of serum C3 complement, antinuclear antibody, and serologies for hepatitis B and C and HIV should be considered. These last studies are particularly appropriate if patients have hematuria, hypertension, a decrease in renal function, or symptoms or signs of extrarenal disease.
Association between proteinuria and cardiovascular disease
Severe persistent proteinuria is almost certainly a long-term risk factor for cardiovascular disease in adolescents with persistent NS. As proteinuria becomes more severe, it induces a variety of disturbances that contribute to cardiovascular disease, such as hypercholesterolemia, hypertriglyceridemia, and hypercoagulability . In some patients, other factors such as hypertension, renal insufficiency, and steroid therapy may also contribute to the risk for cardiovascular disease.
Proteinuria in adolescents with insulin-deficient or insulin- resistant conditions
Although good glycemic control is the first line of defense against renal injury in patients with Insulin Dependent Diabetes Mellitus (IDDM), it has been recognized in recent years that adolescents with long-standing IDDM who have persistent microalbuminuria are at high risk for progressive kidney disease and probably at increased risk for cardiovascular disease . In this patient population, it is appropriate to monitor the urinary albumin excretion rather than total protein excretion . Normal albumin excretion is usually defined as less than 20 g/min/1.73m^sup 2^, microalbuminuria as 20 to 200 g/min/1.73 m^sup 2^, and overt proteinuria as greater than 200 g/min/1.73m^sup 2^. Alternatively, micro-albuminuria may be defined as 30 to 300 mg albumin per gram creatinine on a first morning urine specimen.
Recent years have also seen the recognition that patients with other insulin-resistant states, often associated with obesity, may develop significant levels of proteinuria. The long-term consequences in this population, including cardiovascular disease, have not yet been elucidated, but there is concern that these patients are at high risk. Obesity per se has been associated with proteinuria and glomerulosclerosis with increasing frequency in recent years. Although most of the patients with this condition are adults and most do not develop NS, they are at risk for progressive disease, and some patients have been diagnosed as young as 8 years of age .
Treatment options for persistent proteinuria in the nonnephrotic range
Although dietary protein restriction has not been shown by controlled studies to be beneficial in adolescents with chronic proteinuric renal disease, it seems reasonable to avoid an excess of dietary protein in such patients, because high dietary protein intake may actually worsen proteinuria and does not result in a higher serum albumin.
Blood pressure control
Better preservation of renal function is often seen in patients with renal disease when lower systolic blood pressures are achieved. Certain classes of antihypertensive agents (eg, the angiotensin- converting enzyme inhibitors [ACEi] and the angiotensin II receptor blockers) may, in addition to reducing systemic blood pressure, offer other beneficial effects. Because of these possible \benefits, which include reducing urinary protein excretion and decreasing the risk for renal fibrosis, these agents may be preferred in adolescents with chronic kidney disease associated with persistent proteinuria . However, the long-term benefit of ACEi in such patients remains to be defined.
Spectrum of adolescent-onset nephrotic syndrome
So far there have been only five published studies [1-5] containing specific information about adolescent patients with NS. All of these were retrospective studies, and most included only those patients who underwent kidney biopsy. In the report of the Southwest Pediatric Nephrology Study Group, 31 % of 65 patients had minimal change disease (MCD), 18.5% each had Focal Segmental Glomerulosclerosis (FSGS) and membranous glomerulonephritis (MGN), and 12% had membranoproliferative glomerulonephritis (MPGN) . The investigators observed a significantly higher frequency of MPGN among adolescents than in younger children.
In a recent study by Gulati et al , 63 Indian adolescents with NS were described. FSGS was the most common cause (46.3%) in these adolescent patients. The authors also observed a significantly higher frequency of MPGN (27.5%) among adolescents compared with younger children. In this racially homogeneous Indian population, only 16.3% of the adolescents had MCD. Gulati et al concluded that adolescent-onset NS differs from the childhood variety in having a significantly higher frequency of histopathology other than MCD, especially MPGN.
In another recent report, McKinney et al  reported that 7 of 34 patients (20%) in Yorkshire, United Kingdom who presented with NS between 10 and 15 years of age had steroid-resistant disease; by contrast, only 17 of 160 patients (10%) with NS aged less than 9 years who presented over the same period of study were steroid- resistant. The older children in this study represented 29% of all steroid-resistant cases, but only 16% of the steroid-responsive patients. The overall incidence of NS was lower in the older children (1.1 case per 100,000 persons per year in the 10-15-year age group versus 4.6 cases and 1.9 cases per 100,000 persons per year in the patients aged 1-4 and 5-9 years, respectively).
It is evident from these published reports that more serious forms of glomerular disease (ie, MGN and FSGS) are present more frequently in adolescents with NS than in younger patients with this condition. For example, the frequency of MGN and FSGS in young children with NS is only 2% and 8%, respectively .
Treatment options for children and adolescents with nephrotic syndrome
When to obtain a biopsy and what to expect
The decision to perform a biopsy in all adolescents with NS is not entirely clarified by the reported series. It is necessary to evaluate all aspects of a patient’s clinical presentation-in addition to age-before deciding whether a biopsy should be performed before a trial of therapy. Some pediatric nephrologists believe that many adolescents with NS may be treated without a kidney biopsy, because some will have steroid-responsive minimal-lesion NS and will thus be spared the trauma of a biopsy. However, consideration should be given to performing a pretreatment biopsy in adolescents with NS if they have signs compatible with a diagnosis other than minimal- lesion disease. Both sides of this issue have previously been discussed in detail [13,14] and are beyond the scope of this discussion. This review does not discuss the various therapeutic options that may be selected after the specific diagnosis has been established by the renal biopsy, because most of these are still being evaluated by clinical trials; hence, definitive advice is not available.
In general, a renal biopsy should be strongly considered in the evaluation of adolescents with NS under the following circumstances:
* Persistent gross hematuria (in the absence of infection)
* Persistent hypertension
* Low serum complement levels (C3 or CH50)
* Renal failure not explicable by hypovolemia and prerenal causes After therapy
* Steroid resistance
* Frequent relapses before “third-line” medications such as cyclosporine A, tacrolimus, and levamisole.
The final recommendation regarding the need for a diagnostic renal biopsy should be made by a pediatric nephrologist after reviewing the advantages and disadvantages of “biopsy first” or “trial of therapy first” with the patient and his or her parents.
This section briefly considers the therapy that is usually prescribed for adolescents who are found to have minimal-change NS or in whom the “trial of therapy first” approach is adopted.
Glucocorticoids, usually in the form of prednisone, have been and continue to be the mainstay of treatment in adolescents with idiopathic NS. Several protocols are in current use. A typical treatment course is prednisone, 2 mg/kg/d or 60 mg/m^sup 2^/d (maximum 80 mg/d) in one to three divided doses, for initial treatment. This treatment is continued until the patient becomes free of proteinuriaor, more commonly, for periods of up to 4 to 6 weeks. The patient is then converted to alternate-day treatment (ie, 2 mg/kg or 40 mg/m^sup 2^ [maximum 60 mg] given as a single dose every other morning) . The optimum duration of the course of alternate-day treatment is somewhat controversial and may range from 4 to 12 weeks, depending on the pediatric nephrologist who is involved in the case. Most patients are given 4 to 6 weeks of alternate-day therapy.
Side effects of corticosteroids
Glucocorticoids have many side effects, and it is crucial to discuss these at length with the patient and his or her parents. These medications are often associated with short-term side effects that may result in significant physical and psychological problems for adolescent patients. These include increase in appetite, acne, cushingoid facies, behavioral and psychological changes (eg, mood lability and depression), gastric irritation, and hypertension. Steroid psychosis is rare but can be an extremely serious side effect. Long-term treatment with glucocorticoids can lead to bone demineralization, growth failure, and diabetes mellitus.
Cytotoxic drugs and other immunosuppressive regimens
When serious steroid side effects develop or when there is failure to respond to steroid therapy, other strategies should be considered in patients with minimal-change NS. Cyclophosphamide (Cytoxan) and chlorambucil (Leukeran), each given over a period of 8 to 12 weeks, may be associated with a long-term remission in adolescents with frequently relapsing or steroid-dependent NS . However, these drugs may be associated with a variety of side effects (eg, bone marrow suppression, possibility of future malignancy, oligospermia or azoospermia, ovarian fibrosis); the risk is highest in patients who are close to or in puberty. The cumulative dose of Cyclophosphamide should be restricted to less than 170 mg/kg body weight. In addition to these general side effects, hemorrhagic cystitis may occur with Cyclophosphamide. Seizures occur only-and rarely-with chlorambucil.
A treatment option to be considered in adolescents with steroid- resistant (SR) or steroid-dependent (SD) NS is cyclosporine A (CsA) [16,17]. Unfortunately, many of the patients who respond to CsA tend to relapse once the medication is withdrawn. This relapse is a concern because long-term use of CsA is potentially nephrotoxic. In addition, CsA may cause increases in blood pressure or aggravate pre- existing hypertension. Hypertrichosis and gingival hyperplasia are other common side effects that are particularly troubling for teenagers and often lead to nonadherence with the prescribed therapy. More recently, mycophenolate mofetil has also been reported to be useful in patients with SDNS or SRNS. However, the results of studies using this medication are preliminary.
Adjunctive therapy with angiotensin-converting enzyme inhibitors
ACEi have been used in a variety of renal diseases to reduce proteinuria and thereby lessen the secondary consequences of NS. Available evidence suggests that ACEi may decrease the rate of protein loss by as much as 50%. Hence, it is common for pediatric nephrologists to prescribe an ACEi if an adolescent has nephrotic- range proteinuria that is resistant to specific therapy .
Nonspecific management of nephrotic syndrome in adolescents
Numerous other practical aspects of managing adolescents with NS are important to address with the patients and parents. It is helpful to educate school personnel about nephrotic syndrome and its therapy. Each patient should have an individual assessment for any changes that might be needed in schooling, activities, and diet. Recommendations about sports participation while on high-dose steroids should be approached on an individual basis.
Nutritional counseling about a nutritious, “relatively” junk- food-free diet is important (although it has variable levels of response!). The adoption of a nutritious, relatively low-calorie diet will help patients avoid large weight gains. Salt intake should be limited to control edema and decrease risk of hypertension. In addition, setting a fluid-intake limit of about twice insensible water loss may be helpful in an already edematous patient. Diuretics should be discouraged in most adolescent patients with NS. However, judicious use of diuretics, such as furosemide 1 to 2 mg/kg/d, may be considered if severe edema is present (eg, edema associated with severe scrotal/vulvar swelling, gastrointestinal symptoms, and so on). No indication exists for using diuretics in adolescents with mild edema.
Persistent proteinuria of various degrees of severity in adolescents should be regarded seriously, because recent evidence points to this abnormality’s being associated with chronic kidney disease [1O]. However, it is also important for primary care physicians to be aware that most adole\scents who are found to have proteinuria on a screening urinalysis do not have renal disease, and the proteinuria will usually resolve on repeat testing . Appropriate measures to determine whether the proteinuria is fixed and not orthostatic can and should be conducted expeditiously, because they will allay stress for most patients. For the minority of patients in whom more serious forms of proteinuria exist, timely consultation with a pediatric nephrologist is recommended.
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Ronald J. Hogg, MD
Division of Pediatric Nephrology St. Joseph’s Hospital and Medical Center, 2346 North Central Avenue, Phoenix, AZ 85004, USA
E-mail address: email@example.com
Copyright Hanley & Belfus, Inc. Feb 2005