Nephrotic Syndrome: Pathogenesis and Management

Abstract

After completing this article, readers should be able to: The estimated annual incidence of nephrotic syndrome in healthy children is 2 to 7 new cases per 100,000 children younger than 18 years of age, making it a relatively common major disease in pediatrics. The peak age of onset occurs at 2 to 3 years except for the rare, congenital type of nephrosis. Approximately 50% of affected children are ages 1 to 4 years; 75% are younger than age 10 years. In addition, even the most benign form of the nephrotic syndrome is, by nature, a recurrent disorder, so each new-onset case likely will continue to manifest disease for some time. Nephrotic syndrome is one of the most frequent reasons for referral to a pediatric nephrologist for evaluation, although its insidious onset frequently causes delay in diagnosis.Careful examination of the anatomy of a nephron permits characterization of the glomerular basement membrane as the barrier between the circulation and the external environment. Thus, the glomerular membrane, which permits passage in an adult of approximately 180 L/d of fluid, is the final determinant of how much of the solute originally contained in this volume enters the tubular lumen. The normal glomerular membrane is remarkably selective for protein compared with other solutes (Table 1). Once this selectivity is lost, the ensuing proteinuria defines not only the diagnosis of nephrotic syndrome, but many pathophysiologic consequences as well. It is the purpose of this article to discuss the definition, causes, pathophysiologic consequences, and management of nephrotic syndrome. The emphasis is on the idiopathic form, which most often occurs in children as minimal-change nephrotic syndrome; other types of the nephrotic syndrome are mentioned briefly.As anticipated from the name, the composite of clinical findings can be found either alone or in association with a number of systemic disorders, including toxicities. The sine qua non of the diagnosis of nephrotic syndrome is the presence of urinary protein, with the albumin disproportionately greater than the globulin, deriving from a loss of glomerular membrane selectivity. In the pediatric age group, urinary protein loss of 50 mg/kg per 24 hours or greater is a firm diagnostic criterion. It is imperative to recognize the distinctive origin of the proteinuria in the glomerulus rather than the tubule; nephrotic syndrome may be seen as exclusively glomerular in origin without any associated tubular dysfunction. Additionally, as a syndrome, the clinical picture may be either primary or secondary, and underlying causes must be excluded. The diagnostic criteria are: 1) generalized edema; 2) hypoproteinemia (<2 g/dL [20 g/L]), with disproportionately low albumin in relation to globulin; 3) urine protein (mg/dL) to urine creatinine (mg/dL) ratio in excess of 2 in a first morning void or a 24-hour urine protein that exceeds 50 mg/kg body weight; and 4) hypercholesterolemia (>200 mg/dL [5.17 mmol/L]). The reduced serum albumin, which can fall to as low as 0.5 g/dL (5 g/L), causes a marked reduction in plasma oncotic pressure. Consequently, circulatory volume is lost to the interstitial spaces, resulting in generalized edema. Often, the initial swelling is observed as facial (especially periorbital) and pretibial edema, with prominent swelling of the scrotum or labia also seen. An additional consequence of the lowered oncotic pressure is reduced perfusion of the splanchnic capillary bed, which can cause abdominal pain. Pleural effusions may form, and frank pulmonary edema also may occur, with either or both resulting in tachypnea and chest pain.Levels of serum cholesterol, triglyceride, and lipoprotein cholesterol are consistently elevated. The mechanism(s) underlying these changes are not understood completely, in part due to the complexity of lipid transport and the difficulties inherent in human clinical studies. Increases in very-low density and low-density lipoprotein (VLDL and LDL, respectively) cholesterol are characteristic findings. VLDL-cholesterol is increased as a consequence of decreased hepatic catabolism, thus increasing circulating triglyceride and cholesterol. LDL-cholesterol is increased due to an enhanced synthetic rate. What remains to be elucidated is the cause for these disturbances in hepatic lipid metabolism.Primary nephrotic syndrome may occur at any age, from the neonate to the adult. The neonatal or congenital nephrotic syndrome, also called Finnish congenital nephrosis, is clearly defined as a genetic mutation in the nephrin gene and has been mapped to chromosome 19q13.1. Nephrin is a glomerular basement membrane protein that participates in formation of anionic-rich sites, causing electrochemical repulsion of plasma proteins. The mutation also has been reported in a Mennonite group in Pennsylvania who have no Finnish heritage and is believed to have arisen independent of the Finnish type. Primary childhood nephrotic syndrome rarely appears before 18 months to 2 years of age and peaks in incidence at about 3 years of age.The primary laboratory feature of the nephrotic syndrome is a marked proteinuria, in excess of 50 mg/kg per 24 hours (Table 2). The excreted protein is predominantly albumin, although immunoglobulins (Igs) also are lost. In uncomplicated cases of idiopathic nephrotic syndrome, it is unusual to see gross hematuria in the presence of proteinuria, although microscopic hematuria occurs in a sizeable proportion of cases. For patients who have gross hematuria and proteinuria, IgA nephropathy always must be a diagnostic consideration.In the presence of clinical edema, measurement of serum protein will yield low values; the serum albumin is likely to be 2.0 g/dL (20 g/L) or lower. Albumin concentrations as low as 0.5 g/100 mL can be seen, and the albumin/globulin ratio is commonly less than 1.0. Concomitantly, and directly related to the reduced serum protein, hypocalcemia is found frequently, as reflected in reduced total and ionized fractions. However, hypocalcemia rarely is manifested clinically.Of much greater significance than hypocalcemia to patients who have nephrotic syndrome is the increased concentrations of coagulation factors, especially those of high molecular weight. Thrombin also is increased, while fibrinolytic activity and circulating quantities of platelet adhesion inhibitors are decreased. As a consequence of these changes, as well as the intravascular hypovolemia, affected patients are at greatly increased risk of thrombosis. In addition, IgG in plasma is reduced, which in combination with large steroid doses, may predispose to infection.Children who become oliguric from diminished intravascular volume have a tendency to develop hyperkalemia. The use of diuretics may complicate the electrolyte disturbances further, necessitating close monitoring of serum electrolyte levels during treatment.In the acute stage of childhood nephrotic syndrome, especially during the initial episode, renal biopsy usually is unnecessary. The key indications for biopsy in any renal disorder are the need to make a specific diagnosis for therapeutic reasons or to provide a prognosis. The treatment of initial-onset nephrotic syndrome is the same, irrespective of cause, and the need for determining a prognosis never can outweigh the risks of thrombosis, bleeding, and infection due to a biopsy in the acute stage of the disorder.The subsequent disease course in a patient can help to determine the timing of a renal biopsy. In an uncomplicated case in which proteinuria clears within a few weeks in response to orally administered corticosteroids and normal renal function, the diagnosis is presumed to be minimal-change nephrotic syndrome. If there is no significant proteinuria between relapses that continue to respond promptly to corticosteroids, this diagnosis is strengthened. If the child is younger than 10 years of age at the initial presentation, no renal biopsy need be considered. At age 10 years or older, the increasing risk of underlying primary disease compels the need to obtain a biopsy for histologic diagnosis. In such cases, renal biopsy can be deferred until the child is stable and the family’s anxieties over the immediate medical problems have dissipated.In contrast, when there is poor or no response of the initial episode after 4 to 6 weeks of standard treatment (defined as steroid-resistance disease), biopsy should be considered as soon as the patient is medically stable. In such cases, the biopsy is essential to distinguish the nature and severity of the glomerular process, which may be primary or secondary (Table 3). It should be clear from the plethora of types and causes of glomerular nephropathy that treatments and prognoses vary considerably, making specific diagnosis imperative. Because proteinuria and microscopic hematuria are injury responses of the glomerulus, the need for clarification through renal biopsy is plain. The underlying pathology (Figs. 1 to 5) varies with age; the incidence is summarized in Table 4. The indications for initial kidney biopsies in the nephrotic syndrome are summarized in Table 5.Beyond the issue of renal biopsy for initial diagnosis, there are circumstances in which a subsequent biopsy may be considered. Glomerular injury may evolve over time such that the clinical findings (eg, increasing proteinuria, development of chronic renal insufficiency) change significantly. Such cases may represent progression of a disease that initially was diagnosed as minimal-change nephrosis by biopsy or progressive injury to the kidney by an underlying disease such as lupus nephropathy. In these situations, a second renal biopsy should be considered for evaluation of progressive renal disease.Technological developments in ultrasonography have reduced significantly the risk associated with percutaneous renal biopsy in children. Moreover, the improvements in electron microscopy equipment and technique, coupled with decades of observation, have enhanced the ability of the histopathologist to interpret the specimen accurately. Nonetheless, a renal biopsy is not always essential to good medical care, and its use should be viewed judiciously in all patients.The treatment of primary childhood nephrotic syndrome is supportive and will be determined largely by the patient’s clinical status. Boys can experience scrotal edema, which may cause testicular torsion. Other children may become short of breath due to pulmonary edema; still others may become oliguric and develop a functional azotemia. The latter is due to reduced circulating volume in the vascular space that results in temporary renal insufficiency. Any of these presentations, alone or in combination, demands immediate attention to symptomatic treatment.The unifying factor in this disease is depleted blood volume as a consequence of low oncotic pressure. Therefore, treatment should be directed at returning fluid to the vascular space and encouraging diuresis to avoid volume overload (Table 6). The intuitive solution to the diminished oncotic pressure is to restore serum albumin concentration to better than 2 g/dL (20 g/L) by intravenous infusion. However, the effectiveness of this measure is reduced considerably because of the hypoalbuminemia resulting from glomerular leakage of serum protein. The degree of urinary loss can be illustrated by the hepatic rate of albumin synthesis, which in adults can be as high as 12 to 14 g/d. If a patient becomes hypoalbuminemic at such endogenous rates of replacement, it is apparent that replacement by infusion can only be a temporary remedy. Nonetheless, for a patient who has pulmonary edema or renal shutdown, intravenous albumin (1 g/kg of a 25% solution) can be very effective in mobilizing fluid into the vascular space. The rate of increase in oncotic pressure is directly proportional to the rate of expansion of intravascular volume. Thus, too rapid an infusion will place the child at risk for congestive heart failure. Accordingly, intravenous albumin should be infused continuously over 8 to 12 hours under close supervision.As intravascular space expands, renal perfusion improves, and with it, the opportunity to reduce accumulated fluid volume is enhanced. Administration of a diuretic is the obvious means by which to maximize this opportunity. Keeping in mind that a normal or low serum sodium concentration is likely to represent the result of a dilutional effect, the choice of diuretic should be directed at sodium as well as at water excretion. An ideal choice is a loop diuretic such as furosemide, which can be administered at a dose of 1 to 2 mg/kg intravenously and acts within 15 minutes. Furosemide-induced inhibition of active chloride reabsorption in the ascending loop of Henle results in urinary excretion of sodium, chloride, and water. A portion of the calculated furosemide dose can be administered during the albumin infusion or it all can be administered at the end of the infusion, depending on the volume of urine output and the degree of edema.Debate continues over the true benefit of albumin infusion, and no resolution is in sight. Nonetheless, it is difficult to argue against its use in the clinical settings of pleural effusion, pulmonary edema, or impending renal shutdown due to depleted intravascular volume.The child should be started on oral corticosteroid therapy after a negative tuberculosis skin test result has been determined. Prednisone is the usual drug of choice, and the recommended maximum daily dose is 60 mg/m2 or 2 mg/kg. The daily dose should be maintained for 4 to 6 weeks. Opinion varies regarding this recommendation, ranging from daily treatment administered just long enough to achieve remission to 6 weeks of daily treatment. Following remission, the dose should be kept constant while changing to an alternate-day schedule for an additional 6 weeks. A measurable decrease in urine protein excretion should not be anticipated for at least 7 to 10 days following the initiation of treatment, so the patient’s degree of proteinuria should not determine the length of a hospital stay. Children who have mild-to-moderate edema, no pulmonary edema, and a good diuretic response generally require a hospital stay of no more than 2 to 3 days.Fluid balance must be monitored closely in the early stages of treatment. Optimal nutrition, including high-quality protein in amounts required for growth, is essential because the for albumin replacement is The child should a with sodium for replacement during are key to the therapeutic Other treatment, such as should be If laboratory is to may be at a dose of 50 intravenously and 4 hours intravenously for the treatment to of children who have an initial onset of minimal-change nephrotic syndrome will achieve therapeutic For the few who not experience a remission with of proteinuria within the first 2 to 3 months after are most children who have minimal-change nephrotic syndrome, the proteinuria will clear by the of oral treatment. is a diagnostic to the diagnosis. The of children who are not of proteinuria for at least 3 to days or those proteinuria continues 3 months are as frequent or For many such or treatments may be required (Table on daily or alternate-day oral may be for patients who experience frequent children in remission on such a with If the child can be kept in remission with relatively low steroid in the of this is because it is the least of the the other when high steroid are required for or when are required because the child clearly has a nephrotic the are as well as an and (Table The usual are and each of which can be to achieve an initial remission or to the child relatively more The recommended dose of each is in Table However, each is associated with a rather of systemic and specific which is the key for use as may be over 2 to 3 months to a remission, but after of treatment, more than 50% of patients experience a usually within 2 years. Moreover, in many such the degree of steroid is greater than to the use of the also has been for of a remission in effective in this occurs on drug and Thus, the primary of all in nephrotic syndrome is to use of of the results of a clinical have been for a new for of remission in nephrotic syndrome. The the drug (Table The decreased the rate and remission in children 10 years of age and older, with relatively few However, additional experience with this drug must be before it can be considered for A clinical of the drug in treatment of lupus to with use in treatment of idiopathic nephrotic syndrome has not been can its for use in children be at this (Table such as and may be of use as therapeutic in those very few patients who are to A combination of and has been reported as effective for treatment of the first months of nephrotic syndrome. The of is related to on renal blood and glomerular rather than to so the decrease in proteinuria is not a result of in the disease of renal perfusion may predispose the depleted patient to acute renal monitoring when these minimal-change nephrosis occurs most commonly in there may be problems related to childhood It is clear that no child should during treatment with to remission or with to frequent However, because relapses often are related to use of during are viewed with by some A no of pediatric with to for children who have nephrotic syndrome. Because affected patients are to the of use of the in children than 2 years and in those younger than 2 minimal-change nephrotic syndrome is a disease in the of affected a clear should be between of the disease and those that more likely are related to the treatment. For a patient with is at greater risk for the development of many (eg, which are not the of nephrotic syndrome (Table true of nephrotic syndrome is the tendency to develop (eg, A major of from infection in those who have nephrosis is which results from of the IgG is lost in the and is by loss of factor Other in the may to the intravascular causes diminished splanchnic blood and and a marked tendency to may cause of the to The causing and is a major to the to in nephrotic syndrome and always should be considered in an affected patient who of abdominal pain. should be of the usually by appears as with and associated second major to both and in this disease is is a risk of in children an initial or recurrent episode of nephrotic syndrome. However, there is no to use therapy during remission because is a result of serum protein by renal protein In those very few who have nephrosis, it may be to In all children an acute nephrotic episode, are is experience with an that with platelet in this to a marked for increased platelet increased concentration with urinary loss of increased blood and decreased blood and can be found in of the the renal the pulmonary and the is but has been associated with and even The for this should be considered. coagulation should be on for treatment and judiciously only when on the associated with the nephrotic syndrome generally is not a of clinical Because most cases of minimal-change nephrosis are the generally is within 4 to 6 weeks. However, in more chronic situations, it may become to changes drug often is in the nephrotic syndrome. that the proteinuria may cause the marked that is seen in congenital nephrosis. may be of factor protein, which for the serum concentrations of and Moreover, that also is Because high of also may growth, the of loss of may be by treatment. there is that of to nephrotic the severity of more is required before use of human becomes treatment for disturbances in the nephrotic in minimal-change nephrotic syndrome is approximately with the of due to or which may occur even under the of treatment may occur in the acute of the steroid Thus, although those who have congenital nephrosis are and be to this form of the disorder Nonetheless, the patient who has congenital nephrotic syndrome a therapeutic constant attention to serum protein and fluid monitoring of and treatment of the of children who have minimal-change nephrosis, most are and can be to to a normal its nature, minimal-change nephrotic syndrome results in about of patients experience at least a with a of such relapses over many years. It is to that a child who is at the initial may more than before the disease clinical have reported an between the age of and the length of the disease In most patients who have minimal-change disease very become and have a normal patients who have minimal-change nephrotic syndrome and become in the disease course have glomerular which is a stage of minimal-change disease to which some patients The early clinical of are from minimal-change but at least one of patients disease to to renal within years. In those who have more nephrotic syndrome, with and active urine and those who are than 12 years of age at onset are the most likely to develop However, it is not clear the severity of disease is a true rather than a factor that may be more likely to result in renal and decreased renal perfusion to the nephrotic syndrome the affected to acute renal during an acute renal is defined as a loss of renal that is and no significant injury has due to In the latter there is a high risk of acute tubular which greatly the risk of to the If such chronic renal and the relatively good prognosis of minimal-change those patients chronic renal to renal there is always the of However, for patients who have there is a 25% risk of of in the and nephrotic syndrome occurs after renal independent of it was prognosis for all of nephrotic syndrome (Table 4) in patients younger than years of age is as will continue in remission, 50% will have one or relapses in any and the will develop either nephrosis or nephrosis. The of patients diagnostic renal biopsy. If minimal-change disease is there is a 50% for these children to into remission after a course of and is the child is and for more than 2 years.