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Nephrotic Syndrome Last Updated: April 14, 2005 |
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| Synonyms and related keywords: NS, nephrosis, lipoid nephrosis, primary nephrotic syndrome, primary NS, PNS, idiopathic nephrotic syndrome, idiopathic NS, INS, secondary nephrotic syndrome, secondary NS, minimal change nephrotic syndrome, MCNS, minimal lesion nephrotic syndrome, MLNS, nil disease, steroid-sensitive nephrotic syndrome, SSNS, steroid-resistant nephrotic syndrome, SRNS, steroid-dependent nephrotic syndrome, SDNS, mesangial proliferative glomerulonephritis, MPN, immunoglobulin M nephropathy, focal segmental glomerulosclerosis, FSGS, membranoproliferative or mesangiocapillary glomerulonephritis, MPGN, hypocomplementemic glomerulonephritis, membranous glomerulonephritis, MGN, congenital nephrotic syndrome
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AUTHOR INFORMATION
| Section 1 of 10   |
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| Author: Luther Travis, MD, William W Glauser Professor of Pediatrics and Pediatric Nephrology, Department of Pediatrics, Divisions of Nephrology and Diabetes, University of Texas Medical Branch and Children's Hospital |
| Luther Travis, MD, is a member of the following medical societies:
Academy of Medical Royal Colleges,
Alpha Omega Alpha,
American Association of Diabetes Educators,
American Federation for Medical Research,
International Society of Nephrology, and
Texas Pediatric Society |
| Editor(s): Laurence Finberg, MD, Clinical Professor, Department of Pediatrics, University of California at San Francisco and Stanford University; Robert Konop, PharmD, Director, Clinical Account Management, Ancillary Care Management, Inc;
Adrian Spitzer, MD, Professor, Department of Pediatrics, Albert Einstein College of Medicine; Director of NIH Training Program, Children's Hospital at Montefiore Medical Center;
Howard Trachtman, MD, Program Director, Pediatrics Research, Schneider Children's Hospital, Professor, Department of Pediatrics, Division of Nephrology, Albert Einstein College of Medicine;
and Craig B Langman, MD, Professor, Department of Pediatrics, Northwestern University School of Medicine; Head, Division of Kidney Diseases, Children's Memorial Hospital of Chicago |
Disclosure
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INTRODUCTION
| Section 2 of 10   |
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Background: The term nephrosis, or nephrotic syndrome, had its origin in the early 20th century and was introduced primarily to distinguish it from nephritis, a label used to denote a clinical state associated with hematuria, proteinuria, and a cellular proliferation of the glomerulus. It describes a clinical condition of edema and proteinuria in which the renal histology (light microscopy) demonstrates fatty degeneration of the tubules associated with normal appearing glomeruli. Briefly, the name was modified to lipoid nephrosis after the routine finding of lipid droplets in the urine of affected patients.
The nephrotic syndrome (NS) is a clinical entity characterized by massive loss of urinary protein (primarily albuminuria) leading to hypoproteinemia (hypoalbuminemia) and its result, edema. Hyperlipidemia, hypercholesterolemia, and increased lipiduria are usually associated. Although not commonly thought of as part of the syndrome, hypertension, hematuria, and azotemia may occur. NS generally has a glomerular cause and is currently categorized into primary and secondary forms. The name primary NS (PNS) has replaced, in some circles, the older designation of idiopathic NS (INS), but both terms denote a similar same vagueness as to cause. Included are a variety of clinical as well as pathologic states. The term secondary NS relates to the clinical state associated with other, more clearly defined diseases such as anaphylactoid purpura, systemic lupus erythematosus, diabetes mellitus, sickle cell disease, syphilis, and others. In the following sections, the majority of attention will be devoted to PNS or
INS because of the relative frequency in children.
The subcategories of PNS are based on histologic descriptions, but clinical-pathological correlations have been made. Even though knowledge of specific causes of NS are too limited for more precise classification, the variants of PNS/INS will be considered as clinical disease states with well-defined histopathologic processes. The histologic type at onset makes it possible to generalize about such things as response to therapy and ultimate prognosis. When possible, the authors use the definitions, descriptions, and nomenclature developed by the International Study of Kidney Diseases in Children (ISKDC). Most attention will be devoted to minimal change nephrotic syndrome (MCNS) and focal segmental glomerulosclerosis (FSGS) with only modest attention to familial or congenital nephrosis, membranoproliferative glomerulonephritis (MPGN), and membranous glomerulonephritis (MGN).
The overall prevalence of NS in childhood is approximately 2-5 cases per 100,000 children. The cumulative prevalence rate is approximately 15.5/100,000. MCNS is the most common form in children, and its prevalence is inversely proportional to the age at onset (ie, the younger the child, the more likely the histology will show minimal abnormalities on light microscopic evaluation of glomerular histology). Histologic variations exist within this category in which some patients demonstrate only fusion and smudging of the epithelial cell podocytes while others may demonstrate mild changes within the glomerular mesangium consisting of either proliferation or sclerosis. Since patients with MCNS have the highest rate of responsiveness to standard therapy and the best long-term prognosis, the separation of MCNS from others is important.
IgM mesangial nephropathy (IgM nephropathy) may be a separate entity from MCNS. Assignment of type of NS by histologic criteria is based predominately on light microscopic findings. Most patients with isolated IgM mesangial immunofluorescent staining present clinical characteristics similar to those with MCNS. Whether the finding of immune deposits of IgM alters either response to therapy or subsequent course is controversial.
Focal segmental glomerulosclerosis (FSGS) is the second most common histologic subtype seen in children and appears to be increasing in frequency. It is not a single disease entity, and attempts to portray it as a uniform entity has led to some confusion in the literature with regard to natural history. FSGS is always a histopathologic diagnosis, and its clinical presentation will vary according to the etiology or cause of the histologic lesion. FSGS may manifest in a fashion that is indistinguishable from MCNS, but it may also be found only after years of clinical nephrotic syndrome when earlier biopsies have been interpreted as MCNS. FSGS is a known consequence of hyperfiltration and is regularly seen in patients with reflux nephropathy and in some patients with a single kidney whose other has been lost because of conditions such as multicystic dysplastic kidney disease.
Membranoproliferative glomerulonephritis (MPGN) may manifest as nephrotic syndrome, particularly in older children and adolescents. Its clinical picture is more closely associated with a nephritic picture, but on occasion it may appear similar to MCNS or FSGS. Membranous glomerulonephritis (MGN) accounts for less than 1% of the cases of NS in childhood and adolescence and is often associated with hepatitis or other viral disease. Congenital nephrotic syndrome becomes a consideration when nephrosis appears during the first year of life and particularly in those instances in which the clinical syndrome starts in the first few months. Pathophysiology: Heavy proteinuria (albuminuria) is the hallmark of this condition and the primary abnormality in NS. The degree of proteinuria varies considerably from one child to another. Some children will excrete as much as 15 g/m2/24 hours, and the minimal excretion compatible with the diagnosis is around 1 g/m2/24 hours (approximately 40 mg/m2/hour).
The initiating event that produces proteinuria remains unknown. PNS is believed to have an immune pathogenesis, but the precise nature of the process has yet to be defined. That PNS is related to lymphocyte dysfunction has been suggested, and various studies lend credence to this hypothesis. A highly cationic plasma protein that may neutralize the anionic charge on the glomerular capillary wall has been described in nephrotic children. Other investigators have noted a decrease in immune responsiveness and related this to alterations in either T-lymphocyte number and/or function. The presence of suppresser cytokines or lymphokines has been postulated, and various investigators have shown changes in interleukin-8, interferon-g, IGF-1, TGF-a, and vascular permeability factor (VPF). The role of the kinin system is also under investigation, because urinary excretion of kinins is increased during exacerbations of the disease. More recently, alterations in
ceratin molecules expressed in the epithelial cell podocyte,especially nephrin, podocin, and a-actin, have been shown to have a role in the pathogenesis of the proteinuria. Other researchers have not felt nephrin to be involved in children with MCNS. The rate of apoptosis in circulating T-lymphocytes has been found to be increased, and a role for reduced antioxidant defense has been postulated. Despite the regular finding of elevated levels of IgE and an association with atopy in steroid-responsive NS, current data merely suggest a common immune activation rather than a direct association. Leptin is now being investigated for its role in the pathogenesis since, in MCNS, serum levels are low at onset of the disease and are associated with elevated serum levels of TGF-b1. Additionally, some evidence still exists that genetic factors may be involved in the pathogenesis.
In PNS, the glomerular capillary permeability to albumin is selectively increased, and this increase in filtered load overcomes the modest ability of the tubules to reabsorb protein. This selective proteinuria (as seen in MCNS) is quite different than the more unselective proteinuria observed in cases of glomerulonephritis. Part of this increase in albumin excretion may be because of the smaller size of the albumin molecule, but since the excretion of some even smaller weight plasma proteins is not proportionally increased, the presence of other factors is obvious. At least 2 hypotheses are proposed to account for this increased permeability. The traditional hypothesis relates to changes in the anionic composition of the glomerular basement membrane (GBM). In the normal state, the endothelial side of the glomerular capillary is negatively charged because of the presence of a variety of polyanions along this surface. Thus, the negatively-charged protein, albumin, is less likely to be filtered.
In experimental nephrosis and in some children with primary NS, studies have demonstrated a decrease in the normal content of sialic acid (a polyanion) from the basement membrane. While such has not been confirmed by all investigators, this deficiency may allow for an increased transport of anionic plasma components. In such a state, permeability of the glomerular basement membrane would be selectively altered, increasing capillary transport of anionically charged particles such as albumin.
An alternative proposal to explain the heavy proteinuria invokes a primary role for the epithelial cell podocytes. Flattening, retraction, and effacement of the podocyte foot processes is a constant feature of heavy proteinuria. In the traditional viewpoint, these changes are considered as consequences of the proteinuria. Other investigators believe that primary distortions of the slit diaphragm filaments are present and that a redistribution of nephrin from the podocyte slit pores into the cytoplasm.
Hypoalbuminemia is the result of the increased urinary loss of protein. Other factors, however, may contribute to the hypoalbuminemia, among them decreased synthesis, increased catabolism, and increased gastrointestinal losses. Even though most studies have shown that the albumin synthesis rate is not decreased, the capacity to increase hepatic production appears insufficient to compensate for the large urinary losses.
Edema appears to be the natural consequence of the hypoalbuminemia. The classic explanation for edema formation is a decrease in plasma oncotic pressure (as a consequence of low serum albumin) causing an extravasation of plasma water into the interstitial space. The resulting contraction in plasma volume would theoretically lead to a decrease in renal perfusion and hence to stimulation of the renin-angiotensin system. This hormonal effect coupled with an increase in the synthesis and secretion of antidiuretic hormone (related to the decrease in effective plasma volume) would lead to an increase in renal tubular reabsorption of sodium and water. The net result of the combination of Starling forces, reduction in renal perfusion (GFR), and increased hormonal activity would be avid reabsorption of both sodium and water, leading to either maintenance or furthering of the edema.
While the above hypothesis on the pathogenesis of edema is attractive, certain experimental data do not completely support this traditional concept. First, the plasma volume (PV) has not always been found to be decreased and, in fact, in most adults, measurements of PV have shown it to be increased. Only in young children with MCNS have most (but not all) studies demonstrated a reduced PV. Additionally, most studies have failed to document elevated levels of renin, angiotensin, or aldosterone, even during times of avid sodium retention. Active sodium reabsorption also continues despite actions that should suppress renin effects (ie, albumin infusion, ACEI administration). Coupled with these discrepancies is the fact that, in the steroid-responsive nephrotic, diuresis usually begins before plasma albumin has significantly increased and before plasma oncotic pressure has changed. Some investigators have demonstrated a blunted responsiveness to atrial natriuretic peptide (ANP) despite higher than normal
circulating plasma levels of ANP.
Thus, that the precise cause of the edema and its persistence is uncertain should be apparent. A complex interplay of a variety of physiologic factors (ie, decreased oncotic pressure, increased activity of aldosterone and vasopressin, diminished atrial natriuretic hormone, activities of various cytokines and physical factors within the vasa recti) probably contribute to the accumulation and maintenance of edema. Frequency:
- In the US: PNS is an uncommon condition, and, during their entire practice experience, most pediatricians see only 1-3 patients with the condition. The reported annual incidence rate is 2-5 per 100,000 children younger than 16 years. The cumulative prevalence rate is approximately 15.5 per 100,000 individuals.
Mortality/Morbidity: The morbidity and mortality of the NS is dependent, in large degree, on the etiology of the disease and its histologic subtype. As such, these subjects will be discussed within their specific headings.
- The mortality rate depends almost entirely on the type of disease causing the heavy urinary loss of albumin. The long-term prospect of complete remission in persons with MCNS is greater than 70% with a reported cumulative mortality rate (at 20 y postonset) of less than 15% (range in various studies, 5-15%). Conversely, only 24% of patients with FSGS are in remission after 20 years, and the cumulative mortality rate is greater than 50% (see Prognosis).
- The morbidity rate is substantial. Even in its mildest form, MCNS is often a chronic disease that requires the following:
- Hospitalization, in some instances
- A prolonged period of treatment
- Frequent monitoring both by parents and by physician
- Administration of medications associated with significant adverse events
- A high rate of recurrence (ie, relapses in >60% of patients)
- The potential for progression to chronic renal failure (CRF)
- In patients who demonstrate multiple relapses, the potential problems are associated with the need for long-term immunosuppression therapy that predisposes to serious infections, decreases in growth velocity, behavioral changes, obesity, cataracts, hypertension, osteoporosis, osteomalacia, nephrolithiasis, diabetes mellitus, hirsutism, gingival hypertrophy, and other issues.
Race:
- Clear differences in racial predilection to NS and maybe even a more pronounced difference in the types of NS acquired within a geographic area exist, but the definitive data supporting this are lacking. In the United Kingdom, the potential in persons with Indian ancestry is increased. In the United States, differences in frequency of NS between the Caucasian, African-American, and Hispanic are not apparent, but the percentage of Hispanic patients exhibiting FSGS (ratio of FSGS:MCNS) is much greater.
Sex: In children younger than 8 years at onset, the ratio of males to females varies from 2:1 to 3:2 in various studies. In older children, adolescents and adults, the male to female prevalence is approximately equal. ISKDC data indicate that 66% of patients with either MCNS or FSGS are male, whereas, for MPGN, 65% are female.
Age: In children who develop NS while younger than 18 years, approximately 75% are under the age of 6 years with peak incidence between 2-3 years. The younger the child at onset (with the exception of the first few months of life), the greater the likelihood that the lesion is MCNS. With onset before age 5 years, the likelihood is >90%; the risk for FSGS and MPGN is 7% and 1%, respectively. Conversely, with onset after age 10, the risk for MCNS drops to ~50%, and the risk for FSGS and MPGN is almost 30% and 20%, respectively.
History: - Regardless of the type of NS (the histopathologic type), the major clinical manifestation is edema, which is the presenting symptom in about 95% of children. The edema in the early phase is intermittent and insidious; even its very presence may not be appreciated. It usually appears first in areas of low tissue resistance (ie, periorbital, scrotal, and labial regions) and may progress either rapidly or quite slowly. Ultimately, it becomes generalized and can be massive (anasarca). It is typically dependent in nature, more noticeable in the face in the morning (upon arising) and predominately in lower extremities later in the day. It is pitting in nature. In cases with marked edema, the skin may ooze clear fluid and appear thinner than usual.
An occasional child with NS will present with gross hematuria. The frequency of macrohematuria depends on the histologic subtype of NS. It is more common in those patients with MPGN than in other causes, but its frequency in MCNS has been reported to be as high as 3-4% of cases. Statistically, a higher percentage of patients with FSGS have microhematuria than those with MCNS, but this is not helpful in differentiating between types of NS in the individual patient. Oliguria is a common occurrence whatever the etiology.
Regardless of the type of NS, anorexia, irritability, fatigue, abdominal discomfort, and diarrhea are common. If ascites is marked, respiratory distress is not uncommon. An occasional child will present with fever and septic picture; the peritoneum is often the site of the infection. Streptococcus pneumoniae is the most frequent organism responsible for peritonitis in this population, but Staphylococcus aureus and Escherichia coli are commonly recovered. Symptoms of a urinary tract infection are occasionally present.
A history of a respiratory tract infection immediately preceding the first clinical signs of the disease is frequent, but the relevance to causation is uncertain. A history of prior allergic events is common, and atopy has been reported in approximately 40-50% of children with MCNS. A hypersensitivity event (ie, insect sting, ant bites, poison ivy, immunizations, etc.) has clearly preceded the onset in some cases and may be considered etiologically significant. The peak incidence of NS appears to have a seasonal variation. A few children have been reported with major food allergies, and, in some, ultimate remission has been associated only with dietary elimination programs.
Physical: The most common clinical finding of edema is present in more than 95% of cases. The degree is usually greatest in those patients with MCNS. It may be mild and localized only to those areas where tissue resistance is low (eg, periorbital area, scrotum, labia). Generalized edema is common and is dependent and pitting in character. Ascites is common, and anasarca may be present. In those children with marked ascites, there may be mechanical restriction to breathing and the child may manifest compensatory tachypnea. The child usually demonstrates a pallor that is greater than laboratory evidence of anemia would suggest.
Hypertension may be present; ISKDC studies demonstrated that approximately 30% of patients with MCNS have both systolic and diastolic pressures above the 90th percentile for age. When values above the 98th percentile were used to denote an abnormality, then approximately 20% had systolic pressures that were elevated and about 13% of the diastolic pressures were aberrant. The percentage of children with nephrosis who exhibit hypertension is higher with other subsets such as children with FSGS and, particularly so, in patients with MPGN in which hypertension may be severe.
Other consistent abnormalities of the physical state are unusual. Signs of a concurrent upper respiratory tract infection may be present, and some children will have overt evidence of an atopic state with varying degrees of eczema. An occasional child will show evidence of an insect sting or bite. Abdominal tenderness is unusual in the absence of a peritoneal infection.
On rare occasions, the child with nephrosis may demonstrate signs of either an arterial or venous thrombosis near the onset of disease. These thromboses, which may involve either the extremities or internal vessels, occur secondary to the hypercoagulable state of such patients. Early recognition is essential if the organ involved is to be salvaged. Causes: - Edema, the predominant clinical feature, is ultimately the result of the urinary loss of large amounts of albumin from the serum with a consequent lowering of the serum albumin concentration.
- The cause for the maintenance and progression of the edema is less certain (see Pathophysiology).
- The GFR is often reduced by a mild-to-moderate degree, and the ability of the renal tubules to aggressively reabsorb sodium and water is enhanced. Oliguria and edema ensue.
- The edema first collects in those sites where tissue resistance is low, such as the periorbital area and in the scrotum.
- Later, the edema becomes generalized.
- The etiology of the hypertension is probably multifactorial.
- In some patients with elevated blood pressure (BP), particularly in small children with MCNS, the PV is low, and the associated tachycardia suggests an increase in sympathetic nervous system activity. In such patients, the BP falls following an infusion of albumin.
- In most older patients with NS, the PV is either normal or increased. In some of these patients, BP returns to normal with diuresis.
- Plasma renin levels have been reported variously as either normal or slightly increased; however, the response to blockade of the renin-angiotensin system does not support this as the primary cause of the hypertension.
- Various cytokines known to have pressor effects are increased and may be the primary cause of hypertension.
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DIFFERENTIALS
| Section 4 of 10 |
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Acute Poststreptococcal Glomerulonephritis
Angioedema
Heart Failure, Congestive
Nephritis
Nephrotic Syndrome
Obesity
Oliguria
Protein-Losing Enteropathy
Proteinuria
Systemic Lupus Erythematosus
Other Problems to be Considered:
An approach to the differential diagnosis should be looked upon as a 2-step process. First is the question of what other conditions are likely to manifest similarly (ie, edema). Allergic reactions are probably the most commonly confused condition, and how often the child with new onset nephrosis is initially felt to have some form of allergic reaction as a cause for the periorbital edema is striking. Other conditions that may produce facial or generalized edema in children of this age group include congenital heart disease and congestive heart failure, severe hepatic disease associated with hypoalbuminemia, protein-losing enteropathy (infants with cystic fibrosis, particularly), and congenital defects in albumin synthesis.
The key to determining that renal disease is responsible for the initial clinical presentation is an examination of the urine for protein and cellular elements. Most patients with MCNS have proteinuria without hematuria, but the presence of microhematuria does not eliminate this diagnosis from consideration. The proteinuria is predominately selective with a high ratio of albumin to globulins. The proteinuria from patients with FSGS is less selective but is still more so than that from patients with MPGN. In the latter disease, hematuria is routinely present. |
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Lab Studies:
- The key to determining that renal disease is responsible for the initial clinical presentation is an examination of the urine for protein and cellular elements. Most patients with MCNS have proteinuria without hematuria, but the presence of microhematuria does not eliminate this diagnosis from consideration. The proteinuria is predominately selective with a high ratio of urinary albumin to globulin (UA/G). In patients with FSGS, proteinuria is less selective but still more so than in patients with MPGN. In individuals with MPGN, hematuria is routinely present. Although measurements of protein selectivity are not performed routinely in the United States, clinical studies from Europe confirm the utility of this test.
- The magnitude of proteinuria varies with the state of disease activity and with the histologic abnormality.
- The amount of protein in a random urine sample of a patient with NS usually exceeds 100 mg/dL, and values as high as 1000 mg/L are common. Protein to creatinine ratios (normal, <0.2) may vary from 1-20, suggesting 24-hour protein excretions of 1-20 g.
- According to the ISKDC definitions, the lowest amount of urinary protein consistent with the diagnosis of NS is 40 mg/m2/h or approximately 1000 mg/m2/d.
- Patients with MCNS and MN usually excrete larger amounts of protein than patients with other histologic subtypes. However, MN is rare in children.
- The major protein excreted in any form of NS is albumin, but the UA/G ratio in excreted urine is influenced greatly by the histologic subtype.
- Hematuria may be present, and its frequency depends on the subtype of NS.
- Microscopic hematuria is present at the onset of the disease in 20-30% of patients with MCNS, but it disappears thereafter. By contrast, microscopic hematuria is consistently present in 80-100% of patients with MPGN and in 60% of patients with MN.
- Patients with FSGS have hematuria more often than patients with MCNS, but the presence of hematuria cannot be used to distinguish between the 2 conditions.
- Although unusual in persons with MCNS, macroscopic hematuria has been reported.
- Hypoalbuminemia is the second of the cardinal laboratory features of NS, whatever the histopathologic subtype.
- The concentration of serum albumin compatible with NS is less than 2.5 g/dL.
- The serum concentration of albumin is indirectly correlated with the magnitude of proteinuria; thus, patients with MCNS, in general, have lower concentrations than those with other forms of NS.
- Values as low as 0.5 g/dL are not uncommon.
- Hyperlipidemia is a common feature of NS and, in general, correlates inversely with the concentrations of serum albumin.
- The low density lipoprotein and very low density lipoprotein cholesterol concentrations are elevated, whereas the high density lipoprotein cholesterol level is decreased.
- Values for lipids may remain moderately elevated for as many as 1-3 months after complete remission of proteinuria.
- Renal function is normal in the majority of children at onset of NS, but, even in those patients with MCNS, approximately 25-30% will have mild to moderate reduction of glomerular filtration rate as evidenced by a rise of serum creatinine above the normal range (>95th percentile for age). In MCNS, these elevated values usually return to normal as diuresis occurs. Very marked reductions in renal function or persistent elevation of SCr is more likely to indicate a different histologic subtype even though acute renal failure, which is usually reversible, does occur in MCNS.
- Elevated values for hemoglobin and hematocrit are usual when the patient has marked hypoalbuminemia and is due to the contracted plasma volume. Elevated white blood cell counts are occasionally seen even in the absence of infections. Hyponatremia and reduced serum osmolality are common but are usually factitious because of hyperlipidemia. Hypocalcemia (low total serum calcium) is common in all persons with active NS, but, in most, the ionized serum calcium is in the normal to low-normal range. Serum levels of complement are usually normal except in those patients with MPGN.
Imaging Studies:
- No routine imaging studies are indicated in patients with NS.
- On chest radiographs, pleural effusions are not uncommon, and their presence correlates directly with the degree of edema and indirectly with the serum albumin concentration. Ascites is common.
- Renal ultrasonography usually reveals normal to slightly enlarged kidneys with normal echogenicity. Patients with MPGN often demonstrate larger than normal renal shadows with increased echogenicity.
Procedures:
- A renal biopsy is usually not performed until after a therapeutic trial of glucocorticoids has proved to be unsuccessful. Exceptions to this general rule may be made in the following situations:
- A child older than 10 years at onset of NS
- Coexistence of significant hematuria, hypertension, and azotemia at the onset of NS
- Any child in whom the levels of serum complement (or C3) are depressed
Histologic Findings: If a histologic assessment is made, the findings discovered are, obviously, dependent on the subtype of NS. These will not be discussed in any detail here, and the interested reader is referred to other sources for this. Briefly, the findings are summarized below.
- Minimal-change nephrotic syndrome (MCNS) indicates glomerular morphology that on light microscopic examination is little different from normal. There may be minimal mesangial alterations, but immunoglobulins are usually absent, and no deposits are observed on electron microscopy. The only significant change seen on electron microscopic examination is flattening and fusion of the epithelial cell podocytes.
- Focal global glomerulosclerosis (FGGS) describes a globally sclerotic glomerulus occurring in focal areas with remaining glomeruli being normal. The precise meaning of such a lesion is not always certain since normal glomerular attrition occurs by global sclerosis. For this reason, a normal variant is usually considered to be if <5% of the glomeruli are globally sclerotic.
- Focal segmental glomerulosclerosis (FSGS) describes a lesion in which some glomeruli are involved with segmental sclerosis (one lobule or section within a glomerulus), with the remaining glomeruli being normal. Because this lesion is focal and is often confined to the juxtamedullary nephrons, it may be overlooked on renal biopsy examination. Immunofluorescent microscopy yields a variable picture. In some patients, all classes of immunoglobulins and complement appear to be trapped in the sclerotic area; in others, distinct immune-complex-type, particularly IgM, deposits are found.
- Mesangial proliferative glomerulonephritis (MPN) has only recently been distinguished from MCNS, and some examples of MCNS with mesangial alterations may be inappropriate. Light microscopy reveals minimal to moderate proliferation of the mesangial cells, with some mesangial expansion, but the most striking change is observed with immunofluorescent microscopy, in which IgM, IgG, and C3 are often seen.
- Membranoproliferative glomerulonephritis (MPGN), or mesangiocapillary glomerulonephritis, has a distinctive histologic picture; all glomeruli are involved. Three varieties of MPGN can be described, both with proliferation of cells and extensive immune deposits as demonstrated by immunofluorescent and electron microscopy.
- In membranous glomerulonephritis (MGN), with well-developed lesions, findings on light microscopic examination are typical, but detection of early lesions requires the detail afforded by immunofluorescent and electron microscopy.
- Other lesions, including proliferative glomerulonephritis and chronic glomerulonephritis, occur in <5% of children with NS, and the histologic picture varies with the specific etiology.
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TREATMENT
| Section 6 of 10 |
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Medical Care: The following discussion assumes that all attempts have been made to exclude MPGN and secondary causes of NS. An underlying assumption is that the most likely diagnosis is MCNS or a similar subtype in which reasonable expectations exist that the disease will be responsive to glucocorticoid therapy. Treatment that appears specific (steroids) and treatment that is nonspecific (observation for infections, diet, diuretics, antihypertensives) is discussed here. In addition, only initial treatment is considered here; treatment of nonresponders and those who relapse is discussed later. - Specific therapy
- Initial management
- Glucocorticoid (steroid) therapy has so changed the morbidity and mortality of NS as to make it almost specific and is considered standard. Even though differences in the beliefs among pediatric nephrologists about the specific details of steroid management exist, the feelings are uniform that this is the primary agent of choice.
- After contraindications to the use of high-dose glucocorticoid drugs are eliminated (ie, usually considered to be exclusion of an active infection), oral prednisone or prednisolone is started in a dosage of 2 mg/kg/day (60 mg/m2/d).The total daily dose is usually split into two doses and given daily for 4-8 weeks. Higher dosages or longer courses of daily steroids do not significantly change the response rate in MCNS, but they do increase steroid toxicity. Approximately 90% of patients with MCNS respond to this therapy with complete clearing of proteinuria, but only about 20% of children with FSGS and <5% of those with MPGN experience a clinical remission (defined as a diuresis without complete clearing of proteinuria). The majority of children with MCNS will respond between the 10th and 14th days of such therapy, but a full course of at least 4 weeks of daily therapy is still recommended. Children who do not respond (ie, complete clearing of proteinuria) should be referred to a pediatric nephrologistfor percutaneous renal biopsy and consideration be given to an alternative plan of treatment.
- Maintenance therapy
- Maintenance glucocorticoid therapy is still controversial, not about the need for some period of continuing prednisone but about the duration that such should be given. Following the 4-8 weeks of daily therapy, the standard recommendation has been for the dose (of either prednisone or prednisolone) to be reduced to ~1.5 mg/kg/day (40 mg/m2/d) given as a single dose every other morning for a 4-week period. Based on the author's unpublished experience and other data, such a brief period of maintenance therapy is associated with a higher rate of early recurrence than in those patients in whom the maintenance therapy is continued for between 3-6 months.
- Some investigators have accentuated the steroid effectiveness without increasing the side effects by giving intravenous pulse doses of methylprednisolone. A recent assessment of the Cochrane Database comparing 2 months of steroid therapy with 3 or more months concluded that "the longer duration significantly reduced the risk of relapse at 12-24 months without an increase in adverse events." They subsequently concluded that "...daily prednisone for 4 weeks followed by alternate day therapy for 6 months would be expected to reduce the number of children experiencing a relapse by about 33%." A recent meta-analysis of several controlled studies tends to support this contention.
- Thus, the author's recommendation for management is as follows:
- 4 weeks: intensive (daily) treatment-as above
- 8 weeks: 1.5 mg/kg/d (one dose every other morning)
- 8 weeks: 1.0 mg/kg/d (one dose every other morning)
- 8 weeks: 0.5 mg/kg/d (one dose every other morning)
- Therapy stopped
- Observation for infection: The child with nephrotic syndrome is a prime candidate for infection, and the potential for dissemination is increased if steroids are administered indiscriminately. Thus, the child who is febrile or has evidence of infection should be observed closely for a brief period while appropriate studies are performed. A child from an environment conducive to tuberculosis should be tested. Documented infections should be actively treated, but prophylactic therapy is not usually indicated. Pneumococcal vaccine is indicated in all patients after remission is obtained.
- Diuretic therapy may be beneficial, particularly in children with symptomatic edema. The loop diuretics (furosemide) given orally in usual amounts (~1-2 mg/kg/d) are safe and moderately effective; their administration, however, should be handled with care because plasma volume contraction may already be present, and hypovolemic shock has been observed with overly aggressive therapy. If the edema is sufficiently intense that intravenous diuretic therapy seems indicated, then salt-poor albumin should be infused (usually at 1 gram/kg body weight given IV over 2-4 hours) simultaneously. Diuretics other than loop diuretics (eg, thiazides, spironolactone, metolazone) are generally not potent enough alone to effect diuresis but may give an added effect when combined with furosemide. Metolazone (with or without spironolactone) may be beneficial in combination with furosemide for resistant edema. Patients must be monitored carefully on this regimen. If the child is sent home on diuretic therapy, the
family must have clear guidelines about discontinuing therapy when edema is no longer present.
- Antihypertensive therapy should be given when hypertension is present and particularly if it persists, but caution should be exercised. In some patients the hypertension will respond to diuretics. Angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II receptor antagonist (A2RA) agents are the preferred therapy even though calcium channel blocking agents have been used effectively in short term therapy. In those patients in whom significant proteinuria persists, therapy with ACEI or A2RA are preferred for their antiproteinuric effect.
- Ambulatory monitoring of the child's condition and response to management is a very important aspect of overall management. We have found that the best outcomes occur in children in whom the parents keep an ongoing log (journal, diary, ledger) of their child's treatment and progress. It seems best to initiate this at the beginning of outpatient care. The child's clinical state (ie, presence, absence, degree of edema; blood pressure; illnesses), urine protein results, and treatments can be entered in the log.
Home monitoring of urine protein/albumin is an important aspect of management. All patients and/or parents should be trained to monitor random urine proteins at home by the most simple and inexpensive test available. This is most often accomplished with urine dipsticks but the use of turbidity tests (ie, sulfosalicylic acid) may also be used. The author recommends that the urine be tested once each morning and the results recorded in the log. This becomes particularly helpful after the urine has become free of protein (during maintenance therapy and beyond) since it may give clues about recurrences of the disease before edema occurs, thus allowing earlier initiation of treatment.
Surgical Care: No routine surgical care exists for this condition. On occasion, a patient with NS either presents with or develops clinical signs of an acute surgical abdomen, which is frequently due to peritonitis. The diagnosis can usually be made clinically and confirmed by bacteriologic examination of the peritoneal fluid aspirate. The organism most often responsible for the peritonitis is pneumococcus; however, enteric bacteria may also cause peritonitis. Treatment is medical. Consultations: In most instances, NS is a chronic problem that requires understanding of the pathophysiology and knowledge of treatment options. For these reasons, consultation with a pediatric nephrologist is appropriate for all patients with NS. Referral to a pediatric nephrologist is mandatory for all children with NS whose symptoms fail to respond to initial therapy (ie, complete clearing of proteinuria); in most of these patients, a percutaneous renal biopsy is indicated, and an alternative treatment plan may be desirable. Diet: Diet & fluids: The kidneys of children with active NS exhibit the usual tubular mechanisms for sodium conservation and total body sodium is uniformly increased. With the addition of prednisone therapy, renal sodium excretion is further curtailed. Because free access to salt is known to increase edema, dietary salt intake should be restricted. Limitation of water or fluid intake has not been a part of the usual therapeutic plan, even though, on occasion, a child's thirst may be so stimulated that intake is excessive; if so, moderate restriction may be beneficial. The remainder of the diet should be normal. Alterations in protein intake are not indicated. Activity: A normal activity plan is recommended. Since viral respiratory illnesses are usually responsible for initiating exacerbations of NS, it may be beneficial, if possible, to keep the child away from those who have obvious respiratory tract infections. Limiting exposure to large groups of children with potential infections seems to decrease the number of exacerbations. Do not restrict activity unless the child is severely edematous.
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MEDICATION
| Section 7 of 10 |
|
Prednisone is the first-line therapy for children with NS. Other immunosuppressive medications may be useful in those whose symptoms fail to respond to standard corticosteroid therapy or in those who have frequent relapses.
Drug Category: Glucocorticoids -- All glucocorticoids are effective; however, prednisone or prednisolone is used most commonly. Their specific mode of action in NS is unknown. Drug Name
| Prednisone (Deltasone, Orasone) -- Delta1-derivative of naturally occurring adrenocortical steroids. Suppresses key components of immune system. |
|---|
| Adult Dose | 2 mg/kg/d (60 mg/m2/d) PO divided q8-24h for 6 wk, not to exceed 80 mg/d, followed by 1.5 mg/kg/d (40 mg/m2/d) qod as single dose every other morning for an additional 6-8 wk
Gradually taper downward q8wk by increments of 0.5 mg/kg/d until dose discontinued. General duration of q.o.d. treatment is 4 to 6 months.| Pediatric Dose | Administer as in adults |
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| Contraindications | Documented hypersensitivity; active bacterial, viral, fungal, or any other infection; once antibacterial or antifungal therapy has been initiated and patient begins to respond, administration of prednisone may begin. |
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| Interactions | Decreases effects of salicylates and toxoids (for immunizations); phenytoin, carbamazepine, barbiturates, and rifampin decrease effects of corticosteroids |
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| Pregnancy |
B - Usually safe but benefits must outweigh the risks.
|
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| Precautions | Severity of adverse effects are related directly to total daily dosage, duration of therapy, and mode of administration (qd or qod); assess benefit-to-risk ratio periodically during treatment; virtually all patients treated as recommended develop increased appetite and cushingoid changes (eg, moon facies, truncal obesity, hirsutism), but these changes disappear after therapy is discontinued or reduced significantly in amount
Prolonged treatment with daily steroids usually interferes with linear growth; increased susceptibility to infections during intensive steroid therapy is present, and steroids may mask usual evidence of such infection
Other possible adverse effects include hypertension, hyperglycemia, hypercalciuria, hypokalemia, nephrolithiasis, osteomalacia, and CNS manifestations (eg, behavioral changes, rarely psychosis); patients should review wide range of toxicity to these agents before initiating therapy |
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|
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Drug Name
| Prednisolone (Delta-Cortef, Pediapred, Prelone) -- Delta1-derivative of the naturally occurring adrenocortical steroids. Suppresses key components of immune system. |
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| Adult Dose | 2 mg/kg/d (60 mg/m2/d) PO divided q8-24h for 6 wks; not to exceed 80 mg/d, followed by 1.5 mg/kg/d (40 mg/m2/d) qod as a single dose every am for an additional 6-8 wk
Gradually taper downward q8wk by 0.5 mg/kg/d increments until dose is discontinued (SEE ABOVE under Prednisone)| Pediatric Dose | Administer as in adults |
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| Contraindications | Documented hypersensitivity; Same as with prednisone |
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| Interactions | Decreases effects of salicylates and toxoids (for immunizations); phenytoin, carbamazepine, barbiturates, and rifampin decrease effects of corticosteroids |
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| Pregnancy |
B - Usually safe but benefits must outweigh the risks.
|
|---|
| Precautions | Severity of adverse effects are related directly to total daily dosage, duration of therapy, and mode of administration (eg, whether administered qd or qod); assess benefit-to-risk ratio periodically during prednisone treatment; virtually all patients treated as recommended develop increased appetite and cushingoid changes (eg, moon facies, truncal obesity, hirsutism), but these changes disappear after therapy is discontinued or reduced significantly in amount
Prolonged treatment with daily steroids usually interferes with linear growth; an increased susceptibility to infections during intensive steroid therapy is present, and, on occasion, steroids may mask usual evidence of such an infection
Other possible adverse effects include hypertension, hyperglycemia, hypercalciuria, hypokalemia, nephrolithiasis, osteomalacia, and CNS manifestations (eg, behavioral changes and, rarely, psychosis); patient should review wide range of toxicity to these agents before initiating therapy |
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|
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Drug Category: Diuretics -- Promotes excretion of water and electrolytes by the kidneys. Used to treat heart failure or hepatic, renal, or pulmonary disease when sodium and water retention has resulted in edema or ascites.Drug Name
| Furosemide (Lasix) -- Used when symptomatic edema occurs. Increases excretion of water by interfering with chloride-binding cotransport system, which in turn inhibits sodium and chloride reabsorption in ascending loop of Henle and distal renal tubule. |
|---|
| Adult Dose | 20-80 mg/d PO/IV/IM; titrate up to 600 mg/d for severe edematous states |
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| Pediatric Dose | 1-2 mg/kg/d PO. IV administration at similar doses may be given but only with caution and one should consider simultaneous administration of salt-poor albumin to protect the vascular space. |
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| Contraindications | Documented hypersensitivity; hepatic coma, anuria, and state of severe electrolyte depletion |
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| Interactions | Metformin decreases furosemide concentrations; furosemide interferes with hypoglycemic effect of antidiabetic agents and antagonizes muscle relaxing effect of tubocurarine; auditory toxicity appears to be increased with coadministration of aminoglycosides and furosemide; hearing loss of varying degrees may occur; anticoagulant activity of warfarin may be enhanced when taken concurrently with this medication; increased plasma lithium levels and toxicity are possible when taken concurrently with this medication |
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| Pregnancy |
C - Safety for use during pregnancy has not been established.
|
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| Precautions | Perform frequent serum electrolyte, CO2, glucose, creatinine, uric acid, calcium, and BUN determinations during first few months of therapy and periodically thereafter |
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Drug Category: Plasma protein -- Used to supplement diuresis in patients with edema. Increases oncotic pressure to urge a fluid shift from interstitial tissues.Drug Name
| Albumin (Albuminar, Buminate) -- Raises oncotic pressure, and thus supplements the diuretic effect of furosemide. |
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| Adult Dose | 25 g (100 mL of 25%) IV; administer with furosemide |
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| Pediatric Dose | 1 g (4 mL of 25%)/kg IV infused over 1-2 h; administer with furosemide |
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| Contraindications | Documented hypersensitivity; anemia; heart failure |
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| Interactions | None reported |
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| Pregnancy |
C - Safety for use during pregnancy has not been established.
|
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| Precautions | Rapid infusion may cause hypotension; caution in renal or hepatic dysfunction due to protein load; may cause hemolysis or acute renal failure when dilute with sterile water; caution with increased intravascular volume |
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FOLLOW-UP
| Section 8 of 10 |
|
Further Inpatient Care:
- Admitting all new-onset patients with NS to the hospital is not necessary. Individually address the decision on whether to admit the child or to investigate and initiate treatment on an outpatient basis.
- Possible medical indications for admission include the following:
- Massive edema with compromise of respiratory excursion due to ascites and/or pleural effusion
- Anuria or severe oliguria
- Significant respiratory infection
- Hospital admission may be necessary because of social reasons.
- Length of hospitalization is usually brief and is followed by careful supervision in an ambulatory setting.
Further Outpatient Care:
- Ambulatory monitoring of the child's condition and response to treatment is a very important aspect of the overall management of NS.
- The best outcomes occur when parents and/or caregivers keep an ongoing log (eg, journal, diary, ledger) of the child's treatment and progress. This routine should be instituted at the beginning of outpatient care. The child's clinical state (eg, presence, absence, degree of edema; BP; illnesses), urine protein results, and medicine should be entered in the log.
- Home monitoring of urine protein and/or albumin is an important aspect of management of NS.
- Train all patients and/or parents to monitor urine proteins at home by the simplest and most inexpensive test available. This can be accomplished with urine dipsticks or turbidity tests (ie, sulfosalicylic acid).
- Instruct the patient with NS and/or parents to test the urine once each morning and to list the results in the log. The record becomes particularly helpful after the urine is free of protein (eg, during maintenance therapy and beyond) because it provides clues about recurrences of the disease before edema occurs, thus allowing early initiation of treatment.
In/Out Patient Meds:
- Administer prednisone or prednisolone according to the schedule discussed earlier (see Medical Care).
- Other medications are uncommon for most patients with NS; however, some patients require long-term administration of antihypertensives and/or diuretics.
Transfer:
- Refer to a pediatric nephrologist when the child's NS is unresponsive to initial glucocorticoid therapy or when the child's disease relapses early in the course of maintenance therapy.
Deterrence/Prevention:
- Although no proven method exists, limiting the occurrence of relapses is desirable. Many relapses occur following respiratory illnesses. Thus, an attempt to limit exposure to subjects with RTIs may be beneficial.
- Exacerbations of NS also appear to occur following routine immunizations. Delaying routine immunizations until the child is in remission and off medications for approximately 6 months is desirable.
Complications:
- The rate of complications observed is related directly to the subtype of glomerular lesion; thus, patients whose NS is secondary to MCNS have few complications, while those with FSGS, MPGN, and MGN experience high rates of complications.
- Acute renal failure has been noted in individuals with all types of NS but is rare in persons with MCNS.
- Tubulointerstitial nephritis is unusual in individuals with MCNS and common in persons with other histologic subtypes.
- In some patients with NS, tubulointerstitial involvement is associated with glucosuria and aminoaciduria. The presence of these urinary findings suggests the possibility that FSGS is the underlying cause of the nephrotic syndrome.
- Hypertension is a frequent consequence of MPGN and FSGS.
- Progression to CRF is uncommon in individuals with MCNS; however, CRF is observed with increasing frequency in persons with MGN, FSGS, and MPGN.
- The massive loss of urinary protein induces a degree of protein malnutrition in all children with NS; children with NS that fails to respond to therapy and are constantly in a negative protein balance are at greater risk of growth failure and other aspects of malnutrition.
- Hyperlipidemia is the direct result of increased hepatic production of lipids and lipoproteins and is related to the degree and duration of the hypoproteinemia. Hyperlipidemia is rarely of major consequence in patients with MCNS; however, in patients whose condition does not respond to therapy or who have one of the other histologic subtypes, chronic hyperlipidemia may become a major health risk of cardiovascular complications. A role for hyperlipidemia in the progression of the renal disease has also been postulated.
- The low serum protein concentrations are not solely due to albuminuria. Even in patients with selective proteinuria, other small molecular weight anionic proteins are lost in the urine, and serum levels are depleted. Some of these proteins (eg, transferrin) are important for transport of other substances (eg, iron), and consequences may ensue. The loss of opsonins appears responsible for the increased propensity for peritonitis. A loss of some of the anticoagulant proteins may be responsible, at least in part, for the increased tendency for thrombosis, either venous or arterial.
- The primary treatment medication, prednisone or prednisolone, has a very broad range of significant adverse effects. The rate of complications observed with these steroids depends on the dosages used, the frequency of dosing, and the duration of such treatment.
- Mild-to-moderate symptoms (eg, behavioral changes, increased appetite) and cushingoidlike signs (eg, moon facies, truncal obesity, hirsutism) are common during the first 6 weeks of daily therapy but usually begin to subside during the maintenance therapy period and, if steroids are discontinued successfully, usually disappear completely within 3-6 months.
- If longer periods of steroid therapy are required, the risk of complications increases. In addition to an exaggeration of those mentioned above, the complications are more serious neurobehavioral changes (including mild psychoses), obesity, growth arrest, osteopenia, osteoporosis, cataracts, hypertension, hyperglycemia, nephrolithiasis, hyperlipidemia, and others. Risk of these complications increases greatly with repeated episodes of daily steroid administration.
- If steroids must be used for long periods of time, limit the periods of daily steroid administration.
- While the administration of alternate morning steroids does not remove the risk of such complications, it does lower the risk.
- All of the other drugs used for the treatment of NS (eg, diuretics; antihypertensive agents; immunosuppressive agents such as cyclophosphamide, chlorambucil, cyclosporine) have significant individual toxicities. Carefully assess their benefit-to-risk ratios.
Prognosis:
- The prognosis for NS in children depends on the renal histologic findings, and, in large measure, the expected outcome determines the optimal plan of follow-up care. The discussion below focuses primarily on the prognosis for children with MCNS, which is the histologic subtype that accounts for 80% of NS in children.
- Patients whose symptoms do not initially respond to prednisone: Complete unresponsiveness to steroids (with persistence of proteinuria and edema) or partial unresponsiveness (persistence of proteinuria following diuresis and resolution of edema) occurs in approximately 8% of children with MCNS.
- On LM examination, the kidneys of such children do not appear different from the kidneys of children whose symptoms initially respond to steroids. However, many of the patients without steroidal response have IgM in the mesangial area, and this may constitute a different subgroup. Some of these children may also have unrecognized FSGS.
- The few patients with MCNS who are still proteinuric after 6 weeks of daily prednisone therapy ultimately respond during the period of alternate-day prednisone therapy or if alternate-day therapy is continued beyond 6 weeks.
- Seriously consider a diagnosis of FSGS in children who remain nephrotic after a standard course of prednisone therapy (eg, 6 wk daily and 6 wk of alternate-day prednisone in prescribed doses). In such patients, consider therapy with an alkylating agent, such as cyclophosphamide, chlorambucil, or nitrogen mustard.
- Initial (or late) nonresponders to prednisone: Complete unresponsiveness to steroids (with persistence of proteinuria and edema) or partial unresponsiveness (persistence of proteinuria following diuresis and resolution of edema) occurs in ~12-25% of children with NS (~8% with MCNS). Failure to respond strongly suggests the possibility of unrecognized FSGS or some other subtype of glomerular lesion. A renal biopsy is indicated in those who do not respond after the full daily course of steroids.
The majority of the steroid nonresponders with MCNS ultimately respond if alternate-day prednisone therapy is continued. For patients who are partial responders and are, therefore, asymptomatic, this is the most desirable therapy. For children who remain nephrotic after a standard course of prednisone therapy (4-8 wk daily therapy), renal biopsy is usually indicated. If MCNS is confirmed, therapy with an alkylating agent (ie, cyclophosphamide, chlorambucil, nitrogen mustard) should be strongly considered. Controlled studies by the ISKDC in such patients demonstrated that oral cyclophosphamide significantly reduces morbidity by shortening the interval between beginning therapy and time of response when compared to continued alternate day prednisone alone. Several retrospective studies have demonstrated potential advantages of oral cyclophosphamide therapy. An alternative proposal is to administer the alkylating agent intravenously.
Nonresponders who do not have MCNS rarely respond to continued daily prednisone alone, and, in a few controlled trials, the results from therapy are mixed. Most of these patients will have additional pathology seen on either light or immunofluorescent microscopy, and many will eventually exhibit the lesion of FSGS. Tune and colleagues have reported success when a highly structured combination of IV pulse steroids and oral cyclophosphamide are used. Other studies, however, do not suggest significant additional benefit to programs where cyclophosphamide (either orally or by intravenous administration) is added to prednisone.
In steroid-resistant nephrotic syndrome (SRNS), whether appearing early or late in the course of NS, cyclosporin (CSA) appears to be of significant therapeutic benefit. Doses of CSA necessary to induce remission vary and are dependent on multiple factors such as histologic subtype of NS, stage of disease (early or late in course), degree of hyperlipidemia (elevated serum lipids reduce the effectiveness of CSA), etc. Relapses are common when CSA is discontinued, with a greater frequency and more aggressive presence being seen in those patients with FSGS. For this reason, the use of CSA should be considered as a long-term treatment program, and a slow tapering of dosage after months of remission seems desirable. Patients who have FSGS and relapse after discontinuation of CSA may not respond to reinitiation of therapy. Various adverse effects of high-dose and/or long-term CSA management must be considered and may limit its use in some children.
Other immunosuppressive agents have found some success in cyclosporine-resistant NS as well as in those responsive to CSA who also experience significant adverse effects. Another calcineurin inhibitor drug, tacrolimus, has also been found effective in some cases. Other investigators have not found tacrolimus to always be interchangeable with CSA. Mycophenolate mofetil (MMF) has more recently been used successfully in multidrug-resistant NS.
Children with FSGS who progress to end-stage renal disease (ESRD) are at risk for recurrent nephrotic syndrome and FSGS following renal transplantation. Overall, the recurrence risk averages approximately 20-30%. Speculation as to cause has led to the identification of circulating factors responsible for the increase in permeability of the glomerular basement membrane. Plasmapheresis and protein immunoabsorption have been used in these resistant patients on the premise that these circulating factors could be removed. Other investigators have used plasmapheresis along with high-dose CSA, and results seem to support this combination. Recently, use of nonsteroidal anti-inflammatory agents such as indomethacin has been proposed as a modifier of GBM permeability.
- Initial responders to prednisone: Approximately 92% of children with MCNS respond to a standard course of steroids. Thereafter, the results vary considerably, and these patients can be arbitrarily divided into 3 groups: those who rarely, if ever, relapse; those who relapse infrequently; and those who relapse frequently.
- Nonrelapsers: Patients in this category have been reported to account for ~30% (range, 20-50%) of children with MCNS who initially respond to steroids. Detailed analyses of various characteristics of NS and the initial therapeutic regimen have not demonstrated conclusive differences between these children and those who relapse. These patients are thus assumed to be cured of their disease.
- Infrequent relapsers: The criteria for inclusion in this group are defined in different ways by various investigators, and this accounts for the marked differences in the incidence, reported to be 20-50% of patients with MCNS. Generally, the initial relapse occurs after a remission of 3 months or more; the frequency of relapse varies from 0-3 per year, and relapses are usually associated with a respiratory illness (infection or allergy); the relapses tend to respond promptly to steroids; the prognosis for permanent remission is good; and the progression to steroid resistance or renal failure or both is negligible.
Treatment of the infrequent relapser involves brief courses of glucocorticoids for exacerbations that do not resolve spontaneously within 7-10 days. A safe policy with children who have mild to moderate proteinuria without edema is merely to observe their urine for this period, but those who suddenly develop massive proteinuria can progress quickly to edema, and, for these children, therapy should be instituted after 2-3 days. Prednisone (2 mg/kg/d or 60 mg/m2/d in divided doses) should be given until the proteinuria remains resolved for 2 days; then prednisone should be given on alternate mornings (1.5 mg/kg/d as a single AM dose) for 1-3 months. At times a tapering program appears appropriate.
- Frequent relapsers: Patients who frequently relapse present a potentially serious problem, not so much from progression of the renal disease as from the side effects of prolonged steroid therapy; even maintenance prednisone (alternate-day or other forms) has side effects. Increasing numbers of children who have been maintained on such steroid regimens for long periods have ultimately exhibited growth failure, cataracts, osteoporosis, hyperglycemia, behavioral disturbances, and gastrointestinal symptoms. These complications are compounded when, in addition to prolonged maintenance therapy, the child must receive multiple courses of daily steroids because of frequent symptomatic recurrences.
In these children, the initial relapse usually occurs within the first 3 months after initial response and frequently within the first few weeks; the relapses may or may not be associated with a respiratory illness, and they may occur at a frequency of more than three per year. Subsequently, there may be no response to steroids, and the possibility of permanent remission is less likely. In the author's experience, mesangial deposits of IgM are more likely to be found in these children than in the other groups. Frequent relapsers have been reported to account for 25-50% of children with MCNS, with a median figure of approximately 35%.
Frequent relapsers, particularly those with clinical signs of steroid toxicity, should be treated in conjunction with a pediatric nephrologist. Alkylating agents (ie, mostly cyclophosphamide but also chlorambucil and nitrogen mustard) are sometimes effective in the management of these children. When cyclophosphamide was used in a controlled trial in children who were frequent relapsers, >50% were in remission (and receiving no therapy) 2-3 years later. Even in children who do not achieve long-term remission, such therapy tends to increase the intervals between exacerbations and to increase sensitivity to prednisone therapy. Unfortunately, as many as 20% of children obtain little or no benefit from this therapy. The potential for long-term consequences from cytotoxic therapy, for example, sterility or teratogenesis, is real and must be weighed against the desirable effects. Levamisole has had a similar efficacy but has never been available in the United States.
A number of reports proclaim the advantages of cyclosporine in this group of children. It may now be the second most common specific agent used in the treatment of NS. The same concern noted earlier with steroid-resistant NS, development of a dependency on continued cyclosporine use, is also troublesome in this group of patients. Mycophenolate mofetil has also been used successfully in this group of patients.
If cytotoxic therapy is ineffective in prolonging remission, or if a child in remission returns to a frequently exacerbating course, the alternatives are limited. Bolus doses of methylprednisolone, given intermittently, have been tried. If the child can be maintained in remission with alternate-day administration of steroids and if the side effects are negligible, then this is the appropriate course. On the other hand, if steroid toxicity becomes a factor, the most appropriate treatment may be supportive, with long-term diuretic therapy. Some of the nonsteroidal anti-inflammatory agents have been promising in treating some resistant cases of MCNS. These drugs may work by significantly reducing the glomerular filtration rate (GFR) through action on renal prostaglandins.
Patient Education:
- Soon after NS is diagnosed, educate the child and the family about the disease, its management, and its expected course. The family should participate in therapeutic decisions and be encouraged to adhere to the medical regimen. As with all chronic illnesses, address the array of other psychosocial issues.
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MISCELLANEOUS
| Section 9 of 10 |
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Medical/Legal Pitfalls:
- Virtually all potential medicolegal problems can be prevented with the following actions:
- Performing a thorough and complete history
- Performing a complete physical examination
- Informing the parents and/or caregivers and child of the physician's working diagnosis
- Paying attention to the troublesome problems of hypertension, edema, and azotemia
- Reassuring the parents and/or caregivers and child at intervals
- Performing only the necessary examinations and discussing the results with family
- Obtaining consultations as needed with an appropriate explanation of the purpose of the consultation
- Developing a plan of follow-up care
- Keeping the family informed about the child's progress and how this progress relates to the diagnosis
Special Concerns:
- Focal segmental glomerulosclerosis (FSGS): This discussion primarily considers the variety of FSGS that manifests as nephrotic syndrome and, untreated or managed conservatively, is likely to progress to ESRD. FSGS that appears as a consequence of other defined disorders (eg, reflux nephropathy, sickle cell disease, diabetes mellitus, other hyperfiltration syndromes, HIV infections) will not be discussed. In this context, the histologic variant FSGS is often clinically indistinguishable from MCNS and is generally first suspected when a child is partially or completely unresponsive to standard steroid therapy. Although some researchers believe that FSGS represents a progression from MCNS, most believe it is a separate process and may be a manifestation of different types of primary or secondary renal diseases. The frequent detection of deposits by electron microscopy and the finding of mesangial immunofluorescence (IgM, IgG, and occasionally C3), even early in the
course of the process, suggests a pathogenesis different from that of MCNS. FSGS accounts for ~8-12% of all instances of primary NS, and, as noted earlier, its frequency appears to be increasing.
Approximately 85% of children with FSGS are either partially or completely resistant to steroid treatment. Even those patients who respond initially tend subsequently to become either nonresponders or frequent relapsers. For this reason, the reader should refer to the discussion noted above (ie, relative to treatment of steroid-resistant and frequently-relapsing NS) since it would seem redundant if discussed here. Overall, the prognosis for patients with this lesion is generally poor. Approximately 25% of patients progress to ESRD within 2-5 years, and many of the others, despite current therapy, continue to have significant proteinuria or reduced renal function. Even with newer agents, it appears that only 25-40% of patients achieve a remission with normal function.
There is no proven effective therapy for FSGS. Uncontrolled studies of cyclophosphamide and chlorambucil have reported them to be effective, but the results of the controlled ISKDC study suggests no beneficial response from cyclophosphamide. Combined therapy with bolus methylprednisolone, daily prednisone, and alkylating agents has been suggested. Results from such use have given conflicting reports, some in which the results appeared quite encouraging but others in which significant success was not observed. Cyclosporine A and tacrolimus have also been used by a number of investigators, and the results in most reports appear encouraging, while a few have been disappointing. Currently, more success appears to have been achieved with this program than with any other single program. But, with cyclosporine, dependency has been noted and recurrences are common when the drug is discontinued. Results from other immunosuppressive agents such as MMF appear encouraging, but most reports are still anecdotal.
Children with FSGS that progresses to ESRD and who receive transplants have about a 25-40% likelihood of recurrence in the transplanted kidney.
- Membranoproliferative glomerulonephritis (MPGN): MPGN, also known as mesangiocapillary or hypocomplementemic glomerulonephritis, accounts for about 3-8% of children who present with primary NS. MPGN occurs more frequently than this figure suggests, however, because it can also manifest as acute nephritic syndrome, rapidly progressive glomerulonephritis, recurrent macroscopic hematuria, or persistent proteinuria or hematuria discovered on routine examination. In addition, some patients never present a nephrotic picture even though they progress to ESRD.
The cause of MPGN is unknown, but it has occasionally been associated with shunt nephritis (secondary to staphylococcal infections), poststreptococcal glomerulonephritis, polyarteritis, and the syndrome of partial lipodystrophy. In addition, a familial occurrence has sometimes been noted.
The complement system appears to be involved, though the precise mechanisms are not completely understood. Serum concentrations of total hemolytic complement are decreased in >50% of patients, but disorders of the system, as manifested by low serum concentrations of C3, have been seen at some time in >80%. Sera from patients with MPGN and hypocomplementemia frequently contain an anticomplement substance, C3 nephritic factor (C3 NeF). Although the origin and nature of this factor are uncertain, it appears to activate the complement system by cleaving C3 in a manner similar, but not identical, to that of the alternate pathway. There is some evidence that the lower C3 concentrations are the result of decreased synthesis. Serum immune complexes have been detected in a high percentage of patients.
The characteristics vary widely, but in patients who present with NS, distinguishing MPGN from MCNS is usually easy. MPGN with NS has not been reported to occur before age 5 years and is more common during adolescence. The occurrence ratio of females to males is almost 2:1. Most patients present with a nephritic-nephrotic picture. Significant hematuria is almost invariable, along with severe proteinuria. Hypertension and azotemia occur in >50% of patients, and serum concentrations of C3 are initially low in 60-75%.
Biopsy examination indicates that 2 and, perhaps, 3 distinct histopathologic types of disease exist; the differences involve the nature and location of deposits within the kidney. Although differences in pathogenesis may account for these two types, this is uncertain.
A high percentage of untreated patients with all 3 of the lesions appear to progress slowly but relentlessly to ESRD. Actuarial survival curves show ~50% mortality by 9-10 years after onset. Although almost all patients with this histologic entity appear to deteriorate over time, the renal function appears to decline at a more rapid rate in the patient whose initial presentation is NS. Because of this long natural history and because clinical remission may occur while low concentrations of C3 and histologic progression continue, determining whether short-term therapy programs are effective is difficult. Despite this limitation, good evidence appears to exist that long-term, alternate-day prednisone has a beneficial effect on renal mortality. The responses to management schemes appear different, with Type 1 and III having better long-term responses.
- Membranous glomerulonephritis (MGN): MGN is a relatively uncommon lesion in children, accounting for ~1% of NS. For that reason, discussion here will be limited. MGN is characterized by generalized thickening of the basement membrane of the glomerular vessels without cellular proliferation. Immunofluorescent and electron microscope studies have revealed evidence of immune complexes that are first seen on the epithelial portions of the basement membrane and are later found within the membrane itself. That MGN be recognized is important because it may be caused by a number of potentially treatable systemic diseases. Syphilis, toxoplasmosis, hepatitis A and B, malaria, and, in adults, carcinoma have all been reported in association with membranous nephropathy, as has gold therapy; the renal lesion usually resolves if the underlying systemic cause can be eradicated. Some children, however, develop MGN without an identifiable cause. The disease is often seen with renal vein thrombosis, but most
investigators
believe MGN
to be the cause of the thrombosis, rather than the reverse.
The adolescent is more commonly involved during childhood. Most will present with proteinuria that can be either minimal (ie, an asymptomatic patient) or massive (ie, presenting as NS). Hematuria is often present (perhaps in 90% of patients), and macroscopic hematuria is present in 10% of patients. Hypertension and azotemia are rarely present at onset but may develop with time. Tubular dysfunction can be seen.
Treatment data in children are anecdotal since there are no controlled trials. Thus, data on management comes from several clinical trials in adults as well as some long-term, anecdotal reports. These studies are well summarized in the 1999, evidenced-based report and will not be repeated here. Based on the studies reviewed, chlorambucil plus oral steroids represent the best choice for initial therapy. Cyclosporine has been found effective in inducing remission of NS, but suggestive evidence exists that the nephropathy may still be progressive despite clinical improvement. Eradicating the cause, when it can be found, is most important, and symptomatic treatment is beneficial. Spontaneous resolution of MGN has been reported and appears more commonly than in adults.
The course in children with idiopathic MGN is variable, but children who are younger than age 7 years at onset tend to have a better prognosis than those who acquire the disease later. The frequency or progression to eventual renal failure has been reported in adults to vary from 10-60%, and persistence of NS appears to be a poor prognostic sign. Renal transplantation is a viable alternative in such patients.
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