eMedicine Specialties > Pediatrics: General Medicine > Nephrology

Nephrotic Syndrome

Jerome C Lane, MD, Assistant Professor of Pediatrics, Northwestern University Medical School; Attending Physician, Department of Pediatrics, Division of Kidney Diseases, Children's Memorial Hospital, Chicago

Updated: Jun 12, 2009

Introduction

Background

Nephrotic syndrome (NS), also known as nephrosis, is defined by the presence of nephrotic-range proteinuria, edema, hyperlipidemia, and hypoalbuminemia. Nephrotic-range proteinuria in adults is characterized by protein excretion of 3.5 g or more per day. However, because of the great range of body sizes in children, the pediatric definition of nephrotic-range proteinuria is more cumbersome. Nephrotic-range proteinuria in children is protein excretion of more than 40 mg/m²/h. Because 24-hour urine collections are potentially unreliable and burdensome, especially in young children, many pediatric nephrologists instead rely on a single, first-morning urine sample to quantify protein excretion by the ratio of protein to creatinine.¹ A urine protein/creatinine value of more than 2-3 mg/mg indicates nephrotic range proteinuria and correlates with results from 24-hour urine collection.    
 
Nephrotic syndrome is a constellation of clinical findings that is the result of massive renal losses of protein. Thus, nephrotic syndrome is not a disease itself, but the manifestation of many different glomerular diseases. These diseases might be acute and transient, such as postinfectious glomerulonephritis, or chronic and progressive, such as focal segmental glomerulosclerosis (FSGS). Still other diseases might be relapsing and remitting, such as minimal change nephrotic syndrome (MCNS).

The glomerular diseases that cause nephrotic syndrome generally can be divided into primary and secondary etiologies. Primary nephrotic syndrome (PNS), also known as idiopathic nephrotic syndrome (INS), is associated with glomerular diseases intrinsic to the kidney and not related to systemic causes. The subcategories of INS are based on histological descriptions, but clinical-pathological correlations have been made. A wide variety of glomerular lesions can be seen in INS. These include MCNS, focal segmental glomerulosclerosis (FSGS), membranous nephropathy (MN), membranoproliferative glomerulonephritis (MPGN), diffuse mesangial proliferation and others.

By definition, secondary nephrotic syndrome refers to an etiology extrinsic to the kidney. Secondary causes of nephrotic syndrome include Henoch-Schönlein purpura (HSP), systemic lupus erythematosus, diabetes mellitus, syphilis, human immunodeficiency virus (HIV), hepatitis B and C, malignancy, vasculitis, and drug exposure (heroin, mercury, and others), among many other etiologies (see Causes).

Nephrotic syndrome may also be caused by genetic abnormalities. Defects in the nephrin gene (NPHS1) and the Wilms tumor suppressor gene (WT1) have been found in patients with congenital and infantile nephrotic syndrome (ie, nephrotic syndrome presenting before age 1 y). Mutations in the podocin gene (NPHS2) are associated with a familial, autosomal-recessive form of FSGS. Mutations in the α-actinin-4 gene (ACTN4) and the gene TRPC6 are associated with autosomal-dominant forms of familial FSGS. Additionally, other genetic syndromes have been associated with nephrotic syndrome, such as Nail-Patella syndrome. (See Pathophysiology and Causes) 

Infantile nephrotic syndrome is divided into steroid-sensitive (SSNS) and steroid-resistant nephrotic syndrome (SRNS) because response to steroids has a high correlation with histological subtype and prognosis. The landmark study of nephrotic syndrome in children, the International Study of Kidney Disease in Children (ISKDC), found that the vast majority of preadolescent children with INS had MCNS on kidney biopsy.^2,3 Whereas 90% of children with MCNS responded to corticosteroid treatment with remission of their nephrotic syndrome, only 20% of children with FSGS responded to steroids.

This article focuses on INS, primarily SSNS (which primarily consists of MCNS). The treatment and prognosis of SRNS (primarily FSGS in children) is briefly discussed. The discussion of congenital and secondary nephrotic syndrome is beyond the scope of this article.

Pathophysiology

Proteinuria and hypoalbuminemia

The hallmark of INS is massive proteinuria, leading to decreased circulating albumin levels. The initiating event that produces proteinuria remains unknown. INS is believed to have an immune pathogenesis. Studies have shown abnormal regulation of T-cell subsets and expression of a circulating glomerular permeability factor. Evidence of the immune-mediated nature of INS is demonstrated by the fact that immunosuppressive agents, such as corticosteroids and alkylating agents, can result in remission of nephrotic syndrome. Furthermore, nephrotic syndrome has been known to remit during infection with the measles virus, which suppresses cell-mediated immunity. However, the precise nature of the immune pathogenic process has yet to be defined.

A circulating factor may play a role in the development of proteinuria in INS. This can be demonstrated by the rapid development of proteinuria in recurrence of nephrotic syndrome after kidney transplantation, the improvement in nephrotic syndrome in such patients after treatment with plasmapheresis, and the experimental induction of proteinuria in animals by plasma from patients with INS. However, the nature of this circulating factor is not known. Various cytokines and molecules have been implicated, including interleukin (IL)-2, IL-2 receptor, IL-4, IL-12, IL-13, IL-15, IL-18, interferon-γ, tumor growth factor (TGF)-β, vascular permeability factor, nuclear factor (NF)-κB, and tumor necrosis factor (TNF)-α.⁴

The association of allergic responses with nephrotic syndrome also illustrates the role of the immune system in INS. Nephrotic syndrome has been reported to occur after allergic reactions to bee stings, fungi, poison ivy, ragweed, house dust, jellyfish stings and cat fur. Food allergy might play a role in relapses of INS; a reduced-antigenic diet was associated with improved proteinuria and complete remission in one study.⁵ Additionally, INS is 3-4 times more likely in children with human leukocyte antigen (HLA)-DR7. Steroid sensitive INS has also been associated with HLA-B8 and the DQB1 gene of HAL-DQW2. A greater incidence of INS is also observed in children with atopy and HLA-B12.⁶

Perhaps the most exciting development in recent years in understanding the pathophysiology of nephrotic syndrome has occurred in the area of podocyte biology. The glomerular filtration barrier consists of the fenestrated capillary endothelium, the extracellular basement membrane, and the intercalated podocyte foot processes, connected by 35-45 nm slit diaphragms. Nephrotic syndrome is associated with the biopsy finding of fusion (effacement) of podocyte foot processes. This effacement of the podocytes long was thought to be a secondary phenomenon of nephrotic syndrome. Recent thinking, however, has shifted towards the podocyte as playing a primary role in the development of proteinuria. The understanding of the mechanism of the glomerular filtration barrier has greatly expanded with the discoveries of nephrin, podocin, α-actinin-4, CD2AP, and other proteins intimately associated with the podocyte and the slit-diaphragm.  

Nephrin is a transmembrane protein localized to the slit diaphragm and is encoded by the NPHS1 gene on chromosome 19. Mutations in the NPHS1 gene are responsible for congenital nephrotic syndrome of the Finnish type. Podocin is another protein component of the slit diaphragm and is encoded by the NPHS2 gene on chromosome 1. Mutations in the NPHS2 gene are associated with autosomal recessive, steroid-resistant INS with FSGS on biopsy findings. Mutations in α-actinin-4, encoded by the gene ACTN4 on chromosome 19 and TRPC6 on chromosome 11, are associated with autosomal dominant forms of FSGS.⁶

Other genetic forms of nephrotic syndrome continue to shed light on the pathogenesis of INS. Mutations in the developmental regulatory gene WT1 are associated with Denys-Drash syndrome and Frasier syndrome, forms of congenital nephrotic syndrome associated with male pseudohermaphroditism, Wilms tumor (Denys-Drash syndrome), and gonadoblastoma (Frasier syndrome). Nail-patella syndrome, a disorder characterized by skeletal and nail dysplasia as well as nephrotic syndrome, is caused by mutations in the LMX1B gene, which regulates expression of type IV collagen and the podocyte proteins nephrin, podocin, and CD2AP.⁷

The role of alterations in the slit diaphragm in MCNS has not been elucidated. Podocin appears to be expressed normally in MCNS but decreased in FSGS. Mutations in nephrin and podocin do not at this time appear to play a role in steroid-sensitive nephrotic syndrome. However, acquired alterations in slit diaphragm architecture might play a role in INS apart from actual mutations in the genes encoding podocyte proteins. Various authors have reported changes in expression and distribution of nephrin in MCNS.

Coward et al demonstrated that nephrotic plasma induces translocation of the slit diaphragm proteins nephrin, podocin, and CD2AP away from the plasma membrane into the cytoplasm of the podocyte.⁸ These authors also demonstrated the normal plasma might contain factors that maintain the integrity of slit diaphragm architecture and that the lack of certain factors (rather than the presence of an abnormal circulating factor) might be responsible for alterations in the podocyte architecture and development of INS.

Apart from the podocyte and slit diaphragm, alterations in the glomerular basement membrane also likely play a role in the proteinuria of nephrotic syndrome. In INS, 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. In its normal state, the glomerular basement membrane is negatively charged because of the presence of various polyanions along this surface, such as heparan sulfate, chondroitin sulfate, and sialic acid. This negative charge acts as a deterrent to filtration of negatively charged proteins, such as albumin. Experimental models in which the negative charges are removed from the basement membrane show an increase in albuminuria. Children with MCNS have been reported to have decreased anionic charges in the glomerular basement membrane.⁷

Edema

The classical explanation for edema formation is a decrease in plasma oncotic pressure, as a consequence of low serum albumin levels, causing an extravasation of plasma water into the interstitial space. The resulting contraction in plasma volume leads to stimulation of the renin-angiotensin-aldosterone axis and antidiuretic hormone. The resultant retention of sodium and water by the renal tubules contributes to the extension and maintenance of edema.

While the classical model of edema (also known as the "underfill hypothesis") seems logical, certain clinical and experimental observations 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 (such as albumin infusion or ACE inhibitor 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.⁹

Another model of edema formation is known as the "overfill hypothesis." In this model, a primary defect in renal sodium handling is postulated. A primary increase in renal sodium reabsorption leads to net salt and water retention and subsequent hypertension. ANP might play a role is this mechanism; studies have shown an impaired response to ANP in nephrotic syndrome. This ANP resistance, in part, might be caused by overactive efferent sympathetic nervous activity, as well as enhanced tubular breakdown of cyclic guanosine monophosphate. Other mechanisms that contribute to a primary increase in renal sodium retention include overactivity of the Na⁺ -K⁺ -ATPase and renal epithelial sodium channel (RENaC) in the cortical collecting duct and shift of the Na⁺/H⁺ exchanger NHE3 from the inactive to active pools in the proximal tubule.⁹

A more recent theory of edema formation states that massive proteinuria leads to tubulointerstitial inflammation and release of local vasoconstrictors and inhibition of vasodilation. This leads to a reduction in single-nephron glomerular filtration rate and sodium and water retention.⁹

Thus, the precise cause of the edema and its persistence is uncertain. A complex interplay of various physiologic factors (such as 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.

Hyperlipidemia

INS is accompanied by disordered lipid metabolism. Apolipoprotein (apo)-B containing lipoproteins are elevated, including very-low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), and low-density lipoproteins (LDL) and lipoprotein(a), with resultant increases in total cholesterol and LDL-cholesterol. High-density lipoprotein (HDL)-cholesterol is normal or low. Elevations in triglycerides occur with severe hypoalbuminemia. The traditional explanation for hyperlipidemia in INS was the increased synthesis of lipoproteins that accompany increased hepatic albumin synthesis due to hypoalbuminemia. However, serum cholesterol levels have been shown to be independent of albumin synthesis rates.

Decreased plasma oncotic pressure may play a role in increased hepatic lipoprotein synthesis, as demonstrated by the reduction of hyperlipidemia in patients with INS receiving either albumin or dextran infusions. Also contributing to the dyslipidemia of INS are abnormalities in regulatory enzymes, such as lecithin-cholesterol acyltransferase, lipoprotein lipase and cholesterol ester transfer protein.^9,10

Thrombosis

Patients with nephrotic syndrome are at increased risk for thrombosis (see Complications). Various factors play a role in the increased incidence of thrombosis. Abnormalities described in INS include increased platelet activation and aggregation; elevation in factors V, VII, VIII, and XIII and fibrinogen; decreased antithrombin III, proteins C and S, and factors XI and XII; and increased activities of tissue plasminogen activator and plasminogen activator inhibitor-1. These abnormalities in hemostatic factors, combined with potential hypovolemia, immobility, and increased incidence of infection, lead to a hypercoagulable state in INS.^11,6

Infection

Patients with INS are at increased risk of infection, especially with Streptococcus pneumoniae, but other infections are common as well (see Complications). INS is associated with low immunoglobulin (Ig)G levels, which do not appear to be the result of urinary losses. Instead, low IgG levels seem to be the result of impaired synthesis, again pointing to a primary disorder in lymphocyte regulation in INS. Additionally, increased urinary losses of factor B are noted, a cofactor of C3b in the alternative pathway of complement, which plays an important role in the opsonization of encapsulated organisms such as S pneumoniae. Impaired T-cell function may also be present in INS, which contributes to the susceptibility to infection. Finally, the medications used to treat INS, such as corticosteroids and alkylating agents, further suppress the immune system and increase the risk of infection.⁶

Frequency

United States

The reported annual incidence rate is 2-7 cases per 100,000 children younger than 16 years. The cumulative prevalence rate is approximately 16 cases per 100,000 individuals.¹² The ISKDC found that 76.6% of children with INS had MCNS on kidney biopsy findings, with 7% of cases associated with FSGS on biopsy findings.^2,13 Some studies have suggested a change in the histology of INS over the past few decades, although the overall incidence of INS has remained stable. The frequency of FSGS associated with INS appears to be increasing. A review of the literature suggested a 2-fold increase in the incidence of FSGS in recent decades.¹⁴ However, another study found no evidence of an increasing incidence of FSGS.¹⁵

Mortality/Morbidity

Since the introduction of corticosteroids, the overall mortality of INS has decreased dramatically from over 50% to approximately 2-5%. Despite the improvement in survival, INS is usually a chronic, relapsing disease and most patients experience some degree of morbidity, including the following:

• Hospitalization, in some instances
• Frequent monitoring both by parents and by physician
• Administration of medications associated with significant adverse events
• A high rate of recurrence (relapses in >60% of patients)
• The potential for progression to chronic kidney failure and end-stage kidney failure (ESKD)

Additionally, INS is associated with an increased risk of multiple complications, including edema, infection, thrombosis, hyperlipidemia, acute kidney failure, and possible increased risk of cardiovascular disease.

See Complications and Prognosis for a more detailed discussion of the above.

Race

Black and Hispanic children appear to have an increased risk of steroid-resistant nephrotic syndrome and FSGS.^15,16 An increased incidence of INS is reported in Asian children, (6 times the rate seen in European children). An increased incidence of INS is also seen in Indian, Japanese, and Southwest Asian children. Primary, SSNS is rare in Africa, where nephrotic syndrome is more likely to be secondary or steroid-resistant. These variations in ethnic and geographic distribution of INS underscore the genetic and environmental influences in the development of PNS.⁶

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 65% of individuals with MPGN are female.

Age

Of patients with MCNS, 70% are younger than 5 years. Only 20-30% of adolescents with INS have MCNS on biopsy findings. In the first year of life, genetic forms of INS and secondary nephrotic syndrome due to congenital infection predominate.¹²

Clinical

History

Edema is the presenting symptom in about 95% of children with nephrotic syndrome (NS). The edema in the early phase is intermittent and insidious, and its presence may not be appreciated. A common story is for a child present to a primary care practitioner repeatedly for periorbital edema, which is ascribed to "allergies" until the edema progresses. It usually appears first in areas of low tissue resistance (such as the periorbital, scrotal, and labial regions) and can rapidly progress or slowly progress. Ultimately, it becomes generalized and can be massive (anasarca). The edema is pitting and typically depends on nature, is more noticeable in the face in the morning, and is predominately in lower extremities later in the day.

A history of a respiratory tract infection immediately preceding the onset of nephrotic syndrome is frequent, but the relevance to causation is uncertain. Upper respiratory infections, otitis media, and other infections are often associated with relapses of idiopathic nephrotic syndrome (INS) as well. A history of allergy is present in approximately 30% of children. A hypersensitivity event, such as a reaction to bee sting or poison ivy, has been reported to precede the onset of INS.⁶

Children with nephrotic syndrome occasionally present with gross hematuria. The frequency of macrohematuria depends on the histological subtype of nephrotic syndrome. It is more common in those patients with mesangiocapillary glomerulonephritis (MPGN) than in other causes, but its frequency in minimal change nephrotic syndrome (MCNS) has been reported to be as high as 3-4% of cases. Statistically, a higher percentage of patients with focal segmental glomerulosclerosis (FSGS) have microhematuria than those with MCNS, but this is not helpful in differentiating between types of nephrotic syndrome in the individual patient. Given the risk of thrombosis in INS, renal vein thrombosis must be considered in patients with significant hematuria. Rarely, a child can present with other symptoms secondary to thrombosis, such as seizure caused by cerebral thrombosis.

A child might be brought to medical attention for symptoms of infection, such as fever, lethargy, irritability, or abdominal pain due to sepsis or peritonitis. Peritonitis can be mistaken for appendicitis or other cause of acute abdomen unless the child's proteinuria and edema are appreciated.

Anorexia, irritability, fatigue, abdominal discomfort, and diarrhea are common. GI distress can be caused by ascites, bowel wall edema, or both. Respiratory distress can occur, due to either massive ascites and thoracic compression or frank pulmonary edema, effusions, or both.
 
Except in rare cases of familial INS, no significant family history of kidney disease or INS is usually noted. Children are typically healthy prior to onset of INS and, except for history of allergy and atopy noted above, do not usually have a significant past medical history related to INS.

Physical

The most common clinical finding is edema. The edema is pitting and is typically found in the lower extremities, face and periorbital regions, scrotum and labia, and abdomen (ascites). In those children with marked ascites, mechanical restriction to breathing may be present, and the child may manifest compensatory tachypnea. Pulmonary edema and effusions can also cause respiratory distress.

Hypertension can be present and is more common in children with FSGS and MPGN rather than MCNS. Physical findings can also be present due to complications of INS. Abdominal tenderness might indicate peritonitis. Hypotension and signs of shock can be present in children presenting with sepsis. Thrombosis can cause various findings, including tachypnea and respiratory distress (pulmonary thrombosis/embolism), hematuria (renal vein thrombosis), and seizure (cerebral thrombosis).

Causes

• INS
  • MCNS
  • FSGS
  • MPGN
  • Membranous glomerulonephritis (MGN)
  • IgA nephropathy
  • Idiopathic crescentic glomerulonephritis
• Genetic nephrotic syndrome/congenital nephrotic syndrome
  • Finnish-type congenital nephrotic syndrome (NPHS1, nephrin)
  • Denys-Drash syndrome (WT1)
  • Frasier syndrome (WT1)
  • Diffuse mesangial sclerosis (WT1)
  • Autosomal recessive, familial FSGS (NPHS2, podocin)
  • Autosomal dominant, familial FSGS (ACTN4, α-actinin-4; TRPC6)
  • Nail-patella syndrome (LMX1B)
  • Galloway-Mowat syndrome
  • Oculocerebrorenal (Lowe) syndrome
• Secondary nephrotic syndrome
  • Infections
    • Congenital syphilis, toxoplasmosis, cytomegalovirus, rubella
    • Hepatitis B and C
    • HIV/acquired immunodeficiency syndrome (AIDS)
    • Malaria
  • Drugs
    • Penicillamine
    • Gold
    • Nonsteroidal anti-inflammatory drugs (NSAIDs)
    • Interferon
    • Mercury
    • Heroin
    • Pamidronate
    • Lithium
  • Systemic disease
    • Systemic lupus erythematosus
    • Malignancy - Lymphoma, leukemia
    • Vasculitis -Wegener granulomatosis, Churg-Strauss syndrome, polyarteritis nodosa, microscopic polyangiitis, Henoch-Schönlein purpura (HSP)
    • Immune-complex–mediated - Poststreptococcal glomerulonephritis

Differential Diagnoses

Other Problems to Be Considered

See Causes.

Workup

Laboratory Studies

The first step in evaluating the child with edema is to establish whether nephrotic syndrome (NS) is present because hypoalbuminemia can occur in the absence of proteinuria (such as from protein-losing enteropathy), and edema can occur in the absence of hypoalbuminemia (as can occur in angioedema, capillary leak, venous insufficiency, congestive heart failure, and other causes). In order to establish the presence of nephrotic syndrome, laboratory tests should confirm (1) nephrotic-range proteinuria, (2) hypoalbuminemia, and (3) hyperlipidemia. Therefore, initial laboratory testing should include the following:
 

• Urinalysis
  • Microscopic hematuria is present in 20% of cases and cannot be used to distinguish between minimal change nephrotic syndrome (MCNS) and other forms of glomerular disease.
  • RBC casts, if present, are suggestive of acute glomerulonephritis, such as postinfectious nephritis, or a nephritic presentation of chronic glomerulonephritis, such as membranoproliferative glomerulonephritis (MPGN).
  • Granular casts may be present and are non-specific to etiology
  • The presence of macroscopic (gross) hematuria is unusual in MCNS and suggests another cause, such as MPGN, or a complication of idiopathic nephrotic syndrome (INS), such as renal vein thrombosis.
• Urine protein quantification by first-morning urine protein/creatinine or 24-hour urine protein
  • First morning urine protein/creatinine is more easily obtained than 24-hour urine studies, possibly more reliable, and excludes orthostatic proteinuria.
  • Urine protein/creatinine of more than 2-3 mg/mg is consistent with nephrotic-range proteinuria.
  • A 24-hour urine protein level of more than 40 mg/m²/h also defines nephrotic-range proteinuria.
• Serum albumin
  • Serum albumin levels in nephrotic syndrome are generally less than 2.5 g/dL.
  • Values as low as 0.5 g/dL are not uncommon.
• Lipid panel
  • Elevated total cholesterol, low-density lipoprotein (LDL)-cholesterol
  • Elevated triglycerides with severe hypoalbuminemia
  • High-density lipoprotein (HDL)-cholesterol (normal or low)

Once the presence of nephrotic syndrome has been established, the next task is to determine whether the nephrotic syndrome is primary (idiopathic) or secondary to a systemic disorder and, if INS has been determined, whether signs of chronic kidney disease, kidney insufficiency, or other signs exclude the possibility of MCNS. Therefore, in addition to the above tests, the following should be included in the workup:

• Serum electrolytes, BUN and creatinine, calcium, phosphorus, and ionized calcium levels
  • The patient with INS, even MCNS, can present with acute kidney failure due to intravascular volume depletion and/or bilateral renal vein thrombosis.
  • In the absence of the above, elevated BUN and creatinine levels and signs of chronic kidney failure (such as poor growth, anemia, acidosis, hyperkalemia, hyperphosphatemia, elevated parathyroid hormone) suggest a chronic glomerular disease other than MCNS, such as focal segmental glomerulosclerosis (FSGS), membranous nephropathy (MN), MPGN, or immunoglobulin (Ig)A nephropathy.
  • Serum Na levels are low due to hyperlipidemia (pseudohyponatremia), as well as dilution due to water retention.
  • Total calcium levels are low due to hypoalbuminemia, but ionized calcium levels are normal.
• CBC count
  • Increased hemoglobin and hematocrit indicate hemoconcentration and intravascular volume depletion.
  • Platelet count is often increased.
• Testing for HIV, hepatitis B and C
  • To rule out these important secondary causes of nephrotic syndrome, screening for these viruses should be performed in all patients presenting with nephrotic syndrome.
  • Consider checking liver enzymes, such as alanine aminotransferase (ALT) and aspartate aminotransferase (AST), when screening for liver disease.
• C3, C4: Low complement levels are found in postinfectious nephritis, MPGN, and lupus nephritis.
• Antinuclear antibody (ANA), anti–double-stranded DNA antibody (in selected patients): These are used to screen for collagen-vascular disease in patients with systemic symptoms (fever, rash, weight loss, joint pain) or any patient with nephrotic syndrome presenting in later school-age or adolescent years when lupus has a higher incidence.

Patients with INS lose vitamin D–binding protein, which can result in low vitamin D levels, and thyroid binding globulin, which can result in low thyroid hormone levels. Consideration should be given, especially in the child with frequently relapsing or steroid-resistant nephrotic syndrome, to testing for 25-OH-vitamin D; 1,25-di(OH)-vitamin D; free T4; and thyroid-stimulating hormone (TSH).

Age plays an important role in the diagnostic evaluation of nephrotic syndrome. Children presenting with nephrotic syndrome younger than 1 year of age should be evaluated for congenital/infantile nephrotic syndrome. In addition to the above tests, infants should have the following tests:

• Congenital infection (syphilis, rubella, toxoplasmosis, cytomegalovirus, HIV)
• Kidney biopsy (see Procedures)
• Genetic tests for NPHS1 and WT1 mutation as guided by biopsy findings and clinical presentation -WT1 testing for patients with pseudohermaphroditism, Wilms tumor, gonadoblastoma, and diffuse mesangial sclerosis on biopsy; NPHS1 testing for biopsy and clinical findings consistent with Finnish-type nephrotic syndrome

In patients initially or subsequently unresponsive to steroid treatment, in addition to kidney biopsy (see Procedures), consideration should be given to testing for mutations in podocin (NPHS2). When a family history of FSGS is present, consideration should be given to testing for mutations in ACTN4 and TRPC6.

Imaging Studies

Kidney ultrasonography might help to distinguish between MCNS and other chronic kidney disease, but findings are usually nonspecific. In all cases of nephrotic syndrome, the kidneys are usually enlarged due to tissue edema. Increased echogenicity is usually indicative of chronic kidney disease other than MCNS, in which echogenicity is usually normal. A finding of small kidneys indicates chronic kidney disease other than MCNS and is usually accompanied by elevated serum creatinine levels.

Chest radiography is indicated in the child with respiratory symptoms. Pleural effusions are common, although pulmonary edema is rare. Chest radiography also should be considered prior to steroid therapy to rule out tuberculosis (TB) infection, especially in the child with positive or previously positive Mantoux test or prior treatment for TB.

Other Tests

Mantoux test (purified protein derivative [PPD]) should be performed prior to steroid treatment to rule out TB infection. Mantoux testing can be performed concurrent to starting steroid treatment, as treatment with steroids for 48 hours prior to reading the PPD does not mask a positive result and the risk associated with 2 days of steroids are minimal (if tests results are positive, steroids should be immediately stopped). In children with positive PPD, previously positive PPD, or prior treatment for TB, chest radiography should be performed.

Procedures

A kidney biopsy is not indicated for first presentation of PNS in the child between 1-8 years of age, unless history, physical findings, or laboratory results indicate the possibility of secondary NS or primary nephrotic syndrome (PNS) other than MCNS. Kidney biopsy is indicated in patients younger than 1 year, when genetic forms of congenital nephrotic syndrome are more common, and in patients older than 8 years, when chronic glomerular diseases such as FSGS have a higher incidence. In select preadolescent patients older than 8 years, empirical steroid treatment can be considered prior to kidney biopsy, but this should occur only under the care of a pediatric nephrologist experienced with nephrotic syndrome.

Kidney biopsy should also be performed when history, examination, or laboratory findings indicate secondary nephrotic syndrome or kidney disease other than MCNS. Thus, a kidney biopsy is indicated if patients have symptoms of systemic disease (eg, fever, rash, joint pain), laboratory findings indicative of secondary nephrotic syndrome (eg, positive ANA findings, positive anti–double-stranded DNA antibody findings, low complement levels), elevated creatinine levels unresponsive to correction of intravascular volume depletion, and/or a relevant family history of kidney disease. Finally, in patients who are initially or subsequently unresponsive to steroid treatment, kidney biopsy should be performed because steroid unresponsiveness has a high correlation with prognostically unfavorable histology findings such as FSGS or MGN.

Histologic Findings

If a kidney biopsy is performed as indicated above (see Procedures), various histological findings can be present, depending on the etiology of the nephrotic syndrome. A detailed discussion of the various types of INS and histological findings is beyond the scope of this article. Briefly, the most common histological types of INS are as follows:

• MCNS indicates glomerular morphology that on light microscopic (LM) examination is little different from normal. Minimal mesangial hypercellularity may be present. Immunofluorescent microscopy (IF) usually reveals no presence of immune deposits. Occasionally, mesangial IgM deposition may be seen on IF. Some consider the presence of IgM to be separate entity (IgM nephropathy), whereas others consider this to be a variant of MCNS. The presence of IgM may indicate a more difficult course of nephrotic syndrome, with frequent relapses, steroid dependence, or steroid resistance, although the overall prognosis is still usually favorable. The only significant change seen on electron microscopy (EM) is flattening and fusion of the podocyte foot processes (effacement).⁶
• Diffuse mesangial proliferation (DMP) refers to increased mesangial matrix and increased mesangial hypercellularity. IF findings are negative and EM reveals the typical foot process effacement of MCNS. Patients with DMP have an increased incidence of steroid-resistance, although whether these patients are at increased risk for progression to kidney failure is unclear.⁶
• FSGS describes a lesion in which, as seen on LM, discrete segments of the glomerular tuft reveal sclerosis (segmental); some glomeruli are involved, and others are spared (focal). Adhesion of the glomerular tuft to Bowman capsule (synechiae) is observed. Glomerular hypertrophy is common. Interstitial fibrosis and tubular atrophy are often present and correlate with the severity of disease. IF reveals IgM and C3 trapped in the sclerotic areas. As in MCNS, EM reveals effacement of the podocyte foot processes. Additionally, EM reveals obliteration of capillary lumens by fine granular and lipid deposits. A subtype of FSGS, in which the glomerular tufts demonstrate collapse of capillaries (collapsing glomerulopathy) on LM, has a poorer prognosis and high rate of progression to end-stage kidney failure (ESKD). FSGS is not a specific disease but a histopathological finding that can be associated with INS but can also be found in a wide variety of other conditions, including HIV nephropathy,heroin nephropathy, reflux nephropathy, obstructive uropathy, renal hypoplasia, hypertension, obesity, and Alport syndrome. As always, clinical and histopathological correlations must always be made when considering the findings evident on kidney biopsy.⁶
• MPGN is also known as mesangiocapillary glomerulonephritis. Glomeruli are typically lobulated in appearance on LM findings and demonstrate mesangial proliferation. Silver stain may reveal characteristic duplication of the glomerular basement membrane ("tram-track" appearance). IF findings reveal characteristic capillary deposition of C3. Three types of MPGN are recognized and can be distinguished by electron microscopy findings according to the location of immune deposits. Type 1 is subendothelial; type 2 has ribbonlike, dense intramembranous deposits; and type 3 is subendothelial and subepithelial. Some controversy surrounds the existence of type 3 MPGN as a distinct entity or a variant of type 1.¹⁷
• MN is a rare finding in INS of childhood, comprising only approximately 1% of biopsies, whereas in adult INS, MN can be found in 25-40% of cases. LM typically reveals thickening of the glomerular basement membrane. Silver stain may reveal characteristic "spikes," resulting from protrusion of basement membrane around immune deposits. IF reveals fine granular IgG and complement staining along the periphery of the glomerular capillary wall. EM reveals subepithelial electron-dense deposits.¹⁸

The reader is referred to other articles regarding histology of congenital nephrotic syndrome, and secondary forms of nephrotic syndrome due to lupus, vasculitis, and other etiologies.

Staging

Various staging schemes are recognized for the different histological lesions of INS. In general, when referring to kidney biopsy, the severity and chronicity of the disease is determined by the extent of tubulointerstitial fibrosis. The greater the extent of fibrosis, the greater the irreversibility of the disease and the poorer the prognosis, regardless of histological subtype. 

Treatment

Medical Care

A trial of corticosteroids is the first step in treatment of idiopathic nephrotic syndrome (INS) in which kidney biopsy is not initially indicated. Thus, patients aged 1-8 years with normal kidney function, no macroscopic (gross) hematuria, no symptoms of systemic disease (fever, rash, joint pain, weight loss), normal complement levels, negative antinuclear antibody (ANA) findings, negative viral screens (ie, HIV, hepatitis B and C), and no family history of kidney disease may be considered for steroid treatment prior to kidney biopsy. In select preadolescent patients older than 8 years, empirical steroid treatment can be considered prior to kidney biopsy; however, this should occur only under the care of a pediatric nephrologist experienced with nephrotic syndrome.

Kidney biopsy should be performed prior to any immunosuppressive treatment, including steroids, in patients younger than 1 year or older than 8 years and patients with recurrent gross hematuria, relevant family history of kidney disease, symptoms of systemic disease, positive viral screens, and/or laboratory findings possibly indicative of secondary nephrotic syndrome or INS other than minimal change nephrotic syndrome (MCNS), such as sustained elevation in serum creatinine levels, low C3/C4 levels, positive ANA findings, and positive anti–double-stranded DNA antibody findings. In these cases, histology guides treatment, and steroids may or may not be indicated depending on the underlying etiology.

The treatment of steroid-sensitive INS, steroid-dependent and frequently-relapsing INS, steroid-resistant nephrotic syndrome (SRNS) and FSGS are discussed in detail below. The treatment of mesangiocapillary glomerulonephritis (MPGN), membranous nephropathy (MN), congenital nephrotic syndrome, and secondary nephrotic syndrome (eg, lupus nephritis and vasculitis) are beyond the scope of this article.

• Corticosteroid (steroid) treatment (MCNS, INS that does not require initial biopsy)
  • Induction therapy:
    • Exclude active infection or other contraindications prior to steroid therapy.
    • The original ISKDC protocol recommended oral prednisone or prednisolone at 60 mg/m²/d (2 mg/kg/d) daily for 4 weeks.
    • Traditionally, the total daily dose was split into two doses. However, a single daily dose of steroids has equal efficacy to split dosing and fewer side effects.¹⁹  
    • Subsequent studies have shown that a longer, 6-week rather than 4-week, period of initial steroid treatment reduces the subsequent rate of relapse. Thus, many centers now prescribe the initial daily steroids for 6 weeks.²⁰
  • Maintenance therapy (following above induction therapy)
    • Original guidelines recommended oral prednisone or prednisolone at 40 mg/m² (or 1.5 mg/kg) given as a single dose on alternate days for 4 weeks.
    • Subsequent studies demonstrated that a longer alternate day maintenance period of 6 weeks resulted in a lower rate of relapse.²⁰
    • Thus, many centers now recommend daily induction steroid treatment for 6 weeks, followed by alternate day maintenance therapy for another 6 weeks.
    • Following 6 weeks of alternate day treatment, steroids may be stopped or slowly tapered over a variable length of time.
    • Longer duration of alternate-day steroid treatment may further reduce the number of children with subsequent relapses. An assessment of the Cochrane Database concluded that, after the initial daily steroid induction phase, continuation of alternate day steroids for 6 months could reduce the subsequent relapse rate by 33% compared with shorter alternate-day treatment.²¹ No adverse effects were noted with the longer steroid treatment, although the authors cautioned the adequate randomized controlled trials comparing shorter versus long-term alternate day steroid treatment still needed to be conducted.²¹
  • Relapse therapy
    • For infrequent relapses, steroids are resumed, although for a shorter duration than treatment during initial presentation
    • Prednisone 2 mg/kg/d(60 mg/m²/d) given as a single morning dose is administered until proteinuria has resolved for at least 2 days.
    • Following remission of proteinuria, prednisone is reduced to 1.5 mg/kg (40 mg/m²) given as a single dose on alternate days for 4 weeks. Steroids may then be stopped or gradually tapered.
• Other therapy (all patients):
  • Pneumococcal vaccine should be administered to all patients upon presentation, to reduce the risk of bacterial infection and peritonitis.
  • Diuretic therapy may be beneficial, particularly in children with symptomatic edema. The loop diuretics (furosemide) given orally in usual amounts (approximately 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. Metolazone 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 and careful communication with the family should continue
  • When a patient presents with anasarca and signs of intravascular volume depletion (such as high hematocrit indicative of hemoconcentration), consideration should be given to administration of 25% albumin, although this is controversial. Rapid administration of albumin can result in pulmonary edema. The authors' practice has been to administer 25% albumin at a dose of 1 g/kg body weight given as a continuous infusion over 24 hours. Intravenous albumin may be particularly useful in diuretic resistant edema, and in patients with significant ascites and/or scrotal, penile or labial edema.
  • 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. ACE inhibitors or angiotensin II receptor blocker (ARB) agents may also contribute to reducing proteinuria but should be used cautiously in the presence of acute kidney failure or volume depletion because their use can worse kidney function in these settings. Adolescent women must also be counseled regarding use of birth control with chronic ACE inhibitors or ARB due to risk of birth defects, and pregnancy testing should be considered before starting these agents. Calcium channel blockers and beta-blockers may also be used as first-line agents for hypertension.
  • Home monitoring of urine protein and fluid status is an important aspect of management. All patients and parents should be trained to monitor first morning urine proteins at home with urine dipstick. Weight should be checked every morning as well, and a home logbook should be kept recording the patient’s daily weight, urine protein levels, and steroid dose if being treated. Families and patients are instructed to call for any edema, weight gain, or urine protein findings of 2+ or more for more than 2 days. Urine testing at home is also useful in monitoring response (or nonresponse) to steroid treatment.
• Frequently relapsing nephrotic syndrome and steroid-dependent nephrotic syndrome (SDNS)
  • Frequently relapsing nephrotic syndrome is defined as steroid-sensitive nephrotic syndrome (SSNS) with 2 or more relapses within 6 months or more than 3 relapses within a 12-month period.
  • SDNS is defined a as SSNS with 2 or more consecutive relapses during tapering or within 14 days of stopping steroids.
  • For frequently relapsing nephrotic syndrome and SDNS, the clinical evidence is inadequate to support a preferred method of treatment. Therefore, practitioners must rely on their clinical experience and discuss the potential advantages and disadvantages of each treatment with families and patients.²²
  • Alkylating agents (cyclophosphamide [CYP], chlorambucil, nitrogen mustard) offer the benefit of possible sustained remission after a defined course of treatment, although with the risk of infertility and other side effects (see Complications).
    • Calcineurin-inhibitors (eg, cyclosporine [CSA], tacrolimus [TAC]) are useful steroid-sparing agents, but prolonged courses of treatment are needed, nephrotic syndrome tends to recur when treatment is stopped, and nephrotoxic injury may occur.
    • An increased risk of seizures is noted with chlorambucil.¹² Additionally, a higher incidence of infections and leukopenia may be seen with chlorambucil compared with CYP.²³ Because of these risks, and the need to give nitrogen mustard intravenously, the authors have used cyclophosphamide as the preferred alkylating agent
    • Cyclophosphamide (2–2.5 mg/kg daily) is given orally for 8-12 weeks.
    • Steroids are usually overlapped with initiation of CYP then tapered.
    • An influential study found that a 12 week course of cyclophosphamide was more effective than an 8-week course in producing sustained remission of nephrotic syndrome.²⁴ However, a subsequent randomized trial did not reach this same conclusion,²⁵  and the optimal duration of cyclophosphamide treatment is still unclear at this time.
    • Patients must have weekly CBC counts to monitor for leukopenia.
    • Patients must also maintain adequate hydration and take CYP in the morning (not at bedtime) to limit the risk of hemorrhagic cystitis. Families must be counseled to report gross hematuria, fever, or severe illness.
  • Calcineurin-inhibitors
    • CSA can be used in those children who fail to respond to, or subsequently relapse after, treatment with CYP, or for children whose families object to use of CYP. Because CSA can cause hirsutism and gingival hyperplasia, the authors' practice has been to use TAC instead of CSA, although limited studies are available regarding the effectiveness of TAC compared with CSA.
    • Initial doses of CSA are started at 5–6 mg/kg daily divided every 12 hours, adjusted for trough concentrations of 50–125 ng/mL. Low-dose steroids are continued for a variable length of time; as many as 40% of patients may need to remain on steroids during CSA treatment to maintain remission.¹²
    • Kidney function and drug levels must be carefully monitored due to the risk of CSA induced nephrotoxicity.
    • Trough levels correlate poorly with area-under-the-curve (AUC) pharmacokinetics and may not represent true exposure to CSA. levels obtained 2 hours after administration (C2) have better correlation with AUC.²⁶
    • TAC trough levels correspond better to AUC than CSA, allowing better determination of dosing and exposure with TAC than with CSA.²⁶
    • TAC is started at a dose of 0.1 mg/kg daily divided every 12 hours and adjusted to keep trough level about 5-10 ng/mL.²⁷ Our practice is to use the lowest possible dose that sustains remission and to aim for a trough level of around 5 ng/mL. As with CSA, continuing low-dose steroids is often necessary to maintain remission, although some patients may eventually be able to discontinue steroid treatment.
    • With CSA and TAC, kidney function and drug levels should be carefully monitored. Consideration should be given to kidney biopsy after prolonged treatment to monitor for calcineurin-inhibitor induced nephrotoxicity and fibrosis.
    • TAC (0.1-0.2 mg/kg/d) or CSA (5-6 mg/kg/d) have similar efficacy in inducing remission in patients with idiopathic SRNS at 6 months and 1 year when combined with alternate-day low-dose corticosteroids and enalapril.²⁸ Relapse was significantly greater in those who received CSA compared with TAC. TAC also decreased blood cholesterol levels to a greater extent and resulted in less incidents of nephrotoxicity that necessitated discontinuance than CSA. Cosmetic adverse effects (eg, hypertrichosis, gum hypertrophy) were significantly more frequent in the CSA group (P <0.001). TAC therapy is a promising alternative to CSA because of the lower relapse risk and lack of cosmetic adverse effects.
  • Levamisole: is an anthelmintic drug that has immune-modulating effects and can be effective in reducing the relapse rate in frequently relapsing nephrotic syndrome. However, it is unavailable in the United States. Side effects include leukopenia, hepatic dysfunction, agranulocytosis, vasculitis, and encephalopathy. Levamisole is prescribed at a dose of 2.5 mg/kg given on alternate days .¹²
  • Mycophenolate mofetil (MMF): Although small studies have shown MMF to be effective in reducing the number of relapses in frequently relapsing nephrotic syndrome and SDNS, adequate randomized controlled trials still need to be performed. The authors have found MMF to be a useful steroid-sparing agent in stable patients (without excessive edema, need for hospitalizations and without other serious complications) whose families wish to avoid the possible side effects of CYP, CSA, or TAC. However, response to MMF varies and is less reliable than other treatments. MMF is started at a dose of 600 mg/m² twice daily. CBC counts should be monitored for bone-marrow suppression, and liver function test findings should occasionally be monitored for hepatic toxicity.
• SRNS and FSGS
  • Adequate randomized controlled trials have not yet been reported to give sufficient evidence to guide treatment of SRNS.²⁹
  • A current, National Institutes of Health (NIH)-sponsored, multicenter, randomized clinical trial has recently concluded enrollment and will compare CSA versus MMF for treatment of FSGS.³⁰
  • The most frequently recommended treatment for FSGS and SRNS is CSA. Approximately 36% of children with SRNS may achieve remission with CSA.²⁹ CSA is dosed as above for FRNS and SDNS. However, higher doses and trough levels may be required to achieve remission in SRNS and FSGS.¹² TAC may be effective as well, although studies are limited at this time.³⁰
  • Most studies to date have shown no clear benefit to the use of alkylating agents in FSGS and SRNS.⁶
  • A controversial treatment involves high-dose, intravenous methylprednisolone tapered over 78 weeks, in combination with alternate day oral prednisone and with the addition of CYP or chlorambucil if remission is not achieved in the first 10 weeks. The authors reported a 52% remission rate in SRNS.³¹ However, subsequent studies using this protocol have not duplicated the initial success. The risk of steroid toxicity and infection, as well as lack of sufficient evidence for the effectiveness of this protocol, have dampened enthusiasm for this treatment.
  • The use of an ACE inhibitor, such as enalapril, either alone or in combination with an ARB agents, such as losartan, has been shown to reduce proteinuria in FSGS/SDNS and should be considered in all patients, even in the absence of hypertension. Accordingly, ACE inhibitors and ARB agents should be considered as preferred agents in patients with hypertension. ACE inhibitor and ARB treatment may also have a renoprotective effect and slow progression of renal disease by inhibiting pathways of fibrosis.³⁰

Surgical Care

No routine surgical care is indicated for this condition. Occasionally, a patient with nephrotic syndrome 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, nephrotic syndrome 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 nephrotic syndrome. Referral to a pediatric nephrologist is mandatory for all children with nephrotic syndrome whose symptoms fail to respond to initial therapy (complete remission of proteinuria); in most of these patients, a percutaneous renal biopsy is indicated, and an alternative treatment plan may be desirable.

Diet

A sodium restricted diet should be maintained while a patient is edematous and until proteinuria remits. Thereafter, a normal diet can be followed. During severe edema, careful and modest fluid restriction may be appropriate but the patient must be monitored closely for excessive intravascular volume depletion. Protein restriction is not indicated, except in cases of acute or chronic kidney failure when severe azotemia is present and, even then, protein restriction should be done carefully as to avoid impaired somatic growth.

Activity

A normal activity plan is recommended. Because viral respiratory illnesses are often associated with relapses of nephrotic syndrome, keeping children with INS away from those who have obvious respiratory tract infections may be beneficial. However, children should not be kept out of school and should have as normal a routine as possible.

Medication

Prednisone is the first-line therapy for children with nephrotic syndrome (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.

Glucocorticoids

All glucocorticoids are effective; however, prednisone or prednisolone is used most commonly. Their specific mode of action in nephrotic syndrome is unknown.

Prednisone (Deltasone, Orasone)

Delta1-derivative of naturally occurring adrenocortical steroids. Suppresses key components of immune system.

Dosing

Adult

Pediatric

2 mg/kg/d (60 mg/m²/d) PO given as a single daily dose in the morning for 6 wk, not to exceed 60 mg/d, followed by 1.5 mg/kg (40 mg/m²) as single dose every other morning for an additional 6 wk, then discontinue or gradually taper
For relapses, 2 mg/kg/d (60 mg/m²/d) PO given as a single daily dose in the morning, not to exceed 60 mg/d, until urine protein negative for 2 d; followed by 1.5 mg/kg (40 mg/m²) as single dose every other morning for 4 wk, may then be discontinued or gradually tapered

Interactions

Decreases effects of salicylates and toxoids (for immunizations); phenytoin, carbamazepine, barbiturates, and rifampin decrease effects of corticosteroids

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

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

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 daily treatment can interfere with linear growth; increased susceptibility to infections during intensive therapy; may mask usual evidence of infections
Other possible adverse effects include hypertension, hyperglycemia, hypercalciuria, hypokalemia, nephrolithiasis, osteomalacia, and CNS manifestations (eg, behavioral changes, rarely psychosis)

Prednisolone (Delta-Cortef, Pediapred, Prelone)

Delta1-derivative of the naturally occurring adrenocortical steroids. Suppresses key components of immune system.

Dosing

Adult

Pediatric

2 mg/kg/d (60 mg/m²/d) PO given as a single daily dose in the morning for 6 wk, not to exceed 60 mg/d, followed by 1.5 mg/kg (40 mg/m²) as single dose every other morning for an additional 6 wk, then discontinue or gradually taper
For relapses, 2 mg/kg/d (60 mg/m²/d) PO given as a single daily dose in the morning until urine protein negative for 2 days; not to exceed 60 mg/d; followed by 1.5 mg/kg (40 mg/m²) as single dose every other morning for 4 wk, may then be discontinued or gradually tapered

Interactions

Decreases effects of salicylates and toxoids (for immunizations); phenytoin, carbamazepine, barbiturates, and rifampin decrease effects of corticosteroids

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

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

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 daily treatment can interfere with linear growth; increased susceptibility to infections during intensive therapy may occur; may mask usual evidence of infections
Other possible adverse effects include hypertension, hyperglycemia, hypercalciuria, hypokalemia, nephrolithiasis, osteomalacia, and CNS manifestations (eg, behavioral changes, rarely psychosis)

Diuretics

Promotes excretion of water and electrolytes by the kidneys. These agents are used to treat heart failure or hepatic, renal, or pulmonary disease when sodium and water retention has resulted in edema or ascites.

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.

Dosing

Adult

Pediatric

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.

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

Contraindications

Documented hypersensitivity; hepatic coma, anuria, and state of severe electrolyte depletion

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Perform frequent serum electrolyte, CO₂, glucose, creatinine, uric acid, calcium, and BUN determinations during first few months of therapy and periodically thereafter

Metolazone (Zaroxolyn)

Increases excretion of sodium, water, potassium and hydrogen ions by inhibiting reabsorption of sodium in distal tubules. Metolazone may be used to augment diuretic response during treatment with furosemide.

Dosing

Adult

Pediatric

Children: 0.2-0.4 mg/kg/d PO divided q12-24h
Dose generally limited to 2.5-5 mg total cumulative daily dose

Interactions

May decrease effect of anticoagulants, sulfonylureas, and gout treatments; anticholinergics and amphotericin B may increase toxicity; effects may decrease when used concurrently with bile acid sequestrants, NSAIDs, or methenamine; when administered concurrently, increases toxicity of anesthetics, diazoxide, digitoxin, lithium, loop diuretics, antineoplastics, allopurinol, calcium salts, vitamin D, and nondepolarizing muscle relaxants

Contraindications

Documented hypersensitivity; hepatic coma or anuria

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Caution in hepatic or renal disease, diabetes mellitus, gout, or lupus erythematosus

Plasma protein

These agents are used to supplement diuresis in patients with edema. Increases oncotic pressure to urge a fluid shift from interstitial tissues.

Albumin (Albuminar, Buminate)

Raises oncotic pressure, and thus supplements the diuretic effect of furosemide.

Dosing

Adult

Pediatric

1 g/kg of 25% concentration (ie, 25 g/100 mL) IV given as a continuous infusion over 24 h; administer with furosemide

Interactions

None reported

Contraindications

Documented hypersensitivity; anemia; heart failure; respiratory distress; pulmonary edema

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

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. May cause pulmonary edema or congestive heart failure if administered too quickly, or in patients with severe intravascular volume expansion.

Immunosuppressive agents

These drugs may be used for frequently relapses (despite corticosteroid therapy) or to attempt steroid-sparing therapy.

Cyclophosphamide (Cytoxan)

Cyclic polypeptide that suppresses some humoral activity. Chemically related to nitrogen mustards. Activated in the liver to its active metabolite, 4-hydroxycyclophosphamide, which alkylates the target sites in susceptible cells in an all-or-none type reaction. As an alkylating agent, the mechanism of action of the active metabolites may involve cross-linking of DNA, which may interfere with growth of normal and neoplastic cells.
Biotransformed by cytochrome P-450 system to hydroxylated intermediates that break down to active phosphoramide mustard and acrolein. Interaction of phosphoramide mustard with DNA considered cytotoxic.
When used in autoimmune diseases, mechanism of action is thought to involve immunosuppression due to destruction of immune cells via DNA cross-linking.
In high doses, affects B cells by inhibiting clonal expansion and suppression of production of immunoglobulins. With long-term low-dose therapy, affects T cell functions.
Successfully has been used in conditions that require immunosuppression. Highly effective for frequently relapsing steroid-sensitive nephrotic syndrome; half of the children enter a prolonged remission. Researchers have formulated various protocols for different renal pathological lesions.

Dosing

Adult

Pediatric

Frequently-relapsing and steroid-dependent nephrotic syndrome: 2-2.5 mg/kg PO daily for 8-12 wk

Interactions

Allopurinol may increase risk of bleeding or infection and enhance myelosuppressive effects; may potentiate doxorubicin-induced cardiotoxicity; may reduce digoxin serum levels and antimicrobial effects of quinolones; toxicity may increase with chloramphenicol; may increase effect of anticoagulants; coadministration with high doses of phenobarbital may increase leukopenic activity; thiazide diuretics may prolong cyclophosphamide-induced leukopenia; coadministration with succinylcholine may increase neuromuscular blockade by inhibiting cholinesterase activity

Contraindications

Documented hypersensitivity; severely depressed bone marrow function

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Regularly examine hematologic profile (particularly neutrophils and platelets) to monitor for hematopoietic suppression; regularly examine urine for RBCs, which may precede hemorrhagic cystitis; administer in morning (not before bedtime) to maintain hydration and decrease risk of hemorrhagic cystitis

Cyclosporine (Sandimmune, Neoral)

An 11-amino acid cyclic peptide and natural product of fungi. Acts on T-cell replication and activity.
Specific modulator of T-cell function and an agent that depresses cell-mediated immune responses by inhibiting helper T-cell function. Preferential and reversible inhibition of T lymphocytes in G0 or G1 phase of cell cycle suggested.
Binds to cyclophilin, an intracellular protein, which, in turn, prevents formation of interleukin 2 and the subsequent recruitment of activated T cells.
Has about 30% bioavailability but marked interindividual variability. Specifically inhibits T-lymphocyte function with minimal activity against B cells. Maximum suppression of T-lymphocyte proliferation requires that drug be present during first 24 h of antigenic exposure.
Suppresses some humoral immunity and, to a greater extent, cell-mediated immune reactions (eg, delayed hypersensitivity, allograft rejection, experimental allergic encephalomyelitis, and graft-vs-host disease) for various organs.

Dosing

Adult

Pediatric

5-6 mg/kg/d PO divided q12h; target trough level ranges between 50-125 ng/mL

Interactions

Carbamazepine, phenytoin, isoniazid, rifampin, and phenobarbital may decrease cyclosporine concentrations; azithromycin, itraconazole, nicardipine, ketoconazole, fluconazole, erythromycin, verapamil, grapefruit juice, diltiazem, aminoglycosides, acyclovir, amphotericin B, and clarithromycin may increase cyclosporine toxicity; acute renal failure, rhabdomyolysis, myositis, and myalgias increase when taken concurrently with lovastatin; methylprednisolone and cyclosporine mutually inhibit one another resulting in increased plasma levels of each drug

Contraindications

Documented hypersensitivity; uncontrolled hypertension or malignancies; do not administer concomitantly with PUVA or UVB radiation in psoriasis since it may increase risk of cancer

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Evaluate renal and liver functions often by measuring BUN, serum creatinine, and serum bilirubin levels and liver enzymes; may increase risk of infection and lymphoma; reserve IV use only for those who cannot take PO

Tacrolimus (Prograf)

Immunomodulator produced by the bacteria Streptomyces tsukubaensis. Mechanisms of action similar to cyclosporine. Primarily used in transplants but used in Behçet disease to treat uveitis.

Dosing

Adult

Pediatric

0.1 mg/kg/d PO divided q12h; adjust dose to maintain trough level about 5 ng/mL

Interactions

Caution with drugs associated with renal dysfunction, including aminoglycoside, amphotericin B, cisplatin, and others (can enhance nephrotoxicity); concentrations may be increased in presence of diltiazem, nicardipine, nifedipine, verapamil, clotrimazole, fluconazole, itraconazole, ketoconazole, clarithromycin, erythromycin, troleandomycin, cisapride, metoclopramide, bromocriptine, cimetidine, cyclosporine, danazol, methylprednisolone, and protease inhibitors; concentrations may decrease when administered with carbamazepine, phenobarbital, phenytoin, rifabutin, and rifampin

Contraindications

Documented hypersensitivity (including hypersensitivity reactions to tacrolimus or HCO-60 [polyoxyl 60 hydrogenated castor oil])

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Insulin-dependent diabetes reported in 20% of patients using tacrolimus for transplants, which is reversible in 15% after 1 year and in 50% after 2 years; increased risk for African American and Hispanic patients; nephrotoxicity, neurotoxicity, hyperglycemia, hyperkalemia, tremor, headache, and increased risk of lymphomas and other malignancies (especially skin tumors) may occur; anaphylaxis, hypertension, myocardial hypertrophy, gastrointestinal abnormalities, arthralgias, cramps, asthma, and bronchitis have been reported with its use

Mycophenolate mofetil (CellCept)

Inhibits inosine monophosphate dehydrogenase (IMPDH) and suppresses de novo purine synthesis by lymphocytes, thereby inhibiting their proliferation. Inhibits antibody production.

Dosing

Adult

Pediatric

600 mg/m² PO bid

Interactions

In combination with either acyclovir or ganciclovir may result in higher levels for both interacting drugs due to competition for renal tubular excretion; aluminum/magnesium present in some antacids, and cholestyramine containing products may decrease absorption, reducing levels (do not administer together); probenecid may increase levels of mycophenolate; salicylates and azathioprine may increase toxicity; may decrease levonorgestrel AUC; may decrease live virus vaccine immune response; when administered in combination with theophylline may increase free fraction levels of theophylline; may reduce blood levels hormones contained in oral contraceptives and could reduce effectiveness

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Increases risk for infection (monitor blood count); severe renal impairment (CrCl <25 mL/min) may have increased adverse effects due to increased free MPA; caution in active peptic ulcer disease; incidence of malignancies and lymphoma consistent with that reported for other immunosuppressants (0.9%); commonly causes constipation, nausea, diarrhea, urinary tract infection, and nasopharyngitis; rare reports include interstitial lung disorders, colitis, pancreatitis, intestinal perforation, GI hemorrhage, gastric ulcers, duodenal ulcers, and ileus; do not chew, crush, or cut Myfortic tab; women of childbearing potential must have a negative serum or urine pregnancy test must be completed within one week of beginning MMF and must receive contraceptive counseling and use effective contraception; continue contraception for 6 wk following discontinuing

Follow-up

Further Inpatient Care

• Admitting all new-onset patients with nephrotic syndrome (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:
  • Anasarca, especially when resistant to outpatient therapy and/or accompanied by respiratory compromise, massive ascites or scrotal/perineal or penile edema.
  • Significant hypertension
  • Anuria or severe oliguria
  • Peritonitis, sepsis, or other severe infection
  • Significant respiratory infection
  • Significant azotemia
• Hospital admission may be necessary because of social reasons and often is useful on initial presentation of idiopathic nephrotic syndrome (INS) in order to provide intensive education of the family regarding INS and long-term management at home.

Further Outpatient Care

• Ambulatory monitoring of the child's condition and response to treatment is a very important aspect of the overall management of nephrotic syndrome.
• Home monitoring of urine protein and fluid status is an important aspect of management. Parents and/or caregivers should be trained to monitor first morning urine proteins at home with urine dipstick. Weight should be checked every morning as well and a home logbook should be kept recording the patient’s daily weight, urine protein and steroid dose if being treated.
• Families and patients are instructed to call for any edema, weight gain, or urine testing 2+ or more for protein for more than 2 days. Rapid detection of relapse of proteinuria by home testing of urine can allow early initiation of steroid treatment before edema and other complications develop. Urine testing at home is also useful in monitoring response (or nonresponse) to steroid treatment.

Inpatient & Outpatient Medications

• See Medical Care.

Transfer

• Because of the complexity of care of INS in all but the simplest of cases, the lack of strong clinical evidence in treatment, and the great deal of experience required in successfully managing these patients, care of the patient with INS should always be performed in consultation with a pediatric nephrologist.
• In cases that have initially been managed by the primary care specialist, referral to a pediatric nephrologist is mandatory in cases of frequently relapsing nephrotic syndrome, steroid-dependent nephrotic syndrome (SDNS), steroid-resistant nephrotic syndrome (SRNS), secondary nephrotic syndrome, and situations in which a kidney biopsy is necessary (see Workup).

Deterrence/Prevention

• Yearly influenza vaccination is recommended to prevent serious illness in the immunocompromised patient, as well as to prevent this possible trigger of relapse.
• Pneumococcal vaccination should be administered to all patients with INS to reduce the risk of pneumococcal infection. Vaccination should be repeated every 5 years while the patient continues to have relapses.
• Routine childhood vaccines with live virus strains are contraindicated in patients taking steroids and until off steroid treatment for a minimum of 1 month.³² Care must be taken in administering live viral vaccines to children in remission with frequently relapsing nephrotic syndrome who might need to restart steroid therapy shortly after vaccination.
• Because of the high risk of varicella infection in the immunocompromised patient, in the nonimmune patient, postexposure prophylaxis with varicella-zoster immune globulin is recommended. Patient with varicella-zoster infection should be treated with acyclovir and carefully monitored.¹² Varicella immunization is safe and effective in patients with INS who are in remission and off steroid treatment (with the usual precautions for administering live viral vaccines to patients who have received steroids).³³
• Routine, nonlive viral vaccines should be administered according to their recommended schedules. Despite the former belief that routine immunization can trigger relapse of nephrotic syndrome, no solid evidence suggests this, and the risk of these preventable childhood illnesses exceeds the theoretical, unproven risk for triggering relapses.

Complications

• Infection
  • Before the advent of corticosteroids, a high mortality rate due to infection in patients with INS was observed.
  • Even after the availability of steroids, the ISKDC reported a mortality rate of 1.5% in children with INS.³⁴
  • Peritonitis and sepsis are the most common and serious infections. Peritonitis occurs at a rate of approximately 2-6% and may be accompanied by sepsis or bacteremia.
  • The predominant bacterial causes are Streptococcus pneumonia and Gram-negative enteric organisms such as Escherichia coli.³⁵
  • Various infections can also occur, including meningitis, cellulitis, viral infections, and others. Varicella is a particular concern in immunosuppressed patients and can be lethal. Prompt recognition and treatment with acyclovir (or postexposure prophylaxis with varicella-zoster immune globulin [VZIG]) is essential. Routine childhood varicella immunization has alleviated some of the concern regarding this complication.
  • Infection, viral or bacterial, can trigger relapse of INS and further complicate the course of the condition.
  • Pneumococcal vaccine should be administered to all patients with INS to reduce the risk of pneumococcal disease. Patients should be revaccinated every 5 years for the duration of their course of INS.
• Thrombosis
  • The incidence rate of thromboembolic complications (TEC) is about 1.8-5% but may be underestimated. One study found the subclinical rate of pulmonary embolism to be 28% using scintigraphic pulmonary ventilation and perfusion studies.³⁶
  • Incidence is higher in adults and children with secondary nephrotic syndrome. The incidence is especially high in membranous nephrotic syndrome.³⁷
  • Renal vein thrombosis, deep vein thrombosis, and pulmonary embolism (PE) are the most frequently encountered TEC in children.
  • Other venous sites of thrombosis include the superior sagittal sinus, other cerebral venous sites, and the inferior vena cava.
  • Arterial thrombosis, although less common than venous TEC, can occur and has been reported at the axillary, subclavian, femoral, coronary, and mesenteric arteries.³⁷
  • Initial treatment of TEC includes thrombolysis with anticoagulants (such as heparin) and/or fibrinolytic agents (tissue plasminogen activator, streptokinase, urokinase).³⁶
  • Following TEC, warfarin is often prescribed for a period of as long as 6 months.¹²
  • Empirical prophylactic anticoagulation is not routinely indicated in INS. Some practitioners advocate the use of chronic, low-dose aspirin in patients with chronic nephrotic syndrome (eg, frequently relapsing nephrotic syndrome, SDNS, SRNS). However, adequate controlled trials examining the use of aspirin have not been performed.³⁶
• Hyperlipidemia
  • Nephrotic syndrome results in hypercholesterolemia, hypertriglyceridemia, high low-density lipoprotein (LDL) cholesterol, and low high-density lipoprotein (HDL) cholesterol (see Pathophysiology).
  • Lipid abnormalities generally resolve when nephrotic syndrome is in remission.
  • Dietary modification does not appear to be effective in limiting hyperlipidemia during active nephrotic syndrome.³⁸
  • Chronic hyperlipidemia has been linked to increased risk of atherosclerosis and coronary artery disease.¹²
  • Chronic hyperlipidemia has also been associated with progression of renal disease. However, the small studies to date of lipid-lowering agents in pediatric INS have not shown an improvement with these agents in proteinuria or progression of renal disease.¹⁰
  • Dyslipidemias in adults with nephrotic syndrome have been successfully treated with statins (simvastatin, lovastatin), fibrates (gemfibrizil), bile-acid binding resins (cholestyramine), and probucol.
  • Children with INS have been effectively treated with probucol, but this agent has been associated with prolonged QT interval and is not available in the United States. Gemfibrozil has also been shown to be effective in childhood nephrotic syndrome in small studies.³⁸
  • Small studies have shown that simvastatin and lovastatin are well-tolerated and effective in childhood INS. Total cholesterol, triglycerides, and LDL cholesterol were reduced by 42%, 44%, and 46%, respectively. No changes in proteinuria, hypoalbuminemia, or progression of renal disease were noted.^5,39,38
  • In order to monitor for treatment associated rhabdomyolysis, children treated with statins should have creatine kinase prior to initiating therapy and every 6-12 weeks after starting treatment. Patients and families should be instructed to report muscle soreness, tenderness, or pain. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels should be measured before initiating treatment and about every 3 months thereafter to monitor for liver toxicity.³⁸
  • Long-term safety studies regarding statins in pediatrics are lacking, and routine use of statins were not recommended at this time by an expert panel. The only drugs recommended at this time by the panel are bile acid sequestrants.³⁸
• Acute kidney failure (AKF)
  • AKF is a rare complication of INS, occurring in about 0.8% of cases.⁴⁰
  • Causes include rapid progression of underlying disease (nephrotic syndrome other than minimal change nephrotic syndrome [MCNS], secondary nephrotic syndrome), bilateral renal vein thrombosis, acute interstitial nephritis (AIN) due to drug therapy (eg, antibiotics, nonsteroidal anti-inflammatory agents [NSAIDs], diuretics), and acute tubular necrosis (ATN) due to hypovolemia or sepsis.⁴⁰ Use of ACE inhibitors or angiotensin II receptor blockers (ARBs) in conjunction with volume depletion can also precipitate AKF.
  • In most cases, AKF is reversible with remission of nephrotic syndrome, correction of intravascular volume contraction, and/or removal of inciting agent in AIN.⁴⁰
  • Fever, rash, arthralgia and eosinophilia with a "bland" urinalysis (minimal cellular elements) in the presence of AKF are typical for AIN. However, obvious clinical symptoms may be absent except for the AKF and unremarkable urinalysis. Gross hematuria, flank pain, and thrombocytopenia may be signs of renal vein thrombosis. Hemoconcentration in the patient with anasarca might indicate intravascular volume depletion.
• Side effects of drug therapy
  • Corticosteroids
    • Behavioral changes, increased appetite, and Cushingoid signs (rounded, or "moon" facies) are common during the first 6 weeks of daily therapy but usually begin to subside during the alternate-day maintenance therapy period and, if steroids are successfully discontinued, usually disappear completely within 3-6 months
    • If longer periods of steroid therapy are required, the risk of complications increases. Complications of chronic steroid therapy may include infection, obesity, growth delay, osteopenia, avascular hip necrosis, cataracts, hypertension, hyperglycemia, nephrolithiasis, and hyperlipidemia.
    • Nutritional counseling and an exercise regimen may help to limit weight gain during steroid therapy.
    • Consideration should be given to monitoring of bone density by dual energy X-ray absorptiometry (DEXA) in patients on long-term steroids.
  • Diuretics: Loop diuretics (furosemide, bumetanide) commonly cause hypokalemia and contraction alkalosis. Serum electrolytes should be monitored and electrolyte abnormalities treated as indicated. Metolazone may augment these side effects. The use of potassium-sparing diuretics (spironolactone, amiloride) may help to limit hypokalemia.
  • Albumin: Infusion of 25% albumin can result in pulmonary edema and congestive heart failure. It should be used cautiously and sparingly only in those patients with hemoconcentration and/or diuretic-resistant edema. In the authors' experience, slow infusion of 1 g/kg as a continuous infusion over 24 hours helps to limit complications.
  • Calcineurin inhibitors: Cyclosporine (CSA) and tacrolimus (TAC) can cause increased susceptibility to infection, direct nephrotoxicity, hyperkalemia, and hypertension. CSA can also cause hirsutism and gingival hyperplasia, whereas TAC can cause impaired glucose tolerance and overt diabetes.
  • Alkylating agents: Cyclophosphamide (CYP), chlorambucil, and nitrogen mustard can cause dose-related infertility, azoospermia, oligospermia, amenorrhea, nausea, and hair loss. Hair loss, when it occurs, is usually mild and not cosmetically significant in the doses used for most types of INS. Alkylating agents can also cause myelosuppression and increased susceptibility to infection. CYP can cause hemorrhagic cystitis and increased incidence of bladder malignancy. The risk of infertility rises above a cumulative CYP dose of 200 mg/kg .
  • Mycophenolate mofetil (MMF): Side effects of MMF include cramps, diarrhea, GI distress, myelosuppression, and increased susceptibility to infection.
  • Antihypertensive agents: Side effects of blood pressure medications can include hyperkalemia and AKF (ACE inhibitors, ARBs), hypotension, bradycardia (beta-blocker), fatigue, sedation (clonidine), and electrolyte disturbances (diuretics), among many other side effects.

Prognosis

• Steroid-responsive INS
  • Patients who remain responsive to steroids with remission of proteinuria, even with frequent relapses, generally have a good prognosis. The ISKDC found that 93% of children with INS who responded to steroids had MCNS revealed on kidney biopsy findings.³ In contrast, patients who did not initially respond to steroids had histology other than MCNS in 75% of cases.
  • About 90% of children with MCNS (but only 20% of children with focal segmental glomerulosclerosis [FSGS]) achieve remission after the initial course of steroid treatment. Despite the generally favorable prognosis in patients who respond to steroids, the ISKDC reported a 60% rate of subsequent relapses, which can lead to complications, increased morbidity, and decreased quality of life.³ A longer course of initial steroid treatment (12 wk rather than the original ISKDC protocol of 8 wk) may reduce the rate of subsequent relapse to 36%,²⁰  which still represents a large number of patients who undergo repeated courses of immunosuppression, with possible hospitalizations, edema, infections, medication side effects, and other comorbidities. 
  • A long-term study of 398 children with INS found that the percentage of children who became free of relapses during the course of their disease rose from 44% one year after diagnosis to 69% at 5 years and 84% 10 years after diagnosis.^41,12  Although most children with INS who respond to steroids achieve long-term remission, relapses may continue into adulthood. Older studies suggested that more than 90% of children achieve long-term remission without further relapses by puberty. However, this has recently been challenged by surveys indicating a rate of relapse during adulthood as high as 27-42%.
  • A study of 42 adult patients with a history of childhood INS found that 33% of patients continued to relapse into adulthood. Fortunately, overall morbidity (eg, bone disease, infections, malignancies, cardiovascular complications) remained low, and patients had normal adult height, body mass index (BMI), and kidney function. Predictors of adult relapse included the number of relapses during childhood and the use of immunosuppressant medications other than steroids (CSA, chlorambucil, CSY).⁴²
• SRNS
  • Approximately 10% of patients overall with INS do not respond to an initial trial of steroids (2% of patients with MCNS do not respond to steroids). Additionally, about 1-3% of patients who initially do respond to steroids later become resistant to treatment ("late non-responders").⁶
  • Most patients who do not achieve remission of proteinuria with steroids have kidney biopsy findings other than MCNS. The most common diagnosis in these patients is FSGS.
  • More than 60% of patients with nephrotic syndrome and FSGS who fail to achieve remission with any treatment progress to end-stage kidney disease (ESKD). In contrast, only 15% progression to ESKD is observed in patients with FSGS who achieve remission by any treatment.⁴³ Gipson et al reported a 90% reduction in the risk of progression to ESKD in patients with INS who achieved remission.⁴⁴  
  • Thus, steroid-resistant INS has a good prognosis if remission of proteinuria can be achieved by other medications. Failure to respond to treatment (ie, failure to achieve remission) and kidney insufficiency at presentation are predictors of poor outcome and progression to ESKD.⁴⁵

Patient Education

• Soon after nephrotic syndrome is diagnosed, the patient and family should be educated about the disease, its management, and its expected course. The family should participate in therapeutic decisions and should be encouraged to adhere to the medical regimen. As with all chronic illnesses, many psychosocial issues may need to be addressed, including behavior, adherence to medication, adequate parental/caretaker supervision, medical insurance, missed work and school due to hospitalizations and outpatient visits, and many other important issues. Consultation with social workers and mental health care workers may be useful.
• Links to resources for parents can be found at the Web sites for the American Society of Pediatric Nephrology (ASPN) and the National Kidney Foundation.

Miscellaneous

Medicolegal Pitfalls

Potential medical/legal problems include the nephrotic syndrome:

• Failure to recognize secondary causes of nephrotic syndrome
• Failure to monitor for and recognize complications of nephrotic syndrome, such as infection and thrombosis
• Failure to thoroughly educate the patient and family regarding home monitoring and care of idiopathic nephrotic syndrome (INS) and how to recognize signs of relapse and complications such as peritonitis and other infections
• Continuation of corticosteroids for too long with resultant steroid toxicity in the patient with frequently-relapsing, steroid-dependent, or steroid-resistant nephrotic syndrome and failure to initiate alternative treatments, such as cyclophosphamide or cyclosporine
• Failure to refer to a pediatric nephrologist for complicated nephrotic syndrome (frequently relapsing, steroid-dependent, or steroid-resistant): Even in simple cases of INS, successful management requires a considerable amount of expertise. Complications, need for biopsy, or necessity of alternative treatments might not be readily apparent to the practitioner with limited experience with nephrotic syndrome.

Special Concerns

As with all chronic illnesses, many psychosocial issues may need to be addressed, including behavior, adherence to medication, adequate parental/caretaker supervision, medical insurance, missed work and school due to hospitalizations and outpatient visits, and many other important issues. Consultation with social workers and mental health care workers may be useful.

References

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Keywords

nephrotic syndrome, 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, Henoch-Schönlein purpura, HSP, systemic lupus erythematosus, diabetes mellitus, syphilis, HIV, hepatitis B, hepatitis C, Wilms tumor, Denys-Drash syndrome, Frasier syndrome

Contributor Information and Disclosures

Author

Jerome C Lane, MD, Assistant Professor of Pediatrics, Northwestern University Medical School; Attending Physician, Department of Pediatrics, Division of Kidney Diseases, Children's Memorial Hospital, Chicago
Disclosure: Nothing to disclose.

Medical Editor

Laurence Finberg, MD, Clinical Professor, Department of Pediatrics, University of California at San Francisco and Stanford University
Laurence Finberg, MD is a member of the following medical societies: American Medical Association
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
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Managing Editor

Adrian Spitzer, MD, Professor, Department of Pediatrics, Albert Einstein College of Medicine; Director of NIH Training Program, Children's Hospital at Montefiore Medical Center
Adrian Spitzer, MD is a member of the following medical societies: American Academy of Pediatrics, American Federation for Medical Research, American Pediatric Society, American Society of Nephrology, American Society of Pediatric Nephrology, International Society of Nephrology, and Society for Pediatric Research
Disclosure: Nothing to disclose.

CME Editor

Howard Trachtman, MD, Program Director, Pediatrics Research, Schneider Children's Hospital, Department of Pediatrics, Division of Nephrology, Professor, Albert Einstein College of Medicine
Howard Trachtman, MD is a member of the following medical societies: American Society of Hypertension, American Society of Nephrology, American Society of Pediatric Nephrology, and Society for Pediatric Research
Disclosure: Nothing to disclose.

Chief Editor

Craig B Langman, MD, The Isaac A Abt, MD, Professor of Kidney Diseases, Feinberg School of Medicine, Northwestern University; Division Head of Kidney Diseases, Children's Memorial Hospital, Chicago
Craig B Langman, MD is a member of the following medical societies: American Academy of Pediatrics, American Society of Nephrology, and International Society of Nephrology
Disclosure: Amgen Grant/research funds None; Altus Pharmaceuticals Grant/research funds None; Genzyme Grant/research funds None; Merck Grant/research funds None; NIH Grant/research funds None

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