The nephrotic syndrome consists of proteinuria, hypoalbuminemia, and hyperlipidemia with or without edema. In children <10 years, the most common cause is minimal change disease which frequently responds to corticosteroid therapy and has a good long term prognosis. Failure to respond to steroid therapy suggests a poor long term renal prognosis. Proteinuria found incidentally in teens is often caused by orthostatic proteinuria, a benign condition without long term sequelae.
Proteinuria
Proteinuria is typically diagnosed by urine dip-stick. If proteinuria is found, especially in a teenager, it should be confirmed with a first morning urine specimen. Quantitation of proteinuria can be done either with a 24 hour urine or, more conveniently, a first morning spot specimen for urine protein/creatinine ratio. A value <0.2 (mg/mg) is considered normal and a value >2 is consistent with the nephrotic syndrome.
Proteinuria on a day or upright specimen and absent on a first morning or recumbent specimen is diagnostic for orthostatic or postural proteinuria. This is a common finding in healthy adolescents and teens and is felt to be a benign condition without long term sequelae.
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Tubular proteinuria can be diagnosed when the dip-stick is negative or trace (it measures urinary albumin) and there is protein noted on a quantitative specimen (see above). This discordance indicates abnormal losses of low molecular weight proteins that are normally reabsorbed in the proximal tubule and is indicative of abnormal tubular function as seen in interstitial nephritis or some autosomal recessive renal syndromes such as nephronophthesis or Dent’s Disease. If necessary, quantitation of tubular proteinuria can be estimated by measuring urine β2 microglobuliln or α retinol binding protein excretion. Alternatively, tubular proteinuria can be estimated by subtracting total urinary protein from total urinary albumin.
The Nephrotic Syndrome
The definition of the nephrotic syndrome requires that the patient have:
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Albuminuria
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Hypoalbuminemia
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Hyperlipidemia
Edema is a common presenting symptom but is not required to make the diagnosis. Most children with the nephrotic syndrome present with dramatic edema. They initially are often misdiagnosed as having an allergic reaction. The most common form of the nephrotic syndrome in children under 5-8 years of age is minimal change disease which has a good response to corticosteroid therapy and an excellent long term prognosis. As children reach puberty less favorable forms of glomerular disease such as focal segmental glomerulosclerosis (FSGS) are more common which have variable responses to therapy and a more worrisome long term prognosis.
Younger children usually are initially treated with corticosteroids as they have a high chance of responding to this medication. Teenagers or a child who has an unusual presentation – such as having hypertension, cellular casts in the urine, or signs of systemic disease leading to the nephrotic syndrome – should have a renal biopsy done before commencing immunosuppressive therapy.
Approximately 85% of children under the age of 5 will have MCNS. Typically they present with the gradual onset of what can be quite marked edema. There is not usually a prodromal illness and patients usually are normotensive. The urine has 4+ proteinuria and the sediment has microhematuria in about 30% of cases but otherwise is benign. Simple screening laboratory work to rule out secondary causes (see below) is appropriate and placement of a PPD should occur promptly. Renal biopsy is not indicated for these children. Initial therapy includes:
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Prednisone at 2 mg/kg/day to a maximum of 60 mg for 6 weeks, tapered to 60% of initial dose given q.o.d. for 4-6 weeks and then stopped.
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Dietary sodium restriction.
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Judicious use of diuretics (usually a loop diuretic) if the edema is causing clinical symptoms.
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Prophylactic antibiotics are not indicated.
90% of children will respond by their urine becoming protein free within 4 weeks of commencing therapy and 95% within 6 weeks. Response is accompanied by a brisk diuresis and an often dramatic weight loss.
At least two thirds of children with MCNS will have a relapse. A relapse is defined as 2+ or greater proteinuria for 3 consecutive days. It should be treated with 2 mg/kg/day prednisone until response or remission occurs which is defined as negative or trace proteinuria for 3 consecutive days. Prednisone is tapered to 60% of daily dose given q.o.d. for 4 weeks and then stopped. Relapses are most common in the years immediately following initial diagnosis and then usually become less frequent.
As long as the child continues to respond to steroids, he/she most likely has MCNS and an excellent long term prognosis and renal biopsy is not indicated.
While edematous, children with nephrotic syndrome are at risk for infection, due to tissue stasis, urinary losses of IgG complement factors B and D, and immunosuppressive therapy. Encapsulated organisms such as s. pneumoniae are most common pathogens. Spontaneous bacterial peritonitis is the most worrisome acute infection. This is a medical emergency and must be diagnosed (preferably by peritoneal tap and culture) and treated promptly. The most common organisms are strep pneumoniae and E. Coli. Skin infections can rapidly progress to cellulitis in an edematous child.
Efforts should be made to ensure that children with nephrotic syndrome are fully vaccinated, including with the 23-valent pneumococcal vaccine. Ideally, vaccines should be administered during remission or on alternate day or no steroids. If a child has not previously been immunized for varicella or had chickenpox and is exposed, severe complications can occur.
Children with nephrotic syndrome are also at risk of thromboembolic disease, most commonly of the renal vein, inferior vena cava, deep veins of the legs, and sagittal sinus. This is a result of loss of anti-coagulant factors in the urine, over production of pro-coagulant factors by the liver, and possibly central hypovolemia. Routine anticoagulation is generally not recommended, and ambulation and mobility should be encouraged. Some physicians recommend low dose aspirin while in relapse.
Once the child has responded to therapy and is no longer edematous, the principal complications are those related to prolonged steroid use including weight gain, cushingoid facies and habitus, delayed growth, and increased risk of infection.
About 10% of children under 5 to as many as 60-70% of older teenagers will fail to respond to initial steroid therapy. Clinical hints of a lesser likelihood of steroid response include an older age, hypertension at presentation, cellular casts in the urinary sediment, nephrotic syndrome without much edema, and African American race. A renal biopsy is required to make a diagnosis and plan therapy. The most common lesion seen is focal and segmental glomerulosclerosis (FSGS) with membranous glomerulonephritis (MGN) and membranoproliferative (MPGN) being less common.
Treatment of FSGS is unsatisfactory. Several recent large multicenter trials have been unsuccessful in identifying effective therapy. If FSGS is secondary to another disease such as HIV, then control of the primary disease is the most effective therapy. About 30-40% of patients with favorable histology will respond to immunosuppressive medications such as calcineurin inhibitors by decreasing proteinuria and edema, however this response should be differentiated from the complete cessation of proteinuria which defines a response in MCNS.
All patients with persistent proteinuria should be treated with anti-proteinuric medications such as ACE inhibitors and/or ARB’s which have shown to delay progression. Control of hyperlipidemia should be attempted.
FSGS – Causes
Recently FSGS has been subclassified (See Figure 1). ‘Tip’ lesion has the best prognosis while ‘collapsing’ has the worst. A careful evaluation for possible primary causes of FSGS should occur depending on the pathology and to a lesser extent the family history.
Figure 1.
Various forms of FSGS (courtesy of Charles Jennette)
If collapsing FSGS is diagnosed, viral etiologies such as HIV and parvovirus should be ruled out. As many as 30% of patients in some Northern European studies have a mutation in NPHS2 causing their FSGS. They would not be expected to respond to immunosuppressive therapy. The list of mutations that can cause FSGS has grown dramatically in the last decade (see Table I). FSGS can also be caused by conditions that cause overwork of the glomeruli such as morbid obesity or in people born with an insufficient nephron mass due to renal hypo- or dysplasia or extreme prematurity.
Table I.
| Syndrome | Inheritance | Locus | Gene | Protein |
|---|---|---|---|---|
| Isolated DMS | AR | 11p13 | WT1 | WT1 |
| Denys Drash | AD | 11/13 | WT1 | WT1 |
| Frasier | AD | 11p13 | WT1 | WT1 |
| Recessive familial FSGS | AR | 1q25 | NPHS2 | podocin |
| Finnish CNS | AR | 19q13 | NPHS1 | nephrin |
| Recessive Nephrotic syn | AR | 10q23-24 | NPHS3/PLCE1 | PLCE1 |
| Pierson | AR | 3q21 | LAMB2 | laminin B2 |
| Nail-patella | AD | 9q34.1 | LMX1b | Lmx1b |
| SRNS with deafness | AR | 14q24.2 |
The list of mutations that can cause FSGS has grown dramatically in the last decade (Table 1). Nearly all the mutations relate to the podocyte (See Figure 2). The podocyte is the final barrier to glomerular filtration. The slit membrane between podocytes is made up of a lipid raft containing nephrin which serves as an important mechanical barrier to urinary protein loss. Also, the podocyte is strongly negatively charged effectively repelling negatively charged albumin.
Figure 2.
Podocyte from Gbadegesin R, et al. Pediatr Nephrol 2011;26:1001-1015
A mutation in NPHS1, which codes for nephrin leads to the Finnish type of congenital nephrotic syndrome. This is clinically characterized by prenatal polyhydramnios and severe, often life threatening edema in infancy with very severe proteinuria. NPHS2 codes for podocin which serves as a protein anchor for nephrin. Podocin mutations usually present with proteinuria in the first decade, but late onset disease has also been described. The Wilm’s Tumor Inhibitor gene (WT-1) is critical for normal podocyte development and maintenance. Mutations in WT-1 cause the nephrotic syndrome in syndromes that often also have genital abnormalities. Denys Drash (male pseudohermaphroditism, nephrotic syndrome, and often Wilm’s tumor) and Frasier Syndrome (female phenotype in an XY child with FSGS and gonadoblastomas) are examples of this. Mutations in LAMB2, alpha-actinin-4, TRPC6, NF2, and other genes are also described. Children with monogenic forms of FSGS do not respond to immunosuppressive therapy.
High risk polymorphisms in apolipoprotein L1 (APOL1) is associated with FSGS in African American children, and likely portends more aggressive disease.
There are at least two possible mechanisms for the amelioration of proteinuria by calcineurin inhibitors. They block T cell activation at IL-2. It is postulated that, at least in some patients, T cells may be involved in producing a circulating factor (a lymphokine) that causes podocyte damage. This is best shown by the nearly immediate occurrence of proteinuria after renal transplant in some patients with FSGS. Another mechanism may be the mechanical effect of cyclosporin in stabilizing synaptopodin, an important element in the cytoskeleton of podocytes.
Although some patients with minimal change nephrotic syndrome often are initially diagnosed as having allergic symptoms due to the periorbital edema, as the edema worsens and does not respond to therapy and a urinalysis is obtained, the diagnosis is unmistakable. Proteinuria distinguishes the edema of the nephrotic syndrome from the dependent edema of congestive heart failure or severe liver disease.
The etiology of minimal change nephrotic syndrome is unknown. There has been speculation for many years that MCNS is related to T cell activation since the action of the most effective medications – corticosteroids, alkylating agents, and calcineurin inhibitors – are all, at least in part, at the T cell. However, thus far no convincing evidence for this hypothesis has arisen. The fact that many children relapse after an intercurrent viral infection lends some weak support to this hypothesis.
Proteinuria should be confirmed with either a 24 hour urine for protein excretion or, more conveniently, a first morning spot specimen for urine protein/creatinine ratio. A value <0.2 (mg/mg) is considered normal and a value >2 is consistent with the nephrotic syndrome. A careful urinalysis should be done to ensure there are no formed elements suggestive of an inflammatory glomerulonephritis (e.g. RBC casts). Serum albumin, creatinine, glucose and cholesterol should be measured.
Screening for secondary causes of nephrotic syndrome depends somewhat on the clinical situation. In most cases a C3 complement and an ANA are sufficient in most children. A low C3 suggests either MPGN or possibly SLE. Hepatitis B, C and HIV studies should be obtained for high risk patients. A positive ANA must be confirmed by more definitive testing such as anti-double stranded DNA.
Routine imaging typically has no role in the diagnosis or therapy of the nephrotic syndrome, except that most centers do renal biopsies with the aid of real-time ultrasound guidance.
A renal biopsy is indicated in a child with nephrotic syndrome who has failed to respond to corticosteroid therapy or a newly diagnosed child who has atypical clinical findings suggestive of a diagnosis other than steroid responsive minimal change disease. These would include an older age at presentation (>12 years), hypertension, an ‘active’ urine sediment (many RBC’s or RBC casts), or renal insufficiency. A renal biopsy is also reasonable in an otherwise asymptomatic child with significant persistent proteinuria (U/Pc>1.0) on first morning urines.
See above under minimal change nephrotic syndrome.
What to do for the child with persistent edema
Some children who fail to respond to steroids have troublesome persistent edema. Careful attention to sodium restriction is essential. As these children are nearly always hypoalbuminemic, diuretic therapy must be carefully prescribed to avoid excessive prerenal azotemia, which may lead to acute kidney injury. Sometimes infusion of 1 gm/kg of 25% albumin prior to diuretic administration is useful (see below). This should be done only in hospital by an experienced physician.
Loop diuretics at a dose of about 1 mg/kg are often used, sometimes combined with a thiazide diuretic. The combination of furosemide and metolazone is reserved for the most resistant edema. Hypokalemia is a common complication.
Albumin and furosemide infusion
This is used in hospital for severe edema, such as symptomatic pleural effusion or ascites, severe genital edema, or to help clearing cellulitis in an edematous area. It should not be used for routine treatment of edema. Typically, it is given once or at most twice every 24 hours at a dose of 1 gram/kg of 25% albumin over about 4 hours. Furosemide 1 mg/kg i.v. is given 2-3 hours into the infusion and then again at the end of the infusion.
The patient needs to be closely monitored for hypertension and hypotension. Treatment should be continued only until the indication for treatment is improved. Acute renal failure is an unusual but well recognized complication. Hypokalemia is common. Because of the risks involved, this therapy should be prescribed only in consultation with a pediatric nephrologist.
What about the child with very frequent relapses of steroid sensitive NS?
Relapses of the nephrotic syndrome occur in 60-70% of children with steroid sensitive (minimal change) nephrotic syndrome. About half of these children may have frequent relapses defined as more than two relapses in a 6 month period. If the child is experiencing side effects from the frequent relapses, or more commonly from the prednisone used to treat the relapses, then adjunctive therapy should be considered. The most commonly observed troublesome side effects are behavior changes, hypertension, growth retardation and excessive weight gain. Less common side effects are posterior subcapsular cataracts, osteopenia, and parental “fatigue” due to managing a chronic illness.
Adjuvant therapy includes:
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Cyclophosphamide 1-2 mg/kg p.o. for 8-12 weeks. This will allow a steroid free remission of up to 2 years in 70-80% of patients.
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Calcineurin inhibitors (cyclosporin or tacrolimus). These are effective in most patients allowing tapering off of steroids, but prompt relapse frequently occurs when these medications are discontinued.
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Mycophenolate mofeteil (MMF). This is less well studied but probably allows a steroid free remission in at least half of children as long as the medication is continued.
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Rituximab. Rituximab is an anti-CD20 monoclonal antibody that depletes B-cells. There is mounting evidence that B-cell depletion therapy with rituximab may benefit children with frequently relapsing or steroid dependant minimal change disease by prolonging remission and reducing cumulative steroid exposure.
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Low dose continuous or q.o.d. steroid therapy.
These therapies are all potentially toxic and should be prescribed only in consultation with a pediatric nephrologist.
As long as the child remains steroid sensitive, renal biopsy is not indicated.
The most common side effect of prolonged prednisone therapy for the nephrotic syndrome include Cushingoid facies and habitus, behavior changes, hypertension, growth retardation and excessive weight gain. Less common side effects are posterior subcapsular cataracts, and osteopenia.
Alkylating agents, such as cyclophosphamide, used in patients with frequent relapses may cause severe leukopenia, transient alopecia, and in higher doses bladder irritation. Long term potential side effects of gonadal damage and carcinogenesis are worrisome.
Calcineurin inhibitors require close monitoring of blood levels as they have a narrow therapeutic to toxic ratio. All are potentially nephrotoxic and increase blood pressure and infectious risks. Common side effects of cyclosporin include hirsutism and gingival hypertrophy.
Mycophenolate may cause GI upset, leukopenia, and increased risk of viral infections.
Side effects of Rituximab include infusion reactions and increased susceptibility to infection. There is limited data, however, regarding the long term effects of Rituximab.
Patients with the nephrotic syndrome who are steroid sensitive generally have a good long term prognosis. Only about 5-10% will eventually become steroid resistant and have a progressive glomerulonephritis.
On the other hand, steroid resistant patients often progress to renal insufficiency at a rate that varies greatly between pathological diagnoses and individual patients.
Although orthostatic proteinuria is common, affecting 3-5% of normal teenagers, nephrotic syndrome is uncommon with an estimated incidence of about 1:40,000 children annually.
Secondary forms of the nephrotic syndrome can arise as a complication of a primary disease process. Viral infections such as hepatitis B and C, HIV, and parvovirus B19, can lead to the nephrotic syndrome. Bacterial infections such as secondary syphilis and coagulase negative staphylococcal infections of shunts or prostheses may cause an immune complex associated nephrotic syndrome. Of course, nephrotic syndrome can be a prominent feature in most forms of glomerulonephritis, including acute post-streptococcal glomerulonephritis, IgA glomerulonephritis, membranoproliferative glomerulonephritis, and membranous nephritis.
Systemic lupus nephritis patients often have marked proteinuria and nephrosis. Nephrotic syndrome can be caused by a paraneoplastic syndrome, especially in patients with Hodgkin’s Disease. Diabetes mellitus is the most common cause of nephrotic syndrome in older adults, but is unusual in pediatrics.
As discussed above, various mutations affect the structure and or function of the podocyte leading to proteinuria. Some of the infectious agents cause an immune complex nephritis while the mechanism of damage of other pathogens is uncertain.
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Untreated, the nephrotic syndrome will lead to anasarca, malnutrition, and eventual death from infection.
Patients with steroid resistant disease, such as FSGS, are at high risk for eventual progression to end stage renal disease requiring dialysis and/or transplantation.
While edematous, these children are at risk for infection, with spontaneous bacterial peritonitis being the most worrisome. This is a medical emergency and must be diagnosed (preferably by peritoneal tap and culture) and treated promptly. The most common organisms remains strep pneumoniae and E. Coli. Skin infections can rapidly progress to cellulitis in an edematous child.
Because of urinary loss of factors that inhibit coagulation and possibly related to central hypovolemia, nephrotic patients in relapse are at risk of thromboembolism. Some physicians recommend low dose aspirin while in relapse.
Once the child has responded to therapy and is no longer edematous, the principal complications are those related to prolonged steroid use including weight gain, cushingoid facies and habitus, delayed growth, and increased risk of infection.
Analysis of possible genetic causes of FSGS can be obtained (genetests.org), some on a clinical basis and others on a research basis. The yield of such investigations is likely highest in infancy and early childhood. Those children with a family history of the nephrotic syndrome should be evaluated for genetic causes.
With the exception of infectious etiologies, there are no known preventative measures to decrease the risk of the nephrotic syndrome.
D’Agati, VD, Fogo, AB, Bruijn, JA, Jennette, JC. “Pathologic classification of focal segmental glomerulosclerosis: a working proposal”. Am J Kidney Dis. vol. 43. 2004. pp. 368-382. (This article describes the various pathological types of FSGS.)
Gipson, DS, Massengill, SF, Yao, L, Nagaraj, S, Smoyer, WE, Mahan, JD. “Management of childhood onset nephrotic syndrome”. Pediatrics. vol. 124. 2009. pp. 747-57. (A method of treating steroid sensitive nephrotic syndrome based on the practice patterns of North American pediatric nephrologists. There is also a discussion of steroid resistant nephrotic syndrome.)
Hodson, EM, Willis, NS, Craig, JC. “Interventions for idiopathic steroid-resistant nephrotic syndrome in children”. Cochrane Database Syst Rev. 2010 Nov 10. pp. CD003594(Meta-analysis.)
Hahn, D, Hodson, EM, Willis, NS, Craig, JC. “Corticosteroid therapy for nephrotic syndrome in children”. Cochrane Database Syst Rev. 2015 Mar 18. pp. CD001533(Meta-analysis.)
Hodson, EM, Willis, NS, Craig, JC. “Non-corticosteroid treatment for nephrotic syndrome in children”. Cochrane Database Syst Rev. 2008 Jan 23. pp. CD002290(Meta-analysis.)
Ravani, P, Bonanni, A, Rossi, R. “Anti-CD20 Antibodies for Idiopathic Nephrotic Syndrome in Children”. CJASN. 2016 April. pp. 710-720. (A mini-review of the use of Rituximab in children with nephrotic syndrome.)
Teo, S, Walker, A, Steer, A. “Spontaneous bacterial peritonitis as a presenting feature of nephrotic syndrome”. J Paediatr Child Health. 2013 Dec. pp. 1069-1071. (A recent and concise review of spontaneous bacterial peritonitis in the nephrotic syndrome.)
Sampson, M, Hodgin, J, Kretzher, M. “Defining nephrotic syndrome from an integrative genomics Perspective”. Pediatr Nephrol. 2015. pp. 51-63. (Reviews integrative genomic approaches to classifying nephrotic syndrome.)
Ng, DK, Robertson, CC, Woroniecki, RP. “APOL1-associated glomerular disease among African-American children: a collaboration of the Chronic Kidney Disease in Children (CKiD) and Nephrotic Syndrome Study Network (NEPTUNE) cohorts”. Nephrology Dialysis Transplantation. April 2016. (Recent data regarding APOL1 mutations in African American children with renal disease.)
Sadowski, CE, Lovric, S, Ashraf, S. “A Single-Gene Cause in 29.5% of Cases of Steroid-Resistant Nephrotic Syndrome”. Journal of the American Society of Nephrology. vol. 26. 2015. pp. 1279-1289.
Sethna, CC. “Treatment of FSGS in Children”. Advances in chronic kidney disease. vol. 21. 2014-03. pp. 194-199. (A review of treatments for FSGS in children.)
Ongoing controversies regarding etiology, diagnosis, treatment
The search for a circulating agent that causes recurrence of FSGS in a renal transplant has been ongoing for two decades. The rapidity of onset of proteinuria in some patients, especially post renal transplantation, clearly indicates that a circulating factor must be present, but several promising assays have not survived repeat testing.
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