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Nephrotic syndrome, idiopathic
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(nephrosis)
It is the most common kidney disease in children: 2 to 7 cases/100,000 children per year. 70 % of the cases begin before 5 years of age.
The diagnostic triad is:
- proteinuria > 50 mg/kg/day, with foaming urines
- hypoproteinaemia
- widespread, soft, painless edema: due to the retention of Na and the reduction in plasma oncotic pressure.
It is the result of a massive urinary loss of proteins. The pathophysiology is variable and not well known:
- immune dysfunction; modified podocytes of the glomeruli are found at electron microscopy
- glomerular pathology due to variable causes: immunologic or infectious
- structural anomaly of the filtration barrier:
According to a genetic point of view:
- NPHS1 [MIM 256 300], due to a mutation of the NPHS1 gene (19q13.12) coding for nephrin, causing the Finnish-type nephrotic syndrome (see this term)
- NPHS2 [MIM 600 995], mutation of the podocin gene (1q25-q31)
- NPHS3 [MIM 610 725], mutation of the PCLE1 gene (10q23.33)
- NPHS4 [MIM 256 370], mutation of the WT1 gene (11p13), associated with Denys-Drash syndrome
- NPHS5 [MIM 614 199], mutation of the LAMB2 gene (3p21.31), which can also cause Pierson syndrome
- NPHS6 [MIM 614 196], mutation of the PTPRO gene (12p12.3)
- NPHS7 [MIM 615 008], mutation of the DGKE gene (17q22), which may also be associated with the development of an atypical uremic-hemolytic syndrome of infancy
- NPHS8 [MIM 615 244], mutation of the ARHGDIA gene (17q25.3)
- NPHS9 [MIM 615 573], mutation of the COQ8B gene (19p13.2)
- NPHS10 [MIM 615 861], mutation of EMP2 gene (16p13.13)
- NPHS11 [MIM 616 730], mutation of the NUP107 gene (12q15), other mutations of which are associated with Galloway-Mowat syndrome
- NPHS12 [MIM 616 892], mutation of the NUP93 gene (16q13)
- NPHS13 [MIM 616 893], mutation of the NUP205 gene (7q33)
- NPHS14 [MIM 615 575], or RENI syndrome (acronym for Renal Endocrine Neurologic Immune) due to a mutation of the SGPL1 gene (10q22.1)
- NPHS15 [MIM 617 609], mutation of the MAGI2 gene (7q21.11)
- NPHS16 [MIM 617 783], mutation of the KANK2 gene (19p13.2)
- NPHS17 [MIM 618 176], mutation of the NUP85 gene (17q25.1)
- NPHS18 [MIM 618 177], mutation of the NUP133 gene (1q42.13), which may be associated with Galloway-Mowat syndrome
- NPHS19 [MIM 618 178], mutation of the NUP160 gene (11p11.2)
- NPHS20 [MIM 301 028], mutation of the TBC1D8B gene (Xq22.3)
- NPHS21 or NPHS 25 [MIM 618 594], mutation of the AVIL gene (12q14.1)
- NPHS22 [MIM 619 155], mutation of the NOS1AP gene (1q23.3)
- NPHS23 [MIM 619 201], mutation of the KIRREL1 gene (1q23.1)
- NPHS24 [MIM 619 263], mutation of the DAAM2 gene (6p21.2)
- NPHS26 [MIM 620 049], mutation of the LAMA5 gene (20q13.33)
As there is confusion in the literature between nephrotic syndrome (clinical description) and focal segmental glomerulosclerosis (histological image of a frequent cause of nephrotic syndrome) other genetic causes have been classified under the acronym FSGS (focal segmental glomerulosclerosis).
These are
- FSGS1 [MIM 603 278], mutation of the ACTN4 gene (19q13.2)
- FSGS2 [MIM 603 965], mutation of the TRPC6 gene (11q22.1)
- FSGS3 [MIM 607 832], mutation of the CD2AP gene (6p12.3)
- FSGS4 [MIM 612 551], mutation of the APOL1 gene (22q12.3)
- FSGS5 [MIM 613 327], mutation of the INF2 gene (14q32.33)
- FSGS6 [MIM 614 131], mutation of the MYO1E gene (15q22.2)
- FSGS7 [MIM 616 002], mutation of the PAX2 gene (10q24.31)
- FSGS8 [MIM 616 302], mutation of the ANLN gene (7p14.2)
- FSGS9 [MIM 616 220], mutation of the CRB2 gene (9q33.3)
The likelihood of a genetic cause increases as the age of onset decreases (< 1 year of age). Most of these cases concern only a few families.
- presence of a circulating factor modifying the permeability of the filtration barrier: heparanase, hemopexine, angiopoietin-like 4 (ANGPTL4), cardiotrophin-like cytokine 1, soluble urokinase plasminogen activator receptor (suPAR).
The nephrotic syndrome is said to be 'pure' if it is not accompanied by high blood pressure, hematuria or renal failure.
It is said 'steroid-sensitive' if it responds favorably to corticosteroids within less than a 4 weeks period time, with a variable risk of relapse when the treatment is stopped, or 'steroid-resistant' with a high risk of evolution towards chronic renal failure. Most genetic forms are cortico-resistant.
The most common form is the primitive idiopathic nephrotic syndrome. Its histological picture at biopsy is either:
- a glomerulopathy with minimal glomerular lesions ("minimal changes")(NPHS6): 90 % of cases are cortiocresistant
- a diffuse mesangeal proliferation (NPHS6)
- a segmental and focal glomerulosclerosis (or hyalinosis) (NPHS6 or FSGS 1): 20 % of cases are corticosensitive.
The onset is often brutal, after a viral infection. It is more common in boys. There seems to be a genetic predisposition for the steroid-sensitive forms: HLA-DQA1 and HLADQB1 polymorphism are frequently observed.
Less frequent, non-idiopathic forms are:
- associated with a rare genetic diseases: Alport, Frasier, Pierson, nail-patella, Denys-Drash, Galloway-Mowat, Finnish-type nephrotic syndrome.
- forms secondary to immune glomerulonephritis: extramembranous or membranoproliferative glomerulonephritis (generally "impure"), sickle cell anemia
- forms secondary to a systemic disease: rheumatoid purpura, lupus (generally "impure")
- forms due to a medication: NSAID's, D-penicillamine, bisphosphonates, rifampicin
- forms due to infection: perinatal (CMV, toxoplasmosis, rubella) or later (hepatitis B or C, HIV1, malaria, chicken pox)
- forms secondary to malignancy: thymoma, lymphoma, leukemia
The treatment is:
- salt-free diet, water restriction
- corticosteroid therapy for 8 to 12 weeks with a starting dose of 60 mg/m2/day. In case of corticosensitivity, proteinuria improves in 1 to 2 weeks time. However, 60 % of corticosensible cases present at least one relapse that requires restarting corticosteroid therapy. These relapses are often preceded by an infectious episode
- in case of corticoresistance, immunosuppressants: levamisole (anthelminthic with immunomodulating properties), cyclophosphamide, cyclosporine, tacrolimus, mofetil, rituximab, mizoribine
- in some cases, a conversion enzyme inhibitor or an antagonist of the angiotensin 2 receptors can be added to decrease proteinuria, especially if high arterial blood pressure is present.
- sometimes, IV albumin administration; diuretics with caution (can worsen the hypovolemia).
The complications of the nephrotic syndrome are:
- infections due to decreased IgG levels: notably, spontaneous bacterial peritonitis (Str. pneumoniae), pneumonia (Str. pneumoniae, H. influenzae, St. aureus...)
- thrombosis: usually venous, more rarely arterial due to thrombocytosis and a decreased plasma level of antithrombin III, protein C and S and to fibrinolysis disorders
- anemia
- hyperlipemia (cholesterol, triglycerides) and its cardiovascular complications
- acute renal failure in a context of hypovolemia, sepsis or interstitial nephritis caused by NSAIDs, or chronic renal failure in case of corticoresistance
- complications of corticosteroid therapy.
Anesthetic implications:
check the electrolytes, serum creatinine, complete blood count; corticosteroid replacement therapy in case of treatment with cortisone; venous access difficulties and risk of thrombosis (central venous access); antibiotic prophylaxis. The nephrotic syndrome is the only situation where hypoalbuminemia is not offset by an increase in α1 -glycoprotein: the existence of nephrotic syndrome therefore results in a significant decrease in the protein binding of local anesthetics and other anesthetic drugs.
References :
Updated: January 2025