Nephrotic syndrome is diagnosed by fulfilling two defining characteristics: urine protein excretion (nephrotic range proteinuria) >50 mg/kg per day, and hypoalbuminemia defined as serum albumin <3 g/dL (30 g/L).
●Nephrotic syndrome is a result of injury to the glomerular filtration barrier, which increases its permeability. (See 'Pathogenesis' above.)
●The most common form of childhood nephrotic syndrome is idiopathic nephrotic syndrome. It is characterized by diffuse foot process effacement on electron microscopy and minimal changes (called minimal change disease [MCD]), primary focal segmental glomerulosclerosis (FSGS), or mesangial proliferation on light microscopy. MCD is particularly likely in children under the age of six. (See 'Idiopathic nephrotic syndrome' above and'Epidemiology' above.)
●Idiopathic nephrotic syndrome generally presents with edema, usually first noted as periorbital edema. The edema can become generalized and massive (anasarca) resulting in peripheral edema, ascites, umbilical or inguinal hernias, scrotal or vulva swelling, and/or pleural effusions. (See 'Clinical manifestations' above.)
●Macroscopic hematuria and elevated blood pressure may be present. The presence of either one of these findings makes it less likely that MCD is present, and another renal disease should be considered. (See 'Clinical manifestations' above.)
●The diagnosis of childhood nephrotic syndrome is generally based upon the characteristic clinical and laboratory findings of edema, nephrotic range proteinuria, and hypoalbuminemia. (See 'Diagnosis' above.)
●In children with nephrotic syndrome who have a high probability of having MCD based upon clinical and laboratory findings, we recommend empiric therapy with oral prednisone, thus avoiding renal biopsy (Grade 1B). Renal biopsy is performed in patients who fail to respond to steroid therapy (steroid-resistant nephrotic syndrome) and in those who are less likely to initially respond to steroid therapy. (See "Treatment of idiopathic nephrotic syndrome in children", section on 'Steroid-resistant nephrotic syndrome' and 'Minimal change disease' above.)
●The differential diagnosis includes other diseases that present with edema; these disorders are easily differentiated from nephrotic syndrome by the presence of nephrotic range proteinuria and hypoalbuminemia (See'Differential diagnosis' above.)
Normal glomerular capillary wall
High power electron micrograph shows the three layers of the normal glomerular capillary wall: the fenestrated endothelium (Endo); the glomerular basement membrane (GBM); and the epithelial cell with its foot processes (FP). The foot processes are separate by slit pores which are closed by a thin membrane, the slit diaphragm (arrow). In terms of permeability to macromolecules, the GBM and the slit diaphragms are the major sites of size-selectivity, while the endothelium and GBM are the major sites of charge-selectivity.
Courtesy of Helmut Rennke, MD.
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Light microscopy in minimal change disease
Light micrograph of an essentially normal glomerulus in minimal change disease. There are only 1 or 2 cells per capillary tuft, the capillary lumens are open, the thickness of the glomerular capillary walls is normal, and there is neither expansion nor hypercellularity in the mesangial areas in the central or stalk regions of the tuft (arrows).
Courtesy of Helmut G Rennke.
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Normal glomerulus
Light micrograph of a normal glomerulus. There are only 1 or 2 cells per capillary tuft, the capillary lumens are open, the thickness of the glomerular capillary wall (long arrow) is similar to that of the tubular basement membranes (short arrow), and the mesangial cells and mesangial matrix are located in the central or stalk regions of the tuft (arrows).
Courtesy of Helmut G Rennke, MD.
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Electron microscopy in minimal change disease
Electron micrograph in minimal change disease showing a normal glomerular basement membrane (GBM), no immune deposits, and the characteristic widespread fusion of the epithelial cell foot processes (arrows).
Courtesy of Helmut Rennke, MD.
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Electron micrograph of a normal glomerulus
Electron micrograph of a normal glomerular capillary loop showing the fenestrated endothelial cell (Endo), the glomerular basement membrane (GBM), and the epithelial cells with its interdigitating foot processes (arrow). The GBM is thin, and no electron-dense deposits are present. Two normal platelets are seen in the capillary lumen.
Courtesy of Helmut G Rennke, MD.
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Mechanism of proteinuria in FGS
Dextran sieving profiles in patients with heavy proteinuria and the nephrotic syndrome due to focal glomerulosclerosis (FGS). A fractional dextran clearance of 1 represents complete filtration. Patients with FGS have decreased clearance of smaller dextrans, but increased clearance of dextrans with a radius above 52 Å, suggesting an increased number of larger pores.
Data from Guasch A, Hashimoto H, Sibley RK, et al. Am J Physiol 1991; 260:F728.
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Causes of edema in childhood
| Generalized edema |
| Increased capillary hydrostatic pressure |
| Increased plasma volume from sodium and water retention |
| Heart failure |
| (Localization can be seen in some cardiac disease) |
| Primary renal disease |
| Acute glomerulonephritis |
| Renal failure (acute/chronic) |
| Nephrotic syndrome |
| Drug induced |
| Vasodilators (eg, minoxidil) |
| Dihydropyridine calcium channel blockers (eg, nifedepine and amlodipine) |
| Venous obstruction |
| Hepatic cirrhosis |
| Decreased capillary oncotic pressure (Hypoalbuminemia) |
| Nephrotic syndrome |
| Liver failure |
| Protein losing enteropathy |
| Protein malnutrition (kwashiorkor) |
| Increased capillary permeability |
| Burn |
| Sepsis |
| Localized edema |
| Increased capillary hydrostatic pressure |
| Venous obstruction |
| Extrinsic compression (tumor or lymphadenopathy) |
| Venous thrombosis |
| Increased interstitial hydrostatic pressure |
| Lymphatic obstruction |
| Primary |
| Turner syndrome |
| Noonan syndrome |
| Milroy's disease |
| Lymphedema praecox |
| Secondary |
| Lymphadenitis |
| Granulomatous lymphangitis |
| Autoimmune disease (juvenile idiopathic arthritis & Crohn's disease) |
| Increased capillary permeability |
| Angioedema |
| Allergic reaction |
| Hereditary angioedema |
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Treatment of idiopathic nephrotic syndrome in children
In children with nephrotic syndrome (NS) who have a high probability of having minimal change disease (MCD) based on clinical and laboratory findings, we recommend empiric therapy with oral prednisone, thus avoiding renal biopsy (Grade 1B).
We start with oral prednisone at a dose of 60 mg/m2 per day (maximum of 60 mg/day). When proteinuria disappears, prednisone is continued at the same daily dose for 30 days, followed by alternate-day therapy (at the same dose). Alternate-day therapy is tapered over a one- to two-month period. (See 'Initial pharmacologic therapy' above.)
●Most children with idiopathic NS will respond to steroid therapy. After six months of initial steroid therapy, approximately 40 percent of children with steroid-responsive NS will not relapse, 10 to 20 percent will have less than four relapses, and the remaining will have frequent relapses and/or relapse while on steroid therapy (steroid-dependent). (See 'Steroid response' above.)
●Approximately 90 percent of responding patients attain complete remission within the first four weeks of steroid therapy, and the remaining 10 percent respond after an additional two to four weeks of steroid therapy. (See'Time to response' above.)
●Children with steroid-responsive NS, who are frequent relapsers and/or are steroid-dependent, often develop evidence of steroid toxicity. In these patients, we recommend treatment with a nonsteroidal agent to maintain remission while reducing steroid dosing and toxicity (Grade 1B). (See 'Nonsteroidal therapy' above.)
•In our practice, our initial steroid-sparing agent of choice is levamisole, if it is available. If this is not the case, mycophenolate mofetil (MMF) is our preferred drug for patients with significant steroid toxicity. (See'Levamisole' above and 'Mycophenolate' above.)
•Other experts in the field have suggested the use of a 12-week course of cyclophosphamide in patients with frequently relapsing NS, but do not recommend this regimen in those with steroid-dependent NS, as the long-term remission rate is much lower and does not warrant the significant potential toxicity. (See 'Alkylating agents' above.)
•Although cyclosporine is effective in inducing or maintaining remission in patients with frequently relapsing or steroid-dependent NS, sustained remission requires prolonged treatment and increases the risk of nephrotoxicity. As a result, in our practice, cyclosporine is only used in patients who fail to maintain remission after a course of MMF or cyclophosphamide without a significant steroid dose. (See 'Calcineurin inhibitors'above.)
•Ten percent of children will fail to respond to steroid therapy. These children with steroid-resistant nephrotic syndrome (SRNS) are at increased risk for developing end-stage renal disease (ESRD). (See 'Outcome based upon response' above and "Steroid-resistant idiopathic nephrotic syndrome in children".)
Cumulative rate of remission in response to steroids in MCD
The rate of response of minimal change disease (MCD) to corticosteroid therapy is lower in adults compared with children, and more prolonged therapy is required to achieve a remission.
Adapted with permission from: Nakayama M, Katafuchi R, Yanase T, et al. Steroid responsiveness and frequency of relapse in adult-onset minimal change nephrotic syndrome. Am J Kidney Dis 2002; 39:503.
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