Nephrotic Syndrome Etiology Idiopathic nephrotic syndrome (90%) Minimal change disease (85%) Focal segmental glomerulosclerosis (10%) Mesangial proliferation (5%) Glomerulonephritis; Membranous nephropathy; and membranoproliferative glomerulonephritis (10%)

Idiopathic Nephrotic Syndrome Approximately 90% of children with nephrotic syndrome have idiopathic nephrotic syndrome Male:female ratio (2:1) Peak incidence: 2 – 6 yr The initial episode and subsequent relapses may follow minor infections and, occasionally, reactions to insect bites, bee stings, or poison ivy. more common in males than in females (2:1) and most commonly appears between the ages of 2 and 6 yr.

Idiopathic Nephrotic Syndrome Minimal Change Disease Mesangial Proliferation Focal segmental glomerulosclerosis Light Microscopy Normal or minimal increase in mesangial cells and matrix Diffuse increase in mesangial cells and matrix Mesangial proliferation and segmental scarring

Idiopathic Nephrotic Syndrome Minimal Change Disease Mesangial Proliferation Focal segmental glomerulosclerosis Immunofluorescence Negative Trace to 1+ mesangial IgM and/or IgA staining IgM and C3 staining in the areas of segmental sclerosis

Idiopathic Nephrotic Syndrome Minimal Change Disease Mesangial Proliferation Focal segmental glomerulosclerosis Electron Microscopy Effacement of epithelial foot processes Increased numbers of mesangial cells and matrix; effacement of the epithelial cell foot processes Segmental scarring of the glomerular tuft with obliteration of the glomerular capillary lumen

Idiopathic Nephrotic Syndrome Minimal Change Disease Mesangial Proliferation Focal segmental glomerulosclerosis Steroid response >95% 50% 20% Focal segmental glomerulosclerosis The disease is frequently progressive, ultimately involving all glomeruli, and leads to end-stage renal failure in most patients.

Characteristics Proteinuria Hypoalbuminemia Edema Hyperlipidemia >3.5 g/24 hr in adults >40 mg/m2/hr in children Spot urine protein to creatinine ratio >2.0 Hypoalbuminemia <2.5 g/dl Edema Hyperlipidemia

Proteinuria Results from increased permeability of glomerular basement membrane (GBM) to plasma protein There is hypoalbuminemia bec you excrete protein in the urine The cause of the increased permeability is not well understood. In minimal change disease, it is possible that T-cell dysfunction leads to alteration of cytokines, which causes a loss of negatively charged glycoproteins within the glomerular capillary wall. In focal segmental glomerulosclerosis, a plasma factor, perhaps produced by lymphocytes, may be responsible for the increase in capillary wall permeability.

Degrees of proteinuria Types of proteinuria Mild less than 0.5g/m2/day Moderate 0.5 – 2g/m2/day Severe more than 2g/m2/day Selective proteinuria: where proteins of low molecular weight .such as albumin, are excreted more readily than protein of HMW Non selective : LMW+HMW are lost in urine

Hypoalbuminemia Due to hyperproteinuria Mainly albumin There is hypoalbuminemia bec you excrete protein in the urine

Edema  plasma oncotic pressure  transudation of fluid from the intravascular compartment to the interstitial space  intravascular volume  renal perfusion (activates RAAS)  tubular reabsorption of sodium  water retention urinary protein loss leads to hypoalbuminemia, which causes a decrease in the plasma oncotic pressure and transudation of fluid from the intravascular compartment to the interstitial space. The reduction in intravascular volume decreases renal perfusion pressure, activating the renin-angiotensin-aldosterone system, which stimulates tubular reabsorption of sodium. The reduced intravascular volume also stimulates the release of antidiuretic hormone, which enhances the reabsorption of water in the collecting duct.

Hyperlipidemia Hypoalbuminemia stimulates generalized hepatic protein synthesis Diminished catabolism of lipids Hypoalbuminemia stimulates generalized hepatic protein synthesis, including synthesis of lipoproteins. In addition, lipid catabolism is diminished, as a result of reduced plasma levels of lipoprotein lipase, related to increased urinary losses of this enzyme.

Complications Infection (major) Bacterial peritonitis – most frequent Sepsis Pneumonia Cellulitis UTI Commonly caused by S. pneumoniae and E.coli nfection is the major complication of nephrotic syndrome. Children in relapse have increased susceptibility to bacterial infections owing to urinary losses of immunoglobulins and properdin factor B, defective cell-mediated immunity, immunosuppressive therapy, malnutrition, and edema/ascites acting as a potential "culture medium."

Complications All children with nephrotic syndrome should receive polyvalent pneumococcal vaccine (if not previously immunized), ideally administered when the child is in remission and off of daily prednisone therapy. Nonimmune nephrotic children in relapse exposed to varicella should receive varicella zoster immune globulin (VZIG) within 72 hr of exposure. Influenza vaccine should be given on a yearly basis.

Complications Thromboembolic events Prophylaxis is not indicated increased prothrombotic factors (fibrinogen, thrombocytosis, hemoconcentration, relative immobilization) decreased fibrinolytic factors (urinary losses of antithrombin ill, proteins C and S) Prophylaxis is not indicated Prophylactic anticoagulation is not recommended in children unless they have had a previous thromboembolic event. Overaggressive diuresis should be avoided and use of indwelling catheters limited because these factors may increase the likelihood of clotting complications.

Prognosis Steroid-responsive nephrotic syndrome Repeated relapses Decrease in frequency as the child grows older The majority of children with steroid-responsive nephrotic syndrome have repeated relapses, which generally decrease in frequency as the child grows older.

Prognosis Children who respond to steroids rapidly and those who have no relapses during the first 6 mo after diagnosis tend to follow an infrequently relapsing course

Prognosis Steroid-resistant nephrotic syndrome most often caused by focal segmental glomerulosclerosis Generally have a much poorer prognosis These children develop progressive renal insufficiency, ultimately leading to end-stage renal failure requiring dialysis or renal transplantation.

Prognosis Recurrent nephrotic syndrome develops in 30-50% of transplant recipients with focal segmental glomerulosclerosis. A subset of patients will relapse while on alternate-day steroid therapy or within 28 days of stopping prednisone therapy. Such patients are termed steroid dependent. Patients who respond well to prednisone therapy but relapse four or more times in a 12-mo period are termed frequent relapsers. Children who fail to respond to prednisone therapy within 8 wk are termed steroid resistant.

Prevention Cannot be totally prevented Usually follows minor infections, reactions to insect bites, bee stings, or poison ivy

BioPsychoSocial It is important to indicate to the family that: The child with steroid-responsive nephrotic syndrome will not develop chronic renal failure The disease is generally not hereditary, and The child (in the absence of prolonged cyclophosphamide therapy) will remain fertile. Cyclophosphamide has been shown to prolong the duration of remission and to reduce the number relapses in children with frequently relapsing and steroid-dependent nephrotic syndrome. The potential side effects of the drug (neutropenia, disseminated varicella, hemorrhagic cystitis, alopecia, sterility, and increased risk of future malignancy) should be carefully reviewed with the family before initiating treatment.

BioPsychoSocial To minimize the psychological effects of the condition, the physician should emphasize that the child should be considered normal when in remission and may have unrestricted diet and activity, without the need for urine testing for protein. Cyclophosphamide has been shown to prolong the duration of remission and to reduce the number relapses in children with frequently relapsing and steroid-dependent nephrotic syndrome. The potential side effects of the drug (neutropenia, disseminated varicella, hemorrhagic cystitis, alopecia, sterility, and increased risk of future malignancy) should be carefully reviewed with the family before initiating treatment.

BioPsychoSocial Affected children may attend school and participate in physical activities as tolerated.