Nephrotic Syndrome

DEFINITION:
  • Nephrotic syndrome is a clinical complex characterized by a number of renal and extrarenal features, most prominent of which are
  1. Proteinuria (in practice > 3.0 to 3.5gm/24hrs),
  2. Hypoalbuminemia,
  3. Edema,
  4. Hypertension
  5. Hyperlipidemia,
  6. Lipiduria and
  7. Hypercoagulabilty(result of Loss of Antithrombin III)
PATHOPHYSIOLOGY:
  • Proteinuria :The glomerular structural changes damage to the endothelial surface, the glomerular basement membrane, or the podocytes..
  • Hypoalbunemia : It is due to both the proteinuria and due to the increase renal catabolism (in tubules).
  • Metabolic consequences of proteinuria
  1. Infection
  2. Hyperlipidemia and atherosclerosis
  3. Hypocalcemia and bone abnormalities
  4. Hypercoagulability
  5. Hypovolemia
  • Infection in NS:
  1. Urinary immunoglobulin losses
  2. Edema fluid acting as a culture medium
  3. Protein deficiency
  4. Decreased bactericidal activity of the leukocytes
  5. Immunosuppressive therapy
  6. Urinary loss of a complement factor (properdin factor B) that opsonizes certain bacteria
  • Hyperlipedemia :
  1. Due to increase hepatic lipoprotein synthesis that is triggered by reduced oncotic .
  2. Defective lipid catabolism has also important role.
  3. LDL and cholesterol are increased in majority of patients whereas VLDL and triglyceride tends to rise in patients with severe disease.
  4. It increases the relative risk for MI 5.5 fold and coronary death 2.8 fold.
  • Hypercoagulability :Multifactorial in origin
  1. Increase urinary loss of antithrombin III.
  2. Altered levels and/or activity of protein C & S.
  • Hyperfibronogenemia due to increase hepatic synthesis.
  1. Impaired fibrinolysis due to decrease plasminogen.
  2. Increase platelet aggregability – relative immobility - haemoconcentragtion from hypovolemia. – hyperlipidemia
  3. Alteration in endothelial function
  4. Hypocalcemia :
  • low serum albumin level.
  • Hypovolemia :Hypovolemia occurs when hypoalbuminemia decreases the plasma oncotic pressure, Resulting in a loss of plasma water into the interstitium and causing a decrease in circulating blood volume
ETIOLOGY:
  • Primary causes include-
  1. Minimal-change nephropathy(70-90% children and 10- 15%inadult)
  2. Focal glomerulosclerosis (15%inadult)
  3. Membranous nephropathy (30%inadult)
  4. Mesangial proliferative glomerulonephritis .
  5. Rapidly progressive glomerulonephritis
  • Secondary causes include
  1. Diabetes mellitus
  2. Lupus erythematosus
  3. P. malariae
  4. Amyloidosis and paraproteinemias
  5. Viral infections (eg, hepatitis B, hepatitis C, HIV )
  6. Preeclampsia

Gene Chromosome Protein Location Disease
NPHS l 19 13q nephrin slipt diaphragm Nephrotic syndrome of finnish
NPHS2 125-31(-1 podocin slit diaphragm Steroid resistant nephrotic syndrome

SYMPTOMS & SIGNS:
  •  Anorexia, 
  • Malaise, 
  • Puffy eyelids, 
  • Retinal sheen, 
  • Abdominal pain, 
  • Wasting of muscles, and 
  • Edema:(due to Hypoalbuminemia) the edema is mobile - detected in the eyelids in the morning and in the ankles after ambulation
  • Muehrcke lines in nails 
  • Focal edema may be the reason for seeking help for such complaints as:
  1. Difficulty breathing (pleural effusion or laryngeal edema), 
  2. Substernal chest pain (pericardial effusion), 
  3. Scrotal swelling, 
  4. Swollen knees (hydroarthrosis), 
  5. Swollen abdomen (ascites), and 
  6. Abdominal pain from edema of the mesentery.
  • An early sign of NS is frothy urine. 
  • At presentation,proteinuria is usually > 2 gm/m2/day, or a urine protein/creatinine ratio is > 2 
  • Orthostatic hypotension and even shock may develop in children.
  • Finnish of nephrotic syndrome is caused by defect in Nephrin protein
  • Adults may be hypo-, normo-, or hypertensive. 
  • Oliguria and even Acute renal failure may develop because of hypovolemia and diminished perfusion.
  • Prolonged NS may result in nutritional deficiencies, including 
  1. Protein malnutrition:
  2. Proteins increased in nephrotic syndrome Fibrinogen,Lipoproteins ( due to increased synthesis )
  3. Proteins decreased in nephrotic syndrome Albumin, Transferrin, Cholecalciferol binding protein,Thyroxin binding globulin
  4. Myopathy, 
  • Decreased total Ca++, tetany 
  • Spontaneous peritonitis and opportunistic infections 
  • Coagulation disorders, with decreased fibrinolytic activity 
  • Episodic hypovolemia, are a serious thrombotic risk ( renal vein thrombosis).
  • Hypertension with cardiac and cerebral complications
  • Hyperlipidemia and hypercholesterolemia, secondary to increased hepatic synthesis of lipoproteins and decreased clearance of lipoproteins from the circulation.
  • Hyperlipidemia in these patients also cause systemic atherosclerosis.
  • Marked reduction of HDL receptor protein expression also contribute to increased atherosclerosis.
  • All of these, acts as predisposing factors for the development of coronary artery disease.
DIAGNOSIS: 
  •  Urinalysis
  1. Urine sediment examination 
  2. Urinary protein measurement (24-hr) 
  3. Serum albumin >2.5g/dl l
  4. Serologic studies for infection and immune abnormalities 
  5. Renal ultrasonography 
  6. Renal biopsy
MANAGEMENT:
  • Specific treatment 
  1. In minimal-change nephropathy, glucocorticosteroids, such as prednisone, are used. 
  2. Children who relapse may be treated with rituximab
  3. In some lupus nephritis, prednisone and cyclophosphamide are useful 
  4. Secondary amyloidosis with nephrotic syndrome may respond to anti-inflammatory treatment of the primary disease. 
  5. Oral cyclosporine for Steroid resistant nephrotic syndrome secondary to FSGS not responsive to methylprednisolone 
  • Management Diet and activity
  1. The diet in patients with nephrotic syndrome should provide adequate energy (caloric) intake and adequate protein (1-2 g/kg/d). 
  2. Management Acute Nephrotic Syndrome in Adults 
  3. Diuretics will be needed; furosemide, spironolactone, and even metolazone may be used. Volume depletion may occur with diuretic use, which should be monitored. 
  4. Anticoagulation has been advocated by some for use in preventing thromboembolic complications, 
  • Long-Term Monitoring- Follow-up care in patients with nephrotic syndrome includes 
  1. Immunization, 
  2. Treatment of relapses of steroid-responsive nephrotic syndromes, 
  3. Monitoring for steroid toxicity, and
  • Monitoring of diuretic and angiotensin antagonist regimens.
  1. Minhibitors and 
  2. ARBedication Summary 
  3. Corticosteroids (prednisone)
  4. Cyclophosphamide
  5. Cyclosporine 
  6. Rituximab
  7. Mycophenolate
  8. Diuretics 
  9. ACE 
Exam Question
  • In nephrotic syndrome Transferrin, Albumin & Ceruloplasmin are reduced
  • Oral cyclosporine for Steroid resistant nephrotic syndrome secondary to FSGS not responsive to methylprednisolone
  • Edema in nephrotic syndrome is due to Hypoalbuminemia & Sodium and water retention
  • Finnish of nephrotic syndrome is caused by defect in Nephrin protein
  • The most common gene defect in idiopathic steroid resistant nephrotic syndrome NPHS 2
  • Action of Tolbutamide, Diazepam & Valproate is reduced with nephrotic syndrome and hypoalbuminemia.
  • Nephrotic syndrome increases the susceptibility to coronary artery disease
  • Hypercoagulation in nephrotic syndrome is a result of Loss of Antithrombin III
  • Muehrcke lines in nails are seen in nephrotic syndrome
  • Nephrotic syndrome is the hall mark of Membranous Glomerulopathy,Minimal change disease & Focal segmental Glomerulosclerosis
  • Basic abnormality in a case of nephrotic syndrome is proteinuria
  • Membranoproliferative glomerulonephritis is common in both nephritic syndrome and nephrotic syndrome
  • Patient with nephrotic syndrome on longstanding corticosteroid therapy may develop Hyperglycemia,Neuropsychiatric symptoms & Suppression of the pituitary adrenal axis
  • Patient with congenital nephrotic syndrome requires renal biopsy
  • Serum albumin level below 2.5g/dl l is seen in nephrotic syndrome in child
  • Hyperglycemia ,Neuropsychiatric symptoms & Suppression of the pituitary adrenal axis are the side effects of long term steroid therapy in nephrotic syndrome
  • Malaria causing nephrotic syndrome is P. malariae
  • Most common cause of nephrotic syndrome in adult in Membranous glomerulonephritis
  • Most common cause of nephrotic syndrome in children is Minimal change disease
  • A child had hematuria and nephrotic syndrome (minimal change disease) shows Glomerular function is lost due to loss of poly charge on both sites of glomerular foot process Lipid cast are seen in Nephrotic syndrome
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