Nephrotic Syndrome

Nephrotic syndrome is a collection of signs and symptoms indicating damage to the glomerular basement membrane and the podocytes. With most of the injury focusing on the podocytes. It is characterised:

• Massive proteinuria of > 3g/24 hours (P:CR > 300 mg/mmol, A:Cr > 250 mg/mmol). In children, 40 mg per square meter body surface area per hour.
• Hypoalbuminemia with plasma albumin < 3.0 g/dL.
• Peripheral edema
• Hyperlipidemia and lipiduria

The causes of nephrotic syndrome can be broadly classified into primary causes which encompass diseases that are intrinsic to the kidney and secondary causes that are systemic in nature.

• Pathophysiology
  • The main event leading to nephrotic syndrome is structural damage of the glomerular filtration barrier by the following mechanisms:
    • Deposition of circulating immune complexes in the glomerulus
    • Antibody deposition in the glomerulus which react with endogenous glomerular antigens or planted (foreign) antigens
    • Systemic diseases such as systemic lupus nephritis, hypertension and diabetes mellitus
  • This leads to loss of the structural integrity and negative charge of the glomerular filtration barrier causing an abnormal loss of protein which causes a compensatory increase in hepatic protein synthesis.
  • For a while this bridges the gap in protein loss but when loss exceeds the capacity for compensation the following occurs:
    • Low albumin levels: leading to reduced colloid osmotic pressure hence a shift of fluid into the interstitium causing edema
    • Loss of antithrombin, proteins C and S – these are clotting inhibitors hence their loss leads to a hypercoagulable state increasing the risk of thrombosis
    • Loss of thyroglobulin – this is a protein responsible for transporting thyroxine hence its loss causes hypothyroidism as thyroxine cannot be moved around the body
    • Loss of Vitamin D binding proteins – leading to reduced levels of Vitamin D and concurrent reduced calcium absorption – hypocalcemia
    • Loss of plasma proteins – leading to reduced drug binding hence increased free drug concentrations
    • Loss of immunoglobulins – causing an increased risk of infection
    • Loss of transferrin – leading to reduced iron levels as iron is transported by transferrin
  • To compensate for reduced intravascular oncotic pressure due to low plasma protein levels (particularly albumin) the liver increases production of cholesterol, triglycerides and lipoproteins causing hyperlipidaemia and lipiduria.
  • Due to the shift of fluid from the intravascular space into the interstitium, hypovolemia occurs stimulating the renin-angiotensin-aldosterone system (RAAS) and antidiuretic hormone secretion.
  • This causes increased reabsorption of sodium and water in the renal tubules so as to restore intravascular volume.
  • Sodium retention causes hypertension and exacerbates edema due to increased water reabsorption
• Signs and symptoms
  • Edema
    • Facial edema (first sign of nephrotic syndrome in children )
    • Dependent edema (presents in adults)
    • Generalized edema (presents over time as increasing weight, ascites, pleural and pericardial effusion)
  • Frothy urine – due to lipiduria
  • Hypertension – due to sodium retention (in some cases)
  • Frequent infections – meningococcal and pneumococcal infections
  • Symptoms of hypocalcemia such as tetany, muscle spasms and paraesthesia
  • Symptoms of hypocalcemia such as tetany, muscle spasm and paraesthesia
  • Increased risk of clotting
    • History of deep vein thrombosis; leg pain, swelling
    • History of pulmonary embolism; dyspnea, palpitations, chest pain, hemoptysis
    • Renal vein thrombosis
  • Other symptoms of underlying disease
• Investigations
  • Urinalysis
    • Nephrotic-range proteinuria will be apparent by 3+ or 4+ readings
    • Casts
    • Glycosuria (diabetes)
  • 24 hour urine protein: can be done for an accurate measure of proteinuria
  • Protein:Creatinine ratio (P:CR): a spot sample of urine (first morning urine sample)
    • 300 mg/mmol (3 mg/mg) confirms nephrotic proteinuria.
  • UECs
    • Raised serum creatinine (>4 mg/dL indicates seriously impaired renal function)
  • Serum albumin
    • Less than the normal range of 3.5 to 4.5 g/dL
  • Lipid profile
    • Total cholesterol and triglyceride levels are typically increased
  • Hepatitis B and C serolgy
  • HIV testing
  • Syphilis
  • Antinuclear antibody (ANA)
  • Anti–double stranded DNA (anti-dsDNA) antibodies
  • C3 and C4 omplement
  • HBA1c
  • Random blood sugar testing
  • Serum or urine protein electrophoresis
  • KUB ultrasound: done to ensure the patient has 2 kidneys as having one kidney increases the risk of developing focal glomerulosclerosis and is a contraindication for renal biopsy
    • Increased renal echogenicity is consistent with intrarenal fibrosis.
  • Renal biopsy
  • Phospholipase A Receptor (PLA R) antibodies: PLA R is a transmembrane receptor found on podocytes. Autoantibodies targeting this receptor have been found in 70% of idiopathic membranous nephropathy cases.
    • There is a strong correlation between levels of this antibody and clinical disease activity. Therefore it helps in monitoring disease activity and treatment efficiency.
• Indications for renal biopsy
  • Congenital nephrotic syndrome
  • Age older than 8 years at onset
  • Steroid resistance
  • Frequent relapses or steroid dependency
  • Significant nephritic manifestations
  • Adult nephrotic syndrome of unknown origin
• Treatment of oedema
  • Dietary sodium restriction
  • Fluid restriction <1.5 L a day
  • Loop diuretics (high-dose furosemide or torsemide)
  • Other diuretics e.g. oral thiazide or spironolactone can be used
  Furosemide binds to albumin but due to reduced albumin levels there will be decreased delivery of the drug to the kidney. Albuminuria will increase binding of the drug in the tubular lumen causing it to be lost in urine. For these reasons, furosemide is given in high doses. Consider giving albumin since it is difficult to achieve satisfactory diuresis especially if the serum albumin level is less than 1.5 g/dL.
• Treatment of odema
  • Dietary protein restriction
  • Thiazide diuretic
  • RAAS inhibitors such as ACE inhibitors and ARBs
    • Reduce proteinuria
    • Treats hypertension secondary to sodium retention
• Treatment of hyperlipidemia
  • Statins
• Treatment and prevention of infection
  • Penicillin can be started in children with overt edema
  • Treat bacterial infections promptly
  • Non-immune patients with varicella should receive immunoglobulin therapy if exposure to chickenpox occurs, and acyclovir should be started if the patient develops chickenpox
  • Routine immunizations (Pneumococcal and influenza vaccinations) should be deferred until there are no relapses and the patient has been off immunosuppressants for at least three months.
• Definitive treatment in children
  • Corticosteroids are mainly used for idiopathic nephrotic syndrome.
  • In cases with frequent relapse, steroid dependency or steroid resistance:
    • Cyclophosphamide
    • Mycophenolate mofetil (MMF)
    • Calcineurin inhibitors
    • Rituximab
• Definitive treatment in adults
  • Corticosteroids (prednisone) combined with cylcophosphamide, tacrolimus or cyclosporin can achieve remission
  • Treatment of underlying disease such as strict glycemic control in diabetic patients
• Complications of nephrotic glomerulonephritis
  • Infection
  • Hypocalcemia and bone abnormalities
  • Hyperlipidemia and atherosclerosis increasing the risk for cardiovascular disease
  • Hypercoagulability
  • Hypovolemia
  • Hypertension due to reduced kidney function and fluid retention
  • Edema of the gut could cause defective absorption resulting in malnutrition
  • Ascites and pleural effusions
  • Generalized edema
  • Respiratory distress
  • Sepsis
  • Peritonitis
  • Thromboembolism
  • Failure to thrive
  • Urinary loss of hormone binding proteins such as thyroxine binding globulin thus causing reduced low hormone levels