Nephrotic syndrome

Nephrotic syndrome is a clinical syndrome which includes the following clinical features:

• Features which are always present:
  • Nephrotic-range proteinuria (> 3,5 g/day)
  • Hypoproteinaemia, hypoalbuminaemia
  • Oedema (periorbital/leg oedema, anasarca, ascites, hydrothorax)
• Features which are often present:
  • Dyslipidaemia
  • Hypercoagulability (loss of anticoagulant proteins)
  • Increased risk of infections
  • Shrinkage of kidneys

Protein loss of 3,5 g/day is referred to as nephrotic-range proteinuria.

Etiology

• Primary
  • Minimal change disease/nephropathy
  • Focal segmental glomerulosclerosis (FSGS)
  • Membranous glomerulonephritis/nephropathy
• Secondary
  • Diabetic nephropathy
  • Amyloid nephropathy
  • SLE

In adults, membranous glomerulonephritis and FSGS are the most common causes.

In children, minimal change disease accounts for almost all cases of nephrotic syndrome.

Pathomechanism

Heavy proteinuria occurs due to the damage of the podocytes and due to loss of the negative charge of the glomerular basement membrane. The liver can synthesize up to approximately 3,5 g albumin per 24 hours, and so a protein loss of 3,5 g/day will eventually lead to hypoalbuminaemia.

The name minimal change disease comes from the fact that light microscopy and immunofluorescence show only minimal changes. Electron microscopy shows characteristic changes in the foot processes, though.

The name focal segmental glomerulosclerosis refers to the fact that not all glomeruli are involved (focal), not all parts of the glomeruli are involved (segmental), and that interstitial tissue accumulate in the glomeruli (glomerulosclerosis).

Membranous glomerulonephritis occurs due to immune complexes in the glomerular basement membrane.

Due to the loss of antithrombotic proteins (ATIII, protein C & S), patients with nephrotic syndrome have increased risk for thromboembolism, especially DVT or renal vein thrombosis. Due to the loss of immunoglobulins, there’s an increased risk for infections, especially pneumococcal. Due to the increased synthetic activity of the liver to compensate for the lost albumin, triglyceride and LDL levels increase, causing dyslipidaemia.

Clinical features

Patients with nephrotic syndrome almost always present with periorbital oedema and/or oedema in the legs. They typically experience periorbital oedema in the morning and pitting oedema during the day, due to gravity. Patients may also experience foamy urine due to nephrotic-range proteinuria.

Some patients, especially with FSGS, may experience nephroso-nephritic syndrome rather than nephrotic syndrome. Nephroso-nephritic syndrome is a sort of combination of nephrotic and nephritic syndromes, with features of both, usually nephrotic syndrome with haematuria and hypertension.

Diagnosis and evaluation

Severe proteinuria can be easily detected with the semiquantitative urine analysis, which usually gives three or four crosses.

Kidney biopsy is indicated in all cases where it’s suspected that the nephrotic syndrome is primary. If secondary, it’s not always necessary.

Membranous glomerulonephritis is special in that anti-phospholipase A2 receptor (anti-PLA2R) antibodies are present in the serum and so serology can be enough to diagnose it. If kidney biopsy is performed, anti-PLA2R deposition is visible on immunofluorescence.

Kidney biopsy is not indicated in children with nephrotic syndrome, as it’s assumed that they have minimal change disease until proven otherwise. If the treatment does not help, we can start to think of other causes, especially FSGS.

Treatment

The most important treatment of primary nephrotic syndrome is steroids (methylprednisolone) + another immunosuppressant, usually cyclophosphamide. For secondary nephrotic syndrome, immunosuppressants are ineffective and the underlying cause must be treated.

For minimal change disease, non-specific renoprotective + steroids for a few months gives complete remission in almost all cases. There are three possible outcomes: 1) complete remission, 2) steroid-resistance (progression despite steroid treatment), or 3) steroid-dependence (relapse after stopping steroids). In case of 2 or 3 we must add cyclophosphamide or cyclosporine to the steroid.

For FSGS, the treatment is the same as for minimal change, however complete remission is less common, and steroid-resistance and dependence are more common. In fact, many patients with steroid-resistance minimal change disease actually are actually misdiagnosed and rather have FSGS.

Many cases of membranous glomerulonephritis spontaneously resolve within 3 – 6 months, so instead of initiating immunosuppressive therapy early we give only non-specific renoprotective therapy for 3 – 6 months. If remission hasn’t occurred after that, we initiate immunosuppression (steroid + cyclophosphamide).

Proteinuria and dyslipidaemia are dangerous for the kidney, and so in all cases of nephrotic syndrome it’s important to initiate non-specific renoprotective treatment to reduce proteinuria and dyslipidaemia. This usually includes either ACEi or ARB combined with an MRA for the proteinuria, as well as statin (+ ezetimibe if necessary) for dyslipidaemia. Furosemide (+ thiazide if necessary) is used to decrease the oedema. LMWH is indicated to prevent thromboembolism if the serum albumin level is < 25 g/L.

Non-specific renoprotective treatment also includes salt restriction, protein intake restriction, a Mediterranean diet, and exercise.

Complications

• Thromboembolism (DVT, renal vein thrombosis)
• Infection
  • Cellulitis
  • Pneumonia
• Dyslipidaemia
• Loss of vitamin D -> bone disease
• Progression to chronic kidney disease

Prognosis

The prognosis depends on the underlying histological diagnosis. Many adult patients will progress to chronic kidney disease. Most children will achieve remission, but recurrences are usual.