Nephrotic Syndrome

See also:
Acute Renal Failure,
Chronic Renal Failure,
Acute Nephritis and Nephrosis,
Interstitial Nephritides and Nephrotoxins,
Glomerulonephritis.

Nephrotic syndrome is a pattern of presentation of renal disease, rather than a single pathological entity or diagnosis. It comprises the following elements:

• Stimulation of the liver to increase synthesis of all plasma proteins (including the lipoproteins), due to their low level in the blood.
• Reduction of lipoprotein catabolism due to reduced levels of lipoprotein lipase in blood.

In the US, its annual incidence among children is reported to be 2–7 cases per 100,000.² Incidence varies among adults depending on the incidence of underlying causes for the condition, particularly diabetes mellitus.

Primary renal diseases

• Minimal-change nephrotic syndrome (~85% of childhood cases)
• Focal segmental glomerulosclerosis (~9% of childhood cases)
• Mesangial proliferative glomerulonephritis (~2% of childhood cases)
• Membranous nephropathy (~3% of childhood cases)
• Membranoproliferative glomerulonephritis

Secondary renal diseases

• Postinfectious causes, e.g. Group-A beta-haemolytic streptococci, TB, malaria, syphilis, viruses such as VZV, HBV, HIV, infectious mononucleosis.
• Collagen vascular diseases, e.g. SLE, rheumatoid arthritis, polyarteritis nodosa, Henoch-Schönlein purpura, vasculitides.
• Metabolic diseases, e.g. diabetes mellitus, amyloidosis.
• Inherited disease, e.g. Alport's syndrome, hereditary nephritis, sickle cell disease.
• Malignant disease, e.g. multiple myeloma, leukaemia, lymphoma, carcinoma of breast/lung/colon/stomach.
• Medications, e.g. NSAIDs, captopril, lithium, gold, diamorphine, interferon-alpha, penicillamine, probenecid and many others.
• Toxins, e.g. bee sting, snake bites, phytotoxins.
• Pregnancy, e.g. pre-eclampsia.
• Transplant rejection.

Symptoms

• In children facial swelling is a common presenting feature, with periorbital oedema often being the first evidence that something is wrong; oedema may progress to involve the whole body.
• Adults tend to present with peripheral oedema affecting the ankles and legs, which may progress to involve the whole body.
• Some patients may notice frothiness of their urine.
• Hypercoagulability may manifest as venous or arterial thrombosis, e.g. DVT, MI.
• Recurrent infections and/or general fatigue, lethargy, poor appetite, weakness or episodic abdominal pain may cause presentation to a doctor.

Signs

• Oedema of dependent parts or generalised oedema are the main clinical findings.
• Facial oedema may be found in children.
• Occasionally, severely hypoalbuminaemic cases may have pleural effusions or ascites.
• Urinalysis will reveal gross proteinuria.
• Hypertension and haematuria are not usually found but may affect a minority of cases.

• To find underlying cause of syndrome, direct future management and establish baseline of severity/monitor response to treatment
• Urinalysis and urine microscopy/culture and sensitivity
• Urinary protein:urinary creatinine ratio
• Light-chain urinary protein excretion (?myeloma)
• 24-hour urinary protein excretion
• U&E, creatinine
• Serum albumin
• Serum lipids
• FBC
• Hepatitis B and C serology
• Serology for other possible infective aetiologies including HIV if thought relevant
• Cryoglobulins/serum protein electrophoresis/autoantibody profile if relevant
• CXR to exclude malignancy and exclude other causes of oedema
• Renal tract ultrasound to assess size and structural condition of kidneys (obstructed or small kidneys may contraindicate renal biopsy).

Most cases will require renal biopsy to determine the exact underlying cause of the condition; children under 8 years old usually have minimal-change nephrotic syndrome and so may be spared this investigation, especially if they are steroid-responsive. Adults with an obvious cause (e.g. diabetes with evidence of other complications) may be spared a biopsy at the discretion of a renal specialist. Other investigations to diagnose less usual causes such as abdominal fat/gingival biopsy to detect amyloidosis may be needed in place of or in addition to a renal biopsy.

• Most cases do not require acute hospitalisation.
• Indications for acute admission include:
  • Severe generalised oedema, particularly if pleural effusion/oedema causing respiratory compromise
  • Tense scrotal/labial oedema
  • Complications of the nephrotic state (e.g. sepsis, pneumonia, MI, DVT, growth failure)
  • Inability to comply with therapy/inability to cope with condition in family/independently
  • Any features of a possible nephritic syndrome such as haematuria, hypertension and impaired renal function parameters
• Reduce salt intake in diet (avoid processed foods and adding salt to food).
• Give diet with adequate calorific intake and sufficient protein content (1–2 g/kg daily).³
• Hyperlipidaemia – does not initially require therapy but may do so if prolonged.³
• Fluid restriction is not usually necessary (if severe enough to need this then may need admission).³
• Referral to a renal service for urgent outpatient assessment is advisable, to confirm the mode of presentation and direct any future investigations/therapy.
• Oedema is treated through diuretic therapy with furosemide (~1mg/kg/day) ± spironolactone (~2mg/kg/day).
• Check weight regularly to assess response to diuretics and ensure fluid retention is not worsening, or that patient is over-diuresed.
• Patients with very low albumin levels may not respond to diuretics and may require admission to receive intravenous albumin therapy.
• Some children with severe oedema may be prescribed antibiotic prophylaxis against infection and this should usually be on the advice of a renal specialist.
• Most children will have minimal-change nephrotic syndrome and usually respond to a trial of steroid therapy under the direction of a renal specialist.
• Other forms of nephrotic syndrome are less treatment responsive; ACE inhibitors are frequently used in adults to some effect.
• In children who do not respond to steroids, and in some adults, treatment may be with other immunomodulatory drugs such as cyclophosphamide, cyclosporin and levamisole.

• This is highly variable depending on the underlying cause.
• Congenital nephrotic syndrome usually carries a very poor prognosis.
• Outlook for the vast majority of children with minimal-change nephrotic syndrome is excellent; response to steroids is the norm, although there may be relapses and a need to use alternative immunomodulatory drugs.
• Adult prognosis is variable and largely related to the underlying cause, its severity, progression and response to any treatment used to modify it.