Nephrotic Syndrome & Proteinuria

 

• Background

  Definition and classification

  • Proteinuria is a marker of intrinsic kidney disease, indicating glomerular basement membrane leak or tubule damage.
  • In health, urine protein excretion is usually <150 mg/day. ⅔ are Tamm-Horsfall proteins, ⅓ are albumin. Pathological proteinuria primarily involves excess albumin loss.
  • Classification by 24 hour albumin excretion: normal <30 mg, microalbuminuria 30-300 mg (not detectable on dipstick), [macro]albuminuria 300-3000 mg, nephrotic syndrome >3 g.
  • Nephrotic syndrome is clinically-relevant proteinuria: anything less is usually asymptomatic and only relevant as a marker of underlying disease.

  Causes

  Significant proteinuria (>1 g/day) is nearly always due to glomerular disease.

  Modest proteinuria (<1 g/day) is commoner and due to various cause including:

  • Tubulointerstitial disease.
  • Glomerular disease.
  • Upper or lower UTI.
  • Kidney stones.
  • 'Benign' causes i.e. not indicative of serious kidney disease: orthostatic proteinuria (early morning test will exclude this), exercise, fever, heart failure.

  Glomerular disease

  Primary glomerulonephritis, especially:

  • Minimal change disease.
  • Focal segmental glomerulosclerosis.
  • Membranous glomerulonephritis.
  • Membranoproliferative glomerulonephritis.

  Secondary:

  • Diabetic nephropathy.
  • Pre-eclampsia
  • Autoimmune: SLE, vasculitis.
  • Infiltrative: amyloidosis, sarcoidosis, myeloma.
  • Infectious: infectious endocarditis, HBV, HCV, HIV, malaria, EBV.

• Presentation

  Effects of urine albumin loss:

  • ↓Oncotic pressure → oedema.
  • Frothy urine.

  NEPHROTIC:

  • Non-proliferative glomerulonephritis and Elevated glucose (diabetes) are the commonest causes.
  • Proteinuria
  • Hyper or hypotension. Though usually normotensive, patients can develop ↑BP from fluid retention (though HTN is much commoner in nephritic syndrome), or ↓BP due to fluid loss from vessels (commoner in kids).
  • Retinopathy is usually already present if diabetic.
  • Oedema. Often in legs in adults, and in face (especially periorbital) in kids. Spreads up from legs to groin, abdomen (ascites), lungs (pleural effusion or pulmonary oedema), and eventually can cause anasarca (generalised oedema).
  • Thrombosis: liver compensates for protein loss by increasing production of proteins including clotting factors, and kidney loses anti-coagulants e.g. AT3. Leads to DVT, PE.
  • Infection risk: urinary loss of IgG.
  • ↑Cholesterol: compensatory liver production of lipoproteins. Leads to IHD.

• Investigations

  Testing pathway:

  • If protein detected on dipstick, rule out benign temporary cause e.g. orthostatic, fever, exercise. Dipstick only detects albumin >100 mg/L, so in patients with CKD, ACR is used to screen for proteinuria.
  • If persistent, quantify proteinuria and do bloods.
  • If nephrotic syndrome confirmed, renal biopsy may be needed to find or confirm the cause. Not required if specific diagnosis is very likely e.g. minimal change disease in kids.
  • If significant proteinuria but not nephrotic, just arrange regular review.

  Quantify protein:

  • 24 hr urine collection rarely done now, and instead a spot sample – ideally in the morning – is done for ACR or PCR.
  • Urine albumin-creatinine ratio (ACR): microalbuminuria if >2.5 mg/mmol (men) or >3 mg/mmol (women), proteinuria if >30 mg/mmol, nephrotic syndrome if >250 mg/mmol.
  • Urine protein-creatinine ratio (PCR): proteinuria if >45 mg/mmol, nephrotic syndrome if >300 mg/mmol.
  • ACR is more sensitive than PCR at lower protein levels (ACR <70 mg/mmol).

  Urinalysis:

  • MC+S to exclude UTI.
  • Look for cell casts.
  • Protein electrophoresis.

  Bloods:

  • ↓Albumin
  • ↑Total cholesterol.
  • Glucose: diabetes.
  • U+E: assess renal function.
  • LFT: may show other causes of ↓albumin or fluid retention.
  • Coag: clotting abnormalities.
  • CRP: may be elevated in autoimmune disease.

  Investigations of cause:

  • Serum Ig and electrophoresis.
  • Immunology: complement, dsDNA, ANCA, RF.
  • Microbiology: HBV, HCV, HIV.

  Imaging:

  • Kidney US is often useful, especially if there is abnormal kidney function. Needed before biopsy.
  • CXR: pleural effusion.

• Management

  • Proteinuria: ACEi or ARBs reduce intraglomerular pressure, reducing protein excretion.
  • Oedema: salt ± fluid restriction, and high dose loop diuretic. Weigh regularly to monitor.
  • Hyperlipidaemia: statin if prolonged.
  • Thrombotic risk: anticoagulation if clot occurs, but not prophylactically.
  • Glomerulonephritis or autoimmune disease: immunosuppression may be needed.

• Diabetic nephropathy

  • Defined as macro- or microalbuminuria in a patient with diabetes.
  • Due to microvascular damage of glomeruli from ↑glucose.
  • Retinopathy should be present as eyes usually affected before kidneys. Consider non-diabetic cause if retinopathy absent.
  • Can be definitively diagnosed by biopsy, but rarely needed.