Nephrotic syndrome

Incidence

Age

Sex

Geography

Aetiology
- consists of heavy urinary protein loss, hypoalbuminaemia and oedema
- in adults, 3-5 grams of protein loss a day are required to cause hypoproteinaemia; less in children
- a normal liver synthesises albumin at 10-12g/day; however, there is some catabolism of albumin filtered at the glomeruli that takes place in the kidney
- in nephrotic syndrome, there is markedly increased catabolism of albumin - hence the apparent protein excretion is lower than might be expected.

- structural damage to glomerular basement membrane -> increase in size and numbers of pores
- reduction of fixed negative charge in glomerular capillary wall -> proteinuria

Pathophysiology of oedema
- classical explanation - hypoalbuminaemia -> reduced oncotic force retaining fluid within blood vessels -> salt and water escapes into extravascular compartment -> reduced blood volume -> activation of renin-angiotensin-aldosterone system -> increased salt and water reabsorption in kidney -> more oedema
- contrary to the classical explanation, blood volume often remains normal, plasma renin is often normal, and sodium retention often occurs before hypoalbuminaemia - intrarenal mechanisms of salt retention?

Causes
- all types of glomerulonephritis; most commonly membranous disease in adults
- minimal change nephropathy is most common cause in children
- diabetic glomerulosclerosis
- amyloidosis
- drugs - e.g. penicillamine (probably through forming hapten), captopril, metals (e.g. gold)
- allergies - e.g. poison ivy, pollens, bee stings, cow's milk - evidence of causal relationships is lacking.
- renal artery stenosis is probably a complication rather than a cause

NOT associated
- reflux nephropathy
- chronic tubulo-interstitial nephritis
- renal TB
- polycystic renal disease

Presentation
History
- ? allergies
- ? family Hx renal disease
- urine may be reported as becoming frothy - this coincides with onset.

Examination
- oedema ± ascites
- oedema may be periorbital, or involve the arms or genitals
- (raised JVP and signs of pulmonary oedema may be present; these are not parts of the syndrome, but due to coexisting renal or cardiac failure)
- features of underlying disorder - e.g. SLE
- exclude primary cardiac failure and liver disease

Investigations
24 hour urinary protein - greater than 3-5g / day in an adult
Serum albumin concentration - less than 30 g/L
Lipid profile - LDL cholesterol elevated, HDL cholesterol normal; hypertriglyceridaemia common
Serum urea and creatinine - renal function
Creatinine clearance - GFR

Further investigations to determine cause:
- urine microscopy (red cells and red-cell casts in glomerulonephritis)
- throat swab / serum ASO titre
- serum C3 complement (depleted in complement-mediated glomerulonephritis)
- ANAs (SLE); also anti-dsDNA, ANCA, anti-GBM if ANA-positive
- HBV surface antigen/HCV antibody
- cryoglobulins
- serum electropheresis - reduced serum albumin; monoclonal paraprotein band in multiple myeloma
- blood glucose (diabetes)
Selective protein clearance:
- clearance of large molecular weight protein (e.g. IgG compared with smaller molecule (e.g. albumin)
- selective protein leak in minimal-change glomerulonephropathy, early diabetes, renal amyloidosis
- unselective protein leak in severe glomerulonephritides
- used to exclude minimal-change nephropathy in children - i.e. renal biopsy may be required if there is an unselective protein leak

Renal biopsy
- used when management will be affected by result - e.g. is a steroid-sensitive minimal change lesion present?
- not indicated in young children with selective red cell leak and no red cells/casts in urine
- not indicated in long-standing diabetes with retinopathy or neuropathy
- not indicated in patients on drugs which may cause nephrotic syndrome (e.g. penicillamine) - trial without drugs first

Macro - see glomerulonephritis

Micro

Staging

Serum markers

Management
- dietary sodium restriction + thiazide diuretic (e.g. bendrofluazide)
- if unresponsive, add frusemide 40-120 mg daily + amiloride 5 mg daily
- monitor serum potassium
- normal protein intake - high protein diets are not beneficial
- infusion of albumin only in diuretic-resistant patients and those with oliguria and uraemia in the absence of severe renal damage

Minimal-change lesions
- prednisolone 60 mg daily for eight weeks corrects protein leak in 95% of children
- in adults, response rates are lower and spontaneous remission occurs; therefore withhold steroids if mild disease
- steroid-resistant cases may respond to cyclophosphamide; no more than 2 courses in children (complications include azoospermia)
- cyclosporin can be used in regularly relapsing cases; must be continued long term to prevent relapse on stopping treatment; monitor serum levels and excretory function as potentially nephrotoxic

Prognosis Minimal-change disease
- if remission lasts more than 4 years, relapse is unlikely

Complications
Renal artery stenosis - hypercoagulable; sluggish circulation?

Venous thrombosis
- hypercoagulable state due to loss of clotting factors and increased hepatic production of fibrinogen
- avoid prolonged bedrest
- prolonged anticoagulation once renal vein thrombosis has occurred
- long term prophylactic anticoagulation in membranous glomerulonephritis (high risk)

Sepsis
- increased susceptibility to disease partly due to loss of Ig in urine
- early detection and aggressive treatment rather than long-term antibiotic prophylaxis

Oliguric renal failure
- low blood volume and hypertension -> renal ischaemia
-> sensitive to further insults, e.g. blood loss, septicaemia -> acute tubular necrosis
- albumin infusion + mannitol or other diuretic may initiate diuresis

Lipid abnormalities
- ? increased rick of myocardial infarction or peripheral vascular disease
- treat with HMG-CoA reductase inhibitor

Nephrology index

Main Page

Incidence
Age
Sex
Geography
Aetiology	- consists of heavy urinary protein loss, hypoalbuminaemia and oedema - in adults, 3-5 grams of protein loss a day are required to cause hypoproteinaemia; less in children - a normal liver synthesises albumin at 10-12g/day; however, there is some catabolism of albumin filtered at the glomeruli that takes place in the kidney - in nephrotic syndrome, there is markedly increased catabolism of albumin - hence the apparent protein excretion is lower than might be expected. - structural damage to glomerular basement membrane -> increase in size and numbers of pores - reduction of fixed negative charge in glomerular capillary wall -> proteinuria Pathophysiology of oedema - classical explanation - hypoalbuminaemia -> reduced oncotic force retaining fluid within blood vessels -> salt and water escapes into extravascular compartment -> reduced blood volume -> activation of renin-angiotensin-aldosterone system -> increased salt and water reabsorption in kidney -> more oedema - contrary to the classical explanation, blood volume often remains normal, plasma renin is often normal, and sodium retention often occurs before hypoalbuminaemia - intrarenal mechanisms of salt retention? Causes - all types of glomerulonephritis; most commonly membranous disease in adults - minimal change nephropathy is most common cause in children - diabetic glomerulosclerosis - amyloidosis - drugs - e.g. penicillamine (probably through forming hapten), captopril, metals (e.g. gold) - allergies - e.g. poison ivy, pollens, bee stings, cow's milk - evidence of causal relationships is lacking. - renal artery stenosis is probably a complication rather than a cause NOT associated - reflux nephropathy - chronic tubulo-interstitial nephritis - renal TB - polycystic renal disease
Presentation	History - ? allergies - ? family Hx renal disease - urine may be reported as becoming frothy - this coincides with onset. Examination - oedema ± ascites - oedema may be periorbital, or involve the arms or genitals - (raised JVP and signs of pulmonary oedema may be present; these are not parts of the syndrome, but due to coexisting renal or cardiac failure) - features of underlying disorder - e.g. SLE - exclude primary cardiac failure and liver disease
Investigations	24 hour urinary protein - greater than 3-5g / day in an adult Serum albumin concentration - less than 30 g/L Lipid profile - LDL cholesterol elevated, HDL cholesterol normal; hypertriglyceridaemia common Serum urea and creatinine - renal function Creatinine clearance - GFR Further investigations to determine cause: - urine microscopy (red cells and red-cell casts in glomerulonephritis) - throat swab / serum ASO titre - serum C3 complement (depleted in complement-mediated glomerulonephritis) - ANAs (SLE); also anti-dsDNA, ANCA, anti-GBM if ANA-positive - HBV surface antigen/HCV antibody - cryoglobulins - serum electropheresis - reduced serum albumin; monoclonal paraprotein band in multiple myeloma - blood glucose (diabetes) Selective protein clearance: - clearance of large molecular weight protein (e.g. IgG compared with smaller molecule (e.g. albumin) - selective protein leak in minimal-change glomerulonephropathy, early diabetes, renal amyloidosis - unselective protein leak in severe glomerulonephritides - used to exclude minimal-change nephropathy in children - i.e. renal biopsy may be required if there is an unselective protein leak Renal biopsy - used when management will be affected by result - e.g. is a steroid-sensitive minimal change lesion present? - not indicated in young children with selective red cell leak and no red cells/casts in urine - not indicated in long-standing diabetes with retinopathy or neuropathy - not indicated in patients on drugs which may cause nephrotic syndrome (e.g. penicillamine) - trial without drugs first
Macro	- see glomerulonephritis
Micro
Staging
Serum markers
Management	- dietary sodium restriction + thiazide diuretic (e.g. bendrofluazide) - if unresponsive, add frusemide 40-120 mg daily + amiloride 5 mg daily - monitor serum potassium - normal protein intake - high protein diets are not beneficial - infusion of albumin only in diuretic-resistant patients and those with oliguria and uraemia in the absence of severe renal damage Minimal-change lesions - prednisolone 60 mg daily for eight weeks corrects protein leak in 95% of children - in adults, response rates are lower and spontaneous remission occurs; therefore withhold steroids if mild disease - steroid-resistant cases may respond to cyclophosphamide; no more than 2 courses in children (complications include azoospermia) - cyclosporin can be used in regularly relapsing cases; must be continued long term to prevent relapse on stopping treatment; monitor serum levels and excretory function as potentially nephrotoxic
Prognosis	Minimal-change disease - if remission lasts more than 4 years, relapse is unlikely
Complications	Renal artery stenosis - hypercoagulable; sluggish circulation? Venous thrombosis - hypercoagulable state due to loss of clotting factors and increased hepatic production of fibrinogen - avoid prolonged bedrest - prolonged anticoagulation once renal vein thrombosis has occurred - long term prophylactic anticoagulation in membranous glomerulonephritis (high risk) Sepsis - increased susceptibility to disease partly due to loss of Ig in urine - early detection and aggressive treatment rather than long-term antibiotic prophylaxis Oliguric renal failure - low blood volume and hypertension -> renal ischaemia -> sensitive to further insults, e.g. blood loss, septicaemia -> acute tubular necrosis - albumin infusion + mannitol or other diuretic may initiate diuresis Lipid abnormalities - ? increased rick of myocardial infarction or peripheral vascular disease - treat with HMG-CoA reductase inhibitor