Case 14.3 – Nephrotic Syndrome / Glomerulonephritis

Pathophysiology of oedema

A. Low plasma oncotic pressure

Low serum albumin due to:

• Increased loss - nephrotic syndrome
• Decreased synthesis – liver failure
• Malnutrition / malabsorption

B. Increased capillary permeability

Leakage of proteins into the interstitium, reducing the osmotic pressure gradient which draws fluid into the lymphatics and blood

• Local – infection / inflammation
• Systemic – severe sepsis
• Drug-related, e.g. calcium channel blockers

C. Increased hydrostatic pressure

High venous pressure / obstruction

• Deep venous thrombosis or venous insufficiency – local oedema
• Pregnancy
• Pelvic tumour
• Congestive heart failure
• Intravascular volume expansion (iatrogenic, renal failure, Conn's syndrome)

Lymphatic obstruction

• Infection – filariasis, lymphogranuloma venereum (Chlamydia trachomatis)
• Malignancy
• Radiation injury
• Congenital abnormality

Signs of oedema - increasing ankle swelling, facial swelling – the latter excludes local factors e.g. venous thrombosis or insufficiency. The presence of cloudy urine and 3+ proteinuria on urine analysis focuses the problem to the kidneys. The symptoms of tiredness and feeling unwell and the appearance of apparent pallor are non-specific in determining the underlying cause.

Enquire about a recent, apparent viral upper respiratory tract infection as a potential trigger for the current condition. The history "generally is well with no significant medical problems" makes the conditions that would be possible differential diagnoses e.g. congestive cardiac failure, cirrhosis, myxoedema, acute glomerulonephritis, less likely. Diabetes, as a potential cause, would have manifested with other symptoms.

Nephrotic syndrome is not a disease, it refers to the secondary phenomena that occur when substantial amounts of protein are lost in the urine. The syndrome is characterized by:

• Heavy, overt proteinuria – usually > 3.5grms/24 hours (urine may be frothy)
• Hypoalbuminaemia (\<30g/l)
• Oedema and generalized fluid retention
• Hyperlipidaemia
• Intravascular volume depletion with hypotension (or expansion with hypertension) may occur

Nephrotic syndrome is 15 times more common in children than adults. The diseases that cause nephrotic syndrome always affect the glomerulus.

24-HR urine protein	Protein/creatinine ratio¹ (random sample)	Significance
< 0.03g	<3.5 (female)² < 2.5 (male)²	Normal
0.03 – 0.3g	˜ 3.5 – 15 ²,⁴	Microalbuminuria
0.3 – 0.5g	˜ 15 – 50³	Dipsticks positive
0.5 – 2.5g	˜ 50 – 250³	Source equivocal
> 2.5g	>250³	Glomerular disease likely
> 4.0g	>400³	Nephrotic range – always glomerular

¹Urine protein (mg/l) / urine creatinine (mmol/l)
²Usually measured as albumin/creatinine ratio
³Usually measured as total protein/creatinine ratio
⁴Not detectable with standard dipsticks but can be detected with specific 'albustix'

Filtration of low molecular weight anionic plasma proteins across the glomerular basement membrane is normally prevented by a negatively charged filtration barrier, which consists of proteoglycan molecules of heparan sulfate. In persons with nephrotic syndrome, the concentration of heparan sulphate mucopolysaccharide in the basement membrane is lower, and large amounts of protein cross the barrier and are excreted.

High glomerular permeability leads to hyperalbuminuria and, eventually, to hypoalbuminaemia. In turn, this lowers the plasma colloid osmotic pressure, causing greater transcapillary filtration of water and the development of oedema.

There is no evidence of decreased albumin synthesis in patients with nephrotic syndrome.

The structural changes believed to be responsible for causing proteinuria are (1) damage to the endothelial surface, causing loss of the negative charge, (2) damage to the glomerular basement membrane (3) effacement of the foot processes (attached to the visceral surface of the glomerular basement membrane, the bases form the filtration slits).

In the nephrotic state, levels of almost all lipids are elevated. Two pathogenic processes are operative, including (1) hypoproteinuria stimulating generalized protein synthesis in the liver, including the lipoproteins, and (2) diminution of lipid catabolism caused by reduced plasma levels of lipoprotein lipase.

Urinary immunoglobulin losses lower the patient's resistance to infections and increase the risk of serious sepsis and peritonitis. The loss of antithrombin III and plasminogen via urine and the simultaneous increase in clotting factors, especially factors I,VII, VIII, and X, increases the risk for arterial thrombosis, venous thrombosis, and pulmonary embolism, which occurs in 5% of children with nephrotic syndrome.

The following investigations aid in determining the aetiology and in planning and monitoring treatment.

• Urinalysis, urine microscopy, testing for the ratio of urinary protein to urinary creatinine and a determination of light chain protein excretion (amyloid as primary cause)
• Blood tests – serum creatinine, urea nitrogen, serum albumin and serum lipids. Full blood count, hepatitis B and C serology, antinuclear antibodies, serum complement levels, cryoglobulins, serum (or urine) protein electrophoresis. Antistreptolysin O titres, EBV IgM, IgG (depending on recent history)
• These tests help determine possible causes – postinfectious, collagen vascular disease e.g. SLE, leukaemia, lymphoma, hepatitis B, infectious mononucleosis etc
• Renal ultrasound to help establish the presence of 2 kidneys that are of normal size and architecture ie devoid of cysts and vascular malformations
• Renal biopsy to establish the nature and extent of renal disease in order to judge the prognosis and need for treatment

INDICATIONS

• Acute renal failure that is not adequately explained
• Chronic renal failure with normal-sized kidneys
• Nephrotic syndrome or glomerular proteinuria in adults
• Nephrotic syndrome in children that has atypical features or is not responding to treatment
• Isolated haematuria or proteinuria with renal characteristics or associated abnormalities

CONTRAINDICATIONS

• Disordered coagulation or thrombocytopaenia. Aspirin and other agents causing platelet dysfunction should be omitted for elective biopsies
• Uncontrolled hypertension
• Kidneys < 60% predicted size
• Solitary kidney (except transplants) (relative contraindication)

COMPLICATIONS

• Pain, usually mild
• Bleeding into urine, usually minor but may produce clot colic and obstruction
• Bleeding around the kidney, occasionally massive and requiring angiography with intervention, or surgery
• Arteriovenous fistula, rarely significant clinically

Feature	Mechanism	Consequence	Management
Hypoalbuminaemia	Urinary protein losses exceed synthetic capacity of the liver	Reduced oncotic pressure Oedema	Diuretics and a low sodium diet
Avid sodium retention	Low oncotic pressure and intravascular volume Secondary hyperaldosteronism ± Primary defect in renal sodium excretion	Oedema	(care to avoid over-diuresis)
Hyperlipidaemia	Non-specific increase in lipoprotein synthesis by liver in response to low oncotic pressure	High rate of atherosclerosis	Lipid-lowering drugs (e.g HMG CoA reductase inhibitors)
Hypercoagulability	Relative loss of inhibitors of coagulation (e.g antithrombin III, protein C and S) and increase in liver synthesis of procoagulant factors	Venous thromboembolism	Case for routine anticoagulation in all patients with chronic or severe nephrotic syndrome
Infection	Hypogamma globulinaemia (urinary losses)	Pneumococcal infection	Consider vaccination esp. in children

Note: This is a comprehensive table summarizing major glomerular diseases. Key patterns include:

Minimal change: Normal on light microscopy except fusion of podocyte foot processes on electron microscopy. No immune deposits. Unknown pathogenesis. Associated with atopy, HLA-DR7, drugs. Presents as acute nephrotic syndrome, good response to corticosteroids. Dominant cause of idiopathic nephrotic syndrome in childhood.

Focal segmental glomerulosclerosis (FSGS): Segmental scars in some glomeruli. Primary FSGS presents as idiopathic nephrotic syndrome but less responsive to treatment than minimal change. Secondary FSGS associated with healing of previous glomerular injury, HIV infection, heroin misuse, morbid obesity.

Membranous nephropathy: Thickening of GBM with granular subepithelial IgG. Antibodies to podocyte surface antigen. Associated with HLA-DR3, drugs, heavy metals, hepatitis B, malignancy. Common cause of adult idiopathic nephrotic syndrome.

IgA nephropathy: Increased mesangial matrix and cells with mesangial IgA deposits. Very common disease with range of presentations, usually including haematuria and hypertension. May be associated with liver disease.

Post-infection glomerulonephritis: Diffuse proliferation of endothelial and mesangial cells with subendothelial immune deposits. Immune response to streptococcal infection. Now rare in developed countries. Presents with severe sodium and fluid retention, hypertension, haematuria, oliguria. Usually resolves spontaneously.

Goodpasture's disease (anti-GBM): Usually crescentic nephritis with linear IgG along GBM. Autoimmunity to α3 chain of type IV collagen. Associated with HLA-DR15 and lung haemorrhage. Treat with corticosteroids, cyclophosphamide and plasma exchange.

Lupus nephritis: Almost any histological type with always positive and often profuse immune deposits. Some anti-DNA antibodies also bind to glomerular targets. Very variable presentation. Responds to cytotoxic therapy in addition to prednisolone.

Acute renal failure (ARF) refers to a sudden and usually reversible loss of renal function, which develops over a period of days or weeks and is usually accompanied by a reduction in urine volume. There are many possible causes and it is frequently multifactorial.

URINARY TRACT OBSTRUCTION

• Suggested by a history of loin pain, haematuria, renal colic or difficulty micturition but often clinically silent
• Can usually be excluded by renal ultrasound - essential in any patient with unexplained acute renal failure
• Prompt relief of the obstruction restores renal function

VASCULAR EVENT

• Due to major vascular occlusion or small-vessel diseases, notably malignant hypertension and haemolytic uraemic syndrome/thrombotic thrombocytopaenic purpura
• May be precipitated by ACE inhibitors in critical renal artery stenosis
• Urine usually shows minimal abnormalities but there may be haematuria in renal infarction

RAPIDLY PROGRESSIVE GLOMERULONEPHRITIS (RPGN)

• Typically significant (dipsticks 3+) haematuria and proteinuria (often with red cell casts or 'glomerular' red cells)
• Sometimes associated with systemic features (e.g. systemic vasculitis, systemic lupus erythematosus (SLE), Goodpasture's (anti-GBM) disease)
• Useful blood tests include: antineutrophil cytoplasmic antibodies (ANCA), antinuclear antibodies (ANA), anti-GBM antibodies, complement, immunoglobulins
• Renal biopsy shows aggressive glomerular inflammation, usually with crescent formation

ACUTE INTERSTITIAL NEPHRITIS

• Usually caused by an adverse drug reaction
• Characterized by small amounts of blood and protein in urine, often with leucocyturia
• Kidneys are normal size
• Requires cessation of drug and often prednisolone treatment

DRUGS

For example:

• Haemodynamic effects (e.g NSAIDs, ACE inhibitors)
• Acute allergic interstitial nephritis
• Direct toxicity to the tubule (e.g. aminoglycosides – gentamycin, tobramycin)