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Nephrotic end of the spectrum

Educational resources for renal medicine

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Most definitions of nephrotic syndrome are something like this, requiring heavy proteinuria, lowered serum albumin, and oedema.

Features

Oedema is really a feature of nephrotic syndrome, not a complication, and it is caused not just by low serum albumin lowering oncotic pressure, but by avid renal sodium retention.

Complications

It is managed by sodium restriction and diuretics. It may be very diuretic resistant in severe cases and require combinations of diuretics, and sometimes intravenous treatment. However if fluid loss is too rapid there is a risk of electrolyte disturbances and even pre-renal failure.

Infection risk is probably largely due to loss of immunoglobulins. The major risk is from the polysaccharide-encapsulated bacteria, pneumococci and meningococci, against both of which immunization can now give a good degree of protection.

Venous thrombosis - DVT or pulmonary embolus - is sometimes the presenting feature of nephrotic syndrome but can occur at any time and may involve the renal veins. If there is a spontaneous thrombotic event then presumably anticoagulation should last as long as the nephrotic syndrome, but prophylactic heparin should be used if there is any increased risk, for example immobility or long-distance air travel.

Cholesterol rises to extremely high levels in many patients. Most clinicians prescribe statins if there is is continuing proteinuria. Although there is no controlled trial evidence in this patient group, it is known that there is a greatly increased risk of cardiovascular disease.

Here then are the 3+2 diseases, and here is their position on the spectrum.

 

Biopsy 1 – Minimal change

Now here is the first condition.

The appeareances are ... completely normal by light microscopy, earning this condition the name minimal change disease. However electron microscopy shows loss of foot process structure.

[needs FP fusion pics ... meantime descr over beginning next slide]

Minimal change nephropathy

Minimal change disease is the most common cause of nephrotic syndrome in Western Europe, though there are racial variations as well as geographical. It responds to corticosteroids and does not cause renal failure, but management can be difficult because of its tendency to relapse in many cases, mostly in children and young adults.

Response to treatment

This graph illustrates the response to steroid therapy, which is rapid in children. Where this disease is the commonest cause of childhood nephrotic syndrome, as in the UK, this response can be used as a diagnostic test, sparing most children a renal biopsy.

Adult line

In adults the response is slower and less complete, and there is a stronger probability of alternative diagnoses, so a renal biopsy is required unless it's obvious what the cause of nephrotic syndrome is, for example in a patient with longstanding diabetes and other microvascular complications, and a documented progression over years.

 

Biopsy 2 - FSGS

Here is the second biopsy.

It shows ... a rather solid looking pink segment at 6 o'clock, with normal looking segments on either side of it - a segmental scar. This is focal segmental glomerulosclerosis: focal meaning affecting only some glomeruli, segmental referring to the pattern within a single glomerulus. FSGS, little segmental scars.

In this context we are talking about a patient with new nephrotic syndrome, that is primary FSGS with nephrotic syndrome. However the appearance of lots of little scars can occur in other conditions, and some of these are listed here.

FSGS - causes of appearance

Primary FSGS

Concentrating on the primary condition, here are its key features.

It may be steroid responsive in a similar manner to minimal change disease, though steroid treatment may need to be prolonged to achieve remission. If there is a response to steroids, that is a good prognostic sign, as many with this diagnosis experience a progressive extension of the scarring to affect more and more glomeruli, over weeks or months or longer, often leading to end stage renal failure. Podocyte damage appears to be caused by a circulating factor which in some cases leads to development of proteinuria and recurrence of the disease within hours of transplanting a healthy kidney. The factor has so far eluded attempts at identification.

 

Biopsy 3 - Membranous

Now the third biopsy.

Here you can see ... a fairly uniformly thickened GBM - you couildn't cut yoruself on these capillary loops - and there is some increase in mesangium.

Immunofluorescence ... antigens diagram

Immunofluorescence shows a granular pattern of IgG decorating the outside of all the capillary loops. This is located under podocytes - subepithelial - and seems to be due to autoantibodies binding to a target on the surface of podocytes and becoming cross-linked there. The target in man is not yet know.

IF again - then text on Membranous

Membranous nephropathy is the third common renal disease that casues pure nephrotic syndrome in adults. A small proportion of cases can be attribute to drugs or toxins - usually penicillamine or gold prescribed for rheumatoid arthritis - and if so, stopping the responsible agent leads to slow recovery. Chronic hepatitis B and cancer may also cause it, but most are an idiopathic autoimmune condition in which a crude rule of thirds operates. A third get bettern, a hrid remain nephrotic, and a third deteriorate. Immunosuppressive therapy seems to increase the remission rate, but it is hazardous, so that it is reserved for patients who have demonstrated that they are deteriorating. Randomized controlled trials are under way.

Diabetic nephropathy

The remaining two conditions are architecture-altering diseases although it is possible that they also involve direct injury to podocytes.

Here is diabetic nephropathy, showing thickened GBM, increased mesangial matrix, and great nodules of deposited basement membrane-like matrix material. The thickened GBM could be a consequence of podocyte stress, but the podocytes certainly hate this very abnormal environment. They leak, heavy proteinuria is a prominent feature of diabetic nephropathy, and diabetic nephrotpathy is an important cause of endstage renal disease. ACE inhibitors have had a dramatic effect on the incidence and progression of this disease however, and this may be due to a direct effect on podocytes.

Amyloidosis

In amyloidosis the deposited material is amyloid fibrils, whichmay be made of immunoglobulin light chaines in B cell disorders, known as AL amyloid, or the acute phase protein serum amyloid A component, AA amyloid, and there are other rare variants too. Amyloid has this characteristic 'apple-green' birefringence when observed under polarise dlight.

Amyloid affects other organs too, but nephrotic syndrome is a common presentation. Renal failure will occur unless amyloid fibril formation can be stopped by reducing production of the precursor protein, for example by reversing the inmmune or infective cause of the inflammation giving rise to AA amyloid, or by anti-plasma cell treatment for AL amyloid. Involvement of other organs is particularly severe in AL amyloid, in which the heart, autonomic nerves, and gut are major targets.

 
Page last modified 04.03.2012, 23:16 by Neil Turner. edrep and edren are produced by the Renal Unit at the Royal Infirmary of Edinburgh and Univ. Edinburgh. CAUTIONS and Contact us. Note that the information published here is primarily intended for education, not for clinical care.