As a house officer and even as a registrar this is something I found difficult. Now as a renal registrar, I feel much more comfortable with it. However, I know I wasn’t alone in finding it challenging, as this is something we often get phoned about. I’ll go through it here but you can always find more on the Buku Medicine App, in the renal module (free on Apple and Android App stores).
In a nutshell this is when the kidneys leak far too much protein. The filtering unit of the kidney is called the glomerulus. The glomerular basement membrane usually stops protein passing through. If the basement membrane is damaged (specifically the epithelial cells- the ‘podocytes’) the membrane becomes leaky and protein ends up in the urine.
It consists of the triad of:
Patients with nephrotic syndrome typically present with new onset peripheral oedema which can often be quite marked. They may also complain of shortness of breath (pleural effusions or pulmonary oedema), abdominal swelling (ascites), weight gain (from the fluid retention) or hypertension. They may also have noted foamy or frothy urine.
On examination they are often hypertensive and markedly fluid overloaded.
They often have a normal creatinine on their bloods. If measured their serum albumin will be low and their lipids will be high. A urine dipstick will have +++ protein.
If you’re suspecting nephrotic syndrome the key investigations are:
Occasionally the cause of peripheral oedema is misdiagnosed as heart failure if the serum albumin is not dramatically reduced, so all patients with “?new heart failure” should have a urine dip and urine PCR if serum albumin is low.
Many hospitalised patients with a severe inflammatory response (for example due to sepsis) or decompensated liver cirrhosis will have low serum albumin and peripheral oedema, so getting the urinalysis and urine PCR is the key to diagnosis.
If a patient fulfils the diagnostic criteria above, or even just has lots of protein in their urine, discuss them with renal. I will go through what they might do next below.
In the meantime, there are a few extra diagnostic and management steps.
There are a number of conditions which can cause nephrotic syndrome. The renal team will try to figure out what the cause is through careful history and investigation. Ultimately, many people need a renal biopsy to help differentiate between the causes. In addition the causes can be primary or secondary – see table.
|Disease on biopsy||
Primary amyloidosis or secondary to chronic inflammatory response e.g. rheumatoid arthritis, bronchiectasis
|Minimal change disease||
Hodgkin’s lymphoma, NSAIDs, lithium
Malignancies, SLE and other autoimmune disorders, hepatitis B and C, NSAIDs, penicillamine, infection
|Focal segmental glomerulosclerosis (FSGS)||
Obesity, hypertension, sickle cell disease, HIV, hepatitis C, heroin, pamidronate
Plasma cell dyscrasias, autoimmune disease, hepatitis B and C, essential cryoglobulinaemia
There are many causes of nephrotic syndrome. In some cases it is secondary to a systemic disease such as myeloma, amyloidosis and diabetes. Diabetes is the most common cause of the nephrotic syndrome. In general when diabetes is thought to be the most likely cause of the nephrotic syndrome, we do not perform a biopsy and the treatment is with an ACE inhibitor or Angiotensin receptor blocker.
It is important not to miss myeloma or amyloid as the cause of nephrotic syndrome. This may be diagnosed for the first time on a renal biopsy, however, the preliminary tests e.g. serum free light chains may already point to this diagnosis.
In nephrotic syndrome due to myeloma and amyloid the treatment is focused on treating the systemic disease e.g. chemotherapy for myeloma.
The most common primary causes are minimal change disease, membranous nephropathy and FSGS.
This is most commonly seen in children and young people but can present at any age. They classically present with sudden onset marked peripheral oedema.
Diagnosis: after the history and investigations above, renal biopsy is the investigation of choice. The biopsy is usually normal by light microscopy and immunofluorescence but electron microscopy reveals diffuse effacement of the podocyte foot processes.
Treatment is most commonly with high dose steroids. Minimal change typically has an excellent response to this. Tacrolimus and rituximab are alternatives, occasionally as first line but more typically for refractory disease or relapses. Minimal change disease typically responds excellently to treatment.
More commonly affects older people. Hypertension is commonly seen. VTE is very common, even when compared to other causes of the nephrotic syndrome. In most cases it is caused by an antibody against the phospholipase A2 receptor – this can now be tested on a commercially available blood test.
Diagnosis is still usually confirmed with a biopsy, but if a biopsy is contraindicated making the diagnosis by the presence of anti PLA2R antibodies is acceptable.
Light microscopy usually shows thickening of the basement membrane. Occasionally ‘spikes’ in the basement membrane can be seen. Immunofluorescence will show granular capillary IgG±C3.
Electron microscopy shows subepithelial electron dense deposits and foot process effacement.
Mild membranous nephropathy is usually treated with ACE inhibitors and lifestyle advice alone. More severe membranous is treated with tacrolimus, rituximab or the ‘Ponticelli regimen’ – a combination of cyclophosphamide and prednisolone.
FSGS is a pattern that is commonly seen on renal biopsy – it can be idiopathic or can be secondary to another process affecting the kidney.
It is diagnosed on renal biopsy. Light microscopy shows a focal (affecting some, but not all glomeruli) and segmental (affecting part, but not all, of the glomerulus). Mesangial expansion, glomerular sclerosis and endocapillary hypercellularity are all often seen. Immunofluorescence does not show any immune deposits. Electron microscopy shows foot process effacement and podocyte degeneration.
Treatment is often started with high dose steroids, as in minimal change disease. Other options include tacrolimus and rituximab. FSGS typically responds less well to treatment than minimal change disease.