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February 2008: Identifying and managing nephrotic syndrome in adults

What are the main features of nephrotic syndrome?

How can proteinuria be treated?

How can complications be avoided?

What are the main features of nephrotic syndrome?

How can proteinuria be treated?

How can complications be avoided?

Nephrotic syndrome is characterised by proteinuria with peripheral oedema, hypoalbuminaemia and hypercholesterolaemia (see box 1,below). It is a relatively uncommon condition, with an incidence of three new cases per 100,000 per year in adults.1

41176271Thus an average practice will see one case every one or two years. Nephrotic syndrome presents in many diverse ways, reflecting either the primary process or one of the many systemic complications. Patients may be treated in hospital or in the community.


Nephrotic syndrome occurs when the kidney leaks protein. What little protein is filtered under normal circumstances by the glomerulus is reabsorbed by renal tubules, and the small amount of protein healthy people excrete is mainly tubular in origin.

In nephrotic syndrome, a loss of glomerular charge or structural changes in the glomerular basement membrane can lead to a massive loss of albumin and other plasma proteins.

The causes of nephrotic syndrome are classified as primary (idiopathic) or secondary glomerular disease.

Primary glomerular disease

Most cases of nephrotic syndrome are caused by primary glomerular disease. Membranous nephropathy is the most common cause of nephrotic syndrome in white patients, occuring in around 33% of cases, while focal segmental glomerulosclerosis causes 50-57% of cases among black patients.2

Secondary glomerular disease

41176272Secondary causes of nephrotic syndrome are listed in box 2, left. Of these, the most common is diabetic nephropathy. Amyloidosis is also an important cause; one study found that AL amyloid nephropathy accounted for 10% of all cases.3

Presenting features

Patients commonly present with peripheral oedema and nephrotic syndrome should be considered as a differential diagnosis in any patient presenting with new onset oedema.

It is often first noticed around the eyes and can become severe, with lower leg and genital oedema as well as ascites and pleural and pericardial effusions.

Patients frequently report that their urine is frothy. This is because proteinuria alters the surface tension, allowing bubbles to form.

Jugular venous pressure is usually normal or low and blood pressure is normal or raised.

Hyperlipidaemia is classically associated with nephrotic syndrome and eruptive xanthomas can appear. Patients' nails often show white bands caused by persistent hypoalbuminaemia.


41176273Nephrotic syndrome has systemic consequences (see table 1,left). These result, in part, from significant changes in protein levels caused by loss of low molecular weight proteins in the urine and overproduction of proteins in the liver.

Patients can present with a complication of nephrotic syndrome, with the actual diagnosis being made later.


Patients with nephrotic syndrome are at increased risk of thromboembolic events, which can result in pulmonary embolism. This is linked to imbalances in prothrombotic and antithrombotic factors, as well as impaired thrombolytic activity.

The most common sites of thrombosis in adults with nephrotic syndrome are the deep veins of the legs and the renal veins. Deep vein thrombosis (DVT) and renal vein thrombosis have been reported in 15% and 30% of patients with nephrotic syndrome respectively.

Membranous nephropathy is particularly associated with venous thrombosis, and the risk is increased in patients with a serum albumin <20-25 g/l.3-5

Patients with a confirmed thrombosis require anticoagulant therapy, first with heparin and then warfarin. Currently, there are no randomised controlled trials to guide prophylactic anticoagulation therapy. The accepted common practice in nephrology is not to screen patients for thromboses and to treat patients with a serum albumin <20g/l and proteinuria of >3g/24 hours prophylactically. Patients with normal renal function can have fractionated (low molecular weight) heparin, but those with moderate chronic kidney failure need unfractionated heparin. Warfarin is used for long-term anticoagulation.


Infection occurs in up to 20% of adult patients and is a significant cause of morbidity and, occasionally, mortality. Cellulitis is common, especially in severely oedematous limbs.

There is no consensus on the use of antibiotic and vaccine prophylaxis and a Cochrane review in 2004 was unable to recommend any interventions for preventing infection.6

Acute renal failure

Acute renal failure, or acute kidney injury, is a rare, spontaneous complication. It can also be caused by excessive diuresis, interstitial nephritis related to diuretic or NSAID use, sepsis or renal vein thrombosis.

Patients older than 60 years and children are at increased risk. Patients with acute renal failure may require dialysis and can take weeks to recover.


GPs should assess a patient's clinical condition, identify any complications and try to determine the underlying cause. All patients will require referral to a nephrologist for further management and, in adults, a renal biopsy.

History taking is key in pinpointing the cause of nephrotic syndrome.

It is important to note any features suggestive of systemic disease, drug history (especially any recent or new medication, including OTC preparations) and any acute or chronic infections.

Nephrotic syndrome is associated with malignancy, particularly of the lung and large intestine.

Investigations are used to assess the patient's current clinical status and to determine the underlying cause (see table 2, attached).

Assessment of renal function, including serum urea, creatinine and estimated glomerular filtration rate (eGFR) is important. Patients should have dipstick urinalysis to identify any haematuria (suggesting glomerulonephritis) and proteinuria (3-4+ protein suggests possible nephrotic syndrome). Protein loss should be quantified.

A spot urine sample to determine protein:creatinine ratio is almost as accurate, less prone to error and provides a quicker result than 24-hour urine collection. A protein:creatinine ratio >300-350mg/mmol indicates possible nephrotic syndrome.

Renal ultrasound is used to assess renal size and morphology. It should be performed early, and urgently if renal vein thrombosis is suspected.

Specific immunological tests are not essential in primary care but are of great value in pinpointing an underlying cause.



The underlying cause of oedema in patients with nephrotic syndrome is sodium retention. However, the process is complex, controversial and not fully understood.

Patients with oedema often require admission for intravenous diuretics. The aim of treatment is to create a negative sodium balance by limiting dietary sodium (<100 mmol/day), restricting fluids (eg to 1.5 litres/day) and using diuretics. However, aggressive diuresis can cause electrolyte disturbances, acute renal failure and thromboembolism resulting from haemoconcentration.


Proteinuria is the best independent predictor of progression in all renal disease,7 and its reduction or elimination is one of the main goals of treatment. In some cases this can be achieved by treating the underlying pathology, but in most patients additional measures are needed. Strategies to limit protein excretion also help to reduce oedema.

ACE inhibitors, either on their own or in conjunction with angiotensin-II receptor antagonists, are the mainstay of therapy, although their full antiproteinuric effect can take several weeks to manifest. Proteinuria reduction can occur without a change in blood pressure and combination therapy is more effective.8

Patients on these therapies require regular monitoring of plasma electrolytes.


Hyperlipidaemia is a common feature of nephrotic syndrome. Numerous abnormalities occur, including increases in LDL cholesterol and triglycerides and alterations in HDL cholesterol levels. There is evidence of increased cardiovascular events in patients with nephrotic syndrome, which could be related to lipid abnormalities, but there are no prospective trials that show whether early treatment alters cardiovascular morbidity or mortality.

Treating the underlying cause of nephrotic syndrome and thereby reducing proteinuria will improve or resolve dyslipidaemia.

Dietary changes

Muscle wasting is a major problem in severe nephrotic syndrome and patients have a greatly increased albumin turnover.

The optimum protein intake for such patients is not clear. However, a low protein diet may cause a negative nitrogen balance and malnutrition, and is not recommended.

Primary glomerular disease

The primary glomerular diseases that can cause nephrotic syndrome have differing renal prognoses and treatment strategies. There is still no consensus on the treatment of the different primary causes of nephrotic syndrome nor any randomised controlled trials. Hence, long-term control of nephrotic syndrome is difficult to achieve in a significant minority of patients.

Nephrologists frequently use immunosuppressive agents to treat primary glomerular diseases. GPs need to be aware of these therapies as patients may experience significant side-effects.


The prognosis of adult nephrotic syndrome is variable, reflecting the many different aetiologies. Some patients resolve spontaneously, or with ACE inhibitor or angiotensin-II receptor antagonist therapy, after a few weeks. In other patients, nephrotic syndrome is refractory to many courses of often complicated therapies.


Nephrotic syndrome is a common renal condition that can present in many diverse ways, including oedema, dyslipidaemia, breathlessness, low plasma albumin and proteinuria.

Investigation and general management strategies are hampered by a lack of a guiding evidence base. Large randomised trials are needed to ensure further progress.

Neph box1 Neph box2 Table1 Neph Table 2: Investigations in patients with nephrotic syndrome Nephrotic syndrome Useful information

The Royal Infirmary of Edinburgh renal unit provides information for patients and GPs and referral guidelines for all renal conditions, including nephrotic syndrome

The UK National Kidney Foundation is a registered charity providing information for patients

Key points Authors

Dr Richard Hull
specialist registrar in nephrology, South West Thames Renal and Transplantation Unit

Dr David Goldsmith
consultant kidney specialist, Guy's Hospital

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