Diagnosis and care of nephrotic syndrome

Nephrotic syndrome is a common presentation of renal disease. It is characterised by the triad of heavy proteinuria (>3g/day), oedema and hypoalbuminaemia (<35g/l). It is recommended that all patients with nephrotic syndrome should be under the care of a renal physician.

Early referral and detection of relapses can result in improved outcome and reduced risk of complications. It is important for GPs to be aware of the differential diagnoses, general management principles and complications associated with the disease.

Pathophysiology
In nephrotic syndrome, the glomerular basement membrane becomes 'leaky' to protein. Protein is lost in the urine and the amount retained in the blood decreases; this results in a reduced plasma oncotic pressure and fluid to escape from the intravascular space.

Consequently, the most common presenting clinical features are peripheral oedema, swelling of the eyelids and face, ascites and frothy urine due to the presence of protein.

Causes
Nephrotic syndrome can be a manifestation of systemic diseases such as diabetes, systemic lupus erythematosus (SLE), amyloidosis or myeloma; a drug reaction; or a primary renal disease. Common causes vary with the patient's age (see box).

Minimal change disease is usually associated with normal renal function and a good prognosis, although patients may experience frequent relapse. Most flare-ups can be managed with short courses of high-dose corticosteroids, although some patients may require more vigorous immunosuppression, for example cyclophosphamide.

Focal segmental glomerulosclerosis (FSGS) has a poor steroid-response rate (10-30 per cent), although prolonged courses have been reported to improve response. In patients who do not respond to steroids, alternative agents include ciclosporin or cyclophosphamide. Mycophenolate mofetil has recently shown benefit in patients with FSGS.

Membranous nephropathy has a number of causes, including malignant disease, auto-immune diseases such as rheumatoid arthritis and drugs such as gold or penicillamine. It can also be idiopathic.

The association with malignant disease increases with the patient's age, and development of nephrotic syndrome may precede, coincide with or follow the diagnosis of malignancy.

Older patients with nephrotic syndrome should therefore be assessed rigorously for malignant disease.

With the increasing incidence of diabetes, diabetic glomerulosclerosis has become the most common cause of nephrotic syndrome in the elderly. Strategies to reduce proteinuria in this condition, such as ACE inhibitors and angiotensin II receptor blockers, have also shown benefit in controlling diabetic nephropathy.

Investigations
When nephrotic syndrome is suspected, recommended initial investigations include 24-hour urine collection to measure protein levels (or protein/creatinine ratio), urine microscopy, blood tests including FBC, clotting, ESR, U&Es, albumin, cholesterol and blood glucose. The patient should be weighed regularly.

Management of histopathological variants of nephrotic syndrome include strict control of BP, control of oedema, management of hypercholesterolaemia and prevention of venous thrombosis.

In those cases of nephrotic syndrome secondary to an underlying disease process, treatment also needs to be directed towards the primary condition such as control of blood glucose in diabetes, chemotherapy in myeloma and immunosuppression in SLE.

To resolve oedema, a low salt diet is recommended (<2g sodium/day), along with the use of diuretics such as furosemide. The aim should be to reduce oedema gradually.

Weight loss should be monitored regularly and patients encouraged to keep a weight chart at home. More rapid fluid loss leaves the patient at risk of hypotension.

Many causes of nephrotic syndrome are relapsing and remitting. Providing patients with urine dip sticks for self-monitoring of proteinuria can allow early detection of relapse so appropriate management can be instituted sooner.

Preventing complications
There are a number of potential complications of nephrotic syndrome. An important complication is the increased risk of thromboembolism (DVT, pulmonary embolism, renal vein thrombosis). This is thought to be due to the loss of antithrombin III and other factors that protect against thrombosis. Some patients are given prophylactic anticoagulation, although there are no randomised controlled trials to support this.

Renal vein thrombosis is more common among patients with membranous nephropathy. Presenting features may include acute loin pain, haematuria and deteriorating renal function.

Patients with nephrotic syndrome also have an increased susceptibility to certain infections, particularly those due to Streptococcus pneumoniae. Patients are also more susceptible to iron deficiency due to loss of iron tranferrin.

Another complication of nephrotic syndrome is hypercholesterolaemia. While this tends to resolve with treatment of nephrotic syndrome, treatment with a statin is often recommended.

Dr French is SHO in renal medicine and Dr Banerjee is consultant nephrologist at St George's Hospital, London.

The Renal Association: www.renal.org.

Crew R J, Radhakrishnan J, Appel G. Complications of the nephrotic syndrome and their treatment. Clin Nephrol 2004;62:245-59.