Nephrotic SyndromeBackground

Peter Topham and Richard Glassock

Key Point: A urinary protein:creatinine ratio (UPCR) of >300 mg/mmol Cr (>3000 mg P/gm Cr) in a 'spot' morning urine sample is usually taken as 'nephrotic-rangeproteinuria' in an adult.

Key Point: Nephrotic Syndrome (NS) is not a specific disease and is defined biochemically by the presence of persistent 'nephrotic-range' proteinuria andhypoalbuminaemia (<30 g/L). Oedema is variably present.

Nephrotic syndrome is not a disease. It is a description of group of associated clinical features and laboratory abnormalities. These include abnormalities of liver metabolism,including excess synthesis of fibrinogen by the liver; and alterations in hepatic lipid synthesis and turnover. Many patients will have hypercholesterolaemia, and (initially)normal renal function. Other important complications are venous thrombosis, infection, and malnutrition (negative nitrogen balance)..In the kidney there is damage to the glomerular filtration barrier which allows the passage of proteins, that are normally not filtered by the glomerulus, from the blood into theurine. This loss of protein lowers blood protein (and albumin) levels.

Retention of sodium and water occurs and results in oedema. This is due to alterations in distal tubule (and collecting duct) function which leads to increased renal avidity forsodium chloride. This process is discussed further in the Pathophysiology sections (below).

Nephrotic syndrome is a common reason for admission to a renal unit. It has many underlying causes, but the risks to the patient, and the general management, are broadlysimilar irrespective of the underlying cause.

Overall, NS is generally more common in adults; only minimal change disease is more common in children. The diagnosis is based on the presence of nephrotic rangeproteinuria; combined with history, physical examination, serological testing, and usually a renal biopsy. The treatment and prognosis depend on the cause.

Pathophysiology of Nephrotic Syndrome

Hypoalbuminaemia

Hypoalbuminaemia is predominantly due to urinary losses of protein, although a contribution from protein catabolism by tubular epithelial cells may also be relevant. Whitebands in the nails (Muehrcke's bands) are a characteristic sign of hypoalbuminaemia.

In response, hepatic albumin synthesis in increased but is insufficient to prevent the fall in serum albumin concentration. The increase in hepatic protein synthesis is non-specific and therefore the concentrations of proteins that are not lost in the urine may actually increase in nephrotic patients. This leads to some of the other consequences ofNS including hypercholesterolaemia and hypercoagulability.

Proteinuria

Nephrotic range proteinuria is almost invariably due to glomerular disease. Under normal circumstances the passage of most plasma proteins (particularly albumin) into theurine is prevented by the glomerular capillary wall (GCW).

The GCW is a trilaminar structure comprised of fenestrated glomerular endothelial cells, the glomerular basement membrane (GBM), and podocytes. It is richly decoratedthroughout with an anionic glycocalyx which electrostatically repels negatively charged proteins. In addition, the structure of the GBM and the podocyte intercellular junctions(slit-diaphragms) restricts the passage of proteins according to molecular size.

Proteinuric disease is usually associated with structural or functional changes in the GCW. In particular, it is now recognised that most nephrotic diseases are associated withpodocyte injury and dysfunction (manifest on electron microscopy as foot process effacement), and the loss of anionic charge in the glomerular capillary wall. Thus proteinuriausually results from a loss of both charge and size selectivity in the GCW.

The precise mechanism underlying these changes is unknown for most diseases; but in inflammatory conditions, a variety of cytokines, eicosanoids, and complementcomponents (eg C5b-9, TNF-alpha, interleukin-1β) may be implicated.

Haemodynamic changes in the glomeruli induced by angiotensin II and noradrenaline may also promote proteinuria. Experimentally, an increase in intraglomerular pressureresults in proteinuria; and the corollary of this is, that currently available antiproteinuric therapies work through reducing intraglomerular pressure.

The precise mechanisms involved in the various diseases that are associated with nephrotic range proteinuria vary widely. Antibody-mediated, immune-complex-mediated,complement-mediated and cell-mediated processes have all been implicated in the primary forms of the clinical disorder.

In Minimal Change Disease (MCD) and Focal Segmental Glomerulosclerosis (FSGS), evidence suggests that circulating cells (T-cells and other) may secrete permeabilityfactors; or alternatively down-regulate an inhibitor of permeability factor in response to unidentified etiologic agents. In Membranous Nephropathy, immune complexes areformed in situ by reaction of a circulating auto-antibody (anti-phospholipase A2 receptor antibody) and its relevant auto-antigen on podocytes.

Other possible factors include: hereditary defects in proteins that are integral to the slit diaphragms and GBM of the glomeruli; activation of complement leading to damage ofthe glomerular epithelial cells; and loss of the negatively charged groups attached to proteins of the GBM and glomerular epithelial cells.

Haraldsson (2008) has reviewed the properties of the GBM, and mechanisms of proteinuria. And, in 2009 Machuca et al reviewed molecular and clinical findings in the field ofgenetics of NS, providing a better understanding of the complex physiology of the glomerular filtration barrier.

Oedema

Oedema is thought to result from two distinct mechanisms:

Underfill ModelThis is thought to be more common in children. The reduced plasma oncotic pressure promotes the translocation of fluid from the vascular compartment into the extracellularfluid compartment. The reduction in plasma volume stimulates both activation of the renin-angiotensin-aldosterone system, and release of vasopressin, which results in sodium

Prevalence %

Children Young Adults Middle and Old Age

Minimal change disease 77 23 18

Focal segmental glomerulosclerosis 8 18 15

Mesangiocapillary glomerulonephritis 7 13 15

Membranous nephropathy 2 10 34

Other proliferative GN 6 30 15

Amyloid 0 2 16

and water reabsorption in the distal nephron. Capillary hydrostatic pressure is increased and this promotes further fluid movement into the extravascular compartment.

Overfill ModelThis results primarily from a defect of sodium excretion in the distal nephron. The cause of the natriuretic defect is unclear but may relate to the tubulointerstial inflammationthat often accompanies proteinuria. Sodium retention results in an increased blood volume associated with suppressed vasopressin and angiotensin/aldosterone levels. Theincreased intra-capillary hydrostatic pressure and the low oncotic pressure favours movement of fluid into the extravascular compartment.

In addition, sodium retention that accompanies the reduced GFR in patients with CKD and/or AKI can also contribute.

These mechanisms are discussed in more detail by Humphreys (1994), Kooman (2003) and Rondon-Berrios (2011).

Epidemiology and Causes

Epidemiology

Nephrotic syndrome can occur at any age. Causes vary by age, with children more likely to have primary causes, and adults more likely to have secondary causes.

One of the first papers to try to assess the incidence of NS was by Sharpstone (1969). It is now thought to be higher than the 9 per million population per year suggested inthis paper.

Key point: the incidence of nephrotic syndrome is about 30 cases per million per year (pmpy) in adults; and about 50 pmpy in children.

These data probably underestimate the true incidence since some patients with diabetic nephropathy (for example) may not be referred for specialist assessment, unlessadvanced CKD develops. Nephrotic syndrome can therefore be regarded as an uncommon disease, in terms of who gets referred to a Renal Unit. Thirty pmpy is about aquarter of incident cases of ESRD in the UK (about 110 pmp).

Diabetic nephropathy is the most common secondary cause of NS in adults. Black and asian people therefore have a higher incidence of nephrotic syndrome than docaucasians. HIV-associated nephropathy (HIVAN) is a complication of HIV infection that is unusual in caucasians. Nephrotic syndrome due to focal and segmentalglomerulosclerosis (FSGS) appears to be over-represented in African-American children, as compared with Caucasian children.

In the elderly population, amyloidosis and monoclonal immunoglobulin deposition diseases are relatively frequent causes of NS.

In adults, there is a male predominance in the occurrence of nephrotic syndrome, as there is for CKD in general. This male over-representation is also seen in paraneoplasticmembranous nephropathy. However, lupus nephritis affects mostly women.

Common Causes of Nephrotic Syndrome

Causes

Key point: the most common primary causes are minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS) and membranous nephropathy (MN).

Key point: secondary causes account for < 10% of childhood cases but > 50% of adult cases, most commonly diabetic nephropathy, SLE, amyloidosis (an under-recognised cause, and responsible for approximately 5% of cases), chronic viral infection and cancer.

Primary Causes

Minimal change disease (MCD)Membranous nephropathy (MN)Focal segmental glomerulosclerosis (FSGS). 'Familial' FSGS can occur late in life (and consists of autosomal dominant and recessive forms)IgA nephropathy (uncommon presentation)Mesangiocapillary (Membranoproliferative) GN (MCGN / MPGN)Rapidly progressive GN and vasculitis (more commonly presents as AKI)Fibrillary and Immunotactoid GN

Secondary Causes

Metabolic

Type 1 and 2 diabetes mellitus (Diabetic Nephropathy)

Immunological

SLEHenoch-Schönlein purpuraSerum sicknessSjögren's syndromeMixed essential (IgG/IgM) cryoglobulinaemia

Neoplastic

Carcinoma (eg, bronchus, breast, colon, stomach, kidney)LeukaemiaLymphomaMelanomaMultiple myeloma / amyloidosisMonoclonal immunoglobulin deposition diseases (MIDD)Primary AL Amyloidosis

Drugs

GoldHeroinInterferons alfa, beta and gammaLithiumMercury (organic and inorganic)PamidronateProbenecidPenicillamineNSAIDs and many othersAndrogen abuse

Infective

Bacterial (Infective endocarditis, Leprosy, Syphilis, Mycoplasma)Protozoan (Filariasis, Helminthic infections, Malaria, Schistosomiasis, Toxoplasmosis)Viral (Epstein-Barr virus, Hepatitis B and C, HIV)Allergic (Antitoxins, Insect stings, Poison ivy or oak, Snake venom)

Congenital/Hereditary

Hereditary nephritis (Alport's syndrome)Sickle cell diseaseCongenital nephrotic syndrome (Finnish type)Pierson’s syndromeNail-patella syndromeDenys-Drash syndromeFabry's diseaseInherited Podocyte protein mutations (Podocin, alpha Actinin IV, etc)

Physiological (adaptation to reduced nephron mass)

Morbid obesityOligomeganephroniaVon Gierke’s diseaseVesico-ureteric refluxDysautonomia

Miscellaneous

Chronic allograft nephropathyMalignant hypertensionPre-eclampsiaSarcoidosisCastlemann Disease

Causes by Age

Clinical

Common presenting symptoms may be nonspecific and include oedema, anorexia and malaise. Frothy urine (caused by high concentration of protein in the urine) is a morespecific presenting complaint. Fluid retention in NS does NOT produce symptoms of heart failure.

Shortness of breath in NS is most often related to pleural effusions or pulmonary embolism. Pulmonary oedema virtually never occurs in NS unless there is some organicdisease of the heart present as well. Heart failure is often the initial (incorrect) diagnosis - until the urine is examined for proteinuria. This is understandable; NS is uncommon,

congestive cardiac failure (CCF) is not.

Classical signs may develop, including peripheral oedema. Oedema may obscure signs of muscle wasting. Notes: patients may present with a complication (eg DVT) rather than a primary symptom. Also, many cases are now diagnosed by routine biochemical monitoring of chronicdiseases (eg SLE and diabetes).

Symptoms

Key point: periorbital oedema - in children this is a common presentation. It is usually first noticed in the morning. It is rare to see this in other forms of oedema.

Key point: peripheral oedema - adults tend to present with peripheral oedema affecting the ankles and legs, often progressing with upright ambulation.

Breathlessness without chest pain may indicate pleural effusions (often bilateral); pulmonary oedema does not occur in 'pure' NS (with no additional cardiac disease)Breathlessness with chest pain: pulmonary embolism, myocardial infarctionFrothy urineHypercoagulability - may manifest as venous or arterial thrombosis, eg DVT, PE or myocardial infarctionAbdominal pain - can be non-specific and episodic. May be due to ascites which may rarely be complicated by spontaneous bacterial peritonitis. In children, mesentericoedema may be the cause. Liver distension is NOT part of NS, unless other heart disease (such as amyloidosis or diabetic cardiovascular disease) is concomitantly presentNon-specific - recurrent infections and/or anorexia, malaise and weakness.

Signs

Oedema - which may be gravity dependent or generalised (particularly in children) is the predominant clinical sign. This includes periorbital oedema (especially in children),lower-limb oedema, oedema of the genitals, ascites, and pleural effusionsLeukonychia (white nails) or if nephrotic syndrome is transient; parallel white lines in fingernail beds (Muehrcke's bands)Xanthelasma may rarely develop as a result of the associated hyperlipidaemia

Common (and Important) Complications

Nephrotic syndrome causes urinary loss of macromolecular proteins, primarily albumin but also opsonins, immunoglobulins, erythropoietin, transferrin, hormone-bindingproteins (including thyroid-binding globulin and vitamin D-binding protein), and antithrombin III. Deficiency of these and other proteins contribute to a number of complications.There are three common, and important, complications:

Infection

Historically infection was a common cause of death in childhood nephrotic syndrome. With the advent of effective treatment with steroids, infection is now less of a problem butremains a significant concern in developing countries.

The characteristic infections are primary peritonitis (usually pneumococcal) and cellulitis (β-haemolytic streptococci).

The pathogenesis of the increased infection risk is multi-factorial:

Oedema results in fragile skin that can breakdown easily, and dilution of local humoral defences. In addition it provides fluid collections in which bacteria can grow easilyUrinary loss of IgG and complement components (particularly Factor B)Urinary loss of zinc and transferring (required for lymphocyte function)Neutrophil and T-lymphocyte dysfunction

Hypercoagulability and Thromboembolism

10% of nephrotic adults and 2 to 3% of children will have a clinically apparent thrombotic complication. Thrombosis of the deep leg veins or renal veins are most common.Subclinical thrombosis can be identified in up to 50% of adults and 28% of children when sought.

Thrombotic episodes are typically venous, but arterial involvement can rarely occur. The risk of thrombosis is inversely proportional to the serum albumin concentration, and isincreased markedly below 20g/l.

Membranous nephropathy is more frequently complicated by thrombotic events than other causes of nephrotic syndrome. The reason for this is unknown.

The pathogenesis of the increased thrombotic risk is multifactorial:

Physical factors (immobility, haemoconcentration, increased blood viscosity)Urinary loss of antithrombin III (and other clotting factors including factors IX, X, XI, XII)Increased hepatic synthesis of procoagulant clotting factors (eg fibrinogen and factros V and VII)Enhanced platelet function (enhanced prostaglandin metabolism, altered membrane lipids, increased VWF)Abnormal endothelial function (possibly related to dyslipidaemia)

Hyperlipidaemia

This is very common in nephrotic patients (over 90% of patients with more than 3g proteinuria per day will have serum cholesterol > 5.2 mmol/l). Therefore hyperlipidaemia isusually included in the definition of nephrotic syndrome.

Serum cholesterol concentrations may be extremely elevated and exceed 10mmol/l in 25% of patients. Triglyceride concentrations are more variable. The degree ofhyperlipidaemia correlates inversely with the serum albumin concentration. The enhanced hepatic lipoprotein synthesis is stimulated primarily by reduced plasma oncoticpressure.

The nephrotic lipid profile is regarded as atherogenic (increased LDL (particularly the more atherogenic LDL III), IDL and VLDL; increased lipoprotein (a); reduced HDL-2 and -3) and it is accepted that nephrotic patients (with the exception of those with minimal change disease) have a 5-fold increased risk of cardiac death.

Hyperlipidaemia may also independently promote progressive renal dysfunction. Hyperlipidaemia results from:

Increased hepatic synthesis of very low density lipoprotein (VLDL).This leads to a downstream increase in both intermediate-density lipoprotein (IDL), and low-densitylipoprotein (LDL)Reduced catabolism of lipoproteins due to inhibtion of endothelial lipoprotein lipase activity. This further increases VLDL levelsUrinary loss of high density lipoprotein (HDL-3) and reduced activity of lecithin cholesterol acyltransferase (LCAT) leading to reduced levels of the cardioprotective HDL-2

Other Complications

Hypocalcaemia

This is common in nephrotic syndrome, but rather than being a true hypocalcaemia, it is usually caused by a low serum albumin level. Nonetheless, low bone density andabnormal bone histology are reported in association with nephrotic syndrome. This could be caused by urinary losses of vitamin D–binding proteins, with consequenthypovitaminosis D and, as a result, reduced intestinal calcium absorption.

Thyroid dysfunction

Changes in thyroid function tests occur. Amongst patients previously hypothyroid, there can be an increased dose requirement for thyroid replacement hormone - secondary toloss of thyroid-binding globulin. Total thyroxine is usually low but free T4 and thyroid-stimulating hormone levels are usually normal.

Protein wasting / negative nitrogen balance

Many nephrotic patients become seriously wasted during the course of their illness. Loss of 10 to 20% of lean body mass is not uncommon but this is often masked by theoedema.

It results from a combination of urinary protein loss and enhanced tubular catabolism of protein. Increasing protein intake (> 1.5g protein /kg/day) can be counterproductivesince it increases intraglomerular hydrostatic pressure and increases proteinuria, without any effect on serum albumin.

Protein restriction (0.8g/kg/day or less), may reduce proteinuria, but tends to worsen the negative nitrogen balance.

Coronary artery disease in adults

This occurs secondary to hyperlipidemia, hypertension and hypercoagulability. Nephrotic patients have a 5-fold excess risk of cardiac death.

Hypertension in adults

This is probably the result of renal sodium retention, which may be compounded by a reduced GFR.

Acute kidney injury

Patients with nephrotic syndrome are at risk of developing acute renal insufficiency. This is most common in adults with minimal change and FSGS. It is usually present at thetime of the initial presentation with the nephrotic syndrome and only unusually develops after diagnosis.

AKI can be due to either:

The disease process itself

Hypovolaemia severe enough to cause AKI is very rare but can be seen in severe and rapidly developing nephrotic syndrome due to MCD, particularly in adults. In severenephrosis, intrarenal oedema can occur which cause tubular and vascular compressionTransformation of underlying glomerulopathy (eg crescentic change in a patient with Membranous Nephropathy or IgA nephroapthy)

or

Complications of the disease process or treatment

Excessive diuresis causing hypovolaemia, and then acute tubular necrosisInterstitial nephritis due to use of diuretics or NSAIDsHaemodynamic effects of ACEi or ARBsSepsisBilateral acute renal vein thrombosis (very rare)

Note: these diagnoses should be actively excluded; i.e. it should not be assumed that hypovolaemia is associated with hypoalbuminaemia secondary to the underlying diseaseprocess. It may be multifactorial. Koomans (2001) has reviewed the pathophysiology of AKI in the nephrotic syndrome.

Proximal tubular dysfunction (acquired Fanconi syndrome)

Glucosuria, aminoaciduria, potassium depletion, phosphaturia, and proximal (type 2) renal tubular acidosis can occur; either secondary to reabsorption of proteins causing toxiceffects on proximal tubular cells - or less commonly from tubular injury secondary to the underlying disease process.

Chronic kidney disease

With the exception of minimal change disease, nephrotic range proteinuria is associated with an increased risk of progressive renal dysfunction. The risk is proportional to thedegree of proteinuria and is largely independent of the underlying cause.

While the link between proteinuria and progressive renal disease may be due to the severity of the underlying glomerular disorder, there is increasing evidence that proteinuriais a mediator of tubulointerstial inflammation and fibrosis. In support of this, strategies that reduce proteinuria also limit the development of tubulointerstitial fibrosis and renalimpairment.

Investigation

A urinary protein:creatinine ratio (UPCR) of >300mg/mmol Cr (>3000mg P/gm Cr) in a 'spot' morning urine sample is usually taken as 'nephrotic-range proteinuria' in an adult.Nephrotic syndrome is not a specific disease and is defined biochemically by the presence of persistent 'nephrotic-range' proteinuria and hypoalbuminaemia (<30 g/L).

However calculations based on random specimens may be less reliable when creatinine excretion is high (eg during athletic training) or low (eg cachexia). Nonetheless,calculations based on random specimens are usually preferred to 24 hour collection because random collection is more convenient and less prone to error (eg due to lack ofadherence); more convenient testing improves monitoring during treatment.

It is not adequate only to look for proteinuria on urinary dipstick; as there are causes of nephrotic syndrome (such as myeloma) where losses of globulins predominate.Proteinuria, as indicated on dipstick testing, is caused by albuminuria. The cause may be suggested by clinical findings (eg diabetes, SLE, pre-eclampsia, cancer).

Key Point: when the cause is unclear, additional (eg serological) testing and renal biopsy are indicated.

Tests for proteinuria are reviewed in an Australasian Guideline (CARI, 2004), and by Kashif (2003), who also presents a good summary of how to investigate proteinuria.

Other Urine Tests

Urine dipstick

This is used as a qualitative method of assessing proteinuria; and to check for non-visible haematuria.

Midstream urine (MSU; for microscopic examination of the urine sediment)

Microscopy may demonstrate RBCs and casts (hyaline, granular, fatty, waxy, RBC, or epithelial cell). Lipiduria, the presence of free lipid or lipid within tubular cells (oval fatbodies), within casts (fatty casts), or as free globules, strongly suggests a glomerular disorder causing nephrotic syndrome. Urinary cholesterol can be detected with plainmicroscopy and demonstrates a Maltese cross pattern under crossed polarised light. Sudan staining must be used to show triglycerides.

Blood Tests

Complete blood count and red cell indicesCoagulation screen (if renal biopsy is being considered)Serum creatinine, urea, electolytes, fasting glucose, HbA1CLiver function tests - to exclude liver pathology, and assess albumin levelLipids - total cholesterol and triglyceride levels are typically increased, often very high. Lipids can also be used to monitor treatmentNote: it is not routinely necessary to measure levels of hormone-binding proteins, caeruloplasmin, transferrin, thyrogloblin etc; but these levels may be low

Key Point: note and record the serum albumin level, in the first and subsequent appointments. This is partly to make the diagnosis (it should be < 30g/L), and partly toassess need for anticoagulation. Warfarin should be considered if the albumin is <20 g/L and does not increase rapidly with treatment of the underlying condition. Serumalbumin is used to monitor the response to therapy, as well as the urinary protein excretion rate.

Soluble immunology tests

Anti-nuclear antibody and dsDNA antibodies (SLE)Complement factors (C3 and C4): Low C3 and/or C4 in SLE; Low C4, Normal C3 in cryoglobulinaemia; Low C3 Normal C4 in MPGNAnti-neutrophil cytoplasmic antibodies MPO and PR3Angiotension converting enzyme (ACE) (raised in sarcoidosis)Serum (and urine) protein electrophoresis (myeloma)Immunoglobulins (A, G, M) (IgA nephropathy, myeloma)Serum free light chains (myeloma / Light chain deposition disease)

Microbiology and Virology

Hepatitis B (membranous nephropathy), and C (cryoglobulinaemia)HIV (FSGS and increased risk of AKI on HAART)

Imaging

Chest X-ray or CT of chest - looking for pleural effusion, and a carcinoma that is underlying 'cause' of the nephrotic syndromeRenal ultrasound - to check for the presence of two kidneys, the size and shape of the kidneys, and to exclude urinary tract obstruction

Also consider:Doppler ultrasound of the leg veins, in suspected deep vein thrombosisDoppler ultrasound of the renal veins (or CT / MR venography), if renal vein thrombosis is suspectedVentilation-perfusion ('VQ') nuclear medicine lung scan, or CT pulmonary angiography (CTPA), for pulmonary embolism

Renal Biopsy

Renal biopsy under ultrasound control is useful for diagnosis, treatment and prognosis. Specific biopsy findings are discussed under the individual disorders. This should beconsidered in all cases of nephrotic syndrome, except:

1. In young (pre-pubertal) children (with no family history of renal disease). Idiopathic nephrotic syndrome in children is most likely minimal change disease and is usuallypresumed without biopsy; unless there are atypical features (non-visible haematuria, reduced complement levels, renal impairment, non-response to steroids)

2. If the pathological diagnosis is very likely on basis of the clinical examination (eg pre-eclampsia or diabetic nephropathy)3. If the patient is frail, and it is thought that a biopsy will have no effect on management decisions

Note: the presence of a solitary kidney is a relative and not absolute contra-indication to renal biopsy

The role of renal biopsy has been debated (Adu, 1996) but it has been shown to influence management in NS in 85% of cases (Richards, 1994).

Treatment

Treat the underlying cause

Treatment is based on the nature of the underlying glomerular lesion which emphasises the necessity of establishing a tissue diagnosis by undertaking a renal biopsy.

Whatever the cause, the most important part of the treatment, is to remove (or treat) the underlying problem. In pre-eclampsia that may mean delivery of the baby. Pre-eclampsia usually gets better quickly when this is done. In some glomerulonephritides immunosuppression is indicated.

Other treatment of underlying disorders may include prompt treatment of infections (eg staphylococcal endocarditis, malaria, syphilis, schistosomiasis), allergic desensitisation(eg for poison oak or ivy and insect antigen exposures), and stopping drugs (eg gold, penicillamine).

Charlesworth et al (2008) has reviewed the treatment of nephrotic syndrome.

In addition, the clinical consequences of the nephrotic syndrome need to be addressed for as long as nephrosis persists.

General measures

Oedema

No guidelines or randomised trials are available on this subject. An underlying cause of the oedema is sodium retention, but the underlying process is complex, controversial,and not fully understood. The key to treatment is to create a negative sodium balance. Patients often need to limit their dietary sodium intake (<100 Na+ mmol/day; 3 gNaCl/day), restrict their fluid intake (1.5 litres/day), and take diuretics. We recommend reversing the oedema slowly, with a target weight loss of 0.5-1 kg a day, becauseaggressive diuresis can cause electrolyte disturbances, acute kidney injury, and thromboembolism as a result of haemoconcentration.

Loop diuretics like furosemide are usually used, but drug absorption may be affected by oedema of the gut wall; so large doses of intravenous diuretic are often used forrefractory cases. Common diuretics are mostly protein bound so their activity may be affected by heavy proteinuria once filtered across the glomerulus. Thiazide diuretics orpotassium sparing diuretics are often added to try to improve the poor responses sometimes found with loop diuretics. They are synergistic for distal inhibition of sodiumreabsorption.

The use of IV albumin infusion is controversial. Most physicians will not use an albumin infusion unless hypotension and volume depletion are unequivocally present. It is rarelyeffective and can be harmful. Patients with very low albumin levels may not respond to diuretics and may require admission to receive intravenous albumin therapy. Intravenousalbumin probably acts by increasing delivery of the diuretic to its site of action and by expanding the plasma volume. It is often used in hypotensive patients in whomconventional treatment is failing. However, its use is not supported by evidence from (albeit small and limited) studies; and it can have harmful effects, such as anaphylaxis,hypertension, and pulmonary oedema.

Finally, patients resistant to these measures may require mechanical ultrafiltration although this may precipitate acute kidney injury.

Some children with severe oedema may be prescribed antibiotic prophylaxis against infection.

An approach to the management of oedema is shown below:

Proteinuria

Given the evidence that persistent heavy proteinuria predicts progressive renal dysfunction, reduction of proteinuria is a critical therapeutic goal. In the absence of diseasespecific therapy, a number of approaches are available. Anti-proteinuria therapy works mainly by altering glomerular haemodynamics to reduce intraglomerular hydrostaticpressure.

RAS inhibition

The most commonly used anti-proteinuria drugs are inhibitors of the renin-angiotensin system (ACE inhibitors and ARBs). These result in efferent arteriolar dilatation andthereby reduce intraglomerular hydrostatic pressure. They may also have a role in blocking the cellular effects of angiotensin II on podocytes. It has been suggested that the

concurrent use of ACE inhibitors and ARBs may provide an additive anti-proteinuric and reno-protective effect although there is no trial evidence to support this view. Thecombination may also be harmful so this approach can not be recommended at the present time.

When ACE inhibitors or ARBs are used the serum potassium concentration needs to be carefully monitored. Hyperkalaemia can usually be managed with dietary measures.The anti-proteinuric benefit of RAS blockade can be eliminated by excessive sodium intake. Therefore, the dietary sodium intake should be limited to less than 80 mmol/day.

Low protein diet

Dietary protein restriction reduces intraglomerular pressure (via constriction of afferent arterioles). However, in nephrotic patients dietary protein restriction risks making thenegative nitrogen balance worse. It is therefore recommended that dietary protein intake should be 0.8g/kg/day plus 1g of protein per gram of proteinuria.

Other pharmacological approaches

NSAIDs and ciclosporin both cause afferent arteriolar constriction, and dipyridamole causes efferent arteriolar dilatation. They have all been used in nephrotic patients but theclear benefit (and safety) of RAS inhibition have lead to them being used less commonly.

In morbidly nephrotic patients with an inadequate response to RAS inhibition, NSAIDs can be very effective. They may, however, precipitate acute kidney injury, particularly involume depleted patients - and therefore need to be used very cautiously.

Nephrectomy

Rarely, the nephrotic syndrome can be very severe and resistant to treatment. In such patients the complications of nephrotic syndrome can become potentially lifethreatening. In such patients, nephrectomy, dialysis and intensive nutrition may be the preferred treatment.

Nephrectomy can be achieved surgically, radiologically by renal artery embolisation, or medically using high dose diuretics, RAS inhibitors, and NSAIDs.

Hyperlipidaemia

The increased risk of cardiovascular disease in nephrotic patients could be related to the lipid abnormalities but no prospective trials have shown that lipid-lowering treatmentimproves survival in patients with NS. Furthermore, there is no evidence at all that treatment with statins slows the rate of progression of CKD (see SHARP trial; Baigent, 2011).Of note, many patients spontaneously remit or go into remission with treatment.

The severity of hyperlipidaemia is proportional to the degree of proteinuria. Therefore successful disease-specific treatment or anti-proteinuria treatment usually leads to animprovement in the lipid profile. Dietary fat restriction has only a modest effect on hyperlipidaemia in nephrotic patients.

Statins (HMG CoA reductase inhibitors) are the most commonly used agents for the treatment for nephrotic hyperlipidaemia. LDL cholesterol can be reduced by 35 – 40% andtriglycerides by 15 – 30%. Lipoprotein (a) concentrations are not affected. Statins are generally safe and indeed there is some evidence to suggest that statins may reduceproteinuria. Reversible myopathy can complicate statin use. Rarely this can lead to rhabdomyolysis and acute kidney injury. Serum creatine kinase levels (and liver functiontests) should be monitored after the initiation of a statin.

Fibrates have a less potent effect on LDL cholesterol than statins, and since lowering LDL is the main aim in nephrotic patients, fibrates are uncommonly used. Fibrate-inducedmuscle injury is also more common in patients with renal impairment.

Key Point: As a 'rule of thumb', in most patients, lipid lowering agents are not necessary initially. But if lipids are not controlled after 2 months of therapy, specificlipid lowering therapy is indicated.

Infection

All patients should receive pneumococcal vaccination if not otherwise contraindicated.

Hypercoagulability and Anticoagulation

Historical case series reported that deep vein thrombosis of the lower limb occurred in 8% and renal vein thrombosis occurred in up to 22% of patients (Singhal, 2006). Moderndata differ, however. A retrospective study reviewing coding data from discharged patients in the United States found deep vein thrombosis occurred in 1.5% and renal veinthrombosis in 0.5% of patients with nephrotic syndrome (Kayali, 2008).

Another retrospective cohort study found an eight times higher absolute risk of venous thromboembolism, with the greatest risk occurring in the first six months after diagnosis.Case series have shown that membranous nephropathy is particularly associated with venous thrombosis, and the risk of venous thrombosis is higher when serum albumin is<20-25 g/l (Bellomo, 1993).

Prophylactic anticoagulation (see Glassock, 2007)

The role of anticoagulation in nephrotic patients without evidence of thrombosis is unclear. Relatively immobile patients (eg during hospitalisation, with a serum albumin lessthan 25g/l) should be given low-dose anticoagulation (eg heparin 5000 units bd subcutaneously) until normal mobility has returned.

Many clinicians would also administer full-dose anticoagulation to those at particularly high-risk of thromboembolic events, ie serum albumin <20g/l, underlying membranousnephropathy, substantial proteinuria ( >10g/day). This is particularly true when additional risk factors are present, eg reduced mobility, massive oedema, heart failure,substantial diuresis. The evidence base to support this approach is however weak.

The response to heparin may be blunted due to reduce levels of antithrombin III. Therefore higher doses may be necessary. In contrast, the response to warfarin is enhancedbecause of reduced protein binding. This is of particular relevance during remission of proteinuria, when the anticoagulant effect of a stable dose of warfarin decreases.

An alternative approach is treatment with aspirin and dipyridamole, which may also be beneficial given the associated cardiovascular risk.

Therapeutic anticoagulation

Patients with clinically apparent thromboembolic disease should be anticoagulated with heparin followed by warfarin.

Treatment should be continued for the duration of the nephrotic syndrome (or at least until serum albumin rises above 25g/l) unless the risks of anticoagulation becomeprohibitive.

The optimal treatment of clinically silent thromboembolism is less clear cut. Asymptomatic pulmonary emboli should prompt full anticoagulation, and most clinicians would fullyanticoagulate those with silent deep venous thrombosis.

Specific measures

The treatment of the specific causes of nephrotic syndrome is dealt with in their respective sections.

Prognosis

This is very variable depending on the underlying cause. The prognosis and response to treatment is determined by the character of the underlying glomerular lesion.Spontaneous remissions are common in MCD and MN but uncommon in FSGS, IgA nephropathy and MPGN. Congenital nephrotic syndrome usually carries a very poorprognosis.

The outlook for the vast majority of children with MCD is excellent, with good response to steroids; although there may be relapses and a need to use alternativeimmunosuppression. Corticosteroids have reduced the overall mortality rate in children with MCD to around 3%.

In a study by Donadio (1988), of 140 patients with idiopathic membranous nephropathy - 89 of whom received no treatment with corticosteroids or immunosuppressive drugs,and 51 of whom were treated primarily with short-term courses of prednisone alone - it was found that survival rates were the same as those expected for the generalpopulation.

In secondary nephrotic syndromes, morbidity and mortality are related to the primary disease process (eg, diabetes, SLE, amyloidosis).

In diabetic nephropathy, however, the magnitude of proteinuria itself relates directly to mortality. There is often a good response to angiotensin blockade, with reduction ofproteinuria to low, sub-nephrotic levels. True remission is uncommon, however. Cardiovascular morbidity and mortality increase as kidney function declines, and some patientswill eventually need dialysis or a kidney or kidney-pancreas transplant.

In primary AL amyloidosis, prognosis is not good, especially with cardiac involvement. However, with aggressive management many cases can enjoy prolonged survival. Insecondary AA amyloidosis, remission of the underlying cause, such as rheumatoid arthritis or chronic infection, is followed by remission of the amyloidosis and its associatednephrotic syndrome.

In all cases, prognosis may be worsened by the following:

Superimposed opportunistic infectionPoorly controlled hypertensionSignificant renal impairmentPersisting nephrotic range proteinuria unresponsive to treatementThromboses in cerebral, pulmonary, peripheral, or renal veins

Recurrence rate is high after kidney transplantation in patients with FSGS, membranous nephropathy, IgA nephropathy, and mesangiocapillary glomerulonephritis (especiallytype II) but rather low in SLE.

Summary

Top Tips: Nephrotic syndome is not a disease. You need to find the cause

1. A urinary protein:creatinine ratio (UPCR) of >300 mg/mmol Cr (>3000 mg P/gm Cr) in a 'spot' morning urine sample is usually taken as 'nephrotic-range proteinuria' inan adult

2. Nephrotic Syndrome (NS) is not a specific disease and is defined biochemically by the presence of persistent 'nephrotic-range' proteinuria and hypoalbuminaemia (<30g/L). Oedema is variably present

3. Primary 'causes' (eg minimal change disease) are morphological 'diagnoses' found to underlie primary NS. They have uncertain causation, ie are idiopathic4. Secondary 'causes' include lupus nephritis, diabetic nephropathy and cancer5. In children periorbital oedema and ascites are common presentations. Adults tend to present with peripheral oedema6. Renal biopsy is usually not done in young children (pre-puberty) with a presentation of NS without known cause7. Note and record the serum creatinine and albumin levels in the first and subsequent appointments. Urinary PCR and serum lipid levels are also used to monitor

treatment8. Infection, venous thrombosis and hyperlipidaemia are common and important complications9. Hyperlipidemia only resolves if NS goes into complete remission. It cannot be controlled by diet alone. The value of pharmacological treatment of hyperlipidemia is

uncertain since there are no RCTs of lipid-lowering agents in NS10. In view of the risk of thromboembolism, it is common practice is to administer prophylactic anticoagulants if the serum albumin is persistently <20 g/L and there is at

least one additional risk factor for VTE, but only if there is no contraindication to anticoagulation11. Management involves treating the underlying problem, loop diuretics for oedema, ACE inhibitors, HMG CoA reductase inhibitors, and anticoagulation in some patients.

Immunosuppression (e.g. steroids and/or cytotoxic agents) is used for some primary causes

References

Articles

Adu D. The nephrotic syndrome: does renal biopsy affect management? Nephrol Dial Transplant 1996; 11(1): 12-13

Baigent C et al. The effects of lowering LDL cholesterol with simvastatin plus ezetimibe in patients with chronic kidney disease (Study of Heart and Renal Protection): arandomised placebo-controlled trial. The Lancet 2011; 377 (9784): 2181 - 2192

Bellomo R, Atkins RC. Membranous nephropathy and thromboembolism: is prophylactic anticoagulation warranted? Nephron 1993; 63: 249-54

Bright, Richard: Reports of Medical Cases with a View of Illustrating the Symptoms and Cure of Diseases by a Reference to Morbid Anatomy. London, Longmans, Green & Co.,1827-1831;, 2 vols., xvi, 231 pp

Cameron JS. Five hundred years of the nephrotic syndrome: 1484-1984. Ulster Med J; 1985; 54(Suppl): S5–S19

Cameron JS. Milk or albumin? The history of proteinuria before Richard Bright. Nephrol Dial Transplant 2003; 18 (7): 1281-1285

Charlesworth JA et al. Adult nephrotic syndrome: Non-specific strategies for treatment. Nephrology 2008; 13(1): 45-50

Cotugno D. De ischiade nervosa commentarius. 3rd ed. Vienna: Graffer, 1770. Cap XVIII: Sic etiam urina inventa particeps coaguli, 28-29 (Translations of Cotugno can befound in: Dock W. Some early observers of albuminuria. Ann Med Hist 1922; 4: 287-290)

Cotugno D. Cap XVIII. Sic etiam urina inventa particeps coaguli. In: De ischiade nervosa commentarius. Graeffer,Vienna: 1774: 28–29This book ran to several editions during the following decade

Dekkers F. Exercitationes practicae circa Medendi Methodum. Boutensteyn and Luchtmans, Leiden: 1694: 338–339. This book was popular, and ran to several editions up to

1717

Donadio JV Jr, Torres VE, Velosa JA, Wagoner RD, Holley KE, Okamura M. Idiopathic membranous nephropathy: the natural history of untreated patients. Kidney Int 1988;33(3): 708-15

Glassock RJ. Prophylactic anticoagulation in nephrotic syndrome: a clinical conundrum. J Am Soc Nephrol 2007; 18(8): 2221-5

Haraldsson B, Nyström J, Deen WM. Properties of the Glomerular Barrier and Mechanisms of Proteinuria. Physiol Rev 2008; 88(2): 451-487

Hull RP, Goldsmith DJA. Nephrotic syndrome in adults. BMJ 2008; 336(7654): 1185–1189Good review article

Humphreys MH. Mechanisms and management of nephrotic edema. Kidney Int 1994; 45: 266-281

Kashif W et al. Proteinuria: How to evaluate an important finding. Cleveland Clinic Journal of Medicine 2003; 70(6): 535-547. Good review article

Kayali F, Najjar R, Aswad F, Matta F, Stein PD. Venous thromboembolism in patients hospitalized with nephrotic syndrome. Am J Med 2008; 121: 226-30

Kodner C. Nephrotic Syndrome in Adults: Diagnosis and Management. Am Fam Physician 2009; 80(10):1129-1134A well written review, which weighs up the strength of evidence for various interventions

Koomans HA. Pathophysiology of acute renal failure in idiopatic nephrotic syndrome. Nephrol Dial Transplant 2001; 16: 221-4

Koomans HA. Pathophysiology of oedema in idiopathic nephrotic syndrome. Nephrol Dial Transplant 2003; 18(S6): vi30–vi32

Kulshrestha S, Grieff M, Navaneethan SD. Interventions for preventing thrombosis in adults and children with nephrotic syndrome (protocol). Cochrane Database Syst Rev2006; 2: CD006024

Leiter L. Nephrosis. Medicine (Baltimore) 1931; 10: 135-242

Machuca E Benoit G Antignac C. Genetics of nephrotic syndrome: connecting molecular genetics to podocyte physiology. Hum Mol Genet 2009; 18(R2): R185-R194

Morgagni GB. De sedibus et causis morborum. Venice: Remondini, 1761: epist. 40, art, 21

Richards NT, Darby S, Howie AJ, et al. Knowledge of renal histology alters patient management in over 40% of cases. Nephrol Dial Transplant 1994; 9: 1255–1259

Rondon-Berrios H. New insights into the pathophysiology of oedema in nephrotic syndrome. Nefrologia 2011; 31(2): 148-154

Singhal R, Brimble KS. Thromboembolic complications in the nephrotic syndrome: pathophysiology and clinical management. Thromb Res 2006; 118: 397-407

Sharpstone P, Ogg CS, Cameron JS. Nephrotic Syndrome Due to Primary Renal Disease in Adults:I. Survey of Incidence in South-east England. British Medical Journal 1969; 2: 533-535

Von Müller, F. Morbus Brightii. Verhandl. d. Deutsch Path Gesellsch 1905; 9:64–99

Wells WC. Observations on the dropsy, which succeeds scarlet fever. Trans Soc Improv Med Chir Knowl 1812; 3: 167–186 (given November 4 1806)

Wells WC. On the presence of the red matter and serum of the blood in the urine of dropsy which has not originated in scarlatina. Tr Soc Improve Med Chir Knowl 1812; 3:194-240

Zwinger T. Paedoiatreia practica. Basel, 1722: cap 119. Anasarca puerorum

Books

The Nephrotic Syndrome. J. S. Cameron, Richard J. Glassock (Editor). Dekker. 1988

Treatment of Primary Glomerulonephritis. Edited by C. Ponticelli and RJ Glassock. 2nd Edition. Oxford Medical Publishers, Oxford. 2009

Curriculum

Podocyte Disorders: Core Curriculum 2011J. Jefferson A et al. AJKD; 2011; 58(4): 666-677

Guidelines

Australasian Guideline (CARI). Chronic Kidney Disease Guidelines. Urine Protein as Diagnostic Test, 2004

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The information provided in this pdf is only a guideline. It should not be used as a basis for the diagnosis or treatment of any medical condition. Your patient may be different