Nephrotic syndrome in adults

Abstract

The nephrotic syndrome is one of the best known presentations of adult or paediatric kidney disease. The term describes the association of (heavy) proteinuria with peripheral oedema, hypoalbuminaemia, and hypercholesterolaemia (box 1). Protein in the urine (“coagulable urine”) was first described in 1821, 15 years before Richard Bright’s celebrated series of descriptions of “albuminous urine.”1

#### Box 1 Diagnostic criteria for nephrotic syndrome

Nephrotic syndrome has an incidence of three new cases per 100 000 each year in adults.2 It is a relatively rare way for kidney disease to manifest compared with reduced kidney function or microalbuminuria as a complication of systemic diseases, such as diabetes and raised blood pressure.3

#### Summary points

Patients with nephrotic syndrome can present to primary or secondary care with diverse symptoms that reflect the primary process or with one of the many systemic complications of the syndrome.4 Although nephrotic syndrome is relatively common in renal practice, it is seen only rarely in primary or secondary care. This can result in a delayed or overlooked diagnosis, especially as many other conditions have similar symptoms. For example, severe peripheral (leg) oedema is seen in congestive cardiac failure, hypoalbuminaemia can be caused …

Full text

CLINICAL REVIEW
Nephrotic syndrome in adults
RichardPHull,DavidJAGoldsmith
The nephrotic syndrome is one of the best known
presentations of adult or paediatric kidney disease. The
term describes the association of (heavy) proteinuria
with peripheral oedema, hypoalbuminaemia, and
hypercholesterolaemia (box 1). Protein in the urine
(“coagulable urine”) was first described in 1821,
15 years before Richard Bright’s celebrated series of
descriptions of “albuminous urine.”
1
Nephrotic syndrome has an incidence of three new
cases per 100 000 each year in adults.
2
It is a relatively
rare way for kidney disease to manifest compared with
reduced kidney function or microalbuminuria as a
complication of systemic diseases, such as diabetes and
raised blood pressure.
3
Why should I read this article?
Patients with nephrotic syndrome can present to
primary or secondary care with diverse symptoms
that reflect the primary process or with one of the many
systemic complications of the syndrome.
4
Although
nephrotic syndrome is relatively common in renal
practice, it is seen only rarely in primary or secondary
care. This can result in a delayed or overlooked
diagnosis, especially as many other conditions have
similar symptoms. For example, severe peripheral (leg)
oedema is seen in congestive cardiac failure, hypo-
albuminaemia can be caused by severe liver disease or
advanced malignancy, and periorbital oedema is seen
in allergic reactions. This article deals with adults only,
as the management of nephrotic syndrome is very
different in children.
Owing in part to a lack of randomised trials,
systematic reviews, and guidelines on the management
of nephrotic syndrome, some uncertainty exists
regarding its investigation and management. No high
quality trials of treatment or interventions are available
to inform the management of this rare condition, which
has a complex and diverse aetiology. On the basis of the
best available evidence and expert consensus, this
article aims to provide an update on the causes,
pathophysiology, relevant investigations, complica-
tions, and treatment of nephrotic syndrome in adults.
What conditions can cause nephrotic syndrome?
A wide range of primary (idiopathic) glomerular
diseases and secondary diseases can cause the syn-
drome.
Pathophysiology of nephrotic syndrome
Increased glomerular permeability to large molecules,
mostly albumin but other plasma proteins too, is the
essential pathological process in nephrotic syndrome
of any aetiology. Proteinuria causes a fall in serum
albumin, and if the liver fails fully to compensate for
urinary protein losses by increased albumin synthesis,
plasma albumin concentrations decline, leading to
oedema formation. Interstitial oedema forms either as
a result of a fall in plasma oncotic pressure from urinary
loss of albumin or from primary sodium retention in
the renal tubules.
56
Primary (idiopathic) glomerular disease
Most cases of nephrotic syndrome are caused by
primary glomerular diseases (table). Thirty years ago
idiopathic membranous nephropathy was the most
common primary cause of the syndrome.
7
The
incidence of other glomerular diseases, particularly
focal segmental glomerulosclerosis, has increased and
pronounced racial differences. Membranous nephro-
pathy remains the most common cause in white
patients, whereas focal segmental glomerulosclerosis
is the most common cause in black patients (50-57% of
cases).
78
Sources and selection criteria
We searched PubMed with the terms
“
nephrotic syndrome
”
,
“
epidemiology
”
,
“
glomerulonephritis, membranous
”
,
“
glomerulosclerosis, focal
”
,and
“
minimal change
nephropathy
”
. We also searched the Cochrane library for the limited number of systematic
reviews on this subject and referred to the Oxford Textbook of Clinical Nephrology (3rd
edition) for guidance on appropriate areas to cover for this article.
Box 1 Diagnostic criteria for nephrotic syndrome
Proteinuria greater than 3-3.5 g/24 hour or spot urine
protein:creatinine ratio of >300-350 mg/mmol
Serum albumin <25 g/l
Clinical evidence of peripheral oedema
Severe hyperlipidaemia (total cholesterol often
>10 mmol/l) is often present
Guy
’
s Hospital Ren al Unit, London
SE1 9RT
Correspondence to: D J A Goldsmith
david.goldsmith@gstt.nhs.uk
BMJ 2008;336:1185-9
doi:10.1136/ bmj.39576.709711.80
BMJ |24 MAY 2008 |VOLUME 336 1185
For the full versions of these articles see bmj.com

Secondary glomerular disease
A wide range of diseases and drugs can cause nephrotic
syndrome (box 2). Diabetic nephropathy is a common
cause, reflecting the increasing prevalence of diabetes.
Amyloid is also an important cause, with immuno-
globulin light chain amyloid nephropathy accounting
for 10% of cases in one series.
7
How do I assess patients who present with nephrotic
syndrome?
The aims are to assess the current clinical state of the
patient
—
to ensure that no complications of the disease
are present
—
and to start formulating whether a
primary or secondary cause underlies the syndrome,
as this informs referral. Almost all patients should be
referred to a nephrologist for further management. In
children, a paediatric nephrologist will supervise
investigation and treatment.
What are the key points in the patient
’
shistory?
The history is key in pinpointing the cause of nephrotic
syndrome. It is important to note any features
suggestive of systemic disease, the drug history
(especially newly prescribed or “over the counter”
drugs), and any acute or chronic infections. Membra-
nous nephropathy has an association with cancer,
particularly of the lungs and large bowel. Although rare
in clinical practice, suspicion should be raised,
especially in elderly patients. It is useful to take a
family history because the syndrome has several
congenital causes, such as Alport’s syndrome (box 2).
What clinical signs accompany nephrotic syndrome?
Nephrotic syndrome should be part of the differential
diagnosis for any patient with new onset oedema.
Oedema associated with nephrotic syndrome is often
first noticed periorbitally and can become severe
—
patients may develop oedema of the lower leg and
genitals as well as ascites, pleural effusions, and
pericardial effusions (box 3).
Which investigations should be performed?
No guidelines are available for the investigation of
nephrotic syndrome. The sequence of investigations in
box 4 is typical of those used to assess the patient’s
current clinical status and identify the underlying cause
of the syndrome. Assessing the patient’s renal function
is a key part of this; serum urea and creatinine should be
measured and an estimated glomerular filtration rate
calculated. Dipstick testing of the urine for haematuria
(which would suggest glomerulonephritis) and protein-
uria (3-4+ protein indicates the nephrotic range) is
essential, as is measuring the amount of protein loss.
We recommend using a spot (preferably early morn-
ing) urine sample for a protein:creatinine ratio or an
albumin:creatinine ratio as these tests are less prone to
error, give quicker results, and have been shown, in
cross sectional longitudinal studies, to be as accurate as
24 hour urine collections.
310
A protein:creatinine ratio
value greater than 300-350 mg/mmol indicates
nephrotic range proteinuria. Renal ultrasound is used
to assess renal size and morphology and may need to be
performed urgently if signs of renal vein thrombosis are
present (such as flank pain, haematuria, renal impair-
ment
—
using, for example, Doppler examination of the
renal veins).
Complications of nephrotic syndrome
The nephrotic syndrome has systemic consequences
(box 5). They result, in part, from significant changes in
the protein environment of the body as a result of
overproduction of proteins in the liver and loss of low
molecular weight proteins in the urine.
Is there a significant risk of thromboembolism?
Patients with nephrotic syndrome are at increased risk
for thromboembolic events. Imbalances of prothrom-
botic and antithrombotic factors as well as impaired
thrombolytic activity occur.
11
Intravascular volume
depletion; the use of diuretics; immobilisation; and
procoagulant diatheses, such as protein C and protein S
deficiencies, or antiphospholipid antibodies, are
important contributing factors. The most common
sites of thrombosis in adults are in the deep veins of the
lower limb. Thrombosis can also occur in the renal
veins and can cause pulmonary embolism. Arterial
thrombosis can also rarely occur in patients with
nephrotic syndrome.
12
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.
11 13-15
Modern data differ, however. A recent
retrospective study reviewing coding data from dis-
charged patients in the United States found deep vein
thrombosis occurred in 1.5% and renal vein thrombo-
sis in 0.5% of patients with nephrotic syndrome.
16
Another recent retrospective cohort study found an
eight times higher absolute risk of venous thrombo-
embolism, with the greatest risk occurring in the first
six months after diagnosis.
17
Case series have shown
that membranous nephropathy is particularly
associated with venous thrombosis,
11-15
and the risk of
venous thrombosis is higher when serum albumin is
<20-25 g/l.
13
Should all patients receive prophylactic anticoagulation?
No randomised control trials are available to guide the
decision of who is given prophylactic anticoagulation
and for how long.
13 18 19
A Cochrane review protocol,
Primary glomerular diseasesthat can cause nephrotic syndrome
79
Disease
Frequency of disease (%) as a cause of nephrotic syndrome
1960s and 1970s
1990s to the presentPatients <60 years Patients >60 years
Focal segmental glomerulosclerosis 15 2 35
Membranous glomerular disease 40 39 33
Minimal change glomerular disease 20 20 15
Membranoproliferative glomerular disease
(for example, IgA)
70 14
Other glomerular disease 18 39 3
Box 2 Secondary causes
of nephrotic syndrome
Other diseases
Diabetes mellitus
Systemic lupus
erythematosus
Amyloidosis
Cancer
Myeloma and lymphoma
Drugs
Gold
Antimicrobial agents
Non-steroidal anti-
inflammatory drugs
Penicillamine
Captopril
Tamoxifen
Lithium
Infections
HIV
Hepatitis B and C
Mycoplasma
Syphilis
Malaria
Schistosomiasis
Filariasis
Toxoplasmosis
Congenital causes
Alport
’
ssyndrome
Congenital nephrotic
syndrome of the Finnish
type
Pierson
’
ssyndrome
Nail-patella syndrome
Denys-Drash syndrome
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1186 BMJ |24 MAY 2008 |VOLUME 336

published in 2006, reviewed this subject, but the
paucity of trials means that the authors used only a
pooled meta-analysis of the available data and non-
randomised evidence for their study.
20
Screening for
thrombosis is not thought to add value to the decision
making process and was not recommended in a recent
expert commentary.
19
General factors such as immo-
bility, oedema, coexisting prothrombotic tendency,
and a previous history of thromboembolic events need
to be taken into account, but no “threshold”of
proteinuria or hypoalbuminaemia has been identified
as a trigger for the use of anticoagulation. Common
practice among nephrologists is to anticoagulate with
heparin and then warfarin if serum albumin is less than
20 g/l and proteinuria is within the nephrotic range.
21
The decision of when and how to anticoagulate a
patient with nephrotic syndrome should be made after
careful consultation with a nephrology team (because,
for example, a renal biopsy cannot safely or easily be
done with systemic anticoagulation).
Is infection an important problem?
Infection has been reported in up to 20% of adult
patients with nephrotic syndrome.
22
Patients have an
increased susceptibility to infection because of low
serum IgG concentrations, reduced complement
activity, and depression of T cell function.
23
A variety
of infectious complications, particularly bacterial
infections, such as cellulitis, can occur. Views on the
use of antibiotic and vaccine prophylaxis are conflict-
ing. No trials have assessed the use of prophylactic
antibiotics in adults. A Cochrane review in 2004 was
not able to recommend any interventions for prevent-
ing infection.
24
Can nephrotic syndrome cause acute renal failure?
Acute renal failure (acute kidney injury) is a rare
spontaneous complication of nephrotic syndrome.
25
It
can also be caused by excessive diuresis, interstitial
nephritis related to the use of diuretics or non-steroidal
anti-inflammatory drugs, sepsis, or renal vein throm-
bosis. Renal impairment of a more chronic nature can
reflect damage to the kidneys from systemic or primary
renal conditions (such as amyloidosis or diabetes).
Reviews of case reports suggest that older patients (and
children), and those with heavier protein loss, are most
at risk. Patients may need dialysis and can take weeks to
recover.
25
How can nephrotic syndrome be treated?
What is the best way to treat oedema?
No guidelines or randomised trials are available on this
subject. The 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 mmol/day; 3 g/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, because aggressive diuresis can cause
electrolyte disturbances, acute renal failure, and
thromboembolism as a result of haemoconcentration.
Box 3 Clinicalsigns of
nephrotic syndrome
Oedema
Periorbital oedema
Lower limb oedema
Oedema of the genitals
Ascites
Low albumin
Tiredness
Leuconychia
Breathlessness
Pleural effusion
Fluidoverload(high
jugular venous pressure)
Acute renal failure
Breathlessness with
chest pain
Thromboemboli
Dyslipidaemia
Eruptive xanthomata
Xanthelasmata
Other
Frothy urine
Box 4 Sequence of investigations for a person presenting
with nephrotic syndrome
Confirm proteinuria present
Urine dipstick positive (2/3/4+)
Check for concomitant invisible (microscopic)
haematuria
Urine dipstick positive (1/2/3+)
Exclude urine infection
Midstream urine to exclude active urinary tract infection
—
microscopy, culture, and sensitivity
Measure amount of proteinuria
Early morning urinary protein:creatinine ratio or albumin:
creatinine ratio (mg/mmol)
Typically >300-350 mg/mmol in nephrotic syndrome
Basic blood testing
Full blood count and coagulation screen
Renal function including plasma creatinine and estim ated
glomerular filtration rate
Liver function tests to exclude concomitant liver pathology
Bone profile
—
corrected (for albumin) plasma calcium
Check for other systemic diseases and causes of
nephrotic syndrome
C reactive protein and erythrocyte sedimentation rate
Glucose
Immunoglobulins, serum and urine electrophoresis
Autoimmune screen if an underlying autoimmune disease
is suspected
—
antinuclear antibody (ANA), antidouble
stranded DNA antibody (dsDNA), and complement values
(C3 and C4)
Hepatitis B and C and HIV (after obtaining informed
consent)
Chest x ray and abdominal or renal ultrasound scan
(especially if renal function is abnormal)
To check for pleural effusion or ascites
To check for the presence of two kidneys, their size and
shape, and the absence of obstruction
Be vigilant for complications such as
thromboembolism
Doppler ultrasound of leg veins in suspected deep vein
thrombosis
Abdominal ultrasound, renal vein Doppler scan,
venography of the inferior vena cava, computed
tomography and magnetic resonance imaging of the
abdomen if renal vein thrombosis is suspected
V/Q nuclear medicine lung scan, computed tomography
pulmonary angiography for pulmonary embolism
Investigate the underlying renal and systemic cause of
nephrotic syndrome
Renal biopsy under ultrasound
Make histological preparations for light microscopy,
immunofluoresence or immunoperoxidase, electron
microscopy
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BMJ |24 MAY 2008 |VOLUME 336 1187

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 for refractory cases. Common diuretics are mostly
protein bound so their activity may be affected by
heavy proteinuria once filtered across the glomerulus.
Thiazide diuretics or potassium sparing diuretics are
often added to try to improve the poor responses
sometimes found with loop diuretics. They are
synergistic for distal inhibition of sodium reabsorption.
Intravenous albumin has been used to improve
diuresis, and it 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 whom conventional 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.
26
Does proteinuria need specific treatment?
Proteinuria is one of the most important adverse
prognostic factors for progression to end stage renal
failure in chronic renal disease.
27 28
One of the main
goals of treating nephrotic syndrome is to reduce or
eliminate proteinuria. In some patients, this can be
achieved by treating the underlying pathology, but
additional measures are needed in most. Strategies to
limit protein excretion also help correct oedema.
Angiotensin converting enzyme inhibitors, either on
their own or together with angiotensin II receptor
antagonists, have become the mainstay of treatment as
a result of evidence from randomised controlled trials
and meta-analyses.
29-31
Proteinuria can be reduced
without a change in blood pressure and combined
treatment reduces proteinuria more effectively than
single agents alone.
29 31 32
The use of these agents
mandates regular monitoring of plasma electrolytes
and their full antiproteinuric effect can take some weeks
to manifest. Several older treatments, such as high dose
non-steroidal anti-inflammatory drugs, have appreci-
able side effects and are rarely used now. In severe and
uncontrollable proteinuria with incapacitating symp-
toms, especially with complications such as renal
dysfunction and malnutrition, patients may need single
or bilateral nephrectomy or renal embolisation. In
practice this is a rare outcome.
Should we treat dyslipidaemia?
Hyperlipidaemia of nephrotic syndrome is charac-
terised by increases in low density lipoprotein choles-
terol and triglyceride and alterations in high density
lipoprotein concentrations.
33
Increased cardiovascular
events in nephrotic patients could be related to lipid
abnormalities.
34
No prospective trials have shown that
treatment improves survival, but a meta-analysis and
post hoc subgroup analyses show that statins have a
small protective effect on the progression of renal
damage.
34-37
Of note, many patients spontaneously
remit or go into remission with treatment. Treating the
underlying cause of nephrotic syndrome and thereby
reducing proteinuria will improve or resolve the
dyslipidaemia.
Do patients need a special diet?
Muscle wasting is a major problem in severe nephrotic
syndromeand patients have a greatly increased albumin
turnover. Because of a lack of evidence, the optimal
protein intake for such patients is not clear. A low
protein diet runs the risk of negative nitrogen balance
and malnutrition and so is not recommended.
38
Who should be referred for targeted investigation and
treatment?
We recommend that all new cases are discussed
urgently with local kidney specialists with a view to
urgent referral for investigation and treatment. Only
rarely is this not necessary (for example, a patient with
established diabetic nephropathy, whose protein loss
increased to the nephrotic range, might initially be
managed by further titration of angiotensin converting
enzyme inhibitors and angiotensin II receptor
antagonists).
Box 5 Complications of nephrotic syndrome
Thromboembolism
Deep vein thrombosis or renal vein thrombosis, which can lead to pulmonary embolism
Arterial thrombosis (very rare)
Infection
Cellulitis
Bacterial infections, such as pneumonia and cellulitis
Bacterial peritonitis (rare)
Viral infections in immunocompromised patients
Other complications
Hyperlipidaemia
Loss of vitamin D (via binding protein) leading to bone disease
Acute renal failure
ADDITIONAL EDUCATIONAL RESOURCES
Resources for healthcare professionals
Goldsmith DJ, Jayawardene S, Ackland P, eds. ABC of kidney disease. Oxford: Blackwell
Publishing, 2007
Davison AMA, Cameron JS, Grunfeld JP, Ponticelli C, Ypersele CV, Ritz E, et al, eds. Oxford
textbook of clinical nephrology. 3rd ed. Oxford: Oxford University Press, 2005
Burden R, Tomson C. Identification, management, and referral of adults with chronic kidney
disease: concise guidelines. Clin Med 2005;5:635-42. www.renal.org/eGFR/eguide.html
Resources for patients
Renal Unit of the Royal Infirmary of Edinburgh (http://renux.dmed.ed.ac.uk/edren/index.
html)
—
Excellent source of information about renal disease for patients and non-specialist
practitioners
National Kidney Federation UK (www.kidney.org.uk)
—
A collection of disease resources
under the
“
medical information
”
heading
CLINICAL REVIEW
1188 BMJ |24 MAY 2008 |VOLUME 336

Conclusions
Nephrotic syndrome can present in diverse ways in
multiple healthcare settings and has important com-
plications. Investigating and managing the syndrome is
made more challenging by the lack of a guiding
evidence base, but strategies derived from expert
consensus are available for its initial management. All
patients presenting with nephrotic syndrome should be
discussed with local kidney specialists before embark-
ing on further investigations and management. Large
randomised trials in the management of the nephrotic
syndrome, and in glomerular disease in general, are
urgently needed to achieve further progress.
RPH and DJAG contributed equally to the design, writing, and editing of this
article. DJAG is guarantor.
Competing interests: None declared.
Provenance and peer review: Commissioned; externally peer reviewed.
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SUMMARY POINTS
Nephrotic syndrome is a relatively rare but important manifestation of kidney disease
It has serious complications and must be part of the differential diagnosis for any patient
presenting with new onset oedema
It can be caused by a wide range of primary (idiopathic) and secondary glomerular diseases
All patientsshould be referred to a nephrologist for further investigation, which(often) includes
a renal biopsy
Initial management should focus on investigating the cause, identifyingcomplications, and
managing the symptoms of the disease
CLINICAL REVIEW
BMJ |24 MAY 2008 |VOLUME 336 1189