InnovAiT, 13(3), 159–163

Nephrotic syndrome
Dr Thuvaraka Ware
GP & Core Medical Trainee 2, London
Email: thuvaraka.ware@nhs.net

N ephrotic syndrome is characterised by proteinuria, hypoalbuminaemia and oedema.

The renal function is often normal and symptoms may mimic other common patholo-
gies presenting in the community. The underlying aetiology is more heterogenous in adults
compared with children, further confounding the diagnostic process and leading to delays
in recognition. It is a relatively rare presentation in primary care, but the consequences of
nephrotic syndrome can be significant. Complications include hyperlipidaemia, hypercoa-
guability, increased risk of infection and end-stage renal failure. It is, therefore, important
to diagnose, investigate and manage nephrotic syndrome appropriately.

The RCGP curriculum and nephrotic syndrome

The role of the GP in the kidney and urology clinical topic guide is to:
. Identify and manage acute kidney injury (AKI), including taking early action, such as stopping medications, to reduce the
risk of AKI
. Be alert to possible indicators of urinary tract malignancy
. Know when to refer and when not to refer, avoiding futile investigation and escalation and encouraging supportive care
Emerging issues, knowledge and skills relevant to this article include:
. Increasing awareness that a significant proportion of AKI starts in the community, so GPs have a key role in early
identification and management
. Knowledge of typical and atypical presentations
. Identification of risk factors
. Recognition of diagnostic features and differential diagnosis
. Appropriate and relevant investigation
. Interpretation of test results

Pathophysiology
Nephrotic syndrome is an overarching term to describe a
heterogenous group of different disorders. Although there
are several pathophysiological processes contributing to the
phenotype, at the core appears to be glomerular dysfunction
(Gupta et al., 2018). This leads to the classic triad of protein-
uria (greater than 3.5 g/day in adults and greater than 40 mg/
m2 in children), hypoalbuminaemia and oedema (Vivarelli
et al., 2017). Patients with proteinuria in the absence of the
other features have nephrotic-range proteinuria, usually attrib-
uted to underlying glomerular disease.
Proteinuria
The filtration of albumin by the glomerulus is usually restricted
by its overall net negative charge and large size. Any albumin
that does leak out is reabsorbed in the proximal tubule. In
nephrotic syndrome there is a failure of this process, suggest-
ing a problem with the glomerular filter. Abnormalities of
podocytes and/or the slit diaphragm are thought to be respon-
sible. Proteinuria itself will lead to tubulointerstitial inflamma-
tion and fibrosis, contributing to worsening renal function;
proteinuria is also an independent risk factor for cardiovascu-
lar disease (Matsushita et al., 2010).

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Hypoalbuminaemia
Proteinuria may contribute to the subsequent hypoalbuminae-
mia, but the liver should be able to produce sufficient albumin
to compensate for these losses. There are a number of theories
to explain the continued loss of albumin. For example, circu-
lating cytokines may alter albumin production by the liver
(Gupta et al., 2018).
Oedema
There are two broad hypotheses for the development of
oedema in nephrotic syndrome (Gupta at al., 2018). The
‘underfill’ hypothesis is that low oncotic pressure secondary
to hypoalbuminaemia leads to sodium and water retention in
the extracellular space. Conversely the ‘overfill’ hypothesis
suggests that the proteinuria leads to an increase in sodium,
and thus, water resorption in the tubules.
Associated features
The reduced plasma oncotic pressure can lead to increased
lipid metabolism in the liver, leading to hyperlipidaemia
(Agrawal et al., 2018). There is also increased production of
procoagulant factors, increased urinary loss of anticoagulant
factors (antithrombin III) and a functional change in platelets,
leading to a prothombotic state in patients with nephrotic syn-
drome, especially in membranous nephropathy (Mirrakhimov
et al., 2014). The loss of immunoglobulins and complement
through the leaky glomerulus can increase the risk of infec-
tion. The underlying pathology and proteinuria itself can also
lead to acute kidney injury (AKI) and in some cases, end-stage
renal failure if left untreated.
Aetiology
The causes of nephrotic syndrome can be divided into primary
(idiopathic) disorders of the glomerulus and secondary pathol-
ogies leading to glomerular dysfunction (Box 1).
The main primary causes of nephrotic syndrome are
minimal change disease (MCD), membranous nephropathy
(MN), focal and segmental glomerulosclerosis (FSGS) and
mesangiocapillary (membranoproliferative) glomeruloneph-
ritis (MCGN). MCD is more common in children, FSGS in
young adults and MN in older patients.
Assessment
Presentation
The authors own experience of having nephrotic syndrome is
documented in Box 2.
As in Box 2, many patients present with non-specific symp-
toms, or with the classic peripheral and periorbital oedema. If
profound oedema is left untreated, this may progress to ana-
sarca (gross generalised oedema with subcutaneous fluid
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Box 1. Causes of nephrotic syndrome.
Primary
. Membraneous nephropathy
. Minimal change nephropathy
. Focal and segmental glomerulosclerosis
. Mesangiocapillary (membranoproliferative)
glomerulonephritis
Secondary
. Autoimmune (systemic lupus erythematosus (SLE),
rheumatoid arthritis, vasculitides)
. Metabolic (diabetes, amyloid)
. Hereditary (Alports, sickle cell disease)
. Malignancy (myeloma, leukaemia, lymphoma, breast,
lung, colon)
. Infection (Hepatitis B/C, human immunodeficiency
virus, malaria, syphilis, mycoplasma)
. Drugs (non-steroidal anti-inflammatory drugs, capto-
pril, lithium, gold, diamorphine)
. Toxins (bee-stings)
. Pregnancy
accumulation and organ failure) and symptoms thereof.
These include breathlessness from pleural effusions, heart fail-
ure or ascites, and symptoms and signs of AKI. Patients may
also notice frothy urine secondary to heavy proteinuria (the
detergent effect). The low albumin can manifest as leukony-
chia in the nails and tiredness.
If nephrotic syndrome is suspected, look for other clues
that might point to a secondary pathology. For example,
look for new rashes suggesting vasculitis or lupus. In an
older patient with risk factors and constitutional symptoms, it
is important to consider cancer. A family history in younger
patients is useful as a number of renal diseases leading to
nephrosis are congenital (Alport’s syndrome). A comprehen-
sive drug history is also important, especially with nephrosis in
the context of AKI.
Investigation
No National Institute for Health and Care Excellence (NICE)
guidelines for the investigation of nephrotic syndrome cur-
rently exist, although there are guidelines for the investigation
of diseases that can lead to nephrotic syndrome, like MCD.
Box 3 summaries the main tests one should consider when
investigating patients with possible nephrotic syndrome.
In primary care, a urine dip (to exclude nephritic syndrome
and underlying glomerulonephritis (GN)) and blood tests to
look for kidney injury are vital as the results will guide the
urgency of referral to secondary care. In nephritic syndrome,
the pathophysiology appears to include an increase in glom-
erulus porosity by a variety of immune-mediated processes.
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Box 2. Patient narrative.
During my second GP training year I began to feel tired all
the time, out of proportion with my day-to-day activities. I
had just recovered from a protracted bout of sinusitis, for
which I had taken daily paracetamol and non-steroidal anti-
inflammatory drugs (NSAIDs) for 2 weeks. Coincidentally, or
otherwise, the symptoms resolved after a short course of
penicillin. So, when I started to feel tired, I put it down to
a combination of post viral fatigue, having a busy hospital
job, managing a toddler at home and revising for member-
ship exams.
It was not until a few weeks after this that I noticed per-
ipheral pitting oedema up to the mid calves by the end of
each day. I attributed this to prolonged standing, rather
illogically as it had not happened before. It was not until
I developed quite profound periorbital oedema, worse
each morning, that I thought it could be nephrotic syn-
drome. I was unwilling to commit to this diagnosis and
like all good primary care physicians, tried to use time as
a diagnostic tool (plus various antihistamine/ antibacterial
eye drops in case this was secondary infection).
However, my urine dip had 4þ protein with a UPCR greater
than 900 and my albumin was 20. I was not hypertensive,
had normal renal function and did not have haematuria. The
renal registrar saw me fairly promptly and I was transferred
to the tertiary unit for a renal biopsy as a day case. This
confirmed minimal change disease, which is unusual in
adults, but luckily for me, was steroid responsive. The neph-
rologists could not say for certain what the aetiology was but
felt that the sinusitis and NSAIDs may have played a part.
After 6 months of high-dose steroids (accompanied by a
surplus of energy, useful for finishing GP training, but
sadly also by an increased appetite), I was in remission
and managed to wean off my steroids without the need
for a steroid-sparing agent. After 4 years of outpatient
follow up I was discharged.
On reflection, the symptoms were so insidious and non-
specific, that had I been an older, multi-morbid patient, the
diagnosis may have been delayed and increased my
chances of complications, such as clots or infection. This
experience highlighted the need for cautious review of
very common presentations in primary care, like swollen
ankles and feeling tired all the time.
Box 3. Investigating nephrotic syndrome.
. Bloods to include full blood count, renal function, liver
function tests, clotting and lipid profile
. Urine microscopy
. Urinary protein/ albumin: creatinine ratio
. Immunological and serological screen
. US kidneys
. Renal biopsy
Although they are distinct clinical syndromes, sometimes there
is an overlap in presentation between nephrotic and nephritic
syndromes, for example in MCGN, which can present as
either. The key differences between the two are highlighted
in Table 1.
A spot test for protein-to-creatinine ratio provides suffi-
ciently accurate information and is more practical than obtain-
ing a 24-hour urine collection, which remains the gold
standard.
All patients with nephrotic syndrome will require referral to
nephrology, however, a discussion with the on-call nephrolo-
gist or paediatrician may be useful at this point to avoid delay
in further management. Many adults may also require a renal
biopsy to guide treatment. The majority of children with neph-
rotic syndrome hase idiopathic MCD and respond to steroids
(Eddy and Symons, 2003). Therefore, they are less likely to
need a biopsy, and would only require one if steroid resistant.
Principles of management
This is multifaceted and should be organised by the secondary
care nephrology team. Its primary aims are to address the
underlying aetiology (if there is one) and complications of
nephrosis (Fig. 1). The oedema can be treated with salt restric-
tion and diuresis with a loop diuretic (Gupta et al., 2018). For
example, furosemide 40 mg once a day (OD) and titrate up to
250 mg OD. One should aim for a weight loss of 0.5 to 1 kg a
day. If this is proving difficult to achieve and in profound
oedema, the patient may need admission for intravenous diur-
esis to overcome oral malabsorption caused by gut oedema.
Add on diuretics that act synergistically with high-dose loop
diuretics are thiazide-types, such as metolazone (2.5–5 mg a
day) (Crew et al., 2004), and should be used cautiously with
regular blood tests to monitor for electrolyte disturbances. This
combination, however, is not always successful and there are
case reports of resistant oedema (Gupta et al., 2018).
Proteinuria can be treated with angiotensin converting
enzyme inhibitor (ACEi) or angiotensin receptor blocker
(ARB) medications, which are also first line for hypertension
in these patients (Matsushita et al., 2010). The risk for throm-
bosis is raised, especially with very low albumin less than
20 g/L or if the patient has underlying membranous nephro-
pathy. Prophylactic low-molecular-weight heparin in high-risk
patients may be an option and should be guided by the neph-
rologist, as there is no robust evidence currently available to
recommend this action (Mirrakhimov et al., 2014). Treatment
should only cease when the nephrosis is resolved. Patients are
additionally at an increased risk of infection due to loss of
immunoglobulins and complement through impaired glomer-
uli, however, there is no current consensus for the role of
prophylactic antibiotics (Wu et al., 2012).
Minimal change disease
Minimal change disease is the most common cause of neph-
rotic syndrome in children (Eddy and Symons, 2003) and con-
tributes between 15 and 25% of adult presentations (Vivarelli
et al., 2017). The name is derived from the relatively minimal
change seen on light microscopy of fixed tissue; electron
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Table 1. Nephrotic versus nephritic syndrome.

Nephrotic syndrome Nephritic syndrome
Urine Heavy proteinuria, urine looks frothy Micro/macro haematuria and red cell casts
Renal Can be normal/ mildly deranged Significant reduction in eGFR and oliguria
function
Blood Can be normal to mildly elevated Moderate-to-severe hypertension
pressure

Associated Peripheral oedema, hypoalbuminaemia, May include features of underlying GN

features hypercholesterolaemia like a rash in vasculitis
Common As described in Box 1. Primary: IgA nephropathy, Post streptococcal GN
causes Secondary: Rapidly progressive GN (Goodpasture’s
syndrome, vasculitis), MCGN GN (SLE/ hepatitis B/C),
Henoch Schonlein purpura

event, the histology has to be reviewed to ensure the diagnosis

Figure 1. Principles of management. is correct and other immunosuppressive agents can be con-
sidered such as ciclosporin or tacrolimus.

Salt and fluid
restricon
Reduce Treat
proteinuria dyslipidaemia
Principles of
management
Consider
ancoagulaon
Treat infecon
microscopy is required to visualise the podocyte foot process
effacement that characterises this disease. Although a biopsy is
sometimes necessary in adults, this is rarely required in chil-
dren. The aetiology is often idiopathic, but can also be sec-
ondary to medication such as non-steroidal anti-inflammatory
drugs NSAIDS and antimicrobials, haematological malignan-
cies and rarely infections such as tuberculosis or human
immunodeficiency virus (HIV).
Beyond symptomatic treatment as described above, MCD is
usually steroid responsive and the majority of adults will go
into remission within 3 months (Kidney Disease: Improving
Global Outcomes (KDIGO), 2012). Relapse rates are quoted as
between 30 and 70%, and clearly those patients who have
recurrent relapses will be more difficult to treat. In this
Membranous nephropathy
MN is the most common cause of non-diabetic nephrotic syn-
drome worldwide in adults, more prevalent in women
between the fourth and sixth decades of life (Couser, 2017).
Most presentations are idiopathic in nature and require a
biopsy to guide treatment. Microscopy shows a thickened
basement membrane with immunofluorescence highlighting
granular IgG deposition in the capillary walls. Secondary
causes include malignancy, which may or may not be pre-
ceded by nephrotic syndrome by several years; its develop-
ment may also be the sign of a cancer relapse.
Management of both primary and secondary MN requires
symptomatic treatment (Fig. 1) and for the latter, one should
treat the underlying condition. For primary MN, one third of
patients spontaneously remit, another third will have persist-
ent mild proteinuria and the last third will progress to end-
stage renal failure. For this reason, after diagnosis patients are
observed for a short period to detect remission. If there is
deterioration clinically or biochemically, disease-modifying
treatment can be considered. Current advice is for a course
of alternating monthly cycles of steroids with alkylating agents
such as cyclophosphamide for 6 months, and evaluation of the
response thereafter (KDIGO, 2012).
Focal and segmental glomerulosclerosis
FSGS is both a disease process and histological diagnosis
describing sclerosis of parts (segmental) of some (focal) of
the glomeruli (NICE, 2016). Primary (idiopathic) FSGS is the
main cause of nephrotic syndrome in black patients, for whom
there is a worse prognosis as compared with other ethnicities.
They can also present with heavy proteinuria. It can recur in
transplanted kidneys and may be associated with

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hypertension, renal dysfunction and microscopic haematuria
(D’Agati et al., 2011). Although secondary FSGS presents with
less hypoalbuminaemia and proteinuria, it is more likely to
lead to chronic hidney disease. Causes include infection, like
HIV, and any cause of progressive renal scarring such as vas-
culitis or pre-eclampsia.
Almost half the patients will progress to end-stage renal
failure if left untreated. The mainstay of treatment for primary
FSGS causing nephrotic syndrome is steroids, bearing in mind
that FSGS is slower to respond than, for example, MCD (NICE,
2016). Patients usually require a minimum of 4 weeks treat-
ment. Those that do not respond to this can be considered for
calcineurin inhibitors such as ciclosporin or tacrolimus.
Rituximab may also be an option for refractory cases, how-
ever, the recommendations are drawn from observational stu-
dies with low participant numbers (NICE, 2016). Secondary
FSGS will not be as steroid responsive and requires reduction
in intraglomerular pressure and treatment of the underlying
cause (D’Agati et al., 2011).
Mesangiocapillary (membranoproliferative)
glomerulonephritis
This term describes the histology found on renal biopsy of
these patients: intense glomerular hypercellularity due to
mesangial proliferation and glomerular basement membrane
thickening (Sethi and Fervenza, 2012). As with the above
causes of nephrotic syndrome, this can be a primary and
References and further information
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nephrotic syndrome: Mechanisms and treatment. National
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Couser WG (2017) Primary membranous nephropathy. Clinical
Journal of the American Society of Nephrology 12(6): 983–997.
DOI: 10.2215/CJN.11761116.
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erythematosis. There are currently no evidenced-based treat-
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steroids and monoclonal antibodies may have a role in man-
agement (Sethi and Fervenza, 2012).
KEY POINTS
. Nephrotic syndrome is caused by a diversity of disease
processes and can present non-specifically and/or simi-
lar to common pathologies seen in primary care
. It is a rare, but important, presentation of kidney disease
with serious complications that include thrombosis,
infection and renal failure
. Investigation focuses on finding the underlying aetiology
. Management is multifaceted focusing on symptom man-
agement and ensuring that any underlying aetiology if
found, is treated
. All patients require referral to the nephrology team and
may require a renal biopsy
ORCID iD
Thuvaraka Ware https://orcid.org/0000-0002-8713-3329
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