Nephrotic syndrome in adults: Role of

Rituximab

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 Nephrotic Syndrome

• Damage to the glomeruli allows proteins, such as albumin, to

pass through into the nephron tubules and be lost in urine,
giving rise to three clinical features that define NS:
• Proteinuria (defined as loss of >3.5g of protein in
urine over 24 hours)

• Hypoalbuminaemia (<30g/L of albumin in the

blood)

• Peripheral oedema​
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 Nephrotic Syndrome

• Nephrotic syndrome has an incidence of three new cases per

100 000 each year in adults.

• 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.

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 Damage to the cells comprising the
glomerulus can result in nephrotic syndrome

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 Complications

Result from compensatory overproduction of

proteins by the liver

High levels of lipids in the blood

(hyperlipidaemia)

Thromboembolism

Increased risk of infection​

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Pathophysiology

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 Pathophysiology

Glomerular filtration barrier (GFB), a membrane that restricts the passage of

serum proteins by size and charge.

It consists of three layers: Capillary endothelial cells; Glomerular

basement membrane (GBM); Epithelial cells (podocytes)​.

In NS, injuries to the GFB increase permeability to

serum proteins through changes in its charge-selective
or size-selective properties, causing proteinuria​
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 Complications

One or more changes, including damage to the podocytes,

capillary endothelial cells and disruption of the GBM function
may be seen in any one type of NS​​.

Injury to podocytes — the major target of injury in

diseases causing primary NS — is commonly caused
by immune complex deposition or complement
protein activation

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 Symptoms

Progressive oedema,
mainly observed in the
lower limbs

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 Symptoms

Periorbital (around the

eyes), genital area and
abdomen (ascites)

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 Symptoms

Urine may appear frothy owing

to high concentrations of
protein

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 Complications of nephrotic
syndrome and contributing
factors
Complications Contributing factors

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 Complications of nephrotic
syndrome and contributing
factors
Complications Contributing factors

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Causes and risk factors

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 Causes

• In adults, FSGS accounts for between 35% and 50% of

nephrotic causes.

• FSGS is not a single disease, but rather a pattern of kidney

injury characterised by segmental areas of mesangial collapse
and sclerosis in some glomeruli​​.

• The cause is usually idiopathic but may be secondary (e.g. drug

use, HIV and obesity)​.

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 Causes

• MN is one of the most common causes of NS in adults and may

be owing to primary or secondary causes (e.g. infections, drugs,
autoimmune disorders and cancer).

• Among adult patients with primary MN, 70–80% of patients

have circulating antibodies to the M-type receptor of the anti-
phospholipase A2 receptor (anti-PLA2R) located on the
podocyte membrane.

• Measuring these antibodies can help distinguish primary MN​.

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 Causes

• MCD is so called because light microscopy on histology often

reveals normal glomeruli and is the most common cause of NS
in children, accounting for 90% of cases, although it can also
occur in adults​.

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 Diagnosis
• Confirmation of proteinuria is initially carried out by a dipstick urinalysis.

• The amount of protein is quantified by either a 24-hour urine collection or a spot

urine protein-to-creatinine ratio (uPCR) with >3.5g/24 hours or
uPCR>300mg/mmol indicative of nephrotic-range proteinuria​​.

• Basic blood biochemistries:

• Urea and creatinine to assess renal excretory function
• Total cholesterol to detect severe hyperlipidaemia (e.g. >10 mmol/L)
• Serum albumin for thromboembolic risk
• Thyroid function tests for hypothyroidism
• Monitoring vitamin D and calcium levels for bone disorders​ 18
 Diagnosis
• Autoimmune screen (undertaken if an autoimmune disease, such as systemic lupus erythematosus, is
suspected)

• Virology screen (undertaken to determine whether HIV or hepatitis B or C are causes)

• HbA1c and fasting glucose – to exclude diabetes mellitus as a cause

• Serum free light chains or urine protein electrophoresis – may suggest amyloidosis or multiple myleloma

• Renal ultrasound to assess renal size and morphology

• Renal biopsy to determine histologic type, including immunofluorescence and electron microscopy​
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 Management
Nephrotic syndrome treatment response definitions

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 Management
Treatment algorithm as per Kidney Disease Improving Global Outcomes guidelines

a: frequently relapsing MCD: ≥2 relapses

over a 6-month period (or ≥4 over 12
months)
b: corticosteroid-dependent MCD:
relapse during or within 2 weeks of
prednisolone completion
c: corticosteroid-resistant FSGS:
proteinuria persisting >3.5g/day or uPCR
>3500 mg/g (350mg/mmol) with <50%
reduction from baseline despite
prednisolone treatment for at least 16
weeks
Source: Kidney Disease Improving Global
Outcomes​ 21
Nephritic vs Nephrotic
Syndrome
 ANCA ‐
Rituximab associated
vasculitis
 ANCA associated
Vasculitis

Antineutrophil cytoplasmic antibodies (ANCA)-associated

vasculitis is a group of autoimmune disorders that
predominantly affects small vessels.
Expert Opinion on Biological Therapy, 2020, 20:8, 899-910
 ANCA associated
Vasculitis
• ANCAs comprise three distinct diseases:

• Granulomatosis with polyangiitis (GPA, formerly Wegener’s

granulomatosis) – Rituximab is approved

• Microscopic polyangiitis (MPA) - Rituximab is approved

• Eosinophilic granulomatosis with polyangiitis (EGPA,

formerly Churg–Strauss syndrome)

Expert Opinion on Biological Therapy, 2020, 20:8, 899-910

 Rituximab – ANCA associated
Vasculitis

N = 785 Dose: 4×375 mg/m2/wk

Expert Opinion on Biological Therapy, 2020, 20:8, 899-910

 Rituximab – ANCA associated
Vasculitis
• Rituximab should be used as first-line therapy with
corticosteroids to induce remission of severe ANCAs.

• The current maintenance regimen has been extended to at

least 18 months but its optimal duration remains unknown.

• Recent data suggest the possibility to extend treatment to 4

years.

Expert Opinion on Biological Therapy, 2020, 20:8, 899-910

 Systemic lupus
Rituximab
erythematous
 Systemic Lupus Erythematous –
Lupus Nephritis

• Systemic lupus erythematosus

is a multisystem autoimmune
disease that commonly affects
the kidneys.

• Production of autoantibodies
and deposition of immune
complexes in Kidney

Drug Design, Development and Therapy 2019

 Rituximab – Lupus
Nephritis

Number of Studies = 24 Dose: 4×375 mg/m2/wk

N = 940

Drug Design, Development and Therapy 2019

 Rituximab – Lupus
Nephritis
• The Total remission was 73.4%.

• In controlled trials, RTX was associated with a higher probability of TR (OR

=2.02, 95% CI: 1.23–3.32, P=0.01).

• RTX treatment significantly decreased proteinuria (P=0.01) as well as the renal

activity index in patients with LN (P=0.01).

• In controlled trials, the relative risks of the adverse events of infection and
infusion reaction were not notably different between the two groups.

Drug Design, Development and Therapy 2019

 Membranous
Rituximab
nephropathy
 Membranous
Nephropathy
• Membranous nephropathy is the most common cause of
primary nephrotic syndrome among adults.

• Mtype PLA2R autoantibody was identified in 70% to 80% of

patients.

• PLA2R is a type I transmembrane protein.

Kidney Int Rep (2021) 6, 881–893

 Rituximab – Membranous
Nephropathy

Number of Studies = 12 Duration: 12 -24 Months

N = 587 Total Remission : 44 -88%
Dose: 4×375 mg/m2/wk

• As per updated KDIGO guidelines Rituximab is a promising new first-line

treatment option for primary Membranous Nephropathy.

Kidney Int Rep (2021) 6, 881–893

Rituximab Cryoglobulinemia
 Cryoglobulinemia
• Cryoglobulinemia is characterized by the presence of
cryoglobulins in the serum.

• This may result in a clinical syndrome of systemic inflammation

(most commonly affecting the kidneys and skin) caused by
cryoglobulin-containing immune complexes.

• Cryoglobulins are circulating proteins,

specifically immunoglobulins (i.e., IgG, IgM, IgA or light chains).

Am J Nephrol 2016;43:251–260
 Rituximab –
Cryoglobulinemia

Am J Nephrol 2016;43:251–260
 Rituximab – Cryoglobulinemia

• Aim: Evaluation of very long-term effects of rituximab to

patients with severe mixed cryoglobulinemia

• Methods: Prospective, single-center open study, N = 31

• Treatment: Dose of 375 mg/m 2 , according to a ‘4 + 2’ protocol

(days 1, 8, 15 and 22 plus 1 dose 1 and 2 months later)
No other immunosuppressive drugs were added
Response was evaluated over a very long-term follow-
up

Am J Nephrol 2016;43:251–260
 Rituximab –
Cryoglobulinemia
• Results: Cryoglobulinemic nephropathy significantly improved
during follow-up, starting from the 2nd month after
Rituximab (serum creatinine from 2.1 to 1.5 mg/dl, p ≤
0.05; 24-hour proteinuria from 2.3 to 0.9 g/24 h, p ≤
0.05).

Survival rate = 75% at 6 years

Probability of remaining symptom-free for 10 years without any

therapy was of about 60% after a single ‘4 + 2’ infusion cycle,
while the probability of living symptom free 5 years after
relapsing was 80% if given the same treatment.
• Conclusion: Very effective and safe in the treatment of the most
severe cases of mixed cryoglobulinemia.
Am J Nephrol 2016;43:251–260
 Focal segmental
Rituximab
glomerulosclerosis
 Focal segmental
glomerulosclerosis
• Focal segmental
glomerulosclerosis (FSGS)
is the leading glomerular
cause of ESRD.

• When glomeruli become

damaged or scarred
(sclerosis), proteins begin
leaking into the urine
(proteinuria).

Clinical Kidney Journal, 2021, vol. 14, no. 4, 1042–1054

 Rituximab – Focal segmental
glomerulosclerosis

Number of Studies = 9 Duration: 6 - 12 Months

N = 112 Total Remission : ~ 75%
Dose: 4×375 mg/m2/wk

Braz. J. Nephrol. (J. Bras. Nefrol.) 2020;42(1):77-93

 Rituximab – Minimal change
Disease

Oncotarget, 2018, Vol. 9, (No. 48), pp: 28799-28804

 Rituximab – Minimal change
Disease
Evolution of Proteinuria

Oncotarget, 2018, Vol. 9, (No. 48), pp: 28799-28804

 Rituximab – Minimal change
Disease
Laboratory data at last follow-up

Oncotarget, 2018, Vol. 9, (No. 48), pp: 28799-28804

 Rituximab – Minimal change
Disease

• Age 45–73 years, treated with RTX (4 weekly doses of 375 mg/m2).

• Proteinuria decreased from 11,2 (23–4.8) g/24 hours to 0.6 (0–2) g/24 hours after 6 months, and to 0.4 (0–
1, 4) g/24 h in the 4 pts with the longer follow-up.

• Creatinine decreased from 1.95 (0.5–5) mg/dl to 0.88 (0.6–1.3) mg/l. Five patients achieved a complete
renal remission, while in 1 pt proteinuria decreased by 75%.

• RTX successfully depleted CD19 lymphocytes in 100% of pts for at least 6 months.

• No clinically relevant adverse events have been observed.

Oncotarget, 2018, Vol. 9, (No. 48), pp: 28799-28804

 Summary
Treatment of NS involves addressing the
Further management is aimed at assessing
underlying cause, as well as taking steps to
and managing the potential complications of
reduce proteinuria, including an angiotensin-
nephrotic syndrome, including the risk of
converting-enzyme inhibitor, good blood pressure
thromboembolism, hypercholesterolaemia
control and management of oedema via sodium
and infection.
and fluid restriction, and the use of diuretics.

Anti-CD20 therapies such as Rituximab have become an

important treatment strategy of several
glomerulonephritis.

Oncotarget, 2018, Vol. 9, (No. 48), pp: 28799-28804

 Summary
The use of high-dose
rituximab protocols may
obtain good clinical
responses.
Some patients would need
much lower doses to obtain
remission and avoid relapses
and are treated unnecessarily
with high doses and/or
repeated treatments.

Rituximab use is now widely recommended
by new Kidney Disease Improved Outcome
(KDIGO) guidelines in membranous
nephropathy and in frequent-relapsing,
steroid-dependent minimal change disease
or focal segmental glomerulosclerosis.
Oncotarget, 2018, Vol. 9, (No. 48), pp: 28799-28804
Rituximab also affects T cell and
myeloid cell functions, while
repopulating naïve B cells appear
with a more activated phenotype,
as compared to their pre-
rituximab baseline counterparts.
 Rituximab

Minimal
Minimal change
change disease
disease
ANCA‐associated
ANCA‐associated vasculitis
vasculitis
Membranous
Membranous Nephropathy
Nephropathy
Focal
Focal segmental
segmental
glomerulosclerosis
glomerulosclerosis
Cryoglobulinemia
Cryoglobulinemia

SLE
SLE –– Lupus
Lupus Nephritis
Nephritis
Others
Others
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