Transfusion and Apheresis Science 62 (2023) 103681
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Transfusion and Apheresis Science
journal homepage: www.elsevier.com/locate/transci
Review
The role of plasmapheresis in the pulmonary-renal syndrome
Kaatje le Poole *, Hans Vrielink
Sanquin Blood Supply, Department of Transfusion Medicine, Plesmanlaan 125, 1066 CX Amsterdam, the Netherlands
A pulmonary renal syndrome is diagnosed when the combination of a
rapid progressive glomerulonephritis (RPGN) and diffuse pulmonary
hemorrhage (DAH) are present. Both are severe disease manifestations
that are associated with a considerable morbidity and mortality. Most
frequently, the underlying cause is a small vessel vasculitis due to anti-
neutrophil cytoplasmatic antibody (ANCA) associated vasculitis (AAV)
or anti-glomerular basement membrane disease. Other vasculitis’s and
connective tissue diseases such as Systemic Lupus Erythematosus and
Rheumatoid Arthritis present the more rare causes of this syndrome.
Patients presenting with a pulmonary renal syndrome may have
various non-specific symptoms. DAH can cause acute respiratory failure
or have a more insidious course with dyspnea, cough, chest pain and
hemoptysis. In one third of the patients with DAH hemoptysis is absent.
RPGN is associated with systemic symptoms such as fatigue and malaise.
Once renal function is seriously decreased, severely impaired symptoms
based on metabolic dysregulation (i.e. hyperkalemia and acidosis) and
fluid overload will occur.
AAV is a group of auto-immune diseases characterized by inflam­
mation of small vessels and in most cases the presence of ANCA. Serum
ANCA’s are directed to either leucocyte protein 3 (PR3) or myelopro­
teinase (MPO), which are both proteins present in the primary granules
of the neutrophils [1]. In anti-GBM disease circulating auto-antibodies
are directed to the noncollagenous-1 domain of type IV collagen fibers
present in the basement membrane of the glomerulus and the capillaries
of the lung [2].
Plasmapheresis or plasma exchange therapy (PEX) has the ability to
remove pathogenic antibodies from the blood and in addition it clears
pro-inflammatory mediators (complement fractions, clotting factors and
cytokines). In the treatment of the pulmonary renal syndrome caused by
AAV as well as anti-GBM disease, plasmapheresis is used as part of an
induction therapy. Induction therapy is based on three principles; to
clear the pathogenic auto-antibodies as quick as possible, to halt auto-
antibody production and to decrease the inflammatory response. Dur­
ing plasmapheresis, autoantibodies are cleared from the blood
compartment by removing the plasma in which they are dissolved.
Plasmapheresis is based on the technique of separation of blood in its
different components. Separation can be achieved with: centrifugation,
during which separation is achieved based on weight by centrifugal
forces and filtration, during which plasma is separated from blood based
* Corresponding author.
E-mail address: k.lepoole@sanquin.nl (K. le Poole).
https://doi.org/10.1016/j.transci.2023.103681
Available online 24 February 2023
1473-0502/© 2023 Elsevier Ltd. All rights reserved.
on seize by using a semipermeable membrane. The separated plasma is
removed and replacement fluid is re- infused with the remainder of the
blood components. Rituximab or cyclophosphamide are used to halt
auto-antibody production and steroids to decrease inflammation.
The use of plasmapheresis has been advocated for the treatment of
the pulmonary renal syndrome caused by AAV, although the literature
does not clearly support a clinical benefit [3]. Most of the published
studies have small number of patients and lack information on the
precise treatment schedule. The MEPEX trial was conducted and ran­
domized between a treatment schedule of steroids and cyclophospha­
mide with or without PEX in patients that were diagnosed with AAV
with a creatinine of > 500 µmol/l or dialysis with or without DAH. After
3 months, a significant reduction in the percentage of patients with
ESRD was seen, but no effect of mortality. However after almost 4 years
the advantage for the patients treated with PEX was lost and no longer a
difference in ESRD could be found between the treatment groups [4].
Even though the effect on renal survival was lost after four years, in
terms of quality of life, the postponing dialysis or renal transplant can
make a difference. The number of patients with DAH was to small to
allow a subgroup analysis. Because the role of PEX in induction therapy
forms only a small part of the therapeutic arsenal it could be questioned
if the outcomes after 4 years can be attributed solely to the induction
regimen.
Another view is that the loss of advantage in renal survival could be
explained by to much chronic damage and this has led to the PEXIVAS
study in which patients with a less impaired renal function could be
included. In 2020 the results of the PEXIVAS trial were published. Pa­
tients with an eGFR< 50 or DAH and were treated with Rituximab or
cyclophosphamide in combination with a standard or reduced dose of
prednisolone with or without PEX. No difference in the primary outcome
of death or ESRD was found and the reduced dose of corticosteroids was
non-inferior to the standard dose. In the subgroup analysis of the pa­
tients with DAH also no significant differences were found [5]). It was
debated that lack of evidence on the presence of chronic damage to the
kidney could explain the lack of difference between the PEX and no-PEX
group. Also selection bias in favor of non-severe cases could be a possible
explanation for the absence of a significant effect of PEX.
For patients renal pulmonary syndrome caused by anti-GBM disease,
Lockwood et al. described the first case treated successfully treated with
K. le Poole and H. Vrielink
PEX [6]. The low incidence of anti-GBM disease hampers the ability to
easily conduct randomized controlled trials (RCTs), but in 1985 a small
RCT showed a clear benefit for PEX in anti-GBM over treatment with
prednisolone and cyclophosphamide alone [7]. However, in patients
that were depend on dialysis or presented with high creatinine values
the chance of renal recovery is nihil.
Although a substantial improvement has been made in the treatment
of the renal-pulmonary syndrome over the past 100 years, renal
outcome is often poor. In addition, there is a considerable therapy
related morbidity and mortality. This has spurred the search for new
treatment options.
Immunoadsorption (IAS) is a plasmapheresis technique during
which the plasma is first separated from the blood with centrifugal or
filtration technique. Thereafter the plasma is passed through a column
covered with a ligand that exhibits antigen specificity for the autoanti­
body (mostly IgG) or pathogenic factor present. Because the cleared
plasma is returned to the patient, there is no need for a substitution fluid.
A second advantage is that a greater blood volume compared to PEX can
be treated leading to a faster reduction in auto-antibodies [8]. In pa­
tients with anti-GBM disease IAS treatment resulted faster decline in
anti-GBM titers and preservation of renal function in all patients free of
dialysis at the moment of diagnosis (unpublished data by the courtesy of
C Franssen UMCG, the Netherlands).
In both AAV as anti-GBM disease plasma levels and kidney biopsies
show an increase in complement breakdown products. In the recent
years, several pharmaceutical options to act on the complement cascade
have become available for treatment. In AAV, a number of studies
looked at the possibility of reducing corticosteroid exposure by treat­
ment with a C5a receptor inhibitor (Avacopan) and have shown an
Transfusion and Apheresis Science 62 (2023) 103681
reduction in adverse events that are possibly related to corticosteroid
use [9]. Two case reports describe the successful use of Eculizumab, a C5
antibody, to treat patients with anti-GBM disease [10].
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