Therapeutic plasma exchange (PLEX) is a type
of therapy where a patient’s plasma volume is removed over a period of a few
hours, through a process of centrifugation of blood with subsequent separation
of its constituents, and replaced by different types of colloid fluids, most
commonly Albumin or Fresh Frozen Plasma (FFP). Its most frequent use in nephrology is for certain
glomerulopathies such as ANCA-associated vasculitis, anti-GBM disease, recurrence
of idiopathic FSGS post-transplant and atypical HUS. The data with regards to
PLEX use for these indications is mostly historical and based on mechanistic
concepts which led to multiple observational studies and reports claiming
efficacy. There are very few randomized trials directly comparing PLEX to other
therapies and a review of the data (see table summary of KDIGO recommendations)
has really brought me a new perspective on what justifies our use of PLEX for
renal disease.
of therapy where a patient’s plasma volume is removed over a period of a few
hours, through a process of centrifugation of blood with subsequent separation
of its constituents, and replaced by different types of colloid fluids, most
commonly Albumin or Fresh Frozen Plasma (FFP). Its most frequent use in nephrology is for certain
glomerulopathies such as ANCA-associated vasculitis, anti-GBM disease, recurrence
of idiopathic FSGS post-transplant and atypical HUS. The data with regards to
PLEX use for these indications is mostly historical and based on mechanistic
concepts which led to multiple observational studies and reports claiming
efficacy. There are very few randomized trials directly comparing PLEX to other
therapies and a review of the data (see table summary of KDIGO recommendations)
has really brought me a new perspective on what justifies our use of PLEX for
renal disease.
Table: KDIGO recommendations on PLEX use
for glomerular disease
for glomerular disease
|
|
KDIGO recommendation
|
Grade
|
|
Anti-GBM disease
|
We recommend initiating immunosuppression with
cyclophosphamide and corticosteroids plus plasmapheresis in all patients with anti-GBM GN except those who are dialysis-dependent at presentation and have 100% crescents in an adequate biopsy sample, and do not have pulmonary hemorrhage |
1B
|
|
Start treatment for anti-GBM GN without delay once
the diagnosis is confirmed. If the diagnosis is highly suspected, it would be appropriate to begin high-dose corticosteroids and plasmapheresis while waiting for confirmation |
Not graded
|
|
|
ANCA-associated vasculitis
|
We recommend the addition of plasmapheresis for
patients requiring dialysis or with rapidly increasing SCr |
1C
|
|
We suggest the addition of plasmapheresis for
patients with diffuse pulmonary hemorrhage |
2C
|
|
|
We suggest the addition of plasmapheresis for patients
with overlap syndrome of ANCA vasculitis and
anti-GBM GN, according to proposed criteria and
regimen for anti-GBM GN |
2D
|
|
|
Post-transplant FSGS
|
We suggest plasma exchange if a biopsy shows minimal
change disease or FSGS in those with primary FSGS as their primary kidney disease |
2D
|
|
Atypical HUS
|
Not mentioned in KDIGO guidelines
|
|
Adapted
from: Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group.
KDIGO clinical practice guideline for the care of kidney transplant recipients.
American journal of transplantation: official journal of the American Society
of Transplantation and the American Society of Transplant Surgeons. 2009
Nov;9:S1; and Kasiske BL, Zeier MG, Chapman JR, Craig JC, Ekberg H, Garvey CA,
Green MD, Jha V, Josephson MA, Kiberd BA, Kreis HA. KDIGO clinical practice
guideline for the care of kidney transplant recipients: a summary. Kidney
international. 2010 Feb 2;77(4):299-311.
from: Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group.
KDIGO clinical practice guideline for the care of kidney transplant recipients.
American journal of transplantation: official journal of the American Society
of Transplantation and the American Society of Transplant Surgeons. 2009
Nov;9:S1; and Kasiske BL, Zeier MG, Chapman JR, Craig JC, Ekberg H, Garvey CA,
Green MD, Jha V, Josephson MA, Kiberd BA, Kreis HA. KDIGO clinical practice
guideline for the care of kidney transplant recipients: a summary. Kidney
international. 2010 Feb 2;77(4):299-311.
Anti-GBM disease
Anti-GBM disease
has always been regarded as a sine qua non indication for PLEX. I still remember
my first teachings on anti-GBM disease in medical school which were were it causes
lung hemorrhage, it causes acute kidney injury and it is treated with
plasmapheresis. When reviewing the literature, I was surprised to find only
a single randomized trial on the use of PLEX in anti-GBM disease. This a study published
in 1985 in Medicine by Johnson et al where they randomized 17 (yes, only
17!) patients with biopsy and serology proven anti-GBM disease to either
Prednisone + PO Cyclophosphamide (N=9) vs PLEX + Prednisone + PO
Cyclophosphamide (N=8). Patients at baseline were not equally matched as the
patients in the conventional group had higher serum creatinine (SCr) at start
of therapy and had more severe disease on biopsy. Indeed, 5/8 biopsies
available had >70% gloms with crescents in the conventional group vs only
1/7 in the PLEX group had > 50% gloms with crescents. They did find that
more patients were dialysis dependent at the end of the study in the
conventional group (6/9) vs the PLEX group (2/8). Four patients in the PLEX
group had improvement in their renal function vs only 1 in the conventional
group. These patients who had improvement were the ones with lower SCr at
presentation. Eight patients had pulmonary hemorrhage (4 in each group) and all
these episodes were treated with IV Methylprednisone pulse and responded
promptly. There were only 3 deaths in all, 1 in conventional and 2 in PLEX
group. Anti-GBM titers became undetectable much more quickly with PLEX, after
about 2 months. Overall, it is somewhat surprising that what we consider such a
strong indication for PLEX is supported by only 1 randomized trial showing
improved renal survival with PLEX, where the groups were unevenly matched. What is also important to consider with
anti-GBM disease is the possible futility of treatment in patients with most
severe disease. A review of anti-GBM
disease in the UK from 1980-1984 by Savage et al looked at outcomes
for 108 patients. There were 69 patients who were dialysis dependant
on presentation. At 8 weeks, none were off dialysis (51 on dialysis and 18
dead). Out of 12 who presented with a SCr>600umol/L, only 1 had improvement
in renal function (other 11 either on dialysis or dead). Another British study published in
2001 in the Annals of Medicine by Levy et al retrospectively looked at all
anti-GBM disease treated at the Hammersmith hospital in since 1975.
They had 71 patients, 39 of which were dialysis-dependant on presentation. Only
2 were off dialysis at 1 year follow-up. When looking at outcomes
based on biopsies, they found that 23% of patients with >50% crescents
survived off dialysis and that 3 patients survived off dialysis despite >70%
crescents. However, no patients with 100% crescents recovered renal function.
Together, these results certainly seem to suggest that patients with severe
anti-GBM disease presenting dialysis dependent have very little chance of
recovery and may not benefit at all from immunosuppressive therapy and PLEX.
While a trial of treatment may still be indicated, I believe a rapid
re-assessment of the patient’s condition and need for continued
immunosuppressive therapy is indicated given the high infectious risks with
treatment. Patients with 100% crescents on an adequate biopsy are very unlikely
to get any benefit and should probably just be managed conservatively.
has always been regarded as a sine qua non indication for PLEX. I still remember
my first teachings on anti-GBM disease in medical school which were were it causes
lung hemorrhage, it causes acute kidney injury and it is treated with
plasmapheresis. When reviewing the literature, I was surprised to find only
a single randomized trial on the use of PLEX in anti-GBM disease. This a study published
in 1985 in Medicine by Johnson et al where they randomized 17 (yes, only
17!) patients with biopsy and serology proven anti-GBM disease to either
Prednisone + PO Cyclophosphamide (N=9) vs PLEX + Prednisone + PO
Cyclophosphamide (N=8). Patients at baseline were not equally matched as the
patients in the conventional group had higher serum creatinine (SCr) at start
of therapy and had more severe disease on biopsy. Indeed, 5/8 biopsies
available had >70% gloms with crescents in the conventional group vs only
1/7 in the PLEX group had > 50% gloms with crescents. They did find that
more patients were dialysis dependent at the end of the study in the
conventional group (6/9) vs the PLEX group (2/8). Four patients in the PLEX
group had improvement in their renal function vs only 1 in the conventional
group. These patients who had improvement were the ones with lower SCr at
presentation. Eight patients had pulmonary hemorrhage (4 in each group) and all
these episodes were treated with IV Methylprednisone pulse and responded
promptly. There were only 3 deaths in all, 1 in conventional and 2 in PLEX
group. Anti-GBM titers became undetectable much more quickly with PLEX, after
about 2 months. Overall, it is somewhat surprising that what we consider such a
strong indication for PLEX is supported by only 1 randomized trial showing
improved renal survival with PLEX, where the groups were unevenly matched. What is also important to consider with
anti-GBM disease is the possible futility of treatment in patients with most
severe disease. A review of anti-GBM
disease in the UK from 1980-1984 by Savage et al looked at outcomes
for 108 patients. There were 69 patients who were dialysis dependant
on presentation. At 8 weeks, none were off dialysis (51 on dialysis and 18
dead). Out of 12 who presented with a SCr>600umol/L, only 1 had improvement
in renal function (other 11 either on dialysis or dead). Another British study published in
2001 in the Annals of Medicine by Levy et al retrospectively looked at all
anti-GBM disease treated at the Hammersmith hospital in since 1975.
They had 71 patients, 39 of which were dialysis-dependant on presentation. Only
2 were off dialysis at 1 year follow-up. When looking at outcomes
based on biopsies, they found that 23% of patients with >50% crescents
survived off dialysis and that 3 patients survived off dialysis despite >70%
crescents. However, no patients with 100% crescents recovered renal function.
Together, these results certainly seem to suggest that patients with severe
anti-GBM disease presenting dialysis dependent have very little chance of
recovery and may not benefit at all from immunosuppressive therapy and PLEX.
While a trial of treatment may still be indicated, I believe a rapid
re-assessment of the patient’s condition and need for continued
immunosuppressive therapy is indicated given the high infectious risks with
treatment. Patients with 100% crescents on an adequate biopsy are very unlikely
to get any benefit and should probably just be managed conservatively.
ANCA-associated vasculitisAnother frequent
indication for PLEX in glomerular disease is ANCA-associated vasculitis and
thankfully there is a bit more data to guide us here. The best data comes from
the MEPEX trial
by Jayne et al published in JASN in 2007 where 137 patients with biopsy/serology
proven ANCA vasculitis and SCr > 500umol/L were randomized to either PLEX (7
exchanges in 14 days) or IV methylprednisolone (1g IV daily x 3), both in combination
with oral Cyclophosphamide and Prednisone. Patients with severe lung hemorrhage
requiring mechanical ventilation were excluded. Just over 2/3 of patients were
dialysis-dependent on presentation. They found that treatment with PLEX had a
better renal recovery (alive and off dialysis and SCr<500umol/L) at 3 months
than IV steroids (70% vs 49% respectively, P=0.02). The HR for ESRD at 12
months for PLEX vs IV steroids was 0.47 (0.24-0.91, P=0.03). Survival however
was not significantly different (19 deaths in PLEX group vs 16 in IV steroids
group) and most deaths were due to infections (19), lung hemorrhage (6) or
cardiovascular disease (4) and very few due to vasculitis. A sub-study
of the MEPEX trial by Van Wingaarden et al found that for patients
requiring dialysis on presentation and with severe tubular atrophy on biopsy,
the point at which patients would get more benefit for renal survival from
treatment over risk of death from treatment was when they had 18% or more
normal glomeruli for IV steroids group as opposed to only 2% normal glomeruli for
PLEX. This suggests that patients with most severe disease are more likely to
reap renal benefit from treatment when they are given PLEX. In 2013, Walsh et
al published the long
term follow-up data from the MEPEX trial and found that the short term
benefit seen in MEPEX was lost. Indeed, for patients treated with PLEX there
was no significant improvement in the composite of ESRD or death (HR 0.81,
0.53-1.23; P=0.32) nor in the outcome of ESRD (0.64, 0.40-1.05; P=0.08). At
final follow-up, half the patients died and 2/3 were either dead or on
dialysis, reaffirming the poor prognosis of severe ANCA vasculitis. A meta-analysis of all
randomized trials looking at PLEX for ANCA vasculitis by Walsh et al in
2011 found PLEX to be associated with a 20% risk reduction in the composite of
ESRD-death (HR 0.80, 0.65-0.99) and a 36% reduction in ESRD (HR 0.64,
0.47-0.88) but no effect on death (RR 1.0, 0.71-1.42). The authors did warn
though that overall most trials were small, none of them individually found a
significant result for the composite of ESRD-death and they had notable
methodological flaws such as randomization concealment was only performed in
4/9 trials and the methods of concealment weren’t described in any. Hopefully,
the PEXIVAS
study which is now nearing completion and should be presented at the
upcoming ASN Kidney Week 2017 (hopefully as a late-breaking trial) will help
clarify the role for PLEX in ANCA vasculitis. For now, it would seem that PLEX
is indicated for patients presenting with severe renal failure due to
ANCA-vasculitis as it improves renal survival, without a mortality benefit
though.
indication for PLEX in glomerular disease is ANCA-associated vasculitis and
thankfully there is a bit more data to guide us here. The best data comes from
the MEPEX trial
by Jayne et al published in JASN in 2007 where 137 patients with biopsy/serology
proven ANCA vasculitis and SCr > 500umol/L were randomized to either PLEX (7
exchanges in 14 days) or IV methylprednisolone (1g IV daily x 3), both in combination
with oral Cyclophosphamide and Prednisone. Patients with severe lung hemorrhage
requiring mechanical ventilation were excluded. Just over 2/3 of patients were
dialysis-dependent on presentation. They found that treatment with PLEX had a
better renal recovery (alive and off dialysis and SCr<500umol/L) at 3 months
than IV steroids (70% vs 49% respectively, P=0.02). The HR for ESRD at 12
months for PLEX vs IV steroids was 0.47 (0.24-0.91, P=0.03). Survival however
was not significantly different (19 deaths in PLEX group vs 16 in IV steroids
group) and most deaths were due to infections (19), lung hemorrhage (6) or
cardiovascular disease (4) and very few due to vasculitis. A sub-study
of the MEPEX trial by Van Wingaarden et al found that for patients
requiring dialysis on presentation and with severe tubular atrophy on biopsy,
the point at which patients would get more benefit for renal survival from
treatment over risk of death from treatment was when they had 18% or more
normal glomeruli for IV steroids group as opposed to only 2% normal glomeruli for
PLEX. This suggests that patients with most severe disease are more likely to
reap renal benefit from treatment when they are given PLEX. In 2013, Walsh et
al published the long
term follow-up data from the MEPEX trial and found that the short term
benefit seen in MEPEX was lost. Indeed, for patients treated with PLEX there
was no significant improvement in the composite of ESRD or death (HR 0.81,
0.53-1.23; P=0.32) nor in the outcome of ESRD (0.64, 0.40-1.05; P=0.08). At
final follow-up, half the patients died and 2/3 were either dead or on
dialysis, reaffirming the poor prognosis of severe ANCA vasculitis. A meta-analysis of all
randomized trials looking at PLEX for ANCA vasculitis by Walsh et al in
2011 found PLEX to be associated with a 20% risk reduction in the composite of
ESRD-death (HR 0.80, 0.65-0.99) and a 36% reduction in ESRD (HR 0.64,
0.47-0.88) but no effect on death (RR 1.0, 0.71-1.42). The authors did warn
though that overall most trials were small, none of them individually found a
significant result for the composite of ESRD-death and they had notable
methodological flaws such as randomization concealment was only performed in
4/9 trials and the methods of concealment weren’t described in any. Hopefully,
the PEXIVAS
study which is now nearing completion and should be presented at the
upcoming ASN Kidney Week 2017 (hopefully as a late-breaking trial) will help
clarify the role for PLEX in ANCA vasculitis. For now, it would seem that PLEX
is indicated for patients presenting with severe renal failure due to
ANCA-vasculitis as it improves renal survival, without a mortality benefit
though.
Post-transplant FSGS
It is sad to say
that there are unfortunately no other prospective trials studying the role of
PLEX for glomerular disease. While the use of PLEX for recurring idiopathic
FSGS post-transplant is recommended (the rationale being the removal of some as
of yet unidentified pathogenic plasma permeability factor), the data is purely
observational. A review
of 77 case-reports and case-series, totalling 423 patients with recurrence
of FSGS post renal transplant, published in BMC Nephrology in 2016 showed that
overall 71% of patients achieved complete or partial remission. Factors most
associated with response were male sex and starting treatment within 2 weeks of
recurrence. However, the lack of control group prevents us from establishing a
clear benefit from PLEX itself. Also, the treatment regimens were extremely varied
and it is unclear exactly how much PLEX, for how long should it be given and
which replacement fluid to use. Finally, the frequent use of PLEX in these
patients who are already on immune-suppressing drugs may predispose to even
more infections given the removal of Immunoglobulins by PLEX.
that there are unfortunately no other prospective trials studying the role of
PLEX for glomerular disease. While the use of PLEX for recurring idiopathic
FSGS post-transplant is recommended (the rationale being the removal of some as
of yet unidentified pathogenic plasma permeability factor), the data is purely
observational. A review
of 77 case-reports and case-series, totalling 423 patients with recurrence
of FSGS post renal transplant, published in BMC Nephrology in 2016 showed that
overall 71% of patients achieved complete or partial remission. Factors most
associated with response were male sex and starting treatment within 2 weeks of
recurrence. However, the lack of control group prevents us from establishing a
clear benefit from PLEX itself. Also, the treatment regimens were extremely varied
and it is unclear exactly how much PLEX, for how long should it be given and
which replacement fluid to use. Finally, the frequent use of PLEX in these
patients who are already on immune-suppressing drugs may predispose to even
more infections given the removal of Immunoglobulins by PLEX.
Atypical HUS
Similar to FSGS,
the use of PLEX for atypical HUS is based purely on observational data (case
reports and case series). The rationale behind its use for this indication
certainly makes sense by removing defective complement factors and replacing
properly functioning complement factors to halt the overactivity of the
alternative pathway. Patients diagnosed with TMA are often started on PLEX
promptly while awaiting results of diagnostic testing (Shiga toxin E. Coli
cultures, ADAMSTS13 level and complement pathway factor levels and mutations).
If diagnostic tests suggest an alternative complement pathway disease, it will
be maintained until Eculizumab is available. Unfortunately, while most
observational studies suggest an initial response around 60% to PLEX, this is
mostly a hematologic response and patients will often become dialysis
dependent.
the use of PLEX for atypical HUS is based purely on observational data (case
reports and case series). The rationale behind its use for this indication
certainly makes sense by removing defective complement factors and replacing
properly functioning complement factors to halt the overactivity of the
alternative pathway. Patients diagnosed with TMA are often started on PLEX
promptly while awaiting results of diagnostic testing (Shiga toxin E. Coli
cultures, ADAMSTS13 level and complement pathway factor levels and mutations).
If diagnostic tests suggest an alternative complement pathway disease, it will
be maintained until Eculizumab is available. Unfortunately, while most
observational studies suggest an initial response around 60% to PLEX, this is
mostly a hematologic response and patients will often become dialysis
dependent.
Conclusion
Overall the
evidence to support the use of PLEX for the treatment of glomerular diseases is
not great. While anti-GBM disease and lung hemorrhage are considered some of
the strongest indications for PLEX, this is not firmly supported by good prospective
data. The best evidence is for its use is in severe ANCA-vasculitis and with
the upcoming PEXIVAS study results hopefully this will further help us in our
decision making. I think it is great that such a large study such as PEXIVAS
(over 700 patients) for such a rare disease has been able to come to completion
and this highlights the importance of proper collaboration to conduct
prospective studies in GN. Hopefully this will inspire us to continue to strive
for well-designed studies to guide us in the treatment of our patients.
evidence to support the use of PLEX for the treatment of glomerular diseases is
not great. While anti-GBM disease and lung hemorrhage are considered some of
the strongest indications for PLEX, this is not firmly supported by good prospective
data. The best evidence is for its use is in severe ANCA-vasculitis and with
the upcoming PEXIVAS study results hopefully this will further help us in our
decision making. I think it is great that such a large study such as PEXIVAS
(over 700 patients) for such a rare disease has been able to come to completion
and this highlights the importance of proper collaboration to conduct
prospective studies in GN. Hopefully this will inspire us to continue to strive
for well-designed studies to guide us in the treatment of our patients.
David Massicotte-Azarniouch
Nephrology Fellow, University of Ottawa
