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Rheumatol Int (2011) 31:15451547

DOI 10.1007/s00296-011-2041-5

REVIEW ARTICLE

Methotrexate for rheumatoid arthritis patients


who are on hemodialysis
Hasanein Al-Hasani Euthalia Roussou

Received: 18 February 2011 / Accepted: 10 July 2011 / Published online: 22 July 2011
Springer-Verlag 2011

Abstract Methotrexate (MTX) can be toxic to patients


suffering from end stage renal disease (ESRD) on hemodialysis even at low doses. This increase in toxicity is more
notable in terms of bone marrow suppression in the form of
pancytopenia. Many methods of elimination including
dialysis itself have been proven ineffective, and alternate
treatments with anti-TNF alpha blockers can be considered.
Keywords Methotrexate  Rheumatoid arthritis 
Hemodialysis  End stage renal failure

Brief description of end stage renal disease


and methotrexate
End stage renal disease (EDRD) is defined as reduced renal
function (less than 10% of normal capacity) requiring
dialysis or kidney transplantation for survival. Patients are
put on chronic dialysis, (Hemodialysis (HD) for the large
majority of them), in order to improve the patients functional status and increase patients survival. HD results in a
dramatic reversal of uremic symptoms by removing toxic
H. Al-Hasani  E. Roussou
Barts and The London School of Medicine and Dentistry,
Turner Street, London E1 2AD, UK
H. Al-Hasani  E. Roussou
Barking Havering and Redbridge University Hospitals NHS
Trust, King George Hospital, Barley Lanes, Goodmayes,
Ilford, Essex IG3 8YB, UK
E. Roussou (&)
Department of Rheumatology and Rehabilitation,
King George Hospital, Barley Lane, Goodmayes,
Ilford, Essex IG3 8YB, UK
e-mail: thaliaroussou@hotmail.com

waste products that accumulate in patients with ESRD and


may also remove drugs. It is therefore necessary to balance
the fraction of the drug removed by HD to avoid excess
removal and therefore loss of efficacy, with compromised
renal function to avoid over dosage and drug toxicity. This
is achieved through meticulous dosing [1, 2].
The number of patients on chronic dialysis is increasing
by an annual growth rate of 5% in Western countries due to
an aging population and to type II diabetes that is the
largest and fastest-growing single disease that requires
therapy with HD. Other causes of severe kidney damage
include infection, glomerulonephritis, hypertension, and
drug reactions [3].
Methotrexate (MTX) is a widely used disease modifying
anti-rheumatic drug that is commonly used as a first line
treatment in rheumatoid arthritis (RA). At similar doses, it can
be used to treat other inflammatory diseases such as bullous
pemphigoid, psoriasis, and Crohns disease. At higher doses,
it can be used to treat neoplastic diseases [4]. MTX is a folic
acid antagonist that inhibits the dihydrofolate reductase
involved in the synthesis of puric and pyrimidic bases. In
patients with normal renal function, the recommended dose in
RA ranges between 7.5 and 15 mg/week but in the recent
years even dosages up to 30 mg weekly can be used.
MTX-induced renal failure is difficult to be treated as
MTX is distributed in the tissues. MTX is poorly cleared by
HD, [5] but the clearance through HD is greater than
through peritoneal dialysis [6, 7].

Methotrexate pharmacokinetics and changes that occur


during hemodialysis
The primary mode of excretion of MTX is via the kidneys
by glomerular filtration and proximal tubular secretion.

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During HD, drugs should be adjusted based on plasma


dosage and clinical and biological tolerance. The observation that very low doses of MTX can have severe or fatal
consequences in HD patients has resulted in their use being
contraindicated in these patients altogether. The French
health authorities have deemed that MTX even at low
doses in as much as 2.5 mg/week is contraindicated in
patients with significant renal impairment. The pharmacokinetics of MTX is variable and unpredictable; even with
meticulous dosing, this can lead to ineffective renal
clearance because of great volume distribution and poor
binding to serum albumin [8]. This is shown by higher
plasma levels and increased half-life in HD patients with
the drug levels remaining elevated after 3 weeks even in a
small dose of 2.5 mg, where in patients with a normal renal
function a half-life of 310 h has been documented. Direct
renal toxicity occurs rarely with MTX treatment, but cases
of nephrotic syndrome and renal failure have been described, although few in numbers [3, 9].

Toxicity manifested in the form of pancytopenia


in patients on hemodialysis
What seems to be a pattern progressing in the literature is
one of renal failure as a separate entity to RA and a significant risk factor for pancytopenia combined with the toxicity
of MTX intensified by the HD. Pancytopenia is present in
3% of patients with normal renal function; dosage of MTX
was the most predictive of pancytopenia severity. One of the
major relevant risk factors included hypoalbunemia [2, 12].
This is of great importance as MTX is partially bound to
albumin and low serum albumin would potentiate toxicity of
MTX, and this can occur through the hepatotoxic side effects
of MTX. Aspirin can also cause hypoalbunemia. Further to
this, ESRD can further reduce the albumin levels. Other risk
factors for pancytopenia include advanced age, low serum
folate level (exacerbated by trimethoprim and sulfamethoxazole), elevated mean corpuscular volume, concurrent use
of NSAIDs (reduce the tubular secretion of methotrexate
and enhance its toxicity), and medication with more than 5
drugs, which is likely judging by the many concomitant
diseases in patients with ESRD [2, 12].
Pancytopenia in patients with ESRD can prove fatal and
can develop suddenly without any warning signs, and
physicians should be aware of this, as it can occur as early
as 3 days from the first dose of MTX. There have been 12
cases reported so far of patients on low-dose MTX who
were on HD and developed pancytopenia. From those 12
patients referred in the literature, 4 patients died, while 8
patients survived [2]. Methods to try to eliminate MTX
included hemoperfusion, hemodialysis, and plasmapheresis. What was certain from these studies is that even low

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Rheumatol Int (2011) 31:15451547

doses of MTX such as 2.5 mg, if not fatal in this cohort can
cause severe pancytopenia for several weeks with placement in a sterile room as even the immunosuppression of
low-dose MTX can lead to opportunistic infection [10, 11].
Since the pharmacokinetics of patients with both RA
and renal disease have not been studied, no dosing recommendations are available as of yet. Some authors suggest that MTX should be reduced to 2.5 mg/week in these
patients while some have based their recommendation
based on creatinine clearance most notably with a creatinine clearance of less than 10 mL/min while others say it is
contraindicated in any patient with a creatinine clearance
of less than 50 mL/min [2].

Halting methotrexate toxicity in hemodialysis patients


by attempted removal
As much as HD might be contributory in MTX toxicity, it
has been used to remove MTX from patients. Whether it is
affective in altering clinical outcome remains uncertain as
only 4 patients have undergone HD treatment for MTX
toxicity with 2 surviving and 2 dying [10]. The difficulty of
MTX removal by dialysis is owed to the fact that MTX
undergoes polyglutamination, which alters the spectrum of
the enzyme inhibition by the drug and causes retention of
the polyglutamated metabolites of MTX within the cell,
and all but one of these are less effective than MTX as an
inhibitor of dihydrofolate reductase [1214]. In a comparison of HD with peritoneal dialysis in the removal of
MTX, it was found that HD has a greater removal affect
than peritoneal dialysis within the first hour of dialysis but
after this frequent hourly exchanges of peritoneal dialysis
would provide the best elimination thereafter [7, 12].
Many authors believe that MTX should be avoided in
patients on dialysis; altogether, the recent development of
recombinant carboxypeptidase-G2, a bacterial enzyme that
cleaves MTX into tiny fragments, has provided a potential
alternative route of elimination. This approach appears to
be more effective than removal attempt by dialysis. Its use
lowered plasma MTX concentrations to non-toxic levels
(by 98% in 15 min) much in advance of the development
of pancytopenia; rebounds, however, occurred in 60% of
patients therefore no recommendations can be made
regarding this enzyme [15].

Shift toward anti-TNF antagonists?


As patients with RA and ESRD are difficult to treat, different strategies have been employed. In a study infliximab,
a monoclonal TNF antagonist, has been used successfully
[16]. Additionally the proteinuria of renal amyloidosis due

Rheumatol Int (2011) 31:15451547

to RA has shown signs of stabilization, improvement [17],


or complete resolution [18].
In another small retrospective study of 11 patients with
impaired renal function, treatment with aTNF-a using infliximab (6 patients), etanercept (7 patients), adalimumab (2
patients), or all 3 sequentially (2 patients) has shown no
negative effect on patients with kidney disease [19]. As
with MTX, the pharmacokinetics of aTNF-a drugs are
unknown and unpredictable; although for those administered subcutaneously (etnercept and adalimumab), the
absorption process begins once from the site of administration the drugs move to the circulation through which
they penetrate various tissues [20]. However, unlike MTX,
these drugs were well tolerated by patients on HD and
maintain their efficacy at doses prescribed for normal renal
function. Infliximab has the lowest volume of distribution
among the available TNF antagonists with normal renal
function that indicates that the distribution of infliximab
outside the blood circulation and the inflamed tissue is
limited; this is unlike MTX that is actively transported
across cell membranes and is widely distributed into body
tissues. Low release of MTX from third space accumulations may prolong the terminal half-life and may increase
the risk of drug toxicity with high doses. These differences
between MTX and infliximab predict the potential use of
infliximab, and possibly other anti-TNF biologicals, in the
treatment of RA patients with ESRD on HD [21].

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Conclusion
There are an increasing number of clinicians that recommend not prescribing MTX to dialysis patients even at low
doses. This increase in toxicity is more notable in terms of
bone marrow suppression. Many methods of elimination
have been proven ineffective, and prospective methods still
require much research.
The effects of ESRD in MTX-induced pancytopenia can
be separated into three groups. Directly through compromised function, indirectly through HD and risk factor
drugs, and independent factors, whether that be attributes
or concomitant illnesses to ESRD that increase the severity
of pancytopenia. All three of these groups contribute to the
difficulty in determining safe MTX dosages and it becomes
even harder to predict leaving us with the adage it is
better to be safe than sorry.

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References

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