Rheumatology Advance Access originally published online on May 25, 2008
Rheumatology 2008 47(8):1259; doi:10.1093/rheumatology/ken189
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Comment on: Kidney disease in RA patients: prevalence and implication on RA-related drugs management: the MATRIX study
Department of Rheumatology, Warwick Hospital, Warwick, UK
Correspondence to: J. Bateman, Department of Rheumatology, Warwick Hospital, Lakin Road, Warwick CV34 5BW, UK. E-mail: James.Bateman{at}SWH.nhs.uk
SIR, We read with interest the paper by Karie et al. [1].
We wish to highlight an issue regarding MTX prescribing and toxicity in chronic kidney disease (CKD) in patients with RA and report a case that has changed clinical practice in our unit [2].
A 77-yr-old female with a 40-yr history of RA, was stable on MTX therapy (original dose 15 mg once weekly). Following a gradual rise in serum creatinine (up to 170 µmol/l) MTX was stopped. It was later restarted at lower dose at the patient's request (following a consultant renal physician opinion and investigations into the cause of the renal impairment). Her disease was then well controlled on a low dose of MTX 10 mg once a week. Other disease-modifying drugs (DMARDs) were considered but had failed in past. At the MTX restart her estimated glomerular filtration rate (EGFR) was calculated by the Cockroft–Gault formula to be 24 ml/min (Stage 4 CKD, creatinine 200 µmol/l). The patient went on to regular blood monitoring over the next 15 months on 10 mg MTX once weekly with a normal full blood count and stable renal function.
She was admitted with non-specific malaise having had diarrhoea 
2 weeks earlier. Parameters recorded 16 days prior to her admission revealed a normal full blood count (white blood cell, differential platelet count) and static renal function. Her admission blood tests revealed a pancytopaenia, with an admission creatinine of 196 µmol/l. There had been no dosing error (tablet count), no new concomitantly prescribed medications and the tablet strength was checked by the hospital pharmacy. Bone marrow biopsy showed evidence of bone marrow failure with no other specific diagnostic features.
Despite intravenous folinic acid, anti-microbial treatment and multi-organ support in our Critical Care unit she died 7 days into her admission. Post-mortem showed no other major abnormalities and cause of death was reported as MTX toxicity.
Although there is limited published data on MTX clearance in CKD, trial data suggests that with an EGFR of <45 ml/min the expected 8 h level for a 10 mg dose is 0.11 µmol/l, with a half-life (t1/2) of 22 h [3]. On admission, the free MTX level (30 h post dose) was 0.13 µmol/l. We presume that the episode of diarrhoea and vomiting prior to her admission had resulted in dehydration with a subsequent drop in renal clearance of MTX, leading to MTX/metabolite accumulation and subsequent toxicity.
This case highlights the dangers of MTX in CKD, even at reduced dose, and what can be falsely reassuring blood monitoring leading up to an adverse event. Following on from this experience we have instigated a number of changes to our clinical practice.
First, we now give written advice to all patients on MTX who have a significant inter-current illness, particularly those with CKD, to omit MTX until a full recovery has ensued. This will hopefully reduce accumulation of MTX and toxicity.
Second, we have arranged for the EGFR [calculated by the abbreviated Modification of Diet in Renal Disease Study (MDRD) equation as recommended by the UK Chronic Kidney Disease Guidelines] to be added to our computerized DMARD blood monitoring system. We are also asking for routine EGFR measurements on all our patients on blood monitoring for MTX.
Finally, we have reviewed our computerized monitoring system to identify all patients on MTX who have reduced EGFR and we are currently undertaking a case note review. To date, we have identified 18 patients with CKD Stage 4 (of 879 patients on MTX) under follow-up in our unit, on a reduced dose of MTX (the age range is 61–77, prevalence 2%). This is significant as Karie et al. describe no patients with CKD Stage 4 in their study. We suspect MTX is being used more commonly in an increasing elderly group of patients with added comorbidities.
The Renal Association provide both an online calculator for EGFR and have produced helpful online (and downloadable) EGFR tables that are practical and easily used by both Specialist Nurses and Rheumatologists in satellite clinics, etc [4]. This information can be used to make judgements on MTX dosage. There are a number of conflicting sources of advice for MTX dosing in CKD and there is a need for national guidelines for the dosing of MTX in CKD [5, 6].
Disclosure statement: The authors have declared no conflicts of interest.
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- Karie S, Gandjbakhch F, Janus N, et al. Kidney disease in RA patients: prevalence and implication on RA-related drugs management: the MATRIX study. Rheumatology (2008) 47:350–4.
[Abstract/Free Full Text] - Penfold R, Bateman J, Bakewell R, Rigby S. Fatal pancytopaenia due to methotrexate: were the guidelines followed. Poster presentation. In: Midland Rheumatology Society Annual Meeting (2007) November.
- Bressolle F, Bologna C, Kinowski JM, Sany J, Combe B. Effects of moderate renal insufficiency on pharmacokinetics of methotrexate in rheumatoid arthritis patients. Ann Rheum Dis (1998) 57:110–3.
[Abstract/Free Full Text] - The Renal Association. Prediction of GFR from age and serum creatinine. (11 March 2008, date last accessed). http://www.renal.org/CKDguide/full/eGFRtables.pdf.
- Ashley C, Currie A. The renal drug handbook. (2003) 2nd edition. Oxford: Radcliff Medical Press.
- Joint Formulary Committee. British National Formulary. (2008) 58th edition. London: British Medical Association and Royal Pharmaceutical Society of Great Britain.
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  S. Karie, V. Launay-Vacher, F. Gandjbakhch, N. Janus, S. Rozenberg, P. Bourgeois, and G. Deray Comment on: Kidney disease in RA patients: prevalence and implication on RA-related drugs management: the MATRIX study: reply Rheumatology, August 1, 2008; 47(8): 1259 - 1260. [Full Text] [PDF]
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