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Rheumatology Advance Access originally published online on January 31, 2008
Rheumatology 2008 47(3):350-354; doi:10.1093/rheumatology/kem370
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© The Author 2008. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Kidney disease in RA patients: prevalence and implication on RA-related drugs management: the MATRIX study

S. Karie1, F. Gandjbakhch2, N. Janus1, V. Launay-Vacher1, S. Rozenberg2, C. U. Mai Ba1, P. Bourgeois2 and G. Deray1

1Department of Nephrology and 2Department of Rheumatology, Pitié-Salpêtrière Hospital, Paris, France.

Correspondence to: S. Karie, Department of Nephrology, Hôpital Pitié-Salpêtrière, 47–83, boulevard de l’hôpital, 75013 Paris, France. E-mail: svetlana.karie{at}psl.aphp.fr


   Abstract
Top
 Abstract
Introduction
 Materials and methods
 Results
 Discussion
 Conclusion
 References
 
Objectives. The prevalence of kidney disease (KD) indicators together with the profile of RA drugs prescribed in RA patients was investigated in the MATRIX study (MeThotreXate And Renal Insufficiency).

Methods. Renal function (RF) was assessed using Cockcroft–Gault (CG) and abbreviated Modification of Diet in Renal Disease (aMDRD) study formulae.

Results. Serum creatinine (SCr) was normal in 81.4% of the 129 patients included. According to the National Kidney Foundation (NKF) classification, the distribution by stage of KD was, using the aMDRD and CG formulae, as follows: stage 1: 11.3% and 11.4%; stage 2: 20.0% and 20.3%; stage 3: 15.0% and 24.1%; stage 4: 0% and 1.3%; stage 5: 0%. Proteinuria, haematuria and leucocyturia were observed in 16%, 17% and 20% of the patients, respectively. Using the aMDRD and CG formulae, 36% and 38% of the prescriptions made in patients with glomerular filtration rate (GFR) <60 ml/min required a dosage adjustment. Among the patients with GFR <60 ml/min, 83–90% received at least one drug that required a dosage adjustment and 67–70% received at least one drug that was potentially nephrotoxic, according to aMDRD or CG formulae, respectively. Five (50%) and 8 (47%) patients did not have appropriate MTX dosage adjustment according to their stage of KD with aMDRD or CG formulae, respectively.

Conclusion. Systematic estimation of RF with CG or aMDRD formulae and urine dipstick are necessary in RA patients. In patients with KD at high risk for drug toxicity, dosage should be adapted to RF.

KEY WORDS: Renal function, Drugs, Dosage adjustment


   Introduction
Top
 Abstract
 Introduction
Materials and methods
 Results
 Discussion
 Conclusion
 References
 
RA is a systemic disorder that primarily involves the joints, but renal involvements are common [1]. There are several potential causes of nephropathy in patients with RA: drug-related renal disease, where drugs such as NSAIDs and DMARDs [gold compounds, D-penicillamine, cyclosporin and methotrexate (MTX)] are used, secondary renal amyloidosis and various types of glomerulonephritis (GN). There are only few studies to evaluate renal function (RF) and histological renal status in RA patients and these prospective studies have been realized with old RA therapeutics that are not so used nowadays. Indeed, since 2000, treatments for RA have changed a lot and renal consequences may be different. These studies have shown that mesangial proliferative GN is the most frequent histological lesion: 34% of biopsies from 158 Japanese RA patients with urinary abnormalities and/or renal dysfunction in a period between 1979 and 1996 [2], and 36% of renal biopsies from 110 Finnish RA patients with clinical renal disease during the years 1976–92 [3]. Membranous GN was found in 31 and 17% of RA patients in the previously mentioned studies performed in Japan and Finland, respectively [2, 3]. Membranous GN may closely relate to gold or D-penicillamine therapies that were largely used in the past. Other causes of renal disease in RA patients can be rapidly progressive GN due to microscopic polyangiitis [4], IgA nephritis, minimal change glomerulopathy, focal proliferative GN and interstitial nephritis [3].

Despite many potential causes of renal disease in RA patients, data on the prevalence of renal disorders in RA are scanty. Karstila et al. [5] assessed the frequency of abnormal clinical renal findings in a population of 103 RA patients. In those patients, 9% had isolated haematuria, 5% had isolated proteinuria, 1% had combined haematuria and proteinuria and 3% had isolated renal insufficiency [defined as a serum creatinine (SCr) ≥100 µmol/l in women and ≥115 µmol/l in men]. However, SCr alone is a poor marker of renal dysfunction, particularly in patients with muscle wasting, which often is associated with RA [6]. Karstila study was performed in 1988, before the National Kidney Foundation (NKF) classification according to which the RF is defined as kidney damage or decrease in glomerular filtration rate (GFR) <60 ml/min/1.73 m2 estimated from SCr and equations, such as the abbreviated Modification of Diet in Renal Disease Study (aMDRD) [7] formula or the Cockcroft–Gault (CG) [8] formula. Kidney damage is defined by structural or functional abnormalities of the kidney, with or without decreased GFR, that can lead to decreased GFR, manifested by either pathological abnormalities or markers of kidney damage, including abnormalities in the composition of the blood or urine, or abnormalities in imaging tests. To date, there are no data in the literature on the prevalence of kidney disease (KD) in RA patients according to new NKF classification.

In patients with RA, precise estimation of RF is particularly important. Some drugs used for the treatment of RA such as NSAIDs, sulphasalazine or MTX may have serious toxic effects when used in patients with even mild renal insufficiency. Blix et al. [9] showed that of the 808 patients admitted in the departments of internal medicine and rheumatology, all but six patients with GFR <60 ml/min/1.73 m2 used two or more renal risk drugs. The dosage of RA-related drugs used in patients with renal insufficiency will, therefore, frequently require dosage reduction to avoid severe toxicities.

The aim of the MATRIX study was to determine the prevalence of KD indicators, including proteinuria, haematuria, uninfectious leucocyturia and GFR reduced in RA patients. This study also aimed at describing the profile of RA-related drugs prescribed regarding the need for dosage adjustment and potential nephrotoxicity. This study was not designed to identify the potential causes of RF abnormalities observed in our patients.


   Materials and methods
Top
 Abstract
 Introduction
 Materials and methods
Results
 Discussion
 Conclusion
 References
 
Patients
Patients with confirmed RA seen at the rheumatology department were prospectively included from 18 April to 31 July 2006. Each patient could be included once. Patients were excluded from the study when they were presenting the following situations: being <18 yrs, having acute renal failure, having renal replacement therapy or being pregnant.

The following data were obtained for each patient: sex, age, weight, height, SCr, haemoglobin, serum albumin, CRP, ESR, RA (type, duration, other systemic autoimmune diseases associated), diabetes and hypertension history.

Assessment of hypertension
Hypertension was diagnosed if at least one of the following criteria was present:

  • patient knows he/she is hypertensive,
  • patient received anti-hypertensive drug therapy and
  • systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥ 90 mmHg the day of visit to the hospital.

Assessment of KD
The MATRIX examination included measurement of SCr, proteinuria and abnormal urinary sediments from single urine dipsticks realized the day of the visit in the department of rheumatology. Level of KD was estimated from the GFR calculated from SCr using two formulae:

  • CG formula: GFR (ml/min) = k x (140 – age) x body weight/SCr (in µmol/l). where, k = 1.04 (female) or 1.23 (male).
  • aMDRD formula: GFR (ml/min/1.73 m2) = kx 186 x [SCr]–1.154 x [age]–0.203 where, k = 1 (male) or 0.742 (female); SCr in mg/dl.

Kidney damage was suggested by the presence of proteinuria (≥1+), haematuria (≥1+) or uninfectious leucocyturia (≥1+ without nitrite).

KD prevalence was estimated from apparent kidney damage and kidney function and categorized according to the NKF classification [10] as follows:

  • Stage 1: GFR ≥90 ml/min: normal kidney function with markers of kidney damage.
  • Stage 2: GFR 60–89 ml/min: mild reduction of GFR with markers of kidney damage.
  • Stage 3: GFR 30–59 ml/min: moderate reduction of GFR.
  • Stage 4: GFR 15–29 ml/min: severe reduction of GFR.
  • Stage 5: GFR <15 ml/min: kidney failure.

The upper limit of SCr at the Pitié-Salpêtrière hospital central laboratory was 106 µmol/l for men and 80 µmol/l for women during the study.

Anaemia was defined using the World Health Organization (WHO) definition: haemoglobin <12 g/dl for women and 13 g/dl for men [11].

RA-related drugs
We collected data concerning DMARDs (MTX, leflunomide, sulfasalazine, cyclosporin, D-penicillamine, hydroxychloroquine, infliximab, etanercept, adalimumab, rituximab) and the symptomatic treatment (NSAIDs, glucocorticoids, acetaminophen, acetylsalicylic acid, proton pump inhibitors) used in RA patients.

Those requiring dosage adjustment were identified in accordance with recommendations from individual Summary of Product Characteristics in the Vidal Dictionary [12] and from specific reference book on drug dosage adjustment in patients with renal insufficiency [13]. Drugs related to RA were then classified as ‘Yes’ when adjustment was required, ‘No’ when adjustment was not necessary, and ‘ND’ when no data were available in the literature during the study. To obtain profiles of RA-related drugs with regard to renal tolerance, an exhaustive literature search was performed using PubMed [14]. If, at least one case of nephrotoxicity was retrieved, the therapy was classified as ‘Yes’, meaning ‘potentially nephrotoxic’. Therapies were labelled ‘No’ when no cases had been found or there were no suggestions of potential renal toxicity. We considered patients in stages 1 and 2 to have adequate kidney function in relation to drug therapy, while patients with stages 3–5 had impaired RF and were in need of special attention with regard to drug therapy.


   Results
Top
 Abstract
 Introduction
 Materials and methods
 Results
Discussion
 Conclusion
 References
 
Clinical and demographic characteristics
One hundred and twenty-nine (109 women, 20 men) patients were included. The large majority of patients was seen in outpatient clinics (70%). Table 1 displays their demographic and clinical characteristics.


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  		TABLE 1. Demographic and clinical characteristics of RA patients in MATRIX studya

 
The prevalence of KD
Of 129 patients, 102 (79.1%) patients had available data for SCr and 19 of them (18.6%) had an abnormal SCr level.

Using aMDRD formula (SCr and urinary dipstick available for 80 patients), a total of 37 patients (46.3%) were found to have KD according to the NKF classification. The stage distribution was as follows: 43 patients (53.8%) had normal kidney function (≥60 ml/min/1.73 m2) without kidney damage; 9 patients (11.3%) had normal kidney function with kidney damage (stage 1); 16 patients (20.0%) had mild renal insufficiency with kidney damage (stage 2); 12 patients (15.0%) had moderate renal insufficiency (stage 3); there were no patients with stages 4 or 5 of KD (Table 2).


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  		TABLE 2. Prevalence of KD in RA patients according to NKF classification in MATRIX study patients

 
Using CG formula (SCr, weight and urinary dipstick available for 79 patients), the prevalence of patients with KD was more frequent and reached 57.0% (45 patients). However, the number of patients having stages 1 and 2 of KD was the same as with the aMDRD formula: 9 (11.4%) and 16 (20.3%) patients, respectively. There was an increase in the number of patients with stage 3 and stage 4 KD: 19 (24.1%) and 1 (1.3%) patients, respectively. There were no patients with stage 5 KD (Table 2).

A GFR <60 ml/min/1.73 m2 was observed in 12 (15.0%) and 20 (25.3%) patients when calculated using the aMDRD or CG formula, respectively.

The prevalence of proteinuria and abnormal urinary sediment
Ninety-nine (76.7%) patients had available data for urinary dipsticks. Among these patients, proteinuria was detected in 16 (16.2%), haematuria in 17 (17.2%) and uninfectious leucocyturia in 20 (20.2%) patients, respectively. Combined proteinuria and haematuria was observed in three (3.0%) patients.

The prevalence of anaemia
A total of 102 patients (86 women, 16 men) had available data for serum haemoglobin and anaemia was found in 19 of them (18.6%): in 6 (37.5%) men and in 13 (15.1%) women. Within the whole population of MATRIX patients, three (2.9%) patients had serum haemoglobin lower than 11 g/dl. Serum haemoglobin was not linked to GFR.

RA-related drugs
The study population of 129 patients had 158 prescriptions for DMARDs and 194 prescriptions for symptomatic treatments, resulting in a total number of prescriptions of 352 and a mean number of 2.7 drugs per patient. The prescriptions comprised 22 different drugs (Table 3).


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  		TABLE 3. RA-related drugs most often prescribed to patients in MATRIX study

 
According to the literature, 143 (40.6%) prescriptions were potentially nephrotoxic, 190 (54.0%) needed a dosage adjustment in case of renal insufficiency and for 48 (13.6%) no data were available on their use in case of renal insufficiency.

Using the aMDRD formula, of the 33 prescriptions made in MATRIX patients with GFR <60 ml/min/1.73 m2, 12 (36.4%) required a dosage adjustment. For four (12.1%) prescriptions there were no available data concerning their administration in these patients (Table 4). Of 12 patients with GFR <60 ml/min/1.73 m2, 10 (83.3%) received at least one drug that required a dosage adjustment and 8 (66.7%) received at least one drug that was potentially nephrotoxic.


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  		TABLE 4. Prescription of renal risk drugs (drugs for which dose adjustments are recommended + drug for which no data were available in the literature during the study + drugs potentially nephrotoxic) in MATRIX study according to aMDRD formula and CG formula (between brackets)

 
Using CG formula, of the 56 prescriptions made in MATRIX patients with GFR <60 ml/min/1.73 m2, 21 (37.5%) required a dosage adjustment; 17 (80.9%) were represented by MTX. For seven (12.5%) prescriptions there were no available data on their administration in renal insufficiency patients (Table 4). Of 20 patients with GFR <60 ml/min/1.73 m2, 18 (90.0%) received at least one drug that required a dosage adjustment and 14 (70.0%) received at least one drug that was nephrotoxic.

MTX was prescribed in 106 (82.2%) patients. Out of 106 patients, 101 and 104 patients had available data for duration and dosage of MTX treatment, respectively. The mean duration of MTX treatment was 4.6 ± 4 yrs (range 0–17). The mean weekly dose was 15.5 ± 4.7 mg (range 5–25) (Table 5). MTX was prescribed in 10 and 17 patients with GFR <60 ml/min/1.73 m2, using the aMDRD and CG formulae, respectively. Five (50.0%) and eight (47.0%) patients did not have appropriate MTX dosage adjustment with regard to their RF with aMDRD or CG formulae, respectively.


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  		TABLE 5. History of MTX treatment in patients in MATRIX studya

 

   Discussion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
Conclusion
 References
 
We found that KD was highly prevalent in our population of RA patients and that its frequency is clearly underestimated in clinical practice if physicians base their diagnosis on SCr measurements and if urine dipstick is not systematically used in practice. Of the patients, 46.3–57.0% had either a GFR reduction or a renal abnormality on urine dipstick whereas SCr was normal in 81.4% of the patients.

SCr is not appropriate for evaluating RF if not interpreted together with the sex, the age and the weight of the patient. These parameters represent the muscle mass of the patient, and therefore the creatinine production rate. It is, therefore, of crucial importance that RF is evaluated with the appropriate tools in all patients including RA patients by estimating GFR calculated using the CG or aMDRD formula. To date there are no precise data allowing recommending the use of one formula rather than the other, in RA patients as well as in the general population. Most often, differences between the two formulae in terms of RF are weak. Only one study compared CG and the complete MDRD formulae [using blood urea nitrogen (BUN), serum albumin, race and SCr] in the population of 33 patients with RA [15]. Endogenous creatinine clearance was determined by a 24-h urine collection. The authors concluded that the CG formula is preferable to predict RF in those patients. However, we cannot extrapolate these data because we used the abbreviated version of the MDRD formula not including BUN and serum albumin.

Renal involvement in RA is clinically meaningful because it worsens the course of primary disease and increases mortality. Thomas et al. [16] demonstrated that when compared with the general population, subjects hospitalized for RA are significantly more likely to have a recorded cause of death due to renal failure: hazard ratio (HR) 3.1 (95% CI 2.5, 3.9) for males, and HR 3.5 (3.0, 4.0) for females. Micro-albuminuria and proteinuria are associated with increased cardiovascular mortality in the general population [17, 18] and in RA patients [19]. Proteinuria may be the first clinical sign in many renal disorders, for example, in amyloidosis and mesangial proliferative GN. In the present study, proteinuria was observed in 16% of the patients.

Inadequate estimation of the patient's RF may lead to ignorance of medications needing dose adjustment or inappropriate drugs in KD. Furthermore, using potentially nephrotoxic drugs will also require specific monitoring and, when available, specific prevention methods to help reduce the risk for renal toxicity, especially in patients with already abnormal RF. In the MATRIX study, of the 352 prescriptions, 41% were potentially nephrotoxic and 54% needed a dosage adjustment in case of renal insufficiency.

If the nephrotoxicity of NSAIDs and high-dose MTX are well recognized [20], the role of the low-dose MTX used in RA is not clear [21]. About 90% of the absorbed MTX is excreted in the urine unchanged within 48 h by glomerular filtration and tubular secretion. In patients affected by RA and having normal RF, the recommended doses are within a range of 5–15 mg/week. This dose can be increased by steps of 2.5–5.0 mg, up to a maximal dose of 25 mg/week. The elimination half-life of MTX increases (for instance, 120 h in a peritoneal dialysis patient [22] as compared with 8 h in normal RF patients) and the total clearance decreases with the degree of renal impairment [23]. The use of MTX even at very low doses (2.5 mg once a week) and after a single administration in patients with a GFR <15 ml/min/1.73 m2 may have severe or even fatal consequences [24]. MTX prescription is thus not recommended in patients with a GFR <15 ml/min/1.73 m2 [13, 25]. In patients with stages 3 and 4 KD (GFR between 15 and 60 ml/min/1.73 m2), the initial dose range is 2.5–7.5 mg/week, which then may be increased up to a maximal dose of 12.5 mg/week (50% of the dose normally used) [13]. In the present study, nearly half of patients with GFR <60 ml/min/1.73 m2 did not have appropriate MTX dosage adjustment with regard to their stage of KD.

The findings of our study are subject to at least two limitations. First, proteinuria and urine sediment were used to determine kidney damage for categorizing persons as having stages 1 and 2 KD, but abnormal imaging tests are also used to determine kidney damage. However, such tests were not available in the MATRIX study. As a result, kidney damage and reported prevalence of stages 1 and 2 KD might be underestimated. Second, estimates for stages 1 and 2 reflect KD indicators, rather than actual disease, because two urine samples were not available in the MATRIX study to assess persistent proteinuria and confirm the presence of kidney damage. Thus, KD in this report might be overestimated.


   Conclusion
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Conclusion
References
 
This prospective observational study showed that the prevalence of KD indicators in RA patients is common. Nearly half of the RA patients are presenting a KD according to NKF classification. Systematic estimation of GFR with CG or aMDRD formula even at levels of SCr usually considered as ‘normal’ and assessment of urine dipstick is necessary in RA patients. The necessity of a dose adjustment or drug avoidance is underestimated in clinical practice: half of the patients in our study did not have appropriate MTX dosage. In patients with KD at high risk for drug toxicity, dosage should be adapted to RF and the use of nephrotoxic therapies should be avoided whenever possible.

Formula

Disclosure statement: The authors have declared no conflicts of interest.


   References
Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 Conclusion
 References
 

  1. Braun A, Zeier M. Rheumatoid arthritis and the kidney: uneasy companions. Nephron Clin Pract (2004) 96:c105–6.[CrossRef][Web of Science][Medline]
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Submitted 1 October 2007; revised version accepted 11 December 2007.
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Comment on: Kidney disease in RA patients: prevalence and implication on RA-related drugs management: the MATRIX study
Rheumatology, August 1, 2008; 47(8): 1259 - 1259.
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