Effect of Low-Dose Methotrexate on eGFR and Kidney Adverse Events: A Randomized Clinical Trial

Abstract

Background 

Low-dose methotrexate (LD-MTX) is contraindicated in advanced CKD, but kidney safety in normal kidney function or mild-to-moderate CKD is less clear.

Methods 

We performed a secondary analysis for eGFR and kidney AEs using the randomized double-blind, placebo-controlled Cardiovascular Inflammation Reduction Trial. Adults with cardiovascular disease and diabetes and/or metabolic syndrome were randomly allocated to oral LD-MTX (target dose 15–20 mg/week) or placebo. All participants took folic acid 1 mg 6 days/week. Exclusion criteria included systemic rheumatic disease and creatinine clearance <40 ml/min. The least-squares mean ΔeGFR from baseline was calculated at each study visit; the difference in eGFR between LD-MTX and placebo was compared. We used Cox proportional hazard models to compare rates of kidney AEs for LD-MTX versus placebo.

Results 

A total of 2391 participants were randomized to LD-MTX and 2395 to placebo. At baseline, the mean age was 66 years, 19% were female, and mean eGFR was 80.0 ml/min per 1.73 m² (54% had Stage 2 CKD and 18% had Stage 3 CKD). Median follow-up was 23 months. The LD-MTX group had less decline in eGFR than placebo (difference in least-squares mean ΔeGFR from baseline to on-treatment visits: 0.93 ml/min per 1.73 m², 95% confidence interval [95% CI], 0.45 to 1.40, P<0.001). There were 138 (incidence rate [IR], 2.97 per 100 person-years) kidney AEs in the LD-MTX group and 184 (IR, 3.99 per 100 person-years) among placebo (hazard ratio [HR] 0.73, 95% confidence interval [95% CI], 0.59 to 0.91) during safety laboratory monitoring.

Conclusions 

These results demonstrate the kidney safety of LD-MTX among patients with normal kidney function or mild-to-moderate CKD at baseline.

Low-dose methotrexate (LD-MTX, ≤25 mg weekly) serves as the cornerstone in the treatment of many inflammatory diseases such as rheumatoid arthritis (RA).^1,2 MTX is primarily excreted by the kidneys and, typically in high doses for oncologic indications, can lead to AKI due to precipitation of the drug in tubules.^3,4 Therefore, MTX (either at a low or high dose) is contraindicated in advanced kidney disease (creatinine clearance <30 ml/min). Early studies in RA suggested that LD-MTX may lead to decreased eGFR over time.^5,6 However, these studies predated the routine use of folic acid supplementation to mitigate MTX-associated toxicities and lacked comparator groups. Therefore, the kidney safety of LD-MTX among individuals without advanced CKD is unclear.

To address this issue in a contemporary setting, we analyzed the Cardiovascular Inflammation Reduction Trial (CIRT), a large, randomized, double-blind, placebo-controlled trial of LD-MTX for the prevention of atherosclerotic cardiovascular events.⁷ We previously reported that participants in CIRT randomized to LD-MTX had a higher risk for adverse events (AEs) such as hepatotoxicity, pneumonitis, and skin cancer compared with placebo.^89–10 We conducted secondary analyses using data from CIRT to investigate the effects of LD-MTX on eGFR and kidney AEs.

Methods

Study Population and Design

As described elsewhere,^7,11 CIRT was a multisite study from 417 centers in North America, designed to test whether LD-MTX as compared with placebo might reduce rates of atherosclerotic events. The study population consisted of individuals with a known history of myocardial infarction or multivessel coronary artery disease, and diabetes and/or metabolic syndrome. Individuals with known systemic rheumatic diseases were excluded. Because LD-MTX is excreted by the kidneys, potential participants were excluded before baseline if creatinine clearance was <40 ml/min, as calculated by the Cockcroft-Gault equation.¹² Patients with moderate or large pleural effusions or ascites were excluded because LD-MTX may accumulate in these compartments. Further details on the inclusion and exclusion criteria and study design, including the sample size and power calculation, have been reported elsewhere.^7,11 The trial started enrolling participants in 2013 and was stopped in April 2018; final safety visits were conducted in December 2018. We planned secondary safety analyses.¹³ AEs of interest, including kidney outcomes, were blindly adjudicated as part of the conduct of the trial. CIRT was approved by the Mass General Brigham Institutional Review Board. The trial was registered at ClinicalTrials.gov (Identifier NCT01594333). We abided by the guidelines laid out by the Declaration of Helsinki.

Patient and Public Involvement

This research was conducted without patient involvement. Patients and the public were not invited to comment on the study design and were not consulted to develop patient relevant outcomes or interpret the results. Patients and the public were not invited to contribute to the writing or editing of this document for readability or accuracy.

Run-In Period and Randomization

Participants were required to complete a 5- to 8-week active run-in phase using oral LD-MTX 10–15 mg/week with folic acid 1 mg the other 6 days. Those who tolerated LD-MTX in the active run-in (including maintaining creatinine clearance ≥40 ml/min) were randomly assigned to LD-MTX or placebo. Randomization was stratified by site, type of index cardiac event (multivessel coronary disease alone or myocardial infarction), time since the index event (≥6 or <6 months), and metabolic syndrome alone or with diabetes. Further details on randomization have already been reported.⁷ Blood was banked for research purposes, and the inflammatory biomarkers C-reactive protein (CRP) and interleukein (IL)-6 were measured at baseline.

Follow-Up and Laboratory Monitoring

The initial weekly dose of LD-MTX or placebo after randomization was 15 mg/week. After 16 weeks, the study drug was increased to a maximum of 20 mg/week if all safety criteria were met. Participants attended in-person study visits to obtain safety laboratory values every 4 weeks until a stable dosage was achieved, then every 8 weeks thereafter. Medical monitors, blinded to treatment assignment, who had expertise in managing LD-MTX, provided direction on dose changes and temporary stops of study drug on the basis of laboratory monitoring results. A computerized titration algorithm instructed sites to adjust study drug in both treatment arms on the basis of kidney function and other safety laboratory parameters (possible weekly doses of 5 mg, 10 mg, 15 mg, or 20 mg).¹¹ Related to kidney function, study drug dose increased toward the maximum dose of 20 mg if creatinine clearance was ≥40 ml/min on safety laboratory measures. Study drug dose was maintained or decreased (only for the 20 mg dose) if creatinine clearance was ≥30 but <40 ml/min. Finally, study drug was temporarily stopped for creatinine clearance <30 ml/min.¹¹ The study drug could be reinitiated if creatinine clearance improved on a subsequent safety laboratory measure. The titration algorithm also randomly mandated some sham dosing changes in the placebo arm to maintain blinding. The study drug could be permanently discontinued for serious clinical events (e.g., hemodialysis initiation) after discussion with the medical monitor. Participants were followed for up to 5 years.

eGFR

The primary outcome in this analysis was change from baseline to on-treatment eGFR. We used the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula to calculate eGFR at each study visit that serum creatinine (SCr) was measured.¹⁴ For these analyses, we calculated eGFR at the following time points: before run-in (2 months before baseline), baseline (after run-in completion and immediately before randomization), 3 months after baseline, and every 6 months after baseline. Due to concerns that the race coefficient in the CKD-EPI formula may falsely overestimate eGFR for Black participants,¹⁵ we also calculated eGFR without the race coefficient in sensitivity analyses.

Kidney AEs on Safety Laboratory Monitoring

We defined presence and severity of kidney AEs at each follow-up study visit using safety laboratory results, compared with baseline using the 2012 Kidney Disease: Improving Global Outcomes classification.¹⁶ Urine studies, including output and albuminuria, were not measured, so change in SCr from baseline was used. Mild kidney AEs on safety laboratory monitoring were defined as SCr 1.5–2× baseline, moderate was SCr 2–3× baseline, and severe was SCr ≥3× baseline. In an additional analysis, we analyzed change in SCr between baseline and final study visit to evaluate whether changes may have persisted during the entire study.

Kidney AEs during Clinical Care

We also identified kidney AEs that occurred during clinical care outside of the SCr measured for research purposes at follow-up study visits. Adjudication methods have previously been reported.¹³ Kidney AEs were blindly adjudicated using a standardized form (Supplemental Appendix) that captured date of onset and classified by likelihood (possible, probable, definite) and severity (mild, moderate, and severe). New initiation of kidney replacement therapy such as hemodialysis was also recorded. For this analysis, we only considered probable or definite kidney AEs.

We also analyzed a composite outcome defined by an international consensus¹⁷ that included the first of any of these events: new dialysis, eGFR <15 ml/min per 1.73 m² on two consecutive safety labs, or decline from baseline eGFR of ≥40%, ≥50%, or ≥57% on two consecutive safety labs.

CKD Stage

We defined CKD stage using accepted eGFR cutoff points at each study visit (baseline and follow-up) that measured SCr.¹⁸ Because urine studies were not collected in CIRT, we combined normal kidney function and CKD Stage 1 into a single category on the basis of eGFR >90 ml/min per 1.73 m². CKD Stage 2 was described as eGFR 60 to <90 ml/min per 1.73 m², CKD Stage 3 eGFR 30 to <60, CKD Stage 4 eGFR 15 to <30, and CKD Stage 5 eGFR <15. There were no participants with CKD Stage 4 or 5 at baseline due to the exclusion criteria, but some progressed to these stages during follow-up.

Statistical Analysis

The exposure variable in all analyses was treatment group (random assignment to LD-MTX compared with placebo as reference). We followed a modified intention-to-treat strategy that censored participants 180 days after study drug discontinuation. An additional analysis used an intention-to-treat approach without censoring at study drug discontinuation.

The primary outcome was the difference in the least-squares mean change of eGFR from baseline to all study follow-up time points, comparing the LD-MTX with placebo groups. We used a generalized linear mixed model to account for repeated measures after baseline using a random effects model. The null hypothesis was a difference in least-squares mean ΔeGRF of 0 ml/min per 1.73 m² between the treatment groups. We tested for a possible difference over follow-up by including an interaction term between study drug assignment and time after baseline. We graphically presented the eGFR for each treatment group and each study follow-up time point. In an additional analysis, we compared differences in eGFR slopes from baseline for each treatment group. We used a linear mixed-effects model on the basis of a single slope starting at the initial postrandomization kidney function (3 months) to obtain annualized slope (in units of ml/min per 1.73 m² per year), adjusted for baseline eGFR. To further investigate possible changes related to timing of the intervention, we also performed analyses for the acute (≤3 months after randomization) and chronic (>3 months) periods of follow-up, using identical methods for calculating eGFR slope and the same definition for chronicity as a previous large meta-analysis of 47 randomized controls trials.¹⁹

We calculated the incidence rates for kidney AEs (any event and by severity level) at study visits for each group. We used Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (95% CIs) for the first kidney AE, comparing LD-MTX with placebo (without covariates). Each analysis was performed separately, investigating time to first event of the severity level being considered as the outcome. We used similar methods for first clinical kidney AEs and new dialysis initiation. As an alternative analysis, we performed the severity analyses for AE severity as an ordinal scale (no AE, mild, moderate, severe; mutually exclusive on the basis of highest level experienced), comparing LD-MTX to placebo using ordinal regression. The effect size is interpreted as the odds of being one level higher on the ordinal scale for LD-MTX compared with placebo.

We also compared the change in CKD stage from baseline to final follow-up study visit. This analysis was also stratified according to baseline CKD stage (Normal/Stage 1, Stage 2, Stage 3). We also examined differences between study arms in CKD stage migration from baseline to final study visit using proportional odds model, treating the stages as ordinal levels. In an additional analysis, we restricted the sample to those with baseline CKD stage of Normal/Stage 1 and Stage 2 to investigate worsening in CKD stage at the final study visit. We considered three separate outcomes at the final study visit: CKD Stage 3 or worse (eGFR <60 ml/min per 1.73 m²), CKD Stage 3b or worse (eGFR <45 ml/min per 1.73 m²), or CKD Stage 4 or worse (eGFR <30 ml/min per 1.73 m²), assessing for differences between the LD-MTX and placebo groups using chi-squared tests.

We analyzed subgroups on the basis of the following baseline characteristics: sex, age (<65 or ≥65 years), race, above or below median eGFR, CKD stage (Normal/Stage 1, Stage 2, Stage 3), diabetes, nonsteroidal anti-inflammatory drug use, obesity, CRP level (<2 or ≥2 mg/L and quartiles 1–3 or quartile 4), and IL-6 level (quartiles 1–3 or quartile 4). We reported the P values for the interaction terms between the treatment group and each subgroup variable for the differences in least-squares mean ΔeGFR from baseline to study follow-up time points. In sensitivity analyses, we removed the race coefficient from the CKD-EPI formula for eGFR from the primary analysis and in the subgroup analysis by race. We also repeated the primary analysis but used an intention-to-treat approach that did not censor after study drug continuation.

A two-sided P<0.05 was considered statistically significant. No adjustments were made for multiple comparisons in this exploratory study. All analyses were conducted in SAS (Cary, NC, version 9.4).

Results

Baseline Characteristics

Among the 9321 people who entered screening for the trial, 6158 began the active run-in phase, and 4786 were randomized and included in this analysis. Of those randomized, 2391 were allocated to LD-MTX and 2395 to placebo. Baseline characteristics were similar across study arms: 19% were female, median age was 65 years, and 85% were White (Table 1). The baseline median eGFR was 80.0 ml/min per 1.73 m², and 18% had CKD Stage 3.

Table 1. - Baseline characteristics of randomized participants in the CIRT (n=4786)

Characteristics, Median (Interquartile Range) or n (%)	Low-Dose Methotrexate	Placebo
	(n=2391)	(n=2395)
Sex, F	461 (19.3)	437 (18.3)
Age, yr	65.6 (59.7, 71.8)	66.0 (59.8, 71. 7)
Race
White	2008 (84.0)	2059 (86.0)
Black	194 (8.1)	156 (6.5)
Asian	89 (3.7)	92 (3.8)
American Indian or Alaska Native	6 (0.3)	7 (0.3)
Native Hawaiian or other Pacific Islander	4 (0.2)	6 (0.3)
Multiple	15 (0.6)	9 (0.4)
Other	75 (3.1)	66 (2.8)
eGFR a , ml/min per 1.73 m2	80.2 (65.5, 91.6)	79.1 (63.9, 91.4)
Serum creatinine, mg/dl	0.97 (0.84, 1.12)	0.97 (0.84, 1.14)
Serum albumin, g/dl	4.30 (4.20, 4.50)	4.30 (4.20, 4.50)
CKD stage b
Normal or Stage 1	705 (29.5)	662 (27.6)
Stage 2	1272 (53.2)	1301 (54.3)
Stage 3	414 (17.3)	432 (18.0)
Current smoker	267 (11.2)	270 (11.3)
Alcohol use
Rarely or never	1487 (62.2)	1473 (61.5)
≤1 drink/week	514 (21.5)	520 (21.7)
>1 drink/week	390 (16.3)	402 (16.8)
Diabetes	1620 (67.8)	1615 (67.4)
Hypertension	2153 (90.1)	2169 (90.6)
Body mass index, kg/m2	31.6 (28.1, 35.7)	31.3 (28.0, 35.5)
Systolic blood pressure, mm Hg	128 (118, 139)	128 (118, 139)
Diastolic blood pressure, mm Hg	74 (67, 80)	74 (67, 80)
Weekly study drug dosage, mean, SD	14.9 (4.5)	15.3 (4.3)
Aspirin use	1562 (53.7)	1495 (50.9)
Other NSAID use	217 (9.1)	195 (8.1)
Insulin use	515 (17.7)	535 (18.2)
ACE inhibitor or ARB use	1740 (72.8)	1728 (72.2)
Beta blocker use	1873 (78.3)	1910 (79.8)
Diuretic use	514 (21.5)	534 (22.3)
Thiazide use	245 (10.3)	233 (9.7)
Proton pump inhibitor use	594 (24.8)	576 (24.1)
Spironolactone use	95 (4.0)	109 (4.6)
Glycated hemoglobin, %	6.6 (6.0, 7.5)	6.5 (5.9, 7.5)
C-reactive protein, mg/L	1.63 (0.77, 3.42)	1.53 (0.74, 3.82)
Il-6, pg/ml	2.55 (1.67, 3.91)	2.46 (1.68, 3.82)

IQR, interquartile range; F, female; NSAID, nonsteroidal anti-inflammatory drug; ACE, angiotensin-converting enzyme; ARB, angiotensin-receptor blocker.

^aeGFR was calculated using the CKD-EPI equation.

^bCKD stages were defined as: Normal/Stage 1 eGFR ≥90; Stage 2 eGFR 60 to <90; Stage 3 eGFR 30 to <60; Stage 4 eGFR 15 to <30; Stage 5 eGFR <15 ml/min per 1.73 m².

Change in eGFR

Median follow-up was 23 months (maximum 54 months), and mean study drug dose was 16 mg/week (similar in both arms). The least-squares mean ΔeGFR between baseline and each study time point for both study arms is shown in Figure 1. In the primary modified intention-to-treat analysis, the difference in least-squares mean ΔeGFR throughout all follow-up comparing LD-MTX and placebo was 0.93 ml/min per 1.73 m² (95% CI, 0.45 to 1.40; P=0.001). Results were similar in the intention-to-treat analysis (0.94 ml/min per 1.73 m², 95% CI, 0.46 to 1.41; P=0.001) and after removing the race coefficient from the CKD-EPI Equation (0.93 ml/min per 1.73 m², 95% CI, 0.46 to 1.40, P=0.001). The slope difference of eGFR comparing LD-MTX to placebo was 1.06 ml/min per 1.73 m² per year (95% CI, 0.60 to 1.51, P<0.001). We found no statistically significant interaction between study drug assignment and follow-up time. We found similar results when restricting the analyses to the acute (≤3 months postrandomization) and chronic (>3 months) periods of follow-up (Supplemental Table 1).

Figure 1.: Least-squares mean change of eGFR from baseline to each study time point according to random assignment of LD-MTX or placebo ( n =4786). eGFR was calculated using the CKD-EPI equation.

Kidney AEs

The incidence rates of kidney AEs from follow-up study visits and clinical kidney AEs are shown in Table 2. At follow-up study visits on safety laboratory measures, there were 138 (incidence rate, 2.97 per 100 person-years) kidney AEs in the LD-MTX group and 184 (incidence rate, 3.99 per 100 person-years) in the placebo group (HR, 0.73; 95% CI, 0.59 to 0.91). Most of these AEs were mild, and these were reduced in the LD-MTX arm compared with placebo (HR, 0.77, 95% CI, 0.61 to 0.96). There were two severe kidney AEs in the LD-MTX compared with four in the placebo arm (HR, 0.49; 95% CI, 0.09 to 2.70). Results were similar when only considering changes between baseline and the final study visit (Supplemental Table 2). In the ordinal analysis of kidney AE severity on safety labs, the LD-MTX group had an odds ratio of 0.74 (95% CI, 0.25 to 0.92, P=0.008) compared with the placebo group (i.e., significantly less likely to have more severe kidney AEs).

Table 2. - Rates and HR for kidney adverse events for LD-MTX compared with placebo (n=4786)

	Low-Dose Methotrexate (n=2391)		Placebo (n=2395) (Reference Group)
Counts	Events (n)	Rate per 100 Person-years (95% Confidence Interval)	Events (n)	Rate per 100 Person-years (95% Confidence Interval)	Hazard Ratio (95% Confidence Interval)
SCr collected at study follow-up visits on safety laboratory monitoring
Any event a	138	2.97 (2.52 to 3.50)	184	3.99 (3.47 to 4.60)	0.73 (0.59 to 0.91)
Mild (SCr 1.5–1.9× baseline)	134	3.00 (2.54 to 3.54)	172	3.93 (3.40 to 4.55)	0.77 (0.61 to 0.96)
Moderate (SCr 2–2.9× baseline)	15	0.32 (0.20 to 0.54)	20	0.44 (0.28 to 0.68)	0.74 (0.38 to 1.44)
Severe (SCr ≥3× baseline)	2	0.04 (0.01 to 0.17)	4	0.09 (0.03 to 0.23)	0.49 (0.09 to 2.70)
Adjudicated clinical kidney adverse events
Any event a	37	0.80 (0.58 to 1.11)	42	0.92 (0.68 to 1.24)	0.87 (0.56 to 1.36)
Mild	24	0.52 (0.35 to 0.77)	25	0.55 (0.37 to 0.81)	0.95 (0.55 to 1.67)
Moderate	11	0.24 (0.13 to 0.43)	11	0.24 (0.13 to 0.43)	1.00 (0.43 to 2.29)
Severe	4	0.09 (0.03 to 0.23)	8	0.17 (0.09 to 0.35)	0.50 (0.15 to 1.64)
New dialysis	1	0.02 (0.00 to 0.15)	3	0.07 (0.02 to 0.20)	0.34 (0.04 to 3.17)

^aKidney adverse event presence and severity was defined according to Kidney Disease: Improving Global Outcomes classification.

There were 37 blindly adjudicated clinical kidney AEs in the LD-MTX arm and 42 in the placebo arm (HR, 0.87; 95% CI, 0.56 to 1.36). Four participants initiated dialysis during follow-up, one in the LD-MTX and three in the placebo group (HR, 0.34; 95% CI, 0.04 to 3.17). There was no statistically significant association of LD-MTX with the ordinal severity scale for clinical kidney AEs (odds ratio, 0.88; 95% CI, 0.56 to 1.37). When considering the composite outcome that included new dialysis and sustained eGFR reduction, there was also no statistically significant difference between the LD-MTX and placebo groups (Supplemental Table 2).

Change in CKD Stage

Figure 2 shows the results of our analyses comparing baseline and final CKD stages in the LD-MTX with placebo arms. Overall, 14% of the LD-MTX group had worsened CKD stage from baseline to the final visit compared with 16% of the placebo group (P=0.11). Among those who began the study with CKD Stage 2, 11% of those assigned to LD-MTX progressed to CKD Stage 3 or worse during follow-up, whereas 14% of placebo worsened (P=0.007). There was no statistically significant difference between arms in the proportion of participants who entered the study with normal kidney function or CKD Stage 1 and then worsened into CKD Stage 2 or beyond (27% versus 28%, P=0.91). When examining change in ordinal CKD stage from baseline to final study visit, LD-MTX had an odds ratio of 0.94 (95% CI, 0.85 to 1.03, P=0.18) compared with placebo.

Figure 2.: Comparison of baseline and final CKD stages* by assignment to LD-MTX or placebo ( n =4786). Purple shading means worsening compared with the baseline CKD stage. Blue shading means improvement compared with the baseline CKD stage. PBO, placebo.

After restricting the analysis to participants with CKD Normal/Stage 1 or Stage 2 at baseline (n=3789), 144 (7.5%) of those randomized to LD-MTX had CKD Stage 3 or worse at the final study visit, compared with 194 (10.4%) of the placebo group (P=0.004, Supplemental Table 3). However, only four participants in each group (0.2%) had CKD Stage 4 or worse at the final study visit (P=0.99).

Subgroup Analyses

Figure 3 shows the results of subgroup analyses for differences in least-squares mean ΔeGFR throughout all follow-up comparing LD-MTX to placebo. The subgroups examined included baseline age, sex, race, nonsteroidal anti-inflammatory drug use, diabetes, obesity, eGFR, CKD stage, and inflammatory marker levels. There was no evidence of effect modification by any of these factors (all P for interaction >0.05). Similar effects on the differences in least-squares mean ΔeGFR of LD-MTX versus placebo were observed among participants in the highest quartiles of CRP or IL-6 at baseline. In the subgroup analysis for race, the results did not change when the race coefficient was removed from the CKD-EPI formula (P for interaction=0.12 with the race coefficient, and P for interaction=0.11 without the race coefficient).

Figure 3.: Subgroup analyses stratified according to baseline characteristics. Results show differences in the least-squares mean change of eGFR from baseline to all study follow-up time points comparing the LD-MTX with placebo groups (n=4786). BMI, body mass index; NSAID, nonsteroidal anti-inflammatory drug.

Discussion

These results demonstrate the kidney safety of LD-MTX. Participants in the trial were required to have normal kidney function or mild-to-moderate CKD because LD-MTX is excreted primarily through the kidneys. Those randomized to LD-MTX had modestly but statistically significantly less decline in eGFR from baseline compared with the placebo group. Participants randomized to LD-MTX had 27% reduced risk of kidney AEs on laboratory measures. Although the LD-MTX group had fewer and less severe clinical kidney AEs than the placebo group, the difference between study arms generally did not approach statistical significance. Therefore, the possible beneficial kidney effects of LD-MTX should be considered hypothesis generating and the clinical significance is unclear.

High-dose MTX given intravenously for use in cancer is known to cause acute kidney toxicity in some patients, due to precipitation of the drug in tubules, particularly in the presence of acidic urine.^3,4 Due to this possibility and primarily kidney excretion, MTX (either at a low or high dose) is contraindicated in patients with advanced CKD, typically defined as creatinine clearance <30 ml/min.²⁰ LD-MTX has been used for nononcologic indications for decades, but its effects on the kidney among those with normal kidney function or mild-to-moderate CKD had not been previously established. Two small uncontrolled studies in patients with RA showed decline in kidney function after LD-MTX initiation, but this may have been due to the known natural history of eGFR decline over time.^5,6 These studies were also performed before the routine use of folic acid or leucovorin supplementation (known to ameliorate LD-MTX side effects and increase excretion^21,22) and many of these participants were regularly taking concomitant nonsteroidal anti-inflammatory drugs to treat RA symptoms, perhaps contributing to kidney dysfunction. Another recent retrospective study among patients with RA reported that those on higher doses of MTX had more decrease in eGFR over 1 year compared with patients on lower doses of MTX.²³ That observational study may be susceptible to confounding and there was no comparator group not treated with MTX.

Prior studies showed that intravenous high-dose MTX can induce oxidative stress in rat kidneys,^2425–26 but this may not apply to the doses typically used for systemic rheumatic diseases that we studied. Less is known about the possible effects, either beneficial or harmful, of LD-MTX on kidney outcomes among patients with normal kidney function or mild-to-moderate CKD. Altered immunity is known to be important for specific kidney conditions, such as GN,²⁷ and has been posited as a possible mechanism contributing to CKD in the general population.²⁸ However, to our knowledge, CIRT is the first large trial suggesting that altering the immune system through LD-MTX may have beneficial kidney effects. This potentially beneficial effect of LD-MTX on eGFR seemed most pronounced in the first 12 months after randomization, with less clear effect thereafter. Other medications known to have beneficial effects on CKD, such as canagliflozin, temporarily worsen kidney function before a long-term beneficial effect,²⁹ whereas we observed differences in ΔeGFR even early after randomization. Although there was no statistical interaction between study drug assignment and follow-up time on differences in ΔeGFR, some of the later follow-up time points did not have a statistically significant difference. The median follow-up was 23 months so there may have been limited power at later follow-up time points to detect true differences. We note that many participants had normal CRP and IL-6 levels at baseline, and the effect of LD-MTX was similar even for those in the highest quartiles of these inflammatory markers. It was previously reported that LD-MTX did not lower levels of inflammatory markers in CIRT.⁷ Thus, the suggestion of improved kidney outcomes may not be directly related to systemic inflammation. LD-MTX affects many biologic pathways,³⁰ and it is unclear which of these may be the most responsible for the results that we report. Future studies examining the roles of LD-MTX and other immunomodulators in CKD progression are needed and may help identify specific biologic targets.

We previously reported⁸ that kidney AEs were significantly reduced in CIRT participants randomized to LD-MTX and that the final median eGFR (calculated by the Modification of Diet in Renal Disease equation³¹) of the LD-MTX group was significantly higher than the placebo group, but the clinical significance of these findings was not clear.³² This report extends those initial findings by using the CKD-EPI formula to calculate eGFR, providing the trajectory of eGFR changes over follow-up, including more granular detail on type and severity of kidney AEs, and presenting changes in CKD stages. The slower decline in eGFR in the LD-MTX compared with placebo was observed in all subgroups analyzed.

Limitations

CIRT was primarily designed to test whether LD-MTX could prevent atherosclerotic cardiovascular events. Therefore, these post hoc results suggesting beneficial effect of LD-MTX on kidney disease should be treated as exploratory and could be due to chance. It is possible that LD-MTX may lower SCr levels without altering kidney function. We find this unlikely because the LD-MTX group still had a eGFR decline over time and generally had lower rates of clinical kidney outcomes than placebo, albeit many without statistical significance. Future confirmatory studies should include other markers of kidney dysfunction such as proteinuria, iohexol, or cystatin-C levels, and be powered to detect differences in clinical kidney outcomes. Most participants maintained preserved kidney function throughout this trial, with few progressing to advanced CKD or experiencing severe kidney AEs. Therefore, the clinical significance of our findings on preventing progression of CKD remains unclear.

This analysis suggests the potential for a beneficial signal of LD-MTX related to CKD progression. However, LD-MTX did not reduce atherosclerotic cardiovascular events compared with placebo, the primary outcome of CIRT.⁷ This finding contrasts with results from another immunomodulator trial, CANTOS (Canakinumab Anti-Inflammatory Thrombosis Outcomes Study), where canakinumab (an IL-1β inhibitor) lowered the rate of recurrent cardiovascular events compared with placebo.³³ However, there were no substantive effects of canakinumab on indices of kidney function in CANTOS.³⁴ This implies the possible beneficial effects of LD-MTX on CKD progression may be related to inhibition of specific inflammatory pathways, rather than general anti-inflammatory effects. Placebo-controlled trials evaluating the possible effects of another immunomodulator, ziltivekimab (an IL-6 inhibitor), on cardiac and kidney outcomes are underway.^20,35

These results strongly suggest that LD-MTX is safe to use in patients with normal kidney function or mild-to-moderate CKD. We note the results should not be extrapolated to patients with more advanced kidney disease because these patients were excluded. LD-MTX should continue to be contraindicated in patients with advanced kidney disease (eGFR <30 ml/min) due to the known potential for serious AEs with high circulating levels of MTX.²⁰ The study excluded patients with systemic rheumatic diseases because LD-MTX is already clinically indicated in this population. Although it is possible there could be a different relationship between LD-MTX and kidney outcomes in patients with systemic rheumatic diseases, we reported that LD-MTX increased risk for several AEs in CIRT, such as hepatotoxicity, pneumonitis, cytopenias, and skin cancer,^89–10 known AEs from LD-MTX for use in systemic rheumatic diseases.¹³ Finally, CIRT was predominantly composed of older White men, so it is possible these results may not be generalizable to other more diverse populations.

In this double-blind, randomized, placebo-controlled trial, LD-MTX was not associated with worse kidney function or kidney outcomes compared with placebo among patients with cardiovascular disease. Rather, participants who began with normal kidney function or mild-to-moderate CKD randomized to LD-MTX had less decline in kidney function and reduced rate of kidney AEs than placebo on safety laboratory monitoring.

Disclosures

D.H. Solomon reports receiving research support from AbbVie, Amgen, CorEvitas, Corrona, Genentech, Janssen, and Pfizer; and reports other interests/relationships via UpToDate Royalties. J. Sparks reports performing consultancy for Bristol Myers Squibb, Gilead, and Pfizer unrelated to this study. M. Sparks reports receiving research funding from Renal Research Institute; reports receiving honoraria from Elsevier Nephrology Secrets; reports being a scientific advisor or member of the American Board of Internal Medicine on the Nephrology Board, Board of Directors of NephJC, Editorial Boards of American Journal of Kidney Diseases, ASN Kidney News, KCVD Membership and Communications Committee of the American Heart Association, Council for the Kidney in Cardiovascular Disease Scientific and Clinical Education Lifelong Learning Committee of the American Heart Association, Kidney360, Kidney Medicine, and the National Kidney Foundation North Carolina Medical Advisory Board. P. Ridker reports receiving research support from Amarin, Kowa, theNational Heart, Lung, and Blood Institute, Novartis, and Pfizer; and reports serving as a consultant to Agepha, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, CiviBioPharm, Corvidia, Flame, Janssen, Inflazome, Novartis, Novo Nordisk, Omeicos, SOCAR, and Uptton; and reports patents and inventions with Celera Corporation, and The Brigham and Women's Hospital, Inc. All remaining authors have nothing to disclose.

Funding

This work was supported by National Institutes of Health grants R01 HL119718 and U01 HL101422. J. Sparks is also supported by the National Institute of Arthritis and Musculoskeletal and Skin Diseases (grant numbers K23 AR069688, R03 AR075886, L30 AR066953, P30 AR070253, and P30 AR072577), the Rheumatology Research Foundation (R. Bridge Award), and the R. Bruce and Joan M. Mickey Research Scholar Fund.