Long-term renal and cardiovascular risks of tacrolimus in patients with lupus nephritis

Abstract

Background: Despite continuous advancement, treatment of lupus nephritis (LN) remains challenging. Recent guidelines now include a regimen incorporating tacrolimus as a first-line treatment option. Even though tacrolimus is effective in combination with mycophenolate and corticosteroids, concerns remain regarding long-term use, given its association with increased cardiovascular risks including nephrotoxicity, hypertension, dyslipidemia and hyperglycemia in kidney transplant recipients. However, in LN, long-term evaluations and head-to-head comparisons are lacking and thus the safety profile remains ill-defined. We hypothesized that chronic toxicity also occurs in LN patients. Therefore, this study aimed to assess long-term cardiovascular and renal outcomes of tacrolimus in LN patients.

Methods: This observational cohort study examined adult LN patients treated with tacrolimus, assessing renal outcomes, hypertension, diabetes, dyslipidemia, cardiovascular events and the Framingham risk score. The results were compared with a control group of CNI-naïve LN patients.

Results: Of the 219 LN patients in this study, 43 (19.6%) had tacrolimus exposure. Over a median follow-up of 7.1 years, tacrolimus use was associated with significant kidney function decline (6.8 mL/min/1.73 m2, versus 0.8 in the control group). The incidence of end-stage kidney disease was similar. Cardiovascular event incidence was equally low in both groups. The 10-year risk of coronary heart disease was lower in the tacrolimus group, primarily due to age differences. HbA1c levels were higher in the tacrolimus group (37.4 mmol/mol) than in controls (33.6 mmol/mol), although the incidence of diabetes was similar. There were no differences in the occurrence of hypertension or dyslipidemia.

Conclusions: Our study demonstrated that tacrolimus exposure was associated with long-term kidney function loss in LN patients. Although cardiovascular risk factors and events were similar to patients never exposed to tacrolimus, there may be an increased risk of developing diabetes. Therefore, our study supports vigilance towards renal adverse effects in LN patients treated with tacrolimus.

Keywords: calcineurin inhibitors; cardiovascular; chronic renal insufficiency; lupus nephritis; tacrolimus.

Graphical Abstract

Figure 1:

Treatment groups. Flow diagram of the formation of the treatment groups.

Figure 2:

Analyses. Schematic display of the by-exposure and on-treatment analyses.

Figure 3:

Kidney outcomes. (A) eGFR decline (mL/min/1.73 m²) in the tacrolimus group compared with the control group. Boxes represent medians and whiskers represent maximum values. (B) eGFR change in the tacrolimus group in both the by-exposure as well as the on-treatment analysis, compared with the control group. Boxes represent medians and IQRs, *P < .05. (C) Univariate linear regression analysis of the relation between duration of tacrolimus use and eGFR change.