Both stroke and chronic kidney disease (CKD) are common public health concerns that caused 143.2 million disability-adjusted life years (DALYs) and 41.5 million DALYs in 2019, respectively (1), and often occur as comorbidities (2). Renal impairment is an independent risk factor for serious cardiovascular disease, including stroke (3, 4). While studies have reported an association between renal impairment and poor functional outcome in patients with acute ischemic stroke (AIS) (5, 6), data are more limited in those who receive intravenous thrombolysis and BP-lowering treatment where the risk of intracerebral hemorrhage (ICH) and other adverse outcomes may be increased (7–10).

The blood pressure (BP) arm of the International Enhanced Control of Hypertension and Thrombolysis Stroke Study (ENCHANTED) trial showed that intensive BP-lowering treatment did not improve clinical outcomes after AIS, despite reducing the risk of intracranial hemorrhage (11). It is unknown as to whether there is an interaction between intensive BP-lowering treatment and renal function on clinical outcomes in this patient group. On the one hand, intensive BP control may cause potential renal impairment from a decrease in renal perfusion pressure and blood flow, and this may in turn lead to a higher risk of cerebral bleeding and poor functional outcome. Moreover, BP variability may be influenced by renal functional status in relation to therapeutic and psychological resistance (12). On the other hand, intensive BP-lowering treatment may have added benefits in “high-risk” patients with renal impairment who receive intravenous thrombolysis for AIS. Thus, we conducted a post-hoc analysis of the ENCHANTED trial to assess the prognostic significance of renal impairment and its interaction with the randomized treatment on clinical outcomes in thrombolyzed AIS patients.

Overall, 2,151 patients (mean age 66.9 years; 38.0% women) with available baseline renal function data were involved in this analysis, as outlined in Supplementary Figure 1 . Baseline median eGFR was 86.9 (IQR 68.6–108.6) mL/min/1.73 m², with 993 (46.2%), 822 (38.2%), and 336 (15.6%) patients identified as normal (G₁), mild impairment (G₂), and moderate-to-severe impairment (G₃) of renal function. Demographic and clinical characteristics by baseline renal function category are outlined in Table 1 . Patients with decreased eGFR were older, had more severe neurological impairment, and had greater frequency of hypertension, coronary artery disease, other heart disease, AF, diabetes mellitus, hypercholesterolemia, use of antiplatelet and glucose-lowering agents, and premorbid symptoms.

Supplementary Figure 2 depicts SBP management profiles in patients with different baseline renal functions, overall and by randomized treatment groups. Mean SBP within 7 days was higher in patients with moderate-to-severe impairment of eGFR (G₃) than in the other two groups (p < 0.0001), in both BP-lowering groups.

There was no statistically significant association of impaired renal function with either death or major disability [mRS scores 3 to 6; adjusted odds ratio (aOR) 1.06, 95% confidence interval (CI) 0.78–1.45; p = 0.940 for trend] or major disability (mRS scores 3 to 5, aOR 1.01, 95% CI 0.72–1.43; p = 0.708 for trend) at 90 days. However, patients with stage G₃ had nearly two-fold greater odds of death compared to those with stage G₁ (aOR 1.77, 95% CI 1.05–2.99; p = 0.031 for trend) within 90 days ( Table 2 ). There is no multicollinearity in covariates in the above models. A non-linear association between baseline eGFR as a continuous variable and death after adjustment for other variables is shown in Figure 1 , and the OR of death was statistically significantly increased where the eGFR was <60 mL/min/1.73 m².

There was no statistically significant interaction between stages of renal function and randomized treatment effect on clinical outcomes, including for an ordinal shift in mRS scores (p for interaction = 0.192) ( Figure 2 ) and others ( Table 3 ). In fractional polynomial analysis, no significant interaction effect on death was shown between continuous eGFR value and randomized treatment. Patients with decreased eGFR at baseline did not increase the risk of death significantly in the intensive BP-lowering group (p for interaction = 0.853) ( Supplementary Figure 3 ).

Patients with decreased eGFR had a higher risk of sICH according to the SITS-MOST and other definitions ( Supplementary Table 1 ). A series of splines display the non-linear relationship between baseline continuous eGFR (eGFR 60 mL/min/1.73 m² as the reference) and sICH. For eGFR <60 mL/min/1.73 m², the OR for sICH increased with decreased baseline eGFR ( Supplementary Figure 4 ). Patients with decreased eGFR had a higher risk of death caused by the direct effects of acute ischemic stroke and non-vascular reasons ( Supplementary Table 2 ). There was no significant interaction between renal impairment and the three subgroups on mortality ( Figure 3 ). However, we found that the risk of mortality was significantly higher in the Asian subgroup than in the non-Asian subgroup. In the Asian group, stage G₂ had nearly two-fold greater odds of death compared to those with stage G₁ (aOR 1.79, 95% CI 1.08–2.98) and stage G₃ (more than two-fold) (aOR 2.36, 95% CI 1.25–4.49) ( Figure 3 ).

In this post-hoc analysis of the ENCHANTED BP arm, moderate-to-severe impairment of eGFR was adversely associated with mortality and risk of sICH but not with functional outcome in thrombolyzed patients with AIS. We also found that patients with moderate-to-severe renal impairment maintained a higher SBP compared to those with normal or mild renal impairment, regardless of the randomized treatment allocation. There was no evidence of heterogeneity in the effect of intensive BP-lowering treatment on death according to different renal function groups.

Renal dysfunction was proven to increase mortality in critical illnesses including AIS (8, 17–20). Our study further adds to this knowledge by defining the association specifically in thrombolyzed AIS and is consistent with an earlier analysis of the ENCHANTED alteplase-dose arm and other studies (8, 21). The relationship between eGFR and mortality was non-linear, and the odds of death were statistically significantly higher in patients whose baseline eGFR was less than 60 mL/min/1.73 m². Potential explanations are that patients with renal impairment exhibit other organ dysfunction, which increases the risk of death (22). We did not find any statistically significant association between renal impairment and disability, as observed in other studies (23, 24), but ICH was higher in those patients with pre-existing renal impairment, which may have potentiated effects on the coagulation system and morphologically changed blood vessel walls through interactions between the endothelium and platelets (25, 26). Patients with renal impairment have varying degrees of systematic inflammation, which also influences the risk of bleeding (27), while dialysis treatment is known to produce a hypocoagulable state and exacerbate the likelihood of ICH (28). Thus, weighing up the potential risks and benefits of thrombolysis treatment in patients with chronic kidney disease can be challenging.

In our study, patients with severe renal impairment had more hypertension and higher baseline BP and maintained higher BP over the subsequent 7 days compared to those with normal or mildly reduced renal function, which potentially reflects the complex interaction between renal function and response to BP-lowering treatment in AIS, as shown elsewhere (12). Renal impairment is a common cause of hypertension, and there was a higher frequency of history of hypertension at baseline in the G₃ compared to the other two groups (29). The higher mean SBP achieved within 6 h raises the possibility that renal impairment contributes to the therapeutic resistance to antihypertensive agents through such mechanisms as increased sympathetic activity, alterations in the renin–angiotensin–aldosterone system, vascular aging and atherosclerosis, and sodium dysregulation from reduced functioning nephrons and lowered glomerular filtration rate (29, 30). Of course, clinicians may have also altered the intensity of their BP-lowering treatment from concerns about inducing renal impairment in such high-risk patients (31).

There was no heterogeneity in the BP-lowering treatment effect on death across different stages of renal impairment. Although the rate of death appeared higher in the intensive BP-lowering group with decreased eGFR, this finding lacked precision due to small numbers. This might be a reminder for clinicians to be cautious about the use of intensive BP-lowering treatment in patients with known renal impairment, but more data are needed to confirm this finding. Subgroup analysis results of ethnicity found that renal impairment might lead to a higher risk of mortality in Asians. As there was no heterogeneity, more studies are needed in the future to confirm it.

The strengths of our study include the prospective design with high rates of follow-up, treatment compliance, and rigorous assessment of outcomes in a relatively large sample of patients with a broad range of characteristics. Our analyses included the use of restricted cubic spline models and various sensitive analyses to describe the relationship between eGFR and outcomes. However, our study has limitations that include the dataset pertaining to a clinical trial population where most patients were of Asian ethnicity where the CKD-EPI equation, which was derived from North American and European populations, may have measurement bias. Selection bias may have also led to the exclusion of patients with severe AIS where the risks of intensive BP-lowering treatment were perceived to be high, thus further limiting the generalizability of our findings. Furthermore, the use of baseline/admission eGFR as the exposure marker may be misleading as serum creatinine is prone to elevation by acute illness (32), and the definitions for renal impairment normally require persistence of eGFR <60 mL/min per 1.73 m² for at least 3 months in the absence of a reversible condition (33). Finally, the ENCHANTED trial did not demonstrate an improvement in functional outcomes, primarily due to the minimal difference in mean SBP between the intensive BP-lowering group and the control group. Consequently, a post-hoc analysis might inherently possess limitations in addressing the research question of this article.

In summary, our analysis of the ENCHANTED BP arm clinical trial dataset has shown that renal impairment predicts higher mortality in thrombolyzed AIS patients. Patients with reduced eGFR might also have a higher risk of sICH. Uncertainty persists as to whether intensive BP-lowering treatment confers benefits over guideline-recommended treatment in AIS patients with renal impairment.