Stroke Outcomes Provide Some Clarity on Kidney-Brain Connection

Recognizing that not all chronic kidney disease (CKD) is the same, researchers are starting to separate the individual contributions of kidney dysfunction and kidney damage to stroke outcomes, opening the door to more specific interventions.

In a longitudinal cohort study of Japanese stroke patients, CKD was an independent predictor of recurrent stroke (adjusted HR 1.19, 95% CI 1.09-1.30) and death (adjusted HR 1.40, 95% CI 1.31-1.50) within approximately 4 years even after accounting for traditional cardiovascular risk factors, reported Ryu Matsuo, MD, PhD, of Kyushu University in Fukuoka, Japan, and colleagues.

Probing further into the underlying pathological conditions of CKD, they found that whereas worse estimated glomerular filtration rate (eGFR) was associated with an increased risk of recurrent stroke, only the highest level of proteinuria was associated with excess risk:

• Mild to moderate kidney dysfunction (eGFR 45-59 mL/min/1.73 m²): adjusted HR 1.13, 95% CI 1.02-1.25

• Moderate to severe kidney dysfunction (eGFR <45 mL/min/1.73 m²): adjusted HR 1.22, 95% CI 1.09-1.37

• Kidney damage (proteinuria ≥2+): adjusted HR 1.25, 95% CI 1.07-1.46

However, any level of eGFR impairment and proteinuria were associated with increased mortality, the Fukuoka Stroke Registry investigators reported in Stroke.

“These findings suggest that both kidney dysfunction and kidney damage are independent risk factors for recurrent stroke and death in patients with ischemic stroke, but increase the risks of cardiovascular outcomes in different ways,” Matsuo’s group said.

“Further studies are warranted to validate the impacts of kidney dysfunction and kidney damage on cardiovascular risks and to determine whether interventions for these pathological conditions are effective in improving the cardiovascular outcomes in patients with ischemic stroke,” the study authors concluded.

The CDC estimates that about 37 million U.S. adults have CKD, with most cases undiagnosed. CKD tends to worsen without treatment and may reach end-stage renal disease requiring dialysis or kidney transplant. Diabetes and high blood pressure are the leading causes of kidney failure.

Matsuo’s team said the question of whether impaired kidney function, kidney damage, individually or both, are involved in cardiovascular outcomes has been controversial. Prior studies had produced mixed results in the CKD-stroke sphere.

“Though CKD is a putative risk factor for stroke, the mechanisms by which CKD impacts stroke risk have proven difficult to elucidate, as many risk factors for CKD are also risk factors for stroke. Understanding the impact of CKD on outcomes after stroke poses similar challenges,” commented vascular neurology fellow Samuel Bruce, MD, MA, and stroke specialist Neal Parikh, MD, MS, both of Weill Cornell Medicine in New York City.

In an accompanying editorial, they stressed that based on the work from Matsuo and colleagues, “going beyond serum creatinine is necessary to more fully understand the impact of CKD on stroke outcomes.”

“While the authors’ findings do not have immediate, direct clinical implications, it is noteworthy that when treating conditions linked with CKD, such as hypertension and diabetes, treatment options include drugs with nephroprotective properties,” Bruce and Parikh wrote. “Whether such drugs should be used preferentially to improve poststroke outcomes should be investigated.”

Matsuo and colleagues cited research showing that renin-angiotensin-aldosterone system inhibitors and SGLT2 inhibitors can slow kidney dysfunction and kidney damage.

The observational cohort study prospectively followed 12,576 patients with ischemic stroke (mean age 73 years; 41.3% of whom were women) who were enrolled into the multicenter Fukuoka Stroke Registry from 2007 to 2019.

During the median follow-up of 4.3 years, 19.7% of patients had recurrent stroke (48.0 per 1,000 patient-years) and 32.1% died (67.3 per 1,000 patient-years).

The study was unable to control for long-term treatments or medications taken during follow-up, however.

The investigators also acknowledged the exclusion of stroke patients undergoing renal replacement therapy, whose anuria precluded proteinuria assessment using a urine dipstick test. Another study limitation was a population that was ethnically homogeneous due to registry enrollment limited to a small area of Japan.

“These data do not clarify whether kidney dysfunction and kidney damage, as opposed to upstream factors such as hypertension, are causally linked to poststroke outcomes,” Bruce and Parikh said. “However, the findings do justify asking whether different aspects of CKD pathophysiology may be targeted to improve stroke outcomes.”