Slight Declines in Kidney Function Portend CV Trouble for Young Adults

Young adults with kidney function below what is expected for their age but not yet at the threshold for chronic kidney disease (CKD) have a greater risk for adverse cardiovascular outcomes in the coming years, a large, retrospective study indicates.

Even at an estimated glomerular filtration rate (eGFR) of 90 to 99 mL/min/1.73 m², adults younger than 40 had significantly higher risks of MACE and MACE plus heart failure compared with better renal function, lead author Junayd Hussain, BSc (University of Ottawa and ICES, Ottawa, Canada), and colleagues report.

The magnitude of the increased risk grew at lower levels of kidney function.

The relationship between subclinical eGFR declines and cardiovascular events “was a bit surprising and concerning, and we showed it in many different ways,” senior author Manish Sood, MD (ICES and The Ottawa Hospital), told TCTMD, noting that the associations were not as pronounced in older age groups.

“In other words, young people should have higher kidney function, slight reductions are meaningful and have some connections with cardiac disease, and [this relationship] is not being recognized,” he said. There’s a one-size-fits-all approach to diagnosing kidney disease—with CKD defined as an eGFR below 60 mL/min/1.73 m²—across all age groups. “Maybe we need to change what we’re doing,” Sood added.

While it’s not clear, at this point, what to do in response to a subclinical decline in renal function “just recognizing that this is a problem is the first step,” Sood said. This then lays the groundwork for future studies investigating whether the risk of CV events can be modified in this context, he added.

In the meantime, young people with renal function that is lower than expected based on age should be monitored for disease progression and screened for other, more-established cardiovascular risk factors, Sood advised. In addition, it couldn’t hurt to implement lifestyle changes like exercising, eating a healthy diet, and quitting smoking, he said, noting that the information gleaned from the current study could help motivate individuals: “The same things that improve your heart health improve your kidney health.”

Even Slight Declines Influence Risk

CVD is a growing problem among young adults, driven by rises in obesity, sedentary lifestyles, diabetes, and hypertension. But it remains unclear what subclinical reductions in kidney function are contributing to the problem. The tricky part, Sood said, is that kidney function naturally declines with age, but there is just one cutoff used to define CKD. What that means is that a younger person would have to lose a relatively greater proportion of kidney function—perhaps more than 50%—before reaching a clinical diagnosis of CKD than would an older person.

“That’s a lot of potential kidney loss before anything is being done or these people are even on the radar,” Sood said.

For the current study, published online ahead of the September 26, 2023, issue of the Journal of the American College of Cardiology, the investigators sought to establish just how much CV risk is conveyed by slight declines in renal function. They turned to healthcare datasets from the province of Ontario, focusing on more than 8.7 million adults ages 18 to 65 (mean age 41.3; 52% women), including about 3.6 million younger than 40.

I think we have to start considering whether we should have different levels of what we recognize as kidney disease or kidney impairment based on age. Manish Sood

Mean eGFR was 113.6 mL/min/1.73 m² in those ages 18 to 39, 101.8 mL/min/1.73 m² in those ages 40 to 49, and 93.1 mL/min/1.73 m² in those ages 50 to 65. The age-specific standards across those three age groups were set at 100 to 109, 90 to 99, and 80 to 89 mL/min/1.73 m², respectively. Follow-up lasted a median of 9.2 years.

In all three age groups, risk of MACE (CV mortality, ACS, or ischemic stroke) increased in a stepwise fashion across declining categories of eGFR. For any given category, the relative risk increase was greater in young adults than in others, despite the lower absolute risk. At an eGFR of 70 to 79 mL/min/1.73 m², for example, the hazard ratio for MACE was 1.31 (95% CI 1.27-1.40) in the youngest adults, 1.09 (95% CI 1.06-1.12) for those in their 40s, and 1.07 (95% CI 1.05-1.08) for those ages 50 to 65. Similar patterns were seen for MACE plus heart failure.

In young adults, there was already an elevated MACE risk at an eGFR of 90 to 99 mL/min/1.73 m² (HR 1.09; 95% CI 1.06-1.13).

These findings were bolstered by additional analyses that took into account a prior history of CVD, albuminuria at the start of the study, and repeated eGFR measurements.

Time to Pay More Attention to the Kidney

In an accompanying editorial, Daniel Duprez, MD, and David Jacobs Jr, PhD (both from the University of Minnesota, Minneapolis), make the case that it’s time to more-routinely assess kidney function in young and middle-aged adults.

Practice guidelines already contain guidance around the impact of factors like age, sex, ethnicity, blood pressure, lipids, glucose, and smoking when it comes to primary CVD prevention, and the current study “and our CARDIA work provide evidence to expand these disease prevention guidelines,” they write.

“Given these new findings and other supportive meta-analyses, routine measurement of both eGFR and urine albumin excretion, the latter based simply on an untimed urine sample, in addition to the current battery of tests used in routine medical screening, is generally warranted to guide preventive measures as well as to treat CKD,” they say.

Speaking with TCTMD, Duprez said kidney function is one of the most ignored risk factors for CVD, indicating that that should change based on information from this study and others. It’s unlikely to be an undue burden on clinicians who are already ordering other tests.

“It’s so easy and it’s so cheap to check the albuminuria in the urine and if somebody does the lab, it’s very easy to obtain eGFR. So it doesn’t cost too much,” Duprez said. It’s not clear how often such monitoring should occur, he added, but “at least from time to time, if you want to do the risk factors, include renal function and albuminuria.”

He predicted that such an approach could perhaps help stave off the development of more-severe kidney disease and ultimately reduce healthcare costs over the long term.

Additional studies are needed, Sood said, pointing to questions around how slight reductions in eGFR compare with established cardiovascular risk factors and how they might add predictive value to existing heart health risk calculators.

Taking a broader view, Sood hopes these findings may get the medical community thinking about whether using a single cutoff for CKD is the best approach.

“I think we have to start considering whether we should have different levels of what we recognize as kidney disease or kidney impairment based on age.” Manish Sood