Nearly 37 million Americans, or 15%, have chronic kidney disease (CKD), but 9 in 10 adults with the condition are not aware of their diagnosis. A recent study from Stanford University found that screening asymptomatic adults over the age of 35 years would be a cost-effective strategy for identifying patients with CKD before they develop severe illness.
What should primary care providers be doing differently?
The current standard of care is to screen people with underlying conditions that put them at higher risk of developing CKD, most commonly diabetes and hypertension. That’s why the American Diabetes Association recommends annual screening for CKD in patients with type 1 diabetes as well as those with type 2 diabetes.
And the American Heart Association (AHA) released an advisory last year that defined cardiovascular-kidney-metabolic (CKM) syndrome, a constellation of conditions that often occur together: obesity, diabetes, CKD, and cardiovascular disease. They propose a staged approach to identifying and monitoring CKM throughout the lifespan, which includes regular monitoring of the urine albumin-creatinine ratio in patients who have developed diabetes, hypertension, metabolic syndrome, or any signs of kidney disease.
But despite recognition from the subspecialty professional societies of the importance of screening persons with risk factors — additional conditions are obesity and family history of CKD — real-world implementation lags.
Sylvia Rosas, MD
Sylvia Rosas, MD, is a nephrologist and associate professor of medicine at Harvard University in Cambridge, Massachusetts, who also serves as president of the National Kidney Foundation. In an interview with Medscape Medical News, she cited several alarming facts about the state of CKD screening in the United States.
“Of people with diabetes who have insurance, only 40% get both the glomerular filtration rate (GFR) and the albumin performed, and for those who have hypertension, only 10%,” Rosas said. She is referring to a urine spot test that measures the amount of albumin in the urine, which is then paired with a serum measurement of creatinine to estimate the glomerular filtration rate. Both tests are needed to detect the asymptomatic stages of CKD, because the presence of albumin in the urine usually precedes drops in the GFR, which indicates more serious disease.
Rosas said she is frustrated by the low rate of testing compared with other commonly recommended preventive screenings, given the low cost and simplicity of assessment. Serum creatinine often is obtained as part of a routine chemistry panel, and the albumin test requires a single spot urine test. Yet, in 2018, 61% of US adults aged 50-75 years had received a colonoscopy in the past 10 years. Compared with the high price and inconvenience of undergoing colonoscopy, Rosas has trouble believing that “we cannot get more than 40% of people [with diabetes] to pee in a cup.”
But the biggest issue is that if people with risk factors don’t get screened before they develop symptoms of CKD, it is often too late to avoid dialysis or the need for transplantation.
Nisha Bansal, MD
The early warning symptoms are few, according to Nisha Bansal, MD, a professor in the department of nephrology at the University of Washington in Seattle. “New hypertension is a really important early sign,” Bansal said. “We know kidney disease almost certainly causes hypertension, so I would definitely think about screening for kidney disease.” Other findings on exam are the appearance of new edema or signs of fluid retention in the hands or around the eyes, along with findings in the urine of albumin, protein, or blood.
But most patients don’t have any symptoms in the early stages, and they can be nonspecific. “It is fatigue and some nausea,” Rosas said. “It’s only way at the end that you start vomiting, get itchy, or have hiccups.” Data from the Centers for Disease Control and Prevention have shown that over one third of patients at high risk for kidney failure are unaware of their disease. According to Rosas, these are patients who often receive the diagnosis of CKD and start dialysis the same day.
Why Not Screen Everyone?
For many conditions, like HIV or different types of cancer, the US Preventive Services Task Force (USPSTF) recommends broad screening of asymptomatic individuals so that early treatment can improve outcomes.
But when the USPSTF considered the question in 2012 of whether adults should be screened for CKD regardless of symptoms, it found little evidence that early detection could change the course of their illness. At that time, the standard of care for treating early stages of CKD generally focused on treating the comorbid conditions, such as diabetes, hypertension, and cardiovascular disease.
But the equation has changed with the availability of new drugs to treat CKD, such as sodium-glucose cotransporter 2 (SGLT2) inhibitors and mineralocorticoid receptor antagonists (MRAs).
“I consider these blockbuster drugs,” Bansal said. “For the first time in decades, we’re showing that this class of medications, the SGLT2 inhibitors, substantially reduce risk of loss of kidney function.”
Expressed in the lumen of the proximal renal tubules, SGLT2 reabsorbs filtered glucose from the tubular lumen. Inhibition of SGLT2 promotes urinary glucose excretion and reduces sodium reabsorption, increasing delivery of sodium to the distal tubule. The first SGLT2 inhibitor, canagliflozin, was approved in 2013 for use as an antihyperglycemic agent but subsequently was shown to have serendipitous benefits for the heart and kidneys.
Clinical trials have documented reductions in the risk for cardiovascular events in patients with type 2 diabetes, as well as decreases in the risk for progression to end-stage renal disease, cardiovascular mortality, and hospitalization for heart failure. Updated international guidelines from 2022 recommend treating all patients with type 2 diabetes and CKD with an estimated GFR ≥ 20 mL/min/1.73 m2 with an SGLT2 inhibitor.
But several trials of SGLT2 inhibitors also demonstrated benefits in reducing the risk for cardiovascular-related death or hospitalization for heart failure, even in patients without diabetes. Although initial approval from the US Food and Drug Administration was limited to patients with diabetes and heart failure, the agency has recently expanded its indications to include adults with CKD who do not have diabetes.
Bansal said she was happy to see this widening of the indications, which makes more patients eligible to receive SGLT2 inhibitors. “I really think this early CKD group is a great group to consider for those medications,” she said.
Bansal also pointed out that MRAs are another class of drugs with an interesting history. Earlier steroidal MRAs were found to have anti-inflammatory and antifibrotic properties, and in 1960 spironolactone was approved for use as a diuretic for the management of edema, primary aldosteronism, and hypertension. But even as their use in cardiology rose, MRAs had less utility for CKD, given adverse events such as hyperkalemia and hormonal effects like gynecomastia.
But the latest generation of nonsteroidal MRAs (nsMRAs) has higher selectivity for the mineralocorticoid receptor than sex-steroid hormone receptors, reducing androgenic side effects and preventing elevated potassium. Finerenone, the only nsMRA approved in the United States, has been shown in clinical trials to reduce the incidence of cardiovascular events (death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure) and CKD outcomes, including kidney failure, decrease in estimated GFR, or death from renal causes.
EPIC Changes Coming?
In light of treatment advances that offer hope of preventing progression of CKD in patients identified early, both the National Kidney Foundation and the American Kidney Fund lobbied the USPSTF in 2022 to conduct a fresh review of recent data to evaluate the need for updated screening recommendations.
The task force completed development of a research plan and collection of public comments in early 2023 and is now reviewing evidence before developing a draft recommendation.
A team of health policy researchers from Stanford is hoping that some of their recently published work will attract the panel’s attention. The first study, published in 2022, evaluated the cost-effectiveness of dapagliflozin, an SGLT2 inhibitor that has been shown to reduce mortality by 48% in CKD patients without diabetes.
The Stanford team found that adding dapagliflozin to standard care for these patients improved life expectancy by 2 years and reduced the percentage of those who needed dialysis or kidney transplant from 17% to 11%.
Marika Cusick
More recently, Marika Cusick, a doctoral candidate in health policy at the Stanford School of Medicine in Stanford, California, served as first author of an evaluation of the cost-effectiveness of screening asymptomatic adults. “We assessed screening for albuminuria in conjunction with conventional CKD therapy in addition to this new SGLT2 inhibitor class of drugs,” she said. They projected how this might change CKD progression in US adults who are aged 35 or older compared with standard therapy alone.
The findings were favorable. “A one-time screening would result in a reduction of 398,000 cases of kidney replacement therapy [defined as needing either dialysis or renal transplant] among 158 million US adults who are currently aged 35-75 years,” Cusick told Medscape Medical News.
In terms of quality-adjusted life years (QALYs), a one-time screening at age 55 years yielded an incremental cost-effectiveness ratio of $86,300 per QALY. Screening every 10 years between the ages of 35 and 75 years cost less than $100,000 per QALY gained.
Doug Owens. MD
According to Doug Owens, MD, professor and chair of the department of health policy at Stanford School of Medicine, “There’s a societal decision about how much are we willing to pay for additional length and quality of life. And this fits within what is generally considered reasonable for the US.”
For example, in the United States, screening for breast cancer among women aged 40-64 years costs $51,000 per QALY, whereas screening for lung cancer using USPSTF guidelines ranges from $72,639 to $156,774 per QALY.
A former member of the USPSTF, Owens predicted that the current review process would take at least another year. Meanwhile, he and Cusick are hoping that their work influences the USPSTF to recommend screening asymptomatic adults. “Increasing the awareness of these drugs and their effectiveness is a crucial first step,” he said.
Although adherence to current recommendations for screening of people at risk is poor, Rosas suggested that the USPSTF guidelines would be more influential in changing practice among primary care physicians than subspecialty guidelines would.
“When you have a recommendation like that, they’re putting it in the electronic health record,” she said. By adding best practice alerts to their electronic health record systems, health systems can make it easier for primary care doctors to check all the boxes.
In line with the AHA’s holistic approach towards managing cardiovascular illnesses, CKD, and metabolic disease, Bansal suggested an additional strategy: “I think we’re moving toward more interdisciplinary care models, where primary care doctors, nephrologist, cardiologists, and endocrinologists — all of us — should be working together in a collaborative care model, to help break down some of these barriers in terms of screening as well as implementation of these therapies.”
Bansal, Cusick, and Owens reported no financial conflicts of interest. Rosas receives funding from AstraZeneca and Bayer for serving on advisory boards and clinical research funding, as well as funding from the National Institute of Diabetes and Digestive and Kidney Diseases for clinical trials.
Ann Thomas is a pediatrician and epidemiologist living in Portland, Oregon.
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