VA Research: A Better Way to Treat Kidney Disease

Experts at the San Francisco VA are pioneering a more accurate – and race-independent – measure of kidney function.

By Craig Collins

On Sept. 23, 2021, the American Society of Nephrology (ASN) and the National Kidney Foundation (NKF) released a joint statement titled “Removing Race from Estimates of Kidney Function.” Of the more than 37 million American adults with kidney disease, a disproportionate number are people of color. The work of the organizations’ joint Task Force on Reassessing the Inclusion of Race in Diagnosing Kidney Disease had, after countless hours of research, analysis, and discussion, arrived at the conclusion that the way kidney function was currently assessed – using equations that included race as a factor – is a likely contributor to these worse outcomes.

As part of the joint statement, the president of the NKF, Paul M. Palevsky, MD, – who is also chief of the Pittsburgh VA Medical Center’s renal section – said: “The use of race in clinical algorithms normalizes and reinforces misconceptions of racial determinants of health and disease. We must move beyond this if we are to address the racism and racial disparities that impede the care of people with kidney disease.”

Both the ubiquitous kidney function test, used for decades, that measures creatinine, and the test measuring cystatin C require a simple blood draw, but the latter test has proven to be more accurate.

The work discussed by the ASN/ NKF Task Force included that of Michael Shlipak, MD, MPH, associate chief of medicine for research at the San Francisco Veterans Affairs Health Care System (SFVA) and a professor of medicine, epidemiology, and biostatistics at the University of California-San Francisco (UCSF). For nearly 20 years, Shlipak has been looking for better measures of kidney function, and he’s been joined in recent years by Michelle Estrella, MD, MHS, chief of nephrology at the San Francisco VA and an associate professor of medicine at UCSF. Both are co-leaders – Estrella as executive director, Shlipak as scientific director – of UCSF’s Kidney Health Research Collaborative, a worldwide consortium of scientists dedicated to improving kidney health.

What does race have to do with kidney function? In their joint statement, the NKF and ASN point out that “race is a social, not a biological, construct.” Nevertheless, the standard test used to measure kidney health for more than seven decades continues to include race in its interpretation as an estimate of kidney function.

Michael Shlipak, MD, MPH, associate chief of medicine for research for the San Francisco Veterans Affairs Health Care System (SFVA) and professor of medicine, epidemiology, and biostatistics at the University of California-San Francisco (UCSF), and Michelle Estrella, MD, MPS, chief of nephrology at SFVA and an associate professor of medicine at UCSF, are co-leaders of UCSF’s Kidney Health Research Collaborative and are promoting a test of kidney function that is more accurate than the current one.

Shlipak and Estrella are among a growing number of medical professionals who want to do better – and they’re promoting a test of kidney function they have helped to prove is more accurate.

THE PROBLEM(S) WITH CREATININE

Kidneys perform a variety of functions to balance blood components and keep the body healthy: They regulate electrolytes; maintain fluid and acid/ base balance; help the body absorb amino acids, glucose, and other compounds; produce hormones; activate vitamin D; remove toxins from the blood; and regulate blood pressure.

The primary measure of how well kidneys are working is the rate at which their microscopic clusters of capillaries – the glomeruli – are filtering waste and extra water out of the blood while retaining the proteins and blood components the body needs. This is expressed as the glomerular filtration rate, or GFR – essentially, how much blood is filtered by the kidneys each minute. In 1926, a Danish physiologist was the first to estimate GFR by measuring the level of creatinine – a breakdown product of muscle activity – in the blood.

World War II veteran Spencer Moore is greeted by a former service member at the conclusion of the ceremony to mark the 60th anniversary of the integration of the armed forces in the Capitol Rotunda, Washington, D.C., July 23, 2008. The most popular kidney function test used today has over-emphasized race in equations associated with creatinine levels, and this has created treatment disparities for Black patients.

While it has been the standard measure of kidney function ever since, using serum creatinine alone to measure GFR, say Shlipak and Estrella, is a fundamentally flawed approach. “Our muscles are full of creatine,” said Shlipak. “And after we are active, as muscle repairs itself, it dumps out creatine that becomes creatinine in the blood. Therefore, the more active you are, the more creatinine comes from your muscles and has to be eliminated from the body.”

Estrella pointed out that serum creatinine levels are clearly affected by variables that have nothing to do with kidney function. “Our veterans,” she said, “who tend to be older, and some of whom are frail, may have misleadingly low creatinine.” As a result, when such patients’ creatinine levels are used to estimate GFR, their kidney disease may go undetected or its degree of severity underestimated.

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Likewise, many active-duty military service members may have elevated creatinine levels despite having healthy kidneys – something that came to Shlipak’s attention when he was working with his colleagues in the military to develop the VA/DOD Clinical Practice Guidelines for the Management of Chronic Kidney Disease. In fact, these highly fit service members “just had so much muscle that they were making a ton of creatinine, which created the illusion that they had kidney disease.”

Creatinine, Shlipak said, is a good test of kidney function in average, reasonably healthy people who don’t use their muscles too much, or too little – but those are not the people most at risk for kidney disease. “So there’s this irony that the sicker you are, and the more likely you are to have kidney disease, the less likely we are to be able to detect it accurately with creatinine.”

RACE AND KIDNEY HEALTH INEQUITIES

The medical community has long been aware of the pitfalls involved in relying on serum creatinine and has attempted to refine and weigh factors in the equation used to arrive at a reliable estimated GFR (eGFR). The eGFR equations commonly used today, known as the MDRD and CKD-EPI, include age, sex, and race to approximate the unknown quantity of creatinine that each individual produces. The idea is that if you could accurately account for the amount of creatinine that a person makes, then the blood creatinine level would only reflect kidney function, the rate of creatinine being filtered out into urine.

Why race? Several studies have indicated that Black patients, for reasons that are only partly understood, have slightly higher average measured GFR than non-Black patients with the same age, sex, and serum creatinine. The most recent version of the CKD-EPI formula, updated in 2009, automatically adjusted the eGFR of any Black patient by a factor of 15.9 percent.

Race-based considerations in measuring kidney function – in making any medical judgments – are on their way out, Shlipak said; he’s physically active, and if he theoretically had an identical twin who was bedridden, the difference in their serum creatinine would be huge even if they had identical kidney function. In contrast, a man his age of African descent with the same kidney function, and who worked out about as much would show a much smaller difference in serum creatinine, if any. Race, Shlipak said, “is not nearly as important a factor for determining creatinine production as other health factors, so it has been over-emphasized by these equations.”

The 300th Sustainment Brigade conducting a brigade 5-kilometer run. Many members of the U.S. military may have elevated creatinine levels despite having healthy kidneys, simply because they have more muscle mass and thus more creatinine in their bodies.

Boosting Black patients’ creatinine eGFR by 16 percent – essentially, making their kidney function look 16 percent better than a white patient evaluated with the same formula – has had consequences. An article published in the Journal of General Internal Medicine in October 2020 reviewed records for 57,000 patients in the Boston area and found that a third of the Black patients would have had their disease classified as more severe if the same eGFR formula had been used for them as for white patients. [1]

The study identified 64 cases in which patients’ recalculated score would have qualified them for placement on a kidney transplant waitlist – but none was referred or evaluated for a transplant. That’s a huge, potentially life-altering, consequence – and it’s dramatic enough to overshadow more subtle implications for veterans’ health care. “I think our reliance on creatinine,” said Estrella, “leads to missed opportunities – to start medications, for example, that we know decrease the risk for heart disease and slow the progression of kidney disease.” As she pointed out, most of those opportunities arise within the primary care settings where most patients with kidney disease are treated.

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“The biggest killer in our patients with kidney disease is heart disease,” Estrella said. “For these patients with kidney disease, if we could detect the kidney disease earlier, then I think we would be more aggressive in starting medications like ACE-inhibitors or statins to lower their risk of heart disease.” Lifestyle interventions, such as diet and exercise and quitting smoking, can also alter the course of kidney disease – but only if the clinicians detect a problem with kidney function and inform patients of their risk.

Despite the good intentions the medical community had when incorporating race to calculate eGFR, Shlipak said, “it certainly has adverse consequences, it’s terrible for morale, and it leads some patients to lose trust in their medical care.” For all those reasons, the use of race in the eGFR formula is on its way out. “The VA is committed to taking race out of creatinine equations by the end of calendar year 2021.”

A BETTER MEASURE: CYSTATIN C

The good news is that there is – and has been, for two decades – a more reliable measure of GFR. “The concept of GFR,” said Shlipak, “is that you try to find some blood protein that is exclusively eliminated through the kidney, such that the blood level is a direct indicator of kidney function. So the ideal marker would be something that’s produced at such a steady rate that the amount that’s in the blood is determined only by the kidney, and not influenced by differences in our body size, our activity level, or how sick we are.”

More than 40 years ago, a pair of Swedish scientists discovered just such a protein in human biological fluids and observed it in high plasma concentration in patients with advanced renal failure: cystatin C, a protein secreted by most cells in the body and found in virtually all tissues and bodily fluids. [2] Like creatinine, cystatin C levels are measured in the blood. They are also mostly independent of age and muscle mass.

Cystatin C comes from all our cells. “And all humans, roughly, make about the same amount of cystatin C,” said Shlipak. “There’s a slight fudge factor for gender and age, but it’s a lot less than for creatinine. It’s a lot more of a direct relationship of cystatin C to GFR.”

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Cystatin C enables accurate GFR estimations without requiring race-based adjustments in the equation. To Estrella, the use of a new marker has the added benefit of turning attention away from the Black/white dichotomy of discussions around creatinine. “A large number of our veterans are non-Black and nonwhite,” she said, “and I think cystatin C may actually offer more accurate GFR estimations in those populations as well, although they’re less well studied.”

In separate studies, cystatin C has also been shown to predict higher risks of heart disease, stroke, and death among older people with no known kidney problems. Creatinine measures largely miss those risks.

The bad news – so far – is that almost no clinicians are using cystatin C as a test to estimate GFR. That’s predominantly because the test has not been available, so clinicians have not had experience using the test. Very few – about 7 percent – of U.S. hospital laboratories are currently set up to perform a cystatin C test. “Most doctors have never heard of it,” Shlipak said. “So we have a huge task to educate clinicians that there is this better test.”

Sgt. 1st Class Rob Harmon shows off his “Donor” bracelet and Kai Johns his “Recipient” bracelet before undergoing kidney transplant surgery April 27, 2017, at MedStar Georgetown University Hospital in Washington, D.C. They became friends in the Army more than 20 years ago. The more accurate cystatin C test will likely mean treatment for kidney disease will begin earlier, and more patients will be assessed as qualifying to be placed on the kidney transplant list.

Both Estrella and Shlipak say that, by far, the biggest obstacle toward the inclusion of cystatin C in estimating GFR is institutional inertia: The creatinine eGFR formula is simply the way things have always been done. The perceived expense and/or difficulty of cystatin C testing have also been cited as obstacles to cystatin C adoption.

The better news is that these assumptions are easily disproven: “It’s a $5.00 test,” Shlipak said. “It can generally run on the machine that already sits in the hospital lab, and in our lab, the results come back as fast as creatinine – within an hour.” A growing number of institutions – recently and most notably the NKF and the ASN – have already called for change, and momentum is clearly on the side of a race-free test of kidney function using cystatin C.

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Neither Shlipak nor Estrella think clinicians should focus solely on cystatin C; for some patients, an equation that combines the two markers will work well, and there is a small subset in whom cystatin C might not work well. “But our main message for the DOD and VA is that cystatin C has to be available,” said Shlipak. Since 2019, the cystatin C test has been part of the VA/ DOD kidney care practice guidelines. “We recommended that both military personnel and veterans need access to cystatin C testing, to make sure we’re getting kidney function measurement right.”

Chuanyi Mark Lu, MD, chief of lab medicine service at the SFVA and professor and vice chair of the department of laboratory medicine at UCSF, led the adoption of routine cystatin C testing at the SFVA in 2012, recognizing its potential to improve patient care. As interest and demand for cystatin C grows nationally, Lu has prepared SFVA to serve as a reference lab for other VA facilities across the network to help them bring in cystatin C testing to the local laboratories. For clinicians and patients without local access to cystatin C testing, the SFVA clinical lab can serve as a “sendout” laboratory so that all veterans can receive optimal testing of their kidney function when needed.

The expert team at the SFVA is committed to helping make the cystatin C testing available to all veteran patients and their health care providers.

1. Ahmed, S., Nutt, C.T., Eneanya, N.D. et al. Examining the Potential Impact of Race Multiplier Utilization in Estimated Glomerular Filtration Rate Calculation on African-American Care Outcomes. Journal of General Internal Medicine, 36, 464–471. https://doi. org/10.1007/s11606-020-06280-5

2. H. Löfberg & A. O. Grubb. Quantitation of y-trace in human biological fluids: Indications for production in the central nervous system, Scandinavian Journal of Clinical and Laboratory Investigation, 39:7, 619-626, DOI: https://doi. org/10.3109/00365517909108866

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