AUTHOR COMMENTARIES - 2010
April 2010

Photo credit: Peter Howard.

Josef Coresh Featured Paper Interview

According to Essential Science IndicatorsSM from Thomson Reuters, the paper, "Prevalence of chronic kidney disease in the United States" (Coresh J, et al., JAMA-J. Am. Med. Assn. 298[17]: 2038-47, 7 November 2007), was among the 20 most-cited Hot Papers over all fields. It is now a Highly Cited Paper in Clinical Medicine with 355 citations to its credit up to December 31, 2009. Lead author Dr. Josef Coresh's record in the database includes 164 papers, the majority of which are classified under Clinical Medicine, cited a total of 9,736 times between January 1, 1999 and December 31, 2009. Dr. Coresh is a Professor at the Johns Hopkins Bloomberg School of Public Health, where is the Director of the Cardiovascular Epidemiology Training Program and the George W. Comstock Center for Public Health Research and Prevention.

In the interview below, he talks with ScienceWatch.com correspondent Gary Taubes about this paper and his work in chronic kidney disease.

  What prompted your initial research interest in chronic kidney disease and how did it involve into epidemiological studies?

I was working in heart diseases in the 1980s, when Paul Whelton made me aware that the epidemiology of kidney disease was really just beginning. I started getting involved in that in the early 1990s, and it turns out there were really fundamental things that had to be done.

By 2002, I was the vice-chairman of a working group that was developing standardized criteria for chronic kidney disease. We defined the broader range of kidney disease in the population and the 2007 JAMA paper is an update of the trends for that.

  Why do you think the epidemiology of kidney disease was just beginning in the 1980s, or roughly 20-30 years behind heart disease epidemiologies?

Until then, nephrologists were focused on doing dialysis, which is an amazing technology that keeps people from dying and was a technological advancement in the 1950s and 1960s. That was the core of the discipline, but that's really about the sickest people. It's like looking at heart disease and focusing only on heart failure, while saying, "Well, heart attacks, they happen early and they're kind of hard to track."

Still, the number of people on dialysis has grown exponentially in the last 40 years. Now there's half a million people on dialysis in the US, but that's only the tip of the iceberg for chronic kidney disease. Those are the most severe cases.

Another problem is that because kidney disease is less common than heart disease, if we want to do a prospective cohort study, we need the cohort to be larger. But the less common the disease, the less funding there is. So it's hard to do the larger cohort, because you can't get the money.

It turns out to be no coincidence that people like me came into the field from studying chronic heart disease, because the cohorts we had built for heart disease, the bigger ones, could also tell us about kidney disease. So this national effort in learning about heart disease can reap additional dividends in learning about kidney disease, particularly since much of kidney disease has a vascular basis.

  What cohorts did you use for your highly cited 2007 JAMA paper?

That paper is about prevalence of chronic kidney disease, and the prevalence is best estimated from the National Health and Nutrition Surveys (NHANES). We used NHANES 3 as the baseline. That ran from 1988 to 1994. And then we used NHANES 1999-2004 as the follow-up data a decade later.

  How did the prevalence change between the two surveys?

What we found was that the prevalence of chronic kidney disease, which was already high in our NHANES 3 work, was actually increasing over the subsequent decade. It also turns out that there are methodological nuances that require careful calibration of creatine. Depending exactly how you do that calibration, the rise we saw could be somewhere between a large rise and a small rise.

"Chronic kidney disease is complex enough that it's not going to be a one-pill intervention." Photo credit: Keith Weller.

There seems to be a rise either way, both in the prevalence of low kidney function, estimated from high creatine, and from high albumin in the urine, which is an indicator of early kidney damage. Both of those were increasing.

  How do you explain that increase?

The increase in the prevalence of albuminuria can be explained by the increasing prevalence of diabetes. That was the biggest factor. Together we looked at diabetes, obesity, hypertension, and age and demographic distribution of the population, minorities as well. African-Americans, for instance, have more albuminuria.

So the distribution of albuminuria can be explained, although that doesn't mean it's not important. If we have more diabetes, then we're going to have more kidney disease. But that doesn't mean it's not a problem. The increasing prevalence of low kidney function—signified by high levels of creatine—we can explain some of that, but not all of it.

  Would you consider the creatine calibration issue to be the most challenging aspect of the research?

Yes, that was the hardest part. I've been involved in that since the late 1990s. When we got our very first estimates, the assay values seemed too high to be consistent with what we thought was reasonable. So we got permission to get specimens from the freezer and we analyzed them and compared them to what we'd get with current laboratory methods.

We also worked with NIST, the National Institute of Standards and Technology, to get them to assign a value to a reference sample, and then we measured that reference sample using what we thought was a very good method—an enzymatic creatine method—and we then compared that enzymatic method on several hundred samples frozen from both the NHANES surveys. We got frozen specimens and again recalibrated the NHANES survey assays.

It turns out that if you look carefully, any estimates over time are hard to get consistent. The advantage we had is we tested samples from both surveys at once, so we were calibrating both of them at the same time. The results should be as comparable as anybody can get them, but even then small differences could remain—and these are the nuances in this kind of research—that's why we did a conservative trend analysis as well.

On a graph, the mean creatine level in the population goes up as well as the tail of those people with the highest creatine levels and low kidney function. What if the change in the mean wasn't the whole population shifting, but a statistical artifact? What if we shifted that down, what's left? It turns out what's left is about half of what we had seen before.

So the unadjusted trend would have been a prevalence of low GFR—glomerular filtration rate—with an odds ratio of 1.47. The conservative trend ratio has that down at 1.17. I worked on that for two years wanting to make sure we had those numbers as right as possible.

  What do you see as the major trends in kidney disease research now that it's well-established and better-funded?

There's been a big trend in the literature to define the full range of outcomes of kidney disease. In the last decade that has gotten increasing recognition. Early reports on chronic kidney disease emphasized some outcomes, but there's been recognition that the ranges of outcome are much wider than we thought.

The most obvious outcome is kidney failure and going on dialysis, but that's still relatively infrequent, which is a good thing. But chronic kidney disease patients, even those not on dialysis, die more frequently than people without kidney disease. Part of that is that kidney disease is correlated with heart disease, diabetes, hypertension, and stroke. Some of that is a marker; some might be a cause. Teasing that out is quite difficult.

  If you prevent the complications of kidney disease, do you prevent or delay the deaths?

One of the things we've looked at is kidney disease anemia—low hematocrit (a low red cell count) caused by kidney disease. We hoped that correcting anemia would undo some of the complications of kidney disease, but the recent clinical trials taking that as a strategy have been disappointing.

If you raise hematocrit all the way to normal, you get an increase in strokes. So hematocrit is a complicated variable to correct, because of the side effects. It could be helpful if we protect from some of the other metabolic complications of kidney disease, including abnormalities of calcium and phosphate. And kidney disease clearly aggregates with hypertension, so treatment of hypertension is an incredibly important mainstay of preventing further complications. Treatment of diabetes will obviously be helpful, because kidney disease is a microvascular complication of diabetes.

We still need a lot of clinical trials to test all these strategies. We're still very much where hypertension and hypercholesterolemia were in the 1970s, in that the biggest trials are still yet to come for a lot of these strategies. And we still have to fully define the problem before we can define all the solutions.

  What other aspects of the problem remain to be defined?

There are now articles by many of my colleagues looking at the wider range of complications, from heart disease and kidney failure to acute kidney injury and the complications of drug toxicity and what's called contrast toxicity. When people get a CT scan or a coronary angiogram, they usually get contrast to make the imaging better, but many of those contrast agents are toxic to the kidney. So that's a known complication, but it hasn't been completely quantified yet as to how many people have that and how severe a complication it is.

Infections are also a complication in patients with kidney disease. The immune system is somewhat compromised. There are some interesting articles about the higher rates of pneumonia and the higher rates of mortality for pneumonia in patients with kidney disease.

Another unfortunate problem we're dealing with is that patients with kidney disease seem to be at elevated risk of morbidity and mortality but they very frequently receive less treatment than the average patient. I think that's partially explained by these patients being of a lower socioeconomic status, and it's partly because of the physicians' concerns for complications.

"Now there's half a million people on dialysis in the US, but that's only the tip of the iceberg for chronic kidney disease."

It's also partly because some of the original clinical trials tended to exclude people with kidney disease because the investigators were worried about complications. So we don't have as much evidence for these highest-risk patients and they're getting the least treatment. That in turn elevates their risk even more.

  Is this a common problem with chronic kidney disease—that patients don't get the treatment they need?

There's been a wave of papers recently discussing that, documenting levels of treatment and of awareness of patients with kidney disease. In our 2007 JAMA paper, we did a little of this.

We pointed out that the awareness of people who had weak or failing kidneys in 1999 to 2004 was low. Those with stage 3 kidney failure—weak or failing kidneys—only 11% of the men and 5% of the women were aware of it. If they had albuminuria on top of that, the awareness rose to 23%. And if they were at stage 4, which is severe kidney disease, the awareness was still only 4%. That's the stage right before dialysis, where three-fourths or more of kidney function is lost. Still, less than half of them reported knowing having weak and failing kidneys.

Other papers showing that patients with kidney disease are often under-treated are very important since they indicate that unfortunately often we are doing just the wrong thing—treating patients at high risk less rather than more.

  What do you think explains the increase in chronic kidney disease that you reported in 2007?

In terms of protein in the urine, albuminuria, we saw an 18% increase between the two surveys. When we adjusted for the older age of the population, for sex, race, diagnosed hypertension and diabetes, and higher BMI over time, that increase becomes only 3%, and it's no longer statistically significant. So almost all is explained by these other factors with the obesity and diabetes epidemic being the dominant factor.

  What do you think the causal connection is between diabetes and higher BMI and kidney disease?

Some of the causal connections are very clear. Obesity clearly causes diabetes, and since we've had an obesity epidemic, that explains the subsequent diabetes epidemic. Diabetes and hyperglycemia clearly cause what's called microvascular disease, and kidney disease is one of those microvascular diseases.

So diabetes is the leading cause of people being on dialysis, and diabetics develop albuminuria. That's been known for a long time. In the clinical trials, when we improve diabetes control, it clearly reduces the level of albuminuria.

In some sense, part of the impetus for that 2007 paper was this idea, given the fact that we're seeing a diabetes epidemic, are we seeing an increase in the prevalence of kidney disease? And we are.

The picture is quite complicated, though, because kidney failure itself increased exponentially for a number of decades. It's still increasing, but now a lot of the increase is driven by the aging population. If we adjust for the demographic trend of the last few years, the adjusted rates of kidney failure and dialysis have flattened out.

This could be due to improved diabetes and hypertension treatment. But it's only been a few years. It's not clear yet whether the increase in the early stages of the disease that we're seeing will lead to a further increase in dialysis rates as well.

After albuminuria appears, it typically takes two decades before you end up on dialysis. So it will take another decade before we know the full consequences of the diabetes epidemic in the 1990s.

  If we lived in an ideal world and you had unlimited resources to do your research, what studies would you do that you can't do now?

I would do randomized trials of comprehensive interventions to improve the care of chronic kidney disease patients. Chronic kidney disease is complex enough that it's not going to be a one-pill intervention. We were lucky with heart disease. If statins knock cholesterol low enough you get an amazing effect. We have ACE inhibitors that are incredibly good for kidney disease, but that's just one step. We're going to need more. There are a lot of treatments that are actually available but they're not necessarily implicated.

One of the sad facts of public health and epidemiology is that if we only did the things we know how to do—if we got all hypertension under control, for example—we could make major strides. If we got diabetes under reasonable control, if we had glycemia controlled, and potentially some physical activity, that would do much better.

I'm a big believer in direct lifestyle interventions, but nobody can patent them. If you discover that doing all these things is good for you, it's hard to capitalize on that. If I had unlimited resources, I would test pretty intensive interventions in chronic kidney disease to see whether we can reduce the progression at all stages.

It would have to be somewhat tailored to the stage, so we would start at the earliest stages of diabetes and hypertension. We would treat those, and use ACE inhibitors to lower proteinuria, and potentially test a number of other things. It would have to be done one at a time, or together.

At later stages, when there are more complications, we'd have to treat the complications to see if we can decrease the progression to dialysis; if we can decrease heart attacks and mortality. We have some trials going for those kinds of interventions, but some are quite small and they're not very comprehensive.

Josef Coresh, M.D., Ph.D.
Johns Hopkins Bloomberg School of Public Health
Baltimore, MD, USA

Josef Coresh's current most-cited paper in Essential Science Indicators, with 854 cites:

Coresh J, et al., "Prevalence of chronic kidney disease and decreased kidney function in the adult US population: Third National Health and Nutrition Examination Survey," Amer. J. Kidney Dis. 41(1): 1-12, January 2003. Source: Essential Science Indicators from Clarivate.

Additional information:

Note: this interview pertains the to the paper, Coresh J, et al., "Prevalence of chronic kidney disease in the United States," JAMA-J. Am. Med. Assn. 298(17): 2038-47, 7 November 2007, with 355 cites.

KEYWORDS: CHRONIC KIDNEY DISEASE, HEART DISEASES, DIALYSIS, PREVALENCE, NHANES, CREATINE, KIDNEY DAMAGE, ALBUMINURIA, DIABETES, HYPERTENSION, AGE, DEMOGRAPHICS, GLOMERULAR FILTRATION RATE, OUTCOMES, KIDNEY FAILURE, STROKE, MARKER, MORTALITY, KIDNEY DISEASE ANEMIA, HEMATOCRIT, ACUTE KIDNEY INJURY, DRUG TOXICITY, CONTRAST TOXICITY, INFECTIONS, SOCIOECONOMIC STATUS, TREATMENT LEVELS, CAUSAL CONNECTIONS, LIFESTYLE INTERVENTIONS.