Predicting Kidney Disease -- Read the Urine


This article chronicles a very interesting discourse between two physicians - Dr. Henry Black and Dr. Lynda Szcech, published online in the April 01, 2011 edition of Medscape Internal Medicine. Dr. Henry Black is a Clinical Professor of Internal Medicine at New York University School of Medicine, and also the immediate past President of The American Society of Hypertension. He is a former nephrologist, in the sense that he no longer practices nephrology actively. Dr. Lynda Szczech is currently a Consultant nephrologist at Duke University.

Basically, they discussed recent trials in hypertension and nephrology, particularly some new observations and some new things coming. And how practicing physicians can apply such to their own day-to-day patient care. I initially intended to edit this very interesting discourse, but finally decided to publish the most relevant parts of it as it is on Medscape so as not to tamper with the flavor (meant for physicians). Happy reading!

Henry R. Black, MD: I'd like to begin with the AASK trial, which was the African American Study of Kidney disease. It was a 5-year trial comparing individuals with renal disease who didn't develop it from diabetes. This is an important thing to remember because this was nondiabetic renal disease. The comparison was to try to get people to 2 different goals, under 120 and under 140 systolic.

That's not exactly what the AASK investigators did. They used mean blood pressure, which is something that nephrologists do. So it was a mean 107 or mean of 92, which calculates to about 120/80 or 140/90. They compared 3 different treatment arms, one with the calcium channel blocker Amlodipine, one with the beta-blocker Metoprolol, and finally with the ACE [angiotensin-converting enzyme] inhibitor Ramipril.

Now the important conclusions were with those with proteinuria, especially in the amlodipine group, which was stopped early because there seemed to be problems. The other 2 groups went on with no difference. To many people's surprise, there was no difference in outcomes whether it was aggressive treatment, that is down to a mean blood pressure of 92, or less aggressively with a mean blood pressure of 107.

Relevance to the nephrology community

Lynda A. Szczech, MD: Well, I think, as in many trials, it was a little disappointing at the time when it first came out. I believe those results were published in 2002. Does that sound right?

Dr. Black: Maybe a little later than that but a little while ago.

Dr. Szczech: It was counterintuitive. How could lowering blood pressure not slow the progression of kidney disease?

Dr. Black: We thought the lower the better, didn't we?

Dr. Szczech: Right, of course. I mean you live by intention to treat. You die by intention to treat, and that's the trial's perspective. The story continues to evolve, as you know, with the most recent New England Journal of Medicine paper.

Dr. Black: Well, tell me about that. What did that show?

Dr. Szczech: In September, the cohort results were published in addition to the trial results. The AASK trial, of course, continued to follow patients for a period more than 5 years following completion of the trial, in which everyone was treated to the same standard of care, which is 130/80 or below. The New England Journal of Medicine paper combined the trial results with the cohort results and did an interesting thing where they subgrouped on clinically relevant parameters.

The most notable parameter of course, which you mentioned, was proteinuria. It gets into the very complex world that nephrology is becoming in terms of life not being about just glomerular filtration rate (GFR) but stratifying risk based on the complicated mix of the 2 parameters: GFR and proteinuria.

So what did it show? It showed -- not definitively but very nicely in this subgroup analysis --- that a reduction in blood pressure may benefit those patients with proteinuria. They stratified based on 220 mg or greater because I think that was the median proteinuria. Blood pressure reduction may be beneficial in those people with greater proteinuria. It may not be as beneficial or doesn't seem to cause a positive effect in those people with limited proteinuria.

Dr. Black: So now we have 10-year follow-up instead of 5. Some people may say, well, if you have 15 you might see it. Do you think that's a reasonable idea?

Dr. Szczech: I think that there's a lot that goes into measuring kidney function. There's the normal oscillation of kidney function over time. There are differences in the etiologies of kidney function and differences in rates of progression. So, given that this was one of the first trials of its kind, it did its best to power itself to find a difference but just didn't have the power to see a difference, particularly in subgroups and particularly when they analyzed by intention to treat.

So the possibility that the first trial -- that first 5 years of follow-up -- might have been slightly underpowered I think is very reasonable. We have to, of course, guard against over-interpretation; that which can happen after the trial is said and done, because if everybody looks at that paper [on the subgroup analyses] in the September 2010 New England Journal of Medicine article, there's actually 1 component of the limited proteinuria group that actually did worse with the lower blood pressure goal.

Dr. Black: Could that have been by chance?

Dr. Szczech: It could happen by chance. But the odds of that 1 subgroup happening by chance and then the majority of the subanalyses in the proteinuria groups happening by chance are very limited. But it does pull into our awareness these retrospective analyses of subgroups and how we really need dedicated trials.

But I'm glad that you brought this up because it really gets at the bigger picture of the complexity of nephrology. I don't know if you were aware of The Lancet paper in May 2010 from the Chronic Kidney Disease (CKD) Prognosis Consortium. This was a group that was led by Andy Levey. and the whole consortium was funded by the National Kidney Foundation. It set out to understand what is beyond just creatinine clearance or GFR. How do we really use these measures to understand risk and progression?

It's really a very similar message to the AASK cohort continued analysis results. In this paper, which I encourage everybody to look at it because it has data on 1.5 million people, lesser GFR is, of course, bad. It's associated with increased all-cause mortality and increased cardiovascular mortality. But you have to stratify on the degree of proteinuria. It brings into light how significant proteinuria is as a risk factor predictor irrespective of GFR.

Dr. Black: But AASK used people who didn't have diabetic renal disease. Did The Lancet study include people with any form of renal disease?

Dr. Szczech: It was a conglomeration, a meta-analysis of several cohorts, and many of them are population based. Some of them are trials, but many of them are population-based cohorts. It's about as generalizable as you can really be.

Dr. Black: But are you confident that putting people in databases and observational studies together with people in trials has the impact of a well-done large-enough prospective trial?

Dr. Szczech: Well, I don't know that The Lancet paper really gives us a sense for blood pressure goal as much as it really sort of underscores what AASK is telling us. If AASK is telling us that 1 size may not fit all for people with lesser GFR then we need to look at people with proteinuria differently from people without proteinuria.

The CKD Prognosis Consortium paper looks at people with lesser GFR and reiterates that message in terms of the correlation between the presence of eGFR being lower in outcome and that proteinuria makes just about any eGFR more deadly, if you will. It makes it worse in terms of its association with morbidity and mortality.

Those people that calculate low, like my father who calculates at 60 and has absolutely gorgeous kidneys -- just because he's older; he's had a couple of birthdays. With his normal albumin excretion, his increased risk associated with an eGFR of 60 is a hair, not really significant.

Dr. Black: Well, how happy are you with the eGFR calculations? Now [GFRs that AASK used were] very, very accurately measured. We now use eGFRs and we get those back from the lab. Are they really reliable enough to make decisions on? Or should we not worry so much about them, but rather do albumin creatinine ratios or 24-hour urines for albumin or morning urines or some other way to assess proteinuria?

Dr. Szczech: I love this discussion because, in terms of research, the misclassification that happens with eGFR just calculated from serum creatinine is tremendous and makes it problematic. But in terms of real life, the oscillation in serum creatinine and the oscillation in eGFR is what it is. It's cheap and easy to measure. We have to really drive home to people who are using this measure -- nephrologists, primary care physicians, cardiologists, endocrinologists, you name it -- that there's going to be a roller coaster of serum creatinine. You can compare value with inpatients and look for trends. So I'm glad that you brought up that point.

Dr. Black: How many would you do before you decided you really knew what it was?

Dr. Szczech: Well, 2 points define a line. On the other hand, it might not be a line with a direction that is really indicative of underlying disease prognosis. I think that the way to answer that question is probably to look at the subgroup and think about the guidelines, the clinical practice guidelines that have been developed for that subgroup, because those guidelines are developed with that range in mind.

The standard of care I believe in someone on hydrochlorothiazide is to get electrolytes twice a year. In someone with HIV, the standard of care is somewhere between once a year and twice a year. As eGFR declines, if you look at the National Kidney Foundation's guidelines, the frequency with which you should check should be increased.

What we really need to do is to bring into the standard of care the routine practice of measuring labs in people who are at risk for kidney disease. And this seems like a no-brainer.

The real message for physicians

Dr. Black: The real message here, to me at least, is that, when we have a series of techniques we can use or series of treatments we can use, the better we can stratify people's risk, the better we're going to do. We'll treat the people who need to be treated aggressively and spare the people who don't need to be treated aggressively from the problems that come with treatment.

I just want to ask one quick question before we close. The Systolic Blood Pressure Intervention Trial (SPRINT) study, were you involved in that?

Dr. Szczech: Part of the motivation of that paper was based on our concern that we were labeling people like my father with a calculated lower eGFR without kidney disease as having kidney disease. Part of the motivation behind that analysis was to be able to look at people within that stage II kidney disease area and really see how to isolate those people with stage II kidney disease at greater risk.

Dr. Black: So let me ask you, what is the primary care physician to do when faced with someone with an eGFR of 63 or 64? Repeated it's 58. Repeated again it's 61. What should they do?

Dr. Szczech: Look at the urine. The urine is gold. It's not just yellow, but it's pure liquid gold. It tells you exactly what you need to know about the vasculature. I'll take this opportunity to use something that I'm hoping is going to become a cliché. That when you look into the eyes of someone with diabetes and you see retinopathy, you think, "Oh, my gosh, that person's blood vessels! They're not so healthy. And I can see that in their retina." I would like the primary care physician to look at the urine for the presence of albuminuria. Remember that the last cell that that urine goes through is the endothelial cell, and they see albuminuria and go, "Oh, my gosh; that person's blood vessels -- they're not as nice as they could be."

Dr. Black: What do you recommend they measure and how should they do it?

Dr. Szczech: I think that the easiest way to do this is with a spot specimen, not a 24-hour urine collection because everybody hates the job. No one wants to put it in their refrigerator. But [take] a random specimen -- it doesn't have to be first in the morning -- for albumin and creatinine, and then divide the two. The ratio of the two is roughly the number of milligrams of albumin they put out for 24 hours. That is probably the easiest way to do it. The frequency depends on the subgroup. People with diabetes and more comorbid factors probably need to have it done more often.

Dr. Black: But what number do you use to worry about?

Dr. Szczech: Oh, that's a beautiful question. We're playing volleyball. You just set me up for the spike.

Dr. Black: That was the idea.

Dr. Szczech: We used to think that 31 mg per day was bad. So, if you put out 31 mg per day of albumin, you were in bad shape. But 29, oh, you were in good shape.

Dr. Black: But that's a 24-hour urine. I'm talking about the spot urine you recommended. What number do you act on?

Dr. Szczech: The ratio roughly correlates to the number of milligrams you put out for 24 hours. So that's why you can go back and forth when you're talking about it.

Dr. Black: So you look at the total amount of protein in that spot and the total amount of creatinine in that spot and then you infer how much it's going to be over a 24-hour period.

Dr. Szczech: Correct, correct. The epidemiologic data, which is really echoed in The Lancet May paper with the CKD Prognosis Consortium, really demonstrates that it's linear; that there's nothing magic about 30. That the lower the better and that 5 is better than 10 and 10 is better than 15.

Dr. Black: Well, one more question, since you're on that, because I think we've looked at this in trials. There was a time that colleagues of mine, and yours as well, wanted us to eliminate all albumin from the urine, even if that meant giving ACE inhibitors and angiotensin II receptor blockers (ARBs) and direct renin inhibitors and everything you could do. That's turned out not to work. In TRANSCEND, for example, and in ONTARGET, that, in fact, was done. So how do you reconcile those 2 ideas?

Dr. Szczech: I think albuminuria as a marker of badness vs confers the badness is probably what we're looking at here.

Dr. Black: So, just because there's a risk doesn't mean that we know the best way to apply benefit to get the risk to go away.

Dr. Szczech: Right. If someone were to find microalbuminuria or macroalbuminuria, trying to make it go away is definitely a good thing. But it's really just the tip of the iceberg as to what it is a marker of. It means cardiovascular risk, and that's the most important thing. So just focusing on making that number go away by ACE inhibitors ramping that dose up, ARBs ramping that dose up to the exclusion of vitamin D repletion, statins, and some of the other things that we know can lower cardiovascular risk is really to have your blinders on.

Dr. Black: Good. I want to thank you very much for allowing me to pick your brain. It's full of lots of goodies, and I appreciate your time.

Dr. Szczech: Oh, you're so kind. Thank you so much.

Also read: Low Bicarbonate Levels Linked to Early Death In Healthy Senior Citizens

1). Henry R. Black, Lynda A. Szczech. Predicting Kidney Disease -- Read the Urine. Medscape Cardiology. Medscape News and Perspectives 2011. Accessed 24 June 2011. Available here:

1 comment:

  1. summary here is that PROTEIN TRAFFIC ACROSS THE GLOMERULUS DAMAGES IT and contributes in no small way to glomerular damage.


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