Progressing to ESRD: Are All BP Goals the Same?
Progressing to ESRD: Are All BP Goals the Same?
George Bakris, MD: Hello. I'm Dr. George Bakris, Professor of Medicine and Director of the Hypertensive Diseases Center at the University of Chicago Pritzker School of Medicine in Chicago, Illinois. We are here today with Dr. Carmen Peralta, Assistant Professor of Medicine in the Section of Nephrology at the University of California, San Francisco, and we are going to discuss the level of blood pressure control and progression of kidney disease, specifically the importance of blood pressure goals. Should we be at < 130/80 as the current guidelines suggest or should we go to < 140/90 as some future guidelines are going to say? Carmen has some very nice data that have recently been published that will help us to understand this.
Carmen A. Peralta, MD: Thank you for having me. It's a pleasure to speak with you.
Dr. Bakris: It's my pleasure. Why don't you tell us a little bit about what the key program is and what you actually did in your study?
Dr. Peralta: Our main interest is in trying to understand the association between level of blood pressure and progression from chronic kidney disease to end-stage renal disease (ESRD). We used data from KEEP, the Kidney Early Evaluation Program. It is the largest screening program in the United States, and probably in the world, for kidney disease, sponsored by the National Kidney Foundation. KEEP has screening programs in 48 states and has screened about 160,000 people to date. They are screened for high-risk factors of kidney disease even though blood pressure is measured at the time of the screening. We attempted to understand the association between the level of blood pressure at the screening and the risk for progression to ESRD in this large cohort.
Dr. Bakris: What did you find? What were your results?
Dr. Peralta: We studied systolic and diastolic blood pressures separately, and what we found was that persons whose systolic blood pressure was between 130 and 140 mm Hg did not have any particular advantage compared with persons whose blood pressure was less than 130 when it comes to progression to ESRD. We did find that higher systolic blood pressure was indeed associated with higher risk for ESRD, but it appears that the risk starts at about 140.
Results for diastolic blood pressures were interesting. We found that if it was less than 90 mm Hg, if diastolic blood pressure was too low, there were somewhat higher rates of progression to ESRD. However, this was not statistically significant. What was also very interesting about the study is that because this represents people from the community who just walk into a screening, it was alarming to find that more than a third of persons who walked into a screening had very high levels of uncontrolled blood pressure, above 150 mm Hg systolic.
Dr. Bakris: This is interesting. I want to note 2 points about this study that I think are very important. I think nephrologists and other physicians do not have an appreciation for very low diastolic blood pressures and the consequences of that. Everybody talks about the J curve, but I think people are unclear about whether they are talking about blood pressure overall, diastolic, or systolic. It is very clear, both in the cardiology literature and the renal literature, that low diastolic pressures, especially levels below 60, are associated with worse outcomes. In the heart, it's pretty straightforward. Coronary perfusion is reduced, and especially if you have coronary disease, that is thought to be a link to something that isn't very good in terms of outcome. What do you think is going on as far as the kidney?
Dr. Peralta: That is a very important point. First, I must clarify that KEEP is another great venue in which to study that question. I think one of the things we must consider is what systolic and diastolic blood pressure represents. As you know, the arteries stiffen as one ages. I believe that this phenomenon of having a higher systolic blood pressure but a normal to lower diastolic blood pressure is a reflection of this stiffness. Multiple studies have shown that persons with chronic kidney disease are likely to have stiffer arteries than persons without chronic kidney disease. I think that makes it a lot more challenging. As to what is going on with the kidney that may make this low diastolic pressure harmful, I think there are probably multiple pathways, but one of them relates to the blood flow to the glomerulus and the wave that reaches the arterioles at the glomerular level. I think a low diastolic blood pressure may be a reflection of losing the ability to have very smooth oscillations that are sinusoidal. In fact, the oscillations become a peak-and-valley type of pressure into the kidney, which will then injure the small arterioles that are not capable of withstanding that sort of pressure wave.
Dr. Bakris: I agree with you. I think this is a mechanism that is greatly important and needs to be evaluated, certainly on a basic science level. One of the things you also looked at was pulse pressure. For cardiovascular outcomes, we know that pulse pressure doesn't add a lot more than systolic blood pressure does. But in this study, did people with the highest pulse pressure at baseline have a relatively greater progression to ESRD? Would somebody with a blood pressure of 160/70 do worse than somebody who is at 160/90?
Dr. Peralta: That's a great question. From our data, it appears that persons with higher pulse pressure were indeed at higher risk of developing ESRD. It's difficult to separate the concept of pulse pressure from the actual components that make the pulse pressure. When we adjust for systolic blood pressure in that model, pulse pressure still appears to be associated with higher risk, but it is no longer statistically significant. This is how I interpret those findings: It's not that pulse pressure is not important, but in the clinical setting, perhaps knowing the pulse pressure may not give you any additional information about that person's risk. However, I do believe that it is a representation of a person's physiology and that it should be taken into account. We have some other studies in persons with preserved glomerular filtration rates (GFRs). Looking at measures of both pulse pressure and elasticity by tonometry, we are finding that persons who have worse arterial elasticity or higher pulse pressures are at increased risk for progression and incident chronic kidney disease, even before their GFR reaches 60 mL/min/1.73m. I believe this is a crucial point that needs to be the topic of future research in nephrology.
Dr. Bakris: I fully agree with you. I want to share with you data that we published back in 2003 from the RENAAL study. We looked at pulse pressures at baseline and outcomes in people with diabetic nephropathy, and we found that the people with the highest pulse pressures fit with what you are talking about. We assumed that they were at highest risk, but it turns out that those people had the best outcome in terms of slowing progression to [ESRD] compared with people with better pulse pressures. It's not that people with lower pulse pressures didn't do as well, but statistically, if you had a wide pulse pressure, maybe you were at higher risk and the drug had a greater effect. They are not only at higher risk; they are the ones you really need to chase because they will have a better benefit.
Dr. Peralta: Certainly. That brings up a very good point that you mentioned, which is that in RENAAL, the patients had diabetic nephropathy. In KEEP, it was a mixed population. I happen to believe that the disease we call hypertension is not necessarily the same process in everyone. It's certainly reflected as a high number on a tool or sphygmomanometer, but in different persons it may actually be different processes and different alterations of the vasculature. I think pulse pressure is a clue to some type of disease in people in whom stiffness is a major component. In other persons, maybe it's less so. As you very well know from the ACCOMPLISH trial and other recently published studies, there are certain combinations of drugs that may result in the same lowering of blood pressure and also lower the stiffness, resulting in improved outcomes. That is still an open question, but for example, in kidney disease, we know that persons with proteinuria behave differently than persons without proteinuria. Not only is proteinuria a risk factor for progression in and of itself, but in randomized controlled trials (though the overall effect is null as far as tighter blood pressure), this subgroup of persons with proteinuria does benefit from lower blood pressure targets. I think that nephrology and the world of hypertension need to really start understanding that all hypertensive patients are not the same and that we need to start identifying clues to guide us to the type of treatment or goal that is appropriate for each patient. Proteinuria may be one of those, pulse pressure may be one of those, but it is still a major endeavor that has not been well studied in nephrology. I think that understanding these subgroups that may benefit from the lower thresholds or different drug combinations is a crucial point that we need to address.
Dr. Bakris: Absolutely on target. Just a few weeks ago at the American Society of Hypertension Meeting in New York, this was a major focus of controversy and debate. One of the things that came out of that meeting is that certain genes that affect collagen subtypes are clearly abnormal in some people, contributing to earlier vascular stiffness and more resistant blood pressure that is difficult to control. It really is a panoply of things that play a role, and they are definitely some of the early identifiers that give us a hint as to whether these people are going to do well. Do you have any final thoughts? I think we covered a number of things. Before I summarize them, I will give you the last word.
Dr. Peralta: I appreciate that. What I would like to say is just how important blood pressure is, not just in kidney disease but in general. I think there are a lot of other issues that we need to consider and think about in hypertension, understanding that it is not just in the setting of chronic kidney disease but in age groups as well -- what to do with the very young and what to do with the very old as these populations increase in the United States. I think what we discussed today about pulse pressure and proteinuria will probably end up being important clues in those extreme age groups to understanding who may actually benefit from treatment. I hope that the research community is open to the idea of understanding blood pressure on an individual level rather than making statements that are generalized to all.
Dr. Bakris: I very much appreciate that. I want to thank you for joining me. In short, you may be reading soon in guidelines that everybody should be below 140/90 and that it doesn't really matter what is going on. However, I think Carmen makes an excellent point, with which I agree, and that is that we still need to individualize treatment because there clearly are subgroups that do see a reasonable benefit if you get them below 130/80. I think we need to identify those groups and move in that direction. Clearly, this is a large investigational area. The National Kidney Foundation and many other groups are doing a lot of research in this area. There is a huge initiative from the National Institutes of Health and the National Institute of Diabetes and Digestive and Kidney Diseases in this area. Things are coming, so stay tuned. I want to thank you, Carmen, very much for sharing the data with us. I hope that the audience got a lot out of this and is understanding better some of the guidelines that will be coming down the pike. Thank you very much for joining us, and have a good day.
Dr. Peralta: Thank you.
George Bakris, MD: Hello. I'm Dr. George Bakris, Professor of Medicine and Director of the Hypertensive Diseases Center at the University of Chicago Pritzker School of Medicine in Chicago, Illinois. We are here today with Dr. Carmen Peralta, Assistant Professor of Medicine in the Section of Nephrology at the University of California, San Francisco, and we are going to discuss the level of blood pressure control and progression of kidney disease, specifically the importance of blood pressure goals. Should we be at < 130/80 as the current guidelines suggest or should we go to < 140/90 as some future guidelines are going to say? Carmen has some very nice data that have recently been published that will help us to understand this.
Carmen A. Peralta, MD: Thank you for having me. It's a pleasure to speak with you.
Dr. Bakris: It's my pleasure. Why don't you tell us a little bit about what the key program is and what you actually did in your study?
Dr. Peralta: Our main interest is in trying to understand the association between level of blood pressure and progression from chronic kidney disease to end-stage renal disease (ESRD). We used data from KEEP, the Kidney Early Evaluation Program. It is the largest screening program in the United States, and probably in the world, for kidney disease, sponsored by the National Kidney Foundation. KEEP has screening programs in 48 states and has screened about 160,000 people to date. They are screened for high-risk factors of kidney disease even though blood pressure is measured at the time of the screening. We attempted to understand the association between the level of blood pressure at the screening and the risk for progression to ESRD in this large cohort.
Dr. Bakris: What did you find? What were your results?
Dr. Peralta: We studied systolic and diastolic blood pressures separately, and what we found was that persons whose systolic blood pressure was between 130 and 140 mm Hg did not have any particular advantage compared with persons whose blood pressure was less than 130 when it comes to progression to ESRD. We did find that higher systolic blood pressure was indeed associated with higher risk for ESRD, but it appears that the risk starts at about 140.
Results for diastolic blood pressures were interesting. We found that if it was less than 90 mm Hg, if diastolic blood pressure was too low, there were somewhat higher rates of progression to ESRD. However, this was not statistically significant. What was also very interesting about the study is that because this represents people from the community who just walk into a screening, it was alarming to find that more than a third of persons who walked into a screening had very high levels of uncontrolled blood pressure, above 150 mm Hg systolic.
Dr. Bakris: This is interesting. I want to note 2 points about this study that I think are very important. I think nephrologists and other physicians do not have an appreciation for very low diastolic blood pressures and the consequences of that. Everybody talks about the J curve, but I think people are unclear about whether they are talking about blood pressure overall, diastolic, or systolic. It is very clear, both in the cardiology literature and the renal literature, that low diastolic pressures, especially levels below 60, are associated with worse outcomes. In the heart, it's pretty straightforward. Coronary perfusion is reduced, and especially if you have coronary disease, that is thought to be a link to something that isn't very good in terms of outcome. What do you think is going on as far as the kidney?
Dr. Peralta: That is a very important point. First, I must clarify that KEEP is another great venue in which to study that question. I think one of the things we must consider is what systolic and diastolic blood pressure represents. As you know, the arteries stiffen as one ages. I believe that this phenomenon of having a higher systolic blood pressure but a normal to lower diastolic blood pressure is a reflection of this stiffness. Multiple studies have shown that persons with chronic kidney disease are likely to have stiffer arteries than persons without chronic kidney disease. I think that makes it a lot more challenging. As to what is going on with the kidney that may make this low diastolic pressure harmful, I think there are probably multiple pathways, but one of them relates to the blood flow to the glomerulus and the wave that reaches the arterioles at the glomerular level. I think a low diastolic blood pressure may be a reflection of losing the ability to have very smooth oscillations that are sinusoidal. In fact, the oscillations become a peak-and-valley type of pressure into the kidney, which will then injure the small arterioles that are not capable of withstanding that sort of pressure wave.
Dr. Bakris: I agree with you. I think this is a mechanism that is greatly important and needs to be evaluated, certainly on a basic science level. One of the things you also looked at was pulse pressure. For cardiovascular outcomes, we know that pulse pressure doesn't add a lot more than systolic blood pressure does. But in this study, did people with the highest pulse pressure at baseline have a relatively greater progression to ESRD? Would somebody with a blood pressure of 160/70 do worse than somebody who is at 160/90?
Dr. Peralta: That's a great question. From our data, it appears that persons with higher pulse pressure were indeed at higher risk of developing ESRD. It's difficult to separate the concept of pulse pressure from the actual components that make the pulse pressure. When we adjust for systolic blood pressure in that model, pulse pressure still appears to be associated with higher risk, but it is no longer statistically significant. This is how I interpret those findings: It's not that pulse pressure is not important, but in the clinical setting, perhaps knowing the pulse pressure may not give you any additional information about that person's risk. However, I do believe that it is a representation of a person's physiology and that it should be taken into account. We have some other studies in persons with preserved glomerular filtration rates (GFRs). Looking at measures of both pulse pressure and elasticity by tonometry, we are finding that persons who have worse arterial elasticity or higher pulse pressures are at increased risk for progression and incident chronic kidney disease, even before their GFR reaches 60 mL/min/1.73m. I believe this is a crucial point that needs to be the topic of future research in nephrology.
Dr. Bakris: I fully agree with you. I want to share with you data that we published back in 2003 from the RENAAL study. We looked at pulse pressures at baseline and outcomes in people with diabetic nephropathy, and we found that the people with the highest pulse pressures fit with what you are talking about. We assumed that they were at highest risk, but it turns out that those people had the best outcome in terms of slowing progression to [ESRD] compared with people with better pulse pressures. It's not that people with lower pulse pressures didn't do as well, but statistically, if you had a wide pulse pressure, maybe you were at higher risk and the drug had a greater effect. They are not only at higher risk; they are the ones you really need to chase because they will have a better benefit.
Dr. Peralta: Certainly. That brings up a very good point that you mentioned, which is that in RENAAL, the patients had diabetic nephropathy. In KEEP, it was a mixed population. I happen to believe that the disease we call hypertension is not necessarily the same process in everyone. It's certainly reflected as a high number on a tool or sphygmomanometer, but in different persons it may actually be different processes and different alterations of the vasculature. I think pulse pressure is a clue to some type of disease in people in whom stiffness is a major component. In other persons, maybe it's less so. As you very well know from the ACCOMPLISH trial and other recently published studies, there are certain combinations of drugs that may result in the same lowering of blood pressure and also lower the stiffness, resulting in improved outcomes. That is still an open question, but for example, in kidney disease, we know that persons with proteinuria behave differently than persons without proteinuria. Not only is proteinuria a risk factor for progression in and of itself, but in randomized controlled trials (though the overall effect is null as far as tighter blood pressure), this subgroup of persons with proteinuria does benefit from lower blood pressure targets. I think that nephrology and the world of hypertension need to really start understanding that all hypertensive patients are not the same and that we need to start identifying clues to guide us to the type of treatment or goal that is appropriate for each patient. Proteinuria may be one of those, pulse pressure may be one of those, but it is still a major endeavor that has not been well studied in nephrology. I think that understanding these subgroups that may benefit from the lower thresholds or different drug combinations is a crucial point that we need to address.
Dr. Bakris: Absolutely on target. Just a few weeks ago at the American Society of Hypertension Meeting in New York, this was a major focus of controversy and debate. One of the things that came out of that meeting is that certain genes that affect collagen subtypes are clearly abnormal in some people, contributing to earlier vascular stiffness and more resistant blood pressure that is difficult to control. It really is a panoply of things that play a role, and they are definitely some of the early identifiers that give us a hint as to whether these people are going to do well. Do you have any final thoughts? I think we covered a number of things. Before I summarize them, I will give you the last word.
Dr. Peralta: I appreciate that. What I would like to say is just how important blood pressure is, not just in kidney disease but in general. I think there are a lot of other issues that we need to consider and think about in hypertension, understanding that it is not just in the setting of chronic kidney disease but in age groups as well -- what to do with the very young and what to do with the very old as these populations increase in the United States. I think what we discussed today about pulse pressure and proteinuria will probably end up being important clues in those extreme age groups to understanding who may actually benefit from treatment. I hope that the research community is open to the idea of understanding blood pressure on an individual level rather than making statements that are generalized to all.
Dr. Bakris: I very much appreciate that. I want to thank you for joining me. In short, you may be reading soon in guidelines that everybody should be below 140/90 and that it doesn't really matter what is going on. However, I think Carmen makes an excellent point, with which I agree, and that is that we still need to individualize treatment because there clearly are subgroups that do see a reasonable benefit if you get them below 130/80. I think we need to identify those groups and move in that direction. Clearly, this is a large investigational area. The National Kidney Foundation and many other groups are doing a lot of research in this area. There is a huge initiative from the National Institutes of Health and the National Institute of Diabetes and Digestive and Kidney Diseases in this area. Things are coming, so stay tuned. I want to thank you, Carmen, very much for sharing the data with us. I hope that the audience got a lot out of this and is understanding better some of the guidelines that will be coming down the pike. Thank you very much for joining us, and have a good day.
Dr. Peralta: Thank you.