THE ROLE OF URIC ACID IN THE PROGRESSION OF CKD Mehmet Kanbay, Istanbul, Turkey

Transcription

1 THE ROLE OF URIC ACID IN THE PROGRESSION OF CKD Mehmet Kanbay, Istanbul, Turkey Chairs: Gerjan Navis, Groningen, The Netherlands Kamil Serdengecti, Istanbul, Turkey Dr. M. Kanbay Division of Nephrology Department of Medicine Istanbul Medeniyet University School of Medicine Istanbul, Turkey Slide 1 Dear Chairs. Slide 2

2 As you all know, uric acid may cause kidney disease in three forms by causing nephrolithiasis, by precipitating in tubules mostly seen in malignancy and by causing some metabolic changes, after that it may cause progression of kidney disease. My talk will focus on this, first I will discuss how uric acid may cause the progression of kidney disease and whether it has a role in the development of hypertension and the last part of my talk will focus on whether lowering uric acid therapy should be a target therapy for CKD or not. Slide 3 Uric acid is an end product of purine, it occurs by xanthine oxidoreductase enzyme, some factors may increase uric acid levels in CKD. These are reduced GFR, diuretic use, increased renal vascular incidence and co-existence of insulin resistance also. Slide 4

3 We still do not know which one is the chicken and which one is the egg. There are two hypotheses. Slide 5 Really uric acid may have a role in the development of cardiovascular disease, CKD, and hypertension

4 Slide 6 or may not have a role in the development of cardiovascular disease, CKD, hypertension but might be associated. Slide 7

5 Here one of the most important difficulties is to relate uric acid, as a pathogenic factor, in hypertension, cardiovascular disease, CKD is the abundance of other potential confounders. Slide 8

6 But if we show an association between uric acid levels and hypertension in observational studies, after that, if we show it in clinical basic experimental studies that high uric acid may cause increased blood pressure, may have a role in the progression of CKD and whether if it causes some hemodynamic changes especially in the kidney. Also in experimental studies if it is shown the beneficial effect of lowering uric acid and if proven at the end of this research in human studies, we may say that high uric acid levels might have a role or is an independent factor for hypertension, cardiovascular disease and also for CKD. Slide 9 In this review, we included all studies with long-term follow-up and patients with this study higher than 100. Slide 10

7 As you see here, in almost all studies showed that high uric acid level predicts the development of hypertension in the long-term follow-up even after adjusted for well-known established risk factors for hypertension such as age, BMI, family history, and alcohol intake. Slide 11 A recent meta-analysis investigated this association, they included 18 prospective studies, more than 55,000 subjects and they showed an independent risk factor for development of hypertension. They also found that the overall risk for incident hypertension increased 13% per 1 mg/dl increase in serum uric acid levels. Slide 12

8 So, in the light of this study we may speculate that baseline high uric acid levels might predict the development of hypertension. Slide 13 What about the association between uric acid level and the kidney disease progression? Slide 14

9 Yes, some big studies say that high uric acid level might be an independent risk factor for kidney disease progression. Slide 15 However, some other big studies say that no, it might be associated but not independent from other established risk factors. So, there are contradictory results here. Slide 16

10 As you all know, at the beginning of the 19th century the prevalence of hypertension was less than 10%. Nowadays it is higher than 30%. In the same line as the other Slide 17 is that cardiac partner, we know it well, uric acid level is going up decade after decade

11 because of this some epidemiologists speculate that the higher uric acid level might have an additional risk for the increased incidence of hypertension. Slide 18 From the USA, Daniel Feig and Richard Johnson did a study, they included 125 adolescent population with hypertension. They aimed to look at the association between uric acid level and primary or essential hypertension. Slide 19

12 They showed that patients with primary hypertension have significantly higher uric acid levels compared to secondary hypertension, white coat hypertension and the control group. Slide 20 Another study from our group, we investigated the association between the diurnal blood pressure variation and uric acid level and they included 112 newly diagnosed primary hypertensive subjects. We performed in all subjects ABPM measurements Slide 21

13 and we showed that if patients have primary hypertension, they significantly have higher uric acids levels. It is also true for CRP levels. If these hypertensive subjects are non-dippers, they also have significantly higher uric acid levels, CRP levels compared to dipper hypertensive subjects. Slide 22 Also we showed that uric acid also has a positive correlation between CRP levels so we may also speculate that in the light of this study high uric acid levels might have a role also in the development of high inflammation. Slide 23

14 What about the role of uric acid in kidney disease? I'll first mentioned some experimental studies and then clinical studies. Slide 24 As I mentioned before uric acid is an end product of purine. In other mammals, there is an enzyme that degrades uric acid to Allantoin by inhibiting this enzyme with Oxonic acid and rats become hyperuricemic. Slide 25

15 Firstly, Sánchez-Lozada from Florida showed that high uric acid increases glomerular pressure and if these are treated with allopurinol, glomerular pressure becomes normal. Slide 26 In another study from the same group, they also showed that high uric acid level increases glomerular size in rats and if they're treated with allopurinol, also glomerular size becomes normal. Slide 27

16 Another study showed that hyperuricemic rats' glomerulus become sclerotic after several weeks. Slide 28 This is very important study by Kang they investigated the role of uric acid in kidney disease progression. They had four groups; one sham, one CKD group, one hyperuricemic CKD group and the other one treated with allopurinol.

17 Slide 29 They showed that the rats with hyperuricemia have significantly higher systolic blood pressure, higher creatinine levels, higher proteinuria and these rats have mostly higher glomerulosclerosis. But if these rats treated with allopurinol, as you see here, there are significant improvements in all four parameters. Slide 30

18 Also high uric acid increases renin expression, also increases renin release. If these rats treated with allopurinol expression and release of renin decreases Slide 31 and also increases oxidative stress, inflammation, angiotensin 2 levels Slide 32

19 and at the same time also decreases NO levels. Slide 33 Also from Richard Johnson's group, they did a study, they showed that high uric acid level causes an increased blood pressure in rat studies. If these rats treated with allopurinol, as you see here, blood pressure going down and down. Slide 34

20 So in the light of these experimental studies we may speculate that high uric acid may have a role in the development of hypertension and chronic kidney disease progression. What about clinical studies? In this study from our group, we investigated the effect of treatment of hyperuricemia with allopurinol on blood pressure, kidney function and proteinuria in patients with normal kidney function. Slide 35 They included 48 hyperuricemic and 21 normal uricemic patients and they followed all subjects for 3 months. Slide 36

21 In the end Slide 37 as you see here, there isn't any significant change in the control group. Slide 38

22 However, if you look at the allopurinol group, you can see that there is a significant improvement in kidney function, CRP levels and also in blood pressure. Slide 39 Another study from Spain, this is a very important and interesting study. Slide 40

23 They aimed to look at the effect of allopurinol on kidney disease progression, cardiovascular events and the rate of hospitalization. They had 113 CKD subjects with stage 3 and they treated 50 of these patients with allopurinol, others recruited as control group. For baseline parameters, there isn't any significant difference between the two groups. Slide 41

24 You can see here Slide 42 that after 24 months follow-up in the control group you can see the decrease in GFR values although it is not significant. But in the allopurinol group you can see an increase even if it is not significant, you can see the decrease in GFR values in the control group, you can see an increase in the allopurinol group. Slide 43

25 They compared the delta change between two groups and it becomes significant. What about cardiovascular events? Slide 44 In the allopurinol treated group, the number of the cardiovascular event is significantly lower compared to the control group. Slide 45

26 In the light of this study, we may conclude that allopurinol treatment slows the progression of kidney disease, decreases cardiovascular events and also decreases inflammation in patients with stage 3. Slide 46 Another in an interesting study form Daniel Feig form Texas, they looked at the effect of allopurinol on blood pressure in a newly diagnosed essential hypertensive subject. Slide 47

27 This is a randomized double-blinded placebo controlled design. They had 30 children, all were pharmacologically naïve Slide 48 and in the end in subjects whose uric acid levels was below 5 mg/dl in these subjects 86% of these subjects became normotensive without any antihypertensive treatment. However, in the control group only one subject became normotensive. Slide 49

28 Also there is a meta-analysis published in the journal of clinical hypertension. They concluded 10 studies and they looked at the effect of allopurinol treatment Slide 50 on blood pressure and you can see here, that allopurinol treatment has a beneficial effect on lowering the systolic blood pressure as well. Slide 51

29 Also allopurinol treatment has a beneficial effect on endothelial function in many of the studies. So also it has a beneficial effect on endothelial function also. Slide 52 In summary, high uric acid increases angiotensin 2 levels, decreases NO levels, increases

30 oxidative stress mostly by NADPH oxidase activity and also it causes some muscular smooth muscle cell changes. In the end it causes microvascular disease and because of this hypertension may develop. So if --- of high uric acid level before it causes micro muscular disease we may postpone the development of hypertension or prevent the development of hypertension also we may have a beneficial or additional effect on kidney disease progression. Slide 53 Also hyperuricemia has adverse effects on the cardiovascular system by increasing the activation of the renin angiotensin system, it also causes cardiovascular smooth muscle cell proliferation and decreases NO levels and also has some adverse effects on brain. Also as I showed before treatment of hyperuricemia has beneficial effects on blood pressure, kidney function, inflammation and endothelial function. Slide 54

31 So hyperuricemia is an independent risk factor or might be an independent risk factor for the development of hypertension, might have a role in kidney disease progression. We still do not know, hyperuricemia might be a prognostic marker like CRP or might be a pathogenic factor for this disease, we still do not know. Also uric acid might be a strong surrogate marker to predict the development of future hypertension and lowering uric acid agents might be defined as a new antihypertensive or cardiorenal protective drug. Also in the light of these studies, we may speculate that hyperuricemia might be a new cardiorenal toxin. Slide 55 Which populations should we treat? We still do not know the correct answer to this. But in at risk populations uric acid lowering therapies might be associated with lower blood pressure, Slide 56

32 lower rate of GFR loss and reduce the rate of the development of cardiovascular events. But do not forget we do not have enough evidence to recommend to treat hyperuricemic patients. Because these studies are small studies the quality of these studies is moderate, the followup period relatively short and because of this we still need strong well-designed with longterm follow-up studies. Slide 57 Thank you for your attention. Slide 58

33 Chairman: Thank you doctor Kanbay for a beautiful overview. Question: In chronic kidney disease patients with non-symptomatic hyperuricemia, what's your recommended uric acid level above which we have to treat hyperuricemia? Prof. Kanbay: We still do not know the correct answer to this. In my opinion, one measurement of uric acid level is not enough to give a decision to whether these patients are hyperuricemic or not. In the current knowledge the indications for treatment of hyperuricemia is higher than 10. But in my clinical practice mostly I have treated patients higher than 8 but this is my opinion. Question: I have an additional question for you. Let's say uric acid is mainly a reason for concern in kidney patients and we have a lot of questions on that. In proteinuric patients, at least, we have to reduce dietary sodium to get the proteinuria down or RAS blockade and what happens is that the uric acid goes up very much. Often gout is something that prevents me from achieving adequate volume control in the patients. Could you comment on that? Prof. Kanbay: In my opinion, there might be a threshold for limiting the sodium level. We do not know after which level sodium restriction causes an increase in uric acid levels. We do basic research and also clinical research and we still do not know the correct answer to your question. But in my opinion, sodium restriction should be the most important part because we have enough evidence that high sodium level is more dangerous than uric acid level so we may restrict. But in my clinical practice, mostly I don't see too much hyperuricemia after sodium restriction. It causes slight increases. Chairman: Ok thank you. Well then, if there are no more questions we thank again the speakers and also the audience for their participation and good luck for the rest of the congress. Thank you.