Dr. Mehmet Kanbay Department of Medicine Division of Nephrology Istanbul Medeniyet University School of Medicine Istanbul, Turkey.

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van den Meiracker, Rotterdam, The Netherlands Claudia R.C. Van Roeyen, Aachen, Germany Dr.

1 The uric acid dilemma: causal risk factor for hypertension and CKD or mere bystander? Mehmet Kanbay, Istanbul, Turkey Chairs: Anton H. van den Meiracker, Rotterdam, The Netherlands Claudia R.C. Van Roeyen, Aachen, Germany Dr. Mehmet Kanbay Department of Medicine Division of Nephrology Istanbul Medeniyet University School of Medicine Istanbul, Turkey slide 1 Dear Chairs, dear colleagues. slide 2

2 In my talk, I will discuss how uric acid may be a risk factor for cardiovascular disease, kidney disease and hypertension. At the end of my talk, should we treat hyperuricemia or not? slide 3 As we know, uric acid may cause kidney disease in 3 forms by urate nephropathy, mostly seen in kidney disease with precipitates in tubules, mostly seen in malignancy and also by nephrolithiasis. slide 4

Uric acid is an end product of a high purine/protein diet and a high cell turnover and some factors may increase uric acid level in kidney disease, these are reduced GFR, diuretic

3 Uric acid is an end product of a high purine/protein diet and a high cell turnover and some factors may increase uric acid level in kidney disease, these are reduced GFR, diuretic use, increased renal vascular resistance and coexistence of insulin resistance also. slide 5 If you look at the nephronal handling of uric acid, almost 100% of uric acid is filtered from

slide 6 So, uric acid may cause kidney disease, hypertension or cardiovascular disease but uric acid may not cause cardiovascular disease, kidney disease and hypertension.

4 glomeruli and only 10% of uric acid is excreted from the urine. So, if you want to decrease uric acid levels, we should lower the synthesis and intake of uric acid from our diet. slide 6 So, uric acid may cause kidney disease, hypertension or cardiovascular disease but uric acid may not cause cardiovascular disease, kidney disease and hypertension. We still do not know which one is the chicken and which one is the egg. slide 7 Because here is one of the most important difficulties to relate uric acid as an independent pathogenic factor for these diseases is the abundance of other potential confounders which are associated with hypertension, cardiovascular disease and CKD also. slide 8

But if we show in observational studies an association between high uric acid levels and hypertension, kidney disease and cardiovascular disease.

disease and cardiac events and if you also prove it in human studies, we may say that uric acid is an independent risk factor for these diseases.

5 But if we show in observational studies an association between high uric acid levels and hypertension, kidney disease and cardiovascular disease. If we show it also in experimental studies and in the experimental studies if we show the beneficial effect of lowering uric acid levels in blood pressure, kidney disease and cardiac events and if you also prove it in human studies, we may say that uric acid is an independent risk factor for these diseases. slide 9 Many studies with long-term follow-up after adjustment for well-known risk factors for hypertension show that uric acid is an independent risk factor for the development of hypertension. slide 10

6 A recent meta-analysis investigated this. This study included 18 prospective studies with higher than subjects and showed that high uric acid levels increase the development of hypertension. slide 11

7 In this study, they showed that the overall risk for incident hypertension increases 13% per 1 mg/dl increase in serum uric acid level. slide 12 So, we may say that high uric acids levels predict the development of hypertension in the long term. slide 13 What about the association between the progression of kidney disease and uric acid level? Yes, some big studies say that uric acid is a risk factor for the progression of kidney disease even after adjustment for well-known risk factors for kidney disease progression. But some other studies say, no, there might be an association but uric acid may not be a risk factor for the progression of kidney diseases. slide 14

8 What about the prevalence of hyperuricemia in hypertension, CKD and cardiovascular disease? Many studies have shown that the prevalence of hyperuricemia is significantly high in patients with hypertension, CKD, diabetes and also cardiovascular disease patients. slide 15 In epidemiological studies, as we know the prevalence of hypertension is significantly going up. At the beginning of the 19th century, it was less than 10 but nowadays it is higher than 30. slide 16

Epidemiologists also look at what the mean uric acid change has been during these decades. They have also shown that the serum uric acid level is going up decade by decade.

slide 17 One of the studies from the population investigated the effect of uric acid level on the progression of kidney disease and they defined the CKD according to whether egfr is less than 60

9 Epidemiologists also look at what the mean uric acid change has been during these decades. They have also shown that the serum uric acid level is going up decade by decade. Because of this, epidemiologists speculate that high uric acid may be an answer for the increased prevalence of hypertension too. slide 17 One of the studies from the population investigated the effect of uric acid level on the progression of kidney disease and they defined the CKD according to whether egfr is less than 60 ml/min or serum creatinine levels for men 1.4 and for women 1.2 higher than this. In this study, there isn't any data regarding proteinuria or albuminuria and in this study they showed that high uric acid level is an independent risk factor for the progression of kidney disease even after well-known risk factors for CKD progression. slide 18

They divided the study population according to gender and also in two groups according to hyperuricemic

10 Another study from China looked at the effect of hyperuricemia on the development of new onset microalbuminuria. They divided the study population according to gender and also in two groups according to hyperuricemic and non-hyperuricemic group slide 19 and they showed that high uric acid predicts the development of microalbuminuria even after adjustment for well-known risk factors for microalbuminuria too. slide 20

In the same study, they divided the study population into three groups according to the serum uric acid level less than 5, between 5 and 7 and higher than 7.

11 In the same study, they divided the study population into three groups according to the serum uric acid level less than 5, between 5 and 7 and higher than 7. In the overall study population and even after dividing the study population according to gender, high uric acid is a risk factor for the development of microalbuminuria in the long-term follow-up. slide 21 In another study from the USA, Richard Johnson's group looked at the association between the primary hypertension and serum uric acid level in the adolescent population.

slide 22 They showed that if a patient has primary hypertension, these patients have significantly higher levels of uric acid level compared to subjects with secondary hypertension, cohort and

12 slide 22 They showed that if a patient has primary hypertension, these patients have significantly higher levels of uric acid level compared to subjects with secondary hypertension, cohort and control group. slide 23 In another study from our group, we looked at the effect of serum uric acid level on the diurnal blood pressure variation, we included 112 newly diagnosed hypertensive subjects and 50 control subjects. slide 24

We performed ABPM to all subjects and we found that in patients with hypertension, serum uric acid levels and CRP levels significantly higher compared to control

If you look at the nondipping pattern patients, these patients also have significantly higher levels of uric acid level and CRP levels compared to dipping patterns.

13 We performed ABPM to all subjects and we found that in patients with hypertension, serum uric acid levels and CRP levels significantly higher compared to control groups. If you look at the nondipping pattern patients, these patients also have significantly higher levels of uric acid level and CRP levels compared to dipping patterns. So, we may say that uric acid might have a role in the development of non-dipping patterns in essential hypertensive subjects. slide 25 What about the association between uric acid level and inflammation? In this study, we also showed that there is a positive correlation between uric acid level and CRP levels too. slide 26

14 What about experimental studies? slide 27 As we know, in animals there is an enzyme uricase, it degrades uric acid to allantoin, which is not as toxic as uric acid. Because of this, by inhibiting this enzyme in animals named oxonic acid, animals become hyperuricemic.

rats. If these rats treated with allopurinol and serum uric

15 slide 28 In this study, Sànchez Losada's group from Mexico showed that high uric acid causes glomerular hypertension in rats. If these rats treated with allopurinol and serum uric acid becomes normal, also glomerular pressure becomes normal. slide 29

slide 30 Another study showed that if rats are exposed to hyperuricemia in the long-term,

16 Another study from the USA showed that high uric acid also causes glomerular hypertrophy and if it is treated with allopurinol, the glomerular hypertrophy improves. slide 30 Another study showed that if rats are exposed to hyperuricemia in the long-term, the risk of development of glomerulosclerosis is significantly higher compared to normouricemic rats. slide 31

slide 32 They showed that if these animals have high uric acid levels, these rats have significantly high levels of systolic blood pressure, serum creatinine levels, proteinuria and

17 This is one of the cornerstone studies in this area. Kang from Korea in this experimental study looked at the effect of uric acid levels in the progression of CKD0 proteinuria and blood pressure. slide 32 They showed that if these animals have high uric acid levels, these rats have significantly high levels of systolic blood pressure, serum creatinine levels, proteinuria and glomerulosclerosis. If it is treated with allopurinol or we may say that if we lower uric acid levels in these animals, they found a significant improvement in all these parameters. slide 33 In another study some investigators showed that high uric acid levels also did not cause these effects also increases the expression of renin release. slide 34

and it decreases vitamin D levels and if it is treated with febuxostat,

18 Also a recent study published in Mexico showed that high uric acid levels suppresses 1 alpha dehydroxylase, slide 35 vitamin D expression and it decreases vitamin D levels and if it is treated with febuxostat, active vitamin D levels are significantly increased in this experimental model.

19 slide 36 Also as I mentioned before high uric acid increases the inflammation and angiotensin II levels slide 37

showed that allopurinol decreases blood pressure levels

20 and also decreases nitric oxide levels. slide 38 In experimental models, this is the first that showed that allopurinol decreases blood pressure levels in hyperuricemic rats as much as lowering sodium levels in these rats. slide 39

In this study, we looked at the effect of lowering uric acid levels with allopurinol on

21 What about the clinical studies that investigate the effect of allopurinol or lowering uric acid levels? In this study, we looked at the effect of lowering uric acid levels with allopurinol on kidney function, proteinuria and blood pressure. slide 40 We included 48 hyperuricemic and 21 normouricemic patients and we followed all patients for 3 months. slide 41

22 In the end, we didn't find any significant changes in the control group. However, in the allopurinol group, we found a significant improvement in inflammation, systolic and diastolic blood pressure and also kidney function. slide 42 Another study from the USA looked at the anti-hypertensive effect of allopurinol on a newly diagnosed hyperuricemic adolescent population. slide 43

23 In this study, they included 30 children and all the pharmacological and newly diagnosed essential hypertensive subjects slide 44 and they found that slide 45

24 if these subjects were treated only with allopurinol except two patients, they found a significant improvement in all hypertensive, hyperuricemic patients. We may say that allopurinol or lowering uric acid levels with allopurinol has antihypertensive effects. slide 46 Some meta-analysts investigated this. In this meta-analysis group included 10 studies that looked at the effect of lowering uric acid with allopurinol on blood pressure and they found slide 47

25 that lowering hyperuricemia with allopurinol improves blood pressure. slide 48

Also, some studies looked at the effect of lowering uric acid level with allopurinol on the development of cardiac events in CKD populations. slide 49 This is a study from Spain.

They followed the study population for 24 months and they looked at in this study the progression of kidney disease, cardiac events and hospitalisation.

26 Also, some studies looked at the effect of lowering uric acid level with allopurinol on the development of cardiac events in CKD populations. slide 49 This is a study from Spain. They included 113 CKD patients, half started allopurinol and the other group was recruited as a control group. They followed the study population for 24 months and they looked at in this study the progression of kidney disease, cardiac events and hospitalisation. For baseline characteristics, there isn't any significant difference between both groups. slide 50 At the end of this study in the control group, they found a slow decline in kidney function. In the allopurinol group although it is not significant, they found an improvement in kidney function. In the end,

27 slide 51 they compared the delta change in the control group and in the allopurinol group and they found this significant. So, we may say that allopurinol may also retard the progression of kidney disease in the CKD population. slide 52 In the same study, they looked at the effect of cardiac events compared to allopurinol treated and allopurinol control group. They found that a number of cardiac events, significantly low in patients on allopurinol treatment. slide 53

28 So, we may say that according to this study, allopurinol lowers the progression of kidney disease, decreases the number of cardiac events and also improves inflammation in CKD patients with stage 3. slide 54 A recent meta-analysis published in NDT looked at the effect of lowering uric acid levels on kidney progression. In this meta-analysis, they included 8 studies slide 55

the light of this study we could not have a good decision on the effect of lowering uric

29 but the inclusion criteria of all these studies are different: different outcomes, different follow-up periods, very, very different doses of allopurinol because of this in the light of this study we could not have a good decision on the effect of lowering uric acid on renal outcome. slide 56 In this study, they showed that lowering uric acid levels slide 57

30 has beneficial effects slide 58 on the progression of kidney disease also. slide 59

What about the effect of lowering uric acid levels on endothelial function? In this study, we included 72 hyperuricemic and 33 non-uricemic patients.

baseline and 4 months after follow-up. slide 60 We found that allopurinol improves endothelial function significantly.

31 What about the effect of lowering uric acid levels on endothelial function? In this study, we included 72 hyperuricemic and 33 non-uricemic patients. We gave half of these hyperuricemic patients allopurinol and we followed all the study population for 4 months and we measured FMD, endothelial function at baseline and 4 months after follow-up. slide 60 We found that allopurinol improves endothelial function significantly. So it may also decrease cardiac events because we know a significant association between the endothelial dysfunction and development of cardiac events. So we may say that allopurinol also has some cardioprotective effects.

32 slide 61 A recent study looked at the association between the allopurinol treatment and arterial stiffness. They also showed that allopurinol improves arterial stiffness too. slide 62

33 In this meta-analysis, we looked at the effect of lowering uric acid level on endothelial function. slide 63 In this meta-analysis, we included only 11 studies and we found that slide 64 lowering uric acid levels with allopurinol improves endothelial slide 65

34 function significantly. slide 66 As a conclusion, we may say that high uric acid causes an increase in the angiotensin II levels and a decrease in nitric oxide levels. Because of these changes, we have an increased oxidative stress and because of this we have increased blood pressure and all this causes some changes in vascular smooth muscle cells because of this we have arteriosclerosis that impairs auto regulation. slide 67

Because of these changes we have endothelial dysfunction, an increase in coronary artery disease, CKD, hypertension, heart failure, stroke and gout also.

35 Because of these changes we have endothelial dysfunction, an increase in coronary artery disease, CKD, hypertension, heart failure, stroke and gout also. slide 68 Many studies showed that lowering uric acid levels causes an improvement in blood pressure, kidney function, inflammation and endothelial function also. slide 69

36 What about the dose of allopurinol? We should adjust the dose according to kidney function and also if we give allopurinol to a renal-transplanted patient, we should avoid to use allopurinol with other therapies but we do not need to adjust those if we use febuxostat. slide 70 But there are still some questions that need answering. Should we treat asymptomatic hyperuricemia? We still do not know the answer to this? Should we treat hyperuricemia in CKD? If the answer to this question is yes, what should the threshold to treat hyperuricemia be? What

should the target serum uric acid level be in these diseases? Do all uric acid level lowering agents have the same effects or does allopurinol have some anti-oxidative effects?

37 should the target serum uric acid level be in these diseases? Do all uric acid level lowering agents have the same effects or does allopurinol have some anti-oxidative effects? Because of this does this drug have extra beneficial effects? Also what should the duration of the therapy be? slide 71 As a conclusion, uric acid might be a risk factor for the development of hypertension, for progression of kidney disease and cardiovascular disease, hyperuricemia, a risk factor also might be a prognostic factor like CRP and lowering uric acid might a be a new antihypertensive and cardioprotective agent, and we may define hyperuricemia as a new cardiorenal toxin. Thank you for your attention.

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

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