1. Uric Acid and Hypertension
Oussama Hassan, MD
ERA-EDTRA Fellow
Royal London Hospital - Barts Health NHS Trust, London, UK
Uric acid suffered a long years of ignorance in which it was considered a metabolically inert substance. However recent years witnessed resurrection of interest in UA

2. Overview of uric acid

3. History!
Historically, the association of hyperuricemia with hypertension has been recognized since the early 1800 with early investigators such as Frederick Mahomed, Alexander Haig, and Nathan Smith Davis, hypothesizing that uric acid might be a cause of hypertension or renal disease

4. Haig in 1890 linked uric acid to elevated blood pressure and even wrote a textbook that espoused a diet to lower uric acid and blood pressure.
Folin introduced a biochemical method for measuring uric acid in 1919, and by the early-1920s, the first studies linking an elevated serum uric acid level with blood pressure

5. Urodonal, a drug consisting of theobromine and methenamine, was introduced in the French market as a treatment to lower uric acid as a means to treat hypertension (arteriolosclerosis) and obesity. This drug was not effective in treating high uric acid levels.

6. Definition
There is no universally accepted definition of hyperurecemia
7mg/dl is used as the cut off for the upper limit
Above this value (6.8mg/dl) serum urate concentration exceeds the solubility limit

7. Uric Acid Generation pathway
Humans lack uricase
This scheme present the metabolism of uric acid and mechanisms resulting in hypertension and renal disease.
Note that humans lack uricase which we think it was lost during evolution. The lack of uricase caused an increase in uric acid level and helped humans during evolution to cope with metabolic oxidative stress.

9. How is urate processed by the kidney
Four-component model for urate excretion :
1- Filtration
2- Almost complete reabsorption
3- Secretion
4- Postsecretory
reabsorption in a linear distribution along the
length of the proximal tubule
In this review article published in 2012 by Dr. Lipkowitz in Georgetown,

10. How is urate processed in the kidney
> 70% of hyperuricemia is due to under-excretion
The predominant mode of urate transport is reabsorption
5% to 10% of filtered urate is excreted in the urine
The proximal tubule has the capacity to dramatically increase urate reabsorption => more than 99% of filtered urate can be reabsorbed even if the filtered load is increased fourfold by urate infusion

11. Mechanism of hypertension

12. The present study done by Mazzali et al
The present study done by Mazzali et al. aimed to develop a model of mild hyperuricemia that did not result in intrarenal urate crystal deposition for the purpose of directly examining whether uric acid can modulate blood pressure (BP) or cause renal injury

13. Uric acid and BP in rats OA: oxonic acid (uricase inhibitor)
After administration of oxonic acid (uricase inhibitor) to the rats, we notice an increase in the BP as well as an increase in the uric acid level => so we can say that there is a correlation between oxonic acid / uric acid and HTN.
However to be sure that this is related to Uric acid level and not to oxonic acid administration, they performed additional studies in which they used either xanthine oxidase inhibitor, allopurinol, or a uricosuric agent, benziodarone.
OA: oxonic acid (uricase inhibitor)

14. Uric acid and BP in rats
A and B, Rats placed on Oxonic Acid-2% diet that were also administered allopurinol did not show the increase in BP (A) and had a normalization of serum uric acid levels (B). C and D, A similar effect on BP (C) and serum uric acid (D) occurred in a separate experiment in which rats were treated with benziodarone
Allopurinol: XO inhibitor; Benziodarone: uricosuric agent

15. Uric acid and BP in rats
We can conclude from this study that rats with high level of uric acid are associated with higher level of blood pressures. And this mechanism is not related to the drug causing the elevation in uric acid since treatment with uricosuric agents at the same time with uricase inhibitor, we had normalization of the BP.

16. From animal models to humans
In this study the author followed for 6 years men without metabolic syndrome
They included 3037 men

17. Study concluded that: pts with UA > 7 after 5years, 70% of them they developed HTN while the in the control group only 25% developed HTN

18. This is a prospective case control study, they followed around 1500 males (750 in each group). They concluded that the relative risk of dev HTN in male < 60 of age is around 2.01 while in males > 60 of age is 0.87 in patient with high uric acid level

20. Box and whisker plot
Children with primary HTN had the highest level of UA in comparision with secondary and white coat hypertension. We noticed that the UA level in secondary and white coat HTN are equivalent to the control group with no HTN

21. Serum UA plotted against BP
As the uric acid level increases, the S and D BP level increases. And this is almost a positive Pearson correlation

22. Postulated pathophysiology of Hypertension in hyperuricemia
So far we where able to identify a positive correlation between high uric acid levels and HTN, however what is the pathophysiology of hyperuricemia induced HTN ?

23. OA: oxonic acid; AP: allopurinol
A striking finding: juxtaglomerular renin content was increased and macula densa NOS1 expression was reduced => changes expected to result in both afferent and efferent arteriolar vasoconstriction => typical findings in many models of hypertension
Effect of hyperuricemia on NOS1 expression in the macula densa, which is involved in regulating afferent arteriolar tone and tubuloglomerular feedback.
As shown in Table 2, the number of NOS1-positive cells in the macula densa was decreased in hyperuricemic rats. The decrease in NOS1-positive cells was prevented by allopurinol treatment (Table 2).
Same thing concerning renin expression which increase with increasing uric acid level and decrease by decreasing the uric acid level.
OA: oxonic acid; AP: allopurinol

24. Enalapril or L-Arginine Prevents Hypertension and Renal Disease in Hyperuricemic Rats
Treatment with enalapril (RAS blockade) or L-arginine (a substrate for NO production) reverse the effect of hyperuricemia and we have return to baseline in level of renin and NOS1
OA: oxonic acid
LS: low salt diet

25. UA and RAS

26. UA and Nitric oxide

27. Correlation of UA and NO
Effect of uric acid on bovine aortic endothelial cells
Increase in UA levels causes a decrease in NO production

28. Uric acid stimulates VSMC proliferation and contributes to atherogenesis by increasing PDGF
Beside the effect of uric acid on the vasoactive molecules, uric acid affects the VSMC proliferation.
Study done in 1991 by RAO et al. UA stimulates vascular smooth muscle cells proliferation by stimulating the PDGF. The VSMC proliferation contributes to atherogenesis and HTN

29. Hyperuricemia and arteriolopathy
The arteriolopathy is related to the activation of the RAAS and not to the hypertension itself, since we can see in this slide that control of HTN does not prohibit the media to lumen ratio change seen in hyperuricemic patients.

30. Hyperuricemia and arteriolopathy
This arteriolopathy is related to the activation of the renin angiotensin system. Since blocking the RAAS with either enalapril or losartan, the media to lumen ratio did not change much in comparison with the control group.

31. Uric acid and Sodium
Measurements: blood pressure, blood tests, a detailed questionnaire, and urinary measurements on a fasting timed collection after a 300-mg lithium carbonate capsule was taken the night before the investigation

32. Uric acid and Sodium
In conclusion, the strong positive association between serum uric acid level and amount of sodium reabsorbed at nephron sites proximal to the distal tubule suggests a link between renal sodium handling and metabolic abnormalities like hyperurecemia

33. And the increase in uric acid level leads to activation of => go to next slide to show details about how uric acid causes injury

34. Mechanism of HTN induced by UA
Increase Blood
Pressure

35. Proposed mechanism for Uric acid mediated HTN

36. Uric acid and Hypertension
“People who are subject to this high blood pressure … frequently belong to gouty families, or have themselves suffered from the symptoms of this disease”
Frederick Mahomed. Lancet i:400, 1879

37. Thank you