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

Overview of uric acid

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

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

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.

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

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.

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,

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

Mechanism of hypertension

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

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)

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

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.

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

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

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

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

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

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 ?

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

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

UA and RAS

UA and Nitric oxide

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

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

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.

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.

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

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

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

Mechanism of HTN induced by UA Increase Blood Pressure

Proposed mechanism for Uric acid mediated HTN

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

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