Hypertension is one of the most significant modifiable risk factors for cardiovascular, cerebrovascular, and renal disease and is a significant public health problem in the world.[1] The burden has risen significantly over the past decades, with currently an estimated 1.4 billion adults aged 30–79 years suffering from hypertension, which is around a third of all adults in this age group.[2] Notably, only about 23% of adults with hypertension have their blood pressure sufficiently controlled, and around two-thirds of those with hypertension are in low- and middle-income countries.[3] Although effective antihypertensive treatment is available, many people still have inadequate

use of such treatment, which is a significant clinical problem and contributes to myocardial infarction, stroke, heart failure, chronic kidney disease, and premature death.[4]

Resistant hypertension is a complex type of hypertension.[5] It is usually defined as blood pressure above the recommended target despite treatment with three antihypertensive agents with different mechanisms of action, which are used at the maximum tolerated doses, or controlled blood pressure that requires 4 or more antihypertensive drugs.[6] Current recommendations suggest that resistant hypertension exists in about 8.5%–20% of all adults with hypertension, but ranges depending on the population and definition used. Patients with resistant hypertension often have obesity, diabetes, chronic kidney disease, and evidence of target-organ damage and have significantly higher cardiovascular and renal risks than patients whose hypertension is more easily controlled.[7]

There is growing evidence that abnormalities in purine metabolism and renal excretion of uric acid may play a role in the pathogenesis and maintenance of hypertension.[8] Serum uric acid (SUA) has been linked to endothelial dysfunction, oxidative stress, inflammatory responses, activation of the renin–angiotensin system, and impaired renal sodium handling, which are all thought to contribute to high blood pressure.[9] Recent longitudinal studies have shown that increased SUA and SUA that is poorly controlled or progressively higher is linked to an increased risk of hypertension.[8] In a 2024 retrospective cohort of 6,052 people without hypertension, the odds of developing hypertension increased with worsening SUA control, with the highest category having over two times the risk of the best SUA-control group.[10]

Serum uric acid alone might not be sufficient to assess the uric acid metabolism–renal function relationship.[9] The serum uric acid/creatinine (UA/Cr) ratio is closely related to renal creatinine clearance and may give some additional information by taking uric acid into account relative to renal function.[11] There has been emerging evidence that suggests its clinical relevance. In a large population study of 8,571 people, higher UA/Cr ratios were an independent predictor of hypertension, with the top quartile having significantly higher odds of hypertension than the lowest quartile. The association was not linear, implying that the UA/Cr ratio might also reflect metabolic and renal interactions that are not independent of serum uric acid or creatinine.[11]

However, very little is known about this emerging evidence specifically regarding the UA/Cr ratio in the context of patients with either good or resistant hypertension. There is a need for a biochemical marker that is easily accessible to help better stratify those with resistant hypertension and to give clues into the metabolic and renal profile of those who are hard to treat. Thus, the serum UA/Cr ratio may be used to distinguish the resistant groups from the controlled groups and might have potential as a marker of resistance in patients with hypertension, which is an inexpensive laboratory-derived parameter. The present study aimed to compare the serum uric acid-to-creatinine ratio between controlled hypertension and resistant hypertension.

A comparative cross-sectional analysis was performed at the hospital level to compare the serum uric acid/creatinine (UA/Cr) ratio of controlled hypertension patients with resistant hypertension patients. The research was carried out in the Department of Internal Medicine, Shaikh Zayed Hospital, Lahore. Patients who visited the outpatient hypertension clinic and the medical outpatient department were consecutively screened based on the already set eligibility criteria. Resistant hypertension was defined as blood pressure being above the recommended treatment goal, despite treatment with three antihypertensive agents from three different classes, including a diuretic agent, at maximum tolerated doses, or controlled BP requiring four or more antihypertensive agents. Controlled hypertension was defined as having blood pressure under the recommended target range and being under antihypertensive treatment, but not meeting the criteria for resistant hypertension. This study was carried out for 6 months between 1st September, 2025 and 28th February, 2026. The sample size was determined with OpenEpi version 3.01 for comparing two independent groups based on the mean serum uric acid level, which was 375.2±92.8 µmol/L among patients with resistant hypertension compared with 325.2±71.1 µmol/L among patients with controlled hypertension. A two-sided 95% confidence level, 80% power, and an allocation ratio of approximately 1:1, a sample size of 132 participants (66 per group) was estimated.[12] Data were collected using non-probability sampling in a consecutive sampling technique. Patients 18 years of age and older who were diagnosed with primary hypertension were included. Patients were eligible if they had been treated with antihypertensive drugs for at least three months at a stable dose. Patients in the controlled hypertension group had a blood pressure that was well controlled on their current antihypertensive treatment, and they did not meet the criteria for resistant hypertension. Patients were categorised into the resistant-hypertension group if, despite three or more antihypertensive drugs administered at maximally tolerated doses, including a diuretic, their blood pressure was still above target, or if they needed four or more antihypertensive drugs to control their blood pressure. The classification was based on the analysis of the patient's treatment and repeated blood pressure measurements. Secondary hypertension, acute kidney injury, severe chronic kidney disease, active gout, concurrent use of uric acid-lowering agents, severe hepatic disease or malignancy, pregnancy, acute infection, and severe cardiovascular instability were exclusion criteria. Where clinically appropriate, patients on medications that are known to significantly affect serum uric acid were excluded. People with missing clinical data or data that did not include serum uric acid or serum creatinine were excluded from the final analysis. Patients with a history of poor compliance with antihypertensive therapy or who had been diagnosed with white-coat hypertension were also excluded to reduce misclassification of white-coat hypertension. Demographic and clinical data were obtained after obtaining informed consent (written) and recorded on a structured data-collection proforma. Data on age, sex, duration of hypertension, smoking, diabetes mellitus, dyslipidaemia, body mass index, relevant comorbidities, family history of hypertension and current antihypertensive drug treatment were collected. Special focus was on the type and quantity of antihypertensive drugs prescribed such as angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, calcium-channel blockers, beta-blockers, and diuretics. Treatment history was reviewed to differentiate between true resistant hypertension and suboptimal treatment and/or poor adherence. The same method was applied in a recent study of resistant hypertension where demographic, clinical, medication, biochemical, and renal-function variables were systematically obtained. Measurements of blood pressure were taken with a validated automated sphygmomanometer after the subject had sat quietly for 5 minutes or more. A proper cuff size was applied based on the patient's arm circumference. Two measurements were taken at least 1 minute apart, and the average was taken. If there was a substantial discrepancy between the measurements, an additional reading was obtained, and the average of the closest readings was used. Standardized equipment was used for measuring weight and height and calculating BMI (kg/m2). After overnight fasting (8-12 hours), a venous blood sample was collected from each person in an aseptic manner. Standardized automated biochemical assays were used to measure serum uric acid and serum creatinine in the hospital's central laboratory. The serum UA/Cr ratio was then determined as serum uric acid concentration/serum creatinine concentration, both in compatible units. In addition, renal function was also estimated by the calculation of estimated glomerular filtration rate, when applicable. The collected data were coded and analyzed in IBM SPSS Statistics 26.0. Continuous variables were tested for normality by means of the Shapiro–Wilk test and were presented as mean ± standard deviation for normally distributed variables and median with interquartile range for non-normally distributed variables. Categorical variables were presented as frequencies and percentages. The primary outcome, serum UA/Cr ratio, was compared between the controlled and resistant hypertension groups. The independent-samples t-test was used for continuous variables with a normal distribution; when variables were not normally distributed, the Mann–Whitney U test was used. The chi-square test was used to compare categorical variables. This correlation between the UA/Cr ratio and resistant hypertension was further analyzed by binary logistic regression analysis. The multivariable model included potential confounding factors such as age, sex, body mass index, duration of hypertension, diabetes mellitus, dyslipidemia, renal function, and number of antihypertensive medications. Adjusted odds ratios with 95% confidence intervals were given. Pearson's correlation was used for normally distributed variables, and Spearman's rank correlation was used for non-normally distributed variables, with the UA/Cr ratio compared to systolic and diastolic blood pressure. Multivariable regression was performed after checking for multicollinearity. A two-sided p-value <0.05 was considered statistically significant.

A total of 132 patients were included, with 66 in each group. Patients with resistant hypertension were significantly older and had a longer hypertension duration and higher BMI compared to those with controlled hypertension. The incidence of diabetes mellitus and dyslipidaemia was also significantly higher in the resistant hypertension group, and there was no significant difference between groups for sex, smoking, or family history of hypertension. (Table 1) Resistant hypertension patients had much higher SBP and DBP and were more likely to be taking more antihypertensive medications. The resistant hypertension group had a higher proportion using calcium channel blockers, beta blockers, and diuretics, with a similar proportion using ACE inhibitors/ARBs. (Table 1 and Table 2)

Patients with resistant hypertension had significantly elevated levels of serum uric acid and creatinine, but significantly decreased eGFR. Patients with resistant hypertension also had a significantly higher primary outcome (serum UA/Cr ratio) than those with controlled hypertension. (Table 2) The serum UA/Cr ratio showed significant positive correlations with systolic blood pressure, diastolic blood pressure, and age, duration of hypertension, BMI, serum uric acid, and the number of antihypertensive drugs. However, strong negative correlations were found between serum creatinine and eGFR. (Table 3)

The following variables were significantly associated with resistant hypertension on univariable analysis: Age, BMI, diabetes mellitus, dyslipidemia, duration of hypertension, eGFR, UA/Cr, and number of antihypertensive medications. The association of these variables with resistant hypertension remained significant after multivariable adjustment (p < 0.001 for each). A one-unit increment in the UA/Cr ratio was linked to marginally greater odds of resistant hypertension (34%). (Table 4)

Table 1. Comparison of demographic and clinical characteristics between controlled and resistant hypertension groups (n=132)

Table 2. Comparison of antihypertensive treatment and biochemical parameters between the two groups

Table 3. Correlation of serum UA/Cr ratio with blood pressure and clinical variables

Table 4. Binary logistic regression analysis of factors associated with resistant hypertension

In the present study, serum uric acid-to-creatinine (UA/Cr) ratio was found to be significantly elevated in patients with resistant hypertension compared with patients with controlled hypertension. Patients with resistant hypertension also had higher concentrations of serum uric acid and creatinine and lower eGFR values, and the UA/Cr ratio was still associated with resistant hypertension after adjustment for relevant clinical and renal parameters. The results indicate that the UA/Cr ratio may reflect the overall effect of uric-acid metabolism and renal function and might thus be useful in the assessment of the more difficult-to-control hypertensive phenotype. Higher serum uric acid was also observed in patients with resistant hypertension, as noted in the 2025 study by He et al, who evaluated 386 patients with hypertension who had higher BMI, serum uric acid, blood glucose, and hypertension duration among the patients with resistant hypertension. They also defined their multivariable analysis as independent factors for resistant hypertension: elevated serum uric acid and elevated serum creatinine.[12] This similarity is significant because our study also showed that the resistant group had higher uric acid and creatinine levels, and that treatment was more resistant for a longer duration, indicating a possible metabolic and renal component of treatment resistance. There is also population-level evidence of associations between the UA/Cr ratio and hypertension, consistent with our finding that the ratio was very elevated in resistant hypertension. The researchers analyzed data from 8,571 participants in the China Health and Nutrition Survey and found that the people in the highest quartile of UA/Cr ratio had significantly higher odds of hypertension than those in the lowest quartile, with no association between the two remaining after the researchers accounted for other risk factors. Their limited cubic spline analysis also showed a non-linear relationship. Their study used a measurement of hypertension instead of resistant hypertension, but the direction of association is consistent with our finding that a higher UA/Cr ratio was associated with BP more difficult to control.[11] The study by Kawamoto et al. is another report confirming the clinical significance of the UA/Cr ratio.[13] A higher baseline UA/Cr ratio was an independent predictor of all-cause mortality in the 2023 prospective cohort of 2017 hypertensive patients, and uric acid and creatinine alone were not independent predictors.[11] This finding further supports the notion that the ratio should be assessed rather than either individual parameter, and supports our observation that the combined index was independently associated with resistant hypertension after adjusting for renal function and other potential confounders. Our study showed that there was a positive correlation between UA/Cr ratio and both systolic and diastolic blood pressure, which aligned with the results of a later Japanese study by Kawamoto et al. (2025).[14] During that prospective study over 3 years, an increase was correlated with a higher rate of hypertension, and significant associations with both systolic and diastolic blood pressure were found for the UA/Cr ratio. The results indicated that the relationship between the ratio and blood pressure does not seem to be restricted to the presence or absence of hypertension, but can be extended throughout the blood pressure range. This correlation between uric acid and blood pressure has also been shown to be true in serum uric acid studies. Tian et al also studied 11,488 patients with prehypertension, and found that elevated baseline uric acid and elevated uric acid change over time were independent risk factors for progression to hypertension.[15] In another 10-year Japanese study of 28,990 persons, Mori et al. showed that serum uric acid was linked to an increase in systolic blood pressure over the years, especially in women.[16] These longitudinal data serve to substantiate our observation in the cross sectional study that patients with higher blood pressure burden presented with higher UA/Cr values. A cross-sectional study in Beijing also demonstrated a strong relationship between uric acid and hypertension, according to Dong et al. Their results indicated that this relationship remained even after they accounted for other metabolic factors that could be involved, suggesting that uric acid might play a role in the process of hypertension development, rather than simply being a result of raised blood pressure.[17] Our findings support this idea, proposing that this relationship could also be relevant in treatment resistance after the onset of hypertension. Other large-scale observational studies have yielded the same results. He et al. performed a large cross-sectional study in adults of Chinese origin and found that serum uric acid levels were significantly related to hypertension.[18] A similar study of 8,469 Chinese adults also found baseline levels of S-urinary acid were associated with increased incidence of hypertension over time, after adjusting for various covariates.[19] In addition to our study, these studies suggest that uric acid abnormalities could be a significant metabolic marker of high blood pressure in various populations. The study by Lin et al. 2024 is significant as it focused on uric acid changes, not on a single measurement. In 6,052 initially normotensive individuals, the more poorly the participants controlled their uric acid, the higher the probability of developing hypertension, with the participants who had the poorest uric acid control having more than double the probability.[10] In our study, we did not evaluate the longitudinal trajectory of uric acid levels, but the increased UA/Cr ratio seen in resistant hypertension is consistent with the overall findings that persistent abnormalities in uric-acid metabolism are associated with increased blood-pressure burden. These data are clinically plausible and align with data correlating uric acid with renal dysfunction and vascular injury in people with resistant hypertension. In the Kailuan cohort, An et al. studied 7,444 patients with hypertension and found that increased levels of serum uric acid were linked to arterial stiffness, which is a significant indicator of vascular target-organ damage.[20] This may, in fact, be a reciprocal phenomenon: renal impairment may also exacerbate the elevation of UA/Cr, and high blood pressure may worsen renal and vascular injury. Zeng et al., in the analysis of NHANES 2024 data on 11,346 hypertensive patients, also showed the prognostic value of the UA/Cr ratio. They found that they could model the relationship between UA/Cr and mortality as a nonlinear relationship, characterized by a point of inflection at a UA/Cr ratio of about 4.3 and an increased risk of mortality beyond this point.[21] Likewise, in another NHANES study from 2024, involving a sample of 15,269 adults with hypertension, another relationship was observed between UA/Cr and cardiovascular and all-cause mortality.[22] These studies assessed prognosis instead of resistant hypertension, but this data is in agreement with the clinical relevance of the ratio as a composite biochemical marker related to both metabolic and renal status. The present study contributes to the emerging data suggesting a relationship between uric acid-related metabolic and renal abnormalities and hypertension severity and clinical outcomes. Our study specifically compared the controlled hypertension with resistant hypertension and showed that the UA/Cr ratio remained an independent determinant of treatment resistance, whereas other studies have looked at incident hypertension, blood pressure levels, arterial stiffness, and mortality. The results therefore indicate that the UA/Cr ratio could be a readily available, inexpensive biochemical marker that identifies patients at higher risk for resistant hypertension. However, multicenter studies with larger sample sizes, ambulatory blood-pressure monitoring, assessment of blood pressure medication adherence, and longitudinal measurements of UA/Cr should be performed to assess its predictive and clinical value. Limitations There were a few limitations to this study. Since it was a cross-sectional study, it was not possible to determine whether there was a causal relationship between the serum UA/Cr ratio and resistant hypertension. The findings may not be applicable to other populations because of the relatively small and single-center sample. Resistant hypertension was defined based on clinical treatment and blood pressure measurements instead of using ambulatory blood pressure monitoring, which could have led to misclassification. Several factors were considered as possible confounders, but residual confounding due to dietary purine intake, salt intake, physical activity, medication adherence, and genetic factors was not completely ruled out. In addition, the serum uric acid and creatinine were evaluated only at one time point, which did not allow evaluation of changes in the UA/Cr ratio over time. This study should be replicated in larger, multicenter, prospective trials to confirm the results and to clarify the prognostic value of the UA/Cr ratio in resistant hypertension.

Patients with resistant hypertension had a significantly elevated serum uric acid/serum creatinine ratio compared with those with controlled hypertension, and this ratio was an independent risk factor for resistant hypertension after controlling for other demographic, metabolic, and renal parameters. The results of this study indicate that the UA/Cr ratio could potentially be a biochemical marker that is easy to obtain and easily available for identification of patients that are more likely to develop treatment-resistant hypertension. However, it should only be used routinely in clinical practice if it is proven in larger prospective and multicenter studies.

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