Introduction:

3.4. Blood pressure and treatment regimens

4. Discussion

4.1. General description of the study

This study revealed the prevalence of chronic kidney disease (i.e. stage 3 CKD and above) and associated factors among 255 middle age adults with uncontrolled hypertension in Sulaymaniyah. The overall prevalence of CKD based on the Modification of Diet in Renal Disease (MDRD) equation was 93 (36.5%), and 34 (13.3%) based on the Cockcroft-Gault equation (CG). The difference between estimated prevalence based on MDRD and CG equation could be due to the lack of standardization of creatinine assay in CG formula [25]. This is supported by evidence from a recent systematic review conducted in Africa showed that the pooled prevalence of CKD among hypertensive patients was 34.5% ranging from 13% to 51% from a systematic review conducted in Africa [26].

The estimated prevalence of CKD is lower than findings from another study from South Korea that showed 59.5% of type 2 diabetes patients had CKD [13]. This is also lower than findings from a cross-sectional study conducted in Tigray teaching hospitals among 578 adults that showed 43.3% [27], a cross-sectional study conducted in Ekiti State, Southwest Nigeria showed that 57.1% [28]. The difference could be due difference in age of study participants, for example, in our study we included people above 40 years, while the South Korean study included patients above 65 years of age.

However, this finding is higher than findings from a study conducted in Northwest Amhara Referral Hospitals that showed 17.6% [29], a study conducted in Cairo that showed 33% [30], and study conducted in Asian populations that showed 10.5% in China, 9.6% in Hong Kong, 12.8% in India,  9.9% in Japan, 5.0% in Singapore, 20% in South Korea, and 8.3% in Taiwan [31], and a study conducted among 23,120 US adults with hypertension between 1999 to 2018 that revealed 8.9% [32], and  Kidney Early Evaluation Program (KEEP) study that showed 15% prevalence of CKD (eGFR <60 ml/min) [33]. The variation can be attributed to geographic variation, sociodemographic factors, the type of patients involved, the eGFR estimation method used, and definitions used for CKD in these studies. For example, most of studies evaluated the prevalence of CKD among adult hypertensive patients. While this study evaluated the prevalence of CKD among adults aged 45 years and above with uncontrolled hypertension. The study conducted among the Asian population reported CKD attributable to hypertension. However, this study reported all forms of CKD irrespective of the case. In addition to this, some studies used the Cockcroft-Gault equation for estimating GFR. The modification of diet in renal diseases (MDRD) equation is used for estimating GFR in this study.

Regarding salt intake, the mean salt consumption of participants in this study was 1.23 ± 0.56 ranging from 0.5 to two teaspoonfuls per servings. This means if the daily serving is on average three meals, the average salt consumption will be 3.69 ± 0.56 ranging from 1.5 to 6 teaspoonfuls of salt (i.e. 3.45 to 13.8 grams of sodium). The salt consumption is 1.5 to 6 times higher than the recommended daily intake.  The recommended daily sodium intake for patients with hypertension is about one teaspoonful of sodium chloride (i.e. 2.3 g sodium) per day to reduce hypertension-related CVD and renal outcomes [34].  A pooled data from a systematic review showed that reduced sodium intake led to lowering of SBP by 3.4 mm Hg and DBP by 4.1 mm Hg in adult patients with hypertension. Similarly, an increase in potassium intake (90–120 mmol/d) reduced SBP by 5.3 mmHg and diastolic BP by 3.1 mm Hg [35]. Therefore, reducing sodium intake and increasing potassium intake can contribute for reducing the current alarming prevalence of CKD and uncontrolled glycemia and dyslipidemia among patients with uncontrolled hypertension.

Concerning fruit consumption, the mean number of fruit servings per day was 1.93 ± 0.82 ranging from 1 to three (150 to 450 grams).  Similarly, the mean vegetable intake per day was 2.56 ± 1.12 ranging from one to four (i.e. 75 to 300 grams). Standard service for vegetables is 75g (½ cup cooked broccoli, spinach, carrots or pumpkin, or 1 medium tomato), and fruits 150 g (1 medium apple, banana, orange or pear, 2 small apricots, kiwi fruits or plums) respectively. WHO recommends a minimal quantity of 400 grams of fruits and vegetables per day to reduce the risk of developing cardiovascular diseases. The recent systematic review revealed that reductions in risk were observed up to 800 g/day for fruits and vegetables, and 550 g/day for fruits [24]. Increasing fruit and vegetable consumption can improve the outcomes of patients with uncontrolled hypertension.

The overall medication adherence level was good 212 (83.1%) [23]. This finding is higher than findings from the study conducted in Pakistan that showed 64% adherence [36], and a similar study conducted in Malaysia that showed 60.7% adherence [37]. However, better adherence to treatment is not translated into good outcomes as evidenced by uncontrolled diabetes and dyslipidemia in the study population. This could mean adhering to suboptimal drug therapy will not have a significant effect on blood pressure and associated comorbidities control. Treatment intensification based on evidence-based guidelines is critical for improving outcomes of patients with uncontrolled hypertension.

4.2. Treatment of uncontrolled hypertension and comorbidities 

Regarding treatment regimens, about one-half 127 (49.8%) of patients were using two antihypertensive medicines. The most commonly prescribed antihypertensives were hydrochlorothiazide and amlodipine 98 (38.4%) followed by hydrochlorothiazide 52(20.4%). Regarding the triple combination, one-half of 10 (50%) patients was taking hydrochlorothiazide (HCT) + Amlodipine + Spironolactone followed by HCT + Amlodipine + Eplerenone 50%. This treatment is suboptimal and not supported by evidence-based guidelines. The recommended treatment regimen for hypertension with or without CKD should start with two-drug combinations (ACEI or ARB + CCB or diuretic), then optimize the dose of these drugs or escalate to three-drug combinations (ACEI/ARB + CCB + diuretic), then optimization of dose for the regimen and ensuring treatment adherence or moving to addition of fourth drug for resistant hypertension ACEI/ARB + CCB + diuretic + Spironolactone or eplerenone or α-blocker or β-blocker [12]. The regimen for patients with hypertension diabetes, and or CKD should include renin angiotensin aldosterone system (RAAS) blockers (ACEIs or ARBs) in combination with calcium channel blockers or thiazide diuretics. After dose optimization to a tolerable dose for these two antihypertensives, the third agent should be added. The addition of spironolactone should be the fourth option after treatment optimization and ensuring treatment adherence. The addition of eplerenone should be considered if the patients cannot take spironolactone. The four major drug classes (ACE inhibitors, ARBs, dihydropyridine CCBs, and thiazide or thiazide-like diuretics) are recommended as first-line BP-lowering medications, either alone or in combination.  When BP is still uncontrolled under maximally tolerated triple-combination (RAS blocker, CCB, and diuretic) therapy, and after adherence is assessed, spironolactone should be added and the patient should be considered resistant. If spironolactone is not tolerated, eplerenone or other MRA, or beta-blockers (if not already indicated), should be considered. Eplerenone may need to be dosed higher (50–200 mg) for effective BP lowering.  Only thereafter should hydralazine, other potassium-sparing diuretics (amiloride and triamterene), centrally acting BP-lowering medications, or alpha-blockers be considered [17, 18, 38]. This suboptimal treatment could be due to the dual physician practice policy [15], and the rampant drug promotion practice in the region and the in the study area [39]. Therefore, it is important to set rules to control medical promotion to improve treatment adherence to evidence-based guidelines.

More than three-fourths of patients had diabetes comorbidity 191 (74.9%). The treatment of comorbid diabetes was suboptimal as evidenced by uncontrolled hyperglycemia in almost all (96.34%) type diabetes patients. The mean HbA1C% was 8.96 ± 0.98% ranging from 6 to 11%. Regarding type 2 diabetes medicines prescribed 91 (47.6%) were taking Empagliflozin followed by Sitagliptin 50mg + Metformin 500mg 100 (52.4%). The inclusion of SGLT2-inhibitors and GLP-1 agonists seems rational with the aim of having the renoprotective and cardioprotective effect of these medicines. These are also supported by evidence-based guideline treatment recommendations for type 2 diabetes including Optimizing glucose, blood pressure control, and reducing blood pressure variability to reduce the risk or slow the progression of CKD and reduce cardiovascular risk [40]. In nonpregnant people with diabetes and hypertension, either an ACE inhibitor or an ARB is recommended for patients with CKD (eGFR <60 mL/min/1.73 m2) to prevent the progression of kidney disease and reduce cardiovascular events. For people with type 2 diabetes and CKD, the use of a sodium-glucose cotransporter 2 (SGLT2) inhibitor is recommended to reduce CKD progression and cardiovascular events in individuals with eGFR ≥20 mL/min/1.73m2 and urinary albumin ranging from normal to ≥200 mg/g creatinine.  In addition to this, glucagon-like peptide 1 agonist, or a nonsteroidal mineralocorticoid receptor antagonist (fineronone) are recommended for cardiovascular risk reduction in people with type 2 diabetes and CKD (if eGFR is ≥25 mL/min/1.73 m2) [12, 40]. Treatment intensification along with non-pharmacologic therapies can improve diabetes control and kidney outcomes in patients with uncontrolled hypertension.

About obesity and overweight, 198 (77.6%) of patients with uncontrolled hypertension were obese (BMI > 30 kg/m2). The management of obesity should focus on reducing medications associated with weight gain. Several medications approved obesity medications have been shown to improve glycemia in people with type 2 diabetes and delay progression to type 2 diabetes in at-risk individuals, and some of these agents (e.g., liraglutide and semaglutide) have an indication for glucose-lowering as well as weight management [20]. Despite the use of semaglutide in these patients, the proportion of obesity is high. These require multifaced programs to reduce obesity and overweight including enhancing physical activity, making roads safe for walking for patients who cannot engage in heavy physical activities, engaging patients in diabetes self-management education programs, smoking secession programs, and reducing sodium intake by involving all relevant stakeholders.

All patients have poorly controlled dyslipidemia. LDL-cholesterol level was, 141.11 ± 11.7 mg/dL ranging from 120 to 160 mg/dL (good value < 100 mg/dL). Mean total cholesterol 233.8 ± 15.49 ranging from 210 to 260 mg/dL (optimal < 200mg/dL). Mean HDL level 40.26 ± 3.15 mg/dL ranging from 35 to 45 mg/dL (optimal ≥ 60 mg/dL). All patients were candidates for high-intensity statin therapy and taking statins [Atorvastatin 162 (63.5%), and Rosuvastatin 93 (36.5%)] and none of them achieved the LDL-cholesterol and total cholesterol treatment targets.  For patients with uncontrolled dyslipidemia despite a maximum dose of high-intensity statin use. It is important to re-emphasize non-pharmacologic therapies including reducing dietary saturated fatty acids (SFAs) and or replacing SFAs with monounsaturated fatty acids (MUFAs) or polyunsaturated fatty acids, improving glucose control since there is a direct relationship between glucose metabolism and fat metabolism. Reducing intake of high glycemic index foods, and reducing weight is important to reduce LDL-cholesterol total cholesterol, and triglycerides (weight reduction improves insulin sensitivity). The addition of non-statin lipid-lowering agents like ezetimibe is important to reduce CVD risk in patients with uncontrolled hypertension [21].

4.2. Factors associated with CKD among patients with hypertension

Male patients had a 26% lower [AOR=0.26, 95% CI, 0.011-0.061, p=0.00] risk of having CKD when compared with their female counterparts.  This is supported by findings from a study conducted in Peru that showed male sex as a risk factor for the development of CKD [22], a global burden of disease study also showed that the elderly population and males were found the highest ASIR and ASDR [41], and a study conducted in Iran that showed being female (30.3% versus 24%) is risk factors for CKD [42], and a 2022 update on epidemiology of CKD showed that CKD is more prevalent in women, racial minorities, and in people experiencing diabetes mellitus [43]. However, this is against a systematic review and meta-analysis from six cohorts involving 2,382,712 individuals that showed the RR for incident CKD or ESRD was 23% lower in women than in men [44]. The difference in risk of other comorbidities like diabetes, and access to health care difference could partly explain the gender-based difference in CKD prevalence. The contradicting evidence concerning sex differences in risk for developing CKD needs future strong multi-sectoral studies

Patients with a BMI of 30-99.9kg/m² were 2.8 times [AOR=2.78, 95% CI, 1.188-6.521, p=0.018] more likely to have CKD when compared with patients having a BMI of 25-29.9kg/m². This is supported by evidence from a CKD prevalence survey conducted in Iran among 9781 Iranian adults aged 30-73 years that showed that obesity (BMI ≥ 30) (11.25%) as a major risk factor for CKD. Followed by Hypertriglyceridemia (9.21%), LDL ≥ 130 (7.12%), Hypercholesterolemia (5.2%), diabetes (5.05%), smoking (3.73%), and high blood pressure (2.82%) [42]. Another study from Tigray teaching hospitals revealed overweight and obesity as independent and positive predictors of CKD among uncontrolled hypertensive patients [27]. This could be due to obesity-associated insulin resistance, and type 2 diabetes [43]. The Obese patients might not adhere to their lifestyle management as evidenced by 24 (42.1%) of overweight and 96 (48.5%) of obese patients consuming more than 2.3 grams of sodium per day. Therefore, designing strategies to improve patients’ outcomes with a great emphasis on obese patients can improve the outcomes of patients with uncontrolled hypertension.

Patients having a family history of diabetes in first-degree relatives were 2.6 times (AOR=2.6, 95% CI, 0.273-0.778, p=0.004) more likely to develop CKD when compared to having a family history of diabetes in second-degree relatives. This is supported by evidence from a similar study that revealed a family history of diabetes in first-degree relatives is independently associated with a rapid decline in eGFR in the current relatively young studied patients [45]. This could be due to the increased risk of type 2 diabetes among patients with a family history of diabetes and type 2 diabetes was co-variate with CKD in this study population. 

4.3. Strengths and limitations

The strengths of this study rely on its methodology of data collection, and tools used for it. The tools based on the UpToDate evidence-based guidelines were used. The prevalence of CKD was estimated by the reliable equation MDRD and glycemic control status was evaluated by using fasting blood glucose and HbA1C% to avoid variation among these two parameter results. However, being a cross-sectional study, it is not possible to find a causal link between predictor variables and CKD. In addition, the self-reported medication adherence could overestimate the medication adherence.

5. Conclusion

The prevalence of chronic kidney disease among middle age adults with uncontrolled hypertension in the study area was high. Management of hypertension comorbid diabetes and dyslipidemia is not supported by current evidence-based guidelines. Being male, being obese (BMI of 30-39.9kg/m²), and having a family history of diabetes in first-degree relatives were factors independently associated with CKD among adults with uncontrolled hypertension. Therefore, addressing these problems based on evidence-based guidelines can improve the outcomes of patients with uncontrolled hypertension. For researchers willing to conduct similar studies, it is imperative to evaluate the prevalence of CKD in all age populations in multiple settings using strong study designs.

7. Abbreviations and Acronyms

aTRH: Apparent Treatment Resistant Hypertension; ACEIs: Angiotensin Converting Enzyme Inhibitors; BP: Blood Pressure; CPG: Clinical Practice Guideline; CVD: Cardiovascular Diseases; DBP: Diastolic Blood Pressure; DRI/UL: Dietary Reference Tolerable Upper Intake Level; HDL: High-Density Lipoprotein; LDL: Low-Density Lipoprotein; LMICs: Low- and Middle-income Countries; MI: Myocardial Infarction; NCDs: Non-Communicable Diseases; NSAIDs: Non-Steroidal Anti-inflammatory Drugs; OSA: Obstructive Sleep Apnea; RAAS: Renin Angiotensin Aldosterone System; SBP: Systolic Blood Pressure; VLDL: Very Low-Density Lipoprotein; WHO: World Health Organization

8. Declarations

Ethical Consideration

Ethical clearance was obtained from Komar University of Science and Technology, ethical review board with approval reference letter of krc021024/2024. After clarifying the study objective and confidentiality of the information; written informed consent to participate was obtained from all participants before data collection.

Consent for publication

All authors read the full version of this manuscript and agreed to publish. Similarly, consent to publish was obtained from all participants before data collection.

Data availability statement        

All the data reported in the manuscript are publicly available upon the official request of the corresponding author upon acceptance of the manuscript.

Competing interests

The authors declare that they have no competing interests.

Funding

None

Contributors    

All the authors read and approved the manuscript. MMS conceived the research, framed the formatted the design, and conducted the data analysis; ABG, ZN, and TM participated in the data analysis, reviewed the manuscript writing process, and polished the manuscript. MMS participated in the data analysis, reviewed the manuscript writing process, polished the manuscript, and developed the manuscript for publication. The guarantor of the study is MS. The author accepts full responsibility for the finished work and/or the conduct of the study, has access to the data, and controls the decision to publish.

Acknowledgments

We want to thank Komar University of Science and Technology for providing us with the opportunity to participate in a research project; a chance to advance our professional careers. We would also like to thank the participants of this study; without their willingness, it would be impossible to conduct this research. Finally, we would like to thank all the staff of Komar University of Sciences and Technology, the College of Medicine, and the Department of Pharmacy for their technical and material support during manuscript development, including access to the internet.