Authors

• Damir Šečić — Faculty of Medicine, University of Sarajevo, Sarajevo, Bosnia and Herzegovina — ORCID: 0000-0002-2116-7892
• Adnan Turohan — Health Care Centre Sarajevo, Sarajevo, Bosnia and Herzegovina — ORCID: 0000-0002-3557-4923
• Edin Begić — General Hospital “Prim. dr. Abdulah Nakaš“, Sarajevo, Bosnia and Herzegovina — ORCID: 0000-0001-6842-262X
• Šekib Sokolović — Clinical Center University of Sarajevo, Sarajevo, Bosnia and Herzegovina — ORCID: 0000-0001-6321-4186
• Damir Rebić — Clinical Center University of Sarajevo, Sarajevo, Bosnia and Herzegovina — ORCID: 0000-0003-4296-9453
• Ehlimana Mušija — Clinical Center University of Sarajevo, Sarajevo, Bosnia and Herzegovina — ORCID: 0000-0002-5667-0279
• Jasna Kusturica — Faculty of Medicine, University of Sarajevo, Sarajevo, Bosnia and Herzegovina — ORCID: 0000-0002-4120-7230
• Aida Kulo Ćesić — Faculty of Medicine, University of Sarajevo, Sarajevo, Bosnia and Herzegovina — ORCID: 0000-0002-5891-3780
• Esad Pepić — Faculty of Medicine, University of Sarajevo, Sarajevo, Bosnia and Herzegovina — ORCID: 0000-0002-4957-3868
• Jasmin Mušanović — Faculty of Medicine, University of Sarajevo, Sarajevo, Bosnia and Herzegovina — ORCID: 0000-0002-2900-9397
• Azra Metović — Faculty of Medicine, University of Sarajevo, Sarajevo, Bosnia and Herzegovina — ORCID: 0000-0003-2305-4995

Abstract

To determine whether there are differences between serum creatinine levels, estimated glomerular filtration rate (GFR) according to the Modification of Diet in Renal Disease Study (MDRD) equation, creatinine clearance, and estimated GFR obtained by the Cockcroft-Gault method related to age, stage, and duration of arterial hypertension. The study included 124 patients with arterial hypertension who were examined at the Clinic for Heart, Rheumatism and Blood Vessels, Clinical Center University of Sarajevo. All patients were examined, and data about the duration and stage of hypertension were taken. Kidney function was assessed using serum creatinine, estimated GFR according to the MDRD equation, creatinine clearance estimated by the Cockcroft-Gault method (eCrCl CG ) and its corrections for body surface area (eCrCl CG1.73 ), body mass index (eCrCl CGBMI ), both body surface area and body mass index (eCrCl CGBMI1.73 ), and estimated GFR using the Cockcroft-Gault method (eGFR CGBMI1.73 ). There was a significant difference in values in MDRD equation estimated GFR, eCrCl CGBMI , eCrCl CGBMI1.73 , and eGFR CGBMI1.73 in patients with different stages and durations of hypertension, which was not found by analysis of serum creatinine values. Estimated GFR and eCrCl are more sensitive markers of kidney impairment than serum creatinine values, and their assessment should be introduced as a routine screening in the detection of early stages of chronic kidney disease in primary care settings, especially in patients with arterial hypertension.

Keywords

glomerular filtration rate, cardiovascular diseases, screening, primary health care

DOI

Full Text

## Introduction The National Kidney Foundation defines chronic kidney disease as kidney damage that lasts for more than 3 months and is caused by structural or functional disorders of the kidneys, with or without a decrease in glomerular filtration rate (GFR), manifesting as histological abnormalities or disturbances in blood, urine, or kidney function. The term “chronic kidney failure” is used to describe the terminal (fifth) stage of chronic kidney disease. (1) Chronic kidney disease is one of the leading causes of mortality and morbidity in the world. (1-3) The prevalence of kidney disease has been constantly increasing over the last decade, in parallel with the rapid increase in diabetes mellitus and arterial hypertension, representing a major public health problem with enormous impact on quality of life and economic status. (1, 4, 5) Early detection and treatment reduce the progression of chronic kidney disease toward end-stage kidney failure. (6-8) The most common causes of morbidity and mortality in patients with chronic kidney disease are cardiovascular ones. (9) Arterial hypertension can cause glomerular damage, microalbuminuria, and proteinuria. (3-5) Increase in blood pressure is associated with a significant decrease in GFR (1.1-6.2 mL/min/year). (6) Therapy with angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) has shown a renoprotective effect and reduction in proteinuria in patients with arterial hypertension. (5) This renoprotective effect is based on the blockage of the conversion of angiotensin I to angiotensin II and the consequent dilatation of the efferent arterioles and reduction of intraglomerular pressure. (7, 10, 11) Early detection of kidney disease with the use of screening tests to reveal high-risk groups of patients, such as those with arterial hypertension and diabetes mellitus, is very important and cost-effective. (12-14) Creatinine clearance values always refer to the average body surface area of adults (1.73 m2), but because body surface area differs significantly between obese and slim individuals, creatinine values need to be corrected for actual body surface area. (4) In clinical practice, estimation of GFR is widely accepted as the best indicator of kidney function. (13) Normal GFR in young adults is greater than 90 mL/min/1.73 m2, averaging 125 mL/min/1.73 m2. (1) Measurement of creatinine and inulin clearance is used to assess GFR. (1) Assessment of kidney function can be done using glomerular filtration, according to the MDRD (Modification of Diet in Renal Disease Study) equation, while clearance of creatinine is determined by the Cockcroft-Gault method (eCrClCG) and its correction for body surface area (eCrClCG1.73). (1, 5, 12, 13) Additionally, creatinine clearance determined by the Cockcroft-Gault method corrected for body mass index (eCrClCGBMI) and body surface area (eCrClCGBMI1.73) and estimated GFR using the Cockcroft-Gault method (eGFRCGBMI1.73) can be used for assessment of kidney function. (1, 5, 13) The aim of this study was to determine whether there are differences between serum creatinine levels, estimated GFR according to the MDRD equation, creatinine clearance, and estimated GFR obtained by the Cockcroft-Gault method related to age, stage, and duration of arterial hypertension. ## Patients and Methods ## Patients and study design This cross-sectional study was conducted in the Clinic for Heart, Rheumatism and Blood Vessels, Clinical Center University of Sarajevo, during March 2019. The study included 124 inpatients (n=124) with a diagnosis of arterial hypertension. Among other anamnestic data collected during physical examination, data was also collected from patient medical records on the cause, duration, and stage of arterial hypertension, as well as on antihypertensive therapy and smoking habits. Criteria for inclusion in the study were: more than 18 years old, diagnosis of arterial hypertension, and measured serum creatinine values during the examination. Criteria for exclusion were: pre-existing diagnosis of chronic kidney disease of non-hypertensive ethology of any stage, chronic dialysis, diagnosis of acute and chronic heart failure, amputation of lower extremities, presence of active cancer or cancer in the anamnestic data, and pregnancy. Ethical approval was obtained from the Ethical Committee, Clinical Center University of Sarajevo. ## Methods Assessment of the stage of arterial hypertension (grade I, II, and III) was performed based on the relevant guidelines for the management of arterial hypertension. (5) Assessment of kidney function was performed with: serum creatinine levels (µmol/L), MDRD equation (mL/min/1.73 m2), eCrClCG (mL/min), eCrClCG1.73 (mL/min), eCrClCGBMI (mL/min), eCrClCGBMI1.73 (mL/min), and eGFRCGBMI1.73(mL/min/1.73 m2). ## Statistical analysis The results of the study were processed using descriptive and inferential statistics. The Kolmogorov-Smirnov test was used to assess the distribution of the data, and the data with the normal distribution was reported as arithmetic mean (X) and standard deviation (SD). Comparisons of numerical data between groups were done using the y Student’s t-test and one-way analysis of variance (ANOVA). The chi-square test of Independence and the Fisher’s exact test were used for evaluation of the association of categorical variables. All results of the statistical analysis at the level of p2=4.818, p2=6.278; p10 years | 32 (25.8%) | 18.4 ± 8.39 | | | **Hypertension stage** | I | 56 (45.2%) | 6.8 ± 6.99 | | II | 56 (45.2%) | 8.8 ± 6.37 | | | III | 12 (9.6%) | 12.3 ± 13.69 | | [†] SD=standard deviation ### TABLE 2: Frequency of usage of different drugs and drug combinations in the treatment of arterial hypertension in relation to the stage and duration of the disease. | **Characteristic** | **Characteristic** | **Antihypertensive treatment** — **ACE inhibitor** — **n (%)** | **Antihypertensive treatment** — **ARB** — **n (%)** | **Antihypertensive treatment** — **Diuretic+ACE inhibitor / Diuretic+ARB** — **n (%)** | **Antihypertensive treatment** — **Ca-blocker** — **n (%)** | **Antihypertensive treatment** — **Nitro-derivates** — **n (%)** | | --- | --- | --- | --- | --- | --- | --- | | Disease | HTA | 39 (43.8%) | 10 (11.2%) | 43 (48.3%) | 30 (33.7%) | 43 (48.3%) | | HTA/DM | 16 (45.7%) | 4 (11.4%) | 17 (48.6%) | 12 (34.3%) | 29 (82.9%) | | | Sex | female | 26 (43.3%) | 8 (13.3%) | 27 (45.0%) | 24 (40%) | 31 (51.7%) | | male | 29 (45.3%) | 6 (9.4%) | 33 (51.6%) | 18 (28.1%) | 41 (67.2%) | | | Age (years) | 35-45 | 3 (42.9%) | 0 (0.0%) | 4 (57.1%) | 2 (28.6%) | 4 (57.1%) | | 46-55 | 8 (61.5%) | 1 (7.7%) | 4 (30.8%) | 4 (30.8%) | 7 (53.8%) | | | 56-65 | 28 (50.0%) | 6 (10.7%) | 25 (44.6%) | 18 (32.1%) | 30 (53.6%) | | | 66-75 | 14 (38.9%) | 6 (16.7%) | 18 (50.0%) | 13 (36.1%) | 24 (66.7%) | | | 76-85 | 2 (16.7%) | 1 (8.3%) | 9 (75.0%) | 5 (41.7%) | 7 (58.3%) | | | HTA duration (years) | 10 | 9 (28.1%) | 3 (9.4%) | 21 (65.6%) | 16 (50.0%) | 17 (53.1%) | | | HTA stage | I | 29 (51.8%) | 3 (5.4%) | 23 (41.1%) | 12 (21.4%) | 31 (55.4%) | | II | 22 (39.3%) | 10 (17.8%) | 30 (53.6%) | 20 (35.7%) | 33 (58.9%) | | | III | 4 (33.3%) | 1 (8.3%) | 7 (58.3%) | 10 (83.3%) | 8 (66.7%) | | | Smoking | Yes | 41 (47.1%) | 9 (10.3%) | 41 (47.1%) | 34 (39.1%) | 54 (62.1%) | | No | 14 (37.8%) | 5 (13.5%) | 19 (51.4%) | 8 (21.6%) | 18 (48.6%) | | [†] ACE inhibitor=angiotensin converting enzyme inhibitor; ARB=angiotensin receptor blocker; Ca blocker=calcium blocker; HTA=hypertension; DM=diabetes mellitus There was a significant relation between the eGFRCGBMI1.73 and the age (p=0.001) (**Table 3**). For each 10-year age increase, the average value of eGFRCGBMI1.73 decreased by 11.03 mL/min/1.73 m2. Additionally, with each 10-year age increase the average value of the estimated GFR with the MDRD formula decreased by 5.24 mL/min/1.73 m2. Furthermore, there was a significant difference in the values MDRD formula-estimated GFR, eCrClCGBMI, eCrClCGBMI1.73, and eGFRCGBMI1.73 in subjects with different stages and different average illness duration (**Table 4**). If serum creatinine was used, no significant difference was observed between groups regarding the progression of arterial hypertension. ### TABLE 3: Evaluation of kidney function according to sex. | **Kidney function** | **All patients** **(n=124)** | **Sex** — **Women** **(n=60)** | **Sex** — **Men** **(n=64)** | **p** | | --- | --- | --- | --- | --- | | Serum creatinine (µmol/L) | 89.7 ± 20.49 | 84.4 ± 20.97 | 94.8 ± 19.02 | 0.005 | | MDRD (mL/min/1.73 m2) | 72.0 ± 18.24 | 66.4 ± 16.27 | 77.4 ± 18.65 | 0.001 | | eCrClCG (mL/min) | 82.5 ± 28.49 | 72.3 ± 19.43 | 92.2 ± 32.39 | 0.001 | | eCrClCG1.73 (mL/min) | 70.6 ± 19.41 | 66.6 ± 15.32 | 74.3 ± 22.20 | 0.027 | | eCrClCGBMI (mL/min) | 74.4 ± 24. 27 | 65.6 ± 17.04 | 82.6 ± 27.30 | 0.001 | | eCrClCGBMI1.73 (mL/min) | 63.4 ± 16.96 | 60.2 ± 14.10 | 66.5 ± 18.99 | 0.038 | | eGFRCGBMI1.73 (mL/min/1.73 m2) | 50.6 ± 19.04 | 46.8 ± 15.80 | 54.3 ± 21.29 | 0.030 | [†] MDRD=estimated glomerular filtration rate according to the MDRD (Modification of Diet in Renal Disease Study) equation; eCrClCG=clearance of creatinine estimated by the Cockcroft-Gault method; eCrClCG1.73=correction for body surface area; eCrClCGBMI=correction for body mass index; eCrClCGBMI1.73=correction for body surface area and body mass index; eGFRCGBMI1.73=estimated GFR using the Cockcroft-Gault method; p=level of significance ### TABLE 4: Evaluation of kidney function according to sex in relation to the stage of arterial hypertension and average duration of disease. | **Kidney function** | **Average disease duration (in years)** — **6.8** — **Disease stage** — **I (Mean ±SD)** | **Average disease duration (in years)** — **8.8** — **Disease stage** — **II (Mean ±SD)** | **Average disease duration (in years)** — **12.3** — **Disease stage** — **III (Mean ±SD)** | **p** | | --- | --- | --- | --- | --- | | Serum creatinine (µmol/L) | 87.0 ± 19.19 | 92.1 ± 20.68 | 91.9 ± 26.14 | 0.404 | | MDRD (mL/min/1.73 m2) | 76.5 ± 19.42 | 68.8 ± 15.65 | 66.0 ± 21.12 | 0.039 | | eCrClCG (mL/min) | 88.7 ± 29.41 | 78.7 ± 25.71 | 71.8 ± 33.66 | 0.071 | | eCrClCG1.73 (mL/min) | 75.1 ± 20.45 | 67.4 ± 17.15 | 64.8 ± 22.29 | 0.060 | | eCrClCGBMI (mL/min) | 80.5 ± 25.40 | 70.0 ± 20.83 | 66.9 ± 29.91 | 0.038 | | eCrClCGBMI1.73 (mL/min) | 68.1 ± 18.00 | 59.8 ± 14.30 | 59.2 ± 20.20 | 0.024 | | eGFRCGBMI1.73 (mL/min/1.73 m2) | 55.6 ± 20.16 | 46.8 ± 16.21 | 45.7 ± 22.74 | 0.031 | [†] MDRD=estimated glomerular filtration rate according to the MDRD (Modification of Diet in Renal Disease Study) equation; eCrClCG=clearance of creatinine estimated by the Cockcroft-Gault method; eCrClCG1.73=correction for body surface area; eCrClCGBMI=correction for body mass index; eCrClCGBMI1.73=correction for body surface area and body mass index; eGFRCGBMI1.73=estimated GFR using the Cockcroft-Gault method; p=level of significance; SD=standard deviation ## Discussion Research has shown that patients predominantly receive polytherapy for arterial hypertension, which is a trend in modern cardiology. (5) Classification of arterial hypertension in stages in relation to blood pressure values on examination is not an optimal clinical approach. Additionally, as demonstrated in this study, the duration of hypertension does not affect the stage of hypertension. The use of renoprotective and cardioprotective drugs is imperative. (5) Slower progression of kidney disease has been demonstrated in patients with diabetes mellitus and arterial hypertension if they used ACE inhibitors or ARBs. (14, 15) When it is not possible to include one of these medications in the therapy, non-hydropyridine calcium channel blockers are recommended. (5) Therapy with ACE inhibitors and ARBs shows a renoprotective effect and reduction in proteinuria in patients with arterial hypertension. Combinations of ACE inhibitors and diuretics and ARBs and diuretics were the most-prescribed combinations. The National Kidney Foundation suggests the use of a fixed cut-off value of estimated GFR to define chronic kidney diseases, those values being GF2 with a three-month chronicity. (16) This recommendation is not reasonable, as it does not take into account differences in age and sex, which are non-negotiable. Research has verified significant differences in the values of MDRD formula-estimated GFR, eCrClCGBMI, eCrClCGBMI1.73, and eGFRCGBMI1.73 in subjects with different stages and different average illness durations, which has not been demonstrated for serum creatinine. Rule et al. conducted a study on 365 potential kidney donors to define age- and sex-related reference values for GFR and serum creatinine values. (17) GFR was measured using iothalamate clearance, and the abbreviated MDRD equation (eGFR-MDRD) and the Cockcroft-Gault method were used for its estimation. (17) It decreased significantly with increased age and was much lower in women compared with men. The average estimated GFR of men whose average age was 20 was 129 mL/min with a decline of 4.6 mL/min per decade. In women of the same age, the estimated GFR was 123 mL/min with a decline of 7.1 mL/min/decade. GFR values corrected for body mass index were significantly different for age, but not for sex. (17) Additionally, patients who were on average 20 years old had a GFR of 111 mL/min/1.73 m2, with a decline of 4.9 mL/min/1.73 m2 with every decade. (17) Velde et al. examined the correlation of estimated GFRs (for different methods and different age groups) and cardiovascular events in 8047 subjects. (18) The following equations were used to estimate GFR: the MDRD equation, the chronic kidney disease-epidemiology collaboration (CKD-EPI) equation, the cystatin C-based equation, the combined serum creatinine and cystatin C Quadratic Equation, and 24-hours creatinine clearance. (18) They concluded that all of the methods used to estimate GFR were significantly correlated with cardiovascular events in patients who are less than 60 years old, while 24-hour creatinine clearance showed a significant correlation with cardiovascular events in subjects who are 60 or more years old. Milojkovic et al. investigated the correlation between essential arterial hypertension and hypertensive nephropathy among 283 subjects as well as the prevalence of risk factors for the development of atherosclerotic changes. (19) A significant correlation was found between a positive anamnesis, arterial hypertension, smoking, and dyslipidemia in relation to the prevalence of hypertensive nephropathy. (19) The estimated GFR according to the MDRD equation was in a significant inversely proportional relationship with duration and stages of arterial hypertension, and the same relationship was found between eCrClCGBMI1.73 and eGFRCGBMI1.73 and the duration and stage of arterial hypertension. (19) Research has shown that the habit of smoking is still a large problem for patients in Bosnia and Herzegovina, and preventive programs aiming to reduce progression of atherosclerotic disease should be part of the daily work of medical doctors in primary health care. The limitations of the present study were, firstly, the small number of patients used to assess optimal pharmacological treatment, and secondly, the treatment modality of diabetes mellitus was not taken into account, which could have affected the results. Additionally, distribution of ACE inhibitors or ARBs to individual patients while taking into account their pharmacodynamics and pharmacokinetic properties, would be an important approach in assessing the renoprotective effects of the drugs. ## Conclusion Estimated GFR and eCrCl are more sensitive markers of kidney impairment than serum creatinine values, and their assessment should be introduced as a routine screening in the detection of early stages of chronic kidney disease in primary care settings, especially in patients with arterial hypertension.

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