INTRODUCTION

Many diseases including chronic kidney disease (CKD) exhibit gender differences in risk profile, pathophysiologic mechanisms, symptomatology, and response to treatment [1]. During the reproductive years, estrogens mediate prostaglandin-induced vasodilatation, higher serum potassium, suppressed renin-angiotensin-aldosterone system (RAAS), and sympathetic activity in females [2, 3] while testosterone is toxic to the renal tubules [3]. In the first post-menopausal decade, there is equilibration between the risk of and protection from CKD in both genders. Thereafter, the cardiovascular risk associated with CKD is higher in females than males [1-4].

During acute inflammatory states, women mount greater responses than men, and in the process, suffer greater tissue injuries but recover better compared to men [5, 6]. In chronic inflammatory conditions, females mount lesser responses, comparably suffering mild cellular destruction but with poorer recovery, except, in connective tissue diseases [5]. Chronic kidney disease is commonly associated with cardiovascular disease, acid-base imbalance, extracellular volume (ECV) expansion, proteinuria, dyslipidemia, anemia, increased morbidity, and mortality. The prevalence of CKD in the United States is higher in females while the incidence of end-stage kidney disease (ESKD) is higher in males [1].

Worldwide, females are less likely to seek medical treatment for illnesses, a bias that is heightened in low-income nations (LINs) particularly in sub-Saharan Africa, occasioned by socioeconomic differences, ethnic, and cultural practices. These cultural imbalances favor men's higher educational attainment, better employment opportunities, and capability to fund treatment during illnesses [7-9]. Women are known to commence maintenance hemodialysis (MHD) later than men, and the mortality rate in CKD is reported to be higher in them [6]. Women possess greater sodium chloride co-transporters (NCC) receptor activity that could impact the treatment outcome in CKD significantly [10, 11].

Renal function decline with aging and gender differences in CKD progression rate could also depend on body weight with obesity, known to impact positively during kidney functional decline, reported to be more common in women with CKD [12]. Thiazides, commonly used in controlling the blood pressure and the expanded ECV, exert greater diuresis in females from differential NCC activity [9]. Gender differences in the cut-off values of markers of kidney dysfunction don’t commonly have universal application, hence, males’ serum levels of creatinine, potassium, and anion gap in CKD could be deleterious for females, as saturation percent (SPO₂), serum bicarbonate concentration (SBC), hematocrit (HCT) and albumin that are adequate for females may increase CKD progression rate in males [13].

Much literature on gender differences in CKD is available in developed nations but in LINs, even with greater socioeconomic and cultural differences, literature is scarce. We studied the risk profile, epidemiologic, clinical, radiological, and laboratory findings, and response to drug treatment in CKD cohorts in Nigeria, and explore gender differences.

MATERIALS AND METHODS

This was a hospital-based comparative study conducted at the Nephrology and hypertension clinics of Babcock University Teaching Hospital, Ilishan-Remo, Nigeria, from August 2019 to July 2021. Eighty-two males and sixty-two females who were receiving treatment at Babcock University Teaching Hospital, Ilishan-Remo, met the kidney disease outcome quality initiative (KDOQI) 2012 diagnostic criteria [14], were 16 years or older, gave informed consent, and were studied. Participants with infections, kidney transplants, liver disease, and malignancy were excluded. Participants’ data were taken from an interviewer-administered questionnaire, history, physical examination, laboratory results, and the participants’ case files, from where, their age, gender, family history, and the etiology, type, and duration of CKD were retrieved

The height (meters) and weight (kilogram) were measured according to standardized protocols and the body mass index (BMI) was calculated in kg/m². The blood pressure was taken at rest with the participants’ back and arms rested on support. Two on-the-spot urine samples were taken for a dip strip urinalysis to determine specific gravity (SG), pH, and proteinuria, and a Micra Albustic test to determine urine albumin creatinine ratio (UACR). The Micra strip was taken from its container (immediately closed) and the paddy strip end was completely immersed in the urine covering the full length of the pads for 50 seconds. Removal of the strip was done by rolling it against the edge of the universal bottle to remove any excess urine. The strip pad color was matched against the “strip pad color” inscribed on the strip container and the results were documented. The combi 10 dip strip was taken from the container and the end containing the pad was immersed into the urine to cover the strip pad and removed after 60 seconds by rolling it against the edge of the universal bottle to remove excess urine. The result based on the matching color was documented.

Blood was taken from a peripheral vein into a Lithium heparin bottle to determine the serum electrolytes, urea, creatinine, and uric acid using an autoanalyzer (Roche Diagnostics GmbH, Mannheim Germany). The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula [15] was used to calculate the creatinine-based glomerular filtration rate (GFR). About 1-2 mL of blood was taken into a micropipette for determination of the hematocrit using a hematocrit centrifuge.

Data was analyzed using SSPS 22. Continuous variables, as mean with standard deviation, were compared using paired student’s t-test while categorical variables, as proportions and frequencies, were compared using Chi-square or fisher’s exact test, P-value <0.05 was considered statistically significant. Variables with P < 0.025 from the univariate model were entered as adjustment variables in multivariate analyses to determine independent associates of the female gender [16].

This study was approved by the Babcock University Human Research Ethics Committee (NHREC/24/01/2018 and BUHREC501/19).

Definitions

In this study, we did not use kidney biopsy in classifying CKD by etiology.

Hypertension-Associated CKD (HACKD): kidney disease arising from long-standing hypertension, prevalent in the elderly and late middle age.

Chronic Glomerulonephritis: kidney disease that leads to hypertension, common in the young and early middle age with or without a preceding history of pharyngitis or skin sepsis

Chronic Interstitial Nephritis: kidney disease arising from significant exposure to exogenous nephrotoxins after ruling out other risk factors/causes of CKD.

Hypertension: BP >140/90 mmHg [17].

Diabetes: Fasting blood sugar >126mg/dL or diagnosis or use of antidiabetic drugs [18].

Proteinuria: dip strip protein >1+ [19].

Microalbuminuria: Urine albumin creatinine ratio >30mg/g (3.4mg/mmoL) [20].

Anemia: Hematocrit <39% [21].

Hypoalbuminemia: Serum albumin <35mg/dL [22].

Hyperuricemia: Males >0.42mmol/L, Females >0.36mmol/L [23].

RESULTS AND DISCUSSION

A total of 144 (82 males and 62 females) participants were studied. The mean ages of the population, males, and females were 48.8 ± 15.9 years, 47.9 ± 16.8 years, and 50.5 ± 14.73 years respectively. Seven percent of males but 11.1% of females were >60 years, P=0.003. The mean BMI of males and females was 26.6 ± 4.3 kg/m² and 26.5 ± 4.8 kg/m² respectively, P=0.8. The BMI, systolic and diastolic BP (Table 1) were higher in males than females, P=0.04, P=0.001, and P=0.002 respectively.

BMI-body mass index, SBP-systolic blood pressure, DBP-diastolic blood pressure

A greater proportion of the cohorts had HACKD (44.4%), jointly followed by CGN (19.4%) and CIN (19.4%) (Table 2), 6.9% had obstructive uropathy and 9.7% had other causes. The proportion of men with CGN was higher than females while the proportion of women with CIN was higher than men.

The proportion of men that took RAAS inhibitors, erythropoietin, and vitamin D analogs was higher than females, P<0.001, P=0.02, and P=0.003 respectively (Table 3). The proportion of women that took calcium channel blockers (CCBs), sodium bicarbonate, and phosphate binders were higher than men, P=0.001, P=0.001, and P<0.001 respectively.

RAASIs-renin-angiotensin aldosterone system inhibitors, ACEIs-angiotensin-converting enzymes inhibitors, ARBs-angiotensin receptors blockers

As CKD worsened down the stages, the percentage of affected women increased (Table 4). The mean age, BMI, systolic and diastolic BP were 48.8 ± 15.9 years, 26.53 ± 4.51 kg/m², 146.8 ± 10.2 mmHg, and 93.7 mmHg respectively. The mean serum sodium, potassium, bicarbonate, and anion gap of the cohorts were 136.7mmol/L, 4.1mmol/L, 21.2mmol/L, and 15.7mEq respectively. The mean creatinine, GFR hematocrit, and serum albumin were 179.1 ± 14.2 umol/L, 37.2 ± 7.4 ml/min, 32.7 ± 4.4%, and 44.1 ± 8.6 g/dL respectively.

BMI-body mass index, BP-blood pressure, eGFR-estimated glomerular filtration rate

The men, compared with women, were more likely to use erythropoietin and be hypertensive, P=0.04 and P=0.03 respectively (Table 5). Hyponatremia, MA elevated AG and microalbuminuria were more common in women than in men, P=0.001, P<0.001, 0.004, and 0.04 respectively. The cortical thickness and kidney volumes were lower in women than men, P=0.02 and P=0.03 respectively.

OR-odds ratio, TIN-tubulointerstitial nephritis, BMI-body mass index BP-blood pressure, eGFR-estimated glomerular filtration rate, ACR-albumin creatinine ratio

From the multivariate model, aging (OR-3.28, CI-2.69-387), hyponatremia (OR-4.74, CI-2.10-6.33), MA (OR-4.14, CI-1.46-4.92 (Table 6), elevated creatinine (OR-3.06, CI-2.83-3.99), low eGFR (R-O4.82, CI2.68-4.95) and hypoalbuminemia (OR-4.56, CI-3.45-7.49) were independently associated with the female gender.

aOR-adjusted odds ratio, CI-95% confidence interval, eGFR-glomerular filtration rate