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ORIGINAL ARTICLE
Year : 2023 | Volume
: 22
| Issue : 2 | Page : 160-166
Original research gender differences in recovering from cardiac and vascular surgery associated acute kidney injury: A six-year retrospective comparative study in Nigeria
Peter Kehinde Uduagbamen1, Michael Sanusi2, Olumide Baz Udom2
1 Division of Nephrology and Hypertension, Department of Internal Medicine, Bowen University/Bowen University Teaching Hospital, Ogbomosho; Division of Nephrology and Hypertension, Department of Internal Medicine, Ben Carson (Snr) School of Medicine, Babcock University/ Babcock University Teaching Hospital, Ilishan-Remo, Nigeria
2 Tristate Heart and Vascular Centre, Ben Carson (Snr) School of Medicine Babcock University/Babcock University Teaching Hospital, Ilishan-Remo, Nigeria
Correspondence Address:
Peter Kehinde Uduagbamen
Division of Nephrology and Hypertension, Department of Internal Medicine, Bowen University/Bowen University Teaching Hospital, Ogbomosho
Nigeria
Source of Support: None, Conflict of Interest: None
CheckDOI: 10.4103/aam.aam_81_21
Abstract
Introduction: Gender differences exist in the demographic, clinical characteristic and outcome of patients with cardiac and vascular surgery (CVS) associated acute kidney injury (AKI). Materials and Methods: This retrospective study had a total of 88 participants for which socio-demographic, clinical and laboratory (serum electrolyte, full blood count, urine analysis and urine volume, creatinine, and glomerular filtration rate) data of participants were taken preoperative and postoperative days 1, 7, and 30. Results: A total of 88 (66 males and 22 females) participants were studied. Diseases of the heart valves were more common in females than males. The mean age of the participants was 65.9 ± 6.9 years, with males 65.1 ± 7.6 years and females 68.3 ± 8.4 years, P = 0.02. Before surgery, a significantly greater proportion of females had kidney dysfunction compared to males, P = 0.003. Valvular surgery and coronary bypass were the most common surgeries. The proportion of emergency surgeries and admissions <7 days were significantly higher in females than males, P = 0.04 and P = 0.02, respectively. Full recovering from AKI was significantly higher in males as partial recovery and death were significantly lower in them, P = 0.02. Of the 35 (39.8%) who had dialysis, 85.7% recovered fully, 5.7% became dialysis, and dependent while 8.6% died. The predictors of nonrecovery from CVS-AKI were female gender, elderly, preoperative kidney dysfunction and AKI stage 3. Conclusion: Males with AKI were younger than the females. Valvular surgeries were most common. Background kidney dysfunction and advance age were risk factors for AKI. Postoperative, AKI was commoner in males who were more likely to recover full kidney function. Optimizing patient preparation could reduce the incidence of CVS-AKI.
Abstract in French Résumé
Introduction: Il existe une différence entre les sexes dans les caractéristiques démographiques, cliniques et les résultats des patients atteints d'IRA associée à une chirurgie cardiaque et vasculaire. Méthodes: Cette étude rétrospective a eu un total de 88 participants pour lesquels les données socio-démographiques, cliniques et de laboratoire (électrolytes sériques, numération globulaire complète, analyse d'urine et volume d'urine, taux de créatinine et de filtration glomérulaire) des participants ont été prises avant et après l'opération. jours 1, 7 et 30. Résultats: Au total, 88 participants (66 hommes et 22 femmes) ont été étudiés. Les maladies des valves cardiaques étaient plus fréquentes chez les femmes que chez les hommes. L'âge moyen des participants était de 65,9 ± 6,9 ans, avec des hommes de 65,1 ± 7,6 ans et des femmes de 68,3 ± 8,4 ans, P = 0,02. Avant la chirurgie, une proportion significativement plus élevée de femmes avaient un dysfonctionnement rénal par rapport aux hommes, P = 0,003. La chirurgie valvulaire et le pontage coronarien étaient les chirurgies les plus courantes. La proportion de chirurgies d'urgence et d'admissions de moins de 7 jours était significativement plus élevée chez les femmes que chez les hommes, P = 0,04 et P = 0,02 respectivement. La récupération complète de l'IRA était significativement plus élevée chez les hommes, car la récupération partielle et la mort étaient significativement plus faibles chez eux, P = 0,02. Sur les 35 (39,8%) qui ont été dialysés, 85,7% se sont complètement rétablis, 5,7% sont devenus dépendants de la dialyse tandis que 8,6% sont décédés. Conclusion: Les hommes atteints d'IRA étaient plus jeunes que les femmes. Les chirurgies valvulaires étaient les plus courantes. Le dysfonctionnement rénal de base et l'âge avancé étaient des facteurs de risque d'IRA. Après l'opération, l'IRA était plus fréquente chez les hommes qui étaient plus susceptibles de récupérer une fonction rénale complète. L'optimisation de la préparation des patients pourrait réduire l'incidence de CVS-AKI.
Mots-clés: Chirurgie cardiaque et vasculaire associée insuffisance rénale aiguë, dialyse, récupération de la fonction rénale, chirurgie valvulaire
Keywords: Cardiac and vascular surgery associated acute kidney injury, dialysis, recovering of kidney function, valvular surgery
Introduction 
Sexual dimorphism affects the course and outcome of kidney disease.[1] Cardiac and vascular surgery (CVS) associated acute kidney injury (AKI) results from ischemia-reperfusion (IR) induced by reduced renal blood flow and hemodilution during cardiopulmonary bypass (CPB).[2] Tubular damage from IR could be potentiated by testosterone, just as estrogen is reported to be reno-protective.[3] Similarly, sex hormones could influence the recovery course as endothelium releases nitric oxide (eNO), other vasodilators while suppressing pro-inflammatory mediators.[4] Literature is still unavailable on gender implication on AKI outcome after CVS in sub-Sahara Africa hence this study, to reduce the knowledge gap.
Materials and Methods Study design and location
This retrospective comparative study was conducted at the Tristate Heart and Vascular Center, a high-dependency cardiac and vascular surgical center dedicated to providing cardiac and vascular repair, replacement, and implantation procedures in South Western Nigeria. The hospital receives patients across all ages from all parts of Nigeria and neighboring West and Central African nations.
Data collection
Data of patients who had cardiac and/or major vascular surgery from January 2015 to December 2020 in the center were retrieved from perioperative charts, case notes, intensive care unit (ICU) charts, and the center's database. Variables retrieved were: age, sex, major presenting complaints, body mass index, type of cardiac and/or vascular disease, duration of disease, surgery duration, previous surgical procedure related to disease, elective/emergency surgery, mean arterial pressures (MAPs), heart rate, duration of hospital stay until discharge or death and comorbidities (heart failure, chronic liver disease, chronic kidney disease, sickle cell anemia, and stroke or cancer). Also retrieved were urinalysis, arterial blood gases, serum electrolyte, urea and creatinine, glomerular filtration rate (GFR), full blood count, erythrocyte sedimentation rate and blood glucose tests on postoperative day 1 (POD 1), POD 7 and POD 30 and results of fasting lipids and liver function (preoperative and POD 30), infections and daily fluid charts.
Exclusion criteria
Participants <16 years, surgery 30 days before index surgery, repeat surgeries for the same condition, missing data, end-stage kidney disease, brain death, and death within 24 h postsurgery.
AKI was defined and staged according to the kidney disease improving global outcome (KDIGO) criteria.[5]
Definitions of terms
AKI: Increase in serum creatinine by 0.3 mg/dl (26.5 umol/L) within 48 h, or increase in serum creatinine, ×1.5 from baseline, known or presumed to have occurred within the previous 7 days or urine volume (UO) <0.5 ml/kg/h for 6 h[5]AKI Stage 1: Serum creatinine rise of ≥26 umol/L within 48 h or 150%–199% of baseline within 7 days or UO <0.5 ml/kg per hour for more than 6 hAKI Stage 2: Serum creatinine 200%–299% of baseline within 7 days or UO <0.5 mls/kg per hour for more than 12 hAKI Stage 3: Serum creatinine ≥300% of baseline within 7 days or concentration of ≥354 umol/L within 48 h or ≥50% rise from baseline within 7 days or any requirement for renal replacement therapy (RRT) or OU <0.3 ml/kg per hour for 24 h or anuria for 12 hKidney dysfunction: GFR <60 ml/min[6]Acute kidney disease (AKD): Diagnostic criteria for AKI persistent for up to 1 month[7]Sepsis: Culture confirmed or suspected microbial infection, with at least 2 of temperature >38°C or <36°C, pulse rate >90/min, respiratory rate >20 cycles/min, white cell count of >11,000 cells/mm3 or <4000 cells/mm3[8]Hypovolemia: Fluid loss with features of dehydration and changes in the hemodynamics such as tachycardia and hypotensionHypotension: Blood pressure (BP) <90/60 mmHg[9]Intra-operative hypotension: MAP fall >20 mmHg for >5 min[10]Hypertension: BP >140/90 mmHg or physician-diagnosed hypertension or using BP lowering drugs to control BP[11]Intraoperative hypertension: MAP rise >10 mmHg[10]Diabetes: Fasting blood glucose >126 mmol or glycated hemoglobin A1c ≥6.5 or physician-diagnosed diabetes[12]Anemia: Hematocrit <33%[13]Hypoalbuminemia: Serum albumin <35 mg/dl[14]Metabolic acidosis: Serum bicarbonate <22 mmol/l[15]Standard base excess: <−2 mEq1-1[15]Anion gap (AN): Sodium + Potassium – Chloride – Bicarbonate[15]Elective surgery: Procedure scheduled in advanceEmergency surgery: Procedure not scheduled in advance, with or without attaining stable preoperative hemodynamic stabilityMajor surgery: Open heart surgery requiring total intravenous anesthesia Prolonged surgery: Surgery lasting more than 2 h (120 min)Total intravenous anesthesia (TIVA): (involving the whole body).Clinical outcomes
Complete recovery of kidney function: Serum creatinine returns to preinduction value or less[16]Partial recovery of kidney function: Reduced severity of AKI grade but not less than stage 1.[16] AKD: Progression of AKI beyond POD 30[7]Death: Death after 24 h of admission into the ICU, up to POD 30.Statistical analysis
Data were analyzed using the Statistical Package for Social Sciences (SPSS) version 22.0 (IBM Inc., NY, USA). Continuous variables were presented as means or medians and categorical variables were presented as proportions. Paired t-test was used to determine the association between continuous variables that were normally distributed and continuous variables that were not normally distributed and were compared using the Mann–Whitney U-test. Associations between categorical variables were compared using the Chi-square test or Fisher's exact test when <5 observations were recorded. Multivariate analyses were conducted to identify independent predictors of AKI in which variables with a P < 0.25 on univariate analysis were entered, to determine independent associates of “recovering from AKI” with backward elimination to adjust for confounders.[17] It is reported that the use of P < 0.05 oftentimes does not identify all important variables. Associations between variables were considered significant for P < 0.05. Ethical clearance: The Institutional Ethical Committee on Human Research of Babcock University approved the study (BUHREC558/19, NHREC/24/01/2018) and this research followed the tenets of the Declaration of Helsinki.
Results A total of 311 participants had CVS, of this, the 88 (28.3%) that had AKI were studied. Diseases of the heart valve were more common in females than males. Aortic valve disease, followed by 3-vessel disease, was the most common diagnosis while visible resonance Raman (VRR) followed by VRR with coronary artery bypass grafting (CABG), was the most common surgery done [Table 1]. The mean age of the study population was 65.9 ± 6.9 years. Sixty-six (75.0%) males and 22 (25.0%) females had AKI with a mean age of 65.1 ± 7.6 years and 68.3 ± 8.4 years, respectively. In the population that had surgery, 31.6% of the males and 21.4% of the females had CVS-AKI. In the CVS-AKI population, 86.4% of the males and 77.3% of the females had full recovering of kidney function, 4.5% and 9.1% had partial recovering while 9.1% and 13.6% died, respectively. Compared with males, a greater proportion of the females was elderly (P = 0.03), had emergency surgery (P = 0.04), and spent <7 days on admission, P = 0.02 [Table 2]. Females had a higher proportion of participants with background kidney dysfunction than males, P = 0.003. Forty (45.5%) participants were scheduled for dialysis of which only 35 (39.8%) had dialysis. One (2.0%) out of the 48 not scheduled for dialysis, the 5 (100%) that could not make dialysis and 3 (8.6%) of the 35 dialyzed died. Males were more likely to have complete recovering from AKI than females, who were more likely to die from CVS-AKI, P = 0.03 [Table 3]. Within the elderly population, females were less likely to recover from AKI than males, P = 0.002. The proportion of females with CVS-AKI that had dialysis was less compared to males, P = 0.04. From multivariate regression analysis [Table 4], the predictors of nonrecovery from CVS-AKI were, female gender (odds ratio [OR]-3.12, confidence Interval [CI]- 0.56–8.22), elderly (OR4.1, CI- 0.32–9.47), preoperative kidney dysfunction (OR- 3.65, CI- 1.15–8.94), and AKI stage 3 (OR- 7.36, CI- 0.85–12.54).
Table 4: Regression analysis showing predictors of nonrecovering from acute kidney injury Discussion We found gender differences in the recovery of participants with CVS-AKI. There was a preponderance of males who were younger, had a higher risk of having AKI, a higher tendency to recovery and a lower tendency to die from CVS-AKI than females. In the AKI population, full recovery was found in 86.0% of males and 77.3% of females, partial recovery was found in 4.5% and 9.1% while mortality was found in 9.1% and 13.6%, respectively. The incidence of preoperative kidney dysfunction and comorbidities were more common in the females. The male preponderance in this study is similar to findings by Srisawat et al.[18] who reported that with the KDIGO criteria, the risk for CVS-AKI was more in males but showed no sexual bias using the RIFLE criteria. IR injury was reported to have occurred in males after 30 min of bilateral renal ischemia but after 60 min in females.[19] KDIGO, however, found a higher incidence of hospital-acquired AKI (HA-AKI) in females.[6] Similarly, Neugarten et al.[20] in a systematic review of 64 studies using the three AKI criteria, overall, found no gender differences in incidence but using the KDIGO-AKI criteria (as in this study), they found a CVS-AKI incidence of 28.5% in males and 27.0% in females. The reported high prevalence of hypertension in males in the general population could have contributed to this pattern of presentation. The presence of testosterone rather than the absence of estrogens is reported to be a major contributory factor in the etiology and progression of kidney disease due to its pro-inflammatory and apoptotic effects on the renal tubules.[3] Males were more likely to recover full kidney function despite been more likely than females, to develop CVS-AKI. This recovery advantage of males over females mirrors findings by KDIGO.[6] Iran-Nejad et al.[21] and Aryamanesh et al.[22] who, using animal models, reported a higher incidence of male rats recovery from AKI than females. Our findings are in contrast to findings of reno-protection associated with females which have been attributed among other things, to the protective effect of estrogens from the hydroxyl group at C3 position of the A ring of the steroid molecule.[23] In addition, females are reported to possess more protein kinase B (Akt), a substance with anti-apoptotic features coupled with the opening of the voltage-gated potassium channels (KATP) that decreases calcium influx.[19],[24] Testosterone inhibit adenosine mediated vasodilatation, its low concentration in females therefore contributes to the relative protection from CVS-AKI seen in them.[25] Despite numerous studies that reported relative female protection in AKI, persistence of AKI and mortality were commoner in females in our study. This finding mirrors several studies that found female gender as an independent risk factor for CVS-AKI and increase in morbidity and mortality rates contrary to findings in noncardiac surgery-associated AKI.[26],[27],[28] Considering the mean age of 68.3 ± 8.4 years for the females cohorts, it is apparent that it was predominantly a postmenopausal population. Obialo et al.[29] and Schiff et al.[30] reported that the reno-protection associated with females was lost in postmenopausal age due to reductions in estrogen and its tissue and vascular protective properties. Overall, female presentation is delayed in our local setting due to factors associated with cultural belief, low economic power, and educational attainment.[31] The higher incidence of emergency surgeries and comorbidities, associated with a poorer control of the hemodynamics that resulted from a delayed presentation by female cohorts most likely obliterated any residual renal survival advantage of the females.
Background kidney dysfunction was more common among females and this mirrors findings by Mehta et al.[26] and this could also have heightened their CVS-AKI-associated morbidity and mortality. Stevens et al.[32] found the creatinine clearance a better measure of assessing kidney function than serum creatinine. Operative mortality is reported to increase 3-fold in cardiac surgery, and with preoperative kidney dysfunction, mortality risk is increased 8-fold.[33] Though we did not assess the effect of nephrotoxins in our study, the smaller weight of females, with constitutional higher body fats and volume of distribution, higher levels of perioperative drug nephrotoxicity could have contributed to their poorer treatment outcome. Females were reported to present late for coronary artery revascularization and cardiac valve repair hence higher morbidities like cardiovascular diseases, found in them, as in our study (and this was also reported by Mehta et al.) could have contributed to their poor treatment outcome compared with males.[26],[27],[28] Later presentation of females could be multifactorial, one, the anti-inflammatory and anti-apoptotic effects of estrogens in female reproductive age that delays the emergence of symptoms,[19],[26] and second, the health-seeking bias against women due to cultural practices, educational and economic limitations (quite common in sub-Saharan Africa) could also be contributory The hemodilution in CPB is reported to further increase the severity of renal injury in females due to their lower hematocrit just as hemodilution is reported to limit the detection rate of AKI episodes in cardiac bypass surgeries.[3] In a renal registry with multicenter studies, in a population study of 503,478 patients who had isolated CABG, females were found to have a lower risk of CVS-AKI (OR- 0.94, 95% CI- 0.89–1.00) and with lower morbidity and mortality. And yet in the same registry, women were found to have a heightened risk of CVS-AKI and its adverse effects hence the authors concluded that there was no gender difference in the risk for CVS-AKI and its complications. The incidence of dialysis treatment in our study was 39.8%, and it is higher than the 10%–25% range found by Kumar and Suneja in the US, who also reported that RRT in CVS-AKI increased the mortality by up to 50%.[33] Late presentation, delayed nephrologist review, higher comorbidity profile, financial constraint, and suboptimal hemodynamics may play part in this wide difference. Females were less likely to have dialysis treatment and this contrast with findings by Wilson et al.[34] Since the proportion of females increased with AKI stage in our study, we infer that their relatively lesser dialysis sessions are most likely related to cultural and economic limitations.[31] The threshold for dialysis is not strictly based on widely applied criteria, this allows a wide center-to-center variations in prescribing dialysis. The close involvement of the kidneys, heart, and vasculature in body hemodynamics further makes AKI resulting from CVS of great clinical significance. IR injury leads to a complex inflammatory cascade involving renal endothelial tissues, inflammatory mediators, chemokines, and complement activation leading to the upregulation of adhesion molecules leukocytes activation and sequestration, and tubular injury.[2],[19] Endothelin A release mediates vasoconstriction and there is the translocation of sodium-potassium adenosine triphosphate (N + K + ATP) from the basolateral to the apical membrane. The resulting loss of polarity causes increased transcellular sodium transport in the proximal tubules which delivers a high sodium load to the distal tubules, with increased intracellular calcium release which mediates apoptotic and necrotic processes.[21] It is reported that testosterone mediates inflammatory tubular damage and that castration reduces the risk of AKI in males only while oophorectomized females are reported to be at a higher risk of nonrecovery from AKI.[4] The capacity of the kidneys to recover from kidney injury is based on endothelial release of nitric oxide (eNO), protein kinase β and suppression of endothelin A. Also needed for post-injury renal recovery is induction of hypoxia inducible factor (HIF) and inducible NO activities, restoration of cellular polarity, and increased transcellular sodium transport with reduced intracellular calcium availability and activity.[2],[19] We infer that the higher incidence of lower MAP, intraoperative hypotension, and intraoperative use of inotropes in females than males (which can be associated with females' later presentation and their greater involvement in emergency surgeries), among other factors, contributed to their lower likelihood of recovery from AKI. This fact is further buttressed by the higher incidence of use of TIVA in females. Vives et al. had reported that optimizing patients' hemodynamics reduced the incidence and adverse outcome of CVS-AKI.[2] The higher incidence of preoperative sepsis in females, which could have contributed to the lower recovery rate in them might not be unrelated to the higher incidence of emergency surgeries where optimization of hemodynamics might not have been achieved. Medeiros et al.[35] found sepsis a culprit for increased morbidity and mortality in CVS-AKI. The lesser tendency to recover from CVS-AKI in females compared to males could be associated with factors ranging from genetic to clinical to socioeconomic and cultural differences from males.[26],[31] Considering the fact that females appeared to possess survival advantages over males genetically, optimizing the clinical, socioeconomic, and cultural deficits in them before CVS could obliterate or even reverse the poor treatment outcome associated with CVS-AKI in them.
This study is not without limitations. The duration of CPB was not documented. We could not determine the degree and severity of the comorbidities and other risk factors not adequately entered in the covariates that were used in the multivariate analysis. We did not assess the effects of nephrotoxins on participants' kidney function. Creatinine for GFR determination was not analyzed on a daily basis, so short-term episodes of AKI could have been missed.
Conclusion Gender differences exist in perioperative CVS-AKI. There was a male preponderance though females were older and had more preoperative kidney dysfunction, sepsis, and comorbidities hence preoperative optimization was less likely in them. Valve dysfunction was the most common dialysis and their repair and replacement were the most common surgeries performed. The male cohorts were more likely to develop CVS-AKI, to have dialysis treatment, and to recover fully from CVS-AKI. Partial recovering and death were more common in females. Dialysis significantly lowered the mortality rate. Optimizing the modifiable risk factors before surgery could significantly improve the treatment outcome in CVS-AKI, particularly in females.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
References 
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