The Effects of Race on Acute Kidney Injury

Racial disparities in incidence and outcomes of acute kidney injury (AKI) are pervasive and are driven in part by social inequities and other factors. It is well-documented that Black patients face higher risk of AKI and seemingly have a survival advantage compared to White counterparts. Various explanations have been advanced and suggested to account for this, including differences in susceptibility to kidney injury, severity of illness, and socioeconomic factors. In this review, we try to understand and further explore the link between race and AKI using the incidence, diagnosis, and management of AKI to illustrate how race is directly related to AKI outcomes, with a focus on Black and White individuals with AKI. In particular, we explore the effect of race-adjusted estimated glomerular filtration rate (eGFR) equation on AKI prediction and discuss racial disparities in the management of AKI and how this might contribute to racial differences in AKI-related mortality among Blacks with AKI. We also identify some opportunities for future research and advocacy.


Introduction
Race can be defined "as a hierarchal human-grouping system, generating social classifications to identify, distinguish and marginalize some groups across nations, regions and the world. Race divides human populations into groups often based on physical appearance, social factors and cultural backgrounds" [1]. Race is a socio-political concept that is inseparably linked to health outcomes in individuals from minority racial status worldwide [2]. Race is not a biological concept.
Racial disparities in clinical outcomes of several health conditions are very common [3]. Such disparities have been reported in AKI, where Black race is associated with a higher risk of AKI compared to non-Black race [4]. Moreover, the prevalence of dialysis-requiring AKI is increasing annually, and Black race is an independent risk factor for initiation of dialysis in AKI patients [4][5][6][7][8]. This phenomenon is thought to be due to the close interplay of clinical, socioeconomic, and genetic risk factors [9], which are driven by structural racial category [10].
Acute kidney injury describes the sudden loss of kidney function, characterized by ≥0.3 mg/dL (≥26.5 µmol/L) rise in serum creatinine within 48 h or an increase in serum creatinine ≥1.5 times over baseline, which is known or presumed within the prior 7 days, or reduced urinary output of < 0.5 mL/kg/h within 6 h [11]. Given that AKI has significant clinical consequences, including higher hospitalization rates, increased hospital length of stay, increased in-hospital and post-hospitalization mortality, and higher risk of progression to chronic kidney disease [12][13][14][15], understanding and addressing how race directly affects patients with AKI is crucial to improving the diagnosis, treatment, and outcomes of AKI in minority racial groups.
In this review, we use the incidence, diagnosis, and management of AKI to illustrate how race is directly related to AKI outcomes, with a focus on Black and White individuals with AKI. We examine racial disparities in COVID-19-related AKI. In particular, we explore the effect of a race-adjusted estimated glomerular filtration rate (eGFR) equation on AKI prediction and discuss racial disparities in the management of AKI and how this might contribute to racial differences in AKI-related mortality among Blacks with AKI.

Racial Disparities in the Incidence of AKI
Previous studies have reported that Black patients have a disproportionately higher risk of AKI when compared with White patients [4,8,[16][17][18][19][20][21][22]. Using self-reported Black and White participants from the Atherosclerosis Risk in Communities (ARIC) study, Grams et al. [4] investigated the impact of race on the incidence of AKI-related hospitalizations. The authors in the large, prospective, community-based studies involving 10,588 African-American and Caucasian participants followed up for 13 years reported significantly higher incidence of AKI in Blacks, with a 30% higher risk in Blacks compared to Whites. After a sequential multivariable model, the risk increased to 50% following the inclusion of age and sex, suggesting that Blacks are at a greater risk of AKI despite their younger age. However, the risks were not significantly different among those participants with major mediators such as obesity, diabetes, or hypertension, which are more common in Blacks compared to Whites. The authors further showed that the relationship between race and AKI was significantly weakened with adjustment for socio-economic indicators such as access to health insurance and total annual family income.
Similarly, other studies have reported significantly higher incidence of AKI along racial lines among specialized populations, including patients with diabetes [17], trauma [20], and those undergoing procedures such as percutaneous coronary intervention [8,21] and knee surgery [19].
In contrast to the findings of Grams et al. [4] in the ARIC study, Muiru and his colleagues, in the Chronic Renal Insufficiency Cohort (CRIC) Study, a multicenter prospective study, observed that Blacks had a 22% greater hazard for AKI hospitalization than the Whites, and showed that the racial disparities in AKI were due to the differences in prehospitalization baseline clinical risk factors such as diabetes, blood pressure, and proteinuria [22]. Thus, this suggested that the increased risk of AKI among Black individuals may be mitigated through targeted screening and tighter control of blood pressure to lower proteinuria. Taken together, all these findings highlight the need for future studies to untie the "Gordian knot" between socio-economic determinants of AKI from those that might be biologic, if any.
Moreover, according to the 2018 USRDS annual data report [23], using data from the Medicare, Clinformatics TM , (OptumInsight, Eden Prairie, MN, USA) and Veterans Affairs patient population, a higher proportion of Black patients had AKI compared to Whites or Asians. Among Medicare patients aged 66 years and older, AKI incidence rates were 34.3%, 23%, and 25.9% in Black, White, and Asian patients, respectively, and for Optum Clinformatics™ (OptumInsight, Eden Prairie, MN, USA) patients aged 22 years and older, the incidence of AKI among Black, White, and Asian patients was 9.4%, 7.4%, and 3.3%, respectively. The hospitalized Veterans Affairs populations showed a similar trend-the incidence of AKI was 30.4%, 24.1%, and 24.2% among Black, White, and Asian Americans, respectively. These data therefore highlight differences in AKI incidence by race. Table 1 summarizes the evidence related to the incidence, management, and outcome of AKI in Black and White races.

Race, APOL1 Status, and Incidence of AKI
Considering the well-established genetic susceptibility for kidney disease among Black populations [33,34], it was not surprising that Privratsky et al. [35] demonstrated a greaterthan-two-fold rise in postoperative serum creatinine among Black patients with high-risk APOL1 status undergoing cardiac surgery. However, a previous study by Grams et al. [4] showed that APOL1 high-risk variant was not significantly associated with higher risk of AKI. This study was limited by reliance on billing codes to ascertain AKI, thereby resulting in ill-defined AKI phenotypes. Given that there are several recent reports of association between high-risk APOL1 status and increased risk of AKI among patients infected with severe acute respiratory coronavirus 2 (SARS-CoV-2) [35][36][37][38][39][40][41], further studies are needed to elucidate APOL1 biology, its role in well-defined AKI cases, and its possible modifying effect on progression to CKD after injury.

Race and COVID-19-Related AKI
Acute kidney injury is a well-recognized complication of SARS-CoV-2 infection, with an incidence rate of 20% among hospitalized patients and greater than 50% among the critically ill patients [42]. Since the first case of SARS-CoV-2 infection which causes coronavirus disease 2019 (COVID-19) was reported in Wuhan, China, racial disparities in the development, severity, and outcomes of this disease have become increasingly reported [43][44][45]. According to the Centers for Disease Control, Blacks had a 1.1 times higher rate of COVID-19 patients, 2.3 times higher rate of COVID-19 hospitalization, and 1.7 times higher COVID-19 mortality rate than Whites [46]. Accordingly, several previous studies have reported that Black patients with COVID-19 had approximately 1.2-2.2 times increased odds of developing in-hospital AKI compared to their White counterparts [47][48][49][50]. Even though the exact mechanism of racial disparities in risk of COVID-associated AKI is yet to be elucidated, some possible mechanisms have been proposed. Genetic polymorphisms involving ACE2, IL-6, and AChE genes are closely associated with higher burden of COVID-19 disease and these gene polymorphisms have been shown to be more common in Black individuals [51,52]. In addition, Black populations are exposed to a higher risk of vitamin D deficiency, and it has been proposed that Vitamin D plays a protective role against COVID-19 infectivity and severity through its ability to modulate the immune system by suppressing T helper-1 functions and potentiating expression of the regulatory T cells, thereby causing less severe cytokine storm [53,54]. Hence, Black patients may face higher risk of cytokine storm and associated systemic and intrarenal inflammation. Table 2 summarizes studies highlighting association between race and COVID-19-induced AKI.

Race-Adjusted eGFR and AKI Prediction
The use of race-adjusted eGFR is controversial in nephrology [58]. Low eGFR is a strong predictor of AKI and is routinely used by clinicians to predict the risk of AKI following contrast-related procedures [59]. Traditionally, eGFR is estimated using the Modification of Diet in Renal Disease (MDRD) and Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula that includes a correction factor for Black race [60,61]. Remarkably, the inclusion of the race correction factor in the eGFR equation is methodologically flawed because it does not take into account the ancestral diversity among Black patients and patients with mixed racial background, and the fact that it is subjective as a result of self-identification of race. Consequently, in recognition of the fact that race is a social construct with only limited utility in medicine, the National Kidney Foundation and the American Society of Nephrology have now recommended the removal of the race correction factor in eGFR calculation [62], necessitating exclusion of race variables in the new eGFR equations that are currently being developed [63]. In a preprint research study, which used data from the American College of Cardiology (ACC) National Cardiovascular Data Registry (NCDR) CathPCI Registry, Huang and his colleagues demonstrated the impact of removing race from eGFR equations for predicting AKI. The authors showed that the inclusion of the race correction factor significantly underestimated risk for AKI among Black populations (predicted 7.6% vs. observed 10.2%) while marginally overestimating AKI risk among the non-Black population (predicted 7.4% vs. observed 7.1%). However, when the race correction factor was removed, the underestimation of AKI risk was partially corrected among Black patients (predicted 8.2%), and the underestimation was further reduced (predicted 10.1%) by including race as an independent predictor in the AKI model [64]. Hypothetically, eliminating race correction factor from eGFR equations can potentially influence diagnostic and treatment decisions that will take into account each patient's body habitus, comorbidities, and lifestyle considerations [65,66].

Racial Disparities in the AKI-Related Mortality
Even though African Americans (Blacks) in the general population are at a higher risk of cardiovascular and non-cardiovascular mortality when compared to Whites [67,68], several reports have suggested that a paradox exists for individuals with AKI, with Black patients having better survival rates than their White counterparts [15,26,69]. Waikar et al. [26], in their study of hospitalized acute renal failure patients between 2000 and 2003 using the Nationwide Inpatient Sample, showed a survival advantage among Black patients with AKI compared to their White counterparts, with Black patients having 16% (95% confidence interval, 10-20%) lower odds for death than White patients with AKI. In our study that included data of 11,567 AKI patients managed at the University of Virginia Health System, we demonstrated that Black patients had lower in-hospital mortality than Whites, with adjusted odds ratio 0.82, 95% confidence interval 0.70-0.96, p = 0.0015. Following further analysis, we also extended the findings of the previous workers by demonstrating Black patients had lower 90-day post-hospitalization mortality and better long-term survival advantage when compared to their White counterparts [15]. Similarly, data from the United States Renal Data System (2021 USRDS Annual Data Report) also showed a survival advantage for Black populations compared to White populations after 24 months' follow-up; Black patients had 38,6% death rates compared to 41.7% death rates in White patients. Previously postulated explanations for this paradoxical finding such as increased access to health care due to medical insurance, "reverse epidemiology" of cardiovascular risk factors, differences in susceptibility to kidney injury, severity of illness, or the response to uremia, warrant additional well-designed investigation [15,26].
Interestingly, like AKI patients, Black patients with end-stage renal disease (ESRD) had also been documented to have lower mortality rates than Whites, and many well-described mediators of paradoxical survival advantage observed among ESRD patients may also be relevant in AKI patients. Most importantly, the similar findings of improved survival for Black patients with AKI and ESRD compared to White patients may suggest that the response to uremia or its treatment may vary by race [26]. Furthermore, previous studies have documented racial differences in biologic processes underlying the pathogenesis of AKI and ESRD, such as interactions between APOL1 genotype and cause of kidney disease [70], abnormalities in endothelial functions [71,72], oxidative stress [73], and inflammation [74]. It is plausible that these biologic factors may account for the paradoxical survival advantage by AKI/ESRD status among Black patients. Further population-based genetic studies in AKI and ESRD patients are warranted to confirm these findings.

Racial Disparities in the Management of AKI
Patients with AKI are at increased risk of progressive chronic kidney disease (CKD) [75], including ESRD, where they are exposed to additional racial health disparities that impact on AKI outcomes. In addition to facing AKI-related racial disparities, compared to White patients, Black patients receive less intensive hemodialysis and inferior hemodialysis access [76], and are less likely to be offered renal transplantation [77]. Socioeconomic status and limited access to healthcare play a role regarding the racial inequities in the treatment and outcomes of kidney disease. For example, as a result of low income, poor access to healthcare, and lack of health insurance, late referral of Black and/or poor patients with kidney disease for care by a nephrologist prevents these patients from receiving optimal care [78,79]. Figure 1 illustrates how sociocultural factors influences racial/ethnic minority health with implications for progression of AKI to CKD/ESRD. Notably, attempts have been made recently to improve the quality of healthcare with efforts targeted at eliminating racial and ethnic disparities in health, and this may have major implications for the prevention, diagnosis, and treatment of kidney disease [80][81][82]. Mortality rates in patients with AKI remain high in spite of the skyrocketing cost of the health insurance-funded program. It is conceivable that elimination of these racial disparities would improve outcomes in patients with AKI.
In conclusion, the racial disparities in the incidence, social and biologic determinants,  Figure 1. Sociocultural influences on racial/ethnic minority health with implications for progression of acute kidney injury to chronic kidney disease. Adapted with permission from Ref. [6]. 2022, Elsevier.
Notably, attempts have been made recently to improve the quality of healthcare with efforts targeted at eliminating racial and ethnic disparities in health, and this may have major implications for the prevention, diagnosis, and treatment of kidney disease [80][81][82]. Mortality rates in patients with AKI remain high in spite of the skyrocketing cost of the health insurance-funded program. It is conceivable that elimination of these racial disparities would improve outcomes in patients with AKI.
In conclusion, the racial disparities in the incidence, social and biologic determinants, diagnosis, and outcomes of AKI are well-documented and vary between Black and White populations. Disparities in health outcomes as a result of socioeconomic status are discriminating and unjust. Therefore, it is very important to disentangle socioeconomic determinants of AKI such as individual-level income, education, and insurance from those that are biologic risk factors such as diabetes, hypertension, obesity, and cardiovascular disease, which are pervasive in Black populations. Moreover, in order to improve the healthcare of disenfranchised ethnic minorities globally, it is imperative to address lingering racial and ethnic health disparities across the spectrum of kidney disease that continue to perpetuate limited educational opportunities, socioeconomic imbalances, and limited access to healthcare delivery to improve health outcomes of disadvantaged racial minorities with AKI.