Sex and Acute Kidney Injury

Enigmas abound in the clinical care and research related to acute kidney injury (AKI). Unfortunately, little conversion of research findings to changes in patient care has occurred.

The complexities associated with staging clinical AKI and identifying the timing of the insult, as well as the inability to identify characteristics that clearly define why and how certain patients recover while others progressively decline in renal function—some leading to chronic kidney disease (CKD)—all lead to an unsatisfying status of care for patients. Likewise, discordant findings in pre-clinical models of AKI have led to more questions than answers.

Sex remains a variable that has not often been examined specifically. Older studies, in both clinical and basic science investigations, have focused on male-only populations, owing to the lower incidence of AKI in females, or have been of mixed sex. Insufficient power in these latter studies to examine sex as a variable has resulted in an assumption of understanding without proper consideration that females may in fact exhibit different biology. With the advent of a focus on inclusion of women and females in research studies advocated by the National Institutes of Health NIH (1), a new awareness of the distinctions between women and men, and female and male subjects, is evolving.

Recent clinical studies are targeting female sex as a variable. At times, however, these studies are complicated by the inclusion of women across an age spectrum that includes the menopausal shift. In addition, the reality of comorbidities in patients has made deciphering a sex-specific effect challenging. Studies in which the initiation of the insult can be identified in advance (e.g., cardiac procedures, renal transplantation) are few and have had conflicting outcomes, perhaps owing to the presence of preexisting kidney or vascular disease, which may mask a female sex–defined protection.

The key is to remain persistent in our curiosity and perseverance to uncover the amazing physiology and pathophysiology of kidneys, male and female, so that robust changes can come to the care of patients with AKI.

Basic science studies into the injury and reparative mechanisms in AKI allow for better precision in defining the insult and also allow for the absence of other comorbidities. A caveat to such studies of AKI is the lack of complete concordance between rodent models of AKI and the multiple manifestations of human AKI. As noted by ASN Past President Bruce Molitoris, MD, FASN, and colleagues a number of years ago, AKI models are “imperfect, but indispensable” (2).

Two primary rodent models of AKI are renal ischemia-reperfusion injury (IRI), which is induced by clamping the renal pedicle, or systemic administration of a toxin, principally cisplatin, heavy metals, or other nephrotoxins. IRI is further complicated by variations in clamping of one kidney only, with or without contralateral nephrectomy, or bilateral pedicle clamping, often with varying durations of ischemia. Dosing schemes for administering a nephrotoxin may also vary, both in absolute amount as well as temporal administration differences, and a variety of agents may be used.

Notably, these studies rely on our basic understanding of renal physiology, much of which has been done in male rodents. Mechanistic studies of sex-specific differences in AKI are only beginning to be done, and clearly more research is needed. One overriding question worthy of investigation is deciphering why females, both humans and rodents in our models, exhibit a decreased susceptibility to AKI. In that distinction may lie novel and innovative treatments that can be applied to men and women, as well as new biomarkers to help stage and effectively treat preemptively in the course of injury.

As Albert Einstein said, “If we knew what it was we were doing, it would not be called research, would it?” The key is to remain persistent in our curiosity and perseverance to uncover the amazing physiology and pathophysiology of kidneys, male and female, so that robust changes can come to the care of patients with AKI.

March 2018 (Vol. 10, Number 3)

References

1. National Institutes of Health. Consideration of sex as a biological variable in NIH-funded researchhttps://grants.nih.gov/grants/guide/notice-files/NOT-OD-15-102.html.

2. Lieberthal W, Nigam SK. Acute renal failure. II. Experimental models of acute renal failure: imperfect but indispensable. Am J Physiol Renal Physiol 2000; 278:F1–F12.