Sexually dimorphic adaptations to hyperkalemia in rats with chronic kidney disease

Background: Hyperkalemia (HK) is a potentially life-threatening sequelae and an independent risk factor for poor renal and cardiovascular outcomes in patients with chronic kidney disease (CKD). Men with non-dialysis CKD reportedly have higher serum potassium levels and a greater prevalence of HK when compared to women. HK is also associated with worse cardiovascular outcomes in men than in women with CKD, possibly due to differences in the pathophysiology of kidney disease or hypertension. Our mechanistic understanding of these sex-related variations in clinical outcomes is limited, in part, by a lack of a robust animal model predictably exhibiting HK on the background of CKD. Here, we developed a model of diet-induced HK in 5/6 nephrectomized (Nx) Sprague-Dawley (SD) rats to test the hypothesis that, in the face of a hyperkalemic insult, female rats with CKD maintain higher urinary K + excretion rates and lower serum K + levels when compared to males. Methods: We established a rat model of chronic HK that is driven by dietary intervention. To do this, ten 12-week-old SD rats of both sexes underwent 5/6-nephrectomy (Nx). After a 7-day recovery period, 5/6 Nx rats were switched from a regular chow containing 1% to a 10% KCl diet for 7 days to achieve persistent HK. To assess progression of HK, blood was drawn via lateral vein sampling at D1, D2, D4, and D7 on 10% KCl diet and at the same time points after rats were switched back to a regular chow. Urine was also collected at D1 and D7 on the 10% KCl diet, as well as D1 and D7 after switching back to a regular chow. Urinary electrolyte excretion rates were calculated and normalized to body weight. At the endpoint, the remaining kidney was fixed and stained with picrosirius red to assess fibrosis. Results: Circulating K + levels were 4.76±0.3 mEq/L in males and 4.81±0.7 mEq/L in females on a regular K + intake one week after 5/6 Nx. Serum K + significantly increased when the rats were placed on a 10% KCl diet, reaching 8.8±0.9 mEq/L in males and 7.4±0.6 mEq/L in females at D7 (p<0.0001). Urinary K + excretion was 64.3±22.8 umol/gBW*24hr in females and 40.4±13.6 umol/gBW*24hr in male rats at D7 on a 10% KCl diet (p<0.001). After rats were switched back to a regular chow for 7 days, urinary K + excretion returned to pre-HK levels (7.35±0.9 and 12.5±2.4 umol/gBW*24hr for males and females respectively) and serum K + levels reached 5.46±0.4 mEq/L in males and 5.21±0.7 mEq/L in females. Renal fibrosis levels were almost twofold lower in 5/6 Nx post-HK female rats when compared to males (P=0.03). Conclusions: Our study establishes 5/6 Nx rats on a 10% KCl diet as a rigorously manageable model of chronic hyperkalemia on the background of CKD. 5/6 Nx male rats challenged with a high K + intake develop more severe hyperkalemia and renal fibrosis than females, whereby females have a greater ability to excrete K + with urine, despite the equivalent loss of renal mass after 5/6 Nx. This work was supported by the National Institute of Diabetes and Digestive and Kidney Disease 396 (NIDDK) R01DK125464 grant to MM. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.