#2526 Sex differences in chronic kidney disease-related complications and mortality across levels of glomerular filtration rate
Authors: Lombardi Gianmarco , Ferraro Pietro Manuel , De Tomi Elisa , Bargagli Matteo , Spasiano Andrea , Gambaro Giovanni 
Published: May 2024

Abstract

Background and Aims
Chronic kidney disease (CKD) is a growing global health concern. In recent years, studies have increasingly focused on the differential risk profile of diseases between men and women. Current evidence suggests that sex-linked biological and behavioral differences may play a key role in influencing the incidence, prevalence, and outcomes of diseases. Similarly, previous studies have demonstrated a differential risk profile in the prevalence, progression, and outcomes of CKD between men and women. Recent research has indicated sex disparities in CKD-related complications, yet the impact of sex differences on critical kidney function levels that trigger these complications and mortality remains inadequately documented.

Method
We investigated sex-specific disparities in CKD-related complications and mortality according to eGFR levels. We analyzed NHANES data spanning from 1999 to 2018, including adult participants with an eGFR of 15-150 ml/min per 1.73 m². The outcomes were CKD-related complications (hypertension, anemia, CV diseases, acidosis, hyperphosphatemia, hyperparathyroidism) and all-cause and cause-specific mortality (CV mortality and non-CV mortality). Sex-stratified multivariable logistic and Cox regression models yielded odds ratios (ORs) and hazard ratios (HRs) for the relationship between eGFR categories and outcomes. Sex-stratified natural splines were used to explore the relationship between continuous eGFR and outcomes and identified eGFR thresholds of statistical significance. Values of eGFR over which the log-odds (for CKD-related complications outcomes) or log-hazard (for all-cause and cause-specific mortality outcomes) was found to be significantly different from zero (i.e., 95% CI for the smooth term did not contain zero) were identified as thresholds of statistical significance.

Results
The study included 49, 562 participants (50.31% women, 49.68% men). Multivariable logistic regression demonstrated a significant eGFR association with all CKD-related complications, exhibiting a linear trend across eGFR categories. Modeling eGFR as a natural spline revealed varied significance thresholds between sexes for anemia and hyperparathyroidism. We found a significantly (P &lt; 0.05) higher proportion of women with anemia downstream an eGFR cut-off of 69 mL/min per 1.73 m2, which was lower than the cut-off in men; a significantly higher proportion of men with anemia was observed downstream an eGFR cut-off of 76 mL/min per 1.73 m2. However, the relationship was more pronounced in women than in men; thus, at an eGFR cut-off of 41 mL/min per 1.73 m2, the proportion of women with anemia was significantly higher (P &lt; .05) (Figure).
Similarly, a higher proportion of women with hyperparathyroidism were observed downstream an eGFR cut-off of 73 mL/min per 1.73 m2, which was lower than in men; a significantly higher proportion of men (P &lt; .05) was observed downstream an eGFR cut-off of 89 mL/min per 1.73 m2 (Figure). Furthermore, although no sex differences were observed in terms of eGFR thresholds for hyperphosphatemia, a more pronounced relationship was observed in men. Thus, at an eGFR cut-off of 38 mL/min per 1.73 m2, the proportion of men with hyperphosphatemia was significantly higher (P &lt; .05) than that of women (Figure).
We observed substantial but not statistically significant differences between men and women in the thresholds of statistical significance for CV (significance appeared at a higher eGFR in men) and non-CV mortality (significance appeared at a higher eGFR

Conclusion
Research shows sex disparities in most CKD-related complications. Men develop anemia and hyperparathyroidism earlier, women show steeper anemia increase. Men have higher CV mortality risk. As eGFR decreased, men faced a higher risk of CV mortality at a higher eGFR threshold than women.