ESKD Carries Higher Cardiovascular Burden in Girls Than Boys

Childhood  mortality rates are declining overall. In the general population, mortality is higher in boys in most regions of the world, due in part to more accidents, prematurity, respiratory distress during infancy, and sepsis occurring postpuberty. In girls, inferior survival is associated with poverty, marginalization, and a sociocultural preference for male offspring.

Mortality in pediatric end-stage kidney disease (ESKD) is more than 30% times higher than in the general population. According to data from the United States Renal Data System on 14,024 children receiving kidney replacement therapy (KRT), girls have a higher risk of mortality (hazard ratio, 1.36; 95% CI, 1.25-1.50) due to their higher risk of cardiovascular death. Overall mortality rates in children with functioning grafts are declining; nevertheless, the proportion of cardiovascular mortality is unchanged and is ~20 % higher in girls.

Among children with ESKD, cardiovascular events are the most common causes of death, accounting for about one-third of deaths in children on dialysis and a quarter of pediatric kidney transplant recipients. Post-transplant mortality associated with cardiovascular causes is higher than that related to nonfunctioning grafts.

In adults, pulse wave velocity (PWV), a measure of vascular stiffness, is a predictor of cardiovascular mortality and is associated with a faster decline in estimated glomerular filtration rate (eGFR). Aortic PWV can be measured noninvasively and reproducibly in children. In previous studies, even after transplantation, PWV was higher in children with CKD compared with healthy peers.

Among pediatric patients, girls are less likely to undergo preemptive transplantation and show poorer graft survival compared with boys. Other data indicate a higher susceptibility among girls for cyclosporin A-associated hypertension, a possible contributor to poorer graft survival and increased cardiovascular mortality.

Rizky I. Sugianto, PhD, and colleagues conducted a study to examine the course of arterial stiffness in children with ESKD who underwent kidney transplantation, either preemptively or following prior dialysis. The study outcome of interest was potential differences between boys and girls. Results were reported online in Kidney International [].

The current study, 4C-T (Cardiovascular Comorbidity in Children and Chronic Kidney Disease—Transplantation), is a substudy of the 4C study, a prospective observational study that included 704 patients 6 to 17 years of age with CKD, with an eGFR <60 mL/min/1.73 m2 who were not yet receiving KRT enrolled between 2009 and 2011.

The substudy included 235 children undergoing preemptive transplantation (n=150) or following prior dialysis (n=85). Of the 235 total cohort, 34% (n=80) were girls. Of the total cohort, 196 had observations prior to and following transplantation, 36 only before transplantation, and three only after transplantation. Longitudinal analyses (median/maximum follow-up time of 6/9 years) were performed using linear mixed regression models and further stratified by the categories of time: pre-kidney replacement therapy and post-transplantation. The analyses for PWV  z scores (PWVz) were performed in three analysis steps: all data comprising the whole observation time and then divided into two separate analyses according to transplantation: pre-transplantation and post-transplantation.

There were no differences between girls and boys in eGFR at inclusion and the last visit pre-transplantation, age at inclusion and transplantation, time from eGFR ≥30 mL/min/1.73 m2 to transplantation, and time on dialysis. At the time of the last visit prior to transplantation, girls showed significantly lower height, systolic blood pressure, hemoglobin, sodium, calcium, uric acid, and higher high-density lipoprotein than did boys.

PWVz increased by 0.095 per year since inclusion (P<.0001), independent of the underlying kidney disease (P=.64). In the mixed model, PWVz was 0.295 higher in girls (P=.045) than in boys.

In a comparison between the study population and a cohort of healthy children with comparable height, the healthy children demonstrated considerably lower PWVz (median –0.28) at study inclusion. PWVz did not increase with time in the healthy children (PWVz –0.048 per year; P=.27) and did not differ between girls and boys.

A total of 230 patients were included in an analysis of the effect of sex on PWV prior to transplantation. Compared with boys, girls showed a higher PWVz increase of 0.15 per year (P=.039). In a final covariate model of 158 patients, delta eGFR was a strong predictor for PWVz in girls. A decline in eGFR of –4 mL/min/1.73 m2 per year prior to transplantation was associated with a higher PWVz of 0.16 in girls (P=.017) compared with boys. In both sexes, there were associations between higher diastolic blood pressure z score and higher low-density lipoprotein and a higher PWVz.

There were 199 patients included in an analysis of the effect of sex on PWV following transplantation. PWVz for girls was 0.44 higher than that for boys (P=.02). For both sexes, PWVz increased by 0.12 per year post-transplantation and by 0.25 per year on dialysis (P=.006). There was no interaction detected between time and sex.

In an additional analysis of 195 patients screened for potential covariates using the basic model, PWVz increased by 0.13 per year post-transplantation (P<.0001) and by 0.19 per year on dialysis (P=.03). There was an association between a one-point higher PWVz at the last pre-transplantation visit and a post-transplantation PWVz increase of 0.36 (P<.0001). The association of female sex and higher PWVz persisted (P=.01).

In girls, a decline of 4 mL/min/1.73 m2 in eGFR per year pre-transplantation was associated with a PWVz increase of 0.22 after transplantation (P=.039). There was also a significant association between a longer time to transplantation (>12 months) and a higher PWVz of 0.57 in girls (P=.017). In both sexes, PWVz increased further after transplantation and was positively associated with time on dialysis and diastolic blood pressure.

The researchers cited a potential selection bias as a limitation to the study findings, as well as a possible limit to the generalizability of the findings due to the study population being predominantly White.

In conclusion, the authors said, “The observed higher susceptibility of girls for cardiovascular organ damage in conjunction with kidney disease progression highlights the importance of a closer attention to cardiovascular and kidney function parameters early in the disease course in female patients. Importantly, girls are more vulnerable toward eGFR decline and when exposed to a longer waiting time to transplantation. Early interventions and a faster access of girls to transplantation are crucial to tackle the sex differences in cardiovascular and mortality risk. Strict blood pressure control and management of dyslipidemia are of importance for both sexes.”

Takeaway Points

  1. Girls with kidney failure face higher mortality rates than do boys, with cardiovascular complications representing the most common causes of death in both sexes.
  2. Increased aortic pulse wave velocity (PWV) is highly predictive for cardiovascular events and mortality. To uncover potential differences between girls and boys, researchers conducted a study to examine the course of arterial stiffness in children with end-stage kidney disease who underwent kidney transportation.
  3. The study revealed that girls with advanced chronic kidney disease are more susceptible to develop vascular stiffening compared with boys, a difference that persists after kidney transplantation and may contribute to the higher mortality rates in girls with kidney failure.