Associate Professor Sradha Kotwal

Sex-specific differences in kidney structure and function as well as the impact of hormonal changes over a female’s reproductive life stages are largely ignored in kidney disease research and in treatment guidelines.

An article in The Lancet Series on CKD [link here], said “…systematic acknowledgment, exploration, and reporting of these differences is required in future research” in order to improve CKD outcomes.

“Policy makers, scientific organisations, journal editors, and funders can insist on appropriate consideration of the potential for sex differences in policy initiatives, new research ventures, and research dissemination,” it said.

“Individuals can take ownership of considering the potential for sex differences when designing, reporting, and reviewing research. To make a sizable impact, sex heterogeneity must be acknowledged in education programmes across preclinical, clinical, and pharmaceutical sciences.”

It also said that, without change, artificial intelligence and machine learning will bake in the findings from unrepresentative data and further exacerbate bias.

Sex differences

The authors, including nephrologist Associate Professor Sradha Kotwal from the Prince of Wales Hospital and The George Institute for Global Health, said some of the sex differences in females include smaller kidney size, reduced glomerular filtration rate, lower vasoconstriction, and reduced proximal but higher distal sodium excretion.

“Sex hormones and genes further affect insulin-sensitivity, lipid metabolism and storage, and glucose homeostasis, driving sex differences in metabolic response to novel therapeutics for diabetes and obesity, although still yielding benefits for both sexes for kidney and cardiovascular outcomes,” they said.

They said hormonal variation throughout the menstrual cycle, during pregnancy, breastfeeding, and with concomitant oral contraceptive use might result in alterations to renal clearance, gastrointestinal transit, haemodynamic accommodations, and others.

“For example, renal clearance is thought to be highest during the luteal phase of the menstrual cycle, but the effect of this finding on pharmacokinetics has been understudied. These fluctuating hormonal effects, without parallels in males, could substantially affect drug concentrations, efficacy, and adverse events.”

They noted that there was a major missed opportunity for CKD screening during pregnancy.

“Abnormalities identified during pregnancy (eg, proteinuria) are often inappropriately attributed to other causes, such as urinary tract infections, or assumed to be related to pre-eclampsia, and these abnormalities do not typically trigger appropriate follow-up.”

As well, women were less likely than men to receive testing or monitoring for CKD, referral to specialists, and cardiovascular risk management.

“Where biochemical data support a diagnosis, women are less likely to be coded as having CKD, and less likely to receive guideline-directed therapy, including statins, ACE inhibitors, and SGLT2 inhibitors,” they said.

“Differences in health-seeking behaviour (related to gender roles, social factors, or biological differences in symptom experience) and higher rates of polypharmacy and treatment-related adverse events observed in females than in males, likely contribute to disparities in CKD treatment and outcomes.”

Research gaps

The authors said that preclinical models of CKD could be improved to further understanding of sex differences between males and females and throughout the life course of females.

For example: “3D kidney organoids can be developed from adult stem cells derived from male or female-specific stem cell lineages, and evidence from non-kidney (uterus) organoids shows the potential to develop organoid models that can respond to the dynamic effects of reproductive hormones.”

Meanwhile clinical trials had to go further than just increasing female participation and reporting sex-stratified efficacy and safety outcomes.

For example: “Where evidence of therapeutic safety and effect on CKD outcomes is particularly sparse (eg, in breastfeeding females), dedicated exploration is required,” they said.

“Disentangling the influence of gender on sex disparities requires dedicated study. These fundamental issues must be addressed to ensure that our knowledge of CKD continues to expand in a responsible and safe manner,” they concluded.

Another paper in the Series [link here] explored the challenges for therapeutic decision making in CKD given factors such as multimorbidity, frailty, and polypharmacy.

“Although ongoing developments in CKD therapeutics are welcome, if we fail to acknowledge the clinical complexity of CKD populations in the developing evidence, there will continue to be downstream consequences for clinical guidance and implementation strategies,” it said.

“Pivotal trials of novel therapeutics for CKD do not adequately represent the communities they seek to treat. The generalisability of trial evidence to many patients with CKD, including older individuals, females, and those living with high levels of multimorbidity and frailty, is therefore uncertain.”

An editorial in the journal [link here] said new knowledge and understanding of CKD as a heterogeneous condition “…promises a more targeted and person-centred approach.”

“With better care for different needs, the aim should be not only to halt progression and reduce mortality, but also to improve quality of life.”