The sex chromosome complement can influence gene transcription independently of sex hormones, resulting in age-specific, sex-specific, and tissue-specific variations in gene expression. Differences in hypertension and kidney disease risk between females and males can partially be attributed to differential expression of sex chromosome genes. A number of genes responsible for inherited kidney disorders are located on the X chromosome. Since males possess only one active X chromosome, these disorders tend to manifest more frequently in male individuals. However, the clinical presentation of X-linked kidney conditions in female carriers is increasingly recognized. Both the sympathetic nervous system and the renin-angiotensin-aldosterone system (RAAS) are regulated by sex chromosomes and hormones. For instance, the sympathetic neurotransmitter tyrosine hydroxylase is upregulated by the Sry gene, which has been linked to hypertension in male spontaneously hypertensive rats. Genes encoding angiotensin type 2 receptor and ACE2 are located on the X chromosome, so an increased dose of these genes may contribute to the relative cardiorenal protective effects seen in females. Both estrogen and the X chromosome push the RAAS toward the cardiorenal protective depressor pathways, which counter the classical actions of angiotensin II at the predominant angiotensin type 1 receptor, in females. In contrast, the Y chromosome and testosterone shift the RAAS balance toward the prohypertensive pressor arm, which may contribute to increased risk of kidney disease in males.

Sex differences in global gene expression in the F344 rat kidney across the lifespan have been identified, with specific periods of sexually dimorphic gene expression linked to functional categories such as xenobiotic metabolism, immune cell activity, and inflammatory responses. Multiomics approaches combining RNA-seq, ATAC-seq, and proteomics to examine gene expression, chromatin accessibility, and protein expression in the proximal tubules of male and female mice have revealed numerous sex-biased genes and proteins linked to kidney functions, including metabolic and transport processes. In wild-type and ERbetaKO mice, the kidney had the third largest number of genes regulated by E2. Hundreds of genes are expressed differently between males and females, and these differences can be tissue specific. ^, For example, genes for renal sodium transporters show differential expression between male and female rats in an age-dependent manner, which may contribute to sex differences in pressure natriuresis and long-term blood pressure regulation and risk of kidney disease. ^, For example, the proximal tubule in female rats showed greater phosphorylation of Na ⁺ /H ⁺ exchanger isoform 3 (NHE3), distribution of NHE3 at the microvilli base, and blunted expression of Na ⁺ /Pi cotransporter 2, claudin-2, and aquaporin 1 compared with the proximal tubule of male rats. The distal nephrons of female rats have been shown to have a greater total and phosphorylated Na ⁺ /Cl ⁻ cotransporter (NCC), claudin-7, and cleaved forms of epithelial Na ⁺ channel (ENaC) α and γ subunits.

Overall, the lower fractional Na ⁺ reabsorption observed in females is likely due primarily to their smaller transport area and lower NHE3 and claudin-2 expression levels. Notably, unlike most Na ⁺ transporters whose expression levels are lower in females, Na ⁺ -glucose cotransporter 2 (SGLT2) expression levels are 2.5-fold higher in females. Model simulations indicate that the increased SGLT2 expression in females may help compensate for their smaller tubular transport area, allowing them to achieve a level of hyperglycemic tolerance comparable with that of males.

Sex differences exist in kidney physiology and disease, underpinned by the biological actions of sex hormones. The kidney is a key regulator of sex hormones in persons living with CKD. ^, Hormonal effects drive differences in kidney physiology between males and females. Differences in vascular, inflammatory, antioxidant, and other cytoprotective pathways that modify risk of kidney disease and its consequences may relate to baseline sex differences or adaptations to different exposures or injury. However, the exact influence of sex hormones on kidney function and disease remains elusive.

Equations used to estimate eGFR commonly use a sex/gender covariate, although in the case of an individual in whom sex assigned at birth and gender identity differs, it is unclear which variable results in a closer estimation of true GFR. Substantial differences in eGFR equation performance exist between transgender men and transgender women treated with gender-affirming hormone therapy (GAHT), although the performance of CysC-based compared with Cr-based eGFR equations may be less dependent on whether sex assigned at birth or gender identity is used in the calculation. A systematic review and meta-analysis to characterize the change in serum creatinine, other kidney function biomarkers, and GFR in transgender persons initiating masculinizing and feminizing GAHT reported that after 12 months of GAHT initiation, there was an increase in serum creatinine in transgender men but no associated change in serum creatinine in transgender women. In a cohort of transgender individuals treated with GAHT for 12 months, cystatin C-based eGFR increased with estradiol and antiandrogen therapy and decreased with testosterone therapy. A single-center cross-sectional study of inpatients reported a lower prevalence of AKI and CKD in transgender individuals receiving GAHT compared with those not receiving GAHT. In a prospective cohort of 23 individuals treated for three months with feminizing GAHT, mGFR and kidney perfusion increased (+3.6% and +9.1%, respectively; P < 0.05) without increased glomerular pressure. In 21 individuals treated with masculinizing GAHT, mGFR and kidney perfusion remained unchanged after three months of treatment. At present, a holistic approach, taking into account the person’s sex assigned at birth, sex hormone configuration (e.g., GAHT use and/or gonadectomy), and gender identity, with shared decision making between the individual living with or at risk of kidney disease and the provider, and measuring GFR directly at important clinical decision-making points is advised. ^,

Men have higher measured GFR compared with women but appear to have faster decline with age. Data from population-based studies suggest that kidney function declines faster in males (i.e., steeper slope of eGFR decline) than in females. For example, the Dutch PREVEND study reported a mean eGFR slope of −0.55 ± 1.47 mL/min/1.73 m ² per year in men compared with −0.33 ± 1.41 mL/min/1.73 m ² per year in women. Multiple sex-related factors likely contribute to this faster GFR decline in men. Males have increased activation and tissue responsiveness of the renal RAAS. The male renal vasculature becomes increasingly nitric oxide-dependent with age compared with the female renal vasculature ; thus any kidney disease interfering with nitric oxide production could cause CKD to progress more quickly in males compared with females.

Among healthy Norwegian adults, the age-related decline in iohexol-measured GFR (mGFR) was faster in men than women. Between the ages of 50 and 72 years, women had a lower mGFR than men, but by a mean age of 72 years, women had a higher mGFR due to a slower rate of kidney function decline. This observation aligns with the higher prevalence of CKD stage 3 in women and the greater incidence of dialysis and kidney transplantation in men. Of note, individuals with major chronic diseases (including diabetes, cardiovascular disease, or kidney disease) or CKD risk factors (e.g., smoking) were excluded from this study, suggesting the difference in mGFR decline between men and women may be more reflective of biological or sex-related mechanisms rather than lifestyle behaviors, although this remains speculative.

Previous studies have examined differences between women and men in CKD progression, with conflicting results. First, a meta-analysis examining the risk of CKD progression in 68 cohort studies of patients with nondiabetic CKD concluded that men progress to kidney failure faster than women. Subsequently, a patient-level meta-analysis of 11 randomized trials using angiotensin-converting enzyme (ACE) inhibitors in patients with CKD concluded that the rate of CKD progression was more rapid in women compared with men. Another patient-level meta-analysis of 46 cohort studies (2,051,158 participants [54% women]) from Europe, North and South America, Asia, and Australasia from general population ( n = 1,861,052), high-risk ( n = 151,494), and CKD ( n = 38,612) cohorts showed no evidence of a sex difference in associations of eGFR and urinary albumin-creatinine ratio (ACR) with kidney failure risk. These conflicting conclusions are likely due to several factors including the mixed nature of included studies (e.g., population-based studies vs. referral to nephrology, observational vs. randomized studies), differences in populations (e.g., primarily premenopausal vs. postmenopausal women), and where some studies report loss of eGFR and others report kidney replacement therapy (KRT) initiation as the primary outcome. Kidney failure as an endpoint can be problematic due to competing risks, as death is more likely to occur than progression to kidney failure, and men die earlier than women. Moreover, older women tend to choose conservative management rather than KRT compared with men. ^,

Higher albuminuria in men compared with women may explain their faster progression to kidney failure. A general population cohort reported that men were 3.45 (95% CI 2.23–5.33) times more likely than women to experience worsening of albuminuria. In another general population cohort, higher albuminuria at baseline was associated with a decline in eGFR in men but not in women with 7-year follow-up data. Adjusting for albuminuria nullified any sex difference in the rate of eGFR loss or progression to dialysis in patients referred to nephrology care in Sweden, suggesting that albuminuria may be a mediator of the higher risk in men. Men had a 50% higher risk of kidney failure than women in a pooled analysis of four Italian observational cohort studies of patients with moderate to advanced CKD, which may be partly attributed to higher levels of proteinuria in men. In a cohort of patients with diabetic kidney disease referred to nephrology, men had greater albuminuria and a more rapid decline in eGFR compared with women; albuminuria predicted rapid CKD progression in men but not women.

Gender factors may also play a role in the greater risk of CKD progression observed in men compared with women with CKD. While men are more frequently prescribed ACE inhibitors and statins, ^, they also exhibit higher rates of behavioral cardiovascular risk factors that influence risk of CKD, such as smoking and alcohol consumption, and are more likely to have poorer dietary habits. In contrast, women tend to adopt primary cardiovascular prevention strategies more readily.

The prevalence of the causes of CKD differs by sex. The lower rate of congenital abnormalities of the kidney and urinary tract among females may help to explain the lower incidence of CKD among females compared with males in the adolescent population. Diabetes mellitus is the leading cause of CKD in both men and women, affecting a similar proportion of each group in the non–dialysis-dependent stage. ^, Hypertension, a well-established risk factor for cardiovascular disease, also contributes to the development and progression of CKD to kidney failure in both men and women. Blood pressure is higher in men than women, but women have an accelerated age-related rise in blood pressure that begins around the fifth decade of life with increasing cardiovascular disease risk beginning at lower thresholds of SBP for women than for men. Whether this also applies to CKD risk is unknown. CKD is discussed further in Chapter 50 .

Other specific causes of CKD appear to be more prevalent in either men or women. While lupus nephritis is more frequent in women, all other primary glomerular diseases are more common in men, although the sex ratios may vary at different life stages. While ANCA-associated vasculitis (AAV) glomerulonephritis may have a slight male predominance in younger populations, older patients (aged >75 years) are more likely to be female, particularly those with myeloperoxidase (MPO)-ANCA vasculitis. Approximately 20% of AAV risk appears to be genetic, with sex-specific genetic risks identified, particularly in microscopic polyangiitis (MPA). ^, Lupus and ANCA vasculitis are discussed further in Chapter 31 , Chapter 32 .

Although there is increasing recognition of sex- and gender-related divergence in disease course and complications, to-date guidelines for the management of CKD and its complications remain sex and gender blind. The current evidence landscape for sex-based differences in risk factors and complications of CKD is outlined in Fig. 22.4 .

Current evidence landscape for sex-based differences in risk factors and complications of chronic kidney disease.

Reprinted with permission from ref.

The practice of extrapolating findings based on men to women may account for differences in dialysis management and complications of CKD. ^, For example, estimating dialysis adequacy using Kt/V (where K=dialyzer clearance of urea, t=dialysis time, and V=the distribution volume of urea) assumes a constant urea distribution volume across all individuals, although female muscle mass, a surrogate for lean body mass, is typically lower than that of males. This assumption may lead to underestimation of dialysis needs in women, potentially resulting in underdialysis.

Men are more likely than women to receive arteriovenous fistulas, which are considered the preferred vascular access approach ; women are more likely to receive dialysis through an arteriovenous graft or central venous catheter. This disparity may be attributed to nephrologists’ concerns about smaller vascular diameters in women that could complicate cannulation; however, there is no strong evidence supporting the idea that women have smaller veins. Females tend to have slower maturation rates and experience lower rates of primary, primary-assisted, and secondary patency; require more procedures per patient to achieve maturation; and maintain fistula patency.

Women are less likely than men to be deceased or live donor kidney transplant recipients ^, ; this difference may be partly explained by the fact there are more men than women who progress to kidney failure. Women may also be more risk averse to aggressive treatment options. Women tend to have higher panel reactive antibodies due to the immune reaction associated with pregnancy, and the prevalence of human leukocyte antigen immunization increases with parity. However, gender disparities in access to kidney transplantation are perceived by nephrologists to be exacerbated by gender norms and values, stigma and prejudice, and educational and financial disadvantages. While women are more likely to be living kidney donors, men are more likely to be deceased kidney donors. Compared with men, women with kidney failure are 45% less likely to discuss kidney transplant with their health care provider; this gap only widens with advancing age. In participants aged 66 to 75 years, women had 29% less access to kidney transplant than men, and women older than age 75 years had 59% less access to transplant than men of the same age. The distribution of KRT treatment modality is illustrated in Fig. 22.5 . Transplantation is discussed further in Chapter 69 .

Distribution of kidney replacement treatment modality in men and women.

The portions of men and women on kidney replacement therapy who have kidney transplants or are receiving dialysis in various European countries, the United States, Australia, and New Zealand. The proportions of patients who have kidney transplants are similar in men and women.

Reprinted with permission from ref ; Boenink R, Astley ME, Huijben JA, et al. The ERA Registry annual report 2019: summary and age comparisons. Clin Kidney J. 2021;15:452–472; U.S. Renal Data System. 2022 USRDS Annual Data Report: epidemiology of kidney disease in the United States. < https://adr.usrds.org/2021 >;2022; and Australia and New Zealand Dialysis and Transplant Registry. ANZDATA Registry. 44th Report, Chapter 1 : Incidence of Kidney Failure with Replacement Therapy. < http://www.anzdata.org.au >;2021.

Sex differences in cause-specific mortality vary by age, treatment modality, dialysis vintage, diabetes status, and cause of death. In American adults receiving maintenance hemodialysis over a 20-year period, survival rates were similar between women and men, with median survival times of 2.72 (IQR, 1.16–5.21) and 2.69 (IQR,1.17–5.19) years, respectively. Overall, women had a 9% and 15% higher likelihood of infection and withdrawal-related mortality compared with men, respectively. Conversely, women had a 7% and 10% lower likelihood of cardiovascular- and cancer-related mortality, respectively, compared with men. Of note, women (vs. men) aged 18 to 44 years had higher likelihood of excess mortality across all specific causes (including a 40% increased risk of withdrawal compared with men of the same age), while women (vs. men) aged >75 years had a lower likelihood.

However, younger women and women with diabetes on dialysis had lower life expectancy and higher mortality than men, particularly from noncardiovascular causes, ^{, ,} mainly due to infection-related deaths. ^, Women on PD may also face a higher risk of sepsis and peritonitis-related deaths than men.

An ERA Registry study linked higher noncardiovascular mortality in women on dialysis or with kidney transplants to a greater prevalence of multisystem disease, particularly systemic lupus erythematosus, and more frequent use of catheters for vascular access in women. ^{, , ,} An ANZDATA study confirmed that women had an 8% higher risk of all-cause mortality in the first 5 years after dialysis initiation, mainly due to higher rates of infection-related deaths and dialysis withdrawals. Women are also more likely to die from dialysis withdrawal, possibly due to more elderly women living alone without caregivers. ^{, ,}

In patients older than 45 years of age initiating dialysis, men, especially those without diabetes, face a higher risk of cardiovascular mortality, mainly from myocardial infarction and bleeding. After age 40, men are more likely to die from malignancies than women, similar to trends in the general population. This may partly explain why women with kidney transplants have higher life expectancies than men, although the survival advantage is still smaller than in the general population. ^{, ,}

A systematic review and meta-analysis showed men were at marginally higher risk of cardiovascular mortality than women among the CKD population, with borderline significance. A pooled analysis of more than 2 million participants showed that men had higher cardiovascular and all-cause mortality at all eGFR levels, but the risk of cardiovascular mortality increased more steeply in women as eGFR declined. In early CKD stages, women are at lower cardiovascular risk than men, but this difference diminishes at lower eGFR levels. For instance, in a Swedish study of 30,000 CKD stages 3–5 patients, cardiovascular mortality was 20% higher in men than women, but no sex difference was found in stage 5 nondialysis patients. These findings suggest that the cardioprotective effect of female sex decreases as CKD progresses. ^{, , ,}