Sex Differences in CKD Progression

Implementing individualized treatment
in the era of precision medicine calls for examining sex-specific data.
Previous studies have established the importance of sexual dimorphisms for
hypertension and cardiovascular complications regarding disease presentation,
likelihood of disease progression, and response to treatment. There are few
data available on the impact of sex on chronic kidney disease (CKD); the
mechanisms underlying the observed sex disparity in the epidemiology of kidney
diseases.

Researchers in Italy, led by Roberto
Minutolo, MD, PhD, recently conducted a pooled analysis of four Italian
observational cohort studies to examine the association between sex and CKD.
Results of the analysis were reported in the American Journal of Kidney
Diseases [2020;75(1):30-38].

The researchers sought to evaluate
the potential effect of sex on CKD progression in analyses of data on men and
women with moderate to advanced CKD in a multicohort study group regularly
followed up in renal clinics in Italy. The four studies in the analysis were
conducted in 40 nephrology clinics in Italy. The primary aim of the four
studies differed but they shared similar inclusion and exclusion criteria. Each
cohort enrolled consecutive patients with CKD under stable nephrology care for
at least 6 months.

In all four cohorts, participating
nephrologists collected demographic information and clinical history. Physical
examinations were performed, including assessment of height, body weight, blood
pressure, and medication profile. Data were collected in anonymous electronic
case reports and subsequently sent to the coordinating centers for quality
assessment, storage, and analyses.

For the current analysis, the primary
outcome of interest was time to end-stage renal disease (ESRD), defined as
maintenance dialysis or kidney transplantation. For time to ESRD, death before
ESRD was a competing event. Secondary end points included time to all-cause
mortality and the slope of change in estimated glomerular filtration rate
(eGFR).

The initial pooled cohorts included
3212 individuals. Of those 148 were duplicate patients, 13 had missing
information, and 716 had eGFR >45 mL/min/1.73 m², resulting in an
analysis cohort of 2335 individuals (1311 men and 1024 women). In the four
cohorts, sex distribution as similar. There were no differences in age and the
prevalence of diabetes between men and women; the prevalence of smokers, left
ventricular hypertrophy, and history of cardiovascular disease was higher in
men than in women.

On average, eGFR was 1.6 mL/min/1.73
m² lower in women, and women had a different prevalence of CKD
stage. Mean eGFR was similar in men and women in stage 3B and stage 4 CKD; it
was slightly higher in women in stage 5 CKD. Proteinuria was higher in men
compared with women: 56.3% of men and 46.2% of women had protein excretion
>0.5 g/d (P<.001).

Blood pressures were similar in men
and women; achievement of blood pressure <130/80 mm Hg was also similar
between the two groups. In terms of number of antihypertensive drugs and use of
renin-angiotensin system inhibitors, calcium channel blockers, and
beta-blockers, the two groups were similar; women used diuretics more
frequently compared with men. Prescription of statins and antiplatelet drugs
was similar between the two groups; women received erythropoiesis-stimulating
agents more frequently than men (20.8% vs 15.0%; P<.001). Women
adhered more frequently to nonpharmacological recommendations for CKD;
intensity of nephrology care was similar between the groups.

During a median follow-up of 4.21
years, there were 727 ESRD events (295 in women and 432 in men); the overall
incidence rate was 7.92 per 10 person-years (7.19/100 person-years in women and
8.53/100 person-years in men. When taking into account the competing risk for
death prior to development of ESRD, the analysis of cumulative incidence of
ESRD was higher in men overall and by CKD stage subgroup. In the entire cohort,
the adjusted risk for ESRD was 50% greater in men than in women. The higher
risk for men persisted across CKD stages (range, 52% in stage 3b to 41% in
stage 5).

Results of multivariable survival
analysis demonstrated a significant interaction between sex and proteinuria (P=.02)
in predicting risk of ESRD. The relative risk for ESRD for men versus women was
dependent on proteinuria levels, with the rate becoming significantly greater
in men at protein excretion of ~0.5 g/d or greater. The results suggested that
a male patient with CKD with protein excretion of 1 g/d has a 50% higher risk
for progressing to ESRD than a female patient with the same level of
proteinuria.

In secondary outcome analysis, 471
patients died during follow-up (196 women and 275 men); the incidence rate was
similar in the two groups (4.77/100 person-years in women and 5.43/100
person-years in men). In the entire cohort, the adjusted risk for death was
higher in men than in women; the difference was not statistically significant
but was consistent across CKD stage.

Decline in eGFR over time was
assessed in patients who had at least one eGFR post-baseline assessment: 98.2%
of the cohort (n=2292). In mixed-regression analysis, there was a significant
difference in eGFR reduction between men and women. Adjusted eGFR change was
–1.79 mL/min/1.73 m² in women and –2.09 mL/min/1.73 m² in
men. Sex differences in the rate of eGFR decline were not different across CKD
stages.

There were some limitations to the
analysis cited by the authors, including the relatively large sample size in
the context of the study setting; persistence of results following
stratification for the four cohorts; and simultaneous evaluation of ESRD and
mortality.

The researchers said, “In conclusion,
in elderly patients with moderate to advanced CKD under nephrology care, the
risk for progression to ESRD is 50% higher in men than in women, irrespective
of CKD stage, and men experience a steeper eGFR decline compared with women.
Proteinuria levels may modify the association between sex and renal risk.”

Takeaway Points

1. Researchers in Italy conducted a
   pooled analysis from four cohort studies to examine the association between sex
   and progression of chronic kidney disease (CKD); the cohorts included elderly
   patients treated at nephrology clinics in Italy.
2. The primary outcome of interest was
   end-stage renal disease (ESRD) (defined as requiring maintenance dialysis or
   kidney transplant); secondary outcomes were all-cause mortality and decline in
   estimated glomerular filtration rate.
3. The adjusted risks for ESRD and
   mortality were higher in men; the finding was consistent across stages of CKD.