Stone Composition as a Function of Age and Sex

Discussion

Our study identified important demographic and seasonal features that are associated with the type of stone that a given patient is likely to form. Younger women are more susceptible to HA stones, whereas UA stone composition increases markedly in both sexes after the age of 50 years. CaOx stones are the most common stones across the age and sex spectra, but they are particularly common in middle-aged men. Finally, this study suggests that the warmer summer weather increases the risk to pass certain types of stones (CaOx and UA) but not others (HA and ST).

This study is consistent with a historical series from other large referral laboratories that reported that about 80% of stones are composed of CaOx and/or HA (1–3). The most recent large series of a central laboratory for Veterans Administration facilities across the United States (6) found several important trends, including an increasing likelihood of calcium phosphate stones in a given individual as the number of stone events increased (6). However, this study sampled mostly men (98%), and the data were not stratified by age. Importantly, our data do suggest an increasing proportion of apatite and decreasing proportion of CaOx stones in the elderly, which is consistent with these prior findings of a shift toward apatite stones with time. Men are at higher risk for kidney stones overall (7), possibly because of a greater tendency for urine that is oversaturated for CaOx (8) and diet tendencies that raise CaOx supersaturations (e.g., higher protein intake in men [9]). In one report, the urinary supersaturation for both CaOx and UA increased in men during warmer months, whereas these levels remained relatively flat across seasons for women (10). We found that women were particularly more likely than men to have HA stones. Perhaps related, women stone formers are at increased risk of urinary tract infection (11), which in turn, could raise urinary pH from infection with organisms that contain urease and favor HA supersaturations. Overall, this study highlights that the factors that drive stone formation in younger women likely differ the factors that drive stone formation in the older and more common stone formers (men).

Other published data also support the idea that HA stones are more common in women than men and that the average amount of calcium phosphate in mixed CaOx stones is increasing over recent decades (12). In this prior study from a large referral stone clinic, calcium phosphate stones began at a younger age (29.8 years) than CaOx stones (33.6 years), and they were associated with a relatively higher urinary pH and calcium excretion (12). In a separate report from the same referral stone clinic, urine pH was also noted to be higher in a group of both men and women who transformed from CaOx to calcium phosphate (13). Hormonal status might play some role in the observed sex differences in stone composition. Older women, likely to be postmenopausal (i.e., above age 50 years), have stone compositions quite similar to men of the same age. Analysis of two large cohorts of women suggests that kidney stone risk may increase after menopause (14,15). In general, younger women have been observed to have higher urinary pH and citrate, lower urinary calcium, and higher calcium phosphate supersaturation. However, postmenopause urinary calcium tends to rise (16,17). In two studies, urinary pH and citrate both tended to be higher in postmenopausal women on estrogen replacement than women not on estrogen replacement (16,17). These observations suggest that postmenopausal changes make older women more similar to men in their risk of stones, and this may explain the lack of sex differences in stone composition in the older age ranges.

Our data also show that UA stones become increasingly common with age >50 years old in both sexes. Indeed, by age 90 years, UA stones are almost as common as CaOx stones. Two large stone analysis laboratories in Germany (18) and France (19) have reported a similar trend toward formation of UA stones in the elderly, and population-based data from Olmsted County, Minnesota (20) reported similar findings. Possibly, this observation has to do with changes in kidney function associated with aging. CKD is often associated with type 4 renal tubular acidosis, which in turn, is characterized by decreased renal ammoniagenesis and more acidic urine (21) that favors UA supersaturation (22). Furthermore, urinary calcium excretion is reduced among those with declining GFR, perhaps making calcium stones less likely (23). Obesity, insulin resistance, and diabetes, which are also more common with aging, are associated with lower urinary pH and UA stones (24,25).

It has been widely accepted that kidney stones are more common among adult men. Our data suggest that, not only is the composition of stones different in younger women, containing relatively more HA, but the number formed is also greater among adolescent girls (10–19 years old) and young adult women (20–29 years old) as opposed to men. In this current study, women accounted for about 60% of submitted stones between 10 and 29 years of age. Several larger cohorts of stone-forming adolescents also found a preponderance of women in this age group (26,27), and analysis of National Health and Nutrition Examination Survey data between 1976 and 1994 suggested that 20- to 29-year-old women had an approximately 50% higher prevalence of stones than men of the same age (28). Thus, the weight of evidence suggests that more research is needed to understand the factor(s) that mediate kidney stone risk in younger women and that these factors likely differ from those in older men (and perhaps, older women).

Finally, our data suggest that the environment has effects on certain stone types, but perhaps not others. Patients were more likely to submit a CaOx or UA stone during the summer months. Increased urinary concentration because of insensible water loss in warm weather will increase urinary supersaturations for both UA and CaOx. Alternatively, other stone compositions did not vary with calendar month. ST stones are caused by infection with a urease-positive organism, and one might speculate that seasonal effects on urinary concentration would be less important. For apatite and BR stone compositions, increased urinary pH has the dominant effect to increase calcium phosphate supersaturations as opposed to urinary concentrations of calcium and phosphate (29). The effect of aggressive hydration in settings where patients are prone to concentrating their urine (e.g., warm summer) might be less beneficial for calcium phosphate or ST stones compared with CaOx or UA.

This study has potential weaknesses. No clinical data are available for these individuals other than age, sex, and the referral site submitting the stone. Thus, we are not able to separate first time versus recurrent stones or compare stone composition with the number of stone events. There is no clear denominator (catchment population) for these data to determine the prevalence of each stone composition. Nevertheless, the very large number of stones available for this study allowed us to detect clear trends in the case mix of stone composition, which suggest important age, sex, and seasonal effects.

In conclusion, most of stones formed in the United States are CaOx followed by HA. Together, CaOx and HA account for over 80% of stones submitted to a large referral laboratory. However, demographics have significant associations with the likelihood of forming a given stone type. Younger women are more susceptible to HA stones. Men of all ages are particularly susceptible to CaOx stones. Older individuals of both sexes make progressively more UA stones.