There are three stages of the calcium absorption: the absorption of the intestine, kidney and bone, which jointly maintain the balance of calcium ions in the body. The formation mechanism of kidney stone can be seen in Figure 2. The absorption of calcium ions in the small intestine can account for 90% of the total absorption[27], which is the most important part of calcium absorption. The other organs, the large intestine and colon, do not exceed 10% of the total absorption, besides, the calcium absorption needs energy that is mainly supplied by mitochondria. So the absorptive capacity is determined by the mitochondria integrity[27]. Then the calcium goes into the cells. It combines with oxalate to form calcium oxalate. The physicochemical process of CaOx kidney stone formation is mainly composed of four steps: crystalline nucleation, crystal growth, crystal accumulation, and crystal retention.
By means of the data from the National Center for Health Statistics (NHANES), from 2015 to 2018, we initially conducted the multiple regression of the calcium intake and kidney stones. (Table 1) The P for trend in model 3 is 0.068.(Table 2) ([OR] 0.9999, [CI] 0.9998–1.001 in model 3.) Whether calcium intake was included as a continuous or classification variable, the final result was that calcium intake was not associated with kidney stones. We reckon that calcium supplementation in the diet is not related to whether to have kidney stones at all. But in our view, some confounding factors might be connected with kidney stone.
Table 1
Characteristics of the participants
CALCIUM quartile(mg)
|
Q1
|
Q2
|
Q3
|
Q4
|
P-value
|
N
|
2434
|
2432
|
2436
|
2436
|
|
Vitamin D (mg)
|
2.1 ± 4.8
|
3.2 ± 4.2
|
4.6 ± 4.7
|
7.7 ± 6.9
|
< 0.001
|
BMI (kg/m2)
|
29.3 ± 7.9
|
29.5 ± 7.8
|
29.6 ± 7.8
|
29.5 ± 7.6
|
0.15
|
Kidney stone
|
Yes
|
267 (11.0%)
|
263 (10.8%)
|
246 (10.1%)
|
248 (10.2%)
|
0.681
|
Alcohol drinking
|
Yes
|
325 (13.4%)
|
317 (13.0%)
|
300 (12.3%)
|
388 (15.9%)
|
< 0.001
|
Diabetes
|
Yes
|
410 (16.8%)
|
404(16.6%)
|
373 (15.3%)
|
306 (12.6%)
|
< 0.001
|
Gender
|
Male
|
990 (40.7%)
|
1063 (43.7%)
|
1171 (48.1%)
|
1483 (60.9%)
|
< 0.001
|
Age
|
< 40
|
675 (27.7%)
|
714 (29.4%)
|
801 (32.9%)
|
925 (38.0%)
|
< 0.001
|
40–60
|
816 (33.5%)
|
874 (35.9%)
|
841 (34.5%)
|
847 (34.8%)
|
> 60
|
943 (38.7%)
|
844 (34.7%)
|
794 (32.6%)
|
664 (27.3%)
|
Race
|
Mexican American
|
290 (11.9%)
|
343 (14.1%)
|
409 (16.8%)
|
450 (18.5%)
|
< 0.001
|
Other Hispanic
|
262 (10.8%)
|
291 (12.0%)
|
281 (11.5%)
|
264 (10.8%)
|
Non-Hispanic White
|
689 (28.3%)
|
783 (32.2%)
|
915 (37.6%)
|
1012 (41.5%)
|
Non-Hispanic Black
|
743 (30.5%)
|
566 (23.3%)
|
471 (19.3%)
|
405 (16.6%)
|
Other Race-Including Multi-Racial
|
450 (18.5%)
|
449 (18.5%)
|
360 (14.8%)
|
305 (12.5%)
|
Statue
|
Citizen by birth or naturalization
|
2099(86.2%)
|
2070 (85.1%)
|
2074 (85.1%)
|
2067 (84.9%)
|
0.531
|
Education
|
Not graduate from high school
|
579 (23.8%)
|
513 (21.1%)
|
471 (19.3%)
|
470 (19.3%)
|
< 0.001
|
Marriage
|
Married or living with partner
|
1980 (81.3%)
|
1999 (82.2%)
|
2014 (82.7%)
|
1981 (81.3%)
|
0.536
|
Income ($)
|
≥ 20000
|
1746 (71.7%)
|
1847 (75.9%)
|
1907 (78.3%)
|
1920 (78.8%)
|
< 0.001
|
Numbers that do not add up to 100% are attributable to missing data
|
Table 2
Association between calcium intake(mg) and the kidney stone.
|
Model1 Odds ratio (95% CI)
|
Model2 Odds ratio (95% CI)
|
Model3 Odds ratio (95% CI)
|
Calcium(mg)
|
0.9999 (0.9998, 1.0001)
|
0.9999 (0.9998, 1.0000)
|
0.9999 (0.9998, 1.0001)
|
Calcium quartile
|
Q1
|
Reference(1)
|
Reference(1)
|
Reference(1)
|
Q2
|
0.9841(0.8217,1.1786)
|
0.9288(0.7726,1.1165)
|
0.9365(0.7784,1.1268)
|
Q3
|
0.9117(0.7591,1.0949)
|
0.8286(0.6866,1.0001)
|
0.8449(0.6975,1.0235)
|
Q4
|
0.9199(0.7663,1.1044)
|
0.8159(0.6739,0.9879)
|
0.8468(0.6883,1.0419)
|
P for trend
|
0.268
|
0.036
|
0.068
|
Outcome variable: Kidney Stone
Exposure variable: Calcium
Model 1 adjusts for: None
Model 2 adjust for: Gender; Age; Race
Model 3 adjust for: Alcohol drinking; Diabetes; Vitamin D; BMI; Gender; Age; Race; Statue; Education; Marriage; Income
Table 3
|
Statistics
|
Kidney stone
|
P-value
|
Calcium(mg)
|
907.3311 ± 570.6161
|
0.9999(0.9998, Reference(1)001)
|
0.37
|
Diabetes
|
Yes
|
1493 (15.3317%)
|
Reference(1)
|
|
No
|
8245 (84.6683%)
|
0.4994 (0.4282, 0.5825)
|
< 0.000001
|
Alcohol drinking
|
Yes
|
1330 (13.6578%)
|
Reference(1)
|
|
No
|
6728 (69.0902%)
|
0.7883 (0.6594, 0.9425)
|
0.009048
|
Missing
|
1680 (17.2520%)
|
0.6742 (0.5349, 0.8498)
|
0.000842
|
Vitamin D (mg)
|
4.3980 ± 5.6592
|
0.9944 (0.9825, 1.0065)
|
0.37
|
BMI
|
29.4828 ± 7.7761
|
1.0175 (1.0093, 1.0258)
|
0.000027
|
Gender
|
Male
|
4707 (48.3364%)
|
Reference(1)
|
|
Female
|
5031 (51.6636%)
|
0.7104 (0.6236, 0.8093)
|
< 0.000001
|
Age
|
< 40
|
3115 (31.9881%)
|
Reference(1)
|
|
40–60
|
3378 (34.6888%)
|
1.8906 (1.5777, 2.2656)
|
< 0.000001
|
> 60
|
3245 (33.3231%)
|
2.4754 (2.0756, 2.9521)
|
< 0.000001
|
Race
|
Mexican American
|
1492 (15.3214%)
|
Reference(1)
|
0.02
|
Other Hispanic
|
1098 (11.2754%)
|
1.3631 (1.0590, 1.7546)
|
Non-Hispanic White
|
3399 (34.9045%)
|
1.6700 (1.3672, 2.0398)
|
< 0.000001
|
Non-Hispanic Black
|
2185 (22.4379%)
|
0.7186 (0.5640, 0.9156)
|
0.01
|
Other Race-Including Multi-Racial
|
1564 (16.0608%)
|
0.7850 (0.6060, 1.0167)
|
0.07
|
Statue
|
Citizen by birth or naturalization
|
8310 (85.3358%)
|
Reference(1)
|
|
Not a citizen of the US
|
1428 (14.6642%)
|
0.5382 (0.4306, 0.6726)
|
< 0.000001
|
Education
|
Not graduate from high school
|
2033 (20.8770%)
|
Reference(1)
|
|
Graduate from high school
|
7705 (79.1230%)
|
0.9539 (0.8148, 1.1168)
|
0.56
|
Marriage
|
Spinsterhood
|
1764 (18.1146%)
|
Reference(1)
|
|
Married or living with partner
|
7974 (81.8854%)
|
1.8845 (1.5388, 2.3079)
|
< 0.000001
|
Income
|
< 20000
|
1628 (16.7180%)
|
Reference(1)
|
|
> 20000
|
7420 (76.1963%)
|
0.9577 (0.8064, 1.1375)
|
0.63
|
Missing
|
690 (7.0856%)
|
0.7709 (0.5672, 1.0479)
|
0.10
|
Patients with kidney stones were often accompanied with obesity and diabetes, so diabetes was also included in the confounding factors in our study. [28] For organ aging in the elderly, we focused on age as classified variables; income affects consumption level and dietary habits, even the treatment for the stone[29], so we also converted income into categorical variables; similarly, different races may have their own unique dietary habits, which is worth studying; and alcohol drinking, which can cause some damage to the kidney[30], we think it may also affect the kidney stones. Out of similar reasons, we also included vitamin D, marriage and gender, into the confounding factors. In Table 3, we can conclude that the kidney stone might be associated among the diabetes, age, alcohol drinking, vitamin D whose P value are below 0.05. While analyzing them, we performed another stratified analysis.
The results showed that in the multiple regression equation, these factors would affect the relationship between calcium intake and kidney stones, but after conducting stratified studies, we found that they did not affect the outcome of developing kidney stones, so we believed that these factors did not affect the relation between calcium intake and kidney stone. Ultimately, these were found as factors largely unrelated to the formation of kidney stone, either. (Table 4)
Table 4
The stratification analysis between kidney stone and calcium intake
|
Model1 Odds ratio (95% CI)
|
Model2 Odds ratio (95% CI)
|
Model3 Odds ratio (95% CI)
|
Separated by
Age
|
< 40
|
1.0000 (0.9998, 1.0003)
|
1.0000 (0.9998, 1.0003)
|
1.0001 (0.9998, 1.0003)
|
40–60
|
1.0000 (0.9998, 1.0002)
|
0.9999 (0.9997, 1.0001)
|
0.9999 (0.9997, 1.0002)
|
> 60
|
1.0000 (0.9998, 1.0002)
|
0.9998 (0.9996, 1.0000)
|
0.9998 (0.9996, 1.0001)
|
Total
|
1.0000 (0.9999, 1.0001)
|
0.9999 (0.9998, 1.0000)
|
0.9999 (0.9998, 1.0001)
|
Separated by Gender
|
Male
|
0.9999 (0.9998, 1.0001)
|
1.0000 (0.9998, 1.0001)
|
1.0000 (0.9999, 1.0002)
|
Female
|
0.9998 (0.9996, 1.0000)
|
0.9997 (0.9995, 1.0000)
|
0.9997 (0.9995, 1.0000)
|
Total
|
0.9999 (0.9998, 1.0000)
|
0.9999 (0.9998, 1.0000)
|
0.9999 (0.9998, 1.0001)
|
Separated by Race
|
Mexican American
|
0.9998 (0.9995, 1.0001)
|
0.9999 (0.9996, 1.0002)
|
0.9999 (0.9996, 1.0003)
|
Other Hispanic
|
0.9996 (0.9992, 1.0000)
|
0.9996 (0.9992, 1.0000)
|
0.9997 (0.9992, 1.0001)
|
Non-Hispanic White
|
0.9999 (0.9998, 1.0001)
|
0.9999 (0.9998, 1.0001)
|
1.0000 (0.9998, 1.0002)
|
Non-Hispanic Black
|
1.0000 (0.9997, 1.0003)
|
1.0000 (0.9996, 1.0003)
|
1.0000 (0.9997, 1.0004)
|
Other Race-Including Multi-Racial
|
0.9998 (0.9994, 1.0002)
|
0.9999 (0.9994, 1.0003)
|
0.9998 (0.9994, 1.0003)
|
Total
|
0.9999 (0.9998, 1.0000)
|
0.9999 (0.9998, 1.0000)
|
0.9999 (0.9998, 1.0001)
|
Separated by Diabetes
|
Yes
|
1.000(0.9997, 1.0002)
|
0.9998 (0.9996, 1.0001)
|
0.9998 (0.9995, 1.0001)
|
No
|
1.0000 (0.9999, 1.0001)
|
0.9999 (0.9998, 1.0000)
|
0.9999 (0.9998, 1.0001)
|
Total
|
1.0000 (0.9999, 1.0001)
|
0.9999 (0.9998, 1.0000)
|
0.9999 (0.9998, 1.0001)
|
Separated by Statue
|
Citizen by birth or naturalization
|
1.0000 (0.9998, 1.0001)
|
0.9999 (0.9997, 1.0000)
|
0.9999 (0.9998, 1.0001)
|
Not a citizen of the US
|
0.9999 (0.9995, 1.0002)
|
0.9999 (0.9995, 1.0003)
|
0.9999 (0.9994, 1.0003)
|
Total
|
1.0000 (0.9998, 1.0001)
|
0.9999 (0.9998, 1.0000)
|
0.9999 (0.9998, 1.0001)
|
Separated by Marriage
|
Spinsterhood
|
0.9999 (0.9996, 1.0002)
|
0.9999 (0.9995, 1.0002)
|
0.9998 (0.9994, 1.0002)
|
Married or living with partner
|
1.0000 (0.9998, 1.0001)
|
0.9999 (0.9997, 1.0000)
|
0.9999 (0.9998, 1.0001)
|
Total
|
1.0000 (0.9998, 1.0001)
|
0.9999 (0.9998, 1.0000)
|
0.9999 (0.9998, 1.0001)
|
Separated by BMI
|
22.0800 ± 4.4909
|
0.9999 (0.9997, 1.0001)
|
0.9998 (0.9996, 1.0000)
|
0.9998 (0.9995, 1.0001)
|
28.5889 ± 1.5748
|
1.0000 (0.9998, 1.0002)
|
1.0000 (0.9998, 1.0002)
|
1.0000 (0.9998, 1.0003)
|
37.7253 ± 5.9583
|
0.9999 (0.9997, 1.0001)
|
0.9998 (0.9996, 1.0000)
|
0.9999 (0.9996, 1.0001)
|
Total
|
0.9999 (0.9998, 1.0001)
|
0.9999 (0.9998, 1.0000)
|
0.9999 (0.9998, 1.0001)
|
Separated by Alcohol Drinking
|
Yes
|
0.9997 (0.9994, 1.0000)
|
0.9996 (0.9993, 0.9999)
|
0.9996 (0.9992, 0.9999)
|
No
|
1.0000 (0.9998, 1.0001)
|
0.9999 (0.9998, 1.0001)
|
1.0000 (0.9998, 1.0001)
|
Missing
|
1.0001 (0.9997, 1.0004)
|
1.0001 (0.9997, 1.0004)
|
1.0001 (0.9998, 1.0005)
|
Total
|
0.9999 (0.9998, 1.0001)
|
0.9999 (0.9998, 1.0000)
|
0.9999 (0.9998, 1.0001)
|
Back to our calcium intake with kidney stones study, it is the same as some studies where kidney stones were not associated with this intake. We all concluded that dietary calcium supplementation was not associated with developing kidney stone. And high intake of dietary calcium or supplemental calcium (500 mg/d) could lower the possibility of kidney stones formation.[31][32] Moreover, calcium intake should not be limited in patients with kidney stones.[14][15] However, some observational studies found that decreasing the calcium intake can lower the risk of first stone. [32][33] But in the long run, we believe that the control of kidney stones by reducing calcium intake is dispensable, given the complex formation[34] causes that calcium intake may have no effect on this. For example, the microbiome play a role.[35] It not only relies on the calcium intake and oxalate, some confounding factors, like vitamin D which can promote the absorption of the calcium from intestinal tract.[36] They may have indirect effects on kidney stones. And in contrast, we believe that drinking enough water is more effective and easier to attain, which can help to promote the excretion of urinary oxalate.[37] Some studies also found that controlling the salt and protein intake is more effective.[38]
Reflecting on our results may be due to insufficient accurate accuracy in the following aspects: We did not classify the types of kidney stones, and a proportion of kidney stones may not be calcium oxalate, unrelated to our study. Moreover, oxalate, one of the forming components of calcium oxalate kidney stones[39], which we did not include in confounding factors. Besides, we did not take the calcium supplement into the consideration and did not classify the kind of the diabetes. There are also some kidney diseases, which probably influence the kidney stone[40][41][42], which we did not study. Furthermore, the calcium absorption is related to some bacteria in the gut[43] and some common drinks, tea and coffee.[44] Therefore, we hope that we can further analyze those factors and exclude the effects of other types of kidney stones on the study in future. Although there are some parts of our study not considered, overall, it still has some advantages. Our study focused on calcium intake in daily life, rather than conducting group experiments from the perspective of calcium supplements, which is more reference and closer to people's daily life. This saves both financial and material resources, and it is convenient and efficient especially during the epidemic. In addition, we have enough and huge database which make our study more objective and general.
Finally, based on our study data, we speculated that dietary calcium supplementation would not increase the risk of developing kidney stones. And the calcium is not the only factor to affect kidney stone formation, many confounding factors which act together may produce very different results. So, the correct prevention method of kidney stones, should have a rational balanced diet and live in a healthy life. [45][46][47] It is neither high calcium intake nor low calcium intake in the long term. You and I work hand in hand to build a healthy world together!