Comparing the effect of calcium citrate supplement with normal calcium diet on metabolic risk factors in recurrent calcium stone formers with idiopathic hyperoxaluria: A randomized clinical trial

doi:10.21203/rs.3.rs-4175220/v1

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Comparing the effect of calcium citrate supplement with normal calcium diet on metabolic risk factors in recurrent calcium stone formers with idiopathic hyperoxaluria: A randomized clinical trial

https://doi.org/10.21203/rs.3.rs-4175220/v1

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Background

Calcium supplementation is only recommended to treat enteric hyperoxaluria, and its effect on idiopathic hyperoxaluria has not been thoroughly assessed. In this study, we compare the effect of calcium citrate supplementation with adequate dietary calcium intake on 24-hour urine (24-U) oxalate, calcium, and calcium oxalate supersaturation index (Ca Ox SS).

Subjects:

In a parallel-group controlled randomized clinical trial, 72 recurrent calcium stone formers with idiopathic hyperoxaluria were recruited from a tertiary stone prevention clinic in 2019–2020. 24-hour urine analyses and filling the 24-hour food recall were done at baseline and after eight weeks of intervention. Finally, 44 patients completed the study protocol. The participants were randomly assigned to receive adequate calcium through diet or taking 800 mg calcium citrate (in two divided doses with lunch and dinner) with a limited intake of dairy products. The study’s outcome was the change of 24-U Ox, Ca, and CaOx SS index after intervention.

Results

Findings showed that both interventions significantly reduced 24-U Ox (B _{Time effect}: -10.06, 95% CI: -13.70, -6.42; p < 0.001) and CaOx SS index (B _{Time effect}: -2.54, 95% CI: -4.06, -1.02; p = 0.001). After adjusting the effect of potential confounders through a Random-effects ML regression, the reduction of 24-U Ox remained significant. There was no significant increase in 24-U Ca in both intervention groups (p = 0.269).

Conclusions

Calcium citrate supplementation effectively reduces 24-U Ox levels comparably to adequate dietary calcium intake, without significantly raising 24-U Ca levels, offering a viable management option for calcium stone formers with idiopathic hyperoxaluria.

Health sciences/Diseases/Kidney diseases

Health sciences/Risk factors

Calcium oxalate

Calcium citrate

Dietary calcium

Hyperoxaluria

Kidney stone

Urolithiasis is a common disease with a high risk of recurrence, and its prevalence has increased worldwide (1). This condition stems from a blend of genetic predispositions and environmental factors, including diet (2, 3). Calcium is the primary component in most urinary stones, accounting for up to 80% of them, and calcium oxalate (CaOx) are the most prevalent urinary stone composition (3).

Hyperoxaluria, defined as urine oxalate levels exceeding 40 mg/day, is a significant risk factor for the calcium oxalate stones formation. However, it manifests in various subtypes, each distinguished by its unique pathogenesis, clinical severity, and therapeutic approach (4). Primary hyperoxalurias (PHs), the most severe form, arises from genetic defects in glyoxylate metabolism, leading to urine oxalate levels above 80 mg/day (5). Enteric hyperoxaluria, commonly resulting from intestinal malabsorption due to conditions like inflammatory bowel disease or surgical interventions like bariatric surgery, represents the primary cause of acquired hyperoxaluria (6). Dietary factors, such as high consumption of oxalate-rich foods or diminished Oxalobacter formigenesis colonization, contribute to dietary hyperoxaluria (6). Lastly, idiopathic hyperoxaluria, a milder yet increasingly prevalent form (6, 7), poses a major risk for calcium oxalate stone formation (8).

Urine oxalate comes from absorbed oxalate from the diet and endogenous oxalate production (9). About 10–72% of urine oxalate could be derived from dietary intake (9). Although dietary oxalate cannot be entirely avoided, restricted consumption of high oxalate foods (spinach, beets, chocolate, nuts, and tea) is a cornerstone in management of urinary hyperoxaluria even in patients with PHs (10). Current recommendations in management of idiopathic hyperoxaluria including oxalate restriction, maintaining normal calcium intake through dietary sources, and treatment of any underlying pathophysiologic conditions (3, 5, 6). However, the advancement in treatment strategies for idiopathic hyperoxaluria, remains limited (5, 11).

The variable nature of oxalate absorption in the intestine is significantly influenced by the presence of calcium in the diet (9, 12). On the other hand, it's well-established that low calcium diets contribute to the risk of stone formation (13–15), yet the literature presents conflicting views on the role of calcium supplementation (16). Moreover, the timing of calcium intake, ideally simultaneous with oxalate-rich foods, is crucial for maximizing its absorption-reducing effect. Since calcium intake from dietary sources (such as dairy products) is not always possible due to limitations in daily life or diseases such as lactose intolerance, finding an alternative for dietary calcium is of great importance in management of idiopathic hyperoxaluria.

The present study aimed to investigate and compare the effect of calcium citrate supplementation with adequate dietary calcium intake on 24-hour urine excretion of oxalate, calcium, and other lithiasis metabolic risk factors in recurrent calcium stone formers with idiopathic hyperoxaluria.

Subjects

This study was a parallel-group controlled randomized clinical trial. Participants were recruited from the stone prevention clinic of Shahid Labbafinejad Medical Center, Tehran (Iran), from 2019 to 2020. Patients were eligible if they have the following criteria: age 18–70 years, having a history of at least two stone episodes (recurrent stone), documented diagnoses of calcium stone (a radio-opaque stone or a CaOx stone composition confirmed by stone analysis (17)). Additionally, participants needed to exhibit idiopathic hyperoxaluria, as evidenced by a 24-hour urine oxalate level falling within the range of 40–80 mg and excluding individuals with a history of primary hyperoxaluria (urine oxalate > 80 mg/day) or enteric hyperoxaluria (past history of intestinal malabsorptive states or gastrointestinal surgery) (5). Patients were not included if they consumed calcium or vitamin D supplements or any medicine that affects oxalate metabolism (such as vitamin B6 and vitamin C), had a history of hepatitis, diabetes mellitus, thyroid diseases, hyperparathyroidism, immunological diseases, cancers, chronic diarrhea, chronic kidney diseases, urinary tract infection, and in case of pregnancy or lactation.

The ethics committee of the Urology and Nephrology Research Center (Shahid Beheshti University of Medical Sciences, Tehran, Iran) approved the study protocol (IR.SBMU.UNRC.93123-19). The trial was registered in the Iranian Registry of Clinical Trials (IRCT20160206026406N3). All the study protocols were performed in accordance with the 1964 Declaration of Helsinki, and informed consent was received from each participant.

Sample size and Randomization

The minimum sample size was computed 25 patients in each group, considering the type one error of 0.05, type 2 error of 0.20, and of 0.8; using the following equation:

. The eligible patients were randomly divided into two intervention groups: the calcium citrate supplementation group (supplement group) and the dietary recommendation group (diet group). We used a simple randomization method with an allocation ratio of 1:1. To eliminate a bias of treatment assignment and produce comparable groups. A random sequence was generated by a computer program before the study. Researchers and participants blinding was not possible due to the differences in the study protocols.

Interventions

For both intervention groups, an appropriate dietary plan was designed for each participant based on their weight, height, and sex for eight weeks, according to the assigned intervention. The diet group was advised to receive adequate calcium from food (1000–1200 mg of calcium per day, divided into meals). For the supplement group patients, the intake of dairy products was limited, and an additional 800 mg of calcium was provided by calcium citrate caplets in two divided doses, with lunch and dinner. Since citrate is an important inhibitor of calcium stone formation (6), we chose calcium citrate supplement instead of other used calcium salts in the current study. Both groups were similar regarding other dietary recommendations (increased fluid intake, oxalate restriction, reduced animal protein intake, increased fruit and vegetable intake, salt intake restriction, and decreased fat intake). The supplement used in the study was calcium citrate produced by Fanda pharmaceutical company, Tehran, Iran. Each caplet contained 200 mg of elemental calcium, and patients received four caplets per day.

Outcomes and assessment

The study’s primary outcome was the changes in 24-hour urine oxalate (24-U Ox). Secondary outcome measures included changes in 24-hour urine calcium (24-U Ca) and relative supersaturations indices of calcium salts, i.e., calcium oxalate supersaturation (CaOx SS) and calcium phosphate supersaturation (CaP SS).

Demographic variables (age, sex) and anthropometric measurements (weight, height, body mass index-BMI) were assessed at baseline. The duration of the disease was computed as the time from the first urinary stone episode to the initiation of the study (in years). Dietary and laboratory variables were assessed before (baseline) and after eight weeks of intervention (follow-up time). The 24-hour urine sample collection and urine metabolite analyses were performed as previously published (18), including 24-hour urine volume, urea, oxalate, calcium, magnesium, creatinine, sodium, potassium, and citrate. Urine pH was assessed by a pH meter in a morning urine sample. The 24-hour urine supersaturation indices were calculated using the original LithoRisk® software (Biohealth, Italy).

For the assessment of dietary intake, a 24-hour food recall questionnaire was completed by a trained nutritionist before and at follow-up time. Dietary intakes were converted to grams of each food intake per day by a manual for Iranian food household measures (19). Food energy and nutrient content were calculated by the USDA food composition table and the Iranian food composition table for some traditional Iranian foods (e.g., traditional bread). The oxalate content of foods was calculated by the USDA and other food oxalate content tables (20, 21).

Statistical analysis

All the statistical analyses were performed using SPSS software version 25.0 (IBM, Chicago, Illinois, USA). Data were described with mean ± standard deviation and frequency (percentage) for quantitative and qualitative variables, respectively. The normality of data distribution was assessed using the Kolmogorov-Smirnov test. The independent sample T test or Mann-Whitney test was also used to compare the mean outcome quantities between the two groups studied. The Chi-Square test was also used to compare qualitative factors between the two groups. ANCOVA test was used to assess the differences in the mean values of the nutrient intakes between groups while considering the influence of the baseline values. The changes in serum variables, 24-hour urine metabolites, and supersaturation indices between groups were compared using random effects modeling.

Finally, multivariable random effects linear regression was performed to assess the changes in 24-U Ox and Ca, adjusting for confounding variables. Dependent variables were 24-U Ox and Ca, while independent variables included study group, time (before vs. after), and confounding variables including age, sex, weight, BMI, intake of vitamin C, calcium, oxalate, and animal protein, as well as 24-hour urine sodium, 24-hour urine citrate, serum creatinine, and phosphorus levels. Beta values, 95% confidence intervals, and p-values were reported for each independent variable, with significance set at p < 0.05.

Of the 250 patients screened for this study, 72 were enrolled and randomly assigned to intervention groups. Of these, 44 patients (23 in the dietary group and 21 in the supplement group) completed the study protocol (Fig. 1). As reported in Fig. 1, voluntary withdrawal related to the Covid 19 crisis was a significant reason for the high-rate sample loss (n = 13). No serious side effects were reported with taking calcium supplement.

As presented in Table 1, participants' demographic and baseline characteristics were similar in both intervention groups. The differences in the mean values of the nutrient intake between groups were examined while considering the baseline intake values. The results are presented in Table 2. Our results showed that the dietary intervention group failed to increase their calcium intake to the recommended level, whereas the calcium citrate group achieved it. This difference was statistically significant (p < 0.001). We also observed a slight decrease in oxalate intake in the dietary intervention group, but not in the calcium citrate group (p = 0.061). To account for the possible effects of these factors on the outcome of interest, we included both calcium and oxalate intake, along with other confounding variables, in our analysis to validate the study findings. This approach enabled us to better examine the relationship between study groups and the outcomes, while controlling for potential sources of variability or confounding.

Table 1

Baseline characteristics of the study participants
Variables			Dietary Intervention (N = 23)	Calcium Citrate Supplement (N = 21)	p-value
Age (years)			52 (11)	48 (9)	0.652^†
BMI (kg/m²)			28.02 (4.66)	27.48 (4.60)	0.932^§
Stone Disease Duration (years)			12.2 (13.0)	14.5 (13.7)	0.611^§
Gender	Female		6 (26.1)	7 (33.3)	0.599^‡
Gender	Male		17 (73.9)	14 (66.7)	0.599^‡
Smoking	Yes		1 (4.5)	2 (9.5)	0.607^‡
Smoking	No		22 (95.5)	19 (90.5)	0.607^‡
Past History of Kidney Stone Interventions	ESWL	Yes	6 (26.1)	6 (28.6)	0.56^‡
	ESWL	No	17 (73.9)	15 (71.4)	0.56^‡
	TUL	Yes	3 (13.0)	4 (19.0)	0.40^‡
	TUL	No	20 (87.0)	17 (81.0)	0.40^‡
	PCNL	Yes	6 (26.1)	5 (23.8)	0.57^‡
	PCNL	No	17 (73.9)	16 (76.2)	0.57^‡
	Open Neplrolithotomy	Yes	3 (13.0)	2 (9.5)	0.54^‡
	Open Neplrolithotomy	No	20 (87.0)	19 (90.5)	0.54^‡
† Independent T test, ‡ Chi square Test, § Mann-Whitney test. Data presented as number (percent)
BMI. Body Mass Index, ESWL. Extracorporeal Shoch Wave Lithotripsy, TUL. Trans Ureteral Lithotripsy, PCNL. Percutaneous Nephrolithotomy.

Table 2

The dietary intake of groups during the the study period.
Nutrient- Mean (SD)	Time	Study Group		p-value ^a
Nutrient- Mean (SD)	Time	Dietary Intervention	Calcium Citrate
Calcium (mg/day)	Before Study	600.1(236.9)	679.8(319.3)	< 0.001
Calcium (mg/day)	During Study	641.3(305.4)	1372.2(193.5)	< 0.001
Oxalate (mg/day)	Before Study	215.3(118.7)	163.9(89.8)	0.061
Oxalate (mg/day)	During Study	180.0(80.2)	171.8(71.7)	0.061
Fluid intake (ml/day)	Before Study	2752.2(987.2)	2692.3(1038.6)	0.932
Fluid intake (ml/day)	During Study	2414.8(956.1)	2426.2(749.5)	0.932
Energy (kcal/day)	Before Study	2210.0(547.6)	2450.9(651.8)	0.521^b
Energy (kcal/day)	During Study	2337.3(411.7)	2400.86(565.6)	0.521^b
Protein (g/day)	Before Study	75.5(23.6)	94.9(36.4)	0.317
Protein (g/day)	During Study	87.9(26.50)	81.92(20.9)	0.317
Animal protein intake (g/day)	Before Study	35.5(19.5)	50.3(33.8)	0.591
Animal protein intake (g/day)	During Study	42.4(21.2)	38.4(18.8)	0.591
Fat (g/day)	Before Study	80.2(28.2)	84.6(31.1)	0.246
Fat (g/day)	During Study	71.8(21.5)	80.2(23.6)	0.246
Carbohydrate (g/day)	Before Study	326.0(111.5)	360.8(103.1)	0.217^b
Carbohydrate (g/day)	During Study	375.4(68.5)	361.1(106.1)	0.217^b
Sugars (g/day)	Before Study	99.9(47.6)	112.1(42.0)	0.229
Sugars (g/day)	During Study	124.3(33.9)	105.3(59.2)	0.229
Fiber (g/day)	Before Study	37.5(17.2)	44.7(20.4)	0.232
Fiber (g/day)	During Study	39.5(18.9)	53.6(33.2)	0.232
Magnesium (mg/day)	Before Study	370.6(167.0)	389.7(156.6)	0.119
Magnesium (mg/day)	During Study	398.7(148.5)	331.8(114.8)	0.119
Phosphorus (mg/day)	Before Study	1287.7(493.4)	1452.0(488.2)	0.299
Phosphorus (mg/day)	During Study	1449.9(498.8)	1310.63(393.7)	0.299
Potassium (mg/day)	Before Study	3059.2(961.3)	3358.9(857.0)	0.966
Potassium (mg/day)	During Study	3249.9(912.5)	3203.4(946.1)	0.966
Sodium (mg/day)	Before Study	2209.2(1050.1)	2594.9(990.8)	0.580
Sodium (mg/day)	During Study	2373.8(995.4)	2330.5(880.9)	0.580
Vitamin B6 (mg/day)	Before Study	1.5(.5)	1.8(.5)	0.224
Vitamin B6 (mg/day)	During Study	1.7(.6)	1.6(.5)	0.224
Vitamin C (mg/day)	Before Study	102.1(141.3)	94.5(65.4)	0.222
Vitamin C (mg/day)	During Study	161.7(250.7)	86.3(59.4)	0.222
^a: P values are based on analysis of covariance (ANCOVA) to adjust for baseline values in order to compare treatment effects at follow-up time point.

Table 3 represents urine and serum variables before and after the intervention. The results showed that urine oxalate excretion was significantly reduced in both groups after eight weeks of intervention (B: -10.06, 95% CI: -13.70, -6.42, p < 0.001); however, there was no significant difference between groups. Line plot in Fig. 2 shows the trend of urine oxalate excretion in both groups during the study period (Fig. 2).

Table 3

Evaluation of 24-hour urine and serum variables of study groups based on the random effects models.
		Dietary intervention	calcium citrate	Time effect		Group effect
		Mean (SD)	Mean (SD)	B(CI)	p-value	B (CI)	p-value
Serum BUN, mg/dl	Before	13.59 (3.34)	12.19 (2.84)	0.89 (0.01,1.77)	0.046	-0.57 (-2.38, 1.23)	0.534
	After	13.67 (3.72)	13.95 (3.52)
Serum Cr, mg/dl	Before	1.15 (0.18)	1.11 (.17)	0.02 (-0.01, 0.05)	0.093	-0.06 (-0.15, 0.03)	0.22
	After	1.20 (0.19)	1.11 (0.16)
Serum Ca, mg/dl	Before	9.40 (0.33)	9.50 (0.49)	-0.18 (-0.31, -0.04)	0.008	0.11 (-0.03, 0.26)	0.140
	After	9.20 (0.28)	9.33 (0.27)
Serum P, mg/dl	Before	3.40 (0.53)	3.54 (0.49)	− .07 (-.21, .05)	0.249	0.11 (-0.15, 0.38)	0.418
	After	3.34 (0.54)	3.44 (0.52)
Urine pH	Before	5.6 (.9)	5.3 (.6)	0.35 (0.03, 0.68)	0.029	-0.14 (-0.58, 0.30)	0.534
	After	5.8(1.0)	5.8 (1.1)
24-U Calcium, mg/ day	Before	178.0 (69.8)	192.1 (59.7)	15.60 (-4.86, 36.06)	0.135	14.85 (-21.45, 51.16)	0.423
	After	192.8 (81.5)	208.5 (75.0)
24-U Oxalate, mg/day	Before	55.2 (8.9)	59.7 (11.1)	-10.06 (-13.70, -6.42)	< 0.001	4.28 (-1.17, 9.74)	0.124
	After	45.3 (14.8)	49.4 (9.4)
24-U Volume, ml/day	Before	2112 (870)	2331 (687)	316.30 (8.78, 623.82)	0.044	218.99 (-222.89, 660.88)	0.331
	After	2428(836)	2181 (618)
24-U Creatinine, mg/day	Before	1.13(.38)	1.12 (.31)	-0.06 (-0.13, 0.01)	0.099	-0.01 (-0.20, 0.18)	0.914
	After	1.07(.44)	1.06 (.30)
24-U Urea, g/day	Before	28.2(10.4)	27.5 (8.7)	-0.67 (-3.52, 2.18)	0.645	1.82 (-2.73, 6.38)	0.433
	After	25.11(9.84)	29.38 (7.39)
24-U Uric acid, mg/day	Before	466.6(174.9)	399.4 (131.5)	-59.34 (-108.42, -10.27)	0.018	-45.06 (-123.18, 33.05)	0.258
	After	386.2(183.0)	363.2 (136.8)
24-U Phosphorus, g/day	Before	.62(.25)	0.62 (0.19)	-0.002 (-0.05, 0.05)	0.918	− .03 (-.14, .07)	0.540
	After	.65(.21)	0.58 (0.17)
24-U Potassium, meq/day	Before	56.7(20.2)	56.2 (20.5)	-14.36 (-21.31, -7.41)	< 0.001	-1.83 (-11.06, 7.38)	0.696
	After	43.6(19.0)	40.4 (20.3)
24-U Sodium, meq/day	Before	150.2(70.0)	160.9 (71.7)	-8.74 (-30.60, 13.11)	0.433	11.87 (-16.48, 40.23)	0.412
	After	140.3 (48.0)	153.3 (55.4)
24-U Citrate, mg/day	Before	675.6 (288.4)	749.1 (432.9)	50.50 (-53.39, 154.39)	0.341	150.62 (-19.20, 320.46)	0.082
	After	652 (279)	880 (358)
24-U Magnesium, mg/day	Before	82.61 (43.1)	84.58 (31.50)	13.48 (0.55, 26.42)	0.041	-0.04 (-20.05, 19.96)	0.997
	After	98.31(40.8)	95.95 (46.55)
CaOx SS	Before	8.353 (3.954)	7.292 (2.314)	-2.54 (-4.06, -1.02)	0.001	-1.10 (-2.85, 0.65)	0.219
	After	5.871 (2.645)	6.783 (2.435)
CaP SS	Before	0.560 (0.738)	0.522 (1.315)	0.34 (-0.02, 0.72)	0.070	-0.14 (-0.81, 0.51)	0.660
	After	1.033 (1.723)	0.737 (1.092)
UA SS	Before	1.327 (1.287)	0.886 (0.513)	− .34 (-0.67, -0.01)	0.042	-0.26 (-0.68, .15)	0.221
	After	0.806 (0.894)	0.714 (0.649)
CI, Confidence interval; BUN, Blood urea nitrogen; 24-U, Cr, Creatinine; 24-hour urine; CaOx SS, Calcium oxalate supersaturation; CaP SS, Calcium phosphate supersaturation; UASS, Uric acid supersaturation.

During the follow-up period, all participants had an increase of 15.6 mg/day in 24-U Ca, although this increase was not statistically significant (B: 15.60, 95% CI: -4.86, 36.06, p = 0.135). It is noteworthy that in the calcium citrate group, on average, 14.85 mg/day of urine calcium was more than the dietary group, which was not statistically significant (B: 14.85, 95% CI: 21.45, 51.16, p = 0.423). In terms of CaOx SS, there was a decreasing trend in both groups during the study, which was statistically significant (B: -2.54, 95% CI: -4.06, -1.02, p = 0.001). Although the reduction was higher in the diet group, there was no significant difference between the two groups (B: -1.10, 95% CI: -2.85, 0.65, p = 0.219).

We evaluated the effects of interventions on 24-U Ox and Ca after adjusting for the potential confounding variables through a Random-effects multivariable linear regression (Table 4).

Table 4

Evaluation of 24-hour urinary oxalate and urinary calcium changes by adjusting the effect of confounding variables.
	Beta	95% CI	p-value
24-hour urine oxalate
Study group (ref = dietary group)	6.78	0.64, 12.92	0.030
Time (ref = before)	-8.61	-13.14, -4.07	< 0.001
Age	-0.04	-0.24, 0.32	0.786
BMI	0.44	-0.19, 1.07	0.173
Vitamin C intake	0.005	-0.01, 0.02	0.457
Calcium intake	-0.003	-0.01, 0.003	0.354
Oxalate intake	-0.006	-0.03, 0.02	0.637
Sex (ref = female)	4.04	-2.27, 10.35	0.210
24-hour urine calcium
Study group (ref = dietary group)	-4.29	-40.61, 32.01	0.817
Time (ref = before)	14.67	-11.36, 40.70	0.269
Age	-3.16	-4.91, -1.42	< 0.001
24-h urine sodium	0.20	-0.03, 0.44	0.10
Calcium intake	0.02	-0.02, 0.05	0.443
24-h urine citrate	0.009	-0.03, 0.05	0.669
Weight	0.93	-0.40, 2.27	0.174
Serum creatinine	1.43	-115.03, 117.90	0.981
Serum phosphorus	15.90	-15,12, 46.93	0.315
Animal protein intake	-0.39	-0.94, 0.15	0.156
Sex (ref = female)	11.48	-36.95, 59.92	0.642

Table 4 indicates that the time variable had a significant effect on 24-hour urine oxalate, (B=-8.61, 95% CI: -13.14, -4.07, p < 0.001). This means that the 24-hour urine oxalate levels decreased over time for both groups, after adjusting for confounding variables. Additionally, the study group variable had a significant effect on 24-hour urine oxalate (B = 6.78, 95% CI: 0.64, 1.92, p = 0.030), indicating that the dietary group had higher 24-hour urine oxalate levels compared to the reference group, both at baseline and follow-up time point. However, neither the study group nor the time variable significantly affected 24-hour urine calcium. his suggests that there were no significant differences in 24-U Ca levels between groups or over time, even after adjusting for confounding variables.

The effect of normal dietary calcium intake on reducing 24-U Ox and decreasing kidney stone formation risk is well-documented in literature (5, 14, 22). Nonetheless, practical constraints such as dietary restrictions or conditions like lactose intolerance often necessitate alternative sources of calcium. The present study was a randomized clinical trial comparing the effect of adequate dietary calcium intake with calcium citrate supplements (800 mg elemental calcium/day divided into two doses with meals) on 24-U Ox and Ca. The results showed a significant decrease in 24-U Ox for both groups, with no significant increase in 24-U Ca, suggesting calcium citrate supplementation as a viable alternative for managing idiopathic hyperoxaluria in calcium stone formers.

Studies on the impact of calcium supplementation on kidney stone risk have yielded mixed results. In the Women's Health Initiative trial, involving over 36,000 postmenopausal women, daily calcium intake of 2,100 mg (1,100 mg from diet, 1,000 mg from supplements) with vitamin D (400 units) was associated with a 17% increased stone formation risk compared to placebo after 7 years, although the increase was not statistically significant among those with placebo (23). Similarly, the Nurse’s Health Study I reported a 20% increased risk in women without a history of kidney stones taking calcium supplements (either as separate supplements or as part of multivitamin preparations), which 67% of them have taken supplements separately from meals or with a low-oxalate meal (24). However, prospective observational studies like Nurse’s Health Study II (8-year) and Health Professionals Follow Up Study (14 years) found no heightened kidney stone risk with supplemental calcium intake (14, 25, 26).

Hess et al. demonstrated that hyperoxaluria has a more significant impact than hypercalciuria on crystal formation in supersaturated urine (13). Therefore, a relatively moderate increase in urine oxalate level can significantly affect urine supersaturation status (27). In the study by Unruh et al. (28), which investigated the oxalate absorption in eight healthy volunteers with a calcium intake of 200 (diet) to 1200 mg (supplement), oxalate absorption decreased over the whole range of increasing the calcium intake. In another study on 18 healthy post-menopausal women (29), supplementation with calcium citrate (800 mg calcium per day) for two weeks showed an increase in 24-U Ca and a decrease in 24-U Ox with no change in CaOx SS index. Regarding the importance of calcium supplement timing, in one study (30), 32 healthy males were assigned to either take 1 g of calcium carbonate with meals three times/day or 3 g at bedtime. After taking the supplement for one week, the participants followed by one month washout period, then crossover between both groups. Results showed that both protocols increased 24-U Ca similarly. However, the 24-U Ox only decreased significantly when the participants took calcium supplements with a meal. Moreover, there was no significant increase in the activity product for calcium oxalate when taking a calcium supplement with a meal. In contrast, consuming calcium supplements at bedtime increased the activity product for calcium oxalate. These discrepancies underscore the complexity of calcium's role in kidney stone formation, influenced by factors such as total calcium intake, dietary patterns, and supplemental timing.

It is worth noting that our study was on kidney stone formers, while the studies mentioned earlier were mostly on healthy participants. Other strengths of our study were controlling participants’ dietary intake, which impacts 24-U Ox and Ca, and a comprehensive approach by assessing urinary supersaturation instead of only calcium and oxalate excretion. Despite its strengths, our study had limitations, including sample loss, partly due to the Covid-19 pandemic. Although the analyses showed a similar loss pattern in study groups, volunteer bias cannot be ruled out. Moreover, participants in dietary intervention groups did not achieve the targeted daily calcium intake of 1000 mg. This shortfall has significant implications for interpreting the study's results and can be understood in the context of the broader, real-world challenges in dietary intervention compliance. Dietary modifications, unlike pharmacological treatments that typically involve taking medication once or twice daily, entail a series of complex and continuous actions throughout the day. These actions range from changing shopping patterns and modifying food preparation techniques to adjusting meal schedules, each requiring considerable effort and ongoing commitment. This difficulty in adherence is supported by Penniston et al. in the realm of kidney stone prevention where 34% of 85 patients were not correctly recall the recommendations for normalizing calcium intake, such as increasing calcium consumption in cases of low intake or timing calcium intake with meals (31).

A comprehensive review on "Calcium supplements benefits and risks"(32) sheds light on the debate over optimal calcium intake levels. While the FAO and WHO advocate for a daily intake of 1300 mg, particularly for postmenopausal women and men over 65, the UK maintains a recommendation of 700 mg for all adults (32). The review also questions the direct link between calcium intake and bone health, suggesting that dietary calcium requirements might be lower than previously suggested. Longitudinal bone density studies propose that satisfactory bone health may be achievable for women consuming half the recommended quantities without additional supplementation (32). Given these considerations, the mean Ca intake of 640 mg in the dietary intervention group may be adequate for achieving favorable reductions in oxalate excretion. Moreover, participants taking calcium supplements in the current study, showed a slight decrease in protein intake, likely due to the omission of dairy products. As dairy is a key source of both calcium and protein, reducing or eliminating it from their diet could explain this effect. Given the influence of protein on calcium excretion, we were unable to include urine calcium assessments specifically for supplemented calcium in our analysis. This limitation should be considered in interpreting our results. Finally, we did not evaluate the vitamin D status of our participants. However, research, such as the Women’s Health Initiative, indicates that combined calcium and vitamin D supplementation may increase the risks of hypercalciuria and kidney stones, particularly in postmenopausal women (33).

Our study highlights that calcium citrate supplementation significantly reduced 24-hour urine oxalate levels in recurrent calcium stone formers with idiopathic hyperoxaluria. However, the difficulty faced by participants in achieving the targeted dietary calcium intake necessitates a cautious approach when comparing the effects of dietary intake and supplementation.

Conflict of interest

The authors declare that there are no conflicts of interest.

Funding

This research received no funding.

Authors’ contributions

S.T., M.T. contributed to the study conception and design. Data collection and writing the first draft of the manuscript was done by S.J. Conducting the trial and investigation process with main revision of the manuscript were performed by S.T., M.T and S.J. Application of statistical and mathematical or other formal techniques to analyze the study data was done by N.B. All authors read and approved the final manuscript.

Acknowledgement

This article is taken from project titled “Comparison of the effect of the calcium citrate supplement with normal calcium diet on metabolic risk factors in recurrent calcium stone formers with hyperoxaluria: a randomized clinical trial” with code number IR. SBMU. UNRC. 93123-19 from ethic committee, that was supported by research and technology in Shahid Beheshti University of Medical Sciences (http://dregistry.sbmu.ac.ir).

Data Availability Statement

The dataset supporting the conclusions of this article is available in the http://dregistry.sbmu.ac.ir or from the corresponding authors on reasonable request.

Khan A. Prevalence, pathophysiological mechanisms and factors affecting urolithiasis. International urology and nephrology. 2018;50(5):799–806.
Howles SA, Wiberg A, Goldsworthy M, Bayliss AL, Gluck AK, Ng M, et al. Genetic variants of calcium and vitamin D metabolism in kidney stone disease. Nature communications. 2019;10(1):5175.
Bargagli M, Ferraro PM, Vittori M, Lombardi G, Gambaro G, Somani B. Calcium and Vitamin D Supplementation and Their Association with Kidney Stone Disease: A Narrative Review. Nutrients. 2021;13(12):4363.
Bhasin B, Ürekli HM, Atta MG. Primary and secondary hyperoxaluria: Understanding the enigma. World journal of nephrology. 2015;4(2):235–44.
Türk C, Neisius A, Petrik A, Seitz C, Skolarikos A, Somani B, et al. EAU Guidelines on Urolithiasis: European Association of Urology; 2021 [cited 2021 July, 8]. Available from: http://uroweb.org/guideline/urolithiasis/.
Partin AW, Wein AJ, Kavoussi LR, Peters CA, Dmochowski RR. Campbell Walsh Wein Urology, E-Book: Elsevier Health Sciences; 2020.
Parvin M, Shakhssalim N, Basiri A, Miladipour AH, Golestan B, Mohammadi Torbati P, et al. The most important metabolic risk factors in recurrent urinary stone formers. Urology journal. 2011;8(2):99–106.
Spradling K, Vernez SL, Khoyliar C, Morgan JB, Okhunov Z, Preminger GM, et al. Prevalence of Hyperoxaluria in Urinary Stone Formers: Chronological and Geographical Trends and a Literature Review. Journal of endourology. 2016;30(4):469–75.
Holmes RP, Goodman HO, Assimos DG. Contribution of dietary oxalate to urinary oxalate excretion. Kidney international. 2001;59(1):270–6.
Siener R, Hoppe B, Löhr P, Müller SC, Latz S. Metabolic profile and impact of diet in patients with primary hyperoxaluria. International urology and nephrology. 2018;50(9):1583–9.
Robertson WG, Hughes H. Importance of mild hyperoxaluria in the pathogenesis of urolithiasis–new evidence from studies in the Arabian peninsula. Scanning microscopy. 1993;7(1):391–401; discussion – 2.
Crivelli JJ, Mitchell T, Knight J, Wood KD, Assimos DG, Holmes RP, et al. Contribution of Dietary Oxalate and Oxalate Precursors to Urinary Oxalate Excretion. Nutrients. 2020;13(1).
Hess B, Jost C, Zipperle L, Takkinen R, Jaeger P. High-calcium intake abolishes hyperoxaluria and reduces urinary crystallization during a 20-fold normal oxalate load in humans. Nephrology Dialysis Transplantation. 1998;13(9):2241–7.
Curhan GC, Willett WC, Rimm EB, Stampfer MJ. A prospective study of dietary calcium and other nutrients and the risk of symptomatic kidney stones. The New England journal of medicine. 1993;328(12):833–8.
Martini LA, Heilberg IP. Stop dietary calcium restriction in kidney stone-forming patients. Nutrition reviews. 2002;60(7 Pt 1):212–4.
Sorensen MD. Calcium intake and urinary stone disease. Transl Androl Urol. 2014;3(3):235–40.
Goldfarb DS, MacDonald PA, Gunawardhana L, Chefo S, McLean L. Randomized controlled trial of febuxostat versus allopurinol or placebo in individuals with higher urinary uric acid excretion and calcium stones. Clinical journal of the American Society of Nephrology: CJASN. 2013;8(11):1960–7.
Noori N, Honarkar E, Goldfarb DS, Kalantar-Zadeh K, Taheri M, Shakhssalim N, et al. Urinary lithogenic risk profile in recurrent stone formers with hyperoxaluria: a randomized controlled trial comparing DASH (Dietary Approaches to Stop Hypertension)-style and low-oxalate diets. American journal of kidney diseases: the official journal of the National Kidney Foundation. 2014;63(3):456–63.
Ghaffarpour M, Houshiar rad A, Kianfar H. The manual for household measures, cooking yields factors and edible portion of food. Tehran: Keshaverzi press; 1999[in persian].
Siener R, Hönow R, Voss S, Seidler A, Hesse A. Oxalate content of cereals and cereal products. Journal of agricultural and food chemistry. 2006;54(8):3008–11.
Byham-Gray LD, Burrowes JD, Chertow GM. Nutrition in kidney disease: Second edition2014. 1-478 p.
Siener R. Nutrition and Kidney Stone Disease. Nutrients. 2021;13(6).
Jackson RD, LaCroix AZ, Gass M, Wallace RB, Robbins J, Lewis CE, et al. Calcium plus vitamin D supplementation and the risk of fractures. The New England journal of medicine. 2006;354(7):669–83.
Curhan GC, Willett WC, Speizer FE, Spiegelman D, Stampfer MJ. Comparison of dietary calcium with supplemental calcium and other nutrients as factors affecting the risk for kidney stones in women. Annals of internal medicine. 1997;126(7):497–504.
Curhan GC, Willett WC, Knight EL, Stampfer MJ. Dietary factors and the risk of incident kidney stones in younger women: Nurses' Health Study II. Archives of internal medicine. 2004;164(8):885–91.
Taylor EN, Stampfer MJ, Curhan GC. Dietary factors and the risk of incident kidney stones in men: new insights after 14 years of follow-up. Journal of the American Society of Nephrology: JASN. 2004;15(12):3225–32.
Asplin JR. Hyperoxaluric calcium nephrolithiasis. Endocrinology and metabolism clinics of North America. 2002;31(4):927–49.
von Unruh GE, Voss S, Sauerbruch T, Hesse A. Dependence of oxalate absorption on the daily calcium intake. Journal of the American Society of Nephrology: JASN. 2004;15(6):1567–73.
Sakhaee K, Poindexter JR, Griffith CS, Pak CY. Stone forming risk of calcium citrate supplementation in healthy postmenopausal women. J Urol. 2004;172(3):958–61.
Domrongkitchaiporn S, Sopassathit W, Stitchantrakul W, Prapaipanich S, Ingsathit A, Rajatanavin R. Schedule of taking calcium supplement and the risk of nephrolithiasis. Kidney international. 2004;65(5):1835–41.
Penniston KL, Wertheim ML, Nakada SY, Jhagroo RA. Factors associated with patient recall of individualized dietary recommendations for kidney stone prevention. European journal of clinical nutrition. 2016;70(9):1062–7.
Reid IR, Bristow SM, Bolland MJ. Calcium supplements: benefits and risks. Journal of internal medicine. 2015;278(4):354–68.
Wallace RB, Wactawski-Wende J, O’Sullivan MJ, Larson JC, Cochrane B, Gass M, et al. Urinary tract stone occurrence in the Women’s Health Initiative (WHI) randomized clinical trial of calcium and vitamin D supplements123. The American journal of clinical nutrition. 2011;94(1):270–7.

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Comparing the effect of calcium citrate supplement with normal calcium diet on metabolic risk factors in recurrent calcium stone formers with idiopathic hyperoxaluria: A randomized clinical trial

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