Reply to: Calcium/Citrate Ratio and Risk of Kidney Stone

Calcium/Citrate Ratio and Risk of Kidney Stone

Does the Urinary Calcium/Citrate Ratio Add to the Diagnostic Workup of Children at Risk of Kidney Stones? A Cross-Sectional Study

We recently published our article entitled “Does the Urinary Calcium/Citrate (UCa/UCi) Ratio Add to the Diagnostic Workup of Children at Risk of Kidney Stones?” in your prestigious journal.[1] We have received a letter to the editor by Beuy Joob and Viroj Wiwanikit. In that letter, the authors acknowledge that our findings are in accordance with the literature, especially the study by DeFoor et al.[2] However, they also highlight that there is sexual variation for urine citrate.[3] In adults and older adolescents, there clearly is a higher urinary citrate excretion in women as compared with that in men.[3] Sex differences of the urinary citrate/creatinine ratio have since then been confirmed in adolescents.[4] These sex differences start with the onset of puberty and may explain the higher prevalence of kidney stones in men.[4] Interestingly, the substantial increase of nephrolithiasis in children and adolescents, however, is among adolescent girls.[5] [6]

Our study by Lee M et al[1] involved 56 males with a median (25th, 75th percentile) age of 8 (3, 15) years and 41 females with a median age of 10 (6.8, 15) years, which was not statistically different (p = 0.2720, Mann Whitney U test). The details of the patients are listed in [Table 1]. This means that most of the patients were prepubertal. As pointed out, the sex differences begin with the onset of puberty.[4] The proposed cutoff for assessing the stone risk therefore holds in our patient cohort and the main conclusion that “U_Ca/U_Ci rather than U_Ci/U_Cr may be more predictive in the clinical setting when evaluating for nephrolithiasis” remains adequate as we did not observe any sex differences for the urinary citrate/creatinine ratio ([Fig. 1]). Unfortunately, our cohort of patients was too small to perform a subanalysis of adolescents, and we did not routinely obtain the Tanner stage to precisely determine the onset of puberty. Therefore, we do acknowledge that more work is needed to assess the utility of the urinary U_Ca/U_Ci as a predictor for nephrolithiasis or urolithiasis in pubertal adolescents. We agree with the conclusion in Joob and Wiwanitkit's letter to the editor that the sex variation should be kept in mind in interpreting U_Ca/U_Ci in adolescents. We do see many adolescent girls with kidney stones who have normal U_Ci/U_Cr but abnormal U_Ca/U_Ci. The reasons for the substantial increase of kidney stones in adolescent girls remain a main question for our ongoing research.

Fig. 1 Comparison of urinary citrate/creatinine ratio in the aforementioned study.[1] There was no significant difference between both sexes.

Table 1 Patient characteristics and comparison of parameters

Group	SF	NSF	Comparison	Test
Number of patients	51	46
Age (years, median and IQR)	8 (3,15)	10 (6.8, 15)	0.1755	Mann Whitney
Female (%)	19 (37.3%)	22 (47.8%)	0.3074	Fisher's exact test
Urinary citrate (mmol/L, median and IQR)	1.55 (0.95, 2.32)	1.675 (0.79, 3.13)	0.7743	Mann Whitney
Urinary calcium (mmol/L, median and IQR)	1.87 (1.21, 4.29)	1.0 (0.26, 2.3)	0.0021	Mann Whitney
Urinary sodium (mmol/L, median and IQR)	77 (30, 121)	107 (48, 154)	0.0963	Mann Whitney
Urinary potassium (mmol/L, median and IQWR)	42 (28, 101)	48 (19, 80)	0.9895	Mann Whitney
Urinary creatinine (µmol/L, median and IQR)	3.4 (1.5, 6.8)	4.6 (1.9, 9.0)	0.3878	Mann Whitney
Urinary oxalate (µmol/L, median and IQR)	189 (111, 291)	134 (38, 290)	0.1438	Mann Whitney
Urinary urate (µmol/L, median and IQR)	1.9 (1, 5.7)	2.3 (1, 12)	0.2544	Mann Whitney
Urinary pH (mean ± SD)	6.6 ± 0.91	6.5 ± 0.98	0.7366	t-test
Urinary specific gravity (median and IQR)	1.010 (1.005, 1.020)	1.015 (1.005, 1.020)	0.1842	Mann Whitney
Urinary citrate/creatinine (mmol/mmol, median and IQR)	0.48 (0.21, 0.90)	0.38 (0.21, 0.86)	0.8784	Mann Whitney
Urinary calcium/creatinine (mmol/mmol, median and IQR)	0.67 (0.31, 1.37)	0.24 (0.11, 0.73)	0.0029	Mann Whitney
Urinary calcium/citrate (mmol/mmol, median and IQR)	1.30 (0.73, 2.78)	0.68 (0.29, 1.83)	0.0114	Mann Whitney
Urinary sodium/potassium (mmol/mmol, mean ± SD)	2.08 ± 1.92	2.50 ± 1.36	0.3185	t-test

Abbreviations: IQR, interquartile range (25th and 75th percentiles); NSF, non-stone formers; SD, standard deviation, SF, stone formers.

Note: Statistically significant differences are in boldface. The comparison column represents the p-value, and in the test column, the test that was used is listed (based on the distribution and data type).

Conflict of Interest

None declared.

• References

• 1 Lee M, Rodriguez Cuellar CI, Nagra R, Wang ZTP, Bhayana V, Filler G. Does the urinary calcium/citrate ratio add to the diagnostic workup of children at risk of kidney stones? A cross-sectional study. J Child Sci. 2019; 9: e1-e6
• 2 DeFoor W, Jackson E, Schulte M, Alam Z, Asplin J. Calcium-to-citrate ratio distinguishes solitary and recurrent urinary stone forming children. J Urol 2017; 198 (02) 416-421
• 3 Perry GM, Scheinman SJ, Asplin JR. Effects of sex on intra-individual variance in urinary solutes in stone-formers collected from a single clinical laboratory. PLoS One 2013; 8 (06) e53637
• 4 Kirejczyk JK, Porowski T, Konstantynowicz J. , et al. Urinary citrate excretion in healthy children depends on age and gender. Pediatr Nephrol 2014; 29 (09) 1575-1582
• 5 Edvardsson VO, Ingvarsdottir SE, Palsson R, Indridason OS. Incidence of kidney stone disease in Icelandic children and adolescents from 1985 to 2013: results of a nationwide study. Pediatr Nephrol 2018; 33 (08) 1375-1384
• 6 Rodriguez Cuellar CI, Wang PZT, Freundlich M, Filler G. Educational review: role of the pediatric nephrologists in the work-up and management of kidney stones. Pediatr Nephrol 2019