The present study confirmed the trend observed over the last decades reporting an increase of the proportion of calcium oxalate stones and a decrease of the proportion of infectious stones (11,18). Less than a fifth of the stones analyzed were pure, suggesting that stone formation was multifactorial in most cases. There was a high proportion of bladder stones in this cohort.
Calcium oxalate stones were predominant, which is consistent with recent reports (19–22). Weddellite and whewellite stones are found in conditions of hypercalciuria or hyperoxaluria, respectively, or both. These conditions can be influenced by dietary factors and intestinal absorption and are more likely to be encountered in patients with predisposing innate urinary conditions (18). Calcium excretion is increased by high intakes of sodium, diets rich in animal proteins (23,24), and high fructose intake (25). Changes over the last decades towards such diets might therefore be responsible for an increased incidence of calcium oxalate stones in children close to the one found in adults.
Although influenced by food intake, oxalate urinary excretion is particularly affected by intestinal oxalate absorption that is increased with digestive inflammation (26). Additionally, the gut microbiome is less diverse in pediatric calcium oxalate-stone formers, with particularly low levels of oxalate-degrading bacteria (7). Alterations of the microbiome diversity could explain the association found between frequent use of antibiotics and stone disease (27).
The formation of AAU stones is also influenced by nutrition but they occur in conditions of undernutrition, notably in case of phosphate-deficient diets, chronic diarrhea, and dehydration (28) and are a major component of endemic bladder stones frequent among young boys in low income countries (20). These stones gradually disappear as health conditions improve (28). As expected, AAU stones were rarely identified in the cohort herein, while they account for 30% of the pediatric stones in low income countries (19,20).
While uric acid stones caused by a low urinary pH and/or excessive purine intakes are common in adults particularly in case of obesity, they remain rare in children (18). Children have a slightly higher urine pH than adults that does not favor uric acid crystallization (29). This could explain why the well-established association between obesity and urolithiasis in adults remains discussed for children (5). Uric acid stones were found herein only in 2 patients who were receiving multiple treatments.
The influence of inherited factors on pediatric urolithiasis varies according to the composition of stones. Cystine stones occur for instance only in case of congenital cystinuria, an autosomal recessive condition (30). The influence of genetic predispositions for the formation of calcium oxalate or calcium phosphate stones is more variable. Some rare monogenic disorders, such as primary hyperoxaluria (31), or Dent’s disease (32), induce a high lithogenic susceptibility. Recent data have revealed that a causative monogenic mutation could be detected in up to 20% of idiopathic urolithiasis and/or nephrocalcinosis (33). Due to an increased risk of CKD in monogenic stone diseases, genetic analyses are particularly indicated in case of early start, familial history, recurrent, and/or bilateral stones. However, innate risks for stone formation are frequently driven by a polygenic susceptibility or a heterozygosity in known genes. Moreover, some risk factors that were considered as purely environmental and cultural, such as dietary habits, might be partially inherited (34,35). Metabolic inherited predisposition such as hypocitraturia or hypercalciuria might also vary regionally (14,36).
Besides dietary and inherited metabolic factors, infections also play an important role. Struvite stones are always caused by infection (1). Their proportion was lower compared to historical cohorts, particularly among males younger than 2 years: only 7% stones contained struvite, whereas Daudon et al. has reported 38% of struvite-containing stones (11). This decrease in infectious stones partially explain why the historical male predominance in pediatric urolithiasis is currently less clear. Over the last fifty years, the trend towards an equilibration of the sex ratio in high income countries has been illustrated by three successive British cohorts, reporting a decrease from 2.9 to 1.3 of the sex ratio between 1966 and 2015 (37–39). The sex ratio found in the present study was close to the one reported in the most recent study (37) but it remains higher among patients with infectious stones.
Unlike struvite stones, carbapatite stones – about one third of the stones identified herein – are not always caused by UTIs (1): they form in alkaline urines induced by either urea-splitting bacterial infection or defect in urine acidification. When patients were screened for metabolic abnormalities, 65% of carbapatite stones were associated with metabolic abnormalities, sometimes leading to a specific diagnosis and management such as thiazide treatment in case of hypercalciuria resistant to dietary measures. It seems therefore essential to systematically screen patients for metabolic abnormalities even in case of UTI in order to optimize therapeutic strategies, especially for older patients without associated CAKUT and for patients with carbapatite stones for which the carbonatation rate is < 15%.
In addition, both the lower proportion of infectious stones and the increased median age of patients with infectious stones compared to historical cohorts (11) likely reflect an improvement in the management of UTIs and CAKUT in young children over the past decades. The development of infectious stones in older patients can be partly explained by infectious stones occurring later in life in patients with severe CAKUT. Another consequence of the high proportion of complex CAKUT was the elevated proportion of bladder stones (14%) compared to recent studies from high income countries (mostly < 10%) (37,40,41). Endemic bladder stones caused by undernutrition are nevertheless still common in some low income countries where they represent up to 50% of the stones below 2 years (42). In the present cohort, bladder stones occurred in different conditions: patients were older and most of them had CAKUT. As previously published, bladder stones in conditions of complex CAKUT are not always infectious and patients must be screened for metabolic factors (43).
Last, the high number of minimal invasive extraction modes reflects the continuous improvement in pediatric urology, and particularly the miniaturization of equipment, and a will to preserve renal development by limiting potential adverse effects of “open” surgical procedures.
The present study has strengths: it is one of the largest series on pediatric urolithiasis in high income countries of the last decade, and data collection is the most recent. However, it also suffers from limitations, mainly because of its retrospective design. Since patients were seen either in nephrology or in urology, a large proportion of patients did not undergo metabolic evaluation, despite current guidelines recommending a systematic complete metabolic evaluation in case of pediatric urolithiasis (44).
In conclusion, this retrospective cohort provided a recent picture of renal stone disease among children followed in a pediatric University hospital in France. The composition of stones has evolved over the last decades: infectious stones are less frequent and occur mostly in association with anatomic or metabolic factors. In contrast, calcium oxalate stones are more frequent, which could be explained by changes in nutritional habits. The high proportion of bladder stones was associated with complex CAKUT. As factors are often combined, a systematic metabolic evaluation of pediatric stone formers remains nevertheless crucial, even when the infectious etiology seems clear. Genetic screening should be considered in case of suggestive situations.