Urinary tract infection (UTI) is one of the most common causes of bacterial infection in children. Various agents are involved in its cause,1 although predisposing genetic factor play each time a larger role. In certain families are UTIs, especially those caused by Escherichia coli (E. coli), more frequent in members of successive generations.2

Moreover, idiopathic hypercalciuria (IH) and hypocitraturia, are the most common cause of kidney stones in both adult and pediatric patients.3 For the same reason, they are also the most common metabolic anomalies observed in children who, without having eliminated kidney stones yet, have genetic predisposition to develop them.4,5 This situation, though not specific to the pediatric age, is known as prelithiasis.6 One of the earliest forms of clinical manifestation in children with prelithiasis is in the form of UTI.7,8

As both conditions, UTIs and prelithiasis, have a genetic basis, we wanted to know whether the family history of urolithiasis in relatives is more common in children diagnosed with UTIs caused by E. coli. Furthermore, a secondary objective was to look whether this condition is related with renal scar and vesicoureteral reflux (VUR). This paper is unprecedented in the medical literature.

The age at diagnosis of the first UTI or ABU was 20.8±31.4 months (range 0.1–132.4 months). 54.8% (n=57) of patients suffered a single pyelonephritis and a further 2.9% (n=3), several pyelonephritis. A single episode of acute cystitis was diagnosed in 4.8% (n=5) of patients and 16.3% (n=17) suffered several episodes. 6.7% (n=7) of patients had been diagnosed with ABU. Lastly, two patients (1.9%) suffered sepsis of urologic origin and in 13 cases (12.5%) the location of the infection in the urine tract could not be properly determined.

Vesicoureteral reflux (VUR) was diagnosed in 21/53 children who underwent a cistosonography. Renal scars were observed in 26/66 patients who underwent a DMSA.

Hypercalciuria was detected in 10/80 cases (12.5%), hypocitraturia in 4/80 (5%) and high calcium/citrate ratio in 28/80 (35%). In total, prelithiasis was found in 38/80 patients (47.5%).

Family history of urolithiasis was established in a total of 71/104 families (68.3%) [22 of first degree (21.2%), 41 of second degree (39.4%) and eight in both degrees (7.7%)].

A relationship was observed with prelithiasis in children with UTI history with a family history of urolithiasis (Table 1) (Odds ratio: 2.93; 95% CI: 1.12–7.67; p=0.03). Table 2 shows the risk of prelithiasis in the cases with renal scar that was 5.3 (p=0.033) and 5.2 in the cases with VUR (p=0.034).

To confirm the connection between the two entities, we studied in this paper the frequency of family history of urolithiasis in a large group of children diagnosed with UTI caused by E. coli. To avoid difficulties of interpretation, we discarded children that were diagnosed with UTI caused by Proteus or other urease-carrying bacteria. In addition, only children with UTI caused by E. coli were selected because of the susceptibility factors that have been recently verified with molecular biology techniques which have been studied in this type of bacteria.18,19 Patients with ABU were considered too because it have been described a connection with UTI either before or after this diagnosis.20,21

The frequency of family history of urolithiasis in our series (68.3%) is much higher than previously described by us in our control population average (28.1%).9 In this regard, as seems reasonable, an association between the presence of prelithiasis in children with UTI and family history of urolithiasis was observed (Table 1). Although the use of a historical cohort can be considered as a methodological limitation, the population in this group is relative homogen due to insularity.

Two different pathogenic sequences for the relationship between UTI and nephrolithiasis have been classically recognized. The first is that in which the UTI would be primary and the stone formation a secondary consequence (infection-induced stones). In the other is the formation of stones and UTI two separate entities (infection-associated stones).

Regarding the first option, Hagar and McGrath suggested in 1925 that urease was involved in the biochemical basis of the formation of kidney stones in cases of UTI, especially in those caused by Proteus.22 A year later, James B. Sumner purified and isolated urease. This author demonstrated that urease was a protein that catalyzes the hydrolysis of urea.23 His discovery led to being awarded the Nobel Prize in Chemistry in 1946. Urea lysis induced by urease increases urinary levels of ammonia, bicarbonate and pH. These chemical changes induce urinary supersaturation and promote crystallization of struvite and carbonate apatite, resulting in crystalline genesis. It indicated also that bacteria can remain within the crystals themselves, which could protect the organisms from being dragged by the urine and be more effective in the production of crystals.

Regarding the second option, it has been described that microcrystals of calcium oxalate monohydrate could damage the epithelial cells of urinary tract, altering their protective role in the urinary tract. Thus, these microcrystals could influence the cellular defense mechanisms as they are attached to urothelial cells and could also be able to activate processes of crystal growth and retention in the renal parenchyma, promoting inflammatory processes and interstitial fibrosis.24 This action would be mediated by glycoproteins and cytokines, which influence the resilience of the urothelial cells25 and therefore favor bacterial invasion.

In recent years, there has been a big step in understanding a narrower association. This time is not between UTIs and stones but between UTIs and prelithiasis, suggesting the existence of common genetic factors. In the 1960s, Antonio Valverde, Spanish urologist located in Córdoba, noted that some children with hypercalciuria had suffered of UTIs.26,27 In 1987, Cervera et al. reported that the frequency of UTI in patients with idiopathic hypercalciuria was 48.9%.7 This association was confirmed in several subsequent series,8,28–31 which contrasts with the frequency of UTI in the control population without hypercalciuria, in which a prevalence was estimated at about 1–2% of boys and 3.5% in girls.32 Similarly and inversely, the frequency series of hypercalciuria in children with UTIs has been described between 20%33 and 44%.34

The rate of increase in the urinary excretion of calcium in our series is not very high. Perhaps it is because many children were studied at a young age; in many cases, idiopathic hypercalciuria is detected after three or four years of age. In recent times, great importance has been given to the calcium/citrate ratio; a value of this ratio above 0.33 indicates that the urine is potentially lithogenic, irrespective of age and the time of collection.17,35,36 The frequency of prelithiasis rises to almost half of the sample (47.5%) if, in addition, we include children with high calcium/citrate and/or hypocitraturia. In our experience we have found that many children with idiopathic hypercalciuria can normalize the urinary calcium excretion in adolescence and at the same time reduce the urinary citrate excretion. We have also observed in the families of some children with idiopathic hypercalciuria, that parents with urolithiasis presented hypocitraturia but with a normal urinary excretion of calcium. It seems as if they were two sides of the same process. Also it described that idiopathic hypercalciuria may be associated with hypocitraturia in the absence of distal renal tubular acidosis.37

The relationship between prelithiasis and renal scarring (Table 2) has not been previously described in the literature as a serious impact with what is mentioned above. The explanation for this association is unknown. As stated before, in recent years there has been a breakthrough in understanding the cause of UTI from the point of view of the host, mostly thanks to molecular biology. In regard to this, mutations and polymorphisms which benefits UTIs have been described in some genes that encode proteins involved in innate immunity.2,3,18,19

These changes would therefore indicate a lower heritable and defensive ability against certain Gram negative bacteria, especially E. coli. It is likely, therefore, that children with prelithiasis are somehow carriers of some of these genetic characteristics which would carry a reduced defense capability against these bacteria7,8,26–31 and thus a greater chance of developing renal scars. Further studies to confirm or deny our findings are necessary.

Still to discuss is the relationship between the diagnosis of prelithiasis and the existence of vesicoureteral reflux (Table 2). In 2003, one of us reported that the prevalence of hypercalciuria was higher in pediatric patients with vesicoureteral reflux than in the general population and that urolithiasis in these patients with this malformation probably have a metabolic origin.38 We also described that hypercalciuria appeared to be inherited as an autosomal dominant trait, although it seemed to be more likely to be inherited from the mother.36 Recent publications have confirmed that the frequency of hypercalciuria is higher in pediatric patients with vesicoureteral reflux compared to healthy children, although their families were not studied.39

The authors have no conflict of interests to declare.