Nephrolithiasis and urinary tract infections: 'the chicken or the egg' dilemma?

The relationship between nephrolithiasis and urinary tract infections (UTIs) is complex and difficult to analyse both on a physiopathological and clinical point of view. To date, research has focused mostly on the ability of bacteria to foster the onset of kidney stones. In particular, nephrolithiasis is traditionally classified into two big groups: (i) calcium kidney stones generally characterized by calcium oxalate and/or calcium phosphate stones and (ii) non-calcium kidney stones consisting in uric acid, cystine, rare forms (i.e. drugs, dihydroxyadenine, ammonium urate) and infectious stones. The latter are generally composed of triphosphate of ammonium and magnesium (struvite) [1]. Infective nephrolithiasis is traditionally considered to be a consequence of a UTI with bacteria, in most cases belonging to Proteus genus, that can produce urease, an enzyme able to split urinary urea, thus rising urinary pH and promoting precipitation and aggregation of struvite crystals following. This process follows a cascade of chemical reactions leading to the infection stones formation (Figure 1) [2]. One of the most typical forms of infective lithiasis is staghorn nephrolithiasis, which is characterized by a unique large-sided calculus completely filling the renal pelvis [3]. One paper by Tavichakorntrakool et al. [4], through an accurate and smart experimental design, suggests a different perspective and confirms that the association between UTIs and nephrolithiasis is far more complex than that suggested by the historical, didactic and perhaps simplistic dichotomic classification. Although this issue has never been thoroughly studied in the literature up to this moment, we can realistically state that there are a large number of cases of nephrolithiasis, which we should traditionally define as metabolic, carrying clinical and laboratory findings of UTIs. This statement is also confirmed by very old research data, such as the ones published in 1957 by Melick and Henneman [5], who found that 34 out of 207 stone formers had a concurrent infection (with positive urine culture), but only 3 among those 34 had the classic struvite nephrolithiasis. In all the other cases, calcium phosphate calculi were documented. The authors interpreted those infections as a consequence of nephrolithiasis, considering that the stone-induced uretheral obstruction is a well-known risk factor for infection. In a 1972 retrospective study, carried out on 725 patients with calcium phosphate stones, 70% resulted infected with a urinary pathogen bug, in most cases Escherichia coli or Proteus spp. [6]. However, the analysis of stone composition revealed a wide heterogeneity, with a large percentage of calculi containing calcium (96%) and oxalate (52%). In spite of the limits of the biochemical stone analysis carried out at the time, certainly not as accurate as the present ones, we can anyway say that only a minority of those patients was suffering from struvite stones. However, the treatment of infection was associated with a lower rate of relapse of nephrolithiasis. If not properly treated, the association between kidney stones and UTIs can lead to the onset of a dreadful complication, which is chronic pyelonephritis. A 1979 study just considered 33 stone formers with chronic pyelonephritis [7], performing urine cultures, cultures of bioptic samples of renal parenchyma and cultures of the calculi surfaces, demonstrating a bacterial growth, respectively, in 18, 33 and 47% cases. The bacteria isolated were highly heterogeneous (Proteus spp., Streptococcus spp., E. coli, Pseudomonas spp. and Klebsiella spp.). The fact of the calculus surface cultures being positive in a high number of cases may be due to a direct pathogenic role of the infection in the formation of stones, instead of subsequently complicating the clinical course. A biochemical analysis of stone composition was not carried out in this study, but it is remarkable that many patients were infected by bacteria that do not produce urease and thus are not usually associated with infective nephrolithiasis. It was actually demonstrated in the following years that ∼35% of kidney stones associated with infection are metabolic stones, thus composed of calcium phosphate and calcium oxalate. Even in those cases, the culture of stone surface was surprisingly positive for uropathogenic bugs; therefore, the proper therapy must be established on the surgical removal of the stone [8]. A study carried out in Sweden in 1989 showed that 28% of the patients admitted in hospital for renal colic