The present series has confirmed that renal stone formers do have distinct papillary changes that may be characterized using the domains of the PPLA scoring system: DP, SP, LC, and RP [
14]. Pathogenesis of renal stone formation is apparently diverse. Three pathways of human kidney stone formation have recently been proposed [
5,
6]. The first pathway is overgrowth on interstitial apatite plaque (Randall’s plaque), which has been suggested to be the main pathway in idiopathic CaO
x nephrolithiasis; in the second pathway crystals deposit in the renal tubules as the starting point for renal stone formation; and the third pathway implies free solution crystallization as seen in patients with urinary stasis [
6]. Our data clearly show that digital endoscopy of the renal collecting system has the potential to differentiate among these underlying pathways. Although our series included a cohort of stone formers with different types of stone composition/stone disease, it was evident that patients with predominantly DP differed from patients with a high degree of RP, in the sense that patients with DP score > 0 almost all had RP score close to 0 (Fig.
3), indicating different underlying stone pathways. These findings were not reflected in clear differences in urinary parameters. Hence, we were not able to confirm previously published data by Kuo et al. that urine calcium, pH and volume predict coverage of renal papilla by Randall’s plaque [
11]. Our data are in line with the study of Linnes et al. [
20], who also were not able to show a clear-cut correlation of plaque with urinary factors. In contrast to our population, the series of Kuo et al. [
11] consisted of a larger number of hypercalciurics with heavy plaque. Our cases clearly illustrate that hypercalciuria may be associated with both plaques and plugs (Figs.
4 and
6). Thus, from our data it seems evident that patients clinically defined as ‘idiopathic CaO
x stone formers’ are not necessarily characterized by identical stone-forming pathways. This was also suggested in the paper of Linnes et al. [
20]. Efforts to prevent stone formation in idiopathic CaO
x nephrolithiasis have so far been insufficient [
21]. Prevention strategies have almost exclusively been based on final urine studies. Since final urine data according to our findings do not clearly reflect a specific pathogenic pathway, treatment aimed at correcting abnormal urine findings thus may not target the cause of stone formation, explaining why preventive therapy is not always effective. In this perspective, phenotypic characterization of kidney stone formers with the aid of modern endoscopy may hold promise for a more individualized and effective approach to prevention.
As expected, uric acid stone formers in our series had acidic urine [
22]. We found uric acid stone formers to have both RP (40%) and DP (60%), confirming previously reported data [
16,
20]. Although the nature and pathogenesis of plaques and plugs among uric acid stone formers remain to be defined, these findings combined with the observations in the CaO
x group may be explained by the fact that CaO
x and uric acid stone formers often share common systemic characteristics (metabolic syndrome) [
23].
In a previous study on biopsy proven MSK, it was found that the most likely mechanism for stone formation in MSK appears to be crystallization due to urinary stasis in dilated inner medullary collecting ducts with subsequent passage of ductal stones into the renal pelvis, where they serve as nuclei for stone formation [
19]. Definitely, DP was the most prominent finding in our limited series of MSK patients, thus supporting previous findings. The MSK patients had a very recognizable pattern of papillary malformation during endoscopy. The clinical phenotype of MSK is unclear because patients with other causes of stone formation may be incorrectly labeled as MSK based on radiologic image studies [
24]. Therefore, the diagnosis of MSK maybe should be based on endoscopical rather than radiological findings, which potentially may result in more homogeneous metabolic findings in this unique population in the future.
Our apatite stone formers were predominantly characterized by DP and only very limited RP, which was also the main finding in the study of Evan et al. [
12]. LC was a characteristic finding in our apatite group, suggestive of advanced papillary injury in this group [
14]. Our findings support apatite stone formation to be distinctly different from idiopathic CaO
x nephrolithiasis and that these patients may be at higher risk for developing chronic kidney disease [
25].
Strength and limitations
A strength in our analysis was that stones were classified with both IR and micro-CT, ensuring a high accuracy in characterizing stone composition [
6]. A limitation was that stones were sampled retrogradely, meaning that the majority of stones were collected subsequent to laser fragmentation and only a subset of stones (papillary stones and smaller free stones that were extracted in toto) could be considered complete stones. This might have affected classification of patients. Furthermore, the relatively small heterogeneous patient population constitutes a limitation, although we attempted to control for this with a prospective, standardized design. The frequency of compound papillae among the patients in our study likely had an effect on the measures of papillary properties, as there are as yet no published guidelines of what would constitute LC in a compound papilla. Similarly, percentage coverage of pitting or plaque, or numbers of plugs/dilated ducts could be affected by this morphology. For example, a fully compound papilla presumably represents the same quantity of renal function as 2 single papillae [
27], but if it had 5 or more plugs/dilated ducts, we scored it a 2 for plugging, which would have increased the average plugging score relative to the same number of plugs/dilated ducts distributed between 2 simple papillae.