The results in our patients indicate that COM papillary calculi result from subepithelial lesions in the tip of the papilla, emerging in a renal calyx. Most lesions undergo calcification by HAP; these deposits grow and erode the epithelium covering the papillae. When these deposits come into contact with urine, they start the development of a COM calculus due to the permanent supersaturation of calcium oxalate in urine and to the high capacity of HAP to act as a heterogeneous nucleant of COM. These calcifications are generated in the thin-loop basement membranes or near the vasa recta[27, 28], both of which are collagen-rich regions . Due to the presence of carboxylate groups, this altered collagen can act as a heterogeneous nucleant of HAP .
The concave zone of papillary calculi can contain a range of calcified lesions, from little HAP residues to typical well-developed HAP plaques, also known as Randall's plaques. The morphology of each calculus and the amount of detected HAP will depend on both the calculus and the location of each calcified injury. HAP plaques may be located in a subepithelial position, altering the epithelium covering the papillae and resulting in the direct deposit of COM crystals on the damaged epithelium . Less frequently, the injury may be in close contact with the epithelium covering the papillae; expansion of the injury may alter the epithelium, allowing the nucleation of COM crystals. These COM calculi will not contain HAP in their starting zone.
These results indicate that COM papillary calculi might be generated from subepithelial lesions on the tip of the renal papillae, and that the morphology of these COM calculi mainly depends on the location of the injury. Hence, the examination of a single calculus does not supply relevant information about the origin of the injury and the severity of the general calculogenesis process. The possible causes of injury may be deduced from the clinical data and lifestyle of each patient . Thus, the papillary injuries in patient 1 may be due to the chronic consumption of drugs to treat her rheumatoid arthritis, as well as to arterial hypertension. The papillary tissue injuries in patients 2 and 3 may have been due to high urinary oxalate, and the injury in patient 4 may have been due to hyperuricemia observed on the clinical history of the patient.
Dystrophic mineralization is commonly observed in soft tissues as a result of injury. Although most soft tissues can undergo calcification, kidney, tendons, and cardiovascular tissues appear particularly prone to developing this pathology . Although the development of tissue calcification depends on a pre-existing injury, which acts as an inducer, the continuation of this process is due to modulators and/or a deficiency in crystallization inhibitors [31–37]. For example, some carboxy proteins, such as osteopontin, can bind to HAP, recruiting macrophages that remove these calcifications or prevent their progression [31–36]. The inhibition of crystallization, preventing HAP development (nucleation and growth), may be due to low-molecular weight-compounds, such as pyrophosphate, magnesium and phytate [2, 37, 38]. The images of the papillae in our patients suggest that many subepithelial calcifications were present in all four, although the number of papillary calculi generated were substantially lower, suggesting that some of these subepithelial calcifications did not progress further and were reabsorbed. An evaluation of Randall’s plaque theory of nephrolithiasis in patients with a unilateral single papillary calculus showed that computed tomography attenuation values (Hounsfield units) of all papillae on the affected side were significantly greater in patients with stone formation than in those without stone formation . In contrast, no significant differences were found between the affected and non-affected sides of patients with stone formation , this demonstrating that not all internal calcification progress further to forming stones.