**6. Summary and conclusions**

The formation of Ca stones in the kidney during crystalluria seems to base on crystal AGN either on Randall's plugs or on plaques. Urine has, as demonstrated by our study, a high inhibitor capacity with respect to CaOx AGN. Coating of crystals by electronegative charged UMs creates zones of electrostatic repulsion between the crystals which under normal conditions and within the short urinary transit time in the kidney hardly can be overwhelmed by diffusion or sedimentation being responsible for particle collision and thus AGN. Zones of electrostatic repulsion are reduced in the presence of pathological UMs with a lack of anionic residues or in concentrated urine with a high ionic strength. UMs with a lack of negatively charged anionic groups create an insufficient surface potential on UM-coated crystals. At high ionic strength, the extent of surface potentials is compressed by an increased accumulation of cations. Under these conditions, zones of electrostatic repulsion probably can be bridged by normal but self-aggregated UMs. Self-AGN occurs by the adsorption of UMs on surfaces especially of HAP with its high affinity to UMs. The AGN of UM-coated particles like urinary crystals or latex beads probably mainly bases on a hydrophobic effect between the large hydrophobic protein segments. This effect can occur either directly between pathological UM coats or is mediated by self-aggregated but normal UMs.

Stone formation on Randall's plugs mainly occurs at high urinary supersaturation with respect to Ca salts as observed in primary hyperoxaluria or in hyperparathyroidism both with high recurrence rates of stone formation. At such states of chronic urinary supersaturation, crystallization already can start in the descending loop of Henle and crystals during their way through the nephron can stick to tubular walls and by sedimentation can accumulate further crystals. Tubular cells damaged by massive crystalluria favor crystal sticking and produce pathological UMs, which enhance crystal AGN. Crystal accumulates are ideal platforms for the adsorption of UMs and their self-AGN and thus for crystal AGN. By such mechanisms, large crystal plugs can be formed which when protruding out from ducts of Bellini into the renal calices may give raise to stone formation. Whereas in hyperparathyroidism nephrolithiasis can be cured by parathyroidectomy, the treatment of primary hyperoxaluria is extremely difficult but not the topic of this chapter. However, in stone metaphylaxis, a high fluid intake is essential which apart from urinary supersaturation also reduces ionic strength and urinary transit time through the collecting ducts and the renal pelvis.

The formation of Randall's plaques (RPLs) being the origin of most idiopathic Ca stones seems to be a complex process of biomineralization. RPLs are frequent but not always connected with stone disease. Even in the case of nephrolithiasis, stone formation on a RPL can take decades, whereas other RPLs in the same kidney can remain stone free [13]. Idiopathic Ca nephrolithiasis often is characterized by long stone free intervals [50]. In these cases, stone formation seems more to be the result of a coincidence of noisy factors than a real disease. A most dangerous constellation is an excessive ingestion of Ox rich food (e.g., chocolate) in combination with a poor fluid intake. After excessive Ox intake, a threefold increase of urinary Ox was observed [23]. High urinary Ox and consecutive crystal concentrations can, as mentioned above, induce the secretion of pathological UMs and destroy epithelial layers of RPLs. The consequence is that HAP deposits come in contact with crystals in a concentrated urine where self-AGN and AGN are enhanced by a high ionic strength and a high UM concentration. Therefore, for idiopathic Ca stone patients, dietary Ox restriction and a high fluid intake are mandatory. However, only the last measure is evidence based [51]; since in studies of stone metaphylaxis, the compliance of patients especially of those with long stone-free intervals often is rather poor.
