Thus, theoretically renal crystal deposition takes minutes, while our data show that stone formation can take decades. Table
3 provides an overview of literature data on observed timelines for precipitation and stone formation. Calcium oxalate crystals are found inside the proximal tubule under extreme conditions like acute and chronic oxalosis both in rat models and in human patients [
15,
29]. Formation and retention of these crystals must have occurred within the passage time for that segment, which is less than a minute [
1]. Under conditions of less extreme but still high renal loading with oxalate, calcium or phosphate or of reduced phosphate reabsorption in the proximal tubule, nucleation of both calcium oxalate and calcium phosphate is expected to occur inside tubules around the bend in the Loop of Henle as was shown in models and in in vitro simulations [
1,
12,
30]. The increase in calcium load that is required to cause this occurs with levels of hypercalcemia found in primary hyperparathyroidism. Blood levels of oxalate are less regulated than those of calcium and respond more to, for instance, dietary loads. The increase in oxalate load required to start nucleation is thus more common and already can occur after eating a bar of pure chocolate [
31]. A likely cause of spontaneous calcium phosphate crystal formation in the loop of Henle is either an increase in plasma phosphate or a decrease in the fractional reabsorption of phosphate in the proximal tubule [
12]. Due to the specific feature of constitutive high pH, especially in the longest loops of Henle [
32], drugs of which the solubility is pH sensitive can also precipitate there [
33]. After the loop of Henle the formation of aggregates becomes more likely as crystals emerging from different nephrons can meet each other [
1]. In stone 1 the oldest central part is such an aggregate. The theoretical time frame for particle retention in the Ducts of Bellini, plugs, is tens of minutes [
1,
12]. The observed timeframe lies within two-and-a-half hours. The time at which recurrent stone formers excreted 200 μ aggregates, in the plug size range after ingesting an oxalate load [
34]. Aggregation will be enhanced when more crystals emerge from the nephrons, thus when supersaturation is increased and when the ability of the urine to inhibit crystal agglomeration is reduced. The latter for instance due to reduced citrate excretion [
6,
7]. In daily life the combination of low agglomeration inhibition and low citrate excretion occurs as a result of a high-protein/high-salt diet [
34]. This is exactly the type of “Western” diet that has been linked to increased risk for urolithiasis. Plug formation as described above was found in 50% of human kidney tissues obtained from patients with calcium oxalate nephrolithiasis who underwent nephrolithotomy or partial nephrectomy before the era of ESWL [
18]. Calcium salt plugs were found within the tubular lumen, attached to the tubular walls or internalized into the tubular cells. In the study that linked stone formation to a reduced ability to prevent crystal agglomeration and reduced excretion of citrate, two of the patients were documented to form and excrete more than 50 stones per year [
6]. This translates into a minimal growth time for a complete stone of around 1 week.
Table 3
Timeline of stone formation
Crystals in proximal tubule [ 15, 29] | Less than a minute | Extreme blood levels |
Crystals in distal nephron parts [ 1, 12, 30] | Minutes | High blood levels |
Plugs in duct of Bellini [ 16‐ 18] | Up to 25 min high renal load, acidification problem | |
Large aggregates in urine [ 35] | One-and-a-half hours | Oxalate load in stone formers |
| 1–2 weeks | Absent inhibition of agglomeration |
Average stone formation | 5 years | Lifestyle risk factors |
Slow stone formation | 23 years | Papillary plaques |
Thus, plugs can be formed quickly. Since a plus remains exposed to urine, outgrowth is not limited by low supply of new material and stone formation may be faster. An encouraging finding is that plugs are more prevalent then stones [
16‐
18]. Apparently there is some balance between plug formation and plug removal. A likely removal mechanism is flushing out (drinking), possibly demonstrated by the presence of dilated ducts. For pH sensitive material dissolution of a plug could theoretically play a role. Calcium oxalate stoneformers without clear hyperoxaluria or hypercalciuria have the lowest presence of tubular plugs. In these patients the plug formation was only linked to a reduced ability to prevent crystal growth. It must be noted that the procedure that was used to measure crystal growth inhibition does not separate effects on crystal growth from effects on crystal aggregation. Following the reasoning above, a majority of this risk-factor-free group will have formed stones through a fixed-particle (plaque) mechanism. They represent the end of the timescale where stone formation can take decades.
In summary we present the timeline of two stones that may represent the two mechanisms of stone formation.
One stone grew slowly but surely over two decades to be removed at a 3 cm size. Its origin is clouded in the past but does coincide with two events of renal trauma. At the time the stone revealed itself by causing colic pain the patient showed no risk factors for stone formation and was considered to be a true “idiopathic” stoneformer. This may well be the type of stoneformer for whom the existing lifestyle measures, which aim to reduce the driving force for crystallization, do not prevent stone formation efficiently, as the first step towards stone formation has already been taken. After the stone was removed three renal calcifications remained in place that can form the nidus for new stones. Whether these will again take decades to grow, what will initiate and speed up the growth process and what can be done to prevent or slow down that growth process are questions for which at present no answers exist. Answering these questions will require more insight into the process of stone growth.
The second stone is an example of a stone that was started from a situation of extreme renal overloading. It grew in a few years, and for this patient, clear risk factors can be identified in his lifestyle. Unfortunately, the extremely high BMI of this patient reflects a low compliance with the lifestyle changes that are needed to prevent new stone formation.