Should we modify the principles of risk evaluation and recurrence preventive treatment of patients with calcium oxalate stone disease in view of the etiologic importance of calcium phosphate? "Beyond the Abstract," by Hans-Göran Tiselius

BERKELEY, CA ( - In view of the common occurrence of calcium oxalate (CaOx) stone disease and the high risk of recurrent stone formation, it is beyond every doubt that recurrence prevention should be part of the medical care of these patients. Unfortunately the success of such measures is, and has been, less good than expected and less efficient than it could be. Two explanations for this outcome can be identified: incomplete understanding of the sequence of events that results in CaOx stone formation and poor patient compliance with treatment programmes that otherwise should be reasonably efficient.

For patients with severe stone formation, our present selection of recurrence preventive regimens is based on analysis of urine composition. Thereby the goal is to identify specific risk factors responsible for abnormal crystallization and subsequently to design a treatment programme with the aim of reducing this risk. In this regard there is an overwhelming experience from 24h urine analysis. This analytical method is extremely popular despite the fact that what we get from these analytical data only reflects the average risk situation during the whole period of one or several specific days.

Recent research has shown that both subepithelial deposits (Randall’s plaque type I) and intratubular plugs (Randall’s plaque type II) of calcium phosphate (CaP) are of importance for precipitation of CaOx. Moreover, the pH-level in urine seems to be of fundamental importance. Measurement of pH in 24h urine is not very informative, particularly if the sample has been stored for some time without preservative. What we need to know is when the pH is low and when it is high. Such extreme values are impossible to discover in urine collected during periods as long as 24h. High urine pH in a pronounced way increases the ion-activity product of CaP. In contrast the direct effect of pH on the ion-activity product and supersaturation of CaOx is small. The effect of low pH-levels for CaOx precipitation is that dissolution of CaP deposits in acid environment results in very high local concentrations of calcium that indirectly can cause very high levels of supersaturation with CaOx. Low urine pH is, thus, an extremely powerful determinant of the risk of CaOx crystallization. Moreover, low urine pH reduces the activity of urine inhibitors of crystallization and causes self-agglomeration of Tamm Horsfall protein and as a result of that aggregation of CaOx crystals. It is of note that stones composed of CaP almost entirely are seen in urine that is constantly alkaline.

The problem is that subepithelial or intratubular deposition of CaP is assumed to be the result of abnormal CaP supersaturation at high nephron levels (loop of Henle and distal part of distal tubules). To what extent this condition can be detected from analysis of final urine (that in calyces and renal pelvis) is not known.

From what has been mentioned above it seems logical to search for specific risk periods for the individual patient and to analyse urine composition in samples collected during shorter periods than 24h. Based on findings on risk factors in such samples, it might be possible to individualize the recurrence preventive treatment in a more precise way. If the recurrence prevention can be concentrated to some less frequently occurring high-risk periods with CaP and/or CaOx precipitation, the recurrence preventive efforts might be less demanding for patients.

From a small number of urine samples collected in 1h fractions, the conclusion was that the risk of CaOx nucleation/crystal growth was highest during late evening, night, and early morning hours. It can also be assumed that the risk of CaP precipitation is highest during the day and relatively soon after meals. Periods with physical exercise pose another risk situation with loss of fluid, low urine flow, and low pH.

If we can find a routine method for urine analysis focused on specific risk periods, and subsequently use that information for individualized recurrence preventive regimens, we can hopefully expect improved compliance, and, accordingly, better recurrence prevention. But only future studies along these lines can show whether these assumptions -- and such therapeutic approaches -- are correct or wrong.

Written by:
Hans-Göran Tiselius, MD, PhD as part of Beyond the Abstract on This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.

Professor em. of Urology, Karolinska Institutet, Stockholm, Sweden

Should we modify the principles of risk evaluation and recurrence preventive treatment of patients with calcium oxalate stone disease in view of the etiologic importance of calcium phosphate? - Abstract

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