The pathogenesis of kidney stone disease has been investigated for over 70 years.^1,2 The principal focus has been the analysis of urine in stone formers (SF) and healthy controls to identify key urinary risk factors.^3,4 Stone researchers have found differences between these groups with respect to promotory metabolic risk factors (excretion of calcium, oxalate, phosphate) and protective factors (excretion of citrate, magnesium, urate and 24 h volume).^5,6,7,8,9 Urinary pH falls into both categories depending on its value.¹⁰ Upward and downward deviations from the normal pH range pose significant risks for different types of stone. Physicochemical ratios of two or more of these urinary components have also been used as predictors of risk.¹¹ Among these is the ion activity product index (AP index) developed by Tiselius.¹² However, the most widely used physicochemical assessment of stone risk is the urinary supersaturation (SS) of stone-forming salts^13,14 and it is closely related equivalent, the urinary supersaturation index (SI).¹⁵ Despite the utilisation of this array of metabolic and physicochemical risk parameters, results have not been consistent in differentiating between SF and healthy controls.¹⁶

The anomaly of stone disease in South Africa is well known – it occurs in the white group (W) but prevalence in the black group (B) is relatively rare.^17,18,19 Several local studies have identified urinary differences between W and B, but these have involved relatively small numbers of participants, have not differentiated between males and females and have focused mainly on comparisons between healthy subjects of both races.^17,19 Each involved relatively few urine collections. As a consequence, results have not unequivocally identified critical metabolic or physicochemical risk factors to fully explain the anomaly. Similarly, on the global stage, stone occurrence has been found to be lower in B than in W, but none has identified compelling arguments to account for this racial difference.^2,20,21,22

We believe that the South African stone anomaly provides a unique human model for investigating urinary stone risk factors in both race groups, which might provide insights into stone pathogenesis locally and on a wider scale. The present study was undertaken with these goals in mind.

Applying conventional risk factors in conjunction with our relative analogous model, we propose that lower excretions of metabolic risk factors (calcium and UA), environmental risk factors (potassium, magnesium, phosphate) and lower values of physicochemical risk factors (SS[Bru], SI[Bru] and ionic strength) in BMC compared to WMC are consistent with lower stone risk in the former group. Although these urinary components might independently determine the lower stone risk in BMC, it is their net collective effect (given by the supersaturation indices SS and SI) that is likely to be more crucial, as they depend on the equilibrium concentrations of all species that are present.³⁰ In this regard, the lower SS(Bru) and SI(Bru) values in BMC compared to WMC are particularly noteworthy, as high supersaturation of Bru has been previously mooted as an initiator of calcium stone formation.^31,32 Factors that determine elevated SS(Bru) include relatively higher urinary calcium, relatively lower urinary citrate and relatively higher urinary pH.³³ Although only higher urinary calcium was observed in WMC in the present study, we believe that the evidence described above is sufficiently compelling to implicate the lower supersaturation of Bru in BMC as a contributory factor towards explaining the lower occurrence of stones in black males.

An opposing interpretation arises from our observations of lower Mg excretion, higher oxalate excretion and higher AP (CaOx) index in our BMC group, each of which indicates an increased risk of stone formation in this group according to conventional thinking.^6,12

Thus, in BMC, there are two categories of competing urinary risk factors. This notion is not new per se. Commentators have promulgated the idea that stone formation occurs when there is an imbalance between inhibitory and promotory risk factors.³⁴ In the present case, the first of these (lower supersaturation of Bru in BMC vs WMC) indicates a relatively lower risk for CaOx stone formation in BMC compared to WMC, while the second (lower Mg excretion, higher Ox excretion and higher AP[CaOx] index) indicates a relatively higher risk. Predicting which way the balance favours is difficult. We argue that the driving force for precipitation and ultimate stone formation is stronger for SS than that for individual urinary components, because the former is determined by all chemical speciation present, including those associated with the individual components themselves.

It is of further relevance to note that the lower SS of Bru was confirmed by two independent calculations (SS and SI), lending further confidence to this argument. The higher AP(CaOx) index in BMC need not be considered in this context as its formula includes both Mg and Ox excretion, which has already been discussed. As such, we speculate that the lower SS(Bru) in BMC might override the competing effects of the second group of urinary risk factors and that it might contribute towards the lower occurrence of stones in black males. If this turns out to be true, it will have implications for CaOx stone formation globally as it supports the previously held view that SS(Bru) may be a crucial risk factor in this process described.^31,32

The preceding paragraphs have focused on differences in the urinary concentrations of risk factors between B and W male controls. However, the absence of significant differences in other critical conventional risk factors also warrants discussion. Examples are urinary citrate excretion and urinary pH among the metabolic factors and CaOx supersaturation values (SS and SI) among the physicochemical factors. All are crucial for determining CaOx stone formation and protection depending on their individual excretion levels,³⁵ yet no differences were observed between BMC and WMC. We speculate that perhaps some conventional risk factors are irrelevant in the urine of BMC. This notion is supported by our findings in SF too, as no differences were noted here as well (MMSF vs WMSF).

Further mystery is cast by a previous South African study in which lower excretions of urate and citrate (both of which indicate higher stone risk⁹) were observed in recurrent BMSF compared to WMSF.³⁶ These authors did not explain the anomaly. Unfortunately, there are no other South African studies of this kind, so further comparisons are not possible. However, inter-race studies between SFs on the global stage warrant inspection. Encouragingly, in one such study, authors reported lower SS calcium phosphate (presumably Bru) in BSF than in WSF,³⁷ which again draws attention to our earlier hypothesis that an inter-race difference in SS(Bru) is a key factor for accounting for the relatively lower stone occurrence in B. In another study, lower urinary calcium and UA excretions in B were observed.³⁸ While the former indicates lower risk, the latter indicates increased risk,⁹ as predicted by the inhibitor-promoter imbalance theory described earlier.

The conflict between the South African study, in which several inter-race differences occurred,³⁶ and our own, in which none were observed, is concerning. However, we note that in the former, authors commented that (for various reasons), they suspected that their urinary citrate and calcium values in BSF might be overestimated and underestimated, respectively.³⁶ Interestingly, they also commented that urine values in BSF approached those in WSF in most respects. As such, we tentatively suggest that our findings are credible.

Given the above comments and discussion, we speculate that the impact on stone protection and formation of some conventional risk factors is impaired in black South Africans by the presence of one or more urinary components, which are unidentified at this time. Although evidence in support of this is lacking, the same view is shared by the only other South African study of this nature, in which the possible roles of glycosaminoglycans and macromolecules were invoked.³⁶

Regarding female controls, differences in relative supersaturation (RSS)(Bru) or SI(Bru) between the races (BFC vs WFC) were not observed. However, in a study involving 24-h urine composition in black and white women in the US, authors reported lower SS(Bru) in black women.³⁸ They also found lower supersaturation of CaOx, lower calcium excretion and higher urinary pH in this group and attributed the lower SS(Bru) to the latter two factors. We speculate that the previously reported lower incidence of stones in non-South African black females^38,39 might be attributed to a combination of these factors, albeit that we were not able to test this proposal in the present study, as explained earlier.

Based on the evidence described in the preceding paragraph regarding relative stone risk between female controls in the two race groups, we cannot conclude with the same level of confidence as we did with our male controls that lower SS(Bru) is a crucial factor contributing towards the relatively lower stone occurrence in black females, but this remains a possibility for future consideration.

Regarding inter-gender comparisons, no differences were observed between black controls (BMC vs BFC), but in white controls, several differences occurred (WMC vs WFC), most of which indicated a higher risk in males. The latter finding is consistent with those in several global studies,^40,41,42 as well as in the only South African studies of this kind.^19,43,44 Of these six studies, only one included race as a variable.¹⁹ As explained earlier, we were unable to compare black stone formers because of the paucity of females in this group. Intergender comparisons in white stone formers did not reveal any differences. As there have not been any inter-gender studies comparing stone occurrence in black South Africans, probably because of stone rarity in the latter group, the present study is unique for its findings. As stone occurrence is historically less frequent in South African B, we tentatively suggest (as we did when speculating on the reasons for the absence of inter-race differences between BMC and WMC) that the action of conventional risk factors differs in the two race groups.

The notion of an involvement of Bru in stone initiation arises again in our inter-gender comparisons, in which we found higher SS(Bru) and SI(Bru) in white males (WMC vs WFC). As was the case when we interpreted our inter-race finding of lower SS(Bru) and SI(Bru) values in BMC compared to WMC, it can be hypothesised that the reason for stones being more prevalent in males than in females might be because of higher Bru excretion in the former, making this group more susceptible to stone formation as predicted by our analogous model.

Regarding comparisons between controls and SF, all differences (with one exception) were indicative of lower risk in controls.⁴⁵ The exception – higher Ox excretion in WFC compared to WFSF – is confounding, given that oxalate excretion has been widely regarded for many years as one of the most important risk factors for this type of stone. This outlier is an example of the promoter-inhibitor imbalance theory described earlier.

It is recognised that the absence of data for BFSF severely limits the scope of the inter-race and inter-gender comparisons, which weakens the overarching conclusions about female cohorts. The present study would have benefitted from a larger number of urine samples from this group, but this was difficult to achieve ab initio, given the rarity of stones in the latter.

In conclusion, we believe that the present study is important for several reasons. Firstly, it is the first inter-race and inter-gender investigation of urine composition in SF and non- SF in South Africa and among the first globally. Secondly, it has achieved its principal objective of shedding light on the South African stone anomaly by identifying lower supersaturation of urinary Bru as a likely cause of this phenomenon. In so doing, it has simultaneously achieved its secondary objective of initiating a better understanding of stone formation globally by confirming the previous conjecture that SS(Bru) is a key role player in this process. Thirdly, it has been suggested that the inhibitory-promotory action of conventional urinary risk factors in South African B do not have the same impact as those in white males, possibly because of differences in the urinary milieu of the two groups.

Fourthly, this study shows that the South African stone setting provides a useful human model for future research in this field. Intriguing questions regarding the South African stone anomaly provide opportunities for aspiring researchers in medical and basic science disciplines to contribute towards a deeper understanding of this disease locally and globally. Regrettably, as noted by Lazarus and Kaestner, there is no contemporary epidemiological study of nephrolithiasis in South Africa.⁴⁶ Unless this changes, the aforementioned aspirations are unlikely to be met.