Renal response to lithogenic and anti-lithogenic supplement challenges in a stone-free population group

Article Outline

• Abstract
• Subjects and methods
• Results
• Discussion
• Acknowledgements
• References
• Copyright

Abstract 

Objective

In South Africa, urolithiasis is extremely rare in the black population, but is common in the white population. The objective of this study was to investigate the individual effects of 5 different dietary and supplemental challenges (high dietary calcium, calcium supplement, vitamin B6 supplement, L-glutamine supplement, and L-cysteine supplement) on the urinary risk factors for calcium oxalate urolithiasis in subjects from both race groups.

Design

Complete Latin Square design.

Setting

University research laboratory.

Subjects

Subjects were recruited from the student cohort of the University of Cape Town (10 male subjects from each race group). Selection criteria were no history of renal or metabolic diseases, and no chronic or acute medication. Subjects served as their own controls.

Intervention

After 7 days on a self-selected standardized diet, a 24-hour baseline urine sample was collected. A second 24-hour urine sample was collected after 5 days on the prescribed dietary or supplemental challenge. These were analyzed for biochemical and physicochemical risk factors. Additionally, 24-hour dietary recall questionnaires were recorded at baseline and after the 5-day test period, and were analyzed using a food analysis program. Statistical analysis of variance was performed on all of the data.

Main outcome measures

Urine composition, relative supersaturation of urinary salts, calcium oxalate metastable limit, and Tiselius risk index.

Results

None of the protocols altered any of the urinary biochemical or physicochemical risk factors in black subjects. In white subjects, the calcium diet significantly increased urinary potassium (P = .0001) and decreased the relative supersaturation of brushite (P = .035); the calcium supplement significantly decreased the Tiselius risk index (P = .014); vitamin B6 supplement significantly decreased urinary calcium (P = .016), urinary phosphate (P = .027), and the relative supersaturation of brushite (P = .004); L-glutamine supplement significantly decreased relative supersaturation of calcium oxalate (P = .01); L-cystine supplement significantly decreased urinary calcium (P = .031) and the Tiselius risk index (P = .013).

Conclusions

Because none of the challenges had an effect on the urinary risk factors in black subjects, it is speculated that a renal or gastrointestinal homeostatic adjustment occurs in this group, thereby keeping urinary concentration of substances in balance.

THE PREVALENCE OF KIDNEY STONES is known to be higher in white subjects than in black subjects.1, 2 Research seeking to identify the reasons for the extremely low incidence of urolithiasis in the South African black population is still inconclusive. Previous studies that have investigated the effect of various lithogenic and prophylactic diets have provided evidence of different renal handling mechanisms between South African black and white subjects.3, 4 In an attempt to shed light on the effect of diet on urinary risk factors for calcium oxalate renal stone formation in the 2 race groups, 5 different dietary supplements have been identified as being of interest.

Many studies have examined the association between intake of dietary and supplemental calcium and the risk for calcium oxalate urolithiasis.5, 6 Curhan et al found that a high intake of dietary calcium decreased the risk for calcium oxalate kidney stone formation, whereas supplemental calcium increased the risk.5 In 2 previous studies we suggested that a low-calcium diet and a low-calcium/high-oxalate diet resulted in different renal handling mechanisms in South African black and white subjects.3, 4 We therefore undertook to explore in this study how the 2 race groups would respond to high dietary and supplemental calcium challenges.

In another study, Curhan et al reported that vitamin B6 intake related inversely to the risk of calcium oxalate kidney stone formation in women.7 Vitamin B6 is a cofactor in the oxalate metabolic pathway. Deficiency of this vitamin has been shown to increase oxalate production and contribute to calcium oxalate urolithiasis.8, 9 Conversely, supplementation reduced the recurrence of calcium oxalate kidney stone formation in hyperoxaluric stone formers.10, 11 Furthermore, it is of interest that we have previously reported a significantly lower dietary B6 intake and a concomitantly higher urinary oxalate level in a small cohort of black subjects compared with white subjects.3 Thus, this study also undertook to investigate the effect of vitamin B6 supplementation on the urinary biochemical risk factors in the 2 race groups.

Urinary cystine is also of interest in the South African context. Whalley et al found that black South Africans have significantly lower urinary levels than white South Africans.12 Furthermore, an in vitro study by Martins et al showed that cystine increased growth and aggregation of calcium oxalate crystals in urine.13 This confirms the observations of other studies that have associated high urinary cystine with increased risk of calcium oxalate calculi.14, 15 In addition, some studies have described an anticystinuric effect of oral supplementation of the amino acid L-glutamine.16, 17 Thus, to examine these effects further in South Africa’s stone-prone white subjects and stone-free black subjects, the amino acid supplements L-cysteine, which is metabolically converted to cystine and is eliminated in the urine,18 and L-glutamine were administered to both race groups in this study.

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Subjects and methods 

The study comprised 10 black and 10 white South African men between the ages of 18 and 28 years who had no metabolic disorder or history of kidney stones. All of the subjects were students at the University of Cape Town with similar social status. Five different dietary challenges were administered using a complete Latin Square design. Each subject followed a standardized self-selected baseline diet (Table 1) with prescribed and clearly defined daily portions of all of the major food groups for 7 days, before ingesting each challenge for 5 days in conjunction with the baseline diet. A self-selected standardized diet was regarded as adequate because most of the volunteers were living in university residences where the (self-selected) food was readily available and was prepared by the same catering company. A washout period of 7 days was observed between the protocols, during which the subjects followed the baseline diet. For the high dietary calcium challenge, 500 mL of plain low-fat yogurt (915 mg calcium per day, Table 2) was added to the standardized diet; for the calcium supplement challenge, 925 mg calcium per day was administered in the form of calcium carbonate (Solgar, Leonia, NJ), taken in 3 equal doses at breakfast, lunch, and dinner; for the vitamin B6 supplement challenge, 50 mg pyridoxine (Solgar) twice daily between meals was added; for the L-glutamine supplement challenge, 1,000 mg L-glutamine (Solgar) twice daily between meals was added; for the L-cysteine supplement challenge, 500 mg L-cysteine (Solgar) per day between meals was added. The dosage and time of intake of the challenges was strictly controlled. The amount of yogurt to be ingested was determined to match the calcium content of the supplement as closely as possible using the Food Quantities Manual of the South African Medical Research Council (Table 2).19 A 24-hour dietary recall questionnaire was recorded on the day of each urine collection to monitor compliance with the dietary protocols.

Table 1. Standardized Baseline Diet

Daily Allowance	Portion Size (1 Portion)
2 milk portions	1 cup (250 ml) milk
	1 cup (250 g) yogurt
Choose any 7 fat portions	1 tsp (5 g) butter
	1 tsp (5 g) margarine
	1 tsp (5 g) sunflower, canola, or olive oil
	1 tsp (5 g) mayonnaise
	(50 g) of an avocado pear
	2 tsp (10 g) peanut butter
Choose any 2 vegetable portions	cup (125 mL/75 g) cooked vegetables
	1 cup (250 mL/140 g) green fresh salad
	∗ See critical food list
Choose any 2 fruit portions	Any medium-sized fruit
	cup (125 mL) fruit juice
	∗ See critical food list
Choose any 18 starch portions	1 slice (35 g) of brown bread
	cup (125 g) cooked porridge
	cup (50 g) cereal
	1 (25 g) Weetbix
	3 (30 g) Provitas
	1 medium (90 g)/2 small (90 g) potatoes
	cup (65 g) (cooked rice, samp, pasta)
	cup (90 g) legumes (eg, lentils, beans, chickpeas, soya)
Choose any 7 protein portions	30 g meat/chicken/fish = 1 matchbox
	45 g cottage cheese = 1 heaped Tbsp
	30 g hard cheese = 1 matchbox
	2 cheese wedges (32 g)/4 tsp (20 g) cheese spread
	1 egg
Choose any 5 sugar portions	1 tsp (5 g) sugar
	200 mL (200 g) pudding
	50 mL cool drink
	2 blocks (10 g) chocolate
	2 (6 g) jelly beans

Table 2. Nutrient Composition of 500 mL Plain Yogurt (High-Calcium Challenge)

A 24-hour urine sample was collected from each subject at baseline (ie, after 7 days on the standardized diet) and after 5 days on the prescribed dietary supplement. Urinary sodium, potassium, calcium, and magnesium were determined by atomic absorption spectroscopy whereas citrate, phosphate, urate, chloride, and creatinine were determined using commercially available assay kits (Boehringer Mannheim, Darmstadt, Germany). Oxalate was quantified using an enzymatic assay involving oxalate decarboxylase (Sigma, St. Louis, MO). An ascorbate oxidase spatula was used to remove L-ascorbic acid.20 Urinary cystine was determined using a spectrophotometic assay21 but was measured only in the baseline urine samples and in those collected after ingestion of the L-glutamine and the L-cysteine supplements. Urine pH and volume were measured routinely. The urinary excretion values were used to determine the Tiselius risk index22 and the relative urinary supersaturations of calcium oxalate, uric acid, and calcium phosphate (brushite).23 Although Tiselius22 provides a mean risk index value for normal male subjects and male stone formers (648 ± 27 and 1,019 ± 38, respectively), these thresholds are likely to change for different study groups. Thus, the Tiselius risk index provides an indication of relative risk rather than absolute risk. In this study the index was used to compare the change in relative risk in response to various dietary protocols. The CaOx metastable limit of each urine sample was determined using a Coulter Multisizer.24 The 24-hour dietary recall questionnaires were analyzed for macronutrients and micronutrients using the computer program Foodfinder (version 6).25 Statistical analysis was performed by analysis of variance at statistical significance of P ≤ .05.

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Results 

There were no significant differences between the mean nutrient intakes at baseline (7 days after the standardized diet) and after the 5-day ingestion period. Table 3 gives mean nutrient values for the former.

Table 3. Mean Dietary Intake of Black and White Subjects on Standardized Diet

Note. Significance at P < .05; ±standard error.

At baseline (Table 4), black subjects had significantly lower urinary calcium (2.4 v 3.9, P = .01), urate (2.4 v 3.4, P < .01), phosphate (18.6 v 28.9, P < .01) and cystine (1.4 v 2.1, P < .01) excretions as well as significantly lower relative supersaturations of CaOx (1.4 v 2.6, P = .01) and brushite (0.7 v 1.8. P < 0.01). Urinary excretion of citrate in blacks and their calcium oxalate metastable limits were significantly higher than in white subjects (2.8 v 1.8, P = .03; 0.09 v 0.05, P < .01, respectively). Other urinary variables were not significantly different from baseline.

Table 4. Urine Variables in Black and White Subjects at Baseline

Abbreviations: MSL, metastable limit; RS, relative supersaturation.

Urine variables after each of the ingested challenges are given in Table 5, Table 6, Table 7, Table 8, Table 9. None of the protocols significantly altered any of the urinary parameters in South African black subjects. However, urinary parameters in white subjects changed significantly after each of the protocols. In this group, the dietary calcium challenge increased urinary potassium (47.1 v 104.3, P < .01) and decreased RS brushite (Table 5, 1.8 v 1.1, P = .03); the calcium supplement significantly decreased the Tiselius risk index (Table 6, 315 v 170, P = .01); the vitamin B6 supplement significantly decreased urinary calcium (Table 7, 3.9 v 2.5, P = .02), urinary phosphate (Table 7, 28.9 v 21.6, P = .03), and RS brushite (Table 7, 1.8 v 0.8, P < .01); the L-glutamine supplement significantly decreased RS of CaOx (Table 8, 2.6 v 1.4, P = .01); finally, the L-cysteine supplement significantly decreased urinary calcium (Table 9, 3.9 v 2.6, P = .03) and the Tiselius risk index (Table 9, 315 v 168, P = .01).

Table 5. Urine Variables in Black and White Subjects After the High Dietary Calcium Challenge

Abbreviations: MSL, metastable limit; RS, relative supersaturation.

Table 6. Urine Variables in Black and White Subjects After the Calcium Supplement Challenge

Abbreviations: MSL, metastable limit; RS, relative supersaturation.

Table 7. Urine Variables in Black and White Subjects After the Vitamin B6 Supplement Challenge

Abbreviations: MSL, metastable limit; RS, relative supersaturation.

Table 8. Urine Variables in Black and White Subjects After the L-Glutamine Supplement Challenge

Abbreviations: MSL, metastable limit; RS, relative supersaturation.

Table 9. Urine Variables in Black and White Subjects After the L-Cysteine Supplement Challenge

Abbreviations: MSL, metastable limit; RS, relative supersaturation.

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Discussion 

Our analysis of nutrient intake confirms compliance by the subjects to the self-selected standardized diet and shows that there are no significant differences in the dietary intakes between the 2 subject groups (Table 3). Although the differences in Table 3 may be of relatively low statistical significance, they may be relevant overall. If such small differences are taken into account, the observed effects may be less pronounced.

The significant differences in the urinary baseline values between white and black subjects are in accordance with the low incidence of kidney stones in this race group because all of these parameters are inversely related to the risk of CaOx urolithiasis. All of these differences have been previously reported, except for that of citrate, which has been found to be consistently lower in black subjects.3, 4, 12, 26 The latter discrepancy might be attributable to our having standardized the fruit and vegetable intake in this study. In our previous study, dietary questionnaires showed noncompliance with fruit ingestion, reflected in the low dietary vitamin C intakes of the black subjects.4 Urinary citrate in this group might be very sensitive to dietary intake, whereas urinary calcium might depend on more complex renal or gastrointestinal mechanisms.

The lower urinary cystine in black subjects agrees with previously reported values12 and is noteworthy, because its possible correlation with low stone incidence in South African black subjects has been suggested before.13

Recent studies have provided compelling evidence of dietary calcium being inversely related to CaOx stone formation.5, 6 In this study the dietary calcium challenge did not induce any statistically significant changes in the urinary parameters of black subjects. However, in white subjects urinary potassium increased significantly and the relative supersaturation of brushite decreased significantly (Table 5). The increase in potassium is accounted for by the high potassium content of the yogurt (1,700 mg potassium per day). Interestingly, the same response was not observed in black subjects, despite the fact that they consumed the identical amount of yogurt. Because urinary potassium has been inversely linked to calcium oxalate urolithiasis as it supposedly alkalinizes the urine, making it less favorable for crystallization,27, 28 the response in white subjects is regarded as favorable. The significant decrease in the relative supersaturation of brushite is also favorable and could be attributable to a host of synergistic factors including the increased urinary volume and decreased urinary calcium, albeit these changes were not statistically significant. Other changes that tended toward significance are the decrease in the relative supersaturation of CaOx, the decrease in Tiselius risk index, and the increase in the metastable limit (Table 5). All of these changes are favorable and are in agreement with recent research that suggests that a high-calcium diet decreases the risk of stone formation.5, 6 Paradoxically, none of these changes are indicated in black subjects, who are inherently at low risk anyway.

Curhan et al have shown that supplemental calcium increases the risk of calcium oxalate stone formation when taken between meals but that it does not pose any threat when taken with meals.29 The explanation that they offer is that in the former case, more unbound calcium (and hence, oxalate) is available for absorption, whereas in the latter case, the converse is true. Our results show that the risk of stone formation (Tiselius risk index) in white subjects actually decreases when the calcium supplement is taken with meals, despite there not being any concomitant decrease in urinary calcium or oxalate. This suggests that a more complex mechanism needs to be invoked to explain the effects of calcium supplementation than has been previously mooted. Moreover, the absence of a similar response in the black subjects suggests different renal handling of calcium supplements in the 2 race groups.

As stated earlier, prolonged vitamin B6 deficiency can induce hyperoxaluria,9 whereas intake of this vitamin seems to be inversely related to CaOx stone formation.7 It is interesting that black subjects have a diet that is traditionally high in oxalate,30 low in calcium,12 and low in vitamin B63 relative to that of white subjects. It is therefore surprising that black subjects do not form CaOx kidney stones and that, in this study, black subjects did not experience any significant changes in their urine biochemistry after vitamin B6 supplementation. There are 2 possible explanations for the latter observation. First, black subjects may have more calcium available to bind oxalate in the gut, forming complexes that are excreted in the feces before being absorbed. However, this is unlikely because calcium intake was controlled in this study; as such, it was approximately equal in the 2 groups. Interestingly, a previous study of ours in which a low-calcium/high-oxalate diet was administered to both race groups increased the urinary oxalate in white subjects but not in black subjects,3 again highlighting this puzzling difference between the groups. Secondly, blacks may have more oxalate-degrading bacteria (Oxalobacter formigenes), thereby resulting in less oxalate being absorbed through the gut. This would also explain their normal baseline urinary oxalate despite their traditional hyperoxalurogenic diet.

Intriguingly, the vitamin B6 supplement had 3 significant effects on urinary risk factors in white subjects, all of which were beneficial: it decreased urinary calcium, phosphate and the relative supersaturation of brushite. Because vitamin B6 is involved with the oxalate metabolic pathway, one would have expected urinary oxalate to decrease after its supplementation. Indeed, some studies have shown this effect,11, 31 whereas in another, no effect was observed.32 We are unable to account for the decrease in urinary calcium. However, with respect to the decrease in urinary phosphate, we draw attention to a study in which a vitamin B6 deficiency was induced in adult rats, resulting in the deposition of phosphate and oxalate crystals in the parenchymal connective tissue of the kidney.9 Thus, we postulate that pyridoxine supplementation in this study might have induced a related but reversed effect, ie, a decrease in urinary phosphate. This effect, together with the decreased excretion of calcium, accounts for the decrease in RS brushite. Pyridoxine has also been found to exert an overall positive effect on urinary risk factors.7, 32 In this context it is worthwhile to note that in this study, the metastable limit increased by 34% and the Tiselius risk index decreased by 32% in white subjects, albeit these changes were not statistically significant.

Previous studies have shown that the administration of glutamine with sodium has an anticystinuric effect.16, 33 However, other studies have not been able to reproduce this effect.34, 35 The absence of an anticystinuric effect in this study might be attributable to the absence of sodium in our glutamine protocol. Surprisingly, this protocol induced a reduction in RS CaOx. This has not been previously reported. We are not able to offer an explanation for this effect, but we speculate that it may be caused by several subtle (but not statistically insignificant) changes that act in concert. The decrease in calcium excretion is an example of such a change. However, of interest in this study is that the reduction in RS CaOx occurred in the white race group but not in the black group.

Although there are no previous reports on the effects of L-cysteine supplementation on urinary risk factors, a direct correlation between sulfur amino acids and urinary calcium has been recorded.36 In this study our observation of a decrease in calcium excretion (with a concomitant decrease in the Tiselius risk index) after ingestion of this supplement is therefore surprising and unexpected and is probably caused by an unknown hepatic or renal mechanism. Notwithstanding this interesting effect, we again draw attention to its absence in the black subjects.

It is of some interest to consider intergroup differences in the urine parameters after each challenge and to compare them with those differences that were originally identified in the baseline values. It is noted that some differences that occurred in the baseline values of the 2 groups were abolished after various diets, whereas others were retained. The difference in urinary calcium and the concomitant difference in RS CaOx observed at baseline did not manifest itself after any of the challenges. In most other cases, differences in urinary parameters that occurred originally in baseline samples also tended to disappear after most of the dietary challenges, although the difference in urinary urate was maintained after 3 such challenges. None of the original differences were reversed. However, new differences were identified after some of the challenges. Noticeable among these were urinary potassium, which was significantly lower in black subjects after the high dietary calcium, supplemental calcium, and glutamine challenges and the Tiselius risk index, which was significantly higher in black subjects after the high dietary calcium, supplemental calcium, and L-cysteine challenges. Although it is recognized that complex mechanisms might be involved in the genesis of these differences, the mere existence of the latter is indicative of different renal handling mechanisms in the 2 groups. More specifically, because calcium ingestion (either via diet or via supplement) seems to be a common factor, perhaps it is in the handling of this nutrient that the main difference may lie. Furthermore, because none of the challenges significantly altered any of the urinary parameters in black subjects, it is reasonable to speculate that the intergroup differences that occurred after ingestion of these challenges are attributable to urinary changes in the white group. This, in turn, suggests that the black group was able to invoke a renal mechanism of resistance to the challenges that the white subjects were unable to summon.

In conclusion, this study had provided convincing evidence of different renal or gastrointestinal handling mechanisms of 5 different dietary challenges in black and white South African subjects. It would seem that the former group (by virtue of their apparent immunity to urolithiasis) is able to maintain a homeostatic balance of urinary solutes and is able to offer renal resistance to dietary challenges. Further investigation of a host of factors such as gastrointestinal transport and absorption, the role of oxalate-degrading bacteria and the renal interactions of calcium, sodium, and cystine in the two race groups is clearly warranted.

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Acknowledgements 

The authors thank the South African National Research Foundation, the South African Medical Research Council, and the University of Cape Town for their financial support.

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