Dialysis Transplantation
Continuing Nephrological Education
‘Bad dietary habits’ and recurrent calcium oxalate nephrolithiasis
Bernhard Hess
Department of Internal Medicine, University Hospital, Berne, Switzerland
calculated according to the formula Case report
[UUrea×V (mmol/day)×0.18]+13 A 32-year-old truck driver had previously been treated
=Protein consumption (g/day) with allopurinol because of hyperuricaemia and gouty
arthritis. After having first formed a kidney stone at
(adapted from [5]);
age 20, he had passed calculi annually for 8 years
before he finally underwent ESWL for bilateral radio- it amounted to 108.1 g or 1.25 g/kg BW per day. The opaque kidney stones. The patient, whose mother had patient’s daily intake of calcium from dairy products, suffered from renal stones, continued to live on a self- estimated by using a questionnaire based on tabulated selected diet, but considerably increased fluid intake. data of the calcium content of dairy products typically Three years later, after he had passed another stone, consumed in Switzerland [6 ], was 1240 mg/day.
bilateral radio-opaque stones (3 stones on the right, 1 Treatment only consisted of dietary advice by a on the left side) were found on plain X-rays of the dietician who instructed the patient to reduce meat abdomen, and the patient was referred for metabolic protein intake to 5–7 servings per week, to lower evaluation of severe recurrent calcium stone disease. consumption of salt-rich foods (sausages, cheese) and Physical examination revealed a 32-year-old man not to add salt during meals. Furthermore, the patient (173 cm, 86.4 kg, body-mass index 28.9 kg/m2) with was told to reduce intake of oxalate-rich foods and to moderate hypertension (150/95 mmHg), but otherwise keep fluid intake high. Within 6 months, he lost 15 kg normal clinical findings. Laboratory analyses were as of weight, and urine chemistries were significantly follows: values for serum creatinine, sodium, potas- altered, as shown in Figure 1. Whereas excretion rates sium, chloride, phosphate, magnesium, albumin, and of oxalate, phosphate and urea were reduced by venous bicarbonate were normal, and uric acid was 40–50%, urinary citrate almost doubled.
high-normal (399mmol/l, upper normal limit 416). Four months later, urine volume remained very high Ionized calcium was 1.25 mmol/l, intact PTH 19 pg/ml (5430 ml/day), but the patient admittedly had (normal range 10–65), and calcitriol 51 pg/ml (25–79). increased his protein consumption, which was now In a 2-h fasting urine, Ca-E was 0.043mmol/l GF calculated to be 102 g/day; this was also reflected by a (normal∏0.037), and pH 5.87; after 3 days of ammo- rise in U
P×V to 57.3 mmol/day. Whereas hypercalciu- nium chloride loading, fasting urine pH dropped to ria (12.98 mmol/day) and hyperoxaluria 5.29, indicating normal urinary acidification [1]. (0.478 mmol/day) persisted, U
Cit×V had fallen into Unfortunately, no stone analysis was available. the low-normal range (1.94 mmol/day). The patient Nevertheless, the diagnosis of recurrent calcium was told to lower meat protein intake more and to nephrolithiasis with idiopathic hypercalciuria, hyp- slightly reduce calcium intake from dairy products eroxaluria, and hypocitraturia was made, based on the towards normal, i.e. 800 mg/day. Another 4 months presence of bilateral radio-opaque calculi and measure- later, the patient’s urine volume was still high ments of main urinary risk factors for stone disease (5800 ml/day), whereas U
Ca×V had normalized [2,3] in two 24-h urines collected on free-choice diet (8.76 mmol/day) as well as protein consumption,
( Table 1). derived from U
Urea×V, had dropped to 81 g/day; this Excessive consumption of protein and salt, an was also reflected by a decrease in U
P×V to aggravating factor for calcium nephrolithiasis [4], was 46.2 mmol/day. On the other hand, U
Cit×V had identified based on measurements of urinary markers increased to 2.56 mmol/day. Surprisingly, U
Ox×V was of protein and salt consumption ( Table 1). Assuming erratically high, i.e. 1.259 mmol/day. Since measure- steady-state conditions, daily protein consumption was ments of urinary glycollate [6 ] had recently become available in our hospital, glycollate excretion rate was determined in the same 24-h urine and found to be
Correspondence and offprint requests to: PD Dr Bernhard Hess,
0.371 mmol/day (normal∏0.700 mmol/day). This pat-
Department of Medicine, University Hospital, CH-3010 Berne,
Switzerland. tern—low-normal urinary glycollate in the presence of
© 1998 European Renal Association–European Dialysis and Transplant Association
Table1.Urinaryvolumeandexcretionratesofurinaryriskfactorsaswellasofmarkersofproteinandsaltconsumption(meansoftwo24-hurinecollections) VolumeU Ca×VU Ox×VU Cit×VU Mg×VU UA×VU P×VU Urea×VU Crea×VU Na×V (ml/day)(mmol/day)(mmol/day)(mmol/day)(mmol/day)(mmol/day)(mmol/day)(mmol/day)(mmol/day)(mmol/day) Patient254312.690.5301.415.574.49564.09528.420.455296.5 Normalmen>1200∏9.00∏0.4401.703.00∏5.00(————————Stronglydiet-dependent————————) Normalwomen>1200∏8.00∏0.4401.902.20∏4.00 Ca,calcium;Ox,oxalate;Cit,citrate;Mg,magnesium;UA,uricacid;P,phosphate;Crea,creatinine;Na,sodium.Normalvaluesarebasedon24-hurinecollectionsin103maleand73female healthyvolunteersonfree-choicediet[3].
rather severe hyperoxaluria—was consistent with hyp- physicochemical reasons outlined elsewhere [14], small increases in urinary oxalate concentration are much eroxaluria of non-metabolic origin [7]. Indeed, diet
history revealed that, in order to keep urine volume more important than relatively large increases in cal- cium for raising the level of urine supersaturation with high during the hot summer season, the patient had
inadvertently ingested up to 2.5 litres/day of ice-tea, calcium oxalate and therefore the risk of calcium stone formation.
which consists mainly of black tea, a well-known source of oxalate [8]. Shortly thereafter, the patient passed another stone, and a plain X-ray film of the
Hypercalciuria abdomen revealed that one of the three calculi previ-
ously demonstrated in the right kidney had vanished.
The patient once more was seen by the dietician. Even after several decades of studies on idiopathic hypercalciuria (IHC ) and renal stone formation, a In a patient with highly active stone disease and
positive family history for kidney stones, other factors recent review only stated that ‘hypercalciuria could cause or contribute to calcium stone formation’ [15].
such as abnormal macromolecular modifiers of crystal
aggregation have to be considered [9]. Therefore, Many studies have addressed the issue of the pathogen- esis of IHC itself, and evidence has been gathered for Tamm–Horsfall glycoprotein ( THP), a major modifier
of crystal aggregation in urine [10], was isolated from increased intestinal absorption of calcium, due to inad- equately elevated serum levels of 1,25(OH )
2 vitamin the patient’s 24-h urines [11]. Compared with control
conditionsin vitro (no THP, 5 mM calcium, 200 mM D3 (calcitriol ), as the primary cause of IHC (reviewed in [16 ]). Thus, a low-calcium diet appeared to be a sodium chloride and pH 5.7) which signify zero percent
inhibition of crystal aggregation, THP from eight straightforward strategy. However, no prospective trial has ever established the efficacy of such a regimen with healthy male controls at 40 mg/l inhibited aggregation
of calcium oxalate crystals by 26.5±9.1% (mean±SE) respect to stone recurrency [17], and evidence has been presented that a low-calcium diet prescribed for years [11]; the patient’s THP, however, inhibited by−18.8%,
indicating promotion of crystal aggregation [11]. At predisposes to osteopenia [18,19].
As in our patient, overconsumption of meat protein the same physicochemical conditions, intrinsic viscosity
of healthy controls was 123±33 ml/g (mean±SE ) [11]; as well as high salt intake are often associated with IHC [4]. Whereas excess sodium intake directly lowers the patient’s THP, however, had a viscosity of
209 ml/g, indicating structural alterations of THP renal tubular calcium reabsorption [20], the link between high meat protein intake and IHC as well as molecules [10,11].
The patient adheres to a high fluid intake and the fact that calcium renal stone formers appear to be hypersensitive to the hypercalciuric action of increased reduced consumption of meat protein and salt, while
trying to avoid oxalate-rich foods and consuming protein intake [21] are not entirely clear. It has been suggested that excess meat protein consumption sufficient calcium from dairy products. He has been
stone-free for almost 6 years. induces an increased endogenous acid production and thus raises urinary net acid excretion; the latter might then inhibit calcium reabsorption along the distal
Discussion nephron and subsequently stimulate bone resorption
and intestinal calcium absorption [4]. We did not, however, find evidence for increased bone turnover in It is generally agreed that elaborate metabolic
evaluation should be recommended in patients with renal stone formers with IHC on free-choice diet [19].
On the other hand, chronic overconsumption of meat recurrent calcium nephrolithiasis, such as in the present
case [12]. In order to obtain an adequate metabolic protein might increase renal mass and thereby the number of 1a-hydroxylase-producing cells, which profile in an ambulatory setting, it appears that three
24-h urine collections under original conditions of might additionally upregulate calcitriol production.
Indeed, it has been demonstrated that renal mass was stone formation, i.e. on free-choice diet, provide more
diagnostic accuracy than one or two, and that the increased in male hypercalciuric calcium stone formers in comparison with normocalciuric stone formers diagnostic yield is highest 4–6 months after a stone
event [3]. Among the acknowledged urinary risk fac- whose protein intake was lower, and that serum calci- triol was positively related to renal mass [22].
tors for recurrent idiopathic calcium nephrolithiasis,
hypercalciuria (39% of cases) is the most frequent one, The observed rise in calcitriol activity in patients with IHC might diminish renal tubular reabsorption followed by hyperoxaluria and low urine volume (32%
each), hypocitraturia (29%), hyperuricosuria (23%) of calcium by direct suppression of PTH production [23]. Indeed, at equal levels of blood ionized calcium, and hypomagnesiuria (19%) [3].
The question arises whether or not these urinary 30 male calcium stone formers with IHC had lower levels of intact PTH (25.3±1.8 pg/ml ) than their 31 abnormalities directly cause calcium stone disease. It
has been known for many years that the volume of normocalciuric counterparts (31.4±1.8 pg/ml, P=
0.017) whose calcitriol levels tended to be lower calcium oxalate crystals in freshly voided urines from
stone formers as well as the severity of stone disease (47.3±2.9 pg/mlvs52.8±3.2 pg/ml in IHC, NS ) [19];
the calcitriol/PTH ratio as an index of calcitriol upreg- do not correlate with urinary calcium excretion, but
strongly depend on urinary oxalate [13]. Indeed, for ulation was 2.53±0.29 in stone formers with IHC,
higher than in normocalciurics (1.66±0.15, P=0.001 possibility whereby hyperoxaluria may occur, i.e.
increased intestinal absorption of oxalate leading to vs IHC ) [19]. Our present patient fitted exactly into
this pattern of relative hypoparathyroidism [19]: non-metabolic hyperoxaluria. In our case, the latter occurred several months after oxaluria had normalized whereas intact PTH level was low-normal (19 pg/ml ),
serum calcitriol concentration amounted to 51 pg/ml, upon reducing meat protein intake and was due to excess consumption of oxalate-rich black tea (ice-tea).
and calcitriol/PTH ratio was high (2.68).
The non-metabolic origin of hyperoxaluria was emphasized by the fact that urinary glycollate excretion
Hyperoxaluria rate was low-normal in the presence of severe
hyperoxaluria.
Excess oxalate consumption, however, is certainly Normally, only 10–15% of urinary oxalate is derived
not the only cause of hyperoxaluria of non-metabolic directly from the diet, the remainder coming from
origin. More often, patients who have been advised a endogeneous production [7]. On the one hand, ascorbic
low-calcium diet exhibit non-metabolic hyperoxaluria, acid is metabolized to oxalate; this is probably not of
since intestinal oxalate absorption increases as a con- clinical significance, since recent studies suggest that
sequence of insufficient oxalate binding by the reduced daily amounts of up to 4 g of ascorbic acid may be
amount of calcium available in the intestinal lumen ingested without significantly increasing urinary
[8]. This mechanism most probably accounts for the oxalate [7]. On the other hand, Robertson [4] has
fact that secondary increases in urinary oxalate excre- emphasized that overconsumption of meat protein
tion on a low-calcium diet have been observed by increases metabolic production of oxalate from pre-
several authors (reviewed in [7]) and that a large cursors such as hydroxyproline and tryptophan.
prospective trial recently demonstrated increasing rates Indeed, positive correlations between oxalate as well
of de novo stone formation with decreasing daily as glycollate, a metabolic precursor of oxalate, with
calcium consumption [25]. Further evidence that urinary markers of protein intake have been described
increasing calcium intake reduces urinary oxalate [7]. Excess meat protein consumption in certain
comes from a preliminary study in healthy male con- patients could therefore be responsible for what has
trols, where we demonstrated that daily ingestion of been named ‘mild metabolic hyperoxaluria’ [24]: in a
2220 mg of oxalate (about 20-fold normal ) together subset of recurrent calcium stone formers, urinary
with 1200 mg of calcium (normal ) induced severe excretion rates of oxalate as well as of glycollate are
hyperoxaluria, whereas subjects remained normo- moderately increased; in some of these patients, remis-
oxaluric when challenged by the large amount of sion may be obtained by pyridoxine therapy [24]. It
3840 mg of calcium together with the otherwise remains to be seen whether or not ‘mild metabolic
unchanged diet [26 ].
hyperoxaluria’ represents an incomplete form of prim-
Finally, one always has to look for secondary ary hyperoxaluria [7]. Unfortunately measurements of
hyperoxaluria in stone patients with intestinal malab- urinary glycollate initially were not available in our
sorption due to inflammatory bowel disease (with or patient; nevertheless the 50% reduction in U
Ox×V
without bowel resection) and after jejunoileal bypass upon lowering protein intake ( Figure 1) strongly sug-
surgery (reviewed in [7]).
gests that excess meat protein may have been a caus- ative factor for hyperoxaluria.
Incidentally, our patient also illustrates the second
Hypocitraturia
Citrate retards rates of crystallization by two means [27]: on the one hand, by complexing calcium, it reduces concentration of ionized calcium and thus urinary supersaturation of calcium oxalate and calcium phosphate; on the other hand, citrate binds to surfaces of calcium-containing crystals, thereby inhibiting crystal growth and aggregation.
Urinary citrate excretion is largely affected by variations in acid–base status [1,27]. Metabolic alkal- osis increases the rate of urinary citrate excretion, whereas metabolic acidosis lowers urinary citrate, because cytosolic acidification increases citrate uptake by proximal tubular cells [1]. Thus, intracellular rather than systemic acid–base variations are the denomin- ators of urinary citrate excretion.
Fig. 1.Relative changes (%) from baseline values (before dietary As demonstrated by our patient, the amount of
advice) of urinary volume and main urinary constituents after 6
dietary acid may greatly modulate urinary citrate excre-
months of reducing meat protein and salt consumption in a 32-year-
tion rate. After considerably reducing meat protein
old man with recurrent calcium nephrolithiasis. Abbreviations as
in Table 1. intake, the patient’s citraturia doubled ( Figure 1).
Indeed, by the acid load that it conveys, excess meat that recurrent calcium renal stone formers may excrete structurally abnormal THP molecules.
protein intake significantly lowers urinary citrate excre-
tion, thereby contributing to reduced inhibition of Available studies indicate a structure–function relationship, i.e. the specific properties of THP directly aggregation of calcium oxalate crystals [28]. On the
other hand, citraturia positively relates to net gastroin- affect its function as a modifier of calcium oxalate crystallization processes [10]. It appears that—when testinal absorption of alkali [27] and to the intake of
a main source of alkali, i.e. vegetable fibres [1]. studied at the very same physicochemical conditions as normal THP—abnormal stone former THP molec- Usually, low alkali consumption and/or excess
intake of meat protein only induce severe hypocitratu- ules have an increased tendency to self-aggregate into viscous, gel-like fibres which act like a glue and allow ria if they are superimposed on a state of relative acid
retention such as incomplete renal tubular acidosis. for crystals to aggregate; this abnormality is likely to be inherited [10].In vitrostudies indicate that hypercal- Indeed, the latter was significantly more frequent in a
series of calcium renal stone formers with low-normal ciuria as well as hypocitraturia might directly affect structure and function of THP molecules with respect citraturia or hypocitraturia (91%) than in those with
normocitraturia (26%) [1]. After a 3-day loading with to aggregation of calcium oxalate crystals [11]. With rising calcium concentrations, THPs from severely ammonium chloride (0.95 mEq/kg/day, divided into
three doses taken 20 min. before meals), fasting urine recurrent calcium renal stone formers exhibit marked increases in intrinsic viscosities and start to promote pH normally falls below 5.32, while venous bicarbonate
remains at20.5 mmol/l [1]; these criteria were mar- crystal aggregation, whereas normal THPs have lower viscosities and act as aggregation inhibitors [11]. When ginally fulfilled by the present patient (urine pH
lowered to 5.29). the concentration of ionized calcium drops due to
Idiopathic calcium nephrolithiasis—simply due to
‘bad eating habits’?
‘Bad eating habits’ with meat protein overcon- sumption, may induce hypercalciuria, hyperoxaluria, hypocitraturia, and hyperuricosuria [4], but do not always lead to calcium renal stone formation and are very often found in people who never form stones [29].
Therefore, other factors such as abnormal macromole- cular modifiers of crystal aggregation [9] have to be considered in cases with extremely high disease activity and positive family history for kidney stones, as in the patient under discussion. In an important study almost 20 years ago, Robertsonet al. [30] demonstrated that under identical conditions of oral oxalate loading, urines of patients with accelerated calcium nephrolithi- asis contained larger calcium oxalate crystals than healthy controls, and that crystals were often fused into large polycrystalline aggregates. Whereas numer- ous tiny microcrystals normally form in human urine, the occurrence of large polycrystalline aggregates is the most important feature which distinguishes recur- rent calcium renal stone formers from healthy people [9]. Since urinary macromolecules appear to be major modifiers of crystal aggregation in human urine [9], the question arises whether structural and functional abnormalities of macromolecules in recurrent stone formers might be responsible for exaggerated crystal aggregation and subsequent stone formation.
Among the various macromolecules present in human urine [31], Tamm–Horsfall glycoprotein ( THP) has gained attention for the following reasons: (1) it is the most abundant protein normally excreted in human urine [10]; (2) THP molecules exhibit peculiar
(a)
(b)
properties, allowing for inhibition or promotion
Fig. 2.Scanning electron-microscopy preparations at×2000 magni-
of crystallization processes, depending on physico- fication. (a) calcium 5 mM/oxalate 0.5 mM+30 mg/l THP from a
chemical solution conditions [10]; and (3) studies by recurrent stone former; (b) calcium 5 mM/oxalate 0.5 mM+30 mg/l of same THP+3.5 mM of citrate. Bar=10mm. For details, see text.
at least three groups [11,32,33] have provided evidence
Table 2.‘Common-sense diet’ as primary therapeutic approach in 9. Hess B, Kok DJ. Nucleation, growth and aggregation of stone- forming crystals. In: Coe FL, Favus MJ, Pak CYC, Parks JH, patients with idiopathic calcium nephrolithiasis
Preminger GM (eds) Kidney Stones: Medical and Surgical Management.Lippincott–Raven, Philadelphia, 1996; 3–32 Fluids 2500–3000 ml/day, regularly distributed over 24 h
$ 10. Hess B. Tamm–Horsfall glycoprotein and calcium nephrolithi-
(drink at bedtime!) asis.Miner Electrolyte Metab1994; 20: 393–398
$ Protein Meat protein 5–7 servings per week, never 2×per 11. Hess B. Zipperle L, Jaeger Ph. Citrate and calcium effects on
day Tamm–Horsfall glycoprotein as a modifier of calcium oxalate
$ Salt 8–10 g/day, no extra salt during meals crystal aggregation.Am J Physiol1993; 265: F784–F791
$ Calcium 800 mg/day from dairy products, preferablywith 12. Uribarri J, Oh MS, Carroll HJ. The first kidney stone.Ann meals to reduce intestinal absorption of oxalate Intern Med1989; 111: 1006–1009
$ Oxalate Avoid excess amounts of oxalate-rich drinks/foods 13. Robertson WG, Peacock M. The cause of idiopathic calcium stone disease: hypercalciuria or hyperoxaluria?Nephron 1980;
26: 105–110
14. Robertson WG, Scurr DS, Bridge CM. Factors influencing the
chelate formation with citrate, however, viscosities of
crystallization of calcium oxalate in urine—critique. J Cryst
these abnormal stone former THPs return to normal,
Growth1981; 53:182–194
and the proteins inhibit crystal aggregation as much
15. Breslau NA. Pathogenesis and management of hypercalciuric
as normal THPs do [11]. Figure 2 (unpublished data) nephrolithiasis.Miner Electrolyte Metab1994; 20: 328–339
depicts calcium oxalate crystals produced from a highly 16. Hess B, Jaeger Ph. The tale of parathyroid function in idiopathic hypercalciuria.Scann Microsc1993; 7: 403–408
supersaturated solution (calcium 5 mM, oxalate
17. Lemann J Jr. Composition of the diet and calcium kidney stones
0.5 mM ) in the presence of 30 mg/l of stone former
(editorial ).N EngI J Med1993; 328: 880–882
THP alone, where crystals are more aggregated with 18. Fuss M, Pepersack T, Van Geel Jet al. Involvement of low-
longer diameters ( Figure 2a) than in presence of the calcium diet in the reduced bone mineral content of idiopathic renal stone formers.Calcif Tissue Int1990; 46: 9–13
same THP together with 3.5 mM of citrate ( Figure 2b).
19. Hess B, Casez J-P, Takkinen R, Ackermann D, Jaeger Ph.
Altogether, the present case illustrates that environ-
Relative hypoparathyroidism and calcitriol up-regulation in
mental factors such as ‘bad eating habits’ are most
hypercalciuric calcium renal stone formers—impact of nutrition.
unlikely to account fully for recurrent calcium nephrol- Am J Nephrol1993; 13: 18–26
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occurs by the interplay of pre-existing (acquired or
21. Goldfarb S. Dietary factors in the pathogenesis and prophylaxis
inherited) abnormalities of urinary macromolecules
of calcium nephrolithiasis.Kidney Int1988; 34: 544–555
with alterations of the chemical composition of urine 22. Hess B, Ackermann D, Essig M, Takkinen R, Jaeger Ph. Renal
(such as hypercalciuria or hypocitraturia). Since the mass and serum calcitriol in male idiopathic calcium renal stone formers: role of protein intake.J Clin Endocrinol Metab1995;
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Acknowledgements.This work was supported by the Swiss National
25. Curhan GC, Willett WC, Rimm EB, Stampfer MJ. A prospective Science Foundation (Grant No.32–43448.95). The author thanks
study of dietary calcium and other nutrients and the risk of Samuel Jordi and Emma Ettinger for performing scanning electron-
symptomatic kidney stones.N Engl J Med1993; 328: 833–838 microscopy.
26. Hess B, Jost C, Takkinen R, Jaeger Ph. High calcium intake prevents hyperoxaluria during severe oral oxalate loading.
Kidney Int1996; 50: 1433–1434 (abstract)
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