1. The purpose of the present study was to examine the effects of various diuretics on intestinal oxalate transport. Transmural oxalate fluxes were measured across isolated, short-circuited tissue segments removed from rabbits and placed in Ussing chambers. 2. The net absorptive flux of oxalate across the distal colon was significantly reduced in the presence of trichlormethiazide at 10 −4 mol/l. In contrast, this diuretic had no effect on oxalate transport in the other intestinal segments examined. Several of the thiazide diuretics tested had some inhibitory effect on colonic oxalate absorption, but at higher concentrations of 10 −3 mol/l or 10 −2 mol/l. 3. We conclude that the previously reported hypooxaluric effects of hydrochlorothiazide and chlorthalidone are most likely not the result of an exclusive or primary effect on intestinal oxalate transport. It is suggested that the reduction in colonic oxalate absorption that was observed with the thiazides probably involves the transport system responsible for oxalate efflux across the basolateral membrane of the colonocyte.

1. To determine whether the multiple changes in the blood chemistry profile induced by calcitriol may be conducive to secondary systemic oxalosis we have studied nine patients on regular dialysis treatment under three different regimens: (1) oral calcitriol, 0.25 μg/daily for at least 6 months. (2) off calcitriol, a 1-month withdrawal of the drug, taken as the baseline study period; (3) intravenous calcitriol, 1 μg three times weekly at the end of dialysis, with tests performed at 1 and 3 months from initiation. 2. Serum concentrations were measured pre- and post-dialysis at the end of each study period. The whole dialysate was used for the determination of the overall calcium and oxalate removal by dialysis. The degree of saturation with calcium oxalate mono-hydrate was estimated by a computer program. Serum calcitriol concentrations were also assessed. 3. Total and ionized serum calcium did not change on average, although mild hypercalcaemia developed in some patients on intravenous calcitriol. There was an increase in plasma level of oxalate during both oral and intravenous calcitriol treatment, but this was less pronounced during intravenous therapy. Removal of oxalate by dialysis was also greater in patients on oral calcitriol. 4. These increases were probably originated from intestinal absorption and secondary to hyper-absorption of dietary calcium. Consequently, the degree of saturation with calcium oxalate before dialysis rose during calcitriol treatment, irrespective of the route of administration. 5. These results emphasize that, in addition to soft tissue calcification due to calcium phosphates, ectopic calcium oxalate crystallization must also be viewed as a potential risk associated with long-term administration of calcitriol.

1. The demonstration of an inheritable anomaly of erythrocyte oxalate transport in ‘primary’ calcium nephrolithiasis suggested that this disease might be a generalized metabolic disorder characterized by a defect in cellular anion transport. 2. To determine whether this anomaly is restricted to oxalate alone, we studied erythrocyte transmembrane urate self-exchange in calcium-oxalate renal stone formers in whom urinary excretion of uric acid is frequently increased. 3. Abnormal urate self-exchange was found in 30% of the patients. The urate self-exchange rate constant was correlated with 24 h urinary excretion of uric acid; the erythrocyte anomaly was also associated with the frequency of hyperuricosuria and a more intense disease activity. Transmembrane urate self-exchange was inhibited by stilbene and heparan sulphate. Morphazinamide administration did not reduce urinary urate excretion in patients with abnormal urate erythrocyte self-exchange. 4. These findings suggest that hyperuricosuria during calcium-oxalate renal stone disease might be due to a cellular defect in urate transport, and further support the hypothesis that idiopathic nephrolithiasis is a metabolic disorder characterized by a defect in cellular anion transport.

1. This study was performed to test the hypothesis that glycosaminoglycans may play an important role in the observed abnormalities in oxalate flux seen in patients with calcium oxalate nephrolithiasis. 2. Oxalate flux rate, erythrocyte membrane glycosaminoglycan content, membrane protein phosphorylation and effect of heparan sulphate on erythrocyte oxalate flux in vitro were studied in control subjects and patients with calcium oxalate nephrolithiasis. 3. In comparison with control subjects, renal stone-formers showed a significantly higher oxalate self-exchange, a lower erythrocyte membrane glycosaminoglycan content and a higher membrane phosphorylation rate. In stone-formers, erythrocyte glycosaminoglycan content correlated inversely with both oxalate flux rate and protein phosphorylation. In vitro , heparan sulphate promoted a significant fall in the rate of oxalate self-exchange. 4. These findings support the hypothesis that a lower erythrocyte membrane content of glycosaminoglycans enhances membrane protein phosphorylation, leading to an increased rate of transmembrane oxalate flux.

1. Both the peroxisomal, flavin-linked glycollate oxidase [( S )-2-hydroxy-acid oxidase; EC 1.1.3.15] and the cytosolic, nicotinamide–adenine dinucleotide (NAD)-linked lactate dehydrogenase ( l -lactate dehydrogenase; EC 1.1.1.27) are thought to contribute to the formation of oxalate from its immediate precursors, glycollate and glyoxylate, but the relative contributions of each enzyme to endogenous oxalate production is not known. 2. In rat liver homogenates, [ 14 C]oxalate production from labelled glycollate is halved and that from labelled glyoxylate is increased fourfold by the addition of either NAD or NADH. 3. In isolated rat hepatocytes, the 3-hydroxy-1 H -pyrrole-2,5-dione derivatives of glycollate, which are specific inhibitors of glycollate oxidase, have a greater effect on glycollate metabolism than on glyoxylate metabolism. 4. These findings are consistent with an important role for lactate dehydrogenase in oxalate formation from glyoxylate. 5. With human and rat liver homogenates and with purified human liver glycollate oxidase and rabbit muscle lactate dehydrogenase, dl -phenyl-lactate (2 mmol/l) completely inhibits glycollate oxidase but has no effect on lactate dehydrogenase. On the other hand, the reduced form of a chemically synthesized, NAD–pyruvate adduct (1 mmol/l) almost completely inhibited lactate dehydrogenase but had no effect on glycollate oxidase. 6. Either alone or in combination, dl -phenyl-lactate and reduced NAD–pyruvate adduct reduce oxalate production from glycollate and glyoxylate in isolated rat hepatocytes, but do not abolish it completely. 7. These findings support a role for another enzyme, probably glycollate dehydrogenase (EC 1.1.99.14), in oxalate production in integrated cell metabolism. 8. In relation to renal oxalate stone disease, these results suggest that the therapeutic inhibition of glycollate oxidase or lactate dehydrogenase would not completely prevent the endogenous formation of oxalate.

1. In order to find out whether hyperoxaluria can be demonstrated in patients on chronic (twice a week) haemodialysis, a group of 13 patients was investigated. These included one patient with proven primary hyperoxaluria, one suspected of having this disease and 11 patients in whom no information was available as to their oxalate metabolism. 2. Oxalate concentrations in haemodialysate fractions and blood samples, taken before and after dialysis, were determined. 3. The patient with primary hyperoxaluria had a plasma oxalate concentration before dialysis above 100 μmol/l and after dialysis above 25 μmol/l, while the oxalate concentration in haemodialysate at the start of dialysis was above 25 μmol/l and at the end above 10 μmol/l. The patient suspected of hyperoxaluria had similar values. Of the remaining 11 patients, one was shown to exhibit a transient hyperoxaluria, but the others showed a normal oxalate metabolism. 4. A plasma oxalate/creatinine concentration ratio exceeding 0.1, and the calculated total quantity of oxalate removed by dialysis exceeding 2 mmol, also enabled a diagnosis of hyperoxaluria to be made. 5. Hyperoxaluria can still be demonstrated in patients, who because of renal failure are subjected to haemodialysis. Measurements of oxalate in haemodialysate and plasma are valuable in cases where kidney transplantations are considered, especially when the particular patient exhibits hyperoxaluria.

1. We have measured glomerular filtration rate (GFR), extracellular fluid volume (ECF), oxalate distribution volume (OxDV), plasma oxalate concentration (P Ox. ), plasma total clearance of oxalate (P C Ox. ), oxalate metabolic pool size [(OxDV) × (P Ox .)], renal clearance of oxalate (RC Ox. ), oxalate excretion, tissue clearance of oxalate (TC Ox .) and tissue oxalate accumulation rate [(T Ox .A) = (T C Ox .) × (P Ox. )] in three patients with type I primary hyperoxaluria (hyperoxaluria with hypergrycollic aciduria) when they were taking pyridoxine and after discontinuation of the vitamin. 2. Seven days after stopping pyridoxine the plasma oxalate concentration, oxalate metabolic pool size and the urinary excretion of oxalate had all increased between seven- and eight-fold in two of the patients. The third patient showed no changes on stopping pyridoxine. 3. These results support the view that pyridoxine acts by reducing oxalate biosynthesis in some patients with type I primary hyperoxaluria. 4. The possible biochemical basis for this effect is discussed.

1. The effect of 1,25-dihydroxyvitamin D [1,25-(OH) 2 D] on dietary oxalate absorption and postprandial urine supersaturation with calcium oxalate was determined in 11 normal subjects. 2. 1,25-(OH) 2 D increased the urinary excretion of orally administered [ 14 C]oxalate in the 8 h period after a liquid meal containing 1.875 mmol of calcium and 0.83 mmol of oxalate ( P < 0.01), and during a 48 h period when the subjects ingested a diet containing 25 mmol of calcium and 3.3 mmol of oxalate/day ( P < 0.01); however, 1,25-(OH) 2 D administration had no effect on [ 14 C]oxalate excretion when calcium was removed from the liquid meal. 3. 1,25-(OH) 2 D increased 24 h urinary oxalate excretion from 28.7 ± 2.1 mmol/mol of creatinine to 36.8 ± 2.6 mmol/mol of creatinine ( P < 0.05) on the 10 mmol/day calcium diet and from 26.4 ± 2.9 to 33.2 ± 2.2 mmol/mol of creatinine ( P < 0.1) on the 25 mmol/day calcium diet. 4. A linear correlation ( r = 0.72) was found between plasma 1,25-(OH) 2 D levels and urinary [ 14 C]oxalate excretion after the liquid meal. 5. 1,25-(OH) 2 D administration produced postprandial supersaturation of urine with calcium oxalate and calcium oxalate crystalluria. 6. These studies suggest that 1,25-(OH) 2 D increases oxalate absorption (and urinary excretion) by increasing calcium absorption, which results in less binding of calcium to oxalate in the intestine; therefore more oxalate is available for absorption. The combined effect of increased calcium and oxalate absorption results in postprandial supersaturation of urine with calcium oxalate, with resultant crystalluria.

1. We have measured the plasma oxalate concentration (P Ox ), urinary oxalate excretion (U Ox ), oxalate equilibrium distribution volume (ODV), oxalate metabolic pool size [(ODV) × (P Ox )], total plasma oxalate clearance (PC Ox ), renal (or dialyser) oxalate clearance (RC Ox ), non-renal oxalate clearance (NRC Ox ) and the tissue oxalate accretion rate (TOA)= [(NRC Ox ) × (P Ox )] in three patients with severe renal failure due to primary hyperoxaluria who were being treated by peritoneal dialysis or haemodialysis, or by renal transplantation. The clearance (either GFR or dialyser) of [ 99m Tc]diethylenetriaminepenta-acetate (DTPA) and the extracellular fluid volume (ECF) measured as [ 99m Tc]DTPA distribution volume were also determined. 2. Negligible amounts of 14 C were found in faeces or as 14 CO 2 in expired air and hence (NRC Ox ) = (PC Ox -RC Ox ). 3. Haemodialysis removed oxalate more efficiently than peritoneal dialysis in the patient where a direct comparison was possible. Neither treatment could keep up with the TOA when performed for clinically acceptable times. 4. The plasma oxalate concentrations calculated from 14 C clearance through the dialyser and the chemically determined concentration of the oxalate in the dialysate were in the range 111–146 μmol/l. This is higher than in normals and in hyperoxaluric patients who are not in renal failure. Hence, although the ODV and ECF are similar to those of hyperoxaluric patients without renal failure and normal control subjects, the oxalate metabolic pool (ODV × P Ox ) is grossly enlarged. 5. In the patient treated by renal transplantation, the oxalate pool size diminished concurrently with the resumption of oxalate excretion but expanded again as renal function decreased due to oxalosis. 6. The quantitative data show that dialysis procedures can only be a temporary holding operation and the prognosis with transplantation remains bad unless excessive oxalate production can be controlled.

1. We have measured the total plasma clearance, renal clearance and equilibrium distribution volume of [ 14 C]oxalate, and the urinary oxalate excretion rate and plasma oxalate levels at approximately 6 month intervals for up to 2.5 years in five patients with primary hyperoxaluria. The renal clearance and distribution volumes of [ 99m Tc]DTPA (diethylenetriaminepenta-acetate) were measured simultaneously to provide estimates of glomerular filtration rate (GFR) and extracellular fluid volume (ECF). The same measurements were made on each of five normal volunteers. 2. Clearances and distribution volumes were measured with a modified single injection technique. 3. The oxalate clearance was two to three times the simultaneously measured GFR in the patients and control subjects. The renal clearance of oxalate was less than the total plasma clearance in the patients. The oxalate distribution volume was approximately 1.5 times the ECF in both the patients and controls. Only small changes were observed over a 2.5 years period in these particular patients. 4. The plasma oxalate concentration was derived from the urinary oxalate excretion rate and the plasma [ 14 C]oxalate clearance. It was raised in the patients. The oxalate removal rate was derived from the total plasma clearance and the plasma oxalate concentration.

1. The renal clearance of [ 14 C]oxalate was assessed by the constant-infusion technique and single-injection technique (plasma sampling only: one-compartment and two-compartment model; plasma and urine sampling). Healthy volunteers and patients with renal stones were studied. 2. Results with the constant-infusion techniques (with and without urine sampling) were not significantly different from each other. 3. The renal clearance of [ 14 C]oxalate measured with the single-injection technique as compared with the constant-infusion technique was overestimated in the single-injection one-compartment model (52%) as well as in the two-compartment model (30%). 4. The calculated level of plasma oxalate in the healthy volunteers ranged from 1·04 to 1·78 μmol/l (mean 1·39). 5. The biological half-life of [ 14 C]oxalate, estimated by the cumulative excretion of 14 C in urine after equilibrium had been established, was 128 min (range: 113–142). 6. The oxalate/creatinine clearance ratio in the healthy volunteers ranged from 1·73 to 2·22 (mean 2·01).

1. Urinary composition was studied in nine healthy adults on unrestricted diet and low-oxalate diet with and without individual oxalate-rich foods. 2. Urine oxalate was constant on the low-oxalate and constant high-oxalate diets and only fluctuated greatly on unrestricted diet. 3. Urine oxalate was mainly due to dietary oxalate which accounts for up to two-thirds of urinary oxalate. 4. Urine oxalate was unaffected by urine volume. 5. Varying percentages of dietary oxalate were absorbed depending on the nature of the foodstuff. 6. Although tea was the main source of dietary oxalate in some people it, like strawberries, did not represent a real risk factor. Chocolates, peanuts, beetroot, rhubarb and spinach were considered as high-risk foods. 7. Calcium oxalate crystalluria at 4°C was increased significantly when the oxalate-rich foods were taken. When urine was examined at 37°C no increase in crystalluria was found.

1. The short- and longer-term effects of ethane-1-hydroxy-1,1-diphosphonate (EHDP), an inhibitor of crystal growth and potential preventive agent against urinary tract stones in man, have been studied. 2. Measurement of urinary excretion of EHDP was used to define the best dosage regimen. When 4·4 mmol of EHDP was given daily in four divided doses the urinary concentration of EHDP achieved was high enough (10 −5 mol/l) to inhibit the crystallization of calcium crystals throughout the day. 3. Nine patients with recurrent calcium stones were given this dose of EHDP daily for 12 months and seven were then studied for a further 12 months under placebo. During treatment with EHDP, inhibitory activity in urine towards precipitation of calcium phosphate was restored from low values to greatly above normal. This could be accounted for by the inhibitory effect of EHDP itself, coupled with an increase in urinary inorganic pyrophosphate. After stopping EHDP the excretion of EHDP rapidly fell to undetectable levels but the excretion of pyrophosphate remained elevated throughout the 12 months of placebo treatment. EHDP also induced a rise in plasma phosphate and an increase in the urinary excretion of oxalic acid and uric acid, but these changes were all fully reversible when EHDP was stopped. 4. The average rate of stone formation per patient per year decreased from 2·4 to 0·2 during treatment with EHDP and remained low during the following 24 months. However, the dose needed for this effect is known to affect bone turnover and mineralization.

1. In order to assess the relative importance of possible pathogenetic factors in the formation of calcium-containing renal stones, a group of 18 patients (12 men, six women) with active, recurrent stone disease were compared with 16 age-matched control subjects (10 men, six women) given an identical diet. 2. Fifteen (83%) of the patients showed at least one, eight (44%) showed two, and one (6%) patient showed three abnormalities that might predispose to stone formation. 3. Increased urinary calcium excretion was the most common abnormality (11 patients, 61%), particularly in the women (83%). 4. A diminished excretion of inhibitors of crystal formation of calcium phosphate was the next most common abnormality, which occurred in eight patients (44%), all of whom were men. It was largely attributable to a diminished excretion of inorganic pyrophosphate (PP i ). The PP i /orthophosphate ratios were also lower in the stone-formers. Significant differences in residual inhibitory activity after enzymatic removal of PP i between control subjects and stone-formers could not be found in 24 h urine samples but were present during certain times of the day. Pyrophosphate showed a higher inhibitory activity in urine than in control solutions, this enhancement being absent in stone-formers. 5. Nine (50%) of the patients, but only one of the control subjects, produced crystal aggregates greater than 50 μm in diameter after an oral load of oxalate.

1. A retrospective cross-sectional study was carried out on data derived from single 24 h urine collections from 246 male idiopathic calcium stone-formers. 2. The daily urine volume and pH and the excretions of calcium, oxalate, phosphate, creatinine and magnesium were related to the time of year when the urine was collected, and the saturation of urine with calcium oxalate and octocalcium phosphate calculated for each month. 3. There were significant seasonal variations in the urinary excretion of calcium and oxalate, each showing a maximum during the summer months and a minimum in the winter. There was no significant seasonal variation in urinary pH, volume, creatinine, phosphate or magnesium. 4. There was a significant increase in the saturation of urine with calcium oxalate and a trend towards higher saturation levels of octo-calcium phosphate in the summer. These changes were dependent only on the seasonal variation in urinary calcium and oxalate and not on urine volume. 5. A retrospective study of the seasonal incidence of stone episodes among these 246 stone-formers showed that the rate of stone passage per month was 50% higher in the summer than in the winter. There was no significant seasonal variation in the incidence of stones removed surgically.