Medical treatment of cystinuria: critical reappraisal of long-term results

PURPOSE: We evaluated long-term results of a contemporary medical therapeutic regimen in patients with cystinuria and analyzed factors predictive of therapeutic success. MATERIALS AND METHODS: A total of 27 adults with cystine urolithiasis were treated at our institution for 1.3 to 32 years (mean 11.6, overall 312 patient-years). We obtained data on the pre-referral period for 274 patient-years overall. Basic therapy included hyperdiuresis and alkalization. The thiols D-penicillamine or tiopronin were added when standard therapy failed to prevent new stones and stone growth or dissolve preexisting stones. X-ray and echography were performed every 4 months during the initial 2 years and every 6 months thereafter. RESULTS: In the pre-referral period 256 stone episodes occurred and 81 urological procedures were performed in 24 patients (0.93 and 0. 29 per patient-year, respectively). Nine patients were treated with added thiols. During the therapeutic period the incidence of stone episodes decreased to 66 (0.20 per patient-year, p <0.001), while the need for urological procedures decreased to 44 (0.14 per patient-year, p <0.001). No further urological procedures were required in 15 patients, including 4 treated with thiols. However, the remaining 12 patients, including 5 treated with thiols, underwent 1 to 7 procedures each (mean 0.26 per patient-year). In the 2 groups mean daily cystine excretion plus or minus standard deviation at baseline (863 +/- 253 versus 761 +/- 270 mg. daily) and mean urinary pH of about 7.4 did not differ significantly. However, daily urine volume was significantly higher in patients with arrested stone formation (3,151 +/- 587 versus 2,446 +/- 654 ml./24 hours, p = 0.006). CONCLUSIONS: Our study provides evidence that a regularly followed medical program based on high diuresis and alkalization with second line addition of thiols may arrest or markedly decrease cystine stone formation and preclude the need for urological procedures in more than half of the patients. However, patients poorly compliant with hyperdiuresis remain at risk for recurrence. We suggest that maintaining a daily urine volume of greater than 3 l. is essential for therapeutic success regardless of whether thiol derivatives are administered.     

Serial crystalluria determination and the risk of recurrence in calcium stone formers

BACKGROUND: Urinary crystal precipitation is the necessary initial step in kidney stone formation. However, clinical relevance of crystalluria in the evaluation of stone formers is disputed. METHODS: We serially determined crystalluria in first-voided morning urine samples, together with full 24-hour urine biochemistry, in 181 patients with idiopathic calcium nephrolithiasis who had formed at least one calcium-oxalate stone and were followed for at least 3 years under our care. All stone events which occurred prior to referral, then after entry in the study were recorded. RESULTS: As compared with 109 patients who had no evidence of stone recurrence during follow-up, the 72 patients who experienced >/= one recurrent stone event had a lower daily urine volume (1.74 +/- 0.06 vs. 2.26 +/- 0.05 L/day (mean +/- SEM) (P < 0.0001), higher urine calcium and oxalate concentrations, and daily calcium excretion, and they had more frequent crystalluria (68% vs. 23% of urine samples) (P < 0.0001). By multivariate Cox regression analysis, the hazard ratio for stone recurrence was 0.32 (95% CI 0.16-0.62) for 1 L increase in daily urine volume, 1.12 (1.09-1.24) for 1 mmol/L increase in urine calcium concentration, 1.24 (1.02-1.50) for 0.1 mmol/L increase in urine oxalate concentration and 27.8 (10.2-75.6) for crystalluria index. CONCLUSION: These data provide evidence that crystalluria, when repeatedly found in early morning urine samples, is highly predictive of the risk of stone recurrence in calcium stone formers. Serial search for crystalluria, a simple and cheap method, may be proposed as a useful tool for the monitoring of calcium stone formers, in addition to urine biochemistry.     

The effect of renal impairment on the pharmacokinetics of oxcarbazepine and its metabolites

We have studied the effect of renal impairment on the pharmacokinetics of oxcarbazepine, its active monohydroxy-metabolite (which predominates in plasma), their glucuronides, and the inactive dihydroxy-metabolite after a single oral dose of oxcarbazepine (300 mg). Six subjects with normal renal function and 20 patients with various degrees of renal impairment participated.The mean areas under the plasma concentration-time curves of oxcarbazepine and its monohydroxy-metabolite were 2–2.5-times higher in patients with severe renal impairment (CL_CR<10 ml·min^–1) than in healthy subjects. The apparent elimination half-life of the monohydroxy-metabolite [19 (SD 3) h] in these patients was about twice that in healthy subjects.The effect of renal impairment on the plasma concentrations of glucuronides was more marked. The renal clearances of the unconjugated monohydroxy-metabolite and its glucuronides (the main compounds recovered in urine) correlated well with creatinine clearance.The maximum target dose in patients with slight renal impairment (CL_CR>30 ml·min^–1) should not be changed. In patients with moderate renal impairment (CL_CR10–30 ml·min^–1) it should be reduced by 50%. In patients with severe renal impairment (CL_CR<10 ml·min^–1), the glucuronides of oxcarbazepine and its monohydroxy-metabolite are likely to accumulate during repeated administration, and dosage adjustment of oxcarbazepine in these patients could not be proposed from this single administration study.     

Piridoxilate-induced calcium oxalate calculi: a new drug-induced metabolic nephrolithiasis

During the last 4 years we collected 27 specimens of calcium oxalate nephrolithiasis in patients receiving long-term treatment with piridoxilate, a drug composed of an equimolar combination of glyoxylate and pyridoxine. The mean duration of treatment was 3.6 years (range 4 months to 10 years) and the mean daily dose was 580 mg. piridoxilate, which contained 160 mg. glyoxylate. Calculi often recurred, with an average number of 9.9 per patient, and an open operation, shock wave lithotripsy or percutaneous nephrolithotomy was required in 22 patients (81 per cent). Oxalate excretion was 727 +/- 246 mumol. per day while on the drug and 382 +/- 201 mumol. per day after the drug was withdrawn. Whewellite was the major component of calculi in all cases but the stones exhibited a peculiar morphological arrangement, with multiple small indentations and a fine mamillary structure. Freshly voided urine specimens contained unusual crystals, which on infrared spectroscopy were composed of calcium oxalate trihydrate, a variety of crystal never observed previously in human urine. Piridoxilate-induced calcium oxalate nephrolithiasis is a new variety of metabolic drug-induced nephrolithiasis. Our observations suggest that even large doses of pyridoxine may be unable to prevent the excessive production of oxalate from glyoxylate.     

A circulating inhibitor of the RBC membrane calcium pump in chronic renal failure.

A humoral inhibitor of the membrane calcium pump was studied in plasma from 28 normal controls, 33 patients receiving long-term hemodialysis, and 26 with chronic renal failure (CRF; creatinine clearance range was 6 to 97 ml/min). Calcium pump activity was measured as the rate of Sr2+ efflux in normal erythrocytes (RBCs) loaded with Sr2+ (a substitute of Ca2+ in the calcium pump). Plasma, and plasma ultrafiltrates from hemodialysis patients strongly inhibited calcium pump activity compared with controls without plasma (36 +/- 18 vs. 25 +/- 12, %INHIBITION/CONTROL, P < 0.05). Inhibition markedly decreased with acute hemodialysis (16 +/- 12 vs. 5 +/- 14, %INHIBITION/NORMAL PLASMA, N = 15, P < 0.001). In CRF, degree of inhibition correlated with the serum creatinine concentration (r = 0.75, P < 0.001). A kinetic study showed that plasma decreased the maximal rate of the Ca2+ pumps (Vmax) without affecting the apparent affinity for internal cations (KSr). Moreover, the plasma inhibitory factor had a low molecular weight, and was dialyzable and heat stable. In conclusion, we found evidence for an RBC membrane calcium pump inhibitor in uremic plasma, which correlates with the degree of renal insufficiency. Possibly, it may increase calcium content in RBCs and other cells and could thus be related to uremic toxicity and/or hypertension.     

Analysis of individual, intraspecific and interspecific variability in quantitative parameters of caprine tooth enamel structure

Qualitative and quantitative features of mammalian tooth enamel structure are increasingly being used in taxonomic and phylogenetic analyses, although the variability shown by these traits has not received adequate consideration. This study evaluates the variability displayed by nine quantitative parameters in deep, intermediate, and superficial molar enamel in the closely related bovids Ovis aries and Capra hircus. These parameters are assessed in terms of the absolute and/or relative variability evinced at a given depth within a single individual, among conspecific individuals, and between species samples. The degrees of relative variability expressed at a given depth are comparable among conspecific individuals and between taxonomic samples. Nevertheless, in many instances, there are significant differences in absolute variability amongst individuals. Also, in four parameters for which individual specimen averages could be calculated, the equality of these means among conspecifics can be rejected. Variability is not equivalent at different enamel depths. The null hypothesis of equality of individual, conspecific variances can be rejected most commonly for parameters measured in deep and superficial enamel, and coefficients of variation also tend to be higher for deep and superficial enamel than for enamel of intermediate depth. The greater variability displayed by deep and especially superficial enamel may be related to the initial onset and the terminal phase of ameloblastic secretory activity. Taxonomic and phylogenetic analyses that utilize quantitative data on enamel structure are valid only if comparisons have been made at equivalent enamel depths.     

Recurrent hematuria in 4 white patients with sickle cell trait

Extensive investigations failed to disclose the etiology of recurrent gross hematuria in 4 white patients of Algerian descent. Hemoglobin electrophoresis revealed sickle cell trait in all cases. The hematuria ceased after bed rest and hydration in 3 patients, and following partial nephrectomy after visualization of the bleeding site at operative nephroscopy in 1. We recommend that hemoglobin electrophoresis be considered when evaluating every patient, black or white, presenting with unexplained hematuria.