Elisa Cicerello

Effect of alkaline citrate therapy on clearance of residual renal stone fragments after extracorporeal shock wave lithotripsy in sterile calcium and infection nephrolithiasis patients

The natural history of post-extracorporeal shock wave lithotripsy residual stone fragments (clearance, growth and aggregation) is incompletely known, even though they are believed to constitute a risk in terms of new stone formation and persistent infection of the urinary tract. We addressed this issue and the hypothesis that alkaline citrate therapy improves residual stone fragment clearance in a 12-month followup study. There were 40 sterile calcium and 30 struvite stone patients with residual fragments after extracorporeal shock wave lithotripsy (diameter less than 5 mm.) consecutively enrolled and randomly assigned to a citrate therapy (6 to 8 gm. per day) or control (hygienic measures only) group. Infection stone patients also received adequate antibiotic therapy throughout the study. Among the patients in the untreated sterile group 21% and 32% were stone-free at 6 and 12 months, respectively. In the infection group these figures were 27% and 40%, respectively. Among the untreated sterile calcium stone patients in whom clearance was not achieved a high percentage experienced residual fragment growth or reaggregation. Citrate therapy significantly improved the stone clearance rate in the sterile (at 6 and 12 months 65% and 74% were stone-free, respectively) and infection (71% and 86%, respectively) stone patients, and prevented residual fragment growth or reaggregation in subjects in whom clearance was not achieved. The data show that growth and persistence are common in the natural history of residual stone fragments. Citrate ameliorated the outcome of these residual fragments by reducing the growth or agglomeration, and by increasing the clearance rate in calcium oxalate and in infection stone patients.

Urinary glycosaminoglycans, sialic acid and lysosomal enzymes increase in nonalbuminuric diabetic patients.

Urinary excretion of glycosaminoglycans (GAGS) and sialic acid (SA), as well as the activity of two renal enzymes related to glycoprotein metabolism, N-acetyl-beta-D-glucosaminidase (NAG) and beta-galactosidase (GAL), and two others unrelated to glycosaminoglycans and glycoprotein metabolism, gamma-glutamyltranspeptidase (gamma-Gt) and angiotensin-I-converting enzyme (ACE), were evaluated in 40 insulin-dependent diabetic patients with normal range albuminuria, 21 patients with mesangial glomerulonephritis, and 30 control subjects. Diabetic and glomerulonephritic patients excreted a significantly higher amount of GAGS and SA, and showed greater NAG and GAL activities; gamma-Gt and ACE levels were within normal ranges. No correlation could be demonstrated between diabetes duration and GAGS, SA, NAG and GAL findings. Moreover, no correspondence between degree of metabolic control, as reflected by glycosylated hemoglobin (HbA1a-c) and GAGS, SA, NAG and GAL emerged.

Abnormal Erythrocyte Charge in Diabetes Mellitus: Link with Microalbuminuria

The anionic charge on the surface of the erythrocyte and the erythrocyte membrane content of sialic acid and acid glycosaminoglycans (GAGs) were evaluated in insulin-dependent diabetic patients who had albumin excretion rates < 300 mg/24 h. In these subjects a statistically significant reduction of erythrocyte anionic charge (RBCCh) and GAGs content in erythrocyte ghosts was shown. In view of the demonstration of a negative correlation between RBCCh and albuminuria after a lysine provocative test, these observations support the hypothesis that the onset of microalbuminuria in human diabetes is sustained by an alteration of glomerular charge and consequently of glomerular charge selectivity.

Effect of Nifedipine on Urinary Calcium and Oxalate Excretion in Renal Stone Formers

Dr. B. Baggio, Institute of Internal Medicine, Postgraduate School of Nephrology, University Hospital, I-35100 Padova (Italy) Dear Sir, Some time ago we had the occasion to observe a hypercalciuric renal stone former who was taking nifedipine for a cardiac problem. In this patient, hypercalciuria was corrected following nifedipine therapy. This observation prompted us to investigate the possible effect of nifedipine on urinary calcium. To date, we have tested the drug in 12 ‘idiopathic’ renal stone formers, of whom 7 were hypercalciuric ( > 300 mg/ day), and 5 hyperoxaluric ( > 33 mg/day), and in 2 primary hyperparathyroid patients. The patients were given a standard diet, and 20 mg/day nifedipine were administered for 1 week. Urinary oxalate (by an enzimatic method Sigma kit), calcium, phosphate and citrate [1] levels were determined before and after 1 week of nifedipine treatment. Compared to baseline values, we observed a significant fall in both calcium and oxalate excretion, and no modifications in urine phosphate and citrate in the stone formers (table I). Furthermore, nifedipine exerted a well defined hypocalciuric effect also in the 2 hyperparathyroid patients (from 600 to 362 mg and from 455 to 160 mg, respectively). The hypocalciuric and hypooxalu-ric effect cannot be attributed to changes in urine output, since no correlation was found between delta urine volume and delta oxalate and calcium excretion (r = 0.030 and r = 0.014, respectively). The magnitude of the decrease in both calcium and oxalate showed a significant correlation with basal values of the 2 ions (r = -0.79; p < 0.01 for calcium, and r = 0.61; p < 0.05 for oxalate). In a previous study, we reported the existence of an anomalous oxalate self-exchange in red blood cell of renal stone formers [2], and since nifedipine seems capable of lowering oxalate urinary excretion, we also investigated the effect of the drug on red blood cell oxalate selfexchange. We observed that after 1 week of treatment, the flux constant K fell from 1.37 ± 0.58SD × 10-2 to 0.30 ± 0.15SD × 10-2 min-1 (t = 6.06; p < 0.001). At the moment we cannot explain the mechanism(s) by which nifedipine lowers calcium and oxalate urinary Table I. Urinary calcium and oxalate excretion

Effects of imidazole-2-hydroxibenzoate on glycosaminoglycan and albumin urinary excretion in type 1 diabetic patients.

The effect of imidazole-2-hydroxibenzoate on urinary excretion rates of glycosaminoglycans and albumin in 22 insulin-dependent diabetics with albumin excretion rates under 300 mg/day was evaluated in a 165-day double blind crossover study. Unlike placebo, the drug reduced glycosaminoglycan and albumin excretion rates significantly after 40 and 60 days of treatment, and the effects were significantly intercorrelated. Moreover, a parallel reduction in urinary excretion of N-acetyl-beta-D-glucosaminidase was also observed. These pharmacological effects may have a positive impact on the subsequent natural history of diabetic nephropathy.

A Critical Evaluation of the Urinary Inhibiting Activity in Idiopathic Calcium Oxalate Nephrolithiasis1,2

In order to obtain new insights into the relevance of inhibitors in whole urine by focusing on their reciprocal interactions, a statistical approach was followed in 35 controls and 27 calcium oxalate (CaOx) recurrent idiopathic stone formers. The inhibiting activity of CaOx crystal growth and the most widely accepted inhibitors (glycosaminoglycans, citrate, magnesium, pyrophosphate), stone constituents (calcium, oxalate, phosphate, urate) and other normal urinary substances were evaluated. It was seen that the inhibitors played a very small role in total inhibiting activity. On the other hand, considering other normal urinary constituents, almost all the inhibiting power of urine on crystal growth could be explained.

Further Studies on the Possible Lithogenetic Role of Uric Acid in Calcium Oxalate Stone Disease

The possible role of uric acid in aggravating recurrent “idiopathic” calcium oxalate (CaOx) nephrolithiasis is still a matter of discussion. Substantially, two hypotheses have been advanced; the first proposes direct induction of CaOx precipitation by uric acid crystals or colloidal uric acid1,2, while the second suggests that uric acid interferes with the glycosaminoglycan (GAGS) inhibitors of CaOx stone formation3–5. Since the urine of CaOx stone formers is generally free from uric acid crystals6,7, theories assigning a primary role to uric acid crystals seem untenable; that there is binding between uric acid and GAGS which reduces GAGS inhibitory activity on CaOx crystal formation seems more feasible, as does the direct action of molecular or colloidal uric acid on CaOx precipitation. The possible existence of a direct bond between uric acid and GAGS is investigated in this study; in addition the likelihood that uric acid directly promotes CaOx precipitation has been evaluated.

Decreased Erythrocyte Glycosaminoglycan Content in Idiopathic Calcium-Oxalate Nephrolithiasis

In red blood cells (RBC) of idiopathic calcium-oxalate stone formers (ISF), we previously demonstrated an abnormal transmembrane self-exchange (SE) of oxalate (1). The molecular basis of this anomaly seems to be an altered phosphorylation state of band-3 protein, the anion-carrier, probably resulting from an increased activity of protein kinases (2). Since glycosaminoglycans (GAG) are known inhibitors of protein kinases, we tested the hypothesis that a fall in GAG concentration in RBC membranes might be responsible for the increased phosphorylation of band-3 protein.

Diagnostic and Therapeutic Approach in Patients with Urinary Calculi

The natural history of urolithiasis includes the risk of recurrence and of the development of chronic kidney and/or bone disease, which is why a thorough clinical and metabolic evaluation of these patients is of the utmost importance at disease onset. This paper is aimed at identifying the type of urolithiasis, the related risk factors, and the corresponding treatment options. The diagnostic and therapeutic approach described here includes 1) accurate history taking to detect secondary nephrolithiasis and screen for the main risk factors for kidney and bone disease; 2) metabolic evaluation graded according to different complexity levels based on the severity of the disease and the presence of risk factors; 3) carrying out appropriate imaging procedures. The resulting information allows to plan treatment based either on general rules of lifestyle and diet, or on selected medical intervention, if necessary. This report, which is based on current guidelines, was produced by the Gruppo Italiano di Studio Multidisciplinare per la Calcolosi Renale. It is addressed to all professionals involved in the management of patients suffering from nephrolithiasis, first of all general practitioners, who often become involved immediately at the onset of the disease.