S. Favaro

Increased Urinary Excretion of Renal Enzymes in Idiopathic Calcium Oxalate Nephrolithiasis

Urinary excretion of gamma-glutamyl transpeptidase, angiotensin I converting enzyme, beta-galactosidase and N-acetyl-beta-glucosaminidase was evaluated in 30 patients with idiopathic calcium oxalate urolithiasis. Higher than normal values were observed and the excretory enzyme pattern suggested tubular damage in patients with stones. A parallel study in the rat showed that an oxalate surcharge can promote increased urinary excretion of these enzymes. It is known that urothelium injury may enhance crystal adhesion. If the damage is primary it may be viewed as a promoting factor. If it is secondary it may be considered a factor capable of increasing salt precipitation.

Increased urinary NO2−/NO3− and cyclic guanosine monophosphate levels in patients with bartter's syndrome: Relationship to vascular reactivity

Nitric oxide (NO) is a potent endogenous vasodilator and plays a pivotal role in the control of vascular tone by the formation of cyclic guanosine monophosphate (GMP). Patients affected by Bartters syndrome have lower than normal vascular reactivity with normohypotension and decreased peripheral resistances in spite of biochemical and hormonal abnormalities typical of hypertension, and it is possible that increased production of NO may be involved in maintaining this reduced vascular response and vasodilatation. We have examined this possibility by studying NO2-/NO3- and cyclic GMP urinary excretions to assess NO production in vivo in seven patients affected by Bartters syndrome compared with seven healthy controls. A group of five patients with hypokalemia other than Bartter syndrome (pseudo-Bartters) was also included in the study to evaluate the effect of hypokalemia on NO production. NO2-/NO3- urinary excretion (0.45 +/- 0.14 v 0.25 +/- 0.04 micromol/micromol urinary creatinine [controls], P < 0.005, v 0.28 +/- 0.05 [pseudo-Bartters], P < 0.01) and cyclic GMP urinary excretion (0.057 +/- 0.028 v 0.022 +/- 0.01 micromol/micromol of urinary creatinine [controls], P < 0.009, v 0.024 +/- 0.004 [pseudo-Bartters], P < 0.02) were increased in patients with Bartters syndrome in comparison with controls and pseudo-Bartters, and a linear correlation between these two parameters was also present (P < 0.001). We conclude that in Bartters syndrome the increased NO2-/NO3- and cyclic GMP urinary excretions point to an increased NO synthesis, which could account for the reduced vascular response of the disease, therefore adding its role in determining the vascular hyporeactivity of Bartters syndrome.

Prevalence of Hyperoxaluria in Idiopathic Calcium Oxalate Kidney Stone Disease

Urinary excretion of oxalate, calcium and urate has been investigated in 88 patients affected by idiopathic calcium oxalate stone disease and in 20 normal subjects. Of these ions, only oxalate was found significantly higher in stone formers. Defining hyperoxaluria as urinary oxalate excretion greater than 2 SD above normal, 50% of stone-forming people were found to be hyperoxaluric. When stone formers were classified in normo- and hyperoxaluric, the prevalence of hypercalciuria, hyperuricuria, family history of stone disease and recurrencies in stone formation was the same in both groups. It is concluded that hyperoxaluria is a frequent finding in finding in idiopathic calcium oxalate renal stone disease.

Intracellular calcium signalling and vascular reactivity in Bartter's syndrome

We investigated patients affected by Bartters syndrome in the attempt to localize the intracellular defect mediating the reduced intracellular Ca2+ mobilization that may be responsible for the decreased vascular reactivity characteristic of Bartters syndrome. Using the formylmethionyl-leucyl-phenylalanine (fMLP) receptor system, which causes, intracellular calcium release, we investigated fMLP-stimulated intracellular inositol 1,4,5-trisphosphate (IP3) production as well as the number and affinity of fMLP receptors in neutrophils from Bartters syndrome patients and healthy controls. Scatchard plot analysis of radioactive fMLP binding to neutrophils indicated that there were no differences in either cell receptor number and affinity for ligand between healthy controls (n = 5) and patients with Bartters syndrome (n = 5): 6,151 +/- 1,431 vs. 7,112 +/- 2,566 receptors/cell; K(D): 0.446 +/- 0.14 vs. 0.454 +/- 0.09 pM of fMLP. 5- and 10-second fMLP-stimulated intracellular IP3 production was instead reduced in patients affected by Bartters syndrome: 2.479 +/- 1.07 vs. 4.073 +/- 1.04 nmol/10(7) cells at 5 s (n = 8; p < 0.01); 1.673 +/- 0.741 vs. 3.766 +/- 1.348 nmol/10(7) cells at 10 s (n = 8; p < 0.005). The results of this study indicate that the anomaly of intracellular calcium mobilization in patients with Bartters syndrome arises from a defect at the postreceptor level. The anomalous calcium signalling that takes place in Bartters syndrome may provide a mechanism for the hyporesponsiveness to pressor stimuli characteristic of these patients.

Kaliuresis in Normal Subjects following Oral Potassium Citrate Intake without Increased Plasma Potassium Concentration

Ingestion of potassium salts typically induces both a kaliuresis and an increase in the systemic plasma potassium concentration. In this study normal healthy adults undergoing water diuresis ingested potassium citrate or sodium citrate (0.5 mmol/kg body weight) or continued without ion ingestion (a time control group). Urine was collected over 20-min intervals and venous blood sampled at midinterval. Intake of potassium citrate led to a significant increase in potassium excretion that began during the first postingestion collection and peaked 60-80 min after intake with a maximal increase in potassium excretion above baseline of 1.60 mumol/min.kg-1. The kaliuresis occurred without changes in plasma potassium concentration, excretion of creatinine or calcium, or urine hypo-osmolality and was associated with a briefer, smaller, and less regular increase in sodium excretion and a pronounced but irregular increase in chloride excretion. Plasma aldosterone was insignificantly elevated above baseline, and the initial increase did not occur until 40-60 min after potassium intake. Intake of sodium citrate did not produce a kaliuresis. The cause of the kaliuresis does not appear to be an increased systemic plasma potassium concentration, an increased plasma level of aldosterone, intake of citrate, or an elevated excretion of sodium. The mechanism inducing the kaliuresis following oral potassium intake in the absence of changes in systemic plasma potassium may involve a reflex initiated at potassium sensors in gut, portal vein, or liver.

Juvenile Renal Stone Disease: A Study of Urinary Promoting and Inhibiting Factors

Urinary excretion of the most widely studied renal stone promoting (calcium, oxalate, uric acid and phosphate) and inhibiting (citrate, magnesium, pyrophosphate and glycosaminoglycans) factors, as well as the Tamm-Horsfall mucoprotein, was evaluated in 14 children with idiopathic calcium nephrolithiasis, 6 children with renal stone disease secondary to excretory malformations and 19 normal controls. No statistically significant differences in urinary excretion of promoting and inhibiting factors were found in children with idiopathic calcium nephrolithiasis but the relationship between promoting and inhibiting factors was changed as shown by an abnormal ratio of oxalate/citrate X glycosaminoglycans. This finding suggests that there is an imbalance between promoting and inhibiting factors in children with idiopathic calcium nephrolithiasis, and it is not detected by assay of each single substance.

Increased urine angiotensin I converting enzyme activity in patients with upper urinary tract infection.

Angiotensin converting enzyme (ACE) is present within the brush border of the tubular cell of the kidney. Since it has a high molecular mass, ACE activity of urine most probably derives only from tubular cells, thus suggesting the potential usefulness of ACE determination as an index of tubular damage. When assayed with the method described, ACE is optimally active at pH 8 with a calcium concentration exceeding 0.75 mmol/l urine, and is chloride independent. Urine dialysis has no effect on ACE activity. ACE is stable at 4 degrees C for 10 days, but it is inactivated by repeated thawing and freezing. The presence of leucocytes and bacteria does not interfere with the assay. Urine ACE activity was evaluated in patients with upper and lower urinary tract infection, nephrolithiasis, chronic glomerulonephritis and essential hypertension and was found to be significantly increased only in patients affected by upper urinary tract infection and nephrolithiasis.

Giovan Battista Morgagni, a Pioneer of Clinical Nephrology

In the 18th century, Giovanni Battista Morgagni was the first to propose that specific signs and symptoms are linked to particular anatomical changes at autopsy and that these changes were the cause of the disease. This paper describes the report by Morgagni wherein he linked the anatomic findings at autopsy, specifically atrophied kidneys, with the signs and symptoms of a disease now known as uremia. From these findings, Morgagni felt that he had identified the factors responsible for the disease as well as its clinical course.

Full Pattern of Urinary Prostaglandins in Bartter’s Syndrome

Dr. Lorenzo Calò, Divisione di Nefrologia, Istituto di Medicina Interna, Università di Padova, Via Giustiniani 2, I-35128 Padova (Italy) Sir, males and 5 females, age range 19–56 years) and in 9 healthy controls cross-matched for sex and age. After Since Gill et al.’s [1] original description of increased urine extraction with organic solvents and silica gel col-urinary excretion of prostaglandin E2 (PGE2) in Bartter’s umn chromatography [3], PGE2 and PGF2α were assayedsyndrome, many controversies have arisen about the role as previously described [4], and 6-keto-PGF,α and TxB2played by prostaglandins in this disease, and it is still by the use of commercially available kits (Amersham, debated whether prostaglandin overproduction is a conAmersham, UK). stant feature and which prostanoid is more frequently As far as the mean urinary excretion is concerned, in involved. Bartter’s syndrome we found a significant increase in Different prostanoids, in fact, sometimes exert oppoPGE2 (627.5 ± 275.6 vs. 359.6 ± 126.6 ng/day; t = 2.62, site effects on renal handling of electrolytes, regulation of p < 0.02) and 6-keto-PGFlα (394.8 ± 190.1 vs. 194.7 ± 40.3renin release and renal action of antidiuretic hormone, ng/day; t = 3.09, p < O.Ol), a significant decrease in TxB2and can counteract the intrarenal action of angiotensin II (123.2 ± 57.3 vs. 184.1 ± 43.9 ng/day; t = 2.47, p < 0.05)in diffferent ways [2]. Therefore, it should be important to and no difference in PGF2α (1,588.6 ± 588.1 vs.know the full urinary pattern of the main arachidonic 1,500.4 ± 488.8 ng/day; t = 0.33, p = n.s.). However, con-acid metabolites in patients affected by Bartter’s synsidering the cutoff values corresponding to eitherdrome to clarify the role played by prostanoids in this mean + 1.64 SD or mean -1.64 SD (i.e. the one-sided 95thsyndrome, but it has never been done. or 5th percentile, respectively), the picture becomes more We have addressed this issue trying to answer two complicated. In fact, PGE2 values were above the upper main questions: which prostaglandin of the cyclooxygelimit in 4 patients, no PGF2α values were above the nornase pathway is more frequently involved in Bartter’s mal range, 6-keto-PGFια values were above the upper

Kidney kallikrein and phospholipase activities in Milan spontaneously hypertensive rats.

Renal kallikrein and phospholipase activities were evaluated in a strain of spontaneously hypertensive rats developed by Dr. Bianchi in Milan (MHR). MHR showed lower than normal kallikrein and phospholipase activities before, at 3 weeks of age and following the development of hypertension. Kallikrein and phospholipase activities were directly correlated both in normotensive and spontenously hypertensive rats. The data suggest that MHR have a genetic defect in kallikrein and phospholipase activities, which may play a pathogenetic role in the development of high blood pressure.