Paracellin-1, a renal tight junction protein required for paracellular Mg2+ resorption.

Epithelia permit selective and regulated flux from apical to basolateral surfaces by transcellular passage through cells or paracellular flux between cells. Tight junctions constitute the barrier to paracellular conductance; however, little is known about the specific molecules that mediate paracellular permeabilities. Renal magnesium ion (Mg2+) resorption occurs predominantly through a paracellular conductance in the thick ascending limb of Henle (TAL). Here, positional cloning has identified a human gene, paracellin-1 (PCLN-1), mutations in which cause renal Mg2+ wasting. PCLN-1 is located in tight junctions of the TAL and is related to the claudin family of tight junction proteins. These findings provide insight into Mg2+ homeostasis, demonstrate the role of a tight junction protein in human disease, and identify an essential component of a selective paracellular conductance.

Renin release by parathyroid hormone in the dog.

Synthetic N-terminal 34 amino acid peptide of bovine parathyroid hormone (PTH) produced a consistent rise in plasma renin activity in saline-loaded dogs when given iv either as a single bolus dose of 400 U or infused steadily in lower dosage over a number of hours. Infusion of as little as 1 U/min produced a significant rise in plasma renin activity, but a greater effect was obtained with 2 U/min. Infusion of 4 U/min had no more effect than 2 U/min. In contrast to transient hypotension after rapid injection of a single large dose, blood pressure did not change significantly during the steady infusion of lower doses of PTH. These findings are compatible with the thesis that an increased distal tubular load of sodium stimulates renin release and suggest that the increased distal sodium absorption after the proximal effects of PTH may be regulated by the renin-angiotensin-aldosterone system.

Response to frusemide in acute renal failure: dissociation of renin and diuretic responses.

Eight hypertensive children with acute post-streptococcal glomerulonephritis were given intravenous frusemide, 2 mg/kg, and the results compared with 8 similar cases not given the diuretic. Mean urine flow increased from 0.24 ml/min/m2 before frusemide to 3.63 ml/min/m2 in the 6 hours afterwards and was still 0.72 ml/min/m2 48 hours later. In contrast mean urine flow remained unchanged over 48 hours in those not given frusemide. Despite similar initial blood pressures the duration of hypertension was much shorter (mean 4.7 days) after frusemide than in the controls (mean 11.0 days) and the edema-free weight was achieved more rapidly (6.8 days compared with 13.9 days). Plasma renin activity (PRA) did not rise after frusemide in the children with acute nephritis. This was in contrast to the rapid rise seen in normal humans thus indicating a dissociation between the diuretic and renin-releasing activities of frusemide in acute nephritis. Seven children with the hemolytic-uremic syndrome or acute tubular necrosis showed no significant change in either urine flow or PRA after frusemide. Frusemide is therefore effective treatment for both hypertension and oliguria in acute nephritis. Failure of PRA to rise indicates that renin release mechanisms are abnormal in renal failure and that PRA levels need to be interpreted with caution in this condition.

Low red cell arachidonic acid in hemolytic uremic syndrome.

A defect in prostacyclin generation has been proposed in hemolytic uremic syndrome (HUS): prostacyclin is formed from arachidonic acid derived from phospholipid and low levels of some phospholipids have been described in HUS cell membranes. Therefore fatty acid content of the red blood cell membranes of 8 children with HUS was compared with 32 children with other renal disease, with 33 patients with non-renal disease and with 8 normal adults. Children with HUS consistently had lower proportions of arachidonic acid (2.7-8.4%) than all other groups (10.1-18.8%) and the mean arachidonic acid level in HUS was very significantly reduced (p less than 0.0001). These findings suggest a reduced availability of arachidonic acid for prostaglandin synthesis in HUS and are consistent with the proposition that arachidonic acid is lost through peroxidative change.

Low red cell arachidonic acid in cyclosporine-treated patients.

Red blood cell phospholipid arachidonic acid concentration was determined in 38 renal transplant recipients on cyclosporine-azathioprine-prednisolone therapy and in a comparable group of 20 patients on azathioprine-prednisolone alone. Samples also were obtained from 18 normal controls and 30 patients with "classical" hemolytic uremic syndrome (HUS). The arachidonic acid content was estimated as the percentage relative to the five principal fatty acids in red blood cell phospholipids (C16:0, C18:0, C18:1 omega 9, C18:2 omega 6, C18:3 omega 6) and quoted as mean value +/- standard deviation. There was a highly significant difference between patients on cyclosporine (14.7 +/- 2.9) and non-cyclosporine-treated transplant recipients (17.1 +/- 2.5; p less than 0.002). This difference was even more significant when patients who had been on cyclosporine for less than 3 months were excluded (14.1 +/- 2.7; p less than 0.001). The mean arachidonic acid content in non-cyclosporine recipients also was significantly less than that in normal controls (19.2 +/- 1.5; p less than 0.005) whilst the HUS patients (11.2 +/- 3.6) had significantly reduced values when compared with all the other groups. Cyclosporine often causes nephrotoxicity and in some cases HUS may develop in cyclosporine-treated transplant recipients. We have found a significant negative correlation between serum creatinine levels and red blood cell phospholipid arachidonic acid levels (r = -0.45; p less than 0.01). We propose that the decreased concentration of arachidonic acid in the cyclosporine-treated group may be related to the development of nephrotoxicity in the long term and may be a useful marker in predicting the early development of nephrotoxicity in these patients.

Nephropathy in cyanotic congenital heart disease.

Three children with cyanotic congenital heart disease who developed transient proteinuria and edema are described. One died of an intercurrent illness but the other two are now well. Renal biopsy findings in all three children demonstrated a mesangial proliferative glomerulonephritis on light microscopy. An unusual ultrastructural appearance of localized electron-dense thickening of the basement membrane of the capillary loops was seen in all three and collagen fibers were present in the mesangium of two. There was slight fusion of foot processes in two specimens and marked fusion in the third. Immunofluorescence in two patients demonstrated IgM staining in both and fibrin in one. The cause of the glomerular lesions is unknown but, among the many possible factors involved, anoxia and increased venous pressure may be important.

Amelogenesis imperfecta and nephrocalcinosis syndrome. Case studies of clinical features and ultrastructure of tooth enamel in two siblings.

This article describes the enamel ultrastructure and clinical features in two siblings with the little known syndrome of Amelogenesis imperfecta and nephrocalcinosis. Nephrocalcinosis was diagnosed by x-ray examination of the abdomen, intravenous pyelography, ultrasonography, and computed tomography scan. Amelogenesis imperfecta was diagnosed from clinical and histologic examinations. The affected enamel was hypoplastic (approximately 0.2 mm thick), positively birefringent, generally aprismatic, porous, and consisted of loosely packed, randomly orientated, thin (approximately 10 nm wide), ribbonlike crystals. The enamel surface was rough, extensively cracked, and covered with ovoid or globular protrusions. Observations showed that in this case hypoplasia, hypocalcification, or hypomaturation defects were present in the same tooth, indicating that both secretory and maturation phases may have been affected. The study suggested the possibility of an abnormality in interstitial matrix, which could lead to dystrophic calcification in the kidney and abnormal tooth enamel formation. It also suggested the possibility of involvement of two separate but closely linked genes.

In vivo determination of intestinal calcium absorption, with scandium-47 used as marker.

The 47scandium/47calcium ratio technique for studying intestinal absorption of calcium in humans offers the following advantages: neither blood sampling nor complete faecal collection are required, and there is no need for an additional marker or for knowledge of the precise dose of calcium isotope administered. In the study this technique was corrected and modified using a new equation that considerably simplifies the determination procedures. The new method was validated in rats with various intestinal calcium absorption rates. The value of scandium as an unabsorbed intestinal marker was confirmed by the use of 46scandium. A mean recovery of 96% was obtained after intragastric administration. The 47scandium/47calcium ratio technique gave results that correlated well with the faecal 47calcium recovery method over a wide range of intestinal calcium absorption rates obtained by treatment with 1,25-dihydroxycholecalciferol or 1-hydroxyethylidene-1,1-biphosphonate. Taking into account the advantages of the 47scandium/47calcium ratio technique, it appears useful not only in small animals but also in outpatients, particularly children.

Urinary nitrite in symptomatic and asymptomatic urinary infection.

The dipstrip test for urinary nitrite is fairly unreliable in symptomatic urinary infections and only 104 (52%) of 200 symptomatic children with urinary infection attending an emergency department had a positive result. The test yielded positive results, however, in 83 of 100 outpatients with largely asymptomatic urinary infection attending a follow up clinic because of known predisposition to urinary infection. This difference was highly significant. The finding of urinary nitrite is highly specific for urinary infection and only 1% of 300 uninfected urine specimens gave a positive result. After addition of a broth culture of Escherichia coli to sterile urine incubation at 37 degrees C for four to six hours was required before the nitrite test yielded positive results. This suggests that frequency of micturition in urinary infection reduces the reliability of the nitrite test. On the other hand, the use of overnight, first morning urine specimens may further improve the sensitivity. If nitrite testing is used for screening for urinary infection at home, however, patients should be warned not to rely on a negative result in the presence of symptoms of urinary infection.

Childhood post-streptococcal glomerulonephritis as a risk factor for chronic renal disease in later life.

OBJECTIVE: To test the hypothesis that post-streptococcal glomerulonephritis (PSGN) in childhood is a risk factor for chronic renal disease in later life. DESIGN: Retrospective cohort study. SETTING: A remote Aboriginal community in the "Top End" of the Northern Territory that experienced two epidemics of PSGN in 1980 and 1987, respectively. PARTICIPANTS: 472 people who were aged 2-15 years during either epidemic. They were categorised by clinical features recorded during the epidemics as having clinically defined PSGN (63), "abnormal urine" (haematuria or proteinuria; 86) or controls (323). OUTCOME MEASURES: Urinary albumin to creatinine ratio (ACR), haematuria (by dipstick urinalysis), blood pressure, serum creatinine level, and calculated glomerular filtration rate (GFR) during community screening in 1992-1998. RESULTS: Overt albuminuria (ACR > 34 mg/mmol) was present at follow-up in 13% of the PSGN group, 8% of the abnormal urine group, and 4% of the control group. The odds ratio (OR) for overt albuminuria in those with a history of PSGN compared with the control group, adjusted for age and sex, was 6.1 (95% CI, 2.2-16.9). Haematuria (>trace) was present in 21% of the PSGN group compared with 7% of the control group (adjusted OR, 3.7; 95% CI, 1.8-8.0). There were no significant differences between the groups in blood pressure, serum creatinine level or calculated GFR. CONCLUSION: In this population, a history of PSGN in childhood is a risk factor for albuminuria and haematuria in later life.

Effect of parathyroid extract on renin release in the dog.

1. A rapid increase in plasma renin activity occurred in dogs after intravenous administration of parathyroid extract. 2. This was not seen after injection of a purer parathormone preparation, or the solution used to dilute the parathyroid extract or calcitonin. 3. A vasoactive compound in parathyroid extract appears to provide the most likely explantation of this effect.

Diphosphonate therapy in nephrocalcinosis.

4 patients with nephrocalcinosis were treated with disodium ethane 1-hydroxy-1, 1-diphosphonate (EHDP) for a period of 13 months. No clinical side-effects were observed and growth proceeded normally. Radiographic changes of osteitis fibrosa cystica developed in 1 child and bone biopsy in 2 children showed defective osteoid mineralisation. It is suggested that EHDP prevented further crystal deposition in 3 children but did not prevent non-calcium stone formation in the 4th child. In view of this and the development of histological and radiographic evidence of osteomalacia and/or secondary hyperparathyroidism in these patients the value of EHDP remains dubious. On the other hand its use may be justified when rapidly increasing calcification is expected, as for example in hyperoxaluria.

Haemolytic-uraemic syndrome after treatment with metronidazole.

This paper describes the clinical features of six children who developed the haemolytic-uraemic syndrome after treatment with metronidazole. These children were older and were more likely to have undergone recent bowel surgery than are other children with this condition. While the involvement of metronidazole in the aetiology of the haemolytic-uraemic syndrome is not established firmly, the action of this drug in sensitizing tissues to oxidation injury and the reported evidence of oxidation changes in the haemolytic-uraemic syndrome suggest a possible link between metronidazole treatment and some cases of the haemolytic-uraemic syndrome.

Computed tomographic assessment of vertebral bone mineral in childhood.

Quantitative computed tomography (QCT) was used to assess trabecular bone mineral concentration in the vertebrae of 132 children, 45 with suspected disorder of bone mineralisation, 54 with thalassaemia and 37 controls. The range for bone mineral concentration in controls, expressed as equivalent K2HPO4 concentrations, was 90-190 mg cm-3. Abnormally low values were seen in all untreated children with idiopathic juvenile osteoporosis, 3/9 steroid recipients, and three patients with osteogenesis imperfecta. Abnormally high values were seen in 10/14 chronic renal failure patients. Comparison of the single and dual-energy methods showed that the single energy method, which has a lower radiation dose and is less prone to error from movement artifact, is satisfactory in most paediatric applications.

Ultrastructural study of tooth enamel with amelogenesis imperfecta in AI-nephrocalcinosis syndrome.

This paper describes the ultrastructure of the affected enamel and the clinical features in two siblings with the syndrome of nephrocalcinosis and amelogenesis imperfecta. Nephrocalcinosis was diagnosed by intravenous pyelography, and confirmed by ultrasonography and CT scan. Amelogenesis imperfecta AI was diagnosed clinically and histologically. Light microscopy showed that the affected enamel surfaces were rough and the enamel was hypoplastic and mainly positively birefringent. Scanning electron microscopy revealed a rough and extensively cracked enamel surface covered with oval shaped blister-like protrusions. TEM showed porous enamel consisting of loosely packed and randomly oriented thin ribbon-like crystals with little or no prismatic structure. Observations showed that hypoplasia together with hypocalcification and/or hypomaturation defects were present in the same tooth, indicating the possibility of an abnormality in interstitial matrix, leading to dystrophic calcification in the kidney and abnormal tooth enamel formation, or alternatively an involvement of two separate but closely linked genes.

Vitamin E treatment of haemolytic uraemic syndrome.

Because low plasma vitamin E concentrations have been reported in patients with haemolytic uraemic syndrome and there is accumulating evidence of lipid peroxidation in this disease, treatment with the antioxidant vitamin E was undertaken in 16 consecutive children with the syndrome. Twelve children had features at presentation suggesting a poor prognosis for recovery but despite this all 16 patients survived and are well three months later. Fifteen children now have normal values for serum creatinine, blood pressure, and urinalysis for protein but one has slight renal impairment. Although this is not a report of a controlled trial, it seems that patients treated with vitamin E have fared considerably better than our previously treated patients with haemolytic uraemic syndrome, even in the presence of early, adverse prognostic features. We suggest that vitamin E alters the natural history of the disease, and in view of the absence of any observed side effects further experience with this treatment is being sought.

Familial hypomagnesaemia--hypercalciuria leading to end-stage renal failure.

Several disorders of hypomagnesaemia of hetary renal origin are now recognised. The cases of two sisters from a consanguineous marriage with the syndrome of renal magnesium wasting, hypercalciuria and nephrocalcinosis are presented. Pathological examination of the heterozygous parental kidneys revealed mild focal interstitial fibrosis. This condition is a previously unreported cause of end-stage renal failure in childhood, and this report suggests that transplantation from heterozygous parental donors can be successfully undertaken without recurrence of the syndrome.

An extreme example of the neonatal form of Bartter's syndrome.

A male infant is described who had polyuria over the 4 months of his life with urine volumes exceeding 1,000 ml/kg per day, severe serum electrolyte losses, metabolic alkalosis and increased plasma renin activity (56 ng/ml per hour). He had a normal blood pressure and glomerular filtration rate when fluid replete. The urine flow rate was about 25% of the glomerular filtration rate. Renal histology showed hyperplasia of the juxtaglomerular apparatus and abnormalities of the proximal tubules. The features of this case suggest an extreme form of Bartter's syndrome presenting from the first days of life.