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.

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.

The multidimensional nature of renal disease: rates and associations of albuminuria in an Australian Aboriginal community.

BACKGROUND: An epidemic of end-stage renal disease (ESRD) is accompanying the rising rates of hypertension, type 2 diabetes and cardiovascular disease among Aborigines in the Northern Territory of Australia. Incidence rates are now 21 times those of nonAboriginal Australians and are doubling every four years. We describe the rates and associations of renal disease in one remote community, which has a current ESRD incidence of 2700 per million, and cardiovascular mortality among the highest in Australia. METHODS: Between 1992 and 1995 a community-wide screening program was conducted, in which the urinary albumin/creatinine ratio (ACR) was used as the chief renal disease marker. More than 90% of the population ages five and older participated. RESULTS: Albuminuria was evident in early childhood and increased dramatically with age; 26% of adults had microalbuminuria and 24% had overt albuminuria. All renal failure developed out of a background of overt albuminuria. ACR was significantly correlated with the presence of scabies at screening, with a history of poststreptococcal glomerulonephritis, which is epidemic and endemic in the community, with increasing body wt, blood pressure, glucose, insulin and lipid levels, and with evidence of heavy drinking. ACR was also significantly and inversely correlated with birth weight. As a result of its association with deteriorating hemodynamic and metabolic profiles, increasing ACR was also correlated with increasing cardiovascular risk score. Direct observations showed, and multivariate models predicted, progressive amplification of ACR when multiple risk factors were present simultaneously. Albuminuria also clustered in families. CONCLUSION: Renal disease in this population is multifactorial, with risk factors related to whole-of-life nutrition, metabolic and hemodynamic profiles, infections, health behaviors, and possibly a family predisposition. Its relationship to low birth weight, and its associations with deteriorating metabolic and hemodynamic profiles, suggest that renal disease is, in part, a component of Syndrome X, which explains the simultaneous increase in metabolic, cardiovascular and renal disease in Aboriginal people. The family clustering might have both environmental and genetic causes, and is under further investigation. Most of the identified risk factors arise out of poverty, disadvantage and accelerated lifestyle change, and the current epidemic can be explained by the confluence of many risk factors in the last few decades. The introduction of effective and sustained programs to address social, economic and educational inequities in all Aboriginal communities, and of screening and renal- and cardiovascular-protective treatment programs for those already afflicted are matters of great urgency.

A familial syndrome of hypocalcemia with hypercalciuria due to mutations in the calcium-sensing receptor.

BACKGROUND: The calcium-sensing receptor regulates the secretion of parathyroid hormone in response to changes in extracellular calcium concentrations, and mutations that result in a loss of function of the receptor are associated with familial hypocalciuric hypercalcemia. Mutations involving a gain of function have been associated with hypocalcemia in two kindreds. We examined the possibility that the latter type of mutation may result in a phenotype of familial hypocalcemia with hypercalciuria. METHODS: We studied six kindreds given a diagnosis of autosomal dominant hypoparathyroidism on the basis of their hypocalcemia and normal serum parathyroid hormone concentrations, a combination that suggested a defect of the calcium-sensing receptor. The hypocalcemia was associated with hypercalciuria, and treatment with vitamin D resulted in increased hypercalciuria, nephrocalcinosis, and renal impairment. Mutations in the calcium-sensing-receptor gene were identified by DNA-sequence analysis and expressed in human embryonic kidney cells (HEK-293). RESULTS: Five heterozygous missense mutations (Asn118Lys, Phe128Leu, Thr151Met, Glu191Lys, and Phe612Ser) were detected in the extracellular domain of the calcium-sensing-receptor gene and shown to cosegregate with the disease. Analysis of the functional expression of three of the mutant receptors in HEK-293 cells demonstrated shifts in the dose-response curves so that the extracellular calcium concentrations needed to produce half-maximal increases in total inositol phosphate in the cells were significantly (P=0.02 to P<0.001) lower than those required for the wild-type receptor. CONCLUSIONS: Gain-of-function mutations in the calcium-sensing receptor are associated with a familial syndrome of hypocalcemia with hypercalciuria that needs to be distinguished from hypoparathyroidism.

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.

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.

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.

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.

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.

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.

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.

Paediatric cadaveric renal transplantation. Initial experience with a triple therapy immunosuppressive regimen.

Since June 1985 ten consecutive paediatric cadaveric renal transplant recipients (aged from 7 to 15 years) have been studied prospectively to evaluate a triple immunosuppressive regime of low-dose cyclosporin A (CyA), azathioprine (AZA) and prednisolone (PNL) with the aim of eliminating PNL from the regime within 6 months. Follow-up has been over 6-18 months. Patient and graft survival are both 100%. Median (range) serum creatinine values at 6 months were 0.09 (0.05-0.14) mmol/l (n = 10) and 0.09 (0.06-0.16) mmol/l (n = 5) at 12 months. Readily reversible acute rejection episodes occurred in five patients (50%); two of these episodes occurred soon after cessation of PNL. Six months post-transplantation, PNL had been discontinued in six patients (60%). After 12 months, three of five patients were still not receiving PNL. Complications included hypertension (seven patients), cytomegaloviral infections (three patients), labial herpes simplex (one patient), leucopenia (two patients), marked hirsutism (four patients) and transient CyA nephrotoxicity (one patient). Following transplantation, all children had growth velocities greater than 5 cm/year and seven have growth patterns which suggest that "catch-up growth" may be occurring. This preliminary study shows that a triple immunosuppressive regime of low-dose CyA, AZA and PNL allows excellent patient survival, graft survival and graft function and has been associated with few complications, including a low incidence of CyA nephrotoxicity. Growth rates are very encouraging and in a high proportion of children it has been possible to discontinue PNL completely.

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.

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.

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.

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.