Albuminuria in a remote South Australian Aboriginal community: results of a community-based screening program for renal disease.

INTRODUCTION: The poverty, poor environmental living conditions and poor health standards experienced by Aboriginal Australians in some communities in rural and remote Australia have been described recently as 'fourth world'. For more than a century Aboriginal people have suffered the effects of dispossession of their land; destruction of their traditional culture and values; and exposure to infectious diseases, alcohol and the Western diet that is high in fat and sugar. Collectively these factors have contributed to the prevalence of chronic disease that afflicts Aboriginal people. In particular, renal disease has emerged during the last decade as a major contemporary health problem for Aboriginal Australians. According to the latest age- and sex-adjusted figures, Aboriginal people now have approximately nine-fold the risk of non-Aboriginal Australians of developing end-stage renal disease. In parts of Australia's Northern Territory, where Aboriginal people represent over 20% of the Territory's population, the rates of end-stage renal disease have been described as 'epidemic', reaching 2700 per million in the Tiwi Islands. In response to a request from the Umoona Tjutagku Health Service in mid 1997, the Renal Unit at Flinders Medical Centre, Adelaide, South Australia, formed a partnership with the health service to conduct a renal-disease screening program for adult members of the Umoona Community at Coober Pedy, a town 850 kilometres north of Adelaide. The partnership was later expanded to include screening for children (conducted by the Renal Unit at the Women's and Children's Hospital, Adelaide, South Australia). The community named the program 'The Umoona Kidney Project'. The Umoona community had recently experienced the dislocation of a number of its older people who suffered from advanced renal disease and were undergoing dialysis in a variety of centres in South Australia and the Northern Territory. As a result, the community had suffered social trauma. Consistent with the community's overall holistic approach to healthcare, the community wanted the renal program to provide a focus for community awareness of and knowledge about chronic disease, as well as to complement existing health programs. OBJECTIVES: The study objectives were to identify the prevalence of risk factors for renal disease, notably albuminuria, in adults from a remote Aboriginal community, and to examine the association of albuminuria with other risk factors; to empower Aboriginal health workers to self-manage a sustainable, community-controlled renal health program; and to assess the reliability and cultural acceptability of point-of-care technology for detecting renal disease. METHOD: The study was a three-year cross-sectional voluntary adult screening program (The Umoona Kidney Project). The study was performed as a partnership between the Flinders Medical Centre Renal Unit and the Umoona Tjutagku Health Service, and it involved nephrologists, medical scientists, Aboriginal health workers and clinical nurses. SETTING: Umoona Tjutagku Health Service, 850 km north of Adelaide. PARTICIPANTS: 158 adult members of the Umoona community: 58 males (37%; mean age = 43.8 years, range 23-78) and 100 females (63%; mean age = 39.6 years, range 18-72). MAIN OUTCOME MEASURES: First morning urine albumin : creatinine ratio measured by the Bayer DCA 2000 point-of-care analyser machine (Bayer Australia, Melbourne, Australia); lying and standing blood pressure; random blood glucose; body mass index; urinalysis. RESULTS: The study found that of screened adults, 29/149 (19%, 95% C.I. 13%-27%) had persistent microalbuminuria and 13/149 (9%, 95% C.I. 4%-14%) had persistent macroalbuminuria; 62/148 participants (42%, 95% C.I. 34%-50%) had overt hypertension; 35/145 participants (24%, 95% C.I. 17%-32%) had diabetes; 3 participants were newly diagnosed as having non-insulin dependent diabetes; 96/148 participants (65%, 95% C.I. 57%-73%) were either overweight or obese. Strong correlation was observed between the progression of albuminuria and age, all blood pressure categories, blood glucose, body mass index and an increasing number of risk factors. CONCLUSIONS: The Umoona Kidney Project identified a significant community burden of previously unknown incipient and established renal disease that required addressing via clinical- and community-based interventions. The DCA 2000 was a reliable instrument for detecting albuminuria on-site in the remote clinical location and was well accepted by Aboriginal health workers and community participants.

Excellent long-term graft survival in low risk, primary renal allografts treated with prednisolone-avoidance immunosuppression.

Primary avoidance of oral corticosteroids for renal transplant recipients is uncommon. The South Australian renal transplant service used a double therapy (DT) regimen of cyclosporin and azathioprine from August 1986 to July 1996 for low risk (first graft, PRA < 50%) allografts. Oral corticosteroid, prednisolone (P), was reserved for severe rejection or two mild rejection episodes, but could be later withdrawn at the physician's discretion. This regimen is associated with more early acute rejection (Russ et al., Clin Transplant 1990: 4: 26). We have now analysed long-term patient survival (PS) and graft survival (GS) for this group. Of 448 transplants in South Australia between August 1986 and July 1996, 295 commenced DT regimen. Ninety-four (31.8%) never received P at any stage post-transplantation (group 1), 96 (32.5%) were placed on P and later weaned (group 2), and 97 (33%) remained on long-term P (group 3). Technical losses, eight (2.7%), within 30 d of transplantation, were excluded from sub-group analysis. PS for the total DT cohort at 1, 5 and 9 yr post-transplantation was 97, 88 and 74%, respectively. GS over the same time period was 88, 75 and 55%, respectively. There was no statistically significant difference in survival compared to other 'low risk' grafts in the rest of Australia during the same time period. Mean serum creatinine concentration (CrC) for the DT group at 3 and 6 months and 1, 3, 5 and 10 yr was not significantly different to the rest of the Australian 'low risk' grafts. In the DT cohort, there were 334 acute rejections ( < 90 d) in 206 patients (70%), but only 42 (12.5%) required anti-lymphocyte antibody therapy (OKT3 or ATG) for rejection. PS at 9 yr was not statistically significantly different between groups 1 and 2, but both groups survived better than group 3 (p < 0.0043). GS for group 1 at 1, 5 and 9 yr post-transplantation was 90, 81 and 73%, respectively; for group 2, 98, 87 and 66%, respectively; and for group 3, 84, 63 and 29%, respectively. Statistical significance was reached in group 1 versus 3 (p < 0.001) and group 2 versus 3 (p < 0.001). In summary, a DT regimen in low risk, first renal allografts gives excellent long-term patient and GS and minimises long-term P, despite a high rate of early acute rejection.

A functional role for the two-pore domain potassium channel TASK-1 in cerebellar granule neurons.

Cerebellar granule neurons (CGNs) are one of the most populous cells in the mammalian brain. They express an outwardly rectifying potassium current, termed a "standing-outward" K(+) current, or IK(SO), which does not inactivate. It is active at the resting potential of CGNs, and blocking IK(SO) leads to cell depolarization. IK(SO) is blocked by Ba(2+) ions and is regulated by activation of muscarinic M(3) receptors, but it is insensitive to the classical broad-spectrum potassium channel blocking drugs 4-aminopyridine and tetraethylammonium ions. The molecular nature of this important current has yet to be established, but in this study, we provide strong evidence to suggest that IK(SO) is the functional correlate of the recently identified two-pore domain potassium channel TASK-1. We show that IK(SO) has no threshold for activation by voltage and that it is blocked by small extracellular acidifications. Both of these are properties that are diagnostic of TASK-1 channels. In addition, we show that TASK-1 currents expressed in Xenopus oocytes are inhibited after activation of endogenous M(3) muscarinic receptors. Finally, we demonstrate that mRNA for TASK-1 is found in CGNs and that TASK-1 protein is expressed in CGN membranes. This description of a functional two-pore domain potassium channel in the mammalian central nervous system indicates its physiological importance in controlling cell excitability and how agents that modify its activity, such as agonists at G protein-coupled receptors and hydrogen ions, can profoundly alter both the neuron's resting potential and its excitability.

A functional spliced-variant of beta 2 subunit of Kv1 channels in C6 glioma cells and reactive astrocytes from rat lesioned cerebellum.

Voltage-gated K(+) channels (Kv1) are important in glia, being required for cell proliferation. Herein, reactive astrocytes from a rat cerebellar lesion were shown to contain Kv1.1, -1.2, -1.3, -1.4, and -1.6 alpha plus beta1.1 subunits, as well as an unusual beta2.1 constituent; the latter was also found in a glioblastoma C6 cell line, together with Kv1.1, -1.3, and -1.6 and beta1.1 subunits. Reverse transcriptase-polymerase chain reaction revealed a novel product of the beta2 gene in C6 cells and reactive astrocytes, but not in cultured astrocytes or rat normal brain. Its cloning identified a variant, Kvbeta2.1A, alternatively spliced between I24 and Y39. Despite this 14 residue deletion, Kvbeta2.1A assembled cotranslationally with Kv1.1 or -1.2 and, when coexpressed with Kv1. 4 in oocytes, increased the inactivation rate of this K(+) current. Whereas the full-length beta2.1 gave a large increase in the amplitude of the Kv1.1 current in oocytes, the effect of beta2.1A varied from a modest elevation of the current to a slight suppression in some cases. In summary, this is the first report of the existence of an alternatively spliced product of the Kvbeta2.1 gene in C6 cells and reactive astrocytes, and supports the involvement of its core region (residues 39 onward) in assembly with alpha subunits while excluding a contribution of the adjacent 14 residues to accelerating the inactivation of Kv1.4.

Heat-induced cobalt entry: an assay for heat transduction in cultured rat dorsal root ganglion neurons.

A histochemical stain to detect cobalt in cells was used to investigate the ionic basis of heat transduction in mammalian primary afferent neurons. Cultured dorsal root ganglion neurons from the adult rat were exposed to 10-min heat stimuli in an extracellular solution containing cobalt ions. When accumulated intracellular cobalt was precipitated, a subpopulation of neurons was darkly stained. The number of neurons stained depended on the intensity of the heat stimulus, ranging from 1.9% at 22 degrees C to 24.0% at 45 degrees C, a range of temperatures transduced by primary afferent nerve endings in vivo. Results of Trypan Blue exclusion experiments demonstrate that the heat-induced stain is not due to membrane damage, suggesting that heat opens a divalent-permeable ion channel. Agents that block many multivalent cation-permeable channels (lanthanum, ruthenium red and amiloride) did not reduce the number of cells that exhibited heat-induced cobalt staining. Heat-evoked cobalt staining provides an in vitro model for the investigation of the ionic mechanisms of thermal transduction in sensory neurons.

Glomerular basement membrane thinning in a patient with hematuria and hemoptysis mimicking Goodpasture's syndrome.

Ultrastructural morphometric studies of glomerular basement membrane (GBM) thickness are described in two renal biopsy specimens from a patient who presented with hemoptysis and hematuria mimicking Goodpasture's syndrome. Significant GBM abnormality, with attenuation as the main lesion, identified in a biopsy specimen taken during active clinical disease appeared to have resolved in a second biopsy specimen taken during the recovery phase. There was no evidence of glomerulonephritis. Concurrent lung biopsy studies showed focal alveolar-capillary wall basal lamina changes of uncertain diagnostic significance. These observations suggest the alternative possibilities that GBM attenuation may be either an acquired consequence of systemic disease or may be part of an hitherto unrecognized primary multisystem abnormality of basal lamina affecting, in this case, glomerular and pulmonary laminae, resulting in hematuria and hemoptysis. The morphometric studies in this case indicate that simple-mean measurements of GBM thickness are inadequate alone for the quantitative study of this lamina because significant inter- and intraglomerular membrane variation, if irregularly distributed, can remain undetected.

On letting go: the patient, haemodialysis and opting out.

The title of this article refers not only to the patient who decides to let go of life, the quality of which on dialysis is such that death is preferable, but also to the family and the renal unit staff who have to let go of the patient who makes this decision. One such case is described in detail since the problem is not one restricted to the treatment of end-stage renal failure alone, but occurs more and more frequently in other branches of medicine and surgery.

An in vivo study of voltage-dependent renal tubular acidosis induced by amiloride.

It has been proposed that most forms of hyperkalemic distal renal tubular acidosis (dRTA) result from a voltage-dependent acidification defect in the cortical collecting tubule (CCT) in which hydrogen and potassium secretion are decreased secondary to a reduced, transepithelial potential difference (PD) arising from impaired sodium reabsorption. The present in vivo study examines one model of hyperkalemic dRTA, induced by chronic amiloride administration, to examine the relationship between urinary excretion of hydrogen and potassium ions and CCT PD in the rat kidney. Chronic administration of amiloride produced a significant metabolic acidosis with a plasma bicarbonate of 21.3 mmol/liter compared to 25.9 mmol/liter in control rats. Plasma potassium was higher in experimental animals (4.9 mmol/liter vs. 3.3 mmol/liter in controls) and was associated with a significantly reduced fractional excretion of potassium of 11.2% versus 37.4% in controls. When animals were loaded with DOCA and infused with 4% sodium sulphate to maximize urine acidification, urine pH was significantly higher in the experimental group (6.35 vs. 5.55 in controls) while the mean PD in cortical collecting tubules was markedly lower at -21.1 mV versus -58.9 mV in controls. These results support a voltage dependent mechanism to explain the defect in hydrogen and potassium ion secretion induced by amiloride.

Glomerular basement membrane abnormalities associated with apparently idiopathic hematuria: ultrastructural morphometric analysis.

In a recent review of 480 renal biopsies, 41 cases were identified in which glomerular basement membrane (GBM) ultrastructural abnormalities were the major lesion. All of the patients had hematuria. None had evidence of immune-mediated glomerulonephritis. Positive family histories of renal disease were present in the majority of cases, and one case of Alport's syndrome was included. Subjectively, the GBM changes were variable but nearly always included membrane thinning. For objective characterization of this glomerular abnormality, a detailed morphometric study of GBM thickness was undertaken: 12 of these patients (study group) were compared with seven patients (control subjects) with subjectively normal glomeruli who underwent biopsy for reasons other than nonsurgical hematuria but who were also thought to have normal glomerular ultrastructure. The seven control subjects had a mean GBM thickness of 394 nm (SD, 19; range, 356 to 432 nm). Of the 12 study group patients, 11 had mean GBM thicknesses significantly different from control values (nine had mean GBM thinning: range, 235 to 327 nm; two had thickening: means, 440 and 469 nm). In the remaining case (Alport's syndrome) the overall mean was normal, but an abnormal distribution of very thin and very thick GBM regions was seen. Of the four apparently normal hematuric patients, significant mean GBM thinning (326 to 347 nm) was demonstrated in three, with an excess of thin GBM in the fourth case, although the mean thickness was normal. Thus, measurable abnormalities were defined in all of the cases of hematuria examined. The GBM measurements confirmed the subjective impression of membrane abnormality, usually attenuation, as the principal finding in this group of hematuric patients. Furthermore, morphometric analysis may reveal subtle changes of GBM thickness missed by subjective assessment.

Effect of cisplatin on the transepithelial potential difference of rat distal tubule.

Cisplatin, an effective anti-tumor agent, has significant effects on renal function including reduced glomerular filtration rate and potassium and magnesium wasting. It has been shown recently that cisplatin increases sodium conductance across the isolated frog skin, an effect which was inhibited by amiloride. The present study investigates the influence of cisplatin on the transepithelial potential difference (PD) of distal nephron segments of the rat kidney. Measurements were made under free-flow conditions and during distal microperfusion. When cisplatin was infused intravenously in a dose of 2 mg/kg/hr, the mean free-flow PD in late distal segments (cortical collecting tubules) increased from -18.5 +/- 1.4 mV (N = 37) to -31.2 +/- 1.4 mV (N = 36) (P less than 0.001). The large negative PD seen with cisplatin was abolished with intravenous amiloride, a mean PD of +0.9 +/- 1.5 mV (N = 22) (P less than 0.001) being obtained, similar to a PD of +1.9 +/- 1.5 mV (N = 39) found in control animals infused with amiloride. Perfusion of individual late distal segments with artificial plasma ultrafiltrate yielded a mean control PD of -12.4 +/- 1.2 mV (N = 21) and a significantly higher PD of -17.5 +/- 1.5 mV (N = 24) (P less than 0.01) when cisplatin (10(-3) M) was added to the perfusate. The addition of amiloride to these perfusates reduced the mean PDs to -3.2 +/- 0.5 mV (N = 19) and -3.6 +/- 0.7 mV (N = 17), respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Origin of positive transepithelial potential difference in early distal segments of rat kidney.

Previous studies from our laboratory indicate that early distal segments of the rat kidney have a positive transepithelial potential difference (PD). The present study investigates the origin of the positive PD. PDs were measured in early distal segments using a technique which allowed simultaneous microperfusion and PD measurement through a single pipette (3 to 6 micron O.D.). Microperfusion with artificial plasma ultrafiltrate resulted in a significantly negative mean PD of -4.9 +/- 0.7 mV (N = 17), in contrast to a positive free-flow PD of +5.7 +/- 1.1 mV (N = 174) (P less than 0.001). Addition of amiloride 10(-4) M to plasma ultrafiltrate changed the PD to +1.7 +/- 0.2 mV (N = 25, P less than 0.001). In contrast, furosemide 10(-4) M had no effect on the perfusion PD. Removal of sodium from the luminal perfusate abolished any effect of amiloride on the perfusion PD. Perfusion with artificial early distal fluid yielded a positive PD of +4.2 +/- 0.2 mV (N = 19). Amiloride increased this PD to +8.3 +/- 0.7 mV (N = 21, P less than 0.001). Subsequent experiments in which the sodium and potassium concentrations of the perfusates were varied indicated that concentration gradients for these ions across the early distal tubule could generate substantial diffusion PDs and that potassium was much more permeant than sodium.(ABSTRACT TRUNCATED AT 250 WORDS)

Glomerulonephritis associated with chronic bacterial infection of a dacron arterial prosthesis.

Glomerulonephritis associated with severe chronic visceral or systemic infection is being increasingly recognized. The development of glomerulonephritis in association with chronic infection of prosthetic material permanently implanted in the circulatory system has been regularly reported since the description of "shunt nephritis" by Black, Challacombe and Ockenden in 1965. Nearly all of these cases have involved ventriculo-vascular shunts. However, this report documents the apparently rare association between glomerulonephritis and chronic bacterial infection of a bifurcate dacron aorto-bifemoral graft. The need for awareness of glomerulonephritis as a cause of acute renal failure in chronic infective states is highlighted.

Effects of feeding and lighting regimes on sugar transport in the rat small intestine.

1. The use of a controlled feeding regime which restricted rats to feeding during the 12 h dark period reduced the variability of sugar transport measurements made with the vascularly perfused intestine. 2. When the timing of the 12 h feeding or lighting periods was shifted by 12 h, pronounced changes in the rate of D-galactose and L-glucose transport were observed. 3. These variations were shown most clearly when the data were expressed as the ratio of the rate of appearance of the actively transported D-galactose to that of the poorly transported L-glucose in the vascular perfusate. This ratio was reduced in those animals studied during their feeding period. The lower ratios in these animals were attributable mainly to an increased rate of transport of L-glucose. 4. Significant reductions in D-galactose/L-glucose ratios were also found when the lighting period was shifted by 12 h, indicating that sugar transport is influenced by the lighting regime as well as by the feeding pattern. 5. An examination of the tissue sugar concentrations under the different feeding and lighting regimes revealed that the variations in sugar transport were associated with changes in the selectivity of the process responsible for the exit of sugars from the mucosa into the vascular bed. This phase of transepithelial transport appeared to be influenced mainly by the lighting cycle.