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Aim: Vascular calcification is prevalent in patients with chronic kidney disease. Abdominal aortic calcification (AAC) can be detected by X-ray, although AAC is less well documented in anatomical distribution and severity compared with coronary calcification. Using simple radiological imaging we aimed to assess AAC and determine associations in prevalent Australian haemodialysis (HD) patients. Methods: Lateral lumbar X-ray of the abdominal aorta was used to determine AAC, which is related to the severity of calcific deposits at lumbar vertebral segments L1 to L4. Two radiologists determined AAC scores, by semi-quantitative measurement using a validated 24-point scale, on HD patients from seven satellite dialysis centres. Regression analysis was used to determine associations between AAC and patient characteristics. Results: Lateral lumbar X-ray was obtained in 132 patients. Median age of patients was 69 years (range 29–90), 60% were male, 36% diabetic, median duration of HD 38 months (range 6–230). Calcification (AAC score ≥ 1) was present in 94.4% with mean AAC score 11.0 ± 6.4 (median 12). Independent predictors for the presence and severity of calcification were age (P = 0.03), duration of dialysis (P = 0.04) and a history of cardiovascular disease (P = 0.009). There was no significant association between AAC and the presence of diabetes or time-averaged serum markers of mineral metabolism, lipid status and C-reactive protein. Conclusions: AAC detected by lateral lumbar X-ray is highly prevalent in our cohort of Australian HD patients and is associated with cardiovascular disease, increasing age and duration of HD. This semi-quantitative method of determining vascular calcification is widely available and inexpensive and may assist cardiovascular risk stratification.

Background/Aims: Many hemodialysis patients receive antiplatelet therapy or warfarin; however, little is known about the effect of this on iron requirements. Given the association of antiplatelet therapy with bleeding we hypothesized that there should be a greater need for iron in such patients, which we tested in this study. Methods: Retrospective 1-year cohort study of 205 chronic hemodialysis patients. The primary outcome variable was total iron dose, which was analyzed according to antiplatelet/warfarin use. Data were also collected on potential confounders, allowing for both unadjusted and adjusted (multiple regression) analysis. Results: 97/205 patients received antiplatelet/warfarin therapy. This group was older, with a higher incidence of macrovascular disease and diabetes and a higher median C-reactive protein (6.0 vs. 3.75 mg/l). Overall, median iron requirement was 1,300 mg/year. In a multiple regression analysis, antiplatelet/warfarin use was associated with an additional iron requirement of 703 mg (95% confidence interval 188–1,220 mg), with the strongest effect observed in patients with normal inflammatory markers. Conclusion: We found a high requirement for iron in patients receiving antiplatelet agents/warfarin. We argue that the most likely mechanism for this association is chronic, low-grade blood loss, although further study is required before causality can be established.

Examination of the urine under the microscope using polarised light is invaluable for detecting and identifying lipid particles. Attention to the shape of these Maltese cross bearing bodies can distinguish conventional fat particles from Fabry bodies with great sensitivity and specificity across a wide phenotypic spectrum. This could be a cheap and rapid tool for screening subjects suspected of having Fabry disease for renal involvement. It remains to be seen whether there is value in integrating polarised light into automated urine microscopy machines, but potentially this could greatly help the pathologist or nephrologist in identifying unusual urinary particles, and broaden the capacity for larger scale screening.

Background: The Ras and Rho family of GTPases serve as essential molecular switches in the downstream signalling of many cytokines involved in the regulation of renal fibroblast activity. Prenylation is a post-translational process critical to the membrane localization and function of these GTPases. We studied the effects of a farnesyltransferase inhibitor BMS-191563 and geranylgeranyltransferase inhibitor GGTI-298 on renal fibrogenesis in vitro. Methods: Functional studies examined the effects of BMS-191563 and GGTI-298 on rat renal fibroblast kinetics, collagen synthesis and collagen gel contraction. Pro-collagen α1(I) mRNA expression was measured by Northern analysis and CTGF expression by Western blotting. Results: Fibroblast proliferation was significantly reduced by both agents. Exposure of fibroblasts to BMS-191563 resulted in a significant reduction in total collagen production and pro-collagen α1(I) mRNA expression, an effect also observed but to a lesser degree with GGTI-298. Both agents significantly reduced CTGF protein expression. Fibroblast-mediated collagen I lattice contraction was decreased at 48 h by GGTI-298, an effect not observed with BMS-191563. Consistent with this finding, marked actin filament disassembly was evident by phalloidin staining of fibroblasts exposed to GGTI-298. Conclusion: BMS-191563 and GGTI-298 exhibit different effects on renal fibroblast function reflecting their predominant roles in inhibiting prenylation of Ras or Rho proteins respectively. Further studies are warranted to establish their potential therapeutic application in the treatment of progressive renal disease.

As several studies indirectly suggest that inhibiting the intracellular breakdown of cyclic nucleotides may inhibit fibrogenesis, this study used membrane permeable cyclic nucleotide analogues to examine the role of cAMP and cGMP signaling pathways in the regulation of renal fibroblast function. Fibroblasts were isolated by explant outgrowth culture of rat kidneys post unilateral ureteric obstruction. Subcultured cells were exposed to 10– 1,000 µM of the cyclic nucleotide analogues 8-bromo-cAMP (8br-cAMP) and 8-bromo-cGMP (8br-cGMP). Functional parameters examined included mitogenesis (thymidine incorporation), collagen synthesis (proline incorporation), myofibroblast differentiation (Western blotting for α-smooth muscle actin; α-SMA) and expression of CTGF (Northern blotting), a TGF-β1-driven immediate early response gene. Serum-stimulated mitogenesis was decreased 27 ± 4% by 100 µM 8br-cAMP (p < 0.01), 49 ± 6% by 1,000 µM 8br-cAMP (p < 0.001) and 43 ± 7% by 1,000 µM 8br-cGMP (p < 0.01). 1,000 µM 8br-cAMP and 8br-cGMP reduced basal collagen synthesis by 80 ± 5 and 60 ± 21% respectively (both p < 0.05). Maximum dose of 8br-cAMP but not 8br-cGMP inhibited basal expression of the differentiation marker α-SMA by 43 ± 33 (p < 0.05), resulted in a more rounded cell morphology and reduced expression of CTGF by 39 ± 24% (p < 0.05). Measurement of mitochondrial activity confirmed that effects were independent of cell toxicity. In conclusion, cyclic nucleotides inhibit fibrogenesis in vitro. Strategies which elevate intracellular cyclic nucleotide concentrations may therefore be therapeutically valuable in preventing the proliferation and activation of fibroblasts in progressive renal disease.

SUMMARY: Background: Numerous prior studies have reported that a substantially higher dose of epoetin is required to maintain haemoglobin (Hb) concentration when patients are switched from a subcutaneous (SC) to intravenous (IV) route of administration. Many of the reported trials, however, involved patients who did not have adequate serum iron levels. It was hypothesized that patients with adequate iron stores who are switched from one route of administration to the other without a change in dose will experience substantially less change in their Hb concentration. Methods: Haemodialysis patients who were iron replete (ferritin 300–800 µg/L, transferrin saturation (TSAT) 25–50%) participated in a prospective, randomized cross-over trial receiving epoetin for 3 months either by SC or IV injection followed by a further 3 months of epoetin via the other route. The principal aim was to determine changes in Hb concentration without altering the weekly epoetin dose. The secondary aim was to assess whether the frequency of dosing (once, twice or thrice weekly) influenced the Hb concentration response. Results: Eighty-one patients (mean age 62 years, 60% male) entered the study and 15 withdrew prior to study completion. Forty-three patients began SC epoetin alfa administration (group A) and 38 on IV (group B). Median ferritin and TSAT at entry for groups A and B were 409 and 394 µg/L (NS) and 31 and 32% (NS), respectively, which remained within the target range during the study. Median epoetin doses for groups A and B were similar (90 vs 93 IU/kg per week, NS). After 3 months, the mean Hb concentration rose for group A (SC; 118.7–121.9 g/L (P = 0.03)) but it fell for group B (IV; 119.1–116.0 g/L (P = 0.019)). Following the change in route of administration, the Hb concentration for group A (IV) fell by 5.1% over 3 months (121.9–115.4, P

SUMMARY: Screening patients with autosomal dominant polycystic kidney disease (ADPKD) for asymptomatic intracranial aneurysms has been proposed as a method of reducing the morbidity and mortality associated with aneurysm rupture. However, recent studies have shown lower spontaneous rupture rates of small aneurysms and higher risks of significant complications with interventions than previously reported. Risk-benefit analysis has not demonstrated any benefit of screening ADPKD patients without a history of subarachnoid haemorrhage (SAH) for intracranial aneurysms, and has suggested that screening might cause harm.

Although accelerated atherosclerosis and arteriosclerosis are common in patients with renal failure, the pathogenesis of these changes is poorly understood. Parathyroid hormone (PTH) levels are elevated in renal failure, and have been linked to uraemic vascular changes in some studies. We examined the in vitro effects of increasing doses of the 1–34 fragment of PTH on human aortic vascular smooth muscle cells (VSMCs). Factors examined were: (1) collagen production using tritiated hydroxyproline incorporation and transcription of procollagen α1(I) mRNA; (2) change in the surface area of collagen I lattices; (3) mRNA transcription of the collagen binding protein β1 integrin; (4) proliferation using tritiated thymidine incorporation, and (5) methyl tetrazolium salt conversion to estimate live cell number after 5 days’ exposure to PTH. PTH at a concentration of 200 pmol/l increased total collagen synthesis (188 ± 25% of control, p < 0.01) as well as transcription of procollagen α1(I) mRNA (136 ± 11% of control, p < 0.005). PTH also increased reorganisation of collagen I lattices (surface area 47 ± 8% of well for control vs. 35.7 ± 2.5 and 34.3 ± 3.0% for PTH 100 and 200 pmol/l, respectively, p = 0.02) and upregulated β1 integrin mRNA expression (160 ± 20% of control at PTH concentration of 200 pmol/l, p < 0.05). PTH had no effect on VSMC proliferation or number at doses up to 200 pmol/l. In conclusion, PTH increases production and reorganisation of collagen by VSMCs in vitro. It is possible that more aggressive control of hyperparathyroidism in patients with renal failure may help to reduce the burden of cardiovascular disease in this patient population.

Background/Aims: Endothelin (ET) has been implicated as an indirect mediator of injury following acute renal ischaemia (ARI). The purpose of this study was to localize and quantitate ET and ETA and ETB receptors following ARI. Methods: A model of ARI, well characterized previously, was produced by 45 min occlusion of the renal pedicle of unilaterally nephrectomized female Sprague-Dawley rats. Animals were sacrificed 1, 2, 4, 8, 16, 32 and 64 days after ischaemia (n = 6). Corresponding control groups with unilateral nephrectomy but no ischaemia were sacrificed after 0, 8 and 64 days. Immunohistochemistry for ET-1, -2 and -3 was performed. Tissue ET levels were calculated by RIA (femtomoles per kidney). Receptor ligand binding studies for ETA and ETB receptors were performed by autoradiography on frozen kidney sections and quantitated by densitometry (relative optical density per square millimetre). Results: The concentration of tissue ET increased from 24 h after ischaemia and remained significantly increased for the duration of the study, reaching a maximum at 8 days. There was a small increase in the non-ischaemic 8-day control group, but this returned to basal levels by day 64. The increase in tissue ET 8 days after ischaemia was localized by immunohistochemistry to renal medullary interstitial cells, damaged tubules at the corticomedullary junction and peritubular capillaries surrounding these damaged tubules. Increases in cortical ETA and ETB receptors were evident 24 h after ischaemia and were maximal 8 days after ischaemia, before returning to basal levels at 16 days. After a small increase 24 h after ischaemia, medullary ETA receptors decreased on day 4 before returning to basal levels on day 8 after ischaemia. Medullary ETB receptors, however, decreased on day 4 after ischaemia and remained low throughout the duration of the study. Conclusion: The previously reported amelioration of pathological changes resulting from the use of ET receptor antagonists after ARI may be related to the quantitative and qualitative changes in tissue ET and ET receptors observed in this study.

SUMMARY: The kinetics of interstitial extracellular matrix remodelling in the kidney following parenchymal cell death were studied after injury was produced by a single application of liquid nitrogen to the surface of the kidney. the size of the injury decreased to 30% of the original size at 4 days and to 5% at 16 days after injury. the primary response to injury consisted of an acute polymorphonuclear infiltration followed by monocyte/macrophage and myofibroblast accumulation from day 2 to 8. Collagen III accumulation increased progressively until day 16 and was inversely related to lesion size. These results demonstrate the time course of cellular events and collagen synthesis in renal tissue remodelling following renal parenchymal cell death.

Summary: Interstitial fibrosis is a final common pathway for many, if not all forms of end-stage renal disease. Although the kidney contains several cell types that are capable of collagen biosynthesis, most in vitro and in vivo studies suggest that fibroblasts generate the principal interstitial matrix collagens. Recent studies have defined a role for myofibroblasts (cells with features of both fibroblasts and smooth muscle cells) in progressive renal interstitial fibrosis. Renal myofibroblasts are hyperproliferative and up-regulated matrix producers, consistent with them being ‘activated’ fibroblasts. Interstitial myofibroblasts also share a number of anatomical, phenotypic and biosynthetic features with the glomerular mesangial cell. the interstitium consists of a complex mixture of inflammatory and fibrogenic mediators. the fibroblast response to this microenvironment includes chemotaxis, proliferation and increased synthetic activity. However, the derivation and fate of the fibroblast/myofibroblast during scarring remains unclear, with migration, proliferation, differentiation and cell death all likely to determine cell number.

Summary: Resolution of tubulointerstitial nephritis represents an important step in limiting renal fibrogenesis. However, the mechanism of this resolution remains poorly understood. to determine if apoptosis has a role in this process, we studied its incidence in an experimental model of renal infection and scarring, induced by direct inoculation of Escherichia coli into the renal cortex of Sprague-Dawley rats. the focal lesion produced was studied in animals killed at various time points up to 100 days post inoculation. Apoptosis was identified by electron microscopy (EM) and in-situ labelling of fragmented DNA using terminal transferasemediated deoxy-uridine-5′-triphospate (UTP) nick end labelling (TUNEL). Results were compared with morphological assessment of tubulointerstitial cellularity and macrophage localization. Terminal transferasemediated UTP nick end labelling localized apoptosis to interstitial cells, tubular casts and occasional tubular epithelia and double labelling demonstrated apoptotic body incorporation in macrophages. Interstitial cellularity was maximum at day 3, decreasing significantly by 100 days (P< 0.01). the incidence of interstitial apoptosis was increased by 3 days and remained significantly higher than day 0 controls throughout (P < 0.05). Tubular cellularity was significantly less than in control animals throughout the experimental time period. Although the rate of tubular apoptosis was increased, this difference was not statistically significant. In conclusion, apoptosis may represent an important mechanism in the reduction of tubulointerstitial cellularity after experimental renal infection. This in turn, may be important in limiting subsequent interstitial scarring.

A 36-year-old man with a history of end-stage renal failure secondary to reflux nephropathy who underwent renal transplantation 18 years earlier presented with acute abdominal pain. He underwent a laparotomy and had a Hartmann's procedure for a ruptured sigmoid diverticulum. Postoperatively his renal function deteriorated, with the serum creatinine level increasing from 0.35 to 0.50 mmol/L. A Tc-99m mercaptoacetyltriglycine (MAG3) renal scan was performed and a urinary leak was initially suspected. However, after correlation with ultrasound and prior surgical notes, this was found to be the result of an unusual collecting system anatomy. The patient's creatinine level gradually returned to baseline. The initial increase in creatinine was attributed to acute tubular injury after the surgery.

Summary: Confocal laser scanning microscopy (CLSM) has potential applications in the fields of embryology, anatomy, physiology and pathology of the kidney. This review focuses upon the principles of confocal microscopy and the ways in which this new technology may affect nephrological diagnostic pathology.

Summary: Future studies aimed at testing therapies to prevent progression of renal failure have much to learn from the past successful and unsuccessful attempts. Given the insensitivity of all other methods, the proper index of renal function for study of progression of renal failure should be radioisotope glomerular filtration marker clearance. Randomized prospective controlled studies are required, and statistical analysis should be designed to allow consideration for patient drop out and covariants. Since compensatory mechanisms come into place as soon as there is any nephron damage, more attention should be paid to studying the progression of renal failure from a normal glomerular filtration rate (GFR) until there is an elevated plasma creatinine level. This suggestion is supported by four under-lying concepts: (i) overall GFR does not fall until about 23% of nephrons are destroyed; (ii) if progression is multifactorial, the later in the progress the more likely that more factors are present to confound issues; (iii) this may allow study of greater patient numbers, since patients who have had renal biopsy or ultrasound diagnosis can be entered before the plasma creatinine is abnormal; (iv) in early stages of disease, issues of concurrent treatment may be less difficult (e.g. diet, phosphate control, hypertension). With diabetes, prognosis and progression has been related to proteinuria. In non-diabetic disease proteinuria has been related to progression, but the effect of alleviation of proteinuria on prognosis has not been intensively studied. There is a need to study the relationships between proteinuria and progression, particularly in early renal disease. At present most therapies are based upon observations in the partially ablated rat model. Other animal models should be developed, and the details of early mechanisms in the rat further clarified. Since we believe progression is likely to be multifactorial in pathogenesis, combination therapies may be required to optimally reduce progression.

AFCKDI RECOMMENDATIONS FOR EARLY DETECTION OF CHRONIC KIDNEY DISEASE 1. Targets Patients with diabetes, hypertension Those with family history of chronic kidney disease (CKD) Individuals receiving potentially nephrotoxic drugs, herbs or substances or taking indigenous medicine Patients with past history of acute kidney injury Individuals older than 65 years 2. Tools Spot urine sample for protein with standard urine Dipstick test (need a repeat confirmatory test if positive) Dipstick for red blood cells (need confirmation by urine microscopy) An estimate of glomerular filtration rate based on serum creatinine concentration 3. Frequency of screening Screening frequency for targeted individuals should be yearly if no abnormality is detected on initial evaluation. 4. Who should perform the screening Doctors, nurses, paramedical staff and other trained healthcare professionals 5. Intervention after screening Patients detected to have CKD should be referred to primary care physicians with experience in management of kidney disease for follow up. A management protocol should be provided to the primary care physicians. Further referral to nephrologists for management will be based on the protocol together with clinical judgment of the primary care physicians with their assessment of the severity of CKD and the likelihood of progression. 6. Screening for cardiovascular disease risk It is recommended that cardiovascular disease risk factors should be screened in all patients with CKD.

Recognised by their de novo expression of alpha-smooth muscle actin (SMA), recruitment of myofibroblasts is key to the pathogenesis of fibrosis in chronic kidney disease. Increasingly, we realise that epithelial-mesenchymal transition (EMT) may be an important source of these cells. In this study we describe a novel model of renal EMT. Rat kidney explants were finely diced on gelatin-coated Petri dishes and cultured in serum-supplemented media. Morphology and immunocytochemistry were used to identify mesenchymal (vimentin+, α-smooth muscle actin (SMA)+, desmin+), epithelial (cytokeratin+), and endothelial (RECA+) cells at various time points. Cell outgrowths were all epithelial in origin (cytokeratin+) at day 3. By day 10, 50 ± 12% (mean ± SE) of cytokeratin+ cells double-labelled for SMA, indicating EMT. Lectin staining established a proximal tubule origin. By day 17, cultures consisted only of myofibroblasts (SMA+/cytokeratin−). Explanting is a reproducible ex vivo model of EMT. The ability to modify this change in phenotype provides a useful tool to study the regulation and mechanisms of renal tubulointerstitial fibrosis.

OBJECTIVE To determine the outcome of patients with end-stage chronic renal failure treated by live donor renal transplantation at the Royal Melbourne Hospital and Royal Children's Hospital between 1973 and 1991, during which time two distinct immunosuppressive regimens were used. DESIGN Data about live donor renal transplant recipients were retrieved from the Australian and New Zealand Dialysis and Transplantation Association Registry, to which we have submitted data on all transplant recipients at six monthly intervals since the commencement of our dialysis and transplant programs. PATIENTS Seventy-two patients with chronic renal failure who received live donor renal transplants during the 19 years from February 1973 to February 1992 were included. MAIN OUTCOME MEASURES Patient survival, transplant survival, transplant function, change in prednisolone requirements, and duration of hospital stay. RESULTS The first 32 patients were treated with immunosuppressive regimens based on combinations of prednisolone and azathioprine ("dual therapy"), while the next 40 patients were treated with combinations of cyclosporin, prednisolone and azathioprine ("triple therapy"). Survival of patients in each group five years after transplantation was 97%. Actuarial graft survival at 5, 10 and 15 years in the dual therapy group was 58%, 52% and 47%, compared with a 5-year actuarial graft survival in the triple therapy group of 96%. There was no statistically significant difference in renal transplant function between the two groups within the first 6 years after transplantation. Twelve of 26 patients (46%) treated initially with triple therapy were able to stop treatment with prednisolone within 12 months of transplantation. Median hospital stay was 12 (range, 6-35) days during the period 1973-1985 and 8 (range, 5-20) days for the 1985-1992 period. CONCLUSION Live donor renal transplantation has provided a highly satisfactory means of treating patients with end-stage chronic renal failure in the short and long term. Our recent experience indicates that excellent patient and graft survival and adequate renal function can be achieved by treating live donor renal transplant recipients with a triple immunosuppressive regimen of low dose cyclosporin, prednisolone and azathioprine.

We performed a prospective randomized trial, comparing the incidence of peritonitis between a flushdisconnect (O-System, Baxter, Deerfield, IL) (OS) and a conventional (System II, Baxter) (CS) continuous ambulatory peritoneal dialysis (CAPD) method. Sixty consenting patients with no significant physical disabilities who commenced CAPD after May 1987 were entered and followed for a minimum of 12 months. Thirty were placed on the OS system and 30 were placed on CS. Age, gender, and time for training did not differ significantly. The period of observation for OS was 375 months; CS was observed for 430 months. OS patients experienced 28 episodes of peritonitis (13.4 months/patient/episode) compared with 88 (4.9 months/patient/episode) in CS (p

Asian Pacific countries include those with the highest incidence of renal failure in the world, the richest and poorest economies and unparalleled diversity of economy, culture and geography. From this come many challenges, but also a strong basis for the introduction of strategies to combat renal diseases. With a rapidly developing scientific community, Asia needs to accept the challenge of becoming a global leader in nephrology in the near future.

• Estimated glomerular filtration rate (eGFR) using the Modification of Diet in Renal Disease formula has been shown to provide unbiased and acceptably accurate estimates of measured GFR across a broad range of individuals with impaired kidney function. • eGFR is superior to measuring serum creatinine (SCr) concentration alone, more accurate than other prediction formulas (such as Cockcroft-Gault) in the setting of reduced kidney function, and more practical and reliable under most circumstances than measuring urinary creatinine clearance. • Routine eGFR reporting with requests for SCr, in concert with clinician education, has been shown to enhance the detection of chronic kidney disease (CKD), resulting in improved cardiac and renal outcomes for patients. • eGFR has been shown to effectively identify individuals at increased risk of adverse drug reactions (even when SCr concentration is in the normal range). For most drugs prescribed in primary care and for most patients of average age and body size, drug dosage adjustments based on eGFR should be similar to those based on Cockcroft-Gault. eGFR should not replace Cockcroft-Gault for determining dosage adjustments for critical-dose drugs that have a narrow therapeutic index. • eGFR has resulted in important spin-off benefits, such as standardisation of laboratory creatinine assays and enhanced public and clinician awareness of CKD. • Clinicians should be aware of the strengths, weaknesses and appropriate use of eGFR. Considerable research effort is being directed towards further refinement of eGFR.

A case of peritoneal calcification in a 44-year-old female treated with peritoneal dialysis for 13 years is reported. The patient, who had secondary hyperparathyroidism and had suffered repeated episodes of catheter-related peritonitis, presented with intraperitoneal bleeding and underwent laparotomy and excision of some of the calcified peritoneal plaques. She remains well on peritoneal dialysis 1 year later with occasional mild intraperitoneal bleeding and reduced peritoneal filtration.

Objective. The objective of this study was to design and implement an efficient pathway to ensure a smooth transition of patients with advanced chronic kidney disease to dialysis. Setting. In our dialysis service, as elsewhere, we recognized that there was an unacceptably high rate of inadequately prepared patients commencing dialysis. Knowledge of clinical practice and research-based guidelines has not in itself changed clinical practice and patient management. Main measures. To address these problems, multidisciplinary process redesign teams reviewed pre-existing arrangements by assessing current practice. The review identified critical points where problems could occur: failure to notify patients to dialysis service, late referral for vascular surgery, and inadequate pre-dialysis education. As a result of this process, we have formulated a modified and coordinated pre-dialysis programme. Results. In association with process redesign, the proportion of patients registered ‘late’ decreased from 29% in July–September 2000 (pre-implementation) to 6% in January–March 2004 ( P < 0.01) with the corresponding median time from registration to commencement of dialysis increasing from

Fibroblasts are universally recognized in situations of tubulointerstitial injury, where their presence has been shown to be a marker of disease progression. The objective of this study was to determine whether the functions of fibroblasts relevant to fibrogenesis can be modified in vitro with dipyridamole. Cells were obtained from obstructed rat renal tissue and characterized on the basis of immunohistochemical findings. Fibroblasts constituted all of the cells from passage 3. Functional parameters were measured in cells cultured with 1, 5, and 50 micromol/L dipyridamole and compared to basal parameters of cells grown in Dulbecco's modified Eagle's medium plus 10% fetal calf serum (control). Northern-blot analysis indicated that dipyridamole decreased procollagen alpha1(I) messenger ribonucleic acid expression (P.05, 50 micromol/L vs control), results that were reflected in a reduction in total collagen secretion as measured on the basis of hydroxyproline incorporation (P.001, 50 micromol/L vs control). Mitogenesis, as measured on the basis of incorporation of tritiated thymidine, was decreased in a dose-dependent fashion by dipyridamole. Likewise, 50 micromol/L dipyridamole reduced cell-population growth to 16.8% +/- 2.1% of basal growth over 3 days (P.001 vs control). Effects of dipyridamole on population growth were prevented by coincubation with a protein kinase G inhibitor peptide (P.001 vs 50 micromol/L dipyridamole; P = not significant vs control). No such effect was observed with inhibitors for protein kinase A (H-89) and protein kinase C (bisindolylmaleimide I). Consistent with a protein kinase G-dependent mechanism, immunofluorescence staining indicated that dipyridamole increased basal expression of the inducible form of nitric oxide synthase. In conclusion, the results of this study demonstrate that at clinically relevant concentrations, dipyridamole inhibits profibrotic activities of renal fibroblasts. Effects on mitogenesis are mediated through a cyclic guanosine monophosphate-protein kinase G effector pathway.

OBJECTIVE To estimate the potential increase in renal donation rates if elderly donors (those over 60 years of age) were considered. DESIGN Patients dying from acute brain damage resulting from stroke were identified using the Royal Melbourne Hospital (RMH) Stroke Service Register. Their records were retrospectively analysed to assess their eligibility as potential renal donors. SETTING One hundred and ninety-eight patients dying from acute brain damage caused by stroke at a large metropolitan teaching hospital (RMH), from May 1987 to December 1990 inclusive. PATIENT ASSESSMENT: Patients were considered "eligible", "ineligible" or "possibly eligible" (requiring further assessment) as donors according to existing strict criteria (see methods) but irrespective of age. RESULTS Of 198 stroke patients dying of brain damage, 92 satisfied the criteria of eligibility for renal donation; 51 of these were over 60 years old, yet only one became a renal donor. CONCLUSION There is good evidence that elderly donors are acceptable for renal transplantation, yet they are not being referred. The consideration of elderly stroke victims as renal donors could have a dramatic effect on decreasing transplant waiting lists, increasing recipient patient well-being, and reducing hospital costs.

This paper prospectively evaluates 33 dual lumen, right atrial catheters inserted into either an external or internal jugular vein by open operation in 29 patients, of whom 15 required haemodialysis and 14 required temporary plasma exchange. The median (range) catheter survival in the haemnodialysis and plasma exchange groups was 108 days (7–334 days) and 61 days (10–116 days), respectively. Life table analysis demonstrated that overall catheter survival was 58% at 200 days. The main causes of catheter failure were infection (four cases), poor flow (three cases) and accidental removal (one case). Another nine catheters were removed electively because of maturation of alternative methods of vascular access (five cases). completion of plasma exchange treatment (three cases), or successful renal transplantation (one case). Long-term silastic catheters, inserted into the right atrium via a jugular vein. have distinct advantages over temporary subclavian vein catheters and external arteriovenous (AV) shunts; this form of access is the method of choice for hamodialysis and plasma exchange patients who require immediate and short- to medium-term vascular access.

To the Editor: Angiotensin-converting–enzyme (ACE) inhibitors have been shown to reduce proteinuria and slow the progression of renal disease.1 Although to date angiotensin II has been the focus of...

Mechanisms of progression of chronic renal failure (CRF) have been well documented in the rat but may not be relevant in man. Factors which may modify clinical CRF include underlying disease, diet, hypertension, intercurrent events, and adverse or beneficial effects of drug therapy. It has been argued that progression in many forms of renal disease is inexorable below a certain level of renal function. In other diseases, eg primary malignant hypertension, analgesic nephropathy, function frequently improves in both the short and long term with appropriate management. Thus knowledge of the nature of the underlying disease is essential in assessing progression. The value of diet in preserving renal function has been debated, particularly the relative roles of protein and phosphate control. In our own unit, a prospective randomized study showed a benefit of protein restriction. Development of accelerated hypertension is an important cause of progression of renal disease and clinical and experimental evidence supports the view that non-accelerated hypertension is also a factor in progression, amenable to treatment. Various intercurrent events may accelerate progression and function may be lost permanently following sepsis, urinary tract obstruction, renal arterial or venous obstruction, hypotension and in some cases pregnancy. Numerous drugs can have deleterious effects on the kidney. The possibility that converting enzyme inhibitors might preserve renal function is attracting attention but in view of their side effects their place in therapy should be determined by prospective controlled studies in which the above factors are carefully considered.

We have studied the clinical features and course of adults with reflex nephropathy and/or primary vesicoureteric reflux, paying particular attention to the differences between males and females, and the presenting features that influence prognosis. In our series of 293 patients, females outnumbered males in the ratio 5:1 and most presented with urinary infection, whereas males most commonly presented with features of renal damage such as proteinuria, hypertension or renal failure. Males more commonly had bilateral scarring and persistent reflux. One hundred and forty-seven patients were followed for two years or more (range 2-19 years); deterioration in renal function occurred in 55 (37 per cent). Risk factors for a rise in plasma creatinine were, in descending order, the presence of proteinuria, an elevated plasma creatinine concentration, bilateral scarring, male sex and the presence of hypertension. Stepwise multiple regression analysis showed that the independent risk factors were proteinuria, elevated plasma creatinine concentration and hypertension; gender and the presence of persistent reflux had no independent influence on the course of renal failure.

A therapeutic trial of plasma exchange was performed in 13 patients with documented progressive IgA nephropathy. Comparison of the rate of deterioration in renal function before, during, and after plasma exchange demonstrated significant improvement during plasma exchange. Seven patients had a slowed rate of deterioration by plasma exchange, but achieved a decrease in serum creatinine level. Favourable response was correlated with rapidity of deterioration preplasma exchange (P less than 0.01) and was apparent within 4 weeks of commencing therapy in those patients who responded. There was no overall difference between the deterioration rates pre- and postplasma exchange. In patients in whom creatinine decreased on plasma exchange, the initiation of subsequent dialysis was delayed.

A variety of fixatives and four immunohistochemical technics were compared for demonstration of binding of monoclonal antibodies to cell surface antigens in tissue sections. Three recently described monoclonal antibodies, directed against the human leukocyte-common antigen (PHM 1) and antigens present on mononuclear phagocytes (PHM 2, PHM 3), were used. Antigen stability to fixation and heat were first assessed by quantitating the resultant effect on binding of the monoclonal antibodies to a macrophage cell line in vitro, using a radiolabeled second antibody. All fixatives affected their binding, but least effect was seen with formaldehyde-based fixatives and ethanol. Sections of formaldehydeand ethanol-fixed lymph nodes were then labeled with monoclonal antibodies, and four developing methods were compared: indirect immunofluorescence, indirect immunoperoxidase, 3-layer heterologous peroxidase-antiperoxidase (PAP), and a 4-layer PAP technic. The 4-layer PAP proved to be the most sensitive technic since all three antibodies were localized successfully while both indirect technics only detected PHM 1, and the heterologous PAP method was not successful with any monoclonal antibody. The best combination of specific labeling and adequate morphology was seen with periodate-lysine-paraformaldehyde (PLP) fixation and the 4-layer PAP method. (

Nine patients with various forms of glomerulonephritis were treated by repeated plasmapheresis which was combined with immunosuppression, and anticoagulant therapy. Improvement in renal function occurred in the seven patients in whom there had been rapid deterioration in renal function. Two patients with gradually deteriorating renal function failed to respond. Plasmapheresis may exert its beneficial effects both by depletion of circulating immune complexes or autoantibodies, and by depletion of important mediators of injury such as fibrinogen and complement.

During a 10 year study of women with reflux nephropathy 20 women had plasma creatinine concentrations in the range 0.2-0.4 mmol/l (2.3-4.5 mg/100 ml). Six experienced pregnancies exceeding 12 weeks' gestation. Pregnancy was associated with rapid deterioration in function in all six, resulting in end stage renal failure in four women within two years after delivery despite adequate control of blood pressure. Of the 14 women who did not have a prolonged pregnancy, four had periods of uncontrolled hypertension, all of which were related to non-compliance or loss from follow up, or both. Uncontrolled hypertension was also associated with accelerated renal failure, and all four women progressed quickly to end stage renal failure. The remaining 10 women were observed for from five to 10 years; in all 10 renal function deteriorated slowly, and none reached end stage renal failure within seven years. It is concluded that pregnancy in patients with reflux nephropathy and moderately severe renal failure has a deleterious effect on renal function.

Dietary protein intake may be an important determinant of the rate of decline in renal function in patients with chronic renal insufficiency. We conducted a prospective, randomized study of the efficacy of protein restriction in slowing the rate of progression of renal impairment. The study lasted 18 months and included 64 patients with serum creatinine concentrations ranging from 350 to 1000 micromol per liter. The patients were randomly assigned to follow either a regular diet or an isocaloric protein-restricted diet (0.4 g of protein per kilogram of the body weight per day). Blood-pressure levels and the balance between calcium and phosphate were similar in the two groups. End-stage renal failure developed in 9 of the 33 patients (27 percent) who followed the regular diet during the study, as compared with 2 of the 31 patients (6 percent) who followed the protein-restricted diet (P less than 0.05). The mean (+/- SE) glomerular filtration rate, as measured by the clearance of 51Cr bound to EDTA, fell from 0.25 +/- 0.03 to 0.10 +/- 0.05 ml per second (P less than 0.01) in the group on the regular diet, whereas it fell from 0.23 +/- 0.04 to 0.20 +/- 0.05 ml per second (P not significant) in the group on the protein-restricted diet. We conclude that dietary protein restriction is effective in slowing the rate of progression of chronic renal failure.

Four patients who presented with severe proliferative glomerulonephritis associated with linear deposition of IgG on the basement membrane have been treated by intermittent massive plasmapheresis. Two patients had all the features of Goodpasture's syndrome. In the other two cases, the characteristic renal lesion was present but there was no pulmonary involvement. In all cases, renal function improved after plasmapheresis while in two, renal function deteriorated after plasmapheresis was stopped. On of these patients responded to a second course of plasmapheresis but failed to respond to a third. This study supports previous reports of the value of plasmapheresis in patients with Goodpasture's syndrome and renal failure in whom recovery without plasmapheresis has not been recorded. The present study emphasizes the importance of continuing treatment for a period of weeks to permit prolonged remission. If treatment is withdrawn too early, rapid deterioration in renal function may result, and unless plasmapheresis is recommenced at once the renal failure may then prove irreversible.

SUMMARY Twenty-two patients with crescentic anti-GBM nephritis or Goodpasture's syndrome with renal impairment were reviewed. All patients were treated with a combination of plasma exchange and immunosuppression. Sixteen patients (73 per cent) showed improvement in renal function (> 30 per cent reduction in serum creatinine level) apparently in response to treatment, and nine patients (41 per cent) made long-term recoveries in renal function. The most important features carrying a bad prognosis were total anuria, and/or a very high percentage of glomeruli showing crescents (> 85 per cent) in the initial renal biopsy. Some patients with other so-called ‘bad’ prognostic features, including severely impaired renal function at presentation, oliguria and the need to institute dialysis had unexpected marked improvement in renal function and/or recovered renal function in the long term provided treatment with plasma exchange was begun promptly and maintained for a sufficient period to allow resolution of the disease process. Renal biopsies at the beginning and later proved to be an extremely valuable guide to the progress and outcome of the disease.