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Background Change in albuminuria has strong biological plausibility as a surrogate endpoint for progression of chronic kidney disease, but empirical evidence to support its validity is lacking. We aimed to determine the association between treatment effects on early changes in albuminuria and treatment effects on clinical endpoints and surrograte endpoints, to inform the use of albuminuria as a surrogate endpoint in future randomised controlled trials.Methods In this meta-analysis, we searched PubMed for publications in English from Jan 1, 1946, to Dec 15, 2016, using search terms including "chronic kidney disease", "chronic renal insufficiency", "albuminuria", "proteinuria", and "randomized controlled trial"; key inclusion criteria were quantifiable measurements of albuminuria or proteinuria at baseline and within 12 months of follow-up and information on the incidence of end-stage kidney disease. We requested use of individual patient data from the authors of eligible studies. For all studies that the authors agreed to participate and that had sufficient data, we estimated treatment effects on 6-month change in albuminuria and the composite clinical endpoint of treated end-stage kidney disease, estimated glomerular filtration rate of less than 15 mL/min per 1.73 m(2), or doubling of serum creatinine. We used a Bayesian mixed-effects meta-regression analysis to relate the treatment effects on albuminuria to those on the clinical endpoint across studies and developed a prediction model for the treatment effect on the clinical endpoint on the basis of the treatment effect on albuminuria.Findings We identified 41 eligible treatment comparisons from randomised trials (referred to as studies) that provided sufficient patient-level data on 29 979 participants (21 206 [71%] with diabetes). Over a median follow-up of 3.4 years (IQR 2.3-4.2), 3935 (13%) participants reached the composite clinical endpoint. Across all studies, with a meta-regression slope of 0.89 (95% Bayesian credible interval [BCI] 0.13-1.70), each 30% decrease in geometric mean albuminuria by the treatment relative to the control was associated with an average 27% lower hazard for the clinical endpoint (95% BCI 5-45%; median R-2 0.47, 95% BCI 0.02-0.96). The association strengthened after restricting analyses to patients with baseline albuminuria of more than 30 mg/g (ie, 3.4 mg/mmol; R-2 0.72, 0.05-0.99]). For future trials, the model predicts that treatments that decrease the geometric mean albuminuria to 0.7 (ie, 30% decrease in albuminuria) relative to the control will provide an average hazard ratio (HR) for the clinical endpoint of 0.68, and 95% of sufficiently large studies would have HRs between 0.47 and 0.95.Interpretation Our results support a role for change in albuminuria as a surrogate endpoint for the progression of chronic kidney disease, particularly in patients with high baseline albuminuria; for patients with low baseline levels of albuminuria this association is less certain. Copyright (c) 2019 Elsevier Ltd. All rights reserved.

Background Off-label use of rituximab in lupus nephritis is reported to be beneficial. While the optimal dose is unknown, the regimen of four intravenous doses of 375 mg/m(2) is commonly employed, despite expense and potential side-effects. Aim To investigate the response to single-dose rituximab, added to standard corticosteroids plus additional immunosuppressive agent, in refractory lupus nephritis. Methods Consecutive consenting patients with refractory lupus nephritis despite steroids plus either cyclophosphamide, mycophenolate or azathioprine were enrolled in this ethics-approved, open-label, prospective study. After baseline assessment, patients received one intravenous infusion of 375 mg/m(2) rituximab. Clinical, biochemical and serological (DsDNA, complement) responses to this dose were analysed. Complete renal response (CR) was defined as normalisation of creatinine, albumin, proteinuria and urinary RBCs and partial response (PR) as ≥50% improvement in at least one parameter, without deterioration in others. B-cell depletion was defined as peripheral CD19 lymphocyte count ≤0.05 × 10(9) /L. Results Fourteen patients were enrolled in the study. All were B-cell-depleted until 8 months post-dose. Eleven patients (79%) responded (2CR, 9PR) at a median time of 5 months, with a 6-month probability of renal response of 43%. Five patients (45%) relapsed at a median time of 17 months. DsDNA titres decreased in 69%. Side-effects were minimal. Conclusions Single-dose rituximab is effective in relapsed/refractory lupus nephritis. Longevity of B-cell depletion with single-dose rituximab is similar to that of four doses with potentially fewer side-effects.

Animal models of chronic kidney disease (CKD) approximate the human condition and are keys to understanding its pathogenesis and to developing rational treatment strategies. The ethical use of animals requires a detailed understanding of the strengths and limitations of each species and the disease model, and the way in which findings can be translated from animals to humans. While not perfect, the careful use of animal experiments offers the opportunity to examine individual mechanisms in an accelerated time frame.

The Kidney Disease: Improving Global Outcomes Clinical Practice Guideline for management of blood pressure (BP) in chronic kidney disease (CKD) supersedes the 2004 Kidney Disease Quality Outcomes Initiative document on this topic. The new guideline has been designed to assist clinical decision making in patients with CKD who are not receiving dialysis. The recommendations in the guideline acknowledge that no single BP target is optimal for all CKD patients and encourage individualization of treatment depending on age, the severity of albuminuria, and comorbidities. In general, the available evidence indicates that in CKD patients without albuminuria the target BP should be ≤140 mm Hg systolic and ≤90 mm Hg diastolic. However, in most patients with an albumin excretion rate of ≥30 mg/24 h (i.e., those with both micro- and macroalbuminuria), a lower target of ≤130 mm Hg systolic and ≤80 mm Hg diastolic is suggested. In achieving BP control, the value of lifestyle changes and the need for multiple pharmacological agents is acknowledged. Use of agents that block the renin-angiotensin-aldosterone system is recommended or suggested in all patients with an albumin excretion rate of ≥30 mg/24 h. Recommendations are almost identical in CKD patients with and without diabetes. Special considerations relevant to children and those of older age and those who have received a kidney transplant are included. Ongoing controversies in BP management in the context of CKD are highlighted along with key areas for future research.

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 Anderson-Fabry disease (AFD) is an X-linked lysosomal storage disorder resulting from the deficiency of trihexosylceramide α-galactosidase (α-Gal A). The diagnosis is often missed or delayed, and specific diagnostic tests (serum α-Gal A activity, genotyping or biopsy) are expensive and not widely available. We evaluated the diagnostic potential of urine microscopy in AFD. Methods We studied 35 male and female AFD patients across a wide phenotypic spectrum and 21 controls with other renal diseases. Fresh urine sediment was examined under phase-contrast microscopy using polarized light for Maltese cross (MC) particles, anti-CD77 antibody to detect globotriaosylceramide (GL3, the substrate of α-Gal A), and anti-podocalyxin antibody to assess podocyte excretion. Results Characteristic MC 2 particles and anti-CD77 binding within vacuolated urinary epithelial cells were both detected in AFD with high sensitivity and specificity (MC 2 detection sensitivity 100%, 95% confidence interval (CI) 85.4-100%, specificity 100%, CI 80.8-100%; anti-CD77-binding sensitivity 97.1%, CI 83.3-99.9, specificity 100%, CI 80.8-100%). Albuminuria (urinary albumin-to-creatinine ratio, ACR) correlated with quantitative particle excretion--in low, intermediate and high MC excretors, and median ACR was 1.6, 6.9 and 20.0 mg/μmol, respectively (analysis of variance P = 0.017). Podocyte staining was positive in ~50% of all AFD patients and was similar in those with and without clinical Fabry nephropathy (FN), whether or not treated with enzyme replacement. Conclusions Targeted urinary microscopy is a non-invasive, inexpensive, accessible and rapid diagnostic technique, especially applicable where serum α-Gal A activity and genotyping are not affordable or available. As the number of urinary MC 2 particles increases with rising albuminuria, the technique may also be useful in assessing FN burden.

Background: The clinical impression of Australian physicians is that systemic lupus erythematosus (SLE) is more prevalent and more severe in Asian patients than in their Caucasian counterparts. The presence and severity of lupus nephritis is a major determinant of prognosis in SLE, and largely determines disease impact. Aim: To analyse the relationships between ethnicity and the prevalence and severity of lupus nephritis (LN) in patients attending a tertiary referral centre (The Royal Melbourne Hospital (RMH)). Methods: The ethnicity of all known patients with biopsy-proven LN was determined according to three definitions of ethnicity – ancestry, country of origin and primary language spoken. The prevalence of Asian ethnicity in the LN cohort was analysed across severity class, and was compared with the prevalences of Asian ethnicity in the general population within the hospital's geographic area, and with that in the relevant RMH cohorts of inpatients and outpatients, over the same time period. Results: Within this single tertiary centre, Asian patients were disproportionately represented in both the systemic lupus erythematosus (SLE) and the LN patient groups, although the distribution of histological severity of LN was not significantly different from Caucasian patients. Conclusion: This study supports the common clinical impression that SLE is more common and more severe in the Asian-Australian population. Asian patients with SLE were more commonly diagnosed with LN. However, the spectrum of histological severity of LN was similar in Asian and Caucasian patients.

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.

Thrombotic thrombocytopenic purpura is a rare condition characterized by microangiopathic haemolytic anaemia, thrombocytopenia, altered neurology, renal impairment and fever. While plasma exchange has reduced mortality from more than 90% to between 10 and 30%, a proportion of cases fail to respond. Rituximab may be efficacious in the management of refractory cases of thrombotic thrombocytopenic purpura. We present two cases in which rituximab was used with successful outcomes. Treatment resulted in resolution of severe clinical and haematological abnormalities in both patients. There has been no relapse after 16 months follow up. Our experience supports the use of rituximab in difficult cases of TTP. Ongoing evaluation of its use is in progress at our institution.

Chronic kidney disease (CKD) is a worldwide public health problem with significant comorbidity and mortality. Improving quality of life and survival of CKD patients necessitates a large number of preventive and therapeutic interventions. To resolve these issues several organizations have developed guidelines, which are difficult to compare comprehensively. The Kidney Disease: Improving Global Outcomes website at http://kdigo.org compares five major guidelines. The section ‘compare guidelines’ covers 41 topics distributed over five major subjects: (1) general clinics; (2) hemodialysis (HD); (3) vascular access for HD; (4) peritoneal dialysis; and (5) chemistries. The tables compare guideline recommendations and the evidence levels on which they are based, with direct links to each of the guidelines. These data show that the different guideline groups tend to propose similar targets, but that nuances in the guideline statements, their rationale, and grading of evidence levels present some discrepancies, although most guidelines are based on the same literature. We conclude that there is an urgent need to harmonize existing guidelines, and for a global initiative to avoid the parallel development of conflicting guidelines on the same topics. The tables displayed on the website offer a basis for structuring this process, a procedure which has recently been initiated by a body composed of the five guideline development groups.

Urine microscopy is an important tool for the diagnosis and management of several conditions affecting the kidneys and urinary tract. In this review, we describe the automated instruments, based either on flow cytometry or digitized microscopy, that are currently in use in large clinical laboratories. These tools allow the examination of large numbers of samples in short periods. We also discuss manual urinary microscopy commonly performed by nephrologists, which we encourage. After discussing the advantages of phase contrast microscopy over bright field microscopy, we describe the advancements of urine microscopy in various clinical conditions. These include persistent isolated microscopic hematuria (which can be classified as glomerular or nonglomerular on the basis of urinary erythrocyte morphology), drug- and toxin-related cystalluria (which can be a clue for the diagnosis of acute kidney injury associated with intrarenal crystal precipitation), and some inherited conditions (eg, adenine phosphoribosyltransferase deficiency, which is associated with 2,8-dihydroxyadenine crystalluria, and Fabry disease, which is characterized by unique urinary lamellated fatty particles). Finally, we describe the utility of identifying "decoy cells" and atypical malignant cells, which can be easily done with phase contrast microscopy in unfixed samples.

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.

Studies have shown that dual therapy with angiotensin-converting enzyme inhibitors (ACEI) and either angiotensin II receptor blockers or aldosterone receptor antagonists is more effective in reducing proteinuria than either agent used alone. The questions that remain are as follows: (1) Which of these agents should be used as dual therapy with the ACEI? (2) Does a higher level of blockade of the renin-angiotensin-aldosterone system with triple therapy offer an advantage over dual blockade? A 3-mo randomized, double-blind, placebo-controlled study was performed in 41 patients with proteinuria >1.5 g/d. Four treatment groups were compared: (1) Ramipril + spironolactone placebo + irbesartan placebo, (2) ramipril + irbesartan + spironolactone placebo, (3) ramipril + irbesartan placebo + spironolactone, and (4) ramipril + irbesartan + spironolactone. The percentage change in protein excretion differed according to treatment arm (ANOVA: F(3,35) = 8.6, P < 0.001). Pair-wise comparison showed that greater reduction in protein excretion occurred in treatment regimens that incorporated spironolactone. The reduction in proteinuria at 3 mo was as follows: Group 1, 1.4%; group 2, 15.7%; group 3, 42.0%; and group 4, 48.2%. The reduction in proteinuria among patients who were taking spironolactone-containing regimens was sustained at 6 and 12 mo. This study suggests that aldosterone receptor blockade offers a valuable adjuvant treatment when used with ACEI therapy for the reduction of proteinuria. Results suggest no advantage of triple blockade over dual blockade of the renin-angiotensin-aldosterone system to reduce proteinuria.

BACKGROUND Statins are antilipidemic agents that exhibit a variety of cellular effects independent of their lipid-lowering action. A retrospective study was undertaken to establish the impact of statins on graft outcome in the first year posttransplantation. METHODS Data from patients with uniform immunosuppression (cyclosporine, mycophenolate mofetil, and prednisolone) who underwent transplantation at the authors' unit from 1997 to 2002 were reviewed. Patients prescribed statins were compared with those not on a statin. Mean change in creatinine clearance (CrCl) from 3 to 12 months posttransplantation was calculated. Histomorphometric analysis was used to quantify fractional interstitial area and collagen III deposition in matched preperfusion and 12-month protocol biopsy specimens. RESULTS Seventy-seven patients met study criteria: statin, n=44 patients; nonstatin, n=33 patients. Median time to commencing a statin was 5 weeks. At 3 months, CrCl (+/-SEM) was similar: 51.6+/-2.9 mL/min (statin) versus 51.3+/-1 mL/min (nonstatin). At 12 months, the mean change in CrCl was 4.1+/-1 mL/min (statin) compared with -2.0+/-1.8 mL/min (nonstatin), resulting in a difference of 6.13 mL/min at 12 months (P

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

Background. Some studies suggest that progression of renal disease is slower in women than in men. However, other factors that are also associated with progression of renal disease have not always been taken into account. Therefore, we undertook this analysis to explore the independent association of renal disease progression with gender.Methods. We analysed a pooled database of patients with non-diabetic renal disease enrolled in 11 randomized controlled trials evaluating the efficacy of angiotensin-converting enzyme inhibitors (ACEIs) for slowing renal disease progression. The primary end point was the combined outcome of doubling of baseline serum creatinine or onset of end-stage renal disease (ESRD). The secondary end point was the onset of ESRD alone. We performed multivariable Cox proportional hazards analysis to study the independent effect of gender on these end points after adjusting for baseline patient characteristics, and changes from baseline to follow-up systolic blood pressure (SBP) and urine protein (UP) excretion.Results. The total number of patients was 1860: 645 (35%) females and 1215 (65%) males. Mean duration of follow-up was 2.2 years. The proportions randomized to ACEI (51%), mean baseline serum creatinine (2.2 mg/dl) and mean age (52 years) were similar for both genders. Mean baseline SBP was greater in women than in men: 151 vs 147 mmHg (P Conclusions. Our findings suggest that the rate of renal disease progression may not be slower, and may even be faster in women compared with men, after adjusting for other factors associated with a faster rate of progression. We caution that most women in our database were of post-menopausal age, and thus our findings may not extend to younger women.

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.

We describe three cases of acute renal failure in young men who ingested wild mushrooms with the intent of producing hallucinations. Two cases remained dialysis dependent and, in these cases, renal biopsy revealed tubulointerstitial nephritis and fibrosis. Similar cases have been reported in other countries, but not in Australia. The most recognized mushroom nephrotoxin is orellanine, however the causative mushroom species and the actual toxin involved in these cases are unknown.

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.

Simultaneous blockade of endothelin A and B receptors in ischemic acute renal failure is detrimental to long-term kidney function. Background There is growing evidence of long-term pathological consequences following renal ischemia. Endothelin (ET) receptor antagonists have proved beneficial in the treatment of ischemic acute renal failure (IARF); however, the long-term outcomes have not been assessed in this disease. Methods Experimental IARF was induced in uninephrectomized female Sprague-Dawley rats ( N = 8) by clamping of the renal pedicle. At 24-hours postischemia, a once-only administration of drug or vehicle was given. One ischemic group received saline only (saline ischemic), and two other ischemic groups received either SB 234551 (ET A receptor antagonist, ET A group) or SB 209670 (ET A and ET B receptor antagonist, ET A /ET B group). A uninephrectomized control group was sham operated to simulate operative conditions without ischemia and was given a once-only saline infusion (sham ischemic). All groups were sacrificed at six-months postischemia. Serum creatinine was assessed daily for one week and then every four weeks. Glomerular filtration rates (GFRs), systolic blood pressure, 24-hour urine collection, and creatinine clearance were performed just prior to sacrifice. Immunohistochemistry for monocytes and macrophages (Mo and Mφ), myofibroblasts (MF, α-SMA), collagen IV, and collagen III was also evaluated. Cell kinetics were studied by immunostaining for proliferating cell nuclear antigen (PCNA) and by TUNEL. Results Urinalysis revealed significant increases in urinary protein and albumin in the ET A /ET B group when compared with all other groups. GFRs and creatinine clearance were also decreased significantly in the ET A /ET B group. Urine albumin, protein, GFR, and creatinine clearance in the ET A group, however, were not different from the sham ischemic and saline ischemic groups. Systolic blood pressure was increased in the saline ischemic group as compared with all other groups. Kidney weights were increased in all ischemic groups, but no differences were observed between the saline ischemic group and ET R antagonist-treated groups. Immunohistochemistry revealed relationships between Mo and Mφ, MF, and tubulointerstitial collagen III, where the saline ischemic and ET A /ET B groups were increased as compared with the sham ischemic and ET A groups. There was no change observed in tubulointerstitial collagen IV accumulation. The largest number of proliferating cells was demonstrated in the ET A /ET B group, whereas apoptotic cells were identified in small amounts in all groups, with the largest number being found in the saline ischemic group. Conclusions Renal ischemia appears to have long-term functional and pathological consequences that can be prevented by treatment with ET A receptor antagonists. Blockade of both ET A and ET B receptors, however, appears to be detrimental to long-term kidney function.

Progressive renal failure results from a triad of glomerulosclerosis, tubulointerstitial fibrosis and vascular sclerosis. The mechanisms by which tubules are injured, and by which the tubular epithelial cell then excites interstitial inflammation culminating in fibroblast activation and fibrosis have become increasingly understood. Most current methods to prevent progressive glomerulosclerosis would inherently prevent tubular injury and interstitial fibrosis. The behaviour and control of the renal fibroblast is being investigated, with the potential for direct interference with its functions.

Orthotopic liver transplantation is used for treatment of liver cirrhosis and organ failure due to chronic hepatitis B infection. However, in the absence of effective antiviral therapy, patients can develop recurrent hepatitis B leading to graft failure. In this report, a review is presented of several European studies that have demonstrated the efficacy of hepatitis B immunoglobulin (HBIg) in lowering the rate of recurrence or the severity of the recurrent infection. Clinical protocols and results of these studies are described in detail. Several important conclusions can be derived from the clinical results. HBIg is most effective when administered in high doses for a long time. Characteristics of the recipients, such as the presence or absence of viral DNA, can also affect the rate of recurrence. Intramuscular injection of HBIg has minimal side effects and results in reduced cost relative to intravenous injection.

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.

Background. No conventional immunosuppressive agent preferentially inhibits antibody production. Studies in experimental animals and in human cells in vitro suggested mycophenolate mofetil (MMF) might have such an effect. If this was the case in vivo it could have significant implications in terms of both MMF toxicity and the rational design of immunotherapeutic regimens. Methods. Subjects were renal transplant recipients (25 patients treated with prednisolone, cyclosporine and azathioprine, and 13 treated with prednisolone, cyclo­ sporine and MMF) and 20 normal controls. The three groups received influenza vaccination, and the anti­ body response to it was measured 4-6 weeks later using a standard haemagglutination assay. Results. MMF profoundly suppressed the humoral immune response to influenza vaccination when added to prednisolone and cyclosporine. This effect could be seen when comparing the rise in the mean titre of antibody after vaccination. It was also reflected in the number of patients mounting responses deemed to be clinically protective by either demonstrating a 4-fold rise in titre or an increase in titre to ~ 40. Conclusions. Suppression of the humoral immune response by MMF has implications for the design of immunization protocols to protect the immuno­ suppressed, and raises the possibility that MMF use may be accompanied by more or different infections than complicate more conventional immunosuppres­ sion. More importantly, consideration should be given to harnessing the relatively specific effect of MMF on antibody production to treat antibody-mediated diseases.

Chronic tubulointerstitial nephritis (TIN) is characterised histologically by tubular cell damage with interstitial changes consisting of infiltration with mononuclear cells in a matrix which is expanded with increased amounts of collagen, proteoglycans and fluid. Chronic TIN is a common final pathway towards chronic renal failure regardless of whether the primary insult is glomerular, as in glomerulonephritis or diabetes, or vascular, as in hypertension or renal ischaemia, or directly affects the tubulointerstitium. In this chapter, we therefore consider these conditions where TIN is the result of direct injury to the tubulointerstitium, focusing on the epidemiology, pathology and clinical presentation.

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.

Background Anaemia of chronic kidney disease increases the risk of death and adverse events, but can be managed using erythropoiesis stimulating agents (ESAs). However, recent evidence suggests that targeting a higher haemoglobin concentration ([Hb]) increases mortality risk, and both higher [Hb] targets and ESA doses have been implicated. Nonetheless, a causative role has not been demonstrated, and this potential relationship requires further appraisal in such a complex patient group. Methods The relationship between the haematopoietic response to ESAs and patient survival in 302 stable, prevalent dialysis patients was explored in a prospective, single-centre study. Clinical and laboratory parameters influencing mortality and ESA resistance were analysed. Patients were stratified into 5 groups, according to their [Hb] and ESA dosage, and were followed for 2 years. Results Little difference in co-morbidities between groups was identified. 73 patients died and 36 were transplanted. Initial analysis suggested a direct relationship between mortality and ESA dosage. However, Cox proportional hazards multivariate analysis demonstrated mortality risk was associated only with age (adjusted HR per year: 1.061, 95% CI 1.031-1.092), dialysis duration (adjusted HR: 1.010, 95% CI 1.004-1.016), peripheral vascular disease (adjusted HR: 1.967, 95% CI 1.083-3.576) and CRP (adjusted HR: 1.024, 95% CI 1.011-1.039). Mortality was increased in patients poorly responsive to ESAs (55.5%). Conclusion ESA dose does not appear to contribute substantially to mortality risk in dialysis patients. Instead, age and co-morbidities appear to be the critical determinants. A poor response to ESAs is a marker of overall poor health status.

A major difficulty in diagnostic urinary microscopy is the need to observe a freshly passed urine specimen. This study illustrates the use of glutaraldehyde (GA) and formaldehyde (FA) to preserve urinary sediment for diagnostic microscopy. GA and FA in whole urine cause a precipitate to form if there is a trace or more of proteinuria. This can be eliminated by centrifugation and fixation of urine sediment. Red blood cells (RBC) and casts are adequately preserved for diagnostic microscopy for at least 3 months. However, subtle changes in RBC morphology consisting of hexagonal distortion and wrinkling of cell margins are seen in some cells. White blood cells (WBC) are less reliably preserved. Diagnostic phase-contrast microscopy can be performed on urine sediment stored at room temperature for up to 3 months after fixation with GA or FA.

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.

A 34-year-old male patient with Fabry disease (OMIM 301500) commenced enzyme replacement therapy (ERT) with Agalsidase alfa, with positive clinical response. Infusion reactions, initially mild and easily managed, commenced during his 13th infusion, and continued over the next 3 years. Severity of reactions subsequently increased despite very slow infusion, extended prophylactic medication and attempted desensitisation, requiring regular intensive care unit (ICU) admissions. Facial oedema and flushing, throat tightness, headache and joint pain typically occurred 4–36 h after completion of most infusions, responding rapidly to subcutaneous adrenaline. Low titre specific IgG seroconversion was noted at 12 months, with subsequent reversion to negative after 5 years, despite persistence of infusion reactions. Specific IgE and skin testing was negative. Trial of ERT product switch to Agalsidase-beta resulted in no improvement in reactions. At 5 years, ERT was ceased in the face of recurrent ICU readmissions. In the face of progressive clinical deterioration, he underwent tracheostomy to allow recommencement of ERT. Two years later, he has clinically improved on regular attenuated dose Agalsidase-beta, administered by slow infusion in a local hospital setting.

Collagen studies in newborn rat kidneys with incomplete ureteric obstruction. Collagen studies in newborn rats with incomplete ureteric obstruction were performed to describe and quantify changes in collagen deposition resulting from urinary tract obstruction at an early developmental age. Incomplete ureteric obstruction was created in three-day-old rats by placing the left ureter in a tunnel formed by the psoas muscle, and sham-operated controls underwent a laparotomy. The rats were sacrificed at 10, 17, 24 or 31 days. Collagen types I, III, IV, and V were localized by indirect immunofluorescence microscopy, the total collagen content of the kidney was quantitated using hydroxyproline analysis, and collagen types I and III were quantitated using cyanogen bromide (CNBr) peptide analysis. Increased immunofluorescent staining for all of the collagens was found in the diffusely widened medullary interstitium of the obstructed kidney, and more focally in the cortical interstitium. Collagen types I, III and V, but not collagen type IV, were also found in bands in the interstitium at the junction of the cortex with the medulla. Increased staining for collagen type IV was found in thickened and tortuous tubular basement membranes (TBM) of the obstructed kidneys. The total collagen content of the obstructed kidney was significantly increased compared to the amounts in both the contralateral kidneys and in the kidneys from sham-operated controls at 24 and 31 days of age (P < 0.01 in each case, Wilcoxon matched pairs rank sum test and Mann Whitney U-test, respectively). The amount of collagen in the kidneys correlated with the degree of hydronephrosis (Spearman correlation test, r = 0.78, P < 0.02). CNBr peptide analysis demonstrated that over 50% of the collagen in the normal neonatal rat kidney was collagen type I and approximately 25% was collagen type III. In the obstructed kidneys most of the collagen was also collagen type I and collagen type III, although the proportion of total collagen comprised by these collagen types was decreased compared with the controls. The amount of collagen type III in the contralateral kidneys was reduced compared to that in the controls. Thus, the neonatal renal response to obstruction resulted in increased amounts of a range of collagens in the interstitium and TBM, and the extent of this response was partially related to the degree of hydronephrosis.

Reflux nephropathy is the cause of 5%-10% of dialysed end-stage renal failure. Once scarring has occurred, the prognosis depends on the severity of initial damage and the presence of proteinuria, which reflects the development of glomerulosclerosis. It is independent of ongoing reflux or infection. Histological appearances highly suggestive of reflux nephropathy can occur in radiologically normal kidneys. Duplex Doppler scans of ureteric orifices suggest these patients may have lateral insertion, suggesting past reflux. Glomerular hypertrophy correlates well with reduced renal function and severe renal scarring, but poorly with focal and segmental glomerulosclerosis, which correlates with proteinuria. Increasing attention is being paid to the tubulo-interstitium and the relationships between the cellular infiltrates (mainly T4 cells) and glomerular, tubular and vascular damage. Control of hypertension, hyperphosphataemia and a low-protein diet are the only currently widely accepted treatments for slowing progression.

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.