The outcomes of patients with kidney failure due to focal segmental glomerulosclerosis (FSGS) in Australia and New Zealand: A cohort study using the Australia and New Zealand Dialysis and Transplant Registry (ANZDATA).

BACKGROUND: The outcomes of patients with focal segmental glomerulosclerosis (FSGS) on kidney replacement therapy (KRT) have not been well described. This study evaluated the outcomes of patients with kidney failure due to FSGS on KRT including dialysis and kidney transplantation. METHOD AND MATERIALS: All adult patients with kidney failure who commenced KRT in Australia and New Zealand from 15th of May 1963 to 31st of December 2018 were retrospectively extracted from the Australia and New Zealand Dialysis and Transplant (ANZDATA) Registry. Outcomes of patients with FSGS were compared to those with other causes of kidney failure (non-FSGS). RESULTS: 85,052 patients commenced KRT during the study period, of whom 2991 (3.5%) were patients with FSGS. Compared to patients with non-FSGS, patients with FSGS experienced similar mortality on dialysis (adjusted hazard ratio [aHR] 0.98, 95% CI 0.90-1.06, p = 0.55) and following kidney transplantation (aHR 0.92, 95% CI 0.73-1.15, p = 0.47). The risk of first kidney allograft loss was higher in patients with FSGS (aHR 1.20, 95% CI 1.04-1.37, p = 0.01). However, when death was analysed as a competing risk, the survival in both groups was similar (sub-hazard ratio [SHR] 1.09, 95% CI 0.94-1.28, p = 0.26). Patients with FSGS had a longer waiting time for kidney transplantation (aHR 0.92, 95% CI 0.86-0.98, p = 0.02) and experienced an increased risk of disease recurrence in the allograft (aHR 1.73, 95% CI 1.35-2.21, p<0.001). Compared to patients with other forms of glomerular disease, patients with FSGS experienced similar dialysis and transplant patient survival and death-censored rate of kidney transplantation and allograft loss but higher rates of primary kidney disease recurrence. CONCLUSION: FSGS was associated with similar dialysis and transplant patient survival and death-censored first allograft loss compared to non-FSGS and other forms of glomerular disease.

Angiojet™ mechanical thrombectomy-induced hemolysis triggering blood-leak alarms.

Blood leak alarms are increasingly rare and may be triggered by rupture of the dialyzer membrane, or intravascular hemolysis. We report two patients who developed hemolysis following Angiojet™ thrombolysis and thrombectomy of thrombosed arteriovenous fistulas, triggering blood leak alarms on hemodialysis, the occurrence of which has not been reported before. AngioJet™-induced hemolysis should be considered in the differential diagnosis for blood leak alarms occurring soon after an intervention on an arterio-venous (AV) fistula.

Membranous nephropathy: Clearer pathology and mechanisms identify potential strategies for treatment.

Primary membranous nephropathy (PMN) is one of the common causes of adult-onset nephrotic syndrome and is characterized by autoantibodies against podocyte antigens causing in situ immune complex deposition. Much of our understanding of the disease mechanisms underpinning this kidney-limited autoimmune disease originally came from studies of Heymann nephritis, a rat model of PMN, where autoantibodies against megalin produced a similar disease phenotype though megalin is not implicated in human disease. In PMN, the major target antigen was identified to be M-type phospholipase A2 receptor 1 (PLA2R) in 2009. Further utilization of mass spectrometry on immunoprecipitated glomerular extracts and laser micro dissected glomeruli has allowed the rapid discovery of other antigens (thrombospondin type-1 domain-containing protein 7A, neural epidermal growth factor-like 1 protein, semaphorin 3B, protocadherin 7, high temperature requirement A serine peptidase 1, netrin G1) targeted by autoantibodies in PMN. Despite these major advances in our understanding of the pathophysiology of PMN, treatments remain non-specific, often ineffective, or toxic. In this review, we summarize our current understanding of the immune mechanisms driving PMN from animal models and clinical studies, and the implications on the development of future targeted therapeutic strategies.

A case of minimal change disease during pregnancy - benefits of early diagnosis and use of corticosteroids.

Nephrotic syndrome presenting in pregnancy is rare and poses a diagnostic and therapeutic challenge. Timing of renal biopsy is important given the increased risk of bleeding and miscarriage, and the choice of immunosuppression is limited due to the teratogenicity profiles of standard drugs. We report and discuss a case of minimal change disease diagnosed by renal biopsy during early pregnancy and treated with corticosteroids throughout the pregnancy. Prompt diagnosis and treatment of glomerular disease in pregnancy are vital to prevent poor maternal and fetal outcomes.

Predictive Models for Recurrent Membranous Nephropathy After Kidney Transplantation.

Recurrent membranous nephropathy (MN) posttransplantation affects 35% to 50% of kidney transplant recipients (KTRs) and accounts for 50% allograft loss 5 y after diagnosis. Predictive factors for recurrent MN may include HLA-D risk alleles, but other factors have not been explored with certainty. Methods: The Australian and New Zealand Dialysis and Transplant registry was used to develop 3 prediction models for recurrent MN (Group Least Absolute Shrinkage and Selection Operator [LASSO], penalized Cox regression, and random forest), which were tuned using tenfold cross-validation in a derivation cohort with complete HLA data. KTRs with MN but incomplete HLA data formed the validation cohort. Model performance was evaluated using area under the receiver operating characteristic curve (AUC-ROC). Results: One hundred ninety-nine KTRs with MN were included, and 25 (13%) had recurrent MN (median follow-up 5.9 y). The AUC-ROCs for Group LASSO, penalized Cox regression, and random forest models were 0.85 (95% confidence interval, 0.76-0.94), 0.91 (0.85-0.96), and 0.62 (0.57-0.69), respectively, in the derivation cohort, with moderate agreement in selected variables between the models (55%-70%). In their validation cohorts, the AUC-ROCs for Group LASSO and penalized Cox regression were 0.60 (0.49-0.70) and 0.73 (0.59-0.86), respectively. Variables of importance chosen by all models included recipient HLA-A2, donor HLA-DR12, donor-recipient HLA-B65, and HLA-DR12 match. Conclusions: A penalized Cox regression performed reasonably for predicting recurrent MN and was superior to Group LASSO and random forest models. These models highlighted the importance of donor-recipient HLA characteristics to recurrent MN, although validation in larger datasets is required.

Immunosuppression therapy for idiopathic membranous nephropathy: systematic review with network meta-analysis.

BACKGROUND: Idiopathic membranous nephropathy is a common cause of nephrotic syndrome in adults. The Kidney Disease Improving Global Outcomes guidelines recommend rituximab or cyclophosphamide and steroids, or calcineurin inhibitor-based therapy. However, there have been few or no head-to-head comparisons of the relative efficacy and safety of different immunosuppression regimens. We conducted a network meta-analysis to evaluate the comparative efficacy and safety of available immunosuppression strategies compared to cyclophosphamide in adults with idiopathic membranous nephropathy. METHODS: We performed a systematic search of MEDLINE, Embase and CENTRAL for randomized controlled trials in the treatment of adults with idiopathic membranous nephropathy. The primary outcome was complete remission. Secondary outcomes were kidney failure, partial remission, estimated glomerular filtration rate, doubling of serum creatinine, proteinuria, serious adverse events, discontinuation of treatment, serious infection and bone marrow suppression. RESULTS: Cyclophosphamide had uncertain effects on inducing complete remission when compared to rituximab (OR 0.35, CI 0.10-1.24, low certainty evidence), mycophenolate mofetil (OR 1.81, CI 0.69-4.71, low certainty), calcineurin inhibitor (OR 1.26, CI 0.61-2.63, low certainty) or steroid monotherapy (OR 2.31, CI 0.62-8.52, low certainty). Cyclophosphamide had a higher probability of inducing complete remission when compared to calcineurin inhibitor plus rituximab (OR 4.45, CI 1.04-19.10, low certainty). Compared to other immunosuppression strategies, there was limited evidence that cyclophosphamide had different effects on other pre-specified outcomes. CONCLUSIONS: The comparative effectiveness and safety of immunosuppression strategies compared to cyclophosphamide is uncertain in adults with idiopathic membranous nephropathy.

Treatment preferences for primary membranous nephropathy: Results of a multinational survey among nephrologists in the South Asia Pacific region.

AIM: There is no clear consensus on how best to treat primary membranous nephropathy (PMN). This study aimed to ascertain prevailing views among nephrologists on their choice of immunosuppressive agents to treat this disease. METHODS: The Australasian Kidney Trials Network conducted a multinational online survey among nephrologists from the South Asia-Pacific region to identify prescribing practices to treat PMN. Survey questions focused on the types of immunosuppressive therapies used, preferred first-line and second-line therapies, indications for starting immunosuppressive therapy, the preferred mode of combining corticosteroid and cyclophosphamide, the use of serum phospholipase A2 receptor antibody testing in clinical practice, indications for anticoagulation, and interest in participating in future clinical trials in PMN. RESULTS: One hundered fifty-five nephrologists from eight countries responded to the online survey. The majority of them were senior nephrologists from Australia and India with significant experience managing patients with PMN. The combination of cyclophosphamide and corticosteroid was the preferred first-line therapy. Of those who used this combination, only 34.8% followed the Kidney Disease Improving Global Outcomes (KDIGO) 2012 guidelines by adding intravenous methylprednisolone. The combination of calcineurin inhibitor with corticosteroid was the most common second-line therapy. Most respondents considered prophylactic anticoagulation if serum albumin was less than 25 g/L. Most nephrologists were keen to participate in a clinical trial with a control arm consisting of cyclophosphamide and corticosteroids. CONCLUSION: The combination of corticosteroid with cyclophosphamide (without intravenous methylprednisolone) is the most commonly reported first-line immunosuppressive therapy for the management of PMN.

Baseline characteristics of patients with atypical haemolytic uraemic syndrome (aHUS): The Australian cohort in a global aHUS registry.

AIMS: To describe the baseline characteristics and treatment of Australian patients diagnosed with atypical haemolytic uraemic syndrome (aHUS) reported to the Global aHUS Registry. METHODS: Descriptive analysis of the Australian cohort with aHUS (n = 106) was undertaken for demographics, disease characteristics and prior treatment with eculizumab; comparing with the global cohort (n = 1688) for certain pre-specified disease characteristics. RESULTS: In Australia, almost two-thirds of patients diagnosed with aHUS were female and over 80% of patients were Caucasians, with similar proportions reported in the global cohort. Less than 6% of patients in the Australia and global cohorts were reported to have a history of autoimmune disease (4% vs 2%, respectively; P = .21) or cancer (5% vs 5%, respectively; P = .93), conditions that have been associated with secondary HUS. In the Australian cohort, 26% had received a kidney transplant and 68% of patients had received eculizumab. Kidneys were the most common organ involvement, followed by gastrointestinal tract (26%) and cardiovascular system (19%), with 35% of patients reported to have had at least two organs involved within 6 months prior to baseline visit or entry into the registry. Complement factor H was the most common pathogenic complement gene variant in the Australian patients. CONCLUSION: Data from the aHUS registry confirms and defines region-specific disease characteristics among a selected group of Australian children and adults with aHUS reported to the registry. Ongoing and more inclusive data will provide further information about temporal trends and treatment outcomes, representing a unique opportunity for clinicians and researchers to further develop knowledge surrounding this rare disease.

Long-term outcomes of patients with end-stage kidney disease due to membranous nephropathy: A cohort study using the Australia and New Zealand Dialysis and Transplant Registry.

BACKGROUND: Clinical outcomes of patients with end-stage kidney disease (ESKD) secondary to membranous nephropathy (MN) have not been well described. This study aimed to evaluate patient and/or allograft outcomes of dialysis or kidney transplantation in patients with ESKD secondary to MN. MATERIAL AND METHODS: All adult patients with ESKD commencing renal replacement therapy in Australia and New Zealand from January 1998 to December 2010 were extracted retrospectively from ANZDATA registry on 31st December 2013. Outcomes of MN were compared to other causes of ESKD. In a secondary analysis, outcomes of MN were compared to all patients with ESKD due to other forms of glomerulonephritis. RESULTS: Of 32,788 included patients, 417 (1.3%) had MN. Compared to other causes of ESKD, MN experienced lower mortality on dialysis (adjusted hazard ratio [aHR] 0.79, 95% CI 0.68-0.92, p = 0.002) and following kidney transplantation (aHR 0.57, 95% CI 0.33-0.97, p = 0.04), had a higher risk of death-censored kidney allograft failure (aHR 1.55, 95% CI: 1.00-2.41, p = 0.05) but comparable risk of overall kidney allograft failure (aHR 1.35, 95% CI 0.91-2.01, p = 0.13). Similar results were obtained using competing-risk regression analyses. MN patients were significantly more likely to receive a kidney transplant (aHR 1.38, 95% CI 1.16-1.63, p<0.001) and to experience primary kidney disease recurrence in the allograft (aHR 4.92, 95% CI 3.02-8.01, p<0.001). Compared to other forms of glomerulonephritis, MN experienced comparable dialysis and transplant patient survival, but higher rates of kidney transplantation, primary renal disease recurrence and death-censored allograft failure. CONCLUSION: MN was associated with superior survival on dialysis and following kidney transplantation compared to patients with other causes of ESKD, and comparable patient survival compared to patients with other forms of glomerulonephritis. However, patients with MN exhibited a higher rate of death-censored allograft loss as a result of primary kidney disease recurrence.

Novel complement factor H gene mutation causing atypical haemolytic uraemic syndrome: early Eculizumab prevents acute dialysis.

We describe the clinical course and response to treatment of atypical haemolytic uraemic syndrome (aHUS) in two sisters presenting to our hospital 6 years apart with a novel complement factor H mutation that has not been described previously in literature and demonstrates the genetic complexity of this ultra-rare disease. The contrast in course and outcome of disease between the two sisters highlights the rapid evolution of management of aHUS, the importance of rapidly establishing a diagnosis, and how minimizing time to eculizumab therapy significantly reduces associated morbidity and mortality.

Arterial line versus venous line administration of low molecular weight heparin, enoxaparin for prevention of thrombosis in the extracorporeal blood circuit of patients on haemodialysis or haemodiafiltration: A randomized cross-over trial.

STUDY OBJECTIVE: The objective of the study is to compare the anti-factor Xa (AXa) level in the blood, after arterial and venous line administration of equivalent doses of enoxaparin for prevention of thrombosis in the extracorporeal blood circuit. DESIGN: The design of the study is a dual centre, prospective, open-labelled randomized crossover, 7 weeks trial. SETTING: The setting of the study is on a patient on long-term haemodialysis (HD) or haemodiafiltration (HDF) using high-flux membrane. PARTICIPANT: There were eight patients on HD and eight on HDF. INTERVENTION: Participants were randomly assigned to receive enoxaparin either through the arterial line or venous line of extracorporeal blood circuit for an initial study interval of 2 weeks, followed by 2 weeks of alternate route administration. During the run-in period of 1 week and the follow-up period of 2 weeks, enoxaparin was administered through the arterial line. OUTCOMES: The primary outcome measure was to compare AXa blood level 4 h after enoxaparin administration. The secondary outcome measures were manual compression time to stop bleeding from arteriovenous fistula, extracorporeal circuit clotting and systemic bleeding episodes. RESULTS: The mean AXa blood level, 4 h after venous circuit administration (0.58 ± 0.21 (HD), 0.82 ± 0.29 (HDF)) of enoxaparin, was significantly greater than that after arterial administration of enoxaparin (0.39 ± 0.25 (HD), 0.39 ± 0.14 (HDF) U/mL), (P < 0.001). CONCLUSION: In patients on HD or HDF, venous line administration of enoxaparin achieves greater 4 h blood AXa level compared with arterial line administration of equivalent dose. Based on this, we suggest a 25% or 50% reduction in the dose of venous line enoxaparin, compared with the dose administered through arterial line in patients receiving either HD or HDF, respectively.

Ten common mistakes in the management of lupus nephritis.

Management of patients with lupus nephritis can be complex and challenging. We suggest that there are some widely held misconceptions about lupus, and unfortunately, these underpin the treatment of many patients. There is little evidence to support the common assumption that intravenous pulse cyclophosphamide is the best treatment for lupus nephritis. Although there is much focus on which immunosuppressive agent to use, too little attention is paid to the proper dose and duration of corticosteroids and concomitant therapy with antimalarial agents. Many clinicians reflexively perform kidney biopsies when these biopsies may be high risk and not influence therapy. There is little emphasis on or awareness of nonadherence to therapy, which is an underappreciated cause of treatment resistance. Resolution of proteinuria and hematuria can take a long time, and immunotherapy should not be intensified based on urine sediment alone. Furthermore, the intensity of the immunosuppression must be considered in the context of lupus nephritis class and duration of kidney damage. Finally, clinicians are aware of the risks of pregnancy in the face of active lupus, but assume that their patients also are aware of this and forget to discuss this with them. With a combined experience of more than 50 years in managing children and adults with lupus, we offer our impression of recurrent mistakes in the management of lupus in general, with a focus on treatment of lupus nephritis.

Glomerular diseases: FSGS.

FSGS is a lesion, not a disease. The separation into primary FSGS (a result of immunologic-mediated injury) versus secondary FSGS (related to a variety of causes) is often difficult. Even when this particular issue is carefully evaluated, the therapeutic implications are not always apparent. Newer literature on both biomarker discovery and on the genetic basis of FSGS is reviewed in this context. In addition, the thorny implications of obesity as it relates to the FSGS lesion are discussed. An overall practical algorithmic approach to the management and treatment of the FSGS lesion that integrates these controversial overlap areas is suggested.

Effects of uric acid-lowering therapy on renal outcomes: a systematic review and meta-analysis.

BACKGROUND: Non-randomized studies suggest an association between serum uric acid levels and progression of chronic kidney disease (CKD). The aim of this systematic review is to summarize evidence from randomized controlled trials (RCTs) concerning the benefits and risks of uric acid-lowering therapy on renal outcomes. METHODS: Medline, Excerpta Medical Database and Cochrane Central Register of Controlled Trials were searched with English language restriction for RCTs comparing the effect of uric acid-lowering therapy with placebo/no treatment on renal outcomes. Treatment effects were summarized using random-effects meta-analysis. RESULTS: Eight trials (476 participants) evaluating allopurinol treatment were eligible for inclusion. There was substantial heterogeneity in baseline kidney function, cause of CKD and duration of follow-up across these studies. In five trials, there was no significant difference in change in glomerular filtration rate from baseline between the allopurinol and control arms [mean difference (MD) 3.1 mL/min/1.73 m2, 95% confidence intervals (CI) -0.9, 7.1; heterogeneity χ2=1.9, I2=0%, P=0.75]. In three trials, allopurinol treatment abrogated increases in serum creatinine from baseline (MD -0.4 mg/dL, 95% CI -0.8, -0.0 mg/dL; heterogeneity χ2=3, I2=34%, P=0.22). Allopurinol had no effect on proteinuria and blood pressure. Data for effects of allopurinol therapy on progression to end-stage kidney disease and death were scant. Allopurinol had uncertain effects on the risks of adverse events. CONCLUSIONS: Uric acid-lowering therapy with allopurinol may retard the progression of CKD. However, adequately powered randomized trials are required to evaluate the benefits and risks of uric acid-lowering therapy in CKD.