Defining causes of death-censored kidney allograft failure: A 5-year multicentre ANZDATA and clinical cross-sectional study.

AIM: Determining specific causes of allograft failure allows a focus on understanding and treating these conditions. Previous studies highlight chronic antibody-mediated rejection as a leading cause of late allograft failure. We sought to define causes of allograft failure in a large cohort of kidney transplant recipients across multiple centres in Australia and New Zealand, including cases previously attributed to chronic allograft nephropathy (CAN). METHODS: All death-censored allograft failures at 9 participating centres between 1 January 2014 to 31 December 2018 were included. Available clinical and biopsy data were reviewed and the "most likely" cause assigned. RESULTS: There were 642 death-censored allograft failures in the study period. Of these, 495 (77.1%) had an informative biopsy performed a median of 13.4 months (IQR 2.5-39.1 months) prior to allograft failure. Rejection of any type was the leading cause of allograft failure (47.5%), comprised chiefly of chronic antibody-mediated rejection (37.4%) and chronic T-cell mediated rejection (6.4%). Other leading causes were undifferentiated interstitial fibrosis and tubular atrophy (10.8%), late medical and surgical complications (8.1%) and recurrent or de novo glomerulonephritis (7.0%). Polyoma viral nephropathy and calcineurin inhibitor toxicity each contributed to <2%. Causes of allograft failure previously attributed to CAN (n = 419, 65.3%) had a similar distribution to the overall cohort, with 43.9% attributed to chronic antibody-mediated rejection. CONCLUSION: To prolong allograft survival, improved strategies are needed to curtail alloimmune responses. Greater understanding of the causes of undifferentiated interstitial fibrosis and tubular atrophy and potential treatments would also be of considerable benefit.

T-cell adoptive immunotherapy for BK nephropathy in renal transplantation.

INTRODUCTION: BK virus (BKPyV) nephropathy occurs in 1%-10% of kidney transplant recipients, with suboptimal therapeutic options. CASE: A 54-year-old woman received a transplant in March 2017. BKPyV was detected at 1.5 × 102  copies/mL within a month, necessitating halving of mycophenolate and addition of leflunomide. Allograft histology in December showed polyomavirus nephropathy treated with intravenous immunoglobulin and cessation of mycophenolate. In February 2018, cidofovir and ciprofloxacin were commenced. In April, tacrolimus was reduced while introducing everolimus. A second graft biopsy in August showed increasing polyoma virus infection and a subsequent biopsy in September for worsening renal function showed 30% of tubular reactivity for simian virus 40 (SV40). Allogeneic BKPyV-reactive T cells were generated from the patient's daughter and infused over 10 sessions starting late September. The fourth allograft biopsy in November 2018 demonstrated involvement of BKPyV in 50% of tubules. Allograft function continued to decline, requiring hemodialysis from December 2018. Allograft nephrectomy after 6 months showed <1% SV40 in preserved tubules and 80% interstitial fibrosis. DISCUSSION: We conclude that the T-cell adoptive immunotherapy reduced BKPyV load significantly despite extensive infection, but attendant fibrosis and tubular atrophy led to graft failure. Early intervention with T-cell therapy may prove efficacious in BKPyV nephropathy.

Real world evaluation of kidney failure risk equations in predicting progression from chronic kidney disease to kidney failure in an Australian cohort.

BACKGROUND: Chronic kidney disease progression to kidney failure is diverse, and progression may be different according to genetic aspects and settings of care. We aimed to describe kidney failure risk equation prognostic accuracy in an Australian population. METHODS: A retrospective cohort study was undertaken in a public hospital community-based chronic kidney disease service in Brisbane, Australia, which included a cohort of 406 adult patients with chronic kidney disease Stages 3-4 followed up over 5 years (1/1/13-1/1/18). Risk of progression to kidney failure at baseline using Kidney Failure Risk Equation models with three (eGFR/age/sex), four (add urinary-ACR) and eight variables (add serum-albumin/phosphate/bicarbonate/calcium) at 5 and 2 years were compared to actual patient outcomes. RESULTS: Of 406 patients followed up over 5 years, 71 (17.5%) developed kidney failure, while 112 died before reaching kidney failure. The overall mean difference between observed and predicted risk was 0.51% (p = 0.659), 0.93% (p = 0.602), and - 0.03% (p = 0.967) for the three-, four- and eight-variable models, respectively. There was small improvement in the receiver operating characteristic-area under the curve from three-variable to four-variable models: 0.888 (95%CI = 0.819-0.957) versus 0.916 (95%CI = 0.847-0.985). The eight-variable model showed marginal receiver operating characteristic-area under the curve improvement: 0.916 (95%CI = 0.847-0.985) versus 0.922 (95%CI = 0.853-0.991). The results were similar in predicting 2 year risk of kidney failure. CONCLUSIONS: The kidney failure risk equation accurately predicted progression to kidney failure in an Australian chronic kidney disease population. Younger age, male sex, lower estimated glomerular filtration rate, higher albuminuria, diabetes mellitus, tobacco smoking and non-Caucasian ethnicity were associated with increased risk of kidney failure. Cause-specific cumulative incidence function for progression to kidney failure or death, stratified by chronic kidney disease stage, demonstrated differences within different chronic kidney disease stages, highlighting the interaction between comorbidity and outcome.

Calciphylaxis, beware the ophthalmic mimic: A case series.

PURPOSE: We present two atypical cases of calciphylaxis presenting with ocular ischemic pathology - both without the hallmark cutaneous manifestations - to raise awareness of this rare yet highly disabling condition. OBSERVATIONS: We report two cases of ophthalmic calciphylaxis presenting as (1) anterior ischemic optic neuropathy (AION) and cilioretinal artery occlusion in a 76-year-old woman with pre-dialysis kidney failure, and (2) AION with contralateral central retinal artery occlusion (CRAO) in a 44-year-old man on hemodialysis. CONCLUSION AND IMPORTANCE: These cases highlight the need for judicious clinical suspicion of calciphylaxis in patients with kidney failure, presenting with microvascular ischemic ophthalmic pathology such as AION or CRAO. Confirmation with temporal artery biopsy is essential to direct targeted individualized multi-disciplinary treatment of calciphylaxis and avoid unnecessary steroid exposure in cases masquerading as giant cell arteritis (GCA).

Design expert software assisted development and evaluation of empagliflozin and sitagliptin combination tablet with improved in-vivo anti-diabetic activities.

Background: The combination of empagliflozin and sitagliptin to treat type-2 diabetes might be more economical and patient compliance with an additive improvement in glycemic control due to complementary modes of action. Aim of the study: To design, formulate and optimize an immediate tablet dosage form containing empagliflozin and sitagliptin utilizing statistically reliable study design followed by in-vitro and in-vivo testing. Method: ology: To determine the effects of copovidone (X1) and croscarmellose sodium (X2) amounts on the dependent variables of disintegration time and percent drug release, the formulation was developed using Design Expert Software v.13's direct compression method-based central composite design optimization study. The formulations' assay, dissolution, friability, hardness, weight variation, disintegration, and anti-diabetic effects were evaluated in comparison to the standard drug. The analysis included the use of high performance liquid chromatography (HPLC) assay methods. Mice were employed to investigate the efficacy of an anti-diabetic drug after they were administered a high-fat diet and two injections of streptozotocin at a dosage of 30 mg/kg BW each. Results: Formulation of F3 out of nine had all in-vitro parameters at the most satisfactory condition. It was found that assay of the best formulation is 100.99% and 100.19% for empagliflozin and sitagliptin respectively. The disintegration time of F3 was found at 5.32 min. Percentage release of empagliflozin in 30 min was found 89.05% while sitagliptin was with 93.76%. The results showed that administration of F3 significantly reduced FBG (68.61%, p < 0.0001), total cholesterol levels (70.29 ± 0.48; p < 0.0001), triglycerides (70.20 ± 0.40, p < 0.0001); HDL levels (52.50 ± 0.31; p < 0.0001), LDL levels (33.34 ± 0.28; p < 0.0001), compared to diabetic control, this effect was comparable to metformin treatment. Conclusion: The direct compression approach has been used to develop, and optimize a new combination tablet incorporating empagliflozin and sitagliptin with better dissolution rate and anti-diabetic action.

Double Pretransplant Positivity for Autoantibodies to LG3 and Angiotensin II Type 1 Receptor Is Associated With Alloimmune Vascular Injury in Kidney Transplant Recipients.

Both angiotensin II receptor autoantibodies (ATRabs) and autoantibodies to LG3 have been linked to kidney graft rejection with alloimmune vascular injury (AVI). We aimed to examine whether positivity for both anti-LG3 and ATRabs is associated with rejection with AVI in kidney transplant recipients. Methods: We performed a retrospective cohort study including consecutive kidney transplant recipients between 2013 and 2017 at a single center. The primary outcome was acute rejection with AVI (Banff grade 2 or 3 T-cell-mediated rejection and/or antibody-mediated rejection) in the first 3 mo posttransplant. The secondary outcome was death-censored allograft loss. The independent variables, anti-LG3 and ATRab, were measured pretransplant. Results: Among the 328 study participants, 68 experienced acute rejection with AVI and 23 experienced graft loss over a median follow-up of 4.5 y. In a multivariable model, double pretransplant positivity for anti-LG3/ATRab was associated with acute rejection with AVI (odds ratio: 2.73, 95% confidence interval: 1.06-7.05). We did not observe an association between double positivity for anti-LG3/ATRab and death-censored graft loss. Conclusions: Double positivity for anti-LG3/ATRabs pretransplant is associated with a higher risk of acute rejection with AVI. Whether therapies that remove antibodies could decrease that risk remains to be studied.Supplemental Visual Abtract: http://links.lww.com/TXD/A494.

Use of herbal medicines during pregnancy in a group of Bangladeshi women.

BACKGROUND: Pregnancy-related illnesses are commonly treated by herbal medicines in our country as well as around the world. OBJECTIVES: The purpose of this study was to find out how common herbal use is among Bangladeshi pregnant women, what factors influence it, and how it affects pregnancy outcomes. METHODS: Random sampling was done among women who gave birth between July and September 2021 in the maternity ward of an NGO-based clinic and were requested to participate in the face-to-face questionnaire-based survey. RESULTS: 275 women (71.80%) out of 383 used herbs during their pregnancy. Only 27.42% of women who used herbs informed their doctors, and 91.03% of users reported no side effects. Most users thought that herbs were safer than allopathic medications (71.8%). The ground behind the choosing herb was suggestion from family members or self-medication (34.73% and 31.83%, respectively). Ginger (Zingiber officinale Roscoe) (73.10%), lemon (Citrus limon L. Burm. F) (71.27%), black seed (Nigella sativa) (66.55%), mustard oil (Brassica Juncea Mane Kancor) (65.45%), and prune (Prunus domestica) (41.45%) were the most widely utilized herbs. The majority of women used herbs on a daily basis. There were statistically significant differences in several socio-demographic characteristics and pregnancy outcomes between herb users and non-users. CONCLUSIONS: The usage of herbs throughout pregnancy is quite prevalent amid Bangladeshi womenfolk, according to this study. Herbs appear to be safe when used often during pregnancy. Furthermore, physicians or medical practitioners have to play a vital role in ensuring the safe usage of herbs among pregnant women.

The HIDDEN Protocol: An Australian Prospective Cohort Study to Determine the Utility of Whole Genome Sequencing in Kidney Failure of Unknown Aetiology.

Early identification of genetic kidney disease allows personalised management, clarification of risk for relatives, and guidance for family planning. Genetic disease is underdiagnosed, and recognition of genetic disease is particularly challenging in patients with kidney failure without distinguishing diagnostic features. To address this challenge, the primary aim of this study is to determine the proportion of genetic diagnoses amongst patients with kidney failure of unknown aetiology, using whole genome sequencing (WGS). A cohort of up to 100 Australian patients with kidney failure of unknown aetiology, with onset <50 years old and approved by a panel of study investigators will be recruited via 18 centres nationally. Clinically accredited WGS will be undertaken with analysis targeted to a priority list of ∼388 genes associated with genetic kidney disease. The primary outcome will be the proportion of patients who receive a molecular diagnosis (diagnostic rate) via WGS compared with usual -care (no further diagnostic investigation). Participant surveys will be undertaken at consent, after test result return and 1 year subsequently. Where there is no or an uncertain diagnosis, future research genomics will be considered to identify candidate genes and new pathogenic variants in known genes. All results will be relayed to participants via the recruiting clinician and/or kidney genetics clinic. The study is ethically approved (HREC/16/MH/251) with local site governance approvals in place. The future results of this study will be disseminated and inform practical understanding of the potential monogenic contribution to kidney failure of unknown aetiology. These findings are anticipated to impact clinical practice and healthcare policy. Study Registration: [https://dora.health.qld.gov.au], identifier [HREC/16/MH/251].

COV-VGX: An automated COVID-19 detection system using X-ray images and transfer learning.

Coronavirus (COVID-19) has been one of the most dangerous and acute deadly diseases across the world recently. Researchers are trying to develop automated and feasible COVID-19 detection systems with the help of deep neural networks, machine learning techniques, etc. In this paper, a deep learning-based COVID-19 detection system called COV-VGX is proposed that contributes to detecting coronavirus disease automatically using chest X-ray images. The system introduces two types of classifiers, namely, a multiclass classifier that automatically predicts coronavirus, pneumonia, and normal classes and a binary classifier that predicts coronavirus and pneumonia classes. Using transfer learning, a deep CNN model is proposed to extract distinct and high-level features from X-ray images in collaboration with the pretrained model VGG-16. Despite the limitation of the COVID-19 dataset, the model is evaluated with sufficient COVID-19 images. Extensive experiments for multiclass classifier have achieved 98.91% accuracy, 97.31% precision, 99.50% recall, 98.39% F1-score, while 99.37% accuracy, 98.76% precision, 100% recall, 99.38% F1-score for binary classifier. The proposed system can contribute a lot in diagnosing COVID-19 effectively in the medical field.

Prevalence of Fabry disease in dialysis patients: Western Australia Fabry disease screening study - the FoRWARD study.

AIM: To determine the prevalence of undiagnosed Fabry Disease (FD) in Western Australian (WA) patients undergoing dialysis. BACKGROUND: FD is a multisystem X-linked lysosomal storage disease caused by deficient activity of alpha-galactosidase-A (α-GAL-A). Affected individuals are at risk of developing small-fibre neuropathy, rash, progressive kidney disease, hypertrophic cardiomyopathy and ischaemic stroke. Diagnosis is often delayed by years or even decades. Screening high risk population such as dialysis patients may identify patients with undiagnosed Fabry disease. METHODS: A cross-sectional study was undertaken of all adult patients receiving dialysis in WA, without previously known FD. After informed consent they were screened for α-GAL-A activity by dried blood spot samples. Low or inconclusive activity were repeated via Centogene in Rostock, Germany with GLA genetic analysis. Ethics approval was granted by Royal Perth Hospital Human Research Ethic Committee REG 14-136; site-specific approval was granted from appropriate authorities; ANZ Clinical Trials Registry U1111-1163-7629. RESULTS: Between February 2015 & September 2017, α-GAL-A activity was performed on 526 patients at 16 dialysis sites. Twenty-nine patients had initial low α-GAL-A; repeat testing & GLA genotyping showed no confirmed FD cases. The causes of false positive rates were thought to be secondary to impaired protein synthesis due to patient malnutrition and chronic inflammation, which is common among dialysis patients, in addition to poor sampling handling. CONCLUSION: Analysis of this dialysis population has shown a prevalence of 0% undiagnosed FD. False positives results may occur through impaired protein synthesis and sample handling.