Risk Stratification to Predict Renal Survival in Anti-Glomerular Basement Membrane Disease.

SIGNIFICANCE STATEMENT: Most patients with anti-glomerular basement membrane (GBM) disease present with rapidly progressive glomerulonephritis, and more than half develop ESKD. Currently, no tools are available to aid in the prognostication or management of this rare disease. In one of the largest assembled cohorts of patients with anti-GBM disease (with 174 patients included in the final analysis), the authors demonstrated that the renal risk score for ANCA-associated vasculitis is transferable to anti-GBM disease and the renal histology is strongly predictive of renal survival and recovery. Stratifying patients according to the percentage of normal glomeruli in the kidney biopsy and the need for RRT at the time of diagnosis improves outcome prediction. Such stratification may assist in the management of anti-GBM disease. BACKGROUND: Prospective randomized trials investigating treatments and outcomes in anti-glomerular basement membrane (anti-GBM) disease are sparse, and validated tools to aid prognostication or management are lacking. METHODS: In a retrospective, multicenter, international cohort study, we investigated clinical and histologic parameters predicting kidney outcome and sought to identify patients who benefit from rescue immunosuppressive therapy. We also explored applying the concept of the renal risk score (RRS), currently used to predict renal outcomes in ANCA-associated vasculitis, to anti-GBM disease. RESULTS: The final analysis included 174 patients (out of a total of 191). Using Cox and Kaplan-Meier methods, we found that the RRS was a strong predictor for ESKD. The 36-month renal survival was 100%, 62.4%, and 20.7% in the low-risk, moderate-risk, and high-risk groups, respectively. The need for renal replacement therapy (RRT) at diagnosis and the percentage of normal glomeruli in the biopsy were independent predictors of ESKD. The best predictor for renal recovery was the percentage of normal glomeruli, with a cut point of 10% normal glomeruli providing good stratification. A model with the predictors RRT and normal glomeruli ( N ) achieved superior discrimination for significant differences in renal survival. Dividing patients into four risk groups led to a 36-month renal survival of 96.4% (no RRT, N ≥10%), 74.0% (no RRT, N <10%), 42.3% (RRT, N ≥10%), and 14.1% (RRT, N <10%), respectively. CONCLUSIONS: These findings demonstrate that the RRS concept is transferrable to anti-GBM disease. Stratifying patients according to the need for RRT at diagnosis and renal histology improves prediction, highlighting the importance of normal glomeruli. Such stratification may assist in the management of anti-GBM disease. PODCAST: This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/JASN/2023_02_27_JASN0000000000000060.mp3.

Identification of an Altered Matrix Signature in Kidney Aging and Disease.

BACKGROUND: Accumulation of extracellular matrix in organs and tissues is a feature of both aging and disease. In the kidney, glomerulosclerosis and tubulointerstitial fibrosis accompany the decline in function, which current therapies cannot address, leading to organ failure. Although histologic and ultrastructural patterns of excess matrix form the basis of human disease classifications, a comprehensive molecular resolution of abnormal matrix is lacking. METHODS: Using mass spectrometry-based proteomics, we resolved matrix composition over age in mouse models of kidney disease. We compared the changes in mice with a global characterization of human kidneymatrix during aging and to existing kidney disease datasets to identify common molecular features. RESULTS: Ultrastructural changes in basement membranes are associated with altered cell adhesion and metabolic processes and with distinct matrix proteomes during aging and kidney disease progression in mice. Within the altered matrix, basement membrane components (laminins, type IV collagen, type XVIII collagen) were reduced and interstitial matrix proteins (collagens I, III, VI, and XV; fibrinogens; and nephronectin) were increased, a pattern also seen in human kidney aging. Indeed, this signature of matrix proteins was consistently modulated across all age and disease comparisons, and the increase in interstitial matrix was also observed in human kidney disease datasets. CONCLUSIONS: This study provides deep molecular resolution of matrix accumulation in kidney aging and disease, and identifies a common signature of proteins that provides insight into mechanisms of response to kidney injury and repair.

Intragraft gene expression in native kidney BK virus nephropathy versus T cell-mediated rejection: Prospects for molecular diagnosis and risk prediction.

Novel tools are needed to improve diagnostic accuracy and risk prediction in BK virus nephropathy (BKVN). We assessed the utility of intragraft gene expression testing for these purposes. Eight hundred genes were measured in 110 archival samples, including a discovery cohort of native kidney BKVN (n = 5) vs pure T cell-mediated rejection (TCMR; n = 10). Five polyomavirus genes and seven immune-related genes (five associated with BKVN and two associated with TCMR) were significantly differentially expressed between these entities (FDR < 0.05). These three sets of genes were further evaluated in samples representing a spectrum of BK infection (n = 25), followed by a multicenter validation cohort of allograft BKVN (n = 60) vs TCMR (n = 10). Polyomavirus 5-gene set expression reliably distinguished BKVN from TCMR (validation cohort AUC = 0.992), but the immune gene sets demonstrated suboptimal diagnostic performance (AUC ≤ 0.720). Within the validation cohort, no significant differences in index biopsy gene expression were identified between BKVN patients demonstrating resolution (n = 35), persistent infection (n = 14) or de novo rejection (n = 11) 6 months following a standardized reduction in immunosuppression. These results suggest that, while intragraft polyomavirus gene expression may be useful as an ancillary diagnostic for BKVN, assessment for concurrent TCMR and prediction of clinical outcome may not be feasible with current molecular tools.

Occupational therapy delivered by specialists versus non-specialists for people with schizophrenia.

BACKGROUND: Schizophrenia is a severe mental health condition that is characterised by positive symptoms, such as hallucinations and delusions; negative symptoms, such as flattened affect, thought disorder (disrupted speech), and lack of motivation; and cognitive symptoms, such as problems with memory and attention. Schizophrenia can occur as an isolated episode, or as a recurring cycle of remission and relapse, and is associated with impairment in psychosocial and occupational functioning.Although antipsychotic drugs are the main treatment for people with schizophrenia, in most countries mental health services usually provide a range of add-on interventions, including occupational therapy. This is a complex intervention designed to support and enable continued participation in daily life through engagement in activities and occupations meaningful to the individual. Occupational therapists are professionals trained to deliver therapy where the emphasis is on improving occupational function and participation rather than treating symptoms, and uses a wide range of methods based on the needs of individuals. However, similar interventions may also be delivered by staff not trained as occupational therapists. OBJECTIVES: To examine the effects of occupational therapy delivered by occupational therapists compared to occupational therapy delivered by any other person for people with schizophrenia. SEARCH METHODS: We searched the Cochrane Schizophrenia Group's Study-Based Register of Trials (including trial registers) on 4 November 2016 and 26 July 2018. SELECTION CRITERIA: All randomised controlled trials evaluating the functional or clinical outcomes of occupational therapy, or both, for people with schizophrenia delivered by occupational therapists compared with occupational therapy for people with schizophrenia delivered by anyone other than occupational therapists. DATA COLLECTION AND ANALYSIS: Review authors independently inspected citations, selected studies, extracted data, and appraised study quality. MAIN RESULTS: The search yielded 1633 records. Of these, we retrieved 17 full-text reports (14 studies) for further scrutiny, which we subsequently excluded as they did not meet our inclusion criteria. AUTHORS' CONCLUSIONS: Currently there are no randomised controlled trials comparing delivery of occupational therapy for people diagnosed with schizophrenia by occupational therapists with delivery of similar interventions by anyone other than occupational therapists. Research studies employing methodologically robust trial designs are needed to establish whether or not there are better outcomes for people with a diagnosis of schizophrenia with occupational therapy that is delivered by trained occupational therapists.

Exploring the Role of Mental Imagery in the Experience of Self-injury: An Interpretative Phenomenological Analysis.

BACKGROUND: Research has implicated causal, mediating and meaningful roles for mental imagery in the experience of psychological distress, including self-injury. AIMS: The present study aimed to further the understanding of this relationship through exploring the lived experiences of mental imagery from the perspective of those who self-injure. METHOD: This study employed an inductive qualitative design using semi-structured interviews and Interpretative Phenomenological Analysis (IPA). Ten participants were recruited from universities in North West England. RESULTS: Three main themes were identified from the analysis: (i) The origins and precipitants of self-injurious imagery; (ii) What it is like to experience self-injurious imagery; and (iii) The meaning and interpretation of self-injurious imagery. CONCLUSIONS: The study findings indicate that mental imagery is an important experience for those who self-injure. Clinical and research implications of the findings are discussed.

Management of early graft candidiasis in a kidney transplant recipient.

Balancing adequate immunosuppression with the risk of infection after renal transplantation remains a challenge. The presence of comorbidities adds to the challenge. Although infrequent, invasive fungal infections result in high morbidity and mortality risk in renal transplant recipients. This can be attributed to the intense immunosuppression in the first 6 months after renal transplantation, minimal symptomatology and the high mortality associated with fungal infections.Due to minimal available evidence, clinical judgement guides management of graft candidiasis. There is a need to develop evidence-based management guidelines for the treatment of fungal infections in renal transplants. Here, we report a case of early-onset candidiasis in a transplanted kidney and present the histological findings, multidisciplinary discussions and treatment given.

A Case of IgG4-Related Disease and Membranous Nephropathy Associated with Thrombospondin Type-1 Domain-Containing 7A.

Background: IgG4-related disease (IgG4-RD) is a systemic multi-organ inflammatory disorder which affects the kidney 20% of the time. Patients with intrinsic IgG4-related kidney disease (IgG4-RKD) often have tubulointerstitial nephritis (TIN) whereas glomerular lesions like membranous nephropathy (MN) are less common. Antibodies to thrombospondin type-1 domain-containing 7A (THSD7A) have been described in primary MN, but never in association with IgG4-RKD. Case Report: We report the first case of IgG4-MN associated with THSD7A antibodies in serum and positivity on glomerular staining, in a 57-year-old Caucasian male with IgG4-RD affecting the pancreas, liver, lacrimal glands, extraocular muscles, and kidneys. This patient presented initially with glomerular disease including significant proteinuria consistent with MN. Glomerular staining for THSD7A antigen and serum THSD7A antibody titres was positive. Treatment with corticosteroids and cyclophosphamide successfully induced remission with resolution of proteinuria, and improvement in renal function. However, despite maintenance azathioprine, the patient relapsed 39 months later. On relapse, there was minimal proteinuria but a significant rise in creatinine. Subsequent renal biopsy showed less glomerular disease and instead a TIN pattern. Subsequent treatment with Rituximab and corticosteroids successfully induced remission. Conclusion: The role of THSD7A autoantibodies in MN is emerging, and as both IgG4-MN and presence of THSD7A antibody are rare occurrences in themselves, we speculate that there may be an undiscovered association between THSD7A and IgG4-MN. Routine testing for THSD7A in IgG4-MN may help to identify the link.

Health Justice for LGBT Youths: Combining Public Health and Human Rights.

As a socially marginalized group, LGBT youths experience elevated rates of physical and mental health problems that are leading causes of mortality due to a variety of factors. Minority stress theory links exposure to stigma with health outcome disparities. Structural stigma including biased laws, policies, and societal norms predicts approximately 20% of elevated suicidality among LGBT youths. Comprehensive public health efforts to reduce mental health disparities among LGBT youths need to address structural stigma. An interdisciplinary Health Justice approach is described, in which public health evidence is integrated with human rights principles in keeping with the bioethical Justice Imperative. In this approach, epidemiological research is used to inform public health efforts to address health disparities in LGBT youths due to structural stigma in a way that is (1) empirical; (2) aimed at basic goals of reducing morbidity and mortality; (3) applicable to diverse cultural contexts; (4) capable of amending stigma-related power and associated health inequities; and (5) guided by human rights principles. By applying human rights principles to public health needs, this approach will help to achieve health equity for LGBT youths.

Gene Expression Profiling in Kidney Transplants with Immune Checkpoint Inhibitor-Associated Adverse Events.

BACKGROUND AND OBJECTIVES: Immune checkpoint inhibitors are increasingly used to treat various malignancies, but their application in patients with kidney transplants is complicated by high allograft rejection rates. Immune checkpoint inhibitor-associated rejection is a novel, poorly understood entity demonstrating overlapping histopathologic features with immune checkpoint inhibitor-associated acute interstitial nephritis, which poses a challenge for diagnosis and clinical management. We sought to improve the understanding of these entities through biopsy-based gene expression analysis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: NanoString was used to measure and compare the expression of 725 immune-related genes in 75 archival kidney biopsies, including a 25-sample discovery cohort comprising pure T cell-mediated rejection and immune checkpoint inhibitor-associated acute interstitial nephritis and an independent 50-sample validation cohort comprising immune checkpoint inhibitor-associated acute interstitial nephritis, immune checkpoint inhibitor-associated T cell-mediated rejection, immune checkpoint inhibitor-associated crescentic GN, drug-induced acute interstitial nephritis, BK virus nephropathy, and normal biopsies. RESULTS: Significant molecular overlap was observed between immune checkpoint inhibitor-associated acute interstitial nephritis and T cell-mediated rejection. Nevertheless, IFI27, an IFN-α-induced transcript, was identified and validated as a novel biomarker for differentiating immune checkpoint inhibitor-associated T cell-mediated rejection from immune checkpoint inhibitor-associated acute interstitial nephritis (validation cohort: P<0.001, area under the receiver operating characteristic curve =100%, accuracy =86%). Principal component analysis revealed heterogeneity in inflammatory gene expression patterns within sample groups; however, immune checkpoint inhibitor-associated T cell-mediated rejection and immune checkpoint inhibitor-associated acute interstitial nephritis both demonstrated relatively more molecular overlap with drug-induced acute interstitial nephritis than T cell-mediated rejection, suggesting potential dominance of hypersensitivity mechanisms in these entities. CONCLUSIONS: These results indicate that, although there is significant molecular similarity between immune checkpoint inhibitor-associated rejection and acute interstitial nephritis, biopsy-based measurement of IFI27 gene expression represents a potential biomarker for differentiating these entities.

Tuning of functional heme reduction potentials in Shewanella fumarate reductases.

The fumarate reductases from S. frigidimarina NCIMB400 and S. oneidensis MR-1 are soluble and monomeric enzymes located in the periplasm of these bacteria. These proteins display two redox active domains, one containing four c-type hemes and another containing FAD at the catalytic site. This arrangement of single-electron redox co-factors leading to multiple-electron active sites is widespread in respiratory enzymes. To investigate the properties that allow a chain of single-electron co-factors to sustain the activity of a multi-electron catalytic site, redox titrations followed by NMR and visible spectroscopies were applied to determine the microscopic thermodynamic parameters of the hemes. The results show that the redox behaviour of these fumarate reductases is similar and dominated by a strong interaction between hemes II and III. This interaction facilitates a sequential transfer of two electrons from the heme domain to FAD via heme IV.

Octaheme tetrathionate reductase is a respiratory enzyme with novel heme ligation.

We have isolated a soluble cytochrome from Shewanella oneidensis that contains eight covalently attached heme groups and determined its crystal structure. One of these hemes exhibits novel ligation of the iron atom by the epsilon-amino group of a lysine residue, despite its attachment via a typical CXXCH motif. This heme is most likely the active site for tetrathionate reduction, a reaction catalyzed efficiently by this enzyme.

The solution structure of a tetraheme cytochrome from Shewanella frigidimarina reveals a novel family structural motif.

The bacteria belonging to the genus Shewanella are facultative anaerobes that utilize a variety of terminal electron acceptors which includes soluble and insoluble metal oxides. The tetraheme c-type cytochrome isolated during anaerobic growth of Shewanella frigidimarina NCIMB400 ( Sfc) contains 86 residues and is involved in the Fe(III) reduction pathways. Although the functional properties of Sfc redox centers are quite well described, no structures are available for this protein. In this work, we report the solution structure of the reduced form of Sfc. The overall fold is completely different from those of the tetraheme cytochromes c 3 and instead has similarities with the tetraheme cytochrome recently isolated from Shewanella oneidensis ( Soc). Comparison of the tetraheme cytochromes from Shewanella shows a considerable diversity in their primary structure and heme reduction potentials, yet they have highly conserved heme geometry, as is the case for the family of tetraheme cytochromes isolated from Desulfovibrio spp.

An octaheme c-type cytochrome from Shewanella oneidensis can reduce nitrite and hydroxylamine.

A c-type cytochrome from Shewanella oneidensis MR-1, containing eight hemes, has been previously designated as an octaheme tetrathionate reductase (OTR). The structure of OTR revealed that the active site contains an unusual lysine-ligated heme, despite the presence of a CXXCH motif in the sequence that would predict histidine ligation. This lysine ligation has been previously observed only in the pentaheme nitrite reductases, suggesting that OTR may have a possible role in nitrite reduction. We have now shown that OTR is an efficient nitrite and hydroxylamine reductase and that ammonium ion is the product. These results indicate that OTR may have a role in the biological nitrogen cycle.

Fumarate reductase: structural and mechanistic insights from the catalytic reduction of 2-methylfumarate.

The soluble fumarate reductase (FR) from Shewanella frigidimarina can catalyse the reduction of 2-methylfumarate with a k(cat) of 9.0 s(-1) and a K(M) of 32 microM. This produces the chiral molecule 2-methylsuccinate. Here, we present the structure of FR to a resolution of 1.5 A with 2-methylfumarate bound at the active site. The mode of binding of 2-methylfumarate allows us to predict the stereochemistry of the product as (S)-2-methylsuccinate. To test this prediction we have analysed the product stereochemistry by circular dichroism spectroscopy and confirmed the production of (S)-2-methylsuccinate.

The role of Thr268 and Phe393 in cytochrome P450 BM3.

In flavocytochrome P450 BM3 there are several active site residues that are highly conserved throughout the P450 superfamily. Of these, a phenylalanine (Phe393) has been shown to modulate heme reduction potential through interactions with the implicitly conserved heme-ligand cysteine. In addition, a distal threonine (Thr268) has been implicated in a variety of roles including proton donation, oxygen activation and substrate recognition. Substrate binding in P450 BM3 causes a shift in the spin state from low- to high-spin. This change in spin-state is accompanied by a positive shift in the reduction potential (DeltaE(m) [WT+arachidonate (120 microM)]=+138 mV). Substitution of Thr268 by an alanine or asparagine residue causes a significant decrease in the ability of the enzyme to generate the high-spin complex via substrate binding and consequently leads to a decrease in the substrate-induced potential shift (DeltaE(m) [T268A+arachidonate (120 microM)]=+73 mV, DeltaE(m) [T268N+arachidonate (120 microM)]=+9 mV). Rate constants for the first electron transfer and for oxy-ferrous decay were measured by pre-steady-state stopped-flow kinetics and found to be almost entirely dependant on the heme reduction potential. More positive reduction potentials lead to enhanced rate constants for heme reduction and more stable oxy-ferrous species. In addition, substitutions of the threonine lead to an increase in the production of hydrogen peroxide in preference to hydroxylated product. These results suggest an important role for this active site threonine in substrate recognition and in maintaining an efficiently functioning enzyme. However, the dependence of the rate constants for oxy-ferrous decay on reduction potential raises some questions as to the importance of Thr268 in iron-oxo stabilisation.

Family members' experience of seeking help for first-episode psychosis on behalf of a loved one: a meta-synthesis of qualitative research.

AIM: Family members often play a vital role in seeking help for loved ones experiencing first-episode psychosis. Understanding this experience is crucial in facilitating the help-seeking process. Qualitative research offers valuable insight into the lived experience of family members who seek help on behalf of a loved one experiencing first-episode psychosis. METHOD: The current research presents a systematic review of qualitative studies exploring the family member experience of seeking help for first-episode psychosis. RESULTS: A meta-synthesis of 13 qualitative studies has revealed four themes relating to family members' experience of seeking help for first-episode psychosis. These include a sense of not knowing, the reaching of crisis point, the impact upon the family member and the mediating role of interactions with others. A further synthesis of translation captures the interaction of these themes within this experience. CONCLUSIONS: The findings provide a novel insight into this experience, suggesting implications for clinical practice. These include a focus upon the facilitation of early positive interactions with family members and for first-episode psychosis to be presented to families in a normalizing manner. The need for future research that examines the experience of those who do not seek help from health services is discussed.

Trauma and psychosis: The mediating role of self-concept clarity and dissociation.

Childhood trauma (CT) and psychosis may be associated. Drawing on the dissociation and social psychological literature, the current study examined the mediating role of structural aspects of self in explaining the relationship between childhood trauma and psychosis. Twenty-nine individuals with psychosis were compared with 31 healthy volunteers regarding childhood trauma, dissociation and self-concept clarity (SCC). High rates of maltreatment were found in the psychosis sample. Additionally, clinical participants reported more dissociation and less self-concept clarity. Mediational analyses were carried out on pooled data from across both clinical and non-clinical samples. These suggested that the influence of physical neglect in increasing the likelihood of experiencing psychosis was explicable through the effects of increased dissociation. Self-concept clarity mediated the relationship between psychosis and total childhood trauma, emotional abuse, physical abuse, emotional and physical neglect. Furthermore, dissociation and self-concept clarity were strongly correlated providing evidence that they may form a unitary underlying concept of 'self-concept integration'. The study provides further evidence of the link between childhood trauma and psychosis. Self-concept integration may be adversely affected by negative childhood experiences, which increases psychosis risk. Methodological limitations, clinical implications and suggestions for future research are considered.

Determination of the orientation of the axial ligands and of the magnetic properties of the haems in the tetrahaem ferricytochrome from Shewanella frigidimarina.

The unambiguous assignment of the nuclear magnetic resonance (NMR) signals of the alpha-substituents of the haems in the tetrahaem cytochrome isolated from Shewanella frigidimarina NCIMB400, was made using a combination of homonuclear and heteronuclear experiments. The paramagnetic (13)C shifts of the nuclei directly bound to the porphyrin of each haem group were analysed in the framework of a model for the haem electronic structure. The analysis yields g-tensors for each haem, which allowed the assignment of some electron paramagnetic resonance (EPR) signals to specific haems, and the orientation of the magnetic axes relative to each haem to be established. The orientation of the axial ligands of the haems was determined semi-empirically from the NMR data, and the structural results were compared with those of the homologous tetrahaem cytochrome from Shewanella oneidensis MR-1 showing significant similarities between the two proteins.

Redox behaviour of the haem domain of flavocytochrome c3 from Shewanella frigidimarina probed by NMR.

Flavocytochrome c3 from Shewanella frigidimarina (fcc3) is a tetrahaem periplasmic protein of 64 kDa with fumarate reductase activity. This work reports the first example of NMR techniques applied to the assignment of the thermodynamic order of oxidation of the four individual haems for such large protein, expanding its applicability to a wide range of proteins. NMR data from partially and fully oxidised samples of fcc3 and a mutated protein with an axial ligand of haem IV replaced by alanine were compared with calculated chemical shifts, allowing the structural assignment of the signals and the unequivocal determination of the order of oxidation of the haems. As oxidation progresses the fcc3 haem domain is polarised, with haems I and II much more oxidised than haems III and IV, haem IV being the most reduced. Thus, during catalysis as an electron is taken by the flavin adenosine dinucleotide from haem IV, haem III is eager to re-reduce haem IV, allowing the transfer of two electrons to the active site.