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For over a century, acute ‘post-streptococcal glomerulonephritis’ (APSGN) was the prototypical form of bacterial infection-associated glomerulonephritis, typically occurring after resolution of infection and a distinct infection-free latent period. Other less common forms of infection-associated glomerulonephritides resulted from persistent bacteraemia in association with subacute bacterial endocarditis and shunt nephritis. However, a major paradigm shift in the epidemiology and bacteriology of infection-associated glomerulonephritides has occurred over the past few decades. The incidence of APSGN has sharply declined in the Western world, whereas the number of Staphylococcus infection-associated glomerulonephritis (SAGN) cases increased owing to a surge in drug-resistant Staphylococcus aureus infections, both in the hospital and community settings. These Staphylococcus infections range from superficial skin infections to deep-seated invasive infections such as endocarditis, which is on the rise among young adults owing to the ongoing intravenous drug use epidemic. SAGN is markedly different from APSGN in terms of its demographic profile, temporal association with active infection and disease outcomes. The diagnosis and management of SAGN is challenging because of the lack of unique histological features, the frequently occult nature of the underlying infection and the older age and co-morbidities in the affected patients. The emergence of multi-drug-resistant bacterial strains further complicates patient treatment.

The mechanisms that promote local inflammatory injury during lupus nephritis (LN) flare are largely unknown. Understanding the key immune cells that drive intrarenal inflammation will advance our knowledge of disease pathogenesis and inform the development of new therapeutics for LN management. In this study, we analyzed kidney biopsies from patients with proliferative LN and identified a novel inflammatory dendritic cell (infDC) population that is highly expressed in the LN kidney, but minimally present in healthy human kidneys. During an agnostic evaluation of immune transcript expression in the kidneys of patients with proliferative LN, the most abundantly overexpressed transcript from isolated glomeruli was FCER1G , which encodes the Fc receptor gamma chain (FcRγ). To identify the cell types expressing FcRγ that infiltrate the kidney in LN, studies were done on kidney biopsies from patients with active LN using confocal immunofluorescence (IF) microscopy. This showed that FcRγ is abundantly present in the periglomerular (PG) region of the kidney and to a lesser extent in the tubulointerstitium (TI). Further investigation of the surface markers of these cells showed that they were FcRγ + , MHC II + , CD11c + , CD163 + , CD5 − , DC-SIGN + , CD64 + , CD14 + , CD16 + , SIRPα + , CD206 − , CD68 − , CD123 − , CD3 − , and CD11b − , suggesting the cells were infDCs. Quantification of the infDCs showed an average 10-fold higher level of infDCs in the LN kidney compared to the healthy kidneys. Importantly, IF identified CD3 + T cells to be adjacent to these infDCs in the PG space of the LN kidney, whereas both cell types are minimally present in the healthy kidney. Thus, we have identified a previously undescribed DC in lupus kidneys that may interact with intrarenal T cells and play a role in the pathogenesis of kidney injury during LN flare.

Voclosporin, a novel calcineurin inhibitor approved for the treatment of adults with lupus nephritis, improved complete renal response rates in patients with lupus nephritis in a phase 2 trial. This study aimed to evaluate the efficacy and safety of voclosporin for the treatment of lupus nephritis. This multicentre, double-blind, randomised phase 3 trial was done in 142 hospitals and clinics across 27 countries. Patients with a diagnosis of systemic lupus erythematosus with lupus nephritis according to the American College of Rheumatology criteria, and a kidney biopsy within 2 years that showed class III, IV, or V (alone or in combination with class III or IV) were eligible. Patients were randomly assigned (1:1) to oral voclosporin (23·7 mg twice daily) or placebo, on a background of mycophenolate mofetil (1 g twice daily) and rapidly tapered low-dose oral steroids, by use of an interactive web response system. The primary endpoint was complete renal response at 52 weeks defined as a composite of urine protein creatinine ratio of 0·5 mg/mg or less, stable renal function (defined as estimated glomerular filtration rate [eGFR] ≥60 mL/min/1·73 m2 or no confirmed decrease from baseline in eGFR of >20%), no administration of rescue medication, and no more than 10 mg prednisone equivalent per day for 3 or more consecutive days or for 7 or more days during weeks 44 through 52, just before the primary endpoint assessment. Safety was also assessed. Efficacy analysis was by intention-to-treat and safety analysis by randomised patients receiving at least one dose of study treatment. The trial is registered with ClinicalTrials.gov, NCT03021499. Between April 13, 2017, and Oct 10, 2019, 179 patients were assigned to the voclosporin group and 178 to the placebo group. The primary endpoint of complete renal response at week 52 was achieved in significantly more patients in the voclosporin group than in the placebo group (73 [41%] of 179 patients vs 40 [23%] of 178 patients; odds ratio 2·65; 95% CI 1·64–4·27; p<0·0001). The adverse event profile was balanced between the two groups; serious adverse events occurred in 37 (21%) of 178 in the voclosporin group and 38 (21%) of 178 patients in the placebo group. The most frequent serious adverse event involving infection was pneumonia, occurring in 7 (4%) patients in the voclosporin group and in 8 (4%) patients in the placebo group. A total of six patients died during the study or study follow-up period (one [<1%] patient in the voclosporin group and five [3%] patients in the placebo group). None of the events leading to death were considered by the investigators to be related to the study treatments. Voclosporin in combination with MMF and low-dose steroids led to a clinically and statistically superior complete renal response rate versus MMF and low-dose steroids alone, with a comparable safety profile. This finding is an important advancement in the treatment of patients with active lupus nephritis. Aurinia Pharmaceuticals.

Background Systemic light chain (AL) amyloidosis is a clonal plasma‐cell neoplasm that carries a poor prognosis. Although AL amyloidosis and Multiple Myeloma (MM) can co‐exist and share various cytogenetic chromosomal abnormalities, little is known about Fluorescent in situ hybridization (FISH) and its prognostic relevance in AL amyloidosis. Aim: The study aims to evaluate the most prevalent FISH cytogenetic abnormalities in AL patients as independent prognostic factors, and assess the impact of cytogenetics on the survival of high‐risk cardiac AL patients. Materials & Methods This retrospective study reviewed 113 consecutive AL patients treated at The Ohio State University (OSU). Patients were divided into subgroups based on FISH data obtained within 90 days of diagnosis. Hyperdiploidy was defined as trisomies of at least 2 chromosomal loci. Primary endpoints were progression free survival (PFS) and overall survival (OS). Kaplan Meier curves were used to calculate PFS and OS. The log‐rank test and Cox proportional hazard models were used to test the equality of survival functions and further evaluate the differences between groups. Results FISH abnormalities were detected in 76% of patients. Patients with abnormal FISH trended toward lower overall survival (OS) (p=0.06) and progression free survival (PFS) (p=0.06). The two most prevalent aberrations were translocation t(11;14) (39%) and hyperdiploidy‐overall (38%). Hyperdiploidy‐overall was associated with worsening PFS (p=0.018) and OS (p=0.03), confirmed in multivariable analysis. Patients with del 13q most frequently had cardiac involvement (p=0.006) and was associated with increased bone marrow plasmacytosis (p=0.02). Cardiac AL patients with no FISH abnormalities had much improved OS (p=0.012) and PFS (p=0.018) Conclusions Our findings ultimately reveal the association of hyperdiploidy on survival in AL amyloidosis patients, including the high‐risk cardiac AL population. Hyperdiploidy in AL amyloidosis patients was associated with poor PFS and OS and cardiac AL patients had a strong association with del 13q.

The International Society of Nephrology/Renal Pathology Society (ISN/RPS) lupus nephritis (LN) classification is under reconsideration, given challenges with inter-rater reliability and resultant inconsistent relationship with treatment response. Integration of molecular classifiers into histologic evaluation can improve diagnostic precision and identify therapeutic targets. This study described the relationship between histological and molecular phenotypes and clinical responses in LN. Renal compartmental mRNA abundance was measured in 54 biopsy specimens from LN patients and correlated to ISN/RPS classification and individual histologic lesions. A subset of transcripts was also evaluated in sequential biopsies of a separate longitudinal cohort of 36 patients with paired samples obtained at the time of flare and at follow up. Unsupervised clustering based on mRNA abundance did not demonstrate a relationship with the (ISN/RPS) classification, nor did univariate statistical analysis. Exploratory analyses suggested a correlation with individual histologic lesions. Glomerular FN1 (fibronectin), SPP1 (secreted phosphoprotein 1), and LGALS3 (galectin 3) abundance correlated with disease activity and changed following treatment. Exploratory analyses suggested relationships between specific transcripts and individual histologic lesions, with the important representation of interferon-regulated genes. Our findings suggested that the current LN classification could be refined by the inclusion of molecular descriptors. Combining molecular and pathologic kidney biopsy phenotypes may hold promise to better classify disease and identify actionable treatment targets and merits further exploration in larger cohorts.

The kidney tubules constitute two-thirds of the cells of the kidney and account for the majority of the organ’s metabolic energy expenditure. Acute tubular injury (ATI) is observed across various types of kidney diseases and may significantly contribute to progression to kidney failure. Non-invasive biomarkers of ATI may allow for early detection and drug development. Using the SomaScan proteomics platform on 434 patients with biopsy-confirmed kidney disease, we here identify plasma biomarkers associated with ATI severity. We employ regional transcriptomics and proteomics, single-cell RNA sequencing, and pathway analysis to explore biomarker protein and gene expression and enriched biological pathways. Additionally, we examine ATI biomarker associations with acute kidney injury (AKI) in the Kidney Precision Medicine Project (KPMP) ( n  = 44), the Atherosclerosis Risk in Communities (ARIC) study ( n  = 4610), and the COVID-19 Host Response and Clinical Outcomes (CHROME) study ( n  = 268). Our findings indicate 156 plasma proteins significantly linked to ATI with osteopontin, macrophage mannose receptor 1, and tenascin C showing the strongest associations. Pathway analysis highlight immune regulation and organelle stress responses in ATI pathogenesis. Acute tubular injury (ATI) significantly contributes to many kidney diseases. Here, the authors identify several immune response and cellular stress plasma proteins linked to ATI severity and acute kidney injury, which may aid in non-invasive ATI assessment.

Staphylococcus infection-associated glomerulonephritis (SAGN) and primary IgA nephropathy (IgAN) are separate disease entities requiring different treatment approaches. However, overlapping histologic features may cause a diagnostic dilemma. An exploratory proteomic study to identify potential distinguishing biomarkers was performed on formalin fixed paraffin embedded kidney biopsy tissue, using mass spectrometry (HPLC–MS/MS) (n = 27) and immunohistochemistry (IHC) (n = 64), on four main diagnostic groups—SAGN, primary IgAN, acute tubular necrosis (ATN) and normal kidney (baseline transplant biopsies). Spectral counts modeled as a negative binomial distribution were used for statistical comparisons and in silico pathway analysis. Analysis of variance techniques were used to compare groups and the ROC curve to evaluate classification algorithms. The glomerular proteomes of SAGN and IgAN showed remarkable similarities, except for significantly higher levels of monocyte/macrophage proteins in SAGN—mainly lysozyme and S100A9. This finding was confirmed by IHC. In contrast, the tubulointerstitial proteomes were markedly different in IgAN and SAGN, with a lower abundance of metabolic pathway proteins and a higher abundance of extracellular matrix proteins in SAGN. The stress protein transglutaminase-2 (TGM2) was also significantly higher in SAGN. IHC of differentially-expressed glomerular and tubulointerstitial proteins can be used to help discriminate between SAGN and IgAN in ambiguous cases.

Immunotactoid glomerulopathy is an uncommon cause of glomerular disease that results from deposits derived from immunoglobulins. This rare disease can occur in native kidneys and in transplant patients. They are present only in 0.5% to 1.4% of native kidney biopsies. Treatment of this disease is directed at the underlying monoclonal gammopathy, infection, and B-cell lymphoproliferative disorders. Prognosis is very guarded with 50% of people developing ESRD within five years of diagnosis. We present an interesting, rare case of recurrent immunotactoid glomerulonephritis which responded appropriately to rituximab therapy.

BackgroundIn AURORA 1, adding voclosporin to mycophenolate mofetil (MMF) and low-dose steroids led to signficant reductions in proteinuria at one year in patients with lupus nephritis (LN). We report on the recently completed AURORA 2 study evaluating voclosporin compared to placebo in patients treated for an additional two years after AURORA 1.MethodsPatients with LN completing AURORA 1 were eligible to continue on the same double-blinded treatment of voclosporin or placebo in AURORA 2; all patients recieved MMF and low-dose steroids. Outcomes assessed over the three year treatment period of both studies included adverse events (AEs), eGFR, urine protein-creatinine ratio (UPCR), good renal outcome and renal flare. Good renal outcome was defined based on achievement of an adequate response (i.e. sustained reduction in UPCR to ≤0.7 mg/mg) and without renal flare (i.e. an increase to UPCR >1 mg/mg from a post-response UPCR of <0.2 mg/mg or an increase to UPCR >2 mg/mg from a post-response UPCR of 0.2 to 1.0 mg/mg), as adjudicated by a blinded Clinical Endpoints Committee.ResultsOverall rates of serious AEs in the voclosporin (26.7% of 116 patients) and control arm (28.0% of 100 patients) were similar. There were no deaths in the voclosporin arm during AURORA 2; four deaths occured in the control arm (pulmonary embolism, n=1; coronavirus infection, n=3). Mean corrected eGFR was within the normal range and stable over the study period. The reductions in UPCR achieved in AURORA 1 were maintained in AURORA 2 and significantly more patients in the voclosporin arm achieved a good renal outcome (66.4% in voclosporin vs 54.0% in control; p-value=0.045). Renal flare occurred in 24 of 101 patients with adequate response in the voclosporin arm and 19 of 73 patients in the control arm (23.8% in voclosporin vs 26.0% in control; p-value=0.662); 69.8% of all patients with renal flares completed study treatment.ConclusionsVoclosporin was well-tolerated over three years of treatment. The significant reductions in proteinuria initially achieved in AURORA 1 were maintained throughout AURORA 2 and more patients in the voclosporin arm achieved a good renal outcome. These data provide evidence of a long-term treatment benefit of voclosporin in patients with lupus nephritis.

Interferon-alpha (IFNα)-responsive gene expression is highly upregulated in the kidneys of patients with active lupus nephritis (LN). Infiltrating plasmacytoid dendritic cells (pDCs) have been postulated to be a source of intrarenal IFNα. In this study we quantified intrarenal pDCs in patients with LN and correlated infiltration with histologic activity and chronicity.Immunohistochemistry (IHC) for BDCA-2, a marker of pDCs and a subset of dendritic cells was used to visualize intrarenal pDCs. All pDCs within a biopsy were counted and the average number of glomerular pDCs and the number of tubulointerstitial pDCs per unit area were determined. The NIH activity and chronicity indices were calculated. IHC for MX1, an IFNα-inducible protein was used to characterize the interferon response.We studied 18 patients with proliferative (70% (n=12)) or proliferative + membranous LN (30%, n=6), 60% (n=11) of whom were de novo diagnoses and 40% (n=7) carried an LN diagnosis for 1–6 years. Patients were biopsied for suspected LN flare. pDCs were found mainly as individual cells within the tubulointerstitium in these kidney biopsies, and were seldom seen within glomeruli. In some biopsies, aggregations of pDCs were found in areas of tubulointerstitial inflammation or surrounding glomeruli. A median (range) of 0 (0–0.82) pDCs/glomerulus and 2.7 (0.77–49) pDC/mm2 of tubulointerstitium were found. There was no evidence of an association between tubulointerstitial pDCs and serum creatinine, proteinuria, activity index, or chronicity index. MX1 immunoreactivity was found in abundance throughout the kidney, including glomerular and tubular epithelial cells, glomerular and tubulointerstitial endothelial cells, vascular wall smooth muscle cells, and infiltrating inflammatory cells. pDCs are thought to be the major source of IFNα in the kidneys of patients with LN. If this is true, our data suggest that very few infiltrating pDCs are needed to initiate a robust IFNα response within the kidneys.