Mitochondrial Dysfunction in Systemic Lupus Erythematosus with a Focus on Lupus Nephritis.

Systemic lupus erythematosus (SLE) is an autoimmune disease affecting mostly women of child-bearing age. Immune dysfunction in SLE results from disrupted apoptosis which lead to an unregulated interferon (IFN) stimulation and the production of autoantibodies, leading to immune complex formation, complement activation, and organ damage. Lupus nephritis (LN) is a common and severe complication of SLE, impacting approximately 30% to 40% of SLE patients. Recent studies have demonstrated an alteration in mitochondrial homeostasis in SLE patients. Mitochondrial dysfunction contributes significantly to SLE pathogenesis by enhancing type 1 IFN production through various pathways involving neutrophils, platelets, and T cells. Defective mitophagy, the process of clearing damaged mitochondria, exacerbates this cycle, leading to increased immune dysregulation. In this review, we aim to detail the physiopathological link between mitochondrial dysfunction and disease activity in SLE. Additionally, we will explore the potential role of mitochondria as biomarkers and therapeutic targets in SLE, with a specific focus on LN. In LN, mitochondrial abnormalities are observed in renal cells, correlating with disease progression and renal fibrosis. Studies exploring cell-free mitochondrial DNA as a biomarker in SLE and LN have shown promising but preliminary results, necessitating further validation and standardization. Therapeutically targeting mitochondrial dysfunction in SLE, using drugs like metformin or mTOR inhibitors, shows potential in modulating immune responses and improving clinical outcomes. The interplay between mitochondria, immune dysregulation, and renal involvement in SLE and LN underscores the need for comprehensive research and innovative therapeutic strategies. Understanding mitochondrial dynamics and their impact on immune responses offers promising avenues for developing personalized treatments and non-invasive biomarkers, ultimately improving outcomes for LN patients.

CD62L on blood basophils: a first pre-treatment predictor of remission in severe lupus nephritis.

BACKGROUND: Basophils were recently shown to contribute to lupus nephritis (LN). This study assessed blood basophil activation markers (BAMs) for the diagnosis of LN severity and as pre-treatment prognostic markers of the response to treatment in patients with severe LN. METHOD: The diagnostic study included all the patients of a monocentric prospective observational cohort built with consecutive patients diagnosed with LN on the basis of a renal biopsy. The prognostic study selected patients of this cohort according to the following inclusion criteria: ≥18 years old, Class III or IV A ± C ± Class V or pure Class V LN at the time of inclusion and treated with an induction treatment for LN. Clinical data and BAMs were obtained at the time of the kidney biopsy. LN remission status was recorded 12 months after induction therapy initiation. Associations between baseline data and histological severity of LN or LN remission were assessed using logistic regression. RESULTS: No significant association was found between BAMs and the histological severity of LN in 101 patients. Among the 83 patients included in the prognostic study, 64 reached renal remission. CD62L expression on blood basophils at baseline was independently negatively associated with remission at 12 months [odds ratio = 0.26, 95% confidence interval 0.08-0.82, P = 0.02 for quantitative CD62L expression >105 (geometric fluorescent intensity) gMFI]. CD62L <105 gMFI was associated with a probability of 0.87 of LN remission in the next 12 months after the start of induction therapy. CONCLUSION: Pre-treatment CD62L expression on blood basophils could be a first predictive biomarker of renal response to induction therapy at 12 months in patients with severe LN.

[Complement system and kidney]. / Complément et rein.

In the last few years, there has been a growing interest in the study of complement, fueleld mainly by the design of complement modulators, especially the C5-blocker eculizumab. The latter has significantly improved the prognosis of some nephropathies, such as the atypical hemolytic uremic syndrome. This breakthrough is a perfect example of fundamental translational research leading to clinical applications for patients. Currently, new molecules are being developed and some of them have already demonstrated clinical efficacy, such as avacopan (C5aR blocker) in ANCA vasculitis. As for kidney transplantation, complement modulators may lead to a new perspective in the treatment of some complications, such as humoral rejection. However, complement modulators carry the side effects, especially the infectious, and high costs.

L'étude du complément bénéficie depuis quelques années d'un regain d'intérêt dû en grande partie à la mise au point de nouveaux modulateurs du complément, notamment le bloqueur du C5, l'éculizumab. Ce dernier a significativement amélioré le pronostic de certaines pathologies rénales, comme le syndrome hémolytique et urémique atypique. Cette avancée est un exemple parfait d'une recherche translationnelle ayant débouché sur des applications cliniques pour les patients. Actuellement, de nouvelles molécules sont en cours de développement et certaines ont déjà démontré une efficacité clinique, comme l'avacopan (bloqueur du C5aR) dans les vasculites à anticorps anticytoplasme des polynucléaires neutrophiles. Du côté de la transplantation rénale, les inhibiteurs du complément pourraient faire évoluer le traitement de certaines complications comme le rejet humoral. Cependant, ces nouvelles thérapies ciblées ont des effets secondaires, notamment infectieux, et un coût important.

Use of oscillometric devices in atrial fibrillation: a comparison of three devices and invasive blood pressure measurement.

BACKGROUND: The use of automated (oscillometric) blood pressure (BP) devices is not validated in atrial fibrillation (AF) patients. OBJECTIVES: To assess the reliability of three oscillometric BP devices, and the agreement with invasive arterial blood pressure(IBP) in AF patients. METHODS: 48 AF patients with randomized sequences of 10 consecutive BP measurements with two pairs of devices: (1) OmronR7™(wrist) and OmronHEM907™(arm); (2) OmronR7™ and Microlife WatchBPhome(arm). Reliability and agreement of each device were assessed by the intra-class correlation coefficient (ICC) for the continuous BP measurements and Bland & Altman methodology, respectively. In 10 additional AF patients, 10 consecutive measurements with IBP and OmronHEM907™, and IBP and Microlife WatchBPhome were performed. RESULTS: The OmronR7™ was not able to obtain any BP Readings. Arm devices presented better ICC for systolicBP(SBP) than for diastolicBP(DBP) (Omron HEM907™:0.94 [0.90; 0.97] vs. 0.77 [0.67; 0.89]; Microlife WatchBPhome:0.92 [0.88; 0.96] vs.0.79 [0.69; 0.89]).The correlation coefficient between Microlife WatchBPhome and IBP computed using the average of repeated measurements from two to ten measurements improved up to the third and remained stable afterwards. The agreement between IBP and SBP, and IBP and DBP, was moderate as illustrated by a wide limit of agreement [-24; 26](SBP) and [-15;17](DBP) for Microlife WatchBPHome, respectively and [-30; 13](SBP) and [-7; 15](DBP) for OmronHEM907. CONCLUSIONS: BP measurement using the two arm oscillometric devices achieved a high reliability for SBP. The agreement between IBP and arm devices was low but using the average of three consecutive measurements improved the results substantially.

Does spontaneous remission occur in polyarteritis nodosa?
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BACKGROUND: Polyarteritis nodosa (PAN) is a systemic vasculitis involving mainly medium-sized arteries and, rarely, small-sized arteries. The diagnosis is principally based on clinical exams, biopsy of an affected organ, and/or arteriography of renal or mesenteric arteries. Once diagnosed, immunosuppressive agents, such as glucocorticoids and cyclophosphamide, are generally introduced as soon as possible. Whether spontaneous remission of PAN occurs is therefore largely unknown. PRESENTATION: We describe the case of a 51-year-old woman who presented with a 4-day-history of intense pain in her left flank, hypertension, fever, microscopic hematuria, and acute renal failure. Contrast-enhanced renal ultrasound strongly suggested bilateral renal infarction. Medical history and an extensive workup allowed to exclude systemic embolism, recreational drug abuse, cardiac arrhythmias, and thrombophilia. A possible diagnosis of PAN was considered; however, within 2 weeks of admission, spontaneous remission of her clinical and biological symptoms occurred without the use of any immunosuppressive treatment. Finally, 3 months later, renal arteriography confirmed the diagnosis of PAN. The patient remains free of symptoms 1 year after initial presentation. CONCLUSION: This case illustrates the importance of considering PAN in the differential diagnosis of renal infarction with inflammatory syndrome and shows that spontaneous remission of renal PAN can occur.
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Multimodal imaging of retinal pigment epithelial detachments in patients with C3 glomerulopathy: case report and review of the literature.

BACKGROUND: To describe the optical coherence tomography angiograhy (OCTA) of drusenoid pigment epithelial detachments (PEDs) in a woman affected by Complement 3 (C3) glomerulopathy, which represents a spectrum of glomerular diseases characterized on fluorescent microscopy by C3 accumulation with absent, or scanty, immunoglobulin deposits. It is due to acquired or genetically defective alternative pathway control and is generally associated with drusen-like deposits in Bruch's membrane, as well as choriocapillaris. These retinal lesions can be associated with choroidal neovascularization and central serous chorioretinopathy (CSCR). OCTA is useful to detect neovascularization without injecting a contrast product, particularly in these patients who may have renal insufficiency. CASE PRESENTATION: A 28-year-old woman affected by C3 glomerulpathy was diagnosed with asymptomatic multiple bilateral PEDs during a routine ophthalmologic consultation. To better characterize the lesions, multimodal imaging was performed and included: optic coherence tomography (OCT), en-face OCT, OCTA, fluorescence and indocyanine angiography. The OCTA clearly identified vascular network rarefaction with decreased choriocapillary vascularization. It confirmed that PEDs associated with C3 glomerulonephritis are not vascularized, but rather of serous type. CONCLUSIONS: Patients affected by C3 glomerulopathy can develop neovascular membranes as retinal complications of pigment epithelial detachments. Optical coherence angiography may be indicated to identify this complication, without injecting any contrast product that could produce further kidney damage.

[Rapidly progressive glomerulonephritis: a diagnostic and therapeutic emergency]. / Glomérulonéphrite rapidement progressive: une urgence diagnostique et thérapeutique.

Rapidly progressive glomerulonephritis (RPG) is a rare clinical syndrome characterized by kidney damage that can lead to irreversible kidney failure. RPG can be caused by primary glomerular disease or can be part of a systemic autoimmune disorder. All RPG have a similar pathophysiology (proliferation of cells in Bowman's capsule and formation of crescents) and clinical evolution (rapidly progressive kidney failure with proteinuria and an active urine sediment). Immunosuppressive therapy and sometimes plasma exchanges are required. Overall- and kidney survival are closely linked to the blood creatinine level at presentation, the percentage of damaged glomeruli, and to the underlying cause. RPG is therefore a diagnostic and therapeutic emergency that needs quick referral to a nephrologist.

ITGAM rs1143679 Variant in Systemic Lupus Erythematosus Is Associated with Increased Serum Calcification Propensity.

OBJECTIVES: CD11B/ITGAM (Integrin Subunit α M) mediates the adhesion of monocytes, macrophages, and granulocytes and promotes the phagocytosis of complement-coated particles. Variants of the ITGAM gene are candidates for genetic susceptibility to systemic lupus erythematosus (SLE). SNP rs1143679 (R77H) of CD11B particularly increases the risk of developing SLE. Deficiency of CD11B is linked to premature extra-osseous calcification, as seen in the cartilage of animals with osteoarthritis. Serum calcification propensity measured by the T50 test is a surrogate marker for systemic calcification and reflects increased cardiovascular (CV) risk. We aimed to assess whether the CD11B R77H gene variant is associated with a higher serum calcification propensity (i.e., a lower T50 value) in SLE patients compared to the wild-type allele (WT). METHODS: Cross-sectional study incorporating adults with SLE genotyped for the CD11B variant R77H and assessed for serum calcification propensity with the T50 method. Participants were included in a multicenter trans-disciplinary cohort and fulfilled the 1997 revised American College of Rheumatology (ACR) criteria for SLE. We used descriptive statistics for comparing baseline characteristics and sequential T50 measurements in subjects with the R77H variant vs. WT CD11B. RESULTS: Of the 167 patients, 108 (65%) were G/G (WT), 53 (32%) were G/A heterozygous, and 6 (3%) were A/A homozygous for the R77H variant. A/A patients cumulated more ACR criteria upon inclusion (7 ± 2 vs. 5 ± 1 in G/G and G/A; p = 0.02). There were no differences between the groups in terms of global disease activity, kidney involvement, and chronic renal failure. Complement C3 levels were lower in A/A individuals compared to others (0.6 ± 0.08 vs. 0.9 ± 0.25 g/L; p = 0.02). Baseline T50 did not differ between the groups (A/A 278 ± 42' vs. 297 ± 50' in G/G and G/A; p = 0.28). Considering all sequential T50 test results, serum calcification propensity was significantly increased in A/A individuals compared to others (253 ± 50 vs. 290 ± 54; p = 0.008). CONCLUSIONS: SLE patients with homozygosity for the R77H variant and repeated T50 assessment displayed an increased serum calcification propensity (i.e., a lower T50) and lower C3 levels compared to heterozygous and WT CD11B, without differing with respect to global disease activity and kidney involvement. This suggests an increased CV risk in SLE patients homozygous for the R77H variant of CD11B.

A stone in the bone.

Primary hyperoxaluria (PH) is a group of diseases due to mutations in genes coding for enzymes involved in oxalate metabolism. Three types of PH are identified depending on the gene mutated. Type 1 is the most frequent with 80% of the cases, while PH2 and PH3 are rarer. The severity of renal involvement varies between the three types. Indeed, between 60% and 80% of PH1 but only 20% of PH2 patients will reach end-stage kidney disease. In PH3 patients, dialysis is uncommon. Because oxalate clearance is impaired in CKD patients, oxalate can precipitate in various organs leading to systemic oxalosis. We report an uncommon presentation of bone oxalosis associated with hypercalcemia in a dialyzed patient. This report emphasizes the difficulties to diagnose primary hyperoxaluria and the challenge of treating dialyzed patients.

A new statistical methodology overcame the defects of the Bland-Altman method.

BACKGROUND AND OBJECTIVES: The Bland and Altman's limits of agreement (LoA) method is the most commonly used statistical method to assess the bias and precision of a new measuring device (it has been cited over 40,000 times as of March 2019). What is less known is that the LoA method can be dramatically misleading. METHODS: A new statistical methodology, which circumvents these deficiencies, has recently been published and made available in the R and Stata statistical packages. We aimed at introducing and illustrating with a small data set on blood pressure (BP) measurements, taken by two different oscillometric devices, the use of this new methodology to a clinical audience. RESULTS: For diastolic BP, the LoA method was particularly misleading, as it identified differential and proportional biases of opposite signs compared with the new methodology. Regarding systolic BP, the LoA method strongly overestimated both the differential and proportional biases, for both devices. CONCLUSION: The LoA method may be dramatically misleading and does not allow one to estimate the precision of each measurement method. We recommend the use of the newly developed statistical methodology instead.

HHV-8-negative multicentric Castleman disease presenting as a crescentic immune complexes membranoproliferative glomerulonephritis.

Multicentric Castleman disease is a rare polyclonal lymphoproliferative disorder mainly associated with two renal manifestations: thrombotic microangiopathy and amyloidosis. Nevertheless, we report here a case of human herpes virus-8 negative multicentric Castleman disease with membranous proliferative glomerulonephritis and extracapillary proliferation. A patient was successfully treated with corticosteroids, anti-CD20 and cyclophosphamide therapy.

Incidence of glomerulonephritis in the western part of Switzerland over the last decade.

BACKGROUND: Glomerulonephritis is a rare yet serious group of diseases with a high risk of progression to end-stage renal disease. For optimal healthcare planning, detailed epidemiological and demographic data are essential. Despite their clinical relevance, these data are largely lacking in Switzerland. OBJECTIVE: The objective of this study was to assess the incidence of the different forms of glomerulonephritis in the western part of Switzerland and its changes over the last 10 years, compared with international data. METHODS: We listed all renal biopsy reports analysed between 2007 and 2016 at the University hospital of Lausanne, the renal pathology reference centre of all hospitals in the cantons of Vaud, Fribourg, Valais and Neuchâtel. Biopsies with a first diagnosis of primary glomerulonephritis were included in the analysis. The incidence was calculated as the number of patients newly diagnosed with glomerulonephritis divided by the number of inhabitants of all the above-mentioned cantons during the year under review, as retrieved from the federal statistical office of Switzerland. RESULTS: We collected biopsy reports from 864 patients between 2007 and 2016; 168 biopsies met the inclusion criteria. The most common primary glomerulonephritis was IgA nephropathy at 32.7% of cases, followed by lupus nephritis (29.8%) and pauci-immune glomerulonephritis (11.9%). Overall, the mean incidence of glomerulonephritis was 1.3/100,000/year. Between 2007 and 2016, the incidence of all glomerulonephritis taken together remained stable. The same was true for the incidence of IgA nephropathy, lupus nephritis and pauci-immune glomerulonephritis. In contrast, we observed a trend towards higher creatinine levels, proteinuria and degree of interstitial fibrosis at diagnosis. CONCLUSION: The incidence of glomerulonephritis in the western part of Switzerland was low and remained stable over time, in line with European data.

Malaria, Collapsing Glomerulopathy, and Focal and Segmental Glomerulosclerosis.

BACKGROUND AND OBJECTIVES: Malaria, a potentially life-threatening disease, is the most prevalent endemic infectious disease worldwide. In the modern era, the spectrum of glomerular involvement observed in patients after malarial infections remains poorly described. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We therefore performed a retrospective multicenter study to assess the clinical, biologic, pathologic, and therapeutic characteristics of patients with glomerular disease demonstrated by kidney biopsy in France within 3 months of an acute malaria episode. RESULTS: We identified 23 patients (12 men), all but 1 of African ancestry and including 10 patients with concomitant HIV infection. All of the imported cases were in French citizens living in France who had recently traveled back to France from an endemic area and developed malaria after their return to France. Eleven patients had to be admitted to an intensive care unit at presentation. Plasmodium falciparum was detected in 22 patients, and Plasmodium malariae was detected in 1 patient. Kidney biopsy was performed after the successful treatment of malaria, a mean of 24 days after initial presentation. At this time, all patients displayed AKI, requiring KRT in 12 patients. Nephrotic syndrome was diagnosed in 17 patients. Pathologic findings included FSGS in 21 patients and minimal change nephrotic syndrome in 2 patients. Among patients with FSGS, 18 had collapsing glomerulopathy (including 9 patients with HIV-associated nephropathy). In four patients, immunohistochemistry with an antibody targeting P. falciparum histidine-rich protein-2 demonstrated the presence of the malaria antigen in tubular cells but not in podocytes or parietal epithelial cells. An analysis of the apoL1 risk genotype showed that high-risk variants were present in all seven patients tested. After a mean follow-up of 23 months, eight patients required KRT (kidney transplantation in two patients), and mean eGFR for the other patients was 51 ml/min per 1.73 m2. CONCLUSIONS: In patients of African ancestry, imported Plasmodium infection may be a new causal factor for secondary FSGS, particularly for collapsing glomerulopathy variants in an APOL1 high-risk variant background.

Syphilis and parvovirus B19 co-infection imitating a lupus nephropathy: A case report.

RATIONALE: Syphilis can share clinical features with autoimmune diseases, such as cutaneous Lupus or rheumatoid arthritis. Moreover, secondary syphilis can have visceral involvement, thus affecting the kidney. Syphilitic nephropathy causes nephrotic syndrome with a classic membranous pattern. We present a unique presentation of a co-infection by syphilis and parvovirus B19 sharing all the biological and histological features of proliferative lupus nephritis (LN). PATIENT CONCERNS: We present a case of a 71-year-old Caucasian male returning from a trip to Asia presenting with nephrotic syndrome with antinuclear antibodies (ANA) positivity. DIAGNOSES: Because of nephrotic syndrome a kidney biopsy was performed. It demonstrated a membranous nephropathy with extracapillary proliferation and a full house pattern (presence of IgA, IgG, IgM and C1Q deposits) on immunofluorescence (IF), highly suggestive of LN class III and V. However, several atypical clinical features notably the age, sex of the patient and the history of travel prompt us to search for another cause of nephropathy. INTERVENTIONS: A serology was positive for syphilis and a PCR in the renal biopsy was also positive for parvovirus B19. Thus, a co-infection by syphilis and parvovirus B19 was funded to be the cause of the renal lesions. OUTCOMES: The proteinuria improved; a course of antibiotic was administrated because of neurologic syphilitic involvement (presence of headache with positive syphilis serology in the CSF). LESSONS: A co-infection by syphilis and parvovirus B19 can share all the biological and histological features of proliferative LN and must be recognized as a cause of pseudo-lupus nephritis.