Complementary Effects of Carbamylated and Citrullinated LL37 in Autoimmunity and Inflammation in Systemic Lupus Erythematosus.

LL37 acts as T-cell/B-cell autoantigen in Systemic lupus erythematosus (SLE) and psoriatic disease. Moreover, when bound to "self" nucleic acids, LL37 acts as "danger signal," leading to type I interferon (IFN-I)/pro-inflammatory factors production. T-cell epitopes derived from citrullinated-LL37 act as better antigens than unmodified LL37 epitopes in SLE, at least in selected HLA-backgrounds, included the SLE-associated HLA-DRB1*1501/HLA-DRB5*0101 backgrounds. Remarkably, while "fully-citrullinated" LL37 acts as better T-cell-stimulator, it loses DNA-binding ability and the associated "adjuvant-like" properties. Since LL37 undergoes a further irreversible post-translational modification, carbamylation and antibodies to carbamylated self-proteins other than LL37 are present in SLE, here we addressed the involvement of carbamylated-LL37 in autoimmunity and inflammation in SLE. We detected carbamylated-LL37 in SLE-affected tissues. Most importantly, carbamylated-LL37-specific antibodies and CD4 T-cells circulate in SLE and both correlate with disease activity. In contrast to "fully citrullinated-LL37," "fully carbamylated-LL37" maintains both innate and adaptive immune-cells' stimulatory abilities: in complex with DNA, carbamylated-LL37 stimulates plasmacytoid dendritic cell IFN-α production and B-cell maturation into plasma cells. Thus, we report a further example of how different post-translational modifications of a self-antigen exert complementary effects that sustain autoimmunity and inflammation, respectively. These data also show that T/B-cell responses to carbamylated-LL37 represent novel SLE disease biomarkers.

Reproducibility of the Oxford classification of immunoglobulin A nephropathy, impact of biopsy scoring on treatment allocation and clinical relevance of disagreements: evidence from the VALidation of IGA study cohort.

BACKGROUND: The VALidation of IGA (VALIGA) study investigated the utility of the Oxford Classification of immunoglobulin A nephropathy (IgAN) in 1147 patients from 13 European countries. Methods. Biopsies were scored by local pathologists followed by central review in Oxford. We had two distinct objectives: to assess how closely pathology findings were associated with the decision to give corticosteroid/immunosuppressive (CS/IS) treatments, and to determine the impact of differences in MEST-C scoring between central and local pathologists on the clinical value of the Oxford Classification. We tested for each lesion the associations between the type of agreement (local and central pathologists scoring absent, local present and central absent, local absent and central present, both scoring present) with the initial clinical assessment, as well as long-term outcomes in those patients who did not receive CS/IS. RESULTS: All glomerular lesions (M, E, C and S) assessed by local pathologists were independently associated with the decision to administer CS/IS therapy, while the severity of tubulointerstitial lesions was not. Reproducibility between local and central pathologists was moderate for S (segmental sclerosis) and T (tubular atrophy/interstitial fibrosis), and poor for M (mesangial hypercellularity), E (endocapillary hypercellularity) and C (crescents). Local pathologists found statistically more of each lesion, except for the S lesion, which was more frequent with central review. Disagreements were more likely to occur when the proportion of glomeruli affected was low. The M lesion, assessed by central pathologists, correlated better with the severity of the disease at presentation and discriminated better with outcomes. In contrast, the E lesion, evaluated by local pathologists, correlated better with the clinical presentation and outcomes when compared with central review. Both C and S lesions, when discordant between local and central pathologists, had a clinical phenotype intermediate to double absent lesions (milder disease) and double present (more severe). CONCLUSION: We conclude that differences in the scoring of MEST-C criteria between local pathologists and a central reviewer have a significant impact on the prognostic value of the Oxford Classification. Since the decision to offer immunosuppressive therapy in this cohort was intimately associated with the MEST-C score, this study indicates a need for a more detailed guidance for pathologists in the scoring of IgAN biopsies.

Safety and complications after three different surface ablation techniques with mitomycin C: a retrospective analysis of 2757 eyes.

BACKGROUND: To evaluate the safety and spectrum of complications of three excimer laser surface ablation techniques (SATs) with an intraoperative application of mitomycin C (MMC) 0.02%. A retrospective, non-comparative large case series. METHODS: SATs were performed on 2757 eyes with a preoperative spherical equivalent (SE) of - 4.41 ± 2.44 and a Wavelight Allegretto 200 platform. Ablation zone diameters between 6.0 and 7.0 mm were used according to mesopic pupil size. All patients were treated with an intraoperative application of MMC for 30 to 90 s depending on refractive error. The mean follow-up time was > 3 months (107 ± 24 days). Complication range and incidence were analyzed retrospectively and safety index was calculated. RESULTS: Two thousand seven hundred and fifty-seven eyes met the inclusion criteria for surface ablation. Two thousand five hundred and seventy-three eyes were assigned to alcohol-assisted photorefractive keratectomy (APRK), 135 eyes to transepithelial photorefractive keratectomy (TPRK), and 49 eyes to off-flap epithelial laser in situ keratomileusis (EpiLASIK/EpiK). Overall, the safety index was 1.06 ± 0.28. Haze was graded according to the Fantes scale. Haze incidence rates were highest in the TPRK group (14.81%) and comparably low in APRK (2.95%) and EpiK (4.08%) groups. CONCLUSIONS: Intraoperative topical application of MMC (0.02%) results in good safety and no severe side effects. However, highest incidence of haze was observed after TPRK. The more frequent peripheral localization of haze might be attributed to large ablation zones and the wavefront optimized ablation profile especially in the PTK modus of the laser platform.

BMI, nephroangiosclerosis and glomerulonephritis: Is there any meeting point?

AIM: Overweight has been related to renal arteriolosclerosis and is able to modify intrarenal haemodynamics. Increasing evidence suggests an association between weight in excess and primary glomerulonephritis (GN). The aim of this study was to evaluate the relationship between nutritional status and intrarenal arterial stiffness in primary GN associated to arteriolosclerosis. We have considered the glomerular diameter (GD) as morphological parameter in overweight and obese patients. METHODS: Clinical, laboratory, anthropometric data and renal Doppler ultrasound were performed immediately before kidney biopsy. RESULTS: Primary GN was diagnosed in 92 patients. Mild arteriolosclerosis was found in 19.6% of patients, moderate in the 20.6%, severe in the 10.9% while nephroangiosclerosis was diagnosed in 8.7% of patients. A positive correlation was found between body mass index (BMI) and renal resistive index (RRI) (P < 0.01, r = 0.34). RRI were significantly higher in patients with severe arteriolosclerosis at kidney biopsy (P < 0.05). Furthermore, higher BMI (P < 0.01) was found in patients with renal arteriolosclerosis than patients without renal arteriolosclerosis (26.1 ± 4.4 kg/m2 vs. 24.4 ± 4.5 kg/m2 ). Finally, in overweight and obesity patients we found a positive correlation between maximal GD and BMI (P < 0.01) and maximal GD and RRI (P < 0.01). CONCLUSION: In overweight and obese patients affected by primary GN, it might be found not only glomerular but also renal vascular lesions. Finally, we believe that nephroangiosclerosis, in combination with weight in excess, is able to modify intrarenal haemodynamic parameters. Moreover, in response to these changes, the renal tissue morphologically promotes a GD increase regardless of the underlying GN.

Kidney Expression of Toll Like Receptors in Lupus Nephritis: Quantification and Clinicopathological Correlations.

Objective. The study aimed at locating and quantifying Toll Like Receptor (TLR) 3, 7, 8, and 9 expression in kidney of patients with lupus nephritis (LN) and correlating them with clinicopathological features. Methods. Kidney sections from 26 LN patients and 4 controls were analyzed by immunohistochemistry using anti-human TLR3, TLR7, TLR8, and TLR9 polyclonal antibodies; the number of TLR-positive nuclei/mm(2) was evaluated on digitalized images. Results. Compared to controls, LN showed a significantly higher amount of glomerular and tubulointerstitial TLR9 (p = 0.003 and p = 0.007), whole and tubulointerstitial TLR3 (p = 0.026 and p = 0.031), and a higher tubulointerstitial TLR7 (p = 0.022). TLR9 positively correlated with activity index (p = 0.0063) and tubular TLR7 with chronicity index (p = 0.026). TLR9 positively correlated with Renal-SLEDAI (p = 0.01). Conclusions. This is the first study quantifying kidney expressions of TLRs in LN patients; the results show an overexpression of TLR3, TLR7, and TLR9 and demonstrate a correlation with clinicopathological indices supporting a role of these mediators in the pathogenesis of LN.

Extracapillary proliferation is an independent predictive factor in Immunoglobulin A nephropathy.

BACKGROUND: Oxford classification of Immunoglobulin A Nephropathy (IgAN) identifies four pathological features as predictors of renal outcome (MEST-score): mesangial proliferation (M); endocapillary proliferation (E); segmental glomerulosclerosis (S); tubular atrophy/interstitial fibrosis (T). In particular extracapillary proliferation (Ex) was not considered as an independent histological variable predicting renal outcome. Recently the VALIGA study provided a validation of the Oxford classification in a large European cohort of IgAN patients and re-stated that Ex is not associated with a worse renal prognosis. We propose a retrospective study to evaluate the predictive value of the MEST-score in a multi-centre, single region group of patients from central Italy and in addition, to investigate Ex as a marker predicting renal outcome. METHODS: One hundred and seven patients were enrolled in this study. Clinical data of each patient were available at diagnosis and follow-up. The median age at diagnosis was 36.7 years; 72% of the patients were males. Histological parameters were those included in the MEST-score of the Oxford classification; in addition, Ex was also assessed. RESULTS: Multiple linear regression models for survey were used. Statistical analysis showed a correlation between the progression of renal decline, in terms of estimated glomerular filtration rate (slope eGFR), and M, S, T. Differently from Oxford and VALIGA studies, no correlation was found with E, while Ex correlated with a decline of eGFR. CONCLUSIONS: Our results suggest that Ex represents an additional independent variable associated with a faster decline of renal function in IgAN.

Kidney Biopsy and Immuno-Rheumatological Diseases: A Retrospective and Observational Study.

Renal involvement is a common occurrence in patients with immuno-rheumatological diseases (IRDs). Several instances of glomerulonephritis (GN) occur in the setting of IRD and complicate the clinical course of an underlying condition. The aim of this study was to observe the spectrum of nephropathies according to age, kidney function, history of IRD at the time of biopsy, and histopathological kidney diagnosis. We evaluated data relating to 699 consecutive kidney native biopsies (female 52.1%) with a median age of 48 years (IQR 34-62) performed in adult patients collected over 15 years. The study population was divided into three groups: patients with kidney histological findings correlated to underlying IRD (Group 1), patients with kidney histological findings not correlated to underlying IRD (Group 2), and patients with kidney histological findings compatible with "de novo" IRD (absent in personal medical history) (Group 3). Kidney involvement related to IRD was found in 25.2% of patients. Group 1 was mostly represented by lupus nephritis (76.6%), with a younger age than Group 3 (p < 0.001) and by a higher percentage of females than other groups (p < 0.001). Group 3 was the most represented by microscopic polyangiitis (50.8%) when compared with the other two groups (p < 0.001). Acute nephritic syndrome (p < 0.001), acute kidney injury (AKI), and abnormal urinalysis (p < 0.001) were more represented in Group 3 than the other groups. In conclusion, IRDs are characterized by different clinical presentations and heterogeneous histological findings. Kidney biopsy remains fundamental to achieving the correct diagnosis and starting targeted therapy.

Gabexate mesylate as treatment in the course of ANCA-negative microscopic polyangiitis.

Patients with small vessel vasculitis present fluctuating antineutrophil cytoplasmic antibodies (ANCA) levels to the point that positive ANCA may be missed even if only up to 10% of patients with microscopic polyangiitis (MPA) are ANCA-negative. The first-line treatment of MPA is the association of steroids and cyclophosphamide, especially in the presence of a rapidly progressive glomerulonephritis. Plasmapheresis, intravenous immunoglobulins, and tumor necrosis factor inhibitors have been proposed as alternative to standard therapy. Disseminated intravascular coagulation (DIC) is a possible event in the course of small vessel vasculitis. Gabexate mesylate is a protease inhibitor able to suppress endothelial cell injury, and it may be administered to treat DIC related to different diseases. In ANCA-associated vasculitis, cytokines play a key role in promoting endothelial damage. DIC-related thrombocytopenia may be misinterpreted as drug-induced because of the immunosuppressive properties of cyclophosphamide. Two cases of ANCA-positive MPA associated with DIC and treated with gabexate are reported in the literature with improvement of both hematological disorder and renal function. Our patient presented a rapidly progressive glomerulonephritis, and the renal biopsy showed MPA, in the absence of ANCA. After two weeks of steroid treatment, our patient developed a DIC. This case represents the first report of ANCA-negative MPA managed with gabexate, which showed improvement of coagulation disorders and kidney function. In conclusion, the anti-inflammatory properties of gabexate could be helpful in MPA at increased bleeding risk when immunosuppressive treatment is contraindicated, even in ANCA-negative vasculitis.

Nephroangiosclerosis not related to hypertension: A matter to resolve in the era of precision medicine.

Nephroangiosclerosis (NAS) associated with hypertension continues to be one of the most causes of end stage renal diseases in Europe, but it is still poorly studied. The prevalence of NAS shows a large variability due to the difference among different countries regarding clinical presentations and the indication to perform renal biopsy. The study aimed to investigate the prevalence in biopsy-proven NAS patients and the association with hypertension and/or glomerulonephritis (GN). We included all patients referred for native kidney biopsy between 2003-2021 at Policlinic Umberto I of Rome. From 837 patients who underwent renal biopsy NAS was diagnosed in 80 (10.5%) patients. Serum creatinine was significantly higher in NAS [2.07 mg/dl (IQR 1.13-5.2) vs 1.1 mg/dl (IQR 0.8-2.1), p < 0.001] compared to patients without NAS. Hypertension was present in 45% of patients with NAS. Proteinuria was significantly higher in patients with mild-moderate NAS compared to patients with severe NAS [2.6 g/die (IQR 1-5) vs 1.5 g/die (IQR 0.86-2.3), p < 0.05]. We did not find any significant differences, including histological features, between NAS patients with hypertension and NAS patients without hypertension (p > 0.05). IgA nephropathy, focal segmental glomerulosclerosis and membranous nephropathy were the most frequent GN associated. In conclusion no specific histological features are reported in NAS with and without hypertension. More information on the phenotype, clinical presentation and markers are needed to improve histological and clinical diagnostics.

Climate Change Dependence in Ex Situ Conservation of Wild Medicinal Plants in Crete, Greece.

Over 80% of the global population addresses their primary healthcare needs using traditional medicine based on medicinal plants. Consequently, there's a rising demand for these plants for both household and industrial use at local, regional, national, and international levels. However, wild harvesting has negatively impacted natural ecosystems. Cultivating medicinal species has been proposed as a conservation strategy to alleviate this pressure. Yet, in this age of global climate change concerns, smallholder farmers' views on the benefits of such cultivation clash with the uncertainties of climate change impacts, amplifying their anxieties. In this context, the climate change dependence of ex situ cultivation of ten wild medicinal taxa with significant ethnopharmacological interest in Crete, Greece, were studied, projecting their potential habitat suitability under various future climate scenarios. The results demonstrated species-specific effects. Based on the potential cultivation area gains and losses, these effects can be categorized into three groups. We also outlined the spatial patterns of these gains and losses, offering valuable insights for regional management strategies benefiting individual practitioners.

Nephrotic syndrome and abdominal arterial bruits in a young hypertensive patient: a case report.

We report the case of a 34-year-old black African hypertensive woman who presented with nephrotic proteinuria, mild renal failure and abdominal bruits on physical examination. The renal Doppler ultrasound revealed bilateral artery stenosis. Thoracoabdominal aortic nuclear magnetic resonance showed a restriction of proximal descending aorta with post-stenotic spindle dilation while abdominal aorta and iliac vessels appeared diffusely stenotic with atherosclerotic plaques and infrequent spindle dilations and right ostial renal artery stenosis. Renal angiography failed to reveal renal artery stenosis. Right renal biopsy showed type 1 membrano-proliferative glomerulonephritis in sclerotic evolution and severe arteriolosclerosis. The particularly early onset of the disease suggests that the pathogenesis of the membrano-proliferative glomerulonephritis may be multifactorial and related to vascular hypoplasia and chronic renal hypoperfusion leading to renin angiotensin system activation. Hyperlipidemia secondary to nephrotic syndrome may have accelerated systemic atherosclerosis and progression of renal disease.

Crescentic glomerulonephritis associated with vascular endothelial growth factor (VEGF) inhibitor and bisphosphonate administration.

Bevacizumab, a vascular endothelial growth factor (VEGF) inhibitor, has been widely used in a variety of malignancies offering substantial clinical benefit. Hypertension and proteinuria are the most commonly reported manifestations of bevacizumab-related nephrotoxicity with the risk increasing along with the dose and with the concomitant use of bisphosphonates. We describe the first case of a patient with small-cell lung cancer who developed diffuse extracapillary necrotizing crescentic glomerulonephritis, temporarily necessitating haemodialysis, following administration of bevacizumab and zolendronate. Renal function improved without any specific treatment and the patient remained off dialysis after withdrawal of bevacizumab-zolendronate. Special caution is required when VEGF inhibitors are combined with bisphosphonates. Such a combination can cause crescentic necrotizing glomerular lesions. Withdrawal of the offending medications may be adequate for the alleviation of this severe glomerulonephritis.

Ask-Upmark kidney and tubulointerstitial nephritis in a woman with severe renal failure.

Ask-Upmark kidney is a rare diagnosis of segmental hypoplasia in pediatric population clinically characterized by severe hypertension potentially treatable with partial to total nephrectomy. Although originally was described only as a congenital anomaly, recent data suggest to be caused by vesicoureteral reflux, either in utero or in early childhood and pyelonephritis. The case we reported indicates that Ask-Upmark kidney should be considered as potential cause of hypertension and renal failure both in children and adults. The renal biopsy is necessary for early diagnosis and may consent to normalize blood pressure with nephrectomy; however, if renal damage is severe and progressive with tubulointerstitial nephritis, surgical management is excluded and renal transplant should be considered.

[Renal biopsy collection (2000-2008) from a single center, the Policlinico Umberto I, Sapienza University, Rome]. / Casistica delle biopsie renali della Sapienza Universita' di Roma - Azienda Policlinico Umberto I: frequenza delle malattie renali biopticamente accertate negli anni 2000-2008.

The collection of data about renal biopsies is an important starting point for clinical and epidemiological studies about kidney disease. The aim of this study was the evaluation of the frequency of the different kidney diseases, their clinical presentation and the demographic features of the population based on renal biopsies performed at our center during the years 2000-2008. Clinical presentations were defined as nephrotic syndrome (NS), urinary abnormalities, macroscopic hematuria, acute renal failure (ARF) and chronic renal failure (CRF). Kidney diseases were divided into five groups: 1) primary glomerulonephritis; 2) secondary glomerulonephritis; 3) tubulointerstitial nephritis (TIN); 4) vascular-disease-associated kidney disease; 5) miscellaneous. Primary glomerulonephritis was the most common (58.64%), followed by secondary glomerulonephritis (27.03%); TIN and vascular diseases were diagnosed in 1.46% and 7.78% of cases, respectively. The most common indications to perform renal biopsies were urinary abnormalities in 45.01% of cases, followed by CRF (21.51%) and NS (21.37%); macroscopic hematuria (6.41%) and ARF (5.70%) were less common. The most common kidney disease in men was IgA nephropathy (27.91%), while lupus nephritis was the most common in women (18.88%). In patients older than 65 years of age membranous glomerulonephritis (34.67%) was the most common kidney disease. The availability of these data is useful to assess the distribution and clinical presentation of kidney diseases among patients hospitalized at the Policlinico Umberto I in Rome.

Corrigendum: Retrospective Analysis of Heartworm (Dirofilia immitis) Prevention Medication Compliance and Economic Value in Dogs in Veterinary Practices in Australia.

[This corrects the article DOI: 10.3389/fvets.2020.602907.].

Retrospective Analysis of Heartworm (Dirofilia immitis) Prevention Medication Compliance and Economic Value in Dogs in Veterinary Practices in Australia.

Background: Canine heartworm (HW) is endemic in Australia. Prevention usually involves monthly topical or oral preventives, or annual injections of extended-release moxidectin (ProHeart SR-12*), hereafter referred to as injectable moxidectin (IM). Poor compliance can leave dogs susceptible to infection. This pharmacoeconomics study used retrospective transactional data from 52 Australian veterinary practices to examine the economic value of compliance, revenue, and patient retention associated with veterinarian-sourced canine HW prevention. Methods: This longitudinal descriptive study utilized anonymized transaction records of 228,185 dogs identified to have visited a veterinary practice at least twice in the period 2010-2015. Purchase compliance against a benchmark of 12 months HW protection per year was measured for IM or monthly HW (MHW) preparations each year and for consecutive years. The average annual cost per dog by preventative modality was also determined. Results: Between 2010 and 2015, of the 228,185 dogs identified, 73.0% recorded either zero or one purchase of HW preventive from their veterinary clinic; 18.7% recorded at least two IM purchases, and 10.6% purchased MHW prevention at least twice. Single-year purchase compliance was 92.8-96.9% for IM vs. 26.9-36.5% for dogs receiving MHW products. Consecutive-year purchase compliance was 76.7% for IM and 24.4% for MHW medications. Dog owners spent $AU108.29/dog/year (Australian dollars) on IM vs. $AU131.96/dog/year on MHW prevention products, which may have treated other parasites concurrently, although repeat MHW purchasers only purchased enough to cover an average of 7.2 months per year. Dogs recording at least two HW prevention transactions generated more revenue for veterinary practices/dog/year compared to dogs with less than two. Finally, dogs receiving IM, especially those that started at <15 months old, had the highest retention rate in this population. Conclusions: In the 5 years from 2010 to 2015, 73% of dog owners who visited a veterinary practice at least twice made less than two purchases of HW preventatives from the veterinary practice. For those with at least two preventative purchases, 76.7% of dogs receiving IM and 24.4% of dogs prescribed with MHW products purchased enough doses to provide continuous protection over the observation period.

Antiphospholipid antibodies and renal involvement.

Antiphospholipid antibodies are a heterogeneous group of autoantibodies associated with the hypercoagulable state affecting all vascular districts with thrombosis named antiphospholipid syndrome (APS). APS is an autoimmune disease with multifactorial etiology that includes cellular, molecular, genetic and pathogenic mechanisms. The APS clinical features are a combination of arterial and/or venous thrombosis, hematological events, recurrent fetal losses, neurological disorders and intra-abdominal manifestations. The renal involvement is associated with both primary and secondary APS. Clinical features include hypertension, renal artery stenosis, thrombotic microangiopathy and other histological manifestations of the nephropathy (APSN), venous renal thrombosis, APSN in the course of systemic lupus erythematosus and renal failure. APSN is an independent risk factor that should be included in the classification criteria for definite APS with characteristic clinical and histological features.