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.

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.

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.

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.].

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.

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.

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.

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.

[Renal manifestation of Autosomal Dominant Polycystic Kidney Disease].

Autosomal dominant polycystic kidney disease affects over 12 million people in the world and is the fourth cause of ESRD. It is the main monogenic kidney disease and causes the progressive formation of cysts leading to renal failure after a few decades. The main manifestations of the disease are observed even at a young age. The early sign of ADPKD is impaired urinary concentrating capacity, due to medullary alteration by cysts, and resistance to vasopressin. These anatomical alterations determine hyperfiltration, altered ammonium transport, nephrolithiasis, and, above all, hypertension even in pediatric age. Activation of the renin-angiotensin-aldosterone system has been shown responsible for the maintenance of high pressure values as well as the growth of cysts and renal fibrosis. Arterial hypertension would be responsible for ventricular hypertrophy. Many recent studies have confirmed the role of pressure control, especially if rigorous, in decreasing the progression of renal disease, and the use of ACE inhibitors seems to have higher efficacy than other antihypertensive drugs. The progression of renal disease is evidenced by the reduction of glomerular filtration which may be minimal in the early years, due to hyperfiltration, but, then, may even exceed 5 ml / min per year, especially when the total kidney volume (TKV) exceeds 1500 ml. In more rapid progression forms, ESRD may appear at about 55 years of age. The main risk factors are age, genetic mutation, familiarity with ESRD, macrohematuria episodes, and early onset hypertension. Some authors have proposed both genetic and clinical scores that can provide guidance on the probability of rapid progression. Other renal manifestations include kidney pain, nephrolithiasis, urinary tract infections and cyst hemorrhage. Renal cell carcinoma is a very rare event.

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.

Phosphodiesterase-5 inhibition preserves renal hemodynamics and function in mice with diabetic kidney disease by modulating miR-22 and BMP7.

Diabetic Nephropathy (DN) is the leading cause of end-stage renal disease. Preclinical and experimental studies show that PDE5 inhibitors (PDE5is) exert protective effects in DN improving perivascular inflammation. Using a mouse model of diabetic kidney injury we investigated the protective proprieties of PDE5is on renal hemodynamics and the molecular mechanisms involved. PDE5i treatment prevented the development of DN-related hypertension (P < 0.001), the increase of urine albumin creatinine ratio (P < 0.01), the fall in glomerular filtration rate (P < 0.001), and improved renal resistive index (P < 0.001) and kidney microcirculation. Moreover PDE5i attenuated the rise of nephropathy biomarkers, soluble urokinase-type plasminogen activator receptor, suPAR and neutrophil gelatinase-associated lipocalin, NGAL. In treated animals, blood vessel perfusion was improved and vascular leakage reduced, suggesting preserved renal endothelium integrity, as confirmed by higher capillary density, number of CD31+ cells and pericyte coverage. Analysis of the mechanisms involved revealed the induction of bone morphogenetic protein-7 (BMP7) expression, a critical regulator of angiogenesis and kidney homeostasis, through a PDE5i-dependent downregulation of miR-22. In conclusion PDE5i slows the progression of DN in mice, improving hemodynamic parameters and vessel integrity. Regulation of miR-22/BMP7, an unknown mechanism of PDE5is in nephrovascular protection, might represent a novel therapeutic option for treatment of diabetic complications.

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.

Renal parenchymal resistance in patients with biopsy proven glomerulonephritis: Correlation with histological findings.

Renal Doppler ultrasound is increasingly used in nephrology for the evaluation of renovascular disease, allograft dysfunction, and chronic nephropathies. We compared intrarenal hemodynamic parameters to biopsy findings of glomerular sclerosis, tubular atrophy, interstitial fibrosis, crescents, arteriolosclerosis, and clinical variables in 100 patients. A positive correlation exists between renal function and percentage of glomerular sclerosis (P <0.01, r = 0.26), conversely a negative correlation exists between glomerular filtrate rate and percentage of glomerular sclerosis(P <0.0001, r = -0.35). The percentage of glomerular sclerosis correlate positively with pulsatile index (PI) (P <0.05, r = 0.21) and renal resistive index (RI) (P <0.05, r = 0.20). The percentage of crescents correlates positively with PI(P <0.05, r = 0.21) and RI (P <0.05, r = 0.20). Classifying arteriolosclerosis in four groups according to a severity scale, from absence to severe, PI (P <0.05) and RI (P <0.01) were significantly different. In the post hoc analysis, the median values of PI and RI are significantly different in patients with severe arteriolosclerosis than others. Ultrasound examination is a non-invasive diagnostic technique used on patients with suspected or established renal disease. Our study shows a close correlation between kidney function, ultrasound parameters, and histological findings. Measurement of renal parenchymal resistance by ultrasound could be used in association with biopsy and glomerular function for the evaluation of renal damage in patients with glomerulonephritis.

Renal Papillary Carcinoma Developed in a Kidney Transplant Recipient With Late IgA-Nephropathy.

With improvements in immunosuppressive therapy, patient and graft survival in renal transplant recipients have been prolonged. Increasing donor age and patient survival rates have been related to an increase in the number of de novo tumors. Posttransplant malignancy in these patients is an important cause of graft loss and death in these patients. Among cancers occurring after a kidney transplant, renal cell carcinoma is the fifth most common malignancy after lymphoproliferative disorders, and skin, gastrointestinal, and lung cancers. When nonmelanoma skin cancers and in situ carcinoma of the cervix are excluded from malignancies, renal cell carcinoma accounts for 2% of all cancers in the general population, which increases to 5% in solid-organ recipients. The majority of renal cell carcinomas found in transplant recipients develop in the recipient 's native kidneys, but only 9% of tumors develop in the allograft itself. Tumors transmitted by donors represent only 0.02% to 0.2% of cases. Most de novo allograft renal cell carcinomas are single tumors. The mechanisms of development of renal cell carcinoma in renal grafts are not completely understood.

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.

AKT2 is essential to maintain podocyte viability and function during chronic kidney disease.

In chronic kidney disease (CKD), loss of functional nephrons results in metabolic and mechanical stress in the remaining ones, resulting in further nephron loss. Here we show that Akt2 activation has an essential role in podocyte protection after nephron reduction. Glomerulosclerosis and albuminuria were substantially worsened in Akt2(-/-) but not in Akt1(-/-) mice as compared to wild-type mice. Specific deletion of Akt2 or its regulator Rictor in podocytes revealed that Akt2 has an intrinsic function in podocytes. Mechanistically, Akt2 triggers a compensatory program that involves mouse double minute 2 homolog (Mdm2), glycogen synthase kinase 3 (Gsk3) and Rac1. The defective activation of this pathway after nephron reduction leads to apoptosis and foot process effacement of the podocytes. We further show that AKT2 activation by mammalian target of rapamycin complex 2 (mTORC2) is also required for podocyte survival in human CKD. More notably, we elucidate the events underlying the adverse renal effect of sirolimus and provide a criterion for the rational use of this drug. Thus, our results disclose a new function of Akt2 and identify a potential therapeutic target for preserving glomerular function in CKD.

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.