Cluster Analysis to Explore Clinical Subphenotypes of Eosinophilic Granulomatosis With Polyangiitis.

OBJECTIVE: Previous studies suggested that distinct phenotypes of eosinophilic granulomatosis with polyangiitis (EGPA; formerly known as Churg-Strauss syndrome) could be determined by the presence or absence of antineutrophil cytoplasmic antibodies (ANCA), reflecting predominant vasculitic or eosinophilic processes, respectively. This study explored whether ANCA-based clusters or other clusters can be identified in EGPA. METHODS: This study used standardized data of 15 European centers for patients with EGPA fulfilling widely accepted classification criteria. We used multiple correspondence analysis, hierarchical cluster analysis, and a decision tree model. The main model included 10 clinical variables (musculoskeletal [MSK], mucocutaneous, ophthalmological, ENT, cardiovascular, pulmonary, gastrointestinal, renal, central, or peripheral neurological involvement); a second model also included ANCA results. RESULTS: The analyses included 489 patients diagnosed between 1984 and 2015. ANCA were detected in 37.2% of patients, mostly perinuclear ANCA (85.4%) and/or antimyeloperoxidase (87%). Compared with ANCA-negative patients, those with ANCA had more renal (P < 0.001) and peripheral neurological involvement (P = 0.04), fewer cardiovascular signs (P < 0.001), and fewer biopsies with eosinophilic tissue infiltrates (P = 0.001). The cluster analyses generated 4 (model without ANCA) and 5 clusters (model with ANCA). Both models identified 3 identical clusters of 34, 39, and 40 patients according to the presence or absence of ENT, central nervous system, and ophthalmological involvement. Peripheral neurological and cardiovascular involvement were not predictive characteristics. CONCLUSION: Although reinforcing the known association of ANCA status with clinical manifestations, cluster analysis does not support a complete separation of EGPA in ANCA-positive and -negative subsets. Collectively, these data indicate that EGPA should be regarded as a phenotypic spectrum rather than a dichotomous disease.

IgG4-related disease: advances in pathophysiology and treatment.

INTRODUCTION: IgG4-related disease (IgG4-RD) is a rare fibro-inflammatory disease affecting multiple organs. In recent years basic and translational research has unveiled the role of different cellular subtypes and cytokines in inducing and perpetuating the pathological process, eventually leading to fibrosis of affected tissues. Hopefully, the growing knowledge of the disease pathogenesis will lead to patient-tailored treatments in the near future. AREAS COVERED: This review focuses on the most recent discoveries concerning the pathogenic mechanisms underlying IgG4-RD and highlights their potential role as specific therapeutic targets. EXPERT OPINION: IgG4-RD is a systemic and multifaceted disease. Its sensitivity to glucocorticoids is well known, however new targeted therapies are emerging that can reduce glucocorticoid exposure and achieve sustained clinical responses. Clinicians managing patients with such a rare and heterogeneous disease must therefore be aware of its varied phenotype and traditional and novel therapeutic strategies.

Kidney transplantation in systemic sclerosis: Advances in graft, disease, and patient outcome.

Systemic sclerosis (SSc) is an immune-mediated rheumatic disease characterized by vascular abnormalities, tissue fibrosis, and inflammation. Renal disease occurring in patients with SSc may have a variable clinicopathological picture. However, the most specific renal condition associated with this disease is the scleroderma renal crisis (SRC), characterized by acute onset of renal failure and severe hypertension. SRC develops in about 20% of cases of SSc, especially in those patients with diffuse cutaneous disease. The prognosis of this condition is often negative, with a rapid progression to end-stage renal disease (ESRD). The advent of the antihypertensive angiotensin-converting enzyme inhibitors in 1980 was associated with a significant improvement in patients' survival and recovery of renal function. However, the prognosis of these patients can still be improved. The dialytic condition is associated with early death, and mortality is significantly higher than among patients undergoing renal replacement therapy (RRT) due to other conditions. Patients with SRC who show no signs of renal functional recovery despite timely blood pressure control are candidates for kidney transplantation (KT). In this review, we reported the most recent advances in KT in patients with ESRD due to SSc, with a particular overview of the risk of disease recurrence after transplantation and the evolution of other disease manifestations.

Anastomotic Pseudoaneurysm in Kidney Transplant: A Challenging Management for a Rare Entity.

PURPOSE: Anastomotic pseudoaneurysms of transplanted kidneys are a very rare complication encountered in less than 1% of cases. They may be devastating, leading to functional impairment, kidney transplantectomy, or death. Treatment has not been standardized, with open surgical repair considered the safest procedure even if it is often complicated by bleeding and graft loss. The purpose of this case report is to describe an endovascular treatment of this condition, consisting of the combination of coil embolization and arterial stenting. CASE REPORT: A 61-year-old woman developed an anastomotic pseudoaneurysm 2 months after kidney transplantation, causing acute kidney injury related to ab-extrinsic stenosis of the transplant renal artery (TRA) and external iliac artery. The pseudoaneurysm was successfully treated by coil embolization, and the arterial patency was restored by the stenting of TRA and external iliac artery. The patient completely recovered kidney function, and after a 6-month-follow-up, creatinine values were stable with normal renal perfusion. CONCLUSION: Endovascular repair through coil embolization and TRA stenting can be a safe and effective option to treat anastomotic pseudoaneurysm in kidney transplant.

Current Perspectives in ABO-Incompatible Kidney Transplant.

For a long time, ABO incompatible living donor kidney transplantation has been considered contraindicated, due to the presence of isohemagglutinins, natural antibodies reacting with non-self ABO antigens. However, as the demand for kidney transplantation is constantly growing, methods to expand the donor pool have become increasingly important. Thus, in the last decades, specific desensitization strategies for ABOi transplantation have been developed. Nowadays, these regimens consist of transient removal of preformed anti-A or anti-B antibodies by using plasmapheresis or immunoadsorption and B-cell immunity modulation by CD20+ cells depletion with rituximab, in association with maintenance immunosuppression including corticosteroids, tacrolimus and mycophenolate mofetil. The outcome in ABOi kidney transplantation have markedly improved over the years. In fact, although randomized trials are still lacking, recent meta analysis has revealed that there is no difference in terms of graft and patient's survival between ABOi and ABO compatible kidney transplant, even in the long term. However, many concerns still exist, because ABOi kidney transplantation is associated with an increased risk of bleeding and infectious complications, partly related to the effects of extracorporeal treatments and the strong immunosuppression. Thus, a continuous improvement in desensitization strategies, with the aim of minimize the immunosuppressive burden, on the basis of immune pathogenesis, antibodies titers and/or ABO blood group, is warranted. In this review, we discuss the main immune mechanisms involved in ABOi kidney transplantation, the pathogenesis of tolerance and the desensitization regimens, including immunoadsorption and plasmapheresis and the immunosuppressive protocol. Finally, we provide an overview on outcome and future perspectives in ABOi kidney transplant.

Precision Nephrology in Patients with Diabetes and Chronic Kidney Disease.

Diabetes is the leading cause of kidney failure and specifically, diabetic kidney disease (DKD) occurs in up to 30% of all diabetic patients. Kidney disease attributed to diabetes is a major contributor to the global burden of the disease in terms of clinical and socio-economic impact, not only because of the risk of progression to End-Stage Kidney Disease (ESKD), but also because of the associated increase in cardiovascular (CV) risk. Despite the introduction of novel treatments that allow us to reduce the risk of future outcomes, a striking residual cardiorenal risk has been reported. This risk is explained by both the heterogeneity of DKD and the individual variability in response to nephroprotective treatments. Strategies that have been proposed to improve DKD patient care are to develop novel biomarkers that classify with greater accuracy patients with respect to their future risk (prognostic) and biomarkers that are able to predict the response to nephroprotective treatment (predictive). In this review, we summarize the principal prognostic biomarkers of type 1 and type 2 diabetes and the novel markers that help clinicians to individualize treatments and the basis of the characteristics that predict an optimal response.

ANCA-Associated Glomerulonephritis and Anti-Phospholipid Syndrome in a Patient with SARS-CoV-2 Infection: Just a Coincidence?

Many reports have described a high incidence of acute kidney injury (AKI) among patients with COVID-19. Acute tubular necrosis has been reported to be the most common damage in these patients, probably due to hemodynamic instability. However, other complex processes may be involved, related to the cytokine storm and the activation of innate and adaptive immunity. Here, we describe a patient who developed an antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis with rapidly progressive glomerulonephritis and lung involvement and an antiphospholipid syndrome soon after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. After viral pneumonia was excluded by bronchoalveolar lavage, the patient has been treated with rituximab for amelioration of kidney function and resolution of thrombosis without any adverse event. We conclude that COVID-19 may trigger autoimmune diseases including ANCA-associated vasculitis. Thus, this diagnosis should be taken in consideration in COVID-19 patients, especially when they develop AKI with active urinary sediment. In addition, considering the relationship between these 2 diseases, SARS-CoV-2 infection should be excluded in all patients with a new diagnosis ANCA-associated vasculitis before starting immunosuppressive therapy.

Occupational Exposures and Smoking in Eosinophilic Granulomatosis With Polyangiitis: A Case-Control Study.

OBJECTIVE: Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. Environmental agents and occupational exposures may confer susceptibility to EGPA, but data are scarce. This study was undertaken to investigate the association between occupational exposures (e.g., silica, farming, asbestos, and organic solvents) and other environmental agents (e.g., smoking) and the risk of EGPA. METHODS: Patients with newly diagnosed EGPA (n = 111) and general population controls (n = 333) who were matched for age, sex, and geographic area of origin were recruited at a national referral center for EGPA. Exposures were assessed using a dedicated questionnaire administered by a specialist in occupational medicine, under blinded conditions. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. RESULTS: Exposures to silica (OR 2.79 [95% CI 1.55-5.01], P = 0.001), organic solvents (OR 3.19 [95% CI 1.91-5.34], P < 0.001), and farming (OR 2.71 [95% CI 1.71-4.29], P < 0.001) were associated with an increased risk of EGPA. Co-exposure to silica and farming yielded an OR of 9.12 (95% CI 3.06-27.19, P < 0.001), suggesting a multiplicative effect between these 2 exposures. Smoking (current and former smokers combined) was significantly less frequent among patients with EGPA compared to controls (OR 0.49 [95% CI 0.29-0.70], P < 0.001). The pack-year index was also lower among patients with EGPA (OR 0.96 [95% CI 0.94-0.98], P < 0.001). The association of silica and farming was primarily aligned with ANCA-positive EGPA, while the association of smoking status and organic solvents was primarily aligned with ANCA-negative EGPA. CONCLUSION: The environment can influence susceptibility to EGPA. Exposure to silica, farming, or organic solvents is associated with an increased risk of EGPA, while smoking is associated with a lower risk. These exposures seem to have distinct effects on different EGPA subsets.

Into Clinical Practice: Diagnosis and Therapy of Retroperitoneal Fibrosis.

PURPOSE OF THE REVIEW: We aim to review the most relevant diagnostic features and treatment options of retroperitoneal fibrosis, in order to provide a useful guide for clinical practice. RECENT FINDINGS: The recent literature highlights the role of imaging studies such as computed tomography, magnetic resonance imaging and positron emission tomography as useful tools for the diagnosis of retroperitoneal fibrosis, with retroperitoneal biopsy being reserved to atypical cases. The treatment approach is mainly conservative and is based on the use of medical therapies plus urological interventions. Medical therapies essentially comprise glucocorticoids and immunosuppressants-either traditional or biological agents such as rituximab. Surgical ureterolysis is only left for refractory cases. Recent findings in retroperitoneal fibrosis highlight the possibility of a non-invasive diagnostic approach and a conservative treatment strategy.

Slowly progressive anti-neutrophil cytoplasmic antibody-associated renal vasculitis: clinico-pathological characterization and outcome.

BACKGROUND: Although rapidly progressive glomerulonephritis is the main renal phenotype of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), slow renal disease progression is sometimes observed. These forms have been rarely discussed; we analysed their prevalence, clinico-pathological characteristics and outcome. METHODS: We screened patients with microscopic  polyangiitis (MPA) and granulomatosis with polyangiitis followed at seven referral centres and selected those with estimated glomerular filtration rate (eGFR) reduction <50% over a 6-month period preceding diagnosis. Data regarding patient features and response to treatment were retrieved. RESULTS: Of 856 patients, 41 (5%) had slowly progressive renal AAV. All had MPA and all but one was P-ANCA/myeloperoxidase (MPO) ANCA-positive. At diagnosis, the median age was 70 years [interquartile range (IQR) 64-78] and extra-renal manifestations were absent or subclinical (interstitial lung lesions in 10, 24%). The median (IQR) eGFR was 23 mL/min/1.73 m2 (15-35); six patients (15%) had started renal replacement therapy (RRT). All had proteinuria (median 1180 mg/24 h, IQR 670-2600) and micro-haematuria. Main histologic findings were extracapillary proliferation at chronic stages and glomerulosclerosis; following Berden's classification, 6/28 biopsies (21%) were 'focal', 1/28 (4%) 'crescentic', 9/28 (32%) 'mixed' and 12/28 (43%) 'sclerotic'. At last follow-up (median 32 months, IQR 12-52), 20/34 patients (59%) treated with immunosuppression had eGFR improvement >25% as compared with diagnosis, while 4/34 (12%) had started RRT. CONCLUSIONS: AAV may present with slow renal disease progression; this subset is hallmarked by advanced age at diagnosis, positive MPO-ANCA, subclinical interstitial lung lesions and chronic damage at kidney biopsy. Partial renal recovery may occur following immunosuppression.

Adult-onset IgA vasculitis (Henoch-Schönlein): Update on therapy.

Immunoglobulin A vasculitis (IgAV, formerly Henoch-Schönlein purpura) is a systemic inflammatory disease affecting small vessels. While it is common and usually benign in childhood, in adults it is rarer has a more severe course. Its main manifestations are cutaneous purpura, arthralgias or arthritis, acute enteritis and glomerulonephritis. Renal involvement is associated with a poor prognosis in adults. The treatment of adult-onset IgAV is still a matter of debate: although in patients with a non-severe phenotype remission can occur spontaneously, more severe cases may need immunosuppressive therapy. There are some areas of uncertainty with respect to the efficacy of immunosuppressive regimens: almost all data come from studies performed in children or from patients with IgA nephropathy and/or IgA-crescentic glomerulonephritis. The only randomised study performed in adults with IgAV and renal involvement showed that immunosuppressive therapy with cyclophosphamide did not improve renal outcome nor did it affect patient survival. The possible efficacy of other drugs is reported only in small case series. Recent evidences show that rituximab could be an effective therapeutic option for adult-onset IgAV, but this also needs to be confirmed in controlled trials. In this review, we focus on therapeutic options for adult-onset IgAV treatment, and discuss the main results of the studies performed so far.

SARS-CoV-2 infection in kidney transplant recipients: Experience of the italian marche region.

BACKGROUND: Infection related to Coronavirus-19 (CoV-2) is pandemic affecting more than 4 million people in 187 countries worldwide. By May 10, 2020, it caused more than 280 000 deaths all over the world. Preliminary data reported a high prevalence of CoV-2 infection and mortality due to severe acute respiratory syndrome related CoV-2 (SARS-CoV-2) in kidney-transplanted patients (KTRs). Nevertheless, the outcomes and the best treatments for SARS-CoV-2-affected KTRs remain unclear. METHODS: In this report, we describe the clinical data, the treatments, and the outcomes of 5 KTRs with SARS-CoV-2 admitted to our hospital in Ancona, Marche region, Italy, from March 17 to present. Due to the severity of SARS-CoV-2, immunosuppression with calcineurin inhibitors, antimetabolites, and mTOR-inhibitors were stopped at the admission. All KTRs were treated with low-dose steroids. 4/5 KTRs were treated with hydroxychloroquine. All KTRs received tocilizumab up to one dose. RESULTS: Overall, the incidence of SARS-CoV-2 in KTRs in the Marche region was 0.85%. 3/5 were admitted in ICU and intubated. One developed AKI with the need of CRRT with Cytosorb. At present, two patients died, two patients were discharged, and one is still inpatient in ICU. CONCLUSIONS: The critical evaluation of all cases suggests that the timing of the administration of tocilizumab, an interleukin-6 receptor antagonist, could be associated with a better efficacy when administered in concomitance to the drop of the oxygen saturation. Thus, in SARS-CoV-2-affected KTRs, a close biochemical and clinical monitoring should be set up to allow physicians to hit the virus in the right moment such as a sudden reduction of the oxygen saturation and/or a significant increase in the laboratory values such as D-dimer.

IgG4-related disease: a clinical perspective.

IgG4-related disease (IgG4-RD) is a recently recognized fibro-inflammatory disorder that can affect almost any organ. Common presentations include major salivary and lacrimal gland enlargement, orbital disease, autoimmune pancreatitis, retroperitoneal fibrosis and tubulointerstitial nephritis. The main histopathological features are a dense, polyclonal, lymphoplasmacytic infiltrate rich in IgG4+ plasma cells, storiform fibrosis and obliterative phlebitis. The precise pathogenic mechanisms of IgG4-RD are still unclear. CD4+ T and B cells, including IgG4-expressing plasmablasts, constitute the major inflammatory cell populations and are believed to cause organ damage and tissue fibrosis. The diagnosis of the disease may be challenging and should be based on specific histopathological findings, typical laboratory and radiological aspects and an appropriate clinical context. The first-line treatment of IgG4-RD is based on glucocorticoids, which are usually efficacious. However, B cell depletion induced by rituximab has also been found to induce remission in steroid-resistant disease or has been used as steroid-sparing agent for relapsing disease. This review provides an update on clinical and therapeutic aspects of IgG4-RD.

Fibrocytes in Chronic Periaortitis: A Novel Mechanism Linking Inflammation and Fibrosis.

OBJECTIVE: Chronic periaortitis (CP) is a rare disease characterized by periaortic and periiliac fibroinflammatory tissue. The pathogenic mechanisms leading to tissue accumulation and activation of fibroblasts are unclear. This study was undertaken to explore the role of fibrocytes, circulating precursors of tissue fibroblasts, in patients with CP. METHODS: We studied 44 patients with newly diagnosed CP and 30 healthy controls. Circulating fibrocytes were identified as Col1+CD45+ cells using flow cytometry. Retroperitoneal tissue biopsy samples from 9 CP patients were stained with anti-type I procollagen, anti-CXCR4, and anti-CD45 antibodies and analyzed by confocal microscopy to detect tissue-infiltrating fibrocytes. Circulating levels and tissue expression of CXCL12, a CXCR4 ligand that promotes fibrocyte homing, were investigated using enzyme-linked immunosorbent assay and immunohistochemistry, respectively. We also characterized T helper polarization in biopsy samples from CP patients and measured serum levels of a panel of cytokines that are hallmarks of T helper responses and capable of influencing fibrocyte differentiation. RESULTS: The frequency of circulating Col1+CD45+ fibrocytes was higher in patients than in controls (P = 0.0371). CD45+proCol1+ and CXCR4+proCol1+ cells were detected in all examined biopsy samples from CP patients. Serum levels of CXCL12 were also higher in CP patients than controls (P = 0.0056), and tissue-infiltrating inflammatory cells intensely expressed CXCL12. Increased serum levels of Th2 cytokines (e.g., interleukin-13 [IL-13] and IL-10) were found in patients, and immunohistochemistry revealed a dominant infiltration of GATA-3+ cells, also indicating Th2 polarization; Th2-skewed responses are known to promote fibrocyte differentiation. CONCLUSION: Our findings indicate that fibrocytes are enriched in the peripheral blood of CP patients and infiltrate target lesions. The accumulation of fibrocytes in the pathologic tissue might be driven by CXCL12, and Th2-skewed immune responses are likely to facilitate their differentiation.