Borderline rejection: To treat or not to treat?

INTRODUCTION: It is unclear whether kidney transplant recipients with a biopsy diagnosis as a "borderline" acute T-cell mediated rejection (TCMR) requires the treatment with intravenous (iv) steroids pulse plus/minus intensification of the maintenance therapy (TRT) in comparison with the simple clinical follow-up (F-UP). METHODS: We retrospectively followed a consecutive series of kidney transplant recipients diagnosed with a borderline acute TCMR at biopsy by surveillance or clinical indication for 12 months and compared TRT and F-UP groups. We evaluated trends in renal function by measuring estimated glomerular filtration rate (eGFR) using multiple regression models. Repeated eGFR measures (REML) were adjusted for potential confounding factors for 12 months. The difference in 12-month eGFR values were observed in the TRT vs F-UP groups, type of biopsy, as well as the surveillance vs. clinical outcomes. RESULTS: Out of 59 included patients, 37% of them were in the TRT group and remaining 63% in the F-UP group. As expected, the TRT group had, at the time of biopsy, lower eGFR value of 39.0 ml/min/m2 [16.5] in comparison to 49.6 [19.6] ml/min/m2 in the F-UP group (P = 0.043), Similarly, the TRT group required more frequent clinical biopsies vs. F-UP group (68% vs. 32%; P = 0.014). However, the TRT group recovered kidney function reaching the eGFR values of the F-UP group at 12 months; the increase being significant only in patients who received indication biopsies (P < 0.001). The estimated adjusted TRT effect on 12-month eGFR change after indication biopsy was improved by +15.8 ml/min/1.73m2 (95%CI: +0.1 to +31.4 ml/min/1.73 m2; P = 0.048 by three-way interaction term) compared to the F-UP group. CONCLUSION: Our preliminary study supports the indication for the treatment of acute borderline TCMR only in cases with biopsies performed by clinical indication.

Detecting, preventing and treating non-adherence to immunosuppression after kidney transplantation.

Medication non-adherence (MNA) is a major issue in kidney transplantation and it is associated with increased risk of rejection, allograft loss, patients' death and higher healthcare costs. Despite its crucial importance, it is still unclear what are the best strategies to diagnose, prevent and treat MNA. MNA can be intentional (deliberate refusal to take the medication as prescribed) or unintentional (non-deliberate missing the prescribed medication). Its diagnosis may rely on direct methods, aiming at measuring drug ingestions, or indirect methods that analyse the habits of patients to adhere to correct drug dose (taking adherence) and interval (time adherence). Identifying individual risk factors for MNA may provide the basis for a personalized approach to the treatment of MNA. Randomized control trials performed so far have tested a combination of strategies, such as enhancing medication adherence through the commitment of healthcare personnel involved in drug distribution, the use of electronic reminders, therapy simplification or various multidisciplinary approaches to maximize the correction of individual risk factors. Although most of these approaches reduced MNA in the short-term, the long-term effects on MNA and, more importantly, on clinical outcomes remain unclear. In this review, we provide a critical appraisal of traditional and newer methods for detecting, preventing and treating non-adherence to immunosuppression after kidney transplantation from the perspective of the practising physician.

Chemotherapy, targeted therapy and immunotherapy: Which drugs can be safely used in the solid organ transplant recipients?

In solid organ transplant recipients, cancer is associated with worse prognosis than in the general population. Among the causes of increased cancer-associated mortality, are the limitations in selecting the optimal anticancer regimen in solid organ transplant recipients, because of the associated risks of graft toxicity and rejection, drug-to-drug interactions, reduced kidney or liver function, and patient frailty and comorbid conditions. The advent of immunotherapy has generated further challenges, mainly because checkpoint inhibitors increase the risk of rejection, which may have life-threatening consequences in recipients of life-saving organs. In general, there are no safe or unsafe anticancer drugs. Rather, the optimal choice of the anticancer regimen results from a careful risk/benefit assessment, from the awareness of potential pharmacokinetic and pharmacodynamic drug-to-drug interactions, and of the risk of drug overexposure in patients with kidney or liver dysfunction. In this review, we summarize general principles that may help the oncologists and transplant physicians in the multidisciplinary management of recipients of solid organ transplantation with cancer who are candidates for chemotherapy, targeted therapy, or immunotherapy.

Acute Kidney Injury (AKI) before and after Kidney Transplantation: Causes, Medical Approach, and Implications for the Long-Term Outcomes.

Acute kidney injury (AKI) is a common finding in kidney donors and recipients. AKI in kidney donor, which increases the risk of delayed graft function (DGF), may not by itself jeopardize the short- and long-term outcome of transplantation. However, some forms of AKI may induce graft rejection, fibrosis, and eventually graft dysfunction. Therefore, various strategies have been proposed to identify conditions at highest risk of AKI-induced DGF, that can be treated by targeting the donor, the recipient, or even the graft itself with the use of perfusion machines. AKI that occurs early post-transplant after a period of initial recovery of graft function may reflect serious and often occult systemic complications that may require prompt intervention to prevent graft loss. AKI that develops long after transplantation is often related to nephrotoxic drug reactions. In symptomatic patients, AKI is usually associated with various systemic medical complications and could represent a risk of mortality. Electronic systems have been developed to alert transplant physicians that AKI has occurred in a transplant recipient during long-term outpatient follow-up. Herein, we will review most recent understandings of pathophysiology, diagnosis, therapeutic approach, and short- and long-term consequences of AKI occurring in both the donor and in the kidney transplant recipient.

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.

Reduced mortality in COVID-19 patients treated with colchicine: Results from a retrospective, observational study.

OBJECTIVES: Effective treatments for coronavirus disease 2019 (COVID-19) are urgently needed. We hypothesized that colchicine, by counteracting proinflammatory pathways implicated in the uncontrolled inflammatory response of COVID-19 patients, reduces pulmonary complications, and improves survival. METHODS: This retrospective study included 71 consecutive COVID-19 patients (hospitalized with pneumonia on CT scan or outpatients) who received colchicine and compared with 70 control patients who did not receive colchicine in two serial time periods at the same institution. We used inverse probability of treatment propensity-score weighting to examine differences in mortality, clinical improvement (using a 7-point ordinary scale), and inflammatory markers between the two groups. RESULTS: Amongst the 141 COVID-19 patients (118 [83.7%] hospitalized), 70 (50%) received colchicine. The 21-day crude cumulative mortality was 7.5% in the colchicine group and 28.5% in the control group (P = 0.006; adjusted hazard ratio: 0.24 [95%CI: 0.09 to 0.67]); 21-day clinical improvement occurred in 40.0% of the patients on colchicine and in 26.6% of control patients (adjusted relative improvement rate: 1.80 [95%CI: 1.00 to 3.22]). The strong association between the use of colchicine and reduced mortality was further supported by the diverging linear trends of percent daily change in lymphocyte count (P = 0.018), neutrophil-to-lymphocyte ratio (P = 0.003), and in C-reactive protein levels (P = 0.009). Colchicine was stopped because of transient side effects (diarrhea or skin rashes) in 7% of patients. CONCLUSION: In this retrospective cohort study colchicine was associated with reduced mortality and accelerated recovery in COVID-19 patients. This support the rationale for current larger randomized controlled trials testing the safety/efficacy profile of colchicine in COVID-19 patients.

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.

Mortality from cancer is not increased in elderly kidney transplant recipients compared to the general population: a competing risk analysis.

BACKGROUND: The impact of cancer on death of elderly kidney transplant recipients has been extensively investigated, but with conflicting results. Unlike their younger counterparts, in elderly kidney transplant recipients cardiovascular and infectious disease may outweigh cancer in causing the patient's death. METHODS: Using competing risk analysis on a large retrospective cohort of kidney transplant recipients, we estimated the cause-specific cumulative incidence and hazard of death in different age categories and calculated standardized mortality ratios (SMRs) to compare mortality rates with the general population. RESULTS: Six thousand seven hundred eighty-nine kidney transplant recipients were followed-up for a median of 9 years. Ten years after transplantation, in transplant recipients aged 20-39, 40-59, and 60+, the cumulative incidence of cancer-related death was 0.6 (95% confidence interval [CI]: 0.3-1.0), 2.9 (2.3-3.6) and 5.3% (3.5-7.5), whereas the SMR was 9.1 (5.5-15.0), 2.0 (1.6-2.5), and 0.8 (0.6-1.0), respectively. At variance with young recipients, the hazard and the cumulative incidence of cardiovascular-related death in elderly recipients was well above that of cancer-related death. CONCLUSIONS: Relative to the general population, cancer-related death is increased in young but not in elderly kidney transplant recipients because of the more marked increased incidence of competing cause of death in the latter category.

Frailty and Sarcopenia in Older Patients Receiving Kidney Transplantation.

Kidney transplantation is the treatment of choice for most of the patients with end-stage renal disease (ESRD). It improves quality of life, life expectancy, and has a lower financial burden to the healthcare system in comparison to dialysis. Every year more and more older patients are included in the kidney transplant waitlist. Within this patient population, transplanted subjects have better survival and quality of life as compared to those on dialysis. It is therefore crucial to select older patients who may benefit from renal transplantation, as well as those particularly at risk for post-transplant complications. Sarcopenia and frailty are frequently neglected in the evaluation of kidney transplant candidates. Both conditions are interrelated complex geriatric syndromes that are linked to disability, aging, comorbidities, increased mortality, and graft failure post-transplantation. Chronic kidney disease (CKD) and more importantly ESRD are characterized by multiple metabolic complications that contribute for the development of sarcopenia and frailty. In particular, anorexia, metabolic acidosis and chronic low-grade inflammation are the main contributors to the development of sarcopenia, a key component in frail transplant candidates and recipients. Both frailty and sarcopenia are considered to be reversible. Frail patients respond well to multiprofessional interventions that focus on the patients' positive frailty criteria, while physical rehabilitation and oral supplementation may improve sarcopenia. Prospective studies are still needed to evaluate the utility of formally measuring frailty and sarcopenia in the older candidates to renal transplantation as part of the transplant evaluation process.

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.

Clinical and Prognostic Significance of Serum IgG4 in Chronic Periaortitis. An Analysis of 113 Patients.

Objective: Chronic periaortitis (CP) is a rare fibro-inflammatory disorder that incorporates idiopathic retroperitoneal fibrosis, inflammatory abdominal aortic aneurysms, and perianeurysmal retroperitoneal fibrosis. CP is included in the spectrum of IgG4-related disease. Since CP patients rarely undergo diagnostic biopsies, serum IgG4 levels are often used to classify CP as IgG4-related. However, the clinical and prognostic significance of serum IgG4 in CP is unknown. Methods: We measured serum IgG4 in active CP patients and compared the clinical characteristics, response to therapy and outcome of patients with high and normal levels. We also tested the diagnostic significance of IgG4 by comparing its levels in CP patients, healthy and disease controls (malignancies, Erdheim-Chester disease, large-, and small-vessel vasculitis). Results: We studied 113 consecutive patients with active CP. Twenty-four (21.2%) had high serum IgG4 (>135 mg/dL). The demographic, laboratory, and clinical characteristics of patients with high and normal IgG4 were similar, and so were the rates of ureteral obstruction and the disease characteristics on CT, MRI, and 18F-FDG-PET. Patients with high IgG4 only had a higher frequency of extra-retroperitoneal fibro-inflammatory lesions (p = 0.005). There were no significant differences in response to therapy and relapses between the two groups. Serum IgG4 levels did not discriminate CP from controls. Conclusions: Serum IgG4 levels are high in a minority of CP patients and do not identify specific clinical or prognostic subgroups; only a higher frequency of extra-retroperitoneal lesions is found in high-IgG4 patients. Serum IgG4 levels do not help in the differential diagnosis between CP and its mimics.

Metabolic risk profile in kidney transplant candidates and recipients.

Metabolic risk factors of cardiovascular disease such as abnormal glucose regulation, obesity and metabolic syndrome, dyslipidaemia, metabolic bone disease, hyperuricaemia and other less traditional abnormalities are common in both kidney transplant candidates and recipients. In kidney transplant candidates, the presence of these risk factors may impede patient access to transplantation by increasing the risk of developing comorbidities while on the waiting list, prolonging the time to wait-listing and, in some patients, eventually jeopardizing their suitability for kidney transplantation or increasing the risk of severe perioperative complications. In transplant recipients, metabolic risk factors may be associated with increased mortality with a functioning graft and with reduced long-term renal graft survival. Although most transplant recipients have no contraindication to the use of drugs that undergo renal excretion, they may be at risk of drug-to-drug pharmacokinetic interactions with anti-rejection medicines. In this review, we have highlighted the main objectives of evaluating the metabolic abnormalities in transplant candidates and recipients, how this evaluation should be carried out in practice and what currently the most valuable treatment strategies are for modifying the associated risks. We conclude that, for every potential transplant candidate, every effort should be made to control metabolic abnormalities causing arterial calcification, which may impede access to transplantation and impair transplant outcome. In transplant recipients, metabolic abnormalities that result from adverse effects of anti-rejection therapy may be effectively controlled by lifestyle changes and judicious use of drugs for the treatment of abnormal glucose metabolism and dyslipidaemia.

Chronic Periaortitis: an Update.

PURPOSE OF REVIEW: We aim to review traditional concepts and recent developments on the nosology, pathophysiology, clinical phenotypes and treatment of chronic periaortitis (CP). RECENT FINDINGS: CP is a rare disorder hallmarked by a periaortic fibro-inflammatory tissue. It can present as an isolated disease, but it can also be associated with other autoimmune and fibro-inflammatory lesions (e.g., fibrosing mediastinitis, sclerosing pancreato-cholangitis) that are part of the spectrum of IgG4-related disease. In a subgroup of patients, it also involves the thoracic aorta (so-called "diffuse periaortitis"), which supports the notion of an inflammatory disorder of large arteries. The pathogenesis of CP is multifactorial: recent studies have elucidated the predisposing role of immunogenetic variants and exposures to environmental agents such as smoking and asbestos. CP is a rare immune-mediated disease that affects the abdominal aorta and the iliac arteries and, in some cases, the thoracic aorta. It may overlap with manifestations of IgG4-related disease, and its treatment comprises glucocorticoids, conventional and biological immunosuppressive agents.

Methotrexate versus cyclophosphamide for remission maintenance in ANCA-associated vasculitis: A randomised trial.

OBJECTIVES: The treatment of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is based on remission-induction and remission-maintenance. Methotrexate is a widely used immunosuppressant but only a few studies explored its role for maintenance in AAV. This trial investigated the efficacy and safety of methotrexate as maintenance therapy for AAV. METHODS: In this single-centre, open-label, randomised trial we compared methotrexate and cyclophosphamide for maintenance in AAV. We enrolled patients with granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA), the latter with poor-prognosis factors and/or peripheral neuropathy. Remission was induced with cyclophosphamide. At remission, the patients were randomised to receive methotrexate or to continue with cyclophosphamide for 12 months; after treatment, they were followed for another 12 months. The primary end-point was relapse; secondary end-points included renal outcomes and treatment-related toxicity. RESULTS: Of the 94 enrolled patients, 23 were excluded during remission-induction or did not achieve remission; the remaining 71 were randomised to cyclophosphamide (n = 33) or methotrexate (n = 38). Relapse frequencies at months 12 and 24 after randomisation were not different between the two groups (p = 1.00 and 1.00). Relapse-free survival was also comparable (log-rank test p = 0.99). No differences in relapses were detected between the two treatments when GPA+MPA and EGPA were analysed separately. There were no differences in eGFR at months 12 and 24; proteinuria declined significantly (from diagnosis to month 24) only in the cyclophosphamide group (p = 0.0007). No significant differences in adverse event frequencies were observed. CONCLUSIONS: MTX may be effective and safe for remission-maintenance in AAV. TRIAL REGISTRATION: clinicaltrials.gov NCT00751517.