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BACKGROUND: Minimal Change Disease (MCD) and Focal Segmental Glomerulosclerosis (FSGS) are a spectrum of disease causing the nephrotic syndrome (NS), characterised by proteinuria with debilitating oedema, as well as a high risk of venous thromboembolic disease and infection. Untreated, 50-60% patients with FSGS progress to end stage kidney disease after 5 years. These diseases respond to immunosuppression with high dose glucocorticoids, but 75% will relapse as the glucocorticoids are withdrawn, leading to significant morbidity associated with prolonged use. In children, the B cell depleting monoclonal antibody rituximab reduces relapse risk, but this drug has not been tested in randomised controlled trial in adults. METHODS: 130-150 adults with new or relapsing MCD/FSGS, from UK Renal Units, are being randomised to receive either rituximab (two 1 g infusions two weeks apart) or placebo. Partipicipants are recruited when they present with nephrosis, and all are treated with glucocorticoids as per KDIGO guidelines. Once in remission, prednisolone is withdrawn according to a pre-specified regimen. If in remission at 6 months, participants receive a further dose of trial drug. If they relapse, they are unblinded, and if they have received placebo, they are offered open label rituximab with protocolised prednisolone as in the main phase of the trial. The primary end point is time from remission to relapse. A number of secondary endpoints will be assessed including the effect of rituximab on: (1) NHS and societal resource use and hence cost: (2) safety: (3) other measures of efficacy, such as achievement of partial and complete remission of NS and the preservation of renal function: (4) health status of participant. TRIAL REGISTRATION: TURING received ethical approval on 14 Jun 2019 - REC reference: 19/LO/0738. It is registered on EudraCT, with ID number: 2018-004611-50, with a start date of 2019-06-14.
Subject(s)
Cost-Benefit Analysis , Glomerulosclerosis, Focal Segmental , Nephrosis, Lipoid , Nephrotic Syndrome , Rituximab , Humans , Rituximab/therapeutic use , Double-Blind Method , Nephrosis, Lipoid/drug therapy , Glomerulosclerosis, Focal Segmental/drug therapy , Nephrotic Syndrome/drug therapy , Recurrence , Immunologic Factors/therapeutic use , Immunologic Factors/economics , Treatment Outcome , Adult , Randomized Controlled Trials as TopicABSTRACT
Posttransplant malignancies are an important complication of solid organ transplantation. Kidney transplant recipients are at particularly high risk of cancer development. The most relevant risk factors of carcinogenesis are the use of immunosuppressive agents and oncogenic viral infections. Additionally, immune dysregulation caused by these factors may predispose to various types of organ damage. Paraneoplastic glomerular diseases are one of the most interesting and understudied cancer manifestations. The appropriate diagnosis of paraneoplastic glomerular damage can be challenging in kidney transplant recipients, due to factors inherent to concomitant medication and common comorbidities. Recent advances in the field of molecular and clinical nephrology led to a significant improvement in our understanding of glomerular diseases and their more targeted treatment. On the other hand, introduction of novel anticancer drugs tremendously increased patients' survival, at the cost of kidney-related side effects. Our review aims to provide insights into diagnosis and treatment of paraneoplastic glomerular diseases, with a special attention to kidney transplant recipients.
Subject(s)
Glomerulonephritis , Kidney Transplantation , Paraneoplastic Syndromes , Humans , Kidney Transplantation/adverse effects , Paraneoplastic Syndromes/etiology , Risk Factors , Glomerulonephritis/etiology , Immunosuppressive Agents/adverse effects , Immunosuppressive Agents/therapeutic use , Postoperative Complications/etiology , Postoperative Complications/epidemiology , Graft SurvivalABSTRACT
This study aims to figure out the worldwide prevalence of anticancer therapy-associated acute kidney injury (AKI) and tubulointerstitial nephritis (TIN) and the relative risk of each cancer drug. We conducted an analysis of VigiBase, the World Health Organization pharmacovigilance database, 1967-2023 via disproportionate Bayesian reporting method. We further categorized the anticancer drugs into four groups: cytotoxic therapy, hormone therapy, immunotherapy, and targeted therapy. Reporting odds ratio (ROR) and information component (IC) compares observed and expected values to investigate the associations of each category of anticancer drugs with AKI and TIN. We identified 32,722 and 2056 reports (male, n = 17,829 and 1,293) of anticancer therapy-associated AKI and TIN, respectively, among 4,592,036 reports of all-drug caused AKI and TIN. There has been a significant increase in reports since 2010, primarily due to increased reports of targeted therapy and immunotherapy. Immunotherapy exhibited a significant association with both AKI (ROR: 8.92; IC0.25: 3.06) and TIN (21.74; 4.24), followed by cytotoxic therapy (7.14; 2.68), targeted therapy (5.83; 2.40), and hormone therapy (2.59; 1.24) for AKI, and by cytotoxic therapy (2.60; 1.21) and targeted therapy (1.54; 0.61) for TIN. AKI and TIN were more prevalent among individuals under 45 years of age, with a female preponderance for AKI and males for TIN. These events were reported in close temporal relationship after initiation of the respective drug (16.53 days for AKI and 27.97 days for TIN), and exhibited a high fatality rate, with 23.6% for AKI and 16.3% for TIN. These findings underscore that kidney-related adverse drug reactions are of prognostic significance and strategies to mitigate such side effects are required to optimize anticancer therapy.
Subject(s)
Acute Kidney Injury , Antineoplastic Agents , Nephritis, Interstitial , Humans , Acute Kidney Injury/chemically induced , Acute Kidney Injury/epidemiology , Nephritis, Interstitial/chemically induced , Nephritis, Interstitial/epidemiology , Male , Female , Antineoplastic Agents/adverse effects , Middle Aged , Adult , Aged , Prevalence , Databases, Factual , PharmacovigilanceSubject(s)
Antibodies, Antineutrophil Cytoplasmic , Glomerulonephritis , Humans , Glomerulonephritis/immunology , Glomerulonephritis/etiology , Glomerulonephritis/diagnosis , Child , Antibodies, Antineutrophil Cytoplasmic/blood , Antibodies, Antineutrophil Cytoplasmic/immunology , Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis/diagnosis , Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis/immunology , Age Factors , Adolescent , Child, Preschool , Male , FemaleABSTRACT
BACKGROUND: To examine the agreement of different calculated estimated glomerular filtration rate (eGFR) formulas and measured creatinine clearance (CrCI) at the primary diagnosis of muscle-invasive bladder cancer (MIBC). MATERIALS AND METHODS: We performed a multicenter analysis of patients with MIBC, treated with cisplatin-based neoadjuvant chemotherapy (NAC) and radical cystectomy (RC), or with RC alone, between 2011 and 2021. Baseline eGFR was computed using 4 calculated serum equations including Cockcroft-Gault (CG), MDRD, CKD-EPI 2009, and race-free CKD-EPI 2021. To examine the association between calculated eGFR and measured CrCI, subgroup analyses were performed among patients in whom measured 24-hour urine CrCl was determined. Cisplatin-ineligibility was defined as CrCI and/or eGFRâ <â 60 mL/minute per 1.73 m2. RESULTS: Of 956 patients, 30.0%, 33.3%, 31.9%, and 27.7% were found to be cisplatin-ineligible by the CG, MDRD, CKD-EPI, and race-free CKD-EPI equations (Pâ =â .052). The concordance between calculated eGFR formulas was rated substantial (Cohen's kappa (k): 0.66-0.95). Among the subgroup (nâ =â 245) with measured CrCl, 37 (15.1%) patients had a CrCI less than 60 mL/minute. Concordance between measured CrCl and calculated eGFR was poor (ĸ: 0.29-0.40). All calculated eGFR formulas markedly underestimated the measured CrCI. Specifically, 78%-87.5% of patients with a calculated eGFR between 40 and 59 mL/minute exhibited a measured CrCIâ ≥â 60 mL/minute. CONCLUSIONS: Comparing calculated eGFR formulas, similar percentages of patients with MIBC were deemed cisplatin-ineligible. However, a significant number of patients could be upgraded by being cisplatin-fit based on measured CrCI, particularly when the calculated eGFR was falling within the gray range of 40-59 mL/minute.
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AIMS/HYPOTHESIS: Non-adherence to medication is a frequent barrier in the treatment of patients with type 2 diabetes mellitus, potentially limiting the effectiveness of evidence-based treatments. Previous studies have mostly relied on indirect adherence measures to analyse outcomes based on adherence. The aim of this study was to use LC-MS/MS in urine-a non-invasive, direct and objective measure-to assess non-adherence to cardiometabolic drugs and analyse its association with kidney and cardiovascular outcomes. METHODS: This cohort study includes 1125 participants from the PROVALID study, which follows patients with type 2 diabetes mellitus at the primary care level. Baseline urine samples were tested for 79 cardiometabolic drugs and metabolites thereof via LC-MS/MS. An individual was classified as totally adherent if markers for all drugs were detected, partially non-adherent when at least one marker for one drug was detected, and totally non-adherent if no markers for any drugs were detected. Non-adherence was then analysed in the context of cardiovascular (composite of myocardial infarction, stroke and cardiovascular death) and kidney (composite of sustained 40% decline in eGFR, sustained progression of albuminuria, kidney replacement therapy and death from kidney failure) outcomes. RESULTS: Of the participants, 56.3% were totally adherent, 42.0% were partially non-adherent, and 1.7% were totally non-adherent to screened cardiometabolic drugs. Adherence was highest to antiplatelet and glucose-lowering agents and lowest to lipid-lowering agents. Over a median (IQR) follow-up time of 5.10 (4.12-6.12) years, worse cardiovascular outcomes were observed with non-adherence to antiplatelet drugs (HR 10.13 [95% CI 3.06, 33.56]) and worse kidney outcomes were observed with non-adherence to antihypertensive drugs (HR 1.98 [95% CI 1.37, 2.86]). CONCLUSIONS/INTERPRETATION: This analysis shows that non-adherence to cardiometabolic drug regimens is common in type 2 diabetes mellitus and negatively affects kidney and cardiovascular outcomes.
Subject(s)
Diabetes Mellitus, Type 2 , Medication Adherence , Tandem Mass Spectrometry , Humans , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/urine , Male , Female , Middle Aged , Aged , Chromatography, Liquid/methods , Cardiovascular Diseases/urine , Cardiovascular Diseases/drug therapy , Cohort Studies , Kidney/metabolism , Kidney/physiopathology , Kidney/drug effects , Hypoglycemic Agents/therapeutic use , Cardiovascular Agents/therapeutic use , Liquid Chromatography-Mass SpectrometryABSTRACT
Introduction: Glomerulonephritis is frequent in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and crucial to disease outcomes. We conducted a detailed assessment of renal pathology in Japanese patients with AAV, and developed a new score that would predict renal outcome. Methods: Two hundred twenty-one patients who were diagnosed with AAV and underwent a kidney biopsy were enrolled. Data on glomerular, tubular, interstitial, and vascular lesions from kidney biopsies were analyzed; the 3 established classification and prognostic scoring systems (Berden Classification, Mayo Clinic/RPS Chronicity Score [MCCS], and ANCA Renal Risk Score [ARRS]) were validated. Further, we developed a new prognostic score by including variables relevant for Japanese patients with ANCA-glomerulonephritis. Results: Median follow-up was 60 months (interquartile range: 6-60). End-stage kidney disease (ESKD) risk prediction by the MCCS and the ARRS was confirmed. Moreover, our analysis identified 4 items with significant ESKD risk prediction capacity, namely percentage of cellular, fibrocellular, and fibrous crescents; and sclerotic glomeruli. Based on our findings, we created a score evaluating the percentage of these lesions to total glomeruli, the Percentage of ANCA Crescentic Score (PACS). The area under the receiver operating characteristic (ROC) curve evaluating PACS was 0.783. The PACS had a comparable performance as the ARRS in predicting ESKD. The optimal PACS cut-off for ESKD risk over 60 months was 43%. In addition, the percentage of cellular crescents and presence of interstitial inflammation were independent predictors of kidney function recovery. Conclusion: We developed a new score predicting renal prognosis using histopathological data of Japanese patients with ANCA-glomerulonephritis. Studies are needed to validate our results in international cohorts.
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Introduction: Ultracyclists expose themselves to extreme physical challenges. This study aimed to elucidate the effects of ultracycling on electrolyte and fluid balance and investigate the potential occurrence of peripheral edema. Methods: A total of 4 clinical visits were performed before, during, and after a 6-day bicycle ride in 13 ultracyclists (5 female, 8 male) including serial laboratory analyses of blood and urine, bioelectrical impedance, and echocardiography. Throughout the ride, participants continuously tracked fluid intake, measured extremity circumferences daily, and self-tested urinary electrolytes using a point-of-care testing device. Portrait photos were judged by 20 physicians for occurrence of facial and eyelid edema. Results: Participants covered a mean distance of 1205 km and 19,417 vertical meters. From baseline to day 6, body weight remained stable (P = 0.479); however, body composition changed with increasing total body water (TBW) (+1.98 l ± 1.37, P = 0.003) and plasma volume (+18.86 % ± 10.7, P < 0.001). A significant increase in N-terminal pro brain natriuretic peptide (NT-proBNP) (+297.99 ng/l ± 190.42, P < 0.001) until day 6 indicates concomitant cardiac volume overload. Swelling of face and eyelids peaked on day 5 (both P ≤ 0.033). On recovery, changes partly resolved. Although urinary sodium concentration showed a nadir on day 4 (-32.18 mmol/l ± 23.88, P = 0.022), plasma osmolality (+5.69 mmosmol/kg ± 5.88, P = 0.004) and copeptin (+38.28 pg/ml ± 18.90, P < 0.001) increased steadily until day 6. Conclusion: Ultracycling over multiple days induces extracellular volume expansion, peripheral edema, and cardiac volume overload. Renal sodium and water retention is likely contributing to this condition.
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Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis consists of two main diseases, granulomatosis with polyangiitis and microscopic polyangiitis, and remains among the most devastating and potentially lethal forms of autoimmune inflammatory disease. Granulomatosis with polyangiitis and microscopic polyangiitis are characterised by a necrotising vasculitis that can involve almost any organ, and have generally been studied together. The diseases commonly affect the kidneys, lungs, upper respiratory tract, skin, eyes, and peripheral nerves. Granulomatous inflammation and multinucleated giant cells are key pathological hallmarks of granulomatosis with polyangiitis, but are absent in microscopic polyangiitis. Many immune system events are essential to disease aetiopathogenesis, such as activation of the alternative complement pathway, neutrophil activation via complement receptors, and the influx of inflammatory cells, including monocytes and macrophages. These cells perpetuate inflammation and lead to organ damage. During the 21st century, the management of ANCA-associated vasculitis has moved away from reliance on cytotoxic medications and towards targeted biological medications for both the induction and maintenance of disease remission. Earlier diagnosis, partly the result of more reliable ANCA testing, has led to improved patient outcomes and better survival. Reductions in acute disease-related mortality have now shifted focus to long-term morbidities related to ANCA-associated vasculitis and their treatments, such as chronic kidney disease and cardiovascular disease. Therapeutic approaches in both clinical trials and clinical practice still remain too reliant on glucocorticoids, and continued efforts to reduce toxicity from glucocorticoids remain a priority in the development of new treatment strategies.
Subject(s)
Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis , Autoimmune Diseases , Granulomatosis with Polyangiitis , Microscopic Polyangiitis , Humans , Granulomatosis with Polyangiitis/diagnosis , Granulomatosis with Polyangiitis/drug therapy , Microscopic Polyangiitis/diagnosis , Microscopic Polyangiitis/drug therapy , Antibodies, Antineutrophil Cytoplasmic/therapeutic use , Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis/diagnosis , Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis/drug therapy , InflammationABSTRACT
BACKGROUND: Methimazole (MMI) and propylthiouracil (PTU) are commonly used for patients with thyrotoxicosis. Agranulocytosis and antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is associated with high morbidity and mortality, requiring appropriate interventions. In this study, we compared adverse drug effects associated with MMI and PTU using a real-world large pharmacovigilance database. METHODS: We searched all Individual Case Safety Reports reported to be associated with MMI and PTU, from VigiBase between 1967 and June 2, 2021. We conducted disproportionality analysis (case/non-case analysis) to analyze the difference in reported adverse drug reactions (ADRs) between antithyroid drugs (case) and the entire database (non-cases). We further analyzed information for the cases of agranulocytosis and AAV. RESULTS: Among 11 632 cases of ADRs reported after MMI intake, agranulocytosis occurred in 1633 cases and AAV occurred in 41 cases. For 5055 cases of ADRs reported after PTU intake, agranulocytosis occurred in 459 cases and AAV occurred in 110 cases. Agranulocytosis occurred after a median of 28 days after PTU intake and 33 days after MMI intake. More than 95% of the agranulocytosis cases were classified as serious, but most of them (65.1% for PTU and 70.4% for MMI) were reported to have recovered after dechallenge actions; mostly drug withdrawal. AAV occurred after a median of 668 days after PTU intake, and 1162 days after MMI intake. CONCLUSIONS: This is a pharmacoepidemiological study investigating agranulocytosis and AAV caused by MMI and PTU. Through this research, we could provide more specific insights into a safe prescription of antithyroid drugs in a real-world setting.
Subject(s)
Agranulocytosis , Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis , Antithyroid Agents , Databases, Factual , Methimazole , Pharmacovigilance , Propylthiouracil , Antithyroid Agents/adverse effects , Humans , Agranulocytosis/chemically induced , Agranulocytosis/epidemiology , Propylthiouracil/adverse effects , Methimazole/adverse effects , Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis/chemically induced , Female , Male , Middle Aged , Adult , Adverse Drug Reaction Reporting Systems/statistics & numerical data , Aged , World Health Organization , Young Adult , AdolescentABSTRACT
The histopathological lesions, minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) are entities without immune complex deposits which can cause podocyte injury, thus are frequently grouped under the umbrella of podocytopathies. Whether MCD and FSGS may represent a spectrum of the same disease remains a matter of conjecture. Both frequently require repeated high-dose glucocorticoid therapy with alternative immunosuppressive treatments reserved for relapsing or resistant cases and response rates are variable. There is an unmet need to identify patients who should receive immunosuppressive therapies as opposed to those who would benefit from supportive strategies. Therapeutic trials focusing on MCD are scarce, and the evidence used for the 2021 Kidney Disease: Improving Global Outcomes (KDIGO) guideline for the management of glomerular diseases largely stems from observational and pediatric trials. In FSGS, the differentiation between primary forms and those with underlying genetic variants or secondary forms further complicates trial design. This article provides a perspective of the Immunonephrology Working Group (IWG) of the European Renal Association (ERA) and discusses the KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases focusing on the management of MCD and primary forms of FSGS in the context of recently published evidence, with a special emphasis on the role of rituximab, cyclophosphamide, supportive treatment options and ongoing clinical trials in the field.