Immune checkpoint inhibitor use in oncology is increasing rapidly. We sought to determine the frequency, severity, cause, and predictors of AKI in a real-world population receiving checkpoint ...inhibitors.
We included all patients who received checkpoint inhibitor therapy from May 2011 to December 2016 at Massachusetts General Hospital. Baseline serum creatinine, averaged 6 months before checkpoint inhibitor start date, was compared with all subsequent creatinine values within 12 months of starting therapy. AKI was defined by Kidney Disease: Improving Global Outcomes criteria for fold changes in creatinine from baseline. Sustained AKI events lasted at least 3 days and was our primary outcome. The cause of sustained AKI was determined by chart review. Cumulative incidence and subdistribution hazard models were used to assess the relationship between baseline demographics, comorbidities, and medications, and sustained AKI and potential checkpoint inhibitor-related AKI.
We included 1016 patients in the analysis. Average age was 63 (SD 13) years, 61% were men, and 91% were white. Mean baseline creatinine was 0.9 mg/dl (SD 0.4 mg/dl), and 169 (17%) had CKD (eGFR<60 ml/min per 1.73 m
) at baseline. A total of 169 patients (17%) experienced AKI, defined by an increase in creatinine at least 1.5 times the baseline within 12 months; 82 patients (8%) experienced sustained AKI and 30 patients (3%) had potential checkpoint inhibitor-related AKI. The first episode of sustained AKI occurred, on average, 106 days (SD 85) after checkpoint inhibitor initiation. Sixteen (2%) patients experienced stage 3 sustained AKI and four patients required dialysis. Proton pump inhibitor use at baseline was associated with sustained AKI.
AKI is common in patients receiving checkpoint inhibitor therapy. The causes of sustained AKI in this population are heterogenous and merit thorough evaluation. The role of PPI and other nephritis-inducing drugs in the development of sustained AKI needs to be better defined.
Immune checkpoint inhibitors (ICIs) are the standard of care for the treatment of several cancers. While these immunotherapies have improved patient outcomes in many clinical settings, they bring ...accompanying risks of toxicity, specifically immune-related adverse events (irAEs). There is a need for clear, effective guidelines for the management of irAEs during ICI treatment, motivating the Society for Immunotherapy of Cancer (SITC) to convene an expert panel to develop a clinical practice guideline. The panel discussed the recognition and management of single and combination ICI irAEs and ultimately developed evidence- and consensus-based recommendations to assist medical professionals in clinical decision-making and to improve outcomes for patients.
Immune checkpoint inhibitors (CPIs), monoclonal antibodies that target inhibitory receptors expressed on T cells, represent an emerging class of immunotherapy used in treating solid organ and ...hematologic malignancies. We describe the clinical and histologic features of 13 patients with CPI-induced acute kidney injury (AKI) who underwent kidney biopsy. Median time from initiation of a CPI to AKI was 91 (range, 21 to 245) days. Pyuria was present in 8 patients, and the median urine protein to creatinine ratio was 0.48 (range, 0.12 to 0.98) g/g. An extrarenal immune-related adverse event occurred prior to the onset of AKI in 7 patients. Median peak serum creatinine was 4.5 (interquartile range, 3.6–7.3) mg/dl with 4 patients requiring hemodialysis. The prevalent pathologic lesion was acute tubulointerstitial nephritis in 12 patients, with 3 having granulomatous features, and 1 thrombotic microangiopathy. Among the 12 patients with acute tubulointerstitial nephritis, 10 received treatment with glucocorticoids, resulting in complete or partial improvement in renal function in 2 and 7 patients, respectively. However, the 2 patients with acute tubulointerstitial nephritis not given glucocorticoids had no improvement in renal function. Thus, CPI-induced AKI is a new entity that presents with clinical and histologic features similar to other causes of drug-induced acute tubulointerstitial nephritis, though with a longer latency period. Glucocorticoids appear to be a potentially effective treatment strategy. Hence, AKI due to CPIs may be caused by a unique mechanism of action linked to reprogramming of the immune system, leading to loss of tolerance.
Objective
Late‐onset neutropenia (LON) is an underrecognized complication of rituximab treatment. We undertook this study to describe its incidence, risk factors, clinical features, management, and ...recurrence.
Methods
We conducted a single‐center retrospective cohort study of 738 adult patients with autoimmune disease who were treated with rituximab to induce continuous B cell depletion. The primary outcome measure was LON, defined as an unexplained absolute neutrophil count of <1,000 cells/µl during B cell depletion. Secondary outcome measures included incidental diagnosis, fever, sepsis, filgrastim use, and recurrent LON. We assessed predictors of LON using Cox proportional hazards regression models. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) were calculated.
Results
We identified 107 episodes of LON in 71 patients. The cumulative incidence at 1 year of B cell depletion therapy was 6.6% (95% CI 5.0–8.7). The incidence rate during the first year was higher compared to thereafter (7.2 cases per 100 person‐years 95% CI 5.4–9.6 versus 1.5 cases per 100 person‐years 95% CI 1.0–2.3). Systemic lupus erythematosus and combination therapy with cyclophosphamide were each independently associated with an increased risk of LON (adjusted HR 2.96 95% CI 1.10–8.01 and 1.98 95% CI 1.06–3.71, respectively). LON was not observed in minimal change disease or focal segmental glomerulosclerosis. The majority of episodes (59.4%) were asymptomatic. Fever and sepsis complicated 31.3% and 8.5% of episodes, respectively. Most patients (69%) were treated with filgrastim. Rituximab rechallenge occurred in 87% of patients, of whom 21% developed recurrent LON.
Conclusion
LON is common and often incidental. Most cases are reversible and respond well to filgrastim. However, LON can be associated with serious infections and thus warrants vigilant monitoring.
Immune checkpoint inhibitors (ICPIs) have transformed the landscape of oncology, but are associated with a variety of autoimmune adverse events, including AKI. ICPI-associated AKI (ICPI-AKI) is ...emerging as an increasingly frequent cause of AKI in patients with cancer, and poses unique diagnostic and management challenges to clinicians who care for these patients. In this review, we describe the incidence and risk factors for ICPI-AKI, including proton pump inhibitor use, CKD, and combination immunotherapy. We discuss the limitations of the various definitions used for ICPI-AKI in prior studies, and propose a novel classification system (definite, probable, and possible ICPI-AKI) that recognizes the diagnostic uncertainty inherent in many cases. We discuss the key clinicopathologic features and treatment strategies for ICPI-AKI, including the role of kidney biopsy versus empirical treatment with steroids. We also explore the under-studied area of ICPI use in the setting of solid organ transplantation, where nephrologists and oncologists must balance the risk of rejection versus treating the underlying malignancy. Finally, we summarize existing data on the role of ICPI rechallenge after an episode of ICPI-AKI.
IgG4-related disease and the kidney Cortazar, Frank B; Stone, John H
Nature reviews. Nephrology,
10/2015, Volume:
11, Issue:
10
Journal Article
Peer reviewed
IgG4-related disease (IgG4-RD) is a systemic fibroinflammatory condition that involves almost every organ system. In this Review, we summarize current knowledge of IgG4-RD and its most frequent ...manifestations in the kidney—IgG4-related tubulointerstitial nephritis (TIN) and membranous glomerulonephropathy (MGN). Diagnosis of IgG4-RD relies on histopathology: the typical features are a dense lymphoplasmacytic infiltrate and storiform fibrosis. A high percentage of plasma cells observed within lesions stain positively for IgG4. IgG4-related TIN bears the hallmark pathological findings of IgG4-RD; distinctive radiographic characteristics are also frequently observed with use of contrast-enhanced CT. MGN secondary to IgG4-RD seems to be distinct from idiopathic MGN. Humoral and cell-mediated immunity seem to have roles in the pathophysiology of IgG4-RD, but the details of these roles remain unclear. The IgG4 molecule itself is unlikely to be the primary driver of inflammation; rather, it probably downregulates the immune response. Fibrosis might be caused by activation of innate immune cells by polarized CD4(+) T cells. Glucocorticoids are the standard initial treatment for IgG4-RD, but their long-term adverse effects and the high frequency of relapse and renal damage associated with use of this treatment has prompted a search for more effective options. B-cell depletion and the targeting of plasmablasts are both promising approaches.
B-cell depletion with rituximab has emerged as a first-line therapy for primary membranous nephropathy (MN). However, most patients do not achieve complete remission with rituximab monotherapy. In ...this case series, we report longer-term remission and relapse rates, anti-phospholipase A2 receptor (PLA2R) antibody levels, B-cell levels, and serious adverse events in patients with primary MN who received rituximab combined with an initial short course of low-dose oral cyclophosphamide and a course of rapidly tapered prednisone.
Single-center retrospective case series.
60 consecutive patients with primary MN treated with the combination of rituximab, low-dose cyclophosphamide, and prednisone at the Vasculitis and Glomerulonephritis Center at the Massachusetts General Hospital.
After treatment initiation, median follow-up was 38 (interquartile range IQR, 25-62) months; 100% of patients achieved partial remission, defined as a urinary protein-creatinine ratio (UPCR) < 3 g/g and a 50% reduction from baseline, at a median of 3.4 months. By 2 years after treatment initiation, 83% achieved complete remission, defined as a UPCR < 0.3 g/g. The median time to complete remission was 12.4 months. Immunologic remission (defined by an anti-PLA2R titer < 14 RU/mL) was achieved by 86% and 100% of anti-PLA2R seropositive patients (n = 29) at 3 and 6 months, respectively, after treatment initiation. After 1 year, the median UPCR fell from 8.4 (IQR, 5.0-10.7) to 0.3 (IQR, 0.2-0.8) g/g (P < 0.001). No patient relapsed throughout the duration of B-cell depletion. Relapse occurred in 10% of patients at 2 years after the onset of B-cell reconstitution following the last rituximab dose. Over a combined follow-up time of 228 patient-years, 18 serious adverse events occurred. One death occurred unrelated to treatment or primary MN, and 1 patient progressed to kidney failure requiring kidney replacement therapy.
Absence of a comparison group.
All patients with primary MN treated with combination therapy achieved partial remission and most achieved a durable complete remission with an acceptable safety profile.
Objective
To evaluate the effect of rituximab on pathogenic autoantibodies and total Ig levels, and to identify serious adverse events in patients with antineutrophil cytoplasmic antibody ...(ANCA)–associated vasculitis (AAV) treated with continuous B cell depletion.
Methods
We conducted a retrospective analysis of 239 patients with AAV treated with rituximab‐induced continuous B cell depletion. Two treatment cohorts were analyzed: an induction group (n = 52) and a maintenance group (n = 237). Changes in ANCA titers and total Ig levels over time were evaluated using mixed‐effects models. Risk factors for serious infections during maintenance treatment were evaluated using Poisson regression.
Results
During induction, IgG levels fell at a mean rate of 6% per month (95% confidence interval 95% CI 4, 8%), while ANCA levels declined at a mean rate of 47% per month (95% CI 42, 52%) and 48% per month (95% CI 42, 54%) for patients with antimyeloperoxidase (anti‐MPO) antibodies and those with anti–proteinase 3 (anti‐PR3) antibodies, respectively. During maintenance treatment, with a median duration of 2.4 years (interquartile range 1.5, 4.0 years), IgG levels declined a mean of 0.6% per year (95% CI −0.2, 1.4%). New significant hypogammaglobulinemia (IgG level of <400 mg/dl) during maintenance treatment occurred in 4.6% of the patients, all of whom were in the lowest baseline IgG quartile. Serious infections during maintenance therapy occurred at a rate of 0.85 per 10 patient‐years (95% CI 0.66, 1.1) and were independently associated with an IgG level of <400 mg/dl.
Conclusion
B cell–targeted therapy causes a preferential decline in ANCA titers relative to total IgG levels. Despite prolonged maintenance therapy with rituximab, IgG levels remain essentially constant. Serious infections were rare.
Antineutrophil cytoplasmic antibody-associated vasculitis (AAV) is the most common cause of rapidly progressive glomerulonephritis. ANCAs play an important role in the pathogenesis and diagnosis of ...AAV. The classic renal lesion in AAV is a pauci-immune necrotizing and crescentic glomerulonephritis. Treatment is divided into 2 phases: (1) induction of remission to eliminate disease activity and (2) maintenance of remission to prevent disease relapse. AAV patients with end-stage renal disease require modification of immunosuppressive strategies and consideration for kidney transplantation. An improved understanding of disease pathogenesis has led to new treatment strategies being tested in clinical trials.
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