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Anti−glomerular basement membrane (anti-GBM) disease is characterized by pathogenic autoantibodies targeting the α-3 chain of type IV collagen located in the glomerular and alveolar basement membranes. Clinically, it causes rapidly progressive glomerulonephritis and pulmonary hemorrhage. Observational data and mechanistic rationale have largely informed current treatment strategies, including plasmapheresis, glucocorticoids, cyclophosphamide, and rituximab. However, overall and renal prognosis remain guarded, and advancements in therapy are needed. Emerging data have implicated the complement system in the pathogenesis of anti-GBM disease.1, 2, 3, 4, 5 Eculizumab is an anti-C5 monoclonal antibody that blocks the cleavage of C5, which prevents the formation of C5a, the potent leukocyte chemoattractant, and C5b, the initial reagent in the formation of the membrane attack complex (MAC; also known as C5b-9). This provides an immediate inhibition of the downstream proinflammatory and cytotoxic sequelae of the complement system. Here, we report the use of eculizumab as rescue therapy in 2 patients with progressive anti-GBM disease on standard therapies, which, to our knowledge, has not been reported to date. We also present kidney biopsy results with extensive complement staining that add to a limited but growing body of literature on the possible role of complement in the renal damage from anti-GBM disease.

BackgroundCorticosteroids are the mainstay of treatment for immune checkpoint inhibitor-associated acute kidney injury (ICPi-AKI), but the optimal duration of therapy has not been established. Prolonged use of corticosteroids can cause numerous adverse effects and may decrease progression-free survival among patients treated with ICPis. We sought to determine whether a shorter duration of corticosteroids was equally efficacious and safe as compared with a longer duration.MethodsWe used data from an international multicenter cohort study of patients diagnosed with ICPi-AKI from 29 centers across nine countries. We examined whether a shorter duration of corticosteroids (28 days or less) was associated with a higher rate of recurrent ICPi-AKI or death within 30 days following completion of corticosteroid treatment as compared with a longer duration (29–84 days).ResultsOf 165 patients treated with corticosteroids, 56 (34%) received a shorter duration of treatment and 109 (66%) received a longer duration. Patients in the shorter versus longer duration groups were similar with respect to baseline and ICPi-AKI characteristics. Five of 56 patients (8.9%) in the shorter duration group and 12 of 109 (11%) in the longer duration group developed recurrent ICPi-AKI or died (p=0.90). Nadir serum creatinine in the first 14, 28, and 90 days following completion of corticosteroid treatment was similar between groups (p=0.40, p=0.56, and p=0.89, respectively).ConclusionA shorter duration of corticosteroids (28 days or less) may be safe for patients with ICPi-AKI. However, the findings may be susceptible to unmeasured confounding and further research from randomized clinical trials is needed.

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

Antineutrophil cytoplasmic antibody (ANCA)–associated vasculitis (AAV) is a small vessel necrotizing vasculitis with a predilection for the respiratory tract and kidneys.1,2 Prompt initiation of remission induction immunosuppression is paramount to prevent irreversible organ damage.3 Standard initial therapy for severe AAV consists of cyclophosphamide or rituximab in combination with high-dose glucocorticoids.4,5 In cases of severe pulmonary hemorrhage or rapidly progressive glomerulonephritis, plasma exchange is often added to facilitate rapid removal of ANCA.6 Improved understanding of disease pathogenesis has provided the rationale for targeting the complement pathway in AAV.7 In particular, the anaphylatoxin complement component 5a (C5a) has been identified as a key pathogenic mediator of AAV because of its ability to prime and recruit neutrophils.8 Inhibitors of C5a and the C5a receptor are being evaluated in randomized trials, but are not currently available for clinical use.9 Here, we report the use of eculizumab, a monoclonal antibody against C5, in 2 cases of aggressive AAV with the intention of rapidly inducing remission by inhibiting C5a generation. In both patients, religious beliefs prohibiting the receipt of blood products precluded the use of plasma exchange and cyclophosphamide.

Immune checkpoint inhibitors (ICPIs) have transformed the landscape of oncology, but are associated with a variety of autoimmune adverse events, including acute kidney injury (AKI). ICPI-associated AKI (ICPI-AKI) is emerging as an increasingly frequent cause of AKI in cancer patients, 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 empiric 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 re-challenge following an episode of ICPI-AKI.

BackgroundImmune checkpoint inhibitor-associated acute kidney injury (ICPi-AKI) has emerged as an important toxicity among patients with cancer.MethodsWe collected data on 429 patients with ICPi-AKI and 429 control patients who received ICPis contemporaneously but who did not develop ICPi-AKI from 30 sites in 10 countries. Multivariable logistic regression was used to identify predictors of ICPi-AKI and its recovery. A multivariable Cox model was used to estimate the effect of ICPi rechallenge versus no rechallenge on survival following ICPi-AKI.ResultsICPi-AKI occurred at a median of 16 weeks (IQR 8–32) following ICPi initiation. Lower baseline estimated glomerular filtration rate, proton pump inhibitor (PPI) use, and extrarenal immune-related adverse events (irAEs) were each associated with a higher risk of ICPi-AKI. Acute tubulointerstitial nephritis was the most common lesion on kidney biopsy (125/151 biopsied patients [82.7%]). Renal recovery occurred in 276 patients (64.3%) at a median of 7 weeks (IQR 3–10) following ICPi-AKI. Treatment with corticosteroids within 14 days following ICPi-AKI diagnosis was associated with higher odds of renal recovery (adjusted OR 2.64; 95% CI 1.58 to 4.41). Among patients treated with corticosteroids, early initiation of corticosteroids (within 3 days of ICPi-AKI) was associated with a higher odds of renal recovery compared with later initiation (more than 3 days following ICPi-AKI) (adjusted OR 2.09; 95% CI 1.16 to 3.79). Of 121 patients rechallenged, 20 (16.5%) developed recurrent ICPi-AKI. There was no difference in survival among patients rechallenged versus those not rechallenged following ICPi-AKI.ConclusionsPatients who developed ICPi-AKI were more likely to have impaired renal function at baseline, use a PPI, and have extrarenal irAEs. Two-thirds of patients had renal recovery following ICPi-AKI. Treatment with corticosteroids was associated with improved renal recovery.

Background Despite increasing recognition of the importance of immune checkpoint inhibitor-associated AKI, data on this complication of immunotherapy are sparse. Methods We conducted a multicenter study of 138 patients with immune checkpoint inhibitor-associated AKI, defined as a ≥2-fold increase in serum creatinine or new dialysis requirement directly attributed to an immune checkpoint inhibitor. We also collected data on 276 control patients who received these drugs but did not develop AKI. Results Lower baseline eGFR, proton pump inhibitor use, and combination immune checkpoint inhibitor therapy were each independently associated with an increased risk of immune checkpoint inhibitor-associated AKI. Median (interquartile range) time from immune checkpoint inhibitor initiation to AKI was 14 (6-37) weeks. Most patients had subnephrotic proteinuria, and approximately half had pyuria. Extrarenal immune-related adverse events occurred in 43% of patients; 69% were concurrently receiving a potential tubulointerstitial nephritis-causing medication. Tubulointerstitial nephritis was the dominant lesion in 93% of the 60 patients biopsied. Most patients (86%) were treated with steroids. Complete, partial, or no kidney recovery occurred in 40%, 45%, and 15% of patients, respectively. Concomitant extrarenal immune-related adverse events were associated with worse renal prognosis, whereas concomitant tubulointerstitial nephritis-causing medications and treatment with steroids were each associated with improved renal prognosis. Failure to achieve kidney recovery after immune checkpoint inhibitor-associated AKI was independently associated with higher mortality. Immune checkpoint inhibitor rechallenge occurred in 22% of patients, of whom 23% developed recurrent associated AKI. Conclusions This multicenter study identifies insights into the risk factors, clinical features, histopathologic findings, and renal and overall outcomes in patients with immune checkpoint inhibitor-associated AKI.

Background and Aims Primary Focal Segmental Glomerulosclerosis (FSGS) is the most common primary glomerular disease in patients with end stage renal disease in the United States. Current treatment regimens target reduction in proteinuria, but may have limited response or exhibit disease recurrence. CCX140 is an orally-administered selective small molecule inhibitor of the C-C chemokine receptor 2 (CCR2) under investigation for the treatment reduction of proteinuria in patients with FSGS. The primary objectives of this study were to evaluate the safety and efficacy of CCX140 in patients with FSGS and a urine protein to creatinine ratio (UPCR) of ≥1 g/g. Efficacy was assessed by the change in UPCR. Method Forty-six adult patients with primary or genetic FSGS were randomized into a double-blind, placebo-controlled Phase 2 dose-ranging study designed to evaluate the safety and efficacy of CCX140. Changes of urinary protein excretion estimation (UPCR) from baseline to Week 12 were measured in four blinded treatment groups (three active CCX140 doses of 5 mg once daily, 10 mg and 15 mg twice-daily (BID) vs placebo). Starting at Week 12, all subjects including those in the placebo group received the CCX140, 15 mg BID for an additional 12 weeks, and UPCR changes from Week 12 to Week 24 were assessed. There was a 4-week follow-up period from Week 24 to Week 28 where no CCX140 was administered. Results In the intent to treat (ITT) analysis of UPCR changes at Week 12 relative to baseline, the 15 mg BID CCX140 group exhibited the greatest reduction of UPCR (median reduction from baseline 0.9 g/g or approximately 30%, and approximately 25% reduction from baseline for the geometric mean), but that did not differ significantly from the placebo group (median reduction from baseline 0.45 g/g; or approximately 22%, and approximately 23% reduction from baseline for the geometric mean). Also, after crossover of the blinded portion of the trial to 15 mg BID active dosing, the previous placebo group did not appear to exhibit an additional reduction of UPCR. CCX140 at all doses was well-tolerated, with no serious adverse events (SAEs) during the blinded trial and a numerically lower rate of treatment-emergent adverse events in the CCX140 treatment groups. Conclusion In the study, CCX140 did not demonstrate a therapeutically meaningful reduction in proteinuria relative to the control group after 12 weeks of blinded treatment. The study provides insights into the natural disease progression of patients with primary or genetic FSGS as part of a clinical trial setting.

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.

A Man with Chronic Kidney Disease A 74-year-old man presented for evaluation of his chronic kidney disease before a planned transcatheter aortic-valve replacement. Pancreatitis had been diagnosed 2...

Objective Therapeutic advances in ANCA-associated vasculitis (AAV) have improved patient survival, but mortality rates remain higher than the general population. Glucocorticoids contribute to AAV morbidity and mortality. We examined whether an 8-week glucocorticoid course in combination with rituximab (RTX) would induce disease remission in patients with AAV. Methods Patients with active AAV received an 8-week prednisone taper and RTX 375 mg/m2 weekly for 4 weeks. Patients with severe glomerulonephritis or diffuse alveolar hemorrhage requiring mechanical ventilation were excluded. In-person and telephone visits were scheduled for disease activity assessment. The primary endpoint was complete remission at 24 weeks (no disease activity while being off prednisone with no intercedent relapses). Secondary analysis included comparing study outcomes to historical controls from the Rituximab in AAV (RAVE) trial. Results Fourteen of 20 patients (70%) achieved the primary outcome. The patients in our trial achieved the primary outcome at a rate similar to that of controls from the RAVE trial (adjusted OR 1.31 [0.26–6.56]), had fewer median adverse events per patient (2 versus 8, p Conclusion An 8-week course of prednisone with RTX resulted in a similar rate of complete remission at 6 months as in the RAVE trial, with fewer adverse events but more frequent relapses. Further study of this protocol is warranted in selected patient populations.

Background Patients with frequently relapsing (FR), steroid-dependent (SD) and steroid-resistant (SR) nephrotic syndrome are a therapeutic challenge with limited treatment options. Here, we retrospectively analyze the efficacy and safety of rituximab-induced continuous B-cell depletion in these populations. Methods Patients were included if they were at least 18 years of age and had FR, SD or SR minimal change disease (MCD) or primary focal segmental glomerulosclerosis (FSGS) and were treated with a strategy of continuous B-cell depletion. Partial remission (PR) was defined as a urinary protein:creatinine ratio (UPCR) of ≤3.5 g/g and a 50% reduction in the UPCR from baseline. Complete remission (CR) was defined as a UPCR ≤0.3 g/g. Results We identified 20 patients with MCD (n = 13) or FSGS (n = 7) who fulfilled the inclusion criteria. All patients had either SD (n = 12), SR (n = 7) or FR (n = 1) disease. Patients received a median of nine rituximab doses [interquartile range (IQR) 7.5, 11] and were treated for a median time of 28 months (IQR 23, 41). Prednisone was weaned from a median of 60 mg daily (IQR 40, 60) at rituximab initiation to 4.5 mg daily (IQR 0, 5.5) by 12 months. All patients achieved PR. CR occurred in 11 of 13 patients with FR or SD disease, but only 1 of 7 patients with SR disease (logrank P = 0.01). Four relapses occurred, all in patients with SR disease. Three serious infections occurred over 70.3 patient-years. Conclusion Continuous B-cell depletion is a therapeutic option in the management of complicated nephrotic syndrome. Additional studies are needed to clarify the utility of this strategy.

BackgroundRenal transplantation is the optimal treatment for selected patients with end-stage renal disease (ESRD). However, the survival benefit of renal transplantation among patients with ESRD attributed to granulomatosis with polyangiitis (GPA) is unknown.MethodsWe identified patients from the United States Renal Data System with ESRD due to GPA (ESRD-GPA) between 1995 and 2014. We restricted our analysis to waitlisted subjects to evaluate the impact of transplantation on mortality. We followed patients until death or the end of follow-up. We compared the relative risk (RR) of all-cause and cause-specific mortality in patients who received a transplant versus non-transplanted patients using a pooled logistic regression model with transplantation as a time-varying exposure.ResultsDuring the study period, 1525 patients were waitlisted and 946 received a renal transplant. Receiving a renal transplant was associated with a 70% reduction in the risk of all-cause mortality in multivariable-adjusted analyses (RR=0.30, 95% CI 0.25 to 0.37), largely attributed to a 90% reduction in the risk of death due to cardiovascular disease (CVD) (RR=0.10, 95% 0.06–0.16).DiscussionRenal transplantation is associated with a significant decrease in all-cause mortality among patients with ESRD attributed to GPA, largely due to a decrease in the risk of death to CVD. Prompt referral for transplantation is critical to optimise outcomes for this patient population.

Introduction Remission induction in antineutrophil cytoplasmic autoantibody (ANCA) vasculitis may be complicated by slow response to treatment and toxicity from glucocorticoids. We describe outcomes with a novel remission induction regimen combining rituximab with a short course of low-dose, oral cyclophosphamide and an accelerated prednisone taper. Methods Patients were included in this retrospective study if they had newly diagnosed or relapsing ANCA vasculitis with a Birmingham Vasculitis Activity Score for Wegener Granulomatosis (BVAS-WG) ≥3 and received a standardized remission induction regimen. The primary outcome was complete remission, defined as a BVAS-WG of 0 and a prednisone dose of ≤7.5 mg/d. Results We identified 129 patients who met the inclusion criteria, 31% of whom also received plasma exchange (PLEX) for rapidly progressive glomerulonephritis (RPGN) or diffuse alveolar hemorrhage. Seventy percent of patients had myeloperoxidase (MPO)-ANCA and 9% had relapsing disease. Median time to complete remission was 4 months (interquartile range [IQR] 3.9–4.4), and by 5 months 84% of patients were in complete remission. Prednisone was tapered to discontinuation as tolerated, such that the median prednisone dose at 8 months was 0 mg/d (IQR 0–2.5). In patients with RPGN, proteinase 3–ANCA was associated with a greater increase in eGFR at 6 months compared with MPO-ANCA (16 vs. 5.6 ml/min per 1.73m2; P = 0.028). During the year following remission, 1 major relapse occurred over 122 patient-years. Serious infections occurred more frequently in patients receiving PLEX and were associated with increasing age and diffuse alveolar hemorrhage. Four deaths occurred, 3 of which were associated with serious infections. Conclusion Combination therapy was efficacious, allowed for rapid tapering of high-dose glucocorticoids and was well tolerated.

A 64-year-old man presented with headache, dyspnea, wheezing, cough, and night sweats. He had eosinophilia, sinusitis on CT, and abnormal results on pulmonary-function tests, including an elevated fraction of exhaled nitric oxide. Diagnostic tests were performed.

Background and objectives 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. Design, setting, participants, & measurements 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. Results 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 Conclusions 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.

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.

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.

OBJECTIVE:IgG4-related disease (IgG4-RD) can cause fibroinflammatory lesions in nearly any organ, leading to organ dysfunction and failure. The IgG4-RD Responder Index (RI) was developed to help investigators assess the efficacy of treatment in a structured manner. The aim of this study was to validate the RI in a multinational investigation. METHODS:The RI guides investigators through assessments of disease activity and damage in 25 domains, incorporating higher weights for disease manifestations that require urgent treatment or that worsen despite treatment. After a training exercise, investigators reviewed 12 written IgG4-RD vignettes based on real patients. Investigators calculated both an RI score as well as a physician's global assessment (PhGA) score for each vignette. In a longitudinal assessment, 3 investigators used the RI in 15 patients with newly active disease who were followed up over serial visits after treatment. We assessed interrater and intrarater reliability, precision, validity, and responsiveness. RESULTS:The 26 physician investigators included representatives from 6 specialties and 9 countries. The interrater and intrarater reliability of the RI was strong (0.89 and 0.69, respectively). Correlations (construct validity) between the RI and PhGA were high (Spearman's r = 0.9, P < 0.0001). The RI was sensitive to change (discriminant validity). Following treatment, there was significant improvement in the RI score (mean change 10.5 [95% confidence interval (95% CI) 5.4-12], P < 0.001), which correlated with the change in the PhGA. Urgent disease and damage were captured effectively. DISCUSSION:In this international, multispecialty study, we observed that the RI is a valid and reliable disease activity assessment tool that can be used to measure response to therapy.

Background and objectives Remission in the majority of ANCA vasculitis patients is not sustained after a single course of rituximab, and risk of relapse warrants development of a successful strategy to ensure durable remission. Design, setting, participants, & measurements A retrospective analysis of ANCA vasculitis patients who underwent maintenance therapy using rituximab-induced continuous B-cell depletion for up to 7 years was performed. Maintenance therapy with rituximab was initiated after achieving remission or converting from other prior maintenance therapy. Continuous B-cell depletion was achieved in all patients by scheduled rituximab administration every 4 months. Disease activity, serologic parameters, adverse events, and survival were examined. Results In the study, 172 patients (mean age=60 years, 55% women, 57% myeloperoxidase–ANCA) treated from April of 2006 to March of 2013 underwent continuous B-cell depletion with rituximab. Median remission maintenance follow-up time was 2.1 years. Complete remission (Birmingham Vasculitis Activity Score [BVAS]=0) was achieved in all patients. Major relapse (BVAS≥3) occurred in 5% of patients and was associated with weaning of other immunosuppression drugs. Remission was reinduced in all patients. Survival mirrored survival of a general age-, sex-, and ethnicity-matched United States population. Conclusion This analysis provides evidence for long-term disease control using continuous B-cell depletion. This treatment strategy in ANCA vasculitis patients also seems to result in survival rates comparable with rates in a matched reference population. These findings suggest that prospective remission maintenance treatment trials using continuous B-cell depletion are warranted.

Rationale:IgG4-related disease (IgG4-RD) is a multiorgan disease of unestablished prevalence that is characterized histopathologically by a dense lymphoplasmacytic infiltrate enriched with IgG4-expressing plasma cells and associated with storiform fibrosis. Tubulointerstitial nephritis (TIN)

Background Membranous nephropathy is a common cause of the nephrotic syndrome. Treatment with standard regimens fails to induce complete remission in most patients. We evaluated the efficacy of combination therapy with rituximab, low-dose, oral cyclophosphamide, and an accelerated prednisone taper (RCP) for the treatment of idiopathic membranous nephropathy. Methods We analyzed 15 consecutive patients with idiopathic membranous nephropathy treated with RCP at Massachusetts General Hospital. Seven patients (47%) received RCP as initial therapy, and the other eight patients (53%) received RCP for relapsing or refractory disease. All patients had at least 1 year of follow-up. The co-primary outcomes were attainment of partial and complete remission. Partial remission was defined as a urinary protein to creatinine ratio (UPCR)

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 extra-renal 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 one 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 two 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 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

Inhibitors of the mammalian target of rapamycin (mTOR), sirolimus and everolimus, reduce the incidence of acute rejection following kidney transplantation, but their impact on clinical outcomes beyond 2 years after transplantation is unknown. We examined risks of mortality and allograft loss in a prospective observational study of 993 prevalent kidney transplant recipients who enrolled a median of 72 months after transplantation. During a median follow-up of 37 months, 87 patients died and 102 suffered allograft loss. In the overall population, use of mTOR inhibitors at enrollment was not associated with altered risk of allograft loss, and their association with increased mortality was of borderline significance. However, history of malignancy was the strongest predictor of both mortality and therapy with an mTOR inhibitor. Among patients without a history of malignancy, use of mTOR inhibitors was associated with significantly increased risk of mortality in propensity score-adjusted (hazard ratio [HR] 2.6; 95% CI, 1.2, 5.5; p = 0.01), multivariable-adjusted (HR 3.2; 95% CI, 1.5, 6.5; p = 0.002) and one-to-one propensity score-matched analyses (HR 5.6; 95% CI 1.2, 25.7; p = 0.03). Additional studies are needed to examine the long-term safety of mTOR inhibitors in kidney transplantation, especially among recipients without a history of malignancy.

Congest Heart Fail. 2011;17:133–139. ©2011 Wiley Periodicals, Inc. The authors evaluated the prevalence of hypothyroidism in patients with heart failure (HF) to determine whether there are racial and sex differences and to determine the number of new cases of hypothyroidism. The study included 194 patients in an HF disease management program (HFDMP) in South Florida. Patients were interviewed for a history of hypothyroidism and referred for measurement of thyrotropin. The prevalence of hypothyroidism was calculated by race and sex. The prevalence of hypothyroidism was 18% for all patients with HF and 23% among Hispanics; however, this trend was not statistically significant ( P=.06). More men than women had hypothyroidism ( P=.04). Patients with hypothyroidism had higher mean lipid profiles ( P

Healthy People 2010 aims at immunizing 60% of high-risk adults annually against influenza and once against pneumococcal disease. The aim of this study was to evaluate the use of a standardized approach to improve vaccination rates in patients with heart failure (HF); to determine whether disparities exist based on age, race, ethnicity, or sex at baseline and follow-up; and to evaluate the impact of clinical variables on the odds of being vaccinated. A prospective study of 549 indigent patients enrolled in a systolic HF disease management program (HFDMP) began enrollment from August 2007 to January 2009 at Jackson Memorial Hospital. Patients were interviewed at their initial visit for immunization status; those without vaccinations were offered the vaccines. Prevalence of vaccination (POV) for influenza and pneumococcal disease was obtained at baseline and at follow-up. The odds ratio for being vaccinated was calculated using logistic regression. The study population comprised mostly Hispanic (56%), black (37%), and male (70%) patients, with a mean age of 56 ± 12 years and a mean ejection fraction of 25% ± 10%. The initial POV for both was 22% at baseline. At follow-up, POV improved to 60.5%. Of those not vaccinated at baseline, 17.5% refused vaccination. Odds ratios at baseline for age, race/ethnicity, and sex were 0.99 (P=.99), 0.63 (P=.08), and 0.62 (P=.14), respectively. These did not change significantly at follow-up. Prevalence of vaccination in our cohort was low. Enrollment into the HFDMP improved immunization prevalence without creating age, race, ethnicity, or sex disparities.

Chronic kidney disease is a major public health problem that is associated with increased risks of kidney disease progression, cardiovascular disease and death. Kidney transplantation remains the renal replacement therapy of choice for patients with end-stage kidney disease. Despite impressive strides in short-term allograft survival, there has been little improvement in long-term kidney graft survival, and rates of death with a functioning allograft remain high. Long-term safety profiles of existing immunosuppressive regimens point to a need for continued search for alternative agents. This overview discusses emerging evidence on a few promising therapeutic approaches, juxtaposes conflicting findings and highlights remaining knowledge gaps.

Data on long-term outcomes of users of inhibitors of the mammalian target of rapamycin (mTORI) are lacking in kidney transplantation. In an analysis of 139,370 US kidney transplant recipients between 1999 through 2010, we compared clinical outcomes among users of mTORIs versus calcineurin inhibitors (CNI) in their primary immunosuppresive regimen. During the first 2 years post-transplantation, primary use of mTORIs without CNIs (N=3,237) was associated with greater risks of allograft failure and death compared with a CNI-based regimen (N=125,623); the hazard ratio [HR] of the composite outcome ranged from 3.67 (95% confidence interval [CI], 3.12 – 4.32) after discharge to 1.40 (95%CI 1.26 – 1.57) by year 2. During years 2–8, primary use of mTORIs without CNIs was independently associated with greater risks of death (HR 1.25; 95%CI, 1.11 – 1.41) and the composite (HR 1.17; 95%CI, 1.08 – 1.27) in fully adjusted analyses. The results were qualitatively unchanged in subgroups defined by medical history, immunological risk and clinical course during the index transplant hospitalization. In a propensity-score matched cohort, use of mTORIs was associated with significantly worse outcomes during the first 2 years and greater risks of death (HR 1.21; 95%CI, 1.05 – 1.39) and the composite (HR 1.18; 95%CI, 1.08 – 1.30) in years 2–8. Compared with CNI-based regimens, use of an mTORI-based regimen for primary immunosuppression in kidney transplantation was associated with inferior recipient survival.

Escherichia coli DNA photolyase and cryptochrome 1 isolated from Vibrio cholerae, a member of the CRY-DASH family, are directly compared using a variety of experimental methods including UV-vis and Raman spectroscopy, reduction potential measurements, and isothermal titration calorimetry. The semiquinone form of the cryptochrome has an absorption spectrum that is red-shifted from that of the photolyase, but the Raman spectrum indicates that the FAD binding pocket is similar to that of photolyase. The FADH(-)/FADH* reduction potential of the cryptochrome is significantly higher than that of the photolyase at 164 mV vs NHE, but it also increases upon substrate binding (to 195 mV vs NHE), an increase similar to what is observed in photolyase. The FADH(-)/FADH* reduction potential for both proteins was found to be insensitive to ATP binding. Isothermal titration calorimetry found that photolyase binds tighter to substrate (K(A) approximately 10(5) M(-1) for photolyase and approximately 10(4) M(-1) for cryptochrome 1), and the binding constants for both proteins were slightly sensitive to oxidation state. Based upon this work, it appears that this cryptochrome has significant spectroscopic and electrochemical similarities to CPD photolyase. The thermodynamic cycle of the enzymatic repair in the context of this work is discussed.

Cyclobutane pyrimidine dimer (CPD) photolyases are structure specific DNA-repair enzymes that specialize in the repair of CPDs, the major photoproducts that are formed upon irradiation of DNA with ultraviolet light. The purified enzyme binds a flavin adenine dinucleotide (FAD), which is in the neutral radical semiquinone (FADH(*)) form. The CPDs are repaired by a light-driven, electron transfer from the anionic hydroquinone (FADH(-)) singlet excited state to the CPD, which is followed by reductive cleavage of the cyclobutane ring and subsequent monomerization of the pyrimidine bases. CPDs formed between two adjacent thymidine bases (T T) are repaired with greater efficiency than those formed between two adjacent cytidine bases (C C). In this paper, we investigate the changes in Escherichia coli photolyase that are induced upon binding to DNA containing C C lesions using resonance Raman, UV-vis absorption, and transient absorption spectroscopies, spectroelectrochemistry, and computational chemistry. The binding of photolyase to a C C lesion modifies the energy levels of FADH(*), the rate of charge recombination between FADH(-) and Trp(306)(*), and protein-FADH(*) interactions differently than binding to a T T lesion. However, the reduction potential of the FADH(-)/FADH(*) couple is modified in the same way with both substrates. Our calculations show that the permanent electric dipole moment of C C is stronger (12.1 D) and oriented differently than that of T T (8.7 D). The possible role of the electric dipole moment of the CPD in modifying the physicochemical properties of photolyase as well as in affecting CPD repair will be discussed.

Photolyases and cryptochromes are flavoproteins that belong to the class of blue-light photoreceptors. They usually bind two chromophores: flavin adenine dinucleotide (FAD), which forms the active site, and a light-harvesting pigment, which is a 5,10-methenyltetrahydrofolate polyglutamate (MTHF) in most cases. In Escherichia coli photolyase (EcPhr), the MTHF cofactor is present in substoichiometric amounts after purification, while in Vibrio cholerae cryptochrome-1 (VcCry1) the MTHF cofactor is bound more strongly and is present at stoichiometric levels after purification. In this paper, we have used resonance Raman spectroscopy to monitor the effect of loss of MTHF on the protein-FAD interactions in EcPhr and to probe the protein-MTHF interactions in both EcPhr and VcCry1. We find that removal of MTHF does not perturb protein-FAD interactions, suggesting that it may not affect the physicochemical properties of FAD in EcPhr. Our data demonstrate that the pteridine ring of MTHF in EcPhr has different interactions with the protein matrix than that of MTHF in VcCry1. Comparison to solution resonance Raman spectra of MTHF suggests that the carbonyl of its pteridine ring in EcPhr experiences stronger hydrogen bonding and a more polar environment than in VcCry1, but that hydrogen bonding to the pteridine ring amine hydrogens is stronger in VcCry-1. These differences in hydrogen bonding may account for the higher binding affinity of MTHF in VcCry1 compared to EcPhr.