Real-World Experience With Avacopan in Antineutrophil Cytoplasmic Autoantibody-Associated Vasculitis.

Introduction: Postmarketing data on outcomes of avacopan use in antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV) are lacking. Methods: We performed a multicenter retrospective analysis of 92 patients with newly diagnosed or relapsing AAV who received therapy with avacopan. The coprimary outcome measures were clinical remission at 26 and 52 weeks. We use descriptive statistics and univariate logistic regression to assess outcomes and predictors of remission, respectively. Results: Of the 92 patients, 23% (n = 21) had a baseline estimated glomerular filtration rate (eGFR) < 15 ml/min per 1.73 m2 and 10% on kidney replacement therapy at baseline. Among those with kidney involvement, mean (SD) enrollment eGFR was 33 (27) ml/min per 1.73 m2 with a mean (SD) change of +12 (25) and +20 (23) ml/min per 1.73 m2 at weeks 26 and 52, respectively. In addition to avacopan, 47% of patients received combination therapy of rituximab and low-dose cyclophosphamide, and 14% of patients received plasma exchange (PLEX). After induction, the median (interquartile range [IQR]) time to start avacopan was 3.6 (2.1-7.7) weeks, and the median time to discontinue prednisone after starting avacopan was 5.6 (3.3-9.5) weeks. Clinical remission was achieved in 90% of patients at week 26 and 84% of patients at week 52. Of the patients, 20% stopped avacopan due to adverse events, with the most common being elevated serum aminotransferases (4.3%). Conclusion: A high rate of remission and an acceptable safety profile were observed with the use of avacopan in the treatment of AAV in this postmarketing analysis, including the populations excluded from the ADVOCATE trial.

Obinutuzumab as treatment for ANCA-associated vasculitis.

OBJECTIVES: Rituximab is a standard of care therapy for patients with ANCA-associated vasculitis. When rituximab is contraindicated, or in the case of refractory disease, other treatments are needed. Obinutuzumab is another anti-CD20 antibody for the treatment of haematological malignancies that may induce a deeper B cell depletion compared with rituximab. This article reviews three cases of patients with ANCA-associated vasculitis who were treated with obinutuzumab due to their history of anaphylactic reactions to rituximab. METHODS: Case series of three patients with ANCA-associated vasculitis treated with obinutuzumab. RESULTS: One female patient with microscopic polyangiitis and two male patients with granulomatosis with polyangiitis received obinutuzumab. The treatment was well-tolerated in all patients despite previous anaphylactic reaction to rituximab. Treatment with obinutuzumab was effective in (i) inducing disease remission, (ii) inducing total B cell depletion, and (iii) resulting in undetectable serum titres of ANCA. All three patients were re-treated with obinutuzumab for maintenance of remission. CONCLUSION: Obinutuzumab appears to be a safe and efficacious therapy for patients with ANCA-associated vasculitis who have had refractory disease or a history of anaphylaxis to rituximab. Prospective studies comparing rituximab to obinutuzumab in ANCA-associated vasculitis patients are warranted.

Worsening membranous nephropathy in a patient with GIST treated with sunitinib.

Tyrosine kinase inhibitors (TKI) are anticancer agents widely used for a variety of malignancies including gastrointestinal stromal tumours (GIST). Although generally well-tolerated, TKIs have been associated with a number of adverse events including hypertension, proteinuria and nephrotic syndrome. We present the case of a 70-year-old patient with metastatic GIST on long-standing sunitinib who developed hypertension, oedema and hypoalbuminemia with a rising serum creatinine and was found to have nephrotic syndrome. Workup revealed elevated antiphospholipase A2 receptor (PLA2R) antibody IgG titres and a kidney biopsy confirmed PLA2R-positive membranous nephropathy without findings of thrombotic microangiopathy. Cessation of sunitinib led to reduction in anti-PLA2R antibody IgG titres while resumption, due to concern for cancer progression, led to worsening symptoms. Treatment with rituximab led to undetectable anti-PLA2R IgG titres. We highlight the importance of maintaining a systematic approach for evaluating nephrotic syndrome and provide a case showing that TKIs can exacerbate underlying nephrotic syndrome.

Bevacizumab-associated thrombotic microangiopathy treated with eculizumab: A case series and systematic review of the literature.

BACKGROUND: Bevacizumab is a recombinant monoclonal antibody against the vascular endothelial growth factor A (VEGF-A) ligand that is used in the management of various solid malignancies. The adverse effect profiles of angiogenesis inhibitors, such as bevacizumab, have become increasingly well characterized and include renal manifestations such as hypertension, proteinuria, and thrombotic microangiopathy. Eculizumab inhibits terminal-complement activation and is used to treat atypical hemolytic uremic syndrome. There has been growing usage of eculizumab to treat bevacizumab-associated thrombotic microangiopathy. MATERIALS AND METHODS: We performed a systematic review of the literature to identify full-text articles that describe the use of eculizumab for bevacizumab-associated thrombotic microangiopathy. RESULTS: Our systematic review identified 522 unique articles of which 5 were included in the final review. 9 cases, including 2 new cases presented in this review, were identified in which eculizumab was used in the management of bevacizumab-associated thrombotic microangiopathy. Hematologic parameters and kidney function stabilized or improved in all cases, and the 2 patients who required renal replacement therapy were able to discontinue dialysis. CONCLUSIONS: Given the findings of this systematic review, the use of eculizumab in the treatment of bevacizumab-associated thrombotic microangiopathy warrants further study, particularly in severe cases.

Deferasirox-associated Fanconi syndrome in adult patients with transfusional iron overload.

BACKGROUND AND OBJECTIVES: Deferasirox is an oral chelator approved for iron overload, which has a potential side effect of renal Fanconi syndrome, with proximal tubular dysfunction and tubular acidosis. Monitoring of renal function is recommended, though no standard for monitoring exists. We aim to describe cases of deferasirox-associated Fanconi syndrome in adults and the renal monitoring required to detect these findings. MATERIALS AND METHODS: We present a review of the literature and six cases from our institution of deferasirox-associated partial Fanconi syndrome in adult patients with transfusional iron overload secondary to ß-thalassemia or Diamond Blackfan Anaemia. RESULTS: While prior cases in the literature occurred at high doses of deferasirox, our series included patients on doses as low as deferasirox 10 mg/kg who had been aggressively chelated. All patients had resolution of laboratory abnormalities with drug interruption. CONCLUSION: Rather than chelating to normal iron levels, this series supports prior suggestions that deferasirox dose be reduced if ferritin <500-1000 ng/ml, and also supports dose reduction if liver iron content <3 mg iron per g dry weight or for those undergoing aggressive chelation with rapid decrease in iron. Monitoring with metabolic panel and urinalysis were sufficient to detect clinically significant proximal tubular dysfunction, but should be followed up with additional studies to confirm the diagnosis while deferasirox dose is decreased or held.

Nephrotoxicity From Molecularly Targeted Chemotherapeutic Agents.

The introduction of novel molecularly targeted therapies in the last 2 decades has significantly improved the patient survival compared to standard conventional chemotherapies. However, this improvement has been accompanied by a whole new spectrum of kidney adverse events. Although known as "targeted," many of these agents lack specificity and selectivity, and they have a tendency to inhibit multiple targets including those in the kidneys. Early detection and correct management of kidney toxicities is crucial to preserve kidney functions. The knowledge of these toxicities helps guide optimal and continued utilization of these potent therapies. The incidence, severity, and pattern of nephrotoxicity may vary depending on the respective target of the drug. Here, we review the mechanism of action, clinical findings of kidney adverse events, and their proposed management strategies.

Bortezomib Treatment for Refractory PLA2R-Positive Membranous Nephropathy.

Introduction: B-cell depletion has been shown to be an effective strategy for the majority of patients with membranous nephropathy (MN), and in PLA2R-positive MN, immunologic remission (improvement or elimination of measurable serum anti-PLA2R antibodies) precedes renal remission. Yet, cases exist of patients who do not achieve immunologic remission despite achieving peripheral B-cell depletion. This has led to the hypothesis that some patients have plasma cells that are responsible for producing anti-PLA2R antibodies. Case Presentation: A 66-year-old man with a past medical history of hypertension, hyperlipidemia, and cerebrovascular disease presented with nephrotic syndrome and was diagnosed with PLA2R-positive MN on kidney biopsy. He was refractory to multiple therapies including tacrolimus, and was resistant to rituximab despite having achieved B-cell depletion. He also did not enter into remission with plasmapharesis and cyclophosphamide. He then achieved immediate immunologic remission after treatment with the proteasome inhibitor bortezomib, which is used as first-line therapy for multiple myeloma. Discussion/Conclusion: This case suggests that considering the source of PLA2R antibody production could lead to individualized and targeted therapies for MN.

Hypertension in Cancer Patients and Survivors: Epidemiology, Diagnosis, and Management.

Cancer patients and survivors of cancer have a greater burden of cardiovascular disease compared to the general population. Much of the elevated cardiovascular risk in these individuals is likely attributable to hypertension, as individuals with cancer have a particularly high incidence of hypertension following cancer diagnosis. Treatment with chemotherapy is an independent risk factor for hypertension due to direct effects of many agents on endothelial function, sympathetic activity, and renin-angiotensin system activity as well as nephrotoxicity. Diagnosis and management of hypertension in cancer patients requires accurate blood pressure measurement and consideration of potential confounding factors, such as adjuvant treatments and acute pain, that can temporarily elevate blood pressure readings. Home blood pressure monitoring can be a useful tool to facilitate longitudinal blood pressure monitoring for titration of antihypertensive medications. Selection of antihypertensive agents in cancer patients should account for treatment-specific morbidities and target organ injury.

Incidence and prevalence of hepatitis B and hepatitis C viruses in hemodialysis patients in Lebanon.

AIM: To determine the incidence and the prevalence of hepatitis B and C viral infections in patients on hemodialysis (HD) across Lebanon. METHODS: We reviewed the data registry at the Lebanese Ministry of Public Health where records of monthly hepatitis B surface antigen (HBsAg) and hepatitis C virus (HCV) serology are reported from 60 affiliated HD centers across Lebanon. All patients who were on HD or who started HD between October 2010 and July 2012 were included in the study. Patients from seven HD centers were excluded due to inadequate and incomplete results reporting. During the selected period, HBsAg and HCV serology were available for 3769 patients from 53 HD centers distributed at all Lebanese governorates. The prevalence was calculated by dividing the number of patients with positive HBsAg or HCV serology to the total number of patients. The Incidence was calculated by dividing the number of newly acquired infection to number of patients-years (p-y). Incidence rates at different governorates were compared to each other using two tailed Z test and a P value of < 0.05 was considered significant. RESULTS: Sixty out of 3769 HD patients were found to have positive HBS Ag and 177 out of 3769 were positive for HCV Antibodies. The prevalence of hepatitis B virus (HBV) and HCV in HD patients across Lebanon was 1.6%, and 4.7%, respectively. The comparison of prevalence according to geographic distribution could not be done accurately due to the frequent shift of patients between dialysis centers at different governorates. The incidence rate was 0.27 per 100 p-y for HBV and 0.37 per 100 p-y for HCV. There was no significant difference concerning the incidence of HBV between HD centers at different governorates (all P values > 0.1), but this difference was highly significant concerning the incidence rates of HCV which occurred predominantly in the southern centers (1.47 per 100 p-y) with a P value of 0.00068 and 0.00374 when compared to Mount Lebanon (0.21 per 100 p-y) and the Northern centers (0.19 per 100 p-y), respectively. CONCLUSION: The incidence rate of HBV and HCV is very low in the Lebanese HD centers and their prevalence is decreasing over the last two decades.

Warburg's effect on solid tumors.

Lactic acidosis is the result of imbalance between the systemic formation of lactate and its hepatic metabolism. In cancer patients, lactic acidosis is mainly associated with hematologic malignancies (leukemia and lymphomas) and the mechanism is known as Warburg's effect. We report a 76-year-old male known to have hypertension and coronary artery disease, who presented with abdominal distension and lactic acidosis. His initial evaluation showed multiple liver masses that were biopsied and the patient was diagnosed with undifferentiated carcinoma of unknown primary, involving the liver. The patient had progression of lactic acidosis leading to his death on day-15. As the lactic acidosis was not in the setting of hypoxia or hemodynamic instability, we made the diagnosis of malignancy-associated type B lactic acidosis, also known as the Warburg's effect. Warburg's effect can occur in solid cancer if the tumor involves the liver. It has bad prognostic implications. The use of intravenous bicarbonate as a temporary measure is of controversial benefit, as it can potentially worsen the metabolic acidosis and its use should be limited to patients with very low pH. In cancer patients, the use of lactatebased intravenous fluids can be potentially harmful and can increase the risk of tumor metastasis, at least in animal malignancy models.

Steroid withdrawal in kidney allograft recipients.

This review highlights the aggregate of knowledge obtained from the temporal trend of kidney transplant immune suppression. We will discuss the burden of steroid side effects and their impact on quality of life in kidney allograft recipients, which have led to minimizing steroid exposure. Issues arising since the inception of the concept of steroid withdrawal will be discussed, along with how they have continually led to a shift in research focus on this subject matter. The usefulness of surveillance biopsies and how further elucidation of the pathophysiology of interstitial fibrosis and tubular atrophy could contribute to improving long-term allograft outcomes will also be discussed. We will elaborate on the role of calcineurin inhibitor minimization alongside steroid withdrawal in improving long-term graft survival. Future expectations of subsequent studies with a view to improving overall kidney allograft outcomes by eliminating attendant problems associated with steroids will also be covered.