Hyponatraemia on hospital admission is associated with increased length of stay, healthcare expenditures and mortality. Urine studies collected before fluid or diuretic administration are essential to diagnose the underlying cause of hyponatraemia, thereby empowering admitting teams to employ the appropriate treatment. A multidisciplinary quality improvement (QI) team led by internal medicine residents performed a QI project from July 2020 through June 2021 to increase the rate of urine studies collected before fluid or diuretic administration in the emergency department (ED) in patients admitted with moderate to severe hyponatraemia. We implemented two plan-do-study-act (PDSA) cycles to address this goal. In PDSA Cycle #1, we displayed an educational poster in employee areas of the ED and met with nursing staff at their monthly meetings to communicate the project and answer questions. We also obtained agreement from ED attending physicians and nursing leaders to support the project. In PDSA Cycle #2, we implemented a structural change in the nursing triage process to issue every patient who qualified for bloodwork with a urine specimen container labelled with a medical record number on registration so that the patient could provide a sample at any point, including while in the waiting area. After PDSA Cycle #1, urine specimen collection increased from 34.5% to 57.5%. After PDSA Cycle #2, this increased further to 59%. We conclude that a combination of educational and structural changes led to a significant increase in urine specimen collection before fluid or diuretic administration among patients presenting with moderate-to-severe hyponatraemia in the ED.

Sarcoidosis has a rare and independent association with renal AA amyloidosis and crescentic necrotizing glomerulonephritis. However, coexisting entities in sarcoidosis have not been previously described. Herein, we report a 66-year-old Caucasian woman who presented with generalized fatigue, weight loss, and acute kidney injury in the setting of likely sarcoidosis. Renal biopsy revealed AA amyloid fibrils with fibrocellular crescents. The patient's clinical symptoms and laboratory results improved with high-dose glucocorticoids and azathioprine.

The incidence of pyomyositis in immunocompromised patients with HIV, diabetes, myelodysplastic syndromes, and acute lymphocytic leukemia is well documented. However, there are only a few reports of pyomyositis and myonecrosis in patients with chronic lymphocytic leukemia (CLL). We present a rare case of pyomyositis presenting as myonecrosis secondary to methicillin-resistant Staphylococcus aureus bacteremia in a 72-year-old patient with CLL. Pyomyositis, although rare, warrants increased provider awareness and management, especially among CLL patients who pose diagnostic and treatment challenges.

A 28-year-old man presented to the emergency department with right shoulder pain that radiated to the right arm as well as pain of the right hip and lower back. His medical history is significant for sickle cell disease (SCD) with the HbSS genotype (homozygous for the S globin). He had a hemorrhagic stroke in the setting of venous sinus thrombosis 2 years earlier with no persisting neurologic deficits as well as osteonecrosis of bilateral hips and right knee requiring right total hip arthroplasty and right total knee arthroplasty. His pain started 3 days earlier after he exerted himself performing yard work and had progressively worsened. He described the pain as sharp, throbbing, and 10/10 in severity. The pain did not improve with acetaminophen or oxycodone. He also reported shortness of breath, which had resolved. He did not have fever, chills, chest pain, cough, abdominal pain, diarrhea, or recent trauma. Home medications included apixaban, l-glutamine, hydroxyurea, and folic acid. He had not missed any doses of his medications. He required 2 admissions in the past year for sickle cell pain crisis. Vital signs demonstrated an oral temperature of 37.7°C, blood pressure of 122/82 mm Hg, heart rate of 99 beats/min, respiratory rate of 19 breaths/min, and oxygen saturation of 94% on room air. Physical examination found tenderness to palpation of the right shoulder, right arm, and right hip with limited range of motion secondary to pain. There was no ecchymosis, erythema, or warmth of the shoulder or hip joints. Peripheral pulses were normal. Lungs were clear to auscultation bilaterally. Laboratory evaluation revealed the following (reference ranges provided parenthetically): hemoglobin, 9.0 g/dL (13.5 to 17.5 g/dL); hematocrit, 26.7% (38.3% to 48.6%); platelet count, 267 × 109/L (135 to 317 × 109/L); white blood cell count, 13.2 × 109/L (3.4 to 9.6 × 109/L); neutrophils, 10.29 × 109/L (1.56 to 6.45 × 109/L); lymphocytes, 1.51 × 109/L (0.95 to 3.07 × 109/L); monocytes, 1.09 × 109/L (0.26 to 0.81 × 109/L); eosinophils, 0.03 × 109/L (0.03 to 0.48 × 109/L); basophils, 0.06 × 109/L (0.01 to 0.08 × 109/L); sodium, 134 mmol/L (135 to 145 mmol/L); potassium, 4.1 mmol/L (3.6 to 5.2 mmol/L); bicarbonate, 25 mEq/L (22 to 29 mEq/L); blood urea nitrogen, 11 mg/dL (8 to 24 mg/dL); creatinine, 0.85 mg/dL (0.74 to 1.35 mg/dL); calcium, 9.8 mg/dL (8.8 to 10.2 mg/dL); glucose, 85 mg/dL (70 to 140 mg/dL); and procalcitonin, 0.17 ng/mL (≤0.15 ng/mL). Absolute reticulocyte count was 198 × 109/L (30.4 to 110.9 × 109/L) with a reticulocyte index of 3.1%. His baseline hemoglobin level ranged from 9 to 10 g/dL. Hemoglobin S percentage was 81.5%, which was increased from 69.8% at time of diagnosis. Radiographic examination of the right shoulder showed stable changes of the proximal humerus, suggesting chronic avascular necrosis (Figure). Radiographic examination of the hips and pelvis showed stable right total hip arthroplasty with well-seated components without evidence of loosening. In addition, there was unchanged sequela of left femoral head osteonecrosis. Chest film showed no focal consolidation, pleural effusion, or pneumothorax. Electrocardiographic findings were unremarkable, with no notable ischemic changes. High-sensitivity troponin level was normal.1.Which of the following is the most likely diagnosis?a.Acute avascular necrosisb.Acute coronary syndromec.Opioid-induced hyperalgesiad.Osteomyelitise.Vaso-occlusive crisis (VOC) On evaluation of a patient with SCD and acute pain, it is important to rule out common orthopedic complications of SCD, such as avascular necrosis.1Darbari D.S. Sheehan V.A. Ballas S.K. The vaso-occlusive pain crisis in sickle cell disease: definition, pathophysiology, and management.Eur J Haematol. 2020; 105: 237-246Crossref Scopus (30) Google Scholar Radiography is the initial study of choice when avascular necrosis is suspected clinically. In this case, radiographs of the hips and right shoulder were obtained, which showed evidence of chronic avascular necrosis unchanged from prior films. Whereas this is likely to be a cause of chronic pain for our patient, it would not explain his acute pain. Acute coronary syndrome can be manifested as atypical chest pain or pain of the shoulder or arm. This was appropriately ruled out with a normal electrocardiogram and high-sensitivity troponin level. Opioid-induced hyperalgesia is a type of neuropathic pain that can occur with long-term opioid use.1Darbari D.S. Sheehan V.A. Ballas S.K. The vaso-occlusive pain crisis in sickle cell disease: definition, pathophysiology, and management.Eur J Haematol. 2020; 105: 237-246Crossref Scopus (30) Google Scholar In addition to hyperalgesia (increased pain in response to a stimulus that should provoke pain), patients may also experience allodynia (pain in response to a stimulus that usually does not provoke pain) with escalating opioid dosages. This diagnosis is unlikely as the patient has not taken opioids long term for pain. Impaired immune function and functional asplenia place patients with SCD at risk for development of osteomyelitis.1Darbari D.S. Sheehan V.A. Ballas S.K. The vaso-occlusive pain crisis in sickle cell disease: definition, pathophysiology, and management.Eur J Haematol. 2020; 105: 237-246Crossref Scopus (30) Google Scholar However, in the absence of fever, localized erythema, or swelling, this diagnosis is less likely. Our patient did have a mildly elevated white blood cell count on presentation. Leukocytosis can be seen in sickle cell patients without an infection. Vaso-occlusive crisis is the most likely diagnosis. Patients typically present with a sudden onset and throbbing and sharp pain involving the lower back, joints, or extremities.1Darbari D.S. Sheehan V.A. Ballas S.K. The vaso-occlusive pain crisis in sickle cell disease: definition, pathophysiology, and management.Eur J Haematol. 2020; 105: 237-246Crossref Scopus (30) Google Scholar There is often a prodromal phase of 1 or 2 days with symptoms of numbness, paresthesia, or aches in the associated area.1Darbari D.S. Sheehan V.A. Ballas S.K. The vaso-occlusive pain crisis in sickle cell disease: definition, pathophysiology, and management.Eur J Haematol. 2020; 105: 237-246Crossref Scopus (30) Google Scholar The patient was subsequently admitted to the hospital for management of VOC.2.What initial treatment should be given for this patient's condition?a.Exchange transfusionb.Intravenous fluidsc.Nonsteroidal anti-inflammatory drugs (NSAIDs)d.Opioidse.Simple transfusion Exchange transfusion is not indicated for VOC alone; however, exchange transfusion is used in the setting of acute ischemic stroke, severe acute chest syndrome (ACS), multiorgan failure, acute sickle hepatopathy, and severe sepsis.2Howard J. Sickle cell disease: when and how to transfuse.Hematology Am Soc Hematol Educ Program. 2016; 2016: 625-631Crossref PubMed Scopus (62) Google Scholar There is a role for hydration with intravenous fluids if there is clinical evidence of dehydration to restore the patient to a euvolemic state.1Darbari D.S. Sheehan V.A. Ballas S.K. The vaso-occlusive pain crisis in sickle cell disease: definition, pathophysiology, and management.Eur J Haematol. 2020; 105: 237-246Crossref Scopus (30) Google Scholar,3Brandow A.M. Carroll C.P. Creary S. et al.American Society of Hematology 2020 guidelines for sickle cell disease: management of acute and chronic pain.Blood Adv. 2020; 4: 2656-2701Crossref PubMed Scopus (51) Google Scholar Whereas hydration with intravenous fluids can be a useful adjunctive therapy, it should not preclude adequate pain management. American Society of Hematology guidelines for management of acute pain related to SCD issue a conditional recommendation for 5 to 7 days of NSAIDs in addition to opioids.3Brandow A.M. Carroll C.P. Creary S. et al.American Society of Hematology 2020 guidelines for sickle cell disease: management of acute and chronic pain.Blood Adv. 2020; 4: 2656-2701Crossref PubMed Scopus (51) Google Scholar It is important to consider potential harms of NSAID use, such as renal, vascular, and gastrointestinal toxic effects. Our patient takes apixaban for history of venous sinus thrombosis, and NSAIDs would increase bleeding risk. Thus, NSAIDs would not be appropriate or the first management option. The cornerstone of therapy for VOC is rapid (preferably within 30 minutes) and effective analgesia with opioid medications.1Darbari D.S. Sheehan V.A. Ballas S.K. The vaso-occlusive pain crisis in sickle cell disease: definition, pathophysiology, and management.Eur J Haematol. 2020; 105: 237-246Crossref Scopus (30) Google Scholar An individualized approach based on baseline opioid therapy and prior effective therapy is recommended.1Darbari D.S. Sheehan V.A. Ballas S.K. The vaso-occlusive pain crisis in sickle cell disease: definition, pathophysiology, and management.Eur J Haematol. 2020; 105: 237-246Crossref Scopus (30) Google Scholar,3Brandow A.M. Carroll C.P. Creary S. et al.American Society of Hematology 2020 guidelines for sickle cell disease: management of acute and chronic pain.Blood Adv. 2020; 4: 2656-2701Crossref PubMed Scopus (51) Google Scholar Intranasal and subcutaneous routes of administration should also be considered to prevent delay in administration of analgesia.3Brandow A.M. Carroll C.P. Creary S. et al.American Society of Hematology 2020 guidelines for sickle cell disease: management of acute and chronic pain.Blood Adv. 2020; 4: 2656-2701Crossref PubMed Scopus (51) Google Scholar Simple transfusion is indicated in the case of symptomatic anemia in SCD but not for isolated vaso-occlusive pain.2Howard J. Sickle cell disease: when and how to transfuse.Hematology Am Soc Hematol Educ Program. 2016; 2016: 625-631Crossref PubMed Scopus (62) Google Scholar Iron overload and increased risk of red blood cell (RBC) alloimmunization may result from frequent blood transfusions.2Howard J. Sickle cell disease: when and how to transfuse.Hematology Am Soc Hematol Educ Program. 2016; 2016: 625-631Crossref PubMed Scopus (62) Google Scholar,4Fasano R.M. Booth G.S. Miles M. et al.Red blood cell alloimmunization is influenced by recipient inflammatory state at time of transfusion in patients with sickle cell disease.Br J Haematol. 2015; 168: 291-300Crossref PubMed Scopus (150) Google Scholar He received treatment with a morphine patient-controlled analgesia pump. Subsequently, the morphine patient-controlled analgesia pump was transitioned to oral oxycodone as needed when his pain was better controlled. The following day, a fever developed, with temperature of 38.1°C. He also noted shortness of breath and pleuritic chest pain. Oxygen saturation on room air was 96%. Blood culture specimens were obtained. Electrocardiography revealed sinus tachycardia with a heart rate of 105 beats/min and no ST-segment changes.3.Which of the following is the next most appropriate diagnostic evaluation?a.Arterial blood gasb.Bronchoalveolar lavagec.Computed tomography pulmonary angiography (CTPA)d.D-dimere.Troponin With development of fever, shortness of breath, and pleuritic chest pain, there was clinical concern for ACS. Acute chest syndrome often develops after onset of severe pain and is defined as an acute illness characterized by fever or respiratory symptoms, with a new pulmonary infiltrate on chest imaging.5Howard J. Hart N. Roberts-Harewood M. Cummins M. Awogbade M. Davis B. BCSH CommitteeGuideline on the management of acute chest syndrome in sickle cell disease.Br J Haematol. 2015; 169: 492-505Crossref PubMed Scopus (84) Google Scholar Other signs and symptoms of ACS may include hypoxia, chest pain, skeletal pain, and hemoptysis.5Howard J. Hart N. Roberts-Harewood M. Cummins M. Awogbade M. Davis B. BCSH CommitteeGuideline on the management of acute chest syndrome in sickle cell disease.Br J Haematol. 2015; 169: 492-505Crossref PubMed Scopus (84) Google Scholar Arterial blood gas analysis is useful for confirming hypoxia but is not usually necessary in adult patients with oxygen saturation above 94% on room air, such as in our case. Bronchoalveolar lavage would not be done before confirming a pulmonary infiltrate and is typically needed only if patients are not responding to standard therapy. The appropriate next step is CTPA because chest imaging is needed to confirm the diagnosis of ACS. Whereas ACS can be diagnosed with chest radiography, CTPA can be useful in excluding pulmonary embolism and is recommended if there is a high clinical suspicion of pulmonary embolism.5Howard J. Hart N. Roberts-Harewood M. Cummins M. Awogbade M. Davis B. BCSH CommitteeGuideline on the management of acute chest syndrome in sickle cell disease.Br J Haematol. 2015; 169: 492-505Crossref PubMed Scopus (84) Google Scholar D-dimer testing is not helpful in SCD because levels are typically elevated.5Howard J. Hart N. Roberts-Harewood M. Cummins M. Awogbade M. Davis B. BCSH CommitteeGuideline on the management of acute chest syndrome in sickle cell disease.Br J Haematol. 2015; 169: 492-505Crossref PubMed Scopus (84) Google Scholar With an electrocardiogram showing no ischemic changes, acute coronary syndrome is unlikely, and troponin should be ordered only if other work-up is unrevealing. Our patient's CTPA study found consolidative air space disease in the right lower lobe with no evidence of pulmonary embolism.4.What is the next most appropriate step in management of this patient's condition?a.Exchange transfusionb.Bronchodilator therapyc.Corticosteroidsd.Antibiotic therapye.Inhaled nitric oxide A pulmonary infiltrate was identified along with symptoms of chest pain and shortness of breath, which meets criteria of ACS. Exchange transfusion is warranted for severe clinical features, such as worsening hypoxia, increased respiratory rate, thrombocytopenia, or multilobar disease on chest imaging.2Howard J. Sickle cell disease: when and how to transfuse.Hematology Am Soc Hematol Educ Program. 2016; 2016: 625-631Crossref PubMed Scopus (62) Google Scholar The decision to initiate exchange transfusion should be made only after consultation with a hematologist. Our patient had disease localized to 1 lobe and no significant hypoxia or oxygen requirements; therefore, exchange transfusion was deferred with careful monitoring of evidence of clinical deterioration. Simple transfusion is recommended to be administered early in the hypoxic or symptomatic patient to increase hemoglobin level to greater than 10 g/dL, and failure to improve after simple transfusion is another indication for exchange transfusion.2Howard J. Sickle cell disease: when and how to transfuse.Hematology Am Soc Hematol Educ Program. 2016; 2016: 625-631Crossref PubMed Scopus (62) Google Scholar Bronchodilators should be used only if patients have a history of asthma or evidence of bronchospasm.5Howard J. Hart N. Roberts-Harewood M. Cummins M. Awogbade M. Davis B. BCSH CommitteeGuideline on the management of acute chest syndrome in sickle cell disease.Br J Haematol. 2015; 169: 492-505Crossref PubMed Scopus (84) Google Scholar Corticosteroids are indicated only in the case of acute asthma exacerbation, and there is a risk of rebound sickling with corticosteroid use.5Howard J. Hart N. Roberts-Harewood M. Cummins M. Awogbade M. Davis B. BCSH CommitteeGuideline on the management of acute chest syndrome in sickle cell disease.Br J Haematol. 2015; 169: 492-505Crossref PubMed Scopus (84) Google Scholar Because clinicians can usually not distinguish causes of ACS, patients must be treated empirically for pneumonia, including coverage of atypical organisms such as Mycoplasma and Chalmydophila.5Howard J. Hart N. Roberts-Harewood M. Cummins M. Awogbade M. Davis B. BCSH CommitteeGuideline on the management of acute chest syndrome in sickle cell disease.Br J Haematol. 2015; 169: 492-505Crossref PubMed Scopus (84) Google Scholar Whereas case reports have found benefit with inhaled nitric oxide therapy, there are no randomized controlled trials to support its routine use for ACS.5Howard J. Hart N. Roberts-Harewood M. Cummins M. Awogbade M. Davis B. BCSH CommitteeGuideline on the management of acute chest syndrome in sickle cell disease.Br J Haematol. 2015; 169: 492-505Crossref PubMed Scopus (84) Google Scholar Our patient was prescribed moxifloxacin, a respiratory fluoroquinolone with pseudomonal coverage that can be used for hospital-acquired pneumonia. He also received 1 simple transfusion. During the next 48 hours, he showed improvement in symptoms, including resolution of fever, chest pain, and shortness of breath. On hospital day 4, he was discharged home, with follow-up in the hematology clinic arranged.5.Which of the following medications should be given to prevent recurrence of VOC?a.Crizanlizumabb.Aspirinc.Montelukastd.Rivaroxabane.Simvastatin Crizanlizumab is a humanized monoclonal antibody that inhibits P-selectin.6Ataga K.I. Kutlar A. Kanter J. et al.Crizanlizumab for the prevention of pain crises in sickle cell disease.N Engl J Med. 2017; 376: 429-439Crossref PubMed Scopus (339) Google Scholar The SUSTAIN trial reported that crizanlizumab is associated with significantly lower frequency of pain crises and similar incidence of serious adverse effects in patients with SCD compared with placebo,6Ataga K.I. Kutlar A. Kanter J. et al.Crizanlizumab for the prevention of pain crises in sickle cell disease.N Engl J Med. 2017; 376: 429-439Crossref PubMed Scopus (339) Google Scholar leading to its approval by the Food and Drug Administration (FDA) in 2019. Studies have investigated aspirin and montelukast for management of SCD, and neither drug was found to decrease the frequency or severity of VOC.7Greenberg J. Ohene-Frempong K. Halus J. Way C. Schwartz E. Trial of low doses of aspirin as prophylaxis in sickle cell disease.J Pediatr. 1983; 102: 781-784Abstract Full Text PDF PubMed Scopus (76) Google Scholar,8Field J.J. Kassim A. Brandow A. et al.Phase 2 trial of montelukast for prevention of pain in sickle cell disease.Blood Adv. 2020; 4: 1159-1165Crossref Scopus (1) Google Scholar Anticoagulants like rivaroxaban have a role in managing some complications of SCD, such as thrombotic events; however, there is no evidence to suggest that rivaroxaban prevents VOC. In addition, the patient was already taking apixaban for history of sinus venous thrombosis. Simvastatin is hypothesized to benefit SCD because of its ability to decrease inflammation and to improve endothelial function.9Hoppe C. Jacob E. Styles L. Kuypers F. Larkin S. Vichinsky E. Simvastatin reduces vaso-occlusive pain in sickle cell anaemia: a pilot efficacy trial.Br J Haematol. 2017; 177: 620-629Crossref PubMed Scopus (35) Google Scholar A small pilot study with 19 individuals reported reduction in sickle cell–related pain in patients treated with simvastatin for 3 months.9Hoppe C. Jacob E. Styles L. Kuypers F. Larkin S. Vichinsky E. Simvastatin reduces vaso-occlusive pain in sickle cell anaemia: a pilot efficacy trial.Br J Haematol. 2017; 177: 620-629Crossref PubMed Scopus (35) Google Scholar Larger, randomized controlled trials are needed to further evaluate the efficacy of simvastatin in reducing VOC and hospitalizations in SCD. He returned to the hematology clinic after his hospitalization and was subsequently prescribed monthly intravenous infusions of crizanlizumab. Three months later, he has not required hospitalization for any complication of SCD including VOC. Sickle cell disease, the most common hemoglobinopathy, is due to a mutation in the β-globin gene, producing hemoglobin S (HbS). This altered hemoglobin protein is more likely to polymerize in the deoxygenated state, causing reduced deformability and thus "sickling" of RBCs.1Darbari D.S. Sheehan V.A. Ballas S.K. The vaso-occlusive pain crisis in sickle cell disease: definition, pathophysiology, and management.Eur J Haematol. 2020; 105: 237-246Crossref Scopus (30) Google Scholar,10Kapoor S. Little J.A. Pecker L.H. Advances in the treatment of sickle cell disease.Mayo Clin Proc. 2018; 93: 1810-1824Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar Clinical manifestations of SCD are heterogeneous, depending on the specific genotype. Our patient had HbSS disease, which typically is manifested with severe features of multiorgan involvement. Infections, severe anemia, and VOC are acute complications of SCD that require prompt diagnosis and treatment. It is important to identify potential triggers of VOC, such as dehydration, hypoxia, significant physical or emotional stress, temperature extremes, infection, and select comorbidities.1Darbari D.S. Sheehan V.A. Ballas S.K. The vaso-occlusive pain crisis in sickle cell disease: definition, pathophysiology, and management.Eur J Haematol. 2020; 105: 237-246Crossref Scopus (30) Google Scholar Our patient was a 28-year-old man who presented with VOC, which may have been triggered by his physically exerting himself while performing yardwork. It is also possible that a respiratory infection may have triggered VOC, leading to indiscernible consolidations on chest imaging. He initially had diffuse joint pain but quickly developed systemic symptoms concerning for ACS. This rapid progression of multiorgan involvement is explained by the underlying mechanisms of VOC. The polymerized sickled RBCs from HbSS disease adhere to vascular endothelium and induce chronic inflammation through chemokines. This chronic inflammation promotes microvascular occlusion, large-vessel intimal hyperplasia, thrombosis, bone marrow fat embolization, and ultimately tissue ischemia.1Darbari D.S. Sheehan V.A. Ballas S.K. The vaso-occlusive pain crisis in sickle cell disease: definition, pathophysiology, and management.Eur J Haematol. 2020; 105: 237-246Crossref Scopus (30) Google Scholar Acute chest syndrome can develop when pulmonary tissue and vasculature are involved. Manifestations of ACS can include pulmonary infections, fat embolism, and infarction. The sequelae of ACS can induce a V/Q mismatch, leading to respiratory distress and persistent hypoxia.5Howard J. Hart N. Roberts-Harewood M. Cummins M. Awogbade M. Davis B. BCSH CommitteeGuideline on the management of acute chest syndrome in sickle cell disease.Br J Haematol. 2015; 169: 492-505Crossref PubMed Scopus (84) Google Scholar A mild form of ACS was suspected in our patient because of radiographic evidence of a pulmonary infiltrate, fever, and pleuritic chest pain. Our patient was not found to have significant hypoxia and did not require supplemental oxygen. Acute chest syndrome represents a spectrum of disease, ranging from a mild respiratory illness to respiratory failure, with severe hypoxia associated with a higher transfusion requirement and increased mortality.5Howard J. Hart N. Roberts-Harewood M. Cummins M. Awogbade M. Davis B. BCSH CommitteeGuideline on the management of acute chest syndrome in sickle cell disease.Br J Haematol. 2015; 169: 492-505Crossref PubMed Scopus (84) Google Scholar Because the clinical features of pneumonia also meet the criteria for ACS, treatment of coexisting entities was of utmost importance. In general, the management of SCD involves treating symptomatic anemia and preventing complications of SCD, such as VOC. Hydroxyurea was the first drug approved by the FDA for treatment of homozygous SCD.10Kapoor S. Little J.A. Pecker L.H. Advances in the treatment of sickle cell disease.Mayo Clin Proc. 2018; 93: 1810-1824Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar Hydroxyurea works by increasing fetal hemoglobin production and decreasing intracellular HbS polymerization.10Kapoor S. Little J.A. Pecker L.H. Advances in the treatment of sickle cell disease.Mayo Clin Proc. 2018; 93: 1810-1824Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar Adults with SCD treated with hydroxyurea have fewer episodes of VOC and ACS, require fewer blood transfusions, and have longer overall survival.10Kapoor S. Little J.A. Pecker L.H. Advances in the treatment of sickle cell disease.Mayo Clin Proc. 2018; 93: 1810-1824Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar l-Glutamine, an amino acid precursor for nicotinamide adenine dinucleotide, is another therapy for SCD approved by the FDA. Glutamine and glutathione levels are depleted in erythrocytes in patients with SCD, which is believed to be due to increased oxidation in sickle RBCs and higher l-glutamine consumption.10Kapoor S. Little J.A. Pecker L.H. Advances in the treatment of sickle cell disease.Mayo Clin Proc. 2018; 93: 1810-1824Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar l-Glutamine has been reported to decrease hospitalizations and frequency of VOC and ACS in patients with SCD.1Darbari D.S. Sheehan V.A. Ballas S.K. The vaso-occlusive pain crisis in sickle cell disease: definition, pathophysiology, and management.Eur J Haematol. 2020; 105: 237-246Crossref Scopus (30) Google Scholar,10Kapoor S. Little J.A. Pecker L.H. Advances in the treatment of sickle cell disease.Mayo Clin Proc. 2018; 93: 1810-1824Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar Crizanlizumab, a humanized monoclonal antibody, works by inhibiting P-selectin. P-selectin is responsible for initiating the process of leukocyte adhesion to the endothelium, which is known to contribute to abnormal blood flow in patients with SCD.6Ataga K.I. Kutlar A. Kanter J. et al.Crizanlizumab for the prevention of pain crises in sickle cell disease.N Engl J Med. 2017; 376: 429-439Crossref PubMed Scopus (339) Google Scholar The SUSTAIN trial compared crizanlizumab with placebo in 198 patients with SCD, reporting a lower rate of VOC in the high-dose crizanlizumab group (1.08 per year) compared with placebo (2.91 per year).6Ataga K.I. Kutlar A. Kanter J. et al.Crizanlizumab for the prevention of pain crises in sickle cell disease.N Engl J Med. 2017; 376: 429-439Crossref PubMed Scopus (339) Google Scholar Adverse effects of crizanlizumab include nausea, vomiting, arthralgias, pruritus, and chest pain.6Ataga K.I. Kutlar A. Kanter J. et al.Crizanlizumab for the prevention of pain crises in sickle cell disease.N Engl J Med. 2017; 376: 429-439Crossref PubMed Scopus (339) Google Scholar Voxelotor was the most recent drug to gain FDA approval in the treatment of SCD. Voxelotor is an oral agent that works by inhibiting sickled hemoglobin polymerization. The HOPE trial reported significant improvements in hemoglobin concentrations and reductions in hemolysis markers with voxelotor compared with placebo.11Howard J. Ataga K.I. Brown R.C. et al.Voxelotor in adolescents and adults with sickle cell disease (HOPE): long-term follow-up results of an international, randomised, double-blind, placebo-controlled, phase 3 trial.Lancet Haematol. 2021; 8: e323-e333Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar Future studies are needed to determine the impact of this drug on hospitalizations and mortality in SCD. Allogeneic hematopoietic stem cell transplant (HSCT) is a potentially curative therapy for SCD that works by replacing the patient's hematopoietic stem cells with a donor's cells, allowing normal RBC production.10Kapoor S. Little J.A. Pecker L.H. Advances in the treatment of sickle cell disease.Mayo Clin Proc. 2018; 93: 1810-1824Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar In patients with severe complications of SCD, such as stroke, recurrent episodes of VOC, ACS, recurrent priapism, osteonecrosis, or transfusion-associated alloimmunization, HSCT should be considered.10Kapoor S. Little J.A. Pecker L.H. Advances in the treatment of sickle cell disease.Mayo Clin Proc. 2018; 93: 1810-1824Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar The limited availability of suitable donors along with the risk of complications after transplant, such as infection, graft failure, and graft-vs-host disease, is a barrier to HSCT for most patients.10Kapoor S. Little J.A. Pecker L.H. Advances in the treatment of sickle cell disease.Mayo Clin Proc. 2018; 93: 1810-1824Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar In 2017, a 13-year-old boy with HbSS disease became the first person to be successfully treated with gene therapy.10Kapoor S. Little J.A. Pecker L.H. Advances in the treatment of sickle cell disease.Mayo Clin Proc. 2018; 93: 1810-1824Abstract Full Text Full Text PDF PubMed Scopus (39) Google Scholar Gene therapy, a rapidly evolving field, uses genetically modified autologous stem cells, eliminating the requirement for a donor.12Frangoul H. Altshuler D. Cappellini M.D. et al.CRISPR-Cas9 gene editing for sickle cell disease and β-thalassemia.N Engl J Med. 2021; 384: 252-260Crossref PubMed Scopus (311) Google Scholar Several clinical trials are currently underway to further study the safety and efficacy of gene therapy for SCD. Whereas newer therapies have helped to increase life expectancy and improve morbidity associated with SCD, gene therapy has the potential to soon revolutionize the management of SCD. The authors report no competing interests.

Over the last three decades, increased attention has been given to the representation of historically underrepresented groups within the landscape of pivotal clinical trials. However, recent events (i.e., coronavirus pandemic) have laid bare the potential continuation of historic inequities in available clinical trials and studies aimed at the care of broad patient populations. Anecdotally, cardiovascular disease (CVD) has not been immune to these disparities. Within this review, we examine and discuss recent landmark CVD trials, with a specific focus on the representation of Blacks within several critically foundational heart failure clinical trials tied to contemporary treatment strategies and drug approvals. We also discuss solutions for inequities within the landscape of cardiovascular trials. Building a more diverse clinical trial workforce coupled with intentional efforts to increase clinical trial diversity will advance equity in cardiovascular care.

Edwardsiella tarda (E. tarda) is a gram-negative, facultatively anaerobic bacillus that is associated with gastroenteritis and a host of other extra-intestinal manifestations in humans. However, its impact on the kidneys is unclear. Most literature that has explored this association involves fish, marine life in which E. tarda inhabits. We report a rare case of a 72-year-old female who presented with an acute kidney injury (AKI) associated with newfound minimal change disease, subacute interstitial nephritis, and a severe E. tarda infection. Her clinical course resolved with antibiotics and glucocorticoids.

A 47-year-old woman with a history of myeloperoxidase–anti-neutrophil cytoplasmic autoantibody (MPO-ANCA) microscopic polyangiitis (MPA) in remission, left orbital plasmacytoma in remission, and hypothyroidism presented to the hospital for 1 month of persistent bilateral flank pain. Additionally, she had 2 months of migratory joint pain and a rash that was briefly treated with hydroxychloroquine. Treatment was discontinued because of gastrointestinal upset. Upon evaluation, she also had complaints of mild sinus congestion and right ear fullness, but denied any shortness of breath, fever, chills, cough, hemoptysis, dysuria, urinary frequency and urgency, or routine use of protein pump inhibitors, nonsteroidal anti-inflammatory drugs, diuretics, herbal supplements, or illicit drugs. Home medications included pork thyroid, estradiol, and probiotics.Vital signs revealed an oral temperature of 36.9°C, blood pressure of 113/80 mm Hg, a respiratory rate of 20 breaths/min, a heart rate of 73 beats/min, and an oxygen saturation of 98% on room air. Physical examination was positive for costovertebral angle tenderness (left more than right). Cardiac, pulmonary, and dermatological examinations were unremarkable. Her oral mucosa was moist without ulceration. There was no peripheral edema, synovitis, or tenosynovitis. Initial laboratory testing yielded the following results (reference ranges provided parenthetically): sodium level, 137 mmol/L (135 to 145 mmol/L); potassium level, 3.3 mmol/L (3.6 to 5.2 mmol/L); blood urea nitrogen level, 10 mg/dL (6 to 21 mg/dL); serum creatinine (SCr) level, 1.03 mg/dL (0.59 to 1.04 mg/dL); bicarbonate level, 27 mEq/L (22 to 29 mEq/L); hemoglobin level, 10.7 g/dL (11.6 to 15.0 g/dL); hematocrit level, 32.2 (35.5% to 44.9%); white blood cell (WBC) count, 4.8×109/L ((3.4 to 9.6)×109/L); and peripheral eosinophil count, 0.06×109/L ((0.03 to 0.48)×109/L. Two months before presentation, the patient’s SCr level was 0.6 mg/dL. Urinalysis was significant for 100 mg/dL of protein, moderate hemoglobin, 3 WBCs per high-power field, and 3 red blood cells per high-power field. Urinalysis was negative for bacteria, leukocyte esterase, and nitrites. Urine sodium and creatinine levels were 44 and 46 mmol/L, respectively. A 24-hour urine collection yielded 1.9 g of protein. Computed tomography (CT) urogram without and with intravenous contrast revealed multiple patchy areas of decreased enhancement in both kidneys as well as diffuse urothelial enhancement involving the collecting system and ureters (Supplemental Figure, available online at http://www.mayoclinicproceedings.org). No renal calculi or hydronephrosis was appreciated.1.Which one of the following is the most accurate description of this patient’s kidney function?a.No kidney injuryb.Acute kidney injury (AKI) stage 1c.Acute kidney injury stage 2d.Acute kidney injury stage 3e.Chronic kidney disease (CKD) stage 3Although the patient’s SCr level was within normal limits, it was substantially elevated at 1.03 from 0.6 (170% from baseline). The patient had nonoliguric acute kidney injury (AKI) stage 1, defined per the Kidney Disease: Improving Global Outcomes guidelines as an acute increase in SCr level of 0.3 mg/dL or higher in 48 hours or an increase in SCr level by 150% to 200% or more from baseline or a urine output (UOP) of less than 0.5 mL/kg per hour for 6 to 12 hours. Acute kidney injury stage 2 is an increase in SCr level of more than 200% to 300% from baseline or a UOP of less than 0.5 mL/kg per hour for more than 12 hours. Acute kidney injury stage 3 is an increase in SCr level of more than 300% from baseline, an increase in SCr level to 4 mg/dL or higher, initiation of renal replacement therapy for AKI, a UOP of less than 0.3 mL/kg per hour for more than 24 hours, or anuria (<100 mL of urine per 24 hours). The specific staging of renal injury adds valuable prognostic data. There is an increase in mortality, length of hospital stay, severity of residual CKD, and need for renal replacement therapy with increasing stages of AKI.1Lopes J.A. Jorge S. The RIFLE and AKIN classifications for acute kidney injury: a critical and comprehensive review.Clin Kidney J. 2013; 6: 8-14Crossref PubMed Scopus (299) Google ScholarChronic kidney disease is defined as a decreased glomerular filtration rate of less than 60 mL/min per 1.73 m2 and/or markers of kidney damage for 3 months or more. With the available data, the patient’s SCr level was 0.6 mg/dL and the estimated glomerular filtration rate was higher than 90 mL/min/BSA 2 months before making CKD unlikely. Additionally, she had new onset proteinuria compared to previous urinalyses.We discussed the evaluation of AKI with the patient, explaining the subtle yet significant elevation in her SCr level. She was agreeable to further diagnostic tests and treatments for her condition.2.Which one of the following is the most appropriate next step in the characterization of renal injury?a.Renal ultrasoundb.Retrograde pyelogramc.Urine eosinophilsd.Anti-neutrophil cytoplasmic autoantibody (ANCA) panele.Urine sediment examinationRenal ultrasound and retrograde pyelogram are imaging options that can rule out urinary obstruction. Renal ultrasound is preferred for this indication because of the lack of radiation exposure, easy availability, and low cost. Retrograde pyelograms are invasive and hold possible complications including urinary tract infections and bladder perforation. Nevertheless, ordering further imaging would be unnecessary as a previous CT urogram did not detect nephrolithiasis or hydronephrosis.Testing for urine eosinophils has an insignificant role in characterizing AKI given its lack of sensitivity and specificity for the diagnosis of acute interstitial nephritis (AIN).2Muriithi A.K. Nasr S.H. Leung N. Utility of urine eosinophils in the diagnosis of acute interstitial nephritis [published correction appears in Clin J Am Soc Nephrol. 2018;13(7):1079].Clin J Am Soc Nephrol. 2013; 8: 1857-1862Crossref PubMed Scopus (65) Google Scholar Eosinophiluria may be present in numerous diseases beyond AIN, such as urogenital infections, atheroembolic renal disease, acute tubular necrosis (ATN), rapidly progressive glomerulonephritis, and malignant tumor of bladder.The ANCA panel would be a reasonable test to pursue because of her medical history of MPA. Rising ANCA titers have been modestly associated with future vasculitic relapses.3Wallace Z.S. Miloslavsky E.M. Management of ANCA associated vasculitis.BMJ. 2020; 368: m421Crossref PubMed Scopus (36) Google Scholar,4Jennette J.C. Nachman P.H. ANCA glomerulonephritis and vasculitis.Clin J Am Soc Nephrol. 2017; 12: 1680-1691Crossref PubMed Scopus (162) Google Scholar We noticed that the patient’s MPO antibody titers were increasing over the past 7 years (from 1.5 to >8.0; normal, <0.4). However, an ANCA panel by itself would not be the first step in providing a broad work-up required to evaluate for other causes of AKI, which include pre-renal and intrinsic renal parenchymal damage.Urine sediment examination is the most appropriate next step as it provides key information about the etiology of AKI. It allows clinicians to analyze cellular morphology, assess tubular integrity, and identify the presence of casts and crystals.5Cavanaugh C. Perazella M.A. Urine sediment examination in the diagnosis and management of kidney disease: core curriculum 2019.Am J Kidney Dis. 2019; 73: 258-272Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar Despite careful assessment of volume status, UOP, and fractional excretion of sodium/urea, the diagnosis of pre-renal AKI or ATN can be challenging to make. Manual urine microscopy is helpful in making this distinction and allowing for appropriate prognostication and guidance of therapy. An active urinary sediment would warrant further diagnostics and rapid treatment.The patient’s urinary sediment contained mixed cellular casts predominantly composed of red blood cells and a few WBCs. Renal tubular epithelial cells were also present, which may indicate the presence of concurrent ATN. The patient’s fractional excretion of sodium was 0.7%, which initially supported pre-renal as the etiology of AKI. However, a low fractional excretion of sodium can also be seen in acute glomerulonephritis and contrast-induced nephropathy. Therefore, this highlights the superiority of urine sediment analysis over a simple laboratory value in distinction between pre-renal and intrinsic AKI.Other unremarkable laboratory investigations included blood cultures, urine culture, IgG4 level, hepatitis B (core, surface antigen, and surface antibody) and C antibodies, proteinase 3 level, c-ANCA, cryoglobulins, serum protein electrophoresis without the presence of a monoclonal protein on immunofixation, antinuclear antibody, rheumatoid factor, and anti–cyclic citrullinated peptide. Although κ and λ free light chain concentrations were elevated at 5.33 mg/dL (0.33 to 1.94 mg/dL) and 3.54 mg/dL (0.57 to 2.63 mg/dL), respectively, the κ/λ ratio was 1.51 (0.26 to 1.65).The next step in diagnostic evaluation was renal biopsy, as there was a high suspicion of systemic disease with renal involvement as evidenced by new onset proteinuria, hematuria, and an active urinary sediment.6Dhaun N. Bellamy C.O. Cattran D.C. Kluth D.C. Utility of renal biopsy in the clinical management of renal disease [published correction appears in Kidney Int. 2014;86(6):1268].Kidney Int. 2014; 85: 1039-1048Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar The biopsy consisted of 3 cores of cortex with up to 20 glomeruli. Glomerular findings included segmental tuft hypercellularity with focal glomerular basement membrane breaks, focal necrosis, cellular/fibrocellular crescents, and segmental/global sclerosis. Additionally, there was diffuse moderate acute tubular injury with isometric cytoplasmic vacuolization. Lastly, there was mild to moderate tubulointerstitial fibrosis, mild arteriolar hyalinosis, and moderate arteriosclerosis. There were no neutrophils, eosinophils, or crystals in the tubulointerstitium. Immunofluorescence examination did not reveal any significant staining for IgM, IgG, IgA, C3, κ, or λ. There was no subepithelial, intramembranous, or subendothelial immune complex deposition on electron microscopy.3.On the basis of the imaging, laboratory, and biopsy findings, which one of the following is the most likely diagnosis?a.Acute pyelonephritisb.Immunoglobulin G4–related diseasec.Acute interstitial nephritisd.Myeloma cast nephropathye.Pauci-immune crescentic glomerulonephritisAcute pyelonephritis was considered because of heterogeneous parenchymal echogenicity on CT and flank pain. However, the criterion standard for confirming a diagnosis of pyelonephritis is a urine culture, which was negative for bacterial growth. Additionally, the patient was afebrile with no evidence of leukocytosis. Despite the overall low suspicion of pyelonephritis, ceftriaxone 1 g every 24 hours was initiated for empirical treatment while waiting for the urine culture result. Renal biopsy was completed after a no growth in urine culture.Immunoglobulin G4–related disease is a systemic disease with infiltration of polyclonal lymphocytes and plasma cells, storiform fibrosis, and obliterative phlebitis.7Kamisawa T. Zen Y. Pillai S. Stone J.H. IgG4-related disease.Lancet. 2015; 385: 1460-1471Abstract Full Text Full Text PDF PubMed Google Scholar It was considered in the diagnostic evaluation, particularly in the setting of the patient’s history of orbital plasmocytoma. Immunoglobulin G4 renal disease manifests as tubulointerstitial nephritis with significant immunoglobulin deposits and moderate tissue eosinophilia. Immunofluorescence on kidney biopsy was negative for IgG4, and light microscopy did not exhibit any eosinophils. Immunoglobulin G4 disease is associated with low complement level, peripheral eosinophilia, and elevated serum IgG4 level. Our patient had a normal eosinophil count and serum IgG4 level.Acute interstitial nephritis was a reasonable diagnostic consideration because of the presence of mixed cellular casts. Renal tubular epithelial cells, though most commonly associated with ATN, have been observed in up to 86% of AIN cases.8Nussbaum E.Z. Perazella M.A. Diagnosing acute interstitial nephritis: considerations for clinicians.Clin Kidney J. 2019; 12: 808-813Google Scholar The patient did not display the classic triad of fever, rash, and eosinophilia that can be associated with AIN, although this triad is seen only in a minority of cases. However, the diagnosis could not be ruled out before analyzing the urine sediment and kidney biopsy findings. Acute interstitial nephritis is most commonly attributed to medications followed by autoimmune diseases. The patient was not taking any medications or supplements that would lead to AIN. Lastly, renal biopsy remains the criterion standard for the diagnosis of AIN and, in this case, did not present the typical findings of eosinophils, plasma cells, and lymphocytic infiltrates in the peritubular areas of the interstitium. Myeloma cast nephropathy was an unlikely diagnosis because of negative serum protein electrophoresis, lack of a monoclonal protein on immunofixation, normal serum free light chain ratio, and absence of tubular casts on renal biopsy.On the basis of the renal biopsy findings and the patient’s known history of MPA, pauci-immune focally necrotizing and crescentic glomerulonephritis secondary to MPA was the final diagnosis. The patient’s SCr level continued to rise, peaking at 1.26 mg/dL.4.Which one of the following is the most efficacious induction regimen for this patient’s diagnosis?a.Glucocorticoids and rituximabb.Mycophenolate mofetilc.Methotrexated.Azathioprinee.Therapeutic plasma exchangeIn patients with mild or moderate renal involvement with no diffuse pulmonary hemorrhage, recommended induction therapies include high-dose glucocorticoids followed by intravenous pulse cyclophosphamide or rituximab.4Jennette J.C. Nachman P.H. ANCA glomerulonephritis and vasculitis.Clin J Am Soc Nephrol. 2017; 12: 1680-1691Crossref PubMed Scopus (162) Google Scholar The initial high doses of intravenous glucocorticoids are eventually tapered to daily oral prednisone with subsequent taper over 6 months. Although a cyclophosphamide-based induction regimen is frequently used, it carries significant cumulative dose-dependent adverse effects such as leukopenia, infections, hemorrhagic cystitis, and malignancy. Rituximab, an anti-CD20 monoclonal antibody, is an equally efficacious alternative option. The Rituximab versus Cyclophosphamide for ANCA-associated Vasculitis and Rituximab versus Cyclophosphamide in ANCA-associated Renal Vasculitis trials found that rituximab was noninferior to cyclophosphamide in inducing remission.9Stone J.H. Merkel P.A. Spiera R. et al.RAVE-ITN Research GroupRituximab versus cyclophosphamide for ANCA-associated vasculitis.N Engl J Med. 2010; 363: 221-232Crossref PubMed Scopus (1821) Google Scholar,10Jones R.B. Cohen Tervaert J.W. Hauser T. et al.European Vasculitis Study GroupRituximab versus cyclophosphamide in ANCA-associated renal vasculitis.N Engl J Med. 2010; 363: 211-220Crossref PubMed Scopus (1161) Google Scholar Mycophenolate mofetil and methotrexate have been found to induce remission in less severe cases, but can be associated with higher disease relapse rates. Azathioprine has no role in induction therapy. Therapeutic plasma exchange has been used in severe disease manifested by severe renal failure with or without diffuse pulmonary hemorrhage. However, the Plasma Exchange and Glucocorticoids in Severe ANCA-Associated Vasculitis trial did not find a significant reduction in the incidence of death or end-stage renal disease with adjunctive therapeutic plasma exchange when added to standard of care.11Walsh M. Merkel P.A. Peh C.A. et al.PEXIVAS InvestigatorsPlasma exchange and glucocorticoids in severe ANCA-associated vasculitis.N Engl J Med. 2020; 382: 622-631Crossref PubMed Scopus (236) Google ScholarThe patient received intravenous methylprednisolone 1000 mg for 3 days followed by oral prednisone (1 mg/kg) for 1 month. A slow taper of prednisone, per the Plasma Exchange and Glucocorticoids in Severe ANCA-Associated Vasculitis trial protocol, was initiated afterward. Additionally, she received intravenous rituximab 375 mg/m2 once weekly for 4 doses. The patient tolerated the treatment with no significant adverse effects. At 2-month follow-up, her SCr level improved to 0.85 mg/dL. The protein-to-creatinine ratio decreased to 0.56. Urinalysis revealed resolution of hematuria. Her bilateral flank pain resolved completely.5.Which one of the following is the most appropriate maintenance regimen for this patient’s diagnosis?a.Rituximabb.Trimethoprim-sulfamethoxazolec.Cyclophosphamided.Hydroxychloroquinee.BortezomibIn addition to azathioprine, methotrexate, and mycophenolate mofetil for maintenance of remission, rituximab is often preferred because of its ability to better prevent disease relapse. The MAINRITSAN trial evaluated rituximab vs azathioprine as remission maintenance therapy for ANCA-associated vasculitis (AAV). Rituximab resulted in higher sustained remission at month 28 than did azathioprine with a similar rate of adverse events.12Guillevin L. Pagnoux C. Karras A. et al.French Vasculitis Study GroupRituximab versus azathioprine for maintenance in ANCA-associated vasculitis.N Engl J Med. 2014; 371: 1771-1780Crossref PubMed Scopus (613) Google Scholar Trimethoprim-sulfamethoxazole is indicated for the prophylaxis of Pneumocystis jirovecii pneumonia in patients receiving immunosuppressive agents.3Wallace Z.S. Miloslavsky E.M. Management of ANCA associated vasculitis.BMJ. 2020; 368: m421Crossref PubMed Scopus (36) Google ScholarMaintenance cyclophosphamide is not recommended because of the aforementioned toxicities. There is a lack of data via placebo-controlled trials to support the use of hydroxychloroquine or bortezomib for the treatment of AAV.Our patient will be receiving rituximab for maintenance therapy every 6 months.DiscussionIn summary, this patient with a history of MPA, orbital plasmacytoma, and hypothyroidism presented to our facility with a chief complaint of bilateral flank pain and previous migratory joint pain with intermittent rashes. She was found to have nonoliguric AKI stage 1 associated with proteinuria, hematuria, and active urine sediment. The renal biopsy revealed that her AKI was due to relapse of vasculitis.This case highlights the diagnostic approach and management of patients with AKI secondary to AAV. In our patient, the initial recognition of AKI in the setting of a “normal” SCr level and new onset proteinuria prompted our attention in initiating a thorough work-up and aggressive follow-up treatment. It is important to note the increasing trends in SCr, particularly in patients with lower muscle mass. An AKI may still exist while the SCr level may deceptively appear normal. Beginning with noninvasive tests such as urinalysis, urine electrolytes, and urine sediment analysis provides critical information to pursue additional diagnostic procedures. Manual urine microscopy has fallen out of favor because of technological advances in urine analysis, perceived burden of time, and possible interobserver variability.5Cavanaugh C. Perazella M.A. Urine sediment examination in the diagnosis and management of kidney disease: core curriculum 2019.Am J Kidney Dis. 2019; 73: 258-272Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar However, as found in this case, it was a vital diagnostic tool that allowed us to further characterize AKI in real time, promptly perform a renal biopsy, and initiate life- and organ-saving treatment. If intrinsic renal injury was not identified early on the urine sediment, it is possible that the patient would have progressed to AKI stage 3, potentially requiring renal replacement therapy. As part of this diagnostic work-up, it was equally important to rule out other causes of AKI such as pre-renal or obstructive causes by taking a meticulous history and performing renal imaging. Ultimately, the renal biopsy was critical in making the diagnosis of glomerulonephritis secondary to microscopic polyangiitis.Anti-neutrophil cytoplasmic autoantibody–associated vasculitis is a heterogeneous inflammatory disease affecting small- to medium-sized blood vessels. Severe AAV causes significant organ compromise, which includes diffuse alveolar hemorrhage, glomerulonephritis, mononeuritis multiplex, sensorineural deafness, scleritis, or gangrene.3Wallace Z.S. Miloslavsky E.M. Management of ANCA associated vasculitis.BMJ. 2020; 368: m421Crossref PubMed Scopus (36) Google Scholar Nonsevere disease includes sinonasal involvement, pulmonary nodules, tracheobronchial disease, and arthritis.3Wallace Z.S. Miloslavsky E.M. Management of ANCA associated vasculitis.BMJ. 2020; 368: m421Crossref PubMed Scopus (36) Google Scholar Most patients eventually progress to severe disease, oftentimes initially presenting in the fulminant form. The most common severe sequelae of AAV is renal involvement, with up to 30% of patients progressing to end-stage renal disease. Rarely, vasculitis of the periureteral blood vessels can lead to ureteral abnormalities, which was seen on CT in our patient.Anti-neutrophil cytoplasmic autoantibody–associated vasculitis is subdivided into MPA, granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis, and renal-limited vasculitis with pauci-immune necrotizing glomerulonephritis alone with no evidence for systemic vasculitis. Classifying the specific AAV with serologies (MPO-ANCA, proteinase 3–ANCA, and ANCA-negative) and pathological entity is helpful in predicting the prognosis and response to treatment.4Jennette J.C. Nachman P.H. ANCA glomerulonephritis and vasculitis.Clin J Am Soc Nephrol. 2017; 12: 1680-1691Crossref PubMed Scopus (162) Google Scholar When suspicion is high for AAV on the basis of history taking and physical examination, it is critical to obtain a diagnosis with tissue biopsy because positive outcomes depend on the rapid initiation of effective treatment. The mainstay of treatment in patients with AAV is induction therapy with high-dose glucocorticoids and either cyclophosphamide or rituximab. We highlight the efficacy of rituximab in the induction and maintenance of AAV over conventional immunosuppressants. Our patient responded favorably to treatment, with her laboratory results presenting evidence of renal recovery. Lastly, it is important for patients to adhere to therapy to decrease rates of disease relapse. Frontiers for the treatment of AAV are constantly expanding as more clinical trials study the utility of potential immunomodulators. A 47-year-old woman with a history of myeloperoxidase–anti-neutrophil cytoplasmic autoantibody (MPO-ANCA) microscopic polyangiitis (MPA) in remission, left orbital plasmacytoma in remission, and hypothyroidism presented to the hospital for 1 month of persistent bilateral flank pain. Additionally, she had 2 months of migratory joint pain and a rash that was briefly treated with hydroxychloroquine. Treatment was discontinued because of gastrointestinal upset. Upon evaluation, she also had complaints of mild sinus congestion and right ear fullness, but denied any shortness of breath, fever, chills, cough, hemoptysis, dysuria, urinary frequency and urgency, or routine use of protein pump inhibitors, nonsteroidal anti-inflammatory drugs, diuretics, herbal supplements, or illicit drugs. Home medications included pork thyroid, estradiol, and probiotics. Vital signs revealed an oral temperature of 36.9°C, blood pressure of 113/80 mm Hg, a respiratory rate of 20 breaths/min, a heart rate of 73 beats/min, and an oxygen saturation of 98% on room air. Physical examination was positive for costovertebral angle tenderness (left more than right). Cardiac, pulmonary, and dermatological examinations were unremarkable. Her oral mucosa was moist without ulceration. There was no peripheral edema, synovitis, or tenosynovitis. Initial laboratory testing yielded the following results (reference ranges provided parenthetically): sodium level, 137 mmol/L (135 to 145 mmol/L); potassium level, 3.3 mmol/L (3.6 to 5.2 mmol/L); blood urea nitrogen level, 10 mg/dL (6 to 21 mg/dL); serum creatinine (SCr) level, 1.03 mg/dL (0.59 to 1.04 mg/dL); bicarbonate level, 27 mEq/L (22 to 29 mEq/L); hemoglobin level, 10.7 g/dL (11.6 to 15.0 g/dL); hematocrit level, 32.2 (35.5% to 44.9%); white blood cell (WBC) count, 4.8×109/L ((3.4 to 9.6)×109/L); and peripheral eosinophil count, 0.06×109/L ((0.03 to 0.48)×109/L. Two months before presentation, the patient’s SCr level was 0.6 mg/dL. Urinalysis was significant for 100 mg/dL of protein, moderate hemoglobin, 3 WBCs per high-power field, and 3 red blood cells per high-power field. Urinalysis was negative for bacteria, leukocyte esterase, and nitrites. Urine sodium and creatinine levels were 44 and 46 mmol/L, respectively. A 24-hour urine collection yielded 1.9 g of protein. Computed tomography (CT) urogram without and with intravenous contrast revealed multiple patchy areas of decreased enhancement in both kidneys as well as diffuse urothelial enhancement involving the collecting system and ureters (Supplemental Figure, available online at http://www.mayoclinicproceedings.org). No renal calculi or hydronephrosis was appreciated.1.Which one of the following is the most accurate description of this patient’s kidney function?a.No kidney injuryb.Acute kidney injury (AKI) stage 1c.Acute kidney injury stage 2d.Acute kidney injury stage 3e.Chronic kidney disease (CKD) stage 3 Although the patient’s SCr level was within normal limits, it was substantially elevated at 1.03 from 0.6 (170% from baseline). The patient had nonoliguric acute kidney injury (AKI) stage 1, defined per the Kidney Disease: Improving Global Outcomes guidelines as an acute increase in SCr level of 0.3 mg/dL or higher in 48 hours or an increase in SCr level by 150% to 200% or more from baseline or a urine output (UOP) of less than 0.5 mL/kg per hour for 6 to 12 hours. Acute kidney injury stage 2 is an increase in SCr level of more than 200% to 300% from baseline or a UOP of less than 0.5 mL/kg per hour for more than 12 hours. Acute kidney injury stage 3 is an increase in SCr level of more than 300% from baseline, an increase in SCr level to 4 mg/dL or higher, initiation of renal replacement therapy for AKI, a UOP of less than 0.3 mL/kg per hour for more than 24 hours, or anuria (<100 mL of urine per 24 hours). The specific staging of renal injury adds valuable prognostic data. There is an increase in mortality, length of hospital stay, severity of residual CKD, and need for renal replacement therapy with increasing stages of AKI.1Lopes J.A. Jorge S. The RIFLE and AKIN classifications for acute kidney injury: a critical and comprehensive review.Clin Kidney J. 2013; 6: 8-14Crossref PubMed Scopus (299) Google Scholar Chronic kidney disease is defined as a decreased glomerular filtration rate of less than 60 mL/min per 1.73 m2 and/or markers of kidney damage for 3 months or more. With the available data, the patient’s SCr level was 0.6 mg/dL and the estimated glomerular filtration rate was higher than 90 mL/min/BSA 2 months before making CKD unlikely. Additionally, she had new onset proteinuria compared to previous urinalyses. We discussed the evaluation of AKI with the patient, explaining the subtle yet significant elevation in her SCr level. She was agreeable to further diagnostic tests and treatments for her condition.2.Which one of the following is the most appropriate next step in the characterization of renal injury?a.Renal ultrasoundb.Retrograde pyelogramc.Urine eosinophilsd.Anti-neutrophil cytoplasmic autoantibody (ANCA) panele.Urine sediment examination Renal ultrasound and retrograde pyelogram are imaging options that can rule out urinary obstruction. Renal ultrasound is preferred for this indication because of the lack of radiation exposure, easy availability, and low cost. Retrograde pyelograms are invasive and hold possible complications including urinary tract infections and bladder perforation. Nevertheless, ordering further imaging would be unnecessary as a previous CT urogram did not detect nephrolithiasis or hydronephrosis. Testing for urine eosinophils has an insignificant role in characterizing AKI given its lack of sensitivity and specificity for the diagnosis of acute interstitial nephritis (AIN).2Muriithi A.K. Nasr S.H. Leung N. Utility of urine eosinophils in the diagnosis of acute interstitial nephritis [published correction appears in Clin J Am Soc Nephrol. 2018;13(7):1079].Clin J Am Soc Nephrol. 2013; 8: 1857-1862Crossref PubMed Scopus (65) Google Scholar Eosinophiluria may be present in numerous diseases beyond AIN, such as urogenital infections, atheroembolic renal disease, acute tubular necrosis (ATN), rapidly progressive glomerulonephritis, and malignant tumor of bladder. The ANCA panel would be a reasonable test to pursue because of her medical history of MPA. Rising ANCA titers have been modestly associated with future vasculitic relapses.3Wallace Z.S. Miloslavsky E.M. Management of ANCA associated vasculitis.BMJ. 2020; 368: m421Crossref PubMed Scopus (36) Google Scholar,4Jennette J.C. Nachman P.H. ANCA glomerulonephritis and vasculitis.Clin J Am Soc Nephrol. 2017; 12: 1680-1691Crossref PubMed Scopus (162) Google Scholar We noticed that the patient’s MPO antibody titers were increasing over the past 7 years (from 1.5 to >8.0; normal, <0.4). However, an ANCA panel by itself would not be the first step in providing a broad work-up required to evaluate for other causes of AKI, which include pre-renal and intrinsic renal parenchymal damage. Urine sediment examination is the most appropriate next step as it provides key information about the etiology of AKI. It allows clinicians to analyze cellular morphology, assess tubular integrity, and identify the presence of casts and crystals.5Cavanaugh C. Perazella M.A. Urine sediment examination in the diagnosis and management of kidney disease: core curriculum 2019.Am J Kidney Dis. 2019; 73: 258-272Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar Despite careful assessment of volume status, UOP, and fractional excretion of sodium/urea, the diagnosis of pre-renal AKI or ATN can be challenging to make. Manual urine microscopy is helpful in making this distinction and allowing for appropriate prognostication and guidance of therapy. An active urinary sediment would warrant further diagnostics and rapid treatment. The patient’s urinary sediment contained mixed cellular casts predominantly composed of red blood cells and a few WBCs. Renal tubular epithelial cells were also present, which may indicate the presence of concurrent ATN. The patient’s fractional excretion of sodium was 0.7%, which initially supported pre-renal as the etiology of AKI. However, a low fractional excretion of sodium can also be seen in acute glomerulonephritis and contrast-induced nephropathy. Therefore, this highlights the superiority of urine sediment analysis over a simple laboratory value in distinction between pre-renal and intrinsic AKI. Other unremarkable laboratory investigations included blood cultures, urine culture, IgG4 level, hepatitis B (core, surface antigen, and surface antibody) and C antibodies, proteinase 3 level, c-ANCA, cryoglobulins, serum protein electrophoresis without the presence of a monoclonal protein on immunofixation, antinuclear antibody, rheumatoid factor, and anti–cyclic citrullinated peptide. Although κ and λ free light chain concentrations were elevated at 5.33 mg/dL (0.33 to 1.94 mg/dL) and 3.54 mg/dL (0.57 to 2.63 mg/dL), respectively, the κ/λ ratio was 1.51 (0.26 to 1.65). The next step in diagnostic evaluation was renal biopsy, as there was a high suspicion of systemic disease with renal involvement as evidenced by new onset proteinuria, hematuria, and an active urinary sediment.6Dhaun N. Bellamy C.O. Cattran D.C. Kluth D.C. Utility of renal biopsy in the clinical management of renal disease [published correction appears in Kidney Int. 2014;86(6):1268].Kidney Int. 2014; 85: 1039-1048Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar The biopsy consisted of 3 cores of cortex with up to 20 glomeruli. Glomerular findings included segmental tuft hypercellularity with focal glomerular basement membrane breaks, focal necrosis, cellular/fibrocellular crescents, and segmental/global sclerosis. Additionally, there was diffuse moderate acute tubular injury with isometric cytoplasmic vacuolization. Lastly, there was mild to moderate tubulointerstitial fibrosis, mild arteriolar hyalinosis, and moderate arteriosclerosis. There were no neutrophils, eosinophils, or crystals in the tubulointerstitium. Immunofluorescence examination did not reveal any significant staining for IgM, IgG, IgA, C3, κ, or λ. There was no subepithelial, intramembranous, or subendothelial immune complex deposition on electron microscopy.3.On the basis of the imaging, laboratory, and biopsy findings, which one of the following is the most likely diagnosis?a.Acute pyelonephritisb.Immunoglobulin G4–related diseasec.Acute interstitial nephritisd.Myeloma cast nephropathye.Pauci-immune crescentic glomerulonephritis Acute pyelonephritis was considered because of heterogeneous parenchymal echogenicity on CT and flank pain. However, the criterion standard for confirming a diagnosis of pyelonephritis is a urine culture, which was negative for bacterial growth. Additionally, the patient was afebrile with no evidence of leukocytosis. Despite the overall low suspicion of pyelonephritis, ceftriaxone 1 g every 24 hours was initiated for empirical treatment while waiting for the urine culture result. Renal biopsy was completed after a no growth in urine culture. Immunoglobulin G4–related disease is a systemic disease with infiltration of polyclonal lymphocytes and plasma cells, storiform fibrosis, and obliterative phlebitis.7Kamisawa T. Zen Y. Pillai S. Stone J.H. IgG4-related disease.Lancet. 2015; 385: 1460-1471Abstract Full Text Full Text PDF PubMed Google Scholar It was considered in the diagnostic evaluation, particularly in the setting of the patient’s history of orbital plasmocytoma. Immunoglobulin G4 renal disease manifests as tubulointerstitial nephritis with significant immunoglobulin deposits and moderate tissue eosinophilia. Immunofluorescence on kidney biopsy was negative for IgG4, and light microscopy did not exhibit any eosinophils. Immunoglobulin G4 disease is associated with low complement level, peripheral eosinophilia, and elevated serum IgG4 level. Our patient had a normal eosinophil count and serum IgG4 level. Acute interstitial nephritis was a reasonable diagnostic consideration because of the presence of mixed cellular casts. Renal tubular epithelial cells, though most commonly associated with ATN, have been observed in up to 86% of AIN cases.8Nussbaum E.Z. Perazella M.A. Diagnosing acute interstitial nephritis: considerations for clinicians.Clin Kidney J. 2019; 12: 808-813Google Scholar The patient did not display the classic triad of fever, rash, and eosinophilia that can be associated with AIN, although this triad is seen only in a minority of cases. However, the diagnosis could not be ruled out before analyzing the urine sediment and kidney biopsy findings. Acute interstitial nephritis is most commonly attributed to medications followed by autoimmune diseases. The patient was not taking any medications or supplements that would lead to AIN. Lastly, renal biopsy remains the criterion standard for the diagnosis of AIN and, in this case, did not present the typical findings of eosinophils, plasma cells, and lymphocytic infiltrates in the peritubular areas of the interstitium. Myeloma cast nephropathy was an unlikely diagnosis because of negative serum protein electrophoresis, lack of a monoclonal protein on immunofixation, normal serum free light chain ratio, and absence of tubular casts on renal biopsy. On the basis of the renal biopsy findings and the patient’s known history of MPA, pauci-immune focally necrotizing and crescentic glomerulonephritis secondary to MPA was the final diagnosis. The patient’s SCr level continued to rise, peaking at 1.26 mg/dL.4.Which one of the following is the most efficacious induction regimen for this patient’s diagnosis?a.Glucocorticoids and rituximabb.Mycophenolate mofetilc.Methotrexated.Azathioprinee.Therapeutic plasma exchange In patients with mild or moderate renal involvement with no diffuse pulmonary hemorrhage, recommended induction therapies include high-dose glucocorticoids followed by intravenous pulse cyclophosphamide or rituximab.4Jennette J.C. Nachman P.H. ANCA glomerulonephritis and vasculitis.Clin J Am Soc Nephrol. 2017; 12: 1680-1691Crossref PubMed Scopus (162) Google Scholar The initial high doses of intravenous glucocorticoids are eventually tapered to daily oral prednisone with subsequent taper over 6 months. Although a cyclophosphamide-based induction regimen is frequently used, it carries significant cumulative dose-dependent adverse effects such as leukopenia, infections, hemorrhagic cystitis, and malignancy. Rituximab, an anti-CD20 monoclonal antibody, is an equally efficacious alternative option. The Rituximab versus Cyclophosphamide for ANCA-associated Vasculitis and Rituximab versus Cyclophosphamide in ANCA-associated Renal Vasculitis trials found that rituximab was noninferior to cyclophosphamide in inducing remission.9Stone J.H. Merkel P.A. Spiera R. et al.RAVE-ITN Research GroupRituximab versus cyclophosphamide for ANCA-associated vasculitis.N Engl J Med. 2010; 363: 221-232Crossref PubMed Scopus (1821) Google Scholar,10Jones R.B. Cohen Tervaert J.W. Hauser T. et al.European Vasculitis Study GroupRituximab versus cyclophosphamide in ANCA-associated renal vasculitis.N Engl J Med. 2010; 363: 211-220Crossref PubMed Scopus (1161) Google Scholar Mycophenolate mofetil and methotrexate have been found to induce remission in less severe cases, but can be associated with higher disease relapse rates. Azathioprine has no role in induction therapy. Therapeutic plasma exchange has been used in severe disease manifested by severe renal failure with or without diffuse pulmonary hemorrhage. However, the Plasma Exchange and Glucocorticoids in Severe ANCA-Associated Vasculitis trial did not find a significant reduction in the incidence of death or end-stage renal disease with adjunctive therapeutic plasma exchange when added to standard of care.11Walsh M. Merkel P.A. Peh C.A. et al.PEXIVAS InvestigatorsPlasma exchange and glucocorticoids in severe ANCA-associated vasculitis.N Engl J Med. 2020; 382: 622-631Crossref PubMed Scopus (236) Google Scholar The patient received intravenous methylprednisolone 1000 mg for 3 days followed by oral prednisone (1 mg/kg) for 1 month. A slow taper of prednisone, per the Plasma Exchange and Glucocorticoids in Severe ANCA-Associated Vasculitis trial protocol, was initiated afterward. Additionally, she received intravenous rituximab 375 mg/m2 once weekly for 4 doses. The patient tolerated the treatment with no significant adverse effects. At 2-month follow-up, her SCr level improved to 0.85 mg/dL. The protein-to-creatinine ratio decreased to 0.56. Urinalysis revealed resolution of hematuria. Her bilateral flank pain resolved completely.5.Which one of the following is the most appropriate maintenance regimen for this patient’s diagnosis?a.Rituximabb.Trimethoprim-sulfamethoxazolec.Cyclophosphamided.Hydroxychloroquinee.Bortezomib In addition to azathioprine, methotrexate, and mycophenolate mofetil for maintenance of remission, rituximab is often preferred because of its ability to better prevent disease relapse. The MAINRITSAN trial evaluated rituximab vs azathioprine as remission maintenance therapy for ANCA-associated vasculitis (AAV). Rituximab resulted in higher sustained remission at month 28 than did azathioprine with a similar rate of adverse events.12Guillevin L. Pagnoux C. Karras A. et al.French Vasculitis Study GroupRituximab versus azathioprine for maintenance in ANCA-associated vasculitis.N Engl J Med. 2014; 371: 1771-1780Crossref PubMed Scopus (613) Google Scholar Trimethoprim-sulfamethoxazole is indicated for the prophylaxis of Pneumocystis jirovecii pneumonia in patients receiving immunosuppressive agents.3Wallace Z.S. Miloslavsky E.M. Management of ANCA associated vasculitis.BMJ. 2020; 368: m421Crossref PubMed Scopus (36) Google Scholar Maintenance cyclophosphamide is not recommended because of the aforementioned toxicities. There is a lack of data via placebo-controlled trials to support the use of hydroxychloroquine or bortezomib for the treatment of AAV. Our patient will be receiving rituximab for maintenance therapy every 6 months. DiscussionIn summary, this patient with a history of MPA, orbital plasmacytoma, and hypothyroidism presented to our facility with a chief complaint of bilateral flank pain and previous migratory joint pain with intermittent rashes. She was found to have nonoliguric AKI stage 1 associated with proteinuria, hematuria, and active urine sediment. The renal biopsy revealed that her AKI was due to relapse of vasculitis.This case highlights the diagnostic approach and management of patients with AKI secondary to AAV. In our patient, the initial recognition of AKI in the setting of a “normal” SCr level and new onset proteinuria prompted our attention in initiating a thorough work-up and aggressive follow-up treatment. It is important to note the increasing trends in SCr, particularly in patients with lower muscle mass. An AKI may still exist while the SCr level may deceptively appear normal. Beginning with noninvasive tests such as urinalysis, urine electrolytes, and urine sediment analysis provides critical information to pursue additional diagnostic procedures. Manual urine microscopy has fallen out of favor because of technological advances in urine analysis, perceived burden of time, and possible interobserver variability.5Cavanaugh C. Perazella M.A. Urine sediment examination in the diagnosis and management of kidney disease: core curriculum 2019.Am J Kidney Dis. 2019; 73: 258-272Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar However, as found in this case, it was a vital diagnostic tool that allowed us to further characterize AKI in real time, promptly perform a renal biopsy, and initiate life- and organ-saving treatment. If intrinsic renal injury was not identified early on the urine sediment, it is possible that the patient would have progressed to AKI stage 3, potentially requiring renal replacement therapy. As part of this diagnostic work-up, it was equally important to rule out other causes of AKI such as pre-renal or obstructive causes by taking a meticulous history and performing renal imaging. Ultimately, the renal biopsy was critical in making the diagnosis of glomerulonephritis secondary to microscopic polyangiitis.Anti-neutrophil cytoplasmic autoantibody–associated vasculitis is a heterogeneous inflammatory disease affecting small- to medium-sized blood vessels. Severe AAV causes significant organ compromise, which includes diffuse alveolar hemorrhage, glomerulonephritis, mononeuritis multiplex, sensorineural deafness, scleritis, or gangrene.3Wallace Z.S. Miloslavsky E.M. Management of ANCA associated vasculitis.BMJ. 2020; 368: m421Crossref PubMed Scopus (36) Google Scholar Nonsevere disease includes sinonasal involvement, pulmonary nodules, tracheobronchial disease, and arthritis.3Wallace Z.S. Miloslavsky E.M. Management of ANCA associated vasculitis.BMJ. 2020; 368: m421Crossref PubMed Scopus (36) Google Scholar Most patients eventually progress to severe disease, oftentimes initially presenting in the fulminant form. The most common severe sequelae of AAV is renal involvement, with up to 30% of patients progressing to end-stage renal disease. Rarely, vasculitis of the periureteral blood vessels can lead to ureteral abnormalities, which was seen on CT in our patient.Anti-neutrophil cytoplasmic autoantibody–associated vasculitis is subdivided into MPA, granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis, and renal-limited vasculitis with pauci-immune necrotizing glomerulonephritis alone with no evidence for systemic vasculitis. Classifying the specific AAV with serologies (MPO-ANCA, proteinase 3–ANCA, and ANCA-negative) and pathological entity is helpful in predicting the prognosis and response to treatment.4Jennette J.C. Nachman P.H. ANCA glomerulonephritis and vasculitis.Clin J Am Soc Nephrol. 2017; 12: 1680-1691Crossref PubMed Scopus (162) Google Scholar When suspicion is high for AAV on the basis of history taking and physical examination, it is critical to obtain a diagnosis with tissue biopsy because positive outcomes depend on the rapid initiation of effective treatment. The mainstay of treatment in patients with AAV is induction therapy with high-dose glucocorticoids and either cyclophosphamide or rituximab. We highlight the efficacy of rituximab in the induction and maintenance of AAV over conventional immunosuppressants. Our patient responded favorably to treatment, with her laboratory results presenting evidence of renal recovery. Lastly, it is important for patients to adhere to therapy to decrease rates of disease relapse. Frontiers for the treatment of AAV are constantly expanding as more clinical trials study the utility of potential immunomodulators. In summary, this patient with a history of MPA, orbital plasmacytoma, and hypothyroidism presented to our facility with a chief complaint of bilateral flank pain and previous migratory joint pain with intermittent rashes. She was found to have nonoliguric AKI stage 1 associated with proteinuria, hematuria, and active urine sediment. The renal biopsy revealed that her AKI was due to relapse of vasculitis. This case highlights the diagnostic approach and management of patients with AKI secondary to AAV. In our patient, the initial recognition of AKI in the setting of a “normal” SCr level and new onset proteinuria prompted our attention in initiating a thorough work-up and aggressive follow-up treatment. It is important to note the increasing trends in SCr, particularly in patients with lower muscle mass. An AKI may still exist while the SCr level may deceptively appear normal. Beginning with noninvasive tests such as urinalysis, urine electrolytes, and urine sediment analysis provides critical information to pursue additional diagnostic procedures. Manual urine microscopy has fallen out of favor because of technological advances in urine analysis, perceived burden of time, and possible interobserver variability.5Cavanaugh C. Perazella M.A. Urine sediment examination in the diagnosis and management of kidney disease: core curriculum 2019.Am J Kidney Dis. 2019; 73: 258-272Abstract Full Text Full Text PDF PubMed Scopus (62) Google Scholar However, as found in this case, it was a vital diagnostic tool that allowed us to further characterize AKI in real time, promptly perform a renal biopsy, and initiate life- and organ-saving treatment. If intrinsic renal injury was not identified early on the urine sediment, it is possible that the patient would have progressed to AKI stage 3, potentially requiring renal replacement therapy. As part of this diagnostic work-up, it was equally important to rule out other causes of AKI such as pre-renal or obstructive causes by taking a meticulous history and performing renal imaging. Ultimately, the renal biopsy was critical in making the diagnosis of glomerulonephritis secondary to microscopic polyangiitis. Anti-neutrophil cytoplasmic autoantibody–associated vasculitis is a heterogeneous inflammatory disease affecting small- to medium-sized blood vessels. Severe AAV causes significant organ compromise, which includes diffuse alveolar hemorrhage, glomerulonephritis, mononeuritis multiplex, sensorineural deafness, scleritis, or gangrene.3Wallace Z.S. Miloslavsky E.M. Management of ANCA associated vasculitis.BMJ. 2020; 368: m421Crossref PubMed Scopus (36) Google Scholar Nonsevere disease includes sinonasal involvement, pulmonary nodules, tracheobronchial disease, and arthritis.3Wallace Z.S. Miloslavsky E.M. Management of ANCA associated vasculitis.BMJ. 2020; 368: m421Crossref PubMed Scopus (36) Google Scholar Most patients eventually progress to severe disease, oftentimes initially presenting in the fulminant form. The most common severe sequelae of AAV is renal involvement, with up to 30% of patients progressing to end-stage renal disease. Rarely, vasculitis of the periureteral blood vessels can lead to ureteral abnormalities, which was seen on CT in our patient. Anti-neutrophil cytoplasmic autoantibody–associated vasculitis is subdivided into MPA, granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis, and renal-limited vasculitis with pauci-immune necrotizing glomerulonephritis alone with no evidence for systemic vasculitis. Classifying the specific AAV with serologies (MPO-ANCA, proteinase 3–ANCA, and ANCA-negative) and pathological entity is helpful in predicting the prognosis and response to treatment.4Jennette J.C. Nachman P.H. ANCA glomerulonephritis and vasculitis.Clin J Am Soc Nephrol. 2017; 12: 1680-1691Crossref PubMed Scopus (162) Google Scholar When suspicion is high for AAV on the basis of history taking and physical examination, it is critical to obtain a diagnosis with tissue biopsy because positive outcomes depend on the rapid initiation of effective treatment. The mainstay of treatment in patients with AAV is induction therapy with high-dose glucocorticoids and either cyclophosphamide or rituximab. We highlight the efficacy of rituximab in the induction and maintenance of AAV over conventional immunosuppressants. Our patient responded favorably to treatment, with her laboratory results presenting evidence of renal recovery. Lastly, it is important for patients to adhere to therapy to decrease rates of disease relapse. Frontiers for the treatment of AAV are constantly expanding as more clinical trials study the utility of potential immunomodulators. Supplemental Online Material

A 78-year-old woman athlete presented with malaise and right flank pain. Her medical history was significant for well-controlled hypertension, a duplex collecting system (complete ureteral duplication on the right kidney and partial duplication down to just above the ureterovesical junction on the

ANCA-associated vasculitis is a multiorgan autoimmune inflammatory disease that has a heterogeneous clinical presentation. Our case report provides additional evidence supporting the association between granulomatosis with polyangiitis and myositis. In our patient with proximal muscle weakness and pain, a normal creatine kinase and lack of antibodies to muscular fiber units ruled out primary myositis. Distinct magnetic resonance imaging of the brain within the deep gray matter in addition to positive serologies were consistent with a diagnosis of granulomatosis with polyangiitis. ANCA-associated vasculitis, specifically granulomatosis with polyangiitis, may be overlooked if musculoskeletal manifestations are the presenting symptoms. Prompt and aggressive treatment prevented this patient from experiencing multiorgan failure.

Mortality remains high in septic shock with few new treatment options. Angiotensin II has been recently approved for use in septic shock due to promising results in the ATHOS-3 trial. However, patients with neutropenia were excluded in the trial. This patient population is becoming increasingly common in the intensive care unit as there is an increase in novel biologic therapies and stem cell transplantations for haematological and solid organ malignancies. We present a case of a patient with T-cell acute lymphoblastic leukaemia who received chemotherapy, resulting in neutropenia and septic shock. There was persistent hypotension despite initiating multiple conventional vasopressors. Angiotensin II was attempted with immediate improvement in the blood pressure which resulted in weaning of other vasopressors. This positive haemodynamic response suggests that angiotensin II can successfully be used in neutropenic patients without increasing the overall catecholamine burden of septic shock.

Reactive oxygen species (ROS) have been extensively studied as a cause of male infertility. Oxidative stress (OS) occurs when the physiological redox balance is disrupted, in which excess ROS overwhelm the neutralizing capacity of antioxidants in the seminal plasma. OS attenuates lipid, protein, and DNA integrity, which mandates quick detection of the insult before the downstream consequences are amplified. Currently, there are a number of assays that can detect only individual components of OS. The MiOXSYS system is a novel technology that measures the oxidation-reduction potential (ORP), a direct indicator of OS. It provides a comprehensive measure of OS status, quantifying both oxidants and antioxidants in real time. With a high sensitivity, specificity, and accuracy, the MiOXSYS system provides reference values for OS in semen samples that can help differentiate fertile from infertile semen samples. ORP measurement can be used as an adjunct to basic semen analyses to determine the etiology of male infertility. This chapter outlines a step-by-step protocol for the laboratory measurement of ORP by the MiOXSYS system.

Individuals with posttraumatic stress disorder (PTSD) are at increased risk for cardiovascular disease. We previously reported that a predator-based model of PTSD increases myocardial sensitivity to ischemic injury. Heightened sympathetic signaling has a well-established role in the formation of anxiety associated with PTSD and may also contribute to worsening of myocardial injury in the ischemic heart. Thus, we examined whether suppression of sympathetic tone protects the ischemic heart in rats subjected to this model of PTSD. Rats were treated with saline or clonidine throughout the 31-day stress paradigm. Behavior on the elevated plus maze (EPM) was assessed on Day 32, and hearts were subjected to an ischemic insult on day 33. Stressed rats exhibited increased anxiety on the EPM and significantly larger myocardial infarcts following ischemia. Clonidine reversed the anxiety-like behavior but had no impact on infarct size. In a subsequent experiment, rats were treated with propranolol in their drinking water throughout the stress paradigm. Propranolol had no effect on either anxiety or myocardial sensitivity to ischemic injury. These findings suggest that the myocardial hypersensitivity to ischemic injury observed in this model is not caused by increased sympathetic tone or chronic beta-adrenergic receptor signaling.

Oxidative stress (OS), defined as an overabundance of reactive oxygen species (ROS) or a deficiency of antioxidants, has been linked to sperm damage and male infertility. There are many sources of OS and inflammation including varicocele, tobacco usage, alcohol, obesity/metabolic syndrome, leukocytospermia, sexually transmitted disease (i.e., Neisseria gonorrhoeae, Chlamydia trachomatis, Treponema pallidum), bacterial prostatitis, microorganism mutations leading to more OS, and viral infections (i.e., human immunodeficiency virus, hepatitis). This review is focusing on infection and inflammation-mediated OS, the inflammatory markers underlying pathology, clinical significance in male infertility, and a brief description of the recommended treatment modalities.

Gαi‐coupled receptors play important roles in protecting the heart from ischemic injury. Regulator of G protein signaling (RGS) proteins suppress Gαi signaling by accelerating the GTPase activity of Gαi subunits. However, the roles of individual RGS proteins in modulating ischemic injury are unknown. In the present study, we investigated the impact of RGS6 deletion on myocardial sensitivity to ischemic injury. Hearts from RGS6 knockout (RGS6 −/− ) and wildtype (RGS6 +/+ ) mice were subjected to 30 min ischemia and 2 hr reperfusion on a Langendorff heart apparatus. Infarcts in RGS6 −/− hearts were significantly larger than infarcts in RGS6 +/+ hearts. RGS6 −/− hearts also exhibited increased phosphorylation of β 2 ‐adrenergic receptors, ERK, and GRK2. Mitochondrial GRK2 as well as caspase‐3 cleavage were increased significantly in RGS6 −/− hearts compared to RGS6 +/+ hearts following ischemia. Chronic propranolol treatment of mice prevented the observed increases in ischemic injury and phosphorylation of ERK and GRK2 observed in RGS6 −/− hearts. Our findings suggest that loss of RGS6 predisposes the ventricle to pro‐death signaling through the β 2 AR‐ERK‐GRK2 signaling axis and provide evidence for a protective role of RGS6 in the ischemic heart. Individuals expressing genetic polymorphisms that suppress the activity of RGS6 may be at increased risk of cardiac ischemic injury. Furthermore, the development of agents that increase RGS6 expression or activity might provide a novel strategy for the treatment of ischemic heart disease. Support or Funding Information This work was supported by the National Institute of General Medicine [GM39561 to RRN], National Cancer institute [CA161882 to RAF], the American Heart Association [14GRNT20460208 to RAF], and an Ohio Northern University Bower and Bennet Endowment Award to BRR

Male infertility affects men worldwide. Oxidative stress (OS), characterized by an overabundance of reactive oxygen species (ROS) or a deficiency of antioxidants, is one of the major causes of male infertility. OS causes damage at the molecular level, which impairs lipids, proteins, and DNA. The cyclic cascade of redox reactions weakens sperm function which leads to poor semen parameters and eventual sterility. There is a need for advanced diagnostic tests that can quickly and accurately detect OS. Most commonly used assays can only measure single constituents of OS. However, the MiOXSYS System introduces a new strategy to detect OS by measuring the oxidation-reduction potential (ORP)--a direct evaluation of the redox balance between ROS and antioxidants. The MiOXSYS System has shown promise as a diagnostic tool in the evaluation of male infertility. This review explores the concept of ORP, details the principle of the MiOXSYS System, and summarizes the findings in clinical studies that support ORP measurement in semen.

Approximately 5 % of the United States population has used methamphetamine at some point in their lifetime. Methamphetamine is known to increase the risk of a myocardial infarction, but it is unclear whether methamphetamine alters the extent of myocardial injury. The first goal of this study was to determine whether repeated methamphetamine exposure alters the extent of injury in the ischemic heart. Adult rats received daily subcutaneous injections of methamphetamine (5 mg/kg) or saline for 10 days, and their hearts were subjected to an ischemic insult on day 11 using a Langendorff isolated heart apparatus. Hearts from methamphetamine‐treated female rats exhibited significantly larger infarcts and significantly suppressed postischemic recovery of contractile function compared to hearts from saline‐treated females. In contrast, infarct size and postischemic recovery of contractile function were unaffected by methamphetamine in males. The second goal was to determine whether prenatal methamphetamine exposure alters myocardial sensitivity to ischemic injury during adulthood. Pregnant rats (F0 generation) received daily injections of methamphetamine (5 mg/kg) or saline throughout the duration of their pregnancy. When the F1 pups reached 8 weeks of age, their hearts were subjected to an ischemic insult. Infarcts were significantly larger in adult female hearts that had been prenatally exposed to methamphetamine compared to control females that were prenatally exposed to saline. In addition, protein kinase C‐ɛ expression and Akt phosphorylation were decreased in hearts from methamphetamine‐exposed females. In contrast, methamphetamine had no impact on infarct size, PKC‐ɛ, or Akt phosphorylation in their male littermates. Others have reported that rat pups (F2) born to parents (F1) that were prenatally exposed to methamphetamine exhibit deficits in sensory‐motor coordination. Thus, F1 rats that had been prenatally exposed to methamphetamine were used as breeders to produce the F2 generation of rats. Hearts from F2 rats were subjected to an ischemic insult when they reached 8 weeks of age. We found no evidence for myocardial hypersensitivity to ischemic injury in the F2 generation that was not directly exposed to methamphetamine. These data provide evidence that a history of adult or prenatal exposure to methamphetamine worsens ischemic injury in the adult heart. This could have significant implications for people who have both ischemic heart disease and a history of adult or prenatal exposure to methamphetamine.Support or Funding InformationThis work was supported by an Ohio Northern University Bower and Bennet Endowment Award to BRR.

Gαi-coupled receptors play important roles in protecting the heart from ischemic injury. Regulator of G protein signaling (RGS) proteins suppress Gαi signaling by accelerating the GTPase activity of Gαi subunits. However, the roles of individual RGS proteins in modulating ischemic injury are unknown. In this study, we investigated the effect of RGS6 deletion on myocardial sensitivity to ischemic injury. Hearts from RGS6 knockout (RGS6−/−) and RGS6 wild-type (RGS6+/+) mice were subjected to 30 minutes of ischemia and 2 hours of reperfusion on a Langendorff heart apparatus. Infarcts in RGS6−/− hearts were significantly larger than infarcts in RGS6+/+ hearts. RGS6−/− hearts also exhibited increased phosphorylation of β2-adrenergic receptors and G protein–coupled receptor kinase 2 (GRK2). Mitochondrial GRK2 as well as caspase-3 cleavage were increased significantly in RGS6−/− hearts compared with RGS6+/+ hearts after ischemia. Chronic propranolol treatment of mice prevented the observed increases in ischemic injury and the GRK2 phosphorylation observed in RGS6−/− hearts. Our findings suggest that loss of RGS6 predisposes the ventricle to prodeath signaling through a β2AR-GRK2–dependent signaling mechanism, and they provide evidence for a protective role of RGS6 in the ischemic heart. Individuals expressing genetic polymorphisms that suppress the activity of RGS6 may be at increased risk of cardiac ischemic injury. Furthermore, the development of agents that increase RGS6 expression or activity might provide a novel strategy for the treatment of ischemic heart disease.

Sleep deprivation is associated with increased risk of myocardial infarction. However, it is unknown whether the effects of sleep deprivation are limited to increasing the likelihood of experiencing a myocardial infarction or if sleep deprivation also increases the extent of myocardial injury. In this study, rats were deprived of paradoxical sleep for 96 h using the platform-over-water method. Control rats were subjected to the same condition except the control platform was large enough for the rats to sleep. Hearts from sleep deprived and control rats were subjected to 20 min ischemia on a Langendorff isolated heart system. Infarct size and post ischemic recovery of contractile function were unaffected by sleep deprivation in male hearts. In contrast, hearts from sleep-deprived females exhibited significantly larger infarcts than hearts from control females. Post ischemic recovery of rate pressure product and + dP/dT were significantly attenuated by sleep deprivation in female hearts, and post ischemic recovery of end diastolic pressure was significantly elevated in hearts from sleep deprived females compared to control females, indicating that post ischemic recovery of both systolic and diastolic function were worsened by sleep deprivation. These data provide evidence that sleep deprivation increases the extent of ischemia-induced injury in a sex-dependent manner.

Methamphetamine is one of the most common illicit drugs abused during pregnancy. The neurological effects of prenatal methamphetamine are well known. However, few studies have investigated the potential effects of prenatal methamphetamine on adult cardiovascular function. Previous work demonstrated that prenatal cocaine exposure increases sensitivity of the adult heart to ischemic injury. Methamphetamine and cocaine have different mechanisms of action, but both drugs exert their effects by increasing dopaminergic and adrenergic receptor stimulation. Thus the goal of this study was to determine whether prenatal methamphetamine also worsens ischemic injury in the adult heart. Pregnant rats were injected with methamphetamine (5 mg·kg−1·day−1) or saline throughout pregnancy. When pups reached 8 wk of age, their hearts were subjected to ischemia and reperfusion by means of a Langendorff isolated heart system. Prenatal methamphetamine had no significant effect on infarct size, preischemic contractile function, or postischemic recovery of contractile function in male hearts. However, methamphetamine-treated female hearts exhibited significantly larger infarcts and significantly elevated end-diastolic pressure during recovery from ischemia. Methamphetamine significantly reduced protein kinase Cε expression and Akt phosphorylation in female hearts but had no effect on these cardioprotective proteins in male hearts. These data indicate that prenatal methamphetamine differentially affects male and female sensitivity to myocardial ischemic injury and alters cardioprotective signaling proteins in the adult heart.

BackgroundRegulator of G protein signaling (RGS) proteins are important modulators of cardiac function. We previously reported that disruption of interactions between RGS proteins and Gαi2 protects the heart from ischemic injury. However, the ability of specific members of the RGS protein family to influence cardiac sensitivity to ischemic injury has not been previously explored. The goal of the present study was to determine how genetic deletion of specific RGS proteins influences myocardial sensitivity to ischemic injury.MethodsHearts from RGS1 knockout (RGS1‐/‐), RGS2‐/‐, RGS2‐/‐ RGS4‐/‐ double knockout, RGS5‐/‐, and RGS6‐/‐ mice, and their respective wildtype (+/+) littermates were subjected to 30 min ischemia and 2 hours reperfusion using the Langendorff isolated heart model. Infarct sizes were measured by triphenyltetrazolium chloride staining.ResultsRGS6‐/‐ hearts had significantly larger infarcts than RGS6+/+ hearts (51 ± 2 % and 34 ± 5 % area at risk, respectively). Importantly, deletion of RGS1, RGS2, RGS4, or RGS5 had no effect on infarct size indicating that this effect was specific for RGS6. We also found that RGS6 expression was significantly decreased in ventricles (but not atria) of RGS6+/+ hearts subjected to ischemia / reperfusion injury.ConclusionThese data demonstrate that expression of RGS6 protects the heart from ischemic injury. Modulating RGS6 may provide a novel therapeutic approach for the treatment of ischemic heart disease.