Usefulness of Alternative Therapy with Hydrocortisone in the Postoperative Management of Severe Primary Aldosteronism.

Mineralocorticoid deficiency (MD) with hyperkalemia is an important complication of adrenalectomy in patients with primary aldosteronism (PA). We herein report a 52-year-old man with refractory hypertension, hypokalemia, and severe renal dysfunction due to PA caused by a right adrenal adenoma. His estimated glomerular filtration rate (eGFR) transiently increased immediately after adrenalectomy but then gradually declined, and he developed hyperkalemia. A postoperative endocrine examination revealed MD. Considering the patient's hypertension and severe renal dysfunction, we administered hydrocortisone instead of fludrocortisone, which improved the hyperkalemia and stopped the decline in the eGFR. Alternative therapy with hydrocortisone may be useful in such patients with MD.

Focal Segmental Glomerulosclerosis Associated with Essential Thrombocythemia.

A 72-year-old man was admitted for examination of proteinuria (9.14 g/day) and leg edema. Essential thrombocythemia (ET) was diagnosed because of thrombocytosis (platelet count, 57.9×104/µL), elevated megakaryocytes in bone marrow biopsy, and JAK2 V617 mutation. Kidney biopsy led to a diagnosis of focal segmental glomerulosclerosis (FSGS) cellular variant (characterized by glomerular capillaries filled with swollen endothelial cells containing foam cells) in 6 glomeruli, FSGS tip variant in 5 glomeruli, and additional FSGS variants in other glomeruli. Affected glomeruli had anti-CD61 antibody staining-positive megakaryocyte infiltrations. ET mayinduce FSGS because megakaryocyte infiltration increases intraglomerular pressure, resulting in hypertension and proteinuria.

Bilateral refractory pneumothorax treated by pleurodesis and bronchial occlusion in a COVID-19 patient.

Coronavirus disease 2019 (COVID-19) has become a worldwide outbreak, and it can cause various symptoms and complications. However, pneumothorax secondary to COVID-19 is relatively uncommon. We herein report a 60-year-old man with bilateral refractory pneumothorax with severe COVID-19. In patients with poor general health and who are difficult to undergo surgery for pneumothorax post-COVID-19, internal treatments such as chest drainage, bronchial occlusion, and pleurodesis are essential to relieving refractory pneumothorax. It also indicates that autologous blood patch pleurodesis is a useful method in terms of efficacy and side effects.

Effect of Gram Stain-Guided Initial Antibiotic Therapy on Clinical Response in Patients With Ventilator-Associated Pneumonia: The GRACE-VAP Randomized Clinical Trial.

Importance: Gram staining should provide immediate information for detecting causative pathogens. However, the effect of Gram staining on restricting the initial antibiotic choice has not been investigated in intensive care units (ICUs). Objective: To compare the clinical response to Gram stain-guided restrictive antibiotic therapy vs guideline-based broad-spectrum antibiotic treatment in patients with ventilator-associated pneumonia (VAP). Design, Setting, and Participants: This multicenter, open-label, noninferiority randomized clinical trial (Gram Stain-Guided Antibiotics Choice for VAP) was conducted in the ICUs of 12 tertiary referral hospitals in Japan from April 1, 2018, through May 31, 2020. Patients aged 15 years or older with a VAP diagnosis and a modified Clinical Pulmonary Infection Score of 5 or higher were included. The primary analysis was based on the per-protocol analysis population. Interventions: Patients were randomized to Gram stain-guided antibiotic therapy or guideline-based antibiotic therapy (based on the 2016 Infectious Disease Society of America and American Thoracic Society clinical practice guidelines for VAP). Main Outcomes and Measures: The primary outcome was the clinical response rate; clinical response was defined as completion of antibiotic therapy within 14 days, improvement or lack of progression of baseline radiographic findings, resolution of signs and symptoms of pneumonia, and lack of antibiotic agent readministration, with a noninferiority margin of 20%. Secondary outcomes were the proportions of antipseudomonal agents and anti-methicillin-resistant Staphylococcus aureus (MRSA) agents as initial antibiotic therapies; 28-day mortality, ICU-free days, ventilator-free days; and adverse events. Results: In total, 206 patients (median [IQR] age, 69 [54-78] years; 141 men [68.4%]) were randomized to the Gram stain-guided group (n = 103) or guideline-based group (n = 103). Clinical response occurred in 79 patients (76.7%) in the Gram stain-guided group and 74 patients (71.8%) in the guideline-based group (risk difference, 0.05; 95% CI, -0.07 to 0.17; P < .001 for noninferiority). Reduced use of antipseudomonal agents (30.1%; 95% CI, 21.5%-39.9%; P < .001) and anti-MRSA agents (38.8%; 95% CI, 29.4%-48.9%; P < .001) was observed in the Gram stain-guided group vs guideline-based group. The 28-day cumulative incidence of mortality was 13.6% (n = 14) in the Gram stain-guided group vs 17.5% (n = 18) in the guideline-based group (P = .39). Escalation of antibiotics according to culture results was performed in 7 patients (6.8%) in the Gram stain-guided group and 1 patient (1.0%) in the guideline-based group (P = .03). There were no significant differences between the groups in ICU-free days, ventilator-free days, and adverse events. Conclusions and Relevance: Results of this trial showed that Gram stain-guided treatment was noninferior to guideline-based treatment and significantly reduced the use of broad-spectrum antibiotics in patients with VAP. Gram staining can potentially ameliorate the multidrug-resistant organisms in the critical care setting. Trial Registration: ClinicalTrials.gov Identifier: NCT03506113.

Thrombotic Microangiopathy, Podocytopathy, and Damage to the Renal Tubules with Severe Proteinuria and Acute Renal Dysfunction Induced by Lenvatinib.

Lenvatinib, a tyrosine kinase inhibitor (TKI), is a stronger inhibitor of vascular endothelial growth factor receptor, fibroblast growth factor receptors 1 to 4, and platelet-derived growth factor receptor (PDGFR) than other TKIs. We herein report a 77-year-old Japanese woman who received the minimum dose of lenvatinib for treatment of hepatocellular carcinoma. Within one month of starting treatment, she developed severe proteinuria, hypertension, and renal dysfunction. A kidney biopsy showed drug-induced thrombotic microangiopathy, podocytopathy, and polar vasculosis. We also observed damage to the renal tubules, where PDGFR is located. To our knowledge, this is the first report of lenvatinib-induced damage to the renal tubules.

Use of biologic agents and methotrexate improves renal manifestation and outcome in patients with rheumatoid arthritis: a retrospective analysis.

BACKGROUND AND PURPOSE: We examined whether advances in treatment strategies from older disease-modifying antirheumatic drugs (DMARDs) to new biologic agents and methotrexate improved renal complications and outcome in patients with rheumatoid arthritis (RA). METHODS: We reviewed records of 156 patients with RA who underwent kidney biopsy at our institute between January 1990 and December 2019. All patients were assigned to one of three periods: period 1, 1990-1999 (n = 48); period 2, 2000-2009(n = 57); period 3, 2010-2019 (n = 51). RESULTS: Membranous nephropathy, nephrosclerosis, AA-amyloidosis, and IgA nephropathy were the four major renal manifestations of RA. AA-amyloidosis was diagnosed by kidney biopsy in 21 patients: period 1, 7 patients (15%); period 2, 10 patients (18%); and period 3, 4 patients (8%). The 4 patients in period 3 were in the years 2010-2014, and no new case of AA-amyloidosis was recorded from 2015 to 2019. In all 21 of the patients with AA-amyloidosis, neither a biologic agent nor methotrexate was administered. Fifteen of the 21 patients required dialysis, and 13 died in periods 1-3 because of amyloid-related cardiac dysfunction less than 2 years after the initiation of dialysis. Two of them are doing well using biologic agent despite dialysis. The remaining three patients who received a biologic agent or methotrexate does not progress to end-stage renal failure. In addition, the other renal complications showing progression to dialysis also decreased over time. CONCLUSION: Advances in treatment strategies have improved renal outcome and reduced mortality in patients with RA.

Asymmetric Henry Reaction of Trifluoromethyl Enones with Nitromethane Using a N,N-Dibenzyl Diaminomethylenemalononitrile Organocatalyst.

A novel N,N-dibenzyl diaminomethylenemalononitrile organocatalyst efficiently promoted asymmetric Henry reactions of trifluoromethyl enones with nitromethane, affording corresponding highly functionalized products in high yields with excellent enantioselectivities (up to 90% ee). This study is the first to report the successful example of the asymmetric 1,2-additions of nitromethane to trifluoromethyl enones.

Diaminomethylenemalononitrile as a Chiral Single Hydrogen Bond Catalyst: Application to Enantioselective Conjugate Addition of α-Branched Aldehydes.

An improved diaminomethylenemalononitrile organocatalyst, bearing a N,N-disubstituted structure, promoted enantioselective conjugate addition reaction of α-branched aldehydes with vinyl sulfone, affording adducts with excellent enantioselectivities (up to 96% ee). Mechanistic studies revealed that the diaminomethylenemalononitrile motif holds the vinyl sulfone substrate using a single hydrogen bond accompanied by multiple weak interactions, including electrostatic C-H⋅⋅⋅O interactions.

Successful endobronchial occlusion in empyema with broncho-pleural fistula secondary to COVID-19 pneumonia: a case report and literature review.

A few cases of empyema secondary to coronavirus disease 2019 (COVID-19) pneumonia have been reported. Here, we report our experience of a successful endobronchial occlusion using endobronchial Watanabe spigots (EWSs) for empyema with broncho-pleural fistula secondary to COVID-19 pneumonia. A 62-year-old man was diagnosed with COVID-19 and progressed to empyema with broncho-pleural fistula. Computed tomography (CT) imaging showed cyst formation and the right B5b was presumed to be a branch dependent on the cyst. The effusion and air in the pleural cavity were well drained, although the air leak persisted. Endobronchial occlusion was performed for right B5a and B5b using 7- and 5-mm EWSs (Novatech, France), respectively, and the air leak ceased. This is the first report of successful treatment of empyema with bronchial fistula with endobronchial occlusion. Air leak secondary to COVID-19 pneumonia with a limited number of air cysts may be a good indication for endobronchial occlusion.

Renal Squamous Cell Carcinoma-related Polymyositis in a Patient with Autosomal Dominant Polycystic Kidney Disease.

A 74-year-old Japanese woman diagnosed with autosomal dominant polycystic kidney disease (ADPKD) was admitted to our institute for the further examination of right-side groin pain developing in the past week. The patient was diagnosed with polymyositis (PM). Diagnostic imaging showed a mass lesion measuring 8 cm and a renal stone in the right kidney. Immediately following surgical resection of the right kidney, the patient's serum CK decreased to the normal range. A histopathological analysis showed well-differentiated squamous cell carcinoma. In conclusion, this case showed a close relationship between the occurrence of squamous cell carcinoma and the development of PM in an ADPKD patient.

A case of thrombotic microangiopathy associated with polymyositis.

A 60-year-old Japanese woman with polymyositis (PM) developed hemolytic anemia (hemoglobin of 7.3 g/dL), thrombocytopenia (platelet of 9.1×104/µL), and acute kidney injury (Cre of 4.7 mg/dL) at 14 days after starting steroid therapy. Renal biopsy revealed glomerular endothelial swelling with fibrin thrombi and fragmented erythrocytes in the capillary lumens. Hemolytic uremic syndrome (HUS) with thrombotic microangiopathy (TMA) was diagnosed. Hemodialysis and plasma exchange/plasma transfusion were initiated, but HUS did not subside. After 45 days, the patient died of hemorrhagic respiratory failure. Autopsy showed fibrin thrombi filling the glomerular vascular pole and the small arteries in most glomeruli, resulting in glomerular collapse and glomerular basement membrane (GBM) duplication. Although renal involvement by PM is rare, HUS/TMA should be remembered as one of the serious renal complications of PM.

Asymmetric Direct Vinylogous Conjugate Addition of Substituted Furanone Derivatives to Benzoyl Acrylonitrile: Stereoselective Synthesis Toward Bicyclic γ-Lactams.

A diaminomethylenemalononitrile organocatalyst efficiently promotes the asymmetric direct vinylogous conjugate additions of α-angelica lactones to benzoyl acrylonitrile derivatives, resulting in the corresponding addition products bearing vicinal tertiary and quaternary stereogenic centers with excellent enantioselectivities (up to 99% ee). This report is the first successful example of the asymmetric conjugate additions of α-angelica lactone to benzoyl acrylonitriles. The chiral γ,γ-disubstituted γ-butenolides obtained can be readily transformed to the bicyclic γ-lactam derivative as a valuable synthetic intermediate.

Alpha-dystroglycan binding peptide A2G80-modified stealth liposomes as a muscle-targeting carrier for Duchenne muscular dystrophy.

Safe and efficient gene therapy for the treatment of Duchenne muscular dystrophy (DMD), a genetic disorder, is required. For this, the muscle-targeting delivery system of genes and nucleic acids is ideal. In this study, we focused on the A2G80 peptide, which has an affinity for α-dystroglycan expressed on muscle cell membranes, as a muscle targeted nanocarrier for DMD and developed A2G80-modified liposomes. We also prepared A2G80-modified liposomes coated with long- and short-chain PEG, called A2G80-LSP-Lip, to improve the blood circulation of liposomes using microfluidics. The liposomes had a particle size of approximately 80 nm. A2G80-LSP-Lip showed an affinity for the muscle tissue section of mice by overlay assay. When the liposomes were administered to DMD model mice (mdx mice) via the tail vein, A2G80-LSP-Lip accumulated efficiently in muscle tissue compared to control liposomes. These results suggest that A2G80-LSP-Lip can function as a muscle-targeting liposome for DMD via systemic administration, and may be a useful tool for DMD treatment.

Hematological Phenotype of COVID-19-Induced Coagulopathy: Far from Typical Sepsis-Induced Coagulopathy.

BACKGROUND: Blood coagulation disorders commonly occur with severe coronavirus disease 2019 (COVID-19). However, there is only limited evidence on differentiating the pattern of the hemostatic parameters from those of typical sepsis-induced coagulopathy (SIC). METHODS: To elucidate the specific pattern of coagulopathy induced by COVID-19 pneumonia, this retrospective, observational study targeted consecutive adult patients with COVID-19-induced acute respiratory distress syndrome (ARDS) and compared hemostatic biomarkers with non-COVID-19-induced septic ARDS. Multilevel mixed-effects regression analysis was performed and Kaplan-Meier failure curves were constructed. RESULTS: We enrolled 24 patients with COVID-19-induced ARDS and 200 patients with non-COVID-19-induced ARDS. Platelet count, antithrombin activity, and prothrombin time in the COVID-19 group were almost within normal range and time series alterations of these markers were significantly milder than the non-COVID-19 group (p = 0.052, 0.037, and 0.005, respectively). However, fibrin/fibrinogen degradation product and D-dimer were significantly higher in the COVID-19 group (p = 0.001, 0.002, respectively). COVID-19 patients had moderately high levels of thrombin-antithrombin complex and plasmin-alpha2-plasmin inhibitor complex but normal plasminogen activator inhibitor-1 level. CONCLUSIONS: The hematological phenotype of COVID-19-induced coagulopathy is quite different from that in typical SIC characterized by systemic hypercoagulation and suppressed fibrinolysis. Instead, local thrombus formation might be promoted in severe COVID-19.

Genetics May Predict Effectiveness of Tolvaptan in Autosomal Dominant Polycystic Kidney Disease.

BACKGROUND: Tolvaptan is the only therapeutic drug for autosomal dominant polycystic kidney disease (ADPKD). The influence of mutations in polycystic kidney disease 1 and 2 genes (PKD1 and PKD2) on the treatment effects of tolvaptan is not well documented in the literature. METHODS: We retrospectively evaluated the relationship between genotype and the efficacy of tolvaptan in 18 patients with ADPKD who had been treated at Toranomon Hospital and undergone genetic testing between April 2016 and February 2020. RESULTS: The annual change in estimated glomerular filtration rate (ΔeGFR/y) from before to after tolvaptan was from a median of -5.5 to -2.5 mL/min/1.73 m2 in the PKD1 truncating group, -3.3 to -2.4 mL/min/1.73 m2 in the PKD1 non-truncating group, -3.1 to -1.6 mL/min/1.73 m2 in the PKD2 group, and -1.9 to -2.6 mL/min/1.73 m2 in the group with no PKD1/2 mutation. The median degrees of improvement of ΔeGFR/y were 2.5 (45%), 0.4 (10%), 0.6 (28%), and -0.7 (-37%) mL/min/1.73 m2, respectively. Compared with the group of patients with any PKD1/2 mutation, the group with no PKD1/2 mutation showed significantly less improvement in ΔeGFR/y with tolvaptan (0.6 vs. -0.7 mL/min/1.73 m2, respectively; p = 0.01) and significantly less improvement in the annual rate of increase in total kidney volume (TKV) with tolvaptan (-6.7 vs. -1.1%, respectively; p = 0.02). CONCLUSION: Patients with ADPKD and no PKD1/2 mutation showed less improvement in ΔeGFR/y and the annual rate of increase in TKV with tolvaptan. Detecting PKD1/2 mutations may be useful for predicting the effectiveness of tolvaptan.

The Clinical and Histopathological Feature of Renal Manifestation of TAFRO Syndrome.

INTRODUCTION: Thrombocytopenia, anasarca, myelofibrosis, renal dysfunction, and organomegaly (TAFRO) syndrome is a severe subtype of idiopathic multicentric Castleman's disease, characterized by thrombocytopenia, anasarca, fever, reticulin myelofibrosis, and organomegaly. Renal complication of this disease can be life-threatening and sometimes requires hemodialysis, but it has not been elucidated in detail. METHODS: Case-series was designed to evaluate the renal histology of patients with TAFRO syndrome treated at our hospital. RESULTS: Seven patients were eligible to the criteria. All of them had severe diuretic-resistant anasarca and 6 of 7 had mild proteinuria (<1 g daily). On light microscopy, all patients showed glomerular endotheliopathy characterized by endothelial cell swelling and a double contour of the glomerular basement membrane with mesangiolysis or mesangial loosening. Immunofluorescent staining and electron microscopy did not detect immune deposits in any patient. Electron microscopy revealed endothelial cell swelling with diffuse expansion of the subendothelial space, loss of mesangial architecture, and loss of endothelial cell fenestrations. Treatment with glucocorticoids and molecular-targeting agents, including tocilizumab and rituximab, improved renal dysfunction and anasarca. In 4 of 7 patients with persistent thrombocytopenia, hemorrhagic events occurred despite platelet transfusion or thrombopoietin receptor antagonist therapy. CONCLUSION: Severe diuretic-resistant anasarca with mild proteinuria and severe glomerular endotheliopathy were common characteristics of renal dysfunction due to TAFRO syndrome. In addition, endothelial changes mediated via interleukin (IL)-6 and vascular endothelial growth factor (VEGF) that lead to vascular hyperpermeability and water leakage might contribute to anasarca, because molecular-targeting therapy directed against IL-6 or VEGF improved renal dysfunction and severe endothelial damage.

Characteristic Renal Histology of a 81-Year-Old Patient with a 30-Year History of Diabetes Mellitus: A Case Report.

A renal histology of an 81-year-old man with a 30-year history of diabetes mellitus (DM), as well as diabetic retinopathy and neuropathy, was examined. The patient's blood pressure was controlled within the normal range (less than 140/75 mmHg) using antihypertensive agents including angiotensin receptor blocker. Edematous management was achieved by a strict salt diet (less than 6 g/per day). However, this patient's glycemic control was poor with HbA1c 8-10%. Serum creatinine was 0.87 mg/dL and estimated globular filtration rate (eGFR) was 64 ml/min/1.73m2. Urinary protein excretion was 1.5 g/day. This patient's renal biopsy showed linear staining for IgG along the GBM by immunofluorescence microscopy, but light microscopy showed almost intact glomeruli, and the GBM was not thickened as revealed by electron microscopy with a width of 288-368 nm (< 430 nm). While arteriolar hyalinosis was severe, and polar vasculosis was observed around the glomerular vascular pole. This case indicates that long-standing hyperglycemia may induce polar vasculosis by the mechanism of angiogenesis, but diabetic glomerulopathy can become minor change, only when hypertension and edematous management could be controlled strictly.

Rapidly progressive glomerulonephritis caused by tegafur/gimeracil/oteracil resulted in diabetes nephropathy, in a patient with minor risk of diabetes nephropathy: a case report.

A 79-year-old Japanese male with a history of type 2 diabetes mellitus (T2DM) for 16 years was admitted to evaluate possible renal disease. The T2DM was well controlled in this patient using nutrition therapy without the need for any diabetes medication, and both diabetes retinopathy and proteinuria were negative. At the age of 78 advanced colorectal cancer (stage IIIa) was diagnosed and laparoscopic-assisted colectomy was performed. Following this procedure, the patient began treatment with tegafur/gimeracil/oteracil (S-1), 80 mg twice daily for 28 days of 42-day cycle. The patient received S-1 for 6 months, during which time, serum albumin decreased from 3.0 g/dL to 1.1 g/dL, urinary protein increased from negative to 3.0 g/day, and serum creatinine increased from 0.9 mg/dL to 2.1 mg/dL. Treatment with S-1 was discontinued, and furosemide 180 mg and prednisolone 30 mg treatment was initiated; however, serum creatinine levels continued to increase to 7.2 mg/dL and proteinuria continued to increase reaching a nephrotic range. A disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) activity was decreased to 27.0%. Renal biopsy showed Kimmelstiel-Wilson nodules, while immunofluorescence intensity of IgG subclass was IgG1 dominant, which was not compatible with diabetic nephropathy (DN). Plasma exchange was not affected. However, hemodialysis was initiated.The results of this investigation suggest that when S-1 monotherapy is performed in the case with DN, rapidly progressive glomerulonephritis (RPGN) may develop due to a condition similar to thrombotic microangiopathy, even in patients with a minor risk factor of DN.

Denosumab for dialysis patients with osteoporosis: A cohort study.

Evidence for the efficacy of denosumab in HD patients is limited. Accordingly, here we report a study on the safety and efficacy of denosumab in these patients. We prospectively followed 324 patients (121 HD and 203 non-HD patients) receiving denosumab between June 2013 and May 2018, assessing changes in bone mineral density (BMD) and bone metabolic markers, and noting side-effects. Annual changes in BMD at the lumbar spine in HD and non-HD patients from baseline were, respectively, 6.7 ± 11.1% and 7.5 ± 10.2% (p = 0.60), those at the femoral neck were 4.3 ± 7.9% and 3.1 ± 9.5% (p = 0.32), and those at the distal radius were -0.5 ± 6.4% and 0.2 ± 13.0% (p = 0.66). The prevalence of hypocalcemia (<8.5 mg/dL) was significantly higher in HD than in non-HD patients (35.6% vs 5.4%, p < 0.001). The median elapsed time between the first injection of denosumab and the occurrence of hypocalcemia was 7 days in HD patients. The decrease of serum calcium was greater in patients with higher TRACP5b, corticosteroid use, and those without CaCO3 supplementation. Our study suggests that denosumab was equally as effective in HD as non-HD patients. However, careful hypocalcemia monitoring, for at least 4 weeks, is recommended for HD patients.

Corticosteroid reduction by addition of cetirizine and montelukast in biopsy-proven minimal-change nephrotic syndrome concomitant with allergic disorders.

Recent reports suggest helper T-cell abnormalities in minimal-change nephrotic syndrome (MCNS), which often complicate allergic disorders that show a similar helper T-cell profile with Th2/Th17 predominance. However, the effect of anti-allergy therapy on MCNS remains unknown. This retrospective study included 51 patients with biopsy-proven MCNS recruited between November 2012 and October 2015, with follow-up through November 2017. We analyzed relapse and temporal daily corticosteroid dose with and without co-administration of histamine H1 receptor antagonist, cetirizine, and cysteinyl-leukotriene receptor antagonist, montelukast, as well as between baseline and after follow-up. Thirteen patients were treated with cetirizine and montelukast in addition to conventional therapy, whereas 38 patients were treated by conventional therapy only, consisting of corticosteroids and immunosuppressants. To adjust for baseline clinical characteristics, a 1:1 propensity score-matched model was applied. The clinical characteristics of the two groups after matching were similar at baseline. The treatment group showed a significant reduction in the lowest daily dose of oral prednisolone throughout the entire treatment course after the study compared to that of baseline (p < 0.025), which was not observed in the control group (p = 0.37), and showed significantly higher percentage of patients establishing corticosteroid-free state for the first time throughout the entire treatment course by addition of cetirizine and montelukast compared to the control group (p < 0.025). The study shows, for the first time, the steroid sparing effect of cetirizine and montelukast in addition to conventional treatment in MCNS patients with concomitant allergies.