Is Podocytopathy Associated with Gross Hematuria after COVID-19 Vaccination in Patients with Immunoglobulin A Nephropathy?

We experienced three cases of a fever and subsequent severe, prolonged gross hematuria after COVID-19 vaccination. A kidney biopsy revealed immunoglobulin A (IgA) nephropathy, and electron microscopy showed two types of podocytopathy (podocyte damage): loss of foot processes from the glomerular basement membrane and foot process effacement. Mesangial interposition was also present in cases 1 and 3 but not in case 2. Podocytopathy is known to be a cause of proteinuria; however, the reactions to COVID-19 vaccination described here suggest that it may also be related to hematuria in IgA nephropathy.

Relationship between false lumen morphology and entry tear in acute type A aortic dissection.

OBJECTIVES: This study aimed to investigate the relationship between false lumen morphology and the size, aortic segment and position of the entry tear for acute type A aortic dissection. METHODS: The records of patients who underwent emergency operation for acute type A aortic dissection in our institution between April 2011 and May 2022 were examined. Data regarding size, location and position of the entry tear and preoperative computed tomography findings were reviewed. The relationship of these variables with false lumen morphology was examined and retrospectively compared according to tear size. RESULTS: Of 243 cases, characteristics of the entry tear, visualized during surgery, were confirmed in 134 cases (age = 70.9 ± 12.6 years, male = 45.5%). Tear sizes at different aortic segments were not significantly different (P = 0.376). Tears posterior to the lesser curvature were significantly smaller than those anterior to the greater curvature (P = 0.004). A thrombosed false lumen was associated with a significantly smaller tear size and position on the posterior to the lesser curvature side in aortic cross-section (all P < 0.001). Multivariate analysis showed that tear size, the presence of re-entry and tear position anterior to the greater curvature were independent predictors of a patent false lumen. CONCLUSIONS: In acute type A aortic dissection, larger tear size, the presence of re-entry and tear position anterior to the greater curvature are risk factors for a patent false lumen. Although the results of this study are valid only for patients in whom intimal tears were detected during aortic surgery, this trend may provide information for pathophysiology of the disease.

Improvement of Light Chain Proximal Tubulopathy without Crystals in IgGλ-type Monoclonal Gammopathy of Undetermined Significance Using Bortezomib and Dexamethasone.

A 70-year-old woman with acute kidney injury, a high serum Creatinine (Cr) level (3.91 mg/dL), and proteinuria (protein/Cr ratio 1.59 g/gCr) was admitted. Serum IgG λ-type and urinary λ-type M proteins were observed. A bone marrow examination indicated monoclonal gammopathy of undetermined significance (MGUS). A renal biopsy showed distended proximal tubular cells, and immunofluorescence identified tissue positive for proximal tubular cell λ light chains. Electron microscopy identified fibril-like structures in the lysosomes. The patient was diagnosed with light chain proximal tubulopathy without crystals in IgG λ-type MGUS and treated with bortezomib and dexamethasone therapy, which improved her renal function.

Morphological and etiological analyses of C3 and non-C3 glomerulonephritis in primary membranoproliferative glomerulonephritis using periodic acid-methenamine silver stain electron microscopy: a retrospective multicentered study.

This study elucidated the etiology of C3 glomerulonephritis (C3GN) and non-C3GN with primary membranoproliferative glomerulonephritis (MPGN) using transmission electron microscopy (TEM) and periodic acid-methenamine silver stain (PAM-EM). Thirty-one primary MPGN cases were analyzed by TEM and PAM-EM to distinguish among MPGN I, MPGN II, MPGN III Burkholder subtype (MPGN IIIB), and Anders and Strife subtype (MPGN IIIA/S). Each case was also classified into C3GN or non-C3GN according to the standard C3GN definition using immunostaining. Four cases of MPGN II met C3 glomerulopathy; whereas, four cases of MPGN IIIB did not meet C3 glomerulopathy. Seven of 11 cases (64%) of MPGN I without GBM disruption and 7 of 12 cases (58%) of MPGN IIIA/S with GBM disruption met the non-C3GN criteria with significant immunoglobulins' deposition. Regardless of the C3GN or non-C3GN diagnosis, the deposits in primary MPGN I and MPGN IIIA/S exhibited ill-defined, amorphous, and foggy characteristics similar to those found in postinfectious GN but were different from immune complex (IC) deposits seen in MPGN IIIB. Not only C3GN but also non-C3GN was due to mechanisms other than IC deposition as found in postinfectious GN. Consequently, GBM disruption of MPGN IIIA/S was not due to IC deposition.

The first autopsy case of Epstein-Barr virus-positive marginal zone lymphoma that deteriorated after COVID-19 vaccination.

This is the first autopsy case of Epstein-Barr virus-positive marginal zone lymphoma (EBV + MZL) with an other iatrogenic immunodeficiency-associated lymphoproliferative disorders (LPD) (methotrexate [MTX]-associated LPD) that deteriorated after the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine. This case had a unique immunophenotype. A 71-year-old female patient with rheumatoid arthritis receiving MTX presented with fatigue 1 week after the SARS-CoV-2 vaccination. She was hospitalized due to hepatorenal dysfunction and pancytopenia. Computed tomography revealed systemic lymphadenopathy. Her physical condition deteriorated, and the patient died. The autopsy revealed systemic lymphadenopathy comprising medium-sized atypical lymphocytes and scattered Hodgkin/Reed-Sternberg (H/RS)-like cells. An immunohistochemical examination showed that atypical lymphocytes were positive for CD79a and MUM-1 and some were positive for CD20 and IRTA-1. H/RS-like cells were immunoreactive for CD30 and CD15 and ringed by T cells. Both cell types were positive for EBV-encoded small RNA. The majority of H/RS-like cells were positive for CD20, whereas a small number of CD3-positive cells were admixed. We herein presented the first autopsy case of EBV + MZL that deteriorated after the SARS-CoV-2 vaccination.

Polar vasculosis is associated with better kidney outcome in type 2 diabetes with biopsy-proven diabetic kidney disease: A multicenter cohort study.

AIMS/INTRODUCTION: This multicenter cohort study retrospectively assessed the association between polar vasculosis and the progression of diabetic kidney disease (DKD) in type 2 diabetes. MATERIALS AND METHODS: We enrolled 811 patients with type 2 diabetes, biopsy-proven DKD, and proteinuria (≥0.15 g/g creatinine [g/day]). The association between polar vasculosis and other kidney lesions was explored. The outcome was DKD progression defined as a composite of renal replacement therapy initiation or 50% decline in estimated glomerular filtration rate (eGFR) from baseline. RESULTS: Of the 811 cases, 677 (83.5%) had polar vasculosis. In multivariate logistic regression analysis, subendothelial widening of the glomerular basement membrane, glomerulomegaly, glomerular class in the Renal Pathology Society classification ≥IIb, vascular lesions, age, eGFR, and hemoglobin A1c were positively associated with polar vasculosis, whereas interstitial fibrosis and tubular atrophy (IFTA) was negatively associated with polar vasculosis. During a median follow-up of 5.2 years, progression of DKD occurred in 322 of 677 (7.4 events/100 person-years) and 79 of 134 (11.4 events/100 person-years) cases with and without polar vasculosis, respectively. Kaplan-Meier analysis showed that polar vasculosis was associated with lower cumulative incidences of DKD progression. Multivariate Cox regression analyses showed that polar vasculosis was associated with a lower risk of DKD progression, regardless of eGFR or proteinuria subgroups. These associations between polar vasculosis and better kidney outcome were unchanged considering all-cause mortality before DKD progression as a competing event. CONCLUSIONS: This study showed that polar vasculosis of DKD was associated with less advanced IFTA and a better kidney outcome in type 2 diabetes with proteinuria.

Seasonal variations in renal biopsy numbers and primary glomerular disease features based on the Japan renal biopsy registry.

We analyzed the seasonal variations in the number of renal biopsies and clinical characteristics of primary glomerular disease in Japan using the Japan Renal Biopsy Registry (J-RBR). We retrospectively collected clinical and pathological data of patients with primary glomerular disease who were registered in the J-RBR between 2007 and 2018. Immunoglobulin A nephropathy (IgAN), minimal change nephrotic syndrome (MCNS), membranous nephropathy (MN), and postinfectious acute glomerulonephritis (PIAGN) constituted the four major glomerular disorders included in this study (total, 13,989; IgAN, 9121; MCNS, 2298; MN, 2447; and PIAGN, 123). The number of patients with IgAN or MCNS was higher during summer. However, no overt seasonal variations were observed in patients with MN or PIAGN. Subgroup analyses suggested that in the patients with IgAN, more renal biopsies of severe cases were performed during winter, probably owing to age and blood pressure. Furthermore, more renal biopsies of severe cases were performed during spring and winter in patients with MCNS even after adjusting for the abovementioned host factors. This study suggests that seasonal factors influence the decision to perform renal biopsy as well as the pathogenesis of primary glomerular disease. Thus, our findings may provide important insights regarding the pathophysiology of primary glomerular disease.

Early Enhancement with Contrast-Enhanced Ultrasonography Relates to the Number of Small-Diameter Neovessels in the Carotid Plaque.

BACKGROUND AND PURPOSE: Intraplaque neovessels (INVs) have been recognized as a major cause of intraplaque hemorrhage and subsequent vulnerability of the carotid plaque. However, the exact mechanisms by which INVs cause intraplaque hemorrhage remain unclear. Various sizes of INVs coexist in carotid plaques pathologically, and we hypothesized that the size of INVs would be associated with carotid plaque histology, particularly in terms of intraplaque hemorrhage. Detection method of INV is important when determining whether carotid plaques are vulnerable, and contrast-enhanced ultrasonography (CEUS) is one of the most useful methods to detect them. The purpose of this study was to examine the relationship between findings from CEUS and vascular pathology obtained by carotid endarterectomy (CEA). We focused on associations between small and large INVs evaluated by CEUS and histologically defined intraplaque hemorrhage. METHODS: Participants comprised 115 patients (mean age, 73.0 ± 7.2 years; 96 men) who underwent preoperative CEUS and underwent CEA. CEUS findings were evaluated as vascular grade at 0 min (Vas-G0) and 10 min (Vas-G10) after contrast injection. Plaques were histologically evaluated quantitatively for the total area of intraplaque hemorrhage, cholesterol, and calcification and the thinnest fibrous cap. Immunohistochemical studies were conducted using anti-CD-34 antibody as a marker for endothelial cells. INVs were divided into two groups depending on diameter: small INVs, <50 µm; and large INVs, ≥50 µm. The numbers of small and large blood vessels in the plaque were quantified histologically. Associations of small and large INVs with CEUS, plaque histology, and clinical findings were assessed by uni- and multivariable analyses. RESULTS: Multivariable analyses indicated that CEUS Vas-G0 was associated with the 4th quartile of the number of small INVs compared with other quartiles, and Vas-G10 was associated with the 4th quartile of the number of large INVs. Histologically, the presence and area of intraplaque hemorrhage were associated with the number of small INVs, while the increased number of large INVs was associated with infrequent plaque disruption and thicker fibrous cap. CONCLUSIONS: Our study showed that early phase enhancement in the CEUS can help identify plaque vulnerability by predicting a larger number of small INVs. This information can also help determine treatment strategies for carotid plaque.

A case of crescentic glomerulonephritis induced by afatinib for lung adenocarcinoma.

Afatinib is a second-generation, oral, epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI). One of the most common adverse effects of affatinib is diarrhea, which may lead to acute kidney injury (AKI) due to severe plasma volume loss; however, no case of glomerular injury directly induced by afatinib has been reported to date. Here, we describe the case of a 53-year-old Japanese male patient with advanced lung adenocarcinoma who twice developed AKI requiring dialysis, once after starting and once after increasing the dose of afatinib. Although serum anti-neutrophil cytoplasmic antibodies were negative, crescentic glomerulonephritis with no immune deposits was confirmed on kidney biopsy. No vasculitis-like signs were observed in other organs, such as lung, skin, or peripheral nerves. Afatinib was considered the cause of glomerular damage and was immediately discontinued; corticosteroids were administered. Renal function gradually recovered thereafter, with serum creatinine levels at ~ 2.3 mg/dL after second-line therapy with bevacizumab and atezolizumab. Several cases of cutaneous leukocytoclastic vasculitis have been reported in patients treated with other EGFR-TKIs; therefore, afatinib-induced vasculitis may lead to crescentic glomerulonephritis. Although afatinib-induced glomerular injury is extremely rare and has an unclear mechanism, renal function and urinary findings need to be closely monitored.

Glomerulonephritis and Interstitial Nephritis Originating from Vasculitis of the Interlobular Arteries of the Kidney in a Patient with Eosinophilic Granulomatosis with Polyangiitis.

Eosinophilic granulomatosis with polyangiitis (EGPA) is a type of antineutrophil cytoplasmic antibody-associated vasculitis. Patients often present with peripheral neuropathy and purpura, suggesting impairment of small vessels, especially capillaries. However, medium-sized vessels and small vessels with a vascular diameter larger than that of capillaries may also be impaired, causing atypical findings. We report a case of EGPA treated with corticosteroids, cyclophosphamide, and mepolizumab. Renal biopsy revealed vasculitis of the interlobular arteries as the cause of glomerulonephritis and interstitial nephritis. This case suggests the importance of considering vessels upstream of capillaries dominant EGPA as a differential diagnosis in patients with eosinophilia.

Clinicopathological discordance in biopsy-proven nephrosclerosis: a nationwide cross-sectional study of the Japan Renal Biopsy Registry (J-RBR).

BACKGROUND: Patients with nephrosclerosis display heterogenous clinical phenotypes, often leading to a clinical diagnosis discordant with pathological nephrosclerosis diagnosis. However, little is known about clinical factors associated with clinicopathological discordance of biopsy-proven nephrosclerosis. METHODS: In a cross-sectional study of 891 patients with biopsy-proven nephrosclerosis registered in the Japan Renal Biopsy Registry (J-RBR) between July 2007 and June 2016, we examined clinical characteristics associated with a pre-biopsy clinical diagnosis discordant with pathological nephrosclerosis diagnosis using multivariable logistic regression with adjustment for relevant clinical characteristics. RESULTS: Overall, the mean (SD) age was 58.6 (13.7) years; 67.6% of patients were male; and 63.2% were on antihypertensive drugs. The median estimated glomerular filtration rate (eGFR) was 43.8 mL/min/1.73 m2 and the median proteinuria was 0.5 g/day. Of the 891 patients, 497 (55.8%) had a clinical diagnosis discordant with pathological nephrosclerosis diagnosis, with chronic nephritic syndrome being the most common (> 75%) discordant clinical diagnosis. After multivariable adjustment, age (odds ratio 1.34, [95% confidence interval, 1.16-1.55], per 10 years increase), eGFR (1.10 [1.00-1.21], per 10 mL/min/1.73 m2 increase), and proteinuria (1.20 [1.03-2.16], per 1 g/day decrease) were found to be significantly associated with the clinicopathological discordance. CONCLUSIONS: Patients with older age, higher eGFR, and lower proteinuria had significantly higher likelihood of being clinically diagnosed with other glomerular disease in patients with biopsy-proven nephrosclerosis. Our findings highlight the heterogeneous clinical phenotypes of nephrosclerosis and suggest the need for continuous improvement of clinical diagnostic accuracy as well as for wider kidney biopsy indications for nephrosclerosis.

Serum hemoglobin concentration and risk of renal function decline in early stages of diabetic kidney disease: a nationwide, biopsy-based cohort study.

BACKGROUND: Prognosticating disease progression in patients with diabetic kidney disease (DKD) is challenging, especially in the early stages of kidney disease. Anemia can occur in the early stages of kidney disease in diabetes. We therefore postulated that serum hemoglobin (Hb) concentration, as a reflection of incipient renal tubulointerstitial impairment, can be used as a marker to predict DKD progression. METHODS: Drawing on nationally representative data of patients with biopsy-proven DKD, 246 patients who had an estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2 at renal biopsy were identified: age 56 (45-63) years; 62.6% men; Hb 13.3 (12.0-14.5) g/dL; eGFR 76.2 (66.6-88.6) mL/min/1.73 m2; urine albumin-to-creatinine ratio 534 (100-1480) mg/g Crea. Serum Hb concentration was divided into quartiles: ≤12, 12.1-13.3, 13.4-14.5 and ≥14.6 g/dL. The association between serum Hb concentration and the severity of renal pathological lesions was explored. A multivariable Cox regression model was used to estimate the risk of DKD progression (new onset of end-stage kidney disease, 50% reduction of eGFR or doubling of serum creatinine). The incremental prognostic value of DKD progression by adding serum Hb concentration to the known risk factors of DKD was assessed. RESULTS: Serum Hb levels negatively correlated with all renal pathological features, especially with the severity of interstitial fibrosis (ρ = -0.52; P < 0.001). During a median follow-up of 4.1 years, 95 developed DKD progression. Adjusting for known risk factors of DKD progression, the hazard ratio in the first, second and third quartile (the fourth quartile was reference) were 2.74 [95% confidence interval (CI) 1.26-5.97], 2.33 (95% CI 1.07-5.75) and 1.46 (95% CI 0.71-3.64), respectively. Addition of the serum Hb concentration to the known risk factors of DKD progression improved the prognostic value of DKD progression (the global Chi-statistics increased from 55.1 to 60.8; P < 0.001). CONCLUSIONS: Serum Hb concentration, which reflects incipient renal fibrosis, can be useful for predicting DKD progression in the early stages of kidney disease.

Focal segmental glomerulosclerosis and concurrent glomerular microangiopathy after long-term imatinib administration.

A 79-year-old Japanese man was admitted to our hospital because of proteinuria and kidney dysfunction. He was diagnosed with chronic myeloid leukemia 13 years before and was treated with imatinib. Deep molecular response was achieved but he developed 1+ proteinuria in the first year, which gradually worsened thereafter. Imatinib was discontinued 12 years later but proteinuria and kidney dysfunction were progressive. Percutaneous kidney biopsy revealed mild mesangial hyper-cellularity and matrix increase, swelling of endothelial cells, and partial double contours of glomerular tufts. Subendothelial edema in the interlobular artery was also noted. Immunofluorescence was not remarkable. Electron microscopy revealed endothelial injury with severe sub-endothelial edema. Since imatinib had already been discontinued, conservative therapy with maximal dose of azilsartan was administered. A second biopsy was performed 1 year later because of further deterioration of kidney function, which revealed markedly increased global glomerulosclerosis and severe interstitial fibrosis and tubular atrophy. Segmental glomerulosclerosis with podocyte hyperplasia was also observed. Electron microscopy revealed glomerulosclerotic changes and partially attenuated endothelial injury. Two and a half years later, proteinuria reduced, progression of kidney dysfunction slowed, and he was independent on dialysis therapy. Molecular response of chronic myeloid leukemia was also maintained. The clinical course suggested that endothelial and podocyte injuries were induced by imatinib, and that the nephrotoxic effects lasted for a few years after discontinuation.

Nephrotic Syndrome Associated with Buerger's Disease.

We herein report a 43-year-old woman with Buerger's disease who presented with nephrotic syndrome, renal dysfunction, and mild hypertension. A kidney biopsy revealed focal segmental glomerulosclerosis (FSGS), but there were no findings associated with frequent secondary FSGS or a history of long-term hypertension. A small focal renal infarction was seen on 99mTc-dimercaptosuccinic acid renal scintigraphy, suggesting that FSGS was due to renal microinfarction associated with Buerger's disease. After the commencement of angiotensin-converting enzyme inhibitor therapy, the hypertension immediately improved, along with significant attenuation of proteinuria. Renal ischemia by vasoconstriction of the glomerular efferent arterioles in association with Buerger's disease may result in glomerular hyperfiltration followed by FSGS.

Two-year longitudinal trajectory patterns of albuminuria and subsequent rates of end-stage kidney disease and all-cause death: a nationwide cohort study of biopsy-proven diabetic kidney disease.

INTRODUCTION: Data on the association between longitudinal trajectory patterns of albuminuria and subsequent end-stage kidney disease (ESKD) and all-cause mortality in diabetic kidney disease (DKD) are sparse. RESEARCH DESIGN AND METHODS: Drawing on nationally representative data of 329 patients with biopsy-proven DKD and an estimated glomerular filtration rate above 30 mL/min/1.73 m2 at the time of biopsy, we used joint latent class mixed models to identify different 2-year trajectory patterns of urine albumin to creatinine ratio (UACR) and assessed subsequent rates of competing events: ESKD and all-cause death. RESULTS: A total of three trajectory groups of UACR were identified: 'high-increasing' group (n=254; 77.2%), 'high-decreasing' group (n=24; 7.3%), and 'low-stable' group (n=51; 15.5%). The 'low-stable' group had the most favorable risk profile, including the baseline UACR (median (IQR) UACR (mg/g creatinine): 'low-stable', 109 (50-138); 'high-decreasing', 906 (468-1740); 'high-increasing', 1380 (654-2502)), and had the least subsequent risk of ESKD and all-cause death among the groups. Although there were no differences in baseline characteristics between the 'high-decreasing' group and the 'high-increasing' group, the 'high-decreasing' group had better control over blood pressure, blood glucose, and total cholesterol levels during the first 2 years of follow-up, and the incidence rates of subsequent ESKD and all-cause death were lower in the 'high-decreasing' group compared with the 'high-increasing' group (incidence rate of ESKD (per 1000 person-years): 32.7 vs 77.4, p=0.014; incidence rate of all-cause death (per 1000 person-years): 0.0 vs 25.4, p=0.007). CONCLUSIONS: Dynamic changes in albuminuria are associated with subsequent ESKD and all-cause mortality in DKD. Reduction in albuminuria by improving risk profile may decrease the risk of ESKD and all-cause death.

Quantification of Carotid Plaque Histology Using iPlaque Software.

The iPlaque software package can use integrated backscatter (IB) values of carotid plaque to extract information on tissue composition. The aim of this study was to evaluate the association between the plaque histologic classification and IB values evaluated by iPlaque. In 49 patients undergoing carotid endarterectomy, IB values of whole carotid plaque were measured using iPlaque from the long-axis ultrasonographic image. Histologic findings of resected plaques were defined using the classification of the American Heart Association. The average IB values were statistically compared with the classification. Plaque samples from 49 patients were categorized into V, VI and VII, (13, 32 and 4 cases, respectively). Both the average and standard deviation of the IB values in each plaque sample significantly differed among the three classifications (p = 0.001). The IB of carotid plaque obtained by iPlaque analysis was associated with its histologic characteristics.

An autopsy case of aortic dissection due to giant cell arteritis.

Giant cell arteritis (GCA) is a systemic vasculitis affecting mainly large and medium-sized arteries. GCA sometimes involves the aorta and its major branches and causes aortic dissection as a rare complication. We have experienced an autopsy case of aortic dissection due to GCA. The patient was an 87-year-old Japanese woman with Stanford type A aortic dissection who died 7 days after admission. Two years previously she had been diagnosed as having abdominal aortic aneurysm and undergone endovascular aneurysm repair (EVAR). Although she had no characteristic symptoms of GCA, autopsy revealed marked granulomatous inflammation in the dissected area and coronary arteries. Active arteritis was evident not only in the arteries of the upper extremity but also those in the lower extremity. Granulomatous inflammation was not evident in the aneurysm. The aortic dissection might have been an initial manifestation of GCA. We report the regions of GCA extension and its histology in detail.

Two cases of idiopathic multicentric Castleman disease with nephrotic syndrome treated with tocilizumab.

We report two cases of idiopathic multicentric Castleman disease (iMCD) with nephrotic syndrome (NS) treated with tocilizumab. Case 1 was a 58-year-old man diagnosed with iMCD prior to the onset of NS. Renal biopsy revealed membranous nephropathy, which was considered to be secondary membranous nephropathy associated with iMCD. Case 2 was a 49-year-old woman diagnosed with iMCD prior to NS. Renal biopsy revealed renal amyloidosis positive for Congo red staining and amyloid A protein immunostaining. In both the cases, the proteinuria improved after the initiation of glucocorticoid and tocilizumab therapy. Tocilizumab may be a good therapeutic choice for iMCD with NS.