Gross Hematuria after the COVID-19 mRNA Vaccination: Nationwide Multicenter Prospective Cohort Study in Japan.

BACKGROUND: In the past three years, cases of gross hematuria (GH) after the vaccination for coronavirus disease 2019 (COVID-19) in IgA nephropathy (IgAN) patients have been frequently reported worldwide. However, the post-event renal prognosis of these patients, their clinical backgrounds, and underlying mechanisms remain unknown. Therefore, we conducted a nationwide multicenter prospective cohort study in Japan. METHODS: We analyzed laboratory findings at the time of the first presentation to the hospital, and 3 and 6 months after in patients with GH after the vaccination, and histopathological findings in their kidney biopsy specimens. Moreover, changes in pathological biomarkers of IgAN such as galactose-deficient IgA1 (Gd-IgA1) and its immune complexes (ICs) were also evaluated. RESULTS: During the study period, 127 newly presenting with GH after the vaccination were enrolled, with a clear female bias (73.2%). GH was observed after the second or subsequent vaccinations in most patients (92.9%). Of the 37 patients undergoing kidney biopsy prior to the vaccination, 36 patients had been diagnosed with IgAN/IgA vasculitis (IgAV). In remaining 90 patients, 69 of the 70 who newly underwent kidney biopsy were diagnosed with IgAN (N=67)/IgAV (N=2). Their histopathology did not show a high incidence of acute lesions such as endocapillary hypercellularity and crescentic lesions. Most cases showed a temporary increase in proteinuria, but no sustained worsening in renal function. Among the biomarkers measured, serum Gd-IgA1 and ICs were comparable throughout the observation period, however, only urinary Gd-IgA1 was increased at the time of GH. CONCLUSIONS: We found that GH after the vaccination is more likely to occur in IgAN/IgAV patients, with a female bias, but without progressive exacerbation of renal function. Although further investigation is needed regarding causal relationship between vaccination and GH, this study provides many insights into the molecular mechanisms of GH.

Fractional excretion of total protein predicts renal prognosis in Japanese patients with primary membranous nephropathy.

Background: Primary membranous nephropathy (pMN) is one of the most common types of glomerulonephritis, with a third of patients progressing to renal insufficiency. Various prognostic factors have been reported, of which urinary protein and renal function are the most critical parameters. Fractional excretion of total protein (FETP) indicates protein leakage that accounts for creatinine kinetics and serum protein levels. In this study, we investigated the association between FETP and renal prognosis in pMN. Methods: We retrospectively identified 150 patients with pMN. FETP was calculated as follows: (serum creatinine × urine protein)/(serum protein × urine creatinine) %. We divided the patients into three groups according to FETP values and compared the clinicopathological findings. The primary outcome was an estimated glomerular filtration rate (eGFR) decrease of ≥30% from the baseline level. Results: FETP was associated with urinary protein and renal function, Ehrenreich and Churg stage, and global glomerulosclerosis. The primary outcome was observed in 38 patients (25.3%), and the frequency of the primary outcome was higher in the high FETP group (P = .001). FETP is higher than protein-creatinine ratio (PCR) in the area under the curve. In the multivariate analysis adjusted for age, eGFR, PCR and treatment, FETP was significantly associated with primary outcome (adjusted hazard ratio, 8.19; P = .019). Conclusions: FETP is a valuable indicator that can reflect the pathophysiology and is more useful than PCR as a predictor of renal prognosis in patients with Japanese pMN.

Active flare of IgA nephropathy during long-term therapy with anti-tumor necrosis factor-α antibody drugs for Crohn's disease: three case reports and literature review.

In recent years, increasing numbers of reports have described new onset or active disease flare of IgA nephropathy (IgAN) during administration of TNF-α inhibitor (TNFi) therapy for chronic inflammatory diseases. Crohn's disease (CD) is the most common indication for TNFi therapy in this clinical setting, but the underlying etiology of IgAN in such patients remains unclear. We report our experience with three patients who developed acute worsening of preexisting urinalysis abnormalities and kidney dysfunction approximately 2 to 6 years after TNFi administration for CD. Kidney biopsies at the time of kidney disease flare revealed IgAN in two patients and IgAN complicated by acute tubulointerstitial nephritis in one patient. The CD and IgAN in all three patients were successfully managed with additional corticosteroid therapy and tonsillectomy without discontinuing TNFi therapy. The clinical course of our patients and similar patients described in the literature suggests that TNFi therapy for CD is associated with a relatively high risk for new onset or disease flare of IgAN. This report discusses the possible involvement of Th1/Th2 imbalance on the immunological background of CD or IgAN.

Gross Hematuria Following SARS-CoV-2 Infection in IgA Nephropathy: A Report of 5 Cases.

Gross hematuria after upper respiratory tract infections is a well-known characteristic symptom of immunoglobulin A nephropathy (IgAN). In recent years, there have been several reports of existing or newly diagnosed patients with IgAN susceptible to gross hematuria after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination. However, reports of patients with IgAN and gross hematuria after SARS-CoV-2 infection are extremely rare despite a considerable number of patients with coronavirus disease 2019 (COVID-19) who preferentially present with upper respiratory symptoms. Here, we report the cases of 5 Japanese patients with IgAN who developed gross hematuria associated with SARS-CoV-2 infection. These patients presented with fever and other COVID-19-related symptoms, followed by the appearance of gross hematuria within 2 days, which lasted for 1-7 days. Acute kidney injury occurred after gross hematuria in 1 case. In all cases, microhematuria was identified before gross hematuria associated with SARS-CoV-2 infection, and it persisted after the gross hematuria episode. Because repeated gross hematuria and persistent microhematuria may lead to irreversible kidney injury, the clinical manifestations of patients with IgAN during the COVID-19 pandemic should be carefully monitored.

Persistent SARS-CoV-2 Infection in a Patient with Nephrotic Syndrome under Rituximab Therapy: Successful Treatment with a Combination of Remdesivir and Monoclonal Antibodies.

Rituximab is an effective treatment for frequently relapsing/steroid-dependent nephrotic syndrome, but there is concern about infections caused by humoral immunodeficiency. We herein report a case of prolonged (>7 weeks) severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. A 24-year-old man with minimal change disease treated with rituximab developed SARS-CoV-2 infection. The clinical response to remdesivir was soon transiently abolished. Treatment with casirivimab and imdevimab (REGEN-COV) monoclonal antibodies in combination with remdesivir resulted in complete clearance of the infection. The REGEN-COV antibody cocktail may improve the outcome of SARS-CoV-2 infection in patients with humoral immunodeficiency.

IgA nephropathy with glomerular capillary IgA deposition following SARS-CoV-2 mRNA vaccination: a report of three cases.

IgA nephropathy (IgAN) cases histopathologically showing glomerular capillary IgA deposition represent a rare subtype of primary IgAN. Patients with IgAN categorized to this subtype often exhibit heavy proteinuria, advanced histological findings, and are resistant to therapies. Here, we report three cases of biopsy-proven IgAN with glomerular capillary IgA deposition who presented acute deterioration of urinalysis findings following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccinations. Case 1 was recurrent IgAN. Case 2 and Case 3 were newly diagnosed cases with subclinical microhematuria and proteinuria history. All three cases showed gross hematuria and acute exacerbations of proteinuria following SARS-CoV-2 mRNA vaccinations. In all three cases, kidney biopsy findings showed IgA deposition in glomerular capillary walls in addition to mesangial and para-mesangial areas; acute glomerular lesions, such as intra- and extracapillary proliferations were identified, indicating the possibility of a potentially severe type of IgAN. Therefore, attention should be paid to patients with de novo or relapsing IgAN showing marked capillary IgA deposition following SARS-CoV-2 vaccination.

Long-Term Renal Survival in Antineutrophil Cytoplasmic Antibody-Associated Glomerulonephritis With Complement C3 Deposition.

INTRODUCTION: Recent studies have revealed the pivotal role of complement activation in the pathogenesis of antineutrophil cytoplasmic antibody-associated glomerulonephritis (ANCA-GN). This study investigated the clinicopathologic and prognostic significance of glomerular C3 deposition in the renal histopathology of patients with ANCA-GN. METHODS: We retrospectively identified 142 patients with ANCA-GN from 6 hospitals in Japan (2004-2020). C3 deposition was defined as C3 staining ≥1+ on a scale of 0 to 2+ using direct immunofluorescence (IF). The primary composite end points included a 30% reduction in estimated glomerular filtration rate (eGFR), end-stage kidney disease (ESKD), and death. We compared clinicopathologic features and long-term outcomes between patients with and without C3 deposition. RESULTS: C3 deposition was observed in 56 of 142 kidney biopsy samples (39.4%). Patients with C3 deposition had a lower serum C3 level (P = 0.002). During a median follow-up of 2.9 (interquartile range: 0.2-5.7) years, 69 events occurred and the cumulative event-free survival rate at 5 years was significantly lower in the C3-positive group than in the C3-negative group (log-rank: P = 0.002). In multivariable analysis, C3 deposition was significantly associated with the composite end points after adjusting for age, sex, baseline eGFR, serum C3 level, treatment, and the percentage of normal glomerulus, cellular crescents, global sclerosis, and interstitial damage (adjusted hazard ratio [HR] = 2.02, 95% confidence interval: 1.20-3.40, P = 0.008). CONCLUSION: This study revealed that ANCA-GN patients with glomerular C3 deposition on IF had worse renal and overall survival rates.

Negative impact of proteinuria on circulating myeloid dendritic cells.

BACKGROUND: A decrease in absolute numbers (abs.) of circulating dendritic cells (DCs) and recruitment into target organs has been reported, but whether the level of proteinuria associates with circulating DC abs. has not been clarified. METHODS: We conducted a cross-sectional study of 210 patients with kidney disease aged 21-96 years who were admitted to our hospital for kidney biopsy in 2007-2010. For accuracy, the level of proteinuria was thoroughly measured by 24-h urine collection from patients in their admitted condition. The abs. of total DCs (tDCs), myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) was measured by three-color fluorescence-activated cell sorting (FACS). Patients were divided into four groups based upon the quartile of each DC abs. and one-way ANOVA, and multivariable-adjusted regression analyses were performed. RESULTS: Quantile analysis showed that the level of daily proteinuria decreased with increasing blood mDC abs., with mean proteinuria levels (g/day) of 2.45, 1.68, 1.68, 1.10 for those in mDC abs. quartiles ≤ 445, < 686, < 907, ≥ 907 cells/102 µL (p = 0.0277), respectively. Multivariate-adjusted regression analysis revealed that the mDC abs. was negatively associated with proteinuria (95% CI - 57.0 to - 8.5) and positively associated with male gender (95% CI 66.2-250.5). Independent associations were also shown between pDCs abs. and estimated glomerular filtration rate (eGFR) (95% CI 0.14-2.67) and C-reactive protein (95% CI - 49.4 to - 9.9) and between tDCs abs. and male gender (95% CI 54.5-253.6) and C-reactive protein (95% CI - 80.5 to - 13.4). CONCLUSION: We first reported that circulating mDC abs. has a negative association with the level of proteinuria.

Clinical and Pathological Characteristics of Elderly Japanese Patients with IgA Vasculitis with Nephritis: A Case Series.

Objective This case series aimed to identify the clinical and pathological characteristics of elderly patients (≥60 years) with biopsy-proven IgA vasculitis with nephritis (IgAVN). Methods The clinical and pathological presentation and treatment outcomes were compared between two groups. Patients Patients with IgAVN who were ≥19 years old at the time of their renal biopsy were divided into elderly (≥60 years) and adult (19-59 years) groups. Results Of the 23 patients in our study, 13 were elderly. In the elderly group, the median age at the diagnosis was 68 years (range, 60-85 years), with a median follow-up period of 15 months (range, 3-80 months). Twelve elderly patients had comorbidities, including hypertension, diabetes mellitus, chronic kidney disease, cardiovascular disease, and malignancies. A decrease in the estimated glomerular filtration rate, as well as massive proteinuria and rapidly progressive nephritic syndrome, were more frequent in the elderly group than in the adult group. Furthermore, renal pathological changes, including cellular or fibrocellular crescents, interstitial fibrosis, tubular atrophy, and arteriosclerosis, were more severe among elderly patients than adult patients. All elderly patients were treated with glucocorticoids and had no incidence of end-stage renal disease at the final follow-up; in addition, nine elderly patients had reduced proteinuria with a preserved renal function. Adverse events, including infection, diabetes mellitus, and vascular disorders, were identified in nine patients. Three elderly patients died from severe infections. Conclusion IgAVN in elderly patients is characterized by severe renal involvement. Elderly patients are at higher risk than adults for treatment-related adverse events.

Effect of adipose-derived mesenchymal stem cell transplantation on vascular calcification in rats with adenine-induced kidney disease.

Previous studies have investigated the use of mesenchymal stem cells (MSCs) to treat damaged kidneys. However, the effect of adipose-derived MSCs (ASCs) on vascular calcification in chronic kidney disease (CKD) is still poorly understood. In the present study, we explored the potential of ASCs for the treatment of CKD and vascular calcification. CKD was induced in male Sprague-Dawley rats by feeding them a diet containing 0.75% adenine for 4 weeks. ASCs transplantation significantly reduced serum inorganic phosphorus (Pi) as compared to that in the control. The histopathology of the kidneys showed a greater dilation of tubular lumens and interstitial fibrosis in the control group. Calcium and Pi contents of the aorta in the ASCs transplantation group were lower than those in the control group. Von Kossa staining of the thoracic aorta media revealed that ASCs transplantation suppressed vascular calcification. Thus, this study revealed that autogenic ASCs transplantation inhibits kidney damage and suppresses the progression of vascular calcification in the CKD rat model, suggesting that autogenic ASCs transplantation is a novel approach for preventing the progression of CKD and vascular calcification.

Embryonic kidney function in a chronic renal failure model in rodents.

BACKGROUND: Rapid advancements have been made in alternative treatments for renal diseases. Our goal for renal regeneration is to establish a kidney graft derived from human embryonic tissues. In this study, we investigated the effects of host renal failure on the structure and activity of transplanted embryonic kidney and bladder, and found that diuretics effectively induced urine production in the transplanted kidney. METHODS: Uremic conditions were reproduced using a 5/6 renal infarction rat model. An embryonic kidney plus bladder (embryonic day 15) was isolated from a pregnant Lewis rat and transplanted into the para-aortic area of a 5/6 renal-infarcted Lewis rat. Following growth, the embryonic bladder was successfully anastomosed to the host ureter. RESULTS: We assessed graft function in terms of survival rates and found no differences between normal (n = 5) and renal failure (n = 8) groups (median survival: 70.5 vs 74.5 h; p = 0.331) in terms of survival, indicating that the grafts prolonged rat survival, even under renal failure conditions. Furosemide (n = 9) significantly increased urine volume compared with saline-treated controls (n = 7; p < 0.05), confirming that the grafts were functional. We also demonstrated the possibilities of an in vivo imaging system for determining the viability of transplanted embryonic kidney with bladder. CONCLUSION: The results of this study demonstrate that transplanted embryonic kidney and bladder can grow and function effectively, even under uremic conditions.

Correction: Adipose Tissue-Derived Mesenchymal Stem Cells in Long-Term Dialysis Patients Display Downregulation of PCAF Expression and Poor Angiogenesis Activation.

[This corrects the article DOI: 10.1371/journal.pone.0102311.].

Intra-arterial catheter system to repeatedly deliver mesenchymal stem cells in a rat renal failure model.

BACKGROUND: Mesenchymal stem cell therapy in renal failure is rarely used because of low rates of cell engraftment after systemic delivery. Repeated intra-arterial cell administration may improve results; however, no current delivery method permits repeated intra-arterial infusions in a rat model. In this study, we developed an intra-arterial delivery system for repeated stem cell infusion via the aorta, catheterizing the left femoral artery to the suprarenal aorta under fluoroscopic guidance in rats with adenosine-induced renal failure. METHODS: First, we compared our intra-arterial catheter system (C group, n = 3) with tail vein injection (V group, n = 3) for engraftment efficacy, using mesenchymal stem cells from luciferase transgenic rats. Rats were infused with the cells and euthanized the following day; we performed cell-tracking experiments using a bioluminescence imaging system to assess the distribution of the infused cells. Second, we assessed the safety of the system over a 30-day period in a second group of six rats receiving infusions every 7 days. RESULTS: Cells infused through our delivery system efficiently engrafted into the kidney, compared with peripheral venous infusion. In five of the six rats in the safety study, the delivery system remained patent for at least 9 days (range, 9-24 days). Complications became evident only after 10 days. CONCLUSION: Our intra-arterial catheter system was effective in delivering cells to the kidney and permitted repeated injection of cells.

Urine excretion strategy for stem cell-generated embryonic kidneys.

There have been several recent attempts to generate, de novo, a functional whole kidney from stem cells using the organogenic niche or blastocyst complementation methods. However, none of these attempts succeeded in constructing a urinary excretion pathway for the stem cell-generated embryonic kidney. First, we transplanted metanephroi from cloned pig fetuses into gilts; the metanephroi grew to about 3 cm and produced urine, although hydronephrosis eventually was observed because of the lack of an excretion pathway. Second, we demonstrated the construction of urine excretion pathways in rats. Rat metanephroi or metanephroi with bladders (developed from cloacas) were transplanted into host rats. Histopathologic analysis showed that tubular lumina dilation and interstitial fibrosis were reduced in kidneys developed from cloacal transplants compared with metanephroi transplantation. Then we connected the host animal's ureter to the cloacal-developed bladder, a technique we called the "stepwise peristaltic ureter" (SWPU) system. The application of the SWPU system avoided hydronephrosis and permitted the cloacas to differentiate well, with cloacal urine being excreted persistently through the recipient ureter. Finally, we demonstrated a viable preclinical application of the SWPU system in cloned pigs. The SWPU system also inhibited hydronephrosis in the pig study. To our knowledge, this is the first report showing that the SWPU system may resolve two important problems in the generation of kidneys from stem cells: construction of a urine excretion pathway and continued growth of the newly generated kidney.

Adipose tissue-derived mesenchymal stem cells in long-term dialysis patients display downregulation of PCAF expression and poor angiogenesis activation.

We previously demonstrated that mesenchymal stem cells (MSCs) differentiate into functional kidney cells capable of urine and erythropoietin production, indicating that they may be used for kidney regeneration. However, the viability of MSCs from dialysis patients may be affected under uremic conditions. In this study, we isolated MSCs from the adipose tissues of end-stage kidney disease (ESKD) patients undergoing long-term dialysis (KD-MSCs; mean: 72.3 months) and from healthy controls (HC-MSCs) to compare their viability. KD-MSCs and HC-MSCs were assessed for their proliferation potential, senescence, and differentiation capacities into adipocytes, osteoblasts, and chondrocytes. Gene expression of stem cell-specific transcription factors was analyzed by PCR array and confirmed by western blot analysis at the protein level. No significant differences of proliferation potential, senescence, or differentiation capacity were observed between KD-MSCs and HC-MSCs. However, gene and protein expression of p300/CBP-associated factor (PCAF) was significantly suppressed in KD-MSCs. Because PCAF is a histone acetyltransferase that mediates regulation of hypoxia-inducible factor-1α (HIF-1α), we examined the hypoxic response in MSCs. HC-MSCs but not KD-MSCs showed upregulation of PCAF protein expression under hypoxia. Similarly, HIF-1α and vascular endothelial growth factor (VEGF) expression did not increase under hypoxia in KD-MSCs but did so in HC-MSCs. Additionally, a directed in vivo angiogenesis assay revealed a decrease in angiogenesis activation of KD-MSCs. In conclusion, long-term uremia leads to persistent and systematic downregulation of PCAF gene and protein expression and poor angiogenesis activation of MSCs from patients with ESKD. Furthermore, PCAF, HIF-1α, and VEGF expression were not upregulated by hypoxic stimulation of KD-MSCs. These results suggest that the hypoxic response may be blunted in MSCs from ESKD patients.