Background Severe acute respiratory syndrome Coronavirus 2 has rapidly spread worldwide, with acute kidney injury (AKI) as one of the manifestations with unknown causal mechanisms. We aimed to investigate tubular injury by assessing tubular markers and their association with the severity of Coronavirus disease 2019 . Methods We examined the associations between laboratory markers and urinary levels of N-acetyl-β-d-glucosaminidase (uNAG), β2-microglobulin (u β2MG), α1-microglobulin (u α1MG), and liver-type fatty acid binding protein (L-FABP). We studied 18 COVID-19 patients without previous chronic kidney disease and analyzed the relationship between the urinary biomarkers and inflammatory markers in patients with severe (n = 7) or non-severe (n = 11) COVID-19, defined by requirements of supplemental oxygen. Results Fourteen patients (78%) showed abnormal urinalysis findings and two (11%) developed AKI. Patients with severe COVID-19 had significantly higher levels of proteinuria, uNAG, uβ2MG, uα 1MG, and L-FABP than those with non-severe disease. Serum levels of interleukin-6 (IL-6) were significantly higher on admission in all severe COVID-19 cases and correlated with the levels of L-FABP, uβ2MG, uα1MG, uNAG, and proteinuria. Moreover, the changes in serum IL-6 (ΔIL-6) levels from baseline to 7 days after admission significantly correlated with ΔL-FABP and Δuβ2MG. Conclusions Levels of tubular injury markers, especially L-FABP and uβ2MG, were significantly associated with IL-6 levels even in patients with no evident AKI. This suggests that L-FABP and uβ2MG could be useful as early detective biomarkers for COVID-19 associated renal injury.
Dysregulation of mucosal immunity may play a role in the pathogenesis of IgA nephropathy (IgAN). However, it is unclear whether the nasal-associated lymphoid tissue (NALT) or gut-associated lymphatic tissue is the major induction site of nephritogenic IgA synthesis. To examine whether exogenous mucosal antigens exacerbate the pathogenesis of IgAN, we assessed the disease phenotypes of IgAN-onset ddY mice housed germ-free. These mice were transferred to a specific pathogen-free environment and divided into three groups: challenged with the Toll-like receptor 9 (TLR9) ligand CpG-oligodeoxynucleotide, fecal transplantation, and the untreated control group. The levels of aberrantly glycosylated IgA and IgG-IgA immune complexes were measured in the serum and supernatant of cultured cells purified from the NALT, mesenteric lymph nodes, and Peyer's patch. Although the germ-free IgANonset ddY mice did not develop IgAN, they showed aggravation of kidney injury with mesangial IgA deposition after transfer to the specific pathogen-free state. The NALT cells produced more aberrantly glycosylated IgA than those from the mesenteric lymph node and Peyer's patch, resulting in induction of IgG-IgA immune complexes formation. Additionally, TLR9 enhanced the production of nephritogenic IgA and IgG-IgA immune complexes by nasal-associated lymphoid but not gut-associated lymphatic cells. Furthermore, the germ-free IgAN-onset ddY mice nasally immunized with CpG-oligonucleotide showed aggravation of kidney injury with mesangial IgA deposition, whereas those that received fecal transplants did not develop IgAN. Thus, NALT is the major induction site of the production of aberrantly glycosylated IgA in murine IgAN.
The aim of the study was to assess the efficacy/safety of once- (100 mg q.d.) or twice-daily (50 mg b.i.d.) sitagliptin 100 mg/day in Japanese patients with type 2 diabetes (T2DM). In this randomized, double-blind study, 80 patients with inadequate glycemic control (HbA1c=6.5-10%; FPG =15.0 mmol/l) were randomized equally to sitagliptin 100 mg q.d., 50 mg b.i.d. or placebo for 4 weeks. At baseline and Week 4, frequent blood sampling was performed to assess 24-h weighted mean glucose (24-h WMG). Patients in the efficacy analyses (n=76) had a mean baseline HbA1c of 7.7%. At Week 4, least-squares mean changes in 24-h WMG were reduced with sitagliptin 100 mg q.d. and 50 mg b.i.d. versus placebo (-1.9, -1.6, and -0.5 mmol/l, respectively; p<0.001). Sitagliptin significantly improved FPG and 2-h PPG compared to placebo. No significant differences in 24-h WMG, FPG, or 2-h PPG were observed between the sitagliptin groups. Sitagliptin was well tolerated with no hypoglycemic events. In Japanese patients with T2DM, sitagliptin 100 mg/day provided substantial and continuous 24-h glucose-lowering over 4 weeks. The same glucose-lowering efficacy and tolerability were observed with sitagliptin 100 mg/day whether administered as a once-daily or twice-daily regimen. These results support a once-daily dosing regimen in Japanese patients with T2DM.
In several cases with IgA nephropathy (IgAN), differential diagnosis is difficult due to the complication with other systemic diseases which can induce secondary IgAN. Recently, we demonstrated that immunostaining with galactose-deficient IgA1specific monoclonal antibody (KM55 mAb) specifically showed positive in primary IgAN cases. Here, we report four cases which we could make definitive diagnosis by immunohistological analysis using KM55 mAb. The underlying systemic diseases are rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), hepatitis C (HCV) and Crohn's disease (CD). Renal pathological findings in the four cases revealed mesangial proliferative glomerulonephritis with IgA and C3 deposits. Immunostaining with KM55 mAb was positive for three cases complicated with RA, SLE and CD, respectively. Thus, these three cases were diagnosed as primary IgAN and treated with tonsillectomy and steroid pulse therapy. These three cases finally achieved clinical remission. On the other hand, the case with HCV showed negative for KM55. Finally, we diagnosed as HCV-related nephropathy and successfully treated by antiviral agents. These cases suggested KM55 mAb is a strong tool to differentiate primary IgAN from secondary IgAN.
Immunoglobulin A (IgA) nephropathy (IgAN) is the most common type of primary glomerulonephritis, often progressing to renal failure. IgAN is triggered by IgA deposition in the glomerular mesangium by an undefined mechanism. Here, we show that grouped ddY (gddY) mice, a spontaneous IgAN model, produce serum IgA against mesangial antigens, including βII-spectrin. Most patients with IgAN also have serum anti–βII-spectrin IgA. As in patients with IgAN, IgA + plasmablasts accumulate in the kidneys of gddY mice. IgA antibodies cloned from the plasmablasts carry substantial V-region mutations and bind to βII-spectrin and the surface of mesangial cells. These IgAs recognize transfected and endogenous βII-spectrin exposed on the surface of embryonic kidney–derived cells. Last, we demonstrate that the cloned IgA can bind selectively to glomerular mesangial regions in situ. The identification of IgA autoantibody and its antigen in IgAN provides key insights into disease onset and redefines IgAN as a tissue-specific autoimmune disease.
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