Successful treatment with rituximab of immunotactoid glomerulopathy exhibiting nephrotic syndrome
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As immunotactoid glomerulopathy (ITG) is a very rare primary glomerular disease, no standard treatment has been established. It has been reported that ITG progresses to end-stage renal disease at a high rate. Here, we report a case of ITG exhibiting nephrotic syndrome treated by administration of a single dose of rituximab every 6 months for 4 years. In this case, complete remission (CR) was not achieved with steroids alone, but was achieved through long-term depletion of B cells by administration of rituximab. This is the first report that single-dose rituximab every 6 months for 4 years not only achieved CR of ITG, but also allowed steroid tapering.
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Biopsy-proven vancomycin-induced acute kidney injury: a case report and literature review.

BACKGROUND: Vancomycin is the first-line antibiotic for methicillin-resistant Staphylococcus aureus and coagulase-negative strains. The risk of vancomycin-induced acute kidney injury increases with plasma vancomycin levels. Vancomycin-induced acute kidney injury is histologically characterized by acute interstitial nephritis and/or acute tubular necrosis. However, only 12 biopsy-proven cases of vancomycin-induced acute kidney injury have been reported so far, as renal biopsy is rarely performed for such cases. Current recommendations for the prevention or treatment of vancomycin-induced acute kidney injury are drug monitoring of plasma vancomycin levels using trough level and drug withdrawal. Oral prednisone and high-flux haemodialysis have led to the successful recovery of renal function in some biopsy-proven cases. CASE PRESENTATION: We present the case of a 41-year-old man with type 1 diabetes mellitus, who developed vancomycin-induced acute kidney injury during treatment for Fournier gangrene. His serum creatinine level increased to 1020.1 µmol/L from a baseline of 79.6 µmol/L, and his plasma trough level of vancomycin peaked at 80.48 µg/mL. Vancomycin discontinuation and frequent haemodialysis with high-flux membrane were immediately performed following diagnosis. Renal biopsy showed acute tubular necrosis and focal acute interstitial nephritis, mainly in the medullary rays (medullary ray injury). There was no sign of glomerulonephritis, but mild diabetic changes were detected. He was discharged without continuing haemodialysis (serum creatinine level, 145.0 µmol/L) 49 days after initial vancomycin administration. CONCLUSIONS: This case suggests that frequent haemodialysis and renal biopsy could be useful for the treatment and assessment of vancomycin-induced acute kidney injury, particularly in high-risk cases or patients with other renal disorders.

His267 is involved in carbamylation and catalysis of RuBisCO-like protein from Bacillus subtilis.

Ribulose-1,5-bisphosphate carboxylase/oxygenase (RuBisCO) and RuBisCO-like protein (RLP) from Bacillus subtilis catalyze mechanistically similar enolase reactions. Both enzymes require carbamylation of the ε-amino group of the active site lysine during activation to generate the binding site of the essential Mg(2+) ion. His267 forms a possible hydrogen bond with the carbamate of the active site Lys176 in B. subtilis RLP. This active site histidine is completely conserved in RLPs and RuBisCO. H267Q, H267N and H267A mutant enzymes required higher CO(2) concentrations for maximal activity than wild-type enzyme, suggesting that the histidine is involved in high affinity for activator CO(2) in Bacillus RLP. These mutations showed weak effects on the catalysis of RLP, whereas this residue is reportedly essential for catalysis in RuBisCO but is not involved in the carbamylation. The different functions of the active site histidine in RLP and RuBisCO are discussed.

Plausible novel ribose metabolism catalyzed by enzymes of the methionine salvage pathway in Bacillus subtilis.

The methionine salvage pathway (MSP) recycles reduced sulfur from 5-methylthioribose. Here we propose a novel ribose metabolic pathway performed by MSP enzymes of Bacilli. MtnK, an initial catalyst of MSP, had significant ribose kinase activity, with Vmax and Km values of 2.9 µmol min(-1) mg of protein(-1) and 4.8 mM. Downstream enzymes catalyzed the isomerization of ribose-1-phosphate and subsequent dehydration, enolization, dephosphorylation, and dioxygenation.

An evolutionally conserved Lys122 is essential for function in Rhodospirillum rubrum bona fide RuBisCO and Bacillus subtilis RuBisCO-like protein.

Ribulose-1,5-bisphosphate carboxylase/oxygenase (RuBisCO) and RuBisCO-like protein (RLP) catalyze similar enolase-type reactions. Both enzymes have a conserved non-catalytic Lys122 or Arg122 on the beta-strand E lying in the interface between the N- and C-terminal domains. We used site-directed mutagenesis to analyze the function of Lys122 in the form II Rhodospirillum rubrum RuBisCO (RrRuBisCO) and Bacillus subtilis RLP (BsRLP). The K122R mutant of RrRuBisCO had a 40% decrease in k(cat) for carboxylase activity, a 2-fold increase in K(m) for CO2, and a 1.9-fold increase in K(m) for ribulose-1,5-bisphosphate. K122M and K122E mutants of RrRuBisCO were almost inactive. None of the substitutions affected the thermal stability of RrRuBisCO. The K122R mutant of BsRLP had a 32% decrease in k(cat) and lower thermal stability than the wild-type enzyme. The K122M and K122E mutants of BsRLP failed to form a catalytic dimer. Our results suggest that the lysine residue is essential for function in both enzymes, although in each case, its role is likely distinct.

Increased fibroblast growth factor-21 in chronic kidney disease is a trade-off between survival benefit and blood pressure dysregulation.

Circulating levels of fibroblast growth factor-21 (FGF21) start increasing in patients with chronic kidney disease (CKD) since early stages during the cause of disease progression. FGF21 is a liver-derived hormone that induces responses to stress through acting on hypothalamus to activate the sympathetic nervous system and the hypothalamus-pituitary-adrenal endocrine axis. However, roles that FGF21 plays in pathophysiology of CKD remains elusive. Here we show in mice that FGF21 is required to survive CKD but responsible for blood pressure dysregulation. When introduced with CKD, Fgf21-/- mice died earlier than wild-type mice. Paradoxically, these Fgf21-/- CKD mice escaped several complications observed in wild-type mice, including augmentation of blood pressure elevating response and activation of the sympathetic nervous system during physical activity and increase in serum noradrenalin and corticosterone levels. Supplementation of FGF21 by administration of an FGF21-expressing adeno-associated virus vector recapitulated these complications in wild-type mice and restored the survival period in Fgf21-/- CKD mice. In CKD patients, high serum FGF21 levels are independently associated with decreased baroreceptor sensitivity. Thus, increased FGF21 in CKD can be viewed as a survival response at the sacrifice of blood pressure homeostasis.

RuBisCO-like proteins as the enolase enzyme in the methionine salvage pathway: functional and evolutionary relationships between RuBisCO-like proteins and photosynthetic RuBisCO.

Ribulose-1,5-bisphosphate carboxylase/oxygenase (RuBisCO) is the key enzyme in the fixation of CO(2) in the Calvin cycle of plants. Many genome projects have revealed that bacteria, including Bacillus subtilis, possess genes for proteins that are similar to the large subunit of RuBisCO. These RuBisCO homologues are called RuBisCO-like proteins (RLPs) because they are not able to catalyse the carboxylase or the oxygenase reactions that are catalysed by photosynthetic RuBisCO. It has been demonstrated that B. subtilis RLP catalyses the 2,3-diketo-5-methylthiopentyl-1-phosphate (DK-MTP-1-P) enolase reaction in the methionine salvage pathway. The structure of DK-MTP-1-P is very similar to that of ribulose-1,5-bisphosphate (RuBP) and the enolase reaction is a part of the reaction catalysed by photosynthetic RuBisCO. In this review, functional and evolutionary relationships between B. subtilis RLP of the methionine salvage pathway, other RLPs, and photosynthetic RuBisCO are discussed. In addition, the fundamental question, 'How has RuBisCO evolved?' is also considered, and evidence is presented that RuBisCOs evolved from RLPs.

MtnBD is a multifunctional fusion enzyme in the methionine salvage pathway of Tetrahymena thermophila.

To recycle reduced sulfur to methionine in the methionine salvage pathway (MSP), 5-methylthioribulose-1-phosphate is converted to 2-keto-4-methylthiobutyrate, the methionine precursor, by four steps; dehydratase, enolase, phosphatase, and dioxygenase reactions (catalyzed by MtnB, MtnW, MtnX and MtnD, respectively, in Bacillus subtilis). It has been proposed that the MtnBD fusion enzyme in Tetrahymena thermophila catalyzes four sequential reactions from the dehydratase to dioxygenase steps, based on the results of molecular biological analyses of mutant yeast strains with knocked-out MSP genes, suggesting that new catalytic function can be acquired by fusion of enzymes. This result raises the question of how the MtnBD fusion enzyme can catalyze four very different reactions, especially since there are no homologous domains for enolase and phosphatase (MtnW and MtnX, respectively, in B. subtilis) in the peptide. Here, we tried to identify the domains responsible for catalyzing the four reactions using recombinant proteins of full-length MtnBD and each domain alone. UV-visible and ¹H-NMR spectral analyses of reaction products revealed that the MtnB domain catalyzes dehydration and enolization and the MtnD domain catalyzes dioxygenation. Contrary to a previous report, conversion of 5-methylthioribulose-1-phosphate to 2-keto-4-methylthiobutyrate was dependent on addition of an exogenous phosphatase from B. subtilis. This was observed for both the MtnB domain and full-length MtnBD, suggesting that MtnBD does not catalyze the phosphatase reaction. Our results suggest that the MtnB domain of T. thermophila MtnBD acquired the new function to catalyze both the dehydratase and enolase reactions through evolutionary gene mutations, rather than fusion of MSP genes.

A case of very large intrahepatic bile duct adenoma followed for 7 years.

A 70-year-old man was referred to our hospital due to abnormal liver function. A tumor of 92 mm × 61 mm was detected on ultrasound screening of the left liver lobe. Although the tumor was suspected to be intrahepatic bile duct carcinoma, he had chronic heart disease and was unable to undergo surgery. Therefore, he was followed without further testing. No increase in tumor serum markers or tumor size was observed for the subsequent 7 years. We continued to suspect intrahepatic bile duct carcinoma, and we decided to perform a tumor biopsy. Tumor biopsy findings indicated intrahepatic bile duct adenoma (BDA), which is a rare benign epithelial liver tumor typically ranging from 1 mm to 20 mm. We herein report a case of very large BDA followed for 7 years.