Published papers

Because end-stage renal disease patients undergoing hemodialysis frequently take acid suppressants for the treatment or prevention of gastrointestinal diseases, it is important to clarify the drug-interactions between acid suppressants and phosphate binders on the control of serum phosphate levels. In the present study, we examined whether the phosphate-lowering effects of three phosphate binders, lanthanum carbonate (LC), ferric citrate hydrate (FCH), and sucroferric oxyhydroxide (SFOH), were affected by proton pump inhibitors (PPIs) in maintenance hemodialysis patients. Laboratory data for 71 patients who had been newly prescribed one of the three phosphate binders were examined. LC at a dosage of 500 ± 217 mg/day significantly decreased serum phosphate levels by −18% in the absence of a PPI (n = 9), while a dosage of 700 ± 230 mg/day only decreased it by −3% in the presence of a PPI (n = 10). Thus, the efficacy of LC in reducing serum phosphate levels was significantly hindered by the presence of PPIs. FCH significantly decreased serum phosphate levels by −18% in the absence of a PPI (n = 7, FCH: 571 ± 189 mg/day) and by −17% in the presence of a PPI (n = 20, FCH: 638 ± 151 mg/day). The decrease in serum phosphate levels by SFOH (393 ± 197 mg/day) was −7% in the absence of a PPI (n = 7), and SFOH at a dosage of 556 ± 316 mg/day significantly decreased serum phosphate levels by −13% in the presence of a PPI (n = 18). These results suggest that the phosphate-lowering effect of LC, but not of FCH or SFOH, is diminished in the presence of PPIs in hemodialysis patients.

Consensus regarding kidney transplantation feasibility in patients with chronic myeloid leukemia (CML) well controlled by tyrosine kinase inhibitors has not yet been achieved. Here, we report a patient with CML well controlled by tyrosine kinase inhibitors who developed end-stage renal disease during treatment and underwent kidney transplantation. CML activity has been carefully and successfully controlled for 4 years post-transplant. Very cautious dose adjustment and temporary cessation of nilotinib were required because kidney function fluctuated in reference to the doses of nilotinib.

Plasma exchange (PE) is performed for patients with autoimmune blistering diseases by using multiple vascular access routes. We retrospectively examined the safety and the efficacy of PE using direct femoral vein puncture (FVP) technique, by comparing with that using double-lumen catheter (DLC). The troubles related to vascular route, such as catheter occlusion, insufficient blood flow and hematoma, were not different between the FVP group (4.6%) and the DLC group (6.7%), whereas access-related infections occurred more frequently in the DLC group (6.7%) than the FVP group (0.4%). Regarding the efficacy, the removal rate of autoantibodies in PE using the FVP technique was similar or lower, as compared with that using the DLC. These results suggest that PE with the FVP technique is able to be performed safely in patients with autoimmune blistering diseases, although the removal of autoantibodies is not superior to that using the DLC.

Background: Cyclosporine A (CsA) is an essential immunosuppressant in organ transplantation. However, its chronic nephrotoxicity is an obstacle to long allograft survival that has not been overcome. Nuclear factor-κB (NF-κB) is activated in the renal tissue in CsA nephropathy. In this study, we aimed to investigate the effect of the specific NF-κB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), in a rat model of CsA nephrotoxicity. Methods: We administered CsA (15 mg/kg) daily for 28 days to Sprague-Dawley rats that underwent 5/6 nephrectomy under a low-salt diet. We administered DHMEQ (8 mg/kg) simultaneously with CsA to the treatment group, daily for 28 days and evaluated its effect on CsA nephrotoxicity. Results: DHMEQ significantly inhibited NF-κB activation and nuclear translocation due to CsA treatment. Elevated serum urea nitrogen and creatinine levels due to repeated CsA administration were significantly decreased by DHMEQ treatment (serum urea nitrogen in CsA + DHMEQ vs CsA vs control, 69 ± 6.4 vs 113.5 ± 8.8 vs 43.1 ± 1.1 mg/dL, respectively, p < 0.0001; serum creatinine in CsA + DHMEQ vs CsA vs control, 0.75 ± 0.02 vs 0.91 ± 0.02 vs 0.49 ± 0.02 mg/dL, respectively, p < 0.0001), and creatinine clearance was restored in the treatment group (CsA + DHMEQ vs CsA vs control, 2.57 ± 0.09 vs 1.94 ± 0.12 vs 4.61 ± 0.18 ml/min/kg, respectively, p < 0.0001). However, DHMEQ treatment did not alter the inhibitory effect of CsA on urinary protein secretion. The development of renal fibrosis due to chronic CsA nephrotoxicity was significantly inhibited by DHMEQ treatment (CsA + DHMEQ vs CsA vs control, 13.4 ± 7.1 vs 35.6 ± 18.4 vs 9.4 ± 5.4%, respectively, p < 0.0001), and these results reflected the results of renal functional assessment. DHMEQ treatment also had an inhibitory effect on the increased expression of chemokines, monocyte chemoattractant protein-1, and chemokine (c-c motif) ligand 5 due to repeated CsA administration, which inhibited the infiltration of macrophages and neutrophils into the renal tissue. Conclusions: These findings suggest that DHMEQ treatment in combination therapy with CsA-based immunosuppression is beneficial to prevent the development of CsA-induced nephrotoxicity.

Bullous pemphigoid (BP) is an autoimmune subepidermal blistering disease. Although several cases of BP in end-stage renal disease patients receiving peritoneal dialysis (PD) or hemodialysis have been reported, the incidence of BP in these patients remains unknown. We recently experienced three PD patients diagnosed with BP. The skin injury was likely to be a trigger of BP in all the three PD patients. Nifedipine and icodextrin exposures were possible factors directly or indirectly affecting the onset of BP, because they were common in the three cases. We also report that the incidence of BP in PD patients was 3/478.3 person-years in a single-center 10-year study. This case series with a literature survey describes that the skin and tissue injuries are potential triggers responsible for the onset of BP in dialysis patients and that the incidence of BP in these patients seems to be much higher than that in the general population.

Background: Patients with anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive dermatomyositis (DM) are frequently accompanied by rapidly progressive-interstitial lung disease (RP-ILD). They are often refractory to intensive immunosuppressive therapy and have poor prognosis. Case presentation: A 73-year-old woman presented with fever, cold symptoms, and skin eruption for a month. She also exhibited muscle weakness on upper extremities slightly. The titer of anti-MDA5 antibody was extremely high, and computed tomography showed ground glass opacity and reticular shadows in the lungs. She was diagnosed as anti-MDA5 antibody-positive classical DM-associated RP-ILD and treated with intensive immunosuppressive therapy. However, the titer of anti-MDA5 antibody did not decrease satisfactorily, and plasma exchange was alternatively initiated. The titer decreased remarkably, and she obtained disease remission. Similarly, a 63-year-old woman presented with stiffness of the neck and hands, fever and cough. She was also diagnosed as anti-MDA5 antibody-positive classical DM-associated RP-ILD, because she had skin eruptions, slight muscle weakness, an elevation in anti-MDA5 antibody, and RP-ILD. She was unresponsive to intensive immunosuppressive therapy, but plasma exchange successfully improved the titer of anti-MDA5 antibody, the symptoms, and the findings of computed tomography. Conclusions: Although anti-MDA5 antibody-positive DM-associated RP-ILD has a high mortality rate, this report suggests the usefulness of plasma exchange to improve the prognosis.

A 61-year-old woman with a 4-year history of maintenance hemodialysis due to end-stage renal disease of unknown cause was admitted because of a recurrent fever and abdominal pain lasting for 3 months. She had rheumatoid arthritis as a complication and had taken sulfasalazine for over 4 years. Laboratory data revealed thrombocytopenia, hypocomplementemia, a high C-reactive protein level, and positivity for antinuclear antibody and anti-double strand DNA antibody. Gallium scintigraphy showed pericarditis, pleuritis, and peritonitis. Nonscarring alopecia was also noted. She was diagnosed as having systemic lupus erythematosus (SLE). Drug-induced lupus elicited by sulfasalazine was ruled out because the symptoms did not improve even after the discontinuation of the drug upon admission. Oral prednisolone treatment markedly improved her symptoms and laboratory data. However, she later died of sepsis arising from proctitis on day 71 of admission. This report underscores the necessity of considering new-onset SLE in patients with unexplained fever and serositis, including pleuritis, peritonitis, or pericarditis, even if they are receiving maintenance dialysis.

Background: End-of-life medical care for patients receiving maintenance hemodialysis (HD) therapy has become an increasingly important issue worldwide. Thus far, no clear indicators and/or biomarkers exist regarding the timing of HD therapy withdrawal. Methods: To clarify the perimortem circumstances, we examined temporal changes in multiple clinical parameters during the last 10 serial HD sessions of 65 terminal patients with end-stage renal disease who had undergone maintenance HD and died in our hospital. Results: The results showed that, while most of the laboratory data were unaltered, the physical parameters, such as systolic blood pressure and consciousness levels, gradually and significantly deteriorated toward the last HD session prior to death. The frequency of the use of vasopressors and O2 inhalation tended to increase. The accumulation of such severe conditions was observed at the last HD session. Of interest, the accumulation of severe conditions at the last HD session in patients with malignancies was significantly less than those with cardiovascular diseases or infectious diseases. The accumulation of severe conditions at the last HD session did not differ between patients who withdrew HD versus those who continued HD. Conclusion: The results of the present study suggest that predicting the timing of maintenance HD therapy withdrawal is likely to be difficult and that the timing of maintenance HD therapy termination may differ among patient groups with distinct comorbid conditions.

Background: Diarrhea is one of the symptoms occasionally seen in patients initiating hemodialysis. When they have diarrhea, they need several additional cares for defecation during the hemodialysis sessions and for infection control at dialysis facilities. Methods: We retrospectively examined the prevalence and the characteristics of the patients with diarrhea initiating hemodialysis. Data were collected from medical records. Results: Of 243 patients who initiated hemodialysis therapy, 46 patients (19%) had diarrhea. The age, gender, and etiology of end-stage renal disease did not differ between the patients with diarrhea and those without diarrhea. Body weight in the patients with diarrhea was lighter than those without diarrhea. The prevalence of concomitant diseases, such as cardiovascular diseases, malignancies, and diabetes, was not different between the groups, whereas the patients with diarrhea were complicated more frequently with infectious diseases. Antibiotics and steroids had been used more frequently in the patients with diarrhea (59% and 26%, respectively) than those without diarrhea (10% and 10%, respectively). Inflammatory markers, such as white blood cell numbers, C-reactive protein levels, and body temperature, were significantly higher in the patients with diarrhea. Serum levels of total protein, albumin, and creatinine were significantly lower in the patients with diarrhea, while urea nitrogen levels did not differ between the groups. Conclusion: Results of the present study showed, for the first time, that 19% of the patients initiating hemodialysis had diarrhea and suggest that incident hemodialysis patients with infectious diseases and those under treatment with antibiotics and/or steroids are high-risk for diarrhea.

Homozygous mutations in SLC4A4, which encodes the electrogenic Naþ/HCO3- cotransporter (NBCe1), cause proximal renal tubular acidosis associated with extrarenal symptoms. Although 17` mutated sites in SLC4A4 have thus far been identified among patients with proximal renal tubular acidosis, the physiological significance of other nonsynonymous single-nucleotide variants (SNVs) remains largely undetermined. Here, we investigated the functional properties of SNVs in NBCe1. From the National Center for Biotechnology Information dbSNP database, we identified 13 SNVs that have not previously been characterized in the highly conserved, transmembrane domains of NBCe1-A. Immunocytochemical analysis revealed that the I551F variant was present predominantly in the cytoplasm in human embryonic kidney (HEK)-293 cells, whereas all other SNVs did not show as dramatic a change in subcellular distribution. Western blot analysis in HEK-293 cells demonstrated that the I551F variant showed impaired glycosylation and a 69% reduction in cell surface levels. To determine the role of I551 in more detail, we examined the significance of various artificial mutants in both nonpolarized HEK-293 cells and polarized Madin-Darby canine kidney cells, which indicated that only I551F substitution resulted in cytoplasmic retention. Moreover, functional analysis using Xenopus oocytes demonstrated that the I551F variant had a significantly reduced activity corresponding to 39% of that of the wild-type, whereas any other SNVs and artificial I551 mutants did not show significant changes in activity. Finally, immunofluorescence experiments in HEK-293 cells indicated that the I551F variant retained wild-type NBCe1-A in the cytoplasm. These data demonstrate that the I551F variant of NBCe1-A shows impaired transport activity predominantly through cytoplasmic retention and suggest that the variant can have a dominant negative effect by forming complexes with wild-type NBCe1-A.

Background: Iliopsoas abscess is a relatively rare but serious infectious disease. Infectious disease is one of the major causes of death among patients receiving hemodialysis for end-stage renal disease (ESRD). Case presentation: We experienced three cases of iliopsoas abscess in patients receiving hemodialysis. The infection route was distinct in each case. A 79-year-old woman with ESRD due to autosomal dominant polycystic kidney disease exhibited bilateral iliopsoas abscesses caused by bacterial contamination during a lumbar epidural block procedure. A 60-year-old woman with ESRD due to diabetic nephropathy was diagnosed as having an iliopsoas abscess, caused by the direct invasion of bacteria from a renal abscess. A 78-year-old woman who started hemodialysis because of nephrosclerosis developed an iliopsoas abscess caused by the hematogenous spread of bacteria from emphysematous cystitis. All three cases were treated with antibiotics and/or percutaneous drainage. A survey of published reports suggested that iliopsoas abscess can be caused by infection through a variety of routes in hemodialysis patients. Conclusion: Because hemodialysis patients are at a high risk of infection because of their immunocompromised state, physicians should pay close attention to infection prevention. If iliopsoas abscess is suspected, examinations such as computed tomography, magnetic resonance imaging, and blood culture sampling should be conducted promptly, followed by appropriate treatment with antibiotics and/or drainage.

We here report a case of SAPHO (synovitis-acne-pustulosis-hyperostosis-osteitis) syndrome with hypercalcemia. The patient was diagnosed with SAPHO syndrome at the age of 54, because he exhibited osteitis and hyperostosis around the sternoclavicular joints and the temporomandibular joints bilaterally and had past medical history of palmoplantar pustulosis. At the age of 67, he exhibited appetite loss and nausea. Corrected serum calcium was 13.0 mg/dl. Adequate hydration was recommended, and his calcium levels returned to the normal range without any medical treatment. Although speculative, his hypercalcemia was considered to be caused by an increased bone activity in SAPHO syndrome. This is the first report describing transient hypercalcemia in a patient with SAPHO syndrome.

Alström syndrome (AS) is an extremely rare disease accompanied by blindness, hearing loss, obesity, type 2 diabetes, dilated cardiomyopathy, and progressive hepatic and renal dysfunction. The life span of AS patients rarely exceeds 50 years, and thus there are very few reports describing the implementation of renal replacement therapy for these patients. We here report a case of AS patient who exhibited dilated cardiomyopathy, end-stage renal disease, and hepatic cirrhosis. He underwent hemodialysis therapy more than 3 years. Although he eventually died of amiodarone-induced multiple organ damage in the lungs and liver, the present case suggests that hemodialysis therapy can be a choice of renal replacement therapy for AS patients with end-stage renal disease.

Purpose: Iron-based phosphate binders, including ferric citrate hydrate (FCH) and sucroferric oxyhydroxide (SFOH), have been used for the treatment of hyperphosphatemia in end-stage renal disease patients on dialysis. However, the long-term efficacy and safety of these agents have not yet been clearly elucidated. Methods: Laboratory data of 56 hemodialysis patients who had been prescribed either FCH (n = 33) or SFOH (n = 23) were retrospectively examined. Results: We showed that both FCH and SFOH significantly and consistently decreased serum phosphate concentrations in the patients undergoing maintenance hemodialysis during the 36-month observation period. Serum levels of calcium, intact parathyroid hormone, as well as hemoglobin levels were unaltered. No overshoot of parameters of iron metabolism, such as transferrin saturation and serum ferritin levels, was observed, and serum ferritin level remained under 300 ng/mL in most patients. A trend towards decrease in the doses of erythropoiesis-stimulating agents used and frequency of intravenous iron use was observed in both treatment groups. No severe adverse drug reactions were observed in either the patients receiving FCH or SFOH. Conclusion: The results of the present study suggest that the iron-based phosphate binders, FCH and SFOH, decrease serum phosphate concentrations consistently and are safe to use over the long-term in maintenance hemodialysis patients.

Since the coronavirus disease 2019 (COVID-19) pandemic continues and a new variant of the virus has emerged, the COVID-19 vaccination campaign has progressed. Rare but severe adverse outcomes of COVID-19 vaccination such as anaphylaxis and myocarditis have begun to be noticed. Of note, several cases of new-onset antineutrophil cytoplasmic antibody-associated vasculitis (AAV) after COVID-19 mRNA vaccination have been reported. However, relapse of AAV in remission has not been recognized enough as an adverse outcome of COVID-19 vaccination. We report, to our knowledge, a first case of renal-limited AAV in remission using every 6-month rituximab administration that relapsed with pulmonary hemorrhage, but not glomerulonephritis, following the first dose of the Pfizer-BioNTech COVID-19 vaccine. The patient received the COVID-19 vaccine more than 6 months after the last dose of rituximab according to the recommendations. However, his CD19+ B cell counts were found to be increased after admission, indicating that our case might have been prone to relapse after COVID-19 vaccination. Although our case cannot establish causality between AAV relapse and COVID-19 mRNA vaccination, a high level of clinical vigilance for relapse of AAV especially in patients undergoing rituximab maintenance therapy following COVID-19 vaccination should be maintained. Furthermore, elapsed time between rituximab administration and COVID-19 mRNA vaccination should be carefully adjusted based on AAV disease-activity.

Unplanned dialysis initiation is associated with poor outcomes. It is controversial whether patients with advanced chronic kidney disease (CKD) should receive renin-angiotensin system (RAS) inhibitor therapy. The aim of this study was to evaluate the effect of RAS inhibitor therapy in patients with advanced CKD on the incidence of unplanned dialysis initiation. This single-center, retrospective study included patients who started maintenance dialysis at our hospital between April 2014 and March 2021. Patients who initiated dialysis within 6 months of nephrology referral or after kidney transplant were excluded. Among 334 patients (aged 70.0 [59.0–79.0] years; 28.4% women), 186 (55.7%) and 148 (44.3%) had planned and unplanned dialysis initiation, respectively. Multivariate logistic regression analysis revealed that the use of RAS inhibitors was significantly associated with a lower incidence of unplanned dialysis initiation (odds ratio [OR], 0.36; P < 0.01). Female sex (OR, 0.41; P < 0.05), use of potassium binders (OR, 0.28; P < 0.001), earlier referral to nephrology (OR, 0.39; P < 0.01), and earlier discussion of renal replacement therapy (OR, 0.33; P < 0.001) were also significantly associated with a lower incidence, whereas older age (OR, 1.28; P < 0.05), higher Charlson Comorbidity Index (OR, 1.24; P < 0.05), and faster decline in kidney function (OR, 1.29; P < 0.01) were associated with a higher risk of unplanned dialysis initiation. RAS inhibitor therapy in patients with advanced CKD is associated with a lower risk of unplanned dialysis initiation.

Background: Thymus and activation-regulated chemokine (TARC), which induces a Th2-dominated inflammation, is a well-known biomarker that reflects the severity of atopic dermatitis. The present study aimed to evaluate TARC as a Th2-associated marker with chronic kidney disease-associated pruritus (CKD-aP) in patients with peritoneal dialysis (PD). Methods: This single-centre cross-sectional study included patients who underwent PD in our hospital between August 2020 and July 2021. The severity and impaired quality of life (QOL) of CKD-aP were assessed using the visual analogue scale (VAS) and Japanese version of the 5-D itch scale (5D-J), respectively. Results: A total of 48 patients with PD were included in the present study. Age and dialysis vintage were (mean ± SD) 64.8 ± 12.0 year and (median (IQR)) 38.5 (11.5–91.5) month, respectively. VAS and 5D-J scores were 3.3 ± 2.0 and 10.5 (9.0–12.0), respectively. Serum TARC level was 481.5 (278.9–603.4) pg/mL (upper limits of normal 450 pg/mL) and significantly correlated with VAS (r = 0.39, p = 0.006) and 5D-J score (r = 0.37, p = 0.009). Multivariate linear analysis revealed that higher serum TARC level was significantly associated with VAS (p < 0.001) and 5D-J score (p < 0.001). Furthermore, the serum brain natriuretic peptide level tended to be associated with VAS (p = 0.060) and 5D-J score (p = 0.029). Conclusion: Serum TARC level is an independent predictor of the severity and impaired QOL of CKD-aP in patients with PD, and TARC might be involved in the pathogenesis of CKD-aP.