Kouichi Hirayama

Serum Levels of BAFF and APRIL in Myeloperoxidase Anti-Neutrophil Cytoplasmic Autoantibody-Associated Renal Vasculitis: Association with Disease Activity

Background: A proliferation-inducing ligand (APRIL) and the B cell activation factor belonging to the tumor necrosis factor family (BAFF) have proven to be key factors in the selection and survival of B cells, and a higher concentration of BAFF has been shown to contribute to autoreactive B cell survival and elevated autoantibody production. Here, serum BAFF and APRIL levels were investigated to analyze their association with disease activity in myeloperoxidase anti-neutrophil cytoplasmic autoantibody (MPO-ANCA)-associated renal vasculitis. Methods: APRIL and BAFF levels in serum obtained from 37 patients with MPO-ANCA-associated vasculitis were measured by ELISA. Samples were taken from active vasculitis patients, inactive vasculitis patients and inactive vasculitis patients with infectious complications. Results: Although there was no difference in serum APRIL among the active vasculitis, inactive vasculitis and infectious complication patients, serum BAFF was higher in active vasculitis patients than in inactive vasculitis, infectious complication and control patients (for all, p < 0.001). There was no significant correlation between serum APRIL and ANCA titers, but there was a significant correlation between serum BAFF and ANCA titers (r = 0.465, p < 0.001). Conclusion: Excessive BAFF production in MPO-ANCA-associated vasculitis may be one of the factors for autoimmune B cell tolerance, resulting in MPO-ANCA production.

Anti-glomerular basement membrane antibody disease in Japan: part of the nationwide rapidly progressive glomerulonephritis survey in Japan

Anti-glomerular basement membrane (anti-GBM) antibody disease is a rare, but well characterized cause of glomerulonephritis. It is defined by the presence of autoantibodies directed at specific antigenic targets within the glomerular basement membrane. This pattern of rapidly progressive glomerulonephritis and alveolar hemorrhage is often referred to as Goodpasture’s syndrome. The prognosis for patients with anti-GBM antibody disease is poor. In Japan, to improve the prognosis of patients with rapidly progressive glomerulonephritis (RPGN), we conducted a nationwide survey of patients with RPGN and investigated the initial symptoms, laboratory findings including renal biopsy findings, treatment methods, and outcomes. Among patients with RPGN, patients with anti-GBM antibody disease were rare: 6.6% (47/715). Alveolar hemorrhage (Goodpasture’s syndrome) was observed in 23.4% of patients with anti-GBM antibody disease. Most patients with anti-GBM antibody disease had renal failure at the time of diagnosis. The mean serum creatinine level of patients with renal-limited anti-GBM antibody disease was 7.07 ± 4.21xa0mg/dl and that of patients with Goodpasture’s syndrome was 7.99xa0±xa04.31xa0mg/dl. The mean level of crescent formation was 78.99xa0±xa023.54% in patients with anti-GBM antibody disease, and a cellular crescent form was observed in 63.2% of those patients. The prognosis for patients with anti-GBM antibody disease is poor; the renal survival rate at 6xa0months after onset was 20.9%, and the mortality at 6xa0months after onset was 23.3%. To improve the prognosis for anti-GBM antibody disease, it may be necessary to detect this disease in the early stages and to treat it without delay.

Tubulointerstitial nephritis and uveitis syndrome associated with hyperthyroidism

We report a 17-year-old male patient with tubulointerstitial nephritis and uveitis (TINU) associated with hyperthyroidism. He presented with a 2-month history of fatigue, loss of appetite, low-grade fever, and a 12-kg weight loss when he was admitted to our hospital. He had iritis, which was complicated by fibrin in the anterior chamber, diagnosed by slit-lamp examination. On laboratory examinations, deteriorated renal function (blood urea nitrogen level was 25.9u2009mg/dl and creatinine level was 2.82u2009mg/dl) and elevated urinary levels of N-acetyl-β-D-glucosaminidase (33.1u2009U/l) and β2-microglobulin (78u2009600u2009µg/l) were observed. Serum thyroid-stimulating hormone (TSH) was undetectable, at less than 0.01u2009µIU/ml, and free triiodothyronine and free thyroxine were elevated, up to 5.23u2009pg/ml and 2.85u2009ng/dl, respectively. The titers of antithyroglobulin and antithyroid microsomal and TSH-receptor antibodies were not elevated. Abdominal and thyroidal ultrasonography showed evident bilateral enlargement of the kidneys and diffuse enlargement of the thyroid gland. Iodine-123 scintigraphy showed low uptake in the thyroid gland. The biopsied renal specimen showed mild edema and severe diffuse infiltration of mononuclear cells and few eosinophils in the interstitium, without any glomerular or vascular abnormalities. Based on the clinical features and pathological findings, a diagnosis of TINU syndrome with associated hyperthyroidism was made. Treatment was started with 30u2009mg/day of prednisolone. The iritis disappeared, and the patients clinical status improved remarkably. This case suggests the possibility of thyroid dysfunction in some patients with TINU syndrome, and we believe thyroid function should be measured in all TINU patients. Moreover, histopathological diagnosis of the thyroid glands before treatment is necessary for TINU patients with thyroid dysfunction.

Vascular endothelial growth factor and soluble fms-like tyrosine kinase-1 in septic shock patients treated with direct hemoperfusion with a polymyxin B-immobilized fiber column.

Abstract:u2002 Sepsis is characterized by a systemic inflammatory response to a microbial pathogen. In sepsis, capillary permeability is a tightly regulated feature of microcirculation in all organ beds and is fundamentally altered. We investigated the vascular endothelial growth factor (VEGF) level as a vascular permeability factor and the soluble fms‐like tyrosine kinase‐1 (Flt‐1) level as an antagonist of the VEGF receptors. Serum VEGF and soluble Flt‐1 levels in 21 patients with septic shock, who were treated with direct hemoperfusion with a polymyxin B‐immobilized fiber column (DHP‐PMX), were measured by enzyme‐linked immunoassay. The VEGF and the soluble Flt‐1 levels were more elevated in patients with septic shock than in controls. Between 14 survivors and 7 non‐survivors, there was no significant difference in VEGF level before the DHP‐PMX therapy, but the soluble Flt‐1 level of survivors was significantly lower than that of non‐survivors. Although there was no significant difference between starting and ending VEGF levels in survivors, in non‐survivors the VEGF level at the end of DHP‐PMX therapy was significantly lower than that at the start. In survivors, the soluble Flt‐1 level at the end of DHP‐PMX therapy was significantly lower than that at the start. On the other hand, in non‐survivors, there was no significant difference between the ending and starting soluble Flt‐1 levels. The soluble Flt‐1 level may be a suitable marker of disease severity and mortality.

Angiopoietin Balance in Septic Shock Patients With Acute Kidney Injury: Effects of Direct Hemoperfusion With Polymyxin B-Immobilized Fiber.

Acute lung injury (ALI) in sepsis is characterized by an increase in microvascular permeability, resulting in pulmonary edema. Several studies have suggested that angiopoietin‐1 and ‐2 play a contributory role in the pathogenesis of ALI. Polymyxin B‐immobilized fiber column hemoperfusion is effective for sepsis‐induced ALI. We investigated the angiopoietin levels before and after direct hemoperfusion with polymyxin B‐immobilized fiber column (PMX) therapy. Enzyme‐linked immunoassay was used to measure the serum angiopoietin‐1 and ‐2 levels in 25 patients with septic shock treated with PMX. Eleven of the 25 patients were diagnosed with ALI. There was a significant positive correlation between the angiopoietin‐1 level and the PaO2/FiO2 ratio, but there was a significant inverse correlation between the angiopoietin‐2 level and the PaO2/FiO2 ratio. The mean angiopoietin‐1 level before PMX therapy in the ALI group was significantly lower and the mean angiopoietin‐2 level was significantly higher than in the non‐ALI group. The mean angiopoietin‐1 level of the ALI patients in response to PMX therapy was increased during PMX therapy, but that of the non‐ALI patients with newly occurring ALI showed a decreased angiopoietin‐1 level. On the other hand, the mean angiopoietin‐2 level of the responders was decreased during PMX therapy, but that of patients with newly occurring ALI showed an increased angiopoietin‐2 level. This result suggested that each angiopoietin‐1 and ‐2 level may play a role in the pathogenesis of ALI and that PMX therapy ameliorates the angiopoietin balance in patients with ALI in sepsis.

Osteomalacia due to Fanconi’s syndrome and renal failure caused by long-term low-dose adefovir dipivoxil

To the Editor Acquired Fanconi’s syndrome is a disorder of the proximal tubules and causes hypophosphatemic osteomalacia, glucosuria, aminoaciduria and metabolic acidosis. The several causes of adult Fanconi’s syndrome include dysproteinemias, glomerular disease, after acute tubular necrosis, tetracycline, cancer chemotherapy agents and toxins [1]. The acyclic nucleoside phosphonates also cause Fanconi’s syndrome as well as renal damage. Among them, adefovir dipivoxil is often used to treat lamivudine-resistant hepatitis B and its nephrotoxicity is dose dependent. Therefore, low-dose use of this drug is recommended to avoid renal tubular damage. Here, we report a case of osteomalacia due to Fanconi’s syndrome caused by low-dose adefovir. A 56-year-old male with chronic hepatitis B infection was referred to our hospital in July 2011 to investigate the cause of renal impairment. He also had a history of cirrhosis and hepatocellular carcinoma. Adefovir at 10 mg a day had been added to lamivudine 100 mg a day in 2007 because of lamivudine resistance. Laboratory data on his first visit to our hospital showed elevated serum creatinine (2.23 mg/dL; 0.6–1.1 mg/dL) and low serum uric acid level (2.7 mg/dL; 3.0–7.5 mg/dL). Hemoglobin, serum albumin and platelet count were 12.6, 4.6 g/dL and 10.9 9 10/lL, respectively. C-reactive protein, alanine, aspartate aminotransferase, blood glucose, and serum levels of immunoglobin G, A, M were all normal. Urinalysis showed proteinuria (726 mg/gCre) and glucosuria with phosphaturia and general aminoaciduria. Urinary N-acetylglucosaminidase and b-2 microglobulin were 19.2 U/L (11.5 U/L), and 45942 lg/L (200 lg/L), respectively. Blood gas analysis showed metabolic acidosis. Computed tomography scan of the abdomen showed normal kidney size with some small calcification. From these results, we diagnosed acquired Fanconi’s syndrome in this patient. The patient also had a history of bone pain and waddling gait due to osteomalacia and had been treated by administration of alfacalcidol 3 lg and dibasic calcium phosphate dehydrate. His serum alkaline phosphatase level was elevated to 674 U/L (104–338 U/L), but serum creatine phosphokinase level was normal. At the first visit to our hospital, the reason for his osteomalacia was not clear, but he was diagnosed with osteomalacia associated with Fanconi’s syndrome after renal examination. Concomitant with this diagnosis, we suspected that adefovir was the cause of the Fanconi’s syndrome, and this drug was reduced to three times a week. After reduction of adefovir, his bone pain and waddling gait was alleviated gradually during ambulatory care. Seven months after the reduction, his proteinuria, glucosuria, phosphaturia and general aminoaciduria had disappeared and renal function was improved (serum creatinine was1.5 mg/dL). From these results, we considered that adefovir might be a cause of renal impairment. Several hypophosphatemic osteomalacia cases induced by low-dose adefovir therapy (10 mg daily) have been reported [2, 3]. In previously reported cases, the symptoms H. Shimohata Y. Ogawa K. Hirayama M. Kobayashi (&) Department of Nephrology, Tokyo Medical University Ibaraki Medical Center, 3-20-1 Chuo, Ami, Inashiki, Ibaraki 300-0395, Japan e-mail: masaki-k@tokyo-med.ac.jp

Serum ratio of soluble triggering receptor expressed on myeloid cells-1 to creatinine is a useful marker of infectious complications in myeloperoxidase-antineutrophil cytoplasmic antibody-associated renal vasculitis

BACKGROUNDnThe contribution of infections to the mortality of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis patients is important and should induce early and careful control of these events. However, the differentiation of infection from active vasculitis is often difficult. The usefulness of serum-soluble triggering receptor expressed on myeloid cells-1 (TREM-1) for detecting the presence of infectious complications regardless of disease activity was investigated.nnnMETHODSnSoluble TREM-1 in serum obtained from 41 patients with myeloperoxidase (MPO)-ANCA-associated vasculitis was measured by an enzyme-linked immunosorbent assay. Twenty-nine samples were from active vasculitis patients, 27 samples from inactive vasculitis patients without infection and 17 samples from inactive vasculitis patients with infectious complications. Serum-soluble TREM-1 was also measured in 10 patients with acute pyelonephritis and 30 patients with chronic kidney disease (CKD).nnnRESULTSnThere was a significant correlation between serum levels of soluble TREM-1 and serum creatinine levels among all patients (r = 0.554, P < 0.0001). The serum-soluble TREM-1/creatinine ratio was higher in inactive vasculitis patients with infectious complications than in active vasculitis, inactive vasculitis without infection and CKD patients (P = 0.0005, P < 0.0001 and P < 0.0001, respectively), but not significantly different to that in acute pyelonephritis patients. On receiver-operating-characteristic curve analysis, a lower-limit value of 9.40 ng/mg for this ratio had a sensitivity of 84.6% and a specificity of 90.8% in differentiating patients with infection from those without infection.nnnCONCLUSIONSnThe serum ratio of soluble TREM-1 to creatinine may be a useful marker for detection of infectious complications in MPO-ANCA-associated vasculitis.

Angiopoietin balance in septic shock patients treated by direct hemoperfusion with polymyxin b-immobilized fiber.

Capillary permeability is a tightly regulated feature of microcirculation in all organ beds; however, in sepsis this feature is fundamentally altered. We previously reported elevated levels of vascular endothelial growth factor and its receptor (fms‐like tyrosine kinase‐1) in patients with septic shock, then investigated two kinds of angiopoietins in those patients. An enzyme‐linked immunoassay was used to measure serum angiopoietin‐1 and ‐2 levels in 12 patients with septic shock who were treated by direct hemoperfusion with a polymyxin B‐immobilized fiber column (DHP‐PMX). The angiopoietin‐1 level was lower in patients with septic shock (7.01u2003±u200310.08u2003ng/mL) than in controls (28.24u2003±u200311.61u2003ng/mL, Pu2003<u20030.001), but the angiopoietin‐2 level was higher in septic shock patients (40.83u2003±u200330.13u2003ng/mL vs. 2.47u2003±u20031.78u2003ng/mL, Pu2003<u20030.001). Between seven survivors and five non‐survivors there was no significant difference in angiopoietin‐1 levels before DHP‐PMX therapy. During DHP‐PMX therapy, however, the angiopoietin‐2 level was significantly decreased in survivors (31.52u2003±u200326.15u2003ng/mL vs. 17.32u2003±u200322.46u2003ng/mL, Pu2003=u20030.035). Moreover, at the end of the therapy, the angiopoietin‐1 level was significantly lower in non‐survivors (1.14u2003±u20031.30u2003ng/mL vs. 10.43u2003±u200313.56u2003ng/mL, Pu2003=u20030.042), but the angiopoietin‐2 level in non‐survivors was significantly higher (70.79u2003±u200340.47u2003ng/mL vs. 17.32u2003±u200322.46u2003ng/mL, Pu2003=u20030.019). The angiopoietin‐2 level may be associated with vascular permeability in septic patients, and angiopoietins may be suitable markers of disease severity and mortality.

MafA-deficient and beta cell-specific MafK-overexpressing hybrid transgenic mice develop human-like severe diabetic nephropathy

Transcription factor MafA is a key molecule in insulin secretion and the development of pancreatic islets. Previously, we demonstrated that some of the MafA-deficient mice develop overt diabetes mellitus, and the phenotype of these mice seems to be mild probably because of redundant functions of other Maf proteins. In this study, we generated hybrid transgenic mice that were MafA-deficient and also over-expressed MafK specifically in beta cells (MafA(-/-)MafK(+)). MafA(-/-)MafK(+) mice developed severe overt diabetes mellitus within 5weeks old, and showed higher levels of proteinuria and serum creatinine. Histological analysis revealed that embryonic development of beta cells in the MafA(-/-)MafK(+) mice was significantly suppressed and the reduced number of beta cells was responsible for the early onset of diabetes. Furthermore, after uninephrectomy, these mice demonstrated three characteristics of human diabetic nephropathy: diffuse, nodular, and exudative lesions. MafA(-/-)MafK(+) mice might be a useful model for the analysis of human diabetic nephropathy.

Blood Flow Analysis of the Head and Lower Limbs by the Laser Doppler Blood Flowmeter During LDL Apheresis

Abstract:u2002 The presence of peripheral arterial disease substantially increases the risk for both morbidity and mortality among end‐stage renal disease patients. Low‐density lipoprotein (LDL) apheresis has been also applied for the treatment of peripheral arterial disease to reduce LDL levels, resulting in the improvement of the blood flow to the ischemic limbs. In this study, we investigated the continuous changes of the tissue blood flows in the lower limbs and head during LDL‐apheresis treatment by a non‐invasive method (the non‐invasive continuous monitoring method (NICOMM) system). In this study, the tissue blood flow in both the head and lower limbs showed a significantly enhancement from before to after treatment. The tissue blood flow in the lower limbs showed a significantly larger improvement than that in the head. The short‐term effects of LDL apheresis were confirmed by using the NICOMM system; thus, this system will be useful for the determination of the appropriate schedule of LDL apheresis for long‐term effectiveness.