Kenichi Oohashi

Tocilizumab improves cardiac disease in a hemodialysis patient with AA amyloidosis secondary to rheumatoid arthritis

A 58-year-old Japanese woman on hemodialysis (HD) was admitted for intractable rheumatoid arthritis. Even after HD was started due to end-stage renal failure in 2004, her arthropathy worsened. A soluble tumor necrosis factor receptor inhibitor (etanercept at 25 mg twice weekly), tacrolimus (2 mg daily), and prednisolone (10 mg daily) had been administered since 2005, but high disease activity had persisted. She was admitted to our hospital in July 2007. C-reactive protein (CRP) was 6.8 mg/dL, and the DAS-CRP score was calculated to be 8.3. The cardiothoracic ratio (CTR) was 62% on a chest radiograph, but dialysis hypotension was remarkable. Left ventricular mass (LVM) was calculated as 320 g using echocardiography. Endoscopic biopsy of the stomach and duodenum revealed heavy deposition of AA amyloid. Etanercept was discontinued and tocilizumab was started at a dose of 320 mg (8 mg/kg) monthly. Even after predonisolone and tacrolimus were tapered gradually and discontinued because of her good response, CRP and DAS-CRP became 0.0 mg/dL and 1.5, respectively. In September 2011, re-evaluation was performed. CTR was reduced to 51% and LVM was decreased to 180 g. Endoscopic biopsy of the stomach and duodenum revealed disappearance of AA amyloid. Although AA amyloidosis of the gastrointestinal tract has already been reported to be improved by tocilizumab, this is the first report on improvement of myocardial hypertrophy as well as dialysis hypotension.

Tocilizumab improves systemic rheumatoid vasculitis with necrotizing crescentic glomerulonephritis

Abstract We report a Japanese woman with systemic rheumatoid vasculitis (SRV) complicated by necrotizing crescentic glomerulonephritis (NCGN). Rheumatoid arthritis first occurred at the age of 19 years, followed by interstitial pneumonia, hepatitis, rheumatoid nodules, mononeuritis multiplex, and hypocomplementemia in chronological order. At the age of 51 years, rapidly progressive renal failure occurred with nephrotic proteinuria, and NCGN with subepithelial deposits was revealed by renal biopsy. Severe destructive changes of multiple joints and scleritis were detected, but anti-neutrophil cytoplasmic antibody was negative on enzyme-linked immunosorbent assays and indirect immunofluorescence. SRV was diagnosed due to involvement of multiple extra-articular organs. An anti-interleukin (IL)-6 receptor antibody (tocilizumab) was started at dosage of 280 mg (8 mg/kg) monthly. After 18 months, her serum creatinine decreased from 1.7 to 1.3 mg/dL, and urinary protein excretion declined from 5.2 to 1.2 g daily. Tocilizumab may be a therapeutic option for SRV associated with NCGN.

Destructive Spondyloarthropathy in Patients on Long-Term Peritoneal Dialysis or Hemodialysis.

Destructive spondyloarthropathy (DSA) is the most serious spinal complication of dialysis‐related amyloidosis in patients on long‐term hemodialysis (HD), but we could not find any information about DSA in patients on peritoneal dialysis (PD) for over 10 years. We retrospectively evaluated factors contributing to DSA in HD and PD patients. Sixty‐seven patients on dialysis for 10 to 19 years were compared between a PD group (n = 23) or a HD group (n = 44). In the PD group, nine patients (39%) developed DSA. The mean age of DSA patients was significantly higher than that of non‐DSA patients (66.2 ± 10.0 vs. 51.0 ± 12.8 years, P = 0.03). The frequency of cervical spine DSA did not show any difference between the PD and HD groups, but the frequency of lumbar spine DSA showed a significant difference (22% vs. 5%, P = 0.04). The serum beta‐2 microglobulin (B2MG) level was significantly higher in PD patients than in HD patients (38.4 mg/L vs. 27.4 mg/L, P = 0.0025). Mechanical stress such as elevation of the intra‐abdominal pressure due to infusion of PD fluid (1500 mL to 2000 mL) for over 10 years might contribute to lumbar DSA in patients on long‐term PD.

A case of familial lecithin-cholesterol acyltransferase deficiency on hemodialysis for over 20 years.

We trace the 34-year history of a member of the first Japanese family in which lecithin-cholesterol acyltransferase (LCAT) deficiency was diagnosed. Marriage between cousins with low LCAT activity was responsible for familial LCAT deficiency (FLD). In 1976, a 27-year-old Japanese man was noted to have FLD based on proteinuria, hematuria, grayish corneal opacity and low LCAT activity (9.83%). Genetic analysis showed insertion of G-G-C coding glycine at codon 141. Total cholesterol (C) was low at 108 mg/dl and the ratio of C-ester to total C was very low (12%), while the lecithin (phosphatidylcholine) level was very high (97.3%). When his serum creatinine reached 2.6 mg/dl at the age of 41 years (in 1991), renal biopsy was performed. This showed expansion of the mesangial matrix and irregularly thickened capillary walls with a bubble-like appearance because of lipid deposits consisting of two components (partly lucent vacuolated areas and partly deeply osmiophilic areas). Magnification of the latter deposits showed curvilinear and serpiginous striated membranous structure. Hemodialysis was started in 1990 and has been continued for over 20 years until August 2010. Clinical problems have included AV shunt failure requiring 4 operations and 13 percutaneous transcatheter angioplasty procedures, as well as episodes of hemolytic anemia that subsided after infusion of fresh frozen plasma. Cardiovascular events have not yet occurred, although severe calcification of abdominal aorta has been detected by computed tomography.

What can we learn from a patient on dialysis for 42 years

We performed autopsy on a 60-year-old Japanese man who had received dialysis for 42 years. He started on intermittent peritoneal dialysis in 1968, which was combined with hemodialysis in 1969. His serum calcium-phosphate balance and his blood pressure had been controlled well. Carpal tunnel syndrome occurred in 1984. Then lumbar spinal canal stenosis (SCS) occurred in 1997, followed by cervical SCS in 2000, destructive lumbar spondyloarthropathy (DSA) in 2002, and pathological fracture of the right femoral neck due to an enlarging bone cyst in 2006. All of his surgical specimens showed dialysis-related deposition of beta2MG amyloid (dialysis-related amyloidosis: DRA). Thereafter, lumbar and cervical spinal palsy progressed. In 2009, he developed severe paralytic ileus with dilatation of the sigmoid colon, and subsequently died of peritonitis due to necrotizing cholecystitis. Autopsy showed massive DRA deposits in his intestinal blood vessels and thickened spinal dura, resulting in the above-mentioned intestinal and spinal complications. However, his arterial tree, including the aorta and coronary arteries, showed very little atheroma. Strict control of the Ca-P balance and blood pressure may have prevented cardiovascular disease, while progress in dialysis technology delayed fatal complications of DRA and allowed this patient to survive on dialysis for 42 years.

Intractable membranous lupus nephritis showing selective improvement of subepithelial deposits with tacrolimus therapy: a case report.

A 37-year-old female patient was admitted for evaluation of nephrotic proteinuria refractory to prednisolone and other immunosuppressants in 2004. On admission, urinary protein loss was 16 g/d. Anti-ds DNA antibody was positive and hypocomplementemia was detected. Renal biopsy revealed membranous lupus nephritis. Because 5 cyclophosphamide pulse therapies did not have an effect, tacrolimus was started at 3 mg daily. Proteinuria decreased to 4.8 g/d after 5 months and was < 0.1 g/d in 2009, but antids DNA antibody remained positive and hypocomplementemia persisted. Repeat renal biopsy revealed thinning of the glomerular capillary walls and disappearance of subepithelial electron-dense deposits. However, the subendothelial and mesangial deposits were unchanged. In this patient, proteinuria refractory to various immunosuppressants including cyclosporine A improved after administration of tacrolimus, and selective disappearance of subepithelial deposits was seen histologically. This is the first histological evidence that tacrolimus therapy may cause removal of subepithelial deposits, which are separated from the circulation by the glomerular basement membrane. This finding is supported by experimental data that tacrolimus selectively block the binding of FK-binding protein 12 to transient receptor potential-cation channel 6, resulting in normalization of affected podocytes.