Koji Tsugawa

Combined therapy of enalapril and losartan attenuates histologic progression in immunoglobulin A nephropathy

Abstract Background : It has been reported that combined therapy of angiotensin converting enzyme inhibitor and angiotensin receptor blocker significantly decreases proteinuria in immunoglobulin A (IgA) nephropathy. However, histologic alterations following the therapy have not been reported.

Expression of mRNA for functional molecules in urinary sediment in glomerulonephritis

Recent studies have suggested that gene expression studies using urinary sediment might be a non-invasive approach to assessing activity and pathogenesis in glomerulonephritis. However, little information is available regarding the mRNA expression patterns of functional molecules, such as T-bet, GATA-3, FOXP3, and retinoic acid-inducible gene-I (RIG-I), in urinary sediment, from patients with immunocomplex-mediated glomerulonephritis. Fourteen lupus nephritis (LN) patients, 13 IgA nephropathy (IgAN) patients, and 12 healthy controls were enrolled in the study. The mRNA expressions of T-bet, GATA-3, FOXP3 and RIG-I in urinary sediment were measured using real time quantitative polymerase chain reaction. We also studied the expression of RIG-I in kidney tissue specimens obtained from LN and IgAN patients. Significant differences in the expression patterns of GATA-3, FOXP3 and RIG-I, and marginal differences in T-bet expression, were observed between the three study groups. Immunofluorescent staining for RIG-I was observed in the tissue specimens from the LN patients, but not in those from the IgAN patients. The mRNA expression patterns of T-bet, GATA-3, FOXP3 and RIG-I in urinary sediment differ according to diagnostic category. These results suggest that the measurement of these target gene expressions might be a useful, non-invasive method for clinical monitoring and studying of pathogenesis in glomerulonephritis.

Treatment of difficult cases of systemic-onset juvenile idiopathic arthritis with tacrolimus

Since a proportion of systemic-onset juvenile idiopathic arthritis (SOJIA) patients continue to require long-term corticosteroid therapy for disease control, an effective and safe therapeutic strategy for controlling the activity of refractory SOJIA remains to be established. We report the efficacy of tacrolimus for the treatment of SOJIA in two patients with refractory SOJIA, one of them showing poor response to cyclosporine A. Tacrolimus might be the treatment of choice in selected patients with refractory systemic-onset juvenile idiopathic arthritis. Further studies to confirm the long-term efficacy and safety of tacrolimus in larger numbers of patients are, however, needed.

Low-dose cyclosporine A in a patient with X-linked immune dysregulation, polyendocrinopathy and enteropathy

Successful treatment with oral low-dose cyclosporine A given as a single daily dose is reported in a Japanese patient with immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome. Immune dysregulation, polyendocrinopathy and enteropathy is a rare and potentially fatal X-linked disease (IPEX, OMIM 304790). It is characterised by multiple autoimmune disorders in infancy, that warrants long-term aggressive immunosuppressive therapy [2, 3,6]; however, prolonged use of immunosuppressants may lead to direct toxicity [3]. We previously reported a Japanese infant with IPEX who presented with a novel mutation of the FOXP3gene [5]. The patient was successfully treated by early initiation of oral low-dose cyclosporine A (CsA) given as a single daily dose combined with low-dose prednisolone; for over 3 years he remained free of the both IPEX signs and therapyrelated toxicity. The patient reported here presented with severe secretory diarrhoea at the age of 2 months, and was diagnosed as having IPEX, based on the duodenal biopsy findings (total villous atrophy with crypt hyperplasia), presence of circulating anti-enterocyte antibody (by the immunohistochemical method using the patient’s serum and normal human ileal tissue: when the patient’s serum or control sera were applied to normal mucosa, only the patient’s serum stained the brush border of ileum epithelial cells) and results of sequence analysis of the FOXP3gene: a novel mutation of T1117G substitution in exon 10 [5]. Complete remission was achieved within a short time following prompt initiation of low-dose CsA (2 mg/kg, single daily dose, initially administered intravenously and later switched to oral administration of Neoral before breakfast), combined with prednisolone (0.5 mg/kg, daily). The peak blood levels of oral CsA (1 h post dosing) were maintained at around 700–800 ng/ml, while the trough blood levels of the drug were less than 25 ng/ml. No extra-intestinal signs were encountered, such as type 1 diabetes mellitus, pancreatitis, thyroiditis, haemolytic anaemia, glomerulonephritis or atopic dermatitis. The patient remained reasonably healthy thereafter and developed well under treatment with low-dose oral CsA given as a single daily dose and prophylactic intravenous gamma-globulin administration (200 mg/kg, administered monthly). The prednisolone dose could eventually be tapered to 0.25 mg/kg, daily.

Interferon (IFN)-Induced Protein 35 (IFI35), a Type I Interferon-Dependent Transcript, Upregulates Inflammatory Signaling Pathways by Activating Toll-Like Receptor 3 in Human Mesangial Cells

Background/Aims: Activation of Toll-like receptor 3 (TLR3) signaling followed by type I interferon (IFN) expression is crucial in antiviral and “pseudoviral” immune reactions in renal mesangial cells (MCs). These reactions are probably involved in the pathogenesis of chronic kidney disease (CKD). However, the role of IFN-induced 35-kDa protein 35 (IFI35), a type I IFN-dependent transcript, in glomerular inflammation is unclear. Here, we aimed to investigate the expression and the role of IFI35 in IFN-β/retinoic acid-inducible gene-I (RIG-I)/CCL5 and IFN-β/melanoma differentiation-associated gene 5 (MDA5)/CXCL10 axes in MCs. Methods: We treated human MCs with polyinosinic-polycytidylic acid (poly IC), an authentic double-stranded RNA, then analysed the IFI35 expression by reverse transcription-polymerase chain reaction and western blotting. To examine the regulation of IFI35 expression, we subjected MCs to RNA interference (siRNA) against IFN-β, RIG-I, and MDA5. Results: Activation of TLR3 by poly IC induces the IFI35 expression in MCs. siRNA against IFN-β inhibited poly IC-induced IFI35 expression. Knockdown of IFI35 resulted in a decrease of poly IC-induced RIG-I and MDA5 protein as well as decreased CCL5 and CXCL10 mRNA and protein expression. However, it did not affect the expression of none of phosphorylated signal transducers or activator of transcription (STAT) 1 protein, or RIG-I and MDA5 in mRNA levels. Conclusion: Regional expression of IFI35 and its dysregulation may be involved in the pathogenesis of glomerular inflammation in CKD.

Long‐term intermittent pulse therapy with mizoribine attenuates histologic progression in young patients with severe lupus nephritis: Report of two patients (Brief Communication)

SUMMARY:  Mizoribine (MZR), a novel selective inhibitor of inosine monophosphate dehydrogenase in the de novo pathway, whose mode of action is very similar to that of mycophenolate mofetil, has been successfully applied without serious adverse effects for the treatment of renal diseases. We have previously reported the efficacy and safety of a new MZR treatment regimen, namely, oral MZR intermittent pulse therapy, which we examined based on the observation that it might show superior efficacy to the conventional daily low‐dose MZR regimen on account of the higher peak serum MZR levels, in selected patients with lupus nephritis. Two Japanese patients with severe lupus nephritis (WHO class IV‐G) who were administered long‐term intermittent MZR pulse therapy, and in whom pre‐ and post‐treatment renal biopsies were reported. Post‐treatment renal biopsy confirmed the marked attenuation of histologic progression by the treatment. These clinical observations may lend further support, from the histologic standpoint, to the efficacy of long‐term MZR intermittent pulse therapy for selected patients with active lupus nephritis.

Acute renal failure with encephalopathy following Salmonella enteritidis infection.

Salmonellosis is one of the major causes of food poisoning in Japan. In general, consumption of food contaminated with non-typhi Salmonella causes acute gastroenterocolitis. However, salmonellosis has also been reported to be associated with development of severe extraintestinal multiorgan complications, including rhabdomyolysis (RM), acute renal failure (ARF), and rarely acute encephalopathy [1–5]. In this paper, we report on a patient with systemic lupus erythematosus (SLE) who developed ARF with suspected acute encephalopathy following Salmonella enteritidis infection. The patient was under treatment with immunosuppressive agents. Since patients with SLE are at an increased risk of severe infections [6], this case report may serve to emphasize the importance of prevention of food poisoning and of advocating appropriate hygienic practice in immunocompromised hosts. A 16-year-old Japanese girl with a 3-year history of SLE with WHO class IV disease was referred to our hospital because of drowsiness and disorientation. Although the SLE activity and serum complement levels were reasonably controlled under maintenance therapy with prednisolone (15 mg/day) and azathioprine (75 mg/day), the patient developed acute severe diarrhea, vomiting, and fever after eating a raw egg. She was admitted to a regional hospital with suspected food poisoning. On admission, her body weight was 36.5 kg, which represented a loss of about 1.5 kg over her previous weight recording. Her blood pressure was decreased to 70/36 mmHg. Laboratory studies revealed the following: peripheral white blood cell (WBC) count 11,200/μl, hemoglobin 13.8 g/dl, hematocrit 39.9%, platelet count 193,000/μl, blood urea nitrogen (BUN) 18.2 mg/dl, creatinine 0.9 mg/dl, and Creactive protein (CRP) 5.4 mg/dl. Despite adequate fluid replacement, the patient developed oliguria, drowsiness, and disorientation. Lumbar puncture revealed clear cerebrospinal fluid (CSF), and further examination of the CSF revealed the following: cell count 1 cell/mm, protein 22 mg/dl, glucose 71 mg/dl, and sterile culture. Emergency cranial computed tomographic and electroencephalographic findings were unremarkable. The BUN and serum creatinine increased to 41.5 mg/dl and 4.7 mg/dl, respectively. In addition, the serum level of creatinine kinase (CK) and urinary level of myoglobin also became markedly elevated to 21,307 IU/l (normal: 12–144 IU/l) and 1,073 ng/ml (normal: 0–70 ng/ml), respectively. A diagnosis of ARF caused by RM associated with some central nervous system (CNS) complication was made, and the patient was transferred to our hospital. Physical examination on admission to our hospital revealed that the patient was drowsy. Her blood pressure was 126/76 mmHg. Laboratory studies revealed the following: WBC count 10,590/μl, hemoglobin 13.9 g/100 ml, hematocrit 38.0%, platelet count 119,000/μl, serum total protein 6.6 g/dl, albumin 3.9 g/dl, BUN 63 mg/dl, creatinine 6.8 mg/dl, sodium 137 mmol/l, potassium 4.3 mmol/l, chloride 97 mmol/l, calcium 6.8 mg/dl, CRP 17.8 mg/dl, and CK 29,484 IU/l. Immunological studies revealed the following: IgG 502 mg/dl, IgA 185 mg/dl, IgM 43 mg/dl, C3 76 mg/dl (normal: 79–152 mg/dl), C4 20 mg/dl (normal: 16–38 mg/dl), and complement hemolytic activity 37.4 U/ml (normal: 23–46 U/ml). The serological test for antinuclear antibody was positive at a titer of 1:320, with a homogeneous pattern. Although the blood culture was negative, the stool culture was positive for Salmonella enteritidis. A search for endotoxin in the blood was negative. The levels of the proinflammatory cytokines, interleukin (IL)-6 and IL-8, were analyzed in the CSF specimen obtained at the onset of the salmonellosis. The CSF levels of both cytokines were significantly elevated: IL-6 328 pg/ml (measured by enzyme immunosorbent assay, normal: less than 4.0 pg/ml) and IL-8 327 pg/ml (measured by enzyme-linked immunosorbent assay, normal: less than 2.0 pg/ml). On the T. Nakahata . K. Tsugawa . H. Tanaka (*) Department of Pediatrics, Hirosaki University School of Medicine, 5 Zaifu-cho, Hirosaki, 036-8562, Japan e-mail: hirotana@cc.hirosaki-u.ac.jp

Leukocytapheresis for the treatment of refractory Henoch-Schönlein purpura resistant to both prednisolone and intravenous immunoglobulin therapy

Henoch–Schönlein purpura (HSP) is a childhood disorder, which is the vasculitis of systemic small vessels of unknown etiology. We encountered the dramatic efficacy of leukocytapheresis in a Japanese girl with refractory HSP resistant to combined prednisolone plus intravenous immunoglobulin therapy administration.

Tacrolimus for the treatment of focal segmental glomerulosclerosis resistant to cyclosporine A

Sir,We read with great interest the article by Loeffler et al. [1]referring to the efficacy of tacrolimus (TL) in children withrefractory nephrotic syndrome (NS). However, there is littlepublished information on TL treatment of childhood focalsegmental glomerulosclerosis (FSGS) [1, 2]. In this letter,we report on two pediatric patients with cyclosporine A(CsA)-resistant FSGS in whom successful and rapid clinicalremission and reduction in the dose of prednisolone (PSL)were achieved following TL treatment.Case 1 A 9-year-old Japanese boy was referred to ourhospital with a 2-month history of unremitting steroid-resistant proteinuria. A percutaneous renal biopsy revealedlesions characteristic of FSGS. Despite aggressive immu-nosuppressive therapy, such as methylprednisolone pulsetherapy (MPT), and therapy with cyclophosphamide(CPM), mizoribine (MZR) and CsA at the dose of5.0 mg/kg daily [3], the heavy proteinuria persisted forthe next 6 months. The trough blood level of CsA remainedbetween 111 and 316 ng/ml. Intermittent low-densitylipoprotein (LDL) apheresis, followed by oral PSL at thedose of 1.0 mg/kg daily in combination with CsA, provedto be partially effective. However, the patient developedsevere steroid toxicity, including obesity, short stature,cataract, and osteoporosis.Case 2 An 11-year-old Japanese girl was brought to aregional hospital with an 8-day history of generalizededema. Urinalysis revealed a urinary protein excretion levelof 1,153 mg/dl without hematuria. A percutaneous renalbiopsy revealed lesions characteristic of FSGS. AlthoughMPT was administered followed by oral PSL combinedwith CsA at the dose of 3.0 mg/kg daily, heavy proteinuriapersisted for the next 4 months. The trough blood level ofCsA remained between 120 and 257 ng/ml. The patient wasthereafter referred to our hospital for further examinations.A second renal biopsy revealed lesions of mild CsA-relatednephrotoxicity in about 5% of the interstitium. Therefore,CsA was stopped and replaced by high-dose intermittentMZR [4]. LDL-apheresis was also initiated, which provedto be partially effective. However, another relapse of heavyproteinuria occurred 6 months after the admission. Thepatient subsequently developed severe steroid-inducedosteoporosis.TL treatment After obtaining approval from the ethicscommittee at our institution, both patients were treatedwith TL. The initial TL dose was 4 mg daily, administeredin two divided dose (0.1 mg/kg in case 1 and 0.08 mg/kg incase 2). Timing of the commencement of TL from the onsetof NS was 3 years in case 1 and 18 months in case 2. Thetrough blood level of TL remained in the range of between4.6 and 13.3 ng/ml in case 1, while in case 2, the troughblood level of TL remained in the range of between 4.3 and6.5 ng/ml, despite the TL dose was subsequently increasedto 6 mg (0.12 mg/kg).

Renal artery thrombosis in a pediatric case of systemic lupus erythematosus without antiphospholipid antibodies

A 13-year-old Japanese boy with an 11-month history of systemic lupus erythematosus (SLE) without antiphospholipid antibodies (APAs) suddenly developed severe hypertension, associated with fever and generalized seizures, and mild abdominal pain. Emergency abdominal computed tomography (CT) confirmed left renal artery thrombosis, and a renal scintiscan revealed reduced blood flow to the left kidney. Promptly instituted intravenous anticoagulant therapy was not effective for controlling the infarction-reduced renal arterial blood supply. Moreover, he developed stupor due to central nervous system (CNS) lupus a week after the occurrence of the hypertensive episode. Finally, a percutaneous transluminal angioplasty successfully relieved the occlusion of the left renal artery at its origin. The CNS lupus was also successfully treated with intravenous methylprednisolone pulse therapy combined with intrathecal methotrexate and dexamethasone. Although it is well known that SLE patients with APAs have a high incidence of thrombotic complications, to date, renal artery thrombosis has rarely been reported in young patients. This APA-negative SLE patient unusually manifested renal thrombosis associated with CNS lupus.