Pharmacokinetics and Pharmacodynamics of Luseogliflozin, a Selective SGLT2 Inhibitor, in Japanese Patients With Type 2 Diabetes With Mild to Severe Renal Impairment.

This open-label, parallel-group, multicenter study aimed to assess the effects of renal impairment on the pharmacokinetics, pharmacodynamics, and safety of luseogliflozin. A single 5-mg dose of luseogliflozin was administered to Japanese patients with type 2 diabetes mellitus in the following groups: G1, normal renal function; G2, mild renal impairment; G3a, mild to moderate impairment; G3b, moderate to severe impairment; G4, severe impairment, based on estimated glomerular filtration rate (eGFR; ≥90, 60-89, 45-59, 30-44, 15-29 mL/min/1.73 m2 , respectively). While luseogliflozin pharmacokinetics were similar for patients across all renal function groups, the increase in plasma concentration was slightly slower and maximum concentration was slightly reduced in the lower eGFR groups compared with the other groups. However, luseogliflozin pharmacodynamics were affected by the severity of renal impairment. Urinary glucose excretion (UGE) increased in all groups relative to baseline levels, but the degree of UGE increase was smaller in the lower eGFR groups. Moreover, plasma glucose AUC changes from baseline tended to be smaller in the lower eGFR groups. No clear trends were observed between eGFR and incidence, type, or severity of adverse events. Thus, luseogliflozin administration should be carefully considered, as patients with renal impairment may show an insufficient response to treatment.

Conditional Deletion of Smad1 Ameliorates Glomerular Injury in Progressive Glomerulonephritis.

Matrix expansion and cell proliferation are concomitantly observed in various glomerular injuries. However, the molecular mechanisms responsible for these changes have not been fully elucidated. We have reported that Smad1 is a key signalling molecule that regulates the transcription of type IV collagen (Col4) in mesangial matrix expansion and is thereby involved in glomerular injury in an acute model of glomerulonephritis. In this study, we addressed the role of Smad1 signalling in accelerated nephrotoxic nephritis (NTN), a model of progressive glomerulonephritis, using conditional deletion of Smad1 in Rosa26CreERT2 mice (Smad1-CKO). Mesangial matrix expansion in the Smad1-CKO mice with NTN was significantly inhibited compared with that in wild type mice with NTN, which was consistent with the decrease in Col4 expression level. On the other hand, STAT3 activation and cell proliferation were not influenced by Smad1 deletion in the NTN model. Therefore, we investigated another factor that activates cell proliferation in the absence of Smad1. Id2 induced VEGF secretion and subsequent STAT3 activation, independently of Smad1 expression in mouse mesangial cells. Here we show that Smad1 plays an important role in the development of glomerular injury without affecting cell proliferation, in progressive glomerulonephritis.

Adjusting the 17ß-Estradiol-to-Androgen Ratio Ameliorates Diabetic Nephropathy.

Diabetes is manifested predominantly in males in experimental models, and compelling evidence suggests that 17ß-estradiol (E2) supplementation improves hyperglycemia in humans. We previously generated a severely diabetic transgenic (Tg) mouse model by ß-cell­specific overexpression of inducible cAMP early repressor (ICER) and found that male but not female ICER-Tg mice exhibit sustained hyperglycemia and develop major clinical and pathologic features of human diabetic nephropathy (DN). Thus, we hypothesized that differences in circulating hormone levels have a key role in determining susceptibility to diabetes. Here, we examined whether DN in male ICER-Tg mice is rescued by adjusting the androgen-to-E2 ratio to approximate that in normoglycemic female ICER-Tg mice. We treated hyperglycemic male ICER-Tg mice with orchiectomy (ORX), E2 pellet implantation, or both. E2 pellet implantation at an early stage of DN with or without ORX caused a rapid drop in blood glucose and a dramatic increase in ß-cell number, and it markedly inhibited DN progression [namely, E2 reduced glomerulosclerosis, collagen 4 deposition and albuminuria, and prevented hyperfiltration]. Furthermore, E2 pellet implantation was more effective than ORX alone and induced a remarkable improvement, even when initiated at advanced-stage DN. In contrast, induction of normoglycemia by islet transplant in ICER-Tg mice eliminated albuminuria but was less effective than E2 + ORX in reducing glomerulosclerosis, collagen 4 deposition, and hyperfiltration. These findings indicate that E2 treatment is effective, even after establishment of DN, whereas glucose normalization alone does not improve sclerotic lesions. We propose that E2 intervention is a potential therapeutic option for DN.

Molecular Markers of Tubulointerstitial Fibrosis and Tubular Cell Damage in Patients with Chronic Kidney Disease.

In chronic kidney disease (CKD), progressive nephron loss causes glomerular sclerosis, as well as tubulointerstitial fibrosis and progressive tubular injury. In this study, we aimed to identify molecular changes that reflected the histopathological progression of renal tubulointerstitial fibrosis and tubular cell damage. A discovery set of renal biopsies were obtained from 48 patients with histopathologically confirmed CKD, and gene expression profiles were determined by microarray analysis. The results indicated that hepatitis A virus cellular receptor 1 (also known as Kidney Injury Molecule-1, KIM-1), lipocalin 2 (also known as neutrophil gelatinase-associated lipocalin, NGAL), SRY-box 9, WAP four-disulfide core domain 2, and NK6 homeobox 2 were differentially expressed in CKD. Their expression levels correlated with the extent of tubulointerstitial fibrosis and tubular cell injury, determined by histopathological examination. The expression of these 5 genes was also increased as kidney damage progressed in a rodent unilateral ureteral obstruction model of CKD. We calculated a molecular score using the microarray gene expression profiles of the biopsy specimens. The composite area under the receiver operating characteristics curve plotted using this molecular score showed a high accuracy for diagnosing tubulointerstitial fibrosis and tubular cell damage. The robust sensitivity of this score was confirmed in a validation set of 5 individuals with CKD. These findings identified novel molecular markers with the potential to contribute to the detection of tubular cell damage and tubulointerstitial fibrosis in the kidney.

Japan Renal Biopsy Registry and Japan Kidney Disease Registry: Committee Report for 2009 and 2010.

The Japan Renal Biopsy Registry (J-RBR) was started in 2007 and the Japan Kidney Disease Registry (J-KDR) was then started in 2009 by the Committee for Standardization of Renal Pathological Diagnosis and the Committee for the Kidney Disease Registry of the Japanese Society of Nephrology. The purpose of this report is to describe and summarize the registered data from 2009 and 2010. For the J-KDR, data were collected from 4,016 cases, including 3,336 (83.1 %) by the J-RBR and 680 (16.9 %) other cases from 59 centers in 2009, and from 4,681 cases including 4,106 J-RBR cases (87.7 %) and 575 other cases (12.3 %) from 94 centers in 2010, including the affiliate hospitals. In the J-RBR, 3,165 native kidneys (94.9 %) and 171 renal grafts (5.1 %) and 3,869 native kidneys (94.2 %) and 237 renal grafts (5.8 %) were registered in 2009 and 2010, respectively. Patients younger than 20 years of age comprised 12.1 % of the registered cases, and those 65 years and over comprised 24.5 % of the cases with native kidneys in 2009 and 2010. The most common clinical diagnosis was chronic nephritic syndrome (55.4 % and 50.0 % in 2009 and 2010, respectively), followed by nephrotic syndrome (22.4 % and 27.0 %); the most frequent pathological diagnosis as classified by the pathogenesis was IgA nephropathy (31.6 % and 30.4 %), followed by primary glomerular diseases (except IgA nephropathy) (27.2 % and 28.1 %). Among the primary glomerular diseases (except IgA nephropathy) in the patients with nephrotic syndrome, membranous nephropathy was the most common histopathology in 2009 (40.3 %) and minor glomerular abnormalities (50.0 %) were the most common in 2010 in native kidneys in the J-RBR. Five new secondary and longitudinal research studies by the J-KDR were started in 2009 and one was started in 2010.

Renal disease in the elderly and the very elderly Japanese: analysis of the Japan Renal Biopsy Registry (J-RBR).

BACKGROUND AND OBJECTIVES: Data regarding renal disease in the elderly (age ≥65 years old) and very elderly (age ≥80 years old) Japanese are extremely limited. The aim of this study was to examine the causes of renal disease and their clinical presentations in elderly patients who underwent renal biopsy. DESIGN, SETTING, PARTICIPANTS, AND MEASUREMENTS: From July 2007 to November 2011, all of the elderly native renal biopsy patients who had been registered in the Japan Renal Biopsy Registry (J-RBR; 2802 including 1596 males and 1206 females) were identified. Their data were compared with a control group of 7416 patients who ranged in age from 20 to 64 years old and were registered on the J-RBR over the same period. In addition, the clinical and pathological classifications of 276 very elderly patients were also analyzed. RESULTS: The indications for biopsy were nephrotic syndrome (NS) in 36.2 and 50.7 % of the elderly and the very elderly patients, chronic nephritic syndrome in 31.8 and 17.4 %, and acute kidney injury including rapidly progressive glomerulonephritis in 18.6 and 22.5 %, respectively. Primary glomerular disease was the most frequent diagnosis, followed by MPO-ANCA-positive nephritis, IgA nephropathy (IgAN), and diabetic nephropathy. In primary GN including IgAN, membranous nephropathy (MN) was the most frequent histological type, followed by IgAN and minor glomerular abnormalities. A comparison with the control group showed that MN, MPO-ANCA-positive nephritis, and amyloid nephropathy were more common in the elderly (P < 0.001), and IgAN was less common (P < 0.001). As for nephrotic syndrome in the elderly, MN was the most common histological type, followed by minimal change NS, diabetic nephropathy, amyloid nephropathy, and focal segmental glomerulosclerosis. There was a significant discrepancy between the urinary protein/creatinine ratio and daily proteinuria after the 7th decade of life. CONCLUSIONS: Renal biopsy is a valuable diagnostic tool, even in elderly and very elderly Japanese patients. In the future, modified clinical guidelines for elderly renal disease should be developed.

Serial renal biopsy findings in a case of POEMS syndrome with recurrent acute renal failure.

This report describes a patient presenting with recurrent acute renal failure occurring in the course of POEMS syndrome, a multisystem disease associated with plasma cell dyscrasia. Several combined immunosuppression therapies failed to resolve recurrent acute renal failure; autologous peripheral blood stem cell transplantation was therefore applied. A renal biopsy was performed on each of four occasions when he developed renal dysfunction. The renal biopsy showed typical renal histology of POEMS, membranoproliferative glomerulonephritis-like lesions and narrowing of vessel lumina of various sizes caused by endothelial injury, which progressed to glomerulosclerosis and vessel occlusion. Recurrent acute renal failure might be caused by ischemia due to arterial occlusion. Serum levels of vascular epithelial growth factor (VEGF), which is considered to be a causative factor of endothelial lesions in POEMS syndrome, were not elevated throughout the course of this case.

Dysfunction of fibroblasts of extrarenal origin underlies renal fibrosis and renal anemia in mice.

In chronic kidney disease, fibroblast dysfunction causes renal fibrosis and renal anemia. Renal fibrosis is mediated by the accumulation of myofibroblasts, whereas renal anemia is mediated by the reduced production of fibroblast-derived erythropoietin, a hormone that stimulates erythropoiesis. Despite their importance in chronic kidney disease, the origin and regulatory mechanism of fibroblasts remain unclear. Here, we have demonstrated that the majority of erythropoietin-producing fibroblasts in the healthy kidney originate from myelin protein zero-Cre (P0-Cre) lineage-labeled extrarenal cells, which enter the embryonic kidney at E13.5. In the diseased kidney, P0-Cre lineage-labeled fibroblasts, but not fibroblasts derived from injured tubular epithelial cells through epithelial-mesenchymal transition, transdifferentiated into myofibroblasts and predominantly contributed to fibrosis, with concomitant loss of erythropoietin production. We further demonstrated that attenuated erythropoietin production in transdifferentiated myofibroblasts was restored by the administration of neuroprotective agents, such as dexamethasone and neurotrophins. Moreover, the in vivo administration of tamoxifen, a selective estrogen receptor modulator, restored attenuated erythropoietin production as well as fibrosis in a mouse model of kidney fibrosis. These findings reveal the pathophysiological roles of P0-Cre lineage-labeled fibroblasts in the kidney and clarify the link between renal fibrosis and renal anemia.

An autopsy case of mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) with intestinal bleeding in chronic renal failure.

A 50-year-old man who underwent hemodialysis (HD) at local outpatient HD center due to end-stage renal disease (ESRD) was transferred to our hospital because of pneumonia. He had severe emaciation and past history of congestive heart failure. Presenting symptoms almost consistently involved difficulty in hearing and recurrent attacks of migraine-like headaches. He was diagnosed with dilated cardiomyopathy, showing diastolic mechanical dyssynchrony by tissue Doppler echocardiography. On the day of death, he had hematemesis and hemorrhagic shock. Autopsy revealed perforation of duodenum, and genetic analysis using mitochondrial DNA from cardiac muscle and iliopsoas muscle revealed a 3243A > G mutation in the mitochondrial tRNA(Leu(UUR)) gene, which is related to mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). Multiple organ failure due to the mutation of mitochondrial DNA with gastrointestinal bleeding is not a common.

Durable hematological response and improvement of nephrotic syndrome on thalidomide therapy in a patient with refractory light chain deposition disease.

Light chain deposition disease (LCDD) is a rare disease for which an optimal treatment is not yet available. Here, we report the clinical course of a 32-year-old woman with LCDD who was successfully treated with thalidomide. She presented with nephrotic syndrome. Based on the renal biopsy findings and the presence of monoclonal immunoglobulin light chains in her serum and urine, LCDD was diagnosed. Prednisolone and cytotoxic chemotherapy used for multiple myeloma proved ineffective. We initiated administration of thalidomide (100 mg daily) and dexamethasone (20 mg for 4 days per month). After 8 months of treatment, she achieved complete hematological remission, defined as the disappearance of monoclonal protein and a normalized free light chain ratio, which led to improvement of her renal insufficiency. She has shown sustained hematological and organ response for 31 months with thalidomide therapy. Thus, thalidomide therapy seems to be a promising approach to the treatment of LCDD.

Japan Renal Biopsy Registry: the first nationwide, web-based, and prospective registry system of renal biopsies in Japan.

BACKGROUND: The Committee for the Standardization of Renal Pathological Diagnosis and the Working Group for Renal Biopsy Database of the Japanese Society of Nephrology started the first nationwide, web-based, and prospective registry system, the Japan Renal Biopsy Registry (J-RBR), to record the pathological, clinical, and laboratory data of renal biopsies in 2007. METHODS: The patient data including age, gender, laboratory data, and clinical and pathological diagnoses were recorded on the web page of the J-RBR, which utilizes the system of the Internet Data and Information Center for Medical Research in the University Hospital Medical Information Network. We analyzed the clinical and pathological diagnoses registered on the J-RBR in 2007 and 2008. RESULTS: Data were collected from 818 patients from 18 centers in 2007 and 1582 patients from 23 centers in 2008, including the affiliated hospitals. Renal biopsies were obtained from 726 native kidneys (88.8%) and 92 renal grafts (11.2%) in 2007, and 1400 native kidneys (88.5%) and 182 renal grafts (11.5%) in 2008. The most common clinical diagnosis was chronic nephritic syndrome (47.4%), followed by nephrotic syndrome (16.8%) and renal transplantation (11.2%) in 2007. A similar frequency of the clinical diagnoses was recognized in 2008. Of the native kidneys, the most frequent pathological diagnosis as classified by pathogenesis was immunoglobulin (Ig) A nephropathy (IgAN) both in 2007 (32.9%) and 2008 (30.2%). Among the primary glomerular diseases (except IgAN), membranous nephropathy (MN) was the most common disease both in 2007 (31.4%) and 2008 (25.7%). CONCLUSIONS: In a cross-sectional study, the J-RBR has shown IgAN to be the most common disease in renal biopsies in 2007 and 2008, consistent with previous Japanese studies. MN predominated in the primary glomerular diseases (except for IgAN). The frequency of the disease and the clinical and demographic correlations should be investigated in further analyses by the J-RBR.

Activation of Src mediates PDGF-induced Smad1 phosphorylation and contributes to the progression of glomerulosclerosis in glomerulonephritis.

Platelet-derived growth factor (PDGF) plays critical roles in mesangial cell (MC) proliferation in mesangial proliferative glomerulonephritis. We showed previously that Smad1 contributes to PDGF-dependent proliferation of MCs, but the mechanism by which Smad1 is activated by PDGF is not precisely known. Here we examined the role of c-Src tyrosine kinase in the proliferative change of MCs. Experimental mesangial proliferative glomerulonephritis (Thy1 GN) was induced by a single intravenous injection of anti-rat Thy-1.1 monoclonal antibody. In Thy1 GN, MC proliferation and type IV collagen (Col4) expression peaked on day 6. Immunohistochemical staining for the expression of phospho-Src (pSrc), phospho-Smad1 (pSmad1), Col4, and smooth muscle α-actin (SMA) revealed that the activation of c-Src and Smad1 signals in glomeruli peaked on day 6, consistent with the peak of mesangial proliferation. When treated with PP2, a Src inhibitor, both mesangial proliferation and sclerosis were significantly reduced. PP2 administration also significantly reduced pSmad1, Col4, and SMA expression. PDGF induced Col4 synthesis in association with increased expression of pSrc and pSmad1 in cultured MCs. In addition, PP2 reduced Col4 synthesis along with decreased pSrc and pSmad1 protein expression in vitro. Moreover, the addition of siRNA against c-Src significantly reduced the phosphorylation of Smad1 and the overproduction of Col4. These results provide new evidence that the activation of Src/Smad1 signaling pathway plays a key role in the development of glomerulosclerosis in experimental glomerulonephritis.

[Case of kidney failure with thrombotic microangiopathy lesions in renal biopsy caused by accelerated hypertension in young adult].

A 19-year-old male was admitted to our hospital for the treatment of severe hypertension with renal dysfunction. Two years before admission, his hypertension had been diagnosed as essential hypertension based on a series of examinations when his renal function was not impaired. Visits to his primary physician ended when he developed severe hypertension of 210/140 mmHg, at which time renal dysfunction and serum creatinine of 2.25 mg/dL were discovered. Renin and antidiuretic hormone were slightly elevated, but renal artery stenosis or other abnormalities were not detected by magnetic resonance imaging and computer tomography. After the hypertension was controlled by medication, a renal biopsy was performed to assess renal impairment. Histology demonstrated lesions compatible with thrombotic microangiopathy (TMA) and ischemic lesions, including fibrinoid necrosis, intimal thickening, occlusion in the small arteries, wrinkling and duplication of the glomerular basement membrane with microthrombi, and focal interstitial fibrosis. Renal function ameliorated after the hypertension was controlled. This case suggests that severe and accelerated hypertension can cause TMA with renal impairment even in young people.

Angio-embolization of renal artery pseudoaneurysm after renal biopsy: a case report.

Renal artery pseudoaneurysm is a rare clinical entity that has been reported after renal biopsy, percutaneous renal surgery, penetrating trauma, and rarely blunt renal trauma. We present the case of a 37-year-old man with ruptured renal artery pseudoaneurysm accompanied by massive gross hematuria, urinary clot retention, and bladder tamponade, which were the presenting signs seven hours after renal biopsy. Abdominal CT scan showed a large perinephric, intracapsular hematoma of left kidney. His angiogram revealed a left renal segmental artery pseudoaneurysm that measured 1 cm x 1 cm. He was successfully treated by selective embolization of the arterial branch supplying the pseudoaneurysm.

A case of living-related renal transplant from the donor with membranous nephropathy.

INTRODUCTION: When a patient who had renal replacement therapy becomes older, an elder donor candidate may be considered as a potential donor for living-related transplantation. Elder donor candidate might have pre-existing disease including mild renal dysfunction, such as proteinuria. Marginally appropriate donors might be considered for renal graft because of the shortage of donors. A successful outcome after kidney transplantation from a living-related donor diagnosed as membranous nephropathy is reported. CASE REPORT: A 38-yr-old male had been on continuous ambulatory peritoneal dialysis (CAPD) since the age of 37. His 63-yr-old father had mild proteinuria, and had been diagnosed with membranous nephropathy by needle biopsy at the age of 60. However, renal function of the father was found to be stable for three yr in a preoperative examination for donor; the father had normal renal function except for mild proteinuria. After adequate informed consent, we transplanted a kidney from the father, diagnosed with membranous nephropathy, to his son with a cyclosporine A-based immunosuppression regimen. In both the recipient and the donor, postoperative course was stable without complication such as rejection or infection. At 57 months after transplantation, the serum creatine level was 1.7 mg/dL in the recipient and 1.2 mg/dL in the donor. At 39 months after transplantation, allograft needle biopsy showed mild spike formation with partial thickening of the glomerular basement membrane (GBM). Decreases in electron-dense deposits and electron-lucent washout lesions with thickening of the GBM were observed using electron microscopy. This was diagnosed as Stage IV membranous nephropathy, showing clearance of the immune complexes and histological repair of the GBM. CONCLUSION: Donation of the kidney did not affect the residual renal function of the father with membranous nephropathy. Pre-existing membranous nephropathy itself might show remission after transplantation in the recipient. However, long-term careful observation for both the donor and recipient is required.

Acute renal failure after exercise in a Japanese sumo wrestler with renal hypouricemia.

Familial renal hypouricemia is a hereditary disease characterized by extraordinary high renal uric acid clearance and is associated with acute renal failure (ARF). An 18-year-old sumo wrestler developed ARF after anaerobic exercise. Several hours after the exercise, he had a pain in the loins with oliguria, headache, and nausea. On admission, his serum uric acid was decreased despite the elevation of serum creatinine (9.5 mg/dL). The level of creatine kinase was normal and there was no myoglobinuria or urolithiasis. Magnetic resonance imaging showed no significant abnormality. Renal function improved completely within 2 weeks of hydration treatment. After remission, hypouricemia became obvious (1.0 mg/dL) from the initial level of uric acid (6.1 mg/dL) and fractional excretion of uric acid was 49%. Polymerase chain reaction of a urate anion exchanger known to regulate blood urate level (SLC22A12 gene: URAT1) demonstrated that homozygous mutations in exon 4 (W258X). Both parents showed heterozygous mutation of the URAT1 gene, but both siblings showed no mutation. Thus, we describe a Japanese sumo wrestler of familial renal hypouricemia complicated with anaerobic exercise-induced ARF, with definite demonstration of genetic abnormality in the responsible gene, URAT1.

Differential contribution of organic cation transporters, OCT2 and MATE1, in platinum agent-induced nephrotoxicity.

The mechanism of severe nephrotoxicity caused by cisplatin, but not carboplatin, oxaliplatin, and nedaplatin, is not fully understood. The renal accumulation and subsequent nephrotoxicity of platinum agents were examined in rats. Among these four drugs, only cisplatin induced nephrotoxicity at 2 days after its intraperitoneal administration. The urinary activity of N-acetyl-beta-D-glucosaminidase and expression of kidney injury molecule-1 mRNA and osteopontin were markedly enhanced in the cisplatin-treated rats. Although some markers were affected in the rats administered nedaplatin, only minor histological change was observed. The renal accumulation of cisplatin was much greater than that of the other drugs. In the in vitro study, the cellular accumulation of cisplatin and oxaliplatin was stimulated by the expression of rat (r) OCT2. Oxaliplatin was also transported by rOCT3. A luminal H(+)/organic cation antiporter, rMATE1 (multidrug and toxin extrusion) as well as human (h) MATE1 and hMATE2-K, stimulated the H(+)-gradient-dependent antiport of oxaliplatin, but not of cisplatin. Carboplatin and nedaplatin were not transported by these transporters. In conclusion, the nephrotoxicity of platinum agents was closely associated with their renal accumulation, which is determined by the substrate specificity of the OCT and MATE families.

Glomerulonephritis induced by methicillin-resistant Staphylococcus aureus infection that progressed during puerperal period.

A 28-year-old Japanese woman developed fever, leg edema, purpura, and abdominal pain during the puerperal period, showing nephrotic syndrome with microscopic hematuria. At first she was thought to have Henoch-Shönlein purpura nephritis and was given steroids at another hospital. Because anasarca and massive urinary protein excretion developed, she was referred to our hospital. Renal biopsy specimens showed endocapillary proliferative glomerulonephritis with massive IgA and C3d deposition along the capillary loops and in the mesangium. A bacteriological study detected methicillin-resistant Staphylococcus aureus (MRSA) in cultures of vaginal secretions, urine, stool, and pharyngeal mucus samples. Based on the diagnosis of MRSA nephritis, anti-MRSA therapy with antibiotics was started, and MRSA became negative for each culture, and urinary protein decreased. Two months after the first renal biopsy, a second renal biopsy was performed, which revealed feeble endocapillary proliferation with mild IgA and C3d deposition in the mesangium. This case showed that the delivery procedure can cause MRSA nephritis after MRSA infection, and that steroid therapy should be avoided in the early phase of this type of nephritis.

The role of apheresis therapy for ABO incompatible living donor liver transplantation: the Kyoto University experience.

Liver transplantation is a radical surgical therapy for end-stage liver disease. Although in Japan organ transplantation from brain-dead donors (BDD) has been allowed since October 1997, to date, only 29 liver grafts from BDD have been obtained. Thus, most of the liver transplantations carried out use living-donor liver transplantation (LDLT), and BDD liver transplantation is only used in rare cases. In order to carry out LDLT more safely, apheresis (plasmapheresis: PE) plays a major role in our country because of the prevalence of LDLT wherein later re-transplantation is difficult. Thus, because of a limited donor supply and because the needs of patients with end-stage liver disease is critical, use of grafts from ABO-incompatible (ABO-I) donors might be the only available option. From June 1990 to November 2005, 1100 patients underwent 1151 LDLT cases at Kyoto University Hospital. Additionally, 159 LDLT cases (13.8%) received ABO-I living-donor liver grafts. The role of apheresis in ABO-I LDLT is the reduction of antibody titers such as anti-A or anti-B antibody. We carry out preoperative PE as a general rule for ABO-I cases, and the recipient's antibody level against the donor's blood type is decreased to one eighth of the baseline value before LDLT. Until now, baseline immunosuppressive agents included steroids, tacrolimus and cyclophosphamide. At first, splenectomy was carried out during surgery to suppress antibody production, and intraportal (PV) infusion therapy was carried out to control local disseminated intravascular coagulation (DIC) occurring in ABO-I grafts. At that time, three drugs-methylprednisolone, prostaglandin E1 (PGE1), and gabexate mesylate (FOY) were infused continuously for 3 weeks after LDLT. At present, instead of PV infusion therapy, hepatic artery infusion therapy without splenectomy is adopted because of portal thrombosis, and two drugs- methylprednisolone and PGE1- are infused continuously for 3 weeks following LDLT. Recently, we introduced anti-CD20 monoclonal antibody (Rituximab) instead of splenectomy for B cell deletion before ABO-I LDLT. In the present article, we describe the role of apheresis around ABO-I LDLT based on our recent experiences.

IgM-immune complex glomerulonephritis associated with sarcoidosis.

We present a case of proliferative glomerulonephritis with peculiar IgM deposition associated with sarcoidosis. A 62-year-old woman, who had been diagnosed with sarcoidosis 3 years previously because of abnormalities on chest X-ray radiophotographs and lymph node pathology, was admitted to our hospital for the evaluation of proteinuria and microscopic hematuria. Laboratory findings showed renal dysfunction (creatinine clearance, 52 ml/min), a moderate range of urinary protein (1.51 g/day), and increased serum lysozymes (20.7 microg/ml; normal range, 3.4-8.6 microg/ml). Serum calcium level was within the normal range. Renal biopsy revealed immune complex glomerulonephritis (IgM deposition type) with a membranoproliferative pattern, without granuloma or calcium deposition. Corticosteroid (initial dose of prednisolone [PSL], 1 mg/kg per day) was administered, but neither renal function nor urinary protein improved. She then became nephrotic and her renal function gradually deteriorated. To our knowledge, among uncommon glomerulonephritides with sarcoidosis, five cases of immune complex glomerulonephritis with IgM deposition have been reported. Immune complex glomerulonephritis with IgM deposition is unusual and could be related to sarcoidosis; it may be a characteristic pathology which could provide a clue to elucidate the pathogenesis of sarcoidosis.