Fumi Kishi

SOX9 protein induces a chondrogenic phenotype of mesangial cells and contributes to advanced diabetic nephropathy.

Diabetic nephropathy (DN) is the most important chronic kidney disease. We previously reported that Smad1 transcriptionally regulates the expression of extracellular matrix in DN. Phenotypic change in mesangial cells (MCs) is a key pathologic event in the progression of DN. The aim of this study is to investigate a novel mechanism underlying chondrogenic phenotypic change in MCs that results in the development of DN. MCs showed chondrogenic potential in a micromass culture, and BMP4 induced the expression of chondrocyte markers (SRY-related HMG Box 9 (SOX9) and type II collagen (COL2)). Advanced glycation end products induced the expression of chondrocyte marker proteins downstream from the BMP4-Smad1 signaling pathway in MCs. In addition, hypoxia also induced the expression of BMP4, hypoxia-inducible factor-1α (HIF-1α), and chondrocyte markers. Overexpression of SOX9 caused ectopic expression of proteoglycans and COL2 in MCs. Furthermore, forced expression of Smad1 induced chondrocyte markers as well. Dorsomorphin inhibited these inductions. Glomerular expressions of HIF-1α, BMP4, and chondrocyte markers were observed in diabetic nephropathy mice. These positive stainings were observed in mesangial sclerotic lesions. SOX9 was partially colocalized with HIF-1α and BMP4 in diabetic glomeruli. BMP4 knock-in transgenic mice showed not only similar pathological lesions to DN, but also the induction of chondrocyte markers in the sclerotic lesions. Here we demonstrate that HIF-1α and BMP4 induce SOX9 expression and subsequent chondrogenic phenotype change in DN. The results suggested that the transdifferentiation of MCs into chondrocyte-like cells in chronic hypoxic stress may result in irreversible structural change in DN.

Dual involvement of growth arrest-specific gene 6 in the early phase of human IgA nephropathy.

Background Gas6 is a growth factor that causes proliferation of mesangial cells in the development of glomerulonephritis. Gas6 can bind to three kinds of receptors; Axl, Dtk, and Mer. However, their expression and functions are not entirely clear in the different glomerular cell types. Meanwhile, representative cell cycle regulatory protein p27 has been reported to be expressed in podocytes in normal glomeruli with decreased expression in proliferating glomeruli, which inversely correlated with mesangial proliferation in human IgA nephropathy (IgAN). Methods The aim of this study is to clarify Gas6 involvement in the progression of IgAN. Expression of Gas6/Axl/Dtk was examined in 31 biopsy proven IgAN cases. We compared the expression levels with histological severity or clinical data. Moreover, we investigated the expression of Gas6 and its receptors in cultured podocytes. Results In 28 of 31 cases, Gas6 was upregulated mainly in podocytes. In the other 3 cases, Gas6 expression was induced in endothelial and mesangial cells, which was similar to animal nephritis models. Among 28 podocyte type cases, the expression level of Gas6 correlated with the mesangial hypercellularity score of IgAN Oxford classification and urine protein excretion. It also inversely correlated with p27 expression in glomeruli. As for the receptors, Axl was mainly expressed in endothelial and mesangial cells, while Dtk was expressed in podocytes. In vitro, Dtk was expressed in cultured murine podocytes, and the expression of p27 was decreased by Gas6 stimulation. Conclusions Gas6 was uniquely upregulated in either endothelial/mesangial cells or podocytes in IgAN. The expression pattern can be used as a marker to classify IgAN. Gas6 has a possibility to be involved in not only mesangial proliferation via Axl, but also podocyte injury via Dtk in IgAN.

An Autopsy Case of Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis, and Stroke-Like Episodes (MELAS) with Intestinal Bleeding in Chronic Renal Failure

Abstract 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 tRNALeu(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.

A case of rapid amelioration of hepatitis C virus-associated cryoglobulinemic membranoproliferative glomerulonephritis treated by interferon-free directly acting antivirals for HCV in the absence of immunosuppressant

Mixed cryoglobulinemic syndrome, which is a systemic vasculitis characterized by the immune complex deposition in small- and medium-sized arteries and most often due to chronic hepatitis C virus (HCV) infection, sometimes clinically manifests as refractory glomerulonephritis or nephritic syndrome. Patients with mixed cryoglobulinemic nephropathy who have a rapidly progressive glomerulonephritis should receive immunosuppressive therapy. After disease stabilization, patients should receive concurrent therapy for the underlying HCV infection. The standard therapy of a chronic HCV infection is IFN monotherapy or IFN combined with ribavirin; however, after the introduction of direct-acting antivirals (DAAs), the standard therapy for patients with HCV genotype 1 has dramatically changed. We report a case of HCV-associated cryoglobulinemic membranoproliferative glomerulonephritis (MPGN) successfully treated by daclatasvir and asunaprevir, which are IFN-free DAAs for HCV, in combination with angiotensin II receptor blocker without immunosuppressive therapy. The patient developed severe nephrotic syndrome with progressive kidney dysfunction. Blood examination revealed a high copy number of HCV-RNA (6.4 log IU/mL, type 1), cryoglobulinemia, paraproteinemia of IgM-κ, and hypocomplementemia. Histological analysis showed MPGN type 1. These findings were compatible with those observed in HCV-associated cryoglobulinemic MPGN. This case offers original evidence for the application of newer generation of IFN-free DAAs in the treatment of HCV-associated cryoglobulinemic nephropathy.

MPO-ANCA-Positive Anti-glomerular Basement Membrane Antibody Disease Successfully Treated by Plasma Exchange and Immunosuppressive Therapy

Anti-glomerular basement membrane (GBM) antibody disease is clinically manifested as rapidly progressive glomerulonephritis (RPGN) with crescentic changes. The renal prognosis is poor. We report here the case of a 61-year-old woman with myeloperoxidase antineutrophil cytoplasmic antibody (MPO-ANCA)-positive anti-GBM antibody disease. This patient was referred to our hospital because of RPGN. Anti-GBM antibody was positive with a titer of 38 EU. The MPO-ANCA titer was 65 EU. Chest imaging examination revealed pulmonary multiple nodules. ANCA-associated vasculitis was suspected. Renal pathology revealed cellular crescents in 13 out of 17 glomeruli. Immunofluorescence with anti-IgG antibody, anti-C3 antibody, and anti-fibrin antibody showed linear staining along the glomerular capillary walls. Based on these findings, the patient was diagnosed with anti-GBM antibody disease. Hemodialysis was started because of uremic syndrome with elevated serum creatinine (6.84 mg/dL). In addition, treatment with plasma exchange using 3.6 L (90 mL/kg) of fresh frozen plasma combined with an oral dose of 40 mg of prednisolone was initiated. Within 3 weeks, both types of autoantibodies became undetectable. Subsequently, this patient achieved dialysis independence and remission of glomerulonephritis. No adverse effects were observed. In patients with MPO-ANCA-positive anti-GBM antibody disease, intensive therapy predominantly with plasma exchange might be operative, even though renal function is less likely to recover.

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 × 1 cm. He was successfully treated by selective embolization of the arterial branch supplying the pseudoaneurysm.

A Case of Lambda Light Chain Non-crystalline Proximal Tubulopathy with IgD Lambda Myeloma

Light Chain Proximal Tubulopathy (LCPT) is a rare form of paraprotein-related kidney disease in which monoclonal free light chains damage the proximal renal tubular epithelial cells. We herein report the case of a 78-year-old woman who presented with anemia and kidney dysfunction. Serum and urine protein electrophoresis analyses revealed a monoclonal IgD and λ free light chains. Proximal tubular injury and the accumulation of λ light chains were found by kidney biopsy. Electron microscopy revealed no organized structure suggestive of crystals. LCPT was caused by IgD lambda myeloma and bortezomib and dexamethasone therapy led to very good partial response (VGPR) without a worsening of the kidney function.

Urinary type IV collagen excretion is involved in the decline in estimated glomerular filtration rate in the Japanese general population without diabetes: A 5-year observational study

Urinary type IV collagen (U-Col4) and albumin excretion is evaluated to monitor the development of diabetic kidney disease. However, U-Col4 excretion in the general population without diabetes has not yet been fully elucidated. In this study, 1067 participants without diabetes and with urinary albumin-creatinine ratio <300 mg/gCr (normo- or microalbuminuria) who underwent an annual health examination in 2004 were enrolled and observed for 5 years. They were divided according to the amount of U-Col4 or urinary albumin excreted. The decline in estimated glomerular filtration rate (eGFR) was calculated. In participants with eGFR ≥80 mL/min, abnormal U-Col4 excretion was indicated as a significant independent risk factor for 10% eGFR change per year, which is one of the prognostic factors for the development of end-stage kidney disease. Moreover, in contrast to urinary albumin excretion, U-Col4 excretion was not related to age or kidney function, suggesting that some individuals with abnormal U-Col4 excretion can have an independent hidden risk for the development of kidney dysfunction. In conclusion, it is important to measure U-Col4 excretion in the general population without diabetes to determine changes in renal features in every individual and help detect future complications such as diabetic kidney disease. If U-Col4 excretion is abnormal, kidney manifestation should be carefully followed up, even if the kidney function and urinalysis findings are normal.

Influential factors on serum albumin concentration in hospitalized chronic kidney disease patients

BACKGROUND Serum albumin concentration (SAC) is a prognostic factor that is affected by many factors such as postural change, liver function and food intake. Chronic kidney disease (CKD) patients excrete proteinuria, have low-protein diet, and receive glucocorticoid therapy. No one has evaluated the most influential factors on SAC in CKD patients. METHODS A retrospective study. Hospitalized CKD patients with less than 1 g/gCreatinine proteinuria receiving glucocorticoid therapy (n=28), with 1 or more g/gCreatinine proteinuria not receiving glucocorticoid therapy (n=36), and with 1 or more g/gCreatinine proteinuria receiving glucocorticoid therapy (n=39) were enrolled. SAC, hemoglobin, proteinuria and blood pressure at the last outpatient check-up before hospitalization, on the second day of hospitalization, at the last laboratory examination before discharge, as well as at the first outpatient follow-up after discharge were analyzed. RESULTS SAC decreased on the second day of hospitalization and increased at the first outpatient follow-up significantly in all groups. Unexpectedly, the change of SAC was irrelevant to the amount of proteinuria. CONCLUSIONS SAC was affected by not only proteinuria, but also postural change, physical activity, and food in CKD patients. SAC should be analyzed by standardizing a patients condition during phlebotomy. J. Med. Invest. 64: 146-152, February, 2017.

Shunt Nephritis and Pyogenic Spondylitis With a Positive PR3-ANCA Associated With Chronically Infected Ventriculoatrial Shunt

INTRODUCTION S hunt nephritis is a rare complication mostly described in the setting of chronic infection of ventriculoatrial (VA) shunts inserted for the treatment of congenital or acquired hydrocephalus. The diagnosis of shunt nephritis is challenging and may be overlooked. We report a case of successfully treated shunt nephritis and pyogenic spondylitis with positive antiproteinase 3 antineutrophil cytoplasmic antibody (PR3-ANCA) in a patient who presented with acute kidney injury.