Novel α-Galactosidase A Mutation (K391E) in a Young Woman With Severe Cardiac and Renal Manifestations of Fabry Disease.

Fabry disease, an X-linked lysosomal storage disorder due to α-galactosidase A deficiency, is associated with dysfunction of various cell types and results in a systemic vasculopathy. We describe a 29-year-old woman with Fabry disease presenting with severe cardiac and renal manifestations. Gene analysis demonstrated a novel mutation (K391E) in the GLA gene. Enzyme replacement therapy (ERT) was started with agalsidase-ß after confirming the diagnosis of Fabry disease, resulting in normalization of LV systolic function and improvement of renal function. As early therapy is crucial for preventing life-threatening sequelae, clinicians should consider Fabry disease in young patients presenting with cardiac and renal disease without any likely causes.

Renal thrombotic microangiopathy associated with chronic humoral graft versus host disease after hematopoietic stem cell transplantation.

Thrombotic microangiopathy (TMA) is a known complication of hematopoietic stem cell transplantation (HSCT). The pathogenesis of TMA is controversial but considered to involve various factors such as total body irradiation, use of calcineurin inhibitors for prophylaxis against graft versus host disease (GVHD), viral infection, and GVHD. Herein we describe a case with renal TMA after HSCT, which was probably associated with antibody-mediated endothelial cell injury from chronic GVHD (termed here 'chronic humoral GVHD'). A 49-year-old man presented two years after HSCT with renal dysfunction and proteinuria but without the clinical features of TMA. Histopathological examination of renal biopsy showed chronic glomerular endothelial cell injury with double contour of the glomerular basement membrane, microthrombi and the deposition of complement split product C4d along the glomerular capillaries. Renal tubulitis and peritubular capillaritis were also noted with a multilayered basement membrane and patchy C4d deposition on peritubular capillaries. These findings resemble those of chronic antibody-mediated rejection after kidney transplantation. Furthermore, C4d deposition suggests complement activation. Although circulating anti-blood type and anti-human leukocyte antigen antibodies were not detected, the renal TMA in this case was probably associated with chronic humoral GVHD.

Renal thrombotic microangiopathy associated with chronic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation.

Thrombotic microangiopathy (TMA) is a major complication after hematopoietic stem cell transplantation (HSCT). In this study, we examined the clinical and pathologic features of 2 patients and 5 autopsy cases with HSCT-associated renal TMA to clarify the association between graft-versus-host disease (GVHD) and renal TMA. The median interval between HSCT and renal biopsy or autopsy was 7 months (range 3-42 months). Clinically, acute and chronic GVHD occurred in 7 and 4 patients, respectively. Clinical evidence for TMA was detected in 2 patients, while chronic kidney disease developed in all patients. The main histopathological findings were diffuse endothelial injury in glomeruli, peritubular capillaries (PTCs), and small arteries. In addition, all cases showed glomerulitis, renal tubulitis, and peritubular capillaritis with infiltration of CD3+ T cells and TIA-1+ cytotoxic cells, suggesting that GVHD occurred during the development of TMA. Diffuse and patchy C4d deposition was noted in glomerular capillaries and PTCs, respectively, in 2 biopsy and 2 autopsy cases, suggesting the involvement of antibody-mediated renal endothelial injury in more than 50% of renal TMA cases. In conclusion, the kidney is a potential target of chronic GVHD that may induce the development of HSCT-associated TMA. Importantly, some cases are associated with chronic humoral GVHD.

Effects of selective LDL apheresis on plasma concentrations of ICAM-1, VCAM-1 and P-selectin in diabetic patients with arteriosclerosis obliterans and receiving maintenance hemodialysis.

BACKGROUND: Arteriosclerosis obliterans (ASO) is a serious complication in patients with end-stage renal disease (ESRD) caused by diabetic nephropathy. Adsorption of low-density lipoprotein (LDL) has been performed to treat ASO. While efficacy of this treatment has been reported in limb ischemia, the mechanism underlying the benefit remains unclear. We investigated how LDL adsorption affected soluble adhesion molecules; P-selectin, an endothelial and platelet activation marker; inflammatory cytokines such as interleukin (IL)-1beta, IL-6 and tissue necrosis factor (TNF)-alpha; and lipids in serum. METHODS: Selective LDL adsorption by dextran sulfate columns (LDL apheresis) was performed weekly for 10 weeks to treat eight hemodialysis patients with ASO, ESRD, and type 2 diabetes mellitus. Serum was sampled before and immediately after apheresis. RESULTS: LDL apheresis was performed safely. After LDL apheresis lipid concentrations were significantly reduced and clinical findings, such as Fontaine's classification and ankle brachial pressure index values, were improved. Pretreatment concentrations of soluble intercellular and vascular cell adhesion molecules (sICAM-1 and sVCAM-1) and also P-selectin were higher in patients than healthy controls. After apheresis these decreased, especially P-selectin. IL-1beta, IL-6, and TNF-alpha concentrations before apheresis were similar to those in controls and were unaffected by treatment. CONCLUSION: Effectiveness of LDL apheresis against ASO may involve decreased endothelial cell and platelet activation.

Enzyme replacement therapy for Fabry disease: morphologic and histochemical changes in the urinary sediments.

BACKGROUND: Fabry disease is an X-linked lysosomal storage disease resulting from deficient activity of the enzyme alpha-galacotsidase A. Accumulation of glycosphingolipids, especially globotriaosylceramide, leads to renal damage in Fabry disease. In patients with Fabry disease, the urinary sediment contains excreted glycosphingolipids. With enzyme replacement therapy for Fabry disease now currently available, we examined whether the urinary sediment could be used to noninvasively monitor effectiveness of enzyme replacement therapy. METHODS: Four male patients with hemizygous classical Fabry disease received recombinant alpha-galactsidase A biweekly, and urinary sediments were assessed at 3-month intervals. RESULTS: The morphologic and immunohistochemical changes in urinary sediment at 6 and 18 months suggested that accumulations of glycosphingolipids in renal tissues were cleared by enzyme replacement. CONCLUSION: Examination of urinary sediments could serve as noninvasive monitoring of the effect of therapy in patients with Fabry disease.

Factors influencing outcome in Guillain-Barré Syndrome: comparison of plasma adsorption against other treatments.

OBJECTIVE: This study was performed to evaluate which factors influence the outcome of Guillain-Barré Syndrome (GBS), focusing on the choice of treatments. METHODS: Sixty-three GBS patients were retrospectively studied and the following factors were evaluated: sex, age, days from onset of disease to the start of treatment, severity of symptoms, prior infection, autonomic dysfunction, bulbar palsy, anti-ganglioside antibody, and disease form, as well as the choice of treatment. Plasma adsorption (PA, n=39), plasma exchange (PE, n=14), or immunoglobulin treatment (IVIg, n=10) were performed in this study. Outcomes were evaluated using the functional grading scale (FGS) of Hughes. RESULTS: The number of days needed for one functional grade improvement was significantly longer in the elderly, the severe symptom group, and patients with acute motor axonal form, and days needed for two functional grade improvement was significantly longer in the elderly, patients with autonomic dysfunction, and acute motor axonal form. The choice of treatments (PA, PE, or IVIg) did not significantly influence the outcome as determined by both univariate and multivariate analysis. CONCLUSION: Although patient age, symptoms, and disease form influenced the outcome, treatment methods did not significantly influence the outcome. Since PA does not result in a risk of unknown infection, choosing a PA treatment may be justified, especially for patients (or doctors) who may be anxious about a possibility of unknown infection.

Cardiovascular manifestations of Fabry disease and the novel therapeutic strategies.

Fabry disease is an inherited lysosomal storage disorder characterized by a pathological intracellular glycosphingolipid deposition. The disease is caused by a deficit in the lysosomal enzyme alpha-galatosidase A, the gene for which is located in the X chrosomal region Xq 22. Globotriaosylceramide (Gb3) accumulate progressively in multi-organ vulnerable cells throughout the body, including cardiovascular, renal, and cerebrovascular systems. The present manuscript is to review cardiovascular and renal manifestations of Fabry disease and the new diagnostic procedures for earlier detection and the therapeutic assessments of this disease. We are applying noninvasive cardiovascular and microcirculation analysis methods and novel cardiac biomarkers. Novel therapeutic strategies for this disease have been developing in recent years, which include the clinically introduced enzyme infusion replacement therapy and experimentally developing gene-transfer therapy. We have reported that AAV-mediated muscule-directed gene transfer is very effective for long-term systemic delivery of alpha-gal A (25% of normal mice enzyme activity), resulting in complete clearance of multi-organs Gb3 accumulation. Echocardiographic and immunohistochemical examination demonstrated structural improvement of cardiac hypertrophy. When and to whom the novel therapeutic strategies should be applied to obtain the maximum efficacy and safety remain to be established.

Crossed cerebellar diaschisis in patients with cortical infarction: logistic regression analysis to control for confounding effects.

BACKGROUND AND PURPOSE: Crossed cerebellar diaschisis (CCD) refers to reduced metabolism and blood flow in the cerebellar hemisphere contralateral to a cerebral lesion. Many cortical areas have been reported to cause CCD without consideration of confounding factors. We performed single-photon emission computed tomography (SPECT) in patients with cortical infarction to identify regions independently related to CCD, controlling for possible confounding effects. METHODS: Patients with unilateral cortical infarction (n=113; 75 male, 38 female; mean+/-SD age, 66+/-13 years) underwent SPECT of the brain with N-isopropyl-p-[(123)I]iodoamphetamine ((123)I-IMP). Regional cerebral blood flow was measured autoradiographically. Asymmetry indices (AIs) were calculated on the basis of ratios representing symmetrical regional cerebral blood flow in the cerebellum and 16 cerebral regions. CCD was defined as AI for cerebellum >0.1. AIs for 16 cortical regions were considered for both dichotomous and continuous variables for analysis of CCD occurrence by means of backward logistic regression. RESULTS: For dichotomized variables, hypoperfusion of postcentral (odds ratio [OR]=7.607; 95% CI, 2.299 to 25.174) and supramarginal (OR=3.916; 95% CI, 1.394 to 11.003) regions independently influenced CCD. For continuous variables, hypoperfusion of postcentral (OR=1.044; 95% CI, 1.019 to 1.068) and supramarginal (OR=1.021; 95% CI, 1.001 to 1.041) regions (and, as a negative factor, medial occipital regions; OR=0.942; 95% CI, 0.895 to 0.991) independently influenced CCD. CONCLUSIONS: Many cortical areas apparently do not contribute to CCD. Correspondence of CCD between dichotomized and continuous analyses suggests that location of a lesion, not severity, is the main determinant of CCD.

Blood pressure control in patients with chronic kidney disease.

Chronic kidney disease (CKD) is defined as either kidney damage or an estimated glomerular filtration rate (eGFR) of less than 60 mL/min/1.73 m2 for more than 3 months. Kidney damage is defined as pathological abnormalities or markers of damage, including abnormalities in blood or urine tests or imaging studies. CKD is classified as stage 1 to 5 on the basis of eGFR. Cardiovascular disease (CVD) carries a reciprocal risk of loss of kidney function in patients with chronic kidney disease (CKD) and with the development of kidney disease. CVD is a major cause of morbidity and mortality in patients with CKD. Blood pressure control in patients with CKD aims to prevent CVD and provide renoprotection. The renin-angiotensin system (RAS) is involved in every stage of the progression of CKD and is, therefore, a critical link in the pathologic relationship between hypertension and renal disease. The first-line agents for controlling blood pressure are inhibitors of the RAS: angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers. These agents have been shown to have renoprotective effects in addition to their ability to control blood pressure. In CKD, the target blood pressure is less than 130/80 mm Hg, or 125/75 mm Hg, if amount of urinary protein is more than 1 g/day. To achieve the target blood pressure, other classes of antihypertensive agents, such as diuretics and calcium channel blockers, should be administered in addition to angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers.

A patient with idiopathic cholesterol crystal embolization: effectiveness of early detection and treatment.

A 72-year-old man was admitted to our hospital because of progressive renal dysfunction persisting for 1.5 months. Physical examination showed livedo reticularis of the toes of both feet, peripheral edema, and gait disturbance due to the toe pain. The levels of blood urea nitrogen (50.0 mg/dL) and creatinine (2.81 mg/dL) were elevated, and eosinophilia (10%, 870/µL) was noted. A biopsy of the area of livedo reticularis revealed cholesterin crystals. The patient had not undergone angiography, anticoagulation therapy, or antithrombotic treatment. Idiopathic cholesterol crystal embolization was diagnosed. Transesophageal echocardiography revealed intimal thickening of the aorta and plaque. Oral steroid therapy was started because of the progressive renal dysfunction. After steroid therapy, the symptoms improved. Early diagnosis and treatment are important. Renal dysfunction is a common symptom in elderly patients. Cholesterol crystal embolization should also be considered as a cause of unexplained renal dysfunction, especially in such patients.

Thrombosis in Japanese patients with Fabry disease.

Fabry disease is an X-linked lysosomal storage disease resulting from deficient activity of the enzyme alpha-galactosidase (alpha-Gal) A. It has been postulated that the accumulation of globotriaosylceramide in the endothelial cells of blood vessels may lead to thrombosis of the brain and other tissues. Recently, enzyme replacement therapy (ERT) for Fabry disease is available. A high incidence of thrombotic accidents in Fabry disease has been postulated. However, a systemic study on thrombosis in cases of Fabry disease has not been undertaken. To clarify the incidence of thrombosis in Fabry disease, we screened 65 patients with Fabry disease (49 hemizygotes and 16 heterozygotes) from 39 unrelated Japanese families. We found that ten patients with Fabry disease (7 hemizygous males and 3 heterozygous females) had experienced thrombotic accidents, under 45-years-old in 8 cases. These 10 patients showed the gene mutations of classical Fabry disease. Nine of these thrombotic patients developed brain infarctions, one man who had the complication of recurrent thrombophlebitis, and the remaining woman showed central retinal artery occlusion and thrombophlebitis. We demonstrated a high incidence of thrombosis in Fabry disease (15%). ERT should be performed in patients not only in hemizygous males but also in heterozygous females and started at their early ages.

A case of lupus nephritis with diffuse podocytic infolding into the glomerular basement membrane.

In this manuscript, we describe a case of lupus nephritis with diffuse podocytic infolding in the glomerular basement membrane (GBM). A 23-year-old woman presenting with proteinuria, leukopenia, a high value of antinuclear antibody, and positive for anti-dsDNA and anti-Sm antibodies was diagnosed with systemic lupus erythematosus. A renal biopsy was performed which showed diffuse change in the GBM and focal segmental mesangial hypercellularity under light microscopy. The GBM showed diffuse mild thickening and diffuse irregular stippling (bubble-like appearance) on staining with periodic acid-silver methenamine. However, spike formation was only occasionally seen. An immunofluorescence study was conducted which revealed fine granular deposition of IgG (2+) along the glomerular capillary walls; however, granular deposits of C1q (1+) and C3 (1+) were primarily detected in the mesangial areas. Diffuse irregular GBM thickening with dispersed distribution of microspheres and microtubules was observed using electron microscopy. In addition, these structures were chiefly detected on the epithelial side of the GBM. Since these structures seemed to connect to podocytes, we believed that the formation of these microspheres and microtubules is caused by the infolding of podocytes. This case shows a unique pathological finding, and may belong to a new glomerular disease entity characterized by podocytic infolding. After a renal biopsy, the patient received oral prednisolone 0.8 mg/kg day initially, and her complete remission status continued for 5 years.

Severe thiamine deficiency resulted in Wernicke's encephalopathy in a chronic dialysis patient.

A 64-year-old male patient with diabetic nephropathy had been treated with maintenance hemodialysis therapy for 4 years, and had developed disturbed consciousness. The disturbance was firstly noticed by a primary care doctor who recognized slow responses in conversation. Prior to developing this symptom, the patient had noticed a loss of appetite for about 2 weeks. During a period of observation at an outpatient clinic, the symptoms became worse. He was admitted to a primary care hospital for 10 days, but his consciousness level deteriorated and he became unconscious (JCS 200). About 1 month after the onset of symptoms, the patient was transferred to our hospital. A brain computed tomography (CT) scan and magnetic resonance imaging (MRI) showed typical abnormal lesions in the aquaduct of the midbrain and thalamus, and a diagnosis of Wernicke's encephalopathy was made. In addition, the patient's serum thiamine level was extremely low (7 ng/ml). He received immediate treatment with intravenous thiamine administration (150 mg/day), and this significantly improved his symptoms (JCS 2). Dialysis patients may develop water-soluble vitamin deficiency as a result of the combination of reduced oral intake and increased loss of vitamins into the dialysate. Wernicke's encephalopathy should be considered as one of many causes of disturbed consciousness in hemodialysis patients. A rapid diagnosis and adequate treatment are essential in order to minimize long-term neurological sequelae.

Acute posterior leukoencephalopathy in a patient with nephrotic syndrome.

Reversible posterior leukoencephalopathy syndrome is one of the most serious complications of immunosuppressive therapy. The clinical features include headache, altered mental functioning, seizures, cortical blindness and other visual disturbances, with hypertension. The neuroimaging studies reveal predominant posterior leukoencephalopathy. Usually, antihypertensive therapy and reduction or withdrawal of immunosuppressive agents have been reported to resolve the neurological deficits and imaging abnormalities within a few weeks. We discuss here a 51-year-old woman with nephrotic syndrome who developed acute leukoencephalopathy during combination therapy with prednisolone and cyclosporine. She developed severe headache, visual disturbance, consciousness disturbance, and generalized tonic clonic convulsion. A computed tomography scan (CT) revealed low-density areas in the subcortices of the parietal and occipital lobes. Magnetic resonance imaging (MRI) disclosed a high signal intensity area on T2-weighted images and a low signal intensity area on T1-weighted images in the same lesions. Follow-up brain CT and MRI were performed several times. Three weeks after the first study, these lesions had completely resolved, but she had persistent altered consciousness for more than 1 year.