NT-pro BNP level at dialysis initiation is a useful biomarker for predicting hospitalization for ischemic heart disease.

BACKGROUND: Patients with end-stage kidney disease (ESKD) are at high risk of cardiovascular disease including stroke, heart failure, and ischemic heart disease (IHD). To prevent the occurrence and progression of CVD, a reliable prognostic cardiac biomarker is essential. We investigated the prognostic value of NT-proBNP for each incident type of CVD. METHODS: Male patients from the Ibaraki Dialysis Initiation Cohort (iDIC) study with preserved serum samples from dialysis initiation day (n = 212) were analyzed. Patients were classified into four groups according to quartiles of baseline NT-pro BNP levels. The relationship between NT-proBNP levels at the initiation of dialysis and the subsequent incidence of hospitalization events due to IHD, heart failure, and stroke was analyzed. RESULTS: The incidence rate for hospitalization due to IHD was significantly higher in the highest NT-proBNP category (Log rank p = 0.008); those of stroke and heart failure showed no significant differences among quartiles. Cox proportional hazards regression analysis revealed that serum NT-proBNT was the only prognostic factor for hospitalization for IHD after adjustment by major known IHD risk factors. (HR, 1.008; 95% confidence interval, 1.002-1.014; p = 0.01) The ROC curve analysis for the incidence of hospitalization due to IHD showed that NT-proBNP had an area under the curve (AUC) of 0.759 (95% CI 0.622-0.897; p = 0.004) at a cut-off value of 956.6 pg/mL. CONCLUSION: NT-proBNP measurement at the initiation of dialysis therapy is useful to predict later hospitalization for IHD. TRIAL REGISTRATION: UMIN000010806.

Treatment of Fabry Nephropathy: A Literature Review.

Fabry disease is an X-linked inherited lysosomal storage disorder with a deficiency of α-galactosidase A activity, which results in the intracellular accumulation of globotriaosylceramide (Gb3) and related glycosphingolipids in various organs. Fabry nephropathy is one of the major complications of Fabry disease, and kidney damage is often related to cardiovascular disease and mortality. The treatment of Fabry nephropathy thus helps prolong life expectancy. Two treatment options for Fabry nephropathy and cardiopathy are now commercially available: enzyme replacement therapy (agalsidase α agalsidase ß, and a biosimilar of agalsidase ß) and pharmacological chaperone therapy (migalastat). In this review, we summarize the efficacy of these treatment options for Fabry nephropathy with respect to renal function, proteinuria, and renal pathological findings. We also describe the importance of adjunctive therapy for Fabry nephropathy.

Staphylococcus aureus Infection-Related Glomerulonephritis with Dominant IgA Deposition.

Since 1995, when we reported the case of a patient with glomerulonephritis with IgA deposition that occurred after a methicillin-resistant Staphylococcus aureus (MRSA) infection, many reports of MRSA infection-associated glomerulonephritis have accumulated. This disease is being systematized as Staphylococcus infection-associated glomerulonephritis (SAGN) in light of the apparent cause of infection, and as immunoglobulin A-dominant deposition infection-related glomerulonephritis (IgA-IRGN) in light of its histopathology. This glomerulonephritis usually presents as rapidly progressive glomerulonephritis or acute kidney injury with various degrees of proteinuria and microscopic hematuria along with an ongoing infection. Its renal pathology has shown several types of mesangial and/or endocapillary proliferative glomerulonephritis with various degrees of crescent formation and tubulointerstitial nephritis. IgA, IgG, and C3 staining in the mesangium and along the glomerular capillary walls have been observed on immunofluorescence examinations. A marked activation of T cells, an increase in specific variable regions of the T-cell receptor ß-chain-positive cells, hypercytokinemia, and increased polyclonal immune complexes have also been observed in this glomerulonephritis. In the development of this disease, staphylococcal enterotoxin may be involved as a superantigen, but further investigations are needed to clarify the mechanisms underlying this disease. Here, we review 336 cases of IgA-IRGN and 218 cases of SAGN.

The effect of sodium-glucose cotransporter 2 inhibitor (tofogliflozin) on renal tubular damage in diabetic patients without albuminuria.

PURPOSE: The sodium-glucose cotransporter 2 (SGLT2) inhibitors comprise a new class of glucose-lowering drugs for individuals with diabetes. Large-scale clinical trials indicated that SGLT2 inhibitors have both a cardiovascular-protective and renal-protective effects. A reduction in glomerular hyperfiltration and a decrease in albuminuria are suspected as the main causes of SGLT2 inhibitors' renoprotective effect. The effects of SGLT2 inhibitors on tubular damage in non-albuminuric diabetic patients are unclear. METHODS: The SGLT2 inhibitor tofogliflozin (20 mg, 1 × /day) was orally administered to 14 non-albuminuric diabetic patients. Serum and urine samples were collected at baseline (before) and after the start of tofogliflozin treatment. Hemoglobin A1c, hemoglobin, estimated glomerular filtration rate (eGFR), body weight, and blood pressure (BP) were analyzed as clinical parameters at baseline and 1, 3, and 6 months later. Urinary neutrophil gelatinase-associated lipocalin (NGAL) and N-acetyl-ß-D-glucosaminidase were measured as tubular damage markers and the urinary 8-hidroxydeoxyguanosine (8-OHdG) values were measured as an oxidative stress marker at baseline and at 1 and 3 months. RESULTS: Compared to baseline, the patients' HbA1c values and body weights were significantly decreased post-tofogliflozin administration, and their eGFR values were decreased at 3 months but recovered at 6 months; the hemoglobin concentrations were significantly increased at 3 and 6 months and the urinary NGAL level tended to be decreased at 3 months. No significant changes in blood urea nitrogen, BP, NAG, urine sodium concentration, or urinary 8-OHdG values occurred. The effect of this SGLT2 inhibitor was not influenced by the use of an angiotensin receptor blocker or dipeptidyl-peptidase 4 inhibitor. CONCLUSION: For individuals with non-albuminuric diabetes, tofogliflozin has a good glucose-lowering effect and might have a tubular-protective effect.

LMX1B-associated nephropathy that showed myelin figures on electron microscopy.

The mutation of LIM homeodomain transcription factor LMX1B gene leads to nail-patella syndrome (NPS), which is characterized by dysplastic nails, hypoplastic patellae, iliac horns and nephropathy. The characteristic renal histological finding of NPS nephropathy is irregular thickening of the glomerular basement membrane with patchy lucent areas, including deposits of bundles of type III collagen fibrils revealed by electron microscopy (EM). Fabry disease is a lysosomal storage disorder caused by a deficiency of α-galactosidase A activity, and the characteristic EM finding is a lamellated membrane structure (myelin figures). We present the case of a male with LMX1B-associated nephropathy (LAN) who showed focal segmental glomerulosclerosis (FSGS) on light microscopy, and myelin figures and slight deposits of collagen fibrils on EM, without findings of glomerular basement membrane abnormality suggestive for NPS. A 21-year-old Japanese-Brazilian man was admitted to hospital for an investigation of the cause of proteinuria and decreased renal function. A renal biopsy was performed to investigate the cause of renal damage. Fabry disease was initially considered, based on the presence of myelin figures on EM, but since he had normal α-galactosidase A activity, this initial diagnosis was denied, and the patient was subsequently diagnosed with FSGS. At 22 years after that renal biopsy, the patient was incidentally diagnosed with LAN when NM_002316:3c.746G > A:p.(Arg249Gln) LMX1B variant was identified in his older brother by a pre-transplantation examination, and the same mutation was confirmed in the patient. Myelin figures revealed by EM might become one of the clues for the diagnosis of LAN.

Serum 20S proteasome levels are associated with disease activity in MPO-ANCA-associated microscopic polyangiitis.

BACKGROUND: Proteasomes are found in both the cell nucleus and cytoplasm and play a major role in the ubiquitin-dependent and -independent non-lysosomal pathways of intracellular protein degradation. Proteasomes are also involved in the turnover of various regulatory proteins, antigen processing, cell differentiation, and apoptosis. To determine the diagnostic value of serum proteasome in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), we investigated patients with AAV at various stages of the disease. METHODS: Serum 20S-proteasome was measured by ELISA in 44 patients with MPO-ANCA-associated microscopic polyangiitis (MPA) and renal involvement. Thirty of the patients provided serum samples before the initial treatment, and 30 provided samples during remission; 16 provided samples at both time points. RESULTS: The mean serum 20S-proteasome level was significantly higher in the active-vasculitis patients (3414.6 ± 2738.9 ng/mL; n = 30) compared to the inactive-vasculitis patients (366.4 ± 128.4 ng/mL; n = 30; p <  0.0001) and 40 controls (234.9 ± 90.1 ng/mL; p <  0.0001). There were significant positive correlations between the serum 20S-proteasome level and the Birmingham Vasculitis Activity Score (BVAS) (r = 0.581, p <  0.0001), the ANCA titer (r = 0.384, p <  0.0001), the white blood cell (WBC) count (r = 0.284, p = 0.0042), the platelet count (r = 0.369, p = 0.0002), and the serum C-reactive protein (CRP) level (r = 0.550, p < 0.0001). There were significant negative correlations between the serum 20S-proteasome level and both the hemoglobin concentration (r = - 0.351, p = 0.0003) and the serum albumin level (r = - 0.460, p < 0.0001). In a multiple regression analysis, there was a significant positive correlation between the serum 20S-proteasome level and only the BVAS results (ß = 0.851, p = 0.0009). In a receiver operating curve analysis, the area under the curve for the serum 20S-proteasome level was 0.996, which is higher than those of the WBC count (0.738) and the serum CRP level (0.963). CONCLUSION: The serum level of 20S-proteasome may be a useful marker for disease activity in AAV.

An Adult Patient with Alagille Syndrome Showing Mainly Renal Failure and Vascular Abnormality without Liver Manifestation.

Alagille syndrome is an inherited multisystemic disorder. We herein report an atypical case of a Japanese adult patient with Alagille syndrome. He had been diagnosed with Alagille syndrome as an infant based on a liver biopsy. At 27 years of age, he needed to start hemodialysis therapy, but an arteriovenous fistula was not created because his peripheral blood vessels were too narrow. He also had a recurrent brain infarction due to cerebral vascular stenosis. Alagille syndrome is generally recognized as a pediatric hepatic disease, but general physicians should be aware of its potential existence with renal involvement and vascular abnormalities.

Clinical course and pathological findings of two late-onset Fabry hemizygous patients including mulberry cell counts after enzyme replacement therapy.

Fabry disease is an X-linked inherited lysosomal storage disorder caused by a deficiency of α-galactosidase A activity, resulting in the intracellular accumulation of globotriaosylceramide and related glycosphingolipids. The phenotypes of Fabry disease in both males and females are grouped into two categories: the classical type and the late-onset type. The classical type shows general symptoms including angiokeratoma(s), acroparesthesia, hypohidrosis, corneal opacity, and gastrointestinal symptoms from an early age. The late-onset type shows cardiac or renal (or both) symptoms from a late age. We present herein the clinical course and pathological findings of two late-onset hemizygous Fabry patients after the initiation of enzyme replacement therapy (ERT), along with their mulberry cell counts during treatment. One patient's case was a renal-variant type without general symptoms; he showed stable renal function and mild proteinuria but little histological improvement with no change in the mulberry cell count during ERT. The other patient had a cardiac-variant type with renal pathological abnormality. He achieved a mild improvement of renal pathological findings, and his mulberry cell count gradually decreased during the treatment. These findings indicate that monitoring the mulberry cell count might help assess the efficacy of ERT, as a renal pathology tool.

The relationship between serum magnesium levels and mortality in non-diabetic hemodialysis patients: A 10-year follow-up study.

Introduction Recently, although there are many reports showing that serum magnesium concentration is a predictor of mortality in dialysis patients, the observation periods of those reports were of short duration, typically around 12 months. Thus, we investigated this relationship over a longer follow-up period. Methods This retrospective, observational study included a total of 83 non-diabetic hemodialysis patients. The follow-up period was 120 months. Patients were divided into two groups, those with serum magnesium ≥2.5 mg/dL (Mg ≥2.5 mg/dL group) and serum magnesium <2.5 mg/dL (Mg <2.5 mg/dL group), and Kaplan-Meier analysis and Cox proportional hazards analysis were conducted. In addition to the above analysis, single and multiple regression analysis were performed at baseline to reveal the relationship between serum magnesium and clinical parameters. Findings During the follow-up period, 31 out of 83 patients died. Kaplan-Meier analysis showed a significantly higher incidence of death in the Mg <2.5 mg/dL group (log-rank test 4.951, P = 0.026). Multivariate Cox proportional hazards analysis showed a 62% decreased risk of mortality in the Mg ≥2.5 mg/dL group compared to the Mg <2.5 mg/dL group after adjustment for several confounding factors. Simple correlation coefficient analysis showed positive correlations of serum magnesium levels with serum creatinine, phosphorus, high-density lipoprotein, ankle-brachial index and KT/V, and a negative correlation with age. Multiple linear regression analysis showed that the ankle-brachial index was the only parameter that had a positive and significant correlation with the serum magnesium level. Conclusion Our study demonstrated that higher serum magnesium levels were associated with improved survival in non-diabetic hemodialysis patients.

Microscopic polyangiitis associated with thymic tumor: a case report and review of the literature.

BACKGROUND: Thymic hyperplasia and thymic epithelial tumor (thymoma) have been associated with a variety of autoimmune diseases. Renal involvement has been reported in patients with thymoma. Minimal change disease and membranous nephropathy are frequently observed in glomerular lesions of thymoma patients, but ANCA-associated renal vasculitis is rare. We present a case of thymoma-associated microscopic polyangiitis with positivity for three ANCAs: MPO-ANCA, PR3-ANCA and azurocidin-ANCA. CASE PRESENTATION: An 89-year-old Japanese woman was admitted to our hospital following an episode of general fatigue, nausea, muscle weakness of the lower limbs, and ophthalmoplegia. On urinalysis, proteinuria, hematuria, and cellular casts were observed. Elevated levels of serum creatinine and C-reactive protein were also demonstrated, and MPO-, PR3- and azurocidin-ANCA were detected on serological examination. Renal biopsy showed pauci-immune crescentic glomerulonephritis. We therefore diagnosed rapidly progressive glomerulonephritis due to microscopic polyangiitis. Acetylcholine-receptor antibody was also detected. Chest computed tomography and MRI revealed a lobulated tumor in the anterior mediastinum. We thus also diagnosed myasthenia gravis with thymoma. CONCLUSION: Considering the patient's triple-ANCA positivity, thymic diseases may be associated with the pathogenesis of ANCA-associated vasculitis due to central T-cell tolerance. A further accumulation of cases is needed, because thymectomy does not always induce the remission of thymoma-associated autoimmune diseases.

A Case of Proliferative Glomerulonephritis with Monoclonal IgG Deposits That Showed Predominantly Membranous Features.

In 2004, the novel category of monoclonal IgG deposition disease has been proposed and termed "proliferative glomerulonephritis with monoclonal IgG deposits" (PGNMID). This disease is characterized by membranoproliferative glomerulonephritis and staining for a single light-chain isotype and gamma heavy-chain subclass. A 76-year-old male who had monoclonal gammopathy was referred to our hospital because of proteinuria. The renal biopsy showed diffuse thickening of the glomerular capillary walls with focal mesangial proliferation. On immunofluorescence study, only IgG1 among the four subclasses and lambda light chains were detected mainly in the glomerular capillary walls. From these results, we diagnosed our case as PGNMID showing predominantly membranous features. Almost all pathological findings on light microscopy of PGNMID are membranoproliferative GN or endocapillary proliferative GN, while membranous GN cases are rare. Here, we present the case of PGNMID that showed predominantly membranous features on light microscopy.

Urinary mulberry cells and mulberry bodies are useful tool to detect late-onset Fabry disease.

Fabry disease is an X-linked lysosomal storage disorder caused by a lack of α-galactosidase A activity, which leads to the accumulation of globotriaosylceramide in various organs. A complete lack of α-galactosidase A activity in a hemizygous male is the classical phenotype, and some hemizygous males show primarily cardiac and/or renal symptoms that appear in adulthood; this is called the variant type or the late-onset type. The kidney and heart are the major target organs, with damage to these organs related to mortality. Thus, in Fabry patients, early detection and early treatment are critical to longevity. Here, we present a 55-year-old Japanese male patient who was diagnosed with late-onset Fabry nephropathy with cardiomyopathy but with no abnormal urinary findings except for urinary mulberry cells and mulberry bodies. In spite of the absence of abnormal urinary findings, the light microscopic and electron microscopic pathological findings showed extensive deposition of globotriaosylceramide to podocytes. In this paper, we propose that the presence of mulberry cells and mulberry bodies can be used for the earlier detection of Fabry nephropathy, especially the late-onset type.

A Renal Variant of Fabry Disease Diagnosed by the Presence of Urinary Mulberry Cells.

Fabry disease is a lysosomal storage disorder caused by a deficiency of α-galactosidase A. This disease is classified into two types, namely a classical and variant type. We herein present the case of a 36-year-old man who showed a renal variant of Fabry disease and was diagnosed at an early stage by the presence of mulberry cells. He had no history of general symptoms except for proteinuria. The presence of mulberry cells caused us to suspect Fabry disease and he was thereafter diagnosed to have a renal variant of Fabry disease based on the findings of a renal biopsy, a mutation analysis and a low level of α-galactosidase A activity.

Retention of acetylcarnitine in chronic kidney disease causes insulin resistance in skeletal muscle.

Insulin resistance occurs frequently in patients with chronic kidney disease. However, the mechanisms of insulin resistance associated with chronic kidney disease are unclear. It is known that an increase in the mitochondrial acetyl-CoA (AcCoA)/CoA ratio causes insulin resistance in skeletal muscle, and this ratio is regulated by carnitine acetyltransferase that exchanges acetyl moiety between CoA and carnitine. Because excess acetyl moiety of AcCoA is excreted in urine as acetylcarnitine, we hypothesized that retention of acetylcarnitine might be a cause of insulin resistance in chronic kidney disease patients. Serum acetylcarnitine concentrations were measured in chronic kidney disease patients, and were significantly increased with reduction of renal function. The effects of excess extracellular acetylcarnitine on insulin resistance were studied in cultured skeletal muscle cells (C2C12 and human myotubes), and insulin-dependent glucose uptake was significantly and dose-dependently inhibited by addition of acetylcarnitine. The added acetylcarnitine was converted to carnitine via reverse carnitine acetyltransferase reaction, and thus the AcCoA concentration and AcCoA/CoA ratio in mitochondria were significantly elevated. The results suggest that increased serum acetylcarnitine in CKD patients causes AcCoA accumulation in mitochondria by stimulating reverse carnitine acetyltransferase reaction, which leads to insulin resistance in skeletal muscle.

Serum decoy receptor 3 levels are associated with the disease activity of MPO-ANCA-associated renal vasculitis.

Type 17 T-helper (Th17) cells have been suggested to be involved in the pathogenesis of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Th17 cell proliferation is promoted by tumor necrosis factor (TNF)-like ligand 1A (TL1A), which binds to death receptor 3 (DR3) expressed on Th17 cells. Decoy receptor 3 (DcR3) is known to block the TL1A-DR3 pathway by binding TL1A. To evaluate the Th17-TL1A systems as disease activity markers in AAV, we investigated the serum levels of TL1A and DcR3 in AAV patients. Serum IL-17, IL-23, TL1A, and DcR3 were measured by ELISA in 24 AAV patients with microscopic polyangiitis before the initial treatment, 24 AAV patients during remission, and 20 control subjects. There were no significant differences in serum IL-17, IL-23, and TL1A levels among the active-vasculitis patients, inactive-vasculitis patients, and controls. The mean serum DcR3 level was significantly higher in the active-vasculitis patients than in the inactive-vasculitis patients and controls (P < 0.0001, respectively). There were significant positive correlations between the serum DcR3 levels and Birmingham Vasculitis Activity Score (BVAS), myeloperoxidase (MPO)-ANCA titers, white blood cell counts, serum creatinine levels, and serum C-reactive protein levels. In a multiple regression analysis, there was a significant positive correlation between the serum DcR3 level and BVAS (ß = 0.650, P = 0.0462). The mean BVAS level was significantly higher in the active-vasculitis patients with high serum DcR3 levels than in those with the low serum DcR3 levels (P = 0.0202). The serum level of DcR3 may be a useful marker for disease activity in AAV.

Hyperthyroidism associated with obesity-related glomerulopathy-like pathologic features.

Thyroid dysfunction is related to many kidney diseases. We herein present the case of a 39-year-old woman who exhibited obesity-related glomerulopathy-like pathologic features in combination with hyperthyroidism. She displayed hyperthyroidism in spite of receiving anti-thyroid drug treatment, with massive proteinuria (4.5 g/gCr). A renal biopsy demonstrated glomerular hypertrophy (average diameter, 280 µm) and an increased number of capillary vessels, both of which are compatible with a diagnosis of obesity-related glomerulopathy. Following thyroidectomy, the proteinuria gradually decreased in association with an improvement in hyperphagia and normalization of the thyroid function. Obesity-related nephropathy associated with hyperthyroidism is very rare. In this report, we discuss the relationship between hyperthyroidism and obesity-related glomerulopathy-like pathologic features.

Overexpression of Mafb in podocytes protects against diabetic nephropathy.

We previously showed that the transcription factor Mafb is essential for podocyte differentiation and foot process formation. Podocytes are susceptible to injury in diabetes, and this injury leads to progression of diabetic nephropathy. In this study, we generated transgenic mice that overexpress Mafb in podocytes using the nephrin promoter/enhancer. To examine a potential pathogenetic role for Mafb in diabetic nephropathy, Mafb transgenic mice were treated with either streptozotocin or saline solution. Diabetic nephropathy was assessed by renal histology and biochemical analyses of urine and serum. Podocyte-specific overexpression of Mafb had no effect on body weight or blood glucose levels in either diabetic or control mice. Notably, albuminuria and changes in BUN levels and renal histology observed in diabetic wild-type animals were ameliorated in diabetic Mafb transgenic mice. Moreover, hyperglycemia-induced downregulation of Nephrin was mitigated in diabetic Mafb transgenic mice, and reporter assay results suggested that Mafb regulates Nephrin directly. Mafb transgenic glomeruli also overexpressed glutathione peroxidase, an antioxidative stress enzyme, and levels of the oxidative stress marker 8-hydroxydeoxyguanosine decreased in the urine of diabetic Mafb transgenic mice. Finally, Notch2 expression increased in diabetic glomeruli, and this effect was enhanced in diabetic Mafb transgenic glomeruli. These data indicate Mafb has a protective role in diabetic nephropathy through regulation of slit diaphragm proteins, antioxidative enzymes, and Notch pathways in podocytes and suggest that Mafb could be a therapeutic target.

Human parvovirus B19-induced acute glomerulonephritis: a case report.

Human parvovirus B19 (HPV B19) infection is well known as a cause of erythema infectiosum in children. Acute glomerulonephritis due to HPVB19 infection is rarely observed in adults. Here, we present the case of a 45-year-old female who showed acute glomerulonephritis induced by HPVB19 infection with various autoantibodies. She had proteinuria (175 mg/g creatinine) and hematuria (20-29 erythrocytes per high-power field) in a urinalysis, and various autoantibodies such as antinuclear antibodies, proteinase-3-antineutrophil cytoplasmic antibodies (PR3-ANCA), antiglomerular basement membrane (GBM) antibodies, and anticardiolipin antibodies in a blood examination. A renal biopsy showed that endocapillary proliferative glomerulonephritis comprised of mononuclear cell infiltration. By using immunofluorescence microscopy, IgG, IgA, IgM, C3, C4, and C1q deposits were detected mainly in glomerular capillaries. Electron-dense deposits were detected in the subendothelial area and mesangial area by using electron microscopy. All symptoms and abnormal laboratory data were self-improved. Our patient's case may provide a clue to the etiology of ANCA-associated vasculitis or lupus nephritis.

A case of focal segmental glomerulosclerosis with myeloid bodies.

The presence of myeloid bodies in electron microscopy is a characteristic finding of Fabry's disease. Here, we present a male patient, whose renal biopsy findings suggested the coexistence of focal segmental glomerulosclerosis and Fabry's disease, because of the presence of segmental hyalinosis and/or sclerosis in glomeruli and myeloid bodies in electron microscopy. But finally, Fabry's disease was excluded as a diagnosis because the α-galactosidase A activity in leukocyte and plasma in this patient was within normal limits. After renal biopsy, although he received medication including steroid therapy, his renal function gradually decreased to end-stage renal failure and hemodialysis was initiated. Until now, he does not exhibit any specific symptoms. In conclusion, our case suggests that occasional myeloid bodies in renal biopsy specimens should be interpreted with caution.