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.

The Immunobiological Agents for Treatment of Antiglomerular Basement Membrane Disease.

Combination therapy with glucocorticoids, cyclophosphamide, and plasmapheresis is recommended as the standard treatment for anti-glomerular basement membrane (anti-GBM) disease, but the prognosis of this disease remains poor. Several immunobiological agents have been administered or are expected to be useful for anti-GBM disease in light of refractory disease or the standard treatments' tolerability. Many data regarding the use of biologic agents for anti-GBM disease have accumulated, verifying the effectiveness and potential of biologic agents as a new treatment option for anti-GBM disease. Tumor necrosis factor (TNF) inhibitors were shown to be useful in animal studies, but these agents have no clinical use and were even shown to induce anti-GBM disease in several cases. Although the efficacy of the TNF-receptor antagonist has been observed in animal models, there are no published case reports of its clinical use. There are also no published reports of animal or clinical studies of anti-B-cell-activating factor, which is a member of the TNF family of agents. Anti-interleukin (IL)-6 antibodies have been demonstrated to have no effect on or to exacerbate nephritis in animal models. Anti-C5 inhibitor was observed to be useful in a few anti-GBM disease cases. Among the several immunobiological agents, only rituximab has been demonstrated to be useful in refractory or poor-tolerance patients or small uncontrolled studies. Rituximab is usually used in combination with steroids and plasma exchange and is used primarily as an alternative to cyclophosphamide, but there is insufficient evidence regarding the efficacy of rituximab for anti-GBM disease, and thus, randomized controlled studies are required.

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.

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.

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.

New onset of immunoglobulin G4-related disease in a patient with relapsing polychondritis.

Relapsing polychondritis (RP) is a rare systemic autoimmune disorder characterized by the episodic and progressive deterioration of cartilage inflammation. Approximately 30% patients with RP have concurrent disease. However, there have been no previous reports of RP complicated by immunoglobulin G4-related disease (IgG4-RD). Here we report the case of a 67-year-old male who developed IgG4-RD approximately 20 years after RP diagnosis. The association between IgG4-RD and RP remains unclear.

The efficacy of a multidisciplinary team approach in critical limb ischemia.

The aim of the present study was to clarify the characteristics of Japanese critical limb ischemia (CLI) patients and analyze the rates of real-world mortality and amputation-free survival (AFS) in all patients with Fontaine stage IV CLI who were treated with/without revascularization therapy by an intra-hospital multidisciplinary care team. All consecutive patients who presented with CLI at Showa University Fujigaoka Hospital between April 2008 and March 2014 were prospectively registered. The intra-hospital committee consisted of cardiologists, plastic surgeons, dermatologists, diabetologists, nephrologists, cardiovascular surgeons, and vascular technologists. The primary endpoint of this study was all-cause mortality and AFS during the follow-up period. The present study included 145 patients with Fontaine stage IV CLI. The mean age was 76.5 ± 10.2 years. The all-cause mortality rate during the follow-up period (15.5 ± 16.1 months) was 21.4 %. The AFS rate during the follow-up period (14.1 ± 16.4 months) was 58.6 %. A multivariate Cox proportional hazards regression analysis found that age >75 years and hemodialysis were significantly associated with all-cause mortality; and that age >75 years, Rutherford 6, and wound infection were significantly associated with AFS. A multidisciplinary approach and comprehensive care may improve the outcomes and optimize the collaborative treatment of CLI patients. However, all-cause mortality remained high in patients with Fontaine stage IV CLI and early referral to a hospital that can provide specialized treatment for CLI, before the occurrence of major tissue loss or infection, is necessary to avoid primary amputation.

Influence of acute kidney injury on the time to complete remission in adult minimal change nephrotic syndrome: a single-centre study.

AIM: Acute kidney injury (AKI) is a common complication of minimal change nephrotic syndrome (MCNS), particularly in adults. We evaluated the prevalence of AKI at the onset of adult MCNS and analyzed the influence of AKI on the duration of achieving complete remission (CR). METHODS: A retrospective, single-centre, dynamic cohort study was conducted with biopsy-proven, first-onset, adult MCNS patients treated with corticosteroids. Fifty-three consecutive patients diagnosed with MCNS from January 2000 to April 2014 were enrolled. Age, gender, daily urinary protein excretion, and serum creatinine levels were measured. To evaluate AKI during induction, we used the Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guidelines for AKI and judged AKI stage according to the fluctuations in serum creatinine levels during the first 4 weeks of starting corticosteroid therapy. RESULTS: Twenty patients (37.7%) met the AKI criteria and all 53 patients achieved CR within 1 year. Kaplan-Meier analysis showed that the median time to CR was significantly longer in patients with AKI than in patients without AKI. Cox proportional hazard analysis showed that the hazard ratio (HR) associated with the presence of AKI for achieving CR within 4 weeks was 0.36 after adjustment for age, gender, serum albumin, daily urinary protein excretion, hypertension, administration of 25% albumin, and methylprednisolone pulse therapy. A graded association was also observed between AKI stage and HR for achieving CR. CONCLUSIONS: The prevalence of AKI is high in adult patients with MCNS during induction therapy. AKI is an independent factor that delays the time to CR.

Absence of mesangial C1q deposition is associated with resolution of proteinuria and hematuria after tonsillectomy plus steroid pulse therapy for immunoglobulin a nephropathy.

INTRODUCTION AND AIMS: Deposition of C1q occurs in 0 to 45% of patients with IgAN. In order to identify whether mesangial C1q deposition in IgAN is a novel marker for the response to tonsillectomy plus steroid pulse therapy (TSP), we studied the association between mesangial C1q deposition in IgAN and the remission rate after TSP therapy for IgAN. METHODS: We conducted a retrospective cohort study at a single Japanese center. We analyzed data on 110 patients diagnosed with IgA nephropathy who received TSP between January 2003 and December 2012. Positive C1q findings were defined as diffuse mesangial C1q deposition. The study outcome was the resolution of abnormal urinary findings and was defined as negative proteinuria and negative occult blood 1 year after steroid pulse therapy. RESULTS: In all enrolled cases, 69 patients (62.7%) went into remission. Ten out of 24 (41.7%) C1q-positive patients experienced remission, and 59 out of 86 (68.6%) C1q-negative patients experienced remission. Multiple logistic regression model analysis showed that the absence of C1q deposition increased the odds ratio for remission (odds ratio 4.41; 95% confidence interval 1.33-15.75, p = 0.017). CONCLUSIONS: These results suggest that the absence of diffuse C1q deposition in the mesangial area of the glomerulus in patients with IgA nephropathy is a positive predictive sign for a response to TSP and is associated with the resolution of urinary abnormalities 1 year after TSP.

Impact of the new risk stratification in the 2011 Japanese Society of Nephrology clinical guidelines for IgA nephropathy on incidence of early clinical remission with tonsillectomy plus steroid pulse therapy.

BACKGROUND: In 2011, the Japanese Society of Nephrology (JSN) published new clinical guidelines for IgA nephropathy (IgAN) with a new risk stratification based on clinical and histological severity. For classification, patients are divided into four groups (low, medium, high, and very high risk). However, differences in responsiveness to each treatment among different groups remain unclear. We evaluate the responsiveness of tonsillectomy plus steroid pulse (TSP) therapy using the new risk stratification. METHODS: We retrospectively reviewed 111 IgAN patients with TSP therapy between January 2003 and January 2013. Study patients were divided into three groups [low- (n = 40), medium- (n = 43) and high-/very high-risk group (n = 28)]. The primary outcome was clinical remission (CR). The observation period was 1 year following tonsillectomy. RESULTS: 57 out of 111 patients (51.4 %) reached CR. The CR incidence was 70.0, 41.9 and 39.3 % (the low-, the medium- and the high-/very high-risk group, respectively). The incidence of CR was significantly higher in the low-risk group (P = 0.013). In a multivariate logistic regression analysis, both the medium- and the high-/very high-risk group showed significantly lower incidence of inducing CR than the low-risk group [(odds ratio 0.324; 95 % confidence interval 0.106-0.939, P = 0.041) (odds ratio 0.239; 95 % confidence interval 0.058-0.910, P = 0.040), respectively]. CONCLUSIONS: The new risk stratification in the 2011 JSN clinical guidelines for IgAN had a positive impact on early CR of TSP therapy.

Reversible posterior leukoencephalopathy syndrome after blood transfusion in a patient with end-stage renal disease.

A 42-year-old female end-stage renal disease (ESRD) patient with reversible posterior leukoencephalopathy syndrome (RPLS) post-transfusion during initiation of hemodialysis is reported. Eleven days after the onset of illness, we diagnosed encephalopathy as a grand mal seizure resulting from diffuse cerebral edema. One reason for the delayed diagnosis was that her symptom, a throbbing headache that occurred during her first dialysis, indicated dialysis disequilibrium syndrome. We must bear in mind that a small amount of transfusion could cause RPLS even during the first dialysis. To our knowledge, this is the first case report on RPLS after blood transfusion in an ESRD patient.