Th17 Cell Induction by Adhesion of Microbes to Intestinal Epithelial Cells.

Intestinal Th17 cells are induced and accumulate in response to colonization with a subgroup of intestinal microbes such as segmented filamentous bacteria (SFB) and certain extracellular pathogens. Here, we show that adhesion of microbes to intestinal epithelial cells (ECs) is a critical cue for Th17 induction. Upon monocolonization of germ-free mice or rats with SFB indigenous to mice (M-SFB) or rats (R-SFB), M-SFB and R-SFB showed host-specific adhesion to small intestinal ECs, accompanied by host-specific induction of Th17 cells. Citrobacter rodentium and Escherichia coli O157 triggered similar Th17 responses, whereas adhesion-defective mutants of these microbes failed to do so. Moreover, a mixture of 20 bacterial strains, which were selected and isolated from fecal samples of a patient with ulcerative colitis on the basis of their ability to cause a robust induction of Th17 cells in the mouse colon, also exhibited EC-adhesive characteristics.

Manipulating the growth environment through co-culture to enhance stress tolerance and viability of probiotic strains in the gastrointestinal tract.

IMPORTANCE: The viability of probiotics in the human gastrointestinal tract is important, as some reports indicate that the health benefits of live bacteria are greater than those of dead ones. Therefore, the higher the viability of the probiotic strain, the better it may be. However, probiotic strains lose their viability due to gastrointestinal stress such as gastric acid and bile. This study provides an example of the use of co-culture or pH-controlled monoculture, which uses more stringent conditions (lower pH) than normal monoculture to produce probiotic strains that are more resistant to gastrointestinal stress. In addition, co-cultured beverages showed higher viability of the probiotic strain in the human gastrointestinal tract than monocultured beverages in our human study.

The renal pathological findings in Japanese HIV-infected individuals with CKD: a clinical case series from a single center.

BACKGROUND: Chronic kidney diseases (CKD) have emerged as a significant cause of morbidity and mortality in patients infected with human immunodeficiency virus (HIV). However, the detailed study of renal pathological findings currently remains unclear in these Japanese patients. METHODS: A retrospective cohort study was undertaken to investigate renal pathological findings between January 1996 and July 2016. Our study included 20 Japanese HIV-infected patients with CKD; 10 cases had undergone renal biopsies, and 10 cases had undergone autopsies, respectively. Moreover, in the 10 biopsied patients, their clinical courses as well as renal outcomes after renal biopsy were also reviewed. RESULTS: All of the patients had received combination antiretroviral therapy (cART). The 10 biopsy cases (mean age, 54 ± 14 years and duration of cART, 8 ± 5 years) included three cases of diabetic nephropathy (DMN), two of IgA nephropathy, two of cART-induced tubulointerstitial nephritis (TIN), one of minimal change disease, one case of only finding intrarenal arterioles, and one case without abnormal findings. Among those patients, their clinical courses were preferable except for in the DMN cases. In the autopsy cases (mean age, 52 ± 10 years and duration of cART, 5 ± 5 years), no distinct mesangial or membranous abnormalities were detected. Mild to moderate tubulointerstitial atrophies were observed in six cases. Intrarenal arteriosclerosis was identified in nine cases, and the proportion of global glomerulosclerosis seen was 8.4 ± 12.5%/100 glomeruli. CONCLUSION: DMN and cART-induced TIN was noted in the biopsy cases. In the autopsy cases, renal arteriosclerosis, global glomerulosclerosis, and tubulointerstitial atrophy were remarkable. Early diagnosis of kidney diseases should be crucial to introduce optimal management, including controlling rigorous comorbidities and appropriate use of cART, to prevent further progression of CKD.

Histopathological and functional changes in a single-dose model of combretastatin A4 disodium phosphate-induced myocardial damage in rats.

Cardiotoxicity is a concern in the development of microtubule-disassembling agents (MDAs) as vascular-disrupting agents of tumors. This study investigated cardiotoxicity in rats induced by a single-dose of combretastatin A4 disodium phosphate (CA4DP), an MDA and discussed the use of this rat model in nonclinical studies of MDAs. First, CA4DP (120 mg/kg) was administered to rats intravenously, and cardiac histopathology and blood biomarkers were examined after 0.5, 24, and 72 h. Next, CA4DP (120 mg/kg) was administered to rats intravenously, and the electrocardiography and echocardiography results were analyzed. The results showed that at 0.5 h after dosing, plasma creatine kinase (CK), CK-muscle/brain (CK-MB), and fatty acid binding protein 3 levels increased. At 24 h, lactate dehydrogenase (LDH)-1, CK, and CK-MB levels increased, and multifocal vacuolar degeneration of myocardial cells was observed in the apical inner layer. At 72 h, LDH-1 levels were increased, and multifocal myocardial necrosis was observed in the interventricular septum and inner layer of the apex of left ventricular wall. Furthermore, at 0.5 h, heart rate (HR), ejection fraction (EF), and cardiac output (CO) decreased. At 24 h, CO decreased. Finally, at 72 h, HR, EF, and CO decreased, and depression of the T-wave amplitude was observed. In conclusion, myocardial injury, bradycardia, and depressed cardiac function were induced in rats by a single-dose of CA4DP. The lesion distribution and electrocardiographic features suggested that myocardial injury was induced by ischemia. These findings are similar to MDA-induced cardiotoxicity in humans, and this rat model will prove useful in studies of the cardiotoxicity in humans.

Prevalence, incidence and prognosis of chronic kidney disease classified according to current guidelines: a large retrospective cohort study of rheumatoid arthritis patients.

BACKGROUND: The prevalence, incidence and prognosis of chronic kidney disease (CKD) have not been fully understood in rheumatoid arthritis (RA) patients. METHODS: A retrospective cohort study was performed in 1077 RA patients from July 2004 to June 2014. CKD was defined as either proteinuria ≥1+ or estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 or both, according to the current CKD classification with risk categories for future death, end-stage renal disease and cardiovascular disease. The cumulative incidence of mortality and CKD was analyzed using the Kaplan-Meier method. The association of each outcome with known risk factors was analyzed using multivariate Cox proportional hazards regression models. Hazard ratios (HRs) with 95% confidence intervals (CIs) for mortality and incidence of CKD were calculated for estimation. RESULTS: The mean follow-up period was 51.5 ± 39.6 months, and the cumulative mortality was 20.6% over 10 years. The prevalence of any CKD was 24.5% at enrollment. Preexisting CKD was significantly associated with future death [HR 1.64 (95% CI 1.05-2.57)]. This association was the most robust in very-high-risk CKD [HR 4.76 (95% CI 2.24-9.51)]. The cumulative incidence of CKD over time was 59.5% in 813 patients who did not have prior CKD. Aside from the commonly known risk factors, the use of prednisolone and nonsteroidal anti-inflammatory drugs increased the likelihood of death [HR 1.75 (95% CI 1.11-2.79)] and incident CKD [HR 1.44 (95% CI 1.13-1.86)]. CONCLUSIONS: The incidence of CKD increases over time among RA patients and prevalent CKD may be an insidious risk factor linked to increased mortality in RA patients.

Increased non-HDL-C level linked with a rapid rate of renal function decline in HIV-infected patients.

BACKGROUND: The risk of developing CKD is increased in HIV-infected patients; however, the relationship between renal function decline and lipid abnormalities currently remains unclear in these patients. METHODS: A retrospective cohort study was conducted on 661 HIV-infected patients, whose estimated glomerular filtration rates (eGFRs) were consecutively measured over 6 years. The rate of declines in eGFR per year was calculated, with decreases being evaluated using a linear mixed effect model. The distribution of decreases in eGFR ≥ 30 % from baseline during the follow-up period was compared across quartiles of non-high-density lipoprotein cholesterol (HDL-C) levels using the Cochran-Armitage test. A multivariate logistic regression model was built to examine the relationship between dyslipidemia and decreases in eGFR. RESULTS: The prevalence of CKD increased from 8.5 to 21.2 % during the follow-up. The average of 6 annual eGFR decline rates was 2.01 ± 0.09 ml/min/1.73 m2/year, which was more than 6-fold higher than that of age-matched controls. The distribution of decreases in eGFR significantly increased across the quartiles of non-HDL-C (p value for trend = 0.0359). Non-HDL-C levels greater than the median value of the cohort were identified as a significant risk factor for decreased eGFR [odds ratio (95 % confidence interval), 1.77 (1.07-3.00)]. CONCLUSION: Increased non-HDL-C levels are a risk factor for renal function decline in HIV-infected patients.

Combretastatin A4 disodium phosphate-induced myocardial injury.

Histopathological and electrocardiographic features of myocardial lesions induced by combretastatin A4 disodium phosphate (CA4DP) were evaluated, and the relation between myocardial lesions and vascular changes and the direct toxic effect of CA4DP on cardiomyocytes were discussed. We induced myocardial lesions by administration of CA4DP to rats and evaluated myocardial damage by histopathologic examination and electrocardiography. We evaluated blood pressure (BP) of CA4DP-treated rats and effects of CA4DP on cellular impedance-based contractility of human induced pluripotent stem cell-derived cardiomyocytes (hiPS-CMs). The results revealed multifocal myocardial necrosis with a predilection for the interventricular septum and subendocardial regions of the apex of the left ventricular wall, injury of capillaries, morphological change of the ST junction, and QT interval prolongation. The histopathological profile of myocardial lesions suggested that CA4DP induced a lack of myocardial blood flow. CA4DP increased the diastolic BP and showed direct effects on hiPS-CMs. These results suggest that CA4DP induces dysfunction of small arteries and capillaries and has direct toxicity in cardiomyocytes. Therefore, it is thought that CA4DP induced capillary and myocardial injury due to collapse of the microcirculation in the myocardium. Moreover, the direct toxic effect of CA4DP on cardiomyocytes induced myocardial lesions in a coordinated manner.

Serum hepcidin-25 level linked with high mortality in patients with non-Hodgkin lymphoma.

Hepatic hepcidin-25 production is stimulated by systemic inflammation, and it interferes with the body's utilization of iron, leading to anemia. A 1-year prospective study was conducted to elucidate an association of serum hepcidin-25 concentration with mortality in anemic patients with non-Hodgkin lymphoma (NHL). Serum hepcidin-25 levels were measured in 50 NHL patients using liquid chromatography-tandem mass spectrometry. The patients were stratified into a high- and a low-hepcidin-25 group according to the median of serum hepcidin-25 concentrations. Factors associated with hemoglobin (Hb) were determined by multivariate regression analysis, incorporating serum hepcidin-25 and inflammatory markers including ferritin and interleukin-6 (IL-6) as covariates. The association between serum hepcidin-25 and mortality was analyzed using both the Kaplan-Meier method and a multivariate proportional hazards regression model. The median of serum hepcidin-25 concentrations was 49.8 (0.6-269) ng/mL, a level approximately nine times greater than the reference value for healthy individuals. Hb level was significantly lower in the high than in the low-hepcidin-25 group. Serum hepcidin-25 was extracted as the significant factor associated with Hb, but neither ferritin nor IL-6 was. The cumulative mortality was significantly greater in the high than in the low-hepcidin-25 group (56.0 vs. 24.0 %; P = 0.0222). The mortality risk for the presence of high hepcidin-25 was four times greater (hazard ratio [95 % confidence interval]: 3.66 [1.12-16.4]). In conclusion, serum hepcidin-25 levels are elevated in anemic NHL patients, and in this study, the group with higher hepcidin-25 levels manifested advanced anemia and poor survival.

Comparison of cystatin C and creatinine to determine the incidence of composite adverse outcomes in HIV-infected individuals.

BACKGROUND: Cystatin C is an overall biomarker of pathophysiologic abnormalities that accompany chronic kidney disease (CKD). The utility of cystatin C is not fully understood in an HIV-infected population. METHODS: This prospective study investigated 661 HIV-infected individuals for 4 years to determine the incidence of adverse outcomes, including all-cause mortality, cardiovascular disease, and renal dysfunction. The risk of developing the outcomes was discriminated with a 4 color-coded classification in a 3 × 6 contingency table, that combined 3 grades of dipstick proteinuria with 6 grades of estimated glomerular filtration rate (eGFR) calculated using either serum creatinine (eGFRcr) or cystatin C (eGFRcy): green, low risk; yellow, moderately increased risk; orange, high risk; and red, very high risk. The cumulative incidence of the outcomes was assessed by the Kaplan-Meier method, and the association between color-coded risk and the time to outcome was evaluated using multivariate proportional hazards analysis. RESULTS: Compared with eGFRcr, the use of eGFRcy reduced the prevalence of risk ≥ orange by 0.8%. The adverse outcomes were significantly more likely to occur to the patients with baseline risk category ≥orange than those with ≤ yellow, independent of risk categories based on eGFRcr or eGFRcy. However, in multivariate analysis, risk category ≥orange with eGFRcy-based classification was significantly associated with adverse outcomes, but not the one with eGFRcr. CONCLUSIONS: Replacing creatinine by cystatin C in the CKD color-coded risk classification may be appropriate to discriminate HIV-infected patients at increased risk of a poor prognosis.

Urinary liver-type fatty acid-binding protein linked with increased risk of acute kidney injury after allogeneic stem cell transplantation.

Stem cell transplantation (SCT) involves a great risk of acute kidney injury (AKI). Urinary liver-type fatty acid-binding protein (uL-FABP) is a sensitive biomarker to detect kidney damage before an increase in serum creatinine (Cr); however, the utility of uL-FABP is not fully understood in the platform of SCT. A prospective study was conducted in 84 allogeneic SCT recipients to ascertain a link between the uL-FABP level before preparative procedures and AKI incidence after SCT. The association between them was analyzed using Gray's method and a multivariate Fine-Gray proportional hazards regression model. The recipients were stratified into high and low uL-FABP groups, according to the reference value for healthy subjects (8.4 µg/g Cr). AKI developed more frequently in the high (n = 20) than low (n = 64) group (55.0% versus 26.6% at day 30, P = .005), and high uL-FABP was an independent risk for the emergence of AKI (hazard ratio, 2.78; 95% confidence interval, 1.24 to 6.22, P = .01). In conclusion, increased baseline uL-FABP, which may indicate previous incipient kidney injury, is linked with a high risk of AKI after allogeneic SCT.

Measurements of procalcitonin facilitate targeting of endotoxin adsorption treatment in febrile neutropenic patients suffering from shock.

Immediate initiation of hemoperfusion treatment with polymixin B immobilized fiber (PMX-DHP) is a potent strategy to improve hemodynamics in septic patients with critical circulatory failure. However, it is often difficult to accurately and rapidly differentiate between bacterial infections and non-infectious causes of shock in acutely critically-ill patients. Procalcitonin (PCT) measurements may assist in the early identification of bacterial infection/sepsis and determination of severity in such patients. We present two febrile neutropenic (FN) patients who developed severe shock after chemotherapy for hematological malignancies. PCT levels were markedly elevated in both patients (≥ 10 ng/ml), suggesting a high likelihood of bacterial infectious etiology as the cause of their shock, and thus they were promptly treated with PMX-DHP. Measurements of PCT may facilitate targeting of PMX-DHP treatment among FN patients suffering from shock, which may lead to better prognosis.

Proteinuria is a simple sign of systemic inflammation that leads to a poor prognosis in individuals affected with non-Hodgkin lymphoma.

BACKGROUND: The clinical significance of proteinuria has not been fully understood among patients who are affected with non-Hodgkin lymphoma (NHL). METHODS: A 1-year prospective cohort study was conducted to ascertain the association between proteinuria and mortality in 46 hospitalized NHL patients. Proteinuria was defined as persistent dipstick test >= 1+, and the urinary protein creatinine ratio (UPCR),as a quantitative index of protein excretion, was measured simultaneously. A multivariable linear regression model was constructed to determine factors associated with UPCR. Statistical associations between proteinuria and time to mortality were analyzed using the Kaplan-Meier method and multivariable proportional hazards regression analysis, adjusted for covariates including disease severity, renal function, and serum interleukin-6(IL-6) concentration. RESULTS: The prevalence of proteinuria was 15.2% in the NHL patients. UPCR was significantly associated with the serum IL-6 level (standardized beta = 0.360, p = 0.0440). The cumulative mortality was significantly higher in proteinuric patients than in non-proteinuric patients, with a graded relationship between the severity of UPCR and mortality. The mortality risk increased with increasing UPCR grade: the hazard ratio (95% confidence interval) was 4.90 (1.29 - 32.3) for UPCR 30 - 300 mg/gand 17.8 (2.84 - 150) for UPCR > 300 mg/g, respectively, when UPCR < 30 mg/g was set as the reference. CONCLUSIONS: Proteinuria is a simple sign of coexisting systemic inflammation due to NHL and a harbinger of a poor prognosis.

Classification of human immunodeficiency virus-infected patients with chronic kidney disease using a combination of proteinuria and estimated glomerular filtration rate.

BACKGROUND: In 2012, the Kidney Disease: Improving Global Outcomes (KDIGO) updated the 2002 Kidney Disease Outcomes Quality Initiative (KDOQI) clinical practice guideline for chronic kidney disease (CKD). The 2012 KDIGO guideline elaborated the identification and prognosis of CKD by combining albuminuria with estimated glomerular filtration rate (eGFR). Identification of CKD with a high risk for a poor prognosis was investigated in human immunodeficiency virus (HIV)-infected individuals by applying the new guideline. METHODS: A total of 1,447 HIV-infected patients (1,351 male, 96 female; mean age 44.4 ± 11.5 years) were classified using a combination of eGFR and dipstick proteinuria, as a convenient alternative to albuminuria. Proteinuria was classified into 3 grades-(A1) - and +/- , (A2) 1+ and 2+ , and (A3) 3+ and 4+. eGFR was classified into 6 grades-(G1) ≤90, (G2) 60-89, (G3a) 45-59, (G3b) 30-44, (G4) 15-29, and (G5) <15 mL/min/1.73 m(2). RESULTS: Mean CD4 cell count was 487 ± 214 /µL, with 80.7 % of patients having an undetectable HIV-RNA level. The prevalence of CKD stage ≤2 and stage ≥3 classified according to KDOQI staging was 93.4 and 6.6 %, respectively. Using the new KDIGO classification, the prevalence of CKD with either a low (green) or moderately increased (yellow) risk was 96.9 %, while the prevalence for a high (orange) and very high (red) risk was 3.1 %. CONCLUSION: The use of the new KDIGO classification may reduce the prevalence of HIV-infected CKD individuals who are at high risk for a poor prognosis by nearly a half.

Cardiotoxic changes of colchicine intoxication in rats: electrocardiographic, histopathological and blood chemical analysis.

The microtubule inhibitor colchicine is cardiotoxic and is suggested to impair impulse formation and conduction. However, little is known about the electrocardiographic (ECG) changes induced by colchicine in experimental animals and the detailed pathogenesis of its cardiotoxicity. Therefore, we analyzed cardiotoxicity in colchicine-treated rats using electrocardiographic, histopathological and blood-chemistry approaches. A telemetry device for transmitting ECG data was implanted into male Crl:CD(SD) rats, and ECG tracings were obtained. At 6 weeks of age, 1.25 mg/kg colchicine was injected intravenously once daily for 2 consecutive days, and ECG waveforms and heart rate variability were analyzed. Furthermore, 1.25 mg/kg colchicine or vehicle was injected for 1 or 2 consecutive days in other rats at 6 weeks of age. One day after the final dosing, heart and blood samples were taken for histopathological and bloodchemical examination. ECG analysis revealed a prolonged RR interval, QRS duration, PR interval and QT interval. Heart rate variability analysis showed an increase in high frequency (HF) components as an index of parasympathetic nervous activity. In blood chemical examinations, colchicine induced high levels of parameters of cardiac injury and low levels and/or variations in Ca, inorganic phosphorus, potassium and chloride. Histopathologically, colchicine-treated rats showed eosinophilic granular degeneration and cytoplasmic vacuolation of ventricular myocardial cells but no remarkable change in the atrioventricular node. Not only blood chemical and histopathological changes but also ECG changes were induced in colchicine-treated rats, which indicated a decrease in myocardium excitability and conductivity, and these changes might be related to increased parasympathetic nervous activity and low blood Ca levels.

Cell wall polysaccharide enhances Lacticaseibacillus paracasei strain Shirota growth in milk and contributes to acid and bile tolerance.

LCPS-1, a cell wall polysaccharide (CWPS), is bound to the cell wall of the probiotic Lacticaseibacillus paracasei (formerly known as Lactobacillus casei) strain Shirota (LcS). Generally, the role of CWPS in the viability and survivability of bacteria is yet to be fully understood. This study aimed to elucidate the role of LCPS-1 in the viability and survivability of LcS. A mutant strain completely lacking LCPS-1 was constructed and evaluated for growth in bovine and soy milk and susceptibility to acid and bile. The growth of the mutant in bovine and soy milk temporarily stalled after the late logarithmic phase while wild-type LcS continued growing, resulting in a significantly lower number of viable cells for the mutant strain (p < 0.01). Significantly higher cell death relative to that of the wild-type strain was observed for the mutant strain following acid treatment at pH 3.0 (p < 0.01), with 60 and 92 % survival, respectively. The absence of LCPS-1 also reduced the survival rate of LcS cells from 3.3 to 0.8 % following 0.2 % bile treatment. The survival rate of the mutant after consecutive treatment with acid and bile was 19 %, while 73 % of the wild-type LcS survived. These results indicate that LCPS-1 leads to higher LcS growth in milk and improves tolerance to acid and bile. This study reveals the contribution of probiotic bacterial CWPS to acidic and gastrointestinal stress tolerance. Based on these findings, characterizing and modifying CWPS in probiotic strains could enhance manufacturing yields and improve gastrointestinal stress tolerance after consumption by hosts, ultimately advancing the development of more effective probiotics.

Elevation of Urinary Liver-Type Fatty Acid-Binding Protein Is a Harbinger of Poor Patient Prognosis after Allogeneic Stem Cell Transplantation.

Several recent studies have demonstrated that urinary levels of liver-type fatty acid-binding protein (L-FABP) can be used to stratify the prognosis of cardiac disease, cardiac intensive care unit admission, cirrhosis, and coronavirus disease 2019. Our initial prospective study revealed that urinary L-FABP (uL-FABP) was associated with a high probability of acute kidney injury after stem cell transplantation (SCT); however, the relevance of elevated uL-FABP to the prognosis of patients undergoing SCT remains to be determined. We aimed to investigate whether uL-FABP levels can be used to stratify patient prognosis after SCT. To achieve this aim, we conducted a new long-term follow-up study using data from patients enrolled in our preceding prospective cohort study. Patients were classified into high and low uL-FABP groups based on levels measured at baseline (ie, before initiating the conditioning regimen), using an uL-FABP cutoff of 8.4 µg/gCr, which was determined based on data from healthy adults. uL-FABP levels were also measured on days 0, 7, and 14 after SCT. Cox proportional hazard regression was used to examine the effects of each factor on survival outcomes, and Fine-Gray regression was used in the presence of competing risks. Multivariate analysis incorporating confounders was then performed for factors with P < .1 in univariate analysis. In total, 20 of 84 patients (23.8%), 57 of 84 patients (67.9%), 34 of 49 patients (69.4%), and 34 of 46 patients (73.9%) were classified into the high uL-FABP group at baseline and on days 0, 7, and 14, respectively. The 5-year overall survival (OS) rate was 23.9% in the high uL-FABP group and 68.9% in the low uL-FABP group. The multivariate analysis identified a high uL-FABP level at baseline as a significant prognostic factor for poor OS (hazard ratio [HR], 3.54; P = .002). The 5-year cumulative incidence rate for nonrelapse mortality (NRM) was 50.0% in the high uL-FABP group and 19.9% in the low uL-FABP group. In the multivariate analysis, high uL-FABP at baseline was a significant prognostic factor for NRM (HR, 3.37; P = .01). uL-FABP levels did not significantly stratify the cumulative incidence of relapse (HR, 2.13; P = .11). uL-FABP levels on days 0, 7, and 14 were not significant predictors of survival. High uL-FABP level before initiation of conditioning significantly influences OS and NRM following SCT, whereas a high uL-FABP level at any point after the conditioning regimen does not. Our results show that measuring uL-FABP level at baseline may be a simple way to predict survival in patients undergoing SCT.

S100A12 gene expression is increased in peripheral leukocytes in chronic kidney disease stage 4-5 patients with cardiovascular disease.

BACKGROUND/AIMS: S100A12 induces vascular inflammation contributing to the development of atherosclerosis. Serum S100A12 concentration is shown to be elevated in patients with chronic kidney disease (CKD), however the reason remains unclear. METHODS: Transcriptional levels of S100A12 and RAGE (receptor for advanced glycation end products) were measured in peripheral leukocytes by quantitative real-time RT-PCR. Subjects were 40 patients with CKD stage 4-5, 20 of whom were affected with cardiovascular disease (CVD), and 20 healthy subjects. Serum concentrations of S100A12 and soluble RAGE were measured using enzyme-linked immunosorbent assay. RESULTS: The serum concentration of S100A12 was significantly higher in CKD patients than in healthy subjects (78.5 ± 70.5 vs. 23.7 ± 19.2 ng/ml, p = 0.0035), but that of soluble RAGE was not. The relative quantity of S100A12 mRNA was significantly greater in leukocytes from CKD patients than in those from healthy subjects [mean (95% confidence interval of the mean): 3.1 (2.2-3.9) vs. 1.2 (0.8-1.7), p = 0.0001], however that of RAGE mRNA was not. The serum concentration of S100A12 was significantly correlated with the relative quantity of S100A12 mRNA among uremic CKD patients (r(2) = 0.656, p < 0.0001). Both the serum concentration and gene expression of S100A12 were significantly higher in patients who had CVD than in those who did not. CONCLUSION: Excessive expression of the S100A12 gene in uremic leukocytes is relevant to its increased serum concentration, particularly in those affected with CVD.

Impact of cystatin C elevation and albuminuria on probability of adverse outcomes in HIV-infected men receiving HAART.

BACKGROUND: Highly active antiretroviral therapy (HAART) has contributed to the longevity of human immunodeficiency virus (HIV)-infected patients; however, improved survival has been accompanied by an increase in the prevalence of kidney disease. Kidney disease may be partly responsible for higher morbidity in HIV-infected patients than in HIV-uninfected subjects. METHODS: A total of 515 well-controlled HIV-infected men on HAART was enrolled in a 3-year prospective cohort study. The incidence of cancer and CVD was investigated over time. The impact of cystatin C elevation and albuminuria at baseline on the incidence of each disease was examined. Albuminuria was estimated by determining the albumin-to-creatinine ratio (ACR). The cumulative incidence of cancer and CVD was analyzed using the Kaplan-Meier method, stratified by the presence and absence of elevated cystatin C and albuminuria biomarkers. Cox proportional hazards analysis was used to calculate the hazards ratio (HR) and 95% incidence interval (CI) of each biomarker, adjusted for known risk factors. RESULTS: All participants completed the 3-year follow-up study. During the follow-up period, cancers and CVD developed in 13 (2.5%) and 14 (2.7%) participants, respectively. The Kaplan-Meier estimates were significantly increased for cancer incidence in patients with cystatin C elevation and for CVD in those with albuminuria. The HR (95% CI) of cystatin C elevation for occurrence of cancer was 6.09 (1.30 - 24.6) and the HR (95% CI) of ACR ≥ 20 mg/g for CVD was 8.97 (2.20 - 60.8). CONCLUSIONS: Cystatin C elevation and/or albuminuria at baseline in HIV-infected men undergoing HAART may be associated with poor prognosis.

A case of IgA nephropathy associated with mycosis fungoides that developed into rapidly progressive glomerulonephritis.

A 53-year-old Japanese male was diagnosed with atopic dermatitis and initiated treatment with a local dermatologist in February 2001. A routine medical check-up revealed proteinuria, microscopic hematuria and slight elevation of serum creatinine level in spring 2006. He was referred to our hospital for nephrology consultation and followup.In December 2009, he developed a sudden high fever of greater than 39 °C with sore throat. In addition, his serum creatinine level greatly increased to 4.6 mg/dl. His prevalent renal illness was thought to be rapidly progressive glomerulonephritis (RPGN). Soon after admission, kidney and skin biopsies were performed. The kidney specimens showed that the glomeruli had proliferative mesangial cells strongly positive for anti-IgA antibody, 75% of which manifested fibrocellular crescentic formation surrounding the Bowman's capsules. His skin disease was pathologically proven to be mycosis fungoides(MF). It is likely that his kidney disease was exacerbated by the upper respiratory tract infection and converted to RPGN. Ash is kidney function rapidly declined, hemodialysis therapy was initiated and he remains on chronic dialysis therapy. This is a serious case of IgA nephropathy associated with MF,which developed into RPGN and subsequent end-stage renal disease.

[Prevalence of chronic kidney disease among HIV-infected individuals in Japan--a report from two tertiary hospitals].

BACKGROUND: The improved survival of subjects with human immunodeficiency virus (HIV) has been accompanied by an increased prevalence of chronic kidney disease (CKD). Epidemic of CKD among those with HIV has not yet been evaluated in multiple tertiary hospitals in Japan. METHODS: A cross-sectional study was conducted in 2011 at Tokyo Metropolitan Komagome Hospital (TMKH) and Tokyo Medical University Hospital (TMUH). A total of 1482 HIV-infected subjects (1384 men, 98 female, mean age: 44.2 +/- 11.4 years old) were consecutively enrolled in the study. Random urine and blood samples were collected to study prevalence of CKD. CKD was diagnosed as a decrease in glomerular function and/or proteinuria and classified into 5 stages based on National Kidney Foundation guidelines. The estimated glomerular filtration rate based on serum creatinine was calculated using the 3-variable equation, constructed by the Japanese Society of Nephrology. Proteinuria was defined as > or = 1+ on urine dipstick examination. All electronic medical charts were reviewed to determine comorbidities, including hypertension and diabetes mellitus (DM). The proportion of subjects receiving tenofovir disoproxil fumarate (TDF) was investigated. Risk factors for CKD were determined using multivariate logistic regression analysis. RESULTS: The mean CD4 cell count was 487 +/- 216/microL and 80.5% had undetectable HIV-RNA level in the combined cohort. Of the 90.2% of subjects taking antiretroviral agents, 61.5% was using TDF. The prevalence of overall CKD and CKD > or = stage 3 was 12.9% and 6.7%, respectively, both of which were nearly 3-fold higher in the TMKH cohort (p < .0001). Mean age and proportional prevalent hypertension and DM were significantly higher in the TKMH cohort than in the TMUH cohort. Multivariate analysis showed significant CKD to be associated with age > or =50 years (odds ratio [OR], 2.81), hypertension (OR, 3.04), and DM (OR, 2.05). CONCLUSIONS: CKD prevalence was 12.9% among combined cohorts, but differed significantly between them. Differences in age distribution and the proportion of comorbidities, including hypertension and DM, are likely involved.