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.

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.

Hematuria Alone or in Combination with Proteinuria Is a Harbinger of Poor Prognosis in Patients with Non-Hodgkin Lymphoma.

BACKGROUND: Screening for hematuria is essential during health checkups in the general population. However, urine examinations in patients with cancer tend to be overlooked. This study attempted to demonstrate the novel utility of urinalysis in the assessment of the prognosis of non-Hodgkin lymphoma (NHL). METHODS: A longitudinal, retrospective cohort study was conducted to examine the association between hematuria and mortality in 294 patients with NHL. Urinalysis was performed using a dipstick test. A multivariate, logistic regression model was constructed to evaluate factors associated with the presence of hematuria. Statistical association between hematuria and the time to all-cause mortality was analyzed using Kaplan-Meier analysis, followed by multivariate proportional hazards regression analysis adjusted for covariates that might be related to mortality. RESULTS: The prevalence of hematuria alone and in combination with proteinuria was 11.6 and 5.1%, respectively. C-reactive protein was a significant factor associated with the presence of hematuria (OR [95% CI] 1.17 [1.03-1.34], p = 0.0194). The cumulative mortality was significantly higher in patients with hematuria alone (51.1%), proteinuria alone (47.1%), and both (66.7%), than in those with neither (24.3%). Moreover, the presence of hematuria alone was significantly associated with all-cause mortality (hazard ratio [95% CI] 1.78 [1.10-3.50], p = 0.0455), and patients with concomitant proteinuria were at the highest risk (4.01 [1.71-8.33], p = 0.0001). CONCLUSIONS: In patients with hematuric NHL, systemic inflammation is likely to develop to such a great extent that kidney damage occurs. Therefore, the presence of hematuria, alone or especially in combination with proteinuria, predicts a poor prognosis of NHL.

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 of Chronic Kidney Disease and Poor Diagnostic Accuracy of Dipstick Proteinuria in Human Immunodeficiency Virus-Infected Individuals: A Multicenter Study in Japan.

BACKGROUND: Chronic kidney disease (CKD) has become one of the common comorbid conditions affecting the human immunodeficiency virus (HIV) population. Human immunodeficiency virus-infected individuals are at increased risk of developing CKD, and they are likely to experience faster progression of renal dysfunction compared with HIV-uninfected individuals. Albuminuria represents not only kidney damage but also manifests metabolic syndrome and vascular dysfunction. METHODS: We conducted a multicenter, cross-sectional study involving 2135 HIV-infected individuals in Japan to test the prevalence of CKD and proteinuria/albuminuria. Urine sample was analyzed by both dipstick test and albumin-to-creatinine ratio (ACR) assay. Chronic kidney disease was classified according to the Kidney Disease Outcomes Quality Initiative (K/DOQI) and Kidney Disease: Improving Global Outcomes (KDIGO) guidelines. The diagnostic performance of dipstick test to detect albuminuria (ACR ≥30 mg/g) was evaluated. RESULTS: The prevalence of CKD, evaluated by K/DOQI and KDIGO guidelines, was 15.8% and 20.4%, respectively. Age, total cholesterol level, prevalence of hypertension, diabetes mellitus, and hepatitis C infection tended to increase, whereas levels of hemoglobin, serum albumin, and CD4 cell count tended to decrease as CKD risk grades progressed. Proteinuria and albuminuria were present in 8.9% and 14.5% of individuals, respectively. Dipstick test ≥1+ to detect albuminuria had an overall sensitivity of 44.9% and specificity of 97.2%. CONCLUSIONS: The KDIGO guideline may enable physicians to capture HIV-infected patients at increased risk more effectively. The sensitivity of dipstick proteinuria to detect albuminuria is so poor that it may not serve as an alternative in HIV-infected individuals.

An Overview of Kidney Disease Following Hematopoietic Cell Transplantation.

Hematopoietic stem cell transplantation (SCT) recipients are exposed to a large amount of anti-cancer drugs, immunosuppressors, and irradiation during the peri-SCT period. Thus, they have to overcome serious adverse events related to unavoidable but toxic procedures, including organ disorders. In particular, acute kidney injury (AKI) is one of the most critical complications, because it influences the mortality of patients. A few patients who survive AKI may develop nephrotic syndrome, and precedent AKI is also closely associated with chronic and progressive loss of the renal function in post-SCT patients. These kidney diseases place a heavy burden on SCT patients, both medically and economically. Therefore, hematologists who evaluate SCT should be fully aware of the development of these kidney diseases after SCT. We herein review the common course of kidney disease development following allogeneic SCT to provide healthcare professionals with practical information on renal disease in SCT patients.

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.

Emergence of Dipstick Proteinuria Predicts Overt Nephropathy in Patients Following Stem Cell Transplantation.

BACKGROUND: Stem cell transplantation (SCT) places a heavy burden on the kidneys, often resulting in renal dysfunction or nephrotic syndrome. This study attempted to show that early-onset proteinuria predicts the development of overt nephropathy. METHODS: A total of 831 patients who received allogeneic SCT were surveyed. Excluding those with prior kidney disease and those lacking in an observation period ≥1 year after SCT, 251 patients were eligible for the study. Dipstick proteinuria ≥1+ within 1 year after SCT was defined as 'incident proteinuria', and subsequent persistence of an estimated glomerular filtration rate of <60 ml/min/1.73 m2 at 1 year or longer after SCT was defined as 'incident chronic kidney disease (CKD)'. Between-group differences were analyzed using the chi-square or Mann-Whitney U test. Factors associated with the incidence of CKD were investigated by multivariate Cox proportional regression analysis. Kidney-biopsied tissue was examined in all nephrotic syndrome patients. RESULTS: The mean duration of follow-up was 4 years. Thirty-four (13.5%) and 66 (26.3%) patients developed incident proteinuria and incident CKD, respectively. Nine (3.6%) patients developed nephrotic syndrome mainly due to membranous nephropathy. The incidence of CKD was significantly greater in patients with incident proteinuria than those without (61.8 vs. 20.7%, p < 0.0001), and incident dipstick proteinuria was a significant risk for incident CKD (hazard ratio 4.39, 95% CI 2.44-7.73, p < 0.0001). CONCLUSION: SCT patients who manifest dipstick proteinuria are predisposed to overt nephropathy. Routine monitoring of the urine dipstick test is strongly recommended, as it facilitates early nephrology care for post-SCT patients.

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.

New Insight into Atherosclerosis in Hemodialysis Patients: Overexpression of Scavenger Receptor and Macrophage Colony-Stimulating Factor Genes.

BACKGROUND: Scavenger receptors (SRs) play a pivotal role in atherogenesis. The mechanism of atherosclerosis, which is specific to hemodialysis (HD) patients, was studied on the basis of SR gene expressions. METHODS: The gene expressions of SR type A (SR-A) and CD36 were studied in peripheral monocytes by real-time reverse transcription polymerase chain reaction. Data were compared between HD (n = 30) and age-matched control subjects (n = 10). Serum levels of macrophage colony-stimulating factor (M-CSF) were measured with enzyme-linked immunosorbent assay to test its role in SR expression. The statistical differences and associations between two continuous variables were assessed using the Mann-Whitney U test and Pearson's correlation coefficient, respectively. RESULTS: The relative quantities of SR mRNAs were significantly greater in HD patients than in controls [median (interquartile range): SR-A, 1.67 (0.96-2.76) vs. 0.90 (0.60-1.04), p = 0.0060; CD36, 1.09 (0.88-1.74) vs. 0.74 (0.64-0.99), p = 0.0255]. The serum concentration of M-CSF was significantly higher in HD patients than in controls [1, 121 (999-1,342) vs. 176 (155-202) pg/ml, p < 0.0001]. In addition, the relative quantity of M-CSF mRNA was significantly greater in HD patients than in controls [0.79 (0.42-1.53) vs. 0.42 (0.28-0.66), p = 0.0392]. The serum M-CSF levels were positively correlated with both the relative quantity of SR-A mRNA (r2 = 0.1681, p = 0.0086) and that of CD36 mRNA (r2 = 0.1202, p = 0.0284) in all subjects (n = 40). CONCLUSION: HD patients are predisposed to atherosclerosis as a consequence of their enhanced monocyte SR expressions. SRs and M-CSF are potential therapeutic targets for atherosclerosis in this high-risk population.

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.

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.

Epidemiology, clinical characteristics, and management of chronic kidney disease in human immunodeficiency virus-infected patients.

Antiretroviral therapy has markedly reduced acquired immune deficiency syndrome-related deaths and opportunistic infectious diseases. This has resulted in prolonged survival of individuals infected with the human immunodeficiency virus (HIV). However, this improvement in survival has been accompanied by an increase in the incidence of chronic kidney disease (CKD) and end-stage renal disease. CKD is now epidemic among HIV-infected populations in both Western and Eastern countries. Risk factors associated with CKD in HIV-infected populations include aging, hypertension, diabetes mellitus, co-infection with hepatitis C virus, a low CD4 cell count, and a high HIV viral load. Clinical experience has shown that HIV-infected individuals often have one or more concurrent risk factors for CKD. The cumulative effect of multiple risk factors on the development of CKD should be noted in this population. Glomerular disease directly related to HIV infection, so-called HIV-associated nephropathy, remains an important cause of CKD among a limited HIV population of African descent, but is less likely to be common among other urban HIV populations. The impact of exposure to nephrotoxic antiretroviral agents on the development of kidney disease is both an old and a new concern. In particular, the association of tenofovir with kidney tubular injury has been an area of great interest. The findings regarding tenofovir's adverse effect on long-term kidney function vary among studies. The early identification and treatment of CKD is recommended for reducing the burden of patients requiring dialysis in HIV-infected populations. Periodic monitoring of urinary concentrations of albumin, protein, and tubular injury markers such as low-molecular-weight proteins may be useful for the early diagnosis of patients at risk for incident CKD. This review focuses on recent epidemiology, clinical characteristics, and management of CKD in a contemporary HIV-infected population.

Atazanavir nephrotoxicity.

Atazanavir is commonly used as one of the key drugs in combination antiretroviral therapy for human immunodeficiency virus (HIV). However, atazanavir has the potential to yield its crystalline precipitation in urine and renal interstitial tissues, leading to crystalluria, urolithiasis, acute kidney injury (AKI) or chronic kidney disease (CKD). In epidemiological studies, atazanavir/ritonavir alone or in combination with tenofovir has been associated with increased risk of progression to CKD. However, renal biopsies were not provided in these studies. Case reports showing an association between atazanavir use and tubulointerstitial nephritis among HIV-infected individuals provide clues as to the potential causes of atazanavir nephrotoxicity. We now review atazanavir-related kidney disease including urolithiasis, renal dysfunction and interstitial nephritis and illustrate the review with a further case of atazanavir-associated kidney injury with sequential renal biopsies. There are two forms of atazanavir-associated tubulointerstitial nephritis: acute tubulointerstitial nephritis that may develop AKI rapidly (in weeks) after initiation of atazanavir, and chronic tubulointerstitial nephritis that may develop progressive CKD slowly (in years) with granuloma and intrarenal precipitation of atazanavir crystals as well as crystalluria. Caution should be exercised when prescribing atazanavir to patients at high risk of CKD, and therapy should be reevaluated if renal function deteriorates, especially associated with crystalluria and hematuria.

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.

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.

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.

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.

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.