Efficacy and safety of anticoagulant therapy in three specific populations with sepsis: a meta-analysis of randomized controlled trials.

UNLABELLED: ESSENTIALS: Most anticoagulant therapy has failed to demonstrate a survival benefit in the overall sepsis population. We conducted separate meta-analyses of anticoagulant therapy in three different populations. Survival benefit was observed only in the septic disseminated intravascular coagulation (DIC) population. Further randomized controlled trials should focus on specific populations with septic DIC. BACKGROUND: Although many preclinical trials have indicated the effectiveness and safety of anticoagulant therapy as an adjuvant therapy against sepsis, there is little evidence to support its effectiveness to reduce mortality in the overall population with sepsis in clinical situations. However, several studies suggested that specific anticoagulant therapy may potentially reduce mortality in patients with sepsis-induced disseminated intravascular coagulation (DIC). OBJECTIVE: We investigated whether the survival benefit of anticoagulant therapy might pertain to the coagulopathic population with sepsis. METHODS: We conducted separate meta-analyses of randomized controlled trials for anticoagulant therapy in three different populations: (i) overall population with sepsis, (ii) population with sepsis-induced coagulopathy, and (iii) population with sepsis-induced DIC. We searched MEDLINE, Scopus, and the Cochrane Central Register of Controlled Trials comparing anticoagulant therapy with placebo or no intervention in sepsis patients. We measured all-cause mortality as the primary outcome and bleeding complications as the secondary outcome. RESULTS: We analyzed 24 trials enrolling 14 767 patients. There were no significant reductions in mortality in the overall sepsis population and the population with sepsis-induced coagulopathy. Otherwise, we observed significant reductions in mortality (risk ratio 0.72, 95% confidence interval 0.62-0.85) in the population with sepsis-induced DIC. As adverse events, bleeding complications tended to increase similarly with anticoagulant therapy in all three populations. CONCLUSION: Although associated with an increased risk of bleeding, anticoagulant therapy resulted in no survival benefits in the overall sepsis population and even the population with sepsis-induced coagulopathy; beneficial effects on mortality were observed only in the population with sepsis-induced DIC.

Resolution of primary amyloidosis by melphalan and prednisolone: a case report.

We here report a case of a 50-year-old man who showed histologically evident resolution of primary amyloidosis by melphalan and prednisolone. The patient was admitted to our hospital for further evaluation of nephrotic syndrome and remarkable hepatomegaly with refractory ascites, on September 11, 1998. Laboratory tests at presentation showed nephrotic syndrome with slight renal impairment and elevation of the enzymes of the biliary system. Monoclonal light chains were not detected in the serum or urine by immunoelectrophoresis. A renal biopsy revealed global deposition of amyloid in all glomeruli, interstitium and blood vessels. Immunofluorescence staining was positive for kappa light chains. Liver biopsy specimens showed extensive deposition of amyloid along sinusoid walls. Bone marrow aspiration contained 7% plasma cells but no clusters or abnormal cells. Based on these findings, systemic AL- (amyloid light chain) amyloidosis was diagnosed, and the treatment with combinations of melphalan and prednisolone was started from October 1998 at intervals of 4-6 weeks. Renal impairment progressed, resulting in the initiation of maintenance hemodialysis in February 1999. Reinfusion of ascitic fluid into the hemodialysis circuit had been performed from March 1999 for refractory ascites, and ascites disappeared in July 1999. Furthermore, urinary output increased after 14 courses of chemotherapy. Renal function gradually ameliorated with a concomitant reduction in the enzymes of biliary system, and finally hemodialysis was discontinued in April 2001. Sixteen courses of chemotherapy were administered by April 2001. Proteinuria was negative in August 2001. A second renal biopsy was performed on November 20, 2001, which showed markedly decreased amyloid deposition and a proliferation of mesangial cells and increase in matrix in various degrees. We report a case of a patient with primary amyloidosis who was successfully treated by melphalan and prednisolone, resulting in marked resolution of renal amyloidosis.

Brown tumor of the thoracic spine in a patient on long-term hemodialysis.

A 39-year-old woman on long-term hemodialysis presented with a history of rapidly progressive paraplegia. Radiological examination showed a compression fracture of seventh thoracic vertebra and expansive mass lesion in the posterior elements of the fourth thoracic vertebra. Laboratory tests on admission showed serum calcium of 11.9 mg/dl, phosphate 6.0 mg/dl, and the high-sensitive parathyroid hormone level of 139,191 pg/ml measured by radioimmunoassay. Percutaneous biopsy of the expansive mass showed a large number of multinucleated giant cells in a fibroblastic stroma containing abundant hemosiderin. Tumor resection and anterior interbody fusion with artificial bone graft was performed on 14th hospital day. Paraplegia gradually improved postoperatively. Total parathyroidectomy and autotransplantation of parathyroid gland were subsequently performed. Nodular hyperplasia was evident in the parathyroid glands by light microscopy. Brown tumor is rarely found in vertebral bone and this is the sixth case of such tumor in secondary hyperparathyroidism.

A multicenter prospective randomized controlled trial of the efficacy of mild hypothermia for severely head injured patients with low intracranial pressure. Mild Hypothermia Study Group in Japan.

OBJECT: The criteria for the use of mild hypothermia (34 degrees C) in severely head injured patients have not been standardized. A prospective randomized controlled trial was conducted to determine whether mild hypothermia is essential in the treatment of severely head injured patients with low intracranial pressure (ICP). METHODS: At 11 medical centers, 91 severely head injured patients with an admission Glasgow Coma Scale score of 8 or less in whom ICP could be maintained below 25 mm Hg by conventional therapies were divided randomly into two groups: the mild hypothermia group (HT group, 45 patients) and the normothermia group (NT group, 46 patients). Patients in the HT group were exposed to mild hypothermia (34 degrees C) for 48 hours, followed by rewarming at 1 degrees C per day for 3 days, whereas patients in the NT group were exposed to normothermia (37 degrees C) for 5 days. The two groups were similar with respect to prognostic factors, and there was no difference in clinical outcome at 3 months postinjury. During treatment, there was a significantly greater use of neuromuscular blocking agents in the HT group (p = 0.011). During the initial 2 weeks postinjury, the incidences of pneumonia, meningitis, leukocytopenia, thrombocytopenia, hypernatremia, hypokalemia, and hyperamylasemia were significantly higher in the HT than in the NT group (p < 0.05). CONCLUSIONS: Mild hypothermia should not be used for the treatment of severely head injured patients with low ICP because this therapy conveys no advantage over normothermia in such patients.

A case of persistent acute allograft glomerulopathy with long-standing stable renal function.

Acute allograft glomerulopathy (AAG) characterized by hypercellularity, enlargement of endothelial cells, infiltration of glomeruli by mononuclear cells and webs of PAS-positive material has been reported as an unusual but distinct form of acute rejection in kidney transplant recipients. We present a case of persistent AAG proven by serial biopsies. The patient was 53 years old when she received kidney transplantation from her mother. The immunosuppressants were methylprednisolone, azathioprine and FK506. She developed several acute rejections and received antirejection therapy. The patient transferred to our hospital 15 months after transplantation. Serum creatinine was 2.11 mg/dL. The level of serum creatinine was gradually elevated from 2.11 mg/dL to 3.09 mg/dL. Graft biopsy, performed 16.5 months after transplantation, represented prominent intraglomerular infiltration of mononuclear cells, segmental thickening of glomerular basement membrane (GBM) with double contour, grade 1 tubulitis, marked accumulation of mononuclear cells in peritubular capillaries and margination of mononuclear cells in a small artery. It was diagnosed as acute allograft glomerulopathy (AAG). Intravenous methylprednisolone pulse therapy, discontinuation of FK506 and administration of cyclosporin (CYA) resulted in decrease of serum creatinine. To evaluate histological evolution of AAG we performed two subsequent biopsies over 3 yr. Severe glomerulitis persisted as a prominent feature 8 months later and still existed 53.4 months after transplantation with decreased severity. The extent of GBM reduplication also decreased, but the percentage of glomerular sclerosis increased gradually. Multi-layering of basement membrane of peritubular capillary and interstitial fibrosis also increased. The prominence of infiltration of mononuclear cells in peritubular capillary was unchanged. At the last follow-up, i.e. 71 months after transplantation, her serum creatinine was 1.34 mg/dL. Neither proteinuria nor haematuria was observed. We consider that our immunosuppressive treatment has been successful so far, because the patient is still maintaining stable graft function since the transplantation over 6 yr ago. It is thus suggested that AAG per se probably has no influence on acute aggravation of graft function, but AAG and capillaritis in peritubular capillaries may cause an evolution of chronic allograft nephropathy, resulting in a slowly progressive deterioration of graft function.

A case of fever of unknown origin with severe stomatitis in renal transplant recipient resulting in graft loss.

We present a case of fever of unknown origin and life-threatening stomatitis developed about 60 months after renal transplantation. He was 15 yr old at the transplantation. Bacterial, fungal, and viral infections were not evident. Fever and stomatitis were resistant to acyclovir and to any anti-bacterial or anti-fungal treatment. Graft biopsy revealed a small focus of acute vascular rejection, but the findings were not severe enough to be an etiology of the fever in this case. The administration of cyclosporine (CYA) was stopped 19 d before graftectomy, but the clinical picture was unchanged. Fever and stomatitis was resolved immediately after graftectomy and the discontinuation of immunosuppressants such as mizoribine (MZ) and prednisolone. Pathological changes of the graft included chronic transplant glomerulopathy, acute glomerulitis, and lymphocyte infiltration in peritubular capillaries. Thus we suppose that immunosuppressants were the cause of both fever and stomatitis in this case. We speculate that a fever in this case might be due to the immunosuppressant itself, i.e., CYA or MZ, or viral infection probably herpes-simplex virus infection. It is probably the immunosuppressive state per se that may cause the resistance of his muco-cutaneous lesion to anti-viral agent.

Cerebral ischemia as a causative mechanism for rapid progression of brain atrophy in chronic hemodialysis patients.

BACKGROUND: It has been found that brain atrophy develops more rapidly in patients with end-stage renal failure after initiation of dialysis therapy. The present study was designed to analyze the relationship between brain atrophy and asymptomatic ischemic brain lesions. PATIENTS AND METHODS: Magnetic resonance imaging (MRI) was performed for the evaluation of brain atrophy and ischemic lesions. Brain atrophy was assessed by the ventricular-brain ratio (VBR), calculated as the ratio of the ventricular area to the whole brain area on the maximum MRI slice. The severity of periventricular hyperintensity (PVH) and the number of lacunae were also regarded as ischemic brain lesions. Fifty-five patients undergoing maintenance hemodialysis (HD) without clinically overt neurological signs and symptoms, with a mean age of 52 +/- 11 (SD) years and a mean HD duration of 7 +/- 6 (SD) years were subjected. VBR and its relationship to ischemic brain lesion data were compared to those in 35 non-HD patients (controls), with a mean age of 42 +/- 14 (SD) years. RESULTS: The VBR, the number of lacunae and the severity of PVH tended to increase with age in HD. The VBRs at all age groups were significantly higher in HD than in controls (7.0 vs 3.7% at the 4th decade, p < 0.05; 8.4 vs 5. 9% at the 5th decade, p < 0.05; 9.6 vs 5.4% at the 6th decade, p < 0.05; and 11.6 vs 6.3% at the 7th decade, p < 0.05). HD patients had significantly higher number of lacunae and had more advanced PVH than did controls. Both the number of lacunae and the severity of PVH were significantly correlated to VBR in HD. CONCLUSION: In conclusion, the rapid progression of brain atrophy was related to the asymptomatic ischemic brain lesions in our HD patients. Such data indicated that cerebral ischemia might be a causative mechanism of brain atrophy in chronic hemodialysis patients.

The features of psychological problems and their significance in patients on hemodialysis--with reference to social and somatic factors.

AIM: For the purpose of identifying the features of psychological problems and their significance in patients on hemodialysis, we analyzed how psychological problems are affected by social and somatic factors. SUBJECTS AND METHODS: The subjects all consisted of patients on hemodialysis at the Kidney Center of Fukuoka Red Cross Hospital between December 1994 and December 1996. We used the Cornell medical index health questionnaire on neurosis and the "easily upset or irritated", State-trait anxiety inventory to determine both state and trait anxiety, the Self rating Depression Scale on depression and divided into the patients who demonstrated each psychological problem and those who did not, and then analyzed the psychological problems between the two groups with reference to somatic and social factors which may have led the patients to develop their respective psychological problems. RESULTS: According to a chi-square analysis, neurosis, clinical trait anxiety and clinical state anxiety were all more closely related to somatic factors than to social factors. In contrast to neurosis and anxiety, more social factors than somatic factors were related with "easily upset or factors were related with" easily upset or irritated". "Easily upset or irritated" was significantly related to living with a spouse or with children. In addition, depression was related to various factors including both somatic and social factors. In a stepwise multiple logistic regression analysis, the presence of restless legs also correlated with all the psychological symptoms investigated in this study. The prevalence of depression was also related to the degree of awareness regarding the cause of renal failure (p < 0.01). CONCLUSION: Our results thus revealed the features of the psychological problems and their significance in patients on hemodialysis.

A case of late onset cyclosporine-induced hemolytic uremic syndrome resulting in renal graft loss.

A case of late onset hemolytic uremic syndrome (HUS) associated with cyclosporine (CYA) is described in this report. A 50-yr-old man with end-stage renal failure due to immunoglobulin A (IgA) nephropathy received a renal transplant from his wife. Human leucocyte antigen was completely unmatched. Immunosuppressant was a combination of prednisolone, azathioprine, and CYA. He was discharged 1 month after transplantation, with no episode of acute rejection. Twenty-one months after transplantation, his platelet count and hematocrit began to decrease and lactate dehydrogenase began to increase. Graft biopsy showed thrombotic microangiopathy and recurrent IgA nephropathy. Graft function was rapidly deteriorated and methylprednisolone pulse therapy was not effective. Twenty-five months after transplantation, he returned to a regular hemodialysis. Hemolysis was immediately improved after a reduction of the dose of CYA to 50 mg/d. The trough level of CYA was less than 200 ng/mL in most periods of his clinical course. Blood pressure was high throughout the clinical course. Although acute vascular rejection or malignant hypertension could also cause a thrombotic microangiopathy, CYA was most likely a cause of HUS in the present case because of the following reasons: neither anti-acute rejection therapy nor an adequate control of his blood pressure was effective in improving clinical features of HUS; hemolysis and thrombocytopenia disappeared immediately after the reduction of the dose of CYA to 50 mg/d. It has been reported that HUS carried poor prognosis only when occurring shortly after transplantation in cadaver kidney recipients. The present transplant was from a living donor and HUS occurred 21 months after transplantation and was severe enough to result in graft loss. High blood pressure might be one of the predisposing factors of HUS associated with CYA in the present case. CYA should be stopped and other alternative immunosuppressants should be given in cases of acute graft deterioration with hemolysis and thrombocytopenia, irrespective of the interval from transplantation, CYA dose, or CYA trough level.

Glomerular score as a prognosticator in IgA nephropathy: its usefulness and limitation.

Glomerular sclerosis, mesangial hypercellularity, extracapillary lesions, interstitial fibrosis, and vascular sclerosis have been reported to be the significant pathologic prognosticators in IgA nephropathy (IgAN). We developed our own scoring for the following main glomerular changes in 248 patients with IgAN: 1) glomerular hypercellularity (mesangial and endocapillary), 2) segmental lesions such as tuft adhesion, crescent and segmental sclerosis, 3) global glomerular sclerosis. Indices of each lesion were semiquantitatively determined. The sum of these three indices was defined to be a glomerular score. We found that a glomerular score significantly related to the outcome of patients with IgAN in univariate life table analysis. We also semiquantitatively determined total score including tubulo-interstitial and vascular lesions as well as glomerular score and compared the predictive power as a prognosticator between glomerular score and total score. Using Cox's proportional Hazard model and log-likelihood ratio test, we confirmed that predictive power of glomerular score was better than that of total score. Furthermore, we assessed the reproducibility of glomerular score using Kappa statistics. Three pathologists read 100 biopsies which were randomly selected from the materials and all pathologists read them twice. A value of Kappa between the first and second observation of pathologist A, B and C was 0.68, 0.71 and 0.60, respectively. Values of Kappa between Pathologist A and B were ranging from 0.45 to 0.47, those between Pathologist A and C from 0.30 to 0.36, and finally those between Pathologist B and C were ranging from 0.12 to 0.23. Therefore, intra-observer reproducibility was nearly excellent. And inter-observer reproducibility between Pathologist A and B was satisfactory. However, inter-observer reproducibility between Pathologist A and C and between B and C was not satisfactory. We feel our scoring system is very convenient and easy to be understood as a prognosticator in patients with IgAN. It, however, should be used by one pathologist because of excellent intra-observer reproducibility and rather unsatisfactory inter-observer reproducibility.

[Organ transplant network in Japan: current status and its role].

The Role of Organ Transplant Network are the encouragement of the organ transplantation and fair organ sharing. Its principled are united, neutral open and nonprofit organization, so as to secure the fair and quick organ sharing based on the uniform allocation policy. Japan Kidney Transplant Network was established in 1995 nad reorganized into multi-organ sharing network, Japan Organ Transplant Network in 1997, when Japan Organ transplant Act was enacted. It consists of transplant coordinators, physicians, transplant surgeons, kidney banks, local administration, academic standings, other organization/associations and others. There are several committee, in which special subjects on organ transplantation and related matters are consulted, and review system in which each case is assessed and judged. And principal and essential items are decided by the board of members and then by the general assembly. The new computer system was introduced and registrants data are renewed every year, and recipient selection is done based on the latest registrants data. Standardized HLA examination tray was introduced and class II antigen was examined by means of DNA typing since 1997, which enabled more precise and accurate search. Hereafter, the education and encouragement of transplant coordinators to raise themselves and the more effective and extended distribution of donor cards are indispensable to promote organ donation/transplantation.

Sudden death in chronic dialysis patients.

METHODS: Causes of sudden death were investigated in 113 chronic dialysis patients who died during the 10-year period from July 1979 to January 1989; postmortem examination was performed on 93 of the cases (autopsy rate; 82.3%). Sudden death was regarded as death 24 h after the onset of acute illness in patients without any restriction in their daily activities. There were 35 sudden death cases out of the 93 autopsied chronic dialysis patients. We analysed the causes of sudden death for all chronic dialysis patients and for those who died suddenly. RESULTS: The mean age of the 93 cases was 61.4 +/- 10.5 years (+/-SD). Stroke was the most frequent cause of death (24 cases, 25.8%) in the 93 autopsied cases. This was followed by cardiac disease in 18 (19.4%), infectious disease in 16 (17.2%), malignancy in 14 (15.1%), and dissecting aortic aneurysm in 5 (5.4%). The mean age of the 35 sudden death cases was 60.9 +/- 10.9 years. Of the 35 sudden death cases in chronic dialysis patients, dissecting aortic aneurysm was the most common cause of sudden death (5 cases, 14.3%), followed by cerebral haemorrhage in three (8.6%), acute subdural haematoma in three (8.6%), acute myocardial infarction in two (5.7%), cerebral infarction in two (5.7%), and subarachnoidal haemorrhage in one (2.9%). CONCLUSIONS: Dissecting aortic aneurysm, leading frequently to stroke as a cause of sudden death in chronic dialysis patients, at least in Japan, should be carefully differentiated from other cardiac diseases in chronic dialysis patients, such as severe atherosclerosis.

The effect of azelastin hydrochloride on pruritus and leukotriene B4 in hemodialysis patients.

Pruritus is a very common complication in chronic hemodialysis (HD) patients, however the exact mechanism for this affliction is still not known. Anti-histaminics usually failed to alleviate uremic pruritus. In others, an anti-allergic drug, which inhibits the release of chemical mediators, such as leukotrienes or histamine from mast cells, was reported to be effective. We evaluated the values of leukotriene B4 and interleukin 6 in HD patients with pruritus and the effect of an anti-allergic drug on these factors. Leukotriene B4, interleukin-6, C3a, C5a, the number of eosinophil and IgE at 0, 15 and 180 minutes after the start of regular HD in 11 HD patients suffering from pruritus and as well as in 11 HD patients without pruritus were examined. These HD patients in both groups showed significantly higher (p < 0.001) values of leukotriene B4 and C3a compared to healthy non-HD subjects. There was no difference in the leukotriene B4, interleukin-6, IgE, C3a and C5a levels between the patients with and without pruritus. Two mg/day of azelastin hydrochloride, an anti-allergic drug was orally given to the pruritus group for 3 weeks. In 5 of 11 patients, the pruritus symptoms disappeared, while in 4 of 11 they improved. Independent of the effect of the drug on pruritus, leukotriene B4 levels significantly decreased compared with those before the administration of this drug in the pruritus group (p < 0.01). Interleukin 6, C3a, C5a and the number of eosinophils demonstrated no significant change. In conclusion, although azelastin hydrochloride was effective in treating pruritus and also suppressed leukotriene B4 levels in hemodialysis patients, the high leukotriene B4 activity itself did not seem to be related to the development of pruritus in these patients.