Protein C and protein S deficiencies may be related to survival among hemodialysis patients.

BACKGROUND: Thrombophilia due to protein C (PC) and protein S (PS) deficiencies is highly prevalent among patients with stage 5 chronic kidney disease and is reported to arise due to extracorporeal circulation during hemodialysis (HD). This study aimed to evaluate the relationship between HD treatment and thrombophilia. METHODS: A total of 114 Japanese patients on maintenance HD (62 men, 52 women) were followed during 2008-2011. Their survival rates were compared against the duration of HD. Prior to each HD, coagulation/fibrinolysis parameters and PC and PS activities were measured using standard techniques. The patients were divided into two groups: Group 1, with PC and/or PS deficiencies (n = 32), and Group 2, without PC and PS deficiencies (n = 82). The influence of such deficiencies and duration of dialysis on survival was examined. Time-to-event analysis was applied using Kaplan-Meier estimates, and the log-rank test was proposed to test the equivalence of relative survival data. Hazard ratios and 95% confidence intervals (CI) were calculated. RESULTS: Of the 114 patients, 37 died (Group 1, 22; Group 2, 15). The hazard ratio (95% CI) was higher (p = 0.004) in Group 1 than Group 2. Gene analyses of PC and PS were performed in 14 patients from Group 1. No mutations in either protein were observed. We analyzed the causes of death in both groups; however, the estimated thrombophilia-related incidence of death could not be determined due to small sample size of HD patients. CONCLUSIONS: Our results suggest that PC and PS deficiencies may be related to survival in HD patients. However, this finding warrants additional research.

Significance of a Family-based Study of Hereditary Thrombosis: A Single-family Case Series of Protein C Deficiency.

Thrombophilia is a serious unpredictable complication caused by gene mutations, resulting in anticoagulant deficiencies. We herein report a single-family case series of protein C (PC) deficiency. Case 1 involved a Japanese man whose PC deficiency resulted in severe systemic thrombosis. The patients in cases 2 and 3 were his daughters who were diagnosed with PC deficiency via carrier screening in 2001 and later both became pregnant. Owing to appropriate treatments during pregnancy, they did not develop thrombosis and safely gave birth to healthy infants. This family case series suggests that appropriate knowledge concerning thrombophilia helps prevent future emergencies.

Current international status of home hemodialysis.

Three times weekly home hemodialysis (HHD) was introduced shortly after the initiation of chronic hemodialysis (HD) treatment in 1960. HHD eliminates the need of transportation to and from the dialysis unit and by allowing patients to set their own dialysis schedule, decreases the burden of treatment on their personal and professional lives. HHD has been found more economical and more highly associated with better patient survival than in-center dialysis. Nevertheless, the global prevalence of HHD decreased between 1980 and 2000 due to the increased availability of dialysis units and continuous ambulatory peritoneal dialysis, advances in cadaveric kidney transplantation, and several other factors. However, the availability of HHD at a frequency of more than 3 times/week, the typical frequency of conventional HD (CHD), in such forms as brief HD sessions of 2-3 h 5-6 days/week and nocturnal HD (NHD) has led to reversals in this trend. Frequent HHD, such as short daily HD (SDHD) and NHD instead of 3 times/week CHD, has been found to significantly improve hypertension, left ventricular mass, renal anemia, quality of life and mortality. On the other hand, NHD has been found to significantly improve hypertension, left ventricular mass, renal anemia, quality of life, malnutrition, mortality and phosphate clearance. Many observational clinical studies and one randomized controlled trial of SDHD and/or NHD have been conducted, and compact and convenient dialysis machines have been developed and used for HHD. The most recent data reported in the national and local registries of selected countries indicate that the prevalence of HHD among all dialysis patients from 2008 to 2010 varied from 0 to 3.3% except in New Zealand and Australia, where it was 16.3 and 9.3%, respectively. As HHD appears to be a more effective and economical dialysis modality than in-center CHD, its prevalence is likely to increase in the future.

Rapidly progressive cryoglobulinemic glomerulonephritis.

The clinical course of cryoglobulinemic glomerulonephritis (CGGN) is usually slowly progressive, and only a minority of these patients progress to end-stage renal failure. This report describes an atypical case of a patient with CGGN who demonstrated a rapidly progressive and irreversible renal deterioration. After presenting with symptoms of an upper respiratory infection, the patient exhibited oliguric acute renal failure, which was followed by systemic efflorescence accompanied by a fever. The laboratory analyses of his serum revealed the patient to be cryoglobulin-positive with markedly decreased serum C4 levels and an increased anti-streptolysin O titer. A serological test for the hepatitis C virus was negative. A renal biopsy showed that the patient had diffuse endocapillary and extracapillary proliferation together with marked endoluminal thrombi and subendothelial deposits in glomeruli. An electron microscopic examination demonstrated the presence of electron-dense subendothelial, subepithelial and huge intraluminal deposits with a specific annular and cylindrical structure. These features were consistent with active and severe CGGN. Despite aggressive treatment with corticosteroid pulses and a plasma exchange, a second renal biopsy demonstrated further advanced renal injury and revealed no signs of recovery.

uPAR (CD87) as a biocompatibility marker of dialysis membrane.

BACKGROUND/AIMS: Hemodialysis (HD) therapy may lead to functional changes in patient leukocytes. For example, the upregulation of inflammatory cytokines, such as IL-1beta and TNFalpha, has been well characterized. However, these findings do not explain the entire response of leukocytes in HD. In this study, we carried out a comprehensive gene expression analysis in leukocytes treated with various dialysis membranes using DNA microarrays. The identified gene has the potential to be a new marker for testing dialysis membrane biocompatibility. METHODS: Gene expression profiles were compared between a group of leukocytes treated with various dialysis membranes and an untreated group by using DNA microarray analysis. Expression was confirmed by quantitative RT-PCR. The expression of the gene product (leukocyte surface protein) was examined in 20 chronic HD patients by flow cytometry. RESULTS: In addition to the inflammatory cytokines, the urokinase plasminogen activator receptor (uPAR or CD87) gene was induced in leukocytes treated with each dialysis membrane. The extent of induction depended on the membrane's material composition. The expression of the uPAR (CD87) protein on leukocytes was markedly increased in patients undergoing dialysis therapy. The magnitude of uPAR (CD87) protein expression was correlated with clinical findings, i.e., the degree of leukopenia and the expression of adhesion molecules. CONCLUSIONS: The gene and protein expression of uPAR (CD87) depended on the dialysis membrane material and correlated closely with clinical findings. These results suggest that uPAR has the potential to serve as a marker not only for clinical use but also for the development of new dialysis membranes.

Significance of screening for Fabry disease among male dialysis patients.

BACKGROUND: Fabry disease is an X-linked disorder resulting from a deficiency of the lysosomal enzyme alpha-galactosidase A(alpha-Gal A). Renal insufficiency is a very important manifestation and affects the prognosis of patients. Recently, a renal variant type that is characterized by low plasma alpha-Gal A activity and a milder phenotype, but which progresses to end-stage renal failure, has been reported. In this study, we clarified the incidence of this atypical variant of Fabry disease in hemodialysis patients. METHODS: We measured plasma alpha-Gal A activity in 450 male dialysis patients who had never been diagnosed with Fabry disease. RESULTS: The mean of the alpha-Gal A activity of the patients was 9.75 +/- 3.20 nmol/h/ml, while the controls with classical Fabry (n = 3) were 0.52-1.04 nmol/h/ml. Among the patients, one patient was found to exhibit low alpha-Gal A activity in plasma (3.18 nmol/h/ml) and in leukocytes (0.639 nmol/h/mg). This patient was a 43-year-old Japanese man who had been on regular dialysis since the age of 23. He did not present typical clinical signs of classical Fabry, such as acroparesthesias or hypohidrosis, but did present renal insufficiency and severe left ventricular hypertrophy which had developed only recently, suggesting a variant form of Fabry disease. Sequencing of the DNA of this patient revealed a deletion of a single amino acid of valine in 10252. CONCLUSIONS: A case of an atypical variant of Fabry among 450 male dialysis patients (0.22%) was found in the survey. This indicates the potential for undiagnosed Fabry disease among dialysis patients. The results of this study indicate the significance of screening for Fabry disease among male dialysis patients.

[Interstitial pneumonia and nephritis with Sjögren's syndrome: successful treatment with corticosteroid therapy].

A Sixty eight-year-old man complained of shortness of breath on exercise since the spring of 2001. An abnormal lung shadow was pointed out on chest X-ray and progression of renal dysfunction and high gamma globulinemia were detected out on blood examination. He was admitted to the Department of Respiratory Disease in our hospital in March 2003, because of bilateral lower lung interstitial shadow, severe anemia (Hb 7.9 g/dl), and renal dysfunction (S-Cr 1.9 mg/dl). He was found to have hypergammaglobulinemia (IgG 2,997 mg/dl), positive RO/SS-A antigen, high serum KL-6 level (2,050 U/ml), and increased urinary excretion of beta2-microglobulin (beta2MG). Both Gum test and Schirmer test results were positive. Lip biopsy showed cell infiltration to the salivary glands and he was diagnosed as having Sjogren's syndrome. Renal biopsy showed diffuse interstitial cell infiltration and a Trans Bronchoscopic Lung Biopsy (TBLB) showed fibrotic thickness and lymphocyte infiltration in the alveolar septum. Accordingly, he was diagnosed as having Sjögren's syndrome complicated with both interstitial nephritis and interstitial pneumonitis. He was treated by high-dose corticosteroid therapy and anticoagulant heparin. His laboratory data showed that both serum KL-6 and urinary beta2MG were reduced. Chest CT showed remarkable improvement of the interstitial shadow. A second renal biopsy performed at ten weeks after the beginning of treatment showed remarkable improvement of the interstitial cell infiltration. This is a rare case of Sjögren's syndrome complicated with interstitial nephritis and interstitial pneumonitis, treated successfully with high-dose corticosteroid therapy. Both complications showed immediate improvement with high-dose corticosteroid therapy, suggesting that early steroid therapy is effective for both complications.