Impact of the Presence and Duration of Donor-Specific Antibodies on Renal Function

Background

Although anti-human leukocyte antigen (HLA) antibodies (DSA) is associated with graft loss, 3 things remain unclear: whether the duration and strength of DSA affect renal function; what mean fluorescence intensity (MFI) cut-off should be used; and whether the DSA effect is additive in case of multiple DSAs.

Methods

A study was made of 63 patients who received living donor kidney transplants with clonal deletion protocol and were followed up for 18 months with reduced doses of immunosuppressants. DSA was tested for monthly, using Luminex Mixed and Single Antigen beads (One Lambda, Inc., Canoga Park, CA, USA). Decrease of estimated glomerular filtration rate (eGFR) was obtained at baseline and 18 months after transplantation. Association of renal damage and DSAs was compared using several DSA models with several MFI cut-offs.

Results

Additive DSA models always showed better association with renal damage than comprehensive models. When calculating the DSA effect in additive models, “proxy-area under the curve” (AUC)—a triangular approximation of the actual AUC—showed better association with renal damage than did DSA duration (R² = 0.105 vs 0.087). Adjusting for other factors, 27% of the variation of GFR change was explained by proxy-AUC. No significant change of association occurred if the MFI cut-off level changed from 1000 to 3000.

Conclusion

Our results support the association of DSA with development of longitudinal renal damage. The clinical interpretation may be similar at MFI cut-offs of 1000, 2000, and 3000. An additive DSA effect may be expected in patients with multiple DSAs. Our study suggests the importance of frequently checking for DSA and reducing their MFI value to minimize renal damage by the antibodies.     

Intractable diffuse pulmonary diseases: Manual for diagnosis and treatment

This manual has been compiled by a joint production committee with the Diffuse Lung Disease Assembly of the Japanese Respiratory Society (JRS) to provide a practical manual for the epidemiology, diagnosis, and treatment of intractable diffuse pulmonary diseases. The contents are based upon the results of research into these diseases by the Diffuse Pulmonary Diseases Study Group (principal researcher: Sakae Homma) supported by the FY2014–FY2016 Health and Labor Sciences Research Grant on Intractable Diseases.This manual focuses on: 1) pulmonary alveolar microlithiasis, 2) bronchiolitis obliterans, and 3) Hermansky-Pudlak Syndrome with interstitial pneumonia. As these are rare/intractable diffuse lung diseases (2 and 3 were first recognized as specified intractable diseases in 2015), there have not been sufficient epidemiological studies made, and there has been little progress in formulating diagnostic criteria and severity scales; however, the results of Japan's first surveys and research into such details are presented herein. In addition, the manual provides treatment guidance and actual cases for each disease, aiming to assist in the establishment of future modalities.The manual was produced with the goal of enabling clinicians specialized in respiratory apparatus to handle these diseases in clinical settings and of further advancing future research and treatment.     

Evidence that intracellular magnesium is present in cells at a regulatory concentration for protein synthesis.

When extracellular magnesium is reduced by a factor of 50 (from 1.0 to 0.02 mM), the total intracellular magnesium of a spontaneously transformed clone of 3T3 cells decreases by 30-50%. Protein synthesis rates in these cells were measured as the intracellular magnesium decreased. Protein synthesis rates and magnesium content were found to decrease in parallel with each other. At 3 hr, a decrease to 84% of control values of magnesium content was accompanied by a decrease to 85% of control values of leucine incorporation rates. A larger inhibition had occurred by 12 hr, when the magnesium had decreased to 67% and leucine incorporation rates had decreased to 57%. When magnesium was restored to magnesium-deprived cells, both magnesium content and leucine incorporation increased about 2-fold by 1 hr. In the experiments reported here, initial small changes in magnesium content are associated with changes in protein synthesis rates. This strongly suggests that magnesium is present at a regulatory rather than excess concentration for protein synthesis. The results are consistent with a role for intracellular magnesium in the regulation of protein synthesis and support the hypothesis that magnesium has a central role in the regulation of metabolism and growth.     

A cytotoxic monoclonal antibody detecting a novel B cell membrane antigen expressed predominantly on cells bearing surface membrane immunoglobulin

A new human B lymphocyte membrane antigen, CB2, has been detected by a mouse monoclonal IgM antibody. CB2 appears to be predominantly expressed on normal and malignant cells expressing surface membrane immunoglobulin (SmIg). By indirect immunofluorescence, the number of CB2-positive cells in normal peripheral blood correlated well with the number of SmIg-positive cells. Cytotoxicity studies on isolated cell populations showed that CB2 was present on normal B cells isolated from the spleens of 52 donors and on peripheral blood B cells from 8 donors. Monocytes, T cells, granulocytes, platelets, and red cells were CB2 negative. Only malignant cells expressing SmIg were positive. These included B-CLL, B lymphoma, prolymphocytic leukemia, and B lymphoma cell lines Daudi, Raji, and Conception. SmIg-negative leukemia cells, such as common acute lymphoblastic leukemia, acute and chronic myelogenous leukemia, and T cell leukemias, were negative. Blocking studies with human immunoglobulin suggests that the CB2 antigen is not directed against immunoglobulin determinants. Immunoperoxidase studies on normal lymph node sections show that CB2-positive cells are predominantly present in the mantle region of the follicle, whereas B1- positive cells are mainly in the germinal center.     

Accelerated telomere length shortening in granulocytes: a diagnostic marker for myeloproliferative diseases

OBJECTIVE: The telomere in mature myeloid cells derived from abnormal progenitor cells of myeloproliferative diseases (MPDs) may shorten more rapidly than that in T lymphocytes, which are considered to be derived from normal clones. To test this hypothesis, we measured telomere lengths in granulocytes and T lymphocytes from patients with MPDs and compared them with those from normal individuals. MATERIALS AND METHODS: Granulocytes and T lymphocytes were separated from the peripheral blood of 65 patients with MPDs (25 chronic myelogenous leukemia [CML], 16 polycythemia vera, 19 essential thrombocythemia, 5 chronic idiopathic myelofibrosis) and 35 normal individuals. Genomic DNA from each cell fraction was subjected to Southern blot hybridization to determine the mean telomere length. RESULTS: Telomere lengths in granulocytes from patients with MPDs were significantly shorter than those from normal individuals (vs CML, p = 0.002; vs other MPDs, p < 0.0001). However, there was no statistical difference in telomere length in T lymphocytes between MPD patients and normal individuals (vs CML, p = 0.35; vs other MPDs, p = 0.85). DeltaTRF (terminal restriction fragment) in patients with MPDs, which is defined as the difference in telomere length between granulocytes and T lymphocytes, was significantly longer than that in normal individuals. CONCLUSIONS: The results support the disease theory that MPDs result from extensive proliferation of myeloid progenitor cells, leading to accelerated telomere length shortening in mature granulocytes. An increase in DeltaTRF over the standard value (>1.74 kb) may be useful for discriminating leukocytosis due to MPDs from reactive leukocytosis.     

Magnesium reverses inhibitory effects of calcium deprivation on coordinate response of 3T3 cells to serum

Deprivation of Ca(2+) in crowded cultures of 3T3 cells inhibits the onset of DNA synthesis. By raising [Mg(2+)] to 15 mM the inhibition produced by Ca(2+) deprivation can be fully overcome. Sparse cultures are not inhibited by a similar deprivation of Ca(2+), and therefore are not stimulated by supranormal [Mg(2+)]. The time course of stimulation of the onset of DNA synthesis by supranormal [Mg(2+)] in low [Ca(2+)] is the same as that produced by serum in physiological concentrations of Ca(2+) and Mg(2+). Concentrations of Mg(2+) > 20 mM in low [Ca(2+)] reverse the stimulation, and [Mg(2+)] >/= 30 mM kills many cells. In contrast to the stimulation by 15 mM Mg(2+), supranormal [Ca(2+)] has no effect on the onset of DNA synthesis in cultures inhibited by Mg(2+) deprivation, if the formation of insoluble Ca-P(i) complexes is prevented. Neither Na(+) nor K(+) reproduces the effects of Mg(2+). The uptake of uridine is another parameter of the coordinate response of 3T3 cells to serum stimulation that is inhibited by Ca(2+) deprivation, and supranormal [Mg(2+)] also reverses this inhibition. The results support the thesis that the coordinate response of growth and metabolism to external effectors is regulated by the availability of Mg(2+) within the cell and that the inhibitory effects of Ca(2+) deprivation are indirect and caused by a reduction in the availability of Mg(2+).     

Cancer-specific health-related quality of life in children with brain tumors

Purpose

To understand the influence of disease and treatment on the health-related quality of life (HRQOL) of children with brain tumors, compared to the HRQOL of children with other cancers, from the viewpoints of children and parents.

Methods

A total of 133 children aged 5–18 years and 165 parents of children aged 2–18 completed questionnaires of the Pediatric Quality of Life Inventory Cancer Module (Pain and Hurt, Nausea, Procedural Anxiety, Treatment Anxiety, Worry, Cognitive Problems, Perceived Physical Appearance, and Communication scales); higher scores indicate a better HRQOL. The Cancer Module scores, weighted by age and treatment status, were compared to those obtained in a previous study of children with other cancers (mostly leukemia).

Results

The weighted mean scores for Pain and Hurt (effect size d = 0.26) and Nausea (d = 0.23) from child reports and the scores for Nausea (d = 0.28) from parent reports were higher for children with brain tumors than scores for children with other cancers. The scores for Procedural Anxiety (d = ?0.22) and Treatment Anxiety (d = ?0.32) from parent reports were lower for parents of children with brain tumors than the scores for parents of children with other cancers. The child-reported Pain and Hurt score of the Cancer Module was higher (d = 0.29) and in less agreement (intraclass correlation coefficient = 0.43) with scores from the Brain Tumor Module, indicating that assessments completed with the Cancer Module misesteem pain and hurt problems in children with brain tumors.

Conclusions

The profiles of cancer-specific HRQOL in children with brain tumors differ from those of children with other cancers; we therefore suggest that these children receive specific psychological support.     

Gastric carcinoma with an invasive micropapillary carcinoma component showing HER2 gene amplification and CD10 expression: A case report and review of the literature

An 81‐year‐old man was referred to our hospital because gastric cancer was detected on screening esophagogastroduodenoscopy. Surgical resection of the tumor was performed. It was 25 × 20 mm in size and swollen lymph nodes were present nearby. Lymphadenectomy was also performed. Histopathologically, the tumor reached the proper muscle layer via venous invasion. There were three components that constituted the tumor, that is, 40% of mass was invasive micropapillary carcinoma (IMPC), 40% was papillary adenocarcinoma and 20% tubular adenocarcinoma. Vascular invasion was prominent. Immunohistochemistry revealed that the tumor showed an entirely intestinal mucin phenotype, being positive only for CD10 and negative for MUC2, MUC5AC, and MUC6. HER2 staining score ranged from 2+ to 3+, depending on the components described above. HER2 gene amplification was present in all the components according to dual‐color in situ hybridization. The metastatic lymph nodes were similar to the primary site in morphology and immunohistochemistry, but HER2 amplification was higher in the lymph nodes. The IMPC component with HER2 amplification is rarely seen and its positivity for CD10 is an unexpected finding for gastric IMPC. Hence, this is a highly unusual case judging by the literature; further studies are needed to clarify the nature of gastric IMPC.     

Hodgkin's disease preceded by unique neurological symptoms

This is the first case report of Hodgkin's disease (HD) which showed both remission and exacerbation of neurological signs before a confirmed diagnosis of HD. The episodes occurred three times and multiple lesions were involved. Immunoabsorption plasmapheresis and double filtration plasmapheresis were effective for the first episode, whereas, corticosteroids partly improved the second and third episodes. Fever and lymph node swelling were apparent afterward and she was diagnosed as having HD from a supraclavicular lymph node biopsy. The remaining neurologic deficits responded to chemotherapy and radiotherapy. The neurological symptoms were considered as a paraneoplastic syndrome of HD.     

Twelve years' experience with national sharing of HLA-matched cadaveric kidneys for transplantation

BACKGROUND: In October 1987, the United Network for Organ Sharing (UNOS) established a national kidney-sharing program to increase the number of HLA-matched transplantations. Since then, over 7500 cadaveric kidneys have been shipped to centers in 48 states for transplantation to HLA-matched patients. We evaluated the efficacy of the program during its first 12 years of operation. METHODS: We compared the rates of rejection and actuarial graft survival for 7614 HLA-matched and 81,364 HLA-mismatched cadaveric kidney transplantations reported to the UNOS Scientific Registry between October 1987 and September 1999. To assess the effects of the extended period of ischemia associated with shipping HLA-matched kidneys, we identified 3562 pairs of cadaveric kidneys in which one kidney went to an HLA-matched recipient and the other went to an HLA-mismatched recipient. RESULTS: The estimated 10-year rate of graft survival was 52 percent for HLA-matched transplants, as compared with 37 percent for HLA-mismatched transplants. The estimated half-lives of the transplants were 12.5 years and 8.6 years, respectively, and the mean duration of cold ischemia was 23 hours and 22 hours, respectively. After adjustment for the effects of demographic characteristics, at 10 years the overall rates of graft survival and the rates of functional-graft survival (with data censored on patients who died with a functioning graft) were 10 percent and 11 percent higher, respectively, for HLA-matched transplants than for HLA-mismatched transplants. Among 3562 pairs of kidneys, HLA-matched transplants had higher rates of survival, a lower incidence of episodes of rejection, and a lower risk of loss as a result of rejection. CONCLUSIONS: A superior graft outcome with little increase in the duration of cold ischemia justifies national sharing of HLA-matched kidney transplants.