Radiation-induced afferent arteriolar endothelial-dependent dysfunction involves decreased epoxygenase metabolites

Chronic kidney disease is a known complication of hematopoietic stem cell transplant (HSCT) and can be caused by irradiation at the time of the HSCT. In our rat model there is a 6- to 8-wk latent period after irradiation that leads to the development of proteinuria, azotemia, and hypertension. The current study tested the hypothesis that decreased endothelial-derived factors contribute to impaired afferent arteriolar function in rats exposed to total body irradiation (TBI). WAG/RijCmcr rats underwent 11 Gy TBI, and afferent arteriolar responses to acetylcholine were determined at 1, 3, and 6 wk. Blood pressure and blood urea nitrogen were not different between control and irradiated rats. Afferent arteriolar diameters were not altered in irradiated rats. Impaired endothelial-dependent responses to acetylcholine were evident at 3 and 6 wk following TBI. Nitric oxide synthase (NOS), cyclooxygenase (COX), and epoxygenase (EPOX) contribution to acetylcholine dilator responses were evaluated. NOS inhibition with NG-nitro-l-arginine methyl ester (l-NAME) reduced acetylcholine responses by 50% in controls and 90% in 3-wk TBI rats. COX inhibition with indomethacin did not significantly alter the acetylcholine response in the presence or absence of l-NAME. EPOX inhibition with N-methylsulfonyl-6-(2-propargyloxyphenyl)hexanamide significantly decreased acetylcholine responses (35%) in controls but did not significantly alter acetylcholine responses (4%) in TBI rats. Biochemical analysis revealed decreased urinary EPOX metabolites but no change in COX, NOS, or reactive oxygen species at 3 wk TBI. Taken together, these results indicate that afferent arteriolar endothelial dysfunction involves a decrease in EPOX metabolites that precedes the development of proteinuria, azotemia, and hypertension in irradiated rats.

Download Full-text

Total body radiotherapy in paediatric hematopoietic stem cell transplant patients – a single centre experience over 15 years

Pediatric Hematology Oncology Journal ◽

10.1016/j.phoj.2017.11.075 ◽

2017 ◽

Vol 2 (2) ◽

pp. S22-S23

Author(s):

Dhaarani J. Subathira ◽

Janos Stumpf ◽

Rathna Devi ◽

C. Sanjay ◽

U. Ramya ◽

...

Keyword(s):

Stem Cell ◽

Hematopoietic Stem Cell ◽

Hematopoietic Stem Cell Transplant ◽

Stem Cell Transplant ◽

Cell Transplant ◽

Single Centre ◽

Hematopoietic Stem ◽

Transplant Patients ◽

Single Centre Experience ◽

Total Body

Download Full-text

Donor-Cell Leukemia After Hematopoietic Stem Cell Transplant: a Retrospective Review of a Single Center's Experience

Blood ◽

10.1182/blood.v118.21.1997.1997 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1997-1997

Author(s):

Katie Washburn ◽

George B. Selby ◽

S. Terence Dunn ◽

Jennifer L. Holter Chakrabarty

Keyword(s):

Stem Cell ◽

Hematopoietic Stem Cell Transplant ◽

Stem Cell Transplant ◽

Donor Cell ◽

Cell Transplant ◽

Cell Leukemia ◽

Hematopoietic Stem ◽

Total Body ◽

Mismatched Donor ◽

Donor Cell Leukemia

Abstract Abstract 1997 Donor-cell leukemia (DCL) is a rare complication of allogeneic hematopoietic stem cell transplant (ASCT) with a reported incidence varying from 0.1% to 5.0% of all post-transplantation relapses. However, the incidence is likely to be highly underestimated due to the difficulty in making the diagnosis. In the 1970s and 1980s, diagnosis of DCL relied on cytogenetic and fluorescence in situ hybridization studies in sex-mismatched donor/recipient pairs. Recent advances in molecular-based laboratory methods have considerably improved our ability to identify and confirm DCL in ASCT patients, especially when there is not a sex-mismatch between donor and recipient. Recently, an algorithm has been proposed by Wang et al. 2011 (Am J Clin Pathol 135;525–40) to help make the diagnosis of DCL in ASCT patients who develop overt leukemia or a clonal cytogenetic abnormality using these new advanced techniques. We retrospectively evaluated all patients who underwent ASCT at our center for acute leukemia from 2005 to present. Out of 43 patients, 6 apparent DCLs were documented using short tandem repeat (STR) analysis (12 separate loci examined); each ASCT patient relapsed with the full complement of donor STRs. Our data confirms that the true incidence of DCL is likely underestimated, since within our select population, we had a 14% incidence of DCL. Of note, 1/6 were sex mismatches, 3/6 received cord blood transplants, 4/6 cases were ABO mismatches, and 4/6 cases were AML (Table 1). Our findings concur with sparse available reports in the literature that purport there may be a shorter time to relapse in patients who are undergoing ASCT for malignant reasons; indeed, our average latency period was 14 months as opposed to 24 months found by Wang et al. However, we did not find that a disproportionate number of sex-mismatched donor/recipient pairs developed DCL; in fact, nearly all of our DCLs arose in the setting of a sex-matched pair. The apparent increased incidence in cord blood transplants, sex-mismatched donor/recipient pairs and ABO-mismatched transplants needs to be assessed in a large-scale registry using standard methodologies, which could help identify and define potential causes of DCL.Table 1:Patient Characteristics with Donor-Derived LeukemiaSexAge (years)Leukemia TypeTransplant TypeTime to Relapse (months)Sex MismatchABO MismatchChemotherapy PreparationM22ALLunrelated donor15NoYesalemtuzumabF1AMLrelated sibling14NoNoBu/Cy/Mito1M24AMLunrelated double-cord blood40NoNoTVTG2M20AMLunrelated donor5NoYesCy/TBI3M26AMLunrelated double-cord blood10.5YesYesFlu/Cy/TBI4M26ALLunrelated double-cord blood3.5NoYesFlu/Cy/TBI41. busulfan, cytarabine, mitoxantrone2. topotecan, vinorelbine, thiotepa, gemcitabine3. cyclophosphamide & total body irradiation4. fludarabine, cyclophosphamide & total body irradiation Disclosures: No relevant conflicts of interest to declare.

Download Full-text