Faculty Bibliography

Late effects of total- or partial-body irradiation include chronic kidney injury (CKI), which increases morbidity and mortality. Glomerular filtration rate (GFR) is the gold standard measure of kidney function. Renal function markers, such as blood urea nitrogen (BUN) and serum creatinine (Cr), may not be higher than reference ranges until 50% or more of nephrons are affected. Currently available methods to measure GFR are difficult and expensive, requiring multiple blood draws or timed urine collections, but their use can provide a framework for the development of simpler GFR estimates. The measurement of iohexol clearance is a validated tool used to determine GFR in veterinary patients. In this study, we aimed to determine if the Schwartz formula as used in human pediatric medicine can estimate GFR in rhesus macaques. We hypothesized that iohexol-GFR would correlate with the Schwartz formula-estimated GFR (eGFR) in irradiated and non-irradiated rhesus macaques. Twelve rhesus macaques [age 5-14 years (mean 7 years); 5 females, 7 males] with a range of BUN levels were selected for comparison to 4 non-irradiated controls (2 females, 2 males). Irradiated animals were divided by BUN into 3 groups: BUN ≤20 mg/dL (n = 4), BUN >20-24 mg/dL (n = 4), and BUN ≥25 mg/dL (n = 4). Baseline serum chemistry and urinalysis were used to assess renal function. For measurement of GFR, macaques were maintained under general anesthesia and received an intravenous injection of iohexol (2 mL/kg, 300 mg I/mL). Whole blood was collected at 10, 30, 60 and 90 min post-iohexol injection. Plasma iohexol concentrations were determined by mass spectrometry. GFR was calculated from the peak iohexol concentration and trapezoidal area under the curve (tAUC). The iohexol-GFR significantly correlated with the Schwartz formula-eGFR. In macaques with renal irradiation doses below 6 Gy, GFR was higher for males than females. GFR was lower in macaques with renal irradiation doses greater than 6 Gy compared to macaques with renal doses less than 6 Gy. We conclude that use of the Schwartz formula can provide a rapid, non-invasive, cost-effective, and accurate estimation of GFR to aid in the clinical assessment of renal function in irradiated rhesus macaques.

RATIONALE AND OBJECTIVES/UNASSIGNED:The accurate, non-invasive, and rapid measurement of renal cortical fibrosis is needed for well-defined benchmarks of permanent injury and for use of anti-fibrotic agents. It is also needed for non-invasive and rapid assessment of the chronicity of human renal diseases. MATERIALS AND METHODS/UNASSIGNED:We have used a non-human primate model of radiation nephropathy to develop a novel method of size-corrected CT imaging to quantify renal cortical fibrosis. RESULTS/UNASSIGNED:Our method has an area under the receiver operating curve of 0.96, which is superior to any other non-invasive method of measuring renal fibrosis. CONCLUSION/UNASSIGNED:Our method is suitable for immediate translation to human clinical renal diseases.

Introduction: Systemic treatments for metastatic or unresectable renal cell carcinoma (mRCC) are rapidly evolving. This study aimed at investigating challenges in the care of mRCC to inform future educational interventions for health care providers (HCPs). Materials and Methods: The sequential mixed-method design consisted of a qualitative phase (semistructured interviews) followed by a quantitative phase (online surveys). Participants included US-based medical oncologists, nephrologists, physician assistants, nurse practitioners, and registered nurses. Interview transcripts were thematically analyzed. Survey data was descriptively and inferentially analyzed. Results: Forty interviews and 265 surveys were completed. Analysis revealed four challenges in the care of mRCC patients. A challenge in staying current with emerging evidence and treatment recommendations was found with 33% of surveyed HCPs reporting suboptimal skills interpreting published evidence on the efficacy and safety of emerging agents. A challenge weighing patient health and preferences in treatment decisions was found, especially among HCPs with 3 to 10 years of practice (37%) who reported suboptimal skills in assessing patients"™ tolerance to side effects. Promoting a collaborative care approach to the management of immune-related adverse events was a challenge, specifically related to barriers involving nephrologists (eg, diverging treatment goals). Breakdowns in communication were reported (46% of HCPs), especially in the monitoring of side effects and treatment adherence. Conclusion: This study revealed key challenges faced by HCPs when treating and managing patients with mRCC across multiple providers. Future interventions (eg, community of practice) should aim to address the identified gaps and promote a team-based approach to care that strengthens the complementary competencies of HCPs involved.

Angiotensin converting enzyme (ACE) inhibitors are effective countermeasures to chronic radiation injuries in rodent models, and there is evidence for similar effects in humans. In rodent models ACE inhibitors are effective mitigators of radiation injury to kidney, lung, central nervous system (CNS) and skin, even when started weeks after irradiation. In humans, the best data for their efficacy as radiation countermeasures comes from retrospective studies of injuries in radiotherapy patients. We propose that ACE inhibitors, at doses approved for human use for other indications, could be used to reduce the risk of chronic radiation injuries from deep-space exploration. Because of the potential interaction of ACE inhibitors and microgravity (due to effects of ACE inhibitors on fluid balance) use might be restricted to post-exposure when/if radiation exposures reached a danger level. A major unresolved issue for this approach is the sparse evidence for the efficacy of ACE inhibitors after low-dose-rate exposure and/or for high-LET radiations (as would occur on long-duration space flights). A second issue is that the lack of a clear mechanism of action of the ACE inhibitors as mitigators makes obtaining an appropriate label under the Food and Drug Administration Animal Rule difficult.

Radiation nephropathy is renal injury caused by a sufficient dose of irradiation. It can result from external beam irradiation or internal irradiation as might occur from therapeutic radioisotopes. Its usual clinical presentation is as chronic kidney disease occurring some months after irradiation, and it can evolve to end-stage-renal-disease. While the immediate cellular injury from irradiation depends on radiolysis of water and oxidative DNA damage, there is no conclusive evidence for chronic persistent oxidative stress or inflammation as the cause of the multi-tissue scarring that ensues. Antagonists of the renin-angiotensin system are effective treatments for experimental radiation nephropathy but their preferential value in human clinical medicine is unproven.
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Inflammation is commonly cited as a mechanism of delayed effects of acute radiation exposure (DEARE). Confirmation of its presence could provide significant insight to targeted use of treatments or mitigators of DEARE. We sought to quantify the presence of cellular inflammation in kidneys of non-human primates that developed acute and chronic kidney injury after a partial body irradiation exposure. We show herein that cellular inflammation is not found as a component of either acute or chronic kidney injury. Other mechanistic pathways of injury must be sought.

PURPOSE/UNASSIGNED:The hemorrhagic syndrome is a major cause of morbidity and mortality associated with the acute radiation syndrome (ARS). We previously characterized the dose-response relationship for total body irradiation (TBI)-induced ARS in the New Zealand White (NZW) rabbit. Thrombocytopenia, hemorrhage, and anemia were strongly associated with morbidity/mortality during the first three weeks post-TBI. The objective of the current study was to further characterize the natural history of thrombocytopenia, hemostatic dysfunction and hemorrhage in the rabbit model at a TBI dose range to induce ARS. METHODS/UNASSIGNED: 6) were included as a comparator. Animals were treated with minimal supportive care including pain medication, antibiotics, antipyretics for temperature >104.8 °F, and fluids for signs of dehydration. Animals were culled at pre-determined timepoints post-TBI, or for signs of imminent mortality based on pre-defined euthanasia criteria. Hematology parameters, serum chemistry, viscoelasticity of whole blood, coagulation tests, and coagulation factor activities were measured. A gross exam of vital organs was performed at necropsy. RESULTS/UNASSIGNED:Findings in this study include severe neutropenia during the first week post-TBI followed by thrombocytopenia and severe acute anemia with petechial hemorrhages of the skin and hemorrhage of the vital organs during the second to third weeks post-TBI. Abnormalities in whole blood viscoelastometry were observed concurrent with thrombocytopenia and hemorrhage. Antithrombin activity was significantly elevated in animals after exposure to 7.5 Gy, but not 7.0 Gy TBI. CONCLUSIONS/UNASSIGNED:The hemorrhagic syndrome in the rabbit model of TBI recapitulates the pathogenesis described in humans following accidental or deliberate exposures. The rabbit may present an alternative to the rodent model as a small animal species for characterization of the full spectrum of multiorgan injury following TBI and early testing of promising medical countermeasures.