Stenosis of the glomerulotubular neck in progressive chronic kidney disease.

BACKGROUND: Morphology and morphometric evaluation of lesions beyond conventional parameters can inform the pathophysiology of chronic kidney disease (CKD). We sought to determine whether the occurrence of glomerulotubular neck stenoses associates with progressive CKD. METHODS: We evaluated the normal parenchyma from radical nephrectomies removed for tumor between 2000 and 2021 and analyzed cortex for stenoses of the glomerulotubular neck. Stenosis of the glomerulotubular neck is defined a focal narrowing for which the draining tubule has a greater diameter than at the neck. Progressive CKD was defined as dialysis, kidney transplantation, sustained eGFR <10 ml/min per 1.73m2 or sustained 40% decline from the post-nephrectomy eGFR. Each case of progressive CKD was age-sex-matched to 2 controls without progressive CKD. Logistic regression models assessed the risk of progressive CKD with stenotic necks adjusting for other histological features, kidney function, and CKD risk factors. RESULTS: There were 65 cases with a mean of 255 glomeruli and 130 controls with a mean of 329 glomeruli. Among both cases and controls, 5% of glomeruli showed visible glomerulotubular necks. The proportion of necks that were stenotic was higher in cases than controls (35% vs. 11%, p<0.0001). Stenotic necks associated with progressive CKD independent of other histologic and clinical characteristics. CONCLUSION: Glomerulotubular neck stenosis is associated with development of progressive CKD.

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 N(G)-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.

Epoxyeicosatrienoic acid analogue mitigates kidney injury in a rat model of radiation nephropathy.

Arachidonic acid is metabolized to epoxyeicosatrienoic acids (EETs) by CYP epoxygenases, and EETs are kidney protective in multiple pathologies. We determined the ability of an EET analogue, EET-A, to mitigate experimental radiation nephropathy. The kidney expression of the EET producing enzyme CYP2C11 was lower in rats that received total body irradiation (TBI rat) compared with non-irradiated control. At 12 weeks after TBI, the rats had higher systolic blood pressure and impaired renal afferent arteriolar function compared with control, and EET-A or captopril mitigated these abnormalities. The TBI rats had 3-fold higher blood urea nitrogen (BUN) compared with control, and EET-A or captopril decreased BUN by 40-60%. The urine albumin/creatinine ratio was increased 94-fold in TBI rats, and EET-A or captopril attenuated that increase by 60-90%. In TBI rats, nephrinuria was elevated 30-fold and EET-A or captopril decreased it by 50-90%. Renal interstitial fibrosis, tubular and glomerular injury were present in the TBI rats, and each was decreased by EET-A or captopril. We further demonstrated elevated renal parenchymal apoptosis in TBI rats, which was mitigated by EET-A or captopril. Additional studies revealed that captopril or EET-A mitigated renal apoptosis by acting on the p53/Fas/FasL (Fas ligand) apoptotic pathway. The present study demonstrates a novel EET analogue-based strategy for mitigation of experimental radiation nephropathy by improving renal afferent arteriolar function and by decreasing renal apoptosis.

A single center's approach to discriminating donor versus host origin of renal neoplasia in the allograft kidney.

Renal cell carcinoma (RCC) in the allograft of kidney transplant recipient (KTR) patients is rare and may represent a de novo process arising from the transplanted organ or metastasis from a clinically undetectable host primary. Determination of host versus donor origin is important for staging and management. We report our experience utilizing Penta-C (PC) and Penta-D (PD) short-tandem repeat (STR) microsatellite analysis to discriminate between host and donor origin of RCC identified in renal allografts. We identified 5 KTR patients with RCC in the allograft kidney. The PC and PD microsatellite analysis was applied to tumor, host, and donor formalin-fixed, paraffin-embedded tissue sections and/or fresh blood leukocytes to identify the origin of the neoplastic cells. The PC and PD microsatellite alleles were robustly amplified in all samples. Each case showed one or more informative alleles indicating that the neoplastic cells originate from donor tissue. Allele frequency data indicate that by using both PC and PD markers, we will be able to discriminate between host and donor cell of origin in over 99% of cases. The PC and PD microsatellite analysis is a convenient, robust, and efficient strategy to determine donor versus host origin or RCC in transplant kidney specimens.

Correction: Lenarczyk et al. T Cells Contribute to Pathological Responses in the Non-Targeted Rat Heart following Irradiation of the Kidneys. Toxics 2022, 10, 797.

In the original publication [...].

Identifying the Needs of Health Care Providers in Advanced First-Line Renal Cell Carcinoma: A Mixed-Methods Research.

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.

A New Method for Estimating Glomerular Filtration Rate in Rhesus Macaques (Macaca mulatta).

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.

Measurement of renal cortical fibrosis by CT scan.

Rationale and objectives: 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: 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: 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: Our method is suitable for immediate translation to human clinical renal diseases.

Chronic kidney disease among high school students of Kinshasa.

BACKGROUND: Chronic kidney disease (CKD) is a major worldwide health problem. However, its burden among adolescents and young adults is unknown, especially in sub-Saharan Africa. The aim of this study was to investigate its prevalence in the school environment. The concordance of usual formulas used to estimate renal function was also assessed. METHODS: In an epidemiological cross sectional study, a random sample of 524 pupils (263 boys, mean age of 18.7 ± 1.4 years) from school environment of Kinshasa were studied. Recorded parameters of interest were anthropometric, proteinuria, serum creatinine and estimated glomerular filtration rate (eGFR) according to the Schwartz formula using uncalibrated creatinine levels from one random measurement. CKD was defined as the presence of kidney damage (daily proteinuria ≥ 300 mg) and/or reduced kidney function (eGFR < 60 ml/min/1.73 m2). Concordances between eGFR according to Schwartz, Cockcroft-Gault (C-G) indexed for BSA and modification of diet in renal disease (MDRD) study equations were computed using the kappa coefficient. RESULTS: The prevalence of CKD by the Schwartz formula was 1.5%. By stage, 0.8% had CKD stage 1 (proteinuria with normal eGFR) and 0.8% had CKD stage 3 (eGFR, 30 to 59 ml/min/1.73 m2). The prevalence of proteinuria ≥ 300 mg/day was 1% (one case had 2.7g/day). Agreement between eGFR according to Schwartz formula and the MDRD formula was excellent (kappa: 88.8%). Although correlations between all formulas were excellent (0.99; 0.87, and 0.89), agreement was poor between eGFR according to Schwartz and C-G indexed BSA equation (kappa: 52.7%) and, poorer with C-G unadjusted for BSA (kappa: 26.9%). CONCLUSION: In the large African city of Kinshasa, 2% of high school students have CKD. This high prevalence rate emphasizes the need for appropriate detection and prevention measures in this vulnerable young age population group.

Angiotensin converting enzyme (ACE) inhibitors as radiation countermeasures for long-duration space flights.

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.

T Cells Contribute to Pathological Responses in the Non-Targeted Rat Heart following Irradiation of the Kidneys.

Heart disease is a significant adverse event caused by radiotherapy for some cancers. Identifying the origins of radiogenic heart disease will allow therapies to be developed. Previous studies showed non-targeted effects manifest as fibrosis in the non-irradiated heart after 120 days following targeted X-irradiation of the kidneys with 10 Gy in WAG/RijCmcr rats. To demonstrate the involvement of T cells in driving pathophysiological responses in the out-of-field heart, and to characterize the timing of immune cell engagement, we created and validated a T cell knock downrat on the WAG genetic backgrou nd. Irradiation of the kidneys with 10 Gy of X-rays in wild-type rats resulted in infiltration of T cells, natural killer cells, and macrophages after 120 days, and none of these after 40 days, suggesting immune cell engagement is a late response. The radiation nephropathy and cardiac fibrosis that resulted in these animals after 120 days was significantly decreased in irradiated T cell depleted rats. We conclude that T cells function as an effector cell in communicating signals from the irradiated kidneys which cause pathologic remodeling of non-targeted heart.

The Natural History of Acute Radiation-induced H-ARS and Concomitant Multi-organ Injury in the Non-human Primate: The MCART Experience.

ABSTRACT: The dose response relationship and corresponding values for mid-lethal dose and slope are used to define the dose- and time-dependent parameters of the hematopoietic acute radiation syndrome. The characteristic time course of mortality, morbidity, and secondary endpoints are well defined. The concomitant comorbidities, potential mortality, and other multi-organ injuries that are similarly dose- and time-dependent are less defined. Determination of the natural history or pathophysiology associated with the lethal hematopoietic acute radiation syndrome is a significant gap in knowledge, especially when considered in the context of a nuclear weapon scenario. In this regard, the exposure is likely ill-defined, heterogenous, and nonuniform. These conditions forecast sparing of bone marrow and increased survival from the acute radiation syndrome consequent to threshold doses for the delayed effects of acute radiation exposure due to marrow sparing, medical management, and use of approved medical countermeasures. The intent herein is to provide a composite natural history of the pathophysiology concomitant with the evolution of the potentially lethal hematopoietic acute radiation syndrome derived from studies that focused on total body irradiation and partial body irradiation with bone marrow sparing. The marked differential in estimated LD50/60 from 7.5 Gy to 10.88 Gy for the total body irradiation and partial body irradiation with 5% bone marrow sparing models, respectively, provided a clear distinction between the attendant multiple organ injury and natural history of the two models that included medical management. Total body irradiation was focused on equivalent LD50/60 exposures. The 10 Gy and 11 Gy partial body with 5% bone marrow sparing exposures bracketed the LD50/60 (10.88 Gy). The incidence, progression, and duration of multiple organ injury was described for each exposure protocol within the hematopoietic acute radiation syndrome. The higher threshold doses for the partial body irradiation with bone marrow sparing protocol induced a marked degree of multiple organ injury to include lethal gastrointestinal acute radiation syndrome, prolonged crypt loss and mucosal damage, immune suppression, acute kidney injury, body weight loss, and added clinical comorbidities that defined a complex timeline of organ injury through the acute hematopoietic acute radiation syndrome. The natural history of the acute radiation syndrome presents a 60-d time segment of multi-organ sequelae that is concomitant with the latent period or time to onset of the evolving multi-organ injury of the delayed effects of acute radiation exposure.

A New Zealand White rabbit model of thrombocytopenia and coagulopathy following total body irradiation across the dose range to induce the hematopoietic-subsyndrome of acute radiation syndrome.

PURPOSE: The purpose if this study was to develop a rabbit model of total body irradiation (TBI) -induced thrombocytopenia and coagulopathy across the dose-range which induces the hematopoietic subsyndrome of the acute radiation syndrome (H-ARS). METHODS: Twenty male New Zealand White rabbits were assigned to arms to receive 6-MV of TBI at a dose of 6.5, 7.5, 8.5 or 9.5 Gy. Animals were treated with moderate levels of supportive care including buprenorphine for pain management, antibiotics, antipyretics for rectal body temperature >104.8 °F, and fluids for signs of dehydration. Animals were closelyfollowed for up to 45 days after TBI for signs of major morbidity/mortality. Hematology and serum chemistry parameters were routinely monitored. Hemostasis parameters were analyzed prior to TBI, 2 and 6 hours post-TBI, and at the time of euthanasia. RESULTS: Animals developed the characteristic signs and symptoms of H-ARS during the first-week post TBI. Animals became thrombocytopenic with signs of severe acute anemia during the second week post TBI. Moribund animals presented with petechia and ecchymosis of the skin and generalized internal hemorrhage. Multiorgan dysfunction characterized by bone marrow failure, gastric ileus, acute renal toxicity, and liver abnormalities were common. Severe abnormalities in coagulation parameters were observed. CONCLUSIONS: The presentation of bone marrow failure and multiorogan injury associated with ARS in the New Zealand White rabbit model is consistent with that described in the canine, swine, non-human primate, and in humans. The hemorrhagic syndrome associated with the ARS in rabbits is characterized by thrombocytopenia and hemostasis dysfunction, which appear to underlie the development of multiorgan dysfunction following TBI to rabbits. Taken together, the rabbit recapitulates the pathogenesis of ARS in humans, and may present an alternative small animal model for medical countermeasure pilot efficacy screening, dose-finding and schedule optimization studies prior to moving into large animal models of TBI-induced ARS.

Characterization of the hemorrhagic syndrome in the New Zealand white rabbit model following total body irradiation.

PURPOSE: 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: Fifty male NZW rabbits were randomized to receive 7.0 or 7.5 Gy of 6 MV-derived TBI. Sham-irradiated controls (n = 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: 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: 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.

Lack of Cellular Inflammation in a Non-human Primate Model of Radiation Nephropathy.

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.

Detection and quantification of renal fibrosis by computerized tomography.

OBJECTIVES: Reliable biomarkers for renal fibrosis are needed for clinical care and for research. Existing non-invasive biomarkers are imprecise, which has limited their utility. METHODS: We developed a method to quantify fibrosis by subject size-adjusted CT Hounsfield units. This was accomplished using CT measurements of renal cortex in previously irradiated non-human primates. RESULTS: Renal cortex mean CT Hounsfield units that were adjusted for body size had a very good direct correlation with renal parenchymal fibrosis, with an area under the curve of 0.93. CONCLUSIONS: This metric is a promising and simple non-invasive biomarker for renal fibrosis.