An Overlap of Anticoagulant-Related and IgA Nephropathy: A Case Report.

Introduction: Anticoagulant-related nephropathy (ARN) is an increasingly recognized cause of acute kidney injury (AKI), initially associated with warfarin use. Supratherapeutic warfarin levels were implicated in kidney toxicity. With the widespread adoption of direct oral anticoagulants (DOACs), it becomes imperative to understand their potential risk for ARN and its clinical presentation. Case Presentation: We report a case of a 64-year-old male prescribed DOAC for paroxysmal atrial fibrillation management, presenting with heart failure and worsening AKI. Hematuria and mild proteinuria were also observed. Despite management attempts, AKI persisted, prompting a kidney biopsy. Histopathological examination revealed acute tubular injury with numerous intratubular red blood cell casts consistent with ARN. Additionally, findings indicative of IgA nephropathy (IgAN), including mesangial hypercellularity and IgA dominant deposition, were noted. Conclusion: This case underscores the emerging risk of ARN associated with DOACs and emphasizes the potential exacerbation of ARN in the presence of underlying glomerular diseases such as IgAN. Clinicians should maintain a high index of suspicion for ARN in patients on anticoagulation therapy, particularly DOACs, who present with AKI and urinary abnormalities, as early recognition and intervention are crucial in preventing further renal damage.

Pulsed Laser Deposition of Epitaxial SrTiO3/Sr3Al2O6 Templates as a Water-Soluble Sacrificial Layer for GaAs Growth and Lift-Off.

Despite the record-high efficiency of GaAs solar cells, their terrestrial application is limited due to both the particularly high costs related to the required single-crystal substrates and epitaxial growth. A water-soluble lift-off layer could reduce costs by avoiding the need for toxic and dangerous etchants, substrate repolishing, and expensive process steps. Sr3Al2O6 (SAO) is a water-soluble cubic oxide, and SrTiO3 (STO) is a perovskite oxide, where a SAO ≈ 4 × a STO ≈ (2√2)a GaAs. Here, the pulsed laser-deposited epitaxial growth of SrTiO3/Sr3Al2O6 templates on STO and Ge substrates for epitaxial GaAs growth was investigated, where SAO works as a sacrificial layer and STO protects the hygroscopic SAO during substrate transfer between deposition chambers. We identified that the SAO film quality is strongly dependent on the growth temperature and the O2 partial pressure, where either a high T or a high P(O2) improves the quality. XRD spectra of the films with optimized deposition parameters showed an epitaxial STO/SAO stack aligned to the STO (100) substrate, and TEM analysis revealed that the grown films were epitaxially crystalline throughout the thickness. The STO/SAO growth on Ge substrates at a high T with no intentional O2 flow resulted in some nonepitaxial grains and surface pits, likely due to partial Ge oxidation. GaAs was grown by metalorganic vapor-phase epitaxy (MOVPE) on STO/SAO/STO templates. Lift-off after dissolving the sacrificial SAO in water resulted in free-standing ⟨001⟩ preferentially oriented polycrystalline GaAs.

Development and Use of Human Recombinant 64Cu-rHCF as a Kidney Glomerulus-Targeted Contrast Agent for Positron Emission Tomography.

In this work, we develop recombinant human cationic ferritin (rHCF) as a contrast agent to detect glomeruli in the kidney using positron emission tomography (PET). We first expressed recombinant human ferritin (rHF) in E. coli and then functionalized and radiolabeled it with Copper-64 (64Cu) to form 64Cu-rHCF. Intravenously injected 64Cu-rHCF bound to kidney glomeruli and was detected by PET. A subchronic toxicity study after an intravenous injection of rHCF revealed no significant toxicity. The development of rHCF is an important step toward the potential clinical translation of CF to detect the nephron number in humans.

Non-therapeutic laparotomies in military trauma (2009-2014).

BACKGROUND: Combat casualties are frequently injured in austere settings where modern imaging modalities are unavailable. Exploratory laparotomies are often performed in these settings when there is suspicion for intra-abdominal injury. Prior studies of combat casualties reported non-therapeutic laparotomy (NTL) rates as high as 32%. Given improvements in combat casualty care over time, we evaluated NTLs performed during later years of the wars in Iraq and Afghanistan. METHODS: Military personnel with combat-related injuries (6/1/2009-12/31/2014) who underwent exploratory laparotomy based on concern for abdominal injury (i.e. not performed for proximal vascular control or fecal diversion) and were evacuated to Landstuhl Regional Medical Center (Germany) before being transferred to participating U.S. military hospitals were assessed. An NTL was defined as a negative laparotomy without substantial intra-abdominal injuries requiring repair. Characteristics, indications for laparotomy, operative findings, and outcomes were examined. RESULTS: Among 244 patients who underwent laparotomies, 41 (16.8%) had NTLs and 203 (83.2%) had therapeutic laparotomies (i.e. positive findings). Patients with NTLs had more computed tomography scans concerning for injury (48.8% vs 27.1%; p = 0.006), less penetrating injury mechanisms (43.9% vs 71.9%; p < 0.001), and lower Injury Severity Scores (26 vs 33; p = 0.003) compared to patients with therapeutic laparotomies. Patients with NTLs were also less likely to be admitted to the intensive care unit (70.7 vs 89.2% for patients with therapeutic laparotomies; p = 0.007). No patients with NTLs developed abdominal surgical site infections (SSI) compared to 16.7% of patients with therapeutic laparotomies (p = 0.002). There was no significant difference in mortality between the groups (p = 0.198). CONCLUSIONS: Our proportion of NTLs was lower than reported from earlier years during the wars in Iraq and Afghanistan. No infectious complications from NTLs (i.e. abdominal SSIs) were identified. Nevertheless, surgeons should continue to have a low threshold for exploratory laparotomy in military patients in austere settings with concern for intra-abdominal injury.

An expert discussion on the atypical hemolytic uremic syndrome nomenclature-identifying a road map to precision: a report of a National Kidney Foundation Working Group.

The term atypical hemolytic uremic syndrome has been in use since the mid-1970s. It was initially used to describe the familial or sporadic form of hemolytic uremic syndrome as opposed to the epidemic, typical form of the disease. Over time, the atypical hemolytic uremic syndrome term has evolved into being used to refer to anything that is not Shiga toxin-associated hemolytic uremic syndrome. The term describes a heterogeneous group of diseases of disparate causes, a circumstance that makes defining disease-specific natural history and/or targeted treatment approaches challenging. A working group of specialty-specific experts in the thrombotic microangiopathies was convened to review the validity of this broad term in an era of swiftly advancing science and targeted therapeutics. A Delphi approach was used to define and interrogate some of the key issues related to the atypical hemolytic uremic syndrome nomenclature.

Immunoglobulin A vasculitis with periorbital edema and severe renal involvement: A case report.

Immunoglobulin A (IgA) vasculitis, or Henoch-Schonlein purpura, is the most common systemic vasculitis in children, clinically presenting as palpable purpura in combination with arthritis, gastrointestinal involvement, or kidney injury. Subcutaneous edema is reported in patients with IgA vasculitis, and it commonly affects the lower extremities, especially around joints. Here, we report a case of IgA vasculitis with a rare presentation of edema isolated to the periorbital area in a 7-year-old boy, who subsequently developed crescentic glomerulonephritis with nephrotic range proteinuria. Isolated periorbital edema is an uncommon cutaneous feature of IgA vasculitis.

Pandemic burden in low-income settings and impact of limited and delayed interventions: A granular modelling analysis of COVID-19 in Kabwe, Zambia.

OBJECTIVES: Pandemic response in low-income countries (LICs) or settings often suffers from scarce epidemic surveillance and constrained mitigation capacity. The drivers of pandemic burden in such settings, and the impact of limited and delayed interventions remain poorly understood. METHODS: We analysed COVID-19 seroprevalence and all-cause excess deaths data from the peri-urban district of Kabwe, Zambia between March 2020 and September 2021 with a novel mathematical model. Data encompassed three consecutive waves caused by the wild-type, Beta and Delta variants. RESULTS: Across all three waves, we estimated a high cumulative attack rate, with 78% (95% credible interval [CrI] 71-85) of the population infected, and a high all-cause excess mortality, at 402 (95% CrI 277-473) deaths per 100,000 people. Ambitiously improving health care to a capacity similar to that in high-income settings could have averted up to 46% (95% CrI 41-53) of accrued excess deaths, if implemented from June 2020 onward. An early and accelerated vaccination rollout could have achieved the highest reductions in deaths. Had vaccination started as in some high-income settings in December 2020 and with the same daily capacity (doses per 100 population), up to 68% (95% CrI 64-71) of accrued excess deaths could have been averted. Slower rollouts would have still averted 62% (95% CrI 58-68), 54% (95% CrI 49-61) or 26% (95% CrI 20-38) of excess deaths if matching the average vaccination capacity of upper-middle-, lower-middle- or LICs, respectively. CONCLUSIONS: Robust quantitative analyses of pandemic data are of pressing need to inform future global pandemic preparedness commitments.

Risk Factors and Outcomes of Late Posttraumatic Seizures in Combat-Related Traumatic Brain Injury.

INTRODUCTION: Post-traumatic seizures (PTSs) contribute to morbidity after traumatic brain injury (TBI). Early PTS are rare in combat casualties sustaining TBI, but the prevalence of late PTS is poorly described. We sought to define the prevalence and risk factors of late PTS in combat casualties with computed tomography evidence of TBI. METHODS: From 2010 to 2015, 687 combat casualties were transferred to a military treatment facility and included in the Department of Defense Trauma Registry. 71 patients with radiographic evidence of TBI were analyzed. Data collection included demographics, injury characteristics, interventions, medications, and outcomes. RESULTS: Of the 71 patients with evidence of TBI, 66 patients survived hospitalization and were followed. No patients had early PTS, and most received antiepileptic drugs (AEDs) for prophylaxis. At a median follow-up of 7.4 y, late PTS occurred in 25.8% of patients. Patients with late PTS were more severely injured (median Injury severity score 30 versus 24, P = 0.005) and required more blood products (18 units versus 2, P = 0.045). Patients with late PTS were more likely to have had a penetrating TBI (76.5% versus 38.8%, P = 0.01), multiple types of intracranial hemorrhage (94.1% versus 63.3%, P = 0.02), and cranial decompression (76.5% versus 28.6%, P = 0.001). Six-month Glasgow outcome scores were worse (3.5 versus 4.1 P = 0.001) in the late PTS population. No significant relationship was observed between administration of AEDs for early PTS prophylaxis and late PTS. CONCLUSIONS: Combat casualties with TBI suffering late PTS are more severely injured and require more blood products. Penetrating TBI, intracranial hemorrhage, and need for cranial decompression are correlated with late PTS, and associated with worse Glasgow Outcome Score. The administration of prophylactic AEDs for early PTS was not associated with a difference in rates of late PTS.

Clinicopathologic Features of Antibrush Border Antibody Disease.

Introduction: Antibrush border antibody disease (ABBA) is an autoimmune tubulointerstitial kidney disease that primarily affects older individuals and results in progressive kidney failure. It is rare with only 20 reported cases. Here, we describe a case series to further define the clinicopathologic spectrum and natural history, and to inform management. Methods: We identified 67 patients with ABBA who underwent kidney biopsy, including 65 native and 2 transplants. Demographics, clinical findings, and laboratory data were obtained. Histopathologic data included light microscopy, immunofluorescence, electron microscopy and immunostaining for LRP2, CUBN, and AMN. Follow-up data, including treatment(s), laboratory values, and outcomes, were available from 51 patients. Results: Patients with ABBA were predominantly male with a median age of 72 years. Median serum creatinine was 2.7 mg/dl, proteinuria was 2.8 g/day, and hematuria was present in two-thirds of the patients. Tubular injury with LRP2-positive tubular basement membrane (TBM) deposits were seen in 94.2% of patients. Thirty-eight patients (56.7%) had a second kidney disease, commonly glomerular diseases with high-grade proteinuria. These diseases included podocytopathies, membranous nephropathy (MN), IgA nephropathy, diabetic glomerulopathy, lupus nephritis (LN), crescentic glomerulonephritis (GN), tubulointerstitial nephritis, and involvement by lymphoma. The majority of patients were treated with immunosuppression. Of those patients with follow-up, 29.4% achieved remission, 70.6% had no response, and 52.8% required dialysis or were deceased. Untreated patients were at the highest risk. Conclusion: ABBA is a rare autoimmune kidney disease that often occurs with other kidney diseases. Although the overall prognosis of ABBA is poor, there is potential benefit from immunosuppression.

Clinical Characteristics and Histopathology in Adults With Focal Segmental Glomerulosclerosis.

Rationale & Objective: Few data are available regarding histological features at the time of focal segmental glomerulosclerosis (FSGS) diagnosis among diverse real-world populations. This study describes clinical and histological characteristics and correlates of histological disease severity in adults with FSGS who underwent a clinical kidney biopsy. Study Design: Real-world cohort study with data derived from health records. Setting & Participants: Adults with FSGS by kidney biopsies from Arkana Laboratories from January 1, 2016 to May 31, 2020. Exposure: Race, chronic kidney disease stage, nephrotic proteinuria, age, sex, and hypertension. Outcomes: Severe histological disease, defined as global glomerulosclerosis in >50% of glomeruli and >25% interstitial fibrosis and tubular atrophy (IFTA). Analytical Approach: Demographic, clinical, and histological characteristics were compared between race groups. Correlates of severe disease were analyzed using multiple logistic regression. Results: Among 2,011 patients with FSGS, 40.6% were White, and 23.6% Black. White patients were older (52.8 vs 45.5 years, P < 0.001) with a higher estimated glomerular filtration rate (eGFR) than Black patients (53.5 vs 43.1 mL/min/1.73 m2, P < 0.001). A higher proportion of Black patients had global glomerulosclerosis ≥50% (32.1% vs 14.6%, P < 0.001) or IFTA >50% (34.6% vs 14.7%, P < 0.001). Severe histological disease was more likely in Black patients (OR, 2.46; 95% CI, 1.59-3.79; P < 0.001). A higher proportion of patients with nephrotic than nonnephrotic proteinuria exhibited diffuse foot process effacement. Limitations: Unequal representation across United States regions, missing demographic and clinical data, and lack of data on primary versus secondary FSGS, treatments, or outcomes. Conclusions: Black patients were more frequently diagnosed at younger age with lower eGFR and more severe histological disease compared with White patients. Timelier identification of FSGS could increase the opportunity for therapeutic intervention, especially for high-risk patients, to mitigate disease progression and complications. Plain-Language Summary: Focal segmental glomerulosclerosis (FSGS) accounts for around one-quarter of diagnoses derived from clinical kidney biopsies in the United States. Limited data are available regarding the classes and distribution of histological features at FSGS diagnosis among diverse real-world populations. Analyzing data from US patients who underwent kidney biopsy and were diagnosed with FSGS, we showed that up to half of patients had features of severe histological disease. Of this overall population, Black patients were more frequently diagnosed at a younger age but with more severe histological disease than White patients. The work highlights the need for timelier diagnosis of FSGS to enable intervention at an earlier disease stage.

Triangulation of Routine Antenatal HIV Prevalence Data and Adjusted HIV Estimates in Mozambique.

BACKGROUND: Routine health system data are central to monitoring HIV trends. In Mozambique, the reported number of women receiving antenatal care (ANC) and antiretroviral therapy for prevention of mother-to-child transmission (PMTCT) has exceeded the Spectrum-estimated number of pregnant women since 2017. In some provinces, reported HIV prevalence in pregnant women has declined faster than epidemiologically plausible. We hypothesized that these issues are linked and caused by programmatic overenumeration of HIV-negative pregnant women at ANC. METHODS: We triangulated program-reported ANC client numbers with survey-based fertility estimates and facility birth data adjusted for the proportion of facility births. We used survey-reported ANC attendance to produce adjusted time series of HIV prevalence in pregnant women, adjusted for hypothesized program double counting. We calibrated the Spectrum HIV estimation models to adjusted HIV prevalence data to produce adjusted adult and pediatric HIV estimates. RESULTS: ANC client numbers were not consistent with facility birth data or modeled population estimates indicating ANC data quality issues in all provinces. Adjusted provincial ANC HIV prevalence in 2021 was median 45% [interquartile range 35%-52% or 2.3 percentage points (interquartile range 2.5-3.5)] higher than reported HIV prevalence. In 2021, calibrating to adjusted antenatal HIV prevalence lowered PMTCT coverage to less than 100% in most provinces and increased the modeled number of new child infections by 35%. The adjusted results better reconciled adult and pediatric antiretroviral treatment coverage and antenatal HIV prevalence with regional fertility estimates. CONCLUSIONS: Adjusting HIV prevalence in pregnant women using nationally representative household survey data on ANC attendance produced estimates more consistent with surveillance data. The number of children living with HIV in Mozambique has been substantially underestimated because of biased routine ANC prevalence. Renewed focus on HIV surveillance among pregnant women would improve PMTCT coverage and pediatric HIV estimates.

Raising Systemic Blood Pressure to Delay Irreversible Intestinal Ischemia in a Swine Model of Proximal Superior Mesenteric ArteryOcclusion.

INTRODUCTION: Acute proximal superior mesenteric artery (SMA) occlusion is highly lethal, and adjuncts are needed to mitigate ischemic injury until definitive therapy. We hypothesized that raising mean arterial pressure (MAP) >90 mmHg with norepinephrine may delay irreversible bowel ischemia by increasing gastroduodenal artery (GDA) flow despite possible pressor-induced vasospasm. METHODS: 12 anesthetized swine underwent laparotomy, GDA flow probe placement, and proximal SMA exposure and clamping. Animals were randomized between conventional therapy (CT) versus targeted MAP >90 mmHg (MAP push; MP) where norepinephrine was titrated after 45 min of SMA occlusion. Animals were followed until bowel death or 4 h. Kaplan-Meier bowel survival, mean normalized GDA flow, and histology were compared. RESULTS: 12 swine (mean 57.8 ± 7.6 kgs) were included, six per group. Baseline weight, HR, MAP and GDA flows were not different. Within 5 min following SMA clamping, all 12 animals had an increase in MAP without other intervention from 81.7 to 105.5 mmHg (29.1%, P < 0.01) with a concomitant 74.9% increase in GDA flow as compared to baseline (P < 0.01). Beyond 45 min postclamp, MAP was greater in the MP group as intended, as were GDA flows. Median time to irreversibly ischemic bowel was 31% longer for MAP push animals (CT: 178 versus MP: 233 min, P = 0.006), Hazard Ratio of CT 8.85 (95% CI: 1.86-42.06); 3/6 MP animals versus 0/6 CT animals with bowel survived to predetermined end point. CONCLUSIONS: In this swine model of acute complete proximal SMA occlusion, increasing MAP >90 mmHg with norepinephrine was associated with an increase in macrovascular blood flow through the GDA and bowel survival. Norepinephrine was not associated with worse bowel survival and a MAP push may increase the time window where ischemic bowel can be salvaged.

Corrigendum to "Clinicopathological Characteristics of Adult IgA Nephropathy in the United States" [Kidney International Reports Volume 8, Issue 9, September 2023, Pages 1792-1800].

[This corrects the article DOI: 10.1016/j.ekir.2023.06.016.].

Shiga toxin targets the podocyte causing hemolytic uremic syndrome through endothelial complement activation.

BACKGROUND: Shiga toxin (Stx)-producing Escherichia coli hemolytic uremic syndrome (STEC-HUS) is the leading cause of acute kidney injury in children, with an associated mortality of up to 5%. The mechanisms underlying STEC-HUS and why the glomerular microvasculature is so susceptible to injury following systemic Stx infection are unclear. METHODS: Transgenic mice were engineered to express the Stx receptor (Gb3) exclusively in their kidney podocytes (Pod-Gb3) and challenged with systemic Stx. Human glomerular cell models and kidney biopsies from patients with STEC-HUS were also studied. FINDINGS: Stx-challenged Pod-Gb3 mice developed STEC-HUS. This was mediated by a reduction in podocyte vascular endothelial growth factor A (VEGF-A), which led to loss of glomerular endothelial cell (GEnC) glycocalyx, a reduction in GEnC inhibitory complement factor H binding, and local activation of the complement pathway. Early therapeutic inhibition of the terminal complement pathway with a C5 inhibitor rescued this podocyte-driven, Stx-induced HUS phenotype. CONCLUSIONS: This study potentially explains why systemic Stx exposure targets the glomerulus and supports the early use of terminal complement pathway inhibition in this devastating disease. FUNDING: This work was supported by the UK Medical Research Council (MRC) (grant nos. G0901987 and MR/K010492/1) and Kidney Research UK (grant nos. TF_007_20151127, RP42/2012, and SP/FSGS1/2013). The Mary Lyon Center is part of the MRC Harwell Institute and is funded by the MRC (A410).

Clinicopathological Characteristics of Adult IgA Nephropathy in the United States.

Introduction: IgA nephropathy (IgAN) is a progressive autoimmune kidney disease and a leading cause of glomerular disease that can result in kidney failure (KF). The median age at diagnosis is 35 to 37 years and approximately 50% of patients will progress to KF within 20 years. We aimed to enhance the understanding of renal histology and chronic kidney disease (CKD) stage at the time of IgAN diagnosis using a large real-world biopsy cohort. Methods: This retrospective cohort study evaluated biopsy data and clinical characteristics from adult patients within the US who were diagnosed with IgAN between January 1, 2016 to May 31, 2020. Descriptive statistics were summarized and relationship(s) between each Oxford Classification (MEST-C) component score with 24-hour proteinuria or CKD stage were examined using regression analysis. Results: A total of 4375 patients (mean age 47.7 years, 62.7% male) met eligibility criteria. Mild to moderate mesangial hypercellularity (47.3%), segmental sclerosis (65.0%), tubular atrophy ≥25% (57.4%), and crescents (18.5%) were identified; and 74.6% of patients were at CKD stage ≥3. Proteinuria ≥1 g/d was associated with higher MEST-C scores, and the odds of mesangial hypercellularity, segmental sclerosis, tubular atrophy, and crescents increased with CKD stage. Conclusion: Most patients with IgAN in our US cohort were diagnosed at CKD stage ≥3 and had high MEST-C scores and proteinuria that are suggestive of significant disease burden at the time of kidney biopsy. Strategies are required to raise awareness and promote earlier detection of asymptomatic urinary abnormalities before extensive irreversible kidney damage has occurred.

Assessing the utility of pregnant women as a sentinel surveillance population for malaria in Geita, Tanzania, 2019 - 2021.

OBJECTIVES: Estimates of malaria burden and intervention uptake in Africa are primarily based on household surveys. However, their expense and infrequency limit their utility. We investigated whether data collected during antenatal care (ANC) can provide relevant information for decision-makers. METHODS: Malaria test positivity rates and questionnaire data from ANC attendees at 39 health facilities were compared to questionnaire data and positivity rates among children from two cross-sectional surveys in the facilities' corresponding catchment areas. RESULTS: Trends in parasitemia among ANC attendees were predictive of trends in parasitemia among children at the council level (mean absolute error 6.0%). Primigravid ANC attendees had the lowest rates of net ownership (modeled odds ratio [OR] 0.28, 95% CI 0.19-0.40) and use (OR 0.58, 95% CI 0.42-0.79). ANC attendees reported higher levels of care-seeking (OR 1.78, 95% CI 1.48-2.14), malaria testing (OR 4.16, 95% CI 3.44-5.04), and treatment for children with fever (OR 7.66, 95% CI 4.89-11.98) compared to women surveyed in households, raising concerns about social desirability bias disproportionately impacting ANC surveys. CONCLUSION: ANC surveillance is an effective strategy for tracking trends in malaria burden. More work is required to elucidate the value of administering questionnaires to ANC attendees.

Using mortuary and burial data to place COVID-19 in Lusaka, Zambia within a global context.

Reported COVID-19 cases and associated mortality remain low in many sub-Saharan countries relative to global averages, but true impact is difficult to estimate given limitations around surveillance and mortality registration. In Lusaka, Zambia, burial registration and SARS-CoV-2 prevalence data during 2020 allow estimation of excess mortality and transmission. Relative to pre-pandemic patterns, we estimate age-dependent mortality increases, totalling 3212 excess deaths (95% CrI: 2104-4591), representing an 18.5% (95% CrI: 13.0-25.2%) increase relative to pre-pandemic levels. Using a dynamical model-based inferential framework, we find that these mortality patterns and SARS-CoV-2 prevalence data are in agreement with established COVID-19 severity estimates. Our results support hypotheses that COVID-19 impact in Lusaka during 2020 was consistent with COVID-19 epidemics elsewhere, without requiring exceptional explanations for low reported figures. For more equitable decision-making during future pandemics, barriers to ascertaining attributable mortality in low-income settings must be addressed and factored into discourse around reported impact differences.