Peripheral Transcriptomics in Acute and Long-Term Kidney Dysfunction in SARS-CoV2 Infection.

Background: Acute kidney injury (AKI) is common in hospitalized patients with SARS-CoV2 infection despite vaccination and leads to long-term kidney dysfunction. However, peripheral blood molecular signatures in AKI from COVID-19 and their association with long-term kidney dysfunction are yet unexplored. Methods: In patients hospitalized with SARS-CoV2, we performed bulk RNA sequencing using peripheral blood mononuclear cells(PBMCs). We applied linear models accounting for technical and biological variability on RNA-Seq data accounting for false discovery rate (FDR) and compared functional enrichment and pathway results to a historical sepsis-AKI cohort. Finally, we evaluated the association of these signatures with long-term trends in kidney function. Results: Of 283 patients, 106 had AKI. After adjustment for sex, age, mechanical ventilation, and chronic kidney disease (CKD), we identified 2635 significant differential gene expressions at FDR<0.05. Top canonical pathways were EIF2 signaling, oxidative phosphorylation, mTOR signaling, and Th17 signaling, indicating mitochondrial dysfunction and endoplasmic reticulum (ER) stress. Comparison with sepsis associated AKI showed considerable overlap of key pathways (48.14%). Using follow-up estimated glomerular filtration rate (eGFR) measurements from 115 patients, we identified 164/2635 (6.2%) of the significantly differentiated genes associated with overall decrease in long-term kidney function. The strongest associations were 'autophagy', 'renal impairment via fibrosis', and 'cardiac structure and function'. Conclusions: We show that AKI in SARS-CoV2 is a multifactorial process with mitochondrial dysfunction driven by ER stress whereas long-term kidney function decline is associated with cardiac structure and function and immune dysregulation. Functional overlap with sepsis-AKI also highlights common signatures, indicating generalizability in therapeutic approaches. SIGNIFICANCE STATEMENT: Peripheral transcriptomic findings in acute and long-term kidney dysfunction after hospitalization for SARS-CoV2 infection are unclear. We evaluated peripheral blood molecular signatures in AKI from COVID-19 (COVID-AKI) and their association with long-term kidney dysfunction using the largest hospitalized cohort with transcriptomic data. Analysis of 283 hospitalized patients of whom 37% had AKI, highlighted the contribution of mitochondrial dysfunction driven by endoplasmic reticulum stress in the acute stages. Subsequently, long-term kidney function decline exhibits significant associations with markers of cardiac structure and function and immune mediated dysregulation. There were similar biomolecular signatures in other inflammatory states, such as sepsis. This enhances the potential for repurposing and generalizability in therapeutic approaches.

Novel Therapies in APOL1-Mediated Kidney Disease: From Molecular Pathways to Therapeutic Options.

Apolipoprotein L1 (APOL1) high-risk variants confer an increased risk for the development and progression of kidney disease among individuals of recent African ancestry. Over the past several years, significant progress has been made in understanding the pathogenesis of APOL1-mediated kidney diseases (AMKD), including genetic regulation, environmental interactions, immunomodulatory, proinflammatory and apoptotic signaling processes, as well as the complex role of APOL1 as an ion channel. Collectively, these findings have paved the way for novel therapeutic strategies to mitigate APOL1-mediated kidney injury. Precision medicine approaches are being developed to identify subgroups of AMKD patients who may benefit from these targeted interventions, fueling hope for improved clinical outcomes. This review summarizes key mechanistic insights in the pathogenesis of AMKD, emergent therapies, and discusses future challenges.

Joint Modeling of Clinical and Biomarker Data in Acute Kidney Injury Defines Unique Subphenotypes with Differing Outcomes.

BACKGROUND: AKI is a heterogeneous syndrome. Current subphenotyping approaches have only used limited laboratory data to understand a much more complex condition. METHODS: We focused on patients with AKI from the Assessment, Serial Evaluation, and Subsequent Sequelae in AKI (ASSESS-AKI). We used hierarchical clustering with Ward linkage on biomarkers of inflammation, injury, and repair/health. We then evaluated clinical differences between subphenotypes and examined their associations with cardiorenal events and death using Cox proportional hazard models. RESULTS: We included 748 patients with AKI: 543 (73%) of them had AKI stage 1, 112 (15%) had AKI stage 2, and 93 (12%) had AKI stage 3. The mean age (±SD) was 64 (13) years; 508 (68%) were men; and the median follow-up was 4.7 (Q1: 2.9, Q3: 5.7) years. Patients with AKI subphenotype 1 ( N =181) had the highest kidney injury molecule (KIM-1) and troponin T levels. Subphenotype 2 ( N =250) had the highest levels of uromodulin. AKI subphenotype 3 ( N =159) comprised patients with markedly high pro-brain natriuretic peptide and plasma tumor necrosis factor receptor-1 and -2 and low concentrations of KIM-1 and neutrophil gelatinase-associated lipocalin. Finally, patients with subphenotype 4 ( N =158) predominantly had sepsis-AKI and the highest levels of vascular/kidney inflammation (YKL-40, MCP-1) and injury (neutrophil gelatinase-associated lipocalin, KIM-1). AKI subphenotypes 3 and 4 were independently associated with a higher risk of death compared with subphenotype 2 and had adjusted hazard ratios of 2.9 (95% confidence interval, 1.8 to 4.6) and 1.6 (95% confidence interval, 1.01 to 2.6, P = 0.04), respectively. Subphenotype 3 was also independently associated with a three-fold risk of CKD and cardiovascular events. CONCLUSIONS: We discovered four AKI subphenotypes with differing clinical features and biomarker profiles that are associated with longitudinal clinical outcomes.

Plasma Soluble Tumor Necrosis Factor Receptor Concentrations and Clinical Events After Hospitalization: Findings From the ASSESS-AKI and ARID Studies.

RATIONALE & OBJECTIVE: The role of plasma soluble tumor necrosis factor receptor 1 (sTNFR1) and sTNFR2 in the prognosis of clinical events after hospitalization with or without acute kidney injury (AKI) is unknown. STUDY DESIGN: Prospective cohort. SETTING & PARTICIPANTS: Hospital survivors from the ASSESS-AKI (Assessment, Serial Evaluation, and Subsequent Sequelae of Acute Kidney Injury) and ARID (AKI Risk in Derby) studies with and without AKI during the index hospitalization who had baseline serum samples for biomarker measurements. PREDICTORS: We measured sTNFR1 and sTNFR2 from plasma samples obtained 3 months after discharge. OUTCOMES: The associations of biomarkers with longitudinal kidney disease incidence and progression, heart failure, and death were evaluated. ANALYTICAL APPROACH: Cox proportional hazard models. RESULTS: Among 1,474 participants with plasma biomarker measurements, 19% had kidney disease progression, 14% had later heart failure, and 21% died during a median follow-up of 4.4 years. For the kidney outcome, the adjusted HRs (AHRs) per doubling in concentration were 2.9 (95% CI, 2.2-3.9) for sTNFR1 and 1.9 (95% CI, 1.5-2.5) for sTNFR2. AKI during the index hospitalization did not modify the association between biomarkers and kidney events. For heart failure, the AHRs per doubling in concentration were 1.9 (95% CI, 1.4-2.5) for sTNFR1 and 1.5 (95% CI, 1.2-2.0) for sTNFR2. For mortality, the AHRs were 3.3 (95% CI, 2.5-4.3) for sTNFR1 and 2.5 (95% CI, 2.0-3.1) for sTNFR2. The findings in ARID were qualitatively similar in terms of the magnitude of association between biomarkers and outcomes. LIMITATIONS: Different biomarker platforms and AKI definitions; limited generalizability to other ethnic groups. CONCLUSIONS: Plasma sTNFR1 and sTNFR2 measured 3 months after hospital discharge were independently associated with clinical events regardless of AKI status during the index admission. sTNFR1 and sTNFR2 may assist with the risk stratification of patients during follow-up.

Pre-operative kidney biomarkers and risks for death, cardiovascular and chronic kidney disease events after cardiac surgery: the TRIBE-AKI study.

BACKGROUND: Soluble tumor necrosis factor receptor (sTNFR)1, sTNFR2, and plasma kidney injury molecule-1 (KIM-1) are associated with kidney events in patients with and without diabetes. However, their associations with clinical outcomes when obtained pre-operatively have not been explored. METHODS: The TRIBE-AKI cohort study is a prospective, multicenter, cohort study of high-risk adults undergoing cardiac surgery. We assessed the associations between pre-operative concentrations of plasma sTNFR1, sTNFR2, and KIM-1 and post-operative long-term outcomes including mortality, cardiovascular events, and chronic kidney disease (CKD) incidence or progression after discharge. RESULTS: Among 1378 participants included in the analysis with a median follow-up period of 6.7 (IQR 4.0-7.9) years, 434 (31%) patients died, 256 (19%) experienced cardiovascular events and out of 837 with available long-term kidney function data, 30% developed CKD. After adjustment for clinical covariates, each log increase in biomarker concentration was independently associated with mortality with 95% CI adjusted hazard ratios (aHRs) of 3.0 (2.3-4.0), 2.3 (1.8-2.9), and 2.0 (1.6-2.4) for sTNFR1, sTNFR2, and KIM-1, respectively. For cardiovascular events, the 95% CI aHRs were 2.1 (1.5-3.1), 1.9 (1.4-2.6) and 1.6 (1.2-2.1) for sTNFR1, sTNFR2 and KIM-1, respectively. For CKD events, the aHRs were 2.2 (1.5-3.1) for sTNFR1, 1.9 (1.3-2.7) for sTNFR2, and 1.7 (1.3-2.3) for KIM-1. Despite the associations, each of the biomarkers alone or in combination failed to result in robust discrimination on an absolute basis or compared to a clinical model. CONCLUSION: sTNFR1, sTNFR2, and KIM-1 were independently associated with longitudinal outcomes after discharge from a cardiac surgery hospitalization including death, cardiovascular, and CKD events when obtained pre-operatively in high-risk individuals. Pre-operative plasma biomarkers could serve to assist during the evaluation of patients in whom cardiac surgery is planned.

Systematic Review and Meta-Analysis of Plasma and Urine Biomarkers for CKD Outcomes.

BACKGROUND: Sensitive and specific biomarkers are needed to provide better biologic insight into the risk of incident and progressive CKD. However, studies have been limited by sample size and design heterogeneity. METHODS: In this assessment of the prognostic value of preclinical plasma and urine biomarkers for CKD outcomes, we searched Embase (Ovid), MEDLINE ALL (Ovid), and Scopus up to November 30, 2020, for studies exploring the association between baseline kidney biomarkers and CKD outcomes (incident CKD, CKD progression, or incident ESKD). We used random-effects meta-analysis. RESULTS: After screening 26,456 abstracts and 352 full-text articles, we included 129 studies in the meta-analysis for the most frequently studied plasma biomarkers (TNFR1, FGF23, TNFR2, KIM-1, suPAR, and others) and urine biomarkers (KIM-1, NGAL, and others). For the most frequently studied plasma biomarkers, pooled RRs for CKD outcomes were 2.17 (95% confidence interval [95% CI], 1.91 to 2.47) for TNFR1 (31 studies); 1.21 (95% CI, 1.15 to 1.28) for FGF-23 (30 studies); 2.07 (95% CI, 1.82 to 2.34) for TNFR2 (23 studies); 1.51 (95% CI, 1.38 to 1.66) for KIM-1 (18 studies); and 1.42 (95% CI, 1.30 to 1.55) for suPAR (12 studies). For the most frequently studied urine biomarkers, pooled RRs were 1.10 (95% CI, 1.05 to 1.16) for KIM-1 (19 studies) and 1.12 (95% CI, 1.06 to 1.19) for NGAL (19 studies). CONCLUSIONS: Studies of preclinical biomarkers for CKD outcomes have considerable heterogeneity across study cohorts and designs, limiting comparisons of prognostic performance across studies. Plasma TNFR1, FGF23, TNFR2, KIM-1, and suPAR were among the most frequently investigated in the setting of CKD outcomes.

Adequacy of hemodialysis in acute kidney injury: Real-time monitoring of dialysate ultraviolet absorbance vs. blood-based Kt/Vurea.

BACKGROUND: Current guidelines recommend monitoring the adequacy of hemodialysis (HD) treatments in patients with acute kidney injury (AKI). Blood-based methods for calculating urea such as reduction ratio (URR) and single-pool Kt/Vurea (spKt/Vurea) require pre- and post-HD blood urea nitrogen (BUN) measurements. This study aims to compare real-time monitoring of urea clearance using dialysate ultraviolet absorbance (UV) with laboratory-measured spKt/Vurea. METHODS: We conducted a single-center, retrospective study among hospitalized patients with AKI, who required intermittent hemodialysis (IHD). Those patients whose dialysis dose was simultaneously monitored by spKt/Vurea and UV-absorbance (UV-spKt/Vurea) were included in the study. The statistical correlation between both methods was assessed by means of the Pearson moment product correlation, Mann-Whitney U-test and Bland-Altman analysis of agreement. RESULTS: Thirty patients with AKI were evaluated. There was no statistical difference between the mean spKt/Vurea calculated by traditional methods and the mean UV-spKt/Vurea. (1.37 ± 0.37 vs. 1.28 ± 0.36, P = 0.12, CI: 95%). A Pearson moment correlation analysis revealed a close agreement between both methods (r = 0.79, P < 0.001). Furthermore, Bland-Altman analysis showed that >95% of the data points were confined within the upper and lower levels of agreement. CONCLUSION: In this pilot study of patients with AKI, UV-spKt/Vurea correlated with standard blood-based spKt/Vurea and may be a useful tool to monitor dialysis adequacy. Larger studies evaluating multiple UV and blood-based measurements per patient and a more diverse AKI population are needed to confirm this initial observation.

SGLT2 Inhibitors: Emerging Roles in the Protection Against Cardiovascular and Kidney Disease Among Diabetic Patients.

PURPOSE OF REVIEW: Type 2 diabetes mellitus (T2DM) is a prevalent disease with the severe clinical implications including myocardial infarction, stroke, and kidney disease. Therapies focusing on glycemic control in T2DM such as biguanides, sulfonylureas, thiazolidinediones, and insulin-based regimens have largely failed to substantially improve cardiovascular and kidney outcomes. We review the recent findings on sodium-glucose co-transporter type 2 (SGLT2) inhibitors which have shown to have beneficial cardiovascular and kidney-related effects. RECENT FINDINGS: SGLT2 inhibitors are a new class of diabetic medications that reduce the absorption of glucose in the kidney, decrease proteinuria, control blood pressure, and are associated with weight loss. SGLT2 inhibitors provide complementary therapy independent of insulin secretion or action with proved glucose-lowering effects. Recent placebo-controlled clinical trials have demonstrated that these medications can decrease cardiovascular death, progression of kidney disease, and all-cause mortality in diabetic and non-diabetic patients. Interestingly, SGT2 inhibitors such as dapagliflozin have also proven to decrease heart failure admissions and cardiovascular endpoints in non-diabetic patients, suggesting pleiotropic effects. The exact mechanisms responsible for reductions in atherosclerotic heart disease, need for kidney replacement therapy, and progressive kidney disease remain unknown. While regulation of glomerular hyperfiltration, albuminuria, and natriuresis may be part of the explanation, it is possible that complex cellular effects including energy balance optimization, downregulation of oxidative stress, and modulation of pro-inflammatory signaling pathways are associated with favorable outcomes observed in large clinical studies. CONCLUSION: SGLT2 inhibitors are novel antidiabetic medications with immense utility in the management of patients with T2DM. Furthermore, SGLT2 inhibitors have demonstrated to reduce the progression to advanced forms of kidney disease and its associated complications. These medications should be front and center in the management of patients with diabetic kidney disease with and without chronic kidney disease as they confer protection against cardiovascular/renal death and improve all-cause mortality. Future studies should evaluate the benefits and implications of early initiation of SGLT2 inhibitors, as well as the long-term effects of this therapy.

Immune reconstitution, glomerulonephritis, and successful treatment with rituximab.

BACKGROUND: Alemtuzumab can induce secondary autoimmunity affecting multiple organs. While kidney involvement is uncommon, it can be associated with devastating forms of glomerulonephritis (GN). CASE PRESENTATION: A 32-year-old African American woman presented with hypertension, proteinuria, and progressive renal failure. Her medical history was remarkable for secondary progressive multiple sclerosis (SPMS). She had received her first induction dose of alemtuzumab 1 year prior to presentation. Upon evaluation, she had scanning speech, multidirectional nystagmus, and mild edema. Her serum creatinine was 2 mg/dL. Urine studies revealed proteinuria and microscopic hematuria. Her serologic tests were positive for c-antineutrophil cytoplasmic antibodies (> 1 : 640). In addition, she was found to have new-onset severe thyroid dysfunction with antibodies against thyroglobulin and thyroid peroxidase. Kidney biopsy was diagnostic for pauci-immune crescentic GN. The patient was treated with methylprednisolone and rituximab with subsequent renal, thyroid, and neurological recovery. CONCLUSION: This is an atypical case of GN following therapy with alemtuzumab. We hypothesize that immune reconstitution may be a potential mechanism. Alemtuzumab is a new treatment for SPMS that can be associated with GN. Practice guidelines should address the management of its renal complications.

Gastric Pseudotumor due to Fasciola hepatica.

A 71-year-old man presented with abdominal pain and weight loss. He had epigastric tenderness on examination. Basic studies revealed anemia and eosinophilia. A computed tomography scan showed a mass in the anterior wall of the stomach. Endoscopic studies revealed a subepithelial lesion in the same area. An exploratory laparotomy was conducted to rule out any malignancy, revealing a mass fixed to the transverse colon and stomach. Biopsy samples showed eosinophilic nodules and multiple cystic structures compatible with Fasciola hepatica. The patient was treated with triclabendazole with complete resolution. Gastric pseudotumor secondary to F. hepatica is a rare but treatable disease.

Controversies in the Management of Secondary Hyperparathyroidism in Chronic Kidney Disease.

Secondary hyperparathyroidism is a frequent complication of chronic kidney disease that begins early in the course of renal insufficiency as an adaptive response to maintain mineral homeostasis. This complex disorder affects the bone, leading to an increase in fracture risk and is associated with increased risks of vascular calcification and mortality. PURPOSE OF REVIEW: In this review, we examine the different strategies available to manage secondary hyperparathyroidism. Particularly, we focus on the adequate control of serum phosphorus by restricting intake and the use of phosphate binders, correction of hypocalcemia while minimizing calcium burden, and reduction in PTH levels through the use of vitamin D sterols and calcimimetics. RECENT FINDINGS: It was observed that although numerous agents directed at the correction of these abnormalities have demonstrated effectiveness on biochemical markers, there is still a relative scarcity of studies demonstrating treatment effectiveness as measured by hard clinical outcomes. In addition, most agents have side effects that may limit their use, even in patients in which the treatment has demonstrated efficacy in controlling these parameters. There is still controversy as to what therapeutic regimens to choose for a particular patient and what parameter should be used to follow their effects, including outcomes, side effects, pill burden, and costs, among others. In the present article, we analyze controversial aspects of the different therapeutic agents available. Although many tools and regimens are available, no one by itself is enough for an adequate management of the patient. But rather, combined therapy and individualization of approaches are recommended for better results. We suggest that new studies analyzing the effectiveness of therapeutic approaches to the management of secondary hyperparathyroidism should be directed not only to controlling parathyroid hormone levels but also to the evaluation of long-term outcomes, based on modification of morbidity, mortality, and end organ impact, while reducing side effects and controlling costs, among others.

Stress and a sedentary lifestyle are associated with irritable bowel syndrome in medical students from Peru: a cross-sectional study.

BACKGROUND: Previous studies suggest that medical students may have higher rates of irritable bowel syndrome as compared to the general population. We hypothesized lifestyle characteristics may be associated to irritable bowel syndrome. METHODS: A cross-sectional survey was conducted in 2015 among students in their fourth, fifth, sixth and seven years of a medical school in Peru. Volunteer participants responded to questions pertaining to demographics, surveys including the Rome III criteria and the Self-reported Stress questionnaire. Regression models were performed to establish variables independently associated with irritable bowel syndrome. RESULTS: Out of 452 students, 346 responded the survey (response rate: 76.5%; female rate: 47%; median age: 22 years). The irritable bowel syndrome prevalence in respondents was 9.5% (95% confidence interval: 6.7%-13.1%). On univariate analysis, being a senior medical student (odds ratio: 2.8; 95% confidence interval: 1.3-5.9; P < 0.01), mental illness (odds ratio: 3.3; 95% confidence interval: 1.6-6.8; P = 0.002), psychiatric medication use (odds ratio: 2.8; 95% confidence interval: 1.4-5.9; P = 0.005), sedentary lifestyle (odds ratio: 4.4; 95% confidence interval: 1.8-11; P = 0.001) and stress (odds ratio: 4.4; 95% confidence interval: 2.1-9.3; P < 0.001) were associated to irritable bowel syndrome. On a multivariate analysis, a sedentary lifestyle (odds ratio: 3.2; 95% confidence interval: 1.25-8.20; P = 0.01) and stress (odds ratio: 3.0; 95% confidence interval: 1.35-6.67; P < 0.01) were independently associated with irritable bowel syndrome. CONCLUSION: The prevalence of irritable bowel syndrome in medical students from Peru is slightly lower compared to the global prevalence of irritable bowel syndrome. Stress and a sedentary lifestyle were independent risk factors associated with irritable bowel syndrome. Our study suggests that lifestyle modifications and stress coping techniques could have an impact to reduce the rates of irritable bowel syndrome in medical students.

Soil-Transmitted Helminthiasis in Children from a Rural Community Taking Part in a Periodic Deworming Program in the Peruvian Amazon.

Children in the Peruvian Amazon Basin are at risk of soil-transmitted helminths (STH) infections. This study aimed to determine the prevalence of STH infection in children from a rural Amazonian community of Peru and to elucidate epidemiological risk factors associated with its perpetuation while on a school-based deworming program with mebendazole. Stool samples of children aged 2-14 years and their mothers were analyzed through direct smear analysis, Kato-Katz, spontaneous sedimentation in tube, Baermann's method, and agar plate culture. A questionnaire was administered to collect epidemiological information of interest. Among 124 children, 25.8% had one or more STH. Individual prevalence rates were as follows: Ascaris lumbricoides, 16.1%; Strongyloides stercoralis, 10.5%; hookworm, 1.6%; and Trichuris trichiura, (1.6%). The prevalence of common STH (A. lumbricoides, T. trichiura, and hookworm) was higher among children aged 2-5 years than older children (31.6% versus 12.8%; P = 0.01). In terms of sanitation deficits, walking barefoot was significantly associated with STH infection (OR = 3.28; CI 95% = 1.11-12.07). Furthermore, STH-infected children more frequently had a mother who was concomitantly infected by STH than the non-STH-infected counterpart (36.4% versus 14.1%, P = 0.02). In conclusion, STH infection is highly prevalent in children from this Amazonian community despite routine deworming. Institutional health policies may include hygiene and sanitation improvements and screening/deworming of mothers to limit the dissemination of STH. Further studies are needed to address the social and epidemiological mechanics perpetuating these infections.

Strongyloides stercoralis hyperinfection syndrome: a deeper understanding of a neglected disease.

Strongyloides stercoralis hyperinfection syndrome (SHS) is a life-threatening condition that warrants early detection and management. We describe the pathogenesis, organ-specific clinical manifestations, and risk factors associated to this condition. A comprehensive review of the literature was conducted in PubMed, LILACS, EBSCO and SciELO by using the keywords: "hyperinfection syndrome"; "Strongyloides stercoralis"; "disseminated strongyloidiasis"; "systemic strongyloidiasis", "pathogenesis" and "pathophysiology". Relevant articles on this topic were evaluated and included by consensus. Also, a secondary search of the literature was performed. Articles in English and Spanish language were included. SHS has been described in tropical and sub-tropical regions. However, there is growing evidence of cases detected in developed countries favored by increasing migration and the advance in immunosuppressive therapies for oncologic and inflammatory diseases. SHS is characterized by massive multiplication of larvae, typically in immunocompromised hosts. Clinical manifestations vary according to the organ involved and include diarrhea, intestinal bleeding, alveolar hemorrhages, heart failure, jaundice, bacteremia among others. Despite advances in the understanding of this condition, fatality rates are near 90%. Clinicians should consider SHS in the differential diagnosis of acutely ill patients with multiple organ damage and epidemiological risk factors. Adverse outcomes are common, especially with delayed anti-parasitic treatment.