Hemopexin reverses activation of lung eIF2α and decreases mitochondrial injury in chlorine-exposed mice.

We assessed the mechanisms by which nonencapsulated heme, released in the plasma of mice after exposure to chlorine (Cl2) gas, resulted in the initiation and propagation of acute lung injury. We exposed adult male and female C57BL/6 mice to Cl2 (500 ppm for 30 min), returned them to room air, and injected them intramuscularly with either human hemopexin (hHPX; 5 µg/g BW in 50-µL saline) or vehicle at 1 h post-exposure. Upon return to room air, Cl2-exposed mice, injected with vehicle, developed respiratory acidosis, increased concentrations of plasma proteins in the alveolar space, lung mitochondrial DNA injury, increased levels of free plasma heme, and major alterations of their lung proteome. hHPX injection mice mitigated the onset and development of lung and mitochondrial injury and the increase of plasma heme, reversed the Cl2-induced changes in 83 of 237 proteins in the lung proteome at 24 h post-exposure, and improved survival at 15 days post-exposure. Systems biology analysis of the lung global proteomics data showed that hHPX reversed changes in a number of key pathways including elF2 signaling, verified by Western blotting measurements. Recombinant human hemopexin, generated in tobacco plants, injected at 1 h post-Cl2 exposure, was equally effective in reversing acute lung and mtDNA injury. The results of this study offer new insights as to the mechanisms by which exposure to Cl2 results in acute lung injury and the therapeutic effects of hemopexin.NEW & NOTEWORTHY Herein, we demonstrate that exposure of mice to chlorine gas causes significant changes in the lung proteome 24 h post-exposure. Systems biology analysis of the proteomic data is consistent with damage to mitochondria and activation of eIF2, the master regulator of transcription and protein translation. Post-exposure injection of hemopexin, which scavenges free heme, attenuated mtDNA injury, eIF2α phosphorylation, decreased lung injury, and increased survival.

Bacterial exopolysaccharide amendment improves the shelf life and functional efficacy of bioinoculant under salinity stress.

AIM: Bacterial exopolysaccharide (EPS) possesses numerous properties beneficial for the growth of microbes and plants under hostile conditions. The study aimed to develop a bioformulation with bacterial EPS to enhance the bioinoculant's shelf-life and functional efficacy under salinity stress. METHODS AND RESULTS: High EPS-producing and salt-tolerant bacterial strain (SD2) exhibiting auxin-production, phosphate-solubilization, and biofilm-forming ability was selected. EPS-based bioformulation of SD2 improved the growth of three legumes under salt stress, from which pigeonpea was selected for further experiments. SD2 improved the growth and lowered the accumulation of stress markers in plants under salt stress. Bioformulations with varying EPS concentrations (1% and 2%) were stored for 6 months at 4°C, 30°C, and 37°C to assess their shelf-life and functional efficacy. The shelf life and efficacy of EPS-based bioformulation was sustained at higher temperature, enhancing pigeonpea growth under stress after six months of storage in both control and natural conditions. However, the efficacy of non-EPS-based bioformulation declined following four months of storage. The bioformulation modulated bacterial abundance in the plant's rhizosphere under stress conditions. CONCLUSIONS AND IMPACT STATEMENT: The study brings forth a new strategy for developing next-generation bioformulations with higher shelf-life and efficacy for salinity stress management in pigeonpea under saline conditions.

The interplay of inflammation, exosomes and Ca2+ dynamics in diabetic cardiomyopathy.

Diabetes mellitus is one of the prime risk factors for cardiovascular complications and is linked with high morbidity and mortality. Diabetic cardiomyopathy (DCM) often manifests as reduced cardiac contractility, myocardial fibrosis, diastolic dysfunction, and chronic heart failure. Inflammation, changes in calcium (Ca2+) handling and cardiomyocyte loss are often implicated in the development and progression of DCM. Although the existence of DCM was established nearly four decades ago, the exact mechanisms underlying this disease pathophysiology is constantly evolving. Furthermore, the complex pathophysiology of DCM is linked with exosomes, which has recently shown to facilitate intercellular (cell-to-cell) communication through biomolecules such as micro RNA (miRNA), proteins, enzymes, cell surface receptors, growth factors, cytokines, and lipids. Inflammatory response and Ca2+ signaling are interrelated and DCM  has been known to adversely affect many of these signaling molecules either qualitatively and/or quantitatively. In this literature review, we have demonstrated that Ca2+ regulators are tightly controlled at different molecular and cellular levels during various biological processes in the heart. Inflammatory mediators, miRNA and exosomes are shown to interact with these regulators, however how these mediators are linked to Ca2+ handling during DCM pathogenesis remains elusive. Thus, further investigations are needed to understand the mechanisms to restore cardiac Ca2+ homeostasis and function, and to serve as potential therapeutic targets in the treatment of DCM.

Inhibition of RUNX1 blocks the differentiation of lung fibroblasts to myofibroblasts.

Pathological fibrosis contributes to progression of various diseases, for which the therapeutic options are limited. Idiopathic pulmonary fibrosis (IPF) is one such progressive and fatal interstitial fibrotic disease that is often characterized by excessive accumulation of extracellular matrix (ECM) proteins leading to stiff lung tissue and impaired gas exchange. However, the molecular mechanisms underlying IPF progression remain largely unknown. In this study, we determined the role of Runt-related transcription factor 1 (RUNX1), an evolutionarily conserved transcription factor, in the differentiation of human lung fibroblasts (HLFs) in vitro and in an animal model of bleomycin (BLM)-induced lung fibrosis. We observed that the expression of RUNX1 was significantly increased in the lungs of BLM-injected mice as compared to saline-treated mice. Furthermore, HLFs stimulated with transforming growth factor ß (TGF-ß) showed significantly higher RUNX1 expression at both mRNA and protein levels, and compartmentalization in the nucleus. Inhibition of RUNX1 in HLFs (using siRNA) showed a significant reduction in the differentiation of fibroblasts into myofibroblasts as evidenced by reduced expression of alpha-smooth muscle actin (α-SMA), TGF-ß and ECM proteins such as fibronectin 1 (FN1), and collagen 1A1 (COL1A1). Mechanistic studies revealed that the increased expression of RUNX1 in TGF-ß-stimulated lung fibroblasts is due to enhanced mRNA stability of RUNX1 through selective interaction with the RNA-binding profibrotic protein, human antigen R (HuR). Collectively, our data demonstrate that increased expression of RUNX1 augments processes involved in lung fibrosis including the differentiation of fibroblasts into collagen-synthesizing myofibroblasts. Our study suggests that targeting RUNX1 could limit the progression of organ fibrosis in diseases characterized by abnormal collagen deposition.

Increased m6A-RNA methylation and FTO suppression is associated with myocardial inflammation and dysfunction during endotoxemia in mice.

Endotoxemia triggers life-threatening immune and cardiovascular response that leads to tissue damage, multi-organ failure, and death. The understanding of underlying molecular mechanisms is still evolving. N6-methyladenosine (m6A)-RNA modification plays key regulatory role in numerous biological processes. However, it remains unclear whether endotoxemia alters RNA methylation in the myocardium. In the current study, we investigated the effect of lipopolysaccharide (LPS)-induced endotoxemia on m6A-RNA methylation and its implications on myocardial inflammation and left ventricular (LV) function. Following LPS administration, mice showed increases in m6A-RNA methylation in the myocardium with a corresponding decrease in the expression of fat mass and obesity-associated protein (FTO, an m6A eraser/demethylase). The changes were associated with a significant increase in expression of myocardial inflammatory cytokine genes, such as IL-6, TNF-α, IL-1ß, and reduced LV function. Moreover, rat cardiomyoblasts (H9c2) exposed to LPS showed similar changes (with increase in m6A-RNA methylation and inflammatory cytokine genes, whereas downregulation of FTO). Furthermore, methylated RNA immunoprecipitation assay showed hypermethylation and increase in the expression of IL-6 and TNF-α genes in LPS-treated H9c2 cells as compared to untreated cells. Interestingly, FTO knockdown in cardiomyocytes mimicked the above effects. Taken together, these data suggest that endotoxemia-induced m6A methylation might play a critical role in expression of cardiac proinflammatory cytokines, and modulation of m6A methylation might limit myocardial inflammation and dysfunction during endotoxemia.

MicroRNA-181c-5p modulates phagocytosis efficiency in bone marrow-derived macrophages.

OBJECTIVE AND DESIGN: Phagocytosis and clearance of apoptotic cells are essential for inflammation resolution, efficient wound healing, and tissue homeostasis. MicroRNAs are critical modulators of macrophage polarization and function. The current study aimed to investigate the role of miR-181c-5p in macrophage phagocytosis. MATERIALS AND METHODS: miR-181c-5p was identified as a potential candidate in microRNA screening of RAW264.7 macrophages fed with apoptotic cells. To investigate the role of miR-181c-5p in phagocytosis, the expression of miR-181c-5p was assessed in phagocyting bone marrow-derived macrophages. Phagocytosis efficiency was measured by fluorescence microscopy. Gain- and loss-of-function studies were performed using miR-181c-5p-specific mimic and inhibitor. The expression of the phagocytosis-associated genes and proteins of interest was evaluated by RT2 profiler PCR array and western blotting, respectively. RESULTS: miR-181c-5p expression was significantly upregulated in the phagocyting macrophages. Furthermore, mimic-induced overexpression of miR-181c-5p resulted in the increased phagocytic ability of macrophages. Moreover, overexpression of miR-181c-5p resulted in upregulation of WAVE-2 in phagocyting macrophages, suggesting that miR-181c-5p may regulate cytoskeletal arrangement during macrophage phagocytosis. CONCLUSION: Altogether, our data provide a novel function of miR-181c-5p in macrophage biology and suggest that targeting macrophage miR-181c-5p in injured tissues might improve clearance of dead cells and lead to efficient inflammation resolution.

Management of abiotic stresses by microbiome-based engineering of the rhizosphere.

Abiotic stresses detrimentally affect both plant and soil health, threatening food security in an ever-increasing world population. Sustainable agriculture is necessary to augment crop yield with simultaneous management of stresses. Limitations of conventional bioinoculants have shifted the focus to more effective alternatives. With the realization of the potential of rhizospheric microbiome engineering in enhancing plant's fitness under stress, efforts have accelerated in this direction. Though still in its infancy, microbiome-based engineering has gained popularity because of its advantages over the microbe-based approach. This review briefly presents major abiotic stresses afflicting arable land, followed by an introduction to the conventional approach of microbe-based enhancement of plant attributes and stress mitigation with its inherent limitations. It then focuses on the significance of the rhizospheric microbiome and possibilities of harnessing its potential by its strategic engineering for stress management. Further, success stories related to two major approaches of microbiome engineering (generation of synthetic microbial community/consortium, and host-mediated artificial selection) pertaining to stress management have been critically presented. Together with bringing forth the challenges associated with the wide application of rhizospheric microbiome engineering in agriculture, the review proposes the adoption of a combinational scheme for the same, bringing together ecological and reductionist approaches for improvised sustainable agricultural practices.

The Medicago truncatula Sugar Transport Protein 13 and Its Lr67res-Like Variant Confer Powdery Mildew Resistance in Legumes via Defense Modulation.

Obligate biotrophic pathogens like the pea powdery mildew© (PM) Erysiphe pisi establish long-term feeding relationships with their host, during which they siphon sugars from host cells through haustoria. Plants in turn deploy sugar transporters to restrict carbon allocation toward pathogens, as a defense mechanism. Studies in Arabidopsis have shown that sugar transport protein 13 (STP13), a proton-hexose symporter involved in apoplasmic hexose retrieval, contributes to bacterial and necrotrophic fungal resistance by limiting sugar flux toward these pathogens. By contrast, expression of Lr67res,a transport-deficient wheat STP13 variant harboring two amino acid substitutions (G144R and V387L), conferred resistance against biotrophic fungi in wheat and barley, indicating its broad applicability in disease management. Here, we investigated the role of STP13 and STP13G144R in legume-PM interactions. We show that Medicago truncatula STP13.1 is a proton-hexose symporter involved in basal resistance against PM and indirectly show that Lr67res-mediated PM resistance, so far reported only in monocots, is transferable to legumes. Among the 30 MtSTPs, STP13.1 exhibited the highest fold induction in PM-challenged leaves and was also responsive to chitosan, ABA and sugar treatment. Functional assays in yeast showed that introduction of the G144R mutation but not V388L abolished MtSTP13.1's hexose uptake ability. Virus-induced gene silencing of MtSTP13 repressed pathogenesis-related (PR) gene expression and enhanced PM susceptibility in M. truncatula whereas transient overexpression of MtSTP13.1 or MtSTP13.1G144R in pea induced PR and isoflavonoid pathway genes and enhanced PM resistance. We propose a model in which STP13.1-mediated sugar signaling triggers defense responses against PM in legumes.

ACC deaminase positive Enterobacter-mediated mitigation of salinity stress, and plant growth promotion of Cajanus cajan: a lab to field study.

Salinity is a major abiotic stress that negatively impacts plant health and soil microbiota. ACC (1-aminocyclopropane carboxylic acid) deaminase producing microorganisms act as natural stress busters that protect plants from different kinds of stresses. The study focused on the isolation of potent, indigenous, multi-trait ACC deaminase producers. The shortlisted ACC deaminase producers were checked for their ability to promote growth of Cajanus cajan, and mitigate stress under laboratory conditions followed by validation of their potency in naturally saline field conditions. Physiological stress markers were assessed to evaluate the impact of salinity in plants treated with ACC deaminase producer, compared to controls. Further, the contribution of ACC deaminase in stress mitigation was demonstrated by using a chemical inhibitor for ethylene biosynthesis. This study presents a polyphasic approach, transitioning from the rhizospheric soil to the laboratory to validation in the field, and puts forth a promising eco-friendly alternative for sustainable agriculture. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s12298-021-01031-0.

Homologous recombination-mediated repair of DNA double-strand breaks operates in mammalian mitochondria.

Mitochondrial DNA is frequently exposed to oxidative damage, as compared to nuclear DNA. Previously, we have shown that while microhomology-mediated end joining can account for DNA deletions in mitochondria, classical nonhomologous DNA end joining, the predominant double-strand break (DSB) repair pathway in nucleus, is undetectable. In the present study, we investigated the presence of homologous recombination (HR) in mitochondria to maintain its genomic integrity. Biochemical studies revealed that HR-mediated repair of DSBs is more efficient in the mitochondria of testes as compared to that of brain, kidney and spleen. Interestingly, a significant increase in the efficiency of HR was observed when a DSB was introduced. Analyses of the clones suggest that most of the recombinants were generated through reciprocal exchange, while ~ 30% of recombinants were due to gene conversion in testicular extracts. Colocalization and immunoblotting studies showed the presence of RAD51 and MRN complex proteins in the mitochondria and immunodepletion of MRE11, RAD51 or NIBRIN suppressed the HR-mediated repair. Thus, our results reveal importance of homologous recombination in the maintenance of mitochondrial genome stability.

Glutaminolysis Promotes Collagen Translation and Stability via α-Ketoglutarate-mediated mTOR Activation and Proline Hydroxylation.

Glutaminolysis is the metabolic process of glutamine, aberration of which has been implicated in several pathogeneses. Although we and others recently found a diversity of metabolic dysregulation in organ fibrosis, it is unknown if glutaminolysis regulates the profibrotic activities of myofibroblasts, the primary effector in this pathology. In this study, we found that lung myofibroblasts demonstrated significantly augmented glutaminolysis that was mediated by elevated glutaminase 1 (Gls1). Inhibition of glutaminolysis by specific Gls1 inhibitors CB-839 and BPTES as well as Gls1 siRNA blunted the expression of collagens but not that of fibronectin, elastin, or myofibroblastic marker smooth muscle actin-α. We found that glutaminolysis enhanced collagen translation and stability, which were mediated by glutaminolysis-dependent mTOR complex 1 activation and collagen proline hydroxylation, respectively. Furthermore, we found that the amount of the glutaminolytic end product α-ketoglutarate (α-KG) was increased in myofibroblasts. Similar to glutaminolysis, α-KG activated mTOR complex 1 and promoted the expression of collagens but not of fibronectin, elastin, or smooth muscle actin-α. α-KG also remarkably inhibited collagen degradation in fibroblasts. Taken together, our studies identified a previously unrecognized mechanism by which a major metabolic program regulates the exuberant production of collagens in myofibroblasts and suggest that glutaminolysis is a novel therapeutic target for treating organ fibrosis, including idiopathic pulmonary fibrosis.

Metabolic characterization and RNA profiling reveal glycolytic dependence of profibrotic phenotype of alveolar macrophages in lung fibrosis.

Metabolic reprogramming has been intrinsically linked to macrophage activation. Alveolar macrophages are known to play an important role in the pathogenesis of pulmonary fibrosis. However, systematic characterization of expression profile in these cells is still lacking. Furthermore, main metabolic programs and their regulation of cellular phenotype are completely unknown. In this study, we comprehensively analyzed the expression profile and main metabolic programs in alveolar macrophages from mice with or without experimental pulmonary fibrosis. We found that alveolar macrophages from both bleomycin and active TGF-ß1-induced fibrotic mouse lungs demonstrated a primarily profibrotic M2-like profile that was distinct from the well-defined M1 or any of the M2 subtypes. More importantly, we found that fibrotic lung alveolar macrophages assumed augmented glycolysis, which was likely attributed to enhanced expression of multiple key glycolytic mediators. We also found that fatty acid oxidation was upregulated in these cells. However, the profibrotic M2-like profile of fibrotic lung alveolar macrophages was not dependent on fatty acid oxidation and synthesis or lipolysis, but instead on glycolysis, in contrast to the typical IL-4-induced macrophages M(IL-4). Additionally, glutaminolysis, a key metabolic program that has been implicated in numerous pathologies, was not required for the profibrotic M2-like phenotype of these macrophages. In summary, our study identifies a unique expression and metabolic profile in alveolar macrophages from fibrotic lungs and suggests glycolytic inhibition as an effective antifibrotic strategy in treating lung fibrosis.

Renal Functional Reserve in Acute Kidney Injury Patients Requiring Dialysis.

The incidence of acute kidney injury (AKI) has increased in the recent past. Patients with AKI have an increased risk of mortality. They are also at increased risk of developing chronic kidney disease (CKD). AKI can lead to irreversible loss of renal function despite complete clinical recovery. Currently, no tools are available to diagnose this subclinical loss of renal function. Renal functional reserve (RFR) can serve as an essential tool for analyzing this subclinical loss of renal function, and patients with loss of RFR post-AKI may be closely followed for the development of CKD. This prospective observational study, conducted at the Department of Nephrology, Jawaharlal Institute of Postgraduate Medical Education & Research (JIPMER), aimed to investigate RFR in 223 patients with AKI requiring dialysis. The study excluded patients with CKD and obstructive uropathy. Methods included RFR assessment three months post-AKI recovery, utilizing technetium-99m (Tc-99m) diethylenetriaminepentaacetic acid (DTPA) plasma clearance during amino acid infusion. Statistical analyses and logistic regression were applied, receiving ethical approval. Results revealed a high in-hospital mortality rate of 78.02%, associated with elevated Sequential Organ Failure Assessment (SOFA) scores. Among 24 patients with complete AKI recovery, the RFR at three months was 10.06% (interquartile range (IQR) 5.60-20.15), with the measured GFR significantly lower than the estimated glomerular filtration rate (GFR). The study concludes that AKI requiring dialysis is linked to high mortality and emphasizes the predictive value of SOFA scores. Additionally, RFR testing at three months post-recovery provides insights into potential long-term impacts on renal function. This study contributes valuable insights into the prognosis of AKI patients requiring dialysis. It underscores the need for further research on RFR as a diagnostic tool and the lasting consequences of AKI.

Identification and development of Tetra-ARMS PCR-based screening test for a genetic variant of OLA1 (Tyr254Cys) in the human failing heart.

Obg-like ATPase 1 (OLA1) protein has GTP and ATP hydrolyzing activities and is important for cellular growth and survival. The human OLA1 gene maps to chromosome 2 (locus 2q31.1), near Titin (TTN), which is associated with familial dilated cardiomyopathy (DCM). In this study, we found that expression of OLA1 was significantly downregulated in failing human heart tissue (HF) compared to non-failing hearts (NF). Using the Sanger sequencing method, we characterized the human OLA1 gene and screened for mutations in the OLA1 gene in patients with failing and non-failing hearts. Among failing and non-failing heart patients, we found 15 different mutations in the OLA1 gene, including two transversions, one substitution, one deletion, and eleven transitions. All mutations were intronic except for a non-synonymous 5144A>G, resulting in 254Tyr>Cys in exon 8 of the OLA1 gene. Furthermore, haplotype analysis of these mutations revealed that these single nucleotide polymorphisms (SNPs) are linked to each other, resulting in disease-specific haplotypes. Additionally, to screen the 254Tyr>Cys point mutation, we developed a cost-effective, rapid genetic screening PCR test that can differentiate between homozygous (AA and GG) and heterozygous (A/G) genotypes. Our results demonstrate that this PCR test can effectively screen for OLA1 mutation-associated cardiomyopathy in human patients using easily accessible cells or tissues, such as blood cells. These findings have important implications for the diagnosis and treatment of cardiomyopathy.

Nephrotic Syndrome Due to Sunitinib: A Rare Complication of Treatment of Renal Cell Carcinoma.

This case report details a 62-year-old male with a history of right renal cell carcinoma (RCC) who developed sunitinib-induced nephrotic syndrome during treatment. The patient had a complex medical history, including a right nephrectomy in 2009, brain metastasis excisions in 2011 and 2012, and prolonged sunitinib therapy. Hypothyroidism, hypertension, and various surgeries further complicated his clinical picture. In April 2022, the patient presented with bilateral pedal edema, acute kidney injury superimposed on chronic kidney disease, and proteinuria. Upon examination, the decision was made to discontinue sunitinib, leading to the resolution of nephrotic syndrome. Adjustments in thyroxine dosage were made, and pharmacological interventions were employed to manage proteinuria and renal dysfunction. A multidisciplinary approach involving oncologists, nephrologists, and endocrinologists was essential in achieving a favorable outcome. The case highlights the intricate balance required in managing patients undergoing targeted cancer therapies, emphasizing the importance of vigilant monitoring, prompt intervention, and a collaborative approach for optimal patient care.

A Rare Case of Autoimmune Disorder as a Trigger for Atypical Hemolytic Uremic Syndrome.

Autoimmune diseases may act as a trigger for atypical hemolytic uremic syndrome (aHUS). Triggers for aHUS may include autoimmune diseases, infections, metabolic conditions, pregnancy, and transplants. aHUS-mediated injury to various organs, especially kidneys, can be life-threatening. Here, we present the case of a young female who had perinuclear antineutrophil cytoplasmic antibody (p-ANCA)-associated vasculitis and was diagnosed with aHUS. We consider underlying autoimmune p-ANCA-associated vasculitis as a trigger for aHUS in this case.

Renal Aspergillosis Complicating Renal Allograft Transplantation: A Case Report.

Renal aspergillosis is a rare yet potentially devastating complication following renal allograft transplantation. We present the case of a 45-year-old male with a history of crescentic IgA nephropathy who underwent renal allograft transplantation from his mother. Despite initial favorable progress, he developed post-transplant renal dysfunction attributed to active antibody-mediated rejection. Subsequently, he presented with signs of systemic infection and graft dysfunction, leading to the diagnosis of renal aspergillosis. Despite aggressive management, including antifungal therapy and cessation of immunosuppression, the patient progressed to renal graft cortical necrosis, necessitating nephrectomy. This case underscores the challenges in diagnosing and managing renal aspergillosis in transplant recipients and highlights the importance of early recognition and prompt intervention to improve outcomes in such cases.

Bortezomib-Induced Superficial Vasculitis in a Kidney Transplant Recipient: A Rare Case.

Bortezomib is a frequently administered immunosuppressive agent in kidney transplantation. A 30-year-old male kidney transplant recipient developed an atypical reaction on the left hand in terms of spider-like extensions, indicating erythematous inflammation along the superficial veins after bortezomib intravenous administration. The inflammation spontaneously resolved after three weeks with a bortezomib dose reduction. Nephrologists must be familiar with the potential cutaneous bortezomib-induced adverse effects.

Dapagliflozin-Induced Erythrocytosis in Chronic Kidney Disease: A Rare Occurrence.

Erythrocytosis, a rare adverse effect associated with sodium-glucose cotransporter 2 inhibitors (SGLT2i), has been reported in diabetic patients, but its occurrence in those with chronic kidney disease (CKD) remains underrecognized. Here, we present two cases of dapagliflozin-related erythrocytosis in diabetic patients with CKD, highlighting the need for increased awareness among clinicians. Despite the established efficacy of SGLT2i in managing type 2 diabetes mellitus (T2DM) and its cardiovascular benefits, erythrocytosis poses a potential complication, necessitating thorough understanding and monitoring. While the precise mechanism of SGLT2i-induced erythrocytosis remains unclear, hypotheses include hemoconcentration and modulation of iron metabolism. Notably, our cases demonstrate a rapid onset of erythrocytosis, possibly exacerbated by CKD, emphasizing the importance of vigilant hemoglobin monitoring, especially in CKD patients on SGLT2i therapy. Timely discontinuation of dapagliflozin resulted in a significant reduction in hemoglobin levels, underscoring the critical role of early intervention in preventing erythrocytosis-related complications. This report advocates for routine hematological evaluation in CKD patients treated with SGLT2i to promptly detect and manage erythrocytosis, enhancing patient safety and improving clinical outcomes.

A Case of NELL-1-Positive Membranous Nephropathy With Acute Kidney Injury Due to Bilateral Renal Vein Thrombosis.

Membranous nephropathy (MN) is a significant cause of nephrotic syndrome in non-diabetic adults. It can be primary, attributed to autoantibodies targeting podocyte antigens, or secondary to various disorders. Although rare, nerve epidermal growth factor-like 1 (NELL-1)-associated MN presents diagnostic and management challenges. Thrombotic complications such as renal vein thrombosis (RVT) are recognized but less reported, especially in NELL-1-positive MN. We report a 43-year-old male with NELL-1-positive MN complicated by acute kidney injury (AKI) due to bilateral RVT, treated successfully with thrombolysis. Histopathological analysis confirmed MN with specific immunohistochemical staining for NELL-1. Treatment included immunosuppressive therapy and tailored anticoagulation. This case emphasizes recognizing thrombotic complications in MN, particularly in NELL-1-positive cases. Further research is needed to explore serum anti-NELL-1 antibodies as biomarkers and optimal anticoagulation strategies in MN patients at risk of thrombotic events to improve outcomes and guide personalized management.