Ocular Mucous Membrane Pemphigoid: The Effect of Risk Factors at Presentation on Treatment Outcomes.

PURPOSE: Analyze the influence of risk factors at presentation in the long-term immunosuppressive therapy (IMT) outcomes of ocular mucous membrane pemphigoid (OMMP). DESIGN: Retrospective multicenter study. PARTICIPANTS: Patients with OMMP seen at the Duke Eye Center, Tecnologico de Monterrey, and Hospital Clinic of Barcelona from 1990 to 2022. METHODS: Data at presentation on demographics, direct immunofluorescence, ocular findings, sites of extraocular manifestations (EOMs), and previous treatments in patients with a clinical or laboratory diagnosis of OMMP, were analyzed with multivariable analysis and Kaplan-Meier plots to identify factors associated with adverse outcomes. MAIN OUTCOME MEASURES: (1) Inflammatory control (no conjunctival inflammation in both eyes at 3 months on IMT); (2) relapse (new-onset inflammation after absolute control in either eye); (3) progression (≥ 1 cicatrizing stage progression in either eye); and (4) vision loss (≥ 2 Snellen lines). RESULTS: A total of 117 patients (234 eyes), 61% (71/117) of whom were women, with a mean age of 66.6 (SD: 12.4) years (range: 37-97 years) and median follow-up of 34 months (interquartile range: 16-66 months; range: 3-265 months), were enrolled. Inflammatory control was achieved in 57% of patients (67/117), with high-risk EOM (HR-EOM), including esophageal, nasopharyngeal, and/or genital involvement (adjusted odds ratio [aOR]: 12.51; 95% confidence interval [CI]: 2.61-59.99; P = 0.002) and corneal scarring (aOR: 3.06; 95% CI, 1.15-8.14; P = 0.025), as significant risk factors for persistent inflammation. Disease relapse, progression, and vision loss occurred in 20% of patients (23/117), 12% of patients (14/117), and 27% of patients (32/117), respectively. Baseline corneal scarring was a risk factor for relapse (adjusted hazard ratio: 4.14; 95% CI: 1.61-10.62; P = 0.003), progression (aOR: 11.46; 95% CI: 1.78-73.75; P = 0.010), and vision loss (aOR: 3.51; 95% CI: 1.35-9.10; P = 0.010). HR-EOM was associated with stage progression (aOR, 34.57; 95% CI, 6.57-181.89; P<0.001) and vision loss (aOR, 8.42; 95% CI, 2.50-28.42; P = 0.001). No significant differences were found between IMT regimes and relapse (P = 0.169). CONCLUSIONS: Ocular mucous membrane pemphigoid presenting with HR-EOMs and corneal scarring has an increased risk of stage progression and vision loss. Corneal scarring and severe inflammation at baseline were associated with an increased risk of relapse. A disease progression staging system incorporating both the HR-EOMs and corneal involvement is required to predict the visual outcome of OMMP better. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Adalimumab to treat noninfectious pediatric chronic anterior uveitis: a case series.

PURPOSE: Evaluate the response to adalimumab (ADA) in pediatric chronic anterior uveitis (pCAU). METHODS: Retrospective chart review of pCAU patients treated with ADA. Outcomes evaluated included the proportion of patients achieving zero ocular inflammation and discontinuation of topical corticosteroids, visual outcomes, and incidence of uveitis recurrences after ≥ 12 months of prescribing ADA. Incidence and risk factors for developing anti-adalimumab antibodies (AAAs) were also evaluated. RESULTS: Of 27 children aged 11 years, 16 (59%) were Caucasian and 6 (22%) African Americans. Thirteen (48%) patients had idiopathic pCAU, 12 (44%) had juvenile idiopathic arthritis (JIA) related pCAU, and 2 (7%) had tubulointerstitial nephritis and uveitis syndrome. At baseline, African American children had worse visual acuity (p = 0.026). At 1 year, 21 (78%) children achieved zero ocular inflammation (remission). Risk factors associated with non-remission were being African American (20% vs. 94%, p = 0.003) and experiencing ≥ 1 episode of uveitis recurrence (100% vs. 0%, p < 0.001). Six episodes of uveitis recurrence were documented in five children, four of whom were African American. Topical corticosteroids were discontinued in 83% of children, and visual acuity remained stable for 1 year. Twelve children were tested for AAAs due to arthritis or uveitis flare-ups, with five (42%) being positive. No significant factors were associated with the development of AAAs. CONCLUSIONS: We found that ADA is effective in controlling inflammation, reducing the need for topical corticosteroids, and maintaining visual acuity in pCAU. There appears to be racial differences in African American children who had worse baseline disease and poorer outcomes. Studies are necessary to understand better and address these disparities.

Diabetic Nephropathy and COVID-19: The Potential Role of Immune Actors.

Nowadays, type II diabetes mellitus, more specifically ensuing diabetic nephropathy, and severe COVID-19 disease are known to be closely associated. The exact mechanisms behind this association are less known. An implication for the angiotensin-converting enzyme 2 remains controversial. Some researchers have started looking into other potential actors, such as neuropilin-1, mitochondrial glutathione, vitamin D, and DPP4. In particular, neuropilin-1 seems to play an important role in the underlying mechanism linking COVID-19 and diabetic nephropathy. We suggest, based on the findings in this review, that its up-regulation in the diabetic kidney facilitates viral entry in this tissue, and that the engagement of both processes leads to a depletion of neuropilin-1, which was demonstrated to be strongly associated with the pathogenesis of DN. More studies are needed to confirm this hypothesis, and research should be directed towards elucidating the potential roles of all these suggested actors and eventually discovering new therapeutic strategies that could reduce the burden of COVID-19 in patients with diabetic nephropathy.

Immune Checkpoint Inhibitor-Induced Diabetes Mellitus: Potential Role of T Cells in the Underlying Mechanism.

Immunotherapy is now a recognized treatment option for several types of cancer. However, some cancer patients treated with immune checkpoint inhibitors (ICIs) are subject to immune-related adverse events, including induced diabetes mellitus. The exact role and molecular/genetic action of ICIs in diabetes are still not well understood. Elucidating the underlying mechanisms in a proper fashion would allow better refining of biomarkers that would help diagnose patients at risk of altered immune system homeostasis, but would also hold the potential of new therapeutic options for diabetes. In the present narrative review, we propose to discuss the case of autoimmune diabetes following treatment with ICIs and the role of ICIs in the pathophysiology of diabetes. We also present some scarce available data on interesting potential immune therapies for diabetes.

COVID-19 and diabetes mellitus: how one pandemic worsens the other.

In light of the most challenging public health crisis of modern history, COVID-19 mortality continues to rise at an alarming rate. Patients with co-morbidities such as hypertension, cardiovascular disease, and diabetes mellitus (DM) seem to be more prone to severe symptoms and appear to have a higher mortality rate. In this review, we elucidate suggested mechanisms underlying the increased susceptibility of patients with diabetes to infection with SARS-CoV-2 with a more severe COVID-19 disease. The worsened prognosis of COVID-19 patients with DM can be attributed to a facilitated viral uptake assisted by the host's receptor angiotensin-converting enzyme 2 (ACE2). It can also be associated with a higher basal level of pro-inflammatory cytokines present in patients with diabetes, which enables a hyperinflammatory "cytokine storm" in response to the virus. This review also suggests a link between elevated levels of IL-6 and AMPK/mTOR signaling pathway and their role in exacerbating diabetes-induced complications and insulin resistance. If further studied, these findings could help identify novel therapeutic intervention strategies for patients with diabetes comorbid with COVID-19.

Deep-learning based analysis of in-vivo confocal microscopy images of the subbasal corneal nerve plexus' inferior whorl in patients with neuropathic corneal pain and dry eye disease.

PURPOSE: To evaluate and compare subbasal corneal nerve parameters of the inferior whorl in patients with dry eye disease (DED), neuropathic corneal pain (NCP), and controls using a novel deep-learning-based algorithm to analyze in-vivo confocal microscopy (IVCM) images. METHODS: Subbasal nerve plexus (SNP) images of the inferior whorl of patients with DED (n = 49, 77 eyes), NCP (n = 14, 24 eyes), and controls (n = 41, 59 eyes) were taken with IVCM and further analyzed using an open-source artificial intelligence (AI)-based algorithm previously developed by our group. This algorithm automatically segments nerves, immune cells, and neuromas in the SNP. The following parameters were compared between groups: nerve area density, average nerve thickness, average nerve segment tortuosity, junction point density, neuroma density, and immune cell density. RESULTS: 160 eyes of 104 patients (63 % females), aged 56.8 ± 15.4 years, were included. The mean nerve area density was significantly lower in the DED (P = 0.012) and NCP (P < 0.001) groups compared to the control group. The junction point density was lower in the NCP group compared with control (P = 0.001) and DED (P = 0.004) groups. The immune cell density was higher in the DED group compared with controls (P < 0.001). CONCLUSIONS: Deep-learning-based analysis of IVCM images of the corneal SNP inferior whorl distinguished a decreased mean nerve area density in patients with DED and NCP compared with controls and an increased immune cell density in patients with oGVHD- and SS-associated DED. These findings suggest that the inferior whorl could be used as landmark to distinguish between patients with DED and NCP.

Clinical Course and Outcomes of Autoimmune Versus Non-Autoimmune Surgically Induced Scleral Necrosis: A Multicentric Comparative Study.

BACKGROUND: To analyze the clinical course and outcomes of autoimmune vs. non-autoimmune surgically induced scleral necrosis (SISN). METHODS: Multicentric, retrospective, comparative cohort study. Eighty-two eyes of 70 patients with SISN were classified according to pathogenic mechanism into autoimmune vs. non-autoimmune. Main outcome measures included necrosis onset, type of surgery, associated systemic disease, visual acuity, and treatment were analysed in patients followed for ≥ 6 months. RESULTS: Forty-six (65.7%) patients were women, and the median age was 66 (range: 24-90) years. Most patients (82.9%) had unilateral disease. The median time between surgery and SISN onset was 58 (1-480) months. Thirty-one (37.8%) eyes were classified as autoimmune, and 51 (62.2%) as non-autoimmune SISN. Autoimmune SISN was associated with a shorter time between the surgical procedure and SISN onset than non-autoimmune cases (median of 26 vs. 60 months, p = 0.024). Also, autoimmune SISN was associated with cataract extraction (93.5% vs. 25.5%, p < 0.001), severe scleral inflammation (58.1% vs. 17.6%, p < 0.001), and higher incidence of ocular complications (67.7% vs. 33.3%, p = 0.002) than non-autoimmune cases. Remission was achieved with medical management alone in 44 (86.3%) eyes from the non-autoimmune and in 27 (87.1%) from the autoimmune group (p = 0.916). Surgical management was required in 11 (13.4%) eyes, including two requiring enucleations due to scleral perforation and phthisis bulbi. CONCLUSIONS: Eyes with autoimmune SISN had a higher rate of cataract surgery, severe scleral inflammation, and ocular complications. Early SISN diagnosis and appropriate management, based on clinical features and pathogenic mechanisms, are critical to avoid sight-threatening complications.

Open-Source Automated Segmentation of Neuronal Structures in Corneal Confocal Microscopy Images of the Subbasal Nerve Plexus With Accuracy on Par With Human Segmentation.

PURPOSE: The aim of this study was to perform automated segmentation of corneal nerves and other structures in corneal confocal microscopy (CCM) images of the subbasal nerve plexus (SNP) in eyes with ocular surface diseases (OSDs). METHODS: A deep learning-based 2-stage algorithm was designed to perform segmentation of SNP features. In the first stage, to address applanation artifacts, a generative adversarial network-enabled deep network was constructed to identify 3 neighboring corneal layers on each CCM image: epithelium, SNP, and stroma. This network was trained/validated on 470 images of each layer from 73 individuals. The segmented SNP regions were further classified in the second stage by another deep network as follows: background, nerve, neuroma, and immune cells. Twenty-one-fold cross-validation was used to assess the performance of the overall algorithm on a separate data set of 207 manually segmented SNP images from 43 patients with OSD. RESULTS: For the background, nerve, neuroma, and immune cell classes, the Dice similarity coefficients of the proposed automatic method were 0.992, 0.814, 0.748, and 0.736, respectively. The performance metrics for automatic segmentations were statistically better or equal as compared to human segmentation. In addition, the resulting clinical metrics had good to excellent intraclass correlation coefficients between automatic and human segmentations. CONCLUSIONS: The proposed automatic method can reliably segment potential CCM biomarkers of OSD onset and progression with accuracy on par with human gradings in real clinical data, which frequently exhibited image acquisition artifacts. To facilitate future studies on OSD, we made our data set and algorithms freely available online as an open-source software package.

Noxious effects of riot control agents on the ocular surface: Pathogenic mechanisms and management.

Riot Control Agents (RCAs) are chemical compounds used by law enforcement agencies to quell violent demonstrations as an alternative to lethal force and as part of police/military training. They are also known as tear gases because of the hallmark ocular irritation and lacrimation they cause. The most common RCAs include oleoresin capsicum (contained in Mace and pepper spray), chlorobenzylidene malononitrile, dibenzoxazepine, and chloroacetophenone (previously the main content of Mace); some of which have been in use for decades. Their immediate incapacitating effects are mediated through polymodal afferent fibers innervating the corneal surface, inducing the release of peptides that cause neurogenic inflammation. Although previously thought to have only transient effects on exposed patients more severe complications such as corneal stromal opacities, corneal neovascularization, neurotrophic keratopathy, conjunctival necrosis, and pseudopterygium can occur. Concerningly, the lack of research and specific therapies restrict the current management to decontamination and symptom-tailored support. This manuscript will provide an overview of the toxic mechanisms of RCAs, their clinical manifestations, and current therapy after exposure to tear gases.

Ocular surface disease: a known yet overlooked side effect of topical glaucoma therapy.

Ocular surface disease (OSD), a disorder affecting the lacrimal and meibomian glands and the corneal and conjunctival epithelium, is a well-known complication of topical glaucoma therapy. OSD can present as a new or pre-existing condition that virtually any anti-glaucoma formulation can exacerbate. As such, both glaucoma and OSD frequently coexist. Typical OSD symptoms include ocular discomfort, redness, burning, and dryness, whereas signs include periorbital and eyelid skin pigmentation, conjunctival scarring, and superficial punctate keratitis. Pressure-lowering eyedrops can cause toxic, allergic, and inflammatory reactions on the ocular surface. The latter can result from either preservatives or direct toxicity from the active molecule. Although usually mild, OSD can cause significant symptoms that lead to poor quality of life, decreased compliance to therapy, glaucoma progression, and worse visual outcomes. Given the chronic nature of glaucoma, lack of curative therapy, and subsequent lifelong treatment, addressing OSD is necessary. This manuscript aims to provide an up-to-date overview of OSD's signs, symptoms, and pathogenic mechanisms from glaucoma therapy toxicity.

Delayed presentation of surgically induced scleral necrosis after I-BRITE procedure treated with immunosuppressive therapy.

Surgically induced scleral necrosis (SISN) is an uncommon complication of ocular procedures. Cosmetic eye-whitening surgery involves conjunctival and Tenon's capsule dissection, cautery, and mitomycin C application. We report the case of a 36-year-old white woman referred to our clinic for severe pain, scleral inflammation, and necrosis in both eyes 9 years after I-BRITE, an elective eye-whitening procedure. An extensive workup yielded negative results. The patient improved with aggressive lubrication and topical and high-dose systemic prednisone (60 mg), with recurrence upon steroid tapering. Concomitant weekly methotrexate was added, resulting in inflammatory control and allowing discontinuance of topical and oral steroids.

VEGF-A: A Novel Mechanistic Link Between CYP2C-Derived EETs and Nox4 in Diabetic Kidney Disease.

Diabetes is associated with decreased epoxyeicosatrienoic acid (EET) bioavailability and increased levels of glomerular vascular endothelial growth factor A (VEGF-A) expression. We examined whether a soluble epoxide hydrolase inhibitor protects against pathologic changes in diabetic kidney disease and whether the inhibition of the VEGF-A signaling pathway attenuates diabetes-induced glomerular injury. We also aimed to delineate the cross talk between cytochrome P450 2C (CYP2C)-derived EETs and VEGF-A. Streptozotocin-induced type 1 diabetic (T1D) rats were treated with 25 mg/L of 12-(3-adamantan-1-yl-ureido)-dodecanoic acid (AUDA) in drinking water for 6 weeks. In parallel experiments, T1D rats were treated with either SU5416 or humanized monoclonal anti-VEGF-A neutralizing antibody for 8 weeks. Following treatment, the rats were euthanized, and kidney cortices were isolated for further analysis. Treatment with AUDA attenuated the diabetes-induced decline in kidney function. Furthermore, treatment with AUDA decreased diabetes-associated oxidative stress and NADPH oxidase activity. Interestingly, the downregulation of CYP2C11-derived EET formation is found to be correlated with the activation of the VEGF-A signaling pathway. In fact, inhibiting VEGF-A using anti-VEGF or SU5416 markedly attenuated diabetes-induced glomerular injury through the inhibition of Nox4-induced reactive oxygen species production. These findings were replicated in vitro in rat and human podocytes cultured in a diabetic milieu. Taken together, our results indicate that hyperglycemia-induced glomerular injury is mediated by the downregulation of CYP2C11-derived EET formation, followed by the activation of VEGF-A signaling and upregulation of Nox4. To our knowledge, this is the first study to highlight VEGF-A as a mechanistic link between CYP2C11-derived EET production and Nox4. ARTICLE HIGHLIGHTS: Diabetes is associated with an alteration in cytochrome P450 2C11 (CYP2C11)-derived epoxyeicosatrienoic acid (EET) bioavailability. Decreased CYP2C11-derived EET bioavailability mediates hyperglycemia-induced glomerular injury. Decreased CYP2C11-derived EET bioavailability is associated with increased reactive oxygen species production, NADPH oxidase activity, and Nox4 expression in type 1 diabetes. Decreased CYP2C11-derived EET formation mediates hyperglycemia-induced glomerular injury through the activation of the vascular endothelial growth factor A (VEGF-A) signaling pathway. Inhibiting VEGF signaling using anti-VEGF or SU5416 attenuates type 1 diabetes-induced glomerular injury by decreasing NADPH oxidase activity and NOX4 expression.

Wessely corneal ring phenomenon: An unsolved pathophysiological dilemma.

The cornea is a densely innervated avascular tissue showing exceptional inflammatory and immune responses. The cornea is a site of lymphangiogenic and angiogenic privilege devoid of blood and lymphatic vessels that limits the entry of inflammatory cells from the adjacent and highly immunoreactive conjunctiva. Immunological and anatomical differences between the central and peripheral cornea are also necessary to sustain passive immune privilege. The lower density of antigen-presenting cells in the central cornea and the 5:1 peripheral-to-central corneal ratio of C1 are two main features conferring passive immune privilege. C1 activates the complement system by antigen-antibody complexes more effectively in the peripheral cornea and, thus, protects the central corneas' transparency from immune-driven and inflammatory reactions. Wessely rings, also known as corneal immune rings, are noninfectious ring-shaped stromal infiltrates usually formed in the peripheral cornea. They result from a hypersensitivity reaction to foreign antigens, including those of microorganism origin. Thus, they are thought to be composed of inflammatory cells and antigen-antibody complexes. Corneal immune rings have been associated with various infectious and noninfectious causes, including foreign bodies, contact lens wear, refractive procedures, and drugs. We describe the anatomical and immunologic basis underlying Wessely ring formation, its causes, clinical presentation, and management.

Ocular Surface Inflammatory Disorders (OSID): A Collective of Systemic Etiologies Which Cause or Amplify Dry Eye Syndrome.

The ocular surface inflammatory disorders (OSID) are caused by systemic disorders that conduct a persistent inflammatory reaction in the ocular adnexal connective tissues, such as the conjunctiva, lacrimal gland (LG) and meibomian glands (MGs), which cause an inflammatory dry eye. The etiologies of OSID are a subset of systemic pathologies such as graft versus host disease, Sjögren's syndrome, allergies, cicatrizing conjunctivitis, and more. These cause a purely inflammatory dry eye syndrome as a consequence of the persistent surrounding inflammation in the adnexal tissues, which is distinct from the age-related dry eye disease. A limitation toward management of these conditions is the lack of available biomarkers that can detect presence of inflammation and quantify damage on the conjunctiva and LG, even though these are considered to be drivers of the inflammatory milieu. The OSID and dry eye syndrome are caused by different immune cells which are not exclusively limited to T cell lymphocytes, but rather derive from an orchestrated multicellular immunologic response. Recognition of this syndrome is crucial to direct research in a direction that clarifies the potential role of inflammation and its associated immune phenotype on the conjunctiva and adnexal ocular tissues in OSID and dry eye syndrome. On this paper, we review the basic and clinical research evidence for the existence of OSID with focus on the different immune cells involved, the target tissues and potential consequences and OSIDs diagnostic and therapeutic implications.

Pharmacological regulation of cytochrome P450 metabolites of arachidonic acid attenuates cardiac injury in diabetic rats.

Diabetic cardiomyopathy (DCM) is a well-established complication of type 1 and type 2 diabetes associated with a high rate of morbidity and mortality. DCM is diagnosed at advanced and irreversible stages. Therefore, it is of utmost need to identify novel mechanistic pathways involved at early stages to prevent or reverse the development of DCM. In vivo experiments were performed on type 1 diabetic rats (T1DM). Functional and structural studies of the heart were executed and correlated with mechanistic assessments exploring the role of cytochromes P450 metabolites, the 20-hydroxyeicosatetraenoic acids (20-HETEs) and epoxyeicosatrienoic acids (EETs), and their crosstalk with other homeostatic signaling molecules. Our data displays that hyperglycemia results in CYP4A upregulation and CYP2C11 downregulation in the left ventricles (LV) of T1DM rats, paralleled by a differential alteration in their metabolites 20-HETEs (increased) and EETs (decreased). These changes are concomitant with reductions in cardiac outputs, LV hypertrophy, fibrosis, and increased activation of cardiac fetal and hypertrophic genes. Besides, pro-fibrotic cytokine TGF-ß overexpression and NADPH (Nox4) dependent-ROS overproduction are also correlated with the observed cardiac functional and structural modifications. Of interest, these observations are attenuated when T1DM rats are treated with 12-(3-adamantan-1-yl-ureido) dodecanoic acid (AUDA), which blocks EETs metabolism, or N-hydroxy-N'-(4-butyl-2-methylphenol)Formamidine (HET0016), which inhibits 20-HETEs formation. Taken together, our findings confer pioneering evidence about a potential interplay between CYP450-derived metabolites and Nox4/TGF-ß axis leading to DCM. Pharmacologic interventions targeting the inhibition of 20-HETEs synthesis or the activation of EETs synthesis may offer novel therapeutic approaches to treat DCM.

Thyroid Dysfunctions Due to Immune Checkpoint Inhibitors: A Review.

AIM: Immune checkpoint inhibitors are anti-cancer drugs associated with adverse events that result from releasing the immune system against self-antigens while attacking cancer cells. Thyroid dysfunctions are among the most common associated adverse events. MATERIALS AND METHODS: We conducted a systematic search of the literature in 2 databases: PubMed and Medline. Articles that reported thyroid adverse events of immune checkpoint inhibitors were reviewed. Thyroid disorders include hyperthyroidism and hypothyroidism and are most commonly seen with programmed cell death protein 1 and programmed death-ligand 1 inhibitors. CONCLUSIONS: Thyroid disorders are common side effects seen with check point inhibitors and are treated, depending on the clinical situation, by adequate hormonal replacement, thionamides, corticosteroids or observation only. The use of high dose corticosteroids has not been established as a treatment of thyroid toxicities. Thyroid function tests screening should be a part of baseline laboratory testing of all patients undergoing treatment with immune checkpoint inhibitors.

Immunomodulatory Approaches in Diabetes-Induced Cardiorenal Syndromes.

Immunomodulatory approaches are defined as all interventions that modulate and curb the immune response of the host rather than targeting the disease itself with the aim of disease prevention or treatment. A better understanding of the immune system continues to offer innovative drug targets and methods for immunomodulatory interventions. Cardiorenal syndrome is a clinical condition that defines disorders of the heart and kidneys, both of which communicate with one another through multiple pathways in an interdependent relationship. Cardiorenal syndrome denotes the confluence of heart-kidney relationships across numerous interfaces. As such, a dysfunctional heart or kidney has the capacity to initiate disease in the other organ via common hemodynamic, neurohormonal, immunological, and/or biochemical feedback pathways. Understanding how immunomodulatory approaches are implemented in diabetes-induced cardiovascular and renal diseases is important for a promising regenerative medicine, which is the process of replacing cells, tissues or organs to establish normal function. In this article, after a brief introduction on the immunomodulatory approaches in diseases, we will be reviewing the epidemiology and classifications of cardiorenal syndrome. We will be emphasizing on the hemodynamic factors and non-hemodynamic factors linking the heart and the kidneys. In addition, we will be elaborating on the immunomodulatory pathways involved in diabetes-induced cardiorenal syndrome namely, RAS, JAK/STAT, and oxidative stress. Moreover, we will be addressing possible therapeutic approaches that target the former pathways in an attempt to modulate the immune system.