Cardiorenal Impact of Anti-Cancer Agents: The Intersection of Onco-Nephrology and Cardio-Oncology.

BACKGROUND: The evolving landscape of cancer treatments has introduced new challenges, particularly related to adverse events associated with chemotherapeutic agents. To address these challenges, the fields of cardio-oncology and onco-nephrology have arisen, focusing on the management of cardiotoxicity and nephrotoxicity attributable to anti-cancer drugs. SUMMARY: Numerous intersections between these disciplines exist, including onco-hypertension (HTN) and cardiorenal toxicities induced by chemotherapeutic agents. Additionally, immune checkpoint inhibitors (ICIs) may cause myocarditis and nephritis. This paper aimed to explore the intersection between cardio-oncology and onco-nephrology. A detailed review will be undertaken, focusing on onco-HTN and the cardiorenal toxicities of chemotherapeutic agents, with a specific emphasis on the adverse effects associated with ICIs. KEY MESSAGES: Multidisciplinary collaboration among oncologists, cardiologists, nephrologists, and other healthcare professionals is crucial for developing tailored approaches to optimize treatment efficacy while minimizing the risk of cardiovascular and renal complications, ultimately enhancing patient outcomes in modern oncology practice.

MAPK/NF-κB signaling mediates atrazine-induced cardiorenal syndrome and antagonism of lycopene.

Atrazine (ATZ) is the most prevalent herbicide that has been widely used in agriculture to control broadleaf weeds and improve crop yield and quality. The heavy use of ATZ has caused serious environmental pollution and toxicity to human health. Lycopene (LYC), is a carotenoid that exhibits numerous health benefits, such as prevention of cardiovascular diseases and nephropathy. However, it remains unclear that whether ATZ causes cardiorenal injury or even cardiorenal syndrome (CRS) and the beneficial role of LYC on it. To test this hypothesis, mice were treated with LYC and/or ATZ for 21 days by oral gavage. This study demonstrated that ATZ exposure caused cardiorenal morphological alterations, and several inflammatory cell infiltrations mediated by activating NF-κB signaling pathways. Interestingly, dysregulation of MAPK signaling pathways and MAPK phosphorylation caused by ATZ have been implicated in cardiorenal diseases. ATZ exposure up-regulated cardiac and renal injury associated biomarkers levels that suggested the occurrence of CRS. However, these all changes were reverted, and the phenomenon of CAR was disappeared by LYC co-treatment. Based on our findings, we postulated a novel mechanism to elucidate pesticide-induced CRS and indicated that LYC can be a preventive and therapeutic agent for treating CRS by targeting MAPK/NF-κB signaling pathways.

Role of DPP4 and DPP4i in Glucose Homeostasis and Cardiorenal Syndrome.

The objective of the review led to the pursuit of adopting dipeptidyl peptidase-4 inhibitors (DPP4i) as a novel pharmacotherapy in diabetes mellitus (DM) and cardiorenal syndrome (CRS). The CRS is defined as the co-existence of myocardial ischemia with renal failure. At present, the commercially available drugs enhance insulin secretion or action. However, most of the drugs are associated with adverse effects, such as weight gain or hypoglycemia. As a result, newer therapies with better safety and efficacy profiles are being explored. The DPP4 protease enzyme is involved in cardiovascular and renal diseases in association with over-expressed cytokines. The novel characteristic of DPP4i is to control the elevated blood glucose levels in response to nutrient ingestion without causing hypoglycemia. Also, DPP4i are indirectly involved in reducing myocardial ischemia by promoting cardioprotective peptides. They protect the glucagon-like peptide 1 (GLP-1) from the deteriorating effect of the DPP4 enzyme. The GLP-1 receptors (GLP-1R) are abundantly expressed in renal and cardiovascular tissue. The overexpression of GLP-1R will confer protection of the heart and kidney during CRS. DPP4i were found to significantly clear plasma glucose by the simultaneously activating natural thrombolytic system and increasing insulin levels. They can be used in the early stages of the disease, including pre-diabetes or obesity combined with impaired incretin response, while the combination of DPP4i with metformin or thiazolidinediones as insulin sensitizers offers an additional improvement in the treatment of DM. With its positive attributes in a host of associated parameters of interest, DPP4i are studied extensively in the present review.

Cardiorenal Syndrome Triggered by Slowly Progressive Drugs Toxicity-Induced Renal Failure along with Minimal Mitral Disease: A Case Report.

BACKGROUND: We report the case of a 93-year-old patient with normal left ventricular function and severe mitral annulus calcification, with mild mitral steno-insufficiency. CASE PRESENTATION: She had developed creeping drugs-induced renal toxicity that is generally totally overlooked, due mainly to statins, a proton pump inhibitor, and aspirin. The Na and fluid retention, along with hypertension that ensued, although not severe, caused acute heart failure (sub-pulmonary edema) by worsening the mitral insufficiency. This occurred due to a less efficient calcific mitral annulus contraction during systole and an increasing mitral transvalvular gradient, as the transvalvular mitral gradient has an exponential relation to flow. After the suspension of the nephrotoxic drugs and starting intravenous furosemide, she rapidly improved. At 6 months follow-up, she is stable, in an NYHA 1-2 functional class, despite the only partial recovery of the renal function. CONCLUSION: Progressive renal failure can functionally worsen even minimal mitral valvulopathy. Drug-induced nephrotoxicity can always be suspected in case of renal failure of unknown etiology. The suspension of the culprit drugs can improve renal function and dramatically improve the clinical symptoms even in a nonagenarian.

Catalytic iron mediated renal stress responses during experimental cardiorenal syndrome 1 ("CRS-1").

Cardiorenal syndrome I (CRS-1) denotes a state in which acute kidney injury occurs in the setting of acute heart failure (AHF). Isoproterenol (Iso) administration is widly used as an AHF model by transiently inducing extreme tachycardia, hypotension, and myocyte apoptosis and/or necrosis. To gain potential insights into renal manifestations of CRS-1, mice were subjected to the Iso-AHF model (50 mg Iso/kg), followed by renal functional and renal cortical assessments over 4 hours Iso induced acute azotemia (doubling of BUN, plasma creatinine) and significantly reduced renal plasma flow (prolonged plasma para-amino-hippurate clearance). Although no morphologic tubular injury was identified, marked increases in renal cortical 'stress markers' (NGAL, HO-1, IL-6, MCP-1 mRNAs) and oxidant stress (decreased glutathione, increased malondialdehyde) were observed. These changes were catalytic Fe dependent, given that the iron chelator desferrioxamine (DFO) significantly blunted, or completely reversed, these renal cortical abnormalities. Despite these acute changes, no lasting renal injury was observed (assessed over 3 days). To determine whether Iso directly impacts tubular cell integrity, cultured proximal tubule (HK-2) cells were exposed to Iso. Substantial Fe dependent cell injury (decreased MTT uptake), and Fe independent increases in HO-1/IL-6 mRNA expression were observed. We conclude that Iso-induced AHF is a useful reversible model of CRS-1. Despite its largely hemodynamic ('pre-renal') nature, Fe-mediated oxidative stress and pro-inflammatory reactions are induced. These arise, at least in part, from direct Iso- induced tubular cell toxicity, rather than simply being secondary to Iso-mediated hemodynamic events. Finally, Iso-triggered renal cytokine production can potentially contribute to 'organ cross talk' and a systemic pro-inflammatory state.

The guanylate cyclase C agonist linaclotide ameliorates the gut-cardio-renal axis in an adenine-induced mouse model of chronic kidney disease.

BACKGROUND: Cardiorenal syndrome is a major cause of mortality in patients with chronic kidney disease (CKD). However, the involvement of detrimental humoral mediators in the pathogenesis of cardiorenal syndrome is still controversial. Trimethylamine-N-oxide (TMAO), a hepatic metabolic product of trimethylamine generated from dietary phosphatidylcholine or carnitine derived by the gut microbiota, has been linked directly with progression of cardiovascular disease and renal dysfunction. Thus, targeting TMAO may be a novel strategy for the prevention of cardiovascular disease and chronic kidney disease. METHODS: Linaclotide, a guanylate cyclase C agonist, was administered to adenine-induced renal failure (RF) mice and changes in renal function and levels of gut-derived uremic toxins, as well as the gut microbiota community, were analyzed using metabolomic and metagenomic methods to reveal its cardiorenal effect. RESULTS: Linaclotide decreased the plasma levels of TMAO at a clinically used low dose of 10 µg/kg in the adenine-induced RF mouse model. At a high concentration of 100 µg/kg, linaclotide clearly improved renal function and reduced the levels of various uremic toxins. A reduction in TMAO levels following linaclotide treatment was also observed in a choline-fed pro-atherosclerotic model. Linaclotide ameliorated renal inflammation and fibrosis and cardiac fibrosis, as well as decreased the expression of collagen I, transforming growth factor-ß, galectin-3 (Gal-3) and ST2 genes. Plasma levels of Gal-3 and ST2 were also reduced. Because exposure of cardiomyocytes to TMAO increased fibronectin expression, these data suggest that linaclotide reduced the levels of TMAO and various uremic toxins and may result in not only renal, but also cardiac, fibrosis. F4/80-positive macrophages were abundant in small intestinal crypts in RF mice, and this increased expression was decreased by linaclotide. Reduced colonic claudin-1 levels were also restored by linaclotide, suggesting that linaclotide ameliorated the 'leaky gut' in RF mice. Metagenomic analysis revealed that the microbial order Clostridiales could be responsible for the change in TMAO levels. CONCLUSION: Linaclotide reduced TMAO and uremic toxin levels and could be a powerful tool for the prevention and control of the cardiorenal syndrome by modification of the gut-cardio-renal axis.

Pretreatment of carprofen impaired initiation of inflammatory- and overlapping resolution response and promoted cardiorenal syndrome in heart failure.

Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) are commonly used to control pain, inflammation, and limit the cardinal signs of injury in humans. However, prolonged use of NSAIDs increases the risk of heart attack (myocardial infarction; MI) and the subsequent risk of heart and renal failure. The molecular and cellular mechanism of action for this adverse effect, particularly along the cardiorenal network, is incomplete. To define the mechanism, carprofen (CAP), an NSAID was administered at the dose of 5 mg/kg to C57BL/6 male mice for two weeks. After last dose of CAP treatment mice were subjected to permanent occlusion of coronary artery that induces irreversible cardiac remodeling while maintaining naive and MI-controls. After MI, cardiac pathology and dysfunction were confirmed, along with additional measurements of kidney function, histology, and injury markers, such as plasma creatinine. CAP treatment increased plasma creatinine levels and subsequently, myocardial structural disorganization increased. Kidney neutrophil gelatinase associated lipocalin (NGAL) and protein expression were increased post-MI. After two weeks CAP treatment, the expression of pyrogenic pro-inflammatory cytokines TNF-α and IL-1ß was increased compared to non-CAP treated mice, indicative of amplified inflammatory response. There was also evidence that renal injury of both the post-CAP treatment controls and post-CAP MI were much greater than the non-CAP treated naïve controls, as serum creatinine and NGAL levels were elevated along with obvious structural impairment of the glomerulus. Therefore, CAP treatment tampers with the acute inflammatory response that promotes cardiorenal syndrome and non-resolving inflammation post-MI in acute heart failure.

A novel model of reno-cardiac syndrome in the C57BL/ 6 mouse strain.

BACKGROUND: The end stage renal disease population has a 20 fold higher incidence of cardiovascular mortality compared to the overall population. The development of reno-cardiac syndrome in these patients will result in cardiovascular events to be the cause of 50% of fatalities. There is therefore a need to research improved therapeutic strategies to combat renal cardiac pathologies. Murine in vivo models contribute greatly to such research allowing for specific genetic modification and reduced miscellany, however there is currently no reliable model of reno-cardiac syndrome in the most common genetically modified mouse strain, the C57BL/6. In this study we have manipulated an established model of chronic renal disease using adenine infused diet and prolonged the course of its pathology achieving chronic renal failure and subsequent reno-cardiac syndrome in the C57BL/6 mouse. METHODS: Eight week-old male C57BL/ 6 mice were acclimatised for 7 days before administration of a 0.15% adenine diet or control diet for 20 weeks. Cardiac function was assessed in mice at week 20 by echocardiography. At experiment termination blood and urine samples were analysed biochemically and organ dysfunction/injury was determined using immunoblotting and immunohistochemistry. RESULTS: Administration of 0.15% adenine diet caused progressive renal failure resulting in reno-cardiac syndrome. At endpoint uraemia was confirmed by blood biochemistry which in the adenine fed mice showed significant increases in serum creatinine, urea, calcium (P < 0.0001) potassium (P < 0.05), and a significantly reduced glomerular filtration rate (P < 0.05). Reno-cardiac syndrome was confirmed by a significantly increased heart to body weight ratio (P < 0.0001) and echocardiography which showed significant reductions in percentage of ejection fraction, fractional shortening, fractional area change, (P < 0.0001) and an increase in left ventricular end diastolic volume (P < 0.05). Immunoblotting of kidney and heart tissue showed increased apoptosis (caspase 3) and fibrosis (fibronectin) and increases in the cardiac levels of phosphorylated Akt, and renal total Akt. Immunohistochemistry for α-SMA, collagen 1 and collagen 3 further confirmed fibrosis. CONCLUSIONS: We present a novel regimen of adenine diet which induces both chronic kidney disease and reno-cardiac syndrome in the C57/BL6 mouse strain. The non-surgical nature of this model makes it highly reproducible compared to other models currently available.

Biochemical and electrocardiographic studies on the beneficial effects of gallic acid in cyclophosphamide-induced cardiorenal dysfunction.

Background Cardiac toxicity is one of the life-threatening complications of cancer therapy. Cyclophosphamide (CYP) is an alkylating agent with potent antineoplastic and immunosuppressive properties and possibly the most widely used antineoplastic agent. Chronic cardiotoxicity associated with CYP is characterized by progressive heart failure developing from weeks to years after therapy. Methods In this study, rats were administered with (60 mg/kg and 120 mg/kg) alone or in combination with single intraperitoneal (200 mg/kg) administration of CYP for 7 days. CYP was only administered on day 1. Results The administration of CYP led to a significant (p<0.05) increase in cardiac and renal malondialdehyde (MDA) contents and hydrogen peroxide (H2O2) generation. Also, the activities of catalase (CAT), glutathione peroxidase (GPx), glutathione-S-transferase (GST) and reduced glutathione (GSH) levels were significantly (p<0.05) reduced following CYP treatment. A significant (p<0.05) increase in serum myeloperoxidase (MPO) activity was recorded in rats administered CYP only. Electrocardiogram (ECG) showed a significant (p<0.05) increase in heart rate (HR) accompanied by transient decrease in QRS duration. Histologic examination revealed architectural anarchy of both heart and kidney of rats that received only CYP. Conclusions In this study, treatment with gallic acid (60 mg/kg and 120 mg/kg) restored the enzymic and non-enzymic antioxidants and also attenuated cardiotoxic and nephrotoxic effect of CYP through free radical scavenging activity, anti-inflammatory and improvement of antioxidant defence system.

Alterations in blood pressure, antioxidant status and caspase 8 expression in cobalt chloride-induced cardio-renal dysfunction are reversed by Ocimum gratissimum and gallic acid in Wistar rats.

The protective abilities of the chloroform extract of Ocimum gratissimum (COG) and gallic acid against cobalt chloride (CoCl2) - induced cardiac and renal toxicity were evaluated. Rats were exposed to CoCl2 (350ppm) for 7 days, either alone, or in combination with COG (100 and 200mg/kg) or gallic acid (120mg/kg). CoCl2 given alone, caused significant increases (p<0.05) in oxidative stress parameters (hydrogen peroxide, H2O2 and malondialdehyde, MDA) and increased expression of the apoptotic initiator caspase 8 in the heart and kidneys. There was significant reduction (p<0.05) in reduced glutathione (GSH) in cardiac and renal tissues; reduction in superoxide dismutase (SOD) activity in the kidneys and adaptive increases in Glutathione S-transferase (GST) and catalase (CAT). CoCl2 also produced significant reduction (p<0.05) in systolic (SBP), diastolic (DBP) and mean arterial (MAP) blood pressures. Oral COG and gallic acid treatment significantly reduced (p<0.05) the levels of H2O2 and MDA; with reduced expression of caspase 8 and restoration of GSH levels, GPx, SOD and CAT activities, howbeit, to varying degrees in the heart and kidneys. COG (200mg/kg) was most effective in restoring the blood pressures in the rats to near control levels. CoCl2-induced histopathological lesions including myocardial infarction and inflammation and renal tubular necrosis and inflammation were effectively ameliorated by the treatments administered. This study provides evidence for the protective roles of O. gratissimum and gallic acid by modulation of CoCl2-induced alterations in blood pressure, antioxidant status and pro-apoptotic caspase 8 in Wistar rats.

Diuretics in heart failure: practical considerations.

This review discusses the role of diuretics in heart failure by focusing on different classifications and mechanisms of action. Pharmacodynamic and pharmacokinetic properties of diuretics are elucidated. The predominant discussion highlights the use of loop diuretics, which are the most commonly used drugs in heart failure. Different methods of using this therapy in different settings along with a comprehensive review of the side-effect profile are highlighted. Special situations necessitating adjustment and the phenomenon of diuretic resistance are explained.