We report a case of misdiagnosed tuberous sclerosis complex (TSC) in a patient without TSC gene variant presenting with bilateral renal angiomyolipomas and seizures in the context of strong family history of polycystic kidney disease. Clinical diagnosis of tuberous sclerosis complex was made and treatment with everolimus reduced size of renal angiomyolipomas. In this case, report we discuss the association between tuberous sclerosis complex and polycystic kidney disease and novel treatment for TSC. Tuberous sclerosis complex (TSC) is an autosomal dominant tumour suppressor gene disorder characterised by the development of hamartomatous and cystic growths in multiple organs including the central nervous system (CNS), skin, heart, kidneys and lungs . TSC hasA 21-year-old male university student of Chinese heritage presented to an Australian teaching hospital with intermittent bilateral flank pain, more pronounced on the right in 2017. Medical history was significant for febrile convulsions and focal seizures during adolescent years. There was a reported history of polycystic kidney disease (PKD) and mild hypertension. He was not taking any prescribed or over the counter medications. Family history was significant for polycystic kidney disease in his father and paternal grandfather, the latter of which required renal replacement therapy in his 7th decade. Clinical examination revealed hypertension with blood pressure of 140/85 mmHg. The remainder of the cardiorespiratory examination was unremarkable. Abdominal examination revealed non-tender palpable kidneys bilaterally, without clinical evidence of polycystic changes. There were two hypopigmented lesions on the anterior chest wall measuring 15 mm × 0.5 mm that did not fluoresce under Wood’s Lamp examination. There was one hyperpigmented lesion on the lower trunk that was not well circumscribed. Bedside ophthalmological examination was undertaken, identifying likely retinal hamartomas, however, their presence was unable to be confirmed through formal ophthalmological assessment.2. Urine studies demonstrated no proteinuria, hematuria or leukocyturia and was negative for bacterial growth. Kidney ultrasound identified normal sized kidneys at 10.9 cm (left) and 10.4 cm (right). Multiple, bilateral AMLs were identified with the largest measuring 8 cm in diameter in the right kidney. Multiphase contrast enhanced computerised tomography (CT) of the abdomen confirmed ultrasound findings and the dominant AML underwent angioembolisation. Following the procedure, flank pain resolved completely. Progress abdominal CT three months later showed a significant reduction in the size of the largest AML, measuring 3 cm in diameter  > 90 mL/min/1.73 mdiameter .16p 13.3, but were negative. Subsequent testing using Multiplex ligation-dependent probe amplification for causative genes TSC1 and TSC2 were also negative, potentially secondary to somatic mosaicism for pathogenic TSC gene variants, intronic variants or non-hereditary causes.Due to loss to follow-up, the patient was next reviewed by his nephrologist after three years. In the interim, he had developed focal seizures affecting his right hand and was referred to a neurologist. Neurological evaluation included an electroencephalogram (EEG) that demonstrated moderate amplitude, symmetrical and visually responsive 9–10 Hz alpha rhythm and low amplitude irregular 18–25 Hz beta activity fronto-centrally. There was increased alpha activity with 3 min of hyperventilation and no change on photic stimulation, there was no epileptiform activity or asymmetry. Magnetic resonance imaging (MRI) of the brain showed three areas of focal cortical thickening in keeping with cortical tubers the largest measured 25 mm × 18 mm . One corThe patient was again lost to follow due to the impacts of the coronavirus (COVID-19) pandemic. He re-presented to the outpatient nephrology clinic with right sided flank pain in April 2022, with no associated hematuria. A kidney ultrasound demonstrated enlargement of one of the previously known AMLs, now measuring 5.8 cm in diameter. He commenced treatment with everolimus 5 mg daily, a mammalian target of rapamycin (mTOR) inhibitor with evidence of decrease in AML size. On repeat imaging 6 weeks after treatment initiation, the lesion had reduced to 4.8 cm . Kidney TSC1 and TSC2, however, up to two-thirds of patients have de novo mutations and 15–20% of patients have no genetic variant identified through standard genetic testing, as was seen in our case [TSC1/TSC2 loci or intronic variants. Next generation sequencing and skin tumor DNA assessment of patients with negative initial genetic testing found genetic variants in 85%, including mosaicism in 58% and intronic mutations in 40% [TSC1 and TSC2 encode Hamartin and Tuberin respectively. These proteins form a heterodimer that integrates cell signals to regulate mTOR activity [We have presented a mild case of TSC mosaicism with an atypical clinical history and negative genetic testing. TSC is a heterogenous disorder with a spectrum of clinical manifestations. Most commonly, it presents with seizures, often with severe cognitive impairment and variable involvement of other organs . While Aactivity .TSC1 or TSC2 even without clinical features, though identification of variants is not necessary to make the diagnosis [The diagnostic criteria for TSC were developed in 2012 and updated in 2021 . The criiagnosis , as in oTSC2 gene is found in close association to the ADPKD gene PKD1. Patients with contiguous deletion at 16p13.3 typically present with more severe features of TSC and PKD [DICER1 mutation [Kidney manifestations are common in patients with TSC, including development of enlarging AMLs. AMLs exceeding 3 cm in diameter are at significantly increased risk of spontaneous rupture, leading to retroperitoneal haemorrhage in up to 21% of patients [mutation . In TSC,mutation . Particumutation .The mainstay of TSC management has traditionally been supportive, involving monitoring for enlargement of subependymal giant cell astrocytomas (SEGAs), a common neurological manifestation, and kidney AMLs to thresholds necessitating surgical intervention. However, three recent studies EXIST-1, 2 and 3 and their long-term outcome data have confirmed the role of mTOR inhibitors in reducing tumour growth rates in SEGAs, AMLs and dermatological manifestations ,8. FurthEXIST-1 confirmed the role of everolimus in treating SEGAs in children. This study included 117 patients randomised 2:1 to everolimus titrated to a trough concentration of 5–15 ng/mL versus placebo. Thirty-five percent of the everolimus group reached the primary endpoint of a 50% reduction in volume of SEGA compared to 0% in the placebo arm. Reductions in tumour volume were evident by 12 weeks on MRI and no cases of progression of SEGA were seen in the everolimus group . The opeEXIST-2 included 118 patients with mean age 32 randomised 2:1 to everolimus at a standard dose of 10 mg/day versus placebo. Twenty-nine percent of the patients included had a kidney AML exceeding 8 cm in diameter while almost 40% had undergone previous intervention. By weeks 24 and 96, 55% and 64.5% of treated patients had reached primary efficacy endpoint of at least a 50% reduction from baseline in sum of volumes of target AML lesions, compared to 0% of the placebo group . EXIST-3 explored the role of adjunctive everolimus in treatment-resistant seizures associated with TSC. This study included 366 patients (median age 10) with treatment-resistant epilepsy randomised 1:1:1 to placebo, low-exposure everolimus (target trough 3–7 mg/mL) or high-exposure everolimus (target trough level 9–15 ng/mL). This study showed a dose–response relationship with a 25% or greater reduction in seizure frequency observed in 37.8% of patients in the placebo arm compared to 52.1% in the low-exposure and 70% in the high-exposure arm. Regression modelling in this study demonstrated that every 15 days of treatment resulted in a 4.8% reduction in seizure frequency. This effect may be related to mTOR inhibitors exhibiting antiepileptic effects by altering signaling pathways and protein expression [There is significant side-effect burden from mTOR inhibitors. Common adverse effects include stomatitis, nasopharyngitis, headache, cough, hypercholesterolemia and acne-like skin lesions . The majWe have presented a complex case of TSC with negative genetic studies, diagnosed clinically with kidney AML and CNS manifestations. Current evidence suggests that treatment of kidney AML with oral mTOR inhibitor everolimus be commenced when AML size exceeds 3 cm in diameter. Imaging of these lesions should be performed annually and angioembolisation is recommended as second line treatment . There i


The overriding goal of the treatment of patients is its effectiveness and safety. However, all medications currently being used also exert some adverse pharmaceutical reactions, which may be regarded as an unintended but inevitable cost of pharmacotherapy. The kidney, as the main organ that eliminates xenobiotics, is an organ especially predisposed and vulnerable to the toxic effects of drugs and their metabolites during their excretion from the body. Moreover, some drugs  have a “preferential” nephrotoxicity potential, and their use is associated with an increased risk of kidney damage. Drug nephrotoxicity is, therefore, both a significant problem and a complication of pharmacotherapy. It should be noted that, currently, there is no generally recognized definition of drug-induced nephrotoxicity and no clear criteria for its diagnosis. This review briefly describes the epidemiology and diagnosis of drug-induced nephrotoxicity and characterizes its pathomechanisms, including immunological and inflammatory disturbances, altered kidney blood flow, tubulointerstitial injury, increased lithogenesis–crystal nephropathy, rhabdomyolysis, and thrombotic microangiopathy. The study also lists the basic drugs with nephrotoxicity potential and provides a short overview of the preventive methods for reducing the risk of drug-related kidney damage developing. The kidneys are small organs  located retroperitoneally on the posterior abdominal wall and found between the transverse processes of T12 and L3. Human kidneys account for only about 0.2–0.5% of total body weight, but they receive as much as 20% of the cardiac output. Despite their small size, kidneys are essential for life due to the high renal blood flow value and the role of the kidneys as the main point of elimination of xenobiotics, potentially nephrotoxic substances that are delivered to the organ in relatively high concentrations. Thus, it is reasonable to assume that the kidneys and urinary tract are privileged targets of the noxious actions of drugs and other xenobiotics [Kidneys carry out a lot of integrated functions aimed at maintaining the homeostasis of the body, including: the control of the composition and volume of body fluids; electrolytes and acid-base balance; the long-term regulation of blood pressure in a sodium-dependent manner; and the synthesis and secretion of several hormones  . HoweverDrugs and their metabolites are eliminated from the body in the urine by both glomerular filtration and tubular secretion. The ultrafiltrate formed as a result of glomerular filtration is modified by the tubular transport taking place mostly in the proximal tubules. In the context of nephrotoxicity, it is important that the tubular cell uptake of potentially nephrotoxic compounds occurs via the apical (via endocytosis/pinocytosis and other passive or active transport pathways) or basolateral (via the peritubular capillaries) membranes of the proximal tubules. In the process of tubular uptake, the family of active transporters, being organic anion transporters (OAT) for negatively charged drugs and organic cation transporters (OCT) for positively charged drugs, as well as sodium dicarboxylate transporters or other active transport pumps, are involved . OverallDrug-induced nephrotoxicity, also less frequently named drug-induced kidney disease (DIKD), is a common clinical problem. It is estimated to affect as many as 14–26% of adult and 16% of pediatric patients . HoweverAlthough there is no standard definition, DIKD is defined as any damage to the kidneys caused directly or indirectly by drugs, which leads to kidney dysfunction. DIKD is usually classified according to the predominant pathomechanism responsible for kidney damage development or based on the time of the course, with the latter division including both acute and chronic DIKD forms. Acute DIKD is recognized as a 0.5 mg/dL or 50% rise in serum creatinine over a 24–72 h time frame after a minimum of 24–48 h of drug exposure ,11. BaseConsidering the problem of the difficult clinical description of drug nephrotoxicity and a lack of an unequivocal consensus on its diagnosis, a novel framework of drug-related nephrotoxicity diagnostic and therapeutic procedures has been proposed by Awdishu and Mehta, which focuses on risk assessment, early recognition, targeted response, timely renal support and rehabilitation, and research into the epidemiology and pathophysiology—otherwise known as the rules of the “6R’s of drug-induced nephrotoxicity” . They arRisk: Risk factors for drug-induced nephrotoxicity include patient, kidney, and drug-related factors. They are listed in Recognition: In order to improve the diagnosis of kidney drug-related dysfunction, it was assumed that the phenomenon may take the form of one of four phenotypes based on clinical presentation, these being acute kidney injury, glomerular disturbances, tubular disturbances, and nephrolithiasis. Primary and secondary clinical criteria should be revealed to support the specific phenotype recognition, and in the case of acute kidney injury, acute kidney disease, and chronic kidney disease, an appropriate timeframe based on the KDIGO findings characteristic for these diseases should also be demonstrated ,12. The In each of the particular phenotypes listed in Response: The response to the treatment depends on the phenotype, the severity of the injury, and the underlying disease indicative of the particular drug. Therefore, during the treatment of nephrotoxicity, concurrent risk factors for kidney injury must be taken into account, such as hypertension, hyperglycemia, and anemia; in order to minimalize the possible drug interactions that could worsen kidney damage .Renal support: Implementing kidney support  during the treatment of kidney dysfunction enables the removal of the offending drug from the blood, minimalizing the resulting damage and supporting the kidneys in achieving their recovery. However, the decision to subject a patient to dialysis/hemodialysis in the course of drug-induced kidney dysfunction is complex, and the procedure is usually only implemented in patients with severe kidney damage and in the case of nephrotoxic drugs, characterized by a sufficiently high free-fraction that can be removed by dialysis .Renal rehabilitation: Rehabilitation and the clinical monitoring of patients presenting drug-induced nephrotoxicity symptoms involve the repeated evaluation of the kidney functions in order to assess the potential reversibility and to avoid re-exposure to the offending drug. Furthermore, the aim is to report all of the adverse effects that may have occurred during the administration of potentially nephrotoxic agents. A valuable diagnostic tool facilitating the individualization of treatment and contributing to improving the safety of therapy is therapeutic drug monitoring (TDM) in the blood. The procedure should be employed, if available, as it may prevent the further development of nephrotoxicity . As alreResearch: The last “R” in the approach proposed by Awdishu and Mehta  is reseaIn addition to the above-mentioned classification, based on the 4 main drug-induced nephrotoxicity phenotypes proposed by Awdishu and Mehta , there iIn general, several mechanisms underlying the development of drug-related nephrotoxicity can be distinguished: inflammatory and immune-related mechanisms leading to acute or chronic glomerulonephritis or interstitial nephritis; altered intraglomerular hemodynamics, triggering acute kidney injury; tubular cell toxicity with the risk of acute tubular necrosis; crystal nephropathy; and rhabdomyolysis or thrombotic microangiopathy.Inflammatory and immune mechanisms: Drugs can cause inflammatory and immune reactions in all segments of the nephrons, such as in the glomerulus, tubular cells, and the interstitium. The immunocomplex and hapten-mediated mechanisms may be recognized, and drugs can induce the production of antibodies against them and form immune complexes. These complexes can deposit in the glomeruli, contributing to glomerular damage (glomerulonephritis), but also “leak” into the interstitial microcirculation, binding to the basal membrane of the renal tubules, initiating interstitial inflammation. The most reported causative agents for glomerulonephritis are gold compounds, hydralazine, lithium, propylthiouracil, and non-steroidal anti-inflammatory drugs (NSAIDs) . Some drThe so-called Chinese herb nephropathy was reported for the first time in young Belgian women who were using Chinese herbal slimming remedies. Since then, patients with aristolochic acid nephropathy have been reported worldwide. In vivo and in vitro experiments have revealed some mechanisms of aristolochic acid nephropathy, such as endoplasmic reticulum stress and injury, increasing oxidative stress injury, initiation and sustaining an immune-mediated inflammatory mechanism, and kidney tubular epithelial cell transdifferentiation. Microscopically, the typical findings involve extensive interstitial fibrosis with atrophy and loss of tubules located in the superficial cortex and progressing toward the inner cortex. The interstitium is usually significantly hypocellular, and glomerular lesions mainly include ischemic, microcystic, obsolescent glomeruli, occasional thrombotic microangiopathy-like lesions, and/or focal segmental sclerosis-like lesions. Moreover, apart from nephrotoxicity, aristocholic acid has been proven to be implicated in the genesis of urothelial carcinoma occurring in the renal pelvis and upper ureter ,29.The chronic, long-term administration of non-opioid analgesics  is linked with an increased risk of chronic tubulointerstitial nephritis development. The chronic ingestion of these drugs in high doses (more than 1 g daily for more than two years) is believed to result in chronic interstitial inflammatory changes that disrupt the vascular system causing ischemia and leading to scarring and fibrosis. The outcome is papillary necrosis and CKD development ,19,20,21Altered intraglomerular hemodynamics and acute kidney injury: Glomerular filtration is a result of glomerular blood flow. The size of the kidney filtration fraction is determined by the effective arterial blood volume and the regulation of the vascular resistance of the afferent and efferent arterioles. The relaxation of the glomerular afferent arterioles and the contraction of the efferent arterioles provide for the maintaining of, and the autoregulation of, intraglomerular pressure and preserving GFR and urine output. The relaxation of afferent arterioles is controlled by the prostaglandins, while the contraction of the efferent ones is regulated by angiotensin II ,37. ThusTaking into account drugs interfering with the RAA system, it should be emphasized that both ACEI and ARB are seldom truly nephrotoxic, although their effect on intrarenal hemodynamics can cause a reversible reduction in the glomerular filtration rate (GFR), without structural damage, and eventually, ultimately AKI development. Such a damaging effect on the kidneys is potentially possible in patients with an already existing impairment of glomerular autoregulation, based on the prostaglandin-mediated vasodilation of the afferent arteriole and angiotensin-mediated vasoconstriction of the efferent arteriole; congestive cardiac failure, chronic kidney disease, or in the setting of reduced renal perfusion  . On the The nephrotoxicity potential of ACEIs/ARBs may also result from drug interactions. The simultaneous chronic use of ACEI/ARB and NSAID is an example of possible drug interaction with a high potential for nephrotoxicity, especially in elderly patients. The risk is even increased when a diuretic agent is also administered (“triple whammy interaction”). One observational study analyzed the frequency of adverse reactions in patients over 75 years of age with multiple diseases receiving polypharmacotherapy. In the study, 12 patients were prescribed the ACEI/NSAID combination. It was then revealed that two of them developed acute renal failure, of whom one died and the other recovered after the discontinuation of both drugs. Moreover, four patients showed deterioration in renal function, which returned to normal after at least one of the drugs was stopped. Renal function remained stable in six patients. Therefore, it can be concluded that in elderly patients, ACEI and NSAID should not be used chronically, especially with an additional combination of diuretics . In anotMoreover, some drugs  may lead to the vasoconstriction of the afferent vessels in a prostaglandin-independent manner, also leading to kidney function impairment ,19,20,21Tubular cell toxicity and acute tubular necrosis: As mentioned in the introduction, the proximal tubules are particularly vulnerable to the effects of nephrotoxins, including drugs. Drug-related tubular injury is triggered after drug reabsorption and their entering the tubular cells. Intracellularly, drugs may cause mitochondrial dysfunction, which impairs the energy management in the tubular cells, disrupting their integrity and adherence to the basement membrane. There is also the over-expression of adhesive proteins and increased oxidative stress. The increase in intracellular calcium concentration activates the proteases, which initiates the pathway involved in inflammation development and cell death through apoptosis or necrosis. Moreover, the transport functions of cells are disturbed, and the filtrate leaks back from the tubular lumen into the interstitial tissue. Ultimately, the tubular cells are exfoliated into the lumen of the tubules and form obstructive conglomerates, which increase intra-tubular pressure and inhibit GFR. Finally, a complex set of pathophysiological disorders known as acute tubular necrosis (ATN) develops. Drugs that are considered to exert their complex nephrotoxic action in such a way include aminoglycosides, amphotericin B, antiretroviral drugs, cis-platinum, iodinated contrast agents, foscarnet, and bisphosphonates ,19,20,21It is estimated that up to 25% of all patients treated with aminoglycoside develop nephrotoxicity. Aminoglycosides exert their noxious effects as renal tubular toxicity, reduced glomerular filtration, and a reduction in renal blood flow. Aminoglycosides are polycationic agents that are subject to apical tubular uptake from the urinary space via endocytosis/pinocytosis after binding to megalin/cubulin receptors. These drugs are then translocated into lysosomes (followed by the inhibition of degrading enzymes), the Golgi body, the endoplasmic reticulum, and inside the mitochondria where they induce apoptosis and necrosis. Lysosomal injury is associated with membrane and organelles damage (“myeloid bodies”), increased oxidative stress, and mitochondrial dysfunction. Finally, energy failure in the tubules develops and contributes to the loss of their integrity and disturbances of numerous transmembrane transporters impairing tubular reabsorption. In the glomerulus, aminoglycosides increase intracellular calcium levels and induce mesangial smooth muscle contraction, which leads to decreased GFR. The reduction in renal blood flow is caused by increased vascular resistance in the renal vascular bed, resulting from endothelin and thromboxane release ,44,45.Amphotericin B is an anti-fungal agent used in many systemic infections, and this drug has high nephrotoxic potential. The mechanism of kidney damage induced by amphotericin B involves directly affecting the cell membrane resulting in increased permeability, as well as indirect effects produced by the activation of intrarenal mechanisms (tubuloglomerular feedback), the release of mediators (thromboxane A2), and changes in intracellular calcium levels. The most known consequences of amphotericin B therapy are tubular damage and the acute decrease of renal blood flow and filtration rate leading to AKI ,47.Antiretroviral drugs are another example of tubulopathy-potential agents. Treatment with acyclovir, foscarnet, tenofovir, adefovir, cidofovir and didanosine, lamivudine, stavudine, or zidovudine have all been associated with a risk of ATN development in HIV-infected patients. On the other hand, the administration of protease inhibitors  is associated with the risk of intratubular precipitation of drug metabolites, due to their poor solubility ,49.Tenofovir, as a nucleotide reverse transcriptase inhibitor, is a substrate for the organic anion transporter 1 (OAT-1) located in the proximal tubular basolateral membrane. This drug accumulates in the proximal tubular cells and causes mitochondrial toxicity, likely through the depletion of mitochondrial DNA, leading to energetic failure, cellular dysfunction, and/or death. Consequently, proximal tubule damage is the most recognized form of the nephrotoxicity of antiretroviral drugs, and this dysfunction usually improves after tenofovir withdrawal. However, only 40% of patients achieve complete renal recovery .Cisplatin enters the renal tubules after uptake by basolateral transporters , and intracellularly, it is able to activate signaling pathways leading to cell apoptosis . Moreover, cisplatin causes increased oxidative stress and induces TNF-α production in the tubular cells, which triggers a robust activation of intrinsic and extrinsic apoptotic cascades and endonucleases. Many of these same pathways contribute to the cytotoxic actions of cisplatin in tumor cells. Cisplatin may also induce vasocontraction in the renal vasculature, leading to ischemic tubular cell death and a decreased glomerular filtration rate (GFR). Taking all of the above issues together, these pathological events may result in AKI development ,52.Iodine contrast agents are significant nephrotoxic compounds. Estimates indicate that they account for up to 11% of AKI episodes in hospitalized patients, especially those with pre-existing renal dysfunction or diabetes mellitus, in whom a standard hydration protocol was not administered during imaging ,54. DespBisphosphonates are regarded to be the class of drugs with an attributed low incidence of adverse kidney effects. After dosage, between 27% and 62% of these drugs bind to bone minerals, and the remainder is not metabolized, being excreted via the kidneys; predominantly by both passive glomerular filtration and active transport in renal proximal tubular cells. Although bisphosphonates are generally well tolerated, the demonstration of their kidney adverse events, revealed in postmarketing clinical studies, has resulted in the inclusion of “warnings” on the prescribing information of all bisphosphonates, regarding the use of these agents in patients with severe renal impairment (CrCl <35–30 mL/min). The nephrotoxicity of bisphosphonates (predominantly induced by zoledronate or pamidronate) is mainly dependent on the route of administration; given orally, bisphosphonates are not associated with significant nephrotoxicity, however, nephrotoxicity is a potential limiting factor to the use of intravenous (IV) bisphosphonates, and their nephrotoxicity is both dose-dependent and infusion time-dependent. Pamidronate use has been associated with nephropathy based on focal segmental glomerulosclerosis, whereas zoledronate has mostly been associated with direct tubular toxic effects ,57,58.Crystal nephropathy: Kidney damage may also result from the precipitation and deposition of insoluble compounds, forming crystals and fine concretions within the tubular fluid, after exceeding their solubility; this, however, depends on the urinary concentration of the poorly soluble drug and its metabolites, as well as the urinary pH. This phenomenon occurs mainly in the distal tubules and initiates secondary changes in the renal interstitium. Drugs regarded as being associated with an increased risk of the ability to form intrarenal crystal deposition mostly include sulphonamides, triamterene, antiretroviral drugs used in HAART therapy , antacids , methotrexate, quinolones , and some antibiotics  ,19,20,21Rhabdomyolysis: Rhabdomyolysis is defined as a pathological condition of skeletal muscle cell damage, leading to the release of toxic intracellular material into blood circulation. The key pathophysiological finding in this disorder is an increase of intracellular free ionized calcium due to either cellular energy depletion or direct plasma membrane rupture. Initially, the increased calcium level contributes to the intensification of the skeletal muscle cell contractility. Finally, the consequence of the increased intracellular calcium is the activation of several proteases, mitochondrial dysfunction, and increases in the production of reactive oxygen species, ultimately resulting in skeletal muscle cell death and release of their content into the blood . ClinicaTo sum up, any drug which directly impairs the production or use of adenosine triphosphate (ATP) in the skeletal muscle, or increases their energy requirements, which cannot be compensated for due to inefficient production, or alters calcium metabolism by the sarcoplasmic reticulum, may be an etiological factor of rhabdomyolysis. In addition, drug-induced indirect mechanisms of rhabdomyolysis may be distinguished, including ischemia, as a result of prolonged immobilization from drug overdosage with CNS depressants, thus impairing the delivery of oxygen and nutrients, drug-induced delirium, choreoathetosis, or dystonic reactions and seizures (which increase muscle activity and the demand for ATP) . Thus, dThrombotic microangiopathy: Thrombotic microangiopathy (TMA) is a clinical entity resulting in excessive and uncontrolled thrombosis in capillaries and arterioles induced by endothelial injury. TMA encompasses a heterogenous group of disorders characterized by microangiopathic hemolytic anemia, thrombocytopenia, and microthrombi leading to occlusive vascular thrombosis and ischemic damage or even infarction of the end organ . The primary forms of TMA are thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS) ,70. DrugFor many drugs, the molecular mechanism of their nephrotoxic action has been clarified. The common, complex, interconnected elements of nephrotoxic action at the molecular level involve the activation of signal transducers and intracellular messengers, DNA damage, mitochondrial dysfunction, oxidative stress, sustained inflammatory response, and the activation of apoptotic pathways. Pathomechanisms of nephrotoxicity at the molecular level can be traced to the example of cisplatin. It seems that cisplatin-induced kidney damage has been described in the largest and most detailed way.Cisplatin is predominantly excreted by the kidneys and the drug accumulates in the kidneys. This drug affects mostly proximal tubules, and glomeruli and distal tubules are affected subsequently. The concentration of the drug in tubular epithelial cells is five times greater than in blood. Therefore, even non-toxic blood levels may reach toxic levels in the kidneys. After filtrating into the urine, cisplatin enters the tubular cells via passive diffusion or transport-mediated facilitated diffusion with the participation of basolateral organic cation transporters (OCT), and reaches high concentrations in the proximal tubular cells of the inner renal cortex and outer medulla (S3 segment). Inside the tubular cells, cisplatin forms cross-links within and between DNA chains leading to the activation of various cellular responses, including the signaling of DNA damage, cell cycle checkpoints, DNA repair, and cell death. The drug also accumulates in the mitochondria of tubular cells and impairs mitochondrial bioenergetics due to the inducement of oxidative stress, and the release of pro-apoptotic factors, which ultimately lead to renal tubular cell death ,74,75. ASimilar molecular abnormalities to those seen with cisplatin nephrotoxicity have been reported for other drugs, e.g., aminoglycosides , amphotericin B, antiviral agents  or radiocontrasts because those agents are responsible for AKI development, in the form of acute tubular necrosis, with oxidative stress and necroinflammation as the main underlying mechanisms .In conclusion, taking into account the molecular description of drug-induced kidney damage, it is important to emphasize the importance of the inflammatory process and the increased oxidative stress ongoing in the kidney tissues, with the release of mediators  sustaining the course of inflammatory reactions and as a consequence of pathological damage and tissue remodeling.The most important and obvious preventive factor in reducing the incidence of drug-induced kidney dysfunction is the knowledge of the nephrotoxic potential of the drugs used in the treatment of the patient and the ability to predict the consequences of pharmacotherapy on kidney function. The early and proper recognition of nephrotoxicity symptoms is of key importance and allows for rapid therapeutic intervention and even the withdrawal of the drug used so far. Drug-induced nephrotoxicity, similarly to other kidney diseases, can be diagnosed with simple blood and/or urinary tests, including blood creatinine and urea nitrogen measurement; the estimation of GFR by creatinine clearance; and qualitative and quantitative evaluation of the blood/urine for new biomarkers indicating kidney function. So far, the greatest experience in experimental research, in a clinical setting, is associated with selected protein markers such as cystatin C (a marker of GFR), nephrin, podocin , kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin-1 (NGAL-1), liver type fatty acid binding protein (FABP), and osteopontin . These laboratory parameters are increasingly used in the diagnosis of either AKI or CKD. Moreover, certain markers such as asymmetric dimethylarginine, inflammatory/fibrosis parameters , and Klotho-FGF23 axis raise the most interest as the best selective markers of CKD. A detailed description of the diagnostic application of these markers is beyond the scope of this paper and can be found in numerous reviews dealing specifically with this issue ,89,90,91In clinical assessment, drug-related nephrotoxicity can manifest with AKI , nephrotic syndrome, renal tubular dysfunction, or CKD symptoms. Thus, it is necessary to carefully assess the clinical symptoms appearing in the patient because many kidney disturbances in the initial phases are mildly symptomatic and may be overlooked. General principles for reducing drug-induced nephrotoxicity involve identifying patients at increased cumulative risk of nephrotoxicity and then continuously monitoring kidney function in treated patients, especially when introducing any drug to a patient that is known to be nephrotoxic ,96.The most important issue of safe pharmacotherapy is the individualization of drug dosage, reducing the risk of adverse drug reactions, including kidney damage. Hence, it is crucial to precisely determine the doses of drugs used in the patient, adjusting them to kidney and liver functions. This is possible based on the determination of the individual GFR values in each patient undergoing pharmacotherapy. It is also worth mentioning that most drugs eliminated in the urine do not require dosage adjustment until the creatinine clearance declines below 50 mL/min . The basIf it is necessary to use drugs with significant potential nephrotoxicity, detailed recommendations are developed to prevent their harmful effects on the kidneys. For example, reference can be made to the prophylactic use of antioxidant compounds  that reduce free radical damage in the course of the use of drugs that increase oxidative stress in kidney tissues, e.g., during treatment with vancomycin , cyclophPharmacotherapy implemented for the patient must be effective, but also safe. Kidney damage may be an unintended but possible side-effect of treatment due to this organ being preferentially vulnerable to damage due to exposure to drugs and metabolites during their excretion stage. Hence, the development of drug-induced kidney damage is a possible complication, especially in patients with pre-existing kidney dysfunction and other risk factors. The risk of drug-related nephrotoxicity significantly increases in patients with either primary kidney diseases or numerous diseases outside the kidneys and undergoing polypharmacy with numerous interacting drugs. Each treatment must be individualized, with precise dosage selection based on the functional status of the patient’s kidneys and liver, and covered by the continuous monitoring of renal function, especially in the case of administering drugs with proven nephrotoxic effects, as discussed in this paper. It should be emphasized that some drugs may induce a nephrotoxic effect using several complementary mechanisms . Therefore, the use of many drugs, especially when administered chronically and in high doses, significantly increases the risk of kidney damage. Some substances, such as contrast agents (iodinated and gadolinium), lithium salts, cis-platinum, cyclosporin A, aminoglycosides, and amphotericin B, are characterized by a high intrinsic nephrotoxicity potential, and in the presence of such substances, particular vigilance and continuous monitoring of kidney function are required.


Diabetic kidney disease (DKD) is the most common chronic kidney disease (CKD) and has the highest prevalence of end-stage kidney disease (ESKD) globally, owing mostly to the rise in Type 2 diabetes mellitus (T2DM) correlated with obesity. Current research suggested that the immune response and inflammation may play a role in the pathophysiology of T2DM. The systemic immune-inflammation index (SII) is a novel and integrated inflammatory biomarker that has not yet been linked to DKD. We aimed to identify the potential relationship between SII and DKD.2 assessed by using the Chronic Kidney Disease Epidemiology Collaboration algorithm), albuminuria , or both in T2DM patients. To investigate the independent association between SII and DKD, weighted univariate and multivariable logistic regression analyses and subgroup analyses were performed.In the National Health and Nutrition Examination Survey (NHANES) between 2011 and 2018, the current cross-sectional study was conducted among adults with T2DM. SII was calculated as the platelet count × neutrophil count/lymphocyte count. DKD was diagnosed with impaired glomerular filtration rate  had DKD for the diagnosis. After adjustment for covariates, multivariable logistic regression revealed that a high SII level was associated with increased likelihood of DKD . Subgroup analyses and interaction tests revealed that age, gender, estimated glomerular filtration rate (eGFR), urine albumin-to-creatinine ratio (ACR), body mass index (BMI), hypertension, hyperlipidemia, anti-inflammation therapy (yes or no), metformin use (yes or no), and insulin use (yes or no) had no significant dependence on this positive relationship .Our results indicate that the higher SII level is associated with DKD in T2DM patients. The SII could be a cost-effective and straightforward approach to detecting DKD. This needs to be verified in further prospective investigations. Since the increased prevalence of Type 2 diabetes mellitus (T2DM) associated with obesity in recent decades, diabetic kidney disease (DKD) has been the most common chronic kidney disease (CKD) and the leading cause of end-stage kidney disease (ESKD), accounting for over 50% of all cases of ESKD globally –3. BesidPrevious research has shown that many factors, such as metabolic disturbances and hemodynamic abnormalities induced by hyperglycemia and insulin resistance (IR), play an important role in the progression of DKD . FurtherNumerous studies have demonstrated that inflammation contributes to the deterioration of kidney function. The high-sensitivity C-reactive protein (hs-CRP) is a systemic inflammatory marker that has been associated with the progression of DKD in T2DM patients , 16. AccThe systemic immune-inflammation index (SII) is an integrated and innovative inflammatory marker, and was calculated by platelet count × neutrophil count/lymphocyte count. The SII index was originally used to estimate the prognosis of patients with hepatocellular carcinoma (HCC) by Hu et al. , it was The traditional strategies for prevention and treatment of DKD include management of hyperglycemia, hypertension, and hyperlipidemia. For patients with T2DM, lifestyle changes and metformin remain the first-line treatments. With breakthroughs in research on the pathophysiology of DKD, some novel treatments targeting renal inflammation, fibrosis, and oxidative stress have gradually entered clinical practice. Actually, some drugs that are beneficial in alleviating the progression of DKD have anti-inflammatory properties. The drugs of anti-inflammation therapy in T2DM patients include metformin, angiotensin-converting enzyme inhibitors (ACEI), angiotensin II receptor blockers (ARB), sodium-glucose cotransporter 2 inhibitor (SGLT2i), dipeptidyl peptidase-4 inhibitor (DDP-4i), glucagon-like peptide 1 receptor agonists (GLP-1RA), nonsteroidal selective MRA finerenone, etc , 35–39. Inflammation has been attributed to kidney damage. However, the role of SII in T2DM patients with DKD remains unclear. We hypothesized that a higher SII would be associated with an increased likelihood of DKD in T2DM patients. Therefore, the purpose of our study was to investigate the relationship between SII and DKD among T2DM patients in the National Health and Nutrition Examination Survey (NHANES) in the United States and determine the value of SII and DKD.https://www.cdc.gov/nchs/nhanes/.Data were downloaded from the NHANES, a nationally representative cross-sectional survey designed and conducted by the National Center for Health Statistics (NCHS). The survey samples the U.S. population using a stratified, multistage probability approach and offers health and nutrition statistics on the non-institutionalized civilian population in the United States. The NCHS Research Ethics Review Board authorized the survey, verifying that all participants provided informed consent. Detailed statistics are accessible at To evaluate the participants’ nutritional and physical health, standardized in-home interviews, physical examinations, and laboratory tests were carried out at mobile examination centers. 39156 participants were involved in four NHANES cycles from 2011-2018. We excluded 10424 participants under the age of 18 years, 7054 with missing SII, 308 without urine albumin-to-creatinine ratio (ACR), 421 with missing estimated glomerular filtration rate (eGFR), 16798 without T2DM, and 214 with pregnancy. Eventually, 3937 participants were enrolled in the study Figure 13 cells/μl) were measured using automated hematology analysis devices. The following formula is utilized to calculate SII  a previously reported diagnosis by medical professionals, or (2) fasting plasma glucose ≥7.0 mmol/L, or (3) glycosylated hemoglobin (HbA1c) ≥6.5 mmol/L, or (4) taking diabetes drugs. The urine albumin/creatinine ratio was used to compute the ACR. The eGFR scores were calculated using the Chronic Kidney Disease Epidemiology Collaboration algorithm . ACR ≥30patients .2). According to World Health Organization standards, participants’ BMI was classified as<25, 25-29.9, and ≥30 kg/m2, corresponding to normal weight, overweight, and obesity, respectively , BMI, systolic blood pressure (SBP), and diastolic blood pressure (DBP). Serum creatinine (Scr), blood urea nitrogen (BUN), serum uric acid (SUA), total cholesterol (TC), triglycerides (TG), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and glycohemoglobin were included in the biochemical profile. Health risk factors include hypertension, hyperlipidemia, MetS, atherosclerotic cardiovascular disease, and chronic heart failure. DM-related treatment included the anti-inflammation therapy, metformin use, insulin use, ACEI use, and ARB use. The complete measurement techniques for these variables were easily accessed at 2), eGFR , ACR , hypertension (yes or no), hyperlipidemia (yes or no), anti-inflammation therapy (yes or no), metformin use (yes or no), and insulin use (yes or no). In order to analyze the heterogeneity of correlations among different subgroups, interaction analyses were included as well. Missing values for existing examples of those variables were filled in using the mode for categorical variables or the median for continuous variables. The “nhanesR” package was used to extract and analyze the data. P<0.05 was regarded as statistically significant.Given the complex sampling survey, weighted analyses were performed according to the recommendations of the NHANES. The weighted student’s t-test (continuous variables) or weighted chi-square test (categoric variables) were utilized to compare differences in baseline characteristics between the non-DKD and DKD groups in T2DM patients. The receiver operating characteristics curve was used to determine the optimal cutoff value of the SII level. Weighted univariate logistic regression analysis and multivariate logistic regression analysis were used to evaluate the correlation between SII and DKD in different models. In Model 1, confounding variables were not adjusted. In Model 2, age, race, education, and smoking status were adjusted. In Model 3, age, gender, race, PIR, educational levels, smoking status, hypertension, hyperlipidemia, MetS, anti-inflammation therapy, metformin use, insulin use, SBP, DBP, glycohemoglobin, BUN, SUA, TC, TG, ALT, AST, ASCVD, and CHF were adjusted. To determine the potential effect moderators, patients were divided into subgroups based on their age (< 60 or ≥ 60years), sex , BMI  male patients to 1897 (48.18%) female patients; 1510 (38.35%) participants were categorized as having DKD in our study. Age, poverty income ratio, smoking status, hypertension, hyperlipidemia, anti-inflammation therapy, metformin use, insulin use, ARB use, SBP, DBP, SII, glycohemoglobin, Scr, BUN, SUA, eGFR, TG, ACR, ASCVD, and CHF were significantly different between the two groups . Sex, race, education levels, MetS, ACEI use, BMI, TC, ALT, and AST did not differ between T2DM patients with and without DKD. 1071 (45.81%) and 524 (36.75%) patients received anti-inflammation therapies in non-DKD and DKD groups, respectively. Among all patients, 63 and 23 patients took ACEI and ARB, respectively. Because the amount of ACEI or ARB use was small and had no significance in statistical analysis, we wouldn’t analyze ACEI or ARB use independently. The clinical and biochemical characteristics of the participants with DKD and non-DKD were shown in We converted SII from a continuous variable to a categorical variable and created a number of models to evaluate the independent effects of SII with and without DKD. Participants who did not complete high school had 30% higher likehood of DKD than those who completed high school (p=0.03). Compared with T2DM patients who had a former smoking history, never and now smoking patients had 30.3% and 34.3% lower likelihood of DKD, respectively . Compared with non-hypertension, non-hyperlipidemia, non-MetS, not using insulin participants, non-ASCVD, and non-CHF patients, hypertension, hyperlipidemia, MetS, using insulin, ASCVD, and CHF patients, had 1.523 times, 32.5%, 18%, 1.3 times, 1.11 times, and 2.468 times higher odds of DKD, respectively . Compared with T2DM patients who did not receive anti-inflammation therapy and take metformin, patients who received anti-inflammation therapy and took metformin had 31.3% and 34.9% lower likelihood of DKD, respectively . Per unit increase in SBP, glycohemoglobin, BUN, serum uric acid, and TG, the odds of DKD were elevated by 2.7% (p< 0.0001), 22.1% (p< 0.0001), 41.1% (p< 0.0001), 0.5% (p< 0.001), and 9.3% (p = 0.003), respectively.2 (p=0.01) and ACR< 30 mg/g. For participants who used metformin, a positive association between SII and DKD was also observed, while this association did not meet the statistical significance . The interaction test showed that there was no significant difference among each stratification in the association between SII and DKD, indicating that there was no significant dependence of age, gender, eGFR, ACR, BMI, hypertension, hyperlipidemia, anti-inflammation therapy, metformin use, and insulin use on this positive association (all p for the interaction > 0.05, The results of our subgroup analysis showed that there were inconsistent associations between SII levels and DKD Figure 2The incidence of diabetes worldwide has considerably increased with the growth of the global economy. T2DM prevalence continues to expand globally, with 537 million individuals aged 20 to 79 years suffering from DM in 2021 . AccordiTo the best of our knowledge, this is the first study to show the relationship between SII and DKD in participants with T2DM. We discovered that SII levels were clearly greater in DKD patients than in non-DKD patients. According to subgroup analysis and an interaction test, this connection was consistent in a diverse demographic setting. Furthermore, high SII levels were associated with an increased likelihood of DKD, providing concrete evidence for further clinical and basic investigation.Numerous studies have shown the vital role of chronic inflammation in the development of DKD in diabetic individuals. The genome-wide transcriptome analysis revealed a high prevalence of inflammatory signaling pathways in DKD . DKD, asSII was calculated by counting three kinds of circulatory immune cells: neutrophils, lymphocytes, and platelets . The SIISome drugs seem to have a beneficial effect on patients with T2DM and CKD. There is a lot of evidence that metformin has anti-hyperglycemic and reno-protective properties that might relate to the mechanisms of anti-inflammation . ACEI anIn our study, age, PIR, smoking status, hypertension, hyperlipidemia, MetS, BUN, SUA, TG, ASCVD, and CHF were all identified as risk factors for DKD in individuals with T2DM, which is consistent with prior research . In an aSII was a widely available method with a non-intrusive methodology, simple accessibility, and low cost. The potential for therapeutic use is indeed positive. Our research has its own advantages. First, the sample size is sufficient, and the sample selection is representative. Second, to get more trustworthy results, we adjusted for confounding variables. However, the study’s shortcomings call for cautious interpretation of the findings. First, the cross-sectional study design precluded us from establishing a causal association. Secondly, despite the fact that we made adjustments for several relevant confounders, we were incapable of totally ruling out the impact of additional potential confounding variables. Thirdly, while SII is simple to quantify in clinical practice, the loss of neutrophils, lymphocytes, and platelet counts is frequent and may contribute to selection bias. Finally, while we adjusted for a number of possible confounders, additional unmeasured confounders may exist, such as duration of DM, insulin type, drug dosage, and medications, to affect the conclusion. Therefore, future research with a larger number of participants and more accurate measurement is still necessary to define the causal relationship.In our study, we proved that SII levels were significantly higher in T2DM patients with DKD than in the subjects with non-DKD, and SII levels are associated with an increased likelihood of DKD in T2DM patients, which may have predictive and diagnostic significance in clinical practice. To validate our findings, further extensive prospective investigations are still required.https://www.cdc.gov/nchs/nhanes/.The publicly available datasets presented in this study can be found in online repositories. These data can be found here: The studies involving human participants were reviewed and approved by National Center for Health Statistics Research Ethics Review Board. The patients/participants provided their written informed consent to participate in this study.WG and LS put forward the conception and design of the study. WG and YcS collected and analyzed the data. YS, HD, YC, QY, and HF made the tables and figures. All the authors drafted and revised the paper. All the authors contributed to the article and approved the final version of the manuscript.


Patients scheduled for cardiac surgery are often accompanied by cardiac dysfunction and hemodynamic instability. However, the conventional induction strategy for anesthesia using high-dose intravenous anesthetics is often associated with persistent and recurrent hypotension after tracheal intubation. The purpose of this study is to investigate the effects of topical airway anesthesia on the hemodynamic profile of patients undergoing cardiac surgery during the induction period.This is a superiority, single-blind, randomized controlled study with two parallel groups. Participants scheduled to undergo elective cardiac surgery will be allocated into two blocks according to the New York Heart Association (NYHA) classification and then randomly assigned to the following two groups at a 1:1 ratio: the conventional induction group and the combined topical airway anesthesia induction group. The combined topical airway anesthesia induction strategy includes aerosol inhalation airway anesthesia, subglottic airway anesthesia, and general anesthesia induction using low-dose intravenous anesthetics. The primary outcome is the area under the curve (AUC) of blood pressure below baseline mean arterial pressure (MAP) from 3 to 15 min after endotracheal intubation. Secondary outcomes include the AUC above baseline MAP and below baseline MAP at other time points, the highest and lowest arterial blood pressure values during the induction period, type and dose of vasoactive drugs, incidence of arrhythmias, cardiac function, and the incidence of postoperative hoarseness and sore throat.The study will explore whether aerosol inhalation airway anesthesia and subglottic airway anesthesia could reduce the incidence and duration of hypotension during the induction period in patients undergoing cardiac surgery.www.ClinicalTrials.gov (NCT05323786).This trial was registered on  Anesthesia induction is one of the most challenging periods in cardiac surgery, especially in patients with left ventricular dysfunction . AnestheTo our knowledge, the ideal anesthesia induction strategy for cardiac surgery patients involves not only to provide adequate depth of anesthesia during endotracheal intubation, but also to stabilize hemodynamics after tracheal intubation. Conventionally, cardiac surgery patients are induced by using high-dose intravenous anesthetics to inhibit endotracheal intubation stress . HoweverPrevious studies , 9 have This is a randomized, controlled, single-blind, superiority study, parallel group with 1:1 allocation ratio. This study was approved by the Research Ethics Committee of the First Affiliated Hospital of Shandong First Medical University and was registered on Clinicaltrials.gov (registration number: NCT05323786). This study will be conducted at The First Affiliated Hospital of Shandong First Medical University, Ji'nan City, Shandong Province. All procedures will be performed in accordance with the most recent version of the Declaration of Helsinki.This study protocol will be performed according to the following standard protocol items: Recommendations for Interventional Trials (SPIRIT) statement . A flowcFrom 1 April 2022 to 31 December 2022, participants scheduled to undergo elective cardiac surgery will be recruited from The First Affiliated Hospital of Shandong First Medical University. Participants will be selected for study enrollment according to the inclusion and exclusion criteria prior to surgery. Participants who meet the inclusion criteria and provide signed informed consent will be enrolled in this study. The participant can withdraw from the study at any time .The following patients will be enrolled in the study: (1) patients older than 18 years and younger than 75 years; (2) patients scheduled to undergo elective cardiac surgery; (3) patients with New York Heart Association (NYHA) class II–III; and (4) patients providing signed informed consent for the clinical study.The following patients will be excluded from the study: (1) patients who unable to cooperate in accepting topical airway anesthesia ; (2) patients with left heart assist devices prior to surgery; (3) patients with extracorporeal membrane oxygenation (ECMO) prior to surgery; (4) patients with aortic dissection; (5) patients with difficult airway; (6) patients allergic to lidocaine; (7) patients with atrioventricular block; and (8) patients who have participated in other clinical studies during the last 3 months.t-test with a sample size of 39 patients in each group will achieve 80% power to detect a ratio of 0.700 when the ratio under the null hypothesis is 1.000. The coefficient of variation of the original scale is 0.6. Based on Hannam et al.  class II–III and will then be randomly assigned to the conventional induction group and the combined topical airway anesthesia induction group within each block in a 1:1 ratio based on a computer-generated random number table . The ranSequentially numbered, opaque sealed envelopes (SNOSE), locked in the investigator's office, will be used to ensure concealment until participant identification. Participants will be automatically included in the trial when the numbered envelopes are opened, and the numbers on each envelope would ensure that all participants are enrolled after being randomly assigned. Recruitment records will be established, and exclusion of patients will also be recorded.In this study, a single blind method will be used. The anesthesiologist responsible for the management of perioperative anesthesia will prepare the experimental drugs before the participant enters the room. Participants will be unaware of the group allocation. In addition, researchers responsible for postoperative follow-up and outcome data collection will also be unaware of group allocation. Unblinding will be performed at the end of the statistical analysis. Additionally, emergency blinding will be performed in the event of severe adverse events.For the combined topical airway anesthesia induction group, 10 mL of 2% lidocaine in a nebulizer and 3 mL of 2% lidocaine in a syringe will be prepared. For the conventional induction group, sham lidocaine  in a nebulizer and 3 mL normal saline in a syringe will be prepared.After admission to the operating room, participants will be connected to the electrocardiogram (ECG), pulse oxygen saturation, noninvasive blood pressure, and bispectral index (BIS) of the electroencephalograph (EEG). A catheter will be inserted into the radial artery to monitor invasive blood pressure.Before general anesthesia induction, the combined topical airway anesthesia induction group will receive aerosol inhalation using 10 mL of 2% lidocaine, and the conventional induction group will receive aerosol inhalation using 10 mL of normal saline. Aerosol inhalation will last for 15 min with high flow oxygen (8–10 L/min) . The aerAfter completion of atomization inhalation, general anesthesia induction will begin. At the beginning of general anesthesia induction, midazolam (0.05 mg/kg) and etomidate (0.2–0.3 mg/kg) will be administered intravenously. When BIS is <50, the anesthesiologist will administer atracurium (0.6 mg/kg) and sufentanil (0.15–0.3 μg/kg). All participants will be in Trendelenburg position (15–30°) during the induction period. In the conventional induction group, the anesthesiologist who is in charge of the intraoperative anesthesia will decide the dosage of sufentanil according to the physical condition of the participant and the hemodynamic changes during the induction period. The dosage of sufentanil will be recorded.After 3–5 min of administration of intravenous induction drugs, subglottic airway anesthesia will be performed using 3 mL 2% lidocaine  or 3 mL normal saline  with a tracheal topical anesthesia kit .Tracheal intubation will be performed 3–5 min after subglottic anesthesia. After endotracheal intubation, the anesthesiologist will decide whether to start propofol infusion according to the BIS value and will adjust the infusion rate to maintain the BIS value between 40 and 60. Target-controlled infusion (TCI) with propofol (1 μg/mL) will be initiated.The hemodynamic variables of the participants, which include arterial blood pressure (systolic blood pressure (SBP), diastolic blood pressure (DBP), MAP and HR, will be recorded at baseline , at the beginning of aerosol inhalation (T1), at the beginning of general anesthesia induction (T2), at the completion of subglottic airway anesthesia (T3), at the completion of tracheal intubation (T4), and during central venous catheterization (T5) .Variables related to cardiac systolic and diastolic function and effective blood volume, including left ventricular ejection fraction (LVEF), E:E' (the ratio of the E peak and E'), E:A (the ratio of the E peak and A peak), tricuspid annular plane systolic excursion (TAPSE), and respiratory variation in inferior vena cava diameter (deltaIVC), will be evaluated using a transthoracic probe before induction of the anesthesia and transesophageal echocardiography (TEE) after placement of transesophageal echocardiography (TEE) probe.During the induction period, the anesthesiologist will decide whether to use vasoactive drugs as needed. After repeated use of the same vasoactive drug more than three times, the vasoactive drug will be continuously infused. The type, times, and total dose of the vasoactive drugs will be recorded. If the MAP or HR increases by more than 15% from baseline and the BIS is >60, the anesthesiologist will administer 30 mg of propofol, which may be administered repeatedly as needed. If the MAP or HR increases by more than 15% from baseline and the BIS is <60, the anesthesiologist will administer 10 mg of urapidil or 10 mg of esmolol, which could be administered repeatedly. If the MAP decreases over 15% from baseline and HR is <50 beats per minute (bpm), 1 mg of dopamine will be administered. If the MAP decreases more than 15% from baseline and HR is >50 bpm, 1 μg norepinephrine will be administered.The outcomes will be evaluated by independent researchers who have been trained prior to the study.The primary outcome is the area under the curve (AUC) below baseline MAP from 3 to 15 min after endotracheal intubation, define as the MAP-time integral . We defiSecondary outcomes include the following variables: (1) AUC above baseline MAP  and below baseline MAP  from the beginning of general anesthesia induction to 3 minutes after endotracheal intubation; (2) the highest and lowest arterial blood pressure  from the beginning of general anesthesia induction to 15 min after endotracheal intubation; (3) administration of vasoactive drugs from the beginning of general anesthesia induction to 15 min after endotracheal intubation, including times, dosage, and type; (4) incidence and type of arrhythmias, including atrioventricular block, atrial fibrillation, and premature beat; (5) preoperative cardiac systolic function, evaluated by LVEF. LVEF% = (left ventricular end diastolic diameter-left ventricular end systolic diameter)/left ventricular end diastolic diameter × 100%; (6) preoperative and intraoperative cardiac diastolic function, represented by E:E' and E:A; (7) TAPSE is a commonly used variable of right ventricular systolic function; (8) effective blood volume, measured by deltaIVC; (9) the incidence and severity of postoperative hoarseness 24 and 48 h after surgery will be evaluated using the Grade, Roughness, Breathiness, Asthenia, and Strain (GRBAS) scale. This tool includes 5 items. Each item is a 4-point scale, ranging from 0, normal to 3, severely impaired , 17.Demographic data, including age, sex, height, and weight, will be recorded. The American Society of Anesthesiologists (ASA) score and the New York Heart Association (NYHA) classification will be evaluated. Patients diagnosed with pre-existing cardiovascular disease (CVD), diabetes mellitus, liver disease, kidney disease, lung disease, or brain disease will be identified. Smoking history, alcohol consumption, and medication history  will also be recorded. Laboratory tests , electrocardiogram, echocardiographic diagnosis, and coronary angiographic diagnosis will be collected. After admission to the operating room, baseline MAP will be collected. Heart rate, blood pressure, and MAP values will be recorded every 5 s during the post-induction study period. Furthermore, variables related to cardiac systolic and diastolic function  and effective blood volume  will be collected before induction and after tracheal intubation.The relevant data from the participants will be collected by independent researchers. Standardized data collection files will be used to ensure completeness and quality. Outcomes will be measured by two researchers who have been trained using a standardized Case Report Form (CRF). All personal data will be stored on a different locked computer in a secure room at the hospital. An Excel database will be established on the basis of the CRF files. Two researchers will complete the relevant information in time and accurately. Data will be transmitted directly by hand from research members to the locked computer, never via mail or the Internet. Once sensitive data are entered into the computer, any written documents that would allow participants to be identified will be destroyed to avoid information leakage. Only researchers will have access to the electronic data.P < 0.05 will be considered statistically significant and all reported P-values will be two-sided. During the study design period, we consulted the Center for Big Data Research in Health and Medicine with study design, sample size calculation, and statistical analysis plan.All statistical data analyses will be performed using SPSS v25.0  statistical software. We will perform intention-to-treat and per-protocol analyses for the primary outcome. Normally distributed variables will be expressed as the mean ± standard deviation (SD) and compared with Student's t-test. Categorical variables will be compared using the χ2 test or Fisher's exact test, as appropriate. Non-normal distributed continuous variables will be expressed as median (IQR) and evaluated using the Mann-Whitney U-test. A value of We will make great efforts to limit loss to follow-up within 5%, such as excluding patients who may be unwilling to participate in the follow-up before randomization, completing each follow-up as fast as possible, and streamlining the experimental procedure during follow-up. If the rate of loss to follow-up exceeds 5%, multiple imputations will be performed to deal with incomplete data.In this single-center, superiority, single-blind, randomized, controlled trial, our aim is to investigate whether topical airway anesthesia combined with intravenous anesthesia can reduce hemodynamic fluctuations during the induction period in patients undergoing cardiac surgery.Our study has multiple strengths. First, Wieczorek et al.  argued tThe study was reviewed and approved by the Research Ethics Committee of the First Affiliated Hospital of Shandong First Medical University [YXLL-KY-2021(080)]. The participants will provide written informed consent to participate in the trial. The results of this study will be distributed in international peer-reviewed journals.At the time of protocol manuscript submission, the recruitment of the participants has started and is ongoing.ML conceived and designed the study and designed the method for statistical analyses. WD, TC, XS, and CQ will recruit and screen the participants. HZ and CW will participate in performing random assignment concealment and blinding. ML, WD, TC, XS, and CQ will participate in the data collection. ML, WD, JW, and YL will participate in the data analysis. WD and ML participated in drafting this manuscript. YW and ML provided the supervision support. All authors contributed to the article and approved the submitted version.This study was supported by Qilu Special Clinical Research Project from Shandong Medical Association (YXH2022ZX02088).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. 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Background and Objectives: Consequences of partial nephrectomy (PN), intraoperative hypotension (IOH) and postoperative neutrophil to lymphocyte ratio (NLR) may cause postoperative acute kidney injury (AKI) and in long-term-chronic kidney disease (CKD). Our study aimed to identify the AKI incidence after PN, to find clinically significant postoperative AKI and renal dysfunction, and to determine the predictor factors. Materials and Methods: A prospective observational study consisted of 91 patients who received PN with warm ischemia, and estimated preoperative glomerular filtration rate (eGFR) ≥ 60 mL/min and without abnormal albuminuria. Results: 38 (41.8%) patients experienced postoperative AKI. Twenty-one (24.1%) patients had CKD upstage after 1 year follow-up. Sixty-seven percent of CKD upstage patients had AKI 48 h after surgery and 11% after 2 months. All 15 (16.5%) patients with CKD had postoperative AKI. With IOH, OR 1.07, 95% CI 1.03–1.10 and p < 0.001, postoperative NLR after 48 h  was the major risk factor of AKI. In multivariate logistic regression analysis, the kidney’s resected part volume  and IOH  were retained as statistically significant prognostic factors for detecting postoperative renal dysfunction. The independent risk factor for clinically significant postoperative AKI was only IOH . Only AKI with the CKD upstage group has a statistically significant effect (p < 0.0001) on eGFR 6 and 12 months after surgery. Conclusions: The presence of AKI after PN is not rare. IOH and NLR are associated with postoperative AKI. The most important predictive factor of postoperative AKI is an NLR of over 3.5. IOH is an independent risk factor for clinically significant postoperative AKI and together with kidney resected part volume effects postoperative renal dysfunction. Only clinically significant postoperative AKI influences the reduction of postoperative eGFR after 6 and 12 months. Kidney cancer is a neoplasm of renal parenchyma and the most common histopathological subtype of the kidney is renal clear cell carcinoma . AccordiIntraoperative hypotension (IOH), caused by low systemic vascular resistance during anesthesia, parenchymal injury to the renal system and blood loss are all common events during PN and may lead to a sudden and temporary loss of RF. Recently published data showed that, besides creatinine, neutrophil to lymphocyte ratio (NLR) can be a practical predictor of AKI and associated with the reduced survival rate of patients who underwent PN ,19,20. AThe aim of our study was to identify the AKI incidence after PN due to renal lesion, and find clinically significant postoperative AKI and renal dysfunction. Determine the predictor factors of those conditions among patients with estimated glomerular filtration rate (eGFR) ≥ 60 mL/min, no presence of abnormal albuminuria and renal failure history.A prospective observational study was conducted in Vilnius University Hospital Santaros Klinikos between January 2018 and December 2019. The study was approved by the Vilnius Regional Biomedical Research Ethics Committee  13 December 2016 and the State Data Protection Inspectorate. The study was conducted in accordance with the Declaration of Helsinki.2. eGFR = 141 × minα × max−1.209 × 0.993Age × 1.018 [if female] × 1.159 [if African American], where: Scr is serum creatinine in µmol/L, κ is 61.9 for females and 79.6 for males, α is −0.329 for females and −0.411 for males, min indicates the minimum of Scr/κ or 1, and max indicates the maximum of Scr/κ or 1.The study population consisted of individuals over 18 years old, on whom were performed open or laparoscopic PN with warm ischemia due to kidney masses with preoperative eGFR by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equal to or more than 60 mL/min/1.73 mWe excluded patients with abnormal albuminuria, history of AKI, CKD and kidney surgery, pregnant or planning pregnancy because it would be difficult to clearly understand the nature of renal function decline. Patients with hyperkalemia without uremia and hyperuricemia were also excluded because of the initial loss of nephron function due to kidney disease resulting in renal retention of potassium and uric acid. Moreover, we excluded only patients with unregulated hypertension and diabetes mellitus avoiding faster nephropathy.2/air fraction 0.5, with FiO2 55%, and inspiratory fresh gas flow of 1 L/min were used. In the postoperative period, 1 mg/kg IV tramadol and 75 mg IM diclofenac were used as painkillers. During open PN extra spinal anesthesia 7.5 mg of 0.5% heavy bupivacaine was administered in combination with the 0.1–0.2 mg morphine sulfate dose after local anesthesia with lidocaine 40 mg. Infusion by sodium chloride 0.9% 2000–3500 mL was performed during all surgery time.Endotracheal intubation was used. Fentanyl infusion was performed before induction (0.5–1 mcg/kg bolus in 30–60 s) and it continued (0.015–1 mcg/kg/lBW/min) during PN. Induction continued with propofol 1–2 mg/kg. For relaxation, 1 mg/kg/lBW rocuronium was used. Sevoflurane 1 minimum alveolar concentration, OAll patients’ treatment options were chosen under the same protocol. PN was offered to patients with tumor ≤ 7 cm (T1 stage).Open partial nephrectomy:The position was a full-flank position and an extended lumbar incision was made above the 11th or 12th rib. The main artery was clamped using a bulldog clamp. Incision of the renal capsule was made sharply by a scalpel. The tumor was separated bluntly from the surrounding parenchyma. The absorbable gelatin sponge for hemostasis was placed on the cut surface and Vicryl sutures were used to approximate the remaining renal parenchyma with a mattress suture.Laparoscopic partial nephrectomy:Performed by a transabdominal approach, four ports were placed when the lesion was on the left side and an additional one if it was on the right. The main renal artery was clamped with a bulldog clamp. For resection of the tumor, scissors were used in warm ischemia time. Hemostasis was achieved by central suturing with non-absorbable clips and hemostatic sponge.We collected clinical and laboratory data, including age, gender, body mass index (BMI), white blood cells (WBC), neutrophils and lymphocytes percent, calculated neutrophil to lymphocyte ratio (NLR) and divided into two groups (more than 3.5 (increased) and more than nine (severely increased)), serum creatinine (sCr), urine albumin-creatinine ratio (uACR), fasting glucose, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides and spot urine, standardized nephrometry scoring system (R.E.N.A.L. Nephrometry Score) to quantify the anatomical characteristics of renal masses on CT imaging before PN. We also analyzed surgery data such as duration, ischemia and IOH time. The resected kidney parts were fixed with formalin and grossed by a surgical pathologist according to the departmental standard operating procedure. The gross pathologic measurements of the resected part and kidney tumors were performed using a standard plastic centimeter scaled ruler with 0.1-cm markings. Measurements were recorded in three dimensions after formalin inflation and fixation and serial sectioning of the surgical specimen.2 for more than 3 months and abnormal albuminuria as albumin creatinine ratio in a single urine sample of ≥3 mg/mmol.We defined AKI as a blood creatinine increase of 1.5 times within 48 h: I stage -sCr 1.5–1.9 times higher baseline; II stage-sCr 2.0–2.9 times higher baseline; III stage-sCr 3.0 times higher baseline. Metabolic syndrome (MetS) was presented if three or more of the following five criteria were met: waist circumference ≥ 102 cm in men or ≥88 cm in women, blood pressure ≥ 130/85 mmHg, fasting triglyceride (TG) level ≥ 1.7 mmol/L, fasting high-density lipoprotein (HDL) cholesterol level less than 1.03 mmol/L in men or 1.29 mmol/L in women and fasting blood glucose ≥ 5.6 mmol/L.RF was grouped using CKD class  preoperatively and 12 months after surgery. CKD upstage was defined as a new-onset developed lowest CKD class 12 months from PN. CKD was defined as eGFR < 60 mL/min/1.73 mPatients were divided into three groups according to CKD upstage status and AKI, see Statistical analysis was performed using the R statistical software package V 4.0.2 (2020-06-22) , Rstudio Version 1.3.959 © 2009–2020 RStudio, PBC, IBM SPSS Statistics V.23, G*Power V. 3.1.9.4 Universität Düsseldorf, Germany. Interval and ratio variables were described by minimum (Min) and maximum (Max) values, means and standard deviations (SD), medians, first quartiles (Q1) and third quartiles (Q3), and interquartile deviations (IQR 75%). Shapiro–Wilk and Kolmogorov–Smirnov (K–S) tests were used to check the data for normality. Nominal and ordinal variables were characterized by frequencies and percentages across the corresponding subset of the sample. To assess the statistically significant difference among the independent groups we used Fisher’s chi-squared test.p < 0.05) were shown.Univariate analyses were performed with postoperative AKI and clinically significant renal dysfunction as the dependent variables and sociodemographic factors , laboratory data , surgery data  as the independent variables, but only the statistically significant  on postoperative AKI and clinically significant postoperative renal dysfunction, we created models based on logistic regression equations with optimization to evaluate the independent effects of each covariate by controlling the effects of other variables. The receiver operating characteristic (ROC) curve was used to determine the optimal cut-off value. The same variables with S = 0.1 − <0.3 we have a small effect, when rS = 0.3 − <0.5, we have a moderate effect and, when rS ≥ 0.5, we have a large effect. To measure the effect size between eGFR after 6 and 12 months of clinically significant postoperative AKI (AKI with CKD), AKI without CKD and non-AKI groups, we used the Omega squared (ω2) effect size. We will assume that, when ω2 = 0.1 − <0.06 we have a small effect, when ω2 = 0.06 − <0.14, we have a moderate effect and, when ω2 ≥ 0.14, we have a large effect. To increase the accuracy of estimates, in addition, we used Bayesian parameter estimation and Bayesian hypothesis testing.To measure the effect size between eGFR after 6 and 12 months and postoperative AKI clinically significant postoperative renal dysfunction groups, we used the Hedge effect size. We will assume that when rp-value was less than 0.05 (p < 0.05) and a statistical test power of 1-ß was equal to 0.95 (1-ß = 0.95).Relationships between variables were considered statistically significant when the A total of 91 patients were agreed on and included in the study. The demographic and clinical characteristics of study participants are summarized in Out of 91 study patients, 38 (41.8%) had developed postoperative AKI, 36 patients had I stage and 2-with II stage, 21 (24.1%) patients had CKD upstage 1 year from PN. Sixty percent of CKD upstage group patients had AKI 48 h after surgery. After 2 months, the AKI amount decreased from 38 cases to 11. All 15 (16.5%) patients with CKD after 12 months follow up had AKI.2, p < 0.001. There were more AKI patients with MetS (31 (81.6%) vs. 27 (50.9), p = 0.004), estimated blood loss during PN (400.0 (217.5) vs. 300.0 (220.0) mL, p = 0.005), longer IOH time (30.0 (30.0) vs. 0.0 (10.0) min, p < 0.001). Moreover, a higher volume of resected kidney part (70.6 (71.0) vs. 41.0 (53.7) mL, p = 0.026), tumor (38.0 (51.6) vs. 18.9 (42.6), p = 0.048), removed parenchymal (24.5 (21.7) vs. 20.7 (15.9), p = 0.049) in AKI patients.The median (IQR) age of AKI patients included in the study was 69.0 (13.0) years. The median preoperative eGFR of AKI patients was lower than in non-AKI—78.5 (21.5) vs. 93.0 (11.0) mL/min 1.72 mp = 0.083), but the first group had older patients, median years (IQR) 71.0 (12.0) vs. 63.0 (13.0), p = 0.02. Moreover, the frequencies of the CCI score, patients with MetS, longer ischemia and IOH time, higher resected kidney’s part, removed tumor and parenchymal volume, and estimated blood loss volume during surgery were all significantly higher in the patients with clinically significant postoperative kidney dysfunction (p < 0.05). Upon creatinine, NLR was significantly higher in patients that developed AKI than in patients without AKI (median (IQR) 5.7 (6.5) vs. 3.3 (1.3), p < 0.001) and still significantly higher after clinically significant postoperative kidney dysfunction group formation (median (IQR) 4.5 (2.7) vs. 3.5 (2.8), p = 0.017).The preoperative eGFR categories between the postoperative kidney dysfunction group and the non-clinically significant postoperative kidney dysfunction group was not significantly different , it was evident that postoperative NLR after 48 h was the major risk factor of AKI development , see Age, estimated blood loss > 500 mL during PN, IOH and NLR > 3.5 were potential predictors for AKI development. With IOH  for AKI with an area under the ROC curve of 0.881 .In the ROC analysis , NLR witThe potential predictors of clinically significant postoperative kidney dysfunction after PN are summarized in p < 0.001) and IOH  were retained as statistically significant prognostic factors for detecting clinically significant postoperative kidney dysfunction after PN.Older age, higher CCI score, estimated blood loss during PN more than 500 mL, longer intraoperative and ischemia times, higher removed parenchymal and resected part volumes were potential predictors for clinically significant postoperative kidney dysfunction development. In multivariate logistic regression analysis , the kidp < 0.0001), which had an area under the ROC curve of 0.940 , IOH and higher volume of resected kidney were determined as an optimum cut-off value for predicting postoperative renal dysfunction . On the other hand, preoperative eGFR ≥ 90 mL/min and a removed kidney‘s parenchymal volume of less than 30 mL reduced the risk of clinically significant postoperative AKI.In p < 0.0001), with a significant effect size. Moreover, splitting postoperative AKI into a clinically significant postoperative AKI group (AKI with CKD upstage) and AKI without CKD showed that only the AKI with CKD upstage group had a statistically significant effect (p < 0.0001) on eGFR 6 and 12 months after surgery in the compartment with the AKI group without CKD upstage and non-AKI patients. A detailed visualization of renal function is summarized in In Our study showed that patients with IOH are associated with clinically significant postoperative AKI after PN and NLR of over 3.5 at a 1.5 times increased risk of postoperative AKI and postoperative eGFR decline after 6 and 12 months influenced by clinically significant postoperative AKI.RF is generally better preserved after PN than after RN due to a higher amount of nephron preservation and the preserved parenchymal volume has been detected as a primary indicator of postoperative RF . HoweverIn most cases of the use of conventional diagnostic criteria of AKI, the incidence of AKI after partial nephrectomy was reported to be 20–54% ,27. Thesp = 0.031), male sex , and larger tumor size  were associated with a significant increase in the likelihood of AKI at discharge. BMI above normal weight was not associated with greater eGFR decline per month post-RPN [p < 0.001. Based on univariate  and multivariate analysis , BMI emerged as a predictor of AKI [Increased BMI could be an independent predictor for AKI after PN due to adherent peripheral fat which can increase the complexity of surgery by limiting kidney mobilization and isolation of the renal hilum. Sood et al.’s study from the National Surgical Quality Improvement Database, which included 141,802 patients across most common surgeries, demonstrated that overweight patients have an increased risk of complications, including kidney injury. However, in all techniques of nephrectomies BMI had no effect on perioperative complications . Rosen epost-RPN . Anotherr of AKI . The resp < 0.001 [p = 0.024) and postoperative AKI . Other studies also did not indicate MetS as a direct AKI predictor, but it can strongly predict perioperative complications after PN [The MetS influence of perioperative outcomes after PN has been poorly investigated, but it can be a reason for higher AKI rates. This result is based on the presence of at least three out of five  MetS components . Z. Liu  < 0.001 . In our after PN . The strp < 0.001). Patients with lower preoperative eGFR were significantly associated with advanced age, larger tumor size, male sex, history of smoking, hypertension and longer ischemia time. Only advanced age, lower preoperative eGFR and longer ischemia time were independent predictors of decreasing renal function after surgery [2 were significantly more likely to recover after RF decrease [p = 0.001) and renal dysfunction , but in conjunction with other factors preoperative eGFR ≥ 90 mL/min statistically significantly reduces the risk of only clinically significant postoperative AKI .Winer et al.’s study performed an analysis of 387 patients who underwent PN and found that increases in postoperative RF occurred in a substantial number of patients. This increase was most pronounced in younger patients with higher preoperative eGFR . The multivariate model of this study revealed that high tumor complexity, but not its size, was the only independent predictor for AKI after surgery. During our study we measured blood loss by collecting samples from a pump tank and weighing operating bondage. Results showed that a median blood loss of more than 500 mL during PN could significantly increase the odds of kidney injury. We suggest that this factor is not the main predictor of AKI, but should be used in conjunction with WIT, IOH and preoperative glomerular status influence oxygenated blood distribution in the parenchyma. Moreover, we measured real tumor volume in the resected sample and resected part volume; we found no association with postoperative AKI.The interaction between intraoperative blood loss and the relationship between postoperative AKI was evaluated by Kawamura et al. . They fop = 0.11) and with 2.8-fold increased risk to have CKD after PN and radical nephrectomy [p = 0.028). Our study demonstrated that an NLR higher than 3.5 predicts postoperative AKI in patients after PN , but not clinically significant postoperative AKI. Another fact of our study is that the probability of postoperative renal dysfunction is minimal when NLR less than three or more than nine.During PN, the surgeon inflicts kidney parenchymal injury which causes non-bacterial inflammation. Local inflammation can play an important role in the initiation and progression of AKI after PN and hematological results could be associated with AKI. Known studies have focused on biomarkers, such as NGAL and KIM-1, to detect AKI . Howeverhrectomy . MoreoveTwelve months of follow-up with our patients showed that 14 (15%) patients developed CKD 6 months after surgery and this amount increased to 15 cases 12 months after surgery. Comparing patients with AKI 48 h after PN with eGFR 6 and 12 months after surgery, we found that the postoperative AKI after PN is associated with lower eGFR due to the influence of clinically significant postoperative AKI.Our study has several limitations. Firstly, the small size of the study impacts the precision of estimates and parameters of interest and makes it difficult to determine which preoperative, intraoperative variable is more closely associated with postoperative AKI. Larger studies will be required to confirm our findings. Secondly, using another AKI criterion would probably increase sample size. Furthermore, we examined IOH by non-invasive monitoring of arterial pressure and all episodes of a patient’s IOH were summarized in one attempt due to the difficult accounting of intermittent data. Lastly, our study results show renal function changes after warm ischemia PN with main artery clamping. We did not carry out long-term follow-up and evaluate long-term postoperative eGFR changes.This study has some strengths. This is the first study of independent risk factors for postoperative renal dysfunction and the evaluation of clinically significant postoperative AKI in Lithuania. We showed the potential influence of NLR on predicted rates of postoperative AKI after PN.Our study demonstrates that the presence of AKI after PN is not rare and it affects long-term RF in patients without CKD. IOH and NLR are associated with postoperative AKI in patients who underwent PN. The most important predictive factor of postoperative AKI is an NLR of over 3.5. IOH is independent risk factor for clinically significant postoperative AKI and, together with kidney resected part volume, affects postoperative renal dysfunction. Only clinically significant postoperative AKI influences the reduction of postoperative eGFR after 6 and 12 months.


Chronic kidney disease (CKD) is a condition that involves the deterioration of renal function over the course of months to years. Various clinical manifestations occur at the initial insult to the kidney, ranging from subtle changes in metabolic and volume control to asymptomatic hematuria, hypertension, and diabetes. The kidneys can adapt to damage or injury, but if left untreated, then there is a possibility of a gradual decline in renal function that progresses to kidney failure that requires dialysis. The rate of progression between stages of CKD is based upon the underlying disease, presence of comorbidity conditions, treatments, socioeconomic status, genetics, and ethnicity. If an individual’s renal function progresses to kidney failure, then patients may experience a constellation of signs and symptoms that include hyperkalemia, volume overload, hypertension, anemia, and bone disorders. Classification or staging of CKD provides a guide to management and stratification of risk for progression to kidney failure.In this report, we describe a 47-year-old African American male who reported a 25-year history of intermittent homelessness, cocaine, and heroin use but remained free from drug use for 10 years before presenting to our clinic. The patient was diagnosed with hypertension and stage 3 kidney disease in his 30s but was unable to have regular follow-up appointments with a physician due to a lack of access to care. The patient presented asymptomatic with an estimated glomerular filtration rate of 14 mL/min and creatinine of 5.42 mg/dL. We stabilized his hypertension and consulted nephrology to assess the need and timing for dialysis. Once approved for Medicare, the patient was able to be seen within 72 hours and started on dialysis shortly after. He is currently awaiting a kidney transplant.In this case, we describe and highlight the gaps in care for the medically uninsured, specifically patients with CKD. Our patient was diagnosed with stage 3 kidney disease 17 years before presenting to the Gary Burnstein Clinic. The gaps in accessible healthcare prevented him from accessing treatments he desperately needed. We also highlight the achievements and barriers free health clinics face on a day-to-day basis when trying to manage complex medical needs. We were able to provide high-quality healthcare to bridge the gap in access to care and ultimately get the patient the proper treatment. The Kidney Disease Improving Global Outcomes (KDIGO) CKD guidelines diagnose CKD as decreased estimated glomerular filtration rate (eGFR) . However, uninsured patients’ ineligibility for Medicare often cannot and will not follow this recommendation due to cost, which can cause their CKD to progress to a more advanced disease [While Medicare covers patients with advanced CKD requiring dialysis, there is no health coverage for patients with earlier stages of CKD that are younger than 65 and do not have a disability qualifying them for Medicare . Patient disease .The non-white race is a widely recognized risk factor for the progression of CKD to ESRD . Black CDelaying care with a nephrologist is associated with a greater risk of unplanned first dialysis, more complications, greater hospital costs, and increased length of hospitalization within the first three months of dialysis . AdditioThis case highlights the gaps in care for uninsured patients with CKD. While our patient was diagnosed with hypertension and stage 3 kidney disease in his 30s, his health coverage status prevented him from regularly accessing care for his hypertension and seeing a specialist at an earlier stage of kidney disease. Additionally, despite having kidney failure for years (GFR of 14 mL/min), Medicare was not approved until his GFR deteriorated to 6 mL/min. For uninsured patients, starting Medicare coverage until they are considered ESRD causes many patients to forego much-needed care in the earlier stages of CKD. By treating patients prior to kidney failure, Medicare can potentially avoid the high costs of ESRD and improve morbidity and mortality for many uninsured CKD patients.