Renal Function Research Articles

Estimating measured creatinine clearance for critically ill trauma patients with presumed normal kidney function.

In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. The intent of this study was to evaluate the predictive performance of two common methods for estimating kidney function in critically ill trauma patients with presumed normal kidney function. A retrospective analysis of 2 common methods for estimating kidney function, the Cockcroft-Gault (CG) and Chronic Kidney Disease Epidemiology Collaboration (2021 CKD-EPI) equations, was undertaken for adult trauma patients. Patients with a 24-hour urine collection for determination of measured creatinine clearance (mCrCl) within 4 to 14 days after admission were included in the study. Patients with a serum creatinine concentration of >1.5mg/dL or who required dialysis were excluded. The 200 patients included in the study had a median (IQR) mCrCl of 184 (141-233) mL/min; both the CG and CKD-EPI equations were biased towards underpredicting mCrCl, with median (IQR) values of 135 (100-177) mL/min and 135 (113-155) mL/min, respectively (P < 0.001). One hundred twenty-two patients had augmented renal clearance (ARC), defined as an mCrCl of >129mL/min/1.73m2, and those patients had a median (IQR) mCrCl of 216 (188-265) mL/min; both the CG and CKD-EPI equations were biased towards underpredicting mCrCl in patients with ARC: the median (IQR) estimates were 160 (126-197) mL/min and 147 (129-164) mL/min, respectively (P < 0.001). For those without ARC (n = 78), the median (IQR) mCrCl was 125 (98-153) mL/min; both the CG and CKD-EPI equations underpredicted mCrCl, with median estimates of 98 (76-116) mL/min and 112 (92-132) mL/min, respectively (P < 0.001). The CKD-EPI equation outperformed the CG method for all markers of precision in patients without ARC (P < 0.003). Common predictive equations for assessing kidney function in critically ill patients with traumatic injuries underpredicted mCrCl, especially in those with ARC.

Pancreatitis in Association with Primary Hyperparathyroidism due to Ectopic Intrathymic Parathyroid Adenoma in a Pediatric Patient

ABSTRACT Primary hyperparathyroidism leads to increased serum parathyroid hormone levels resulting in hypercalcemia. Ectopic intrathymic parathyroid adenomas account for 6%–16% of all parathyroid adenomas and are rare in children but should be considered in cases with hypercalcemia. Early and timely diagnosis can preserve end-organ damage and bone and renal function.

Von Willebrand factor polymorphism (rs1063856) as a risk factor for portal vein thrombosis in chronic liver diseases

Abstract Background Due to its well-established involvement in clot formation, von Willebrand factor (vWF) has been held responsible for decades as a risk factor for arterio-venous thrombosis. It is currently unclear how genetic differences in vWF genes relate to the incidence of portal vein thrombosis (PVT). Thus, the aim of this study was to evaluate the significance of vWF:Ag level and vWF gene polymorphism (rs1063856) as risk factors for PVT in patients with chronic liver disease (CLD). Subjects and methods This research of 70 individuals with CLD comprised 30 without PVT and 40 with PVT. Twenty patients with PVT-linked hepatocellular carcinoma (HCC) and 20 patients with non-HCC-PVT comprised the two subgroups from the 40 PVT patients. Additionally, 30 healthy volunteers of the same age and gender as the patients were included in the study as a control group. Tests for liver and renal function, coagulation profile, complete blood count, hepatitis virus markers, and vWF:Ag level were conducted. The identification of the vWF gene polymorphism (rs1063856) was assessed using real-time PCR. Results When comparing CLD patients with PVT to those without PVT and the healthy control group, there was a substantial rise in the vWF: Ag level. Additionally, compared to instances of benign PVT, the vWF:Ag levels were considerably greater in malignant PVT. CLD patients with PVT had higher frequencies of the vWF (rs1063856) AA genotype and A alleles (37.5% and 61.3%, respectively) than did control and non-PVT cases. Patients with the AA genotype showed the highest serum levels of vWF antigen, followed by those with the TA genotype. Conclusion vWF (rs1063856) AA gene polymorphism has a strong correlation with vWF plasma level and may be a risk factor for PVT development in CLD patients. These findings should be included in the risk assessment model to determine and guide management for those patients.

Effect of Riociguat on Adenine-Induced Chronic Kidney Disease in Rats

Riociguat is a soluble guanylate cyclase (sGC) activator that increases the levels of cyclic guanosine monophosphate (cGMP). cGMP is known to play a key role in regulating kidney function. This research sought to investigate the possible protective effects of riociguat on the kidneys in the context of chronic kidney disease (CKD). CKD was induced in male Wistar rats through adenine administration. A total of 24 rats were allocated into four groups and administered treatments over a period of 35 days. Group 1 received a normal diet and a vehicle (carboxymethylcellulose (0.5%)), serving as the control. Group 2 received adenine (0.25% w/w) in the feed and a vehicle. Groups 3 and 4 received adenine in the feed (0.25% w/w) plus riociguat (3 mg/kg/day) and riociguat (10 mg/kg/day), respectively. Adenine administration significantly elevated systolic blood pressure, plasma creatinine, urea, and neutrophil gelatinase-associated lipocalin (NGAL). Furthermore, adenine reduced creatinine clearance and increased the urinary albumin-to-creatinine ratio and urinary N-Acetyl-β-D-Glucosaminidase (NAG). Histopathologically, adenine caused renal tubular necrosis and fibrosis. Furthermore, adenine elevated the plasma concentration of interleukins (IL-1β and IL-6) and tumor necrosis factor-alpha (TNF-α). Adenine significantly increased renal malondialdehyde (MDA) and reduced glutathione reductase (GR), superoxide dismutase (SOD), catalase (CAT), and total antioxidant capacity (TAC). Treatment with riociguat attenuated adenine-induced hypertension, improved kidney function, and ameliorated histopathological changes. Riociguat also reduced kidney injury markers, inflammation, and renal oxidative stress. The renoprotective effect of riociguat is probably due to anti-inflammatory and antioxidant actions. This indicates that riociguat may have the potential to slow the progression of kidney damage in chronic kidney disease (CKD).

Renal Tubular Epithelial Cell-Derived IL-7 Drives Expansion and Protective Effects of Double-Negative T Cells in Acute Kidney Injury.

Previous studies have demonstrated that double-negative (DN) αβ T cells play an important role in immune responses during ischemic acute kidney injury (AKI). Here, we investigate the role of γ-chain cytokines in driving DN T cell proliferation in steady state and AKI, focusing on IL-2, IL-7, and IL-15. We assessed DN T cell proliferation in vitro in response to IL-2, IL-7, and IL-15, with co-culture experiments using renal tubular epithelial cells (RTECs) and IL-7 blockade. In vivo, wild-type and IL-7r knockout mice were studied to evaluate the impact of IL-7 on DN T cell expansion and kidney function during AKI. Human RTECs confirmed the relevance of these findings. All three cytokines promoted DN T cell proliferation in vitro, with IL-7 inducing the most robust expansion. Co-culture experiments showed RTECs as a key IL-7 source, and blockade reduced DN T cell expansion. In vivo, IL-7 complexes administered to wild-type mice increased DN T cells and selectively expanded the PD-1+ subset. IL-7 deficiency worsened renal outcomes during AKI. Human RTECs activated peripheral human DN T cells in vitro. These results establish IL-7 as pivotal for DN T cell expansion and highlight RTECs' role in DN T cell homeostasis.

Incidence and potential predictors of SGLT2 inhibitor initiation in acutely hospitalized patients with heart failure.

In an effort to expedite the publication of articles, AJHP is posting manuscripts online as soon as possible after acceptance. Accepted manuscripts have been peer-reviewed and copyedited, but are posted online before technical formatting and author proofing. These manuscripts are not the final version of record and will be replaced with the final article (formatted per AJHP style and proofed by the authors) at a later time. The purpose of this study was to assess the incidence of sodium-glucose cotransporter 2 (SGLT2) inhibitor initiation in hospitalized patients with heart failure and determine what potential factors may influence use. A single-center, retrospective cohort analysis was conducted of hospitalized patients with heart failure. The primary outcome was the incidence of SGLT2 inhibitor initiation. Secondary outcomes included the rates of use of other guideline-directed medical therapy, identification of factors associated with initiation of SGLT2 inhibitors, and reasons why SGLT2 inhibitors were not initiated. A total of 503 patients were included. The overall incidence of SGLT2 inhibitor initiation was 18% across all heart failure types, with 30% incidence in heart failure with reduced ejection fraction, 2.2% incidence in heart failure with mildly reduced ejection fraction (HFmrEF), and 5.7% incidence in heart failure with preserved ejection fraction (HFpEF). Logistic regression analysis showed that older age (odds ratio [OR], 0.97; 95% confidence interval [CI], 0.95-0.99; P = 0.009) and the presence of HFpEF (OR, 0.37; 95% CI, 0.17-0.77; P = 0.007) or HFmrEF (OR, 0.22; 95% CI, 0.05-0.69; P = 0.02) were negatively associated with SGLT2 inhibitor initiation. Presence of an angiotensin-converting enzyme inhibitor, angiotensin 2 receptor blocker, or angiotensin receptor/neprilysin inhibitor (OR, 2.14; 95% CI, 1.16-4.05; P = 0.017) or a β-blocker (OR, 3.78; 95% CI, 1.62-10.37; P = 0.004) was positively associated with the addition of an SGLT2 inhibitor, as was a cardiology consult (OR, 8.29; 95% CI, 2.36-52.83; P = 0.005). Providers rarely documented the reason for not prescribing an SGLT2 inhibitor, but the most commonly cited reasons were deferral to the outpatient setting (5.6%) and concern for renal function (4.6%). Use of SGLT2 inhibitors remains low despite recommendations advocating for their use in heart failure, with these agents specifically underutilized in HFpEF and HFmrEF at this institution.

Comprehensive management application of sulodexide on proteinuria: 2 case reports

Proteinuria is an important sign of kidney function decline and one of the common clinical manifestations in patients with chronic kidney disease and diabetic kidney disease, which are often accompanied by a gradual decline in kidney function. Therefore, effective management of proteinuria is of great significance for delaying the progression of kidney disease and protecting kidney function. Sulodexide is a mixture of fast-moving heparin and dermatan sulfate with anticoagulant, thrombolytic, anticardiovascular, lipid-lowering, and renal-protective effects. It has potential application value in the comprehensive management of proteinuria. This study reported two different chronic disease cases to explore the comprehensive management application of sulodexide in patients with long-term poor proteinuria control. Case 1 is a 45 years-old male with type 2 diabetes mellitus and hypertension accompanied by persistent proteinuria and intermittent edema in both legs. Case 2 is a 52 years-old female with chronic nephritis and rheumatoid arthritis accompanied by persistent proteinuria and edema in both legs. Two patients showed a decrease in urinary protein levels and stable control of the remaining signs of disease after the addition of sulodexide to their comprehensive treatment regimens, indicating that sulodexide plays an important role in the comprehensive management of proteinuria.

Maternal and infant outcomes of pregnancy after kidney transplantation: a retrospective cohort study.

To investigate the effect of postoperative pregnancy on maternal-infant outcomes and transplanted kidney function in kidney transplantation (KT) recipients. Our study included 104 KT recipients and 104 non-KT women who delivered at four hospitals affiliated with Zhejiang University School of Medicine from December 2015 to November 2023. In the KT group, kidney function showed a downward trend after delivery, and most patients recovered normal kidney function within 6months postpartum. Tacrolimus blood concentration during pregnancy averaged (6.1 ± 1.4)μg/L, increasing to (7.1 ± 2.6)μg/L on the second day after delivery, indicating an upward trend in postpartum concentrations. Compared to the non-KT group, the KT group had higher prevalences of gestational hypertension (33.7% vs. 3.3%), gestational diabetes mellitus (21.2% vs. 17.5%), intrahepatic cholestasis of pregnancy (5.8% vs. 1.7%), placental abruption (1.9% vs. 0.8%), and preterm birth rate (79.8% vs. 9.2%) but had a lower prevalence of fetal growth restriction (8.3% vs. 21.7%). Univariate analysis showed that pre-pregnancy estimated glomerular filtration rate (eGFR), penatal eGFR, gestational hypertension, and preeclampsia may influence neonatal outcomes. Binary logistic regression analysis showed that preeclampsia (odds ratio [OR] = 133.89, 95% confidence interval [CI]: 1.27-156.20, P = 0.031) and hypertension during pregnancy (OR = 5.81, 95% CI: 1.02-33.27, P = 0.048) were risk factors, and glomerular filtration rate during pregnancy (OR = 0.95, 95% CI: 0.90-0.99, P = 0.026) was a protective factor. Although pregnancies in KT recipients are considered high-risk, the overall risks are manageable. Strengthening the management of KT recipients with reproductive intent is recommended to improve maternal and infant outcomes.

Kidney Fibrosis In Vitro and In Vivo Models: Path Toward Physiologically Relevant Humanized Models.

Chronic kidney disease (CKD) affects over 10% of the global population and is a leading cause of mortality. Kidney fibrosis, a key endpoint of CKD, disrupts nephron tubule anatomy and filtration function, and disease pathomechanisms are not fully understood. Kidney fibrosis is currently investigated with in vivo models, that gradually support the identification of possible mechanisms of fibrosis, but with limited translational research, as they do not fully recapitulate human kidney physiology, metabolism, and molecular pathways. In vitro 2D cell culture models are currently used, as a starting point in disease modeling and pharmacology, however, they lack the 3D kidney architecture complexity and functions. The failure of several therapies and drugs in clinical trials highlights the urgent need for advanced 3D in vitro models. This review discusses the urinary system's anatomy, associated diseases, and diagnostic methods, including biomarker analysis and tissue biopsy. It evaluates 2D and in vivo models, highlighting their limitations. The review explores the state-of-the-art 3D-humanized in vitro models, such as 3D cell aggregates, on-chip models, biofabrication techniques, and hybrid models, which aim to mimic kidney morphogenesis and functions. These advanced models hold promise for translating new therapies and drugs for kidney fibrosis into clinics.

Impact of nitroglycerin-induced vasodilation on stroke volume and diuretic response in acute heart failure: A protocol for a mechanistic trial.

Acute heart failure is a clinical syndrome characterized by cardiac dysfunction and neurohumoral activation, encompassing complex underlying pathophysiology which may vary across phenotypes. Nitroglycerine is a nitrate donor with vasodilatory effects on both venous capacitance vessels and arterial resistance vessels in higher doses, typically used with the aim of reducing congestion, preload, and afterload. A limited number of studies have proposed that nitroglycerin could promote diuresis and natriuresis. However, the exact hemodynamic effects of nitroglycerin remain uncertain in the clinical setting of acute decompensated heart failure. We hypothesize that intravenous nitroglycerin induces a significant increase in stroke volume and urinary output while lowering cardiac filling pressures. This will be a prospective single-center interventional clinical study of 21 patients hospitalized with a diagnosis of AHF. Patients are examined before and after administration of intravenous nitroglycerin. To characterize hemodynamic phenotypes of AHF, continuous estimates of stroke volume will be obtained, and total blood volume estimated. Vital signs and estimates of peripheral perfusion will be recorded continuously. Measures of cardiac function, renal function, volume status, and autonomic function will be assessed sequentially. This study will assess the acute effects of vasodilation on stroke volume and urinary output in hospitalized patients with AHF. Furthermore, characterizing the hemodynamic profile of the patient prior to vasodilation may help explore which patients will benefit from vasodilation.

Therapeutic Potential of Ginger-supplemented Diet in Reversing Lead-induced Nephrotoxicity

Background: The flowering plant ginger, scientifically known as Zingiber officinale offers numerous health benefits, including immune support. Its bioactive compounds such as shogaols and gingerols, contribute to its antioxidant and anti-inflammatory properties. Objective: To access ginger (Zingiber officinale) as a protective agent against Nephrotoxicity induced by Lead by accessing the levels of inflammatory markers (Interleukin -6, Tumor Necrosis Factor), kidney function (Creatinine), and general kidney morphology. Methods: Twenty-four (24) female Wistar rats weighing 150-170g were carefully divided into four groups (6 per group) and housed in plastic cages. The groups were Groups A (Control), B (the Lead), C [Lead and ginger (1%)], and D [Lead and ginger (5%)]. The rats were treated for 28 days, the control and the Lead groups were fed with normal rat diets and distilled water, while the Lead and ginger group was fed with ginger supplemented diet. On day 29, the rats were sacrificed using cervical dislocation following animal ethical guidelines. Blood samples were collected from the apex of the heart (intracardiac puncture), stored in a heparinized bottle, and centrifuged to undergo further analysis (creatinine, interleukin 6, and Tumor Necrosis Factor). The kidney was removed and fixed in 10% neutral buffered formalin. The organ was then processed for histological analysis. Results: The results showed a statistically significant increase (P&lt;0.05) in the levels of creatinine, Tumour Necrotic Factor Alpha (TNF-alpha), and Interleukin-6 (IL-6) in group B compared to group A. While a statistically significant decrease (P&lt;0.05) was observed in groups C and D compared to group B. Histomorphological distortion was observed in group B compared to group A, while the lesion was reversed in groups C and D. Conclusion: This study found that ginger has substantial health benefits for kidney tissues, particularly in nephrotoxicity caused by lead. Its ability to preserve kidney tissue, decrease inflammation, and improve kidney function highlights its significance as a treatment option for preventing or lessening kidney harm associated with toxic substances or underlying health issues. Further investigations are necessary to explore the possible adverse effects or contraindications that could be associated with ginger supplements or ginger-supplemented diets in humans.

Endotoxin-Retentive Filters for the Online Preparation of Ultrapure Dialysis Fluid and Non-Pyrogenic Substitution Fluid: A Critical Review and Reference Guide

Poor water treatments and concentrates to prepare dialysis fluids favor bacterial growth-producing pyrogens (e.g., endotoxins) that may cross hemodialysis, particularly high-flux, membranes. This puts hemodialysis patients at risk of acute bacteremia, pyrogenic reactions, long-term complications, loss of residual renal function, and poor nutritional status. Consequently, regulatory bodies worldwide recommend using ultrapure dialysis fluid for routine hemodialysis. Requests are also growing for the online production of sterile non-pyrogenic substitution fluid from ultrapure dialysis fluid. This way, large volumes of infusion solution may be safely and economically produced, enabling more end-stage kidney disease patients to benefit from the greater capacity of hemodiafiltration to remove toxins than purely diffusive hemodialysis treatment. Ultrapure dialysis and substitution fluids are often produced upstream from hemodialyzers by online filtration of standard dialysis fluid through cascades of bacteria- and endotoxin-retentive filters (ETRFs). Commercial ETRFs differ for membranes, operation, performance, duration and maintenance protocols, connection to a dialysis machine, disinfection procedures, and replacement schedule. Although suboptimal ETRF choice may increase treatment costs, the difficulty in gathering comparative information on commercial ETRFs complicates their selection. To aid dialysis centers in selecting the most convenient and suitable ETRF for their needs, herein, relevant characteristics of commercial ETRFs are reported and critically reviewed for a quick yet effective comparison.

Effect of Hepatic Impairment or Renal Impairment on the Pharmacokinetics of Aficamten.

Aficamten, a small-molecule, selective cardiac myosin inhibitor, is under development for the treatment of symptomatic obstructive hypertrophic cardiomyopathy (oHCM). Aficamten is primarily eliminated by hepatic metabolism with renal excretion playing a minor role. The objective of this investigation was to evaluate the pharmacokinetics (PK) of aficamten in moderate hepatic impairment or mild to moderate renal impairment to inform dosing recommendations in HCM patients with mild or moderate hepatic impairment or mild to moderate renal impairment. The impact of hepatic impairment on the PK of single-dose aficamten 20 mg was evaluated in a phase 1 single-dose, open-label, parallel-group study, in healthy participants with moderate (n = 8) hepatic impairment (Child-Pugh B classification) versus participants with normal hepatic function (n = 8). Safety was monitored throughout. The effect of renal impairment on aficamten PK was assessed using population PK (PopPK) modelling of phase 2/3 clinical data in patients with oHCM. Aficamten PK was similar in participants with moderate hepatic impairment and those with normal hepatic function. No serious or severe treatment-emergent adverse events or clinically significant laboratory abnormalities were reported. There were no clinical meaningful differences in aficamten exposure in patients with oHCM with mild or moderate renal impairment and those with normal renal function. No clinically relevant changes in aficamten PK were observed in participants with moderate hepatic impairment. Population PK analysis indicated mild or moderate renal impairment and had no statistically or clinically significant impact on aficamten PK in patients with oHCM. Aficamten dose adjustment may not be necessary in patients with mild or moderate hepatic or renal impairment.

Associations of acute kidney injury with oral anticoagulants: a disproportionality analysis of the Food and Drug Administration Adverse Event Reporting System (FAERS) database

ABSTRACT Objective The FDA Adverse Event Reporting System (FAERS) was used to evaluate the associations between oral anticoagulants (OACs) and acute kidney injury (AKI). Methods Disproportionality analysis was applied to data in the FAERS database from January 2004 to December 2023 to detect adverse events (AEs) for various OACs. The adjusted reporting odds ratios (RORs) calculated using multiple logistic regression were used to explore the risk factors for OACs-associated AKI. Results The crude RORs for the associations of AKI with warfarin, rivaroxaban, dabigatran, apixaban, and edoxaban were 1.35, 2.14, 2.98, 1.33, and 3.56, respectively. The risk of OACs-associated AKI was affected by age and sex, being higher in those aged 65 years and males. The adjusted RORs for rivaroxaban, dabigatran, apixaban, and edoxaban were 1.26, 1.67, 0.65, and 2.06, respectively.Nearly 50% of AKI cases occurred within the first 2 months, and each OAC was of the early-failure type. Hospitalization and mortality rates for AKI patients after OACs were 45.53% and 22.98%, respectively. Conclusions The study revealed a strong association between AKI and OACs, emphasizing the need for regular renal function monitoring , especially in elderly male patients. Further in-depth research is needed to confirm these exploratory findings.

Role of microvascular pericyte dysfunction in antibody-mediated rejection following kidney transplantation.

To investigate the role of microvascular pericyte dysfunction in antibody-mediated rejection (ABMR) of transplanted kidneys. A total of 160 patients who underwent kidney transplantation in our hospital from 2004 to 2020 were enrolled, divided into 4 groups: ABMR group (n = 79), TCMR group (n = 20), mixed rejection group (n = 25) and control group (n = 36). Postoperative renal function indicators were compared, and immunohistochemical and immunofluorescence staining was performed on graft tissues and mice models using the pericyte marker PDGFR-β. An in vitro pericyte dysfunction model was co-cultured with vascular endothelial cells for functional assessment through Western blotting, PCR, and wound healing tests. KEGG pathway analysis from the GEO database identified gene expression changes in pericytes, which were further analyzed using electron microscopy and Western blot techniques. There were statistically significant differences in creatinine, urea nitrogen, urine protein, and eGFR among the groups over time, with ABMR displaying the poorest outcomes. Immunohistochemistry revealed lower pericyte expression in ABMR, which was confirmed in mouse model studies showing reduced PDGFR-β expression in ABMR. KEGG analysis highlighted decreased autophagy in pericyte dysfunction, supported by electron microscopy and Western blot findings indicating reduced autophagy and pericyte damage, which could be reversed by chloroquine. ABMR episodes worsened the long-term prognosis of transplanted kidneys. pericyte dysfunction appears to be one of the crucial causes of poor prognosis in ABMR patients. In vitro studies demonstrated that dysfunction of microvascular pericytes can result in damage to vascular endothelial cells, with autophagy impairment being a significant mechanism contributing to pericyte dysfunction.

Effect of cubebin against streptozotocin-induced diabetic nephropathy rats via inhibition TNF-α/NF-κB/TGF-β: in vivo and in silico study

Cubebin, a dibenzyl butyrolactone lignan belonging to several distinct families, including Aristolochiaceae, Myristicaceae, Piperaceae, and Rutaceae, and possesses several pharmacological activities, including analgesic, anti-inflammatory, antioxidant, and vasodilatory. The current study aimed to evaluate the effect of cubebin on streptozotocin (STZ)-evoked diabetic nephropathy (DN). DN is a well-identified complication of diabetes mellitus (DM) characterized by renal hypertrophy that progressively declines kidney function. Wistar rats were randomly divided into groups- normal, STZ control (65 mg/kg/body weight), and STZ + cubebin (10 and 20 mg/kg). Biochemical parameters such as glucose levels, kidney parameters, lipid profile, oxidative stress, endogenous antioxidant markers, inflammatory cytokines and histopathology were performed. Molecular docking [(PDB ID: TNF-α (7JRA), NF-κB (1SVC), TGF-β1 (3TZM)] and dynamic simulation (MDS) were also performed with the selected target. STZ-induced DN was changes in these parameters. In contrast, DN + cubebin at 10 and 20 mg/kg doses improved the biochemical parameters and histological changes. Furthermore, molecular docking and simulation studies showed a binding affinity with negative binding energy with TNF-α (7jra, − 11.342 kcal/mol), TGF-β1 (3tzm, − 9.162 kcal/mol) and NF-κB (1svc, − 6.665 kcal/mol). The results of MDS provided insight into the mechanisms that associate proteins TNF-α, NF-κB, and TGF-β1 in conformational dynamics upon binding to cubebin. In conclusion, these findings exhibit a potential effect of cubebin in STZ-evoked DN rats.

Beyond SGLT2: proximal tubule transporters as potential drug targets for chronic kidney disease.

The proximal tubule is responsible for reabsorbing about 60% of filtered solutes and water and is critical for the secretion of metabolic waste products, drugs and toxins. A large number of highly specialized ion channels and transport proteins belonging to the SLC and ABC transporter families are involved. Their activity is directly or indirectly linked to ATP consumption and requires large quantities of energy and oxygen supply. Moreover, the activity of these transporters is often coupled to the movement of Na+ ions thus influencing also salt and water balance, as well as transport and regulatory processes in downstream segments. Because of their relevance for systemic ion balance, for renal metabolism or for affecting regulatory processes, proximal tubule transporters are attractive targets for existing drug and for novel strategies to reduce kidney disease progression or to alleviate the consequences of decreased kidney function. In this review, the relevance of some major proximal tubule transport systems as drug targets in individuals with chronic kidney disease (CKD) is discussed. Inhibitors of the sodium-glucose cotransporter 2, SGLT2, are now part of standard therapy in patients with CKD and/or heart failure. Also, indirect inhibition of Na+/H+-exchangers by carbonic anhydrase inhibitors and uricosuric drugs have been used for decades. Inhibition of phosphate and amino acid transporters have recently been proposed as novel principles to remove excess phosphate or to protect the proximal tubule metabolically, respectively. In addition, organic cation and anion transporters involved in drug and toxin excretion may serve as targets of new drugs. The advantages and challenges associated with (novel) drugs targeting proximal tubule transport are discussed.

Iron and ferroptosis in kidney disease: molecular and metabolic mechanisms

Maintaining iron homeostasis is necessary for kidney functioning. There is more and more research indicating that kidney disease is often caused by iron imbalance. Over the past decade, ferroptosis’ role in mediating the development and progression of renal disorders, such as acute kidney injury (renal ischemia-reperfusion injury, drug-induced acute kidney injury, severe acute pancreatitis induced acute kidney injury and sepsis-associated acute kidney injury), chronic kidney disease (diabetic nephropathy, renal fibrosis, autosomal dominant polycystic kidney disease) and renal cell carcinoma, has come into focus. Thus, knowing kidney iron metabolism and ferroptosis regulation may enhance disease therapy. In this review, we discuss the metabolic and molecular mechanisms of iron signaling and ferroptosis in kidney disease. We also explore the possible targets of ferroptosis in the therapy of renal illness, as well as their existing limitations and future strategies.

Metabolomic Insights into Smoking-Induced Metabolic Dysfunctions: A Comprehensive Analysis of Lipid and Amino Acid Metabolomes

Background: Cigarette smoking is a leading cause of preventable mortality, largely due to the absence of effective, non-invasive biomarkers for early disease detection. Profiling serum metabolomics to identify metabolic changes holds the potential to accelerate the detection process and identify individuals at risk of developing smoking-related diseases. Objectives: This study investigated the biochemical and metabolomic changes induced by nicotine exposure, with a focus on disruptions in amino acid, lipid, and carbohydrate metabolism. Methods: Liquid chromatography–tandem mass spectrometry (LC-MS/MS) was employed to observe significant disruptions in lipid and amino acid metabolism, along with alterations in key metabolic pathways. A total of 400 smokers and 100 non-smokers were included to evaluate the biomarkers related to insulin resistance, blood lipid profile, inflammation, and kidney and liver function. Results: The results demonstrated significantly elevated (p &lt; 0.05) levels of glycemic markers in smokers, including fasting blood glucose; glycated hemoglobin (HbA1c); and inflammatory markers such as interleukin-6 (IL-6) and C-reactive protein (CRP). Smokers also exhibited dyslipidemia, with increased total cholesterol (154.888 ± 35.565) and LDL levels (117.545 ± 24.138). Impaired liver and kidney function was evident, with significantly higher levels (p &lt; 0.05) of AST, ALP, ALT, blood urea nitrogen, and creatinine in smokers. A total of 930 metabolites were identified, of which 343 exhibited significant alterations (p &lt; 0.05) in smokers compared to non-smokers. Among these, 116 metabolites were upregulated, and 127 were downregulated. Metabolomic pathway analysis revealed eight significant pathways. The study also identified three lipid metabolites specific to smokers and seven unique to non-smokers. Through LC-MS/MS, fragments of phenylalanine, tryptophan, valine, histidine, carnitine, and sphinganine were detected. Several lipidomic changes associated with insulin resistance and cardiovascular complications were observed. Cadmium (Cd) levels were higher in smokers than non-smokers (1.264 ppb vs. 0.624 ppb) and showed a strong negative correlation (R2 = 0.8061, p-value = 0.015) with serum zinc (Zn), likely due to Cd displacing Zn in proteins and causing nephrotoxicity through accumulation. Conclusions: This study highlights the distinct metabolic disruptions caused by smoking that could serve as potential biomarkers for the early detection of metabolic diseases. It emphasizes the importance of metabolomics in identifying systemic indicators of smoking-related health issues, providing new opportunities for preventive and therapeutic interventions.

The prevalence, clinical features, and long-term outcome of patients with primary Sjögren’s syndrome with renal involvement

This multicenter, retrospective longitudinal study identified primary Sjögren’s syndrome (pSS) patients with clinically significant renal involvement, and analyzed factors associated with predisposition. To investigate clinical features and long-term prognosis of renal involvement, we compared the clinical outcomes for the entire cohort based on the presence or absence of renal involvement. Among 1306 pSS patients (mean age, 51 ± 12 years; 98% female), 36 (2.8%) had renal involvement; 17 patients had tubular involvement, 15 had glomerular involvement, one had both, and 3 were unclassified. The presence of anti-La antibodies was associated with renal involvement. Over the median 5-year follow-up period, the renal function did not change significantly; however, 44% of patients with renal involvement showed impaired renal function at the last visit. Impaired renal function at the last visit was inversely associated with baseline renal function and hemoglobin levels. Among the entire cohort, the prevalence of lymphoproliferative disease (LPD) was significantly higher in pSS patients with renal involvement than those without. Renal involvement is a rare manifestation of pSS; however, it is associated with impaired renal function and LPD. Therefore, screening for renal involvement is important for preserving renal function and early detection of LPD.