Impact of Pretransplant C-Reactive Protein, Neutrophiles, Platelets, and Albumin Levels on Recipient Survival After Simultaneous Pancreas and Kidney Transplantation.

BACKGROUND: Long-lasting diabetes mellitus type 1 and end-stage renal disease induce severe metabolic and immunologic deterioration. Pretransplant C-reactive protein (CRP) and albumin (ALB) levels impact kidney transplantation. We evaluated the effects of preoperative CRP, ALB, neutrophils (NEU), and platelet (PLT) counts on 1- and 5-year recipient survival after simultaneous pancreas and kidney transplantation (SPK). METHODS: Among 103 SPK recipients, the parameters were as follows: CRP (mean: 4.5 ± 4.97 mg/L); NEU (mean: 5.12 ± 2.13 × 103/mm3); PLT (mean: 244 ± 84 × 103/mm3); ALB (mean 4.5 ± 0.75 g/dL) were obtained before transplantation. Cox regression, uni-, multivariate analysis for 1- and 5-year survivals were performed with 95% CIs, and the area under the receiver operating characteristic (ROC) curve (AUC) was assessed. RESULTS: In Cox regression, ALB <3.65 g/dL significantly affected 1- and 5-year survivors with hazard ratios of 8 (95% CI, 1.5-38.28; P < .05) and 3.13 (95% CI, 1.45-6.73; P < .05), respectively. In univariate analysis, we found significantly decreased 1-year survival when PLT <180×103/mm3, ALB <3.65 g/dL, NEU >5.8×103/mm3 and CRP >2.25 mg/L with odds ratios (OR) of 6.75 (95% CI, 2.12-21.15); 4.05 (95% CI, 1.3-12.09); 2.97 (95% CI, 1.02-8.64) and 5.51 (95% CI, 1.67-18.19), respectively. Independent factors for 5-year survival were CRP, ALB, and PLT with OR of 4.72 (95% CI, 1.67-13.29), 3.31 (95% CI, 1.18-9.25), and 4.2 (95% CI, 1.39-12.68), respectively. In multivariate analysis, we built 2 models for 1-year survival. Model 1 (ALB+PLT) with ORs of 3.12 (95% CI, 0.97-10.07) and 5.55 (95% CI, 1.67-18.4); and model 2 (CRP+PLT) with ORs of 5.51 (95% CI, 1.5-17.3) and 4.3 (95% CI, 1.2-15.06), respectively. The AUC for models 1 and 2 were 0.74 and 0.759, respectively. CONCLUSIONS: NEU, PLT, ALB, and CRP levels assessed before transplantation are independent factors for 1- and 5-year SPK recipient survival.

Influence of xanthine oxidase inhibitors on all-cause mortality in adults: a systematic review and meta-analysis.

Xanthine oxidase inhibitors, including allopurinol and febuxostat, are the first-line treatment of hyperuricemia. This meta-analysis investigated the association between urate-lowering therapy and all-cause mortality in different chronic diseases to match its users and non-users in a real-world setting. Overall, 11 studies were included, which reported adjusted hazard ratios for all-cause mortality over at least 12 months. Meta-analysis of all included studies showed no effect of the therapy on all-cause mortality. However, subgroup analyses showed its beneficial effect in patients with chronic kidney disease (14% risk reduction) and hyperuricemia (14% risk reduction), but not in patients with heart failure (28% risk increase). Urate-lowering therapy reduces all-cause mortality among patients with hyperuricemia and chronic kidney disease, but it seems to increase mortality in patients with heart failure and should be avoided in this subgroup.

Correlation of gestational age and age at death in sudden infant death syndrome: another pointer to the role of critical developmental period?

BACKGROUND: Filiano and Kinney proposed a triple-risk model for the sudden infant death syndrome (SIDS) that involves the intersection of three risks: (1) a vulnerable infant, (2) a critical developmental period in homeostatic control, and (3) an exogenous stressor(s). The primary evidence for the role of a critical developmental period in SIDS etiology is the peak of cases around the third month of life. Independently, several studies pointed to correlation between gestational age and age at death in SIDS, but used that to assess the SIDS risk for preterm infants, ignoring further ramifications. METHODS: We did a detailed analysis of CDC data spanning over two decades (1983-2011). We focused not only on the correlation between two age variables (gestational and age at death), but also on the possibility of misdiagnosis. Also, we attempted to account for potential biases in the data induced by the ICD-9/ICD-190 transition or the "Back to Sleep" campaign. RESULTS: The peak of deaths in the third month of life, that was the main argument for the role of the critical development period, wasn't unique to SIDS. However, we confirmed an almost linear and negative correlation between gestational age and the week of death due to SIDS. This pattern (slope of correlation < 0 and significance of correlation p < 0.05) is characteristic of SIDS among all diseases analyzed in the study. CONCLUSIONS: We interpret the results as the evidence of the role of the critical development period in SIDS etiology. Possibly more attention in the future research should be put to theories that are based on homeostatic control.

Impact of Body Mass Index on All-Cause Mortality in Adults: A Systematic Review and Meta-Analysis.

Background: Obesity is a risk factor for many diseases, diagnosed by calculating body mass index (BMI). Methods: To find an association between BMI and mortality in adults, we searched PubMed for articles published in the 21st century. Our review included 82 original studies, comprising 2.7 million patients and 23.4 million patient years. Results: The meta-analysis showed a U-shaped relationship between BMI and all-cause mortality risk, with the lowest mortality in the BMI range of 25-30 kg/m2. Subgroup analysis showed a J-shaped relationship, with greater risk in the highest BMI range (>35 kg/m2). Among the elderly, BMI values <20 kg/m2 were associated with the highest risk. Among diabetic patients, a U-shaped relationship was noticed, again with the highest risk in the lowest (<20 kg/m2) and highest BMI range (>35 kg/m2). Among patients with cardiovascular disease, the risk increased with BMI values <25 kg/m2 but did not noticeably change for BMI exceeding that value. Among cancer patients, the relationship was less pronounced than in other subgroups, with a slightly higher risk (>35 kg/m2). Conclusions: Our results show that the lowest mortality is observed among patients with BMI 25-30 kg/m2. Reduction of body mass should not be a universal recommendation in clinical practice, but it should be individualized.

Chimeric Antigen Receptor T Cell Therapy for Pancreatic Cancer: A Review of Current Evidence.

Chimeric antigen receptor (CAR) T-cell therapy has revolutionized the treatment of malignant and non-malignant disorders. CARs are synthetic transmembrane receptors expressed on genetically modified immune effector cells, including T cells, natural killer (NK) cells, or macrophages, which are able to recognize specific surface antigens on target cells and eliminate them. CAR-modified immune cells mediate cytotoxic antitumor effects via numerous mechanisms, including the perforin and granzyme pathway, Fas and Fas Ligand (FasL) pathway, and cytokine secretion. High hopes are associated with the prospective use of the CAR-T strategy against solid cancers, especially the ones resistant to standard oncological therapies, such as pancreatic cancer (PC). Herein, we summarize the current pre-clinical and clinical studies evaluating potential tumor-associated antigens (TAA), CAR-T cell toxicities, and their efficacy in PC.

The relationship between EMG high frequency and low frequency band amplitude changes correlates with tissue inorganic phosphate levels.

Assessing inorganic phosphate levels seems crucial in deciphering the biochemical state of organisms or tissues. The concentration of inorganic phosphate in blood is an order of magnitude smaller than in tissues and, on top of that, it is dynamically used to fill temporary gaps in tissues. This is the reason blood inorganic phosphate level is considered a poor proxy for tissue levels. Therefore, tissue biopsy seems to be the dominant method when assessing inorganic phosphate levels for instance in muscles. In this study, we attempted to derive a non-invasive biomarker for phosphate tissue levels. We analyzed surface electromyography signals taken during 31P spectroscopy of leg muscles in five adult pigs. We induced hypophosphatemia via 20 minutes-long hyperventilation. It turned out that the proportion of the amplitude of the low frequency band and the high frequency band is significantly (p=0.002) correlated with the relative phosphate levels. The electromyographic signal did not correlate significantly with pCO2 levels in the blood, suggesting that the changes in the signal are a result of inorganic phosphate levels, not hyperventilation. The results might lead to the development of a real-time phosphate fluctuations measurement procedure.

Impact of Blood Pressure on Risk of Graft Failure or Death Among Patients After Kidney Transplantation in a 10-Year Observational Period: A Single-Center Retrospective Analysis.

BACKGROUND Hypertension is a risk factor for graft failure and mortality among kidney transplant recipients (KTRs). The aim of the study was to examine blood pressure (BP) as a factor that contributes to graft failure or death during a 10-year observation period. MATERIAL AND METHODS The study group comprised 70 KTRs who were treated according to their clinical state. Data were collected at 1 month and 1 year after transplantation and included office and ambulatory BP monitoring (ABPM) BP values, eGFR, proteinuria, and BMI. During the observation period, 6 patients died, and 10 lost the graft, but not during the first year. RESULTS Office and ABPM BP values were within normal ranges and did not differ from each other. eGRF and BMI were higher at 1 year compared to 1 month after transplantation, and proteinuria decreased. Among those who died, DBP was lower compared to those of survivors with graft failure. Proteinuria and donor age were positively correlated with BP. CONCLUSIONS Monitoring of BP and adequate treatment of hypertension resulting in BP values within normal values among KTRs contribute to longer survival of the graft and recipient. Older donor age and proteinuria could predict post-transplant hypertension. Low diastolic BP of the recipient could increase the risk of death among KTRs. Despite the fact that ABPM is the blood pressure measurement method of choice, appropriate standard office measurement could also be used for BP monitoring.

Evaluation of selected parameters of inflammation, coagulation system, and formation of extracellular neutrophil traps (NETs) in the perioperative period in patients undergoing endovascular treatment of thoracoabdominal aneurysm with a branched device (t-Branch).

Extracellular Neutrophils Traps (NETs) and their formation, known as NETosis, have become pivotal in the pathogenesis of aortic aneurysm development. This study investigates the NETosis markers with the assessment of selected parameters of inflammation and coagulation system in patients with thoracoabdominal aortic aneurysms in the pre-and postop period undergoing t-Branch stent-graft implantation. The study included 20 patients with thoracoabdominal aortic aneurysms. Three markers double-stranded DNA (dsDNA), single-stranded DNA (ssDNA), and citrullinated H3 histones (Cit-H3) were tested at three-time points from patients' blood. The parameters of NETosis, inflammation, and coagulation system were examined in the preoperative period (within 24 h before surgery) and in the postoperative period (on the 3rd and 5th postoperative day). Free-circulating DNA (cfDNA) was isolated from the blood using the MagMAXTM Cell-Free DNA Extraction Kit. Double-stranded DNA (dsDNA) and single-stranded DNA (ssDNA) were then quantified using the Qubit dsDNA HS Assay Kit and the Qubit ssDNA Assay Kit. Cit-H3 concentration was determined by enzyme immunoassay ELISA (Cayman). The results revealed the significance of NETs secretion in response to the complex processes after stent-graft implantation. All NET markers increased shortly after surgery, with histones being the first to return to preoperative levels. The lack of normalization of dsDNA and ssDNA levels to preoperative levels by the last postoperative blood collection demonstrates NETs reorganization. The increase in the number of neutrophils was not related to the expansion of postoperative NETosis. The study reveals a new marker of NETosis, ssDNA, that has not been studied so far. The implantation of a stent graft in a patient with TAAA triggers an inflammatory response manifested by an increase in inflammatory parameters. One of the hallmarks of inflammation is the activation of neutrophil extracellular traps.

Renal cancer secretome induces migration of mesenchymal stromal cells.

BACKGROUND: Advanced renal cell carcinoma (RCC) is therapeutically challenging. RCC progression is facilitated by mesenchymal stem/stromal cells (MSCs) that exert remarkable tumor tropism. The specific mechanisms mediating MSCs' migration to RCC remain unknown. Here, we aimed to comprehensively analyze RCC secretome to identify MSCs attractants. METHODS: Conditioned media (CM) were collected from five RCC-derived cell lines (Caki-1, 786-O, A498, KIJ265T and KIJ308T) and non-tumorous control cell line (RPTEC/TERT1) and analyzed using cytokine arrays targeting 274 cytokines in addition to global CM proteomics. MSCs were isolated from bone marrow of patients undergoing standard orthopedic surgeries. RCC CM and the selected recombinant cytokines were used to analyze their influence on MSCs migration and microarray-targeted gene expression. The expression of genes encoding cytokines was evaluated in 100 matched-paired control-RCC tumor samples. RESULTS: When compared with normal cells, CM from advanced RCC cell lines (Caki-1 and KIJ265T) were the strongest stimulators of MSCs migration. Targeted analysis of 274 cytokines and global proteomics of RCC CM revealed decreased DPP4 and EGF, as well as increased AREG, FN1 and MMP1, with consistently altered gene expression in RCC cell lines and tumors. AREG and FN1 stimulated, while DPP4 attenuated MSCs migration. RCC CM induced MSCs' transcriptional reprogramming, stimulating the expression of CD44, PTX3 and RAB27B. RCC cells secreted hyaluronic acid (HA), a CD44 ligand mediating MSCs' homing to the kidney. AREG emerged as an upregulator of MSCs' transcription. CONCLUSIONS: Advanced RCC cells secrete AREG, FN1 and HA to induce MSCs migration, while DPP4 loss prevents its inhibitory effect on MSCs homing. RCC secretome induces MSCs' transcriptional reprograming to facilitate their migration. The identified components of RCC secretome represent potential therapeutic targets.

Hybrid Immunity Provides the Best COVID-19 Humoral Response in Immunocompromised Patients with or without SARS-CoV-2 Infection History.

Immunization against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has significantly limited the spread of coronavirus disease 2019 (COVID-19) and reduced the associated complications, especially mortality. To prolong immunity, an immune booster was implemented. We evaluated the role of SARS-CoV-2 infection history in the vaccination schedules of kidney and liver transplant recipients and patients with chronic kidney disease (CKD). To this end, we retrospectively analyzed the data of 78 solid organ transplantation (SOT) recipients and 40 patients with immunoglobulin A (IgA) nephropathy as representatives of the CKD group. Patients received two or three doses of the BNT162b2 vaccine. At the follow-up, antibody (Ab) titer, graft function, COVID-19 history, and patients' clinical condition were assessed. Ab level was higher after two doses in patients with a COVID-19 history over three doses in patients with no COVID-19 history. Compared to three doses, subjects who were administered two doses had a longer median time to infection. Positive antibodies, in response to the third dose, were not observed in up to 8.4% of SOT patients. The results show that the vaccination schedule should take into account the vaccine response rate and COVID-19 history. So-called hybrid immunity appears to be most efficient at providing humoral responses against SARS-CoV-2 infection in immunocompromised patients.

Development of a novel method for the simultaneous detection of trimethylamine N-oxide and creatinine in the saliva of patients with chronic kidney disease - Its utility in saliva as an alternative to blood.

Chronic kidney disease (CKD) is associated with increased levels of creatinine and other uremic toxins (UTs), which impaired kidneys cannot filtrate. Typically, CKD is diagnosed by calculating the estimated glomerular filtration rate using serum creatinine or cystatin C levels. In pursuit of more sensitive and reliable biomarkers of kidney dysfunction, scientific attention has turned towards other UTs, such as trimethylamine N-oxide (TMAO), successfully quantified in standard matrices, blood and urine. However, less invasive monitoring of kidney function can be performed using an alternative diagnostic biofluid, saliva, which has been shown to contain clinically relevant concentrations of renal function markers. Accurate quantitative estimation of serum biomarkers using saliva measurements can only be achieved provided that there is a tight saliva-serum correlation for the analyte of interest. Therefore, we aimed to verify the correlation between saliva and serum levels of TMAO in CKD patients using newly developed and validated quantitative liquid chromatography coupled to mass spectrometry (LC-MS) method for simultaneous detection of TMAO, and creatinine - the conventional marker of renal impairment. Secondly, we applied this method to quantify TMAO and creatinine levels in the resting saliva of CKD patients collected with a standardised method involving swab-based collectors. A good linear correlation was obtained between the concentration of creatinine in serum and resting saliva of CKD patients (r = 0.72, p = 0.029) and even better in the case of TMAO (r = 0.81, p = 0.008). The analysed validation criteria were fulfilled. No significant influence of the type of swab in the Salivette® device on creatinine and TMAO concentrations in saliva was detected. Our study indicates that saliva can be successfully used in the non-invasive monitoring of renal failure in CKD by measuring salivary TMAO concentrations.

Breaking Antimicrobial Resistance: High-Dose Amoxicillin with Clavulanic Acid for Urinary Tract Infections Due to Extended-Spectrum Beta-Lactamase (ESBL)-Producing Klebsiella pneumoniae.

BACKGROUND Carbapenems are the primary treatment for urinary tract infections (UTIs) caused by extended-spectrum beta-lactamase (ESBL)-producing Klebsiella pneumoniae. However, the recurrence rate is high, and patients often require rehospitalization. We present the results of an observational study on patients with recurrent UTIs who were treated in an outpatient setting with maximal therapeutic oral doses of amoxicillin with clavulanic acid. MATERIAL AND METHODS All patients had pyuria and ESBL-producing K. pneumoniae in urine culture. The starting dosage was 2875 g of amoxicillin twice daily and 125 mg of clavulanic acid twice daily. We down-titrated the doses every 7-14 days and continued prophylactic therapy with amoxicillin/clavulanic acid at 250/125 mg for up to 3 months. We defined therapeutic failure as ESBL-positive K. pneumoniae in urine culture during therapy and recurrence as positive urine culture with the same strain within 1 month after the end of treatment. RESULTS We included 9 patients: 7 kidney graft recipients, 1 liver graft recipient, and 1 patient with chronic kidney disease. We observed no therapeutic failures and no recurrences in the study group during the study period. In 1 case, the patient experienced a subsequent UTI caused by ESBL-producing K. pneumoniae 4 months after completing the therapy. CONCLUSIONS In conclusion, it is possible to break the resistance of ESBL-producing K. pneumoniae strains with high doses of oral amoxicillin with clavulanic acid. Such treatment could be an alternative to carbapenems in select cases.

Omics are Getting Us Closer to Understanding IgA Nephropathy.

During the last decade, thanks to omics technologies, new light has been shed on the pathogenesis of many diseases. Genomics, epigenomics, transcriptomics, and proteomics have helped to provide a better understanding of the origin and heterogeneity of several diseases. However, the risk factors for most autoimmune diseases remain unknown. The successes and pitfalls of omics have also been observed in nephrology, including immunoglobulin A nephropathy (IgAN), the most common form of glomerulonephritis and a principal cause of end-stage renal disease worldwide. Unfortunately, the immense progress in basic research has not yet been followed by the satisfactory development of a targeted treatment. Although, most omics studies describe changes in the immune system, there is still insufficient data to apply their results in the constantly evolving multi-hit pathogenesis model and thus do to provide a complete picture of the disease. Here, we describe recent findings regarding the pathophysiology of IgAN and link omics studies with immune system dysregulation. This review provides insights into specific IgAN markers, which may lead to the identification of potential targets for personalised treatment in the future.

The Role of COX-2 and PGE2 in the Regulation of Immunomodulation and Other Functions of Mesenchymal Stromal Cells.

The ability of MSCs to modulate the inflammatory environment is well recognized, but understanding the molecular mechanisms responsible for these properties is still far from complete. Prostaglandin E2 (PGE2), a product of the cyclooxygenase 2 (COX-2) pathway, is indicated as one of the key mediators in the immunomodulatory effect of MSCs. Due to the pleiotropic effect of this molecule, determining its role in particular intercellular interactions and aspects of cell functioning is very difficult. In this article, the authors attempt to summarize the previous observations regarding the role of PGE2 and COX-2 in the immunomodulatory properties and other vital functions of MSCs. So far, the most consistent results relate to the inhibitory effect of MSC-derived PGE2 on the early maturation of dendritic cells, suppressive effect on the proliferation of activated lymphocytes, and stimulatory effect on the differentiation of macrophages into M2 phenotype. Additionally, COX-2/PGE2 plays an important role in maintaining the basic life functions of MSCs, such as the ability to proliferate, migrate and differentiate, and it also positively affects the formation of niches that are conducive to both hematopoiesis and carcinogenesis.

Concentrations of Transition Metal Ions in Rat Lungs after Tobacco Smoke Exposure and Treatment with His-Leu Dipeptide.

Tobacco smoking is deleterious to the lungs because it exposes them to many toxic substances. These include transition metal ions, such as cadmium. However, there is a lack of information about the influence of endogenous metal-binding peptides, such as His-Leu (HL), on the lung distribution of transition metals in smokers. To address this, we administered HL subcutaneously to rats exposed to tobacco smoke for six weeks, then we measured the concentrations of transition metal ions in the lungs. We found that exposure to tobacco smoke elevates the concentrations of Cd(II) and Cu(II). Administration of the HL peptide, whose elevation is a consequence of angiotensin receptor blocker anti-hypertension therapy, increases the concentration of Fe in the lungs of rats exposed to smoke. These findings suggest that smoking is a risk factor for patients receiving angiotensin receptor blockers to treat hypertension.

Crosstalk between microRNA and Oxidative Stress in Heart Failure: A Systematic Review.

Heart failure is defined as a clinical syndrome consisting of key symptoms and is due to a structural and/or functional alteration of the heart that results in increased intracardiac pressures and/or inadequate cardiac output at rest and/or during exercise. One of the key mechanisms determining myocardial dysfunction in heart failure is oxidative stress. MicroRNAs (miRNAs, miRs) are short, endogenous, conserved, single-stranded non-coding RNAs of around 21-25 nucleotides in length that act as regulators of multiple processes. A systematic review following the PRISMA guidelines was performed on the evidence on the interplay between microRNA and oxidative stress in heart failure. A search of Pubmed, Embase, Scopus, and Scopus direct databases using the following search terms: 'heart failure' AND 'oxidative stress' AND 'microRNA' or 'heart failure' AND 'oxidative stress' AND 'miRNA' was conducted and resulted in 464 articles. Out of them, 15 full text articles were eligible for inclusion in the qualitative analysis. Multiple microRNAs are involved in the processes associated with oxidative stress leading to heart failure development including mitochondrial integrity and function, antioxidant defense, iron overload, ferroptosis, and survival pathways.

Effect of Statins on All-Cause Mortality in Adults: A Systematic Review and Meta-Analysis of Propensity Score-Matched Studies.

Statins are lipid-lowering medications used for the prevention of cardiovascular disease (CVD), but the pleiotropic effects of statins might be beneficial in other chronic diseases. This meta-analysis investigated the association between statin use and mortality in different chronic conditions. Eligible studies were real-world studies that compared all-cause mortality over at least 12 months between propensity score-matched statin users and non-users. Overall, 54 studies were included: 21 in CVD, 6 in chronic kidney disease, 6 in chronic inflammatory diseases, 3 in cancer, and 18 in other diseases. The risk of all-cause mortality was significantly reduced in statin users (hazard ratio: 0.72, 95% confidence interval: 0.66−0.76). The reduction in mortality risk was similar in CVD studies (0.73, 0.66−0.76) and non-CVD studies (0.70, 0.67−0.79). There were no significant differences in the risk reduction between cohorts with different diseases (p = 0.179). The greatest mortality reduction was seen in studies from Asia (0.61, 0.61−0.73) and the lowest in studies from North America (0.78, 0.73−0.83) and Australia (0.78, 0.62−0.97). There was a significant heterogeneity (I2 = 95%, tau2 = 0.029, p < 0.01). In conclusion, statin use was associated with a significantly reduced risk of all-cause mortality in real-world cohorts with CVD and non-CVD.

The Different Patterns of Over-the-Counter Nonsteroidal Anti-Inflammatory Drugs or Analgesics Use in Patients with Chronic Kidney Disease and the General Population.

Nonsteroidal anti-inflammatory drugs (NSAIDs) and analgesics are the most commonly used drugs worldwide and their availability over-the-counter is increasing. The aim of this study was to examine the frequency of their use as well as the awareness of the associated risk of side effects in patients with chronic kidney disease (CKD) compared to the patients at general practice (GP) offices. We found that 88.5% of the CKD and 97.1% of the GP group used NSAIDs and/or analgesics (p < 0.0001). Paracetamol was chosen the most often by both study groups, but the proportion of patients taking paracetamol was significantly higher in the CKD group (p < 0.006). On the contrary, the proportion of patients taking ibuprofen was significantly higher in GP group (p < 0.0001). Furthermore, almost 37% of CKD and 60% of GP patients never consult with their doctor before taking NSAIDs or analgesics. The influence of advertisements on the decision to take these drugs was found to be marginal in both groups. In conclusion, the NSAIDs and/or analgesics use is very common. The differences between the studied cohorts in self-decision making and the type of drugs used between the studied cohorts warrant tailored educational approaches.

Label-Free Mass Spectrometry-Based Quantitative Proteomics to Evaluate the Effects of the Calcium-Sensing Receptor Agonist Cinacalcet on Protein Expression in Rat Brains and Livers.

BACKGROUND Cinacalcet is a calcium-sensing receptor agonist that is clinically approved for the treatment of secondary hyperparathyroidism in chronic kidney disease and hypercalcemia in patients with parathyroid carcinoma. This study aimed to use quantitative mass spectrometry-based label-free proteomics to evaluate the effects of cinacalcet on protein expression in rat brains and livers. MATERIAL AND METHODS We randomly assigned 18 Wistar rats to 2 groups: an untreated control group (n=6) and a group treated with cinacalcet at a dose corresponding to the maximum dose used in humans (2 mg/kg/body weight, 5 days/week) divided into 7-day (n=6) and 21-day (n=6) treatment subgroups. A mass-spectrometry-based label-free quantitative proteomics approach using peptides peak area calculation was used to evaluate the changes in protein expression in examined tissues. Bioinformatics analysis of quantitative proteomics data was done using MaxQuant and Perseus environment. RESULTS No changes in protein expression were revealed in the 7-day treatment subgroup. We detected 10 upregulated and 3 downregulated proteins in the liver and 1 upregulated protein in the brain in the 21-day treatment subgroup compared to the control group. Based on Gene Ontology classification, all identified differentially expressed proteins were indicated as molecular functions involved in the enzyme regulator activity (36%), binding (31%), and catalytic activity (19%). CONCLUSIONS These findings indicate that long-term cinacalcet therapy can impair phase II of enzymatic detoxication and can cause disturbances in blood hemostasis, lipid metabolism, and inflammatory mediators or contribute to the acceleration of cognitive dysfunction; therefore, appropriate patient monitoring should be considered.

Osteopontin-A Potential Biomarker for IgA Nephropathy: Machine Learning Application.

Many potential biomarkers in nephrology have been studied, but few are currently used in clinical practice. One is osteopontin (OPN). We compared urinary OPN concentrations in 80 participants: 67 patients with various biopsy-proven glomerulopathies (GNs)-immunoglobulin A nephropathy (IgAN, 29), membranous nephropathy (MN, 20) and lupus nephritis (LN, 18) and 13 with no GN. Follow-up included 48 participants. Machine learning was used to correlate OPN with other factors to classify patients by GN type. The resulting algorithm had an accuracy of 87% in differentiating IgAN from other GNs using urinary OPN levels only. A lesser effect for discriminating MN and LN was observed. However, the lower number of patients and the phenotypic heterogeneity of MN and LN might have affected those results. OPN was significantly higher in IgAN at baseline than in other GNs and therefore might be useful for identifying patients with IgAN. That observation did not apply to either patients with IgAN at follow-up or to patients with other GNs. OPN seems to be a valuable biomarker and should be validated in future studies. Machine learning is a powerful tool that, compared with traditional statistical methods, can be also applied to smaller datasets.