Nephrotoxicity as a Complication of Chemotherapy and Immunotherapy in the Treatment of Colorectal Cancer, Melanoma and Non-Small Cell Lung Cancer.

Acute kidney injury is a common complication of many medical procedures, including those used in cancer treatment. Both chemotherapy and immunotherapy may result in deterioration of kidney function, which may lead to an increase in mortality among patients with cancer. Antineoplastic agents can affect any element of the nephron, leading to the appearance of clinical symptoms such as proteinuria, hypertension, electrolyte disorders, glomerulonephritis, acute and chronic interstitial nephritis and acute kidney injury. The medical literature describing renal complications occurring during chemotherapeutic and immunotherapeutic treatment in neoplasms, such as colorectal cancer, non-small cell lung cancer and melanoma, was analysed. The immune system plays an important role in controlling the development of neoplasms and fighting them. Oncological treatment algorithms include immunotherapy as monotherapy, combined with chemotherapy or chemotherapy as monotherapy. In the treatment of the above-mentioned neoplasms immunotherapeutics are used, such as checkpoint inhibitors (CPI) (i.e., ipilimumab, pembrolizumab, nivolumab, atezolizumab), vascular endothelial growth factor (VEGF) inhibitors (i.e., bevacizumab, ramucirumab) and a variety of chemotherapeutic agents (irinotecan, capecitabine, oxaliplatin, gefitinib, erlotinib, gemcitabine, cisplatin, paclitaxel, carboplatin, doclitaxel, vinorelbine, topotecan, etoposide). In our article, we focused on the number and type of renal complications as well as on the time of their manifestation when using specific treatment regimens. Our analysis also includes case reports. We discussed treatment of immunological complications and adjustments of the dose of chemotherapeutic agents depending on the creatinine clearance. Analysing the data from the literature, when two immunotherapeutic agents are used together, the number of recorded renal complications increases. Bevacizumab and ramucirumab are the cause of the largest number of renal complications among the immunotherapeutic agents described above. Cisplatin is the best-described substance with the greatest nephrotoxic potential among the chemotherapeutic agents. Crucial for renal complications are also cancer stage, previous chemotherapy and other risk factors of AKI such as age, comorbidities and medications used. Due to the described complications during oncological treatment, including kidney damage, it seems necessary to elaborate standards of cooperation between oncologists and nephrologists both during and after treatment of a patient with cancer. Therefore, it is necessary to conduct further research and develop algorithms for management of a cancer patient, especially during such an intensive progress in oncology.

Selected cardiovascular risk factors in early stages of chronic kidney disease.

Cardiovascular diseases, including hypertension, congestive heart failure, myocardial infarction, stroke and atherosclerosis, are common in patients with chronic kidney disease. Aside from the standard biomarkers, measured to determine cardiovascular risk, new ones have emerged: markers of oxidative stress, apoptosis, inflammation, vascular endothelium dysfunction, atherosclerosis, organ calcification and fibrosis. Unfortunately, their utility for routine clinical application remains to be elucidated. A causal relationship between new markers and cardiovascular diseases in patients with chronic kidney disease remains to be established. First of all, there is a lack of large, randomized trials. Moreover, most studies focus on patients with end-stage renal disease as well as on dialysed patients. In such patients, cardiovascular diseases are already present and advanced while early detection of cardiovascular disease risk factor in patients with early-stages of chronic kidney disease would allow more precise prognosis and, as a result, changes in treatment algorithm. In this article, we conduct a comprehensive review of literature for publications relating to cardiovascular risk factors in patients with early-stages of chronic kidney disease. Overall, there are many encouraging advances in detection of cardiovascular risk factors that are making the future more promising for patients suffering from chronic kidney disease.

Basic inflammatory indices and chosen neutrophil receptors expression in chronic haemodialysed patients.

AIM OF THE STUDY: End stage renal disease (ESRD) patients on chronic haemodialysis (HD) are immuno-compromised and prone to infection. Toll-like receptors (TLRs) play a role as both primary sensors of pathogen invasion and activators of inflammatory reaction. To test if the immune impairment in HD patients is connected with the defective expression of the neutrophil TLRs, we aimed to examine their expression and chosen inflammatory indices. MATERIAL AND METHODS: We tested CD14, TLR4, and TLR9 expressions on neutrophils using flow cytometry. Soluble CD14, C-reactive protein (CRP), and mannose-binding lectin (MBL) concentrations were tested using the ELISA method in 31 ESRD patients on chronic haemodialysis programs and in 17 healthy control subjects. RESULTS: Neutrophil TLR4 and TLR9 expressions did not differ significantly compared to the controls. The ESRD patients had markedly increased CRP and sCD14 levels alongside decreased MBL concentrations and neutrophil CD14 expression. The TLR4 expression correlated well with both TLR9 and CD14 neutrophil expressions; however, the increased CRP in the blood did not correlate with the MBL concentration or TLR expression. CONCLUSIONS: The chronic program of haemodialysis and biochemical disorders in ESRD patients result in a low-grade chronic inflammation with no significant impact on the expression of neutrophil TLR4 and TLR9.

Clinical and prognostic usefulness of soluble urokinase plasminogen activator receptor in hemodialysis patients.

PURPOSE: Considering its prognostic usefulness and the relationship with chronic kidney disease, we analyzed the clinical utility of soluble urokinase plasminogen activator receptor (suPAR) in end-stage renal disease patients undergoing hemodialysis treatment. We focused on the association between suPAR levels and clinical outcomes, especially those related to cardiovascular events and mortality as well as the effect of hemodialysis on the protein levels. METHODS: We enrolled 64 patients. Blood samples for laboratory tests were collected before and after the midweek hemodialysis. The concentration of suPAR was assessed using suPARNostic ELISA, ViroGates. RESULTS: Spearman rank analyses showed a positive association between suPAR and creatinine, cystatin C, galectin 3, N-terminal prohormone of brain natriuretic peptide and troponin T (p < 0.05). In ROC analysis, the suPAR concentration equal to 11.5 ng/mL was established to be the cutoff value for the prediction of mortality in the analyzed patients. Simultaneous analysis of creatinine and suPAR increased the predictive value of the latter-the area under curve increased to 0.84 (95% CI 0.70-0.94, p < 0.0001). Logistic regression analysis revealed that increase in the suPAR level was associated with the increase in odds ratio for death by 1.3 (95% CI 1.1-1.6, χ2 = 8.2, p = 0.004). In multivariable analysis, the prediction power of suPAR appeared to be stronger after including creatinine (p = 0.0005). CONCLUSIONS: Elevated suPAR levels provide independent information on mortality risk in patients undergoing hemodialysis. The protein appears not to cross the dialysis membrane; thus, blood collection before the second hemodialysis session seems to give reliable information on the suPAR level for clinical interpretation.

Hemodialysis Decreases the Concentration of Accumulated Plant Phenols in the Plasma of Patients on Maintenance Dialysis: Influence of Residual Renal Function.

Plant phenols may accumulate in end-stage kidney disease. The effect of hemodialysis on their plasma concentration remains poorly determined. Contingent on concentration, health-promoting or noxious effects occur; therefore, we assessed plasma concentration in hemodialyzed patients. In total, 21 maintenance hemodialyzed patients with diuresis < 500 mL per day (with oliguria), nine hemodialyzed patients with diuresis ≥ 500 mL per day (without oliguria) and 31 healthy volunteers were included. Nine phenolic acids were identified with high-performance liquid chromatography and total polyphenol concentration was determined with the Folin-Ciocalteu method in pre- or post-hemodialysis plasma and pre- or intra-hemodialysis dialysate. The concentration of total polyphenols was 27% higher in pre-hemodialysis plasma than in that of controls (0.95 ± 0.18 mmol/L [P < 0.0001]). The concentration of total polyphenols was higher in patients with oliguria (1.01 ± 0.17) than in those without (0.84 ± 0.13 mmol/L), despite the former having more intense hemodialysis (Kt/V 1.29 ± 0.31 and 0.77 ± 0.25, respectively). Pre-hemodialysis phenolic acid concentration in patients undergoing dialysis exceeded reference values by 3 to 34 times (3-hydroxyphenylacetic acid and vanillic acid, respectively), from 0.69 (dihydrocaffeic acid) to 169.3 µmol/L (hippuric acid). The concentration of six phenolic acids (3-hydroxyhippuric, caffeic, dihydrocaffeic, hippuric, homovanillic, and vanillic acid) was 1.1 (homovanillic) to 11.3 (3-hydroxyhippuric) times higher in patients with oliguria than in those without. 4-hydroxyhippuric acid occurred more in the plasma of patients with oliguria than in those without oliguria. A single hemodialysis session decreased total polyphenol concentration by 16% and phenolic acids from 30% (caffeic) to 58% (vanillic and 3-hydroxyphenylacetic acid) and these compounds appeared in the dialysate. The percentage decrease (Δ%) of creatinine concentration correlated with the Δ% of total polyphenols and five phenolic acids (3-hydroxyphenylacetic, dihydrocaffeic, hippuric, homovanillic, and vanillic acid). Urea Δ% and Kt/V correlated only with the Δ% of homovanilic acid. The results demonstrate that phenols accumulate variably in hemodialyzed patients and are differently eliminated during hemodialysis. Residual renal function ensures a lower concentration of plasma phenols.

Are Markers of Cardiac Dysfunction Useful in the Assessment of Cardiovascular Risk in Dialysis Patients?

BACKGROUND: Cardiovascular morbidity and mortality of dialysis patients are major problems in this group of patients. METHODS: The purpose of this study was also to evaluate whether any of the studied markers are better than troponin in early detection of the occurrence of ventricular arrhythmias and prolongation of QT interval. This study included 45 patients undergoing hemodialysis. ECG Holter and echocardiographic examination were performed before and after dialysis. The concentrations of markers: copeptin, GDF-15, HFABP and troponin were measured with the use of ELISA tests. RESULTS: We observed significantly higher QT (p=0.004), QTc (0.018), right atrium volume (p=0.006) and concentrations of copeptin (p<0.0001) and H-FABP (p<0.0001) as well as smaller left atrium volume (p<0.0001) and width of inferior vena cava (p<0.0001) after dialysis than before it. Significantly longer QT and higher copeptin levels were seen in patients with ventricular arrhythmia. A trend between the increase in copeptin concentration and H-FABP level and the presence of ventricular arrhythmias was also noted. CONCLUSION: Generally, we failed to find any strong predictor of post-dialysis ventricular arrhythmia or the prolongation of QT, however, it seems that copeptin may have prognostic value, but this has to be analyzed in large studies.

The occurrence of atrial fibrillation in dialysis patients and its association with left atrium volume before and after dialysis.

PURPOSE: Atrial fibrillation is a serious problem, especially in patients on dialysis. The prevalence of AF in this group of patients is higher than in general population and associated with increased mortality. The aim of this study was to assess the risk of the occurrence of atrial fibrillation related to intradialysis hypotension and left atrium volume enlargement associated with dialysis. The influence of dialysis session on: E/E', V LA, E/A, E', V RA and the width of inferior vena cava of RV was analyzed. METHODS: This study included 40 patients on hemodialysis. Echocardiographic examination was performed to assess heart condition and function, the presence of LVH and systolic and diastolic function disturbances, LV mass, LA size, LAV, RAV, E/A, E', E/E, ejection fraction in all patients before and after dialysis. Moreover, all patients had ECG Holter continuously recording heart's rhythm before and after dialysis to assess the occurrence of atrial fibrillation related to dialysis session. RESULTS: The analysis of differences in echocardiographic parameters before and after dialysis demonstrated significantly greater left atrium volume, right atrium volume, width of inferior vena cava and e' parameter before dialysis in comparison with post-dialysis state. Significantly higher incidence of AF after dialysis was seen. Volume of left atrium exceeding 32 mm (cutoff value) was observed significantly more often in patients before dialysis. No association was observed between left ventricle mass and left atrium volume. CONCLUSIONS: The dialysis procedure may be a trigger for atrial fibrillation and thus AF preventive measures should be introduced in dialysis patients.

Lipoprotein Subfractions, Uric Acid and Cardiovascular Risk in End-Stage Renal Disease (ESRD) Patients.

BACKGROUND: Chronic kidney disease (CKD) is a worldwide public health problem and an independent risk factor for cardiovascular disease (CVD). OBJECTIVE: We assessed cardiovascular risk in end-stage renal disease (ESRD) patients and evaluated the relationship between serum uric acid (SUA) and lipoprotein subfractions. METHODS: The study group consisted of 66 patients on dialysis and a control group of 25 healthy volunteers. Concentration of high-density lipoproteins (HDL) and low-density lipoproteins (LDL) subfractions were analysed using a Lipoprint™. Lipid profiles and SUA were measured. RESULTS: There were significant differences in the distribution of HDL1-HDL5 subfractions levels, which were significantly higher in patients with impaired renal function than in the control group (p≤0.013 for all comparisons). HDL7-HDL10 subfractions were significantly more prevalent in healthy volunteers compared with CKD patients (p≤0.001 for all comparisons). The analysis of LDL subfractions revealed significant differences only in IDL-B (p<0.05), IDL-A (p<0.05) and LDL2 (p<0.001) between patients with CKD stage 5 and controls. CONCLUSION: Our study demonstrated that higher SUA level might be associated with lower prevalence of CVD among haemodialysis patients. An elevated SUA concentration in haemodialysis population may be a marker of better nutritional status and also represent the antioxidant properties SUA.

Combination drug versus monotherapy for the treatment of autosomal dominant polycystic kidney disease.

INTRODUCTION: Despite progress in the understanding of pathogenetic mechanisms of organ cyst formation in autosomal dominant polycystic kidney disease, current treatment methods are insufficient. Experimental studies and clinical trials target at inhibition of cysts development and to slowing CKD progression. AREAS COVERED: The purpose of this analysis is to overview available literature regarding treatment of ADPKD. The most important recent events concerning ADPKD treatment are: the results of TEMPO 3/4 study and the registration of tolvaptan in the treatment of patients with CKD stage I-III and rapidly progressive ADPKD by EMA. ERA-EDTA recommendations for use of tolvaptan in ADPKD of 2016 will be useful for the identification of patients with rapid progression of disease who will benefit most from treatment. Clinical trials concerning inhibitors of mTOR and SSAs have not delivered convincing evidence of their effectiveness. Usefulness of statins in ADPKD require confirmation in adults. The HALT-PKD study confirmed that inhibition of RAA system slows progression of ADPKD. EXPERT OPINION: Current treatment of ADPKD involves: the optimization of life style and combined pharmacological treatment with ACE inhibitors or angiotensin receptor blockers, statins (patients with lipid disorders and cardiovascular disease) and tolvaptan (patients with stage I-III CKD and rapidly progressive ADPKD).

Impact of Continuous Erythropoietin Receptor Activator on Selected Biomarkers of Cardiovascular Disease and Left Ventricle Structure and Function in Chronic Kidney Disease.

Background. Cardiovascular morbidity and mortality are very high in patients with chronic kidney disease (CKD). The purpose of this study is to evaluate the impact of continuous erythropoietin receptor activator (CERA) on selected biomarkers of cardiovascular disease, left ventricle structure, and function in CKD. Material and Methods. Peripheral blood was collected from 25 CKD patients before and after CERA treatment and 20 healthy subjects. In serum samples, we assessed inflammatory markers (IL-1ß, TNF-RI, TNF-RII, sFas, sFasL, MMP-9, TIMP-1, and TGF-ß1), endothelial dysfunction markers (sE-selectin, sICAM-1, and sVCAM-1), and volume-related marker (NT-proBNP). All subjects underwent echocardiography and were evaluated for selected biochemical parameters (Hb, creatinine, and CRP). Results. Evaluated biomarkers and echocardiographic parameters of left ventricle structure were significantly increased but left ventricle EF was significantly decreased in CKD patients compared to controls. After CERA treatment, we observed a significant increase of Hb and left ventricle EF and a significant decrease of NT-proBNP and MMP-9. There was a significant negative correlation between Hb and TNF-RI, sICAM-1, and IL-1ß. Conclusions. Our results indicate that selected biomarkers related to cardiovascular risk are significantly increased in CKD patients compared to controls. CERA treatment has anti-inflammatory action, diminishes endothelial dysfunction, and improves left ventricle function in these patients.

Evaluation of Endothelial (dys)Function, Left Ventricular Structure and Function in Patients with Chronic Kidney Disease.

BACKGROUND: Endothelial dysfunction is involved in the pathogenesis of atherosclerosis and cardiovascular complications in chronic kidney disease (CKD). Asymmetric dimethylarginine (ADMA), an endogenous inhibitor of endothelial nitric oxide synthase (eNOS), is considered as a marker of endothelial dysfunction. The aim of this study was to evaluate serum ADMA, eNOS concentration and left ventricular structure and function in CKD patients and to assess the impact of the type of dialyzer on serum ADMA and eNOS concentrations after a haemodialysis (HD) session. MATERIAL AND METHODS: Peripheral blood was collected from 35 predialysis CKD patients, 40 CKD patients on HD and 15 healthy subjects. Patients on HD were divided into two groups according to the dialyzer used based on polynephron or cellulose membranes. Plasma ADMA and eNOS concentrations were assessed. All subjects underwent echocardiography and were evaluated for selected biochemical parameters. RESULTS: We found significantly higher serum ADMA (p<0.05) and significantly lower eNOS (p<0.05) concentration in CKD patients compared with healthy subjects. Both dialyzers significantly reduced serum ADMA concentration (p<0.05) but none of the analysed dialyzers showed superiority when comparing the results. We showed that stage V CKD patients, who had the highest serum ADMA concentration had the lowest left ventricle ejection fraction (LVEF) and the highest left ventricle mass (LVM) and left ventricular end diastolic diameter (LVEDd). CONCLUSIONS: Our results supports the presence of endothelial dysfunction in CKD patients. Correlation between elevated serum AMDA concentration and disadvantageous changes in left ventricular structure and function may indicate an important role of endothelial dysfunction in cardiovascular complications in CKD patients.

Impact of anemia treatment with methoxy polyethylene glycol-epoetin beta on polymorphonuclear cells apoptosis in predialysis patients with chronic kidney disease.

BACKGROUND: Some data in literature indicate increased apoptosis of polymorphonuclear cells (PMNs) in chronic kidney disease (CKD), what seems to be connected with anemia. Erythropoiesis-stimulating agents, used in anemia treatment in CKD may affect cells apoptosis. Aim of this study was to investigate impact of anemia treatment with methoxy polyethylene glycol-epoetin beta (CERA) on PMNs apoptosis in predialysis patients with CKD. METHODS: Percentage of early and late apoptotic PMNs was measured by flow cytometry based on annexin V and propidium iodide binding. CD90 (Fas), CD95L (FasL), CD16 and CD11b expression on PMNs were evaluated by flow cytometry after incubation with respective monoclonal antibody. RESULTS: Percentage of PMNs in early and late apoptosis in CKD patients before CERA treatment was significantly higher to control group, which was accompanied by significantly higher Fas and Fas-L expression and significantly lower expression of CD16. CERA treatment downregulated significantly percentage of early, apoptotic PMNs but percentage of late apoptotic cells did not change and was still significantly higher to control group. In all investigated groups we observed a significant negative correlation between hemoglobin concentration and percentage of apoptotic PMNs, as well as Fas and FasL expression and significant positive correlation between Hb and CD16 expression. CONCLUSIONS: Our results indicate that PMNs apoptosis is increased in predialysis patients with CKD and anemia treatment with CERA may diminish readiness of PMNs to undergo apoptosis. This antiapoptotic impact of anemia treatment with CERA seems to concern early apoptotic PMNs before they undergo to late, irreversible stage of apoptosis.

Effect of methoxy polyethylene glycol-epoetin beta on oxidative stress in predialysis patients with chronic kidney disease.

BACKGROUND: There is data in the literature indicating increased oxidative stress in chronic kidney disease (CKD). Erythropoiesisstimulating agents (ESAs), which are commonly used to treat anemia in patients with CKD, seem to have an antioxidant action, which could be a part of nephroprotection. The aim of the current study was to investigate the effect of a long half-life ESA, methoxy polyethylene glycol-epoetin beta (Mircera), on some markers of oxidative stress in predialysis patients with CKD. MATERIAL AND METHODS: Peripheral blood was collected from 28 predialysis CKD patients 2 times, before Mircera treatment and after achieving target hemoglobin (Hb), and 15 healthy subjects (control group). Superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and catalase (CAT) activity in erythrocytes were measured according to commonly used methods as a function of the antioxidant defense system. To assess reactive oxygen species (ROS) production, malondialdehyde (MDA) concentration in erythrocytes and in plasma was measured according to a commonly used method. RESULTS: SOD, GSH-Px, and CAT activity were similar, but plasma and erythrocyte MDA concentrations were significantly higher in CKD patients before ESA treatment in comparison to the control group. SOD, GSH-Px, and CAT activity was significantly higher, but plasma and erythrocyte MDA concentrations were significantly lower, in CKD patients after ESA treatment in comparison to these patients before treatment. We did not find a significant correlation between Hb concentration and SOD, GSH-Px, and CAT activity and plasma, as well as erythrocyte MDA concentrations. Analysis of all investigated groups showed a significant negative correlation between Hb concentration and plasma MDA concentration. CONCLUSIONS: Our results suggest that treatment of anemia with methoxy polyethylene glycol-epoetin beta may inhibit oxidative stress in predialysis patients with CKD by enhancing the antioxidant defense system and reducing ROS production.

The influence of the pleiotropic action of erythropoietin and its derivatives on nephroprotection.

Erythropoietin (EPO) is traditionally described as a hematopoietic cytokine or growth hormone regulating proliferation, differentiation, and survival of erythroid progenitors. The use of EPO in patients with chronic kidney disease (CKD) was a milestone achievement in the treatment of anemia. However, EPO involves some degree of risk, which increases with increasing hemoglobin levels. A growing number of studies have assessed the renoprotective effects of EPO in acute kidney injury (AKI) or CKD. Analysis of the biological effects of erythropoietin and pathophysiology of CKD in these studies suggests that treatment with erythropoiesis-stimulating agents (ESAs) may exert renoprotection by pleiotropic actions on several targets and directly or indirectly slow the progression of CKD. By reducing ischemia and oxidative stress or strengthening anti-apoptotic processes, EPO may prevent the development of interstitial fibrosis and the destruction of tubular cells. Furthermore, it could have a direct protective impact on the integrity of the interstitial capillary network through its effects on endothelial cells and promotion of vascular repair, or modulate inflammation response. Thus, it is biologically plausible to suggest that correcting anemia with ESAs could slow the progression of CKD.                         The aim of this article is to discuss these possible renoprotection mechanisms and provide a comprehensive overview of erythropoietin and its derivatives.

[Anti-inflammatory action of myoinositol in renal insufficiency]. / Przeciwzapalne dzialanie mioinozytolu w przewleklej niewydolnosci nerek.

AIM OF THE STUDY: Release of prostaglandin E2 (PGE2) and leukotrien B4 (LTB4) in vitro by resting and PHA-stimulated peripheral blood mononuclear cells (PBMNC) in the presence of three concentrations of myoinositol (30, 300, 600 micromol/l) was investigated. MATERIAL AND METHODS: We examinated 10 uremic patients on regular hemodialysis treatment and 10 healthy subjects (control group). RESULTS: Release of PGE2 and LTB4 by resting and PHA-stimulated PBMNC was significantly lower in the presence of myoinositol in concentrations generally obserwed in the blood serum of chronic uraemic patients on regular hemodialysis treatment (600 micromol/l) in both investigated groups, while it remained unchanged in the presence of myoinositol in the concentration observed in normal blood serum (30 micromol/l). CONCLUSION: The results seem to indicate that myoinositol, in the concentrations found in uremic blood serum, may possibly exert antiinflammatory actions.