Immunohistochemical Evaluation of Renal Biopsy with Anti-PD1 and p53 to Solve the Dilemma between Platinum- and Pembrolizumab-Induced AKI: Case Report and Review.

Introduction: The combination therapy of platinum and pembrolizumab looks like a promising treatment in advanced non-small-cell lung cancer. However, both platinum-based chemotherapy and pembrolizumab can lead to AKI. AKI can occur due to acute tubular necrosis or interstitial nephritis. It is essential to identify the drug responsible for renal damage. For this purpose, we used new immunohistochemistry markers (p53 and anti-PD1 analysis). Case Description: A 77-year-old female patient with advanced non-small-cell lung cancer received the PD-1 inhibitor pembrolizumab and platinum-based chemotherapy carboplatin. The patient, after 60 days, experienced AKI. A kidney biopsy was performed, and two new immunohistochemical techniques for p53 (experimental markers of ATN from platinum) and anti-PDL1 (experimental markers of PD-1 inhibitors nephritis) were employed. Renal biopsies revealed severe tubular damage. No infiltration was detected, and the immunohistochemical assessment of PDL-1 was negative. The expression of p53 was positive. The renal biopsy suggested platinum-induced acute tubular necrosis. After discontinuing steroids and reducing carboplatin, the patient continued with pembrolizumab, and their renal function returned to normal within two months. Discussion: Combining checkpoint inhibitors and platinum-based therapies may result in AKI. The standard method of examining kidney tissue may not provide sufficient information about the effects of these drugs on the kidneys. To address this issue, we recommend incorporating an assessment of the analysis of the expression of PDL1 and p53. This personalized approach will help identify the best treatment option for the patient while ensuring the best possible cancer treatment plan.

MicroRaman spectroscopy detects the presence of microplastics in human urine and kidney tissue.

There is a growing concern within the medical community about the potential burden of microplastics on human organs and tissues. In this study, we investigated by microRaman spectroscopy the presence of microplastics in human kidneys and urine. Moreover, an open-access software was developed and validated for the project, which enabled the comparison between the investigated spectra and a self-created spectral database, thus enhancing the ability to characterize polymers and pigments in biological matrices. Healthy portions of ten kidneys obtained from nephrectomies, as well as ten urine samples from healthy donors were analyzed: 26 particles in both kidney and urine samples were identified, with sizes ranging from 3 to 13 µm in urine and from 1 to 29 µm in kidneys. The most frequently determined polymers are polyethylene and polystyrene, while the most common pigments are hematite and Cu-phthalocyanine. This preclinical study proves the presence of microplastics in renal tissues and confirms their presence in urine, providing the first evidence of kidney microplastics deposition in humans.

Using Renal Elastography to Predict the Therapeutic Response of Nephrological Patients.

BACKGROUND: The standard method for assessing chronic renal damage is renal biopsy, which has limitations due to its invasiveness. Ultrasound elastography is a non-invasive technique that quantifies tissue elasticity and can be used to determine Young's modulus (YM). Although this breakthrough technology has been successfully employed to evaluate liver stiffness and the extent of fibrosis, its application in kidney-related conditions still needs improvement. METHODS: Our study aimed to verify the correlation between renal elastography and the chronic histological score determined via renal biopsy, evaluate the correlation between elastography and response to treatment in the short-term follow-up (6 months), and compare elastography data between renal disease patients (AKD-P) and healthy controls (HP). RESULTS: The analyzed population consisted of 82 patients (41 HP and 41 AKD-P). The AKD-P were divided into responders (R) or non-responders (NR) based on the criteria established by the guidelines. No association was found between renal stiffness and chronic histological score. Elastography data revealed median YM values of 6.15 kPa for AKD-P and 12.2 kPa for HP, with a statistically significant difference. The median YM values of the R and NR groups were 7.4 KPa and 5.6 KPa, respectively (p = 0.037). CONCLUSIONS: Patient responsiveness was associated with YM, with lower values observed in the NR group. We also found that the healthy controls exhibited significantly higher YM values than the renal disease population.

Microplastics and Kidneys: An Update on the Evidence for Deposition of Plastic Microparticles in Human Organs, Tissues and Fluids and Renal Toxicity Concern.

Plastic pollution became a main challenge for human beings as demonstrated by the increasing dispersion of plastic waste into the environment. Microplastics (MPs) have become ubiquitous and humans are exposed daily to inhalation or ingestion of plastic microparticles. Recent studies performed using mainly spectroscopy or spectrometry-based techniques have shown astounding evidence for the presence of MPs in human tissues, organs and fluids. The placenta, meconium, breast milk, lung, intestine, liver, heart and cardiovascular system, blood, urine and cerebrovascular liquid are afflicted by MPs' presence and deposition. On the whole, obtained data underline a great heterogeneity among different tissue and organs of the polymers characterized and the microparticles' dimension, even if most of them seem to be below 50-100 µm. Evidence for the possible contribution of MPs in human diseases is still limited and this field of study in medicine is in an initial state. However, increasing studies on their toxicity in vitro and in vivo suggest worrying effects on human cells mainly mediated by oxidative stress, inflammation and fibrosis. Nephrological studies are insufficient and evidence for the presence of MPs in human kidneys is still lacking, but the little evidence present in the literature has demonstrated histological and functional alteration of kidneys in animal models and cytotoxicity through apoptosis, autophagy, oxidative stress and inflammation in kidney cells. Overall, the manuscript we report in this review recommends urgent further study to analyze potential correlations between kidney disease and MPs' exposure in human.

Rationale for the evaluation of renal functional reserve in allogeneic stem cell transplantation candidates: a pilot study.

Background: The main purpose of our study was to evaluate the ability of renal functional reserve (RFR) to stratify the risk of acute kidney injury (AKI) occurrence within 100 days of hematopoietic stem cell transplantation (HSCT) and to predict any functional recovery or the onset of chronic kidney disease. A secondary aim was to identify the clinical/laboratory risk factors for the occurrence of AKI. Methods: The study design is prospective observational. We enrolled 48 patients with normal basal glomerular filtration rate (bGFR) who underwent allogenic HSCT. A multiparameter assessment and the Renal Functional Reserve Test (RFR-T) using an oral protein load stress test were performed 15 days before the HSCT. Results: Different RFRs corresponded to the same bGFR values. Of 48 patients, 29 (60%) developed AKI. Comparing the AKI group with the group that did not develop AKI, no statistically significant difference emerged in any characteristic related to demographic, clinical or multiparameter assessment variables except for the estimated GFR (eGFR). eGFR ≤100 mL/min/1.73 m2 was significantly related to the risk of developing AKI (Fisher's exact test, P = .001). Moreover, RFR-T was lower in AKI+ patients vs AKI- patients, but did not allow statistical significance (28% vs 40%). In AKI patients, RFR >20% was associated with complete functional recovery (one-sided Fisher's exact test, P = .041). The risk of failure to recover increases significantly when RFR ≤20% (odds ratio = 5.50, 95% confidence interval = 1.06-28.4). Conclusion: RFR identifies subclinical functional deterioration conditions essential for post-AKI recovery. In our cohort of patients with no kidney disease (NKD), the degree of pre-HSCT eGFR is associated with AKI risk, and a reduction in pre-HSCT RFR above a threshold of 20% is related to complete renal functional recovery post-AKI. Identifying eGFR first and RFR second could help select patients who might benefit from changes in transplant management or early nephrological assessment.

Brief Communication PD1-related Nephrotoxicity: Optimizing Its Clinical Management Through Histopathologic Features.

Immune-related nephrotoxicity (ir-N) is a rare adverse event of immune-checkpoint(s) inhibitors (ICI) therapy and its clinical management is still debated. Among 501 consecutive ICI-treated patients at our Institution, 6 who developed an ir-N with clinical signs suggestive for an acute kidney injury underwent kidney biopsy. Histology showed an acute tubule-interstitial nephritis, simulating the scenario of acute T-cell-mediated kidney transplant rejection. Thus, the management of allograft kidney rejection routinely utilized at our clinic was implemented, leading to rapid renal function improvement. Histologic features supporting the definition of an immune-mediated acute kidney injury in ICI-treated patients may help optimizing the clinical management of ir-N.

Exposure to b-LED Light While Exerting Antimicrobial Activity on Gram-Negative and -Positive Bacteria Promotes Transient EMT-like Changes and Growth Arrest in Keratinocytes.

While blue LED (b-LED) light is increasingly being studied for its cytotoxic activity towards bacteria in therapy of skin-related infections, its effects on eukaryotic cells plasticity are less well characterized. Moreover, since different protocols are often used, comparing the effect of b-LED towards both microorganisms and epithelial surfaces may be difficult. The aim of this study was to analyze, in the same experimental setting, both the bactericidal activity and the effects on human keratinocytes. Exposure to b-LED induced an intense cytocidal activity against Gram-positive (i.e, Staphylococcus aureus) and Gram-negative (i.e., Pseudomonas aeruginosa) bacteria associated with catheter-related infections. Treatment with b-LED of a human keratinocyte cell line induced a transient cell cycle arrest. At the molecular level, exposure to b-LED induced a transient downregulation of Cyclin D1 and an upregulation of p21, but not signs of apoptosis. Interestingly, a transient induction of phosphor-histone γ-H2Ax, which is associated with genotoxic damages, was observed. At the same time, keratinocytes underwent a transient epithelial to mesenchymal transition (EMT)-like phenotype, characterized by E-cadherin downregulation and SNAIL/SLUG induction. As a functional readout of EMT induction, a scratch assay was performed. Surprisingly, b-LED treatment provoked a delay in the scratch closure. In conclusion, we demonstrated that b-LED microbicidal activity is associated with complex responses in keratinocytes that certainly deserve further analysis.

[The genetic basis of post-bone marrow transplant thrombotic microangiopathy: is this the last piece of the puzzle?]

Transplant-associated thrombotic microangiopathy (TA-TMA) is a complication of hematopoietic stem cell transplantation (HSCT) associated with kidney injury and significant mortality. Recent studies indicate that dysregulation of the alternate complement pathway may be at the basis of the development of TA-TMA. Currently, there are no pre-transplant screening tools to identify patients at risk. To explore the mechanism of TA-TMA, we performed a genetic study that allowed us to identify the deletion of the CFHR3-CFHR1 region in homozygosity. We report the clinical case of a 47-year-old woman who underwent haploidentical HSCT complicated by TA-TMA confirmed by renal biopsy. The patient discontinued treatment with calcineurin inhibitors (potential inducers of TA-TMA) with a brief introduction of prednisone until complete resolution of renal damage and microangiopathy. Identifying genetic variants that affect the mechanism of the alternate complement pathway could help in the stratification of the risk of TA-TMA and in implementing a personalized therapeutic approach.

Serum Cardiac Biomarkers in Asymptomatic Hemodialysis Patients: Role of Soluble Suppression of Tumorigenicity-2.

INTRODUCTION: Cardiovascular events (CVE) remain the leading cause of mortality in hemodialysis (HD) patients. The ability to assess the risk of short-term CVE is of great importance. Soluble suppression of tumorogenicity-2 (sST2) is a novel biomarker that better stratifies risk of CVE than troponins in patients with heart failure. Few studies have investigated the role of sST2 in the HD population. The aim of this single-center study was to assess the predictive ability of sST2 on CVE in comparison to high-sensitive cardiac troponin I (hs-cTnI) and B-type natriuretic peptide (BNP) in HD patients. METHODS: This study used a prospective, observational cohort design. We enrolled 40 chronic HD patients asymptomatic for chest pain and without recent history of acute coronary syndrome. We tested sST2 pre-/post-HD, hs-cTnI, and BNP. Demographic/dialytic/echocardiographic data were evaluated. We recorded the number of CVE for 12 months. The patients were classified into 2 groups: those who developed CVE and those who did not. RESULTS: Ten of the 40 patients (25%) developed CVE during a 12-month follow-up. Increased sST2 levels (p < 0.0001) as well as hs-cTnI and BNP are predictive of CVE. When analyzing biomarkers as binary variables for values above or below the normal range, the correlation remained significant only for sST2 (p = 0.001). A small variation in sST2 levels before and after HD sessions was found (-2.1 ng/mL). sST2 was correlated with left ventricular (LV) echocardiographic data: LV mass index (p = 0.0001), LV ejection fraction (p = 0.01), and diastolic bulging of septum (p = 0.015). BNP and sST2 combination increased the prediction of CVE in a statistical model. CONCLUSION: Our study confirms that sST2 is useful for stratifying CV risk in the HD population. sST2 can be evaluated simply as a dichotomous value higher or lower than the normal range, making it easily interpretable. Dialysis and residual diuresis did not affect significantly sST2. A multimarker approach that incorporates sST2 and BNP may improve the prediction of CVE.

Monitoring the Patient Following Radio-Cephalic Arteriovenous Fistula Creation: Current Perspectives.

Autogenous radial-cephalic direct wrist arteriovenous fistula (RC-AVF) in the non-dominant arm is the gold standard for dialysis vascular access. However, the RC-AVF non-maturation rate is significant (≃ 40%) due to an increasingly elderly and comorbid population incidence. A detailed identification of the biological cascade underlying arteriovenous fistula (AVF) maturation could be the key to clinical research aimed at identify the group of patients at risk of primary AVF failure. Currently, careful post-operative monitoring remains the most crucial aspect to overcome the problem of impaired maturation. Up to 80% of patients with immature RC-AVF have problems potentially solvable with early endovascular or surgical correction. Physical examination by experienced practitioners in conjunction with duplex ultrasound examination (DUS) can identify physical signs of non-maturation, understand the underlying cause, and drive for a tailored early planning to treat the complication. New approaches for the early assessment of AVF maturation are under study. Techniques to promote RC-AVF maturation performed through the administration of pre-or peri-operative drugs have missed up to now to prove an efficacy in improving fistula success. The new techniques tested after surgery appear to hold future promise for improving fistula maturation.

First case report of using Ofatumumab in kidney transplantation AB0 incompatible. / PRIMO CASE REPORT DI UTILIZZO DELL' OFATUMUMAB NEL TRAPIANTO RENALE AB0 INCOMPATIBILE.

Modern methods for desensitization protocol rely heavily on combined apheresis therapy and Rituximab, a chimeric (murine and human) anti-CD20 antibody used in AB0 incompatible kidney transplants. Severe infusion related reactions due to the administration of Rituximab are reported in 10% of patients. These adverse reactions may hinder the completion of the desensitization protocol. Therefore, it's useful to test alternative B cell depleting therapies. Our clinical case focuses on a 41-year-old male who developed an adverse infusion reaction following the administration of Rituximab and was given Ofatumumab as an alternative treatment. Ofatumumab is a fully humanized monoclonal anti-CD20 antibody. As a fully humanized antibody, Ofatumumab may avoid immunogenic reactions. The patient tolerated the administration of the drug showing no signs of adverse side effects and with good clinical efficacy. Our case report suggest that Ofatumumab is a valid alternative B cell depleting agent.

Encapsulating peritoneal sclerosis.

The purpose of this best practice is to briefly define what has now been accepted regarding encapsulating peritoneal sclerosis (EPS), highlighting the latest developments and outlining future lines of research. The medical therapy that can be proposed (to be discussed individually, verifying the individual features of the patient) appears to include steroids, tamoxifen, and sirolimus or everolimus, with blood levels maintained at reference values for post-transplantation therapy. In view of the high incidence of relapse also in responders, it appears appropriate to continue therapy for prolonged periods, at least for 6 months. Moreover, a surgical assessment is indicated, especially for patients with intestinal symptoms including subocclusion status. To date the prevention of EPS is an unresolved issue. The recommended measures include the accurate prevention and best treatment of acute peritonitis, the use of biocompatible dialysis fluids (there is no consensus on their exact definition) and the monitoring of ultrafiltration characteristics and peritoneal membrane transport. Other recommended measures are the extensive use of renin-angiotensin- aldosterone axis inhibitors for the treatment of arterial hypertension in PD and the exclusion of beta- blockers. Other suggested strategies are tamoxifen prophylaxis in cases at risk and to adopt personalized immunosuppressive protocols for patients with PD who undergo renal transplantation.