COVID-19 associated Mucormycosis (CAM): Implications for perioperative physicians - A narrative review

Mucormycosis once considered a rare disease with an incidence of 0.005 to 1.7 per million, has become one of the greatest menaces during the coronavirus disease (COVID-19) pandemic. India alone has contributed to nearly 70% of the global caseload of COVID-associated mucormycosis (CAM) and it had even been declared as a notifiable disease. Second wave of COVID-19 pandemic saw a steep rise in the incidence of mucormycosis and these patients have been presenting to anesthesiologists for various surgical procedures due to its primary or secondary sequelae. Rhino-orbito-cerebral mucormycosis (ROCM) is the commonest manifestation and is caused by Rhizopus arrhizus. Injudicious use of corticosteroids in vulnerable patients could have been a major contributing factor to the sudden rise in ROCM during the pandemic. Concerns related to anesthetic management include COVID-19 infection and post COVID sequalae, common presence of uncontrolled diabetes mellitus, possibility of difficult mask-ventilation and/or intubation, various drug therapy-associated adverse effects, and interaction of these drugs with anesthetic agents. Thorough preoperative optimization, multidisciplinary involvement, perioperative care, and vigilance go a long way in improving overall outcomes in these patients. Copyright © 2022 Saudi Journal of Anesthesia Published by Wolters Kluwer - Medknow.

Melatonin for prevention of acute kidney injury in patients treated with intravenous polymyxin B: a double-blind, placebo-controlled randomized clinical trial.

OBJECTIVES: To evaluate the effect of melatonin versus placebo on the incidence of acute kidney injury (AKI) in patients treated with polymyxin B. METHODS: We performed a single-centre, double-blind, randomized clinical trial (NCT03725267) of 30-mg oral melatonin versus placebo for patients treated with intravenous polymyxin B. Patients aged ≥18 years receiving polymyxin B for ≤48 hours were eligible. Melatonin or placebo pills were administered until the end of polymyxin B treatment or for a maximum of 14 days. The main outcome was any level of AKI. RESULTS: Eighty-eight patients were randomized: 44 in the melatonin group and 44 in the placebo group. The study ended prematurely because of polymyxin B shortage during the COVID-19 pandemic. The patients' mean age was 63.6 ± 17.3 years, and 60.2% of the patients were men. Forty-six (52.3%, 23 in each group) patients developed AKI during the follow-up period. The incidence rate of AKI was 81.9/1000 and 77.4/1000 patients per day in melatonin and placebo groups, respectively (hazard ratio, 1.09; 95% CI, 0.61-1.94; p 0.78). Renal failure and 30-day mortality were similar between the groups. Moreover, the incidence of AKI was not different in pre-specified sub-groups. DISCUSSION: Melatonin initiated in the first 48 hours of therapy did not reduce the incidence of AKI in patients treated with polymyxin B.

HIV at 40: kidney disease in HIV treatment, prevention, and cure.

Four decades after the first cases of HIV were reported, kidney disease remains an important comorbidity in people with HIV (PWH). Both HIV-associated nephropathy and immune complex kidney disease were recognized as complications of HIV infection in the early years before treatment was available. Although the introduction of effective antiretroviral therapy in the late 1990s resulted in dramatic improvements in survival and health in PWH, several commonly used antiretroviral agents have been associated with kidney injury. HIV infection and treatment may also promote the progression of comorbid chronic kidney disease due to traditional risk factors such as diabetes, and HIV is one of the strongest "second hits" for the high-risk APOL1 genotype. Unique considerations in the management of chronic kidney disease in PWH are largely related to the need for lifelong antiretroviral therapy, with potential for toxicity, drug-drug interactions, and polypharmacy. PWH who develop progressive chronic kidney disease are candidates for all modalities of kidney replacement therapy, including kidney transplantation, and at some centers, PWH may be candidates to serve as donors for recipients with HIV. Transplantation of kidney allografts from donors with HIV also offers a unique opportunity to study viral dynamics in the kidney, with implications for kidney health and for research toward HIV cure. In addition, HIV-transgenic animal models have provided important insights into kidney disease pathogenesis beyond HIV, and experience with HIV and HIV-related kidney disease has provided important lessons for future pandemics.

Renoprotective Effects of Luteolin: Therapeutic Potential for COVID-19-Associated Acute Kidney Injuries.

Acute kidney injury (AKI) has been increasingly reported in critically-ill COVID-19 patients. Moreover, there was significant positive correlation between COVID-19 deaths and renal disorders in hospitalized COVID-19 patients with underlying comorbidities who required renal replacement therapy. It has suggested that death in COVID-19 patients with AKI is 3-fold higher than in COVID-19 patients without AKI. The pathophysiology of COVID-19-associated AKI could be attributed to unspecific mechanisms, as well as COVID-19-specific mechanisms such as direct cellular injury, an imbalanced renin-angiotensin-aldosterone system, pro-inflammatory cytokines elicited by the viral infection and thrombotic events. To date, there is no specific treatment for COVID-19 and its associated AKI. Luteolin is a natural compound with multiple pharmacological activities, including anticoronavirus, as well as renoprotective activities against kidney injury induced by sepsis, renal ischemia and diverse nephrotoxic agents. Therefore, in this review, we mechanistically discuss the anti-SARS-CoV-2 and renoprotective activities of luteolin, which highlight its therapeutic potential in COVID-19-AKI patients.

Real World Experience Utilizing Donor Kidneys at Risk for Acute Kidney Injury with Belatacept Based Maintenance Immunosuppression

Purpose: The demand for kidney transplant continues to rise, and limited supply has encouraged acceptance of marginal donor organs, such as those at risk for acute kidney injury (AKI). We evaluated the utilization of such organs (defined as donation after cardiac death, pediatric donors, kidneys with a cold ischemic time >24 hrs, terminal serum creatinine (SCr) >2mg/dL or rising SCr with decreasing urine output at donation) at our center who were discharged on belatacept based maintenance immunosuppression with mycophenolate and steroids (BBMS). Method(s): This retrospective, descriptive study examined kidney transplant recipients (KTR) who received AKI organs and were discharged on BBMS between 1/2019-4/2021. Primary outcome assessed graft function and rejection at 6 & 12 months (mos) post-transplant (txp). Secondary outcomes evaluated graft failure, mortality, infection, DSA & changes to BBMS. All outcomes were evaluated at 1yr if records were available. Result(s): 68 KTR w/1 yr results & 52 w/6 mo results on BBMS were included. Baseline characteristics (Table 1) show most KTR received a DCD or en bloc organ and lymphocyte depleting induction. Mean eGFR improved from 1 to 6 mo post-txp and was stable through 1yr. Episodes of biopsy proven rejection were more common during the first 6mos post-txp. There were 2 deaths during the study period, due to COVID, and no graft failures. Twelve KTR developed DSA. There were 21 KTR with CMV viremia, mostly in moderate risk group, & 12 with BK viremia. Table 4 shows changes to BBMS occurred in 32 KTR. Most KTR required multiple BBMS changes with most common dose adjustments to mycophenolate due to leukopenia or neutropenia. Conclusion(s): Utilization of AKI organs with BBMS in KTR at our center resulted in no graft failures & sustained eGFR despite more rejection episodes during the first 6mos post-txp. Although 32 KTR had changes to BBMS, only 5 KTR had rejection following a change. Incidence of CMV was common but did not impact KTR outcomes. Overall, BBMS could be a promising option in AKI organs to avoid nephrotoxicity associated with CNI based regimens. These findings suggest the need to further evaluate the impact of long-term outcomes associated with changes made to BBMS in AKI donor organs.

DAPTOMYCIN-INDUCED EOSINOPHILIC PNEUMONITIS

SESSION TITLE: Drug-Induced Lung Injury Pathology Case Posters SESSION TYPE: Case Report Posters PRESENTED ON: 10/19/2022 12:45 pm - 01:45 pm INTRODUCTION: Daptomycin is an antibiotic that exerts its bactericidal effect by disrupting multiple aspects of bacterial cell membrane function. It has notable adverse effects including myopathy, rhabdomyolysis, eosinophilic pneumonitis, and anaphylactic hypersensitivity reactions. CASE PRESENTATION: A 46-year-old male with a history of type 2 diabetes presented with a 1-week history of dyspnea and productive cough. 2 weeks prior, he was started on vancomycin for MRSA osteomyelitis of the right foot, but was switched to daptomycin due to vancomycin induced nephrotoxicity. On presentation he was afebrile, tachycardic 100, hypertensive 183/109, tachypneic to 26, hypoxemic 84% on room air, which improved to 94% on nasal cannula. Chest exam noted coarse breath sounds in all fields and pitting edema of lower extremities were present. Labs showed leukocytosis of 15.2/L, Na of 132 mmol/L, and creatinine 3.20mg/dL (normal 1 month prior). COVID-19 testing was negative. Chest X-ray noted new bilateral asymmetric opacifications. Daptomycin was discontinued on day 1 of admission, he was started on IV diuretics and ceftaroline. Further study noted peripheral eosinophilia. Computed tomography of the chest showed bilateral centrally predominant ground-glass infiltrates with air bronchograms and subcarinal and paratracheal lymphadenopathy. On day 4, he underwent bronchoscopy with bronchoalveolar lavage. Cytology noted 4% eosinophil with 43% lymphocytes. Eventually, oxygen requirements and kidney function returned to baseline. He was discharged on ceftaroline for osteomyelitis DISCUSSION: Daptomycin-induced acute eosinophilic pneumonitis (AEP) often results in respiratory failure in the setting of exposure to doses of daptomycin >6mg/kg/day. It is characterized by the infiltration of pulmonary parenchyma with eosinophils and is often associated with peripheral eosinophilia. AEP has been associated with certain chemicals, non-steroidal anti-inflammatory agents, and antibiotics including daptomycin. Renal dysfunction is associated with an increased risk for developing AEP. The mechanism for daptomycin-induced lung injury is unknown but is believed to be related to daptomycin binding to pulmonary surfactant culminating in epithelial injury. Diagnostic criteria include recent daptomycin exposure, fever, dyspnea with hypoxemic respiratory failure, new infiltrates on chest radiography, BAL with > 25% eosinophils, and clinical improvement following daptomycin discontinuation. Our patient met four out of six criteria;we believe that BAL results were due to discontinuing daptomycin days before the procedure was performed. Sometimes stopping daptomycin is enough for recovery, however, steroids may be beneficial and were used in some of the cases reported in the literature CONCLUSIONS: Clinicians should consider AEP in a patient on Daptomycin presenting with respiratory failure, as timely discontinuation favors a good prognosis Reference #1: Uppal P, LaPlante KL, Gaitanis MM, Jankowich MD, Ward KE. Daptomycin-induced eosinophilic pneumonia - a systematic review. Antimicrob Resist Infect Control. 2016;5:55. Published 2016 Dec 12. doi:10.1186/s13756-016-0158-8 Reference #2: Kumar S, Acosta-Sanchez I, Rajagopalan N. Daptomycin-induced Acute Eosinophilic Pneumonia. Cureus. 2018;10(6):e2899. Published 2018 Jun 30. doi:10.7759/cureus.2899 Reference #3: Bartal C, Sagy I, Barski L. Drug-induced eosinophilic pneumonia: A review of 196 case reports. Medicine (Baltimore). 2018;97(4):e9688. doi:10.1097/MD.0000000000009688 DISCLOSURES: No relevant relationships by Chika Winifred Akabusi No relevant relationships by Shazia Choudry No relevant relationships by Hector Ojeda-Martinez No relevant relationships by Mario Torres

HIGH RESPONSES RATES WITH SINGLE AGENT BELANTAMAB MAFODOTIN IN RELAPSED SYSTEMIC AL AMYLOIDOSIS

Background: Systemic AL amyloidosis is an incurable relapsing plasma cell disorder. Despite therapeutic advances, there are no approved treatments for relapse disease. Treatment is often challenging due to underlying organ dysfunction. Belantamab mafodotin is an antibody-drug conjugate targeting B-cell maturation antigen with approval for relapsed refractory myeloma. In multiply pre-treated myeloma, the DREAMM-2 phase II trial showed an overall response rate of 32% for those with 2.5 mg/kg dose administered every three weeks with 2/3rd patients reporting keratopathy. A small case series of 6 patients with relapsed AL amyloidosis (Zhang et al , ASH 2021) was recently reported and a phase 2 trial is recruiting for patients with refractory amyloidosis (NCT04617925). Aims: We report our initial results using Belantamab monotherapy for the treatment of patients with AL amyloidosis with relapsed disease. Methods: Data for consecutive patients who were administered Belantamab at a specialist referral centre, National Amyloidosis Centre, University College London, was analysed. Results: Eleven patients were included 8 male, 3 female. Median age at Belantamab initiation was 65 (range 42-74) years. Eight patients had λ AL-type and three κ AL-type. At diagnosis, median involved free light-chain concentration was 534 (range 73-7181) mg/l. A median of two organs involved at baseline (range 1-3): 4 had cardiac involvement (half Mayo stage 2;half Mayo stage 3a) and 8 had renal involvement. The median prior lines of therapy was 3 (range 2-5) with all exposed to prior immunomodulatory drugs, proteasome inhibitors and 73% to anti-CD38 antibody treatments. Thirty-six percent had relapsed after melphalan-conditioned autologous stem cell transplantation. A median of 3 cycles of belantamab were delivered (range 1-8). The most frequent adverse event was ocular toxicity which was experienced in 8 patients (grade 1-3), necessitating dose modification of the three-weekly schedule. One patient developed transient grade 1 dyspnoea and liver dysfunction. No patients developed cytopenias, unlike previous reports (Zhang et al , 2021), nor infections beyond COVID (2 patients mild with no hospital admissions). The majority of the cohort required dose reduction either at initiation (patient 4, due to end stage renal failure;patient 11, post-renal transplant) or during therapy (n=5;three to 1.9mg/kg, two to 1.25mg/kg) due to ocular toxicity. Only one patient remained on the standard dose of 2.5mg/kg for >3 cycles. Ocular toxicity improved after treatment interruption (drug intervals 4-6 weeks) and no patients required complete treatment cessation. One patient is too early to assess response. Haematological responses (PR or better) were seen in 7 patients with 3 complete responses and two very good partial responses (VGPR) which are ongoing. Both renal patients (patients 4 and 11) commenced a dose of 1.25mg/kg and sustained a VGPR with no additional toxicity. Patient 3 had a 42% reduction in sFLC after two doses but then a prolonged gap due to keratopathy and has lost the response. There were no cardiac or renal toxicities observed. Summary/Conclusion: Belantamab mafodotin demonstrates significant activity in patients with heavily pre-treated AL amyloidosis with 70% achieving a ≥PR. Apart from keratopathy requiring dose modification, no other substantial toxicity was observed. Two patients with renal impairment (stage V CKD and ESRD) and one patient post-renal transplant tolerated treatment with no additional toxicity. Belantamab mafodotin shows promise in treatment of relapsed AL and needs further prospective trials.

Bromoacetic acid causes oxidative stress and uric acid metabolism dysfunction via disturbing mitochondrial function and Nrf2 pathway in chicken kidney.

Since the outbreak of COVID-19, widespread utilization of disinfectants has led to a tremendous increase in the generation of disinfection byproducts worldwide. Bromoacetic acid (BAA), one of the common disinfection byproducts in the environment, has triggered public concern because of its adverse effects on urinary system in mammals. Nevertheless, the BAA-induced nephrotoxicity and potential mechanism in birds still remains obscure. According to the detected content in the Taihu Lake Basin, the model of BAA exposure in chicken was established at doses of 0, 3, 300, 3000 µg/L for 4 weeks. Our results indicated that BAA exposure caused kidney swelling and structural disarrangement. BAA led to disorder in renal function (CRE, BUN, UA) and increased apoptosis (Bax, Bcl-2, caspase3). BAA suppressed the expression of mitochondrial biogenesis genes (PGC-1α, Nrf1, TFAM) and OXPHOS complex I genes (ND1, ND2, ND3, ND4, ND4L, ND5, ND6). Subsequently, BAA destroyed the expression of Nrf2 antioxidant reaction genes (Nrf2, Keap1, HO-1, NQO1, GCLM, GCLC). Furthermore, renal oxidative damage led to disorder in uric acid metabolism genes (Mrp2, Mrp4, Bcrp, OAT1, OAT2, OAT3) and exacerbated destruction in renal function. Overall, our study provided insights into the potential mechanism of BAA-induced nephrotoxicity, which were important for the clinical monitoring and prevention of BAA.

TOXICITY OF REMDESIVIR AS TREATMENT OF NONCRITICALLY ILL COVID-19 PATIENTS

Background and importance Remdesivir is currently included in clinical guidelines for COVID-19 treatment. Although safety data were published in ACTT-1, the toxicity of this drug in regular clinical practice is still unknown. Aim and objectives In this study we aimedd to describe remdesivir's toxicity in patients only requiring supplemental lowflow oxygen (no high-flow oxygen requirements or other noninvasive ventilation at start of treatment). Material and methods Retrospective cohort including patients treated with remdesivir following Spanish Medicines and Health Products Agency criteria (non-critical patients requiring low-flow oxygen) between August and October 2020 in a tertiary- level hospital. Exclusion criteria were being under 18 years of age and participation in clinical trials with remdesivir. The percentage of adverse reactions occurring in the 14 days following on from the beginning of treatment was the primary outcome. Secondly, the number of treatment discontinuations were assessed. Categorical variables were expressed as proportions while continuous values were formulated as median and interquartile range (IQR). Results 264 patients were included (59.2% men, mean age 66 years;IQR 54-82). In the 14 days following on from the beginning of treatment, an adverse reaction (AR) was reported in 146 (55.3%) patients. In 91 (34.5%) of them it was grade ≥2 AR, in 31 (11.7%) grade ≥3 and in 8 (3.0%) of them grade ≥4. Median of days until toxicity began was 3.5 days (IQR 1.2-9.0). The most common AR was an increase in transaminases, which happened in 114 (43.2%) patients, 29.1% of them being grade ≥3 and 3.9% grade ≥4. Regarding renal toxicity, an increase in serum creatinine occurred in 51 (19.8%) patients, 27.5% of them being grade ≥3 and 9.8% grade ≥4. One patient suffered a grade 3 anaphylactic reaction during infusion and another one developed hepatitis during the follow-up period. Two more patients suffered gastrointestinal toxicity (grade 1-2 nausea and diarrhoea). During the study period, 31 (12.1%) patients discontinued remdesivir treatment,12.5% of them due to AR or toxicity related to the drug. Conclusion and relevance Increased transaminases was the most common AR in this population, matching remdesivir's European Public Assessment Report (EPAR) specifications, followed by an increase in the serum creatinine levels (frequency not detailed on the EPAR). However, only 12.5% of treatment discontinuations were due to adverse reactions or toxicity linked to remdesivir. Further investigation is needed to unravel the degree of involvement of the drug in this toxicity.

ACUTE RENAL FAILURE IN COVID-19 PATIENTS IN A LATIN AMERICAN HEALTH INSTITUTION

BACKGROUND AND AIMS: Acute renal failure in hospitalized patients for COVID- 19 occurs in 3%-28% and is a poor prognostic factor. The mechanisms of renal involvement are not completely clarified. However, it has been evaluated that the presentation of renal failure increases adverse outcomes. METHOD: Prospective observational study of all the cases that were admitted for COVID-19 between January and December 2021. Clinical and analytical data of kidney complications in patients with COVID-19 were collected. RESULTS: A total of 306 patients with a mean age of 70.2 years, 75.1% men and with previous chronic kidney disease in 29.7% were analyzed. A total of 50.8% had severe pneumonia or acute respiratory distress syndrome and 22.9% required admission to the ICU. Proteinuria was registered in 77.6% and hematuria in 67.6%. A total of 20.9% of the patients required renal replacement therapy. Renal failure was of prerenal etiology in 59.2%, acute tubular necrosis in the context of sepsis in 23.5%, glomerular in 8.1% and due to tubular toxicity in 9.2%. The median stay was 15 days, and 31.7% died. Patients who developed kidney failure during admission had higher C-reactive protein, LDH, and D-dimer values, more severe lung involvement, more need for ICU admission, and greater need for renal replacement therapy. CONCLUSION: Hypovolemia and dehydration are common causes of acute kidney injury in COVID-19 patients. Those who develop renal complications have a worse pulmonary, renal and systemic prognosis profile. We point out that monitoring an individualized management of blood volume can be decisive in preventing worse outcomes.

COVID-19-RELATED ASPECTS OF MORPHOLOGICAL AND PATHOPHYSIOLOGICAL CHANGES IN THE KIDNEYS

The paper presents the pathomorphological changes in the kidneys of patients, who died from severe COVID-19, and analyzed the literature to substantiate the possible pathophysiological patterns of their development. The material for the study was pieces of kidneys taken during autopsy of 16 deceased with severe COVID-19 without a history of kidney disease. Pathological changes in COVID-19-related acute kidney injury were manifested by non-specific changes in the glomeruli, the presence of blood clots in the blood vessels, dystrophy, necrosis, and desquamation of the epithelial cells of the nephron tubules. Pathological changes in the kidney structures resulted from both the direct nephrotoxic effect of the SARS-CoV-2 virus and the indirect effect of systemic hypoxia, hypercoagulation, hyperventilation. Moreover, cross-organ damage covering the lung-kidney and heart-kidney axes was not excluded. Systemic endothelial dysfunction presumably plays one of the key roles in the development of acute kidney injury. Thus, the present study reveals the potential pathogenetic links of COVID-19-related acute kidney injury.

Remdesivir in the Treatment of COVID-19: A Propensity Score-Matched Analysis from a Public Hospital in New York City Assessing Renal and Hepatic Safety.

While the relative efficacy of remdesivir as a therapeutic agent in selected patients with COVID-19 has been established, safety concerns have been raised regarding potential nephrotoxicity and hepatotoxicity. Our main objective was to investigate the kidney- and liver-related safety outcomes in patients with COVID-19 treated with remdesivir in a public hospital in New York. A propensity score-matched retrospective study was conducted in hospitalized patients with COVID-19 from 1 June 2020 to 10 March 2021. A total of 927 patients were included in this study (remdesivir: 427, non-remdesivir: 500; women: 51.8%; median age 61 years; median BMI: 28.5 kg/m2). Matching without replacement yielded a cohort of 248 patients (124 in each group). In the matched cohort, the remdesivir group had a significantly lower rate of acute kidney injury (AKI) (12.1% vs. 21.8%, p = 0.042), a lower rate of acute liver injury (ALI) on the verge of statistical significance (7.3% vs. 14.5%, p = 0.067), and non-significantly lower death rate (13.7% vs. 16.1%, p = 0.593) compared to the non-remdesivir group. Multivariable analyses revealed that patients treated with remdesivir were found to be associated with a significantly lower likelihood for AKI (OR: 0.40; 95% CI: 0.24-0.67, p < 0.001), no association was found for ALI (OR: 0.68; 95% CI: 0.35-1.30, p = 0.241), while a trend towards an association of patients treated with remdesivir with a lower likelihood for in-hospital death was observed (OR: 0.57; 95% CI: 0.32-1.01, p = 0.053). In conclusion, no safety concerns with regards to renal and liver outcomes were raised in patients with COVID-19 treated with remdesivir. Instead, there were signals of possible nephroprotection and improved in-hospital mortality.

A Review on Current Side Effects of Used Drugs During Treatment of Patients With COVID-19

Background: Coronavirus disease 2019 (COVID-19) is a contagious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). To increase the success in treating patients with COVID-19, many drug suggestions and some clinical studies are shared in the literature. However, the combination of several drugs with other clinical care has improved patients’ conditions. And this review discusses some side effects of Covid-19 drugs’ adverse effects. Objectives: Here, we have shortly reported the recent updates on the most common and plausible drugs for treating COVID-19 patients. We also compare these treatment options based on their impact on symptom management, inpatient length of stay, and overall morbidity and mortality. Methods: An extensive literature search was performed through PubMed, Scopus, Web of Science, and Google Scholar. Most of the keywords used were: "COVID-19", "Side effects of used drugs," "Treatment of COVID-19", "Risk factors," "Organ damage," and "Methods of diagnosis and treatment." Results: Anti-inflammatory, antimicrobial, and vitamin supplements do not have obvious benefits, but there is limited information to consider. Other factors and drugs such as improved plasma, eculizumab, immunoglobulins, IgG1-neutralizing monoclonal antibodies, remidseiver, steroids, and tosilizumab have shown potential effects on patient’s length of hospital stay and mortality. Currently, there is no evidence that any other vaccines, apart from those specifically designed for the SARS-Cov-2 virus, will protect against COVID-19. Conclusion: Since the prevention of the COVID-19 virus is a new issue in the medical world, there is no known effective treatment option in this area, and the prevention of its adverse side effects has not been conclusively proven. Of course, the occurrence of side effects in patients undergoing treatment such as hepatotoxicity, retinal damage, nephrotoxicity, and cardiotoxicity proves that the necessary caution should be used in drug combination methods.

Are we looking for Monoclonal Gammopathy of Renal Significance ( MGRS )? An audit of investigations in current clinical practice

Monoclonal gammopathy of unknown significance (MGUS) is a premalignant condition defined as the presence of a monoclonal protein with no evidence of plasma cell/B-cell-related malignancy. The risk of progression from MGUS to a related malignancy is approximately 1% per year. MGUS patients are closely monitored for signs of progression allowing for rapid initiation of treatment. In 2012, the International Kidney and Monoclonal Gammopathy Research Group (IKMG) introduced the term Monoclonal Gammopathy of Renal Significance (MGRS). MGRS is the clonal proliferation of a nephrotoxic monoclonal protein without meeting the criteria for any other plasma cell/B-cell malignancy. The diagnosis of MGRS allows for the initiation of urgent treatment required to prevent further deterioration in renal function. Updated diagnostic criteria from the IKMG made renal biopsy essential for diagnosis of MGRS. Consequently, the IKMG set out an algorithm to guide clinicians on when to consider a renal biopsy. The parameters measured to evaluate the need for a renal biopsy include urine albumin creatinine ratio (ACR). This audit was conducted in the Clatterbridge Cancer Centre Liverpool (CCC-L) a leading cancer centre in the Northwest of England. Urine ACR was chosen as the parameter to audit as it is a cheap, non-invasive, quantitative investigation. The primary outcome of this audit is to assess the number of MGUS patients who had an ACR measured at diagnosis in the Myeloma clinic from January 2014 to December 2020. Data were collected retrospectively from electronic clinic letters and notes. The date of diagnosis was defined as the date of clinic letter in which diagnosis was first confirmed. Patients were considered to have had an ACR performed at diagnosis if ACR was measured between 28 days prior to and post the date of diagnosis. ACR performed during disease was defined as any ACR measured from 28 days prior to date of diagnosis and date of death/data collection. Data from 503 patients (249 females, 254 males) were analysed. The median age at diagnosis was 73. Table 1 shows data for patients who had an ACR measurement performed at diagnosis and during disease. There is a trend towards greater compliance to measuring ACR at diagnosis in successive years from 2014 to 2019 (Table 1). This trend reverses in 2020 when only 40.0% of patients had an ACR measured at diagnosis. For all patients where ACR was performed during disease;56.8% ( n = 179) had the highest ACR measurement of <3.0 mg/mmol with only 14.0% ( n = 44) having the highest ACR measurement of >30.0 mg/mmol. If ACR was performed at diagnosis it was more commonly repeated if the value was higher;the frequencies with which ACR was repeated were 85.7% ( n = 12), 65.1% ( n = 28) and 28.4% ( n = 31) when ACR value at diagnosis was >30.0 mg/mmol, 3.0-30.0 mg/mmol and <3.0 mg/mmol respectively. This audit has shown an increased recognition for the importance of ACR measurement with increased compliance year on year. A likely hypothesis for the reduced measurements in 2020 is the need for remote clinic appointments during the Coronavirus 2019 (Covid-19) pandemic. Following IKMG guidelines 14.0% ( n = 44) of patients would be advised to have a renal biopsy due to their ACR measurement of >30.0 mg/ mmol. Further evaluation of this patient cohort is required to audit compliance with other parameters suggested by the IKMG. A diagnostic pathway to be used at the earliest opportunity for MGUS patients may then be developed..

Tolerability and epidemiology of nephrotoxicity associated with conventional amphotericin B therapy: a retrospective study in tertiary care centers in Palestine.

BACKGROUND: In the light of recent years, an increase in the number of life-threatening infections due to various fungi has been observed, especially in tertiary care centres. With Amphotericin B labelled as the first choice in treating these infections, one of its common side effects, nephrotoxicity, along with hypokalemia, were studied to determine the epidemiology, risk factors, and protective measures. METHODOLOGY: The study was a retrospective observational chart review study in which patients were receiving conventional Amphotericin B in two tertiary hospitals in Palestine from January 2018 to December 2020 were evaluated for the development of hypokalemia and nephrotoxicity; according to the KDIGO criteria. A total of 117 patients were included in the study. Patients who have received the drug intermittently, in fewer than two doses, through non-IV routes and patients under the age of 12 were excluded. The data collected included, but were not limited to, age, gender, comorbidities, Amphotericin B treatment details, medications, COVID-19 status, risk factors, and hypothesized protective measures. RESULTS: The incidence of conventional Amphotericin B nephrotoxicity and hypokalemia was 46% and 33%, respectively. With a roughly equal representation of both genders and a median age of 52 years in a range of 13-89. No association between the variables and the development of nephrotoxicity was found. However, a 3.4 increased risk (p-value = 0.01) of developing hypokalemia in females compared to males was observed. CONCLUSION: Our research has shown a relatively lower yet consistent, incidence of conventional amphotericin B nephrotoxicity and hypokalemia compared to literature with gender being a risk factor for developing hypokalemia.

Current update on theranostic roles of cyclophilin A in kidney diseases

Cyclophilin A (CyPA) or peptidylprolyl isomerase A (PPIA), an immunophilin with peptidyl-prolyl cis/trans isomerase (PPIase) activity, is an abundant cellular protein widely expressed across various cell types and tissues, including the kidney. Expression of CyPA in the kidney is relatively higher in proximal tubular epithelial cells than others along the nephron. Alterations in expression and secretion of CyPA play important roles in physiological processes and pathophysiology of several diseases affecting the kidney. Herein, we provide a brief overview of CyPA structural biology and present the current update on its theranostic roles in various kidney diseases, including diabetic nephropathy, acute kidney injury, chronic kidney disease, renal fibrosis, and nephrotoxicity associated with organ transplantation. Notably, the diagnostic/prognostic role for urinary CyPA in several of these kidney diseases is promising. Finally, future perspectives on the CyPA research, especially targeting CyPA for therapeutics, are discussed. A comprehensive understanding of the theranostic roles of CyPA in kidney diseases is expected to provide novel insights into the design of new therapeutic interventions and prevention strategies.

The potential of remdesivir to affect function, metabolism and proliferation of cardiac and kidney cells in vitro.

Remdesivir is a prodrug of a nucleoside analog and the first antiviral therapeutic approved for coronavirus disease. Recent cardiac safety concerns and reports on remdesivir-related acute kidney injury call for a better characterization of remdesivir toxicity and understanding of the underlying mechanisms. Here, we performed an in vitro toxicity assessment of remdesivir around clinically relevant concentrations (Cmax 9 µM) using H9c2 rat cardiomyoblasts, neonatal mouse cardiomyocytes (NMCM), rat NRK-52E and human RPTEC/TERT1 cells as cell models for the assessment of cardiotoxicity or nephrotoxicity, respectively. Due to the known potential of nucleoside analogs for the induction of mitochondrial toxicity, we assessed mitochondrial function in response to remdesivir treatment, early proteomic changes in NMCM and RPTEC/TERT1 cells and the contractile function of NMCM. Short-term treatments (24 h) of H9c2 and NRK-52E cells with remdesivir adversely affected cell viability by inhibition of proliferation as determined by significantly decreased 3H-thymidine uptake. Mitochondrial toxicity of remdesivir (1.6-3.1 µM) in cardiac cells was evident by a significant decrease in oxygen consumption, a collapse of mitochondrial membrane potential and an increase in lactate secretion after a 24-48-h treatment. This was supported by early proteomic changes of respiratory chain proteins and intermediate filaments that are typically involved in mitochondrial reorganization. Functionally, an impedance-based analysis showed that remdesivir (6.25 µM) affected the beat rate and contractility of NMCM. In conclusion, we identified adverse effects of remdesivir in cardiac and kidney cells at clinically relevant concentrations, suggesting a careful evaluation of therapeutic use in patients at risk for cardiovascular or kidney disease.

Traditional Chinese medicine-associated nephrotoxicity and the importance of herbal interactions – an overview

Herbal traditional Chinese medicines (TCMs) are an increasingly popular alternative therapy globally. Due to the complex chemical composition of herbal products, and with research showing that consumers from Western countries are more likely to take multiple herbal products at one time, the lack of understanding of the potential side effects of herbal TCM may pose a significant risk to health and wellbeing. This may be particularly so now that herbal preparations are being promoted for the prevention and treatment of COVID-19 symptoms, often in association with Western medicines such as paracetamol. Of interest are the potential adverse effects of herbal TCMs on the kidney. Many factors can lead to the development of renal injury including intrinsic toxicity, plant misidentification, adulteration, contamination, and of increasing importance, interactions with conventional drugs and other herbs. This review evaluates and summarises some of the key aspects of TCM-induced nephrotoxicity and the current scope of herb-drug and herb-herb interaction that may cause adverse effects.