Cefepime-induced encephalopathy in an older patient with polypharmacy and renal insufficiency: a case report.

The world population is rapidly aging. Societal aging poses many challenges for individuals, families, nations, and the global healthcare system. Therefore, geriatric care is a crucial issue that demands our attention. In this case report, we describe a woman in her early 70s with multiple comorbidities, polypharmacy, and renal insufficiency who developed cefepime-induced encephalopathy with moderate to severe cerebral dysfunction during treatment of a urinary tract infection. The patient's consciousness level gradually improved, and no further seizures were observed following the discontinuation of cefepime for several days. This case report underscores the fact that polypharmacy and medication safety are significant concerns that are often overlooked when caring for older patients. The report also highlights the increased susceptibility of older individuals to antibiotic-associated adverse reactions during the management of infectious diseases. Therefore, optimization of antibiotic therapy for older patients is a critical issue that requires thorough investigation and consideration in geriatric care.

Integrated analysis of blood DNA methylation, genetic variants, circulating proteins, microRNAs, and kidney failure in type 1 diabetes.

Variation in DNA methylation (DNAmet) in white blood cells and other cells/tissues has been implicated in the etiology of progressive diabetic kidney disease (DKD). However, the specific mechanisms linking DNAmet variation in blood cells with risk of kidney failure (KF) and utility of measuring blood cell DNAmet in personalized medicine are not clear. We measured blood cell DNAmet in 277 individuals with type 1 diabetes and DKD using Illumina EPIC arrays; 51% of the cohort developed KF during 7 to 20 years of follow-up. Our epigenome-wide analysis identified DNAmet at 17 CpGs (5'-cytosine-phosphate-guanine-3' loci) associated with risk of KF independent of major clinical risk factors. DNAmet at these KF-associated CpGs remained stable over a median period of 4.7 years. Furthermore, DNAmet variations at seven KF-associated CpGs were strongly associated with multiple genetic variants at seven genomic regions, suggesting a strong genetic influence on DNAmet. The effects of DNAmet variations at the KF-associated CpGs on risk of KF were partially mediated by multiple KF-associated circulating proteins and KF-associated circulating miRNAs. A prediction model for risk of KF was developed by adding blood cell DNAmet at eight selected KF-associated CpGs to the clinical model. This updated model significantly improved prediction performance (c-statistic = 0.93) versus the clinical model (c-statistic = 0.85) at P = 6.62 × 10-14. In conclusion, our multiomics study provides insights into mechanisms through which variation of DNAmet may affect KF development and shows that blood cell DNAmet at certain CpGs can improve risk prediction for KF in T1D.

Plasmapheresis combined with rituximab treatment of a case of thrombotic thrombocytopenic purpura with Sjögren syndrome and renal impairment: A case report.

RATIONALE: Thrombotic thrombocytopenic purpura (TTP) is a rare thrombotic microangiopathy caused by reduced activity of the von Willebrand factor-cleaving protease (ADAMTS13), which can be life-threatening. The patient reported in this case study also had concurrent Sjögren syndrome and renal impairment, presenting multiple symptoms and posing a great challenge in treatment. PATIENT CONCERNS: A 25-year-old woman in the postpartum period visited the hospital due to indifference in consciousness for more than 1 day following cesarean section 8 days prior. DIAGNOSIS: Notable decreases were observed in platelets, hemoglobin, creatinine, and ADAMTS13 levels. After a consultative examination by an ophthalmologist, she was diagnosed with retinal hemorrhage in the right eye and dry eye syndrome in both eyes. INTERVENTIONS: Having been diagnosed with TTP with Sjögren syndrome and renal impairment, she received repeated treatments with plasmapheresis combined with rituximab. OUTCOMES: Following treatment and during the follow-up period, the patient's platelet counts and bleeding symptoms significantly improved. LESSONS: TTP has a high mortality rate, and when combined with Sjögren syndrome and renal impairment, it poses an even greater challenge in treatment. However, after administering standard plasmapheresis combined with rituximab treatment, the treatment outcome is favorable.

Safety of Janus kinase inhibitors compared to biological DMARDs in patients with rheumatoid arthritis and renal impairment: the ANSWER cohort study.

Data on the safety of Janus kinase inhibitors (JAKis) in patients with renal impairment are lacking. This study aimed to investigate the safety of JAKis compared to biological (b) DMARDs in patients with rheumatoid arthritis (RA) and renal impairment. We used a multi-centre observational registry of patients with RA in Japan (the ANSWER cohort). We assessed the drug retention rates of b/targeted synthetic DMARDs with different modes of action (tumour necrosis factor inhibitors (TNFis), immunoglobulins fused with cytotoxic T-lymphocyte antigen (CTLA-4-Ig), interleukin-6 receptor inhibitors (IL-6Ris), and JAKis) in patients with RA stratified by pre-treatment estimated glomerular filtration rate (eGFR) levels. The time to discontinuation of bDMARDs or JAKis was analysed using a multivariate Cox proportional hazards model This study included 3775 patients, who were classified into three groups (the normal group (eGFR ≥ 60 mL/min/1.73 m2): 2893 patients; CKDa group (eGFR 45-60 mL/min/1.73 m2): 551; and CKDb group (eGFR < 45 mL/min/1.73 m2): 331). In the CKDb group, the 12-month drug retention rate due to adverse events (AE) was the lowest in patients treated with JAKi (TNFi: 93.1%; IL-6Ri: 94.1%; CTLA-4-Ig: 92.3%; JAKi: 75.1%). In the normal and CKDa groups, drug retention rates due to AE were similar among patients treated with bDMARDs and JAKi. In contrast, drug retention rates due to inefficacy were similar between bDMARDs and JAKis in all groups. In the Cox-proportional model, in the CKDb group, TNFi, IL-6Ri, and CTLA-4-Ig showed lower incidence of drug discontinuation due to AE than JAKis (TNFi: hazard ratio = 0.23 (95% confidence interval 0.09-0.61), IL-6Ri: 0.34 (0.14-0.81), CTLA-4-Ig: 0.36 (0.15-0.89)). JAKis showed the lowest drug retention due to AE in patients with moderate-to-severe and severe renal impairment (eGFR < 45 mL/min/1.73 m2). Physicians should pay more attention to renal function when using JAKis than when using bDMARDs.

Development and validation of a nomogram for predicting the occurrence of renal dysfunction after treatment of immune checkpoint inhibitor: a retrospective case-control study.

PURPOSE: The administration of immune checkpoint inhibitors (ICIs) may lead to renal adverse events, notably including renal dysfunction. To early predict the probability of renal dysfunction after ICIs therapy, a retrospective case-control study was conducted. METHODS: Clinical information on ICIs-treated patients was collected. Multivariable logistic regression was applied to identify risk factors for renal dysfunction after ICIs treatment. Moreover, a nomogram model was developed and validated internally. RESULTS: A total of 442 patients were included, among which 35 (7.9%) experienced renal dysfunction after ICIs treatment. Lower baseline estimated glomerular filtration rate (eGFR) (OR 0.941; 95% CI 0.917 to 0.966; p<0.001), concurrent exposure of platinum(OR 4.014; 95% CI 1.557 to 10.346; p=0.004), comorbidities of hypertension (OR 3.478; 95% CI 1.600 to 7.562; p=0.002) and infection (OR 5.402; 95% CI 1.544 to 18.904; p=0.008) were found to be independent associated with renal dysfunction after ICIs treatment. To develop a predictive nomogram for the occurrence of renal dysfunction after ICIs treatment, the included cases were divided into training and validation groups in a ratio of 7:3 randomly. The above four independent risk factors were included in the model. The area under the receiver operating characteristic curves of the predictiive model were 0.822 (0.723-0.922) and 0.815 (0.699-0.930) in the training and validation groups, respectively. CONCLUSIONS: Lower baseline eGFR, platinum exposure, comorbidities of hypertension and infection were predictors of renal dysfunction in ICIs-treated patients with cancer. A nomogram was developed to predict the probability of renal dysfunction after ICIs treatment, which might be operable and valuable in clinical practice.

Re-discover the value of protein binding assessments in hepatic and renal impairment studies and its contributions in drug labels and dose decisions.

One of the key pharmacokinetic properties of most small molecule drugs is their ability to bind to serum proteins. Unbound or free drug is responsible for pharmacological activity while the balance between free and bound drug can impact drug distribution, elimination, and other safety parameters. In the hepatic impairment (HI) and renal impairment (RI) clinical studies, unbound drug concentration is often assessed; however, the relevance and impact of the protein binding (PB) results is largely limited. We analyzed published clinical safety and pharmacokinetic studies in subjects with HI or RI with PB assessment up to October 2022 and summarized the contribution of PB results on their label dose recommendations. Among drugs with HI publication, 32% (17/53) associated product labels include PB results in HI section. Of these, the majority (9/17, 53%) recommend dose adjustments consistent with observed PB change. Among drugs with RI publication, 27% (12/44) of associated product labels include PB results in RI section with the majority (7/12, 58%) recommending no dose adjustment, consistent with the reported absence of PB change. PB results were found to be consistent with a tailored dose recommendation in 53% and 58% of the approved labels for HI and RI section, respectively. We further discussed the interpretation challenges of PB results, explored treatment decision factors including total drug concentration, exposure-response relationships, and safety considerations in these case examples. Collectively, comprehending the alterations in free drug levels in HI and RI informs treatment decision through a risk-based approach.

Sex Differences in Cardiovascular Outcomes in Patients With Kidney Failure.

BACKGROUND: Cardiovascular disease is the leading cause of mortality in patients with kidney failure, and their risk of cardiovascular events is 10 to 20 times higher as compared with the general population. METHODS AND RESULTS: We evaluated 508 822 patients who initiated dialysis between January 1, 2005 and December 31, 2014 using the United States Renal Data System with linked Medicare claims. We determined hospitalization rates for cardiovascular events, defined by acute coronary syndrome, heart failure, and stroke. We examined the association of sex with outcome of cardiovascular events, cardiovascular death, and all-cause death using adjusted time-to-event models. The mean age was 70±12 years and 44.7% were women. The cardiovascular event rate was 232 per thousand person-years (95% CI, 231-233), with a higher rate in women than in men (248 per thousand person-years [95% CI, 247-250] versus 219 per thousand person-years [95% CI, 217-220]). Women had a 14% higher risk of cardiovascular events than men (hazard ratio [HR], 1.14 [95% CI, 1.13-1.16]). Women had a 16% higher risk of heart failure (HR, 1.16 [95% CI, 1.15-1.18]), a 31% higher risk of stroke (HR, 1.31 [95% CI, 1.28-1.34]), and no difference in risk of acute coronary syndrome (HR, 1.01 [95% CI, 0.99-1.03]). Women had a lower risk of cardiovascular death (HR, 0.89 [95% CI, 0.88-0.90]) and a lower risk of all-cause death than men (HR, 0.96 [95% CI, 0.95-0.97]). CONCLUSIONS: Among patients undergoing dialysis, women have a higher risk of cardiovascular events of heart failure and stroke than men. Women have a lower adjusted risk of cardiovascular mortality and all-cause mortality.

Exploring pathogenesis and biomarkers through establishment of a rat model of male infertility with liver depression and kidney deficiency.

OBJECTIVES: To establish a rat model that accurately replicates the clinical characteristics of male infertility (MI) with Liver Depression and Kidney Deficiency (LD & KD) and investigate the pathogenesis. METHODS: After subjecting the rats to chronic restraint stress (CRS) and adenine treatment, a series of tests were conducted, including ethological assessments, evaluations of reproductive characteristics, measurements of biochemical parameters, histopathological examinations, and analyses of urinary metabolites. Additionally, bioinformatics predictions were performed for comprehensive analysis. RESULTS: Compared to the control, the model exhibited significant manifestations of MI with LD & KD, including reduced responsiveness, diminished frequency of capturing estrous female rats, and absence of mounting behavior. Additionally, the kidney coefficient increased markedly, while the coefficients of the testis and epididymis decreased significantly. Sperm counts and viabilities decreased notably, accompanied by an increase in sperm abnormalities. Dysregulation of reproductive hormone levels in the serum was observed, accompanied by an upregulation of proinflammatory cytokines expressions in the liver and kidney, as well as exacerbated oxidative stress in the penile corpus cavernosum and testis. The seminiferous tubules in the testis exhibited a loose arrangement, loss of germ cells, and infiltration of inflammatory cells. Furthermore, utilizing urinary metabolomics and bioinformatics analysis, 5 key biomarkers and 2 crucial targets most closely linked to MI were revealed. CONCLUSION: The study successfully established a clinically relevant animal model of MI with LD & KD. It elucidates the pathogenesis of the condition, identifies key biomarkers and targets, and provides a robust scientific foundation for the prediction, diagnosis, and treatment of MI with LD & KD.

Novel likely pathogenic variant in the EYA1 gene causing Branchio oto renal syndrome and the exploration of pathogenic mechanisms.

OBJECTIVE: Branchio-oto-renal syndrome (BOR, OMIM#113,650) is a rare autosomal dominant disorder that presents with a variety of symptoms, including hearing loss (sensorineural, conductive, or mixed), structural abnormalities affecting the outer, middle, and inner ear, branchial fistulas or cysts, as well as renal abnormalities.This study aims to identify the pathogenic variants by performing genetic testing on a family with Branchio-oto-renal /Branchio-otic (BO, OMIM#602,588) syndrome using whole-exome sequencing, and to explore possible pathogenic mechanisms. METHODS: The family spans 4 generations and consists of 9 individuals, including 4 affected by the BOR/BO syndrome. Phenotypic information, including ear malformation and branchial cleft, was collected from family members. Audiological, temporal bone imaging, and renal ultrasound examinations were also performed. Whole-exome sequencing was conducted to identify candidate pathogenic variants and explore the underlying molecular etiology of BOR/BO syndrome by minigene experiments. RESULTS: Intra-familial variability was observed in the clinical phenotypes of BOR/BO syndrome in this family. The severity and nature of hearing loss varied in family members, with mixed or sensorineural hearing loss. The proband, in particular, had profound sensorineural hearing loss on the left and moderate conductive hearing loss on the right. Additionally, the proband exhibited developmental delay, and her mother experienced renal failure during pregnancy and terminated the pregnancy prematurely. Genetic testing revealed a novel heterozygous variant NM_000503.6: c.639 + 3 A > C in the EYA1 gene in affected family members. In vitro minigene experiments demonstrated its effect on splicing. According to the American College of Medical Genetics (ACMG) guidelines, this variant was classified as likely pathogenic. CONCLUSION: This study highlights the phenotypic heterogeneity within the same family, reports the occurrence of renal failure and adverse pregnancy outcomes in a female patient at reproductive age with BOR syndrome, and enriches the mutational spectrum of pathogenic variants in the EYA1 gene.

Predicting the risks of kidney failure and death in adults with moderate to severe chronic kidney disease: multinational, longitudinal, population based, cohort study.

OBJECTIVE: To train and test a super learner strategy for risk prediction of kidney failure and mortality in people with incident moderate to severe chronic kidney disease (stage G3b to G4). DESIGN: Multinational, longitudinal, population based, cohort study. SETTINGS: Linked population health data from Canada (training and temporal testing), and Denmark and Scotland (geographical testing). PARTICIPANTS: People with newly recorded chronic kidney disease at stage G3b-G4, estimated glomerular filtration rate (eGFR) 15-44 mL/min/1.73 m2. MODELLING: The super learner algorithm selected the best performing regression models or machine learning algorithms (learners) based on their ability to predict kidney failure and mortality with minimised cross-validated prediction error (Brier score, the lower the better). Prespecified learners included age, sex, eGFR, albuminuria, with or without diabetes, and cardiovascular disease. The index of prediction accuracy, a measure of calibration and discrimination calculated from the Brier score (the higher the better) was used to compare KDpredict with the benchmark, kidney failure risk equation, which does not account for the competing risk of death, and to evaluate the performance of KDpredict mortality models. RESULTS: 67 942 Canadians, 17 528 Danish, and 7740 Scottish residents with chronic kidney disease at stage G3b to G4 were included (median age 77-80 years; median eGFR 39 mL/min/1.73 m2). Median follow-up times were five to six years in all cohorts. Rates were 0.8-1.1 per 100 person years for kidney failure and 10-12 per 100 person years for death. KDpredict was more accurate than kidney failure risk equation in prediction of kidney failure risk: five year index of prediction accuracy 27.8% (95% confidence interval 25.2% to 30.6%) versus 18.1% (15.7% to 20.4%) in Denmark and 30.5% (27.8% to 33.5%) versus 14.2% (12.0% to 16.5%) in Scotland. Predictions from kidney failure risk equation and KDpredict differed substantially, potentially leading to diverging treatment decisions. An 80-year-old man with an eGFR of 30 mL/min/1.73 m2 and an albumin-to-creatinine ratio of 100 mg/g (11 mg/mmol) would receive a five year kidney failure risk prediction of 10% from kidney failure risk equation (above the current nephrology referral threshold of 5%). The same man would receive five year risk predictions of 2% for kidney failure and 57% for mortality from KDpredict. Individual risk predictions from KDpredict with four or six variables were accurate for both outcomes. The KDpredict models retrained using older data provided accurate predictions when tested in temporally distinct, more recent data. CONCLUSIONS: KDpredict could be incorporated into electronic medical records or accessed online to accurately predict the risks of kidney failure and death in people with moderate to severe CKD. The KDpredict learning strategy is designed to be adapted to local needs and regularly revised over time to account for changes in the underlying health system and care processes.

Safety and efficacy of nivolumab therapy in patients with metastatic renal cell carcinoma and impaired kidney function.

INTRODUCTION: Patients with renal insufficiency, usually defined as those with creatinine clearance < 40 mL/min, were excluded from pivotal clinical trials, especially in studies involving nivolumab therapy in patients with renal cell carcinoma (RCC). The aim of the study is to evaluate the efficacy and safety of nivolumab in patients with metastatic RCC (mRCC) stratified according to creatinine clearance. MATERIAL AND METHODS: Data from mRCC patients treated with nivolumab were retrospectively analyzed. Patients were classified into two categories according to their estimated glomerular filtration rate (eGFR); the first category (C1) included patients with eGFR < 40 mL/min/1.73 m2 and the second category (C2) included those with eGFR ≥ 40 mL/min/1.73 m2. RESULTS: Of the 95 patients enrolled, 1. group included 26 patients (27.4%) and 2. group included 69 patients (72.6%). None of the pts in category 1 were on hemodialysis. Overall incidence of adverse events was not statistically different between the two groups (P = .469). The overall response rate ORR was 50% in the first group and 42.0% in the second group (P = .486). Median overall survival (OS) was longer with 23.3 months in the 2. group versus 11 months in the 1. group (P = .415). CONCLUSION: Renal insufficiency is a common problem in patients with advanced renal cancer since they often undergo nephrectomy and their renal function may also worsen while receiving tyrosine kinase inhibitor therapy. We found that there is no significant difference in the safety and efficacy of nivolumab treatment between two groups. Nivolumab appears to be a safe and effective agent in patients with renal impairment.

Real-World Registry on the Pharmacotherapy of Multiple Myeloma and Associated Renal and Pulmonary Impairments in the Greater Gulf Region: Protocol for a Retrospective Real-World Data Study.

BACKGROUND: Multiple myeloma (MM) is the second-most common cancer among hematological malignancies. Patients with active disease may experience several comorbidities, including renal insufficiency and asthma, which may lead to treatment failure. The treatment of relapsed or refractory MM (RRMM) has been associated with multiple factors, causing a decline in progression-free survival as well as overall survival with subsequent lines of therapy. Data about the characteristics of this group of patients in the Greater Gulf region are lacking. OBJECTIVE: The primary objective of this study is to describe the disease characteristics and various treatment approaches or regimens used in the management of patients with RRMM in the Greater Gulf region. METHODS: We will conduct a regional, retrospective study collecting real-world and epidemiological data on patients with MM in countries of the Greater Gulf region. Medical records will be used to obtain the required data. Around 150 to 170 patients' records are planned to be retrospectively reviewed over 6 months without any cross-sectional or prospective intervention. Cases will be collected from Saudi Arabia, the United Arab Emirates, Kuwait, Oman, and Qatar. Descriptive as well as analytical statistics will be performed on the extracted data. The calculated sample size will allow us to estimate the percentages of RRMM cases with acceptable precision while complying with the challenges in light of data scarcity. We will obtain a comprehensive description of the demographic profile of patients with MM; treatment outcomes; the proportion of patients with MM with renal impairment and asthma, chronic obstructive pulmonary disease, or both at the time of diagnosis and any subsequent point; and data related to treatment lines, regimens, and MM-associated morbidities. RESULTS: Patient medical records were reviewed between June 2022 and January 2023 for eligibility and data extraction. A total of 148 patients were eligible for study inclusion, of whom 64.2% (n=95) were male and 35.8% (n=53) were female. The study is currently in its final stages of data analysis. The final manuscript is expected to be published in 2024. CONCLUSIONS: Although MM is a predominant hematological disease, data on its prevalence and patients' characteristics in the Greater Gulf region are scarce. Therefore, this study will give us real-world insights into disease characteristics and various management approaches of patients with MM in the Greater Gulf region. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/49861.

[Guideline for the diagnosis and management of multiple myeloma-related renal impairment (2024 version)].

Renal impairment is a common complication of multiple myeloma (MM). All patients with MM should be assessed for the presence and severity of renal impairment. The clinicopathological manifestations of MM-related renal impairment are diverse and complex; accordingly, except for light-chain nephropathy, which can often be diagnosed without biopsy based solely on clinical criteria, a renal biopsy is needed for an accurate diagnosis. Supportive care, such as adequate hydration, is required for all patients with MM-related renal impairment. The guideline provide the principles for dose adjustment of the drugs used for MM with renal impairment, including proteasome inhibitors, immunomodulators, monoclonal antibodies, small molecule inhibitors, and alkylating agents, as well as those used for myeloma bone disease. Autologous stem cell transplantation (ASCT) and chimeric antigen receptor T-cell immunotherapy (CAR-T) are effective in patients with moderate renal impairment and are tolerated by the patients. The Chinese Hematology Association; the Chinese Geriatrics Association, Society of Hematology; and the Chinese Research Hospital Association, Society of Nephrology asked experts to collate information on current progress in clinical research relating to MM with renal impairment. This guideline was developed based on the gathered data combined with the latest international consensus and clinical practice guidelines.