Sarcopenia, adiposity and large discordance between cystatin C and creatinine-based estimated glomerular filtration rate in patients with cancer.

BACKGROUND: Creatinine-based estimated glomerular filtration rate (eGFRCRE) may overestimate kidney function in patients with sarcopenia. While cystatin C-based eGFR (eGFRCYS) is less affected by muscle mass, it may underestimate kidney function in patients with obesity. We sought to evaluate the relationship between body composition defined by computed tomography (CT) scans and discordance between creatinine, eGFRCRE and eGFRCYS in adult patients with cancer. METHODS: This study is a cross-sectional study of consecutive adults with cancer with an abdominal CT scan performed within 90 days of simultaneous eGFRCRE and eGFRCYS measurements between May 2010 and January 2022. Muscle and adipose tissue cross-sectional areas were measured at the level of the third lumbar vertebral body using a validated deep-learning pipeline. CT-defined sarcopenia was defined using independent sex-specific cut-offs for skeletal muscle index (<39 cm2/m2 for women and <55 cm2/m2 for men). High adiposity was defined as the highest sex-specific quartile of the total (visceral plus subcutaneous) adiposity index in the cohort. The primary outcome was eGFR discordance, defined by eGFRCYS > 30% lower than eGFRCRE; the secondary outcome was eGFRCYS > 50% lower than eGFRCRE. The odds of eGFR discordance were estimated using multivariable logistic regression modelling. Unadjusted spline regression was used to evaluate the relationship between skeletal muscle index and the difference between eGFRCYS and eGFRCRE. RESULTS: Of the 545 included patients (mean age 63 ± 14 years, 300 [55%] females, 440 [80.7%] non-Hispanic white), 320 (58.7%) met the criteria for CT-defined sarcopenia, and 136 (25%) had high adiposity. A total of 259 patients (48%) had >30% eGFR discordance, and 122 (22.4%) had >50% eGFR discordance. After adjustment for potential confounders, CT-defined sarcopenia and high adiposity were both associated with >30% eGFR discordance (adjusted odds ratio [aOR] 1.90, 95% confidence interval [CI] 1.12-3.24; aOR 2.01, 95% CI 1.15-3.52, respectively) and >50% eGFR discordance (aOR 2.34, 95% CI 1.21-4.51; aOR 2.23, 95% CI 1.19-4.17, respectively). A spline model demonstrated that as skeletal muscle index decreases, the predicted difference between eGFRCRE and eGFRCYS widens considerably. CONCLUSIONS: CT-defined sarcopenia and high adiposity are both independently associated with large eGFR discordance. Incorporating valuable information from body composition analysis derived from CT scans performed as a part of routine cancer care can impact the interpretation of GFR estimates.

Adverse kidney outcomes of CDK 4/6 inhibitors for metastatic breast cancer.

Cyclin-dependent kinase (CDK) 4/6 inhibitors have significantly improved overall and progression free survival of patients with metastatic breast cancer, but their effect on short and long-term kidney function is unknown. We found that early, mild estimated glomerular filtration rate (eGFR) decline was common in patients treated with CDK 4/6 inhibitors; however, severe kidney injury is rare and long-term eGFR decline is uncommon.

Medication-Related Adverse Events and Discordancies in Cystatin C-Based vs Serum Creatinine-Based Estimated Glomerular Filtration Rate in Patients With Cancer.

Importance: Serum creatinine-based estimated glomerular filtration rate (eGFRcr) may overestimate the glomerular filtration rate (GFR) in patients with cancer. Cystatin C-based eGFR (eGFRcys) is an alternative marker of GFR. Objective: To determine whether the therapeutic drug levels and adverse events (AEs) associated with renally cleared medications were higher in patients with cancer whose eGFRcys was more than 30% lower than their eGFRcr. Design, Setting, and Participants: This cohort study analyzed adult patients with cancer at 2 major academic cancer centers in Boston, Massachusetts. These patients had their creatinine and cystatin C measured on the same day between May 2010 and January 2022. The date of the first simultaneous eGFRcr and eGFRcys measurement was considered to be the baseline date. Exposure: The primary exposure was eGFR discordance, defined as an eGFRcys that was more than 30% lower than the eGFRcr. Main Outcomes and Measures: The primary outcome was risk of the following medication-related AEs within 90 days of the baseline date: (1) supratherapeutic vancomycin trough level greater than 30 µg/mL, (2) trimethoprim-sulfamethoxazole-related hyperkalemia (>5.5 mEq/L), (3) baclofen toxic effect, and (4) supratherapeutic digoxin level (>2.0 ng/mL). For the secondary outcome, a multivariable Cox proportional hazards regression model was used to compare 30-day survival of those with vs without eGFR discordance. Results: A total of 1869 adult patients with cancer (mean [SD] age, 66 [14] years; 948 males [51%]) had simultaneous eGFRcys and eGFRcr measurement. There were 543 patients (29%) with an eGFRcys that was more than 30% lower than their eGFRcr. Patients with an eGFRcys that was more than 30% lower than their eGFRcr were more likely to experience medication-related AEs compared with patients with concordant eGFRs (defined as eGFRcys within 30% of eGFRcr), including vancomycin levels greater than 30 µg/mL (43 of 179 [24%] vs 7 of 77 [9%]; P = .01), trimethoprim-sulfamethoxazole-related hyperkalemia (29 of 129 [22%] vs 11 of 92 [12%]; P = .07), baclofen toxic effects (5 of 19 [26%] vs 0 of 11; P = .19), and supratherapeutic digoxin levels (7 of 24 [29%] vs 0 of 10; P = .08). The adjusted odds ratio for vancomycin levels more than 30 µg/mL was 2.59 (95% CI, 1.08-7.03; P = .04). Patients with an eGFRcys more than 30% lower than their eGFRcr had an increased 30-day mortality (adjusted hazard ratio, 1.98; 95% CI, 1.26-3.11; P = .003). Conclusions and relevance: Results of this study suggest that among patients with cancer with simultaneous assessment of eGFRcys and eGFRcr, supratherapeutic drug levels and medication-related AEs occurred more commonly in those with an eGFRcys more than 30% lower than their eGFRcr. Future prospective studies are needed to improve and personalize GFR estimation and medication dosing in patients with cancer.

Brief Report: Use and Side Effects of Sodium-Glucose Transporter 2 Inhibitors Among US People With HIV With Clinical Indications.

BACKGROUND: Sodium-glucose transporter 2 (SGLT2) inhibitors have been approved for treatment of diabetes mellitus (DM), chronic kidney disease, and heart failure, but little is known about prescription levels and safety profiles among people with HIV (PWH). METHODS: We leveraged data from the US Mass General Brigham electronic healthcare database to determine the use/uptake of SGLT2 inhibitors among PWH with type II diabetes (DM2) (with or without chronic kidney disease, proteinuria, or heart failure) and to assess rates of adverse events among PWH with DM2 taking SGLT2 inhibitors. RESULTS: Among eligible PWH with DM2 receiving care at US Mass General Brigham (N = 907), SGLT2 inhibitors were prescribed to 8.8%. SGLT2 inhibitors were prescribed to a fraction of eligible PWH with DM2 and a concomitant diagnosis of chronic kidney disease (3.8%), proteinuria (13.2%), or heart failure (8.2%). PWH with DM2 on SGLT2 inhibitors experienced side effects (urinary tract infection, diabetic ketoacidosis, and acute kidney injury) at rates comparable with PWH with DM2 prescribed glucagon-like peptide-1 agonists. Rates of mycotic genitourinary infections were higher among those prescribed SGLT2 inhibitors (5% vs. 1%, P = 0.17), but no cases of necrotizing fasciitis ensued. CONCLUSIONS: Additional studies are needed to characterize population-specific salutary and adverse effects of SGLT2 inhibitors among PWH and potentially augment prescription rates when guideline indicated.

Kidney function in patients with ovarian cancer treated with poly (ADP-ribose) polymerase (PARP) inhibitors.

BACKGROUND: Poly (ADP-ribose) polymerase inhibitors (PARPi) have revolutionized the treatment of ovarian cancer; however, real-world data on kidney function among patients treated with PARPi are lacking. METHODS: We identified adults treated with olaparib or niraparib between 2015 and 2021 at a major cancer center in Boston, MA, USA. We determined the incidence of any acute kidney injury (AKI), defined as at least a 1.5-fold rise in serum creatinine from baseline in the first 12 months following PARPi initiation. We calculated the percentage of patients with any AKI and sustained AKI and adjudicated the etiologies by manual chart review. We compared trajectories in estimated glomerular filtration rate (eGFR) among PARPi-treated and carboplatin and paclitaxel-treated patients with ovarian cancer, matched by baseline eGFR. RESULTS: Of 269 patients, 60 (22.3%) developed AKI, including 43 of 194 (22.1%) olaparib-treated patients and 17 of 75 (22.7%) niraparib-treated patients. Only 9 of 269 (3.3%) had AKI attributable to the PARPi. Of the 60 patients with AKI, 21 (35%) had sustained AKI, of whom 6 had AKI attributable to the PARPi (2.2% of the whole cohort). eGFR declined within 30 days post-PARPi initiation by 9.61 (SD = 11.017) mL/min per 1.73 m2 but recovered by 8.39 (SD = 14.05) mL/min per 1.73 m2 within 90 days after therapy cessation. There was no difference in eGFR at 12 months post-therapy initiation in patients receiving PARPi or controls receiving carboplatin and paclitaxel (P = .29). CONCLUSIONS: AKI is common following PARPi initiation as is a transient decline in eGFR; however, sustained AKI directly attributable to the PARPi and long-term eGFR decline are uncommon.

Medication-related adverse events in patients with cancer and discrepancies in cystatin C- versus creatinine-based eGFR.

Background: Creatinine-based estimated glomerular filtration rate (eGFRCRE) may overestimate kidney function in patients with cancer. Cystatin C-based eGFR (eGFRCYS) is an alternative marker of kidney function. We investigated whether patients with an eGFR discrepancy, defined as eGFRCYS >30% lower than the concurrent eGFRCRE, had an increased risk of adverse events resulting from renally-cleared medications. Patients and Methods: We conducted a cohort study of adult patients with cancer who had serum creatinine and cystatin C measured on the same day between May 2010 and January 2022 at two academic cancer centers in Boston, MA. The primary outcome was the incidence of each of the following medication-related adverse events: 1) supratherapeutic vancomycin levels (>30µg/mL); 2) trimethoprim-sulfamethoxazole-related hyperkalemia (>5.5mEq/L); 3) baclofen-induced neurotoxicity; and 4) supratherapeutic digoxin levels (>2.0ng/mL). Results: 1988 patients with cancer had simultaneous eGFRCYS and eGFRCRE. The mean age was 66 years (SD±14), 965 (49%) were female, and 1555 (78%) were non-Hispanic white. eGFR discrepancy occurred in 579 patients (29%). Patients with eGFR discrepancy were more likely to experience medication-related adverse events compared to those without eGFR discrepancy: vancomycin levels >30µg/mL (24% vs. 10%, p=0.004), trimethoprim- sulfamethoxazole-related hyperkalemia (24% vs. 12%, p=0.013), baclofen-induced neurotoxicity (25% vs. 0%, p=0.13), and supratherapeutic digoxin levels (38% vs. 0%, p=0.03). The adjusted OR for vancomycin levels >30µg/mL was 2.30 (95% CI 1.05 - 5.51, p = 0.047). Conclusion: Among patients with cancer with simultaneous assessment of eGFRCYS and eGFRCRE, medication-related adverse events occur more commonly in those with eGFR discrepancy. These findings underscore the importance of accurate assessment of kidney function and appropriate dosing of renally-cleared medications in patients with cancer.

Autoimmunity and COVID-19 - The microbiotal connection.

BACKGROUND AND AIMS: The novel SARS-CoV-2 has been rattling the world since its outbreak in December 2019, leading to the COVID-19 pandemic. The learning curve of this new virus has been steep, with a global scientific community desperate to learn how the virus is transmitted, how it replicates, why it causes such a wide spectrum of disease manifestations, resulting in none or few symptoms in some. Others are burdened by an intense immune response that resembles the cytokine storm syndrome (CSS), which leads to severe disease manifestations, often complicated by fatal acute respiratory distress syndrome and death. Research efforts have been focusing on finding effective cures and vaccinations for this virus. The presence of SARS-CoV-2 in the gastrointestinal (GI) tract, represented by several GI manifestations, has led to its investigation as a target for the virus and as an indicator of disease severity. The response of the microbiome (which is heavily linked to immunity) to the novel SARS-CoV-2 virus, and its role in igniting the exaggerated immune response has therefore become a focus of interest. The objective of our study was to gather the data connecting between the microbiome, the GI tract and COVID-19 and to investigate whether these reported alterations in the gut microbiome bear any resemblance to those seen in lupus, the prototypical autoimmune disease. Confirming such changes may become the steppingstone to potential therapies that may prevent transmission, progression and immune related manifestations of COVID-19, via manipulation of the gut microbiota. METHODS: We performed an extensive literature review, utilizing the Pubmed search engine and Google Scholar for studies evaluating the microbiome in COVID-19 patients and compared results with studies evaluating the microbiome in lupus. We searched for the terms: microbiome, dysbiosis, COVID-19, SARS-CoV-2, gastrointestinal as well as lupus and autoimmune. While there were hundreds of articles which referred to gastrointestinal manifestations in COVID-19, to date only 4 studies investigated the gastrointestinal microbiome in this setting. We compared the similarities between microbiome of COVID-19 patients and lupus patients. RESULTS: We found that there are several similar processes of immune dysregulation in patients with COVID-19 and in those with lupus, with several other alterations seen in other pathological states. Some of these similarities include loss of microbiota biodiversity, increased representation of pathobionts, which are microbes associated with inflammation and disease (i.e Proteobacteria) and a relative decrease of symbionts, which are protective microbes, associated with anti-inflammatory properties (i.e Lactobacillus). Compromise to the intestinal barrier has also been reported in both. CONCLUSIONS: We conclude that the gastrointestinal tract contributes to the disease manifestations in COVID-19. Whether gastrointestinal dysbiosis is the cause or effect of gastrointestinal manifestations and several severe systemic manifestations, which may be the response to an increased pro-inflammatory environment, is still debatable and warrants further investigation. Given the resemblance of the microbiome in COVID-19 patients to that seen in lupus patients, it becomes clearer why several therapies used in autoimmune conditions are currently under investigation for the treatment of COVID-19 patients. Moreover, these findings should promote further investigating the utility of manipulation of the microbiome, via nutritional supplementation or even fecal transplantations, interventions that may alter the course of the disease, and potentially prevent disease transmission at low cost and low risk.

The microbiome links between aging and lupus.

BACKGROUND AND AIMS: Many forms of immune dysregulation, which lead to inflammaging and senescence, have been demonstrated in patients with systemic lupus erythematosus (SLE; lupus) and in the aging population. The discovery of the microbiome and its association with human health and pathology has led it to be the center of investigation as a major contributor to the pathogenesis of immunosenescence in both populations. Similar alterations to the microbiome in the form of dysbiosis, that are demonstrated in both aging and in lupus patients, may help explain the significant overlap in clinical manifestations seen in these groups. METHODS: We performed an extensive literature review, utilizing the Pubmed search engine and Google Scholar for studies evaluating the microbiome in two groups, elderly populations and lupus patients (both murine and human models), between the years 2000-2019. We searched for the terms: microbiome, dysbiosis, lupus, elderly, aging and inflammaging, which yielded hundreds of articles, of which 114 were used for preparation of this paper. We compared the similarities between the populations. RESULTS: We found that the similar processes of immune dysregulation, in both aging populations and lupus patients, extend to the microbiome, in the form of dysbiosis. Some of these similarities include loss of microbiota biodiversity, increased representation of microbes that are associated with inflammation and disease (i.e Proteobacteria, Bacteroidetes), a relative decrease in protective microbes with "anti-inflammatory" properties (i.e Firmicutes) and a subsequent compromise to the intestinal barrier, leading to leakage of proinflammatory microbial components in both groups. CONCLUSIONS: We conclude that there are several similar alterations in the composition and function of the microbiome of lupus patients and aging individuals, leading to immunosenescence, which may also be a contributing mechanism in lupus. It seems in fact that the microbiome of SLE may actually be analogous to immunosenescence. This knowledge may help the continuous efforts in finding a solution for both conditions.

Severe esophageal injury after radiofrequency ablation - a deadly complication.

Various degrees of esophageal injury have been described after radiofrequency ablation performed for treatment of atrial fibrillation. The main mechanism of injury is thermal and may lead to a range of esophageal mucosal changes, some clinically insignificant, however when deep ulceration occurs, this may be further complicated by perforation and mediastinitis, a rare but life threatening sequelae. We present a case of a severe esophageal injury leading to mediastinitis, with interesting endoscopic findings.

The microbiome and systemic lupus erythematosus.

The microbiota, which is comprised of the collective of all microbes inhabiting the gut and its effect on the human host in which it resides, has become a growing field of interest. Various parameters of health and disease have been found to be associated with the variation in the human gut microbiome. In recent years, many studies have demonstrated an important role of gut microbes in the development of various illnesses including autoimmune diseases, such as type 1 diabetes, rheumatoid arthritis, and multiple sclerosis. Although the mechanism of the disease involves both genetic and environmental factors, lupus has been found to be affected by the composition of the microbes lining the intestines. Several recent studies have suggested that alterations of the gut microbial composition may be correlated with SLE disease manifestations, while the exact roles of either symbiotic or pathogenic microbes in this disease have yet to be explored. Elucidation of the roles of gut microbes in SLE will shed light on how this autoimmune disorder develops and provide opportunities for improved biomarkers of the disease and the potential to probe new therapies. This new knowledge, along with that enabling alteration in composition of the gut microbiome, via diet modification, antibiotic, and probiotics, may bring forward a new era in the future of lupus treatment.

The role of intravenous immunoglobulins in the treatment of rheumatoid arthritis.

Intravenous immunoglobulins (IVIGs) are beneficial and safe for various diseases other than primary immunodeficiencies. Over the years, IVIG has been given for autoimmune diseases as an off-label adjunct therapy. While other biologic agents are indicated for rheumatoid arthritis (RA), IVIG may have a role for specific subgroups of RA patients where anti-cytokine blockers or rituximab may be unwarranted. Such subgroups may include patients with vasculitis, overlap rhupus syndrome, severe infections with active disease, and pregnancy. In addition, IVIG may be considered for juvenile chronic arthritis (JCA) and adult Still's disease. We review the literature for IVIG treatment in RA patients and for these subgroups.