Ablation of the carboxy-terminal end of MAMDC2 causes a distinct muscular dystrophy.

The extracellular matrix (ECM) has an important role in the development and maintenance of skeletal muscle, and several muscle diseases are associated with the dysfunction of ECM elements. MAMDC2 is a putative ECM protein and its role in cell proliferation has been investigated in certain cancer types. However, its participation in skeletal muscle physiology has not been previously studied. We describe 17 individuals with an autosomal dominant muscular dystrophy belonging to two unrelated families in which different heterozygous truncating variants in the last exon of MAMDC2 co-segregate correctly with the disease. The radiological aspect of muscle involvement resembles that of COL6 myopathies with fat replacement at the peripheral rim of vastii muscles. In this cohort, a subfascial and peri-tendinous pattern is observed in upper and lower limb muscles. Here we show that MAMDC2 is expressed in adult skeletal muscle and differentiating muscle cells, where it appears to localize to the sarcoplasm and myonuclei. In addition, we show it is secreted by myoblasts and differentiating myotubes into to the extracellular compartment. The last exon encodes a disordered region with a polar residue compositional bias loss of which likely induces a toxic effect of the mutant protein. The precise mechanisms by which the altered MAMDC2 proteins cause disease remains to be determined. MAMDC2 is a skeletal muscle disease-associated protein. Its role in muscle development and ECM-muscle communication remains to be fully elucidated. Screening of the last exon of MAMDC2 should be considered in patients presenting with autosomal dominant muscular dystrophy, particularly in those with a subfascial radiological pattern of muscle involvement.

Prevention, Diagnosis, Evaluation, and Treatment of Hepatitis C Virus Infection in Chronic Kidney Disease: Synopsis of the Kidney Disease: Improving Global Outcomes 2018 Clinical Practice Guideline.

This article has been corrected. The original version (PDF) is appended to this article as a Supplement. Description: The Kidney Disease: Improving Global Outcomes (KDIGO) 2018 clinical practice guideline for the prevention, diagnosis, evaluation, and treatment of hepatitis C virus (HCV) infection in chronic kidney disease (CKD) is an extensive update of KDIGO's 2008 guideline on HCV infection in CKD. This update reflects the major advances since the introduction of direct-acting antivirals (DAAs) in the management of HCV infection in the CKD population. Methods: The KDIGO work group tasked with developing the HCV and CKD guideline defined the scope of the guideline, gathered evidence, determined topics for systematic review, and graded the quality of evidence previously summarized by the evidence review team. The GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach was used to appraise the quality of evidence and rate the strength of the recommendations. Searches of the English-language literature were conducted through May 2017 and were supplemented with targeted searches for studies of DAA treatment and with abstracts from nephrology, hepatology, and transplantation conferences. A review process involving many stakeholders, subject matter experts, and industry and national organizations informed the guideline's final modification. Recommendation: The updated guideline comprises 66 recommendations. This synopsis focuses on 32 key recommendations pertinent to the prevention, diagnosis, treatment, and management of HCV infection in adult CKD populations.

New insights into the rational use of HCV+ organs worldwide.

Hepatitis C (HCV) is a worldwide health problem. Effective therapies for HCV infection, coupled with an increase in deceased donors due to the opioid epidemic, have led to the broader availability and the use of HCV-infected donor organs, including HCV nucleic acid test-positive (NAT+) donors in HCV-negative recipients. In this review, we discuss the prevalence of HCV infection, trends in the use of HCV-infected donors, and outcomes for those who receive HCV-seropositive or HCV NAT+ donor organs. We discuss management considerations such as hepatitis B reactivation, selection of the optimal direct-acting antiviral regimen, and potential complications. We also present a framework for the rational use of HCV-infected donor organs in the future.

ß2-Glycoprotein I/IgA Immune Complexes: A Marker to Predict Thrombosis After Renal Transplantation in Patients With Antiphospholipid Antibodies.

BACKGROUND: Antiphospholipid syndrome is characterized by recurrent thrombosis and gestational morbidity in patients with antiphospholipid autoantibodies (aPLs). Predictive value of the presence of aPLs is low, and new markers are necessary to identify aPL carriers at higher risk and take preventive measures on them. The presence of circulating immune complexes of IgA bound to ß2-glycoprotein I (B2A-CIC) has been associated with occurrence of acute thrombotic events. In this work we study its possible predictive value for the appearance of acute thrombotic events in patients who are going to undergo transplant surgery, a well-known trigger of acute thrombotic events in aPL carriers. METHODS: We performed a follow-up study based on the Magnum 12+12 Cohort of patients who received a kidney transplant (n=1339). Three groups were established: group 1 patients who were positive for IgA anti-ß2-glycoprotein I (aB2GP1) and B2A-CIC (n=125); group 2 patients who were positive only for IgA aB2GP1 (n=240); and control group, patients who were negative for IgA aB2GP1 (n=974). Levels of autoantibodies and B2A-CIC were quantified immediately before the transplant surgery and patients were followed up for 6 months. RESULTS: In group 1, 46.4% of patients experienced any type of thrombosis versus 10.4% in group 2 (P<0.001) and 8.6% in the control group (P<0.001). The incidence of graft thrombosis in group 1 (31.2%) was significantly higher than that observed in group 2 (3.3%, P<0.001) and the control group (2.6%, P<0.001). In a multivariate analysis, the presence of B2A-CIC was an independent variable to experience any type of posttransplant thrombosis (hazard ratio, 6.72; 95% confidence interval, 4.81-9.37) and, prominently, for graft thrombosis (hazard ratio, 14.75; 95% confidence interval, 9.11-23.89). No significant differences were found between B2A-CIC-negative and control group patients. CONCLUSIONS: The presence of B2A-CIC is a predictor of acute thrombotic events. Patients who were positive for IgA aB2GP1 only are at risk of experiencing thrombosis if they are B2A-CIC positive. If they are B2A-CIC-negative patients, they have the same risk as the control group. Treatments to prevent acute thrombotic events should focus on B2A-CIC-positive patients.

Executive summary of the 2018 KDIGO Hepatitis C in CKD Guideline: welcoming advances in evaluation and management.

Infection with the hepatitis C virus (HCV) has adverse liver, kidney, and cardiovascular consequences in patients with chronic kidney disease (CKD), including those on dialysis therapy and in those with a kidney transplant. Since the publication of the original Kidney Disease: Improving Global Outcomes (KDIGO) HCV Guideline in 2008, major advances in HCV management, particularly with the advent of direct-acting antiviral therapies, have now made the cure of HCV possible in CKD patients. In addition, diagnostic techniques have evolved to enable the noninvasive diagnosis of liver fibrosis. Therefore, the Work Group undertook a comprehensive review and update of the KDIGO HCV in CKD Guideline. This Executive Summary highlights key aspects of the guideline recommendations.

Reelin protects from colon pathology by maintaining the intestinal barrier integrity and repressing tumorigenic genes.

We previously reported that reelin, an extracellular matrix protein first known for its key role in neuronal migration, reduces the susceptibility to dextran sulphate sodium (DSS)-colitis. The aim of the current study was to determine whether reelin protects from colorectal cancer and how reelin defends from colon pathology. In the colon of wild-type and of mice lacking reelin (reeler mice) we have analysed the: i) epithelium cell renewal processes, ii) morphology, iii) Sox9, Cdx2, Smad5, Cyclin D1, IL-6 and IFNγ mRNA abundance in DSS-treated and untreated mice, and iv) development of azoxymethane/DSS-induced colorectal cancer, using histological and real time-PCR methodologies. The reeler mutation increases colitis-associated tumorigenesis, with increased tumours number and size. It also impairs the intestinal barrier because it reduces cell proliferation, migration, differentiation and apoptosis; decreases the number and maturation of goblet cells, and expands the intercellular space of the desmosomes. The intestinal barrier impairment might explain the increased susceptibility to colon pathology exhibited by the reeler mice and is at least mediated by the down-regulation of Sox9 and Cdx2. In response to DSS-colitis, the reeler colon increases the mRNA abundance of IL-6, Smad5 and Cyclin D1 and decreases that of IFNγ, conditions that might result in the increased colitis-associated tumorigenesis found in the reeler mice. In conclusion, the results highlight a role for reelin in maintaining intestinal epithelial cell homeostasis and providing resistance against colon pathology.

Isolated De Novo Antiendothelial Cell Antibodies and Kidney Transplant Rejection.

BACKGROUND: Studies analyzing the role of antiendothelial cell antibodies (AECAs) in large series of kidney transplant recipients are scarce, and HLA, MHC (major histocompatibility complex) class I-related chain A (MICA), and angiotensin II type 1 receptor have not been formally excluded as targets. STUDY DESIGN: Retrospective study of a cohort of kidney transplant recipients. SETTING & PARTICIPANTS: 324 kidney transplant recipients who were negative for anti-HLA, anti-MICA, and anti-angiotensin II type 1 receptor antibodies were tested for AECAs in pre- and posttransplantation serum samples. PREDICTORS: AECA-positive (preformed [pre+/post+] vs de novo [pre-/post+]) versus AECA-negative (pre-/post-) before or after transplantation. OUTCOMES: Patient mortality, transplant loss, and acute rejection events. RESULTS: 66 (20%) patients were AECA positive (39 [12%] preformed, 27 [8%] de novo) and 258 (80%) were AECA negative. During a follow-up of 10 years, 7 (18%) AECA pre+/post+ patients had rejections compared with 14 (52%) AECA pre-/post+ and 57 (22%) AECA pre-/post- recipients (OR, 3.80; P=0.001). AECA pre-/post+ status emerged as an independent risk factor for transplant rejection compared to the AECA pre-/post- group (OR, 5.17; P<0.001). However, AECA pre+/post+ and AECA pre-/post+ patients did not show higher risk for either patient death (ORs of 1.49 [P=0.7] and 1.06 [P=0.9], respectively) or transplant loss (ORs of 1.22 and 0.86, respectively; P for both = 0.8) compared to the AECA pre-/post- population. LIMITATIONS: Retrospective study. Posttransplantation sera were collected before or after rejection, entailing a nearly cross-sectional relationship between the exposure and outcome. Lack of identification of precise antigens for AECAs. CONCLUSIONS: De novo AECAs may be associated with rejection. These antibodies might serve as biomarkers of endothelium damage in kidney transplant recipients.

Controlled randomized study comparing the cardiovascular profile of everolimus with tacrolimus in renal transplantation.

Left ventricular hypertrophy (LVH) regression after kidney transplantation may be influenced by immunosuppression. In a 24-month open-label, multicenter, phase-IV study, 71 kidney allograft recipients without previous acute rejection, showing eGFR >40 ml/min and proteinuria <500 mg/day and between 6 months and 3 years post-transplantation, were randomized to receive everolimus (EVR) + mycophenolic acid (MPA) or were maintained on tacrolimus (TAC) + MPA. The aim was to assess whether the conversion to EVR could reduce left ventricular mass index (LVMi) at month-24. LVMi at month-24 decreased without differences between groups (TAC: 54.0 vs. 48.2 g/m2.7 ; EVR: 53.4 vs. 49.4 g/m2.7 ). The LVH prevalence at baseline and month-24 was 59.4% and 40.6% in TAC group and 57.1% and 50.0% in EVR group. EVR conversion was associated with nearly disappearance of concentric LVH and concentric remodeling pattern. The procollagen type I N-terminal propeptide at month-24 showed greater reduction in EVR group (51.6 vs. 58.2 mg/l; P = 0.004). Conversion from TAC to EVR was associated with a significant improvement of eGFR (P = 0.0315, ancova). Adverse events were similar between groups without rejection episode or graft loss. Conversion from TAC to EVR did not further reduce LVMi after 24 months, although its effect on concentric LVH deserves further investigation (NCT01169701).

Association of early kidney allograft failure with preformed IgA antibodies to ß2-glycoprotein I.

In the current immunosuppressive therapy era, vessel thrombosis is the most common cause of early graft loss after renal transplantation. The prevalence of IgA anti-ß2-glycoprotein I antibodies (IgA-aB2GPI-ab) in patients on dialysis is elevated (>30%), and these antibodies correlate with mortality and cardiovascular morbidity. To evaluate the effect of IgA-aB2GPI-ab in patients with transplants, we followed all patients transplanted from 2000 to 2002 in the Hospital 12 de Octubre prospectively for 10 years. Presence of IgA-aB2GPI-ab in pretransplant serum was examined retrospectively. Of 269 patients, 89 patients were positive for IgA-aB2GPI-ab (33%; group 1), and the remaining patients were negative (67%; group 2). Graft loss at 6 months post-transplant was significantly higher in group 1 (10 of 89 versus 3 of 180 patients in group 2; P=0.002). The most frequent cause of graft loss was thrombosis of the vessels, which was observed only in group 1 (8 of 10 versus 0 of 3 patients in group 2; P=0.04). Multivariate analysis showed that the presence of IgA-aB2GPI-ab was an independent risk factor for early graft loss (P=0.04) and delayed graft function (P=0.04). There were no significant differences regarding patient survival between the two groups. Graft survival was similar in both groups after 6 months. In conclusion, patients with pretransplant IgA-aB2GPI-ab have a high risk of early graft loss caused by thrombosis and a high risk of delayed graft function. Therefore, pretransplant IgA-aB2GPI-ab may have a detrimental effect on early clinical outcomes after renal transplantation.

A metabolomic approach to dry eye disorders. The role of oral supplements with antioxidants and omega 3 fatty acids.

PURPOSE: We used nuclear magnetic resonance spectroscopy of hydrogen-1 nuclei ((1)H NMR S) to analyze the metabolic profile of reflex tears from patients with dry eye disorders. METHODS: We performed a prospective case-control study involving 90 participants: 55 patients diagnosed with dry eye syndrome (DESG) and 35 healthy subjects (control group, CG). From the DESG, two subgroups were formed: mild DES (n=22) and moderate DES (n=33). Participants were prescribed an oral nutraceutic supplementation containing antioxidants and essential polyunsaturated fatty acids to be taken as three capsules per day for 3 months. Reflex tears (20-30 µl) were collected from the tear meniscus of both eyes of each subject with a microglass pipette. Nuclear magnetic resonance (NMR) spectra were acquired with a standard one-dimensional pulse sequence with water suppression; 256 free induction decays were collected into 64,000 data points with 14 ppm spectral width. RESULTS: Basal tears showed a differential metabolomic profile between groups. Almost 50 metabolites were identified by H cholesterol, N-acetylglucosamine, glutamate, amino-n-butyrate, choline, glucose, and formate were detected before supplementation and choline/acetylcholine after supplementation. The metabolic profile of the tears was statistically different between groups, as well as before and after supplementation. CONCLUSIONS: Our data indicate that DES induces changes in the tear metabolic profile that can be modified with appropriate oral supplementation with antioxidants and essential polyunsaturated fatty acids.

Differences in gluten metabolism among healthy volunteers, coeliac disease patients and first-degree relatives.

Coeliac disease (CD) is an immune-mediated enteropathy resulting from exposure to gluten in genetically predisposed individuals. Gluten proteins are partially digested by human proteases generating immunogenic peptides that cause inflammation in patients carrying HLA-DQ2 and DQ8 genes. Although intestinal dysbiosis has been associated with patients with CD, bacterial metabolism of gluten has not been studied in depth thus far. The aim of this study was to analyse the metabolic activity of intestinal bacteria associated with gluten intake in healthy individuals, CD patients and first-degree relatives of CD patients. Faecal samples belonging to twenty-two untreated CD patients, twenty treated CD patients, sixteen healthy volunteers on normal diet, eleven healthy volunteers on gluten-free diet (GFD), seventy-one relatives of CD patients on normal diet and sixty-nine relatives on GFD were tested for several proteolytic activities, cultivable bacteria involved in gluten metabolism, SCFA and the amount of gluten in faeces. We detected faecal peptidasic activity against the gluten-derived peptide 33-mer. CD patients showed differences in faecal glutenasic activity (FGA), faecal tryptic activity (FTA), SCFA and faecal gluten content with respect to healthy volunteers. Alterations in specific bacterial groups metabolising gluten such as Clostridium or Lactobacillus were reported in CD patients. Relatives showed similar parameters to CD patients (SCFA) and healthy volunteers (FTA and FGA). Our data support the fact that commensal microbial activity is an important factor in the metabolism of gluten proteins and that this activity is altered in CD patients.

Kinetics of peripheral blood lymphocyte subpopulations predicts the occurrence of opportunistic infection after kidney transplantation.

Serial monitoring of peripheral blood lymphocyte subpopulations (PBLSs) counts might be useful in predicting post-transplant opportunistic infection (OI) after kidney transplantation (KT). PBLSs were prospectively measured in 304 KT recipients at baseline and post-transplant months 1 and 6. Areas under receiver operating characteristic curves were used to evaluate the accuracy of different subpopulations in predicting the occurrence of overall OI and, specifically, cytomegalovirus (CMV) disease. We separately analyzed patients not receiving (n = 164) or receiving (n = 140) antithymocyte globulin (ATG) as induction therapy. In the non-ATG group, a CD8(+) T-cell count at month 1 <0.100 × 10(3) cells/µl had negative predictive values of 0.84 and 0.86 for the subsequent occurrence of overall OI and CMV disease, respectively. In the multivariate Cox model, a CD8(+) T-cell count <0.100 × 10(3) cells/µl was an independent risk factor for OI (adjusted hazard ratio: 3.55; P-value = 0.002). In the ATG group, a CD4(+) T-cell count at month 1 <0.050 × 10(3) cells/µl showed negative predictive values of 0.92 for the subsequent occurrence of overall OI and CMV disease. PBLSs monitoring effectively identify KT recipients at low risk of OI, providing an opportunity for individualizing post-transplant prophylaxis practices.

Bone metastases as the initial presentation of hepatocellular carcinoma. Two case reports and a literature review.

Hepatocellular carcinoma (HCC) is the most common primary tumor of the liver and is the fifth most common cancer in the world; its incidence has been increasing in recent years. Extrahepatic spread is present at the time of diagnosis in only about 5 to 15% of patients. Skeletal metastasis of HCC occurs less frequently compared with other cancers and is considered a rare primary form of presentation. We report two cases of unsuspected HCC presenting with multiple bone lesions as the initial presentation. The first patient was a 76-year-old man with symptoms of fatigue and back pain. The PET-CT revealed the hypercaptant bone lesions and a liver lesion. The pathology report showed that the metastases were positive for the hepatic marker HEPAR-1, indicating that they had originated from the HCC. The second patient was a 56-year-old man. He presented to the emergency department for right shoulder pain and weakness of the entire right arm with no history of trauma. During hospitalization, the patient became quadriplegic. MRI revealed osseous blastic lesions in the cervical vertebrae and right shoulder. A CT-guided biopsy was performed in the cervical lesion and showed poorly differentiated carcinoma. Immunohistochemistry staining was positive for HEPAR-1. In conclusion, this cases show an unusual presentation of HCC with skeletal metastasis.

Heterogeneity between diagnostic tests for IgA anti-beta2 glycoprotein I: explaining the controversy in studies of association with vascular pathology.

IgA antibeta 2 Glycoprotein I (ß2GPI) antibodies test can identify some patients with antiphospholipid syndrome (APS) that are negative for other isotypes. Controversy exists because some studies have reported a strong association of these antibodies with vascular disease, while others have not confirmed this observation. Our hypothesis is that these contradictory results may be due to differences among commercial diagnostic kits. To answer this question, we have compared the results obtained with several of the most commonly used commercial IgA anti ß2GPI antibodies (aß2GPI) diagnostic assays on specimens from individuals suspected of having APS. Sera from 69 patients (37 positive and 32 negative for IgA aß2GPI) were analyzed with seven different commercial ELISA kits for IgA aß2GPI, following instructions and cutoffs provided by the manufacturer. Our results showed important differences in the sensitivity and specificity of the different assays. Two of the seven kits tested had a sensitivity level below 65% for IgA aß2GPI, and three showed levels of specificity lower than 80%. Some commercial kits to detect IgA aß2GPI are suboptimal. Variability between kits may account for the discrepancy in results obtained and for the lack of consensus concerning their clinical significance. It is important that the scientific community work to standardize assay performance so that the true clinical significance of this important clinical marker can be clearly established.

Membranous glomerulopathy in renal allograft: an ultrastructural study of 17 cases.

BACKGROUND: Membranous glomerulopathy is a common complication of renal allograft. However, its incidence and prognosis are not well defined, because an undetermined number of them pass undiagnosed under the generic epigraph of chronic allograft nephropathy. MATERIALS AND METHODS: To assess the diagnostic refinement supplied by electron microscopy to conventional light and immunofluorescence procedures the authors reviewed 17 cases of electron microscopy-confirmed membranous glomerulonephritis in kidney allograft. In addition, they searched for other features of graft injury, particularly lesions associated with alloimmune reaction, in order to evaluate the contribution of each lesion to the long-term outcome of the allograft. RESULTS: In 4 of the 17 cases of their series the diagnosis of membranous glomerulopathy was made by electron microscopy. In addition, in 5 samples, lesions of chronic alloimmune rejection were present (in 4 cases the diagnosis was based on electron microscopy findings). At the end point of the study, 3 of the 5 patients with chronic alloimmune injury were in dialysis, 1 had died with functioning allograft, and the fifth suffered severe renal failure but was not in dialysis. On the other hand, 3 of the 12 patients without evidence of alloimmune injury had returned to the dialysis program. CONCLUSIONS: Electron microscopy is a useful tool in the assessment of renal allograft pathology and can provide additional morphological features of prognostic relevance.

Evaluation of Changes in Hydration and Body Cell Mass with Bioelectrical Impedance Analysis after Exercise Program for Rheumatoid Arthritis Patients.

Rheumatoid arthritis (RA) is a debilitating disease that can result in complications such as rheumatoid cachexia. While physical exercise has shown benefits for RA patients, its impact on hydration and body cell mass remains uncertain. The presence of pain, inflammation, and joint changes often restrict activity and make traditional body composition assessments unreliable due to altered hydration levels. Bioelectrical impedance is a commonly used method for estimating body composition, but it has limitations since it was primarily developed for the general population and does not consider changes in body composition. On the other hand, bioelectrical impedance vectorial analysis (BIVA) offers a more comprehensive approach. BIVA involves graphically interpreting resistance (R) and reactance (Xc), adjusted for height, to provide valuable information about hydration status and the integrity of the cell mass. Twelve women with RA were included in this study. At the beginning of the study, hydration and body cell mass measurements were obtained using the BIVA method. Subsequently, the patients participated in a six-month dynamic exercise program encompassing cardiovascular capacity, strength, and coordination training. To evaluate changes in hydration and body cell mass, the differences in the R and Xc parameters, adjusted for height, were compared using BIVA confidence software. The results showed notable changes: resistance decreased after the exercise program, while reactance increased. BIVA, as a classification method, can effectively categorize patients into dehydration, overhydration, normal, athlete, thin, cachectic, and obese categories. This makes it a valuable tool for assessing RA patients, as it provides information independent of body weight or prediction equations. Overall, the implementation of BIVA in this study shed light on the effects of the exercise program on hydration and body cell mass in RA patients. Its advantages lie in its ability to provide comprehensive information and overcome the limitations of traditional body composition assessment methods.

3D Printing and processing of miniaturized transducers with near-pristine piezoelectric ceramics for localized cavitation.

The performance of ultrasonic transducers is largely determined by the piezoelectric properties and geometries of their active elements. Due to the brittle nature of piezoceramics, existing processing tools for piezoelectric elements only achieve simple geometries, including flat disks, cylinders, cubes and rings. While advances in additive manufacturing give rise to free-form fabrication of piezoceramics, the resultant transducers suffer from high porosity, weak piezoelectric responses, and limited geometrical flexibility. We introduce optimized piezoceramic printing and processing strategies to produce highly responsive piezoelectric microtransducers that operate at ultrasonic frequencies. The 3D printed dense piezoelectric elements achieve high piezoelectric coefficients and complex architectures. The resulting piezoelectric charge constant, d33, and coupling factor, kt, of the 3D printed piezoceramic reach 583 pC/N and 0.57, approaching the properties of pristine ceramics. The integrated printing of transducer packaging materials and 3D printed piezoceramics with microarchitectures create opportunities for miniaturized piezoelectric ultrasound transducers capable of acoustic focusing and localized cavitation within millimeter-sized channels, leading to miniaturized ultrasonic devices that enable a wide range of biomedical applications.

Upfront Cytoreductive Nephrectomy for Metastatic Renal Cell Carcinoma Treated with Immune Checkpoint Inhibitors or Targeted Therapy: An Observational Study from the International Metastatic Renal Cell Carcinoma Database Consortium.

BACKGROUND: The role of upfront cytoreductive nephrectomy (CN) for metastatic renal cell carcinoma (mRCC) in the era of immune checkpoint inhibitors is unclear. OBJECTIVE: To evaluate the relationship between upfront CN and clinical outcomes in the setting of mRCC treated with immune checkpoint inhibitors or targeted therapy. DESIGN, SETTING, AND PARTICIPANTS: Using the International Metastatic RCC Database Consortium, we retrospectively identified patients diagnosed with de novo mRCC treated with immune checkpoint inhibitors or targeted therapy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Overall survival (OS) was compared between the two groups using the Kaplan-Meier method and multivariable Cox regressions adjusting for known prognostic factors. RESULTS AND LIMITATIONS: We identified a total of 4639 eligible patients with mRCC. Among the 4202 patients treated with targeted therapy and 437 patients treated with immune checkpoint inhibitors, 2326 (55%) and 234 (54%) patients received upfront CN prior to treatment start. In multivariable analyses, CN was associated with significantly better OS in both the immune checkpoint inhibitor-treated (hazard ratio [HR]: 0.61; 95% confidence interval [CI], 0.41-0.90, p = 0.013) and the targeted therapy treatment (HR: 0.72; 95% CI, 0.67-0.78, p < 0.001) group. There was no difference in OS benefit of CN between the immune checkpoint inhibitor and targeted therapy treatment groups (interaction p = 0.6). Limitations include selection of patients from large academic centers and the retrospective nature of the study. CONCLUSIONS: Upfront CN is associated with a significant OS benefit in selected patients treated by either immune checkpoint inhibitors or targeted therapy, and still has a role in selected patients in the era of immune checkpoint inhibitors. PATIENT SUMMARY: Before effective systemic therapies were available for metastatic kidney cancer, surgical removal of the primary (kidney) tumor was the mainstay of treatment. The role of removing the primary tumor has recently been called into question given that more effective systemic therapies have become available. In this study, we find that removal of the primary kidney tumor still has a benefit for selected patients treated with highly effective modern systemic therapies, including targeted therapies and immune checkpoint inhibitors.

Impact of healthcare inequities on survival in Mexican patients with metastatic renal cell carcinoma.

Introduction: The survival of patients with metastatic renal cell carcinoma (mRCC) has improved dramatically due to novel systemic treatments. However, mRCC mortality continues to rise in Latin America. Methods: A retrospective, multicenter study of patients diagnosed with mRCC between 2010-2018 in Mexico City was conducted. The aim of the study was to evaluate the impact of healthcare insurance on access to treatment and survival in patients with mRCC. Results: Among 924 patients, 55.4%, 42.6%, and 1.9% had no insurance (NI), social security, (SS) and private insurance (PI), respectively. De novo metastatic disease was more common in NI patients (70.9%) compared to SS (47.2%) and PI (55.6%) patients (p<0.001). According to IMDC Prognostic Index, 20.2% were classified as favorable, 49% as intermediate, and 30.8% as poor-risk disease. Access to systemic treatment differed by healthcare insurance: 36.1%, 99.5%, and 100% for the NI, SS, and PI patients, respectively (p<0.001). NI patients received fewer lines of treatment, with 24.8% receiving only one line of treatment (p<0.001). Median overall survival (OS) was 13.9 months for NI, 98.9 months for SS, and 147.6 months for NI patients (p<0.001). In multivariate analysis, NI status, brain metastases, sarcomatoid features, bone metastases, no treatment were significantly associated with worse OS. Conclusion: OS in mRCC was affected by insurance availability in this resource-limited cohort of Mexican patients. These results underscore the need for effective strategies to achieve equitable healthcare access in an era of effective, yet costly systemic treatments.