Rituximab or Cyclosporine in the Treatment of Membranous Nephropathy

Background: B-cell anomalies play a role in the pathogenesis of membranous nephropathy. B-cell depletion with rituximab may therefore be noninferior to treatment with cyclosporine for inducing and maintaining a complete or partial remission of proteinuria in patients with this condition. Methods: We randomly assigned patients who had membranous nephropathy, proteinuria of at least 5 g per 24 hours, and a quantified creatinine clearance of at least 40 ml per minute per 1.73 m(2) of body-surface area and had been receiving angiotensin-system blockade for at least 3 months to receive intravenous rituximab (two infusions, 1000 mg each, administered 14 days apart; repeated at 6 months in case of partial response) or oral cyclosporine (starting at a dose of 3.5 mg per kilogram of body weight per day for 12 months). Patients were followed for 24 months. The primary outcome was a composite of complete or partial remission of proteinuria at 24 months. Laboratory variables and safety were also assessed. Results: A total of 130 patients underwent randomization. At 12 months, 39 of 65 patients (60%) in the rituximab group and 34 of 65 (52%) in the cyclosporine group had a complete or partial remission (risk difference, 8 percentage points; 95% confidence interval [CI], -9 to 25; P=0.004 for noninferiority). At 24 months, 39 patients (60%) in the rituximab group and 13 (20%) in the cyclosporine group had a complete or partial remission (risk difference, 40 percentage points; 95% CI, 25 to 55; P<0.001 for both noninferiority and superiority). Among patients in remission who tested positive for anti-phospholipase A(2) receptor (PLA2R) antibodies, the decline in autoantibodies to anti-PLA2R was faster and of greater magnitude and duration in the rituximab group than in the cyclosporine group. Serious adverse events occurred in 11 patients (17%) in the rituximab group and in 20 (31%) in the cyclosporine group (P=0.06). Conclusions: Rituximab was noninferior to cyclosporine in inducing complete or partial remission of proteinuria at 12 months and was superior in maintaining proteinuria remission up to 24 months. (Funded by Genentech and the Fulk Family Foundation; MENTOR ClinicalTrials.gov number, .) In a randomized, controlled trial involving patients with membranous nephropathy, rituximab was noninferior to cyclosporine in inducing complete or partial remission of proteinuria at 12 months and was superior in maintaining proteinuria remission for up to 24 months.Genentech; Fulk Family Foundation6 month embargo; published July 4, 2019This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

The genetic architecture of membranous nephropathy and its potential to improve non-invasive diagnosis

Membranous Nephropathy (MN) is a rare autoimmune cause of kidney failure. Here we report a genome-wide association study (GWAS) for primary MN in 3,782 cases and 9,038 controls of East Asian and European ancestries. We discover two previously unreported loci, NFKB1 (rs230540, OR = 1.25, P = 3.4 × 10−12) and IRF4 (rs9405192, OR = 1.29, P = 1.4 × 10−14), fine-map the PLA2R1 locus (rs17831251, OR = 2.25, P = 4.7 × 10−103) and report ancestry-specific effects of three classical HLA alleles: DRB1*1501 in East Asians (OR = 3.81, P = 2.0 × 10−49), DQA1*0501 in Europeans (OR = 2.88, P = 5.7 × 10−93), and DRB1*0301 in both ethnicities (OR = 3.50, P = 9.2 × 10−23 and OR = 3.39, P = 5.2 × 10−82, respectively). GWAS loci explain 32% of disease risk in East Asians and 25% in Europeans, and correctly re-classify 20–37% of the cases in validation cohorts that are antibody-negative by the serum anti-PLA2R ELISA diagnostic test. Our findings highlight an unusual genetic architecture of MN, with four loci and their interactions accounting for nearly one-third of the disease risk

Pilot Study of Return of Genetic Results to Patients in Adult Nephrology

Background and objectives: Actionable genetic findings have implications for care of patients with kidney disease, and genetic testing is an emerging tool in nephrology practice. However, there are scarce data regarding best practices for return of results and clinical application of actionable genetic findings for kidney patients. Design, setting, participants and measurements: We developed a Return of Results workflow in collaborations with clinicians for the retrospective re-contact of adult nephrology patients who had been recruited into a biobank research study for exome sequencing and were identified to have medically actionable genetic findings. Results: Using this workflow, we attempted to re-contact a diverse pilot cohort of 104 nephrology research participants with actionable genetic findings encompassing 34 different monogenic etiologies of nephropathy and five single-gene disorders recommended by the American College of Medical Genetics and Genomics for return as medically actionable secondary findings. We successfully re-contacted 64 (62%) participants and returned results to 41 (39%) individuals. In each case, the genetic diagnosis had meaningful implications for the patients’ nephrology care. Through implementation efforts and qualitative interviews with providers, we identified over 20 key challenges associated with returning results to study participants, and found that physician knowledge gaps in genomics was a recurrent theme. We iteratively addressed these challenges to yield an optimized workflow, which included standardized consultation notes with tailored management recommendations, monthly educational conferences on core topics in genomics, and a curated list of expert clinicians for cases requiring extra-nephrologic referrals. Conclusions: Developing the infrastructure to support return of genetic results in nephrology was resource-intensive, but presented potential opportunities for improving patient care

The genetic architecture of membranous nephropathy and its potential to improve non-invasive diagnosis

Membranous Nephropathy (MN) is a rare autoimmune cause of kidney failure. Here we report a genome-wide association study (GWAS) for primary MN in 3,782 cases and 9,038 controls of East Asian and European ancestries. We discover two previously unreported loci, NFKB1 (rs230540, OR = 1.25, P = 3.4 × 10-12) and IRF4 (rs9405192, OR = 1.29, P = 1.4 × 10-14), fine-map the PLA2R1 locus (rs17831251, OR = 2.25, P = 4.7 × 10-103) and report ancestry-specific effects of three classical HLA alleles: DRB1*1501 in East Asians (OR = 3.81, P = 2.0 × 10-49), DQA1*0501 in Europeans (OR = 2.88, P = 5.7 × 10-93), and DRB1*0301 in both ethnicities (OR = 3.50, P = 9.2 × 10-23 and OR = 3.39, P = 5.2 × 10-82, respectively). GWAS loci explain 32% of disease risk in East Asians and 25% in Europeans, and correctly re-classify 20-37% of the cases in validation cohorts that are antibody-negative by the serum anti-PLA2R ELISA diagnostic test. Our findings highlight an unusual genetic architecture of MN, with four loci and their interactions accounting for nearly one-third of the disease risk

Clinical features and outcomes of elderly hospitalised patients with chronic obstructive pulmonary disease, heart failure or both

Background and objective: Chronic obstructive pulmonary disease (COPD) and heart failure (HF) mutually increase the risk of being present in the same patient, especially if older. Whether or not this coexistence may be associated with a worse prognosis is debated. Therefore, employing data derived from the REPOSI register, we evaluated the clinical features and outcomes in a population of elderly patients admitted to internal medicine wards and having COPD, HF or COPD + HF. Methods: We measured socio-demographic and anthropometric characteristics, severity and prevalence of comorbidities, clinical and laboratory features during hospitalization, mood disorders, functional independence, drug prescriptions and discharge destination. The primary study outcome was the risk of death. Results: We considered 2,343 elderly hospitalized patients (median age 81 years), of whom 1,154 (49%) had COPD, 813 (35%) HF, and 376 (16%) COPD + HF. Patients with COPD + HF had different characteristics than those with COPD or HF, such as a higher prevalence of previous hospitalizations, comorbidities (especially chronic kidney disease), higher respiratory rate at admission and number of prescribed drugs. Patients with COPD + HF (hazard ratio HR 1.74, 95% confidence intervals CI 1.16-2.61) and patients with dementia (HR 1.75, 95% CI 1.06-2.90) had a higher risk of death at one year. The Kaplan-Meier curves showed a higher mortality risk in the group of patients with COPD + HF for all causes (p = 0.010), respiratory causes (p = 0.006), cardiovascular causes (p = 0.046) and respiratory plus cardiovascular causes (p = 0.009). Conclusion: In this real-life cohort of hospitalized elderly patients, the coexistence of COPD and HF significantly worsened prognosis at one year. This finding may help to better define the care needs of this population

The “Diabetes Comorbidome”: A Different Way for Health Professionals to Approach the Comorbidity Burden of Diabetes

(1) Background: The disease burden related to diabetes is increasing greatly, particularly in older subjects. A more comprehensive approach towards the assessment and management of diabetes’ comorbidities is necessary. The aim of this study was to implement our previous data identifying and representing the prevalence of the comorbidities, their association with mortality, and the strength of their relationship in hospitalized elderly patients with diabetes, developing, at the same time, a new graphic representation model of the comorbidome called “Diabetes Comorbidome”. (2) Methods: Data were collected from the RePoSi register. Comorbidities, socio-demographic data, severity and comorbidity indexes (Cumulative Illness rating Scale CIRS-SI and CIRS-CI), and functional status (Barthel Index), were recorded. Mortality rates were assessed in hospital and 3 and 12 months after discharge. (3) Results: Of the 4714 hospitalized elderly patients, 1378 had diabetes. The comorbidities distribution showed that arterial hypertension (57.1%), ischemic heart disease (31.4%), chronic renal failure (28.8%), atrial fibrillation (25.6%), and COPD (22.7%), were the more frequent in subjects with diabetes. The graphic comorbidome showed that the strongest predictors of death at in hospital and at the 3-month follow-up were dementia and cancer. At the 1-year follow-up, cancer was the first comorbidity independently associated with mortality. (4) Conclusions: The “Diabetes Comorbidome” represents the perfect instrument for determining the prevalence of comorbidities and the strength of their relationship with risk of death, as well as the need for an effective treatment for improving clinical outcomes

Antidiabetic Drug Prescription Pattern in Hospitalized Older Patients with Diabetes

Objective: To describe the prescription pattern of antidiabetic and cardiovascular drugs in a cohort of hospitalized older patients with diabetes. Methods: Patients with diabetes aged 65 years or older hospitalized in internal medicine and/or geriatric wards throughout Italy and enrolled in the REPOSI (REgistro POliterapuie SIMI—Società Italiana di Medicina Interna) registry from 2010 to 2019 and discharged alive were included. Results: Among 1703 patients with diabetes, 1433 (84.2%) were on treatment with at least one antidiabetic drug at hospital admission, mainly prescribed as monotherapy with insulin (28.3%) or metformin (19.2%). The proportion of treated patients decreased at discharge (N = 1309, 76.9%), with a significant reduction over time. Among those prescribed, the proportion of those with insulin alone increased over time (p = 0.0066), while the proportion of those prescribed sulfonylureas decreased (p &lt; 0.0001). Among patients receiving antidiabetic therapy at discharge, 1063 (81.2%) were also prescribed cardiovascular drugs, mainly with an antihypertensive drug alone or in combination (N = 777, 73.1%). Conclusion: The management of older patients with diabetes in a hospital setting is often sub-optimal, as shown by the increasing trend in insulin at discharge, even if an overall improvement has been highlighted by the prevalent decrease in sulfonylureas prescription

Prescription appropriateness of anti-diabetes drugs in elderly patients hospitalized in a clinical setting: evidence from the REPOSI Register

Diabetes is an increasing global health burden with the highest prevalence (24.0%) observed in elderly people. Older diabetic adults have a greater risk of hospitalization and several geriatric syndromes than older nondiabetic adults. For these conditions, special care is required in prescribing therapies including anti- diabetes drugs. Aim of this study was to evaluate the appropriateness and the adherence to safety recommendations in the prescriptions of glucose-lowering drugs in hospitalized elderly patients with diabetes. Data for this cross-sectional study were obtained from the REgistro POliterapie-Società Italiana Medicina Interna (REPOSI) that collected clinical information on patients aged ≥ 65 years acutely admitted to Italian internal medicine and geriatric non-intensive care units (ICU) from 2010 up to 2019. Prescription appropriateness was assessed according to the 2019 AGS Beers Criteria and anti-diabetes drug data sheets.Among 5349 patients, 1624 (30.3%) had diagnosis of type 2 diabetes. At admission, 37.7% of diabetic patients received treatment with metformin, 37.3% insulin therapy, 16.4% sulfonylureas, and 11.4% glinides. Surprisingly, only 3.1% of diabetic patients were treated with new classes of anti- diabetes drugs. According to prescription criteria, at admission 15.4% of patients treated with metformin and 2.6% with sulfonylureas received inappropriately these treatments. At discharge, the inappropriateness of metformin therapy decreased (10.2%, P &lt; 0.0001). According to Beers criteria, the inappropriate prescriptions of sulfonylureas raised to 29% both at admission and at discharge. This study shows a poor adherence to current guidelines on diabetes management in hospitalized elderly people with a high prevalence of inappropriate use of sulfonylureas according to the Beers criteria

Clinical features and outcomes of elderly hospitalised patients with chronic obstructive pulmonary disease, heart failure or both

Background and objective: Chronic obstructive pulmonary disease (COPD) and heart failure (HF) mutually increase the risk of being present in the same patient, especially if older. Whether or not this coexistence may be associated with a worse prognosis is debated. Therefore, employing data derived from the REPOSI register, we evaluated the clinical features and outcomes in a population of elderly patients admitted to internal medicine wards and having COPD, HF or COPD + HF. Methods: We measured socio-demographic and anthropometric characteristics, severity and prevalence of comorbidities, clinical and laboratory features during hospitalization, mood disorders, functional independence, drug prescriptions and discharge destination. The primary study outcome was the risk of death. Results: We considered 2,343 elderly hospitalized patients (median age 81&nbsp;years), of whom 1,154 (49%) had COPD, 813 (35%) HF, and 376 (16%) COPD + HF. Patients with COPD + HF had different characteristics than those with COPD or HF, such as a higher prevalence of previous hospitalizations, comorbidities (especially chronic kidney disease), higher respiratory rate at admission and number of prescribed drugs. Patients with COPD + HF (hazard ratio HR 1.74, 95% confidence intervals CI 1.16-2.61) and patients with dementia (HR 1.75, 95% CI 1.06-2.90) had a higher risk of death at one year. The Kaplan-Meier curves showed a higher mortality risk in the group of patients with COPD + HF for all causes (p = 0.010), respiratory causes (p = 0.006), cardiovascular causes (p = 0.046) and respiratory plus cardiovascular causes (p = 0.009). Conclusion: In this real-life cohort of hospitalized elderly patients, the coexistence of COPD and HF significantly worsened prognosis at one year. This finding may help to better define the care needs of this population