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Individuals with lupus nephritis (LN) are at high risk of adverse maternal and fetal outcomes in pregnancy. Outside of pregnancy, proliferative lesions on kidney biopsies are associated with disease progression, but these have not been consistently associated with increased risk in pregnancy. This retrospective, single-center study examines how histologic findings, the timing from kidney biopsy to pregnancy, and the clinical features in the first trimester are associated with preterm birth among individuals with LN. Among 35 deliveries in 31 women, the mean gestational age at delivery was 33.8 weeks. The presence of a urine protein-to-creatinine ratio >0.5 g/g in the first trimester was associated with preterm delivery (81% vs. 36%, p = 0.04). Preterm birth was more common in individuals with glomerular crescents on biopsy (89% in those with >20% crescents vs. 50% in those with <20%, p = 0.06). A pregnancy occurring within 2 years after a kidney biopsy was more likely to result in preterm birth than if the biopsy was performed more than 2 years prior to conception (82% vs. 23%, p = 0.01). The time from diagnostic biopsy may be a surrogate for disease activity, and a 2-year delay from biopsy might allow sufficient time to achieve disease remission. Overall, these data could aid family planning discussions and promote preconception disease optimization for patients and their providers.
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Rationale & Objective: About 25%-40% of patients with inflammatory bowel disease (IBD) may have extraintestinal manifestations, mainly involving the liver, skin, and joints. Kidney involvement in patients with IBD has been reported, but there are no estimates of its prevalence in population-based studies in the United States. We compared the frequency of acute kidney injury (AKI) among hospitalizations with IBD with that among hospitalizations with collagen vascular diseases and hospitalizations with neither condition. Study Design: Retrospective, population-based cohort study. Setting & Participants: Healthcare Cost and Utilization Project-Nationwide Inpatient Sample database. Outcomes: AKI and AKI requiring dialysis. Analytical Approach: Regression models were used to compare the occurrence of AKI among groups. Inverse probability of treatment weighting was applied to balance groups on covariates. Results: The final sample comprised 5,735,804 hospitalizations, including 57,121 with IBD, 159,930 with collagen vascular diseases, and 5,518,753 with neither IBD nor collagen vascular diseases. AKI was observed in 13%, 15%, and 12.2% of hospitalizations with IBD, collagen vascular diseases, and the general population, respectively. When adjusting for demographic, hospital, and clinical characteristics using inverse probability of treatment weighting, hospitalizations with IBD had higher odds of being diagnosed with AKI than both those with collagen vascular diseases (odds ratio [OR], 1.32; 95% confidence interval [CI], 1.27-1.38) and the general population (OR, 1.27; 95% CI, 1.23-1.31) and also had higher odds of being diagnosed with AKI requiring dialysis than those with collagen vascular diseases (OR, 1.59; 95% CI, 1.31-1.94) or than the general population (OR, 1.45; 95% CI, 1.25-1.68). Limitations: Cross-sectional analysis, underreporting of International Classification of Diseases codes, and analyses relevant to in-hospital stays only. Conclusions: The prevalence and risk of AKI among hospitalizations with IBD is greater than that of hospitalizations with collagen vascular diseases and the general population. Coexisting kidney disease should be considered among patients with a known diagnosis of IBD.
As a nephrologist, we have evaluated many patients with inflammatory bowel disease with various forms of kidney disease, both inflammatory and noninflammatory. Based on a multitude of factors, we have always wondered if there are shared immune mechanisms between the gut and kidney that could explain the underlying inflammation in both organs. In addition, based on recent studies of other autoimmune/inflammatory diseases, there is growing interest in the role of the gut microbiome (microorganisms that reside in our gut) and its influence on the immune system as well as how both the altered microbiome and immune system affect the kidneys. As a first step, we wanted to understand if some forms of kidney disease are more prevalent in patients with inflammatory bowel disease than in the general population, which possibly suggests a shared pathogenesis.
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Severe infections associated with the use of strong immunosuppressive medication are a leading cause of morbidity and mortality in patients with ANCA vasculitis (AV). While guidelines conditionally recommend trimethoprim-sulfamethoxazole (TMP-SMX) prophylaxis for Pneumocystis jirovecii pneumonia in AV patients, robust evidence on prophylaxis strategies is lacking. This scoping review aimed to assess the existing evidence on infection prophylaxis in AV patients, identify knowledge gaps, and guide future study design. A comprehensive search of six databases and relevant references identified original studies in English from January 1, 2000, to July 31, 2020. Inclusion criteria encompassed studies evaluating the impact of any antimicrobial prophylaxis strategy on infection-related outcomes in AV patients receiving immunosuppressive treatment. Studies were screened by four researchers using a blinded approach. Data was extracted by two reviewers, with differences resolved via consensus in consultation with a third reviewer. Nineteen studies met inclusion criteria, including two randomized trials and 17 cohort studies, with TMP-SMX being the most commonly assessed prophylactic strategy. The studies varied in sample sizes, outcomes measured, prophylactic strategies employed, and proportion of patients who received the regimen. Most cohort studies included no or limited control of potential confounding factors. This scoping review suggests significant variation in AV patients' receipt of TMP-SMX and alternative infection prophylaxis approaches. Observational studies using large secondary healthcare databases with rigorous designs are needed to provide high-quality evidence of the real-world effectiveness of antimicrobial prophylactic regimens, to improve clinical decision-making and quality of care for AV patients receiving immunosuppressive treatment.
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Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos , Neumonía por Pneumocystis , Combinación Trimetoprim y Sulfametoxazol , Humanos , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/tratamiento farmacológico , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/complicaciones , Combinación Trimetoprim y Sulfametoxazol/uso terapéutico , Neumonía por Pneumocystis/prevención & control , Inmunosupresores/uso terapéutico , Profilaxis AntibióticaRESUMEN
The role of stressors, insect bites, and infections on disease relapse of ANCA vasculitis has yet to be entirely explored, with limited retrospective studies focused on disease onset from small participant cohorts. Our study analyzes longitudinal survey data from 2011-2022 to evaluate this perspective from a large ANCA vasculitis cohort. We collected surveys every three to six months to obtain information on self-reported psychological stressors and significant life events, insect bites, and infections throughout clinical disease. We defined cohorts as those who relapsed (Relapse Cohort) and controls as those who did not relapse (Remission Cohort) during the study period. Survey responses were retrospectively reviewed during a 15-month timeframe prior to relapse or during 15 months of remission and categorized by type of stress event, insect bite, and infections at every available 3-month interval. There were no significant differences in stress and insect bites between the relapse and remission cohorts. Patients who relapsed reported more frequent upper respiratory infections and other infections, such as those affecting the skin and eyes, but there were no significant differences in the incidence of pulmonary or urinary infections compared to the remission cohort. There was a significant difference in reported upper respiratory infections 9 to 15 months prior to the relapse date, indicating a remote history of infections as a potentially significant physical stressor that may contribute to disease relapse. More frequent patient-reported infections, specifically upper respiratory infections, may contribute to patient vulnerability to relapse. Counseling and close monitoring of patients after infectious symptoms could aid in earlier detection of disease flares. Future studies are essential to further understand the importance of distal risk factors and how they impact relapse.
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Regulation of autoreactive cells is key for both prevention and amelioration of autoimmune disease. A better understanding of the key cell population(s) responsible for downregulation of autoreactive cells would provide necessary foundational insight for cellular-based therapies in autoimmune disease. Utilizing a mouse model of anti-myeloperoxidase (MPO) glomerulonephritis, we sought to understand which immune cells contribute to downregulation of the anti-MPO autoimmune response. MPO-/- mice were immunized with whole MPO to induce an anti-MPO response. Anti-MPO splenocytes were then transferred into recipient mice (Rag2-/- mice or WT mice). Anti-MPO titers were followed over time. After anti-MPO splenocyte transfer, WT mice are able to downregulate the anti-MPO response while anti-MPO titers persist in Rag2-/- recipients. Reconstitution with WT splenocytes into Rag2-/- recipients prior to anti-MPO splenocyte transfer enabled mice to downregulate the anti-MPO immune response. Therefore, wildtype splenocytes contain a cellular population that is capable of downregulating the autoimmune response. Through splenocyte transfer, antibody depletion experiments, and purified cell population transfers, we confirmed that the regulatory T cell (Treg) population is responsible for the downregulation of the anti-MPO autoimmune response. Further investigation revealed that functional Tregs from WT mice are capable of downregulating anti-MPO antibody production and ameliorate anti-MPO induced glomerulonephritis. These data underscore the importance of functional Tregs for control of autoimmune responses and prevention of end-organ damage due to autoimmunity.
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Autoinmunidad , Modelos Animales de Enfermedad , Glomerulonefritis , Ratones Noqueados , Peroxidasa , Linfocitos T Reguladores , Animales , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , Glomerulonefritis/inmunología , Glomerulonefritis/terapia , Ratones , Peroxidasa/metabolismo , Peroxidasa/inmunología , Autoanticuerpos/inmunología , Bazo/inmunología , Regulación hacia Abajo , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Traslado Adoptivo , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/terapia , Ratones Endogámicos C57BLRESUMEN
RATIONALE & OBJECTIVE: The influence of obesity on cardiorenal outcomes in individuals with glomerular disease is incompletely known. This study examined the association between obesity and kidney and cardiovascular outcomes in children and adults with glomerular kidney disease. STUDY DESIGN: Prospective, multicenter, observational study. SETTING & PARTICIPANTS: Participants in the Cure Glomerulonephropathy Network (CureGN) who were≥5 years of age at enrollment. EXPOSURE: Adult body mass index (BMI) groups: 20-24 (healthy) versus 25-34 (overweight/class 1 obesity) versus≥35 (class 2-3 obesity); and pediatric BMI percentiles: 5th-84th (healthy) versus 85th-94th (overweight) versus≥95th (obese). OUTCOME: A composite kidney outcome (40% estimated glomerular filtration rate [eGFR] decline or kidney failure) and a composite cardiovascular outcome (myocardial infarction, stroke, heart failure, or death). ANALYTICAL APPROACH: Time to composite primary outcomes by BMI strata were estimated using Kaplan-Meier analysis. The adjusted associations between BMI and outcomes were estimated using Cox proportional hazards analysis. RESULTS: The study included 2,301 participants (1,548 adults and 753 children). The incidence of the primary kidney end point was 90.8 per 1,000 person-years in adults with class 2-3 obesity, compared with 58.0 in normal weight comparators. In the univariable analysis, class 2-3 obesity was associated with the primary kidney outcome only in adults (HR, 1.6 [95% CI, 1.1-2.2], P=0.006) compared with the healthy weight groups. In the multivariable adjusted analysis, class 2-3 obesity did not remain significant among adults when controlling for baseline eGFR and proteinuria. Adults with class 2-3 obesity had an incidence of 19.7 cardiovascular events per 1,000 person-years and greater cardiovascular risk (HR, 3.9 [95% CI, 1.4-10.7], P=0.009) in the fully adjusted model. LIMITATIONS: BMI is an imperfect indicator of adiposity. Residual confounding may exist from socioeconomic factors. CONCLUSIONS: Among adult patients in CureGN, class 2-3 obesity is associated with cardiovascular but not kidney outcomes when adjusted for potential confounding factors. PLAIN-LANGUAGE SUMMARY: Obesity is a risk factor for adverse heart and kidney outcomes in patients with chronic kidney disease, but whether it is associated with these outcomes in patients with glomerulonephropathy is not known. This study used existing data from a large sample of adults and children with glomerular diseases to address this question. The findings suggest that obesity increases the risk of cardiovascular but not kidney disease events in adult patients with glomerular disease.
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BACKGROUND: Hispanic/Latino individuals are less likely to receive optimal treatment for chronic kidney disease than non-Hispanic whites. This may be particularly detrimental for women of reproductive age as chronic kidney disease increases risk for infertility, menstrual irregularities, and pregnancy loss. While these maternal outcomes have been associated with advanced chronic kidney disease, their occurrence in early chronic kidney disease is unclear. OBJECTIVES/DESIGN: Using baseline (2008-2011) and second study visit (2014-2017) data from the Hispanic Community Health Study/Study of Latinos, we retrospectively assessed the prevalence of chronic kidney disease as well as the association between chronic kidney disease and self-reported infertility, cessation of menses, hysterectomy, and nonviable pregnancy loss (experienced at less than 24 weeks gestation) in women of reproductive age (18-45 years). METHODS: Multivariable survey logistic regression analyses determined the unadjusted and multivariable-adjusted prevalence odds ratios with 95% confidence intervals between chronic kidney disease and the separate outcomes. RESULTS: Among 2589 Hispanic/Latino women included (mean age = 31.4 years), 4.6% were considered to have chronic kidney disease. In adjusted analyses, women with chronic kidney disease did not have a significantly increased odds of infertility (odds ratio = 1.02, 95% confidence interval = 0.42-2.49), cessation of menses (odds ratio = 1.25, 95% confidence interval = 0.52-3.04), or hysterectomy (odds ratio = 1.17, 95% confidence interval = 0.61-2.25) compared to those without chronic kidney disease. In those with chronic kidney disease, the adjusted odds of a nonviable pregnancy loss occurring after baseline visit were increased (odds ratio = 2.11, 95% confidence interval = 0.63-7.02) but not statistically significance. CONCLUSION: The presence of early stage chronic kidney disease did not confer a significant risk of infertility, cessation of menses, or nonviable pregnancy loss.
The Hispanic Community Health Study/Study of Latinos is a population-based study of over 16,000 Hispanic/Latino individuals throughout the United States. Within this cohort, we assessed the prevalence of chronic kidney disease in women of reproductive age (1845 years old) and the associations between kidney disease and infertility, cessation of menses, and nonviable pregnancy loss (loss occurring before the 24th week of pregnancy). We found that kidney disease affected 1 in 20 women of reproductive age and those with kidney disease were more likely to have obesity, diabetes, and hypertension. Compared to those without kidney disease, the presence of kidney disease did not increase risk of infertility, cessation of menses, or nonviable pregnancy loss.
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Infertilidad , Insuficiencia Renal Crónica , Embarazo , Humanos , Femenino , Adulto , Adolescente , Adulto Joven , Persona de Mediana Edad , Factores de Riesgo , Prevalencia , Salud Pública , Estudios Retrospectivos , Hispánicos o Latinos , Insuficiencia Renal Crónica/epidemiologíaRESUMEN
RATIONALE & OBJECTIVE: Kidney transplant patients with glomerulonephritis (GN) as their native disease commonly have received pretransplant immunosuppression (PTI). This may contribute to the immunosuppression burden potentially increasing the risk for infections after transplantation. STUDY DESIGN: Single-center, retrospective cohort study. SETTING & PARTICIPANTS: Recipients of a kidney transplant from January 2005 until May 2020 at a tertiary care university teaching hospital. EXPOSURE: Patients with GN as their native kidney disease who received PTI for treatment of GN (n=184) were compared with nondiabetic recipients of kidney transplants who did not receive PTI (n = 579). OUTCOME: First occurrence after transplantation of an infection outcome, either viral (BK or cytomegalovirus [CMV] infection) or bacterial. ANALYTICAL APPROACH: Cox regression analysis adjusted for age at transplant, sex, race, donor type, year of transplant surgery, dialysis vintage, receipt of T-cell depleting induction, and CMV transplant status. RESULTS: Over a median follow-up period of 5.7 years, patients with GN PTI were not at an increased risk for developing any first viral infection compared with controls (adjusted HR [AHR] 0.69 [95% CI, 0.52-0.91]) nor at increased risk for specific viral infections: BK infection 19.6% vs 26.3% (AHR 0.72 [95% CI, 0.50-1.05]) or CMV infection, 24.5% vs 29.0% (AHR, 0.76 [95% CI, 0.54-1.07]), respectively. There was also no increased risk of developing a first bacterial infection: 54.5% vs 57.5% (AHR, 0.90 [95% CI, 0.71-1.13]). These findings of no increased risk for infection were independent of the type of PTI used (cyclophosphamide, rituximab, mycophenolate mofetil, or calcineurin inhibitor) or the type of T-cell depleting induction therapy (alemtuzumab or antithymocyte globulin) administered. LIMITATIONS: Single-center study, no data on methylprednisone use for PTI, unmeasured confounding. CONCLUSIONS: Use of PTI for the treatment of GN was not associated with an increased risk of viral (BK or CMV) or bacterial infection after transplantation. Additional surveillance for infection after transplantation for patients who received PTI may not be necessary. PLAIN-LANGUAGE SUMMARY: Many kidney transplant patients have glomerular disease as the cause of kidney failure. These patients may be exposed to immunosuppression before transplantation, which could increase the risk for infections after receipt of a transplanted kidney. We identified kidney transplant recipients at a university teaching hospital who received immunosuppression before transplant for the treatment of glomerular kidney disease. We examined their risk for infection after transplantation by comparing it with the risk among transplant patients who were not exposed to immunosuppression before transplant. We observed no increased risk for infection after exposure to prior immunosuppression. Therefore, patients exposed to significant amounts of immunosuppression before transplantation may not require special surveillance or medication adjustment for fear of infection after their receipt of a kidney transplant.
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Glomerulonefritis , Inmunosupresores , Trasplante de Riñón , Humanos , Trasplante de Riñón/efectos adversos , Masculino , Femenino , Glomerulonefritis/epidemiología , Glomerulonefritis/etiología , Estudios Retrospectivos , Persona de Mediana Edad , Inmunosupresores/efectos adversos , Inmunosupresores/uso terapéutico , Adulto , Infecciones por Citomegalovirus/epidemiología , Infecciones por Citomegalovirus/etiología , Infecciones por Citomegalovirus/inmunología , Terapia de Inmunosupresión/efectos adversos , Terapia de Inmunosupresión/métodos , Infecciones Bacterianas/epidemiología , Infecciones Bacterianas/etiología , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiologíaRESUMEN
BACKGROUND: CKD of unknown etiology (CKDu) disproportionately affects young people in Central America who lack traditional CKD risk factors (diabetes and hypertension) and has instead been variably linked to heat stress, occupational and environmental exposures, nephrotoxic medications, and/or genetic susceptibility. This study aimed to estimate the prevalence of CKD and identify risk factors for traditional CKD and CKDu in Nicaragua. METHODS: Surveys and assessment for CKD markers in urine and serum were performed in 15-59 year olds in households of the León municipality of Nicaragua. The survey included questions on demographics, health behaviors, occupation, and medical history. Participants with CKD were subdivided into traditional CKD and suspected CKDu based on history of diabetes, hypertension, or other specified conditions. A multinomial logistic regression model was used to identify factors associated with traditional CKD and suspected CKDu, compared to the non-CKD reference group. RESULTS: In 1795 study participants, CKD prevalence was 8.6%. Prevalence in males was twofold higher than females (12% vs 6%). Of those with CKD, 35% had suspected CKDu. Both traditional CKD and CKDu were associated with male sex and increasing age. Traditional CKD was associated with a family history of CKD, history of urinary tract infections, and lower socioeconomic status, while CKDu was associated with drinking well water and a lower body mass index. CONCLUSIONS: Both traditional CKD and CKDu are significant burdens in this region. Our study supports previous hypotheses of CKDu etiology and emphasizes the importance of CKD screening.
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Diabetes Mellitus , Hipertensión , Insuficiencia Renal Crónica , Adolescente , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Hipertensión/epidemiología , Hipertensión/complicaciones , Nicaragua/epidemiología , Prevalencia , Insuficiencia Renal Crónica/epidemiología , Factores de Riesgo , Enfermedades Renales Crónicas de Etiología Incierta/epidemiologíaRESUMEN
BACKGROUND: Treatment requirements of antineutrophil cytoplasmic autoantibody vasculitis (AV) and high comorbidity burden among patients with AV may lead to higher potential for polypharmacy and its associated adverse outcomes, including adverse drug events, nonadherence, drug-drug interactions, and higher costs. Medication burden and risk factors associated with polypharmacy in patients with AV have not been well-characterized. OBJECTIVE: To characterize medication burden and examine prevalence of and risk factors for polypharmacy in the first year after diagnosis with AV. METHODS: We conducted a retrospective cohort study using 2015-2017 Medicare claims to identify incident cases of AV. We counted the number of unique generic products dispensed to patients in each of the 4 quarters after diagnosis and categorized medication count as high (≥10 medications), moderate (5-9 medications), or minimal or no polypharmacy (<5 medications). We used multinomial logistic regression to examine associations of predisposing, enabling, and medical need factors with having high or moderate polypharmacy. RESULTS: In 1,239 Medicare beneficiaries with AV, high or moderate polypharmacy was most common in the first quarter after diagnosis (83.7%), with 43.2% taking 5 - 9 medications and 40.5% taking at least 10. The odds of high polypharmacy were greater in all quarters for patients with eosinophilic granulomatosis with polyangiitis compared with granulomatosis with polyangiitis, ranging from 2.02 (95% CI = 1.18 - 3.46) in the third quarter to 2.96 (95% CI = 1.64-5.33) in the second quarter. Older age, diabetes, chronic kidney disease, obesity, a higher Charlson Comorbidity Index score, coverage with Medicaid/Part D low-income subsidy, and living in areas with low education or persistent poverty were risk factors for high or moderate polypharmacy. CONCLUSIONS: Medicare beneficiaries with newly diagnosed AV experienced a high medication burden, with more than 40% taking at least 10 medications and the highest rates among those with eosinophilic granulomatosis with polyangiitis. Patients with AV may benefit from medication therapy management interventions to manage complex drug regimens and reduce risks associated with polypharmacy. DISCLOSURES: Dr Derebail receives personal fees from Travere Therapeutics, Pfizer, Bayer, Forma Therapeutics, UpToDate, outside of the submitted work. The content is solely the responsibility of the authors and does not represent the official views of the National Institutes of Health or the Department of Veterans Affairs. Dr Thorpe receives royalties from SAGE Publishing for activities unrelated to the submitted work. This research is supported by internal funds from the University of North Carolina, as well as the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under award number R21AI160606 (PI: C. Thorpe).
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Síndrome de Churg-Strauss , Granulomatosis con Poliangitis , Humanos , Anciano , Estados Unidos/epidemiología , Medicare , Anticuerpos Anticitoplasma de Neutrófilos , Estudios RetrospectivosRESUMEN
BACKGROUND: Disparity in CKD progression among Black individuals persists in glomerular diseases. Genetic variants in the apolipoprotein L1 ( APOL1 ) gene in the Black population contribute to kidney disease, but the influence in membranous nephropathy remains unknown. METHODS: Longitudinally followed participants enrolled in the Glomerular Disease Collaborative Network or Cure Glomerulonephropathy Network were included if they had DNA or genotyping available for APOL1 (Black participants with membranous nephropathy) or had membranous nephropathy but were not Black. eGFR slopes were estimated using linear mixed-effects models with random effects and adjusting for covariates and interaction terms of covariates. Fisher exact test, Kruskal-Wallis test, and Kaplan-Meier curves with log-rank tests were used to compare groups. RESULTS: Among 118 Black membranous nephropathy participants, 16 (14%) had high-risk APOL1 genotype (two risk alleles) and 102 (86%) had low-risk APOL1 genotype (zero or one risk alleles, n =53 and n =49, respectively). High-risk APOL1 membranous nephropathy participants were notably younger at disease onset than low-risk APOL1 and membranous nephropathy participants that were not Black ( n =572). eGFR at disease onset was not different between groups, although eGFR decline (slope) was steeper in participants with high-risk APOL1 genotype (-16±2 [±SE] ml/min per 1.73 m 2 per year) compared with low-risk APOL1 genotype (-4±0.8 ml/min per 1.73 m 2 per year) or membranous nephropathy participants that did not identify themselves as Black (-2.0±0.4 ml/min per 1.73 m 2 per year) ( P <0.0001). Time to kidney failure was faster in the high-risk APOL1 genotype than low-risk APOL1 genotype or membranous nephropathy participants that were not Black. CONCLUSIONS: The prevalence of high-risk APOL1 variant among Black membranous nephropathy participants is comparable with the general Black population (10%-15%), yet the high-risk genotype was associated with worse eGFR decline and faster time to kidney failure compared with low-risk genotype and participants that were not Black.
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Apolipoproteína L1 , Glomerulonefritis Membranosa , Insuficiencia Renal Crónica , Humanos , Apolipoproteína L1/genética , Apolipoproteínas/genética , Progresión de la Enfermedad , Genotipo , Tasa de Filtración Glomerular/genética , Glomerulonefritis Membranosa/genética , Riñón , Insuficiencia Renal Crónica/genética , Insuficiencia Renal Crónica/epidemiología , Factores de Riesgo , Población Negra/genéticaRESUMEN
A GWAS of patients with anti-neutrophil cytoplasmic antibodies (ANCAs) found an association between proteinase-3 ANCA (PR3-ANCA) and a single nucleotide polymorphism (rs62132293) upstream of PRTN3, encoding PR3. The variant (G allele) was shown to be an expression quantitative trait locus in healthy controls, but the clinical impact remains unknown. Longitudinally followed patients with ANCA and healthy controls were genotyped. Gene expression was quantified by real-time quantitative PCR from leukocyte RNA. Plasma PR3 was quantified by ELISA. Among patients, variant carriers had elevated leukocyte PRTN3 expression compared with noncarriers (C/G vs. C/C and G/G vs. C/C). Healthy controls had low PRTN3 regardless of genotype. Myeloperoxidase (MPO) expression did not differ by genotype. PRTN3 expression correlated with circulating PR3, and variant carriers had higher plasma PR3 compared with noncarriers. Among variant carriers, there was an increased risk of relapse in patients with PR3-ANCA versus MPO-ANCA. The risk allele marked by rs62132293 is clinically significant as it is associated with increased autoantigen and may, in part, explain increased relapse in PR3-ANCA. Our results underscore the role of autoantigen availability in ANCA vasculitis.
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Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos , Anticuerpos Anticitoplasma de Neutrófilos , Mieloblastina , Humanos , Autoantígenos/metabolismo , Mieloblastina/genética , Peroxidasa , RecurrenciaRESUMEN
BACKGROUND: Kidney transplant patients with glomerulonephritis (GN) as their native disease may receive significant amounts of pre-transplant immunosuppression (PTI), which could increase the risk for development of malignancy post-transplant. METHODS: We conducted a single-center, retrospective study of kidney transplant recipients from January 2005 until May 2020. Patients with GN as their native kidney disease who received PTI for treatment of GN (n = 184) were compared with a control cohort (n = 579) of non-diabetic, non-PTI-receiving kidney transplant patients. We calculated hazard ratios (HR) with 95% confidence intervals (95% CI) for outcomes of first occurrence of solid or hematologic malignancy, non-melanoma skin cancer (NMSC) and post-transplant lymphoproliferative disorder (PTLD). RESULTS: Over a median follow-up of 5.7 years, PTI for GN was associated with significantly increased risk for malignancy compared with controls [13.0% vs 9.7%, respectively; adjusted HR 1.82 (95% CI 1.10-3.00)], but not for NMSC [10.3% vs 11.4%, respectively; adjusted HR 1.09 (95% CI 0.64-1.83)] or PTLD [3.3% vs 3.1%, respectively; adjusted HR 1.02 (95% CI 0.40-2.61)]. The risk for malignancy was significantly increased in those who received cyclophosphamide [HR 2.59 (95% CI 1.48-4.55)] or rituximab [HR 3.82 (95% CI 1.69-8.65)] pre-transplant, and particularly in those who received both cyclophosphamide and rituximab, but not for calcineurin inhibitors or mycophenolate. CONCLUSION: The use of PTI for treatment of GN, especially cyclophosphamide or even with rituximab, is associated with increased risk for development of solid or hematologic malignancy post-transplant. These data highlight potential risks with treatment of GN and underscore the importance of post-transplant malignancy surveillance in this patient population.
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Glomerulonefritis , Neoplasias Hematológicas , Trasplante de Riñón , Trastornos Linfoproliferativos , Neoplasias , Humanos , Trasplante de Riñón/efectos adversos , Estudios Retrospectivos , Rituximab/efectos adversos , Terapia de Inmunosupresión/efectos adversos , Glomerulonefritis/etiología , Ciclofosfamida , Neoplasias/etiología , Neoplasias/complicaciones , Trastornos Linfoproliferativos/epidemiología , Trastornos Linfoproliferativos/etiología , Receptores de Trasplantes , Factores de RiesgoRESUMEN
Introduction: Granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA), 2 major clinicopathologic variants of antineutrophil cytoplasmic autoantibody (ANCA) vasculitides, are mostly associated with proteinase 3 (PR3)-ANCA and myeloperoxidase (MPO)-ANCA, respectively. Less is known regarding the uncommon forms of ANCA vasculitis, PR3-ANCA MPA and MPO-ANCA GPA. Methods: In this cohort study we detailed the clinical presentation and outcome of patients with PR3-ANCA MPA and MPO-ANCA GPA from the Glomerular Disease Collaborative Network (GDCN) inception cohort. Baseline clinical manifestations, relapses, end-stage kidney disease (ESKD), and survival were compared within MPA cases by PR3-ANCA (n = 116) versus MPO-ANCA (n = 173) and within GPA cases by PR3-ANCA (n = 108) versus MPO-ANCA (n = 43). Fisher's exact test and Wilcoxon two sample test were used for comparisons. Proportional hazards models were used to evaluate the development of relapses, ESKD, and death. Results: Patients with PR3-ANCA MPA were younger (53 years vs. 62 years, P = 0.0007) and had increased prevalence of joint involvement (56% vs. 40%, P = 0.0115) and ear, nose, and throat (ENT) involvement (44% vs. 26%, P = 0.002) than MPO-ANCA MPA. Relapses, ESKD, and survival were similar between both MPA subsets. Within the GPA group, patients with MPO-ANCA GPA were older (61 years vs. 46 years, P = 0.0007) and more likely female (56% vs. 35%, P = 0.027) than PR3-ANCA GPA patients. MPO-ANCA GPA was also characterized by less prevalent ENT manifestations (58% vs. 77%, P = 0.028) and neurologic manifestations (5% vs. 25%, P = 0.0029), and increased ESKD and mortality. Conclusions: PR3-ANCA MPA and MPO-ANCA GPA are clinicopathologically distinct subsets of ANCA vasculitis that differ from MPO-ANCA MPA and PR3-ANCA GPA. Although the impact of these differences on the clinical management and outcome warrants further evaluation, these results support the recommendation of including both the phenotypic diagnosis and ANCA serotype in the diagnosis of ANCA vasculitis.
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Objectives: T regulatory cells (Tregs) are a heterogeneous group of immunoregulatory cells that dampen self-harming immune responses and prevent the development of autoimmune diseases. In anti-neutrophil cytoplasmic autoantibody (ANCA) vasculitis, Tregs possess diminished suppressive capacity, which has been attributed to the expression of a FOXP3 splice-variant lacking exon 2 in T cells (FOXP3Δ2 CD4+ T cells). However, the suppressive capacity of Tregs varies between subsets. We evaluated the frequency of Treg subsets in ANCA vasculitis as a potential explanation for diminished suppressive capacity. Methods: We developed a custom mass cytometry panel and performed deep immune profiling of Tregs in healthy controls, patients with active disease and in remission. Using these data, we performed multidimensional reduction and discriminant analysis to identify associations between Treg subsets and disease activity. Results: Total Tregs were expanded in ANCA vasculitis, which was associated with remission and the administration of rituximab and/or prednisone. The frequency of FOXP3Δ2 CD4+ T cells did not distinguish disease activity and this population had high expression levels of CD127 and lacked both CD25 and Helios, suggesting that they are not conventional Tregs. The frequency of CXCR3+, CD103+ and CCR7+ Tregs distinguished disease activity, and the combination of the frequency of these three Treg subsets segregated active patients from patients in remission and healthy controls. From these three subsets, the frequency of CXCR3+ Tregs distinguished patients with active disease with renal involvement. Conclusion: Treg heterogeneity can discriminate disease activity and should be explored as a biomarker of disease activity in ANCA vasculitis.
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BACKGROUND: Antineutrophil cytoplasmic antibody (ANCA) vasculitis (AV) is a complex group of autoimmune disorders affecting blood vessels in multiple organ systems. Delays in diagnosis are common because AV symptoms can be nonspecific and present heterogeneously. This may result in increased health care utilization in the months preceding diagnosis. OBJECTIVE: To examine whether Medicare beneficiaries with AV experienced increased health care utilization and costs in the year before the first diagnosis recorded in claims, relative to beneficiaries without AV. METHODS: This retrospective cohort study used 2015-2016 Medicare Part A/B claims and Part D prescription drug data. Beneficiaries with newly diagnosed AV were identified by having 1 or more inpatient claims or 2 or more noninpatient claims 7 or more days apart in 2016 with an International Classification of Diseases, Tenth Revision, Clinical Modification code for AV, with no AV claims in the year prior. Beneficiaries with AV were matched 1:1 on age and sex to beneficiaries without any diagnoses for any type of systemic vasculitis in 2016. Beneficiaries with Part A/B coverage (AB, n = 1,460) and Part A/B/D coverage (ABD, n = 3,252) were analyzed separately. We estimated generalized linear mixed models with a negative binomial distribution to compare health care costs and utilization by AV status. RESULTS: Beneficiaries with AV had approximately 3 times higher Medicare Part A/B payments (incidence rate ratio [95% CI]: AB: 2.94 [2.44-3.53]; ABD: 2.95 [2.64-3.29]) and 2.5 times higher beneficiary Part A/B payments (AB: 2.47 [2.14-2.84]; ABD: 2.62 [2.40-2.87]) vs beneficiaries without AV. Beneficiaries with AV experienced significantly higher utilization across all categories, with the largest differences observed in hospital outpatient visits (AB: 2.69 [2.22-3.27]; ABD: 3.08 [2.73-3.47]). CONCLUSIONS: In the year prior to AV diagnosis, Medicare beneficiaries have significantly higher health care costs and utilization than beneficiaries without AV. DISCLOSURES: Dr Huang was supported by the University of North Carolina and GlaxoSmithKline Health Outcomes Fellowship during the time of the study and reports current employment at Horizon Therapeutics, Deerfield, IL. Dr Nguyen received predoctoral funding through a fellowship appointment sponsored by Bristol Myers Squibb during the time of the study and reports current employment at GlaxoSmithKline, Collegeville, PA. Dr Derebail receives personal fees from Travere Therapeutics, Bayer, and UpToDate, outside of the submitted work. The views expressed are those of the authors and do not represent the views of the Department of Veteran Affairs. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.
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Medicamentos bajo Prescripción , Vasculitis , Anciano , Estados Unidos , Humanos , Medicare , Anticuerpos Anticitoplasma de Neutrófilos , Estudios Retrospectivos , Costos de la Atención en SaludRESUMEN
INTRODUCTION: Lupus nephritis (LN) may present with thrombotic microangiopathy (TMA) on kidney biopsy, the impact of which on outcomes is unclear. This study examined the prognostic importance of LN with TMA on kidney biopsy, including response to therapy and long-term outcomes. METHODS: We conducted a single-center, retrospective study of all cases of LN with concomitant TMA on kidney biopsy in the Glomerular Disease Collaborative Network database. Controls were individuals with LN without TMA matched to cases based on demographic and clinical variables. Outcomes were remission at 6- and 12-months, end-stage kidney disease (ESKD) and death. Logistic regression and Cox proportional hazards models were used to ascertain the risks for outcomes, with adjustment for serum creatinine and proteinuria. RESULTS: There were 17 cases and 28 controls. Cases had higher creatinine, higher proteinuria and greater chronicity on biopsy at baseline compared to controls. The rates of remission at 6-months and 12-months were similar between cases and controls (6-months 53.9% vs 46.4%, adjusted OR 2.54, 95% CI 0.48, 13.37; 12-months 53.9% vs 50.0%, adjusted OR 2.95, 95% CI 0.44, 19.78). Cases were at greater risk for ESKD in univariate analysis (HR 3.77; 95% CI 1.24, 11.41) but not when adjusting for serum creatinine and proteinuria (HR 2.20; 95% CI 0.63, 7.71). There was no significant difference in the risk of death between cases and controls. CONCLUSION: Lupus nephritis with renal TMA likely responds to therapy similarly to those without TMA; risk for ESKD is not significantly increased, although the influence of renal function and proteinuria in larger samples is needed.
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Fallo Renal Crónico , Lupus Eritematoso Sistémico , Nefritis Lúpica , Microangiopatías Trombóticas , Biopsia , Creatinina , Humanos , Riñón/patología , Fallo Renal Crónico/complicaciones , Fallo Renal Crónico/etiología , Lupus Eritematoso Sistémico/complicaciones , Nefritis Lúpica/complicaciones , Nefritis Lúpica/tratamiento farmacológico , Nefritis Lúpica/patología , Pronóstico , Proteinuria/complicaciones , Estudios Retrospectivos , Microangiopatías Trombóticas/complicaciones , Microangiopatías Trombóticas/etiologíaRESUMEN
The aim of this study was to investigate the impact of suboptimal 25-hydroxyvitamin D (25-VitD) and cholecalciferol (VitD3 ) supplementation on the pharmacokinetics of oral midazolam (MDZ) in control subjects and subjects with chronic kidney disease (CKD). Subjects with CKD (n = 14) and controls (n = 5) with suboptimal 25-VitD levels (<30 ng/mL) were enrolled in a 2-phase study. In phase 1 (suboptimal), subjects were administered a single oral dose of VitD3 (5000 IU) and MDZ (2 mg). In phase 2 (replete) subjects who achieved 25-VitD repletion after receiving up to 16 weeks of daily cholecalciferol were given the identical single oral doses of VitD3 and MDZ as in phase 1. Concentrations of MDZ and metabolites, 1'-hydroxymidazolam (1'-OHMDZ), and 1'-OHMDZ glucuronide (1'-OHMDZ-G) were measured by liquid chromatography-tandem mass spectrometry and pharmacokinetic analysis was performed. Under suboptimal 25-VitD, reductions in MDZ clearance and renal clearance of 47% and 87%, respectively, and a 72% reduction in renal clearance of 1'-OHMDZ-G were observed in CKD vs controls. In phase 1 versus phase 2, MDZ clearance increased in all control subjects, with a median (interquartile range) increase of 10.5 (0.62-16.7) L/h. No changes in MDZ pharmacokinetics were observed in subjects with CKD between phases 1 and 2. The effects of 25-VitD repletion on MDZ disposition was largely observed in subjects without kidney disease. Impaired MDZ metabolism and/or excretion alterations due to CKD in a suboptimal 25-VitD state may not be reversed by cholecalciferol therapy. Suboptimal 25-VitD may augment the reductions in MDZ and 1'-OHMDZ-G clearance values observed in patients with CKD.
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Colecalciferol , Insuficiencia Renal Crónica , Humanos , Colecalciferol/uso terapéutico , Midazolam/farmacocinética , Vitamina D , Vitaminas , Insuficiencia Renal Crónica/tratamiento farmacológicoRESUMEN
BACKGROUND: PR3-ANCA vasculitis has a genetic association with HLA-DPB1. We explored immunologic and clinical features related to the interaction of HLA-DPB1*04:01 with a strongly binding PR3 peptide epitope (PR3225-239). METHODS: Patients with ANCA vasculitis with active disease and disease in remission were followed longitudinally. Peripheral blood mononuclear cells from patients and healthy controls with HLA-DPB1*04:01 were tested for HLA-DPB1*04:01 expression and interaction with a PR3 peptide identified via in silico and in vitro assays. Tetramers (HLA/peptide multimers) identified autoreactive T cells in vitro. RESULTS: The HLA-DPB1*04:01 genotype was associated with risk of relapse in PR3-ANCA (HR for relapse 2.06; 95% CI, 1.01 to 4.20) but not in myeloperoxidase (MPO)-ANCA or the combined cohort. In silico predictions of HLA and PR3 peptide interactions demonstrated strong affinity between ATRLFPDFFTRVALY (PR3225-239) and HLA-DPB1*04:01 that was confirmed by in vitro competitive binding studies. The interaction was tested in ex vivo flow cytometry studies of labeled peptide and HLA-DPB1*04:01-expressing cells. We demonstrated PR3225-239 specific autoreactive T cells using synthetic HLA multimers (tetramers). Patients in long-term remission off therapy had autoantigenic peptide and HLA interaction comparable to that of healthy volunteers. CONCLUSIONS: The risk allele HLA-DPB1*04:01 has been associated with PR3-ANCA, but its immunopathologic role was unclear. These studies demonstrate that HLA-DPB1*04:01 and PR3225-239 initiate an immune response. Autoreactive T cells specifically recognized PR3225-239 presented by HLA-DPB1*04:01. Although larger studies should validate these findings, the pathobiology may explain the observed increased risk of relapse in our cohort. Moreover, lack of HLA and autoantigen interaction observed during long-term remission signals immunologic nonresponsiveness.