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Organic Pollutant Exposure and CKD: A Chronic Renal Insufficiency Cohort Pilot Study

Charytan, David M; Wu, Wenbo; Liu, Mengling; Li, Zhong-Min; Kannan, Kurunthachalam; Trasande, Leonardo; Pal, Vineet Kumar; Lee, Sunmi; Trachtman, Howard; Appel, Lawrence J.; Chen, Jing; Cohen, Debbie L.; Feldman, Harold I.; Go, Alan S.; Lash, James P.; Nelson, Robert G.; Rahman, Mahboob; Rao, Panduranga S.; Shah, Vallabh O; Unruh, Mark L
ORIGINAL:0017117
ISSN: 2590-0595
CID: 5634782

Precision nephrology identified tumor necrosis factor activation variability in minimal change disease and focal segmental glomerulosclerosis

Mariani, Laura H; Eddy, Sean; AlAkwaa, Fadhl M; McCown, Phillip J; Harder, Jennifer L; Nair, Viji; Eichinger, Felix; Martini, Sebastian; Ademola, Adebowale D; Boima, Vincent; Reich, Heather N; El Saghir, Jamal; Godfrey, Bradley; Ju, Wenjun; Tanner, Emily C; Vega-Warner, Virginia; Wys, Noel L; Adler, Sharon G; Appel, Gerald B; Athavale, Ambarish; Atkinson, Meredith A; Bagnasco, Serena M; Barisoni, Laura; Brown, Elizabeth; Cattran, Daniel C; Coppock, Gaia M; Dell, Katherine M; Derebail, Vimal K; Fervenza, Fernando C; Fornoni, Alessia; Gadegbeku, Crystal A; Gibson, Keisha L; Greenbaum, Laurence A; Hingorani, Sangeeta R; Hladunewich, Michelle A; Hodgin, Jeffrey B; Hogan, Marie C; Holzman, Lawrence B; Jefferson, J Ashley; Kaskel, Frederick J; Kopp, Jeffrey B; Lafayette, Richard A; Lemley, Kevin V; Lieske, John C; Lin, Jen-Jar; Menon, Rajarasee; Meyers, Kevin E; Nachman, Patrick H; Nast, Cynthia C; O'Shaughnessy, Michelle M; Otto, Edgar A; Reidy, Kimberly J; Sambandam, Kamalanathan K; Sedor, John R; Sethna, Christine B; Singer, Pamela; Srivastava, Tarak; Tran, Cheryl L; Tuttle, Katherine R; Vento, Suzanne M; Wang, Chia-Shi; Ojo, Akinlolu O; Adu, Dwomoa; Gipson, Debbie S; Trachtman, Howard; Kretzler, Matthias
The diagnosis of nephrotic syndrome relies on clinical presentation and descriptive patterns of injury on kidney biopsies, but not specific to underlying pathobiology. Consequently, there are variable rates of progression and response to therapy within diagnoses. Here, an unbiased transcriptomic-driven approach was used to identify molecular pathways which are shared by subgroups of patients with either minimal change disease (MCD) or focal segmental glomerulosclerosis (FSGS). Kidney tissue transcriptomic profile-based clustering identified three patient subgroups with shared molecular signatures across independent, North American, European, and African cohorts. One subgroup had significantly greater disease progression (Hazard Ratio 5.2) which persisted after adjusting for diagnosis and clinical measures (Hazard Ratio 3.8). Inclusion in this subgroup was retained even when clustering was limited to those with less than 25% interstitial fibrosis. The molecular profile of this subgroup was largely consistent with tumor necrosis factor (TNF) pathway activation. Two TNF pathway urine markers were identified, tissue inhibitor of metalloproteinases-1 (TIMP-1) and monocyte chemoattractant protein-1 (MCP-1), that could be used to predict an individual's TNF pathway activation score. Kidney organoids and single-nucleus RNA-sequencing of participant kidney biopsies, validated TNF-dependent increases in pathway activation score, transcript and protein levels of TIMP-1 and MCP-1, in resident kidney cells. Thus, molecular profiling identified a subgroup of patients with either MCD or FSGS who shared kidney TNF pathway activation and poor outcomes. A clinical trial testing targeted therapies in patients selected using urinary markers of TNF pathway activation is ongoing.
PMID: 36442540
ISSN: 1523-1755
CID: 5409132

Use of patient portals to support recruitment into clinical trials and health research studies: results from studies using MyChart at one academic institution

Sherman, Scott E; Langford, Aisha T; Chodosh, Joshua; Hampp, Carina; Trachtman, Howard
Electronic health records (EHRs) are often used for recruitment into research studies, as they efficiently facilitate targeted outreach. While studies increasingly are reaching out to potential participants through the EHR patient portal, there is little available information about which approaches are most effective. We surveyed all investigators at one academic medical center who had used the Epic MyChart patient portal for recruitment. We found that messages were typically adapted for a large group, but not tailored further for individual subgroups. The vast majority of studies sent a message only once. Recruitment costs were modest, averaging $431/study. The results show some promise for recruiting through the patient portal but also identified ways in which messages could be optimized.
PMCID:9614350
PMID: 36325306
ISSN: 2574-2531
CID: 5358682

Clinical Outcomes of Patients with C3G or IC-MPGN Treated with the Factor D Inhibitor Danicopan: Final Results from Two Phase 2 Studies

Nester, Carla; Appel, Gerald B; Bomback, Andrew S; Bouman, Koenraad Peter; Cook, H Terence; Daina, Erica; Dixon, Bradley P; Rice, Kara; Najafian, Nader; Hui, James; Podosh, Steven D; Langman, Craig B; Lightstone, Liz; Parikh, Samir V; Pickering, Matthew C; Sperati, C John; Trachtman, Howard; Tumlin, James; de Vries, Aiko Pj; Wetzels, Jack F M; Remuzzi, Giuseppe
INTRODUCTION/BACKGROUND:C3 glomerulopathy (C3G) is an ultrarare, chronic and progressive nephropathy mediated by dysregulation of the alternative pathway of complement (AP), with poor prognosis and limited treatment options. Targeted inhibition of proximal AP through factor D (FD) blockade represents a rational treatment approach. We present two phase 2 proof-of-concept clinical studies of the orally active FD inhibitor danicopan in patients with C3G and immune complex-mediated membranoproliferative glomerulonephritis (IC-MPGN) (NCT03369236 and NCT03459443). METHODS:A double-blind, placebo-controlled study in patients with C3G and a single-arm, open-label study in patients with C3G or IC-MPGN treated with danicopan are reported. The studies evaluated pharmacokinetic/pharmacodynamic (PK/PD), efficacy, and safety outcomes. The co-primary endpoints were change from baseline in composite biopsy score and the proportion of patients with a 30% reduction in proteinuria relative to baseline at 6 or 12 months. RESULTS:Optimal systemic concentrations of danicopan were not achieved for complete and sustained inhibition of AP, although there was evidence that blockade of FD reduced AP activity shortly after drug administration. Consequently, limited clinical response was observed in key efficacy endpoints. While stable disease or improvement from baseline was seen in some patients, response was not consistent. The data confirmed the favorable safety profile of danicopan. CONCLUSION/CONCLUSIONS:While demonstrating a favorable safety profile, danicopan resulted in incomplete and inadequately sustained inhibition of AP, probably due to limitations in its PK/PD profile in C3G, leading to lack of efficacy. Complete and sustained AP inhibition is required for a clinical response in patients with C3G.
PMID: 36423588
ISSN: 1421-9670
CID: 5384392

Baseline Clinical Characteristics and Complement Biomarkers of Patients with C3 Glomerulopathy Enrolled in Two Phase 2 Studies Investigating the Factor D Inhibitor Danicopan

Podos, Steven D; Trachtman, Howard; Appel, Gerald B; Bomback, Andrew S; Dixon, Bradley P; Wetzels, Jack F M; Cook, H Terence; Parikh, Samir V; Pickering, Matthew C; Tumlin, James; Langman, Craig B; Lightstone, Liz; Sperati, C John; Daina, Erica; Bouman, Koenraad Peter; Rice, Kara; Thanassi, Jane A; Huang, Mingjun; Nester, Carla; Remuzzi, Giuseppe
INTRODUCTION/BACKGROUND:C3 glomerulopathy (C3G) is a rare, progressive kidney disease resulting from dysregulation of the alternative pathway (AP) of complement. Biomarkers at baseline were investigated in patients with C3G who participated in two phase 2 studies with the factor D (FD) inhibitor, danicopan. METHODS:Patients with biopsy-confirmed C3G, proteinuria ≥500 mg/day, and estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2 were enrolled into two studies (NCT03369236 and NCT03459443). Biomarker analysis was performed for patients with C3G confirmed by central pathology laboratory re-evaluation. Complement and clinical biomarkers, biopsy composite score, and activity and chronicity indices were assessed at baseline and analyzed by pairwise Spearman correlation analysis. RESULTS:Twenty-nine patients were included in the analysis (median [interquartile range] age: 24.0 [10.0] years). Systemic complement AP activation was evident by reduced median concentrations of C3 and C5, elevated sC5b-9, and normal C4, relative to reference ranges. C3 showed strong pairwise correlations with C5 and sC5b-9 (r = 0.80 and -0.73, respectively; p < 0.0001). Baseline Ba and FD concentrations were inversely correlated with eGFR (r = -0.83 and -0.87, respectively; p < 0.0001). Urinary concentrations of sC5b-9 were correlated with both plasma sC5b-9 and proteinuria (r = 0.69 and r = 0.83, respectively; p < 0.0001). Biopsy activity indices correlated strongly with biomarkers of systemic AP activation, including C3 (r = -0.76, p < 0.0001), whereas chronicity indices aligned more closely with eGFR (r = -0.57, p = 0.0021). CONCLUSION/CONCLUSIONS:Associations among complement biomarkers, kidney function, and kidney histology may add to the current understanding of C3G and assist with the characterization of patients with this heterogenous disease.
PMID: 36404708
ISSN: 1421-9670
CID: 5383952

Efficacy and Safety of Immunosuppressive Therapy in Primary Focal Segmental Glomerulosclerosis: A Systematic Review and Meta-analysis

Caster, Dawn J; Magalhaes, Barbara; Pennese, Natali; Zaffalon, Andrea; Faiella, Marina; Campbell, Kirk N; Radhakrishnan, Jai; Tesar, Vladmir; Trachtman, Howard
Rationale & Objective/UNASSIGNED:Focal segmental glomerulosclerosis (FSGS) is a rare condition that can lead to kidney function decline and chronic kidney failure. Immunosuppressants are used to treat primary FSGS. However, their efficacy and safety in FSGS are not clearly established. We assessed current knowledge on clinical effectiveness and safety of immunosuppressants for primary FSGS. Study Design/UNASSIGNED:Systematic review of randomized controlled trials, interventional nonrandomized controlled trials, observational studies, retrospective studies, and registries. Setting & Participants/UNASSIGNED:Patients with primary and genetic FSGS. Selection Criteria for Studies/UNASSIGNED:Medline, EMBASE, and the Cochrane Central Register of Controlled Trials were searched for English-language, primary-FSGS studies from inception to 2019. Clinical outcomes were changes from baseline in proteinuria, kidney function, and kidney survival. Data Extraction/UNASSIGNED:2 investigators independently screened studies and extracted data. Analytical Approach/UNASSIGNED:Study results were summarized using random-effects models either as ratios of means between follow-up and baseline measurements or as HRs. Results/UNASSIGNED:). Immunosuppressant therapy had an uncertain effect on reducing the chronic kidney failure risk. Hypertension and infections were the most commonly reported adverse events. Limitations/UNASSIGNED:Heterogeneity in study designs, patient populations, and treatment regimens; no access to individual patient-level data. Conclusions/UNASSIGNED:This systematic review supports proteinuria reduction with immunosuppressant therapy in primary FSGS over varying follow-up periods. The effects of immunosuppressants on kidney survival remain uncertain. This review underscores the need for better-designed and adequately controlled studies to assess immunosuppressant therapy in patients with primary FSGS.
PMCID:9399559
PMID: 36032548
ISSN: 2590-0595
CID: 5337482

Determinants of medication adherence in childhood nephrotic syndrome and associations of adherence with clinical outcomes

Wang, Chia-Shi; Troost, Jonathan P; Wang, Yujie; Greenbaum, Larry A; Gibson, Keisha; Trachtman, Howard; Srivastava, Tarak; Reidy, Kimberly; Kaskel, Frederick; Sethna, Christine B; Meyers, Kevin; Dell, Katherine M; Tran, Cheryl L; Hingorani, Sangeeta; Lemley, Kevin V; Lin, Jen-Jar; Gipson, Debbie S
BACKGROUND:Pediatric patients with nephrotic syndrome take medications long-term with significant toxicity and complex regimens, yet data on medication adherence are limited. METHODS:In a multicenter observational study of patients with nephrotic syndrome, NEPTUNE (NCT01209000), we surveyed caregivers of patients <19 years old and adolescent patients on medication adherence during longitudinal follow-up beginning in June 2015. Data extraction was in October 2020. We described the proportion of nonadherent patients at first survey. Participant social and economic factors, condition-related factors, therapy-related factors, and patient-related factors were examined for relationships with nonadherence by generalized linear mixed models using the longitudinal data. In exploratory fashion, we assessed the relationship between adherence and subsequent steroid response classification by binary logistic regression and adherence with healthcare utilization by Poisson regression. RESULTS:A total of 225 participants completed a median of 3 surveys during follow-up (IQR, 2-5), with a total of 743 surveys. Overall, 80 (36%) reported nonadherence with medications. In adjusted analysis, older age (per 1 year; OR 1.08; 95% CI, 1.03 1.12), lower maternal educational level (≥ high school vs. < high school; OR 0.47; 95% CI 0.25 to 0.89), and increased parent and self-identification of medications barriers (per 1 point; OR 1.57; 95% CI, 1.15-2.15) were significantly associated with nonadherence. No relationship between nonadherence and subsequent frequency of healthcare utilization was observed. A trend toward increased subsequent steroid resistance classification was seen with nonadherence, though not statistically significant. CONCLUSIONS:Medication nonadherence is common in pediatric nephrotic syndrome. Investigations into the use of surveys in the clinic setting to identify at-risk patients and ways to support families over time are needed. A higher resolution version of the Graphical abstract is available as Supplementary information.
PMID: 34796395
ISSN: 1432-198x
CID: 5049662

Urinary Polycyclic Aromatic Hydrocarbons in a Longitudinal Cohort of Children with CKD: A Case of Reverse Causation? [Case Report]

Jacobson, Melanie H; Wu, Yinxiang; Liu, Mengling; Kannan, Kurunthachalam; Lee, Sunmi; Ma, Jing; Warady, Bradley A; Furth, Susan; Trachtman, Howard; Trasande, Leonardo
Background/UNASSIGNED:Air pollution, which results in the formation of polycyclic aromatic hydrocarbons (PAHs), has been identified as a cause of renal function decline and a contributor to CKD. However, the results of cross-sectional studies investigating personal, integrated biomarkers of PAHs have been mixed. Longitudinal studies may be better suited to evaluate environmental drivers of kidney decline. The purpose of this study was to examine associations of serially measured urinary PAH metabolites with clinical and subclinical measures of kidney function over time among children with CKD. Methods/UNASSIGNED:-isoprostane) were assayed in urine samples. Results/UNASSIGNED:Children were followed over an average (SD) of 3.0 (1.6) years and 2469 study visits (mean±SD, 4.0±1.6). Hydroxynaphthalene (NAP) or hydroxyphenanthrene (PHEN) metabolites were detected in >99% of samples and NAP concentrations were greater than PHEN concentrations. PHEN metabolites, driven by 3-PHEN, were associated with increased eGFR and reduced proteinuria, diastolic BP z-score, and NGAL concentrations over time. However, PAH metabolites were consistently associated with increased KIM-1 and 8-OHdG concentrations. Conclusions/UNASSIGNED:Among children with CKD, these findings provoke the potential explanation of reverse causation, where renal function affects measured biomarker concentrations, even in the setting of a longitudinal study. Additional work is needed to determine if elevated KIM-1 and 8-OHdG excretion reflects site-specific injury to the proximal tubule mediated by low-grade oxidant stress.
PMCID:9255870
PMID: 35845343
ISSN: 2641-7650
CID: 5278572

Efficacy and Safety of ACE Inhibitor and Angiotensin Receptor Blocker Therapies in Primary Focal Segmental Glomerulosclerosis Treatment: A Systematic Review and Meta-Analysis

Campbell, Kirk N; Pennese, Natali; Zaffalon, Andrea; Magalhaes, Barbara; Faiella, Marina; Caster, Dawn J; Radhakrishnan, Jai; Tesar, Vladimir; Trachtman, Howard
Rationale and Objective/UNASSIGNED:Angiotensin-converting enzyme inhibitor or angiotensin receptor blocker therapy (renin-angiotensin-aldosterone system [RAAS] inhibitor) to control proteinuria in primary and genetic focal segmental glomerulosclerosis (FSGS) follows guidelines based on other proteinuria-related kidney diseases. There is no consensus on the efficacy and safety of RAAS inhibitor therapies in primary and genetic FSGS. This systematic review assessed the effects of RAAS inhibitor therapy on kidney outcomes in these patients. Study Design/UNASSIGNED:Systematic review of randomized controlled trials, interventional nonrandomized studies, observational studies, and retrospective studies. Setting & Study Populations/UNASSIGNED:Patients with primary and genetic FSGS. Selection Criteria for Studies/UNASSIGNED:PubMed, Cochrane Library, and Embase. Data Extraction/UNASSIGNED:2 investigators independently screened studies and extracted data. Analytical Approach/UNASSIGNED:Results were summarized as the ratio of means (ROM) between baseline and follow-up measurements or as the hazard ratio using random-effects models. Results/UNASSIGNED:30 publications were selected; 5 were controlled trials (4 randomized controlled trials). 8 assessed RAAS inhibitor monotherapy, while the rest studied RAAS inhibitors in combination with other drugs, mainly immunosuppressants. On average, a 32% proteinuria reduction (ROM, 0.68; 95% CI, 0.47-0.98) and no change in creatinine clearance (ROM, 0.95; 95% CI, 0.77-1.16) from baseline to the last reported follow-up was observed in patients treated with RAAS inhibitor monotherapy. When a RAAS inhibitor was combined with other drugs, a 72% proteinuria reduction was observed from baseline to the last reported follow-up (ROM, 0.24; 95% CI, 0.08-0.75). The published data did not allow for the assessment of the effects of RAAS inhibitor monotherapy on estimated glomerular filtration rate and end-stage kidney disease risks. Limitations/UNASSIGNED:Large study heterogeneity in design, patient populations, and treatment regimens. No access to individual patient-level data. Conclusions/UNASSIGNED:This review supports the tendency to observe a proteinuria reduction with RAAS inhibitors in patients with primary FSGS. RAAS inhibitor monotherapy was associated with maintained kidney function, as shown by no change in creatinine clearance. Strong evidence to quantify the effects of RAAS inhibitor monotherapy on end-stage kidney disease and glomerular filtration rate was lacking. Larger, well-designed clinical trials are needed to better understand the effects of RAAS inhibitors on primary FSGS.
PMCID:9065901
PMID: 35518835
ISSN: 2590-0595
CID: 5216422

Improving Clinical Trials for Anticomplement Therapies in Complement-Mediated Glomerulopathies: Report of a Scientific Workshop Sponsored by the National Kidney Foundation

Bomback, Andrew S; Appel, Gerald B; Gipson, Debbie S; Hladunewich, Michelle A; Lafayette, Richard; Nester, Carla M; Parikh, Samir V; Smith, Richard J H; Trachtman, Howard; Heeger, Peter S; Ram, Sanjay; Rovin, Brad H; Ali, Shadab; Arceneaux, Nicole; Ashoor, Isa; Bailey-Wickins, Laura; Barratt, Jonathan; Beck, Laurence; Cattran, Daniel C; Cravedi, Paolo; Erkan, Elif; Fervenza, Fernando; Frazer-Abel, Ashley A; Fremeaux-Bacchi, Veronique; Fuller, Lindsey; Gbadegesin, Rasheed; Hogan, Jonathan J; Kiryluk, Krzysztof; le Quintrec-Donnette, Moglie; Licht, Christoph; Mahan, John D; Pickering, Matthew C; Quigg, Richard; Rheault, Michelle; Ronco, Pierre; Sarwal, Minnie M; Sethna, Christine; Spino, Cathie; Stegall, Mark; Vivarelli, Marina; Feldman, David L; Thurman, Joshua M
Blocking the complement system as a therapeutic strategy has been proposed for numerous glomerular diseases but presents myriad questions and challenges, not the least of which is demonstrating efficacy and safety. In light of these potential issues and because there are an increasing number of anticomplement therapy trials either planned or under way, the National Kidney Foundation facilitated an all-virtual scientific workshop entitled "Improving Clinical Trials for Anti-Complement Therapies in Complement-Mediated Glomerulopathies." Attended by patient representatives and experts in glomerular diseases, complement physiology, and clinical trial design, the aim of this workshop was to develop standards applicable for designing and conducting clinical trials for anticomplement therapies across a wide spectrum of complement-mediated glomerulopathies. Discussions focused on study design, participant risk assessment and mitigation, laboratory measurements and biomarkers to support these studies, and identification of optimal outcome measures to detect benefit, specifically for trials in complement-mediated diseases. This report summarizes the discussions from this workshop and outlines consensus recommendations.
PMID: 34571062
ISSN: 1523-6838
CID: 5086962